A mild and effective method to synthesize carbazolones by CuI/L-proline-catalyzed intramolecular arylation

Article abstract of DOI:10.1055/s-2007-991079

Substituted carbazol-4-ones and 3,4-dihydrocyclo-pental indole-1-ones could be prepared in good yields via the intramolecular coupling reaction of N-2-iodoaryl enaminones in the presence of Cul/L-proline under mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991079

LETTER
2699
A Mild and Effective Method to Synthesize Carbazolones by
CuI/L-Proline-Catalyzed Intramolecular Arylation
Synthesis of
C
h
arbazolonesaoyu Yan, Haihong Wu, Nan Wu, Yongwen Jiang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai, 200062, P. R. of China
Fax +86(21)62233424; E-mail: ywjiang@chem.ecnu.edu.cn
Received 5 April 2007
reaction temperature required was too high (100 °C) even
when using iodoaryl enaminones as the substrates.4b
In 1982, Suzuki and co-workers5 reported a CuI-promoted
Abstract: Substituted carbazol-4-ones and 3,4-dihydrocyclo-pen-
tal indole-1-ones could be prepared in good yields via the intra-
molecular coupling reaction of N-2-iodoaryl enaminones in the
presence of CuI/L-proline under mild reaction conditions.
cyclization of N-2-haloaryl enaminones to carbazolones
Key words: intramolecular cross-coupling, catalysis, 2-iodoaryl by using stoichiometric amounts of CuI. The reaction con-
enaminone, L-proline
ditions required high temperature (X = I, 105–120 °C;
X = Br, 160–170 °C) and hence the scope of the substrates
was very narrow. In recent years, CuI-catalyzed coupling
reactions of activated methylene compounds to aryl ha-
lides have been conducted under relatively mild condi-
tions by employing some special ligands.6–8 For example,
Buchwald described the coupling of aryl iodides and di-
ethyl malonate in the presence of catalytic amounts of
copper(I) iodide and 2-phenylphenol.6a Ma also devel-
oped a series of copper-catalyzed coupling reactions using
L-proline and other amino acids as effective promoters.7
Carbazolones are very important building blocks in total
synthesis of many natural products and biologically active
compounds.1 These include murrayaquinone A,1a com-
pound 1 (a potassium-channel blocker),1b ondansetron
(a potent 5-HT3 receptor agonist),1c and compound 2
(a HIV-integrase inhibitor, Figure 1).1d
O
O
Table 1 CuI/L-Proline-Catalyzed Intramolecular Coupling Reac-
tion of N-2-Iodoaryl Enaminone Under Various Conditionsa
MeO
N
N
O
O
O
H
O
I
CuI/
L-proline
base, solvent
1
N
murrayaquinone A
O
N
H
H
O
OH
4a
3a
F
OH
N
Entry Ligand
Base
Solvent
Temp Yield
(°C)
N
O
(%)b
58
74
79
82
75
82
92
55
68
54
64
N
N
1
2
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
–
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
70
2
ondansetron
80
Figure 1 Biologically active carbazolones
3
90
A variety of methods have been utilized to obtain carba-
zolones. One of the basic synthetic routes is Fischer indole
synthesis.2 However, the use of the highly acidic reaction
conditions limited the scope of the reactions. Recently,
Chen reported the palladium-catalyzed intramolecular
cyclization of bromoaryl enaminones to synthesize tetra-
hyhrocarbazole-4-ones.3 The reaction was carried out at
140 °C and only simple substrates (methyl-substituted
aryl enaminones) were employed. Other palladium-cata-
lyzed methods have also been developed.4 However, the
4
100
90
5
Cs2CO3 DMSO
6
NaOH
KOH
KOH
KOH
KOH
KOH
DMSO
DMSO
DMSO
DMF
90
7
90
8
90
9
L-Proline
L-Proline
L-Proline
90
10
11
i-PrOH
80
EtOH–H2O (10:1) 80
SYNLETT 2007, No. 17, pp 2699–2702
Advanced online publication: 27.09.2007
DOI: 10.1055/s-2007-991079; Art ID: W06707ST
© Georg Thieme Verlag Stuttgart · New York
1
6
.1
0
.
2
0
0
7
a Reaction conditions: N-2-iodoaryl enaminone (1 mmol), CuI (0.1
mmol), L-proline (0.2 mmol), base (4 mmol), solvent (4 mL), 24 h.
b Isolated yields.

2700
S. Yan et al.
LETTER
Using the same strategy, we reported a mild CuI/L-pro- 7). However, Cs2CO3 and NaOH provided slightly lower
line-catalyzed arylation reaction of acetylacetone or ethyl yields (entries 5 and 6). In the absence of L-proline, the
cyanoacetate at 90 °C in DMSO.9 We now report the reaction gave only 55% yield at 90 °C using KOH as the
intramolecular arylation of N-2-iodoaryl enaminones to base (entry 8), which indicated that L-proline was neces-
carbazol-4-ones or 3,4-dihydrocyclopental indole-1-ones sary to ensure a good product yield. In addition, a switch
in the presence of CuI/L-proline system under relatively in the solvent to DMF, i-PrOH, or mixed solvents (EtOH–
mild conditions.
H2O, 10:1) gave lower yields (entries 9–11). On the basis
of the above studies, we concluded that using L-proline as
the ligand, DMSO as the solvent, 4 equivalents of KOH as
the base, and carrying out the reaction at 90 °C were the
optimized conditions.
The intramolecular cyclization was first conducted on N-
2-iodoaryl enaminone 4a catalyzed by 10 mol% CuI and
20 mol% L-proline. This reaction proceeded well at 70 °C
in DMSO in the presence of K2CO3 to produce carbazolo-
ne 3a in 58% yield (Table 1, entry 1). Higher yields were
observed by raising the reaction temperature (entries 2–4).
Among the bases tested, KOH gave the best result (entry
Table 2 L-Proline-Promoted CuI-Catalyzed Intramolecular Coupling Reaction of N-2-Iodoaryl Enaminones 4a,12
O
O
O
O
R1
R2
I
CuI (10 mol%)
L-proline (20 mol%)
R1
R2
I
R1
R2
( )n
( )n
( )n
KOH, DMSO
90 °C
cat. TsOH
toluene, reflux
N
H
NH2
N
H
R3
R3
R3
5
4
3
Entry
1
Enaminone
Yield (%)b from 5 Carbazolone
Yield (%)b from 4
O
O
I
84
92
N
H
N
H
4a
3a
O
O
F
I
F
2
3
4
5
60
91
75
79
96
N
H
N
H
4b
3b
O
O
Cl
I
Cl
62
78
48
N
H
N
H
4c
3c
O
O
Br
I
Br
N
H
N
H
4d
3d
O
O
I
N
H
N
H
4e
3e
O
O
F3C
I
F3C
6
33
93
N
H
N
H
3f
4f
Synlett 2007, No. 17, 2699–2702 © Thieme Stuttgart · New York

LETTER
Synthesis of Carbazolones
2701
Table 2 L-Proline-Promoted CuI-Catalyzed Intramolecular Coupling Reaction of N-2-Iodoaryl Enaminones 4a,12 (continued)
O
O
O
O
R1
R2
I
CuI (10 mol%)
L-proline (20 mol%)
R1
R2
I
R1
R2
( )n
( )n
( )n
KOH, DMSO
90 °C
cat. TsOH
toluene, reflux
N
H
NH2
N
H
R3
R3
R3
5
4
3
Entry
7
Enaminone
Yield (%)b from 5 Carbazolone
Yield (%)b from 4
O
O
I
45
82c
N
H
N
H
4g
3g
O
O
I
8
61
61
O2N
N
O2N
N
H
H
4h
3h
O
O
O2N
I
O2N
9
10
11
12
84
–
N
H
N
H
4i
3i
O
O
O
MeOOC
I
MeOOC
52
–
N
H
N
H
4j
4j
O
MeOOC
I
MeOOC
52
62d
N
H
N
H
4j
3j
O
O
I
42
62
N
H
N
MeO
MeO
3k
H
4k
O
O
F
I
F
13
14
45
96
84
N
N
H
H
3l
4l
O
O
I
20
MeO
N
H
MeO
N
H
4m
3m
a Reaction conditions: N-2-iodoaryl enaminone 4 (1 mmol), CuI (0.1 mmol), L-proline (0.2 mmol), KOH (4 mmol), DMSO (4 mL), N2, 90 °C,
24 h.
b Isolated yields.
c CuI (0.2 mmol) and L-proline (0.4 mmol) were added, 100 °C.
d K2CO3 (2 mmol) was added.
Synlett 2007, No. 17, 2699–2702 © Thieme Stuttgart · New York

2702
S. Yan et al.
LETTER
(2) (a) Rodriguez, J.-G.; Temprano, F.; Esteban-Calderon, C.;
Martinez-Ripoll, M. J. Chem. Soc., Perkin Trans. 1 1989,
2117. (b) Kudzma, L. V. Synthesis 2003, 1661.
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43, 1621. (b) Sørensen, U. S.; Pomb-Villar, E. Helv. Chim.
Acta 2004, 87, 82.
(5) Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031.
(6) (a) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727. (c) Antilla, J. C.;
Buchwald, S. L. Org. Lett. 2001, 3, 2077. (d) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(7) (a) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693.
(b) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
16050. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
(d) Zhu, W.; Ma, D. Chem. Commun. 2004, 888. (e) Ma,
D.; Liu, F. Chem. Commun. 2004, 1934. (f) Zhu, W.; Ma,
D. J. Org. Chem. 2005, 70, 2696.
The reaction scope was further explored with different N-
2-iodoaryl enaminones (Table 2). According to a known
procedure,10 we synthesized a series of substituted o-io-
doanilines 5 which were then subsequently converted into
the corresponding iodoaryl enaminones 4 in moderate to
good yields by the reactions of substituted o-iodoaniline 5
with 1,3-cyclohexanedione or 1,3-cyclopentanedione in
the presence of catalytic amount of TsOH.11 It was found
that both electron-rich and electron-deficient iodoaryl
enaminones 4 were suitable candidates for the intramolec-
ular coupling reactions, giving the desired carbazolones 3
in good yields. When enaminone 4g with two methyl
groups was employed, a good yield was obtained at ele-
vated reaction temperature (100 °C) and in the presence of
CuI (20 mol%) and L-proline (40 mol%, entry 7). Notice-
ably, the reaction of enaminone 4h, derived from 2-iodo-
5-nitrophenylamine, gave the corresponding carbazolone
3h in 61% yield, while using enaminone 4i derived from
2-iodo-4-nitro-phenylamine did not react under similar
conditions (entry 8 vs. entry 9). Under our optimized con-
ditions, reaction of enaminone 4j did not produce carba-
zolone 3j (entry 10). On the other hand, changing the base
to K2CO3 (2 equiv) gave 3j in 62% yield (entry 11). It is
possible that the use of KOH led to the hydrolysis of
methyl ester of 4j. When 1,3-cyclopentadione was used,
the corresponding tricyclic compounds 3l and 3m were
obtained in satisfactory yields (entries 13 and 14).
(8) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607.
(9) Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731.
(10) (a) Sy, W. Synth. Commun. 1992, 22, 3215. (b) Fujita, K.;
Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R.
Org. Lett. 2004, 16, 2785. (c) Crich, D.; Rumthao, S.
Tetrahedron 2004, 60, 1513.
(11) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215.
(12) Typical Experimental Procedure for the Synthesis of
N-2-Iodoaryl Enaminone 4
In summary, we reported here that CuI/L-proline was a
useful catalytic system for the intramolecular arylation of
N-2-iodoaryl enaminone compounds to afford carbazol-4-
ones and 3,4-dihydrocyclopental indole-1-ones. In con-
trast with previous processes,3,4b,5 the present reaction
worked at relatively low temperature, used an inexpensive
catalytic system, and was applicable to a wide variety of
substrates. The carbazol-4-ones and 3,4-dihydrocyclo-
pental indole-1-ones in great diversity were obtained in
good yields.
A mixture of 2-iodobenzenamine (2.18 g, 10 mmol), 1,3-
cyclohexanedione (1.12 g, 10 mmol), and TsOH·H2O (190
mg, 1 mmol) in 30 mL of toluene was refluxed for 6 h. The
cooled mixture was washed with H2O and brine and was
dried over Na2SO4. After removal of the solvent in vacuum,
the residue was chromatographed on silica gel using PE–
EtOAc (1:1) as the eluent to afford 3-(2¢-iodophenyl-
amino)cyclohex-2-enone (4a, 2.63 g, 84%)
Synthesis of Carbazol-4-one 3
A mixture of 3-(2¢-iodophenylamino)cyclohex-2-enone (4a,
313 mg, 1 mmol), CuI (19 mg, 0.1 mmol), L-proline (23 mg,
0.2 mmol), and KOH (224 mg, 4 mmol) in 4 mL of DMSO
was heated at 90 °C under nitrogen atmosphere for 24 h. The
cooled solution was poured into H2O and extracted with
EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. After removal of the solvent in
vacuum, the residue was chromatographed on silica gel
using PE–EtOAc (1:1) as the eluent to afford tetrahydro-
carbazol-4-one (3a, 170 mg, 92%).
Acknowledgment
The authors are grateful to National Natural Science Foundation of
China (grants 20502007 and 20602012) for their financial support.
References and Notes
(1) (a) Bouaziz, Z.; Nebois, P.; Poumaroux, A.; Fillion, H.
Heterocycles 2000, 52, 977. (b) Gao, Y.; Shen, D. WO
2006044232, 2006. (c) Coates, I. H.; Oxford, A. W.; North,
P. C.; Miller, T.; Baxter, A. D.; Hammond, K. I. EP 385721,
1990. (d) Li, X.; Vince, R. Bioorg. Med. Chem. 2006, 14,
2944.
Synlett 2007, No. 17, 2699–2702 © Thieme Stuttgart · New York