Microwave-assisted novel synthesis of amino-thieno[3,2-b]pyridines under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.08.075

In the presence of a catalytic amount of ytterbium(III) triflate and under microwave irradiation, mixtures of 2-amino-3-thiophenecarbonitriles, ketones, and silica gel afforded smoothly the corresponding amino-thieno[2,3-b]pyridine derivatives in one step. A wide variety of ketones were tested under these conditions. The reactions proceeded rapidly and afforded the desired products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.08.075

Tetrahedron Letters 51 (2010) 5718–5720
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Tetrahedron Letters
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Microwave-assisted novel synthesis of amino-thieno[3,2-b]pyridines under
solvent-free conditions
Weike Su a, , Shaozheng Guo a, Zhi Hong a,b, Ren’er Chen b
⇑
a Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
b School of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of a catalytic amount of ytterbium(III) triflate and under microwave irradiation, mixtures
of 2-amino-3-thiophenecarbonitriles, ketones, and silica gel afforded smoothly the corresponding amino-
thieno[2,3-b]pyridine derivatives in one step. A wide variety of ketones were tested under these condi-
tions. The reactions proceeded rapidly and afforded the desired products in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 May 2010
Revised 14 July 2010
Accepted 24 August 2010
Keywords:
Microwave-assisted
Solvent-free
Ytterbium triflate
Amino-thieno[2,3-b]pyridine derivatives
Combes reaction
Thieno[2,3-b]pyridinederivativesareofchemicaland pharmaco-
logical interests due to their isosterism with quinolines and isoquin-
olines, twoimportantheterocyclesinvolvedinmanyalkaloids. Some
of them have been used as herbicides, fungicides, pesticides, medi-
cines, and dyes.1,2 Thus, the synthesis of thieno[2,3-b]pyridines has
attractedmuchattention;three generalrouteshavebeendeveloped.
The most well-known and exploited route to thieno[2,3-b]pyridine
derivatives involves the direct condensation of 2-amino-3-thioph-
enecarbonitriles with ketones under AlCl3, ZnCl2 or SnCl4 catalyzed
in refluxing solution with azeotropic removal of water.3
Microwave(MW) activation asa non-conventional energysource
has emerged as a powerful technique to promote a variety of chem-
ical reactions and has become a very popular and useful technology
in organic chemistry.4 The combination of solvent-free conditions
and MW irradiation leads to large reductions in reaction times,
enhancement in conversions and selectivity, and has several fea-
tures of the eco-friendly approach, termed green chemistry.5 Strict
comparisons with conventional heating have been reported only
rarely, so specific MW effects have not been particularly studied.
During the last decade, rare earth metal triflates, a new type of Le-
wis acid, were widely used in organic synthesis because of their low
toxicity, high stability, ease of handling, water tolerance, and recov-
erability from water that could effectively promote several carbon–
carbon and carbon–heteroatom bond-forming reactions.6 We have
reported Yb(OTf)3-catalyzed one-pot synthesis of 1,3-thiazolidin-
2-imines from epichlorohydrin and thioureas,7a Yb(OTf)3-catalyzed
condensation reaction of b-naphthol and aldehyde in ionic liquids: a
green synthesis of aryl-14H-dibenzo[a,j] xanthenes,7b synthesis of
substituted 1,3-oxazolidines by ytterbium(III) triflate-catalyzed
[3+2] cycloaddition of N-arylimines and epoxides.7c As a part of
continuing program to explore the novel uses of rare earth metal tri-
flates in organic reactions, we discovered a novel one-step synthesis
R1
R2
CN
NH2
R1
NH2
N
O
R4
R3
5 mol% Yb(OTf)3
R3
+
R2
R4
S
MW, silica gel, 5 min
-
S
R1,R2= -(CH2)4
R1,R2= -(CH2)3
R1,R2= CH3
-
-
R4= CH3, Ph, p-F-Ph, p-Cl-Ph
m-Cl-Ph, 2-Py, p-Me-Ph
P-MeO-Ph, p-NO2-Ph
R3,R4= -(CH2)4
R3,R4= -(CH2)3
R3= CH3, H
-
R1=Ph,R2= H
Scheme 1. Yb(OTf)3-catalyzed microwave-assisted synthesis of thieno[2,3-b]pyri-
dine derivatives.
H2N
S
O
CN
NH2
5-mol% Lewis acid
+
MW, silica gel, 5 min
or solvent, reflux, 6h
S
N
1
2
3a
⇑
Corresponding author. Tel./fax: +86 (571) 88320752.
E-mail address: pharmlab@zjut.edu.cn (W. Su).
Scheme 2. Yb(OTf)3-catalyzed microwave-assisted synthesis of 3a.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.075

W. Su et al. / Tetrahedron Letters 51 (2010) 5718–5720
5719
Table 1
In this work, we describe the ytterbium(III) triflate-catalyzed 2-
amino-3-thiophenecarbonitriles and ketones cyclization affording
the corresponding amino-pyridines derivatives in a single syn-
thetic step (Scheme 1).
Effect of catalyst, microwave, and solvent on the formation of product 3a
Catalyst
Cat. (mol %)
Solvent
Conditions
Yielda,b (%)
ZnCl2
5
5
5
5
5
None
None
None
None
None
None
None
None
Toluene
Toluene
Xylene
DMF
MW, 5 min
MW, 5 min
MW, 5 min
MW, 5 min
MW, 5 min
MW, 3 min
MW, 5 min
MW, 5 min
Reflux, 6 h
MW, 5 min
Reflux, 6 h
Reflux, 6 h
23
26
82
52
93
82
95
0
63
21
71
73
The synthesis started from 2-amino-3-thiophene-carbonitriles
which were prepared in one step from ketones, malononitrile, and
sulfur with morpholine as a catalyst in the refluxing ethanol via
the classic Gewald reaction.8 In order to explore the preparation of
thieno[2,3-b]pyridinederivatives, a model reaction was made to test
the reaction condition. 2-Amino-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carbonitrile (5 mmol), acetophenone (5 mmol), and Lewis
acid (0.25 mmol) were ground with silica gel (0.5 g) under micro-
wave irradiation for 5 min (indicated by TLC) (Scheme 2).9 A series
of traditional Lewis acids such as ZnCl2 and Zn(OAc)2 were chosen
to promote the cyclization reaction, and 9-amino-7-phenyl-
1,2,3,4-tetrahydro-benzo-thieno[2,3-b]pyridine (3a) were obtained
in low yields (23% and 26%, respectively) (Table 1, entries 1 and 2).
Meanwhile, several metal triflates were also used, and the results
were compared to those traditional Lewis acids with a remarkable
improvement in the similar condition (Table 1, entries 3–5). In addi-
tion, the amount of catalyst, solvents, and reaction time were also
tested (Table 1, entries 6–13). It was shown that of the seven cata-
lystsused, Yb(OTf)3 gavethehighestyield(93%)forthedesired prod-
uct under solvent-free microwave assistance (Table 1, entry 5).
On the basis of the above-mentioned results, this process was
then extended to other substituted 2-amino-3-thiophene-carbo-
nitriles and ketones to investigate its scope and generality (Scheme
3). The results are listed in Table 3.
Zn(OAc)2
Zn(OTf)2
Cu(OTf)2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
None
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
5
10
—
5
5
5
5
a
Compounds 1 and 2 (5 mmol) were used.
Isolated yields based on compound 3a.
b
R1
R2
CN
NH2
R1
NH2
R4
O
5 mol% Yb(OTf) 3
MW, silica gel, 5 min
R3
+
R2
R4
S
R3
S
N
2
3
1
Scheme 3. Yb(OTf)3-catalyzed microwave-assisted synthesis of 3a.
Table 2
Reusability of Yb(OTf)3 catalyst together with silica gel
Recycle no.
Catalyst recovered (%)
Isolated yielda,b (%)
It can be seen that altering the substituent groups on the 2-ami-
no-3-thiophenecarbonitriles showed little effect on the yields; sev-
eral kinds of 2-amino-3-thiophene-carbonitriles containing
cycloalkyl, alkyl, or aryl groups easily undergo with cycloalkanone,
acetone, or substituted acetophenone to give the corresponding
amino-thieno[2,3-b]pyridines in good to excellent yields (Table 2,
entries 1–24). Among the substituents on arone (2), electron-with-
drawing substituents improved the efficiency of the addition reac-
tion, and 3i, 3s, and 3w were obtained in excellent yields (96%,
93%, and 96%; Table 2, entries 9, 19, and 23, respectively), while
1
2
3
98
98
97
93
92
90
a
Reactions were carried out under solvent-free microwave assistance.
Yield refers to pure product after column chromatography.
b
of thieno[2,3-b]pyridine derivatives catalyzed by Yb(OTf)3 under
solvent-free conditions in good to excellent yields.
Table 3
a
Microwave-assisted synthesis of thieno[2,3-b]pyridine derivatives catalyzed by Yb(OTf)3
Entry
Reactant 1
Reactant 2
Products
Yieldb(%)
R1
R2
R3
R4
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
–(CH2)4–
C6H5–
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
93
81
92
89
90
88
91
93
96
87
85
81
75
85
87
86
89
84
93
89
90
92
96
85
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)4–
CH3
CH3
H
H
H
H
H
H
H
p-Cl–C6H4–
m-Cl–C6H4–
p-F–C6H4–
p-CH3O–C6H4–
p-NO2–C6H4–
p-CH3–C6H4–
2-C5H4N–
–(CH2)4–
–(CH2)3–
C6H5–
H
H
H
H
H
H
p-Cl–C6H4–
m-Cl–C6H4–
p-F–C6H4–
p-CH3–C6H4–
p-NO2–C6H4–
3s
3t
3u
3v
3w
3x
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
–(CH2)4–
–(CH2)4–
p-Cl–C6H4–
p-CH3O–C6H4–
p-NO2–C6H4–
H
H
H
p-Cl–C6H4–
a
Reactions were carried out under solvent-free microwave assistance.
Yield refers to pure product after column chromatograph.
b

5720
W. Su et al. / Tetrahedron Letters 51 (2010) 5718–5720
(TfO)3Yb
Yb(OTf)3
Yb(OTf)
R1
R2
N
3
R4
N
CN
NH2
R4
O
R1
C
R1
R2
C
R3
+
R3
R3
R2
S
R4
N
N
S
S
H
A
B
C
NH
N
NH2
R1
R1
R4
R3
R4
R3
R2
R2
S
S
N
D
3
Scheme 4. A possible mechanism of Yb(OTf)3-catalyzed cyclization reaction of 2-amino-3-thiophenecarbonitriles and ketones.
the electron-donating substituent methoxyl improved the effi-
ciency of the cycloaddition reaction, giving the desired product
with yields (93% and 92%, Table 2, entries 8 and 22, respectively).
The structure of 3 was identified by 1H NMR, 13C NMR, IR, and MS.
Our attention was then turned to the possibility of recycling the
catalyst from the reaction media since the recovery and reuse of
the catalyst are highly preferable for a greener process. At comple-
tion of the reaction, the resulting mixture was dissolved by EtOAc
and filtered; the filter cake was washed by EtOAc to remove the or-
ganic impurities. The catalyst together with silica gel was recov-
ered almost quantitatively. The reusability of the catalyst was
investigated by using 2-amino-4,5,6,7-tetrahydro-benzo[b]thio-
phene-3-carbonitrile and cyclo-hexanone as model substrates.
After three recycles, the catalyst still had a high activity and gave
the corresponding product in fairly good yield (Table 2, recycle
no. 3).
References and notes
1. (a) Lohray, B. B.; Lohray, V. B.; Srivastava, B. K. Bioorg. Med. Chem. 2004, 17,
4557–4564; (b) Thompson, A. M.; Bridges, A. J.; Fry, D. W. J. Med. Chem. 1995,
38, 3780–3788; (c) Rewcastle, G. W.; Palmer, B. D.; Thompson, A. M. J. Med.
Chem. 1996, 39, 1823–1835; (d) Smaill, J. B.; Palmer, B. D.; Rewcastle, G. W. J.
Med. Chem. 1999, 42, 1803–1815; (e) Merja, B. C.; Joshi, A. M.; Parikh, K. A.
Indian J. Chem., Sect. B 2004, 4, 909–912.
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I.; Egawa, M.; Tobe, A.; Morinaka, Y. Bioorg. Med. Chem. Lett. 1995, 5, 1495–
1500; (b) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 7, 1027–1032.
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1343; (b) Seck, P.; Thomae, D.; Kirsch, G. J. Heterocycl. Chem. 2008, 45, 853–857.
4. (a) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984–7989; (b) De la Hoz,
A.; Diaz-Ortis, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem. 2000, 3659–3673; (c)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (d)Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002.
5. (a) Loupy, A.; Petit, A.; Hamelin, J.; Jacquault, P.; Mathé, D. Synthesis 1998,
1213–1234; (b) Handlon, A. L.; Yu, G. Synlett 2005, 111–114; (c) Varma, R. S.
Green Chem. 1999, 1, 43–55; (d) Tanaka, K. In Solvent-free Organic Synthesis;
Wiley-VCH: Weinheim, 2003.
A possible mechanism of Yb(OTf)3-catalyzed cyclization reac-
tion of 2-amino-3-thiophene-carbonitriles and ketones is rational-
ized in Scheme 4. Referring to the literature,10 we supposed that
the reaction proceeded through an SN2-type pathway. The ketones
were first coordinated to Yb(OTf)3 generating a highly reactive
intermediate A, which reacted with 2-amino-3-thiophenecarbo-
nitriles to give a stabile intermediate B. Then the nitrile group of
B coordinated to Yb(OTf)3 to give a highly reactive intermediate
C, which undergoes a ring-closing process, giving the final product
amino-thieno[2,3-b]pyridine 3.
In summary, we have demonstrated that the ytterbium triflates
are an effective catalyst for cyclization.11 By using Yb(OTf)3 as a
catalyst, microwave irradiation, and under solvent-free reaction
conditions, the novel one-pot modified Combes reaction gave
excellent yield and the reaction time was shortened from 18 h to
5 min. In addition, the catalyst can be easily recovered and reused.
It not only led to economical automation but also reduces hazard-
ous pollution to achieve environmentally friendly processes. This
microwave-assisted and Yb(OTf)3-catalyzed novel one-pot synthe-
sis of amino-thieno[2,3-b]pyridine therefore is a simple, high-
yielding, time-saving, and environmentally friendly process.12
6. (a) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 2001,
42, 3193–3195; (b) Li, J. J.; Su, W. K.; Lin, J. D.; Chen, M.; Li, J. Synth. Commun.
2005, 35, 1929–1937; (c) Curini, M.; Epifano, F.; Maltese, F.; Rosati, O.
Tetrahedron Lett. 2002, 43, 4895–4897; (d) Bagley, M. C.; Dale, J. W.; Hughes,
D. D. Synlett 2001, 1523–1526.
7. (a) Su, W.; Liu, C.; Shan, W. Synlett 2008, 725–727; (b) Su, W.; Yang, D.; Jin, C.
Tetrahedron Lett. 2008, 49, 3391–3394; (c) Yu, C.; Dai, X.; Su, W. Synlett 2007, 4,
0646–0648.
8. (a) Gewald, K. Z. Chem. 1961, 11, 349; (b) Gewald, K. Z. Chem. 1962, 2, 305; (c)
Gewald, K. Z.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94.
9. Khalilzadeh, M. A.; Hosseini, A.; Tajbakhsh, M. J. Heterocycl. Chem. 2007, 44,
535–538.
10. (a) Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89; (b) Johnson, W. S.; Matthews, F. J.
J. Am. Chem. Soc. 1944, 66, 210; (c) Bergstrom, F. W. Chem. Rev. 1944, 35, 156;
(d) Born, J. J. Org. Chem. 1972, 37, 3952.
11. (a) Appukkuttan, P.; Eycken, E. V. Eur. J. Org. Chem. 2008, 1133–1155; (b) Wang,
J. X.; Jia, X. F.; Meng, T. J.; Xin, L. Synthesis 2005, 2838–2844; (c) Ollevier, T.; Li,
Z. Eur. J. Org. Chem. 2007, 5665–5668.
12. Typical procedure for the preparation of compound 3a: (a) Without microwave
assistance in toluene: To
a mixture of 2-amino-3-thiophene-carbonitrile
(5 mmol), acetophenone (5 mmol) was added Yb(OTf)3 (0.25 mmol) in
toluene (10 mL). The mixture was heated to reflux. The progress of the
reaction was monitored by TLC. The resulting mixture was washed with water
(2 Â 10 mL). The organic layer was dried (Na2SO4) and evaporated, and the
crude product was purified by column chromatography [eluent: hexane/EtOAc
(95:5)] to provide 9-amino-7-phenyl-1,2,3,4-tetrahydro-benzo-thieno[2,3-
b]pyridine. Yb(OTf)3 was recovered from water.
(b) By microwave assistance under solvent-free condition: To a mixture of 2-
amino-3-thiophenecarbonitrile (5 mmol), acetophenone (5 mmol) and
Yb(OTf)3 (0.25 mmol) were mixed together in dry silica gel (0.5 g). The
mixture was then brought up to 300 W for 5 min under microwave irradiation.
The reaction was monitored by TLC. At completion of the reaction, the resulting
mixture was purified directly by column chromatography [eluent: hexane/
EtOAc (95:5)] to provide 9-amino-7-phenyl-1,2,3,4-tetrahydrobenzo-
thieno[2,3-b]pyridine (3a). Yb(OTf)3 and silica gel were recovered and
reused. Compound 3a yield 93%; orange needles; mp 212–213 °C (Petroleum
ether/EtOAc 3:1); IR(KBr): 3483 and 3329, 2937, and 2833, 1621, 1444, 845,
Acknowledgments
The authors are grateful to the National Natural Science Foun-
dation of China (20876147), the Zhejiang Natural Science Founda-
tion (Y4090346), and the Opening Foundation of Zhejing Provincial
Top Key Pharmaceutical Discipline for the financial support.
and 773 cmÀ1 1H NMR(400 MHz, DMSO): d 1.82 (d, J = 2.8, 4H, 2CH2), 2.74 (s,
;
Supplementary data
2H, CH2), 3.00 (s, 2H, CH2), 6.09 (s, 2H, NH2),7.06 (s, 1H, CH), 7.36–7.40 (m, 1H,
CH), 7.44–7.48 (m, 2H, 2CH) 7.89–97 (m, 1H, CH); 13C NMR(100 MHz, DMSO): d
18.6, 22.3, 25.2, 25.8, 101.6, 118.2, 126.2, 127.2, 128.4, 128.6, 130.6, 139.1,
150.9, 152.7, 161.6; MS: m/z 232 (100%).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.075.