richter indole and pyrrole synthesis: 9/1/04 group meeting · richter 9/1/04 indole and pyrrole...

Richter

Disclaimer:This lecture will only cover methodology for the construction of the indole and pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, which would be the topic of another series of lectures.

Partial List of Transforms Discussed:

1. Batcho-Leimgruber Indole Synthesis2. Reissert Indole Synthesis3. Hegedus Indole Synthesis4. Fukuyama Indole Synthesis5. Sugasawa Indole Synthesis6. Bischler Indole Synthesis7. Gassman Indole Synthesis8. Fischer Indole Synthesis9. Japp-Klingemann Indole Synthesis10. Buchwald Indole Synthesis11. Bucherer Carbazole Synthesis12. Japp-Maitland Carbazole Synthesis13. Larock Indole Synthesis14. Bartoli Indole Synthesis15. Castro Indole Synthesis16. Hemetsberger Indole Synthesis17. Mori-Ban Indole Synthesis18. Graebe-Ullmann Carbazole Synthesis19. Madelung Indole Synthesis20. Nenitzescu Indole Synthesis21. Piloty Pyrrole Synthesis22. Barton-Zard Pyrrole Synthesis23. Huisgen Pyrrole Synthesis24. Trofimov Pyrrole Synthesis25. Knorr Pyrrole Synthesis26. Hantzsch Pyrrole Synthesis27. Paal-Knorr Pyrrole Synthesis28. Zav'Yalov Pyrrole Synthesis29. Wolff Rearrangement

Indole:

Nature: – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone), serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar – Biosynthesis of tryptophan

Reactivity:

– Isoelectronic with naphthalene (slightly lower stabilization energy) – Indole has a higher stabilization energy than benzene – Very weakly basic: pKa of protonated indole: –2.4 – Protonation occurs at C–3 preferentially – Easily oxidized (atmospheric oxygen) – very electron rich – Less prone to oxidation of EWG's on the ring – less electron rich – Electrophilic attack occurs at C–3 (site of most electron density) – C–3 is 1013 times more reactive to electrophilic attack than benzene – C–2 is the second most reactive site on the molecule, but most easily functionalized by directed lithiation – pKa of N–H is 16.7 (20.9 DMSO) – N–1 is the most nucleophilic site on indole – Nucleophilic substitution at benzylic carbons enhanced – Regiospecific functionalization of the carbocycle is difficult without pre-functionalization of the ring (i.e. halogenation)

glucose15

Steps

CO2H

NH2

anthranilate

3

Steps NH

serine

tryptophan

NH

C–3C–4

C–6C–2

C–5

C–7

9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

NH

Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

1

2

3

4567

8

9

1011 12 N

H

NH

NH

NHN

HNH

NH

NH

NH

NH

NH

NH

NH2

X

NH2

NH2

NH2

NH2

Y

X

O

S

NHCl

NHOH

X

NHNH2 ONH2NH2

Y

X

NH

X

NH

X

NH

R+O

NH O

X

NH

X

O

NH O

O

NH

NH

NH

NH

X

H2N

O

O

NH

R

R

+ + +

+

+

+

+

++

1a 1b

1c

1d

3a

3b

3c3d

8a

8b

8c

9a

9b

9c

13

RingContracton

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Disconnection 1a:

Batcho-Leimgruber Indole Synthesis:

– Typical [H] = H2, Pd/C; hydrazine, Raney Ni – Other side products from reductive cyclization include N–O – Yields: 50's – 90's

Variants:

– If R = carbonyl, use KF / 18-c-6 / i-PrOH for the Henry reaction – Use classic Henry conditions otherwise –Typical [H] = Fe, Fe/SiO2 – Yields: 40's – 90's

NO2

MeR

NMe

MeOMe

OMe

NH NO2

RN

RNH

[H]

NO2

MeR

NO2

RNO2

RNH

[H]

CH3NO2

RNO2

HNO3

Disconnection 1a:

– 1: Reduction, then acid – 2: Reduction, then acid – 3: Oxidation, then reduction, then acid Can oxidize the alcohol and not the aniline with Ru(PPh3)2Cl2 Can convert the nitro-alcohol into indole with Pd/C or Rh/C and Ru(PPh3)2Cl2 – 4: Reduction of nitro and cyano (one or two steps), then acid – 5: Wacker oxidation, reduction, then acid – 6: Ozonolysis, reduction, then acid

Reissert Indole Synthesis:

R

ONH2

R

ONO2

OCOR

NO2

R

OHNO2

CN

NO2NO2

R

NO2

1 2

3

45

6

Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030

NO2

Me Base

(CO2Et)2

CO2Et

ONO2

[H]NH

CO2Me


Sundberg, R.J. Indoles.

Disconnection 1b:

Palladium Synthesis:

– X can be either H, Ac, Ms, TFA – The intermediate organopalladium can be intercepted – Yields: 40's – 90's

Disconnection 1c:

– Reductive cyclization mediated by (EtO)3P or PdCl2/PPh3/SnCl2 and CO – Migratory aptitudes unknown – Unknown mechanism – does not involve a nitrene

Disconnection 1d:

Hegedus Indole Synthesis:

– Applied to the total synthesis of rac-aurantioclavine by Hegedus (Hegedus, L.S. J. Org. Chem. 1987, 52, 3319)

– Applied to the total synthesis of arcyriacyanin A by Steglich (Steglich, W. Chem. Eur. J. 1997, 3, 70)

Disconnection 1–Misc.:

Fukuyama Indole Synthesis:

NHX

PdII

NH

R

R

PdII NH

R

R'

NH

R

R'M

H+

NO2

R

NO2

R

R

NH

R

NH

R

R

NH2

PdII, then [H] or

PdII, Cu(OAc)2,benzoquinone

NH

Me

Hegedus, L.S. J. Am. Chem. Soc. 1976, 98, 2674; ibid 1978, 100, 5800; e.g. Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.

NH

HN

NH

Br I

NTs

Br

NH

NH

HN

O O

NH

R

SnBu3SnH

AIBN NH

R



Disconnection 2:

Pyrrone Diels-Alder:

– Little regiocontrol observed in most reactions – pyrrole-quinodimethanes are not stable and therefore not amenable for Diels-Alders directly

Disconnection 3a:

Sugasawa Indole Synthesis:

– Requires very strong Lewis Acids so many functionalities are not stable – Choice of second Lewis acid depends on substitution pattern

Bischler Indole Synthesis:

– Not very general: requires HBr (1 eq) and 200+ oC – Mechanism?

Disconnection 3b:

Gassman Indole Synthesis:

– Good regiocontrol observed with ortho or para substitution – ortho/para methoxy substituents failed completely

Disconnection 3c:

– Quite mild, if the O-vinyl derivatives can be synthesized

Gassman, P.G. J. Am. Chem. Soc. 1974, 96, 5495; Sundberg, R.J. Indoles.

NH

O

O

NH

NH2

CN

Cl+

BCl3

ZnCl2, AlCl3or TiCl4

NH2

CN NaBH4

NaOMe NH

NH2

+X

Ar

O

NH

Ar

NHR

R'

1. t-BuOCl2.

3. base

S R''O R

N

SMe

R''

R'

Raney-Ni RN

R''

R'

NAc

OH

NR

O-

NR

OH

•

H

Z

O

O

O

OMe

NH

O

Li2PdCl4

NH

RR

acid


Sundberg, R.J. Indoles; Buchwald S.L. J. Am. Chem. Soc. 1998, 120, 6621

Disconnection 3d:

Fischer Indole Synthesis:

– Common acids: HCl, H2SO4, PPA, BF3/AcOH, ZnCl2, FeCl3, AlCl3, CoCl2, NiCl2, TsOH – Regioselectivity not great with unsymmetrical ketones – Tolerates a wide range of substitution – Product regioselectivity affected by choice of acid, solvent, temperature

Japp-Klingemann Modification:

Buchwald Modification:

Pharmaceutical Applications of the Fischer Indole Synthesis:

Disconnection 3d:

Bucherer Carbazole Synthesis:

Japp-Maitland Condensation:


Larock Indole Synthesis: (Larock, R.C. J. Org. Chem. 1998, 63, 7652)

– Base additives vary by reaction – High functional group tolerance – Bulkier R group placed at C–2 of the indole

Bucherer, H.T. J. Prakt. Chem. 1908, 77, 403; Japp, F.R. ; Maitland, W.J. J. Chem. Soc. 1903, 83, 273

NHNH2 R

OR'

+ acid

NH

R'

RH2O

N2+ R

O+ acid

NH

R'

CO2R''D

CH2R'OR''

O

Br

R

NNH

R'+

1. Pd//BINAP

2. TsOH NH

R'

R

N

N

SO

O

O

OBnO

NH2•MsOHMK-677Merck

T, 1997, 53, 10983

NH

NMe

MeS

O

HN

O

MeImitrex®Glaxo

e.g. Heterocycles, 2000, 53, 665

X

NHNH2

+ NaHSO3

acid NH

Mechanism?

OH NHNH2

0.5 eq

HCl NH

NH

I

R

+R'

R''

Pd(OAc)2

Base NR

R''

R'


X=OH, NH2

Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071


Bartoli Indole Synthesis:

– Mechanism? – Only works well with 2-substituted nitrobenzenes

Castro Indole Synthesis:

Disconnection 4:

Hemetsberger Indole Synthesis:

– Formed by condensation of aromatic aldehyde with a-azoester with NaOEt, under very carefully controlled conditions to prevent N2 loss – Yields = 30's – 90's – Unknown mechanism – not a nitrene insertion reaction

Disconnection 5:

Stepwise:

One pot:

Disconnection 6:

Disconnection 7:

NO2R

BrMg

R' R''+

NH

R''

R'

R

NH2

I+

R

NH

RCuOTf

CO2R

N3

CO2RN

NH

CO2RD

N(TMS)2

Br1. Zn2. CuCN, LiCl

3. RCOCl NH

R

NHX

1. 2.2 BuLi

2. RCO2Me NH

R

X = TMS, Boc

N

NH

CHORO2C


O

HO

N

NH

CHORO2C

TBDMSTf

OH

NHR

O

TsOHNH

R


2 eq

Disconnection 8a:

Heck Approach:

– Yields = 70's – 90's – Choice of base and protecting group on the nitrogen can affect the yield

More Palladium:

– Can intercept the intermediate organopalladium species – Any organozinc reagent can be used to transmetallate.

Mori-Ban Indole Synthesis:

– Requires stoichiometric nickel – Yields only about 50%.

Disconnection 8b:

More Palladium:

– Works best with an EWG on the olefin

Photochemical:

Disconnection 8c:

Acid Catalyzed Cyclization:

– LA commonly ZnCl2 – Can also use ketals with BF3 or TiCl4


Graebe-Ullmann Carbazole Synthesis:

– Mechanism? – Generally problematic and not widely applicable

NH

X

NH

Sundberg, R.J. Indoles; Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803.

NR'

XR Pdo

NR'

R

Pdo;

RZnCl

R

NMe

Cl

NMe

(Ph3P)4Ni

NR'

X CO2R

NR'

CO2R

Pd(OAc)2

NH

NH

hn

taut.

NX

NX

LAO R

RX = TFA, alkyl, solfonyl

NPh

NN

D

NH

Sundberg, R.J. Indoles; Graebe, C.; Ullmann, F. Ann. 1896, 291, 16


Disconnection 9a:

Madelung Synthesis:

– Yields = 40's – 90's

Variant of Madelung:

– Where X is a phosphorous, nitrogen, silicon, or oxygen to stabilize a negative charge – If X is phosphorous, then it is an intramolecular Wittig.

Disconnection 9b:

Base/Acid Catalyzed closure:

Disconnection 9c:

McMurray Type Closures:

Disconnection 10:

Diels-Alder:

– Works best when matched

Disconnection 11:

Diels-Alder:

– Works best when matched

Disconnection 12:

Nenitzescu Synthesis:

– Mechanism? – Substitution on the quinone ring is acceptable and predictable – Substitution on the enamine is tolerated, but R' is best as an EWG – Used in the synthesis of LY311727 (Lilly)


NAr N

Ar

Acid or

Base

Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055

R

NH O

3 BuLiNH

X

NH O

BaseNH

O

RR

NAr N

Ar

TiCl3

Zn

O

O

NH

NH

EDG

EWGEWG

EDG

NH

NH

EWG

EDG

EWG

EDG

O

O NH

R''R

H R'D

NR''

HOR'

R'

NBn

CO2NH2P

MeO

O

OMe


R

Disconnection 13:

Wolff Rearrrangement:

From Quinolines:

Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000

N

ON2 hn

NO

Ph

NH

CO2H

N+

O-Ph

hn

NH

CHO

Ph

Pyrrole:

Nature: – Very abundant in nature – Found in porphyrins, natural products, drugs – Isolated industrially from coal tar and/or bone oil

Reactivity:

– Protonation occurs at C–2 preferentially – Easily oxidized (atmospheric oxygen) – very electron rich – Quickly colorizes upon exposure to air – Less prone to oxidation of EWG's on the ring – less electron rich – Decomposition and polymerization rapid with acid – Electrophilic attack occurs at C–2 (site of most electron density) – C–3 is the second most reactive site on the molecule – pKa of N–H is 23 (DMSO) – N–1 is the most nucleophilic site on pyrrole

NH

C–3

C–2


Mass, G. Science of Synthesis. Thieme. New York: 2001

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

RingContraction

RingExpansion

12

3

4

5

67

891011

12

13

14

15

1617 18


Mass, G. Science of Synthesis. Thieme. New York: 2001

Disconnection 1:

Palladium with Alkenes:

– Exists mainly in the tautomeric form

Palladium with Alkynes:

Disconnection 2:

Disconnection 3:

Disconnection 3:

Piloty Synthesis:

– Mechanism?

Disconnection 4:

Thermal Cyclization:

Carbene Insertion:

Disconnection 5:

Rhodium:

N OR

PdCl2

NH

OH

NCbz

NCbz

Pd/C

TEA, MeOH

Ts NC

Ph

CO2Et

CN+ NaOEt

NH

CNPh

Ph

Ph

O O Ph

PhHO+

NH4OAc

AcOH NH

PhPh

PhPh

O

H2NNH2

CoI2, D NH

MeMe

EtEt

N3

CO2EtNH

CO2EtD

R'

O

R

NHR'''

R''1. TMSCLiN2

2. MnO2 NR'''

R'R

R''

PhNH2

H2, CO

[Rh], PPh3 NH

Ph


Mass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000

Disconnection 5 Continued:

Iron:

Niobium:

2-Aminopyrroles:

From Cyclopropenes:

Disconnection 6:

Barton-Zard Pyrrole Synthesis:

– Original Barton-Zard used NO2 as the LG.

Bis-Nucleophile/Bis-Electrophile:

Extrusion (Huisgen Pyrrole Synthesis):

– X is usually S or NR

Disconnection 7:

Knorr Pyrrole Synthesis:

Trofimov Pyrrole Synthesis:

NPh

Ph

NH

Ph

MeMe

Fe2(CO)9

MeLi; tBuBr

NR

Ph

NbCl3RHN O

PhOMe

Ph

NbO

Ph

OMe

NR

ONbPh

Me

NR

PhMe

PhPh

R''

R'N

R R'''NC

D NR

NHR'''

R''R'

Ar

ClN

RR'+

hn

or D NR

Ar

R'

RR'

LGCN CO2R''

+

+base

NR

CO2R''

RR'

Ph

OO

Ph

EtO2C NPh

CN+ KOtBu

NPh

CN

PhPh

N+

XPh

-ODMAD

NPh

MeO2CCO2Me

R NH2

R' O

O R'''

R''

O

+

NH

R'''

COR''R'

R

NOH NH


Base


Disconnection 7 Continued:

Hantzsch Pyrrole Synthesis:

Formal 3+2:

Stepwise:

Ugi Approach:

Disconnection 8:

Paal-Knorr Pyrrole Synthesis:

– Can access the diketone in-situ by reduction of the bis-cyano compound – Can access via reduction of the g-nitro ketone

Palladium:

Zav'Yalov Pyrrole Synthesis:

+

+

+

R

OBr

H2N R

R''

NH

R'

R''

R

NBn

NO2

R D

NBn

R

R NNMe2

R IO

O 1. Base2. Acid

3. H2, Ni NHR

R

O

Ph

NH3Cl

HO2C CN

NC

RCHO

NO

NC O Ph

RO

HN

NMeO

NCPh

RCONCy

CH2N2

R'

OR''

O

RNH2+

NRR'

R''

PdCl2, Cu(OAc)2;

AgBF4, PPh3, BnNH2 NBn

O

OAc Pd(PPh3)4

BnNH2 NBn

R'R

O

NMe2

NH2HO2C

R''+

R'R

O

NH

CO2HR''

Ac2O

TEA NAc

R'R

R''



Disconnection 9:

Wolff Rearrangement/Photolytic:

Reductive Ring Contractions:

Disconnection 10:

Base Catalyzed:

McMurray Type Coupling:

Disconnection 11:

Disconnection 12:

Allenes:

Rhodium:

Cobalt:

N

N2

O NH

CO2H

N+

O-N3

hn

hn

NH

CN

N

N ClAr

CO2Et NHMeO2C

CO2Et

Zn

HOAc

NN

CO2Me

MeO2C

MeOZn

HOAc NHMeO2C

OMe

CO2Me

N

R

ClKOtBu

NH

R

R

O

R'

NHR''

O

TiCl3

Zn NH

R'R''

R

R

O

R'

NHR''

H CO2Et

N2+ Cu(acac)2

NR''

R'EtO2C

R

• CO2MeTsN

Ph1. PPh32. DDQ

3. NaOMe NH

Ph

CO2Me

CN CO2EtR

O

R'R''

O

+

+ Rh2(CO)12

NH

CO2Et

R''R'

R

PhOH

R1. Co2(CO)62. BF3•OEt2

3.( )n

HNMeO2C

Me

PhN

R

( )n

CO2Me

LDA, DDQ

n=1n=2

NH

RPh

MeO2CNH

R

BnMeO2C

1. BuLi;

2. BuLi;NBn

NN Br OMe

OMe

Ph NPh NPh

Ph

PhNHPh

Ph

Ph

OMeOMe

Btacid



Disconnection 13:

Disconnection 14:

Disconnection 15:

Palladium:

Titanium:

Zirconium:

Disconnection 16:

Disconnection 17:

Disconnection 18:

From Cyclopropanes:

From Cyclobutanes:

Ph O

H CO2MeCN

CO2MeCN+ DBU

NH

CO2Me

PhMeO2C

RNH2

OR'

EtNO2 SmCl3

R'NR

R'

NR

MeR'

R'

Ph Ph

TMSCN

PdCl2

or NiCl2+

NH

N(TMS)2

PhPh

NC

R R'Ti(OiPr)4

2 iPrMgClTi(OiPr)2

R

R'

R'' NR'''

CONR'''

R''

R'R

LiNPh

TMSCp2(Me)ZrCl

Cp2ZrNTMS

Ph Ph

CO NH

PhPh

RCHO

R'NH2 R''CO2H

PhNC

YXN+

OR''O-

RR' N

R'

R

XY

R''

R''1. BuLi

2.

R

OBr

R'' O

R

R'NH2

NR'

R

R''

CO2MeN

Phhn

NR'

MeO2C

Ph

NR

BzO SPh

PhS

AlEt2Cl

NR

SPh


Selected Syntheses:

Strychnine: Woodward (Classics I)

Strychnine: Overman (Classics I)

N

O

N

OH

H

H

H

NHNH2

OOMe

OMe

PPA

NH

OMe

OMe

Fischer Indole Synthesis

N

O

N

OH

H

H

H

NHMeO2C

N

H

OH

MeO2C

N

H

OH

NH2HO

Disconnection 1a

Selected Syntheses:

Isochrysohermidin: Boger (Classics II)

Aspidophytine: Corey (Classics II)

NMe

NMe

O

O

MeO

MeO

OH

MeO2C

CO2Me

HO

N N

NN

MeOMeO

CO2MeCO2Me

MeO2C

MeO2C

NH

NH

CO2Me

CO2Me

MeO

MeO

MeO2C

CO2Me

Disconnection 9

NMe

N

H

O O

MeO

MeO

MeOOMe

NO2

NO2 Fe, AcOHsilica gel

NHMeO

OMeBatcho-Leimgruber Indole Synthesis Variant

Syntheses were only included if they synthesized the indole or pyrrole


Selected Syntheses:

Vinblastine: Fukuyama (Classics II)

Mitosene: Rebek (J. Org. Chem. 1984, 49, 5164)

Selected Syntheses:

Lipitor®: Pfizer (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)

MsO NH

THPO

S

CO2Bn

CO2Bn

nBu3SnH

AIBNNHMsO CO2Bn

CO2Bn

OTHP

NH

N

NMe

N

CO2Me

OHOAc

H

HMeOMeO2C

OH

H

Fukuyama Indole Synthesis

N

NHO

-O2COH

OHF

N

OHO2C

F

OO

CONHPh

Ac2O

N

F

OO

CONHPh

Huisgen Pyrrole Synthesis

CONHPhO

OF

N

F

OEtEtO

CONHPh

H2N OEt

OEt

Paal-Knorr Pyrrole Synthesis

N

OCONH2

OMe

NH2O

OH2N

O

N+

O-

OAc

MeO2C DMADN

CO2Me

OAc

MeO2CMeO2C

Huisgen Pyrrole Synthesis



Selected Syntheses:

Axert®: Janssen (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)

Hapalindole G: Fukuyama (J. Am. Chem. Soc. 1994, 116, 3125)

Disconnection 8a

NH

SN

OO

NH2

SN

OOI

N

O CF3

CO2Me

Pd(OAc)2

Bu4NBrTEA N

H

SN

OO

CO2Me


NH

NCHH

H

Cl

H

Cl

O

S

LiOMeMe

O

1.

2. HgCl2, HClO4NAlloc

H

H

Cl

O

NHAlloc Disconnection 1a


Selected Syntheses:

Ketorolac®: Syntex (Muchowski, Adv. Med. Chem. 1992, 1, 109) – 1st Generation strategies utilize pyrrole syntheses – Process synthesis uses annulation starting from pyrrole

O

NCO2HH

NH

CO2Me

CO2MeHO

OBr

NCO2Me

CO2Me

HO

Hantzsch Pyrrole Synthesis

OMeO OMe

H2NOH

AcOHN

HO

Paal-Knorr Pyrrole Synthesis

richter indole and pyrrole synthesis: 9/1/04 group meeting · richter 9/1/04 indole and pyrrole...

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