Efficient Pd-catalyzed amination of heteroaryl halides

Article abstract of DOI:10.1021/ol0514754

(Chemical Equation Presented) The Pd-catalyzed amination of a variety of heteroaryl halides has been accomplished by utilizing bulky electron-rich biaryl phosphine ligands. In particular, we report the first couplings of amines with chloro- and bromoindoles bearing a free NH, as well as the first Pd-catalyzed aminations of a 5-halopyrimidine.

Full text of DOI:10.1021/ol0514754

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3965-3968
Efficient Pd-Catalyzed Amination of
Heteroaryl Halides
Mark D. Charles, Phillip Schultz, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received June 23, 2005
ABSTRACT
The Pd-catalyzed amination of a variety of heteroaryl halides has been accomplished by utilizing bulky electron-rich biaryl phosphine ligands.
In particular, we report the first couplings of amines with chloro- and bromoindoles bearing a free NH, as well as the first Pd-catalyzed
aminations of a 5-halopyrimidine.
The Pd-catalyzed formation of C-N bonds is a rapidly
expanding area of research.1 Since the first general and
efficient procedures were discovered,2 efforts toward increas-
ing the substrate scope and efficiency have been investigated.
In some cases, the use of alternative bases or solvents can
be beneficial; however, electronic and steric tuning of the
supporting ligand has had the most impact on increasing
reactivity and efficacy in these processes.1 A few years ago
we reported the use of biaryl monophosphine ligands for a
variety of Pd-catalyzed reactions.3 These ligands have been
shown to be very effective in C-N bond-forming pro-
cesses.4,5 In this paper, we describe their use in the Pd-
catalyzed amination of several heteroaryl halides.
As heterocycles represent a very important class of
compounds in biology and pharmaceuticals,6 the selective
functionalization of these molecules is of great interest. The
use of Pd-catalyzed C-N coupling with heteroaryl substrates
has been documented in many instances.1,7-12 We sought to
expand the scope of heterocyclic substrates that could be
utilized, with a particular focus on employing substrates not
amenable toward nucleophilic aromatic substitution.
(6) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles
in Life and Society; John Wiley & Sons: Weinheim, 1997.
(7) (a) Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D.
R. Tetrahedron Lett. 2000, 41, 7731-7735. (b) Watanabe, M.; Yamamoto,
T.; Nishiyama, M. Chem. Commun. 2000, 133-134. (c) Ogawa, K.; Radke,
K. R.; Rothstein, S. D.; Rasmussen, S. C. J. Org. Chem. 2001, 66, 9067-
9070. (d) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2003, 68, 2861-2873.
(1) (a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; John Wiley &
Sons: Weinheim, 2004. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (c) Hartwig, J. F. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-I., de Meijere, A., Eds.; Wiley-Interscience: Weinheim, 2002.
(2) (a) Guram, A. S.; Rennels, R, A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348-1350. (b) Driver, M. S.; Hartwig, J. F. Tetrahedron
Lett. 1995, 36, 3609-3612.
(8) Hooper, M. W.; Hartwig, J. F. Organometalllics 2003, 22, 3394-
3403.
(9) Selected examples: (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371-1375. (b) Kamenecka,
T. M.; Lanza, T.; de Laszlo, S. E.; Li, B.; McCauley, E. D.; Van Riper, G.;
Egger, L. A.; Kidambi, U.; Mumford, R. A.; Tong, S.; MacCoss, M.;
Schmidt, J. A.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 2002, 12, 2205-
2208. (c) Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611-4614.
(10) Yin, J. J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 4, 3481-3484.
(11) Hong, Y.; Tanoury, G. J.; Wilkinson, S. H.; Bakale, R. P.; Wald,
S. A.; Senanayake, C. H. Tetrahedron Lett. 1997, 38, 5607-5610.
(12) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry:
Pergamon: Oxford, 2000.
(3) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722-9723.
(4) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174.
(5) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
10.1021/ol0514754 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/10/2005

The bulky electron-rich biaryl ligands discovered within
our group were employed for these reactions (Scheme 1).
These ligands are commercially available13 and air stable;
the reaction setup is experimentally simple and does not
require the use of a glovebox.
thianaphthene provided only moderate yields of products.
By utilizing 2 or 3, higher conversions and yields were
obtained (Table 1). At 0.5-1 mol % Pd, 3 proved to be
superior to 2. Anilines and cyclic secondary amines were
viable substrates. However, reactions with acyclic secondary
amines afforded low yields of desired products, as extensive
amounts of hydro-dehalogenated material were formed. This
result is consistent with the recent proposal that reductive
elimination is the problematic step for reactions of these
classes of substrates.8 Curiously, this paper also suggests,
on the basis of stoichiometric model studies, that the coupling
of aniline with halothiophenes should be inefficient. The
result shown in entry 5 (Table 1) is in conflict with this
supposition.
Scheme 1. Bulky Biaryl Electron-Rich Ligands Used in the
Amination of Heterocycles
Although chloro- and bromopyridines have been employed
as effective coupling partners in Pd-catalyzed amination
reactions,9 simple 5-bromopyrimidines have, to the best of
our knowledge, not been used. Utilizing 1-3, a number of
amines could be coupled with 5-bromopyrimidine in good
to excellent yields (Table 2). In particular, functionalized
anilines were viable coupling partners in the presence of a
weak base, K3PO4 (Table 2, entries 2-4).
We began by investigating the amination of bromo- and
chlorothiophenes, a topic that has been examined by several
groups.7 However, the substrate scope remains limited, and
only reactions with bromothiophene derivatives have afforded
products in acceptable yields. Although 1 has been employed
in various C-N bond-forming processes, its use for the
amination of 2- and 3-chlorothiophene as well as 3-bromo-
Table 2. Pd-Catalyzed Amination of 5-Bromopyrimidinea
Table 1. Pd-Catalyzed Amination of Thiophenesa
a Reaction conditions: 1 mol % Pd2dba3, 4 mol % ligand, 1.4 equiv of
NaOt-Bu, 1.2 equiv of amine in toluene at 100 °C. b Yields are an average
of two runs. c General procedure 1 (Supporting Information) was used.
d Pd(OAc)2 was used in place of Pd2dba3.
a Reaction conditions: 2 mol % Pd2dba3, 8 mol % ligand, 1.4 equiv of
base, 1.2 equiv of amine in toluene at 100 °C. b Yields are an average of
two runs. c General procedure 1 (Supporting Information) was used. d K3PO4
was used in place of NaOt-Bu.
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Org. Lett., Vol. 7, No. 18, 2005

Table 3. Pd-Catalyzed Amination of Benzoxazoles and
Benzothiazolesa
Table 4. Pd-Catalyzed Amination of Haloindolesa
a Reaction conditions: 1 mol % Pd2dba3, 4 mol % ligand, 2.2 equiv of
LiHMDS, 1.2 equiv of amine in THF at 65 °C. b Yields are an average of
two runs. c General procedure two was used.
formed. The reaction of N-methylaniline and an equimolar
mixture of 2-bromopyrimidine and 5-bromopyrimidine with
1 yielded only a trace amount of the amination product
derived from 5-bromopyrimidine. Since the coupling of
5-bromopyrimidine with N-methylaniline proceeds in excel-
lent yield (Table 2, entry 1), it is likely that 2-bromo-
pyrimidine is a catalyst poison. Although the exact mecha-
nism of catalyst poisoning is unknown, it is possible that
the oxidative addition product of 2-bromopyrimidine to the
catalyst renders it inactive.
Our next focus was on the amination of benzothiazoles
and benzoxazoles. Although activated benzothiazoles and
benzoxazoles have been used as coupling partners in Pd-
catalyzed amination processes,9a,14 no examples of aminations
with the nonactivated counterparts are known.
a Reaction conditions: Pd2dba3/ligand ratio ) 1:4, 1.4 equiv of NaOt-
Bu, 1.2 equiv of amine in toluene at 100 °C. b Yields are an average of
two runs. c General procedure 1 (Supporting Information) was used.
d Reaction was performed at 25 °C. e Reaction was performed at 50 °C.
f Reaction was performed at 70 °C. g K3PO4 was used in place of
NaOt-Bu.
These substrates were effectively coupled with a variety
of amines in good to excellent yields (Table 3). One
exception includes the reactions of 2-methyl benzothiazole
and benzoxazoles with alkylamines. In these cases, lower
yields resulted (Table 3, entry 2), which we attribute to the
deprotonation of the 2-methyl substituent by NaOt-Bu
followed decomposition or formation of unidentified side
products. For example, the reaction of 2-methyl-5-chloro-
benzoxazole with piperidine proceeded to full conversion,
but only a 50% yield of product was isolated. Replacing the
2-methyl group with a phenyl moiety16 in the benzoxazole
suppressed any side reactions; the reaction of 2-phenyl
benzoxazole with piperidine proceeded to nearly quantitative
yield (Table 3, entry 7).
Unfortunately, the reactions of alkylamines with 5-bromo-
pyrimidine were inefficient. We note that we have previously
shown that primary amines can be coupled with 5-bromo-
pyrimidine in high yield using a Cu catalyst.14
Attempts to couple 2-bromopyrimidine with various
amines did not yield any of the desired product. This was a
surprising result, as oxidative addition should be more rapid
to 2-bromopyrimidine than to 5-bromopyrimidine.15 The
coupling of 2-chloropyrimidine with amines has been
reported to occur in excellent yield utilizing the chelating
ligand, Xantphos.10
To distinguish differences in reactivity between 2- and
5-bromopyrimidine, a competition experiment was per-
(13) Ligands used in this report are commercially available from Strem
and Aldrich.
(14) Kwong, F. K.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796.
(15) See ref 12, pp 375-376.
(16) 2-Phenyl-5-chlorobenzoxazole was synthesized in 53% isolated yield
in an analogous fashion to a published procedure, using trimethyl orthoben-
zoate in place of trimethyl orthoformate. Kunz, K. R. Org. Prep. Proc. Int.
1990, 22, 613-618.
Org. Lett., Vol. 7, No. 18, 2005
3967

The products from the coupling of 2-chlorobenzothiazole
with piperidine, dibutylamine, and indole were isolated in
92, 97, and 73% yield, respectively (Table 3, entries 3-5).
In fact, the reaction of piperidine with 2-chlorobenzothiazole
proceeded to full conversion at room temperature. However,
it is important to note that when this reaction is conducted
under the same conditions, in the absence of catalyst, a 62%
yield of product is obtained via a nucleophilic aromatic
substitution pathway. As shown (Table 3, entry 8), a
functionalized aniline could be used if K3PO4 was employed.
51% of the desired product. However, acceptable yields for
the coupling of 6-chloroindole with piperidine were only
obtained with 1. Attempts to effect the amination of
5-chloroindole with amines such as n-Bu2NH resulted in
competitive incorporation of an NH2 group derived from the
LiHMDS.
In conclusion, we have expanded the scope of the Pd-
catalyzed amination to include a range of activated and
nonactivated heteroaryl chlorides and bromides. 5-Bromo-
pyrimidine and unactivated benzoxazoles and benzothiazoles
are viable substrates. Additionally, we have demonstrated
the first aminations of 5- and 6-haloindoles containing a free
indolic NH group.
Finally, 5-bromoindole and 6-chloroindole, both possessing
a free NH, were viable coupling partners with anilines and
acyclic and cyclic secondary alkylamines (Table 4). These
transformations are particularly useful, as extra protection/
deprotection steps are not required. Using a procedure we
reported a few years ago,17 in these examples 2.2 equiv of a
strong base, LiHMDS, were employed. The use of weaker
bases such as Cs2CO3 was found to be ineffective. Best
results were obtained by utilizing 4 for the reactions with
5-bromoindole with aniline and morpholine (Table 4, entries
1 and 2). The more difficult reaction with n-Bu2NH afforded
Acknowledgment. We thank Johnson and Johnson PRD,
LLC, and the National Institutes of Health (GM58160) for
funding. We also thank Tim Barder for assistance in
preparing the manuscript.
Supporting Information Available: Detailed experi-
mental procedures and characterization data of each com-
pound. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885-
2888.
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