C O M M U N I C A T I O N S
Table 2. Iron-Catalyzed Coupling Reaction of an Alkyl Halide with
an Aryl Grignard Reagent
with complete loss of the optical purity, the results indicate that
the reaction is not a simple nucleophilic substitution but rather
involves a radical-related reaction.
a
Stereochemical probes provided further mechanistic insight. The
arylation of exo-2-bromonorbornene proceeded in high yield with
retention of the stereochemistry (entry 17). trans- and cis-1-Bromo-
4-tert-butylcyclohexane reacted to give the product of the same
diastereomeric composition rich (96%) in the more stable trans-
product (entries 18-19). These results suggest that the intermediate
responsible for the C-C bond-forming step undergoes stereochem-
ical mutation and is rather bulky. One plausible possibility is an
“
iron-bound radical” intermediate as suggested for living radical
8,9
polymerization under iron and ruthenium catalysis. This hypoth-
esis would merit further consideration from mechanistic and
synthetic viewpoints.
A useful feature of the present reaction is the functional group
compatibility. Functional groups, such as alkoxycarbonyl and
N-indolyl group (entries 20-21), as well as alkenyl and alkynyl
groups (data not shown) in the alkylating reagent survive under
the reaction.
Acknowledgment. We thank the Ministry of Education, Culture,
Sports, Science, and Technology of Japan for financial supports, a
Grant-in-Aid for Specially Promoted Research, a Grant-in-Aid for
Young Scientists (A) (KAKENHI 14703011) and 21st Century COE
Program for Frontiers in Fundamental Chemistry. K.M. thanks
Hayashi Memorial Foundation for Female Natural Scientists for a
predoctoral fellowship.
Supporting Information Available: Experimental details and
spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(
(
(
1) Cf. Holleman, A. F. Lehrbuch der Organischen Chemie; Vereinigung
Wissenschaftlicher Verleger: Berlin and Leipzig, 1920.
2) Cf. Kuwajima, I.; Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1982,
1
04, 1025-1030.
3) (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2002,
4
1, 4137-4139. (b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
1
4726-14727.
a
The reaction was carried out at a 1 mmol scale under the slow-addition
(4) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-
694. (b) Donkervoort, J. D.; Vicario, J. L.; Jastrzebski, J. T. B. H.; Gossage,
R. A.; Cahiez, G.; van Koten, G. J. Orgnomet. Chem. 1998, 558, 61-69.
(c) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
b
conditions unless otherwise noted. Reaction temperature was 0 °C in entries
1
-3, 11, 14, and 17-21 and 25 °C in entries 4-10, 12, and 15 unless
c
otherwise noted. 1.2 equiv of Grignard reagent was used unless otherwise
noted. The yield refers to the one determined by GC or H NMR with an
internal standard unless otherwise noted. See details in Supporting Informa-
tion. Isolated yield. The large-scale experiment in the text using 1.3 equiv
of Grignard reagent. 1.5 equiv of Grignard reagent was used. 2.0 equiv
2
002, 41, 4056-4059. (d) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu,
d
1
H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222-4223. (e) Terao, J.;
Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646-
5647. A recent review see: C a´ rdenas, D. J. Angew. Chem., Int. Ed. 2003,
42, 384-387.
e
f
g
h
i
(5) (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122,
978-979. (b) Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E. Org.
Lett. 2003, 5, 1373-1375.
of Grignard reagent was used. Grignard reagent was added to a mixture
j
of bromocyclohexane, FeCl3, and TMEDA. 1.8 equiv of Grignard reagent
was used. k The reaction temperature was 40 °C. l 0.5 mmol scale.
(6) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487-1489.
(b) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron 1994, 50.
6
1
1
2
017-6028. (c) Reddy, C. K.; Knochel, P. Angew. Chem., Int. Ed. Engl.
996, 35, 1700-1701. (d) Cahiez, G.; Avedissian, H. Synthesis 1998,
199-1205. (e) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett
001, 1901-1903. (f) F u¨ rstner, A.; Leitner, A.; M e´ ndez, M.; Krause, H.
Acyclic secondary alkyl halides gave similar results with those
of cyclic ones, while 2-chlorobutane turned out to be less reactive
and required 1.5 equiv of Grignard reagent and slightly higher
temperature (40 °C) (entries 11-13). Interestingly, primary alkyl
halides are much less reactive than the corresponding secondary
halides. 1-Iodooctane and 1-bromooctane gave octylbenzene in high
yield, but the corresponding chloride gave the desired product in
only 45% yield because of the formation of octane and octenes
J. Am. Chem. Soc. 2002, 124, 13856-13863. (g) F u¨ rstner, A.; M e´ ndez,
M, Angew. Chem., Int. Ed. 2003, 42, 5355-5357.
(
3
7) Other additives including phosphine ligands and other iron catalysts (FeF ,
Fe(BF
Information for details.
4 3 3 2 5
) , Fe(acac) , FeCl , Fe(CO) ) were not effective. See Supporting
(
8) Wakioka, M.; Baek, K.-Y.; Ando, T.; Kamigaito, M.; Sawamoto, M.
Macromolecules 2002, 35, 330-333 and references therein.
(9) The iron-catalyzed cross-coupling of 6-bromo-1-hexene with PhMgBr gave
exclusively hex-5-enylbenzene (65%) under the slow-addition conditions
at 25 °C. Under the conditions shown in eq 1 (at 25 °C), however, the
product of a 5-exo-radical-cyclization/coupling process was obtained in
(ca. 50% yield) (entries 14-16). Tertiary halides were consumed
as rapidly as secondary halides but gave a mixture of the reduction
and the elimination products. Combined with the fact that the
reaction of (S)-2-bromooctane (99.5% ee) with PhMgBr took place
1
0% yield along with the formation of hex-5-enylbenzene (52%).
JA049744T
J. AM. CHEM. SOC.
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