Synthesis of Substituted 4-, 5-, 6-, and 7-Azaindoles from Aminopyridines via a Cascade C-N Cross-Coupling/Heck Reaction

Article abstract of DOI:10.1021/acs.orglett.6b01500

A practical palladium-catalyzed cascade C-N cross-coupling/Heck reaction of alkenyl bromides with amino-o-bromopyridines is described for a straightforward synthesis of substituted 4-, 5-, 6-, and 7-azaindoles using a Pd₂(dba)₃/XPhos/t-BuONa system. This procedure consists of the first cascade C-N cross-coupling/Heck approach toward all four azaindole isomers from available aminopyridines. The scope of the reaction was investigated and several alkenyl bromides were used, allowing access to different substituted azaindoles. This protocol was further explored for N-substituted amino-o-bromopyridines.

Full text of DOI:10.1021/acs.orglett.6b01500

Letter
pubs.acs.org/OrgLett
Synthesis of Substituted 4‑, 5‑, 6‑, and 7‑Azaindoles from
Aminopyridines via a Cascade C−N Cross-Coupling/Heck Reaction
†
†
̃
Marina J. D. Pires, Diogo L. Poeira, Sara I. Purificac a̧ o, and M. Manuel B. Marques*
LAQV@REQUIMTE, Departamento de Química, Faculdade de Cien
Caparica, 2829-516 Caparica, Portugal
̂
cias e Tecnologia, Universidade Nova de Lisboa, Campus de
*
S Supporting Information
ABSTRACT: A practical palladium-catalyzed cascade C−N
cross-coupling/Heck reaction of alkenyl bromides with amino-
o-bromopyridines is described for a straightforward synthesis
of substituted 4-, 5-, 6-, and 7-azaindoles using a Pd (dba) /
2
3
XPhos/t-BuONa system. This procedure consists of the first
cascade C−N cross-coupling/Heck approach toward all four
azaindole isomers from available aminopyridines. The scope of
the reaction was investigated and several alkenyl bromides
were used, allowing access to different substituted azaindoles. This protocol was further explored for N-substituted amino-o-
bromopyridines.
zaindoles are bioisosteres of the indole nucleus, a
privileged structure, which have enticed the interest of
availability of aminopyridines, they have been scarcely explored
on cascade reactions toward azaindole synthesis.
A
1
,2
the scientific community for their physicochemical
and
To our knowledge, the reported cascade methods toward the
azaindole nucleus involving amino-ortho-halogenated pyridines
rely on reaction with ketones via formation of an imine
intermediate followed by Heck reaction of the corresponding
3
,4
pharmacological properties with potential applications in the
field of medicinal chemistry. Recently, several bioactive
azaindole have been described, including the synthetic
analogues of the natural variolins, possessing CDK (cyclin-
16,17
enamine.
However, azaindoles are only attained in good
5
,6
7−11
dependent kinase) inhibitory activity among others.
Due
yields when either cyclic ketones under microwave conditions,
pyruvate derivatives, or activated aromatic ketones are used.
Strategies to obtain imine/enamine from deactivated ketones
and amino-ortho-halogenated pyridines are scarce; they
generally require harsh reaction conditions; they possess low
to their important value, methods for the synthesis of
azaindoles and derivatives have attracted considerable interest
12,13
from the scientific community.
Common synthetic strategies to prepare azaindoles rely on
the use of aminopyridines, followed by building up the pyrrole
ring. The strategy parallels the indole synthesis starting from
anilines. However, the electron-deficient nature of the pyridine
ring alters the electronic properties of the conjugated system in
such a way that many classic indole synthetic methods are not
functional group tolerance; and chemo- and stereoselectivity
16,24
are compromised.
Furthermore, these imine intermediates
are very prone to hydrolysis. Consequently, metal-catalyzed
approaches toward imines and enamines have been devel-
25,26
oped.
Simultaneously to our work, Nolan and co-workers
14
as efficient or simply do not work. Several synthetic routes to
reported the α-arylation of stable preformed imines from 3-
amino-o-chloropyridines to achieve the corresponding 4- and 6-
azaindoles, yet for 5- and 7-azaindoles the method proved to be
prepare azaindole from aminopyridines have been developed,
14
involving classic Pd-catalyzed reactions, such as Sonogashira
1
5
16,17
(
(
Scheme 1A, eq 1), Heck (Scheme 1A, eq 5),
and Suzuki
22
unsuitable.
1
8
Scheme 1A, eq 6) couplings; Pd-catalyzed reactions, also
Our group has been employing metal-catalyzed cross-
applied for the indole synthesis, such as the Larock indole
19
coupling reactions for the preparation of bioactive heterocycles
synthesis (Scheme 1A, eq 2); and the reported methods by
27,28
20
21
such as indole and benzimidazole.
Herein, we report a
Lautens (Scheme 1A, eq 3) and Cacchi (Scheme 1A, eq 4).
practical method to synthesize azaindoles, indole bioisosteres,
from amino-o-bromopyridines and alkenyl bromides via a Pd-
catalyzed cascade amination/Heck coupling (Scheme 1B). Our
initial intent was to achieve substituted azaindoles using
imines/enamines as key intermediates, obtained from com-
mercially available amino-o-bromopyridines and aryl ketones.
We turned our attention to the preparation of imine/enamine
Nevertheless, these methods were shown to have some
drawbacks such as being not fully regioselective, having a
limited substrate scope, or requiring the preparation of a
specific molecular template. Additionally, most methods are
restricted to the preparation of only one or two azaindole
1
2,22
isomers.
Aminopyridines are challenging starting materials in metal-
2
3
catalyzed reactions due to the chelating properties of the
pyridine ring and especially due to their electronics; each
aminopyridine has a distinct reactivity. Thus, despite the
Received: May 24, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01500
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (A) Reported Synthetic Routes for the
Preparation of Azaindoles from Aminopyridines. (B)
Cascade Alkenyl Amination/Heck Reaction Involving
Amino-o-Bromopyridines
amino-o-bromopyridines were chosen as starting materials.
Prompted by the bromine positioned ortho to the amine group,
a cascade C−N/Heck reaction seems to occur, consisting of an
efficient route toward the challenging azaindole core.
In order to established the reaction conditions, 4-amino-3-
bromopyridine (1a) and α-bromostyrene 2a were used as
29
models and t-BuONa as base (Table 1). After confirmation of
Table 1. Influence of Pd/Ligand (L) and Solvent in the
Cascade Alkenyl Amination/Heck Reaction
3
a/4a
time
(h)
(yield,
b
entry cat. (mol %)
L
base (equiv)
solvent
toluene
%)
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
Pd(OAc)2
5)
L1 t-BuONa
24
24
24
96
48
24
24
48
24
24
24
24
24
24
24
3a
(
(2)
a
a
a
a
d
d
d
d
c
Pd (dba)3
L1 t-BuONa
toluene
toluene
toluene
toluene
toluene
t-BuOH
t-BuOH
toluene
toluene
dioxane
dioxane
t-BuOH
t-BuOH
4a /3a
2
(
5)
(2)
Pd (dba)3
L2 t-BuONa
3a
2
(
5)
(2)
Pd (dba)3
L3 t-BuONa
3a
2
(
5)
(2)
Pd (dba)3
L4 t-BuONa
3a
2
(
5)
(2)
e
e
e
e
e
e
e
Pd (dba)3
L5 t-BuONa
4a (29)
4a (26)
4a (27)
4a (34)
4a (50)
4a (29)
4a (42)
4a (57)
4a (69)
4a (35)
2
(
4)
(3)
Pd (dba)3
L5 t-BuONa
2
(
4)
(3)
Pd (dba)3
L5 t-BuONa
2
(
4)
(3)
Pd (dba)3
L6 t-BuONa
2
(
4)
(3)
f
0
1
2
3
4
5
Pd (dba)3
L6 t-BuONa
2
(
10)
(3)
derivatives via Pd catalysis using Buchwald ligands (Figure 1).
In the designed strategy, the first synthetic step consisted of a
d
d
d
f
Pd (dba)3
L6 t-BuONa
2
(
4)
(3)
Pd (dba)3
L6 NaHMDS
(3)
2
(
4)
Pd (dba)3
L6 t-BuONa
2
(
4)
(3)
Pd (dba)3
L6 t-BuONa
2
(
10)
(3)
d
e
Pd (dba)3
L6 t-BuONa
toluene: t-
2
(
4)
(3)
BuOH
(
1:1)
d
1
6
t-BuONa
t-BuOH
24
(
3)
a
Conditions: 1a (1 equiv), 2a (1 equiv), a 1:2 molar ratio of Pd/
b
ligand, c = 0.25 M, temp = 105−110 °C. Imine 3a and azaindole 4a
1
c
d
were detected by TLC and H NMR; yield after isolation. Traces. 1
1 equiv), 2 (1.5 equiv), a 1:2 molar ratio of Pd/ligand, base (3 equiv),
(
e
f
c = 0.1 M, temp = 105−110 °C. Traces of imine. 10 mol % of
Pd (dba) and 20 mol % of L6 were used.
2
3
the imine 3a formation, the first attempts on the synthesis of
azaindole 4a consisted of a search for the best catalytic system
Figure 1. Buchwald ligands studied (L).
(
Table 1, entries 1−5). When Pd(OAc) was used as palladium
2
source, SPhos (L1) as ligand, and t-BuONa as base in toluene,
only the imine 3a was observed (Table 1, entry 1). Under the
same reaction conditions but with Pd (dba) as catalyst, traces
Buchwald−Hartwig amination of alkenyl bromides that has
been reported to involve in situ imine/enamine formation.
It was expected that primary aminobromopyridines would
give the corresponding imine products that are in tautomeric
equilibrium with the less stable enamine (Scheme 1B).
Gratifyingly, the azaindole nucleus could be observed when
2
3
of the azaindole 4a were detected (Table 1, entry 2). On
pursuing the best Pd/ligand system, different Buchwald
30,31
ligands
were tested (Figure 1), e.g., bulky electron-rich
biphenyl phosphines (DavePhos, L5; SPhos, L1; JohnPhos, L4;
B
DOI: 10.1021/acs.orglett.6b01500
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
JackiePhos, L2; and XPhos, L6) and a bidentate ligand
Scheme 2. Scope of Cascade Alkenyl Amination/Heck
a
(
XantPhos, L3).
When L2, L3, and L4 were employed, only the imine
Reaction with Amino-o-bromopyridines 1
product 3a was observed (Table 1, entries 3, 4 and 5,
respectively). Furthermore, longer reaction times did not
promote the formation of 4a (Table 1, entries 4 and 5). The
use of L5 (Table 1, entry 6) led to the formation of azaindole
4
a, but the reaction was still not complete, and after isolation a
29% yield was achieved. At this point, we decided to investigate
t-BuOH as solvent in combination with L5, but without
significant improvements (Table 1, entries 7 and 8).
Subsequently, L6 was considered as ligand and a 34% yield
of 4a was achieved (Table 1, entry 9). The catalyst loading was
explored, and increasing the amount of the catalytic system to
1
0 mol % of Pd (dba) and 20 mol % of L6 led to 50% yield
2 3
(
Table 1, entry 10).
Next we investigated the use of dioxane as solvent, and a
slightly lower yield was observed when t-BuONa was used as
base (Table 1, entries 9 vs 11). When a stronger base such as
NaHMDS was used, 4a was isolated in 42% yield (Table 1,
entry 12).
Surprisingly, L6 in t-BuOH gave azaindole 4a as the only
product in 57% yield (Table 1, entry 13). Best results were
obtained using the previous conditions with a higher catalyst
loading (10 mol % of Pd (dba) and 20 mol % of L6, Table 1
2
3
entry 14) with 69% of 4a. A mixture of toluene/t-BuOH (1:1)
was also tested (Table 1, entry 15), although it was shown to be
less efficient than t-BuOH alone. Moreover, no reaction
occurred in the absence of the catalyst (Table 1, entry 16).
With the optimized reaction conditions in hand, the scope of
the reaction was studied with respect to the four types of
commercially available amino-o-bromopyridines: 4-amino-3-
bromopyridine (1a); 3-amino-2-bromopyridine (1b); 3-
amino-4-bromopyridine (1c); and 2-amino-3-bromopyridine
a
Conditions: 1 (1 equiv), 2 (1.5 equiv), Pd (dba) (4 mol %), XPhos
2
3
b
(8 mol %), t-BuONa (3 equiv), 0.1 M t-BuOH. A 69% yield was
achieved with 10 mol % of Pd (dba) and 20 mol % of L6.
2
3
(
1d) with various alkenyl bromides 2 (Scheme 2).
Initial experiments were carried with amino-o-bromopyr-
present method is suitable for the preparation of 2-substituted
and 2,3-disubstituted azaindoles, representing a direct and
regioselective approach.
idines 1 and α-bromostyrene 2a. The 3-amino-2-bromopyridine
1b) gave the best result with 82% yield, followed by 1a (57%),
c (48%) and 1d (19%), as a consequence of the differences of
(
1
It was anticipated that N-substituted aminobromopyridines
would provide the corresponding enamine, promoting the
intramolecular Heck reaction (Scheme 1B). Due to the interest
in a straightforward access to 1,2-diarylazaindoles, this approach
would consist of a simple route, avoiding, for example, the N-
arylation of 2-substituted azaindoles, that has been shown to be
aminopyridines reactivity.
The results obtained for 1b with 2a encouraged us to explore
this aminopyridine with some other alkenyl bromides. Thus, 2-
bromo-2-butene (cis/trans) (2b) was reacted with 1b to furnish
12,32,33
2
,3-dimethyl-4-azaindole (4e) in 28% yield. β-Bromostyrene
difficult for the 2-substituted azaindoles.
Thus, we
(cis/trans) 2c was also tested under the selected reaction
efficiently prepared N-phenylamino-o-bromopyridines (5a−d)
34
conditions to attain 3-phenyl-4-azaindole, but in trace amounts,
isolated from a very complex mixture, detected by H NMR
by reacting 1 with iodobenzene in high to excellent yields
(79−99%) using Pd (dba) (4 mol %) L3 (8 mol %) and t-
1
2
3
(see the SI). These results suggest that beyond 1b electronics
BuONa (2 equiv) (see the SI).
alkenyl bromide substitution also influences the cascade
reaction success.
In the first attempts, the reaction of N-phenylaminobromo-
pyridines 5a−d with 2a did not seem to occur under the
previous conditions. The same result was observed when the
reaction was performed with 2b. These results did not surprise
us, given that N-arylated aminopyridines 5 are more sterically
hindered than the corresponding primary aminopyridines, even
though when DavePhos L5 was employed as ligand the 1,2-
diphenyl-4-azaindole was isolated in low yield (see the SI). This
result suggests that this route might indeed furnish 1,2-
diarylated azaindoles; however, a careful Pd/ligand optimiza-
tion is required. Currently, the N-arylation of the azaindole
nucleus can be performed according to the reported
Furthermore, 2-bromo-1-butene (2d) was used with the four
amino-o-bromopyridines 1, and the azaindoles 4f−i were
obtained in moderate yields. In the expectation that cyclic
alkenyl bromides would afford more stable imines/enamines,
the bromide 2e was also reacted with the different amino-
pyridines 1. Gratifyingly, azaindole 4j was obtained in 85%
yield, and the other azaindoles 4k−m were also obtained in
moderate yields.
Vinyl bromide 2f was reacted with 1a−d; however, only 7-
azaindole was observed in 9% yield (see the SI). Once again,
the results obtained suggest that the presence of an alkyl/aryl
substituent geminal to the bromine at the alkenyl moiety might
favor azaindole formation. These observations indicate that the
32,33,35−38
procedures.
In summary, we have developed a novel straightforward
synthesis of substituted 4-, 5-, 6-, and 7-azaindoles using a
C
DOI: 10.1021/acs.orglett.6b01500
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Pd (dba) /XPhos/t-BuONa system. This is the first example of
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2
3
a cascade amination/Heck reaction of alkenyl bromides with
amino-o-bromopyridines. The cascade approach proved to be
successful when readily available primary aminopyridines were
used. Lastly, several alkenyl bromides were employed, allowing
access to various substituted azaindoles. Therefore, this route
constitutes a novel platform for ready access to the indole
bioisostere core, an important scaffold in medicinal chemistry
and material science.
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ASSOCIATED CONTENT
Supporting Information
■
(
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01500.
(
3
307−3310.
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AUTHOR INFORMATION
Corresponding Author
(
■
(
5
(
5
*E-mail: mmbmarques@fct.unl.pt.
Author Contributions
†
D.L.P. and S.I.P. contributed equally to this work.
(
Notes
Bismuto, A.; Buccolini, G.; Curcio, M.; Cavallo, L.; Nolan, S. P. ACS
The authors declare no competing financial interest.
Catal. 2016, 6, 2930−2938.
(
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We thank to the FC&T for fellowship SFRH/BD/89518/2012.
This work was supported by the Associated Laboratory for
Sustainable Chemistry- Clean Processes and Technologies-
LAQV which is financed by national funds from FCT/MEC
UID/QUI/50006/2013) and cofinanced by the ERDF under
the PT2020 Partnership Agreement (POCI-01-0145-FEDER-
07265). The NMR spectrometers are part of The National
NMR Facility, supported by Fundaca para a Ciencia e
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D
DOI: 10.1021/acs.orglett.6b01500
Org. Lett. XXXX, XXX, XXX−XXX