A convenient synthesis of 3-formyl-2-thioacetamide-indole derivatives via the one-pot reaction of indolin-2-thiones, isocyanides and chloroacetylchloride

Article abstract of DOI:10.1016/j.tetlet.2015.11.044

An efficient method has been developed to construct 3-formyl-2-thioacetamide-indoles via a one-pot, two-step procedure involving condensation of isocyanides with indolin-2-thiones to give a 3-aminomethylene-indolin-2-thione intermediate, followed by regio

Full text of DOI:10.1016/j.tetlet.2015.11.044

Accepted Manuscript
A Convenient Synthesis of 3-Formyl-2-thioacetamide-indole Derivatives via
the One-Pot Reaction of Indolin-2-thiones, Isocyanides and Chloroacetylchlor-
ide
Mostafa Kiamehr, Firouz Matloubi Moghaddam, Mehran Sadeghi Erami
PII:
S0040-4039(15)30352-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.044
TETL 46984
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 September 2015
11 November 2015
13 November 2015
Please cite this article as: Kiamehr, M., Moghaddam, F.M., Erami, M.S., A Convenient Synthesis of 3-Formyl-2-
thioacetamide-indole Derivatives via the One-Pot Reaction of Indolin-2-thiones, Isocyanides and
Chloroacetylchloride, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.044
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Graphical Abstract
A Convenient Synthesis of 3-Formyl-2-
thioacetamide-indole Derivatives via the
One-Pot Reaction of Indolin-2-thiones,
Isocyanides and Chloroacetylchloride
Mostafa Kiamehr,* Firouz Matloubi Moghaddam,* Mehran Sadeghi Erami
1

A Convenient Synthesis of 3-Formyl-2-thioacetamide-indole Derivatives via the One-Pot
Reaction of Indolin-2-thiones, Isocyanides and Chloroacetylchloride
Mostafa Kiamehr,a,b * Firouz Matloubi Moghaddam,b, * Mehran Sadeghi Eramib
a Department of Chemistry, Faculty of Science, University of Qom, Ghadir Blvd, P.O. Box 3716146611, Qom, Iran
b Laboratory of Organic Synthesis and Natural Product, Department of Chemistry , Sharif University of Technology
P. O. Box 11155-9516 Tehran, Iran
*Corresponding author. Tel.: +98-25-32103093; fax: +98-25-32103059
E-mail address: mkiamehr@yahoo.com, m.kiamehr@qom.ac.ir
*Corresponding author. Tel.: +98-21-66165309; fax: +98-21-66012983
E-mail address: matloubi@sharif.edu
Abstract
An efficient method has been developed to construct 3-formyl-2-thioacetamide-indoles via a one-pot, two-step
procedure involving condensation of isocyanides with indolin-2-thiones to give a 3-aminomethylene-indolin-2-
thione intermediate, followed by regioselective reaction with chloroacetylchloride and subsequent hydrolysis.
Keyword: Indolin-2-thiones, Isocyanide, Methylene-indolin-2-thiones, Indole derivatives
Introduction
Indole is a very important heterocycle that forms a main skeletal framework of a large number of biological and
pharmacological molecules.1 The importance of indole and its derivatives is evident from the growing volume of
4
literature in the fields of pharmaceuticals,2 natural products,3 agrochemicals, and synthesis.5 Owing to their high
importance, the development of efficient syntheses of indole derivative continues to attract significant attention.6
Among the various derivatives, indole-based sulfides and sulfoxides are of particular interest because of their
medicinal properties.7-12 Biological activities such as antiviral,7 HIV-1 reverse transcriptase inhibition,8 protein
tyrosine kinase inhibition,9 antitumor,10 antihyperlipidemic11 and antiulcer activity12 have been reported.
The utility of isocyanides as an electrophile is well established and this type of reactivity has been observed in the
13
case of strong nucleophiles. Although several Lewis acid promoted additions of weak nucleophiles, specifically,
electron-rich aromatic compounds, onto isocyanides have been reported to date,14 surprisingly such species have
rarely been exploited in organic synthesis.15 Previously we have reported the electrophilic reaction of cyclohexyl
isocyanide with indoline-2-thiones to obtain cyclohexylaminomethylene-indolin-2-thiones, which, upon reaction
with α-halocarbonyl compounds, produced a natural product-like thieno[2,3-b]indole framework. 16 In the context of
2

our continued interest in the application of indolin-2-thiones as substrates for the synthesis of natural product-like
indole derivatives,17 and broadening the synthetic utility of isocyanides as electrophiles in organic synthesis, we
herein introduce a new and efficient synthesis of 3-formyl-2-thioacetamide-indole derivatives 5 via the one-pot two-
step reaction of indolin-2-thiones 1, isocyanides 2 and chloroacetylchloride 4 (Scheme 1). This reaction is based on
the condensation of isocyanides with indolin-2-thiones to give 3-aminomethylene-indolin-2-thiones 3, followed by
regioselective reaction with chloroacetylchloride and subsequent hydrolysis to give 3-formyl-2-thioacetamide-
indoles 5. To the best of our knowledge, the present report is the first example of the use of an isocyanide in which it
splits into two parts which are both incorporated in the final product.
Scheme 1. One-pot two step synthesis of 3-formyl-2-thioacetamide-indole 5a.
Results and discussion
As a model reaction, indolin-2-thione derivative 1a and cyclohexyl isocyanide 2a were stirred in water for 6
hours at 60-65 °C. The condensation reaction proceeded well and the desired cyclohexylaminomethylene-indolin-2-
thione 3a was produced in good yield. To our surprise, the subsequent reaction of 3a and chloroacetylchloride 4
with K2CO3 at room temperature was very sluggish and the desired product 5a was only formed in 14% yield (Table
1, entry 1). We then examined the effect of base and solvent in the above reaction (Table 1). CH3CN gave the most
satisfactory result in comparison with other solvents (Entry 5). Varying the base (NaOH and NaHCO3) and its
absence significantly reduced the yield (Table 1, entries 7-9). When the first step of the reaction was performed at
room temperature or H2O was omitted in the second step, the desired product was not formed (Table 1, entry 6 and
11). Increasing the temperature reduced both steps reactions time (Table 1, entry 10 and 13). The best result was
obtained using two equivalents of base and chloroacetylchloride 4, to give the product in 85% yield (Table 1, entry
15).
Table 1. Effect of solvent, temperature and base on the two step synthesis of 3-formyl-2-thioacetamide-indole 5a
First step
Entry Solvent Temp. Time
Second step
Base Temp. Time
Yielda
(%)
14
Second
solvent
CH3CN
(2 mL)
H2O
(1 mL)
H2O
(1 mL)
(°C)
(h)
6
(°C)
(h)
5
H2O
60-65
K2CO3
(1 equiv.)
K2CO3
(1 equiv.)
K2CO3
rt
1
2
3
(7 mL)
CH3OH
(7 mL)
60-65
22
22
rt
rt
5
5
8
C6H5CH3 60-65
(7 mL)
20
(1 equiv.)
3

DMF
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
CH3CN
(7 mL)
60-65
60-65
rt
22
22
22
22
22
22
14
14
14
14
14
14
H2O
(1 mL)
H2O
(1 mL)
H2O
(1 mL)
H2O
(1 mL)
H2O
(1 mL)
H2O
K2CO3
(1 equiv.)
K2CO3
(1 equiv.)
K2CO3
(1 equiv.)
NaOH
(1 equiv.)
NaHCO3
(1 equiv.)
-
rt
5
5
5
5
5
5
5
5
5
2
2
2
5
4
5
rt
58
0
rt
rt
6
60-65
60-65
60-65
reflux
reflux
reflux
reflux
reflux
reflux
17
30
10
58
0
7
rt
8
rt
9
(1 mL)
H2O
(1 mL)
-
K2CO3
(1 equiv.)
K2CO3
(1 equiv.)
K2CO3
(2 equiv.)
K2CO3
(2 equiv.)
rt
10
11
12
13
14
15b
rt
H2O
(1 mL)
H2O
(1 mL)
H2O
(1 mL)
H2O
(1 mL)
rt
63
65
48
85
50-55
reflux
50-55
K2CO3
(2 equiv.)
K2CO3
(2 equiv.)
a) Yield of isolated product.
b) Two equivalents of chloroacetylchloride 4 were used.
Under the optimized reaction condition,18 a series of 3-formyl-2-thioacetamide-indole derivatives 5 were
synthesized using a various indolin-2-thiones 1 and isocyanide derivatives 2 (Table 2). The two step reaction
sequences proceeded smoothly and the desired compounds were isolated by silica gel column chromatography.
The structures of the products were established from their NMR spectroscopic data (1H NMR, 13C NMR, DEPT)
and IR as well as elemental analyses.18 The characteristic signals for 5a–h in the 1H NMR spectra were a singlet for
the –SCH2CO group between 3.03 and 3.59 ppm, a broad singlet for the CONH group between 5.91–6.12 ppm in
CDCl3 and 8.39–8.42 ppm in DMSO-d6, and another singlet for the CHO group between 10.11–10.42 ppm. The
corresponding signals of the –SCH2, –CONH and –CHO groups in the 13C NMR spectra appeared between 39.6–
42.2 ppm, 165.7–167.8 ppm and 186.3–187.2 ppm, respectively.
Table 2. Synthesis of 3-formyl-2-thioacetamide-indole derivatives 5a-h.a
Yieldb
(%)
Indolin-2-thiones
Isocyanides
Product
85
2a
80
4

2a
88
76
72
78
87
90
1a
1b
1c
1a
1c
2b
2b
2c
a) Reagents and conditions: First step; CH3CN (7 mL), reflux, 14 h. Second step; ClCH2COCl (2 equiv.), K2CO3 (2
equiv.), H2O (1 mL), 50-55oC, 2 h.
b) Yield of isolated product.
A plausible mechanism for the first step of the reaction involving the synthesis of compound 3 has previously
been reported by our group.16 The formation of 3-formyl-2-thioacetamide-indole derivatives 5 can be rationalized by
the initial S-alkylation of compound 3 with chloroacetylchloride 4, affording intermediate imine 6, followed by N-
acylation and hydrolysis to afford the desired products 5a-h (Scheme 2).
Scheme 2. Proposed mechanism for the synthesis of 3-formyl-2-thioacetamide-indole derivatives 5a-h.
Conclusion
In summary, we have reported a new and efficient one-pot, two step synthesis of 3-formyl-2-thioacetamide-
indoles from various indoline-2-thiones, isocyanides and chloroacetylchloride. The present procedure has the
5

advantages of high yield and mild reaction conditions. Further studies to extend the scope and synthetic utility of 3-
formyl-2-thioacetamide-indole for the conversion into thieno[2,3-b]indoles are currently in progress.
Acknowledgment
We gratefully acknowledge partial financial support from the Research Council of Sharif University of
Technology for three months sabbatical leave in summer 2014.
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18. To a stirred suspension of indolin-2-thiones 1a–c (0.5 mmol) in CH3CN (7 mL) were added isocyanide
derivative 2a–c (0.5 mmol). The reaction mixture was stirred at reflux for 14 h and the progress of the
reaction monitored by TLC. After reaction completion, chloroacetylchloride 4 (2 mmol), K2CO3 (2 mmol)
and H2O (1 mL) were added to the mixture. The reaction was stirred at 50-55 °C for 2 h. After reaction
completion, the solvents were evaporated and the residue subjected to SiO2 column chromatography
(EtOAc–hexane, 1:3) to obtain pure products 5a-h. N-Cyclohexyl-2-((3-formyl-1-methyl-1H-indol-2-
o
yl)thio)acetamide (5a): yellow powder, mp: 164–166 C, yield; 85%. IR (KBr): 3299, 3072, 2923, 2849,
1664, 1630, 1538, 1457, 1369, 1130, 744 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.97–1.30 (5H, m, CH2),
1.54–1.73 (5H, m, CH2), 3.48 (2H, s, SCH2C=O), 3.59–3.65 (1H, m, CONHCH), 3.93 (3H, s, NCH3), 6.05
(1H, bs, –NHC=O), 7.30–7.37 (3H, m, Ar–H), 8.27 (1H, d, J = 7.9 Hz, Ar–H), 10.32 (1H, s, CH=O). 13C
NMR (125 MHz, CDCl3): δ = 25.1 (CH2), 25.7 (CH2), 31.1 (NCH3), 33.1 (CH2), 41.6 (SCH2), 49.3 (CH),
110.6 (CH), 120.4 (C), 121.7 (CH), 123.9 (CH), 125.3 (CH), 125.7 (C), 138.5 (C), 140.6 (C), 166.3
(CONH), 186.6 (CHO). Anal.Calcd for C18H22N2O2S: C, 65.42; H, 6.71; N, 8.48%. Found: C, 65.55; H,
6.78; N, 8.40%.
7

Highlight bullet points
New way to synthesis of the 1,2,3-three substituted indole-based sulfides.
A new and efficient one-pot, two step synthesis of 3-formyl-2-thioacetamide-indoles.
Isocyanide splits into two parts and both are incorporated in the final products.
Regioselective reaction of aminomethylene-indolin-2-thione with chloroacetylchloride.
8