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H. S. Lee et al. / Tetrahedron Letters 50 (2009) 6480–6483
1. DABCO (1.2 equiv)
aq THF, rt, 10 min
DBU (1.5 equiv)
DMF, rt, 1 h
SCH2COOEt
COOMe
DDQ (2.5 equiv)
3a (89%) + 4a (4%)
1a
III + IV (86%)
Ph
ODCB, 110 oC, 3 h
2. 2a (1.0 equiv), 30 min
II (88%)
Scheme 3.
DBU (2.5 equiv)
DMF, rt, 4 h
1a
+
COOMe
COOEt
(i) partial hydrolysis
(ii) Michael addition
DDQ (2.5 equiv)
Ph
4a (51%) + 3a (12%)
IV
ODCB, 110 oC, 2 h
(major pathway)
SAc
O
SAc
VIII
EtO
III + IV (85%)
2d
partial hydrolysis
(minor pathway)
1a
2a
I
III
Scheme 4.
Tetrahedron 2008, 64, 4511–4574; (c) Declerck, V.; Martinez, J.; Lamaty, F.
Chem. Rev. 2009, 109, 1–48; (d) Ciganek, E.. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1997; Vol. 51, pp 201–350; (e) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (f) Drewes, S. E.; Roos,
G. H. P. Tetrahedron 1988, 44, 4653–4670; (g) Kim, J. N.; Lee, K. Y. Curr. Org.
Chem. 2002, 6, 627–645; (h) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean
Chem. Soc. 2005, 26, 1481–1490; (i) Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049–3052; (j) Krishna, P. R.; Sachwani, R.; Reddy, P. S. Synlett 2008, 2897–
2912; (k) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron
of VII was carried out similarly, however, we obtained the desired
thiophene 3j in low yield (26%) along with unexpected thiophene 6
in 27%. The mechanism for the deacetylative aromatization to com-
pound 6 could be explained as shown in Scheme 2.5e–g When the
phenoxide of DDQ attacks the hydrogen atom (path a) 3j could
be formed whereas when the anion attacks the carbonyl group of
the acetyl moiety (path b) compound 6 could be formed.9
In order to synthesize the minor product 4a in an increased
yield, we prepared II from 1a via the corresponding DABCO salt
as shown in Scheme 3.3a,10 Compound II was prepared in good
yield (88%). Treatment of II with DBU in DMF afforded a mixture
of tetrahydrothiophene intermediates in 86%. However, subse-
quent DDQ oxidation produced 3a (89%) as the major product
again, unfortunately. Based on the experimental results, we could
conclude that the secondary adduct II might be isomerized to the
thermodynamically more stable primary adduct I, under the condi-
tions of DBU/DMF, to produce III to a large extent.
Thus we examined another route for the synthesis of 4a as shown
in Scheme 4. The reaction of 1a and 2d, a protected form of 2a, could
produce VIII and the intermediate VIII could be transformed to IV
through a partial hydrolysis of the thioacetate group11 and intramo-
lecular Michael reaction. Actually, we obtained a mixture of tetrahy-
drothiophenes in 85% yield. Treatment of this mixture with DDQ
afforded 4a in an increased yield (51%) in comparison with 5% (entry
1 in Table 1). However, compound 3a was obtained together in low
yield (12%) through the pathway comprising of a partial hydrolysis
of 2d to 2a and the sequential processes involving the formation of
I and III, as shown in Scheme 4.
In summary, we developed an efficient synthetic process of 2,3,4-
trisubstituted thiophenes from Baylis–Hillman adducts via the
sequential SN20 reaction of thiols, intramolecular Michael addition,
and DDQ oxidation. This is the first example for the synthesis of thio-
phenes from Baylis–Hillman adducts and the studies on the synthe-
sis of differently substituted thiophenes are currently underway.
2. For our recent synthesis of aromatic compounds from Baylis–Hillman adducts,
see: (a) Kim, H. S.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50,
3154–3157; (b) Kim, K. H.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1249–
1251; (c) Kim, S. H.; Kim, K. H.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 2008, 49,
1948–1951; (d) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron
Lett. 2008, 49, 1670–1673; (e) Lee, H. S.; Kim, S. H.; Gowrisankar, S.; Kim, J. N.
Tetrahedron 2008, 64, 7183–7190; (f) Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron
Lett. 2007, 48, 4119–4122; (g) Kim, S. J.; Kim, H. S.; Kim, T. H.; Kim, J. N. Bull.
Korean Chem. Soc. 2007, 28, 1605–1608; (h) Kim, E. S.; Kim, K. H.; Kim, S. H.;
Kim, J. N. Tetrahedron Lett. 2009, 50, 5098–5101.
3. For the synthesis of sulfur-containing compounds from Baylis–Hillman
adducts, see: (a) Yadav, L. D. S.; Rai, V. K. Tetrahedron Lett. 2009, 50, 2414–
2419; (b) Cha, M. J.; Song, Y. S.; Han, E.-G.; Lee, K.-J. J. Heterocycl. Chem. 2008,
45, 235–240; (c) Cha, M. J.; Song, Y. S.; Lee, K.-J. Bull. Korean Chem. Soc. 2006, 27,
1900–1902.
4. For the synthesis and biological activities of poly-substituted thiophene
derivatives, see: (a) Piller, F. M.; Knochel, P. Org. Lett. 2009, 11, 445–448. and
further references cited therein; (b) Liang, F.; Li, D.; Zhang, L.; Gao, J.; Liu, Q.
Org. Lett. 2007, 9, 4845–4848; (c) Noguchi, T.; Hasegawa, M.; Tomisawa, K.;
Mitsukuchi, M. Bioorg. Med. Chem. 2003, 11, 4729–4742; (d) Fernandez, M.-C.;
Castano, A.; Dominguez, E.; Escribano, A.; Jiang, D.; Jimenez, A.; Hong, E.;
Hornback, W. J.; Nisenbaum, E. S.; Rankl, N.; Tromiczak, E.; Vaught, G.;
Zarrinmayeh, H.; Zimmerman, D. M. Bioorg. Med. Chem. Lett. 2006, 16, 5057–
5061; (e) Karthikeyan, S. V.; Perumal, S.; Balasubramanian, K. K. Tetrahedron
Lett. 2007, 48, 6133–6136; (f) Alberola, A.; Andres, J. M.; Gonzalez, A.; Pedrosa,
R.; Pradanos, P. Synth. Commun. 1990, 20, 2537–2547; (g) Shindo, M.;
Yoshimura, Y.; Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto, K.;
Shishido, K. Org. Lett. 2007, 9, 1963–1966.
5. For the dehydrogenative aromatization with DDQ, see: (a) Walker, D.; Hiebert,
J. D. Chem. Rev. 1967, 67, 153–195; (b) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978,
78, 317–361; (c) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2005, 46,
5387–5391; (d) Lee, K. Y.; Kim, S. C.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26,
2078–2080; For deacetylative aromatization, see: (e) Boots, S. G.; Johnson, W.
S. J. Org. Chem. 1966, 31, 1285–1287; (f) Cross, A. D.; Carpio, H.; Crabbe, P. J.
Chem. Soc. 1963, 5539–5544; (g) Weidmann, R. Bull. Soc. Chim. Fr. 1971, 912–
917.
6. Typical procedure for the synthesis of compound 3a: To a stirred solution of 1a
(234 mg, 1.0 mmol) and 2a (120 mg, 1.0 mmol) in DMF (2 mL) was added
DBU (381 mg, 2.5 mmol) and the mixture was stirred at room temperature for
60 min. The reaction mixture was poured into dilute HCl solution and
extracted with ether. Drying with MgSO4, removal of solvent, and column
chromatographic purification process (hexanes/ether, 10:1) afforded a crude
mixture of III and IV as colorless oil, 244 mg (83%). To the crude
tetrahydrothiophenes (III + IV, 176 mg, 0.6 mmol) in o-dichlorobenzene
(0.5 mL) was added DDQ (341 mg, 1.5 mmol) and heated to 110 °C for 3 h.
After removal of solvent under reduced pressure and column
chromatographic purification process (hexanes/ether, 10:1) we obtained 3a
(160 mg, 92%) and 4a (9 mg, 5%). Other thiophenes were synthesized
similarly and the representative spectroscopic data of 3a, 4a, 3h, 3i, 5, and
6 are as follows.
Acknowledgments
This study was financially supported by Special Research Pro-
gram of Chonnam National University, 2009. Spectroscopic data
were obtained from the Korea Basic Science Institute, Gwangju
branch.
References and notes
1. For the general review on Baylis–Hillman reaction, see: (a) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Singh, V.; Batra, S.