Friedel-crafts 3-(2-bromobenzoylation) of indoles and intramolecular direct arylation: An efficient route to indenoindolones

Article abstract of DOI:10.1055/s-0031-1289663

An efficient two-step approach, comprising the Friedel-Crafts reaction of 2-bromobenzoyl chlorides with indoles to give 3-(2-bromobenzoyl)indoles and their palladium-catalyzed intramolecular direct arylation to give indenoindolones, has been developed. 3-

Full text of DOI:10.1055/s-0031-1289663

PAPER
619
Friedel–Crafts 3-(2-Bromobenzoylation) of Indoles and Intramolecular Direct
Arylation: An Efficient Route to Indenoindolones
An
Efficient
R
a
oute to Ind
n
e
noindolone
k
ar K. Guchhait,* Maneesh Kashyap
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar,
Punjab 160 062, India
Fax +91(172)22146; E-mail: skguchhait@niper.ac.in
Received 2 November 2011; revised 5 December 2011
dation.1d Recently, a method for the reductive cyclization
Abstract: An efficient two-step approach, comprising the Friedel–
of 3-hydroxy-2-(2-nitrophenyl)-1H-inden-1-ones was re-
Crafts reaction of 2-bromobenzoyl chlorides with indoles to give 3-
(2-bromobenzoyl)indoles and their palladium-catalyzed intramo-
lecular direct arylation to give indenoindolones, has been devel-
ported.7 However, these methods suffer from either con-
taining many reaction steps, or limitations in the
oped. 3-(2-Bromobenzoyl)indoles were crucial intermediates; the generation of molecular diversity in the products, and/or
method was successful with N-unprotected or N-protected indoles.
they require harsh reaction conditions that are not amena-
This approach affords a convenient preparation of diverse substitut-
ble to drug discovery research. Accordingly, the develop-
ed and functionalized indenoindolones in good to high yields from
ment of an efficient rapid diversity-feasible synthesis of
easily accessible starting materials. Several moieties, which are
indenoindolone is significant. We envisioned an approach
commonly integrated into bioactive compounds, can be incorporat-
that involved Friedel–Crafts 3-acylation of indole8 for the
ed with ease by this synthesis.
preparation of 3-(2-haloaroyl)indoles and their subse-
Key words: acylation, arylation, catalysis, coupling, heterocycles,
indoles, Lewis acids, palladium
quent indole C2-arylation9 as an efficient route to inde-
noindolones (Scheme 1). A method of palladium-
catalyzed intramolecular arylation/cyclization of 3-(2-io-
dobenzoyl)indoles in the synthesis of indenoindolone is
Indenoindole derivatives possess a wide range of pharma-
known.10 However, our attempts to prepare 3-(2-iodoben-
ceutical activity such as anticancer, anti-Alzheimer’s dis-
zoyl)indoles via 3-acylation of indole following our re-
ease, inhibitors of protein kinase CK2, ligands of the MT3
cently developed zirconium(IV) chloride mediated
melatonin binding site, and antioxidant in lipid-peroxida-
method8a,11 provided a poor (42%) yield of product. The
tion process.1 Their structural resemblance to heterotetra-
process mediated by aluminum(III) chloride, a Lewis acid
cycle-containing potent therapeutic agents and drugs is
traditionally used in Friedel–Crafts reactions, resulted in a
remarkable.2 Indenoindolones are also used as intermedi-
further decreased in the product yield.12 These reactions
ates in the synthesis of potential therapeutic agents.1c,e,3
caused considerable poly-aroylation and Mannich-type
Current approaches to the synthesis of indeno[1,2-b]in-
indole oligomerizations as side reactions. Since indole is
dol-10(5H)-ones include: (1) the preparation of ben-
a nucleophilic arene, these competing reactions are com-
zylidene phthalide in four steps and its rearrangement to
mon in acylation reactions with less reactive acylating
indane-1,3-dione mediated by strong base followed by re-
agents under Friedel–Crafts acidic conditions.8 The iodo-
ductive cyclization,1a,b,e (2) lithium diisopropylamide in-
benzoylation of indole was relatively disfavored possibly
duced anionic N→C carbamoyl migration of 2-aryl-1-
due to the fact that the bulky and electron-donating iodo
(carbamoyl)indoles, Boc derivatization, and lithium
functionality at the 2-position in 2-iodobenzoyl chloride
2,2,6,6,-tetramethylpiperidide induced cyclization,4 (3)
lowered the electrophilic reactivity of the carbonyl carbon
cyclocarbonylation of NH-protected 3-iodo-2-phenylin-
in the donor–acceptor aroyl–Lewis acid complex or aroyl
doles,5 (4) Fischer indolization reaction of arylhydrazone
cation. On the other hand, the 2-iodoarene motif in 3-(2-
derivatives of indan-1-one to afford indenoindole and
iodobenzoyl)indoles is required for effecting intramolec-
subsequent benzylic oxidation,6 and (5) reaction of cyclic
ular arylation by the reported method.
enaminone with ninhydrin, de-dihydroxylation, and oxi-
O
R2
ClOC
Br
1. aroylation
R2
R3
R3
2. intramolecular arylation
N
R1
N
R1
1
2
4
R1 = H, alkyl
Scheme 1 Two-step approach to the synthesis of indenoindolones
SYNTHESIS 2012, 44, 619–627
x
x
.x
x
.2
0
1
1
Advanced online publication: 02.01.2012
DOI: 10.1055/s-0031-1289663; Art ID: Z103511SS
© Georg Thieme Verlag Stuttgart · New York

620
S. K. Guchhait, M. Kashyap
PAPER
We reasoned that, in contrast to other halo analogues, 3- protected indoles. In contrast, for unprotected indoles, po-
(2-bromobenzoyl)indoles could be prepared in good tassium carbonate was detrimental and cesium acetate
yields via Friedel–Crafts acylation and be potential pre- was found to be best. The highest yield of product for the
cursors for intramolecular direct indole C2–H bond aryla- intramolecular arylation of 3-(2-bromobenzoyl)-1-meth-
tion with suitable catalysis. Herein, we describe an yl-1H-indole (3a) was obtained utilizing Pd(dp-
efficient two-step approach to the Friedel–Crafts acyla- pf)2Cl2·CH2Cl2 as catalyst, potassium carbonate as base,
tion of indole and palladium-catalyzed intramolecular and N,N-dimethylformamide as solvent (entry 5). Varia-
arylation reaction for the synthesis of indenoindolones. tion in equivalence of potassium carbonate revealed that
We first attempted the preparation of 3-(2-bromoben- two equivalents were sufficient (entries 4–6). For the in-
zoyl)indole via zirconium(IV) chloride mediated Friedel– tramolecular arylation of 3-(2-bromobenzoyl)-1H-indole
Crafts acylation of indole with 2-bromobenzoyl chloride.8 (3f), the reaction with palladium(II) acetate, triphe-
The reaction afforded the products in good yields for var- nylphosphine, cesium acetate, in N,N-dimethylacetamide
ious indoles and aroyl chlorides. Realizing the feasibility solvent was found to be best (entry 9). The reduced yields
of the method for the preparation of diverse 3-(2-bro- of products while using cesium pivalate or potassium car-
mobenzoyl)indoles, our investigation then focused on bonate and pivalic acid (entries 11 and 12) indicated that
finding a catalyst and conditions effective for intramolec- the concerted metalation deprotonation process was not
ular direct indole C2-arylation of 3-(2-bromobenzoyl)in- favorable for this arylation. The experimental procedures
doles. 3-(2-Bromobenzoyl)-1H-indole (3f) and 3-(2- for both Friedel–Crafts aroylation and intramolecular ary-
bromobenzoyl)-1-methyl-1H-indole (3a) were chosen as lation reactions using this approach are simple and
model substrates for the classes of NH-unprotected 3- straightforward.
aroylindoles and NH-protected 3-aroylindoles, respec-
With the optimized two-step protocol in hand for the syn-
tively. The results of our evaluation of catalysts, ligands,
thesis of indenoindolones, we next set out to explore the
bases, and solvents are summarized in Table 1. It was
scope. To our delight, various 2-bromoaroyl chlorides 2a–
f, and NH-unprotected 1e,f and protected indoles 1a–d
produced diverse indenoindolones 4a–o in good to high
yields (Table 2). No intermolecular arylation product
found that the base has a crucial influence on the direct
arylation of unprotected and protected indoles. Potassium
carbonate was found to be better than cesium acetate for
Table 1 Evaluation of Catalysts, Reagents, and Conditions for Intramolecular Arylationa
O
O
catalyst
base
solvent (anhyd)
130 °C, N2
Br
N
N
R
R
3a R = Me
3f R = H
4a R = Me
4f R = H
Entry
Catalyst (5 mol%)
Base (equiv)
Solvent
Time (h) Ligand (10 mol%) Yielda (%)
4a
84
82
85
98
97
80
n.r.
48
55
–
4f
1
2
Pd(OAc)2
K2CO3 (3)
K2CO3 (3)
K2CO3 (2)
K2CO3 (3)
K2CO3 (2)
K2CO3 (1)
K2CO3 (2)
CsOAc (2)
CsOAc (2)
KOAc (2)
CsOPiv (2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMA
DMA
DMA
DMA
DMF
3
6
–
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
78
PdCl2
–
3
Pd(PPh3)4
9
–
4
Pd(dppf)2Cl2·CH2Cl2
Pd(dppf)2Cl2·CH2Cl2
Pd(dppf)2Cl2·CH2Cl2
NiCl2(PPh3)2
Pd(dppf)2Cl2·CH2Cl2
Pd(OAc)2
2
–
5
2
–
6
4
–
7
24
3
–
8
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
9
3
83
10
11
12
13
Pd(OAc)2
14
14
24
3
34
Pd(OAc)2
–
42
Pd(OAc)2
K2CO3 (2), PivOH (2)
CsOAc (2)
–
10
Pd(OAc)2
–
65
a Isolated yields; n.r. = almost no reaction even after 14 h.
Synthesis 2012, 44, 619–627
© Thieme Stuttgart · New York

PAPER
An Efficient Route to Indenoindolones
621
formed in this protocol. Several moieties, which are com- The electrophilic carbopalladation of nucleophilic arenes
monly integrated into bioactive compounds, could be in- such as indole with palladium(II) catalysts or arylpalladi-
corporated at ease using this two-step approach. The um(II) complex is known in literature.13 In this intramo-
feasibility of NH-unprotected indoles as substrates in this lecular indole C2-arylation, a similar mechanism may
protocol provides the opportunity for various further occur (Scheme 2). Palladium(0) undergoes oxidative ad-
chemical manipulations such as N-glycosylation and side dition to 3-(2-bromobenzoyl)indole and forms an arylpal-
chain incorporation, which are of therapeutic importance. ladium complex A. Intramolecular electrophilic
carbopalladation at the C3 position of the indole produces
the palladacycle B, subsequent palladium-migration from
positions C3 to C2 in the indole ring gives palladacycle C,
and deprotonation of C constructs palladacycle D; this in
The commercial availability or easy synthetic accessibili-
ty to the starting materials (various substituted indoles and
2-bromoaroyl chlorides), a simple two-step approach, and
the generality of the protocol offers the opportunity to
turn results in direct indole C2-H functionalization. The
generate substitutional/functional-diversity in indenoin-
reductive elimination of palladacycle D affords indenoin-
dolones.
dolone product and regenerates palladium(0).
Table 2 Friedel–Crafts 2-Bromobenzoylation of Indoles and Intramolecular Arylation: Synthesis of Indenoindolonesa
O
O
O
R2
R2
Friedel–Crafts
indole-3-aroylation
intramolecular
indole-C2-arylation
R3
R2
Cl
R3
+
R3
step 1
step 2
N
R1
Br
Br
N
R1
N
R1
1
2
3
4
Entry Indole
Aroyl chloride
Timeb Friedel–Crafts product
(h)
Yieldc Timed Indenoindolone
(%)c (h)
Yielde
(%)
O
O
O
Cl
1
6
72
68
62
45
2
97
78
87
81
N
Me
Br
N
N
Br
Me
Me
1a
2a
3a
4a
O
O
O
Cl
2
6.5
3.5
N
Br
N
N
Bn
Br
Bn
Bn
1b
2a
3b
4b
O
O
MeO
MeO
O
MeO
Cl
3
6.5
3
N
Br
N
N
Me
Br
Me
Me
1c
2a
4c
3c
O
O
Ph
O
Ph
Ph
Cl
4
7
3.5
N
Me
Br
N
N
Br
Me
Me
1d
2a
3d
4d
4e
OMe
O
O
O
MeO
OMe
OMe
Cl
OMe
OMe
5
6.5
60
4
74
N
Br
MeO
OMe
2b
Br
N
Me
N
MeO
Me
1a
Me
3e
© Thieme Stuttgart · New York
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622
S. K. Guchhait, M. Kashyap
PAPER
Table 2 Friedel–Crafts 2-Bromobenzoylation of Indoles and Intramolecular Arylation: Synthesis of Indenoindolonesa (continued)
O
O
O
R2
R2
Friedel–Crafts
indole-3-aroylation
intramolecular
indole-C2-arylation
R3
R2
Cl
R3
+
R3
step 1
step 2
N
R1
Br
Br
N
R1
N
R1
1
2
3
4
Entry Indole
Aroyl chloride
Timeb Friedel–Crafts product
(h)
Yieldc Timed Indenoindolone
(%)c (h)
Yielde
(%)
O
O
O
Cl
6
6
64
3
83
84
72
N
Br
H
N
H
N
Br
H
1e
2a
3f
4f
MeO
O
O
O
MeO
MeO
Cl
7
7
54
58
52
57
54
3.5
N
H
Br
N
H
N
Br
H
1f
2a
4g
3g
OMe
O
O
O
OMe
MeO
Cl
8
6.5
4
N
H
Br
N
N
Br
O
H
H
1e
2c
4h
3h
MeO
O
O
OMe
MeO
MeO
OMe
MeO
Cl
Cl
9
7
4
68
71
67
N
H
Br
N
H
N
Br
O
H
1f
2c
3i
4i
O
O
OMe
OMe
OMe
MeO
10
7
4
OMe
N
H
Br
N
N
MeO
Br
O
H
H
1e
2d
3j
4j
MeO
O
O
OMe
MeO
MeO
OMe
OMe
MeO
Cl
Cl
11
7.5
4.5
OMe
N
H
Br
N
H
N
H
MeO
Br
O
1f
2d
3k
4k
O
OMe
O
MeO
OMe
OMe
OMe
OMe
12
6.5
7.5
55
51
4.5
4.5
67
64
N
H
MeO
OMe
2b
Br
O
Br
N
H
N
MeO
H
1e
3l
4l
O
MeO
O
MeO
OMe
MeO
MeO
Cl
OMe
13
OMe
N
H
MeO
OMe
2b
Br
N
Br
N
H
OMe
H
OMe
MeO
1f
3m
4m
Synthesis 2012, 44, 619–627
© Thieme Stuttgart · New York

PAPER
An Efficient Route to Indenoindolones
623
Table 2 Friedel–Crafts 2-Bromobenzoylation of Indoles and Intramolecular Arylation: Synthesis of Indenoindolonesa (continued)
O
O
O
R2
R2
Friedel–Crafts
indole-3-aroylation
intramolecular
indole-C2-arylation
R3
R2
Cl
R3
+
R3
step 1
step 2
N
R1
Br
Br
N
R1
N
R1
1
2
3
4
Entry Indole
Aroyl chloride
Timeb Friedel–Crafts product
(h)
Yieldc Timed Indenoindolone
(%)c (h)
Yielde
(%)
O
O
O
F
F
Cl
F
14
7
47
61
3.5
77
81
N
H
Br
N
N
Br
H
H
1e
2e
3n
MeO
4n
O
O
O
MeO
MeO
Cl
15
6
3
N
H
Br
N
N
Br
H
H
1f
2f
3o
4o
a Reaction conditions: step 1: indole 1 (1.3 mmol), 2-bromobenzoyl chloride 2 (1 mmol), ZrCl4 (1.5 mmol), DCE, addition at 0 °C, 0 to 30 °C,
then continuation at 30 °C; step 2 (entries 1–5): 3-(2-bromobenzoyl)indole 3a–e (1 mmol), Pd(dppf)2Cl2·CH2Cl2 (5 mol%), K2CO3 (2 equiv),
DMF, 130 °C; step 2, entries 6–15: 3-(2-bromobenzoyl)indole 3f–o (1 mmol), Pd(OAc)2 (5 mol%), Ph3P (10 mol%), CsOAc (2 equiv), DMA,
130 °C.
b Reaction time for step 1.
c Yield(%) of isolated product in step 1.
d Reaction time for step 2.
e Yield (%) of isolated product in step 2.
sity in the products, and a simple experimental procedure
that provides high yields of products.
O
O
Pd(II)
Br
Pd(0)Ln
N
R
The starting materials and solvents were used as received from
commercial sources without further purification. 1H and 13C spectra
were recorded in CDCl3, DMSO-d6, or CD3OD on a 400 MHz spec-
trometer using TMS as internal standard. Melting points determined
are uncorrected. All new compounds were characterized by physi-
cal and spectroscopic data; compounds 3a,8a 4a,14a 4f,14b 4h–k6 had
physical and spectroscopic data corresponding to those given in the
literature.
N
R
O
O
Ln–2Pd
Pd(Ln–2)Br
A
N
N
D
R
R
O
3-(2-Bromobenzoyl)-1-methyl-1H-indole (3a); Typical
Procedure8a
O
X–
+
PdLn–2
base
To a soln of 1-methyl-1H-indole (1a, 170.5 mg, 1.3 mmol) in anhyd
DCE (1.5 mL) at 0 °C under N2 were added 2-bromobenzoyl chlo-
ride (2a, 218 mg, 1 mmol) in anhyd DCE (1.5 mL) by a syringe and
ZrCl4 (349.5 mg, 1.5 mmol). The reaction temperature was gradu-
ally increased to 30 °C and the reaction was then continued at 30 °C.
On completion (TLC monitoring) after 6 h, the resultant mixture
was quenched with H2O (5 mL) and extracted with EtOAc (2 × 30
mL). The combined organic layers were washed with water (2 × 10
mL), dried (anhyd Na2SO4), and concentrated under vacuum. Col-
umn chromatographic purification of the crude mass (silica gel,
EtOAc–petroleum ether) provided 3a (225.3 mg, 72%) as a white
solid; mp 150–152 °C. Spectroscopic data was identical to that in
the literature.8a
PdLn–2
H
N
N
R
B
X–
C
R
Scheme 2 Proposed mechanism for intramolecular direct arylation
In conclusion, we have developed a two-step approach,
zirconium(IV) chloride mediated Friedel–Crafts 3-acyl-
ation of indoles with 2-bromobenzoyl chlorides and in-
tramolecular direct arylation, for the synthesis of
indenoindolones. This protocol offers several significant
advantages including the employment of commercially/
synthetically accessible starting materials, the use of only
two reaction steps, substitutional and/or functional diver-
1-Benzyl-3-(2-bromobenzoyl)-1H-indole (3b)
Brownish-black solid; yield: 265 mg (68%); mp 107–109 °C.
IR (KBr): 3097, 1633, 1520 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 619–627

624
S. K. Guchhait, M. Kashyap
PAPER
1H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 7.3 Hz, 1 H), 7.64 (d,
J = 7.7 Hz, 1 H), 7.45–7.29 (m, 10 H), 7.12 (d, J = 6.0 Hz, 2 H), 5.32
(s, 2 H).
13C NMR (100 MHz, CDCl3): d = 189.7, 142.5, 138.4, 137.3, 135.5,
133.2, 130.5, 129.0, 128.7 (2 CH), 128.2, 127.1, 126.7 (2 CH),
123.9, 123.2, 122.7, 119.5, 116.5, 110.4, 50.9.
MS (APCI): m/z = 390 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C22H16BrNNaO:
3-(2-Bromobenzoyl)-5-methoxy-1H-indole (3g)
White solid; yield: 178 mg (54%); mp 203–205 °C.
IR (KBr): 3352, 2925, 1737, 1606, 1216, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.72 (br s, 1 H), 7.90 (s, 1 H), 7.65
(d, J = 7.8 Hz, 1 H), 7.43–7.30 (m, 5 H), 6.96 (m, 1 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.3, 156.7, 142.3, 135.1, 133.2,
131.2, 130.5, 128.7, 127.0, 126.5, 119.5, 117.5, 114.8, 112.3, 103.5,
55.8.
412.0313; found: 412.0318.
MS (APCI): m/z = 330 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C16H12BrNNaO2:
351.9949; found: 351.9953.
3-(2-Bromobenzoyl)-5-methoxy-1-methyl-1H-indole (3c)
White solid; yield: 213 mg (62%); mp 175–177 °C.
IR (KBr): 3119, 2953, 1729, 1614, 1215, 1031 cm–1.
3-(2-Bromo-5-methoxybenzoyl)-1H-indole (3h)
White solid; yield: 191 mg (58%); mp 140–143 °C.
IR (KBr): 3362, 2970, 1738, 1609, 1235, 1017 cm–1.
1H NMR (400 MHz, CD3OD): d = 8.09 (d, J = 7 Hz, 1 H), 7.46 (s,
1 H), 7.44 (d, J = 2.6 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.18–7.15
(m, 2 H), 6.89–6.86 (m, 2 H), 3.70 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 192.4, 160.3, 144.5, 138.8,
138.5, 135.0, 127.0, 124.8, 123.7, 122.7, 117.7, 117.6, 115.3, 113.2,
110.4, 56.2.
1H NMR (400 MHz, CDCl3): d = 7.89 (s, 1 H), 7.63 (d, J = 7.7 Hz,
1 H), 7.41–7.37 (m, 2 H), 7.32–7.30 (m, 1 H), 7.22 (d, J = 8.8 Hz, 1
H), 7.19 (s, 1 H), 6.97 (dd, J = 8.8, 2.4 Hz, 1 H), 3.90 (s, 3 H), 3.74
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.6, 156.8, 142.5, 138.9, 133.2,
132.7, 130.4, 128.6, 127.3, 127.0, 119.5, 115.7, 114.3, 110.7, 103.8,
55.8, 33.8.
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C17H14BrNNaO2:
366.0106; found: 366.0106.
MS (APCI): m/z = 330 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C16H12BrNNaO2:
351.9949; found: 351.9949.
3-(2-Bromobenzoyl)-1-methyl-5-phenyl-1H-indole (3d)
Yellow oil; yield: 175 mg (45%).
IR (neat): 3191, 1603, 1423 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.36 (s, 1 H), 7.74–7.66 (m, 6
H), 7.52–7.46 (m, 5 H), 7.35–7.34 (m, 1 H), 3.85 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 189.1, 142.6, 141.5, 141.3,
137.7, 135.7, 133.3, 131.4, 129.4 (2 CH), 129.0, 128.0, 127.4, 127.3
(2 CH), 126.9, 123.1, 119.7, 119.0, 115.3, 112.0, 33.7.
3-(2-Bromo-5-methoxybenzoyl)-5-methoxy-1H-indole (3i)
White solid; yield: 187 mg (52%); mp 137–139 °C.
IR (KBr): 3271, 2936, 1737, 1604, 1215, 1017 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.72 (br s, 1 H), 7.57–7.53 (m, 1
H), 7.47 (s, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.31 (s, 1 H), 6.99–6.96
(m, 1 H), 6.92–6.90 (m, 2 H), 3.85 (s, 3 H), 3.81 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 192.3, 160.3, 158.0, 144.5,
138.5, 136.0, 135.0, 119.4, 117.7, 117.2, 115.3, 114.8, 113.9, 110.4,
104.4, 56.2, 56.0.
MS (APCI): m/z = 390 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C22H16BrNNaO:
412.0313; found: 412.0311.
MS (APCI): m/z = 360 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C17H14BrNNaO3:
3-(2-Bromo-3,4,5-trimethoxybenzoyl)-1-methyl-1H-indole (3e)
Yellowish-white solid; yield: 242 mg (60%); mp 78–80 °C.
IR (KBr): 1737, 1628, 1217, 1025 cm–1.
382.0055; found: 382.0055.
1H NMR (400 MHz, DMSO-d6): d = 8.18 (d, J = 6.8 Hz, 1 H), 7.78
(s, 1 H), 7.55 (d, J = 7.4 Hz, 1 H), 7.35–7.27 (m, 2 H), 6.95 (s, 1 H),
3.88 (s, 3 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.81 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 188.4, 153.0, 150.7, 143.4,
141.0, 138.3, 138.1, 128.7, 126.3, 123.8, 121.7, 114.8, 111.3, 108.4,
105.3, 61.3, 61.2, 56.6, 33.6.
MS (APCI): m/z = 404 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C19H18BrNNaO4:
3-(2-Bromo-4,5-dimethoxybenzoyl)-1H-indole (3j)
White solid; yield: 205 mg (57%); mp 230–233 °C.
IR (KBr): 3418, 2970, 1737, 1605, 1216, 1028 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.13 (d, J = 6.4 Hz, 1 H), 7.68
(s, 1 H), 7.50 (d, J = 6.4 Hz, 1 H), 7.24–7.22 (m, 3 H), 7.06 (s, 1 H),
3.83 (s, 3 H), 3.75 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 189.3, 150.2, 148.2, 137.4,
137.3, 134.8, 126.0, 123.6, 122.6, 121.6, 116.3, 116.1, 112.8, 112.5,
109.5, 56.4, 56.2.
426.0317; found: 426.0319.
MS (APCI): m/z = 360 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C17H14BrNNaO3:
3-(2-Bromobenzoyl)-1H-indole (3f)
White solid; yield: 191 mg (64%); mp 195–198 °C.
IR (KBr): 3359, 2970, 1738, 1614 cm–1.
382.0055; found: 382.0046.
1H NMR (400 MHz, CDCl3): d = 9.12 (br s, 1 H), 7.63 ( dd, J = 8,
3-(2-Bromo-4,5-dimethoxybenzoyl)-5-methoxy-1H-indole (3k)
Off-white solid; yield: 210 mg (54%); mp 207–209 °C.
IR (KBr): 3152, 2955, 1733, 1625, 1602, 1463, 1259, 1026 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.74 (s, 1 H), 7.69 (s, 1 H), 7.48
(d, J = 8.6 Hz, 1 H), 7.30 (s, 1 H), 7.13 (s, 1 H), 6.97 (d, J = 8.6 Hz,
1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.83 (s, 3 H).
0.9 Hz, 1 H), 7.43–7.28 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 190.4, 142.3, 136.6, 135.3, 133.2,
130.5, 128.6, 127.0, 125.6, 124.1, 123.1, 122.4, 119.5, 117.6, 111.6.
MS (APCI): m/z = 300 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C15H10BrNNaO:
321.9843; found: 321.9842.
Synthesis 2012, 44, 619–627
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An Efficient Route to Indenoindolones
625
13C NMR (100 MHz, DMSO-d6): d = 189.2, 156.1, 150.2, 148.2,
137.4, 134.8, 132.2, 126.8, 116.2 (2 CH), 113.6, 113.5, 112.4,
109.5, 103.3, 56.4, 56.2, 55.7.
MS (APCI): m/z = 390 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C18H16BrNNaO4:
5-Methylindeno[1,2-b]indol-10(5H)-one (4a); Typical Proce-
dure for 4a–e
3-(2-Bromobenzoyl)-1H-methyl-1H-indole (3a, 313 mg, 1.00
mmol) was added to an oven-dried round-bottom flask under N2.
K2CO3 (2 equiv), Pd(dppf)2Cl2·CH2Cl2 (5 mol%), and anhyd DMF
(2 mL) were subsequently added. The resulting mixture was then
stirred at 130 °C. On completion of the reaction (TLC monitoring)
after 2 h, H2O (5 mL) was added to the mixture and it was extracted
with EtOAc (2 × 30 mL). The combined organic layers were
washed with H2O (10 mL), dried (anhyd Na2SO4), and concentrated
under vacuum. Column chromatographic purification of the crude
mass (silica gel, EtOAc–petroleum ether), provided 4a (226 mg,
97% yield) as a reddish solid; mp 215–217 °C. Spectroscopic data
are in accord with literature values.14a
412.0160; found: 412.0162.
3-(2-Bromo-3,4,5-trimethoxybenzoyl)-1H-indole (3l)
Yellowish-white solid; yield: 214 mg (55%); mp 98–100 °C.
IR (KBr): 3322, 2933, 1610, 1238, 1105, 1007 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.0 (br s, 1 H), 8.15 (d, J =
5.8 Hz, 1 H), 7.70 (s, 1 H), 7.50 (d, J = 6.6 Hz, 1 H), 7.25–7.24 (m,
2 H), 6.95 (s, 1 H), 3.83 (s, 6 H), 3.79 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 189.0, 153.0, 150.7, 143.4,
138.4, 137.7, 137.4, 125.9, 123.7, 122.7, 121.6, 116.0, 112.9, 108.4,
105.3, 61.3, 61.2, 56.7.
MS (APCI): m/z = 390 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C18H16BrNNaO4:
5-Benzylindeno[1,2-b]indol-10(5H)-one (4b)
Orange solid; yield: 241 mg (78%); mp 192–193 °C.
IR (KBr): 2927, 1714, 1684 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85–7.82 (m, 1 H), 7.47–7.45 (m,
1 H), 7.37–7.30 (m, 3 H), 7.23–7.16 (m, 7 H), 7.02–7.00 (m, 1 H),
5.51 (s, 2 H).
412.0160; found: 412.0153.
13C NMR (100 MHz, CDCl3): d = 185.1, 158.7, 142.6, 141.1, 135.5,
134.7, 132.0, 129.6, 129.1, 128.1, 126.2, 123.6, 123.3, 123.2, 123.0,
120.8, 118.5, 115.5, 111.0, 48.7.
MS (APCI): m/z = 310 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C22H15NNaO: 332.1051;
3-(2-Bromo-3,4,5-trimethoxybenzoyl)-5-methoxy-1H-indole
(3m)
Yellowish-white solid; yield: 214 mg (51%); mp 159–162 °C.
IR (KBr): 3312, 2931, 1602, 1269, 1111, 1010 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.99 (br s, 1 H), 7.63 (s, 2 H),
7.40 (d, J = 8.6 Hz, 1 H), 6.93 (s, 1 H), 6.88 (d, J = 8.6 Hz, 1 H),
3.82 (s, 6 H), 3.79 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 188.9, 156.1, 153.0, 150.7,
143.4, 138.5, 137.7, 132.2, 126.7, 115.8, 113.7, 113.6, 108.3, 105.3,
103.1, 61.3, 61.2, 56.7, 55.7.
MS (APCI): m/z = 420 [M (79Br) + H+].
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C19H18BrNNaO5:
found: 332.1051.
8-Methoxy-5-methylindeno[1,2-b]indol-10(5H)-one (4c)
Orange solid; yield: 229 mg (87%); mp 178–179 °C.
IR (KBr): 2929, 1735, 1367, 1216, 1152, 1072 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.43–7.41 (m, 1 H), 7.23–7.21 (m,
2 H), 7.19–7.15 (m, 2 H), 7.10 (d, J = 8.9 Hz, 1 H), 6.78 (dd, J = 8.9,
3.8 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H).
442.0266; found: 442.0259.
13C NMR (100 MHz, CDCl3): d = 184.9, 158.4, 157.0, 141.4, 137.8,
134.8, 131.8, 129.5, 123.6, 123.1, 118.1, 114.6, 113.0, 111.3, 102.3,
55.7, 31.8.
MS (APCI): m/z = 264 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H13NNaO2: 286.0844;
3-(2-Bromo-5-fluorobenzoyl)-1H-indole (3n)
White solid; yield: 149 mg (47%); mp 173–177 °C.
IR (KBr): 3449, 2953, 1722, 1610 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.13 (d, J = 6.6 Hz, 1 H), 7.77–
7.74 (m, 1 H), 7.71 (s, 1 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.43 (d, J =
8.4 Hz, 1 H), 7.34–7.23 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 188.0, 161.5 (d, J = 245 Hz,
1C), 144.5, 137.7 (d, J = 38 Hz, 1C), 135.1 (d, J = 8 Hz, 1C), 125.8,
123.9, 122.8, 121.6, 118.5, 118.3, 116.4, 116.2, 115.7, 113.0.
found: 286.0841.
5-Methyl-8-phenylindeno[1,2-b]indol-10(5H)-one (4d)
Yellowish-brown solid; yield: 250 mg (81%); mp 168–170 °C.
IR (KBr): 2927, 1672 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01 (m, 1 H), 7.67–7.65 (m, 2 H),
7.46–7.43 (m, 4 H), 7.36–7.22 (m, 5 H), 3.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 184.9, 159.2, 141.3, 137.0, 131.9,
129.7, 128.7 (2 CH), 127.3 (2 CH), 127.0, 125.7, 123.4, 123.3,
122.6, 119.2, 118.3, 110.7, 31.8.
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C15H9BrFNNaO:
339.9749; found: 339.9747.
3-(2-Bromo-2-naphthoyl)-5-methoxy-1H-indole (3o)
White-orange solid; yield: 231 mg (61%); mp 203–205 °C.
IR (KBr): 3470, 3166, 1620, 1595, 1456, 1275, 1132 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.36 (s, 1 H), 8.08 (s, 1 H), 8.00
(t, J = 8.6 Hz, 2 H), 7.71 (s, 1 H), 7.63–7.62 (m, 3 H), 7.41 (d, J =
8.6 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 189.3, 156.2, 139.8, 137.8,
134.4, 132.3, 131.9, 131.5, 128.7, 128.2, 127.6, 127.3, 126.8, 116.7,
116.4, 113.7, 113.6, 103.3, 55.7.
HRMS (ESI): m/z [M + Na]+ calcd for C22H15NNaO: 332.1051;
found: 332.1045.
2,3,4-Trimethoxy-5-methylindeno[1,2-b]indol-10(5H)-one (4e)
Orange solid; yield: 239 mg (74%); mp 143–145 °C.
IR (KBr): 2929, 1727, 1217, 1152, 1072 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.73–7.71 (m, 1 H), 7.23–7.12 (m,
3 H), 6.96 (s, 1 H), 4.05 (s, 3 H), 4.01 (s, 3 H), 3.91 (s, 3 H), 3.90 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 183.8, 159.3, 154.9, 146.2, 144.9,
143.0, 137.4, 123.4, 123.1, 122.4, 120.0, 119.3, 114.4, 110.8, 105.2,
61.2, 60.9, 56.5, 31.6.
HRMS (ESI): m/z [M (79Br) + Na]+ calcd for C20H14BrNNaO2:
402.0106; found: 402.0100.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 619–627

626
S. K. Guchhait, M. Kashyap
PAPER
MS (APCI): m/z = 324 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO4: 346.1055;
1H NMR (400 MHz, DMSO-d6): d = 7.58–7.53 (m, 1 H), 7.45–7.43
(m, 1 H), 7.30–7.27 (m, 1 H), 7.19–7.12 (m, 4 H).
found: 346.1053.
13C NMR (100 MHz, DMSO-d6): d = 182.8, 163.9 (d, J = 247 Hz,
1 C), 158.8, 142.1, 131.0, 123.7, 123.5, 123.0, 120.9, 119.8, 118.2,
118.0, 114.2, 112.0, 111.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H8FNNaO: 260.0488;
found: 260.0488.
Indeno[1,2-b]indol-10(5H)-one (4f); Typical Procedure 4f–o
3-(2-Bromobenzoyl)-1H-indole (3f, 299 mg, 1.00 mmol) was added
to an oven-dried round-bottom flask under N2. CsOAc (2 equiv),
Ph3P (10 mol%), Pd(OAc)2 (5 mol%), and anhyd DMA (2 mL) were
subsequently added. The resulting mixture was then stirred at 130
°C. On completion of the reaction (TLC monitoring) after 3 h, H2O
(5 mL) was added to the mixture and it was extracted with EtOAc
(2 × 30 mL). The combined organic layers were washed with H2O
(10 mL), dried (anhyd Na2SO4), and concentrated under vacuum.
The column chromatographic purification of the crude mass (silica
gel, EtOAc–petroleum ether) provided 4f (182 mg, 83% yield) as a
reddish solid; mp 333–336 °C. Spectroscopic data are in accord
with literature values.14b
10-Methoxybenzo[5,6]indeno[1,2-b]indol-12(7H)-one (4o)
Yellowish-brown solid; yield: 242 mg (81%); mp >300 °C.
IR (KBr): 3446, 3212, 1666, 1209, 1056 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.94 (d, J = 7.8 Hz, 1 H), 7.90–
7.88 (m, 2 H), 7.64 (s, 1 H), 7.56–7.46 (m, 2 H), 7.39 (d, J = 8.8 Hz,
1 H), 7.12 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 7.8, 2.4 Hz, 1 H), 3.79
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 183.5, 158.0, 156.6, 139.7,
137.5, 135.4, 133.9, 130.6, 130.2, 129.4, 129.0, 127.7, 123.3, 118.7,
118.1, 114.9, 113.8, 102.3, 55.8.
8-Methoxyindeno[1,2-b]indol-10(5H)-one (4g)
Orange solid; yield: 184 mg (74%); mp 256–260 °C.
IR (KBr): 3225, 2928, 1736, 1217, 1153, 1072 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.72–7.70 (m, 1 H), 7.51–7.33
(m, 5 H), 6.93 (d, J = 8.7 Hz, 1 H), 3.86 (s, 3 H).
MS (APCI): m/z = 300 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C20H13NNaO2: 322.0844;
found: 322.0839.
13C NMR (100 MHz, CD3OD): d = 193.9, 157.8, 142.1, 137.5,
133.7, 133.4, 133.0, 132.3, 130.7, 129.9, 129.6, 129.4, 114.9, 113.7, Acknowledgment
104.6, 56.0.
MS (APCI): m/z = 250 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C16H11NNaO2: 272.0687;
We gratefully acknowledge financial support from CSIR, New
Delhi for this investigation.
found: 272.0687.
References
2,3,4-Trimethoxyindeno[1,2-b]indol-10(5H)-one (4l)
Reddish solid; yield: 207 mg (67%); mp 202–205 °C.
IR (KBr): 3172, 1661, 1521, 1442, 1230, 1065 cm–1.
(1) (a) Bal, C.; Baldeyrou, B.; Moz, F.; Lansiaux, A.; Colson, P.;
Kraus-Berthier, L.; Leonce, S.; Pierre, A.; Boussard, M. F.;
Rousseau, A.; Wierzbicki, M.; Bailly, C. Biochem.
Pharmacol. 2004, 68, 1911. (b) Wierzbicki, M.; Boussard,
M. F.; Rousseau, A.; Boutin, J. A.; Delagrange, P. US
6,844,445, 2005. (c) Shao, D.; Zou, C.; Luo, C.; Tang, X.;
Li, Y. Bioorg. Med. Chem. Lett. 2004, 14, 4639.
1H NMR (400 MHz, DMSO-d6): d = 7.47 (d, J = 6.8 Hz, 1 H), 7.40
(d, J = 7.4 Hz, 1 H), 7.12–7.06 (m, 2 H), 6.90 (s, 1 H), 3.95 (s, 3 H),
3.85 (s, 3 H), 3.79 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 183.8, 157.4, 155.3, 146.5,
144.9, 142.4, 136.4, 123.5, 122.9, 122.7, 119.2, 119.1, 114.0, 113.3,
105.7, 61.9, 61.0, 56.9.
MS (APCI): m/z = 310 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C18H15NNaO4: 332.0899;
(d) Hemmerling, H.-J.; Götz, C.; Jose, J. WO 2008,040,547,
2007. (e) Boussard, M. F.; Truche, S.; Rousseau-Rojas, A.;
Briss, S.; Descamps, S.; Droual, M.; Wierzbicki, M.; Ferry,
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Baldeyrou, B.; Schifano-Faux, N.; Grandclaudon, P.;
Couture, A.; Ryckebusch, A. Bioorg. Med. Chem. 2010, 18,
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Wallace, N.; Ault, M.; Crooke, J.; Barbay, J. K.; Wang, A.;
Leonard, K.; Powell, M. T.; Alford, V.; Hall, D.; Rupert, K.
C.; Heintzelman, G. R.; Hansen, K.; Bullington, J. L.;
Scannevin, R. H.; Carroll, K.; Lampron, L.; Westover, L.;
Russell, R.; Branum, S.; Wells, K.; Damon, S.; Youells, S.;
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Dreher, J.; Dunkel, U.; Kohfeld, S.; Preu, L.; Weber, H.;
Ehlert, J. E.; Mutschler, B.; Totzke, F.; Schachtele, C.;
Kubbutat, M. H. G.; Baumann, K.; Kunick, C. J. Med. Chem.
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M.; Ferandin, Y.; Lozach, O.; Lemcke, T.; Kegel, S.;
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2,3,4,8-Tetramethoxyindeno[1,2-b]indol-10(5H)-one (4m)
Reddish solid; yield: 217 mg (64%); mp 222–225 °C.
IR (KBr): 2929, 1736, 1455, 1217, 1152, 1072 cm–1
.
1H NMR (400 MHz, DMSO-d6): d = 7.27 (d, J = 8.8 Hz, 1 H), 6.95
(d, J = 2.3 Hz, 1 H), 6.90 (s, 1 H), 6.68 (dd, J = 8.8, 2.3 Hz 1 H),
3.94 (s, 3 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.76 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 183.2, 156.7, 155.2, 146.4,
144.9, 137.1, 136.6, 123.8, 119.2, 114.7, 113.3, 112.0, 105.6, 101.4,
61.8, 61.0, 56.9, 55.7.
MS (APCI): m/z = 340 (M + H+).
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO5: 362.1004;
found: 362.1006.
2-Fluoroindeno[1,2-b]indol-10(5H)-one (4n)
Reddish solid; yield: 183 mg (77%); mp 220–222 °C.
IR (KBr): 2957, 1736, 1365, 1216 cm–1.
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Synthesis 2012, 44, 619–627
© Thieme Stuttgart · New York

PAPER
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An Efficient Route to Indenoindolones
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