Efficient Pd-catalyzed amination reactions for heterocycle functionalization

Article abstract of DOI:10.1021/ol101929v

The Pd-catalyzed amination of unprotected benzo-fused heterocycles is reported, which allows for greater flexibility and efficiency in the modification of this important class of molecules. The generality of these simple and efficient procedures is demonstrated through the synthesis of a wide variety of structural types.

Full text of DOI:10.1021/ol101929v

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4442-4445
Efficient Pd-Catalyzed Amination
Reactions for Heterocycle
Functionalization
Jaclyn L. Henderson and Stephen L. Buchwald*
Department of Chemistry, Room 18-490, Massachusetts Institute of Technology,
Cambridge Massachusetts 02139, United States
sbuchwal@mit.edu
Received August 16, 2010
ABSTRACT
The Pd-catalyzed amination of unprotected benzo-fused heterocycles is reported, which allows for greater flexibility and efficiency in the
modification of this important class of molecules. The generality of these simple and efficient procedures is demonstrated through the synthesis
of a wide variety of structural types.
Indoles, indazoles, and benzimidazoles feature prominently
in pharmaceuticals, agrochemicals, dyes, and novel materials
(Figure 1).1-6 However, despite their utility, they are often
overlooked during the development of cross-coupling meth-
ods.7-9 Investigations into their use as nucleophiles in C-N
cross-coupling reactions have been conducted; however, there
(1) Renhowe, P. A.; Pecchi, S.; Shafer, C. M.; Machajewski, T. D.;
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Frennesson, D.; Gottardis, M.; Greer, A.; Hansel, S.; Hurlburt, W.; Jacobson,
B.; Krishnananthan, S.; Lee, F. Y.; Li, A.; Lin, T.-A.; Liu, P.; Ouellet, C.;
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Figure 1. Pharmacologically active compounds containing amino-
1H-indazoles and benzimidazoles.
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have been few reports employing the heteroaryl halides as
the electrophilic component.10-12 As a result, the majority
of cross-coupling processes employing these substrates utilize
the N-protected heteroaryl halide to avoid complications
associated with the reactive N-H functional group, such as
homocoupling or catalyst deactivation.13,14 In addition to
adding extra synthetic steps, protecting group strategies can
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10.1021/ol101929v  2010 American Chemical Society
Published on Web 09/22/2010

be particularly problematic in the case of benzimidazoles
and indazoles. Mixtures of N-1 and N-2/3 protected regioi-
somers are often formed, which can display different
reactivities under cross-coupling conditions.15-17 A general
method for the amination of unprotected haloheterocycles
would thus offer a valuable tool for the synthesis of these
important molecules.
couplings with both aromatic and aliphatic secondary amines
(Scheme 1). Moreover, a range of functional groups are well
Scheme 1
.
Cross-of Coupling Bromo-indazoles with Secondary
Aminesa
The development, by our group, of new phosphine ligands,
along with Pd-precatalysts for the rapid generation of
monoligated Pd(0) species, has resulted in robust and general
catalyst systems for C-N cross-coupling reactions.18,19 Such
systems should be ideal for addressing the challenges of
selectivity and functional group tolerance posed by these
benzofused heterocyclic halides.
We recently reported an efficient protocol for the Pd-
catalyzed C-N cross-coupling of bromo and chloro 7-aza-
indoles, using our Pd-precatalyst systems (Figure 2) in
a Reaction conditions: bromoindazole (0.5 mmol), amine (0.6 mmol),
L1 (1 mol %), P1 (1 mol %), LiHMDS (1.2 mmol, 1 M in THF). Isolated
yields are for an average of at least two runs. b 2 M solution of HNMe2 in
THF. c HCl salt of amine. d 3.4 equiv ofLiHMDS (1.7 mmol). e L2 (1 mol
%), P2 (1 mol %).
Figure 2. Ligands and precatalysts used herein.
combination with LiHMDS.20 This method would be of even
greater appeal if it were applicable to a wider range of
heterocyclic halides, allowing the synthesis of a variety of
amino-heterocycles.
We were pleased to discover that under the same reaction
conditions as developed for azaindoles, using a RuPhos based
catalyst system (P1) and LiHMDS in THF as the base, 4-,
5- and 6-bromo-indazoles underwent efficient C-N cross-
tolerated. In particular, pharmacologically relevant and
functionally complex amines, such as the 4-(4-chlorophenyl)-
4-hydroxypiperidine from haloperidol21 (1i), underwent this
transformation in good yields. Notably, in cases where a
bromoheterocycle was combined with an amine containing
an aryl chloride, no reaction of the chloride was observed
(1b, 1f, 1i).
We next examined the coupling of 4-, 5-, and 6-bromoin-
dazoles with primary amines, using the BrettPhos precatalyst
(P3, Figure 2), which is often the preferred ligand for cross-
coupling reactions of this type.19 Using this system both
aliphatic and heteroaromatic amines could be incorporated
in high yields (Scheme 2).
Whereas a wide variety of amines could be employed,
electron-deficient secondary anilines, such as 4-N-methy-
laminobenzonitrile and N-methylaminopyridines, proved to
be uniquely challenging coupling partners. Only trace
amounts of the desired products were detected after extended
reaction times, with increased catalyst loading, or with
various bases. We hypothesized that the reductive elimination
of these substrates might be slow as a result of their reduced
nucleophilicity, and thus we reasoned that a more bulky
phosphine ligand might be more effective in facilitating this
step.22 Indeed, we found that a t-BuXPhos-derived catalyst
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(21) Vangveravong, S.; McElveen, E.; Taylor, M.; Xu, J. B.; Tu, Z.;
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Org. Lett., Vol. 12, No. 20, 2010
4443

aromatic and aliphatic nitriles (3b and 3c), ketones (3a), and
protected aldehydes (3e). This method was also effective in
the cross-coupling of halo-benzotriazoles. Commercially
available 5-chlorobenzotriazole, which has not previously
been utilized for Pd-catalyzed C-N cross-coupling reactions,
reacted effectively (Scheme 4), using a slightly higher
temperature.
Scheme 2
.
Cross-Coupling of Bromo-indazoles with Primary
Aminesa
Scheme 4.
Cross-Coupling Reactions of 5-Chlorobenzotriazolea
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), L3 (1 mol
%), P3 (1 mol %), LiHMDS (1.2 mmol, 1 M in THF). Isolated yields are
for an average of at least two runs. b L2 (1 mol %), P2 (1 mol %), LiHMDS
(1.7 mmol). Amine used as HCl salt.
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), LiHMDS
(1.2 mmol, 1 M in THF). Isolated yields are an average of two runs. b L1
(1 mol %), P1 (1 mol %). c L3 (1 mol %), P3 (1 mol %), 65 °C. d 3.4
equiv (1.7 mmol) of LiHMDS used. e Amine used as HCl salt. f MeNH2 (2
M in THF).
system (P2) is effective for these substrates (1g, 3c).
However, even using this bulkier phosphine ligand, second-
ary 2-aminopyridines (N-methyl- and N-benzyl-2-aminopy-
ridine) remained unreactive. Of the primary amines exam-
ined, we also found that 2,2,2-trifluoroethylamine and
cyclopropylamine did not undergo successful cross-coupling
reactions using BrettPhos (P3).23 Again, the use of t-
BuXPhos (P2) allowed an efficient coupling in the case of
2,2,2,-trifluoroethylamine (2c), although it too was ineffective
in the case of cyclopropylamine (2d).24,25
We next sought to extend the reaction scope to include
halo-benzimidazoles. Both chloro- and bromo-benzimida-
zoles underwent cross-coupling reactions efficiently using
the standard procedures, with RuPhos (P1) or BrettPhos (P2)
precatalysts (Scheme 3). Although some base-sensitive
groups, particularly nitro and ester groups, are not tolerated,
the cross-coupling can be applied to amines containing
We have previously published a brief account of the cross-
coupling of halo-indoles with simple amines using an XPhos-
based catalyst system,11 and we wished to demonstrate the
expanded substrate scope that could be achieved using the
procedure reported herein (Scheme 5). Of the commercially
available 4-, 5-, and 6- halogenated indoles examined, all
participated in successful cross-coupling reactions. Reactions
of both chloroindoles and bromoindoles proceeded with
similar yields, although similarly to chlorobenzotriazole,
chloroindoles required an elevated temperature to achieve
full conversions. Notably, although reactions of 5-iodoindole
were equally efficient when combined with primary amines
(5h,5i), it was considerably less effective when reacted with
secondary amines (5d), in agreement with our previous
findings.26 Functional group compatibility was demonstrated
for both the indole and amine components Via the successful
incorporation of a carboxylic acid (5c), a urea (5b), an aryl
chloride (5b), and a phenolic OH group (5j).
Scheme 3.
Cross-Coupling Reactions of Halo-benzimidazolesa
The absence of examples of 7-substituted heterocyclic
electrophiles in the previous tables is notable. Cross-coupling
reactions of these particular substrates, with both primary
and secondary amines, were found to be particularly chal-
lenging. However, through the use of extended reaction
times, reasonable yields could be obtained in a number of
cases (Scheme 6).
(23) Both of these amines inhibit cross-coupling reactions using
BrettPhos precatalyst (P3) under the standard conditions used in Table
2.
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), LiHMDS
(1.2 mmol, 1 M in THF). Isolated yields are an average of two runs. b L1
(1 mol %), P1 (1 mol %). c L2 (1 mol %), P2 (1 mol %). d L3 (1 mol %),
P3 (1 mol %). e 3.4 equiv (1.7 mmol) of LiHMDS used. f Amine used as
HCl salt. g 16 h.
(24) Kalasinsky, V. F.; Powers, D. E.; Harris, W. C. J. Phys. Chem.
1979, 83, 506–510.
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(26) Fors, B. P.; Davis, N. R.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 5766–5768.
4444
Org. Lett., Vol. 12, No. 20, 2010

Scheme 5
.
Cross-Coupling Reactions of Halo-indolesa
Scheme 6
.
Cross-Coupling of 7-Haloheterocycles with Primary
and Secondary Aminesa
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), LiHMDS
(1.2 mmol, 1 M in THF). Isolated yields are an average of two runs. b L1
(1 mol %), P1 (1 mol %). c L3 (1 mol %), P3 (1 mol %). d L3 (2 mol %),
P3 (2 mol %). e LiHMDS (1 M in toluene). f 80 °C.
tion to a wide range of related heterocyclic systems, allowing
the synthetic chemist to rapidly obtain interesting and
complex molecules.
Acknowledgment. This activity is supported by an
educational donation provided by Amgen and from the
National Institutes of Health Grant (GM-58160) to whom
we are grateful. We also acknowledge the efforts of Sarah
M. McDermott, Department of Chemistry, Massachusetts
Institute of Technology.
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), LiHMDS
(1.2 mmol, 1 M in THF). Isolated yields are an average of two runs. b L1
(1 mol %), P1 (1 mol %). c L3 (1 mol %), P3 (1 mol %). d 80 °C. e 3.4
equiv (1.7 mmol) of LiHMDS used. f 16 h.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products.This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have reported selective, efficient, and
robust general procedures for the functionalization of un-
protected benzofused-heterocyclic halides using Pd-catalyzed
C-N cross-coupling. These procedures should find applica-
OL101929V
Org. Lett., Vol. 12, No. 20, 2010
4445