Direct synthesis of polysubstituted 2-aminothiophenes by Cu(ii)-catalyzed addition/oxidative cyclization of alkynoates with thioamides

Article abstract of DOI:10.1039/c4ob01534g

A facile and direct synthetic method was developed for the construction of structurally important 2-aminothiophenes in moderate to excellent yields (up to 91%), via Cu(ii)-catalyzed addition/oxidative cyclization of readily available thioamides with alkynoates under an air atmosphere. This journal is

Full text of DOI:10.1039/c4ob01534g

Organic &
Biomolecular Chemistry
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PAPER
Direct synthesis of polysubstituted
2-aminothiophenes by Cu(II)-catalyzed
addition/oxidative cyclization of alkynoates
with thioamides†
Cite this: Org. Biomol. Chem., 2014,
12, 8473
Li-Shi Ge, Zheng-Lin Wang, Xing-Lan An, Xiaoyan Luo* and Wei-Ping Deng*
Received 21st July 2014,
Accepted 29th August 2014
A facile and direct synthetic method was developed for the construction of structurally important
2-aminothiophenes in moderate to excellent yields (up to 91%), via Cu(II)-catalyzed addition/oxidative
cyclization of readily available thioamides with alkynoates under an air atmosphere.
DOI: 10.1039/c4ob01534g
www.rsc.org/obc
suitable acyclic precursors.5 A representative example of the
latter strategy is the Gewald reaction,6 which utilizes elemental
Introduction
2-Aminothiophenes are not only the key structural units in bio- sulfur for the introduction of the thiophene sulfur atom and
logically active pharmacophores and natural products,1 such offers a highly efficient route for the preparation of 2-amino-
as olanzapine,1a tinoridine, T-62,1b strontium ranelate (Fig. 1)1c thiophenes from simple starting materials under mild con-
and other biologically active compounds,1d–j but also employed ditions (Fig. 2, eqn (a)).7 Additionally, thioamides are a class of
as useful building blocks in synthetic organic chemistry.2 In practical and readily available compounds which emerged as
addition, 2-aminothiophene derivatives have been successfully powerful synthons in construction of heterocycles because of
used for the preparation of functional materials which show their multiple active centers,8 2-aminothiophenes can also be
various practical applications such as dyes, photoelectric easily synthesized from thioamides (Fig. 2, eqn (b)).9 In the
materials and other applications.3
development of new methods for oxidative activation of sp3
In view of the synthetic versatility of 2-aminothiophenes, C–H bonds and the corresponding coupling,10 we recently
many synthetic methods have been developed for the synthesis demonstrated a facile and efficient approach to aminothio-
of 2-aminothiophenes.4 Methods reported for the construction phenes from thioamides via 2,3-dichloro-5,6-dicyanobenzo-
of 2-aminothiophenes can be divided into two categories: (1) quinone (DDQ)-mediated oxidative coupling, in which DDQ
functionalization of simple thiophenes;4b–g (2) annulation of was used as the oxidant and reaction reagent (Fig. 2, eqn (c)).11
Recently, the copper catalyzed construction of heterocycles
from alkynoates has drawn great attention.12,13 To the best of
Fig. 1 Biologically active 2-aminothiophene derivatives.
Shanghai Key Laboratory of Functional Materials Chemistry, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237, China.
E-mail: xyluo@ecust.edu.cn, weiping_deng@ecust.edu
†Electronic supplementary information (ESI) available. CCDC 998117.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob01534g
Fig. 2 The strategies for synthesis of 2-aminothiophenes.
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our knowledge, although many attempts towards the synthesis this result, we then optimized the reaction conditions. Firstly,
of polysubstituted thiophenes have been made,14,15 investi- a series of copper salts such as Cu2O, CuCl, Cu(OTf)2, CuBr,
gations on the Cu-catalyzed formation of 2-aminothiophenes and Cu(OAc)2, and other catalysts, ZnCl2 and FeCl3, were exam-
from alkynoates and thioamides by oxidative processes have ined. It was found that Cu(OAc)2 was the most efficient catalyst
not been reported (Fig. 2, eqn (d)). Therefore, from the point in this reaction (Table 1, entries 2–8). However, no desired
of view of structural diversity of 2-aminothiophenes, develop- product was observed without the catalyst (Table 1, entry 9).
ment of efficient synthetic methods is still in great demand. Next, the solvent effect was investigated, and DMA was found
Herein, we would like to describe an efficient method to con- to be the optimal solvent of choice (Table 1, entries 10–17).
struct polysubstituted 2-aminothiophenes via copper(II)-catalyzed Decreasing the amount of Cu(OAc)2 to 5 mol% gave a slightly
addition/oxidative cyclization of alkynoates with thioamides.
lower yield of 3aa (Table 1, entry 18).
Notably, there was no obvious influence on the reaction
under O2 instead of air conditions (Table 1, entry 19).
However, when the reaction was carried out under a N2 atmos-
phere, only a trace amount of the product was observed
(Table 1, entry 20). It was further found that no desired
product was obtained at room temperature or 50 °C (Table 1,
entries 21 and 22), while at a higher temperature, the yield of
3aa slightly decreased (Table 1, entry 23). Moreover, the usage
of various additives also did not improve the yields of 3aa
(Table 1, entries 24–26). Therefore, the combination of 1a (1.0
equiv.), 2a (1.2 equiv.) and 10 mol% Cu(OAc)2 in DMA at 80 °C
under an air atmosphere was chosen as the optimal reaction
conditions (Table 1, entry 7), providing 2-aminothiophene 3aa
in 68% yield.
Results and discussion
Initially, we investigated the reaction of N,N-dimethyl-3-oxo-3-
phenylpropanethioamide (1a) and dimethyl acetylenedicarboxy-
late (DMAD) (2a) using CuI as the catalyst at 80 °C in N,N-
dimethylacetamide (DMA). The desired product dimethyl 4-
benzoyl-5-(dimethylamino)thiophene-2,3-dicarboxylate (3aa)
was obtained in 54% yield (Table 1, entry 1). Encouraged by
Table 1 Optimization of reaction conditionsa
With the above optimal conditions in hand, we then explored
the scope of this synthetic protocol as shown in Scheme 1. It
was found that β-ketothioamide substrates 1b–1e all reacted
smoothly giving the corresponding 2-aminothiophenes in good
yields (Scheme 1, 3ba–3ea). The treatment of methyl, ethyl,
Temp
(°C)
Yieldb
(%)
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
CH3CN
EtOAc
Toluene
DCE
CuI
Cu2O
CuCl
CuBr
Cu(OTf)2
FeCl3
Cu(OAc)2
ZnCl2
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
r.t.
50
100
80
80
80
54
58
56
42
55
48
68
0
8
9c
—
0
10
11
12
13
14
15
16
17
18d
19e
20f
21
22
23
24h
25i
26j
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
58
54
42
62
58
63
50
40
62
68
Trace
nrg
0
DMSO
THF
CH3NO2
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
58
30
54
52
a Reagents and conditions: 1a (0.2 mmol), 2a (0.24 mmol), and 10 mol
% of catalyst were heated in the solvent (2 mL) under air. b Isolated
yields. c Dihydrothiophene 4b was isolated in 26% yield. d 5 mol% of
the catalyst was used. e Under oxygen. f Under a N2 atmosphere 4a was
isolated in 46% yield. g nr: no reaction. h 10 mol% KOAc was added.
i 10 mol% AcOH was added. j 10 mol% SnCl2 was added.
Scheme 1 Synthesis of 2-aminothiophenes from dialkyl acetylenedi-
carboxylates and thioamides. Reaction conditions:
1 (0.2 mmol),
2 (0.24 mmol) and Cu(OAc)2 (0.02 mmol) in 2 mL DMA at 80 °C under air,
which was stirred until the reaction was completed as judged by TLC;
yields are of the isolated products.
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Fig. 3 ORTEP view and atom numbering scheme for 3aa.
tert-butyl and benzyl 3-(dimethylamino)-3-thioxopropanoate with
DMAD resulted in the formation of 3fa–3ia in excellent yields
(80–88%). In addition, the substrates 3-(dimethylamino)-N,N-
dimethyl-3-thioxopropanamide 1j and dithioamide 1k, as well
as 2-cyano-N,N-dimethylethanethioamide 1l, can also be trans-
formed to the corresponding 2-aminothiophenes 3ja, 3ka and
3la in moderate to good yields. The N,N-dimethyl thioamide
motif was replaced with diethyl, morpholine and methylphenyl
functionalities, the reactions still underwent smoothly
affording the corresponding products in good to excellent
yields (Scheme 1, 3ma–3pa). However, the reaction of N-mono-
substituted β-ketothioamide with DMAD led to an unknown
mixture. Moreover, a subtle change of the ester group of thio-
amides from methyl (2a) to ethyl (2b) also showed excellent
reactivity providing 2-aminothiophene 3gb in 87% yield. Single
crystal X-ray diffraction analysis of 3aa confirmed the structure
of 2-aminothiophene (Fig. 3).16,17
Scheme 2 Proposed reaction pathway.
Conclusions
In conclusion, we first demonstrated a facile method for the
direct synthesis of polysubstituted 2-aminothiophenes via
copper(II)-catalyzed addition/oxidative cyclization of alkynoates
with thioamides under mild conditions. From a synthetic point
of view, this protocol represents a facile and straightforward
approach for the construction of 2-aminothiophenes in a one
pot process, which might be useful in biological scenarios.
It is worth mentioning that when the reaction was carried
out under a N2 atmosphere (Table 1, entry 20), a Michael
addition product 4a was isolated in 46% yield, which can be
further converted to thiophene 3aa in 80% yield under the
optimized reaction conditions. It indicates that compound 4a
is the key intermediate of this thiophene formation reaction.
Additionally, dihydrothiophene 4b was isolated in 26% yield
when the reaction was carried out without the catalyst
(Table 1, entry 9). Based on these findings and previous
results,12,18,19 a proposed mechanism of this transformation is
illustrated in Scheme 2. Initially, 1a is activated with Cu(II) to
form I, which subsequently couples with 2a resulting in the
Michael adduct II and regenerating the catalyst.12,17 Intermedi-
ate 4a, a double bond migration product from intermediate II,
is then subjected to Cu(II)-catalyzed aerobic oxidative C–H acti-
vation to afford radical IV, which can easily cyclize to form a
dihydrothiophene intermediate V. Finally, a copper-catalyzed
dehydrogenation of V affords 2-aminothiophene 3aa. Alter-
natively, intermediate III, an enol-tautomer of intermediate II,
could be subjected to a spontaneous cyclization to afford dihydro-
thiophene 4b via the non-oxidative cyclization pathway.
Subsequent dehydrogenation of the dihydrothiophene 4b deli-
vers the final 2-aminothiophene 3aa. However, this possible
reaction pathway was ruled out by the fact that only a trace
Experimental
General information
Melting points were obtained in open capillary tubes using
micro melting point apparatus which were uncorrected. Mass
spectra were recorded on a TOF mass spectrometer by the EI
method. 1H nuclear magnetic resonance (NMR) spectra were
recorded using CDCl3 (δH = 7.26 ppm) as the solvent at
ambient temperature on the 400 MHz spectrometer. Data are
presented as follows: chemical shift (in ppm), integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and
m = multiplet), coupling constant (J/Hz) and interpretation.
13C NMR spectra were recorded by broadband spin decoupling
for CDCl3 (δC = 77.2 ppm) at ambient temperature on
100 MHz. Chemical shift values are reported in ppm on the
scale. Infrared spectra were recorded for thin films. TLC (thin-
layer chromatogram) was performed using commercially pre-
pared 100–400 mesh silica gel plates, and visualization was
effected at 254 or 365 nm. Unless otherwise noted, all reagents
and solvents were used as purchased. N,N-dimethylacetamide
was dried and distilled from magnesium sulfate under nitrogen.
General procedure for the preparation of polysubstituted
2-aminothiophenes 3
amount of the product 3aa was observed under the optimized Thioamide compound 1 (0.2 mmol) and alkynoate 2 (0.24 mmol)
reaction conditions.
were added to a solution of Cu(OAc)2 (0.02 mmol) in dry DMA
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(2 mL) under an air atmosphere. The resulting mixture was 68.3, 52.5, 52.2, 44.8, 31.8, 29.3, 29.2, 29.1, 26.0, 22.7, 14.1.
stirred at 80 °C until the reaction was completed as judged by HRMS (EI-TOF) calcd for C25H33NO6S [M]+ 475.2029, found:
TLC. After cooling to room temperature, the resulting mixture 475.2028. IR (film): 3072, 2927, 1739, 1709, 1641, 1598, 1571,
was diluted with water and extracted with ethyl acetate. The 1515, 1410, 1346, 1252, 1168, 1089, 1029, 829, 773, 723,
ethyl acetate layer was washed with brine, and dried over an- 639 cm−1
hydrous Na2SO4. After the solvent was evaporated in vacuo,
.
Trimethyl 5-(dimethylamino)thiophene-2,3,4-tricarboxylate
the residue was purified by column chromatography on (3fa). A white solid (80% yield), Rf = 0.20 (petroleum ether–
100–200 mesh silica gel to afford pure aminothiophene com- ethyl acetate = 4 : 1). Mp: 132–134 °C. 1H NMR (400 MHz,
pounds 3.
CDCl3) δ 3.91 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.05 (s, 6H).
Dimethyl 4-benzoyl-5-(dimethylamino)thiophene-2,3-dicarb- 13C NMR (100 MHz, CDCl3) δ 168.9, 166.0, 162.3, 161.2, 142.0,
oxylate (3aa). A yellow solid (68% yield), Rf = 0.20 (petroleum 111.7, 108.7, 52.8, 52.2, 51.8, 45.4. HRMS (EI-TOF) calcd for
ether–ethyl acetate
(400 MHz, CDCl3) δ 7.78 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1742, 1704, 1534, 1451, 1422, 1403, 1350, 1281, 1248, 1209,
1H), 7.42 (t, J = 7.6 Hz, 2H), 3.79 (s, 3H), 3.48 (s, 3H), 2.90 1136, 1091, 1002, 828, 772, 620 cm−1
(s, 6H).13C NMR (100 MHz, CDCl3) δ 190.8, 165.8, 165.2, 161.4,
4-Ethyl 2,3-dimethyl 5-(dimethylamino)thiophene-2,3,4-tri-
=
5 : 1). Mp: 134–136 °C. 1H NMR C12H15NO6S [M]+ 301.0620, found: 301.0621. IR (KBr): 2953,
.
141.5, 138.5, 133.0, 129.5, 128.4, 117.0, 111.7, 52.4, 52.2, 45.0. carboxylate (3ga). A white solid (84% yield), Rf = 0.20 (petro-
HRMS (EI-TOF) calcd for C17H17NO5S [M]+ 347.0827, found: leum ether–ethyl acetate = 4 : 1). Mp: 114–116 °C. 1H NMR
347.0824. IR (KBr): 3059, 2953, 1734, 1694, 1638, 1595, 1517, (400 MHz, CDCl3) δ 4.21 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.77
1430, 1396, 1358, 1291, 1242, 1214, 1080, 1021, 998, 786, 770, (s, 3H), 3.04 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz,
695, 651 cm−1
.
CDCl3) δ 168.8, 166.0, 161.9, 161.2, 141.9, 111.7, 108.9, 60.8,
Dimethyl 4-acetyl-5-(dimethylamino)thiophene-2,3-dicarb- 52.7, 52.2, 45.4, 14.0. HRMS (EI-TOF) calcd for C13H17NO6S [M]+
oxylate (3ba). A white solid (70% yield), Rf = 0.20 (petroleum 315.0777, found: 315.0776. IR (KBr): 2957, 1737, 1715, 1699,
ether–ethyl acetate
(400 MHz, CDCl3) δ 3.94 (s, 3H), 3.80 (s, 3H), 2.99 (s, 6H), 2.41 642 cm−1
(s, 3H).13C NMR (100 MHz, CDCl3) δ 192.9, 168.6, 166.4, 161.3,
4-tert-Butyl 2,3-dimethyl 5-(dimethylamino)thiophene-2,3,4-
=
5 : 1). Mp: 164–165 °C. 1H NMR 1522, 1433, 1399, 1347, 1275, 1211, 1086, 1010, 833, 774,
.
140.7, 122.4, 113.7, 53.1, 52.4, 46.3, 28.7. HRMS (EI-TOF) calcd tricarboxylate (3ha). A yellow oil (88% yield), Rf = 0.20 (petro-
for C12H15NO5S [M]+ 285.0671, found: 285.0672. IR (KBr): leum ether–ethyl acetate = 5 : 1). 1H NMR (400 MHz, CDCl3)
2956, 1748, 1704, 1647, 1526, 1409, 1389, 1355, 1271, 1235, δ 3.91 (s, 3H), 3.77 (s, 3H), 3.03 (s, 6H), 1.48 (s, 9H). 13C NMR
1116, 1086, 1017, 820, 760, 554 cm−1
.
(100 MHz, CDCl3) δ 168.1, 165.9, 161.4, 161.3, 141.8, 111.4,
Dimethyl 5-(dimethylamino)-4-propionylthiophene-2,3-dicarb- 110.6, 81.7, 52.6, 52.1, 45.2, 28.0. HRMS (EI-TOF) calcd for
oxylate (3ca). A yellow solid (65% yield), Rf = 0.20 (petroleum C15H21NO6S [M]+ 343.1090, found: 343.1091. IR (KBr): 2985,
1
ether–ethyl acetate = 5 : 1). Mp: 88–90 °C. H NMR (400 MHz, 1741, 1694, 1522, 1438, 1396, 1358, 1296, 1216, 1164, 1124,
CDCl3) δ 3.92 (s, 3H), 3.79 (s, 3H), 2.95 (s, 6H), 2.73 (q, J = 1090, 1013, 856, 646 cm−1
.
7.3 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3)
4-Benzyl 2,3-dimethyl 5-(dimethylamino)thiophene-2,3,4-tri-
δ 197.8, 167.6, 166.3, 161.4, 140.6, 122.3, 113.8, 53.1, 52.4, carboxylate (3ia). A white solid (81%, yield), Rf = 0.20 (petro-
46.2, 34.6, 8.9. HRMS (EI-TOF) calcd for C13H17NO5S [M]+ leum ether–ethyl acetate = 6 : 1). Mp: 107–109 °C. 1H NMR
299.0827, found: 299.0830. IR (KBr): 2959, 1708, 1677, (400 MHz, CDCl3) δ 7.40–7.31 (m, 5H), 5.20 (s, 2H), 3.77
1519, 1408, 1351, 1281, 1228, 1192, 1088, 1049, 1002, 897, 760, (s, 3H), 3.50 (s, 3H), 3.05 (s, 6H). 13C NMR (100 MHz, CDCl3)
580 cm−1
.
δ 169.3, 165.8, 161.6, 161.2, 141.9, 135.4, 128.8, 128.5, 128.4,
Dimethyl 5-(dimethylamino)-4-pivaloylthiophene-2,3-dicarb- 111.9, 108.5, 66.9, 52.4, 52.2, 45.5. HRMS (EI-TOF) calcd for
oxylate (3da). A yellow solid (61% yield), Rf = 0.20 (petroleum C18H19NO6S [M]+ 377.0933, found: 377.0934. IR (KBr): 3026,
1
ether–ethyl acetate = 5 : 1). Mp: 71–73 °C. H NMR (400 MHz, 2946, 1745, 1695, 1524, 1440, 1410, 1349, 1277, 1126, 1199,
CDCl3) δ 3.81 (s, 3H), 3.79 (s, 3H), 2.81 (s, 6H), 1.21 (s, 9H). 1090, 963, 775, 697, 634 cm−1
.
13C NMR (100 MHz, CDCl3) δ 211.1, 165.0, 161.4, 161.3, 138.4,
Dimethyl 5-(dimethylamino)-4-(dimethylcarbamoyl)thiophene-
126.0, 117.0, 52.8, 52.4, 45.8, 45.7, 27.5. HRMS (EI-TOF) calcd 2,3-dicarboxylate (3ja). A yellow solid (68% yield), Rf = 0.20
for C15H21NO5S [M]+ 327.1140, found: 327.1141. IR (KBr): (petroleum ether–ethyl acetate = 2 : 1). Mp: 126–128 °C.
2958, 1740, 1696, 1506, 1432, 1413, 1383, 1330, 1284, 1215, 1H NMR (400 MHz, CDCl3) δ 3.84 (s, 3H), 3.76 (s, 3H), 3.00
1128, 1094, 1054, 1018, 890, 761, 574 cm−1
.
(s, 3H), 2.96 (s, 6H), 2.93 (s, 3H).13C NMR (100 MHz, CDCl3)
Dimethyl 5-(dimethylamino)-4-(4-(octyloxy)benzoyl)thiophene- δ 166.1, 165.4, 161.4, 159.9, 139.7, 113.7, 112.3, 52.8, 52.1,
2,3-dicarboxylate (3ea). A yellow oil (69% yield), Rf = 0.20 43.4, 38.6, 34.9. HRMS (EI-TOF) calcd for C13H18N2O5S [M]+
(petroleum ether–ethyl acetate = 7 : 1). 1H NMR (400 MHz, 314.0936, found: 314.0937. IR (KBr): 2950, 1725, 1706, 1628,
CDCl3) δ 7.76 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.00 1516, 1443, 1412, 1338, 1282, 1240, 1092, 1008, 744, 658 cm−1
.
(t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.55 (s, 3H), 2.89 (s, 6H),
Dimethyl 5-(dimethylamino)-4-(dimethylcarbamothioyl)thio-
1.83–1.74 (m, 2H), 1.46–1.41(m, 2H), 1.38–1.26 (m, 8H), 0.88 phene-2,3-dicarboxylate (3ka). A yellow solid (50% yield), Rf =
(t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 189.7, 165.3, 0.20 (petroleum ether–ethyl acetate = 3 : 1). Mp: 96–98 °C.
164.9, 163.3, 161.5, 141.5, 131.9, 131.0, 117.4, 114.1, 111.5, 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 3.78 (s, 3H), 3.50
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(s, 3H), 3.23 (s, 3H), 2.97 (s, 6H). 13C NMR (100 MHz, CDCl3) acetate = 5 : 1). Mp: 54–56 °C. 1H NMR (400 MHz, CDCl3)
δ 193.5, 165.5, 161.4, 156.8, 139.7, 121.2, 112.9, 52.7, 52.2, δ 4.38 (q, J = 7.2 Hz, 2H), 4.21–4.29 (m, 4H), 3.06 (s, 6H), 1.39
43.5, 43.2, 42.8. HRMS (EI-TOF) calcd for C13H18N2O4S2 [M]+ (t, J = 7.2 Hz, 3H), 1.32–1.28 (m, 6H).13C NMR (100 MHz,
330.0708, found: 330.0706. IR (KBr): 2949, 1723, 1708, 1686, CDCl3) δ 100.2, 99.4, 98.5, 98.2, 93.4, 86.1, 85.2, 73.3, 73.2,
1516, 1403, 1277, 1227, 1163, 1090, 1007, 931, 830, 749, 73.1, 69.2, 61.4, 61.3, 61.3. HRMS (EI-TOF) calcd for
640 cm−1
Dimethyl 4-cyano-5-(dimethylamino)thiophene-2,3-dicarboxy- 1733, 1689, 1522, 1413, 1342, 1200, 1093, 1027, 774, 630 cm−1
late (3la). A white solid (38% yield), Rf = 0.20 (petroleum Dimethyl 2-(1-(dimethylamino)-3-oxo-3-phenyl-1-thioxopropan-
ether–ethyl acetate
3 : 1). Mp: 180–182 °C. 1H NMR 2-ylidene)succinate (4a). A yellow oil (46% yield), Rf = 0.20
.
C15H21NO6S [M]+ 343.1090, found: 343.1089. IR (KBr): 2981,
.
=
(400 MHz, CDCl3) δ 3.95 (s, 3H), 3.80 (s, 3H), 3.30 (s, 6H). (petroleum ether–ethyl acetate = 5 : 1). 1H NMR (400 MHz,
13C NMR (100 MHz, CDCl3) δ 167.2, 163.6, 160.5, 141.8, 115.3, CDCl3) δ 8.14 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 6.9 Hz, 1H), 7.47
111.9, 84.3, 53.3, 52.5, 43.5. HRMS (EI-TOF) calcd for (t, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.58 (s, 4H), 3.46(s, 4H), 3.35
C11H12N2O4S [M]+ 268.0518, found: 268.0516. IR (KBr): 2953, (s, 3H).13C NMR (100 MHz, CDCl3) 191.2, 189.6, 169.0, 164.6,
2200, 1734, 1712, 1544, 1440, 1420, 1343, 1276, 1226, 1090, 148.2, 134.8, 132.4, 129.0, 127.4, 122.5, 51.3, 51.1, 42.9, 40.7,
1008, 828, 753, 647 cm−1
Dimethyl 4-(4-bromobenzoyl)-5-(diethylamino)thiophene- found: 349.0981.
2,3-dicarboxylate (3ma). A yellow solid (56% yield), Rf = 0.20 Dimethyl 4-benzoyl-5-(dimethylamino)-2,3-dihydrothiophene-
.
33.8. HRMS (EI-TOF) calcd for C17H19NO5S [M]+ 349.0984,
(petroleum ether–ethyl acetate = 10 : 1). Mp: 119–121 °C. 2,3-dicarboxylate (4b). A yellow oil (26% yield), Rf = 0.2 (petro-
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.6 Hz, 2H), 7.56 (d, leum ether–ethyl acetate = 2 : 1). 1H NMR (400 MHz, CDCl3)
J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.64 (s, 3H), 3.17 (q, J = 7.1 Hz, δ 7.53 (d, J = 6.5 Hz, 2H), 7.41–7.33 (m, 3H), 4.53 (d, J = 1.8 Hz,
4H), 1.03 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) 1H), 4.35 (d, J = 1.8 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 2.89
δ 189.9, 165.3, 164.2, 161.2, 141.2, 136.3, 131.7, 131.2, 128.2, (s, 6H). 13C NMR (100 MHz, CDCl3) δ 186.9, 173.2, 170.2,
118.5, 113.0, 52.7, 52.3, 49.8, 11.8. HRMS (EI-TOF) calcd for 169.0, 142.4, 130.3, 128.2, 127.6, 101.2, 56.3, 53.2, 52.7, 49.1,
C19H20BrNO5S [M]+ 453.0246, found: 453.0245. IR (KBr): 3085, 45.3. HRMS (EI-TOF) calcd for C17H19NO5S [M]+ 349.0984,
2948, 1745, 1707, 1639, 1583, 1502, 1454, 1405, 1357, 1250, found: 349.0986.
1141, 1085, 1031, 1005, 848, 772, 663, 593 cm−1
.
Trimethyl 5-(diethylamino)thiophene-2,3,4-tricarboxylate
(3na). A white solid (75% yield), Rf = 0.20 (petroleum ether–
ethyl acetate = 10 : 1). Mp: 90–92 °C. 1H NMR (400 MHz,
Acknowledgements
CDCl3) δ 3.92 (s, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.40 (q, J = This work was financially supported by the Fundamental
7.1 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H).13C NMR (100 MHz, CDCl3) Research Funds for the Central Universities and the Natural
δ 167.1, 166.2, 162.5, 161.3, 141.8, 112.0, 110.1, 52.8, 52.3, Science Foundation of China (no. 21172068).
51.8, 49.7, 12.2. HRMS (EI-TOF) calcd for C14H19NO6S [M]+
329.0933, found: 329.0932. IR (KBr): 2950, 1732, 1706, 1505,
1441, 1405, 1344, 1266, 1091, 1022, 759, 619 cm−1
.
Notes and references
Trimethyl 5-morpholinothiophene-2,3,4-tricarboxylate (3oa).
A white solid (87% yield), Rf = 0.20 (petroleum ether–ethyl
acetate = 5 : 1). Mp: 158–160 °C. 1H NMR (400 MHz, CDCl3)
δ 3.91 (s, 3H), 3.84 (t, J = 4.6 Hz, 4H), 3.80 (s, 3H), 3.76 (s, 3H),
3.26 (t, J = 4.6 Hz, 4H).13C NMR (100 MHz, CDCl3) δ 169.4,
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51.9. HRMS (EI-TOF) calcd for C14H17NO7S [M]+ 343.0726,
found: 343.0727. IR (KBr): 2957, 1751, 1701, 1483, 1395, 1337,
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1
ether–ethyl acetate = 5 : 1). Mp: 55–57 °C. H NMR (400 MHz,
CDCl3) δ 7.33–7.23 (m, 2H), 7.12–7.03 (m, 3H), 3.93 (s, 3H),
3.82 (s, 3H), 3.44 (s, 3H), 3.40 (s, 3H). 13C NMR (100 MHz,
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.
Triethyl 5-(dimethylamino)thiophene-2,3,4-tricarboxylate
(3gb). A white solid (87% yield), Rf = 0.20 (petroleum ether–ethyl
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