Chapter 1

MULTI-COMPONENT REACTIONS FOR THE SYNTHESIS OF. DIVERSE HETEROCYCLIC SCAFFOLDS

Chapter 1 Multi-Com

1.1. Introduction

2009

Multi-component reactions (MCRs) are convergent reactions, in which three or more starting

materials react to form a product, where basically all or most of the atoms contribute to the newly

formed product (Figure 1). 1 In an MCR, a product is assembled according to a cascade of

elementary chemical reactions. Thus, there is a network of reaction equilibria, which all finally

flow into an irreversible step yielding the product. The challenge is to conduct an MCR in such a

way that the network of pre-equilibrated reactions channel into the main product and do not yield

side products. The result is clearly dependent on the reaction conditions: solvent, temperature,

catalyst, concentration, the kind of starting materials and functional groups. Such considerations

are of particular importance in connection with the design and discovery of novel MCRs?

A Product A + B - Product Product

1CR 2CR MCR

Figure 1. A divergent ]-component reaction and convergent 2- and multi-component reactions

In the drug discovery process, MCR offers many advantages over traditional approaches. With

only a limited number of chemists and technicians, more scaffold synthesis programs can be

achieved within a shorter time. With one-pot reactions, each synthesis procedure (weighing of

reagents, addition of reagents, reaction/time control) and work-up procedure (quenching,

extraction, distillation, chromatography, weighing, and analysis) needs to be performed only

once, in contrast to multi-step synthesis. MCRs are compatible with a solution phase approach,

thus enabling a simple monitoring, and they are easily amenable to automation. Moreover, each

scaffold is expandable from a low number of compounds (scouting library) to a larger library.

Thus, "hit-to-lead" transitions are normally accomplished easily and promptly. Certain

physicochemical properties can be built into a library, e.g. lipophilicity and aqueous solubility,

molecular weight, numbers ofhydrogen donors and acceptors, and the number of rotatable bonds,

as well as the polar surface area. Finally, scale-up is often possible from a preclinical lab-scale

(mg, gram) to clinical exploratory amounts (kg) using the same type of chemistry? Drug

molecules derived from MCR are very cost effective which, is the need of the hour.

The usefulness of a reaction is correlated to several factors: the number of bonds which are

formed in one sequence, which Tietze6 has referred to as the bond-forming efficiency (BFE, or

bond-forming economy); moreover, to the increase in structural complexity (structure economy);

and finally, to its suitability for general application. Multi-component reactions have attracted

2

Chapter 1 Multi-Com

2009

considerable interest owing to their exceptional synthetic efficiency. The BFE is an important

measure to determine the quality of a multi-component reaction (Figure 2).

I

dN~ +

NC

N

MeOH, 20°C

Figure 2. Two example of isocynide based MCRs with high bond forming efficacy (BFE). The 3-

CR of shown above of a fJ-aminothiocarboxylic acid, an aldehyde and a 2,2-dimethylamino-1-

isocyano alkene affords a complex molecule under mild conditions, with two heterocycles in the

product that are not present in the starting materials: a fJ-lactam and a thiazole. During this one­

pot transformation 1 C-C, 2 C-S and 2 N-C bonds are formed. 4 Below: In the second isocynide

based MCR, the isocyanoacetamide reacts four times in a highly ordered manner creating three

heterocyclic rings with the concomitant formation. of five chemical bonds (3 C-C bonds, 2 C-N

bonds) and a minima/loss of molecular weight. 5

Unlike the usual stepwise formation of individual bonds in the target molecule, the defining

attribute of MCRs is the inherent formation of several bonds in one operation without isolating

the intermediates, changing the reaction conditions, or adding further reagents. It is obvious that

adopting such strategies would allow the minimization of both waste production and the

expenditure of human labor. The products are formed simply by mixing the corresponding set of

starting materials. Since the structures of the products carry portions of all the reactants

employed, MCRs that have a high attendant BFE assure a marked increase in molecular

complexity and diversity. A wide variation among these starting materials opens up versatile

opportunities for the synthesis of compound libraries. The generalization to as many available

starting materials as possible is an indispensable characteristic for the most general application.

Multi-component reactions thus address the requirements for efficient high-throughput synthesis

of compounds in a cost- and time-effective manner. Reactions that build up carbon-carbon,

carbon-nitrogen and other carbon-heteroatom bonds and at the same time introduce heteroatom-

3

Chapter 1 Multi-Com

2009

containing functionality into the structural framework are especially attractive for the rapid

construction of organic molecules.

Briefly speaking the application of MCRs m organic synthesis IS tremendously increasing

because-

1. They offer a wealth of products, while requiring only a minimum of effort.

2. As opposed to the classical way to synthesize complex molecules by sequential synthesis,

MCRs allow the assembly of complex molecules in one pot.

3. The structure of the reaction product is easily diversified by systematic variation of each

input.

4. The starting materials are either commercially available or easily prepared.

5. The number of theoretically accessible compounds is extremely large.

By nature, MCRs are by no means restricted to a particular application, but rather they can be

used advantageously in any area of modern chemistry-based technology. Recent applications of

MCRs unrelated to drugs include EPR-spin labeling, biocompatible materials, e.g. for artificial

eye lenses, polymers with novel properties, chiral phases for HPLC, natural product synthesis,

peptide-nucleic acids and agrochemicals. However in present review, we are focusing its

application in heterocyclic synthesis which is also very important because majority of drugs and

pharmaceutically important compounds belongs to heterocycles.

The application of MCRs in the synthesis of heterocycles is known since prebiotic era. Nature,

utilizes this for the synthesis of many important biomolecules such as adenine, one of the major

constituents of DNA and RNA, was prebiotically formed by the condensation of five molecules

of HCN, a plentiful component of pre biotic atmosphere, in a multi-component reaction catalyzed

by NH3

(Scheme 1).7 In a similar way other nucleic bases have been generated via multi-

component reactions involving HCN and H20.

5HCN

Scheme 1. Prebiotic synthesis of adenine

A growing number of products, including many heterocycles, can be prepared by MCRs just by

mixing three or more educts, and in many cases practically quantitative yields of pure products

can be obtained. A three-component reaction (a-aminoalkylations of nucleophiles) began in the

middle of the 19th century8 and Hantzsch introduced the syntheses of heterocycles (1,4-

4

Chapter 1 Multi-Com

2009

dihydropyridincs and pyrroles) by MCRs in the 1880s.9 Another significant contribution made by

Biginelli (1891) who synthesized 3,4-dihydropyrimidinones via a three-component coupling of an

aldehyde, urea and ~-keto esters. 10 Robinson ( 1917) was first to synthesize the naturally occurring

alkalo id tropinone (an N-hcterocycle) using Mannich reaction. 11

The MCRs of the isocyanides (Ugi and Passcrini reaction and related MCRs) arc also very

important in the synthesis of diverse heterocyclic scaffolds. Many natural products have been

synthesized by MCRs. Today a large number of MCRs are known and many of them have been

successfully applied to the synthesis of heterocycles (Figure 3 ).

1 . ~0xaztnes 1.~ Thlazules

R, ciR, R,DR,

I I R, ~ ~

I R 0 R1

1,4-0.hydropyrdtne Benzopyrans

R~JSXR' R~JOXR' R N R, R N R, R' R'

Thannes Oxa 21nes

R>y,o )- }- R

R, 0 Pyrazohdones

O.OXOianes

OH 0 OH

Dynemycm

~ HOJ__;N_.I

HO 'o Swainson•ne

R

::. ~( f R,

H R2

Oxazlplnes

'- I 0 0

R

<>R, H R,

lr.atep.ne

WO <;IH OH

OCONH 2 < OH H OH

o I ""' 0"0 "~~ OH Pancrallstahn

FR66979

Figure 3. Examples of heterocyclic scaffolds targeted using MCRs

5

Chapter 1 Multi-Com

2009

Although MCRs are important tools to synthesize almost all class of heterocyclic compounds,

there is no comprehensive review on MCR derived heterocycles. Most important reviews on

MCRs are isocyanide based MCRs, 12 MCR derived synthesis of natural products 13 and synthesis

of heterocycles by transition metal mediated MCRs. 14 We are presenting here the MCR derived

synthesis of heterocyclic scaffolds of all classes. The classification has been made according to

the size of heterocyclic ring (3 membered, 4 membered, 5 membered, 6 membered and large

heterocycles). Further classification has been made according to the number and type of

heteroatom in the ring.

1.2. Three membered heterocyclic compounds

1.2.1. Aziridines

The smallest possible saturated azaheterocycle, aziridine, is well-known to organic chemists for

its tremendous potential in organic synthesis and medicinal chemistry.15 Although aziridines are

highly reactive, this skeleton occurs in several natural products and many synthetic compounds of

biological interest also contain the aziridine framework in their structures (Figure 4).

\7

M~~ 0, yf55CONH, N 'P(ORh

H2N e N~N I I ~R1 '

Y-A VN OMe N

NH I

VN N N\7 0 . COOR2 0

Anticancer and antibiotic Anticancer Ant~eukemic Antibiotic

Figure 4. Aziridine containing bioactive compounds

Aziridines are the precursors for the synthesis of various types of nitrogen-containing

compounds, which are biologically important, such as P.lactams, azinomycins,

tetrahydropyridines, indolizidine and pyrrolizidine alkaloids, allylic amines, and amino acids

amino alcohols etc.16 •

A literature survey reveals an extensive investigation of the synthesis and chemistry of aziridines

since the first synthesis by Gabriel in 1888.17 Although numerous methods have been reported for

the synthesis of substituted aziridines, 18 carbene transfer to the imine double bond (C=N) is one

of the most efficient method.19 However, when imines derived from aliphatic aldehydes were

used, the carbene transfer was unsatisfactory and aziridines were obtained in low yields. Another

drawback was the considerable amount of the side products obtained during the course of

reaction. In order to rule out these difficulties in aziridine synthesis many transition metals

catalyzed MCRs were developed.

6

Chapter 1 Multi-Com

2009

Ishii et af0 reported a three-component coupling reactions of aliphatic aldehydes, aliphatic

amines and ethyl diazoacetate leading to the corresponding aziridine derivatives by the use of

[Ir( cod)Cl]z as a catalyst under mild conditions (Scheme 2). The procedure is equally applicable

to both the aromatic as well as aliphatic aldehyde. Aziridine derivatives are prepared in high

stereoselectivity (cis:trans >95:5). Instead ofTHF, ethanol was also found suitable solvent for the

reaction. It is also noteworthy that the yields are little affected when reactions are carried out in

the presence of water.

Cat [lr(cod)Cih

... THF, -1o0c, 3h

Scheme2.

The one pot coupling of aldehyde, amine and ethyl diazoacetate were further investigated and

improved by Yadav et al.21 They found Bi(OTt)r[Bmim]PF6 as a reusable catalyst system for the

preparation of cis aziridines. LiCl04 was also found equally effective for cis aziridation of imines.

With LiCl04 stereoselectivity (cis/trans) was found 82 to 100%. No side products such as

enamines or diethyl maleate were obtained.

Budynina et al22 reported a three-component, one-pot reactions of tetranitro- and

bromotrinitromethanes, alkoxyacetylenes and diazomethane or bicyclobutylidene, yielding gem­

dinitroaziridines via sequential electrophile transfer followed by [3+2]-cycloaddition. Electron

rich alkynes, such as ethoxyacetylene and l-ethoxy-1-butyne, reacted as dipolarophiles with

dinitronitronates to provide unstable 3,3-dinitro- 2,3-dihydroisoxazoles, which then underwent a

spontaneous rearrangement (a 1,3-sigmatropic rearrangement) to afford gem-dinitroaziridines

(Scheme 3). The reaction generally occurs with high regioselectivity and gem-dinitroaziridines

are exclusively obtained.

Scheme3.

7

Chapter 1 Multi-Com

1.3. Four membered heterocycles

1.3.1. J3-Lactams

2009

The most important heterocycles with four-membered rings are the antibiotics (penicillins and

cephalosporins series), both of which contain the azetidinone ring (Figure 5).23 The chemistry of

azetidinones, or P-lactams, as they are also called, was explored thoroughly during the intensive

research into penicillin structure and synthesis that took place during World War II. However, a

practical synthesis of penicillin was not achieved, untill959.

H H2N~N S

COOH 0 OJ=r~oy zY>=r-r COOH

COOH 0

Cephalosporin Benzylpenicillin

Figure 5.

The development of efficient routes to synthesize [3-lactams is an area of significant research

interest.24 This has been driven, largely due the importance of these molecules as constituents of

antibiotics, ranging from penicillin-based substrates to a number of more recently developed

compounds (e.g., penems, cephems, monobactams, carbapenems, and trinems).25 [3-Lactams have

also been demonstrated to be important synthons in organic synthesis26 and to be monomers in the

generation of polyamides (e.g., poly(p.peptides)).27 The classical and improved methods for 13-

lactam synthesis were recently reviewed?8

1.3.1.1. 13-Lactams via 1, 3-dipolar cycloaddition

The reaction of aldehydes with alkyl/aryl-hydroxylamine hydrochlorides generates nitrones

which undergo 1 ,3-dipolar cycloaddition with olefms to yield isoxazolidines. When the olefin

contains a cyclopropane ring at least on its one terminal, the resulting isoxazolidines undergoes

ethylene elimination with simultaneous formation of 13-lactams.

Based on this unprecedented fragmentation of 5-spirocyclopropanated isoxazolidines to P­lactams, Zanobini et al have developed a one-pot three-component reaction for the direct

conversion of certain alkyl/aryl-hydroxylamine hydrochlorides, aldehyde and bicyclopropylidene

to furnish 3-spirocyclopropanated 2-azetidinones (Scheme 4).29 The reaction has been carried out

in intramolecular way to yield many biologically important 13-lactam compounds.30

8

Chapter 1 Multi-Com

R1 = alkyl or aryl

Scheme4.

+

R2 = H, COOR

-

NaOAc, EtOH

80-100°C(MW)

(49-78%)

2009

Li and Zhao31 reported a three-component reaction of N-substituted hydroxylamines, aldehydes,

and phenylacetylene catalyzed by CuCV2,2'-bipyridine in the presence of NaOAc under neat

conditions affording to the corresponding 13-lactams in good to excellent yields (Scheme 5).

~ RCHO + MeNHOH.HCI + v SchemeS.

5 mol% CuCI, 5 mol% 2,2'-bipyridine

30 mol% NaOAc, 1 eq. KHC03

70°C, neat

PhJ )-~,

R Me

N-benzylhydroxylamine is also very effective for this three-component 13-lactam formation. Since

the benzyl group on the 13-lactam nitrogen atom can be removed readily by standard

hydrogenolysis, the three-component reaction provides a very effective method for the synthesis

of 13 -lactams that do not have any substituent on the nitrogen atom.

1.3.1.2. 13-Lactams via transition metal mediated CO insertion

Transition-metal catalysis serves as a useful tool, where the diverse reactivity of metal complexes

can be used to mediate the coupling of traditionally unreactive precursors. This approach not only

can provide a straightforward overall synthesis but also is amenable to structural diversification.

Dhawan et ae2 reported the application of this approach to the construction of the amino acid­

based 13 -lactam core, the functional structure of many biologically relevant 13-lactams. This was

done by considering the structure to be comprised of four units, two imines, acid chloride, and

carbon monoxide (scheme 6), brought together in a palladium-catalyzed reaction. Considering the

nature of the building blocks, this provides a modular method to construct a 13-lactam, where five

separate substituents can be independently varied in a single-pot reaction.

9

Chapter 1 Multi-Com

Scheme 6. Transition metal mediated multi-component approach to fJ-lactams.

2009

This multi-component process is directly amenable to structural diversification. The formation () -

lactams proceeds smoothly with a number of imines and acid chlorides, all generating product in

good yields and as a trans isomer. Both aryl and alkyl acid chlorides can be employed. However,

the yields of P-lactams are lower with electron-withdrawing substituents on the imines.

Palladium-catalyzed carbonylation of the allyl phosphate in the presence of imines, under CO

pressure is highly stereoselective reaction since the formation of the trans- or the cis- /i'-lactam

depends on the imine used for the coupling. An imine conjugated with a carbonyl group gives the

cis-~-lactam, whereas the unconjugated imine gives the trans isomer (Scheme 7). But when allyl

bromide,33 allylacetate,34 allyl phenyl ether,35 allyl carbonate36 or allylsulfone37 were used under

similar reaction conditions no reaction products, or just traces of P-lactams, were formed.

H H Ph ~~:~ .. ~

J--N, o 0 R

Scheme 7.

Troisi et al 38 found that simple allyl halides of different structures, under CO pressure, in the

presence of Et3N, a catalytic amount of Pd(OAch, and triphenylphosphane as ligand, undergo a

[2+2] cycloaddition reaction with various imines. The reaction is highly regio and stereoselective.

~-Lactams are formed in good yields and with trans diastereoselectivity (Scheme 8).

CO (400 psi).100 °C +

SchemeS.

10

Chapter 1 Multi-Com

1.3.1.3. P-Lactams via Ugi reaction

2009

Aliphatic ~-amino acids have been tremendously used in the U gi reaction, resulting in a

monocyclic B-lactam library. Gedey et al reported a parallel liquid-phase synthesis of ~-lactams,

utilizing cyclic B-amino acids in an Ugi four-center three-component reaction (U-4C-3CR).39

Recently,~ -lactam libraries were synthesized using the Ugi four-centre three-component reaction

(U-4C-3CR), in aqueous medium.40 The ~-lactam libraries are generated using aliphatic or

aromatic aldehydes, cyclic ~-amino acids and cyclohexyl or tert-butyl isocyanide (Scheme 9).

The concentration is a determining factor in this reaction. Precipitation occurs when less water­

soluble ~-amino acids and an appropriate amount of water were used. In this way, the reactions

are complete in 1 day at room temperature, as compared with a 3 days reaction in methanol. It

should be noted that the relatively poor solubility of the different aldehydes in aqueous medium

reduce their applicabilio/. The diastereomeric ratio of the product ranged from 60: 40 to 100: 0.

When the B -amino acid component contained a norbornane or norbornene skeleton, the

quantitatively diastereoselective reactions were observed. Comparison of the diastereomeric

ratios obtained in the aqueous phase or in an organic solvent did not reveal appreciable

differences. However, the yields were slightly better in water than in organic media.

--(OOH : + ,_

NH2

Scheme 9.

Alicyclic P-lactams have been synthesized via the Ugi reaction on a solid support.41 Via the Ugi

4-centre 3-component reaction (U-4C-3CR), bicyclic cis-2-azetidinone derivatives were

synthetised from cyclic P-amino acids on Super Acid Sensitive Resin (Sasrin). 2, 3 or 4-

Formylbenzoic acid was immobilised on the resin through its carboxy function. The U-4C-3CR

was also carried out in solution, making use of scavenger resins for purification.

Five sets of 27 -membered combinatorial libraries of alicyclic p -lactams were prepared via liquid­

phase Ugi 4-center 3-component reactions (U-4C-3CR) utilizing 3 different cis P-amino acids, 3

different isonitriles and 5x3 sets of aldehydes.42 Through combinations of the building blocks of

one ofthese libraries, all of the possible sublibraries were also generated.

A multi-component reaction of P-aminothiocarboxylic acids, aldehydes, and 3-dimethylamino-2-

isocyanoacylate is described by Domling et al.43 During the course of this reaction two

heterocyclic moieties, a thiazole and a P-lactam ring, are formed simultaneously and under mild

11

Chapter 1 Multi-Com

2009

conditions (Scheme 10). The increase in molecular complexity here is dramatic as 2 C-N, 2 C-S

and 1 C-C bonds are formed in a one-pot, multi-component reaction.

I

+ OHC~ + iN~ MeOOC NC

y\0 i- ~ 11 MeOOC NC~~o __ _

JJ_ 1 ~JrcOOM• N SH ~N

~I I

SchemelO.

1.3.2. Aza-J3-Lactams

Fr N"' S )=l

MeOOC

1-Me,NH

__(7=-o N

Yr)-{ COOMe

Naskar et al44 reported the synthesis of aza-13-lactams via tandem Petasis-Ugi multi-component

condensation and 1,3-diisopropylcarbodiimide (DIC) condensation reaction. Compound 1 were

generated via a Petasis three-component condensation reaction followed by Boc deprotection

(Scheme 11 ). Upon evaporation of the crude reaction mixture, the resulting hydrazine salts were

treated directly with one equivalent each of aldehyde and an isocyanide in aqueous methanol.

Stirring for 24 h at room temperature, provided 2 in 23-79% yields after purification. The reaction

does not proceed well without water.

(1) Petasis ~1 ~ H2N~"OH

(2) de Boc 1 R2

)-N=C=N--< ~

Scheme 11.

12

Chapter 1 Multi-Com

1.4. Five membered heterocycles

2009

Five membered heterocyclic compounds are very rich in nature. Five member heterocyclic rings

generally contain IN, 2N, 3N, IO, 20, IS, IN+ IO, IN+ IS, IN+ 20, etc as heteroatoms.

1.4.1. Five membered heterocycles containing one heteroatom

1.4.1.1. Pyrrolidine derivatives

1.4.1.1.1 Pyrrolidines via 1, 3-Dipolar cycloaddition

Pyrrolidine derivatives are generally synthesized by I ,3-dipolar cycloaddition of azomethine

ylides with alkenes. Azomethine ylides are planar molecules composed of one nitrogen atom and

two terminal sp2 carbons, and have four rr electrons spread over the three-atom C-N-C unit

(Figure 6). The I, 3--dipolar cycloaddition of azomethine ylides with alkene or alkyne is a very

effective method for the construction of pyrrolidine- and pyrrole-rings in the synthesis of

pyrrolidine and pyrrole-containing molecules. These molecules are very important

pharmaceuticals, natural alkaloids, organic catalysts, and building blocks in organic synthesis.45

As with other cycloaddition reactions, it is generally accepted that the I ,3-dipolar cycloaddition

of azomethine ylides follows a concerted pathway and proceeds according to the Woodward­

Hoffman rules. However, a stepwise pathway can not be ruled out.46

Base

Azomethine Ylide

Figure 6.

Reaction of secondary amines like 2-picolylamine and aldehydes yields imines which readily

tautomerized to azomethine ylides (Figure 7). The azomethine ylide has been made to undergo a

[3+2] cycloaddition reaction with a number of dipolarophiles.47 The azomethine ylides has also

been trapped in [60] fullerene48 and [70] fullerene.49

N H U .R

Figure 7.

The reaction of a-amino acid esters (acyclic or cyclic) with aldehydes or activated ketones

generates azomethine ylids. The reaction has been applied for the synthesis of polysubstituted

13

Chapter 1 Multi-Com onent Reactions

2009

pyrrolidines50 spirooxindolo pyrrolidines, spirooxindolo thiapyrrolizidines51 and prolines

(Scheme 12).52 The cycloaddition are generally highly regioselective.

Ph H ·--cNl + n + ~1R1 0 0 Moe

Scheme 12.

MgBr2.0EI2

(10 mol%)

THF, Reflux

X ;=/

----The azomethine ylides are generated from the reaction of a-amino acids and aldehydes or

activated ketones. The azomethine ylide has been coupled with a number of conjugated olefins to

yield pyrrolidines (Scheme 13).53 The azomethine ylide generated by the reaction of amino acids

and aldehydes has also been trapped in fullerenes. 54

H c&r Toluene _,....N'-./COOH + HCHO + --:....:::..:.==:.:::...---..

Reflux 0

r-\ MeCN (,__ /-coOH + Ph·--::;:::::::::=::-R -----

N Reflux H

Schemel3.

~ Vo)\__tf,

R

The reaction of a-diazo esters with imines generates transient azomethine ylids. The ylide thus

generated is then reacted with various dienophiles to generate pyrrolidine derivatives in a highly

convergent manner. 55 The reaction is catalyzed by transition metal salts (Scheme 14).

14

Chapter 1 Multi-Com

Scheme 14.

2009

2,5-trans

Galliford et al reported a catalytic, multi-component approach employing dipolarophile derived

from isatin.56 They synthesized Spiropyrrolidinyloxindole compounds in moderate to excellent

yield via a highly diastereoselective Cu(l)-catalysed three-component assembly reaction of an

imine, diazo-compound and substituted olefin dipolarophile (Scheme 15).

Cu(l)

Scheme 15.

Xu et al have synthesized chiral multi-functionalized pyrrolines by a ruthenium porphyrin

catalyzed three-component coupling reaction (Scheme 16).57 In a one-pot reaction, ruthenium

porphyrins catalyzed in situ generation of chiral azomethine ylides from chiral diazo esters and

imines. Asymmetric 1 ,3-dipolar cycloaddition reactions of the chiral azomethine ylides with

dipolarophiles afforded the corresponding pyrrolines in good yields and high diastereoselectivity

(up to 92% de).

Toluene 60°C

~' Ar ~ o·52' .--

Ar1

Ph

[Ru(2, 6-CI2TPP)CO]

Scheme16.

1.4.1.1.2. Pyrrolidines via ring opening of cyclopropanones

Pyrrolidines are synthesized via the reaction of the aldimines, generated in situ by the reaction of

primary amines or anilines and aldehydes, with various 1, 1-cyclopropanediesters in the presence

of Lewis acids like Yb(OTt)3,58 Mgi/9 or Et2All (Scheme 17).60

15

Chapter I Multi-Com

R'~ + R'cHO +

Scheme17.

R3 b<COOMe

COOMe

Yb(OTf)J ( 1 Omol%)

1.4.1.1.3. Pyrrolidines via isocyanide based MCRs

R

2009

KD 1 '

R2 N I 3 R

trans cis

Isocyanides base multi-component reactions are very important in the synthesis of heterocycles.

Ugi reaction is a well known isocyanide based reaction. It has been successfully applied in the

synthesis of pyrrolidines. A three-component coupling reaction of arynes, isocyanides and N­

tosylaldimines has been developed to offer modest to high yields of diverse 2-iminoisoindolines

in one step (Scheme 18). Intermediacy of arynes in the coupling has been verified by the reaction

of unsymmetrical arynes. 61

CCTMS

~ + OTf

RNC

Scheme 18.

KF, 18-crown-6 +

THF, rt

~R ~NTs

Ar

Nair et al reported an efficient multi-component reaction of N-tosylimines, DMAD, and

isocyanides for the synthesis of2-aminopyrrole systems (Scheme 19).62

co rM· MeOOC

()NC Benzene, I ~ I + + .. h rt, 18h 0 COO Me 95%

Scheme19.

Zhu et al reported a sequencia! two-step reaction involving an Ugi four-component reaction (Ugi-

4CR) and a palladium-catalyzed intramolecular amidation of aryl iodide for rapid access to

functionalized oxindole.63 Microwave heating was used to accelerate and to improve the

efficiency of the intramolecular Buchwald-Hartwig reaction (Scheme 20).

16

Chapter 1 2009 Multi-Com onent Reactions

(a) MeOH, rt R3

(b) Pd(dba)z (5 mol%) 0~ N-R1

R1NH2 aCHO R2- ligand, K2C03 (2 eqiv) w~o _,::;.

+ I f..l.W, 100°C

R3COOH R4NC R4 PhMe/MeCN = 3/1

Scheme 20.

The zwitter ion generated from the reaction of dimethyl acetylenedicarboxylate and isocyanides

reacts with various quinoneimides to afford the corresponding spiroiminolactams in good yields

(Scheme 21).64

NS02Ph N~ COOMe

Ph02SN~COOMe ¢· COO Me

111 +

(YNC _______ _. ~ Benzene, 80 °c

4h, 64%

NCOPh COO Me v

Scheme21. NCOPh Yamamoto et a! reported a palladium-catalyzed three-component coupling reaction of aryl

isocyanides, allyl methyl carbonate, and trimethylsilyl azide in the presence of Pd2(dba)J.CHCh

(2.5 mol %) and dppe (1,2-bis(diphenylphosphino)ethane) (10 mol %).65 This palladium­

catalyzed reaction has been utilized for the synthesis ofN-cyanoindoles (Scheme 22).

R>(~~~y~R1 U .. _t- ~OCOOMe + TMSN~ NC

Scheme22.

1.4.1.1.4. Pyrrolidines via miscelleneous MCRs

2.5 mol% Pd(dba)J.CHCI3

10 mol% (2-furylhP

Octane, 100°C

An efficient one-pot synthesis of the pyrrolidines based on a multi-component domino reaction

between imines and 3-nitro-1-propanol methanesulfonate has been developed (Scheme 23).66

RCHO +

Scheme23.

MgS04 R'NH2 ------ RCH=NR'

02N~OMs

DABCO (Cat)

or Basic AI203

o2ND ,. N

R ' R'

17

Chapter 1 Multi-Com

2009

Palacios et al have reported a simple and efficient synthesis of3-amino-1,5-dihydro- 2H-pyrrol-2-

(JfiE~.~7 Th"'"" cyclic dehyoro·amiPo acid derivatives with a stereogenic center at the 5-position

WwTI,O oBtuim:d ~y uw ttll:E{iRfl of twg l!qutvnlont!.' of <~mine to f>,y-un:satur!lted keto esters. These

cyclic enamines were obtained by the thn;c-aamponsfif featnitm <>f mh:vl oyruvmc. nmi="'" Mtd

aldehydes (Scheme 24).

COOEt

oA +

y

EtOOC>=

R2HN

Scheme24.

e H

+

Azoulay et al reported a three-component synthesis of stereo-defined 4-benzylidene-( or

alkenylidene)-pyrrolidines from simple, readily available starting materials (Scheme 25).68 This

one-pot process is initiated by a conjugate addition of a propargylamine to a gem-diactivated

olefin subsequently followed by a carbopalladation involving an aryl halide (or vinyl triflate).

Y= 0, NR Scheme25.

EWG'T(EWG

~ + R3 Pd

()_ - X

Base

X= I, Br, OTt

Cadiemo et al reported an efficient a one-pot multi-component reaction for the preparation of

fully substituted pyrroles, from readily accessible secondary propargylic alcohols, 1 ,3-dicarbonyl

compounds and primary amines (Scheme 26).69 The reaction is catalyzed by the system [Ru(Tt3-2-

C3H,Me)(CO) (dppf)] [SbF6]/CF3C02H (dppf: 1,1 '-bis(diphenylphosphanyl)ferrocene). The

reaction involves initial propargylation of the 1,3-dicarbonyl compound promoted by CF3C02H

and subsequent condensation between the resulting y-keto alkyne and the primary amine to afford

a propargylated 13-enamino ester or ketone, which undergoes a ruthenium- catalyzed 5-exo-dig

annulation to form the final pyrrole.

18

Chapter 1 Multi-Com

CF3COOH (50 mol%)

Catalyst ( 5 mol%) ..

THF

2009

Catalyst= dppf: 1 ,1 '-bis(diphenylphosphanyl)ferrocene ). Scheme26.

Alizadeh et al have developed an effective route to maleimides, which involves the reaction of an

enamine derived from the addition of a secondary amine to a dialkyl acetylenedicarboxylate with

an arylsulfonyl isocyanate (Scheme 27).70

Dry ether

rt

Scheme27.

The four-component reaction of ethyl 4-chloroacetoacetate with aromatic aldehydes and

ammonium acetate in a 1:2:1 molar ratio provided a simple and rapid access to highly

functionalised pyrrolidines, ethyl 1-acety 1-4-hydroxy-5-[hydroxy( ary !)methyl]-2-aryl-2,3-

dihydro-lH-pyrrole-3-carboxylates stereoselectively (Scheme 28).71

0 0 CIJJ_ + 2 ArCHO + NH40Ac

OEt

Scheme28.

1.4.1.2. Furan derivatives

1.4.1.2.1. Furan derivatives via isocyanide based MCRs

EtOH

Reflux

HO COOEt

Ar .. 0·'H H··M.)::--H

OH ~ Ar 0

Reaction of dimethyl acetylenedicarboxylate (DMAD) with isocyanides or with in situ generated

carbenes yields a zwitterionic species. The zwitterionic species is highly reactive and is trapped

by aldehydes and quinones to yield dihydrofuran derivatives in good yields.72 The reaction is

quite simple. All the three starting materials DMAD, isocyanide and aldehydes or ketone are

taken in stoichiometric amounts in dry benzene or toluene and refluxed to get highly

functionalized furan derivatives. From the diversity point of view the isocyanide could be

aliphatic or aromatic, aldehydes may also be taken aliphatic or aromatic. The reaction is not good

19

Chapter 1 Multi-Com

2009

with simple ketone but gives good yields with activated ketones like isatins,73 1,2-diketones74 and

a-keto cyanides (Scheme 29).75

COO Me

~~~ + RNC COO Me [

MeOOC _ 8COOMe1

e(o N I

R

[

MeOOC _ 8COOMe1

e(o +

~ R

~0 ~N)=-

H

~~~ooMe + :(OMe lM~x:Mej-[:::~cooMe1 OMe N--[ OMe

COOMe I"

Scheme29.

RCHO

MeOOJ:i__C COOMe Y' ~

HN R1 I 0

R

MeOOC COOMe

MeON--R MeO

The reaction of isocyanides, aldehydes and enols (1 ,3-dicarbonyls) is also a very popular method

for the synthesis of furan derivatives. The reaction probably proceeds with initial formation of an

intermediate by the reaction of aldehydes and isocyanides which is then attacked by enols to yield

the furan derivatives. Teimouria et al reported a regioselective three-component condensation

reaction of 2-hydroxy-1 ,4-naphthoquinone, isocyanides and a variety of aldehydes yielding to

linear naphtho[2,3-b ]-furan-4,9-dione derivatives (Scheme 30). 76

Scheme30.

~OH Toluene, •eflu•

0

Shabani et al reported an environment-friendly three component condensation reactions of N.N­

dirnethylbarbituric acid, 4-nitrobenzaldehyde and alkyl or aryl isocyanides to afford the

corresponding furo[2,3-d]pyrimidine-2,4(1H,3H)-diones, in water, in high yields (Scheme 31).77

+

Scheme31.

0 ....... )l /

N N

0~0

I . O~H.N 0 ,R

~ I ;j NH /

0 R1

20

Chapter I Multi-Com

2009

Fan et al reported a piperidine catalyzed reaction of cyclohexyl isocyanide with various aldehydes

and 1,3-dicarbonyl compounds.78 The protocol offers facile and efficient synthesis of 5-hydroxy-

2H-pyrrol-2-one derivatives from readily available starting materials in high yields (Scheme 32).

Toluene +

Piperidine, 100 °C

Scheme32.

5-Acylamino butenolides were assembled by a multi-component reaction (MCR) of isocyanides,

glyoxals, and acetophosphonic acid diethylesters, followed by a intramolecular Wittig-type

reaction.79 The reaction can be performed either in one pot or with the isolation of the

intermediate Passerini product. This versatile reaction offers three independent inputs displayed

in the final product (Scheme 33).

R1

A + HOOC PO(OEt)2

+

Scheme33.

1.4.1.2.2. Foran derivatives via transition metal mediated MCRs

Many transition metals mediated MCRs are now available for the synthesis of furan derivatives.

The one-pot assembly of 4-alkoxy-3-iodo-2-pyridones, terminal alkynes, and organic halides has

been achieved by integration of two sequential palladium-mediated cross-coupling reactions­

Sonogashira and Wacker-type heteroannulation processes-and subsequent deprotection of the

alkoxy group to afford furo[2,3-b]pyridones (Scheme 34).80

R1 ~"-1 ____ R_2x ____ __

N 0 Pd(O) I

0 R2

05-R' N 0

~I wlN~O .ql Pd(O)/Cu(l)

R I

R R

~ Scheme34. ~ L A one-pot reaction between equimolecular amounts of various propargyl alcohols, Michael

acceptors and unsaturated halides (or triflates) in the presence of a palladium (0) catalyst provides

~ a simple and flexible entry into highly substituted 3-arylidene-(or 3-alkenylidene-)

l..; tetrahydrofurans (Scheme 35). The efficiency of this palladium-mediated three-component

reaction has been shown to be strongly influenced by the nature of the catalyst-system, and in this

TH-17189 21

/

-­.. _ ........

Chapter 1 Multi-Com

2009

regard, a palladium(O) catalyst generated in situ by reduction of PdCh(PPh3) 2 with n-butyllithium

has been found particularly effective.81

Base +

cat Pd

Scheme35.

A three-component cyclization-coupling reaction catalyzed by palladium has been developed,

producing poly substituted furans in good yields from readily available substrates (Scheme 36).82

R1 = CH 3 , Ph

Scheme36.

+ Arl ~R'

Ar 0

Reaction of zirconacyclopentenes with 2 equiv. of the same aldehydes in the presence of 1 equiv.

of CuCl affords tetrahydrofuran derivatives in good isolated yields upon hydrolysis with aqueous

3 N HCl (Scheme 37). Oxazirconacycloheptenes, generated in situ from zirconacyclopentenes

with one aldehyde was found to be the reactive intermediate. When treated with a second

aldehyde and CuCl, an oxazirconacycloheptene gave a tetrahydrofuran derivative comprised of

four different components involving an alkyne, an ethylene and two different aldehydes, thus

providing the first one-pot synthesis of important tetrahydrofuran derivatives from four­

components. 83

+

Scheme37.

R (EtMgBr) + '=o

R' + ~0

CP2Zn/CuCI

e H

~R' R

Duan et al reported a three-component cyclization-coupling reaction of propargyl carbonate, 13-keto esters, and aryl iodide catalyzed by palladium, producing poly substituted furans in good

yields (Scheme 38).84 This three-component cyclization-coupling protocol provides an efficient

access to a variety of polysubsituted furans and shows some advantages in terms of its simple

operation, easily availability, and diversity of the starting material.

22

Chapter 1 Multi-Com

~ ./OCOOCH3 /~COOR1

+ 1/j +

Scheme 38.

2009

Ar-X

(98 2)

Satoh et al synthesized naphthofuran-2(3H)-one analogues by three-component tandem reaction

using 1- or 2-naphthols, aldehydes, and carbon monoxide in the presence of a palladium catalyst

(Scheme 39).85

+ co Acid

Scheme39.

1.4.1.2.3. Furan derivatives via miscellaneous MCRs

The reaction of N-alkyl-3-oxobutanamides, derived from the addition of amines to the diketene,

and dibenzoylacetylene in the presence of triphenylphosphoine results the synthesis of highly

functionalized furans (Scheme 40).86

HNYs::O Ph

I I ~ 0 R Ph

0

CO Ph

111 +

CO Ph

+ 0~ 0

Scheme40.

1.4.1.3. Thiophene derivatives

Thiophene derivatives are synthesized by Gewald Reaction. It is a multi-component condensation

between sulfur, an a-methylene carbonyl compound and an a-cyanoester resulting to the

formation of 2-aminothiophenes (Scheme 41 ).

+ NJOR2 +

Scheme41.

First step in the process is a Knoevenagel Condensation, but the remainder of the sequence is not

known in detail (Scheme 42)

23

Chapter 1 Multi-Com

R~ + R"O~ ~ R"O~ "S"

2009

-- I !J R' R' CN CN R'

H~N S

0 OR" R

?

Scheme42.

Recently a microwave-promoted synthesis of 2-aminothiophenes by multi-component reactions

of a ketone with an active nitrile and elemental sulfur under KF-alumina catalysis was described

(Scheme 43).87

X = CN or COOEt

Scheme43.

KF-Aiumina

Microwave 3.5-Bmin

KF-Aiumina

Ethanol, Reflux 3.5-?h

R2Jrf-NH2 55-92%

R2Jrf-NH2 48-91%

1.4.2. Five membered heterocycles containing two heteroatoms

1.4.2.1. Pyrazolidines

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl

isocyanides and electron-deficient acetylenic esters with phthalhydrazide, leads to a

inylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the

phthalhydrazide to produce dialkyl 3-( alkyl amino)-5, 1 0-dioxo-5, 1 0-dihydro-1 H -pyrazolo[ 1 ,2-

b]phthalazine-1,2-dicarboxylates in fairly good yields at room temperature (Scheme 44).88

Acetone R-NC +

rt, 48h

Scheme44.

Xie et a! have synthesized pyrazoles via a sequential one-pot, three-component reaction of

iodochromone, arylboronic acid, and hydrazine by Suzuki coupling and condensation (Scheme

24

Chapter 1 Multi-Com

2009

45).89 This method provides facile construction of these heterocycle libraries that are applicable

for biological screening.

0 rol ()B(OH)z + I

.& 0

Scheme45.

1) 2% Pd(PPh 3)4, 2 eq K2C03

THF-H20, reflux

2) 1.5 eq NH2NH2, rt

Mori eta! reported a four component coupling of a terminal alkyne, hydrazine (hydroxylamine),

carbon monoxide, and an aryl iodide to furnish pyrazole or isoxazole derivatives in the presence

of a palladium catalyst (Scheme 46).90 The reaction proceeds at room temperature and an ambient

pressure of carbon monoxide in an aqueous solvent system. Hydrazine and hydroxylamine play

dual roles as a component of ring formation and an activating agent for the carbonylative

coupling reaction.

--Ar__.::::::::;. + Aq. RNHNH2

(H2NOH)

Scheme46.

1.4.2.2. Imidazolidines

PdCI2(PPh3)2

rt 1 atm

Due to their diverse range of biological activities, imidazo-heterocycles are recognized as

privileged structures making these structural motifs attractive targets for library preparation.

Rousseau et al reported a zinc chloride catalyzed the one-pot, three component synthesis of

imidazo [1,2-a] pyridines from a range of substrates using either conventional heating or

microwave irradiation (Scheme 47).91 This methodology affords a number of imidazo [1,2-a]

pyridines in reasonable yields and short reaction times without any significant optimization of the

reaction conditions.

~NH2

~N

Scheme47.

25

Chapter 1 Multi-Com

2009

Bencsik et al synthesized a large collection of highly pure imidazo[ 1 ,2-a ]heterocycles by

expanding three component coupling of aldehydes, 2-aminoheterocycles, and isonitriles (Scheme

48).92 Global diversity around these heterocycles was further enhanced in two ways: first through

regioselective partial reduction of imidazo[1,2-a]pyrazines to afford the tetrahydro variants and

second through development of novel and extremely mild conditions for Mannich bond formation

at the C-3 position of imidazo[l,2-a]pyridines. Through in silico evaluation of the drug-like

properties of the final library, they achieved a high value screening library of approximately 7500

compounds with a 92% rule-of-five compliance.

Scheme48.

(a) 5 mol % Sc(OTfh, CH2CI2-MeOH

(b) HCI, dioxane-CH2CI2

Alizadeh et al described an effective route to functionalized hydantoin derivatives involving the

reaction of a urea derivative resulting from the addition of a primary amine to an arylsulfonyl

isocyanate, and an alkyl propiolate or dialky1 acetylenedicarboxylate in the presence of

triphenylphosphine (Scheme 49).93 The reactive 1:1 intermediate obtained from the addition of

triphenylphosphine to the alkyl propiolate or dialkyl acetylenedicarboxylate was trapped by NH­

acids such as the urea derivative to produce functionalized hydantoin derivatives.

R

COOR Scheme49.

Illgen et a1 described a three-component, one-pot condensation yielding 1H-imidazol-4-yl-

pyridines from aldehydes, o-picolylamines, and isocyanides. They have investigated the scope

and limitations of the reaction (Scheme 50).94

+ R"-NC MeOH

0

A R' H Lewis acid

Scheme 50.

26

Chapter 1 Multi-Com 2009

Porwal et al described a multi-component reaction that converts aryl/heteroaryl aldehydes

efficiently into arylmethylene 2-thiohydantoins (Scheme 51).95

+ KSCN

Scheme 51.

H RyN

_)-_)=s 0 N

H

Matsuoka et al have synthesized enantiopure !-substituted, 1 ,2-disubstituted, and 1 ,4,5-

trisubstituted imidazoles by using the multi-component condensation of a 1 ,2-dicarbonyl

compound, an aldehyde, a 1, 2-amino alcohol, and ammonium acetate (Scheme 52).96

R1 R2

>----< H2N OH

Scheme 52.

NH40Ac, MeOH, 80°C

5h

1.4.2.3. lsoxazoles and Oxazoles

Isoxazolidines are synthesized by 1 ,3-dipolar cycloaddition of nitrones derived in situ from

aldehydes and aryl hydroxylamine, with electron deficient olefins (Scheme 53). The reaction is

accelerated by 1-butyl-3-methylimidazoliurn based ionic liquids and improved yields of

isoxazolidines are obtained with high regio- and diastereoselectivity.97

R-CHO + PhNHOH -- [

EWG = CN, COO Me, COMe

Scheme 53.

Lijun et al reported an efficient and general one-pot, four-component condensation resulting to

the formation of substituted 2-oxazolines, which are found in several families of bioactive natural

products (Scheme 54).98 In this reaction the Passerini product is also obtained as side product but

increasing the quantities of ammonia and benzoic acid and by replacing methanol as solvent with

2,2,2-trifluoroethanol, the yield of Ugi product could be enhanced. This multi-component

synthesis reported here rapidly assembles promising lead compounds containing this heterocyclic

system for use in drug discovery endeavors.

27

Chapter 1 Multi-Com anent Reactions

OlPh

OMs

Scheme 54.

PhCOOH 0 H-o

)l~Ph Ph O

Ugi product

2009

0NH

+ BzO~O OMs Ph

Passerini pruduct

Maghsoodlou et al reported a three component reaction of 2-fluorobenzaldehyde, phenanthroline

and cyclohexyl or 2,6-dimethylphenyl isocyanide resulting to the formation of N-cyclohexyl-1 0-

(2-fluorophenyl)-8aH-oxazolo[3,2-a ][1, 1 O]phenanthroline and N-(2,6-dimethylphenyl)- 1 0-(2-

fluorophenyl)-8aH-oxazolo[3,2-a] [ 1,1 O]phenanthroline (Scheme 55).99

XF v Scheme 55.

+ RNC rt

Wang reported a one-pot, isocyanide based MCR leading to the synthesis of oxazole derivatives

(Scheme 56). 100

Scheme 56.

Black et al reported a copper(!) and zinc(II) catalyzed, routes to construct secondary

propargylamides in one-pot procedures from aldehydes, LiN(TMS)z, acid chlorides, and alkynes.

This reaction has been subsequently used to provide a one-pot synthesis of oxazoles from four

simple building blocks (Scheme 57). 101

1. 0 °C, Hexane, R1COCI

2. R2 -

RCHO + LiN(TMSh -----------10%Cul, 20% BF3, iPr2NEt

3. 50% NaH, 30 min Scheme 57.

28

Chapter 1 Multi-Com anent Reactions

2009

1.4.2.4. Thiazoles

Substituted 2-acyloxymethyl thiazoles have been assembled by a multi-component reaction of

methyl 3-(N,N-dimethylamino)-2-isocyanoacrylate, aldehydes and thiocarboxylic acid under

Lewis acid catalysis (Scheme 58). 102

I

+ + iN" MeOOC NC

MeOOCyN R2

~H o s o--{

R1

Scheme 58. Bioactive natural product

R.eaction of a cyclic amino acid with acetelene dicarboxilic acid esters and acetic anhydride above

100 °C yields a 1 ,3-dihydropyrrolo[l ,2-c ]thiazole derivative which has been used in the synthesis

of substuted pyrroles (Scheme 59).103

-i--<COOH

SYNH +

R

fScheme 59.

0 0

+ )lo)l__ 110-120 °C

E E

LtJ( N l._

R

Srivastava et al synthesized 4-thiazolidinones by DCC mediated three-component reaction of

amine, aldehyde and mercaptoacetic acid (Scheme 60).104 The products were obtained in

::tuantitative yields and amenable to scale-up operations. The yields of the thiazolidinones were

independent of the nature of the reactants.

RN~ + R1CI-O cr ~

HS OCC, lliF

Clline cr Mercarto adds

Cllino ocid esters 4-thiazolicinooes

fScheme 60.

Dubreuil et al prepared a small library of 4-thiazolidinones by a one-pot three-component

condensation under microwave dielectric heating (Scheme 61). 105

R2 0 -y--Zs R,N--(

R1

4-Thiazolidinone

fScheme 61.

:> RNH2 +

Amine

R2

R1CHO + HS~OH 0

Aldehyde Mercapto acid

29

Chapter 1 Multi-Com

1.4.2.5. Oxaphospholes

2009

Esmaeili et a! 106 and Yavari et a! 107 simultaneously reported a three component reaction of N­

alkyl isatin, acetelene dicarboxylic acid ester and (PPh3) 3 resulting to the formation of spiro-2,5-

dihydro-1 ,2-A.5- oxaphospholes (Scheme 62). The procedure has the advantage that the reaction is

performed under neutral conditions, and the starting material can be used without any activation

or modification.

~0+ xJl)_ti)=

R

Scheme 62.

COOR1

Ill + P(Ph3h

COOR1

R

1.4.2.6. Dioxolanes

r.t.

Nair reported a three-component reaction of acyclic carbonyl ylides generated from

dicarbomethoxycarbene and aldehydes with 1,2- and 1,4-diones is described. The reaction

afforded the corresponding spiro-dioxolanes in good yields (Scheme 63). 108

0

+ N,C(CO.,Me)2 0 .

o ?.$f.v-o 1-0--- + ~ : :;o-MeOOC 0

COOMe MeOOC COOMe

Scheme63.

1.4.3. Five membered heterocycles containing three heteroatoms

1.4.3.1. Triazoles

1 ,2,3-Triazoles are generally synthesized by transition metal catalyzed 1 ,3-dipolar cycloaddition

reaction of terminal alkynes with in situ generated alkyl azides. Alkyl azides are generated by the

reaction of trimethylsilyl azide with secondary alcohols109 allyl carbonates110 and sodium azide

with alkyl bromide (Scheme 64). 111

30

Chapter 1 Multi-Com anent Reactions

~OCOOMe +

/'-- + R Br

Scheme64.

Cu(OTfb Cu(O)

CH 3N02 , 60°C

+ R----H

Cu(O), CuS04, MW

2009

cat Cu(l)

Hy-N h _N_;=

R N

cat Pd(O)

H R1, __) R r--.. , _/

N.::-N·N

>90% yield

100% regioselective

1,2,4-triazolidines are synthesized by a ruthenium porphyrin catalyzed three-component coupling

reaction of a-diazo esters, imines and dialkyl azodicarboxylates (Scheme 65).112 The reaction

proceeds with in situ generation of azomethine ylides from adiazo esters and 1mmes.

Stereoselective 1,3-dipolar cycloaddition reactions of the azomethine ylides with dialkyl

azodicarboxylates gives the corresponding 1,2,4-triazolidines in good yields. Using chiral 8-

phenylmenthanol a-diazo ester as the carbenoid source, chiral 1,2,4-triazolidines have been

obtained in good diastereoselectivity.

lh fOOEt ~ r-N + N=N + roEt

Ph I EtOOC N2

Ru catalyst pooEt

EtOOC, -N pEt J )····~ Ph f'i 0

Toluene, 45°C, 12 h

Ph

Scheme65.

1.4.3.2. Oxadiazoles

Adib et al synthesized 1 ,2,4-oxadiazoles from a one-pot, three-component reaction between

nitriles, hydroxylamine, and aldehydes under microwave irradiation and solvent-free conditions

in excellent yields (Scheme 66).113

ArCN +

Scheme 66.

AcOH (Cat)

MW (1 min)

_~1NOH Ar~

NH2

Ar'CHO

MW (3 min)

Ar'-...--N II '}-Ar N-o

31

Chapter 1 Multi-Com

1.5. Six membered heterocycles

1.5.1. Six membered heterocycles having one heteroatom

1.5.1.1. Pyridine derivatives

2009

Six membered heterocycles containing single nitrogen are pyridine derivatives. Biologically the

most important simple single nitrogen containing heterocycle is I ,4-dihydropyridine. I ,4-

Dihydropyridines (1,4-DHPs) are a class of model compounds of NADH coenzyme which

mediates hydrogen transfer reactions in biological systems. 1,4-DHPs have been established as

one of the first line drugs for treatment of hypertension because of their promising depressor

effect and relatively good tolerability. Felodipine, amlodipine, nifedipine and nicardipine (Fig. 8)

are among the best selling drugs in the pharmaceutical industry. 1,4-DHPs have been extensively

studied because of the biological significance of these compounds to the NADH redox process as

well as their therapeutic functions for treatment of a variety of diseases, such as cardiovascular

disorders, cancer and AIDS.

£1

....:;. Cl

MeOOC COOEt

I N H

FigureS.

Nicardipine

COOH

Cerivastatin

The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component

organic reaction between an aldehyde such as formaldehyde, 2 equivalents of a ~-keto ester such

as ethyl acetoacetate and a nitrogen donor such as ammonium acetate or ammonia (Scheme 67).

0 0 RCHO + 2 II II +

R 1~0R2

Scheme67.

R

R200C~COOR2

JJl R1 N R1

H

32

Chapter 1 Multi-Com

2009

The initial reaction product is a dihydropyridine which can be oxidized in a subsequent step to a

pyridine. The driving force for this second reaction step is aromatization (Scheme 68.

R

R2ooc~cooR2 HN03

Jl Jl -----R1 N R1

H

Scheme 68.

1) KOH

2) CaO. heat

We have demostrated effect of ultrasonic irradiation over Hantzsch dihydropyridine synthesis in

aqueous micelles (Scheme 69). 114

RCHO + 2 ~ ~ + ~OR1

Scheme69.

R

R100C)()(COOR

1

p-TsOH I I ------Aq. Micelles

)))))))

N H

Direct aromatization of 1,4-dihydropyridines has been reported using ferric chloride115 or

alluminium chloride and subsquent oxidation with H20 2 under microwave irradiation116 in a one­

pot synthesis in water. The four component Hantzsch reaction has been modified to a three

component reaction by taking amino crotonate in the place of amonia and aceto acetate ester

(Scheme 70).117

~HBoc ROOC

("coosn :l CHO + O

ROOCll

+~ H2N

Scheme 70.

~HBoc

xXOOBn ROOC COOR

I N H

In Hantzsch reaction two molecules of acetoacetate ester are used resulting to the formation of

symmetrical compound. We replaced the second molecule of acetoacetate ester by cyclic 1,3-

diketones, thus, unsymmetrical product (polyhydroquinoline derivative) was formed. The

reaction was catalyzed by organocatalyst like proline and cinchona alkaloids. The catalytic

efficiency of various small organocatalysts such as L-proline, trans- 4-hydroxy-L-proline, L­

thiaproline, DL-phenylglycine, and cinchonidine was studied under aqueous, organic, and solvent

free conditions (Scheme 71).118 We have also carried out the enzymatic variant of this reaction.

Bakers' yeast was foung to catalyze the four component reaction of aldehyde, dimedone,

acetoacetate ester and ammonium acetate to form the polyhydroquinoline derivatives. 119

33

Chapter 1 Multi-Com anent Reactions

2009

L-Proline

RCHO+ room. temp.

Scheme 71.

We have successfully carried out an organocatalyzed three-component reaction of

cinnamaldehydes, acetoacetate esters and anilines resulting to the formation of 1,4-

dihydropyridines under solvent free conditions (Scheme 72).120

0 R1J +

CHO

Scheme 72.

L-Proline

Solvent free

Quinoline derivatives are synthesized by a well known Povarov reaction, a chemical reaction

described as a formal cycloaddition between an aromatic imine and an alkene. The imine in this

organic reaction is a condensation reaction product from an aniline type compound and a

benzaldehyde type compound. The alkene must be electron rich which means that functional

groups attached to the alkene must be able to donate electrons. Such alkenes are enol ethers and

enamines. The reaction mechanism for the Povarov reaction to the quinoline is outlined in

scheme 73. In step one aniline and benzaldehyde react to the Schiff base in a condensation

reaction. The Povarov reaction requires a lewis acid such as boron trifluoride to activate the imine

for an electrophilic addition of the activated alkene. This reaction step forms an oxonium ion

which then reacts with the aromatic ring in a classical electrophilic aromatic substitution. Two

additional elimination reaytions create the quinoline ring structure.

OEt

n~ ~~

N Ph

Scheme 73.

~-~N--lPh H

ro N Ph H

5-Methoxy substituted quinolines are a common structural feature in a number of biologically

active quinoline alkaloids, for example 9-methoxycamptothecin, 9-methoxymappicine ketone and

S-9-methoxymappicine. This latter alkaloid is also known as nothapodytine A (Figure 9).121

34

Chapter 1 Multi-Com onent Reactions

2009

R R R

0 R = H,OMe H

Figure 9. Luotonin A precursor and a range of bioactive quinoline alkaloids isolated from

nothapodytes foetida with and without substituent at C9.

The reaction depicted in scheme 74 illustrates the Povarov reaction with an imine and an enamine

in the presence of yttrium triflate as the lewis acid. 122 This reaction is regioselective because the

iminium ion preverentially attacks the nitro ortho position and not the para position. The nitro

group is a meta directing substituent but since this position is blocked, the most electron rich ring

position is now ortho and not para. The reaction is also diastereoselective because the enamine

addition occurs with a preference for trans addition without formation of the cis isomer.

Yb{OTfh

~0 N02 N

.··'~

Scheme 74. regio- and diastereoselective Povarov reaction

An efficient liquid-phase synthesis technique for the construction of 2,3-dihydro-4-pyridones on

soluble polymer support has been developed, which utilized one-pot reaction of Danishefsky's

diene with aldehydes and polymer-supported amine (Scheme 75). 123

2~ 0 0

ArCHO

OMe )_ Zo(C10,).6H,O

+ "'- OSiMe,

1) 0.5 N NaOH

2) 2N HCI

Scheme 75.

Shindoh et al reported a Tf2NH catalyzed multi-component Povarov reaction aniline, aldehyde,

and allylsilane, to provide substituted quinolines (Scheme 76).124

35

Chapter 1 Multi-Com

Scheme 76.

y CHO

2009

TIPS

+ Toluene, 60 °c

Pyrindines and quinolines were synthesized in good yields in a one-pot three-step four­

component process by a coupling-isomerization-Stork-enamine alkylation-cyclocondensation

sequence of an electron poor (hetero)aryl halide, a terminal propargyl alcohol, a cyclic N­

morpholino alkene and ammonium chloride (Scheme 77). 125

OH Ar1-Hal + (

Ar2

Cyclocondensation

Coupling iso marisation

sequence

Ar1 = EWG(het)aryl Ar2 = {het)aryl Scheme 77.

Microwave-assisted three-component cyclocondensation of barbituric acids, benzaldehyde and

alkyl nitriles proceeds in the absence or presence of triethylamine to afford pyrano[2,3-

d]pyrimidines. Similarly amiriouracils or 6-hydroxyaminouracils were synthesized under identical

conditions to yield pyrido[2,3-d]pyrimidines, all in high yields (Scheme 78). 126

R2 Scheme 78.

PhCHO +

X= NH2 , NHOH

MW

Polysubstituted pyridines are prepared in good yield and with total regio-control by the one-pot

reaction of an alkynone, 1 ,3-dicarbonyl compound and ammonium acetate in alcoholic solvents

(Scheme 79). This three-component heteroannulation reaction proceeds under mild conditions in

the absence of any additional acid catalyst and has been used in the synthesis of dimethyl

36

Chapter 1 Multi-Com

2009

sulfomycinamate, the acidic methanolysis degradation product of the sulfomycin family of

thiopeptide antibiotics. 127

Ethanol, reflux

24h

Scheme 79.

A three-component reaction involving isoquinoline, dimethyl butynedioate and electrophilic

styrenes has been developed (Scheme 80). The reaction proceeds through a Huisgen 1,4-dipolar

cycloaddition pathway .128

w + N

COO Me

Ill+ ~CN COOMe Cl

Scheme SO.

THF, rt

23h

2:1

Cl

COO Me COOMe

+

COO Me COOMe

Cl

Evdokimov et al have developed a three-component reaction of salicylaldehydes, thiols and 2

equiv of malononitrile that leading to the formation of a series of compounds incorporating 2,4-

diamino-3- cyano-5-sulfanylbenzopyrano[2,3-b ]pyridine framework (Scheme 81 ). 129

Benzopyrano[2,3-b ]pyridine is an important privileged medicinal scaffold.

R2VCHO

I .b + R1 OH

R Scheme81.

EtOH, reflux 2 + RSH

A one-pot, four-component reaction of 1-(phenylsulfinyl)- or 1-(4-chlorophenylsulfmyl)propan-

2-one, aromatic aldehydes and ammonium acetate in a 1:2:1 molar ratio affords a series of 2,6-

diaryl-2,3-dihydro-IH-pyridin-4-ones (Scheme 82). This reaction proceeds presumably via a

double Mannich reaction-elimination tandem sequence. 130

EtOH HN~ Ar'~O

Scheme82.

3?

Chapter 1 Multi-Com

2009

Trimethylchlorosilane (TMSCl) promoted multi-component reaction (MCR) of

ethylenediamine(s), diverse carbonyl compounds, and isocyanides has been developed for the

synthesis of a variety of highly substituted 3,4,5,6-tetrahydropyrazin-2-amines including

corresponding spirocyclic compounds (Scheme 83). 131

(+/-)

Scheme 83.

p Q +

0

TMSCI

(+/-)

Mediated by trifluoromethanesulfonic acid, ethynyl ketene-S,S-acetals was reacted in a one-pot

procedure with various arylamines and aldehydes under mild conditions to give the corresponding

quinoline derivatives in good to high yields via a consecutive arylimine formation, regiospecific

aza-Diels-Alder (Povarov) reaction, and reductive amination (Scheme 84). 132

~s ~s--- ": R

Scheme84.

Privileged medicinal scaffolds based on the structures of 2-amino-3,5-dicyano-6-

sulfanylpyridines and the corresponding 1,4-dihydropyridines have been prepared via a single­

step, three-component reaction of aldehydes with various thiols and malononitrile (Scheme 85).

Mechanistic studies revealed that 1 ,4-dyhidropyridines undergo oxidation by the intermediate

Knoevenagel adducts rather than by air oxygen. Although the latter process undermines the yields

of pyridines, it results in the formation of substituted enaminonitriles, promising anti­

inflammatory agents. 133

Base + R'SH

Ethanol, reflux

Scheme85.

R

NC~CN or Jl Jl

H2N N SR' H

38

Chapter 1 Multi-Com

2009

Three-component reactions with ortho-alkynylbenzaldehydes, pnmary amines, and

pronucleophiles (Nu-H), such as CHCh, proceeded to give 1,2-dihydroisoquinoline derivatives in

good to high yields in the absence of any catalysts under mild reaction conditions (Scheme 86). 134

+ NuH No catalyst ~M-R'

vJ R

Scheme 86.

1.5.1.2. Pyran derivatives

Jia et a! have described a simple one-pot three-component reaction involving isatin, activated

methylene reagent, and 1,3-dicarbonyl compounds for the synthesis of a series of spirooxindoles

derivatives in water (Scheme 87). 135

Scheme87.

The reaction of an aldehyde, malononitrile and a phenol in water at reflux in the presence of

cetyltrimethylammonium chloride (CT ACI) as catalyst affords a one-pot synthesis of 2-amino-2-

chromenes (Scheme 88).136

R2

R3X}OH I +

R4 .fi

R5 Scheme88.

110°C,6h

Several bis-pyrano-1,4-benzoquinones have been synthesized by a double domino Knoevenagel

hetero Diels-Alder reaction (Scheme 89).137 The synthetic approach is highly efficient allowing

the construction of complex polycyclic scaffolds with six new cr-bonds. These reactions

performed more efficiently and more rapidly using microwave irradiation.

39

Chapter 1 Multi-Com

VO OH

+

HO

0 Scheme 89.

2009

R ~ +

Sodium bromide catalysed three-component cyclocondensation of aryl aldehydes, alkyl nitriles

and dimedone proceeds under microwave irradiation in solvent free conditions to give highly

functionalised tetrahydrobenzo[b ]pyrans in excellent yields (Scheme 90). 138

+ AO ___ M_W __ _

+A NaBr

R1 = CN, CONH2 , COOEt Scheme 90.

A new type of multi-component reaction is described in which five organic molecules form a

cyclohexane ring. Aryl aldehydes, malononitrile and acetone in the presence of a catalytic amount

of sodium acetate are stereoselectively cyclized into cis-4-dicyanomethylene-2,6-

diarylcyclohexane-1, 1-dicarbonitriles in 3~0% yields (Scheme 91 ). 139

Electrolysis, 0.03F/mol

+ CN

Scheme 91.

Concise synthesis of defucogilvocarcin M was achieved via the [2 + 2 + 2] approach to a­

phenylnaphthalene structure (Scheme 92). 140

0 Dfucogilvocarcin M

Scheme 92. ·

c__---,> ~n

Ui

40

Chapter 1 Multi-Com onent Reactions

2009

Isocyanides, dimethyl acetylenedicarboxylate, and cyclobutene-1 ,2-diones react in one-pot to

afford novel spirocyclic compounds with double insertion of the isocyanide (Scheme 93).141

R R

0 COOMe

IJI

CH2CI2

+ + RNC rt,24h

R1 0 COOMe

R Scheme93.

1.5.2. Six membered heterocycles having two heteroatoms

1.5.2.1. Pyrimidine derivatives

RN

The most studied MCR derived six membered heterocycles containing two nitrogens are 3,4-

dihydropyrimidinone derivatives which are also known as Biginelli compounds. The compounds

exhibit a broad range of biological activities like calcium channel modulator, a-la antagonist,

antihypertensive, antiviral and anticancer (Figure 10). Thus a plethora of methods have been

developed for the synthesis of Biginelli compounds.

EtOOC

Nitractin (antiviral) Monastrol (anticancer)

N/CONH2

I NA-0 H

SQ 32926 (antihypertensive)

Figure 10. Biologically active 3,4-dihydropyrimidinone(thione)

We have synthesized 3,4-dihydropyrimidinones via a TiC14-MgCh catalyzed three component

condensation of aldehyde, 2-keto ester and urea/thiourea (Scheme 94).142 We have also developed

the enzymatic variant of the reaction. 143

RCHO +

Scheme 94.

0 0

~OR1 + 100 °C Solvent free

Chen et a! have successfully synthesized asymmetric 3,4-dihydropyrimidinones using chiral

binaphthyl phosphate as catalyst.144 Wang et al reported an iron (III) catalyzed the three-

41

Chapter 1 Multi-Com onent Reactions

2009

component Biginelli-like cyclocondensation reaction to afford the corresponding 5-unsubstituted

3,4-dihydropyrimidin-2-(IH)-ones in high yields (Scheme 95). Ferric chloride catalyzed

Biginelli-like reactions of urea, aldehydes and ketones furnished diaryl-3,4-dihydropyrimidin-2-

(1 H)-ones. 145

+ Urea Reflux

Scheme 95.

4,6-Diaryl-3,4-dihydropyrimidine-2(1H)-thione were synthesized in a sequential one-pot three

component reaction of aldehydes, acetophenones and thiourea in alkaline ethanol (Scheme 96). 146

These compounds exhibited in vitro antitumour activity with moderate to excellent growth

inhibition against a panel of 60 cell lines of leukemia, non-small cell lung cancer melanoma,

ovarian cancer, prostate cancer and breast cancer.

a~ F

Scheme 96.

__ro L~

R

NaOH, EtOH

Cl F

Dandia et al have developed a one-pot solvent-free procedure for the synthesis of fluorinated 2,3-

disubstituted quinazolin-4(3H)-ones by three-component cyclocondensation of anthranilic acid,

phenyl acetyl chloride and substituted anilines under microwave irradiation (Scheme 97). The

reaction is generalized for o-, m- and p-substituted anilines with electron-donating and -

withdrawing groups to give quinazolin-4(3H)-ones. Synthesized compounds have been screened

for their anti-fungal activity.147

QCOOH +

NH2 Scheme 97.

MW/4-5min

Neat

~-Ar V .. ~Ph

N

Spiro-fused heterocycles were synthesized in good to high yields by a pseudo four-component

reaction of an aldehyde, urea and a cyclic 13-diester or a 13-diamide such as Meldrum's acid or

42

Chapter 1 Multi-Com

2009

barbituric acid derivatives using microwave irradiation under solvent-free conditions (Scheme

98).148

RCHO

X= 0, Z = CMe2 X= NH or NMe, Z =CO

Scheme 98.

Solvent free

MW/4min

An acid catalyzed three component reaction of 2-oxosuccinic acid, urea and aldehyde has been

developed and exploited to expeditiously synthesize a diverse set of 5-unsubstituted 3,4-

dihydropyrimidin- 2(1H)-ones in high yield (Scheme 99). Electron-rich as well as electron­

deficient aldehydes proved to be excellent substrates for the cyclo-condensation. Pyrimidones

were prepared using standard cyclization conditions and more effectively synthesized using a

unique set of conditions (i.e., TFA in refluxing dichloroethane). The carboxylic acid appendage

on C(6) offers functionality capable of a wide variety oftransformations.149

0 0

HO~OH +

0 Scheme 99.

RCHO Acid

+ Urea

Shabani et al have developed a multi-component synthesis of highly substituted 1, 6-

dihydropyrazine-2,3-dicarbonitrile derivatives starting from simple and readily available inputs.

Simply stirring an ethanol solution of 2,3-diaminomaleonitrile, a ketone, and an isocyanide in the

presence of a catalytic amount of p-toluenesulfonic acid provides highly substituted 1,6-

dihydropyrazine-2,3-dicarbonitrile derivatives in good to excellent yields at ambient temperature

(Scheme 100).150

rt

NCrNH2 +

NC NH2

p-TsOH, EtOH

SchemelOO.

The 1 ,4-dipole derived from isoquinoline and DMAD has been shown to react readily with N-

tosylimines resulting in the diastereoselective synthesis of 2H-pyrimido [2,1-a] isoquinoline

derivatives (Scheme 10 1). 151

43

Chapter 1 Multi-Com

Scheme 101.

COO Me

111 +

COO Me aNTs

-R ~

DME

rt, 3h

2009

~ ~JC~N COOMe+

/N Ts , COOMe

OR I

2,4,6-Tri(hetero )aryl-substituted pyrimidines has been synthesized in a three-component one-pot

process based upon a coupling- isomerization sequence of an electron-poor (hetero)aryl halide

and a terminal propargyl alcohol subsequently followed by a cyclocondensation with amidinium

salts (Scheme 1 02). 152

+ heat

Scheme 102.

TMS-ynones are versatile synthetic equivalents of a-keto aldehydes and can be readily

synthesized in an atom-economical fashion by coupling (bet) aroyl chlorides and (TMS)­

acetylene with only one equivalent of triethylamine under Sonogashira conditions. This mild

ynone synthesis is a suitable entry to 2,4-disubstituted pyrimidines in the sense of a one-pot three­

component reaction, i.e., a coupling-addition- cyclocondensation sequence (Scheme I 03).153

heat rt

0

Ar~ TMS

Amidinium salt 0 II + - SiMe3 Ar_...x.,._CI

[Pd-Cu) 1 Eq Et3N

Scheme 103.

A diastereoselective three-component reactions of 3,4-dihydro-(2 H)-pyran with urea/thiourea­

aldehyde mixtures leading to hexahydro-4-phenyl-IH-pyrano[2,3-d]pyrimidin-2(8aH)-ones or

hexahydro-4-phenyl-IH-pyrano[2,3-d]pyrimidine-2(8aH)-thiones were developed by Zhu et al

(Scheme 104).154 The authors have proposed that reaction proceed via intermediacy of N­

acyliminium ions which undergo a hetero [4 + 2] cycloaddition with alkenes.

Reflux RCHO + + 0

0

TMSCI, DMF

Scheme 104.

44

Chapter 1 Multi-Com

1.5.2.2. Oxazine derivatives

2009

The reaction between alkyl or aryl isocyanides and dialkyl acetylene dicarboxylates in the

presence of 4,5-diphenyl-1 ,3-dihydro-2H-imidazol-2-one provides a simple one-pot entry into the

synthesis of polyfunctional imidazo[2,1-b][1,3]oxazine derivatives of potential synthetic and

pharmaceutical interest (Scheme 1 05). 155

... R-NC + II +

Ph

J[>=o Ph N

H

Acetone

rt

Scheme 105.

A new one-pot procedure for the efficient synthesis of novel 3-substituted morpholin-2-one-5-

carboxamide derivatives using commercially available glycolaldehyde dimer as a bifunctional

component with various a-amino acids and isocyanides by the Ugi five-center three-component

reaction (U-5C-3CR) has been developed (Scheme 106).156

+ -40 °c- rt

Scheme 106.

The reaction ofnitrones, formed in situ by reaction ofhydroxylamines with aldehydes, with 1,1-

cyclopropanediesters results in the formation of tetrahydro-1 ,2-oxazines via a homo 3 + 2 dipolar

cycloaddition (Scheme 1 07). This three-component coupling allows for the formation of a diverse

array of cycloadducts with excellent diastereoselectivity (>95%) and yields (66-96%). The

procedure has been used in the two-step preparation of congeners of the FR900482 skeleton.157

Scheme 107.

1.5.2.3. Thiazines

R~ pooR [_/-COOR

Tb(OTf)a

MCRs have been successfully applied for the construction of six membered heterocycles

containing one nitrogen and one sulphur heteroatom in the ring. The Ugi four-component

condensation between 5-oxo-3-thiacarboxylic acids, benzylamines and cyclohexyl isocyanide in

methanol gave 5-oxothiomorpholine-3-carboxamides in high yields (Scheme 1 08). 158

45

Chapter 1 Multi-Com

Scheme 108.

2009

MeOH

A three-component reaction of pyridine, thiophthalimide and acyl chloride yielding a tricyclic

1 ,2-dihydropyridines in good regio- and stereoselectively has been reported. 159 The authors have

proposed a mesomeric betaine as a key intermediate for [4+2]-cycloaddition reaction with

thiocarbonyl compounds (Scheme 1 09).

6. N

s

~NR +

X

6 N

s

~NH X

Scheme 109.

The one-pot, three-component condensation of alkynes, urea or thiourea, and aldehydes results to

the formation of 2-amino-4 H-1 ,3-oxazines or 2-amino-4 H-1 ,3-thiazines (Scheme 11 0). 160

R

tr R1 X NH2

TFA/AcOH

X =O,S Scheme 110.

The one-pot, four-component reaction of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate/ethyl 2-[(2-

ethoxy-2-oxoethyl)- sulfonyl]acetate, an aromatic aldehyde and pyrrolidine provides a rapid and

facile access to new ethyl 3-aroyl-1-benzyl-2,2-dioxo-4- aryloctahydro-2-pyrrolo[2,1-

c ][1 ,4]thiazine-1-carboxylates/diethyl l-benzyl-2,2-dioxo-4-aryloctahydro-2-pyrrolo[2, 1-

c ][1 ,4]thiazine-1 ,3- dicarboxylates (Scheme 111 ). 161

Scheme Ill.

2ArCHO + 0 N H

EtOH

46

Chapter 1 Multi-Com

1.6. Seven membered and higher heterocycles

2009

One-pot MCRs have been successfully applied in the synthesis of seven membered heterocycles.

1.6.1. Benzodiazepine derivatives

A three-component reaction of aromatic aldehydes, ethylenediamine, and ~-keto esters was

originally developed by Fujioka et al (Scheme 112).162 The reaction was carried out in

dichloroethane using p-toluene sulphonic acid as catalyst. In this reaction, ~-keto esters react at

the y-position which is generally unreactive to produce the seven-membered ring compounds.

Products have secondary amines and ~-enamino esters, which serve in further fictionalizations to

produce molecular diversity.

ArCHO +

Schemel12.

+ p-TsOH.H20

DCE

The scope of the reaction was further expanded by taking o-phenykenediamine in the place of

ethylenediamine thus leading to formation of 1 ,5-benzodiazepine derivatives (Scheme 113).163

Scheme113.

0 0

+~OR + ArCHO CsFsCOOH, DCE

Reflux

OR

cc~fa H Ar

The reaction was further simplified by Jean et al. They carried out the one-pot stereoselective

reaction under solvent- and catalyst-free conditions in high yields. This green and experimentally

simple sequence results in a high increase in molecular complexity and diversity. Moreover,

water is the only byproduct liberated during the reaction (Scheme 114).164

.Ar

+ ·:~~(NH)!

NH"''X 0 NR2

ArCHO

Scheme114.

47

Chapter 1 Multi-Com anent Reactions

2009

A green and efficient one-pot three-component synthesis of 2,4-disubstituted-3 H-benzo[

b][l,4]diazepines has been reported by Palimkar et al. 165 The methodology initially involves the

formation of ynones via coupling of a wide range of acid chlorides with terminal alkynes

catalyzed by Pd(OAc)2 under copper, ligand and solvent-free conditions in just 10 min at rt

followed by the Michael addition and cyclocondensation of a-phenylenediamines added in situ

using water as a solvent at reflux temperature (Scheme 115). In addition, the structure of the

benzodiazepine was confirmed to be the diimino molecule and not the enamine by X-ray

crystallographic analysis of the benzodiazepine. The methodology has been successful in

achieving the twin green chemistry objectives of a solvent and ligand free operation and the use

of water as a non-hazardous, inexpensive and readily available solvent in the sequential reaction

steps performed in situ, thus combining the features of both economic and environmental

advantages.

R~NH2

~ NH2

Scheme 115.

(1) Pd(OAc)2, Et3N, rt

(2) OPD, H20, 100 °C

2,4-Di(hetero)aryl substituted 2,3-dihydro 1,5-benzodiazepines, oxazepines, and thiazepines were

readily synthesized in a three component one-pot process initiated by a coupling-isomerization

sequence of an electron poor (hetero)aryl halide and a terminal propargyl alcohol subsequently

followed by a cyclocondensation with 2-amino, 2-hydroxy, or 2-mercapto anilines (Scheme

116).166

Pd-Cu, THF, Et3N +

Ar1 =Electron deficient (hetero)aryl, Ar2 =Aryl, X= NH, 0, S Scheme116.

Indole-fused benzo-1,4-diazepines were synthesized by copper-catalyzed domino three­

component coupling-indole formation- N-arylation under microwave irradiation from a simple N­

mesyl-2-ethynylaniline. This method was also applicable to the formation of heterocycle-fused

1 ,4-diazepines (Scheme 117).167

48

Chapter 1 Multi-Com

~ ~ ... ., + (HCHO)n

NHMs

Scheme 117.

RHN~ + --~ X

Additive deprotection

r ~~~xl: Mannich type U ...... reaction NHMs

CatCuX

~h l N-arylation

~~r-x-u J

2009

Indole fonnation

1 ,3-Dianions are popular intermediates in many synthetic transformations. 168 When 1- and 3-

positions ate functionalized differently, such dianions have nucleophilic sites of different

reactivity. This makes them valuable for MCRs, since different electrophiles can be trapped in

sequential and regioselective manner, leading to complex reaction products that would otherwise

be difficult to prepare. Langer et al recently managed to synthesized medium size lactones by

multiple anion capture reactions of 1 ,3-dianions (Scheme 118).169

0 Ph~ 1)KH

Ph 2) n-BuLi

Scheme 118.

eH.8

Ph'('_~-

Ph

CIVCI

ee ~ PhMPh o'\L_/p

Ph -------cl 'cl ~

)Cyo Ph~o

Ph Ph Ph

0 0

0)-_{ Ph, ),_ p r "--!-Ph

Ph Ph

Similar observations were made when dianions of 2-methylbenzimidazole were treated with one

equivalent of benzophenone and then with phthalic dichloride giving a nine membered

heterocycle in 19 % yield (Scheme 119).170

~NT ~N

H

Scheme 119.

c¢a y ro=;~Ph1 0 0 :rN-'\:: l Ph \Jyo

0

19%

49

Chapter 1 Multi-Com

1. 7. Conclusion

2009

Nitrogen, oxygen and sulphur containing heterocycles are common structural elements in many

natural products and pharmacologically active substances. Accordingly, development of efficient

methods for the synthesis of heterocyclic compounds has been challenging organic chemists for

over a century. In the course of the time, MCRs have proved a convenient tool for the

construction of many classes of heterocyclic compounds. In this review, heterocycles are

categorized by the size of the ring and type as well as number of heteroatoms present in the ring.

The methods that have been published so far for the synthesis of heterocycles are also categorized

which provides some insight into logic of multi-component reaction in general. Many interesting

examples have been put forward and it has become evident that almost all classes of heterocycles

are now accessible by means of flexible multi-component procedures. As has been emphasized,

MCRs aie well appreciated tool for generation of moderate to large libraries of related

heterocyclic compounds that are to be screened for pharmacological activity or ligands for novel

transition metal catalysis. MCR chemistry with its tremendous advantages in terms of accessible

chemical structure space, diversity and efficiency can help to achieve more rapidly technological

and scientific advancements. With incredible foresight, Ivar Ugi recognized already in 1961 that

MCR is ideally suited to probe structure-activity relationships via the synthesis of "large

collections of compounds", which nowadays are referred to as libraries. The labor efficiency and

the access to such an enormous chemical structure space is a major driving force behind the

recent flurry of activity in MCR research and patent applications. It has now become an

interesting area of research. in organic synthesis. It seems a safe prediction that the use of MCRs

for the fast, efficient discovery and development of novel materials will dramatically increase in

the near future.

50

2009

1.8. References

1. Domling, A.; Ugi, I. Angew. Chern. Int. Ed. 2000,39, 3168-3210.

2. Domling, A. Org. Chern. Highlights 2004, April 5.

3. Hulme, C.; Gore, V. Curr. Med. Chern. 2003, IO, 51-80.

4. Kolb, J.; Beck, B.; Domling, A. Tetrahedron Lett. 2002, 43,6897-6901.

5. Fayol, A.; Zhu, J. Org. Lett. 2005, 7, 239-242.

6. Tietze, L. F. Chern. Rev. 1996,96, 115-136.

7. Glaser, R.; Hodgen, B.; Farrelly, D.; McKee, E.; Astrobiology 2007, 7, 455-470.

8. Strecker, S. Liebigs. Ann. Chern. 1850,27-51.

9. (a) Hantzsch, A. Ber. Dtsch. Chern. Ges. 1890. (b) Hantzsch, A. Ann. Chern., 1882, 215,

1-82.

10. Biginelli,P.Ber.Dtsch. Chern. Ges.1891,24, 1317-1319.

11. Robinson, R. J. Chern. Soc. 1917, 111, 762-768.

12. (a) Zhu, J. Eur. J. Org. Chern. 2003, 1133-1144 (b) Nair, V. et al Ace. Chern.

Res. 2003,36, 899-907. (c) Domling, A.; Ugi, I. Angew. Chern.Int. Ed. 2000, 39,

3168-3210.

13. Tietze, L. F.; Modi, A. Med Res Rev, 2000,20,304-322.

14. Souza, D. M.D.; Muller, T. J. J. Chern. Soc. Rev. 2007, 36, 1095-1108.

15. (a) Padwa, A.; Murphee, S. S. Prog. Heterocycl. Chern. 2003, 15, 75. (b) Sweeney, J. B.

Chern. Soc. Rev. 2002, 31, 247-258. (c) Zwanenburg, B.; ten Holte, P. Top. Curr.

Chern. 2001,216,93-124. (d) Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109-117.

16. (a) Brimacombe, J. S.; Hanna, R.; Tucker, L. C. N.J. Chern. Soc., Perkin Trans. I,

1983, 2277. (b) Martens, J.; Scheunemann, M. Tetrahedron Lett. 1991, 32, 1417-1418.

(c) Tanner, D. Angew. Chern., Int. Ed. Engl., 1994,33, 599-619.

17. Gabriel, S. Ber. Dtsch. Chern. Ges. 1888,21, 1049.

18. (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J, Am. Chern. Soc., 1994, 116, 2742-

2753. (b) Li, Z.; Conser, K. R.; Jacobsen, E. N.J. Am. Chern. Soc. 1993, 115, 5326-

5327. (c) Miller, P.; Baud, C.; Jacquier, Y. Tetrahedron, 1996, 52, 1543-1548. (d)

Baret, P.; Buffet, H.; Pierre, J. L. Bull. Soc. Chirn. Fr. 1972,2493.

19. (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chern., Int. Ed. Engl. 1995,

34, 676-678. (b) Zhu, Z.; Espenson, J. H. J. Org. Chern. 1995, 60, 7090. (c) Zhu, Z.;

51

2009

Espenson, J. H. J. Am. Chern. Soc., 1996, 118, 9901. (d) Casarrubios, L.; Perez, J. A.;

Brookhart, M.; Templeton, J. L. J. Org. Chern., 1996, 61, 8358.

20. Kubo, T.; Sakaguchi, S.; Ishii, Y. Chern. Commun., 2000, 625-626.

21. (a) Yadav, J. S.; Reddy, B. V. S.; Rao, M.S.; Reddy, P. N. Tetrahedron Lett. 2003, 44,

5275-5278. (b) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. N.; Rao, M.S.; Synthesis 2003,

1387-1390.

22. Budynina, E. M.; Averina, E. B.; lvanova, 0. A.; Kuznetsova, T. S.; Zefirov, N. S.

Tetrahedron Lett. 2005, 46, 657-659.

23. (a) Morin, R. B.; Gorman, M. Chemistry and Biology of 13-Lactam Antibiotics;

Academic Press: New York, 1982; Vols. 1-3. (b) Thirkettle, J. E.; Schofield, C. J.;

Walter, M. W. Amino Acids Pept. Proteins 1997, 28, 281-333.

24. Ratcliffe, R. W.; Albers-Schonberg, G. In Chemistry and Biology of 13-~Lactam

Antibiotics; Morin, R. B.; Gorman, M.; Eds.; Academic Press: New York, 1982; Vol. 2.

25. (a) Recent Advances in the Chemistry of ~Lactam Antibiotics; Brown, A. G., Roberts,

S. M., Eds.; The Royal Society of Chemistry: London, 1985. (b) Flynn, E. H.

Cephalosporins and Penicillins: Chemistry and Biology; Academic Press, New York,

1972. (c) Singh, G. S. Mini Rev. Med. Chern. 2004, 4, 93-109. (d) Singh, G. S. Mini

Rev. Med. Chern. 2004, 4, 69-92.

26. (a) Ojima, 1.; Delaloge, F. Chern. Soc. Rev. 1997, 26, 377-386. (b) Alcaide, B.;

Almendros, P. Chern. Soc. Rev. 2001,30,226-240.

27. (a) Cheng, J.; Deming, T. J. J. Am. Chern. Soc. 2001, 123, 9457-9458. (b) Eldred, S. E.;

Pancost, M. R.; Otte, K. M.; Rozema, D.; Stahl, S. S.; Gellman, S. H. Bioconjugate

Chern. 2005,16,694-699.

28. Singh, G. S. Tetrahedron 2003, 59, 7631.

29. Zanobini, A.; Brandi, A.; de Meijere, A. Eur. J. Org. Chern. 2006, 1251-1255.

30. Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Sa1alin, J.; Brandi, A. J. Am. Chern.

So~ 2000,122,8075-8076.

31. Zhao, L.; Li, C.-J. Chern. Asian. J. 2006, 1 -2, 203-209.

32. Dhawan, R.; Dghaym, R. D.; St. Cyr, D. J.; Arndtsen, B. A. Org. Lett. 2006, 8, 3927-

3930.

33. (a) Torii, S.; Okumoto, H.; Sadakane, M.; Hai, A. K. M. A.; Tanaka, H. Tetrahedron

Lett. 1993, 34, 6553-6558. (b) Tanaka, H.; Hai, A. K. M.A.; Sadakane, M.; Okumoto,

H.; Torii, S. J. Org. Chern. 1994, 59, 3040-3046.

52

2009

34. (a) Murahashi, S.; Imada, Y.; Taniguchi, Y.; Higashiura, S. J. Org. Chern. 1993, 58,

1538-1545. (b) Murahashi, S.; Imada, Y.; Taniguchi, Y.; Higashiura, S. Tetrahedron

Lett. 1988, 29, 4945-4948.

35. Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron Lett. 1980, 21, )475-

1478.

36. (a) Tsuji, J.; Sato, K.; Okumoto, H. J. Org. Chern. 1984, 49, 1341-1344. (b) Tsuji, J.;

Sato, K.; Okumoto, H. Tetrahedron Lett. 1982,23,5189-5190.

37. Trost, B. M.; Schmuff, N. R.; Miller, M. J. J. Am. Chern. Soc. 1980, 102, 5979-5981.

38. Troisi, L.; De Vitis, L.; Granito, C.; Epifani, E.; Eur. J. Org. Chern. 2004, 1357-1362.

39. Gedey, S.; Vander Eycken, J.; Fulolp, F. Org. Lett., 2002,4, 1967-1969.

40. Kanizsai, 1.; yonfa1vi, S.; Szakonyi, Z.; Sillanpand, R.; Fulop, F. Green Chern., 2007, 9,

357-360.

41. Gedey, S. Vander Eycken, J.; Fulop, F. Lett. Org. Chern., 2004, 1, 215-220.

42. Gedey, S.; Vainiotalo, P.; Zupko, 1.; Peter de Witte, A. M.; Fulop, F. J. Heterocycl.

Chern., 2003,40,951-956.

43. Kolb, J.; Beck B.; Domling, A.; Tetrahedron Lett. 2002, 43, 6897-6901.

44. Naskar, D.; Roy, A.; Seibel, W. L.; West L.; Portlock D. E. Tetrahedron Lett. 2003, 44

6297-6300.

45. Najera, C.; Sansano, J. M. Angew. Chern. Int. Ed. 2005, 44, 6272-6276.

46. Houk, K. N.; Gonzalez, J.; Li, Y. Ace. Chern. Res. 1995,28, 81-90.

47. Grigg, R.; Gunaratne, H. Q. N.; Sridharan, V.; Thianpatanagul, S.; Tute, M. X.

Tetrahedron Lett. 1983, 24, 4363--4366.

48. Troshin, P. A.; Peregudov, A. S.; Miihlbacher, D.; Lyubovskaya, R. N. Eur. J. Org.

Chern. 2005, 3064-3074.

49. Troshin, P. A.; Alexander S. Peregudov, Svetlana M. Peregudova, and Rimma N.

Lyubovskaya Eur. J. Org. Chern. 0000, 0-0

50. Tnivnicek, M.; Potacek, M. Arkivoc, 2001, 5, 156-163.

51. (a) Poomachandran, M.; Raghunathan, R. Tetrahedron 2006, 62, 11274-11281. (b) Lo,

M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. 0.; Schreiber, S. L. J. Am.

Chern. Soc. 2004, 126, 16077-16086.

52. Draffin, W. N.; Harwood, L. M.; Synlett 2006, 6, 857-860.

53. (a) Subramaniyan, G.; Jayashankaran, J.; Raghunathan, R.; Synth. Commun. 2005, 35,

2189-2193. (b) Gamer, P.; Hu, J.; Parker, Christopher, G.; Youngs, W. J.; Doug, M.

53

2009

Tetrahedron Lett 2007, 48, 3867-3870. (c) Pardasani, R. T.; Pardasani, P.; Jain, A.;

Arora, K.; Indian J. Chern., Sect. B: Org. Chern. Incl. Med. Chern. 2006,45, 1204-1209.

54. Zhang, J.; Yang, W.; Wang, S.; He, P.; Zhu, S.; Synth. Commun. 2005, 35, 89-96.

55. Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A.; Org. Lett.,. 2003, 5,

3487.

56. Galliford, C. V.; Martenson, J. S.; Stern, C.; Scheidt, Karl A.; Chern. Commun.,

2007,631-633.

57. Xu, H.-W.; Li, G.-Y.; Wong, M.-K.; Che, C.-M.; Org. Lett., 2005, 7, 5349.

58. Carson, C. A.; Kerr, M. A. J. Org. Chern. 2005, 70, 8242-8244.

59. Huang, W.; O-Donnell, M.-M.; Bi, G.; Liu, J.; Yu, L.; Baldino, C. M.; Bell, A. S.;

Underwood, T. J. Tetrahedron Lett. 2004,45, 8511-8514.

60. Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 4, 2002,3147-3150.

61. Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A.; Tetrahedron Lett. 2004, 45, 8659-

8662.

62. Nair, V.; Vinod, A. U.; Rajesh, C.; J. Org. Chern. 2001, 66, 4427-4429.

63. Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett., 2006,8,4351.

64. Nair, V.; Dhanya, R.; Viji, S. Tetrahedron 2005, 61, 5843-5848.

65. Kamijo, S.; Yamamoto, Y. J. Am. Chern. Soc. 2002, 124, 11940-11945.

66. Baricordi, N.; Benetti, S.; Biondini, G.; De Risi, C.; Pollini, G. P. Tetrahedron Lett.

2004,45,1373-1375.

67. Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chern. 2006,2843-2850.

68. Azoulay, S.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2002,43,9311-9314.

69. Cadiemo, V.; Jos, Gimeno, Nebra, N. Chern. Eur. J. 2007, 00, 0-0.

70. Alizadeh, A.; Movahedia, F.; Esmaili, A. A. Tetrahedron Lett. 2006,47,4469-4471.

71. Devi, N. S.; Perumal, S. Tetrahedron 2006,62,5931-5936.

72. (a) Nair, V.; Bindu, S.; Ba1agopal, L. Tetrahedron Lett 2001, 42, 2043-2044 (b) Nair,

V.; A. Vinod, U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Verma, R. L.; Viji, S.;

Mathew, S.; Srinivas, R. Tetrahedron 2003,59, 10279-10286.

73. Esmaeili, A. A.; Darbanian, M. Tetrahedron 2003,59,5545-5548.

74. Nair, V.; Menon, R. S. ; Deepthi, A.; Devi, B. R.; Biju, A.T. Tetrahedron Lett 2005, 46,

1337-1339.

75. Teimouri, M. B.; Shaabani, A.; Bazhrang, R.; Tetrahedron 2006,62, 1845-1848.

76. Teimouria, M. B.; Khavasib, H. R. Tetrahedron 2007,63, 10269-10275.

54

2009

77. Shabani, A.; Teimouria, M. B.; Bijanzadehb, H. R.; Tetrahedron Lett. 2002, 43, 9151-

9154.

78. Fan, M.-J.; Qian, B.; Zhaoa, L.-B.; Lianga, Y.-M.; Tetrahedron 2007, 63, 8987-8992.

79. Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Do1mling, A. Org. Lett. 2001, 3, 2875-

2878.

80. Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett., 2003,5,2441-2444.

81. Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme, G. J. Org. Chern.

2001,66,175-179.

82. Duan, X.-H.; Liu, X.-H.; Guo, L.-N.; Liao, M.-C.; Liu, W.-M.; Liang, Y.-M. ; J. Org.

Chern. 2005, 70, 6980-6983.

83. Zhao, C.; Lu, J.; Lia, Z.; Xia, Z. Tetrahedron 2004, 60, 1417-1424.

84. Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu, W.-M.; Liang, Y.-M. J. Org.

Chern. 2005, 70, 6980-6983.

85. Satoh, T.; Tsuda, T.; Kushino, Y.; Miura, M.; Nomura, M.; J. Org. Chern. 1996, 61,

6476-6477.

86. Alizadeh, A.; Zohreh, N.; Rostamnia, S. Tetrahedron 2007, 63, 8083-8087.

87. Sridhar, M.; Rao, R. M.; Baba, N.H. K.; Kumbhare, R. M. Tetrahedron Lett 2007, 48,

3171-3172.

88. Teimouri, M. B. Tetrahedron 2006,62, 10849-10853.

89. Xie, F.; Cheng, G.; Hu, Y. J. Comb. Chern. 2006, 8, 286-288.

90. Ahmed, M. S.M.; Kobayashi, K.; Mori, A. Org. Lett., 2005, 7, 4487.

91. Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079-4082.

92. Kercher, T.; Rao, C.; Bencsik, J. R.; Josey, J. A. J. Comb. Chern. 2007, 9, 1177.

93. A1izadeh, A.; Sheikhi, E. Tetrahedron Lett. 2007, 48, 4887-4890.

94. Illgen, K.; Nerdinger, S.; Behnke, D.; Friedrich, C.; Org. Lett. l005, 7, 39-42.

95. Porwal, S.; Kumar, R.; Maulik, P. R; Chauhana, P. M. S. Tetrahedron Lett 2006, 47,

5863-5866.

96. Matsuoka, Y.; Ishida, Y. Sasaki, D.; Saigo, K. Tetrahedron 2006, 62, 8199-8206.

97. Yadav, J. S.; Reddy, B.V.S.; Sreedhar, P.; Murthy, C.V.S.R; Mahesh, G.; Kondaji, G.;

Nagaiah, K. Journal of Molecular Catalysis A: Chemical2007, 270, 160-163.

98. Lijun Fan, Emil Lobkovsky, Bruce Ganem, Org. Lett., 2007,9,2015-2017.

99. Maghsoodlou, M. T.; Marandi, G.; Hazeri, N.; Aminkhanib A.; Kabiri, R. Tetrahedron

Lett 2007,48,3197-3199.

55

2009

100. Wang, Q.; Ganem, B. Tetrahedron Lett. 2003,44, 6829-6832.

101. Black, D. A.; Arndtsen B. A. Tetra~edron 2005,61, 11317-11321.

102. Henkel, B.; Beck, B.; Westner, B.; Mejat, B.; Domling, A. Tetrahedron Lett

2003,44,8947-8950.

103. Pinho e Melo, T. M.V.D.; Soares, M. I. L.; Nunes, C. M. Tetrahedron, 2007, 63, 1833-

1841.

104. Srivastava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002,58,7619-7624.

105. Fraga-Dubreuil, J.; Bazureau, J.P. Tetrahedron 2003, 59, 6121-6130.

106. Esmaeili, A. A.; Amini, S.; Bodaghi, A. Synlett, 2007, 1452-1454.

107. Yavari, 1.; Hossaini, Z.; Sabbaghan M.; Ghazanfarpour-Datjani, M. Tetrahedron 2007,

63, 9423-9428.

108. Nair, V.; Mathai, S.; Mathewa, S.C.; Rath, N. P. Tetrahedron 2005, 61,2849-2856.

109. Sreedhar, B.; Reddy, P. S.; Krishna, V. R.; Tetrahedron Lett 2007,48, 5831-5834.

110. (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2004, 69, 2386-2393. (b)

Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,7786-7787.

111. Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; der Eycken, E. V. Org. Lett. 2004, 6, 4223.

112. Wang, M.-Z.; Xu, H.-W.; Liu, Y.; Wong, M.-K.; Che, C.-M. Adv. Synth. Catal. 2006,

348,2391-2396.

113. Adib, M.; Jahromi, A. H.; Tavoosi, N.; Mahdavi, M.; Bijanzadeh, H. R. Tetrahedron

Lett. 2006, 47, 2965-2967.

114. Kumar, A.; Maurya, R. A. Synlett, 2008, 883-885.

115. Xia, J.-J.; Wang, G.-W. Synthesis 2005: 2379-2383.

116. Sharma, S.D.; Hazarika, P.; Konwar, D. Catal. Commun. 2008,9,709-714.

117. Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron, 2004,60,2311-2326.

118. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946-1952.

119. Kumar, A.; Maurya R. A. Tetrahedron Lett. 2007, 48, 3888-3890.

120. Kumar, A.; Maurya, R. A. Tetrahedron, 2008, 64,3477-3482.

121. (a) Wu, T.S.; Chan, Y. Y.; Leu, Y. L.; Chern, C.Y.; Chen, C.F. Phytochem. 1996, 42,

907. (b) Bodger, D. L.; Hong, J. J. Am. Chem. Soc. 1998, 120, 1218.

122. Stevenson, P. J.; Graham, I. Arkivoc 2003, 139-144.

123. Guo, H.; Ding, K. Tetrahedron Lett. 2003,44,7103-7106.

124. Shindoh, N.; Tokuyama, H.; Takasu, K. Tetrahedron Lett. 2007, 48, 4749-4753.

56

2009

125. Yehia, N. A.M.; Polborn, K.; Muller, T. J. J. Tetrahedron Lett 2002,43,6907-6910.

126. Devi, 1.; Kumar, B.S. D. Bhuyana, P. J. Tetrahedron Lett 2003,44, 8307-8310.

127. Xiong, X.; Bagley, M. C.; Chapaneri, K. Tetrahedron Lett. 2004, 45, 6121-6124.

128. Nair, V.; Devi, B. R.; Varma, L. R. Tetrahedron Lett. 2005, 46, 5333-5335.

129. Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedova, I. V.;

Kornienkob, A. Tetrahedron Lett 2006,47,9309-9312.

130. Devi, N. S.; Perumal, S. Tetrahedron Lett 2007, 48, 5627-5629.

131. Kysil, V.; Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.; Churakova, M.;

Ivachtchenko, A. Tetrahedron Lett. 2007,48, 6239-6244.

132. Zhao, Y.-L.; Zhang, W.; Wang, S.; Liu, Q. J. Org. Chem. 2007, 72, 4985-4988.

133. Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8,

899-902.

134. Asao, N.; Iso, K.; Yudha S. S. Org. Lett. 2006,8,4149-4151.

135. Zhu, S.-L.; Jia, S.-J.; Zhang, Y. Tetrahedron 2007, 63, 9365-9372.

136. Ballini, R.; Bosica, G.; Conforti, M. L.; Maggi, R.; Mazzacani, A.; Righi, P.; Sartori, G.

Tetrahedron 2001, 57, 1395-1398.

137. Jimenez-Alonso, S.; Estevez-Braun, A. Ravelo, A. G.; Zaratea, R.; Lopeza, M.;

Tetrahedron 2007, 63,3066-3074.

138. Devi, 1.; Bhuyan, P. J. Tetrahedron Lett. 2004,45, 8625-8627.

139. Elinson, M. N.; Vereshchagin, A. N.; Feducovich, S. K.; Zairnovskaya, T. A.;

Starikova, Z. A.; Belyakova, P. A.; Nikishina, G. I. Tetrahedron Lett. 2007, 48, 6614-

6619.

140. Takemura, 1.; Imura, K.; Matsumoto, T.; Suzuki, K. Org. Lett. 2004, 6, 2503-2505.

141. Nair, V.; Menon, R. S.; Deepthi, A.; Devi, B. R.; Biju, A. T. Tetrahedron Lett. 2005,

46, 1337-1339.

142. Kumar, A.; Maurya R. A. J. Mol. Catal. A: Chem 2007, 272, 53-56.

143. Kumar, A.; Maurya R. A. Tetrahedron Lett. 2007, 48,4569-4571.

144. Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2006, 128,

14802-14803

145. Wang, Z.-T.; Xu, Li-W. Xia, C.-G.; Wanga, H.-Q. Tetrahedron Lett. 2004, 45, 7951-

7953.

146. Holla, B.S.; Rao, B.; S.; Sarojini, B. K.; Akberali, P.M. Eur. J. Med Chem 2004, 39,

777-783.

57

2009

147. Dandia, A.; Singh, R.; Sarawgi, P. Journal of Fluorine Chemistry 2005,126,307-312.

148. Shaabani, A.; Bazgir, A. Tetrahedron Lett. 2004,45, 2575-2577.

149. Bussolari, J. C.; McDonnell, P. A. J. Org. Chern. 2000,65, 6777-6779.

150. Shabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chern. 2007, 72, 6309-6311.

151. Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.; Gonnade, R. C.; Org. Lett.

2002, 4, 3575-3577.

152. Mulller, T. J. J.; Braun, R.; Ansorge, M.; Org. Lett. 2000,2, 1967-1970.

153. Karpov, A. S.; Mulller, T. J. J. Org. Lett. 2003,5, 3451-3454.

154. Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Org. Lett. 2006,8,2599-2602.

155. Adib, M.; Ghanbary, K.; Mostofia, M.; Bijanzadeh, H. R. Tetrahedron 2005, 61, 2645-

2648.

156. Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D.; H.; Koh, H. Y.; Kim, Y. Org

Lett. 2001, 3, 4149-4152.

157. Young, I. S.; Kerr, M.A. Org. Lett. 2004, 6, 139-141.

158. Marcaccini, S.; Pepino, R.; Torroba, T.; Miguelc, D.; Garcia-Valverdeb, M.

Tetrahedron Lett. 2002, 43, 8591-8593.

159. Yamada, S.; Misono, T.; Morita, C.; Nunami, N. Tetrahedron Lett. 2003, 44, 7365-

7367.

160. Pan, S. H.; Y.; Zhu, Y.; Wu, A. Org. Lett. 2005, 7, 3797-3799.

161. Indumathi, S.; Kumar R. R.; Perurnal, S. Tetrahedron 2007, 63, 1411-1416.

162. Fujioka, H.; Murai, K.; Kubo, 0.; Ohba, Y.; Kita, Y. Org. Lett. 2007,9, 1687-1690.

163. Murai, K.; Nakatani, R.; Kita, Y.; Fujioka, H. Tetrahedron, 2008,64, 11034-11040

164. Enrique, S.; Thierry, C.; Jean, R. Synlett 2008, 1313-1316.

165. Palirnkar, S. S.; Lahoti R. J.; Srinivasan, K. V.; Green Chern., 2007, 9, 146-152.

166. Muller, T. J. J.; Braun, R. U.; Fourth International Electronic Conference on Synthetic

Organic Chemistry (ECSOC-4), www.mdpi.org/ecsoc-4.htm, September 1-30,2000

167. Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 3535-3538.

168. Katritzky, A. R.; Fali, C. N.; Li, J. J. Org. Chern. 1997, 62,4148.

169. Langer, P.; Doring, M.; Goris, H.; Eur. J. Org. Chern. 2001, 1511.

170. Beckert, R.; Mayer, R.; Wiss, Z. Techn. Univers. Dresden 1987, 2, 36.

58