Radical, one-step approach to o-chlorophenyl thioethers from xanthates. A rapid access to vinylsilanes

Article abstract of DOI:10.1021/ol801348u

(Chemical Equation Presented) Xanthates have been readily converted into o-chlorophenyl thioethers using a one-step procedure conducted under radical conditions. In some selected cases, these aryl thioethers were successfully oxidized to the corresponding sulfoxides and sulfenic acid elimination afforded the corresponding vinylsilanes.

Full text of DOI:10.1021/ol801348u

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3579-3582
Radical, One-Step Approach to
o-Chlorophenyl Thioethers from
Xanthates. A Rapid Access to Vinylsilanes
Matthieu Corbet, Zorana Ferjancˇic´, Be´atrice Quiclet-Sire, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, De´partement de Chimie,
Ecole Polytechnique, 91128 Palaiseau, France
zard@poly.polytechnique.fr
Received June 14, 2008
ABSTRACT
Xanthates have been readily converted into o-chlorophenyl thioethers using a one-step procedure conducted under radical conditions. In
some selected cases, these aryl thioethers were successfully oxidized to the corresponding sulfoxides and sulfenic acid elimination afforded
the corresponding vinylsilanes.
Xanthate (dithiocarbonate) transfer radical chemistry has
proven over the years to be a useful tool in organic synthesis.1
It enables the formation of carbon-carbon bonds in both
inter- and intramolecular fashions and allows the expedient
construction of a broad range of structures. Of particular
interest is the modification of the xanthate group in the
product using either radical or ionic chemistry.2,3 Even
though much has been done, there are certainly many
interesting reactions still to be uncovered.
In this paper, we report a novel radical transformation of
the dithiocarbonate group to aryl thioethers and more
specifically to o-chlorophenyl thioethers. The ability to
synthesize thioether functional groups is of special interest
because of their importance in organic synthesis as a key
entry point into the rich chemistry of sulfoxides and sulfones.
Their preparation from the thiol is commonly achieved via
standard nucleophilic substitutions or nucleophilic aromatic
substitutions in basic media, but other methods are known,
and recent examples include palladium- or copper-catalyzed
cross-coupling reactions.4
(1) For general reviews, see: (a) Zard, S. Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 672. (b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur
Silicon Relat. Elem. 1999, 153, 137. (c) Zard, S. Z. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, p 90. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002. (f)
Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
If we consider xanthates as potential starting materials for
the synthesis of thioethers, one could envision hydrolyzing the
dithiocarbonate functional group to the corresponding thiol,5
and further nucleophilic substitution would lead to the desired
product. This classical two-step strategy is now well established
in our laboratory (eq 1).6 Some limitations exist when R3 is an
(2) For examples utilizing radical chemistry, see: (a) Liard, A.; Quiclet-
Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 5877. (b) Bertrand, F.;
Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. 1999, 38, 1943. (c)
Barbier, F.; Pautrat, F.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Synlett
2002, 811. (d) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org. Lett. 2003,
5, 1645. (e) Ouvry, G.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2003, 5,
2907
.
(4) For recent and representative examples, see: (a) Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309, and references cited therein.
(b) Cai, L.; Cuevas, J.; Peng, Y.-Y.; Pike, V. W. Tetrahedron Lett. 2006,
47, 4449, and references cited therein.
(3) For examples utilizing ionic chemistry, see: (a) Boivin, J.; Boutillier,
P.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2529. (b) Lusinchi, M.; Stanbury,
T. V.; Zard, S. Z. Chem. Commun. 2002, 1532. (c) Quiclet-Sire, B.; Sanchez-
Jimenez, G.; Zard, S. Z. Chem. Commun. 2003, 1408. (d) Corbet, M.; Zard,
(5) Mori, K.; Nakamura, Y. J. Org. Chem. 1969, 34, 4170.
(6) Boutillier, P.; Zard, S. Z. Unpublished results.
S. Z. Org. Lett. 2008, 10, 2861
.
10.1021/ol801348u CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society

aryl group, since the latter needs to be rather activated for
nucleophilic aromatic substitution to occur.
starting xanthate 4 (path C). The stabilized adduct radical 6
is too hindered to dimerize (or does so reversibly) and cannot
disproportionate. It can therefore only undergo fragmentation
by rupture of the C-S bonds (path D) leading simply to the
starting xanthate 4 and the same radical 5. Thus, the reaction
of the initial radical (5) with its xanthate precursor is
reversible and degenerate. As a consequence, the effective
lifetime of 5 in the medium increases considerably, since it
is continuously being regenerated. Now, addition to sterically
hindered disulfide 2 becomes possible, and aryl thioethers
(7) can be obtained (path E). Thiyl radical 8 can capture
carbon radical 5 to also give the desired product or combine
with another thiyl radical to return disulfide 2; it cannot,
however, propagate the chain process, and a stoichiometric
amount of DLP is therefore needed.
However, if one considers a possible one-step approach to
aryl thioethers from xanthates, a radical-based strategy appears
as a good alternative method to the ionic route. First attempts
to obtain phenyl thioethers under radical conditions using lauroyl
peroxide (DLP) as the initiator and phenyl disulfide as the
thioether source in 1,2-dichloroethane (DCE) were disappoint-
ing. The reactions could not be readily driven to completion,
and unacceptable amounts of sulfides derived from direct
reaction of the radicals from the initiator were formed. However,
the use of o-chloro-substituted disulfide 2 gave significantly
better results. From a mechanistic point of view, it is clear that
the chlorine atom of 2 offers its neighboring sulfur atom enough
steric protection to limit unwanted direct attack by the undecyl
radicals (1) from the initiator (DLP), leading to undesired
thioether 3 (path A, Scheme 1).
Scheme 1
.
Reaction Manifold for the Synthesis of Aryl
Thioethers (7)
Figure 1. Xanthate adducts 4a-o.
To investigate the scope and limitations of this new radical
exchange process, several xanthate adducts (4a-o, Figure
1) were first synthesized in good yield by treatment of various
starting xanthates and excess olefins in degassed, refluxing
solutions of DCE with substoichiometric amounts of DLP.7
A noteworthy result is obtaining reduced compound 4′m
(11% isolated yield) along with the desired enantiopure cis-
The primary radical from DLP has no other choice than
to attack the sulfur atom of the thiocarbonyl moiety of
xanthate 4, thus initiating the desired reaction (path B). The
radical 5 produced can add to the thiocarbonyl group of the
Scheme 2. Synthesis of cis-Decalins 4m and 4′m
(7) (a) For the synthesis of 4b, see ref 3b. (b) For the synthesis of 4c,
see: Briggs, M. E.; Zard, S. Z. Synlett 2005, 334. (c) For the synthesis of
4d,n, see: Corbet, M.; de Greef, M.; Zard, S. Z. Org. Lett. 2008, 10, 253.
(d) Compound 4e was a gift from Dr. A. Cordero-Vargas (DCSO, Ecole
Polytechnique). (e) For the synthesis of 4g, see: Dublanchet, A.-C.; Lusinchi,
M.; Zard, S. Z. Tetrahedron 2002, 58, 5715. (f) For the synthesis of 4h,
see: Ferjancˇic´, Z.; Quiclet-Sire, B.; Zard, S. Z. Synthesis 2008, in press.
(g) Compound 4i was a gift from Dr. T. V. Stanbury (DCSO, Ecole
Polytechnique). (h) For the synthesis of 4o, see: de Greef, M.; Zard, S. Z.
Org. Lett. 2007, 9, 1773. (i) For the preparations of 4a,f,j-m and their
precursors in detail, see the Supporting Information.
3580
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Synthesis of o-Chlorophenyl Thioethers 7a-oa
a General experimental procedure: a magnetically stirred solution of 4a-o (1 equiv) and disulfide 2 (2 equiv) in DCE (1 mL/mmol of 2) was refluxed
for 15 min. DLP (20 mol %) was then added, and additional DLP (20 mol %) was added every hour until total consumption of 4a-o or until no evolution
was observed (TLC analysis). The mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel to yield the desired compounds (7a-o). b Isolated yields. c Yields based on recovered starting material. d 8%
of the corresponding vinylsilane 14 was detected by 1H NMR. e This compound was obtained as a single diastereoisomer. f Yield based on the 1H NMR of
a mixture of compound 7m with the corresponding monothioether.
decalin 4m (41%) (Scheme 2). In this case, the reaction did
not go to completion, and the more DLP was added, the more
the proportion of reduced compound 4′m increased (TLC
analysis).
thioethers (7a-o) were synthesized in moderate to good
yields (Table 1).10
In most cases, the reaction did not go to completion
(starting material was not always recovered), and in some
cases 4 equiv of DLP were needed. Purification by flash
chromatography was sometimes complicated because of the
similar polarity of the starting materials (4a-o) and the
products (7a-o). The low yield obtained with compound
7a (33%, entry 1) can be explained by the steric hindrance
caused by the trimethylsilyl group. In contrast, better yields
were obtained when the latter was one carbon away from
the thioether (entries 3, 10, and 11). For examples where
This surprising result is related to one we observed in our
laboratory some years ago when carbohydrates containing a
xanthate group were reduced under radical conditions with the
help of cyclohexane (the solvent) acting as a hydrogen donor.8
What is most likely happening in this case is that DCE (the
solvent) acts as the hydrogen donor, and it is the acetate group
that governs the polar effect needed for the reduction to occur.
No reduction product was indeed observed when the same
reaction was carried out in the absence of the acetate.9
With xanthate adducts 4a-o in hand, we were able to
proceed with our novel reaction, and several o-chlorophenyl
(9) Bergeot, O.; Corsi, C.; El Qacemi, M.; Zard, S. Z. Org. Biomol.
Chem. 2006, 4, 278.
(10) For the preparation of disulfide 2, see: (a) McKillop, A.; Koyunc¸u,
D.; Krief, A.; Dumont, W.; Renier, P.; Trabelsi, M. Tetrahedron Lett. 1990,
31, 5007.
(8) Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118, 9190.
Org. Lett., Vol. 10, No. 16, 2008
3581

Table 2. Oxidation and Elimination of Aryl Thioethers 7j,k,l,oa
Scheme 3. Example of the Utilization of Vinylsilane 13
vinylsilanes were successfully obtained this way (entries 1
and 2). Remarkably, the regioselectivity of the elimination
was complete, furnishing only the vinylsilane.12 In the case
of 7j, partial deprotection of the dioxolane moiety was
observed during the elimination process, but acidic treatment
of the crude reaction mixture gave compound 13 in 70%
yield along with a good E/Z selectivity (97:3, entry 1).12
Compound 7k was treated under the same reaction
conditions as 7j, and vinylsilane 14 was obtained in 72%
yield over two steps (entry 2). It is worth noting that in the
absence of PPh3 this reaction gave several byproducts and
the desired compound (14) was isolated in low yield (22%).
Under similar conditions, aryl thioether 7l gave regioisomers
15 and 16 in good yield (80%) but poor regioselectivity (2:
3, entry 3). A sulfenic acid trap was not compulsory in this
case. Alkene 17 could also be obtained in a yield comparable
to the one previously reported (78% against 81%).7h
Finally, as an illustration of the importance and versatility
of vinylsilanes in organic synthesis,13 compound 13 was
converted into vinyl iodide 18 using N-iodosuccinimide (NIS)
in acetonitrile (77%),14 with retention of olefin geometry
(Scheme 3). The latter successfully underwent Sonogashira
coupling with phenyl acetylene in acetonitrile using a Pd(II)
catalyst to afford enyne 19 in excellent yield (92%).15
In summary, we have developed a novel one-step, radical
approach to aryl thioethers. A number of xanthates were
successfully transformed into the corresponding aryl thio-
ethers. The easy access to valuable vinylsilanes in only three
steps from simple xanthate adducts is worthy of note and
underscores the synthetic potential of this functional group
exchange process.
a The thioethers were oxidized to the corresponding sulfoxides with
m-CPBA (1 equiv), and sulfenic acid elimination was realized in refluxing
toluene with PPh3 (1 equiv). b Isolated yields. c Deprotection was achieved
with 1 N HCl in acetonitrile. d No PPh3 was added; regioisomers were
separated but compound 16 was contaminated with an unidentified impurity;
1
ratio based on the H NMR of the mixture of both regioisomers.
the formation of tetralones was expected to be a serious
competing side reaction (entries 2, 3, 5, and 9), no significant
amounts were detected. To our surprise, in the course of the
reaction leading to thioether 7k (entry 11), 8% of eliminated
product corresponding to the E-vinylsilane 14 (see Table 2)
was formed. The origin of this side product is unclear and
remains to be determined. Interestingly, compound 7l (entry
12) was obtained as a single diastereoisomer from a starting
mixture of distereoisomeric xanthates 4l. In the case of the
reaction of 4m (entry 13), it was mistakenly stopped
prematurely and furnished a mixture of desired compound
7m (45%) and monothioether (16%). However, we were
unable to determine the regiochemistry of the latter; i.e., we
do not know if the remaining xanthate function is at the cyclic
junction or R to the gem-dimethyls. But, if we take into
account the previous observation of reduced compound 4′m
(vide supra), one can deduce that the thioether is most likely
at the cyclic junction. If it was the other way round, some
reduced compound should have been detected. This would
also indicate that the reaction leading to the thioether is faster
than the hydrogen abstraction from the solvent. Although
the yield of 7n was rather moderate (37%, entry 14), it was
remarkable that no product resulting from a potential 5-exo
cyclization/cyclopropane ring-opening was observed. The
synthesis of compound 7o enabled us to compare the ionic
method (i.e., aminolysis of the xanthate group followed by
arylation of the resulting thiol with p-fluoronitrobenzene)7h
with our radical-based approach, and we were glad to see
that the yields were relatively close (76% for the one-step
radical method against 80% for the two-step ionic route).7h
Some of these aryl thioethers were oxidized and the
resulting sulfoxides eliminated (Table 2).11 A couple of
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801348U
(11) For a general review, see: (a) Trost, B. M. Chem. ReV. 1978, 78,
363.
(12) A similar observation was made some time ago, but no satisfactory
explanation has been given, nor has this led to any synthetic applications,
presumably because of the difficulty encountered in accessing the required
precursors. See: (a) Ochiai, M.; Tada, S.-I.; Sumi, K.; Fujita, E. J. Chem.
Soc., Chem. Commun. 1982, 281.
(13) For general reviews, see: (a) Chan, T. H.; Fleming, I. Synthesis
1979, 761. (b) Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986, 86,
857. (c) Fleming, I.; Barbero, I. A.; Walter, D. Chem. ReV. 1997, 97, 2063.
(d) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61.
(14) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647.
(15) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125,
13954.
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Org. Lett., Vol. 10, No. 16, 2008