An efficient one-pot synthesis of substituted 2-aminothiophenes via three-component gewald reaction catalyzed by l -proline

Article abstract of DOI:10.1055/s-0029-1219917

An efficient one-pot procedure for the direct catalytic synthesis of substituted 2-aminothiophenes catalyzed by l-proline under mild reaction conditions has been developed. A variety of functionalized 2-aminothiophene scaffolds were assembled in high yields by this catalytic protocol. Low catalyst loading, simple procedure, and high yields are the important attributes of this methodology.

Full text of DOI:10.1055/s-0029-1219917

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0029-1219917
©
Georg Thieme Verlag KG Stuttgart · New York 2009
Thieme

Supporting Information
An Efficient One-Pot Synthesis of Substituted 2-Aminothiophenes via
Three-Component Gewald Reaction Catalyzed by L-Proline
Tao Wang, Xian-Gui Huang, Jia Liu, Bo Li, Jin-Jin Wu, Kai-Xian Chen,
Wei-Liang Zhu, Xiao-Yong Xu* and Bu-Bing Zeng*
School of Pharmacy, East China University of Science and Technology,
1
30 Meilong Road, Shanghai 200237, P. R. China and
Shanghai Key Laboratory of Chemical Biology, Shanghai 200237, P. R. China
E-mail: zengbb@ecust.edu.cn or xyxu@ecust.edu.cn
List of contents
(
(
(
1) General Information
2) Spectral data
S2
S2-S4
S6-S41
1
13
3) Spectra ( H NMR, C NMR, MS) of compounds

(
1) General Information
Commercial reagents and solvents were used without further purification, unless
1
13
otherwise stated. H and C NMR spectra were recorded on a 400 MHz NMR, and
1
tetramethylsilane (TMS) was used as a reference. Data for H NMR are reported as
follows: chemical shift (ppm), and multiplicity (s = singlet, d = doublet, t = triplet, q =
1
3
quartet, m = multiplet, bs = broad singlet). Data for C NMR are reported as ppm. All
products were isolated by flash chromatography on silica gel 300-400 mesh with ethyl
acetate/petroleum as the eluent.
[
1-9]
The spectral data of known compounds were in accordance with those reported.
(
2) Spectral data
[
1]
Ethyl 2-amino-4,5,6,7,-tetrahydrobenzo[b]thiophene-3-carboxylate (Table 2, entry 1)
1
CO Et
3
H NMR (400 MHz, CDCl ): δ = 5.94 (bs, 2H), 4.28 (q, J = 4.0 and 12.0
2
Hz, 2H), 2.74-2.71 (m, 2H), 2.52-2.51 (m, 2H), 1.81-1.75 (m, 4H), 1.35 (t,
13
NH2 J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl
3
): δ = 166.1, 161.7, 132.5,
S
117.6, 105.8, 59.4, 26.9, 24.5, 23.3, 22.8, 14.5.
3
a
[
1]
2
-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (Table 2, entry 2)
1
H NMR (400 MHz, CDCl
3
): δ = 4.56 (bs, 2H), 2.52-2.46 (m, 4H),
.85-1.73 (m, 4H); C NMR (100 MHz, CDCl ): δ = 160.1, 132.3, 120.6,
NH2 115.5, 88.6, 24.5, 24.1, 23.4, 22.1.
CN
13
1
3
S
3
b
Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Table 2, entry 3)
[
2]
1
CO Et
H NMR (400 MHz, CDCl
2.0 Hz, 2H), 2.89-2.85 (m, 1H), 2.63-2.52 (m, 2H), 2.16-2.10 (m,
NH2 1H), 1.84-1.81 (m, 2H), 1.35-1.31 (m, 4H), 1.04 (d, J = 8.0 Hz, 3H);
3
): δ = 5.93 (bs, 2H), 4.26 (q, J = 8.0 and
2
1
1
3
S
3
C NMR (100 MHz, CDCl ): δ = 166.1, 161.8, 132.1, 117.2, 105.7,
3
c
59.4, 32.7, 31.1, 29.5, 26.7, 21.5, 14.5.

[
3]
2
-Amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (Table 2, entry 4)
1
CN
H NMR (400 MHz, CDCl
3
): δ = 4.63 (bs, 2H), 2.61-2.54 (m, 2H),
2
.51-2.44 (m, 1H), 2.16-2.10 (m, 1H), 1.93-1.84 (m, 2H),
1
3
NH2
1.44-1.34 (m, 1H), 1.06 (d, J = 8.0 Hz, 3H); C NMR (100 MHz,
S
CDCl ): δ = 160.2, 131.9, 120.2, 115.5, 88.5, 32.2, 30.3, 29.8, 24.3,
3
+
2
1.4; MS (EI) m/z 192 (M ), 150 (100 %).
3
d
Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (Table 2,
[4]
entry 5)
1
CO Et
H NMR (400 MHz, CDCl
3
): δ = 5.98 (bs, 2H), 4.27(q, J = 8.0 and
2
1
6.0 Hz, 2H), 3.38 (d, J = 4.0 Hz, 2H), 2.87-2.84 (m, 2H), 2.67 (t, J =
13
NH2 8.0 Hz, 2H), 2.45 (s, 3H), 1.34 (t, J = 8.0 Hz, 3H); C NMR (100
MHz, CDCl ): δ = 165.9, 162.4, 130.6, 114.2, 104.9, 59.4, 53.2, 52.3,
45.3, 27.3, 14.4.
N
S
3
3
e
2
-Amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile (Table 2, entry 6)
[
5]
1
CN
H NMR (400 MHz, CDCl
3
): δ = 4.71 (bs, 2H), 3.39 (s, 2H),
13
2
.74-2.71 (m, 2H), 2.66-2.61 (m, 2H), 2.46 (s, 3H); C NMR (100
NH2 MHz, CDCl
3
): δ = 160.5, 130.6, 117.7, 115.1, 88.4, 52.8, 51.6, 45.2,
N
+
S
24.8; MS (EI) m/z 193 (M ), 150 (100 %).
3
f
6
-tert-Butyl 3-ethyl 2-amino-4,5-dihydrothieno[2,3-c]pyridine-3,6(7H)-dicarboxylate (Table 2,
[4]
entry 7)
1
CO Et
H NMR (400 MHz, CDCl
3
): δ = 6.03 (bs, 2H), 4.35 (s, 2H), 4.27
2
(
q, J = 8.0 and 16.0 Hz, 2H), 3.62 (t, J = 4.0 Hz, 2H), 2.81 (s, 2H),
13
NH2 1.48 (s, 9H), 1.34 (t, J = 4.0 Hz, 3H); C NMR (100 MHz,
N
S
CDCl
): δ = 165.7, 162.7, 154.6, 131.3, 113.6, 104.7, 79.9, 59.5,
Boc
3
+
3
g
42.7, 40.5, 28.4, 27.1, 14.4; MS (EI) m/z 326 (M ), 269 (100 %).
tert-Butyl 2-amino-3-cyano-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (Table 2,
[6]
entry 8)
1
CN
H NMR (400 MHz, CDCl
3
): δ = 4.60 (bs, 2H), 4.35 (s, 2H), 3.66
13
(
s, 2H), 2.58 (s, 2H), 1.48 (s, 9H); C NMR (100 MHz, CDCl ): δ
3
NH2 = 161.5, 154.6, 131.0, 116.3, 115.0, 87.4, 80.4, 42.0, 41.3, 28.3,
N
+
S
24.6; MS (EI) m/z 279 (M ), 222 (100 %).
Boc
3
h
[
4]
Ethyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (Table 2, entry 9)
1
CO Et
H NMR (400 MHz, CDCl
): δ = 6.10 (bs, 2H), 4.56 (s, 2H), 4.27 (q, J =
3
2
8
.0 and 16.0 Hz, 2H), 3.91 (t, J = 4.0 Hz, 2H), 2.84-2.81 (m, 2H), 1.34 (t,
13
NH2 J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl
14.7, 105.3, 65.1, 64.6, 59.6, 27.7, 14.4.
): δ = 165.8, 162.4, 130.3,
3
O
S
1
3
i

Ethyl 2-amino-5,7-dihydro-4H-spiro[benzo[b]thiophene-6,2'-[1,3]dioxolane]-3-carboxylate
[4]
(
Table 2, entry 10)
1
H NMR (400 MHz, CDCl
3
): δ = 5.84 (bs, 2H), 4.22 (q, J = 8.0 and
CO Et
2
1
1
2.0 Hz, 2H), 3.99 (s, 4H), 2.89 (t, J = 4.0 Hz, 2H), 2.70 (s, 2H),
13
.87 (t, J = 4.0 Hz, 2H), 1.30 (t, J = 8.0 Hz, 3H); C NMR (100
): δ = 165.9, 162.8, 131.4, 114.1, 108.3, 104.9, 64.6,
9.4, 34.8, 31.5, 25.5, 14.4.
NH2
O
MHz, CDCl
3
S
O
5
3j
2
-Amino-5,7-dihydro-4H-spiro[benzo[b]thiophene-6,2'-[1,3]dioxolane]-3-carbonitrile (Table
[
7]
2
, entry 11)
1
3
H NMR (400 MHz, CDCl ): δ = 4.67 (bs, 2H), 4.02 (s, 4H),
CN
13
2
1
3
.73-2.71 (m, 4H), 1.92 (s, 2H); C NMR (100 MHz, CDCl ): δ =
60.9, 131.4, 117.4, 115.2, 108.2, 88.2, 64.7, 34.7, 30.9, 23.2; MS
NH2
O
O
+
(
EI) m/z 236 (M ), 150 (100 %).
S
3
k
Ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (Table 2, entry
[8]
1
2)
1
CO Et
H NMR (400 MHz, CDCl
3
): δ = 5.78 (bs, 2H), 4.27 (q, J = 4.0 and
2
1
2.0 Hz, 2H), 2.98-2.96 (m, 2H), 2.58-2.55 (m, 2H), 1.85-1.79 (m, 2H),
1
3
NH2 1.66-1.59 (m, 4H), 1.34 (t, J = 8.0 Hz, 3H); C NMR (100 MHz,
CDCl ): δ = 165.9, 159.9, 137.9, 121.2, 107.5, 59.5, 32.1, 28.7, 28.6,
27.8, 26.9, 14.4.
S
3
3
l
[
9]
2
-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (Table 2, entry 13)
1
CN
3
H NMR (400 MHz, CDCl ): δ = 4.28 (bs, 2H), 2.62 (t, J = 4.0 Hz, 2H),
1
3
2
.58 (t, J = 4.0 Hz, 2H), 1.82-1.79 (m, 2H), 1.66-1.64 (m, 4H);
C
NH2 NMR (100 MHz, CDCl
): δ = 157.9, 136.8, 123.8, 91.9, 31.8, 29.4,
3
S
2
9.1, 28.0, 27.2.
3
m
[
2]
Ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (Table 2, entry 14)
1
CO Et
3
H NMR (400 MHz, CDCl ): δ = 5.87 (bs, 2H), 4.26 (q, J = 4.0 and 12.0
2
Hz, 2H), 2.86-2.82 (m, 2H), 2.76-2.71 (m, 2H), 2.36-2.31 (m, 2H), 1.34 (t,
13
3
NH2 J = 4.0 Hz, 3H); C NMR (100 MHz, CDCl ): δ = 166.5, 165.7, 142.6,
S
121.2, 102.7, 59.3, 30.7, 28.8, 27.2, 14.4.
3n
[
9]
2
-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (Table 2, entry 15)
1
CN
H NMR (400 MHz, CDCl
3
): δ = 4.81 (bs, 2H), 2.73-2.66 (m, 4H),
.36-2.34 (m, 2H); C NMR (100 MHz, CDCl ): δ = 165.7, 141.9, 125.0,
NH2 115.8, 84.1, 29.2, 28.4, 27.3.
1
3
2
3
S
3o

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1
1
1
1
1
1
1
1
. 6 0
. 6 1
. 6 3
. 6 4
. 6 5
. 6 7
. 8 0
. 8 1
. 8 2
3
.05
4
2
.01
.02
2
2
2
2
2
2
. 5 6
. 5 7
. 5 9
. 9 6
. 9 8
. 9 9
2.00
2.01
4
4
4
4
. 2 6
. 2 7
. 2 9
. 3 1
2
.00
5
. 7 9
1
.85
7
. 2 7

1
4 . 4 2
2
2
6 . 9 0
7 . 8 3
2
2
3
8 . 5 9
8 . 6 7
2 . 1 0
5
9 . 5 2
7
7
7
6 . 7 5
7 . 0 7
7 . 3 9
1
1
0 7 . 5 0
2 1 . 2 0
1
3 7 . 9 1
1
1
5 9 . 9 5
6 5 . 9 7