Iron-catalyzed cross-coupling of alkenyl sulfides with grignard reagents

Article abstract of DOI:10.1021/ol047504c

(Chemical Equation Presented) The iron-catalyzed cross-coupling reaction of alkenyl sulfides with Grignard reagents is described. While the cross-coupling proceeds efficiently at alkenyl-S bonds, almost no cross-coupling takes place at aryl-S bonds, attesting to a unique selectivity of iron catalysis. The beneficial effect of potentially coordinating 2-pyrimidyl group on sulfur is also described.

Full text of DOI:10.1021/ol047504c

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1219-1222
Iron-Catalyzed Cross-Coupling of
Alkenyl Sulfides with Grignard Reagents
Kenichiro Itami,* Shohei Higashi, Masahiro Mineno, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Nishikyo-ku, Kyoto 615-8510, Japan
itami@sbchem.kyoto-u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp
Received December 6, 2004
ABSTRACT
The iron-catalyzed cross-coupling reaction of alkenyl sulfides with Grignard reagents is described. While the cross-coupling proceeds efficiently
at alkenyl S bonds, almost no cross-coupling takes place at aryl S bonds, attesting to a unique selectivity of iron catalysis. The beneficial
effect of potentially coordinating 2-pyrimidyl group on sulfur is also described.
−
−
The transition-metal-catalyzed cross-coupling reactions are
undoubtedly one of the most versatile and efficacious
carbon-carbon bond-forming reactions, and the development
of improved catalysts and reagents continues to evolve at a
rapid pace.1 During the past three decades of extensive
worldwide research, palladium or nickel has emerged as a
favorite among transition metals. While recently discovered
active Pd and Ni catalysts have substantially broadened the
scope of coupling components (both donors and acceptors),2
we felt that the search for alternative transition metals that
effect these useful processes would be also important from
both scientific and practical (environmental) points of view.
literature,4 including extensive studies by the Fu¨rstner group
where aryl chloride and tosylate can be coupled with
Grignard reagents.4v,w,y Moreover, Nakamura, Hayashi, and
Fu¨rstner discovered very recently that iron salts can serve
as efficient catalysts for the “hard-to-achieve” cross-coupling
reaction using alkyl halides, which represents an important
advance in cross-coupling chemistry.5
During the course of our investigation using alkenyl
2-pyrimidyl sulfides in multisubstituted olefin synthesis,6,7
we found that the cross-coupling between styryl 2-pyrimidyl
sulfide (1) and PhMgBr proceeded smoothly under the
influence of Fe(acac)3 catalyst at room temperature to give
trans-stilbene in 43% yield (Scheme 1). The cross-coupling
Iron is extremely interesting in this regard because it is
the most abundant metal after aluminum in the earth’s crust
(5%) and, hence, much cheaper than palladium and nickel.
In 1971, Kochi and Tamura reported iron-catalyzed effective
substitution reaction of alkenyl halides with Grignard
reagents as a first example of effective cross-coupling of an
sp2 carbon electrophile.3 Since this pioneering work, reports
on iron-catalyzed cross-coupling have appeared in the
Scheme 1
(1) (a) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Cross-Coupling Reactions;
Miyaura, N., Ed.; Topics in Current Chemistry Vol. 219; Springer: New
York, 2002.
(2) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(b) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384.
did not take place at the 2-pyrimidyl-S bond.8 Nevertheless,
this is the first example of iron-catalyzed cross-coupling
reaction using alkenyl sulfides. In view of the apparent
significance of iron catalysis, we set out to investigate the
10.1021/ol047504c CCC: $30.25
© 2005 American Chemical Society
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iron-catalyzed cross-coupling using alkenyl sulfides as
coupling components.9
with p-MeOC6H4MgBr (3.0 equiv) in the presence of
Fe(acac)3 (5 mol %) in THF at room temperature (Scheme
2). After usual workup, we found that p-methoxystyrene 3
To examine whether the 2-pyrimidyl group is essential or
not in this cross-coupling, phenyl vinyl sulfide (2) was treated
(3) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b)
Tamura, M.; Kochi, J. K. Synthesis 1971, 303. (c) Tamura, M.; Kochi, J.
J. Organomet. Chem. 1971, 31, 289. (d) Neumann, S. M.; Kochi, J. K. J.
Org. Chem. 1975, 40, 599. (e) Smith, R. S.; Kochi, J. K. J. Org. Chem.
1976, 41, 502. (f) Kwan, C. L.; Kochi, J. K. J. Am. Chem. Soc. 1976, 98,
4903. (g) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351.
Scheme 2
(4) Alkenyl halides/Grignard reagents: (a) Molander, G. A.; Rahn, B.
J.; Shubert, D. C.; Bonde, S. E. Tetrahedron Lett. 1983, 24, 5449. (b) Cahiez,
G.; Avedissian, H. Synthesis 1998, 1199. (c) Dohle, W.; Kopp, F.; Cahiez,
G.; Knochel, P. Synlett 2001, 1901. (d) Fakhfakh, M. A.; Franck, X.;
Hocquemiller, R.; Figade`re, B. J. Organomet. Chem. 2001, 624, 131. (e)
Ho¨lzer, B.; Hoffmann, R. W. Chem. Commun. 2003, 732. Alkenyl halides/
organolithium reagents: (f) Walborsky, H. M.; Banks, R. B. J. Org. Chem.
1981, 46, 5074. Alkenyl halides/organomanganese reagents: (g) Cahiez,
G.; Marquais, S. Tetrahedron Lett. 1996, 37, 1773. (h) Cahiez, G.; Marquais,
S. Pure Appl. Chem. 1996, 68, 53. (i) Fu¨rstner, A.; Brunner, H. Tetrahedron
Lett. 1996, 37, 7009. Alkenyl sulfones/Grignard reagents: (j) Fabre, J. L.;
Julia, M.; Verpeaux, J. N. Tetrahedron Lett. 1982, 23, 2469. (k) Alvarez,
E.; Cuvigny, T.; du Penhoat, C. H.; Julia, M. Tetrahedron 1988, 44, 111.
(l) Alvarez, E.; Cuvigny, T.; du Penhoat, C. H.; Julia, M. Tetrahedron 1988,
44, 119. Acyl halides/Grignard reagents: (m) Percival, W. C.; Wagner, R.
B.; Cook, N. C. J. Am. Chem. Soc. 1953, 75, 3731. (n) Fiandanese, V.;
Marchese, G.; Martina, V.; Ronzini, L. Tetrahedron Lett. 1984, 25, 4805.
(o) Ritter, K.; Hanack, M. Tetrahedron Lett. 1985, 26, 1285. (p) Cardel-
licchio, C.; Fiandanese, V.; Marchese, G.; Ronzini, L. Tetrahedron Lett.
1987, 28, 2053. (q) Dell′Anna, M. M.; Mastrorilli, P.; Nobile, C. F.;
Marchese, G.; Taurino, M. R. J. Mol. Catal. A: Chem. 2000, 161, 239. (r)
Reddy, C. K.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1700.
Thioesters/Grignard reagents: (s) Cardellicchio, C.; Fiandanese, V.; Marchese,
G.; Ronzini, L. Tetrahedron Lett. 1985, 26, 3595. Allylic phosphates/
Grignard reagents: (t) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett
1991, 513. (u) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron
1994, 50, 6017. Aryl halides (triflates)/Grignard reagents: (v) Fu¨rstner, A.;
Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609. (w) Fu¨rstner, A.; Leitner,
A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856. (x)
Quintin, J.; Franck, X.; Hocquemiller, R.; Figade`re, B. Tetrahedron Lett.
2002, 43, 3547. (y) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003,
42, 308. (z) Hocek, M.; Hockova´, D.; Dvrˇa´kova´, H. Synthesis 2004, 889.
(5) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Nagao, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(c) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955. See
also: (d) Brinker, U. H.; Ko¨nig, L. Chem. Ber. 1983, 116, 882. (e) Nishii,
Y.; Wakasugi, K.; Tanabe, Y. Synlett 1998, 67. (f) Bedford, R. B.; Bruce,
D. W.; Frost, R. M.; Goodby, J. W.; Hird, M. Chem. Commun. 2004, 2822.
(6) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem. Soc.
2004, 126, 11778.
is exclusively produced in this reaction (74% yield). 4-Meth-
oxybiphenyl 4 (product derived from the cross-coupling at
the phenyl-S bond) was obtained only in 2% yield as judged
by GC and NMR analysis.
As for catalyst precursor, FeCl3, FeCl2, and Fe(OAc)2 can
also be used in this cross-coupling, albeit in somewhat lower
yields. In all cases examined, 3 was exclusively produced.
The organozinc reagents were found not to be applicable in
this cross-coupling. The addition of coordinating additives
such as TMEDA (N,N,N′,N′-tetramethylethylenediamine),
2,2′-bipyridyl, and 1-methyl-2-pyrrolidinone (NMP), which
exert beneficial effects in the reported iron catalysis only
had detrimental effects in this cross-coupling.
The control experiment using diphenyl sulfide (5) un-
doubtedly corroborated that the iron-catalyzed cross-coupling
at aryl-S bond is extremely sluggish (Scheme 3). This is in
Scheme 3
(7) For our related works on multisubstituted olefin synthesis, see: (a)
Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Nokami, T.; Yoshida, J. J.
Am. Chem. Soc. 2000, 122, 12013. (b) Itami, K.; Nokami, T.; Yoshida, J.
J. Am. Chem. Soc. 2001, 123, 5600. (c) Itami, K.; Nokami, T.; Ishimura,
Y.; Mitsudo, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577.
(d) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670.
(e) Itami, K.; Ushiogi, Y.; Nokami, T.; Ohashi, Y.; Yoshida, J. Org. Lett.
2004, 6, 3695. (f) Itami, K.; Tonogaki, K.; Ohashi, Y.; Yoshida, J. Org.
Lett. 2004, 6, 4093.
(8) This observation is in line with the finding of Fu¨rstner that cross-
coupling took place at the pyrimidyl-Cl bond rather than pyrimidyl-S
bond when 4-chloro-2-methylthiopyrimidine was treated with Grignard
reagent in the presence of Fe(acac)3 catalyst.4w
(9) There are many reports on nickel- or palladium-catalyzed cross-
coupling reaction using sulfides. For early works, see: (a) Okamura, H.;
Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43. (b) Wenkert, E.; Ferreira,
T. W.; Michelotti, J. Chem. Soc., Chem. Commun. 1979, 637. (c) Takei,
H.; Miura, M.; Sugimura, H.; Okamura, H. Tetrahedron Lett. 1979, 1447.
(d) Okamura, H.; Takei, H. Tetrahedron Lett. 1979, 3425. For a review,
see: (e) Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89. For recent examples, see:
(f) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 3189. (g) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S.
J. Am. Chem. Soc. 1999, 121, 9449. (h) Liebeskind, L. S.; Srogl, J. J. Am.
Chem. Soc. 2000, 122, 11260. (i) Savarin, C.; Srogl, J. Liebeskind, L. S.
Org. Lett. 2000, 2, 3229. (j) Angiolelli, M. E.; Casalnuovo, A. L.; Selby,
T. P. Synlett 2000, 905. (k) Shimizu, T.; Seki, M. Tetrahedron Lett. 2002,
43, 1039. (l) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (m)
Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G.
Synlett 2002, 447. (n) Reference 6.
a sharp contrast to the usual Pd- or Ni-catalyzed processes
where both alkenyl and aryl compoments can participate in
cross-coupling. The emergence of such bond selectivity
(alkenyl-S . aryl-S) is extremely intriguing not only from
a mechanistic point of view but also from a synthetic point
of view.
Next, we examined the cross-coupling of 2 with several
Grignard reagents to roughly grasp the scope of this new
cross-coupling procedure (Table 1).10 As already mentioned,
the reaction with p-MeOC6H4MgBr proceeded smoothly to
give p-methoxystyrene in 74% yield (entry 1). On the other
hand, the reactions using m-MeOC6H4MgBr and o-MeOC6H4-
MgBr furnished the cross-coupling products in much lower
yields (entries 2 and 3). Unfortunately, alkynyl Grignard
reagents were not applicable in this cross-coupling (entry
4). However, the use of alkyl Grignard reagent (C12H25MgBr)
1220
Org. Lett., Vol. 7, No. 7, 2005

iron salts and Grignard reagents undergoes carbometalation
across CdC bond of alkenyl sulfides to give â-phenylthio-
substituted organoiron species, which undergoes 1,2-elimina-
tion of PhS-[Fe] species to afford the cross-coupling
products (olefins). The transmetalation of PhS-[Fe] species
with Grignard reagents regenerates organoiron species to
complete a catalytic cycle.11,12
Table 1. Iron-Catalyzed Cross-Coupling of 2 with Various
Grignard Reagents
This addition/elimination mechanism explains the afore-
mentioned alkenyl-S bond selectivity easier than those
described above. However, we must stress that these dis-
cussions are purely speculative with no evidence. Clearly,
more experimental data must be accumulated to elucidate
the mechanism.
In addition to the Grignard reagents employed (Table 1),
it was found that the structure of alkenyl sulfides also affect
the efficiency of the present iron-catalyzed cross-coupling
(Scheme 4). For example, the use of styryl phenyl sulfide in
Scheme 4
a Determined by GC and NMR analysis using an internal standard. The
number in parentheses is the isolated yield.
resulted in the production of 1-tetradecene in 65% yield
(entry 5). Overall, the efficiency of this newly developed
cross-coupling reaction was found to be highly dependent
on Grignard reagents employed.
Although detailed study has not been conducted at present,
the mechanism of this newly developed iron-catalyzed cross-
coupling using alkenyl sulfides is of great interest. In the
related cross-coupling using alkenyl halides, Kochi has
proposed a mechanism based on oxidative addition of alkenyl
halide to Fe(I) followed by transmetalation with Grignard
reagent and reductive elimination.3e Very recently, Fu¨rstner
has proposed an alternative mechanism based on Fe(II)/Fe(0)
cycle for iron-catalyzed cross-coupling of aryl halides with
Grignard reagents.4w Although it might be possible to assume
that the cross-coupling described herein proceeds through a
mechanism similar to either of these mechanisms, we feel
that it is not necessarily easy to explain the observed bond
selectivity (alkenyl-S . aryl-S) with such mechanisms.
In nickel- and palladium-catalysis, cross-coupling reactions
are known to take place at both alkenyl-S and aryl-S bonds.
place of vinyl phenyl sulfide as coupling partner resulted in
the substantial decline in cross-coupling efficiency (74% f
31%; Schemes 2 and 4). However, the yield was substantially
increased when the phenyl group of styryl phenyl sulfide
was replaced with the 2-pyrimidyl group (31% f 59%;
Scheme 4).13 Although the beneficial effect of 2-pyrimidyl
group on sulfur has not been clearly understood yet, we
presume that the 2-pyrimidyl group might be acting as a
directing group to a certain iron species to help the reacting
CdC bond to coordinate to iron through complex-induced
proximity effect.14
As an alternative to these mechanisms, we surmise that
an addition/elimination mechanism might be also possible.
Thus, organoiron species generated by the reaction between
(11) Such an addition/elimination sequence has been proposed for the
reaction of organocopper reagents with â-alkylthio-substituted R,â-unsatu-
rated carbonyl compounds. (a) Coates, R. M.; Sowerby, R. L. J. Am. Chem.
Soc. 1971, 93, 1027. (b) Posner, G. H.; Brunelle, D. J. J. Org. Chem. 1973,
38, 2747. (c) Posner, G. H.; Brunelle, D. J. J. Chem. Soc., Chem. Commun.
1973, 907. (d) Gammill, R. B.; Bryson, T. A. Tetrahedron Lett. 1975, 3793.
(12) There are some reports on the iron-catalyzed addition reactions
(carbometalation) of organometallic reagents across alkenes and alkynes.
(a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122,
978. (b) Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E. Org. Lett.
2003, 5, 1373. (c) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba,
Y.; Hosomi, A. Angew. Chem., Int. Ed. 2001, 40, 621.
(10) Typical Procedure. To a mixture of Fe(acac)3 (17.7 mg, 0.05 mmol)
and phenyl vinyl sulfide (2; 135.5 mg, 1.0 mmol) in dry THF (1.0 mL)
was slowly added a solution of p-MeOC6H4MgBr (3.0 mmol, 0.5 M) in
THF at -78 °C under argon. The resultant mixture was further stirred at
room temperature for 21 h. The yield of p-methoxystyrene was determined
to be 74% as judged by GC analysis using n-pentadecane as an internal
standard. Usual aqueous workup followed by purification by gel permeation
chromatography (CHCl3) afforded p-methoxystyrene (88.2 mg, 66%) as a
pale yellow oil. All products listed in Table 1 exhibited spectral data in
agreement with literature values.
(13) Styryl 2-pyrimidyl sulfide was prepared by the Mizoroki-Heck-type
arylation of vinyl 2-pyrimidyl sulfide with iodobenzene under the influence
of Pd[P(t-Bu)3]2 catalyst and triethylamine (99% yield).6
Org. Lett., Vol. 7, No. 7, 2005
1221

In summary, we found the iron-catalyzed cross-coupling
of alkenyl sulfides with Grignard reagents. Aryl and alkyl
Grignard reagents are applicable in this cross-coupling. While
the cross-coupling proceeds efficiently at alkenyl-S bonds,
almost no cross-coupling takes place at aryl-S bonds,
attesting to a unique selectivity of iron catalysis. In connec-
tion with these results, an addition/elimination mechanism
has been proposed as a possible alternative to the generally
accepted cross-coupling mechanism.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science.
Note Added after ASAP Publication. The journal title
in ref 4z was incorrectly listed as Synlett, not Synthesis, in
the version published ASAP March 8, 2005; the correct
version was published March 9, 2005.
(14) For reviews on directed chemical reactions: (a) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (b) Beak, P.; Meyers,
A. I. Acc. Chem. Res. 1986, 19, 356. (c) Snieckus, V. Chem. ReV. 1990,
90, 879. (d) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552. (e) Whisler, M. C.; MacNeil, S.; Snieckus,
V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
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