Three-component reaction of isocyanide with dialkyl acetylenedicarboxylate and alkyl mercaptan: Preparation of new derivatives of stable ketenimines

Article abstract of DOI:10.1080/17415993.2014.978330

Three-component synthesis of stable ketenimines containing a sulfur group based on a capture profile of a zwitterionic intermediate is described. Thus, the reactions of zwitterions, generated from isocyanide and dialkyl acetylenedicarboxylate, react with alkyl mercaptans in CH₂Cl₂ to afford ketenimines in good yields.

Full text of DOI:10.1080/17415993.2014.978330

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Three-component reaction
of isocyanide with dialkyl
acetylenedicarboxylate and alkyl
mercaptan: preparation of new
derivatives of stable ketenimines
Afshin Sarvarya, Shabnam Shaabanib, Nasim Ghanjib & Ahmad
Shaabanib
a Department of Chemistry, Faculty of Science, Babol University of
Technology, Babol, Iran
b Department of Chemistry, Shahid Beheshti University, G. C.; P.
O. Box 19396-4716, Tehran, Iran
Published online: 17 Nov 2014.
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To cite this article: Afshin Sarvary, Shabnam Shaabani, Nasim Ghanji & Ahmad Shaabani
(2014): Three-component reaction of isocyanide with dialkyl acetylenedicarboxylate and alkyl
mercaptan: preparation of new derivatives of stable ketenimines, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2014.978330
To link to this article: http://dx.doi.org/10.1080/17415993.2014.978330
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Journal of Sulfur Chemistry, 2014
http://dx.doi.org/10.1080/17415993.2014.978330
SHORT COMMUNICATION
Three-component reaction of isocyanide with dialkyl
acetylenedicarboxylate and alkyl mercaptan: preparation of
new derivatives of stable ketenimines
Afshin Sarvarya∗, Shabnam Shaabanib, Nasim Ghanjib and Ahmad Shaabanib,∗
aDepartment of Chemistry, Faculty of Science, Babol University of Technology, Babol, Iran; bDepartment
of Chemistry, Shahid Beheshti University, G. C.; P. O. Box 19396-4716, Tehran, Iran
(Received 18 September 2014; accepted 15 October 2014)
Three-component synthesis of stable ketenimines containing a sulfur group based on a capture profile
of a zwitterionic intermediate is described. Thus, the reactions of zwitterions, generated from isocyanide
and dialkyl acetylenedicarboxylate, react with alkyl mercaptans in CH2Cl2 to afford ketenimines in good
yields.
R2
CO2
R2
O2C
H
l
C
2C 2
R3
N
C
R3
R1
N
C
+
+
SH
R1
S
rt, 3 h
R2
R2
CO2
CO2
68-85%
Only alkyl mercaptans
Keywords: organosulfur; ketenimine; multicomponent reaction; isocyanide; zwitterion
1. Introduction
−
The formation of carbon–sulfur (C S) bonds is a valuable goal in organic synthesis, because
organosulfur compounds are broadly present in nature and play a key role in the biochemistry of
almost all living organisms.[1] Also, organosulfur compounds are inescapably present in many
synthetic drugs and bioactive natural products.[2] Interestingly, all of the 10 top selling drugs in
2012 were organosulfur compounds.[3]
Ketenimines are important intermediates that can be used in a wide range of chemical
transformations. They are involved in inter- or intra-molecular cycloaddition reactions for the
synthesis of a large variety of cyclic compounds.[4] Additionally, ketenimines participate in
nucleophilic, electrophilic, and radical addition reactions.[5] The syntheses of ketenimines have
= =
been divided into four classes in which (i) substitution reactions of heterocumulenes (C C O,
= =
C C S), (ii) substitution of nitrogen on nitrile anion or nitrile radical, (iii) addition reactions
of isocyanide with acetylene, cyclopropenone, or carbene, and (iv) elimination-rearrangement
*Corresponding authors. Emails: a.sarvary@nit.ac.ir; a-shaabani@cc.sbu.ac.ir
c
ꢀ 2014 Taylor & Francis

2
A. Sarvary et al.
Me
Me
CO2
MeO2C
S
H
l
N
C
C
2C 2
+
N
C
SH
+
rt, 3 h
e
M
CO2
4a
72%
CO2
1a
3a
2a
Scheme 1. Synthesis of ketenimine 4a.
reactions.[6, 7] Recently, ketenimines have been prepared by isocyanide-based multicompo-
nent reactions (IMCRs).[8, 9] In these cases, addition of alkyl or aryl isocyanide to dialkyl
acetylenedicarboxylate (DAAD) generates highly reactive zwitterionic intermediates, which are
trapped by NH acid-like amides [8–10] and oximes [11] leading to the formation of stable
ketenimines.
Continuing with these studies aimed at exploiting the utility of IMCRs for the prepara-
tion of elaborated ketenimines,[12] herein we illustrate the synthesis of ketenimine compounds
containing a sulfur group based on a capture profile of zwitterionic intermediates.
2. Results and discussion
An initial study was performed using the reaction of ethanethiol (1a), dimethyl acetylenedicar-
boxylate (DMAD, 2a), and tert-butyl isocyanide (3a) in CH2Cl2 at room temperature (rt). To our
delight, we observed the formation of product 4a in 72% yield after 3 h (Scheme 1). A survey
of different solvents including toluene, THF, CH3CN, DMF, MeOH, and EtOH (Table 1, Entries
3–7) demonstrated that product 4a was formed in slightly lower yields (Table 1, Entries 3–8).
The formation of compounds 4a was confirmed by IR, NMR (1H and13C) spectral data. The IR
spectra revealed the presence of an absorption band at 2065 cm−1 corresponding to the C C N
= =
stretching frequency. The 1H NMR spectrum of 4a exhibited a singlet at 4.28 ppm, ascribable to
the CH proton, 2 singlets identified as 2 methoxy groups at 3.69 and 3.78 ppm, a quartet band
at δ 2.62 ppm (2H, CH2S), a singlet at 1.40 ppm (9H, CMe3), and a triplet at 1.15 ppm (3H,
CH3). The 13C NMR spectra display the characteristic signals of all carbons corresponding to
the structure of compound 4a (showed 11 distinct resonances).
The scope and limitations of this three-component reaction were explored by using of five
alkyl mercaptans, two DAAD and three alkyl isocyanides. The results show that the three-
component reaction is general affording the expected ketenimine compounds 4a–h in good
yields. Note that these reactions are synthetically useful because they form complex structures
= =
and two importance bonds (C–S and C C N). As shown in Table 2, this protocol proceeded
Table 1. Solvent effect on the preparation of 4a.
Entry
Solvent
Temp. (°C)
Yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
Toluene
THF
CH3CN
DMF
Room temp.
Reflux
72
71
58
60
67
52
Trace
Trace
Room temp.
Room temp.
Room temp.
Room temp.
Room temp.
Room temp.
MeOH
EtOH

Journal of Sulfur Chemistry
Table 2. Ketenimine derivatives (4a–h) formed containing a sulfur group.
3
Entry
R1
R2
R3
Product
Yield (%)
e
CO2M
N
C
S
e
M
O C 4a
2
1
2
Me
Me
72
76
e
CO2M
N
C
S
e
M
O C 4b
2
CO2Et
S
N
C
EtO C 4c
2
3
4
5
Et
Et
Et
70
68
81
CO2Et
N
C
S
EtO C 4d
2
CO2Et
N
C
S
EtO2
C 4e
CO2Me
N
C
S
MeO2C
4f
6
Me
80
CO2Me
S
N
C
MeO2C
4g
7
8
Me
Et
77
85
CO2Et
S
N
C
OMe
Si
EtO2
C
MeO Si
MeO OMe
OMe
OMe
4h
efficiently and led to ketenimine derivatives 4a–h containing a sulfur group in good yields
(Table 2).
In a continuation of our research, thiophenol and benzyl mercaptan were used as reagents
in similar reactions and conditions. In these two cases, the expected ketenimines were not
obtained and instead the respective vinyl thioethers 5a–b were isolated from the reaction mix-
tures (Scheme 2). The formation of 5a–b can be explained as a result of the addition of the
respective thiols to the C–C triple bond of DMAD. These results are probably due to the higher
nucleophilicity of these mercaptans in comparison with the isocyanide.[13]
Plausible mechanisms for the formations of compounds 4 and 5 are depicted in Scheme 3.
Simple nucleophilic additions of thiophenol or benzyl mercaptan species to DMAD produce
vinyl thioethers 5a–b. But in the presence of alkyl mercaptans, zwitterionic intermediate B was
initially formed from the reaction of isocyanide with the acetylenic ester. The protonation of

4
A. Sarvary et al.
Scheme 2. Synthesis of vinyl thioethers 5a–b.
Scheme 3. Proposal mechanism.
intermediate B by the alkyl mercaptan and the subsequent attack of the resulting anion D on the
positively charged species C afforded ketenimine 4 (Scheme 3).
3. Conclusions
In summary, we have explored an efficient and easy method for the preparation of keten-
imine derivatives containing a sulfur group through the reaction of the zwitterions derived from
isocyanides and DAAD with alkyl mercaptans in CH2Cl2 at room temperature. The present pro-
cedure has advantages such as availability of the starting material, good yields of products, and
mild reaction conditions without the need to use any catalyst or other means of activation.
4. Experimental
1
IR spectra were recorded on a Shimadzu IR-470 spectrometer. H and 13C NMR spectra were
recorded with CDCl3 as the solvent, on a Bruker DRX-300 Avances pectrometer operating at
1
300.1 MHz for H and 75.5 MHz for 13C. The chemical shifts are reported in ppm relative to
TMS (internal reference). The coupling constants are reported in Hz. For the 1H NMR, the mul-
tiplicities of signals are indicated by the following abbreviations: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; and bs, broad singlet. The chemicals used in this work were purchased
from Merck and Fluka chemical companies. The progress of the reactions was monitored by
TLC. Purification of products was performed by column chromatography (using silica gel 60
and n-hexane:AcOEt (4:1)).

Journal of Sulfur Chemistry
5
4.1. General procedure for the preparation of 4a–h (exemplified to 4a)
4.1.1. Synthesis of dimethyl 2-((tert-butylimino)methylene)-3-(ethylthio)succinate (4a)
To a magnetically stirred solution of ethanethiol (0.06 g, 1.0 mmol) and DMAD (0.14 g, 1.0
mmol) in CH2Cl2 (5 mL) was added, tert-butyl isocyanide (0.08 g, 1.0 mmol). The mixture was
stirred for 3 h at room temperature. After completion of the reaction as indicated by TLC, the
solvent was removed under vacuum. The obtained residue was chromatographed on a silica gel
column using a mixture of n-hexane and AcOEt (4:1) as eluent to yield 4a as a yellow oil (0.20 g,
72%); IR (KBr) νmax = 2934, 2065, 1739, 1696 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.15
(3H, t, 7.2 Hz, CH3), 1.40 (9H, s, (CH3)3), 2.62 (2H, q, 7.2 Hz, SCH2), 3.69 (3H, s, OCH3), 3.78
(3H, s, OCH3), 4.28 (1H, s, CH–S) ppm; 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 26.2
=
=
(CH3), 42.3(CH2S), 51.7, 52.5 (OCH3), 58.3 (C–N), 62.2 (CHS), 63.5 (C C), 167.2 (N C),
=
169.4, 171.4 (C O) ppm.
4.1.1.1. Dimethyl 2-((cyclohexylimino)methylene)-3-(ethylthio)succinate (4b) Yellow oil
1
(0.24 g, 76%); IR (KBr) νmax = 2929, 2055, 1741, 1701 cm−1; H NMR (300 MHz, CDCl3):
δ = 1.13 (3H, t, 7.4 Hz, CH3), 1.17–1.92 (10H, m, 5CH2 of cyclohexyl), 2.53 (2H, q, 7.4 Hz,
SCH2), 3.56 (3H, s, OCH3), 3.60 (3H, s, OCH3), 3.71 (1H, bs, CH–N), 4.18 (1H, s, CH–S) ppm;
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 23.9, 25.1, 28.5, 33.1, 33.2 (CH2), 42.2 (CH2S),
=
=
=
51.5 (CHN), 52.3, 52.9 (OCH3), 60.6 (CHS), 61.7 (C C), 166.6 (N C), 169.2, 171.3 (C O)
ppm.
4.1.1.2. Diethyl 2-((cyclohexylimino)methylene)-3-(ethylthio)succinate (4c) Yellow oil (0.24
g, 70%); IR (KBr) νmax = 2933, 2061, 1735, 1690 cm−1
;
1H NMR (300 MHz, CDCl3):
δ = 0.81–1.96 (19H, m, 3CH3, and 5CH2 of cyclohexyl), 2.65 (2H, bs, SCH2), 3.80 (1H, bs, CH–
N), 4.12–4.17 (4H, m, 2OCH2),4.28 (1H, s, CH–S) ppm; 13C NMR (75 MHz, CDCl3): δ = 13.9,
14.1, 14.3 (CH3), 23.8, 24.7, 25.2, 33.1, 33.2 (CH2), 42.4 (CH2S), 50.9 (CHN), 60.4 (CHS), 60.6
=
=
=
(C C), 61.5, 62.2 (OCH2), 167.4 (N C), 169.1, 171.0 (C O) ppm.
4.1.1.3. Diethyl 2-((tert-butylimino)methylene)-3-(butylthio)succinate (4d) Yellow oil (0.23
g, 68%); IR (KBr) νmax = 2973, 2057, 1734, 1694 cm−1; 1H NMR (300 MHz, CDCl3): δ = 0.88
(3H, t, 7.1 Hz, CH3), 0.81–1.96 (19H, m, 2CH3,CH3CH2CH2 and (CH3)3), 2.63 (2H, bs, SCH2),
4.13–4.17 (4H, m, 2OCH2), 4.25 (1H, s, CH–S) ppm; 13C NMR (75 MHz, CDCl3): δ = 13.0,
13.7, 14.6 (CH3), 22.0 (CH2), 29.4 (CH3), 30.8 (CH2), 43.6 (CH2S), 60.3 (CN), 61.4 (CHS), 61.8
=
=
=
(C C), 63.9, 64.0 (OCH2), 168.0 (N C), 169.1, 170.9 (C O) ppm.
4.1.1.4. Diethyl 2-(butylthio)-3-((2,4,4-trimethylpentan-2-ylimino)methylene)succinate (4e)
Yellow oil (0.32 g, 81%); IR (KBr) νmax = 2982, 2041, 1727, 1683 cm−1; 1H NMR (300 MHz,
CDCl3): δ = 0.88–1.64 (30H, m, (CH3)3, (CH3)2, CH2, 2CH3, CH3CH2CH2), 2.64–267 (2H,
m, SCH2), 4.13–4.23 (4H, m, 2OCH2), 4.30 (1H, s, CH–S) ppm; 13C NMR (75 MHz, CDCl3):
δ = 13.2, 14.3, 14.5 (CH3), 22.7 (CH2), 29.4, 31.2 (CH3), 31.4, 31.8 (CH2), 43.6 (CH2S), 51.4
=
=
(CMe2), 51.9 (C–N), 54.7 (CHS), 59.8 (C C), 60.9, 61.5 (OCH2), 167.9 (N C), 170.0, 171.3
=
(C O) ppm.
4.1.1.5. Dimethyl 2-(cyclohexylthio)-3-((2,4,4-trimethylpentan-2-ylimino)methylene)succinate
(4f) Yellow oil (0.32 g, 80%); IR (KBr) νmax = 2998, 2037, 1708, 1691 cm−1; 1H NMR (300
MHz, CDCl3): δ = 0.88–1.97(33H, m, (CH3)3, (CH3)2, CH2, 2CH3, and 5CH2 of cyclohexyl),
2.68 (1H, bs, SCH of cyclohexyl), 3.64 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.33 (1H, s, CH–
S) ppm; 13C NMR (75 MHz, CDCl3): δ = 25.7, 26.9, 28.8 (CH2), 31.5, 31.7 (CH3), 33.2, 33.3,

6
A. Sarvary et al.
=
33.7 (CH2), 44.5 (CHS), 51.4, 52.4 (OCH3), 52.5 (CCH2), 54.6 (C–N), 56.6 (CHS), 65.1 (C C),
=
=
165.86 (N C), 171.0, 172.6 (C O) ppm.
4.1.1.6. Dimethyl 2-((tert-butylimino)methylene)-3-(cyclohexylthio)succinate (4g) Yellow
oil (0.26 g, 77%); IR (KBr) νmax = 2929, 2054, 1714, 1701 cm−1; 1H NMR (300 MHz, CDCl3):
δ = 1.19–1.96 (19H, m, (CH3)3, 5CH2 of cyclohexyl), 2.79 (1H, bs, SCH of cyclohexyl), 3.64
(3H, s, OCH3), 3.67 (3H, s, OCH3), 4.28 (1H, s, CH–S) ppm; 13C NMR (75 MHz, CDCl3):
δ = 25.6, 25.9, 26.0 (CH2), 30.2 (CH3), 33.2, 33.4 (CH2), 41.2 (CHS), 44.5 (C–N), 51.7, 52.5
=
=
=
(OCH3), 62.2 (CHS), 64.3 (C C), 167.6 (N C), 169.4, 171.9 (C O) ppm.
4.1.1.7. Diethyl 2-((cyclohexylimino)methylene)-3-(3-(trimethoxysilyl)propylthio)succinate (4h)
Yellow oil (0.40 g, 85%); IR (KBr) νmax = 2929, 2054, 1714, 1701 cm−1; 1H NMR (300 MHz,
CDCl3): δ = 073–2.01 (20H, m, SiCH2CH2, 2CH3, 5CH2 of cyclohexyl), 2.69–2.71 (2H, bs,
SCH2), 3.57 (9H, s, 3OCH3), 3.86 (1H, bs, CH–N), 4.14–4.23 (4H, m, 2OCH2),4.30 (1H, s,
CH–S) ppm; 13C NMR (75 MHz, CDCl3): δ = 14.2, 14.3 (CH3), 15.2, 20.1, 24.8, 24.9, 25.8,
=
32.9, 33.1 (CH2), 40.8 (CH2S), 51.4 (CHN), 53.3 (OCH3), 60.5 (CHS), 60.8 (C C), 62.0, 62.3,
=
=
166.8 (N C), 169.2, 171.5 (C O) ppm.
4.1.1.8. Dimethyl 2-(phenylthio)maleate (5a) Yellow oil (0.13 g, 51%); IR (KBr) νmax
=
1738, 1714 cm−1
;
1H NMR (300 MHz, CDCl3): δ = 3.41 (3H, s, OCH3),3.67 (3H, s,
OCH3),6.41 (1H, s, C CH), 7.20–7.53 (5H, m, H-Ar) ppm; 13C NMR (75 MHz, CDCl3):
=
=
=
δ = 51.7, 52.1 (OCH3), 119.0 (HC C), 128.7, 131.1, 133.5, 133.8 (C–Ar), 150.1 (HC C),
=
165.2, 168.0 (C O) ppm.
4.1.1.9. Dimethyl 2-(benzylthio)maleate (5b) Colorless solid. M. p. 70–72°C,[14] IR (KBr)
νmax = 1721, 1708, 1597 cm−1; 1H NMR (300 MHz, CDCl3): δ = 3.69 (3H, s, OCH3),3.74(3H,
s, OCH3), 4.29 (2H, s, SCH2), 4.35 (1H, s, C CH), 7.23–7.56 (5H, m, H-Ar) ppm; 13C NMR (75
=
=
MHz, CDCl3): δ = 38.6 (CH2), 52.7, 53.8 (OCH3), 117.2 (HC C), 124.7, 126.6, 126.1, 132.9
=
=
(C–Ar), 144.5 (HC C), 159.8, 160.7 (C O) ppm.
Funding
We gratefully acknowledge financial support from the Research Council of Babol University of Technology and Shahid
Beheshti University.
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