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2018

Development of a One Pot [4+2]/r[4+2] 2-Pyridone Synthesis and Development of a One Pot [4+2]/r[4+2] 2-Pyridone Synthesis and

the Fluorescence of 2-Pyridone Azafluorenones the Fluorescence of 2-Pyridone Azafluorenones

Nicholas Angello College of William and Mary - Arts & Sciences, 2014nickangello@gmail.com

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Recommended Citation Recommended Citation Angello, Nicholas, "Development of a One Pot [4+2]/r[4+2] 2-Pyridone Synthesis and the Fluorescence of 2-Pyridone Azafluorenones" (2018). Dissertations, Theses, and Masters Projects. Paper 1550153876. http://dx.doi.org/10.21220/s2-s0ga-cq17

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Development of a One Pot [4+2]/r[4+2] 2-Pyridone Synthesis and the Fluorescence of 2-Pyridone Azafluorenones

Nicholas Henry Angello

Manassas, Virginia

Bachelor of Science, College of William & Mary, 2017

A Thesis presented to the Graduate Faculty of The College of William & Mary in Candidacy for the Degree of

Master of Science

The Department of Chemistry

College of William & Mary August, 2018

© Copyright by Nicholas H. Angello 2018

ABSTRACT

We report the concise synthesis of several tricyclic 2-pyridones via a one pot sequence involving an aldol condensation, alkene isomerization, intramolecular Diels-Alder cycloaddition, and selective retro-Diels-Alder cycloreversion. The starting materials are synthesized in one step from cheap and commercially available precursors. The intermediate [2.2.2]diazabicycloalkene cycloadducts can be isolated. The retro-Diels-Alder occurs at easily accessible temperatures due to base acceleration. Simple derivatization of the tricyclic products afforded azafluorenones with unprecedented fluorescent activity due to the pyridone motif.

i

TABLE OF CONTENTS

Acknowledgements iii

Dedication iv

List of Tables v

List of Figures vi

List of Schemes vii

Chapter 1. Background 1

Properties of 2-Pyridones 2

2-Pyridone Natural Products and Total Synthesis 3

Pyridone Derivatization 11

Synthetic Approaches to Pyridones 14

Conclusion 22

Works Cited 23

Chapter 2. Reaction Development 33

Unsuccessful Substrates 47

Expanding the Scope 49

Conclusion 53

Works Cited 54

Experimental 55

Chapter 3. The Fluorophores Fluorene and Fluorenone 72

Synthesis and Fluorescence of Azafluorenones 74

Conclusion 77

Works Cited 78

Experimental 80

ii

Appendix Supporting Information for Chapter 2 84

Supporting Information for Chapter 3 123

iii

ACKNOWLEDGEMENTS Thanks Dr. S. I came to William & Mary to work in your laboratory, and I couldn’t be happier with how it turned out. Thank you for being patient with me; I know it took a while for us to be on the same page. I appreciated chemistry before joining your lab, but you made me decent at it. For that I’ll always be thankful. I’m glad I stayed for my Master’s and that you helped create the opportunity for me to do so. I’m calling you Jonathan after I leave. William & Mary is an excellent institution to learn chemistry. I would like to acknowledge Professor Abelt for his humor in teaching Advanced Organic, Professor Harbron for her depth in Organic Spectroscopy, and of course Professor Scheerer for teaching Organic Synthesis like a synthetic chemist should. I did not expect to enjoy Professor Pike’s Advanced Inorganic as much as I did. Likewise, Professor Kidwell’s Physical Chemistry was very challenging and satisfying. I can’t imagine a better education than I was given at this cute little college over the past 4 years. Thanks to my former lab mates Jill Williamson, Matt Nelli, Jacob Robins, and Kyu Kim. Jill was an excellent mentor and I really appreciate you all accepting me into your social circle. I missed each of you when you graduated. I hope you’re all enjoying grad school or the industry.

Thanks to my current lab members and the summer 2018 crew Adam Wang, Bob Wiley, Devin Mickles, Michelle Townsend, and Avery Boice. All of you made the lab atmosphere very fun during my Master’s. I’m glad we barbecued. I would feel bad if I didn’t acknowledge Eric Roos, my mentee. You were one of the funniest people I’ve ever worked with. Just do more chemistry and less business. Trust me, it’s more fun.

iv

To Deeksha.

v

LIST OF TABLES

1.1 Pyridone substitution strategies 13-14

2.1 Diels-Alder/retro-Diels-Alder optimization 37

2.2 Optimization of the retro-Diels-Alder 39

2.3 Retro-Diels-Alder reaction screening 40

2.4 One pot substrate scope 43

2.5 Modified one pot procedure to produce cycloadducts 44

vi

LIST OF FIGURES

1.1 Naturally occurring pyridine compounds 1

1.2 Structure of 2- and 4-pyridones 2

1.3 Tautomerization and dimerization of pyridones 3

1.4 Niche applications of pyridones 3

1.5 Camptothecin and derived therapeutics 4

1.6 Structure of huperzine A and B 5

1.7 Lycopodium pyridone alkaloids 7

1.8 Streptomyces pyridone alkaloids 7

1.9 Strychnine and naturally derived pyridones 8

1.10 N-methoxy pyridone alkaloids 8

1.11 4-Hydroxy pyridone alkaloids 9

1.12 4,N-Dihydroxy pyridone alkaloids 10

1.13 Polycyclic pyridone alkaloids 10

1.14 Recently discovered pyridone natural products 11

3.1 Fluorene and derived compounds 72

3.2 Fluorenone and related compounds 73

3.3 Azafluorenes synthesized for fluorescent studies 74

vii

LIST OF SCHEMES

1.1 Pyridone nucleus revealed at the end of Huperzine A synthesis,

with concomitant decarboxylation 6

1.2 Dramatic rate enhancement in the base catalyzed Diels-Alder of 3-

hydroxypyridones 12

1.3 [4+4] photodimerization of tethered dipyridones 12

1.4 Strategies to reveal masked pyridones 15

1.5 Classical condensation reaction 15

1.6 Modern condensation reaction 16

1.7 Aromatization of N-tosyl hydropyridones 16

1.8 Electrocyclic ring closures of isocyanates and acyl ketenes 17

1.9 [2+2+2] Metallocyclization with double stereodifferentiation 18

1.10 Pentadehydro-Diels-Alder reaction yielding pyridines 19

1.11 [3+2] cycloaddition/elimination of an isomünchnone 19

1.12 Diels-Alder/retro-Diels-Alder strategies for pyridines 20

1.13 Early [4+2]/r[4+2] strategy for pyridones from pyrazines 20

1.14 Recent [4+2]/r[4+2] strategy for pyridones from pyrazinones 21

1.15 [4+2]/r[4+2] strategy for pyridones from oxazinones 21

1.16 Scheerer lab strategy for pyridones from diketopiperazines 22

2.1 One pot reaction plan 33

2.2 Starting material synthesis 34

2.3 Initial success in the aldol condensation 34

2.4 Optimized aldol condensation 35

2.5 Attempts to isolate lactim ethers 36

2.6 Unexpectedly high yielding one pot process 42

2.7 r[4+2] of an ethereal substituted cycloadduct 45

viii

2.8 r[4+2] of a phenyl substituted cycloadduct 46

2.9 r[4+2] of a TMS substituted cycloadduct 46

2.10 Unsuccessful [4+2] of a pyridyl substituted aldol product 47

2.11 Substituted diketopiperazine starting material synthesis 47

2.12 Unsuccessful [4+2] of a diketopiperazine substituted aldol product 48

2.13 Aliphatic aldehydes produce an undesired byproduct 49

2.14 Azaanthracene reaction plan 50

2.15 Starting material synthesis for 6,6,6 tricyclic pyridones 50

2.16 Stepwise sequence to azaanthracene 52

3.1 Synthesis of Azafluorenones from Azafluorenes 75

3.2 Synthesis of Chloropyridine Azafluorenones 76

3.3 Synthesis of a 2-Phenyl Azafluorenone 76

3.4 Synthesis of a 2-Methoxy Azafluorenone 77

1

Chapter 1

2-Pyridones: Background and Prior Syntheses

Background

Nitrogen containing heterocycles are some of the most ubiquitous structural

motifs in natural products and leading pharmaceutical drugs.1 Of the nearly two

thousand unique FDA approved small molecule pharmaceuticals, 84% contain

nitrogen, while 59% contain at least one nitrogen heterocycle. Pyridine is an aromatic

six-membered ring equivalent to benzene with a nitrogen replacing a methine group.

It is one of the most common N-heterocyclic motifs found in pharmaceuticals, second

in prevalence only to its saturated piperidine counterpart. Pyridines comprise

essential human nutrients such as niacin (vitamin B3), nicotinamide, and pyridoxine

(vitamin B6).2 Nicotinamides are precursors to the coenzymes nicotinamide adenine

dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NAPH), which

act as electron carriers for cellular respiration (Figure 1.1).3

Figure 1.1 Naturally occurring pyridine compounds

Pyridines in a higher oxidation state, as an aromatic amide, are referred to as

pyridones. 2- or 4-Pyridones exist, named for the relative placement of the carbonyl

2

to the nitrogen in the ring (Figure 1.2). This thesis is focused on 2-pyridones only, as

4-pyridones encompass differing classes of natural products which have their own

synthetic challenges. From here on, references to “pyridones” will refer only to 2-

pyridones.

Figure 1.2 Structure of 2- and 4-pyridones

2-Pyridones are naturally occurring compounds with unique and varied

structural and aggregate properties, and promising bioactivities. 2-Pyridones are

secondary metabolites formed by a wide variety of species. Synthesis of the 2-

pyridone structural motif has a long history in synthetic organic chemistry and many

complex natural product total syntheses of pyridone-containing alkaloids have been

completed.4

Properties of 2-Pyridones

2-Pyridones exists in two tautomeric forms, as an equilibrium between 2-

pyridone and 2-hydroxypyridine.5 2-Pyridones form hydrogen bonded dimers with the

N and O atoms of both tautomers (Figure 1.3),6 as well as stable crystalline complexes

with amino acids.7 This unique functionality has been used to make molecular

aggregates of dipyridones8 as well as self-assembling, surface-rolling molecular

machines called nanocars.9 Pyridone hydrogen bonding strength increases in

presence of strong hydrogen bonding solvents, such as hexafluoroisopropanol

(HFIP).10 Intrinsic tautomer preference has been a subject of debate, as there is less

3

than a 2 kcal difference between the hydroxypyridine and pyridone tautomers, which

differs by computational method and by state.11

Figure 1.3 Tautomerization and dimerization of pyridones

N-Substituted pyridones have differing properties and varying utility. N-Fluoro

pyridones have been used as mild fluorinating agents.12 N-Etherealpyridones, the

alkylated derivatives of N-hydroxypyridones present in many natural products, form

carbon and oxygen centered radicals upon exposure to UV light, potentially causing

photooxidative damage to DNA.13, 14 Pyridones have been fused to

borondipyrromethene (BODIPY) dyes, red-shifting their fluorescent emissions, for use

as unsymmetrical fluorescent probes (Figure 1.4).15

Figure 1.4 Niche applications of pyridones

2-Pyridone Natural Products and Total Synthesis

There are far too many pyridone natural products to detail individually. Instead,

the natural products with the most historical synthetic effort will be discussed first.

Then, selected compounds representative of natural product families will be

4

presented to highlight both the overall structural variety found in 2-pyridone natural

products and the naturally occurring substitutions to the 2-pyridone core.

Camptothecin was first isolated in 1966 from Camptotheca acuminate, a plant

used in Chinese Traditional Medicine.16 The compound showed high anticancer

activity, leading to initial total syntheses in the 1960s and 1970s.17 Interest waned

when it failed clinical trials. In the 1980s, it was discovered that camptothecin

modulated DNA topoisomerase I, renewing interest in the compound as a selective

anti-cancer agent. After two international meetings dedicated solely to camptothecin,

the analogues topotecan and irinotecan were developed and subsequently approved

by the FDA. Topotecan is used in the treatment of ovarian cancer and lung cancer,

while irinotecan is used for colon cancer and small cell lung cancer (Figure 1.5).17

Figure 1.5 Camptothecin and derived therapeutics

There are over a hundred completed total syntheses of camptothecin and

analogues, but special recognition should go to the work accomplished by

Danishefsky,18, 19 Boger,20 and Lu.21 Danishefsky accomplished a concise synthesis

of the racemate in 1993. Boger synthesized the (+) enantiomer in 2002. Finally, in

2012, Lu completed a synthesis of enantiopure camptothecin in 11 steps and 14%

overall yield, in a scalable synthesis requiring no chromatography. The synthetic

efforts over the past fifty years have led to camptothecin being commercially available

5

from chemical suppliers in gram quantities.

Huperzine A and B were first isolated in 1985 from the firmoss Huperzia serrata

(Figure 1.6).22 The huperzine alkaloids belong to the Lycopodium family of related

clubmoss derived natural products. Huperzine A displays antibacterial and

insecticidal properties, but its acetylcholinesterase inhibition drew interest in the

compound as a medication against Alzheimer’s disease.23 However, clinical trials to

treat Alzheimer’s with huperzine A did not succeed, with some studies showing little

cognitive benefit.24 A meta-analysis of random clinical trials suggested the drug was

beneficial but that many of the trials had poor methodological quality,25 a likely reason

as to why western medicine adopted alternative acetylcholinesterase inhibitors. Still,

a recent study showed that a low concentration of huperzine A increased the

proliferation of neural stem cells in adult mice,26 opening the drug to newer treatments

involving directed stem cells.27

Figure 1.6 Structure of huperzine A and B

First synthesized in 1989 by Kozikowski,28 enantiopure syntheses followed

shortly after.29 Huperzine A, while readily available from natural sources and sold in

herbal remedies,30 has been synthesized extensively30-34 due to the challenge of

efficiently constructing its multiply fused-rings. The Herzon group accomplished the

synthesis in the fewest formal steps (8, typical syntheses are 10-20), highest yield

(35-45%) and on a multigram scale.33 Tudhope and coworkers adapted the prior

6

syntheses to process chemistry, furnishing 275 grams in a single, cGMP-compliant

pass which is scalable to kilograms and bypasses chromatography.34 A common

characteristic of these syntheses is using 2-methoxypyridine as a synthon for 2-

pyridone, to be revealed at the end (Scheme 1.1). This has the advantage of avoiding

pyridone reactivity (and chromatographic polarity) throughout the synthesis and

preventing the potent and highly skin permeable bioactivity of huperzine A until the

end.33

Scheme 1.1 Pyridone nucleus revealed at the end of Huperzine A synthesis, with

concomitant decarboxylation

While Huperzine A and many derivatives35-37 have been synthesized, there has

been less effort dedicated to the wider family of Lycopodium alkaloids. The

Lycopodium alkaloids constitute over 200 members and include increasingly complex

fused-heterocycles (Figure 1.7). The Sarpong group achieved early success with first

syntheses of the tetracyclic lyconadin A38 and lycoposerramine R,39 again using 2-

methoxypyridine as a masked pyridone. Subsequently, Waters synthesized (–)-

lyconadin C40 and Takayama completed a second synthesis of lycoposerramine-R,41

with both opting to form the pyridone ring in a semifinal step, through electrocyclic or

condensation reactions, respectively.

7

Figure 1.7 Lycopodium pyridone alkaloids

Streptomyces produce a wide variety of secondary metabolites with antitumor

and antibiotic properties. One such family are the “streptonigroids,” of which

streptonigrone was first synthesized by Boger and coworkers in 199342 and later by

Chan.43 The iromycins, isoform specific nitric oxide synthase inhibers,44 have been

synthesized by Zezschwitz et al.45 The Streptomyces derived 5-hydroxypyridone

A58365A was discovered to be a nanomolar inhibitor of angiotensin-converting

enzyme (ACE),46 an enzyme associated with cardiovascular disease. The desirability

of preventing heart disease, the leading cause of death in the United States,47 led to

four unique total syntheses of A58365A48-51 (Figure 1.8).

Figure 1.8 Streptomyces pyridone alkaloids

Strychnine-derived pyridones have been isolated from both Strychnos nux-

vomica52 and Kopsia arborea, named stryvomitine and Kopsiyunnanine-I,

respectively (Figure 1.9). Strychnine is a small vertebrate pesticide and poison, with

8

historical use dating back to 1640.53 The molecule is considered a “classic in total

synthesis,” as synthetic efforts have spanned the past 70 years.54 Kopsiyunnanine-I

was synthesized from strychnine by Takayama and coworkers.55

Figure 1.9 Strychnine and naturally derived pyridones

The N-methoxypyridone leporin A was isolated from Aspergillius leporis, and

was shown to inhibit the growth of the corn earworm Helicoverpa zea as well as the

gram-positive bacteria Bacillus subtilis.56 It was synthesized in 1996 by Lu and Snider

in 8 steps and 4% yield.57 Another N-methoxypyridone, YCM1008A, derived from

Fusarium, was discovered to be a Ca2+ signaling inhibitor and was synthesized by

Hosokawa et al (Figure 1.10).58

Figure 1.10 N-methoxy pyridone alkaloids

4-Hydroxypyridones, typically derived from tetramic acid with a biosynthetic

oxidative ring expansion,59-61 form a class of compounds with antifungal and antitumor

properties.62 4-Hydroxypyridones include ilicicolin H, synthesized by the D’Antuono

9

group63 and sambutoxin, synthesized by Williams and coworkers (Figure 1.11).64 The

aforementioned iromycins also fall under this classification.

Figure 1.11 4-Hydroxy pyridone alkaloids

4,N-Dihydroxypyridones include tenellin65 and its related family of antifungal

compounds,66-69 as well as the antibiotic akanthomycin.70 The antitumor drug

candidate TMC-69-6H, isolated from cultured Chrysosporium, has been synthesized

several times due to its selective phosphatase inhibition.71-73 The atropoisomers

cordypyridone A and B are comparatively structurally simple, but have antimalarial

properties presumably due to their action as siderophores (iron transporting small

molecules). They were synthesized in concise fashion by Chai and coworkers.74

Didymellamide A, recently discovered from the marine fungi Stagonosporopsis

cucurbitacearum, displays antifungal activity against azole-resistant C. albicans.

(Figure 1.12).75

10

Figure 1.12 4,N-Dihydroxy pyridone alkaloids

Polycyclic pyridones include the bicyclic antifungal furopyridone CJ16-170,

synthesized by Che and Snider,76 and the anticancer Louisanin family, synthesized

most recently by Kaila Margrey of the Scheerer Lab.77 The pentacyclic,

monoterepenoid indole-containing molecule naucline was recently isolated from the

bark of Nauclea officinalis, a traditional Chinese medicine (Figure 1.13).78

Figure 1.13 Polycyclic pyridone alkaloids

New pyridone natural products have been isolated periodically over the past

half century, with the past decade seeing a new family of pyridones every year. There

are, understandably, too many to list individually.79 Some recent highlights (Figure

1.14) are the arthpyrones (2015)80 and campyridones (2016),81 which are ring-fused

11

ethereal metabolites of 4-hydroxypyridones. In the same class as these are the

hypocrellutins (2018), isolated from the scale-insect pathogenic fungus Hypocrella

discoidea.82 While showing no activity in biological assays, I find hypocrellutin A

structurally beautiful.

Figure 1.14 Recently discovered pyridone natural products

Pyridone Derivatization

While present as a bioactive motif in a wide variety of natural products, the

pyridone nucleus has also been used as a starting point for many complex

compounds. N-Protected pyridones are susceptible to Diels-Alder [4+2] cycloaddition,

but their aromatic character and electron deficiency makes this process slow, with

reaction times ranging from days to a month at 100 °C.83-85 This rate can be enhanced

substantially using 3-hydroxypyridones and an alkylamine base catalyst, furnishing

only endo cycloadducts in half an hour at ambient temperatures, and in excellent

yields (Scheme 1.2).86 A chiral β-amino alcohol organocatalyst can make this reaction

enantioselective.87 Inverse-electron-demand Diels–Alder (IEDDA) reactions have

12

also been optimized to ambient temperatures, though the rate is still slow (24-48h).88

Scheme 1.2 Dramatic rate enhancement in the base-catalyzed Diels-Alder of

3-hydroxypyridones

Intramolecular [4+4] and [2+2] photodimerization of tethered dipyridones offer

a unique route to unusual 8- and 11-membered ring systems (Scheme 1.3).89, 90

Pioneered by Scott Sieburth over a couple decades and a dozen publications, the

methodology has been expanded to (tethered) furans,91 enynes,92, 93 pyrones,94, 95

and benzenes.96 Trans or cis ring fusion (8 membered or larger) can be controlled by

solvent effects, as the molecular orientation depends on the H-bonding dimerization

of pyridones.97 The methodology was used to prepare an intermediate to taxol.98

Intermolecular reactions are possible, but are lower yielding and less selective.99

Scheme 1.3 [4+4] photodimerization of tethered dipyridones

Direct derivatization of 2-pyridones has been achieved at most positions. N

13

and O can be alkylated with simple SN2 chemistry, or more mildly with coupling100-102

conditions. N-Alkylation is typically dominant, especially in polar solvents with alkali

salts. O-alkyl products can be formed exclusively with the use of silver salts, nonpolar

solvents, and sterically bulky electrophiles.103 The C6 position can be accessed

through methoxymethyl (MOM) directed zincation/magnesiation104 or pyridyl-directed

Rh or Pd C-H alkylation, arylation,105 alkynylation,106 and borylation.107 Iron catalysis

furnished aryl substitution at the C3 position,108 while a gold catalyst installed an

alkyne at C5.106 These results are summarized in Table 1.

Table 1 Pyridone substitution strategies

Pyridone Conditions Product

i) Alkali metal (Na, K) ii) R-X DMF

i) Ag2CO3 ii) R-X

benzene

Ar-I CuI, DMCDA, K2CO3

toluene

Ar2IOTf Cs2CO3

DCE, 120 °C

i) TMP2Zn·2LiCl·2MgCl2 THF, -10 °C, 72h

ii) Ar-I

R-BF3K (Cp*RhCl2)2 (5 mol%)

AgSbF6 (20 mol%) DCE 40-100 °C

R= alkyl, aryl

B2pin2 [Rh(OMe)(cod)]2 (2 mol%)

THF

14

(Cp*RhCl2)2 (5 mol%) Zn(OTf)2 (15 mol%)

DCE 80 °C

Si-EBX AuCl (5 mol%)

TFA Dioxane 80 °C

R= alkyl, H

ArB(OH)2 Fe(NO3)3·9H2O (10 mol%)

K2S2O8, K2CO3 1:1 DCE:H2O 70 °C

air

Synthetic Approaches to Pyridones

The synthesis of the pyridone nucleus has been a longstanding challenge

dating back to the 1920s,109 and has been reviewed on a few occasions.4, 110 Select

recent examples of synthetic strategies will be presented in context, rather than

repeating the prior reviews.

The interconversion of 2-substituted pyridines to pyridones is a common tactic

in natural product synthesis. 2-halopyridines and 2-alkoxypyridines can be liberated

by simple hydrolysis, which is aided by the preformation of pyridinium salts.111 O-

benzyl pyridines can be cleaved at ambient temperatures by simple hydrogenation112

or ruthenium catalyzed photoreduction.113 Demethylation of O-Me pyridines is

commonly afforded by sodium ethanethiolate (NaSEt) at elevated temperatures (120

°C) (Scheme 1.4).38

15

Scheme 1.4 Strategies to reveal masked pyridones

Condensation reactions are some of the oldest and most fundamental

reactions in organic chemistry. They were the first avenues of assembling pyridones,

via the aldol condensation and subsequent imine condensation of an α-cyano amide

with a β-diketone in the presence of piperidine (scheme 1.5).109

Scheme 1.5 Classical condensation reaction

Such reactions have been accomplished with varying synthons114 to produce

large libraries of simple substituted pyridones.115 A typical modern procedure involves

a diketone, a substituted amine, and an electron deficient alkene heated in one pot

(Scheme 1.6).116 These reactions work best when run neat with microwave heating,

which limits their scale. The necessity of electron withdrawing groups (typically esters

or nitriles) also narrows the scope to substituted pyridones. The Vilsmeier-Haack

16

reaction has been used to form pyridones in a similar fashion.117

Scheme 1.6 Modern condensation reaction

It is worth mention that N-tosylated hydropyridones can be easily deprotected

and aromatized through simple base mediated elimination (Scheme 1.7).118 This

transformation, while limited by the acidity of the C6 proton, is quantitative and very

powerful within specific contexts (such as ring closing metathesis119).

Scheme 1.7 Aromatization of N-tosyl hydropyridones

Electrocyclic ring closure of either (A) an isocyanate with an alkene or (B) an

imine with an acylketene offers a unique route to ring-fused pyridones (Scheme 1.8).

Isocyanates are typically furnished by Curtius rearrangement, historically with

trimethylsilyl azide120 and modernly with diphenyl phosphoryl azide (DPPA).121

Ketenes have been prepared by either ring-opening cyclobutanes122 or cleavage of

Meldrum’s acid derivatives.123 This chemistry has led to a variety of tri- and bicyclic

pyridones, as well as furan and thiazole fused pyridones. The major downsides are

17

potentially high temperatures required (up to 180 °C) and starting material synthesis.

Scheme 1.8 Electrocyclic ring closures of isocyanates and acyl ketenes

Metallocyclization was developed over the past couple decades for the

synthesis of pyridones. The [2+2+2] metallocyclization of dialkynes with nitriles,

isocyanates, and isothiocyanates have been reviewed previously,124 utilizing iridium,

rhodium, and zinc. By this method, only substituted pyridones (typically alkyl) can be

made in a high yield, but thio derivatives can also be easily accessed. Other limitations

include starting material synthesis (diynes and ketene type functional groups), as well

as ligand optimization. Ollivier et al. most recently made a variant of this reaction

which is enantioselective of biaryl atropisomers. This was accomplished through a

strategy termed ‘double stereodifferentiation,’ making use of rhodium in tandem with

a chiral phosphine and a chiral silver counterion (Scheme 1.9).125 The optimization of

this reaction is relatively interesting. It progresses at room temperature (rather than

80 °C) if the Rh(cod)Cl2 catalyst is hydrogenated prior to use, as cyclooctadiene (cod)

can be reduced, leaving a more accessible active site. There is also a pre-mixing time

necessary to optimally form the chirality-transferring ion pair.

18

Scheme 1.9 [2+2+2] Metallocyclization with double stereodifferentiation

Thermal cycloaddition, where two unsaturated components form a new ring in

a concerted and energetically favorable process, is conceptually the most

straightforward route to six membered rings, with a rich history dating back to the work

by Otto Diels and Kurt Alder in the late 1920s. By definition, cycloadditions form new

σ bonds at the expense of π bonds. This means, in order to form aromatic

heterocycles via cycloaddition, it requires either two π components in the starting

materials (alkynes or equivalent), or a subsequent event that reestablishes

aromaticity (elimination or cycloreversion). The former approach, termed a dehydro-

Diels-Alder, has historically only been used to form benzenoids126 until very recently

when Hoye and coworkers developed a pentadehydro-Diels-Alder which produced

pyridines (Scheme 1.10).127 This approach has not been extended to pyridones, but

presumably could give a pyridone precursor (e.g. 2-alkoxypyridine) if the starting

alkyne was appropriately alkoxy-substituted. The limitations of this approach are

starting material synthesis and the required tether which leaves behind a fused 5-

membered ring.

19

Scheme 1.10 Pentadehydro-Diels-Alder reaction yielding pyridines

The more common approach to aromatic heterocycles via cycloaddition relies

on the formed cycloadduct containing an instability which allows for favorable,

selective cycloreversion. [3+2] Cycloaddition (involving 1,3-dipoles), has yielded

pyridones with the subsequent elimination or extrusion of one atom bridges of either

oxygen, sulfur, or nitrogen, in the cases of isomünchnones,128 thiomünchnones,129, 130

or carbanionic pyrroloimidazoles,131 respectively (Scheme 1.11). Münchnones and

derivatives are prone to rearrangement (and therefore generally low yielding), and

their synthesis can be lengthy.

Scheme 1.11 [3+2] cycloaddition/elimination of an isomünchnone

[4+2] Cycloaddition and subsequent cycloreversion is preferable to [3+2] as it

avoids charged intermediates and precursors. Additionally, the retro-Diels-Alder can

be very favorable and proceed spontaneously when the extruded two atom bridge

produces a neutral gas such as N2 or HCN, in the case of (cyclic) azines, or CO2 in

the case of oxazinones (Scheme 1.12). While this technique has been used to a great

extent by Boger and coworkers,132 the methodology is typically limited to pyridines.

20

Scheme 1.12 Diels-Alder/retro-Diels-Alder strategies for pyridines

There are relatively few examples of [4+2]/r[4+2] reactions yielding pyridones.

First is that of Sammes et al.,133 who reacted hydroxypyrazines with diester-

acetylenes. The cycloadduct existed with two lactam bridges, either of which could be

extruded with heat (Scheme 1.13).

Scheme 1.13 Early [4+2]/r[4+2] strategy for pyridones from pyrazines

Sammes later expanded this methodology to derivatives of pyrimidines or

pyrazinones, but either high temperatures (150-200 °C) or strong acid (HCl) was

required to affect retro-Diels-Alder. The latter transformation was recently reported134

between electron deficient pyrazinones and alkynyl boronates, offering a favorable

route to relatively simple pyridones which can be derivatized and coupled at the C5

position (Scheme 1.14). Drawbacks include high temperature (180 °C), neat heating,

and modest yield (51-68%).

21

Scheme 1.14 Recent [4+2]/r[4+2] strategy for pyridones from pyrazinones

The other precedent is from an oxazinone by Shioiri et al.135 This oxazinone is

formed transiently from the reaction of an acyl isocyanate with a silyl ketene, and then

undergoes a Diels-Alder/retro-Diels-Alder when reacted with dienophiles (Scheme

1.15). The degree of unsaturation in the precursors limits substitution to the C4 and

C5 positions, with C6 always containing an aryl group to enable the reaction

electronics. The oxazinones were not isolated because they were prone to hydrolyze

“within a few minutes.” Still, the evolution of CO2 is a favorable process that inspires

continued interest in oxazinones.

Scheme 1.15 [4+2]/r[4+2] strategy for pyridones from oxazinones

Our lab’s efforts towards pyridones began with Kaila Margrey.136 First, glycine

or proline derived diketopiperazines containing a lactim O-methyl ether were

synthesized in four steps and moderate yield. They were then reacted with an

aromatic aldehyde containing an alkyne tether, in an aldol condensation. The

22

resultant exocyclic alkene could be isomerized into the ring with an organic base,

transiently forming a pyrazinone which would undergo a Diels-Alder at 100 °C. The

produced cycloadduct contained a lactim o-methyl ether which was too stable for

retro-Diels-Alder (up to 200 °C). Following demethylation and acetylation, the now

imide bridge was extruded at temperatures conveniently accessed through

microwaved toluene (~200 °C), furnishing tri- and tetracyclic pyridones (Scheme

1.16).

Scheme 1.16 Scheerer lab strategy for pyridones from diketopiperazines

Conclusion

2-Pyridone is a unique structural motif that occurs naturally in a wide variety of

pharmacologically relevant natural products. The desirability of these natural products

has driven synthetic interest in pyridones for the past 70 years. Synthesis and

derivatization of pyridones remains challenging due to its unique physical and

electronic properties. While there are methods of synthesizing pyridones, each has

its advantages and disadvantages. Diels-Alder/retro-Diels-Alder processes have low

reaction thresholds and can quickly furnish polycyclic heterocycles. There are few

examples of [4+2]/r[4+2] processes yielding pyridones, so we sought to improve on

the Margrey synthesis.

23

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99. Mederski, W.; Lefort, M.; Germann, M.; Kux, D., N-aryl heterocycles via coupling reactions with arylboronic acids. Tetrahedron 1999, 55 (44), 12757-12770.

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101. Li, X. H.; Ye, A. H.; Liang, C.; Mo, D. L., Substituent Effects of 2-Pyridones on Selective O-Arylation with Diaryliodonium Salts: Synthesis of 2-Aryloxypyridines under Transition-Metal-Free Conditions. Synthesis 2018, 50 (8), 1699-1710.

102. Hopkins, G. C.; Jonak, J. P.; Minnemey.Hj; Tieckelm.H, ALKYLATIONS OF HETEROCYCLIC AMBIDENT ANIONS .2. ALKYLATION OF 2-PYRIDONE SALTS. Journal of Organic Chemistry 1967, 32 (12), 4040-&.

103. Ziegler, D. S.; Greiner, R.; Lumpe, H.; Kqiku, L.; Karaghiosoff, K.; Knochel, P., Directed Zincation or Magnesiation of the 2-Pyridone and 2,7-Naphthyridone Scaffold Using TMP Bases. Org. Lett. 2017, 19 (21), 5760-5763.

104. Peng, P.; Wang, J.; Jiang, H.; Liu, H., Rhodium(III)-Catalyzed Site-Selective C–H Alkylation and Arylation of Pyridones Using Organoboron Reagents. Org. Lett. 2016, 18 (20), 5376-5379.

105. Li, Y. Y.; Xie, F.; Li, X. W., Formal Gold- and Rhodium-Catalyzed Regiodivergent C-H Alkynylation of 2-Pyridones. Journal of Organic Chemistry 2016, 81 (2), 715-722.

106. Miura, W.; Hirano, K.; Miura, M., Rhodium-Catalyzed C6-Selective C-H Borylation of 2-Pyridones. Org. Lett. 2016, 18 (15), 3742-3745.

107. Modak, A.; Rana, S.; Maiti, D., Iron-Catalyzed Regioselective Direct Arylation at the C-3 Position of N-Alky1-2-pyridone. Journal of Organic Chemistry 2015, 80 (1), 296-303.

108. Wenner, W.; Plati, J. T., DERIVATIVES OF 2-PYRIDONE. Journal of Organic Chemistry 1946, 11 (6), 751-759.

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111. Cheng, D.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T., Synthetic entries to substituted bicyclic pyridones. Org. Lett. 2007, 9 (25), 5175-5178.

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112. Heo, J. N.; Song, Y. S.; Kim, B. T., Microwave-promoted synthesis of amino-substituted 2-pyridone derivatives via palladium-catalyzed amination reaction. Tetrahedron Letters 2005, 46 (27), 4621-4625.

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114. Fujii, M.; Nishimura, T.; Koshiba, T.; Yokoshima, S.; Fukuyama, T., 2-Pyridone Synthesis Using 2-(Phenylsulfinyl)acetamide. Org. Lett. 2013, 15 (1), 232-234.

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116. Hairui, B.; Rongrong, S.; Xuebing, C.; Lijuan, Y.; Chao, H., Microwave‐Assisted,

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120. Macmillan, J. H.; Washburne, S. S., INTERACTION OF CARBONYL-COMPOUNDS WITH ORGANOMETALLIC AZIDES .5. SORBOYL CHLORIDE AND ITS CONVERSION TO AN ALPHA-PYRIDONE. Journal of Organic Chemistry 1973, 38 (17), 2982-2984.

121. Nishiyama, T.; Hatae, N.; Hayashi, K.; Obata, M.; Taninaka, K.; Yamane, M.; Oda, S.; Abe, T.; Ishikura, M.; Hibino, S.; Choshi, T., ONE-POT SYNTHESIS OF FUSED 2-PYRIDONES FROM HETEROARYLACRYLIC ACID VIA CURTIUS REARRANGEMENT AND MICROWAVE-ASSISTED THERMAL ELECTROCYCLIZATION. Heterocycles 2017, 95 (1), 251-267.

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123. Pemberton, N.; Jakobsson, L.; Almqvist, F., Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation. Org. Lett. 2006, 8 (5), 935-938.

124. Tanaka, K., RHODIUM-CATALYZED 2+2+2 CYCLOADDITION FOR THE SYNTHESIS OF SUBSTITUTED PYRIDINES, PYRIDONES, AND THIOPYRANIMINES. Heterocycles 2012, 85 (5), 1017-1043.

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125. Auge, M.; Feraldi-Xypolia, A.; Barbazanges, M.; Aubert, C.; Fensterbank, L.; Gandon, V.; Kolodziej, E.; Ollivier, C., Double-Stereodifferentiation in Rhodium-Catalyzed 2+2+2 Cycloaddition: Chiral Ligand/Chiral Counterion Matched Pair. Org. Lett. 2015, 17 (15), 3754-3757.

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128. Moore, D. R.; Mathias, L. J., NEW 2-PYRIDONE DERIVATIVES VIA 1,3-DIPOLAR CYCLOADDITIONS OF NOVEL MESOIONIC COMPOUNDS. Journal of Organic Chemistry 1987, 52 (8), 1599-1601.

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130. Arevalo, M. J.; Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Light, M. E.; Palacios, J. C., Construction of C-nucleosides diversified by 3+2 cycloaddition from a sugar-based mesoionic ring. Tetrahedron 2006, 62 (29), 6909-6917.

131. Musicki, B., REACTION OF PYRROLO 1,2-C IMIDAZOLE MESOMERIC BETAINES WITH DIPHENYLCYCLOPROPENONE DERIVATIVES. Journal of Organic Chemistry 1991, 56 (1), 110-118.

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136. Margrey, K. A.; Hazzard, A. D.; Scheerer, J. R., Synthesis of 2-Pyridones by Cycloreversion of [2.2.2]- Bicycloalkene Diketopiperazines. Org. Lett. 2014, 16 (3), 904-907.

33

Chapter 2

Development of a One Pot [4+2]/r[4+2] 2-Pyridone Synthesis

Reaction Development

Inspired by the Margrey precedent, we sought to create a more expedient route

to similar tricyclic pyridones starting from commercially available materials. We began

with an aldol condensation between a simple diketopiperazine 1 and an aromatic

alkynylbenzaldehyde, yielding 2. From there, we envisioned trapping the lactam as

lactim ether 3, and afterwards isomerizing the exocyclic alkene into the ring to form

pyrazinone 4. Precedented cycloadditions with pyrazinones led us to be confident that

4, if formed, would spontaneously react intramolecularly with the alkyne tether,

forming 5 in a Diels-Alder [4+2] cycloaddition. We believed we could then selectively

extrude one of the bridges of 5 in a retro-Diels-Alder reaction, to yield tricyclic pyridone

6 (Scheme 2.1).

Scheme 2.1 One pot reaction plan

To this end, we made diacetyldiketopiperazine 1 by the quantitative bis-

acetylation of glycine anhydride using acetic anhydride. For the other reactant, we

performed our initial studies with the commercially available 2-ethynylbenzaldehyde

34

7, but later expanded to a variety of alkynyl-substituted benzaldehydes through known

Sonogashira couplings (Scheme 2.2).1 Coupling materials, aside from catalysts used

at 4-7 mol%, were typically a few dollars per gram.

Scheme 2.2 Starting material synthesis

With starting materials in hand, we attempted the sequence stepwise. To our

pleasant surprise, the aldol condensation was quite facile with 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) in dimethylformamide (DMF) at room

temperature, owing to the imide functionality (Scheme 2.3). In contrast, the Margrey

precedent required the stronger lithium hexamethyldisilazide (LiHMDS).

Scheme 2.3 Initial success in the aldol condensation

The reaction predominantly forms the kinetically favored and desired Z alkene

8, though it can isomerize up to 10% of the E isomer if allowed to react longer than

the required 1-1.5h reaction time (e.g., overnight). The first attempt was exceptional,

35

isolating the aldol product in 93% yield (7 mmol scale), after it precipitated out of the

workup solution due to its poor solubility in EtOAc. This ended up being quite difficult

to replicate, as too little EtOAc would carry through the small percentage of E isomer,

and too much EtOAc would precipitate less and give a low yield. It was crucial that

the aldol product be isolated upon workup, as recrystallization turned out to be

difficult2 and column chromatography was low yielding (~30%), due to low solubility

in EtOAc and high polarity. We found that the inorganic base Cs2CO3 also worked

well and allowed us to avoid acidic workup. A reaction mixture of 1:1 DMF:toluene

gave reliable precipitation upon dilution with Et2O/di-H2O, and the crystals were rinsed

with the same mixture. This optimized procedure gave the pure Z isomer in 85% yield,

and this yield proved typical upon replication (Scheme 2.4). The procedure is quite

general and has been applied to other diketopiperazine aldol products in our

laboratory.

Scheme 2.4 Optimized aldol condensation

Attempts to form and isolate a lactim ether were not successful. A variety of

silylating agents were tried, such as di-tert-butyldichlorosilane (TBSCl),

hexamethyldisilazane (HMDS), bis(trimethylsilyl)acetamide (BSA), and tert-

butyldimethylsilyl trifluoromethanesulfonate (TBSOTf). It is reasonable to assume the

lactim o-silyl ether products were formed but hydrolyzed back to starting material upon

workup. Meerwein’s salt (trimethyloxonium tetrafluoroborate) was used to form the

36

lactim o-methyl ether. This was marginally successful, but mass recovery and

subsequent isolated yield were unacceptably low (<30%) (Scheme 2.5).

Scheme 2.5 Attempts to isolate lactim ethers

Next, we paired a silylating agent with a base to avoid isolating the lactim o-

silyl ether and promote alkene isomerization and subsequent Diels-Alder. With DBU

as a base and BSA as a silylating agent in DMF at 120 °C, we were surprised to find

that the isolated product was not the cycloadduct 9, but the cycloreversion product 10

(entry 1). This prompted further investigation which is summarized in Table 2.1.

37

Table 2.1 Diels-Alder/retro-Diels-Alder optimization

Refluxing toluene (110 °C) offered similar results to DMF at 120 °C, allowing

us to avoid working with high boiling DMF (entry 2). When the reaction was run with

temperature increasing in increments, no reaction was observed until 85 °C (block

setting), which consumed starting material and gave a new spot by TLC. This turned

out to be the cycloadduct 9 (entry 3). The inorganic base Cs2CO3 deacylated the imide

bridge at elevated temperatures, leading to no desired products (entry 4). Later, we

discovered that using the weak base triethylamine (NEt3) afforded only the

cycloadduct at 120 °C (entry 5). We doubted that NEt3 was really required, but studies

without it showed no reaction (entry 6). Substoichiometric amounts of DBU gave a

mixture of the two products, meaning that at least one equivalent of DBU was required

to affect the retro-Diels-Alder (entry 7).

The yield for entry 5 was variable. BSA could cause up to 15% of byproducts

related to acetamide. In the cases where these were acceptably low (>95% purity),

38

the cycloadduct did not need to be purified and yield would reach 90%. Other attempts

required purification, which decreased the yield to ~60-80%, as there was a degree

of degradation on the column. This issue was avoided by switching to

chlorotrimethylsilane (TMSCl), as its only byproduct is gaseous HCl. Use of TMSCl

lead to quantitative formation of cycloadduct 9 (entry 8), and cleaner production of 10

(entry 9). This result should not be understated. Typically, TMSCl and alkylamines

such as NEt3 are only used freshly distilled. Both of the reagents were always used

out of a bottle for this work, which is why higher equivalents of each were used. Less

reagent (2 equiv TMSCl, 3 equiv NEt3) worked fine if fresh, but the fact that these

reactions work just as well with old TMSCl and NEt3 speaks to their robustness and

ease of replication.

The low yield of the retro-Diels-Alder requires elaboration. The reaction was

run fifteen different times with varying amounts of reagents, reaction time, workup,

and purification/derivatization techniques. Nothing improved the situation, which in

retrospect, was caused by the unfortunate physical properties of pyridone 10. By

typical procedure, pyridone 10 is isolated in reasonable mass recovery (<70%) with

~30% DBU-related impurities. It can be purified, but due to its polarity and poor

solubility it tends to adhere to a CHCl3/MeOH column. Even in the most optimized

conditions, this translates to a <30% isolated yield. There is also always a large

amount of black powder precipitate isolated during workup. The black powder is

effectively insoluble in all but the most polar and high boiling solvents such as DMF

and dimethylsulfoxide (DMSO). Initially it appeared as if this was an insoluble

pyridone hydrate dimer, as it constituted over 100% mass recovery while appearing

to be pure 10 (with water) in deuterated DMSO 1H NMR spectroscopy. Repeated,

39

excessive washings of the precipitate with EtOAc removed 10 from the solid. The

precipitate alone appeared polymeric.3 Pyridones are known to polymerize near their

melting point (190-210 °C);4 While temperatures do not reach this high, base

promoted polymerization is not uncommon,5 especially with strong organic bases

such as DBU.6

Due to the difficulty of recovering pure pyridone from the Diels-Alder/retro-

Diels-Alder, our attention shifted to probing the reactivity of the retro-Diels-Alder in

isolation. To this end, cycloadduct 9 was produced in large scale and subjected to

varied conditions (Table 2.2).

Table 2.2 Optimization of the retro-Diels-Alder

It was immediately apparent from these reactions that greater than an

equivalent of DBU was required, but that there was no real difference in rate observed

40

for a moderate excess (entry 1), which was used when convenient (e.g., small scale).

Vast excesses of DBU yielded no product (entry 2). DBU at higher temperatures

(entry 3) produced 10 but with a minor decrease in purity. Weaker bases (entry 4, 5)

did not affect retro-Diels-Alder, even under forcing conditions. The threshold for retro-

Diels-Alder is higher than in the Margrey precedent, as only pure starting material was

observed after heating to 200 °C in toluene in the microwave (entry 6). Heating 9

directly on a hotplate at 200 °C afforded 10 but with impurities and the insoluble

polymer (entry 7). The presence of silylating reagent (one pot conditions) made

minimal difference as long as there was excess base (entry 8).

As the DBU based optimization studies seemed to reach a dead end, we

sought to screen a wide range of reagents which could potentially promote the retro-

Diels-Alder (Table 2.3). Included in this table is the isomeric impurity 10i which is

caused via acyl transfer. This impurity is formed in ~20% conversion when heated

neat (i.e., thermally).

41

Table 2.3 Retro-Diels-Alder reaction screening

Refluxing pyridine, even when used as the solvent, returned starting material

(entry 2). Subjecting 9 to acidic conditions via acetic acid or trifluoroacetic acid (entry

3, 4) also returned starting material. The Lewis acids scandium triflate and copper

triflate (entry 5, 6) primarily deacylated the material, but also produced a byproduct

which we were not able to identify. This byproduct was red in visible light but

constituted only a few mass%, and was therefore difficult to characterize. The strong

base sodium hydride (entry 7) afforded a 1:1 mixture of 10 and 10i. This was quite

impure but occurred at a lower temperature than DBU (80 °C). The strong base

LiHMDS (entry 8) gave only very impure, trace product. 7-Methyl-1,5,7-

triazabicyclo[4.4.0]dec-5-ene (MTBD), a base 1.5 pKa units stronger than DBU, also

afforded a 1:1 mixture at 80 °C and a comparable result to DBU at 110 °C (entry 9).

The phosphazene base tert-butylimino-tri(pyrrolidino)phosphorene (BTTP), a base

4.5 pKa units higher than DBU, only deacylated the material at 60 °C, but afforded

the desired product 10 at 110 °C (entry 10). However, the phosphazene proved

inseparable from 10 via chromatography.

At this point in the investigation, it had been a couple years of part-time effort

as an undergraduate student. Having accepted the poor yield of the retro-Diels-Alder

as a fact of life, a final effort was made to couple the aldol condensation with the other

steps, such that the chemistry would be more convenient to replicate. Considering the

first two steps are nearly quantitative, the expected 27% yield over 3 steps translated

into an average ~65% yield per step, which is respectable enough to report in the

literature. Much to our surprise, including the aldol condensation in the one pot

process gave a 67% overall yield (Scheme 2.6).

42

Scheme 2.6 Unexpectedly high yielding one pot process

The work-up for this reaction began typically, by diluting the reaction using

EtOAc and quenching with an appropriate amount of 0.1M HCl. However, during the

subsequent Büchner filtration, the black solid precipitate was non-existent, and

seemingly all of the product washed through the filter pad. The crude residue

contained only minor impurities, and was clean enough to use without purification,

affording a 67% yield upon replication. It is important to note that a small amount of

precipitate appeared after neutralization with NaHCO3. This solid was the less soluble

impurity 10i, which constituted 20% conversion by mass. When the reaction was

replicated with additional DMF added during workup, 10i was solvated and the

reaction afforded an 88% yield with a 5:1 mixture of 10:10i. Though 10i was not found

during stepwise DBU experiments, the high yield of 10 and the ease of avoiding 10i

during workup is preferable.

Efforts to understand why the one pot process is cleaner than the stepwise

reaction, and why polymeric material is formed during the stepwise reaction, have not

been successful. As previously mentioned, silylating reagents have no effect on the

retro-Diels-Alder. Therefore, the only principal difference between the one pot and

stepwise processes is the elimination of acetate during the aldol condensation.

Attempting the retro-Diels-Alder with an equivalent of acetic acid and excess DBU

(i.e., DBU buffered acetate), showed no difference from other stepwise r[4+2]

43

attempts. Though the one pot must use DMF to solvate DKP 1, the retro-Diels-Alder

has been previously shown to behave identically in either DMF or toluene.

Substrate Scope

With a functional one pot [4+2]/r[4+2] 2-pyridone synthesis in hand, our efforts

turned to examining the substrate scope (Table 2.4).

Table 2.4 One pot substrate scope

Alkyl substituents were used to test the reaction’s sensitivity to steric bulk on

the alkyne. The resulting substrates (entry 1, 2) were much more soluble than 10 (R=

H), and were purified after workup using a CHCl3/MeOH flash column. The n-butyl 19

(entry 1) was formed in fair yield (52%), while the t-butyl 20 (entry 2) was isolated in

very good yield (81%). This shows that there is little effect of steric bulk on the

reaction. The lower yield of the n-butyl substrate suggests possible degradation

through reaction at the saturated alkynyl position. Ethereal substrates (entry 3, 4)

appeared to progress normally by TLC, but no product was isolated. Likewise, phenyl

44

substitution (entry 5) showed apparent progression by TLC, but did not yield 23. TMS

(entry 6) progressed to the pyridone, but the silicon was not stable in the product and

only 10 was isolated. The pyridine substituent did not progress by TLC (entry 7).

Finally, the (CH2)2Ph substituent (entry 8) was not used as it was deemed too similar

to the alkyl substrates to make a meaningful contribution towards understanding the

reactivity.

Due to the apparent reaction progression of the unsuccessful substrates, a

modified one pot procedure was developed to quickly access the cycloadduct

structures (Table 2.5).

Table 2.5 Modified one pot procedure to produce cycloadducts

The formed cycloadducts were all normally soluble amorphous (foam-like)

compounds purified via EtOAc/hexanes flash chromatography. The previously

investigated 7 (entry 1) was used to provide a baseline of expected yield, given that

the cycloadducts experience some decomposition during chromatography due to their

acid sensitivity. Tetrahydropyranyl (THP) ether 13 formed cycloadduct 26 in moderate

yield (50%, entry 2), while the benzyl ether 14 formed cycloadduct 27 in good yield

45

(65%, entry 3). This difference can be attributed to the acid sensitivity of THP, which

also existed as a pair of diastereomers due to the chirality of THP. The phenyl

substituted 15 formed cycloadduct 28 in decent yield (67%, entry 4). This process

was rather slow (24h) and had the unusual event of acyl transfer, with both bis-

acetylated material and deacetylated material being isolated. These byproducts

constituted ~10% yield each. The TMS aldehyde 16 gave cycloadduct 29 in moderate

yield (55%), as well as desilylated cycloadduct 9 (11%) (entry 5). The desilylated

material was present in the crude reaction mixture and was not an artifact of

chromatography. The 2-pyridyl aldehyde 17 was surprisingly unreactive, only forming

the aldol condensation product 30 (entry 6).

Treatment of each isolated cycloadduct with DBU had varying effectiveness at

promoting retro-Diels-Alder. In examining the propargylic substrates, the THP

substrate 26 showed initial promise in r[4+2], but interpretation was complicated by

the presence of diastereomers. The benzyl ether 27, being more stable and higher

yielding in the prior step, was used instead. Conventional heating of 27 with DBU

afforded pyridone 22 in acceptable yield (49%, Scheme 2.7).

Scheme 2.7 r[4+2] of an ethereal substituted cycloadduct

Cycloreversion of the phenyl substituted cycloadduct 28 proceeded rather

poorly with DBU and conventional heating, and was twice as slow as other reactions.

Peculiarly, no desired products were isolated if greater than one equivalent of DBU

46

was used. Doubling the concentration (0.1M -> 0.2M) improved the reaction rate to

be within a day. Heating the reaction in the microwave at 200 °C accomplished the

reaction within an hour, but with increased formation of the undesired isomer 23i. The

isolated yields for conventional heating and microwave heating were 16% and 25%,

respectively (Scheme 2.8).

Scheme 2.8 r[4+2] of a phenyl substituted cycloadduct

The TMS substituted cycloadduct 29 reacted similarly to the one pot conditions

upon treatment with DBU. Retro-Diels-Alder occurred in high conversion but only

desilylated pyridone 10 was isolated (Scheme 2.9).

Scheme 2.9 r[4+2] of a TMS substituted cycloadduct

The 2-pyridyl aldol condensation product 30 would not undergo [4+2] Diels-

Alder cycloaddition even under forcing conditions, only degrading the compound

(Scheme 2.10). Previous optimization studies of the [4+2] of 8 produced no desired

products when heated to 200 °C in the microwave, so this was not attempted for this

substrate.

47

Scheme 2.10 Unsuccessful [4+2] of a pyridyl substituted aldol product

Unsuccessful Substrates

Having successfully synthesized tricyclic pyridones, our attention turned to

substituent effects on the diketopiperazine starting material (Scheme 2.11). We

hypothesized that substitution would increase the rate of reactivity. Additionally, this

would offer substitution at the C3 position.

Scheme 2.11 Substituted diketopiperazine starting material synthesis

p-Anisaldehyde 31 was a convenient substituent as it is cheap and UV active.

After a typical aldol condensation yielding 32, the free amide on the diketopiperazine

was acetylated using acetic anhydride and the exocyclic alkene was reduced via

hydrogenation, producing racemic 33. This substrate served as a substituted

diketopiperazine model system. Afterwards, another standard aldol condensation

yielded 34. The aldehyde used in this reaction was 7 so that the alkynyl tether could

48

be utilized in later Diels-Alder chemistry. Yields were typical and not optimized;

acetylation and hydrogenation were expectedly quantitative.

Attempts to transiently form a pyrazinone and affect Diels-Alder of 34 failed in

a similar manner to the pyridyl substrate (Scheme 2.12).

Scheme 2.12 Unsuccessful [4+2] of a diketopiperazine substituted aldol product

Initial subjection of 34 to typical refluxing toluene conditions returned only

starting material. Incremental increases in heating created only further impurities and

no desired product 35. The material was heated in a sealed tube at 130 °C, then a

microwave at 170 °C, and finally a microwave at 200 °C.

Enolizable (that is, aliphatic) aldehydes have been used in one pot Diels-Alder

processes previously by our lab.7 The aldol condensation proceeded normally and

formed 37, but subsequent cycloaddition attempts failed. Attempted reaction in

refluxing toluene afforded zero conversion, so the material was resubmitted in DMF

at 150 °C. This reaction formed only the enolate derived byproduct 38 (Scheme 2.13).

49

Scheme 2.13 Aliphatic aldehydes produce an undesired byproduct

Synthesizing the volatile starting aldehyde 36 was problematic in my hands

and prevented further study. Having referenced its reported boiling point at various

pressures (50 °C at 15 torr, 90 °C at 80 torr), and consulted a pressure-temperature

nomograph, the rotory evaporator was set accordingly low enough temperature and

pressure so as to only evaporate solvents (23 °C, 20 torr). Distilling the aldehyde

directly was not fruitful. Dess-Martin oxidation followed by a column of low boiling

diethyl ether/pet ether resulted in very low mass recovery. A more conservative

approach was attempted using Parikh–Doering oxidation and avoiding rotary

evaporation. Fractions of a column of diethyl ether/pentanes were allowed to sit at

room temperature for two days, during which time the solvents expectedly

evaporated, but the aldehyde did as well. Having lost nearly 35 mmol of material, it

seemed wise to discontinue this substrate.

Expanding the Scope

We next sought to expand the reaction scope to include 6,6,6 tricyclic

pyridones, azaanthracenes (Scheme 2.14).

50

Scheme 2.14 Azaanthracene reaction plan

The additional carbon in the starting aldehyde 39 possesses a propargyl ether

which allowed for a straightforward synthesis of the starting material. We assumed

the aldol condensation to 40 and Diels-Alder to 41 would be relatively straightforward.

Retro-Diels-Alder would proceed with aromatization via elimination of alcohol, yielding

42.

The most expedient route to the starting aldehyde ended up being four steps

(Scheme 2.15).

Scheme 2.15 Starting material synthesis for 6,6,6 tricyclic pyridones

51

The first step followed literature precedent,8 using the inexpensive and

commercially available 43 and affording 44 with 88% yield at a 22 mmol scale. The

following Grignard addition required 1.5 equivalents of commercially available

ethynylmagnesium bromide and formed 45 in 80% yield following chromatography.

Initial studies were performed with an acetate protected alcohol, but downstream

products ended up being too insoluble to manipulate easily. The aliphatic nature of a

tert-butyldimethylsilyl (TBS) ether allowed these latter products to be soluble in typical

organic solvents. NEt3, TBSCl, and 4-dimethylaminopyridine (DMAP) in methylene

chloride was first used to install the TBS group, but it required purification and was

lower yielding than expected (52%). Corey’s conditions9 (TBSCl with imidazole in

DMF) proved superior, furnishing 46 cleanly and in high yield (95%). Cleavage of the

acetal to afford 47 is facile in a range of acidic conditions. It was first accomplished

with a mixture of HCl in THF and later with pyridinium p-toluenesulfonate (PPTS) or

p-toluenesulfonic acid (TsOH) in acetone. TsOH proved to be the quickest and

cleanest of these. Though it is a catalyst, 0.5 equivalents of TsOH proved convenient

because it accomplished complete conversion to 47 in forty minutes; it is essential to

form and use 47 quickly as the produced aldehyde is not stable. In total, 47 was

produced in 66% yield over four steps, with only one chromatographic separation

required after the Grignard addition. Typically, the last two steps and the subsequent

aldol condensation were run within the same day.

With starting material in hand, the reaction sequence was attempted beginning

with the aldol condensation. From the aldol product, various one pot conditions were

tried but did not yield desired products and were difficult to interpret. Best results came

from the stepwise sequence (Scheme 2.16).

52

Scheme 2.16 Stepwise sequence to azaanthracene

Aldehyde 47 was reacted with 1 using Cs2CO3 as base in DMF. A mixture of

toluene and DMF was not used because the aldol condensation product 48 was too

soluble to precipitate readily. Instead, it was purified by chromatography in a 49%

yield. O-silylation, alkene isomerization, and Diels-Alder appeared to have a higher

activation energy than previous substrates, as no reaction was observed under typical

conditions in refluxing toluene. A sealed tube at 130 °C with excess reagents and a

day of reaction time was required for it to go to completion. Heating to this higher

temperature forms triethylamide, a byproduct from deacylation caused by

triethylamine. This necessitated purification by chromatography, affording 49 in a 66%

yield. Cycloadduct 49 proved unstable, degrading over a few days if left at room

temperature. Retro-Diels-Alder also had a higher activation barrier than prior

experiments, with no reaction observed using DBU in refluxing toluene. Microwaving

the same mixture to 200 °C formed azaanthracene 50 with a minor amount of isomeric

product (10-20%). Chromatography gave 50 in a 62% yield. 5 equivalents of DBU

allowed this transformation to occur in an hour. Due to prior studies showing no

53

significant difference in DBU excess on the rate of retro-Diels-Alder, it is presumed

that the higher equivalents of base speed the reaction by hastening the elimination of

silanol. Overall, azaanthracene 50 was synthesized in a 7-step linear sequence of

13% yield, an average yield of 75% per step. While the spectroscopic data is

consistent with a 6,5,6 azaanthracene, the NMR spectra in DMSO-d6 does not match

that reported in the literature.10 A crystal structure is required to determine if this work

produced a regioisomeric product or if the literature is erroneous.

Conclusion

A one pot Diels-Alder/retro-Diels-Alder process was developed to quickly

synthesize tricyclic pyridones from cheap and commercially available starting

materials. Exploration of the substrate scope revealed that alkyl substituents

performed well and that steric strain did not play a large role in the process.

Problematic substrates were subjected to a modified one pot process to form the

desired cycloadducts. These cycloadducts were then converted to the corresponding

pyridones under individualized conditions. Some substrates were not fruitful, such as

the pyridyl substituted aldehyde, a substituted diketopiperazine, and an aliphatic

aldehyde. Expansion of the reaction scope to 6,6,6 tricyclic ring structures furnished

azaanthracene with only slight modification of each step.

54

Works Cited

1. S. Hughes, T.; K. Carpenter, B., Parallel mechanisms for the cycloaromatization of enyne allenes †. Journal of the Chemical Society, Perkin Transactions 2 1999, (11), 2291-2298.

2. Moderate success in recrystallization was found in a very unusual manner. Vacuum distilling methylene chloride at room temperature cooled the Büchner flask significantly due to evaporation, affording crystalline Z aldol at low temperatures. This procedure also crystallized ambient moisture and did not seem amenable or environmentally friendly to scale up, so effort was made to optimize the workup instead.

3. By NMR, the presumed polymer had peaks consistent with the parent pyridone, but with incredible broadening that overlapped entire regions but integrated roughly correctly. This appearance is similar to a pyridone based polymer which we intentionally created through ring opening metathesis polymerization (ROMP) in another project of our lab.

4. Brent, D. A.; Hribar, J. D.; Jongh, D. C. D., PYROLYSIS OF 2-PYRONE, COUMARIN, AND 2-PYRIDONE. Journal of Organic Chemistry 1970, 35 (1), 135-&.

5. Sanderson, J. J.; Hauser, C. R., Base Catalyzed Polymerization of Styrene. Journal of the American Chemical Society 1949, 71 (5), 1595-1596.

6. Weideman, I.; Pfukwa, R.; Klumperman, B., Phosphazene base promoted anionic polymerization of n-butyraldehyde. European Polymer Journal 2017, 93, 97-102.

7. Margrey, K. A.; Chinn, A. J.; Laws, S. W.; Pike, R. D.; Scheerer, J. R., Efficient Entry to the [2.2.2]-Diazabicyclic Ring System via Diastereoselective Domino Reaction Sequence. Org. Lett. 2012, 14 (10), 2458-2461.

8. Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O., Efficient Entry into 2-Substituted Tetrahydroquinoline Systems through Alkylative Ring Expansion: Stereoselective Formal Synthesis of (±)-Martinellic Acid. The Journal of Organic Chemistry 2010, 75 (3), 914-921.

9. Corey, E. J.; Venkateswarlu, A., Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives. Journal of the American Chemical Society 1972, 94 (17), 6190-6191.

10. Manikandan, R.; Jeganmohan, M., Ruthenium-Catalyzed Cyclization of Anilides with Substituted Propiolates or Acrylates: An Efficient Route to 2-Quinolinones. Org. Lett. 2014, 16 (13), 3568-3571.

55

Experimental

General procedure A: aldol condensation / alkene isomerization / Diels-Alder

cycloaddition / retro-Diels-Alder cycloreversion

To a solution of 1,4-diacetylpiperazine-2,5-dione (1 equiv, 0.56-2.3 mmol) in DMF (0.1

M) was added benzaldehyde (1.05 equiv) followed by DBU (1 equiv). The solution

was stirred until consumption of starting material (1-3 h). Additional DBU (5 equiv)

was added followed by TMSCl (4 equiv), and the reaction was heated to 120°C until

consumption of the cycloadduct intermediate (16-24 h). The reaction was cooled to

rt, diluted with EtOAc (30 mL), transferred to a separatory funnel, and quenched with

HCl (1 M, 1-10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The

combined organic layers were neutralized with NaHCO3 (10-50 mL), washed with

brine (10-50 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting

residue was purified by flash column chromatography on silica gel.

General procedure B: aldol condensation / alkene isomerization / Diels-Alder

cycloaddition

To a solution of 1,4-diacetylpiperazine-2,5-dione (1 equiv, 0.13-1.5 mmol) in DMF (0.1

M) was added benzaldehyde (1.05 equiv) followed by DBU (1 equiv). The solution

was stirred until consumption of starting material (1-12 h). NEt3 (5 equiv) was added

followed by TMSCl (4 equiv), and the reaction was heated to 120 °C until consumption

of the aldol condensation intermediate (2-24 h). The reaction was cooled to rt, diluted

with EtOAc (10 mL), transferred to a separatory funnel, and partitioned between

diH2O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The

combined organic layers were washed with brine (30 mL), dried with Na2SO4, filtered,

56

and concentrated in vacuo. The resulting residue was purified by flash column

chromatography on silica gel.

(Z)-1-acetyl-3-(2-ethynylbenzylidene)piperazine-2,5-dione (8).

To a solution of 1 (320 mg, 1.62 mmol) in 1:1 DMF/PhMe (5.4 mL, 0.3 M) was added

7 (210 mg, 1.62 mmol) and Cs2CO3 (554 mg, 1.70 mmol). The reaction was stirred

until consumption of the aldehyde was observed as judged by TLC (1.5 h). The

reaction mixture was diluted with 1:1 Et2O/diH2O (10 mL) and filtered, and the filter

pad was washed successively with additional H2O and Et2O. The resulting

condensation product 8 (370 mg, 1.38 mmol, 85% yield) was afforded as a yellow

solid that was used without further purification: mp 189-191 °C; TLC (60%

EtOAc/hexanes) Rf = 0.67 (UV, KMnO4); IR: 1683, 1631, 1369, 1254, 756 cm−1; 1H

NMR (400MHz, CDCl3): δ 7.80 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.42 (m, 4H), 4.52

(s, 2H), 3.41 (s, 1H), 2.68 (s, 3H), 1.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ

172.4, 162.5, 161.2, 135.8, 133.2, 129.4, 129.2 128.9, 128.8, 122.7, 116.1, 86.7, 82.1,

46.2, 27.3; MS (ES) calcd for C15H12N2O3Na [M + Na]+ 291.0740, found 291.0738.

57

(3S*,9aS*)-11-acetyl-3,4,4a,9-tetrahydro-3,9a-(epiminomethano)indeno[2,1-

b]pyridine-2,10(1H)-dione [Not chiral non racemic] (9).

To a solution of 8 (0.500 g, 1.87 mmol), in PhMe (10.4 mL, 0.18 M) was added NEt3

(944 mg, 9.33 mmol) followed by TMSCl (811 mg, 7.46 mmol). The reaction was

heated to reflux (110°C) for 20 h. After cooling to rt, the reaction mixture was diluted

with diH2O (30 mL) and extracted with EtOAc (30 mL). The organic layer was removed

and the aqueous layer was extracted with additional EtOAc (5 x 20 mL). The

combined organic layers were washed with brine (30 mL), dried with Na2SO4, filtered,

and concentrated in vacuo to afford cycloadduct 9 (0.495 g, 1.85 mmol, 99% yield) as

a pure, amorphous yellow solid: TLC (60% EtOAc/hexanes) Rf = 0.63 (UV, CAM); IR:

1697, 1369, 1333, 1244, 752 cm−1; 1H NMR (400MHz, CDCl3): δ 8.90 (br s, 1H), 7.44

(d, J = 7.4 Hz, 1H), 7.38 (d, J = 3.9 Hz, 2H), 7.30 (m, J = 7.8 Hz, 1H), 4.19 (d, J = 18

Hz, 1H), 3.18 (d, J = 18 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8,

169.3, 168.5, 156.1, 145.2, 132.5, 131.2, 128.1, 126.1, 123.0, 117.0, 70.4, 57.5, 32.7,

25.4; MS (ES) calcd for C15H12N2O3Na [M + Na]+ 291.0740, found 291.0739.

1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (10).

To a solution of 9 (16.5 mg, 0.062 mmol) in PhMe (0.9 mL, 0.07 M) was added DBU

(49 mg, 0.32 mmol). The reaction was heated to 110 °C for 4.5h. After cooling to rt,

the reaction mixture was diluted with Et2O (5 mL), quenched with HCl (0.2 M, 5 mL),

58

and extracted with EtOAc (5 mL). The organic layer was removed and the aqueous

layer was extracted with additional EtOAc (5 x 5 mL). The combined organic layers

were washed successively with NaHCO3 (10 mL) and brine (10 mL), dried with

Na2SO4, filtered, and concentrated in vacuo. The pure compound 10 (3 mg, 0.016

mmol, 27% yield) was obtained following flash column chromatography on silica gel

(elution: 2% to 7% MeOH in CHCl3) as a brown solid. mp 209-211 °C; TLC (5%

MeOH/CHCl3) Rf = 0.18 (UV, KMnO4); IR (film) cm-1 1636, 1470, 773 cm−1; 1H NMR

(400MHz, CDCl3): δ 12.05 (br s, 1H), 7.75 (dd, J = 5.5, 3.5 Hz, 1H), 7.64 (d, J = 5.5

Hz, 1H), 7.52 (d, J = 6.6 Hz, 1H), 7.44 (m, J = 5.5, 3.5 Hz, 2H), 6.83 (d, J = 6.2 Hz,

1H), 3.90 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 163.1, 152.8, 145.0, 139.9, 134.3,

130.5, 128.8, 126.9, 125.3, 121.5, 101.0, 35.2; MS (ES) calcd for C12H9NONa [M +

Na]+ 206.0576, found 206.0577.

1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (10).

Produced according to general procedure A with 1 (461 mg, 2.33 mmol) and 7 (318

mg, 2.44 mmol). The extracted organic residue afforded compound 10 (286 mg, 1.56

mmol, 67% yield) as a brown solid which did not require further purification.

4-butyl-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (19).

59

Produced according to general procedure A with 1 (111 mg, 0.56 mmol) and 11 (110

mg, 0.59 mmol). The pure compound 19 (70 mg, 0.29 mmol, 52% yield) was obtained

following purification by flash column chromatography on silica gel (elution: 2% to 7%

MeOH in CHCl3) as a brown solid: mp 173-175 °C; TLC (5% MeOH/CHCl3) Rf = 0.18

(UV, KMnO4); IR: 2950, 2926, 2862, 2360, 1666, 1371, 1327, 1248, 738 cm−1; 1H

NMR (400MHz, CDCl3): δ 13.18 (br s, 1H), 7.90 (m, 1H), 7.66 (m, 1H), 7.43 (m, 1H),

7.27 (s, 2H), 3.89 (s, 2H), 2.87 (t, ` 7.4 Hz, 2H), 1.67 (m, J = 7.4 Hz, 2H), 1.47 (m, J

= 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 162.5, 151.7,

145.5, 140.6, 132.0, 131.1, 128.2, 126.9, 125.3, 124.0, 118.1, 35.3, 31.7, 30.1, 22.3,

14.0; MS (ES) calcd for C17H17NONa [M + Na]+ 262.1202, found 262.1203.

4-(tert-butyl)-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (20).

Produced according to general procedure A with 1 (118 mg, 0.59 mmol) and 12 (116

mg, 0.62 mmol). The pure compound 20 (114 mg, 0.48 mmol, 81% yield) was

obtained following purification by flash column chromatography on silica gel (elution:

20% to 60% EtOAc in hexanes then 1% to 8% MeOH in CHCl3) as a brown solid. mp

238-240 °C; TLC (5% MeOH/CHCl3) Rf = 0.34 (UV, KMnO4); IR: 2957, 2359, 1648,

743 cm−1; 1H NMR (400MHz, CDCl3): δ 13.17 (br s, 1H), 8.23 (m, 1H), 7.67 (m, 1H),

7.47 (s, 1H), 7.44 (m, 2H), 3.92 (s, 2H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3): δ

162.3, 151.5, 146.1, 140.1, 133.1, 129.5, 127.9, 127.7, 126.9, 126.3, 125.2, 35.6,

33.4, 30.8; MS (ES) calcd for C16H17NONa [M + Na]+ 262.1202, found 262.1203.

60

6-fluoro-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (SI-1).

Produced according to general procedure A with 1 (500 mg, 2.52 mmol) and 2-

ethynyl-4-fluorobenzaldehyde (392 mg, 2.65 mmol). The extracted organic residue

(249 mg, 1.24 mmol, 47% yield) afforded the compound SI-1 as a tan solid with 20%

isomer by NMR. A small amount of sample was recrystallized with hot EtOAc for

analytical purposes. mp 226-228 °C; TLC (10% MeOH/CHCl3) Rf = 0.25 (UV,

KMnO4), IR: 3252, 2854, 1654, 1613, 1472, 1324, 1180, 1024, 780, 611 cm−1; 1H

NMR (400 MHz, DMSO-d6): δ 11.63 (s, 1H), 7.81 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.65

(dd, J = 8.4 Hz, 5.3 Hz, 1H), 7.49 (d, J = 6.7 Hz, 1H), 7.25 (m, 1H), 6.88 (d, J = 6.7

Hz, 1H), 3.70 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 161.8, 160.6, 150.1, 142.1,

140.2, 135.2, 131.9, 126.5, 115.1, 108.7, 99.3, 34.5; MS (ES) calcd for C12H8FNONa

[M + Na]+, 224.0482. Found 224.0483.

(3S*,9aS*)-11-acetyl-4-phenyl-3,9-dihydro-3,9a-(epiminomethano)indeno[2,1-

b]pyridine-2,10(1H)-dione [Not chiral non racemic] (28).

Produced according to general procedure B with 1 (143 mg, 0.72 mmol) and 15 (156

mg, 0.76 mmol). The pure compound 28 (166 mg, 0.48 mmol, 67% yield) was

61

obtained following purification by flash column chromatography on silica gel (elution:

10% to 60% EtOAc in hexanes) as a white amorphous solid. TLC (40%

EtOAc/hexanes) Rf = 0.23 (UV, CAM); IR (film) cm-1 3200, 3050, 2350, 1702, 1330,

1245, 751, 698 cm−1; 1H NMR (400MHz, CDCl3): δ 9.14 (br s, 1H), 7.56 (m, J = 7 Hz,

3H), 7.45 (t, J = 7 Hz, 2H), 7.41 (q, J = 7 Hz, 1H), 7.32 (m, J = 7 Hz, 2H), 7.12 (t, J =

7 Hz, 1H), 6.23 (s, 1H), 4.16 (d, J = 17.7 Hz, 1H), 3.28 (d, J = 17.7 Hz, 1H), 2.57 (s,

3H); 13C NMR (100 MHz, CDCl3): δ 171.6, 171.6, 171.6, 169.6, 168.2, 146.7, 145.3,

134.1, 134.0, 133.0, 130.9, 129.3, 129.0, 128.0, 127.6, 126.1, 123.1, 71.1, 62.9, 32.5,

25.5; MS (ES) calcd for C21H16N2O3Na [M + Na]+ 367.1053, found 367.1055.

4-phenyl-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (23).

To a solution of cycloadduct 28 (92.4 mg, 0.27 mmol) in PhMe (1.3 mL) was added

DBU (163 mg, 1.07 mmol). The reaction was heated to 200 °C for 1 h in the microwave

(300W, temperature mode). The reaction was cooled to rt, diluted with CH2Cl2 (10

mL), transferred to a separatory funnel, and quenched with HCl (0.1 M, 12 mL). The

aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers

were neutralized with NaHCO3 (15 mL), washed with brine (15 mL), dried with

Na2SO4, filtered, and concentrated in vacuo. The compound 23 with 20% isomer (17

mg, 25% yield) was obtained following purification by flash column chromatography

on silica gel (elution: EtOAc, then 5% MeOH in CHCl3). A recrystallization (hot CHCl3

then hexanes) furnished pure compound as a yellow solid, for analytical purposes.

62

mp 254-255 °C; TLC (5% MeOH/CHCl3) Rf = 0.36 (UV, KMnO4); IR (film) cm-1 1645,

1390, 740, 706 cm−1; 1H NMR (400MHz, CDCl3): δ 12.6 (br s, 1H), 7.62 (d, J = 7.5

Hz, 1H), 7.47 (m, 6H), 7.38 (s, 1H), 7.35 (m, J = 7.5 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H),

7.01 (d, J = 7.7 Hz, 1H), 3.94 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 160.4, 148.7,

145.6, 140.3, 136.8, 134.2, 131.6, 130.1, 129.1, 129.0 128.4, 128.3, 126.7, 125.7,

123.5, 117.1, 79.6, 35.5; MS (ES) calcd for C18H13NONa [M + Na]+ 260.1070, found

260.1072.

Conventional heating (non-microwave, 110 °C) gave 16% isolated yield.

(3S*,9aS*)-11-acetyl-4-((benzyloxy)methyl)-3,9-dihydro-3,9a-

(epiminomethano)indeno[2,1-b]pyridine-2,10(1H)-dione [Not chiral non

racemic] (27).

Produced according to general procedure B with 1 (176 mg, 0.89 mmol) and 14 (234

mg, 0.94 mmol). The pure compound 27 (226 mg, 0.582 mmol, 65% yield) was

obtained following purification by flash column chromatography on silica gel (elution:

10% to 60% EtOAc in hexanes) as a white amorphous solid. TLC (40%

EtOAc/hexanes) Rf = 0.2 (UV, CAM); IR (film) cm-1 3220, 2050, 2856, 2352, 1698,

1331, 1244, 740, 600 cm−1; 1H NMR (400MHz, CDCl3): δ 7.43 (d, J = 7.7 Hz, 1H),

7.34 (m, 7H), 7.23 (t, J = 2.5 Hz, 1H), 7.10 (br s, 1H), 6.13 (d, J = 1.84 Hz, 1H), 4.55

(s, 2H), 4.52 (s, 2H), 4.20 (d, J = 17.9 Hz, 1H), 3.28 (d, J = 17.9 Hz, 1H), 2.52 (s, 3H);

13C NMR (100 MHz, CDCl3): δ 171.5, 169.2, 168.5, 150.1, 145.5, 137.2, 132.7, 131.1,

63

130.7, 128.5, 128.0, 128.0, 126.1, 125.0, 72.7, 70.4, 65.6, 59.6, 32.6, 25.5; MS (ES)

calcd for C23H20N2O4Na [M + Na]+ 411.1315, found 411.1314.

4-((benzyloxy)methyl)-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (22).

To a solution of cycloadduct 27 (52 mg, 0.13 mmol) in PhMe (1.3 mL) was added

DBU (61 mg, 0.40 mmol). The reaction was heated to 120 °C for 20 h. The reaction

was cooled to rt, diluted with CH2Cl2 (10 mL), transferred to a separatory funnel,

quenched with HCl (0.1 M, 10 mL), and extracted with CH2Cl2 (3 x 10 mL). The

combined organic layers were neutralized with NaHCO3 (10 mL), washed with brine

(10 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The pure compound

22 (20 mg, 0.066 mmol, 49% yield) was obtained following purification by flash column

chromatography on silica gel (elution: 20% to 60% EtOAc in hexanes and 1% to 8%

MeOH in CHCl3) as a brown solid. mp 188-190 TLC (5% MeOH/CHCl3) Rf = 0.16 (UV,

KMnO4); IR (film) cm-1 2357, 1651, 1541, 1460, 748 cm−1; 1H NMR (400MHz, CDCl3):

δ 12.6 (br s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.43

(m, 2H), 7.36 (s, 2H), 7.35 (s, 2H), 7.32 (m, 1H), 4.76 (s, 2H), 4.64 (s, 2H), 3.90 (s,

2H); 13C NMR (100 MHz, CDCl3): δ 163.0, 152.0, 145.3, 139.9, 137.6, 134.1, 131.4,

128.6, 128.5, 127.9, 127.8, 127.0, 125.1, 124.8, 113.5, 71.8, 67.7, 35.3; MS (ES)

calcd for C20H17NO2Na [M + Na]+ 326.1151, found 326.1151.

64

2-chloro-9H-indeno[2,1-b]pyridine (SI-2).

Compound 10 (50 mg, 0.27 mmol) was dissolved in POCl3 (1 mL, 10.7 mmol) and

sealed in a vial with a Teflon cap. The reaction was heated at 100 °C for 16 h. The

reaction was cooled to rt, diluted with CH2Cl2 (5 mL), and transferred to a separatory

funnel with ice and NaOH (0.2 M, 54 mL). The aqueous layer was extracted with

CH2Cl2 (5 x 5 mL). The combined organic layers were washed with brine (20 mL),

dried with Na2SO4, filtered, and concentrated in vacuo. The extracted organic residue

afforded compound SI-2 (48 mg, 0.24 mmol, 87% yield) as a tan solid which did not

require further purification. mp 130-131 °C; TLC (5% MeOH/CHCl3) Rf = 0.25 (UV,

KMnO4); IR (film) cm-1 1601, 1552, 1409, 1170 cm−1; 1H NMR (400MHz, CDCl3): δ

8.40 (d, J = 5 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.59 (d, J =

5 Hz, 1H), 7.46 (m, J1 = 6.6 Hz, J2 = 7.2 Hz, 2H), 3.93 (s, 2H); 13C NMR (100 MHz,

CDCl3): δ 152.1, 148.4, 147.9, 143.5, 139.0, 136.6, 129.8, 127.4, 125.5, 121.8, 114.1,

36.2; MS (ES) calcd for C12H8ClNH [M + H]+ 202.0418, found 202.0417.

(3R*,9aS*)-11-acetyl-4-(trimethylsilyl)-3,9-dihydro-3,9a-

(epiminomethano)indeno[2,1-b]pyridine-2,10(1H)-dione [Not chiral non

racemic] (29).

65

Produced following general procedure B with 1 (695 mg, 3.51 mmol) and 16 (746 mg,

3.69 mmol). The pure compound 29 (602 mg, 1.93 mmol, 55% yield) was obtained

following purification by flash column chromatography on silica gel (elution: 15% to

65% EtOAc in hexanes) as an amorphous brown solid. Desilylated cycloadduct 9 (108

mg, 0.40 mmol, 12% yield) was formed over the course of the reaction and isolated

in its pure form from the same column. TLC (40% EtOAc/hexanes) Rf = 0.25 (UV,

CAM); IR (film) cm-1 3057, 2917, 2895, 1409, 731 cm−1; 1H NMR (400MHz, CDCl3):

δ 8.56 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H), 7.38 (q, J = 7.7 Hz, 1H), 7.30 (m,

J = 7.7 Hz, 1H), 6.09 (s, 1H), 4.19 (d, J = 17.9 Hz, 1H), 3.20 (d, J = 17.9 Hz, 1H), 2.49

(s, 3H), 0.38 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.6, 169.4, 168.3, 163.3, 146.3,

134.0, 133.5, 127.8, 126.3, 124.7, 71.3, 60.8, 32.6, 25.5, -0.9; MS (ES) calcd for

C18H20N2O3SiNa [M + Na]+ 363.1135, found 363.1137.

1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one (10).

To a solution of 29 (36 mg, 0.12 mmol) in PhMe (1 mL) was added DBU (18 mg, 0.12

mmol). The reaction was heated to 110 °C for 14 h. The reaction was cooled to rt,

diluted with CH2Cl2 (10 mL), transferred to a separatory funnel, and quenched with

HCl (0.1 M, 10 mL). The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The

combined organic layers were neutralized with NaHCO3 (10 mL), washed with brine

(10 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The crude residue

gave desilylated compound 10 and was not purified.

66

1-(2-(diethoxymethyl)phenyl)but-2-yn-1-ol (45).

To a solution of 44 (5.4 g, 26 mmol) in THF (26 mL, 1M) at –78 °C was added 1-

propynylmagnesium bromide (5.5 g, 39 mmol) over 15 minutes via addition funnel.

After stirring for 25 min at –78 ˚C, the reaction was warmed to -40 °C and quenched

with diH2O (26 mL) and saturated NH4Cl (40 mL). The aqueous layer was extracted

with Et2O (2 x 20 mL) and diluted with hexanes (40 mL). The combined organic layers

were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The

pure compound 45 (5.15 g, 20.9 mmol, 80% yield) was obtained following purification

by flash column chromatography on silica gel (elution: 5% to 25% EtOAc in hexanes),

as an orange liquid. TLC: (20% EtOAc in hexane), Rf = 0.20; IR (film) cm-1 3415,

2970, 1051, 995, 750 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 6.9 Hz, 1H),

7.52 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.8 Hz, 6.9 Hz, 1H), 7.32 (dd, J = 7.8 Hz, 6.9

Hz, 1H), 5.89 (s, 1H), 5.80 (s, 1H), 3.90 (d, J = 5.3 Hz, 1H), 3.73-3.51 (m, 4H), 1.92

(s, 3H), 1.24 (t, J = 5.3 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 139.3, 135.9, 129.1,

128.6, 127.9, 127.5, 101.5, 82.9, 78.5, 76.7 62.4, 62.3, 62.2, 15.0, 3.8; Exact mass

calcd for C15H20O3Na [M + Na]+ 271.1304, Found 271.1302.

tert-butyl((1-(2-(diethoxymethyl)phenyl)but-2-yn-1-yl)oxy)dimethylsilane (46).

67

To a solution of 45 (940 mg, 3.8 mmol) in DMF (3.8 mL, 1M) was added imidazole

(620 mg, 9.1 mmol) and TBSCl (699 mg, 6.85 mmol). After 20h, the reaction was

diluted with diH2O (20 mL) and extracted with EtOAc (3 x 10 mL). The combined

organic layers were dried with Na2SO4, filtered, and concentrated in vacuo. The

extracted organic residue (1.3 g, 95% yield) afforded the pure compound 46 as a

yellow oil. TLC: (40% EtOAc in hexane), Rf = 0.44; IR (film) cm-1 2927, 1248, 1051,

835, 775, 752 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz, 1H), 7.59 (d, J

= 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.86 (s, 2H), 3.73-3.49

(m, 4H), 1.75 (s, 3H), 1.29-1.19 (m, 6H), 0.92 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C

NMR (100 MHz, CDCl3): δ 140.6, 134.9, 128.6, 127.1, 126.4, 126.1, 99.1, 81.2, 80.3,

62.0, 61.5, 61.0, 25.9, 18.3, 15.2, 3.8, -4.6, -4.9; Exact mass calcd for C21H34O3SiNa

[M + Na]+ 385.2169, Found 385.2168.

2-(1-((tert-butyldimethylsilyl)oxy)but-2-yn-1-yl)benzaldehyde (47).

To a solution of 46 (4.85 g, 13.4 mmol) in acetone (45 mL, 0.3M) at 0 °C was added

p-toluenesulfonic acid (1.27 g, 6.7 mmol). After 40 minutes, the reaction was

neutralized with saturated NaHCO3 (30 mL) and diluted with diH2O (20 mL). The

solution was extracted with EtOAc (3 x 30 mL). The combined organic layers were

washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated in vacuo.

The extracted organic residue (3.68 g, 99% yield) afforded the pure compound 47 as

a yellow oil. TLC: (40% EtOAc in hexane), Rf = 0.93; IR (film) cm-1 2923, 1695, 1254,

68

837, 781 cm−1; 1H NMR (400 MHz, CDCl3): δ 10.56 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H),

7.65 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 6.00 (s, 1H),

1.80 (s, 3H), 0.89 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3): δ

192.6, 144.6, 133.8, 133.0, 130.6, 128.0, 127.0, 83.1, 62.9, 25.7, 18.2, 3.7, -4.6, -5.0;

Exact mass calcd for C17H24O2SiNa [M + Na]+ 311.1438, Found 311.1438.

(Z)-1-acetyl-3-(2-(1-((tert-butyldimethylsilyl)oxy)but-2-yn-1-

yl)benzylidene)piperazine-2,5-dione (48).

To a solution of 1 (2.6 g, 13.3 mmol) in DMF (26 mL, 0.5 M) was added aldehyde 47

(3.68 g, 13.3 mmol) and cesium carbonate (4.6 g, 14 mmol). The reaction was stirred

until consumption of the aldehyde (1.5 h). The reaction was diluted with diH2O (50mL)

and extracted with EtOAc (4 x 20 mL). The combined organic layers were dried with

Na2SO4, filtered, and concentrated in vacuo. The pure compound 48 (2.77 g, 49%

yield) was obtained following purification by flash column chromatography on silica

gel (elution: 5% to 45% EtOAc in hexanes) as a white solid. mp 136-138 °C; TLC:

(20% EtOAc in hexane), Rf = 0.27; IR (film) cm-1 3242, 2929, 2855, 1709, 1696, 1681,

1366, 1231, 1220, 1036, 835 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.68 (m, 2H), 7.45

(s, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 5.41

(s, 1H), 4.49 (s, 2H) 2.68 (s, 3H), 1.82 (s, 3H) 0.88 (s, 9H), 0.15 (s, 3H), 0.10 (s, 3H);

13C NMR (100 MHz, CDCl3): δ 172.6, 162.4, 159.5, 141.9, 129.8, 129.5, 128.5, 127.9,

69

127.6, 126.6, 119.1, 83.0, 79.2, 63.3, 46.2, 27.3, 25.7, 18.2, 3.7, -4.4, -5.0; Exact

mass calcd for C23H30N2O4SiNa [M + Na]+ 449.1867, Found 449.1867.

(3S*,10aS*)-12-acetyl-5-((tert-butyldimethylsilyl)oxy)-4-methyl-5,10-dihydro-1H-

3,10a-(epiminomethano)benzo[g]quinoline-2,11(3H)-dione [Not chiral non

racemic] (49).

To a solution of 48 (426 mg, 1 mmol) in PhMe (26 mL, 0.5 M) was added NEt3 (606

mg, 6 mmol) and TMSCl (435 mg, 4 mmol). The reaction was heated to 130 °C in a

sealed tube. After 21 h, the reaction was diluted with diH2O (10 mL) and extracted

with EtOAc (3 x 20 mL). The combined organic layers were dried with Na2SO4, filtered,

and concentrated in vacuo. The pure compound 49 (281 mg, 66% yield) was obtained

following purification by flash column chromatography on silica gel (elution: 15% to

45% EtOAc in hexanes), as a white amorphous solid. TLC: (20% EtOAc in hexane),

Rf = 0.271; IR (film) cm-1 2927, 1705, 1333, 1250, 1032, 835, 745 cm−1; 1H NMR (400

MHz, CDCl3): δ 7.40 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.24 (t, J = 6.6 Hz,

1H), 7.19 (s, 1H), 7.07 (s, 1H), 5.67 (s, 1H), 5.33 (s, 1H), 3.50 (m, 2H), 2.38 (s, 3H),

2.12 (s, 3H), 0.77 (s, 9H), 0.07 (s, 3H), -0.11 (s, 3H); 13C NMR (100 MHz, CDCl3): δ

170.8, 169.2, 168.6, 141.5, 136.8, 129.5, 129.1, 127.3, 77.2, 64.1, 60.6, 30.1, 25.5,

25.1, 18.0, 15.8, -4.7; Exact mass calcd for C23H30N2O4SiNa [M + Na]+ 449.1867,

Found 449.1865.

1Indistinguishable from starting material by TLC

70

4-methylbenzo[g]quinolin-2(1H)-one (50).

To a solution of cycloadduct 49 (33 mg, 0.08 mmol) in PhMe (0.1 M) was added DBU

(59 mg, 0.387 mmol). The reaction was heated to 200 °C for 1 h in the microwave

(300W, temperature mode). The reaction was cooled to rt, diluted with EtOAc (3 mL),

transferred to a separatory funnel, and quenched with HCl (0.1 M, 5 mL). The aqueous

layer was extracted with EtOAc (5 x 5 mL). The combined organic layers were

neutralized with NaHCO3 (5 mL), washed with brine (5 mL), dried with Na2SO4,

filtered, and concentrated in vacuo. Compound 50 (10 mg, 62% yield) was obtained

following purification by flash column chromatography on silica gel (elution: 2% to 7%

MeOH and CHCl3), as a white solid. mp 172-174 °C; TLC product: (5% MeOH/CHCl3)

Rf = 0.43 (UV, KMnO4); IR (film) cm-1 3041, 2891, 1672, 1645, 1622, 1500, 1362,

1182, 875, 739 cm−1; 1H NMR (400 MHz, CDCl3): δ 9.76 (br s, 1H), 9.01 (s, 1H), 8.08

(d, J = 9.4 Hz, 2H), 8.00 (d, J = 9.4 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2

Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 2.40 (s, 3H); 1H NMR (400 MHz, DMSO-d6): δ 10.9

(br s, 1H), 8.90 (m, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.57 (t, J =

7.8 Hz, 1H), 6.91 (d, J = 4.6 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ

164.0, 135.4, 134.3, 131.5, 129.4, 129.2, 128.3, 127.9, 126.1, 124.4, 123.7, 122.0,

112.4, 15.7; 13C NMR (100 MHz, DMSO-d6): δ 140.0, 139.5, 136.0, 134.4, 133.3,

71

133.0, 131.2, 130.5, 129.9, 126.9, 126.8, 115.2, 20.2; MS (ES) calcd for C14H11NONa

[M + Na]+ 232.0733, found 232.0732.

72

Chapter 3

The Synthesis and Fluorescence of Azafluorenones

The Fluorophores Fluorene and Fluorenone

Fluorene is a tricyclic 6,5,6 ring system consisting of two benzenes ring-fused

to cyclopentadiene. It is a commercial byproduct of coal tar.1 The hydrogens at the 9

position (the saturated position) are relatively acidic owing to the aromaticity of the

deprotonated cyclopentadienyl moiety. This property allows fluorene to act as a ligand

for transition metals. Fluorene is the precursor to the fluorenylmethyloxycarbonyl

(Fmoc) protecting group used in amide coupling (Figure 3.1).

Figure 3.1 Fluorene and derived compounds

Fluorene fluoresces violet, which has inspired continuous interest in the

molecule as a blue light source. Polyfluorene materials are used in polymer light-

emitting diodes (PLEDs) due to emitting deep blue. During PLED operation a second

green emission band appears which is attributed to oxidative degradation of fluorene

units.2-3 This green emission is strengthened by increased intermolecular interactions

and can be attributed solely to oxidation on the polymeric chain,4-5 or also to formation

of inter-chain aggregates and excimers.6-7 This point is fiercely debated in the

literature, but there is more evidence for the former. Oxidative defects are enhanced

73

by calcium ions present in cathodes; this can be avoided by including a buffer layer

between the cathode and the polyfluorene.8 Additionally, polyfluorenes have been

used as fluorescent chemosensors for explosives detection.9

Fluorenone, the oxidized version of fluorene, can be considered a

conformationally rigid analogue of benzophenone and is a planar system with the

lowest triplet state being π−π*10 (Figure 3.2). Fluorenone fluoresces yellow but

fluorenone based polymers typically fluoresce green and can be photoactivatable.11

Fluorenone has been used as a photosensitizer which catalyzes benzylic C-H

fluorination.12 The interconversion between fluorenone and its reduced counterpart

fluorenol has been shown to reversibly store hydrogen through a catalytic and

electrolytic process.13 Interestingly, fluorenol itself is a promising wakefulness

promoting (eugeroic) drug which is significantly more potent than the widely used

modafinil (brand name Provigil).14 Fluorenone derivatives have been used as probes

for DNA redox chemistry15 and intramolecular charge-transfer (ICT) compounds for

use in nonlinear optics.16 Substituted fluorenone organic crystals can exhibit two color

luminescence switching in the solid state via stimulation with temperature, pressure,

or solvent vapor.17 This switching is caused by intermolecular π−π stacking with

directed packing by hydrogen bonding.

Figure 3.2 Fluorenone and related compounds

Fluorenone has atypical spectroscopic properties which has generated

74

continual interest in its photochemistry. It is a popular model for studying excited state

hydrogen bonding behaviors due to measurable changes in its fluorescence in protic

solvents. Hydrogen bonding is significantly strengthened in fluorenone’s excited state,

decreasing the energy gap between the fluorescent ground and excited states.18 At

the same time, hydrogen bonding quenches fluorescence by promoting radiationless

deactivation via internal conversion (IC),18-19 rather than the intersystem crossing

(ISC) which dominates in aprotic solvents.

Synthesis and Fluorescence of Azafluorenones

We prepared several 6,5,6 tricyclic 2-pyridones through the synthetic

methodology detailed in the second chapter. These molecules are considered

azafluorenes, as they have the fluorene core structure featuring the pyridone motif.

Additionally, a fluoro-substituted azafluorene, 2, was synthesized by Tristan Elmore

with eventual goal of amine substitution to alter downstream fluorescence activity

(Figure 3.3). These azafluorenes were tested for fluorescence via excitation at the

ranges which they absorbed light (330-365 nm excitation). No fluorescence was

observed.

Figure 3.3 Azafluorenes synthesized for fluorescent studies

Next, we oxidized the azafluorenes to azafluorenones to probe their

fluorescent activity. This was accomplished easily and cleanly via cesium carbonate

in dimethyl formamide (Scheme 3.1). The reaction was open to air but was fitted with

a Drierite dessicant tube to avoid ambient moisture.

75

Scheme 3.1 Synthesis of Azafluorenones from Azafluorenes

Both the simple azafluorenone 3 and the fluorine containing azafluorenone 4

showed fluorescent activity when excited at 365 nm. The compounds were

fluorescent in both aprotic tetrahydrofuran and the protic solvent ethanol, but exhibited

minor quenching in ethanol presumably due to hydrogen bonding. Compound 3

showed one main fluorescent peak at 529 nm, which was broadened from 450 nm to

650 nm. Compound 4 showed two fluorescent peaks at 410 nm and 491 nm, with the

latter broadening from 450 nm to 600 nm and having higher intensity. The peak at

410 nm disappeared when 4 was dissolved in ethanol.

We then became curious as to whether the pyridone motif played a significant

role in the fluorescence of the azafluorenones. To this end, we converted the

pyridones to chloropyridines with refluxing phosphoryl chloride (Scheme 3.2). The

fluorescence of chloropyridine azafluorenones 5 and 6 was highly quenched when

excited at 365 nm. 5 appeared not fluorescent at all, whereas the only fluorescent

peak of 6 was the previously minor peak at 410 nm.

76

Scheme 3.2 Synthesis of Chloropyridine Azafluorenones

We next oxidized a phenyl substituted 6,5,6 pyridine (synthesized by Robert

Wiley of our lab) to the azafluorenone under the same conditions as 1 and 2 (Scheme

3.3). 2-Alkylated azafluorenones have been synthesized previously in the literature

(typically en route to larger molecules), but were not examined for their fluorescence

activity. Phenyl azafluorenone 7 absorbed significantly more light than the

chloropyridines 5 and 6, appearing strikingly yellow in visible light. However, 7 showed

no fluorescence when excited at 330 nm and 365 nm, despite absorbing strongly in

these regions.

Scheme 3.3 Synthesis of a 2-Phenyl Azafluorenone

Finally, we oxidized a 2-methoxy 6,5,6 pyridine, which had been previously

synthesized by our lab, into a 2-methoxy azafluorenone (Scheme 3.4). This molecule

absorbed at a lower frequency than previous compounds and showed weak

fluorescence in the yellow region (570 nm) when excited at 270 nm in THF. Ethanol

quenched the fluorescence.

77

Scheme 3.4 Synthesis of a 2-Methoxy Azafluorenone

Conclusion

Azafluorenes and azafluorenones were synthesized in concise fashion and

tested for their fluorescence. The presence of oxygen at the 2-position appears

responsible for the fluorescence of our azafluorenones, which is especially strong in

the compounds containing a pyridone. This is exciting because the pyridone moiety

is not widely explored in regard to its emissive properties. This discovery paves the

way for fluorescent azafluorenone polymers, as the fluorescent emissions observed

in the violet (410 nm), blue (491 nm), and green (529 nm) spectral domains are

industrially valuable.

78

Works Cited 1. Wise, S. A.; Poster, D. L.; Leigh, S. D.; Rimmer, C. A.; Mössner, S.; Schubert, P.; Sander, L. C.; Schantz, M. M., Polycyclic aromatic hydrocarbons (PAHs) in a coal tar standard reference material—SRM 1597a updated. Analytical and Bioanalytical Chemistry 2010, 398 (2), 717-728.

2. Zojer, E.; Pogantsch, A.; Hennebicq, E.; Beljonne, D.; Bredas, J. L.; de Freitas, P. S.; Scherf, U.; List, E. J. W., Green emission from poly(fluorene)s: The role of oxidation. J. Chem. Phys. 2002, 117 (14), 6794-6802.

3. Romaner, L.; Pogantsch, A.; de Freitas, P. S.; Scherf, U.; Gaal, M.; Zojer, E.; List, E. J. W., The origin of green emission in polyfluorene-based conjugated polymers: On-chain defect fluorescence. Adv. Funct. Mater. 2003, 13 (8), 597-601.

4. Kulkarni, A. P.; Kong, X. X.; Jenekhe, S. A., Fluorenone-containing polyfluorenes and oligofluorenes: photophysics, origin of the green emission and efficient green electroluminescence. J. Phys. Chem. B 2004, 108 (25), 8689-8701.

5. Becker, K.; Lupton, J. M.; Feldmann, J.; Nehls, B. S.; Galbrecht, F.; Gao, D. Q.; Scherf, U., On-chain fluorenone defect emission from single polyfluorene molecules in the absence of intermolecular interactions. Adv. Funct. Mater. 2006, 16 (3), 364-370.

6. Chen, X. W.; Tseng, H. E.; Liao, J. L.; Chen, S. A., Green emission from end-group-enhanced aggregation in polydioetylfluorene. J. Phys. Chem. B 2005, 109 (37), 17496-17502.

7. Sims, M.; Bradley, D. D. C.; Ariu, M.; Koeberg, M.; Asimakis, A.; Grell, M.; Lidzey, D. G., Understanding the origin of the 535 nm emission band in oxidized poly(9,9-dioctylfluorene): The essential role of inter-chain/inter-segment interactions. Adv. Funct. Mater. 2004, 14 (8), 765-781.

8. Gong, X. O.; Iyer, P. K.; Moses, D.; Bazan, G. C.; Heeger, A. J.; Xiao, S. S., Stabilized blue emission from polyfluorene-based light-emitting diodes: Elimination of fluorenone defects. Adv. Funct. Mater. 2003, 13 (4), 325-330.

9. Sanchez, J. C.; Trogler, W. C., Efficient blue-emitting silafluorene-fluorene-conjugated copolymers: selective turn-off/turn-on detection of explosives. J. Mater. Chem. 2008, 18 (26), 3143-3156.

10. Yoshihara, K.; Kearns, D. R., SPECTROSCOPIC PROPERTIES OF LOWER-LYING EXCITED STATES OF FLUORENONE. J. Chem. Phys. 1966, 45 (6), 1991-+.

11. Dormán, G.; Nakamura, H.; Pulsipher, A.; Prestwich, G. D., The Life of Pi Star: Exploring the Exciting and Forbidden Worlds of the Benzophenone Photophore. Chemical Reviews 2016, 116 (24), 15284-15398.

12. Xia, J. B.; Zhu, C.; Chen, C., Visible Light-Promoted Metal-Free C-H Activation: Diarylketone-Catalyzed Selective Benzylic Mono- and Difluorination. Journal of the American Chemical Society 2013, 135 (46), 17494-17500.

13. Kato, R.; Nishide, H., Polymers for carrying and storing hydrogen. Polymer Journal 2017, 50, 77.

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14. Dunn, D.; Hostetler, G.; Iqbal, M.; Marcy, V. R.; Lin, Y. G.; Jones, B.; Aimone, L. D.; Gruner, J.; Ator, M. A.; Bacon, E. R.; Chatterjee, S., Wake promoting agents: search for next generation modafinil, lessons learned: part III. Bioorganic & medicinal chemistry letters 2012, 22 (11), 3751-3.

15. Tierney, M. T.; Grinstaff, M. W., Synthesis and characterization of fluorenone-, anthraquinone-, and phenothiazine-labeled oligodeoxynucleotides: 5 '-probes for DNA redox chemistry. Journal of Organic Chemistry 2000, 65 (17), 5355-5359.

16. Li, Y. J.; Liu, T. F.; Liu, H. B.; Tian, M. Z.; Li, Y. L., Self-Assembly of Intramolecular Charge-Transfer Compounds into Functional Molecular Systems. Accounts Chem. Res. 2014, 47 (4), 1186-1198.

17. Yuan, M. S.; Wang, D. E.; Xue, P. C.; Wang, W. J.; Wang, J. C.; Tu, Q.; Liu, Z. Q.; Liu, Y.; Zhang, Y. R.; Wang, J. Y., Fluorenone Organic Crystals: Two-Color Luminescence Switching and Reversible Phase Transformations between pi-pi Stacking-Directed Packing and Hydrogen Bond-Directed Packing. Chem. Mat. 2014, 26 (7), 2467-2477.

18. Liu, Y. H.; Zhao, G. J.; Li, G. Y.; Han, K. L., Fluorescence quenching phenomena facilitated by excited-state hydrogen bond strengthening for fluorenone derivatives in alcohols. J. Photochem. Photobiol. A-Chem. 2010, 209 (2-3), 181-185.

19. Alty, I. G.; Abelt, C. J., Stereoelectronics of the Hydrogen-Bond-Induced Fluorescence Quenching of 3-Aminofluorenones with Alcohols. J Phys Chem A 2017, 121 (27), 5110-5115.

80

Experimental

General procedure A: Synthesis of azafluorenones

To a solution of azafluorene (1 equiv, 0.1-1.6 mmol) in DMF (0.2 M) was added

Cs2CO3 (3 equiv). The vessel was capped with a Drierite-filled tube and allowed to

stir open to atmosphere for 16 h. The reaction was diluted with di-H2O (10 mL) and

extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with

brine (10 mL), dried with Na2SO4, filtered, and concentrated in vacuo.

General procedure B: Synthesis of chloropyridine azafluorenones

Azafluorenone (1 equiv, 0.1-0.2 mmol) was dissolved in POCl3 (0.3 M), sealed in a

vial with a Teflon cap, and heated to 100 °C for 16 h. The reaction was diluted with

CH2Cl2 (10 mL), transferred to a separatory funnel with ice and NaOH (3.1 equiv to

POCl3), and extracted with additional CH2Cl2 (3 x 10 mL). The combined organic

layers were washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated

in vacuo.

1H-indeno[2,1-b]pyridine-2,9-dione (3).

Produced according to general procedure A with 1 (300 mg, 1.64 mmol). The organic

residue afforded compound 3 (130 mg, 0.64 mmol, 40% yield) as a black solid which

did not require further purification. mp 274-275 °C; TLC (5% MeOH/CHCl3) Rf = 0.26

(UV, CAM); IR: 1719, 1620, 1586, 1548, 1175, 1023, 994, 749, 689 cm−1; 1H NMR

(400MHz, DMSO-d6): δ 12.3 (br s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.86 (d, J = 7.2 Hz,

81

1H), 7.63 (t, J = 7.2 Hz, 1H), 7.55 (m, 2H), 6.90 (d, J = 6.3 Hz, 1H); 13C NMR (100

MHz, DMSO-d6): δ 190.6, 162.0, 157.5, 146.8, 139.5, 134.3, 133.9, 132.3, 123.2,

123.1, 116.3, 99.9; MS (ES) calcd for C12H7NO2Na [M + Na]+ 220.0369, found

220.0369.

6-fluoro-1H-indeno[2,1-b]pyridine-2,9-dione (4).

Produced according to general procedure A with 2 (26 mg, 0.13 mmol). The organic

residue afforded compound 4 (12.3 mg, 0.06 mmol, 43% yield) as a dark yellow solid

which did not require further purification. mp 324-326 °C; TLC (10% MeOH/CHCl3) Rf

= 0.38 (UV, KMnO4); IR: 3090, 1707, 1641, 1587, 1471, 1190, 795 cm−1; 1H NMR

(400MHz, DMSO-d6): δ 12.34 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.84 (dd, J1 = 8.4 Hz,

J2 = 2.2 Hz, 1H), 7.61 (dd, J1 = 8.4 Hz, J2 = 5.4 Hz, 1H), 7.32 (m, 1H), 6.93 (d, J = 6.3

Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 188.5, 165.7, 159.8, 156.8, 146.5, 142.2,

129.6, 124.9, 117.8, 116.5, 110.9, 99.6; MS (ES) calcd for C12H6FNO2Na [M + Na]+

238.0274, found 238.0273.

2-chloro-9H-indeno[2,1-b]pyridin-9-one (5).

Produced according to general procedure B with 3 (54.5 mg, 0.23 mmol). The

extracted organic residue afforded compound 5 (39 mg, 0.18 mmol, 79% yield) as a

tan solid which did not require further purification. mp 188-190 °C; TLC (5%

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MeOH/CHCl3) Rf = 0.64 (UV, CAM); IR: 1709, 1587, 1556, 1431, 1412, 1177, 1150,

914, 738 cm−1; 1H NMR (400MHz, CDCl3): δ 8.53 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 7.4

Hz, 1H), 7.63 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 4.9 Hz, 1H); 13C NMR

(100 MHz, CDCl3): δ 189.5, 155.5, 155.4, 147.9, 140.1, 135.1, 133.6, 132.1, 124.9,

124.8, 121.9, 114.6; MS (ES) submitted for C12H6ClNOH [M + H]+

2-chloro-6-fluoro-9H-indeno[2,1-b]pyridin-9-one (6).

Produced according to general procedure B with 4 (30 mg, 0.14 mmol). Purification

by flash column chromatography (elution: 20-60% EtOAc in hexanes) afforded pure

compound 6 (13 mg, 0.06 mmol, 41% yield) as a tan solid. mp 237-240 °C; TLC (10%

MeOH/CHCl3) Rf = 0.74 (UV, KMnO4); IR: 3086, 1711, 1593, 1562, 1352, 1198, 860,

791 cm−1; 1H NMR (400MHz, CDCl3): δ 8.58 (d, J1 = 5.1 Hz, J2 = 1.8 Hz, 1H), 7.80

(ddd, J1 = 8.4, J2 = 5.1, J3 = 1.8 Hz, 1H), 7.45 (dd, J1 = 5.1 Hz, J2 = 1.8 Hz, 1H), 7.35

(dt, J1 = 7.8 Hz, J2 = 2.0 Hz 1H), 7.19 (tt, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H); 13C NMR (100

MHz, CDCl3): δ 187.9, 167.3, 155.8, 153.9, 148.1, 143.1, 129.8, 127.3, 125.3, 119.0,

114.8, 110.1 MS (ES) submitted for C12H5ClFNOH [M + H]+

2-methoxy-9H-indeno[2,1-b]pyridin-9-one (8).

Produced according to general procedure A with SI-2 (21.8 mg, 0.11 mmol). The

extracted organic residue afforded compound 8 (12.2 mg, 0.06 mmol, 56% yield) as

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a yellow solid which did not require further purification. mp 136-138 °C; TLC (50%

CHCl3/hexanes) Rf = 0.30 (Visible light, UV, CAM); IR: 1726, 1306, 1258, 843 cm−1;

1H NMR (400MHz, CDCl3): δ 7.72 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.45

(t, J = 7.5 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 8.0

Hz, 1H), 4.04 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.9, 165.9, 150.6, 142.0,

135.2, 134.8, 131.9, 130.5, 128.6, 124.6, 119.7, 115.5, 54.3; MS (ES) submitted for

C13H9NO2Na [M + Na]+

2-phenyl-9H-indeno[2,1-b]pyridin-9-one (7).

Produced according to general procedure A with SI-1 (28 mg, 0.11 mmol). The

extracted organic residue afforded compound 7 (25 mg, 0.10 mmol, 87% yield) as a

yellow solid which did not require further purification. mp 177-179 °C; TLC (20%

EtOAc/hexanes) Rf = 0.30 (Visible light, UV, CAM); IR: 1727, 1603, 1450, 1302 cm−1;

1H NMR (400MHz, CDCl3): δ 8.05 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 8 Hz 1H), 7.74 (d,

J = 8 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.49 (m, 5H), 7.33 (t, J = 6.8 Hz, 1H); 13C NMR

(100 MHz, CDCl3): δ 192.8, 158.4, 153.3, 141.7, 138.4, 138.1, 135.5, 132.6, 129.8,

129.5, 128.8, 127.0, 124.8, 123.8, 121.0; MS (ES) submitted for C18H11NONa [M +

Na]+

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