Iron-catalyzed oxidative homo-coupling of aryl grignard reagents

Article abstract of DOI:10.1021/ol047509+

(Chemical Equation Presented) Iron-catalyzed homo-coupling of aryl Grignard reagents was successfully developed. A variety of aryl Grignard reagents were efficiently converted into the corresponding symmetrical biaryls in the presence of 1-5 mol % FeCl₃ and a stoichiometric amount of 1,2-dichloroethane.

Full text of DOI:10.1021/ol047509+

ORGANIC
LETTERS
2005
Vol. 7, No. 3
491-493
Iron-Catalyzed Oxidative Homo-Coupling
of Aryl Grignard Reagents
Takashi Nagano and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp
Received December 4, 2004
ABSTRACT
Iron-catalyzed homo-coupling of aryl Grignard reagents was successfully developed. A variety of aryl Grignard reagents were efficiently converted
into the corresponding symmetrical biaryls in the presence of 1−5 mol % FeCl3 and a stoichiometric amount of 1,2-dichloroethane.
Oxidative homo-coupling of aryl-metal reagents is one of
the most efficient synthetic methods for the construction of
a symmetrical biaryl backbone.1 A wide variety of transition
metal halides such as TiCl4,2 TlCl,3 VO(OEt)Cl2,4 FeCl3,5
CoCl2,6 and CuCl27 have been used as oxidants in stoichio-
metric amounts, and catalytic use of the metals in combina-
tion with reoxidants such as molecular oxygen and dibromo-
alkanes has been also examined.8-10 Recent research interests
in oxidative homo-coupling have been limited to palladium-
or copper-catalyzed reactions of organoboron,8 silicon,9 and
tin10 reagents. In the course of our studies on the iron-
catalyzed cross-coupling reaction between aryl Grignard
reagents and alkyl halides possessing â-hydrogens, we found
that homo-coupling of arylmagnesium reagents took place
as a main side reaction, where iron is a catalyst and alkyl
halides act as stoichiometric reoxidants (Scheme 1).11 Homo-
Scheme 1. Homo-Coupling of Grignard Reagents as a Side
(1) (a) AdVanced Organic Chemistry, 4th ed.; March, J., Eds.; John Wiley
& Sons: New York, 1992; pp 725-726. (b) Kauffmann, T. Angew. Chem.,
Int. Ed. Engl. 1974, 13, 219. (c) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(2) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. Tetrahedron
2000, 56, 9601.
Reaction in Iron-Catalyzed Cross-Coupling
(3) (a) McKillop, A.; Elsom, L. F.; Taylor, E. C. J. Am. Chem. Soc.
1968, 90, 2423. (b) Elsom, L. F.; McKillop, A.; Taylor, E. C. Organic
Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 488.
(4) (a) Ishikawa, T.; Ogawa, A.; Hirao, T. Organometallics 1998, 17,
5713. (b) Hirao, T. Coord. Chem. ReV. 2003, 237, 271.
(5) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(6) Kharasch, M. S.; Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316.
(7) Sakellarios, E.; Kyrimis, T. Ber. Dtsch. Chem. Ges. 1924, 57B, 322.
(8) (a) Rao, V. V. R.; Kumar, C. V.; Devaprabhakara, D. J. Organomet.
Chem. 1979, 179, C7. (b) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994,
59, 33. (c) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996,
61, 2346. (d) Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio, S.;
Naeslund, C. G. M.; Deacon, G. B. Synlett 1997, 131. (e) Koza, D. J.;
Carita, E. Synthesis 2002, 2183. (f) Kabalka, G. W.; Wang, L. Tetrahedron
Lett. 2002, 43, 3067. (g) Klingensmith, L. M.; Leadbeater, N. E. Tetrahedron
Lett. 2003, 44, 765. (h) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A.
Tetrahedron Lett. 2003, 44, 1541. (i) Punna, S.; D´ıaz, D. D.; Finn, M. G.
Synlett 2004, 2351. See also ref 9b.
coupling as a side reaction has also been observed in the
literature dealing with iron-catalyzed cross-coupling reac-
tions.12 However, there have been no reports on the selective
homo-coupling of organometallics by iron catalysis. Herein
we report an efficient and practical reaction system for the
iron-catalyzed oxidative homo-coupling of Grignard reagents.
10.1021/ol047509+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/11/2005

Several reaction conditions were examined for the iron-
catalyzed oxidative homo-coupling of 4-methylphenylmag-
nesium bromide (1a) (Table 1). It was found that inexpensive
Table 2. Iron-Catalyzed Oxidative Homo-Coupling of
Grignard Reagentsa
Table 1. Iron-Catalyzed Homo-Coupling of
4-Methylphenylmagnesium Bromide (1a)a
entry
solvent
temp (°C)
oxidant
yield (%)
1
2
3
4
5
6b
Et2O
THF
benzene
THF
THF
Et2O
reflux
rt
40
0
ClCH2CH2Cl (2a)
2a
2a
2a
BrCH2CH2Br (2b)
2a
100
96
99
83
75
99
0
reflux
a Reactions were carried out with 0.52 mmol of 1a. b With 15.0 mmol
of 1a in the presence of 1 mol % FeCl3 for 9 h. Biaryl 3a was isolated by
vacuum sublimation.
1,2-dichloroethane (2a) is an excellent oxidant for the homo-
coupling, giving 4,4′-dimethylbiphenyl (3a) in high yields.
Thus, in the presence of 5 mol % FeCl3 and 1.2 equiv of 2a,
the homo-coupling of the Grignard reagent 1a was complete
in 1 h, in refluxing diethyl ether (entry 1), in THF at room
temperature (entry 2), or in benzene at 40 °C (entry 3), to
afford a quantitative yield of the biaryl 3a. Use of 1,2-
dibromoethane (2b) also gave homo-coupling product 3a
without formation of cross-coupling products, although the
yield of 3a was slightly lower (entry 5). The present oxidative
homo-coupling with 1,2-dichloroethane (2a) can be readily
scaled up to the reaction of 15.0 mmol of the Grignard
reagent 1a using 1 mol % of the FeCl3 catalyst, which gave
99% yield (1.35 g) of biaryl 3a without any byproducts (entry
6).
Table 2 summarizes the results obtained for the oxidative
homo-coupling of other aryl Grignard reagents. Introduction
of methyl groups at the ortho-positions of the aryl Grignard
reagents resulted in somewhat lower yields of the homo-
coupling products (entries 1-3). 4-Methoxy- and 2-methoxy-
phenylmagnesium bromide can be efficiently converted into
the corresponding biaryls 3d and 3e, respectively, under
similar conditions (entries 4 and 5). It is noteworthy that
the present reaction system is tolerant of aryl chloride
functionality (entry 6). Although sterically demanding sub-
a Unless otherwise noted, the reactions were carried out using aryl
Grignard reagents (0.52 mmol), 1,2-dichloroethane (0.62 mmol), and FeCl3
(0.026 mmol) in refluxing Et2O (3 mL). b Isolated yield after column
chromatography. c In THF at room temperature. d In benzene at 60 °C.
strates 1g and 1h required higher reaction temperature and/
or longer reaction time, they gave the corresponding biaryls
3g and 3h in moderate to good yields (entries 7 and 8).
A proposed mechanism for the present iron-catalyzed
homo-coupling is shown in Scheme 2. Oxidative addition
of 1,2-dichloroethane to a low-valent iron complex A,13
generated by the reaction of FeCl3 with Grignard reagent,
forms an alkyl iron intermediate B. â-Halogen elimination
giving ethylene14 and dihaloiron species C,15 followed by
(9) (a) Kang, S.-K.; Kim, T.-H.; Pyun, S.-J. J. Chem. Soc., Perkin Trans.
1 1997, 797. (b) Yamaguchi, S.; Ohno, S.; Tamao, K. Synlett 1997, 1199.
(10) (a) Kanemoto, S.; Matsubara, S.; Oshima, K.; Utimoto, K.; Nozaki,
H. Chem. Lett. 1987, 5. (b) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth,
G. P. J. Org. Chem. 1993, 58, 5434. (c) Shirakawa, E.; Nakao, Y.; Murota,
Y.; Hiyama, T. J. Organomet. Chem. 2003, 670, 132. See also ref 9b.
(11) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(12) (a) Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1971, 31, 289.
(b) Felkin, H.; Meunier, B. J. Organomet. Chem. 1978, 146, 169. (c)
Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002,
124, 13856. (d) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3638.
(13) In the iron-catalyzed Grignard cross-coupling, Fe(I), Fe(II), and
Fe(-II) species are proposed as catalytically active species: see ref 12c
and references therein.
(14) Generation of ethylene was confirmed by trapping the evolved gas
with bromine, which gave 1,2-dibromoethane. See also ref 15.
492
Org. Lett., Vol. 7, No. 3, 2005

Scheme 2. Mechanism for Iron-Catalyzed Homo-Coupling
Scheme 3. Homo-Coupling Reaction Utilizing Directed
Ortho-Metalation
transmetalation of the aryl group from magnesium to iron,
affords a diaryliron intermediate D. Reductive elimination
of the homo-coupling product regenerates catalytically active
species A.
for phenyloxazoline 6, which gave the corresponding biaryl
7 in 63% yield.
Combination of the heteroatom-directed ortho-metalation
technique16 and the present homo-coupling provides a new
one-pot route to 2,2′-disubstituted biaryls (Scheme 3). For
example, methoxymethyl-protected phenol 4 was treated with
n-BuLi to generate the ortho-lithiated phenol derivative.17
Metal exchange with anhydrous magnesium bromide fol-
lowed by subjection to the present homo-coupling reaction
gave the corresponding biaryl 5 in 71% isolated yield.
Transformation of the aryllithium to the corresponding
arylmagnesium reagent is essential for the homo-coupling.
Reaction of the aryllithium reagent under the same conditions
resulted in only 13% yield of the biaryl.18 The ortho-
metalation and homo-coupling sequence was also successful
In summary, we have developed a new and practical
reaction system for oxidative homo-coupling of Grignard
reagents using FeCl3 as a catalyst precursor and 1,2-
dichloroethane as a reoxidant. This reaction system is
applicable to the homo-coupling of various aryl Grignard
reagents and is readily amenable to a large-scale synthesis
of biaryl compounds.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research, the Ministry of
Education, Japan. T.N. thanks the Japan Society for the
Promotion of Science for the award of a fellowship for
graduate students.
(15) For â-Cl elimination on the â-chloroalkyliron species, see: Boone,
H. W.; Athey, P. S.; Mullins, M. J.; Philipp, D.; Muller, R.; Goddard, W.
A. J. Am. Chem. Soc. 2002, 124, 8790.
(16) For a recent review on directed ortho-metalation, see: Snieckus,
V. Chem. ReV. 1990, 90, 879.
(17) Rice, J. E.; Cai, Z,-W. J. Org. Chem. 1993, 58, 1415.
(18) Low yield was also observed in the homo-coupling of phenyllithium
giving biphenyl (38% yield, ether reflux for 1 h).
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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