A R T I C L E S
Fu¨rstner et al.
roots of the field in early contributions to organonickel chem-
istry,6 which themselves were predated by notable reports on
the use of iron salts for the cross coupling of Grignard reagents
with various organic electrophiles.7–9 These results found
surprisingly little echo for a long period of time,10 in part
because they were overshadowed by the triumph of their nickel-
and palladium-based relatives discovered shortly thereafter. It
is only recently that iron-catalyzed processes regain considerable
attention,11 paralleled by an equally growing interest in the use
of cobalt for similar purposes.12 This may be ascribed to the
fact that iron salts are cheap, readily accessible, generally
nontoxic, environmentally benign, and surprisingly effective in
certain cases. Even the most simple iron salts are able to promote
notoriously difficult transformations.13–24 Illustrative examples
are the smooth activation of aryl chlorides14 as well as of
unactivated primary and secondary alkyl halides19–21 which are
particularly challenging substrates in the cross coupling arena.
Despite these impressive preparative advances, a mechanistic
understanding for iron-catalyzed cross coupling is virtually
nonexistent. Because the actual catalysts are usually generated
in situ as ill-defined but highly sensitive and short-lived entities,
their true nature remains largely unknown. Not even a consensus
on the formal oxidation states of the operating species has been
reached, with catalytic cycles shuttling between Fe(-2)/Fe(0),14
Fe(0)/Fe(+2),8d,13c or Fe(+1)/Fe(+3)8c,d,25 being proposed in
the literature. Yet other authors favored mechanisms devoid of
any such redox manifolds, invoking nucleophilic organoferrate
complexes of different composition as the relevant intermediates
in analogy to the well established principles governing, for
example, organocopper chemistry.26,27
Another reason why the mechanistic understanding has
evolved at a surprisingly slow pace must be seen in the general
lack of knowledge about structure and reactivity of organoiron
derivatives devoid of stabilizing ligands.28,29 Because of their
exceptional sensitivity, only very few such compounds have
(14) (a) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem.
Soc. 2002, 124, 13856. (b) Fu¨rstner, A.; Brunner, H. Tetrahedron Lett.
1996, 37, 7009. (c) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed.
2002, 41, 609. (d) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner,
A. J. Org. Chem. 2004, 69, 3943. (e) Seidel, G.; Laurich, D.; Fu¨rstner,
A. J. Org. Chem. 2004, 69, 3950. (f) Fu¨rstner, A.; Schlecker, A.;
Lehmann, C. W. Chem. Commun. 2007, 4277.
(15) Fu¨rstner, A.; Leitner, A.; Seidel, G. Org. Synth. 2005, 81, 33.
(16) (a) Kofink, C. C.; Blank, B.; Pagano; S.; Go¨tz, N.; Knochel, P. Chem.
Commun. 2007, 1954. (b) Dunet, G.; Knochel, P. Synlett 2006, 407.
(c) Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulo, C.; Knochel,
P. Angew. Chem., Int. Ed. 2005, 44, 1654.
(6) (a) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972,
144. (b) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374. (c) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi,
M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.; Kumada, M.
Bull. Chem. Soc. Jpn. 1976, 49, 1958.
(17) Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844.
(18) (a) Fakhfakh, M. A.; Franck, X.; Hocquemiller, R.; Figade`re, B. J.
Organomet. Chem. 2001, 624, 131. (b) Quintin, J.; Franck, X.;
Hocquemiller, R.; Figade`re, B. Tetrahedron Lett. 2002, 43, 3547. (c)
Nee`as, D.; Drabina, P.; Sedla´k, M.; Kotora, M. Tetrahedron Lett. 2007,
48, 4539. (d) Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006, 8,
1771. (e) Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J. Org. Lett.
2005, 7, 1219. (f) Østergaard, N.; Pedersen, B. T.; Skjærbæk, N.;
Vedsø, P.; Begtrup, M. Synlett 2002, 1889. (g) Pridgen, L. N.; Snyder,
L.; Prol, J., Jr J. Org. Chem. 1989, 54, 1523. (h) Dos Santos, M.;
Franck, X.; Hocquemiller, R.; Figade`re, B.; Peyrat, J.-F.; Provot, O.;
Brion, J.-D.; Alami, M. Synlett 2004, 2697. (i) Ho¨lzer, B.; Hoffmann,
R. W. Chem. Commun. 2003, 732. (j) Gue´rinot, A.; Reymond, S.;
Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521. (k) Dongol, K. G.;
Koh, H.; Sau, M.; Chai, C. L. L. AdV. Synth. Catal. 2007, 349, 1015.
(l) Hayashi, Y.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998,
39, 63. (m) Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71,
8957. (n) Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2006, 45, 762.
(o) Boully, L.; Darabantu, M.; Turck, A.; Ple´, N. J. Heterocycl. Chem.
2005, 42, 1423. (p) Nishii, Y.; Wakasugi, K.; Tanabe, Y. Synlett 1998,
67. (q) Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron Lett. 2005,
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(7) For pioneering studies describing “cross coupling” experiments of
Grignard reagents with benzyl bromide or acetyl chloride, see:(a)
Vavon, G.; Chaminade, C.; Quesnel, G. C. R. Hebd. Seances Acad.
Sci. 1945, 220, 850. (b) Percival, W. C.; Wagner, R. B.; Cook, N. C.
J. Am. Chem. Soc. 1953, 75, 3731.
(8) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b)
Tamura, M.; Kochi, J. Synthesis 1971, 303. (c) Neumann, S. M.; Kochi,
J. K. J. Org. Chem. 1975, 40, 599. (d) Smith, R. S.; Kochi, J. K. J.
Org. Chem. 1976, 41, 502. (e) Kochi, J. K. Acc. Chem. Res. 1974, 7,
351. (f) Kochi, J. K. J. Organomet. Chem. 2002, 653, 11.
(9) These results, in turn, are predated by seminal contributions of
Kharasch et al., who investigated the subtle influence of various
transition metal salts, including iron, on the formation and reactivity
of Grignard reagents; cf. Kharasch, M. S.; Reinmuth, O. Grignard
Reactions of Nonmetallic Substances; Constable: London, 1954.
(10) (a) For early uses of iron-catalyzed coupling, see the following for
leading references: Molander, G. A.; Rahn, B. J.; Shubert, D. C.;
Bonde, S. E Tetrahedron Lett. 1983, 24, 5449. (b) Brinker, U. H.;
Ko¨nig, L. Chem. Ber. 1983, 116, 882. (c) Walborsky, H. M.; Banks,
R. B. J. Org. Chem. 1981, 46, 5074. (d) Fabre, J.-L.; Julia, M.;
Verpeaux, J.-N. Tetrahedron Lett. 1982, 23, 2469. (e) Alvarez, E.;
Cuvigny, T.; Herve´du Penhoat, C.; Julia, M. Tetrahedron 1988, 44,
111. (f) Alvarez, E.; Cuvigny, T.; Herve´du Penhoat, C.; Julia, M.
Tetrahedron 1988, 44, 119. (g) Hanack, M.; Ba¨ssler, T.; Eymann, W.;
Heyd, W. E.; Kopp, R. J. Am. Chem. Soc. 1974, 96, 6686. (h)
Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L. Tetrahedron
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26, 1285. (j) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Ronzini,
L. Tetrahedron Lett. 1987, 28, 2053. (k) Yanagisawa, A.; Nomura,
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(19) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6,
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(20) Preliminary communication: Martin, R.; Fu¨rstner, A. Angew. Chem.,
Int. Ed 2004, 43, 3955.
(21) For an iron-catalyzed formal alkyl-aryl(alkyl) cross coupling by
desulfinylative coupling of sulfonyl chlorides with Grignard reagents,
see:(a) Volla, C. M. R.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47,
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(22) (a) Iron-catalyzed C-N coupling: Correa, A.; Bolm, C. Angew. Chem.,
Int. Ed 2007, 46, 8862. (b) Taillefer, M.; Xia, N.; Ouali, A. Angew.
Chem., Int. Ed. 2007, 46, 934. (c) C-O coupling: Bistri, O.; Correa,
A.; Bolm, C Angew. Chem., Int. Ed. 2008, 47, 586.
(11) Reviews:(a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV.
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(23) (a) For the positive effect of iron catalysts on the reactivity of
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(12) Review:(a) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081.
(b) Korn, T. J.; Schade, M. A.; Cheemala, M. N.; Wirth, S.; Guevara,
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8774 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008