© 2009 jeremy malinge -...

NOVEL SYNTHESIS OF HETEROCYCLIC AROMATIC RINGS VIA GOLD CATALYSIS

By

JEREMY MALINGE

A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE

UNIVERSITY OF FLORIDA

2009

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© 2009 Jeremy Malinge

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To Laura, the love of my life

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ACKNOWLEDGMENTS

First and foremost I would like to thank my parents, Sylvie and Michel, my brother, Julien

and all my family for their constant love and support. Even oceans apart, they were always by

my side.

I would like to thank Dr. Aaron Aponick for giving me the opportunity to work in his

group and providing such a great learning experience. I could not have possibly have completed

my project without his scientific guidance and patience toward my frenchness.

I would like to acknowledge my colleagues, Berenger, Carl, Jean and Nick. Special thanks

go to Dr. Chuan-Ying Li and Emmerson Finco Marques with whom I completed this project,

John for his patience during our hood sharing experience and to Lucas for giving me a ride every

weekend to the grocery store.

Finally, I would like to thank Laura for her love and support during this journey.

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TABLE OF CONTENTS page

ACKNOWLEDGMENTS ............................................................................................................... 4

LIST OF TABLES .......................................................................................................................... 6

LIST OF FIGURES ......................................................................................................................... 7

ABSTRACT .................................................................................................................................. 12

CHAPTER

1 BACKGROUND ................................................................................................................... 13

Introduction ............................................................................................................................ 13

Carbon-Carbon Bond Formation Catalyzed by Gold ..................................................... 15

Carbon-Nitrogen Bond Formation Catalyzed by Gold ................................................... 19

Carbon-Oxygen Bond Formation Catalyzed by Gold .................................................... 21

Other Carbon-Heteroatom Bond Formation ................................................................... 23

Gold Catalyzed Reaction as a Key-Step in a Total Synthesis of a Natural Product .............. 25

Conclusion ............................................................................................................................. 26

2 RESEARCH INTERESTS ..................................................................................................... 28

The Aponick Group at the University of Florida ................................................................... 28

Furan, Thiophene and Pyrrole Generalities ........................................................................... 32

Birth of a New Project ........................................................................................................... 37

3 RESEARCH INVESTIGATION ........................................................................................... 40

First Test Reaction ................................................................................................................. 40

Optimization Studies .............................................................................................................. 41

Expansion of the Reaction Scope ........................................................................................... 42

Catalyst Loading Optimization .............................................................................................. 51

Conclusion ............................................................................................................................. 55

4 EXPERIMENTAL PROCEDURES ...................................................................................... 56

APPENDIX: PROTON AND CARBON NMR SPECTRA ......................................................... 71

LIST OF REFERENCES ............................................................................................................ 112

BIOGRAPHICAL SKETCH ...................................................................................................... 115

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LIST OF TABLES

Table page 1-1 Optimization studies for dihydroquinoline and chromene derivatives7 ............................ 19

1-2 Reaction scope for the condensation of amine with dicarbonyls compounds................... 21

3-1 Results of optimization studies ......................................................................................... 41

3-2 Furan rings synthesized using our methodology ............................................................... 49

3-3 Pyrrole and thiophene rings synthesized using our methodology ..................................... 50

3-4 Catalyst loading optimization............................................................................................ 54

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LIST OF FIGURES

Figure page 1-1 Gold assisted hydration of alkynes reported by Fukuda and co-workers ......................... 13

1-2 Total number of publication on gold catalysis per year .................................................... 14

1-3 General mechanistic pathway for coordination chemistry ................................................ 14

1-4 Gold catalyzed oxazoline synthesis................................................................................... 15

1-5 Gold species used in the oxazoline synthesis reported by Fukuda and co-workers .......... 15

1-6 GoldI and goldIII alkoxides stabilized by phosphine-type ligands..................................... 16

1-7 Knoevenagel reaction catalyzed by gold alkoxide ............................................................ 16

1-8 In situ synthesis of a new generation of cationic gold catalysts........................................ 17

1-9 Conia-ene type reaction catalyzed by cationic gold catalyst ............................................. 17

1-10 One pot synthesis of propargyl amine catalyzed by AuIII in water ................................... 17

1-11 Dihydroquinoline synthesis assisted by AuI catalyst ........................................................ 18

1-12 AuI catalyst used by Watanabe and co-workers ................................................................ 18

1-13 One part C-C bond formation/decarboxylation toward quinoline synthesis ..................... 19

1-14 Pyrrole synthesis by gold catalyst ..................................................................................... 19

1-15 Gold catalyzed cyclization of alkenyl carbamates ............................................................ 20

1-16 Green synthesis of β-enaminones via gold catalyzed condensation ................................. 20

1-17 Bicyclic ketal synthesis by Genêt and co-workers ............................................................ 21

1-18 Cascade synthesis of ketal skeletons catalyzed by cationic gold ...................................... 22

1-19 Mechanism for the gold catalyzed cyclization of homopropargylic ethers ...................... 23

1-20 General gold catalyzed cyclization of functionalized allenes. .......................................... 24

1-21 Dihydrothiophene synthesis via gold cyclization of functionalized allenes ..................... 24

1-22 Proposed mechanism to gold catalyzed synthesis of 2-5 dihydrothiophene ..................... 25

1-23 Carbon-sulfur bond formation reaction via gold catalysis ................................................ 25

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1-24 Proposed retro-synthetic pathway for the synthesis of Azaspiracids ................................ 26

1-25 Proposed mechanism for the key gold catalyzed cyclization step .................................... 26

2-1 Spirastrellolide A............................................................................................................... 28

2-2 Target building blocks synthesized via gold catalysis ...................................................... 29

2-3 Gold catalyzed cyclization of monoallylic diols ............................................................... 29

2-4 Proposed mechanistic pathway for tetrahydropyran derivatives synthesis ....................... 30

2-5 Gold catalyzed cyclization of monopropargylic triols ...................................................... 30

2-6 Proposed mechanism of the spiroketal synthesis .............................................................. 31

2-7 Spiroketal reaction scope .................................................................................................. 31

2-8 Unexpected reactivity leading to substituted furan derivatives. ....................................... 32

2-9 Applications of five membered aromatic rings ................................................................. 32

2-10 General Paal-Knorr synthesis scheme for furan and pyrrole synthesis ............................. 33

2-11 Thiophene synthesis via Paal-Knorr-type synthesis ......................................................... 33

2-12 Silver catalyzed synthesis of substituted furans ................................................................ 34

2-13 [Au(TPP)]Cl catalyzed cyclization of allenones ............................................................... 35

2-14 One pot synthesis of halo-substituted furan derivatives catalyzed by palladium ............. 35

2-15 Zinc catalyzed formation of C3-substituted indole derivatives ........................................ 35

2-16 Optimized Trofimov reaction’s scheme affording pyrroles in good yields ...................... 36

2-17 Optimized conditions of the Gewald reaction ................................................................... 36

2-18 Microwave assisted thiophene preparation ....................................................................... 37

2-19 Possible generalization of our methodology ..................................................................... 37

2-20 Planned reaction scope to test the entire substitution pattern............................................ 38

2-21 Proposed mechanism ......................................................................................................... 39

3-1 Synthesis affording the desired cyclization precursor 4.................................................... 40

3-2 Gold catalyzed cyclization of dodec-3-yne-1,2-diol ......................................................... 40

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3-3 Gold catalysts used during the optimization studies ......................................................... 41

3-4 Five step synthesis of the cyclization precursor 13 ........................................................... 42

3-5 Cyclization reaction affording the desired 2,5-substituted furan ...................................... 43

3-6 Attempted synthesis of the 2-3 substituted furan .............................................................. 43

3-7 Conformational restrictions in the attempted cyclization of 15 ........................................ 43

3-8 Preparation of the cyclization precursor 19....................................................................... 44

3-9 Attempted cyclization of 19 .............................................................................................. 44

3-10 Rapid synthesis of three cyclization precursors ................................................................ 45

3-11 Gold catalyzed cyclization synthesis of 2-3-5 substituted furans ..................................... 46

3-12 Gold catalyzed cyclization of 26 ....................................................................................... 46

3-13 General reaction equation for pyrrole derivatives synthesis ............................................. 46

3-14 Preparation of 33 and 34 for the pyrrole synthesis............................................................ 47

3-15 Successful synthesis of pyrrole derivatives ....................................................................... 47

3-16 Successful synthesis of thiophene derivative via gold catalysis ....................................... 48

3-17 Gold catalyzed cyclization using 0.5 mol% of AuCl ........................................................ 51

3-18 Gold cyclization using 0.2 mol% of AuCl ........................................................................ 52

3-19 Gold cyclization using 0.1 mol% of AuCl ........................................................................ 52

3-20 Gold cyclization using 0.01 mol% of AuCl ...................................................................... 52

3-21 Gold catalyzed cyclization using 0.02 mol% of AuCl ...................................................... 53

3-22 Gold cyclization using 0.05 mol% of AuCl ...................................................................... 53

3-23 Final results for the catalyst loading optimization ............................................................ 54

A-1 1H NMR of compound 1 ................................................................................................... 72


A-3 13C NMR of compound 2 .................................................................................................. 74


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A-6 1HNMR of compound 5 .................................................................................................... 77


A-8 1H NMR of compound 13 ................................................................................................. 79

A-9 13C NMR of compound 13 ................................................................................................ 80







A-16 1NMR of compound 20 ..................................................................................................... 87










A-26 1H NMR of the mixture made of compounds 25A and 25B ............................................. 97

A-27 1NMR of compound 30 ..................................................................................................... 98


A-29 1H NMR of compound 33 ............................................................................................... 100

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A-30 13C NMR of compound 33 .............................................................................................. 101











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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the

Requirements for the Degree of Master Of Science

NOVEL SYNTHESIS OF HETEROCYCLIC AROMATIC RINGS VIA GOLD CATALYSIS

By

Jeremy Malinge

August 2009 Chair: Aaron Aponick Major: Chemistry

Over the past decade, gold catalysis has emerged as a useful tool for organic synthesis.

Many desirable properties have been reported in carbon-carbon, carbon-nitrogen and carbon-

sulfur bond forming reactions. The research in this thesis is focused on using gold catalysis in

novel transformations.

A practical synthesis of heterocyclic aromatic rings via gold catalysis is reported herein.

Furans, pyrroles and thiophenes are recurrent moieties in many naturally occurring products and

therefore have been of great interest to the pharmaceutical industry and in material science. The

gold catalyzed cyclization of functionalized propargylic alcohols has been observed and

investigated. A broad range of structurally diverse substrates perform well in the reaction

providing quantitative yields. This new methodology requires mild reaction conditions and the

catalyst loading can be decreased drastically. This new methodology offers an alternative to the

currently known procedures and is advantageous due to the aforementioned benefits.

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CHAPTER 1 BACKGROUND

Introduction

Over the past decade, tremendous effort has been made toward the use of gold complexes

as catalysts in organic synthesis. Traditionally, gold was considered as catalytically inactive due

to the potential formation of gold metal (Au0). Only reactions involving stoichiometric amounts

of gold were therefore investigated. In the mean time, transition-metal catalyzed reactions have

undergone a marked increase, becoming one of the most useful tools in organic chemistry,

allowing new synthetic pathways and improving organic reaction efficiency. In the early

nineties, several improvements were achieved in gold catalysis. Indeed, in 1991, Fukuda and co-

workers reported a gold-catalyzed hydration of unactivated alkynes 1 (Figure 1-1).

Figure 1-1. Gold assisted hydration of alkynes reported by Fukuda and co-workers1

The use of AuIII has shown interesting advantages when compared with classical

transition-metal catalysts such as palladium (Pd). In addition to the non-toxicity of the produced

waste, gold is less expensive than other transition-metals used in catalysis. Also, due to its

reactivity, gold catalysts require low catalyst loading usually between 1 and 5 mol%. Finally, in

contrast to many other catalysts, gold-based catalysts are extremely straightforward to synthesize

and are commercially available. In light of these impressive properties, the scientific community

now considers gold an interesting metal for catalysis. Many research groups throughout the

world have started to investigate the different properties and applications of gold. During the

past ten years, many publications have reported the beneficial properties of gold catalysis toward

carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation (Figure 1-2).

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In many cases, when other catalysts require harsh conditions, gold can be used under very

mild conditions making its use easier. Indeed, developing a protocol which does not interact

with most of the common functional groups present in the target substrate is beneficial and

allows for a great improvement in the selectivity of chemical reactions.

Figure 1-2. Total number of publication on gold catalysis per year2

This aspect becomes more important when a challenging natural product synthesis is

investigated. Having an efficient catalyst for a key step which only requires mild reaction

conditions may save numerous protection-deprotection steps.

Figure 1-3. General mechanistic pathway for coordination chemistry

As a transition-metal, the chemistry of gold has been identified as very similar to

palladium (Pd). Acting as a powerful Lewis acid, it activates π-systems by coordination and

facilitates intra or intermolecular nucleophilic attack. A wide range of substrates can be

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activated by gold catalysis including alkynes, olefins and allenes. Since the early hydration

reactions, the vast potential of gold catalysis has become apparent and many opportunities exist

for the development of new chemistry. The results presented here are convincing proof that gold

will play an important role in the future, due to its wide range of applications in the

pharmaceutical industry as well as in materials science.

Carbon-Carbon Bond Formation Catalyzed by Gold

Tremendous effort has been expended on the development of enantioselective aldol

reactions. Optically active oxazolines are good intermediates for aldol reactions since they can

easily open under acidic conditions. Designing a diastereoselective oxazoline synthesis (Figure

1-4) was a desirable study in the past, and represents one of the first enantioselective gold

catalyzed reactions.

Figure 1-4. Gold catalyzed oxazoline synthesis3

Figure 1-5. Gold species used in the oxazoline synthesis reported by Fukuda and co-workers3

One of the first examples of C-C bond formation catalyzed by gold was reported in 1986

by Hayashi and co-workers. They developed an enantio- and diastereo selective oxazoline

synthesis with the help of a gold catalyst prepared in situ with a chiral ligand (Figure 1-5). The

oxazoline moiety was synthesized in good to excellent yields and high diastereoselectivities

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(Figure 1-4). Hayashi and co-workers emphasized that the use of gold was crucial. Other

transition-metal-based catalysts including copper and silver were tested without success.

In 1996, Komiya isolated goldI and goldIII alkoxides4 (Figure 1-6) which were believed to

be very unstable because of electronic repulsion. They were able to design gold alkoxide species

stabilized by a triphenylphosphine ligand. The species produced were found to be extremely

basic and nucleophilic. Komiya’s group reacted the alkoxides with alkyl cyanoacetate, to afford

a stable organogold intermediate. This methodology was then used in a Knoevenagel-type

reaction with benzaldehyde (Figure 1-7):

Figure 1-6. GoldI and goldIII alkoxides stabilized by phosphine-type ligands

Figure 1-7. Knoevenagel reaction catalyzed by gold alkoxide4

After further investigation, they concluded that the best results were obtained with AuI

alkoxide catalysts. In this work, Komiya and co-workers demonstrated the great potential of

these gold species as catalysts toward C-C bond formation. Since 2003, many research groups

have been taking advantage of the potential of gold catalyst derivatives in organic synthesis.

Toste and co-workers increased the reactivity of the gold alkoxide catalysts based on the in situ

reaction between AuI and AgX (where X= OTf- or some other weakly coordinating counterions)

(Figure 1-8). The Toste group published several articles emphasizing the power of this catalyst

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toward C-C bond formation in a Conia-ene type reaction affording various cyclopentanoid

products5a, 5b (Figure 1-9). During the investigation of the reaction scope, the AuI catalyst

showed an amazing tolerance toward other functional groups and allowed for the preparation of a

wide range of target compounds.

Figure 1-8. In situ synthesis of a new generation of cationic gold catalysts5a, 5b

Figure 1-9. Conia-ene type reaction catalyzed by cationic gold catalyst5a, 5b

Here it should be noted that mild reaction conditions afford excellent yields, highlighting

once again the great potential of gold catalysts toward C-C bond formation. The previous

examples demonstrated the beneficial aspects of gold catalysis. Indeed, Au catalysts usually act

as a strong π-acids and activate non-reactive alkynes toward nucleophilic attack. However, in

2003, Wei and co-workers reported a three component propargylamine synthesis under gold

catalysis conditions6 (Figure 1-10).

Figure 1-10. One pot synthesis of propargyl amine catalyzed by AuIII in water6

Instead of activating alkynes as a Lewis acid, the gold catalyst inserts at the terminal

position forming a gold acetylide. This methodology has been applied to a wide range of

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substrates. The reactions proceeded in remarkable yields in all the cases while being performed

in water. This example highlights the ability of gold catalysts to react by a different manifold

than their typical Lewis acid character, showing reactivity close to Pd catalysts. However, in

contrast to palladium chemistry, gold catalysis is more environmentally friendly, requires lower

catalyst loadings and may be performed in aqueous media. These advantages allow gold

catalysis to be considered a green process. In 2007, Watanabe and co-workers reported a highly

regioselective carbon-carbon bond formation using gold catalysis7. They found that gold was

able to catalyze a carbon-carbon bond formation starting from allene derivatives. Watanabe

group applied this new protocol for a rapid and efficient synthesis of chromene and

dihydroquinoline synthesis (Figure 1-11).

Figure 1-11. Dihydroquinoline synthesis assisted by AuI catalyst7

Figure 1-12. AuI catalyst used by Watanabe and co-workers7

They noticed that the hydroarylation takes place at the central allenic carbon depending on

the substrate structure, leading to the highly selective formation of a six-membered ring. When

other transition-metals such as palladium or platinum provided moderate results, the catalytic

system made from the aforementioned AuI and AgOTf led to great results with a wide range of

quinoline and chromene derivatives (Table 1-1). As a final investigation, they successfully

applied their methodology to the one-pot synthesis of quinolines (Figure 1-13).

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Table 1-1. Optimization studies for dihydroquinoline and chromene derivatives7

Figure 1-13. One part C-C bond formation/decarboxylation toward quinoline synthesis7

Carbon-Nitrogen Bond Formation Catalyzed by Gold

Carbon-nitrogen bond formation is still a challenging process today. It has been shown

that metals can catalyze the addition of amines onto alkynes or alkenes.8a Gold, acting as a

Lewis acid may present an alternative to the use of palladium in the hydroamination of π-

complexes. In this chapter, several examples of carbon-nitrogen bond formation are emphasized.

Figure 1-14. Pyrrole synthesis by gold catalyst8b

In 2005, Toste and co-workers reported a gold-catalyzed synthesis of pyrrole8b (Figure 1-

14). This intramolecular process uses the ability of gold to activate unreactive alkynes. They

were able to obtain a wide scope of polysubstituted pyrroles using (ddpm)Au2Cl2/AgSbF6 as a

catalytic system. In addition to carbon-carbon bond formation, this first example shows the

ability of gold to catalyze carbon-nitrogen bond formation reactions with good results.

1

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Is it possible to perform the same kind of chemistry for hydroamination of alkenes? In

2006, Widenhoefer’s research group answered the previous question by designing a gold-

catalyzed cyclization of alkenyl carbamates9 (Figure 1-15).

Figure 1-15. Gold catalyzed cyclization of alkenyl carbamates

This new protocol provided an efficient synthesis of pyrrolidine derivatives via

hydroamination of alkenes. This gold catalyzed process is efficient in terms of yield and reaction

conditions that produce no hazardous waste.

Besides π-complex activation, gold can catalyze other families of reactions. For example,

in 2003, the Arcadi research group reported a “green synthesis” of β-enaminones catalyzed by

AuIII salts10a (Figure 1-16).

Figure 1-16. Green synthesis of β-enaminones via gold catalyzed condensation10a

A broad reaction scope was studied with a wide range of aliphatic, cyclic and aromatic

amines as well as β-keto-esters (Table 1-2). The simplicity of this new protocol emphasizes

another property of gold catalysis. Other transition –metal catalysts such as AgNO3, Na2PdCl4 or

ZnCl2 have been screened with no success. Interestingly, Arcadi and co-workers showed that

other nucleophiles may be used. For example, phosphorous, sulfur and oxygen based

nucleophiles provided the desired products and were shown to be compatible with gold catalysis.

This last example adds some perspective into the field of gold chemistry. Although gold

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primarily acts as a Lewis acid, similar to other transition-metal catalysts, it can also be used to

catalyze condensation-type reactions.

Table 1-2. Reaction scope for the condensation of amine with dicarbonyls compounds

Carbon-Oxygen Bond Formation Catalyzed by Gold

Extensive research has been performed to explore carbon-oxygen bond formation using

gold catalysis, since its first report by Fukuda. Genêt and co-workers published a very efficient

gold-assisted cyclization of bis-homopropargylic diols11(Figure 1-17).

Figure 1-17. Bicyclic ketal synthesis by Genêt and co-workers12

This protocol, which furnishes a strained compound, emphasizes the strong π acidity of

gold. The clean and easy access of the bicyclic ketal moiety may be useful for the synthesis of

natural products. The following reactions were performed under very mild conditions leading to

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an extended reaction scope. Variously functionalized bis-homopropargylic diols were

successfully synthesized. Finally, they showed that this process can also be catalyzed by AuCl3.

Many other examples were reported regarding the reactivity of propargylic alcohols toward

gold chemistry. Shi and co-workers published the synthesis of ketal skeletons catalyzed by the

catalytic system (Ph3P)AuCl/AgSbF612 (Figure 1-18). Starting from N-tethered alkynyl

epoxides, they demonstrated the feasibility of a cascade process involving activation of the

alkyne by coordination with gold and two successive additions of a nucleophile.

Figure 1-18. Cascade synthesis of ketal skeletons catalyzed by cationic gold

Interestingly, when water was used as a nucleophile, the process provided a fused bicyclic

ketal in moderate yields. However, in the case of a free alcohol, the process led to 2,6-trans

morpholine derivatives with good yields. Surprisingly, both of the reported reaction conditions

are diastereoselective. The efficiency of this new process can be used as a new tool for easy

access to ketal skeletons with possible applications in natural product synthesis.

Chemoselectivity is still a challenge in organic synthesis. Developing a chemoselective

process can save protection/deprotection steps within a long total synthesis. Since Au-catalysis

requires mild reaction conditions, developing a chemoselective protocol with many pendant

substituent may be possible. Floreancig and co-workers reported a chemoselective

tetrahydropyran synthesis starting from a poly-substituted homopropargylic ether13 (Figure 1-

19).

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Figure 1-19. Mechanism for the gold catalyzed cyclization of homopropargylic ethers13

The proposed mechanism involves the gold-assisted hydration of the terminal alkyne

followed by a methoxy elimination affording an α-β unsaturated ketone as an intermediate. In

order to obtain the desired product, the AuI catalyst may then activate the conjugate π-system by

coordination on the double-bond, allowing the nucleophile to attack. As previously described,

the catalyst system made from triphenylphosphine gold chloride and silver hexafluoroantimonate

requires very mild conditions and affords good to excellent yields. No side products were

observed and only one diastereoisomer was isolated.

Other Carbon-Heteroatom Bond Formation

In the previous sections, some of the numerous examples of C-C, C-O and C-N bond

formation reactions catalyzed by gold were reported. The ability of gold to smoothly, selectively

and efficiently catalyze those reactions is still under investigation and the potential of gold

chemistry has not been entirely explored.

Carbon-sulfur bond formation has rarely been investigated. Sulfur based compounds such

as thiols, sulfides or disulfides are believed not to be compatible with transition-metal catalysis.

Indeed, they strongly coordinate to the metal leading a potential gold-catalyzed carbon-sulfur

bond formation to a dead end.

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Krausse and co-workers reported in 2004 reported an efficient gold catalyzed

cycloisomerization of α-hydroxyallenes and α-aminoallene14 to provide the desired cyclic

moiety. (Figure 1-20.).

Figure 1-20. General gold catalyzed cyclization of functionalized allenes.

Since sulfur based heterocycles present a great interest, in material science for example,

Krausse and co-workers attempted to apply the same concept to investigate the reactivity of α-

thioallenes toward gold catalysis14 (Figure 1-21). When other transition-metal catalysts did not

react, AuCl3 furnished reasonable yields with high diastereomeric ratios. Even if the short

reaction time (5 min to 1.5 h) presented some advantages, some of the reaction conditions were

particularly messy producing a lot of side products such as a disulfide product.

Figure 1-21. Dihydrothiophene synthesis via gold cyclization of functionalized allenes

These undesired products may arise from the important affinity between sulfur and gold.

Krausse and co-workers took that property into account and proposed a possible mechanism

involving equilibrium between two gold coordinated species (Figure 1-22). Even if the sulfur

species are difficult to handle, gold chemistry has enabled an efficient synthesis of 2,5-

dihydrothiophene has been achieved. This article provides a good insight of C-S bond formation

reactions catalyzed by gold.

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Figure 1-22. Proposed mechanism to gold catalyzed synthesis of 2-5 dihydrothiophene

Only a few other examples have been reported. Instead of using gold catalyst as a π-

system activator, Arcadi and co-workers used gold chemistry to catalyze a condensation-type

reaction10a (Equation 1-16).

Figure 1-23. Carbon-sulfur bond formation reaction via gold catalysis

This encouraging result should allow for optimism that gold catalysis and sulfur species

may be compatible.

Gold Catalyzed Reaction as a Key-Step in a Total Synthesis of a Natural Product

In 2007, Forsyth and co-workers reported an efficient gold-assisted cyclization affording a

key intermediate in the total synthesis of Azaspiracid.15 As part of a family of marine toxins,

Azaspiracid presents some potential neurotoxic and tumor-promoting properties. In addition,

synthesizing this intermediate may be extremely challenging from a synthetic point of view. The

Forsyth research group attempted the synthesis of the trioxidispiroketal core. To confirm that

gold was the best choice to catalyze such a reaction, several other transition-metal catalysts such

as palladium acetate, silver oxide and mercury dichloride were tested without any success.

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Figure 1-24. Proposed retro-synthetic pathway for the synthesis of Azaspiracids

When AuCl in methanol with PPTS provided the desired bis-spiroketal moiety smoothly

and rapidly, the other catalyst did not afford acceptable results. They proposed that the reaction

involved an intramolecular attack of the gold-activated internal alkyne. Under acidic conditions,

the formed intermediate can rearrange further resonate to the corresponding oxonium ion which

undergoes a second intramolecular nucleophilic attack providing the desired bis-spitoketal

moiety.

Figure 1-25. Proposed mechanism for the key gold catalyzed cyclization step

Conclusion

Gold catalysis has shown interesting properties over the past decade. Since the first gold

catalyzed hydration of an isolated alkyne reported by Fukuda and co-workers,1 a great deal of

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research has been reported on the reactivity of gold catalysts. The in-situ generation of cationic

gold has widely expanded the range of potential substrate showing a great potential for carbon-

carbon and carbon-heteroatom bond formation reaction. When other transition-metal catalysts

require harsh reaction conditions and produce toxic wastes, gold can operate under mild

conditions in innocuous media without any hazardous waste produced. While all the possibilities

that gold can offer have not been totally explored yet, some applications have been reported in

total synthesis. All of the aforementioned advantages set gold catalysis as one of the best choice

to design an efficient green chemistry.

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CHAPTER 2 RESEARCH INTERESTS

The Aponick Group at the University of Florida

The Aponick group at the University of Florida was created in 2006. Since fall of 2006,

our group has directed its research toward the use of gold catalysis in organic synthesis. We are

interested in developing new methodologies to overcome synthetic complications inherent to

total syntheses of biologically active natural products. As emphasized in the previous chapter,

the use of gold chemistry may be an interesting approach to build new synthetic pathways with

high yields and high selectivities.

One of our target molecules is Spirastrellolide A (Figure 2-1). Isolated from the marine

sponge spirostrella coccineamarine,16 Spirastrellolide A is a selective protein phosphatase

inhibitor. Containing 21 stereocenters, this target molecule is a substantial synthetic challenge.

Paterson and coworkers recently reported the total synthesis of Spirastrellolide A in 36 linear

steps.17a, 17b

Figure 2-1. Spirastrellolide A

Our group, however, is focused on the synthesis of challenging building blocks such as

optically pure substituted tetrahydropyrans, which are found in various natural products (Figure

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2-2). By concentrating on these building blocks, our methodologies could prove useful in a more

efficient Spirastrellolide A synthesis.

Figure 2-2. Target building blocks synthesized via gold catalysis

In 2008, Dr. Chuanying Li and Berenger Biannic from our group reported an efficient gold

catalyzed synthesis of tetrahydropyran derivatives. As demonstrated previously, gold catalysis

has been shown to be extremely useful in the formation of C-C and C-X bonds starting from

alkynes or allenes. However, few examples reported the efficiency of gold catalysis with

isolated olefins. Recent literature has reported the hydrofunctionalization of allenes catalyzed by

gold.7 From these reports, a new strategy was envisioned for the synthesis of tetrahydropyran

derivatives. Starting from monoallylic diols, our group reported an efficient gold catalyzed

cyclization furnishing tetrahydropyran derivatives (Figure 2-3).18

Figure 2-3. Gold catalyzed cyclization of monoallylic diols

The optimized catalytic system was found to be in situ generated Ph3PAuOTf and provided

good to excellent yields for a wide range of substrates. Gratifyingly, the reaction proceeded

rapidly under very mild conditions. We hypothesize that the cationic gold catalyst coordinates to

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the alkene, activating the double bond towerd intramolecular nucleophilic attack in an addition-

elimination fashion (Figure 2-4).

Figure 2-4. Proposed mechanistic pathway for tetrahydropyran derivatives synthesis

When, 2,6-disubstituted tetrahydropyrans were produced, this protocol showed high

diastereoselectivity with diastereomeric ratios up to 25:1. In conclusion, our group has

successfully developed an easy and efficient method for selective gold catalyzed cyclizations of

monoallylic diols, affording the tetrahydropyran derivatives rapidly and in high yields.

In a constant effort toward the development of new synthetic pathways, we reported in the

gold assisted synthesis of spiroketal derivatives.19 These derivatives are predicted to be useful

building blocks in the synthesis of natural products. Dr. Chuanying Li and Jean Palmes have

developed a concise gold catalyzed cyclization of mono propargylic triols, furnishing the desired

cyclic ketal derivatives in good yields and short reaction times (Figure 2-5).

Figure 2-5. Gold catalyzed cyclization of monopropargylic triols

Based on our experience with gold catalysis, we hypothesized a possible mechanistic

pathway for the above reaction (Figure 2-6). Starting from the mono propargylic triol, the

cationic gold catalyst could coordinate to the alkyne, activating the triple bond for an

intramolecular nucleophilic attack. The alkoxyallene formed is further activated by the same

catalyst allowing for a second nucleophilic attack to provide the desired spiroketal product.

31

Figure 2-6. Proposed mechanism of the spiroketal synthesis

In previously reported spiroketal syntheses,20 the ring size of the target molecule had

caused the most problems. However, using our methodology, most of the common ring sizes can

be achieved (Figure 2-7). Reaction times were very short and the reaction conditions required

were extremely mild. The optimized catalytic system employed Au[P(t-Bu)2(o-biphenyl)]Cl

/AgOTf and provided, in most of the cases, good to quantitative yields.

Figure 2-7. Spiroketal reaction scope

During studies of the reaction scope, Dr. Chuanying Li observed an unexpected result.

Exposure of 6,6-diphenyl hept-3-yne-1,2,7-triol to standard gold conditions did not lead to the

desired spiroketal derivative, which was confirmed by a similar result with 2-cyclohexyl oct-3-

yne-1,2,8 triol (Figure 2-8). Instead of providing the expected spirocyclic product, the reaction

furnished an unknown compound in quantitative yield in 20 minutes. After further investigation,

the compound was identified as a furan derivative.

32

Figure 2-8. Unexpected reactivity leading to substituted furan derivatives.

The efficient gold catalyzed spiroketal synthesis was reported, however, the furan

derivatives needed to be further explored before publication. Preliminary results showed high

conversion so motivation was set for deeper investigation. After several test reactions, it was

hoped that a more general synthesis of furan, pyrrole and thiophene derivatives could be reached

using gold catalysis.

Furan, Thiophene and Pyrrole Generalities

Five membered aromatic rings such as furans, pyrroles or thiophenes are important

derivatives. Furan and pyrrole rings are especially reoccurring motifs in pharmaceutical targets

and compounds of high biological activity. Thiophene rings, like all sulfur compounds, are rare

in naturally occurring molecules. However, they present a great interest because their electronic

properties are useful in the design of polymer-based solar cells. Due to the range of applications

in medical and material science, a facile synthesis of these compounds is of great interest.

Figure 2-9. Applications of five membered aromatic rings.21, 22, 23

33

One of the first and the most famous syntheses was designed simultaneously by C. Paal

and L. Knorr in 1884.24 Known as the Paal-Knorr synthesis, it involved treatment of a 1,4-

dicarbonyl derivative with concentrated mineral acid. One of the advantages of the Paal-Knorr

synthesis is that all substitution patterns can be obtained in moderate to good yields. In addition,

the interesting feature of this synthesis is that by changing the reaction conditions, it can be

possible to reach the corresponding pyrrole using the same starting material25 (Figure 2-10).

Indeed, treatment of the same dicarbonyl compound with liquid ammonia or ammonium acetate

in glacial acetic acid affords the corresponding pyrrole derivative in good yields. However, the

major drawback in both cases is the use of harsh reaction conditions which are not compatible

with many functional groups.

Figure 2-10. General Paal-Knorr synthesis scheme for furan and pyrrole synthesis

In 1944, Campaigne adapted the general Paal-Knorr reaction scheme toward thiophene

synthesis.26 Condensation of 1,4-dicarbonyl compounds in the presence of an excess sulfur

source such as phosphorous pentasulfide affords the desired thiophene moiety (Figure 2-11).

However, toxic H2S waste is generated during the process.

Figure 2-11. Thiophene synthesis via Paal-Knorr-type synthesis

34

Due to the wide range of applications, synthesis of five membered rings is still of great

interest. Other than the early Paal-Knorr reaction, many research groups throughout the world

continue to explore new synthetic routes. In order to form functionalized furan-type substrates,

two main approaches are currently used. Halogen-metal exchange on a preexisting cyclic

material, followed by electrophilic trapping is the first possibility. The use of a lithium source,

however may be too harsh regarding pendant functional groups. The second approach involves

the construction of the furan, pyrrole or thiophene core starting from an acyclic precursor,

assisted by transition-metal catalysts. This method has received great interest during the past

few years.

Many substrates presented potential for furan synthesis. For example, alk-1-yne-oxiranes

were able to cyclize under AgI and acidic conditions affording the desired furan moiety in

moderate to good yields27 (Figure 2-12).

Figure 2-12. Silver catalyzed synthesis of substituted furans

Since gold catalysis has shown great potential toward C-X (where X=O or N) bond

formation during the past decade, cycloisomerisation of allenones assisted by gold has also been

shown to be a very efficient methodology for furan synthesis28 (Figure 2-13). However, the

efficiency of a methodology should also be judged on the availability of the starting material..

With this concept in mind, Muller and co-workers designed a novel one-pot synthesis of

halofurans through a Suzuki/deprotection/cyclocondensation sequence.29 Starting from an acyl

chloride and a protected propargylic alcohol, they were able to synthesize the desired furan in

modest yields under palladium catalyzed conditions (Figure 2-14).

35

Figure 2-13. [Au(TPP)]Cl catalyzed cyclization of allenones

Figure 2-14. One pot synthesis of halo-substituted furan derivatives catalyzed by palladium

Aside from furan syntheses, modern pyrrole syntheses have also been reported. Many

publications emphasize efficient protocols for indole derivatives. Excellent results were obtained

via Et2Zn assisted cyclization of alkynyl-amides30 (Figure 2-15).

Figure 2-15. Zinc catalyzed formation of C3-substituted indole derivatives

However, for target compounds that were not indole-based derivatives, the yields dropped

drastically. Even if the design of complex pyrrole derivatives such as indole moieties was

extensively studied and reported, methodologies for simple synthesis of alkyl or aryl substituted

pyrrole has not been explored yet. In 2005, a modified-Trofimov reaction was reported that

emphasized the facile preparation of simple pyrrole derivatives in a one-pot reaction.31 The

reactions were tested between a wide range of ketones with hydroxyl-amine and sodium

36

carbonate. The intermediate was then treated with acetylene gas in DMSO, affording the desired

pyrrole moiety in decent yields (Figure 2-16).

Figure 2-16. Optimized Trofimov reaction’s scheme affording pyrroles in good yields

Though yields may need improvement, a reaction starting from readily available ketones

and ethylene gas that provides the desired products product without any catalytic amount of

transition-metal catalyst is remarkably efficient. The formation of simple substituted pyrroles

has been shown, and this protocol could show potential applications in industry.

Finally, other than the initial Paal-Knorr thiophene synthesis, very few publications have

reported new synthetic pathways toward an efficient thiophene derivative synthesis. The most

widely used reaction is the Gewald reaction. Reported in 1966, the Gewald reaction involves the

condensation of a ketone with an activated nitrile in the presence of elemental sulfur. Few

optimization studies were performed32 in order to improve the yields of the original Gewald’s

process (Figure 2-17).

Figure 2-17. Optimized conditions of the Gewald reaction

Even though a potential core for drug synthesis has been successfully obtained, the yield is

still low after optimization and the purification process seems to be extremely difficult. In a

recent report from Sridhar and co-workers, the synthesis of 2-amino thiophene moiety was

improved by the use of KF immobilized on alumina and microwave irradiation of the reaction

37

mixture33 (Figure 2-18). These recent findings showed considerable improvement on Gewald’s

initial process. Of all the cyclic moieties studied in this chapter, thiophene derivatives appear to

be the most challenging to prepare.

Figure 2-18. Microwave assisted thiophene preparation

Birth of a New Project

The unexpected reactivity encountered in Dr. Chuanying Li’s project has revealed a

potentially useful new synthetic pathway for the synthesis of five-membered aromatic rings.

This protocol seemed attractive since it could furnish simple routes to furan, pyrrole and

thiophene derivatives (Figure 2-19). However, we needed to prove that only the 1,2-propargylic

diol functional group was involved in the cyclization reaction.

Figure 2-19. Possible generalization of our methodology

To test our hypothesis, the reactivity of dodec-3-yne-1,2-diol needed to be explored. If this

first test worked, optimization reactions would be scheduled in order to find the best reaction

conditions. It was also decided to apply this synthesis to exploit different substitution patterns

(Figure 2-20) and attempt the synthesis of pyrrole and thiophene derivatives. If all these

38

experiments gave positive results, we envisioned a new synthetic pathway for the synthesis of

useful synthetic building blocks.

Figure 2-20. Planned reaction scope to test the entire substitution pattern

Based on our previous results in gold chemistry, we predicted that the reaction would

proceed following the mechanism outlined in Figure 2-21. Coordination of the gold catalyst to

the internal alkyne should allow for an intramolecular nucleophilic attack leading to intermediate

1. This intermediate could then quickly rearrange via a proton shift providing an oxonium ion

(intermediate 2). Elimination over two steps followed by a proton abstraction would provide the

desired furan product and one molecule of water. Lastly, our protocol would be tested on a large

scale to demonstrate that this methodology could be employed in industrial processes.

R

OH

OH

R

OH

OH

R1

OH

OH

R1R2

OH

OH

R1R2

R

OH

OH

R2

O

O

O

O

O

R

R

R

R1

R1

R1

R2

R2

R2

Goldcatalysis

39

Figure 2-21. Proposed mechanism

40

CHAPTER 3 RESEARCH INVESTIGATION

First Test Reaction

As described in the previous chapter, the first substrate tested was dodec-3-yne-1,2-diol.

Our synthesis started with the protection of the commercially available allyl alcohol as its silyl

ether and was performed under standard conditions to give the desired product in 98% yield.

The residue was then treated with ozone under reductive work up providing the desired aldehyde

in 88% yield. Deprotonation of 1-decyne and addition to aldehyde 2 provided the propargylic

alcohol in 73% yield under standard conditions. Finally the precursor to cyclization was

obtained upon treatment with an excess of TBAF providing a yield of 90% (Scheme 3-1).

Figure 3-1. Synthesis affording the desired cyclization precursor 4

Figure 3-2. Gold catalyzed cyclization of dodec-3-yne-1,2-diol

The first gold cyclization performed employed our standard.19 The desired goldI catalyst

was generated in situ from Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf in THF at 0°C in the

presence of molecular sieves. The reaction proceeded rapidly to the expected mono-substituted

furan within 10 minutes in 88% yield (Figure 3-2).

41

Optimization Studies

Successful reaction of the first gold catalyzed cyclization led us to investigate the reaction

conditions by screening different cationic gold catalysts (Figure 3-3). The conditions and the

results of the optimization studies are reported in the following chart (Table 3-1).

Figure 3-3. Gold catalysts used during the optimization studies

Table 3-1. Results of optimization studies

Without surprise, the reaction did not proceed using tris(triphenylphosphinegold) oxonium

tetrafluoroborate salt (7, entry 2) but gave acceptable results with triphenylphosphine gold

chloride (8, entry 3). The previous conditions required AgOTf as co-catalyst in order to form the

42

active gold cation. Since this additive is light sensitive, it can be difficult to handle. Upon

consideration of the sensitivity of the co-catalyst, it was decided to try AuCl without any

additive. The first attempt yielded satisfactory results (9, entry 4) affording 5 without any

purification needed. Trying to simplify the protocol, the reaction was performed without

molecular sieves (9, entry 5), then with the flask opened to the air (9, entry 6) both giving good

yields. An attempt was made to use water as the solvent (9, entry 7) but the reaction did not

proceed and catalytically inactive residues were observed on the wall of the reaction flask.

Control experiments utilizing acidic conditions (entry 8) and AgOTf alone (entry 9) were not

able to catalyze the reaction, demonstrating the need for the gold catalyst.

Expansion of the Reaction Scope

With the optimal conditions established, the substrate substitution pattern was studied

beginning with the 2,5-substituted furan. Starting from the commercially available

cyclohexanecarboxyaldehyde, addition of vinyl magnesium bromide followed by protection of

the resulting secondary allyl alcohol afforded the desired product 10 in 48% over two steps.

Figure 3-4. Five step synthesis of the cyclization precursor 13

Treatment with ozone under reductive work up formed the expected aldehyde 11 in 55%

yield. Deprotonation of phenylacetylene followed by alkylation of 11 using standard conditions

afforded 40% of 12 which was subsequently treated with an excess of TBAF to provide the

43

desired propargylic diol 13 in 95% yield (Figure 3-4). Exposure of 13 to the optimized gold

conditions provided the 2,5-disubtituted furan 14 within 10 min in 88% yield (Figure 3-5).

Figure 3-5. Cyclization reaction affording the desired 2,5-substituted furan

The next substrate of interest was the 2,3-substituted furan moiety. A rapid synthesis has

been achieved. Starting with commercially available 1-ethynyl-1-cyclohexene, dihydroxylation

using OsO4 was performed affording the cyclization precursor 15 in 32% yield.

Figure 3-6. Attempted synthesis of the 2-3 substituted furan

Unfortunately, none of the gold catalysts were able to catalyze the reaction (Figure 3-6).

According to recent literature reports, we think that gold can activate the terminal C-H bond

through insertion forming a gold acetylide.6, 34 It is believed that gold acetylides are relatively

stable34 making the intramolecular cyclization impossible. In addition, since the dihydroxylation

performed with OsO4 is known to be syn stereospecific,35 the hydroxyl group may be too far

from the alkyne for any reaction to proceed (Figure 3-7).

Figure 3-7. Conformational restrictions in the attempted cyclization of 15

44

To test that hypothesis, another substrate without any conformational issues was tested.

The compound of interest was the 3-substituted furan moiety. Our synthesis began by treating

the previously prepared TBDPS-protected aldehyde 2 with an excess of hexylmagnesium

bromide to produce the expected secondary alcohol 16 in 88% yield. Swern oxidation provided

the corresponding ketone 17 in 73% yield. Ethynylmagnesium bromide was then added to 17

according and the resulting alcohol was then treated with an excess of TBAF to yield the desired

propargylic diol 19 in 65% (Figure 3-8).

Figure 3-8. Preparation of the cyclization precursor 19

Exposure of 19 to optimized gold catalyzed cyclization conditions did not give the

expected results. Indeed, no changes were monitored by TLC, even after 30 minutes. The crude

1H NMR confirmed that the starting material did not react and after column purification, 81% of

19 was recovered (Figure 3-9). It was hypothesized that there was a purity issue and therefore,

the reaction was repeated but instead using Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf in THF at

0°C in the presence of molecular sieves. After 30 minutes, there was no change by TLC and the

1H NMR confirmed once again that the reaction was not proceeding.

Figure 3-9. Attempted cyclization of 19

45

Our hypothesis is that terminal alkynes are not compatible with our protocol because of the

formation of a fairly stable gold acetylide which cannot undergo intramolecular cyclization. To

overcome that issue, it was decided to synthesize a protected terminal alkyne which can be easily

removed if needed. Anticipating any selective deprotection issue, we decided to follow a known

protocol to synthesize our substrate in one step.36 Three substrates were synthesized from the

commercially available acetoin. Deprotonation of 2 equivalents of phenylacetylene and 1-

decyne followed by addition to one equivalent of acetoin provided 2 potential substrates, 20 and

21 respectively, for the synthesis of 2,3,5-substituted furans. The same protocol was used for the

addition of TMS-acetylene on acetoin providing another cyclization precursor 22 (Figure 3-10).

Figure 3-10. Rapid synthesis of three cyclization precursors

Exposure of 20 and 21 to optimized gold conditions afforded the desired 2,3,5-substituted

furan in good to excellent yields. However, the reactivity of 22 observed was not expected

(Figure 3-11). Even though all the starting material was consumed after 15 minutes, the 1H

NMR showed that the reaction formed a mixture of two products 25A and 25B, in 85%. Since

they had the same Rf, they could not be separated by column chromatography and the ratio was

determined by 1H NMR. It is believed that during the reaction, a TMS-shift occurs leading to a

mixture of two products. To confirm this hypothesis, Dr. Chuanying Li synthesized another

silyl-protected propargylic diol but using a bulkier protecting group. Using the same synthetic

46

pathway, 4-(triisopropylsilyl)but-3yne-1,2-diol 26 was synthesized and treated with the catalyst

generated from Ph3PAuCl and AgOTf (Figure 3-12).

Figure 3-11. Gold catalyzed cyclization synthesis of 2-3-5 substituted furans

By increasing the size of the protecting group we were able to control the selectivity of the

reaction. With potential deprotection or coupling reactions it may be possible to have access to

the 2,3-substituted furan.

Figure 3-12. Gold catalyzed cyclization of 26

Once we tested all the substitution patterns, it was decided to apply the protocol for the

synthesis of pyrrole derivatives. According to the general reaction scheme, the substrates of

interest are depicted on Figure 3-13.

Figure 3-13. General reaction equation for pyrrole derivatives synthesis

Our synthesis begins from the easily prepared N-allyl-4-methylbenzenesulfonamide 28.

Oxidative cleavage by ozone of 28 lead only to decomposition, so it was decided to protect the

47

amine with an additional protecting group. Ozonolysis followed by reductive work up formed

the desired aldehyde 30 in 88% yield over two steps. Starting from 30, two different substrates

were synthesized. Deprotonation of phenyl acetylene and 1-decyne with n-BuLi followed by

addition on the aldehyde 30 afforded the desired intermediates 31 and 32. Exposure to

potassium bicarbonate in methanol at reflux provided two different cyclization precursors 33 and

34 (Figure 3-14).

Figure 3-14. Preparation of 33 and 34 for the pyrrole synthesis

Exposure of 33 and 34 to gold catalysis using Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf in

THF at 0°C in the presence of molecular sieves formed the expected pyrroles in very good yields

within 15 minutes (Figure 3-15).

Figure 3-15. Successful synthesis of pyrrole derivatives

In the mean time, Dr. Chuanying Li investigated the potential synthesis of thiophenes

using our methodology. The performed synthesis begins with the Sonogashira coupling between

commercially available phenyl acetylene and vinyl bromide affording the desired enyne 37 in

88% yield which was then treated with m-CPBA providing the desired epoxide moiety 38 in

48

79% yield. Subsequently, 38 was treated with NaHS providing the cyclization precursor 39 in

41% yield. Exposure of 39 to gold catalysis using Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf in

THF at 40°C in the presence of molecular sieves formed the desired thiophene in 90% yield

within 80 minutes (Figure 3-16).

Figure 3-16. Successful synthesis of thiophene derivative via gold catalysis

The previous reactions emphasize the efficiency of our methodology toward the synthesis

of substituted five-membered aromatic rings. This protocol has been shown to be compatible

with most of the substitution patterns and is applicable for furan, pyrrole and thiophene

synthesis. Other substrates with pendant functional groups have been tested by Dr. Chuanying

Li with success but will not be detailed here. The scope of the reaction is reported in the two

following tables (Table 3-2 and 3-3).

49

Table 3-2. Furan rings synthesized using our methodology

50

Table 3-3. Pyrrole and thiophene rings synthesized using our methodology

51

Catalyst Loading Optimization

With these results in hand, it was decided to further investigate the catalyst loading of this

methodology. Most of the reactions were performed with 2 mol% of gold catalyst. Since the

reaction proceeded efficiently within 10 minutes, we naturally thought that the catalyst loading

could be decreased. Since the synthesis of substrates 19 and 20 was achieved in one-step, these

diols were the perfect candidates to quickly provide large amounts of cyclization precursors.

Even if the reaction is extremely clean, the production of a stoichiometric amount of water

during the process may be problematic. Thus we decided to start the investigation by using 0.5

mol% AuCl catalyst in the presence of molecular sieves at 0°C (Figure 3-17).

The cyclization of 19 proceeded smoothly in 25 minutes. It is interesting to note that

besides TLC analysis, the reaction can be monitored by color changes. Indeed, when AuCl is

mixed with the substrate, the mixture’s color is pale yellow. As the reaction is proceding, the

mixture become colorless and when the catalyst is inactive a strong purple color can be observed.

This color may be due to inactive gold residue coating the wall of the reaction flask.

Figure 3-17. Gold catalyzed cyclization using 0.5 mol% of AuCl

We decided to again decrease the catalyst loading while performing the reaction at room

temperature in an attempt to increase the reaction rate (Figure 3-18). The cyclization provided

the desired furan in 70% yield in 30 min. We think that using AuCl, the first 10 minutes of

reaction are very important. Indeed, since AuCl is well known to be extremely reactive, it is

necessary to “keep it busy” and increase the reaction rate before it can crash out of solution

leading to unreactive residues.

PhOH

HO

AuCl (0.5 mol%)

THF, 0 °C, MS 4Å

OPh

19 22, 82% yield

52

Figure 3-18. Gold cyclization using 0.2 mol% of AuCl

Next, we decided to try the cyclization of 20 using 0.1 mol% of catalyst at reflux (Figure

3-19). To our delight, the reaction went to completion within less than 10 minutes affording 23

in a quantitative yield with no purification needed. We think that the reaction is so fast that even

without molecular sieves to trap the water, the reaction went to completion. These results

confirm our hypothesis that the high turnover number compensates for the low catalyst loading.


We decided to lower the catalyst loading once again to 0.01 mol%. However, since the

smallest amount of catalyst that we were able to measure is around 1 mg, 8.55 g of starting

material was needed. With such a large amount of substrate we decided to also increase the

molarity of the reaction in order to perform the reaction with a reasonable amount of solvent. In

addition, we decided to use molecular sieves in order to make sure that water would not

terminate the reaction (Figure 3-20). However, the reaction did not go to completion, affording

only a 4% yield of the cyclized product. We were able to recover 80% of the starting material.


53

Several factors may affect the process. First, the purity of the starting material may be

questionable. Indeed, dealing with such large amounts of starting material makes the possible

impurities below the detection sensitivity of the 1H NMR spectrometer. Also, the amount of

water produced may be too high for the catalyst to proceed during the reaction. Finally, the limit

of this methodology may have been reached. After purification of the recovered substrates, we

tried the reaction with exactly the same conditions, using 0.02 mol% of AuCl (Figure 3-21).

Figure 3-21. Gold catalyzed cyclization using 0.02 mol% of AuCl

Compound 23 was isolated in 34% yield. Monitoring by TLC, indicated that after 15

minutes, the catalyst was inactive. However, 57% of the starting material was recovered and

purified by flash chromatography. Furthermore, the reaction was attempted using 0.05 mol%

with the exact same standard reaction conditions (Figure 3-22).


The reaction proceeded quickly and after 20 minutes, the reaction went to completion.

Filtration of the reaction mixture and purification by column chromatography afforded 23 in

91% yield. All the results are summarized in Table 3-4 and Figure 3-23.

54

Table 3-4. Catalyst loading optimization

Figure 3-23. Final results for the catalyst loading optimization

55

Conclusion

In conclusion, we successfully designed a new and efficient protocol for five membered

aromatic rings synthesis. Our methodology is applicable for furan, pyrrole and thiophene

derivatives. The majority of the substitution patterns have been successfully synthesized. The

desired products were obtained in less than 20 minutes in general and in high yield. Moreover,

Dr. Chuanying Li has also shown our methodology not to be sensitive to pendant functional

groups such as alcohols, cyano groups and protected aldehydes. Finally, the catalyst loading can

be decreased to 0.05 mol% providing an inexpensive synthesis of very useful building blocks.

56

CHAPTER 4 EXPERIMENTAL PROCEDURES

All reactions were carried out under an atmosphere of nitrogen unless otherwise specified.

Anhydrous solvents were transferred via syringe to flame-dried glassware, which had been

cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran (THF), acetonitrile, ether,

dichloromethane and pentane were dried using an mBraun solvent purification system.

Analytical thin layer chromatography (TLC) was performed using 250 µm Silica Gel 60 F254 pre-

coated plates (EMD Chemicals Inc.). Flash column chromatography was performed using 230-

400 Mesh 60Å Silica Gel (Whatman Inc.). The eluents employed are reported as volume:volume

percentages. Proton nuclear magnetic resonance (1H NMR) spectra were recorded using Varian

Unity Inova 500 MHz and Varian Mercury 300 MHz spectrometers. Chemical shift (δ) is

reported in parts per million (ppm) downfield relative to tetramethylsilane (TMS, 0.0 ppm) or

CDCl3 (7.26 ppm). Coupling constants (J) are reported in Hz. Multiplicities are reported using

the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;

Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded using a Varian Unity

Mercury 300 spectrometer at 75 MHz. Chemical shift is reported in ppm relative to the carbon

resonance of CDCl3 (77.00 ppm). Infrared spectra were obtained on a Bruker Vector 22 IR

spectrometer at 4.0 cm-1 resolution and are reported in wavenumbers. High resolution mass

spectra (HRMS) were obtained by Mass Spectrometry Core Laboratory of University of Florida,

and are reported as m/e (relative ratio). Accurate masses are reported for the molecular ion (M+)

or a suitable fragment ion.

General reaction conditions for gold catalyzed reactions.

57

Reaction conditions A: (AuCl (2 mol %), THF, 0°C, open flask.) Dry THF was added to

an open test tube containing AuCl (2 mol %) and cooled to 0°C. A solution of substrate (0.2

mmol) in dry THF (2 mL) was added. After TLC analysis showed the reaction to be complete, it

was filtered through a short plug of silica affording the pure desired product without purification.

Reaction conditions B: (Au [P(t-Bu)2(o-biphenyl)]Cl/AgOTf (2 mol %), THF, 4 Å-MS,

0°C.) Dry THF (1 mL) was added to an aluminum foil covered test tube containing (2-

Biphenyl)di-tert-butylphosphine gold chloride (2.0 mol %), AgOTf (2 mol %) and activated MS-

4Å (20 mg). After stirring 10 minutes, the mixture was cooled to 0°C and a solution of substrate

(2 mmol), in dry THF (2 mL) was added. After TLC analysis showed the reaction to be

complete, it was filtered through a short plug of silica and then purified by flash

chromatography.

allyloxy(tert-butyl)diphenylsilane (1). To a stirred solution containing allyl alcohol (8.4

mmol) and imidazole (10.5 mmol, 1.25 eq. ) was added dropwise TBDPSCl (7 mmol, 0.8 eq.) at

0°C. The reaction mixture was allowed to warm to room temperature over 5 hours. The reaction

was then quenched with 10 mL of ammonium chloride, diluted with 30 mL of ethyl acetate and

extracted 3 times with ethyl acetate. The organic layers were combined and washed with brine

and dried over MgSO4. Purification by flash chromatography (100% hexanes) afforded 2.48 g of

a colorless oil (Rf= 0.85 in hexanes, 98% yield) that satisfactorily matched all previously

reported data.37

(tert-butyldiphenylsilyloxy)acetaldehyde (2). O3 was bubbled through a solution of 1

(0.50 g, 1.69 mmol) in 20mL of CH2Cl2/MeOH (3/1) until the a blue color persisted. Then the

reaction was quenched with 2.3 mmol of DMS (1.7 ml, d = 0.846) and the mixture was allowed

58

to warm to room temperature overnight. The solution was diluted with 30mL of ether, washed

with saturated sodium chloride and dried over MgSO4. Purification by flash chromatography

(10% ethyl acetate in hexanes) afforded 0.45g of a colorless oil (Rf= 0.5 in 10% ethyl acetate in

hexanes, 88% yield) that satisfactorily matched all previously reported data.38

Dodecyne-3-yne-1,2-diol (4) . A solution of n-BuLi in hexanes (2.5 M, 0.6 mL, 1.65

mmol 1.1 eq.) was added dropwise to a solution of n-decyne (0.17 mL, 1.65 mmol, 1.1eq) in dry

THF (10 mL) at -78 °C. The mixture was warmed to -30 °C for 30 min and then returned to -78

°C. A solution of 2 (0.35 g, 1.5 mmol, 1 eq.) in dry THF (5 mL) was added in a dropwise

fashion to the reaction and the mixture was allowed to warm to room temperature over 30 min.

The reaction was quenched with deionized water (10 mL) and extracted with EtOAc. The

combined organic layers were dried over MgSO4 and concentrated. The residue was then treated

with a solution of TBAF (1 M in THF, 3 mL, 3 mmol.) at room temperature. The mixture was

stirred 3 h, quenched with deionized water (5 mL) and extracted with EtOAc (3x15 mL). The

combined organic layers were dried over MgSO4, concentrated, and purified by flash

chromatography (15% EtOAc/Hexanes) to give the product as a white solid (0.1g, 65% over two

steps ). 1H NMR (300 MHz, CDCl3) δ 7.72-7.67 (m, 4H), 7.48-7.36 (m, 6H), 4.52-4.43 (m, 1H),

3.78 (dd, J = 10.2, 3.9 Hz, 1H), 3.70 (dd, J = 10.2, 6.9 Hz, 1H), 2.61 (d, J = 5.1 Hz, 1H), 2.18

(dt, J = 6.9, 1.8 Hz, 2H), 1.54-1.44 (m, 2H), 1.35-1.20 (m, 10H), 1.09 (s, 9H), 0.88 (t, J = 6.9 Hz,

3H). 13C NMR (75 MHz, CDCl3) δ 135.6, 135.5, 133.0, 132.9, 129.9, 129.8, 127.8, 127.7, 86.5,

77.8, 67.9, 63.4, 31.8, 29.1, 29.0, 28.9, 28.5, 26.8, 22.6, 19.3, 18.7, 14.1.

59

2-octylfuran (5). A solution of diol (0.22 mmol) in dry THF (2 mL) was treated with gold

catalyst according to procedure A to afford a colorless oil (43.7 mg, 88%). Rf = 0.9 (10%

EtOAc/hexanes) 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J = 2.1 Hz, 1H), 6.26 (dd, J = 3.0, 2.1

Hz, 1H), 5.96 (dd, J = 3.0, 0.9 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 1.66-1.60 (m, 2H), 1.31-1.27

(m, 10H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 156.6, 140.6, 110.0, 104.5,

31.9, 29.3, 29.2, 29.1, 28.1, 28.0, 22.7, 14.1 which matched all previously reported data.39

tert-butyl(1-cyclohexylallyloxy)dimethylsilane (10). A solution of vinylmagnesium

bromide (1 M in THF, 20 mL, 20 mmol, 1.5 eq.) was added dropwise to a solution of

cyclohexanecarboxaldehyde (1.7 mL, 14 mmol) in dry THF (10 mL) at -78 °C. The mixture was

stirred 2 h and then quenched with NH4Cl (25 mL of a saturated aqueous solution), diluted with

water (50 mL) and extracted with EtOAc. The combined organic layers were dried over MgSO4

and concentrated. The residue was then treated with TBSCl (1 g, 6.6 mmol, 1.1 eq.), Et3N (1.2

mL, 7.2 mmol 1.3 eq.), DMAP (0.2 g, 1.8 mmol, 0.3 eq.) in dry THF (30 mL) at 0 °C. After

TLC analysis showed the reaction to be complete (36 h), the mixture was diluted with Et2O (30

mL) and extracted with EtOAc. The combined organic layers were washed with NH4Cl (25 mL

of a saturated aqueous solution), dried over MgSO4, concentrated, and purified by flash

chromatography (5% EtOAc/Hexanes) to give the product as colorless oil (0.8 g, 48% over two

steps ). Rf = 0.7 (10% EtOAc/hexanes) that satisfactorily matched all previously reported data.40

60

2-(tert-butyldimethylsilyloxy)-2-cyclohexylacetaldehyde (11). O3 was bubbled through

a solution of 10 (0.7 g, 2.75 mmol) in CH2Cl2/MeOH (20 mL, 3/1) at -78 °C until a blue color

persisted. Dimethyl sulfide (2.75 mL, 10 eq.) was then added and the mixture was allowed to

warm to room temperature over 6 h under N2. The solvent was removed under vacuum and the

mixture was purified by column flash chromatography (5% EtOAc/Hexanes) to give the product

as colorless oil (0.4 g, 57%), Rf = 0.5 (5% EtOAc/Hexanes), that satisfactorily matched all

previously reported data.41

1-cyclohexyl-4-phenylbut-3-yne-1,2-diol (13). A solution of n-BuLi in hexanes (2.5 M,

0.6 mL, 0.24 mmol, 1.1 eq.) was added dropwise to a solution of phenylacetylene (0.17 mL, 0.24

mmol, 1.1eq) in dry THF (10 mL) at -78 °C. The mixture was warmed to -30 °C for 30 min and

was returned to -78 °C. A solution of 11 (0.35 g, 0.21 mmol, 1 eq.) in dry THF (5 mL) was

added dropwise to the reaction and the mixture warmed to room temperature over 30 min. The

reaction was quenched with deionized water (10 mL) and extracted with EtOAc. The combined

organic layers were dried over MgSO4 and concentrated. The residue was then treated with a

solution of TBAF (1 M in THF, 0.8 mL, 2 eq.) at room temperature. The mixture was stirred 3

h, quenched with deionized water (5 mL) and extracted with EtOAc. The combined organic

layers were dried over MgSO4, concentrated, and purified by flash chromatography (15%

EtOAc/Hexanes) to give the product as a white solid (0.100 g, 40% over two steps ). Rf = 0.34

OH

OH

61

(30% EtOAc/hexanes). IR (neat) 3399, 2929, 2228, 1490, 1049 cm-1. 1H NMR (300 MHz,

CDCl3): δ 7.45 (m, 2H), 7.30 (m, 3H), 4.50-4.75 (m, 1H), 3.50 (br, 1H), 3.25 (br, 1H), 2.40 (br,

1H), 2.10 (m, 1H), 1.50-1.80 (m, 6H), 1.00-1.25 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 132.0,

131.9, 128.7, 128.5, 122.5, 86.9, 86.6, 79.2, 78.7, 65.2, 64.5, 41.0, 30.0, 29.3, 29.0, 26.5, 25.9;

HRMS (ESI) Calcd for C16H20O2 (2M+Na)+ 511.2819, found 511.2843.

2-cyclohexyl-5-phenylfuran (14). A solution of diol 13 (0.22 mmol) in dry THF (2 mL)

was treated with gold catalyst according to procedure A to afford a pure colorless oil (43.7 mg,

88%). Rf = 0.9 (10% EtOAc/hexanes). IR (neat) 2992, 2856, 2253, 1019, 907, 724 cm-1. 1H

NMR (300 MHz, CDCl3): δ 7.65 (d, J = 6 Hz, 2H), 7.40-7.30 (t, J = 9Hz, 2H), 7.25-7.20 (tt, J =

6.0, 1.5 Hz, 1H), 6.55 (d, J = 3 Hz, 1H), 6.05 (dd, J = 3.0, 1.5 Hz, 1H), 2.70 (m, 1H), 2.10 (m,

2H), 1.90-1.70 (m, 3H), 1.50-1.20 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 161.0, 152.0, 131.6,

128.8, 126.9, 123.5, 106.0, 105.0, 37.6, 31.9, 28.4, 28.2. HRMS (ESI) Calcd for C16H18O (M)+

226.1358, found 226.1345.

1-ethynyl-cyclohexane-1,2-diol (15). A dried flask was charged with 1-ethynyl-

cyclohexene (3.72 mmol), 4-methylmorpholine N-oxide ( 4.02 mmol, 0.84 mL of a 5% solution

of NMO in water) and 40 mL of CH2Cl2. Osmium tetraoxide (0.37 mmol, 264 µL of 4%

solution of OsO4 in water) was then added dropwise and the reaction was stirred during 16 h at

room temperature. The reaction was quenched with 15 mL of a saturated solution of sodium

62

thiosulfate, diluted with water and extracted with EtOAc. The combined layers were washed

with saturated sodium chloride, dried over MgSO4, concentrated and purified by flash column

chromatography (30 % EtOAC/Hexanes) affording the product as a red oil ( 0.17 g, 32%).

1HNMR (CDCl3): δ 1.4 (m, 3H), 1.53 (m, 2H), 1.6 (t, 1H), 1.69 ( t, 1H), 1.8 ( t, 1H), 3.3 (dd, J =

6 Hz, 1H), 3.5 (s, 1H), 4 (s, 1H), 4.5 ( s, 1H). 13CNMR (CDCl3): δ 87.8, 78.3, 74.2, 73, 35, 26.5,

23.

1-(tert-butyldiphenylsilyloxy)octan-2-ol (16). A solution of 2 (6.6 mmol) in 30 mL of

dry THF was treated with hexylmagnesium bromide (4 mL, 8 mmol) at 0°C. The ice bath was

removed and the reaction warmed over 2h to room temperature. The reaction was quenched with

10 mL of HCl (1M), diluted and extracted with ether. The combined organic layers were washed

with brine and dried over MgSO4. 2.16 g of a pure colorless oil was obtained with no

purification needed (Rf=0.5 in 10% ethyl acetate in hexanes, 88% yield). 1H NMR (CDCl3), δ:

0.9 (t, J = 8 Hz, 3H); 1.1 (s, 9H); 1.3 (br, 6H); 1.56 (br, 2H); 2.56 (br, 1H); 3.6 (br, 2H); 7.4 (m,

6H); 7.8 (m, 4H). 13CNMR (CDCl3): δ 135.7, 133.4, 129.9, 127.9, 72.1, 68.2, 33.0, 31.9, 29.5,

27.1, 25.7, 22.8, 19.4, 14, 3.

1-(tert-butyldiphenylsilyloxy)octan-2-one (17). To a solution of oxalyl chloride (8.1

mmol) in dry dichloromethane (25 mL) at -78 °C was slowly added DMSO (1.15 mL, 24.3

mmol, 3 eq.) while keeping the temperature below - 65 °C. After 10 minutes, a solution of 16

(5.4 mmol) in dry dichloromethane (25 mL) was added dropwise to the reaction mixture and the

reaction warmed to room temperature over one hour. The reaction was then quenched with Et3N

63

(3.8 mL, 40.5 mmol, 5 eq.), diluted with 30 mL of ether and poured into 20 mL of a saturated

solution of sodium bicarbonate. After stirring during 15 minutes, the mixture was extracted with

ether, washed with HCl (1M), brine, concentrated and dried over MgSO4. Purification by flash

chromatography (50% CH2Cl2/Hexanes) provided the product as colorless oil (1.3 g, 73%). Rf =

0.4 (50% CH2Cl2/Hexanes). 1H NMR (300 MHz, CDCl3) δ: 0.9 (t, J = 8 Hz, 3H); 1.1 (s, 9H);

1.3 (br, 6H); 1.56 (br, 2H); 2.5 (t, J = 8 Hz, 2H); 4.2 (s, 2H); 7.4 (m, 6H); 7.8 (m, 4H). 13CNMR

(CDCl3): δ 210.4, 135.7, 132.9, 130.1, 128.0, 69.9, 38.7, 31.8, 29.1, 26.9, 23.5, 22.69, 19.4, 14.2.

3-((tert-butyldiphenylsilyloxy)methyl)non-1-yn-3-ol (18). In a dry flask, 17 (0.81mmol)

was disolved in 10 mL of distilled THF at 0°C and treated with ethynylmagnesium bromide (1M

in hexanes,1.6 mmol, 1.6 mL). The mixture was then warmed to room temperature, stirred for

two hours and was quenched with 5mL of HCl (1M). The mixture was then diluted with ether

and extracted with ethyl acetate. The combined layers were then washed with saturated sodium

chloride and dried over MgSO4. Purification by flash column chromatography (10% ethyl

acetate in hexanes) afforded 0.12g (54 %) of a pure colorless oil (Rf=0.3, 10% ethyl acetate in

hexanes). 1H NMR (CDCl3), δ: 0.9 (t, J = 8Hz, 3H); 1.1 (s, 9H); 1.3 (br, 6H); 1.56 (br, 2H); 2.5

(s,1H); 3 (s, 1H); 3.6 (d, J = 12 Hz,1H);3.8 (d, J = 12 Hz,1H); 7.4 (m, 6H); 7.8 (m, 4H).

13CNMR (CDCl3): δ 135.8, 135.7, 134.9, 133.1, 132.9, 130.0, 127.9, 85.5, 72.6, 71.5, 70.6, 38.0,

31.9, 29.7, 27.0, 24.1, 22.8, 19.6, 14.3.

2-ethynyloctane-1,2-diol (19). In a dry flask, 18 (1.3 mmol) in 10 mL of THF was treated

with TBAF (1M, 3.9 mmol, 3 eq.). The reaction stirred overnight at room temperature and was

64

quenched with deionized water (5 mL). The mixture was then diluted with 10 mL of ether and

extracted with ethyl acetate. The combined organic layers were then washed with saturated

sodium chloride and dried over MgSO4. Purification by flash column chromatography (10%

ethyl acetate in hexane) afforded 0.14g of white crystals (65%, Rf=0.3, 40% EtOAc in hexanes).

1H NMR (CDCl3), δ: 0.8 (t, J = 7.2 Hz, 3H); 1.3 (bp, 6H); 1.5 (m, 1H); 1.65 (m, 1H); 2.35 (bp,

1H); 2.5 (s, 1H); 2.85 (bp, 1H); 3.5 (m, 1H); 3.65 (d, J = 9.6 Hz). 13CNMR (CDCl3): δ 84.9,

73.6, 71.9, 69.8, 37.8, 31.9, 29.6, 24.1, 14.2.

3-methyl-5-phenylpent-4-yne-2,3-diol (20). According to a similar known procedure,36

to a solution of phenylacetylene (2.2 mL, 20 mmol) in dry THF (100 mL) was added n-BuLi (21

mmol, 8.4 mL, 2.5 M in hexanes) dropwise at -78 °C. The mixture was warmed to -30 °C for 30

min and was returned to -78 °C. Acetoin (0.9 g, 10 mmol) was added in one portion to the

mixture and stirring was continued for 1 h at room temperature. The reaction was quenched with

NH4Cl (30 mL of a saturated aqueous solution), diluted with water (35 mL) and extracted with

EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by

flash chromatography (10% EtOAc/Hexanes) to give the product as a mixture of

diastereoisomers (0.7 [maj]: 0.3 [min]). RF = 0.15 (30% EtOAc/hexanes) (1.4 g, 73%). IR

(neat) 3393, 2993, 2360, 1498, 1373, 1097, 938. 1H NMR (300 MHz, CDCl3): δ 7.40 (m, 2H),

7.20 (m, 3H), 4.20 (s, 1H, min), 4.10-3.90 (m, 2H, maj), 3.75 (t, J = 7.7 Hz, 1H, min), 3.50 (s,

1H, maj + min), 1.60 (s, 1H), 1.50 (s, 1H), 1.35 (d, J = 9.6 Hz, 3H), 1.30 (t, J = 9.6 Hz , 3H).

13C NMR (75 MHz, CDCl3): δ 133.8 , 131.7, 128.4, 128.2, 122.4, 91.4, 90.0, 85.1, 84.6, 74.2,

65

73.6, 72.3, 71.5, 26.1, 23.0, 18.4, 17.3. HRMS (ESI) Calcd for C12H17O2 (M+Na)+ 213.0866,

found 213.0894.

3-methyltridec-4-yne-2,3-diol (21). According to a similar known procedure,36 to a

solution of decyne (3.6 mL, 20 mmol) in dry THF (100 mL) was added n-BuLi (21 mmol, 8 mL,

2.5 M in hexanes) dropwise at -78 °C. The mixture warmed to -30 °C for 30 min and returned to

-78 °C. Acetoin (0.9 g, 10 mmol) was added in one portion to the mixture and stirring was

continued for an additional 1 h at room temperature. The reaction was quenched with NH4Cl (30

mL of a saturated aqueous solution), diluted with water (35 mL) and extracted with EtOAc. The

combined organic layers were dried over MgSO4, concentrated, and purified by flash

chromatography (10% EtOAc/Hexanes) to give the product as a mixture of diastereoisomers (0.8

[ maj ]: 0.2 [ min ]). RF = 0.10 (10% EtOAc/hexanes) (1.4 g, 73%). IR (neat) 3401, 2929, 2247,

1475, 1374, 1103, 908 cm-1. 1H NMR (300 MHz, CDCl3): δ 3.70 (m, 1H, maj), 3.50 (m, 1H,

min), 3.25 (brs, 1H, min), 3.00 (brs, 1H, maj), 2.80 (brs, 1H, maj), 2.60 (brs, 1H, min), 2.15 (t, J

= 8.6 Hz, 2H), 1.45 (m,2H), 1.40-1.15 (m, 10H), 0.85 (t, J = 6.4 Hz, 3H). 13C NMR (75 MHz,

CDCl3): δ 85.9, 85.4, 82.5, 80.9, 74.5, 73.8, 72.0, 71.2, 31.9, 29.2, 29.1, 28.9, 28.8, 28.7, 26.3,

23.3, 22.7, 18.7, 18.4, 16.9, 14.2. HRMS (ESI) Calcd for C14H26O2 (M+Na)+ 249.1825, found

249.1843.

3-methyl-5-(trimethylsilyl)pent-4-yne-2,3-diol (22). According to a similar known

procedure,36 to a solution of ethynyltrimethylsilane (16 mmol) in dry THF (40 mL) was added to

n-BuLi (17 mmol,17 mL, 1 M in hexanes) dropwise at -78 °C. The mixture warmed to -30 °C

66

for 30 min and returned to -78 °C. Acetoin (8 mmol) was added in one portion to the mixture

and stirring was continued for an additional 1 h at room temperature. The reaction was quenched

with NH4Cl (30 mL of a saturated aqueous solution), diluted with water (35 mL) and extracted

with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified

by flash chromatography (10% EtOAc/Hexanes) to give 0.76 g of white crystals as a mixture of

diastereoisomers (0.7 [ maj ]: 0.3 [ min ]). (Rf=0.2, 30% EtOAc, 51% yield). 1H NMR (300

MHz, CDCl3): δ 3.75 (m, 1H, maj), 3.60 (m, 1H, min), 2.9 (brs, 1H, min), 2.45 (brs, 1H, maj),

2.40 (brs, 1H, maj), 2 (brs, 1H, min), 1.4 (s, 2H, maj + min), 1.28 (d, J = 6 Hz, 3H, min), 1.24 (d,

J = 6 Hz, 3H, maj), 0.00 (s, 9H).

2,3-dimethyl-5-phenylfuran (23). A solution of 20 (0.1 g) in dry THF (3 mL) was treated

with gold catalyst according to procedure A to afford a colorless oil Rf = 0.9 (20%

EtOAc/hexanes), (91.5 mg, 85 %). IR (neat) 2360.4, 2253.7, 908.6, 734, 650.6, 480.6. 1H NMR

(300 MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 8.4 Hz, 2H), 7.20 (t, J = 8.4 Hz),

6.40 (s, 1H), 2.30 (s, 3H), 2.00 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 151.1, 147.4, 131.4,

128.7, 128.5, 126.7, 123.4, 116.3, 108.6, 11.7, 11.1. (ESI) Calcd for C12H12O (M+H)+ 173.0961,

found 173.0961.

2,3-dimethyl-5-octylfuran (24). A solution of 21 (0.1 g) in dry THF (3 mL) was treated

with gold catalyst according to procedure A to afford a pure colorless oil (87 mg, 88%). Rf = 0.9

(20% EtOAc/hexanes). IR (neat) 2911, 2363, 2246, 1571, 1458, 1224, 911, 735. 1H NMR (300

67

MHz, CDCl3): δ 5.8 (s, 1H), 2.6 (t, J = 2 Hz, 2H), 2.2 (s, 3H), 1.9 (s, 3H), 1.7 (m, 2H), 1.4 (m,

10H), 0.9 (t, J = 2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 153.6, 145.1, 114.2, 108.0, 32.3,

31.9, 29.7, 29.6, 28.5, 28.3, 23.0, 14.3, 11.3, 10.0. HRMS (ESI) Calcd for C14H24O (M)+

208.1827, found 208.1820.

(4,5-dimethylfuran-2-yl)-trimethylsilane (25A)/ (4,5-dimethylfuran-3-yl)-

trimethylsilane (25B). A solution of diol 22 (0.1 g) in dry THF (3 mL) was treated with gold

catalyst according to procedure A to afford a mixture of two regioisomers (A/B = 3/2) as a

colorless oil (134 mg, 88%). Rf = 0.9 (20% EtOAc/hexanes).

tert-butyl allyl(tosyl)carbamate (29). Et3N (1.44 mL, 1.1 eq.) and dimethyl-amino-

pyridine (12.7 mg,0.1 mmol, 0.1 eq.) were added to a solution of N-allyl-4-

methylbenzenesulfonamide42 (2 g , 9.46 mmol) in dry CH2Cl2 (60 mL) at 0 °C. The mixture was

treated with Boc2O (2.27 g, 10 mmol, 1.1 eq.) and was stirred until TLC analysis showed the

reaction to be complete (3 h). The mixture was quenched with NH4Cl (25 mL of a saturated

aqueous solution) and extracted with EtOAc. The combined organic layers were dried over

MgSO4, concentrated, and purified by flash chromatography (10% EtOAc/Hexanes) to afford a

white solid (2.89 g, 98%), RF= 0.4 (10% EtOAc/Hexanes), that satisfactorily matched all

previously reported data.43

tert-butyl 2-oxoethyl(tosyl)carbamate (30). O3 was bubbled through a solution of 29 (1

g, 3.2 mmol) in CH2Cl2/MeOH (20 mL, 3/1) at -78 °C until a blue color persisted. DMS (3.2

68

mL, 41.6 mmol, 13 eq.) was then added and the mixture warmed to room temperature over 6 h

under N2. The solvent was removed under vaccum and the mixture was purified by flash column

chromatography (20% EtOAc/Hexanes) to give the product as colorless oil (1.25 g, 89%). Rf =

0.4 (40% EtOAc/Hexanes). IR (neat) 2984.1, 2935.7, 2340.9, 2257.5, 1736, 1359.6, 1170.6,

1147.3, 906.4, 733.8. ). 1H NMR (300 MHz, CDCl3): δ 9.6 (s, 1H), 7.9 (d, J = 8.4 Hz, 2H), 7.3

(d, J = 8.4 Hz, 2H), 4.6 (s, 2H), 2.4 (s, 3H), 1.3 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 195.4,

150.5, 144.8, 136.4, 129.4, 128.4, 85.3, 55.0, 27.8, 21.7. HRMS (ESI) Calcd for C14H19NO5S

(M+Na)+ 336.0876, found 336.0876.

N-(2-hydroxy-4-phenylbut-3-ynyl)-4-methylbenzenesulfonamide (33). A solution of n-

BuLi in hexanes (2.5 M, 1.14 mL, 2.85 mmol, 1.2 eq.) was added dropwise to a solution of

phenylactetylene (0.3 mL, 3.56 mmol 1.5 eq.) in dry THF (10 mL) at -78 °C. The mixture

warmed to -30°C for 30 min and returned to -78°C. A solution of 30 (0.6 g, 2.37 mmol, 1 eq.) in

dry THF (5 mL) was added dropwise to the reaction and the mixture warmed to room

temperature over 30 min. The reaction was quenched with deionized water (10 mL) and

extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated.

The resulting mixture was treated with potassium carbonate (0.59 g, 11.8 mmol, 5 eq.) in MeOH

(20 mL) at reflux during 5 h. The reaction was quenched with deionized water (10 mL) and

extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and

purified by flash chromatography (25% EtOAc/Hexanes) to give the product as a colorless oil

(0.16 g, 45% over two steps). Rf = 0.3 (30% EtOAc/hexanes). IR (neat) 3392.8, 3020.1, 2341.4,

1332.9, 1215.4, 1160.4, 771.1, 669.0 cm-1 . 1H NMR (300 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz,

69

2H), 7.32 (dd, J = 8.4, 1.2 Hz, 1H), 7.2 ( t, J = 8.4 Hz, 5H), 5.78 (t, J = 3.6 Hz, 1H), 4.6 (m,

1H), 3.64 (d, J = 1.2 Hz), 3.3-3.1 (m, 2H), 2.3 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 143.7,

136, 131.9, 129.9, 128.3, 127.2, 122, 86.9, 61.9, 48.9, 21.6. HRMS (ESI) Calcd for C17H17NO3S

(2M+Na)+ 653.1751, found 653.1755.

N-(2-hydroxydodec-3-ynyl)-4-methylbenzenesulfonamide (34). A solution of n-BuLi in

hexanes (2.5 M, 0.83 mL, 2.07 mmol, 1 eq.) was added dropwise to a solution of decyne (0.38

mL, 4.14 mmol 1.2 eq.) in dry THF (10 mL) at -78 °C. The mixture was warmed to -30°C for 30

min and returned to -78°C. A solution of 30 (0.5 g, 2.07 mmol, 1 eq.) in dry THF (5 mL) was

added dropwise to the reaction and the mixture was warmed to room temperature over 30 min.

The reaction was quenched with deionized water (10 mL) and extracted with EtOAc. The

combined organic layers were dried over MgSO4 and concentrated. The resulting residue was

treated with potassium carbonate (0.24 g, 10 mmol, 5 eq.) in MeOH (20 mL) at reflux during 5 h.

The reaction was quenched with deionized water (10 mL), extracted with EtOAc. The combined

organic layers were dried over MgSO4, concentrated, and purified by flash chromatography

(20% EtOAc/Hexanes) to give the product as a colorless oil (0.08 g, 36% over two steps). Rf =

0.2 (30% EtOAc/hexanes). IR (neat) 3385.1, 3020.1, 2400.5, 1558.8, 1337.9, 1215.7, 1160.8,

756.4 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.7 (d, J = 6 Hz, 2H), 7.25 (d, J = 6

Hz, 2H), 5.38 (m, 1H), 4.35 (br, 1H), 3.15 (m, 1H),3.00-2.88 (m, 2H), 2.36 (s, 3H), 2.08 (t, J =

6.5 Hz), 1.4 (m, 2H), 1.2 (m, 10H), 0.82 (t, J = 6.5 Hz). 13C NMR (75 MHz, CDCl3): δ 143.7,

137.0, 129.9, 127.3, 87.6, 78.0, 61.6, 49.3, 32.0, 29.4, 28.7, 22.8, 21.7, 18.8, 14.3. HRMS (ESI)

Calcd for C19H29NO3S (2M+Na)+ 725.3629, found 725.3642.

70

This work was performed with the help of Emmerson Finco Marques.

2-phenyl-1-tosyl-1H-pyrrole (35). A solution of 33 (0.1 g) in dry THF (3 mL) was

treated with gold catalyst according to procedure B to afford a colorless oil (95 mg, 91%). Rf =

0.9 (30% EtOAc/hexanes). IR (neat) 3020.0, 2400.5, 1369.7, 1215.6, 1169.2, 1058.6, 750.6,

668.5 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.43-7.05 (m, 10H), 6.28 (t, J = 3 Hz, 1H), 6.13 (t, J

= 3 Hz, 1H), 2.3 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 144.8, 136.2, 131.6, 131.1, 130.5,

129.5, 128.4, 127.5, 127.3, 124.3, 115.9, 112.2, 66.1, 52.9, 21.8. HRMS (ESI) Calcd for

C17H15NO2S (M+H)+ 298.0896, found 298.0910.

2-octyl-1-tosyl-1H-pyrrole (36). A solution of 34 (0.1 g) in dry THF (3 mL) was treated

with gold catalyst according to procedure B to afford a pure colorless oil (90 mg, 91%). Rf = 0.9

(30% EtOAc/hexanes). IR (neat) 3020.1, 2929.0, 1215.7, 757.4, 668.8 cm-1. 1H NMR (300

MHz, CDCl3): δ 7.6 (d, J = 8.3 Hz, 2H), 7.25 (t, J = 8.3 Hz, 2H), 6.2 (t, J = 3 Hz, 1H), 6 (s,

1H), 2.6 (t, J = 7.5 Hz, 2H), 2.4 (s, 3H), 1.5 (m, 2H), 1.2 (m, 10H), 0.85 (t, J = 9 Hz, 3H). 13C

NMR (75 MHz, CDCl3): δ 144.8, 136.2, 130.1, 126.9, 122.3, 111.8, 111.4, 32.1, 29.4, 28.8,

27.3, 22.9, 21.8, 14.3. HRMS (ESI) Calcd for C19H27NO2S (M+H)+ 334.1835, found 334.1861.

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APPENDIX PROTON AND CARBON NMR SPECTRA

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Figure A-1. 1H NMR of compound 1

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Figure A-3. 13C NMR of compound 2

75


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Figure A-6. 1HNMR of compound 5

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Figure A-16. 1NMR of compound 20

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Figure A-26. 1H NMR of the mixture made of compounds 25A and 25B

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Figure A-27. 1NMR of compound 30

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BIOGRAPHICAL SKETCH

Jeremy Malinge was born on February 25, 1985 in Angers, France. His parents are Michel

and Sylvie Malinge. He attended the Lycée Chevrollier in Angers and graduated from a

baccalaureate program with honors in 2003. Starting fall 2003, he accomplished two years of

intensive preparatory class in Math, Physics and Chemistry in Nantes and entered the Chemistry

and Physics Engineering School of Bordeaux (ENSCPB) in 2005. During his third year of

engineering school, he enrolled in the graduate program in the Department of Chemistry at the

University of Florida-Gainesville His area of specialization is organic synthesis, and his research

was directed by Dr. Aaron Aponick. He received his Master degree from the University of

Florida in the summer of 2009.

© 2009 jeremy malinge -...

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