N-Heterocyclic carbene (NHC)-catalysed atom economical construction of 2,3-disubstituted indoles

Article abstract of DOI:10.1039/c6cc10292a

A novel organocatalytic approach, harnessing the unique reactivities of N-heterocyclic carbenes (NHCs), has been revealed for the construction of indoles. The NHC-catalysed atom economical synthesis of a wide range of 2-substituted indole-3-acetic acid derivatives is displayed. Strategic application of the developed method was demonstrated for a short synthesis of a cyclin-dependent kinase (CDK) inhibitor: paullone.

Full text of DOI:10.1039/c6cc10292a

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DOI: 10.1039/C6CC10292A
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N-Heterocyclic Carbene (NHC) Catalyzed Atom Economical
Construction of 2,3-Disubstituted Indoles
Battu Harish,ab Manyam Subbireddy,a and Surisetti Suresh*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
novel organocatalytic approach harnessing the unique
O
NHMe
O
N
N
N
O
HO
HN
S
HO2C
NH
O
reactivities of N-hererocyclic carbenes (NHCs) has been revealed
for the construction of indoles. The NHC catalysed atom economic
synthesis of a wide range of 2-substituted indole-3-acetic acid
derivatives is displayed. Strategic application of the developed
method was demonstrated for a short synthesis of cyclin-
dependent kinase (CDK) inhibitor, paullone.
O
N
Cl
O
R
Cl
N
N
H
N
H
MeO
Paullones4d
H
D2
Prostaglandin
Cladoniamide G4c
Cyclin-Dependent
FPTase Inhibitor4a
4b
receptor
antagonist
(cytotoxic)
Kinase
Inhibitor
(CDK)
Fig 1 Biologically active 2-substitute indole-3-acetic acid
derivatives.
Y
N
X
R
Historically, the construction of indole nucleus is one of the
most sought after challenges that has received a great deal of
attention from chemistry community over several decades.1
There have been excellent methods developed for the
construction of indole framework ranging from the classical
Möhlau and Fischer indole syntheses to the modern Larock
indole synthesis.2 Many of these syntheses suffer from strong
acidic/basic conditions, use of toxic metal catalysts, low yields,
less stable or expensive starting materials, atom economy
issues and generation of by-products. Considering these
concerns, metal-free approaches utilizing readily available
precursors for the construction of indoles are very much
required and such routes would definitely complement the
hitherto known strategies. Despite the concept of
organocatalysis has marked the significant breakthroughs in
the plethora of organic transformations,3 its application in the
construction of indole nucleus has been very scarcely realized.
2-Substituted indole-3-acetic acid derivatives have gained
considerable attention because they have shown a wide range
of potential biological activity profiles (Figure 1).4 Though
there have been several syntheses reported for these class of
COOR
R
COOR
R
NHC
NHC
COOR
R
:electrophilic
centers
N
2
:nucleophilic
centers
N
X
N
H
I
III
N
Y
R
umpolung
by
A
B
path
via
path
via
N
Y
=
=
:
NHC
X
aza-Breslow
NHC
deoxy-Breslow
X
NR, S
CH, CH2
Y
ROOC
=
Y
N
,
X
NHC
COOR
NHC
H
X
N
R
Y
N
COOR
R
R
N
N
R
H
N
1
IV
H
H
II
Scheme 1 Strategy for NHC catalysed construction of
substituted indoles.
compounds, the methods involve the use of unfriendly
reagents, toxic metals and harsh reaction conditions.5
Recently, Opatz et al. and Lee et al. have reported sodium
cyanide mediated and catalysed reactions, respectively.5i,j
Organocatalytic approaches underpinning atom-economics
would provide alternative route and complement the existing
routes for the construction of these important entities.
However, very few reports are available on the organocatalytic
routes for indole construction in general6 and such routes are
elusive for the synthesis of 2-substituted indole-3-acetic acid
derivatives. For more than a decade, N-heterocyclic carbenes
(NHCs) have emerged as powerful organocatalysts by their
unique reactivities towards electrophiles to reverse their
polarities known as umpolung.7
a.B. Harish, M. Subbireddy, Dr. S. Suresh
Organic and Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology (CSIR-IICT)
Hyderabad 500 007, India
Sheidt and co-workers8 have developed the synthesis of 2-
arylindoles by the addition of acyl anion equivalents,
generated through NHC, to the transient aza-ortho quinine
methides. We envisioned the synthesis of 2-substituted indole-
E-mail: surisetti@iict.res.in; suresh.surisetti@yahoo.in.
b.B. Harish, Dr. S. Suresh
Academy of Scientific and Innovative Research (AcSIR)
CSIR-Indian Institute of Chemical Technology (CSIR-IICT)
Hyderabad 500 007, India.
† Electronic Supplementary Information (ESI) available: Electronic Supplementary
Information (ESI) available: Experimental procedures, spectral data, copies of NMR
spectra for products. See DOI: 10.1039/x0xx00000x
3-acetic acid derivatives from ortho-imino cinnamate
the disconnection approach as shown in the Scheme 1.
2 using
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We hypothesized that NHC can inverse the polarity of
electrophilic centers of either β-carbon of the α,β-unsaturated
ester (via deoxy-Breslow intermediate I)7d,9 or imine carbon
View Article Online
Table 1 Optimization studya
DOI: 10.1039/C6CC10292A
O
N-Heterocyclic Carbene Precatalyst
O
(NHC)
Base
OMe
(via aza-Breslow intermediate III)10 of the precursor
2 that
OMe
Ph
N
THF
would provide a neucleophilic center (through umpolung) and
subsequently add on to the remaining electrophilic center.
This course would eventually lead to cyclization-aromatization
cascade to provide 2-substituted indole-3-acetic acid
derivatives.
N
Ph
60 o 6 h
H
C,
2a
1a
NHCs
Cl-
I-
BF4
N+ C6F5
N+ I-
N+
N
N
N+
N
N+
Cl-
N
Mes
N
Mes
Mes
N
N
S
HO
C
E
A
B
D
Accordingly, we have started our investigations using the
precursor 2a under NHC catalysis settings. Initially, we have
performed the reaction of 2a with the NHC precursors such as
thiazolium (A), imidazolium (B) salts and a base like DBU (Table
1, entries 1-2). However, these reactions were not successful
to provide the desired product. Much to our delight, triazolium
Entry
NHC
A
Base
DBU
DBU
DBU
DBU
DBU
TBD
%yield of 1ab
1
2
3
4
5
6
7
―
―
B
C
85 (90)c
82
NHC precatalyst
C in the presence of DBU has furnished the
D
desired product 1a in high yield (Table 1, entry 3). It is
interesting to note that while bicyclic triazolium NHC
E
―
precatalyst
product 1a in good yield (Table 1, entry 4), triazolium NHC
precatalyst containing N-pentafluorophenyl group has failed
D bearing N-mesityl group has afforded the
C
65
E
C
Cs2CO3
68
to give the product (Table 1, entry 5). DBU was found to give
better yields among the bases screened (Table 1, entries 3 and
6-7). It should be noted that this transformation did not work
with either base or NHC alone.
With the suitable NHC and base in hand, we turned to
perform this transformation sequentially―starting from ortho-
aminocinnamate 3a. Accordingly, 3a and benzaldehyde 4a
were reacted to give the imine 2a. Subsequently, the crude 2a
was subjected to NHC catalysis conditions to obtain the
product 1a in 90% yield (Scheme 2). Later several bases,
solvents and reaction conditions were screened for this
sequential transformation (see supporting information for a
detailed optimization study). It turned out that NHC
aReaction conditions: 2a (0.5 mmol), NHC (30 mol%), base
b
(1.2 equiv), THF (4 mL); Yields are for isolated products;
cReaction was performed at 80 oC for 4 h; Mes: 2,4,6-
trimethylphenyl
COOMe
COOMe
Ph
COOMe
NHC-C/DBU
PhCHO
toluene,
4a
MS
Ph
THF, 80 o 4 h
C,
N
H
4Å
N
2a
NH2
3a
1a
,
90%
Scheme 2 Sequential imine formation―NHC catalysed
construction of methyl 2-(2-phenyl-1H-indol-3-yl)acetate
1a; MS: Molecular Sieves
benzaldehydes have provided the corresponding indloles 1l-n
in very good yields under the NHC catalysis conditions. Indoles
1o-r bearing fluoro and bromo substitutions on the 2-aryl
group have also been synthesized in high yields.
Comparatively, ortho-imino cinnamates primed from
benzaldehydes having electron donating substituents have
resulted in slightly lower yields of the corresponding 2-aryl-
indol-3-acetic esters 1s-w. ortho-imino cinnamates derived
from multisubstituted benzaldehydes bearing halogen and
electron donating groups furnished the corresponding
substituted indole derivatives 1x-y in 69-75% yields. Biphenyl-
4-carboxaldehyde- and 1-naphthaldehyde-derived ortho-imino
cinnamates have also been tested in this transformation to
afford the corresponding indole derivatives 1z and 1aa in 80%
and 62% yields, respectively.
precatalyst
C in the presence of DBU in THF solvent stands out
the best combination amongst the conditions tested.
We then studied the scope of this NHC-catalyzed
transformation. Initially, the scope of the ester group on the
acrylate part has been studied (Scheme 3). All the tested esters
gave comparable yields of the corresponding indole derivatives
1a-c while methyl ester stands out the best. This
transformation was well tolerated with the cinnamide
precursor as the corresponding 2-phenyl substituted indole-3-
acetamide derivative 1d was synthesised in 66% yield. ortho-
Imino cinnamonitrile has also been converted to the
corresponding 2-phenyl 3-indole acetonitrile derivative 1e
under the NHC catalysis settings. Later we turned our
attention to rework on the aniline part―as expected we have
isolated the differently substitued indoles 1f-h in moderate to
good yields. Next the generality of the benzaldehyde part has
been tested using different electron withdrawing groups like
NO2, CN, CF3―all gave high yields of the corresponding indole
derivatives 1i-k. Halogen substituted benzaldehydes have been
used in this sequential transformation―ortho-imino
cinnamates derived from o-, m- and p-substituted chloro
It is interesting to note that different heteroaromatic
aldehydes including pyridyl, quinolinyl, thiophenyl, pyrrolyl
and pyrazolyl aldehyes have proven to be successful to afford
the corresponding variously substituted 2-heteroaryl indol-3-
acetic esters 1ab-af in very good yields (Scheme 4).
2 | J. Name., 2012, 00, 1-3
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part
aniline
acrylate
part
View ArCtiOcOleMOe nline
HetAr
MS
OHC
toluene,
COOMe
COOMe
NHC-C/DBU
OHC
DOI: 10.1039/C6CC10292A
NHC-C/DBU
HetAr
4Å
THF, 80 o 4 h
C,
N
N
HetAr
toluene,
MS
NH2
4Å
THF, 80 o 4 h
C,
H
N
N
NH2
1
H
2
3a
1
aldehyde
2
part
3
aldehyde
part
scope
at aldehyde
aldehydes
part-heteoaromitic
scope
at
part
acrylate
MeOOC
COOMe
MeOOC
COOMe
COOMe
S
Cl
O
COOEt
Ph
tBu
Ph
CN
Ph
COO
Ph
COOMe
N
N
N
N
N
H
N
H
N
Ts
N
N
N
N
H
H
H
1ab 78%
,
Ph
1ae
, 81%
1ad 89%
1ac 82%
,
,
1af 87%
,
Ph
N
N
N
N
H
N
H
H
H
H
Scheme 4 Synthesis of 2-heteroaryl substituted indole-3-
1a
1e 26%
90%
1b
,
,
1c
73%
,
79%
,
1d
,
(74%)
(66%)
acetic acid derivatives.
scope
at
part
aminophenyl
part
acrylate
R''
COOMe
COOMe
COOMe
OHC
R'
MS
NHC-C/DBU
Me
R''
R''
F
4Å
THF, 80 o 4 h
C,
N
R'
R'
toluene,
N
NH2
N
H
H
N
H
N
H
Cl
1
2
aldehyde
part
3
Me
,
1g
α
60%
1h
,
59%
,
scope
1f
at
-unsaturated
81%
aldehyde
aldehydes
MeOOC
,
part-
β
MeOOC
NC
MeOOC
MeOOC
scope
at aldehyde
substituents
part-EWG
COOMe
COOMe
COOMe
N
H
N
H
N
H
N
OMe
N
Cl
H
H
1ag 85%
,
1ah
1ak 56%
,
,
1aj 63%
(56%)
,
1ai 66%
,
CF3
NO2
CN
N
N
Scheme 5 Synthesis of 2-vinyl substituted indole-3-acetic
acid derivatives.
N
H
,
H
H
1k 77%
,
1i
71%
,
1j
88%
scope
at aldehyde
substituents
part-halogen
COOMe
mmol scale
CHO
20
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
toluene,
NHC-C/DBU
Br
N
N
THF, 80 o 4 h
C,
Cl
F
MS
4Å
H
NH2
Br
N
H
,
N
N
N
H
Br
2q
1q
mmol,
H
H
3a
Cl
Cl
16.6
83%
5.71 g
yield
1o
80%
,
1m 74%
1n
76%
,
1l
69%
,
MeOOC
COOMe
COOMe
Scheme 6 Gram scale synthesis of 1q
.
Br
Br
amide bond formation
in tandem
Cu catalyzed N
-arylation
N
H
N
H
85%
O
N
MeOOC
Br
H
1p
F
84%
,
1r 72%
,
1q
,
Br
NH
scope
at aldehyde
substitents
part-EDG
MeOOC
CuI/L-proline
DMSO
COOMe
N
COOMe
N
H
HO
H
NH
60%
4OH
Me
1q
OMe
5
(Paullone)
overall
N
N
H
56%
N
H
H
1t
,
70%
from 2-iodoaniline: 46%
three steps)
(in
1s
,
yield
1u
68%
,
Scheme 7
Retro-synthetic analysis and synthesis of
MeOOC
COOMe
OMe
OMe
OMe
paullone by tandem reaction triggered by copper catalysis.
NMe2
N
N
H
H
HOOC
MeOOC
1w
13%
,
(30%)
Br
1v
,
64%
Br
Lithium
equiv)
hydroxide (4
scope
at aldehyde
halogen substitents
scope
at aldehyde
&
part-EDG
part-polyaromatic
MeOOC
MeOOC
THF-H2
rt,
O
MeOOC
MeOOC
(3:1)
overnight
N
Br
Br
N
H
H
O
1q
6
,
96%
N
N
N
N
H
H
H
H
O
OMe
1y
1aa
62%
,
69%
1z
,
80%
,
1x 75%
,
Scheme 8 Synthesis of 2-(2-(2-bromophenyl)-1H-indol-3-
yl)acetic acid. Yields in parenthesis correspond to the
reactions with isolated imine.
Scheme 3 Synthesis of 2-aryl substituted indole-3-acetic
acid derivatives. Yields in parenthesis correspond to the
reactions with isolated imine.
became interested to exploit the strategy to the synthesis of
paullone. It is worth mentioning that a tandem copper
catalyzed N-arylation followed by amidation of the methyl 2-
(2-(2-bromophenyl)-1H-indol-3-yl)acetate 1q gave the desired
Further, this transformation is not limited to only aromatic
aldehydes as α,β-unsaturated aldehydes have also furnished
the corresponding 2-vinyl substituted indol-3-acetic esters
1ag-ak in moderate to good yields (Scheme 5). With the
aliphatic subtituents like (CH2)2Ph on the aldehyde part, the
desired indole derivative was not obtained under the reaction
conditions.
It is worth noting that the presented method has enabled to
scale up the reaction to a gram scale for the synthesis of
methyl 2-(2-(2-bromophenyl)-1H-indol-3-yl)acetate 1q while
maintaining the high yield (Scheme 6).
paullone
5 in a single step (Scheme 7). The overall yield for the
synthesis of paullone is 46% starting from 2-iodoaniline in
three simple steps. It should be mentioned that while the
same has been synthesized in 12% overall yield starting from
2-iodoaniline in eight steps besides the use of special
precursors.5e
We have also synthesized the indole-3-acetic acid
methyl 2-(2-(2-bromophenyl)-1H-indol-3-yl)acetate by simple
hydrolysis (Scheme 8).
6 of
The synthetic utility of the present transformation has been
demonstrated with the synthesis of a cyclin-dependent kinase
(CDK) inhibitor, paullone.4d In continuation of our interest in
the development of copper catalysed tandem reactions,11 we
In conclusion, an NHC catalyzed novel approach has been
established for the construction of variously substituted 2-
aryl/heteroaryl/vinyl indole-3-acetic acid derivatives. Gram
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Ferenc, Org. Lett., 2006, 8, 4473; (j) S. J. Lee, H.-A. Seo and
scale synthesis of a representative example, methyl 2-(2-(2-
bromophenyl)-1H-indol-3-yl)acetate has been presented. A
short two-step synthesis of cyclin-dependent kinase (CDK)
inhibitor, paullone has been accomplished from N-heterocyclic
carbene catalysed reaction of methyl (E)-3-(2-(((E)-2-
bromobenzylidene)amino)phenyl)acrylate followed by copper
catalysed N-arylation-amidation. Efforts are underway to
investigate the mechanism of the present NHC catalysed
indole construction. Further studies are in progress on
exploring the utilization of the presented concept for suitable
organic synthesis.
We thank the Department of Science and Technology (DST),
India for Fast track grant (SB/FT/CS-055/2012) and CSIR, New
Delhi for financial support as part of XII Five Year plan the
under title ORIGIN (CSC-0108). BH thanks CSIR, MS thanks DST
for financial support.
C.-H. Cheon, Adv. Synth. Catal., 2016, 358, 1566V.iew Article Online
DOI: 10.1039/C6CC10292A
6
7
S. Müller, M. J. Webber and B. List, J. Am. Chem. Soc., 2011,
133, 18534.
For excellent reviews on NHC catalyses, see: (a) D. Enders, O.
Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606; (b)
N. Marion, S. Díez-González and S. P. Nolan, Angew. Chem.
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Scheidt, Aldrichimica Acta, 2009, 42, 55; (d) S. J. Ryan, L.
Candish and D. W. Lupton, Chem. Soc. Rev., 2013, 42, 4906;
(e) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius,
Nature, 2014, 510, 485; (f) R. S. Menon, A. T. Biju and V. Nair,
Chem. Soc. Rev., 2015, 44, 5040; (g) D. M. Flanigan, F.
Romanov-Michailidis, N. A. White and T. Rovis, Chem. Rev.,
2015, 115, 9307.
8
9
M. T. Hovey, C. T. Check, A. F. Sipher and K. A. Scheidt,
Angew. Chem. Int. Ed., 2014, 53, 9603.
For reports on NHC catalysis involving deoxy-Breslow
intermediate prior to 2013, see ref. 7d and references cited
therein; (a) D. Enders, K. Breuer, U. Kallfass and T.
Balensiefer, Synthesis, 2003, 1292; (b) C. E. I. Knappke, A. J.
Arduengo III, H. Jiao, J.-M. Neudörfl and A. J.ꢀvonꢀWangelin,
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