Regioselective aromatic borylation in an inert solvent.

Article abstract of DOI:10.1021/ol0162668

[reaction: see text]. A protocol for performing Rh catalyzed aromatic borylations in cyclohexane has been devised. Borylation at the 5-position of several 1,3-substituted aromatic species ranging from electron-rich (1,3-(NMe(2))(2)C(6)H(4)) to electron-deficient (1,3-(CF(3))(2)C(6)H(4)) yields the corresponding aryl boronate esters. Veratrole was selectively borylated at the 4-position, thus extending regioselectivity to 1,2-substituted benzenes. Selective borylation at the 3-position of an N-protected pyrrole has also been demonstrated, providing a valuable reagent for cross-coupling reactions in a single step.

Full text of DOI:10.1021/ol0162668

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2831-2833
Regioselective Aromatic Borylation in
an Inert Solvent†
Man Kin Tse, Jian-Yang Cho, and Milton R. Smith, III*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
smithmil@msu.edu
Received June 12, 2001
ABSTRACT
A protocol for performing Rh catalyzed aromatic borylations in cyclohexane has been devised. Borylation at the 5-position of several 1,3-
substituted aromatic species ranging from electron-rich (1,3-(NMe2)2C H ) to electron-deficient (1,3-(CF3)2C H ) yields the corresponding aryl
6
4
6 4
boronate esters. Veratrole was selectively borylated at the 4-position, thus extending regioselectivity to 1,2-substituted benzenes. Selective
borylation at the 3-position of an N-protected pyrrole has also been demonstrated, providing a valuable reagent for cross-coupling reactions
in a single step.
Boronic esters and acids are versatile synthons in organic
chemistry. In addition to their role in cross-coupling reac-
tions,1 they also exhibit potent protease inhibition2 and have
been incorporated in chemical sensing schemes.3 Aryl
boronic acids are most economically prepared by reacting
aryl Grignard or aryllithium reagents with trialkyl borates,
followed by hydrolytic workup. Miyaura4 and Masuda5 have
described some clever arylboronate ester syntheses where
the generation of Grignard and lithium reagents is avoided
by using metal catalysts to effect the desired transformation
from borane reagents and halogenated arenes. Since the
halogenated arenes required for these approaches must be
synthesized from hydrocarbon feedstocks, direct routes to
the arylboron reagents from hydrocarbons are attractive.
From calculated BDE’s for B-H, C-H, and B-C bonds,
we realized that synthesis of aryl boronic esters from boranes
and arenes should be feasible, and in 1999 we reported the
first metal-catalyzed reaction of a borane and an arene to
effect the transformation in eq 1.6 It is interesting to note
Ar-H + (RO)2B-H f Ar-B(OR)2 + H2
(1)
that Knochel and co-workers reported uncatalyzed C-H
activations involving alkyl boranes shortly thereafter.7 We
quickly learned that both the Ir precatalysts from our initial
report and the Rh precatalyst that was subsequently utilized
by Hartwig and co-workers8 gave approximately statistical
distributions of meta and para isomers in the borylation of
monosubstituted arenes.6b This apparent steric directing effect
† Preliminary results have been presented: Smith, M. R., III; Cho, J.-Y.
Abstracts of Papers, Pacifichem 2000, Honolulu, HI, December 14-19, 2000;
American Chemical Society: Washington, DC, 2000; INOR 600.
(1) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(2) Palombella, V. J.; Conner, E. M.; Fuseler, J. W.; Destree, A.; Davis,
J. M.; Laroux, F. S.; Wolf, R. E.; Huang, J. Q.; Brand, S.; Elliott, P. J.;
Lazarus, D.; McCormack, T.; Parent, L.; Stein, R.; Adams, J.; Grisham, R.
B. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 15671-15676.
(3) (a) Davis, C. J.; Lewis, P. T.; McCarroll, M. E.; Read, M. W.; Cueto,
R.; Strongin, R. M. Org. Lett. 1999, 1, 331-334. (b) Lewis, P. T.; Davis,
C. J.; Cabell, L. A.; He, M.; Read, M. W.; McCarroll, M. E.; Strongin, R.
M. Org. Lett. 2000, 2, 589-592.
(4) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510. (b) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2000, 611,
392-402.
(5) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2000, 65, 164-168.
(6) (a) Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 1999, 121,
7696-7697. (b) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem.
Soc. 2000, 122, 12868-12869.
(7) (a) Laaziri, H.; Bromm, L. O.; Lhermitte, F.; Gschwind, R. M.;
Knochel, P. J. Am. Chem. Soc. 1999, 121, 6940-6941. (b) Bromm, L. O.;
Laaziri, H.; Lhermitte, F.; Harms, L.; Knochel, P. J. Am. Chem. Soc. 2000,
122, 10218-10219. (c) Varela, J. A.; Pen˜a, D.; Goldfuss, B.; Polborn, K.;
Knochel, P. Org. Lett. 2001, 3, 2395-2398.
(8) Chen, H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995-1997.
10.1021/ol0162668 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/08/2001

Scheme 1
Table 1. Isolated Yields (Based on HBPin) of Arylboronate
Esters from Catalytic Arene Borylations in Cyclohexane Using 2
mol % of Precatalyst 1
can be exploited to selectively derivatize 1,3-substituted
arenes at the 5-position and 1,2-substituted arenes at the
4-position (Scheme 1). The observed selectivity for 1,3-
substituted arenes is particularly important because selective
functionalizations at the 5-position of m-xylene, and more
electron-rich 1,3-substituted arenes, are generally limited to
substitutions by sterically hindered electrophiles.9,10
In 1998, a noteworthy exception was reported by Berry
and co-workers, who developed Ru- and Rh-catalyzed
syntheses of arylsilanes via dehydrogenative coupling of
arenes and silanes where yields were substantially improved
by adding an olefin to provide a hydrogen “sink”.11 An
advantage of the borylation chemistry is that sacrificial olefin
acceptors are not required. Nevertheless, both borylation and
silylation methodologies are important in preparing partners
for coupling reactions.
Our initial reports used the substrate as solvent.6 While
this is not a significant problem for inexpensive substrates
such as benzene, for nonvolatile or valuable substrates the
use of an inert solvent would be preferable. Thus, we have
developed a simple protocol for preparing arylboronate esters
in good to moderate yields where the aromatic substrate is
the limiting reagent. In addition, we have expanded the scope
of selective meta borylation of 1,3-substituted benzenes and
have extended the borylation chemistry to protected pyrrole.
For this study, we used Hartwig’s precatalyst, Cp*Rh(η4-
C6Me6) (1),8 whose reactivity we recently compared to Ir
precatalysts that were utilized in our earlier report on the
catalytic aromatic borylation of C-H bonds. Although the
Ir precatalysts seem to be more selective, their effective
turnover numbers are too low for practical applications. The
preferential activation of the stronger aryl C-H bonds in
the presence of weaker benzylic C-H bonds is significant,
particularly in light of Marder and co-worker’s recent report
a Diborylated isomers were not separated. b Isomer mixture containing
small amounts of PhBPin. c 1,3,4-(OMe)2C6H3(BPin) was isolated in 2%
yield. d m-C6H4(Me)(CH2BPin) was isolated in 6% yield.
of selective benzylic borylation using the precatalyst trans-
Rh(Cl)(PiPr3)2(N2).12 Since solutions of 1 do not readily
borylate secondary or tertiary C-H positions, cyclohexane
was an obvious choice for an inert solvent. Indeed, catalytic
borylations in cyclohexane using 2 mol % of 1 with a modest
excess of pinacolborane (HBPin) gave boronate esters in
reasonable yields (Table 1). Reactions were performed in
sealed vessels at 150 °C until 11B NMR spectra indicated
that most of the borane had been consumed. Crude mixtures
were analyzed by GC-MS and the reported yields are for
isolated products. In cases where isomers were produced,
(9) (a) Voronenkov, A. V.; Aliev, A. A.; Kutrakov, A. V.; Voronenkov,
V. V. Zh. Org. Khim. 1999, 35, 324-326. (b) For selective alkylation of
m-xylene at the 5-position, please see: Fujita, K.; Oomori, H.; Yoshikazu,
H. Mitsubishi Petrochemical Co. Ltd. Jpn. Kokai Tokyo Koho 91 24,021,
1991.
(10) Substitution for hydrogen at the 5-position in 1,3-substituted
benzenes by electrophiles, nucleophiles, and radicals is difficult: March,
J. In AdVanced Organic Chemistry: Reactions, Mechanisms, and Sructure,
4th ed.; John Wiley and Sons: New York, 1992; pp 513-514, 666-668,
686-687.
(11) Boryl intermediates that have been recently proposed in catalytic
borylations8 are analogous to suggested silyl intermediates in Rh-catalyzed
aromatic silylations: Ezbiansky, K.; Djurovich, P. I.; LaForest, M.; Sinning,
D. J.; Zayes, R.; Berry, D. H. Organometallics 1998, 17, 1455-1457.
2832
Org. Lett., Vol. 3, No. 18, 2001

compounds were separated by chromatography, unless
otherwise noted.
Entries 10 and 11 represent extensions of directed bory-
lations to 1,2-substituted arenes and pyrrole. For veratrole,
two isomers were detected by GC in a 99:1 ratio with the
expected major product being 1,2,4-C6H3(OMe)2(BPin). After
chromatographic purification, the major isomer was isolated
in 82% yield. Direct borylations of pyrrole and trimethylsilyl
pyrrole were ineffective. However, selective borylation at
the less hindered 3-position could be achieved by increasing
the steric bulk of the silyl protecting group. The regiochem-
istry of the borylation was verified by preparing the known
phenyl-substituted pyrrole14 via the Suzuki coupling of the
pyrrolyl boronate ester with IC6H5.
We have found that trace solvent impurities can inhibit
catalytic borylations. Hence, the solvent purification outlined
in the Supporting Information should be followed to maxi-
mize yields. With the exception of benzene, the substrates
have been selected to test the generality of sterically directed
borylation.
For benzene three sets of conditions were employed (Table
1, entries 1-3). In the first case, borylation was examined
with equimolar quantities of benzene and HBPin. The
isolated yields of products based on borane as the limiting
reagent are 41% for PhBPin and 33% for C6H4(BPin)2 both
as a 2:1 mixture of meta and para isomers. Using a 4:1 ratio
of benzene to borane, diborylation is minimized and PhBPin
can be isolated in 59% yield. If a moderate excess of HBPin
is used, the major species in the crude reaction mixture are
m-C6H4(BPin)2, p-C6H4(BPin)2, and 1,3,5-C6H3(BPin)3 in an
approximate 1.0:1.2:1.7 ratio as determined from GC and
NMR data. Further purification was not attempted; however,
comparison of the weight of the crude mixture (311 mg) to
the combined weights of HBPin, C6H6, and catalyst (340
mg) indicates efficient conversion to borylated species.
In cyclohexane solvent, 1,3-substitued arenes yield 1,3,5-
substituted aryl boronate esters as major products (entries
4-9). Reactivities for arene substrates were similar except
for 1,3-(CF3)2C6H4, which was substantially more reactive.
In the previous report,6b significant benzylic activation was
observed in neat m-xylene. To determine whether acceptable
yields for methyl-substituted arenes could be obtained, 1
equiv of HBPin was used for the borylation of m-xylene in
cyclohexane. The aryl and benzyl boronate esters were
separated, with the aryl product being favored by a factor
of ∼9:1. For 3-methylanisole, a modest excess of HBPin
was used and the 1,3,5-substituted major product was readily
obtained in 54% yield after chromatography. Entries 7 and
9 demonstrate that preference for borylation at the 5-position
holds for unsymmetrically substituted arenes. We attempted
the borylation of m-dichlorobenzene and found a mixture of
products with unreacted arene, chlorobenzene, ClC6H4(BPin),
and Cl2C6H4(BPin) isomers as the major species. This is not
surprising since we previously observed competitive C-H
and C-F activation using the same precatalyst for borylations
of fluorinated arenes.6b Consequently, no other halogenated
arenes were examined. An attempted borylation of benzoni-
trile led to nitrile reduction instead of aromatic C-H
activation.13
The pyrrole result represents an important extension of
the arene chemistry because selective functionalization at the
3-position is considerably more difficult than at the 2-posi-
tion. For example, the best reported synthesis of 3-iPr3-
i
SiNC4H3(B(OH)2) involves iodination of Pr3SiNC4H4 by
N-iodosuccinamide to afford 3-iPr3SiNC4H3I, generation of
t
the lithiated pyrrole with BuLi, quenching with B(OMe)3,
and hydrolytic workup to afford the boronic acid in 27%
i
yield from Pr3SiNC4H4.14 In a single step, the reaction in
entry 11 provides a stable source of the boronic acid in 81%
yield.
In summary, we have shown that cyclohexane can serve
as an inert solvent for Rh-catalyzed borylations of arenes.
In addition, selective borylation at the 5-position of 1,3-
substituted arenes has been demonstrated for a broader range
of substrates, including dimethyl resorcinol and 1,3-
(NMe2)2C6H4 where functionalizations at the 5-position are
difficult. An example of regioselective borylation of a
symmetric, 1,2-substituted arene has been demonstrated for
i
veratrole. Last, Pr3SiNC4H4 has been selectively borylated
at the less hindered 3-position in high yield.
Acknowledgment. We thank the National Science Foun-
dation (CHE-9817230) and the National Institutes of Health-
National Institute of General Medical Sciences (R01
GM63188-01) for supporting this research.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0162668
(13) Although we have not examined the borylation of aromatic esters
or amides in cyclohexane, we expect that borylations should be feasible
since aromatic C-H activation is preferred over ester or amide reduction
for borylations in the corresponding neat arenes.6b
(12) Shimada, S.; Batsanov, A. S.; Howard, H. A. K.; Marder, T. B.
Angew. Chem., Int. Ed. 2001, 40, 2168-2171.
(14) Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E.; Muchowski, J. M.
J. Org. Chem. 1992, 57, 1653-1656.
Org. Lett., Vol. 3, No. 18, 2001
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