Radical-mediated 5-exo-trig cyclizations of 3-silylhepta-1,6-dienes

Article abstract of DOI:10.1021/jo060024+

Regioselectivity of the sulfonyl radical mediated 5-exo-trig cyclization of 3-silylheptadienyl systems 3a-d has been studied. At low temperature, the reaction of the sulfonyl radical occurs regioselectively at the allylsilane terminus, while a reversal of

Full text of DOI:10.1021/jo060024+

SCHEME 1. 5-Exo-Trig Cyclization of
3-Silylhepta-1,6-dienyl Systems
Radical-Mediated 5-Exo-Trig Cyclizations of
3-Silylhepta-1,6-dienes
Philippe James,† Kurt Schenk,‡ and Yannick Landais*,†
Laboratoire de Chimie Organique et Organome´tallique,
UniVersite´ Bordeaux-I, 351 Cours de la Libe´ration, 33405
Talence Cedex, France, and UniVersite´ de Lausanne, Institut de
cristallographie, BPS Dorigny, CH-1015 Lausanne, Switzerland
of 1 was not a matter of concern as only the allylsilane terminus
could react. We thus envisaged investigating the regiocontrol
which could arise from addition of p-TolSO2SePh onto dienes
3a-d containing an allylsilane moiety at one end and a
monosubstituted olefin or an allylic alcohol moiety at the other
terminus. Selenosulfonylation of dienes is indeed an attractive
method to construct five-membered ring systems, as a new C-C
bond is formed while two functionalities and two new stereo-
genic centers are introduced in a single step.3 We report here
our investigations on the radical mediated addition/cyclization
of sulfur reagents onto dienes of type 3 to give five-membered-
ring systems 4 and 5 and provide a tentative rationalization of
our results.
y.landais@lcoo.u-bordeaux1.fr
ReceiVed January 5, 2006
Preliminary studies were conducted with the simple model
3a4 possessing a single stereogenic center. The results sum-
marized in Table 1 show that under thermal conditions (6 h at
80 °C) a 38/62 mixture of the two regioisomers 4a-5a was
obtained in 53% yield (Table 1, entry 1). Interestingly, when
the reaction was carried out at -70 °C under photochemical
conditions, the ratio was reversed with regioisomer 4a now
largely predominant (entry 3). At room temperature, a nearly
equimolar amount of both regioisomers was obtained, pointing
out again the temperature dependence of the regioselectivity of
this radical process. Compounds 4a and 5a were readily
separated and their structure unambiguously assigned using
Regioselectivity of the sulfonyl radical mediated 5-exo-trig
cyclization of 3-silylheptadienyl systems 3a-d has been
studied. At low temperature, the reaction of the sulfonyl
radical occurs regioselectively at the allylsilane terminus,
while a reversal of regioselectivity is observed at 80 °C. This
general trend has been rationalized on the basis of polar
effects and radical stabilization. Thiyl-mediated radical
cyclization of dienes 3a, 3c-d, 7 with subsequent sulfur atom
transfer was also studied, providing thiabicyclo[3.3.0] skel-
eton in one step with excellent stereocontrol.
1
extensive NMR studies (1D, 2D, COSY, HSQC, and 2D H-
77Se correlations). Compounds 4a and 5a were found to be
diastereomerically pure, possessing the trans-cis relative con-
figuration, in line with our previous reports.2 It is important to
notice that as yields are moderate, one cannot completely rule
out the formation of other stereoisomers of 4a-5a in the reaction
mixture, although 1H NMR of the crude reaction mixture
indicates that if these are formed they are in trace amount. Better
yields and similar regioselectivities were observed with model
3b (entries 4-7), although the ratio 4b/5b at -70 °C was not
as pronounced as with 3a. The structure and the relative
configuration of major 4b were secured through an X-ray
structure determination, supporting the above assignment for
4a. Changing the solvent from benzene to CH2Cl2 (entries 5
and 6) led to a similar ratio indicating that the solvent had little
influence on the regiocontrol outcome. High isolated yield
during selenosulfonylation of 3b (entry 7) is of interest as it
shows that at low temperature the reaction is both regioselective
Radical-mediated 5-exo-trig cyclizations of dienyl systems
have enjoyed much success in the synthesis of five-membered
ring carbocycles and heterocycles.1 Continuing interest in such
processes has prompted a number of research groups to study
the kinetics and the stereochemistry of these reactions. In this
context, we recently initiated a study on the sulfonyl-radical
mediated cyclizations of chiral 3-silylhepta-1,6-dienes such as
1 (Scheme 1), with the aim of investigating the effect of an
allylic silicon group on the stereoselectivity of this process.2
We found that cyclization of 3-silylhepta-1,6-diene 1, led to
the expected cyclopentane 2 with high levels of diastereocontrol
at low temperature, demonstrating the unique role of the silicon
group in this context.2 Interestingly, changing the silicon
substituent with alkyl or alkoxy substituents led to no or a
reversal of stereochemistry, respectively. In this study, regiose-
lectivity during attack of the sulfonyl group on the diene system
* To whom correspondence should be addressed. Tel: (33) 5 40002289. Fax:
(33) 5 40006286.
† Universite´ Bordeaux-I.
(3) (a) Wang, C.; Russell, G. A. J. Org. Chem. 1999, 64, 2346-2352.
(b) Harvey, I. W.; Philips, E. D.; Whitham, G. H. Tetrahedron 1997, 53,
6493-6508. (c) De Riggi, I.; Surzur, J.-M.; Bertrand, M.-P.; Archavlis,
A.; Faure, R. Tetrahedron 1990, 46, 5285-5294. (d) Brumwell, J. E.;
Simpkins, N. S. Tetrahedron Lett. 1993, 34, 1219-1222. (e) De Riggi, I.;
Gastaldi, S.; Surzur, J.-M.; Bertrand, M.-P.; Virgili, A. J. Org. Chem. 1992,
57, 6118-6125.
‡ Universite´ de Lausanne.
(1) (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073-3100. (b)
Majumdar, K. C.; Mukhopadhyay, P. P.; Basu, P. K. Heterocycles 2004,
63, 1903-1958 and references therein.
(2) (a) James, P.; Landais, Y. Org. Lett. 2004, 6, 325-328. (b) James,
P.; Felpin, F.-X.; Landais, Y.; Schenk, K. J. Org. Chem. 2005, 70, 7985-
7995.
(4) For the synthesis of precursors 3a-d, see the Supporting Information.
10.1021/jo060024+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
3630
J. Org. Chem. 2006, 71, 3630-3633

and Maslak,6c who established that a methylsulfonyl radical
reacts with allyltrimethylsilane 2.5 times faster than with hex-
1-ene at 0 °C. Although this polar effect may reflect in part the
regioisomer ratio, other factors may be operative. Attack of a
sulfonyl radical on the allylsilane moiety generates a radical â
to silicon (C2) which is known to be stabilized by 2-3 kcal/
mol.8 Such a weak stabilization may, however, be sufficient to
slow the â-fragmentation process, so that concentration of
intermediate A is more important than that of A′. Rate constants
for â-fragmentation of p-tosyl radical have been estimated in
TABLE 1. Regioselectivity of the Selenosulfonylation of Dienes
3a-d
the range 103-106 s-1 7a
the lower rate being observed with
,
entry
diene 3
solvent
T (°C)
4/5c
yieldd (%)
compounds possessing a substituent able to stabilize the radical
intermediate. Although a â-silyl group does not exert such a
strong â-stabilization, this and the polar effect discussed above
may be sufficient to control the regioselectivity. Then, assuming
than A and A′ cyclize at a similar rate (kc ≈ k′c), accumulation
of the former would ensure the formation of larger amount of
4a-d in the mixture of products. The possibility that B and B′
might interconvert through an intramolecular tosyl group transfer
has also been ruled out based on the results of kinetic studies
on related processes.3a Chairlike conformations such as A and
A′ having the bulky silicon group in pseudoequatorial position
explain the high level of stereocontrol observed and the relative
configuration observed for regioisomers 4a-d and 5a-d.2 In
contrast, the nature of the effects controlling the regioselectivity
of the process at higher temperature (between rt and 80 °C)
appears more difficult to rationalize. Although the allylsilane
olefin is sterically more demanding, this factor is probably not
predominant as the reaction occurs on a site (C1) remote from
the bulky silicon group. An alternative explanation may be
provided, based on a kinetic versus thermodynamic control. At
higher temperature, fragmentation would be faster9 and A and
A′ would thus reach the equilibrium. The regioisomer ratio
would then only rely on the relative energies of cyclization
transition states (Curtin-Hammett regime). When A and A′ are
structurally similar (as is the case with 3a,b having no
substituent at C5), such transition-state energies should be very
close,10 leading to low regiocontrol as is observed experimentally
(Entries 1, 2, and 4-6). Finally, under such conditions a better
regiocontrol in the favor of cyclopentanes 5 (entries 8 and 11)
is only observed when an OH group is present at C5. The exact
nature of the effect of this OH group remains speculative at
this stage, but its presence modifies the reactivity of the â-radical
center, leading to a stabilization of the transition state of
cyclization A′ f B′.2b,8e
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3d
3d
C6H6
C6H6
CH2Cl2
C6H6
C6H6
CH2Cl2
CH2Cl2
C6H6
CH2Cl2
CH2Cl2
C6H6
80a
24b
38:62
45:55
90:10
38:62
56:44
53:47
77:23
25:75
55:45
85:15
11:89
90:10
53
63
58
92
86
85
80
49
70
87
50
61
-70b
80a
24b
24b
-70b
80a
24b
10
11
12
-70b
80a
CH2Cl2
-70b
a AIBN. b hν (sunlamp). c Estimated ratio through 1H NMR of the crude
reaction mixture. d Isolated yield of both isomers.
SCHEME 2. Selenium Group Transfer during
Selenosulfonyation of 3d
and highly stereoselective. The study was then extended to
precursors 3c,d possessing an allylic alcohol function (entries
8-12). As before, good regiocontrol and better yields were
observed at low temperature, with cyclopentanes 4c,d obtained
as major isomers in each case (entries 10 and 12). At 80 °C, a
reversal of regiocontrol was again observed with regioisomers
5c,d formed predominantly. Cyclization of 3d also led at -70
°C to addition product 6d with the stereochemistry as shown
(Scheme 2).5 Although the formation of 6d was poorly
reproducible, this indicates that at low temperature the cycliza-
tion is slow, with the selenium group transfer becoming a
competitive process.
A general trend thus emerges from these results. At low
temperature, the sulfonyl radical species prefers to react at the
allylsilane terminus while at higher temperature the reaction
occurs on the less sterically demanding olefin. Two different
pathways may thus be drawn, as summarized in Figure 1. At
low temperature, the addition of the electrophilic sulfonyl radical
would occur preferentially on the more electron-rich allylsilane
olefin (k1 > k′1, polar effect),6,7 leading to a radical â to silicon
(i.e., A). Such a polar effect has been well studied by Gozdz
This work thus demonstrates that sulfonyl radical addition
to 1,6-dienes possessing olefins of similar reactivities proceeds
yet regioselectively in the first step and is followed by a
stereocontrolled cyclization in the second step to provide useful
polysubstituted cyclopentanes.
The selenosulfonylation was then extended to diene 7 having
two differently substituted olefins.11 Surprisingly, when submit-
(5) The syn relative configuration between SiMe2Ph and SePh was
assigned on the basis of related studies; see: (a) Chabaud, L.; Landais, Y.
Tetrahedron Lett. 2003, 44, 6995-6998. (b) Masterson, D. S.; Porter, N.
D. Org. Lett. 2002, 4, 4253-4256. (c) Chabaud, L.; Landais, Y.; Renaud,
P. Org. Lett. 2002, 4, 4257-4260.
(6) (a) Sakurai, H.; Hosomi, A.; Kumada, M. J. Org. Chem. 1969, 34,
1764-1768. (b) Jarvie, A. W. P.; Rowley, R. J. J. Chem. Soc. B 1971,
2439-2442. (c) Gozdz, A. S.; Maslak, P. J. Org. Chem. 1991, 56, 2179-
2189.
(8) (a) Kawamura, T.; Kochi, J. K. J. Am. Chem. Soc. 1972, 94, 648-
650. (b) Griller, D.; Ingold, K. U. J. Am. Chem. Soc. 1974, 96, 6715-
6720. (c) Jackson, R. A.; Ingold, K. U.; Griller, D.; Nazran, A. S. J. Am.
Chem. Soc. 1985, 107, 208-211. (d) Auner, N.; Walsh, R.; Westrup, J. J.
Chem. Soc., Chem. Commun. 1986, 207-207. (e) d’Antuono, P.; Fritsch,
A.; Ducasse, L.; Castet, F.; James, P.; Landais, Y. J. Phys. Chem. A 2006,
110, 3714-3722.
(9) As mentioned by one referee, fragmentation of the tosyl group is
probably more affected than the 5-exo-trig cyclization by lowering the
temperature due to entropy effects.
(7) (a) Timokhin, V. I.; Gastaldi, S.; Bertrand, M.-P.; Chatgilialoglu, C.
J. Org. Chem. 2003, 68, 3532-3537. (b) Wagner, P. J.; Sedon, J. H.;
Lindstrom, M. J. J. Am. Chem. Soc. 1978, 100, 2579-2580.
(10) Lusztyk, J.; Maillard, B.; Deycard, S.; Lindsay, D. A.; Ingold, K.
U. J. Org. Chem. 1987, 52, 3509-3514.
J. Org. Chem, Vol. 71, No. 9, 2006 3631

FIGURE 1. Regioselectivity of the selenosulfonylation of dienes 3a-d.
SCHEME 3. Attempt of Cyclization of Diene 7
formation of thiabicyclo[3.3.0] skeleton in one step in moderate
to good yields but with generally low stereocontrol.16b-e Having
demonstrated that high level of 1,2- and 1,5-stereocontrol could
be reached during 5-exo-trig cyclization of our systems,2 we
investigated the thiyl-mediated cascade with the 3-silahepta-
1,6-dienes 3a,c,d and 7. This would generate the required
cyclopentane skeleton without the regiochemical issue described
above. Precursors 3a,c,d were thus treated with (t-BuS)2 under
irradiation and led to the expected bicyclic systems 10a-c in
reasonable yields and interestingly as single isomers having the
trans-cis relative configuration (Table 2, entries 1-3). Com-
pound 7 led to 10d as a mixture of two stereoisomers in a 2:1
ratio (entry 4). It is noteworthy that 10d is prepared in
41% overall yield starting form butadiene and PhMe2SiCl.11
Attempted 6-exo-trig cyclization using precursor 1111 led to a
complex mixture of products (entry 5). Reactions were usually
complete in less than 3 h and thus appear to be much faster
and stereoselective than those described in the literature on
related systems lacking the allylic silicon group.16b-d This
may reflect again the matched polarity between the electrophilic
thiyl radical and the allylsilane olefin. The reaction is thought
to proceed though the addition of a thiyl radical to one of the
olefin (likely at the allylsilane terminus, vide supra), followed
by the cyclization through a chairlike transition state such as A
or A′ (Figure 1) and termination by homolytic substitution at
sulfur.16a Only the cis ring junction is obtained as the trans
isomer (probably formed in very low amount) and cannot react
with the sulfur center in the termination step to form the
heterocycle.
ted to the above conditions at -70 °C, 7 led to a mixture of
inseparable products in which the desired cyclopentane was
present in low amount (<30%) (removal of the PhSe group
using Bu3SnH or H2O2 led to the desired cyclopentanes
confirming the structure of the cyclized product) (Scheme 3)
(Supporting Information). Interestingly, when the reaction was
carried out in a more concentrated medium, using 2 equiv of
p-TolSO2SePh, the addition product 8a (as a 9:1 mixture of
syn/anti stereoisomers) and the desilylated diene 8b were
isolated. This and the formation of addition product 6d (Scheme
2) further indicate that the 5-exo-trig cyclization is rather slow
at -70 °C. After purification, 8a was treated with 1 equiv of
p-TolSO2SePh at -70 °C. While no reaction occurred at this
temperature, 8a was converted into 8b upon warming to room
temperature,12 indicating that 8b is probably formed through
â-elimination5,13 of the â-selenosilane moiety under the reaction
conditions.14,15
In summary, we have reported above a rapid method to access
3-thiabicyclo[3.3.0]octane systems in a regio- and stereoselective
manner. Our studies also shed light on the regiocontrol arising
Finally, we studied the thiyl-mediated radical cyclization of
our diene with sulfur atom transfer.16 This cascade process is
particularly useful to functionalize dienyl systems with the
allylsilane moiety under the reaction conditions, followed by a rapid
electrophilic 5-exo cycloetherification. For a similar process, see: Akiyama,
T.; Ishida, Y. Synlett 1998, 1150-1152.
(11) Terao, J.; Oda, A.; Ikumi, A.; Nakamura, A.; Kuniyasu, H.; Kambe,
N. Angew. Chem., Int. Ed. 2003, 42, 3412-3414.
(12) Treatment of 8a under irradiation (sunlamp) without p-TolSO2SePh,
at temperatures ranging from -70 °C to rt, led to no reaction.
(13) Guindon, Y.; Gue´rin, B.; Chabot, C. C.; Ogilvie, W. W. J. Am.
Chem. Soc. 1996, 118, 12528-12535.
(14) The exact mechanism of the elimination process 8a f 8b, under
such conditions, is unknown, and one cannot exclude the â-elimination of
the silicon group through an ionic pathway.
(15) An ionic process and the formation of a â-silyl carbocation
intermediate may be invoked for the Mn2(CO)10-mediated radical func-
tionalization of diene 3c, which unexpectedly provided tetrahydrofuran 9
as a unique diastereomer, without a trace of the product resulting from
addition of the CCl3 group. This probably results from a protonation of the
(16) (a) Schiesser, C. H.; Wild, L. M. Tetrahedron 1996, 52, 13265-
13314. (b) Harrowven, D. C.; Hannam, J. C.; Lucas, M. C.; Newman, N.
A.; Howes, P. D. Tetrahedron Lett. 2000, 41, 9345-9349. (c) Harrowven,
D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 4443-
4444. (d) Harrowven, D. C.; Hannam, J. C. Tetrahedron 1999, 55, 9341-
9346. (e) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron 2001,
57, 791-804.
3632 J. Org. Chem., Vol. 71, No. 9, 2006

TABLE 2. Thiyl Radical Mediated Cyclization of
3-Silahepta-1,6-dienes
Experimental Section
Typical Experimental Procedure for the Selenosulfonylation
of 3-Silylhepta-1,6-dienes 3a-d under Irradiation. A mixture
containing diene 3a-d (1 equiv) and p-TolSO2SePh (1 equiv) in
degassed CH2Cl2 (0.013 M) under a nitrogen atmosphere was
irradiated at - 70 °C with a sunlamp (placed at 10-15 cm of the
flask) until complete consumption of starting material as shown
by TLC. The solvent was then evaporated and the residue purified
by chromatography (petroleum ether or petroleum ether/ethyl
acetate) to afford 4a-d/5a-d.
Typical Experimental Procedure for the Selenosulfonylation
of 3-Silylhepta-1,6-dienes 3a-d under Thermal Conditions. In
a flask equipped with a condenser were dissolved diene 3a-d (1
equiv) and p-TolSO2SePh (1 equiv) in degassed benzene (0.013
M) under a nitrogen atmosphere. AIBN was added (0.1 equiv by
portions every 1-1.5 h), and the mixture was heated under reflux
until complete consumption of starting material as shown by TLC.
The solvent was then evaporated and the residue purified by
chromatography (petroleum ether or petroleum ether/ethyl acetate)
to afford 4a-d/5a-d.
Typical Experimental Procedure for the Preparation of Fused
Thiabicyclo[3.3.0]octanes 10a-d. A degassed solution of diene
3a,c,d or 7 (1 equiv) and di-tert-butyl disulfide (5 equiv) in hexane
(0.05 M) under a nitrogen atmosphere was irradiated using a high-
pressure mercury lamp in a quartz cell at +10 °C until complete
consumption of starting material as shown by TLC. The brown
solution was then concentrated under vacuum and the product
purified by chromatography (petroleum ether or petroleum ether/
ethyl acetate) to give 10a-d.
Acknowledgment. This work was supported by the Minis-
te`re de la Recherche et de la Technologie through a Ph.D. grant
to P.J. Y.L. gratefully acknowledges the Institut Universitaire
de France and the CNRS for financial support. Finally, we thank
M. Berlande, Dr. D. Bassani, and Dr. F. Robert (Universite´
Bordeaux-I) for technical assistance.
a Isolated yield.
Supporting Information Available: Experimental proce-
dures and copies of 1H and 13C NMR spectra for all products
3-10. X-ray crystallographic data for compound 4b (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
from radical addition of sulfonyl radicals onto dienes possessing
an allylsilane moiety. At low temperature, excellent regio-
control in the favor of the attack at the allylsilane moiety is
observed. Polar effects and stabilization of the â-silyl radi-
cal may be at the origin of the control of the regioselectivity.
Such cyclopentanes bearing several stereochemically defined
contiguous stereogenic centers should be valuable interme-
diates in the synthesis of recently discovered isoprostanoids17
and more generally of ubiquitous cyclopentane-containing
natural products.2b,18
JO060024+
(17) Taber, D. F.; Xu, M.; Hartnett, J. C. J. J. Am. Chem. Soc. 2002,
124, 13121-13126.
(18) (a) Wang, R.; Shimizu, Y. J. Chem. Soc., Chem. Commun. 1990,
413-413. (b) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000,
39, 3258-3261. (c) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.;
Takase, S.; Hino, M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123-
130.
J. Org. Chem, Vol. 71, No. 9, 2006 3633