Synopsis

SYNOPSIS The Thesis entitled “Studies directed towards the total synthesis of FR-901464 and development of Novel Synthetic methodologies” has been divided into three chapters.

Chapter-I: This chapter divided into two sections Section A and Section B. Section A: This section describes the introduction to cancer, including some of potent anticancer marine macrolides and the approaches cited in the literature for the total synthesis of FR901464. Section B: This section describes the studies directed towards total synthesis of FR-901464. Chapter-II: This chapter deals with the eletrophilic substitution reactions of indoles and This chapter subdivided into three sections.

Section A: This section describes InBr3-catalysed sulfonation of indoles: a facile synthesis of 3-sulfonyl indoles. Section B: This section describes ferric(III) chloride-promoted eletrophilic thiocyanation of aromatic and hetero aromatic compounds.

Section C: This section deals Bi(OTf)3 as mild, efficient and cost-effective catalyst for the alkylation of N-heterocycles with epoxides. Chapter-III: This chapter describes the development of new methodologies, which is further subdivided into three sections. Section A: This section describes the iodine/MeOH as a novel and versatile reagent system for the synthesis of α-ketothiocyanates. Section B: This section deals ceric(IV) ammonium nitrate: A novel reagent for the synthesis of homoallyl alcohol. Section C: This section describes triphenylphosphine: An efficient catalyst for transesterification of β-ketoesters.

i Synopsis

Chapter I Section A: An introduction to cancer, including some of potent anticancer marinemacrolides and the approaches cited in the literature towards the total synthesis of FR901464. Section B: Studies towards the total synthesis of FR901464 from isopropyledene glyceraldehydes and D-ribose as starting materials. INTRODUCTION: In search for natural products exhibiting with anti-cancer activity new modes of action, the Fujisawa group isolated FR901463 (1), FR901464 (2) and FR901465 (3) from the culture broth of a pseudomonas sp. No.2663 as a novel transcriptional activator. These natural products lower the mRNA levels of p53, p21, c- myc, and E2F-1 in MCF-7 cells at 20 nM and induces apparent apotosis in MCF-7 cells

with the impressive LC50 of 0.5 nM. They also exhibits an antitumour activity in a mouse model at remarkably low concentrations. Three were closely related structural features (Figure 1), differing only in the substitution pattern about right-hand pyran ring.

Me Me OAc Me Me O O O OH FR901463 (1) N HO H Me Cl OH

Me Me OAc Me O OMe O OH FR901464(2) N Me HO H O

Me Me OAc Me OMe O O OH FR901465 (3) N Me HO OH H O

Figure 1. Structures of FR9014639 (1), FR 901464(2) and FR901465 (3)

ii Synopsis

Retrosynthetic Analysis:

19 5' OAc 16 O 17 O O 1 11 5 OH N 1' 20 HO H O (2) 18

O OAc O O OH + + HO O OH H2N 6 4 5

O O O OH O OPMB + BnO O O 7 8 9 10

O O HO OH HO OH Cl O O H HO OH O epichlorohydrin (R)-isopropylidene 1,3 propanediol D-Ribose glyceraldehyde

11 12 13 14

Scheme 1

iii Synopsis

Synthesis of the chiral fragment 4 was started with the racemic epichlorohydrin (11) as the readily available starting material. Accordingly, epicholorohydrin was converted into the MPM protected glycidol 15 by treating with NaH and MPMOH in THF at 0 ºC in 82% yield.

NaH, THF O (R, R) Jacobsen's catalyst O Cl + MPMOH OPMB 82% H2O (0.55 equvi), 36 h 11 15 OH O HO OPMB + OPMB

7 16 H H N N Co (R,R)-Salen-Co(III)(OAc)Complex O O OAc (R, R) Jacobsen's catalyst

Scheme 2 Figure 2 The solvent free kinetic resolution of the racemic epoxide 15 with

0.55 equiv. of H2O in the presence of 0.003 mol% Co(III)(OAc) complex [(R,R)-N,N bis- (3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-Co(III)-acetate)][(Figure 2)] afforded chiral epoxide 7 (45% yield) and diol 16 after 36 h of stirring at room temperature. The chiral epoxide 7 was reduced to secondary alcohol with LiAlH4 at room temperature in 89% yield. The secondary alcohol 17 was protected as its silyl ether with

TBDPSCl and imadazole with catalytic amount of DMAP in dry CH2Cl2 at room temperature to afforded 18 in 98% yield. The compound 18 on p-methoxy benzyl group deprotection using DDQ in dichloromethane and water in the ratio (9:1) as a solvent system furnished alcohol 19 in 80% yield. Oxidation of primary alcohol 19 with oxalyl chloride, dimethylsulfoxide with triethylamine at 78 oC afforded its corresponding aldehyde 20 in 79% yield. The aldehyde 20 was converted into α, β-unsaturated ester 21 in 61% yield. On treatment with bis-(2,2,2-trifluoroethyl)(methoxy-carbonyl methyl)]phosphonate and NaH in dry THF at 78 ºC. Hydrolysis of α,β-unsaturated ester with LiOH in MeOH: H2O (20:1) afford carboxylic acid 22 in 74% yield.

iv Synopsis

OTBDPS OH O LiAlH , THF TBDPSCl, Imdazole OPMB OPMB 4 OPMB 0 oCto rt , 89% DMAP, CH2Cl2 0 oC, 98% 7 17 18 OTBDPS OTBDPS DDQ (COCl) , DMSO,Et N 2 3 O CH Cl : H O (9:1) OH 2 2 2 CH Cl , 78 oC, 79% o 2 2 0 C to rt, 80% 19 20

(CF CH O) P(O)CH COOCH OTBDPS OTBDPS 3 2 2 2 3 LiOH. THF o CO Me CO2H NaH, THF, 78 C to rt , 68% 2 MeOH-H2O 21 74% 22

Scheme 3

Alkynylation of isopropelidene glyceraldehyde with propyne gas, n-BuLi in THF at 0 oC furnished a mixture of inseparable isomers of homopropargylic alcohols 23 in 73% yield.

Oxidation of homopropargylic alcohols with PCC in CH2Cl2 at room temperature gave ketone 24 in 80% yield.

O O O O CH3-C CH O H PCC O Zn (BH ) Ether o 4 2, n-BuLi, THF, -78 C CH2Cl2, 2 h 40 to 20 oC O 73% OH 80% 86% O 12 23 24

O O O O BnBr, NaH HO OH HCl, MeOH THF, 75% THF, 80% OH OBn OBn 25 26 27 Scheme 4 For the good diastereoselectivity, keto compound 24 was subjected to chelation

o controlled metal reduction as the Zn(BH4)2 at 40 C furnished required major anti and minor syn isomer as inseparable mixture in ratio of 60:40 (by HPLC). Benzyl protection

v Synopsis of secondary alcohol 25 was performed using benzyl bromide and sodium hydride with catalytic amount of TBAI at 0 oC furnished 26 in 75% yield. Acetonide deprotection was achieved adding 2N HCl in MeOH to the compound 26 at 25 oC in 88% yield.

TsO OH HO OH O K CO , MeOH TsCl, Et3N,CH2Cl2 2 3 0 oC, 90% DMAP, 0oC, 78% OBn OBn OBn

27 28 29

O O Lindlar's catalyst OH HO H2/Pd-BaSo4 DIBAL-H, CH2Cl2 poision with quinoline o 0 C, 67% BnO DCC, DMAP 85% OBn 5 oC, 2 h 85% 30 8

o O OAC a. SnBr4, CH2Cl2, -78 C O O b. BF3.OEt3, HOAc DIBAL-H, Ac2O Pyridine, DMAP o BnO o BnO 12 h, -78 C c. I2, CH2Cl2, -78 C o d. InCl3, CH2Cl2, 78 - 0 C 31 32 e. TMSCl\ NaI

O

BnO

33 Diol was treated tosyl chloride,Scheme 5 triethylamine and DMAP at 0 oC to furnish mono tosyl compound 28 in 78% yield.

o Tosyl compound 28 was treated with K2CO3 in MeOH at 0 C to obtain epoxide with 90% yield. Epoxide compound 29 is subjected to the Lindlar’s catalyst, triple bond reduced to cis double bond to afford compound 30 with 85% yield. Reduction of epoxide 30 with DIBAL-H afforded mixture of diastereomers which are separated easily

vi Synopsis in column chromatography. The secondary alcohol 8 was key intermediate for the synthesis of pyran ring system of molecule. The compound 8 was then coupled with 1- butenoic acid using DCC and DMAP 5 oC to afford ester 31 in 85% yield. And the

o compound 31 was treated with DiBAL-H, Ac2O was then pyridine and DMAP at 78 C to furnish the acetate 32 in 80% yield. The acetate was then subjected to many Lewis acids at different reaction conditions but failed to obtain compound 33. The fragment 9 was started with propanediol 13 benzylation of diol with benzyl bromide, sodium hydride and catalytic amount of TBAI at 0 oC furnished benzyloxy propanol 34 in 80% . Benzyloxy propane diol was subjected swern oxidation with oxalylchloride, DMSO and triethylamine furnished aldehyde 35 in 81%. The aldehyde 35 was subjected to C3 witting reaction in benzene at room temperature afforded to α, β-unsaturated ester exclusively (E) isomer 36 in 86% yield.

BnBr, NaH (COCl) , DMSO HO OH 2 BnO O o HO OBn THF, 0 C, 80% Et3N, CH2Cl2 13 34 80% 35

CO Et Ph3PC (Me) CO2Et 2 BnO DIBAL-H, CH2Cl2 BnO OH Benzene, 86% 0 oC, 90%

36 37

+ - CH3Ph3PBr (COCl)2, DMSO BnO O BnO t , 0 oC Et3N, CH2Cl2 KO Bu 75% 80% THF 38 39 o a. Li\Liq NH3, -78 C HO b. AllylTMS (2 eq) o I2 (2 eq), 0 C 40 c. Li\ Napthalene, -70 oC Reduction of α, β unsaturated ester Scheme 6 36 with DIBAL-H at 0 oC gave alcohol 37 in 90% yield. The compound 37 was treated oxalyl chloride, DMSO and

triethylamine in CH2Cl2 to afford corresponding aldehyde 38 in 80% yield. The

vii Synopsis

aldehyde 38 was treated methyltriphenylphosphoniumbromide with tBuOK at 0 oC furnished diene 39 in 75% yield. Debenzylation of alcohol was tried with different reaction conditions gave undesired product. Optimization of this protocol is modern progress in our labotaratory.

O O OH OMe O OMe HO 2,2 DMP HO I Acetone I2, TPP, Toluene MeOH-HCl Imadazole HO OH O O O O 70% 120 oC, 63% D-Ribose 41 42 14

O CH3 CH3 OH CH3 Br DMP, CH2Cl2 Zn, THF Sonication O O O O 3.5 h, 74% 67% 44 43

O OH O O OH NaIO , CH OsO4, NMO. H2O 4 3 CH THF, Water O O 3 THF + Water O O 71%

45 10

a. 2 N HCl, 80 oC b.PPTS, MeOH CH3 O OH

c. I2, MeOH, rt HO d. TFA, THF, H2O , reflux O e. PTSA, MeOH , rt 46 Synthesis of fragment 4 was started with

Schemcommerciallye 7 available starting material D-ribose 12. Treatment of D-ribose with 2,3 dimethoxy propane, 2% methanolic HCl and acetone at room temperature furnished the compound 41 in 70% yield. Alcohol 41 was treated iodine, imadazole and TPP in toluene at 120 oC to furnish iodo compound 42.

viii Synopsis

Iodo compound was subjected allylation with 3-bromo-2-methyl-propene, Zn in THF on sonication for 4 h to obtain homoallyl alcohol 43 in 74% yield. The secondary alcohol 43

o was oxidized with Dess-Martin periodinane in CH2Cl2 at 0 C to afford corresponding keto compound in 60% yield. The compound 44 was treated with catalytic amount of

OsO4 and NMO at room temperature furnish diol 45. Treatment of diol 45 with NaIO4

impregnated over silica gel in CH2Cl2 furnished diketo compound 10 in 87% yield. The diketo compound when subjected acetonide deprotection with PPTS in MeOH afforded intractable mixture of products. The compound 10 was exposed to various reagents to obtain pyran ring 46. In this case also it ended up with intractable mixture of products. Optimization of this protocol is modern progress in our laboratory. Chapter II: This section deals with eletrophilic substitution reactions of indoles with the various Lewis acids. Section A: indoles react smoothly with sulfonyl chlorides in the presence of a catalytic amount of indium tribromide at ambient temperature to afford the corresponding 3- arylsulfonyl indole derivatives in high yields with high regioselectivity. Arylsulfones and sulfoxides are interesting functional groups possessing manifold reactivity for conversion to a variety of organosulphur compounds in the field of drugs and pharmaceuticals. In particular, arylsulphones have received much attention as powerful anti-HIV-1 agents. Indol-3-yl and pyrrol-2-yl aryl sulfones are found to be highly potent and structurally novel non-nucleoside reverse transcriptase inhibitors (NNTRIs) for example L-737, 126 and PAS.

O NH Cl S O O O 2 O S O N N NH2 H O Cl In view of the L-737, 126 importance of Figure 3 PAS indolyl aryl sulfones as non-nucleoside reverse transcriptase inhibitors, an easily handled reagent with one-pot approach for their synthesis is needed. In recent years, indium halides have evolved as mild and water tolerant Lewis acid imparting high

ix Synopsis

regio-, stereo- and chemoselectivity in various organic transformations. Compared to conventional Lewis acids, indium halides have advantages of water stability, recyclability and operational simplicity. Particularly, indium tribromide is found to be a more effective catalyst than conventional Lewis acids in promoting various transformations including glycosidation, thioacetalization, cyanation of ketones and conjugate addition reactions. We highlight our results on the eletrophilic sulfonylation indoles with sulfonyl chlorides using a catalytic amount of indium bromide. Thus, treatment of indole 1 (R

= H) with phenylsulfonylchloride 2 (Ar = Ph) in the presence of 10% InBr3 in 1, 2 dichloroethane afforded 3-phenylsulfonyl-1H-indole 3b in 87% yield (scheme 1).

SO2Ar R R InBr3 X + ArSO2Cl X N ClCH2CH2Cl, reflux N H H 1 2 3

R = H, Br, OCH3, Et Ar = phenyl, p-chlorophenyl, p-tolyl

X = H, CH3, COOEt Scheme 1 A variety of indoles reacted smoothly with sulfonylchlorides under similar conditions to give the corresponding 3-arylsulfonyl indole derivatives in high yields. In all cases, the reactions proceeded efficiently in dichlroethane at reflux temperature with activated indoles gave the products in excellent yields. However, the treatment of N-protected indoles such as N-ethyl or N-methyl derivatives with p-toluene sulfonylchloride in dichloromethane at 75-80 oC for 7-9 h afforded the corresponding 3-phenylsulfonyl indole derivatives in 65 and 70% yields, respectively. The best results were obtained when indium tribromide was used as the catalyst. However, in the absence of catalyst the reaction of phenyl sulfonylchloride and indole did not furnish any product even after long reaction time

x Synopsis

In summary, indium tribromide was found to be a novel and highly efficient Lewis acid catalyst for the direct synthesis of 3-arylsulfonyl indole derivatives from indoles and arylsulfonyl chlorides under mild reaction conditions. Section B: Ferric(III) chloride-promoted electrophilicthiocyanation of aromatic and heteroaromatic compounds. The electrophilic thiocyanation of aromatics and heteroaromatics is an important carbonheteroatom bond formation in organic synthesis. Aryl or heteroaryl thiocyanates are useful intermediates in the synthesis of sulfur containing heterocycles. Furthermore, aryl thiocyanates can be easily transformed into various sulfur-containing functional groups such as thiophenols by reduction with lithium aluminum hydride and aryl nitriles/disulphides by aromatic Grignard reagents. Thus, the direct thiocyanation of aromatic systems is of prime importance. Consequently, several methods have been developed for the thiocyanation of arenes using a variety of reagents under various conditions. In contrast, only limited number of reagents such as N-halosuccinimides (NCS or NBS), ceric ammonium nitrate (CAN) and acidic K-10 clay have been reported for the thiocyanation of indoles. However, many of these methods involve the use of strongly acidic or oxidizing conditions and toxic metal thiocyanate and permit only low conversions, especially in case of aryl-amines. Furthermore, some require high temperatures to obtain satisfactory results. Since organ sulfur compounds have become increasingly useful and important in the field of drugs.

FeCl3 has emerged as a potential catalyst in effecting various organic transformations due to its high catalytic ability, ease of handling, economic viability, experimental simplicity and easy availability. We wish to disclose a simple, convenient and efficient protocol for the thiocyanation of indoles, oxindoles and aryl

amines using anhydrous FeCl3 is an inexpensive and readily available catalyst. Initially, we have attempted the electrophilic thiocynation of 2-methylindole (1) as a model

substrate with two equivalents of ammonium Thiocyanate using anhydrous FeCl3 as novel oxidant. The reaction went to completion within three hours at room temperature and the product, 3-thiocyanatoindole (2b), was obtained in 92% yield (Scheme 2).

SCN FeCl3 + NH4SCN N CH3 CH Cl rt H 2 2 N CH3 xi H 1 2b Synopsis

Scheme 2

Interestingly, various substituted indoles reacted efficiently with ammoniumthiocyanate to afforded the corresponding 3-thiocyanato indole derivatives. Like indoles, N-methyloxindole, N-benzyloxindole and isatin also reacted well under similar conditions to give 5-thiocyanato derivatives. Interestingly, the non-activated compound N-acetylinidole was also converted to the corresponding derivative in good yield. Moreover, treatment of arylamines such as aniline, 2-chloro-3-methylaniline, N,N-dimethylaniline, N-ethyl aniline, 3-nitroaniline and 2,5-dichloroaniline with ammonium thiocyanate in the presence of anhydrous FeCl3 resulted also in the formation of aryl thiocyanates in high yields (Scheme 3).

R R SCN FeCl3 + NH SCN 4 CH2Cl2, rt H2N R1 H2N R1 2 1 Scheme 3

In case of aryl amines, the products were obtained with high para-selectivity. In all cases, the reactions proceeded smoothly at room temperature with high regioselectivity. The products were characterized by 1H NMR, IR and mass spectroscopic data and also by comparison with authentic samples. In the absence of catalyst, the reaction did not take place even after long reaction time 24 h.

In summary, we have described a simple, convenient and efficient protocol for the thiocyanation of aromatics and heteroaromatics using anhydrous FeCl3 as a novel catalyst. The notable features of this procedure are mild reaction conditions, high conversions, greater regioselectivity, economic viability of the reagents and simple

xii Synopsis

experimental/product isolation procedure which makes it a useful and attractive alternative process for the preparation of aryl thiocyanates.

Section C: Bi(OTf)3 as Mild, efficient and cost-effective catalyst for the alkylationof N- heterocycles with epoxides. Indole is a key structural motif in many pharmacologically and biologically active compounds as well as in natural products. In addition, pyrrole derivatves are also important intermediates, not only for the synthesis of drugs, pigments and pharmaceuticals, but also for the development of functional organic materials. Epoxides are well known carbon eletrophiles capable of reacting with various nucleophiles and their ability to under regioselective ring opening reactions contributes largely to their synthetic value. However, these methods often involve the use of expensive reagents, drastic conditions, longer reaction times, unsatisfactory yields especially in case of aliphatic epoxides and entail undesirable side reactions due to polymerization or rearrangements of oxiranes. Therefore, new catalytic systems are being continuously explored in search of improved efficiencies and cost effectiveness. Recently, bismuth(III) triflates has attracted the attention of synthetic organic chemists because of its low cast and ease of preparation even on multi-gram scale in the laboratory from commercially available bismuth(III) oxide and trifilic acid. In continuation of our interest on the use of metal triflates as the Lewis acid catalyst for various transformations, we here in report another remarkable catalytic activity of bismuthtriflate in the regioselective ring opening of oxiranes with indoles, pyrroles and imidazole. Thus, treatment of indole (2) with styrene oxide (1) in the presence of 10

o mol% of Bi(OTf)3 in dichloromethane at 40 C afforded 2-(3-indolyl)-2-phenylethanol (3a) in 85% yield (Scheme 4). Ph OH O 10 mol% Bi(OTf)3 + CH Cl , reflux. Ph N 2 2 H N H Scheme 4 1 Similarly, N- 2 3 methyl- and N- benzylindoles reacted efficiently with styrene oxide to produce 2-(3-indolyl)-2-

xiii Synopsis phenylethanols in good yields. Interestingly, glycidylarylethers also underwent cleavage with indole, N-methyl and N-benzylindole to afforded the corresponding tryptohol derivative 6 as the major isomer along with the minor amount 7 in high yields (Scheme 5).

OH OPh OAr O 10 mol% Bi(OTf) + 3 + PhO N CH2Cl2, rt OH N N R R R 4 5 7 6

R = H, CH3, benzyl Ph = p-Me-C6H4, p-Cl-C6H4, p-F-C6H4, b-napthyl

Scheme 5

We attempted the alkylation of pyrroles with styrene oxide. The reaction was highly regioselective affording the corresponding C-alkylated pyrroles 9 as the major isomer along with a minor amount of 10 (Scheme 6).

Ar OH 10 mol% Bi(OTf)3 O OH + + N CH2Cl2, reflux. N N Ph R R Ar R 9 8 10 R = CH3, H Scheme 6 In summary, this methodology describes a simple and efficient protocol for the alkylation of indoles, pyrroles, imidazole and benzotriazoles with epoxides using

catalytic amount of Bi(OTf)3. The notable features of this procedure are mild reaction conditions, greater selectivity, cleaner reaction profiles, simplicity in operation and low cost of the catalyst that make it a useful and convenient procedure for the alkylation of N-heterocyclic with aryl and alkyl epoxide. Chapter: III

xiv Synopsis

SectionA: This section deals with Iodine/MeOH as a novel and versatile reagent system for the synthesis of α-ketothiocyanates. The direct -thiocyanation of ketones is an important carbon-heteroatom bond forming reaction in organic synthesis. -ketothiocyanates are useful intermediates in the synthesis of sulfur containing heterocyclic such as thiazoles. Some of these heterocycles exhibit herbicidal and other important biological activities. In addition to this, the thiocyanato group is found in several anticancer natural products formed by deglycosylation of glucosinolates derived from cruciferous vegetables. Thus, the direct thiocyanation of ketones is of prime importance. Consequently, various methods have been developed for the -thiocyanation of ketones using a variety of reagents under diverse reaction conditions. However, these classical methods involve multi-step synthetic sequences and often harsh reaction conditions and also the yields are typically low because of the poor nucleophilicity of thiocyanate. Direct thiocyanation of ketones has been reported using the dichloroiodobenzene/lead (II)thiocyanate reagent system, which works well with silyl enol ethers. Furthermore, many of these reported methods involve the use of a large excess of strong oxidizing agents and toxic metal thiocyanates resulting in low conversions due to the formation of complex mixtures of products. Molecular iodine has received considerable attention as an inexpensive, nontoxic, readily available reagent for various organic transformations, affording the corresponding products with high selectivity in excellent yields. The mild Lewis acidity associated with iodine has led to its use in organic synthesis using catalytic to stoichiometric amounts.

In continuation of our interest on the use of molecular iodine for various transformations, we here in report the first direct and metal catalyst-free synthesis of - ketothiocyanates by -thiocyanation of enolizable ketones with ammonium thiocyanate under neutral conditions. Initially, we studied the -thiocyanation of acetophenone 1 as a model substrate with 2 eq. of ammonium thiocyanate using 1 eq. of molecular iodine

xv Synopsis in refluxing methanol. The reaction went to completion in 6 h and 1-phenyl-2- thiocyanatoethanone (2a) was obtained in 85% yield (Scheme 7).

O O SCN

I2 CH3 + NH4SCN MeOH, reflux

2a 1 Scheme 7 Interestingly, various substituted ketones, such as 3-chloroacetophenone, 2- trifluoromethylacetophenone and 2-acetylnaphthalene, reacted efficiently with ammonium thiocyanate to afforded the corresponding -thiocyanato ketones in high yields. Like acetophenones, cyclic ketones such as 1-tetralone, 2-phenylchroman-4-one, cyclopentanone, 2-methylcyclohexanone, 4,4-dimethylcyclohex-2-enone, cycloheptanone and cyclododecanone reacted well under similar conditions to give - ketothiocyanates . Similarly, the -keto ester, chroman-2, 4-dione also afforded the corresponding 3-thiocyanato-chroman-2, 4-dione in good yield (Scheme 8).

O O SCN I2 + NH4SCN O O MeOH, reflux O O

Scheme 8

Probably, the reaction proceeds via the formation of active thiocyanogen, (SCN)2 from molecular iodine and ammoniumthiocyanate as reported earlier in literature. Thus formed thiocyanogen reacts rapidly with enolizable ketones to produce - ketothiocyanates.

In summary, molecular iodine has proved to be a useful and novel reagent for selective thiocyanation of ketones to produce -ketothiocyanates in high yields. The experimental procedure is simple, convenient and the reaction conditions are amenable to scale-up.

xvi Synopsis

Section B: Ceric(IV) ammonium nitrate: A novel reagent for the synthesis of homoallyl alcohol. Homoallylic alcohols are valuable intermediates in the synthesis of many complex molecules and which can be easily converted to many important building blocks in the synthesis of natural products. In the total synthesis of natural products having the homoallyl alcohols, as the intermediate requires an additional step for protection of the free secondary alcohols to proceed further. In general homoallylic alcohols can be prepared by the allylation of carbonyl compounds with organ metallic compounds, such as alkyltrialkyl and allyltriarylstannes. Consequently, several methods have been developed for the allylation of aldehydes with allyl metals including Lewis, Bronsted acid and organ metallic reagent catalyzed allylation reactions in organic and aqueous media, ionic liquids and polyethylene glycol. Very recently, β-cyclodextrin promoted allylation of aldehyde as well as in a mixture of organic and aqueous medium has been reported. Generally tight binding of the product homoallylic alcohol to the Lewis acid catalyst results in poor turnover, there by necessitating the use of stoichiometric amount of Lewis acid. Therefore, development of simple, convenient and environmentally benign catalytic approaches for the synthesis of homoallylic alcohols is still desirable. Ceric ammonium nitrate has emerged as powerful single electron transfer reagent in many carbon-carbon bond forming reactions. Herein, we wish to report that ceric ammonium nitrate (CAN) is a mild and highly efficient catalyst for the allylation of aldehydes with allylstannes under neutral conditions (Scheme 9). The treatment of benzaldehyde with allylstannes in the presence of 5 mol% CAN in acetonitrile afforded 1-phenyl-3- buten-1ol in 95% yield. Similarly, various aliphatic, aromatic, heterocyclic and α, β-unsaturated aldehydes converted to the corresponding homoallylic alcohols in excellent yields by using this procedure.

In all the cases, the reaction proceeded efficiently at ambient temperature with high chemo selectivity. No bis-allylated products are obtained with methoxy-substituted aryl aldehydes, which are normally observed in the allylation reactions of methoxybenzaldehydes with allyltrimethylsilane. Acid sensitive aldehydes such as

xvii Synopsis

furfural, 2-phenylacetaldehyde and cinnamaldehyde were also smoothly reacted with allyltin to afforded the corresponding homoallylic alcohols in excellent yields. In case of 2-phenylpropanal, the product was obtained as a diastereomeric mixture of syn and anti in 3:1 ratio. The chemo selectivity of the present method was further studied by using the keto aldehydes.

OH

R-CHO + SnBu3 CAN rt R CH3CN, 1 , 2 Scheme 9

Interestingly, ketones reacted smoothly and rapidly with tetraallytin in the presence of ceric ammonium nitrate to afford the corresponding homoallylic alcohols in excellent yields (Scheme 10).

O OH Sn CAN + R R 4 R 1 CH3CN rt R1 , 3 4

Scheme 10 In case of 2-methylcyclohexanone, the product was obtained as cis-adduct. Similarly, benzoin afforded the corresponding homoallyl alcohol as syn-adducts. In summary, this methodology describes a rapid and highly efficient protocol for the allylation of carbonyl compounds with allyl tin reagents using a cheap and readily available reagent, cerium ammonium nitrate under mild and neutral conditions.

Section C: This chapter deals triphenylphosphine: An efficient catalyst for transesterification of β-ketoesters. The electrophilic and nucleophilic sites of -ketoesters represent an important class of organic building blocks for the synthesis of a number of complex biologically active natural products of pharmaceuticals, agrochemicals and polymers. The esterification and transesterification are very important reactions in synthetic organic chemistry laboratories as well as academic laboratories for the preparation of polyesters from

xviii Synopsis

alcohols and acids or esters. The use of these synthons in organic synthesis is more advantageous than ester synthesis due to the availability of several -ketoesters in the market. The transesterification reaction of -ketoesters has been recognized as one of the most significant processes in producing other -ketoesters. These reactions can be made spontaneous by using Dean-Stark apparatus or high temperature conditions. However, they are very often catalyzed for a high efficiency, faster reaction rates and milder conditions. Thus, a number of procedures catalyzed by a variety of protic acids, Lewis acids, solid catalysts organic or inorganic basic catalysts and enzymes have been reported in the literature. But many of these catalysts have drawbacks such as expensive or difficult to prepare, toxic, require longer reaction time, unsuitable for acid sensitive functional groups, low selectivity and large amounts of solid supports which would eventually result in the generation of a large amount of toxic waste. Due to the environmental demand, there has been considerable interest in developing a new catalyst for organic reactions that would be mild, easily available at low-cost, high performance in transformation and wide applicability is desirable.

We reported that the triphenylphosphine as an efficient catalyst for transesterification of -ketoester with various alcohols. In a typical experimental procedure, the methylacetoacetate (2 mmol), propargyl alcohol (2 mmol) and tripheyl phosphine (10 mol %) were refluxed in toluene to obtained the corresponding transesterification product in very good yields. The reaction was completed in 6.0 h. However, no transesterification was observed when the reaction was carried out in the absence of catalyst over 24 h.

O O O O TPP R OH R OR R2 OH R OR 1 1 Toluene 2 reflux 3 1 2 Scheme 11 A variety of -ketoesters such as methyl, cycloalkyl and phenyl acetoacetates were underwent transesterification with a wide range of alcohols like propargyl, butyl, prenyl, benzyl, octyl, 2-chloroethyl, phenyl ethyl, allyl and menthols. In all the cases, the reactions were completed in 6-8 h, with high efficiency. It is important to note that the

xix Synopsis propargyl alcohol, menthol and prenol have been effectively catalyzed by triphenylphosphine, to obtain the corresponding products in excellent yield. In conclusion, we have demonstrated a novel and efficient protocol for the transesterification of -ketoesters with various alcohols using triphenylphosphine in catalytic amount as a novel catalyst. This method offers significant advantages such as mild reaction conditions faster reaction rates, high yields, greater selectivity, readily availability of the catalyst and no side products.

xx