C O M M U N I C A T I O N S
functionalizations of π-deficient nitrogen heteroaromatics.12 Reac-
tions with other electrophiles (benzaldehyde and pivalaldehyde) also
proceeded maintaining the regioselectivities (4b,c, 6b′,c, 8b,c, eqs
2-4).13 Benzaldehyde functioned only as an electrophile, and
deprotonative functionalization of benzaldehyde was not observed.
The regioselectivities of these reactions with azines are quite
noteworthy. The reactions proceeded at the most remote position
from the ring nitrogens, and pyridazine and pyrimidine display
unique regioselectivities in deprotonative functionalization, which
is the opposite of the directed ortho metalation.1,11 In H-D exchange
of azines, similar kinetic acidities have been reported. The pair-
pair electron repulsion is present in the transition state for
deprotonation, and that is considered to be a reason for the acidity
pattern.14 We have a speculation that unique regioselectivities of
reactions with t-Bu-P4 base may be the result of the same effect of
pair-pair electron repulsions.
Intrigued by the exciting results of azines, we then investigated
the deprotonative functionalization of benzene derivatives. 4-Bro-
mobenzonitrile (9) was treated with t-Bu-P4 base in the presence
of benzophenone and ZnI2 in toluene, and the reaction proceeded
chemoselectively at the 3-position (10a)15 in 55% yield (60% yield
in THF). Without ZnI2, the reaction did not proceed (eq 5, Table
1). Surprisingly, the orientation of the reaction is the opposite of
the deprotonative metalation using TMP-zincate.16 Reactions with
other electrophiles were also examined. Benzaldehyde and pivala-
ldehyde were used as electrophiles in the reaction of 4-bromoben-
zonitrile (9) in THF, and the appropriate 1,2-adducts (10b,c)15 were
obtained in 86%, 87% yield, respectively (eq 5, Table 1).
References
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Table 1. Deprotonative Functionalization of 4-Bromobenzonitrile
(9) An interesting reaction of benzothiazole with t-Bu-P4 base has been
reported in ref 6a. Also, similar chemistry of thiazoles without metallic
bases has been developed with 2-(trimethysilyl)thiazoles, see: (a) Pink-
erton, F. H.; Thames, S. F. J. Heterocycl. Chem. 1971, 8, 257-259. (b)
Dondoni, A. Pure Appl. Chem. 1990, 62, 643-652.
(10) For deprotonative functionalizations of 3-bromopyridine using a metallic
base, see: (a) Effenberger, F.; Daub, W. Chem. Ber. 1991, 124, 2119-
2125. (b) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151-
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(11) The deprotonative functionalization of pyridazine and pyrimidine using a
metallic base has been reported, see: Ple´, N.; Turck, A.; Couture, K.;
Que´guiner, G. J. Org. Chem. 1995, 60, 3781-3786.
a One equivalent of t-Bu-P4 base was uitilized.
(12) Deprotonative functionalizations of azines often have undesirable side
reactions: Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajin, J. AdV.
Heterocycl. Chem. 1991, 52, 187-304.
In summary, a novel type of deprotonative functionalization of
aromatics was achieved with unique regioselectivities and excellent
chemoselectivity using t-Bu-P4 base and ZnI2 in the presence of
an electrophile. Further investigations on the scope and limitations
of this reaction and mechanistic studies, especially on the role of
ZnI2, are underway.
(13) The reaction of pyridazine with benzaldehyde provided benzoyl product
6b′ via deprotonative functionalization and subsequent oxidation, not the
expected alcohol.
(14) Zoltewicz, J. A.; Grahe, G.; Smith, C. L. J. Am. Chem. Soc. 1969, 91,
5501-5505.
(15) The regiochemistry of 10a-c was determined by a reduction reaction in
the presence of a Pd catalyst and ammonium formate, and the debromi-
nated products were identified by comparing them with authentic
specimens and analogues.
(16) The deprotonative metalation of 4-bromobenzonitrile with TMP-zinc-
ate and subsequent treatment with benzaldehyde yielded 5-bromo-
3-phenylphthalide via deprotonative zincation at the 2-position with a
trace amount of the 3-adduct: Imahori, T.; Kondo, Y., unpublished
data.
Acknowledgment. This work was partly supported by a Grant-
in-Aid for Scientific Research (No. 14044008) from the Ministry
of Education, Science, Sports and Culture, Japan.
Supporting Information Available: Experimental details and
spectroscopy of the products (PDF). This material is available free of
JA0342300
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