Ruthenium-catalyzed S-propargylation of thiols enables the rapid synthesis of propargylic sulfides

Article abstract of DOI:10.1021/ja027750o

A new and highly efficient catalytic system based on CpRuClL2 is proposed for the S-propargylation of thiols by propargylic carbonates under neutral conditions, in which specific requirements inherent to the different reactivities of aliphatic and aromatic thiols are achieved by tuning both the nature of the ancillary ligand L and the experimental conditions. Copyright

Full text of DOI:10.1021/ja027750o

Published on Web 10/09/2002
Ruthenium-Catalyzed S-Propargylation of Thiols Enables the Rapid Synthesis
of Propargylic Sulfides
Teruyuki Kondo, Yusuke Kanda, Atsushi Baba, Kenji Fukuda, Ayako Nakamura, Kenji Wada,
Yasuhiro Morisaki, and Take-aki Mitsudo*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
Received July 18, 2002
Scheme 1a
Propargylic sulfides and their derivatives are biologically active
compounds,1 as well as attractive building blocks in the synthesis
of sulfur-containing functional monomers.2 The most promising and
straightforward method for preparing propargylic sulfides is the
transition-metal complex-catalyzed substitution reaction of pro-
pargylic alcohol derivatives with sulfur nucleophiles such as thiols.
However, this type of reaction has not yet been reported, while a
detailed study was performed on propargylic substitution of
carbonucleophiles.3 The widespread belief that organosulfur com-
pounds are catalyst poisons may have precluded intensive research
in this area.4 Recent progress in the catalytic synthesis of propargylic
sulfides without poisoning of the catalyst has included (1) Ce-
exchanged Zeolite-catalyzed reactions of cyclohexanethiol and
benzenethiol with propargyl bromide5 and (2) the thiolate-bridged
diruthenium complex-catalyzed reaction of 4-methylbenzenethiol
with 1-phenylprop-2-yn-1-ol.6 However, these two reactions have
serious drawbacks. In the former, the substrates bearing functional
groups sensitive to acidic conditions cannot be used.5 In the latter,
the ruthenium catalyst used is very specific, and it is easy to
speculate that no reaction occurs with internal propargylic alcohols
via a reaction mechanism involving an (allenylidene)ruthenium
intermediate.6
On the basis of our study of π-allylruthenium chemistry7
combined with ruthenium-catalyzed sulfur chemistry,8 we recently
succeeded in developing the first ruthenium-catalyzed allylic
substitution of thiols,9 which has prompted us to examine ruthenium
catalysts for use in the propargylic substitution of thiols. After many
trials, we finally found a novel ruthenium-catalyzed S-propar-
gylation of both aromatic and aliphatic thiols with internal pro-
pargylic carbonates under neutral conditions. We report here the
development of this new ruthenium-catalyzed reaction which
enables a rapid synthesis of propargylic sulfides.
Treatment of benzenethiol (2a) with methyl 3-phenylprop-2-ynyl
carbonate (1a) in the presence of 10 mol % CpRuCl(cod) [Cp )
cyclopentadienyl, cod ) 1,5-cyclooctadiene] in N-methylpiperidine
at 100 °C for 0.5 h under an argon atmosphere gave the
corresponding aryl propargylic sulfides, phenyl 3-phenylprop-2-
ynyl sulfide (3a), in quantitative yield. In contrast to the earlier
work on the ruthenium-catalyzed S-allylation of thiols,9 the present
reaction required elevated temperatures over 80 °C and an ap-
propriate solvent, that is, N-methylpiperidine7c,d,10 (vide infra), since
propargylic carbonates are less reactive than allylic carbonates.3b
First, the effect of the catalyst was examined in the synthesis of
3a from 1a and 2a. Among the catalysts examined, only CpRuCl-
(cod) (3a, >99%) and CpRuCl(PPh3)2 (3a, 66%) showed high
catalytic activity. Other di- and zerovalent ruthenium complexes,
a Figures in the parentheses are GLC yield. bFor 1 h. cFor 3 h. dFor 8 h.
eFor 2 days.
such as Cp*RuCl(cod) [Cp* ) pentamethylcyclopentadienyl],
CpRuCl(CO)2, RuCl2(PPh3)3, RuH2(PPh3)4, [RuCl2(CO)3]2, Ru3-
(CO)12, and Ru(η6-cot)(dmfm)2 [cot ) 1,3,5-cyclooctatriene, dmfm
) dimethyl fumarate] were almost ineffective. Cp*RuCl(cod)
showed no catalytic activity. This means that tuning of both the
steric and electronic conditions of the active ruthenium center is
highly important for the success of the present reaction.11 No
reaction occurred with Pd(PPh3)4, which is a highly active catalyst
for the stereoselective addition of organic disulfides to alkynes,12
or RhCl(PPh3)3, which is also an active catalyst for the highly regio-
and stereoselective hydrothiolation of alkynes with thiols.13 Thus,
the present reaction is characteristic of ruthenium catalysts.
The use of an appropriate solvent is also critically important.
No reaction occurred in toluene, 1,4-dioxane, DMF, or propionitrile
as a solvent. Only tertiary amines such as N-methylpiperidine (3a,
>99%), and triethylamine (3a, 92%) were suitable as solvents for
the present reaction. These results strongly suggest that amines such
as N-methylpiperidine act as both a suitable ligand for an active
ruthenium intermediate and a solvent to prevent catalyst poisoning
by thiols.10
The S-propargylation of several aromatic thiols (2) with pro-
pargylic carbonates (1) proceeded smoothly with a CpRuCl(cod)
catalyst in N-methylpiperidine, and the results are summarized in
Scheme 1.
In all cases, propargylic carbonates (1) were completely con-
sumed to give the corresponding aryl propargylic sulfides (3a-g)
in good to high isolated yields. Allenylic sulfides, which sometimes
became a main product in the reactions of propargylic compounds
with sulfur compounds,14 and Vicinal-dithioethers, which may be
derived from the double thiolation of a (σ-allenyl)ruthenium
intermediate, were not obtained at all (vide infra). The substituents
at the terminal acetylenic carbon in 1 and the electron-donating
and -withdrawing substituents on the aromatic ring in 2 did not
affect the reaction. Note that the trimethylsilyl-substituted propar-
gylic carbonate, 1d, gave the corresponding propargylic sulfide in
* To whom correspondence should be addressed. E-mail: mitsudo@
scl.kyoto-u.ac.jp.
9
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J. AM. CHEM. SOC. 2002, 124, 12960-12961
10.1021/ja027750o CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2a
References
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(10) The S-propargylation of 2a with 1a in toluene actually proceeded in the
presence of a catalytic amount of CpRuCl(cod) (10 mol %) and
N-methylpiperidine (20 mol %) to give 3a in 73% yield, which strongly
suggests that N-methylpiperidine acts as a suitable ligand for an active
ruthenium species as well as a simple solvent. For other examples, see:
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a Figure in the parentheses is GLC yield.
only 46% yield because of the desilylation of the starting 1d and
the product 3h. As can be readily seen from Scheme 1, general
internal propargylic carbonates are suitable substrates for the present
reaction. Functional groups such as OCH3 and Cl on the phenyl
substituent in 1a were also tolerated. Unsubstituted terminal
propargylic carbonates are poor substrates for the present reaction.15
Surprisingly, CpRuCl(cod) was totally inefficient for the S-
propargylation of aliphatic thiols such as octanethiol (4a) with 1a.
It has been pointed out that ruthenium-catalyzed reactions require
highly careful tuning of the reaction conditions with substrates to
obtain products in high yields and selectivities.11 By screening the
catalysts again, we finally found that CpRuCl(PPh3)2 is specifically
effective for the S-propargylation of aliphatic thiols (4) (Scheme
2). Since the coordination ability of aliphatic thiols (4) is higher
than that of aromatic thiols (2), a more basic ligand such as PPh3
is needed to prevent catalyst poisoning by thiols.
While the reaction mechanism is not yet clear, we now believe
that the (σ-propargyl)ruthenium complex16 is a key intermediate
in the present reaction. N-Methylpiperidine and PPh3 may contribute
to the formation of this (σ-propargyl)ruthenium intermediate. It has
been found that propargylic compounds add oxidatively to transition
metals to give either (σ-allenyl)metal complexes or (σ-propargyl)-
metal complexes.17 Generally, (σ-allenyl)metal complexes were
generated from terminal propargylic compounds.18 Internal pro-
pargylic compounds gave (σ-propargyl)metal complexes because
of the bulkiness of the terminal substituent on the alkyne moiety.18b
If the present reaction proceeds via a (σ-allenyl)ruthenium inter-
mediate, Vicinal-dithioethers by double nucleophilic thiolation of
a (σ-allenyl)ruthenium intermediate as well as allenylic sulfides
should be obtained as in the palladium-catalyzed reaction of
propargylic compounds with nucleophiles.3a,c However, the present
reaction exclusively gave the corresponding propargylic sulfides
without the formation of allenylic sulfides or Vicinal-dithioethers
(vide supra), which suggests that the present reaction proceeds via
the (σ-propargyl)ruthenium intermediate.
(15) Further, the reaction of 2a with a secondary propargylic carbonate, methyl
1,3-diphenylprop-2-ynyl carbonate (1e), is quite complicated. The yield
of the normal S-propargylic substitution product, phenyl 1,3-diphenylprop-
2-ynyl sulfide, was low (>10%), while the addition of diphenyl disulfide
generated from 2a to the triple bond in 1e as well as reduction of a OCO2-
Me group occurred to give unexpected (Z)-1,2-bis(phenylthio)-1,3-
diphenylprop-1-ene (6a) in an isolated yield of 38%. Further studies are
apparently required for these reactions using secondary and tertiary
propargylic carbonates.
(16) For (σ-propargyl)ruthenium complexes, see: (a) Shuchart, C. E.; Willis,
R. R.; Wojcicki, A. J. Organomet. Chem. 1992, 424, 185. For Rh, see:
(b) Kayan, A.; Wojcicki, A. Inorg. Chim. Acta 2001, 319, 187 and
references therein.
In conclusion, simple and readily available ruthenium complexes
of the type CpRuClL2 were found to act as efficient catalysts for
the synthesis of propargylic sulfides via S-propargylation of
aromatic or aliphatic thiols under neutral conditions. This reaction
may complement the previously reported thiolato-bridged diruthe-
nium complex-catalyzed S-propargylation of thiols with terminal
propargylic alcohols.6 This reaction should also open up new
opportunities in transition-metal complex-catalyzed sulfur chemistry.
Acknowledgment. This work was supported in part by a Grants-
in-Aid for Scientific Research (B) from the Japan Society for the
Promotion of Science. T.K. acknowledges financial support from
the UBE Foundation, General Sekiyu Research & Development,
Encouragement & Assistance Foundation, and the Yamada Science
Foundation.
(17) For palladium-catalyzed reactions of propargylic compounds via (σ-
propargyl)palladium intermediates, see: (a) Mandai, T.; Matsumoto, T.;
Kawada, M.; Tsuji, J. Tetrahedron Lett. 1993, 34, 2161. (b) Mandai, T.;
Tsujiguchi, Y.; Matsuoka, S.; Tsuji, J. Tetrahedron Lett. 1993, 34, 7615.
(c) Mandai, T.; Matsumoto, T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji, J. J.
Organomet. Chem. 1994, 473, 343.
(18) (a) Elsevier, C. J.; Kleijn, H.; Ruitenberg, K.; Vermeer, P. J. Chem. Soc.,
Chem. Commun. 1983, 1529. (b) Elsevier, C. J.; Kleijn, H.; Boersma, J.;
Vermeer, P. Organometallics 1986, 5, 716. (c) Tseng, T.-W.; Wu, I.-Y.;
Lin, Y.-C.; Chen, C.-T.; Chen, M.-C.; Tsai, Y.-J.; Chen, M.-C.; Wang,
Y. Organometallics 1991, 10, 43.
Supporting Information Available: Complete experimental pro-
cedures and compound characterization data (PDF). This material is
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JA027750O
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