Site-Selective Intermolecular Oxidative C-3 Alkenylation of 7-Azaindoles at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.5b03429

A previously unexplored palladium-catalyzed C-3 selective alkenylation of 7-azaindoles, performed in the presence of Pd(OAc)₂ as the catalyst, PPh₃ as the ligand, Cu(OTf)₂ as an oxidative cocatalyst, and molecular oxygen (O₂) as the terminal oxidant at room temperature, has been reported. This direct alkenylation strategy offers a new approach in functionalizing pharmaceutically important 7-azaindoles.

Full text of DOI:10.1021/acs.orglett.5b03429

Letter
pubs.acs.org/OrgLett
Site-Selective Intermolecular Oxidative C‑3 Alkenylation of
7‑Azaindoles at Room Temperature
Prakash Kannaboina,†,‡ K. Anil Kumar,†,‡ and Parthasarathi Das*,‡
†Academy of Scientific and Innovative Research (AcSIR), Jammu-Campus, Jammu-180001, India
‡Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Jammu-180001, India
S
* Supporting Information
ABSTRACT: A previously unexplored palladium-catalyzed C-3
selective alkenylation of 7-azaindoles, performed in the presence of
Pd(OAc)2 as the catalyst, PPh3 as the ligand, Cu(OTf)2 as an
oxidative cocatalyst, and molecular oxygen (O2) as the terminal
oxidant at room temperature, has been reported. This direct
alkenylation strategy offers a new approach in functionalizing
pharmaceutically important 7-azaindoles.
ransition-metal-catalyzed direct C−H alkenylations of
During the late-stage preparation of this manuscript, a report
on tandem synthesis of carbazoles has appeared that involves a
sequential C-3 alkenylation/C-2 alkenylation/thermal electro-
cyclization. Only two examples of the preparation of α-carbolines
from 7-azaindoles have been supplemented in this report.9
Recently, we have demonstrated regioselective C-2 arylation of
7-azaindoles.10 Based on our previous experiences and ongoing
interest in functionalizing 7-azaindoles,11 we embarked on an
ambitious objective of achieving regioselective C-3 alkenylation
on 7-azaindoles with alkenes as the other coupling partners.
Herein, we describe, distinct from the previous report, C-3
selective alkenylations of 7-azaindoles with various activated/
unactivated alkenes, affording C-3 alkenylated 7-azaindoles at
room temperature in good to excellent yields (Scheme 1).
T
unfunctionalized arenes with simple alkenes, pioneered
by Fujiwara−Moritani in 1967, have emerged as powerful
variants of Heck reactions, featuring higher atom economy and
efficiency.1 However, a fundamental challenge intrinsic to these
oxidative couplings lies with achieving high selectivity. Never-
theless, regioselective alkenylations have successfully been
achieved largely on arenes,2 electron-rich indoles,3 and other
heteroarenes.4 Given the unique chemical reactivity and
structural properties of 7-azaindoles that are structurally related
to indoles/purines, regioselective arylations have been used as
reaction tools to engender functionalized 7-azaindoles relevant
to pharmaceutical interest.5,6 Toward this endeavor, a significant
effort has been directed to identify drug-like compounds by
designing molecules that incorporate 7-azaindoles containing an
alkenyl group. Therapeutically promising kinase inhibitors are
illustrative examples of 7-azaindoles containing a C-3 alkenyl
group (Figure 1).7
Scheme 1. Schematic Representation of Site-Selective C−H
Bond Functionalization of 7-Azaindole
While N-methyl azaindole is largely used as a successful
coupling partner in the C-2-arylation,12 we considered using 7-
azaindoles with a N-protecting group that could be easily
installed and subsequently removed after the desired operation.
In our initial study, (N-Bn)-7-azaindole was considered as a
coupling partner. However, we observed the formation of a
mixture of C2:C3 (1:2) products with a combined 30% yield in
the presence of Pd(OAc)2 (10 mol %) as a catalyst, AcOH as an
Figure 1. C3-Olefinated 7-azaindoles as anticancer agents.
While site-selective alkenylation of indoles and pyrroles merits
extensive discussion,3 alkenylations of 7-azaindoles have only
been reported by classic intramolecular Heck reaction at the C-3
position to introduce desired molecular complexity into the
target molecule in poor yield.8 However, direct intermolecular C-
3 regioselective alkenylation on 7-azaindoles, to the best of our
knowledge, is unprecedented despite the potential in drug
discovery.
Received: December 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03429
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Organic Letters
Letter
additive, and 1,4-dioxane as a solvent when O2 was used as the
terminal oxidant at 60 °C.13 When we changed the protecting
group from benzyl to the more electron-rich p-methoxy benzyl
(PMB) group, we observed improvement in the selectivity
(C2:C3 = 1:3) as well as in the isolated yield (55%). Thus, in our
optimization study for an oxidative Heck-type coupling reaction,
p-methoxy benzyl (N-PMB)-7-azaindole (1a) and n-butyl
acrylate (2a) were chosen as model substrates. To achieve
optimized conditions for the coupling, various ligand/oxidant
combinations were explored, such as 1,10-Phen, bipy and Ag2O,
AgOAc, AgNO3, Ag2CO3 under N2 at 80 °C for 12 h (Table 1,
regioselectivity of Pd-catalyzed 7-azaindole alkenylation could
be controlled with the help of the ligand in combination with the
proper solvent system. We investigated the scope of N-
substitution on the azaindole moiety, using the optimized
conditions and it was observed that only N-alkyl (N-Me, N-Et, N-
PMB) substituted azaindoles proved to be suitable substrates.
The N-Bn-7-azaindole furnished the corresponding C-3
alkenylated products in moderate yield (40%), while the N-Ar
derivative afforded a poor yield (30%). The other derivatives
such as N-Boc, N-Ts, and N-Ac 7-azaindoles remained inert
under these cross-coupling conditions (Supporting Information
Table S1). Addtional results of the reaction condtions (by
varying the Pd-source, catalyst loading, and “oxygen activator”
catechol) can be found in the Supporting Information (for
details, see Tables S2 and S3).
a
Table 1. Optimization of Reaction Conditions
With the optimized conditions in hand, the scope of this
reaction was explored using various PMB-protected 7-azaindoles
and different alkenes as the two coupling partners (Scheme 2).
b
entry
ligand
oxidant
Ag2O
solvent
yield (%)
c
1
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
bipy
DMF
20
50
55
40
20
65
58
70
75
Scheme 2. Substrate Scope of C3-Alkenylation of N-PMB 7-
c
a
2
AgOAc
DMSO
Azaindoles
c
3
AgNO3
DMSO
c
4
Ag2CO3
AgNO3
DMSO
c
5
DMSO
d
6
PPh3
Cu(OAc)2
Cu(OAc)2·H2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
O2
DMSO
d
7
PPh3
DMSO
d
8
PPh3
DMSO
e
9
PPh3
DMSO
e
f
10
PPh3
DMSO/1,4-dioxane
DMSO/1,4-dioxane
DMSO/1,4-dioxane
DMSO/1,4-dioxane
DMSO/1,4-dioxane
DMSO/1,4-dioxane
80[10]
11
12
13
14
PPh3
10
20
10
10
5
PPh3
BQ
PPh3
PhI(OAc)2
K2S2O8
PPh3
e
15
(o-Tol)3P
Cu(OTf)2
a
Reaction conditions: 1a (1.0 equiv), 2a (2.0 equiv), Pd(OAc)2 (10
b
mol %), ligand (20 mol %), oxidant, solvent (1 mL). Isolated yield.
c
d
Oxidant (2.0 equiv) under N2 at 80 °C. Oxidant (1.0 equiv) under
e
f
air at 50 °C. Cu(OTf)2 (50 mol %), O2 (balloon) at rt. Recovered
starting material in brackets.
entries 1−5). Reaction conditions including Pd(OAc)2 (10 mol
%), 1,10-Phen (20 mol %), and AgNO3 (2.0 equiv) in DMSO
under N2 at 80 °C became beneficial, giving exclusively C3-
alkenylated product in 55% isolated yield (Table 1, entry 3). Next
we screened PPh3, with different oxidants (1.0 equiv) [such as
Cu(OAc)2, Cu(OAc)2·H2O, Cu(OTf)2] in DMSO under air at
50 °C for 12 h (Table 1, entries 6−8), and the C3-alkenylated
product was isolated in good yields (58−70%). Interestingly, a
substoichiometric amount of oxidant Cu(OTf)2 (50 mol %)
under O2 (balloon) at room temperature afforded the
alkenylated product with improved yield (75%) in 6 h (Table
1, entry 9). Finally, we found the combination of Pd(OAc)2 (10
mol %), Cu(OTf)2 (50 mol %), PPh3 (20 mol %), and O2
(balloon) at room temperature in DMSO/1,4-dioxane (3:1)
afforded the best yield of 80% in 6 h (Table 1, entry 10). Use of
PPh3 in combination with other oxidants [such as O2, BQ,
PhI(OAc)2, K2S2O8] in DMSO/1,4-dioxane at rt did not provide
any improvement in the yield (Table 1, entries 11−14). Use of
any other phosphine ligand [(o-Tol)3P] in the presence of
oxidant Cu(OTf)2 (50 mol %) in DMSO/1,4-dioxane (3:1)
under O2 at rt was less effective (Table 1, entry 15). This reaction
is completely selective for C3-alkenylation. In no case was any C2-
alkenylated product detected. This demonstrated that the
a
Reaction conditions: N-PMB-7-azaindole (1.0 equiv), alkene (2.0
equiv), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cu(OTf)2 (50 mol
%), O2 (balloon), DMSO/1,4-dioxane (3:1, 1 mL), and rt.
The reactivities of an array of acrylates were first examined. All
the acrylates used in this reaction gave the corresponding E-
products (3a−d) in excellent yields (70−80%). Besides acrylates,
alkenes such as vinyl phosphonates, sulfonates, and acrylonitrile
(3e−g) have been utilized as coupling partners to furnish the
coupled product in moderate yields (40−55%). A series of
differently substituted 7-azaindoles were subjected to alkenyla-
tion with different acrylates. Interestingly, halo substituted 7-
azaindoles are also compatible with this catalytic system,
affording the desired products (3h−n) in moderate to excellent
yields (50−85%), amenable for molecular complexity. Azaindole
aryl substituted at the C5-position coupled smoothly with
methyl/butyl acrylates to furnish the desired E-alkenylated
products (3o−r) in good yields (70−71%). A somewhat reduced
yield (60%) was observed in the case of heteroaryl substituted
azaindoles (3s). Notably, 7-azaindoles diversely substituted at
both the C3- and C5-position are found in many pharmaceuti-
cally designed compounds.14,6c N-Bn and N-Ar 7-azindole
B
DOI: 10.1021/acs.orglett.5b03429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
derivatives were also investigated. In the case of the N-Bn
derivative the yield is 40% (3t−u), whereas the N-Ar derivative
(3v) gave only a 30% yield. In the presence of C3-substitution
(CHO, OAc, Ph), no alkenylation occurred at the C2-position.
Next, we focused on exploring the scope of different acrylates
with N-methyl 7-azaindoles (Scheme 3). As expected, the
Scheme 4. Substrate Scope with Styrenes
Scheme 3. Substrate Scope of C3-Alkenylation of N-Methyl 7-
a
Azaindole
a
Reaction conditions: N-methyl-7-azaindole (1.0 equiv), alkene (2.0
equiv), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cu(OTf)2 (50 mol
%), O2 (balloon), DMSO/1,4-dioxane (3:1, 1 mL), and rt.
a
Reaction conditions: N-methyl-7-azaindole (1.0 equiv), alkene (2.0
equiv), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cu(OTf)2 (50 mol
%), O2 (balloon), DMSO/1,4-dioxane (3:1, 1 mL), and rt.
to afford exclusively the E-alkenylated products (7m−p) in good
yields (50−80%). The 7-azaindole system bearing heteroaryl
substitutions at the C5-position underwent smooth C3-
alkenylation (7q−r) in moderate yields (55−59%).
acrylates and acrylonitrile undergo smooth conversion to give the
E-alkenylated products (5a−i). To make this coupling more
general, we utilized differently substituted azaindoles (5-Br, 4-Cl,
5-Ar, 6-OMe), and the alkeynyaltion occurred exclusively at the
C3-position. 5-Bromo and 4-chloro-7-azaindoles gave the
olefinated products (5d−f) in good yields (60−85%). Two
more 5-aryl substituted N-methyl substituted azaindoles have
also been tested with methyl acrylate, and the products (5g−h)
obtained in these reactions have been isolated in good yields
(70−72%). The 6-OMe substituted 7-azaindole was smoothly
converted into an alkenylated product (5i) in 65% yield. The
nonactivated alkene allyl acetate, however, failed to give the
coupled product.
To understand the reaction better, we propose a plausible
mechanism (Scheme 5).3 Electophilic palladation of 7-azaindole
Scheme 5. Plausible Reaction Mechanism
Oxidative Heck-type reactions have been reported using
styrenes, but with low yields or with a poor substrate scope.15 To
the best of our knowledge it has never been exercised with
azaindole systems. Therefore, the C3-alkenylation was further
investigated with various styrenes (6) bearing electron-with-
drawing or -donating groups on the phenyl ring to afford the
Heck-type product in moderate to good yields as illustrated in
Scheme 4. When subjected for oxidative coupling with N-methyl-
7-azaindole, the electron-neutral styrene gave the desired
product (7a) in 50% yield. Styrenes containing halo substituents
(p-Cl, p-Br) afforded the alkenylated product (7b−c) in excellent
yields (70−80%). A styrene with an electron-donating group (p-
Me) produced the coupled product (7d) in 60% yield. The N-
PMB-protected 7-azaindoles also work well under the optimized
conditions, as the desired products (7e−k) were isolated in
moderate to excellent yields (50−85%); here the electron-
deficient styrenes afforded higher yields (7h−i) than electron-
rich styrenes (7j−k). It is worth mentioning that the α-
substituted styrene provides the olefinated product (7l) through
Pd−H insertion and immediately β-hydride elimination in
moderate yield (50%).16 In this context, 5-bromo and 4-chloro
substituted 7-azaindoles also have been studied with different
styrenes bearing halogen substitution (F, Cl, Br) in the aryl ring
at the C3 position with a Pd(II) species is favorable due to the
greater nucleophilicity of the C3 position, thereby generating
palladated intermediate B. Then this undergoes alkene insertion
to afford intermediate C. This is followed by β-hydride
elimination to deliver the C3-alkenylated product. Pd(0)
generated from the reductive elimination is then oxidized by
Cu(II) to form the active Pd(II) catalyst, thus completing the
catalytic cycle.
Finally, the N-PMB group of 3a was deprotected by using
boron trichloride17 at rt to generate the free NH 7-azaindole (8),
which led us to realize the synthetic utility of this method
(Scheme 6).
In summary, we have demonstrated a Pd-catalyzed C3-
selective alkenylation of 7-azaindole derivatives at rt. An easily
removed protecting group (PMB) and mild reaction conditions
offer significant flexibility in derivatizing these medicinally
C
DOI: 10.1021/acs.orglett.5b03429
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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important heterocycles with an unexplored and/or a challenging
substitution pattern. In view of the growing understanding in
oxidative Heck-type coupling, the reaction described herein has a
reactivity profile that is significantly different than those
previously reported. Detailed mechanistic investigations and
application in synthesizing designed internal alkene-substituted
medicinally important compounds are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03429.
Complete experimental details and characterization data
for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: partha@iiim.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.K. and A.K. thank CSIR and UGC-New Delhi for their research
fellowship. This research work was financially supported by
CSIR-New Delhi (BSC 0108). IIIM communication no. IIIM/
1867/2015.
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DOI: 10.1021/acs.orglett.5b03429
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