Synthesis of indolo- And pyrrolo[1,2-: a] quinoxalinones through a palladium-catalyzed oxidative carbonylation of the C 2 position of indole

Article abstract of DOI:10.1039/c9ob02703c

A methodology that involves the Pd-catalyzed direct C(sp2)-H bond carbonylation of the C₂ position of indole has been introduced for the synthesis of indolo[1,2-a]quinoxalin-6(5H)-ones. The methodology developed herein was used for the synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones. The reaction of N-substituted 2-(1H-indol-1-yl)anilines or 2-(1H-pyrrol-1-yl)anilines and carbon monoxide in the presence of Pd(OCOCF₃)₂ as a catalyst and Cu(OAc)₂ as an oxidant in toluene at 80 °C forms the corresponding quinoxalinones as exclusive products in good yields. The catalytically active C-H activated intermediate Pd complex was isolated and characterized for the first time which on exposure to CO gas in toluene at 80 °C gave the corresponding quinoxalinone derivative. On the basis of isolation of the intermediate, a possible mechanism has been proposed for the C-H activated direct carbonylative annulation of 2-(5-methoxy-1H-indol-1-yl)-N,4-dimethylaniline.

Full text of DOI:10.1039/c9ob02703c

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DOI: 10.1039/C9OB02703C
ARTICLE
Synthesis of Indolo- and Pyrrolo[1,2-a]quinoxalinones through
Palladium-Catalyzed Oxidative Carbonylation of C2 Position of
Indole
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Attoor Chandrasekhar[a] and Sethuraman Sankararaman*[a]
A methodology that involves Pd-catalyzed direct C(sp2)−H bond carbonylation of C2 position of indole has been introduced
for the synthesis of indolo[1,2-a]quinoxalin-6(5H)-ones. The methodology developed was used for the synthesis of
pyrrolo[1,2-a]quinoxalin-4(5H)-ones. The reaction of N-subtituted 2-(1H-indol-1-yl)anilines or 2-(1H-pyrrol-1-yl)anilines and
carbon monoxide in presence of Pd(OCOCF3)2 as a catalyst, Cu(OAc)2 as an oxidant in toluene at 80 oC forms the
corresponding quinoxalinones as exclusive products in good yields. The catalytically active C−H activated intermediate Pd
complex was isolated and characterized for the first time which on exposure to CO gas in toluene at 80 oC gave the
corresponding quinoxalinone derivative. On the basis of isolation of the intermediate, a possible mechanism has been
proposed for the C−H activated direct carbonylative annulation of 2-(5-methoxy-1H-indol-1-yl)-N,4-dimethylaniline.
Reported Work :
(CO insertion at C3 position)
COOH
COOR1
Introduction
Pd(OAc)2, Na2S2O8
ROH
, I2,
Pd(OAc)2
Transition metal catalyzed CO insertion in organic halides or pseudo
halides has become a powerful method for the synthesis of carbonyl
compounds. A variety of carbonylated heterocyclic compounds were
synthesized using methodology that involves Pd-catalyzed
carbonylative annulations1 and they have received considerable
attention since the seminal work of Heck.2 More recently, transition
metal catalyzed oxidative carbonylation of a C(sp2)−H bond has
become the most atom economic and efficient way to incorporate
carbon monoxide in hydrocarbons. The first direct oxidative
carbonylation of arenes was introduced by Fujiwara in 1980 which
involved electrophilic attack on arene by palladium(II).3 The concept
of Pd-catalyzed carbonylation of C(sp2)−H bond was used to
synthesize the various heterocyclic and acyclic compounds,4 but it is
limited to carbonylation of C(sp2)−H of indole derivatives. There are
very few reports available based on oxidative carbonylation of C2
position of indoles (Scheme 1).
CO3, DMF,
24 h
K2
N
(reflux)
35%
AcOH
7 h,
N
100 oC,
Ref = 8
Ref = 5
R
R
COOR1
R1
O
O
PdCl2(PPh3)2, PPh3
Cu(OAc)2, ROH
I
N
R
Pd(Pt
Bu3
)
toluene/
2
DMSO
100 o
R1
N
oC, 24
N
R
CO
CH3
R2
CN,
125
h
Ref = 6
Ref = 7
C
R
Ref = 9
COOR1
Rh(COD)Cl 2
K2S2O8
B(OH)2
Pd(OAc)2, I2, KOH,
CsF, toluene, 80 o
ROH, toluene,
R2
N
110 o
C
N
R
C
R
Ref = 10a
Recent Report :
(Tertiary amine-directed carbonylation)
R1
R1
O
PdCl2, Cu(TFA)2.XH2O
PivOH, CO/O2
R3
N
N
R3
N
N
R3
Dioxane / DMA
100 oC, 48 h
R2
Ref = 10b
R2
This Work :
(CO insertion at C2 position)
C-H carbonylation at C2 position
of indole
CO insertion in Pyrrole or indole
Isolation of intermediate
Six membered ring formation
Acid free
R3
R3
CO
O
N
R1
H
Pd(OCOCF3)2
Cu(OAc)2, O2
toluene, 80 oC, 24 h
N
N
R1
N
Gramscale reaction
Wide substrate scope
R2
R1 = H / CH3 / Ph
R2
Scheme 1. Oxidative carbonylation of indole derivatives
The first direct carbonylation of indoles was reported by Itahara in
1982.5 1-Acetylindole was treated with carbon monoxide in the
presence of Pd(OAc)2 and Na2S2O8 used as an oxidant to give 1-
acetylindole-3-carboxylic acid. Lei and co-workers developed direct
carbonylation of N-substituted and unsubstituted indoles.6 Rh
catalyzed regioselective direct carbonylation of indoles to form
indole-3-carboxylates was introduced by Li and his group.7
Subsequently, Li developed an advanced methodology that uses Pd-
[a]
A. Chandrasekhar and Prof. S. Sankararaman
Department of Chemistry
Indian Institute of Technology Madras
Chennai-600036, India
sanka@iitm.ac.in
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Synthesis and spectral data of
starting materials, CCDC 1971937 (3a), 1971938 (8a), 1971939 (35a) contain the
supplementary crystallographic data. These data can be obtained free of charge
from the Cambridge Crystallographic Data Center.See DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
catalyzed direct carbonylation of free and N-substituted indoles to catalyzed oxidative carbonylation methodology developed was used
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produce the corresponding ester derivatives of indoles.8 A strategy to synthesize the pyrroloquinoxalin-4-ones as well.
DOI: 10.1039/C9OB02703C
that involves oxidative iodination of indole at C3 position and
subsequent Pd(0)-catalyzed carbonylation to yield indole-3-
carboxylate was reported by Arndtsen et al.9 Here they introduced
an electrophilic approach to the Pd-catalyzed carbonylative C−H
functionalization of indole.9 A new methodology that involves
Results and Discussion
The present investigation started with the reaction of 2-(1H-indol-1-
yl)aniline (1) with carbon monoxide in the presence of the
stoichiometric amount of Pd(OAc)2 at 80 C in toluene (Scheme 2).
The reaction proceeded smoothly and 100% conversion was
o
carbonylative Suzuki-Miyaura direct C−H carbonylation of indoles in
observed within 3h. From the reaction, the anticipated C2 C−H bond
the presence of aromatic boronic acids as a coupling partner was
carbonylative annulated product (1a) was obtained in 36% yield
along with 47% of another possible carbonylated product, namely,
1,3(2-(1H-indol-1-yl)phenylurea (1b) isolated by column
introduced by Guan et al. in 2015.10a However, till today the direct
C−H oxidative carbonylation of indoles was demonstrated only at the
C3 position which is more active towards electrophilic reactions. To
chromatography. Both the compounds were characterized by 1H-
the best of our knowledge, very few reports are available based on
NMR, 13C-NMR, IR, and HRMS.
oxidative carbonylation of indoles at C2 position to date.10b Many
CO (balloon)
Pd (OAc)2 (1 equiv)
functional groups are introduced through C−H activation at C2
position of indole11 while no CO insertion is investigated. Herein we
O
N
N
N
N
H
H
NH
toluene, 80 oC, 3 h
N
N
NH2
describe
a methodology involving Pd-catalyzed direct C−H
O
1a, 36%
1b, 47%
1
carbonylation of indoles at C2 position for the synthesis of
indolo[1,2,-a]quinoxalin-6(5H)-ones. The methodology developed
was applied for the synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones.
Scheme 2. Carbonylation of 2-(1H-indol-1-yl)aniline with
stoichiometric Pd(OAc)2.
In order to find a suitable catalytic reaction conditions to improve the
selectivity of reaction towards the formation of indoloquinoxalinone
(1a) as a major product, reaction conditions were optimized by
changing solvents, oxidants and metal sources. Firstly, 1 was treated
with a catalytic amount of Pd(OAc)2 in the presence of Cu(OAc)2 as
Indole is an important structural motif found in various biologically
and pharmaceutically active molecules, agrochemicals, dyes, and
essential oils.12 Since its discovery by Baeyer in 1869, indole has
become an important heterocycle in academics and industries. In
fact, it is the most widely distributed heterocycle found in nature.
Quinoxalinone moiety as core structure has its own importance due
to their wide variety of pharmacological properties, such as
anticancer, anxiolytic, antimicrobial, analgesic, antiallergic activities,
antimicrobial agents, kinases inhibitors, benzodiazepine receptor
agonist, anti-inflammatory, antimicrobial, antidiabetic.13 Some
representative examples of biologically active quinoxalinones are
shown below (Figure 1).
o
an oxidant in toluene under balloon pressure of CO at 80 C. The
reaction was stirred for 12 h to obtain the annulated product 1a in
22% yield. Further reaction conditions were screened and maximum
yield (31%) of 1a was observed when the reaction was performed in
AcOH as a solvent (Table-1). The scope of carbonylation was
investigated with few examples in AcOH solvent. In all cases,
formation of both C2 C−H carbonylative annulated product and urea
derivatives were observed and the remaining starting material was
decomposed. Surprisingly, no urea derivative was observed in the
case of compound 3. This may be due to lack of hyperconjugation of
the t-butyl group in 3 unlike methyl group in 2 which reduces the
nucleophilicity of the amino group. All the products were purified by
column chromatography and thoroughly characterized by
spectroscopic data. In addition, the structure of 3a was established
unequivocally by single crystal X-ray data. Due to the strong
intermolecular hydrogen bonding 3a existed as a centrosymmetric
hydrogen bonded dimer in the crystal.
N
N
N
Br
N
O
N
NH
NH
F3C
N
H
O
N
H
O
O
Ph
anticancer agent
NH
antitumor activity
PARP-1 inhibitor
N
N
N
O
Br
N
CH3
O
O
N
N
N
O
S
NH
N
H
N
R
N
S
F
N
H
H
R= H, Me, F, Cl
druge of nervous system
anti HIV agent
phosphorylase inhibitory activity
Figure 1. Representative examples of biologically active
quinoxalinones.
Mechanistically,the formation of annulated indoloquinoxalinone(1a)
and urea derivative (1b) presumably results from different
processes.17,4b,4d,4q In the proposed catalytic cycle for 1b (Scheme 3),
palladium catalyst reacts with amine group to give amino palladium
complex I by the loss of acetic acid. Subsequently, intermediate I
reacts with carbon monoxide to form amidopalladium intermediate
II followed by deprotonation leading to the formation of isocyanate
III. In the presence of primary amine, III afforded the urea derivatives
(1b). Alternatively, it may be that another molecule of amine (1)
reacts at the Pd center in (II) followed by reductive elimination of
Beccalli et al. reported the synthesis of both pyrrole and indole based
quinoxalinones.14 In 2016 Patel and co-workers developed a
methodology for the synthesis of indoloquinoxalin-6-ones from o-
indolyl-N,N-dialkylamines.15 Zn(II) catalyzed intramolecular N−H
arylation of indole-2-carboxamide for the synthesis of
indoloquinoxalin-6-ones was introduced by Li.16 Our interest in Pd-
catalyzed oxidative carbonylation reactions using CO as a carbon
source4q led us to investigate the Pd-catalyzed C−H carbonylation of
indoles for the synthesis of indoloquinoxalin-6-ones. The Pd-
2 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
O
Pd(0) can give the urea derivative (1b). On the other hand, for the
formation of 1a, Pd catalyst forms a C−H activated cyclic complex IV.
Under the CO atmosphere, complex IV reacts to form cyclic
acylpalladium intermediate V followed by the elimination of AcOH
gives complex VI. Reductive elimination of VI affords the desired
annulated product (1a).
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NH
DOI: 10.1039/C9OB02703C
N
N
H
N
RNH2
1a
1b
CO
N
N
C
O
O
Pd(0)
Cu(OAc)2
R.E
Pd(0)
III
N
-HX
NH
VI
PdX2Ln
N
H
PdLn
X
catalytic cycle
for annulation
catalytic cycle
for urea formation
N
AcOH
O
1
1
O
Table 1. Carbonylation of free 2-(1H-indol-1-yl)anilines
II
OAc
CO
d
P
R1
R1
R1
R1
R2
R2
N
R2
R2
NH2
AcOH
N
CO (balloon)
Pd (OAc)2 (10 mol%)
O
V
H
N
OAc
2
N
a
N
N
N
H
H
NH
P
d
NH2
PdLnX
Cu(OAc)2 (1 equiv.)
Acetic acid, 80oC
N
N
N
I
NH2
O
b
R3
R3
IV
CO
R3
R3
1-7(1 mmol)
substrate
urea derivatives (b)
annulated product (a)
S. No
Time (h)
Scheme 3. Speculative mechanism for the formation of mixture of 1a
and 1b.
O
N
N
N
N
H
H
1
6
NH2
NH
N
N
O
1a (31%)
1
1b (10%)
CO (balloon)
Pd (OAc)2 (10 mol%)
O
O
N
N
O
H
N
N
N
N
CH3
N
CH3
H
H
N
2
4
N
N
NH2
NH
Cu(OAc)2 (1 equiv.)
Acetic acid, 80 oC, 24 h
O
O
Me
Me
Me
2
Me
6a
6
2a (20%)
2b (31%)
Pd(II): 10 mol% = 6a (0%)
1 equiv. = 6a (0%)
O
N
N
3
7
NH2
NH
O
CO (balloon)
Pd (OAc)2 (10 mol%)
N
N
t-Bu
Cl
t-Bu
Cl
3a (41%)
H
3
3a
N
N
Ts
Cl
Cl
Ts
Cu(OAc)2 (1 equiv.)
Acetic acid, 80 oC, 24 h
O
7a
N
7
N
N
N
H
H
Pd(II): 10 mol% = 7a (0%)
1 equiv. = 7a (0%)
N
N
4
10
NH2
NH
O
4b (27%)
4
4a (18%)
Me
Me
Me
Me
Scheme 4. Attempted synthesis of annulated products 6a & 7a
O
5
N
N
N
3
N
H
H
N
NH2
NH
From these observations of the reactions in Scheme 4, we speculated
that acetyl or tosyl groups were decreasing the nucleophilicity of
amine and resulted in no reaction. We thought electron donating
group might help to get carbonylative annulated product by
improving nucleophilicity of amine. Therefore, 1 was treated with
MeI in the presence of CH3Li to get 2-(1H-indol-1-yl)-N-methylaniline
(8). Compound 8 was subjected to CO under standard reaction
conditions (Scheme 5A). Gratifyingly, desired carbonylative
annulated indoloquinoxalinone was isolated in 38% yield as an
exclusive product. There was no urea formation. In another
experiment 8 was treated with carbon monoxide in the presence of
a stoichiometric amount of Pd(OAc)2 under balloon pressure of CO at
80 oC in toluene for 24 h (Scheme 5B). Reaction proceeded smoothly
to give desired product in 88% yield without any urea formation.
N
O
5a (16%)
5b (31%)
5
Our hypothesis that the formation of urea can be controlled by
protecting the free amine group, we reasoned that the following
advantages accompany the use of secondary amine. (1) Reactivity of
primary amine can be reduced by converting it into a secondary
amine (steric hindrance). Therefore, the reaction rate of 1 to I might
be decreased and the problem associated with the formation of the
urea might be reduced. (2) Importantly, the formation of isocyanate
intermediate (III) is not possible with 2o amines. Firstly, 2-(1H-indol-
1-yl)aniline
was
converted
into
N-(2-(1H-indol-1-
yl)phenyl)acetamide (6) and N-(2-(1H-indol-1-yl)phenyl)tosylamide
(7) by treating with acetyl chloride and tosyl chloride respectively.
Both 6 and 7 were treated with carbon monoxide separately under
the optimal reaction conditions (Scheme 4). After 24 h only starting
material was recovered by column chromatography in both cases. In
another set of reactions, both acetyl and tosyl protected indoles (6 &
7) were reacted with carbon monoxide separately in the presence of
a stoichiometric amount of Pd(OAc)2 under balloon pressure of CO at
80 oC in toluene for 24h. In case of acetyl compound 6, trace amount
of annulated product 1a was formed instead of 6a while no reaction
was observed with tosyl substrate (7).
A
O
CO (balloon)
Pd (OAc)2 (10 mol%)
N
N
H
N
N
CH3 Cu(OAc)2 (1 equiv.)
acetic acid, 80 oC, 12h
CH3
8
8a, 38%
B
O
N
CO (balloon)
Pd (OAc)2 (1 equiv.)
toluene, 80 oC, 5h
N
N
H
N
CH3
CH3
8a, 88%
8
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J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
20c
Pd(OCOCF3)2
Toluene
Cu(OAc)2/O2
22
Scheme 5. Selective C2 oxidative carbonylation of 8
-
View Article Online
a = 1 equiv. of additive, b= isolated yields, c=DreOaI:ct1i0o.1n0a3t9/rCo9oOmB02703C
temperature.
In order to find a suitable catalytic reaction conditions for Pd-
catalyzed carbonylation of 2-(1H-indol-1-yl)-N-methylaniline,
reaction conditions were optimized (Table 2). Initially, compound 8
was treated with CO in presence of 10 mol% of Pd(OAc)2 in toluene
at 80 oC. Reaction gave 20% of 8a. Further reaction conditions were
screened with various oxidants. Improvement in reaction yield was
not observed. The yield of 8a was slightly increased when AcOH or
TFA was introduced as an additive to the reaction mixture. Complete
decomposition of starting material was observed when TFA was used
as a solvent. Reaction yield was improved to 70% with more
electrophilic metal catalyst Pd(OCOCF3)2. In the presence of
Pd(OCOCF3)2 as a catalyst, reaction conditions were optimized with
different solvents and oxidants. Best reaction yield was obtained
with reaction conditions of entry 12. The yield of 8a decreased to
46% when TFA used as the additive. There is no improvement in yield
when different Pd sources were tried. No reaction was observed
under Pd free reaction conditions. Under reaction conditions of entry
12, reaction proceeded to give 22% of 8a at room temperature (entry
20).
With optimized reaction conditions in hand, the scope of the
substrates was demonstrated, and results are summarized in Table
3. Substrates with both electron donating or withdrawing groups are
tolerated under optimized reaction conditions. The reaction is more
favored to substrate with electron donating group than the ones with
electron withdrawing group. Methyl at para to amine (9) favored the
CO insertion to give 81% of the corresponding carbonylative
annulated product (9a). Fluoro or Chloro substituted substrates also
reacted well to produce 13a and 14a in 64% 67% yields respectively.
Substrate with cyano group at para to amine, showed low reactivity
and the corresponding carbonylated product (15a) was isolated in
15% yields. It might be due to decreased in nucleophilicity of the
amine. Electron releasing groups or Chloro attached to indole ring of
substrate did not show much difference in reactivity. But indole ring
(22) with strong electron withdrawing group such as NO2 did not
react at all and only starting material was recovered. Substrates (20
and 29) with sterically hindered C2 position also reacted under
standard reaction conditions to give 20a (51%) and 29a (55%).
Azaindole anilines (21 & 30) also reacted with carbon monoxide
under optimized reaction conditions. Only 27% of the annulated
product (31a) was isolated when N-Me (8) is substituted with N-Ph
(31). Attempted synthesis of imidazoquinoxalinone under standard
reaction conditions with 32 and 33 failed to give the annulated
product. All the products (8a-31a) were purified by column
chromatography and thoroughly characterized by spectroscopic
data. In addition, the structure of 8a was established unequivocally
by single crystal X-ray data.
Table 2. Optimization of reaction conditions for Pd-catalyzed
carbonylation 2-(1H-indol-1-yl)-N-methylaniline.
O
CO (balloon)
Pd(II) (10 mol%)
N
N
H
N
N
CH3
CH3 Oxidant (2 equiv.)
Solvent (4 mL),
80 oC, 24h
8a
8
S.No
Metal cat.
Solvent
Additivea
Oxidant
Yieldb
(%)
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Toluene
Toluene
Toluene
Toluene
Cu(OAc)2
CuO
O2
20
Pd-catalyzed carbonylation methodology developed herein was
utilized for the synthesis of pyrroloquinoxalin-4-ones (Table 4). 2-
(1H-pyrrol-1-yl)anilines were found to be more reactive towards
oxidative carbonylative annulations under standard reaction
conditions than 2-(1H-indol-1-yl)anilines and corresponding
annulated products were formed in good yields.
-
-
-
-
15
19
13
BQ
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Toluene
Toluene
Toluene
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
13
24
26
-
AcOH
Table 3. Selective synthesis of indolo[1,2,-a]quinoxalin-6(5H)-ones.
TFA
8
Pd(OAc)2
Pd(OAc)2
TFA
Cu(OAc)2
Cu(OAc)2
0
-
-
-
-
-
-
9
Trifluoroet
hanol
Toluene
19
70
40
75
17
52
46
27
34
30
0
10
11
12
13
14
15
16
17
18
19
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
PdCl2
Cu(OAc)2
AcOH
Cu(OAc)2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Cu(OAc)2/O2
Cu(OAc)2(20
mol%)
O2
-
TFA
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
-
-
-
-
PdCl2(PPh3)2
PdCl2(CH3CN)2
-
4 | J. Name., 2012, 00, 1-3
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ARTICLE
R2
R2
O
View Article Online
O
CO (balloon)
Pd (OCOCF3)2 (10 mol%)
H
N
DOI: 10.1039/C9OB02703C
N
N
N
CH3
CH3
CO (balloon)
H
N
N
R4
R5
R1
N
R4
R5
R1
N
Pd (OCOCF3)2 (10 mol%)
Cu(OAc)2 (2 equiv), O2
toluene (4 mL), 24 h, 80 o
Cu(OAc)2 (2 equiv), O2
toluene(4 mL), 24 h, 80 o
34-39 (0.5 mmol)
C
R
C
34a-39a
N
R
R3
R3
(0.5 mmol)
8a-33a
8-33
O
O
O
O
N
O
N
O
N
N
N
CH3
N
CH3
N
CH3
N
CH3
N
CH3
N
N CH3
H3C
O
34a, 81%
N
H3C
O
36a, 72%
CH3
35a, 94%
35a
O
10a, 68%
9a, 81%
O
8a, 75%
O
H3C
8a
N
H3C
N
CH3
O
O
N
N
N
N
N
CH3
N
CH3
CH3
N
N
CH3
N
CH3
CH3
CH3
N
N
CH3
38a, 82%
37a, 83%
39a, 47%
Cl
F
NC
H3C
11a, 61%
H3C CH3
13a, 64%
12a, 72%
O
14a, 67%
O
F
H3C
N
Cl
O
N
Cl
CH3
O
N
MeO
H3C
CH3
O
N
N CH3
N
N
CH3
N
CO (balloon)
H
N
N
N
CH3
N
CH3
Pd (OCOCF3)2 (10 mol%)
Cu(OAc)2 (2 equiv), O2
toluene(4 mL),
18a, 70%
O
17a, 78%
O
16a, 76%
CH3
15a, 15%
O
NC
H3C
H3C
24h, 80 oC, 73%
35a
35, 1.2 g
O2N
O
N
N CH3
N
N CH3
N
N CH3
N
Scheme 6. Synthesis of 35a in gram scale reaction.
Cl
Cl
N
N
CH3
To understand the reaction mechanism, we attempted to isolate the
reaction intermediate of the carbonylative annulations reaction by
treating 26 with stoichiometric amounts of Pd(OAc)2 in toluene at
room temperature for 24h (Scheme 7). We observed the formation
of complex 26c instead of anticipated acetate bridged dinuclear
complex 26d. To confirm the formation of complex 26c as an
intermediate, it was treated with CO in toluene at 80 oC for 24h.
Complex 26c reacted smoothly with CO to form corresponding
annulated product (26a) in 86% yield. Complex 26c was characterized
by 1H-NMR, 13C-NMR, and HRMS.
22a, 0%
O
20a, 51%
21a, 35%
O
19a, 66%
O
O
Cl
CH3
Cl
MeO
N
N
CH3
N
N
CH3
CH3
N
N
CH3
N
N
H3C
H3C
25a, 60%
26a, 75%
O
H3C
23a, 68%
O
24a, 59%
H3C
H3C CH3
CH3
O
O
N
MeO
MeO
N
N
CH3
N
CH3
N
N
CH3
N
CH3
N
N
CH3
27a, 71%
H3C
28a, 63%
H3C
H3C
30a, 38%
29a, 55%
H3C
H3C CH3
MeO
CH3
Me
O
MeO
MeO
H3C
O
N
N
O
N
O
N
O
N
Pd(OAc)2
N
Pd
N
H
N
N
N
H
Pd
CH3
N
CH3
N
Toluene, r.t,
12 h, 78%
N
CH3
N
H
2
N
H
N
CH3
CH3
H3C
33a, 0%
31a, 27%
32a, 0%
H3C
26
H3C
26d
Not formed
26c
Formed
OMe
CO (balloon)
Toluene,
80 oC, 24 h, 86%
O
N-Methyl-2-(1H-pyrrol-1-yl)aniline was treated with CO under
optimized conditions. The reaction proceeded smoothly to give 34a
in good yield while 35 gave 35a in 94% yield. Fluoro and Chloro
substituted substrates (37 & 38) also reacted well. Only 47% of
carbonylated product was isolated from cyano substrate (39). The
products 34a-39a were purified by column chromatography and
thoroughly characterized by spectroscopic data. In addition, the
structure of 35a is established unequivocally by single crystal X-ray
data. To test the efficiency of the carbonylation reaction under
standard reaction conditions in a gram scale, the reaction was carried
out with 1.2 g (6.5 mmol) of N,4-dimethyl-2-(1H-pyrrol-1-yl)aniline
35 and desired product 35a was obtained in 73% yield (Scheme 6).
MeO
N
N CH3
Pd(0)black
26a
H3C
Scheme 7. Isolation and conformation of intermediate complex 26c.
On the basis of the isolation of intermediate 26c a plausible
mechanism for carbonylative annulation of 2-(5-methoxy-1H-indol-
1-yl)-N,4-dimethylaniline is proposed (Scheme 8). Initially,
Pd(OCOCF3)2 reacts with 26 to produce pallado bicyclic complex I by
the loss of CF3COOH. Coordination of CO with Pd complex I under
carbon monoxide atmosphere results in the formation of
intermediate II. Subsequent migratory insertion of CO followed by
de-protonation of complex II produces cyclic acyl palladium
intermediate (III). The reductive elimination of complex III affords
Table 4. Selective synthesis of pyrrolo[1,2,-a]quinoxalin-4(5H)-ones
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desired carbonylative annulated product 26a along with metal in the solution, Pd(OAc)2 (10 mol%) and Cu(OAc)2 (1 equiv.V)iewweArreticaledOdnelinde.
DOI: 10.1039/C9OB02703C
reduced state. Oxidant (Cu(OAc)2) re-oxidizes the Pd(0) to promote Reaction mixture was flushed thrice with carbon monoxide from a
the catalytic cycle.
balloon and stirred at 80oC under CO atmosphere. Progress of the
reaction was monitored by TLC. After stirring for required time
period (Table 1) reaction mixture was cooled to room temperature.
Solvent was evaporated through rotavapor and crude compound
was diluted with AcOEt followed by quenched with bicarbonate
solution. Organic layer was dried under Na2SO4 and crude compound
was purified by column chromatography (eluant: ethyl acetate/
hexane various ratios).
O
N
MeO
MeO
N
CH3
H
N
Pd(OCOCF3)2
N
CH3
26
26a
Cu(OAc)2 / O2
Pd(0)
2CF3COOH
MeO
H3C
H3C
H3C
Reductive
elimination
MeO
CH3
N
O
CH3
N
H
N
Pd
H
N
N
Spectral data
Indolo[1,2-a]quinoxalin-6(5H)-one (1a): 18
N
CH3
Pd
H3C
CH3
H3C
N
N
I
O
Pale yellow solid, yield 31% (72mg), Mp: 212-214 oC (Lit 215-216 oC),
1H NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H),
8.50-8.48 (m, 1H), 7.93 (d, J = 8.4 Hz,1H), 7.56-7.52 (m, 1H), 7.49 (s,
1H), 7.40-7.36 (m, 2H), 7.33-7.27 (m, 2H); 13C NMR (100 MHz, DMSO-
d6): δ 156.2, 134.2, 129.0, 128.8, 128.5, 125.8, 125.3, 124.8, 123.6,
123.3, 122.7, 117.1, 115.9, 115.0, 105.8; IR (KBr): cm-1 1674; HRMS
(ESI, m/z) Calcd for C15H10N2ONa 257.0685 (M+Na), found 257.068.
1,3-bis(2-(1H-indol-1-yl)phenyl)urea (1b):
H3C
OMe
III
CO
MeO
CH3
CO N
OMe
2H
Migratory
insertion
N
H
CH3
H
Pd
CO
II
H3C
N
N
H3C
OMe
Light brown solid, yield 10% (21 mg), Mp: 152-155 oC, 1H NMR (400
MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 1H), 7.55-7.53 (m, 1H), 7.28-7.23
(m, 1H) , 7.13-7.11 (m, 1H), 7.08-7.01 (m, 3H), 6.88-6.87 (m, 2H), 6.47
(d, J = 3.2 Hz,1H), 6.19 (d, J = 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ 152.2, 136.7, 134.9, 129.2, 129.0, 128.59, 128.52, 128.28, 124.1,
122.9, 122.3, 121.1, 120.7, 110.3, 104.0; IR (KBr): cm-1 3272, 2923,
2855, 1647, 1597, 1546, 1457; HRMS (ESI, m/z) Calcd for C29H23N4O
443.1866 (M+H), found 443.1866.
Scheme 8. A plausible mechanism for C−H carbonylation of 2-(1H-
indol-1-yl)anilines.
Conclusion
A methodology based on Pd-catalyzed oxidative carbonylation of C2
C(sp2)-H bond of indole is demonstrated for the synthesis of
indolo[1,2-a]quinoxalin-6(5H)-ones from corresponding 2-(1H-indol-
1-yl)anilines. The methodology Pd-catalyzed oxidative carbonylation
developed was applied for the synthesis of pyrrolo[1,2-a]quinoxalin-
4(5H)-ones from 2-(1H-pyrrol-1-yl)anilines. 2-(1H-pyrrol-1-yl)anilines
were found to be more reactive towards oxidative carbonylation
than 2-(1H-indol-1-yl)anilines. The carbonylation of simple 2-(1H-
indol-1-yl)anilines produces a mixture of corresponding annulated
product (a) and urea (b). A speculative mechanism for the formation
of mixture (a & b) is proposed. However, the formation of urea
derivatives was controlled by protecting the free amine by N-
methylation. Synthesis of 5,8-dimethylpyrrolo[1,2-a]quinoxalin-
4(5H)-one was performed in a gram scale. The catalytically active C−H
activated intermediate Pd complex was isolated and characterized
which on exposure to CO gas in toluene at 80 oC gave the
corresponding quinoxalinone derivative. On the basis of isolation of
the intermediate, a possible mechanism has been proposed for the
C−H activated direct carbonylative annulations of 2-(5-methoxy-1H-
indol-1-yl)-N,4-dimethylaniline.
2-methylindolo[1,2-a]quinoxalin-6(5H)-one (2a): 19
White solid, yield 20% (50 mg), Mp: 210-222 oC, 1H NMR (400 MHz,
DMSO-d6): δ 11.50 (s, 1H), 8.56 (d, J = 8.8 Hz 1H), 8.24 (s, 1H), 7.91
(d, J = 8 Hz, 1H), 7.55-7.51 (m, 1H), 7.47 (s, 1H), 7.39-7.36 (m, 1H),
7.24 (d, J = 8 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 2.46 (s, 3H); 13C NMR (100
MHz, DMSO-d6): δ 155.8, 133.8, 132.9, 128.7, 128.5, 125.8, 125.5
125.2, 124.9, 122.9, 122.4, 116.6, 115.6, 114.9, 105.5, 20.9; IR (KBr):
cm-1 1673; HRMS (ESI, m/z) Calcd for C16H13N2O 249.1028 (M+H),
found 249.1043.
1,3-bis(2-(1H-indol-1-yl)-4methylphenyl)urea (2b):
o
1
Light orange solid, yield 31% (71 mg), Mp: 97- 99 C, H NMR (500
MHz, CDCl3): δ 7.73 (d, J = 8 Hz,1H), 7.63-7.61 (m, 1H), 7.15-7.08 (m,
3H), 7.01 (d, J = 1.5 Hz, 1H), 6.95-6.94 (m, 2H), 6.55 (d, J = 3 Hz, 1H),
6.1 (s, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 125.6, 136.6,
134.4, 131.9, 129.8, 129.4, 128.6, 128.5, 122.8, 121.1, 120.6, 110.3,
103.8, 20.7; IR (KBr): cm-1 3353, 2924, 2853, 1670, 1598, 1524, 1459;
HRMS (ESI, m/z) Calcd for C31H26N4ONa 493.2004 (M+Na), found
493.1984.
2-tert-butylmethylindolo[1,2-a]quinoxalin-6(5H)-one (3a):
light brown solid, yield 41% (119 mg), Mp: 200-202 oC, 1H NMR (400
MHz, DMSO-d6): δ 11.49 (s, 1H), 8.33 (d, J = 8.8Hz, 1H) 8.26 (s, 1H),
7.91 (s, 8 Hz, 1H), 7.59-7.55 (m, 1H), 7.46 (s, 1H), 7.38-7.29 (m, 3H),
1.38 (s, 9H); 13C NMR (100 MHz, DMSO-d6): δ 156.2, 146.2, 134.0,
129.2, 128.9, 126.2, 126.0, 125.0, 123.4, 122.6, 122.0, 116.9, 114.6,
Experimental Section
General procedure for the synthesis of indolo[1,2,-a]quinoxalin-
6(5H)-ones (1a-5a) and urea derivatives (1b, 2b, 4b, 5b):
To a 25 mL oven dried schlenk round bottom flask, was added 2-(1H-
indol-1-yl)anilines (0.5 mmol) and acetic acid (4 mL). To this clear
6 | J. Name., 2012, 00, 1-3
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112.0, 105.8, 34.9, 31.6; IR (KBr): cm-1 1699; HRMS (ESI, m/z) Calcd White solid, yield 75% (93 mg), Mp: 157-159 oC, 1H NMR (400 MHz,
View Article Online
DOI: 10.1039/C9OB02703C
for C19H18N2ONa 313.1317 (M+Na), found 313.1299.
CDCl3): δ 8.34-8.32 (m, 1H), 8.25 (dd, J = 8.7 Hz, 0.6Hz, 1H), 7.87 (d,
J = 8 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.52-7.40 (m, 1H), 7.38-7.30
9-chloroindolo[1,2-a]quinoxalin-6(5H)-one (4a):
Half white solid, yield 18% (48 mg), Mp: 242-245 C, H NMR (500 (m, 4H), 7.18 (s, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.7,
MHz, DMSO-d6): δ 11.65 (s,1H), 8.54 (d, J = 9.5 Hz, 1H), 8.43-8.41 134.3, 129.9, 129.3, 128.2, 126.8, 125.4, 124.3, 123.4, 123.3, 122.5,
(m, 1H), 7.98 (d, J = 2 Hz, 1H), 7.49 (dd, J = 2 Hz, 9 Hz, 1H), 7.45 (s, 115.7, 115.5, 114.3, 107.0, 29.0; IR (KBr): cm-11651; HRMS (ESI, m/z)
1H), 7.38-7.35 (m, 1H), 7.32-7.28 (m, 2H); 13C NMR (100 MHz, DMSO- Calcd for C16H13N2O 248.095 (M+H), found 248.0947.
d6): δ 155.5, 132.1, 129.9, 129.6, 128.1, 126.8, 125.1, 124.8, 124.5, 2,5-dimethylindolo[1,2-a]quinoxalin-6(5H)-one (9a): 16
123.3, 121.8, 116.8, 116.2, 115.5, 104.8; IR (KBr): cm-1 1675; HRMS White solid, yield 81% (106 mg), Mp: 180-182 oC, 1H NMR (400 MHz,
o
1
(ESI, m/z) Calcd for C15H10N2OCl 269.0476 (M+H), found 269.0474.
1,3-bis(2-(5-chloro-1H-indol-1-yl)phenyl)urea (4b):
CDCl3): δ 8.23 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H),
7.54 (s, 1H), 7.51-7.47 (m, 1H), 7.36-7.33 (m, 1H), 7.20 (d, J = 8.0 Hz,
Light orange solid, yield 27% (67 mg), Mp: 170-175 oC, 1H NMR (500 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.66 (s, 3H), 2.49 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 7.81 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.26-7.23 (m, 1H), MHz, CDCl3): δ 156.6, 134.3, 133.2, 129.3, 128.3, 127.6, 126.6, 125.2,
7.11-7.05(m, 2H), 6.97 (d, J = 9 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 8.5 124.8, 123.2, 122.4, 116.0, 115.5, 114.4, 106.8, 29.0, 21.3; IR (KBr):
Hz, 1H), 6.4 (s, 1H), 6.13 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 152.1, cm-11647; HRMS (ESI, m/z) Calcd for C17H15N2O 263.1179 (M+H),
135.0, 134.4, 129.8, 129.5, 129.4, 128.7, 128.1, 126.4, 124.4, 123.1, found 263.1175.
122.6, 120.6, 111.3, 103.5; IR (KBr): cm-1 3278, 2927, 2855, 1683, 2-isopropyl-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (10a):
o
1
1599, 1530, 1460. HRMS (ESI, m/z) Calcd for C29H21N4OCl2 511.1087 White crystalline solid, yield 68% (98 mg), Mp: 189-191 C, H NMR
(M+H), found 511.1090.
(400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.79 (d, J =
7-methylindolo[1,2-a]quinoxalin-6(5H)-one (5a):
8 Hz, 1H), 7.48 (s, 1H), 7.45-7.41 (m, 1H), 7.29-7.25 (m, 1H), 7.18 (d,
o
1
Half white solid, yield 16% (40 mg), Mp: 216-220 C, H NMR (500 J = 7.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 3.0 (m, 1H), 1.3
MHz, DMSO-d6): δ 11.31 (s, 1H), 8.84 (dd, J = 8.5 Hz, 1.6Hz, 1H), 8.38 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 156.6, 144.4, 134.3,
(d, J = 7.5 Hz, 1H), 7.88(dd, J = 1.5 Hz, 8 Hz, 1H), 7.55-7.51 (m, 1H), 129.4, 128.4, 127.9, 126.7, 125.3, 123.3, 122.4, 122.2, 115.6, 114.3,
7.39-7.35 (m, 1H), 7.30-7.29 (m. 1H), 7.26-7.22(m, 2H), 2.76 (d, J = 3 113.6, 106.8, 33.9, 29.0, 24.3; IR (KBr): cm-11649; HRMS (ESI, m/z)
Hz, 3H); 13C NMR (125 MHz, DMSO-d6): δ 157.4, 132.5, 129.2, 128.1, Calcd for C19H19N2O 291.1492 (M+H), found 291.1489.
125.9, 125.2, 123.9, 123.2, 123.0, 121.7, 120.8, 117.2, 116.3, 115.2, 2-tert-butyl-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (11a):
114.3, 9.56; IR (KBr): cm-1 1671; HRMS (ESI, m/z) Calcd for C16H13N2O White solid, yield 61% (93 mg), Mp: 231-233 oC, 1H NMR (400 MHz,
249.1022 (M+H), found 249.1027.
CDCl3): δ 8.39 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8 Hz, 1H),
1,3-bis(2-(3-methyl-1H-indol-1-yl)phenyl)urea (5b):
7.57 (s, 1H), 7.54-7.50 (m, 1H), 7.38-7.29 (m, 3H), 3.69 (s, 3H), 1.4 (s,
Yellow solid, yield 31% (70 mg), Mp: 82 - 85 C, H NMR (400 MHz, 9H); 13C NMR (100 MHz, CDCl3): δ 156.7, 146.7, 134.2, 129.4, 128.4,
CDCl3): δ 7.88 (d, J = 7.6 Hz, 1H), 7.47-7.45 (m, 1H), 7.23-7.18 (m, 127.6, 126.5, 125.3, 123.4, 122.4, 121.3, 115.3, 114.2, 112.7, 106.8,
1H), 7.1-6.98 (m, 4H), 6.82 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 6.65 (d, J = 1.2 34.9, 31.6, 29.0; ; IR (KBr): cm-11654; HRMS (ESI, m/z) Calcd for
Hz,1H), 6.13 (s, 1H), 2.19 (d, J = 1.2Hz, 3H); 13C NMR (100 MHz, CDCl3): C20H21N2O 305.1648(M+H), found 305.1643.
o
1
δ 152.2, 137.0, 134.7, 129.3, 129.1, 128.8, 128.2, 125.9, 124.1, 122.8, 2,4,5-trimethylindolo[1,2-a]quinoxalin-6(5H)-one (12a):
122.1, 120.1, 119.3, 113.4, 110.1, 9.7; IR (KBr): cm-1 3346, 2922, 2856, White solid, yield 72% (99 mg), Mp: 121-123 oC, 1H NMR (400 MHz,
1681, 1595, 1528, 1455; HRMS (ESI, m/z) Calcd for C31H26N4ONa CDCl3): δ 8.15 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 8 Hz, 1H),
493.2004 (M+Na), found 493.2007.
7.44-7.40 (m, 2H), 7.28-7.24 (m, 1H), 6.84 (s, 1H), 3.64 (s, 3H), 2.53
General procedure for selective synthesis of indolo[1,2,- (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.7, 134.4, 133.7,
a]quinoxlin-6(5H)-ones (8a-21a, 23a-31a) and pyrrolo[1,2,- 129.6, 129.5, 129.1, 128.3, 128.2, 127.7, 125.2, 123.3, 122.4, 114.6,
a]quinoxlin-4(5H)-ones (34a-39a)
114.1, 106.8, 37.5, 23.1, 21.2; ; IR (KBr): cm-11647; HRMS (ESI, m/z)
To a 25 mL oven dried Schlenk round bottom flask were added 2-(1H- Calcd for C18H16N2ONa 299.1155 (M+Na), found 299.1165.
indol-1-yl)aniline derivative or 2-(1H-pyrrol-1-yl)aniline derivative 2-fluoro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (13a): 16
(0.5 mmol, 1 equiv.) and Cu(OAc)2 (2 equiv.) followed by toluene (4 White solid, yield 64% (85 mg), Mp: 216-218 oC, 1H NMR (400 MHz,
mL). Then Pd(OCOCF3)2 (10 mol%) was added. The reaction mixture CDCl3): δ 8.15 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 10.4 Hz, 1H), 7.87 (d, J =
was flushed thrice with carbon monoxide from a balloon and stirred 8.0 Hz, 1H), 7.56 (s, 1H), 7.54-7.50 (m, 1H), 7.40-7.36 (m, 1H), 7.30-
at 80 °C under a CO/O2 balloon atmosphere for 24h. The reaction 7.28 (m, 1H), 7.04-7.00 (m, 1H), 3.68 (s, 3H); 13C NMR (100 MHz,
mixture was cooled to room temperature and diluted with EtOAc (10 CDCl3): δ 159.8, 157.4, 156.2, 134.2, 129.4, 128.0, 127.3, 127.2, 126.4,
mL) then passed through a Celite pad, and washed with EtOAc (20 125.8, 123.4, 122.9, 116.6, 116.5, 113.9, 110.6, 110.4, 107.6, 103.4,
mL). The combined filtrate was concentrated under vacuum, and the 103.1, 29.2; IR (KBr): cm-11655; HRMS (ESI, m/z) Calcd for
crude product was purified by column chromatography on silica gel C16H11N2OFNa 289.0753 (M+Na), found 289.0757.
(eluant: ethyl acetate/hexane).
2-chloro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (14a): 16
Light orange solid, yield 67% (94 mg), Mp: 261-263 oC, 1H NMR (400
MHz, CDCl3): δ 8.25 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.0 Hz,
1H), 7.56 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.26 (s,
Spectral data
5-methylindolo[1,2-a]quinoxalin-6(5H)-one (8a)16:
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2H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.3, 134.2, 129.4, White solid, yield 35% (44 mg), Mp: 201-203 oC, 1H NMR (400 MHz,
View Article Online
DOI: 10.1039/C9OB02703C
128.8, 128.7, 127.9, 127.4, 125.9, 124.0, 123.5, 123.0, 116.6, 115.5, CDCl3): δ 9.84 (d, J = 8.0 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 8
114.1, 107.7, 29.2; ; IR (KBr): cm-11652; HRMS (ESI, m/z) Calcd for Hz, 1H), 7.47 (s, 1H), 7.39-7.30 (m, 4H), 3.72 (s, 3H); 13C NMR (100
C16H12N2OCl 283.0638 (M+H), found 283.0627.
MHz, CDCl3): δ 156.5, 146.8, 145.8, 131.0, 129.4, 127.3, 125.8, 124.8,
5-methyl-6-oxo-5,6-dihydroindolo[1,2-a]quinoxaline-2-carbonitrile 123.8, 121.3, 118.5, 118.4, 115.0, 103.4, 29.1; IR (KBr): cm-11662;
(15a):
HRMS (ESI, m/z) Calcd for C15H12N3O 250.0975 (M+H), found
White solid, yield 15% (21 mg), Mp: 240-242 oC, 1H NMR (400 MHz, 250.0984.
CDCl3): δ 8.53 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.9 (d, J = 8.0 Hz, 1H), 9-chloro-2,5-dimethylindolo[1,2-a]quinoxalin-6(5H)-one (23a): 15
7.61-7.58 (m, 3H), 7.45-7.0 (m, 2H), 3.71(s, 3H); 13C NMR (100 MHz, White crystalline solid, yield 68% (100 mg), Mp: 236-238 oC, 1H NMR
CDCl3): δ 156.3, 134.3, 133.6, 129.4, 128.1, 127.4, 127.0, 126.6, 123.7, (400 MHz, CDCl3): δ 8.08 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.76 (d, J =
123.4, 118.6, 118.5, 116.2, 114.0, 108.6, 106.5, 29.3; IR (KBr): cm-1 1.6 Hz, 1H), 7.41 (s, 1H), 7.39 (dd, J = 2 Hz, 9.2 Hz 1H), 7.21 (d, J = 8.4
2235, 1669; HRMS (ESI, m/z) Calcd for C17H11N3ONa 296.0800 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 156.1,
(M+Na), found 296.0818.
133.4, 132.4, 130.3, 129.4, 128.1, 127.6, 126.1, 125.4, 125.3, 122.3,
115.8, 115.7, 115.3, 105.9, 29.0, 21.3; IR (KBr): cm-11654; HRMS (ESI,
5,9-dimethylindolo[1,2-a]quinoxalin-6(5H)-one (16a): 15
o
1
Pale brown solid, yield 76% (99 mg), Mp: 200-202 C, H NMR (400 m/z) Calcd for C17H13N2OClNa 319.0609 (M+Na), found 319.0621.
MHz, CDCl3): δ 8.24 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.61 (s, 2-tert-butyl-9-chloro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one
1H), 7.46 (s, 1H), 7.32-7.26 (m, 4H), 3.67 (s, 3H), 2.50 (s, 3H);13C NMR (24a):
(100 MHz, CDCl3): δ 156.73, 132.7, 132.0, 129.8, 129.6, 128.1, 127.2, Light cream solid, yield 59% (99 mg), Mp: 146-148 C, H NMR (400
126.8, 124.0, 123.3, 122.6, 115.5, 115.3, 113.9, 106.4, 29.0, 21.4; ; IR MHz, CDCl3): δ 8.26 (s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.45-
(KBr): cm-11649; HRMS (ESI, m/z) Calcd for C17H15N2O 263.1179 7.29 (m, 4H), 3.69 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
o
1
(M+H), found 263.1187.
9-methoxy-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (17a): 16
156.3, 146.9, 132.4, 130.4, 129.5, 128.1, 127.6, 126.0, 125.6, 122.4,
121.8, 115.5, 115.1, 112.5, 105.9, 34.9, 31.6, 29.0; IR (KBr): cm-11657;
White solid, yield 78% (108 mg), Mp: 166-168 oC, 1H NMR (400 MHz, HRMS (ESI, m/z) Calcd for C20H20N2OCl 339.1259 (M+H), found
CDCl3): δ δ 8.28 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.37-7.26 339.1265.
(m, 4H), 7.15 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H); 13C NMR 9-chloro-2,4,5-trimethylindolo[1,2-a]quinoxalin-6(5H)-one (25a):
o
1
(100 MHz, CDCl3): δ 156.5, 155.6, 130.2, 129.8, 129.5, 128.5, 126.6, White crtstalline solid, yield 60% (93 mg), Mp: 175-177 C, H NMR
124.0, 123.3, 116.4, 115.6, 115.18, 115.10, 106.3, 103.2, 55.7, 29.0; (400 MHz, CDCl3): δ 8.09 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 1H),
IR (KBr): cm-11655; HRMS (ESI, m/z) Calcd for C17H15N2O2 279.1128 7.40-7.38 (m, 2H), 6.92 (s, 1H), 3.70 (s, 3H), 2.60 (s, 3H), 2.44 (s, 3H);
(M+H), found 279.1136.
13C NMR (100 MHz, CDCl3): δ 159.2, 133.8, 132.5, 130.6, 130.1, 129.9,
128.2, 128.0, 127.89, 127.85, 125.4, 122.3, 115.5, 113.9, 105.9, 37.5,
9-chloro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (18a): 16
White crystalline solid, yield 70% (98 mg), Mp: 206-208 C, H NMR 23.1, 21.2; IR (KBr): cm-11653; HRMS (ESI, m/z) Calcd for C18H16N2OCl
o
1
(400 MHz, CDCl3): δ 8.19-8.17 (m, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.76 311.0946 (M+H), found 311.0951.
(s, 1H), 7.433 (s, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.34-7.30 (m, 3H), 3.68 9-methoxy-2,5-dimethylindolo[1,2-a]quinoxalin-6(5H)-one (26a):
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.2, 132.4, 130.2, 129.9, 129.2, White solid, yield 75% (109 mg), Mp: 186-188 oC, 1H NMR (400 MHz,
128.2, 126.3, 125.6, 124.6, 123.4, 122.3, 115.8, 115.3, 115.2, 106.1, CDCl3): δ 8.09 (d, J = 9.2 Hz, 1H), 8.0 (s, 1H), 7.44 (s, 1H), 7.21-7.18
29.1; IR (KBr): cm-11657; HRMS (ESI, m/z) Calcd for C16H11N2OClNa (m, 2H), 7.11 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 3.90 (s, 3H),
305.0452 (M+Na), found 305.0454.
3.65 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.4, 155.5,
10-chloro-5-methylindolo[1,2-a]quinoxalin-6(5H)-one (19a):
133.2, 130.2, 129.4, 128.7, 127.5, 126.5, 124.6, 116.2, 115.6, 115.4,
Light orange solid, yield 66% (93 mg), Mp: 235-237 oC, 1H NMR (400 115.2, 106.1, 103.1, 55.7, 28.9, 21.3; IR (KBr): cm-11649; HRMS (ESI,
MHz, CDCl3): δ 8.19 (s, 1H), 8.18-8.16 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), m/z) Calcd for C18H17N2O2 293.1290 (M+H), 293.1260.
7.50 (s, 1H), 7.34-7.30 (m, 4H), 3.68 (s, 3H); 13C NMR (100 MHz, 9-methoxy-2,4,5-trimethylindolo[1,2-a]quinoxalin-6(5H)-one
CDCl3): δ 156.4, 134.2, 131.2, 130.0, 128.8, 127.7, 126.3, 124.7, 124.0, (27a):
123.5, 123.4, 115.8, 115.4, 114.2, 106.8, 29.1; ; IR (KBr): cm-11656; Pale yellow solid, yield 71% (109 mg), Mp: 151-153 oC, 1H NMR (400
HRMS (ESI, m/z) Calcd for C16H12N2OCl 283.0633 (M+H), found MHz, CDCl3): δ 8.04 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.18-
283.0627.
7.15 (m, 2H), 7.06 (d, J = 9.2 Hz, 1H), 6.83 (s, 1H), 3.83 (s, 3H), 3.64 (s,
3H), 2.53 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.5,
5,7-dimethylindolo[1,2-a]quinoxalin-6(5H)-one (20a):
White solid, yield 51% (67 mg), Mp: 201-203 oC, 1H NMR (400 MHz, 155.5, 133.6, 130.5, 129.5, 129.4, 129.3, 128.2, 128.1, 127.6, 116.2,
CDCl3): δ 8.24-8.22 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8 Hz, 115.4, 113.7, 106.2, 103.3, 55.7, 37.5, 23.1, 21.1; IR (KBr): cm-11652;
1H), 7.52-7.49 (m, 1H), 7.38-7.34 (m, 1H), 7.29-7.26 (m, 3H), 3.63 (s, HRMS (ESI, m/z) Calcd for C19H19N2O2 307.1447 (M+H), found
3H), 2.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.0, 132.9, 130.2, 307.1442.
130.0, 127.0, 125.7, 123.7, 123.2, 123.1, 121.8, 121.1, 119.1, 115.3, 2-tert-butyl-9-methoxy-4,5-dimethylindolo[1,2-a]quinoxalin-
115.1, 114.1, 28.6, 10.0; IR (KBr): cm-11639; HRMS (ESI, m/z) Calcd 6(5H)-one (28a):
for C17H15N2O 263.1179 (M+H), found 263.1179.
light orange crystalline solid, yield 63% (105 mg), Mp: 196-198 oC, 1H
5-methyl-7-azaindolo[1,2-a]quinoxalin-6(5H)-one (21a):
NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.48 (s,
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1H), 7.35-7.28 (m, 2H), 7.26 (s, 1H), 7.16 (dd, J = 9.2 Hz, 2.4Hz, 1H), 28.5, 2.1; IR (KBr): cm-11640; HRMS (ESI, m/z) Calcd Vfioewr ACr1ti5cHle1O7Nnl2inOe
3.92 (s, 3H), 3.70 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 241.1341 (M+H), found 241.1367.
DOI: 10.1039/C9OB02703C
156.5, 155.5, 146.7, 130.3, 129.4, 128.8, 127.4, 126.4, 121.1, 116.4, 8-chloro-5-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (37a): 15
115.3, 115.0, 112.3, 106.2, 103.3, 55.7, 34.9, 31.6, 28.9; IR (KBr): cm- White solid, yield 83% (96 mg), Mp: 196-198 oC, 1H NMR (400 MHz,
11660; HRMS (ESI, m/z) Calcd for C21H23N2O 335.1754 (M+H), found CDCl3): δ 7.61 (d, J = 2.0 Hz, 1H), 7.56-7.55 (m, 1H), 7.28-7.26 (m, 1H),
335.1758.
7.22-7.20 (m, 2H), 6.67-6.65 (m, 1H), 3.63 (s, 3H); 13C NMR (100 MHz,
2,5,7-trimethylindolo[1,2-a]quinoxalin-6(5H)-one (29a):
CDCl3): δ 155.3, 129.1, 128.4, 125.5, 124.7, 123.3, 116.8, 116.3,
White solid, yield 55% (76 mg), Mp: 181-183 oC, 1H NMR (400 MHz, 114.7, 113.8, 113.4, 28.6; IR (KBr): cm-11647; HRMS (ESI, m/z) Calcd
CDCl3): δ 8.4 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.83 (d, J = 8 Hz, 1H), for C12H10N2OCl 233.0476 (M+H), found 233.0481.
7.52-7.48 (m, 1H), 7.37-7.33 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.04 (d, 8-fluoro-5-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (38a):
o
1
J = 8 Hz, 1H), 3.61 (s, 3H), 2.85 (s, 3H), 2.48 (s, 3H); 13C NMR (100 White crystalline solid, yield 82% (88 mg), Mp: 213-215 C, H NMR
MHz, CDCl3): δ 158.0, 133.0, 132.9, 130.3, 127.8, 126.9, 125.6, 124.3, (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.37 (dd, J = 2.8 Hz, 9.2 Hz 1H), 7.27-
123.4, 121.7, 121.1, 119.0, 115.7, 115.2, 114.2, 28.6, 21.3, 10.0; IR 7.21 (m, 2H), 7.06-7.01 (m, 1H), 6.67-6.66 (m, 1H), 3.64 (s, 3H); 13C
(KBr): cm-11635; HRMS (ESI, m/z) Calcd for C18H16N2ONa 299.1160 NMR (100 MHz, CDCl3): δ 159.7, 157.2, 155.3, 126.9, 124.8, 124.7,
(M+Na), found 299.1183.
2,5-dimethyl-7-azaindolo[1,2-a]quinoxalin-6(5H)-one (30a):
White solid, yield 38% (50 mg), Mp: 216-218 oC, 1H NMR (400 MHz, 217.0777 (M+H), found 217.0778.
123.4, 117.0, 116.9, 116.3, 113.8, 113.3, 112.5, 112.3, 102.2, 101.9,
28.7; IR (KBr): cm-11649; HRMS (ESI, m/z) Calcd for C12H10N2OF
CDCl3): δ 9.66 (s, 1H), 8.64 (d, J = 4.4 Hz, 1H),, 8.17 (d, J = 8 Hz, 1H), 5-methyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-
7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 carbonitrile (39a):
Hz, 1H), 3.70 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.4, White solid, yield 47% (52 mg), Mp: 221-223 oC, 1H NMR (400 MHz,
146.8, 145.7, 133.8, 130.9, 127.5, 127.2, 125.7, 125.5, 121.3, 118.7, DMSO-d6): δ 8.63 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.59 (s,
118.4, 114.8, 103.3, 29.0, 21.3; IR (KBr): cm-11659; HRMS (ESI, m/z) 1H), 7.07 (s, 1H), 6.71 (s, 1H), 3.54 (s, 3H); 13C NMR (100 MHz, DMSO-
Calcd for C16H14N3O 264.1137 (M+H), found 264.1145.
5-phenylindolo[1,2-a]quinoxalin-6(5H)-one (31a): 18
d6): δ 154.3, 133.5, 129.4, 123.6, 122.3, 119.0, 118.7, 118.6, 117.1,
113.7, 112.8, 104.7, 28.5; IR (KBr): cm-1 2232, 1665; HRMS (ESI, m/z)
White solid, yield 27% (42 mg), Mp: 201-203 oC, 1H NMR (400 MHz, Calcd for C13H10N3O 224.0824 (M+H), found 224.0821.
CDCl3): δ 8.32 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8 Isolation of intermediate complex 26c
Hz, 1H), 7.58 (s, 1H), 7.56-7.52 (m, 2H), 7.48-7.45 (m, 2H), 7.33-7.28 To a 10 mL oven dried reaction tube were added 2-(5-methoxy-1H-
(m, 3H), 7.24-7.20 (m, 1H), 7.03-6.99 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H); indol-1-yl)-N,4-dimethylaniline 26 (0.75 mmol, 200 mg) and toluene
13C NMR (100 MHz, CDCl3): δ 156.6, 136.7, 134.6, 131.2, 130.3, (4 mL). Then Pd(OAc)2 (1 equiv., 168 mg) was added. The reaction
129.45, 129.41, 129.2, 128.4, 126.6, 125.6, 123.9, 123.58, 123.50, mixture was stirred at room temperature. After 24 h, yellow
122.6, 117.8, 115.5, 114.3, 107.7; IR (KBr): cm-11656; HRMS (ESI, m/z) precipitate was formed in reaction medium. Precipitate was filtered
Calcd for C21H15N2O 311.1184 (M+H), found 311.1166.
through Whatman filter paper and washed with hexane. Collected
yellow solid (26c) was dried at room temperature. To isolate the total
5-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (34a): 15
o
1
White crystalline solid, yield 81% (80 mg), Mp: 126-128 C, H NMR amount of complex 26c, filtrate (mother liquor) was concentrated
(400 MHz, CDCl3): δ 7.66 (d, J = 8 Hz, 1H), 7.63 (s, 1H), 7.34-7.29 (m, using rotavapor. Concentrated crude mixture was dissolved in
2H), 7.24-7.21 (m, 2H), 6.65-6.64 (m, 1H), 3.65 (s, 3H); 13C NMR (100 minimum amount of toluene and 10 mL of hexane was added to
MHz, CDCl3): δ 155.7, 130.4, 125.6, 124.1, 123.4, 122.9, 116.0, 115.7, obtain complex 26c as a yellow color precipitate. Then filtered
114.5, 113.3, 112.7, 28.5; IR (KBr): cm-11645; HRMS (ESI, m/z) Calcd through Whatman filter paper and washed with hexane. Collected
for C12H11N2O 199.0871 (M+H), found 199.0856.
yellow solid (26c) was dried at room temperature and finally
combined yellow precipitate 26c dried under high vacuum. The
5,8-dimethylpyrrolo[1,2-a]quinoxalin-4(5H)-one (35a): 15
o
1
White crystalline solid, yield 94% (97 mg), Mp: 152-154 C, H NMR complex 26c was isolated in 78% yield (186 mg).
(400 MHz, CDCl3): δ 7.62-7.61 (m, 1H), 7.47 (d, J = 0.8 Hz, 1H), 7.21- Spectral data
7.18 (m, 2H), 7.13-7.11 (m, 1H), 6.64-6.63 (m, 1H), 3.64 (s, 3H), 2.44 Intermediate complex (26c):
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 155.6, 132.9, 128.1, 126.4, Yellow solid, yield 78% (186 mg), Mp: 197-199 oC, 1H NMR (400 MHz,
123.8, 123.5, 115.9, 115.6, 114.9, 113.1, 112.5, 28.5, 21.0; IR (KBr): CDCl3): δ 10.22 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.34 (d, J
cm-11641; HRMS (ESI, m/z) Calcd for C13H13N2O 213.1028 (M+H), = 2.4 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.99 (dd, J = 9.2 Hz,
found 213.1038.
8-isopropyl-5-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (36a):
2.4 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 3.90 (s, 3H), 2.70 (d,
J = 5.2 Hz, 3H), 2.31 (s, 3H);13C NMR (100 MHz, CDCl3): δ 155.0, 139.0,
Color less oil, yield 72% (86 mg), Mp: 100-102 oC, 1H NMR (400 MHz, 137.3, 136.2, 135.6, 134.0, 126.4, 123.8, 123.3, 120.7, 114.6, 111.6,
CDCl3): δ 7.67 (dd, J = 1.6 Hz, 2.4 Hz 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.23 105.6, 88.4, 56.0, 43.2, 21.4; HRMS (ESI, m/z) Calcd for C34H35N4O2Pd
(s, 1H), 7.21-7.18 (m, 2H), 6.65-6.64 (m, 1H), 3.65 (s, 3H), 3.01 (m, 637.1795 (M+H), found 637.1768.
1H), 1.31 (d, J = 6.8 Hz, 6H);13C NMR (100 MHz, CDCl3): δ 155.6, 144.1, CO insertion and conversion of Intermediate complex 26c to 26a :
128.4, 123.9, 123.8, 123.5, 115.9, 115.7, 113.1, 112.6, 112.4, 33.8, Complex 26c (0.292 mmol, 186 mg) was taken in a 25 mL oven dried
Schlenk round bottom flask and toluene (3 mL) was added. The
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reaction mixture was flushed three times with ‘CO’ from the balloon
and stirred at 80 °C under a CO balloon. After 24h the reaction
mixture was cooled to room temperature and diluted with EtOAc (10
mL) then passed through a Celite pad, and washed with EtOAc (20
mL). The combined filtrate was concentrated under vacuum, and the
crude product was purified by column chromatography on silica gel
to get 26a in 86% yield (147 mg).
Taniguchi, T. Kitamura, K. Takaki, Y. VieFwujAirwticaleraO,nlinJe.
DOI: 10.1039/C9OB02703C
Organomet. Chem. 1999, 580, 290.
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Conflicts of interest
There are no conflicts to declare
Acknowledgements
We thank the Department of Chemistry, IIT Madras for infrastructure
and SAIF, IIT Madras for XRD data, and IIT Madras for financial
support. AC thanks the UGC, New Delhi for a fellowship.
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