A fascinating decade for the synthesis of 1,2-azoles - De Gruyter

DOI 10.1515/hc-2013-0017 Heterocycl. Commun. 2013; 19(2): 79–87

Review

Subhendu Chakroborty* , Chittaranjan Bhanja and Satyaban Jena

A fascinating decade for the synthesis of 1,2-azoles Abstract: 1,2-Azoles comprising pyrazoles, isoxazoles,

and isothiazoles have occupied a distinctive position in

the design and synthesis of novel biologically active com-

pounds that exert remarkable pharmaceutical activities

as medicines and agrochemicals. As a consequence, there

has been an increasing interest among synthetic organic/

medicinal chemists in the development of methodologies

for the rapid access to these heterocycles. In this review,

we have summarized the most significant advances in the

construction of functionalized pyrazoles, isoxazoles, and

isothiazoles reported in the literature up to 2012.

Keywords: 1,2-azoles; isothiazoles; isoxazoles; pyrazoles;

synthesis.

*Corresponding author: Subhendu Chakroborty, Department of

Chemistry, Ravenshaw University, Cuttack 753003, Odisha, India,

e-mail: [email protected]

Chittaranjan Bhanja and Satyaban Jena: Department of Chemistry,

Utkal University, Bhubaneswar 751004, Odisha, India

Introduction Heterocycles are of immense importance in the design and

discovery of new compounds for pharmaceutical applica-

tions. Among them, functionalized pyrazoles, isoxazoles,

and isothiazoles are present in a myriad of medicinally

important natural and synthetic compounds that have

a broad and interesting range of biological activities

including antibacterial [ 1 ], antiviral [ 2 ], antitumor [ 3 ],

antidiabetic [ 4 ], anticancer [ 5 ], anti-inflammatory [ 6 ],

antipyretic [ 7 ], and HIV-1 protease inhibitory activity [ 8 ].

Some representative molecules of this structural motif

are shown in Figures 1 and 2 . Therefore, synthetic metho-

dologies allowing the rapid access to these heterocycles

are highly desirable in organic synthesis and chemical

biology/medicinal chemistry. Some review articles have

been published on pyrazole chemistry in earlier literature

[ 9 , 10 ]; however, to the best of our knowledge there is no

recent literature comprising all three 1,2-azoles, that is,

pyrazoles, isoxazoles, and isothiazoles. This review is

intended to provide updated information regarding the

available methodologies (focusing on the period 2002 –

2012) in the synthesis of functionalized pyrazoles, isoxa-

zoles, and isothiazoles.

1 H -Pyrazoles A simple methodology for the one-pot synthesis of

1,3,5-trisubstituted pyrazoles was reported by Armstrong

et al. [ 11 ] in 2005. The protocol involves the electrophilic

amination of primary amines with N -Boc-oxaziridine

under metal-free conditions that affords synthetically ver-

satile, mono-Boc-protected hydrazines. Condensation of

the hydrazines with symmetrical 1,3-diketons affords the

1,3,5-trisubstitutes pyrazoles (Scheme 1).

In 2006, Boruah and coworkers [ 12 ] reported on a

novel one-pot method for pyrazoles by the reaction of

β -formyl enamides 4 with hydroxylamine hydrochloride

catalyzed by potassium dihydrogenphosphate in acid

medium. The reactions of a broad range of β -formyl ena-

mides such as steroidal, alicyclic, aliphatic, and aromatic

β -formyl enamides give rise to the corresponding pyra-

zoles in high yields (Scheme 2).

Silver(I)-catalyzed regioselective synthesis of 1,3-

and 1,5-substituted pyrazoles was reported by the Chung

group in 2008 [ 13 ]. Under mild reaction conditions, intra-

molecular cyclization of propargyl N -sulfonylhydrazones

8 in the presence of 5 mol% AgSbF 6 as catalyst in dry

dichloromethane affords 1,3,5-substituted pyrazoles 9 at

room temperature. The process involves an intermolecu-

lar migration of the sulfonyl group through the forma-

tion of a tosyl anion and an electron-deficient pyrazolyl

iminium cation as anion pair. N -Monosubstituted pyra-

zoles (R 1 �R 2 �H) are obtained in high yield from a variety

of aryl, alkenyl, and styryl hydrazones. The introduction

of a methyl group at the propargylic position in the styryl

hydrazine 8 slightly decreases the yield of the reaction.

Moreover, 1,3,5-substituted pyrazoles 9 are obtained in

80 S. Chakroborty et al.: Synthesis of 1,2-azoles

1,2-azoles

N O

HO

OHO

NH2

Ibotenic acid

NN

OHO

NH2

1-Pyrazolyl-alanine

NH

SN

Brassilexin

NO

NH2

HOMuscimol

NNH

H2N

Betazole

SNN

N

HN

OCl

Ziprasidone

ON

SO O

H2N MeValdecoxib

NN CF3

SO

O

H2N

MeCelecoxib

Figure 2 1,2-Azoles in natural products and pharmaceutical drugs.

N NN N

Antitumor

Cl

N NH

HN

O

NS

O

Cl

H

Antibacterial

NHN

COOH

HO

Antidiabetic

NN

S

CH

Me

NO

NCl

FCl

Antiviral

Cl

Cl

HN

S N

CN

OH

Antiviral

NH O NCl

O

Anticancer

N

ClCl

OO

ON N

OPhPh

Antibacterial

NS

NC SH

Ph

HIV-1 protease inhibitors

ON

MeS

H2N

O O

Anti-inflammatory

NNtBu

Me

O

Antipyretic activity

Figure 1 Biologically important 1,2-azoles.

S. Chakroborty et al.: Synthesis of 1,2-azoles 81

acceptable yield starting from 4-methoxystyryl hydrazone

(Scheme 3).

An efficient, rapid, and general one-pot synthetic

protocol of 3,5-, 1,3,5-, 3,4,5-, and fused ring-substituted

pyrazoles 13 was reported by Heller and Natarajan in

2006 (Scheme 4) [ 14 ], starting from enolizable ketones 10 ,

acid chlorides 11 , and hydrazines. In the methodology,

the 1,3-diketones (not isolated) so produced are converted

in situ into pyrazoles by treatment with the appropriate

hydrazines. A wide range of functional groups such as

nitriles, alkyl halides, and electrophiles with enoliz-

able moieties are tolerated in the reaction. The reaction

between cyclic saturated ketones and acid chlorides

affords fused pyrazoles in good yields. Moreover, both

benzyl p -chlorophenyl ketone and n -butyl p -chlorophenyl

ketone are coupled with p -methoxybenzoic acid chloride

to give the corresponding 1,3-diketones, which are then

condensed with hydrazine to afford the corresponding

3,4,5-substituted pyrazole derivatives.

Subsequently, Jiang et al. [ 15 ] reported on an effi-

cient and general one-pot procedure for the synthesis

R2N

R1

TsN

R3

5 mol% AgSbF6

CH2Cl2, 15~20°C, 3 h NNTs

R3

R1

R2

8 9

R1 = H, Me R2 = H, Me, Ph R3 = Ph, styryl, alkyl

65-98%

Scheme 3

R1

LiOR2 R3 Cl

OLiHMDS, toluene

0°C, 2 minR1 R3

R2

O O

AcOH, EtOH, THFauto-reflux, 5 min

NNR4

R3R2

R1

10 11 12 13

RNHNH2

R1 = aryl, heteroaryl; R2 = H, n-propyl, Ph; R1/R2 = CH2CH2OCH2, CH2CH2N(Boc)CH2, (CH2)4R3 = aryl, n-C5H11; R

4 = H, Me, Ph

Scheme 4

R-NH2

a. EtO2C

NBocO

CO2Et, CH2Cl2, rt, 72 h

b. NaHCO3 (aq) then MgSO4c. TF A, rt, 0.5 h

d.Et Et

OO, rt, 24 h

NNR

EtEt1

2

3

R = PhCH2CH2, Bn, Ph(CH)Me, Ph, 4-CN-Ph

Scheme 1

CHONHAc

R2R1

NH2OHCHNOH

NHAc

R2

R1

H2PO4

HC

N

R2

R1

NOH

H

H

Ac

H2PO4

NNAc

R2

R1

4 5 6 7

HCl

R1 and R1 = steroidal, alicyclic, aliphatic, and aromatic β-formyl enamide groups

Scheme 2

of pyrazoles from acid chlorides, terminal alkynes, and

hydrazines. Acid chlorides 14 undergo coupling with ter-

minal alkynes 15 to give α , β -unsaturated ynones which,

in situ , are converted into pyrazoles by the cycloaddition

of hydrazines catalyzed by Pd(PPh 3 )

2 Cl

2 /CuI. 3,5-Diaryl-

1 H -pyrazoles 16 are obtained in moderate to good yields

from aryl chlorides and aryl terminal alkynes. However,

the use of aliphatic alkyne, 1-octyne, leads to its corre-

sponding pyrazole derivative in low yield (Scheme 5).

Fully substituted pyrazoles have received a great deal

of attention as they exhibit useful pharmacological and

agrochemical properties. In 2011, Wang et al. reported on

a methodology in which tetrasubstituted pyrazole 19 has

been obtained from 2-azidoacrylate 17 and hydrazine 18

via [3 + 2] cycloaddition reaction in the presence of trieth-

ylamine in moderate to good yields with high regioselec-

tivity (Scheme 6) [ 16 ].

Soon after, Zora and coworkers [ 17 ] reported on the

synthesis of highly substituted 4-iodopyrazole derivatives

by electrophilic cyclization of acetylenic aldehydes and

ketones through the intermediary of hydrazones in the

presence of molecular iodine. The mechanism proposed

by the authors involves an electrophilic addition of I + to


the alkyne, leading to an iodonium ion that undergoes an

electrophilic cyclization via nucleophilic attack of the sec-

ondary nitrogen atom to furnish protonated pyrazole 23 .

Finally, deprotonation with base affords 4-iodopyrazole

derivative 24 (Scheme 7).

In recent years, interest in greener technologies has

favored the development of using alternative reaction

media that circumvent the problems associated with

many of the traditional volatile organic solvents. Adopt-

ing this eco-friendly technology, Yu and coworkers in

2011 [ 18 ] developed a protocol for the synthesis of highly

functionalized pyrazole 27 . Thus, condensation of α , β -

unsaturated carbonyl compound 25 with tosyl hydrazide

26 in water affords trisubstituted pyrazole 27 in high yield

(Scheme 8).

Another strategy based on an environmentally

benign, eco-friendly approach for the synthesis of pyra-

zoles has been developed by Chandak et al. [ 19 ]. The

method involves the condensation of hydrazine/hydrazide

29 with 1,3-diketone 28 using Amberlyst-70 as a recyclable

catalyst which proceeds efficiently at room temperature in

aqueous medium without the use of any organic solvent

affording substituted pyrazole 30 (Scheme 9).

R1 Cl

OPh

1. PdCl2(PPh3)2, CuIEt3N, THF

2. NH2NH2 N NH

PhR1

14 15 16H2O

R1 = Ph, Bn, 2-furyl, 2-thienyl

Scheme 5

PhCOOEt

N3Me N

MeNH

Ph

Et3N

CH3CN, rt, 12 hN

N

Ph

Ph

COOEt

Ph

17 18 19

Scheme 6

R1R2

N NHR3

I2 and/or

NaHCO3

R1R2

NHN

R3

R2R1

NHN

R3

I

NN

H R3

R2I

R1

NaHCO3

-H2CO3 NNR3

R2I

R1

20 21

22 23 24

R1 = alkyl, aryl, heteroaryl, ferrocenylR2 = H, Me, Ph; R3 = alkyl, aryl

-NaI

Scheme 7

R1 R3

O

R2

TsNHNH2

NaOH

PTC, H2O

HNN

R3R1

R2

25 26 27

R1 = Ph, 3-pyridyl, 2-furylR2 = H, Me; R3 = H, Me

Scheme 8

Very recently, Dissanayake and Odom [ 20 ] reported

on an efficient three-component, one-pot reaction for the

preparation of substituted pyrazoles. The strategy involves

a simple titanium complex-catalyzed three-component

coupling of alkynes 32 , isonitriles 33 , and monosubsti-

tuted hydrazines 31 to provide substituted pyrazoles 34 in

a single step. This is the first reported protocol where tran-

sition metal efficiently catalyzes the coupling to produce a

single regioisomer in high yield (Scheme 10).

Isoxazoles The electrophilic cyclization of functionally substituted

alkynes has attracted much attention due to its wide

utility in the preparation of a range of useful, function-

ally substituted heterocycles. In 2005, Waldo and Larock

[ 21 ] reported on an efficient protocol in which the reac-

tion of 2-alkyn-1-one O -methyl oximes 38 with ICl,I 2 ,Br

2 , or

PhSeBr affords 3,5-disubstituted 4-halo(seleno)isoxazoles

39 in good to excellent yields under mild reaction condi-

tions (Scheme 11).

Me

O

R1

O

X

R2

NH

NH2Amberlyst-70, H2O

rt, 5-30 min

NNR2

R1

X

Me

28 29 30

R1 = Me, OEt; R2 = H, Ph, 4-Cl-Ph, CONH2, CSNH2X = H ,Cl, Me

Scheme 9

PhNHNH2 RNC

15% Ti(NMe2)2(pypyr)2

toluene, 100°C, 36 hN

NPh

R31 32 33 34

R = CH2SiHMe3, (CH2)3OTBSpypyr = 2-(2′-pyridyl)-3,5-dimethylpyrrole

-H2NC6H11

Scheme 10


Currently, one-pot reactions are gaining prominence

due to their environmental advantages and cost effec-

tiveness. In 2006, Yavari and Moradi [ 22 ] reported on a

one-pot strategy for the synthesis of isoxazoles 43 from

dialkyl acetylenedicarboxylates or dibenzoylacetylene

with alkyl 2-nitroethanoates 42 in the presence of triph-

enylphosphine (Scheme 12).

Microwave-assisted multicomponent reactions are

efficient and effective methods in the sustainable and

diversity-oriented one-pot synthesis of heterocycles.

Based on consecutive coupling-cycloaddition sequencing

starting with room temperature coupling and subsequent

dielectric heating for completion of the cycloaddition,

M ü ller and coworkers [ 23 ], in 2008, reported on new

avenues to the one-pot synthesis of isoxazole frameworks

in a multicomponent reaction manner. Thus, the Sonoga-

shira coupling of acid chloride 44 with terminal alkyne

R1 Cl

O1.2 H R1

cat. PdCl2(PPh3)2

cat. CuI, Et3N

R1 H

O Li

R1

R2

MnO2 or PCC

R1

OR2

NH2OMe

R1

NR2

OMe

E-X N OR2

ER1

35

36

37 38 39

R1 = H, Ph, n-C6H13, tBu

R2 = Ph, Me, tBu, TIPSE-X = ICl, Br2, PhSeBr

HCl

Scheme 11

PPh3

COOMe

COOMeRO

ONO2

tolueneN

O

CO2RMeOOC

MeOOC

40 41 42 43

R = Me, Et

Δ

Scheme 12

Cl

O

Si(Me)3

[2% PdCl2(PPh3)2, 4% CuI]

Et3N (1 equiv), THF, 1 h, rtO

Si(Me)3

Cl

NOH

Et3N (1.10 equiv)30 min, MW, 90°C O

N

O

(Me)3Si

44 45 46

47

48

SS

SOMe

OMe

Scheme 13

45 , followed by 1,3-dipolar cycloaddition under dielectric

heating of in situ generated nitrile oxide from hydroximi-

noyl chloride 47 furnished isoxazole 48 in moderate to

good yields (Scheme 13).

A dipolar cycloaddition strategy for the synthesis of

substituted isoxazoles with complete regioselectivity at

room temperature was developed by Grecian and Fokin

in 2008 [ 24 ]. Thus, the cycloaddition reaction of nitrile

oxides (generated in situ from hydroximoyl chlorides by

treatment with Et 3 N) and terminal or internal alkynes 15

in the presence of ruthenium(II)-catalyst affords 3,5-di-

and 3,4,5-trisubstituted isoxazoles in excellent yields

and with complete regioselectivity at room temperature

(Scheme 14).

A first environmentally benign protocol using ionic

liquid (IL) as noble solvent for the construction of the isox-

azole ring was reported by the Valizadeh group in 2009

[ 25 ]. The novel method involves the reaction of β -diketone

and hydroxylamine hydrochloride in IL [bmim]Br that pro-

vides biologically active isoxazoles in excellent isolated

yields. The moderate reaction conditions, easy workup

procedure, and recyclability of the nonvolatile IL make

this protocol an environmentally friendly method amena-

ble for scale-up synthesis (Scheme 15).

A versatile and efficient synthesis of a broad

library of isoxazoles 58 was reported by Bhuniya and


coworkers in 2009 [ 26 ] via 1,3-dipolar cycloaddition

(1,3-DC) of aldoximes 55 with dipolarophile 56 or 57 in

the presence of Magtrieve ™ (CrO 2 ), which is an efficient

reagent for the oxidation of aldoximes to nitrile oxides,

the intermediate products in this cycloaddition reaction

(Scheme 16).

Campagne and coworkers [ 27 ] reported on an exqui-

site, efficient one-pot synthesis methodology for the

Ph R1

OO

NH2OH[bmim]Br

NaOH, 65°C

O N

PhR1

52 53 54

[bmim] = 1-n-butyl-3-methylimidazoliumR1 = Ph, 4-Cl-C6H4

HCl

Scheme 15

N

R1

HO X Xor

CrO2, MeCN

80°C, 2hON

X

R1

55 56 57 58

R1 = Ph, 4-Cl-Ph X = Ph, Bn, AcO, TMS

Scheme 16

HO

PhBun

Bun Bun

Bun

PhSO2NHOHFeCl3 (5 mol%)

then Et3N (3 equiv)CH2Cl2, Δ, 2 h

90%

N O

Ph

PhH

N OHPhO2S

Ph

NOH

58

59 60

61

Scheme 17

ClCl

N OH

5 mol % [Cp*RuCl(cod)]

NO

Ph

ClN

OCl

Ph1,2-DCE49

15

50 51

Scheme 14

N

Ph

OMe

COOBut

Pd(CF3COO)2 (10 mol%)CuCl2 (2 equiv)

n-Bu4NBr (1 equiv)Li2CO3 (2 equiv)

NMP, 150°C

NO Ph

H COOBut

62 63 64

BrBr

Scheme 18

construction of substituted isoxazoles 61 . Using N -sul-

fonyl-protected hydroxylamines 59 as binucleophiles,

the propargylic substitutions catalyzed by iron allows

the selective, in situ formation of propargylic oxime

60 from starting propargylic alcohols 58 . The substi-

tuted isoxazoles 61 are obtained in good isolated yields

(Scheme 17).

A series of 3,4,5-trisubstituted isoxazoles exempli-

fied by 64 were prepared by Chen and coworkers [ 28 ] in

2012 from O -methyl oxime substrates through a cascade

process involving a Pd(II)-catalyzed 5-endo-dig cyclization

to form the hetero aryl palladium intermediate, which is

then transformed into another intermediate product after

the loss of a methyl group. The Heck coupling between the

last intermediate product and an alkene affords the trisub-

stituted isoxazole 64 . Electron-withdrawing substituents

on the alkenes increase yields of the final products 64

(Scheme 18).

Dadiboyena and Nefzi [ 29 ] have developed an

efficient parallel solid phase methodology to con-

struct the diversity oriented substituted isoxazoles via

1,3-dipolar cycloaddition reaction. Thus, the cycload-

dition of resin-bound alkenes or alkynes, synthesized

from the corresponding resin-bound carboxylic acids,

with in situ generated nitrile oxides, leads to the for-

mation of the corresponding disubstituted isoxazoles

(Scheme 19).

Very recently Suzuki et al. [ 30 ] developed a two-step

protocol for efficient synthesis of highly functionalized

polycyclic isoxazoles. The method involves 1,3-dipolar

cycloaddition of stable benzonitrile oxides to p -quinone

monoacetals 72 in a regioselective manner, favoring the

formation of 4-acyl cycloadducts 73 , followed by MnO 2 -

mediated dehydrogenation to highly functionalized poly-

cyclic isoxazoles 74 (Scheme 20).


Isothiazoles In 2002, Abd El-Nabi [ 31 ] reported on a methodology for the

synthesis of highly substituted pyrrolo[2,3- c ]isothiazoles.

The method involves the treatment of 1-aryl-5-methoxy-

pyrole-2-one with CS 2 followed by treatment with dimethyl

sulfate in the presence of NaOH and dimethyl sulfoxide

that gives 3-bis(methylsulfonyl)methylene pyrrol-2-one

75 . Compounds 75 are transformed into oximes 76 that

are precursors to functionalized fused isothiazoles 77

(Scheme 21).

HN R1

O tBuOLi, DMSO, 5 h

BrN

R1

O

Cl

NHO

R2

ON N R1

O

R2anhyd. HF

ON N

HR1

O

R2

rt, overnightCH2Cl2, Et3N

65 66 67

68

69 70

90 min, 0°C

R1 = cyclopentyl, 1-cyclopenteneacetyl, piperonyl, PhR2 = 4-Cl-Ph, 2-Cl-6-Cl-Ph

Scheme 19

OMeC

NO

O

O

O

MeO OMe

cycloaddition

O

OMeOMe

Me

ON H

H

- H2

DehydrogenationO

OMeOMe

Me

ON

OMe

OMe

OO

OO

71 72 73

74

1,3-dipolarMe

Scheme 20

NMeO NOH

MeSSMe

Ar

SOCl2, pyridine

NMeO

Ar

NS

SMe

75 76

NMeO O

MeSSMe

Ar

NH2OH

77

HCl

Ar = Ph, p-MeC6H5, p-MeOC6H5

Scheme 21

Shibata et al. [ 32 ] have developed a procedure for

the synthesis of 3,3-disubstituted benzosultams 79 from

benzenesulfonamide 77 . The regiospecific o -lithiation of

N-t -butylbenzenesulfonamide 77 followed by reaction

with ketones afforded the carbinol sulfonamides 78 , which

underwent cyclization to the final products 79 (Scheme 22).

A facile synthesis of 3-substituted isothiazoles fused

to a benzene ring has been developed by Devarie-Baez

and Xian [ 33 ]. The protocol involves the nitrosation of

o -mercaptoacylphenone 80 with isopentyl nitrite to form

an unstable S -nitrosothio intermediate which under-

goes an intramolecular aza-Wittig reaction to furnish the

desired benzisothiazole 81 ( Scheme 23).

In 2011, the Shibasaki group [ 34 ] developed a dis-

tinct approach to enantio-enriched fused isothiazoles

through a cascade of C-C and S-N bond formation reac-

tions promoted by Cu catalysis. The unprecedented route

involves a Cu-catalyzed asymmetric conjugate addition of

allyl cyanide 83 to α , β -unsaturated thioamides 82 by soft

Lewis acid/hard Br ø nsted base/hard Lewis base coopera-

tive catalysis followed by Cu-catalyzed cascade cycliza-

tion to afford isothiazole 84 (Scheme 24).

An efficient one-pot strategy for the synthesis of

steroidal and non-steroidal isothiazoles found in some

SO2NHBut

1. tBuLi, THF

2. R1COR2

THF, -78°C

SO2NHBut

R1

OHR2

TMSCl

NaI, MeCNΔ, 1 h

NHS

OO

R1 R2

R1 = Me; R2 = Me, Ph, 1-naphthyl, 4-methylphenylR1/R2 = (CH2)4, (CH2)5, indanyl

77 78 79

Scheme 22

Me

O

SH

1. isopentyl-ONO (3 equiv), 0°C

2. PPh3 (2.1 equiv), 0°C to rt SN

Me

POPh3

80 81

Scheme 23


natural products and pharmaceuticals has been reported

by Boruah et al. [ 35 ]. Thus, the reaction of ring annelated

β -bromo- α , β -unsaturated aldehydes 86 with a mixture

of sodium thiocyanate and urea as an environmentally

benign source of ammonia under microwave irradiation

(MWI) affords corresponding steroidal and non-steroidal

isothiazole derivatives. These β -bromo- α , β -unsaturated

aldehydes derivatives are efficiently synthesized from cor-

responding cyclic ketones 85 using the Vilsmeier formyla-

tion reaction (Scheme 25).

Conclusion The past decade has seen a considerable expansion in

research on the chemistry of 1,2-azoles due to numerous

applications of these heterocyclic compounds in various

fields such as medicine, agrochemistry, natural product

synthesis, and catalysis. This review critically demon-

strates the synthetic methodologies developed within the

past 10 years for access to these heterocycles. Although

the classical cyclocondensation methods are still the most

commonly used procedures for their construction, new

approaches need to be developed with the aim of increas-

ing both yields and regioselectivities in the preparation

of substituted 1,2-azoles. We hope that this review will be

helpful to those who have a keen interest in the chemistry

of 1,2-azoles.

Acknowledgments: S.C. sincerely acknowledges CSIR,

New Delhi, India for providing financial support through

an SRF fellowship, and C.B. sincerely acknowledges

UGC, ERO, Kolkata, India for providing financial support

through Teacher Fellow Grant.

Received January 27, 2013; accepted February 13, 2013; previously

published online March 25, 2013

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Bn2N R

S

CN

HBn2N

Bn2NS

Me

R

CN

NS

RLi(OC6H4-p-OMe)0°C

toluene, THF, rt

[Cu(CH3CN)4]PF6(R)-DTBM-segphos

CuOTfLi(OC6H4-p-OMe)

82

8384

R = Ph, Me, iPr, p-MeC6H4, p-MeOC6H4, p-FC6H4

Scheme 24

OMe

Me

AcOH

PBr3, DMF, CHCl3

BrMe

Me

AcOH

CHO

NaSCN, urea, DMF

Me

Me

AcOH

NS

MW 360 W, 10 bar, 80%

85 86

87

72%

Scheme 25


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A fascinating decade for the synthesis of 1,2-azoles - De Gruyter