Regioselectivity of ring closure of 2-thia- and 2-sulfonyl-5-methyl-5-hexenyl radicals

Article abstract of DOI:10.1021/ol0267836

(matrix presented) Ring closure of the α-substituted radicals 4 (X = S, SO₂) is observed to be irreversible and to lead to significant amounts of the product of 6-endo cyclization. Indeed, reduction of the sulfonyl-based radical 4 (X = SO₂

Full text of DOI:10.1021/ol0267836

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4065-4067
Regioselectivity of Ring Closure of
2-Thia- and
2-Sulfonyl-5-methyl-5-hexenyl Radicals
Ernest W. Della* and Sean D. Graney
Department of Chemistry, Flinders UniVersity of South Australia, GPO Box 2100,
Adelaide SA 5001, Australia
ern.della@flinders.edu.au
Received August 25, 2002
ABSTRACT
Ring closure of the r-substituted radicals 4 (X ) S, SO ) is observed to be irreversible and to lead to significant amounts of the product of
2
6-endo cyclization. Indeed, reduction of the sulfonyl-based radical 4 (X ) SO ), in which regioselectivity is believed to be controlled by a
2
combination of both steric and FMO interactions, is found to provide an excellent route to the cyclic sulfone 7 (X ) SO ) in high yield.
2
The application of radical cyclization of the 5-hexenyl system
in organic synthesis leading to the preparation of some quite
complex substrates is well-documented.1 Generally, these
rearrangements occur under stereoelectronic control and
frequently yield products via a predominant 5-exo mode of
ring closure. When a modified radical containing a hetero-
atom is employed, the procedure can be exploited for the
synthesis of heterocyclic compounds, and a number of
compounds of commercial and physiological importance
have indeed been synthesized in this way. We have previ-
ously prepared several novel heterocyclic systems containing
nitrogen using both R- and â-ammonio-substituted 5-hexenyl
radicals.2
reveals only scattered examples of the synthesis of sulfur-
based heterocycles via radical methods. These include
cyclizations with a sulfur functionality in the hexenyl chain
at the 3-3 and 4-positions4 and an example of a sulfonylated
radical in the 2-position5. Several useful radical cyclizations
with a sulfur functionality located R- to the radical center
have also been reported, but these yield a cyclic product with
the sulfur functionality external to the ring.6
More recently, we have reported7 the results of a parallel
study of the cyclization of the 2-thia- and 2-sulfonyl-5-
hexenyl radicals 1 (X ) S, SO2) (Scheme 1). It was observed
While oxygen- and nitrogen-containing radical cyclizations
have been studied intensively, an examination of the literature
Scheme 1
(1) (a) For an extensive review on “Radicals in natural product synthesis”
see: Curran, D. P.; Fevig, T. L.; Jasperse, C. P. Chem. ReV. 1991, 91, 1237.
(b) Curran, D. P. Synlett 1991, 63. (c) Neumann, W. P. Synthesis 1987,
665. (d) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke,
K. J.; Trach, F. Org. React. 1996, 48, 301.
(2) (a) Della, E. W.; Smith, P. A. J. Chem. Soc., Perkin Trans. 1 2001,
445. (b) Della, E. W.; Smith, P. A. Tetrahedron Lett. 2001, 42, 481. (c)
Della, E. W.; Smith, P. A. J. Org. Chem. 2000, 65, 6627. (d) Della, E. W.;
Smith, P. A. J. Org. Chem. 1999, 64, 1798. (e) Della, E. W.; Smith P. A.;
Knill, A. M. Chem. Commun. 1996, 14, 1637. (f) Della, E. W.; Knill, A.
M. Tetrahedron Lett. 1996 37, 5805. (g) Della, E. W.; Knill, A. M. J. Org.
Chem. 1996, 61, 7529. (h) Della, E. W.; Knill, A. M. Aust. J. Chem. 1995,
48, 2047.
that mixtures containing substantial quantities of both the
5-endo and 6-exo products 2 and 3 (X ) S, SO2), respec-
(3) Serra, A. C.; da Silva Correa, C. M. M. Tetrahedron Lett. 1991, 32,
6653.
(4) Ponaras, A. A.; Zaim, O. Tetrahedron Lett. 2000, 41, 2279.
10.1021/ol0267836 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/16/2002

tively, of irreversible ring closure were produced. Interest-
ingly, species 1 (X ) SO2) is much more amenable to ring
closure compared to radical 1 (X ) S) under similar
conditions, giving over 95% cyclized products. Nevertheless,
while the mode of cyclization of these radicals is of intrinisic
interest, the procedure does not represent a particularly
convenient entry into sulfur-substituted heterocyclic com-
pounds in view of the mixture of isomeric products so
obtained.
Table 1. Product Ratios from Bu3SnH Reduction of Radicals 1
and 4 (X ) S, SO2)
concn
(M)
T
precursor
radical
(°C) reduced 5-exo 6-endo
8a
4 (X ) S)
4 (X ) S)
4 (X ) S)
4 (X ) SO2) 0.011
4 (X ) SO2) 0.044
0.011
0.011
0.011
80
80
80
80
80
80
80
38.6
35.6
75.7
3.9
8.9
17.1
3.8
7.1
8.3
2.7
2.5
2.3
54.3
56.2
21.6
93.6
88.7
12.8
23.1
9a
9a,b
8a
8a
107
107
We now report a study on the regiochemistry associated
with the cyclization of 5-methyl-substituted radicals 4 (X )
S, SO2) (Scheme 2). By analogy with behavior of the
1 (X ) S)
1 (X ) SO2) 0.013
0.013
70.1
73.1
b
a From this work. Bu3SnH was used in 5-fold excess.
Scheme 2
Table 1. Inspection of the table reveals that the extent of
6-endo versus 5-exo ring closure is enormously enhanced
in the case of the sulfonyl radical 4 (X ) SO2) in which the
ratio of the 5-exo to 6-endo product is 1:37, with little of
the acyclic reduced species 5 (X ) SO2) detected. Under
experimental conditions designed to minimize even further
the extent of reduction,13 the reaction is found to give an
excellent yield (86%) of the substituted cyclohexane 7 (X
) SO2)14 uncontaminated by either isomer 5 (X ) SO2) or
isomer 6 (X ) SO2).
The data within Table 1 further demonstrate that the ratio
of 5-exo to 6-endo products remains constant for radicals 4
(X ) S, SO2) despite changes in concentration, thus
indicating that these reactions occur irreversibly under the
conditions employed in this study.
corresponding all-carbon 5-methyl-5-hexenyl system 4 (X
) CH2), it was anticipated that introduction of a methyl group
at C5 would be accompanied by a reduction in the rate of
5-exo ring closure of species 4 (X ) S, SO2), thus giving an
enhanced yield of the 6-endo product 7 (X ) S, SO2)
compared with isomer 6 (X ) S, SO2). Furthermore, it is
noteworthy that in the case of the R-sulfonyl-substituted
radical, the strong inductively withdrawing influence of the
SO2R group (sp value ) +0.7)8 would be expected to impart
significant electrophilic character onto the radical. Accord-
ingly, given that these reactions are predicted to proceed via
early transition states, regioselectivity is also expected to be
dependent upon the favored interaction of the frontier orbitals
of the reactants.
The selected precursors to the radicals 4 (X ) S, SO2)
under study were the selenides 8 (X ) S, SO2),9 which were
rigorously purified immeditely prior to use. Crich10 has
shown that the presence of PhSeH derived from reaction of
(PhSe)2 with Bu3SnH can introduce undesirable complica-
tions. As a precautionary measure, bistributyltin oxide was
added to the reaction mixture in view of its demonstrated
efficiency as a scavenger of PhSeH.11 Barton ester 9 was
also employed in order to determine whether adventitious
diphenyl diselenide might be influencing the extent of
cyclization.
It is also of interest to compare the behavior of radicals 4
(X ) S, SO2) with that of other R-substituted 5-methyl-5-
(8) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(9) Synthesis of the required substrates and their potential products of
reaction will be described in the full paper. The identity of all compounds
was established by appropriate combustion data as well as GC and NMR
spectroscopic analysis. Spectral data and experimental procedures for new
compounds 5 (X ) SO2), 8 (X ) S, SO2), and 9 are provided in Suppporting
Information.
(10) Crich, D.; Yao, Q. J. Org. Chem. 1995, 60, 84.
(11) Maxwell, B. J.; Smith, B. J.; Tsanaktsidis, J. J. Chem. Soc., Perkin
Trans. 2 2000, 425.
(12) Stock solutions of 8 (X ) S, SO2) were prepared in benzene with
the addition of bistributyltin oxide11 and subjected to standard radical
cyclization conditions (catalytic amount of AIBN; 1.2 equiv of Bu3SnH
injected over 2 min; reaction temperature ) 80°C; reaction time ) 2 h;
cooling and then quenching with CCl4 (X ) S) or CH3I (X ) SO2)).
Reaction mixtures were analyzed by GC, and product ratios were then
determined by utilizing GC response factors for each of the expected
products; these response factors were determined using authentic samples
of 5-7, which had been prepared by standard procedures. In the case of
the Barton ester, precursor 9 was added to a refluxing solution of 1.2 equiv
of Bu3SnH.
(13) A 0.01M solution of (3-methyl-but-3-ene-1-sulfonylmethylselanyl)-
benzene 8 (X ) SO2) (0.135 g, 0.43 mmol) in benzene (40 mL) was
deoxygenated, heated to reflux (80 °C), and then treated with a solution of
Bu3SnH (0.16 g, 0.54 mmol) in deoxygenated benzene (3 mL) containing
a few crystals of AIBN over 15 min. The resulting solution was heated for
an additional 3 h and then cooled; the reaction was quenched with CH3I
and the solution concentrated in vacuo. GCMS analysis of the crude product
revealed the presence of 6 (X ) SO2) in minute amount (ca. 3%). Flash
chromatography on silica (hexane/ether) yielded pure sulfone 7 (X ) SO2)
as a white solid (0.055 g, 86%), mp 118-120 °C (lit.14a mp 119-120 °C),
whose 1H NMR14a and 13C NMR14b spectral data were identical to those
reported.
The results of the behavior of radicals 4 (X ) S, SO2)12
together with those for 1 (X ) S, SO2) are summarized in
(5) Vacher, B.; Samat, A.; Allouche, A.; Laknifli, A.; Baldy, A.; Chanon,
M. Tetrahedron 1988, 44, 2925.
(6) Ke, B.-W.; Lin, C.-H.; Tsai, Y.-M. Tetrahedron 1997, 53, 7805.
(7) Della, E. W.; Graney, S. D. Tetrahedron Lett. 2000, 41, 7987.
(14) (a) Kropp, P. J.; Breton, G. W.; Fields, J. D.; Tung, J. C.; Loomis,
B. R. J. Am. Chem. Soc. 2000, 122, 4280. (b) Barbarella, G.; Dembech, P.
Org. Magn. Res. 1984, 22, 402.
4066
Org. Lett., Vol. 4, No. 23, 2002

attached to C5, in accordance with the effect of a methyl
group at C5 in the system 4 (X ) CH2); at the same time,
there is no steric encumbrance for 6-endo closure, and (b)
frontier molecular orbital interactions, in which the presence
of the highly electron-withdrawing SO2 group attached to
the radical center confers considerable electrophilic character
onto the radical. Thus, in the case of electrophilic radicals
such as 4 (X ) SO2), FMO theory suggests18 that the mode
of ring closure is largely determined by the interaction
between the radical SOMO and the alkene HOMO. For
alkenes of types 1 and 4, the coefficient of the HOMO at
C6 is larger than that at C5, and, accordingly, more favorable
bond formation occurs between the radical center and C6,
favoring the 6-endo product.
The data collected in Table 2 reveal that the attachment
of the two oxygen atoms in 4 (X ) SO2) does not appear to
exert the kind of steric effect on the rate of cyclization as
displayed by gem-dimethyl groups. It is found that the
presence of the methyl groups at C2 leads to an enhanced
rate of 5-exo ring closure in 4 (X ) Me2)16 compared with
that in 4 (X ) CH2),15 a phenomenon referred to as the “gem-
dialkyl effect”.19
Table 2. Ratio of Exo/Endo Products from Some
5-Methyl-5-hexenyl Radicals
radical
T (°C)
5-exo:6-endo
reference
4 (X ) S)
80
80
80
80
102
12:88
2.6:97.4
40:60
68:32
72:28
a
a
15
16
2b
4 (X ) SO2)
4 (X ) CH2)
4 (X ) CMe2)
4 (X ) +NMe2)
a From this work.
hexenyl radicals; these data are included in Table 2. Again,
it can be seen that the proportion of 6-endo product derived
from radical 4 (X ) SO2) is overwhelming.
While the longer C-S bonds would be expected to
facilitate 6-endo closure, as evidenced by the exo/endo ratios
produced in the cyclization of radicals 1 (X ) S, SO2),17 we
believe that the high regioselectivity observed in the case of
radical ring closure of sulfone 4 (X ) SO2) is a combination
of two predominant factors: (a) steric effects, which disfavor
the 5-exo mode of cyclization as a result of the methyl group
We are currently investigating the behavior of the corre-
sponding sulfoxides 1 and 4 (X ) SO).
(15) Beckwith, A. L. J.; Lawrence, T. J. Chem. Soc., Perkin Trans. 2
1979, 1535.
(16) Beckwith, A.; L. J.; Blair, I. A.; Phillipou, G. Tetrahedron Lett.
1974, 2251.
Acknowledgment. We thank the Australian Research
Council for financial support.
(17) Wilt has observed that the corresponding R-silyl-based radical 1
(X ) SiMe2) leads to mixtures of cyclized products 2 (X ) SiMe2) and 3
(X ) SiMe2), albeit in very low yield. (a) Wilt, J. J. Org. Chem. 1981,
103, 5251; Tetrahedron 1985, 41, 3979. (b) Wilt, J. W.; Lustztyk, J.; Peeran,
M.; Ingold, K. U. J. Am. Chem. Soc. 1988, 110, 281.
(18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: London, 1976.
Supporting Information Available: Experimental details
for the preparation and characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Allinger, N. L.; Zalkow, V. J. Org. Chem. 1960, 25, 701.
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