at the expense of 3.18 In the absence of any distinguish-
able differences of a successful reaction that generates 3
to a failed reaction producing hydrolysis products 7 and
8, we proposed that the ratio of monomer 2a to trimer
2b might be critical to the halodeboronation reaction.
Solutions of arylboronic acids are known to exist in
equilibrium with their cyclic anhydrides;19 however, we
1
were unable to determine the ratio of 2a /2b by H, 13C,
19F, or 11B NMR due to the reaction complexity. A sim-
plified model system using commercially available 4-fluo-
rophenylboronic acid (9a ) and tris(4-fluorophenyl)borox-
ine (9b) was used to evaluate our hypothesis (Scheme
4).20 A clear difference in reactivity was observed between
9a and 9b toward halogenation under our reaction condi-
tions. 4-Bromofluorobenzene (10) was formed in only 24%
yield when trimer 9b was brominated with DBDMH
versus an 88% yield of 10 for the bromination of boronic
acid 9a . Chlorination of 9a and 9b with 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) gave 4-chlorofluorobenzene
(11) in 70% and 14% yield, respectively. We then rea-
soned that the use of a base should increase the reactivity
of the trimer toward bromination by formation of the
more nucleophilic borate.21 Indeed, addition of stoichio-
metric NaOMe to trimer 9b increased the yield of 10 to
55% and 11 to 25% after 8 h. Since compound 2a /2b has
shown particular instability in solutions with a basic pH
(g 8.0), catalytic NaOMe was examined in the halode-
boronation of 9b and found to promote the formation of
10 and 11 in remarkably high yields.22
F IGURE 1.
SCHEME 3. Or th om eta la tion -Br om in a tion of
3-F lu or oben zon itr ile
would permit greater control over the exothermic bro-
mination. Although synthesis of the requisite 3-fluoro-
2-(trimethylsilyl)benzonitrile was accomplished,11 treat-
ment of the aryl silane with elemental bromine or DB-
DMH gave only traces of 3.12 Similar results were an-
ticipated for the halodeboronation of 2-cyano-6-fluorophen-
ylboronic acid, since bromination of electron-deficient aryl
boronic acids typically result in formation of the aryl
bromide in poor yields.10d 2-Cyano-6-fluorophenylboronic
acid was prepared as an indeterminable mixture of mon-
omer 2a and trimer 2b (Figure 1)13 in 75% yield by the
addition of LDA to a THF solution of 1 and B(O-i-Pr)3 at
0 °C.14,15 Since the bromodeboronation of 2a /2b failed in
THF, other solvents were evaluated and acetonitrile was
the solvent of choice. After a solvent switch to acetonitrile
via constant volume distillation, bromide 3 was formed
in good yield (65%) by the slow addition of DBDMH to
the boronic acid/anhydride mixture at 25 °C.16,17
Application of the base-catalyzed procedure to the 2a /
2b mixture reproducibly afforded an 85-90% yield of
bromide 3.23-25 More importantly, acetonitrile solutions
of 2a /2b that previously gave hydrolysis products 7 and
8 now provide bromide 3 in 85-90% yield. Based on these
(14) (a) Kristensen, J .; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435-1437. (b) Caron, S.; Hawkins, J . M. J . Org. Chem. 1998,
63, 2054-2055. (c) Li, W.; Nelson, D.; J ensen, M.; Hoerrner, R. S.; Cai,
D.; Larsen, R.; Reider, P. J . Org. Chem. 2002, 67, 5394-5397.
(15) The formation of 3-fluoro-N,N-diisopropylbenzamide was mini-
mized by this addition sequence. While a one-pot deprotonation/
bromination process could be envisioned, an appropriate brominating
agent that is unreactive towards LDA, such as 1,2-dibromotetrafluo-
roethane, was required. 1,2-Dibromotetrafluoroethane is currently
prohibited from use by the EPA under the Clean Air Act 1990 because
of its adverse effects on stratospheric ozone.
(16) Bromination of the crude diisopropyl boronic ester without an
aqueous workup was examined and gave 3 after 2 h at 40 °C in good
yield (79%), but poor purity. However, this route was not amenable to
large-scale synthesis since ester hydrolysis, followed by acid/base
extractions proved necessary to remove the reaction impurities (e.g.,
ethylbenzene introduced from commercial LDA was polybrominated).
Furthermore, a thick, difficult to stir slurry formed upon solvent switch
from THF to acetonitrile.
(17) For discussions regarding the mechanism of boron substitution,
see: (a) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567-
570. (b) Brown, H. C.; Hamaoka, T.; Ravindran, N. J . Am. Chem. Soc.
1973, 95, 6456-6457.
(18) A combined yield of 7 and 8, as much as 100% with respect to
2, has been observed. An apparent pH of 5.0-6.5 (pH test strip) and
a 2.5-5.0% water content (as determined by Karl Fisher titration) were
required of the acetonitrile solution in order to achieve reproducible
results in the bromination reaction. Less water required an extended
age period for the reaction to go to completion (2-12 h) and resulted
in a lower yield of 3 while more water resulted in an increase in
decomposition products.
Upon scale-up of this chemistry, nitrile hydrolysis
products 7 and 8 formed occasionally and unpredictably
(8) The alkylhalide byproducts formed in the reaction were difficult
to remove by distillation and inhibited the crystallization of 3.
(9) (a) Felix, G.; Dunogue`s, J .; Pisciotti, F.; Calas, R. Angew. Chem.,
Int. Ed. Engl. 1977, 16, 488-489. (b) Bennetau, B.; Rajarison, F.;
Dunogue`s, J .; Babin, P. Tetrahedron 1993, 49, 10843-10854. (c) Coe,
P.; Stuart, A.; Moody, D. J . Fluorine Chem. 1998, 92, 27-32.
(10) (a) Ainley, A. D.; Challenger, F. J . Chem. Soc. 1930, 2171-
2180. (b) Melnikoff, N. N. J . Gen. Chem. U.S.S.R. 1936, 6, 636. (c)
Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.; Somayaji, V. Org. Prep.
Proced. Int. 1982, 14, 359-362. (d) Thiebes, C.; Prakash, G. K. S.;
Petasis, N.; Olah, G. Synlett 1998, 2, 141-142.
(11) Fluoro-2-(trimethylsilyl)benzonitrile was prepared by the slow
addition of LDA to a THF solution of 1 and chlorotrimethylsilane at 0
°C.
(12) To a solution of 3-fluoro-2-(trimethylsilyl)benzonitrile in THF
or acetonitrile was added either bromine or DBDMH. The reaction was
heated to 40 °C, aged for several hours, and monitored by HPLC.
(13) While standard instrumental analyses (LC, LC/MS, GC/MS, 1H
NMR, 13C NMR, 19F NMR, or 11B NMR) only resulted in ambiguous
structural assignments of 2-cyano-6-fluorophenylboronic acid, a mix-
ture of monomer 2a , tris(2-cyano-6-fluorophenyl)boroxine (2b ), and
various oligomers could all be present in solution.
(19) (a) Senda, T.; Ogasawara, M.; Hayashi, T. J . Org. Chem. 2001,
66, 6852-6856. (b) Tokunaga, Y.; Ueno, H.; Shimomura, Y.; Seo, T.
Heterocycles 2002, 57, 787-790.
(20) 4-Fluorophenylboronic acid (9a ) was obtained from commercial
sources as mixture of monomer 9a (66%) and trimer 9b (34%). Tris-
(4-fluorophenyl)boroxine (9b) was obtained from commercial sources
and analysis by 1H and 11B NMR showed mostly trimer 9b (86%) while
the remainder of the material is monomer 9a .
J . Org. Chem, Vol. 69, No. 2, 2004 567