Dibenzo[a,c]carbazoles from 2-(2-bromoaryl)-3-arylindoles via a palladium-catalyzed intramolecular C-H functionalization/C-C bond formation process

Article abstract of DOI:10.1039/c2ob26741a

The palladium-catalyzed cyclization of 2-(2-bromoaryl)-3-arylindoles provides a new versatile approach to dibenzo[a,c]carbazoles. The reaction tolerates a variety of useful substituents including chloro, nitro, ether, cyano, keto, and ester groups.

Full text of DOI:10.1039/c2ob26741a

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ARTICLE TYPE
Dibenzo[a,c]carbazoles from 2-(2-bromoaryl)-3-arylindoles via a
palladium-catalyzed intramolecular C-H functionalization/C-C bond
View Online
formation process
Sandro Cacchi, Giancarlo Fabrizi, Antonella Goggiamani,* and Antonia Iazzetti
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
catalyzed functionalization of (hetero)arenes via the activation
The palladium-catalyzed cyclization of 2-(2-bromoaryl)-3-
arylindoles provides new versatile approach to
10 dibenzo[a,c]carbazoles. The reaction tolerates a variety of useful
substituents including chloro, nitro, ether, cyano, keto, and ester
groups.
of inert C-H bonds has attracted a great deal of attention in
recent years.9 Intensive investigations in this area have shown
the great potential of this chemistry as an extremely
50 convenient alternative to classical cross-coupling reactions
based on preactivated (hetero)arenes.
a
Herein we report the results of this study.
The
palladium-catalyzed
reaction
of
alkynyltrifluoroacetanilides
with
organopalladium
R5
R4
15 intermediates generated in situ from palladium(0) species and
(hetero)aryl and vinylic halides or triflates, alkyl halides,
alkynyl halides, and allylic esters has been proved to be a
powerful and versatile tool for the construction of the
substituted indole ring (Scheme 1).1
R3
Br
R5
R3
R4
Pd cat
Br
NHCOCF3
N
H
I
R1
1
2
3
R2
Pd cat
R5
Pd cat
R1
R2X
N
NHCOCF3
H
R1 = H, alkyl, alkenyl, (hetero)aryl
R
2 = (hetero)aryl and alkentyl halide or triflate,
alkyl halide, allylic ester
R3
R4
20
Scheme 1. Palladium-catalyzed synthesis of indoles from
trifluoroacetanilides.
N
H
4
As part of our ongoing studies in this area, we hypothesized
that in the presence of appropriate functional groups this
Scheme 2. Synthesis dibenzo[a,c]carbazoles from 2-[(2-
55 bromoaryl)ethynyl]trifluoroacetanilides.
25 indole synthesis might be exploited to provide a new ready
access to condensed carbazoles. In particular, 2-[(2-
bromoaryl)ethynyl]trifluoroacetanilides 1 were selected as
2-[(2-Bromoaryl)ethynyl]trifluoroacetanilides
1
were
prepared by reacting 2-ethynylanilines10 with 1-bromo-2-
iodoarenes or 2-bromoarylacetylenes with 2-iodoanilines
suitable
substrates
for
the
construction
of
the
[PdCl2(PPh3)2, CuI, (i-Pr)2NH, DMF,
0 °C to rt] and,
dibenzo[a,c]carbazole ring through a process based on an
30 aminopalladation/reductive elimination reaction followed by
an intramolecular C-H functionalization/C-C bond formation
step (Scheme 2).
The stimulus for this study has been provided by the
growing importance of condensed (hetero)aromatic rings in
35 organic material science2 and by their biological acitivity.3 In
this context, carbazole derivatives are particularly attractive.4
For example, bisindolecarbazoles exhibit blue emission5 and
60 subsequently, the resultant cross-coupling products with
trifluoroacetic anhydride. Compounds 1 were then converted
into 2,3-diarylindoles 3 upon treatment with aryl iodides in
the presence of Pd(PPh3)4 and Cs2CO3 in MeCN at 80 °C.
Initial
attempts
to
cyclize
2-[(2-
the
65 bromoaryl)ethynyl]trifluoroacetanilides
1
to
corresponding carbazole derivatives 4 examined the reaction
of 3a (R3 = R4 = H; R5 = 4-MeO) using Pd(OAc)2 as the
source of Pd(0) species. Unfortunately, disappointing results
were obtained with a variety of ligands [PPh3 , dppe, P(t-Bu)3,
70 the latter prepared in situ from HP(Bu-t)3BF411], bases
(K2CO3, K2CO3/MgO, CsOAc), solvents (DMF, toluene), and
reaction temperatures (80-120 °C). Formation of only traces
of the desired carbazole was observed in several cases along
with the N-arylation byproduct 5.
dibenzocarbazole
derivatives
show
photorefractivity
properties.6 The pyridocarbazole ring has been proposed as an
40 appropriate skeleton to design DNA intercalating drugs7 and
indolo,pyrrolocarbazoles have been shown to possess CDK
inhibitory properties.8 In addition, combining our indole
synthesis with
a
cyclization based on
a
C-H
functionalization/C-C bond formation reaction appeared
45 particularly attractive to us. Indeed, direct transition metal-
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 4
OMe
deprotection step to a crude mixture following the cyclization
30 of 7a that had been concentrated under reduced pressure.
Under these conditions, the correspondiong free NH carbazole
View Online
was isolated in 70% overall yield.
This protocol was then used when the process was extended
to include other N-SEM indoles 6. Our preparative results are
35 summarized in Table 2. Several carbazole derivatives bearing
a variety of useful functional groups have been prepared in
good to excellent yield. Cyano, keto, ester, nitro, and chloro
substituents are well tolerated. With indoles bearing meta
substituents on the aryl ring at the C3 position, two
40 regioisomeric carbazole derivatives can form and the nature of
the substituents was found to play an important role in
controlling the composition of the reaction mixture. In the
presence of 3-Me or 3-MeO groups almost equimolar amounts
of the two regioisomers are formed (Table 2, entries 13 and
45 14). However, with the more steric demanding 3-CF3 group
the new C-C bond is formed regioselectively at the less
crowded ortho position (Table 2, entry 3). No evidence of the
regioisomeric derivative was attained. Interestingly, with 6o,
bearing a meta cyano substituent, the new C-C bond is formed
50 preferentially at the more crowded ortho position (Table 2,
entry 15). Such a behavior may be accounted for by the
coordination of the cyano group to the palladium atom of the
arylpalladium complex formed in situ via oxidative addition.
The resultant intermediate would exert a directing effect on
55 the cyclization step.
N
H
N
Br
5
OMe
To avoid the formation of N-arylation byproducts, we
decided to protect the indole NH group. Using 3a as the
substrate, the introduction of several protecting groups was
5
explored.
Tosyl
chloride
and
1-bromo-2-(2-
methoxyethoxy)ethane failed to give the desired protected
indoles. Isovaleryl chloride, ethyl chlorocarbonate, and benzyl
choride afforded the corresponding indole derivatives in 65,
10 66, and 75% yield, respectively. We were pleased to find that
an excellent result could be obtained with 2-
(trimethylsilyl)ethoxymethyl chloride (SEM-Cl). The SEM
derivative 6a was isolated in 95% yield upon treatement of 3a
with SEM-Cl in the presence of NaH in DMF at room
15 temperature for 1h.
With an efficient procedure for the protection of the
starting indole in hands, the cyclization of 6a to the
corresponding carbazole 7a was next investigated.
Table 1. Cyclization of 6a to 7a. [a]
Table 2. Sequential synthesis of carbazoles 4 from N-SEM indoles 6.
[a][b]
OMe
OMe
R5
R5
Br
Pd(OAc)2, PPh3
Cs(OAc)
DMF, 120 °C
R3
Br
R3
R4
R4
N
N
N
SEM
N
SEM
SEM
SEM
6a
7a
20
6
7
Entry
Ligand
(equiv)
Base
Time (h) T (°C) Yield % of
R5
7a [b]
1
2
3
4
5
6
dppe (0.05)
dppe (0.1)
dppe (0.2)
dppe (0.1)
dppe (0.2)
PPh3 (0.2)
K2CO3
K2CO3
K2CO3
CsOAc
CsOAc
CsOAc
7
8
23
7
1.5
0.5
100
120
120
120
120
120
25c
23d
37e
40f
89
R3
n-Bu4NF, 60 °C
from 3.5 h to
overnight
R4
N
H
4
97
[a] Reactions were carried out under a nitrogen atmosphere on a 0.25
mmol scale in 5 mL of DMF using 0.05 equiv of Pd(OAc)2, a
phosphine ligand, and 2 equiv of base. [b] Yields are given for isolated
products. [c] The starting material was recovered in 74% yield. d The
starting material was recovered in 49% yield. e The starting material
was recovered in 37% yield. f The starting material was recovered in
25% yield.
As shown in Table 1, the best result both in term of yield
and reaction time was observed using PPh3 and Cs(OAc) in
DMF at 120 °C (entry 6). The protecting group could be
readily removed by treating the N-SEM carbazole with a THF
25 solution of n-Bu4NF at 60 °C. Furthermore, the
cyclization/deprotection sequence could be successfully
performed, omitting the isolation of the intermediate protected
carbazole, by adding the reagents required for the
2
| Journal Name, [year], [vol], 00–00
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Page 3 of 4
Organic & Biomolecular Chemistry
Entry
N-SEM Indole 6
T
Product Yield %[c]
(h)[d]
R3
R4
R5
OMe
11
12
H
H
4-Me 4-MeO
9
1
View Online
1
2
H
H
H
4-MeO 0.5
4k (61)
N
H
4a (70)
CN
4-Me 4-MeCO
H
4-CN
7
4l (77)
N
H
4b (92)
F3C
13
14
15
H
H
H
H
H
H
3-Me
3-MeO
3-CN
3
4
5
H
H
H
H
H
H
3-CF3
2-Me
24
0.5
5
7m
7m’ (50:50)
7m +7m’(95)
N
H
4c (60)
4d (84)
4n
4n’ (45:55)
4n +4n’(60)
COMe
4-MeCO
N
H
4e (65)
4o
4o’ (75:25)
4o + 4o’ (55)
[a] The numbering of the substituents refers to the starting N-SEM indoles. [b]
Reactions were carried out under a nitrogen atmosphere on a 0.25 mmol
scale in 5 mL of DMF at 120 °C using 0.05 equiv of Pd(OAc)2, 0.2 equiv of
PPh3, and 2 equiv of Cs(OAc). [c] Reaction times refer to the cyclization
step. [d] Yields refer to the cyclization/deprotection sequence and are given
for isolated products.
6
7
H
H
H
H
H
4-EtOCO 24
4f (65)
4-NO2
5
As to the mechanism of the cyclization step, an
intermolecular competition experiment using 8j and the
corresponding indole containing a deuterium labeled 3-phenyl
4g (73)
Cl
5
substituent 8jD suggests that a hydrogen-abstraction step is
not involved in the rate-limiting step.
8
9
H
H
4-Cl
24
D
D
N
H
D
4h (80)
4i (62)
4j (75)
D
D
NC
NC
N
H
H
H
H
9
1
N
Br
Me
Br
Me
8jD
8j
10
No isotope effect was observed when these two compounds
were subjected to cyclization conditions supporting the view
that the reaction proceeds through an electrophilic aromatic
substitution involving the intermediate A.12
NC
10 5-CN
N
H
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 4
4
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R5
H
Pd
X
View Online
R3
60
65
R4
N
5
Br
SEM
A
6
7
To sum up, this paper describes a general protocol for the
synthesis of dibenzo[a,c]carbazoles from 2-(2-bromoaryl)-3-
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5
arylindoles,
readily
available
from
2-[(2-
70
bromoaryl)ethynyl]trifluoroacetanilides. The reaction tolerates
a variety of useful substituents including chloro, nitro, ether,
cyano, keto, and ester groups and proceeds through an
intramolecular palladium-catalyzed C-H functionalization/C-
10 C bond formation process that most probably involves an
electrophilic aromatic substitution.
8
9
75
Acknowledgment
80
We gratefully acknowledge MURST and the University “La
Sapienza” for financial support.
15 Notes and references
85
a Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza,
Università di Roma, P.le A. Moro 5, 00185 Rome, Italy. Fax: +39 (06)
4991 2780; Tel: +39 (06) 4991 2795; E-mail:
antonella.goggiamani@uniroma1.it
90
20 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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3
4
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