Csp3–N bond formation in aminothiophenes by 1,1-dibromo isocyanide: the unexpected 1,5-binucleophilicity of substrates

Article abstract of DOI:10.1007/s13738-017-1195-9

Abstract: The N-cyclohexylcarbonimidoyl dibromide in situ, generated by cyclohexylisocyanide and bromine in reaction with several deactivated 5-acetyl-4-amino-2-methylsulfanyl-3-carbonitrile, appears as a cyclohexyl transformer to the substrate via Csp

Full text of DOI:10.1007/s13738-017-1195-9

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1195-9
ORIGINAL PAPER
3
Csp –N bond formation in aminothiophenes by 1,1‑dibromo
isocyanide: the unexpected 1,5‑binucleophilicity of substrates
1
1
2
Amir Hossein Vahabi · Abdolali Alizadeh · Ayoob Bazgir
Received: 18 June 2017 / Accepted: 12 September 2017
©
Iranian Chemical Society 2017
Abstract The N-cyclohexylcarbonimidoyl dibromide
in situ, generated by cyclohexylisocyanide and bromine
in reaction with several deactivated 5-acetyl-4-amino-
for the ꢀrst time in the ꢀeld of isocyanide-based reactions,
isocyanide is applied as an alkyl transformer agent. Third,
this is the ꢀrst example of coupling aminothiophenes with
a secondary alkyl group. Interestingly, high yield and selec-
tivity, short reaction time, easy puriꢀcation accompany this
protocol. Through this study, we investigated the electronic
eꢁects of substituents linked to acetyl on the eꢂciency of
the reaction. Also, the potential of isocyanide dibromide for
the synthesis of cyclic guanidine is evaluated.
2
-methylsulfanyl-3-carbonitrile, appears as a cyclohexyl
3
transformer to the substrate via Csp –N bond formation
without using any base or catalyst at room temperature. The
present transformation suggests three main innovations.
First, regarding the selective monoalkylation of aromatic
amines, the performed condition is unprecedented. Second,
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-017-1195-9) contains supplementary
material, which is available to authorized users.
*
Abdolali Alizadeh
aalizadeh@modares.ac.ir; abdol_alizad@yahoo.com
1
2
Department of Chemistry, Tarbiat Modares University, P.O.
Box 14115-175, Tehran, Iran
Department of Chemistry, Shahid Beheshti University,
Tehran 1983963113, Iran
Vol.:(0
1
123456789)
3

J IRAN CHEM SOC
Graphical Abstract An efficient, useful and general
of view of both medicinal and synthetic chemists due to their
utility as versatile intermediates in organic synthesis [27, 28].
A review of the literature reveals a lack of enough studies on
direct N-alkylation of aminothiophene [29, 30]. Accordingly,
Hoischen and co-workers demonstrated that N-methylation
of 5-acetyl-4-amino-2-methylsulfanyl-3-carbonitrile substan-
procedure for the synthesis of 5-aroyl-4-cyclohexylamino-
2
-methylsulfanyl-3-thienyl cyanide via one-pot three-com-
ponent reaction of 5-acetyl-4-amino-2-methylsulfanyl-3-car-
bonitrile, cyclohexylisocyanide and bromine in acetonitrile
at room temperature has been described. The major advan-
tages of this protocol are high yield and selectivity, short
reaction time, easy puriꢀcation.
appear as
CSP3-N bond
formation
1
,5- binucleophile
CSP3-N bond
cleavage
NC
NH2
NC
NH
MeCN, rt,
O
O
N
C
Br Br
MeS
MeS
S
S
R
R
BrCN
1
0 examples
up to 95% yield
Advantages: alkylation aromatic amines without using any base
or catalyst at room temperature
3
controlable CSP -N bond formation
high yield and selectivity
3
Keywords Csp –N bond formation · Selective
tially increases their microbicides and herbicides eꢁect. How-
monoalkylation · Isocyanide dihalides · Aminothiophene ·
Tetrasubstituted thiophenes
ever, the reported approaches for N-alkylation of aminothio-
phenes are limited to alkylation with only active alkyl halides
such as methyl iodide and ethyl iodide. There is no report for
3
direct Csp –N bond formation with a secondary alkyl group,
Introduction
to the best of our knowledge.
Generally, beside diꢂculties in controlling the selective
monoalkylation and harsh reaction condition, the presence
of one of the elements, including a base catalyst (for aro-
matic amines), metal catalyst or heat, has been reported in
Nitrogen-containing structures, omnipresent in natural
products, pharmaceuticals and functional polymers/mate-
rials, are among the most valuable classes of compounds
3
[
1, 2]. The development of eꢂcient methodologies for C–N
all documented procedures for Csp –N monoalkylation.
bond formation is a central challenge in organic chemis-
try [3–10]. In this regard, the development of synthetic
approaches for selective mono-N-alkylation has been the
Therefore, inventing a protocol that lacks these three neces-
sary obligations would be of high interest.
In this account, and in continuation of our eꢁorts to
develop facile access to polysubstituted thiophene deriva-
focus of research studies for many decades. The widely
3
3
used substitution reaction (SN ) for Csp –N monoalkyla-
tives [31, 32], we have now established a selective Csp –N
2
tion through direct addition of nucleophile to electrophilic
reagents, such as alkyl halide, often fails due to com-
petitive consecutive overalkylation processes, even if the
monoalkylation for tetrasubstituted thiophenes including
5-acetyl-4-amino-2-methylsulfanyl-3-carbonitrile, without
using any base or catalyst at room temperature.
single equivalent of electrophile is used (Scheme 1) [11,
This is achieved via a one-pot reaction of cyclohexyliso-
cyanide, bromine and the thiophene derivatives. This trans-
formation needs to be considered from several perspectives.
The corresponding aminothiophene, due to deactivation
eꢁect of electron-withdrawing groups in the ortho-position,
is considered as an unreactive substrate. Nevertheless, in
reaction with the in situ generated N-cyclohexylcarbon-
imidoyl dibromide, aminothiophene performs an unusual
3
1
2]. Other available methods for Csp –N monoalkylation
include reductive amination [13, 14], oleꢀn hydroamina-
tion [15, 16], alkylation by alkyl halides equivalents, such
as dialkyl sulfates or sulfonates [17–19], and alkylation by
alcohols (Scheme 1) [20–26].
Thiophenes, as one of the most fundamental sulfur-con-
taining heterocycles, are of particular interest from the point
1
3

J IRAN CHEM SOC
3
Scheme 1 Comparison between Csp –N bond formation methods and this work, substituting cyclohexyl on aromatic amine
function as a 1,5-binucleophile (N and O) partner through
in parts per million (δ) downꢀeld from an internal tetra-
2
2
two consecutive Csp –N and Csp –O substitution reactions,
under absolutely inert condition. In another view, under the
performed condition of this protocol, cyclohexylisocya-
nide appears as cyclohexyl transformer to amine moiety via
methylsilane reference. Coupling constants (J values) are
reported in hertz (Hz), and spin multiplicities are indicated
by the following symbols: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet). Elemental analyses for C, H and
N were performed using a Heraeus CHN–O–Rapid analyzer.
Mass spectra were recorded on a Finnigan-Matt 8430 mass
spectrometer operating at an ionization potential of 20 or
3
Csp –N bond cleavage. To the best of our knowledge, this
is a novel event in the ꢀeld of isocyanide chemistry. More
importantly, this study represents the ꢀrst selective mon-
oalkylation of a secondary alkyl in aminothiophenes as a
representative of aromatic amines that marks the important
feature of this transformation under unique conditions of
free base and free catalyst at room temperature.
1
3
70 eV. Due to very low solubility of the products 3h, no
C
NMR data were obtained for these products.
General experimental procedure for the synthesis
of cyclohexylaminothiophene (3) To a well-stirred solu-
tion of cyclohexylisocyanide (1.0 equiv) in acetonitrile
(1.0 mL) were successively added bromine (1.0 equiv) and,
after 5 min at room temperature, aminothiophene (1 equiv).
After completion of reaction (checked by TLC analysis), the
reaction mixture ꢀltered to give crude product, which was
further washed by acetonitrile to give the pure adducts 3a–k.
Experimental section
Melting points were measured on an Electrothermal 9100
apparatus. IR spectra were recorded as KBr pellets on a
1
Nicolet FT-IR 100 spectrometer. H NMR (300and) and
1
3
C NMR (100 MHz) spectra were obtained using Bruker
DRX-300 AVANCE. All NMR spectra at room temperature
5‑Benzoyl‑4‑cyclohexylamino‑2‑methylsulfanyl‑3‑thienyl
were recorded in DMSO-d . Chemical shifts are reported
cyanide (3a) Yellow powder; mp 166–167 °C; 0.34 g,
6
1
3

J IRAN CHEM SOC
3
yield 95%. IR (KBr): 3413 (NH), 2226 (CN), 1628 (C=O),
(1H, d, J = 7.5 Hz, CH of Ar), 8.41 (1H, s, CH of Ar).
HH
1
13
1
595, 1537 and 1509 (Ar). H NMR (300 MHz, DMSO-d ):
C NMR (75 MHz, DMSO): 17.2, 24.1, 25.1, 30.7, 49.6,
6
1
.04–1.87 (10H, m, 5CH ), 2.67 (3H, s, SMe), 2.91–2.95
97.0, 106.0, 112.7, 122.4, 126.2, 131.1, 133.8, 141.5, 148.2,
2
+
(
1H, m, CH–N), 7.48–7.60 (3H, m, CH
and 2CH
of
meta
157.4, 164.4, 183.0. (EI, 70 eV): 401 (M , 77), 319 (35),
para
3
ph), 7.67 (2H, d, J = 7.2 Hz, CH of ph), 7.92 (1H, brs,
304 (1), 272 (12), 258 (5), 244 (15), 229 (2), 197 (74), 185
(1), 169 (20), 154 (20), 151 (68), 142 (71), 127 (21), 116
(34), 104 (46), 94 (73), 83 (55), 76 (100). Anal. Calcd. for
C H N O S (401.50): C, 56.84; H, 4.77; N, 10.47; Found
HH
1
3
NH). C NMR (75 MHz, DMSO): 17.1, 24.1, 25.1, 30.5,
3
1
2
0.6, 49.6, 97.0, 106.5, 112.9, 127.5, 129.2, 131.8, 140.4,
+
1
56.8, 163.3, 185.9. (EI, 70 eV): 357 (M , 76), 274 (79),
58 (32), 249 (1), 227 (10), 197 (58), 176 (2), 169 (20), 154
1
9
19
3
3 2
C, 56.87; H, 4.77; N, 10.48.
(
16), 142 (53), 121 (25), 105 (92), 94 (26), 84 (24), 77 (100).
Anal. Calcd. for C H N OS (356.50): C, 64.01; H, 5.65;
4‑Cyclohexylamino‑5‑(4‑methoxybenzoyl)‑2‑methylsul‑
1
9
20
2
2
N, 7.86; Found C, 63.99; H, 5.67; N, 7.88.
fanyl‑3‑thienyl cyanide (3e) Orange powder; m.p 177–
1
78 °C; 0.305 g, yield 79%. IR (KBr): 3420 (NH), 2224
1
5
‑(4‑Chlorobenzoyl)‑4‑cyclohexylamino‑2‑methyl‑
(CN), 1629 (C=O), 1602 and 1492 (Ar), 1275 (C–O). H
sulfanyl‑3‑thienyl cyanide (3b) Yellow powder; m.p
NMR (300 MHz, DMSO-d ): 1.08–1.88 (10H, m, 5CH ),
6
2
1
90–191 °C; 0.32 g, yield 83%. IR (KBr): 3406, 3301
2.69 (3H, s, SMe), 2.95 (1H, m, CH–N), 3.82 (3H, s,
1
3
(
NH ), 2218 (CN), 1597 (C=O), 1490, 1398 (Ar). H
OMe), 8.04 (2H, d, J = 8.1 Hz, 2CH of Ar), 7.7 (2H, d,
2
HH
3
13
NMR (300 MHz, DMSO-d ): 1.08–1.88 (10H, m, 5CH ),
J
= 8.4 Hz, 2CH of Ar), 7.86 (1H, brs, NH). C NMR
6
2
HH
2
.68 (3H, s, SMe), 2.95–2.97 (1H, m, CH–N), 7.57 (2H, d,
(75 MHz, DMSO): 17.1, 24.1, 25.1, 30.6, 30.7, 49.7, 55.9,
3
3
J
= 8.1 Hz, 2CH of Ar), 7.70 (2H, d, J = 8.1 Hz, 2CH
97.2, 106.4, 113.1, 114.3, 129.8, 132.8, 156.6, 162.2, 162.4,
HH
HH
1
3
+
of Ar), 7.87 (1H, brs, NH). C NMR (75 MHz, DMSO):
185.0. (EI, 70 eV): 386 (M , 100), 304 (73), 289 (27), 274
1
1
7.1, 24.2, 25.1, 30.6, 30.7, 49.6, 97.1, 106.2, 112.8, 129.3,
29.5, 136.6, 139.1, 157.0, 163.7, 184.5. (EI, 70 eV): 391
(6), 261 (9), 244 (7), 229 (1), 217 (2), 197 (18), 185 (5), 170
(6), 154 (6), 144 (23), 135 (56), 121 (8), 107 (39), 92 (63),
83 (47), 77 (80). Anal. Calcd. for C H N O S (386.52):
+
1
(
(
M , 80), 307 (63), 292 (6), 273 (2), 258 (2), 244 (6), 197
10), 183 (1), 169 (8), 154 (8), 139 (86), 121 (6), 111 (100),
2
0
22
2
2 2
C, 62.15; H, 5.74; N, 7.25; Found C, 62.18; H, 5.72; N, 7.26.
9
4 (12), 84 (11), 75 (36). Anal. Calcd. for C H ClN OS
19 19 2 2
(
390.94): C, 58.37; H, 4.90; N, 7.17; Found C, 50.34; H,
5‑Acetyl‑4‑cyclohexylamino‑2‑methylsulfanyl‑3‑thienyl
4
.91; N, 7.16.
cyanide (3f) White powder; m.p 140–141 °C; 0.235 g,
yield 80%. IR (KBr): 3444 (NH), 2225 (CN), 1682 (C=O).
1
4
‑ C y c l o h e x y l a m i n o ‑ 2 ‑ m e t h y l s u l f a ‑
H NMR (300 MHz, DMSO-d ) δ 1.10–1.90 (10H, m,
6
nyl‑5‑(4‑nitrobenzoyl)‑3‑thienyl cyanide (3c) Pale yel-
5CH ), 2.09 (3H, s, COMe), 2.95–2.97 (1H, m, CH–N),
2
1
3
low powder; m.p 218–219 °C; 0.341 g, yield 85%. IR (KBr):
3.08 (3H, s, SMe), 7.95 (1H, brs, NH). C NMR (75 MHz,
3
423 (NH), 2216 (CN), 1648 (C=O), 1593 (Ar), 1518, 1325
DMSO) δ 17.7 (SMe), 24.2, 25.5, 30.7 (CH ), 32.8 (COMe),
2
1
5
(
NO ). H NMR (300 MHz, DMSO-d ): 1.08–1.89 (10H, m,
49.7 (CH–N), 99.9 (C–CN), 111.8 (CN), 125.6 (C ), 150.5
2
6
2
4
+1
5
CH ), 2.68 (3H, s, SMe), 2.95–2.97 (1H, m, CH–N), 7.84
(C ), 156.7 (C ), 182.3 (C=O). (EI, 70 eV): 295 (M , 100),
212 (67), 197 (95), 183 (12), 169 (63), 155 (50), 142 (80),
125 (20), 111 (17), 94 (35), 84 (50), 72 (37). Anal. Calcd. for
C H N OS (294.43): C, 57.11; H, 6.16; N, 9.51; Found
2
3
(
(
1H, brs, NH), 7.93 (2H, d, J = 8.4 Hz, 2CH of Ar), 8.34
HH
3
13
2H, d, J = 8.4 Hz, 2CH of Ar). C NMR (75 MHz,
HH
DMSO): 17.1, 24.1, 25.1, 30.6, 30.7, 49.6, 96.9, 106.2,
1
4
18
2
2
1
7
12.7, 124.4, 129.0, 145.8, 149.2, 157.4, 164.7, 183.7. (EI,
C, 57.12; H, 6.18; N, 9.49.
+
0 eV): 401 (M , 100), 319 (16), 304 (1), 272 (14), 258
(
(
3), 226 (2), 197 (24), 165 (78), 155 (18), 151 (40), 146
45), 137 (78), 120 (80), 104 (46), 92 (50), 84 (49), 76 (45).
Ethyl 2‑(4‑cyano‑3‑cyclohexylamino‑5‑methylsulfa‑
nyl‑2‑thienyl)‑2‑oxoacetate (3g) Pale green; m.p 193–
Anal. Calcd for C H N O S (401.49): C, 56.84; H, 4.77;
194 °C; 0.271 g, yield 77%. IR (KBr): 3381 (NH), 2220
1
9
19
3
3 2
1
N, 10.47; Found C, 56.89; H, 4.75; N, 10.44.
(CN), 1720, 1602 (C=O). H NMR (300 MHz, DMSO-d ):
6
3
1
.05–1.88 (10H, m, 5CH ), 1.30 (3H, t, J = 6.6 Hz,
2
HH
4
‑ C y c l o h e x y l a m i n o ‑ 2 ‑ m e t h y l s u l f a ‑
OCH CH ), 2.77 (3H, s, SMe), 2.91–2.95 (1H, m, CH–N),
2 3
3
nyl‑5‑(3‑nitrobenzoyl)‑3‑thienyl cyanide (3d) Yellow
4.30 (2H, q, J = 6.9 Hz, OCH CH ), 8.33 (1H, brs, NH).
HH 2 3
1
3
powder; m.p 224–225 °C; 0.325 g, yield 81%. IR (KBr):
C NMR (75 MHz, DMSO): 14.3, 16.6, 24.2, 25.1, 30.7,
3
1
1
411 (NH), 2223 (CN), 1650 (C=O), 1601 and 1496 (Ar),
49.6, 62.8, 95.1, 104.3, 112.7, 159.9, 162.7, 168.7, 170.4.
1
+
530 and 1496 (NO ). H NMR (300 MHz, DMSO-d ):
(EI, 70 eV): 352 (M , 100), 270 (74), 244 (8), 197 (66), 183
2
6
.09–1.89 (10H, m, 5CH ), 2.68 (3H, s, SMe), 3.01–3.03
(6), 169 (46), 155 (26), 142 (90), 107 (15), 94 (33), 84 (53),
72 (30). Anal. Calcd. for C H N O S (352.46): C, 54.52;
2
3
(
1H, m, CH–N), 7.82 (1H, t, J = 7.5 Hz, CH of Ar), 7.85
HH
16 20
2
3 2
3
(
H, brs, NH), 8.14 (1H, d, J = 7.5 Hz, CH of Ar), 8.38
H, 5.72; N, 7.95; Found C, 54.53; H, 5.74; N, 7.98.
HH
1
3

J IRAN CHEM SOC
Methyl 3‑(4‑cyano‑3‑cyclohexylamino‑5‑methylsulfa‑
3.38–3.43 (2H, m, CH N=C), 4.04 (2H, m, CH N–C), 7.93–
2 2
1
3
nyl‑2‑thienyl)‑3‑oxopropanoate (3h) Pink powder; m.p
7.94 (1H, brs, NH), 8.47 (1H, s, NH). C NMR (75 MHz,
DMSO): 19.36, 24.16, 25.00, 30.66, 30.71, 38.60, 42.10,
2
97–298 °C; 0.282 g, yield 80%. IR (KBr): 3338 (NH), 2234
1
+1
(
CN), 1639 (CO Me), 1609 (C=O). H NMR (300 MHz,
140.10, 148.10. (EI, 70 eV): 222 (M , 100), 179 (56), 165
2
DMSO-d ):1.08–1.88 (10H, m, 5CH ), 2.72 (3H, s, SMe),
(44), 138 (23), 124 (36), 97 (57), 85(42), 83 (72), 56 (43).
Anal. Calcd. for C H N Br (302.21): C, 59.70; H, 9.90; N,
6
2
2
.95–2.97 (1H, m, CH–N), 3.85 (2H, s, CH CO Me), 4.05
2 2
11 20
5
(
(
3H, s, CH CO Me), 7.84 (1H, brs, NH). (EI, 70 eV): 352
31.65; Found C, 59.71; H, 9.91; N, 31.65.
2
2
+
M , 88), 270 (30), 238 (50), 223 (4), 212 (5), 197 (100),
1
83 (9), 170 (55), 155 (13), 142 (43), 130 (16), 123 (20),
16 (23), 109 (27), 102 (57), 94 (17), 84 (48), 72 (24). Anal.
1
Results and discussion
Calcd. for C H N O S (352.46): C, 54.52; H, 5.72; N,
1
6
20
2
3 2
7
.95; Found C, 54.51; H, 5.73; N, 7.93.
The cyclohexylisocyanide was chosen as a model input for
starting material. When treated with 1 equivalent of bro-
mine in acetonitrile at room temperature, the cyclohexyliso-
cyanide was totally transformed to the N-cyclohexyldibro-
momethanimine 1a [33]. Also, tetrasubstituted thiophenes 2
were prepared according to our recently reported approach
from cyclic thiourea, ketene dithioacetal and corresponding
primary and secondary α-haloketones [31]. The result of
the reaction of 1a with 2a as a model reaction is given in
Table 1.
Methyl 4‑cyano‑3‑cyclohexylamino‑5‑methylsulfa‑
nyl‑2‑thiophenecarboxylate (3i) White powder; m.p
1
2
99–200 °C; 0.261 g, yield 84%. IR (KBr): 3410 (NH),
1
218 (CN), 1669 (CO Me), 1313 and 1199 (C–O). H NMR
2
(
300 MHz, DMSO-d ): 1.09–1.88 (10H, m, 5CH ), 2.70
6
2
(
3H, s, SMe), 2.95–2.97 (1H, m, CH–N), 3.73 (2H, s, OMe),
13
7
2
1
.84 (1H, brs, NH). C NMR (75 MHz, DMSO): 17.1, 24.2,
5.0, 30.7, 30.8, 49.7, 51.9, 96.5, 98.5, 113.1, 154.5, 160.4,
+
1
62.7 (. (EI, 70 eV):311 (M , 100), 228 (81), 213 (4), 197
Similar to the most derivatives of 1,1-dihalogeno iso-
cyanides, 1a is highly hygroscopic matter and is not stable
enough to be stored for long [34]. El Kaim and co-workers
(90), 185 (18), 170 (27), 154 (9), 142 (36), 125 (7), 109 (25),
9
8 (29), 84 (31). Anal. Calcd. for C H N O S (310.43):
14 18 2 2 2
C, 54.17; H, 5.84; N, 9.02; Found C, 54.17; H, 5.81; N, 9.03.
Table 1 Screening studies of the addition of 1a to 2a
Ethyl 4‑cyano‑3‑cyclohexylamino‑5‑methylsulfa‑
nyl‑2‑thiophenecarboxylate (3k) White powder; m.p
2
2
05–207 °C; 0.282 g, yield 87%. IR (KBr): 3213 (NH),
1
216 (CN), 1693 (C=O), 1276 (C–O). H NMR (300 MHz,
DMSO-d ): 1.08–1.88 (10H, m, 5CH and OCH CH ), 1.28
6
2
2
3
3
(
3H, t, J = 7.2 Hz, OCH CH ), 2.68 (3H, s, SMe), 3.59
HH 2 3
3
(
1H, m, CH–N), 4.31 (2H, q, J = 7.2 Hz, OCH CH ),
HH 2 3
1
3
9
1
1
1
9
5
.03 (1H, brs, NH). C NMR (75 MHz, DMSO): 14.6,
a
Entry
1
Solvent
Time (s)
Yield (%)
8.3, 24.5, 25.1, 31.3, 51.9, 61.9, 106.7, 112.6, 115.4, 150.5,
+
56.1, 160.5. (EI, 70 eV): 324(M , 78), 270 (100), 197 (52),
MeCN
CH Cl
30
70
50
240
130
30
95
91
89
90
86
92
91
74
67
95
70 (32), 155 (27), 142 (12), 125 (14), 117 (23), 109 (63),
b
2
3
4
5
6
7
8
9
1
2
2
4 (45), 84 (38).Anal. Calcd. for C H N O S (324.45): C,
b
15
20
2
2
2
CHCl3
Toluene
THF
5.53; H, 6.21; N, 8.63; Found C, 55.52; H, 6.21; N, 8.60.
b
b
Experimental procedure for the synthesis of bicyclic
guanidine (9) After implementation of the required con-
ditions for the synthesis N-cyclohexylcarbonimidoyl dibro-
mide 1a, 1,4,5,6-tetrahydro-2-pyrimidinylhydrazine 8 was
added to the mixture and reaction stirred for 5 min in room
temperature. The formed precipitate was ꢀltered and further
washed by acetonitrile to give pure adduct (9).
b
DMF
b
DMSO
MeOH
EtOH
–
b
260
310
30
b
0c
MeCN
Reaction performed with 1 mmol of 1a and 1 mmol of 2a in 3 mL of
solvent at 25 °C and the required time for the completion of the reac-
tions obtained by checking TLC in every 10 s
3
N ‑cyclohexyl‑1,2,3,5,6,7‑hexahydro[1, 2, 4]
a
Isolated yield
triazolo[4,3‑a]pyrimidin‑3‑iminehydrobromide (9) Pale
b
Reaction conditions: one pot, after implementing the condition for
yellow powder; m.p 188–189 °C; 0.223 g, yield 74%. IR
synthesis 1a, MeCN was evaporated and interchange of the solvents
1
(
KBr): 3223 and 3280 (NH). H NMR (300 MHz, DMSO-
6
evaluated
c
d ): 1.04–2.00 (12H, m, 6CH ), 2.95–2.98 (1H, m, CH–N),
Dry solvent, under inert atmosphere
2
1
3

J IRAN CHEM SOC
eꢂciently synthesized 1,1-dibromo isocyanides in ace-
tonitrile [33]. Considering the above-mentioned limiting
factors, we envisioned that the whole sequence could be
performed in the same pot with an intermediate change
of solvent. Thus, we performed the addition of 2a to the
in situ generated 1,1-dibromo isocyanide 1a in acetonitrile
Table 2 One-pot tandem reaction of 1a with tetrasubstituted thio-
phenes
(
Table 1, entry 1) that readily led to the monosubstitu-
tion of cyclohexyl on the corresponding aromatic amine
in 95% yield, in about half of a minute. In the next trial,
the resulting mixture from the ꢀrst step (synthesis of 1a)
was evaporated and diluted with a range of solvents for the
evaluation of the eꢂciency of the second step (addition
a
Entry
R
Time
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
4-ClC H
4-NO C H
3-NO C H
4-MeOC H
Me
CO Et
CH CO Me
30 s
30 s
50 s
2 min
4 min
3 min
1 h
3 h
1 min
1 min
3a
95
83
85
81
79
80
77
80
84
87
–
3b
6
4
2
a to 1a) (Table 1, entries 2–9). According to our experi-
ments, using aprotic solvents aꢁorded high yield 86–91%
entries 2–7), but the reaction time for toluene increased
3c
2
6
4
4
3d
2
6
(
3e
6
4
to 4 min. In the case of protic solvents such as MeOH and
EtOH (entries 8 and 9), the overall yield decreased to 74
and 67%, respectively. Also, trying the reaction under inert
atmosphere did not aꢁect the reaction eꢂciency (entry
3f
3g
2
3h
2
2
OMe
OEt
3i
1
0). Therefore, the one-pot strategy without changing sol-
1
1
0
1
3k
vent approved as an ideal condition (Table 1, entry 1).
Next, having obtained the optimal conditions, in order
to investigate the combinatorial potential of the described
protocol, we were interested to see whether this protocol
could be extended to other 1,1-dibromo isocyanides 1 and
tetrasubstituted thiophenes 2. First, the scope of the pro-
cess with a diverse range of 5-acetyl-4-amino-2-methylsul-
fanyl-3-carbonitrile, decorating aromatic and non-aromatic
pendent groups linked to ketone (position 5) on thiophene
nucleus in reaction with 1a was examined (Table 2). It was
observed that the reactions were sensitive to the electronic
nature of the substituents of the ketone substrates.
No reaction
1
2
No reaction
–
Reaction conditions: one pot, 1a (1 mmol), 2 (1 mmol), 3 mL of
MeCN, 25 °C
a
Isolated yield
The results show that the reaction of 1a with thiophene
derivatives 2 bearing electron-withdrawing groups on phe-
nyl ring gave a better yield in a shorter time in compari-
son with the ones with electron-donating groups (Table 2,
entries 1–5). Additionally, the reactions with non-aromatic
motifs aꢁorded good to high yield (Table 2, entries 6–10)
similar to their aromatic counterparts, but for R = CO Et
2
and CH CO Me the reactions were completed in longer
2
2
reaction time (entries 7 and 8). Interestingly, the novel
thiophene structures containing chromene backbone that
synthesized based on our recently published approach [31]
did not take part in this reaction even in the prolonged
reaction time and reꢃux condition (entries 11 and 12). This
implies the pivotal role of electronic eꢁects in the accom-
plishment of the reaction (Scheme 2).
Scheme 2 Aꢁorded adducts 3
The molecular structures of all the compounds (3) were
and ꢀnal adduct demonstrated the absence of isonitrile
1
13
deduced from their elemental analyses and IR, mass, H
(N=C) group in C NMR (see supporting information).
1
3
NMR and C NMR spectra. Although we did not succeed
to analyze the structures by X-ray crystallography, the pri-
mary comparison between starting material (thiophene)
Unfortunately, further experiments in order to extend the
generality of this protocol based on using N-benzylcarbon-
imidoyl dibromide 1b did not result in the desired adduct
under the applied conditions for the synthesis of 3a–k,
1
3

J IRAN CHEM SOC
thus limiting the diversity of the protocol to some extent
(Scheme 5). According to our observation, unlike 3-ami-
nothiophene 2, the guanidium-like substrate underwent two
substitution reactions to produce bicyclic guanidine 9 with-
out further ring opening and cyclohexyl migration.
Due to the lack of using any base or promoter, the synthe-
sis of bicyclic guanidines based on this approach is of high
importance. Because the presence of all or at least one either
a base catalyst, a metal catalyst or heat is found in most
of the documented approaches for the synthesis of cyclic
guanidines [35].
(
Scheme 3).
On the basis of the above results, a possible mechanism
for the formation of 3a–k is illustrated in Scheme 4. It is
believed that the in situ generated N-cyclohexylcarbonimi-
doyl dibromide 1a undergoes two consecutive substitution
reactions from N and O nucleophilic sites of thiophene,
resulting in intermediate 5 with oxazine center. This elec-
tron-rich core that presents in three tautomeric forms bears
ring opening to aꢁord 6. Subsequent 1,3-cyclohexyl shift
on nitrogen, following a nucleophilic attack of the excluded
bromide ion to 7, discards cyanide that leads to produce the
ꢀ
nal adduct.
Conclusions
To investigate the behavior of N-cyclohexylcarbonimi-
doyl dibromide 1a with an alternative bidentate nucleophile,
we studied the treatment of 1a with 1,4,5,6-tetrahydro-2-py-
rimidinylhydrazine 8 as 1,4-binucleophile representative
During the recent decades, the chemistry of isocyanide dihal-
ides [36] has been masked by the prominent names of Ugi
and Passirini couplings [37–43] in isocyanide-based mul-
ticomponent reactions (IMCRs). Herein, we demonstrated
the successful marriage of N-cyclohexylcarbonimidoyl
Scheme 3 Examination of the interaction of 1b with 2a
Scheme 5 Synthesis of bicyclic guanidine 9
Scheme 4 Mechanistic rationalization for the formation of 3
1
3

J IRAN CHEM SOC
dibromide 1a with biologically valuable tetrasubstituted
thiophenes 2, leading to an unpredictable and selective
monosubstitution of cyclohexyl on amine moiety without
using any base or promoter at room temperature. Gratefully,
14. M.H.S.A. Hamid, P.A. Slatford, J.M. Williams, J. Adv. Synth.
Catal. 349, 1555 (2007)
1
5. A.L. Reznichenko, K.C. Hultzsch, Top. Organomet. Chem. 43, 51
(
2013)
16. N. Nishina, Y. Yamamoto, Top. Organomet. Chem. 43, 115 (2013)
17. A.W. Hoꢁmann, Philos. Trans. 140, 93 (1850)
3
the present transformation spontaneously installs Csp –N
1
1
8. G. Guillena, D.J. Ramón, M. Yus, Chem. Rev. 110, 1611 (2010)
9. C. Guérin, V. Bellosta, G. Guillamot, J. Cossy Org. Lett. 13, 3534
bond through two consecutive substitution reactions (N
and O)/ring opening/1,3-cyclohexyl shift on nitrogen dom-
ino sequence. The performed condition of the reaction is
unprecedented in the ꢀeld of alkylation of aromatic amines.
Additionally, using isocyanide as an alkyl transfer agent
(
2011)
20. M. Haniti, S.A. Hamid, C.L. Allen, G.W. Lamb, A.C. Maxwell,
H.C. Maytum, A.J.A. Watson, J.M.J. Williams, J. Am. Chem. Soc.
1
31, 1766 (2009)
2
1. T.T. Dang, B. Ramalingam, S.P. Shan, A.M. Seayad, ACS Catal.
3
through Csp –N bond cleavage is a novel event in the ꢀeld
3
, 2536 (2013)
of isocyanide chemistry. The other remarkable features of
this reaction are quick and trivial to run, high yield, and the
reaction is compatible with the one-pot process. Although
the procedure included limitations in terms of extending the
scope of the reaction to N-benzylcarbonimidoyl dibromide
22. K.-I. Shimizu, N. Imaiida, K. Kon, S.M.A.H. Siddiki, A. Satsuma,
ACS Catal. 3, 1005 (2013)
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3. Y.-H. Chang, Y. Nakajima, F. Ozawa, Organometallics 32, 2210
(
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4. X. Yu, C. Liu, L. Jiang, Q. Xu, Org. Lett. 13, 6184 (2011)
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b, the isocyanide dihalide 1a introduced as the promising
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2
2
6. O. Saidi, A.J. Blacker, M.M. Farah, S.P. Marsden, J.M.J. Wil-
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