Palladium-catalyzed amination of unprotected halo-7-azaindoles

Article abstract of DOI:10.1021/ol101928m

Simple and efficient procedures for the Pd-catalyzed cross-coupling of primary and secondary amines with halo-7-azaindoles(pyrrolo[2,3-b]pyridine) are presented. Previously, no general method was available to ensure the highly selective reaction of the heteroaryl halide in the presence of the unprotected azaindole N-H. Using palladium precatalysts recently reported by our group, such reactions are easily accomplished under mild conditions that can be applied to cross-coupling reactions with a wide array of aliphatic and aromatic amines.

Full text of DOI:10.1021/ol101928m

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4438-4441
Palladium-Catalyzed Amination of
Unprotected Halo-7-azaindoles
Jaclyn L. Henderson, Sarah M. McDermott, 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
Simple and efficient procedures for the Pd-catalyzed cross-coupling of primary and secondary amines with halo-7-azaindoles(pyrrolo[2,3-
b]pyridine) are presented. Previously, no general method was available to ensure the highly selective reaction of the heteroaryl halide in the
presence of the unprotected azaindole N-H. Using palladium precatalysts recently reported by our group, such reactions are easily accomplished
under mild conditions that can be applied to cross-coupling reactions with a wide array of aliphatic and aromatic amines.
Azaindoles have been receiving increased attention from the
pharmaceutical and agrochemical industries over the past
decade, due both to their potential as indole-isosteres and as
interesting core structures in their own right.1,2 The substitu-
tion of a carbon by a nitrogen not only confers altered
electronic properties but also adds a potential hydrogen bond
acceptor, which can form the basis for altering the physi-
cochemical or biological properties of a compound.3 The
close proximity of hydrogen bond donor and acceptor sites
also distinguishes azaindoles as important substructures in
dyes, ligands for transition metals, and novel materials.2,4
Despite their utility, methods for the synthesis and
functionalization of azaindole scaffolds remain limited. The
majority of methods provide N-1, C-2, or C-3 substituted
structures, with few offering general solutions to function-
alization of the pyridine ring.2,5-7 A particularly interesting
subset of these molecules are amino-substituted azaindoles,
which appear in a variety of biologically active molecules
(Figure 1)8-12 and can be particularly challenging or lengthy
to prepare Via reported methods. Amino-7-azaindoles are
often accessed from the corresponding halide Via SNAr
displacement reactions, which typically require high tem-
peratures, extended reaction times, and a large excess of the
amine partner.13 Furthermore, 5-haloazaindoles are not
suitable substrates for SNAr, nor are some amines. Alternative
approaches employ the amino-substituted azaindole as the
key intermediate, which can be challenging to prepare.14
Our approach to the synthesis of amino-azaindoles is to
use Pd-mediated cross-coupling technology15-18 for the
(8) Blake, J.; Gunawardana, I. W.; Le, H. Y.; Mohr, P. J.; Wallace,
E. M.; Wang, B. Pyrrolo[2,3-b]pyridines as CHK1 and CHK2 kinase
inhibitors for the treatment of Various diseases and preparation thereof.
Patent WO 2009089352, 2009
.
(9) Mortimore, M.; Young, S. C.; Everitt, S. R. L.; Knegtel, R.; Pinder,
J. L.; Rutherford, A. P.; Durrant, S.; Brenchley, G.; Charrier, J. D.;
O’Donnell, M. Preparation of 5-cyano-4-(pyrrolo[2,3-b]pyridin-3-yl)pyri-
(1) Lednicer, D. Strategies for Organic Drug Synthesis and Design, 2nd
midines as polo-like kinase (PLK) inhibitors. Patent WO2008/79346 , 2008.
ed.; Wiley: Hoboken, 2009
(2) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J. Y. Tetrahedron
2007, 63, 1031–1064
.
(10) Ruggeri, S. G.; Hawkins, J. M.; Makowski, T. M.; Rutherford, J. L.;
Urban, F. J. Process for preparation of piperidinylaminopyrrolopyrimidines
from actiVated pyrrolopyrimidines and piperidinylamines. Patent WO
.
(3) Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.; Mawer, I. M.;
Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S. B.; Marwood, R.; Patel,
S.; Ragan, C. I.; Leeson, P. D. J. Med. Chem. 1996, 39, 1941–1942.
2007012953 A2, 2007.
(11) Heinrich, T.; Blaukat, A.; Staehle, W.; Greiner, H.; Kordowicz,
M. NoVel aza heterocycles serVing as kinase inhibitors. Patent WO
(4) Hudson, Z. M.; Wang, S. Acc. Chem. Res. 2009, 42, 1584–1596
.
2006114180, 2006.
(5) Merour, J. Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471–506
(6) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z. L.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. ReV. 2007, 36, 1120–1132
(7) Prokopov, A. A.; Yakhontov, L. N. Pharm. Chem. J. 1994, 28, 30–
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(12) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino, S. J. Org.
Chem. 1995, 60, 5899–5904
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10.1021/ol101928m  2010 American Chemical Society
Published on Web 09/22/2010

Figure 2. Biarylphosphine ligands and precatalysts.
halo-indoles and simple amines could be achieved using
LiHMDS as the base, in conjunction with either an XPhos
(L3)- or DavePhos (L6)-based catalyst system.27
An examinination of Pd precatalysts based on our biaryl
phosphine ligands revealed that cross-coupling between
4-chloroazaindole and N-methylpiperazine occurred rapidly
at catalyst loadings as low as 0.5 mol % (Table 1). A
Figure 1. Pharmacologically active compounds containing the
amino-azaindole motif.
reaction of halo-azaindoles with amines. Although azaindoles
have previously been reported to undergo arylation of the
heterocyclic N-H nitrogen in the presence of copper or
palladium catalysts,19,20 the cross-coupling of halo-azaindoles
has received little attention.21-23 Haloazaindoles present a
particular challenge for two reasons: the donor-acceptor
system of the two adjacent nitrogens forms an excellent
chelating ligand for metals, and there is the potential for
homocoupling between the halide and azaindole N-H.
Our recently reported precatalyst systems (Figure 2,
P1-P5),24,25 which are efficiently converted to an active
monoligated Pd(0) complex when exposed to base, provided
a potentially attractive solution to the first problem. We
speculated that the preligated palladium species would prove
more resistant to undesirable azaindole coordination. To
address the second issue of azaindole homocoupling, we
hypothesized that the use of a strong base such as LiHMDS,
which would fully deprotonate both the amine and azaindole
substrates, might reduce the rate of undesired transmetalation
to Pd.26 Previous studies in our group support this hypothesis,
having demonstrated that the cross-coupling of unprotected
Table 1. Catalyst Systems Used for the Coupling of
4-Chloroazaindole and N-Methylpiperazinea
entry Pd source (mol %)
ligand (mol %)
time yield, %
1
2
3
4
5
6
7
8
P1 (0.5)
P2 (0.5)
P3 (0.5)
P4 (0.5)
Pd(OAc)2 (0.5)
Pd2dba3 (0.25)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
L1 RuPhos (0.5)
L2 SPhos (0.5)
L3 XPhos (0.5)
30 min
30 min
30 min
94
81
90
0
80
33
0
L4 t-BuXPhos (0.5) 30 min
L1 RuPhos (1)
L1 RuPhos (1)
rac-BINAP (2)
Xantphos (2)
30 min
30 min
4 h
4 h
0
a Reagents and conditions: 4-chloroazaindole (0.5 mmol), N-methylpip-
erazine (0.6 mmol), LiHMDS (1.2 mmol, 1 M in THF).
(15) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. AdV. Synth.
Catal. 2006, 348, 23–39
.
(16) Tasler, S.; Mies, J.; Langa, M. AdV. Synth. Catal. 2007, 349, 2286–
2300
.
(17) Torborg, C.; Beller, M. AdV. Synth. Catal. 2009, 351, 3027–3043
(18) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
.
combination of RuPhos (L1) and RuPhos precatalyst (P1)
proved to be the most effective system for this transforma-
tion, providing the product in 94% yield after 30 min (Table
1, entry 1), although SPhos (L2) and XPhos (L3) were also
effective (Table 1, entries 2 and 3). Interestingly, Pd(OAc)2
can also be employed in lieu of a Pd precatalyst (Table 1,
entry 5). However, the rate of formation of Pd(0) from
phosphine and Pd(OAc)2 is highly amine-dependent, thus
precatalyst P1 was chosen for subsequent studies.28
Chem. 2006, 4, 2337–2347
(19) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688
.
.
(20) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2,
1403–1406
.
(21) Guillard, J.; Decrop, M.; Gallay, N.; Espanel, C.; Boissier, E.;
Herault, O.; Viaud-Massuard, M. C. Bioorg. Med. Chem. Lett. 2007, 17,
1934–1937
(22) Thibault, C.; L’Heureux, A.; Bhide, R. S.; Ruel, R. Org. Lett. 2003,
5, 5023–5025
(23) Thutewohl, M.; Schirok, H.; Bennabi, S.; Figueroa-Perez, S.
Synthesis 2006, 629–632
(24) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686–6687
(25) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
.
.
.
(26) Biscoe, M. R.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2007, 46, 7232–7235.
.
(27) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7,
3965–3968.
Chem. Soc. 2008, 130, 13552–13554
.
Org. Lett., Vol. 12, No. 20, 2010
4439

Alternative base and solvent combinations were also
examined (Table 2), as there have been isolated reports of
Scheme 1
.
Cross-Couplings of 4-Azaindole with Secondary
Aminesa
Table 2. Examination of Base and Solvent Combinations for the
Cross-Coupling of 4-Chloroazaindolea
entry
base
solvent
temp, °C
time
16 h
16 h
16 h
16 h
16 h
30 min
4 h
yield, %
1
2
3
4
5
6
7
8
9
Cs2CO3
NaOt-Bu
K3PO4
K2CO3
K2CO3
LiHMDS
LiHMDS
LiHMDS
LiHMDS
toluene
toluene
toluene
toluene
tBuOH
THF
dioxane
toluene
THF
110
110
110
110
110
65
80
80
rt
0
7
0
0
0
94b
91b
68b
42b
4 h
16 h
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), L1 (1 mol
%), P1 (1 mol %), LiHMDS (1.2 mmol, 1 M in THF). Isolated yields are
an average of at least two runs. b L1 (0.5 mol %), P1 (0.5 mol %), 30 min.
c 3.6 equiv of LiHMDS.
a Reagents and conditions: 4-chloroazaindole (0.5 mmol), N-methylpip-
erazine (0.6 mmol), L1 (1 mol %), P1 (1 mol %), base (1.2 mmol), solvent
(1 mL). b L1 (0.5 mol %), P1 (0.5 mol %).
employing NaOt-Bu or Cs2CO3 as base for the cross-coupling
reaction of unprotected halo-azaindoles.21-23 We found that
procedures using these bases were ineffective with our
catalyst systems (Table 2, entries 1-5), with LiHMDS in
THF proving optimal in terms of reaction time and temper-
ature. Interestingly, the cross-coupling also proceeded at
room temperature (Table 2, entry 9), although longer reaction
times and higher catalyst loadings were required for complete
conversion. Milder temperatures could be more convenient
for parallel reactions or for those involving sensitive sub-
strates.
Scheme 2.
Cross-Coupling of 5- and 6-Haloazaindolesa
We next applied this Pd-based cross-coupling process to
a range of both aliphatic and aromatic secondary amines with
4-chloroazaindole. High yields and selectivities were ob-
served in all cases examined (Scheme 1).29 By the addition
of an extra equivalent of LiHMDS, amines containing a
second protic functional group could be employed, allowing
access to products containing phenols (1b), aliphatic alcohols
(1e), or more hindered secondary amines (1c). Not unexpect-
edly, 4-bromoazaindole displayed reactivity similar to that
of its chloro analogue (1b).
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), L1 (1 mol
%), P1 (1 mol %), LiHMDS (1.2 mmol, 1 M in THF). Isolated yields are
an average of at least two runs. b 3.6 equiv of LiHMDS. c L1 (2 mol %),
P1 (2 mol %).
Without any alteration of the reaction conditions, we also
found that 5-bromoazaindole (2a-2f), 6-chloroazaindole (2f),
and the related 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2g)
were effective coupling partners with a similarly wide range
of secondary amines (Scheme 2). 5-Bromo-3-chloro-7-
azaindole (2h) underwent reaction exclusively at the 5-posi-
tion, with no diamination or coupling of the chloride
observed.30
(28) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
925–928.
(29) In no instance was arylation of the azaindole N-H nor the formation
of amino-azaindoles through reaction with LiHMDS observed.
(30) In the absence of Pd, the halo-azaindoles do not undergo reaction
with N-methylpiperazine under the reaction conditions.
4440
Org. Lett., Vol. 12, No. 20, 2010

Finally, we explored the cross-coupling of haloazaindoles
with primary amines (Scheme 3). We have previously
underwent efficient cross-coupling with aliphatic, aromatic,
and heteroaromatic amines without any other modification
of the reaction parameters. While again, in some cases,
Pd(OAc)2 can be used as the Pd source, the importance of
using the precatalyst (P5) is highlighted in example 3a. In
cases where the reacting amine lacks a ꢀ-hydrogen atom,
Pd(OAc)2 cannot be reduced, and thus no cross-coupling
occurs. We also found that the addition of extra ligand is
not always necessary. For example, 3a was isolated in a yield
of 88% in both the presence or absence of an extra equivalent
of BrettPhos (L5).
Scheme 3.
Cross-Coupling Using Primary Aminesa
In summary, we have developed operationally simple and
efficient methods for the cross-coupling of unprotected halo-
7-azaindoles with a wide range of primary and secondary
amines. Notably this reaction can be performed in the
presence of a variety of protic functional groups. The success
of these reactions further demonstrates the advantages of
conducting Pd-catalyzed cross-coupling reactions using met-
allacyclic precatalysts such as P1 and P5, as these precata-
lysts permit rapid Pd activation in the presence of a wide
range of substrates.
a Reaction conditions: ArX (0.5 mmol), amine (0.6 mmol), L5 (1 mol
%), P5 (1 mol %), LiHMDS (1.2 mmol, 1 M in THF). Isolated yields are
an average of at least two runs. b No reaction when Pd(OAc)2 (1 mol %)
used in place of P5. c Amine purified before use.
Acknowledgment. This work is supported by an educa-
tional donation provided by Amgen and from the National
Institutes of Health Grant (GM-58160) to whom we are
grateful.
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.
reported that catalyst systems based on BrettPhos (L5) are
superior to other biarylphosphines for the cross-coupling of
primary amines and provide exceptional selectivity for
monoarylation.25 Using this system (P5), haloazaindoles
OL101928M
Org. Lett., Vol. 12, No. 20, 2010
4441