Synthesis of 1,1-disubstituted olefins via catalytic alkyne hydrothiolation/Kumada cross-coupling

Article abstract of DOI:10.1021/ol8012843

(Chemical Equation Presented) Using recently developed methodology for the regioselective formation of branched alkyl vinyl sulfides, we report a convenient route to 1,1-disubstituted olefins. We demonstrate that n-propanethiol successfully undergoes cata

Full text of DOI:10.1021/ol8012843

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3941-3944
Synthesis of 1,1-Disubstituted Olefins
via Catalytic Alkyne Hydrothiolation/
Kumada Cross-Coupling
Anthony Sabarre and Jennifer Love*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, BC, Canada V6T 1Z1
jenloVe@chem.ubc.ca
Received June 6, 2008
ABSTRACT
Using recently developed methodology for the regioselective formation of branched alkyl vinyl sulfides, we report a convenient route to
1,1-disubstituted olefins. We demonstrate that n-propanethiol successfully undergoes catalytic alkyne hydrothiolation with both aryl and aliphatic
alkynes using Tp*Rh(PPh3)2 as the catalyst. The resulting vinyl sulfides undergo Kumada cross-coupling to afford the desired disubstituted
alkene. Both two-step and one-pot procedures are reported.
1,1-Disubstituted olefins are present in many biologically
active molecules and synthetic intermediates.1-3 Examples
of natural products containing this moiety include the
antitumor agent dysidiolide,4 the CNS stimulant kainic acid,5
the microtubule stabilizer laulimalide,6 and the potent
neurotoxin pinnatoxin A.7 The development of reactions for
the selective construction of 1,1,-disubstituted olefins is
therefore an area of considerable interest. Notwithstanding
the significant research efforts to date, methods for as-
sembling 1,1-disubstituted olefins have been developed to a
much lesser extent than those for 1,2-disubstituted olefins.
We envisioned a one-pot procedure for the synthesis of 1,1-
disubstituted olefins from readily available alkynes based on
a sequential catalytic alkyne hydrothiolation/cross-coupling
strategy (Scheme 1). We report herein the results of this
study.
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10.1021/ol8012843 CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

example, Wenkert23-25 and Takei26 independently discov-
ered that vinyl and aryl sulfides could generate 1,2-disub-
stituted olefins via Kumada-type coupling. Both researchers
reported that vinyl sulfides show higher reactivity than aryl
sulfides. Takei later reported that allylic sulfides were also
suitable substrates for the cross-coupling reaction.27 Tri-28
and tetrasubstituted29 olefins have also been generated by
cross-coupling of the corresponding vinyl sulfides. In 1987,
Naso and co-workers reported that 1,1-disubstituted vinyl
sulfides were also suitable substrates for cross-coupling,
although only two examples were given.30,31 We envisioned
that this process could serve as a convenient method for
constructing 1,1-disubstituted olefins.
For the Kumada-type cross-coupling protocol to be
synthetically useful, a variety of 1,1-disubstituted vinyl
sulfides must be readily available. Until recently, the regi-
oselective synthesis of branched alkyl vinyl sulfides had been
elusive. Although there had been several metal-catalyzed
reactions involving thiols that have been reported for the
synthesis of aryl vinyl sulfides,32 reactions involving alkyl
thiols had been explored to a lesser extent.33-35 Our recent
discovery that Tp*Rh(PPh3)2 [Tp* ) hydrotris(3,5-dimeth-
ylpyrazolylborate)] (Figure 1) catalyzes alkyne hydrothiola-
tion of a wide range of alkynes (aliphatic, aromatic, internal)
and thiols to afford 1,1-disubstituted vinyl sulfides in high
yields and selectivity has alleviated this shortcoming.36 As
such, we anticipated that this methodology could be used to
assemble vinyl sulfides for use in Kumada-type cross-coupling.
An ideal vinyl sulfide cross-coupling partner would
undergo efficient cross-coupling and would have a leaving
group of low molecular weight in order to minimize waste.
Scheme 1
.
One-Pot Strategy toward the Synthesis of
1,1-Disubstituted Olefins
A few metal-catalyzed procedures are available for the
formation of 1,1-disubstituted olefins. Among the most
widely used is the cationic Heck reaction8-11 which
involves the use of an organohalide, typically an aryl halide,
and a monosubstituted olefin. Although the corresponding
reactions using alkyl halides have been reported, they have
been limited mainly to activated alkyl halides and those
lacking ꢀ-hydrogens.12-16 Only a few examples of the Heck
reaction involving unactivated alkyl halides have been
published.17 An alternate strategy involves the cross-coupling
of an aryl halide with a vinyl organometallic reagent,
typically derived from a vinyl halide.18,19 A signifiant
drawback to using vinyl halides is the requirement for use
of a strong Lewis or Bronsted acid, such as BBr3 or HBr,
for their synthesis; these harsh conditions have evident
functional group incompatibility. Likewise, although vinyl
triflates can also be used in transition-metal-catalyzed cross-
coupling, their synthesis also presents some functional group
incompatibility.18-21
Other cross-coupling partners, including vinyl sulfides,
have also been reported to undergo cross-coupling.22-29 For
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3942
Org. Lett., Vol. 10, No. 18, 2008

2, respectively). In comparison, the use of a strongly electron-
withdrawing substituent led to a significant decrease in
efficiency and yield (entry 3). We concluded that vinyl
sulfides derived from either unsubstituted or electron-rich
alkynes would serve as suitable substrates for cross-coupling.
Both aliphatic alkynes examined reacted in high isolated
yields and with high selectivity (entries 4 and 5). As such,
both products were deemed to be suitable for further study
in cross-coupling to generate 1,1-disubstituted olefins. It is
noteworthy that we had previously found that alkyl vinyl
sulfides as in entry 5 were prone to isomerization; we have
subsequently found that avoiding the use of chloroform as a
solvent for either chromatography or NMR spectroscopy
precludes this isomerization.
Figure 1. Catalyst for alkyne hydrothiolation: Tp*Rh(PPh3)2.
We selected n-propylthiolate for this role as it is of
comparable mass to bromide, a typical leaving group in
cross-coupling chemistry.
With this series of vinyl sulfides in hand, we were now
poised to test the Kumada-type cross-coupling methodology.
Our initial study focused on the use of isolated alkyl vinyl
sulfides in cross-coupling reactions with various Grignard
reagents (alkyl, vinyl and aryl) using 10 mol % NiCl2(PPh3)2
as the catalyst (Table 2). PhCH2MgCl, ArMgBr, and
In our original communication on catalytic hydrothiolation,
we had established that n-propanethiol reacted in high yield
and selectivity in hydrothiolation, although only one example
was reported.36 Therefore, our first goal was to establish that
hydrothiolation using n-propanethiol could proceed with a
broader range of alkynes in high selectivity and with
acceptable yields.
A variety of aryl and aliphatic alkynes were selected for
study using our previously established conditions for catalytic
hydrothiolation (Table 1). We found that all the alkynes
Table 2. Nickel-Catalyzed Cross-Coupling of Vinyl Sulfide with
Grignard Reagent
Table 1. Catalytic Alkyne Hydrothiolation
a Reaction conducted with 0.1 equiv of NiCl2(PPh3)2, 1 equiv of vinyl
sulfide, and 4 equiv of Grignard reagent (1.0 M in THF or Et2O). b Isolated
yields. c Yield determined by 1H NMR spectroscopy using 1,3,5-trimethoxy-
d
benzene as an internal standard. R1 ) CH3.
TMS-CH2MgCl afforded the desired 1,1-disubstituted olefin
in moderate isolated yields, comparable to those obtained
by Wenkert and Takei.23-26 Higher yields were precluded
by competing homocoupling of the Grignard reagent and
byproduct volatility. Given the superiority of selenium to
sulfur in nickel-catalyzed additions to alkynes,31 vinyl
selenides could also serve as potential cross-coupling partners
for future study. Use of n-butylmagnesium chloride and
vinylmagnesium bromide did not give the desired substituted
olefins. In the latter case, we observe reduction of the vinyl
a Reactions conducted with 0.03 equiv of Tp*Rh(PPh3)2, 1 equiv of
alkyne, and 1.1 equiv of thiol.
investigated reacted with high selectivity. A series of para-
substituted aryl alkynes were chosen to examine the effect
of electronics on the reaction (entries 1-4). Both phenyl-
acetylene and 4-ethynylanisole provided the corresponding
branched vinyl sulfides in good isolated yields (entries 1 and
Org. Lett., Vol. 10, No. 18, 2008
3943

sulfide.23,37 For the reaction using the vinyl sulfide derived
from 4-ethynylanisole, only the desilylated product was
obtained when TMSCH2MgCl was used in cross-coupling
(entry 5). In comparison, the vinyl sulfide derived from
ethynylcyclohexene provided the corresponding allyl silane
in high yield (entry 9). Such allyl silanes have had wide-
spread use for allylation reactions or as nucleophiles in other
cross-coupling processes.38a-d Notably, the cross-coupling
products derived from ethynylcyclohexene are also potential
Diels-Alder substrates.39,40
Table 3. One-Pot Catalytic Alkyne Hydrothiolation/Kumada
Cross-Coupling
Having established the viability of the cross-coupling
methodology for the synthesis of 1,1-disubstituted olefins,
we now turned our attention to feasibility of combining both
the hydrothiolation and cross-coupling steps in a one-pot
procedure. In our initial studies, a 1:1 mixture of 1,2-
dichloroethane/toluene was used as the solvent for hydrothi-
olation, based on previous optimization studies.36 In com-
parison, THF was used for the Kumada-type coupling (Table
2). To facilitate the one-pot procedure, we elected to use
THF as the solvent for both reactions. In a typical experi-
ment, n-propanethiol (0.99 mmol), alkyne (0.9 mmol), and
Tp*Rh(PPh3)2 (0.027 mmol) were dissolved in 2.5 mL of
THF. The mixture was stirred for 2-16 h at rt, and the
reaction progress was monitored by tlc. Upon completion
of hydrothiolation, 10 mL of THF was added, followed by
NiCl2(PPh3)2 (0.072 mmol) and Grignard reagent (3.6 mmol).
The reaction mixture was stirred at 75 °C for 16 h. The
desired 1,1-disubstituted olefins were obtained in isolated
yields comparable or superior (Table 3) to those obtained
using the two-step protocol. The greater efficiency of the
one-pot procedure may result from the need for one fewer
purification step.
a Reactions conducted with 0.027 mmol of Tp*Rh(PPh3)2, 0.9 mmol of
alkyne, 0.99 mmol of thiol, 0.09 mmol of NiCl2(PPh3)2, and 3.6 mmol of
Grignard reagent (1.0 M in THF or Et2O). b Isolated yields. c Yield
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an
d
internal standard. R1 ) CH3.
Furthermore, a one-pot procedure provides comparable or
superior isolated yields to the two-pot process, with the
additional benefit of requiring only a single purification step.
We anticipate that this protocol will be a useful alternative
to existing methodologies for the synthesis of 1,1-disubsti-
tuted olefins from readily available precursors.
In summary, we have shown that Tp*Rh(PPh3)2 catalyzes
alkyne hydrothiolation using n-propanethiol with both ali-
phatic and aryl alkynes. The resulting alkyl vinyl sulfides
can undergo nickel-catalyzed Kumada-type cross-coupling
with Grignard reagents to afford 1,1-disubstituted olefins.
Acknowledgment. We thank the following for support
of this research: University of British Columbia, NSERC
(Discovery Grant, Research Tools and Instrumentation
Grants), AstraZeneca, Merck Frosst, the Canada Foundation
for Innovation, and the British Columbia Knowledge De-
velopment Fund.
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