Iron-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/ja027190t

Simple iron salts such as FeCl_n, Fe(acac)_n (n = 2,3) or the salen complex 4 turned out to be highly efficient, cheap, toxicologically benign, and environmentally friendly precatalysts for a host of cross-coupling reactions of alkyl o

Full text of DOI:10.1021/ja027190t

Published on Web 10/24/2002
Iron-Catalyzed Cross-Coupling Reactions
Alois Fu¨rstner,* Andreas Leitner, Mar´ıa Me´ndez, and Helga Krause
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr,
Germany
Received June 6, 2002. Revised Manuscript Received July 15, 2002
Abstract: Simple iron salts such as FeCln, Fe(acac)n (n ) 2,3) or the salen complex 4 turned out to be
highly efficient, cheap, toxicologically benign, and environmentally friendly precatalysts for a host of cross-
coupling reactions of alkyl or aryl Grignard reagents, zincates, or organomanganese species with aryl and
heteroaryl chlorides, triflates, and even tosylates. An “inorganic Grignard reagent” of the formal composition
[Fe(MgX)2] prepared in situ likely constitutes the propagating species responsible for the catalytic turnover,
which occurs in many cases at an unprecedented rate even at or below room temperature. Because of the
exceptionally mild reaction conditions, a series of functional groups such as esters, ethers, nitriles, sulfonates,
sulfonamides, thioethers, acetals, alkynes, and -CF3 groups are compatible. The method also allows for
consecutive cross-coupling processes in one pot, as exemplified by the efficient preparation of compound
12, and has been applied to the first synthesis of the cytotoxic marine natural product montipyridine 8. In
contrast to the clean reaction of (hetero)aryl chlorides, the corresponding bromides and iodides are prone
to a reduction of their C-X bonds in the presence of the iron catalyst.
Introduction
in the context of parallel synthesis and combinatorial chemis-
try,11 and plays a prominent role in a rapidly growing number
of highly impressive total syntheses of target molecules of
utmost complexity.12,13
The importance of cross-coupling reactions for the formation
of carbon-carbon bonds as well as carbon-heteroatom bonds
can hardly be overestimated.1-9 Within a few decades, this
methodology evolved into a routine tool for the preparation of
fine chemicals and pharmaceutically active compounds in the
laboratory and on the industrial scale,10 is widely appreciated
While a variety of organometallic reagents and organic
electrophiles can be joined by cross-coupling processes, this
field is largely dominated by the use of palladium and nickel
* Address correspondence to this author. E-mail: fuerstner@mpi-
muelheim.mpg.de.
(11) For a timely treatise, see: Handbook of Combinatorial Chemistry: Drugs,
Catalysts, Materials; Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-
VCH: Weinheim, Germany, 2002.
(1) (a) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Cross-Coupling Reac-
tions. A Practical Guide; Miyaura, N., Ed.; Topics in Current Chemistry;
Springer: Berlin, 2002; Vol. 219. (c) Knight, D. W. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
U.K., 1991; Vol. 3, p 481. (d) Palladium in Heterocyclic Chemistry: A
Guide for the Synthetic Chemist; Li, J. J., Gribble, G. W., Eds.; Elsevier:
Oxford, U.K., 2000.
(2) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457.
(3) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (c) Mitchell, T.
N. Synthesis 1992, 803. (d) Duncton, M. A. J.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1999, 1235.
(12) Total syntheses of architecturally complex targets based on cross-coupling
reactions are far too numerous to be covered herein; some of the reviews
cited above provide excellent treatises on this field of applications.
Therefore, only a very limited selection of seminal contributions is given
below. (a) Kishi, Y. Pure Appl. Chem. 1989, 61, 313. (b) Nicolaou, K. C.;
Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem.
Soc. 1993, 115, 4419. (c) Evans, D. A.; Black, W. C. J. Am. Chem. Soc.
1992, 114, 2260. (d) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.;
Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997,
119, 10073. (e) Gyorkos, A. C.; Stille, J. K.; Hegedus, L. S. J. Am. Chem.
Soc. 1990, 112, 8465. (f) Kende, A. S.; Koch, K.; Dorey, G.; Kaldor, I.;
Liu, K. J. Am. Chem. Soc. 1993, 115, 9842. (g) Smith, A. B.; Ott, G. R. J.
Am. Chem. Soc. 1998, 120, 3935. (h) White, J. D.; Tiller, T.; Ohba, Y.;
Porter, W. J.; Jackson, R. W.; Wang, S.; Hanselmann, R. Chem. Commun.
1998, 79. (i) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014. (j) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000,
41, 8371. (k) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(l) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.; Solomon,
M. E.; Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M. Angew. Chem.,
Int. Ed. 1998, 37, 2708. (m) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu,
J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121,
10004. (n) Bringmann, G.; Go¨tz, R.; Keller, P. A.; Walter, R.; Boyd, M.
R.; Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, K. V.; Kelly, T.
R. J. Org. Chem. 1998, 63, 1090. (o) Han, Q.; Wiemer, D. F. J. Am. Chem.
Soc. 1992, 114, 7692. (p) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew.
Chem., Int. Ed. 1998, 37, 1261. (q) Boyce, R. J.; Pattenden, G. Tetrahedron
Lett. 1996, 37, 3501.
(4) Kumada, M. Pure Appl. Chem. 1980, 52, 669.
(5) (a) Negishi, E. Pure Appl. Chem. 1981, 53, 2333. (b) Negishi, E. Acc.
Chem. Res. 1982, 15, 340.
(6) (a) Sonogashira, K. In Metal-catalyzed Cross-coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; p 203. (b)
Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995, 27, 127.
(7) (a) Hiyama, T. In Metal-catalyzed Cross-coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; p 421. (b)
Matsuhashi, H.; Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama,
T. Bull. Chem. Soc. Jpn. 1997, 70, 437. (c) Denmark, S. E.; Sweis, R. F.
J. Am. Chem. Soc. 2001, 123, 6439.
(8) For selected reviews on catalyzed C-heteroatom bond formations, see: (a)
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (b)
Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(9) (a) Kalinin, V. N. Synthesis 1992, 413. (b) Undheim, K.; Benneche, T.
Heterocycles 1990, 30, 1155. (c) Stanforth, S. P. Tetrahedron 1998, 54,
263. (d) Martin, A. R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221. (e)
Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002,
58, 2041. (f) Snieckus, V. Pure Appl. Chem. 1994, 66, 2155.
(10) Beller, M.; Zapf, A.; Ma¨gerlein, W. Chem. Eng. Technol. 2001, 24, 575.
(13) For some examples from our group, see: (a) Fu¨rstner, A.; Weintritt, H. J.
Am. Chem. Soc. 1998, 120, 2817. (b) Fu¨rstner, A.; Konetzki, I. J. Org.
Chem. 1998, 63, 3072. (c) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J.
Org. Chem. 1999, 64, 8275. (d) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J. Org. Chem. 2000, 65, 7990. (e) Fu¨rstner, A.; Dierkes,
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9
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J. AM. CHEM. SOC. 2002, 124, 13856-13863
10.1021/ja027190t CCC: $22.00 © 2002 American Chemical Society

Iron-Catalyzed Cross-Coupling Reactions
A R T I C L E S
complexes as the catalysts.14 They are distinguished by their
wide scope and excellent compatibility with many functional
groups and allow for the reliable transfer of stereochemical
information from the substrates to the products. This profile
usually overcompensates the disadvantages resulting from the
high cost of the palladium precursors, from the need for ancillary
ligands rendering the catalysts sufficiently reactive, from
concerns about the toxicity of nickel salts, and from the extended
reaction times, which are necessary in many cases.
The best substrates for palladium- and nickel-catalyzed cross-
coupling reactions are aryl (alkenyl) iodides, bromides, and
triflates. Only recently have special ligands been designed that
allowed for the scope of these methods to extend to aryl
chlorides, which are the most attractive starting materials due
to their low cost and ready accessibility on a large scale.15,16
Some of these ligands, however, are expensive and/or sensitive
to oxygen and moisture. In view of the foregoing, there remains
ample opportunity to improve upon existing cross-coupling
methodology. In the following, we summarize our investigations
aiming at the development of an alternative strategy based on
the use of iron salts as simple yet highly effective substitutes
for established palladium and nickel catalysts.17 They are not
only very cheap and toxicologically benign, account for short
reaction times even if the cross-coupling reactions are carried
out at or below room temperature, but also allow for activation
of a host of aryl chlorides, triflates, and even tosylates under
“ligand free” conditions.
preceded by publications of Kochi et al., who proposed the use
of iron salts for similar purposes.20 Surprisingly though, the iron-
based methodology attracted much less attention and remained
essentially limited to cross-couplings of Grignard or orga-
nomanganese reagents with alkenyl halides,21 alkenyl sulfones,22
acid chlorides or thiolesters,23 and allylic phosphates;24,25
thereby, the contributions of Cahiez deserve particular mention-
ing, which include demonstrating the generality of the iron-
catalyzed vinylation process and first recognizing the advantages
associated with the use of NMP as a cosolvent.21a-c Successful
applications to aryl halides as substrates, however, have not been
reported.26 Moreover, the mechanism of the iron-catalyzed cross-
coupling remained rather obscure, whereas detailed insights into
most of the prominent palladium- and nickel-catalyzed manifolds
have been gained over the years.1,14,27 It has been speculated
that Fe(0) or Fe(+I) species constitute the catalytically relevant
intermediates, although no secured information as to their
structure or mode of action could be obtained.20,28 Alternatively,
“super-ate” complexes of Fe(+II) have been suggested as the
active species.29
Recent advancements in the field of “inorganic Grignard
reagents”,30 however, render these hypotheses highly unlikely
and call for a re-evaluation of iron-catalyzed cross-coupling
(18) (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.
(19) (a) Yamamura, M.; Moritani, I.; Murahashi, S.-I. J. Organomet. Chem.
1975, 91, C39. (b) Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun.
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Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. (d)
Negishi, E.; van Horn, D. E. J. Am. Chem. Soc. 1977, 99, 3168.
(20) (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.
(21) (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199. (b) Cahiez, G.;
Marquais, S. Pure Appl. Chem. 1996, 68, 53. (c) Dohle, W.; Kopp, F.;
Cahiez, G.; Knochel, P. Synlett 2001, 1901. (d) Molander, G. A.; Rahn, B.
J.; Shubert, D. C.; Bonde, S. E. Tetrahedron Lett. 1983, 24, 5449. (e)
Fu¨rstner, A.; Brunner, H. Tetrahedron Lett. 1996, 37, 7009. (f) Fakhakh,
M. A.; Franck, X.; Hocquemiller, R.; Figade`re, B. J. Organomet. Chem.
2001, 624, 131. (g) Brinker, U. H.; Ko¨nig, L. Chem. Ber. 1983, 116, 882.
(h) Walborsky, H. M.; Banks, R. B. J. Org. Chem. 1981, 46, 5074.
(22) (a) Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Tetrahedron Lett. 1982, 23,
2469. (b) Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Bull. Soc. Chim. Fr. 1985,
772. (c) Alvarez, E.; Cuvigny, T.; Herve´ du Penhoat, C.; Julia, M.
Tetrahedron 1988, 44, 111. (d) Alvarez, E.; Cuvigny, T.; Herve´ du Penhoat,
C.; Julia, M. Tetrahedron 1988, 44, 119.
Results and Discussion
Organometallic Background. Modern cross-coupling chem-
istry emerged in 1972, when Corriu et al. and Kumada et al.
independendly described nickel-catalyzed reactions of Grignard
reagents with alkenyl- and aryl halides.18 The advantages gained
upon replacing nickel by palladium have been discovered shortly
thereafter.19 These seminal disclosures, however, had been
(14) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley: New York, 2002. (b) Tsuji, J. Palladium Reagents
and Catalysts: InnoVations in Organic Synthesis; Wiley: New York, 1996.
(c) Trost, B. M.; Verhoeven, T. R. In ComprehensiVe Organometallic
Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon:
Oxford, U.K., 1982; Vol. 8, p 799.
(15) (a) Grushin, V. V.; Alper, H. Top. Organomet. Chem. 1999, 3, 193. (b)
Stu¨rmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307.
(16) See the following for leading references and literature cited therein: (a)
Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550. (b) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 9722. (c) Singer, R. A.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 1095. (d) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2000, 122, 4020. (e) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
2719. (f) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123. (g) Fu¨rstner, A.; Leitner, A. Synlett 2001, 290. (h) Zapf,
A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153. (i)
Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360. (j) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J.
Org. Chem. 1999, 64, 3804. (k) Herrmann, W. A.; Reisinger, C.-P.; Spiegler,
M. J. Organomet. Chem. 1998, 557, 93. (l) Weskamp, T.; Bo¨hm, V. P.
W.; Herrmann, W. A. J. Organomet. Chem. 1999, 585, 348. (m) Gsto¨ttmayr,
C. W. K.; Bo¨hm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1363. (n) Huang, J.; Nolan, S. P. J. Am.
Chem. Soc. 1999, 121, 9889. (o) Lee, H. M.; Nolan, S. P. Org. Lett. 2000,
2, 2053. (p) Lipshutz, B. H. AdV. Synth. Catal. 2001, 343, 313. (q) Bei,
X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen, J. L. J. Org.
Chem. 1999, 64, 6797. (r) Reetz, M. T.; Breinbauer, R.; Wanninger, K.
Tetrahedron Lett. 1996, 37, 4499. (s) LeBlond, C. R.; Andrews, A. T.;
Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555. (t) Bedford, R. B.; Cazin,
C. S. J. Chem. Commun. 2001, 1540. (u) Liu, S.-Y.; Choi, M. J.; Fu, G. C.
Chem. Commun. 2001, 2408. (v) Li, G. Y.; Zheng, G.; Noonan, A. F. J.
Org. Chem. 2001, 66, 8677. (w) Botella, L.; Na´jera, C. Angew. Chem.,
Int. Ed. 2002, 41, 179. (x) Li, G. Y.; Marshall, W. J. Organometallics
2002, 21, 590.
(23) (a) Percival, W. C.; Wagner, R. B.; Cook, N. C. J. Am. Chem. Soc. 1953,
75, 3731. (b) Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L.
Tetrahedron Lett. 1984, 25, 4805. (c) Dell’Anna, M. M.; Mastrorilli, P.;
Nobile, C. F.; Marchese, G.; Taurino, M. R. J. Mol. Catal. A: Chem. 2000,
161, 239. (d) Reddy, C. K.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1996,
35, 1700. (e) Ritter, K.; Hanack, M. Tetrahedron Lett. 1985, 26, 1285. (f)
Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Ronzini, L. Tetrahedron
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6017. (b) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett 1991, 513.
(25) Further iron-catalyzed reactions comprise mainly carbometalation processes;
see the following for leading references and literature cited therein: (a)
Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A.
Angew. Chem., Int. Ed. 2001, 40, 621. (b) Nakamura, M.; Hirai, A.;
Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978. (c) See also: Reetz, M.
T.; Stanchev, S. J. Chem. Soc., Chem. Commun. 1993, 328.
(26) After publication of our preliminary communication (ref 17), a report on
iron-catalyzed cross-coupling reactions with a small set of aryl bromides
and one aryl chloride has been published, cf.: Quintin, J.; Franck, X.;
Hocquemiller, R.; Figade`re, B. Tetrahedron Lett. 2002, 43, 3547.
(27) (a) Yamamoto, A. J. Organomet. Chem. 2000, 600, 159. (b) Amatore, C.;
Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 1670. (c) Farina, V.;
Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (d) Casado, A. L.; Espinet,
P.; Gallego, A. M. J. Am. Chem. Soc. 2000, 122, 11771 and literature cited
therein.
(28) Lehr, G. F.; Lawler, R. G. J. Am. Chem. Soc. 1984, 106, 4048.
(29) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 386 and literature
cited therein.
(17) For a preliminary communication, see: Fu¨rstner, A.; Leitner, A. Angew.
Chem., Int. Ed. 2002, 41, 609.
9
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A R T I C L E S
Fu¨rstner et al.
Scheme 1
Scheme 3 32
Scheme 2
less than 5 min at ambient temperature and proceeds even at
-60 °C with similar ease. In striking contrast, highly dispersed
and nonpassivated iron metal Fe(0)* powder35 prepared by
reduction of FeCl3 with potassium does not insert at all into
this substrate at room temperature and reacts only very
reluctantly under more forcing conditions.36 Even if one takes
into account that the Fe(0)* slurry, though highly dispersed,
might be kinetically handicapped as compared to its homoge-
neous counterpart, the immense difference in reactivities renders
bare Fe(0) species as the actual carriers of the catalytic turnover
highly unlikely.
More importantly, however, it was found that the suspension
of finely dispersed Fe(0)* particles in THF slowly dissolVes on
treatment with an excess of n-C14H29MgBr (Scheme 3). The
resulting dark brown-black, homogeneous solution catalyzes the
cross-coupling of substrate 1a (X ) Cl) with the residual
Grignard reagent without incident. This experiment shows that
Fe(0) reacts with organomagnesium reagents to give soluble
species that likely contain the metal in formal oxidation states
< 0, as postulated for [Fe(MgX)2]. The fact that iron can exist
in such low oxidatons states has ample precedence in the
classical work of Collman, who has shown that the structurally
well-defined Fe(-II) complex Na2Fe(CO)4 is a highly nucleo-
philic entity bearing a strong resemblance to an “inorganic
Grignard reagent”.37-39
chemistry in a broader context. It is now well established that
FeCl2 reacts with 4 equiv of R-MgX to give a new species of
the formal composition [Fe(MgX)2], an “inorganic Grignard
reagent”, which is readily soluble in ethereal solvents such as
THF (Scheme 1).31 The available information suggests that
[Fe(MgX)2] consists of small clusters incorporating magnesium
and iron centers that are connected via fairly covalent inter-
metallic bonds. Although more structural details are not known
to date,32 the rigorously established stoichiometry of the reaction
depicted in Scheme 1 implies that the reduction process does
not stop once a zerovalent iron species, Fe(0), is formed but
leads to species bearing a formally negatiVe charge at iron. Such
highly nucleophilic entities lacking any stabilizing ligands are
able to oxidatively add to aryl halides.31,33 The resulting
organometallic iron compounds (formally Fe(0))34 are again
alkylated by the excess of the Grignard reagent in analogy to
the case of the elementary steps passed through during the initial
formation of [Fe(MgX)2] from FeCl2 and RMgX. Subsequent
reductive coupling of the organic ligands should then form the
desired product and regenerate the propagating Fe(-II) species
(Scheme 2). This suggests that iron-catalyzed cross-coupling
reactions might be achieved that are far more general than those
previously described.20-24
Although direct spectroscopic investigations of the actual
intermediates involved in the formal catalytic cycle outlined
above are hampered by various factors, most notably by their
extremely high reactivity, thermal instability causing rapid aging,
and paramagnetic character, experimental evidence for all of
the basic features of such a scenario32 is available. The
assumption that formally negatively charged iron centers rather
than Fe(0) complexes are the catalytically competent species is
supported by the following results. Thus, cross-coupling of
4-chlorobenzoic acid methyl ester 1a (X ) Cl) with n-
tetradecylmagnesium bromide in the presence of 5 mol % FeClx
(x ) 2, 3) as the precatalyst is quantitative (>95% GC) within
It is reasonable to assume the presence of a covalent bond
character between the Fe and Mg centers in such [Fe(MgX)2]
clusters in view of the X-ray structure of [(Cp(dppe)Fe(MgBr)‚
3THF], a well-defined complex containing a covalent Fe-Mg
bond of 2.593(7) Å length.40 Further support comes from
spectroscopic data on the closely related complex [Cp(CO)2Fe-
(35) (a) Rieke, R. D.; Sell, M. S.; Klein, W. R.; Chen, T.; Brown, J. D.; Hanson,
M. V. In ActiVe Metals. Preparation, Characterization, Applications;
Fu¨rstner, A., Ed.; VCH: Weinheim, Germany, 1996; p 1. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. Engl. 1993, 32, 164.
(36) It is known, however, that Fe(0)* inserts into C6F5I within 20 h to give
solvated (C6F5)2Fe and FeI2, cf.: (a) Kavaliunas, A. V.; Rieke, R. D. J.
Am. Chem. Soc. 1980, 102, 5944. (b) Kavaliunas, A. V.; Taylor, A.; Rieke,
R. D. Organometallics 1983, 2, 377.
(37) (a) Collman, J. P. Acc. Chem. Res. 1975, 8, 342. (b) Collman, J. P.; Hegedus,
L. S.; Norton, J. R.; Finke, R. G. Principles and Applications of
Organotransition Metal Chemistry, 2nd ed.; University Science Books: Mill
Valley, CA, 1987.
(38) Na2Fe(CO)4 oxidatively inserts into a variety of organic electrophiles, with
the substrate reactivity resembling classical SN2 reactions. However, it is
not sufficiently reactive to insert into nonactivated aryl halides under mild
conditions. Therefore, Na2Fe(CO)4 cannot substitute the structurally more
elusive [Fe(MgCl)2] as a catalyst in cross-coupling reactions. Its lower
reactivity is likely due to the partial back-bonding of the negative charge
at iron into the empty π* orbitals of the CO ligands.
(30) (a) Aleandri, L. E.; Bogdanovic, B. In ActiVe Metals: Preparation,
Characterization, Applications; Fu¨rstner, A., Ed.; VCH: Weinheim,
Germany, 1996; p 299. (b) Aleandri, L. E.; Bogdanovic, B.; Bons, P.; Du¨rr,
C.; Gaidies, A.; Hartwig, T.; Huckett, S. C.; Lagarden, M.; Wilczok, U.;
Brand, R. A. Chem. Mater. 1995, 7, 1153.
(31) Bogdanovic, B.; Schwickardi, M. Angew. Chem., Int. Ed. 2000, 39, 4610.
(32) As a consequence, the catalytic cycle depicted herein is solely meant as a
mnemotic device giving a formal representation but does not imply any
detailed mechanistic or structural information whatsoever.
(33) Siedlaczek, G.; Schwickardi, M.; Kolb, U.; Bogdanovic, B.; Blackmond,
D. G. Catal. Lett. 1998, 55, 67.
(39) Another interesting similarity in the behavior of Collman’s reagent Na2-
Fe(CO)4 and the presumed [Fe(MgCl)2] species is the pronounced effect
of added NMP on their reactivity. It is known that the nucleophilicity of
Na2Fe(CO)4 is 2 × 104 times higher in NMP than in THF.
(34) Several Fe(0)-alkyl and -aryl compounds are known in the literature; for a
review, see: Segnitz, A. In Methoden der Organischen Chemie (Houben-
Weyl), 4th ed.; Segnitz, A., Ed.; Thieme: Stuttgart, Germany, 1986; Vol.
13/9a, p 175.
(40) (a) Felkin, H.; Knowles, P. J.; Meunier, B.; Mitschler, A.; Ricard, L.; Weiss,
R. J. Chem. Soc., Chem. Commun. 1974, 44. (b) Felkin, H.; Knowles, P.
J.; Meunier, B. J. Organomet. Chem. 1978, 146, 151.
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Iron-Catalyzed Cross-Coupling Reactions
A R T I C L E S
MgBr(THF)n].41 In this context, it should also be mentioned
that several other transition metal-magnesium intermetallic
complexes have been characterized in detail either by X-ray
crystallography42 or by in-depth EXAFS studies,43 all of which
indicate a strongly covalent character for the intermetallic bonds.
Catalyst Optimization and Screening of the Substrate
Scope. Under the premise outlined above that the catalytically
competent iron complexes are highly reduced species, one may
anticipate an inherent competition between oxidative addition
via two-electron-transfer processes and single-electron-transfer
steps opening undesired radical manifolds.
Table 1. Screening of Different Iron Precatalysts (5 mol %) and of
Different Nucleophiles in Cross-Coupling Reactions with Two
Representative Aryl Chlorides
In line with this, the aryl bromide 1b (X ) Br) and iodide
1c (X ) I) mainly afford the reduced product 3 (50% and 46%,
respectively) on treatment with n-C6H13MgBr in the presence
of Fe(acac)3 in THF/NMP, whereas the corresponding chloride
1a (X ) Cl) gives the desired cross-coupling product 2 in
virtually quantitative yield (>95% GC); the isolated yield
amounts to 91% on a gram scale (cf. Experimental Section).
Not only is the conversion finished after less than 5 min of
reaction time at 0 °C but it was also found that the uncatalyzed
attack of the Grignard reagent onto the ester group of the
substrate does not compete at all with the iron-catalyzed cross-
coupling reaction. Gratifyingly, the corresponding triflate 1d
(X ) OTf) and even the tosylate 1e (X ) OTs) perform equally
well, providing product 2 in >95% yield (GC) at unprecedent-
edly high reaction rates. This is a significant advancement in
view of the fact that inexpensive tosylates found hardly any
application in conventional palladium- or nickel-catalyzed cross-
coupling reactions because of their lack of reactivity.44,45
As can be seen from Table 1, the cross-coupling reactions of
two representative substrates are hardly dependent on the chosen
iron precatalyst, with Fe(+II) and Fe(+III) salts being equally
effective; therefore, the cheap and nonhygroscopic Fe(acac)3 is
the most appropriate one from the practical point of view. Only
for sec-alkyl Grignard reagents the use of Fe(salen)Cl 446 is
recommended (entry 2). The method, however, was found to
a GC yields. b Fe(salen)Cl refers to complex 4.
to n-alkyl- and sec-alkylmagnesium halides with g2 carbon
atoms, which uniformly react without incident, trialkylzincates
(entry 3) as well as all types of organomanganese reagents
(RMnX, R2Mn, R3MnMgCl)47 (entries 4-6) constitute equally
suitable nucleophiles. In striking contrast, however, the use of
n-BuLi or Et3Al failed to afford any cross-coupling product.48
We tentatively ascribe this distinct behavior to the need to form
a rather covalent Fe-M (M ) Mg, Zn, Mn) bond in the active
species.
The behaviors of vinyl, allyl, and aryl Grignard reagents as
nucleophiles are more complex.26,49 While attempted cross-
coupling reactions of vinyl- and allylmagnesium bromide with
substrate 1a were in vain, the use of phenylmagnesium bromide
resulted in a low yield of the desired cross-coupling product
but mainly led to biphenyl via oxidative dimerization of the
Grignard reagent (entry 7). Importantly, however, the reaction
of PhMgBr with the heterocyclic chloride 5 was found to be
productive (entry 13); in this case, only small amounts of
biphenyl have been detected in the crude mixture. It is well
established in a series of classical papers of Kharasch et al. that
aryl Grignard reagents are catalytically decomposed with the
formation of biaryls in the presence of transition metal salts if
aryl halides are present in the medium, which act as stoichio-
metric oxidizing agents under these conditions.50 The different
behaviors of aryl chloride 1a and its heteroaryl congener 5 are
be highly responsive to the nature of the nucleophile. In addition
(41) McVicker, G. B. Inorg. Chem. 1975, 14, 2087.
(42) (a) [Cp(H)Mo-MgBr(THF)]: Davies, S. G.; Green, M. L. H.; Prout, K. J.
Chem. Soc., Chem. Commun. 1977, 135. (b) [Cp(η3-C3H5)Co-MgBr-
(THF)2]: Jonas, K.; Koepe, G.; Kru¨ger, C. Angew. Chem., Int. Ed. Engl.
1986, 25, 923.
(43) (a) [Pt(MgCl)2(THF)x]: Aleandri, L. E.; Bogdanovic, B.; Du¨rr, C.; Huckett,
S. C.; Jones, D. J.; Kolb, U.; Lagarden, M.; Rozie`re, J.; Wilczok, U. Chem.s
Eur. J. 1997, 3, 1710. (b) [Ti(MgCl)2(THF)x]: Aleandri, L. E.; Bogdanovic,
B.; Gaidies, A.; Jones, D. J.; Liao, S.; Michalowicz, A.; Rozie`re, J.; Schott,
A. J. Organomet. Chem. 1993, 459, 87.
(44) For very recent examples, see: (a) Terao, J.; Watanabe, H.; Ikumi, A.;
Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. (b) Zim, D.;
Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049. (c) Fu,
X.; Zhang, S.; Yin, J.; McAllister, T. L.; Jiang, S. A.; Tann, C.-H.;
Thiruvengadam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573.
(45) For examples describing the activation of mesylates by Ni(0) complexes,
see: (a) Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531. (b)
Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513. (c) Percec, V.; Bae, J.-
Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.
(47) For reviews on organomanganese compounds, see: (a) Cahiez, G. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; pp 925 and 3227. (b) Normant, J.-F.; Cahiez, G.
In Modern Synthetic Methods; Scheffold, R., Ed.; Sauerla¨nder-Salle:
Frankfurt, Germany, 1983; Vol. 3, p 173. (c) Oshima, K. J. Organomet.
Chem. 1999, 575, 1.
(48) In this context, an early observation reported by Corey and Posner, who
studied cross-coupling processes in the presence of stoichiometric amounts
of FeI2, is relevant. They found that the reaction proceeds with MeLi but
invariably failed with n-butyllithium as the nucleophile, cf.: Corey, E. J.;
Posner, G. H. Tetrahedron Lett. 1970, 11, 315.
(46) Prepared in analogy to: Gerloch, M.; Lewis, J.; Mabbs, F. E.; Richards,
A. J. Chem. Soc. A 1968, 112. For a detailed procedure, see the Supporting
Information.
(49) For a convenient and general method for the cross-coupling of vinyl, allyl,
and alkynyl reagents, see ref 16g and: (a) Fu¨rstner, A.; Seidel, G. Synlett
1998, 161. (b) Fu¨rstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165.
9
J. AM. CHEM. SOC. VOL. 124, NO. 46, 2002 13859

A R T I C L E S
Fu¨rstner et al.
Table 2. Cross-Coupling Reactions of Alkyl Grignard Reagents R-MgBr with Aryl and Heteroaryl Chlorides, Tosylates, and Triflates
(Ar-X)a
a All reactions were carried out in THF/NMP using Fe(acac)3 (5 Mol %) as the catalyst.
deemed to reflect the distinctly lower oxidizing potential of the
latter. One might therefore expect the scope of iron-catalyzed
aryl-aryl cross-coupling reactions to be limited to π-electron-
deficient substrates. This profile will be mapped out in more
detail below.
seen from the results compiled in Table 2, a host of moderately
electron-deficient aryl chlorides and tosylates react with good
to excellent yields. This includes various benzene derivatives
substituted with electron-withdrawing substitutents such as
esters, nitriles, sulfonates, sulfonamides, or -CF3 groups as well
as many heterocyclic compounds of the pyridine, pyrimidine,
triazine, quinoline, isoquinoline, carbazole, purine, pyridazine,
pyrazine, quinoxaline, quinazoline, uracil, thiophene, and even
benzothiazole series.52 Particularly noteworthy is the example
shown in entry 42, in which the chloride function at C-6 of the
per-O-acetylated purine-â-D-ribofuranoside is replaced by the
alkyl group of the Grignard reagent in the presence of catalytic
amounts of Fe(acac)3 as the precatalyst. This example clearly
illustrates that the uncatalyzed attack of the organomagnesium
reagent on the rather labile ester protecting groups in this
substrate obviously does not compete with the efficacy of the
Iron-Catalyzed Alkyl-Aryl Cross-Coupling Reactions.
With regard to the substrate scope, the iron-catalyzed cross-
coupling process of alkylmagnesium halides and aromatic
electrophiles turned out to be widely applicable.51 As can be
(50) (a) Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic
Substances; Prentice Hall: New York, 1954. (b) Kharasch, M. S.; Fields,
E. K. J. Am. Chem. Soc. 1941, 63, 2316. (c) Kharasch, M. S.; Nudenberg,
W.; Archer, S. J. Am. Chem. Soc. 1943, 65, 495.
(51) For a recent review showing the importance of alkyl-aryl cross-coupling
chemistry, see: (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544. (b) Tamao, K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991;
Vol. 3, p 435.
9
13860 J. AM. CHEM. SOC. VOL. 124, NO. 46, 2002

Iron-Catalyzed Cross-Coupling Reactions
A R T I C L E S
Scheme 4 a
Scheme 5
a (a) 8-Nonenylmagnesium bromide, Fe(acac)3 (5 mol %), THF/NMP,
0 °C f rt, 81%. (b) (i) BrCH2COOtBu, 40 °C; (ii) F3CCOOH, Et3SiH,
CH2Cl2, 74%.
Scheme 6
iron-catalyzed activation of the C-Cl bond.53 Importantly, even
the unprotected 6-chloropurine containing an acidic N-H bond
undergoes efficient cross-coupling, although an extra equivalent
of the Grignard reagent is necessary for the initial deprotonation
of this site (entry 41); further support for this notion comes
from the transformation of the N-unprotected chlorocarbazole54
shown in entry 39 which is converted into the 1-ethyl derivative,
an antimicrobially active natural product isolated from various
sources such as the plant Hannoa klaineana and the bryozoa
Costaticella hastata and Cribricellina cribraria.55
marine natural product montipyridine 8.59 The fact that this new
method allows the attachment of unsaturated side chains to arene
rings (Table 2 and Scheme 4) complements existing methodol-
ogy for the preparation of substrates required for our ongoing
studies on alkene and alkyne metathesis.60
Yet, another favorable chemoselectivity aspect is evident from
the example shown in entry 30. Whereas nickel-catalyzed
Kumada-Corriu reactions of Grignard reagents are known to
proceed with thioethers as the substrates,56 the iron-catalyzed
variant described herein rigorously distinguishes between the
C-Cl and the C-S bonds, although the latter resides at an
activated 2-position of the pyrimidine ring. Note, however, that,
in the case of electron-rich arenes, the use of aryl triflates is
necessary (entries 13/14, 17/18, 19, 20). The use to this leaving
group allows for the cross-coupling of even rather unreactive
substrates such as a resorcinol derivative (entry 18)57 or the
dibenzofuran (entry 20) in excellent yields.
Some of the products prepared by iron-catalyzed alkyl-aryl
cross-coupling deserve further comment. As an example, the
long chain alkylbenzene sulfonate, shown in entry 15, serves
as a precursor for a biologically degradable detergent,58 while
Scheme 4 summarizes a convenient synthesis of the cytotoxic
Polysubstitution Reactions and Consecutive Cross-Cou-
pling. Some preliminary experiments show that arenes bearing
more than one leaving group X (X ) Cl, OTf) can either be
exhaustively or selectively cross-coupled with suitable Grignard
reagents. Compound 9 (X ) Cl, OTf) served as a prototype
example (Scheme 5). Its treatment with an excess of n-C6H13-
MgBr in the presence of Fe(acac)3 affords the dihexylpyridine
derivative 10 in 73% yield after just 5 min of reaction time.
This outcome must be seen in the light of an experiment
previously described in the literature, in which the reaction of
9 (X ) Cl) with n-C4H9MgBr catalyzed by [NiCl2(dppp)]
required 6 h of reaction time in refluxing Et2O to give 63% of
the corresponding dialkylpyridine derivative 11.61 The obvious
difference in the reaction rates of the iron- versus the nickel-
catalyzed process is fairly representative.
The transformation depicted in Scheme 6 highlights another
favorable aspect of the iron-based cross-coupling methodology.
Isobutylmagnesium bromide (1.1 equiv) was added to a solution
of substrate 9 (X ) OTf) and Fe(acac)3 catalyst in THF/NMP
at 0 °C; after stirring for only 3 min at that temperature, a
solution of n-C14H29MgBr was introduced and the reaction
product was isolated after an overall reaction time of only 8
min, providing product 12 in 71% yield derived from the
consecutive cross-coupling of the two different Grignard
reagents. This example illustrates not only the exceptional
efficiency of this new methodology but also opens new vistas
for practical yet selective polyfunctionalization reactions to be
carried out in “one pot”.
(52) For selected references on conventional cross-coupling reactions of such
substrates, see: (a) Thorsett, E. D.; Stermitz, F. R. J. Heterocycl. Chem.
1973, 10, 243. (b) Pridgen, L. N. J. Heterocycl. Chem. 1975, 12, 443. (c)
Ohsawa, A.; Abe, Y.; Igeta, H. Chem. Pharm. Bull. 1978, 26, 2550. (d)
Yamanaka, H.; Edo, K.; Shoji, F.; Konno, S.; Sakamoto, T.; Mizugaki, M.
Chem. Pharm. Bull. 1978, 26, 2160. (e) Bonnet, V.; Mongin, F.; Tre´court,
F.; Que´guiner, G.; Knochel, P. Tetrahedron 2002, 58, 4429. (f) Bo¨hm, V.
P. W.; Weskamp, T.; Gsto¨ttmayr, C. W. K.; Herrmann, W. A. Angew.
Chem., Int. Ed. 2000, 39, 1602. (g) Babudri, F.; Florio, S.; Ronzini, L.;
Aresta, M. Tetrahedron 1983, 39, 1515. (h) Piccolo, O.; Martinengo, T.
Synth. Commun. 1981, 11, 497.
(53) For a related nickel-catalyzed cross-coupling reaction with a ribofuranosyl
purine in which the hydroxyl groups of the sugar moiety are protected as
more stable tert-butyldimethylsilyl ethers, see: Bergstrom, D. E.; Reddy,
P. A. Tetrahedron Lett. 1982, 23, 4191.
(54) Bracher, F.; Hildebrand, D. Liebigs Ann. Chem. 1992, 1315.
(55) (a) Lumonadio, L.; Vanhaelen, M. Phytochemistry 1984, 23, 453. (b)
Blackman, A. J.; Matthews, D. J.; Narkowicz, C. K. J. Nat. Prod. 1987,
50, 494. (c) Prinseps, M. R.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod.
1991, 54, 1068. (d) Bamgbose, S. O. A.; Dramane, K. L.; Okogun, J. I.
Planta Med. 1977, 31, 193. (e) Bracher, F.; Hildebrand, D. Liebigs Ann.
Chem. 1993, 1335. (f) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 3325.
Iron-Catalyzed Aryl-Heteroaryl Cross-Coupling Reac-
tions. As outlined above, the iron-catalyzed cross-coupling of
aryl Grignard reagents is more senstitive to the chosen elec-
(59) Alam, N.; Hong, J.; Lee, C. O.; Im, K. S.; Son, B. W.; Choi, J. S.; Choi,
W. C.; Jung, J. H. J. Nat. Prod. 2001, 64, 956.
(56) Review: Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89.
(57) For a study on the synthesis and biological activity of alkylresorcinol
derivatives, see: (a) Fu¨rstner, A.; Seidel, G. J. Org. Chem. 1997, 62, 2332.
(b) Fu¨rstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem.sEur. J. 2002,
8, 1856 and literature cited therein.
(58) Kosswig, K. In Ullmann’s Encyclopedia of Industrial Chemistry; VCH:
Weinheim, Germany, 1994; Vol. A25, p 747.
(60) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Fu¨rstner, A.;
Mathes, C.; Lehmann, C. W. Chem.sEur. J. 2001, 7, 5299. (c) Fu¨rstner,
A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108
and literature cited therein.
(61) Tamao, K.; Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.; Suzuki,
K. Tetrahedron 1982, 38, 3347.
9
J. AM. CHEM. SOC. VOL. 124, NO. 46, 2002 13861

A R T I C L E S
Fu¨rstner et al.
Table 3. Cross-Coupling Reactions of Aryl Grignard Reagents
R-MgBr with Heteroaryl Chlorides Ar-Clc
1-3), which exhibit potency as inhibitors of platelet-derived
growth factor receptor tyrosine kinase.64 In terms of yields, the
results compiled in Table 3 are comparable to those obtained
in related palladium- or nickel-catalyzed cross-coupling reactions
of aryl Grignard reagents with π-deficient heterocycles previ-
ously described in the literature,52 whereas the reaction rates of
the iron-catalyzed processes are usually much higher.
Conclusions and Outlook. The reducing ability of Grignard
reagents is one of the major limiting factors in “standard” cross-
coupling reactions of these nucleophiles in the presence of
palladium complexes as catalysts, causing the precipitation of
palladium black and, hence, the arrest of the catalytic turnover.
In sharp contrast, this propensity is the key to success for the
iron-catalyzed processes described herein. These reactions likely
involve highly reduced iron-magnesium intermetallic species
as the actual catalysts formed in situ and proceed at unprec-
edentedly high rates at ambient temperature or below. The fact
that aryl chlorides, triflates, and tosylates are inherently better
substrates than the corresponding bromides or iodides represents
a major advantage in practical terms. The favorable profile of
this new method is further increased by the low cost as well as
the toxicologically and environmentally benign character of the
iron salts used as precatalysts.
Although one may object that the high reactivity of the
C-MgX bond restricts the scope of the iron-catalyzed cross-
coupling methodology, the rapidly growing number of func-
tionalized Grignard reagents65 becoming readily available hold
promise that the method presented herein may bring even
polyfunctional products into reach. The same pertains to the
yet not fully explored potential of functionalized zincates or
manganese reagents as nucleophiles. Further work along those
lines is currently in progress in this laboratory.
a Isolated yield. b Using Fe(salen)Cl 4 as the catalyst. c All reactions were
carried out in THF using Fe(acac)3 (5 mol %) as the catalyst unless stated
otherwise.
Experimental Section
trophile and is preferentially carried out in THF in the absence
of NMP as cosolvent. While electron-rich aryl halides tend to
fail, giving rise to the homocoupling of the Ar-MgX only, the
reaction is applicable to various π-electron-deficient hetero-
cycles.26 This is evident from the data compiled in Table 3,
which include examples from the pyrimidine, pyrazine, triazine,
isoquinoline, quinoxaline, and quinazoline series. In all cases,
varying amounts of biphenyl are formed as byproduct, which
is easily separated by flash chromatography because of its
different polarity. Likewise, cross-coupling with pyridine-3-
magnesium bromide or 2-thienylmagnesium bromide has been
achieved in good yield, whereas reaction with mesitylmagnesium
bromide failed for steric reasons. The results must be seen in
the context of the rapidly growing interest in azine and diazine
natural products, pharmaceuticals, and building blocks for
supramolecular chemistry or material science.62 Special men-
tionings are deserved for 2-phenylquinoline (entry 7), as a simple
alkaloid of the stem bark of Galipea longiflora with potential
antileishmanial activity,63 and the aryl quinoxalines (entries
General Procedures. For details, see the Supporting Infor-
mation.
Representative Procedure for an Iron-Catalyzed Alkyl-
Aryl Cross-Coupling Reaction. Synthesis of 4-Hexylbenzoic
Acid Methyl Ester. A flame-dried two-necked flask is charged
under argon with 4-chlorobenzoic acid methyl ester 1a (1.00 g,
5.86 mmol), Fe(acac)3 (103 mg, 0.29 mmol), THF (35 mL),
and N-methylpyrrolidone (NMP, 3.3 mL). A solution of
n-hexylmagnesium bromide (2 M in Et2O, 3.5 mL, 7.00 mmol)
is added via syringe to the resulting red solution, causing an
immediate color change to dark brown and then finally to violet.
The resulting mixture is stirred for 5-10 min, and the reaction
is diluted with Et2O and is carefully quenched upon the addition
of aq HCl (1M, ∼10 mL). Standard extraction followed by flash
chromatography of the crude product (hexanes/ethyl acetate, 30:
1) provides the title compound as a colorless syrup (1.24 g,
(64) Gazit, A.; App, H.; McMahon, G.; Chen, J.; Levitzki, A.; Bohmer, F. D.
J. Med. Chem. 1996, 39, 2170.
(65) See the following for leading references and literature cited therein: (a)
Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 565. (b) Sapountzis, I.; Knochel, P. Angew.
Chem., Int. Ed. 2002, 41, 1610. (c) Boudier, A.; Bromm, L. O.; Lotz, M.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414. (d) Rottla¨nder, M.;
Boymond, L.; Be´rillon, L.; Lepreˆtre, A.; Varchi, G.; Avolio, S.; Laaziri,
H.; Que´guiner, G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem.s Eur. J. 2000,
6, 767. (e) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.; Rottla¨nder,
M.; Knochel, P. J. Org. Chem. 2000, 65, 4618. (f) Lee, J.; Velarde-Ortiz,
R.; Guijarro, A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428.
(g) Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2000, 39, 2481.
(62) (a) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059. (b) Turck, A.;
Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489. (c)
Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Heterocycl.
Chem. 1991, 52, 187.
(63) (a) Filippi, J. Bull. Soc. Chim. Fr. 1968, 268. (b) Crisp, G. T.; Papadopoulos,
S. Aust. J. Chem. 1989, 42, 279. (c) Fournet, A.; Vagneur, B.; Richomme,
P.; Bruneton, J. Can. J. Chem. 1989, 67, 2116. (d) Koyama, J.; Toyokuni,
I.; Tagahara, K. Chem. Pharm. Bull. 1999, 47, 1038. (e) Fournet, A.;
Barrios, A. A.; Munoz, V.; Hocquemiller, R.; Cave, A.; Bruneton, J.
Antimicrob. Agents Chemother. 1993, 37, 859.
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Iron-Catalyzed Cross-Coupling Reactions
A R T I C L E S
91%). Its analytical and spectroscopic data are in excellent
agreement with those published in the literature.66 1H NMR (300
MHz, CDCl3) δ 7.90 (d, J ) 8.3 Hz, 2H), 7.19 (d, J ) 8.4 Hz,
2H), 3.84 (s, 3H), 2.59 (t, J ) 7.7 Hz, 2H), 1.57 (m, 2H), 1.21-
1.29 (m, 6H), 0.84 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.1, 148.4, 129.2, 128.7, 127.6, 51.8, 35.9, 31.2,
31.0, 28.9, 22.5, 13.9; IR ν 1724 cm-1; MS (EI) m/z (rel
intensity) 220 (50, [M+]), 189 (39), 150 (100), 91 (54), 43 (17).
Representative Procedure for an Iron-Catalyzed Aryl-
Heteroaryl Cross-Coupling Reaction. Synthesis of 2-Phenyl-
quinoxaline. A flame-dried two-necked round-bottom flask is
charged under Ar with 2-chloroquinoxaline (300 mg, 1.82
mmol), the Fe(salen)Cl complex 4 (29 mg, 0.09 mmol), and
THF (10 mL), and the mixture was cooled to -30 °C. A solution
of phenylmagnesium bromide (1 M in THF, 4.2 mL, 4.2 mmol)
is added via syringe to the resulting red solution, causing an
immediate color change to dark brown-black. The resulting
mixture is stirred for 10 min, and the reaction is then diluted
with Et2O and is carefully quenched with brine. Standard
extraction followed by flash chromatography (hexanes/EtOAc,
13:1) provides the title compound as a colorless solid (275 mg,
73%). mp ) 73-75 °C (lit.67 77-78 °C). 1H NMR (400 MHz,
CDCl3) δ 9.32 (s, 1H), 8.21-8.10 (m, 4H), 7.79-7.71 (m, 2H),
7.58-7.49 (m, 3H); 13C NMR (100 MHz, CDCl3) (DEPT) δ
151.79 (C), 143.26 (CH), 142.27 (C), 141.54 (C), 136.75 (C),
130.20 (CH), 130.12 (CH), 129.59 (CH), 129.47 (CH), 129.09
(CH), 127.51 (CH); IR ν 3061, 1545, 1488, 1486, 1313, 769,
750, 687 cm-1; MS (EI) m/z (rel intensity) 206 (100, [M+]),
179 (36), 152 (5), 103 (12), 76 (19), 50 (9).
Acknowledgment. Generous financial support by the Deut-
sche Forschungsgemeinschaft (Leibniz award to A.F.) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
We thank Prof. B. Bogdanovic for valuable discussions con-
cerning the preparation and reactivity of inorganic Grignard
reagents.
Supporting Information Available: Compilation of the
analytical and spectroscopic data of all new compounds.
Procedure for the preparation of the iron-salen complex 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA027190T
(66) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9950.
(67) Bannore, S. N.; Bose, J. L. Indian J. Chem. 1973, 11, 631.
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