Palladium Catalyzed Regioselective C4-Arylation and Olefination of Indoles and Azaindoles

Article abstract of DOI:10.1002/adsc.201801378

A convergent strategy for the synthesis of biologically relevant C4-substituted indole scaffolds was demonstrated using Pd(II)-catalyzed remote C?H functionalization of indoles and azaindoles. The reaction displays high regioselectivity for the C4-positio

Full text of DOI:10.1002/adsc.201801378

Title: Palladium Catalyzed Site-Selective C4-Arylation and Olefination
of Indoles and Azaindoles
Authors: Thrimurtulu Neetipalli, Arnab Dey, Anurag Singh, Kuntal Pal,
Debabrata Maiti, and Chandra Mouleeswara Rao Volla
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801378
Link to VoR: http://dx.doi.org/10.1002/adsc.201801378

10.1002/adsc.201801378
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium Catalyzed Regioselective C4-Arylation and
Olefination of Indoles and Azaindoles
Neetipalli Thrimurtulu, Arnab Dey, Anurag Singh, Kuntal Pal, Debabrata Maiti,*
Chandra M. R. Volla*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400076, India
Phone: +91-2225767188, Fax: +91-2225767152, email: *DM: dmaiti@chem.iitb.ac.in, *CMRV:
Chandra.volla@chem.iitb.ac.in
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
enables the activation of C-H bonds. Later, the
groups of Hu[9] and Ge[10] also demonstrated sp3 C-H
arylation reactions of aliphatic aldehydes using
acetohydrazone and 3-aminopropanoic acid as
transient directing groups respectively. Pd(II)-
catalyzed sp2 C-H activation of benzaldehyde
derivatives was realized by Sorensen and co-workers
for the synthesis of fluorenones.[11] Very recently,
direct ortho sp2 C-H arylation of aryl ketones was
illustrated by Jin and co-workers using glycine.[12]
Despite these advances, transient directing group
mediated Pd(II)-catalyzed C-H functionalization
reactions were largely limited to aryl rings.[13]
Implementation of this strategy for the C-H activation
of heteroaryl rings was less studied.
Abstract. A convergent strategy for the synthesis of
biologically relevant C4-substituted indole scaffolds was
demonstrated using Pd(II)-catalyzed remote C–H
functionalization of indoles and azaindoles. The reaction
displays high regioselectivity for the C4-position of indole-
3-carbaldehydes using glycine as an inexpensive transient
directing group. Notable features of this transformation
include the selective formation of six-membered
palladacyle and excellent functional group tolerance.
Keywords: C-H activation; Palladium; Transient directing
group; Indoles; Regioselective
In the past decade, directing group assisted C–H
activation has been established as an extremely
powerful and efficient strategy for accessing complex
heterocyclic skeletons.[1] Successful execution of
these approaches is also finding applications in
natural product synthesis.[2] Recently, more
challenging distal C–H bond functionalization gained
a lot of attention.[3] Although excellent progress was
made in the transition-metal catalyzed C-H activation
reactions facilitating a variety of directing groups,
only limited reports were available for the aldehyde-
directed C-H functionalization, probably due to the
weak coordinating ability of the carbonyl group.[4]
This issue is often addressed by converting the
aldehyde group into more competent imine or oxime-
directing groups.[5] However, such methods require
additional synthetic steps for the installation and
removal of the directing group, which impede the
overall reaction efficiency. An alternative strategy of
forming the directing group transiently, which will
reversibly bind to the metal-catalyst was suggested by
Jun and co-workers for the Rh-catalyzed
hydroacylation of alkenes with aldehydes.[6,7]
Following similar approach, Yu and co-workers
described an elegant -amino acid mediated Pd(II)-
catalyzed sp3 C-H arylation of o-tolualdehydes and
aliphatic ketones.[8] The bidentate chelation of imine
nitrogen and carboxylate moiety to Pd(II)-catalyst
HO
Me
Me
H
O
Me
H
HO
N
H
O
Me
Me
Me
Me
H
Me
Me
N
OH
H
H
N
H
Me
N
N
H
N
N
H
H
H
Lysergic acid
Agroclavine
cis-Claviciptic acid
Petromindole
Me
N
N
Me
N
Me
H
N
Me
N
O
N
Me
N
H
GSK 1070916 (Aurora B/C Kinase inhibitor)
Figure 1. Biologically active C4-subsutituted indoles and
azaindoles.
On the other hand, indole and azaindole skeletons
are widely present in many natural and unnatural
biologically active compounds and pharmaceuticals
(Figure
1).[14]
Transition-metal
catalyzed
regioselective C-H functionalization of indoles would
offer a direct approach for the construction of diverse
array of indole skeletons.[15] Functionalization of
1
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10.1002/adsc.201801378
Advanced Synthesis & Catalysis
indoles at the C3 and C2-positions were well
established due to the high electron density of the
pyrrolic ring. In contrast, diversification of the
benzenoid moiety of indoles and related heterocycles
such as azaindoles at C4, C5, C6 and C7 positions
has been gaining prominence only recently.[16]
Inspired by the broad occurrence of C4-substituted
indole skeletons, we envisioned developing a
transient directing group mediated bidentate chelation
strategy for the sp2 C–H functionalization at the C4-
position of indole-3-carbaldehydes. The initial
challenge associated with the envisioned project was
the potential competition of C4 position with C2
position.
the C4-arylation of indoles using pivaloyl directing
group (Scheme 1c).[20] A single example of a transient
directing group mediated C4-arylation of N-tosyl-3-
fomylindole was reported by Yu and co-workers
(Scheme 1d).[21] In spite of these elegant reports,
development of a general Pd-catalyzed C4-selective
arylation and olefination of indoles and azaindoles is
highly desirable (Scheme 1e).
We began the investigation using cheap and
commercially available glycine as the transient
directing group for the C4-arylation of N-benzyl-1H-
indole-3-carbaldehyde 1a with iodobenzene 5a.[22]
Using 10 mol% of Pd(OAc)2 and 2.0 equiv. of
o
AgTFA at 110 C, initial solvent screening was
carried out and we were delighted to see the
formation of desired product 6a as a single
regioisomer in 69% of NMR yield in a 1:1 solvent
mixture of AcOH and HFIP (hexafluoroisopropanol).
Compound 6a was unambiguously characterized
through X-ray crystallography.[23] The arylation
proceeded exclusively at the C4-position by selective
a) Prabhu et al. and Jia et al.
R
O
O
H
H
H
Ru(II) cat/Rh(III) cat..
+
R
H
H
N
N
Bn
Bn
b) You et al.
O
H
formation of
a
six-membered palladacycle
Ts
O
H
NH
H
intermediate (vide infra). No C2-arylation product
Cp*Ir(III)-cat.
Ts-N3
1
H
+
H
was observed in the H NMR of the crude reaction
N
H
N
mixture. Based on the observation by Yu and co-
workers,[8] we tested the effect of H2O additive in the
transient directing group mediated C4-arylation and
indeed using an esoteric mixture of AcOH/HFIP/H2O
(1:1:0.1, v/v), we observed the formation of 6a in an
improved NMR yield of 86% (isolated yield of 82%).
The effect of glycine as a transient directing group is
evident as in the absence of glycine no reaction was
observed. Other amino carboxylic or sulfonic acids
were also tested instead of glycine, however only
lower yields were observed in these cases. Using
glycine methyl ester instead of glycine led to no
reaction indicating the importance of the carboxylic
acid moiety for the formation of 5-membered
palladacycle intermediate.
H
c) Shi et al.
O
H
O
t-Bu
Ar
t-Bu
Pd(0) cat./Ag2O
Ar-I
Ar-I
+
H
H
N
N
Bn
Bn
d) Yu et al.
O
O
H
H
H
single example
Ar
H
H
Pd(II) cat.
+
Me Me
N
N
Ts
H2N
COOH
Ts
e) This work
O
O
H
H2N
I
Pd(II)-cat.
O
H
H
H
OH
+
O
H
via
O
N
X
N
X
R
R
Pd
AcO
N
H
H
O
O
H
I
H
H
Pd(OAc)2 (10 mol%)
N
X
+
Glycine (2 eq.), AgTFA(2 eq.),
AcOH/HFIP/H2O, 110 oC
36-72 h
N
R
N
R
R
1-4
5a
6-9
Scheme 1. Overview of the work.
O
O
N
O
H
O
H
H
H
The importance of C4-decorated indoles in natural
product synthesis, materials science and medicinal
chemistry inspired several groups to study
regioselective direct C4 functionalization of indoles.
In 2013, Prabhu and co-workers reported a C4-H
alkenylation of 3-formylindoles using Ru(II)-salts
(Scheme 1a).[17] Jia and co-workers developed
Rh(III)-catalyzed olefination of unprotected indoles
and demonstrated its application in the synthesis of (-
)-agroclavine and (-)-elymoclavine.[18] Around the
same time, an Ir(III)-catalyzed C4-amidation was
illustrated by You and co-workers using sulfonyl
azides (Scheme 1b).[19] Shi and co-workers
established an elegant Pd(0)-catalyzed strategy for
N
N
N
H
Me
Bn
Ts
7a, 48%
8a, 79%
6a, 82%
9a, 80%
CCDC 1823267
Scheme 2. Indole arylation with different N-protecting
groups.
To evaluate the generality of this new transformation,
we tested the role of nitrogen protecting groups
(Scheme 2). Unprotected or N-methyl or N-tosyl
protected 3-formylindoles 2-4 provided the
corresponding C4-arylated products 7a-9a in 48%,
79% and 80% respectively (Scheme 2).
2
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10.1002/adsc.201801378
Advanced Synthesis & Catalysis
R4
R2
O
O
H
O
H
H
H
O
I
I
H
H
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
R3
Glycine (2 eq.), AgTFA (2 eq.),
AcOH/HFIP/H2O, 110 oC
36-72 h
+
+
Glycine (2 eq.), AgTFA (2 eq.),
AcOH/HFIP/H2O, 110 oC
36-72 h
R3
R2
N
N
R1
N
R1
R2
N
R1
R4
R1
R2
5
1 or 2
6 or 7
5
1 or 2
6 or 7
Ph
Me
Me
Me
Me
O
H
O
H
O
H
O
O
H
O
H
H
Me
N
Me
N
N
Bn
N
N
N
Bn
Bn
Bn
Bn
Bn
6m, 82%
6n, 80%
6o, 88%
6a, 82%
6b, 92%
6c, 88%
Me
Me
Me
t-Bu
Ph
Me
O
O
O
O
H
O
H
H
O
N
O
O
H
H
H
Me
Me
N
N
N
Bn
Bn
Bn
N
N
Bn
Bn
Bn
6p, 80%
Me
6q, 80%
6r, 90%
6d, 82%
6e, 83%
6f, 90%
Me
NO2
OMe
O
O
O
H
H
H
O
O
HO
H
H
N
N
Cl
Br
N
Cl
Bn
Bn
Bn
N
N
CCDC 1823266
6s, 71%
6t, 60%
6u, 83%
Bn
6g, 68%
Bn
CCDC 1871890
F3C CF3
6h, 90%
F3C
MeO
O
Me
O
O
O
H
H
O
H
O
H
H
O
H
N
N
N
Br
Br
Br
H
N
N
Bn
Bn
Bn
Bn
6w, 75%
6v, 81%
7v, 40%
N
Bn
CCDC 1823268
6i, 80%
6j, 91%
O
Me
NO2
6k, 45%
Scheme 4. Substrate scope with diverse 3-formylindoles.
O
O
H
H
We further elaborated the scope of this reaction with
differently substituted 3-formylindoles (Scheme 4).
Notably, 2-methyl substituted indole derivative led to
N
N
H
Bn
6l, 60%
7k, 41%
selective sp2
the
corresponding products 6m, 6n in 82% and 80%
respectively. This clearly indicates the preferential
formation of cyclic six membered palladacycle
intermediate by C4-H sp2 C-H activation. The
reaction was also applicable to 6-aryl substituted
indolyl aldehydes (6o-6r). Intriguingly, 6-chloro and
6-bromo indoles provided the corresponding
functionalized products (6s-6v) in synthetically useful
yields. The structures of 6s and 6v were confirmed
unambiguously by X-ray crystallography.[23] In the
case of C5-substituted indole, the reaction was
sluggish and even after prolonged heating, no product
was observed probably because of increased steric
hindrance.
Scheme 3. Substrate scope with diverse aryl iodides.
In order to thoroughly outline the utility of this
method, we systematically tested a number of aryl
iodides. A wide variety of electron rich and electron
poor aryl iodides were investigated. As shown in
Scheme 3, the reaction is compatible with a range of
substituents and 4-tert-butylphenyl iodide (6d) and 4-
biphenyl iodide (6e) did not affect the yield and
selectivity. Several valuable functional groups such
as acetyl (6f), hydroxyl (6g), methoxy (6h, 6i),
trifluoromethyl (6j), keto (6k, 7k) and nitro (6l)
groups were well tolerated at different positions of
the aromatic ring. Hydroxy substituent in the ortho-
position of aryliodide resulted in only a moderate
yield of 68% (6g) probably because of both
unfavourable electronic and steric effects.
3
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10.1002/adsc.201801378
Advanced Synthesis & Catalysis
R2
alcohol derivative 15 in 81% yield (Scheme 7a). The
formyl directing group can be removed easily from
the C4-arylated 3-formylindole 6a under Pd(II)-
catalysis to give 16 in 75% yield (Scheme 7b).[25] Our
initial attempts to isolate any reaction intermediate
met with no success. To gain some insights into the
reaction mechanism, H/D scrambling experiments
were carried out. Under the optimized reaction
conditions, 1a was treated with a mixture of
CH3COOD/HFIP/D2O (1:1:0.1 v/v) and after 6 h
around 7% of H/D scrambling was observed at C4-
position. Interestingly, no significant H/D exchange
was observed at C2-position (Scheme 7c). Analogous
experiment carried in the presence of 5a also showed
no scrambling at the C2-position of 6a and 12% H/D
exchange was observed in the recovered starting
material 1a (Scheme 7d).
O
H
H
O
I
H
Pd(OAc)2 (10 mol%)
+
Glycine (2 eq.), AgTFA(2 eq.),
AcOH/HFIP/H2O, 110 oC
36-72 h
N
N
N
R1
R2
5
N
R1
10
11
Ph
O
H
O
H
O
H
N
N
N
N
Bn
11b, 45%
N
Me
N
Bn
11a, 61%
11c, 51%
Scheme 5. Scope of the reaction with 7-azaindoles.
The versatility of this Pd(II)-catalyzed C–H
activation was further expanded to biologically active
and therapeutically important azaindole core (Scheme
5).[24] As expected, N-methyl azaindole derivative
10a underwent the C H activation to provide C-4
arylated azaindole 11a in 61% using 10 mol% of
Pd(OAc)2. The scope of the reaction with N-benzyl
protected azaindole aldehyde 10b was investigated
with iodobenzene (11b, 45%) and 4-phenyl-
iodobenzene (11c, 51%).
Pd(PPh3)4 (4 mol%)
(a) gram scale and functionalization of products
O
Na2CO3, toluene-EtOH
100 oC
H
B(OH)2
N
Bn
O
O
H
H
H
6o, 83%
standrard
conditions
14
N
N
Br
Br
Bn
Bn
OH
6v, 63% (0.78 g)
1v, 1.0 g (3.2 mmol)
NaBH4 ( 2 eq)
EtOH
Br
N
(b) deformylation reaction
Bn
Gratifyingly, the reaction was not limited to aryl
iodides and alkenyl iodides also under the optimized
reaction conditions found to be useful partners
furnishing the corresponding 4-alkenylated indoles 13.
As demonstrated in Scheme 6, use of 10 mol% of
Pd(OAc)2 and glycine as the transient directing group
allowed the C–H olefination at C-4 position of N-
benzyl or N-methyl-indole-3-carbaldehydes with
benzyl-trans-3-iodoacrylate 12 to afford 13a-d in 55-
63%.
15, 81%
O
H
Pd(OAc)2 (8 mol%)
cyclohexane, 4 Å MS
N
N
140 oC, 24 h
Bn
6a
(c) H/D scrambling experiment
Bn
16, 75%
7%
O
O
H/D
H
H
H
Pd(OAc)2 (10 mol%)
H/D
Glycine (2 eq.), AgTFA (2 eq.),
N
N
CH3COOD/HFIP/D2O, 110 oC
6 h
0%
Bn
[D]n-1a
Bn
1a
(d) H/D scrambling experiment
12%
O
O
OR
O
with 5a
H/D
H
H/D
H
H
O
O
O
H
H
Pd(OAc)2 (10 mol%)
H
H
+
Pd(OAc)2 (10 mol%)
I
OR
Glycine (2 eq.), AgTFA (2 eq.),
CH3COOD/HFIP/D2O, 110 oC
6 h, 12% conversion
+
N
N
Glycine (2 eq.), AgTFA(2 eq.),
AcOH/HFIP/H2O, 110 oC
36-72 h
H/D
0%
Bn
[D]n-1a
R2
N
O
Bn
N
R2
N
R1
0%
R1
1a
Bn
6a
12
1 or 3
13
Scheme 7. Gram scale synthesis, further functionalizations
and mechanistic studies.
O
OBn
O
O
OBn
OBn
O
O
CF3
O
O
O
O
H
H
H
H
N
N
N
N
Br
The probable reaction mechanism for the reaction is
outlined in Scheme 8. Condensation of the 3-
formylindole 1 with glycine provides the intermediate
A. Coordination of imine nitrogen and carboxylate
moiety to Pd(II)-species leads to five membered
palladacycle intermediate B. Preferential formation of
[5,6]-bicyclic palladium intermediate C proceeds via
a regioselective C4-H activation of indoles (instead of
C2-H activation of indoles). Oxidative addition of
aryl iodide onto intermediate C generates Pd(IV)-
species D.[26] Finally reductive elimination of D and
iodide abstraction by silver trifluoroacetate provides
the intermediate F and regenerates the Pd(II)-catalyst.
Hydrolysis of F leads to the formation of C4-
Bn
Me
Bn
Bn
13c, 55%
13a, 62%
13b, 63%
13d, 60%
CCDC 1844210
Scheme 6. Scope of the reaction with vinyl iodides.
To study the scalability of the present method, the
reaction of 1v (1.0 g) with 5a was performed on a
gram scale and 6v was obtained in 63% yield (0.78 g).
The synthetic utility of the C4-arylated indole
derivatives was demonstrated by carrying out Suzuki-
Miyaura coupling of 6v with phenylboronic acid 14
and 6o was isolated in 83% yield. Reduction of 6v
using 2.0 equiv. of NaBH4 gave the corresponding
4
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10.1002/adsc.201801378
Advanced Synthesis & Catalysis
The activity is supported by DST, India (Funding to DM,
SR/NM/NS-1065/2015 (G), SERB (funding to CMRV,
EMR/2015/002047). Financial support was also received from
DST-Fast Track Young Scientist (NT), CSIR for A. S. and K. P.
substituted indolyl aldehydes and transient directing
group glycine.
O
O
HO
HO
O
H2N
O
N
N
Ar
Ar
H
H
References
H
OH
O
H2O
+
H
-H2O
N
N
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R
6
F
R
R
A
Pd(II)X2
N
HX
O
(II)
Pd
R
1
AgTFA
O
N
AgI
O
O
I
Pd(II)
X
H
N
Ar
H
N
B
N
R
E
R
O
N
O
O
O
(II)
HX
(IV)
Pd
I
Pd
N
H
H
Ar
N
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N
R
C
D
R
ArI
Scheme 8. Proposed reaction mechanism.
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on
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CH
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In summary, we have developed a transient directing
group mediated Pd(II)- arylation and
olefination reactions of indoles, proceeding
selectively at the C4-position using commercially
available and cheap glycine as the transient directing
group. The reaction proceeds in the presence of water
under operationally simple conditions for 3-
formylindoles and 3-formylazaindoles.
Experimental Section
Typical experimental procedure for the synthesis of 6a: In
an oven dried 10 mL reaction tube, charged with magnetic
stir-bar, Pd(OAc)2 (4.5 mg, 10 mol%), AgTFA (88 mg, 0.4
mmol), glycine (30 mg, 0.4 mmol), and N-benzyl-1H-
indole-3-carbaldehyde 1a (47 mg, 0.2 mmol) were added.
Commercially available iodobenzene (122 mg, 0.6 mmol),
was added was added to the reaction mixture followed by
acetic acid (1 mL), HFIP (1 mL) and water (0.1 mL) at
room temperature. The reaction tube was capped and
stirred at 110 °C temperature for 24 hours. Upon
completion, the reaction mixture was cooled to room
temperature. The reaction mixture was poured into the
NaHCO3 solution and extracted with ethyl acetate. The
separated organic layer was dried under Na2SO4,
evaporated under reduced pressure and passed through the
column chromatography for purification on silica gel with
petroleum ether and ethyl acetate (19:1) mixture as the
eluent, giving the product 6a (50 mg, 82% yield)
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Advanced Synthesis & Catalysis
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10.1002/adsc.201801378
Advanced Synthesis & Catalysis
UPDATE
Palladium Catalyzed Regioselective C4-Arylation
and Olefination of Indoles and Azaindoles
O
O
O
I
H
X
H
AcO Pd
H
O
Pd
N
H
Adv. Synth. Catal. 2018, Volume, Page – Page
H
+
O
H
H2N
H
N
H
OH
N
X
R
N
X
R
Neetipalli Thrimurtulu, Arnab Dey, Anurag Singh,
Kuntal Pal, Debabrata Maiti,* Chandra M. R.
Volla*
R
Arylation
Alkenylation
C4-selective
7
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