Chapter I: This Chapter Is Divided Into Two Sections; Section a and Section B s1

Abstract

ABSTRACT The thesis entitled “Studies directed towards the total synthesis of Alliacol-A,

Leiocarpin-C, (+)-Goniodiol and development of novel synthetic methodologies” has been divided into three chapters.

Chapter I: This chapter is divided into two sections; Section A and Section B.

Section A: This section describes the introduction and biological activity of styryl lactones and approaches cited in the literature towards the synthesis of (+)-Goniodiol.

Section B: This section describes the enantio- and stereoselective approach to

Leiocarpin-C and (+)-Goniodiol.

Chapter II: This chapter is divided into two sections; Section A and Section B.

Section A: This section describes the introduction and biological activity of Alliacols and approaches cited in the literature towards the synthesis of Alliacol-A, including total synthesis.

Section B: This section describes the enantio- and stereoselective approach to

Alliacol-A: An efficient synthesis and efforts towards the synthesis of Alliacol-A.

Chapter III: This chapter is divided into three sections; Section A, Section B and

Section C.

Section A: First example of activation of polymethylhydrosiloxane with molecular iodine: a facile synthesis of 3,6-dihydropyran derivatives.

Section B: 1-Butyl-3-methyl imidazolium tetra fluroborate([Bmim]BF4) ionic liquid: A novel and recyclable reaction medium for the synthesis of vic-diamines.

Section C: Bi(OTf)3 catalysed synthesis of quinolines, dihydroquninolines, quinoxalines and benzimidazoles.

I Abstract

CHAPTER-I Section A: Introduction and biological activity of Styryl lactones: Styryl lactones represent a new class of natural and synthetic compounds with potential cytotoxicity including antitumour, antifungal and antibiotic properties. Up to now, more than twenty styryl lactones have been isolated from plants and fungi and most of the styryl-lactones are isolated from the genus Goniothalamus (Annonaceae), which are widely distributed throughout Malaysia. A number of these species were used by Malays as traditional medicine to treat various ailments and had been claimed to have connection with an antifertility effects such as procurement of abortion, undefined post- natal treatments and low birth rate. Styryl lactones posses interesting biological properties, in particular antiproliferative activity against cancer cells. Section B: Stereoselective synthesis of Leiocarpin-C and (+)-Goniodiol: Stryryl lactones are natural heterocyclic compounds isolated from Goniothalamus species, which have been found to possess excellent antitumoral and anti fungal properties as well as antibiotic potential. Leiocarpin-C 1 was isolated from the seeds of Goniothalamus leiocarpus (Annonaceae), a tropical plant wide spread in the south of the Yunnan province in china. Leiocarpins found to possess cytotoxic activities against several human tumor cell lines, which was tested in MTT method. (+)-Goniodiol 2 was isolated from the leaves and twigs of Goniothalamus sesquipedalis (Annonaceae) and from the stem bark of Goniothalamus gigantus (Annonaceae). This is a potent and selective cytotoxic compound against human lung carcinoma A-549 (ED50 = 0.12 μg

-1 -1 mL ) and p-388 murine leukemia cells (IC50 = 4.56 μg mL ). There are several successful approaches to the synthesis of (+)-Goniodiol 2, but the biological significance and activity, encouraged us to design a concise and flexible stereoselective route towards the first total synthesis of Leiocarpin-C 1 and also the synthesis of (+)-Goniodiol 2.

OH O OH O

Ph OH Ph OH OH LEIOCARPIN-C 1 (+)-GONIODIOL 2

II Abstract

The retrosynthetic analysis shows that both these lactones can be synthesized from tert- butyldimethylsilyl protected propargylic alcohol 15 and this could be synthesized from the inexpensive and commercially available cinnamyl alcohol 6 and homoallyl alcohol 7 (Scheme 1).

O O OTBS OH OH O OH O Ph OBn Ph Ph OH 15 OH OH 2 1

Ph OH + OH 6 7 Scheme 1

Synthesis of Leiocarpin-C: The choice of any synthetic strategy lies on the availability of the starting materials, selectivity of the reactions, simplicity of the approach and also on the yields of the reactions. The strategy described here was started with the Sharpless asymmetric epoxidation protocol on cinnamyl alcohol 3. Thus the treatment of cinnamyl alcohol 3 with 0.12 equivalents of titanium tetra isopropoxide, 0.15 equivalents of (-)-diethyl D-

o tartarate and 2 equivalents of TBHP in anhydrous CH2Cl2 at -30 C afforded the epoxy alcohol 4 in 82 % yield (Scheme 2).

i O (-)-DET, Ti(O Pr)4, Ph OH Ph OH TBHP, CH2Cl2, -30 oC, 82%. 3 4 Scheme 2

Epoxy alcohol 4 was converted to epoxy chloride 5 using triphenylphosphine and

NaHCO3 in CCl4 at reflux temperature in 88% yield. Accordingly, the epoxy chloride 5 in anhydrous THF was treated with 2 eq. of n-BuLi at –78 oC to get hydroxy alkyne 6

III Abstract in 75% yield. The hydroxyl group of compound 6 was protected as tert- butyldimethylsilyl (TBDMS) ether to give 7 in 92% yield (Scheme 3).

O OH TPP, CCl4, O n-BuLi, THF, Ph OH Reflux, 88%. Ph Cl 72% Ph 4 5 6

TBDMSCl, OTBS

Imidazole, CH2Cl2, Ph 0 oC to r.t, 92%. 7 OBn NaH / BnBr Scheme 3 m-CPBA O OH TBAI, THF OBn DCM, 0 oC 0 oC to r,t., 95% 86% 8 9 10 Scheme 4 The commercially available homoallyl alcohol 8 was converted to its benzyl ether 9 in 95% yield by treating with 2 equivalents of sodium hydride (60% w/v dispersion in oil) and 1.1 equivalents of benzyl bromide in dry THF at 0 oC. Treatment of 9 with 1.2 equivalents of meta-chloroperbenzoic acid in dichloromethane at 0 oC afforded the racemic epoxide 10 in 86% yield (Scheme 4).

The racemic terminal epoxide 10 was subjected to solvent free hydrolytic kinetic resolution employing 0.55 equivalents of water in the presence of 0.005 mol% of (S,S)- salen-Co(III)(OAc) complex [(S,S)-N,N’-bis(3,5-di-tert-butylsalycylidene)-1,2- cyclohexanediamino-Co(III)-acetate] [Jacobsen’s catalyst] (figure 1) to afford the chiral epoxide 11 in 44% yield along with chiral diol 12 in 45% yield (Scheme 5).

Jacobsens's catalyst OBn OBn OH OBn O (0.005 mol%) O H H + HO 0.55 eq. H2O N N 10 Co 11 12 OAc Scheme 5

Figure 1 IV Abstract

(Salen)Co(III)(OAc) complex : Jacobsen’s catalyst (S,S)-N,N’-Bis(3,5-di-tert-butylsalicylidene)1,2-cyclohexanediamino-Co(III)-acetate

The diol 12 obtained so could be easily converted to the epoxide with the required stereochemistry in further three steps, thus obtaining nearly 100% product. The diol 12 was transformed to 11 employing Scheme 6. Thus, the primary hydroxyl group of diol 12 was protected as the TBS ether using 1.0 equivalent of tert-butyldimethylsilyl chloride and imidazole in dry DCM at 0 oC to afford product 13 in 96% yield. The secondary hydroxyl group of compound 13 was tosylated using 1.2 equivalents of para-toluenesulfonyl chloride, triethylamine (2 eq.) and catalytic amount of DMAP in dry DCM at 0 oC to afford 14 in 93% yield. The compound 14 upon treatment with 4 equivalents of tetrabutylammonium fluoride in dry THF at room temperature afforded the chiral epoxide 11 in 93% yield having identical properties with that prepared earlier using resolution (Scheme 6).

TBSCl, OH OBn OH OBn Imidazole TsCl, TEA HO TBSO DCM, 0o C, 96% DCM, 0o C, 93% 12 13

OTs OBn TBAF, THF O OBn TBSO r.t., 93%

14 11 Scheme 6

V Abstract

Epoxide 1-benzyloxy–2-[(2S)–oxiran-2-y1]ethane 11 was opened by alkynyl borane reagent prepared insitu at –78 oC in anhydrous THF by the reaction of lithium acetylide

(from TBS protected propargyl alcohol 7 and n-BuLi) with BF3.OEt2 (Scheme 7) to yield a -hydroxy acetylene derivative 15 in 85% yield.

OTBS OTBS n-BuLi BF3.OEt2 Ph THF, -78 o C THF, -78 oC Ph B 7

OTBS O OBn OH 11 Ph THF, 85% OBn 15

Scheme 7 Deprotection of TBS group of compound 15 using TBAF in anhydrous THF afforded the propargylic alcohol 16 in 85% yield. The propargylic alcohol 16 was reduced to allylic alcohol 17 in 90% yield by refluxing with 3 equivalents of lithium aluminium hydride in dry THF (Scheme 8).

OTBS OH OH TBAF, THF OH Ph Ph 0 oC to r.t, 82% OBn OBn 15 16

OH OH LiAlH4 THF, reflux, Ph OBn 90% 17 Scheme 8 The diol 17 was protected using TBSCl and imidazole in DCM at 0 oC to room temperature to afford 18a in 97% yield. Compound 18a was subjected to Sharpless asymmetric dihydroxylation to afford the diol 19a. The diol 19a was obtained only in 20% yield even after maintaining at 0 oC for 4days, this may be due to the steric

VI Abstract hinderance of TBS groups, therefore the two hydroxyl groups of compound 17 was protected using using MOMCl and N,N-diisopropylethylamine in dry DCM to afford 18b in 92% yield. Compound 18b was subjected to Sharpless asymmetric dihydroxylation to afford the diol 19b in 80% yield (Scheme 9).

OTBS OTBS TBSO OH OTBS a c 97% Ph OBn 20% Ph OBn OH OH OH 18a 19a Ph OBn 17 MOMO OH OMOM b OMOM OMOM c 92% Ph OBn 80% Ph OBn OH 18b 19b

Scheme 9

o Scheme 9: Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, 0 C to r.t (b) MOMCl, DIEPA,

o o CH2Cl2, 0 C to r.t (c) Admix-β, CH3SO2NH2, t-BuOH/H2O (1:1), 0 C

The compound 19b was treated with 2,2-DMP in DCM in the presence of catalytic amount of PTSA at 0 oC afford compound 20b. The benzyl protected hydroxyl group of compound 20b was deprotected using 9:1 DDQ:H2O to afford alcohol 21b (Scheme 10).

MOMO OH OMOM MOMO O OMOM 2,2DMP, Ph OBn PTSA, Ph OBn 90% OH O 19b 20b

MOMO O OMOM DDQ:H2O 9 :1, 85% Ph OH O

21b The free hydroxyl group of Schemecompound 10 21b was oxidized using IBX/DMSO in dry DCM to give aldehyde 22b. The aldehyde 22b was further oxidized in the presence of NaH2PO4 and NaClO2 in DMSO to afford acid 23b (Scheme 11).

VII Abstract

MOMO O OMOM IBX/DMSO MOMO O OMOM CHO Ph OH DCM, 0 oC to r.t, Ph O 70% O

21b 22b

MOMO O OMOM NaH PO , NaClO 2 4 2 COOH Ph DMSO, H2O, 0 oC to r.t, O 85% 23b

Scheme 11 The acid 23b was converted to ester 24b in the presence of diazomethane in ether. The ester 24b was cyclized to Leiocarpin-C 1 using catalytic amount of p-toluenesulphonic acid in methanol in 78 % yield (Scheme 12).

MOMO O OMOM MOMO O OMOM CH N in ether COOH 2 2 COOCH3 Ph 0 oC, 85% Ph O O 23b 24b

MeOH/PTSA OH O reflux, 78% Ph OH OH 1 Scheme 12 Synthesis of (+)-Goniodiol: The compound 1 was treated with 2,2-DMP in DCM in the presence of catalytic amount of PTSA at 0 oC afford compound 25 in 90% yield. The free hydroxyl group of compound 25 was protected using mesyl chloride and triethylamine in DCM to afford compound 26. Compound 26 was treated with DBU in DCM to afford the compound 27. The acetonide deprotection of compound 27 was accomplished using PTSA in MeOH to afford compound 2 (Scheme 13).

VIII Abstract

OH O O O O O 2,2DMP MsCl, Et3N PTSA OH Ph OH Ph DCM, 79% Ph OMs 90% OH O O 1 25 26

DBU O O MeOH/PTSA OH O DCM, 80% r.t, 75% Ph Ph O OH 27 2

Scheme 13

CHAPTER-II Section A: Introduction: Cancer is the most dreaded disease which can be characterized as “any malignant growth or tumor caused by abnormal and uncontrolled cell division; it may spread to other parts of the body through the lymphatic system or the blood stream”. For a long time it has been known that cancer disease may be triggered by viruses of RNA and DNA types playing a lead role, but many of the gross causes of cancer, such as

IX Abstract dietary, environmental and occupational exposure to certain chemical substances or forms of electromagnetic radiation have been elucidated through epidermiological studies. Cancers are classified mainly by the organ in which they originate and by the kind of cell involved. Roughly half of all cancer deaths are caused by cancers of three organs; the lung, the large intestine and the breast. The treatment of cancer involves various combinations of surgery, radiation therapy, immunotherapy and chemotherapy. Cytotoxic drugs are useful in the treatment of many forms of cancer. There over 200 types of cancer and more than 50 cytotoxic drugs are currently available for the treatment of cancer, either on their own or in combination. Section B: Stereoselective approach to Alliacol-A: Alliacol-A, which is a sesquiterpene was isolated from the cultures of Basidiomycete Marasmius alliaceus in 1977. Marasmius alliaceus is a tall thin mushroom native to European beechwood forest. Its name originates from its strong garlicky odour. The other Alliacolides such as Alliacol-B (a), Alliacolide (b), Noralliacolide (c), Hydroxyalliacolide (d) and deoxy alliacolide (e) are epoxy lactones which were isolated from the same fungus. Biogenetically, these fungal sesquiterpenoids are likely to arise from farnesylpyrophosphate. Alliacol-A is a unsaturated lactone which shows significant cytotoxic activity against the cells of ascetic form of Erlich carcinoma at concentration of 10 µg/mL. This activity likely results from nucleophilic addition (i.e., cystiene, often present in enzymes) to the electrophilic α,β-unsaturated lactone. The potency of these metabolites is enhanced due to the presence of polar groups (i.e.,OH).

O O O O

R OH O O O O OH OH b : R = CH3 a d e c : R = H

X Abstract

As a part of ongoing programme towards the synthesis of biologically active molecules based on the simplicity of the reaction and ready availability of the starting materials, we herein, a flexible stereo-selective route has been described for the synthesis of Alliacol-A from inexpensive and commercially available 2-methyl propen-1-ol 2 and (+) Pulegone 9 (Scheme 1).

13 O Fragment C

+ TMS OAc OH TMS Cl O 6 2 15 O 12 9

Fragment A1 Fragment A Fragment B

Scheme 1 Synthesis of fragment A1: The synthesis of fragment A1 begin with commercially available α-methallyl alcohol 2 as illustrated in (scheme 2). Thus, α-methallyl alcohol 2 was converted to dianion 3 on treatment with n-BuLi and TMEDA in anhydrous ether and THF, the dianion 3 in situ was converted to silyl ether 4 using trimethylsilyl chloride in 55%

XI Abstract

yield. The silyl ether 4 on treatment with 1NH2SO4 in THF afforded the hydroxyl trimethyl silane 5 in 90% yield. Acetylation of the hydroxyl trimethyl silane 5 with acetyl chloride in triethylamine furnished the desired acetate 6 in 92% yield (Scheme 2).

n-BuLi TMEDA TMSCl Ether/THF -20 oC to r.t, 55% OH 0 oC to r.t. TMS OTMS Li OLi

1NH2SO4 AcCl, Et3N THF, 90% DCM, 92% TMS OH TMS OAc

Scheme 2 Synthesis of fragment B: The compound 7 was treated with hydrazine hydrate in THF to afford sulpnonohydrazide 8 in 95% yield (Scheme 3).

SO2Cl SO2NH.NH2

NH2.NH2 95%

7 8 Scheme 3

(+)-Pulegone 9 was treated with sulphonohydrazide 8 in HCl and MeOH to afforded (+)-pulegone trisylhydrazone 10 in 80% yield. Trisylhydrazone 10 was converted to diene 11 using n-BuLi and TMEDA in 95% yield. The diene 11 was treated with ozone at -78 oC in DCM using sudan red 7B indicator to afford enone 12 in 30% yield (Scheme 4).

XII Abstract

n-BuLi 2,4,6-triisopropyl benzene TMEDA sulphono hydrazide 8 -78 oC, 95% O HCl, MeOH, 80% N-NHTris

9 10 11

O3, DCM Sudan red 7B 30%

O O 12 12

Scheme 4 Synthesis of fragment C: Cycloaddition of R-(+)-4-methyl cyclohexenone 12 and silyl acetate 6 in the presence of tetrakis(triphenylphosphine)palladium and dppe (bis(diphenylphosphino)ethane) in THF afforded the cyclised product 13 in15% yield (Scheme 5).

(Ph3P)4Pd + dppe, THF TMS OAc reflux, 15% O O 12 6 13 Scheme 5 As the yield is very less instead of silylacetate 6, we protected the hydroxyl group of hydroxyl silane 5 with mesyl chloride and triethylamine in DCM at 0 oC to room temperature to afford compound 14 in 82% yield. The mesylated compound 14 in the presence of LiCl and DMF afforded the chlorotrimethyl silane 15 in 61% yield (Scheme 6).

MsCl, Et3N LiCl, DMF DCM, 0 oC to r.t o 0 C to r.t TMS Cl TMS OH 82% TMS OMs 61% 5 14 15

SchemeXIII 6 Abstract

The chloro trimethylsilane was added to the R-(+)-4-methylcyclohexenone in

o the presence of TiCl4 in DCM at -78 C to afford the addition product 15 in 72% yield. The addition product 16 on treatment with K-OBut in t-BuOH at 0 oC afforded the cyclised product 13 in 60% yield (Scheme 7).

TiCl4, DCM + -78 oC, 72% TMS Cl Cl

O O 15 12 16

K-OBut t-BuOH 0 oC to r.t, 60% O

13 Scheme 7

The double bond of the cyclised product 13 converted to cyclopropane on treatment with diethylzinc and methyliodide in anhydrous benzene under nitrogen atmosphere afforded the product 17 in 70% yield. The cyclopropane ring of compound 17 on

(C H ) Zn 2 5 2 PtO2 CH I ,C H 2 2 6 6 H2 pressure 70% 90% O O O 13 17 18 Scheme 8 treatment with platinum oxide in pressure afforded the gem dimethylated product 18 (Scheme 8).

XIV Abstract

The dimethylated product 18 on treatment with trimethylsilyliodide and hexamethyldisilazane in n-pentane afforded the thermodynamically stable product 19 (Scheme 9).

TMSI HMDS n-Pentane -23 oC to r.t, 95% O OTMS

18 19 Scheme 9 The compound 19 was exposed to various reagents to obtain ,β-unsatured ketone 20, unexpectedly, however a complex mixture of products were obtained and could not be characterized. Work to optimize this protocol is currently being pursued (Scheme 10).

O OTMS O

19 20 O 1

CHAPTER-III Scheme 10 Section A:

 First example of the activation of polymethylhydrosiloxane with molecular iodine: a facile synthesis of 3,6-dihydropyran derivatives

Naturally occurring carbohydrates have been extensively used as chiral pool starting materials in the synthesis of biologically active natural products. Glycals are known to undergo acid-catalyzed allylic rearrangement with various nucleophiles to afford pseudoglycals or 2,3-unsaturated glycosides. Pseudoglycals are versatile chiral building blocks for the synthesis of glycoconjugates and polyether antibiotics.

XV Abstract

In continuation of our interest in the catalytic applications of molecular iodine for various organic transformations, we describe herein the use of molecular iodine as the catalyst for the activation of polymethylhydrosiloxane (PMHS) which is an inexpensive and soluble hydrogen source, for the reduction of glucal acetates via Ferrier rearrangement. Initially, we attempted the allylic transposition of 3,4,6-tri-O-acetyl-D- glucal 1 with PMHS 2 using 2.5 mol% of molecular iodine as the catalyst. The reaction went to completion within 3.0 h and the product 3a was obtained in 92% yield.

O O AcO I2 AcO + PMHS CH Cl , r.t. AcO 2 2 AcO OAc 1a 2 3a Encourage Scheme 1 d by this result we turned our attention to various other glycals. D-Glucal derivatives 3,4,6-tri-O-methyl, 3,4,6-tri-O-allyl and 3,4,6-tri-O-benzyl-D- glucals were all converted into their corresponding 3,6-dihydro-2H-2- pyrans using this procedure. Other glycals such as 3,4,6-tri-O-acetyl-D- galactal, 3,4-di-O-acetyl-L-rhamnal, 3,4-di-O-acetyl-D-xylal and 3,4-di- O-acetyl-D-arabinal also afforded the respective dihydropyran derivatives in high yields under similar conditions. Hexa-O-acetyl-D-lactal derived from the disaccharide, -D-lactose, gave the corresponding 3,6-dihydro- 2H-2-pyran derivative in 87% yield.

O O AcO AcO I O O 2 O O AcO + PMHS AcO OR CH2Cl2, r.t. AcO OAc AcO OAc OAc OAc 1i 2 3i Scheme 2 Similarly, hexa-O-acetyl-D-maltal derived from the disaccharide, -D-maltose, also reacted smoothly with PMHS to afford the corresponding pyran derivative in 85% yield

XVI Abstract

Section-B:

 1-Butyl-3-methylimidazolium Tetrafluoroborate ([Bmim]BF4) Ionic Liquid: A Novel and Recyclable Reaction Medium for the Synthesis of vic-Diamines Aziridines are important intermediates for the synthesis of many biologically active molecules such as aminoacids, heterocycles and alkaloids. Particularly, vic-diamines are biologically, medicinally and synthetically important class of compounds in the field of anti-HIV drugs such as Zanamivir and Oseltamivir phosphate and other pharmaceuticals. The simple and the most straight forward synthetic method for the preparation of vic-diamines is the ring opening of aziridines with amines. Ionic liquids have emerged as a set of green solvents with unique properties such as tunable polarity, high thermal stability and immiscibility with a number of organic solvents, negligible vapour pressure and recyclability. Their high polarity and the ability to solubilize both organic and inorganic compounds can result in enhanced rates of chemical processes and can provide higher selectivities compared to conventional solvents. Accordingly they are emerging as novel replacements for volatile organic solvents in organic synthesis. They are particularly promising as solvents for catalysis.

The treatment of the N-tosylaziridine from styrene with aniline in [bmim]BF4 ionic liquid at room temperature gave the corresponding 2-anilino-2-phenylethylamine derivative 5 in 91% yield. Similarly, p-methyl and p-chlorophenyl-N-tosylaziridines reacted smoothly with arylamines in [bmim]BF4 ionic liquid to afford the corresponding 1,2-diamines 5 in excellent yields. Aryl-N-tosylaziridines underwent cleavage in a regioselective manner with preferential attack at the benzylic position. Alkyl-N- tosylaziridines and cycloalkyl-N-tosylaziridines also underwent cleavage with aromatic amines to give the respective 1,2-diamines 6 in high yields. The cleavage of aziridines with sodium azide proceeded smoothly in ionic liquids to produce β-azidoamines with high regioselectivity.

+ + N N - N N - PF6 BF4

[Bmim]PF 6 [Bmim]BF4 Fig 1 NHTs NHAr [Bmim]BF N-Ts + Ar-NH 4 + 2 r.t. R R NHAr R NHTs XVII 4 5 6 Abstract

R = phenyl, n-hexyl; Ar = aryl, β-napthyl Scheme 3

NHTs [Bmim]BF N-Ts + Ar-NH 4 2 r.t. n n NHAr 4 n = 1,2 7 n = 1,2 Scheme 4

NHTs N3 [Bmim]BF4 N-Ts + NaN + 3 r.t. R R N3 R NHTs

R=phenyl, n-hexyl; 5q=R=phenyl 6r=R=n-hexyl Scheme 5 Section C:

XVIII Abstract

O 1 R =NH2 O

R" R NH2 MeO OMe R" O R' R1 1 1 N R' R =COR Bi(OTf)3 R =H N Catalyst H

1 R =NH2 R"

N R" N

XIX Abstract

 Bi(OTf)3-Catalysed Friedlander Hetero-Annulation: A Rapid Synthesis of 2,3,4-Trisubstituted Quinolines

Quinolines are found to posses a wide spectrum of biological activities such as antimalarial, antibacterial, antiasthamatic, antihypertensive and anti-inflammatory behaviour. Arylsubstituted quinolines are found to exhibit tyrokinase PDGF-RTK inhibiting properties. Various methods such as Skruap, Doebner von miller, Friedlander and combes methods have been developed for the preparation of quinoline derivatives. Friedlander reactions are generally carried out either by refluxing an aqueous or alcoholic solution of reactants in the presence of base or by heating a mixture of the reactants at high temperatures ranging from 150-220 oC in the absence of catalyst. Since quinoline derivatives are increasingly useful and important in drugs and pharmaceuticals, the development of simple, convenient and high yielding protocols is desirable. Recently, bismuth triflate has attracted the attention of synthetic organic chemists because it is inexpensive and it can be readily prepared on multi-gram scale in the laboratory from commercially available bismuth(III) oxide and triflic acid. However, there are no reports on the use of bismuthtriflate for Friedlander quinoline synthesis. In this article, we wish to report a mild and efficient version of the Friedlander annulation for the synthesis of polysubstituted quinolines using a catalytic amount of

Bi(OTf)3. Accordingly, treatment of 2-aminobenzophenone 8 with acetyl acetone 9 in

XX Abstract

the presence of 5 mol% of Bi(OTf)3 resulted in the formation of 3-acetyl-2-meth-yl-4- phenylquinoline 10a in 91% yield.

Ph Ph O O O O 5 mol% Bi(OTf)3 + Ethanol, r.t. NH2 N 8 9 10 Scheme 6 Similarly, various 1,3-diketones such as 1,3-cyclohexanedione and 5,5- dimethylcyclohexanedione and acyclic ketones also reacted efficiently with 2- aminobenzophenone to give the corresponding substituted quinolines. Interestingly, cyclic ketones also underwent smooth condensation with 2- aminoaryl ketones to afford the respective tricyclic quinolines.

R R O O  + 5 mol% Bi(OTf)3 Bi(OTf)

3- NH2 Ethanol, r.t. N

Scheme 7 Catalyzed Condensation of 2,2-DMP with Aromatic Amines: A Rapid Synthesis of 2,2,4-Trimethyl-1,2-Dihydroquinolines

1,2-Dihydroquinoline derivatives are known to exhibit a wide spectrum of biological activities such as antimalarial, antibacterial and anti-inflammatory behavior. In addition, substrates possessing dihydroquinoline motif have been used as lipid peroxidation inhibitors, HMG-CoA reductase inhibitors, ileal bile acid transporter inhibitors and progesterone agonists and antagonists Generally, 1,2-dihydroquinolines are prepared by the condensation of aromatic amines with ketones using a catalytic

amount of H2SO4 via Skraup’s procedure. However, it requires high temperatures, ranging from 145 to 150 oC, under high pressure and long reaction times (2–3 days). Lanthanidetriflates are unique Lewis acids that are currently great interest. In this direction, bismuth triflate has evolved as remarkable Lewis acid catalyst for effecting various organic transformations. Compared to lanthanide triflates, bismuth triflate is

XXI Abstract cheap and is easy to prepare even on a multi-gram scale, from commercially available bismuth oxide and triflic acid. However, there have been no reports on the use of bismuth triflate for Skraup synthesis. In this article, we wish to report a novel and improved version of Skraup’s procedure for the synthesis of 1,2-dihydroquinolines using a catalytic amount of

Bi(OTf)3. Accordingly, treatment of aniline 1 with 2,2-dimethoxypropane 2 in the presence of 5 mol% of Bi(OTf)3 in solvent-free conditions resulted in the formation of 2,2,4-trimethyl-1,2-dihydroquinoline 3a in 90% yield.

MeO OMe 5 mol% Bi(OTf) + 3 NH r.t. N 2 H 11 12 13a Scheme 8 Similarly, various aromatic amines such as mono-, di- and tri-substituted anilines reacted efficiently with 2,2-DMP to give the corresponding 2,2,4-substituted dihydroquinolines. This method is equally effective for both electron-rich as well as electron-deficient aryl amines. Treatment of o-phenylenediamine with 2,2 dimethoxypropane afforded the corresponding 2,2,4-trimethyl-2,3-dihydro-1H-benzo[b] [1,4] diazepine 13I in 92% yield.

NH N 2 MeO OMe 5 mol% Bi(OTf) + 3

NH2 r.t. N H 11 12 13(l-o) Various Scheme 9 substituted o-phenylenediamines such as 5-methyl, 5-nitro, and 4,5-dimethyl derivatives underwent smooth condensation with 2,2-dimethoxypropane to afford the respective 2,3-dihydro-1H-benzo[b][1,4]diazepines in high yields

 Bi(OTf)3 as a Versatile Catalyst for the Rapid Synthesis of 2,3-Disubstituted Quinoxalines in Water

XXII Abstract

The Quinoxaline derivatives represent an important class of nitrogen containing heterocycles as they constitute useful intermediates in organic synthesis. They are well- known in the pharmaceutical industry and have been shown to possess a wide spectrum of biological activities such as antiviral, antibacterial, anti-inflammatory and as kinase inhibitors. The classical method for the preparation of quinoxalines involves the condensation of aryl 1,2-diamines with 1,2-dicarbonyl compounds in refluxing ethanol or acetic acid over a period of 2-12h. Recently, a great attention has been focused on the use of water as green solvent in various organic transformations. In addition to its abundance and for economical and safety reasons, water has naturally become as a substitute and an alternative environmentally benign solvent in organic synthesis. Bismuth triflate has evolved as remarkable Lewis acid catalyst for effecting various organic transformations. In this article, we wish to report a novel procedure for the synthesis of quinoxalines from aryl 1,2-dicarbonyls and 1,2-diamines using 10 mol% of Bi(OTf)3 in water. Accordingly, treatment of benzil 14 with o-phenylenediamine 15 in the presence of 10 mol% of Bi(OTf)3 in water resulted in the formation of 2,3-diphenyl quinoxaline 16a in 97% yield.

O H N N 2 10 mol% Bi(OTf) + 3 H2O, r.t O H2N N

14 15 16a Scheme 10 Similarly, various aryl 1,2-daimines such as mono- and di-substituted amines reacted efficiently with 1,2-dicarbonyl compounds to give the corresponding 2,3-disubstituted quinoxalines. Heteroaryl pyrazines are also referred to as heterocyclic quinoxalines; represent a related class of nitrogen containing heterocycles that attracted our attention. Interestingly, 2,3-diaminopyridine underwent smooth coupling with benzil to afford the corresponding pyrido[2,3-b]pyrazine 16d in 90% yield .

XXIII Abstract

O H N N 2 10 mol% Bi(OTf) + 3 H O, r.t O 2 N H2N N N 14 15 16d  Scheme 11 Bi(OTf)3 as Efficient, Cost-effective and Water Tolerant Catalyst for the Synthesis of 2-Aryl-1-Arylmethyl-1H-Benzimidazoles in Water Benzimidazoles are important biologically active heterocycles possessing selective neuropeptide YY1 receptor antagonists and as 5-lipoxygenase inhibitors for use as novel antiallergic agents, 5-HT3 antagonists in isolated guinea pig ileum, poly(ADP-ribose) polymerase (PARP) inhibitors and factor Xa (Fxa) inhibitors. In addition, they exhibit significant activity against several viruses such as HIV, herpes (HSV-1), RNA influenza and human cytomegalovirus (HCMV). Recently, a great attention has been focused on the use of water as green solvent in various organic transformations. Bismuth triflate has evolved as remarkable Lewis acid catalyst for effecting various organic transformations. However, there have been no reports on the use of bismuth triflate for the synthesis of benzimidazoles.

In continuation of our interest on the catalytic application of Bi(OTf)3, we report herein a mild and rapid synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using a catalytic amount of Bi(OTf)3 in water. Accordingly, treatment of o-phenylenediamine

17 with benzaldehyde 18 in the presence of 10 mol% of Bi(OTf)3 in water resulted in the formation of benzimidazole 19 in 97% yield.

R NH CHO R R" 2 10 mol% Bi(OTf) N + 3 R' NH H2O, r.t. R' N 2 R"

17 18 19 R" R,R'=H ;R=CH3,R'=H; R=CH3,R'=CH3;

R=COC6H5,R'=H Scheme 12 Encouraged by the results obtained with o-phenylenediamine and benzaldehyde, we turned our attention towards various substituted aryl 1,2-diamines and aryl aldehydes.

XXIV Abstract

Interestingly, various mono- and di-substituted aryl 1,2-diamines reacted efficiently with aldehydes to give the corresponding benzimidazoles. The present protocol is equally effective for aromatic aldehydes bearing either electron donating or electron- withdrawing substituents on aromatic ring. Similarly, α-naphthaldehyde and heteroaromatic aldehydes also reacted well with o-phenylenediamine to furnish the corresponding benzimidazoles in good yields.