8
630
J . Org. Chem. 1997, 62, 8630-8631
Dou ble Ra d ica l Cycliza tion /
Sch em e 1
â-F r a gm en ta tion of Acyclic ω-Yn e Vin yl
Su lfid es. Syn th esis of
3
-Vin yld ih yd r oth iop h en e a n d
Dih yd r oth iop yr a n Der iva tives. A New
Exa m p le of a 5-en d o-tr ig Ra d ica l
Cycliza tion
Michel J ournet,* Alain Rouillard, Dongwei Cai and
Robert D. Larsen
Department of Process Research, Merck Research
Laboratories, P.O. Box 2000, R80Y-245,
Rahway, New J ersey 07065-0900
Received September 26, 1997
Free-radical chemistry has greatly expanded the rep-
ertoire of organic chemists over the last two decades and
has proved to be a powerful method for tandem reactions
that allow the formation of multiple carbon-carbon
bonds in a one-pot reaction.1 Radical cyclization and
radical rearrangement-cyclization have been more and
more utilized for the construction of elaborated mol-
ecules.2 Herein, we report a new method for the synthe-
sis of 3-vinyldihydrothiophene and dihydrothiopyran
derivatives 2 via a double radical cyclization/â-fragmen-
tation of acyclic ω-yne vinyl sulfides 1 regio-, chemo-, and
stereoselectively (Scheme 1). This strategy involves five
elemental processes: (i) intermolecular addition of a
stannyl radical onto a terminal triple bond; (ii) 5- or 6-exo-
Ta ble 1. P r ep a r a tion of th e Vin yl Su lfid es 1 a n d Th eir
Ra d ica l Cycliza tion to 2
a
entry
n
R
EWG
yield of 1 (%) /E:Z yield of 2 (%)a
3
trig cyclization of the Z vinyl radical; (iii) â-fragmenta-
92/85:15b
a
b
c
d
e
f
1
1
1
2
2
2
H
CO2Et
64
62
0
73
78
0
tion;4 (iv) 5- or 6-endo-trig cyclization of the sulfur-
centered radical; and (v) â-fragmentation of the tin
radical. Although the 5-endo-trig cyclization (n ) 1) is
c
d
n-C4H9 CO2Et
H
H
n-C4H9 CO2Et
CO2Et CO2Et
65 /45:55
SO2-p-Tol
CO2Et
88/65:35b
b
91/90:10
c
d
5
62 /45:55
known to be a disfavored process, the final fragmenta-
86/37:63d
tion of the stannyl radical would drive the reaction
toward the formation of the heterocycle 2, terminating
the radical chain. In this manner, the process is expected
to be catalytic in tin hydride. In addition, it is notewor-
thy that the stereochemistry of 1 is of no consequence to
the outcome with the formation of the less hindered E
olefin.
a
b
Isolated yield (purified by silica gel chromatography). De-
1
c
termined by the J coupling in the H NMR. The Michael addition
of the thiol was achieved with a catalytic amount of sodium in
ethanol.8 d Determined by 1H NMR-NOE experiment.
∼
65% overall yield. Michael addition of the mercaptans
onto an activated triple bond using N-methylmorpholine
as the base in dichloromethane gave 1 in good yields as
a mixture of separable E and Z isomers.
Different chemical mediators, such as tris(trimethyl-
silyl)silane (TTMSS), Et
AIBN were used to perform the radical cyclization but
the best results were obtained when the reaction was
carried out in a refluxing degassed benzene solution of
The syntheses of the radical precursors (Table 1) were
achieved in four steps from the commercially available
7
3
-butyn-1-ol (n ) 1) and 4-pentyn-1-ol (n ) 2). The
alcohols were first activated as the mesylates, which were
displaced with a mixture of thiolacetic acid and cesium
carbonate6 in acetonitrile. Finally, deprotection with
potassium carbonate in methanol afforded the thiols in
9
10
3
3
B-Ph SnH, and thiophenol-
1
3
a and 1b (or toluene at 80 °C) with 50 mol % of n-Bu -
*
To whom correspondence should be addressed: Tel.: (908) 594-
402. Fax: (908) 594-6703. E-mail: michel_journet@merck.com.
1) For reviews, see: (a) Curran, D. P. Radical Addition Reactions
SnH in the presence of AIBN catalyst at 0.02 M concen-
tration for 4 h.11 The reaction proceeded cleanly with
a regioselective 5-endo-trig cyclization, which gave the
dihydrothiophene derivatives 2a and 2b in 64% and 62%
1
12
(
and Radical Cyclizations and Sequential Radical Reactions. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming I., Eds.;
Pergamon: New York, 1992; Vol. 4, pp 715-831. (b) J asperse, C. P.;
Curran, D. P.; Fevig, T. L. Chem. Rev. (Washington, D.C.) 1991, 91,
1
(
237-1286. (c) Curran, D. P. Synthesis 1988, 417-439 and 489-513.
d) Bunce, R. A. Tetrahedron 1995, 51, 13103-13159. (e) Malacria,
M. Chem. Rev. (Washington, D.C.) 1996, 96, 289-306.
2) For a recent example, see: J ung, M. E.; Rayle, H. L. J . Org.
Chem. 1997, 62, 4601-4609 and references therein.
(7) Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450-458.
(8) Truce, W. E.; Kruse, R. B. J . Am. Chem. Soc. 1959, 81, 5372-
5374.
(
(9) Chatgilialoglu, C. Acc. Chem. Res 1992, 25, 188-194.
(10) Nozaki, K.; Oshima, K.; Utimoto, K. J . Am. Chem. Soc. 1987,
109, 2547-2549.
(3) (a) Stork, G.; Mook, R., J r. Tetrahedron Lett. 1986, 27, 4529-
4
2
532. (b) Stork, G.; Mook, R., J r. J . Am. Chem. Soc. 1987, 109, 2829-
3
(11) In a typical procedure, n-Bu SnH (135 µL, 0.5 mmol) was added
831.
to a degassed benzene solution (50 mL) containing AIBN (14 mg, 0.1
mmol) and 1 (1.0 mmol). The mixture was allowed to reflux (80 °C)
under nitrogen for 4 h, cooled to room temperature, and concentrated
in vacuo to give an oil that was flash chromatographed (silica) with a
5/95 mixture of ethyl acetate and hexane as eluent to give 2 as a
colorless oil.
(4) Russell, G. A.; Ngoviwatchai, P.; Wu, Y. W. J . Am. Chem. Soc.
1
989, 111, 4921-4927.
(
5) (a) Gimisis, T.; Chatgilialoglu, C. J . Org. Chem. 1996, 61, 1908-
1
3
909. (b) Bogen, S.; Malacria, M. J . Am. Chem. Soc. 1996, 118, 3992-
993.
(
6) Strijtveen, B.; Kellogg, R. M. J . Org. Chem. 1986, 51, 3664-
(12) Only the cyclized product 2 and tributyltin hydride could be
evidenced in a clean crude H NMR.
1
3
671.
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