C O M M U N I C A T I O N S
Table 2. Metalation of Various Functionalized Organic Halidesa
zinc exchange reactions turned out to proceed with complete selec-
tivity in iodine(bromine)-triflate mixed substrates (entries 14 and
15).
In conclusion, this report describes a new and highly chemose-
lective procedure for the halogen-metal exchange reaction of
functionalized benzene derivatives containing an ester, amide, or
acidic proton. A wide variety of substrates could be readily metal-
ated under mild and operationally simple reaction conditions, and
the metalated aromatic intermediates could be utilized effectively
for C-C bond formation or transmetalation without any protection.
We are continuing work to expand the scope and synthetic utility
of this methodology and to elucidate the reaction mechanism and
the origin of the unique selectivity with the help of theoretical and
spectroscopic studies.
Acknowledgment. This research was partly supported by the
Astellas Foundation, the Sumitomo Foundation, and a Grant-in-
Aid for Young Scientists (A) from JSPS (to M.U.). We thank Prof.
T. Ohwada for his valuable comments, and Mr. S. Arimoto for
technical assistance.
Supporting Information Available: Experimental procedures and
characterizations (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) Gilman, H. Organic Chemistry; John Wiley and Sons: New York, 1943.
(
2) Increasing attention has been devoted to the protecting-group-free synthesis
driven by the development of powerful and chemoselective transforma-
tions. For example, see: (a) Baran, P. S.; Richter, J. M. J. Am. Chem.
Soc. 2005, 127, 15394. (b) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem.
Commun. 2004, 2288. (c) Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Org.
Biomol. Chem. 2004, 2, 110.
(
3) (a) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2005,
127, 13116. (b) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem.
Soc. 2004, 126, 11146. (c) Kobayashi, M.; Matsumoto, Y.; Uchiyama,
M.; Ohwada, T. Macromolecules 2004, 37, 4339. (d) Uchiyama, M.;
Matsumoto, Y.; Nakamura, S.; Ohwada, T.; Kobayashi, N.; Yamashita,
N.; Matsumiya, A.; Sakamoto, T. J. Am. Chem. Soc. 2004, 126, 8755. (e)
Uchiyama, M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.;
Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514. (f) Uchiyama,
M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934.
(
4) (a) Beak, P.; Musick, T. J.; Chen, C. W. J. Am. Chem. Soc. 1988, 110,
3538. (b) Gallagher, D. J.; Beak, P. J. Am. Chem. Soc. 1991, 113, 7984.
1
13
7
t
(
5) The H, C, and Li NMR spectra of ca. 1.0 M Bu
4
ZnLi
Zn and BuLi (2 equiv) in THF) in THF at -100 °C each
show only singlets (Supporting Information), indicative of a single species.
2
(prepared by
t
t
mixing Bu
2
t
In all the NMR spectra of ca. 1.0 M Bu
4
ZnLi
Zn were detected. The addition
ZnLi solution showed two signals
corresponding to the signal of BuLi and that of Bu
Furthermore, we measured the ESI-MS spectrum of ca. 1.0 M THF
2
in THF at -100 °C, no
t
t
signals corresponding to free BuLi or Bu
2
t
t
of 1 more equiv of BuLi to the Bu
4
2
a
t
Unless otherwise noted, the metalation was carried out using Bu4ZnLi2
1.1 equiv) and substrate (1.0 equiv) in THF under the given conditions,
t
t
4
ZnLi
2
at -100 °C.
(
+
-
and the resultant metalated intermediate was treated with E (allyl bromide
solution of the zincate, and the peak (M ) 299.26), which could be
or benzaldehyde). Isolated yield. Zincate (2.2 equiv) was used. d Benzyl
b
c
t
-
attributed to [ Bu
4
ZnLi] (C16
H
27ZnLi ) 299.22), was clearly observed.
alcohol was obtained as a major product.
The isotopic pattern of this peak was fully consistent with that of
t
-
[
Bu
4
ZnLi] (C16H27ZnLi) (see below). In addition, our preliminary density
functional theory (DFT) study also suggested that the ate complexation
3f
t
t
reaction, essentially no side reaction was observed under our reac-
tion conditions, due to the high chemoselectivity of this reagent. A
π-deficient heteroaromatic moiety also caused no problem (entry
reaction of two molecules of BuLi and one molecule of Bu
2
Zn to give
is energetically favored, that is, highly exothermic (38.4 kcal/
mol; B3LYP/6-31+G(d) and SVP for Zn).
t
4 2
Bu ZnLi
8).
Other organic halides, including bromobenzenes and an alkyl-
iodide, can be also utilized in the halogen-zinc exchange reaction.
Importantly, an iodine moiety is preferable for high chemoselectivity
and mild conditions. In the case of bromobenzene derivatives, higher
reaction temperatures were required for the exchange reactions to
proceed completely. Therefore, in the reaction of p-bromobenzyl
t
alcohol with Bu
4
ZnLi
2
, deprotonation reaction took place prior to
bromine-zinc exchange, and the desired C-C bond formation was
not observed at all (entry 13).
Finally, to investigate the chemoselectivity of this interconver-
(6) The C-C bond-forming reaction with the use of other zincates or
alkyllithiums did not proceed under the same reaction conditions, but
instead undesired reactions occurred.
t
sion, the reactivities of Bu
4
ZnLi
2
with aromatic chloride, triflate,
and halogen-triflate mixed substrates were examined: aromatic
chloride or triflate did not react at all (not shown), and the halogen-
JA058246X
J. AM. CHEM. SOC.
9
VOL. 128, NO. 26, 2006 8405