Solvent-free three-component synthesis of 7-aryl-1,1-dioxothieno[3,2-b] pyran derivatives catalyzed by ammonium acetate

Article abstract of DOI:10.1002/jhet.696

An efficient synthesis of 7-aryl-1,1-dioxothieno[3,2-b]pyran derivatives via the reaction of aryl aldehyde, tetrahydrothiophene-3-one-1,1-dioxide and malononitrile or ethyl 2-cyanoacetate was performed at room temperature catalyzed by ammonium acetate und

Full text of DOI:10.1002/jhet.696

September 2011
Solvent-Free Three-Component Synthesis of 7-Aryl-1,1-
dioxothieno[3,2-b]pyran Derivatives Catalyzed by Ammonium
Acetate
1111
Changsheng Yao,* Xiaodong Feng, Cuihua Wang, Bei Jiang, Chenxia Yu,
Xiangshan Wang, Tuanjie Li, and Shujiang Tu
School of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology on Medical
Plant, Xuzhou Normal University, Xuzhou, Jiangsu 221116, People’s Republic of China
*E-mail: csyao@xznu.edu.cn
Received June 10, 2010
DOI 10.1002/jhet.696
Published online 27 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
An efficient synthesis of 7-aryl-1,1-dioxothieno[3,2-b]pyran derivatives via the reaction of aryl alde-
hyde, tetrahydrothiophene-3-one-1,1-dioxide and malononitrile or ethyl 2-cyanoacetate was performed at
room temperature catalyzed by ammonium acetate under solvent-free conditions. Compared with the
conventional methods, this protocol features mild reaction conditions, high yields, and eco-friendliness.
J. Heterocyclic Chem., 48, 1111 (2011).
INTRODUCTION
decades, solvent-free reaction has gained many applica-
tions in organic synthesis. These processes are not only
environmentally benign but also economically beneficial
because toxic wastes can be minimized or eliminated, so
the costs of wastes treatment are also reduced. An addi-
tional attractive feature is the operational simplicity [9].
By now, many organic transformations have been
reported to proceed efficiently under solvent-free condi-
tions (For recent advances, see: [10]). Besides, the di-
versity generating potential of multicomponent reactions
(MCRs) has been recognized and their utility in prepar-
ing libraries to screen for functional molecules is well
appreciated [11]. Recently, ammonium acetate was
reported to catalyze organic transformations efficiently
[12]. To continue our work on the synthesis of heterocy-
clic compounds via MCRs under solvent-free conditions
[13], here we shall report an efficient and green syn-
thetic route to 7-aryl-1,1-dioxothieno[3,2-b]pyran deriva-
tives 4 via a solventless three-component reaction
(which consists of condensation, Michael addition, and
cyclization) of aryl aldehyde 1, tetrahydrothiophene-3-
one-1,1-dioxide 2, and malononitrile or ethyl cyanoace-
tate 3 catalyzed by NH4OAc (ammonium acetate)
(Scheme 1).
Compounds containing the thienopyran scaffold
include benzothienopyranones, sulphur analogs of fura-
nochromanones and furanocoumarins [1]. These com-
pounds are interesting synthetic targets because of their
potential biological activities, such as antiasthmatic ac-
tivity [2], antihypertensive activity [3]. The synthesized
compounds with thienopyran core unit can act as antag-
onists of the r1 receptor [4]. In addition, some mole-
cules containing five membered cyclic sulphone motif
have the potential to selectively inhibit spontaneous
bladder contractions and can be used as new generation
of KATP channel openers [5].
Due to their diverse biological activities, the synthesis
of thienopyran derivatives has attracted considerable
attention. So far, several methods to prepare these com-
pounds have been reported [6], e. g., the multi-step syn-
thesis of benzothienopyranones and thiafluorenones from
N,N-diethy-ortho-methyl sulfanyl amides [7], the com-
plex preparation of 4-oxo-4H-[1]benzothieno[3,2-b]pyr-
ans from 3-hydroxybenzothienyl-2-methyl ketone and
aromatic aldehydes [8]. However, most of the synthetic
protocols reported have many drawbacks, including pro-
longed reaction time, high temperatures, drastic reaction
conditions, tedious work-up, poor yields, and the use of
organic solvent and/or expensive catalysts. Therefore,
the development of simple, convenient, and environmen-
tally benign approaches for the synthesis of these poten-
tial bioactive compounds is still desirable. In the past
RESULTS AND DISCUSSION
The effect of solvent on the reaction was initially
examined by reacting tetrahydrothiophene-3-one-1,1-
C
V
2011 HeteroCorporation

1112
C. Yao, X. Feng, C. Wang, B. Jiang, C. Yu, X. Wang, T. Li, and S. Tu
Vol 48
Scheme 1
Table 2
Catalyst optimization for the synthesis of 4a under solvent-free media.
Time
(h)
Yield
(%)
Entry
Catalyst
H2SO4
Temperature (ꢁC)
1
2
3
4
5
6
7
8
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
3
3
3
3
3
3
3
3
20
30
35
30
65
55
65
85
FeCl3ꢀ6H2O
MgSO4
TEBA
AlCl3
dioxide 2 (1 mmol), malononitrile 3 (1 mmol) with phe-
nyl aldehyde 1a (1 mmol) catalyzed by ammonium ace-
tate. It was found that if the synthesis was performed in
the organic solvent it gave the expected product, 4a, in
lower yields (20–80%) than under solvent-free condi-
tions (Table 1). For a practical synthesis, solvent-free
condition is the ideal process in terms of environmental
safety.
NaOAc
NaOH
NH4OAc
matic aldehydes with good yields according to Table 5.
However, when the aliphatic aldehyde was applied to
this reaction, no expected product was obtained. To
check the versatility of the methodology, other active
methylene compound such as ethyl cyanoacetate was
added instead of malononitrile. The results indicate an
carboxylic ester in substrates gives a lower yield than
that of a carbonitrile, thus electron-withdrawing effect
may play an important role (Table 5).
To screen for the optimal catalyst for the sovent-free
synthesis, the previous reaction was performed using
H2SO4, FeCl3ꢀ6H2O, MgSO4, TEBA, AlCl3, NaOAc,
NaOH, and NH4OAc as catalysts (10 mol %), respec-
tively (Table 2). As shown in Table 2, NH4OAc was the
best catalyst for this reaction from the viewpoint of
yield.
All of the compounds were characterized by HRMS,
1
FTIR, and H NMR. To further elucidate the structure
To find the best catalyst loading, the aforementioned
reaction was run in 1 mmol scale of substrate using dif-
ferent amounts of catalyst (Table 3). Table 3 shows that
10 mol % amount of ammonium acetate was optimal
under the experimental conditions used.
of products, a single crystal of compound 4m was pre-
pared, and its structure was determined by X-ray diffrac-
tion (Fig. 1) [14].
A possible mechanism for the formation of the prod-
ucts 4 was outlined in Scheme 2. In the initial step,
Knoevenagel condensation between aryl aldehyde and
malononitrle or ethyl cyanoacetate gave intermediate 5.
Michael addition between 5 and 2 then furnished the in-
termediate 6, subsequently underwent isomerized and
intramolecular cyclization to give compounds 4.
To test the proposed mechanism, intermediate 5f, 2-
(3-chlorobenzylidene)malononitrile was prepared via the
condensation of 3-chlorobenzaldehyde and malononitrile
under the same conditions. It can react with 2 to give
the expected product 4f with slightly lower yield (81%)
than the one-pot reaction (85%). The fact supported the
supposed reaction pathway (Scheme 3).
Moreover, the optimal temperature for the reaction
was found to be room temperature (25ꢁC) (Table 4).
Based on the optimized reaction conditions, a series
of
5-amino-2,3,4,7-tetrahydro-7-aryl-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile were synthesized. As shown
in Table 5, the reaction catalyzed by ammonium acetate
under solvent-free conditions gave the corresponding
products in moderate to good yields. The results reveal
that not only electron-rich aryl aldehyde (such as a
methoxy group), but also electron-deficient aryl alde-
hyde (such as a nitro group, halogen) in the multicom-
ponent reactions afforded the corresponding product effi-
ciently under the same conditions. Furthermore, the
reaction system can be successfully applied to heteroaro-
Table 3
Table 1
The effect of catalyst loading on reaction under
solvent-free Media.
Solvent effect on the synthesis of 4a.
Time
(h)
Yield
(%)
Entry
Solvent
THF
CHCl3
Temperature (ꢁC)
Catalyst
(%)
Time
(h)
Yield
(%)
Entry
Temperature (ꢁC)
1
2
3
4
5
6
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
3
3
3
3
3
3
75
20
80
80
70
85
1
2
3
4
5
0
5
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
3
3
3
3
3
52
75
85
72
65
EtOH
t-Butanol
DMF
Solvent-free
10
15
20
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Solvent-Free Synthesis of 5-Methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]
pyrimidine-6-carboxylic Esters Catalyzed by Sulfamic Acid
1113
Table 4
points were determined in open capillaries and are uncorrected.
The single crystal diffraction data were gathered on a Rigaku
Saturn diffractometer.
Temperature optimization for the synthesis of 4a under solvent-free
media.
General procedure for the synthesis of 5-amino-2,3,4,7-
tetrahydro-7-aryl-1,1-dioxothieno[3,2-b]pyran-6-carbonitrile
(4a–4w). Aryl aldehyde 1 (1 mmol), tetrahydrothiophene-3-
one-1,1-dioxide 2 (0.134 g, 1 mmol), malononitrile or ethyl
cyanoacetate 3 (1 mmol), and NH4OAc (0.008 g, 0.1 mmol)
were triturated together in an agate mortar for 25 min. Then
the mixture was kept at room temperature for a certain time
(monitored by TLC). The result mixture was washed with
water and recrystallized from ethanol (95%) to give pure prod-
uct 4. A similar procedure was used in preparing the following
compounds.
Entry
Temperature (ꢁC)
Time (h)
Yield (%)
1
2
3
4
5
6
10
20
3
3
3
3
3
3
70
80
85
82
75
70
Room temperature
30
40
50
In summary, we have developed an efficient, econom-
ical, safe, and environmentally benign procedure for
synthesizing derivatives of dioxothieno[3,2-b]pyran. The
results show that NH4OAc is an efficient catalyst that
could, in priciple, be used as a catalyst in the multicom-
ponent reaction under solvent-free conditions.
5-Amino-2,3,4,7-tetrahydro-7-phenyl-1,1-dioxothieno[3,2-b]
pyran-6-carbonitrile (4a). IR (potassium bromide): 3400,
3324, 2198, 1602, 1512, 1411, 1353, 1298, 1236, 1151, 1112,
;
1049, 867, 650, 601 cmꢂ1 1H NMR (DMSO-d6) (d, ppm):
2.94–3.00 (m, 1H, CH2), 3.09–3.17 (m, 1H, CH2), 3.41–3.52
(m, 2H, CH2), 4.47 (s, 1H, ArCH), 7.25 (s, 2H, NH2), 7.27–
7.29 (m, 3H, ArH), 7.33–7.36 (m, 2H, ArH). HRMS (ESI): m/z
calcd for: 311.0461 [MþNa]þ, found: 311.0466.
5-Amino-2,3,4,7-tetrahydro-7-(2-fluorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4b). IR (potassium bromide): 3438,
3327, 2361, 2342, 2195, 1709, 1647, 1595, 1489, 1459, 1408,
EXPERIMENTAL
Common reagents and materials were purchased from com-
mercial sources and purified by recrystallization or distillation.
Infrared (IR) spectra were recorded on a TENSOR 27 spectro-
photometer in KBr pellet and are reported in terms of fre-
quency of absorption (cmꢂ1). NMR spectra were recorded on
1352, 1304, 1238, 1157, 1142, 1115, 1093, 1054, 758 cmꢂ1
;
1H NMR (DMSO-d6) (d, ppm): 2.95–3.03 (m, 1H, CH2), 3.06–
3.13 (m, 1H, CH2), 3.40–3.52 (m, 2H, CH2), 4.91 (s, 1H,
ArCH), 7.28–7.32 (m, 3H, NH2, ArH), 7.34–7.37 (m, 2H,
ArH), 7.41 (t, J ¼ 8.0 Hz, 1H, ArH). HRMS (ESI): m/z calcd
for: 329.0367 [MþNa]þ, found: 329.0363.
1
a Bruker DPX 400; data for H are reported as follows: chemi-
cal shift (ppm), integration, multiplicity (s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; and br, broad), coupling con-
stant (Hz), and number. HRMS (ESI) were determined by
using microTOF-QIIHRMS/MS instrument (Bruker). Melting
5-Amino-2,3,4,7-tetrahydro-7-(3-fluorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4c). IR (potassium bromide): 3396,
3325, 3216, 2361, 2342, 2195, 1706, 1647, 1605, 1411, 1356,
Table 5
NH4OAc catalyzed the synthesis of compound 4.
Compound number
Ar
R
Time (h)
Yield (%)
Melting point (ꢁC)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
C6H5
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
CN
CN
3
3
3
3
3
3
3
4
4
3
4
3
4
3
3
3
4
4
7
8
7
9
9
85
79
86
80
82
85
86
79
83
87
78
77
82
85
82
85
75
83
50
65
81
40
37
191–193
196–198
192–194
193–194
179–181
193–195
194–196
175–177
170–172
169–171
186–188
197–199
185–187
210–212
199–201
202–204
192–194
183–185
203–205
191–192
177–179
170–172
167–169
CN
CN
CN
CN
3-ClC6H4
4-ClC6H4
CN
CN
CN
CN
CN
CN
CN
CN
4-OCH3C6H4
3-OCH3C6H4
3,4,5-(OCH3)3C6H2
4-CH3C6H4
3-BrC6H4
4-BrC6H4
4-NO2C6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
2-SC4H3
CN
CN
CN
CN
2-OC4H3
4-NO2C6H4
2,4-Cl2C6H3
3-FC6H4
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
4t
4u
4v
4w
3-NO2C6H5
3-ClC6H4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1114
C. Yao, X. Feng, C. Wang, B. Jiang, C. Yu, X. Wang, T. Li, and S. Tu
Vol 48
Scheme 3
ppm): 2.92–3.02 (m, 1H, CH2), 3.09–3.17 (m, 1H, CH2), 3.42–
3.53 (m, 2H, CH2), 4.55 (s, 1H, ArCH), 7.25 (d, J ¼ 7.2 Hz,
1H, ArH), 7.32 (d, J ¼ 7.6 Hz, 3H, NH2 þ ArH), 7.36–7.40
(m, 2H, ArH). HRMS (ESI): m/z calcd for: 345.0071
[MþNa]þ, found: 345.0065.
Figure 1. The crystal structure of 4m.
1297, 1258, 1241, 1148, 1136, 1115, 1052, 694, 506 cmꢂ1; H
NMR (DMSO-d6) (d, ppm): 2.94–3.02 (m, 1H, CH2), 3.05–
3.13 (m, 1H, CH2), 3.41–3.52 (m, 2H, CH2), 4.69 (s, 1H,
ArCH), 7.13–7.20 (m, 2H, ArH), 7.30–7.36 (m, 4H, NH2
ArH). HRMS (ESI): m/z calcd for: 329.0367 [MþNa]þ, found:
1
5-Amino-2,3,4,7-tetrahydro-7-(4-chlorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4g). IR (potassium bromide): 3439,
3329, 3223, 2186, 1701, 1637, 1602, 1490, 1410, 1354, 1295,
þ
1
1242, 1137, 1115, 1088, 1055, 1016, 851, 604, 505 cmꢂ1; H
NMR (DMSO-d6) (d, ppm): 2.93–3.00 (m, 1H, CH2), 3.07–
3.15 (m, 1H, CH2), 3.41–3.52 (m, 2H, CH2), 4.52 (s, 1H,
ArCH), 7.29 (s, 2H, NH2), 7.31 (s, 2H, ArH), 7.40 (d, J ¼ 8.0
Hz, 2H, ArH). HRMS (ESI): m/z calcd for: 345.0071
[MþNa]þ, found: 345.0071.
329.0366.
5-Amino-2,3,4,7-tetrahydro-7-(4-fluorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4d). IR (potassium bromide): 3394,
3329, 3218, 2361, 2343, 2188, 1703, 1654, 1560, 1543, 1509,
1414, 1355, 1294, 1242, 1145, 1117, 1093, 1054, 851 cmꢂ1
;
5-Amino-2,3,4,7-tetrahydro-7-(4-methoxyphenyl)-1,1-dioxo-
thieno[3,2-b]pyran-6-carbonitrile (4h). IR (potassium bro-
mide): 3434, 3343, 3205, 2191, 1702, 1645, 1612, 1469, 1454,
1351, 1301, 1248, 1196, 1148, 1110, 1051, 1027, 977, 844,
1H NMR (DMSO-d6) (d, ppm): 2.93–3.01 (m, 1H, CH2), 3.09–
3.16 (m, 1H, CH2), 3.42–3.52 (m, 2H, CH2), 4.54 (s, 1H,
ArCH), 7.09–7.13(m, 3H, ArH), 7.28 (s, 2H, NH2), 7.36–7.41
(m, 1H, ArH). HRMS (ESI): m/z calcd for: 329.0367
[MþNa]þ, found: 329.0368.
1
790, 771, 730, 653, 604 cmꢂ1; H NMR (DMSO-d6) (d, ppm):
2.91–2.98 (m, 1H, CH2), 3.06–3.14 (m, 1H, CH2), 3.39–3.50
(m, 2H, CH2), 3.74 (s, 3H, CH3), 4.41 (s, 1H, ArH), 6.88 (d, J
¼ 8.4 Hz, 2H, ArH), 7.16 (d, J ¼ 8.4 Hz, 2H, ArH), 7.19 (s,
2H, NH2). HRMS (ESI): m/z calcd for: 341.0566 [MþNa]þ,
found: 341.0567.
5-Amino-2,3,4,7-tetrahydro-7-(2-chlorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4e). IR (potassium bromide): 3443,
3314, 3258, 3207, 2361, 2343, 2199, 1704, 1647, 1594, 1474,
1439, 1348, 1309, 1235, 1147, 1112, 1051, 756, 622 cmꢂ1; H
1
NMR (DMSO-d6) (d, ppm): 2.93–3.01 (m, 1H, CH2), 3.07–
3.14 (m, 1H, CH2), 3.40–3.51 (m, 2H, CH2), 4.52 (s, 1H,
ArCH), 7.14–7.18 (m, 2H, ArH), 7.24 (s, 2H, NH2), 7.29–7.32
(m, 2H, ArH). HRMS (ESI): m/z calcd for: 345.0071
[MþNa]þ, found: 345.0059.
5-Amino-2,3,4,7-tetrahydro-7-(3-methoxyphenyl)-1,1-dioxo-
thieno[3,2-b]pyran-6-carbonitrile (4i). IR (potassium bro-
mide): 3372, 3318, 3256, 3210, 2192, 1706, 1648, 1604, 1586,
1490, 1410, 1355, 1289, 1237, 1153, 1139, 1115, 1050, 698,
1
505 cmꢂ1; H NMR (DMSO-d6) (d, ppm): 2.92–2.99 (m, 1H,
5-Amino-2,3,4,7-tetrahydro-7-(3-chlorophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4f). IR (potassium bromide): 3386,
3323, 3261, 3213, 2344, 2193, 1705, 1652, 1603, 1543, 1509,
1476, 1433, 1414, 1355, 1292, 1236, 1147, 1119, 1079, 1055,
CH2), 3.09–3.16 (m, 1H, CH2), 3.41–3.52 (m, 2H, CH2), 3.74
(s, 3H, CH3), 4.43 (s, 1H, ArCH), 6.79–6.86 (m, 3H, ArH),
7.23 (s, 2H, NH2), 7.27 (d, J ¼ 8.0 Hz, 1H, ArH). HRMS
(ESI): m/z calcd for: 341.0566 [MþNa]þ, found: 341.0567.
5-Amino-2,3,4,7-tetrahydro-7-(3,4,5-trimethoxyphenyl)-1,1-
dioxothieno[3,2-b]pyran-6-carbonitrile (4j). IR (potassium
bromide): 3403, 3329, 3265, 3217, 3184, 2850, 2194, 1710,
1653, 1601, 1471, 1409, 1344, 1294, 1246, 1229, 1198, 1161,
1114, 1053, 1032, 1006, 978, 893, 851, 792, 721, 653, 601
1008, 881, 704, 691, 506 cmꢂ1 1H NMR (DMSO-d6) (d,
;
Scheme 2
cmꢂ1 1H NMR (DMSO-d6) (d, ppm): 2.92–3.00 (m, 1H,
;
CH2), 3.10–3.18 (m, 1H, CH2), 3.45–3.52 (m, 2H, CH2), 3.66
(s, 3H, OCH3), 3.76 (s, 6H, 2 ꢃ OCH3), 4.45 (s, 1H, ArCH),
6.55 (s, 2H, NH2), 7.25 (s, 2H, ArH). HRMS (ESI): m/z calcd
for: 401.0783 [MþNa]þ, found: 401.0778.
5-Amino-2,3,4,7-tetrahydro-7-(4-methylphenyl)-1,1-dioxo-
thieno[3,2-b]pyran-6-carbonitrile (4k). IR (potassium bro-
mide): 3399, 3324, 3214, 2198, 1705, 1647, 1602, 1510, 1412,
1352, 1298, 1237, 1150, 1112, 1049, 601 cmꢂ1 1H NMR
;
(DMSO-d6) (d, ppm): 2.29 (s, 3H, CH3), 2.91–2.99 (m, 1H,
CH2), 3.07–3.14 (m, 1H, CH2), 3.39–3.50 (m, 2H, CH2), 4.40
(s, 1H, ArCH), 7.13 (s, 4H, NH2 þ ArH), 7.18 (s, 2H, ArH).
HRMS (ESI): m/z calcd for: 325.0617 [MþNa]þ, found:
325.0620.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Solvent-Free Synthesis of 5-Methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]
pyrimidine-6-carboxylic Esters Catalyzed by Sulfamic Acid
1115
2H, CH2), 4.65 (s, 1H, ArCH), 6.32–6.39 (m, 2H, ArH), 7.33
(s, 2H, NH2), 7.59 (s, 1H, ArH). HRMS (ESI): m/z calcd for:
301.0259 [MþNa]þ, found: 301.0250.
5-Amino-2,3,4,7-tetrahydro-7-(3-bromophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4l). IR (potassium bromide): 3434,
3339, 3204, 2338, 2191, 1705, 1645, 1612, 1516, 1399, 1351,
1332, 1300, 1248, 1196, 1178, 1148, 1110, 1051, 1027, 844,
Ethyl
5-amino-2,3,4,7-tetrahydro-7-(4-nitrophenyl)-1,1-
653, 604, 536 cmꢂ1
3.01 (m, 1H, CH2), 3.10–3.17 (m, 1H, CH2), 3.42–3.53 (m,
2H, CH2), 4.54 (s, 1H, ArCH), 7.28–7.32 (m, 4H, NH2
;
1H NMR (DMSO-d6) (d, ppm): 2.94–
dioxothieno[3,2-b]pyran-6-carboxlate (4s). IR (potassium bro-
mide): 3420, 3292, 1713, 1676, 1619, 1509, 1407, 1342, 1294,
;
1219, 1147, 1107, 1052, 879, 818, 714, 642, 600 cmꢂ1 1H
þ
NMR (CDCl3) (d, ppm): 1.03 (t, J ¼ 7.2 Hz, 3H, OCH2CH3),
2.98–3.08 (m, 2H, CH2), 3.34–3.46 (m, 2H, CH2), 3.95–4.03 (m,
2H, OCH2CH3), 4.94 (s, 1H, ArCH), 6.54 (s, 2H, NH2), 7.45 (d,
J ¼ 8.4 Hz, 2H, ArH), 8.17 (d, J ¼ 8.4 Hz, 2H, ArH). HRMS
(ESI): m/z calcd for: 403.0570 [MþNa]þ, found: 403.0575.
ArH), 7.47–7.49 (m, 2H, ArH). HRMS (ESI): m/z calcd for:
388.9571 [MþNa]þ, found: 388.9544.
5-Amino-2,3,4,7-tetrahydro-7-(4-bromophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4m). IR (potassium bromide): 3442,
3322, 3216, 3185, 2187, 1703, 1640, 1600, 1491, 1406, 1358,
1287, 1237, 1143, 1118, 1052, 1011, 854, 827, 711, 643, 604,
Ethyl
5-amino-2,3,4,7-tetrahydro-7-(2,4-dichlorophenyl)-
1
530 cmꢂ1; H NMR (DMSO-d6) (d, ppm): 2.93–3.01 (m, 1H,
1,1-dioxothieno[3,2-b]pyran-6-carboxylate (4t). IR (potassium
bromide): 3433, 3400, 3282, 2980, 1707, 1678, 1619, 1587,
1563, 1510, 1473, 1409, 1386, 1351, 1308, 1274, 1214, 1141,
CH2), 3.07–3.14 (m, 1H, CH2), 3.41–3.52 (m, 2H, CH2), 4.51
(s, 1H, ArCH), 7.24 (d, J ¼ 8.4 Hz, 2H, ArH), 7.30 (s, 2H,
NH2), 7.54 (d, J ¼ 8.4 Hz, 2H, ArH). HRMS (ESI): m/z calcd
for: 388.9571 [MþNa]þ, found: 388.9546.
1
1100, 1050, 973, 856, 758, 689, 646, 604, 569 cmꢂ1; H NMR
(DMSO-d6) (d, ppm): 0.95 (t, J ¼ 7.2 Hz, 3H, OCH2CH3),
2.95–3.11 (m, 2H, CH2), 3.37–3.50 (m, 2H, CH2), 3.88 (q, J
¼ 7.2 Hz, 2H, OCH2CH3), 5.07 (s, 1H, ArCH), 7.23 (d, J ¼
8.4 Hz, 1H, ArH), 7.36 (m, 1H, ArH), 7.49 (d, J ¼ 2 Hz, 1H,
ArH), 7.92 (s, 2H, NH2). HRMS (ESI): m/z calcd for:
425.9940 [MþNa]þ, found: 425.9941.
5-Amino-2,3,4,7-tetrahydro-7-(4-nitrophenyl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile(4n). IR (potassium bromide): 3442,
3335, 3213, 2194, 1705, 1639, 1599, 1521, 1407, 1355, 1294,
1238, 1148, 1118, 1050, 1014, 873, 820, 699, 601 cmꢂ1 1H
;
NMR (DMSO-d6) (d, ppm): 2.97–3.05 (m, 1H, CH2), 3.10–
3.17 (m, 1H, CH2), 3.43–3.55 (m, 2H, CH2), 4.74 (s, 1H,
ArCH), 7.41 (s, 2H, NH2), 7.59 (d, J ¼ 8.4 Hz, 2H, ArH),
8.22 (d, J ¼ 8.8 Hz, 2H, ArH). HRMS (ESI): m/z calcd for:
356.0312 [MþNa]þ, found: 356.0310.
Ethyl
5-amino-2,3,4,7-tetrahydro-7-(3-fluorophenyl)-1,1-
dioxothieno[3,2-b]pyran-6-carboxylate (4u). IR (potassium
bromide): 3404, 3297, 2982, 1703, 1670, 1615, 1520, 1484,
1451, 1405, 1352, 1243, 1207, 1148, 1098, 1047, 1002, 975, 872,
762, 726, 698, 681, 634, 600, 557, 522 cmꢂ1; 1H NMR (CDCl3)
(d,ppm): 1.05 (t, J ¼ 7.2 Hz, 3H, OCH2CH3), 2.84–2.92 (m, 1H,
CH2), 2.97–3.05 (m, 1H, CH2),3.32–3.43 (m, 2H, CH2), 3.97–
4.04 (m, 2H, OCH2CH3), 4.83 (s, 1H, ArCH), 6.38 (s, 2H, NH2),
6.88–6.99 (m, 2H, ArH), 7.03–7.15 (m, 2H, ArH). HRMS (ESI):
m/z calcd for: 376.0625 [MþNa]þ, found: 376.0627.
5-Amino-2,3,4,7-tetrahydro-7-(2,4-dichlorophenyl)-1,1-diox-
othieno[3,2-b]pyran-6-carbonitrile (4o). IR (potassium bro-
mide): 3440, 3218, 3026, 2192, 1711, 1700, 1632, 1597, 1559,
1471, 1434, 1407, 1353, 1288, 1244, 1150, 1115, 1059, 1047,
1
1008, 837, 784, 759, 737, 681, 647, 605, 514 cmꢂ1; H NMR
(DMSO-d6) (d, ppm): 2.95–3.02 (m, 1H, CH2), 3.08–3.16 (m,
1H, CH2), 3.42–3.53 (m, 2H, CH2), 4.59 (s, 1H, ArCH), 7.30
(d, J ¼ 8.4 Hz, 1H, ArH), 7.35 (s, 2H, NH2), 7.56(s, 1H,
ArH), 7.60 (d, 1H, J ¼ 8.0 Hz, ArH). HRMS (ESI): m/z calcd
for: 378.9687 [MþNa]þ, found: 378.9678.
Ethyl
5-amino-2,3,4,7-tetrahydro-7-(3-nitrophenyl)-1,1-
dioxothieno[3,2-b]pyran-6-carboxylate (4v). IR (potassium
bromide): 3444, 3305, 1714, 1675, 1624, 1522, 1441, 1353,
1301, 1219, 1149, 1101, 1052, 999, 906, 795, 751, 710, 679,
1
649, 624, 592 cmꢂ1; H NMR (DMSO-d6) (d,ppm): 0.98 (t, J
5-Amino-2,3,4,7-tetrahydro-7-(3,4-dichlorophenyl)-1,1-diox-
othieno[3,2-b]pyran-6-carbonitrile (4p). IR (potassium bro-
mide): 3403, 3329, 3265, 3217, 3184, 2850, 2194, 1710, 1653,
1601, 1471, 1409, 1344, 1294, 1246, 1229, 1198, 1161, 1114,
¼ 8.4 Hz, 3H, OCH2CH3), 2.97–3.04 (m, 1H, CH2), 3.14–3.22
(m, 1H, CH2), 3.41–3.53 (m, 2H, CH2), 3.84–3.96 (m, 2H,
OCH2CH3), 4.75 (s, 1H, ArCH), 7.58–7.71 (m, 2H, ArH), 7.94
(s, 2H, NH2), 8.00–8.10 (m, 2H, ArH). HRMS (ESI): m/z calcd
for: 403.0576 [MþNa]þ, found: 403.0566.
1
1053, 1032, 1006, 978, 893, 851, 792, 721, 653, 601 cmꢂ1; H
NMR (DMSO-d6) (d, ppm): 2.89–3.00 (m, 1H, CH2), 3.04–
3.14 (m, 1H, CH2), 3.40–3.52 (m, 2H, CH2), 4.86 (s, 1H,
ArCH), 6.93–7.02 (m, 2H, ArH), 7.32 (s, 2H, NH2), 7.44 (d, J
¼ 8.4 Hz, 1H, ArH). HRMS (ESI): m/z calcd for: 378.9687
[MþNa]þ, found: 378.9670.
Ethyl
5-amino-2,3,4,7-tetrahydro-7-(3-chlorophenyl)-1,1-
dioxothieno[3,2-b]pyran-6-carboxylate (4w). IR (potassium
bromide): 3415, 3294, 2984, 1704, 1671, 1616, 1520, 1476, 1433,
1402, 1352, 1299, 1243, 1212, 1147, 1048, 728, 700, 623, 598,
548 cmꢂ1; 1H NMR (DMSO-d6) (d,ppm): 1.00 (t, J ¼ 8.4 Hz, 3H,
OCH2CH3), 2.94–3.01 (m, 1H, CH2), 3.13–3.20 (m, 1H, CH2),
3.41–3.50 (m, 2H, CH2), 3.86–3.99 (m, 2H, OCH2CH3), 4.58 (s,
1H, ArCH), 7.15–7.33 (m, 4H, ArH), 7.87 (s, 2H, NH2). HRMS
(ESI): m/z calcd for: 392.0330 [MþNa]þ, found: 392.0332.
5-Amino-2,3,4,7-tetrahydro-7-(thiophen-2-yl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4q). IR (potassium bromide):
3233, 3443, 3323, 3203, 2195, 1709, 1648, 1589, 1437, 1409,
1348, 1302, 1239, 1147, 1055, 1002, 977, 855, 800, 722, 703,
1
649, 620, 596 cmꢂ1; H NMR (DMSO-d6) (d, ppm): 2.94–3.13
(m, 2H, CH2), 3.41–3.53(m, 2H, CH2), 4.93 (s, 1H, ArCH), 7.38
(s, 2H, ArH), 7.42 (s, 2H, NH2), 7.57 (s, 1H, ArH). HRMS
(ESI): m/z calcd for: 317.0025 [MþNa]þ, found: 317.0028.
5-Amino-2,3,4,7-tetrahydro-7-(furan-2-yl)-1,1-dioxothieno
[3,2-b]pyran-6-carbonitrile (4r). IR (potassium bromide):
3383, 3316, 3252, 3209, 3128, 2193, 1702, 1650, 1602, 1414,
1353, 1297, 1241, 1149, 1114, 1053, 928, 883, 842, 767, 737,
Acknowledgment. The authors are grateful for the financial sup-
port by the Natural Science Foundation of China (Numbers
20672090 and 200810102050), the Major Basic Research Project
of the Natural Science Foundation of the Jiangsu Higher Educa-
tion Institutions (09KJA430003), the Natural Science Foundation
of Xuzhou City (XM09B016), the Graduate Foundation of Xuz-
hou Normal University (09YLB030) and the Qing Lan Project
(08QLT001).
688, 645, 598 cmꢂ1 1H NMR (DMSO-d6) (d, ppm): 2.92–
;
3.01 (m, 1H, CH2), 3.06–3.14 (m, 1H, CH2), 3.43–3.53 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1116
C. Yao, X. Feng, C. Wang, B. Jiang, C. Yu, X. Wang, T. Li, and S. Tu
Vol 48
[10] (a) Walsh, P. J.; Li, H. M.; de Parrodi, C. A. Chem Rev
2007, 107, 2503; (b) Hobbs, H. R.; Thomas, N. R. Chem Rev 2007,
107, 2786; (c) Tanaka, K.; Toda, F. Chem Rev 2000, 100, 1025; (d)
Sheldon, R. A. Green Chem 2005, 7, 247.
REFERENCES AND NOTES
[1] Mustafa, A. In Furopyrans and Furopyrones, The Chemistry
of Heterocyclic Compounds; Weissberger, A., Ed.; Wiley Interscience:
New York, London, 1967.
[11] (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem Rev
1997, 97, 449; (b) Zhang, W. Chem Rev 2004, 104, 2531; (c) Dom-
ling, A. Chem Rev 2006, 106, 17; (d) Toure, B. B.; Hall, D. G. Chem
Rev 2009, 109, 4439; (e) Zhang, W. Green Chem 2009, 11, 911; (f)
Sunderhaus, J.; Martin, S. F. Chem Eur J 2009, 15, 1300; (g) Ganem,
B. Acc Chem Res 2009, 42, 463.
[2] Wright, J. B.; Johnson, H. G. J Med Chem 1973, 16, 861.
[3] Pauline, J. S.; James, J. M.; Jeffery, B. P.; Louis, J. F.;
Maud, J. U.; Laurence, B. K.; Edward, G.; Robert, F.; Joseph, S.;
John, B.; Moore, J.; William, M. J Med Chem 1992, 35, 4425.
[4] Christoph, O.; Dirk, S.; Jose, M. V.; Jose, L. D.; Jorg, H.;
Bernhard, W. J Med Chem 2008, 51, 6531.
[12] (a) Zhang, R.; Liang, Y. J.; Zhou, G. Y.; Wang, K. W.;
Dong, D. W. J Org Chem 2008, 73, 8089; (b) Dabiri, M.; Bahramne-
jad, M.; Baghbanzadeh, M. Tetrahedron 2009, 65, 9443; (c) Xing, C.
H.; Li, X. F.; Zhu, S. F.; Zhao, J. W.; Zhu, S. Z. Tetrahedron Lett
2006, 47, 4951; (d) Ramesh, C.; Mahender, G.; Ravindranath, N.; Das,
B. Tetrahedron 2003, 59, 1049.
[5] Michael, J. C.; Murali, G.; William, A. C. Bioorg Med
Chem 2004, 12, 1895.
[6] (a) Chris, P. M.; Michael, D. C.; Heather, A. H. Bioorg
Med Chem Lett 2003, 13, 2399; (b) Tanaka, K.; Kohayakawa, K.; Irie,
T.; Iwata, S.; Taguchi, K. J Fluor Chem 2007, 128, 1094; (c) Eller, G.
A.; Holzer, W. Molecules 2007, 12, 60; (d) Eller, G. A.; Haring, A.
W.; Datterl, B.; Zwettler, M.; Holzer, W. Heterocycles 2007, 71, 87;
(e) Aly, A. A. Chin J Chem 2005, 23, 211.
[13] Yao, C. S.; Lei, S.; Wang, C. H.; Yu, C. X.; Tu, S. J. J
Heterocycl Chem 2008, 45, 1609.
[14] The single-crystal growth was carried out in ethanol at
room temperature. X-ray crystallographic analysis was performed
[7] Pradhan, T. K.; De, A.; Mortier, J. Tetrahedron 2005, 61, 9007.
[8] (a) Muftafa, A.; Asker, W.; Hishmat, O. H.; Ali, M. I.;
Mansour, A. K. E.; Abed, N. M.; Khalil, K. M. A.; Samy, S. M. Tetra-
hedron 1965, 21, 849; (b) Smiles, S.; Mcclelland, L. W. J Chem Soc
1921, 119, 1810.
using
a Rigaku Saturn diffractometer. Crystal data for 4m:
C
14H11BrN2O3S, crystal dimension 0.24 mm ꢃ 0.22 mm ꢃ 0.12 mm,
˚
Monoclinic, space group P 1 21/c 1, a ¼ 8.3743(18) A, b ¼ 14.003(3)
o
3
˚
˚
˚
A, c ¼ 12.673(3) A, b ¼ 103.059(3) , V ¼ 1447.7(5) A , Mr ¼ 367.22,
3
ꢂ1
,
˚
[9] Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
Z ¼ 4, Dc ¼ 1.685 g/cm , k ¼ 0.71070 A, l (Moka) ¼ 2.994 mm
F(000) ¼ 736, S ¼ 0.986, R1 ¼ 0.0364, wR2 ¼ 0.0880.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet