A highly active catalyst for Suzuki-Miyaura cross-coupling reactions of heteroaryl compounds

Article abstract of DOI:10.1002/anie.200600493

(Chemical Equation Presented) Unprecedented activity: Catalysts derived from Pd and bulky dialkylphosphinobiaryl ligands are shown to be highly stable and active in Suzuki-Miyaura reactions of heteroaryl halides and heteroaryl boronic acids/esters (e.g., 3-or 4-pyridine, indole, and N-protected pyrrole derivatives). Furthermore, this catalyst system is not inhibited by the presence of highly basic aminopyridines or aminopyrimidines.

Full text of DOI:10.1002/anie.200600493

Communications
Coupling Reactions
DOI: 10.1002/anie.200600493
A Highly Active Catalyst for Suzuki–Miyaura
Cross-Coupling Reactions of Heteroaryl
Compounds**
Kelvin L. Billingsley, Kevin W. Anderson, and
Stephen L. Buchwald*
In the past two decades, the Suzuki–Miyaura cross-coupling
reaction has evolved into one of the most widely employed
[
1,2]
carbon–carbon bond-forming processes.
Its impact on
organic synthesis is largely attributed to the fact that it
provides a general and applicable method for the formation of
[
3]
biaryls, which are found in polymers, biologically active
[
4]
[5]
[6]
compounds, ligands, and various materials. In recent
years, work by numerous groups has resulted in the produc-
tion of highly active catalyst systems, which allow for
couplings to occur with more challenging substrates, such as
[
7]
unactivated aryl chlorides and hindered boronic acids.
Despite these advances, limitations of the method, to date,
include its inability to maintain the efficacy exhibited in
simple aryl–aryl bond formation when employing nitrogen
heterocycles as one or both of the coupling partners (e.g.,
[
8]
heteroaryl halides and/or heteroaryl boronic acids/esters).
Nitrogen-based heterocycles are ubiquitous in biologically
active compounds, but inclusion of these heterocyclic motifs
have been particularly detrimental to catalyst activity when
[
4]
palladium is used. In addition, for exceptionally challenging
substrates, such as chloroaminopyridines and chloroamino-
pyrimidines, protection of the freeÀNH group or the need to
2
employ chelating ligands, which prevent competitive binding
of the substrate, have been reported to be essential to the
[
9,10]
success of the transformation.
Given the importance of
the Suzuki–Miyaura reaction, particularly in the area of drug
development, an efficient method for the coupling of nitro-
gen-containing heterocyclic substrates would make a signifi-
cant impact.
Herein, we report that extremely active catalysts com-
posed of Pd and dialkylbiphenylphosphino ligands 1 or 2
provide a general system for the Suzuki–Miyaura reaction of
[
*] K. L. Billingsley, K. W. Anderson, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[
**] We thank the National Institutes of Health (GM 46059) and the
National Cancer Institute (Cancer Training Grant GM 5-T32-
CAO9112-30) for support of this work. We are grateful to Merck,
Amgen, and Englehard (Pd(OAc) ) foradditional suppo rt . The
2
Bruker Advance 400 MHz instrument used was purchased with
funding from the National Institutes of Health (GM 1S10RR13886-
01).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3
484
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Angewandte
Chemie
[
a]
challenging heterocyclic substrates, such as aminoheteroaryl
halides (chloroaminopyridines and chloroaminopyrimidines)
and/or heteroaryl boronic acids/esters (e.g., 3- and 4-pyridi-
neboronic acids, pyrrole boronate esters, and indole boronic
acids). After our work was completed, Fu and co-workers
Table 1: Suzuki–Miyaura coupling of chloroaminoheterocycles using ligand 1.
[
b]
Entry Aryl chloride
Boronic acid
Product
Yield [%]
99
reported that a catalyst system comprised of Pd/PCy (Cy =
3
cyclohexyl) was particularly effective in coupling aryl/hetero-
[11]
aryl halides and heteroaryl boronic acids.
1
2
3
4
82
95
Only a few reports can be found on the successful Suzuki–
Miyaura coupling of substrates that possess unprotected
[
c]
79
[
9,12]
amino groups on a heteroaryl moiety.
Traditionally, to
circumvent the problems associated with this functional group
array, the free amino group is protected prior to the cross-
coupling process and must, correspondingly, be deprotected
5
92
[
10]
following the organometallic reaction. Past studies suggest
that binding of the free ÀNH group to the metal center can
2
retard the catalytic cycle; therefore, the basicity of the
aminoheteroaryl moiety should directly correlate to the
efficacy of the Pd-catalyzed process (Scheme 1).
6
7
97
96
[
9a,13]
Although previous reports suggest that chelating ligands are
a necessity for the efficient coupling of unprotected amino-
[
9a]
heteroaromatic compounds, our group has established that
Suzuki–Miyaura reactions that employ the dialkylmonophos-
phino biaryl 1 as the supporting ligand display unprecedented
reactivity while maintaining a broad substrate scope. Thus, in
our initial studies, we utilized a catalyst based upon Pd-
[
c]
8
92
(
OAc) /1 for the coupling of aryl boronic acids with chloro-
2
aminoheterocycles.
[a] Reaction conditions: heteroaryl halide (1.0 equiv), aryl boronic acid (1.2–
À1
1
.5 equiv), K CO (2.0–3.0 equiv), CH CN (1.5 mLmmol
halide), H O
2
A catalyst system that employs 1 as the supporting ligand
proved to be highly active for the cross-coupling of a range of
chloroaminopyridines and chloroaminopyrimidines with aryl
boronic acids that possess functional groups. For example, the
2
À1
3
3
(1.0 mLmmol halide), cat.=Pd(OAc) , L/Pd=2:1. [b] Yield of isolated product
2
based upon an average of two runs. [c] Reaction was conducted using K PO and
3
4
À1
1
,4-dioxane (2.5 mLmmol halide).
derived conditions (Table 1, entry 4). Also, it is
interesting to note that 4-amino-2-chloropyridine,
which is the most basic among these substrates,
reacts in excellent yield with phenylboronic acid
(Table 1, entry 5). To the best of our knowledge, this
result represents the highest yielding Suzuki–
Miyaura coupling with a highly basic chloroamino-
[
9a]
pyridine.
Scheme 1. Basicity of selected aminopyridines.
Similar to the results found for chloroaminopyr-
idines, the Pd(OAc) /1 catalyst system was highly
2
active for the couplings of chloroaminopyrimidines
reaction of 3-amino-2-chloropyridine with 2-methoxyphenyl-
boronic acid smoothly produced the desired biaryl in 99%
yield (Table 1, entry 1). In addition, the sterically hindered
(Table 1, entries 6–8). These reactions proceed in greater than
90% yield for both sterically encumbered heteroaryl halides
and aryl boronic acids. In addition, the reaction of the
electron-deficient boronic acid, 3-acetylphenylboronic acid,
with the 4-amino-5-chloro-2,6-dimethylpyrimidine proceeds
smoothly to produce the highly substituted heterobiaryl in
2
,6-dimethylphenylboronic acid reacted in 82% yield with 5-
amino-2-chloropyridine (Table 1, entry 2), and similarly elec-
tron-deficient boronic acids also react in good yield under the
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3485

Communications
9
6% yield (Table 1, entry 7). This protocol corresponds to the
ciently with sterically hindered aryl chlorides, as the coupling
of 2-chloro-m-xylene with 3-pyridineboronic acid provided
the biaryl in 81% yield (Table 2, entry 1). In addition, a range
of aminopyridines was effectively coupled in excellent yield to
3- and 4-pyridineboronic acids (Table 2, entries 2–4). Sim-
ilarly, commercially available alkoxypyridine boronic acids
reacted in greater than 90% yield with an electron-deficient
heteroaryl chloride (Table 2, entry 6). This protocol repre-
sents a general method for the coupling of pyridine-derived
boronic acids with heteroaryl chlorides.
only method whereby chloroaminopyrimidines are coupled to
hindered aryl boronic acids.
Pyridines are the most common heterocyclic motif found
[
14]
in pharmaceutically active compounds. Thus, preparative
methods of pyridine derivatives remain an essential research
topic in organic synthesis. Despite efforts by numerous
groups, pyridine-derived boronic acids have proved to be a
particularly difficult class of substrate for the Suzuki–Miyaura
[
11,15]
reaction.
The Pd(OAc) /1 catalyst system provided good
2
[
16]
yields for the reaction of pyridine boronic acids with activated
heteroaryl chlorides. For example, the reaction of 3-chloro-
2
The first report of a pyrrole boronic acid was in 1991,
and currently a limited number of citations are found on the
synthesis and utility of pyrrole-based boronic acids and
,5-dimethylpyrazine with 4-pyridineboronic acid provided
[
17]
an 83% yield of the desired heterobiaryl (Table 2, entry 5).
borane derivatives. As pyrroles are found in a variety of
biological systems, we found this lack of
precedent to be of particular interest. We
discovered that employing a boronate ester
instead of the boronic acid allowed for facile
purification of the pyrrole reagent and its
[
a]
Table 2: Suzuki–Miyaura coupling of pyridine boronic acids using ligands 1 or 2.
[
b]
Entry Boronic acid
1
Aryl chloride
Product
Ligand T [8C] Yield [%]
increased stability under the reaction con-
ditions. Thus, A was synthesized in 79%
yield from pyrrole by protection, selective
bromination, and subsequent palladium-
catalyzed boronation (Scheme 2).
2
2
2
2
1
100
120
120
120
100
81
95
95
95
83
Initial studies that employed pyrrole
boronate esters proved to be unsuccessful
as significant reduction of the aryl halide
was detected. However, the addition of
extraneous water to the reaction mixture
minimized the amount of by-product and
increased the overall yield. These condi-
tions proved to be highly efficient for the
coupling with heteroaryl bromides and
activated heteroaryl chlorides at low cata-
lyst loadings. The reaction of A with 5-
bromoindole (Table 2, entry 1) and 2-bro-
mopyridine (Table 2, entry 2) smoothly pro-
duced the heterobiaryls in greater than 90%
yield at Pd loading of 0.25 mol%. In addi-
tion, A was also coupled to 2-bromothio-
phene in nearly quantitative yield with
relatively high turnover numbers (Table 2,
entry 3).
2
3
4
5
[
c,d]
6
7
2
2
100
100
91
91
[
e]
[
(
a] Reaction condiitons: aryl or heteroaryl chloride (1.0 equiv), boronic acid (1.5 equiv), K PO
2.0 equiv), n-butanol (2 mLmmol halide), cat.=[Pd dba ], L/Pd=2:1. [b] Yield of isolated product
3
4
À1
2
3
To examine the differences between the
2- and 3-boronated positions of the pyrrole
unit, N-Boc-pyrrole-2-boronic acid (Boc =
tert-butoxycarbonyl) was prepared by the known directed
based upon an average of two runs. [c] Pd(OAc)2 was used instead of [Pd dba ]. [d] Reaction was
conducted in s-butanol. [e] Reaction was conducted in tert-amyl alcohol.
2
3
However, the catalyst proved to be far less efficacious for the
reaction of unactivated aryl and heteroaryl chlorides.
We have established that a catalyst system based upon
[
18]
metalation strategy.
Significant dimerization or protode-
boronation of the boronic acid was not readily detected under
these conditions in contrast to what was previously repor-
[
Pd dba ] (dba = dibenzylideneacetone) and the more-hin-
2 3
dered ligand 2 afforded good-to-excel-
lent yields for the cross-coupling of a
variety of aryl and heteroaryl chlorides
with pyridine-based boronic acids. We
speculate that use of 2 maximizes the
concentration of [L Pd(Ar)X] (X =
1
halide) intermediates, which may be
particularly important in these cases.
Pyridine boronic acids reacted effi-
Scheme 2. Synthesis of N-(TIPS)-3-pyrrole pinacol borane.
3
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Angew. Chem. Int. Ed. 2006, 45, 3484 –3488

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Chemie
[
17b]
ted.
Under the standard conditions, N-Boc-pyrrole-2-
methods for the cross-coupling of these derivatives with
heteroaryl chlorides. The reaction of 5-indoleboronic acid
with a range of heteroaryl chlorides proceeded in good-to-
[
11]
boronic acid was combined with the sterically encumbered
substrate 2-bromomesitylene to afford the desired product in
8
9% yield (Table 3, entry 4). In addition, this boronic acid
excellent yields. The Pd(OAc) /1 catalyst system was highly
2
active for the reaction of acti-
vated heteroaryl chlorides. The
coupling of N-methyl-5-indole-
[
a]
Table 3: Suzuki–Miyaura coupling of pyrrole and indole boranes using ligands 1 or 2.
boronic acid with 5-chloro-2-
thiophene
resulted in 96% yield of the
biaryl at Pd loading of
carboxaldehyde
[
b]
Entry Boronic acid
1
Aryl chloride
Product
Ligand Pd [mol%] Yield [%]
a
[
[
[
c]
c]
c]
0.25 mol% (Table 3, entry 7).
In addition, this indole boronic
acid smoothly reacted with 3-
chloro-2,5-dimethylpyrazine to
afford the heterobiaryl in 90%
yield (Table 3, entry 8). As sug-
gested in other reports, no sig-
nificant difference in reactivity
for the unprotected heteroaryl
1
1
1
0.25
0.25
0.25
97
91
99
2
3
[
21]
4
5
6
1
1
1
2.0
2.0
2.0
89
84
95
boronic was observed.
5-
Indoleboronic acid was coupled
to several unactivated hetero-
aryl chlorides in ꢀ 75% yield
(Table 3, entries 9 and 10). In
these cases, the temperature of
the reaction had to be raised to
1
208C to facilitate the complete
conversion of the heteroaryl
chloride. The reaction of 5-
indoleboronic acid with 5-
7
8
9
1
1
0.25
2.0
96
90
chlorobenzoxazole
and
2-
amino-5-chloropyridine
pro-
duced the desired heterobiaryl
in 91and 77% yields, respec-
tively (Table 3, entries 9 and
[
e]
1
0). This protocol represents
[
[
d]
d]
2
2
2.0
2.0
91
the only current method by
which indole boronic acids can
be coupled to unactivated het-
eroaryl chlorides.
1
0
77
In summary, we have dem-
[
a] Reaction conditions: aryl or heteroaryl chloride (1.0 equiv), boronic acid (1.5 equiv), K PO (2.0 equiv), n- onstrated that use of catalysts
3 4
À1
butanol (2 mLmmol halide), cat.=[Pd dba ], L/Pd=2:1. [b] Yield of isolated product based upon an comprised of Pd and ligands 1
2
3
average of two runs. [c] [Pd dba ] was used instead of Pd(OAc) . [d] Reaction was conducted at 1208C.
2
3
2
or 2 provide highly stable and
active catalysts for the Suzuki–
[e] s-Butanol was used as the solvent.
Miyaura coupling of pyridine,
reacted in good yield with a variety of heteroaryl halides. The
coupling of N-Boc-pyrrole-2-boronic acid with 5-chloro-2-
thiophene carboxaldehyde and 4-bromoisoquinoline afforded
the heterobiaryls in 84 and 95% yield, respectively (Table 3,
entries 5 and 6). This method is the first general protocol
through which 2- and 3-pyrrole organoboranes may serve as
the nucleophilic component in the Suzuki–Miyaura reaction.
Indoles have been of interest for over a century because of
pyrrole, and indole boronic acids/esters. We also have shown
that this catalyst is not inhibited by the presence of highly
basic aminopyridines or aminopyrimidines, again demonstrat-
ing its high catalytic activity. Further work in applying these
catalytic systems to a wider array of heteroaryl substrates will
be reported in due course.
Received: February 6, 2006
Published online: April 26, 2006
[
19]
the biological activity displayed by many of its derivatives.
Several studies have been conducted on the reactivity of
indole-derived boronic acids under Suzuki–Miyaura condi-
Keywords: amines · boronic acids · cross-coupling ·
heteroaryl halides · Suzuki–Miyaura reaction
.
[
20]
tions.
However, to date, there are only a few general
Angew. Chem. Int. Ed. 2006, 45, 3484 –3488
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www.angewandte.org
3487

Communications
[
18] B. Bray, P. Mathies, R. Naef, D. Solas, T. Tidwell, D. Artis, J.
[
1] A. de Meijere, F. Diederich, Eds. Metal-Catalyzed Cross-
Muchowski, J. Org. Chem. 1990, 55, 6317.
Coupling Reactions, Vol. 2, Wiley-VCH, Weinheim, 2004.
2] a) N. Miyaura, Top. Curr. Chem. 2002, 219, 11; b) A. Suzuki,
Organomet. Chem. 1999, 28, 147.
[19] Indoles (Ed.: W. J. Houlihan), Wiley-Interscience, New York,
1972.
[20] Y. Yang, A. R. Martin, Heterocycles 1992, 34, 1395.
[21] M. Prieto, E. Zurita, E. Rosa, L. Munoz, P. Lloyd-Williams, E.
Giralt, J. Org. Chem. 2004, 69, 6812.
[
[
[
3] M. Kertesz, C. H. Choi, S. Yang, Chem. Rev. 2005, 105, 3448.
4] a) A. Markham, K. L. Goa, Drugs 1997, 54, 299; b) R. Capde-
ville, E. Buchdunger, J. Zimmermann, A. Matter, Nat. Rev. Drug
Discovery 2002, 1, 493; c) J. Boren, M. Cascante, S. Marin, B.
Comin-Anduix, J. J. Centelles, S. Lim, S. Bassilian, S. Ahmed,
W. N. Lee, L. G. Boros, J. Biol. Chem. 2001, 276, 37747.
5] H. Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem. 2000, 65,
[
5334.
[
[
6] S. Lightowler, M. Hird, Chem. Mater. 2005, 17, 5538.
7] a) T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685; b) T. E. Barder, S. L. Buchwald,
Org. Lett. 2004, 6, 2649; c) S. D. Walker, T. E. Barder, J. R.
Martinelli, S. L. Buchwald, Angew. Chem. 2004, 116, 1907;
Angew. Chem. Int. Ed. 2004, 43, 1871; d) H. N. Nguyen, X.
Huang, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11818; e) J.
Yin, M. P. Rainka, X.-X. Zhang, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 1162; f) R. Singh, M. S. Viciu, N. Kramareva, O.
Navarro, S. P. Nolan, Org. Lett. 2005, 7, 1829; g) A. F. Littke, C.
Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020.
[
8] a) I. Kondolff, H. Doucet, M. Santelli, Synlett 2005, 2057;
b) A. E. Thompson, G. Hughes, A. S. Batsanov, M. R. Bryce,
P. R. Parry, B. Tarbit, J. Org. Chem. 2005, 70, 388; also see
references [7a – d].
[
9] A few direct cross-coupling reactions that involve heteroaryl
moieties with unprotected NH groups have been disclosed; see:
2
ref. [8b] and a) T. Itoh, T. Mase, Tetrahedron Lett. 2005, 46, 3573;
b) T. Itoh, K. Sato, T. Mase, Adv. Synth. Catal. 2004, 346, 1859;
c) P. Gunda, L. M. Russon, M. K. Lakshman, Angew. Chem.
2004, 116, 6532; Angew. Chem. Int. Ed. 2004, 43, 6372; d) L. A.
Agrofoglio, I. Gillaizeau, Y. Saito, Chem. Rev. 2003, 103, 1875;
e) T. Tagata, M. Nishida, J. Org. Chem. 2003, 68, 9412; f) M.
Feuerstein, H. Doucet, M. Santelli, J. Organomet. Chem. 2003,
687, 327.
[
10] For examples in which it was essential to protect the amino-
heterocycle, see: a) S. Caron, S. S. Massett, D. E. Bogle, M. J.
Castaldi, T. F. Braish, Org. Process Res. Dev. 2001, 5, 254; b) J. A.
Miller, R. P. Farrell, Tetrahedron Lett. 1998, 39, 6441.
[
11] N. Kudo, M. Perseghini, G. C. Fu, Angew. Chem., 2006, 118,
1304; Angew. Chem. Int. Ed. 2006, 15, 1282.
[
12] During the production of this manuscript, Guram et al. reported
that the use of [PdCl {PtBu (p-RPh)} ] (R = H, NMe , CF ) were
2
2
2
2
3
quite effective as catalysts in the Suzuki–Miyaura coupling of
amino-heteroaryl/heteroaryl chlorides and aryl boronic acids,
see: A. S. Guram, A. O. King, J. G. Allen, X. Wang, L. B.
Schenkel, J. Chan, E. E. Bunel, M. M. Faul, R. D. Larsen, M. J.
Martinelli, P. J. Reider, Org. Lett 2006, ASAP.
[
[
13] S. Wagaw, S. L. Buchwald, J. Org. Chem. 1996, 61, 7240.
14] V. Bonnet, F. Mongin, F. Treꢀcourt, G. Breton, F. Marsais, P.
Knochel, G. Queꢀguiner, Synlett 2002, 1008.
[
15] a) M. Ishikura, M. Kamada, M. Terashima, Heterocycles 1984,
22, 265; b) P. R. Parry, C. Wang, A. S. Batsanov, M. R. Bryce, B.
Tarbit, J. Org. Chem. 2002, 67, 7541; c) G. A. Molander, B.
Biolatto, J. Org. Chem. 2003, 68, 4302; d) C. L. Cioffi, W. T.
Spencer, J. J. Richards, R. J. Herr, J. Org. Chem. 2004, 69, 2210;
e) P. B. Hodgson, F. H. Salingue, Tetrahedron Lett. 2004, 45, 685;
f) T. E. Barder, S. L. Buchwald, Org. Lett. 2004, 6, 2649.
[
[
16] S. Martina, V. Enkelmann, G. Wegner, A. D. Schluter, Synthesis
1991, 613.
17] a) A. Alzarez, A. Guzmen, A. Ruiz, E. Velards, J. Muchowski, J.
Org. Chem. 1992, 57, 1653; b) C. Johnson, G. Stemp, N. Anand, S.
Stephen, T. Gallagher, Synlett 1998, 1025.
3
488
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