Ethylene metathesis of sulfur-containing alkynes

Article abstract of DOI:10.1016/S0040-4039(01)02098-6

Enyne metathesis of sulfur-containing alkynes and ethylene has been achieved. High yields were obtained by use of thiol esters in the alkyne partner for the cross metathesis with ethylene. The necessary reactivity and functional group compatibility were a

Full text of DOI:10.1016/S0040-4039(01)02098-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 209–211
Ethylene metathesis of sulfur-containing alkynes
Jason A. Smulik, Anthony J. Giessert and Steven T. Diver*
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260-3000, USA
Received 20 August 2001; revised 21 September 2001; accepted 5 November 2001
Abstract—Enyne metathesis of sulfur-containing alkynes and ethylene has been achieved. High yields were obtained by use of
thiol esters in the alkyne partner for the cross metathesis with ethylene. The necessary reactivity and functional group
compatibility were achieved through the use of the Grubbs’ second generation benzylidene carbene catalyst. © 2002 Elsevier
Science Ltd. All rights reserved.
There have been tremendous advances in alkene
metathesis due largely to functional group compatibility
of the ruthenium carbenes developed by Grubbs. With
the supporting dihydroimidazole carbene ligand, the
ruthenium carbenes are more active in alkene
metathesis1 and more tolerant of potentially coordinat-
ing functional groups like alcohols and ethers. Despite
these recent advances and the widespread utilization of
metathesis, there has been little application of metathe-
sis to unsaturated organosulfur compounds.2,3 The ear-
liest examples2a,b described ring-closing metathesis
(RCM) using both the Grubbs and Schrock catalysts.
To the best of our knowledge, there have been no
applications using sulfur-containing alkynes. The lim-
ited number of examples of metathesis with sulfur-con-
taining substrates can be partly explained by the fact
that middle to late transition metals used as catalysts
may interact favorably with the soft sulfur atom (e.g.
Pearson hard–soft acid–base theory).4 In metathesis,
any stabilization of species on the catalytic reaction
coordinate could deplete active catalyst and shut down
catalysis. Previous work suggested that the Grubbs’
catalyst 1, possessing the strong sigma-donating N-het-
erocyclic carbene ligand, could overcome coordination
by oxygen in enyne metathesis.5 In this communica-
tion, cross metathesis of sulfur-containing alkynes with
ethylene employing ruthenium carbene 1 is reported
(Scheme 1).
Lack of reactivity or lack of turnover in some alkenes
bearing coordinating functionality has been attributed
to chelated metal carbenes.6 Coordination depends on
the proximity of functional groups to the intermediate
metal carbenes and can result in stabilized chelated
structures or result in catalyst decomposition. How
catalyst 1 overcomes or averts these problems in enyne
metathesis is not well understood, although recent
mechanistic studies explaining the high activity of 1 in
alkene metathesis1b,c provide some important clues. Our
investigation was prompted by the question whether
potentially coordinating sulfur functionality could be
tolerated by the new catalyst 1 as it pertains to syn-
thetic effort in our group directed toward the synthesis
of sulfur-containing natural products. Of more general
interest is the question under what circumstances is
sulfur permissible in ruthenium-catalyzed alkene–
alkyne metathesis.
PG-S
R
PG-S
R
ethylene
(1)
5 mol % [Ru] cat.
Mes
N
N Mes Mes
Cl
N
N Mes
Cl
PCy3
Cl
Ru
Ru
Ru
Cl
Ph
Cl
i-Pr
Cl
Ph
PCy3
PCy3
O
1
2
3
Initial enyne metathesis of propargyl thioethers with
ethylene gas7 gave disappointing results. Using catalyst
1 (5 mol%), the benzyl ether 4A gave only 3% conver-
sion (gc) after 6 h, reaction conditions that result in
complete conversion of the ether 6 to its diene.5 This is
Scheme 1.
* Corresponding author. E-mail: diver@nsm.buffalo.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02098-6

210
J. A. Smulik et al. / Tetrahedron Letters 43 (2002) 209–211
trated in Table 1, thiol esters provide a sufficiently
5 mol % 1
attenuated electronic environment on sulfur to permit
catalyst turnover as evidenced by the excellent chemical
yields. The thiol acetates and thiol benzoates were
prepared by Mitsunobu reaction on the alkynols.8 Eth-
ylene metatheses were conducted using 60–80 psi ethyl-
ene and 5 mol% 1.9 2-Propyne thiol benzoate 7 reacted
to complete conversion after 24 h, which provides the
standard reaction time used throughout the table. In
entry 3, the catalyst 210 gave similarly high conversion
compared to 1, although catalyst 3 performed poorly
(entry 4). Propargylic substitution was well tolerated
for normal alkyl groups (entries 2–3, 6–8). With the
cyclohexenyl substituent (entry 5), higher temperatures
were necessary; however only 64% conversion was real-
ized with 5 mol% catalyst 1 and 70 psi ethylene after 24
h. The rate of conversion slowed considerably after just
a few hours, probably due to accelerated rate of cata-
lyst decomposition at this temperature.6b,c Higher con-
version was achieved simply by spiking the reaction
with an additional 5 mol% 1 after 3 h and then stop-
ping the reaction after 7 h total reaction time. In this
way, 99% conversion was achieved to provide 12 in
98% isolated yield obtained as a 1:1 mixture of
diastereomers. No difference between thiol benzoates
and thiol acetates was apparent (entries 6, 7). Because
of the potential for racemization due to the hard–soft
Lewis acid–base interaction of the sulfur atom with the
ruthenium catalyst, metathesis of an enantiomerically-
enriched thiol ester was investigated. Thiol ester 17
(77% e.e., HPLC, Chiracel OD-H) was converted to its
diene 18, which was obtained of the same enantiomeric
purity as the alkyne substrate as determined by HPLC
(Whelk-o, entry 8).
RS
RS
(2)
60 psi ethylene
5A R = Bn
5B R = Tr
4A R = Bn
4B R = Tr
PG-S
R
[Ru]
PG-S
R
[Ru]
BnO
6
A
B
Scheme 2.
plausibly explained by coordinative stabilization of the
regioisomeric ruthenium vinylidene intermediates, A
and B (Scheme 2). Even the bulky trityl protecting
group gave poor conversion. Trityl ether 4B provided a
10% conversion after 24 h. The Lewis basicity of sulfur
is thought to be responsible for the stability of the
putative chelates. Reduction of the Lewis basicity of
sulfur was believed to be possible through choice of
protecting group. In particular, we considered thiol
esters because of their ready availability and because of
their facile conversion into other sulfur-containing
functionality.
The results for ethylene metathesis for a group of
alkyne thiol esters are presented in Table 1. As illus-
Table 1. Ethylene metathesis with alkyne thiol esters
yield,a (conversion)b
The diene products of Table 1 are useful substrates for
the Diels–Alder reaction. The thermal [4+2] cycloaddi-
tion of crude 10 with dimethylacetylene dicarboxylate
(DMAD) gave a 97% yield of the 1,4-cyclohexadiene 19
(Scheme 3).11 Similarly, cycloaddition of 10 with N-
methylmaleimide gave a 1:1.5 mixture of diastereomers
20 in quantitative yield (Eq. (4) in Scheme 3).
Product
SBz
Entry
1
Alkyne
SBz
95 % (99 %)
7
8
SBz
SBz
(99 %), cat. 1
(99 %), cat. 2
(11 %), cat. 3
87 %
2
3
4
In conclusion, the first examples of sulfur-containing
alkynes undergoing intermolecular metathesis with
ethylene have been documentated. Sulfur located in
the propargylic position was selected as a test case to
explore the viability of enyne metathesis in sulfur-con-
taining natural product synthesis. Applications of
9
10
SAc
SAc
5
98 (99 %)c
11
12
DMAD
CO2Me
CO2Me
SPG
SPG
BzS
BzS
Ph
Ph
(3)
(4)
Ph-H, 80 oC
30 h
10
97 %
99 % (99 %)
19 (97 %)
6
7
13 PG = Ac
15 PG = Bz
14 PG = Ac
16 PG = Bz
O
SAc
N-methylmaleimide
H
SAc
BzS
BzS
Ph
Ph
18 (77 % ee)
N Me
97 %
Ph-H, 80 oC
30 h
8
17 (77 % ee)
H
O
10
20A,B (1:1.5, 99 %)
(a) Isolated yield after 24 h reaction time using 5 mol % 1. (b) Conversion was
determined by gc and is not corrected for response factor. (c) after 7 h with an
additional 5 mol % 1 added after 3 h; reaction heated at 45 oC.
Scheme 3.

J. A. Smulik et al. / Tetrahedron Letters 43 (2002) 209–211
211
metathesis to the synthesis of sulfur-containing natural
products are in progress.
purged with ethylene (4×50 psi) then maintained at room
temperature under 70 psi ethylene with constant stirring
for 24 h. The resulting dark colored solution was filtered
through a plug of silica gel (CH2Cl2) and concentrated in
vacuo (rotary evaporator) to yield 59 mg (87%) of 10 as
a yellow oil. Analytical TLC (1:3 ethyl acetate:hexanes)
Acknowledgements
1
Rf 0.67. H NMR (300 MHz, CDCl3) l 7.95 (d, J=7.2
The authors thank the National Cancer Institute
(R01CA90603-01) for financial support of this work.
J.A.S. gratefully acknowledges the NIH (F31GM20439)
for a pre-doctoral fellowship.
Hz, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.4 Hz, 2H),
6.35 (dd, J=17.7, 11.1 Hz, 1H), 5.40 (d, J=17.7 Hz, 1H),
5.33 (s, 1H), 5.26 (s, 1H), 5.15 (d, J=11.1 Hz, 1H), 4.69
(q, J=7.2 Hz, 1H), 1.60 (d, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3, ppm) l 191.5, 146.5, 136.9, 136.5,
133.3, 128.5, 127.2, 116.7, 114.6, 38.3, 21.0; FT-IR (thin
film, cm−1) 2929, 1657, 1449, 1209, 906, 772, 688, 645;
low resolution FAB-MS, molecular ion calcd for
C13H14OS 218.1, found 241.1 (M+Na).
References
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11. Preparation of cyclohexadiene 19 by cycloaddition: To an
oven-dried Fisher–Porter bottle (90 mL capacity)
equipped with a magnetic stir bar was added 25 mg (30
mmol, 0.05 equiv.) of 1,3-dimesityl-4,5-dihydroimidazol-2-
ylidenetricyclohexylphosphine benzylidene ruthenium
dichloride 1, 114 mg (0.601 mmol, 1.0 equiv.) of 9, 3 mL
CH2Cl2, and the vessel was pressurized to 40 psi of C2H4.
The pressure was released and subsequently flushed four
times and then maintained at 70 psi ethylene for 24 h.
The pressure was released and the crude brown solution
was filtered through a 4 inch plug of silica gel (CH2Cl2)
and concentrated in vacuo. The crude product 10 was
transferred to an oven dried 10 mL rb flask equipped
with magnetic stir bar and reflux condenser to which 70
mL (0.57 mmol, 0.95 equiv.) dimethyl acetylenedicarboxy-
late and 3 mL benzene was added. The solution was
refluxed for 30 h, cooled and purified by column chro-
matography (elution 1:2 ethyl acetate–hexane) to give 19
as a colorless oil (199 mg, 97 % yield); analytical TLC
1
(1:2 ethyl acetate–hexane) Rf 0.3. Data for 19: H NMR
(500 MHz, CDCl3, ppm) l 7.94 (d, J=7.0 Hz, 2H), 7.57
(t, J=7.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 2H), 5.83 (m, 1H),
4.40 (q, J=7.5 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H),
3.21–2.98 (m, 4H), 1.54, (d, J=7.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3, ppm) l 191.3, 168.2, 168.1, 136.9,
133.7, 133.4, 132.4, 132.2, 128.6, 127.2, 119.0, 52.3, 52.2,
43.5, 28.6, 28.5, 19.5. FT-IR (thin film, cm−1) 2956, 1726,
1667, 1433, 1252, 1193, 1050, 901. FAB-MS (NBA, NaI)
molecular ion calcd for C19H20O5S 360.1, found 383.1
(M+Na).
8. Corey, E. J.; Cimprich, K. A. Tetrahedron Lett. 1992, 33,
4099–4102.
9. Representative ethylene metathesis: 2-(thiobenzoyl-
methyl)-1,3-butadiene (10), entry 2 (Table 1): Into an
oven-dried Fisher–Porter bottle (90 mL capacity)
equipped with a magnetic stir bar was added 13 mg 1
(15.6 mmol, 0.05 equiv.), 59.4 mg 9 (0.312 mmol, 1 equiv.)
and 3 mL of freshly distilled CH2Cl2. The vessel was