Cobalt-Catalyzed One-Step Access to Pyroquilon and C-7 Alkenylation of Indoline with Activated Alkenes Using Weakly Coordinating Functional Groups

Article abstract of DOI:10.1021/acs.joc.0c00023

A new strategy for the C(7)-H functionalization of indoline derivatives using first-row transition-metal cobalt has been demonstrated wherein the pivaloyl group acts as a weakly coordinating directing group. Biologically important pyroquilon (tetrahydropyroquinolinone) derivatives have been synthesized in a one-pot manner through selective C(7)-H functionalization and concomitant cyclization. In this process, aromatic C-H and amidic C-N bonds are cleaved, and new C-C and C-N bonds are formed in a step-economical fashion. Further, selective C(7)-H alkenylation of indoline derivatives has also been accomplished using activated alkenes by varying the reaction conditions.

Full text of DOI:10.1021/acs.joc.0c00023

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Article
Cobalt-Catalyzed One-Step Access to Pyroquilon and C-7 Alkenylation of
Indoline with Activated Alkenes Using Weakly Coordinating Functional Group
Shyam Kumar Banjare, Pragati Biswal, and Ponneri Chandrababu Ravikumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00023 • Publication Date (Web): 18 Mar 2020
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The Journal of Organic Chemistry
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Cobalt-Catalyzed One-Step Access to Pyroquilon and C-7 Alkenylation
of Indoline with Activated Alkenes Using Weakly Coordinating
Functional Group
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Shyam Kumar Banjare, Pragati Biswal, and Ponneri Chandrababu Ravikumar*
School of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, HBNI, Jatani,
Odisha 752050, India
OR
Ar
Cp*Co(III)
Ar
Cp*Co(III)
Ag2CO3
DCE, 120 C
Ar
+
.
N
Cu(OAc)2 H2O
N
Piv
O
N
O
HFIP, rt
Piv
27 examples
18 examples
Up to 82% yield
Pyroquilon
Up to 91% yield
CO R
2
 Mild reaction condition
 One step access to Pyroquilon


Weakly coordinating directing group
First report with cobalt on C-7 alkenylation of indoline
 First report with first row tansiton metal
 C(7)-H functionalization followed by cyclization
ABSTRACT: A new strategy for the C(7)-H functionalization of indoline derivatives using first-row transition metal cobalt has
been demonstrated wherein, pivaloyl group is acting as a weakly coordinating directing group. Biologically important pyroquilon
(tetrahydropyroquinolinone) derivatives have been synthesized in a one-pot manner through selective C(7)-H functionalization and
concomitant cyclization. In this process, aromatic C-H and amidic C-N bonds are cleaved, and a new C-C and C-N bonds are
formed in a step-economical fashion. Further, selective C(7)-H alkenylation of indoline derivatives has also been accomplished
using
activated
alkenes
by
varying
the
reaction
conditions.
INTRODUCTION
Indoline and pyrroloquinolinone skeleton exist in numerous pharmaceuticals, biologically active molecules and several drugs.2a-b
The pharmacological activity towards the alzheimers, obesity, asthma, and epilepsy has attracted significant interest in the synthesis
of pyrroloquinoline and its derivatives by the synthetic and medicinal chemists (Figure 1).2
1
N
N
O
N
O
N
O
N
R
R'
R'
aromatase/
aldosterone inhibitor
R' = OMe, Oxoassoanine
R' = OCH2O, Anhydrolycorinone
CYP11B2 inhibitors
Figure 1. Selective examples of bioactive compound bearing pyrroloquinolinone skeleton.
Traditionally, pyrroloquinolinone derivatives have been synthesized by Fischer indole cyclization,3a radical cyclization,3b Michael-
3c
3d-e
type cyclization , and sigmatropic rearrangement. But these processes suffer from many drawbacks such as more number of
synthetic operations, harsh reaction conditions, and functional group incompatibility. Thus, development of a straight forward
4
synthetic procedure, which can overcome these challenges is needed. In recent years, transition metal-catalyzed C-H activation is
being considered as one of the most powerful synthetic protocols due to its step and atom economical properties. Taking note of
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this fact, few research groups have reported the synthesis of pyrroloquinolinone skeleton by intermolecular annulation of indoline
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derivatives with triple bond using second and third row transition metals (Re, Rh, Ru). Also there are few reports for the C-7
6
alkenylation of indoline using second and third row transition metals (Pd, Ru, Rh, Ir). However there is no report on the synthesis
of pyrroloquinolone and C-7 alkenylation of indoline using first row transition metals. In recent years first row transition metal-
7
catalyzed organic transformation is increasingly becoming popular due to its low cost, less toxicity, and easy availability. In this
regard, Ackermann8a and Koley groups have reported copper catalyzed formation of C−S/Se and C−O bonds on indolines at the
8b
8
c
C-7 position, respectively, using strongly coordinating pyrimidyl directing group (Figure 2a). The Punniyamurthy group have also
exploited the strongly coordinating pyrimidyl directing group for the cobalt catalyzed Suzuki−Miyaura type coupling of indolines at
the C-7 position with aryl boronic acid. Recently, we have reported cobalt catalyzed hydroarylation at the C-7 position of indoline
using weakly coordinating directing groups (Figure 2a).8d Use of weakly coordinating directing groups has gained significant
importance over the strongly coordinating directing groups because of its unique reactivity and selectivity.8d,9 To the best of our
knowledge, there is no report on the C-7 alkenylation of indoline as well as the one-step synthesis of pyroquilon
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(tetrahydropyrroloquinolinones)
by
using
first
row
transition
metals.
Previous report
Previous report
(a) 1st row Transition metal catalyzed C-7 fuctionalization8
(b) 2nd & 3rd row Transition metal catalyzed C-7 cyclization5
Cu, Co Cat.
Rh Cat.
N
Ph
Ph
N
DG
X
O
Ph
O
8
a
Ph
X = S, Se: Ackermann
X = O: Koley
DG =
NR2
DG = N-Pym
Strongly coordinating atom "N"
8b
Carboxamide based directing group: Loh5a
8
c
X = Ar : Punniyamurthy
Ar
H
X = C-C: Ravikumar8d
DG = N-Pivaloyl
Weakly coordinating atom "O"
N
DG
Present work
Present work
(c) Cobalt catalyzed C-7 Alkenylation of indoline
O
(d) 1st row Transition metal catalyzed C-7 cyclization
OR
Co Cat.
Co Cat.
Ar
Ar
N
O
O
N
O
DG
DG =
DG =
Pyroquilon
CO R
2
Weakly coordinating atom "O"
1st report with Cobalt
Pivaloyl as a directing group
1st report with 1st row Transition metal
Figure 2. Transition metal-catalyzed C(7)−H functionalization of indoline.
According to the literature precedence, the urea based directing group is well known for the C-H functionalization/annulation to
build pyrroloquinolinone framework (Figure 2b).5,6,10 Herein, we are introducing a one-step access to tetrahydropyrroloquinolinone
framework by intermolecular annulation of indoline (bearing pivaloyl as weakly coordinating directing group) with acrylates by
using Cp*Co catalyst (Figure 2d). With simple modification of conditions this strategy also gives direct access to the C-7
alkenylated indoline, which has the potential for further transformations (Figure 2c).
RESULTS AND DISCUSSION
To test the feasibility of selective C-7 functionalization of indoline, N-pivaloyl indoline 1a and methylacrylate 2a, were subjected to
2 6 2 3 2
Cp*Co(CO)I /AgSbF /Ag CO /Cu(OAc) catalytic system with various solvents such as 1,4-dioxane, toluene and THF (Table 1,
entries 1, 2, & 3). Gratifyingly, we got the pyroquilon in 40% of isolated yield with THF (Table 1, entry 3). Then we proceeded to
test this reaction with a polar protic solvent such as methanol; we did not observe any desired product 3aa (Table 1, entry 4).
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Fluorinated solvents such as trifluoroethanol and hexafluoroisopropanol gave moderate yield, whereas trifluorotoluene (TFT) raised
the yield up to 77% of 3aa (Table 1, entries 5, 6, & 7). Then we screened the reaction in a different chlorinated solvent such as
dichloromethane (DCM), 1, 2-dichlorobenzene (DCB), and 1, 2- dichloroethane (DCE) (Table 1, entries 8, 9, & 10). Interestingly
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with DCE, the yield improved to 82%. In order to improve the yield further, we changed the silver salt to AgNTf
improvement in yield was observed (Table 1, entry 11). To understand the role of the base, we performed a reaction without
AgCO , and we obtained only 12% yield. This result suggests that the base is playing a crucial role in this reaction. To understand
the importance of catalyst, another reaction was setup without Cp*Co(CO)I catalyst. In that case, we did not observe any product
catalyst.
2
, but no
3
2
formation, which confirms that this reaction is catalyzed by Cp*Co(CO)I
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Table 1. Optimization of the tetrahydropyrroloquinolinonea,b
OMe
Cp*Co(CO)I (10 mol %)
2
Ag salt (20 mol %)
N
N
O
Ag CO (1 equiv)
2
3

O
solvent (0.1M), 120 C, 24 h
O
1a
2a
3aa
yield (%)b
entry
1
solvent
Ag salt
1,4-dioxane
AgSbF6
AgSbF6
0
2
3
4
5
6
toluene
THF
0
40
0
AgSbF6
AgSbF6
AgSbF6
MeOH
TFE
46
HFIP
AgSbF6
43
7
8
TFT
DCM
AgSbF6
AgSbF6
AgSbF6
77
21
33
9
1,2-DCB
10
DCE
DCE
DCE
DCE
AgSbF6
AgNTf2
82
80
12
0
11
12
AgSbF , without Ag CO
3
6
2
13
AgSbF , without Cp*Co(CO)I2
6
a
2 2 3
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I (10 mol %), Ag salt (20 mol %), Ag CO (1 equiv), solvent (0.1
b
M), 120 °C, 24 h. Isolated yields.
To further optimize the reaction in terms of directing groups with 2a, various N-substituted indolines were screened under the
optimized reaction conditions (Table 2, entries 1-5). Among all these directing groups, pivaloyl 1a afforded very good yield of 3aa
as well as 4aa (Table 2, entry 1, optimization table S1 for product 4aa is demonstrated in supporting information) whereas, acetyl
and benzoyl substituted indolines gave good yields of 4aa (Table 2, entries 3 & 4). Indoline bearing free -NH and tert-
butyloxycarbonyl directing group could not lead to the formation of their respective products of 3aa and 4aa (Table 2, entries 2 and
5
).
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Table 2. Screening of directing groups for indoline C-7 alkenylation and cyclization.
Cp*Co(CO)I (10 mol %)
Cp*Co(CO)I (10 mol %)
2
2
N
O
AgSbF (20 mol %)
N
AgSbF (20 mol %)
N
6
6
1a
R
Ag CO (1 equiv)
Piv
Cu(OAc) H O (1 equiv)
2.
2
2
3
HFIP (0.1M), rt, 20 h
DCE (0.1M), 120 °C, 24 h
CO Me
COOMe
aa
entry yield of alkenylated product (%)
2
4
2a
3aa
R
yield of pyroquilon 3aa (%)
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4aa, 84%
Piv 1a
82%
4a'a, nr
H 1a'
Ac 1l
nr
nr
4ma, 68%
4
5
4na, 54%
4oa, nr
Bz 1m
Boc 1n
nr
nd
With the optimized reaction condition in hand, the substrate scope of indolines 1 with methyl acrylate 2a were investigated
Scheme 1). The developed methodology worked well with the 2-methyl indoline, 2,3-methyl indoline and 2, 3 fused indoline,
(
giving good yield of respective products (Scheme 1, 3ba, 3ca & 3da).
Scheme 1. Scope of tetrahydropyrroloquinolinonea,b
Cp*Co(CO)I (10 mol %)
2
OMe
AgSbF (20 mol %)
R
R
6
N
O
N
Ag CO (1 equiv)
2
3

DCE (0.1M), 120 C, 24 h
O
O
1
2
3
N
N
N
N
O
O
3ba, 71%
O
O
3aa, 82%
3ca, 63%
3da, 67%
Br
O
Br
N
N
O
N
N
O
O
O
O
3ea, 74%
3fa, 56%
3ga, 68%
3ha, 77%
R
O N
2
N
N
N
O N
N
2
O
O
O
O
3
ia, 57% R = F
3iia, 34% R = Cl
iiia, trace R = I
3ja, nd
3ka, nr
3la, nr
3
a
2 6 2 3
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I (10 mol %), AgSbF (20 mol %), Ag CO (1 equiv), 1,2-
b
Dichloroethane (0.1 M) as a solvent, 120 °C, 24 h. Isolated yields.
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Methoxy substituted indolines gave moderate to good yield (Scheme 1, 3ea, and 3fa). Halo (F, Cl & Br) substituted indolines also
gave moderate to a good yield of the respective product (Scheme 1, 3ia, 3iia, 3ga, and 3ha), whereas only a trace amount of desired
product was formed from iodo substituted indoline (Scheme 1, 3iiia). The structure 3ia was further confirmed by single-crystal x-
ray analysis, which is included in the supporting information, whereas the electron poor indolines afforded an irrelevant result
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1
1
1
1
1
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1
1
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6
2
(Scheme 1, 3ja & 3ka). This might be due to the poor nucleophilicity of the Co−C bond in the electron-withdrawing group (−NO )
substituted indoline making it less prone to undergo olefin insertion from the intermediate III (Scheme 4). We also have performed
the reaction with N-pivaloyl tetrahydroquinoline but, it failed to give the desired annulated product under this reaction condition
(Scheme 1, 3la). Next, to know the effect of the alkoxy substituents, various O-substituted acrylates such as methyl acrylate 2a,
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ethyl acrylate 2b, n-butyl acrylate 2c, tert-butyl acylate 2d, acrylic acid 2e, and phenyl acrylate 2f were subjected to this optimized
reaction condition (Table 3). Except for acrylic acid 2e yields of the product, 3aa was found to be gradually decreasing with an
increase in the chain length of the alkoxide unit. It might be due to the decreasing order of leaving group ability and steric factor.
Table 3. Scope of tetrahydropyrroloquinolinone with various Acrylatesa
Cp*Co(CO)I (10 mol %)
OR
2
AgSbF (20 mol %)
6
N
O
N
Ag CO (1 equiv)
2
3

DCE (0.1M), 120 C, 24 h
O
O
1a
2
3aa
R
yield of 3aab
R = methyl
R = ethyl
(Me)
2a
2b
2c
2d
2e
2f
82%
58%
53%
37%
24%
64%
(Et)
(nBu)
R = n-butyl
t
R = tert-butyl ( Bu)
R = hydrogen (H)
R = phenyl
(Ph)
aReaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I
2
6 2 3
(10 mol %), AgSbF (20 mol %), Ag CO (1 equiv), 1,2-
b
Dichloroethane (0.1 M) as a solvent, 120 °C, 24 h. Isolated yields.
To further optimize the reaction for C-7 alkenylation of indolines, we performed the same reaction by changing the additive from
silver carbonate to copper acetate in the presence of dichloromethane at room temperature. We obtained a 54% yield of alkenylated
product 4aa without any trace of 3aa (hydroarylation and cyclization product). For further confirmation of 4aa, we have taken a
single-crystal x-ray, which is included in the supporting information. Encouraged by this intriguing observation, we have screened
other chlorinated and fluorinated solvent out of which HFIP was found to be the best solvent to drive the reaction towards C-7
alkenylation, giving 84% yield of the desired product (for details see the optimization table S1 included in the supporting
information). After establishing the optimal reaction condition for cobalt catalyzed C-7 alkenylation of indoline, we decided to
evaluate the substrate scope of various indoline derivatives. At first, we tested this condition with N-pivaloylindoline bearing 2-
methyl and 2, 3 dimethyl groups. In both cases, we got a good yield of the C-7 alkenylated product (Scheme 2, 4ba & 4ca). 2,3-
fused indolines also gave good yield (Scheme 2, 4da). While indoline with electron-donating methoxy substituents at C-5 gave
9
1% yield (Scheme 2, 4ea), C-6 methoxy substituted indolines gave only 49% yield (Scheme 2, 4fa) possibly due to steric
hindrance by a methoxy group. Halogenated, bromo, fluoro, chloro, and iodo-indolines gave good yields (Scheme 2, 4ga-4iiia)
5
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whereas, electron-withdrawing 5–NO
2
substituted indoline gave low yield (scheme 2, 4ja) and 6–NO substituted Indoline failed to
2
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8
9
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1
1
1
1
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1
1
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6
produce desire product (scheme 2, 4ka). Also, N-pivaloyl tetrahyroquinoline afforded a trace amount of the desired product
(Scheme 2, 4la).
Scheme 2. Scope of Indoline C-7 Alkenylation with Acylatesa,b
OR2
Cp*Co(CO)I (10 mol %)
2
R1
R1
AgSbF (20 mol %)
N
6
N
O
Cu(OAc).H O (1 equiv)
2
O
HFIP (0.1M), rt, 20 h
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
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0
1
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1
2
3
4
5
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7
8
9
0
CO R
2
2
1
2
4
O
N
N
N
N
N
Piv
Piv
Piv
Piv
Piv
CO Me
CO Me
2
CO Me
2
CO Me
CO Me
2
2
2
4ba, 77%
4ca, 77%
4da, 61%
4ea, 91%
4aa, 84%
Br
Br
R
R
N
N
N
N
O
N
Piv
Piv
Piv
Piv
Piv
CO Me
CO Me
CO Me
CO Me
2
2
2
2
CO Me
2
4
4
4
ia, 61% R = F
iia, 73 R = Cl
iiia, 69% R = I
4ja, 28% R = 5-NO2
4ka, nr R = 6-NO2
4fa, 49%
4ga, 72%
4ha, 82%
N
N
N
N
N
Piv
Piv
Piv
Piv
Piv
CO Me
2
O
OH
O
O
O
O
O
O
4Ia, trace
4ab, 86%
4ac, 76 %
4ad, 57%
4ae, 52%
R' = Ph 4ai, nr
R' = CN 4aj, nr
R' = COMe 4ak, nr
N
N
N
N
Piv
Piv
Piv
Ph
O
Piv
Ph
O
O
O
O
NMe2
R'
4af, 73%
4ag, nr
4ah, nr
a
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I
2
(10 mol %), AgSbF
6 2 2
(20 mol %), Cu(OAc) .H O (1 equiv),
b
Hexafluoroisopropanol (0.1 M) as a solvent, rt, 20 h. Isolated yield.
To understand the reactivity of the various alkoxy substituents on acrylates, we performed the reaction with various acrylates
Scheme 2) and obtained respective alkenylated products in moderate to good yields (Scheme 2, 4aa, 4ab, 4ac, 4ad, and 4af).
(
Notably, the acrylic acid showed good reactivity in the present catalytic system (Scheme 2, 4ae). When (Z)-methyl 3-
phenylacrylate was subjected to the standard reaction condition as a coupling partner, it failed to give the desired product (scheme
2
, 4ag). It appears that a bulky phenyl group at the C-3 position of acrylate is offering steric resistance for its reactivity. Moreover,
to understand the reactivity of the indoline C-7 alkenylation, we have performed the reaction applying the standard condition with
various olefins, which revealed that only olefins bearing ester and acid substituents work well (Scheme 2, 4ah-4ak).
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1
The Journal of Organic Chemistry
Scheme 3. Mechanistic Studies.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
a) H/D exchange studies:
Cp*Co(CO)I (10 mol %)
2
AgSbF (20 mol %)
6
D O
2
N
Cu(OAc)  H O (1 equiv)
N
2
2
Piv
Piv
HFIP (0.1M), rt, 20 h
D/H
(1 equiv)
(10 equiv)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Deuterated at C(7)-H = 21%
(b) Inter molecular parallel experiment for kinetic isotope effect:
Methyl acrylate (4 equiv)
Cp*Co(CO)I (10 mol %)
N
2
N
Piv
AgSbF (20 mol %)
6
Piv
H
Cu(OAc)  H O (1 equiv)
2
2
COOMe
HFIP (0.1M), rt, 30 min.
1a (0.1 mmol)
3aa = 17%
Methyl acrylate (4 equiv)
Cp*Co(CO)I (10 mol %)
N
2
N
Piv
AgSbF (20 mol %)
6
Piv
D
Cu(OAc)  H O (1 equiv)
2
2
COOMe
HFIP (0.1M), rt, 30 min.
1a-d (0.1 mmol)
3aa = 13%
KIE = K /K = 1.3
H
D
(c) Reaction with radical scavengers:
Radical scavenger (0.1 mmol)
Cp*Co(CO)I (10 mol %)
2
N
OMe
N
Piv
Piv
AgSbF (20 mol %)
6
O
Cu(OAc)  H O (1 equiv)
2
2
COOMe
1a
(0.1 mmol)
2a
HFIP (0.1M), rt, 20 h
4
aa
(0.1 mmol)
(d) Competitive studies with different substrates for C-7 alkenylation:
R1
R2
Methyl acrylate (0.1 mmol)
R1
R2
Cp*Co(CO)I2 (10 mol %)
+
N
N
N
AgSbF6 (20 mol %)
N
Piv
Piv
Cu(OAc)  H O (1 equiv)
Piv
2
2
Piv
HFIP (0.1M), rt, 20 h
COOMe
COOMe
R = NO , F
R = OMe
2
1
2
R = NO , 0% R = OMe, 41%
1
2
2
(0.1 mmol)
(0.1 mmol)
R = F, 22%
R = OMe, 27%
2
1
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Page 8 of 22
(
e) Competitive studies with different substrates for cyclization:
F
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
N
F
O
Methyl acrylate (0.1 mmol)
Cp*Co(CO)I2 (10 mol %)
+
N
N
AgSbF6 (20 mol %)
Ag2CO3 (1 equiv)
N
Piv
Piv
DCE (0.1M), 120 °C, 24 h
O
O
(
0.1 mmol)
(0.1 mmol)
yield = 15%
yield = 24%
(
f)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
O
Ag2CO3 (1 equiv)
DCE (0.1M)
120 °C, 24 h
yield of 3aa, trace)
N
N
DCE (0.1M), 120 °C, 24 h
Piv
Piv
(
yield of 3aa, 21%
VI, 60% Recovered
VI, 74% Recovered
3aa
COOMe
VI
COOMe
VI
(g)
Cp*Co(CO)I2 (10 mol %)
AgSbF6 (20 mol %)
Cp*Co(CO)I2 (10 mol %)
O
AgSbF6 (20 mol %)
N
N
N
Ag2CO3 (1 equiv)
DCE (0.1M), 120 °C, 2 h
(yield = 92%)
Ag2CO3 (1 equiv)
Piv
Piv
DCE (0.1M), 120 °C, 24 h
3aa
(nd)
COOMe
VI
COOMe
4aa
To gain insight into the reaction mechanism, we have performed various control experiments (Scheme 3). Deuterium exchange
study was performed on N-pivaloyl indoline 1a in the absence of Michael acceptor 2a with 10 equivalent of D O under the
2
alkenylation condition. We observed 21% deuteration at the C-7 position (Scheme 3a). The ratio of C(7)-H deuteration did not
change much even after continuing the reaction for a longer time, which suggests that the first step might be a reversible step.
Further, we have performed inter molecular parallel experiments for kinetic isotope effect (Scheme 3b) resulting in KIE = 1.3,
which confirms that the first step is not involving in the rate-determining step. The use of radical scavengers such as TEMPO and
BHT (Scheme 3c) did not quench the reaction altogether; this indicates that the reaction is going through the ionic mechanism. In
addition, we have performed a competition study between 1-(5-fluoroindolin-1-yl)-2, 2-dimethylpropan-1-one, and 1-(5-
methoxyindolin-1-yl)-2, 2-dimethylpropan-1-one substrates which gave an almost similar yield of the respective C-7 alkenylated
products (Scheme 3d). Competitive studies for the cyclization reaction was performed between 5-methoxy and 5-fluoro indolines
(Scheme 3e). It concludes that electron-rich indoline reacts faster than electron-poor indoline. Moreover, to understand the role of
Ag
aa (Scheme 3f), and also 60% of VI was recovered. Whereas when VI was heated at 120 ºC in DCE without Ag
AgSbF trace amount of 3aa was observed. In addition to this, the alkylated species VI was subjected to the standard condition for
2
CO
3
in the cyclization reaction, VI was heated at 120 ºC in DCE solvent in the absence catalyst & AgSbF
6
, which gave 21% of
3
2
CO , catalyst &
3
6
cyclization reaction, which resulted in a 92% isolated yield of pyroquilon 3aa within two hours (Scheme 3g). These control
experiments confirm that the formation of 3aa is going through alkylated intermediate VI (Scheme 3f & 3g), and the Co-catalyst is
enhancing the rate of cyclization reaction. Whereas, when 4aa was subjected to the standard condition for cyclization, we did not
observe any cyclized product (Scheme 3g). It might be due to the trans-geometry of the olefin in 4aa.
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Scheme 4. Proposed Catalytic Cycle.
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
[
Cp*Co(CO)I2]
AgSbF6
-OAc, CO32-
AgI
R1
Cu(OAc)2
N
[Cp*Co(III)(X)]
1
a
X = (OAc)2, CO32-
O
oxidation
I
AcOH, HCO3-
cyclometalation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[Cp*Co(I)]
R1
O
V
N
O
R1
N
[Cp*Co(III)]
II
-H elimination &
O
OR2
Co
reductive elimination
4
aa + AcOH

-complex
OR2
formation
O
R1
2
a
N
R1
H
N
O
olefin
[
Cp*Co(III)]
R2O
[Co(III)Cp*]
O
insertion
O
IV
III
R1
[
Cp*Co(III)(X)]
O
N
protodemetalation
R2O
I
O
3aa
R2OH
R1
O
R1
N
depivaloylation
[Cp*Co(III)(X)]
N
H
Co(III)-Lewis acid-assisted
nucleophilic addition
followed by cyclization
O
OR2
O
OR2
VI
[Cp*Co(III)(X)] VII
Based on kinetic studies and literature reports,11,12, we proposed a plausible catalytic cycle (Scheme 4) where Cp*Co(CO)I
reacts with AgSbF to generate an active catalyst I that forms a six-membered cyclometalated species II in the presence of 1a. The
2
6
cationic cobalt(III) species undergoes π-complexation with the Michael acceptor 2a and gives intermediate III, which then
undergoes olefin insertion to give intermediate IV. Then β-hydride elimination followed by reductive elimination gives the desired
product 4aa and cobalt(I) complex V, which is further oxidized by copper acetate to regenerate the active cobalt(III) catalyst I for
the next catalytic cycle. In another pathway, intermediate IV, undergoes proto-demetalation giving intermediate VI, which
undergoes depivaloylation followed by cyclization of VII, giving the desired cyclized product 3aa. It might be due to Lewis acidic
nature of Co-catalyst which is coordinating to the alkylated carbonyl VII and increasing the electrophilicity of the carbonyl carbon
towards the nucleophilic substitution reaction for cyclization.12d
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The Journal of Organic Chemistry
Page 10 of 22
Scheme 5. Synthetic Applications.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(a)
N
O
N
(i) DDQ (2 equiv)
N
(i) 10 N HCl
rt, 12 h
Piv
1,4-dioxane (0.6M)
Piv

120 C, 20 h
COOMe
COOMe
4aa
1,2-dihydropyrroloquinolinone
4
am, 89%
4an, 98%
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
N
(b)
standard
condition
H
+
O
Piv
N
H
H
H
H
Piv
O
H
O
O
1
a
2l
4al, 66%
1
mmol (210 mg) scale reaction :
Cp*Co(CO)I2 (10 mol %)
AgSbF6 (20 mol %)
Cp*Co(CO)I2 (10 mol %)
AgSbF6 (20 mol %)
(c)
N
N
O
N
1
a
Piv
Cu(OAc)2.H2O (1 equiv)
HFIP (0.1M), rt, 20 h
Ag2CO3 (1 equiv)
Piv
O
DCE (0.1M), 120 °C, 24 h
COOMe
aa, 80%, 241 mg
O
2a
4
3aa, 78%, 138 mg
To check the applicability of this transformation, we have performed the oxidation reaction of C-7-olefinated indoline 4aa to get C-
-olefinated indole 4am in 89% yield (Scheme 5a). Interestingly when 4aa was treated with 10N HCl, it led to multiple events in
7
one pot such as (i) deprotection of pivaloyl directing group, (ii) hydrolysis of ester, (iii) isomerization of trans to cis olefin, (iv)
intramolecular amidation giving an excellent yield of 1,2-dihydropyroquinolinone 4an (Scheme 5a). This one-pot process in itself
is a new method for the synthesis of 1,2-dihydropyroquinolinone. This C-H activation methodology also worked well with acrylate
2
l derived from biologically active molecule estrone to give a good yield of 4al (Scheme 5b). To know the synthetic applicability
on a larger scale, we performed a 1 mmol scale reaction, which gave 3aa and 4aa in 78% and 80%, respectively.
CONCLUSION
In summary, we have developed the cobalt-catalyzed one-step synthesis of tetrahydropyrroloquinolinone and C-7 alkenylated
indolines using a weakly coordinating directing group for the first time. By simple modification of reaction conditions, we could
achieve either C(7)-H alkenylation or tetrahydropyrroloquinolinones. The control experiment confirmed that the C-7 alkylated
indoline is the active intermediate for the formation of pyroquilon. In addition, this methodology is further useful for the synthesis
of 1,2-dihydropyrroloquinolinone from C-7 alkenylated indoline just by treatment with 10N HCl, which in itself is a new method.
The developed protocol works well for a wide range of indolines and acrylates.
EXPERIMENTAL SECTION
General Information:8d Reactions were performed using borosil sealed tube vial under N
atmosphere. Column chromatography
2
was done by using 100-200 & 230-400 mesh silica gel of Acme synthetic chemicals company. Gradient elution was performed by
using distilled petroleum ether and ethyl acetate. TLC plates detected under UV light at 254 nm. H NMR, 13C NMR, recorded on
1
3 6
Bruker AV 400 and 700 MHz spectrometers using CDCl & DMSO-d
as the deuterated solvent.14a Multiplicity (s = single, d =
doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet), integration, and coupling constants (J ) in hertz (Hz).
HRMS signal analysis was performed using micro TOF Q-II mass spectrometer, and X-ray analysis was recorded at SCS, NISER.
1
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The Journal of Organic Chemistry
Reagents and starting materials were purchased from Sigma Aldrich, TCI, Avra, Spectrochem, and other commercially available
sources, used without further purification unless otherwise noted.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Abbreviation: DCM (Dichloromethane), rt (Room temperature), Et
Dimethylaminopyridine), TEMPO (2,2,6,6-tetramethylpiperidin-1-yl), PivCl (Pivaloyl chloride), AcOH (Acetic acid), EtOAc
Ethyl acetate), DCM (Dichloromethane), DCE (1,2-Dichloroethane), HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol), DCB (1,2-
3
N (Triethylamine), TFE (Trifluoroethanol), DMAP (4-
(
Dichlorobenzene), TFT (Trifluorotoluene), THF (Tetrahydrofuran), BHT (Butylated hydroxytoluene).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(a) General procedure for preparation of N-acetylindolines / N-pivaloylindolines: Pivaloyl chloride (12.0 mmol) was added in
3
portions to a stirred solution of indoline (10.0 mmol), DMAP (0.1 equiv), Et N (15.0 mmol) in dry DCM (30 mL) at 0 ºC. The
reaction was then allowed to warm to room temperature and stirred overnight. The DCM was removed by rotary evaporation, and
the residue was partitioned between EtOAc (30 mL) and brine (20 mL). The organic layer was collected, and the aqueous layer was
2 4
washed with EtOAc (30 mL x 2). The combined organic layers were dried over Na SO and then filtered. After removal of the
solvent, the residue was purified on silica gel column chromatography to afford the corresponding acylation product.
Characterization of these compounds have been described in the previous reports.14b-d
(b) Reduction of indoles to indolines: To a solution of 3-methylindole (5.2 g, 40 mmol) in acetic acid (30 mL) was added portion-
wise sodium cyanoborohydride (5.0 g, 80 mmol) at 0 ºC, and the mixture was stirred at room temperature. After 2 h, water (50 mL)
was added at 0 ºC and basified with NaOH (5N aqueous solution). Organic material was extracted with CH
washed with brine, dried over anhydrous MgSO
, and concentrated by a rotary evaporator to give indoline.14e
c) General reaction procedure for synthesis of pyroquilon from indoline: To a pre-dried sealed tube under N
2
Cl
2
(100 mL x 3),
, the mixture of
4
(
2
N-pivaloyl indoline 1 (0.1 mmol), acrylate 2 (0.4 mmol), [Cp*Co(CO)I
2
6 2 3
] (10 mol %), AgSbF (20 mol %), Ag CO (1 equiv) and
º
DCE (1 mL) were added and sealed. The reaction mixture was vigorously stirred at 120 C in a heating aluminum block for 24 h.
After 24 h (completion of the reaction as monitored by TLC analysis), the reaction mixture was cooled to room temperature and
diluted with diethyl ether/dichloromethane and passed through a short Celite pad, the solvent was evaporated under reduced
pressure, and the residue was purified by column chromatography using EtOAc/hexane mixture on silica gel to give the pure
product 3.
(d) General reaction procedure for C-7 Alkenylation of Indoline: To a pre-dried sealed tube under N
indoline 1 (0.1 mmol), acrylate 2 (0.4 mmol), [Cp*Co(CO)I ] (10 mol %), AgSbF (20 mol %), Cu(OAc)
1 mL) were added and sealed. The reaction mixture was vigorously stirred at room temperature for 20 h. After 20 h (completion of
2
, the mixture of N-pivaloyl
2
6
2
2
.H O (1 equiv) and HFIP
(
the reaction as monitored by TLC analysis), the reaction mixture was cooled to room temperature and diluted with diethyl
ether/dichloromethane and passed through a short celite pad, the solvent was evaporated under reduced pressure, and the residue
was purified by column chromatography using EtOAc/hexane mixture on silica gel to give the pure product 4.
(
e) General reaction procedure for intermolecular parallel experiment for kinetic isotope effect: Two sets of parallel
experiments were performed by taking the mixture of N-pivaloyl indoline 1a (0.1 mmol) or 2a-d (0.1 mmol) with methyl acrylate
2a (4 equiv), [Cp*Co(CO)I ] (10 mol %), AgSbF (20 mol %), Cu(OAc) .H O (1 equiv) and HFIP (1 mL). The reaction mixture
2
6
2
2
was vigorously stirred at room temperature for 30 min. After 30 min. The reaction mixture was cooled to room temperature and
diluted with dichloromethane and passed through a short celite pad. The solvent was evaporated under reduced pressure, and the
crude mixture was purified by column chromatography using EtOAc/hexane mixture on silica gel to give the pure product 3aa
H D
(K /K = 1.3).
1
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(
f) General reaction procedure for Competition studies with substrates: To a pre-dried sealed tube under N , the mixture of N-
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pivaloyl 5-methoxy indoline 3c (0.1 mmol), N-pivaloyl 5-flouro indoline 3h (0.1 mmol) methyl acrylate 2a (0.1 mmol),
[Cp*Co(CO)I ] (10 mol %), AgSbF (20 mol %), Cu(OAc) .H O (1 equiv) and HFIP (1 mL) were added and sealed. The reaction
2
6
2
2
mixture was vigorously stirred at room temperature for 24 h. After 24 h (completion of the reaction as monitored by TLC analysis),
the reaction mixture was cooled to room temperature and diluted with diethyl ether/ dichloromethane and passed through a short
celite pad, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography using
EtOAc/hexane mixture on silica gel to give the pure product 4ia & 4ea.
(
g) General reaction procedure for Competition studies with substrates: To a pre-dried sealed tube under N
pivaloyl 5-methoxy indoline 3c (0.1 mmol), N-pivaloyl 5-flouro indoline 3h (0.1 mmol) methyl acrylate 2a (0.1 mmol),
Cp*Co(CO)I ] (10 mol %), AgSbF (20 mol %), Ag CO (1 equiv) and HFIP (1 mL) were added and sealed. The reaction mixture
2
, the mixture of N-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
2
6
2
3
was vigorously stirred at 120 ºC in a heating aluminum block for 24 h. After 24 h (completion of the reaction as monitored by TLC
analysis), the reaction mixture was cooled to room temperature and diluted with diethyl ether/ dichloromethane and passed through
a short Celite pad, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography
using EtOAc/hexane mixture on silica gel to give the pure product 3ia & 3ea.
(
h) General reaction procedure for the synthesis of pyroquilon from indoline in 1 mmol scale: To a pre-dried sealed tube
under N , the mixture of N-pivaloyl indoline 1a (1.0 mmol) 210 mg, methyl acrylate 2a (4.0 mmol), [Cp*Co(CO)I ] (10 mol %),
AgSbF (20 mol %), Ag CO (1 equiv) and DCE (1 mL) were added and sealed. The reaction mixture was vigorously stirred at 120
2
2
6
2
3
ºC in a heating aluminum block for 24 h. After 24 h (completion of the reaction as monitored by TLC analysis), the reaction
mixture was cooled to room temperature and diluted with diethyl ether/dichloromethane and passed through a short celite pad, the
solvent was evaporated under reduced pressure, and the residue was purified by column chromatography using EtOAc/hexane
mixture on silica gel to give the pure product 3aa in 78%, 138 mg yield.
(
i) General reaction procedure for C-7 Alkenylation of indoline in 1 mmol scale: To a pre-dried sealed tube under N
mixture of N-pivaloyl indoline 1a (1.0 mmol) 210 mg, methyl acrylate 2a (4.0 mmol), [Cp*Co(CO)I ] (10 mol %), AgSbF (20 mol
%), Cu(OAc) .H O (1 equiv) and HFIP (1 mL) were added and sealed. The reaction mixture was vigorously stirred at room
2
, the
2
6
2
2
temperature for 20 h. After 20 h (completion of the reaction as monitored by TLC analysis), the reaction mixture was cooled to
room temperature and diluted with diethyl ether/dichloromethane and passed through a short celite pad, the solvent was evaporated
under reduced pressure, and the residue was purified by column chromatography using EtOAc/hexane mixture on silica gel to give
the pure product 4aa in 81%, 241mg yield.
(
j) General reaction procedure for oxidation of indoline to indole: A mixture of 4aa (0.1 mmol, 1 equiv), DDQ (2 equiv) 1,4-
o
dioxane (1mL) in a 25 mL sealed tube was heated at 120 C in a heating aluminum block for 20 hours. The reaction mixture was
cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by column
chromatography using EtOAc/hexane mixture on silica gel to give the pure product 4am in 89% yield.
(
k) General reaction procedure for the synthesis of 1,2-dihydropyroquinolinone: A mixture of 4aa (0.1 mmol) in 10N HCl
(
1mL) was added, the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was neutralized with aqueous
4 2 4
NH Cl solution and partitioned between DCM and H O. The organic layer was dried over MgSO , and the solvent was evaporated
under reduced pressure, and the residue was purified by column chromatography using EtOAc/hexane mixture on silica gel to give
the pure product 4an in 98% yield.
(l) General reaction procedure for the synthesis of N-pivaloyl 5-chloro indoline: N-pivaloy Indoline (81.3 mg, 0.4 mmol) was
reacted with iodobenzene diacetate (155 mg, 0.48 mmol) and 1 M HCl (2 mL, 2 mmol) in dichloroethane (2 mL) for 2 hours. The
crude product was purified by column chromatography eluting with 5% ethyl acetate/hexanes to yield, as a colorless oil was
1
5c
observed.
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Experimental characterization data for products:
5
,6-Dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3aa)6e was prepared according to general procedure (c). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a white solid (14 mg, 82% yield) R :
1
0.35 (in 30% EtOAc/Hexane), mp 113-115 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.07 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H),
.92 (t, J = 7.2 Hz, 1H), 4.08 (t, J = 8.4 Hz, 2H), 3.19 (t, J = 8.4 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H). 13C{ H}
1
6
3
(CDCl , 100 MHz): δ 168.0, 141.6, 129.3, 125.7, 123.6, 123.6, 120.6, 45.5, 32.0, 28.1, 24.7. HRMS (ESI) m/z calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
-1
C
11
H11NONa [M+Na] : 196.0738; found: 196.0734. IR (KBr, cm ): 1654.
2
-Methyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ba) was prepared according to general procedure (c). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a colorless liquid (12 mg,
1
7
1% yield) R
f
: 0.30 (in 20% EtOAc/Hexane). H NMR (CDCl
3
, 700 MHz): δ 7.04 (d, J = 7.0 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.92
(t, J = 7.7 Hz, 1H), 4.68-4.64 (m, 1H), 3.41 (dd, J = 16.1, 6.3 Hz, 1H), 3.04-2.99 (m, 1H), 2.92-2.88 (m, 1H), 2.72-2.63 (m, 3H),
13
1
1
.43 (d, J = 6.3 Hz, 3H). C{ H}NMR (CDCl
3
, 175 MHz): δ 168.0, 141.1, 127.9, 125.6, 123.7, 123.6, 120.6, 54.6, 37.0, 32.3, 24.8,
+
-1
2
1.4. HRMS (ESI) m/z calcd for C12 14NO [M+H] : 188.1075; found: 188.1071. IR (KBr, cm ): 1667.
H
1,2-Dimethyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ca) was prepared according to general procedure (c). The
crude reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a colorless liquid (11
1
mg, 63% yield) R
f
: 0.35 (in 20% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 7.04-7.699 (m, 2H), 6.95-6.92 (m, 1H), 4.15-4.10
13
1
(m, 1H), 3.06-2.97 (m, 3H), 2.73-2.59 (m, 2H), 1.46 (d, J = 6.5 Hz, 3H), 1.29 (d, J = 7.5 Hz, 3H). C{ H}NMR (CDCl
3
, 100
MHz): δ 168.2, 140.5, 133.3, 125.8, 123.7, 122.7, 120.5, 63.0, 44.7, 32.3, 24.7, 21.0, 20.5. HRMS (ESI) m/z calcd for C13
H
16NO
+
-1
[M+H] : 202.1226; found: 202.1231. IR (KBr, cm ) 1669.
7
a,8,9,10,11,11a-Hexahydro-4H-pyrido[3,2,1-jk]carbazol-6(5H)-one (3da)14a was prepared according to general procedure (c). The
crude reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow liquid (14 mg,
1
6
7% yield) R
f
: 0.35 (in 20% EtOAc/Hexane). H NMR (CDCl
3
, 700 MHz): δ 7.03 (d, J = 7.7 Hz, 1H), 7.0 (d, J = 7.7 Hz, 1H), 6.96
(t, J = 7.7 Hz, 1H), 4.58-4.55 (m, 1H), 3.49 (t, J = 9.8 Hz, 1H), 3.03-2.98 (m, 1H), 2.93-2.89 (m, 1H), 2.69-2.64 (m, 2H), 2.26-2.23
13
1
(m, 1H), 2.12-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.57-1.55 (m, 2H), 1.36-1.25 (m, 3H). C{ H} NMR (CDCl
3
, 175 MHz): δ 167.3,
1
41.1, 132.2, 125.6, 123.7, 122.0, 120.9, 58.9, 40.6, 32.2, 26.8, 24.8, 24.7, 21.2, 20.9. HRMS (ESI) m/z calcd for C15H18NO
+
-1
[M+H] : 228.1388; found: 228.1386. IR (KBr, cm ): 1667.
8
-Methoxy-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ea) was prepared according to general procedure (c). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (10 mg, 74%
1
yield) R
f
: 0.25 (in 40% EtOAc/Hexane), mp 121-123 ºC. H NMR (CDCl
3
, 400 MHz): δ 6.59 (s, 1H), 6.49 (s, 1H), 4.01 (t, J = 8.4
1
3
1
Hz, 2H), 3.70 (s, 3H), 3.09 (t, J = 8.3 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H). C{ H} NMR (CDCl
3
, 100 MHz):
δ 157.2, 135.2, 130.2, 121.0, 111.4, 109.6, 56.2, 45.6, 31.7, 28.2, 24.9. HRMS (ESI) m/z calcd for C12
H
13NO
2
Na [M+Na]+:
-1
2
26.0844; found: 226.0843. IR (KBr, cm ): 1659.
7
-Methoxy-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3fa)14b was prepared according to general procedure (c). The
crude reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (12 mg,
1
5
6% yield) R
f
: 0.35 (in 30% EtOAc/Hexane), mp 129-131 ºC. H NMR (CDCl
3
, 400 MHz): δ 6.99 (d, J = 8.0 Hz, 1H), 6.46 (d, J =
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.0 Hz, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.81 (s, 3H), 3.10 (t, J = 8.0 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 2.46 (t, J = 8.0 Hz, 2H).
1
2
3
4
5
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1
1
1
1
1
1
1
1
1
1
2
2
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2
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2
2
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
C{ H} NMR (CDCl
3
, 100 MHz): δ 168.1, 156.3, 143.2, 124.0, 122.1, 109.2, 106.1, 56.0, 46.2, 31.4, 27.3, 19.4. HRMS (ESI) m/z
+
-1
2
calcd for C12H14NO [M+H] : 204.1019; found: 204.1008. IR (KBr, cm ): 1662.
9
-Bromo-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ga) was prepared according to general procedure (c). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a colorless solid (17 mg, 68%
1
yield) R
f
: 0.35 (in 30% EtOAc/Hexane), mp 117-119 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.04 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8 Hz,
H), 4.1(t, J = 8.4 Hz, 2H), 3.16 (t, J = 8.4 Hz, 2H), 2.92 (t, J = 8 Hz, 2H), 2.6 (t, J = 8Hz, 2H). 13C{ H} NMR (CDCl
1
, 100 MHz):
H
10BrNONa [M+Na]+:
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 168.0, 142.7, 130.1, 127.6, 126.1, 119.3, 117.7, 45.1, 31.6, 29.4, 24.4. HRMS (ESI) m/z calcd for C11
-1
2
73.9838; found: 273.9842. IR (KBr, cm ): 1667.
-Bromo-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ha) was prepared according to general procedure (c). The crude
8
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (13 mg, 77%
1
yield) R
f
: 0.32 (in 30% EtOAc/Hexane), mp 122-124 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.13 (s, 1H), 7.07 (s, 1H), 4.01 (t, J = 8.4
Hz, 2H), 3.10 (t, J = 8.5 Hz, 2H), 2.88 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ 167.6,
3
+
1
40.8, 131.2, 128.6, 126.7, 122.0, 115.8, 45.6, 31.6, 27.8, 24.5. HRMS (ESI) m/z calcd for C11
H
10BrNONa [M+Na] : 273.9843;
-1
found: 273.9843. IR (KBr, cm ): 1667.
8
-Fluoro-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3ia) was prepared according to general procedure (c). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a pale yellow liquid (11 mg,
1
5
7% yield) R
f
: 0.30 (in 30% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 6.79 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H),
.09 (t, J = 8.4 Hz, 2H), 3.17 (t, J = 8.4 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H). 13C{ H} NMR (CDCl
1
, 175
4
3
MHz): δ 167.5, 160.7, 159.3, 137.6, 130.5 (d, J = 8.7 Hz), 121.3 (d, J = 8.4 Hz), 112.6 (d, J = 24.7 Hz), 111.0 (d, J = 24.8 Hz),
+
4
5.7, 31.5, 28.1 (d, J = 1.7 Hz), 24.7 (d, J = 1 Hz). HRMS (ESI) m/z calcd for C11H11FNO [M+H] : 192.0819; found: 192.0829. IR
-1
(KBr, cm ): 1676.
8
-chloro-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one (3iia) was prepared according to general procedure (c). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a white solid (5 mg, 34%
1
yield) R
f
: 0.35 (in 40% EtOAc/Hexane), mp 113-115 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.20 (s, 1H), 7.13 (s, 1H), 4.08 (t, J = 8.4
Hz, 2H), 3.17 (t, J = 8.4 Hz, 2H), 2.94 (t, J = 8.0 Hz, 2H), 2.66 (t, J = 8.0 Hz, 2H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ 168.0,
3
+
1
40.4, 131.3, 128.7, 126.8, 122.1, 116.2, 45.8, 31.2, 27.8, 24.3. HRMS (ESI) m/z calcd for C11
H
10ClNONa [M+Na] : 230.0343;
-1
found: 230.0342. IR (KBr, cm ): 1739.
(
E)-Methyl 3-(1-pivaloylindolin-7-yl)acrylate (4aa)6e was prepared according to general procedure (d). The crude reaction mixture
f
was purified by column chromatography using silica gel (100-200 mesh size) giving a white solid (24 mg, 84% yield) R : 0.40 (in
1
2
0% EtOAc/Hexane), mp 125-127 ºC H NMR (CDCl
3
, 700 MHz): δ 7.45 (d, J = 16.1 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.23 (d, J
= 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.31 (d, J = 16.1 Hz, 1H), 4.17 (t, J = 7.4 Hz, 2H), 3.77 (s, 3H), 3.06 (t, J = 7.4 Hz, 2H),
13
1
1
.42 (s, 9H). C{ H} NMR (CDCl
3
, 175 MHz): δ 180.0, 168.0, 144.0, 143.1, 135.0, 126.1, 125.6, 125.3, 117.1, 51.8, 51.4, 40.5,
+
-1
3
1.1, 29.1. HRMS (ESI) m/z calcd for C17
H
3
21NO Na [M+Na] : 310.1419; found: 310.1424. IR (KBr, cm ): 1715, 1652.
(E)-Methyl 3-(2-methyl-1-pivaloylindolin-7-yl)acrylate (4ba) was prepared according to general procedure (d). The crude reaction
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow liquid (22 mg, 77% yield) R
f
:
1
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1
0
.45 (in 20% EtOAc/Hexane) H NMR (CDCl
3
, 700 MHz): δ 7.47 (d, J = 16.1 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 5.6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
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4
4
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5
5
5
5
5
5
5
5
6
Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.34 (d, J = 16.1 Hz, 1H), 4.84-4.81 (m, 1H), 3.76 (s, 3H), 3.31-3.28 (m, 1H) 2.54 (d, J = 14.7
1
3
1
Hz, 1H), 1.41 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H). C{ H} NMR (CDCl
3
, 175 MHz): δ 179.4, 168.2, 143.1, 142.8, 134.7, 127.6,
+
1
3
27.7, 125.8, 125.4, 116.8, 57.8, 51.9, 50.0, 38.4, 29.1, 21.0. HRMS (ESI) m/z calcd for C18
H
23NO
3
Na [M+Na] : 324.1576; found:
-1
24.1577. IR (KBr, cm ): 1734, 1653.
(E)-Methyl 3-(2,3-dimethyl-1-pivaloylindolin-7-yl)acrylate (4ca) was prepared according to general procedure (d). The crude
reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow liquid (24 mg, 77%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield) R
f
: 0.30 (in 10% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 7.51-7.43 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 7.6
Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 4.36 (q, J = 6.4 Hz, 1H), 3.8 (s, 3H), 2.78 (q, J = 7.2 Hz, 1H), 1.41 (s, 9H), 1.26 (d, J = 6.4 Hz,
1
3
H), 1.17 (d, J = 7.2 Hz, 3H). 13C{ H} NMR (CDCl
3
, 100 MHz): δ 180.0, 168.1, 142.8, 142.2, 140.0, 127.6, 126.0, 125.8, 125.7,
+
1
16.8, 64.6, 51.9, 45.6, 41.0, 29.4, 21.0, 20.4. HRMS (ESI) m/z calcd for C19
H
26NO
3
[M+H] : 316.1907; found: 316.1914. IR (KBr,
-1
cm ): 1700, 1653.
(E)-Methyl 3-(9-pivaloyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-8-yl)acrylate (4da) was prepared according to general procedure
(d). The crude reaction mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a colourless
1
liquid (17 mg, 61% yield) R
f
: 0.40 (in 20% EtOAc/Hexane), H NMR (CDCl
3
, 700 MHz): δ 7.49 (d, J = 16.1 Hz, 1H), 7.43-7.42
(m, 1H), 7.18-7.15 (m, 2H), 6.33 (d, J = 16.1 Hz, 1H), 4.59-4.55 (m, 1H), 3.76 (s, 3H), 3.48 (t, J = 5.5 Hz, 1H), 2.32 (d, J = 14.7
Hz, 1H), 2.07-2.04(m, 1H), 1.84-1.78 (m, 1H), 1.53 (d, J = 12.6 Hz, 1H), 1.41 (s, 9H), 1.25-1.19 (m, 3H), 1.12-1.06 (m, 1H).
1
3
1
C{ H} NMR (CDCl
29.2, 28.1, 24.9, 23.7, 20.8. HRMS (ESI) m/z calcd for C21
652.
3
, 175 MHz): δ 179.0, 168.1, 144.5, 143.0, 138.0, 127.8, 125.8, 125.1, 124.2, 116.8, 63.7, 52.0, 42.6, 40.7,
+
-1
H
3
28NO [M+H] : 342.2069; found: 342.2065. IR (KBr, cm ): 1717,
1
(E)-Methyl 3-(5-methoxy-1-pivaloylindolin-7-yl)acrylate (4ea) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (24 mg, 91% yield) R :
1
0
6
.35 (in 30% EtOAc/Hexane), mp 114-116 ºC. H NMR (CDCl
3
, 700 MHz): δ 7.45 (d, J = 16.1 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H),
.83 (d, J = 0.7 Hz, 1H), 6.28 (d, J = 16.1 Hz, 1H), 4.16 (t, J = 7.4 Hz, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.00 (d, J = 7.4 Hz, 2H), 1.40
1
(
s, 9H). 13C{ H} NMR (CDCl
3
, 175 MHz): δ 179.6, 167.8, 157.8, 142.7, 137.6, 136.6, 126.4, 117.0, 113.0, 109.6, 56.0, 52.0, 51.6,
+
-1
4
40.4, 31.3, 29.0. HRMS (ESI) m/z calcd for C18H23NO Na [M+Na] : 340.1525; found: 340.1527. IR (KBr, cm ): 1717, 1652.
(E)-Methyl 3-(6-methoxy-1-pivaloylindolin-7-yl)acrylate (4fa) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (15 mg, 49% yield) R :
1
0
6
.30 (in 20% EtOAc/Hexane), mp 109-112 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.41 (d, J = 16.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H),
.64 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 16.4 Hz, 1H), 4.18 (t, J = 7.6 Hz, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 2.98 (t, J = 7.2 Hz, 2H) 1.39
1
(
s, 9H). 13C{ H} NMR (CDCl
3
, 100 MHz): δ 179.9, 168.9, 158.7, 145.7, 139.2, 126.9, 125.6, 119.8, 115.6, 107.8, 56.2, 52.1, 51.7,
+
-1
4
0.6, 30.6, 28.7. HRMS (ESI) m/z calcd for C18H24NO [M+H] : 318.1700; found: 318.1689. IR (KBr, cm ): 1713, 1651.
4
(E)-Methyl 3-(4-bromo-1-pivaloylindolin-7-yl)acrylate (4ga) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (18 mg, 72% yield) R :
1
0
.55 (in 20% EtOAc/Hexane), mp 147-149 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.34 (d, J = 16.0 Hz, 1H), 7.29-7.22 (m, 2H), 6.29
(d, J = 16 Hz, 1H), 4.2 (t, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.1 (t, J = 7.6 Hz, 2H), 1.4 (s, 9H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ
3
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80.1, 167.7, 144.8, 141.9, 135.7, 128.3, 127.1, 125.0, 120.7, 117.2, 51.9, 50.7, 40.7, 32.6, 28.8. HRMS (ESI) m/z calcd for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
-1
C
17 3
H21BrNO [M+H] : 366.0699; found: 366.0703. IR (KBr, cm ): 1709, 1657.
(E)-Methyl 3-(5-bromo-1-pivaloylindolin-7-yl)acrylate (4ha) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (21 mg, 82% yield) R :
1
0.35 (in 20% EtOAc/Hexane), mp 132-134 ºC H NMR (CDCl
3
, 700 MHz): δ 7.51 (d, J = 1.4 Hz, 1H), 7.34-7.32 (m, 2H), 6.27 (d,
J = 15.4 Hz, 1H), 4.17 (t, J = 7.7 Hz, 2H), 3.76 (s, 3H), 3.05 (t, J = 7.7 Hz, 2H), 1.40 (s, 9H). 13C{ H} NMR (CDCl
1
, 175 MHz): δ
3
1
80.0, 167.6, 143.1, 141.5, 137.2, 128.8, 128.3, 127.5, 118.2, 117.9, 52.0, 51.4, 40.6, 30.9, 28.7. HRMS (ESI) m/z calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
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0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
-1
C
17 3
H21BrNO [M+H] : 366.0705; found: 366.0707. IR (KBr, cm ): 1699, 1653.
(E)-Methyl 3-(5-fluoro-1-pivaloylindolin-7-yl)acrylate (4ia) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow liquid (18 mg, 61% yield) R :
1
0
.45 (in 20% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 7.38 (d, J = 15.6 Hz, 1H), 7.07 (d, J = 10.0 Hz, 1H), 6.95 (d, J = 6.8
1
3
1
Hz, 1H), 6.26 (d, J = 16.0 Hz, 1H), 4.2 (t, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 1.4 (s, 9H). C{ H} NMR
CDCl , 175 MHz): δ 180.0, 167.7, 160.7 (d, J = 242.2 Hz), 141.7 (d, J = 1.9 Hz), 140.1 (d, J = 1.9 Hz), 137.2 (d, J = 8.9 Hz),
26.9 (d, J = 8.2 Hz), 117.8, 113.4 (d, J = 24.1 Hz), 111.6 (d, J = 24 Hz), 52.0, 51.6, 40.5, 31.2 (d, J = 1.4 Hz), 28.8. HRMS (ESI)
(
3
1
+
-1
3
m/z calcd for C17H20FNO Na [M+Na] : 328.1319; found: 328.1342. IR (KBr, cm ): 1717, 1653.
(E)-methyl 3-(5-chloro-1-pivaloylindolin-7-yl)acrylate (4iia) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (17 mg, 73% yield) R :
1
0
6
.40 (in 20% EtOAc/Hexane), mp 121-123 ºC. H NMR (400 MHz, CDCl
3
) δ 7.37 (s, 1H), 7.34 (d, J = 16.0 Hz, 1H), 7.26 (s, 1H),
.28 (d, J = 16.0 Hz, 1H) 4.18 (t, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 1.40 (s, 9H). 13C{ H} NMR (100 MHz,
1
CDCl
3
) δ 179.8, 167.5, 142.6, 141.5, 136.9, 130.6, 127.0, 125.9, 125.3, 117.8, 51.9, 51.4, 40.6, 30.9, 28.7. HRMS (ESI) m/z calcd
+
-1
3
for C17H20ClNO Na [M+Na] : 344.1024; found: 344.1029. IR (KBr, cm ): 1739, 1403.
(E)-methyl 3-(5-iodo-1-pivaloylindolin-7-yl)acrylate (4iiia) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (16 mg, 69% yield) R :
1
0.45 (in 20% EtOAc/Hexane), mp 130-132 ºC. H NMR (400 MHz, CDCl
3
) δ 7.69 (s, 1H) 7.53 (s, 1H), 7.30 (m, 1H), 6.27 (d, J =
6.0 Hz, 1H) 6.27 (d, J = 16.0 Hz, 1H), 4.15 (t, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 1.39 (s, 9H). 13C{ H} 13C
1
1
NMR (100 MHz, CDCl ) δ 179.7, 167.5, 143.9, 141.3, 137.4, 134.5, 134.3, 127.9, 117.7, 88.7, 51.9, 51.3, 40.6, 30.6, 28.7. HRMS
3
+
-1
3
(ESI) m/z calcd for C17H21INO [M+H] : 414.0561; found: 414.0543. IR (KBr, cm ): 1741, 1367.
(E)-methyl 3-(5-nitro-1-pivaloylindolin-7-yl)acrylate (4ja) was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (8 mg, 28% yield) R :
1
0
.40 (in 30% EtOAc/Hexane). mp 145-147 ºC H NMR (CDCl
3
, 400 MHz): δ 8.32 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.32 (d, J =
15.9 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 4.28 (t, J = 7.8 Hz, 2H), 3.80 (s, 3H), 3.19 (t, J = 7.8 Hz, 2H), 1.43 (s, 9H). 13C{ H} NMR
1
(CDCl
3
, 100 MHz): δ 180.2, 167.2, 149.4, 145.3, 140.6, 136.4, 125.9, 122.3, 120.5, 119.1, 52.1, 51.72, 40.99, 30.5, 28.7. HRMS
+
-1
(ESI) m/z calcd for C17
20 2 5
H N O Na [M+Na] : 355.1264; found: 355.1246. IR (KBr, cm ): 1716, 1668, 1524, 1295.
(
E)-Methyl 3-(1-acetylindolin-7-yl)acrylate (4ma)15a was prepared according to general procedure (d). The crude reaction mixture
f
was purified by column chromatography using silica gel (100-200 mesh size) giving a colourless liquid (20.4 mg, 68% yield) R :
1
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.40 (in 30% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 7.68 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2
1
2
3
4
5
6
7
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9
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2
2
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Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 4.16 (br, 2H), 3.78 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.20 (br, 3H).
1
3
1
C{ H} NMR (CDCl
3
, 100 MHz): δ 167.7, 143.3, 143.2, 143.1, 126.2, 125.8, 125.6, 116.9, 116.8, 51.9, 51.2, 29.6, 23.8. HRMS
+
-1
(
ESI) m/z calcd for C14H15NO Na [M+Na] : 268.0944; found: 268.0951. IR (KBr, cm ): 1714, 1667.
3
(E)-Methyl 3-(1-benzoylindolin-7-yl)acrylate (4na) was prepared according to general procedure (d). The crude reaction mixture
f
was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow liquid (15 mg, 54% yield) R : 0.35 (in
1
2
0% EtOAc/Hexane). H NMR (CDCl
3
, 400 MHz): δ 7.64 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 16.0 Hz, 1H), 7.50-7.46 (m, 1H), 7.40
0
1
2
3
4
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6
7
8
9
0
1
2
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6
7
8
9
0
1
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7
8
9
0
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4
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6
7
8
9
0
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2
3
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6
7
8
9
0
(t, J = 8.0 Hz, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.20 (d, J = 16.0 Hz, 1H), 4.20 (t, J = 7.6 Hz, 2H), 3.71 (s,
1
3
1
3
1
H), 3.05 (t, J = 7.6 Hz, 2H). C{ H} NMR (CDCl
3
, 100 MHz): δ 170.9, 167.8, 142.4, 142.3, 135.4, 135.2, 131.8, 129.1, 128.7,
+
26.4, 125.9, 125.4, 117.9, 53.9, 51.9, 30.0. HRMS (ESI) m/z calcd for C19
H
17NO
3
Na [M+Na] : 330.1101; found: 330.1094. IR
-1
(
KBr, cm ): 1715, 1653.
(E)-Methyl 3-(1-pivaloyl-1H-indol-7-yl)acrylate (4am)15b was prepared according to general procedure (j) The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a brown solid (18 mg, 89% yield) R :
1
0
.50 (in 20% EtOAc/Hexane), mp 102-104 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.82 (d, J = 15.6 Hz, 1H), 7.59 (m, 2H), 7.46 (d, J =
7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.29 (d, J = 15.6 Hz, 1H), 3.80 (s, 3H), 1.55 (s, 9H). 13C{ H} NMR
1
(CDCl
3
, 100 MHz): δ 179.8, 167.7, 143.7, 135.2, 131.6, 126.8, 124.4, 123.8, 123.6, 122.7, 117.5, 107.8, 51.9, 42.3, 29.3. HRMS
+
-1
(ESI) m/z calcd for C17
H
3
19NO Na [M+Na] : 308.1257; found: 308.1264. IR (KBr, cm ): 1710, 1640.
1
H-Pyrrolo[3,2,1-ij]quinolin-4(2H)-one (4an)13f was prepared according to general procedure (k) The crude reaction mixture was
purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (25 mg, 98% yield) R : 0.45 (in 40%
f
1
EtOAc/Hexane), mp 157-159 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.70 (d, J = 9.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 6.8
Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 9.6 Hz, 1H), 4.46 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H). 13C{ H} NMR (CDCl
1
,
3
2
100 MHz): δ 161.4, 142.8, 137.5, 130.9, 125.3, 123.9, 123.8, 123.5, 118.0, 47.3, 27.4. HRMS (ESI) m/z calcd for C11H11NO Na
+
-1
[
M+Na] : 194.0574; found: 194.0582. IR (KBr, cm ): 1648.
(E)-Ethyl 3-(1-pivaloylindolin-7-yl)acrylate (4ab)6e was prepared according to general procedure (d). The crude reaction mixture
f
was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (24 mg, 86% yield) R : 0.40 (in
1
2
1
0% EtOAc/Hexane), mp 119-121 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.46-7.39 (m, 2H), 7.26-7.22 (m, 1H), 7.10 (t, J = 7.6 Hz,
H), 6.26 (d, J = 16.0 Hz, 1H), 4.24-4.14 (m, 4H), 3.05 (t, J = 7.6 Hz, 2H), 1.41 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H)). 13C{ H} NMR
1
(CDCl
3
, 100 MHz): δ 180.1, 167.0, 144.1, 142.4, 135.0, 126.3, 125.5, 125.4, 117.2, 60.5, 51.4, 40.5, 31.1, 29.1, 15.5. HRMS (ESI)
+
-1
m/z calcd for C18
H
3
23NO Na [M+Na] : 324.1576; found: 324.1575. IR (KBr, cm ): 1705, 1652.
(E)-Butyl 3-(1-pivaloylindolin-7-yl)acrylate (4ac) was prepared according to general procedure (d). The crude reaction mixture was
f
purified by column chromatography using silica gel (100-200 mesh size) giving a colourless liquid (23 mg, 76% yield) R : 0.30 (in
1
2
0% EtOAc/Hexane) H NMR (CDCl
3
, 400 MHz): δ 7.45-7.40 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.30 (d, J
=
16.0 Hz, 1H), 4.17 (t, J = 7.2 Hz, 4H), 3.06 (t, J = 7.6 Hz, 2H), 1.69-1.63 (m, 2H), 1.45-1.42 (m, 11H), 0.95 (t, J = 7.6 Hz, 3H).
1
3
1
C{ H} NMR (CDCl
3
, 100 MHz): δ 180.0, 168.1, 144.0, 142.2, 135.0, 126.0, 125.8, 125.5, 125.3, 117.2, 64.5, 51.4, 40.5, 31.09,
+
-1
3
1
3
1.05, 29.1, 19.5, 14.1. HRMS (ESI) m/z calcd for C20H27NO Na [M+Na] : 352.1889; found: 352.1896. IR (KBr, cm ): 1706,
653.
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(
E)-Tert-butyl 3-(1-pivaloylindolin-7-yl)acrylate (4ad) 6e was prepared according to general procedure (d). The crude reaction
f
mixture was purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (17 mg, 57% yield) R :
1
0
7
.30 (in 20% EtOAc/Hexane), mp 134-136 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.39 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 16.0 Hz, 1H),
.20 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.22 (d, J = 16 Hz, 1H), 4.15 (t, J = 7.6 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 1.50 (s,
9H), 1.41 (s, 9H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ 180.0, 167.1, 144.0, 141.2, 135.1, 126.4, 126.1, 125.5, 125.3, 119.4, 80.3,
3
+
-1
5
1.4, 40.5, 31.2, 29.1, 28.5. HRMS (ESI) m/z calcd for C20
652.
3
H27NO Na [M+Na] : 352.1889; found: 352.1892. IR (KBr, cm ): 1706,
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0
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2
3
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0
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9
0
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9
0
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3
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6
7
8
9
0
(
E)-3-(1-Pivaloylindolin-7-yl)acrylic acid (4ae) was prepared according to general procedure (d). The crude reaction mixture was
purified by column chromatography using silica gel (100-200 mesh size) giving a yellow solid (12 mg, 52% yield) R : 0.30 (in 20%
, 700 MHz): δ 7.54 (d, J = 16.1 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.25 (d, J =
.7 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.28 (d, J = 15.4 Hz, 1H), 4.18 (t, J = 7.0 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 1.41 (s, 9H).
f
1
EtOAc/Hexane), mp 204-206 ºC. H NMR (CDCl
3
7
1
3
1
C{ H} NMR (CDCl
3
, 175 MHz): δ 180.0, 172.1, 145.0, 144.1, 135.0, 126.3, 125.8, 125.7, 125.4, 116.2, 51.4, 40.6, 31.1, 29.1.
+
-1
HRMS (ESI) m/z calcd for C16
H
3
20NO [M+H] : 274.1443; found: 274.1441. IR (KBr, cm ): 1700, 1652.
(E)-Phenyl 3-(1-pivaloylindolin-7-yl)acrylate (4af) was prepared according to general procedure (d). The crude reaction mixture
f
was purified by column chromatography using silica gel (100-200 mesh size) giving a white solid (22 mg, 73% yield) R : 0.35 (in
1
2
0% EtOAc/Hexane), mp 159-161 ºC. H NMR (CDCl
3
, 400 MHz): δ 7.62 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 (t, J
= 7.6 Hz, 2H), 7.27-7.20 (m, 2H), 7.17-7.10 (m, 3H), 6.48 (d, J = 16.0 Hz, 1H), 4.18 (t, J = 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H),
.40 (s, 9H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ 179.9, 165.9, 151.2, 144.4, 144.2, 135.1, 129.6, 126.3, 125.8, 125.7, 125.6,
1
1
3
+
25.4, 122.0, 116.0, 51.3, 40.6, 31.1, 28.8. HRMS (ESI) m/z calcd for C22
H
23NO
3
K [M+K] : 388.1315; found: 388.1337. IR (KBr,
-1
cm ): 1726, 1652.
(E)-13-Methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl 3-(1-pivaloylindolin-7-yl)acrylate
(4al) was prepared according to general procedure (d). The crude reaction mixture was purified by column chromatography using
1
silica gel (100-200 mesh size) giving a white solid (33 mg, 66% yield) R
(CDCl
J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.48 (d, J = 16.0 Hz, 1H), 4.18 (t, J = 7.6 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H), 2.93-2.90 (m, 2H), 2.54-
f
: 0.30 (in 40% EtOAc/Hexane), mp 258-260 ºC. H NMR
3
, 400 MHz): δ 7.60 (d, J = 16.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.92 (d,
2
.47 (m, 1H), 2.43-2.39 (m, 1H), 2.31-2.26 (m, 1H), 2.19-1.95 (m, 5H), 1.68-1.60 (m, 2H), 1.54-1.45 (m, 3H), 1.40 (s, 9H), 0.91 (s,
H). 13C{ H} NMR (CDCl
1
9
3
, 100 MHz): δ 221.2, 180.0, 166.2, 149.1, 144.3, 144.2, 138.2, 137.4, 135.1, 126.6, 126.3, 125.7, 125.6,
1
25.4, 122.1, 119.2, 116.1, 51.3, 50.7, 48.3, 44.5, 40.6, 38.3, 36.2, 31.9, 31.1, 29.7, 28.8, 26.7, 26.1, 29.9,14.1. HRMS (ESI) m/z
+
-1
4
calcd for C34H39NO Na [M+Na] : 548.2771; found: 548.2784. IR (KBr, cm ): 1735, 1659, 1493.
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.
Crystal data for compound 3ia
Crystal data for compound 4aa
Optimization studies, Mechanistic Studies, H and 13C NMR spectra for new and known compounds, Crystallographic data’s and photos
(PDF)
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AUTHOR INFORMATION
Corresponding Author
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Ponneri Chandrababu Ravikumar - School of Chemical Sciences, National Institute of Science Education and Research (NISER)
Bhubaneswar, HBNI, Jatani, Odisha 752050, India
ORCID: https://orcid.org/0000-0002-5264-820X
*E-mail: pcr@niser.ac.in
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Shyam Kumar Banjare - School of Chemical Sciences, National Institute of Science Education and Research (NISER)
Bhubaneswar, HBNI, Jatani, Odisha 752050, India
ORCID: https://orcid.org/0000-0001-5777-7281
Pragati Biswal - School of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar,
HBNI, Jatani, Odisha 752050, India
Notes
The authors declare no competing financial interest
DEDICATION
Dedicated to the memory of late Professor A. Srikrishna, IISc. Bangalore, for his contribution to natural product synthesis and organic
chemistry in general.
ACKNOWLEDGMENT
We are thankful to NISER, Department of Atomic Energy (DAE), Council for Scientific and Industrial Research (CSIR), New
Delhi (Grant 02(0256)/16/EMR II), and Science and Engineering Research Board (SERB), New Delhi (Grant EMRII/2017/001475)
for the financial support. Shyam K. Banjare and Pragati Biswal thank DAE for a research fellowship. We are thankful to Dr. Asit
Ghosh, NISER Bhubaneswar for helpful discussions. We are thankful to Mr. Shreenibas Sa, and Ms. Syamasrit Dash, NISER
Bhubaneswar, for solving single-crystal X-ray data. We are thankful to Dr. G. Satyanarayana and his group, IIT Hyderabad for
needful help. We are also thankful to the research groups of Dr. S. Nembenna, Dr. S. Peruncheralathan Dr. P. Mal, and others at
NISER Bhubaneswar for timely help with some chemicals and helpful discussions.
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