Copper promoted C-N and C-O bond cross-coupling with phenyl and pyridylboronates

Article abstract of DOI:10.1016/S0040-4039(03)00739-1

Acyclic and cyclic esters, as well as anhydride (boroxine) of phenylboronic acids are efficient phenylating agents in copper promoted C-N and C-O bond cross-coupling reactions. The first successful C-N cross-coupling of a heterocyclic boronate with heteroarenes, such as indazole, has been demonstrated.

Full text of DOI:10.1016/S0040-4039(03)00739-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3863–3865
Copper promoted CꢀN and CꢀO bond cross-coupling with
phenyl and pyridylboronates
Dominic M. T. Chan,a,* Kevin L. Monaco,a Renhua Li,b Damien Bonne,b Charles G. Clarkb and
Patrick Y. S. Lamb,*
aDuPont Crop Protection, Stine-Haskell Research Center, PO Box 30, Newark, DE 19714-0030, USA
bBristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 10 February 2003; revised 28 February 2003; accepted 28 February 2003
Abstract—Acyclic and cyclic esters, as well as anhydride (boroxine) of phenylboronic acids are efficient phenylating agents in
copper promoted CꢀN and CꢀO bond cross-coupling reactions. The first successful CꢀN cross-coupling of a heterocyclic boronate
with heteroarenes, such as indazole, has been demonstrated. © 2003 Elsevier Science Ltd. All rights reserved.
Copper promoted cross-coupling with arylboronic acids
is emerging as a popular protocol in the preparation of
aryl ethers, aryl amines, and arylated heterocycles due
to its mild conditions and tolerance of base-sensitive
functionalities.1,2 The technology is especially suited for
expeditious parallel or solid state synthesis of arylated
analogs from the parent NH or OH compounds using
the large library of boronic acids currently available
commercially.3 Since our initial reports,1 significant
progress has been made in broadening the scope,4 as
well as extending the methodology to include the use of
other organometalloids such as arylstannanes,5c aryl-
siloxanes,5 and aryl iodonium salts.6
only 1 equiv. of 1 for comparison although 2 equiv. of
phenylboronic acid are needed for optimum yields.1
Three substrates: a phenol, a basic amine and a urea
were chosen to represent different functional groups
(OH and NH) and relative reactivity. They are 3,5-di-
tert-butyphenol (2), 4-phenylpiperidine (3), and 1-ethyl-
2-benzimidazolinone (4) (Scheme 1). For consistency,
we employed identical reaction conditions and the cor-
responding phenylated products 5, 6, 7 were isolated by
In a continuing effort to identify other efficient arylat-
ing agents and to better understand the controlling
factors of these boronic acid reactions, we undertook a
systematic study on the efficiency of various boronic
acid derivatives (1) in participating in these arylations.
For this investigation we purposely chose phenyl-
boronic acid as the prototypical system because of the
ready availability of its anhydride form (boroxine) and
its ester derivatives, as well as its relative inefficiency in
the N- and O-cross coupling reactions which provides
the necessary latitude for comparison.7 We also used
* Corresponding authors. E-mail: dominic.m.chan@usa.dupont.com;
patrick.lam@bms.com
Scheme 1. Phenylation with boronic acid derivatives.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00739-1

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D. M. T. Chan et al. / Tetrahedron Letters 44 (2003) 3863–3865
flash chromatography under similar fashion. The
results are summarized in Table 1.
exception being the catechol derivative 11 (entry 7),
which appears to be unstable and readily hydrolyzes
back to the acid, and the pincolate 12 (entry 8) pre-
sumably due to steric hindrance. However, there
appears to be no significant difference in efficiency
among these boronates. The overall superior perfor-
mance of triphenylboroxine (entry 2), the cyclic anhy-
dride form of phenylboronic acid, is noteworthy. This
observation is consistent with the report by Evans in
the study of phenol arylation.1b It should also be men-
tioned that we have observed PhB(OH)2 readily con-
verts to (PhBO)3 in methylene chloride at room
It is apparent from this study that the ancillary oxo-lig-
and on the boron has a dramatic influence on these
cross-coupling reactions. In general, the boron esters
are more efficient than phenylboronic acid itself. The
Table 1. Phenylation with 1 equiv. boronic acid deriva-
tives 1
1
temperature by H NMR.8 This dynamic behavior of
boronic acid implies that the active arylating agent in
our earlier study could indeed be the anhydride form
and not the free acid. It is interesting to speculate that
one purpose for the addition of molecular sieves in
Evans’ improvement1b is to promote the formation of
the boroxine form.
Although the current study is performed with the par-
ent phenylboronic acid system and with a limited range
of substrates, it is likely that our conclusion should be
applicable to other substituted arylboronic acid systems
and other substrates in general. The increasing commer-
cial availability of arylboronic esters, and the ease in
which they can be generated from the corresponding
aryl halide precursors using Grignard or palladium-cat-
alyzed diboron chemistry make these attractive reagents
for N- and O-arylations.
The application of cyclic boronates as arylating agents
has been extended to a heterocyclic boronic acid sys-
tem—3-pyridylboronic acid. Since the majority of drugs
on the market contain heterocycles, we are interested in
connecting two heterocyclic units together via our cop-
per-promoted CꢀN cross-coupling reaction. Indeed 3-
pyridylboronic
acid
and
its
corresponding
1,3-propanediol cyclic ester (13)9 both produce the N-
pyridyl products with benzimidazole in reasonable
yields, with the boronate ester being a better arylating
agent (Scheme 2).10 This constitutes the first successful
copper promoted CꢀN cross-coupling involving a hetero-
cyclic boronic acid system.
In summary, we have demonstrated that borate esters
1, together with the previously reported boroxine,1b are
effective arylating agents in the copper-promoted CꢀN
and CꢀO bond cross-coupling reactions. We have suc-
cessfully applied this new discovery in the cross-cou-
pling of
a
3-pyridyl moiety to
a
variety of
Conditions: 1 (1.0 equiv.), anhydrous Cu(OAc)2 (1.0 equiv.), Et3N or
pyridine (2.0 equiv.), CH2Cl2, rt, 24 h.
NH-containing heteroarenes. We continue to expand
the scope of our copper-promoted cross-coupling
reaction.
a Yields are for Et3N, yields for pyridine are in parentheses.
b PhB(OH)2 was purified by recrystallization of commercial material
from water.
c (PhBO)3 was prepared by azeotropic refluxing of PhB(OH)2 in
hexane or toluene for 2–3 h. It typically contains <5% of PhB(OH)2.
0.33 equiv. was used in this case.
Acknowledgements
d Diisopropoxyphenyl borane and 2-phenyl-1,3,2-dixoaborinane (8)
were obtained commercially from Aldrich Chem. Co.
e Boron esters 9, 10, 11 and 12 were prepared by azeotropic refluxing
of PhB(OH)2 and the appropriate diol in toluene.
f 2 equiv. of 9 were used in this run.
We thank Dr. Carl P. Decicco, Dr. Paul S. Anderson,
and Dr. Ruth R. Wexler for the support of this
research.

D. M. T. Chan et al. / Tetrahedron Letters 44 (2003) 3863–3865
3865
4. For application in N-arylation, see: (a) Cundy, D. J.;
Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979–7982; (b)
Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux,
D. Tetrahedron 1999, 55, 12757–12770; (c) Collot, V.;
Bovy, P. R.; Raulto, S. Tetrahedron Lett. 2000, 41,
9053–9057. For O-arylation, see: (d) Jung, M. E.;
Lazarova, T. I. J. Org. Chem. 1999, 64, 2976–2977; (e)
Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3,
1029–1032; (f) Evans, D. A.; Katz, J. L.; Peterson, G. S.;
Hintermann, T. J. Am. Chem. Soc. 2001, 123, 12411–
12413; (g) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W.
Org. Lett. 2001, 3, 139–142; (h) Simon, J.; Salzbrunn, S.;
Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem. 2001, 66, 633–634. For S-arylation, see: (i) Her-
radura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019–2022; (j) Savarin, C.; Srojl, J.; Liebeskind,
L. S. Org. Lett. 2002, 4, 4309–4312. For catalytic systems,
see: (k) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2,
1233–1236; (l) Lam, P. Y. S.; Vincent, G.; Clark, C. G.;
Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415–3418; (m) Antilla, J.; Buchwald, S. L. Org. Lett.
2001, 3, 2077–2079; (n) Collman, J. P.; Zhong, M.;
Zheng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528–
1531; (o) Collman, J. P.; Zhong, M.; Zheng, L.;
Costanzo, S. J. Org. Chem. 2001, 66, 7892–7897.
5. (a) Lam, P. Y. S.; Deudon, S.; Kristin, M. A.; Li, R.; He,
M.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000,
122, 7600–7601; (b) Lam, P. Y. S.; Deudon, S.; Haupt-
man, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–
2429; (c) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C.
G. Tetrahedron Lett. 2002, 43, 3091–3094.
6. Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022–1024.
7. It should be noted that the parent phenyl system is
probably one of the least effective arylating agents in our
chemistry, see Refs. 1a and 4a. Most substituted systems
give much more respectable yields.
8. Interestingly PhB(OH)2 is perfectly stable in d6-DMSO,
the OH protons show up as singlet at l 8.3 ppm.
9. Obtained commercially from Lancaster Synthesis Inc.
10. No cross-coupling occurs between 4-pyridylboronic acid
and the ethyl ester of 3-methyl-5-pyrazole carboxylic
acid. This pyrazole was previously shown to be a good
substrate for N-arylation. We thank Dr. Yun-Long Li for
this observation.
11. A representative procedure is illustrated in the synthesis
of 1-(3-pyridyl)-benzimidazole: A 20 mL vial was charged
with a magnetic stir bar, 12 (109 mg, 0.667 mmol, 2.0
equiv.), benzimidazole (39 mg, 0.333 mmol, 1.0 equiv.),
anhydrous Cu(OAc)2 (91 mg, 0.500 mmol, 1.5 equiv.),
pyridine (1.0 mL of 0.67 M solution in dichloromethane,
0.67 mmol, 2.0 equiv.), and 3 mL dichloromethane. The
reaction was stirred under air at ambient temperature for
12 h. A solution of 3 mL of 4 M NH3 in MeOH was
added. The mixture was filtered through a layer of glass
wool on Celite and purified by silica gel chromatography
(ethyl acetate) to give 35 mg (54%) of 1-(3-pyridyl)-
benzimidazole.
Scheme 2. Copper promoted cross-coupling of heteroarenes
with 13.11,12
References
1. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.;
Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936; (b)
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
1998, 39, 2937–2940; (c) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
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Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Averill, K.; Chan, D. M. T.; Combs, A. P. Synlett 2000,
674–676.
2. For reviews, see: (a) Burgess, K.; Thai, L. Chemtracts-
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C.; Boddy, N. C.; Brase, S.; Winssinger, N. Angew.
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12. The physical data of 1-(3-pyridyl)-benzimidazole: 1H
NMR (CDCl3) l 8.87 (s, 1H), 8.76 (d, J=1.4 Hz, 1H),
8.14 (s, 1H), 7.92–7.86 (m, 2H), 7.58–7.51 (m, 2H),
7.41–7.31 (m, 2H). MS(ES) m/z 196.2 (100%) (M+H)+.
Elemental anal. (C12H9N3) theoretical: C, 73.83%; H,
4.656; N, 21.52; found: C, 73.49%; H, 4.78; N, 21.67.