Sulfur-controlled exo selective aryl radical cyclization onto exo- methylenecycloalkanes

Article abstract of DOI:10.1055/s-1999-2826

The Bu₃SnH-mediated aryl radical cyclization of vinyl sulfides 9 proceeds in an exo selective manner to give fused aromatic compounds 10 which contain a benzylic quaternary carbon center.

Full text of DOI:10.1055/s-1999-2826

1286
LETTER
Sulfur-Controlled Exo Selective Aryl Radical Cyclization onto Exo-
Methylenecycloalkanes
Hiroyuki Ishibashi,* Tetsuya Kobayashi, Daisuke Takamasu
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Fax +81(76)234-4476; E-mail: isibasi@dbs.p.kanazawa-u.ac.jp
Received 25 May 1999
The radical precursors 9a–c were prepared from the ke-
tone 8a–c3b by the Horner-Emmons reaction with the lith-
ium salt of Ph2P(O)CH2SPh.5 A solution of Bu3SnH (1.2
equiv.) and a catalytic amount of azoisobutyronitrile
(AIBN) in benzene was slowly added to a boiling solution
of 9a over a period of 1 h and the mixture was further heat-
ed for 3 h to give the exo cyclization product 10a in 75%
yield as a single stereoisomer. The stereochemistry of the
ring-juncture of 10a proved to be cis based on the nOe ex-
periments of the corresponding desulfurized compound
11a.
Abstract: The Bu3SnH-mediated aryl radical cyclization of vinyl
sulfides 9 proceeds in an exo selective manner to give fused aromat-
ic compounds 10 which contain a benzylic quaternary carbon cen-
ter.
Key words: aryl radical, neophyl rearrangement, vinyl sulfide, rad-
ical cyclization, tributyltin hydride
The control of the regiochemistry of radical cyclizations
is a subject of intense investigation.1 In principle, the ring-
closure of o-bromo-(3-methyl-3-butenyl)benzene (1, X =
CH2) and its related species can occur in an exo or in an
endo manner to give 2 and 3, respectively, under the
Bu3SnH-mediated conditions. The literature indicated
that the product distribution of the cyclizations depended
upon the nature of atom X of 1 or the reaction conditions
employed. The aryl bromides 1 where X = CH22a,b or O,2c
in general, gave a mixture of the exo and the endo cycliza-
tion products 2 and 3, whereas the corresponding aza an-
alog (1, X = NAc) gave only the exo cyclization product
2.2d On the other hand, the bromides 4 having an exo-me-
thylenecycloalkane exclusively gave the endo cyclization
products 5.3a,b This was also the case for the homologous
system 6 which gave the endo cyclization product 7.3c,d,4
Herein we report that the endo selectivity of the cycliza-
tions of 4 and 6 can be shifted to the exo mode by intro-
ducing a phenylthio group at the terminus of their exo-
methylene bonds.
SPh
Br
Br
O
i
( )n
( )n
8a-c
9a-c
ii
PhS
Me
H
iii
( )n
( )n
H
11a-c
10a-c
a; n = 0, b; n = 1, c; n = 2
Scheme 2 i, Ph2P(O)CH2SPh, BuLi, THF, then H3O+; ii, Bu3SnH,
AIBN, benzene, reflux; iii, Raney Ni, EtOH, reflux.
The cyclization of the cyclohexyl congener 9b proceeded
more smoothly to give the exo-cyclization product 10b in
91% yield, whose cis-stereochemistry was confirmed by
its desulfurization to the known compound 11b.6 Com-
pound 9c also gave the exo cyclization product 10c in 82%
yield as a mixture of the cis and the trans-isomers in a ra-
tio of 4.3:1 (determined by the nOe experiments of 11c).
Br
i
+
X
X
X
2
3
1; X = CH2, O, NAc
Br
H
i
The reaction of the homologous compound 13, prepared
from the ketone 12,7 gave also the exo cyclization product
14 in 40% yield along with a trace amount of the endo-cy-
clization product 15. The cis-stereochemistry of the ring-
juncture of 14 was established by the transformation to the
known compound 16.8
( )n
( )n
X
X
H
H
4; n = 0 – 2
5
Br
i
H
The formation of the exo cyclization products 10 (from 9)
and 14 (from 13) may be best explained by assuming that
the intermediate radicals 18 formed by an exo cyclization
of the aryl radicals 17 are highly stabilized by an adjacent
sulfur atom.9,10
6
7
Scheme 1 i, Bu3SnH, AIBN, benzene, reflux
Synlett 1999, No. 8, 1286–1288 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Sulfur-Controlled Exo Selective Aryl Radical Cyclization onto Exo-Methylenecycloalkanes
1287
SPh
Br
.
Bu3Sn•
Br
O
4
i
( )n
21
13
ii
12
.
.
PhS
( )n
( )n
22
23
+
H
Bu3SnH
Me
Bu3SnH
14
15
.
( )n
24
iii
Me
( )n
( )n
H
11
5
Scheme 5
16
Scheme 3 i, Ph2P(O)CH2SPh, BuLi, THF then H3O+; ii, Bu3SnH,
AIBN, benzene, reflux; iii, Raney Ni, EtOH, reflux
Ghatak and his coworkers reported that the bromide 4 (n
=1) gave 5 (n = 1) in 95% yield as a mixture containing a
debrominated product in a ratio of 9:1 under the condi-
tions where the concentration of Bu3SnH in benzene was
maintained at 0.007–0.02 M.3a,b In our laboratory, the
compound 4 (n = 1) was treated with Bu3SnH at a 0.1 M
concentration, which was higher than that employed by
Ghatak, to give a small amount of the exo cyclization
product 11b (n = 1) as a mixture containing the reported
endo cyclization product 5 (n = 1) in a ratio of 1:7. This
result strongly suggests that the exo cyclization of 21 giv-
ing 23 might be the kinetically favored process over the
endo cyclization giving 22. The radicals 23 formed from
21 might rapidly undergo a neophyl rearrangement at a
low Bu3SnH concentration to give the endo cyclization
products 5 via the radical 22.
PhS
SPh
.
.
9
or
13
10
or
14
( )n
( )m
( )n
( )m
H
17
18
PhS
PhS
.
.
20
19
Scheme 4
In summary, the whole sequence of the reactions herein
described can be regarded in a formal sense as an exo cy-
clization of 4 and 6 giving 11 and 16, respectively, since
the sulfur atom of the cyclization products 10 and 14 can
easily be removed by reductive desulfurization. The
present method provides a new synthesis of fused aromat-
ic compounds containing a benzylic quaternary carbon at-
om. An extended application of the method to the
synthesis of natural products is now in progress.
The formation of 15 from 13 may be rationalized in terms
of a partial endo cyclization of the aryl radical 19 followed
by an elimination of the benzenethiyl radical from the re-
sulting intermediate radical 20.
The present results suggest that the endo selective cycliza-
tion of the aryl bromides 4 may be explained by consider-
ing the difference in the stability between the intermediate
radicals 22 and 23 formed by an endo or by an exo cycliza-
tion of the aryl radicals 21. The former might be more sta-
ble than the latter based on stereoelectronic reasons,
thereby resulting in the formation of the endo cyclization
products 5. However, the possibility of the consecutive
exo cyclization of the aryl radicals 21 and the neophyl
rearrangement2c of the resulting radical 23 (via 24) could
not be excluded for the formation of 22. We then reinves-
tigated the reaction of 4 (n = 1).
References and Notes
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(2) (a) Rigollier, P.; Young, J. R.; Fowley, L. A.; Stille, J. R. J.
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J. P.; Ramanathan, H. Tetrahedron Lett. 1988, 29, 45.
Synlett 1999, No. 8, 1286–1288 ISSN 0936-5214 © Thieme Stuttgart · New York

1288
H. Ishibashi et al.
LETTER
(3) (a) Pal, S.; Mukherjee, M.; Podder, D.; Mukherjee, A. K.;
Ghatak, U. R. J. Chem. Soc., Chem. Commun. 1991, 1591. (b)
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(4) For analogous endo selective aryl radical cyclizations, see
Ghosh, K.; Ghosh, A. K.; Ghatak, U. R. J. Chem. Soc., Chem.
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see Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.;
Sato, T.; Ikeda, M. J. Org. Chem. 1995, 60, 1276; Ishibashi,
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M. J. Chem. Soc., Perkin Trans. 1 1997, 2291.
(10) The exo selective aryl radical cyclizations onto the
corresponding oxime ethers have been reported. See Booth, S.
E.; Jenkins, P. R.; Swain, C. J.; Sweeney, J. B. J. Chem. Soc.,
Perkin Trans. 1 1994, 3499.
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Article Identifier:
1437-2096,E;1999,0,08,1286,1288,ftx,en;Y10499ST.pdf
Synlett 1999, No. 8, 1286–1288 ISSN 0936-5214 © Thieme Stuttgart · New York