Palladium-Catalyzed Decarboxylative ortho -Amidation of Indole-3-carboxylic Acids with Isothiocyanates Using Carboxyl as a Deciduous Directing Group

Article abstract of DOI:10.1021/acs.joc.8b00042

Palladium-catalyzed ortho-amidation of indole-3-carboxylic acids with isothiocyanates by using the deciduous directing group nature of carboxyl functionality to afford indole-2-amides is demonstrated. Both C-H functionalization and decarboxylation took place in one pot, and hence, this carboxyl group served as a unique, deciduous (or traceless) directing group. This reaction offers a broad substrate scope as demonstrated for several other heterocyclic carboxylic acids like chromene-3-carboxylic acid, imidazo[1,2-a]pyridine-2-carboxylic acid, benzofuran-2-carboxylic acid, pyrrole-2-carboxylic acid, and thiophene-2-carboxylic acid. In the reaction using 2-naphthoic acid, of the two possible isomers, only one isomer of the amide was exclusively formed. The indole-2-amide product underwent palladium-catalyzed C-H functionalization to afford the diindole-fused 2-pyridones by combining two molecules of the indole moiety, with the elimination of an amide group from one of them, attached at the C3-position for the C-C/C-N bond formation. The structures of key products are confirmed by X-ray crystallography.

Full text of DOI:10.1021/acs.joc.8b00042

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Palladium-Catalyzed Decarboxylative ortho-Amidation of Indole-3-carboxylic
acids with Isothiocyanates Using Carboxyl as a Deciduous Directing Group
R. N. Prasad Tulichala, Mallepalli Shankar, and K C Kumara Swamy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00042 • Publication Date (Web): 19 Mar 2018
Downloaded from http://pubs.acs.org on March 20, 2018
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Palladium-Catalyzed Decarboxylative ortho-Amidation of Indole-3-carboxylic acids with
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Isothiocyanates Using Carboxyl as a Deciduous Directing Group
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R. N. Prasad Tulichala, Mallepalli Shankar and K. C. Kumara Swamy*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, Telangana, India.
Eꢀmail: kckssc@uohyd.ac.in; kckssc@yahoo.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
COOH
R1
R1
H
N
R3
R3-N=C=S
N
H
N
O
Pd(OAc)2
R2
R2
O
Cs2CO3, TBAB
(Air)
H
R3
N
HetAr
HetAr
H
-CO2
COOH
R3 = Ph
Regioselective ortho C-H bond activation (ortho-amidation)
COOH group acting as traceless directing group
Decarboxylation at C3-position and amidation at C2-position
Abstract
Palladiumꢀcatalyzed orthoꢀamidation of indoleꢀ3ꢀcarboxylic acids with isothiocyanates by using
the deciduous directing group nature of carboxyl functionality to afford indoleꢀ2ꢀamides is
demonstrated. Both CꢀH functionalization and decarboxylation took place in a one pot and hence
this carboxyl group served as a unique, deciduous (or traceless) directing group. This reaction
offers a broad substrate scope as demonstrated for several other heterocyclic carboxylic acids
like chromeneꢀ3ꢀcarboxylic acid, imidazo[1,2ꢀa]pyridineꢀ2ꢀcarboxylic acid, benzofuranꢀ2ꢀ
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carboxylic acid, pyrroleꢀ2ꢀcarboxylic acid and thiopheneꢀ2ꢀcarboxylic acid. In the reaction using
2ꢀnaphthoic acid, of the two possible isomers, only one isomer of the amide was exclusively
formed. Thus formed indoleꢀ2ꢀamide underwent palladiumꢀcatalyzed CꢀH functionalization to
afford the diindoleꢀfused 2ꢀpyridones by combining two molecules of indole moiety, with the
elimination of an amide group from one of them, attached at C3ꢀposition for the CꢀC/ CꢀN bond
formation. The structures of key products are confirmed by Xꢀray crystallography.
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Introduction
Transitionꢀmetalꢀcatalyzed CꢀH bond activation and functionalization has emerged as an
efficient and versatile strategy in organic synthesis.1,2 The efficacy of these reactions could be
intensely improved by transforming such catalytic reactions into atomꢀ and stepꢀeconomy
processes and this can be achieved by chelationꢀassisted (directing group) CꢀH bond activation
and functionalization. The use of directing group strategy enables good regioselectivity, wide
substrate scope, and application to total synthesis.2a,b,3 Functional groups that include imine,
anilide, amide, ester, heterocyclic, amine, carboxylic acid, ketone, and hydroxyl have been
employed as directing groups for transition metalꢀcatalyzed direct C–H bond functionalization.4
The strategy to exploit traceless directing group strategy for CꢀH functionalization as well as
removal of the directing group in a oneꢀpot fashion not only avoids additional steps to remove
the undesired directing group from products but also provides high regioselectivity.5
Among the myriad directing groups evaluated so far, carboxyl group can act as deciduous
or traceless directing group for the CꢀH functionalization due to the easy removal of carboxylic
functionality by extrusion of CO2 under transitionꢀmetalꢀmediated conditions allowing traceless
operation of the directing group.5aꢀb,6 By using Pd,7 Rh,8 Ir,9 and Ru10 catalysts, the traceless
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directing group strategy has been implemented for the CꢀH arylation, acyloxylation, borylation,
silylation, amidation and halogenation of arenes. Such reactions were pioneered by the groups of
Satoh and Miura,7a,8a,b Larrosa,7c,e,f,10a Gooßen,6a,b,7h,10dꢀf and others. Moreover, very recent
reports from the groups of Zhao,10c Ackermann,10d Gooßen,10eꢀf and Baidya10g have involved
decarboxylative hydroarylation of alkynes using carboxylic acid as a deciduous directing group
by Ruꢀcatalysis. These reports have clearly demonstrated that carboxylic acids as traceless
directing groups offer to streamline the synthesis of diversely substituted arenes. However,
examples of the use of carboxylic acids as traceless directing groups involved insertion of CꢀH
bond to nonpolar unsaturated alkene and alkynes,6 whereas, that to the polarized CꢀN multiple
bonds are considerably scarce. To our knowledge, only a few reports from the groups of Shi, Li
and coꢀworkers disclosed catalytic systems (Rh and Ru) for the orthoꢀamidation of benzoic acids
with concomitant protodecarboxylation utilizing the carboxyl group as a deciduous directing
group (Scheme 1, eqn ii).8c,e,10a Considerable progress has been made in the transitionꢀmetalꢀ
catalyzed addition of CꢀH bonds to polar CꢀN multiple bonds in recent years.11 In particular,
strategies towards the direct insertion of C−H bonds into iso(thio)cyanates are highly demanding
since they can provide synthetically valuable amides (Scheme 1, eqn iii).8c,e,12,13 However, to the
best of our knowledge, isothiocyanates have not been applied to the CꢀH functionalization
reactions by using traceless directing group strategy. These isothiocyanates react with
nucleophiles in a fashion similar to isocyanates, although reaction rates are usually significantly
lower. More importantly, isothiocyanates tend to be less sensitive to moisture and less unpleasant
to handle, but still possess sufficient degree of reactivity to be very useful reactants.14ꢀ15
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As
a
part of our continuing studies on transition–metalꢀcatalyzed CꢀH
activation/functionalization,16 we report herein [Pd]ꢀcatalyzed CꢀH functionalization (orthoꢀ
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amidation) of indoleꢀ3ꢀcarboxylic acids with isothiocyanates as electrophiles that results in
expedient access to indoleꢀ2ꢀcarboxamides (Scheme 1, eqn iv). Prominent features of our
strategy include: (a) amidation at indole C2 position, (b) high regioselectivity and good substrate
scope, and (c) synthesis of useful indoleꢀ2ꢀamides by using isothiocyanates under mild
conditions.
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Scheme 1. Deciduous Directing Group Assisted Transition-Metal Catalyzed C-H
Functionalization
Results and Discussion
(i) Palladium catalyzed synthesis of indole-2-carboxamides by decarboxylative ortho-
amidation of indole-3-carboxylic acids with isothiocyanates
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We commenced our studies by employing 1ꢀmethylꢀ1Hꢀindoleꢀ3ꢀcarboxylic acid 1a and
phenyl isothiocyanate 2a as model substrates for optimization studies of the palladiumꢀcatalyzed
decarboxylative amidation reaction. Thus the reaction of 1a with 3 equiv of 2a was performed in
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the presence of Pd(OAc)2 and Ag2CO3 in CH3CN solvent at 80 C in open air. In this reaction,
we expected the formation of C2ꢀthioamide but surprisingly we observed the C2ꢀamidation
product 3aa in 45% yield (Table 1, entry 1). Addition of a base like K2CO3 (2.0 equiv) led to
further improvement of yield (entry 2). A sequence of control experiments were performed to
check the role of both [Pd]ꢀcatalyst and Ag2CO3. In the absence of Pd(OAc)2, the desired product
3aa (entry 3) was not formed. Next, the reaction was conducted in the presence of Pd(OAc)2
catalyst but without Ag2CO3. In this case, we observed 61 % of the desired product (entry 4).
From this experiment, we concluded that there was no role of Ag2CO3 in the reaction. Further
investigation on the effect of bases on the reaction outcome showed that Cs2CO3 as a base
provided the best result (Table 1, entries 5ꢀ9). Gratifyingly, a drastic improvement in the yield
was observed when we added the additive like TBAB (tetrabutyl ammonium bromide). Thus the
yield of 3aa was increased to 83% (entry 10). A slight decrease in the yield was observed when
we used O2 (balloon) instead of open air condition (entry 11). Under N2 atmosphere, in closed
condition the desired product was not observed (entry 12). The yield was lowered when the
o
reaction was performed at room temperature (25 C; entry 13). Screening of additives KOAc,
AcOH and AgSbF6 revealed that they were not much effective compared to TBAB (entries 14ꢀ
16). Changing the solvent to DMF decreased the yield of 3aa to 77% (entry 17). Other solvents
like DCE and DMA did not improve the yield (entries 18–19). The [Pd] catalysts like PdCl2,
Pd(OTf)2 were less effective than Pd(OAc)2 (entries 20–21). The desired product was obtained in
40% yield when we used Pd2(dba)3 in the presence of Ag2CO3 (entry 22). We also carried out the
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reaction in presence of [{Cp*RhCl2]2] instead of Pd(OAc)2, only trace amount of the desired
product was observed (entry 23). The reaction by using phenyl isocyanate as the other substrate
also led only to traces of amide (entry 24). The reaction of indoleꢀ3ꢀcarboxylic acid with phenyl
isocyanate gave a complex mixture and only a trace of product could be isolated. This may be
due to the moisture sensitivity of phenyl isocyanate relative to isothiocyanates. In our hands, use
of a lower stoichiometry (1ꢀ2 equiv) of 2a reduced the yield by ca 10%. We have also studied the
effect of other phase transfer catalysts: TBAC (tetrabutylammonium chloride) gave 35% yield of
the product (entry 25), whereas TBAC.xH2O (tetrabutylammonium chloride hydrate) and TBAI
(tetrabutyl ammonium iodide) gave only traces of the product (entries 26ꢀ27). The conclusion
was that the combination of Pd(OAc)2 Cs2CO3 and TBAB in CH3CN solvent at 80 °C for 6 h in
open air (83% yield; Table 1, entry 10) was the optimum condition.
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Table 1. Optimization Study for Palladium Catalyzed Decarboxylative Amidationa
Entry
Catalyst
Oxidant
Base
Additive
Solvent
Yield of
3aa (%)b
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
ꢀ
Ag2CO3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
45
Ag2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
63
Ag2CO3
n.d.
61
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
ꢀ
ꢀ
70
58
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
ꢀ
KOtBu
NEt3
ꢀ
ꢀ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
53
trace
55
8
ꢀ
9
ꢀ
LiOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
83c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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-
TBAB
TBAB
TBAB
TBAB
KOAc
AcOH
AgSbF6
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAC
ꢀ
80d
10e,f
32f,g
65
ꢀ
ꢀ
ꢀ
ꢀ
78
ꢀ
70
ꢀ
77
ꢀ
DCE
trace
70
ꢀ
DMA
ꢀ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
67
Pd(OTf)2
Pd2(dba)3
[{Cp*RhCl2]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
78
Ag2CO3
40f
ꢀ
ꢀ
trace
Traceh
35
Cs2CO3 TBAC.xH2O
Cs2CO3 TBAI
trace
trace
aReaction conditions: indoleꢀ3ꢀcarboxylic acid 1a (0.5 mmol), isothiocyanate 2a (1.5 mmol),
[Pd]ꢀcatalyst (10 mol%), oxidant (1.0 mmol), base (0.5 mmol), additive (0.25 mmol), solvent (2
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b
c
mL), 80 °C (oil bath temperature) for 6 h in open air. Isolated yields. Yield was lower by ca
5
6
d
15% when 5 mol% of Pdꢀcatalyst or by 5ꢀ8% when 20ꢀ30 mol% of TBAB was used. O2
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(balloon) was used. eUnder N2 atmosphere. fStarting material remained. gReaction was performed
at rt (28 °C). h1.5 mmol of isocyanate was used.
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As shown by the examples in Table 2, the above protocol was applicable to the C2ꢀ
amidation of a broad array of indoleꢀ3ꢀcarboxylic acids with isothiocyanates affording good to
excellent yields of indoleꢀ2ꢀcarboxamides. The scope of isothiocyanates was investigated first by
using 1ꢀmethylꢀindoleꢀ3ꢀcarboxylic acid 1a as the partner. Phenyl isothiocyanates bearing
electronꢀrich, electron neutral or electronꢀdeficient groups reacted well with 1a and afforded the
corresponding indoleꢀ2ꢀcarboxamides 3aa-af in excellent yields (71ꢀ90%). The structure of the
compound 3ae was confirmed by single crystal Xꢀray analysis (Figure S1, Supporting
Information). We then examined the scope of the reaction with respect to the indole partner. Nꢀ
protected indoleꢀ3ꢀcarboxylic acids were thus evaluated, and the substrates with protecting
groups nꢀBu, benzyl (Bn), MOM and propargyl provided the indoleꢀ2ꢀcarboxamides 3bb, 3da,
3ea and 3cg respectively, in good yields. Interestingly, tolerance of the terminal triple bond in
the product (3ea) enhances the utility of this protocol. Indoleꢀ3ꢀcarboxylic acids with
substituents at 5ꢀ and 6ꢀpositions on the phenyl ring of indole moiety also reacted smoothly with
phenyl isothiocyanate 2a. Thus, 5,6ꢀdimethoxyꢀ1ꢀmethylꢀindoleꢀ3ꢀcarboxylic acid (1f), 5ꢀ
benzoxyꢀ1ꢀmethylꢀindoleꢀ3ꢀcarboxylic acid (1g) and 5ꢀmethoxyꢀ1ꢀbenzylꢀindoleꢀ3ꢀcarboxylic
acid (1h) reacted well with 2a affording the corresponding 2ꢀamides 3fa, 3ga and 3ha in
excellent yields. 5ꢀmethoxyꢀ1ꢀbenzylꢀindoleꢀ3ꢀcarboxylic acid (1h) reacted well with mꢀchloro
phenyl isothiocyanate (2i) and afforded the corresponding amide 3hi in good yields. Ortho
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substituted phenyl isothiocyanate did not react with the indoleꢀ3ꢀcarboxylic acid perhaps due to
steric effect. The reaction of 5ꢀfluoroꢀ1ꢀmethoxymethylꢀindoleꢀ3ꢀcarboxylic acid with 2c also
gave the corresponding amide 3ic in good yields. We were pleased to find that the amidation
reaction of indoleꢀ3ꢀcarboxylic acids with alkyl isothiocyanates (2g-h) afforded the indoleꢀ2ꢀ
carboxamide (3ag, 3cg and 3ah) in excellent yields (83–90%). Indole or Nꢀmethylindole did not
react under these conditions.
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Table 2. Substrate Scope for the Palladium-catalyzed Decarboxylative Amidation by C-H
Activation of indole-3-carboxylic acids (1) with isothiocyanates (2).a
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9
R
R
COOH
H
Pd(OAc)2 (10 mol %)
Cs2CO3, TBAB
H
R1
N
R1
R3-N=C=S
2a-i
R3
H
N
N
10
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O
CH3CN, air
80 oC, 6 h
R2
R2
1a-i
3
R = H, R1 = H, R2 = Me (1a)
R = H, R1 = H, R2 = n-Bu (1b)
R = H, R1 = H, R2 = Bn (1c)
R = H, R1 = H, R2 = MOM (1d)
R = H, R1 = H, R2 = propargyl (1e)
R = OMe, R1 = OMe, R2 = Me (1f)
R = OBn, R1 = H, R2 = Me (1g)
R = OMe, R1 = H, R2 = Bn (1h)
R = F, R1 = H, R2 = MOM (1i)
R3 = Ph (2a)
R3 = 4-Me-C6H4 (2b)
R3 = 4-MeO-C6H4 (2c)
R3 = 4-Cl-C6H4 (2d)
R3 = 4-CN-C6H4 (2e)
R3 = 4-NO2-C6H4 (2f)
R3 = Bn (2g)
R3 = cyclohexyl (2h)
R4 = 3-chloro (2i)
H
N
H
N
H
N
N
OMe
N
Me
N
O
O
O
Me
Me
Me
3ac; 90%
3ab; 85%
3aa; 83%
H
N
H
N
H
N
N
NO2
N
Cl
N
CN
O
O
O
Me
Me
Me
3af; 71%
3ad; 78%
3ae; 75%
H
N
H
N
H
Ph
N
N
Me
N
N
O
O
O
nBu
Me
3bb; 80%
Me
3ah; 83%
3ag; 90%
H
N
H
N
H
N
Ph
N
N
N
O
O
O
MeO
O
3ea; 76%
Ph
3da; 70%
3cg; 87%
MeO
MeO
Bn
H
N
H
N
H
N
MeO
N
N
N
O
O
O
Ph
Me
Me
3fa; 87%
MeO
3ha; 87%
3ga; 86%
F
Cl
H
H
N
N
N
OMe
N
O
O
Ph
MeO
3hi; 75%
3ic; 68%
aReaction conditions: 1 (0.5 mmol), isothiocyanate 2 (1.5 mmol), Pd(OAc)2 (10 mol %),
Cs2CO3 (0.5 mmol), TBAB (0.25 mmol), CH3CN (2 mL), 80 °C (oil bath temperature)
for 6 h in open air.
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(ii) Application of decarboxylative amidation to other carboxylic acids
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To extend the reaction scope of the above amidation reaction, we proceeded to study the
decarboxylative amidation of heteroaromatic carboxylic acids with phenyl isothiocyanate under
the optimized reaction conditions. The results are summarized in Table 3. As shown in the Table
3, 2Hꢀchromeneꢀ3ꢀcarboxylic acid 4a reacted with 2a via C3ꢀamidation and decarboxylation to
afford compound 5aa (Nꢀphenylꢀ2Hꢀchromeneꢀ4ꢀcarboxamide) in 85% yield (entry 1). This is an
interesting example of amidation as this chromeneꢀ4ꢀcarboxamide product is not known in the
literature. Imidazo[1,2ꢀa]pyridineꢀ2ꢀcarboxylic acid 4b also reacted well with 2a to give the Nꢀ
phenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxamide 5ba in 84% yield. As expected, 1ꢀmethylꢀindoleꢀ
2ꢀcarboxylic acid 4c underwent decarboxylative amidation with phenyl isothiocyanate resulted in
C3ꢀamidation product 5ca in excellent yield (88%, entry 3). Benzofuranꢀ2ꢀcarboxylic acid 4d
and thiopheneꢀ2ꢀcarboxylic acid 4e also reacted smoothly under the optimized conditions to
afford the corresponding 3ꢀsubstituted amides (5da and 5ea) in good yields (entries 4ꢀ5).
Pyrroleꢀ2ꢀcarboxylic acid 4f also produced the amidation product 5fa in moderate yield (entry 6).
What is perhaps more interesting is the reaction using 2ꢀnaphthoic acid, wherein two orthoꢀ
positions are available for amidation. We observed the formation of only the 1ꢀsubstituted isomer
6a as the sole product (Scheme 2).This is perhaps on the expected lines since the αꢀCH is
connected to the other phenyl ring. The yield was moderate (ca 62%) when we used 5 mol% of
the palladium catalyst. We could also accomplish amidation using benzoic acid wherein
compound 6b (cf. Scheme 2) was isolated in decent yields.17
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Table 3. Decarboxylative Amidation of Other Heteroaromatic Carboxylic Acidsa
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entry
1
carboxylic acid
product
yieldb
85
2
3
84
88
4
76
5
6
70
65
aReaction conditions: 4 (0.5 mmol), phenyl isothiocyanate 2a (1.5 mmol),
Pd(OAc)2 (10 mol %), Cs2CO3 (0.5 mmol), TBAB (0.25 mmol), CH3CN (2 mL),
80 °C (oil bath temperature) for 6 h in open air. bIsolated yields.
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Scheme 2. Formation of Substituted Amides 6a-b Using 2-Naphthoic and Benzoic Acids
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(iii) Possible pathway for decarboxylative amidation
To the best of our knowledge, there are no previous reports on the palladium catalyzed
decarboxylative orthoꢀamidation of indoleꢀ3ꢀcarboxylic acids using isothiocyanates. It is
important to note that in these reactions, decarboxylation takes place at C-3, but amidation
takes place at C-2 carbon of the heterocyclic carboxylic acid. Based on the literature reports on
amidation,12ꢀ13 a few palladium catalyzed decarboxylative reactions,7aꢀb, 7g, 18ꢀ19 and on metal
catalyzed decarboxylation through carboxyl group as a traceless directing group,5ꢀ10 a tentative
mechanism to rationalize the decarboxylative amidation reaction is depicted in Scheme 3.
Initially, carboxylic acid 1a reacts with Cs2CO3 to afford cesium carboxylate I, which is
converted to a five membered palladacycle intermediate II. It is likely that TBAB as a phase
transfer catalyst facilitates this process of formation/transfer of I, although we have not
investigated this aspect thoroughly. The palladacycle II is expected to be derived from the
coordination of Pd(OAc)2 to the carboxylic oxygen followed by subsequent orthoꢀCꢀH bond
activation with the elimination of AcOH. Now, phenyl isothiocyanate will enter into the catalytic
cycle and coordinates to the palladium resulting in intermediate III.12ꢀ13 Subsequently, the seven
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membered palladacycle complex IV is generated by insertion of the C=N double bond into the
PdꢀC bond of intermediate III. A new CꢀC bond is formed in this step. Next, in the presence of
AcOH, the cesium carboxylate species V8e is generated with protonation at amidic nitrogen, thus
regenerating the Pd(OAc)2 for the next catalytic cycle. Finally, decarboxylation of V followed by
protonation provides the indoleꢀ2ꢀthioamide VI and Cs2CO3. Thioamide VI may further be
transformed to indoleꢀ2ꢀcarboxamide 3aa by aerobic (O2) oxidation.20 Under the nitrogen
atmosphere, though, we could not isolate VI and this part would require further investigation. It
is true that indoleꢀ2ꢀcarboxamides may be accessible by the corresponding acid chlorides, but
from the chemistry point of view, the route described here is interesting in its own right.
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Scheme 3. Plausible pathway for the formation C-2 amidation product 3aa
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(iv) Utility of indole-2-carboxamides: Synthesis of diindole-fused pyridones via palladium-
catalyzed C-H bond activation
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8
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We aimed for the [Pd]ꢀcatalyzed nitrile insertion reaction banking on our previous result
using indoleꢀ2ꢀcarboxamides by CꢀH and NꢀH bond cleavage.16d However, in the reaction by
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using 3ac in the presence of Pd(OAc)2/ Ag2CO3/ Cs2CO3 system in benzonitrile at 90 C/ 14 h,
rather surprisingly, we obtained the diindole fused 2ꢀpyridone 7 (cf. Scheme 4, 58% yield; Xꢀ
ray) by CꢀC and CꢀN bond formation. The yield was better using MeCN (66%) or DMF (78%)
[see Table S1 in SI for more details]. This unusual formation of diindole fused 2ꢀpyridone
product formation may be feasible by combining two molecules of indole moiety attached at C3ꢀ
position for the CꢀC and CꢀN bond formation with the elimination of one of the amide group
(elimination via amine and CO2). The structure of this diindole fused 2ꢀpyridone 7 was
confirmed by Xꢀray crystallography (Figure S2, SI). Although we could synthesize one more
product 8, generalization to other systems was unsuccessful under the conditions employed. This
part needs further investigation.
Scheme 4. Palladium Catalyzed Synthesis of Diindole-fused 2-Pyridones
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Conclusions
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8
We have developed a new protocol of a palladiumꢀcatalyzed orthoꢀamidation of indoleꢀ3ꢀ
carboxylic acids with isothiocyanates for the synthesis of indoleꢀ2ꢀcarboxamides via CꢀH bond
activation/functionalization using carboxylic group as traceless directing group. This procedure
features high regioselectivity, good substrate scope, and functional group tolerance in terms of
isothiocyanate substrates. It is important to note that in these reactions, decarboxylation takes
place at C-3, but amidation takes place at C-2 carbon. Other heteroaromatic carboxylic acids
are also successfully converted to amidation products under this protocol. In the case of 2ꢀ
naphthoic acid, only one of the two possible isomers of the amide was exclusively formed. We
have also utilized indoleꢀ2ꢀcarboxamides for the synthesis of diindole fused 2ꢀpyridones by
palladiumꢀcatalyzed CꢀH activation. Further work in this area would include lowering the
catalyst load and application in targeted amides.
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Experimental Section
General Comments. 1H (400 MHz or 500 MHz) and 13C (100 MHz or 125 MHz) were recorded
13
in CDCl3 or C6D6 with shifts referenced to SiMe4 (1H, C: δ = 0). IR spectra were recorded on
an FTIR spectrophotometer. Melting points were determined by using a local hotꢀstage melting
point apparatus and are uncorrected. Elemental analyses were carried out on a CHN analyzer.
Mass spectra were recorded using LCꢀMS and HRMS (ESIꢀTOF analyser) equipment. For
column chromatography, silica gel of 100ꢀ200 mesh size was used. Indoleꢀ3ꢀcarboxylic acids 1a-
i were prepared by following literature procedures.21 Isothiocyanates 2a-i and heteroꢀaromatic
carboxylic acids 4d-g are commercially available and are used as such. 2HꢀChromeneꢀ3ꢀ
carboxylic acid 4a, imidazo[1,2ꢀa]pyridineꢀ2ꢀcarboxylic acid 4b and Indoleꢀ2ꢀcarboxylic acid 4c
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were prepared by following literature procedures.22 Analytical grade (AR grade) solvents were
bought from chemical vendors.
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Synthesis of indole-2-carboxamides 3: General procedure. A mixture of indoleꢀ3ꢀcarboxylic
acid (one of 1a-i, 0.5 mmol), isothiocyanate (one of 2a-i, 1.5 mmol), Pd(OAc)2 (10 mol %),
Cs2CO3 (0.5 mmol), and TBAB (0.25 mmol) was taken in a 10 mL round bottomed flask. To
o
this, CH3CN (2 mL) was added and the contents were heated at 80 C for 6 h in open air. The
progress of the reaction was monitored by TLC. After cooling to rt, the solvent was removed
under vacuum, and the crude product was purified by column chromatography by using silica gel
with hexane/ ethyl acetate (9:1) mixture as the eluent to afford the corresponding indoleꢀ2ꢀ
carboxamides 3aa-ah. Compounds 3aa, 3ac, 3ag and 3cg are known.23
1ꢀMethylꢀNꢀ(pꢀtolyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ab): This compound was prepared by using
o
precursors 1a and 2b. Yield: 0.112 g (85%) as white solid; mp: 154–156 C; Rf = 0.52 (9:1
1
hexane/ethyl acetate); IR (KBr) 3251, 1639, 1541, 1458 cmꢀ1; H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.43ꢀ7.36 (m, 2H), 7.22ꢀ7.18 (m,
3H), 6.18 (s, 1H), 4.07 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 139.3, 135.2,
134.2, 132.2, 129.7, 126.0, 124.4, 122.0, 120.7, 120.2, 110.3, 104.3, 31.6, 21.0; HRMS (ESI) m/z
[M+Na]+ Calcd for C17H16N2ONa 287.1161, found 287.1160.
Nꢀ(4ꢀChlorophenyl)ꢀ1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ad): Precursors 1a and 2d were used.
o
Yield: 0.111 g (78%) as white solid; mp: 216–218 C; Rf = 0.48 (9:1 hexane/ethyl acetate); IR
1
(KBr) 3292, 1645, 1516, 1464, 824, 746 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H, NH),
7.69 (dd, J = 8.0 Hz and 0.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.46ꢀ7.36 (m, 4H), 7.23ꢀ7.19 (m,
1H), 7.03 (s, 1H), 4.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 139.4, 136.3, 131.6, 129.5,
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129.2, 125.9, 124.7, 122.0, 121.3, 120.9, 110.3, 104.5, 31.7; HRMS (ESI) m/z [M+H]+ Calcd for
5
6
C16H14ClN2O 285.0794, found 285.0791.
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Nꢀ(4ꢀCyanophenyl)ꢀ1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ae): Precursors 1a and 2e were used.
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Yield: 0.103 g (75%) as white solid; mp: 218–220 C; Rf = 0.50 (9:1 hexane/ethyl acetate); IR
(KBr) 3313, 2228, 1645, 1583, 1459 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.79 (d, J
= 8.5 Hz, 2H), 7.70ꢀ7.67 (m, 3H), 7.46ꢀ7.39 (m, 2H), 7.24ꢀ7.21 (m, 1H), 7.08 (s, 1H), 4.11 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 160.6, 142.0, 139.8, 133.5, 131.1, 125.9, 125.2, 122.3,
121.2, 119.8, 118.9, 110.5, 107.4, 105.3, 31.8; HRMS (ESI) m/z [M+H]+ Calcd for C17H14N3O
276.1137, found 276.1138.
1ꢀMethylꢀNꢀ(4ꢀnitrophenyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3af): Precursors 1a and 2f were used.
o
Yield: 0.105 g (71%) as white solid; mp: 232–234 C; Rf = 0.69 (9:1 hexane/ethyl acetate); IR
(KBr) 3313, 1650, 1609, 1542, 1505, 1340 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.2
Hz, 2H), 8.18 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 6.4 Hz, 1H), 7.47ꢀ7.41 (m, 1H), 7.25ꢀ
7.21 (m, 1H), 7.11 (s, 1H), 4.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 143.8, 139.8,
130.9, 125.9, 125.4, 124.2, 122.3, 121.2, 119.3, 110.5, 105.4, 31.9; HRMS (ESI) m/z [M+H]+
Calcd for C16H14N3O3 296.1035, found 296.1031.
1ꢀButylꢀNꢀ(pꢀtolyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3bb): Precursors 1b and 2b were used. Yield:
o
0.122 g (80%) as white solid; mp: 138–140 C; Rf = 0.67 (9:1 hexane/ethyl acetate); IR (KBr)
3298, 2957, 2921, 1645, 1593, 1454 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.68 (d, J
= 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.21ꢀ
7.16 (m, 3H), 6.98 (s, 1H), 4.59 (t, J = 7.4 Hz, 2H), 2.36 (s, 3H), 1.87ꢀ1.80 (m, 2H), 1.43ꢀ1.33
(m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 138.6, 135.2, 134.2,
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131.8, 129.6, 126.1, 124.2, 122.0, 120.5, 120.3, 110.5, 104.5, 44.5, 32.8, 20.9, 20.2, 13.9; HRMS
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6
(ESI) m/z [M+H]+ Calcd for C20H23N2O 307.1810, found 307.1806.
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1ꢀ(Methoxymethyl)ꢀNꢀphenylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3da): Precursors 1d and 2a were used.
o
Yield: 0.098 g (70%) as white solid; mp: 188–190 C; Rf = 0.28 (9:1 hexane/ethyl acetate); IR
(KBr) 3302, 1644, 1593, 1443, 1086 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.72ꢀ7.67
(m, 3H), 7.59 (d, J = 8.4 Hz), 7.41 (t, J = 7.6 Hz, 3H), 7.29ꢀ7.17 (m, 3H), 5.92 (s, 2H), 3.43 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 139.3, 137.8, 132.9, 129.2, 126.4, 125.2, 124.6,
122.2, 121.6, 120.1, 110.8, 107.9, 74.9, 56.2; HRMS (ESI) m/z [MꢀH]ꢀ Calcd for C17H17N2O2
281.1290, found 281.1293.
NꢀPhenylꢀ1ꢀ(propꢀ2ꢀynꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ea): Precursors 1e and 2a were used.
o
Yield: 0.104 g (76%) as white solid; mp: 151–153 C; Rf = 0.20 (9:1 hexane/ethyl acetate); IR
(KBr) 3365, 3267, 1640, 1526, 1433 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.72ꢀ7.67
(m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.46ꢀ7.40 (m, 3H), 7.29ꢀ7.18 (m, 2H), 7.08 (s, 1H), 5.50 (s,
2H), 2.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2, 138.6, 137.6, 130.9, 129.2, 126.3,
125.1, 124.7, 122.2, 121.4, 120.1, 110.6, 105.7, 78.8, 72.3, 33.9; HRMS (ESI) m/z [M+H]+ Calcd
for C18H15N2O 275.1184, found 275.1189.
5,6ꢀDimethoxyꢀ1ꢀmethylꢀNꢀphenylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3fa): Precursors 1f and 2a were
used. Yield: 0.135 g (87%) as white solid; mp: 198–200 oC; Rf = 0.36 (9:1 hexane/ethyl acetate);
1
IR (KBr) 3308, 1650, 1593, 1464, 1097 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.64
(d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 6.93 (s, 1H),
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6.82 (s, 1H), 4.08 (s, 3H), 4.01 (s, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6,
149.6, 146.2, 138.0, 134.7, 130.3, 124.4, 120.1, 118.7, 104.4, 102.3, 92.5, 56.3, 56.2, 32.0;
HRMS (ESI) m/z [M+Na]+ Calcd for C18H18N2O3Na 333.1215, found 333.1212.
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5ꢀ(Benzyloxy)ꢀ1ꢀmethylꢀNꢀphenylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ga): Precursors 1g and 2a were
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used. Yield: 0.153g (86%) as white solid; mp: 194–196 C; Rf = 0.31 (9:1 hexane/ethyl acetate);
1
IR (KBr) 3267, 1640, 1593, 1464, 1009 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.64
(d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.44ꢀ7.33 (m, 6H), 7.20ꢀ7.12 (m, 3H), 6.92 (s, 1H),
5.14 (s, 2H), 4.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 154.0, 137.8, 137.4, 135.1,
132.3, 129.3, 128.7, 128.0, 127.6, 126.2, 124.6, 120.1, 116.5, 111.3, 104.1, 103.8, 70.8, 31.8;
HRMS (ESI) m/z [M+H]+ Calcd for C23H21N2O2 357.1603, found 357.1601.
1ꢀBenzylꢀ5ꢀmethoxyꢀNꢀphenylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ha): Precursors 1h and 2a were used.
o
Yield: 0.155 g (87%) as white solid; mp: 168–170 C; Rf = 0.27 (9:1 hexane/ethyl acetate); IR
(KBr) 3129, 1649, 1595, 1441, 1025 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.62ꢀ7.59
(m, 2H), 7.40ꢀ7.31 (m, 3H), 7.28ꢀ7.21 (m, 3H), 7.18ꢀ7.11 (m, 4H), 7.01 (s, 1H), 6.98 (dd, J = 9.2
13
Hz and J = 2.4 Hz, 1H), 5.85 (s, 2H), 3.88 (s, 3H); C NMR (125 MHz, CDCl3) δ 160.4, 155.0,
138.3, 137.8, 134.6, 132.2, 129.1, 128.7, 127.3, 126.6, 124.5, 120.7, 120.2, 116.0, 111.9, 104.8,
102.6, 55.8, 48.1; HRMS (ESI) m/z [M+Na]+ Calcd for C23H20N2O2Na 379.1423, found
379.1422.
5ꢀFluoroꢀ1ꢀ(methoxymethyl)ꢀNꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ic): Precursors 1i
o
and 2c were used. Yield: 0.112g (68%) as white solid; mp: 188–190 C; Rf = 0.30 (9:1
1
hexane/ethyl acetate); IR (KBr) 3282, 1645, 1531, 1448, 1077, 1030 cmꢀ1; H NMR (400 MHz,
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CDCl3) δ 8.28 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.52ꢀ7.49 (m, 1H), 7.32ꢀ7.30 (m, 1H), 7.16ꢀ7.11
(m, 1H), 7.07 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.88 (s, 2H), 3.84 (s, 3H), 3.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.7 (d, J = 240.0 Hz), 159.7, 156.9, 135.8, 134.4, 130.7, 126.8, 122.1,
114.4, 113.9 (d, J = 26.0 Hz), 112.0, 111.9, 107.0 (d, J = 5.0 Hz), 106.7, 106.5, 75.2, 56.2, 55.6;
HRMS (ESI) m/z [M+H]+ Calcd for C18H18FN2O3 329.1301, found 329.1303.
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NꢀCyclohexylꢀ1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3ah): Precursors 1a and 2h were used. Yield:
o
0.106 g (83%) as white solid; mp: 175–177 C; Rf = 0.36 (9:1 hexane/ethyl acetate); IR (KBr)
3282, 2931, 1629, 1536, 1464 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.39
(d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 6.81 (s, 1H), 6.08 (s, 1H),
4.06 (s, 3H), 4.00ꢀ3.93 (m, 1H), 2.07ꢀ2.04 (m, 2H), 1.80ꢀ1.76 (m, 2H), 1.49ꢀ1.40 (m, 2H), 1.31ꢀ
13
1.22 (m, 4H); C NMR (125 MHz, CDCl3): δ 161.9, 139.0, 132.6, 126.4, 126.1, 124.0, 123.9,
121.7, 120.5, 110.2, 52.7, 48.5, 33.3, 32.5, 31.6, 25.6, 25.0; HRMS (ESI) m/z: [M+H]+ Calcd for
C16H21N2O 257.1654, found 257.1652.
1ꢀbenzylꢀNꢀ(3ꢀchlorophenyl)ꢀ5ꢀmethoxyꢀ1Hꢀindoleꢀ2ꢀcarboxamide (3hi): Precursors 1h and 2i
o
were used. Yield: 0.147 g (75%) as white solid; mp: 140–142 C; Rf = 0.50 (9:1 hexane/ethyl
acetate); IR (KBr) 3129, 1649, 1595, 1441, 1025, 824, 746 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
7.87 (brs, 1H, NH), 7.76ꢀ7.75 (m, 1H), 7.43ꢀ7.41 (m, 1H), 7.30ꢀ7.20 (m, 5H), 7.14ꢀ7.10 (m, 4H),
7.00ꢀ6.98 (m, 2H), 5.83 (s, 2H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2, 155.1,
138.9, 138.1, 134.8, 134.7, 131.6, 130.0, 128.6, 127.3, 126.5, 126.4, 124.5, 120.1, 117.9, 116.3,
111.9, 104.9, 102.5, 55.8, 48.1; LC−MS m/z 391 [M + 1]+. Anal. Calcd For C23H19ClN2O2: C,
70. 68; H, 4.90; N, 7.17. Found: C, 70.57; H, 4.86; N, 7.09.
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Synthesis of heteroarene/arene-2-carboxamides 5aa-fa and 6: The procedure was the same as
that for 3 using 0.5 mmol of one of the acids 4a-g. Compounds 5ba-ea and 6 are reported in the
literature;24 but 5aa and 5fa are new.
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NꢀPhenylꢀ2Hꢀchromeneꢀ4ꢀcarboxamide (5aa): Precursors 4a and 2a were used. Yield: 0.107 g
o
(85%) as white solid; mp: 136–138 C; Rf = 0.28 (9:1 hexane/ethyl acetate); IR (KBr) 3255,
1
1649, 1595, 1447, 1041 cmꢀ1; H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.60ꢀ7.58 (m, 2H),
7.38ꢀ7.35 (m, 2H), 7.27ꢀ7.24 (m, 1H), 7.18ꢀ7.15 (m, 1H), 7.13 (dd, J = 7.5 Hz and J = 1.5 Hz,
13
1H), 7.10 (s, 1H), 6.97ꢀ6.94 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 1.0 Hz, 2H); C
NMR (100 MHz, CDCl3) δ 163.5, 154.9, 137.5, 131.6, 129.1, 128.5, 127.7, 127.1, 124.7, 121.9,
120.8, 120.3, 116.2, 64.8; HRMS (ESI) m/z [M+H]+ Calcd for C16H14NO2 252.1024, found
252.1027.
1ꢀMethylꢀNꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxamide (5fa): Precursors 4f and 2a were used. Yield:
o
0.065 g (65%) as white solid; mp: 105–107 C; Rf = 0.32 (9:1 hexane/ethyl acetate); IR (KBr)
3303, 1640, 1593, 1443, 1340 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.58 (d, J = 7.6
Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 6.81ꢀ6.72 (m, 2H), 6.18ꢀ6.16 (m, 1H),
4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 138.1, 129.1, 128.8, 125.8, 124.0, 120.1,
112.3, 107.5, 36.9; HRMS (ESI) m/z [M+H]+ Calcd for C12H13N2O 201.1028, found 201.1029.
Nꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀnaphthamide (6a): Precursors 4g and 2b were used. Yield: 0.111 g
o
(80%) as white solid; mp: 175–177 C; Rf = 0.36 (9:1 hexane/ethyl acetate); IR (KBr) 3227,
1647, 1603, 1469, 1030 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.38ꢀ8.36 (m, 1H), 7.96 (d, J = 8.0
Hz, 1H), 7.92ꢀ7.90 (m, 1H), 7.73ꢀ7.71 (m, 2H), 7.61ꢀ7.54 (m, 4H), 7.49 (t, J = 7.8 Hz, 1H), 6.94
(d, J = 9.0 Hz, 2H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.4, 156.7, 134.6, 133.8,
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131.2, 130.9, 130.1, 128.4, 127.3, 126.6, 125.3, 125.0, 124.7, 121.8, 114.3, 55.6; LC−MS m/z
278 [M + 1]+. Anal. Calcd For C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.85; H, 5.38;
N, 5.12.
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Nꢀ(3ꢀmethoxyphenyl)ꢀ1ꢀbenzamide (6b): Benzoic acid (0.820 mmol) and 3ꢀmethoxyꢀ
1
phenylisothiocyanate were used. Yield: 0.137 g (74%). This is a known compound (see SI for H
and 13C NMR).17
Synthesis of diindole-fused pyridones (7-8) via palladium-catalyzed C-H bond
functionalization: General procedure. In an oven dried roundꢀbottomed flask (10 mL), silver
o
carbonate (1.0 mmol) was dried in vacuo (ca 0.2 mm Hg) while heating (ca 100 C) using a hot
air gun for 0.5 h. To this, Pd(OAc)2 (10 mol %), indoleꢀ2ꢀcarboxamide (3ac or 3bb, 1.0 mmol),
Cs2CO3 (0.5 mmol) and DMF (3.0 mL) were added. The RBF was sealed with a stopper and the
o
contents were stirred at 110 C (oil bath temperature) for 14 h. After the completion of the
reaction as monitored by TLC, the mixture was cooled to rt, filtered and extracted with diethyl
ether (3 x 25 mL). The combined organic extract was washed with brine solution (4 x 10 mL).
The organic part was dried over anhyd. Na2SO4, and the solvent was removed using a rotary
evaporator. The crude products were purified by column chromatography (100ꢀ200 mesh silica)
using hexane/ EtOAc (9:1) as eluent to afford the final products 7-8.
6ꢀ(4ꢀMethoxyphenyl)ꢀ5,8ꢀdimethylꢀ6,8ꢀdihydropyrido[2,3ꢀb:5,4ꢀb']diindolꢀ7(5H)ꢀone
(7):
o
Precursor 3aa was used. Yield: 0.079 g (78%) as yellow solid; mp: 245ꢀ247 C; Rf = 0.35 (9:1
hexane/ethyl acetate); IR (KBr) 3055, 2931, 1640, 1469 cmꢀ1; 1H NMR (400 MHz, C6D6) δ 9.06
(d, 1H, J = 8.0 Hz), 8.88 (d, 1H, J = 7.6 Hz), 7.51 (qrt, 2H, J = 7.2 Hz), 7.40 (d, 2H, J = 7.6 Hz),
7.10ꢀ7.06 (m, 4H), 6.83ꢀ6.79 (m, 2H), 4.23 (s, 3H), 3.35 (s, 3H), 2.64 (s, 3H); 13C NMR (100
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MHz, C6D6) δ 160.0, 155.6, 137.6, 136.9, 135.6, 135.2, 132.01, 131.95, 131.9, 130.6, 128.6,
128.0, 127.2, 126.4, 125.3, 120.1, 118.5, 114.2, 113.4, 112.7, 96.4, 54.5, 32.6, 30.5; HRMS
(ESI) m/z [M+H]+ Calcd for C26H22N3O2 408.1712, found 408.1714.
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5,8ꢀDibutylꢀ6ꢀ(pꢀtolyl)ꢀ6,8ꢀdihydropyrido[2,3ꢀb:5,4ꢀb']diindolꢀ7(5H)ꢀone (8): Precursor 3bb was
o
used. Yield: 0.083 g (70%) as yellow solid; mp: 110ꢀ112 C; Rf = 0.24 (9:1 hexane/ethyl
1
acetate); IR (KBr) 3050, 2962, 1650, 1464 cmꢀ1; H NMR (400 MHz, C6D6) δ 9.11 (d, 1H, J =
8.0 Hz), 8.93 (d, 1H, J = 7.6 Hz), 7.55ꢀ7.50 (m, 2H), 7.43ꢀ7.41 (m, 3H), 7.25 (s, 1H), 7.18 (d,
2H, J = 8.0 Hz), 7.01 (d, 2H, J = 8.0 Hz), 3.27 (t, 2H, J = 8.0 Hz), 2.15 (s, 3H), 1.99ꢀ1.93 (m,
2H), 1.47ꢀ1.38 (m, 2H), 1.22ꢀ1.18 (m, 2H), 0.90 (t, 3H, J = 7.4 Hz), 0.79ꢀ0.72 (m, 2H), 0.62 (t,
3H, J = 7.2 Hz); 13C NMR (100 MHz, C6D6) δ 156.7, 141.6, 139.0, 137.64, 137.62, 136.1, 130.3,
130.0, 128.1, 126.8, 125.3, 123.9, 123.0, 122.6, 122.24, 122.16, 121.5, 120.2, 111.2, 110.5, 98.5,
44.9, 44.7, 33.7, 31.4, 21.3, 20.8, 20.3, 14.4, 13.9; HRMS (ESI) m/z [M+H]+ Calcd for
C32H34N3O 476.2702, found 476.2706.
X-ray Data. Xꢀray data for compounds 3ae and 7 were collected using MoKα (λ = 0.71073 Å)
radiation. The structures were solved and refined by standard methods.25
Compound 3ae: C17H13N3O, M = 275.30, Monoclinic, Space group P21/n, a = 16.2541(13), b =
5.0990(3), c = 16.9467(11) Å,
α = 90, β
= 96.534(3), γ = 90, V = 1395.41(17) Å3, Z = 4, µ =
0.129 mmꢀ1, data/restraints/parameters: 3047/0/195, R indices (I> 2σ(I)): R1 = 0.0521, wR2 (all
data) = 0.1242, CCDC No. 1814184.
Compound 7: C26H21N3O2, M = 407.1634, Monoclinic, Space group C2/c, a = 17.005(3), b =
15.917(2), c = 30.298(5) Å,
α
= 90,
β
= 99.023(3), γ = 90, V = 8099(2) Å3 Z = 4, µ = 0.128 mmꢀ
,
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1, data/restraints/parameters: 9774/0/565, R indices (I> 2σ(I)): R1 = 0.1278, wR2 (all data) =
5
6
0.2763, CCDC No. 1814185.
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ASSOCIATED CONTENT
Supporting Information
Figures and CIF files giving ORTEP drawings as shown by Xꢀray crystallography, and copies of
1H/13C NMR spectra of all new products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: kckssc@uohyd.ac.in; kckssc@yahoo.com
Notes
The authors declare no competing financial interest.
Acknowledgments
We thank Department of Science & Technology (DST, New Delhi) for single crystal Xꢀ
ray diffractometer and HRMS facility (PURSE, IRHPA and FIST grants). We also thank UGC
for the UPEꢀII and NRC programs. KCK thanks DST for a J. C. Bose fellowship (SR/S2/JCBꢀ
53/2010) and CSIR (02(0240)/15/EMRꢀII) for funding. RNPT and MS thank UGC (New Delhi)
for fellowships.
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References
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(1) Selected reviews on CꢀH activation: (a) Bergman, R. G. Nature 2007, 446, 391ꢀ393. (b)
Chen, X.; Engle, K. M.; Wang, D.ꢀH.; Yu, J.ꢀQ. Angew. Chem. Int. Ed. 2009, 48, 5094ꢀ
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Rev. 2010, 110, 1147ꢀ1169. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281ꢀ295. (c) Li,
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S. W. Chem. Soc. Rev. 2016, 45, 546ꢀ576 and references cited therein.
(3) Selected reviews on chelationꢀassisted CꢀH functionalization: (a) Daugulis, O.; Do, H.ꢀQ.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074ꢀ1086. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624ꢀ655. (c) Engle, K. M.; Mei, T.ꢀS.; Wasa, M.; Yu,
J.ꢀQ. Acc. Chem. Res. 2012, 45, 788ꢀ802. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2012, 45, 814ꢀ825.
(4) For recent reviews on transition metalꢀcatalyzed C–H bond functionalization by the use of
diverse directing groups, see: (a) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W.
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Org. Chem. Front. 2014, 1, 843ꢀ895. (b) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.;
Zhang, Y. Org. Chem. Front. 2015, 2, 1107ꢀ1295.
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Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906ꢀ6919. (c) Liu, X.; Li, X.; Liu, H.; Guo, Q.;
Lan, J.; Wang, R.; You, J. Org. Lett. 2015, 17, 2936ꢀ2939. (d) Kumar, G. S.; Kumar, P.;
Kapur, M. Org. Lett. 2017, 19, 2494ꢀ2497 and references cited therein.
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(6) For reviews on CꢀH activation using carboxylic acid as a traceless directing group, see: (a)
Dzik, W. I.; Lange, P. P.; Gooßen, L. J. Chem. Sci. 2012, 3, 2671ꢀ2678. (b) Drapeau, M. P.;
Gooßen, L. J. Chem. ─ Eur. J. 2016, 22, 18654ꢀ18677. (c) Wei, Y.; Hu, P.; Zang, M.; Su,
W. Chem. Rev. 2017, 117, 8864ꢀ8907.
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Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 14006ꢀ14008. (c) Cornella,
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