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APPLICATION OF SYNTHETIC HETEROCYCLIC CHEMISTRY
By
ADAM S. VINCEK
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2008
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© 2008 Adam S. Vincek
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To My Family
Martina S. Vincek
William C. & Martha M. Vincek
Penny E. Vincek and Family
Ilse Holzer and Family
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ACKNOWLEDGMENTS
There is no doubt that the Game has its dangers. For that very reason we love it; only the weak are sent out on paths without perils. From The Glass Bead Game, by Hermann Hesse
I thank Alan R. Katritzky, my advisor for his knowledge, kindness, and strength. My special
thanks go to my family. My very special thanks go to my wife, Martina.
I thank Ben Smith, Lori Clark, Eric F. V. Scriven, Zuoquan Wang, Joey Lott, Myong Sang
Kim, Khalid Widyan, Danniebelle Haase, Megumi Yoshioka, Novruz G. Akhmedov, Kazuyuki
Suzuki, Dennis C. Hall, Dazhi Zhang, Janet Cusido, Valerie Rodriguez–Garcia, Khanh Nguyen
Bao Le, Ashraf A. A. Abdel-Fattah, Hongfang Yang, Anamika Singh, Gala Vakulenko, Gwen
McCann, Srinivasa Rao Tala, Kostyantyn Kirichenko, Prabhu Mohapatra, Sasha Kulshyn,
Niveen Khashab, Kapil and Rena Gyanda, and Elisabeth Sheppard my UF mentors and friends
for their various support. I thank Kirk S. Schanze, Ronald K. Castellano, Y. (Charles) Cao, and
Anuj Chauhan, my excellent committee members, for their help and knowledge.
I thank Rolf Krauss, Paul J. Kropp, Wayne and Cristie Brouillette, Julius B. Lucks, Tanja
Wieber, Dorothée Alsentzer, Weixing (William) Li, Johann (Hans) Leban, Gabriel Garcia,
Harald Schmitt, Sergei A. Belyakov, Peter J. Steel, Jan F. Mieses, Cathal Meere, and the Holzers
my mentors and friends for their help and inspiration to obtain my goals.
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TABLE OF CONTENTS page
ACKNOWLEDGMENTS ...............................................................................................................4
LIST OF TABLES...........................................................................................................................8
LIST OF FIGURES .........................................................................................................................9
LIST OF SCHEMES......................................................................................................................10
ABSTRACT...................................................................................................................................19
CHAPTER
1 GENERAL INTRODUCTION ..............................................................................................20
1.1 Opening Remarks.........................................................................................................20 1.2 General Discussion of Amides.....................................................................................20 1.2 General Overview of the Work....................................................................................23 1.4 Aim and Importance of the Work ................................................................................38
2 MICROWAVE ASSISTED C-ACYLATION OF P-YLIDES ..............................................41
2.1 Introduction..................................................................................................................41 2.2 Results and Discussion ................................................................................................44
2.2.1 Protected (α-Aminoacyl)benzotriazoles ............................................................44 2.2.2 Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters .................45 2.2.3 Achiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters ...............48 2.2.4 Peptidic α-Triphenylphosphoranylidene Diastereomers ...................................49
2.3 Conclusions..................................................................................................................52 2.4 Experimental Section ...................................................................................................52
2.4.1 Preparation of N-Protected (α-Aminoacyl)benzotriazoles. 2.5a–g, 2.8a–c......53 2.4.2 Preparation of N-Protected Peptidic α-Triphenylphosphoranylidene Esters,
Under Microwave Irradiation. 2.7a–g, 2.9–11..................................................54 2.4.3 Preparation Under Conventional Heating. 2.7b,d.............................................54 2.4.4 Preparation of P-Ylide Salt. 2.13 ......................................................................56 2.4.5 Preparation of Peptidic Diastereomers. 2.14–15...............................................57
3 SYNTHESES OF 2,4-DIOXO-3-TRIPHENYLPHOSPHORANYLIDENE PYRROLIDINES AND OTHER DISTABILIZED TRIPHENYLPHOSPHORANYLIDENE SUBSTITUTED RINGS .....................................59
3.1 Introduction..................................................................................................................59 3.2 Results and Discussion ................................................................................................67
3.2.1 Methylations and Salt Neutralization.................................................................71 3.2.2 Dibromopyrrolidin-2,4-dione.............................................................................73
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3.2.3 Dibromo-5-hydroxypyrrolidin-2,4-dione...........................................................74 3.2.4 Azido-3-bromopyrrol-2-one ..............................................................................76 3.2.5 Benzotriazolpyrrol-2-one...................................................................................77 3.2.6 Protected (α- and β-aminoacyl)benzotriazoles..................................................77 3.2.7 Protected-γ-amino-β-oxo-α-triphenylphosphoranylidene and N-Cbz-δ-
amino-β-oxo-α-triphenylphosphoranylidene Esters ..........................................78 3.2.8 Dioxotriphenylphosphoranylidene Salts............................................................79 3.2.9 The DOT-Pyrrolidines, DOT-Pyrrolizines, and DOT Piperidine......................81 3.2.10 Protected-γ-amino-β-oxo-α-triphenylphosphoranylidene and N-Cbz-δ-
amino-β-oxo-α-triphenylphosphoranylidene Nitriles....................................83 3.2.11 Dihydropyrrol-3-one Bromide Salts and Tetrahydropyrrolizin-1-one
Dibromide Salt ...............................................................................................84 3.3 Conclusion ...................................................................................................................86 3.4 Experimental Section ...................................................................................................87
3.4.1 Preparation of Dibromide Salt 3.2a ...................................................................87 3.4.2 Preparation of N-Methylated DOT-pyrrolidine 3.2b .........................................88 3.4.3 Preparation of Linear Free Amine 3.2c..............................................................88 3.4.4 Preparation of 3,3-Dibromopyrrolidin-2,4-dione 3.3a.......................................89 3.4.5 Preparation of 3,3-Dibromo-5-hydroxypyrrolidin-2,4-dione 3.3b ....................89 3.4.6 Preparation of 4-Azido-3-bromopyrrol-2-one 3.3c............................................89 3.4.7 Preparation of 4-Benzotriazolpyrrol-2-one 3.3d................................................90 3.4.8 Preparation of N-Acylbenzotriazoles 3.4a–d, 3.13............................................90 3.4.9 Preparation of α-Triphenylphosphoranylidene Esters 3.6a–d...........................91 3.4.10 Preparation of DOT-salts 3.7a–d ...................................................................92 3.4.11 Preparation of DOT-pyrrolidines 3.8a–c, DOT-pyrrolizines, and DOT-
piperidines......................................................................................................93 3.4.12 Preparation of α-Triphenylphosphoranylidene Nitriles 3.10a–d, 3.17..........94 3.4.13 Preparation of 2,4-Dihydropyrrol-3-one Salts 3.11a–c,
Tetrahydropyrrolizin-1-one Salt 3.11d, and Nitrile Salt 3.18 ........................96
4 ENERGETIC IONIC LIQUIDS.............................................................................................97
4.1 Introduction..................................................................................................................97 4.2 Results and Discussion ..............................................................................................100 4.3 Conclusion .................................................................................................................103 4.4 Experimental Section .................................................................................................103
4.4.1 Preparation of N-Alkylimidazoles (Method A) 4.6b,d, 4.7e–g .......................104 4.4.2 Preparation of N-Alkylimidazoles (Method B) 4.6b,d,f,g, 4.7d ......................104 4.4.3 Preparation of 1-Benzoyl-4-methyl- and 1-Benzoyl-2,4-dimethyl-
imidazoles 4.9a,b..............................................................................................105 4.4.4 Preparation of N-Alkylimidazoles (Method C) 4.6h–k ...................................105
5 SYNTHESIS OF CYCLIC KETONE DERIVATIZED TETRASUBSTITUTED trans-IMIDAZOLIDIN-2-ONES...................................................................................................107
5.1 Introduction................................................................................................................107 5.2 Results and Discussion ..............................................................................................110
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5.2.1 Imines...............................................................................................................111 5.2.2 The 1,1-Dipole Equivalents (Bt-Intermediates)...............................................112 5.2.3 Convergent Synthesis of Bt trans-Imidazolidin-2-ones...................................113 5.2.4 Lewis Acid Mediated Synthesis of Cyclic Ketone Derivatized
Tetrasubstituted trans-Imidazolidin-2-ones .....................................................115 5.3 Conclusion .................................................................................................................117 5.4 Experimental Section .................................................................................................117
5.4.1 Preparation of Imines.......................................................................................117 5.4.2 Preparation of Bt-Intermediates.......................................................................118 5.4.3 Preparation of Bt-Imidazolidin-2-ones ............................................................119 5.4.4 Preparation of Cyclic Ketone Tetrasubstituted trans-Imidazolidin-2-ones .....121
6 GENERAL CONCLUSIONS...............................................................................................123
REFERENCES ............................................................................................................................127
BIOGRAPHICAL SKETCH .......................................................................................................141
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LIST OF TABLES
Table page 2-1. Isolated Yields of N-Protected (α-Aminoacyl)benzotriazoles 2.5a–g, 2.8a–c..................45
2-2. Isolated Yields of Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters 2.7a–g….............................................................................................................................46
2-3. Attempted Optimization Reaction Conditions for 2.7b .....................................................47
3-1. Isolated Yields for Intermediates and Five-Membered Products 3.8a–d, 3.11a–d ...........68
3-2. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of Linear 3.2a,c and Cyclic 3.2b….. ..............................................................................................................................72
3-3. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.6a–d, 3.14..............................79
3-4. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.7a–d, 3.15..............................81
3-5. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.8a–d and 3.16 ........................82
3-6. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.10a–d, 3.17............................84
3-7. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.11a–d, and 3.18 .....................86
4-1. Isolated N-Alkylimidazoles 4.6a–k .................................................................................101
4-2. Isolated N-Alkylimidazoles, with Energetic Groups, 4.7a–k..........................................101
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LIST OF FIGURES
Figure page 1-1. Beta-Keto α-Triphenylphosphoranylidene Esters and Nitriles (α, β, and γ).....................28
1-2. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-3-one, Piperidin-2,4-dione, Tetrahydropyrrolizin-1,3-dione, 3-Aminotetrahydropyrrolizin-1-one, and DOT-pyrrolidine..................................................29
1-3. Collaborative Effort: Modular Design of Heterocycles for EILs. ....................................34
2-1. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 20 °C ................................50
2-2. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 60 °C ................................51
2-3. The 31P-NMR of the (DL)Diastereomer 2.15 at 20 °C and 60 °C .....................................51
3-1. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-3-one, Piperidin-2,4-dione, Tetrahydropyrrolizin-1,3-dione, 3-Aminotetrahydropyrrolizin-1-one, and DOT-pyrrolidine..................................................59
3-2. Major Canonical Forms of Peptidic syn-β-Keto α-Triphenylphosphoranylidene anti-Esters and Nitriles ..............................................................................................................69
3-3. Crystal X-ray of 3.8c (Left), and Preliminary X-ray Crystal Structure of 3.11c with Two H2O molecules and Br– (Right) .................................................................................70
3-4. The X-ray Crystal Structure of 3.3b (Left), and Intermolecular Hydrogen Bonding (Right).. ..............................................................................................................................75
4-1. Collaborative Effort: Modular Design of Heterocycles for EILs. ....................................98
5-1. Vicinal Diamino Tethered Ureas .....................................................................................107
5-2. Bioactive Imidazolidin-2-ones.........................................................................................108
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LIST OF SCHEMES
Scheme page 1-1. Amide Resonance Forms ...................................................................................................20
1-2. Acetamide Resonance Forms and Tautomers....................................................................21
1-3. Amide Isomers with Intermediate Barrier .........................................................................22
1-4. Bicyclic Penicillin Substructure.........................................................................................22
1-5. Benzotriazole Influence on Adjacent Carbon ....................................................................23
1-6. Formation of N-Acylbenzotriazole from Carboxylic Acids ..............................................25
1-7. Retrosynthesis for N-Protected Peptidic α-Triphenylphosphoranylidene Esters ..............26
1-8. Applications of β-Keto α-Triphenylphosphoranylidene Esters.........................................26
1-9. Literature Methods for β-Keto α-Triphenylphosphoranylidene Esters .............................27
1-10. Early Reports of DOT-pyrrolidines and DOT-piperidine..................................................30
1-11. Delocalization of N-Methyl-DOT-pyrrolidine 3.2b, Major Canonical Form 3.2b′ ..........31
1-12. Numbering of Substituted 4(or 5)-Monosubstitued Imidazoles ........................................32
1-13. Regioselective N-Alkylation and Quaternization of Nitro-Substituted Imidazole ............33
1-14. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6h–k.................................................34
1-15 Protected-N-(benzotriazol-1-ylmethyl) Benzylamine, 1,1-Dipole Synthon......................36
1-16. Multiple Bond Formation in One Step for Imidazolidin-2-one .........................................37
1-17. Synthetic Overview of Protocols .......................................................................................38
2-1. Applications of β-Keto α-Triphenylphosphoranylidene Esters.........................................41
2-2. Literature Methods for β-Keto α-Triphenylphosphoranylidene Esters .............................42
2-3. Retrosynthesis for N-Protected Peptidic α-Triphenylphosphoranylidene Esters ..............43
2-4. Protected (α-Aminoacyl)benzotriazoles 2.5a–g, 2.8a–c, from Protected Amino Acids...44
2-5. Rotameric Forms of 2.8b ...................................................................................................44
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2-6. Base Free C-Acylation for Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters 2.7a–g......................................................................46
2-7. Unsuccessful C-Acylations, and the Generation of Fmoc-Bt............................................48
2-8. Base Free C-Acylation for Achiral Esters 2.9–2.10 .........................................................49
2-9. Rotameric Forms of 2.10 ...................................................................................................49
2-10. Synthetic Route to (LL)- and (DL)Diastereomers 2.14, 2.15 ...........................................50
3-1. General Methods for the Formation of Bonds aa, bb or cc to Construct 3.1 ......................60
3-2. Direct Intramolecular Wittig Alkenation with Linear DOT Moieties ...............................61
3-3. Indirect Intramolecular Wittig Alkenation with Linear DOT Moieties.............................63
3-4. Delocalization of N-Methylated DOT-pyrrolidine 3.2b, Major Canonical Form 3.2b′ ....63
3-5. Four Applications Using N-Methylated DOT-pyrrolidine ................................................64
3-6. Speculative Applications: Oxidation and Reduction .........................................................65
3-7. Early Reports of DOT-pyrrolidines and DOT-piperidines ................................................66
3-8. Synthetic Route to DOT-pyrrolidines 3.8a–c, DOT-pyrrolizines 3.8d, 5-Amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one Bromides 3.11a–c, and 3-Ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one Dibromide 3.11d ...................................68
3-9. Synthetic Route to DOT-piperidine 3.16, with Isolated Yields.........................................71
3-10. Methylation of 3.7c and 3.8c and Neutralization of 3.7c...................................................72
3-11. Bromination of 3.2b with NBS, For 3.3a ..........................................................................73
3-12. Proposed Mechanism, From 3.2b to Int-1 to Int-2 to 3.3a ...............................................74
3-13. Bromination of 3.2b, with TMSOEt and NBS, For 3.3a and 3.3b ....................................75
3-14. Proposed Mechanism, from 3.3a to 3.3b ...........................................................................76
3-15. Haloazidoalkenation of 3.2b, with TMSN3 and NBS, For 3.3c ........................................77
3-16. Benzotriazolation of 3.2b, with BtCl, For 3.3d .................................................................77
3-17. Acylbenzotriazolation of 3.12, with SOCl2 and BtH, Formed 3.13 ..................................78
3-18. Carbon-Acylation of 3.13, with 3.5, Formed 3.14.............................................................78
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3-19. Rotameric Forms of Ester 3.6d and Nitrile 3.12d .............................................................79
3-20. Deprotection of 3.14, with HBr, For 3.15..........................................................................80
3-21. Method I and Method II, For 3.8c and 3.8d.......................................................................82
3-22. Carbon-Acylation of 3.13, with 3.9, For 3.17....................................................................83
3-23. Deprotection of 3.10c,d, with HBr, For 3.11c,d................................................................85
4-1. Regioselective N-Alkylation and Quaternization of Nitro-Substituted Imidazole ............99
4-2. Targeted Regio-N-alkylated Imidazoles for Generation of Fused Salts..........................100
4-3. Method A and B for Preparation of 1-Alkylimidazoles...................................................100
4-4. Unsuccessful Regiospecific N-Alkylation.......................................................................102
4-5. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6h–k...............................................103
5-1. Multiple Bond Formation in One Step for Imidazolidin-2-one .......................................109
5-2. The N-Boc-N-(benzotriazol-1-ylmethyl) Benzylamine, 1,1-Dipole Synthon in the Stereoselective Synthesis of 1,3,4,5-Tetrasubstituted trans-Imidazolidin-2-ones ...........110
5-3. Synthetic Overview of Protocols .....................................................................................111
5-4. Imine Formation, From Aldehydes and Anilines ............................................................111
5-5. Benzotriazole Intermediate Formation, Two Methods ....................................................112
5-6. Convergent Syntheses, Using the Reported Literature Conditions .................................113
5-7. Optimized Convergent Conditions, Using Literature Reagents ......................................114
5-8. Convergent Synthesis of N-Benzylated trans-Bt-Imidazolidin-2-ones 5.4e,f .................114
5-9. Convergent Synthesis of N-Alkylated trans-Bt-Imidazolidin-2-ones with 5.4g .............115
5-10. Lewis Acid Mediated Synthesis of Reported Cyclohexanone Analog 5.5a ....................115
5-11. Lewis Acid Mediated Synthesis of Two Cyclohexanone Analogs 5.5b,c.......................116
5-12. Lewis Acid Mediated Synthesis of Two Cyclopentanone Analogs 5.5c,e ......................116
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LIST OF ABBREVIATIONS
α alpha locant
[α] specific rotation [expressed without units; the units, (deg.mL)/(g.dm) are understood]
Å angstrom(s)
ACN acetonitrile
Aib aminoisobutyric acid
Ala alanine
anhyd anhydrous
aq aqueous
Asp aspartic acid
β beta locant
Boc tert-butoxycarbonyl
br broad (spectral)
Br- bromide anion
Br+ bromonium cation
BSA N,O-bis(trimethylsilyl)acetamide
Bt benzotriazol-1-yl and benzotriazol-2-yl
BtCl 1-chlorobenzotriazole
BtCH2OH (benzotriazol-1-yl)methanol
BtH 1H-benzotriazole
Bz benzoyl (not benzyl)
Bzl benzyl
C carbon
°C degrees Celsius
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calcd calculated
Cbz benzyloxycarbonyl
CDCl3 deuterated chloroform
CDI carbonyl diimidazole
CHC Center for Heterocyclic Chemistry
chiroptical “chiral-optical” methods of palpating chirality by optical tools [polarimetry, optical rotatory dispersion (ORD), and circular dichroism (CD)]
CGM Center for Green Manufacturing
cm centimeter
CNS central nervous system
δ delta locant
δ chemical shift in parts per million downfield from tetramethylsilane
Δ heat
d doublet (spectral)
D (10-point) dextrorotary (right)
D (12-point) deuterium
DCC N,N′-dicyclohexylcarbodiimide
DCM dichloromethane
DMAP 4-dimethylaminopyridine
DMD 3,3-dimethyl dioxirane
DMF dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d6 deuterated dimethyl sulfoxide
DSC differential scanning calorimetry
DOT di(oxo)triphenylphosphoranylidene
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EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EIL energetic ionic liquid
eq equivalent(s)
Et ethyl
et al. and others
Fmoc 9-fluorenylmethoxycarbonyl
FVP flash vacuum pyrolysis
γ gamma locant
g gram(s)
Gly glycine
Glu glutamine
h hour(s)
H Hydrogen
[H] reduction
HBr hydrobromic acid
HIV human immunodeficiency virus
HRMS high-resolution mass spectrometry
Hz hertz
IL ionic liquid
i iso (as in i-Pr; never i-propyl)
ip ipso locant
i-Pr isopropyl
IR infrared
J coupling constant (in NMR spectrometry)
JCF coupling constant carbon-fluorine (in 13C-NMR spectrometry)
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JCP coupling constant carbon-phosphorus (in 13C-NMR spectrometry)
L (10-point) levorotary (left)
lit. literature (abbreviation used with period)
μ micro
μ-Wave microwave
m multiplet (spectral); meter(s); milli
m meta locant
M+ parent molecular ion
Me methyl
MeI methyl iodide
MHz megahertz
min minute(s)
mol mole(s); molecular (as in mol wt)
mmol millimole(s)
MMP matrix metalloproteinase
MMPP magnesium monoperphthalate
mp melting point
mol wt molecular weight
m/z mass-to-charge ratio
n normal (as in n-butyl, n-Bu)
N nitrogen
NaH sodium hydride
NBS N-bromosuccinimide
NMDA N-methyl-D-aspartate
NMR nuclear magnetic resonance
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o ortho locant
O oxygen
[O] oxidation
OEt ethoxy
OMe methoxy
Oxone® potassium peroxymonosulfate
p para locant
P Phosphorus
Pd(C) palladium on charcoal
Pg protecting group
Ph phenyl
Phe phenylalanine
ppm part(s) per million
Pr propyl
Pro proline
PTSA paratoluene sulfonic acid
P-ylide phosphorus ylide
q quartet (spectral)
R rectus (right) (naming groups around a central carbon) (opposite of S)
rb round bottom
rt room temperature
s singlet (spectral); second(s)
S sinister (left) (naming groups around a central carbon) (opposite of R)
Sar sarcosine
SARM selective androgen receptor modulators
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s-BuLi sec-butyllithium
sec secondary (as in sec-butyl, sec-Bu)
SiO2 silica gel
SOCl2 thionyl chloride
t triplet (spectral)
t tertiary (as in t-Bu; but tert-butyl)
TARS tetramic acid ring system
TBDMS t-butyldimethylsilyl
TEA triethylamine
temp temperature
tert tertiary
Tf trifluoromethansulfonyl (triflyl)
TFA trifluoroacetic acid
TGA thermogravimetric analysis
THF tetrahydrofuran
TLC thin-layer chromatography
TMS trimethylsilyl; tetramethylsilane
Tr (triphenylmethane) trityl
Trp tryptophan
Ts para-toluensulfonyl (tosyl)
UF University of Florida
v:v volume:volume ratio
Val valine
VOC volatile organic compound
W watt(s)
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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
APPLICATION OF SYNTHETIC HETEROCYCLIC CHEMISTRY
By
Adam S. Vincek
May, 2008
Chair: Alan R. Katritzky Major: Chemistry
Benzotriazole is a versatile synthetic auxiliary, widely applied to many organic syntheses. In
our continuous work on benzotriazole methodology, we have developed efficient methods for the
preparation of heterocyclic compounds. The formation of N-protected peptidic α-
triphenylphosphoranylidene esters by the C-acylation of P-ylide esters with N-protected peptidic
(α-aminoacyl)benzotriazoles under microwave irradiation is described. The formation of
distabilized triphenylphosphoranylidene moieties on pyrrolidine, pyrrolizine, and piperidine
rings by the room temperature N-deprotection and cyclization of peptidic α-
triphenylphosphoranylidene esters and nitriles is described. The formation of N-regioalkylated
4-substituted imidazoles by regioselective N-benzoylation and N-alkylation with quaternization,
followed by debenzoylation and dequarternization is described. The formation of
tetrasubstituted trans-imidazolidin-2-ones by treatment of imines with lithiated benzotriazole
intermediates and subsequent treatment with Lewis acid and silylenol ethers to modify the 4- or
5-position is described.
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CHAPTER 1 GENERAL INTRODUCTION
1.1 Opening Remarks
The specific fields of heterocyclic, amino acid, lactam, and ionic liquid chemistry can be
viewed from the single perspective of organic chemistry and are discussed in this work. Amide
bonds are formed in key steps of every main chapter and used for activation, protection, and
cyclization. This general introduction commences with a brief discussion of amides and is
followed by a brief overview to set the relevant chemistry topics in a broad context. In closing
of this general introduction the aim and importance of the work will be stated.
1.2 General Discussion of Amides
Amides are one of the most fundamental functional groups in chemistry and biology, and are
surprisingly robust compared with structurally related derivatives [06N699]. The amide linkage
gains stability from electron delocalization (Scheme 1-1) between the apolar and dipolar
resonance forms, which differ in the location of the double bond [06N699]. The enhanced
stability is maximized if the atoms around the carbon-nitrogen double bond in the dipolar form
are coplanar in order to satisfy the geometrical requirements of the carbon-nitrogen double bond
[06N699].
O
NR RR
O
NR RR
Apolar Dipolar
Scheme 1-1. Amide Resonance Forms
Amides are a good example of a conjugated allylic pi system with the nitrogen lone pair
joined by resonance, or a proton shifting by tautomerization, with a carbonyl group [92MI6].
Conjugated, or delocalized, bonding exists in compounds containing one or more bonding
21
orbitals not restricted to two atoms, but spread out over three or more [92MI34]. Each resonance
form does not have a separate existence but is part of a hybrid whole [92MI6] and only electrons
move. All resonance forms, or canonical forms [92MI34], are valid Lewis structure. The use of
a double-headed, or resonance arrow (↔) between the forms reinforces the notion of electrons in
the double bond spread, or delocalized, across the amide group, which behave as a hybrid
representation of a single structure. Acetamide (Scheme 1-2) is shown with the resonance forms
and a tautomer denoted by the equilibrium arrow (∏). Resonance forms are not in equilibrium
with each other, the atoms remain spatially in the same location, and the actual molecule is in a
lower energy state than any of the resonance forms.
O
NMe HH
OC+
NMe HH
O
NH2N HH
O
NMe H
H
Tautomers
Resonance Forms
Scheme 1-2. Acetamide Resonance Forms and Tautomers
Scudder described tautomerization as the shift of a hydrogen from a carbon adjacent to a
carbon-heteroatom double bond to the heteroatom itself, and the reverse process, in an acid- or
base catalyzed equilibrium [92MI6]. Eliel defined tautomers as readily inter-convertible
constitutional isomers, but, in contrast to conformational isomers and valence bond isomers, in
tautomers there is a change of connectivity of a ligand [94MI23]. Eliel wrote about amide bonds
with an intermediate barrier, the boxed structure in Scheme 1-3, “while the amide isomer shown
is generally implied to differ in conformation (by rotation about the C–N bond) the E/Z
nomenclature of double-bonded species is commonly applied, demonstrating a certain degree of
22
ambivalence in these cases [94MI23]!” In this work we occasionally refer to rotamers, as was
previously describe in the literature [02JP1533], to describe these ambivalent cases which gave
two distinct sets of NMR signals, caused by interconversion between isomers through a bond
rotation in rapidly equilibration.
Me
ON
C6H2(NO2)3
Meδ+
δ-
Me
ON
C6H2(NO2)3
Me Me
ON
C6H2(NO2)3
Me
Z-isomer
Me
ON
C6H2(NO2)3
MeE-isomer
amide barrier 21.0 kcal mol-1
Me
ON
C6H2(NO2)3
Me
Scheme 1-3. Amide Isomers with Intermediate Barrier
The geometry of bicyclic amides, or lactams, are highly twisted, which dramatically affects
the stability and reactivity, and increases the basicity of the nitrogen, which often behaves more
like an amine than a typical planar amide [06N731]. Typical acyclic amides are planar.
However bicyclic lactams, such as the penicillin substructure (Scheme 1-4), cannot exist in a
coplanar dipolar form which inhibits electron delocalization through resonance and destabilizes
the amide bond [06N731]. These intriguing qualities have lead to syntheses of bicyclic lactams
to increase our understanding of this special type of bond — the twisted amide [06N699].
NO
NO
Apolar Dipolar
Scheme 1-4. Bicyclic Penicillin Substructure
23
1.2 General Overview of the Work
Heterocyclic compounds are those which have a cyclic structure with two, or more, different
kinds of atoms in the ring [97MI1]. Arnold Weissberger, in 1953, wrote that “the chemistry of
heterocyclic compounds is one of the most complex branches of organic chemistry [53MI1]”. In
the 1960s several research groups, including that of Alan R. Katritzky, began to fill in practical,
theoretical, and physical gaps due to the molecular complexity of the heterocyclic field; it was
then that “Physical Methods in Heterocyclic Chemistry” and “Advances in Heterocyclic
Chemistry” began to appear [63PMH1, 63AHC1]. The work herein contains examples of the
intrinsic difficulty of heterocyclic chemistry and how success requires understanding of
substituent, electronic, and regiochemical effects, which may change drastically upon a
seemingly minor modification.
Bt Leaving Group
NNN
R
X
Bt Activates α -Cto Proton Loss
NNN
HX
Bt Electron Donor
NNN
X
Y
Scheme 1-5. Benzotriazole Influence on Adjacent Carbon
Hantzsch, in 1888, classified azoles as five-membered polyheteroatomic ring systems
containing at least one tertiary nitrogen [53MI1]. Relatively recently, the last 20 years,
benzotriazole has received special attention in the Katritzky group as a versatile synthetic
auxiliary which offers advantages such as low cost, high stability, low toxicity, and mild acidic
strength (pKa = 8.2). The manipulation of benzotriazole as a highly versatile synthetic auxiliary,
24
and its great importance as a tool for a variety of synthetic reactions, has been periodically
reviewed [98CRV409]. Benzotriazole as a substituent imparts both electron-donor and electron-
acceptor properties to the neighboring atom (Scheme 1-5). The ambivalent character of
benzotriazole allows it to act as leaving group for nucleophilic displacement reactions as well as
an activating group, to facilitate proton abstraction at α-C for the subsequent introduction of
electrophiles.
The α-Amino acids possess a limited but significant number of functional groups, which
facilitate synthetic operations for heterocycles, protection, and deprotection, and are
commercially available, usually in both enantiomerically pure forms for the synthesis of
optically active compounds [02MI25]. Before the mid-1960s, the enantiomeric purity of a chiral
molecule was usually assessed by using chiral-optical (chiroptical) methods [91CRV1441].
Chiroptical methods involve measuring the optical rotation, or “optical purity”, of the sample
using a polarimeter under defined conditions and provided that the measurement is carried out
under rigorously controlled temperature, solvent, and concentration and at a given wavelength of
the incident plane-polarized light, along with appropriate calibrations, then this value may be
equated with “enantiomeric purity” [91CRV1441]. The two major problems with this method of
analysis are the optical purity and enantiomeric purity are not necessary equivalent and the
literature is abound with many examples of incorrect optical rotations for compounds considered
to be enantiomerically pure [91CRV1441]. Sardina and Rapoport wrote, “in a large percentage
of cases the question of the enantiomeric purity of the compounds prepared was not addressed at
all, while in a majority of articles the determination was carried out by chiroptical methods,
which, it must be stressed, are unreliable [96CRV1825].” In this work, optical rotations of some
25
molecules with a stereocenter are reported when previous literature reports already existed, but
are unreliable for the reproduction of enantiomeric purity.
R OH
O(i) BtH, SOCl2
R Bt
O
N -Acylbenzotriazole(i) BtSO2Me
Scheme 1-6. Formation of N-Acylbenzotriazole from Carboxylic Acids
Amide bond formation between amino acid components is a main goal in the synthesis of
many organic compounds of biological interest driving the discovery of peptide coupling
reagents, which have essentially eliminated racemization of the amino acid component and side
reactions [02ARK134]. Two standard methods (Scheme 1-6) used in the Katritzky group to
prepare N-acylbenzotriazoles, a modern peptide coupling reagent, from carboxylic acids are by
either, (i) in situ generation of thionyl bis(benzotriazole) [04S2645], or (ii) using N-
(methylsulfonyl)benzotriazole [02ARK134]. Acylbenzotriazoles have been reported by the
Katritzky group as efficient neutral coupling reagents for chiral N-acylation, regioselective C-
acylation, and O-acylation of aldehydes [04S1806] and as sufficiently reactive to form amide
bonds at ambient temperature, but stable enough to resist side reactions [04S2645]. Protected
(α-aminoacyl)benzotriazoles are efficient reagents for acylation of amino amides [02ARK134],
amino sulfonamides [04ARK14], amino thiol esters [04S1806], small peptides carrying side
chains with alkyl groups [04S2645], small peptides with multi-functional groups [05S397], and
amino ketones [05JOC4993]. Protected N-acylbenzotriazoles, “tame” acid chloride equivalents,
were used for C-acylation of phosphorus ylides (P-ylides) with microwave irradiation to form N-
protected peptidic α-triphenylphosphoranylidene esters in Chapter 2 (Scheme 1-7) and in
Chapter 3.
26
O
NR1 Pg
PPh3
CO2Et+
R3
O
N
BtR1 Pg
R3
PPh3
CO2EtH R2R2μ-Wave
Scheme 1-7. Retrosynthesis for N-Protected Peptidic α-Triphenylphosphoranylidene Esters
Peptidic α-triphenylphosphoranylidene esters and amides have attracted considerable
attention as important intermediates for the preparation of peptidic α-keto esters and of α-keto
amides [94JOC4364, 97JOC8972], compounds which are potential inhibitors of proteolytic
enzymes [92JME451, 93JME2431] and leukotriene A4 hydrolases [93JME211]. The β-Keto α-
triphenylphosphoranylidene esters 2.1 have been used for the preparation (i) of alkynes 2.2 by
flash vacuum pyrolysis (FVP) [85S764, 04T12231], (ii) α,β-diketoesters 2.3 by oxidation ([O])
[94JOC4364, 97JOC8972], and (iii) β-keto esters 2.4 by direct reduction ([H]) (Scheme 1-8).
PPh3
CO2EtR
O
(i) FVP(ii) [O]
(iii) [H]
CO2EtR
OCO2Et
R
O
CO2EtR
O
2.1
2.2
2.3
2.4
(iv) DeprotectionNH
OPPh3
O{Chapter 3}
3.1
R = Cbz-NH-CH2
Scheme 1-8. Applications of β-Keto α-Triphenylphosphoranylidene Esters
Previously reports determined β-Keto α-triphenylphosphoranylidene esters 2.1 are readily
available by C-acylation of (carboxymethylene)triphenylphosphorane (2.6) with a proton
sponge/acid scavenger such as N,O-bis(trimethylsilyl)acetamide (BSA) [90TL5205, 94JOC4364,
95JOC8231] and acyl chlorides [04T12231, 82JOC4955], or cyclic anhydrides [82AJC2077,
85S764], or anhydrides with BSA [92TL6003] (Scheme 1-9). However, acyl chloride and
27
anhydride methods are limited in their applicability for chiral peptidic models due to high
reactivity and byproducts causing potential problems with other functional groups. Carbon-
Acylation methods for chiral N-protected peptidic α-triphenylphosphoranylidene esters have
been reported, by activation of amino acids with carbonyl diimidazole (CDI) requiring 24 h
reaction time [99JA1401], or with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCl) in the presence of 4-dimethylaminopyridine (DMAP) requiring 16 h
reaction time [93JOC4785, 94JOC4364, 97JOC8972]. Therefore, the development of an
expedient, versatile method to C-acylate 2.6 with chiral amino acid derivatives for N-protected
peptidic α-triphenylphosphoranylidene esters is desirable. In Chapter 2 we demonstrate the C-
acylation of 2.6 with chiral, and achiral, N-protected (α-aminoacyl)benzotriazoles, to prepare
chiral, and achiral, N-protected peptidic α-triphenylphosphoranylidene esters under microwave
irradiation.
PPh3
CO2EtR
O2.1
PPh3
H CO2Et
R1
O OH
acid halideswith BSAor μ-Wave
amino acids w/EDCI, DMAP16 hor CDI, 24 h
cyclicanyhydridesoranhydrideswith BSA
O
MeN
TMSTMSBSA =
2.6
Scheme 1-9. Literature Methods for β-Keto α-Triphenylphosphoranylidene Esters
A single cavity microwave synthesizer provides an effective reproducible and safe technique
for promoting a variety of reactions and shortening reaction times while reducing pollution by
28
using less solvent [02MI1, 03ARK68]. Microwaves, a form of electromagnetic radiation
between infrared (IR) and radio frequencies, used in a single cavity synthesizer accelerate
reaction times and reduce the amount of solvent required. The general mechanism behind
microwave technology is that molecules with a permanent dipole become aligned with the
electric field when irradiated with microwaves, oscillation of which changes the molecular
alignment and increases the temperature. Oscillation of the standing microwaves occurs at 4.9 x
109 times per second, causing the electromagnetically radiated molecules to become extremely
agitated, as they align and realign themselves with the oscillating field, creates an intense internal
heat that can escalate as quickly as 10 °C per second [02JCO95]. International convention
dictates that most microwave ovens operate at 12.2 cm (2450 MHz), so not to interfere with
radar or other telecommunications devices.
CO2Et
PPh3
ONH
R
R
CN
PPh3
ONH
R
Rα
ββαγ γ
Figure 1-1. Beta-Keto α-Triphenylphosphoranylidene Esters and Nitriles (α, β, and γ)
Novel distabilized triphenylphosphoranylidene tetramic acids, containing cyclic amide or
lactam functionality, were obtained after room temperature N-deprotection (iv, Scheme 1-8) and
cyclization and exhibited high stability at the triphenylphosphoranylidene moiety. The work
from Chapter 2 was extended in Chapter 3 to obtain not only N-protected peptidic α-
triphenylphosphoranylidene esters but also N-protected peptidic α-triphenylphosphoranylidene
nitriles (Figure 1-1). The versatile distabilized triphenylphosphoranylidene moiety was readily
formed on pyrrolidin-2,4-dione, 5-amino-2,4-dihydropyrrol-3-one, piperidine-2,4-dione,
tetrahydropyrrolizin-1,3-dione, and 3-aminotetrahydropyrrolizin-1-one (Figure 1-2) with a
29
distabilized triphenylphosphoranylidene substituent. Four applications were developed using
2,4-dioxo-3-triphenylphosphoranylidene pyrrolidine.
OONH
OHONH
Pyrrolidin-2,4-dione
DOT moietyPPh3
OONH
DOT-pyrrolidine
ON
5-Amino-2,4-dihydropyrrol-3-one
OON
NH
OO
Piperidin-2,4-dione Tetrahydropyrrolizin-1,3-dione
NH2ON
3-Aminotetrahydropyrrolizin-1-one
NH2
4-Hydroxy-pyrrol-2-one3.1
Figure 1-2. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-
3-one, Piperidin-2,4-dione, Tetrahydropyrrolizin-1,3-dione, 3-Aminotetrahydropyrrolizin-1-one, and DOT-pyrrolidine
The predominant species of pyrrolidin-2,4-dione exists in solution in the enolized form with a
stable lactam bond [93AHC139, 03MI109]. The discovery of the tetramic acid ring system 3.1
(Figure 1-2), a tautomer of pyrrolidin-2,4-dione, in a number of natural products and pigments
coincided with the discovery of their diverse biological activities [93AHC139, 94MI97,
95CRV1981, 00JPP086628, 00MI195, 02MI25, 03MI109]. Pyrrolidin-2,4-dione and 2,4-
dihyropyrrol-3-ones have been identified as N-methyl-D-aspartate (NMDA) receptor antagonists
[99AP309, 05EJM391]. The 2,4-dioxo-3-triphenylphosphoranylidene moiety, or DOT-moiety as
shown on DOT-pyrrolidine (Figure 1-2), adds desirable physical properties such as crystallinity
and stability to aldehydes [87LA649], strong bases [65JOC1015], and high temperatures
[01TL141]. The possible transformation the 2,4-dioxo-3-triphenylphosphoranylidene (DOT)
30
moiety provides when directly incorporated as part of a heterocyclic ring is unexplored and of
considerable interest [01JCD639].
ONH
Cbz
R2
CO2EtPh3P
Ph3P
NHOO
R1
(ii)
(i)
OH
PPh3
NH2
OEtO2C
R1
O +25 °C, 2 h +
EtO2C
R1 NH2
O
31% 26%
1) Pd(C), H22) FVP, 600 oC
FVP, 600 oC
Ph3P
NHOO
R2
EtO2CR2
HN Cbz
F N
O
ON
NN
N PPh3(iii)
60 °CDCM / AcOH
F N
O
OO
PPh3 obtained oncenot reproducible
R1 =O
OF
OTrO
R2 = H (21%)Me (58%)i-Pr (64%)
NH
O
O
O
PPh3
CO2Et+
(iv)
60 °CDCM / AcOH
50%NH
O
O
PPh3
NO2
O PPh3
CO2t-Bu (v) SnCl2
NH2
O PPh3
CO2t-Bu
spontaneous
[78MI7]
[01TL141]
[05MI385]
[73JOC1047]
[87S288]
Scheme 1-10. Early Reports of DOT-pyrrolidines and DOT-piperidine
Earlier reports of DOT-pyrrolidine substructure (Scheme 1-10) include (i) a byproduct during
the preparation of showdomycin [78MI7], (ii) a flash vacuum pyrolysis method (FVP, 600–
900 °C, 102 Torr) which noted difficulties associated with N-deprotection by hydrogenolysis
[01TL141], and (iii) a byproduct without logical explanation of how it might be formed
31
[05MI385]. Anomalous, “spontaneous” [87S288, 04SL353, 05SL2763] cyclizations at rt,
discovered by Aitken, were left unexplained in his publications [99PS577, 01TL141, 03TCC41,
03MI289]. Earlier reports of the DOT-piperidine substructure (Scheme 1-6) reported two
articles of the same molecule as an (iv) unreactive novelty [73JOC1047] or an (v) unwanted
dead-end [87S288].
Ph3P
N+OO
Ph3P
NOO
Me
Ph3P+
NO O
Ph3P+
NOO
3.2bPh Ph
PhPh
3.2b'
Me
MeMe
Scheme 1-11. Delocalization of N-Methyl-DOT-pyrrolidine 3.2b, Major Canonical Form 3.2b′
The extra stabilization afforded by a second carbonyl on linear DOT systems [90TL5925] is
also present in cyclic DOT systems. The DOT moiety resisted refluxing alcoholic base
[73JOC1047, 95T3279], high FVP temperatures [01TL141], and hydrobromic acid (HBr)
[Section 3.2.8], to some extent due to the stable lactam bond and DOT functionality participating
in delocalization (Scheme 1-11) [04SC4119]. The mechanism of the Wittig reaction is debated
to occur either on the time scale of a bond rotation or through an equilibrium process. Although
the Wittig mechanism is intuitively understood as a “4-center mechanism [90JA3905]”, the
inherent stability of the DOT moieties requires further investigation.
Although DOT-pyrrolidines are crystalline, soluble in halogenated and alcoholic solvents, and
have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings [72JOC3458,
73JA7736] they have received little of the attention given to tetramic acids, presumably due to
32
their lack of reactivity. In Chapter 3 we report the first convenient synthesis of DOT-
pyrrolidines, DOT-tetrahydropyrrolizine, DOT-piperidine, 5-amino-4-triphenylphosphonio-2,4-
dihydropyrrol-3-one bromides, and 3-ammonio-2-triphenylphosphonio-tetrahydropyrrolizin-1-
one dibromide. Furthermore we develop four applications using N-methyl-DOT-pyrrolidine,
3.2b.
N
NH
12
34
5 H
R
HN
N
1
2
34
5
H
R
H
H
Scheme 1-12. Numbering of Substituted 4(or 5)-Monosubstitued Imidazoles
The regiospecific N-alkylation of substituted imidazoles, with an amide bond formed for a
protecting group in Chapter 4, allowed the synthesis of novel heterocyclic ionic liquids. Ionic
liquids have been defined as salts with melting temperatures below 100 °C, and composed of
only cations and anions. Molten salts, sometimes considered the ultimate non-volatile organic
solvent, have several properties that compel their use as reaction media [02GC73]. The
numbering around the imidazole ring is shown in Scheme 1-12. Numbering begins at the sp3
nitrogen and proceeds around the ring to assign the smallest possible number to the tertiary
nitrogen. Equilibration between regioisomers, in some cases when the R group in the 4- or 5-
position is a substituent, requires the reassignment of the regiochemistry.
The synthetic efforts were not directed a priori to the preparation of energetic fluids, but
rather to synthesizing new materials to enable the development of links between component
functionality and physical properties. However, the approach broadened and the strategy shifted
from commercially available components to newly synthesized anions and cations. Alkylations
of substituted imidazoles have been studied for almost a century [10JCS1814, 22JCS2616,
24JCS1431, 25JCS573, 60JCS1357, 63BSC2840, 66AF23, 89AJC1281, 91SC427, 95CC9], and
33
were used for medicinal chemistry applications in the late sixties [67JME891, 68JME167,
03JME427, 03BMC2863]. Recently the CHC developed regiospecific N-alkylation for a series
of 1,3-dialkylimidazolium salts containing a strongly electron-withdrawing nitro group directly
attached to the ring (Scheme 1-13) and other strategies for novel EILs [06NJC349].
N
N
MeO2N
NH
NO2N
N
N
O2N
Et
N
NEt
MeO2N
N
NMe
MeO2N
X
Et2SO4,NaOH (aq.)45 oC
Me2SO4
Et2SO4
4.2
X
4.1
4.7c 4.4
4.3
dioxaneref lux
Me2SO4, toluene
MeOTf, toluene20 °C, 72 h
20 °C, 48 h
Scheme 1-13. Regioselective N-Alkylation and Quaternization of Nitro-Substituted Imidazole The regiospecific N-alkylation strategy provided the more sterically hindered 1-
alkylimidazoles 4.6h–k from the 4-substituted imidazoles 4.1e and 4.1f. The reaction sequence
involved an initial benzoylation followed by quaternization with alkyl triflates and base
hydrolysis (Scheme 1-14) [02EJOC2633]. The 1-Benzoyl-4-methyl-imidazole 4.9a and 1-
benzoyl-2,4-dimethyl-imidazole 4.9b were prepared from benzoyl chloride with a twofold excess
of the corresponding 4.1e,f in THF at rt [90S951]. Reaction of 4.9a,b with propyl and hexyl
triflates in toluene at rt for 48 h gave the corresponding quaternary salts 4.10a–d, which
separated from the bulk solvent as oils and were used as intermediates. The salts 4.10a–d
34
hydrolyzed under biphasic aq sodium hydroxide and diethyl ether conditions at rt to give 1-
alkylimidazoles 4.6h–k.
N
NR2
R3 R1
Bz
TfO
NH
NR2
R3PhCOCl
N
NR2
R3
Bz
R1 OTf NaOH
N
NR2
R3 R1
4.6h-k4.9a
b
watertoluene
4.1e (R3 = Me)f (R2,R3 = Me)
4.10 a,b (R1 = n-Pr)c,d (R1 = n-Hex)
Scheme 1-14. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6h–k
Cation Anion
New, functionalized fused salt
Cation Anion
M odular DesignThe diverse structural fuctionalities,appended directly to the heterocyclicion cores, introduced throughout thecollaboration included:-alkyl chains with and withoutenergetic groups;
-strained ring systems;-oxygen-rich functional groups(e.g., OH, ether, epoxide);
-energetic functionalities(e.g., NO2, CN, N3, NH2);-unsaturated functionalities.
Metathesis
-Byproduct
Figure 1-3. Collaborative Effort: Modular Design of Heterocycles for EILs.
The dual nature of ILs allows a unique tunable architectural platform with properties related
to the structure of constituent ions [07MI1111]. The collaborative effort, between the Center for
Heterocyclic Chemistry (CHC) in Gainesville, Florida together with The Center for Green
Manufacturing (CGM) in Tuscaloosa, Alabama, has focused on the development of new
energetic ionic liquids from the perspective of modular design in order to synthesize selected
heterocycles for preparing fused salts (Figure 1-3). The properties of cation and/or anion within
the ionic pair were independently modified, then metathesis could generate new functional
materials [05CC868, 06CEJ4630], which retain the core features of the IL state of matter. The
final materials were monitored by DSC, TGA, and single crystal X-ray crystallography, to
35
examine how the modification to each component influenced decomposition temperature and
melting point.
Over the last several years, typical properties of ionic liquids (ILs) such as high ion content,
liquidity over a wide temperature range, low viscosity, limited-volatility, and high ionic
conductivity have proven to be important drivers supporting numerous advances beyond the
initial investigations of ILs as liquid electrolytes [06NJC349, 04FPE93, 04AJC113]. The
properties of ILs have made it possible to replace damaging solvents which are used in huge
amounts or are hard-to-contain, volatile organic compounds (VOCs), with recyclable, reusable,
and easy to handle materials [99CRV2071, 01CC2399, 02JMC(A)419]. The rethinking,
redesign, and implementation of ILs as “designer” solvents into many current chemical processes
can deliver significant cost and environmental benefits [99CPP223], and lead to new
technologies, e.g. the processing of cellulose [02JA4974], biphasic chemical processes (e.g.,
BASF's BASIL®) [06MI121], photovoltaics [96IC1168, 02CC2972], fuel cell electrolytes,
[02MI185] polymer electrolytes [04EA255], thermal fluids [05MI181], and lubricants
[06MI347].
The synthesis of tetrasubstituted trans-imidazolidin-2-ones was explored in Chapter 5 and
utilized a Boc-amide bond on N-substituted benzotriazoles. The N-Boc-(benzotriazol-1-
ylmethyl) benzylamine was demonstrated by the Katritzky group (Scheme 1-15) [01JOC2858] to
act as a 1,1-dipole equivalent in the stereoselective synthesis of 1,3,4,5-tetrasubstituted
imidazolidin-2-ones. The transition states for the formation of 4,5-disubstitued 1,3-imidazolidin-
2-ones by the reaction of an α-nitrogen carbanion with an imine was described by Kise et al.
[96JOC428], and generally extended to the benzotriazole method. The formation of dipole-
stabilized carbanions adjacent to nitrogen atoms [84CRV471, 96JOC428, 96JA3757] is further
36
directed to lithiate chemoselectively at a carbon adjacent to a benzotriazole residue
[05AGE5867] and in the presence of an imine a highly trans vicinal diamine is formed. Urea
forms spontaneously in most cases. The general benzotriazole protocol enables the introduction
of a variety of substituents into the 4- and 5-position of imidazolidin-2-ones with trans
stereochemistry.
NBoc
Bt
Ph
NCH
BocPh
(i) s-BuLi
N
Bt
Ph
O
Ot-Bu
Li
NN
OR2
H BtHR3
Ph
NBtPh
O
Ot-Bu
Li
R3
N
R2
NBtPh
O
Ot-Bu
LiN
R3
+ R3CH=NR2
R2
trans favored
NBtPh
O
Ot-Bu
Li
N
R3
R2
H H
Scheme 1-15 Protected-N-(benzotriazol-1-ylmethyl) Benzylamine, 1,1-Dipole Synthon
Nitrogen heterocycles containing a vicinal diamine moiety are considered biologically
privileged active structures [06MI101, 07OL2035, 07JA762]. Likewise, nitrogen heterocycles
containing the cyclic urea moiety incorporated as part of the core are found in a broad array of
biologically active molecules [94EP612741, 96MI301, 96JME3514, 02BBA02, 06OL2531] and
provide increased structural rigidity as well as hydrogen bonding possibilities [95TL6647,
37
98TL1477]. The presences of these two potentially bioactive properties encourages the
exploration of vicinal diamino tethered ureas and unsaturated imidazol-2-ones, or saturated
imidazolidin-2-ones in particular for medicinal screening.
(iii)c,b,d
(ii-a)c,d(ii-b)c,d
a
b
5.1
c
(i)a,bNN
OR2 R1
R4 R5HR3 NR2
R3+ N R1Boc
R5
Base
R1 = Ar, R5 =Ph orR1 = (CH2)3 = R5 orR1 = Alk, Bzl, R5 = BtR2 = R3 = Ar, HetAr
d
NCOR2
N R1
R4 R5HR3
NaI
R5
HN
O
R1
O
H2N
PPh3, CBr4Et3N, DCM
R5
HN
O
R1
O
H2N
R1 = SO2Ar, R5 = Alk, ArR3 or R4 = H, Alk, Ar,R6 = Ar or t-bu
R1 = Cbz, R5 = MeR2 = R4 = H, R3 = allyl
R1 = Cbz, R5 = CO2HR2 = R3 = R4 = H
NaOCl
Scheme 1-16. Multiple Bond Formation in One Step for Imidazolidin-2-one
Vicinal diamine and urea formation in one simultaneous step to form imidazolidin-2-one
(Scheme 1-16), was reported in the literature. The C–C bond and urea formation, (i) bonds a and
b, were achieved by coupling of a lithiatied α-nitrogen methylene to imines and intramolecular
cyclization to the Boc-protecting group [96JA3757, 96JOC428, 01JOC2858, 02EJOC301]. The
urea and C–N bond formation, (ii) bonds c and d, were achieved by (ii-a) ring opening of N-
arylsulfonylaziridines with isocyanates in the presence iodide ions [93T7787, 05TL479]; or (ii-b)
dehydration of allyl carbamate with modified conditions (PPh3, CBr4, Et3N) provided allyl
cyanate-to-isocyanate rearrangement with subsequent intramolecular cyclization [06OL5737].
The urea and C–N bond formation, (iii) bonds c, b, and d, were achieved by Hoffman
38
rearrangement [68BCJ2748, 89JME289]. Two step methods for imidazolidin-2-ones involve
either formation of vicinal diamine [98AGE2580, 05OL1641] or cyclic urea [95JME923,
96TL5309, 00AJC73, 03SL1635, 04OL2397, 04SL489, 05T9281] and a cyclization step.
5.2
NN
OR2
H BtHR3
NR2
R3+ NBoc
Bt
NH2R2
+ O
R3 H2N[5.2.1] [5.2.2]
[5.2.3]
[5.2.4]
H H
NN
OR2
HHR3
O
5.3
5.4
5.5
R1R1
R1 R1
Scheme 1-17. Synthetic Overview of Protocols
In Chapter 5 we report the extension of the previous work on Bt-intermediates to form novel
tetra-substituted trans-imidazolidin-2-ones, with a synthetic protocol (Scheme 1-17). The
efficient protocol, section 5.2.1, for imines was based on the reaction of aldehydes to anilines
with the loss of a water molecule. The protocols; section 5.2.2 for Bt-intermediates, section
5.2.3 for the convergent production of trans-Bt-imidazolidin-2-ones; and section 5.2.4 for trans-
imidazolidin-2-ones cyclic ketones were based on the published literature method [01JOC2858].
1.4 Aim and Importance of the Work
My objective in doing this work was to investigate certain aspects of the chemistry of
heterocyclic compounds in relation to amino acids, lactams, and ionic liquids. A common theme
that appeared throughout this work was that of the amide bond. The serendipitous study and
development of interesting synthetic organic chemistry, including some green chemistry, will
39
hopefully lead to novel molecules for the benefit of life, science, and society. My critical
findings provide a solid framework for future investigations in these related areas.
Peptidic α-triphenylphosphoranylidene esters and amides have attracted considerable
attention as important intermediates for the preparation of peptidic α-keto esters and of α-keto
amides, compounds which are potential inhibitors of proteolytic enzymes and leukotriene A4
hydrolases. Therefore, the development of an expedient, versatile method to C-acylate P-ylides
with chiral amino acid derivatives for N-protected peptidic α-triphenylphosphoranylidene esters
is desirable. The N-Protected N-acylbenzotriazoles C-acylation of P-ylides with microwave
irradiation adds to the robust list of N-acylbenzotriazoles applications.
Although DOT-pyrrolidines are crystalline, soluble in halogenated and alcoholic solvents, and
have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings they have
received little of the attention given to tetramic acids. The possible transformation the 2,4-dioxo-
3-triphenylphosphoranylidene (DOT) moiety provides when directly incorporated as part of a
heterocyclic ring is unexplored and of considerable interest. Although the Wittig mechanism is
intuitively understood as a “4-center mechanism”, the inherent stability of the DOT moieties
requires further investigation.
The properties of cation and/or anion within the ionic pair were independently modified, then
metathesis could generate new functional materials, which retain the core features of the IL state
of matter. The regiospecific N-alkylation strategy provided the more sterically hindered 1-
alkylimidazoles for the production of newly synthesized anions and cations. Over the last
several years, typical properties of ionic liquids (ILs) such as high ion content, liquidity over a
wide temperature range, low viscosity, limited-volatility, and high ionic conductivity have
40
proven to be important drivers supporting numerous advances beyond the initial investigations of
ILs as liquid electrolytes.
The synthesis of tetrasubstituted trans-imidazolidin-2-ones utilized a general benzotriazole
protocol to enable the introduction of a variety of substituents into the 4- and 5-position of
imidazolidin-2-ones with trans stereochemistry. The extension of the previous work allowed the
formation of a vicinal diamine and urea in one simultaneous step. The presences of two
potentially bioactive properties encourages the exploration of vicinal diamino tethered ureas and
unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones in particular for medicinal
screening.
41
CHAPTER 2 MICROWAVE ASSISTED C-ACYLATION OF P-YLIDES
2.1 Introduction
Peptidic α-triphenylphosphoranylidene esters and amides have attracted considerable
attention as important intermediates for the preparation of peptidic α-keto esters and of α-keto
amides [94JOC4364, 97JOC8972], compounds which are potential inhibitors of proteolytic
enzymes [92JME451, 93JME2431] and leukotriene A4 hydrolases [93JME211]. The β-Keto α-
triphenylphosphoranylidene esters 2.1 have been used for the preparation (i) of alkynes 2.2 by
flash vacuum pyrolysis (FVP) [85S764, 04T12231], (ii) α,β-diketoesters 2.3 by oxidation ([O])
[94JOC4364, 97JOC8972], and (iii) β-keto esters 2.4 by direct reduction ([H]) (Scheme 2-1).
Further applications of distabilized triphenylphosphoranylidenes are given in Chapter 3, section
3.1.0.
PPh3
CO2EtR
O
(i) FVP(ii) [O]
(iii) [H]
CO2EtR
OCO2Et
R
O
CO2EtR
O
2.1
2.2
2.3
2.4
(iv) DeprotectionNH
OPPh3
O{Chapter 3}
3.1
R = Cbz-NH-CH2
Scheme 2-1. Applications of β-Keto α-Triphenylphosphoranylidene Esters
Beta-Keto α-triphenylphosphoranylidene esters 2.1 are readily available by C-acylation of
(carboxymethylene)triphenylphosphorane (2.6) with a proton sponge/acid scavenger such as
N,O-bis(trimethylsilyl)acetamide (BSA) [90TL5205, 94JOC4364, 95JOC8231] and acyl
chlorides [04T12231, 82JOC4955], or cyclic anhydrides [82AJC2077, 85S764], or anhydrides
with BSA [92TL6003] (Scheme 2-2). However, acyl chloride and anhydride methods are
42
limited in their applicability for chiral peptidic models due to high reactivity and byproducts
causing potential problems with other functional groups. Carbon-acylation methods for chiral N-
protected peptidic α-triphenylphosphoranylidene esters have been reported, by activation of
amino acids with carbonyl diimidazole (CDI) requiring 24 h reaction time [99JA1401], or with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) in the presence of 4-
dimethylaminopyridine (DMAP) requiring 16 h reaction time [93JOC4785, 94JOC4364,
97JOC8972]. Therefore, the development of an expedient, versatile method to C-acylate 2.6
with chiral amino acid derivatives for N-protected peptidic α-triphenylphosphoranylidene esters
is desirable.
PPh3
CO2EtR
O2.1
PPh3
H CO2Et
R1
O OH
acid halideswith BSAor μ-Wave
amino acids w/EDCI, DMAP16 hor CDI, 24 h
cyclicanyhydridesoranhydrideswith BSA
O
MeN
TMSTMSBSA =
2.6
Scheme 2-2. Literature Methods for β-Keto α-Triphenylphosphoranylidene Esters
Acylbenzotriazoles have been reported by the Katritzky group as efficient neutral coupling
reagents for chiral N-acylation, regioselective C-acylation, and O-acylation of aldehydes
[04S1806] and as sufficiently reactive to form amide bonds at ambient temperature, but stable
enough to resist side reactions [04S2645]. Protected (α-aminoacyl)benzotriazoles are efficient
reagents for acylation of amino amides [02ARK134], amino sulfonamides [04ARK14], amino
thiol esters [04S1806], small peptides carrying side chains with alkyl groups [04S2645], small
43
peptides with multi-functional groups [05S397], and amino ketones [05JOC4993]. We have now
demonstrated the C-acylation of 2.6 with chiral, and achiral, N-protected (α-
aminoacyl)benzotriazoles 2.5a–g, and 2.8a–c, to prepare chiral, and achiral, N-protected peptidic
α-triphenylphosphoranylidene esters 2.7a–g, and 2.9–2.11 (Scheme 2-3) under microwave
irradiation.
O
NR1 Pg
PPh3
CO2Et +
2.5a-g, 2.8a-c2.6
2.7a-g2.9-11
R3
O
N
BtR1 Pg
R3
PPh3
CO2EtH R2R2μ-Wave
Scheme 2-3. Retrosynthesis for N-Protected Peptidic α-Triphenylphosphoranylidene Esters
A single cavity microwave synthesizer provides an effective reproducible and safe technique
for promoting a variety of reactions and shortening reaction times while reducing pollution by
using less solvent [02MI1, 03ARK68]. Microwaves, a form of electromagnetic radiation
between infrared (IR) and radio frequencies, used in a single cavity synthesizer accelerate
reaction times and reduce the amount of solvent required. The general mechanism behind
microwave technology is that molecules with a permanent dipole become aligned with the
electric field when irradiated with microwaves, oscillation of which changes the molecular
alignment and increases the temperature. Oscillation of the standing microwaves occurs at 4.9 x
109 times per second, causing the electromagnetically radiated molecules to become extremely
agitated, as they align and realign themselves with the oscillating field, creates an intense internal
heat that can escalate as quickly as 10 °C per second [02JCO95]. International convention
dictates that most microwave ovens operate at 12.2 cm (2450 MHz), so not to interfere with
radar or other telecommunications devices.
44
2.2 Results and Discussion
2.2.1 Protected (α-Aminoacyl)benzotriazoles
The starting N-(Boc- and Cbz-α-aminoacyl)benzotriazoles 2.5a–f (L-configuration), 2.5g (D-
configuration), and 2.8a–c (achiral) were prepared in 29−98% yields (Table 2-1) from the
corresponding N-protected amino acids following procedures recently developed at the Center
for Heterocyclic Chemistry (CHC) at the University of Florida (UF) (Scheme 2-4) [02ARK134,
04S2645, 05S397]. The two rotameric forms of 2.8b gave distinct and separate signals in the
NMR spectra (Scheme 2-5). Novel 2.5e,g and 2.8a–c were supported by 1H-NMR, 13C-NMR,
elemental analyses, and optical rotation.
DCMO
NR1
Pg(i) SOCl2, BtH
2.5b-g2.8a-c
R3
O
N
Bt
R1
Cbz
R3
OHR2 R2
Pg = Boc or Cbz
(ii) BtSO2Me
O
NR1
Boc
R3
BtR2
2.5a
Scheme 2-4. Protected (α-Aminoacyl)benzotriazoles 2.5a–g, 2.8a–c, from Protected Amino Acids
2.8bZ-isomer
E-isomer
O
N
Bt
Me
OOPh
ON
Bt
MeO
OPh
O
N
Bt
Me
OOPh
ON
Bt
MeO
OPh
Scheme 2-5. Rotameric Forms of 2.8b
45
Table 2-1. Isolated Yields of N-Protected (α-Aminoacyl)benzotriazoles 2.5a–g, 2.8a–c
Product Amino Acid Pg R1 R2 R3 Yielda (%)
Lit. Yield (%)
2.5a (L)Alanine (Ala) Boc Me H H 29g 61b
2.5b (L)Ala Cbz Me H H 85 95c
2.5c (L)Valine (Val) Cbz CH(Me)2 H H 91e 91c
2.5d (L)Phenylalanine (Phe) Cbz CH2Ph H H 98 88c
2.5e (L)Aspartic Acid (Asp) (γ-OMe) Cbz CH2CO2Me H H 86e,f –
2.5f (L)Tryptophan (Trp) Cbz CH2-Indol-
3-yl H H 73 95d
2.5g (D)Ala Cbz Me H H 85f –
2.8a Glycine (Gly) Cbz H H H 98f –
2.8b Sarcosine (Sar) Cbz H H Me 84f –
2.8c Aminoisobutyric Acid (Aib) Cbz Me Me H 80f –
aIsolated yield. bLit. [02ARK134]. cLit. [04S2645]. dLit. [05S397]. eReaction by K. Suzuki. fNovel. gMethod (ii) Scheme 2-4.
2.2.2 Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters
The chiral N-protected peptidic α-triphenylphosphoranylidene esters 2.7a–g (Scheme 2-6)
were prepared in 65–90% yields (Table 2-2) from chiral N-(Boc- and Cbz-α-
aminoacyl)benzotriazole 2.5a–f (L-configuration), 2.5g (D-configuration) and
(carboxymethylene)triphenylphosphorane (2.6) in the microwave synthesizer, following the
optimized procedure (Table 2-3). Microwave reactions were carried out in a standard 50 mL rb
(round bottom) flask under controlled, safe, and reproducible conditions. The single cavity
microwave synthesizer maintained a steady temperature with a self-adjusting irradiation
mechanism. Novel 2.7d–g were supported by 1H-NMR, 13C-NMR, elemental analyses, and
optical rotation.
46
O
N
Bt
HR1
ACN O
NR1Pg
PPh3
CO2Et+
μ-Wave (120 W)60 oC, 10 min
2.6
PgH
2.5a-g 2.7a-g
PPh3
H CO2Et
Scheme 2-6. Base Free C-Acylation for Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters 2.7a–g
Table 2-2. Isolated Yields of Chiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters 2.7a–g
Product Amino Acid Pg R1 Yielda (%) [α]23
D Lit. Yield (%)
Lit. [α]23
D
2.7a (L)Ala Boc Me 65 +0.2 54c n/r
2.7b (L)Ala Cbz Me 88 (86)b +25.4 46d +20.3
2.7c (L)Val Cbz CH(Me)2 88 +28.0 88c,49d +28.7
2.7d (L)Phe Cbz CH2Ph 89e (79)b +0.6 – –
2.7e (L)Asp(OMe) Cbz CH2CO2Me 90e,f +0.8 – –
2.7f (L)Trp Cbz CH2-Indol-3-yl 70e +40.0 – –
2.7g (D)Ala Cbz Me 69e –17.5 – – aIsolated yield. bYields obtained in refluxing ACN. cLit. [95MI124] Boc-Protected N-carboxyanydride with 2.6 at rt. dLit. [02JP(1)533] (EDCl, DMAP with N-Cbz-Protected amino acid at rt). eNovel. fReaction by K. Suzuki. gn/r = not reported.
Carbon-acylation conditions were optimized using 2.6 with Cbz-(L)Ala-Bt (2.5b) in three
different solvents, dichloromethane (DCM), acetonitrile (ACN), and toluene (Table 2-3).
Microwave assisted C-acylations performed in DCM, at 36 °C for 30 min gave no detectable
2.7b. Microwave assisted C-acylations performed in toluene, at 110 °C for 10 min formed 2.7b
in 30% yield, along with a byproduct detected by 1H-NMR. Optimized microwave assisted C-
acylation in ACN, at 60 °C for 10 min gave pure 2.7b in 88% yield, after a simple workup by
washing with saturated aq sodium carbonate. Carbon-Acylations of 2.6 with 2.5b and 2.5d in
47
refluxing ACN, using an oil bath heat source, required 12 h to achieve 2.7b (86%) and 2.7d
(79%), respectively. Although using an oil bath heat source generated satisfactory yields, the use
of the microwave assistance significantly shortened the reaction time and reduced the amount of
solvent required. The optimized microwave reaction conditions (60 °C, 120 W, ACN, 10 min)
were applied to the preparation of N-protected peptidic α-triphenylphosphoranylidene esters
2.7a–g (Scheme 2-5, Table 2-2). The microwave protocol afforded fast and clean C-acylation,
and the use of N-protected (α-aminoacyl)benzotriazoles 2.5a–g avoided the need for base.
Table 2-3. Attempted Optimization Reaction Conditions for 2.7b Solvent (1 mL) μ-Wave (W) T (°C) t (h) Yield (%)
DCM (70) 36 0.5 -a
Toluene (200) 110 0.1 30b
ACN (120) 60 0.1 88
ACNd (n/a) 82 12.0 86c
aNo Reaction. bReaction provided undesired byproduct. cYields obtained in refluxing ACN heated by oil bath. d15 mL.
Ester 2.7a was prepared in 54% yield using the corresponding urethane-protected N-
carboxyanhydride with 2.6, by Fehrentz et al. [95MI124]. The urethane-protected N-
carboxyanhydrides are water sensitive [90JA7415], and require several steps for preparation
from N-carboxyanhydrides which exhibit poor stability [87MI22]. Direct couplings of Cbz-Ala-
OH and Cbz-Val-OH with 2.6 were carried out in the presence of EDCl/DMAP, by Aitken et al.,
to produce 2.7b (46%) and 2.7 (49%), respectively [02JP(1)533]. The twelve β-keto α-
triphenylphosphoranylidene esters, by Aitken et al., were obtained in an average 47% yield. By
our microwave assisted method, esters 2.7a–c were obtained in an average 80% yield.
The attempt to C-acylate 2.6 (Scheme 2-7) with Cbz-Glu-Bt [05S397] was unsuccessful. The
attempt to C-acylate 2.6 with Fmoc-Ala-Bt resulted in cleavage of the Fmoc protecting group,
48
which caused the formation of a complex mixture of products. Fmoc-Bt was isolated by column
chromatography. The formation of Fmoc-Bt was explained, by the generation of the
benzotriazole anion, which underwent addition-elimination to the carbonyl carbon of the Fmoc
group.
O
NBt
Fmoc
MeACN
μ-Wave (120 W)60 oC, 10 min
H
Bt
OO+
HN Bt
O
NH2O
Cbz
ACN
μ-Wave (120 W)60 oC, 10 min+
Fmoc-Bt
decomposedreagents
2.6
2.6
+ complexmixture
Scheme 2-7. Unsuccessful C-Acylations, and the Generation of Fmoc-Bt
2.2.3 Achiral N-Protected Peptidic α-Triphenylphosphoranylidene Esters
The achiral N-protected peptidic α-triphenylphosphoranylidene esters 2.9–2.11 (Scheme 2-8)
were prepared from achiral Cbz-N-(aminoacyl)benzotriazoles 2.8a–c and 2.6, under the
optimized microwave conditions (60 °C, 120 W, ACN, 10 min). C-Acylation of 2.6 with Cbz-
Gly-Bt (2.8a) or Cbz-Sar-Bt (2.8b) gave 2.9 (80%) or 2.10 (89%), respectively. On the contrary,
C-acylation of 2.6 with Cbz-Aib-Bt (2.8c) gave 2.11 in 3% yield. Extension of the reaction time
resulted in the decomposition of 2.8c. Presumably the formation of 2.11 was inhibited by steric
hindrance from the two methyl groups at the α-position. The two rotameric forms of 2.10 gave
distinct and separate signals in the NMR spectra (Scheme 2-9). Novel 2.10 and 2.11 were
supported by 1H-NMR, 13C-NMR, and elemental analyses.
49
O
N
Bt
CbzR1
ACN O
NR1
Cbz
PPh3
CO2Et+ μ-Wave (120 W)
2.6R2 R3
R2
R3
2.8a, R1 = R2 = R3 = H2.8b, R1 = R2 = H, R3 = Me2.8c, R1 = R2 = Me, R3 = H
2.9R1 = R2 = R3 = H (80%)2.10R1 = R2 = H, R3 = Me (89%)2.11R1 = R2 = Me, R3 = H (3%)
60 oC, 10 min
Scheme 2-8. Base Free C-Acylation for Achiral Esters 2.9–2.10
2.10
Z-isomer
E-isomer
O
N
PPh3
CO2Et
Me
OOPh
ON
Ph3P CO2Et
MeO
OPh
O
N
PPh3
CO2Et
Me
OOPh
ON
Ph3P CO2Et
MeO
OPh
Scheme 2-9. Rotameric Forms of 2.10
2.2.4 Peptidic α-Triphenylphosphoranylidene Diastereomers
The (LL)Diastereomer, 2.14 (61%) and (DL)Diastereomer, 2.15 (66%) were prepared, to test
retention of the original chirality during microwave irradiation (Scheme 2-10). Novel 2.13, 2.14
and 2.15 were characterized and supported by 1H-NMR, 13C-NMR, elemental analyses, and
optical rotation.
Coupling of (L)phenylalanine methyl ester with α-bromoacetic acid in the presence of N,N′-
dicyclohexylcarbodiimide (DCC) and DMAP gave 2.12 (95%) [03TA1935]. Preparation of 2.13
(81%) was achieved by reaction with triphenylphosphine in a solvent mixture (THF:diethyl ether
= 1:3) [99JA1401]. (LL)Diastereomer 2.14 (61%) was obtained under microwave conditions
50
(60 °C, 120 W, ACN, 10 min) with 2.5b in the presence of equimolar triethylamine. Similarly,
reaction of 2.13 with 2.5g gave (DL)diastereomer 2.15 (66%).
O
OMeNH
Ph
O
PPh3Br
PPh3O
OMeNH
Ph
O
Br
O
OMeNH
PhO
PPh3
O
HN
CbzMe
BrCH2CO2HDCC, DMAP
O
OMeNH
PhO
PPh3
O
HN Me
Cbz
O
OMeH2N
Ph
2.12
95%
2.1381%
2.14
(i)2.5bEt3N
61%
2.15
(i)2.5gEt3N
66%
THF, Et2O
(i) μ-Wave (120 W)60 oC, 10 min, ACN
Scheme 2-10. Synthetic Route to (LL)- and (DL)Diastereomers 2.14, 2.15
Figure 2-1. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 20 °C
51
Figure 2-2. Aromatic 13C-NMR Region of the (DL)Diastereomer 2.15 at 60 °C
Figure 2-3. The 31P-NMR of the (DL)Diastereomer 2.15 at 20 °C and 60 °C
The extent of preservation of original chirality was estimated as >95% by the 1H NMR spectra
of the (LL)- and (DL)diastereomers 2.14 and 2.15, respectively. While the Me group of
enantiopure Ala (LL)diastereomer 2.14 gave a signal at 0.99 ppm, the Me group of the
enantiopure Ala on the (DL)diastereomer 2.15 gave a signal at 0.86 ppm. Optical rotations of the
(LL)diastereomer and (DL)diastereomer were –20.0 and +4.4 respectively. Additionally the 13C-
NMR spectra of the two diastereomers showed a broadening of some signals, and a complex
52
series of signals in the aromatic region, especially between 131.5–132.2 ppm. The aromatic
region 13C-NMR spectra of the (DL)diastereomer 2.15 at 20 °C (Figure 2-1) and at 60 °C (Figure
2-2), showed a sharpening of the signals at higher temperature and the complex multiplet
separated into two sets of doublets. The 31P-NMR spectra of the (DL)diastereomer 2.15 (Figure
2-3) gave two broad singlets at rt, which at 60 °C merged to form one sharp singlet. The
different NMR chemical shifts and optical rotations in opposite directions of the two
diastereomers supported the preservation of chirality.
2.3 Conclusions
The preparation of N-protected peptidic α-triphenylphosphoranylidene esters from N-(Boc- or
Cbz-α-aminoacyl)benzotriazoles was demonstrated under microwave irradiation without base.
Retention of chirality was demonstrated by the synthesis of (LL)- and (DL)diastereomers and
comparison of their optical rotation and NMR spectra. The C-acylation utilized versatile N-
protected (α-aminoacyl)benzotriazoles avoiding the use of base and microwave irradiation
reduced reaction times and solvent. Furthermore this procedure was found to be a convenient
route to the tetramic acid ring system in Chapter 3.
2.4 Experimental Section
Melting points were determined on a capillary point apparatus equipped with a digital
thermometer. NMR spectra were recorded in CDCl3 for 1H (300 MHz) and 13C (75 MHz) with
tetramethylsilane (TMS) as the internal standard, unless otherwise specified. N-Boc- and N-Cbz-
amino acids were purchased from Fluka and Acros, and used without further purification.
Acetonitrile was purchased from Aldrich, and used without distillation. Microwave heating was
carried out with a single cavity Discover® Microwave Synthesizer (CEM Corporation, NC),
producing continuous irradiation at 2455 MHz.
53
2.4.1 Preparation of N-Protected (α-Aminoacyl)benzotriazoles. 2.5a–g, 2.8a–c
Compounds 2.5a (Boc protecting group) [02ARK134], 2.5b–g (Cbz protecting group)
[04S2645, 05S397], and 2.8a–c were prepared by previously reported procedures.
(3S)-4-(Benzotriazol-1-yl)-3-benzyloxycarbonylamino-1-methoxybutan-1,4-dione (Cbz-(L)Asp(OMe)-Bt, 2.5e). (86% yield) Colorless needles (from chloroform / hexane) mp 72–74 °C. [α]23
D = −23.4 (c 1.75, CH2Cl2). 1H NMR δ 3.23 (dd, J = 16.6, 4.8 Hz, 1H), 3.38 (dd, J =
16.6, 4.8 Hz, 1H), 3.65 (s, 3H), 5.14 (s, 2H), 5.90–5.97 (m, 1H), 6.11 (br s, 1H), 7.35 (br s, 5H), 7.51–7.56 (m, 1H), 7.65–7.71 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H). 13C NMR δ 37.2, 51.7, 52.2, 67.4, 114.4, 120.3, 126.6, 128.1, 128.2, 128.5, 130.9, 131.2, 135.9, 145.9, 155.7, 169.2, 170.4. Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 59.76; H, 4.66; N, 14.58.
(2R)-1-(Benzotriazol-1-yl)-2-benzyloxycarbonylaminoprop-1-one (Cbz-(D)Ala-Bt, 2.5g). (85% yield) White microcrystals (from ethyl acetate / hexanes) mp 94–96 °C. [α]23
D = +80.2 (c 2.08, CH2Cl2).
1H NMR δ 1.69 (d, J = 7.0 Hz, 3H), 5.11 (d, J = 12.2 Hz, 1H), 5.17 (d, J = 12.2 Hz, 1H), 5.65 (d, J = 6.9 Hz, 1H), 5.81 (quintet, J = 7.1 Hz, 1H), 7.10–7.45 (m, 5H), 7.50–7.56 (m, 1H), 7.64–7.70 (m, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H). 13C NMR δ 18.9, 50.5, 67.1, 114.3, 120.3, 126.4, 128.1 (2C), 128.4, 130.6, 131.1, 136.0, 145.9, 155.6, 172.2. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.82; H, 4.97; N, 17.25.
1-(Benzotriazol-1-yl)-2-benzyloxycarbonylaminoethan-1-one (Cbz-Gly-Bt, 2.8a). (98% yield) White microcrystals (from chloroform / hexane) mp 106–108 °C. 1H NMR δ 5.10 (d, J = 5.7 Hz, 1H), 5.20 (s, 2H), 5.55 (s, 1H), 7.35–7.39 (m, 5H), 7.51–7.56 (m, 1H), 7.66–7.71 (m, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H). 13C NMR δ 45.0, 67.7, 114.3, 120.6, 126.8, 128.4, 128.5, 128.8, 131.1, 136.2.146.2, 156.7, 168.6. Anal. Calcd for C16H14N4O3: C, 61.93; H, 4.55; N, 18.06. Found: C, 61.98; H, 4.57; N, 17.99.
1-(Benzotriazol-1-yl)-2-benzyloxycarbonyl(methyl)aminoethan-1-one (Cbz-Sar-Bt, 2.8b). (Two rotameric forms) 84% yield. Colorless microcrystals (from ethyl acetate / hexane) mp 45–46 °C. 1H NMR δ 3.17 (s, 3H), 5.12 (s, 1H), 5.15 (s, 1H), 5.17 (s, 1H), 5.23 (s, 1H), 7.20–7.26 (m, 2H), 7.34–7.44, (m, 3H), 7.51–7.57 (m, 2H), 7.65–7.72 (m, 2H), 8.13–8.15 (m, 1H), 8.23–8.28 (m, 1H). 13C NMR δ 35.8, 36.3, 52.4, 52.8, 67.6, 67.8, 114.1, 120.3, 126.4, 126.5, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5, 130.7, 130.8, 131.0, 136.2, 136.4, 145.9, 156.1, 156.9, 167.8, 167.9. Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.82; H, 4.99; N, 17.30.
1-(Benzotriazol-1-yl)-2-benzyloxycarbonylamino-2-methylpropan-1-one (Cbz-Aib-Bt, 2.8c). (80% yield) Colorless needles (from chloroform / hexane) mp 98–100 °C. 1H NMR δ 1.88 (s, 6H), 4.90 (s, 2H), 5.77 (br s, 1H), 7.11–7.20 (m, 5H), 7.47–7.53 (m, 1H), 7.62–7.67 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H). 13C NMR δ 26.0, 58.9, 66.8, 115.0, 119.9, 126.0, 127.8, 128.0, 128.3, 130.5, 131.9, 135.9, 144.8, 155.3, 172.6. Anal. Calcd for C18H18N4O3: C, 63.89; H, 5.36; N, 16.56. Found: C, 63.73; H, 5.22; N, 16.55.
54
2.4.2 Preparation of N-Protected Peptidic α-Triphenylphosphoranylidene Esters, Under Microwave Irradiation. 2.7a–g, 2.9–11
Compounds 2.7a–g, 2.9–11 were prepared in a dry 50 mL rb flask equipped with a condenser
and a magnetic stir bar, charged with a solution of the corresponding 2.5a–g, 2.8a–c (1.1 mmol)
and 2.6 (0.348 g, 1.0 mmol) in ACN (1 mL). The flask containing the reaction mixture was
exposed to microwave irradiation (120 W) for 10 min at 60 °C, and cooled with high-pressure air
through an inbuilt system in the instrument until the temperature fell below 30 °C. The reaction
mixture was diluted with ethyl acetate and washed with a saturated aq sodium carbonate. The
organic layer was collected and dried over anhydrous (anhyd) magnesium sulfate to give the
crude product, which was purified by column chromatography (SiO2, hexane:ethyl acetate = 1:1).
2.4.3 Preparation Under Conventional Heating. 2.7b,d
Compounds 2.7b,d were prepared in a dry 50 mL rb flask equipped with a condenser and a
magnetic stir bar, charged with a solution of the corresponding 2.5b,d (1.1 mmol) and 2.6 (0.348
g, 1.0 mmol) in ACN (15 mL). The reaction mixture was heated in an oil bath at 70–80 °C for
about 12 h until the starting materials were completely consumed (monitored by TLC,
hexanes:ethyl acetate = 1:1). After concentration under reduced pressure, the residue was diluted
with ethyl acetate and washed with saturated aq sodium carbonate. The organic layer was
collected and dried over anhyd magnesium sulfate to give the crude product, which was purified
by column chromatography (SiO2, hexane:ethyl acetate = 1:1).
(4S)-4-tert-Butoxycarbonylamino-1-ethoxy-2-triphenylphosphoranylidenpentan-1,3-dione (Boc-(L)Ala P-Ester, 2.7a). (65% yield) Colorless microcrystals (from ethyl acetate / hexanes) mp 153–155 °C (mp 153–155 °C)lit.[95MI125]. [α]23
D = +0.2 (c 1.67, CH2Cl2). 1H NMR δ 0.75 (t, J
= 7.0 Hz, 3H), 1.38 (s, 9H), 1.43 (d, J = 6.3 Hz, 3H), 3.65–3.95 (m, 2H), 5.38–5.51 (m, 2H), 7.44–7.68 (m, 15H). 13C NMR δ 13.7, 20.1, 28.3, 51.9 (JCP = 8.0 Hz), 58.6, 68.9 (JCP = 110.5 Hz), 78.3, 126.1 (JCP = 93.3 Hz), 128.5 (JCP = 12.6 Hz), 131.7, 133.0 (JCP = 9.7 Hz), 155.2, 166.7 (JCP = 15.5 Hz), 195.5.
(4S)-4-Benzyloxycarbonylamino-1-ethoxy-2-triphenylphosphoranylidenpentan-1,3-dione (Cbz-(L)Ala P-Ester, 2.7b). (86% yield) Colorless microcrystals (from chloroform / hexane),
55
mp 140–142 °C, (mp 140–142 °C)lit.[02JP(1)533]. [α]23 D = +25.4 (c 1.58, CH2Cl2), ([α]20
D = +20.3 (c 1.0005, CH2Cl2))
lit. [02JP(1)533]. 1H NMR δ 0.75 (t, J = 7.0 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H), 3.69–3.82 (m, 2H), 5.06 (s, 2H), 5.49 (quintet, J = 7.1 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 7.27–7.68 (m, 20H). 13C NMR δ 13.7, 20.4, 52.4 (JCP = 8.6 Hz), 58.6, 65.9, 68.8 (JCP = 111.1 Hz), 126.0 (JCP = 93.3 Hz), 127.6 (3C), 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = 2.9 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 155.4, 166.7 (JCP = 14.3 Hz), 194.7. Anal. Calcd for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. Found: C, 71.39; H, 5.78; N, 2.40.
(4S)-4-Benzyloxycarbonylamino-1-ethoxy-5-methyl-2-triphenylphosphoranylidenhexan-1,3-dione (Cbz-(L)Val P-Ester, 2.7c). (88% yield) Colorless microcrystals (from ethyl acetate / hexanes) mp 88–90 °C (mp 88–91 °C)lit.[02JP(1)533]. [α]23
D = +28.0 (c 1.66, CH2Cl2). 1H NMR δ
0.68 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 2.42–2.45 (m, 1H), 3.68–3.85 (m, 2H), 5.06 (s, 2H), 5.52–5.56 (m, 1H), 5.68 (d, J = 8.9 Hz, 1H), 7.39–7.20 (m, 5H), 7.51–7.40 (m, 10H), 7.80–7.63 (m, 5H). 13C NMR δ 13.8, 15.9, 20.7, 32.3, 58.6, 60.4 (JCP = 8.5 Hz), 66.0, 69.8 (JCP = 111.0 Hz), 126.0 (JCP = 93.9 Hz), 127.6 (3C), 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = <2 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 156.6, 166.8 (JCP = 14.2 Hz).
(4S)-4-Benzyloxycarbonylamino-1-ethoxy-5-phenyl-2-triphenylphosphoranylidenpentan-1,3-dione (Cbz-(L)Phe P-Ester, 2.7d). (79% yield) Colorless microcrystals (from ethyl acetate / hexanes) mp 51–53 °C. [α]23
D = +0.6 (c 1.66, CH2Cl2). 1H NMR δ 0.71 (t, J = 7.1 Hz, 3H), 2.83
(dd, J = 13.2, 7.7 Hz, 1H), 3.40 (dd, J = 13.2, 4.4 Hz, 1H), 3.70–3.85 (m, 2H), 4.95 (d, J = 12.8 Hz, 1H), 5.02 (d, J = 12.8 Hz, 1H), 5.58 (d, J = 8.9 Hz, 1H), 5.80–5.87 (m, 1H), 7.16–7.32 (m, 10H), 7.41–7.47 (m, 5H), 7.53–7.66 (m, 10H). 13C NMR δ 13.7, 39.8, 56.8 (JCP = 8.6 Hz), 58.7, 65.9, 70.1 (JCP = 108.8 Hz), 125.9 (JCP = 93.9 Hz) 126.0, 127.5, 127.9, 128.2, 128.5 (JCP = 12.6 Hz), 129.7, 131.7 (JCP = 2.9 Hz) 133.1 (JCP = 9.7 Hz), 137.1, 138.0, 155.7, 166.9 (JCP = 14.3 Hz), 193.5. Anal. Calcd for C39H36NO5P: C, 74.39; H, 5.76; N, 2.22. Found: C, 74.10; H, 5.83; N, 2.58.
(4S)-4-Benzyloxycarbonylamino-1-ethoxy-6-methoxy-2-triphenylphosphoranylidenhexan-1,3,6-trione (Cbz-(L)Asp(OMe) P-Ester, 2.7e). (90% yield) Colorless microcrystals (from ethyl acetate / hexanes) mp 116–118 °C. [α]23
D = +0.8 (c 1.91, CH2Cl2). 1H NMR δ 0.72 (t, J =
6.9 Hz, 3H), 2.82 (dd, J = 14.3, 6.7 Hz, 1H), 3.09 (dd, J = 14.3, 3.4 Hz, 1H), 3.56 (s, 3H), 3.69–3.85 (m, 2H), 5.06 (s, 2H), 5.76–5.81 (m, 1H), 5.91 (d, J = 8.1 Hz, 1H), 7.22–7.72 (m, 20H). 13C NMR δ 13.6, 38.6, 51.5, 53.6 (JCP = 9.2 Hz), 58.8, 66.1, 69.3 (JCP = 109.4 Hz), 125.6 (JCP = 93.9 Hz), 127.5, 127.6, 128.2, 128.5 (JCP = 12.6 Hz), 131.8 (JCP = 2.9 Hz), 133.1 (JCP = 9.7 Hz), 136.9, 155.6, 166.7 (JCP = 14.3 Hz), 171.5, 191.8. Anal. Calcd for C35H34NO7P: C, 68.73; H, 5.60; N, 2.29. Found: C, 68.66; H, 5.65; N, 2.22.
(4S)-4-Benzyloxycarbonylamino-1-ethoxy-5-(indol-3-yl)-2-triphenylphosphoranylidenpentan-1,3,-dione (Cbz-(L)Trp P-Ester, 2.7f). (71% yield) White microcrystals (from chloroform / hexanes) mp 88–90 °C. [α]23
D = +40.0 (c 1.67, CH2Cl2). 1H
NMR δ 0.72 (t, J = 7.0 Hz, 3H), 3.26 (dd, J = 14.7, 6.9 Hz, 1H), 3.51 (dd, J = 14.7, 4.5 Hz, 1H), 3.68–3.83 (m, 2H), 4.97 (s, 2H), 5.70–5.80 (m, 1H), 5.80–5.91 (m, 1H), 6.91 (s, 1H), 7.00–7.40 (m, 15H), 7.40–7.60 (m, 9H), 7.71 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H). 13C NMR δ 13.7, 28.8, 56.5 (JCP = 8.6 Hz), 58.8, 68.3 (JCP = 96.3 Hz), 110.9, 111.5, 119.0, 121.3, 122.9, 125.9 (JCP = 93.3 Hz), 127.6, 127.9, 128.2, 128.5 (JCP = 12.6 Hz), 131.6, 132.0, 132.1, 133.0 (JCP = 9.7 Hz), 135.9,
56
137.0, 155.8, 166.9 (JCP = 13.7 Hz), 193.9. Anal. Calcd for C41H37N2O5P: C, 73.64; H, 5.58; N, 4.19. Found: C, 73.07; H, 5.58; N, 4.16. HRMS m/z Calcd for C41H37N2O5P 669.2513 [M+H]+, Found 669.2523.
(4R)-4-Benzyloxycarbonylamino-1-ethoxy-2-triphenylphosphoranylidenpentan-1,3,-dione (Cbz-(D)Ala P-Ester, 2.7g). (69% yield) Colorless microcrystals (from ethyl acetate / hexane) mp 135–137 °C. [α]23
D = −17.5 (c 2.08, CH2Cl2). 1H NMR δ 0.75 (t, J = 7.1 Hz, 3H), 1.48 (d, J
= 7.1 Hz, 3H), 3.66–3.88 (m, 2H), 5.06 (s, 2H), 5.50 (quintet, J = 6.7 Hz, 1H), 5.86 (d, J = 7.7 Hz, 1H), 7.26–7.68 (m, 20H). 13C NMR δ 13.7, 20.3, 52.4 (JCP = 8.6 Hz), 58.6, 65.8, 68.8 (JCP = 110.5 Hz), 125.8 (JCP = 93.9 Hz), 127.5, 127.6, 128.2, 128.5 (JCP = 12.6 Hz), 131.7, 131.8 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 137.0, 155.4, 166.7 (JCP = 14.3 Hz), 194.8. Anal. Calcd for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. Found: C, 71.20; H, 5.89; N, 2.56.
4-Benzyloxycarbonylamino-1-ethoxy-2-triphenylphosphoranylidenbutan-1,3,-dione (Cbz-Gly P-Ester, 2.9). (80% yield) White microcrystals (from ethyl acetate / hexanes) mp 134–136 °C, (mp 134–136 °C)lit.[95MI124]. 1H NMR δ 0.75 (t, J = 7.0 Hz, 3H), 3.70–3.82 (m, 2H), 4.60 (d, J = 4.0 Hz, 2H), 5.06 (s, 2H), 5.85 (s, 1H), 7.22–7.70 (m, 20H). 13C NMR δ 13.8, 49.3 (JCP = 8.6 Hz), 58.6, 66.1, 68.9 (JCP = 112.8 Hz) 125.7 (JCP = 93.3 Hz), 127.6, 127.7, 128.6 (JCP = 12.6 Hz), 131.9 (JCP = 2.9 Hz), 133.1 (JCP = 9.7 Hz), 136.9, 156.1, 167.3 (JCP = 14.3 Hz), 190.3. Anal. Calcd for C32H30NO5P: C, 71.23; H, 5.60; N, 2.60. Found: C, 71.11; H, 5.79; N, 2.63.
4-Benzyloxycarbonyl(methyl)amino-1-ethoxy-2-triphenylphosphoranylidenbutan-1,3,-dione (Cbz-Sar P-Ester, 2.10). (Two rotameric forms) (89% yield) White microcrystals (from ethyl acetate / hexanes) mp 133–135 °C. 1H NMR δ 0.64 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H), 2.83 (s, 3H), 2.85 (s, 3H), 3.74 (quintet, J = 7.1 Hz, 2H), 4.69 (s, 2H), 5.04 (s, 1H), 5.06 (s, 1H), 7.25–7.70 (m, 20H). 13C NMR δ 13.5, 13.7, 35.5, 36.1, 57.1 (JCP = 8.6 Hz), 57.5 (JCP = 8.0 Hz), 58.2, 66.3, 66.6, 68.6 (JCP = 109.9 Hz), 68.9 (JCP = 111.7 Hz), 125.9 (JCP = 93.3 Hz), 126.0 (JCP = 93.3 Hz), 126.9, 127.2, 127.4, 127.5, 128.1, 128.1, 128.3 (JCP = 12.6 Hz), 128.3 (JCP = 12.6 Hz), 131.5, 131.5, 131.6, 131.8, 131.9, 132.9, 133.0, 133.1, 137.0, 137.3, 156.6, 156.7, 167.5 167.7, 167.9, 191.1 (JCP = 3.4 Hz), 191.6 (JCP = 3.4 Hz). HRMS m/z Calcd for C33H32NO5P 554.2091 [M+H]+, Found 554.2106.
4-Benzyloxycarbonylamino-1-ethoxy-4-methyl-2-triphenylphosphoranylidenpentan-1,3,-dione (Cbz-Aib P-Ester, 2.11). (3% yield) White microcrystals (from ethyl acetate / hexanes) mp 80–81 °C. 1H NMR δ 0.56 (t, J = 7.1 Hz, 3H), 1.63 (s, 6H), 3.58 (q, J = 7.1 Hz, 2H), 5.14 (br s, 2H), 6.79 (s, 1H), 7.25–7.68 (m, 20H). 13C NMR δ 13.5, 25.0, 58.7, 60.1, 60.2, 65.6, 68.9 (JCP
= 109.4 Hz), 127.0 (JCP = 93.9 Hz), 127.4, 127.5, 128.3, 128.5 (JCP = 12.0 Hz), 131.4 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 137.4, 155.8, 167.2 (JCP = 13.2 Hz), 198.2. HRMS m/z Calcd for C34H34NO5P 568.2247 [M+H]+, Found 568.2269.
2.4.4 Preparation of P-Ylide Salt. 2.13
Compound 2.13 was prepared from (L)phenylalanine methyl ester hydrochloride (35.0 g,
162.3 mmol) dissolved in H2O (75 mL) and neutralized with saturated aq sodium carbonate. The
57
alkaline solution was extracted with DCM (100 mL, 4x), dried over anhyd magnesium sulfate,
and filtered. α-Bromoacetic acid (24.8 g, 178.5 mmol), DCC (36.8 g, 178.5 mmol), and DMAP
(1.0 g, 8.1 mmol) were added to (L)phenylalanine methyl ester (29.1 g, 162.3 mmol) in DCM, at
0 °C and stirred for 3 h. The white precipitate was removed by filtration. The filtrate was
collected and concentrated under reduced pressure, to give the crude product, which was purified
by column chromatography (SiO2, hexane:ethyl acetate). N-(2-Bromoacetyl)-(L)Phe-OMe 2.12
(10.0 g, 33.3 mmol) was dissolved in a 1:3 ratio mixture of THF:diethyl ether (160 mL) and
triphenylphosphine (8.7 g, 33.3 mmol) at rt and stirred for 3 days. The white precipitated P-ylide
salt 2.13 was collected by filtration and washed with ethyl acetate [99JA1401].
(2S)-1-methoxy-3-phenyl-2-(2-triphenylphosphonioethan-1-on-1-yl)aminoprop-1-one bromide (2.13). (81% yield) White microcrystals (from DCM / hexanes) mp 155–157 °C. [α]23
D = −9.7 (c 2.08, CH2Cl2). DMSO-d6 1H NMR δ 2.83 (dd, J = 13.9, 8.8 Hz, 1H), 2.97 (dd, J =
13.9, 5.5 Hz, 1H), 3.56 (s, 3H), 4.38–4.43 (m, 1H), 5.02–5.09 (m, 2H), 7.13–7.35 (m, 5H), 7.50–7.91 (m, 15H), 9.07 (d, J = 7.6 Hz, 1H). DMSO-d6
13C NMR δ 30.6 (JCP = 57.3 Hz), 36.5, 52.0, 54.3, 118.6 (JCP = 88.2 Hz), 126.7, 128.3, 129.1, 129.9 (JCP = 13.2 Hz), 133.7 (JCP = 10.3 Hz), 134.8, 136.5, 163.0 (JCP = 4.6 Hz), 170.9. Anal. Calcd for C30H29BrNO3P: C, 64.06; H, 5.20; N, 2.49. Found: C, 63.76; H, 5.18; N, 2.41.
2.4.5 Preparation of Peptidic Diastereomers. 2.14–15
Compounds 2.14–15 were prepared in a dry 50 mL rb flask equipped with a condenser and a
magnetic stir bar, charged with a solution of the P-ylide salt 2.13 (1.12 g, 2.0 mmol),
triethylamine (0.24 g, 2.4 mmol), and 2.5b (0.84 g, 2.6 mmol), or 2.5g, in ACN (1 mL). The
flask containing the reaction mixture was exposed to microwave irradiation (120 W) for 10 min
at a temperature of 60 °C, and cooled with high-pressure air through an inbuilt system in the
instrument until the temperature fell below 30 °C. The reaction mixture was diluted with ethyl
acetate and washed with saturated aq sodium carbonate. The organic layer was collected, dried
over anhyd magnesium sulfate, filtered, and concentrated under reduced pressure, to give the
58
crude products. Final purification was performed by column chromatography (SiO2,
hexane:ethyl acetate = 1:1).
(4S)-4-Benzyloxycarbonylamino-1-[(2S)-(1-methoxy-3-phenylpropan-1-on-2-yl)amino]-2-triphenylphosphoranylidenpentan-1,3,-dione ((LL)Diastereomer, 2.14). (61% yield) White microcrystals (from DCM / hexanes) mp 65–68 °C. [α]23
D = −20.0 (c 2.08, CH2Cl2). 1H NMR δ
0.99 (d, J = 4.8 Hz, 3H), 1.87 (s, 1H), 2.99 (dd, J = 13.5, 8.5 Hz, 1H), 3.12 (dd, J = 13.5, 5.2 Hz, 1H), 3.61 (s, 3H), 4.65–4.72 (m, 1H) 4.95–5.06 (m, 2H), 5.66 (br s, 1H), 7.23–7.70 (m, 26H). 13C NMR δ 20.4, 38.1, 50.5, 51.7, 53.6, 65.9, 72.2 (JCP = 116.8 Hz), 126.1 (d, JCP = 93.3 Hz,), 126.3, 127.5, 127.6, 128.0, 128.1, 128.2, 128.3, 128.5 (JCP = 12.6 Hz), 129.2, 131.5, 131.7, 131.9, 132.9 (JCP = 9.7 Hz), 136.6, 137.0, 155.1, 168.5, 172.6, 191.2. Anal. Calcd for C41H39N2O6P: C, 71.71; H, 5.72; N, 4.08. Found: C, 71.85; H, 5.81; N, 3.75.
(4R)-4-Benzyloxycarbonylamino-1-[(2S)-(1-methoxy-3-phenylpropan-1-on-2-yl)amino]-2-triphenylphosphoranylidenpentan-1,3,-dione ((DL)Diastereomer, 2.15). (66% yield) White microcrystals (from DCM / hexanes) mp 46–48 °C. [α]23
D = +4.4 (c 2.08, CH2Cl2). 1H NMR δ
0.86 (d, J = 6.7 Hz, 3H), 1.90 (s, 1H), 2.98 (dd, J = 13.6, 7.9 Hz, 1H), 3.11 (dd, J = 13.6, 5.4 Hz, 1H), 3.61 (s, 3H), 4.67–4.74 (m, 1H) 5.03 (br s, 2H), 5.60 (br s, 1H), 7.15–7.70 (m, 26H). 13C NMR δ 20.3, 38.1, 50.6, 51.8 (JCP = 4.6 Hz), 53.7, 66.1, 72.8 (JCP = 119.7 Hz), 126.5 (JCP = 93.9 Hz,), 126.5, 127.7, 127.8, 128.3, 128.4, 128.5, 128.7 (JCP = 12.6 Hz), 129.2, 131.7, 131.9, 131.9, 132.0, 132.1, 133.2 (JCP = 9.7 Hz), 136.7, 137.1, 155.3, 169.2, 172.8, 191.5. [13C NMR (CDCl3, 60 oC, aromatic region, Figure 2-2) δ 127.0 (JCP = 93.7 Hz,), 126.5, 127.8,128.3, 128.4, 128.5 (JCP = 12.1 Hz), 128.7 (JCP = 12.6 Hz), 129.3, 131.8 (JCP = 3.3 Hz), 131.9 (JCP = 3.0 Hz), 132.2 (JCP = 9.8 Hz), 133.4 (JCP = 9.8 Hz), 136.7, 137.1.]. Anal. Calcd for C41H39N2O6P: C, 71.71; H, 5.72; N, 4.08. Found: C, 71.34; H, 5.89; N, 3.51.
59
CHAPTER 3 SYNTHESES OF 2,4-DIOXO-3-TRIPHENYLPHOSPHORANYLIDENE PYRROLIDINES AND OTHER DISTABILIZED TRIPHENYLPHOSPHORANYLIDENE SUBSTITUTED
RINGS
3.1 Introduction
The predominant species of pyrrolidin-2,4-dione exists in solution in the enolized form with a
stable lactam bond [93AHC139, 03MI109]. The discovery of the tetramic acid ring system 3.1
(Figure 3-1), a tautomer of pyrrolidin-2,4-dione, in a number of natural products and pigments
coincided with the discovery of their diverse biological activities [93AHC139, 94MI97,
95CRV1981, 00JPP086628, 00MI195, 02MI25, 03MI109]. Pyrrolidin-2,4-dione and 2,4-
dihyropyrrol-3-ones have been identified as N-methyl-D-aspartate (NMDA) receptor antagonists
[99AP309, 05EJM391].
OONH
OHONH
Pyrrolidin-2,4-dione
DOT moietyPPh3
OONH
DOT-pyrrolidine
ON
5-Amino-2,4-dihydropyrrol-3-one
OON
NH
OO
Piperidin-2,4-dione Tetrahydropyrrolizin-1,3-dione
NH2ON
3-Aminotetrahydropyrrolizin-1-one
NH2
4-Hydroxy-pyrrol-2-one3.1
Figure 3-1. Structures of Pyrrolidin-2,4-dione with Enolization, 5-Amino-2,4-dihydropyrrol-3-one, Piperidin-2,4-dione, Tetrahydropyrrolizin-1,3-dione, 3-Aminotetrahydropyrrolizin-1-one, and DOT-pyrrolidine
60
We investigate pyrrolidin-2,4-dione, 5-amino-2,4-dihydropyrrol-3-one, piperidine-2,4-dione,
tetrahydropyrrolizin-1,3-dione, and 3-aminotetrahydropyrrolizin-1-one (Figure 3-1) with a
distabilized triphenylphosphoranylidene substituent. The 2,4-dioxo-3-
triphenylphosphoranylidene moiety, or DOT-moiety as shown on DOT-pyrrolidine (Figure 3-1),
adds desirable physical properties such as crystallinity and stability to aldehydes [87LA649],
strong bases [65JOC1015], and high temperatures [01TL141]. The possible transformation the
2,4-dioxo-3-triphenylphosphoranylidene (DOT) moiety provides when directly incorporated as
part of a heterocyclic ring is unexplored and of considerable interest [01JCD639].
NO CO2H
Me
NHR1
PPh3(PS)
N
O
R3
R4O2C R1
OO
OMe
CO2R
R3NHR1
(vi)a
(v)a
(vii)b
O
N
R2'
N
O
O
R1Me
(viii)b
Δ
OO
O
O
HO
R3
MeMe
NHR1
NOO
R1R3
R2
(iv)a
Δ
O
NY
R2'
R1
R3
(ix)b
(iii)a
Me
O
O
NHR1
O
Me
R3
(i)a
(ii)a
R4OCO2R
BrR3
ON
CO2R
R3
R2
R1(Bzl or PG)H
a
b
base
R1 = Ts
couplingagents
base
R1 = PG
3.1
R1NH2
c
(x)c
MeOH
O
O
NR1
O
R2
R4
R = alkylPG = protecting group
PS = Polystyrene Y = CO2R, CN
CH2Br
NHBzlO
O(xi)c base
R2' = COR4, CO2R, Ar
Scheme 3-1. General Methods for the Formation of Bonds aa, bb or cc to Construct 3.1
61
R3R1
R2 O
R4
PPh3
R1 = R2 = OMeR3 = OCO2PhR4 = CO2BzlR5 = H
(i) Δ
OR1
R2 OR4
O Ph
(ii) 200-220 oC O
O
Ar
59%toluene, 28 h
50-60%sealed tube, 15 h
N
O
O
Bzl
O PPh3
CO2Et N
O
Bzl
OEtO2C
(iv) FVP
67%500 oC, 102 Torr
R1 = R2 = R5 = HR3 = COArR4 = CO2Et
R2
R1
(iii) 180-200 oC
R3
R4
13-31%
neat, 0.5 hR5
-Ph3PCCO
NH
OR4R5
CF3
R5
R1 = R2 = HR3 = NHCOCF3R4 = CO2EtR5 = H, Cl, or Br
R5
R5
R2
R1
R2
R1
Scheme 3-2. Direct Intramolecular Wittig Alkenation with Linear DOT Moieties
Reported syntheses of tetramic acids (Scheme 3-1) are by the formation of bond a, b or c in
3.1. Bond a is made by cyclization of (i) γ-amino-β-keto esters [98AP389, 98CPB587,
99H1427]; (ii) γ-bromoesters [84TL1871, 86TL5285]; (iii) γ-amino cyclic-enol esters
[87H2611]; (iv) 5-(2-amino-1-hydroxyethyliden)-2,2-dimethyl-1,3-dioxan-4,6-diones
(Meldrum’s acid esters) [95MI124, 04M629]; (v) aminomethyl pyrone esters [89TL3217]; or
(vi) aminomethyl isoxazole carboxylic acids [99SL873, 99JP(1)765]. Bond b in 3.1 is formed by
(vii) intramolecular Wittig olefination [88TL2063, 06S3902], of α-triphenylphosphoranylidene
amides with immobilized ylide [04OBC3524, 05T2301]; (viii) intramolecular Dieckmann type
cyclization of succinimides [78JA4237, 87JOC469, 87TL4385] and (ix) other intramolecular
62
Dieckmann cyclizations [50JA1236, 54JCS850, 88JOC1356, 94H1839, 97AGE2454]. Bond c in
3.1 is closed by (x) alcoholysis of spiro-β-lactams [83HCA362]; and (xi) intramolecular
nucleophilic cyclization of γ-bromo β-keto carboxamides [00CPB563].
Examples found in the literature indicated to perform direct intramolecular Wittig alkenation
using a linear DOT moiety (Scheme 3-2) thermal energy was required, which caused problems in
some cases. Two successful cases used DOT in close proximity to (i) carbonate [81CC474] or
(ii) ketone [84TL4389]. The similar case (iii) of DOT with urethane was unsuccessful in
yielding desired quinolone derivatives [94JHC1083], and the mechanism, proposed by Murphy
et al., involved the loss of ketenylidintriphenylphosphorane and ethanol to give an iminoketene
intermediate, which formed fluoroacetyl anthranilate. The cases of (iv) DOT with succinimides,
using flash vacuum pyrolysis (FVP), required extensive efforts to isolate the products in pure
form, which Aitken et al. reported as largely unsuccessful [95JP(1)475].
Examples found in the literature indicated to perform indirect intramolecular Wittig
alkenation using a linear DOT moiety (Scheme 3-3), equilibration or activation bypassed some
of the problems. Equilibration of DOT with an acid functionality [97CJC1322, 99JP(1)3049],
attached by an alkyl chain, form (i) enol-lactones or (ii) halo-enol-lactones rapidly in the
presence of a halogenating reagent [95JP(1)953]. The coupling of γ- [86S41], or (iii) δ-carbonyl
acids with N-phenyliminoketenylidentriphenylphosphorane formed a DOT (iv) which eliminated
urethane upon heating in the presence of ethanol. The deprotected P-ylide underwent internal
Wittig alkenation to form a cyclic olefin [97S107]. The mechanism of the Wittig reaction is
debated to occur either on the time scale of a bond rotation or through an equilibrium process.
Although the Wittig mechanism is intuitively understood as a “4-center mechanism [90JA3905]”,
the inherent stability of the DOT moieties requires further investigation.
63
OPh3P
toluene / EtOH15 h, 67%
(iv) Δ
HNO
Ph
HN
OPhEtO-
MeMe
R1
O
O
MeMe
R1
O
CO2H
R1
MeMe
R1 = OTBDMS
(iii) 80 oCC-
C
+PPh3
N Phtoluene5 h
OEtO2C
PPh3
CbzHNCO2HBzl
CbzHNBzl O
O
EtO2C
(i) Δ
THF, 6 h73%
(ii) 0-rt, Br2
TEA, DCM1 h, E:Z 54:46% Br
O
CbzHNBzl
O
OEtO2C
Ph3P+
+
CbzHNBzl O
O
EtO2CH
Scheme 3-3. Indirect Intramolecular Wittig Alkenation with Linear DOT Moieties
Ph3P
N+OO
Ph3P
NOO
Me
Ph3P+
NO O
Ph3P+
NOO
3.2bPh Ph
PhPh
3.2b'
Me
MeMe
Scheme 3-4. Delocalization of N-Methylated DOT-pyrrolidine 3.2b, Major Canonical Form 3.2b′
The extra stabilization afforded by a second carbonyl on linear DOT systems [90TL5925] is
also present in cyclic DOT systems. The DOT moiety resisted refluxing alcoholic base
[73JOC1047, 95T3279], high FVP temperatures [01TL141], and hydrobromic acid (HBr)
[Section 3.2.8], to some extent due to the stable lactam bond and DOT functionality participating
64
in delocalization (Scheme 3-4) [04SC4119]. The NMR of 3.2b remained unchanged, after
treatment in a sealed tube with 4-nitrobenzaldehyde at 130 °C for three days, confirming its
stability.
Ph3P
NOO
3.3b
3.3c
Me
Br
NOO
Me
3.2b N
O
Me
Br
(ii) NBS (1.4 eq)
(iii) NBS (1.4 eq)
(iv) BtCl (1.1 eq)N
O
MeBt
H
3.3d
Ph
Ph
Ph
Ph
N3
Br
DCM, 5 min88%
DCM, 5 min84%
DCM, 5 min92%
OH
3.3aBr
NOO
MePh
Br(i) NBS (~1.1 eq)
THF, 5 min79%
RCO2H (1.1 eq)
TMSOEt (1.4 eq)
TMSN3 (1.4 eq)
3.3a+
Scheme 3-5. Four Applications Using N-Methylated DOT-pyrrolidine
Although DOT-pyrrolidines are crystalline, soluble in halogenated and alcoholic solvents, and
have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings [72JOC3458,
73JA7736] they have received little of the attention given to tetramic acids. Furthermore as
illustrated in Scheme 3-5 treatment of the N-methylated DOT-pyrrolidine 3.2b with: (i) slight
excess N-bromosuccinimide (NBS, ~1.1 eq) [99MOL219], in the presence of a carboxylic acid
(1.1 eq), formed 3,3-dibromopyrrolidine-2,4-dione 3.3a; (ii) excess NBS (1.4 eq), in the presence
of ethoxytrimethylsilane (EtOTMS, 1.4 eq), gave 3.3a and 3,3-dibromo-5-hydroxypyrrolidine-
2,4-dione 3.3b; (iii) NBS and azidotrimethylsilane (TMSN3) formed haloazidoalkene 3.3c
[01T6203]; (iv) 1-chlorobenzotriazole (BtCl) [98JOC401] gave benzotriazole substituted pyrrol-
65
2-one 3.3d. The versatile stable 2,4-dioxo-3-triphenylphosphoranylidene rings can be readily
formed and easily transformed.
[O]
[H] NOO
Me
NOO
Me
O
Ph
Ph
NO O
MePh
Ph OH
(ii)(i)
(iii)NO
O
Me
Ph
Ph
(iv)
(v)
(i) oxidation; (ii) PhCH2N2; (iii) reduction; (iv) PhCHO; (v) 1) H2O2 / base 2) Et3OBF4
Ph3P
NOO
Me
3.2bPh
Scheme 3-6. Speculative Applications: Oxidation and Reduction
Oxidation and reduction applications are suggested in the literature for the transformation of
linear DOT systems and are generally extended to cyclic N-methylated DOT-pyrrolidine in
Scheme 3-6. (i) Oxidation of triphenylphosphoranylidene on 3.2b with O2, O3, potassium
peroxymonosulfate (Oxone®), sodium periodate, magnesium monoperphthalate (MMPP), or 3,3-
dimethyl dioxirane (DMD) may form α,β-diketo-amide [03T6771, 04JCO181, 07OL949], (ii)
which with phenyldiazomethane may ring expand to form aza-grevellin analogs [00AP211,
03JHC61]; (iii) reduction of triphenylphosphoranylidene on 3.2b with aluminum-amalgam may
form pyrrolidin-2,4-dione [82JOC4963, 86SC299], (iv) which with aldehydes may form
arylidene tetramic acids, (v) which with oxidation and triethyloxonium tetrafluoroborate may
ring expand for another route to aza-grevellin analogs [00AP221].
Earlier reports of DOT-pyrrolidine substructure (Scheme 3-7) include (i) a byproduct during
the preparation of showdomycin [78MI7], (ii) a flash vacuum pyrolysis method (FVP, 600–
900 °C, 102 Torr) which noted difficulties associated with N-deprotection by hydrogenolysis
[01TL141], and (iii) a byproduct without logical explanation of how it might be formed
66
[05MI385]. Anomalous, “spontaneous” [87S288, 04SL353, 05SL2763] cyclizations at rt,
discovered by Aitken, were left unexplained in his publications [99PS577, 01TL141, 03TCC41,
03MI289]. Earlier reports of the DOT-piperidine substructure (Scheme 3-7) reported two
articles of the same molecule as an (iv) unreactive novelty [73JOC1047] or an (v) unwanted
dead-end [87S288].
ONH
Cbz
R2
CO2EtPh3P
Ph3P
NHOO
R1
(ii)
(i)
OH
PPh3
NH2
OEtO2C
R1
O +25 °C, 2 h +
EtO2C
R1 NH2
O
31% 26%
1) Pd(C), H22) FVP, 600 oC
FVP, 600 oC
Ph3P
NHOO
R2
EtO2CR2
HN Cbz
F N
O
ON
NN
N PPh3(iii)
60 °CDCM / AcOH
F N
O
OO
PPh3 obtained oncenot reproducible
R1 =O
OF
OTrO
R2 = H (21%)Me (58%)i-Pr (64%)
NH
O
O
O
PPh3
CO2Et+
(iv)
60 °CDCM / AcOH
50%NH
O
O
PPh3
NO2
O PPh3
CO2t-Bu (v) SnCl2
NH2
O PPh3
CO2t-Bu
spontaneous
[78MI7]
[01TL141]
[05MI385]
[73JOC1047]
[87S288]
Scheme 3-7. Early Reports of DOT-pyrrolidines and DOT-piperidines
67
Previously in Chapter 2, we reported C-acylation of (carboxymethylene)triphenylphosphorane
(3.5) with N-protected peptidic (α-aminoacyl)benzotriazoles (3.4a–d) in the absence of base
under microwave irradiation for the generation of related stereospecific N-protected peptidic α-
triphenylphosphoranylidene esters 3.6a–d [05ARK116]. Hydrogenolysis of N-Cbz-γ-amino-β-
oxo-α-triphenylphosphoranylidene ester 3.6b was attempted and gave DOT-pyrrolidine 3.8b′
(45%) by crystallization, instead of the expected linear free amine. We now report the first
convenient synthesis of DOT-pyrrolidines 3.8a–c, DOT-tetrahydropyrrolizine 3.8d, DOT-
piperidine 3.16, 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one bromides 3.11a–c, and
3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one dibromide 3.11d.
3.2 Results and Discussion
The synthetic route for five-membered systems (Scheme 3-8) involved: C-Acylation of
(carboxymethylene)triphenylphosphorane (3.5) or (triphenylphosphoranylidene)acetonitrile (3.9)
with N-Cbz-(α-aminoacyl)benzotriazoles 3.4a–d under (ii) microwave irradiation gave the
corresponding N-Cbz-γ-amino-β-oxo-α-triphenylphosphoranylidene esters 3.6a–d (66–91%), or
N-Cbz-γ-amino-β-oxo-α-triphenylphosphoranylidene nitriles 3.10a–d (64–85%). The N-
deprotection of 3.6a–d with (iii) HBr formed DOT-salts 3.7a–d (21–99%) cyclized with (iv)
strong base into DOT-pyrrolidines 3.8a–c (97–99%) and DOT-pyrrolizine 3.8d (88%).
Methylation of 3.7c with (vi) methyl iodide (MeI) and sodium hydride (NaH) gave the linear N-
trimethylated salt 3.2a (95%). Methylation of 3.8c (vi) afforded DOT-pyrrolidine 3.2b (92%).
Alternatively simultaneous hydrogenolysis and cyclization of 3.7a–d with (v) palladium on
charcoal (Pd(C)) gave DOT-pyrrolidines 3.8′a–c (45–60%) and DOT-pyrrolizine 3.8′d (45%).
Comparable treatment of nitriles 3.10a–d with (iii) hydrobromic acid caused simultaneous N-
deprotection and cyclization to afford 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one
68
bromides 3.11a–c (70-72%), and 3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one
dibromide 3.11d (66%). Isolated yields for the intermediates and five-membered products are
shown in Table 3-1, with indication of the R1 and R2 substituents.
3.6a-d
3.10a-d
3.5
3.8a-d
3.9
3.7a-d
3.11a-c
ON
Cbz
R1
CO2EtPh3P
R2
O+NH2
R1
CO2EtPh3P+
R2
OR
NCbz
R1 R2
ON
Cbz
R1
CNPh3P Ph3P+
NONH2
R1
Ph3P
NOO
R1R2(ii) (iii) (iv)
2 Br-
3.8c3.2b
(vi)(v)
Br-
(ii) (iii)
3.8'a-d
R2
3.7c3.2a (vi)
CNPh3P
CO2EtPh3P
66 - 95%
64 - 85%
21 - 99%
66-71%
95%
92%
88 - 99%
45 - 60%
(i) SOCl2, BtH, DCM, 1 h(ii) μ-Wave, ACN, 60 °C, 10 min;M ethod I (iii) 33% HBr in AcOH, 5 h; (iv) EtOH, aq base, 5 h;M ethod II (v) 5%Pd(C), H2, EtOH, 48 h;(vi) MeI, NaH, DCM:THF, 16 h
R1 and R2 are def ined in Table 3-1
(i) R = Bt 3.4a-dR = OH
3.11d
Ph3P+
NONH3
+Br-
Br-
Scheme 3-8. Synthetic Route to DOT-pyrrolidines 3.8a–c, DOT-pyrrolizines 3.8d, 5-Amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one Bromides 3.11a–c, and 3-Ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one Dibromide 3.11d
Table 3-1. Isolated Yields for Intermediates and Five-Membered Products 3.8a–d, 3.11a–d
Entry R1 R2 N-Cbz Amino Acid 3.6 3.7 3.8 3.8′ 3.10 3.11
a H H Glycine 91 21a,b 97 60 85 71e
b Me H (L)Alanine 86 99 99 45 79 70e
c CH2Ph H (L)Phenylalanine 83 91 99 45 79 72e
d R1–(CH2)3–R2 (L)Proline 66 90c 88d 45d 64 66d,f
3.8′ yield from Method II. aIsolated as +NH3 monobromide. bHygroscopic. cIsolated as +PPh3 monobromide. dBicyclic. eR2 as lone pair electrons, double bond as shown at N1–C5. fR2 as in table, +NH3/+PPh3 dibromide, double bond at C4–C5 (not at N1–C5).
69
Dominant conformations with respect to the P-atom of syn-β-keto α-
triphenylphosphoranylidene anti-ester [01AXC180, 07PS151] and of syn-β-keto α-
triphenylphosphoranylidene nitrile [07AXC65] in linear systems have been determined by
Castañeda et al., who concluded that it is not reasonable to draw phosphonium ylides bearing
two adjacent stabilizing groups with a classical ylidic double bond [07PS151]. These data
generally extend to peptidic α-triphenylphosphoranylidene esters and nitriles support the view
that the major canonical forms are as shown in Figure 3-2. Planarity allows optimal electron
delocalization [03PS1973] and favorable interactions between cationoid phosphorus and acyl
oxygen, with no indication of slow conformational rotation around linear ylidic centers.
Ph3+P
NH2
-O OR
OEt
H
Ph3+P
NH2
-O
R H
N
peptidyl syn-keto,triphenylphosphoranylidene,
nitrile
peptidyl syn-keto,triphenylphosphoranylidene,
anti-ester
Figure 3-2. Major Canonical Forms of Peptidic syn-β-Keto α-Triphenylphosphoranylidene anti-Esters and Nitriles
In contrast to their linear starting materials the syn-β-keto α-triphenylphosphoranylidene syn-
amide of DOT ring systems cannot exhibit conformational rotation. The structure of 3.8c was
unambiguously confirmed by X-ray crystallography which showed the O–C–C–(P)–C–O atoms
to lie in approximately the same plane, to within 0.003(3) Å (Figure 3-3). The P=C bond length
of 1.732(2) Å and the attached C-C bond lengths (1.422(3) and 1.450(2) Å) and the C=O bond
lengths (1.230(2) and 1.253(2) Å) are all very similar to those in the only two other DOT-
pyrrolidines to have been crystallographically characterized [78MI7, 05MI385]. As is common
with amides, the molecules pack in pairs about a crystallographic center of inversion with N-
70
H…O=C hydrogen bonds. In addition a preliminary X-ray crystallographic study on a highly
twinned crystal was able to confirm the structure of (2RS)-5-amino-2-benzyl-4-
triphenylphosphonio-2,4-dihydropyrrol-3-one bromide hydrate (3.11c). Both 3.8c and 3.11c are
racemic suggesting racemization was caused by the HBr treatment.
Figure 3-3. Crystal X-ray of 3.8c (Left), and Preliminary X-ray Crystal Structure of 3.11c with Two H2O molecules and Br– (Right)
The synthetic route to DOT-piperidine involved: Activation of N-Cbz-β-alanine with (i)
thionyl chloride and BtH gave N-Cbz-(β-aminoacyl)benzotriazole (3.13). Carbon-Acylation of
3.5, or 3.9, with 3.13 under (ii) microwave irradiation gave the corresponding N-Cbz-δ-amino-β-
oxo-α-triphenylphosphoranylidene ester 3.14 (77%), or nitrile 3.17 (63%). Hydrobromic acid
(iii) caused N-deprotection of 3.14 and 3.17 formed DOT-salt 3.15 (92%) and the bromide salt of
δ-ammonio-β-oxo-α-triphenylphosphoranylidene nitrile 3.18 (35%), respectively. Aqueous base
with reflux (iv) cyclized 3.15 into DOT-piperidine 3.16 (65%). The literature FVP method on
3.14 drove a thermal extrusion of triphenylphosphine oxide to form the alkyne byproduct
(Scheme 3-9) [01TL141]. The linear 3.18 failed to cyclize under acidic conditions possibly due
71
to the extra degrees of freedom associated with this salt. The isolated yields for the
intermediates and one DOT-piperidine are shown in Scheme 3-9.
3.14
3.17
3.5
3.16
3.9
3.15
3.18
O HN CbzCO2Et
Ph3P
O NH3+
CO2EtPh3P+
OR
HN Cbz
Ph3P
NHO
O(ii) (iii) (iv)2 Br-
Br-O HN CbzCN
Ph3P
63%
77% 64%92%
O NH3+
CNPh3P
35%
90%
(ii)(iii)
(i) 3.13 R = Bt3.12 R = OH
(i) SOCl2, BtH, DCM, 1 h(ii) ACN, μ-Wave, 60°C, 10 min; (iii) 33% HBr in AcOH, 5 h; (iv) aq base, reflux 15 h
3.16 +2) FVP, 600 oC 34% NH2
CO2Et1) Pd(C), H2
16%01TL141
Scheme 3-9. Synthetic Route to DOT-piperidine 3.16, with Isolated Yields
3.2.1 Methylations and Salt Neutralization
Treatment of 3.7c and 3.8c with methyl iodide gave the N-trimethylated salt 3.2a (95%) and
the N-methylated DOT-pyrrolidine 3.2b (92%). Linear 3.7c was optically inactive. Treatment
of 3.7c with Et3N in DCM cleanly gave the linear free amine 3.2c (Scheme 3-10). A solvent
mixture (THF:DCM = 1:1) was required to unite the base with 3.7c, or 3.8c. The structures of
novel 3.2a,b were supported by 1H-NMR, 13C-NMR (Table 3-2), and elemental analysis.
The 13C-NMR chemical shifts and JPC coupling values of the γ-C, β-keto, α-C=P, and
ester/amide/nitrile/imine carbon signals were recorded throughout the course of reactions (Table
3-2–Table 3-7). The P-(ipso)Ph, P-(ortho)Ph, P-(meta)Ph, and P-(para)Ph carbon signals
remained essentially invariant but were included in the tables for completeness. The 13C-NMR
chemical shifts and JPC values are insensitive to changes in solvent and temp [03PS2505] but
reflect local electron densities [90HAC151]. The magnitude of the JPC value is affected by the
72
distance between carbon and phosphorus and more subtly by local electron density as in the
common case of P-(ortho)Ph and P-(meta)Ph JPC values, which are also influenced by charge
distribution around the ring. Similarly, electron density effects on the β-keto and ester JPC values
were affected by adjacent atoms and ylidic delocalization in distabilized
triphenylphosphoranylidene systems.
3.7c
O+NH3
CO2EtPh3P+
Ph3P
NHOO
2 Br-
92%
3.8c
3.2a
95%
Ph
O+NMe3
CO2EtPh3P+
Ph
Ph
Ph3P
NOO
Me
Ph3.2b
2 Br-
(i)
(i)
(ii)99%
(i) MeI, NaHDCM:THF, 16 h
(ii) EtOH, aq base, 5 h(iii)NEt3, DCM, 1 h
(iii)99%
ONH2
CO2EtPh3P
Ph 3.2c
Scheme 3-10. Methylation of 3.7c and 3.8c and Neutralization of 3.7c
Table 3-2. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of Linear 3.2a,c and Cyclic 3.2b
Entry γ-C β-Keto α-C=P Ester/ Amide P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.2a 71.0 (8.6)
184.4 (6.3)
75.9 (104.2)
166.8 (10.9)a
123.1 (93.3)
132.2 (10.3)
128.2 (13.2)
131.9 (2.9)
3.2b 67.6 (13.2)
193.9 (6.9)
64.1 (123.1)
173.8 (16.6)b
122.7 (92.8)
133.8 (10.9)
128.6 (12.6)
132.6 (2.9)
3.2c 57.2 (7.4)
198.0 (2.9)
69.3 (108.2)
167.2 (14.3)a
126.4 (93.3)
132.9 (9.7)
128.5 (12.6)
131.6 (2.9)
aEster.; bAmide.
The 13C-NMR data (Table 3-2) of linear 3.2a,c and cyclic 3.2b are juxtaposed for general
comparison between uncyclized and cyclized forms. The γ-C signal of 3.2b shifted upfield and
the JPC value increased relative to 3.2a. The β-keto carbon signal of 3.2b shifted downfield, due
to the decreased shielding and JPC values were similar. Both β-keto carbonyls are predicted to
73
exist in the dominant syn conformation with respect to the P-atom. The α-C=P carbon signal of
3.2b was shifted upfield, due to increased shielding, and the JPC value increased. The amide
carbon signal is shifted downfield from the ester carbon signal and the JPC value increased.
Conformational differences between the syn-amide carbonyl and anti-ester carbonyl are, in part,
responsible.
3.2.2 Dibromopyrrolidin-2,4-dione
The 3,3-dibromopyrrolidin-2,4-dione 3.3a (79%) was prepared from 3.2b (Scheme 3-11). 4-
Chlorobenzoic acid and 3.2b were heated under reflux together in THF for 1 h and no reaction
was detected by TLC. Upon addition of NBS the reaction was completed after 5 min of stirring
at rt. This is the first highly versatile [06SL194] 3,3-dibromo-pyrrolidine-2,4-dione 3.3a
reported with a racemic stereocenter [85AP311, 05CC5106] and obtained without Lewis acid
[02JOC7429]. The structure of novel 3.3a was supported by 1H-NMR, 13C-NMR, and elemental
analysis.
+
Cl
O OHTHF
Ph3P
NO
O
Me
Ph3.2b
NO
O
Me
Ph
Br Br
3.3a
NBSrt, 5 min
No Reaction
ref lux
Scheme 3-11. Bromination of 3.2b with NBS, For 3.3a
The proposed mechanism (Scheme 3-12) was initiated by the radical formation of bromine
(Br2) from NBS, shown mechanistically [94MI255] and considered a source of bromonium
cation (Br+). The major canonical form 3.2b′ is brominated to form intermediate-1 (Int-1), as
was postulated for a linear system in the literature [97S673]. Activation of a nucleophile,
carboxylic acid, generates HBr which returns more bromine to the system. Nucleophilic addition
74
on Int-1 eliminates triphenylphosphine oxide in a “4 center mechanism [90JA3905]” and
subsequent bromination of the olefin forms Intermediate-2 (Int-2). Activation of a second
nucleophile, carboxylic acid, generates HBr and the nucleophile adds to release an anhydride
byproduct and form 3.3a.
Ph3P
NOO
Me
Ph
NOO
Me
Ph
Br Br
3.3a
NBS
Ph3P+
N-O
O
Me
Ph
Succinimide
HBrBr2
+PPh3
N-OO
MePh
Int-I
Br+
-OPPh3
3.2b'
Br
NNucO
MePh
Br+
Int-2
-(RCO)2O
Br-
NucH =RCO2H Nuc- =
RCOO-
In Solution
1) Nuc-
2) Br2
Nuc-
Scheme 3-12. Proposed Mechanism, From 3.2b to Int-1 to Int-2 to 3.3a
3.2.3 Dibromo-5-hydroxypyrrolidin-2,4-dione
The 3,3-dibromo-5-hydroxypyrrolidin-2,4-dione 3.3b (88%) was prepared from 3.2b (Scheme
3-13). Ethoxytrimethylsilane (TMSOEt) and NBS were combined in DCM for 2 min and added
to 3.2b dissolved separately in DCM. The reaction was complete after 5 min stirring at rt. The
crude material was added directly to a silica gel column. A mixture of 3.3a and 3.3b (1:1) eluted
together and was detected by 1H- and 13C-NMR signals after purification. White, sheetlike
crystals formed in the CDCl3 NMR solution overnight and were confirmed as (5RS)-5-benzyl-
3,3-dibromo-5-hydroxy-1-methylpyrrolidin-2,4-dione (3.3b) by X-ray crystal analysis (Figure 3-
4, by P. Steel). In this case the molecules pack in chains with the hydroxy hydrogen atom H-
75
bonded to the carbonyl of an adjacent molecule and the crystals were racemic. This is the first
3,3-dibromo-5-hydroxypyrrolidine-2,4-dione ever reported and the structure of 3.3b was
supported by 1H-NMR, 13C-NMR, elemental analysis, and an X-ray crystal structure.
Ph3P
NO
O
Me
Ph3.2b
NO
O
Me
Ph
Br Br
3.3a
NBS (1.4 eq.)
rt, 5 min
TMSOEt (1.4 eq.)N
OO
Me
Ph
Br Br
3.3b
OH
+
Scheme 3-13. Bromination of 3.2b, with TMSOEt and NBS, For 3.3a and 3.3b
Figure 3-4. The X-ray Crystal Structure of 3.3b (Left), and Intermolecular Hydrogen Bonding (Right)
The proposed mechanism (Scheme 3-14) from 3.3a consisted of acid-catalyzed α-
bromination [00MI786], displacement, and loss of ethylene gas. In this case, 3.3a formation
occurred presumably in a mechanism similar to the final step, involving the loss of ethylene gas
[87H617]. Bromination of the enol olefin 3.3a′ forms Intermediate-3 (Int-3). Activation of a
nucleophile, TMSOEt, forms TMSBr and ethoxy anion. Ethoxy addition displaces the Br-atom
76
and regenerates the carbonyl to form Intermediate-4 (Int-4). Protonation and subsequent
deprotonation of OEt with in situ HBr releases ethylene gas to form 3.3b.
NOO
Me
Ph
Br Br
3.3a
NHOO
Me
Ph
Br Br
NOO
Me
Ph
Br Br
OH
3.3b
TMSBr
Br-
TMSOEt
-OEt
-HBr-CH2CH2
Br2
N
HO
O
MePh
Br BrBr+
Int-33.3a'
-TMSBr
NO O
MePh
Br Br
O+
H2CH
Br-H
Int-4
Scheme 3-14. Proposed Mechanism, from 3.3a to 3.3b
3.2.4 Azido-3-bromopyrrol-2-one
The 4-azido-3-bromopyrrol-2-one 3.3c (84%) was prepared from 3.2b (Scheme 3-15).
Azidotrimethylsilane (TMSN3) and NBS were combined in DCM for 2 min and added to 3.2b
separately dissolved in DCM. The reaction was complete after 5 min stirring at rt. The crude
material was added directly to a silica gel column without workup. The pure material
decomposed spontaneously to an unidentifiable brown tar, when left under high vacuum
overnight. Azido-3-bromo-pyrrol-2-one was obtained, where previously reported in the
literature chloro derivatives were used to make β-lactams [78JA2245 79ACC125, 88CRV297],
and bromo derivatives were trapped with triphenylphosphine to make a Staudinger reagent
[80ZC54]. The structure of novel 3.3c was supported by 1H-NMR, 13C-NMR, and HRMS.
77
84%
Ph3P
NOO
Me
Ph3.2b
NN3
O
Me
Ph3.3c
BrNBS, TMSN3
DCM, rtN
O
Me
Ph
Br
was also detected in HRMS
N
[M+H]+ = 279.028
Scheme 3-15. Haloazidoalkenation of 3.2b, with TMSN3 and NBS, For 3.3c
3.2.5 Benzotriazolpyrrol-2-one
The benzotriazolpyrrol-2-one 3.3d (92%) was prepared from 3.2b (Scheme 3-16). 1-
Chlorobenzotriazole (BtCl) and 3.2b were combined and dissolved in a minimum amount of
DCM (<1.0 mL). The reaction was complete after 5 min stirring at rt. The crude material was
added directly to a silica gel column and the purified material was shown to contain a 1:1
mixture of benzotriazole isomers, by 1H- and 13C-NMR. This is the first 4-benzotriazol-1-yl-
pyrrol-2-one reported. The structure of novel 3.3d was supported by 1H-NMR and 13C-NMR.
84%
Ph3P
NOO
Me
Ph3.2b
NNO
Me
Ph
3.3d
NNO
Me
Ph1:1
BtClDCM
NBtO
Me
Ph only the reduced productwas detected in HRMS
[M+H]+ =303.1240
+N
N
NN
Scheme 3-16. Benzotriazolation of 3.2b, with BtCl, For 3.3d
3.2.6 Protected (α- and β-aminoacyl)benzotriazoles
The starting N-Cbz-(α-aminoacyl)benzotriazoles 3.4a–d (90–98%), and N-Cbz-(β-
aminoacyl)benzotriazole 3.13 (90%) (Scheme 3-17) were prepared from the corresponding N-
Cbz amino acids following recently developed procedures [Chapter 2-2.4.1, 04S2645, 04S1806,
05ARK116, 06S411]. The proline derived N-Cbz-(α-aminoacyl)benzotriazole (3.4d) was seen
78
by NMR as two sets of distinct signals due to rotamers. We confirmed the structure of 3.4d,
previously reported by the Katritzky group, with improved resolution of rotamer signals. The
structure of novel 3.13 was supported by 1H-NMR, 13C-NMR, and elemental analysis.
90%3.12
OHO HN Cbz
BtO HN Cbz
(i)
3.13(i) SOCl2, BtH, DCM, rt, 1 h
Scheme 3-17. Acylbenzotriazolation of 3.12, with SOCl2 and BtH, Formed 3.13
3.2.7 Protected-γ-amino-β-oxo-α-triphenylphosphoranylidene and N-Cbz-δ-amino-β-oxo-α-triphenylphosphoranylidene Esters
The N-Cbz-γ-amino-β-oxo-α-triphenylphosphoranylidene esters 3.6a–d (66–91%), and N-
Cbz-δ-amino-β-oxo-α-triphenylphosphoranylidene esters 3.14 (77%) (Scheme 3-18) were
prepared from the corresponding 3.4a–d, 3.13 and (carboxymethylene)triphenylphosphorane
(3.5), following a recently developed procedure [Chapter 2, 05ARK116]. Microwave reactions
were carried out in a standard 50 mL rb flask under controlled and reproducible open vessel
conditions. The single mode microwave irradiation was used at a fixed temp and irradiation
power, which maintained the temp, automatically. The structure of novel 3.14 was supported by
1H-NMR, 13C-NMR (Table 3-3), and elemental analysis.
77%
3.14
O HN Cbz
Ph3PCO2Et
3.13
BtO HN Cbz + Ph3P
CO2Et3.5
(i) (i) ACN, μ-Wave60 °C, 10 min
Scheme 3-18. Carbon-Acylation of 3.13, with 3.5, Formed 3.14
The 13C-NMR γ-C and α-C=P carbon signals of 3.6a–d (Table 3-3) appeared in the ranges
49.3–62.7 ppm (6.3–8.6 Hz) and 68.6–70.1 ppm (108.8–112.8 Hz), respectively. The ylidic
delocalized β-keto and ester carbon signals appeared in the ranges 190.3–195.3 ppm (2.9–4.0
Hz) and 166.7–167.3 ppm (14.3–15.5 Hz), respectively. The β-alanine derived 3.14 signals were
79
mostly inline with those of the other derivatives 3.6a–d. The γ-C carbon signal was shifted
upfield due to increased shielding. The two rotameric forms of proline derived ester 3.6d
(Scheme 3-19) and nitrile 3.12d, gave distinct and separate signals in the 13C-NMR.
Ph3P
R N
O OO Ph
Ph3P
R N+
O -OO
Ph
R = CO2Et or CNZ-isomer
E-isomer
Ph3P
R N
OO
OPh
Ph3P
R N
OO
OPh
Scheme 3-19. Rotameric Forms of Ester 3.6d and Nitrile 3.12d
Table 3-3. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.6a–d, 3.14
3.2.8 Dioxotriphenylphosphoranylidene Salts
Salts of γ-amino-β-oxo-α-triphenylphosphoranylidene esters 3.7a–d (21–99%), and δ-amino-
β-oxo-α-triphenylphosphoranylidene esters 3.15 (92%) (Scheme 3-20) were obtained for Method
I and were prepared from the corresponding 3.6a–d, 3.14 by hydrogenolysis of the N-Cbz group
on 3.6a–d, 3.14, using 33% HBr in acetic acid [00T9763]. Two atom sites N- and P- were
Entry γ-C β-Keto α-C=P Ester P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.6ab 49.3 (8.6)
190.3 (<4.0)a
68.9 (112.8)
167.3 (14.3)
125.7 (93.3)
133.1 (9.7)
128.6 (12.6)
131.9 (2.9)
3.6bb 52.4 (8.6)
194.7 (<4.0)a
68.8 (111.1)
166.7 (14.3)
126.0 (93.3)
133.0 (9.7)
128.5 (12.6)
131.8 (2.9)
3.6cb 56.8 (8.6)
193.5 (<4.0)a
70.1 (108.8)
166.9 (14.3)
125.9 (93.9)
133.1 (9.7)
128.5 (12.6)
131.7 (2.9)
3.6dc 62.2 (7.4)
194.8 (2.9)
68.6 (109.9)
167.3 (15.5)
125.9 (93.9)
132.6 (9.7)
128.1 (12.6)
131.2 (2.9)
3.6dd 62.7 (6.3)
195.3 (2.9)
69.0 (111.1)
167.1 (14.3)
126.1 (93.3)
133.0 (9.7)
128.2 (12.0)
131.3 (2.3)
3.14 39.6 (6.9)
195.5 (3.4)
71.2 (110.5)
167.5 (14.3)
125.9 (93.3)
132.6 (9.7)
128.2 (12.6)
131.3 (2.3)
aSmall couplings not clearly resolved were estimated as less than 4.0 Hz. bLit. [05ARK116]. cRotamer I. dRotamer II.
80
available for salt generation. Detection of a broad signal around 9 ppm in the 1H-NMR spectra
indicated P-salt formation. The salt mixtures were isolated by column chromatography (SiO2).
Extension of the stirring time in the 33% HBr solution for up to 5 h resulted in formation of
dibromide salts, which were easily isolated as white powders by filtration from diethyl ether in
most cases. The highly hygroscopic dibromide salt resulted in a low yield of achiral
monobromide ammonium salt 3.7a (21%) due to loss during isolation. Melting points were
generally not sharp with initial melts to amorphous solids typically in the range between 100–
200 °C, followed by a session of bubbling and recrystallization, which then melted again above
200 °C probably due to the thermal cyclization involving the loss of ethanol. The structures of
novel 3.7a–d, and 3.15, were supported by 1H-NMR, 13C-NMR (Table 3-4), and elemental
analysis.
92%
3.14
O HN Cbz
Ph3PCO2Et
3.15
O +NH3
Ph3P+
CO2Et2Br-
(i)(i) 33% HBr in AcOH, 5 h
Scheme 3-20. Deprotection of 3.14, with HBr, For 3.15
The 13C-NMR γ-C and α-C–P+ carbon signals of 3.7a–d (Table 3-4) appeared in the ranges
45.4–63.6 ppm (8.0–9.7 Hz) and 68.1–69.6 ppm (108.2–111.1 Hz), respectively. The β-keto and
ester carbons appeared in the ranges 185.3–190.5 ppm (4.6–5.7 Hz) and 166.2–166.7 ppm (12.0–
13.2 Hz), respectively. The 13C-NMR signals of the β-alanine derived 3.15 were mostly inline
with the other derivatives 3.7a–d. Cleavage of the Cbz group for the proline derived 3.7d
resulted in 1H- and 13C-NMR spectra free of rotameric signals.
81
Table 3-4. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.7a–d, 3.15
3.2.9 The DOT-Pyrrolidines, DOT-Pyrrolizines, and DOT Piperidine
The DOT-pyrrolidines 3.8a–c and DOT-pyrrolizine 3.8d were prepare by Method I (20–98%)
from the corresponding 3.7a–d, and by Method II (45–60%) from the corresponding 3.6a–d
(Scheme 3-21). The DOT-piperidine 3.16 (Scheme 3-9) was prepared by Method I from 3.15
(60%). The starting salts 3.7a–d, 3.15 were dissolved in ethanol and then aq base was added,
which resulted in precipitation of a white solid. Extraction gave 3.8a–c (97–99%) and 3.8d
(88%) to complete Method I. The achiral 3.15 was heated under reflux in aq base to afford
DOT-piperidine 3.16 (65%). Hydrogenolysis of 3.6a–d with Pd(C) in ethanol required 48 h and
by crystallization gave 3.8′b–d (45%) for Method II. Pyrrolidiz-1,3-dione 3.8d should be
inhibited to delocalize the amide electrons through resonance due to the highly strained, or
twisted, dipolar bicyclic lactam [06N699]. To furnish achiral 3.8′a (60%) heating under reflux
in ethanol was required. We provide supporting characterization for the structures of compounds
3.8a,b,d and 3.16 which were previously reported without characterization. The structure of
novel 3.8c was supported by 1H-NMR, 13C-NMR (Table 3-5), elemental analysis and X-ray.
Entry γ-C β-Keto α-C–P+ Ester P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.7ac 45.4 (8.0)
185.3 (5.7)
69.5 (111.1)c
166.7 (13.2)
124.1 (93.3)
132.9 (10.3)
128.6 (12.6)
132.1 (2.3)
3.7bbf 51.1 (8.6)
190.5 (4.6)
68.1 (109.4)
166.2 (12.6)
124.9 (92.8)
132.8 (9.7)
129.0 (12.6)
132.3 (2.9)
3.7cbef 55.9 (8.6)
189.0 (4.6)
69.1 (108.2)
166.4 (12.0)
124.8 (92.8)
133.0 (9.7)
129.0 (12.6)
132.3 (<4.0)a
3.7dd 63.6 (9.7)
187.7 (5.2)
69.6 (109.9)
166.2 (12.6)
124.2 (93.9)
133.0 (9.7)
128.9 (12.6)
132.5 (2.9)
3.15bf 37.1 (7.4)
192.4 (4.0)
69.7 (109.4)
166.8 (13.2)
125.7 (92.8)
132.8 (9.7)
128.9 (12.6)
132.1 (<4.0)a
aSmall couplings not clearly resolved were estimated as less than 4.0 Hz. b(NH3)+/(PPh3)+ Dibromide. c(NH3)+ Monobromide, α-C=P. d(PPh3)+ Monobromide. epH = 5.0 in water. fNMR done in DMSO-d6
82
92%
3.8c
O NH
Ph3P
3.7c
O+NH3
Ph3P+
CO2Et2Br-
O
(i)
Method I(i) HBr, 5 h(ii) EtOH, aq base, 5 h
Ph Ph
ONH
Ph3PCO2Et
PhCbz
3.6c
45%
(ii)
Method II(iii) H2, Pd(C), EtOH, 48 h
(iii)99%
92%3.8d3.7d
ONH
Ph3P+
CO2Et
(i)
ON
Ph3PCO2Et
Cbz3.6d
45%
(ii)
(iii)
90%
O N
Ph3POBr-
O N
Ph3PO
Highly Twisted
Scheme 3-21. Method I and Method II, For 3.8c and 3.8d
Table 3-5. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.8a–d and 3.16
Entry γ-C β-Keto α-C=P Amide P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.8aa 52.4 (13.2)
194.8 (8.6)
64.2 (122.6)
177.4 (17.4)
122.8 (93.3)
134.0 (10.9)
128.7 (12.6)
132.9 (2.9)
3.8ba 58.0 (13.7)
197.7 (7.4)
62.8 (122.5)
176.2 (16.6)
122.9 (92.8)
133.9 (10.9)
128.7 (12.6)
132.8 (2.3)
3.8c 63.5 (13.2)
195.5 (7.4)
64.0 (122.0)
175.9 (16.0)
122.7 (93.3)
133.9 (10.9)
128.7 (13.2)
132.8 (2.9)
3.8da 69.1 (13.2)
197.6 (8.0)
65.2 (117.4)
179.7 (16.0)
122.6 (92.8)
133.8 (10.9)
128.7 (13.2)
132.8 (2.9)
3.16a 37.1 (9.2)
191.9 (4.6)
70.0 (115.1)
171.1 (10.9)
125.0 (92.8)
133.3 (10.3)
128.2 (12.6)
131.7 (2.9)
apreviously reported without characterization [01TL141].
The 13C-NMR γ-C and α-C=P+ carbon signals of 3.8a–d (Table 3-5) appeared in the ranges
52.4–69.1 ppm (13.2–13.7 Hz) and 62.8–65.2 ppm (117.4–122.6 Hz), respectively. The β-keto
and amide carbon signals appeared in the ranges of 194.8–197.7 ppm (7.4–8.6 Hz) and 175.9–
179.7 ppm (16.0–17.4 Hz), respectively. The piperidine 3.16 13C-NMR signals differed from the
pyrrolidine derivatives 3.8a–d, due to conformational and electronic effects. The γ-C and β-keto
carbon signals, 37.1 ppm (9.2 Hz) and 191.9 ppm (4.6 Hz), shifted upfield and JPC couplings
83
were larger. The α-C=P carbon signal 70.0 ppm (115.1 Hz) shifted downfield and JPC coupling
was smaller. The amide carbon signal, 171.1 ppm (10.9 Hz), shifted upfield and JPC coupling
was smaller, probably due to the extra degrees of freedom allowing a less rigid syn-syn
conformation.
3.2.10 Protected-γ-amino-β-oxo-α-triphenylphosphoranylidene and N-Cbz-δ-amino-β-oxo-α-triphenylphosphoranylidene Nitriles
The N-Cbz-γ-amino-β-oxo-α-triphenylphosphoranylidene nitriles 3.10a–d (64–85%), and N-
Cbz-δ-amino-β-oxo-α-triphenylphosphoranylidene nitriles 3.17 (63%) (Scheme 3-22) were
prepared from the corresponding 3.4a–d, 3.13 and (triphenylphosphoranylidene)acetonitrile (3.9).
The reaction conditions were the same as described in section 3.2.7. Compounds 3.5b,c have
been reported without elemental analysis for the preparation of peptidic α-ketoesters and α-
ketoamides [00T9763, 03T6771]. Compound 3.13 has been reported as an intermediate without
characterization and used as an interesting precursor to β-amino-α-keto esters [94JOC4364,
98TL6889], or to synthesize enantioselective 3-hydroxypyrrolidin-2-ones [99TL1069]. We
report 1H-NMR, 13C-NMR, and elemental analysis to support the structure of 3.17. The
structures of novel 3.10a,b,d were supported by 1H-NMR, 13C-NMR (Table 3-6), and elemental
analysis.
63%3.17
O HN Cbz
Ph3PCN
3.13
BtO HN Cbz + Ph3P
CN3.9
(i) (i) μ-Wave,ACN, 60°C, 10 min
Scheme 3-22. Carbon-Acylation of 3.13, with 3.9, For 3.17
The 13C-NMR γ-C and α-C=P carbon signals of 3.10a–d (Error! Not a valid bookmark self-
reference.) appeared in the ranges 47.5–62.4 ppm (9.0–10.9 Hz) and 46.2–47.9 ppm (126.0–
127.7 Hz), respectively. The α-C=P carbon signal was upfield and JPC coupling was larger for
84
the nitrile derivatives than for the ester derivatives. The β-keto and nitrile carbon signals
appeared in the ranges 189.9–194.9 ppm (3.5–4.0 Hz) and 120.6–121.5 ppm (14.7–15.4 Hz),
respectively. The nitrile carbon signal was upfield and JPC coupling was larger than for the ester
derivatives. The 13C-NMR signals of the β-alanine derived nitrile 3.17 were similar to those of
the other nitrile derivatives 3.10a–d. The two rotameric forms of proline derived N-Cbz-(α-
aminoacyl)-triphenylphosphoranylidene nitrile (3.10d), gave distinct signals (Scheme 3-19).
Table 3-6. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.10a–d, 3.17
Entry γ-C β-Keto α-C=P Nitrile P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.10a 47.5 (10.9)
189.9 (<4.0)a
46.4 (127.7)
120.6 (14.9)
122.3 (93.3)
133.5 (10.3)
129.2 (13.2)
133.3 (3.4)
3.10bb 52.2 (9.0)
194.3 (3.6)
46.5 (127.5)
120.7 (14.9)
122.3 (93.3)
133.2 (10.3)
129.0 (12.6)
131.7 (4.0)
3.10cc 57.2 (9.0)
192.9 (<4.0)a
47.9 (126.0)
121.0 (16.0)
122.4 (93.9)
133.5 (10.3)
129.1 (12.6)
133.2 (3.4)
3.10dd 61.8 (9.1)
194.7 (3.5)
46.2 (126.3)
121.5 (15.4)
122.6 (93.4)
133.2 (10.5)
128.8 (12.6)
132.9 (2.8)
3.10de 62.4 (9.1)
194.9 (3.5)
46.3 (127.0)
121.3 (14.7)
122.9 (93.4)
133.4 (10.5)
128.9 (12.6)
132.8 (2.8)
3.17f 38.6 (9.2)
194.9 (<4.0)a
49.0 (126.0)
121.8 (16.6)
122.6 (93.9)
133.3 (10.3)
129.0 (13.2)
133.1 (2.9)
aSmall couplings not clearly resolved were estimated as less than 4.0 Hz. bLit. [03T6771]. cLit. [00T9763]. dRotamer I. eRotamer II. fLit. [99TL1069].
3.2.11 Dihydropyrrol-3-one Bromide Salts and Tetrahydropyrrolizin-1-one Dibromide Salt
The 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one bromides 3.11a–c (70–72%)
and 3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one dibromide 3.11d (66%) were
prepare from the corresponding 3.10a–d (Scheme 3-23). Simultaneous N-deprotection and
cyclization of 3.10a–d occurred upon treatment with 33% HBr in acetic acid gave 3.11a–d.
Wasserman et al. have reported a byproduct in a similar reaction where the imino functionality
was exocyclic to the ring (Scheme 3-23) [97TL953, 03T6771]. The 1H-NMR signals and
splitting patterns of compounds 3.11a–c indicated phosphonium salts [82AJC2277] had formed
85
and the imino functionality was endocyclic. The 1H-NMR signals and splitting patterns of
compounds 3.11d indicated dibromide salt was formed with the olefin shifted away from the
more strained bicyclic pyrrolizinium salt. The same method applied to N-Cbz-δ-amino-β-oxo-α-
triphenylphosphoranylidene nitrile 3.17 (Scheme 3-9) gave the linear 3.18 (35%). The structures
of novel 3.11a–d, and 3.18 were supported by 1H-NMR, 13C-NMR (Table 3-7), and elemental
analysis.
71%
3.11c
O N
Ph3P+
ONH
Ph3PCN NH2
(i) Br-
Cbz3.10c
(i) 33% HBr in AcOH, 5 h
Ph Ph
66%
3.11d
O N
Ph3P+
ON
Ph3PCN +NH3
(i)Br-
Cbz
3.10d
Br-
O HN Cbz
Et
CNPh3P Ph3P
NHONH
Et
Pd(C), H2
EtOAc ONH2
Et
CNPh3P
O HN Cbz
Et
CNPh3P
isolated ratio 1:1:2[97TL953, 03T6771]
starting material
mp 253-255 oC
mp 238-240 oC
mp 70-80 oC
O N
Ph3P+NH2
Br-
Br-
Highly Twisted
Scheme 3-23. Deprotection of 3.10c,d, with HBr, For 3.11c,d
The 13C-NMR γ-C and α-C=P carbon signals of the 3.11a–d (Table 3-7) appeared in the
ranges 52.2–70.0 ppm (10.3 Hz) and 63.1–65.9 ppm (119.1–127.8 Hz), respectively. The β-keto
and imino carbon signals appeared in the ranges 194.5–197.7 ppm (5.7–6.3 Hz) and 168.8–170.9
ppm (15.5–17.2 Hz), respectively. The 13C-NMR signals of the linear β-alanine derived 3.18
86
differed from those of the pyrrol-3-one series 3.11a–d. Cleavage of the Cbz group for the
proline derived salt 3.11d resulted in 1H- and 13C-NMR spectra free of rotameric signals.
Table 3-7. The 13C-NMR Chemical Shifts, δ in ppm (JPC in Hz) of 3.11a–d, and 3.18
Entry γ-C β-Keto α-C-P+ Imino/Nitrile P-(ip)Ph P-(o)Ph P-(m)Ph P-(p)Ph
3.11a 52.2 (10.3)
194.5 (6.3)
64.8 (125.4)
170.3 (17.2)
119.7 (93.3)
133.6 (10.9)
130.1 (13.2)
134.6 (2.9)
3.11b 58.5 (10.3)
197.7 (5.7)
63.1 (124.3)
168.8 (17.2)
120.1 (93.3)
133.6 (10.9)
130.1 (13.1)
134.6 (2.9)
3.11c 63.3 (10.3)
195.3 (6.3)
64.0 (127.8)
169.3 (16.6)
119.7 (92.8)
133.7 (10.9)
130.0 (12.6)
134.5 (2.9)
3.11da 70.0 (10.3)
196.2 (5.7)
65.9 (119.1)
170.9 (15.5)
119.4 (92.8)
133.5 (10.9)
130.0 (13.1)
134.6 (2.9)
3.18b 33.4 (8.0)
195.0 (4.0)
50.4 (124.3)f
120.8c (16.0)
121.8 (93.3)
133.4 (10.3)
129.3 (13.2)
133.5 (2.3)
aIsolated as +NH3/+PPh3 dibromide, double bond at C4-C5. bLinear. cImino. eNitrile. fα-C=P.
3.3 Conclusion
This is the first convenient method to 2,4-dioxo-3-triphenylphosphoranylidene pyrrolidines,
1,3-dioxo-2-triphenylphosphoranylidene tetrahydropyrrolizine, 2,4-dioxo-3-
triphenylphosphoranylidene piperidine, 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one
bromides, and 3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one dibromide. The
developed Method I was versatile, inexpensive, reproducible, and high yielding. Racemization
was caused by HBr, however the novel linear salts could be cleanly N-methylated or neutralized
without cyclization, or cyclized for distabilized triphenylphosphoranylidene substituted rings.
Crystalline DOT-pyrrolidines, are stable to aldehydes [87LA649], strong bases [65JOC1015],
and high temperatures [01TL141], and represent versatile intermediates. The 13C-NMR
chemical shifts and JPC values provide valuable information for the analysis of distabilized
triphenylphosphoranylidene systems, JPC couplings increased with less partial positive character
and decreased with more partial positive character on the respective carbons.
87
We have developed four novel applications for DOT-pyrrolidines. The first highly versatile
[06SL194] 3,3-dibromopyrrolidine-2,4-dione [85AP311, 05CC5106] with a racemic stereocenter,
was obtained without Lewis acid [02JOC7429]. The first 3,3-dibromo-5-hydroxypyrrolidine-
2,4-dione, was obtained and unambiguously identified by X-ray crystallography. 4-Azido-3-
bromopyrrol-2-one was obtained, where previously reported chloro derivatives were used to
make β-lactams [78JA2245 79ACC125, 88CRV297], and bromo derivatives were trapped with
triphenylphosphine to make a Staudinger reagent [80ZC54]. The first 4-benzotriazolpyrrol-2-
one was obtained. In conclusion the versatile stable 2,4-dioxo-3-triphenylphosphoranylidene can
be practically formed on rings and easily transformed into novel molecules.
3.4 Experimental Section
Melting points were determined on a capillary point apparatus equipped with a digital
thermometer. NMR spectra were recorded in CDCl3, unless otherwise stated in DMSO-d6, with
TMS for 1H (300 MHz) and 13C (75 MHz) as the internal reference. The N-Cbz-amino acids
were purchased from Fluka and were used without further purification. Acetonitrile was freshly
distilled from calcium hydride. Microwave heating was carried out with a single mode cavity
Discover® Microwave Synthesizer (CEM Corporation, NC), producing continuous irradiation at
2455 MHz.
3.4.1 Preparation of Dibromide Salt 3.2a
To a solution of 3.7c (1.0 g, 1.52 mmol) dissolved in a solvent mixture (THF:DCM = v:v =
1:1, 40 mL), NaH 60% on mineral oil (0.610 g, 15.2 mmol) was added and stirred for 1 h.
Methyl iodide (1.0 mL, 15.2 mmol) was added dropwise to the reaction mixture with stirring at rt.
The reaction mixture was stirred for a further 16 h. The solvent mixture was evacuated and the
residue was extracted with DCM. The crude product was filtered and subjected to column
chromatography (SiO2, DCM:methanol = 98:2) to give 3.2a.
88
(4RS)-4-Trimethylammonio-1-ethoxy-5-phenyl-2-triphenylphosphoniopentan-1,3-dione Dibromide (3.2a). (1.01 g, 95%) White needles (from DCM / diethyl ether) mp 189–191 °C. 1H NMR δ 0.38 (t, J = 7.0 Hz, 3H), 2.43 (s, 1H), 3.04–3.08 (m, 1H), 3.23–3.51 (m, 12H), 6.02 (dd, J = 11.2, 3.5 Hz, 1H), 7.08–7.11 (m, 2H), 7.25–7.32 (m, 9H), 7.36–7.52 (m, 7H), 7.48–7.54 (m, 3H). 13C NMR δ 12.6, 32.6, 52.2, 58.8, 71.0 (JCP = 8.6 Hz), 75.9 (JCP = 104.2 Hz), 123.1 (JCP = 93.3 Hz), 126.7, 128.1, 128.2 (JCP = 13.2 Hz), 128.8, 131.9 (JCP = 2.9 Hz), 132.2 (JCP = 10.3 Hz), 133.3, 166.8 (JCP = 10.9 Hz), 184.4 (JCP = 6.3 Hz). Anal. Calcd. for C34H38Br2NO3P: C, 58.38; H, 5.48; N, 2.00. Found: C, 58.22; H, 5.78; N, 1.98.
3.4.2 Preparation of N-Methylated DOT-pyrrolidine 3.2b
To a solution of 3.8c (1.0 g, 2.2 mmol) dissolved in a solvent mixture (THF:DCM = v:v = 1:1,
40 mL), NaH 60% on mineral oil (0.890 g, 22.2 mmol) was added. Methyl iodide (1.4 mL, 22.2
mmol) was added dropwise to the reaction mixture and stirred at rt for 16 h. The solvent mixture
was evacuated and the residue was extracted with DCM. The crude product was filtered and
subjected to column chromatography (SiO2, DCM:methanol = 98:2) to give 3.2b.
(5RS)-5-Benzyl-1-methyl-3-triphenylphosphoranylidenpyrrolidin-2,4-dione (3.2b). (0.95g 92%) White plates (from ethyl acetate) mp 180–182 °C. 1H NMR δ 2.94 (s, 3H), 3.13 (d, J = 4.1 Hz, 2H), 3.93 (t, J = 4.3 Hz, 1H), 7.17–7.25 (m, 5H), 7.36–7.46 (m, 12H), 7.54–7.60 (m, 3H). 13C NMR δ 27.7, 35.0, 64.1 (JCP = 123.1 Hz), 67.6 (JCP = 13.2 Hz), 122.7 (JCP = 92.8 Hz), 126.0, 127.8, 128.6 (JCP = 12.6 Hz), 130.1, 132.6 (JCP = 2.9 Hz), 133.8 (JCP = 10.9 Hz), 136.7, 173.8 (JCP = 16.6 Hz), 193.9 (JCP = 6.9 Hz). Anal. Calcd. for C30H26NO2P: C, 77.74; H, 5.65; N, 2.95. Found: C, 77.45; H, 5.70; N, 2.96.
3.4.3 Preparation of Linear Free Amine 3.2c
To a solution of 3.8c (0.66 g, 1.0 mmol) dissolved in DCM (10 mL), triethylamine (3.0 eq)
was added and stirred for 1 h. The solvent mixture was washed with saturated aq sodium
chloride. The organic layer was dried with anhyd magnesium sulfate, filtered, and removed
under vacuum to give 3.2c.
(4RS)-4-Amino-1-ethoxy-5-phenyl-2-(triphenylphosphoranyliden)pentan-1,3-dione (3.2c). (0.45 g, quantitative) Clear oil, 1H NMR δ 0.63 (t, J = 7.0 Hz, 3H) 1.53 (br s, 2H), 2.50 (dd, J = 12.6, 9.1 Hz, 1H), 3.31 (dd, J = 12.6, 4.9 Hz, 1H), 3.62–3.78 (m, 2H), 4.90–4.95 (m, 1H), 7.14–7.31 (m, 5H), 7.40–7.65 (m, 15H). 13C NMR δ 13.6, 42.4, 57.2 (JCP = 7.4 Hz), 58.4, 69.3 (JCP = 108.2 Hz), 125.8, 126.4 (JCP = 93.3 Hz), 128.1, 128.5 (JCP = 12.6 Hz), 129.6, 131.6 (JCP = 2.9 Hz), 132.9 (JCP = 9.7 Hz), 139.8, 167.2 (JCP = 14.3 Hz), 198.0 (JCP = 2.9 Hz). Anal. Calcd. for C30H26NO2P: C, 75.14; H, 6.10; N, 2.83. Found: C, 74.37; H, 6.06; N, 2.97.
89
3.4.4 Preparation of 3,3-Dibromopyrrolidin-2,4-dione 3.3a
The 4-Chlorobenzoic acid (0.05 g, 0.32 mmol) and 3.2b (0.13 g, 0.28 mmol) were refluxed in
THF (25 mL) for 1 h, no reaction was detected by TLC. Upon the addition of NBS (~0.09 g,
0.32 mmol) the reaction was completed after 5 min of stirring at rt. The organic phase was
washed with saturated aq sodium chloride solution. The crude product was subjected to column
chromatography (SiO2, hexane:ethyl acetate = 4:1), to give 3.3a.
(5RS)-5-Benzyl-3,3-dibromo-1-methylpyrrolidin-2,4-dione (3.3a). (0.08 g, 79%) Yellowish oil. 1H NMR δ 3.05 (s, 3H), 3.23 (d, J = 4.9 Hz, 2H), 4.51 (t, J = 4.9 Hz, 1H), 7.07–7.11 (m, 2H), 7.22–7.33 (m, 3H). 13C NMR δ 29.4, 35.5, 44.7, 66.6, 127.7, 129.9, 129.6, 133.7, 164.8, 194.4. Anal. Calcd. for C12H11Br2NO2: C, 39.92; H, 3.07; N, 3.88. Found: C, 40.45; H, 3.22; N, 3.40.
3.4.5 Preparation of 3,3-Dibromo-5-hydroxypyrrolidin-2,4-dione 3.3b
Ethoxytrimethylsilane (0.057 g, 0.5 mmol) and NBS (0.081 g, 0.5 mmol) were combined in
DCM (1 mL) for 2 min and added to 3.2b (0.15 g, 0.3 mmol) separately dissolved in DCM (1
mL). The reaction was complete after 5 min stirring at rt. The crude product was subjected to
column chromatography (SiO2, hexane:ethyl acetate = 4:1) and allowed a mixture (1:1) of 3.3a
(0.05 g, 44%) and 3.3b (0.05 g, 44%) to be obtained in 88% yield, without workup.
(5RS)-5-Benzyl-3,3-dibromo-5-hydroxy-1-methylpyrrolidin-2,4-dione (3.3b). (0.05 g, 44%) White sheets (from chloroform) mp = 134–136 °C. 1H NMR δ 3.13 (s, 3H), 3.21 (d, J = 8.4 Hz, 1H), 3.32 (d, J = 14.0 Hz, 1H), 4.66 (br s, 1H), 7.05–7.09 (m, 2H), 7.24–7.28 (m, 3H). 13C NMR δ 25.9, 41.1, 42.6, 90.8, 128.1, 129.0, 130.4, 131.8, 165.1, 194.3. Anal. Calcd. for C12H11Br2NO3: C, 38.23; H, 2.94; N, 3.72. Found: C, 37.48; H, 2.82; N, 3.50. Crystal data: C12H11Br2NO3, MW 377.04, monoclinic, space group P21/n, a = 6.8928(5), b = 28.975(2), c = 7.0527(5) Å, β = 110.311(2) o, V = 1320.99(16) Å3, F(000) = 736, Z = 4, T = -170 oC, colorless plate, 0.53 x 0.26 x 0.14 mm, μ (MoKα) = 6.135 mm-1, Dcalcd = 1.896 g.cm-3, 2θmax 53o, wR(F2) = 0.0754 (all 2540 data), R = 0.0268 (2274 data with I > 2σI).
3.4.6 Preparation of 4-Azido-3-bromopyrrol-2-one 3.3c
The N-Bromosuccinimide (0.135 g, 0.76 mmol) and TMS-azide (0.1 mL, 0.76 mmol) were
combined in DCM (5 mL) and added to 3.2b (0.25 g, 0.54 mmol) dissolved in DCM (1 mL).
90
The reaction was stirred at rt for 5 min. The crude product was subjected to column
chromatography (SiO2, hexane:ethyl acetate = 4:1), without workup, to give 3.3c.
(5RS)-4-Azido-5-benzyl-3-bromo-1-methylpyrrol-2-one (3.3c). (0.14 g, 84%) Clear oil. 1H NMR δ 2.93 (dd, J = 14.7, 4.9 Hz, 1H), 2.95 (s, 3H), 3.16 (dd, J = 14.7, 4.2 Hz, 1H), 4.08 (t, J = 4.9 Hz, 1H), 7.07–7.11 (m, 2H), 7.23–7.31 (m, 3H). 13C NMR δ 28.7, 35.8, 63.3, 103.1, 127.4, 128.6, 129.0, 134.0, 149.3, 165.8. C12H11BrN4O HRMS m/z Calcd 307.0194, 309.0174 [M+H]+, Found 307.0190, 309.0119.
3.4.7 Preparation of 4-Benzotriazolpyrrol-2-one 3.3d
The 1-Chlorobenzotriazole (0.7 g, 0.48 mmol) and 3.2b (0.2 g, 0.43 mmol) were dissolved
together in DCM (1 mL). The reaction was stirred at rt for 5 min. The crude product was
subjected to column chromatography (SiO2, hexane:ethyl acetate = 9:1) without workup to give
3.3d.
(5RS)-4-(Benzotriazol-1(2)-yl)-5-benzyl-1-methylpyrrol-2-one (3.3d). (0.12 g, 92%) Yellow microcrystals (from diethyl ether) mp = 124–126 °C. 1H NMR δ (Bt1:Bt2 = 1:1) 2.90 (dd, J = 14.0, 4.9 Hz, 2H), 3.13–3.30 (m, 7H), 3.37–3.50 (m, 2H), 5.21 (t, J = 4.2 Hz, 1H), 5.34 (t, J = 4.2 Hz, 1H), 6.47 (s, 1H), 6.49 (s, 1H), 6.65–6.68 (m, 2H), 6.99–7.02 (m, 2H), 7.11–7.14 (m, 4H), 7.31 (d, J = 8.4 Hz, 1H), 7.40–7.57 (m, 5H), 7.87–7.98 (m, 3H), 8.16 (d, J = 7.7 Hz, 1H). 13C NMR δ 28.8, 29.0, 35.1, 35.8, 62.0, 62.7, 112.5, 115.0, 116.4, 117.6, 118.6, 120.5, 125.3, 125.7, 127.3, 127.4, 128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 131.6, 133.0, 133.5, 143.8, 144.7, 145.2, 145.9, 164.6, 164.7. Anal. Calcd. for C18H16N4O: C, 71.01; H, 5.30; N, 18.41. Found: C, 68.39; H, 4.90; N, 18.53. Reduced product C18H14N4O HRMS m/z Calcd 303.0120, 325.1060 [M+H]+, [M+Na]+ Found 303.1233, 325.1054.
3.4.8 Preparation of N-Acylbenzotriazoles 3.4a–d, 3.13
Compounds 3.4a–d and 3.13 were prepared from the corresponding N-Cbz amino acids (25
mmol) and BtH (3.0 eq) in the presence of thionyl chloride (1.01 eq), following recently
developed procedures [Chapter 2-2.4.1, 05ARK116, 04S2645, 04S1806, 06S411].
(2S)-1-Benzyloxycarbonyl(benzotriazol-1-carbonyl)pyrrolidine (3.4d). (Two rotameric forms) (6.3g, 72%) Clear oil. [α]23
D = –139.6 (c 1.83, DMF)lit.[06S411]. 1H NMR δ 1.99–2.14 (m, 2H), 2.15–2.26 (m, 1H), 2.54–2.68 (m, 1H), 3.64–3.88 (m, 2H), 4.95–5.11 (m, 1H), 5.12–5.24 (m, 1H), 5.83–5.88 (m, 1H), 6.97–7.06 (m, 2H), 7.30–7.42 (m, 3H), 7.50–7.56 (m, 1H), 7.65–7.70 (m, 1H), 8.11–8.16 (m, 1H), 8.19–8.31 (m, 1H). 13C NMR δ 23.7, 24.5, 30.7, 31.6, 46.9, 47.3, 59.2, 60.0, 67.3, 114.3, 114.5, 120.2, 126.4, 127.5, 127.9, 128.1, 128.5, 130.5, 130.6, 145.9,
91
154.0, 154.9, 171.1, 171.6. Anal. Calcd. for C19H18N4O3: C, 65.13; H, 5.18; N, 15.99. Found: C, 64.98; H, 5.24; N, 15.77.
3-(Benzotriazol-1-yl)-1-(benzyloxy)carbonylamino-propan-3-one (3.13). (7.3 g, 90%) White needles (from diethyl ether) mp 111–112 °C. 1H NMR δ 3.66–3.69 (m, 2H), 3.74–3.80 (m, 2H), 5.09 (s, 2H), 5.47 (br s, 1H), 7.28–7.36 (m, 5H), 7.48–7.53 (m, 1H), 7.62–7.67 (m, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H). 13C NMR δ 35.9, 36.1, 66.8, 114.2, 120.2, 126.3, 128.1, 128.5, 130.5, 130.8, 136.2, 146.1, 156.2, 171.2. Anal. Calcd. for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 63.19; H, 4.86; N, 17.41.
3.4.9 Preparation of α-Triphenylphosphoranylidene Esters 3.6a–d
Compounds 3.6a–d and 3.14 were prepared from the corresponding 3.4a–d and 3.13 (1.1
mmol) and 3.5 (0.348 g, 1.0 mmol) in ACN (1 mL) in a dry 50 mL rb flask with a magnetic stir
bar was equipped with a condenser. The flask containing the reaction mixture was exposed to
microwave irradiation (120 W) for 10 min at a temp of 60 °C, and cooled with high-pressure air
through an inbuilt system in the instrument until the temp fell below 30 °C. The reaction
mixture was diluted with ethyl acetate and washed with a saturated aq sodium carbonate solution.
The organic layer was collected, dried over anhyd magnesium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column chromatography (SiO2,
hexane:ethyl acetate = 3:1) to give 3.6a–d.
(2S)-1-Benzyloxycarbonyl-2-(ethoxycarbonyltriphenylphosphoranylidenacetyl)pyrrolidine (3.6d). (Two rotameric forms) (0.38 g, 66%) White microcrystals (from chloroform / hexane) mp 129–130 °C. [α]23
D = –36.4 (c 1.50, CH2Cl2) ([α]20 D = –45.0 (c 1.03, CH2Cl2)lit.[02JP(1)533]. 1H
NMR δ 0.66 (t, J = 7.1 Hz, 3H), 1.75 (br s, 2H), 1.98–2.16 (m, 1H), 2.30–2.50 (m, 1H), 3.35–3.56 (m, 2H), 3.62–3.84 (m, 2H) 4.89–5.27 (m, 2H), 5.64–5.76 (m, 1H), 7.20–7.74 (m, 20H). 13C NMR δ 13.4, 22.7, 23.5, 30.5, 31.5, 46.6, 47.1, 58.0, 58.1, 62.2 (JCP = 7.4 Hz), 62.7 (JCP = 6.3), 65.7, 65.9, 68.7 (JCP = 109.9 Hz), 69.0 (JCP = 111.1 Hz), 125.9 (JCP = 93.9 Hz), 126.1 (JCP = 93.3 Hz), 126.3, 126.9, 127.2, 127.3, 127.9, 128.1 (JCP = 12.6 Hz), 128.2 (JCP = 12.0 Hz), 131.2 (JCP = 2.9 Hz), 131.3 (JCP = 2.3 Hz), 131.6, 131.8, 132.6 (JCP = 9.7 Hz), 133.0 (JCP = 9.7 Hz), 137.1, 137.2, 154.2 (JCP = 4.0 Hz), 167.1 (JCP = 15.5 Hz), 167.3 (JCP = 14.3 Hz), 194.9 (JCP = 2.9 Hz), 195.4 (JCP = 2.9 Hz). Anal. Calcd. for C35H34NO5P: C, 72.53; H, 5.91; N, 2.42. Found: C, 72.19; H, 5.90; N, 2.76.
5-(Benzyloxy)carbonylamino-1-ethoxy-2-triphenylphosphoranylidenpentan-1,3-one (3.14). (0.43 g, 77%) Yellowish needles (from diethyl ether) mp 88–92 °C. 1H NMR δ 0.64 (t, J = 7.0 Hz, 3H), 3.15 (t, J = 5.5 Hz, 2H), 3.40–3.50 (m, 2H), 3.71 (q, J = 7.0 Hz, 2H), 5.06 (s, 2H), 5.57
92
(t, J = 5.1Hz, 1H), 7.23–7.52 (m, 15H), 7.59–7.70 (m, 5H). 13C NMR δ 13.3, 37.2, 39.6 (JCP =6.3 Hz), 58.1, 65.7, 71.2 (JCP =110.5 Hz), 125.9 (JCP = 93.3 Hz), 127.5, 128.0, 128.2 (JCP = 12.6 Hz), 131.3 (JCP = 2.3 Hz), 131.7, 132.6 (JCP = 9.7 Hz), 136.6, 155.9, 167.5 (JCP = 14.3 Hz) 195.5 (JCP = 3.4 Hz). Anal. Calcd. for C33H32NO5P: C, 71.60; H, 5.83; N, 2.53. Found: C, 71.57; H, 5.97; N, 2.45.
3.4.10 Preparation of DOT-salts 3.7a–d
Compounds 3.7a–d and 3.15 were prepared from the corresponding 3.6a–d and 3.14. 3.6c
(2.0 mmol) was stirred for 5 h in 33% HBr in acetic acid (10 mL). The reaction mixture was
diluted with diethyl ether (150 mL) and stirred for 12 h. The white precipitated salt 3.7c was
filtered from the solution and used without further purification.
4-Ammonio-1-ethoxy-2-triphenylphosphoranylidenbutan-1,3-dione Bromide (3.7a). Hygroscopic (0.20 g, 21%) White plates (from DCM / ethyl acetate) mp 101–103 °C. 1H NMR δ 0.67 (t, J = 7.0 Hz, 3H), 3.72 (q, J = 7.0 Hz, 2H), 4.18 (br s, 2H), 6.83 (br s, 3H), 7.47–7.69 (m, 15H). 13C NMR δ 13.4, 45.4 (JCP = 8.0 Hz), 49.8, 58.7, 69.5 (JCP = 111.1 Hz), 124.1 (JCP = 93.3 Hz), 128.6 (JCP = 12.6 Hz), 132.1 (JCP = 2.3 Hz), 132.9 (JCP = 10.3 Hz), 166.7 (JCP = 13.2 Hz), 185.3 (JCP = 5.7 Hz). Anal. Calcd. for C24H25BrNO3P: C, 59.27; H, 5.18; N, 2.88. Found: C, 58.64; H, 5.29; N, 2.52
(4RS)-4-Ammonio-1-ethoxy-2-triphenylphosphoniopentan-1,3-dione Dibromide (3.7b). (1.15 g, 99%) White microcrystals (from DCM / ethyl acetate) mp 147–150 °C. DMSO-d6
1H NMR δ 0.48 (t, J = 7.0 Hz, 3H), 1.45 (d, J = 6.3 Hz, 3H), 3.50–3.64 (m, 2H), 4.89 (t, J = 6.3 Hz, 1H), 7.59–7.69 (m, 15H), 7.80 (br s, 3H), 8.51 (br s, 1H). DMSO-d6
13C NMR δ 13.3, 17.4, 51.1 (JCP = 8.6 Hz), 58.2, 68.1 (JCP = 109.4 Hz), 124.9 (JCP = 92.8 Hz), 129.0 (JCP = 12.6 Hz), 132.3 (JCP = 2.9 Hz), 132.8 (JCP = 9.7 Hz), 166.2 (JCP = 12.6 Hz), 190.5 (JCP = 4.6 Hz). Anal. Calcd. for C25H28Br2NO3P: C, 51.66; H, 4.86; N, 2.41. Found: C, 51.32; H, 4.88; N, 2.35.
(4RS)-4-Ammonio-1-ethoxy-5-phenyl-2-triphenylphosphoniopentan-1,3-dione Dibromide (3.7c). (1.20 g, 91%) White microcrystals (from DCM / ethyl acetate) mp 145–147 °C. DMSO-d6
1H NMR δ 0.46 (t, J = 7.1 Hz, 3H), 2.80 (dd, J = 14.0, 9.2 Hz, 1H), 3.38 (dd, J = 14.0, 4.3 Hz, 1H), 3.50–3.66 (m, 2H), 5.18 (br s, 1H), 5.68 (br s, 3H), 7.25–7.45 (m, 5H), 7.56–7.77 (m, 15H). DMSO-d6
13C NMR δ 13.3, 37.4, 58.9 (JCP = 8.6 Hz), 58.3, 69.1 (JCP = 108.2 Hz), 124.8 (JCP = 92.8 Hz), 126.9, 128.5, 129.0 (JCP = 12.6 Hz), 129.6, 132.3, 133.0 (JCP = 9.7 Hz), 136.0, 166.4 (JCP = 12.0 Hz), 188.9 (JCP = 4.6 Hz). Anal. Calcd. for C31H32Br2NO3P: C, 56.64; H, 4.91; N, 2.13. Found: C, 57.09; H, 4.93; N, 2.22.
(2RS)-2-(Ethoxycarbonyltriphenylphosphonioacetyl)pyrrolidine Bromide (3.7d). (0.95 g, 90%) White microcrystals (from DCM / ethyl acetate) mp 81–83 °C. 1H NMR δ 0.69 (t, J = 7.3 Hz, 3H), 1.61–1.80 (m, 1H), 2.02–2.20 (m, 2H), 2.65–2.84 (m, 1H), 3.16 (br s, 1H), 3.40–3.60 (m, 1H), 3.73–3.85 (m, 3H), 5.38 (br s, 1H), 7.42–7.71 (m, 15H), 10.70 (br s, 1H). 13C NMR δ 13.6, 24.5, 31.8, 46.5, 59.2, 63.6 (JCP = 9.7 Hz), 69.6 (JCP = 109.9 Hz), 124.2 (JCP = 93.9 Hz),
93
128.9 (JCP = 12.6 Hz), 132.5 (JCP = 2.9 Hz), 133.0 (JCP = 9.7 Hz), 166.2 (JCP = 12.6 Hz), 187.7 (JCP = 5.2 Hz). Anal. Calcd. for C27H29BrNO3P: C, 61.61; H,5.55; N, 2.66. Found: C, 61.28; H, 5.45; N, 3.34.
(5-Ammonio-1-ethoxy-2-triphenylphosphoniopentan-1,3-dione) Dibromide (3.15). (1.08 g, 92%) White plates (from DCM / diethyl ether) mp 126–128 °C. DMSO-d6
1H NMR δ 0.50 (t, J = 7.0 Hz, 3H), 2.80–2.95 (m, 2H), 3.22 (t, J = 6.3 Hz, 2H), 3.56 (q, J = 7.0 Hz, 2H), 7.55–7.80 (m, 18H), 9.50 (br s, 1H). DMSO-d6
13C NMR 13.4, 35.3, 37.1 (JCP = 7.4 Hz), 55.1, 57.9, 69.7 (JCP = 109.4 Hz), 125.7 (JCP = 92.8 Hz), 128.9 (JCP = 12.6 Hz), 132.1, 132.8 (JCP = 9.7 Hz), 166.8 (JCP = 13.2 Hz), 192.4 (JCP = 4.0 Hz). Anal. Calcd. for C25H28Br2NO3P: C, 51.66; H, 4.86; N, 2.41; Found: C, 51.35; H, 4.88; N, 2.14.
3.4.11 Preparation of DOT-pyrrolidines 3.8a–c, DOT-pyrrolizines, and DOT-piperidines
Method I: Compounds 3.8a–d were prepared from the corresponding 3.7a–d. Salt 3.7a–d
(1.0 mmol) was dissolved in ethanol (1.0 mL) and added to aq sodium hydroxide (10.0 mL, 7.5
M), which precipitated a white solid almost immediately. Extraction was performed with DCM
after 5 h. Compound 3.16 was prepared from 3.15 (1.0 mmol), following the same procedure
with an added reflux in aq sodium hydroxide (7.5 M) for 15 h.
Method II: Compounds 3.8′a–d were prepared from the corresponding 3.6a–d. A round
bottom flask charged with 3.6a–d (2.0 mmol) and 5% Pd(C) (2 eq) were stirred vigorously in
ethanol, under a hydrogen atmosphere for 48 h. The reaction mixture was filtered through celite
and diluted with ethyl acetate to crystallize 3.8′a–d.
3-Triphenylphosphoranylidenpyrrolidin-2,4-dione (3.8a). (0.35 g, 97%) (Method I 20%) (3.8′a, Method II 0.43 g, 60%) (21%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 222–224 °C. 1H NMR δ 3.79 (s, 2H), 5.40 (br s, 1H), 7.47–7.56 (m, 6H), 7.58–7.74 (m, 9H). 13C NMR 52.4 (JCP = 13.2 Hz), 64.2 (JCP = 122.6 Hz), 122.8 (JCP = 93.3 Hz), 128.7 (JCP = 12.6), 132.9 (JCP = 2.9 Hz), 134.0 (JCP = 10.9 Hz), 177.4 (JCP = 17.4 Hz), 194.8 (JCP = 8.6 Hz). Anal. Calcd. for C22H18NO2P: C, 73.53; H, 5.05; N, 3.90. Found: C, 73.28; H, 4.98; N, 3.88.
(5RS)-5-Methyl-3-triphenylphosphoranylidenpyrrolidin-2,4-dione (3.8b). (0.37 g, 99%) (Method I 98%) (3.8′b, Method II 0.34 g, 45%) (58%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 210–211 °C. 1H NMR δ 1.34 (d, J = 6.7 Hz, 3H), 3.87 (q, J = 6.7 Hz, 1H), 5.30 (s, 1H), 7.40–7.80 (m, 15H). 13C NMR 18.5, 58.0 (JCP = 13.7 Hz), 62.8 (JCP = 122.5 Hz), 122.9 (JCP = 92.8 Hz), 128.7 (JCP = 12.6 Hz), 132.8 (JCP = 2.3 Hz), 133.9 (JCP = 10.9 Hz), 176.2 (JCP = 16.6 Hz), 197.7 (JCP = 7.4 Hz). Anal. Calcd. for C23H20NO2P: C, 73.98; H, 5.40; N, 3.75.
94
Found: C, 73.72; H, 5.38; N, 3.46. HRMS m/z Calcd for C23H20NO2P 373.1226 [M+H]+, Found 373.1215.
(5RS)-5-Benzyl-3-triphenylphosphoranylidenpyrrolidin-2,4-dione (3.8c). (0.45 g, 99%) (Method I = 89%) (3.8′c, Method II 0.40 g, 45%) White plates (from DCM / ethyl acetate) mp 238–242 °C. 1H NMR δ 2.82 (dd, J = 13.7, 8.1 Hz, 1H), 3.18 (dd, J = 13.2, 3.4 Hz, 1H), 4.05–4.08 (m, 1H), 5.17 (s, 1H), 7.20–7.30 (m, 5H), 7.44–7.63 (m, 15H). 13C NMR δ 38.7, 63.5 (JCP = 13.2 Hz), 64.0 (JCP = 122.0 Hz), 122.7 (JCP = 93.3 Hz), 126.3, 128.2, 128.7 (JCP = 13.2 Hz), 129.6, 132.8 (JCP = 2.9 Hz), 133.9 (JCP = 10.9 Hz), 137.8, 175.9 (JCP = 16.0 Hz), 195.5 (JCP = 7.4 Hz). Anal. Calcd. for C29H24NO2P: C, 77.49; H, 5.38; N, 3.12. Found: C, 77.22; H, 5.45; N, 2.76. HRMS m/z Calcd for C29H24NO2P 450.1617 [M+H]+, Found 450.1628. Crystal data: C29H24NO2P, MW 449.460, monoclinic, space group P21/n, a = 10.7276(2), b = 14.2746(3), c = 14.8455(4) Å, β = 90.353(1) o, V = 2273.28(9) Å3, F(000) = 944, Z = 4, T = -180 oC, colorless block, 0.44 x 0.22 x 0.12 mm, μ (MoKα) = 0.148 mm-1, Dcalcd = 1.313 g.cm-3, 2θmax 50o, wR(F2) = 0.0997 (all 4022 data), R = 0.0402 (3788 data with I > 2σI).
(2RS)-2-(Triphenylphosphoranyliden)tetrahydropyrrolizin-1,3-dione (3.8d). (0.35 g, 88%) (Method I 79%) (22′d, Method II 0.36 g, 45%) (60%)lit.[01TL141] White needles (from DCM / ethyl acetate) mp 211–213 °C. 1H NMR δ 1.60–1.73 (m, 1H), 1.88–2.18 (m, 3H), 3.04–3.12 (m, 1H), 3.70 (dt, J = 11.2, 7.5 Hz, 1H) 3.99 (app t, J = 7.7 Hz, 1H), 7.40–7.70 (m, 15H). 13C NMR 27.0, 28.2, 44.6, 65.2 (JCP = 117.4 Hz), 69.1 (JCP = 13.2 Hz), 122.6 (JCP = 92.8 Hz), 128.7 (JCP = 13.2 Hz), 132.8 (JCP = 2.9 Hz), 133.8 (JCP = 10.9 Hz), 179.7 (JCP = 16.0 Hz), 197.6 (JCP = 8.0 Hz). Anal. Calcd. for C25H22NO2P: C, 75.18; H, 5.55; N, 3.51. Found: C, 74.96; H, 5.62; N, 3.47.
3-Triphenylphosphoranylidenpiperidin-2,4-dione (3.16). (0.29 g, 65%) (Method I 60%) (34%)lit.[01TL141] White microcrystals (from DCM / ethyl acetate) mp 241–243 °C. 1H NMR δ 2.42 (t, J = 6.3 Hz, 2H), 3.37 (dt, J = 6.3, 2.8 Hz, 2H), 5.65 (br s, 1H), 7.39–7.53 (m, 9H), 7.64–7.71 (m, 6H). 13C NMR 37.1 (JCP = 9.2 Hz), 37.9, 70.0 (JCP = 115.1 Hz), 125.0 (JCP = 92.8 Hz), 128.2 (JCP = 12.6 Hz), 131.7 (JCP = 2.9 Hz), 133.3 (JCP = 10.3 Hz), 171.1 (JCP = 10.9 Hz), 191.9 (JCP = 4.6 Hz). Anal. Calcd. for C23H20NO2P: C, 73.98; H, 5.40; N, 3.75. Found: C, 74.03; H, 5.55; N, 3.58.
3.4.12 Preparation of α-Triphenylphosphoranylidene Nitriles 3.10a–d, 3.17
Compounds 3.10a–d and 3.17 were prepared from the corresponding 3.4a–d and 3.13 (1.1
mmol) and 3.9 (1.0 mmol), following the procedure developed for α-triphenylphosphoranylidene
esters in section 3.4.9.
4-Benzyloxycarbonylamino-3-oxo-2-triphenylphosphoranylidenbutane nitrile (3.10a). (0.42 g, 85%) White microcrystals (from diethyl ether / hexanes) mp 171–173 °C. 1H NMR δ 4.41 (d, J = 4.3 Hz, 2H), 5.09 (s, 2H), 5.59 (br s, 1H), 7.26–7.40 (m, 5H), 7.42–7.72 (m, 15H). 13C NMR 46.4 (JCP = 127.7 Hz), 47.5 (JCP = 10.9 Hz), 66.4, 120.6 (JCP = 14.9 Hz), 122.3 (JCP = 93.3 Hz), 127.8, 128.3, 129.2 (JCP = 13.2 Hz), 133.3 (JCP = 3.4 Hz), 133.5 (JCP = 10.3 Hz), 136.6, 156.0,
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189.9. Anal. Calcd. for C30H25N2O3P: C, 73.16; H, 5.12; N, 5.69. Found: C, 72.80; H, 5.08; N, 5.59.
(4S)-Benzyloxycarbonylamino-3-oxo-2-triphenylphosphoranylidenpentane nitrile (3.10b). (0.40 g, 79%) White microcrystals (from diethyl ether / hexanes) mp 73–75 °C. [α]23
D = +21.5 (c 1.00, CH2Cl2) ([α]20
D = +18.96 (c 1.00, CHCl3)) lit. [03T6771]. 1H NMR δ 1.53 (d, J = 6.7 Hz, 3H), 4.92–5.02 (m, 1H), 5.08 (s, 2H), 5.75 (d, J = 6.9 Hz, 1H), 7.22–7.36 (m, 5H), 7.40–7.72 (m, 15H). 13C NMR 19.4, 46.5 (JCP = 127.5 Hz), 52.2, 66.0, 120.7 (JCP = 14.9 Hz), 122.3 (JCP = 93.3 Hz), 127.6, 128.2, 129.0 (JCP = 12.6 Hz), 131.7 (JCP = 4.0 Hz), 131.8, 133.2 (JCP = 10.3 Hz), 136.5, 155.2, 194.3. Anal. Calcd. for C31H27N2O3P: C, 73.51; H, 5.37; N, 5.53. Found: C, 73.13; H, 5.38; N, 5.36.
(4S)-Benzyloxycarbonylamino-3-oxo-5-phenyl-2-triphenylphosphoranylidenpentane nitrile (3.10c). (0.44 g, 79%) (78%)lit.[00T9763] White microcrystals (from DCM / diethyl ether) mp 101–103 °C. [α]23
D = +7.6 (c 1.10, CH2Cl2). 1H NMR δ 3.08 (dd, J = 13.9, 7.0 Hz, 1H), 3.34 (dd, J =
13.9, 4.9 Hz 1H), 5.06 (s, 2H), 5.20 (q, J = 7.0 Hz, 1H), 5.58 (d, J = 7.7 Hz, 1H), 7.17–7.23 (m, 5H), 7.25–7.33 (m, 5H), 7.48–7.57 (m, 10H) 7.60–7.66 (m, 5H). 13C NMR 38.7, 47.9 (JCP = 126.0 Hz), 57.2 (JCP = 9.0 Hz), 66.3, 121.0 (JCP = 16.0 Hz), 122.4 (JCP = 93.9 Hz), 126.4, 127.8. 128.1, 128.3, 129.1 (JCP = 12.6 Hz), 129.7, 133.2 (JCP = 3.4 Hz), 133.5 (JCP = 10.3 Hz), 136.8, 155.5, 192.9. Anal. Calcd. for C37H31N2O3P: C, 76.27; H, 5.36; N, 4.81. Found: C, 76.52; H, 5.38; N, 2.94.
(2S)-1-Benzyloxycarbonyl-(cyanotriphenylphosphoranylidenacetyl)pyrrolidine (3.10d). (Two rotameric forms) (0.34 g, 64%) White microcrystals (from DCM / diethyl ether) mp 141–143 °C. [α]23
D = –12.7 (c 1.20, CH2Cl2). 1H NMR δ 1.79–2.12 (m, 3H), 2.29–2.47 (m, 1H),
3.44–3.58 (m, 2H), 4.99–5.27 (m, 3H), 7.21–7.70 (m, 20H). 13C NMR 23.6, 24.4, 30.4, 31.6, 46.2 (JCP = 126.3 Hz), 46.3 (JCP = 127.0 Hz), 46.8, 47.4, 61.8 (JCP = 9.1 Hz), 62.4 (JCP = 9.1 Hz), 66.4, 121.3 (JCP = 14.7 Hz), 121.5 (JCP = 15.4 Hz), 122.6 (JCP = 93.4 Hz), 122.9 (JCP = 93.4 Hz), 126.9, 127.2, 127.4, 127.4, 128.1, 128.2, 128.4, 128.8 (JCP = 12.6 Hz), 128.9 (JCP = 12.6 Hz), 131.8, 131.9, 132.8 (JCP = 2.8 Hz). 132.9 (JCP = 2.8 Hz), 133.2 (JCP = 10.5 Hz), 133.4 (JCP = 10.5 Hz), 136.9, 137.0, 154.2, 154.4, 194.7 (JCP = 3.5 Hz), 194.9 (JCP = 3.5 Hz). HRMS m/z Calcd for C33H29N2O3P 533.1989 [M+H]+, Found 533.1995.
5-Benzyloxycarbonylamino-3-oxo-2-triphenylphosphoranylidenpentane nitrile (3.17). (0.32 g, 63%) White microcrystals (from diethyl ether / hexanes) mp 156–158 °C. 1H NMR δ 2.95 (t, J = 5.9 Hz, 2H), 3.45–3.50 (m, 2H), 5.08 (s, 2H), 5.41 (br s, 1H), 7.24–7.38 (m, 5H), 7.44–7.64 (m, 15H). 13C NMR 36.9, 38.6 (JCP = 9.2 Hz), 49.0 (JCP = 126.0 Hz), 66.1, 121.8 (JCP = 16.6 Hz), 122.6 (JCP = 93.9 Hz), 127.7, 127.8, 128.2, 129.0 (JCP = 13.2 Hz), 133.1 (JCP = 2.9 Hz), 133.3 (JCP = 10.3 Hz), 136.6, 156.0, 195.0. Anal. Calcd. for C31H27N2O3P: C, 73.51; H, 5.37; N, 5.53. Found: C, 73.50; H, 5.37; N, 5.50.
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3.4.13 Preparation of 2,4-Dihydropyrrol-3-one Salts 3.11a–c, Tetrahydropyrrolizin-1-one Salt 3.11d, and Nitrile Salt 3.18
Compounds 3.11a–d and 3.18 were prepared from the corresponding 3.10a–d and 3.17 (1.0
mmol), following the procedure developed in section 3.4.10.
5-Amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one Bromide (3.11a). (0.31 g, 71%) White plates (from DCM / diethyl ether) mp 255–258 °C. 1H NMR δ 3.99 (s, 2H), 7.64–7.71 (m, 12H), 7.74–7.81 (m, 3H), 8.72 (br s, 1H). 13C NMR 52.2 (JCP = 10.3 Hz), 64.8 (JCP = 125.4 Hz), 119.7 (JCP = 93.3 Hz), 130.1 (JCP = 13.2 Hz), 133.6 (JCP = 10.9 Hz), 134.6 (JCP = 2.9 Hz), 170.3 (JCP = 17.2 Hz), 194.5 (JCP = 6.3 Hz). Anal. Calcd. for C22H20BrN2OP: C, 60.15; H, 4.59; N, 6.38; Found: C, 60.11; H, 4.94; N, 5.59.
(2RS)-5-Amino-2-methyl-4-triphenylphosphonio-2,4-dihydropyrrol-3-one Bromide (3.11b). (0.26 g, 70%) White plates (from DCM / diethyl ether) mp 260–262 °C. 1H NMR δ 1.45 (d, J = 7.0 Hz, 3H), 1.72 (br s, 2H), 4.03 (q, J = 7.0 Hz, 1H), 7.63–7.69 (m, 12H), 7.75–7.81 (m, 3H), 8.76 (br s, 1H). 13C NMR 17.3, 58.5 (JCP = 10.3 Hz), 63.1 (JCP = 124.3 Hz), 120.1 (JCP = 93.3 Hz), 130.1 (JCP = 13.1 Hz), 133.6 (JCP = 10.9 Hz), 134.6 (JCP = 2.9 Hz), 168.8 (JCP = 17.2 Hz), 197.7 (JCP = 5.7 Hz). Anal. Calcd. for C23H22BrN2OP: C, 60.94; H, 4.89; N, 6.18; Found: C, 60.58; H, 4.78; N, 5.96.
(2RS)-5-Amino-2-benzyl-4-triphenylphosphonio-2,4-dihydropyrrol-3-one Bromide (3.11c). (0.38 g, 72%) White plates (from DCM / diethyl ether) mp 253–255 °C. 1H NMR δ 1.69 (s, 2H), 3.11 (dd, J = 14.0, 4.9 Hz, 1H), 3,21 (dd, J = 14.0, 3.5 Hz, 1H), 4.28 (t, J = 4.2 Hz, 1H), 7.32–7.42 (m, 11H), 7.54–7.59 (m, 6H), 7.71–7.76 (m, 3H), 9.06 (br d, JHP = 2.1 Hz, 1H). 13C NMR 36.6, 63.3 (JCP = 10.3 Hz), 64.0 (JCP = 127.8 Hz), 119.7 (JCP = 92.8 Hz), 126.8, 128.4, 130.0 (JCP = 12.6 Hz), 130.6, 133.7 (JCP = 10.9 Hz), 134.5 (JCP = 2.9 Hz), 134.9, 169.3 (JCP = 16.6 Hz), 195.3 (JCP = 6.3 Hz). Anal. Calcd. for C29H26BrN2OP + H2O: C, 63.63; H, 5.16; N, 5.12. Found: C, 63.21; H, 4.77; N, 4.94.
(4RS)-3-Ammonio-2-triphenylphosphonio-tetrahydropyrrolizin-1-one Dibromide (3.11d). (0.37 g, 66%) White plates (from DCM / diethyl ether) mp 238–240 °C. 1H NMR δ 1.48–1.59 (m, 1H), 1.93–2.25 (m, 3H), 3.57–3.70 (m, 1H), 3.81–3.88 (m, 1H), 4.02–4.08 (m, 1H), 7.54–7.64 (m, 11H), 7.69–7.79 (m, 4H). 13C NMR 26.7, 27.8, 49.1, 65.9 (JCP = 119.1 Hz), 70.0 (JCP = 10.3 Hz), 119.4 (JCP = 92.8 Hz), 130.0 (JCP = 13.1 Hz), 133.5 (JCP = 10.9 Hz), 134.6 (JCP = 2.9Hz), 170.9 (JCP = 15.5 Hz), 196.2 (JCP = 5.7 Hz). Anal. Calcd. for C25H25Br2N2OP: C, 53.59; H, 4.50; N, 5.00. Found: C, 53.99; H, 4.39; N, 4.52.
1-Ammonio-3-oxo-4-triphenylphosphoranylidenpentan-5-nitrile Bromide (3.18). (0.16 g, 35%) White microcrystals (from diethyl ether / hexanes) mp 238–244 °C. 1H NMR δ 3.17–3.24 (m, 4H), 7.42 (br s, 3H), 7.51–7.68 (m, 15H). 13C NMR 33.4 (JCP = 8.0 Hz), 37.0, 50.4 (JCP = 124.3 Hz), 120.8 (JCP = 16.0 Hz), 121.8 (JCP = 93.3 Hz), 129.3 (JCP = 13.2 Hz), 133.4 (JCP = 10.3 Hz), 133.5 (JCP = 2.3 Hz), 195.0 (JCP = 4.0 Hz). Anal. Calcd. for C23H24BrN2O2P: C, 58.61; H, 5.13; N, 5.94. Found: C, 58.63; H, 5.15; N, 5.39.
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CHAPTER 4 ENERGETIC IONIC LIQUIDS
4.1 Introduction
Over the last several years, typical properties of ionic liquids (ILs) such as high ion content,
liquidity over a wide temperature range, low viscosity, limited-volatility, and high ionic
conductivity have proven to be important drivers supporting numerous advances beyond the
initial investigations of ILs as liquid electrolytes [06NJC349, 04FPE93, 04AJC113]. The
properties of ILs have made it possible to replace damaging solvents which are used in huge
amounts or are hard-to-contain, volatile organic compounds (VOCs), with recyclable, reusable,
and easy to handle materials [99CRV2071, 01CC2399, 02JMC(A)419]. The rethinking,
redesign, and implementation of ILs as “designer” solvents into many current chemical processes
can deliver significant cost and environmental benefits [99CPP223], and lead to new
technologies, e.g. the processing of cellulose [02JA4974], biphasic chemical processes (e.g.,
BASF's BASIL®) [06MI121], photovoltaics [96IC1168, 02CC2972], fuel cell electrolytes,
[02MI185] polymer electrolytes [04EA255], thermal fluids [05MI181], and lubricants
[06MI347].
Safety and environmental issues have limited the ability to safely store and handle high
performance energetic materials [01GC75, 04C409]. The exclusion of hydrazines, metals,
halides, perchlorates, and other hazardous and potentially toxic compounds from the processing
and final energetic material has benefits on reactivity, cost, and handling [02GC407]. The liquid
state, negligible vapor pressure, and high density of ILs should bypass some problems with
current energetic materials and allow for safer transportation, handling, and processing from
early production to end-use. Separated components could be less hazardous than an active
energetic ionic liquid (EIL) fused in the last step of synthesis. Moreover energetic ILs have good
98
thermal stabilities at elevated temperatures and most have reasonable impact values [03PEP174].
Thus, endowing energetic materials with IL behavior rather than merely the liquid state is highly
desirable [05US0269001].
Cation Anion
New, functionalized fused salt
Cation Anion
M odular DesignThe diverse structural fuctionalities,appended directly to the heterocyclicion cores, introduced throughout thecollaboration included:-alkyl chains with and withoutenergetic groups;-strained ring systems;-oxygen-rich functional groups(e.g., OH, ether, epoxide);-energetic functionalities(e.g., NO2, CN, N3, NH2);-unsaturated functionalities.
Metathesis
-Byproduct
Figure 4-1. Collaborative Effort: Modular Design of Heterocycles for EILs.
The dual nature of ILs allows a unique tunable architectural platform with properties related
to the structure of constituent ions [07MI1111]. The collaborative effort, between the Center for
Heterocyclic Chemistry (CHC) in Gainesville, Florida together with The Center for Green
Manufacturing (CGM) in Tuscaloosa, Alabama, has focused on the development of new
energetic ionic liquids from the perspective of modular design in order to synthesize selected
heterocycles for preparing fused salts (Figure 4-1). The properties of cation and/or anion within
the ionic pair were independently modified, then metathesis could generate new functional
materials [05CC868, 06CEJ4630], which retain the core features of the IL state of matter. The
final materials were monitored by DSC, TGA, and single crystal X-ray crystallography, to
examine how the modification to each component influenced decomposition temperature and
melting point.
The synthetic efforts were not directed a priori to the preparation of energetic fluids, but
rather to synthesizing new materials to enable the development of links between component
99
functionality and physical properties. However, the approach broadened and the strategy shifted
from commercially available components to newly synthesized anions and cations. The CHC at
UF, prepared a series of 1,3-dialkylimidazolium salts containing strongly electron-withdrawing
nitro and nitrile groups directly attached to the ring (Scheme 4-1). Alkylations of substituted
imidazoles have been studied for almost a century [10JCS1814, 22JCS2616, 24JCS1431,
25JCS573, 60JCS1357, 63BSC2840, 66AF23, 89AJC1281, 91SC427, 95CC9], and were used
for medicinal chemistry applications in the late sixties [67JME891, 68JME167, 03JME427,
03BMC2863]. Recently the CHC developed regiospecific N-alkylation to generate strategies for
novel EILs [06NJC349].
N
N
MeO2N
NH
NO2N
N
N
O2N
Et
N
NEt
MeO2N
N
NMe
MeO2N
X
Et2SO4,NaOH (aq.)45 oC
Me2SO4
Et2SO4
4.2
X
4.1
4.7c
a
b
4.4
4.3dioxaneref lux
Reaction conditions:a) Me2SO4, toluene,
20 °C, 48 h;b) MeOTf, toluene,
20 °C, 72 h;
Scheme 4-1. Regioselective N-Alkylation and Quaternization of Nitro-Substituted Imidazole To further augment the strategic toolbox of regioalkylation of imidazole and further explore
the role of functional groups on imidazolium cation of the ionic liquid system, the CHC prepared
another series of 1-alkylimidazoles, containing nitro groups or alkyl substituents (Scheme 4-2).
The CGM made on site, picrate and nitrate EIL and measured melting and decomposition
temperatures to evaluate how different functionality and substitution patterns on a cation ring
affected the physical properties of the resulting salts.
100
4.6a-k4.7a-k (w/ energetic group)
N
NR1
R2
R3
R4
R1 = AlkylR2 = H, Me, NO2R3 = H, NO2, CNR4 = H, Me, NO2, CN
N+
NR1
R2
R3
R4
H
N+
NR1
R2
R3
R4
H
NO2
O2N NO2
-O
N+-O
O
O-
Picric Acid
Nitric Acid
[4.6a-k][Picr.]
[4.7a-k][NO3]
Regiospecif icN-alkylatingStrategiesDevelopedby the CHC
Fused salts examined by the CGM
[4.6a-k][NO3]
[4.7a-k][Picr.]
Scheme 4-2. Targeted Regio-N-alkylated Imidazoles for Generation of Fused Salts
4.2 Results and Discussion
Series of N-alkylated imidazoles (i) without energetic groups 4.6a–k (Table 4-1) and (ii) with
energetic groups 4.7a–k (Table 4-2) were used as starting materials for the generation of picrate
and nitrate salts. Unavailable N-alkylimidazoles were prepared using Methods A, B, or C. 1-
Alkyl imidazoles 4.6b,d, 4.7e–g were prepared in 14–84% yields by the alkylation of the
corresponding imidazoles 4.1a–f with corresponding alkyl bromides in ACN in the presence of
potassium carbonate under reflux (Scheme 4-3, Method A) [93SC2611, 03BMC2863].
N
NH
R2
R3
R1Br N
NR1
R2
R3
4.1a (R2 = R3 = R4 = H)b (R2 = Me, R3 = NO2, R4 = H)c (R2 = R4 = H, R3 = NO2)d (R2 = Me, R3 = R4 = H)e (R2 = R4 = H, R3 = Me)f (R2 = R3 = Me, R4 = H)
2
4.6b,d,f,g
M ethod A or BN
N R2
R3
4.6'h-k
R1
R4 R4R4
4.7d-g
+
Regiomeric Mixture
Method A: K2CO3, Bu4NBr, acetonitrile, ref lux;Method B: KOBut, DMF, rt.4.6 see Table 4-14.7 see Table 4.2
Scheme 4-3. Method A and B for Preparation of 1-Alkylimidazoles
101
Table 4-1. Isolated N-Alkylimidazoles 4.6a–k Method
Imidazole R1 R2 R3 R4 A B C 4.6aa Me H H H 4.6b Pr H H H 14b 82b - 4.6ca n-Bu H H H 4.6d n-C6H13 H H H 44b 72b - 4.6ea Me Me H H 4.6f n-Bu Me H H - 87b - 4.6g n-C5H11 Me H H - 92b - 4.6h Pr H H Me - -c 70 4.6i n-C6H13 H H Me - -c 89 4.6j Pr Me H Me - -c 94 4.6k n-C6H13 Me H Me - -c 79
aCommercial Source, bIsolated Yield by D. Zhang, cMixture of Regioisomers by S. Singh
Table 4-2. Isolated N-Alkylimidazoles, with Energetic Groups, 4.7a–k Method
Imidazole R1 R2 R3 R4 A B C 4.7aa Me NO2 H H 4.7ba Et NO2 H H 4.7ca Et H NO2 H 4.7d i-Pr H NO2 H - 78b - 4.7e n-C6H13 H NO2 H 62b - - 4.7f n-Bu Me NO2 H 84b - - 4.7g n-C5H11 Me NO2 H 65b - - 4.7ha Me Me H NO2 4.7ia Me NO2 NO2 H 4.7ja Me H NO2 NO2 4.7ka Me H CN CN
aLit. [06NJC349] bIsolated Yield by Dhazi Zhang.
The alkylation of unsubstituted imidazoles by Method A gave unsatisfactory 14–44% yields.
The lower yields for imidazole derived 4.6a–d were probably caused by the low boiling points of
propyl and i-Pr bromides and the conditions were switched to potassium tert-butoxide in DMF at
rt (Scheme 4-3, Method B). Products 4.6b,d were obtained in yields of 72–82%. Also, Method
B was successfully employed for the preparation of 1-alkylimidazoles 4.6f,g (Table 4-1) and
4.7d (Table 4-2) in yields of 78–92%. However reactions of alkyl bromides with 4-
102
methylimidazole (4.1e) and 2,4-dimethylimidazole (4.1f) in DMF in the presence of potassium
tert-butoxide gave inseparable regiomeric mixtures of N-alkylated products 4.6′h–k.
Regiospecific N-alkylation of 4-methylimidazole with a urea protection was unsuccessful
(Scheme 4-4). The known reaction of 4.1e with phenyl isocyanate readily gives 4-methyl-1-
(phenylcarbamoyl)imidazole (4.8a) [83JHC1103]. Treatment of 4.8a with alkybromide at rt
gave no reaction, and at elevated temperatures dissociation of 4.8a to starting materials occurred
[83JHC1103] to give a regiomeric mixture of N-alkylated products.
N
NMe
NH
O Ph
R1 Brrt
No reaction
40-80 oC N
NMe
R1N
NMe R1
+NH
NMe
-PhNCO R1 Br
4.1eRegiomeric Mixture
4.8a
Scheme 4-4. Unsuccessful Regiospecific N-Alkylation
The regiospecific N-alkylation of 4.1e and 4.1f to 1-alkylimidazoles 4.6h–k was performed
successfully using Method C. The reaction sequence involved an initial benzoylation followed
by quaternization with alkyl triflates and base hydrolysis (Scheme 4-5, Method C)
[02EJOC2633]. The 1-Benzoyl-4-methyl-imidazole 4.9a (96%) and 1-benzoyl-2,4-dimethyl-
imidazole 4.9b (70%) were prepared from benzoyl chloride with a twofold excess of the
corresponding 4.1e,f in THF at rt [90S951]. n-Propyl, i-Pr, and n-hexyl triflates were prepared in
quantitative yields from the corresponding alcohols with trifluoromethane sulfonic anhydride and
pyridine in DCM and used directly after filtration and a short aq workup [75CB2947,
85JOC1872, 84S1039, 85S759, 96TL667]. Reaction of 4.9a,b with propyl and hexyl triflates in
toluene at rt for 48 h gave the corresponding quaternary salts 4.10a–d, which separated from the
103
bulk solvent as oils and were used as intermediates. The salts 4.10a–d hydrolyzed under
biphasic aq sodium hydroxide and diethyl ether conditions at rt to give 1-alkylimidazoles 4.6h–k
(70–94%). Quaternization reaction was not observed on treatment of 4.9a,b with i-Pr triflate
under the same reaction conditions and the corresponding starting imidazoles 4.1e,f were
recovered after base treatment. Concerted dehydration of isopropanol upon N-alkylation of 4-
methylimidazole has been reported [95CC9], which likely occurred with i-Pr triflate. Structures
of the compounds 4.6b,d,f–k, 4.7d–g, and 4.9a,b were supported by their 1H-NMR, 13C-NMR,
and elemental analysis or by reference to the literature.
N
NR2
R3 R1
Bz
TfO
NH
NR2
R3PhCOCl
N
NR2
R3
Bz
R1 OTf NaOH
N
NR2
R3 R1
4.6h-k4.9ab
watertoluene
4.1e (R3 = Me)f (R2, R3 = Me)
R1 OH(a)
(a) = Tf2O, PyridineDCM, rt, 15 min
4.10 a,b (R1 = n-Pr)c,d (R1 = n-Hex)
Scheme 4-5. Regiospecfic N-Alkylation of 1-Alkylimidazoles 4.6h–k
4.3 Conclusion
Alkylation of 4-alkyl and 2,4-dialkylimidazole with alkyl bromides provides a regiomeric
mixture of 1,4-disubstituted and 1,5-disubstituted imidazole. Protection of the N1 with benzoyl
allows regioselective N-alkylation of the 3-position, with triflate quaternization. Debenzoylation
and dequaternization with aq base afforded the more sterically hindered 1-alkylated imidazoles.
Substituted heterocycles continue to be a powerful tool in the search for energetic IL compounds.
4.4 Experimental Section
Melting points were determined on a capillary point apparatus equipped with a digital
thermometer. NMR spectra were obtained in CDCl3 with TMS as the internal standard for 1H
(300 MHz) and 13C (75 MHz). Chemicals were employed as supplied.
104
4.4.1 Preparation of N-Alkylimidazoles (Method A) 4.6b,d, 4.7e–g
Appropriate imidazole 4.1a–c (10 mmol) and alkyl bromide 2 (12 mmol) were mixed with
potassium carbonate (3.32 g, 24 mmol), and tetrabutylammonium bromide (0.032 g, 0.1 mmol)
in ACN (50 mL). The reaction mixture was stirred vigorously and heated under reflux for 2 h.
After cooling to rt, the precipitate was filtered off and washed with ACN. The filtrate was
evaporated, and the crude products were purified by column chromatography using ethyl acetate
and hexane.
4.4.2 Preparation of N-Alkylimidazoles (Method B) 4.6b,d,f,g, 4.7d
Appropriate imidazole 4.1a–f (50 mmol) was dissolved in DMF (10 mL). Potassium tert-
butoxide (6.7 g, 60 mmol) was added at 0–5 °C followed by the addition of appropriate alkyl
bromide 2 (72 mmol). The reaction mixture was stirred at rt overnight. Water (20 mL) was
added to the mixture. The solution was extracted with ethyl acetate (3 × 40 mL). The extract
was washed with brine and dried over anhyd magnesium sulfate. The solvent was evaporated
under reduced pressure (bath 60–70 °C, to remove DMF) and the residue was purified with
column chromatography using ethyl acetate and hexane to give the desired N-alkylimidazoles.
1-Propylimidazole (4.6b)lit.[73AJC2435]. (Method A = 14%) (Method B = 60%) Oil. 1H NMR δ 7.45 (s, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.89 (t, J = 7.1 Hz, 2H), 1.85−1.73 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR δ 136.8, 129.0, 118.5, 48.3, 24.1, 10.8.
1-Hexylimidazole (4.6d)lit.[02JHC287]. (Method A = 44%) (Method B = 72%) Oil. Anal. Calcd for C9H16N2: C, 71.01; H, 10.59; N, 18.40. Found: C, 69.96; H, 10.98; N, 18.39.
1-Butyl-2-methylimidazole (4.6f)lit.[02JHC287]. (Method B = 87%) Oil. Anal. Calcd for C8H14N2: C, 69.52; H, 10.21; N, 20.27. Found: C, 68.91; H, 10.62; N, 20.02.
1-Pentyl-2-methylimidazole (4.6g)lit.[02JHC287]. (Method B = 92%) Oil. Anal. Calcd for C9H16N2: C, 71.01; H, 10.59; N, 18.40. Found: C, 70.25; H, 11.09; N, 17.96.
1-Isopropyl-4-nitroimidazole (4.7d). (Method A = 78%) Plates (from ethyl acetate / hexane) mp 50−53 °C. 1H NMR δ 7.91 (d, J = 1.3 Hz, 1 H), 7.58 (d, J = 1.1 Hz, 1H), 4.56−4.47 (m, 1H), 1.59 (d, J = 6.7 Hz, 6H). 13C NMR δ 147.9, 134.3, 117.3, 50.9, 23.3. Anal. Calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found: C, 46.85; H, 5.82; N, 27.11.
105
1-Hexyl-4-nitroimidazole (4.7e). (Method A = 62%) Microcrystals (from ethyl acetate / hexane) mp 39−41 °C. 1H NMR δ 7.79 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 1.3 Hz, 1H), 4.04 (t, J = 7.1 Hz, 2H), 1.90−1.80 (m, 2H), 1.36−1.28 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR δ 147.9, 135.9, 119.1, 48.3, 30.9, 30.5, 25.8, 22.2, 13.7. Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C, 55.13; H, 7.93; N, 21.10.
1-Butyl-2-methyl-4-nitroimidazole (4.7f). (Method A = 84%) Microcrystals (from ethyl acetate / hexane) mp 58−60 °C. 1H NMR δ 7.71 (s, 1H), 3.94 (t, J = 7.3 Hz, 2H), 2.44 (s, 3H), 1.84−1.74 (m, 2H), 1.46−1.33 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR δ 146.2, 144.5, 119.5, 46.9, 32.1, 19.5, 13.4, 13.0. Anal. Calcd for C8H13N3O2: C, 52.45; H, 7.15; N, 22.94. Found: C, 52.80; H, 7.33; N, 22.87.
1-Pentyl-2-methyl-4-nitroimidazole (4.7g). (Method A = 65%) Microcrystals (from ethyl acetate / hexane) mp 35−37 °C. 1H NMR δ 7.70 (s, 1H), 3.92 (t, J = 7.4 Hz, 2H), 2.44 (s, 3H), 1.85−1.75 (m, 2H), 1.40−1.32 (m, 4H), 0.93 (t, J = 6.7 Hz, 3H). 13C NMR δ 146.3, 144.5, 119.5, 47.2, 29.9, 28.4, 22.1, 13.7, 13.1. Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N, 21.30. Found: C, 55.13; H, 7.90; N, 21.22.
4.4.3 Preparation of 1-Benzoyl-4-methyl- and 1-Benzoyl-2,4-dimethyl-imidazoles 4.9a,b
The appropriate imidazole 4.1e,f (8.21 g, 100.0 mmol), was dissolved in DCM (50 ml) and
cooled to 0 °C, with stirring. Benzoyl chloride (5.8 mL, 50.0 mmol) was added dropwise over 5
min and the reaction mixture warmed to rt over 1 h. The precipitate was filtered and the filtrate
was concentrated on the rotovap under reduced pressure. The solid residue was recrystallized
from hexanes to yield the 1-benzoylated imidazoles 4.9a,b
(4-Methyl-imidazol-1-yl)phenylmethanone (4.9a)lit.[13CB1913]. (64% yield) White needles (from hexanes) mp 69−70 °C. 1H NMR δ 2.22 (s, 3H), 6.80 (s, 1H), 7.35-7.45 (m, 3H), 8.00-8.05 (m, 3H). 13C NMR δ 9.9, 116.1, 127.8, 128.9, 129.8, 130.9, 132.4, 135.4, 173.1. Anal. Calcd for C11H10N2O1: C, 70.95; H, 5.41; N, 15.04. Found: C, 71.26; H, 5.68; N, 14.67.
(2,4-Dimethyl-imidazol-1-yl)phenylmethanone (4.9b). (96% yield) Yellow needles (from hexanes) mp 47−48 °C. 1H NMR δ 2.17 (d, J = 1.0 Hz, 3H), 2.68 (s, 3H), 6.76 (d, J = 1.0 Hz, 1H), 7.50-7.57 (m, 2H), 7.62-7.69 (m, 1H), 7.74-7.77 (m, 2H). 13C NMR δ 10.6, 12.1, 115.6, 127.8, 129.0, 129.7, 130.3, 137.6, 143.2, 173.9. Anal. Calcd for C12H12N2O1: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.80; H, 6.05; N, 13.41.
4.4.4 Preparation of N-Alkylimidazoles (Method C) 4.6h–k
Under a nitrogen atmosphere, the appropriate alkyl triflate (10.0 mmol) was added with a
syringe to the appropriate l-benzoylimidazole 4.9a,b (10.0 mmol) dissolved in toluene (100 mL).
106
After 48 h of stirring, 1-benzoyl-3-alkylimidazolium triflate 4.10a–d (solid quaternary salt for
4.10a, and dense liquid for 4.10b–d) was separated from the reaction mixture. The crude
quaternary salts were added to aq sodium hydroxide (20 mL, 7.5 M) and diethyl ether (20 mL)
and the mixture was stirred for 1 h. The layers were separated and the aq layer was further
extracted with DCM (2 x 30 mL). Organic layers were dried over anhyd magnesium sulfate,
filtered, and dried under reduced pressure. The crude material was purified by column
chromatography on silica gel with DCM and methanol to yield regiospecific 1-N-alkylimidazoles
4.6h–k.
5-Methyl-1-propylimidazole (4.6h)lit.[95CC9]. (70% yield) Clear oil. 1H NMR δ 0.87 (t, J = 7.6 Hz, 3H), 1.61-1.73 (m, 2H), 2.13 (s, 3H), 3.73 (t, J = 7.1 Hz, 2H), 6.69 (s, 1H), 7.33 (s, 1H). 13C NMR δ 7.4, 9.3, 22.4, 44.4, 124.9, 125.2, 135.1. Anal. Calcd for C7H12N2: C, 67.70; H, 9.74; N, 22.56. Found: C, 66.23; H, 10.17; N, 21.91.
1-Hexyl-5-methylimidazole (4.6i). (89% yield) Brown oil. 1H NMR δ 0.88 (t, J = 6.6 Hz, 3H), 1.22-1.38 (m, 6H), 1.63-1.76 (m, 2H), 2.18 (s, 3H), 3.80 (t, J = 7.3, 2H), 6.73 (s, 1H), 7.37 (s, 1H). 13C NMR δ 8.7, 13.4, 21.9, 25.7, 30.2, 30.7, 44.1, 126.1, 126.4, 136.1. Anal. Calcd for C10H18N2: C, 72.24; H, 10.91; N, 16.85. Found: C, 71.89; H, 11.42; N, 16.41.
2,5-Dimethyl-1-propylimidazole (4.6j)lit.[69NKZ704]. (94% yield) Blue oil. 1H NMR δ 0.94 (t, J = 7.4 Hz, 3H), 1.60-1.73 (m, 2H), 2.16 (s, 3H), 2.35 (s, 3H), 3.71 (t, J = 7.6 Hz, 2H), 6.61 (s, 1H). 13C NMR δ 7.7, 9.1, 11.2, 21.7, 43.1, 121.4, 125.3, 141.8. Anal. Calcd for C8H14N2: C, 69.52; H, 10.21; N, 20.27. Found: C, 69.10; H, 10.64; N, 19.65.
1-Hexyl-2,5-dimethylimidazole hydrate(4.6k). (79% yield) Green oil. 1H NMR δ 0.90 (t, J = 6.6 Hz, 3H), 1.25-1.38 (m, 6H), 1.59-1.66 (m, 2H), 2.18 (s, 3H), 2.38 (s, 3H), 3.75 (t, J = 7.7 Hz, 2H), 4.09 (br s, 2H), 6.61 (s, 1H). 13C NMR δ 8.8, 12.2, 13.0, 21.6, 25.5, 29.4, 30.5, 42.7, 122.4, 126.1, 142.8. Anal. Calcd for C11H22N2: C, 66.62; H, 11.18; N, 14.13. Found: C, 67.77; H, 10.84; N, 14.21.
107
CHAPTER 5 SYNTHESIS OF CYCLIC KETONE DERIVATIZED TETRASUBSTITUTED TRANS-
IMIDAZOLIDIN-2-ONES
5.1 Introduction
Nitrogen heterocycles containing a vicinal diamine moiety are considered biologically
privileged active structures [06MI101, 07OL2035, 07JA762]. Likewise, nitrogen heterocycles
containing the cyclic urea moiety incorporated as part of the core are found in a broad array of
biologically active molecules [94EP612741, 96MI301, 96JME3514, 02BBA02, 06OL2531] and
provide increased structural rigidity as well as hydrogen bonding possibilities [95TL6647,
98TL1477]. The presences of these two potentially bioactive properties encourages the
exploration of vicinal diamino tethered ureas and unsaturated imidazol-2-ones, or saturated
imidazolidin-2-ones (Figure 5-1), in particular for medicinal screening.
NN
OR2 R1
R3
Imidazol-2-oneR4
NN
OR2 R1
R4 R5R6R3
Imidazolidin-2-one
Figure 5-1. Vicinal Diamino Tethered Ureas
Planar imidazol-2-ones, exhibit a diverse portfolio of biological activities [66JME858,
95MI115, 98LS297, 99BMC749, 99JME2706, 00TL6387, 00WOP0078750, 02BMC653,
04SL2167, 05SL1322]. Our main focus on imidazolidin-2-one, with a potential for complex
diastereomers, provides an opportunity to study the stereospecific synthesis of a heterocyclic
scaffold of high interest in medicinal chemistry. Imidazolidin-2-one is a key functional unit in
molecules (Figure 5-2) for (i) selective androgen receptor modulators (SARMs) [07JME3015],
(ii) cholinergic agonists [91JME2314], (iii) central nervous system (CNS) depressants
[66JME852], (iv) selective agonism of β3 adrenergic receptors [99BMC755], (v) HIV-1 protease
108
inhibitors [04BMC5685], (vi) matrix metalloproteinase (MMP) inhibitors [01BMC1211], (vii)
farnesyl transferase inhibitors [98USP5780492], and (viii) biotin, a natural occurring molecule of
biological and commercial importance for more than fifty years [07S1159]. The development of
a general and efficient method, which enables the introduction of a variety of substituents into
the 4- and 5-position of imidazolidin-2-ones stereospecifically and in good yields, would be
highly desirable for the generation of combinatorial libraries [99JCC195, 02TL4571, 03OL511].
NN
O
Ph
Ph
OHNS
O
O
MeO
(v) HIV-1 protease inhibitorDu Pont Merck; WO9709150
(vii) Farnesyl transferase inhibitor;Merck & Co.; WO9736892
NN
O
Cl
N
N
CN
NN
O
OHHEt
MeCl
NC
NN
O
Me
SNH
O O
HN
N
HO
(i) SARM (modulator)
(iv) β3 Adrenergic Receptor Agonist
NN
Me
(ii) Cholinergic Agonist (iii) CNS Deppresant
NN
O
NNO
Me ClNMe2
NHN
O
NH
(vi) MMP-13 inhibitor
O
F
OOH
NHHN
S
O
HH
CO2H
(viii) D-(+)-Biotin
Figure 5-2. Bioactive Imidazolidin-2-ones
109
Vicinal diamine and urea formation in one simultaneous step to form imidazolidin-2-one
(Scheme 5-1), was reported in the literature. The C–C bond and urea formation, (i) bonds a and
b, were achieved by coupling of a lithiatied α-nitrogen methylene to imines and intramolecular
cyclization to the Boc-protecting group [96JA3757, 96JOC428, 01JOC2858, 02EJOC301]. The
urea and C–N bond formation, (ii) bonds c and d, were achieved by (ii-a) ring opening of N-
arylsulfonylaziridines with isocyanates in the presence iodide ions [93T7787, 05TL479]; or (ii-b)
dehydration of allyl carbamate with modified conditions (PPh3, CBr4, Et3N) provided allyl
cyanate-to-isocyanate rearrangement with subsequent intramolecular cyclization [06OL5737].
The urea and C–N bond formation, (iii) bonds c, b, and d, were achieved by Hoffman
rearrangement [68BCJ2748, 89JME289]. Two step methods for imidazolidin-2-ones involve
either formation of vicinal diamine [98AGE2580, 05OL1641] or cyclic urea [95JME923,
96TL5309, 00AJC73, 03SL1635, 04OL2397, 04SL489, 05T9281] and a cyclization step.
(iii)c,b,d
(ii-a)c,d(ii-b)c,d
a
b
5.1
c
(i)a,bNN
OR2 R1
R4 R5HR3 NR2
R3+ N R1Boc
R5
Base
R1 = Ar, R5 =Ph orR1 = (CH2)3 = R5 orR1 = Alk, Bzl, R5 = BtR2 = R3 = Ar, HetAr
d
NCOR2
N R1
R4 R5HR3
NaI
R5
HN
O
R1
O
H2N
PPh3, CBr4Et3N, DCM
R5
HN
O
R1
O
H2N
R1 = SO2Ar, R5 = Alk, ArR3 or R4 = H, Alk, Ar,R6 = Ar or t-bu
R1 = Cbz, R5 = MeR2 = R4 = H, R3 = allyl
R1 = Cbz, R5 = CO2HR2 = R3 = R4 = H
NaOCl
Scheme 5-1. Multiple Bond Formation in One Step for Imidazolidin-2-one
The N-Boc-N-(benzotriazol-1-ylmethyl) benzylamine was demonstrated by the Katritzky
group (Scheme 5-2) [01JOC2858], to act as a 1,1-dipole equivalent in the stereoselective
110
synthesis of 1,3,4,5-tetrasubstituted trans-imidazolidin-2-ones. The transition states for the
formation of 4,5-disubstittued 1,3-imidazolidin-2-ones by the reaction of α-nitrogen carbanion
with imines were described by Kise et al. [96JOC428], and generally extended to our
benzotriazole method. The formation of dipole-stabilized carbanions adjacent to nitrogen atoms
[84CRV471, 96JOC428, 96JA3757] is further directed chemoselectively to lithiate at the carbon
adjacent to the benzotriazole residue [05AGE5867] and in the presence of an imine a highly
trans vicinal diamine is formed. Urea formation is spontaneous in most cases.
NBoc
Bt
Ph
NCH
BocPh
(i) s-BuLi
N
Bt
Ph
O
Ot-Bu
Li
NN
OR2
H BtHR3
Ph
NBtPh
O
Ot-Bu
Li
R3
N
R2
NBtPh
O
Ot-Bu
LiN
R3
Trans-Favored
+ R3CH=NR2
R2
Scheme 5-2. The N-Boc-N-(benzotriazol-1-ylmethyl) Benzylamine, 1,1-Dipole Synthon in the Stereoselective Synthesis of 1,3,4,5-Tetrasubstituted trans-Imidazolidin-2-ones
5.2 Results and Discussion
We now report the extension of the previous work on Bt-intermediates to form novel tetra-
substituted trans-imidazolidin-2-ones, with a synthetic protocol (Scheme 5-3). The efficient
protocol, section 5.2.1, for imines was based on the reaction of aldehydes to anilines with the
loss of a water molecule. The protocols; section 5.2.2 for Bt-intermediates, section 5.2.3 for the
convergent production of trans-Bt-imidazolidin-2-ones; and section 5.2.4 for trans-imidazolidin-
2-ones cyclic ketones were based on the published literature method [01JOC2858].
111
5.2
NN
OR2
H BtHR3
NR2
R3+ NBoc
Bt
NH2R2
+ O
R3 H2N[5.2.1] [5.2.2]
[5.2.3]
[5.2.4]
H H
NN
OR2
HHR3
O
5.3
5.4
5.5
R1R1
R1 R1
Scheme 5-3. Synthetic Overview of Protocols
5.2.1 Imines
An efficient method for the preparation of imines was required for the convergent synthesis.
The known method gave imines from the reaction of amines with aldehydes with simultaneous
condensation of a water molecule [89MI769]. Quantitative yields were obtained from the
reactions of aldehydes with aniline (Scheme 5-4), or 4-substituted anilines using a Dean-Stark
apparatus to affect the azeotropic removal of water. The structures of the known imines 5.2a
[05T11148], 5.2b [06OL3175], 5.2c [72JA9113], and 5.2d [05JOC5665] were supported by 1H-
NMR, 13C-NMR, and elemental analysis.
Tolueneref lux
5.2a R1 = Cl, R2 = H5.2b R1 = Me, R2 = H5.2c R1 = Me, R2 = F5.2d R1 = H, R2 = OMe
CHO
R1
NR1
R2
H2N R2+Dean-Stark
Scheme 5-4. Imine Formation, From Aldehydes and Anilines
112
5.2.2 The 1,1-Dipole Equivalents (Bt-Intermediates)
Two efficient protocols were used (Scheme 5-5) for the preparation of Bt-intermediates. The
two-step procedure involved the protection of an amine followed by a coupling causing the
condensation of a water molecule. Furfurylamine was protected with Boc-anhydride to afford N-
Boc-furfurylamine. The N-Boc-furfurylamine was treated with paraformaldehyde, 1H-
benzotriazole, and catalytic p-toluene sulfonic acid (PTSA) to affect the azeotropic remove water,
collected with a Dean–Stark apparatus. The novel benzotriazol-1-ylmethyl furan-2-ylmethyl
tert-butyl carbamate 5.3a (72%) was obtained and supported by 1H-NMR, 13C-NMR, and
elemental analysis.
H2N NBoc
Bt
PTSA
O O
5.3a
1) (Boc)2O, Et3N
2) BtH, (CH2O)n
Dean-Stark 72%
R1H2N
R1N
Boc
Bt 5.3b R1 = Bzl, 70%5.3c R1 = Prn, 71%
PTSA
1) (Boc)2O, Et3N
2) BtCH2OH
Dean-Stark
Scheme 5-5. Benzotriazole Intermediate Formation, Two Methods
Residual paraformaldehyde was tedious to remove from the desired product, even with
column chromatography, and (benzotriazol-1-yl)methanol (BtCH2OH) in place of 1H-
benzotriazole and paraformaldehyde avoided this drawback. Benzylamine and propylamine
were protected with Boc-anhydride to afford N-Boc-benzylamine and N-Boc-propylamine,
respectively. The N-Boc-protected amines were reacted with BtCH2OH and catalytic PTSA to
affect the azeotropic remove water, collected with a Dean–Stark apparatus. The known
113
benzotriazol-1-ylmethyl benzyl tert-butyl carbamate 5.3b (70%) was obtained without the need
for purification. Similarly the novel benzotriazol-1-ylmethyl propyl tert-butyl carbamate 5.3c
(71%) was obtained and was supported by 1H-NMR, 13C-NMR, and elemental analysis.
5.2.3 Convergent Synthesis of Bt trans-Imidazolidin-2-ones
Reproduction of the literature procedure gave undesired products. Treatment of 5.3b, with (i)
s-BuLi in THF at –78 °C for 0.5 h, followed by the addition of imine 5.2a as electrophile,
disappointingly resulted in the isolation of a non-polar diastereomeric oil 5.4a, and recovery of
starting material by column chromatography (Scheme 5-6). Returning to the original imine 5.2d
from the literature, with the literature conditions (ii), resulted again in a non-polar oil. The
column purification results were quantified as recovered starting material (50%), non-polar
diastereomeric oil 5.4b (39%), and uncyclized vicinal diamine 5.4c (11%). Uncyclized vicinal
diamine 5.4c, was detected probably due to quenching at –78 °C. Novel 5.4a and 5.4b
[72BSC3426] were supported by 1H-NMR, 13C-NMR, and elemental analysis. Compound 5.4c
was confirmed by elemental analysis.
5.3b in THFs-BuLi, 1.0 eq
Quenched at-78 oC
4 h at -78 oC1 portion0.5 h then 5.2a
5.2a, 1.0 eqin THF
2)
1)Ph NH
unreacted5.3bby TLC.
5.4a, 31%+
Cl
NH
Ph
MeO5.4b, 39%
recovered5.3b, 50%
NH
Ph
N
Bt
MeOPh
5.4c, Uncyclized, 11%
+
+Boc
5.3b in THFs-BuLi, 1.0 eq
Quenched at-78 oC
4 h at -78 oC1 portion0.5 h then 5.2d
5.2d, 1.0 eqin THF
2)
1)
(i)
(ii)
Scheme 5-6. Convergent Syntheses, Using the Reported Literature Conditions
114
Optimization of the reaction conditions (Scheme 5-7) by addition of s-BuLi in three portions,
each potion added after 1 h, and an additional 3 h at –78 °C, lithiated 5.3b. The imine 5.2d was
added to the lithiated 5.3b and overnight the reaction warmed to rt. Column purification gave
the Bt trans-imidazolidin-2-one 5.4d (28%), reproduced from the literature. The known
structure of 5.4d was supported by 1H-NMR and 13C-NMR.
N
Ph
N
O
Bt
MeO
Ph-78-21 oC 5.4d
Trans 28%
3 portions / 2 h+3 h then 5.2d
5.3b in THFs-BuLi, 1.1 eq
5.2d, 1.1 eqin THF
2)
1)
Overnight
Scheme 5-7. Optimized Convergent Conditions, Using Literature Reagents
N N
O
Bt
PhPh
Me
5.4eTrans 24%
N N
O
Bt
Ph
Me
F5.4f
Trans 23%
-78-21 oC5.3b
5.2b2)
1)
OptimizedConditions
s-BuLi
-78-21 oC5.3b
5.2c2)
1)
OptimizedConditions
s-BuLi
Scheme 5-8. Convergent Synthesis of N-Benzylated trans-Bt-Imidazolidin-2-ones 5.4e,f
Although low yields were occurring, the yields were sufficient to make three novel Bt trans-
imidazolidin-2-one examples. Two N-benzyl derivatives and one N-propyl derivative were
successfully converted to novel trans-Bt-imidazolidin-2-ones by this method (Scheme 5-8). The
optimized convergent conditions were used for the lithiation of 5.3b, followed by addition of
115
5.2b, or 5.2c, to give 5.4e (24%), or 5.4f (23%), respectively. Similarly the optimized
convergent conditions were used for the lithiation of 5.3c, followed by addition of 5.2b, to give
5.4g (24%) (Scheme 5-9). The novel 5.4e–g were supported by 1H-NMR, 13C-NMR, and
elemental analysis.
Ph N N
O
Bt 5.4g
Me
Trans 24%
-78-21 oC5.3c
5.2b2)
1)
OptimizedConditions
s-BuLi
Scheme 5-9. Convergent Synthesis of N-Alkylated trans-Bt-Imidazolidin-2-ones with 5.4g
5.2.4 Lewis Acid Mediated Synthesis of Cyclic Ketone Derivatized Tetrasubstituted trans-Imidazolidin-2-ones
The reproduction of the final literature step (Scheme 5-10) gave the desired cyclohexanone
tetrasubstituted trans-imidazolidin-2-one 5.5a. The Bt trans-imidazolidin-2-one 5.4d was
treated with Lewis acid and cyclohexenyloxytrimethylsilane to smoothly produce 5.5a (70%).
The reproduction of the literature protocol established a viable method to further develop a
general method, which enables the introduction of a variety of substituents into the 4- and 5-
position of imidazolidin-2-ones stereospecifically.
OMe3Si
5.5a
N
Ph
N
OBzl
MeO
O
BF3Et2O
70%5.4d +
Scheme 5-10. Lewis Acid Mediated Synthesis of Reported Cyclohexanone Analog 5.5a
The Lewis acid method was extended to generate two novel cyclohexanone trans-
imidazolidin-2-ones (Scheme 5-11). The trans-Bt-imidazolidin-2-ones 5.4f and 5.4g were
treated with Lewis acid and cyclohexenyloxytrimethylsilane to give 5.5b (57%) and 5.5c (70%),
116
respectively. The two novel cyclohexanone trans-imidazolidin-2-ones were sent to Sanofi-
Aventis for their general use.
OMe3SiBF3Et2O
N N
OBzlPh
Me
O5.5b
70%5.4g
N N
OBzl
Me
F
O5.5c
57%5.4f +
OMe3SiBF3Et2O+
Scheme 5-11. Lewis Acid Mediated Synthesis of Two Cyclohexanone Analogs 5.5b,c
The Lewis acid method was extended to generate two novel cyclopentanone trans-
imidazolidin-2-ones (Scheme 5-12). The Bt trans-imidazolidin-2-ones 5.4f and 5.4g were
treated with Lewis acid and cyclopentenyloxytrimethylsilane to give 5.5d (86%) and 5.5e (47%),
respectively. The two novel cyclopentanone trans-imidazolidin-2-ones were sent to Sanofi-
Aventis for their general use.
86%5.4e N N
O PhPh
Me
O5.5d
47%5.4c
N N
O Ph
Me
F
O5.5e
BF3Et2OO
Me3Si
+
+O
Me3Si
BF3Et2O
Scheme 5-12. Lewis Acid Mediated Synthesis of Two Cyclopentanone Analogs 5.5c,e
117
5.3 Conclusion
The general protocol enabled the introduction of a variety of substituents into the 4- and 5-
position of imidazolidin-2-ones stereospecifically. The low yielding convergent step using s-
BuLi, was a set back for the efficiency this method. General versatility and applicability to a
robust combinatorial library was hampered and requires additional optimization of the
convergent step. Three novel Bt trans-imidazolidin-2-ones were isolated and characterized.
Two of the novel Bt trans-imidazoidin-2-ones were used to successful synthesize four novel
cyclic ketone derivatized tetrasubstituted trans-imidazolidin-2-ones.
5.4 Experimental Section
Melting points were determined on a capillary point apparatus equipped with a digital
thermometer. The NMR spectra were obtained in CDCl3 with TMS as the internal standard for
1H (300 MHz) or the solvent as the internal standard for 13C (75 MHz). Tetrahydrofuran was
freshly distilled from benzophenone and sodium metal prior to use. Dichloromethane was
freshly distilled from sodium metal prior to use. Chemicals were employed as supplied.
5.4.1 Preparation of Imines
Imines 5.2a–d were prepared from their corresponding aniline and aldehyde. Anilines (25
mmol) and aldehydes (25 mmol) were mixed together in toluene (125mL) and heated to reflux.
The azeotropic removal of water was performed using a Dean-Stark apparatus. Toluene was
removed under vacuum. The crude was dissolved in hexane, filtered, and concentrated to obtain
the pure imines.
N-(4-Chlorobenzylidene)aniline (5.2a). (99% yield) White microcrystals (from ethyl acetate / hexanes) mp 61–62 °C (mp 60–61 °C)lit.[05T11148]. 1H NMR δ 7.17 (br s, 3H), 7.30–7.45 (m, 4H), 7.77 (d, J = 7.0 Hz, 2H), 8.33 (s, 1H). 13C NMR δ 120.8, 126.1, 128.9, 129.1, 129.9, 134.6, 137.2, 151.5, 158.7. Anal. Calcd. for C13H10ClN: C, 72.40; H, 4.67; N, 6.49. Found: C, 72.13; H, 4.55; N, 6.39.
118
N-(4-Methylbenzylidene)-aniline (5.2b). (92% yield) Yellow needles (from hexanes) mp 42–43 °C (mp 42–43 °C)lit.[06OL3175]. 1H NMR δ 2.34 (s, 3H), 7.07–7.20 (m, 5H), 7.27–7.32 (m, 2H), 7.71 (d, J = 7.7 Hz, 2H), 8.33 (s, 1H). 13C NMR δ 21.6, 120.8, 125.7, 128.8, 129.1, 129.5, 133.6, 141.8, 152.2, 160.4. Anal. Calcd. for C14H13N: C, 86.11; H, 6.71; N, 7.17. Found: C, 86.69; H, 6.82; N, 7.04.
N-(4-Fluorophenyl)-(4-methylbenzylidene)-amine (5.2c). (98% yield) Orange needles (from hexanes) mp 67–68 °C (mp 67–68 °C)lit.[72JA9113]. 1H NMR 2.40 (s, 3H), 7.04 (t, J = 8.4 Hz, 2H), 7.14–7.18 (m, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 8.36 (s, 1H). 13C NMR δ 21.6, 115.8 (d, JCF = 22.3 Hz), 122.2 (d, JCF = 8.0 Hz), 128.7, 129.5, 133.4, 141.9, 148.1, 160.1, 161.0 (d, JCF = 244.5 Hz). Anal. Calcd. for C14H12FN: C, 78.85; H, 5.67; N, 6.57. Found: C, 78.68; H, 5.85; N, 6.30.
N-Benzylidene-4-methoxybenzenamine (5.2d). (99% yield) White plates (from hexanes) mp 68–70 °C (mp 68–70 °C)lit.[05JOC5665]. 1H NMR δ 3.75 (s, 3H), 6.88 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.39–7.40 (m, 3H), 7.83–7.84 (m, 2H), 8.41 (s, 1H). 13C NMR δ 55.3, 114.2, 112.1, 128.5, 128.6, 130.9, 136.2, 144.6, 158.2, 158.3. Anal. Calcd. for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.24; H, 6.23; N, 6.55.
5.4.2 Preparation of Bt-Intermediates
The Boc-protection: Triethylamine (150 mmol) was added to a solution of amine (150
mmol) in DCM (400 mL) at 0 °C. The Boc-anhydride (150 mmol) was dissolved in a separate
portion of DCM (150 mL) and added to the reaction mixture using an addition funnel over 20
min. The solution was keep at 0 °C for 1 h and warmed overnight. If necessary column
chromatography purification (SiO2, hexane = 100%) could be executed, to yield the pure
intermediates
The Bt-intermediates using paraformaldehyde (Method 1): The tert-Butylfuran-2-
ylmethylcarbamate (25.46 g, 129.1 mmol), 1H-benzotriazole (15.38 g, 129.1 mmol),
paraformaldehyde (3.87 g, 129.1 mmol), and p-toluenesulfonic acid monohydrate (0.61 g, 3.2
mmol) were mixed together in toluene (750 mL). The reaction mixture was heated under reflux,
equipped with a Dean-Stark apparatus for 5h. Column chromatography (SiO2, hexane:DCM =
1:1) was performed to yield benzotriazol-1-ylmethyl furan-2-ylmethyl tert-butyl carbamate (30.6
g, 93.2 mmol) 72% yield.
119
The Bt-intermediates using BtCH2OH (Method 2): The crude N-Boc amines (100 mmol),
and BtCH2OH (100 mmol) were mixed together in toluene (500 mL) and heated to 115 °C, or
fully dissolved, and removed from the heat source. At this point, p-toluenesulfonic acid
monohydrate (~480 mg), was quickly added. Directly afterwards the formation of water was
seen in the reaction flask and azeotropic removal of water was performed with a Dean-Stark
apparatus over 3h. The crude material was heated in diethyl ether and filtered. The solvent was
evacuated to yield pure Bt-intermediates.
Benzotriazol-1-ylmethyl furan-2-ylmethyl tert-butyl carbamate (5.3a). (Amide Tautomers) (Method 1, 72% yield) White prisms (from DCM), mp 80–82 °C. 1H NMR δ 1.50–1.61 (m, 9H), 4.40–4.50 (m, 2H), 6.10–6.16 (m, 2H), 6.21 (s, 1H), 6.27 (s, 1H), 7.29 (s, 1H), 7.34–7.40 (m, 1H), 7.46–7.51 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H). 13C NMR δ 28.1, 42.1, 57.6, 81.6, 108.4, 110.2, 110.9, 119.6, 124.2, 127.7, 132.4, 142.3, 146.2, 150.3, 154.8. Anal. Calcd. for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06. Found: C, 62.47; H, 6.20; N, 16.96.
Benzotriazol-1-ylmethyl benzyl tert-butyl carbamate (5.3b). (Amide Tautomers) (Method 2, 70% yield) White plates (from hexanes) mp 126–127 °C (mp 126–127 °C)lit.[01JOC2858].
Benzotriazol-1-ylmethyl propyl tert-butyl carbamate (5.3c). (Amide Tautomers) (Method 2, 71% yield) White needles (from diethyl ether) mp 98–101 °C. 1H NMR δ 0.82 (t, J = 7.0 Hz, 3H), 1.35–1.60 (m, 11H), 3.21 (t, J = 7.0 Hz, 2H), 6.13 (s, 2H), 7.35–7.40 (m, 1H), 7.46–7.51 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H). 13C NMR δ 11.0, 21.3, 28.1, 47.6, 58.5, 80.9, 111.1, 119.5, 124.1, 127.6, 132.3, 146.2, 155.4. Anal. Calcd. for C15H22N4O2: C, 62.05; H, 7.64; N, 19.30. Found: C, 61.87; H, 7.81; N, 19.54.
5.4.3 Preparation of Bt-Imidazolidin-2-ones
Compound 3.3b (2.0 g, 5.9 mmol) was dissolved in THF (40 mL), in a dry schlenk flask
under nitrogen and cooled to –78 °C. s-Butyllithium (1.4 M, 4.8 mL) was added slowly in 1.6
mL in 3 portions over 3 h. Lithiation, at –78 °C, was allowed for a further 3 h. A solution of
imine (6.6 mmol) in THF (10mL) was slowly added. The reaction was left to warm overnight
and stirred at rt. Quenched with saturated aq ammonium chloride, and extracted with 2 portions
of ethyl acetate. The combined organic layers were washed using brine, dried over anhyd
120
sodium sulfate. Column chromatography purification (SiO2, hexane:ethyl acetate = 9:1) afforded
the desired products
[1-(4-Chlorophenyl)-2-methylbutyl]phenylamine (5.4a). (Mixture of Diastereomers) (31% yield) Brown oil. 1H NMR δ 0.74-0.85 (m, 6H), 1.02–1.17 (m, 1H), 1.34–1.50 (m, 1H), 1.60–1.70 (m, 1H), 3.95 (br s, 1H), 4.07 (d, J = 5.6 Hz, 0.61H), 4.17 (d, J = 4.9 Hz, 0.39H), 6.35 (d, J = 7.7 Hz, 2H), 6.52 (t, J = 7.0 Hz, 1H), 6.93–6.99 (m, 2H), 7.09–7.16 (m, 4H). 13C NMR δ 11.7, 11.9, 14.2, 15.9, 25.2, 26.7, 41.4, 41.7, 60.9, 61.9, 113.1, 117.2, 128.3, 128.4, 128.6, 129.0, 132.2, 132.3, 140.8, 141.5, 147.3. Anal. Calcd. for C17H20ClN: C, 74.57; H, 7.36; N, 5.12. Found: C, 74.77; H, 7.51; N, 5.11.
N-(4-Methoxyphenyl)-1-phenyl-2-methyl-1-aminobutane (5.4b)lit.[72BSC3426]. (Mixture of Diastereomers) (39% yield) Brown oil. 1H NMR δ 0.73–0.84 (m, 6H), 1.00–1.17 (m, 1H), 1.34–1.50 (m, 1H), 1.62–1.68 (m, 1H), 3.52 (s, 3H), 3.65 (br s, 1H), 4.01 (d, J = 5.6 Hz, 0.43H), 4.11 (d, J = 4.9 Hz, 0.57H), 6.32 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 9.1 Hz, 2H), 7.02–7.10 (m, 1H), 7.12–7.17 (m, 4H). 13C NMR δ 11.7, 11.9, 14.3, 15.9, 25.3, 26.7, 41.4, 41.8, 55.5, 62.2, 63.3, 114.1, 114.2, 114.6, 126.4, 126.6, 126.9, 127.3, 127.9, 128.1, 141.9, 142.4, 143.1, 151.5. Anal. Calcd. for C18H23NO: C, 80.25; H, 8.61; N, 5.20. Found: C, 79.95; H, 8.93; N, 5.00.
2-Phenyl-2-(4-methoxyphenylamino)-1-benzotriazol-1-yl-ethyl benzyl tert-butyl carbamate (5.4c). (11% yield) Clear oil. Anal. Calcd. for C33H35N5O3: C, 72.11; H, 6.42; N, 12.74. Found: C, 72.11; H, 6.53; N, 12.62.
(4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-(4-methoxyphenyl)-5-phenylimidazolidin-2-one (5.4d). (28% yield) White needles (from hexanes) mp 155–156 °C (mp 155–156 °C)lit.[01JOC2858]. 1H NMR δ 3.70 (s, 3H), 3.84 (d, J = 15.4 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 5.31 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 9.1 Hz, 2H), 7.07–7.19 (m, 7H), 7.24-7.33 (m, 3H), 7.34–7.42 (m, 5H), 8.07 (d, J = 8.4 Hz, 1H). 13C NMR δ 45.4, 55.3, 64.5, 75.4, 109.6, 114.2, 120.4, 122.4, 124.6, 125.9, 127.7, 128.1, 128.5, 129.0, 129.4, 130.5, 130.7, 134.9, 137.5, 146.8, 156.2, 156.4. Anal. Calcd. for C29H25N5O2: C, 73.25; H, 5.30; N, 14.73. Found: C, 73.12; H, 5.53; N, 14.88.
(4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-phenyl-5-p-tolylimidazolidin-2-one (5.4e). (24% yield) White microcrystals (from hexanes), mp 72–73 °C. 1H NMR δ 2.30 (s, 3H), 3.84 (d, J = 15.5 Hz, 1H), 4.85 (d, J = 15.4 Hz, 1H), 5.32 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 7.02–7.15 (m, 9H), 7.25–7.42 (m, 6H), 7.55 (d, J = 7.7 Hz, 2H), 8.05–8.08 (m, 1H). 13C NMR δ 21.1, 45.4, 63.7, 75.7, 109.6, 119.7, 120.5, 123.9, 124.6, 125.7, 127.8. 128.2, 128.5, 129.1, 130.2, 134.6, 135.1, 137.9, 139.0, 146.9, 155.9, 157.7. Anal. Calcd. for C29H25N5O: C, 75.79; H, 5.48; N, 15.24. Found: C, 74.62; H, 5.90; N, 14.22.
(4S,5S)-4-(Benzotriazol-1-yl)-3-benzyl-1-(4-fluorophenyl)-5-p-tolylimidazolidin-2-one (5.4f). (23% yield) White microcrystals (from hexanes), mp 72–73 °C. 1H NMR δ 2.31 (s, 3H), 3.83 (d, J = 15.4 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 5.27 (d, J = 2.8 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 6.96 (t, J = 9.1 Hz, 2H), 7.03–7.17 (m, 9H), 7.29–7.50 (m, 5H), 8.08 (d, J = 7.7 Hz, 1H). 13C NMR δ 21.1, 45.4, 64.1, 75.4, 109.4, 115.8 (d, JCF = 22.3 Hz), 120.6, 121.8 (d, JCF = 8.0 Hz),
121
124.6, 125.7, 127.9, 128.2, 128.5, 130.2, 134.3, 134.9, 139.2, 146.9, 156.0, 159.2 (d, JCF = 243.9 Hz). Anal. Calcd. for C29H24FN5O: C, 72.94; H, 5.07; N, 14.67. Found: C, 72.62; H, 5.19; N, 14.38.
(4S,5S)-4-(Benzotriazol-1-yl)-1-phenyl-3-propyl-5-p-tolylimidazolidin-2-one (5.4g). (24% yield) White microcrystals (from hexanes), mp 115–117 °C. 1H NMR δ 0.81 (t, J = 7.0 Hz, 3H), 1.34–1.50 (m, 2H), 2.34 (s, 3H), 2.65–2.74 (m, 1H), 3.52–3.62 (m, 1H), 5.30 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 7.02 (t, J = 7.0 Hz, 1H), 7.15–7.27 (m, 6H), 7.38–7.46 (m, 3H), 7.54 (d, J = 7.7 Hz, 2H), 8.12 ( d, J = 7.7 Hz, 1H). 13C NMR δ 10.9, 20.6, 21.1, 42.7, 63.6, 76.4, 109.7, 119.2, 120.6, 123.6, 124.7, 125.5, 128.8, 129.0, 130.3, 130.5, 134.7, 137.9, 139.0, 147.1, 156.1. Anal. Calcd. for C25H25N5O: C, 72.97; H, 6.12; N, 17.02. Found: C, 72.37; H, 6.71; N, 16.37.
5.4.4 Preparation of Cyclic Ketone Tetrasubstituted trans-Imidazolidin-2-ones
A solution of Bt trans-imidazolidin-2-one (0.5 mmol) in DCM (10 mL) was prepared under
nitrogen and cooled to –78 °C. Lewis acid (BF3Et2O, 2.5 mmol) was added and the solution was
stirred for 30 min. Cyclohexenyloxytrimethylsilane (2.5 mmol) was added and stirred overnight.
A precipitate appeared in the final reaction mixture. Quenched with saturated aq ammonium
chloride and extracted with two portions of ethyl acetate. Combined organic layers were washed
with brine, dried over anhyd sodium sulfate. Column chromatography Si-Gel (hexane:ethyl
acetate = 9:1) eluted the desired products.
(4S,5S)-1-Benzyl-3-(4-methoxyphenyl)-5-(2-oxocyclohexyl)-4-phenylimidazolidin-2-one hydrate (5.5a)lit.[01JOC2858]. (70% yield) Clear oil. 1H NMR δ 1.21–1.60 (m, 2H), 1.83–1.97 (m, 2H), 2.02–2.14 (m, 2H), 2.30–2.35 (m, 1H), 2.52–2.56 (m, 1H), 3.66 (s, 3H), 3.92 (t, J = 2.8 Hz, 1H), 4.26 (d, J = 14.7 Hz, 1H), 4.61 (d, J = 3.5 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 6.73 (d, J = 9.1 Hz, 2H), 7.18–7.35 (m, 2H). 13C NMR δ 24.7, 26.4, 27.5, 42.0, 47.5, 54.3, 55.2, 60.2, 63.7, 113.9, 121.8, 126.0, 127.2, 127.9, 128.2, 128.7, 128.8, 132.6, 137.7, 140.8, 155.5, 158.4, 210.2. Anal. Calcd. for C29H32N2O4: C, 73.70; H, 6.82; N, 5.93. Found: C, 72.81; H, 6.44; N, 5.93.
(4S,5S)-1-Benzyl-5-(2-oxocyclohexyl)-3-phenyl-4-p-tolylimidazolidin-2-one (5.5b). (Conformational Isomers) (57% yield) White microcrystals (from hexanes), mp 78–79 °C. 1H NMR δ 1.36–1.63 (m, 4H), 1.87–2.38 (m, 7H), 2.42–2.57 (m, 1H), 3.84–3.92 (m, 1H), 4.21–4.27 (m, 1H), 4.63–4.73 (m, 2H), 6.92–7.34 (m, 12H), 7.41–7.47 (m, 2H). 13C NMR δ 21.1, 24.8, 26.6, 27.7, 42.1, 47.7, 54.8, 60.3, 63.2, 118.2, 119.2, 122.2, 122.7, 125.8, 125.9, 127.3, 128.0, 128.3, 128.5, 128.6, 128.7, 128.8, 128.4, 129.6, 137.6, 137.7, 139.6, 158.1, 210.4. Anal. Calcd. for C29H30N2O2: C, 79.42; H, 6.89; N, 6.39. Found: C, 79.13; H, 6.98; N, 6.53.
(4S,5S)-1-Benzyl-3-(4-fluorophenyl)-5-(2-oxocyclohexyl)-4-p-tolylimidazolidin-2-one (5.5c). (Conformational Isomers) (70% yield) White microcrystals (from hexanes), mp 84–86 °C. 1H NMR δ 1.38–1.67 (m, 4H), 1.90–2.40 (m, 7H), 2.40–2.60 (m, 1H), 3.94 (br s, 1H), 4.33 (d, J =
122
15.4 Hz, 1H), 4.65 (d, J = 3.5 Hz, 1H), 4.70 (d, J = 15.4 Hz, 1H), 6.92 (t, J = 8.4 Hz, 2H), 7.06 (br s, 3H), 7.26–7.44 (m, 8H). 13C NMR δ 20.9, 24.7, 26.5, 27.6, 42.0, 47.5, 54.0, 60.5, 63.2, 115.2 (d, JCF = 22.3 Hz), 121.4 (d, JCF = 8.0 Hz), 125.9, 128.2, 128.7, 129.6, 137.5 (d, JCF = 3.4 Hz), 137.8, 158.2, 158.5 (d, JCF = 242.2 Hz), 210.1. Anal. Calcd. for C29H29FN2O2: C, 76.29; H, 6.40; N, 6.14. Found: C, 76.08; H, 6.68; N, 6.22.
(4S,5S)-1-Benzyl-5-(2-oxocyclopentyl)-3-phenyl-4-p-tolylimidazolidin-2-one (5.5d). (86% yield) White microcrystals (from hexanes), mp 78–80 °C. 1H NMR δ 1.64–2.36 (m, 10H), 3.85 (br s, 1H), 4.17 (d, J = 14.7 Hz, 1H), 4.56 (d, 15.4 Hz, 1H), 4.76 (br s, 1H), 6.96–7.09 (m, 5H), 7.15–7.30 (m, 7H), 7.42 (d, J = 7.7 Hz, 2H). 13C NMR δ 20.2, 21.1, 23.6, 38.2, 47.7, 53.1, 60.9, 63.2, 119.6, 123.0, 125.8, 127.4, 128.3, 128.5, 128.6, 129.7, 136.9, 137.1, 138.0, 139.2, 158.3, 218.0. Anal. Calcd. for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 78.90; H, 6.94; N, 6.77.
(4S,5S)-1-Benzyl-3-(4-fluorophenyl)-5-(2-oxocyclopentyl)-4-p-tolylimidazolidin-2-one (5.5e). (47% yield) White microcrystals (from hexanes), mp 72–73 °C. 1H NMR δ 1.60–2.34 (m, 10H), 3.87 (t, J = 4.2 Hz, 1H), 4.18 (d, J = 15.4 Hz, 1H), 4.53 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 4.2 Hz, 1H), 6.89 (t, J = 9.1 Hz, 2H), 6.99–7.08 (m, 4H), 7.20–7.24 (m, 5H), 7.32–7.37 (m, 2H). 13C NMR δ 20.2, 21.0, 23.5, 38.1, 47.8, 52.7, 60.9, 63.4, 115.3 (d, JCF = 22.3 Hz), 121.6 (d, JCF = 8.0 Hz), 125.9, 127.4, 128.3, 128.5, 129.7, 135.1 (d, JCF = 2.9 Hz), 136.5, 137.0, 138.2, 158.4, 158.7 (d, JCF = 242.8 Hz), 217.8. Anal. Calcd. for C28H27FN2O2: C, 75.99; H, 6.15; N, 6.33. Found: C, 75.71; H, 6.41; N, 6.56.
123
CHAPTER 6 GENERAL CONCLUSIONS
My objective in doing this work was to investigate certain aspects of the chemistry of
heterocyclic compounds in relation to amino acids, lactams, and ionic liquids. A common theme
that appeared throughout this work was that of the amide bond. The serendipitous study and
development of interesting synthetic organic chemistry, including some green chemistry, will
hopefully lead to novel molecules for the benefit of life, science, and society. My critical
findings provide a solid framework for future investigations in these related areas.
Peptidic α-triphenylphosphoranylidene esters and amides have attracted considerable
attention as important intermediates for the preparation of peptidic α-keto esters and of α-keto
amides, compounds which are potential inhibitors of proteolytic enzymes and leukotriene A4
hydrolases. Therefore, the development of an expedient, versatile method to C-acylate P-ylides
with chiral amino acid derivatives for N-protected peptidic α-triphenylphosphoranylidene esters
is desirable. The N-Protected N-acylbenzotriazoles C-acylation of P-ylides with microwave
irradiation adds to the robust list of N-acylbenzotriazoles applications.
In Chapter 2, the preparation of N-protected peptidic α-triphenylphosphoranylidene esters
from N-(Boc- or Cbz-α-aminoacyl)benzotriazoles was demonstrated under microwave
irradiation without base. Retention of chirality was demonstrated by the synthesis of (LL)- and
(DL)diastereomers and comparison of their optical rotation and NMR spectra. The C-acylation
utilized versatile N-protected (α-aminoacyl)benzotriazoles avoiding the use of base and
microwave irradiation reduced reaction times and solvent. Furthermore this procedure was
found to be a convenient route to the tetramic acid ring system in Chapter 3.
Although DOT-pyrrolidines are crystalline, soluble in halogenated and alcoholic solvents, and
have 1H-NMR spectra free of enol signals and 13C-NMR spectra with JPC couplings they have
124
received little of the attention given to tetramic acids. The possible transformation the 2,4-dioxo-
3-triphenylphosphoranylidene (DOT) moiety provides when directly incorporated as part of a
heterocyclic ring is unexplored and of considerable interest. Although the Wittig mechanism is
intuitively understood as a “4-center mechanism”, the inherent stability of the DOT moieties
requires further investigation.
In Chapter 3, the first convenient method to 2,4-dioxo-3-triphenylphosphoranylidene
pyrrolidines, 1,3-dioxo-2-triphenylphosphoranylidene tetrahydropyrrolizine, 2,4-dioxo-3-
triphenylphosphoranylidene piperidine, 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one
bromides, and 3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one dibromide was
described. The developed Method I was versatile, inexpensive, reproducible, and high yielding.
Racemization was caused by HBr, however the novel linear salts could be cleanly N-methylated
or neutralized without cyclization, or cyclized for distabilized triphenylphosphoranylidene
substituted rings. Crystalline DOT-pyrrolidines, are stable to aldehydes, strong bases, and high
temperatures, and represent versatile intermediates. The 13C-NMR chemical shifts and JPC
values provide valuable information for the analysis of distabilized triphenylphosphoranylidene
systems, JPC couplings increased with less partial positive character and decreased with more
partial positive character on the respective carbons.
Furthermore in Chapter 3, we developed four novel applications for DOT-pyrrolidines. The
first highly versatile 3,3-dibromopyrrolidine-2,4-dione with a racemic stereocenter, was obtained
without Lewis acid. The first 3,3-dibromo-5-hydroxypyrrolidine-2,4-dione, was obtained and
unambiguously identified by X-ray crystallography. 4-Azido-3-bromopyrrol-2-one was obtained,
where previously reported chloro derivatives were used to make β-lactams, and bromo
derivatives were trapped with triphenylphosphine to make a Staudinger reagent. The first 4-
125
benzotriazolpyrrol-2-one was obtained. In conclusion the versatile stable 2,4-dioxo-3-
triphenylphosphoranylidene can be practically formed on rings and easily transformed into novel
molecules.
The properties of cation and/or anion within the ionic pair were independently modified, then
metathesis could generate new functional materials, which retain the core features of the IL state
of matter. The regiospecific N-alkylation strategy provided the more sterically hindered 1-
alkylimidazoles for the production of newly synthesized anions and cations. Over the last
several years, typical properties of ionic liquids (ILs) such as high ion content, liquidity over a
wide temperature range, low viscosity, limited-volatility, and high ionic conductivity have
proven to be important drivers supporting numerous advances beyond the initial investigations of
ILs as liquid electrolytes.
In Chapter 4, N-alkylation of 4-alkyl and 2,4-dialkylimidazole with alkyl bromides provided a
regiomeric mixture of 1,4-disubstituted and 1,5-disubstituted imidazole. Protection of the N1
with benzoyl allows regioselective N-alkylation of the 3-position, with triflate quaternization.
Debenzoylation and dequarternization with aq base afforded the more sterically hindered 1-
alkylated imidazoles. Substituted heterocycles continue to be a powerful tool in the search for
energetic IL compounds.
The synthesis of tetrasubstituted trans-imidazolidin-2-ones utilized a general benzotriazole
protocol to enable the introduction of a variety of substituents into the 4- and 5-position of
imidazolidin-2-ones with trans stereochemistry. The extension of the previous work allowed the
formation of a vicinal diamine and urea in one simultaneous step. The presences of two
potentially bioactive properties encourages the exploration of vicinal diamino tethered ureas and
126
unsaturated imidazol-2-ones, or saturated imidazolidin-2-ones in particular for medicinal
screening.
In Chapter 5, the general protocol enabled the introduction of a variety of substituents into the
4- and 5-position of imidazolidin-2-ones stereospecifically. The low yielding convergent step
using s-BuLi, was a set back for the efficiency this method. General versatility and applicability
to a robust combinatorial library was hampered and requires additional optimization of the
convergent step. Three novel Bt trans-imidazolidin-2-ones were isolated and characterized.
Two of the novel Bt trans-imidazoidin-2-ones were used to successful synthesize four novel
cyclic ketone derivatized tetrasubstituted trans-imidazolidin-2-ones.
127
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BIOGRAPHICAL SKETCH
Adam Spencer Vincek was born in 1975, in Topeka, Kansas–USA. Adam spent a majority of
his formative years in Pennsylvania–USA. He studied in Surrey–England from 1991 to 1992.
He began his undergraduate education at the University of North Carolina at Chapel Hill as
continuing studies student in 1995. During his undergraduate studies he received two summer
internships where he developed practical skills in organic synthesis, in 1998 at UAB-
Birmingham, Alabama, and in 2000 at a pharmaceutical company in Baltimore, Maryland. He
was awarded a B.Sc. chemistry degree in 2000. Then, he worked professionally in Munich,
Germany, from 2001 to 2003 conducting organic synthesis with a biotech company, and was first
introduced to hydroxybenzotriazole in order to make biotin hydroxamic acid. He was accepted
into the Ph.D. program at the University of Florida in Gainesville in January 2004.