One-pot syntheses of 2,3-dihydrothiopyran-4-one derivatives by Pd/Cu-catalyzed reactions of α,β-unsaturated thioesters with propargyl alcohols

Article abstract of DOI:10.1021/ol800754w

(Chemical Equation Presented) 2,3-Dihydrothiopyran-4-one derivatives were readily prepared by Pd/Cu-catalyzed reactions between α,β-unsaturated thioesters and propargyl alcohols in the presence of bases. Of note, both carbon-sulfur bonds were cleaved as a result of the single procedure.

Full text of DOI:10.1021/ol800754w

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2469-2472
One-Pot Syntheses of
2,3-Dihydrothiopyran-4-one Derivatives
by Pd/Cu-Catalyzed Reactions of
r,ꢀ-Unsaturated Thioesters with
Propargyl Alcohols
Yasunori Minami, Hitoshi Kuniyasu,* and Nobuaki Kambe*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Suita, Osaka 565-0871, Japan
kuni@chem.eng.osaka-u.ac.jp
Received April 3, 2008
ABSTRACT
2,3-Dihydrothiopyran-4-one derivatives were readily prepared by Pd/Cu-catalyzed reactions between r,ꢀ-unsaturated thioesters and propargyl
alcohols in the presence of bases. Of note, both carbon-sulfur bonds were cleaved as a result of the single procedure.
Recently, thioesters have been extensively employed as
reaction substrates in transition-metal-catalyzed reactions.1–6
For instance, cross-coupling reactions of organometallic
reagents to afford ketones have been studied by several
groups.3–5 In addition, we developed a series of Pt-catalyzed
decarbonylative carbothiolations of alkynes that afford vinyl
sulfides.6 Herein we report the syntheses of 2,3-dihydrothi-
opyran-4-one derivatives 3 by Pd/Cu-catalyzed one-pot
cyclization between R,ꢀ-unsaturated thioesters 1 and prop-
argyl alcohols 2 in the presence of bases (eq 1). These sulfur-
containing six-membered heterocyclic derivatives display a
wide range of biological activities.7
The reaction of CH2dC(Me)C(O)SC6H4NO2-p (1a, 0.4
mmol) with 2-methyl-3-butyn-2-ol (2a, 0.5 mmol) in the
(5) (a) Ikeda, Z; Hirayama, H.; Matsubara, S. Angew. Chem., Int. Ed.
2006, 45, 8200. (b) Ooguri, A.; Ikeda, Z.; Matsubara, S. Chem. Commun.
2007, 4761.
(6) (a) Kuniyasu, H.; Kurosawa, H. Chem. Eur. J. 2002, 8, 2660. (b)
Sugoh, K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.; Tanaka, A.;
Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 5108.
(c) Hirai, T.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2004, 33, 1148. (d)
Hirai, T.; Kuniyasu, H.; Kambe, N. Tetrahedron Lett. 2005, 46, 117. (e)
Hirai, T.; Kuniyasu, H.; Asano, S.; Terao, J.; Kambe, N. Synlett 2005, 1161.
(f) Kuniyasu, H.; Yamashita, F.; Hirai, T.; Ye, J.-H.; Fujiwara, S.; Kambe,
N. Organometallics 2006, 25, 566. (g) Kuniyasu, H.; Kambe, N. Chem.
Lett. 2006, 35, 1320. (h) Yamashita, F.; Kuniyasu, H.; Terao, J.; Kambe,
N. Org. Lett. 2008, 10, 101.
(1) (a) Osakada, K.; Yamamoto, T.; Yamamoto, A. Tetrahedron Lett.
1987, 28, 6321. (b) Kato, T.; Kuniyasu, H.; Kajiura, T.; Minami, Y.; Ohtaka,
A.; Kinomoto, M.; Terao, J.; Kurosawa, H.; Kambe, N. Chem. Commun.
2006, 868
.
(2) (a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050. (b) Kuniyasu, H.; Ogawa, A.; Sonoda, N. Tetrahedron Lett. 1993,
34, 2491
.
(7) (a) Ingall, A. H. In ComprehensiVe Heterocyclic Chemistry II;
Boulton, A. S., McKkillop, A., Eds.; Pergamon Press: Oxford, 1996; Vol.
5, p 501. (b) Schneller, S. W. AdV. Heterocycl. Chem. 1975, 18, 59. (c)
Katrizky, A. R.; Bonlton, A. J. AdV. Heterocycl. Chem. 1975, 18, 76. (d)
Al-Nakib, T.; Bezjak, V.; Meegan, M.; Chandy, R. Eur. J. Med. Chem.
1990, 25, 455. (e) Al-Nakib, T.; Bezjak, V.; Rashid, S.; Fullam, B.; Meegan,
M. Eur. J. Med. Chem. 1991, 26, 221. (f) van Vliet, L. A.; Rodenhuis, N.;
Dijkstra, D.; Wikstrom, H.; Pugsley, T. A.; Serpa, K. A.; Meltzer, L. T.;
Heffner, T. G.; Wise, L. D.; Lajiness, M. E.; Huff, R. M.; Svensson, K.;
Sundell, S.; Lundmark, M. J. Med. Chem. 2000, 43, 2871.
(3) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Tokuyama, H.; Miyazaki, T.;
Yokoshima, S.; Fukuyama, T. Synlett 2003, 1512
.
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(b) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5,
3033. (c) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.; Liebeskind,
L. S. J. Am. Chem. Soc. 2007, 129, 1132. (d) Yang, H.; Liebeskind, L. S.
Org. Lett. 2007, 9, 2993. (e) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S.
J. Am. Chem. Soc. 2007, 129, 15734
.
10.1021/ol800754w CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

presence of PdCl2 (0.004 mmol), CuI (0.04 mol), and Et3N
(0.4 mmol) in DMF (0.5 mL) at 80 °C for 6 h resulted in
the formation of 3a in 34% yield along with byproduct,
including (ArS)2 (10%) (run 1 of Table 1). Single X-ray
Table 1. Pd/Cu-Catalyzed Reaction of 1a with 2aa
Figure 1. ORTEP diagram of 3a.
with tertiary propargyl alcohols (2b, R3 ) R4 ) -(CH2)4-;
2c, R3 ) R4 ) -(CH2)5-; 2d, R3 ) Me, R4 ) Ph) provided
run
M
alkali salt
3a (%)b
1
2
3
4
5
6
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
none
34
40
Na2CO3
K2CO3
Cs2CO3
KOAcd
68 (60)c
60
Table 2. Pd/Cu-Catalyzed One-Pot Syntheses of
2,3-Dihydro-thiopyran-4-one Derivativesa
23
49
19
16
28
45
61
48
e
K2CO3
7f
8g
9h
10
11
12
13
14
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Pd(OAc)2
PdCl2(PhCN)2
PdCl2(PPh3)2
PdCl2 (dppf)
PtCl2
25
14
a Unless otherwise noted, 1a (0.4 mmol), 2a (0.5 mmol), PdCl2 (1 mol
%), CuI (10 mol %), K2CO3 (10 mol %), Et3N (1 equiv), and DMF (0.5
mL) at 80 °C for 6 h. b NMR yield. c Isolated yield. d 20 mol %. e 5 mol
%. f CuI (2 mol %). g CuI (100 mol %). h Et3N (20 mol %).
crystallographic analysis of 3a confirmed the structure to be
a 2,3-dihydrothiopyran-4-one derivative (Figure 1).8 It should
be noted that both C-S bonds of 1a, i.e., the C(O)-S and
Ar-S bonds, were cleaved and the Ar group migrated from
the sulfur of 1a to the oxygen of 2a. Among the alkali salts
examined (runs 2-5), K2CO3 (10 mol %) resulted in the
best yield (60% isolated yield) (run 3). Alteration of the
amounts of K2CO3 (5 mol %) (run 6), CuI (2 mol %, 100
mol %) (runs 7 and 8), or Et3N (20 mol %) (run 9) decreased
the yield of 3a. Other complexes such as Pd(OAc)2 (run 10),
PdCl2(PhCN)2 (run 11), PdCl2(PPh3)2 (run 12), PdCl2(dppf)
(run 13), and PtCl2 (run 14) showed inferior catalytic activity.
Synthesis of 3a required both a Pd and Cu catalyst.
a Unless otherwise noted, 1 (0.4 mmol), 2 (0.5 mmol), PdCl2 (1 mol
%), CuI (10 mol %), K2CO3 (10 mol %), Et3N (1 equiv), and DMF (0.5
mL) at 80 °C. b Isolated yield. c 60 °C. d 1.0 mmol.
the corresponding cyclization products 3b-3d in moderate
yields (runs 2-4). Cyclization with secondary propargyl
alcohol (2e, R3 ) H, R4 ) n-Pen) also gave 3e in 35% yield
(run 5). Propargyl alcohol (2f) gave a complicated mixture
and 3f was not synthesized (run 6). In the thioesters,
replacement of the Me group at R2 with an i-Pr group did
not interfere with cyclization (run 7). 1c (R1 ) Ph, R2 ) H)
was also converted into 3h in 55% yield (run 8). The thioester
with an Me group at R1 and a second Me at R2 (1d)
underwent a similar transformation as a result of reaction
The results of Pd/Cu-catalyzed reactions between various
thioesters (1) and propargyl alcohols (2) under optimized
conditions are summarized in Table 2. The treatment of 1a
(8) Crystal data of 3a: space group monoclinic, P21/a (No. 14) with a
) 11.1771(4), b ) 14.9463(5), c ) 11.0961(6) Å, ꢀ ) 1212.578(1)°, Z )
4, F ) 1.307 g/cm3, R ) 0.074, and Rw ) 0.184. See Supporting Informaion
for crystal data for 3a.
2470
Org. Lett., Vol. 10, No. 12, 2008

with either 2a or 2c (runs 9 and 10). In marked contrast, the
thioester with a p-tolyl group on the sulfur (1e, X ) Me)
gave a complicated mixture (run 11). No reaction took place
with substrate 1f, which had a SC10H21-n group rather than
SC6H4NO2-p (run 12). These results demonstrate that the
SC6H4NO2-p group of thioester 1 is required for the
formation of 3.
(eq 3). These results show that Et3N is essential for the
synthesis of 5 and 3.
To elucidate the reaction pathway, the reaction of 1a with
2a in DMF-d7 at 80 °C was monitored by 1H NMR
spectroscopy (Figure 2). The results suggest that both alkynyl
The reaction pathway proposed for the formation of 3 is
shown in Scheme 1, with 1a and 2a as representative
Scheme 1. Proposed Reaction Pathway
Figure 2. Time course of the Pd/Cu-catalyzed reaction of 1a with
2a.
ketone 4a and vinyl sulfide 5a were converted into 3a. After
4 h, both 4a and 5a disappeared and 3a was the major
product detected, in addition to unidentified byproduct.
Thus, authentic 4a and 5a9 were prepared and the reaction
mechanism was examined in greater detail. Alkynyl ketone
4a (0.4 mmol) reacted with p-NO2C6H4SH (6a, 0.4 mmol)
to give 3a in the presence of Et3N (0.4 mmol) at 80 °C even
without Pd/Cu catalysts, albeit in low yield (40%) (eq 2).
Addition of a catalytic amount of K2CO3 (0.04 mmol) to
the reaction mixture improved the yield of 3a (51%).
However, the yields for both the catalyst-free and K2CO3-
catalyzed reaction of 1a with 2a were lower than that
obtained by the Pd/Cu-catalyzed reaction as a result of
formation of complicated byproduct (compare with run 1 of
Table 2). Without Et3N, neither 3a nor 5a formed. Intramo-
lecular cyclization of 5a (0.2 mmol) proceeded in the
presence of Et3N (0.2 mmol) at 80 °C to afford 3a in 66%
yield, whereas no reaction took place in the absence of Et3N
substrates. First, a Pd/Cu-catalyzed Sonogashira-type reaction
between 1a and 2a gives 4a and 6a,3b and the subsequent
trans-addition of 6a to the yne moiety of 4a affords 5a.10,11
Intramolecular aromatic nucleophilic substitution by the
oxygen anion induces migration of the p-NO2C6H4 group
(10) For addition of thiol to eynone, see: (a) Perlmutter, P. In Conjugate
Addition Reactions in Organic Synthesis; Baldwin, J. E., Magnus, P. D.,
Eds.; Pergamon Press: Oxford, U.K., 1992; Vol. 9, pp 310-322. (b) Blanco,
L.; Bloch, R.; Bugnet, E.; Deloisy, S. Tetrahedron Lett. 2000, 41, 7875.
(c) Gardiner, J. M.; Giles, P. E.; Martin, M. L. M. Tetrahedron Lett. 2002,
43, 5415. (d) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68, 5550. (e)
Hollowood, C. J.; Yamanoi, S.; Ley, S. V. Org. Biomol. Chem. 2003, 1,
1664. (f) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321
.
(11) For copper-catalyzed acylselenation and telluration of alkynes, see:
(a) Zhao, C.-Q.; Huang, X.; Meng, J.-B. Tetrahedron Lett. 1998, 39, 1933.
(b) Zhao, C.-Q.; Li, J.-L.; Meng, J.-B.; Wang, Y.-M. J. Org. Chem. 1998,
(9) The NOE experiment showed that the cis-isomer was exclusively
produced. See Supporting Information for more details.
63, 4170.
Org. Lett., Vol. 10, No. 12, 2008
2471

from sulfur to oxygen.12 Finally, nucleophilic addition of
the resultant S anion to the terminal ene moiety and the
subsequent protonation yield 3a. Maintenance of low con-
centrations of 4a and 6a during the course of the reaction
improve the yield of 3a relative to that obtained by the
reaction of 4a with 6a.
for assistance in obtaining mass spectra with the JEOL JMS-
DX303 instrument. Y.M. would like to thank The Global
COE (center of excellence) Program “Global Education and
Research Center for Bio-Environmental Chemistry” of Osaka
University.
In summary, this study realized the synthesis of 2,3-
dihydrothiopyran-4-one derivatives by Pd/Cu-catalyzed reac-
tions between R,ꢀ-unsaturated thioesters and propargyl
alcohols in the presence of bases. The reactions proceed
through a one-pot sequence as follows: Sonogashira-type
reaction, Michael-addition of thiol to yne moiety, intramo-
lecular aromatic nucleophilic substitution, and cyclization.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800754W
Acknowledgment. Thanks are due to the Instrumental
(12) It has been reported that 2-arylthio-pyridine undergoes nucleophilic
Analysis Center, Faculty of Engineering, Osaka University,
substitution by phenol: (a) Inoue, S. Phosphorus Sulfur 1985, 22, 141.
2472
Org. Lett., Vol. 10, No. 12, 2008