Iron-catalyzed grignard cross-coupling with alkyl halides possessing β-hydrogens

Article abstract of DOI:10.1021/ol049779y

Tris(acetylacetonato)iron(III) (Fe(acac)₃) was found to be an efficient catalyst for the cross-coupling reaction between aryl Grignard reagents and alkyl halides possessing β-hydrogens. The reaction is applicable to secondary alkyl halides as well as primary ones.

Full text of DOI:10.1021/ol049779y

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1297-1299
Iron-Catalyzed Grignard Cross-Coupling
with Alkyl Halides Possessing
â-Hydrogens
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 February 7, 2004
ABSTRACT
Tris(acetylacetonato)iron(III) (Fe(acac)3) was found to be an efficient catalyst for the cross-coupling reaction between aryl Grignard reagents
and alkyl halides possessing â-hydrogens. The reaction is applicable to secondary alkyl halides as well as primary ones.
Transition-metal-catalyzed Grignard cross-coupling with
organic halides is one of the most powerful tools for
constructing a new carbon-carbon bond.1 During the past
three decades, a wide variety of transition-metal catalysts,
based mostly on nickel or palladium metal, have been
demonstrated to be effective for this useful transformation.
Surprisingly, much less attention has been paid to less
expensive iron catalysts for Grignard cross-coupling. Since
Kochi’s pioneering work,2 several reports appeared on iron-
catalyzed cross-coupling,3,4 but they are mostly concerned
with the C(sp2)-X compounds as coupling partners,5 except
one specific example where 2-bromocyclobutanone ethylene-
glycol ketal is the coupling partner.6 Considering the recent
growing interest in cross-coupling with alkyl halides,7-9 it
is important to develop an iron-based catalyst system for this
(4) (a) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
(b) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc.
2002, 124, 13856. (c) Quintin, J.; Franck, X.; Hocquemiller, R.; Figade`re,
B. Tetrahedron Lett. 2002, 43, 3547. (d) Fu¨rstner, A.; Leitner, A. Angew.
Chem., Int. Ed. 2003, 42, 308. (e) Fu¨rstner, A.; Me´ndez, M. Angew. Chem.,
Int. Ed. 2003, 42, 5355. (f) Fu¨rstner, A.; De Souza, D.; Parra-Rapado, L.;
Jensen, J. T. Angew. Chem., Int. Ed. 2003, 42, 5358.
(5) Kochi reported that the reaction between alkyl Grignard reagents and
alkyl halides in THF gave mainly disproportionation products alkanes and
alkenes; thus, no further study for synthetic use was carried out. See ref
2a,c.
(6) Brinker, U. H.; Ko¨nig, L. Chem. Ber. 1983, 116, 882.
(1) For a review: Metal-catalyzed Cross-coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(7) Difficulty of using alkyl halide for cross-coupling has been reviewed,
see: (a) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018. (b) Luh,
T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. ReV. 2000, 100, 3187. (c)
Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384.
(2) (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.
K. 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.
(3) (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) Felkin, H.; Meunier, B. J. Organomet. Chem. 1978,
146, 169. (h) Walborsky, H. M.; Banks, R. B. J. Org. Chem. 1981, 46,
5074.
(8) (a) Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099. (b) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 1945. (c) Netherton, M. R.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 3910. (d) Frisch, A. C.; Shaikh, N.; Zapf, A.;
Beller, M. Angew. Chem., Int. Ed. 2002, 41, 4056. (e) Kirchhoff, J. H.;
Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
13662. (f) Menzel, K.; Fu, G. C.; J. Am. Chem. Soc. 2003, 125, 3718. (g)
Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. (h) Zhou, J.; Fu,
G. C. J. Am. Chem. Soc. 2003, 125, 12527. (i) Zhou, J.; Fu, G. C. J. Am.
Chem. Soc. 2003, 125, 14726. (j) Tang, H.; Menzel, K.; Fu, G. C. Angew.
Chem., Int. Ed. 2003, 42, 5079. (k) Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 1340. (l) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 82.
10.1021/ol049779y CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/13/2004

cross-coupling reaction. Here, we wish to report a new iron-
catalyzed cross-coupling which provides a general method
of forming a carbon-carbon bond between aryl Grignard
reagents and alkyl halides.
Scheme 1. Plausible Mechanism for the Aryl-Alkyl Coupling
As a first set of experiments, several reaction conditions
were examined for the iron-catalyzed reaction of 5-phenyl-
1-bromopentane (2m) with p-tolylmagnesium bromide (1a)
(2.0 equiv) (Table 1). The conditions reported to be best for
Table 1. Distribution of Products in the Reaction of 1a with
2m
reagent, gives alkyliron species B. Transmetalation of an aryl
group from magnesium to iron forming diorganoiron C
followed by reductive elimination of the cross-coupling
product regenerates A. The formation of alkene 4, alkane 5,
and 4,4′-bitolyl (6) as the side products gives us significant
information on the mechanism of the present cross-coupling.
Considering that 5% yield (one equivalent to Fe(acac)3) of
6 is formed at the reduction of catalyst precursor Fe(acac)3,11
the molar ratio of 5 to 6 formed in the catalytic cycle is
always about 1:1 regardless of the reaction conditions (see
Table 1). The amount of 4 is more than that of 5 or 6. These
results can be rationalized by the disproportionation of the
alkyliron halide intermediate B giving dialkyliron D and
dihalide E, which will produce the same amount of alkene
4, alkane 5, and the biaryl 6. The alkene 4 is also provided
by â-hydrogen elimination on the intermediates B and C,
resulting in the formation of more 4 than 5 or 6.
The present iron-catalyzed cross-coupling was applicable
to octyl chloride, iodide, and tosylate under the same
conditions as described above (in refluxing ether for 0.5 h),
although the yields are lower than that for octyl bromide
(2n) (entries 1-4 in Table 2). The cross-coupling of aryl
Grignard reagents substituted with methoxy (1b) and fluoro
(1c) with 2n proceeded as well without troubles (entries 5
and 6). Introduction of methyl groups onto the ortho positions
of the phenyl Grignard reagents resulted in somewhat lower
yield of the cross-coupling products 3dn and 3en (entries 7
and 8). It is noteworthy that secondary alkyl bromides are
good coupling partners as well as the primary alkyl bromides
in this iron-catalyzed reaction. Acyclic and cyclic secondary
alkyl bromides 2p and 2q gave the corresponding cross-
coupling products in around 70% yield on reaction with the
Grignard reagent 1a (entries 10 and 11). Although the yield
product (mmol)
entry
solvent
2m
3a m
4a
5
6b
1
2
3
4c
THF/NMP
THF
Et2O
0.15
0.25
0.27
0.60
0.69
0.25
0.37
0.19
0.18
0.24
0.20
0.12
0.09
0.26
0.25
0.12
0.08
0
0
0
Et2O
a A mixture of olefinic isomers in which 4 is the major component. b The
amount (0.05 mmol) of 6 formed at the reduction of Fe(acac)3 is subtracted
from the total amount of 6 after the catalytic reaction (see ref 11). c The
reaction was carried out in refluxing Et2O.
the cross-coupling of alkyl Grignard reagents with aryl4a,b
and alkenyl halides3a did not fit in well with the present
reaction of the alkyl halide. Thus, the reaction in the presence
of 5 mol % of Fe(acac)3 in THF/NMP (NMP ) N-
methylpyrrolidone) at 20 °C for 0.5 h gave only 25% yield
of the cross-coupling product, 5-phenyl-1-p-tolylpentane
(3am) (entry 1). The alkyl bromide 2m was converted mainly
into 5-phenyl-1-pentene (4) (25%) and 1-phenylpentane (5)
(24%). The formation of a considerable amount of 4,4′-bitolyl
(6) was also observed. The reaction in THF gave similar
results (entry 2). Use of diethyl ether as a solvent in place
of THF greatly improved the yield of the cross-coupling
product 3am (entries 3 and 4). The yield of 3am was
increased to 60% and the formation of side products 4 and
5 was suppressed to some extent. In refluxing ether, the yield
of 3am was 69%.
Based on the mechanism generally accepted for the cross-
coupling reactions catalyzed by transition metals including
iron, a catalytic cycle for the present cross-coupling is
illustrated in Scheme 1. Thus, the oxidative addition of alkyl
halide to a low-valent iron intermediate A,10 which is
generated by the reaction of Fe(acac)3 with the Grignard
(10) In the iron-catalyzed Grignard cross-coupling, Fe(I), Fe(II), and
Fe(-II) species are proposed as catalytically active species: See ref 4b
and references therein.
(11) On addition of an excess amount of p-tolylmagnesium bromide (1a)
to Fe(acac)3 in the absence of alkyl bromides in ether, the formation of
4,4′-bitolyl (6) in an amount equivalent to Fe(acac)3 was observed.
(9) (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J.
Am. Chem. Soc. 2002, 124, 4222. (b) Terao, J.; Ikumi, A.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646. (c) Terao, J.; Naitho, Y.;
Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32, 890.
1298
Org. Lett., Vol. 6, No. 8, 2004

nickel complexes reported recently.8i,k Unfortunately, tertiary
alkyl bromide did not give the cross-coupling product (entry
12).
Table 2. Iron-Catalyzed Coupling of Arylmagnesium Bromide
(1) with Alkyl Halide (2)a
During our studies on the cross-coupling, it was found
that aryl triflates are not reactive toward iron-catalyzed cross-
coupling under the present reaction conditions. It is rather
surprising because Fu¨rstner recently reported4a,b the cross-
coupling of aryl triflates with the alkyl Grignard reagents
by use of the same Fe(acac)3 as a catalyst precursor. Taking
advantage of this finding, a chemoselective cross-coupling
was realized for the substrate 7 which possesses both aryl
triflate and alkyl bromide moieties (Scheme 2). Thus, the
Scheme 2. Iron-Catalyzed Chemoselective Cross-Coupling
reaction of 7 with p-tolylmagnesium bromide (1a) catalyzed
by Fe(acac)3 in refluxing ether gave 69% yield of the cross-
coupling product at the alkyl bromide, leaving the triflate
group intact. The triflate 8 was subjected to the iron-catalyzed
cross-coupling with butylmagnesium bromide according to
Fu¨rstner’s procedures4a,b to give a high yield of the butylated
product 9.
In summary, we have demonstrated that the cross-coupling
between aryl Grignard reagents with primary and secondary
alkyl bromides possessing â-hydrogens is efficiently cata-
lyzed by Fe(acac)3 in refluxing diethyl ether. The choice of
the solvent is very important in this reaction, the reaction in
THF or THF/NMP causing undesired side reactions.
Acknowledgment. This work was 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.
a The reaction was carried out with ArMgBr (1.04 mmol), RX (0.52
mmol), and Fe(acac)3 (0.026 mmol) in refluxing ether for 0.5 h. Alkyl
halides were completely consumed in all entries. b Isolated yield. c Major
side products are 1-octene and octane. d No cross-coupling product was
detected by GC-MS analysis of the crude material.
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.
is still not satisfactory, it is comparable to that obtained in
the reaction with secondary alkyl bromides catalyzed by
OL049779Y
Org. Lett., Vol. 6, No. 8, 2004
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