Efficiency of a ruthenium catalyst in metathesis reactions of sulfur-containing compounds

Article abstract of DOI:10.1021/ol025834w

1,3-Dimesitylimidazol-2-ylidene ruthenium benzylidene catalyst (RuCl₂(=C(H)Ph)(PCy₃)(IMes)) has been successfully employed in ring-closing metathesis reactions of acyclic diene sulfides, disulfides, and dithianes and in self-cross metathesis reactions of ene-sulfides, thioethers and thiols.

Full text of DOI:10.1021/ol025834w

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1767-1770
Efficiency of a Ruthenium Catalyst in
Metathesis Reactions of
Sulfur-Containing Compounds
,†
Gae1lle Spagnol,† Marie-Pierre Heck,* Steven P. Nolan,‡ and
,†,§
Charles Mioskowski*
CEA-CE Saclay, SerVice de Marquage Mole´culaire et de Chimie Bio-organique,
Baˆt 547, De´partement de Biologie Joliot Curie, 91191 Gif sur YVette Cedex, France
heck@dsVidf.cea.fr
Received March 7, 2002
ABSTRACT
1,3-Dimesitylimidazol-2-ylidene ruthenium benzylidene catalyst (RuCl2(dC(H)Ph)(PCy3)(IMes)) has been successfully employed in ring-closing
metathesis reactions of acyclic diene sulfides, disulfides, and dithianes and in self-cross metathesis reactions of ene-sulfides, thioethers, and
thiols.
Over the past few years, olefin metathesis reactions catalyzed
by well-defined alkylidene complexes have evolved into a
widely applicable methodology in organic synthesis.1 To
date, molybdenum (A)2 and ruthenium (B)3 complexes
(Figure 1) are the most routinely used catalysts for ring-
closing metathesis (RCM), cross metathesis (CM), and other
metathesis-type reactions. The commercial availability and
effectiveness of these catalysts now allow olefin metathesis
strategies to be viewed as practical methods for the synthesis
† CEA-CE Saclay.
‡ Department of Chemistry, University of New Orleans, New Orleans,
LA 70148.
§ Laboratoire de Synthe`se Bio-organique, Faculte´ de Pharmacie, Uni-
versite´ Louis Pasteur, 74 route du Rhin, BP24, F-67401 Illkirch, France.
(1) For recent reviews, see: (a) Grubbs, R. H.; Chang S. Tetrahedron
1998, 54, 4413-4450. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 371-388. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036-2056. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043. (e) Roy, R.; Das, S. K. Chem. Commun. 2000, 519-529.
(2) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. (b) Bazan, G.
C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem.
Soc. 1991, 113, 6899-6907.
(3) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Wu, Z.; Nguyen, S. T.;
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Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100-110.
Figure 1. RCM catalysts.
10.1021/ol025834w CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/23/2002

of medium size ring,4 spiro, and polycyclic systems5 and
natural products.6 Although Grubbs’ catalyst (B) exhibits
excellent functional group compatibility, Schrock’s catalyst
(A) displays higher reactivity toward a broad range of
substrates.7
Metathesis reactions on substrates bearing a large range
of functionalities and heteroatoms are fully documented in
the literature, but astonishingly very few examples of
substrates containing sulfur atoms have been so far reported.
Tungsten (C)8 and molybdenum (A)9 catalysts (Figure 1)
were until lately the only two known catalysts to display
efficiency in metathesis reactions on substrates containing
sulfur atoms. Very recently catalyst B was shown to perform
enyne metathesis of sulfur-containing alkynes10 and to
promote RCM reactions of acyclic sulfones and R-thiophos-
phonate.11
oxygen and moisture.16-17 Complex D bears the high
reactivity of A while maintaining the functional group
tolerance of B.
We investigated therefore the potential of D as catalyst in
metathesis involving substrates containing sulfur atoms.
Herein we report the first examples of RCM and self-CM
reactions of a series of acyclic diene sulfur species (sulfides,
disulfides, thioethers) catalyzed by D. We intended to
evaluate its compatibility and effectiveness compared to that
of parent complex B and to performances reported for
catalysts A and C.
The activity of ruthenium complex D in RCM of acyclic
diene sulfides18 was initially investigated. The results are
reported in Table 1.19
In fact, many failures in RCM-type reactions of sulfur
compounds are reported in multistep synthesis and have
compelled authors to revise their synthetic strategy.12 To
overcome this unsatisfactory situation and broaden the scope
of metathesis reactions, we reinvestigated new conditions
and catalysts in order to conduct RCM reactions on sulfur-
containing compounds.
Table 1. RCM of Sulfides
Replacement in catalyst B of one of the phosphine ligands
by a strong electron-donating and sterically hindered N-
heterocyclic carbene13 (e.g., N,N-bis(mesityl)imidazol-2-
ylidene, IMes) led to a new ruthenium catalyst D14 (Figure
1). This catalyst and its saturated imidazol-2-ylidene ana-
logue15 have been reported to improve effectiveness in
metathesis activity, thermal stability, and inertness toward
(4) Yet, L. Chem. ReV. 2000, 100, 2963-3007.
(5) (a) Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org. Chem. 1999,
64, 3354-3360. (b) Wallace, D. J.; Cowden, C. J.; Kennedy, D. J.;
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38, 129-131. (d) Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000,
39, 372-374. (d) Bassindale, M. J.; Hamley, P.; Leitner A.; Harrity, J. P.
A. Tetrahedron Lett. 1999, 40, 3247-3250.
a 0.1 M C7D8, 5 mol % D, 80 °C, 1 h. b 0.1 M C6D6, 5 mol % B, rt, 20
h. c Reference 9a and b. d Reference 8b. e 0.005 M C7H8, 5-10 mol % D,
80 °C, 30 h. nd ) not determined.
(6) For recent examples, see: (a) Harrowven, D. C.; Lucas, M.; Howes,
P. D. Tetrahedron 2001, 57, 9157-9162. (b) Boger, D. L.; Hong, J. J. Am.
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R.; Blanda, G. Chem. Eur. J. 2001, 7, 5286-5298. (d) Nicolaou, K. C.;
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O.; Van Delft, F. L. Chem. Eur. J. 2000, 6, 3095-3115.
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K. Angew. Chem., Int. Ed. Engl. 1992, 31, 628-631. (b) Leconte, M.;
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J.-M.; Ollivier, J. Angew. Chem., Int. Ed. Engl. 1993, 32, 112-115. (d)
Lefebvre, F.; Leconte, M.; Pagano, S.; Mutch, A.; Basset, J.-M. Polyhedron
1995, 14, 3209-3226.
First, we studied substituted diallyl sulfides (entries 1, 3,
4) and allyl-homoallyl sulfide (entry 2) in the presence of 5
(14) (a) Huang, J.; Stevens, E. D.; Nolan, S. P. J. Am. Chem. Soc. 1999,
121, 2674-2678. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R.
H. Tetrahedron Lett. 1999, 40, 2247-2250. (c) Ackermann, L.; Fu¨rstner,
A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999,
40, 4787-4790. (d) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.;
Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1999, 38, 2416-2419. (e)
Jafarpour, L.; Huang, J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999,
18, 3760-3763. (f) Jafarpour, L.; Nolan, S. P. Organometallics 2000, 11,
2055-2057.
(9) (a) Armstrong, S. K.; Christie, B. A. Tetrahedron Lett. 1996, 37,
9373-9376. (b) Shon, Y.-S.; Lee, T. R. Tetrahedron Lett. 1997, 38, 1283-
1286. (c) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155-156. (d)
Miller, J. F.; Termin, A.; Koch, K.; Piscopio, A. D. J. Org. Chem. 1998,
63, 3158-3159. (e) O’Gara, J. E.; Portmess, J. D.; Wagener, K. B.
Macromolecules 1993, 26, 2837-2841.
(15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(16) For recent examples on the use of catalyst D, see: (a) Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204-2207. (b) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan,
S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517-1519. (c) Bourgeois, D.;
Mahuteau, J.; Pancrazi, A.; Nolan, S. P.; Prunet, J. Synthesis 2000, 869-
882. (d) Wagner, J.; Martin Cabrejas, L. M.; Grossmith, C. E.; Papageorgiou
C.; Senia, F.; Wagner, D.; France, J.; Nolan, S. P. J. Org. Chem. 2000, 65,
9255-9260. (e) Heck, M.-P.; Baylon, C.; Nolan, S. P.; Mioskowski, C.
Org Lett. 2001, 3, 1989-1991. (f) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J.
Org. Chem. 2001, 66, 4094-4096.
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43, 209-211.
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K. T.; Hanson, P. R. Synlett 2001, 5, 605-608.
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62, 8620-8621. (b) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999,
55, 8215-8230. (c) Reference 8a.
(17) For related ruthenium olefin metathesis catalysts with saturated NHC
ligand, see: (a) Bielawski, C. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
2000, 39, 2903-2906. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl; M.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783-3784. (c) Morgan, J.
P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153-3155.
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1768
Org. Lett., Vol. 4, No. 10, 2002

mol % of catalyst D. Diallyl sulfide led quantitatively to 2,5-
dihydrothiophene as catalysts A and C do (entry 1). Grubbs'
complex B performed the cyclization in only 12% yield.
Under similar reaction conditions, RCM reaction of one
carbon homologated sulfide furnished 3,6-dihydro-2H-thio-
pyrane in 100% yield, whereas catalyst B failed totally (entry
2).
R-Benzyl diallyl sulfide (entry 3) or dimethallyl sulfide
(entry 4) does not lead to the formation of RCM product.
These results highlight the influence of substituents that slow
the RCM and deactivate the catalyst by complexation of the
metal by heteroatoms, especially by sulfur atoms.7,8b
Moreover, cyclization of an eight-membered ring bearing
a methyl sulfide moiety failed with both catalysts B and D
even under high dilution conditions (entry 5).20
These examples show the efficiency of catalyst D com-
pared to that of catalysts A or C and the low efficacy of
catalyst B in RCM reactions of substrates containing sulfide
functionalities.
Introduction of two methyl groups on the terminal double
bonds (entry 2) led (under standard conditions) to a dramatic
decrease in the formation of RCM product (6% yield), while
dimerization product was observed in 40% yield. Under these
conditions, catalyst B proved to be totally ineffective in
contrast to catalyst A, which gave a 54% yield. These results
clearly show the Schrock catalyst A to be more efficient for
RCM of substituted olefins in this substrate family.
Interestingly, a bicyclic compound obtained by RCM of
an eight-membered ring could be isolated with catalyst D,
whereas catalyst B was totally inefficient under similar
conditions (entry 3).
RCM reaction performed on diallyl [1,3]dithiane failed
completely even under drastic conditions (entry 4), while
the corresponding allyl homoallyl [1,3]dithiane gave the
desired spiro compound in 63% isolated yield by performing
the RCM with catalyst D in toluene (entry 5). Catalyst B
proved to be totally ineffective for substrates bearing
dithioacetal functionalities (entries 4 and 5).
Next we investigated RCM reactions involving disulfide
compounds (Table 2).18,21
Finally, we investigated self-cross metathesis (CM) of
various acyclic allyl thioethers and thiols to examine the
influence of the substituents on the sulfur atom during
metathesis reactions.23 The results are reported in Table 3.
Table 2. RCM of Disulfides
Table 3. Self-Cross Metathesis
a 0.1 M C7D8, 5 mol % D, 80 °C, 2 h. b 0.1 M C6D6, 5 mol % B, rt, 20
h. c Reference 8c. d 0.1 M C7H8, 5 mol % D, 80 °C, 2 h, isolated yield.
e 0.1 M C6H6, 5 mol % B, rt, 24 h. nd ) not determined.
a 0.1 M C7D8, 5 mol % D, 80 °C, 2 h. b 0.1 M CD2Cl2, 5 mol % D,
reflux, 4 h. c 0.1 M C6D6, rt, 24 h or 0.1 M CD2Cl2, 5 mol % B, reflux, 12
h. d Reference 9b. e Plus 40% dimerization product. f 0.005 M C7H8, 10 mol
% D, 80 °C, 4 h, isolated yield. g No RCM in standard concentration or
0.005 M. h 0.1 M C7D8, 5 mol % D, 80 °C, 6 h, isolated yield. nd ) not
determined.
When allyl methyl sulfide was reacted under standard
metathesis conditions with catalysts D or B, the resulting
dimer was obtained in 48% and 20% yields, respectively
Allyl disulfide and 5 mol % of D, refluxed for 4 h in CD2-
Cl2 gave quantitatively 3,6-dihydro-[1,2]dithiine and a 60%
yield when the reaction was conducted in toluene.22 Under
similar conditions catalyst B led to a 15% yield of the desired
product (entry 1). Schrock’s catalyst A, used in 10 mol %
for 1 h in benzene at 20 °C, afforded the cyclic product in
77% yield (entry 1).
(19) Representative Procedure. The metathesis reactions of volatile
compounds were run in deuterated solvent. In a typical reaction, a solution
of acyclic diene sulfide (typical concentration 0.1 M) in dry solvent (toluene-
d8 or CD2Cl2 or CH2Cl2) with a catalytic amount of ruthenium benzylidene
(5 mol %) was weighed in a flask or in a NMR tube and heated to 80 °C
or refluxed (CD2Cl2). Product formation and diene disappearance were
monitored by integration of the allylic methylene picks. The formation of
known cyclic product was confirmed by comparison with literature data.
McIntosh, J. M. Can. J. Chem. 1978, 131-134. McIntosh, J. M.; Siddiqui,
M. A. Can. J. Chem. 1983, 61, 1872-1875. Lozac’h, R.; Braillon, B. J.
Magn. Reson. 1973, 12, 244-260.
(18) When not commercially available, the diene sulfides were synthe-
sized following the reported procedure: Bastien, G.; Surzur, J.-M. Bull.
Soc. Chim. Fr. 1982, II, 84-88.
(20) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108-2109.
Org. Lett., Vol. 4, No. 10, 2002
1769

(entry 1). Despite longer reaction time and catalyst additions,
the yields could not be increased. Schrock’s catalyst A was
reported to lead to a 20% yield.
D was successfully employed in the first cross metathesis
reaction of olefins bearing free thiols. This reactive profile,
combined with a remarkable stability displayed toward
oxygen, moisture, and heat, make catalyst D a very attractive
complex in organic synthesis for substrates containing sulfur
atoms, especially in the construction of structures bearing
dithiane as protective groups.
However, limitations in RCM reactions of sterically
hindered substrates require further investigations with new
catalysts to enlarge the scope of metathesis reactions on
sulfur-containing substrates.
Allyl phenyl sulfide treated with D or B allowed yields
higher than those observed with allyl methyl sulfide (entry
2 vs entry 1). Complex D performed the CM reaction in
quantitative yield, whereas B only afforded 30% yield.
A cross metathesis reaction was then carried out on a
sulfur-protected (as the THF derivative) allylthiol (entry 3).
Dimerization occurs with a 89% yield when using catalyst
D, but the desired product was obtained in 11% yield with
catalyst B.
Acknowledgment. Mr. Alain Valleix is gratefully ac-
knowledged for carrying out mass spectra analyses and for
helpful discussions. We also thank MENRT for providing
financial support to G.S. S.P.N. acknowledges the National
Science Foundation and the Petroleum Research Fund
administered by the ACS for partial support of the work
conducted at the University of New Orleans.
Finally free allyl thiols were tested in CM reaction (entries
4 and 5). Dimerization was observed for the first time for
this class of compound by using D as a catalyst. Noteworthy,
a drop in yield was observed for CM of crotyl (38% yield,
entry 5) compared to that of the corresponding allyl deriva-
tive (45% yield, entry 4). Under similar conditions, catalyst
B proved ineffective (entries 4 and 5).
In conclusion, 1,3-dimesitylimidazol-2- ylidene ruthenium
benzylidene complex D was shown to display catalytic
efficiency similar to that of Schrock’s catalyst A in RCM
and CM reactions of sulfide and disulfide functions.
A RCM reaction of a diene bearing a dithioacetal was
observed for the first time by using catalyst D. In addition,
Supporting Information Available: Experimental pro-
cedure and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025834W
(21) Disulfides were commercially available or were synthesized fol-
lowing the reported procedure: Moore, G. C.; Trego, B. R. Tetrahedron
1962, 18, 205-218.
(23) The unsaturated sulfide substrates were commercially available or
were obtained after allylation of the corresponding thiols or following ref
21.
(22) NMR yield, 40% of starting substrate was recovered.
1770
Org. Lett., Vol. 4, No. 10, 2002