Synthesis of maleate derivatives in isocyanide-baseMCRs: reaction of 2-mercaptobenzoxazole with alkylisocyanides and dialkyl acetylenedicarboxylates

Khatereh Khandan-Barani •

Malek Taher Maghsoodlou • Alireza Hassanabadi •

Mohammad Reza Hosseini-Tabatabaei •

Jilla Saffari • Mehrnoosh Kangani

Received: 16 June 2013 / Accepted: 16 September 2013

� Springer Science+Business Media Dordrecht 2013

Abstract Dialkyl 2-((alkylimino)(2-thioxobenzo[d]oxazol-3(2H)-yl)methyl) maleate

derivatives were obtained from the reaction between alkyl isocyanides, dialkyl acetylene

dicarboxylates, and 2-mercaptobenzoxazole in CH2Cl2 at room temperature in good

yields.

Keywords 2-Mercaptobenzoxazole � MCRs � Isocyanides � One-pot �Acetylenic esters

Introduction

Multi-component reactions (MCRs) are special types of synthetically useful organic

reactions in which three or more different starting materials react to a final product

in a one-pot procedure [1]. MCRs are powerful tools in the modern drug discovery

process and allow the fast, automated, and high-throughput generation of organic

compounds [2]. Multicomponent processes are at a premium for the achievement of

high levels of diversity and brevity, as they allow three or more simple and flexible

building blocks to be combined in practical, one-pot operations, and due to their

inherent simple experimental procedures and their one-pot character, they are

perfectly suited for automated synthesis [3].

Benzoxazole and its derivatives are heterocyclic compounds with a high

therapeutic efficiency. They are of particular interest in medicinal chemistry [4–6].

K. Khandan-Barani (&) � A. Hassanabadi � M. R. Hosseini-Tabatabaei � J. Saffari

Department of Chemistry, Islamic Azad University, Zahedan Branch, P.O. Box 98135-978,

Zahedan, Iran

e-mail: kh_khandan_barani@yahoo.com

M. T. Maghsoodlou � M. Kangani

Department of Chemistry, University of Sistan and Baluchestan, P. O. Box 98135-674,

Zahedan, Iran

123

Res Chem Intermed

DOI 10.1007/s11164-013-1409-4

The literature mentions the antibacterial and antifungal activity for this class of

compounds as being far more efficient than the active substances already available

on the market [7, 8]. The antitumoral [9–12], tuberculostatic [13], antiinflammatory

[14], HIV-1 reverse transcriptase inhibitor [14, 15], and imagistic fluorescent

[16–18] activity should also be mentioned for benzoxazole derivatives [19]. The

reaction of 2-mercaptobenzoxazole with isocyanides has been investigated by Zhu

et al. [20]. In continuation of our research based on MCRs [21–23], we report here

the reaction between alkyl isocyanides 1 and dialkyl acetylenedicarboxylates 2 in

the presence of 2-mercaptobenzoxazole 3 (Scheme 1).

Experimental

Cyclohexyl isocyanide, t-butyl isocyanide, dimethyl acetylenedicaboxylate, diethyl

acetylenedicaboxylate, di-t-butyl acetylenedicaboxylate, and 2-mercaptobenzoxa-

zole were purchased from Fluka, Merck, and Aldrich, and used without further

purification. Melting points and IR spectra were measured on an Electrothermal

9100 apparatus and a JASCO FT-IR spectrometer, respectively. The 1H and 13C

NMR spectra were recorded on Bruker DRX-400 and 500 Avance instruments with

CDCl3 as solvent at 400.1 and 500.1 MHz (1H NMR) and 100.6 and 125.7 MHz

(13C NMR). Mass spectra were recorded on a Shimadzu GC/MS QP 1100 EX mass

spectrometer operating at an ionization potential of 70 eV. Elemental analyses were

performed using a Heraeus CHN–O-Rapid analyzer.

N

O

SH++C

C

CO2R'

CO2R'

R NC CH2Cl2

r.t., 24-48 hr

3

1

4a-c

4

a

b

c

R R' Yield%

Cyclohexyl Me 82

Cyclohexyl Et 80

t-Butyl t-Bu 73

2

a

b

c

R'

Me

Et

t-Bu

1

a

b

R

Cyclohexyl

t-Butyl

2

N

O

S

N

R

R'O2CH

CO2R'

Time

24

48

48

Scheme 1 Synthesis of compounds 4a–c

K. Khandan-Barani et al.

123

General procedure

The process for the preparation of our products is described for 4a as an example. A

solution of cyclohexyl isocyanide (0.13 g, 1.2 mmol) in 3 mL of CH2Cl2 solvent

was slowly added dropwise to a mixture of 2-mercaptobenzoxazole (1 mmol) and

dimethyl acetylenedicaboxylate (0.17 g, 1.2 mmol) in 20 mL of CH2Cl2 solvent at

room temperature for 3 min. After the addition, the solution was stirred for 24 h.

Then, the solvent was removed under reduced pressure and the residue was washed

with a mixture of cold diethyl ether and n-hexane in a 1:3 ratio (2 9 3 mL) to afford

the pure product.

Dimethyl 2-((cyclohexylimino)(2-thioxobenzo[d]oxazol-3(2H)-yl)methyl)

maleate (4a)

Yellow powder, yield 80 %, 0.32 g, m.p. 145–147 �C; IR (KBr) (mmax, cm-1): 1,719

and 1,737 (2 C=O). 1H NMR (400.1 MHz, CDCl3): dH 1.26–1.83 (10H, m, 5CH2),

3.31 (1H, m, CHN), 3.67 and 3.91 (6H, 2 s, 2OCH3), 7.07 (1H, s, CH), 7.13–7.42

(4H, m, Ar–H); 13C NMR (100.6 MHz, CDCl3): dC 23.9, 24.2, 25.6, 33.0 and 33.7

(5CH2 of cyclohexyl), 52.4 and 53.1 (2CO2CH3), 60.7 (N–CH), 109.6, 115.3, 124.8,

125.0, 131.5, 147.6 (Carom), 128.6 (CH), 138.2 (Colefin), 153.1 (C=N), 163.2 and

163.9 (2C=O), 182.5 (C=S); MS, m/e (%) =402 (M?, 8), 371 (3), 252 (94), 170

(100), 151 (33), 83 (61); Anal. Calcd for C20H22N2O5S (402.46): C, 59.69; H, 5.51;

N, 6.96; %. Found: C, 59.76; H, 5.54; N, 6.99 %.

Diethyl 2-((cyclohexylimino)(2-thioxobenzo[d]oxazol-3(2H)-yl)methyl)

maleate (4b)

Yellow powder, yield: 82 %, 0.35 g, m.p. 105–107 �C; IR (KBr) (mmax, cm-1):

1,717 and 1,735 (2C=O). 1H NMR (400.1 MHz, CDCl3): dH 1.30–1.70 (10H, m,

5CH2), 1.55 and 1.83 (6H, 2t, 3JHH = 7.1 Hz, 2CH3), 3.42 (1H, m, NCH), 4.28 and

4.31 (2q, 3JHH = 7.1 Hz, 2OCH2), 6.27 (1H, s, CH), 7.26–7.36 (4H, m, Ar–H); 13C

NMR (100.6 MHz, CDCl3): dC 14.1 and 14.2 (2CH3), 24.0, 24.9 and 34.1 (5CH2 of

cyclohexyl), 53.0 and 53.1 (2OCH2), 62.4 (N–CH), 109.8, 111.4, 124.4, 125.7,

130.4 and 146.5 (Carom), 130.8 (CH), 148.1 (Colefin), 152.0 (C=N), 167.2 and 169.1,

(2C=O), 184.1 (C=S); MS, m/e (%)=430 (M?, 2), 329 (5), 260 (47), 151 (100), 83

(67), 73 (3), 45 (5); Anal. Calcd for C22H26N2O5S (430.52): C, 61.38; H, 6.09; N,

6.51 %. Found: C, 61.50; H, 6.13; N, 6.59 %.

Di-tert-butyl 2-((tert-butylimino)(2-thioxobenzo[d]oxazol-3(2H)-yl)methyl)

maleate (4c)

Pale yellow powder, yield 73 %, 0.34 g, m.p. 148–150 �C; IR (KBr) (mmax, cm-1):

1,719 and 1,742 (2C=O); 1H NMR (500.1 MHz, CDCl3): dH 1.28 (9H, s,

N–C(CH3)3), 1.52 and 1.54 (18H, 2 s, 2OC(CH3)3), 6.92 (1H, s, CH), 7.29–7.67

(4H, m, Ar–H); 13C NMR (125.7 MHz, CDCl3): dC 27.5 (N–C(CH3)3), 27.7 and

28.1 (2OC(CH3)3), 62.1 (N–CMe3), 82.8 and 83.7 (2OCMe3), 110.2, 119.3, 124.7,

Synthesis of maleate derivatives in isocyanide-base MCRs

123

125.1, 129.7, 141.7 (Carom), 135.4 (CH), 141.7 (Colefin), 151.8 (C=N), 162.5 and

163.7 (2C=O), 184.8 (C=S); MS, m/e (%) = 460 (M?, 7), 403 (15), 359 (21), 310

(91), 253 (54), 151 (100), 57 (76); Anal. Calcd for C24H32N2O5S (460.59): C, 62.58;

H, 7.00; N, 6.08 %. Found: C, 62.67; H, 7.06; N, 6.14 %.

Results and discussion

The present research was oriented towards the production of highly substituted

dialkyl 2-((alkylimino)(2-thioxobenzo[d]oxazol-3(2H)-yl)methyl) maleate deriva-

tives 4a–c from the reaction between alkyl isocyanides 1 and dialkyl acetylenedi-

carboxylates 2 in the presence of 2-mercaptobenzoxazole 3 in CH2Cl2 at room

temperature (Scheme 1). It can be seen that, when the R and R’ groups were

changed, the yield was changed too; it was related to stereo effects of Me, Et, t-Bu

and Cyclohexyl groups.

The products 4a–c are stable solids with structures deduced from their IR,1H NMR, 13C NMR, mass spectral data, and elemental analysis. The mass spectra of

these compounds 4a–c displayed molecular ion peaks at appropriate m/e values. The1H NMR spectrum of compound 4a exhibited three multiplet signals at d 1.26–1.83,

3.31, and 7.13–7.42 ppm due to the cyclohexyl ring, N–CH of cyclohexyl, and

aromatic protons, respectively, and two singlet signals at d 3.67 and 3.91 ppm due

C

C

CO2R'

CO2R'

N

C

R

C

N

R

C C

R'O2C CO2R'

+ +

5

HN

O

S

RN C CO2R'

CO2R'H

+

6 7

4a-cN

O

S

1

23a

Scheme 2 Proposed mechanism for the formation of compounds 4a–c

K. Khandan-Barani et al.

123

to methoxy group protons and one singlet signal at d 7.07 ppm due to the proton of

the vinyl group.

The 13C NMR spectrum of 4a showed 20 distinct resonances in agreement with

the proposed structure. The characteristic signals due to the C=N and C=S were

discernible at d 153.1 and 182.5 ppm, respectively. Two ester carbonyls resonated

at d 163.2 and 163.9 ppm. Partial assignment of these resonances is given in the

‘‘Experimental’’ section. The structural assignment made on the basis of the 1H and13C NMR spectra of compound 4a was supported by the measurement of its IR

spectra. The IR spectra of 4a showed strong absorptions at 1,719 and 1,737 cm-1

due to the ester carbonyls. The 1H and 13C NMR spectra of 4b, c are similar to 4aand the results are described in the ‘‘Experimental’’ section.

The plausible way of forming the product is proposed in Scheme 2. It is

reasonable to assume that compound 5 results from the initial addition of alkyl

isocyanide and dialkyl acetylenedicarboxylate [21, 22], and the subsequent

protonation of the 1:1 adduct occurs with 3a. Then, the positively charged ion 6is attacked by the base 7 to form product 4a–c.

Conclusion

The new and interesting structures of maleate derivatives were synthesized. The

presented method has the advantage of being performed under neutral conditions

and requires no activation or modification of the reagent.

Acknowledgment We gratefully acknowledge financial support from the Research Council of

University of Sistan and Baluchestan.

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