Copper-facilitated Suzuki reactions: Application to 2-heterocyclic boronates

Article abstract of DOI:10.1021/ol802556f

(Chemical Equation Presented) The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic coronates generally give low convers

Full text of DOI:10.1021/ol802556f

ORGANIC
LETTERS
2009
Vol. 11, No. 2
345-347
Copper-Facilitated Suzuki Reactions:
Application to 2-Heterocyclic Boronates
James Z. Deng,*,† Daniel V. Paone,*,† Anthony T. Ginnetti,† Hideki Kurihara,‡
Spencer D. Dreher,‡ Steven A. Weissman,‡ Shaun R. Stauffer,† and Christopher
S. Burgey†
Department of Medicinal Chemistry, Merck Research Laboratories,
P.O. Box 4, West Point, PennsylVania 19486, and Department of Process Research,
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
james_deng@merck.com; daniel_paone@merck.com
Received November 5, 2008
ABSTRACT
The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However,
Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I)
facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced
yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic
cycle.
Since the discovery of the palladium-catalyzed Suzuki-
Miyaura reaction, organoboronates have been developed as
powerful reagents for carbon-carbon bond formation due
to their stability, nontoxicity, and functional group compat-
ibility.1 Although numerous ligand systems have been
developed for a wide array of coupling partners, reaction of
electron-deficient boronates such as 2-pyridyl remains chal-
lenging2 and of high interest to the synthetic community,
particularly the pharmaceutical industry. For example, cou-
pling of 2-pyridylboronic acid was unsuccessful under a very
general Suzuki coupling system.2b
It is hypothesized that transmetalation from boron to
palladium of electron-deficient 2-heterocyclic boronates is
slow relative to protodeboronation, leading to poor conver-
sions.3 To address this, recent efforts have focused on
formation of more stable or activated boronates.4 While these
methods perform well for certain substrates, highly electron-
deficient boronates remain problematic.4c Additionally, the
lithium borate salts utilized demonstrate limited stability and
require preparation through metalations which limit func-
tional group tolerance. The use of pinacol boronates is
attractive due to their commercial availability and relative
stability toward air and moisture; however, no general
solution for the direct coupling of 2-pyridylpinacol boronates
has been reported.
We sought to generate in situ a more reactive organometal
species from the corresponding 2-heterocyclic boronic esters,
which could subsequently participate in the palladium-
catalyzed cross-coupling. While copper(I) halides have been
used extensively in Stille reactions,5 there are few reports
about their use in the Suzuki couplings, and the role of copper
† Department of Medicinal Chemistry.
‡ Department of Process Research.
(3) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–
4314. (b) Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-Bas 1974, 93,
21–24. (c) Ishiyama, T; Isahida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813–9816.
(1) Suzuki reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457–2483. (b) Miyaura, N. J. Organomet. Chem. 2002, 653, 54–57.
(2) For Suzuki reactions with heterocyclic boronates, see: (a) Campeau,
L.-C.; Fagnou, K. Chem. Soc. ReV. 2007, 36, 1058–1068. (b) Billingsley,
K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366. (c) Bouillon,
A.; Lancelot, J.-C.; Sopkova de Oliveira Santos, J.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2003, 59, 10043–10049.
(4) (a) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685–
687. (b) Yamamoto, Y.; Takizawa, M.; Yu, X.; Miyaura, N. Angew. Chem.,
Int. Ed. 2008, 47, 928–931. (c) Billingsley, K.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 4695–4698.
10.1021/ol802556f CCC: $40.75
Published on Web 12/18/2008
2009 American Chemical Society

has not been defined.6,4a,b We report herein the successful
copper(I)-facilitated Suzuki coupling of 2-heterocyclic bo-
ronates that is broad in scope; furthermore, mechanistic
investigations suggest a possible role of copper in the
catalytic cycle.
Table 1. Scope of the Electrophilea
Initial survey reactions of 2-pyridyl boronates with Pd-
(dppf)Cl2 gave much higher conversions with CuI additive
relative to the noncopper conditions. Encouraged by these
results, we sought to optimize the reaction conditions using
parallel microscale high-throughput experimentation tech-
niques.7 We rapidly evaluated various parameters including
copper source, ligand, base, and solvent. It was found that
the reactivity of copper salt followed the order CuCl > CuBr,
Cu2O > CuI and that the amount of bipyridyl formation was
minimized with CuCl or Cu2O. Dppf was found to be the
optimal ligand, with DMF and Cs2CO3 as preferred solvent
and base. In addition, we used microscale design of experi-
ments (DOE)8 to determine the optimal temperature (100
°C) and equivalencies of reagents (2:1 of boronate to aryl
halide) and also discovered that the most robust reactions
were acheived when dppf was used as a 2:1 ratio to
palladium.
With these results in hand, we surveyed the scope of the
electrophile using boronate ester 1 (Table 1).9 Reaction of
aryl iodides proceeded in high yield with CuCl (89%, entry
1) relative to the standard Suzuki conditions without CuCl
(22%). This yield enhancement is even more pronounced
when moving to the less reactive bromide and triflate
electrophiles (entries 2 and 3), where almost no conversion
is observed without the use of CuCl, and high yields (88%
and 76%, respectively) are maintained with CuCl. Ortho
substitution is tolerated (entry 4), as are heteroaryl halides
(entries 5 and 6), but the yield is lower for the electron-rich
4-methoxyphenyl bromide in entry 7.
Next, various 2-heterocyclic boronates were examined
(Table 2). Unsubstituted and substituted 2-pyridyl substrates
bearing electron-withdrawing substituents performed well
under these reaction conditions (entries 1-5) with yields
ranging from 70 to 97%. Once again, control reactions
without CuCl gave negligible conversions. Notably, the
highly electron-deficient cyano boronate (entry 6) affords a
63% yield.4c While moderate conversions are observed for
2-pyrazinyl and 2-pyrrolo boronates (entries 7 and 8) without
CuCl, higher yields are achieved with CuCl. Interestingly,
a Reaction conditions: 1.0 equiv of halide, 2.0-2.5 equiv of 2-pyridyl
boronate, 2.0 equiv of Cs2CO3, 5 mol % of Pd(OAc)2, 10 mol % of dppf,
100 mol % of CuCl, 0.1 M DMF, 100 °C, 16 h. b Yields are based on
purification after silica gel chromatography. Conversions are based on
LC/MS. c Isolated yield.
6-substituted 2-pyridyl boronates gave high isolated yields
both with and without CuCl (entries 9 and 10), regardless
of the electronic properties of the 6-substituents.10
We hypothesize that the reaction primarily operates
through the basic Suzuki catalytic cycle (Figure 1). Direct
transmetalation from electron-deficient heterocyclic boronates
to palladium (path A) is relatively slow in comparison with
deboronation (path B). Alternatively, transmetalation to form
a 2-pyridyl copper species (path C) and a second transmeta-
lation to a palladium complex (path D) may provide a more
efficient process, allowing conversion to cross-coupled
product after reductive elimination. The major competing
reaction is the reductive homocoupling of the 2-pyridyl
copper species resulting in 2,2′-pyridine dimer, thus neces-
sitating the use of excess boronate for complete conver-
sions.11
We sought to provide mechanistic support for the proposed
initial transmetalation from boron to copper (path C) by
treating pyridyl boronate 7 with 1 equivt of CuCl at 80 °C
(Scheme 1). After 90 min, homocoupled dimer 8 was
obtained as the major product, characteristic of an intermedi-
ary 2-pyridylcopper species.12a No conversion to 8 was
observed in the control reaction without CuCl, providing
indirect evidence for path C.
(5) (a) Farina, V.; Kapadia, S.; Krishman, B.; Wang, C.; Liebeskind,
L. S. J. Org. Chem. 1994, 59, 5905–5911. (b) Han, X.; Stoltz, B. M.; Corey,
E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. (c) Mee, S. P. H.; Lee, V.;
Baldwin, J. E. Angew. Chem., Int. Ed. 2004, 43, 1132–1136
.
(6) (a) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149–2152.
(b) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, Y.-X.;
Zhang, M.-B.; Hu, X.-C. J. Org. Chem. 2007, 72, 2053–2057. (c) Thathagar,
M. B.; Beckers, J.; Rothenberg, G. J. Am. Chem. Soc. 2002, 124, 11858–
11859
.
(7) Details of similar high-throughput experiments are found in: Dreher,
S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc.
2008, 130, 9257–9259.
(10) A similar phenomenon with C-H insertions was reported: Lewis,
J. C.; Bergman, R. G.; Ellman, J. A J. Am. Chem. Soc. 2007, 129, 5332–
5333.
(8) For a recent example of DOE applied to a Pd-catalyzed reaction,
see: Denmark, S. E.; Butler, C. R. J. Am. Chem. Soc. 2008, 130, 3690–
3704.
(11) This homocoupling is also associated with loss of Cu(I) from the
catalytic cycle. Use of Cu2O minimizes homocoupling and enables a catalytic
copper reaction, as 87% yield is achieved in entry 1, Table 1 with 10 mol
% Cu2O. Conversions are substrate dependent, and efforts to develop more
robust catalytic copper conditions are ongoing.
(9) Though several substrates gave complete conversion within 1 h,
reactions were continued to 16 h as a general protocol. Alternatively,
reactions could be conducted using mircowave irradiation at 160 °C and
were typically complete in 20 min.
346
Org. Lett., Vol. 11, No. 2, 2009

Scheme 1
Table 2. Scope of Heterocyclic Boronates
complete conversion of bromide to 10 was observed. To
specifically address the feasibility of the proposed second
transmetalation from copper to palladium (path D), 9 was
Scheme 2
reacted with the preformed Pd(dppf)-aryl iodide oxidative
addition complex 11.14 After heating in DMF at 100 °C for
60 min, cross-coupled product 12 was obtained in 83% yield.
This reaction also proceeded cleanly at ambient temperature,
though at a much slower rate.
In summary, we have developed a general solution for
the Suzuki coupling of 2-heterocyclic boronates employing
CuCl, with wide scope in both the boronate and electrophile.
Mechanistic studies suggest that the role of copper is to
facilitate the transmetalation of boronates to the palladium
complex. This method may also find utility in other
transformations where transmetalation from boron is prob-
lematic.
a Reaction conditions as in Table 1. b Isolated yield.
To further support the existence of a 2-pyridylcopper
species in the productive path of the proposed catalytic cycle,
Acknowledgment. We thank Professor David MacMillan
of Princeton University for helpful discussions concerning
possible reaction mechanisms.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802556F
(12) (a) Malmberg, H.; Nilsson, M. Tetrahedron 1986, 42, 3981–3986.
(b) Malmberg, H.; Nilsson, M. Tetrahedron 1982, 38, 1509–1510.
(13) It was necessary to increase the concentration of Pd(OAc)2 and
dppf due to competing homocoupling of the preformed 2-pyridylcopper
species.
Figure 1. Possible mechanism.
(14) (a) Driver, M.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232–
8245. (b) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado,
N. J. Am. Chem. Soc. 1987, 109, 2393–2401. (c) Fitton, P.; Johnson, M. P.;
McKeon, J. E. J. Chem. Soc., Chem. Commun. 1968, 6–7.
2-pyridylcopper 912 was independently prepared and reacted
with bromide 4 (Scheme 2). Using 50 mol % of palladium,13
Org. Lett., Vol. 11, No. 2, 2009
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