Synthesis of carbazoles by gold(I)-catalyzed carbocyclization of 2-(enynyl)indoles

Article abstract of DOI:10.1055/s-0030-1259537

A new synthetic protocol for carbazoles through gold(I)-catalyzed intramolecular hydroarylation of (Z)-2-(enynyl)indoles was achieved in good yields. The requisite (Z)-2-(enynyl)indoles were synthesized stereoselectively by trimethylgallium-promoted, Z-selective Wittig olefination of N-alkylindole-2-carboxaldehydes with propargyl ylides. Substrates possessing both alkyl as well as aromatic groups are well tolerated under these reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259537

LETTER
521
Synthesis of Carbazoles by Gold(I)-Catalyzed Carbocyclization of
2-(Enynyl)indoles
G
old(I)-Catalyz
e
h
Synthesis
o
a
f
Carbazol
n
e
s
drasekaran Praveen, Paramasivan Thirumalai Perumal*
Organic Chemistry Division, Central Leather Research Institute (CSIR Laboratory), Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 21 December 2010
volve the use of 3-substituted indole derivatives. We were
interested in the cyclization of 2-substituted indole deriv-
atives, since the C3 of indole is more nucleophilic. Our
initial investigations focused on the synthesis of the requi-
Abstract: A new synthetic protocol for carbazoles through gold(I)-
catalyzed intramolecular hydroarylation of (Z)-2-(enynyl)indoles
was achieved in good yields. The requisite (Z)-2-(enynyl)indoles
were synthesized stereoselectively by trimethylgallium-promoted,
Z-selective Wittig olefination of N-alkylindole-2-carboxaldehydes site 2-(enynyl)indoles by Wittig olefination of N-alkyl-
indole-2-carboxaldehydes7 3 with propargyl ylides8 4.
These substrates were synthesized in good yields by stan-
with propargyl ylides. Substrates possessing both alkyl as well as
aromatic groups are well tolerated under these reaction conditions.
Key words: (Z)-Wittig olefination, 2-(enynyl)indoles, gold cataly-
sis, carbocyclization, carbazoles
dard procedures (Scheme 2). To develop the general syn-
thesis of 2-(enynyl)indoles, Wittig reaction of model
substrates 3a and 4a promoted by n-BuLi (1.5 equiv,
–10 °C,THF) was performed (Scheme 3).
Carbazoles are important heterocyclic scaffolds that serve
as key components in a variety of natural products and bi-
ologically active molecules.1 Thus, it is not surprising that
several synthetic approaches to these molecules have been
described in the literature.2 In contrast, recent work has fo-
cused on the development of transition-metal-catalyzed
methods for the synthesis of carbazoles.3 Of particular
value are Rh(II)-catalyzed synthesis of carbazoles from
biaryl azides,3a Pd(II)-catalyzed cyclization of 2-pheny-
lacetanilides,3b Pd(II)-catalyzed cross-coupling reaction
of 2-iodoanilines with silylaryl triflates,3c Pd(II)-cata-
lyzed oxidative cyclization of 3-(3¢-alkenyl)indoles,3d
Pd(0)-catalyzed cross-coupling of alkynes and N-(3-
iodophenyl)anilines,3e Pd(0)-catalyzed tandem Suzuki
cross-coupling/SNAr of aniline-derived boronic ester with
1,2-dihalobenzene,3f Pd(II)-catalyzed oxidative C–H
bond amination of biaryls,3g and Pt(II)-catalyzed cycliza-
tion of 1-(indol-2-yl)-2,3-allenols.3h Typically, these pro-
tocols involve the use of palladium catalysts. While these
reactions are often useful, a catalytic protocol that accom-
plishes the intramolecular carbocyclization of 2-(eny-
nyl)indoles remains to be developed (Scheme 1). We felt
that such transformations promise to facilitate selective
construction of carbon–carbon bonds at the later stages in
the synthesis of drug molecules and/or natural products.
As part of our ongoing interest in the synthesis of novel
heterocyclic compounds4 under transition-metal cataly-
sis,4b–h we herein report the synthesis of carbazoles via
gold-catalyzed5 intramolecular carbocylization of 2-(eny-
nyl)indoles.
R2
R2
transition-metal catalyst
N
R1
2
N
R1
1
Scheme 1 Synthetic plan for carbazole
The desired enynl product was obtained in 92% yield as a
mixture of E- and Z-isomers in a 45:55 ratio. The isomers
were separated by column chromatography and character-
ized by their spectroscopic data. In the 1H NMR spectrum
of compound 1a¢, the olefinic protons can be readily as-
signed by the appearance of two distinct doublets at d =
6.23 and 6.96 ppm, with coupling constants J = 15.3 and
16.0 Hz, respectively. Similarly, in isomer 1a, the olefinic
protons resonated as two distinct doublets at d = 5.77 and
6.70 ppm, both with coupling constants of J = 11.4 Hz.
Since the coupling constant values for isomer 1a¢ were
greater than for 1a, we assigned 1a¢ as the E- and 1a as Z-
isomer, respectively. Because the alkyne function is in
proximity to the nucleophilic C3-carbon of indole in the
Z-isomer 1a, we believed that it might favor the intramo-
lecular cyclization. For this reason, we focused only on
the catalytic cyclization of Z-isomer 1a leading to the
product 2a by employing nitromethane as solvent at
60 °C. The results, given in Table 1, revealed that 5 mol%
AuCl3, PtBr2, and AgSbF6, respectively, did not led to
product formation (entries 1, 6 and 7). However, the com-
bination of a gold catalyst with a silver co-catalyst9 result-
ed in the formation of the expected product (entries 2–5
and 8). Fruitful results, in terms of product yield, were ob-
tained when 5 mol% AuCl(Ph3P) in combination with 5
mol% AgSbF6 was used as the catalytic system (entry
Recently, gold-catalyzed intramolecular hydroarylation
of indole-tethered propargyl esters6a and propargyl
amines6b have been disclosed. Both of these methods in-
SYNLETT 2011, No. 4, pp 0521–0524
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259537; Art ID: G35010ST
© Georg Thieme Verlag Stuttgart · New York

522
C. Praveen, P. T. Perumal
LETTER
R3
R3
(i) NaH (2.0 equiv), DMF 0 °C, N2
(ii) R2X (3.0 equiv), 0 °C to r.t., N2
cat. H2SO4
COOH
COOMe
MeOH, reflux, 24 h
N
H
N
H
R3
R3
R3
MnO2 (4.0 equiv)
LiAlH4 (0.5 equiv)
COOMe
CHO
CH2OH
CH2Cl2, reflux, 12 h
THF, 0 °C to r.t., N2
N
N
N
R2
R2
R2
3
R1
R1
R1
Ph3P (2.0 equiv)
Br2 (1.5 equiv), Ph3P (2.0 equiv)
CH2Cl2, 0 °C to r.t., N2
toluene, r.t., 24 h
OH
+PPh3Br–
Br
4
Scheme 2 Synthesis of N-alkylindole-2-carboxaldehydes 3 and propargyl ylides 4
mer being formed in 14%. Application of the TMG-pro-
moted Wittig reaction conditions to all the tested
substrates yielded (Z)-2-(enynyl)indoles as the major iso-
mer in good chemical yields.12 With a satisfactory proce-
dure for the stereoselective synthesis of (Z)-2-
(enynyl)indoles in hand, we next turned our attention to
the cyclization of various (Z)-2-(enynyl)indoles under our
previously optimized gold-catalyzed cyclization condi-
tions (Table 1, entry 3).13
+
CHO
N
+PPh3Br–
Me
3a
4a
n-BuLi (1.5 equiv)
–10 °C, THF, N2
92% yield
Table 1 Screening of Carbophilic Lewis Acids for the Carbocy-
clization of (Z)-(Enynyl)indole 1aa
+
Yield (%)b
N
N
Entry
Catalyst
Me
1a' (45%)
Me
1a (55%)
1
2
3
4
5
6
7
8
5 mol% AuCl3
–
5 mol% AuCl3, 5 mol% AgSbF6
5 mol% AuCl(PPh3), 5 mol% AgSbF6
5 mol% AuCl(PPh3), 5 mol% AgBF4
5 mol% AuCl(PPh3), 5 mol% AgOTf
5 mol% PtBr2
20
81
60
35
–
Scheme 3 n-BuLi-promoted Wittig olefination of 3a
3).10 The 1H NMR spectrum of product 2a in CDCl3, ex-
hibited a sharp singlet at d = 2.97 ppm that indicated the
presence of methyl protons attached to an aryl ring. In the
13C NMR spectrum, a peak at d = 20.9 ppm confirmed the
presence of a methyl group attached directly to an aryl
ring. Having optimized the reaction conditions, we ap-
plied the same conditions for the sequential isomerization/
carbocyclization of a mixture of Z- and E-isomers (1a and
1a¢). We found that only the Z-isomer underwent the reac-
tion, and the unreacted E-isomer was recovered quantita-
tively (Scheme 4).
5 mol% AgSbF6
–
5 mol% AuCl(Me3P), 5 mol% AgSbF6
55
a All reactions were carried out in nitromethane at 60 °C under N2.
b Isolated yield.
In order to circumvent this limitation, we envisaged the
stereoselective synthesis of (Z)-2-(enynl)indoles. Recent-
ly, Nishimura et al. reported the Z-selective Wittig reac-
tion of aromatic aldehydes with propargyl ylides using
trimethylgallium (TMG) as base.11 By applying the same
reaction conditions on model substrates 3a and 4a, to our
delight, we obtained the products in excellent overall
yield with the Z-isomer being formed in 79% and E-iso-
Starting materials with a wide range of alkyl substituents
on the indole nitrogen as well as on the alkyne functional-
ity all gave good yields of product (Table 2, entries 1–19).
The reaction time and product yield for all substrates were
found to be similar, irrespective of the nature of the sub-
stituents. However, alkynes possessing aryl groups result-
ed in only moderate yield of products even after a long
AuCl(PPh3P) (5 mol%), AgSbF6 (5 mol%)
1a'
40%
(recovered yield)
1a
55%
+
2a
45%
(obtained yield)
1a'
45%
+
MeNO2, 60 °C, N2
30 min
Scheme 4 Carbocyclization of a mixture of E- and Z-isomers (1a¢ and 1a)
Synlett 2011, No. 4, 521–524 © Thieme Stuttgart · New York

LETTER
Gold(I)-Catalyzed Synthesis of Carbazoles
523
R1
R1
reaction time (entry 20). We also expect that, using this
protocol, substrates such as bromoindoles could lead to
the formation of bromocarbazoles, which could subse-
quently be cross-coupled.14
[Au]
R3
R3
[Au]
••
N
R2
N
Table 2 Gold(I)-Catalyzed Carbocyclization of (Z)-2-(Enynyl)in-
dole 1 to Carbazole 2a
R2
1
1I
Entry (Z)-2-(Enynyl) R1
indole (1)
R2
R3
Carbazole Time Yield
(2)b
2a
2b
2c
2d
2e
2f
(h)
(%)c
[Au]–
1
2
1a
1b
1c
1d
1e
1f
Me
Et
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.30 81
0.20 80
0.20 79
0.20 78
0.45 78
0.40 80
R1
R1
H
R3
R3
3
Pr
– [Au]
N+
R2
N
R2
4
Bu
2
1II
5
pentyl Me
Scheme 5 Tentative mechanism
6
Me
Et
Et
Et
Et
with structurally diverse carbocycles is underway and will
be reported in due course.
7
1g
1h
1i
2g
2h
2i
1.0
79
8
Pr
0.50 73
0.45 75
0.45 75
0.30 80
0.20 77
0.30 78
0.30 71
0.20 83
0.20 80
0.20 76
0.30 75
0.30 74
1.30 50
9
pentyl Et
hexyl Et
Acknowledgment
10
11
12
13
14
15
16
17
18
19
20
1j
2j
One of the authors (C.P.), thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for a research
fellowship.
1k
1l
Me
Et
Bu
Bu
Bu
Bn
Me
Me
Et
2k
2l
References and Notes
1m
1n
1o
1p
1q
1r
1s
1t
Pr
2m
2n
(1) (a) Ito, C.; Itoigawa, M.; Aizawa, K.; Yoshida, K.;
Ruangrungsi, N.; Furukawa, H. J. Nat. Prod. 2009, 72,
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Lancelot, J.-C.; El-Kashef, H.; Sinicropi, M. S.; Legay, R.;
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(d) Mal, D.; Senapathi, B. K.; Pahari, P. Tetrahedron 2007,
63, 3768. (e) Fousteris, M. A.; Papakyriakou, A.;
Me
Me
Et
MeO 2o
MeO 2p
Me 2q
Me 2r
Me 2s
Me 2t
Et
hexyl Et
Et Bu
p-tolyl Me
Koutsourea, A.; Manioudaki, M.; Lampropoulou, E.;
Papadimitriou, E.; Spyroulias, G. A.; Nikolaropoulos, S. S.
J. Med. Chem. 2008, 51, 1048. (f) Knöll, J.; Knölker, H.-J.
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a All reactions were carried out at 60 °C in nitromethane using 5 mol%
AuCl(Ph3P) and 5 mol% AgSbF6.
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(3) (a) Stokes, B. J.; Jovanović, B.; Dong, H.; Richert, K. J.;
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S.; Perumal, P. T. Synlett 2009, 2795. (f) Praveen, C.;
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(g) Praveen, C.; Iyyappan, C.; Perumal, P. T. Tetrahedron
b All products were characterized by IR, 1H NMR, 13C NMR and mass
spectroscopy.
c Isolated yield.
A tentative mechanism to explain the formation of carba-
zole 2 is given in Scheme 5.15 The carbophilic gold cata-
lyst activates alkyne 1 to form a -complex intermediate 1I.
Subsequent nucleophilic attack of the C3-carbon of indole
leads to the 6-endo-dig intermediate 1II. The latter spe-
cies, upon proto-deauration, results in the formation of
carbazole 2.
In summary, an efficient gold-catalyzed protocol for the
carbocyclization of (Z)-2-(enynl)indoles to carbazoles has
been developed. This method offers advantages including
moderate reaction conditions and no formation of by-
products. Further exploration of these transformations
Synlett 2011, No. 4, 521–524 © Thieme Stuttgart · New York

524
C. Praveen, P. T. Perumal
LETTER
mixture was added a solution of N-methylindole-2-
Lett. 2010, 51, 4767. (h) Praveen, C.; Dheenkumar, P.;
Perumal, P. T. Bioorg. Med. Chem. Lett. 2010, 20, 7292.
(i) Praveen, C.; Parthasarathy, K.; Perumal, P. T. Synlett
2010, 1635.
carboxaldehyde (3a; 158 mg, 1.00 mmoL) in THF (5 mL)
and stirring was continued for 5 h. After completion of the
reaction as indicated by TLC, the reaction was quenched
with ice-cold water and extracted with EtOAc (3 × 20 mL).
The organic layer was dried over anhydrous sodium sulfate,
concentrated under reduced pressure, and purified by
column chromatography over silica gel (100–200 mesh) to
afford the pure Z-isomer (154 mg, 79%) and E-isomer (27
mg, 14%). 1-Methyl-2-[(Z)-pent-1-en-3-ynyl]-1H-indole
(1a¢): Brown paste. IR (neat): 2928, 1733, 1430, 1224, 1119
cm–1. 1H NMR (CDCl3, 500 MHz): d = 2.21 (s, 3 H, CH3),
3.71 (s, 3 H, NCH3), 5.77 (d, J = 11.4 Hz, 1 H, indolyl-
CH=CH), 6.70 (d, J = 11.4 Hz, 1 H, indolyl-CH=CH), 7.14–
7.15 (m, 1 H, ArH), 7.21–7.30 (m, 2 H, ArH), 7.55 (s, 1 H,
indolyl-C(3)H), 7.69 (d, J = 7.6 Hz, 1 H, ArH). 13C NMR
(CDCl3, 125 MHz): d = 5.2, 29.5, 78.9, 95.5, 102.9, 108.5,
109.3, 119.9, 121.2, 122.5, 125.3, 127.8, 128.5, 136.1. MS
(EI): m/z = 195 [M+]. Anal. Calcd for C14H13N: C, 86.12; H,
6.71; N, 7.17. Found: C, 85.98; H, 6.76; N, 7.17. 1-Methyl-
2-[(E)-pent-1-en-3-ynyl]-1H-indole(1a): Black paste.
IR (neat): 2917, 1735, 1425, 1222, 1123 cm–1. 1H NMR
(CDCl3, 500 MHz): d = 2.08 (s, 3 H, CH3), 3.78 (s, 3 H,
NCH3), 6.23 (d, J = 15.3 Hz, 1 H, indolyl-CH=CH), 6.75 (s,
1 H, indolyl-C(3)H), 6.96 (d, J = 16.05 Hz, 1 H, indolyl-
CH=CH), 7.12 (t, J = 7.6 Hz, 1 H, ArH), 7.23 (t, J = 7.6 Hz,
1 H, ArH), 7.28 (d, J = 8.4 Hz, 1 H, ArH), 7.59 (d,
J = 7.6 Hz, 1 H, ArH). 13C NMR (CDCl3, 125 MHz): d = 4.7,
29.8, 79.3, 89.5, 99.3, 109.3, 110.4, 120.1, 120.7, 122.2,
127.8, 128.5, 137.4, 138.3. MS (EI): m/z = 195 [M+]. Anal.
Calcd for C14H13N: C, 86.12; H, 6.71; N, 7.17. Found: C,
86.25; H, 6.65; N, 7.10
(5) (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. 2006,
118, 8064. (b) Hashmi, A. S. K.; Hutchings, G. J. Angew.
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(b) Ferrer, C.; Echavarren, A. M. Angew. Chem. Int. Ed.
2006, 45, 1105.
(7) Despite the commercial availability of some N-alkylindole-
2-carboxaldehydes, we prepared other N-substituted indole-
2-carboxaldehydes in our laboratory using literature
procedures, see: (a) Benincori, T.; Marchesi, A.; Pilati, T.;
Ponti, A.; Rizzo, S.; Sannicolò, F. Chem. Eur. J. 2009, 15,
94. (b) Tsotinis, A.; Afroudakis, P. A.; Davidson, K.;
Prashar, A.; Sugden, D. J. Med. Chem. 2007, 50, 6436.
(c) Sechi, M.; Derudas, M.; Dallocchio, R.; Dessì, A.;
Bacchi, A.; Sannia, L.; Carta, F.; Palomba, M.; Ragab, O.;
Chan, C.; Shoemaker, R.; Sei, S.; Dayam, R.; Neamati, N.
J. Med. Chem. 2004, 47, 5298. (d) Li, C.-F.; Liu, H.; Liao,
J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9,
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Sugino, E.; Hibino, S. J. Org. Chem. 1997, 62, 2535.
(8) For the bromination of propargyl alcohols, see: (a) Kwong,
F. Y.; Lee, H. W.; Qiu, L.; Lam, W. H.; Li, Y.-M.; Kwong,
H. L.; Chan, A. S. C. Adv. Synth. Catal. 2005, 347, 1750.
(9) For the synthetic applicability of Au/Ag catalytic systems,
see: (a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 18002. (b) Enomoto, T.;
Obika, S.; Yasui, Y.; Takemoto, Y. Synlett 2008, 1647.
(c) Lee, J. H.; Toste, F. D. Angew. Chem. Int. Ed. 2007, 46,
912. (d) Horino, Y.; Luzung, M. R.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 11364. (e) Ito, Y.; Sawamura, M.;
Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (f) Shi, Z.;
He, C. J. Am. Chem. Soc. 2004, 126, 5964. (g) Hashmi, A.
S. K.; Blanco, M. C.; Kurpejović, E.; Frey, W. Adv. Synth.
Catal. 2006, 348, 709. (h) Hashmi, A. S. K. In Silver in
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2010, Chap. 12, 357–379.
(10) For the use of gold catalysis in hydroarylation reactions,
see: (a) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003,
3485. (b) Tarselli, M. A.; Liu, A.; Gagné, M. R. Tetrahedron
2009, 65, 1785. (c) Shi, Z.; He, C. J. Org. Chem. 2004, 69,
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(13) Typical procedure for the carbocyclization of (Z)-(2-
enynyl) indoles: To an air-dried Schlenk flask under N2
atmosphere was added 5 mol% AuCl(Ph3P) and 5 mol%
AgSbF6, followed by nitromethane (1 mL) and the mixture
was stirred for 15 min at room temperature. A solution of 5a
(1.0 mmoL) in nitromethane (2 mL) was added and the
mixture was stirred at 60 °C. After completion of the
reaction as indicated by TLC, the reaction was quenched in
water and extracted with EtOAc (3 × 20 mL). The organic
layer was dried with anhydrous Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by
column chromatography to afford pure 4,9-dimethyl-
carbazole (2a) as a colorless solid. Mp 105–106 °C (Lit.16
105–105.5 °C). IR (KBr): 3055, 3025, 2952, 2928, 2855,
1625, 1599, 1560, 1467, 1420, 1132 cm–1. 1H NMR (500
MHz, CDCl3): d = 2.97 (s, 3 H, Ar-CH3), 3.89 (s, 3 H,
NCH3), 7.09–7.13 (m, 1 H, ArH), 7.30–7.35 (m, 2 H, ArH),
7.45–7.50 (m, 1 H, ArH), 7.55–7.59 (m, 1 H, ArH), 8.25–
8.29 (m, 1 H, ArH). 13C NMR (125 MHz, CDCl3): d = 20.9,
29.1, 106.2, 108.4, 119.0, 120.7, 121.5, 122.5, 123.6, 125.2,
125.6, 133.6, 141.1, 141.2. MS (EI): m/z = 195 [M+]. Anal.
Calcd for C14H13N: C, 86.12; H, 6.70; N, 7.08. Found: C,
85.95; H, 6.75; 7.20
(11) Nishimura, Y.; Shiraishi, T.; Yamaguchi, M. Tetrahedron
Lett. 2008, 49, 3492.
(12) Typical procedure for the Z-selective Wittig olefination:
To a degassed solution of propargyl ylide 4a (395 mg, 1.2
mmoL) in anhydrous THF (5 mL) under an N2 atmosphere,
was added Me3Ga (1.0 M in hexane, 1.5 mL, 1.5 mmoL) and
the mixture was stirred for 10 min at 0 °C. To this reaction
(14) Hashmi, A. S. K.; Salathé, R.; Frey, W. Eur. J. Org. Chem.
2007, 1648.
(15) (a) Hashmi, A. S. K. Angew. Chem. 2010, 122, 5360.
(b) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2010, 49, 5232.
(16) Hoffmann, D.; Rathkamp, G.; Nesnow, S. Anal. Chem.
1969, 41, 1256.
Synlett 2011, No. 4, 521–524 © Thieme Stuttgart · New York

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