Palladium-catalyzed aminocarbonylation of halo-substituted 7-azaindoles and other heteroarenes using chloroform as a carbon monoxide source

Article abstract of DOI:10.1039/c7cc04339b

A palladium-catalyzed aminocarbonylation of halo-substituted 7-azaindoles utilizing CHCl₃ as the carbonyl source has been developed for the straightforward incorporation of an amide functional group. The protocol was extended to other heteroarenes such as pyrazolopyridines and indazoles. The substrate scope of the reaction with respect to heteroarenes and the amine component is reported. This method offers an alternative avenue for aminocarbonylation of pharmaceutically important heterocycles.

Full text of DOI:10.1039/c7cc04339b

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Palladium-catalyzed aminocarbonylation of halo-substituted 7-
azaindoles and other heteroarenes using chloroform as a carbon
monoxide source
Received 00th January 20xx,
Accepted 00th January 20xx
Prakash Kannaboina,a,b Gaurav Raina,a,b K. Anil Kumar,a,b and Parthasarathi Das a,b,
*
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
Me
A palladium-catalyzed aminocarbonylation of halo-substituted
7-azaindoles utilizing CHCl3 as the carbonyl source has been
Me
O
N
O
NH2
O
Me
NH
NH
O
developed for
a straightforward incorporation of amide
O
functional group. The protocol was extended to other
heteroarenes such as pyrazolopyridines and indazoles. The
substrate scope of the reaction with respect to heteroarenes and
the amine component is reported. This method offers an
alternative avenue for aminocarbonylation of pharmaceutically
important heterocycles.
N
H
NH
N
N
N
N
N
N
H
H
(CH2)5-F
Synthetic Cannabinoid
( NNL-1,2)
EGFR and B-Raf
Dual inhibitor
DF 1012
Cl
N
CF3
N
H
O
N
O
Me
Me
N
N
N
N
Azaindoles are a privileged heterocyclic cores exhibiting significant
biological activities and are utilized as pharmacophores in drug
discovery programs.1 The presence of two neighbouring nitrogen
atoms in a 7ꢀazaindole system, the bioisostere of indole or purine
base, due to their neighbouring hydrogenꢀbond donor and acceptor
properties, have been explored extensively for various therapeutic
indications.2 Two drugs named Vemurafenib and Venetoclax,
containing a 7ꢀazaindole core, recently gained FDA approval, and
several other 7ꢀazaindoleꢀcontaining drugs are in various stages of
clinical development.3 Due to their therapeutic importance, methods
for the synthesis and functionalization of azaindole and derivatives
have attracted considerable interest.4 A particularly interesting subset
of these molecules are therapeuticaly promising amideꢀsubstituted
derivatives (Fig. 1).5 While amide bond formation via transitionꢀ
metal catalyzed direct aminocarbonylation are reported for indole
systems,6 amide bond formation with an azaindole moiety have only
been reported in a traditional way.7
N
N
Me
N
H
Me
CDK8 inhibitor
Granisol (Antiemetic)
Fig. 1 Biologically active 7ꢀazaindole with amide group
other heteroarenes
O
X
N
Pd/L
Amine
Amine
N
N
N
CO
H
N
N
N
1H-pyrazolo[3,4-b]pyridine
PG
7-azaindole
X = I, Br
PG
CHCl3 + KOH
yield up to 81%
28 examples
N
N
H
PG = Me, PMB, Bn
removable PG
chemoselective aminocarbonylation
good functional group tolerability
1H-indazole
Scheme 1 Aminocarbonylation of haloꢀsubstituted 7ꢀazaindoles and
other hetero arenes
Thus, CO surrogate exploration has became an interesting topic in
organic synthesis. Several surrogates such as formic acid,9 formic
acid derivatives10 metal carbonyls,11 acid chlorides,12 silacarboxylic
acids13 and DMF14 have been explored by various groups, including
ours.14b Among the possible candidates, CHCl3 is an attractive CO
surrogate as it is inexpensive and readily available. Literature reports
revealed that in situ generated CO from CHCl3 in the presence of
base has been used in Pdꢀcatalyzed carboxylation,15 Feꢀcatalyzed
Transitionꢀmetalꢀcatalyzed direct carbonylation has become an
efficient method for synthesizing a variety of highly valued
compounds.8 The carbonyl installation can be achieved mainly by
using carbon monoxide (CO). However, the challenge is in the
handling of CO because it is a toxic gas available in pressurized
cylinders, which limits its practical utility.
carbonylation,16
aminocarbonylations,17
Heckꢀtype
domino
a.Medicinal Chemistry Division, Indian Institute of Integrative Medicine
(CSIR), Jammu 180001, India. E-mail: partha@iiim.ac.in
b.Academy of Scientific and Innovative Research (AcSIR), New Delhi-
110025, India
Electronic Supplementary Information (ESI) available: [Full
experimental details and characterization data for all products]. See
DOI: 10.1039/x0xx00000x
cyclization,18 and carbonylative Sonogashira coupling.19 Moreover,
direct amide bond formation via aminocarbonylation of 7ꢀ
azaindoles/pyrazolo pyridines/indazoles to the best of our knowldge
is unprecedented. Based on our previous experiences on
chemoselective Cꢀarylation20 and siteꢀselective Cꢀ3 alkenylation of
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 2015, 00, 1-3 | 1
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7ꢀazaindoles,21 we embarked on this ambitious objective. Herein we With the optimized reaction conditions in hand, the substrate with
report a Pdꢀcatalyzed aminocarbonylation on Nꢀprotected haloꢀ respect to PMB/Meꢀprotected azaindole and amines was
substituted 7ꢀazaindole with various amines using CO generated in investigated, and the results are summarized in Table 2. Various
situ from CHCl3 and KOH (Scheme 1). This protocol is general and amines (acyclic, cyclic and aromatic) have been examined, and the
was extended to another two important heterocycles, 1Hꢀpyrazolo corresponding amides (3a-i) are isolated in good yields (50ꢀ81%).
[3,4ꢀb]pyridine and 1Hꢀindazole, in synthesizing biologically Interestingly, haloꢀsubstituted 7ꢀazaindoles are also compatible with
important amide derivatives.5aꢀb
this catalytic system, and
the reaction
was completely
Our investigation began by carrying out the reaction of 3ꢀiodoꢀNꢀ chemoselective (3j-l). Pyrrolidine gave higher yield (3k, 76%)
PMBꢀ7ꢀazaindole 1a (1.0 equiv) with pyrrolidine 2a (1.3 equiv), compared to nꢀbutylamine and aniline (3j, 3l, 50 and 35%),
KOH (10 equiv), CHCl3 (5.0 equiv), Pd(PPh3)4 (2 mol %), and PPh3 amenable for further molecular complexity. It is worth mentioning
(10 mol %) in a sealed vial under N2. After reaction in toluene at 80 o that under the optimized conditions, no BuchwaldꢀHartwig type (Cꢀ
C for 12 h, the desired product 3 was obtained albeit in 20% yield N bond) crossꢀcoupled products were detected.
(Table 1, entry 1). Control experiments showed that both the CHCl3
and the Pd(OAc)2 catalyst along with base were essential for the Table 2 Cꢀ3 Aminocarbonylation of haloꢀsubstituted 7ꢀazaindolesa
O
reaction (Table 1, entries 2ꢀ3). Without the phosphine ligand, the
Amine
I
Pd(OAc)2 (2 mol %)
dppf (10 mol %)
KOH (10 equiv)
CHCl3 (3 equiv)
toluene, 80 oC, 12 h
yield of target product reduced to 5% compared to the initial
conditions, indicating that the phosphine ligand is beneficial to the
reaction (Table 1, entry 4). Subsequently, different phosphine
ligands TFP, SPhos, JohnPhos, XantPhos, dppf were investigated
and dppf was found to be the most efficient ligand (Table 1, entries
5ꢀ9). Use of DMAP did not provide any improvement in the yield
(Table 1, entry 13). Other Pd sources were also examined in the
presence of 10 mol % dppf. The results show Pd(OAc)2 to be the
more effective catalyst for this reaction compared to PdCl2 and
Pd(PPh3)2Cl2. In addition, different solvents were examined, and
toluene was the best compared with other solvents. Temperatures
lower or higher than 80 °C reduced the yields of the target product.
These results led to the following optimized reaction conditions: 1a
(1.0 equiv), 2a (1.3 equiv), CHCl3 (3 equiv), (10 equiv) of KOH as
the base, and 2 mol % of Pd(OAc)2 and (10 mol % ) of dppf as the
ligand in toluene at 80 °C under N2 for 12 h (Table 1, entry 9).
Amine
N
N
N
N
PG
PG
3a-l
O
O
O
O
NBOC
N
N
N
N
N
N
PMB
N
N
N
PMB
PMB
3c
, 60%
3b
, 57%
3a
, 81%
O
O
H
Me
O
N
N
N
N
OMe
OMe
N
N
N
N
N
N
MeO
PMB
Me
PMB
3f
, 71%
3e
3d
, 50%
, 53%
O
O
O
O
O
S
N
N
N
Table 1 Optimization of the reactionsa
OCF3
N
N
N
N
N
3g
Cl
N
Me
Me
Me
3h, 59%
3i, 72%
, 57%
H
N
O
O
H
O
N
N
Br
Br
N
N
N
N
N
N
Me
Me
3l, 35%
Me
3k, 76%
entry catalyst
ligand
base
solvent
yieldb
Me
3j, 50%
1c
2
3
Pd(PPh3)4
none
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
none
KOH
KOH
none
KOH
toluene
dioxane
toluene
pꢀxylene
20
n.r.
n.r.
5
aReaction conditions: NꢀPGꢀ7ꢀazaindole (1.0 equiv), amine (1.3 equiv),
Pd(OAc)2 (2 mol %), dppf (10 mol %), KOH (10 equiv), CHCl3 (3.0 equiv)
in toluene (1 mL), at 80 oC, 12 h.
4
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TFP
SPhos
JohnPhos KOH
XantPhos KOH
dppf
dppf
KOH
KOH
toluene
toluene
mesitylene n.r.
toluene
toluene
10
8
Next we focused our attention on the aminocarbonylation of the
azine ring of haloꢀsubstituted 7ꢀazaindole. Interestingly, in 7ꢀ
azaindole systems the crossꢀcoupling reaction in the azole ring (2
and 3) positions is well documented, whereas coupling in azine ring
(4, 5 and 6 positions) has rarely been reported.22 Thus, to make this
coupling more general, we utilized both 4ꢀ, and 5ꢀbromo derivatives
with differently substituted (Cꢀ2 aryl, Cꢀ3 alkenyl) 7ꢀazaindoles with
various amines under the optimized conditions (Table 3). In the case
of 4ꢀbromoꢀ7ꢀazaindoles, the desired products (4a-c) are isolated in
excellent yields (61ꢀ70%). When the reaction was carried out with
PMB/Bn/Meꢀprotected 5ꢀbromoꢀ7ꢀazaindole utilizing various
secondary amines, the aminocarbonylation occured smoothly and
afforded the 5ꢀamide substitutedꢀ7ꢀazaindoles (5a-f) in moderate to
62
81(10)
80
KOH
CsOH toluene
H2O
KOH
KOH
KOH
11
PdCl2
dppf
toluene
toluene
toluene
10
12
13d
Pd(PPh3)2Cl2 dppf
Pd(OAc)2 DMAP
53
trace
aReaction conditions: NꢀPMBꢀ7ꢀazaindole (1.0 equiv), amine (1.3 equiv),
Pd(OAc)2 (2 mol %), ligand (10 mol %), base (8ꢀ10 equiv), CHCl3 (3ꢀ8
equiv) solvent (1 mL), under N2; bisolated yield c20 mol % PPh3 was used;
d20 mol % DMAP was used; recovered starting material in parentheses;
n.r. = no reaction
2 | J. Name., 2012, 00, 1-3
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good yields (36ꢀ63%). For amino carbonylation at the Cꢀ5 position In our next attempt, we applied this palladiumꢀcatalyzed
XantPhos has been used as a ligand choice (for details see aminocarbonylation procedure to these type of heterocyclic systems
Supporting Information, Table S1). Interesting to note is that the (Table 4). First, the reaction was carried out with PMBꢀprotected 3ꢀ
olefinic ester (5d) group is well tolerated under the optimized iodo 1Hꢀpyrazolo [3,4ꢀb]pyridine, and the desired amide products
conditions.
(6a-c) were isolated in good yields (57ꢀ70%). A 5ꢀnitroꢀsubstituted
Cꢀ4/Cꢀ5 Aminocarbonylation of haloꢀsubstituted 7ꢀ indazole under went smooth aminocarbonylation to afford the
desired product (7a; 43%), which is amenable to further
Table
3
azaindolesa
Pd(OAc)2 (2 mol %)
ligand (10 mol %)
transformation. The THP protectedꢀ5ꢀbromo indazoles yielded the
O
aminocarbonylated products (7b-c) in moderate yields (36ꢀ40%).
Finally, we focused on exploring the synthesis of Cꢀ3 aryl and Cꢀ5
amideꢀsubstituted 7ꢀazaindole, which was achieved under palladiumꢀ
catalyzed conditions involving haloꢀsubstituted 7ꢀazaindole with
boronic acid followed by CHCl3 and KOH with amine. Accordingly,
two bonds were formed through two distinct reactions by using
palladium as a catalyst in a oneꢀpot (43%) process (Scheme 2).
Amine
Br
N
N
Amine
KOH (10 equiv)
CHCl3 (3 equiv)
toluene, 80 oC, 12 h
N
N
PG
4a-c 5a-f
PG
;
O
O
N
O
N
O
N
F3CO
N
N
N
N
N
N
Me
Me
Me
4a,
4c
, 70%
67%
4b
, 61%
O
O
N
N
N
COBHN
N
N
N
PMB
5b, 58%b
PMB
b
5a
O
, 60%
CO2Me
O
N
N
N
O
N
N
N
Scheme 2 Tandem oneꢀpot crosscoupling
PMB
5d, 52%b
PMB
5c, 36%b
O
O
According to previous literature15b,17 and the above observed results,
a plausible mechanism is proposed in Scheme 3. In the first step, the
oxidative addition of haloꢀsubstituted 7ꢀazaindole on Pd(0)L2 and 1
generates an arylpalladium species A, which provides the
intermediate B by CO insertion (in situ from chloroform and
KOH).17a Thereafter, an amine nucleophile undergoes ligand
displacement, resulting in the formation of complex C.24 Then, the
generated complex C undergoes reductive elimination to afford the
N
N
OMe
O
N
N
S
N
N
Me
bBn
b
5e
, 50%
5f
, 63%
aReaction condition: NꢀPGꢀ7ꢀazaindole (1.0 equiv), amine (1.3 equiv),
Pd(OAc)2 (2 mol %), dppf (10 mol %), KOH (10 equiv), CHCl3 (3.0 equiv)
in toluene (1 mL), at 80 OC, 12 h; b XantPhos (10 mol %), at 80 oC, 12 h.
Pyrazolopyridineꢀ and Indazoleꢀ bearing amide functional groups in
the C3 and C5 positions are biologically important molecules.23,5b
X
final product.
O
Amine
N
N
Table 4 Substrate scope with other heteroarenesa
1
Pd(0)L2
PG
oxidative addition
N
N
PG
L
Product
L
reductive elimination
O
L
Pd(II)
X
L
Pd
Amine
A
N
N
N
PG
N
PG
L
Pd
C
O
L
CO + KCl + H2O
X
Amine
N
PG
N
KOH
CHCl3
B
Scheme 3 Plausible reaction mechanism
In summary, we have developed a Pd catalyzed aminocarbonylation
of haloꢀsubstituted 7ꢀazaindole and related heterocyclic frameworks
with diversified amine nucleophiles using CO generated in situ from
CHCl3 and KOH. The protocol is an extremely convenient and safe
alternative to CO balloons or pressured CO reactors essentially
required for aminocarbonylations. The method allows the modular
Reaction conditions: NꢀPGꢀindazole (1.0 equiv), amine (1.3 equiv), Pd(OAc)2
(2 mol %), dppf (10 mol %), KOH (10 equiv), CHCl3 (3.0 equiv) in toluene
(1 mL), at 80 oC, 12 h; b XantPhos, at 80 oC, 12 h.
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synthesis of aminocarbonylꢀfunctionalized 7ꢀazaindole and related
heteroarenes with high functional group tolerance in good yields and
is directly amenable to structural diversification. We believe this
method will emerge as an alternative for incorporation of the amide
group into medicinally important heterocycles.
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P. K thankful to CSIRꢀNew Delhi and G. R, K. A. K. thankful to
UGCꢀNew Delhi for their research fellowship. This research work
financially supported by CSIRꢀNew Delhi (BSC 0108).
b
c
,
d
e
) X.ꢀ
) X.ꢀ
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