Part 1 development and application of hantzsch ester and hypervalent iodine reagent

v 3.4.2 General Procedure and Compound Characterization Data 68 Chapter 4 TiCl 4 Catalyzed Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters by Hantzsch 1,4-Di

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

2011

i

Acknowledgements

I would like to express my greatest gratitude to my supervisor, Associate Professor Lam Yulin, for her patient guidance, continuous flow of ideas, encouragement and invaluable advice throughout my studies

I would like to express my appreciation to my group members, Ching Shi Min, Fang Zhanxiong, Fu Han, Gao Yaojun, Gao Yongnian, He Rongjun, Kong Kah Hoe, Makam Shantha Kumar Raghavendra, Sanjay Samanta, William Lin Xijie, Woen Susanto, and Wong Lingkai for their help and encouragement during my research

I would also like to thank staff from the NMR, MS, Chromatography laboratories and chemical supplies for their patience to help me greatly in analyzing compounds and purchasing of chemicals

I am also greatful to the National University of Singapore for awarding me the research scholarship

Finally, I would like to thank my family for their support

2.2.1 Synthesis of Polymer-supported Five-membered Heterocycle Amine 24 2.2.1.1 Synthesis of Polymer-supported 5-Amino-3-disubstituted-3H-

Chapter 3 Reduction of Ketimines and Electron-Withdrawing Group Conjugated

Olefins by Polymer-Supported Hantzsch 1,4-dihydropyridine Ester

v

3.4.2 General Procedure and Compound Characterization Data 68

Chapter 4 TiCl 4 Catalyzed Hydrogenation of α,β-Unsaturated Ketones and

Alkylidene Malonic Diesters by Hantzsch 1,4-Dihydropyridine Ester

4.4.2 General Procedure and Compound Characterization Data 84

4.4.2.1 General Procedure for the Synthesis α,β-Unsaturated Ketones 84 4.4.2.2 General Procedure for the Reduction of α,β-Unsaturated Ketones 87 4.4.2.3 General Procedure for the Synthesis of Alkylidene Malonic Diesters 91 4.4.2.4 General Procedure for the Reduction of Alkylidene Malonic Diesters 92

Part 2B

Chapter 5 Applications of o-Iodosophenylphosphoric Acid in Oxidation,

Chlorination and Alkoxylation Reactions

5.4.2 General Procedure and Compound Characterization Data 109

5.4.2.1 Procedure for the Synthesis of 5-4e 109

5.4.2.2 Procedure for the Synthesis of 5-8f 110

5.4.2.3 Procedure for the Synthesis of 5-8g 111

5.4.2.4 Procedure for the Synthesis of 5-10c 111

5.4.2.5 General Procedure for the Phosphine Oxidation by 5-1 112

5.4.2.6 General Procedure for the Sulfide Oxidation by 5-1 112

5.4.2.7 General Procedure for the Alcohol Oxidation by 5-1 112

5.4.2.8 General Procedure for α-Chlorination of the Ketones with 5-1 113

5.4.2.9 General Procedure for α-Alkoxylation of the Ketones with 5-1 113

vii

Summary

This thesis is composed by two parts: Combinatorial Synthesis of N-Containing Heterocycles (Part 1) Development and Application of Hantzsch Ester (Part 2a); Development and Application of Hypervalent Iodine Compounds (Part 2b);

Part 1 of this thesis focuses on combinatorial synthesis of N-containing heterocycles In this project, a microwave-assisted Solid-Phase Synthesis of hetero-annulated 1,3-oxazin-6-ones has been developed Significant rate enhancement was observed for all steps carried out under microwave irradiation and the overall reaction time was dramatically shortened when compared to the conventional procedures A representative set of 20 bi- and tricyclic hetero-annulated 1,3-oxazin-6-ones was prepared

Part 2a comprises two projects (i) Reduction of Ketimines and Electron-Withdrawing Group Conjugated Olefins by Polymer-Supported Hantzsch 1,4-dihydropyridine Ester; (ii) TiCl4Catalyzed Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters by Hantzsch 1,4-Dihydropyridine Ester In the first project, we have demonstrated that the reductions of (i) active alkenes, (ii) ketimines and (iii) (Z)-α-cyano-β-

bromomethylcinnamates and its analogs could be achieved with the polymer supported Hantzsch ester in high yields and chemoselectivity In the second project, we have shown that the TiCl4-catalyzed Hantzsch 1,4-Dihydropyridine Ester reduction of α,β-unsaturated ketones and alkylidene malonic diesters is a rapid and experimentally simple procedure for the preparation of saturated ketones and alkyl malonic diesters

viii

Part 2b is Development and Applications of a Hypervalent Iodine Reagent In this project,

we have demonstrated that the hypervalent iodine compound can be used for the oxiadation

of phosphines, sulphur ethers and alcohols In addition, we have demonstrated α-chlorination,

α-alkoxylation and α-hydroxylation of ketones with the hypervalent iodine compounds All the reactions can be performed efficiency with good yields

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List of Tables

Table 3-1 Solvent screening for reduction of benzylidenemalononitrile 3-2 58

Table 3-2 Reduction of active alkenes using 3-1 59

Table 3-8 Cyclization of (Z)-α-cyano-β-bromomethyl cinnamates and its analogs

by 3-1

65

Table 5-1 Optimization of the reaction condition for oxidation of 5-2a 97

Table 5-6 Optimization of the reaction condition for oxidation of 5-6a to 5-7a 102

x

Table 5-8 Optimization of the reaction condition for α-chlorination of ketones 104

Table 5-10 α-Alkoxylation of various ketones to α-alkoxylated compounds 107

xi

List of Figures

Figure 1-5 General nucleophile- and base-labile linkers and their cleavage reagents 8

Figure 3-2 Reduction of Ketimines and Electron-Withdrawing Group Conjugated

Olefins with 3-1

57

xii

List of Schemes

xiii

List of Abbreviations

phosphate

Tentagel Polystyrene and polyethlene glycol copolymer

xvi

List of Publications

1 Che Jun, Raghavendra Makam S, Lam Yulin Traceless solid-phase synthesis of

heteroannulated 1,3-oxazin-6-ones J Comb Chem 2009, 11, 378-84

2 Che, Jun, Lam, Yulin Polymer-Supported Hantzsch 1,4-Dihydropyridine Ester: an Efficient Biomimetic Hydrogen Source for the Reduction of Ketimines and Electron-

Withdrawing Group Conjugated Olefins Adv Synth Catal 2010, 352, 1752-1758

3 Che Jun, Lam Yulin Rapid and Regioselective Hydrogenation of α,β-Unsaturated Ketones and Alkylidene Malonic Diesters Using Hantzsch Ester Catalyzed by

Titanium Tetrachloride Synlett, 2010, 16, 2415-2420

4 Che Jun, Lam Yulin Development and application of o-iodosophenylphosphoric acid

In preparation

via the carboxyl terminus At the end of the synthesis the peptide produced is detached from

the polymer support by cleaving the ester linkage Merrifield first synthesised a tetrapeptide using this approach.1 He soon developed a machine for automated peptide synthesis2 and synthesised ribonuclease A,3 an enzyme with 124 amino acid residues This technology has

helped pharmaceutical companies to find new drugs quickly, save significant amount of money in preclinical development costs and ultimately changed the fundamental approach to drug discovery.4 In short, this novel approach revolutionalised peptide synthesis and so in recognition of Merrifield’s achievement, he was awarded the 1984 Nobel Prize for Chemistry

1.1.2 Solid-Phase Synthesis

In a typical Solid-Phase synthesis reaction, a resin is reacted with the reagent A under appropriate conditions Subsequent reactions were carried out in a similar manner In this way, the molecule to be synthesized is assembled step by step on the polymer support After

2

the synthesis, the product ABC was cleaved off the support (Figure 1-1) The product is then available for testing in biological assays

Figure 1-1 Solid-Phase Synthesis

1.1.3 Advantages and Disadvantages

Solid-supported chemistry is now a very useful tool in modern organic chemistry.5 It is the method of choice for both research and industrial synthesis of peptides6 and oligonucleotides.7 Compared with the combinatorial solution-phase synthesis, Solid-Phase Synthesis has a lot of advantages Firstly, simple filtration and washing of the solid support can be used as a separation and purification method thus eliminating the tedious and time-consuming workup procedure which is often associated with solution-phase organic synthesis Secondly, synthesis automation is enabled The robots can do all the operations, such as adding reagents, filtration, washing the resin, compounds isolation and analysis Thirdly, a large excess of reagents may be added to drive the reactions to completion Lastly, ease of handling unstable or toxic intermediates that are tethered to the solid support

However, Solid-Phase Synthesis also has some limitations Firstly, chemical processes take longer in Solid-Phase synthesis Secondly, monitoring reactions and characterization of

of the reaction Listed below are some examples of the most commonly used solid supports in Solid-Phase reactions

1.2.1 Polystyrene Resins

Figure 1-2 The internal molecular structure of polystyrene

Polystyrene resins (Figure 1-2) are the most widely used solid supports in the Solid-Phase Synthesis The physicochemical properties of this resin depend heavily on the amount of

4

cross-linking of the polystyrene The addition of 1% DVB as a cross-linker has proven to be

an optimum compromise between good swelling property (low cross-linking) and mechanical stability (high cross-linking) The resulting resin has good swelling properties in many solvents, such as THF, DCM, DMF or toluene In addition, it is stable enough for the working up procedure However, when the protonic solvent like water or methanol was used for the reaction, it would shrink the resin8.Under this situation, it is necessary to perform the reactions in a mixture of good swelling solvent and protonic solvent

1.2.2 Polyethylene Glycol-Containg Polymers

Figure 1-3 TantaGel Resin

As an alternative to the hydrophobic polystyrene resins, hydrophilic copolymers of polystyrene and polyethylene glycol (PEG) were developed The most representative resin is TentaGel Resin (Figure 1-3) which was developed by Bayer and Rapp.9 The resin consists of PEG attached to cross-linked polystyrene through an ether linkage This type of resin combines the advantages of the soluble PEG support with the insolubility and handling characteristics of the polystyrene bead Compared with cross-linked polystyrene resins, TentaGel Resin is also available with various linkers allowing the coupling with a wide variety of building locks Furthermore, it has better swelling ability than the cross-linked polystyrene resins in organic and polar solvents,10 such as water, which makes this support a

1.3 Linkers

Linker is central in the design of a solid-phase organic synthesis scheme as it will dictate whether the compounds stay on the solid phase for assay, or whether mild and selective conditions are available to cleave the compounds away from the support for solution phase assay It is usually a bifunctional molecule that connects the first building block in the solid-phase synthesis to the solid support.12 It may also be considered as a protecting group for the functional groups of the final product

6

Figure 1-4 Acid-labile linkers and their cleavage acids

In the past 40 years, a large variety of linkers have been developed to be used in the multistep organic synthesis Therefore, choosing the right linker for the solid phase synthesis

is crucial There are three main considerations for the selection of a linker Firstly, the linker should be inert to the subsequent reactions performed on the substrate Secondly, the linker

7

should be selectively cleavable to allow the release of the product from the resin throughout the synthesis Lastly, the linker should be chosen to minimize its structural and chemical effects on the sought after properties of the synthesized compounds Various linkers are described below

1.3.1 Acid-labile Linkers

Most of the linkers used today in Solid-Phase Peptide Synthesis are acid-labile linkers

These linkers generally contain a benzylic structure since the stability of the cation formed on cleavage can be easily modulated by the introduction of various electron-donating substituents on the ortho or para positions of the phenyl ring Chemicals such as TFMSA, HF, HBr, TFA, PPTS, AcOH and HFIP can be employed as cleavage reagents Cleavage of the linkers follows the SN1-type mechanism involving the cleavage of the carbon-heteratom bond Figure 1-4 shows some general acid-labile linkers and their cleavage acids The most recent acid-laible linker reported is an ester type linker which upon cleavage releases the glycans as carbamate protected aminoglycosides was successfully employed in the sequential assembly of L-idose and azido glucose monosaccharide building blocks to heparan sulfate precursors.22b

1.3.2 Nucleophile- and Base-labile Linkers

Nucleophile- and base-labile linkers are resins based on classical organic chemistry

reactions ie the compounds are released either by nucleophilic substitution reactions or by an

elimination reaction promoted by a base The reactivity and stability of these linkers are rationalized according to their chemical properties, in particular the pKa of the linker or

9

where the organic compound is attached to the linker-resin via an ester bond In this case, the linker is displaced as an alkoxide, the conjugated base of the alcohol (Figure 1-6)

Figure 1-6 General representation of a nucleophile-labile linker

An example of nucleophile-labile cleavage strategy was reported by Chamoin and coworkers32 (Scheme 1-1) In their synthesis, hydroxy-promoted cleavage releases various kinds of benzoic acids in 71-95% overall yields

Scheme 1-1 Nucleophile promoted cleavage

1.3.2.2 Base-labile Linkers

Base labile linkers generally release the target molecule under basic conditions by an E1cb33 (unimolecular elimination, E1, with formation of a stable anion of the conjugate base, cb) elimination reaction to release the substrate as a leaving group The general structure of this kind of linker consists of an electron–withdrawing group, which enhances the acidity of the α-hydrogen, and a leaving group in the β position (Figure 1-7)

10

Figure 1-7 Generic representative of base labile cleavage process

An example of a base-labile cleavage strategy is shown below (Scheme 1-2) This involves

a classical Hofmann elimination reaction which has been adapted to the Solid-Phase Synthesis in combination with the Michael addition The reaction procedure involves acylation of hydroxylmethylpolystyrene with acrylic chloride to furnish the acrylate on the resin Thereafter, a secondary amine is bound to the resin by Michael addition This is followed by the quaternization of the amine with an alkyl halide and activation of the linker with DiEA to release the tertiary amine by a Hofmann elimination.26, 34

Scheme 1-2 Base promoted cleavage

11

1.3.3 Photo-labile Linkers

Scheme 1-3 Cleavage of a Photo-labile Linker in SPS

The liberation of compounds from the resin by light is an attractive approach since the linkers are completely unreactive to common synthesis conditions Unlike traditional

cleavage which employs chemical reagents, products with functional groups such as

carboxylic acids, carboxyamides, amidines or hydroxyl can be released by irradiation at λ = 320-365 nm This cleavage can be carried out in aqueous solution which makes this approach particularly useful for biological assays The most effective photolinkers known were

developed by Affymax and allowed the release of carboxylic acid as well as carboxamides by ultraviolet light (Scheme 1-3).35 However, Qvortrup35 has recently reported a new photolabile linker for the efficient synthesis and release of NH-1,2,3-triazoles The high purity of released material permits the direct introduction of compounds into aqueous environments, such as buffers normally used in biological assays

1.3.4 Safety-catch Linkers

Safety-catch linkers are completely inert to the synthesis conditions, but have to be chemically transformed to allow the final liberation of the product from the solid phase By definition, the safety-catch principle involves a process based upon conversion the linker to a labile, isolable, and cleavable linker The first carboxyl linker which was used to demonstrate the safety-catch principle was the acyl sulphonamide resin (Scheme 1-4) The resin was

13

Traceless linkers can be cleaved from the resin leaving no residual functionality That means the cleavage leads absolutely to the formation of a C-H bond or a C-C bond on the original position of the attachment, giving alkanes, alkenes, alkyenes or arenes

Aryl silyl systems were the first traceless linkers to be developed and are widely used for the synthesis of compounds containing aromatic hydrocarbons The silicon-phenyl bond which is sensitive to acids can undergo prodesilylation reaction to give unsubstituted phenyls (Scheme 1-5).37 In addition to protodesilylation, other electrophiles can initiate the cleavage

of the aryl-silicon bond For example, halodesilylation with bromine will replace the silicon with a bromide in the final product Ellman has also investigated linkers containing the related element, germanium This metal is more readily cleaved than silicon through electrophilic demetallations with halogens to give aryl halides (Scheme 1-6).38

Scheme 1-5 Aryl silyl system linker and its cleavage condition

Scheme 1-6 Germanium traceless linker and its cleavage condition

14

Sulfur- and selenium-based linkers are another important class of trace linkers Sulfide linkers can be used for aliphatic C-H bond formation by oxidizing the sulfide to sulfone and subsequent reductive cleavage with secondary amine halides (Scheme 1-7).39 The selenium-carbon bond in selenium-based linker is prone to undergo homolytic cleavage to give radicals (Scheme 1-8).38 This linker holds promise for wide applicability, since the starting materials such as alkenes, alkyl halides are widely available, although toxicity of reagents and starting materials have to be considered

Scheme 1-7 Sulfur-based linker example

Scheme 1-8 Selenium-based linker example

1.4 Analytical Methods for Solid-phase Synthesis

15

Organic reactions on solid-phase require different monitoring and analytical methods The process of cleaving and analysing the product is destructive and time-consuming Furthermore, the intermediates may not be stable enough to cleavage condition Thus many on-support analytical techniques have been developed and used for the characterizations of substrates on solid supports

1.4.1 FTIR Methods

The most widely used on-support characterization technique for the monitoring of phase synthesis is FTIR since the method is advantageous in both sensitivity and speed.40 With this method, rapid analysis of trace amounts of sample reveals optimization-related information directly on the solid support In addition, many other FTIR methods have also been demonstrated to be useful for solid phase synthesis, such as DRIFT,41 photoacoustic,42micro-ATR,43 and macro-ATR44 methods

solid-1.4.2 Gel Phase NMR

Due to the restricted mobility and the magnetically inhomogeneous environment throughout the substrate, the NMR spectra of solid-supported substrates appear as broad lines which does not allow for meaningful analysis To circumvent this problem, gel phase NMR was introduced and this involves analyzing solvent swollen resins with a standard liquid NMR probe In gel-phase NMR, the resin is allowed to swell in a solvent so as to provide the molecules with a greater degree of motional freedom This helps in narrowing the NMR

16

resonance to a limited extent and is thus practical only for nuclei with a large chemical-shift range (e.g 13C 19F, 31P NMR)

1.4.3 High-resolution Magic Angle Spinning (HR-MAS) NMR

As proton NMR spectra are crucial in reaction monitoring and structure elucidation, MAS NMR technique is used to solve the line-broadening problem in proton NMR It requires the use of a high resolution MAS probe which allows the magnetic susceptibility-induced line broadening terms to average out by a special angle spinning HR-MAS NMR technique is a useful tool in resin-bound substrates characterization

HR-1.4.4 Spectrophotometric Methods

Spectrophotometric methods have been developed for the analysis of solid-phase peptide synthesis By using molecular markers that react specifically with a functional group, together with UV-visible or fluorescence spectroscopy, quantitative analysis of aldehyde, ketone, hydroxyl and carboxy groups has been done.45 Thus, methods for quantitative analysis of aldehyde, ketone, hydroxyl and carboxy groups have been developed.45b

1.5 Objectives of Our Studies

Fused 1,3-oxazin-6-ones constitute an interesting class of pharmacologically active compounds as they have shown a multitude of biological activities Thus one of the purposes

of this study is to investigate the combinatorial synthesis of N-containing heterocycles

17

The advantages of Solid-Phase Synthesis could be combined with the benefits of solution phase chemistry through the use of polymer-supported reagents Hence another aim of our study is to develop a polymer-supported Hantzsch ester and apply it to various hydrogenation reactions

The chemistry of hypervalent iodine compounds offers multiple advantages over established methods, for example the oxidations and C-C coupling reactions under mild reaction conditions and with a broad tolerance of other functional groups Thus, the third objective of our study is to investigate the development and applications of a hypervalent iodine compounds

1.6 References

1 Merrifield, R B J Am Chem Soc 1963, 85, 2149-54

2 Merrifield, R B.; Stewart, J M.; Jernberg, N Anal Chem 1966, 38, 1905-1914

3 Gutte, B.; Merrifield, R B J Biol Chem 1971, 246, 1922-1941

4 (a) Tuek, C.; Gold, L Science, 1990, 249, 505-510 (b) Andrew, D E.; Jack, W S Nature,

1990, 346, 818-822 (c) Fassina, G.; Verdoliva, A.; Ruvo, M.; Cassani, G J Mol Recogn

1996, 9, 564-570

5 Cironi, P.; Alvarez, M.; Albericio, F Mini Reviews in Medcinal Chemistry 2006, 6, 11-25

6 Verlander, M International Journal of Peptide Research and Therapeutics, 2007, 13,

75-82

18

7 Pon, R T.; Yu, S.; Prabhavalkar, T.; Mishra, T Nucleosides, nucleotides and Nucleic

Acids 2005, 24, 777-781

8 Letsinger, R L.; Mahadevan, V J Am Chem Soc 1965, 87, 3526-3527

9 (a) Bayer, E Angew Chem Int Ed 1991, 30, 113-129 (b) Bayer, E.; Rapp, W Chem Peptides Protein 1986, 3, 3-8

10 Rademann, J.; Grotli, M.; Meldal, M.; Bock, K J Am Chem Soc.1999, 121, 5459-5466

11 Atherton, E.; Clive, D L J.; Sheppard, R C J Am Chem Soc 1975, 97, 6584-6585

12 (a) Arshady, R.; Atherton, E.; Clive, D L J.; Sheppard, R C J Chem Soc Perkin

Trans 1 1981, 529-538

13 (a) Small, P W.; Sherrington, D C J Chem Soc Chem Commun 1989, 1589-1591 (b) Raillard, S P.; Ji, G.; Mann, A D.; Baer, A Org Process Res Dev 1999, 3, 177-183

14 Beaver, K A.; Siegmund, A C.; Speak, K L Tetrahedron Lett 1996, 37, 3213-3214

15 Barany, G.; Merrifield, R B Peptides, 1979, 2, 1-8

16 Hirao, A.; Itsuno, S.; Hattori, I.; Yamaguchi, K.; Nakahama, S.; Yamazaki, N J Chem

Soc Chem Commun 1983, 25-26

17 Barlos, K.; Gatos, D.; Kallitsis, I.; Papaioannou, D.; Sotiriou, P Liebigs Ann Chem

1988, 1079-1080

18 Wang, S S J Am, Chem, Soc 1973, 95, 1328-1333

19 Orlowski, R C.; Walter, R.; Winkler, D J Org Chem 1976, 41, 3701-3705

20 Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P Tetrahedron Lett 1988, 29, 4005-4008

23 Albericio, F Tetrahedron Lett 1991, 32, 1015-1018

24 Fehrentz, J A.; Paris, M.; Heitz, A.; Velek, J.; Liu, C F.; Winternitz, F.; Martinez, J

Tetrahedron Lett 1995, 36, 7871-7874

25 Atherton, E.; Loggan, C J.; Sheppard, R C J Chem Soc Perkin Trans 1981, 538-546

26 Morphy, J R.; Rankovic, Z.; Rees, D C Tetrahedron Lett 1996, 37, 3209-3212

27 Mutter, M.; Bellof, D Helv Chim Acta 1984, 67, 2009-2016

28 Mizoguchi, K.; Shigezane, K.; Takamura, N Chem Pharm Bull 1970, 18, 1465-1474

29 Routledge, A.; Stock, H T.; Flitsch, S L.; Turner, N J Tetrahedron Lett 1997, 38,

8287-8290

30 Parrot, I.; Wermuth, C G.; Hibert, M Tetrahedron Lett 1999, 40, 7975-7978

31 Kroll, F E K.; Morphy, R.; Rees, D.; Gani, D Tetrahedron Lett 1997, 38, 8573-8576

32 Chamoin, R B.; Houldsworth, S.; Snieckus, V Tetrahedron Lett 1998, 39, 4175-4178

33 (a) More O'Ferrall, R A.; Slae, S J Chem Soc B, 1970, 260-268 (b) More O'Ferrall, R

A J Chem Soc B, 1970, 268-274

34 (a) Brown, A R.; Rees, D C.; Rankovic, Z.; Morphy, J R J Am Chem Soc 1997, 119,

3288-3295 (b) Caix-Haumesser, S.; Hanna, I.; Lallemand, J Y.; Peyronel, J F Tetrahedron

36 (a) Backes, B J.; Ellman, J A J Am Chem Soc 1994, 116, 11171-11172 (b) Backes,

B J.; Virgilio, A A.; Ellman, J A J Am Chem Soc 1996, 118, 3055-3056 (c) Golisade, A.; Herforth, C.; Wieking, K.; Kunick, C.; Link, A Bioorg Med Chem Lett 2001, 11, 1783-

1786 (d) Ingenito, R.; Bianchi, E.; Fattori, D.; Pessi, A J Am Chem Soc 1999, 121,

11369-11374

37 Balan Chenera, Joseph A Finkelstein, Daniel F Veber J Am Chem Soc 1995, 117,

11999-12000

38 Stefan Btase, Stefan Dahmen Chem Eur J 2000, 6, 1899-1905

39 Gayo, L M.; Suto, M J Tetrahedron Lett 1997, 38, 211-214

40 (a) Yan, B.; Kumaravel, G Tetrahedron, 1996, 52, 843-848 (b) Yan, B., Kumaravel, B., Anjaria, H., Wu, A., Petter, R C., Jewell, C F., Wareinget, J J R J Org Chem 1995, 60,

21

43 Yan, B.; Fell, J B.; Kumaravel, G J Org Chem 1996, 61, 7467-7472

44 Gremlich, H U.; Berets, S L Appl Spectrosc 1996, 50, 532-536

45 (a) Yan, B.; Li, W J Org Chem 1997, 62, 9354-9357 (b) Yan, B.; Liu, L.; Astor, C A.; Tang, Q Anal Chem 1999, 71, 4564-4571

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Chapter 2 Combinatorial Solid-phase Synthesis of Hetero-annulated 1,3-Oxazin-6-ones

2.1 Introduction

2.1.1 Importance of Fused 1,3-oxazin-6-ones

Fused 1,3-oxazin-6-ones constitute an interesting class of pharmacologically active compounds as they have shown a multitude of biological activities Benzoxazinones, the most widely studied analogs, are found in some naturally occurring antimicrobial and antifungal agents.1 They are known to possess anticoagulative,2 antiviral3 and herbicidal4 activities, are potential inhibitors of HSV-1 andC1r serine protease,5 chymotrypsin and pancreatic elastase6 and have also found applications in materials and polymer science.7 The hetero-annulated oxazinones like thieno[2,3-d]-1,3-oxazinones,8 pyrrolo[2,3-d]-1,3-oxazin-4-ones9 and pyrazolo[3,4-d][1,3]oxazin-4-ones10 are less common in nature but have also attracted much interest because they too have been shown to demonstrate a wide range of biological activities This multifaceted profile bodes well for the interaction of such heterocycles with a variety of biological targets which has consequently led to the development of a number of lead compounds based on the fused 1,3-oxazinone scaffold

Over the years, numerous solution-phase methodologies for the synthesis of fused heterocyclic oxazinone derivatives have been reported.10b, 11 However, to synthesize large libraries more efficiency, we envisage that Solid-Phase Synthesis (SPS) which allows convenient handling and distribution of the synthetic intermediates would offer an attractive alternative pathway To our knowledge, such a process has not been previously demonstrated Thus, we herein describe a convenient traceless Solid-Phase approach to bi- and tricyclic hetero-annulated 1,3-oxazin-6-ones