Gold-catalyzed conjugate addition type reaction of indoles with α,β-enones

Article abstract of DOI:10.1055/s-2004-822903

3-Unsubstituted indoles undergo regioselective alkylation at the 3-position of the indole nucleus through gold-catalyzed conjugated addition type reaction with α,β-enones. 3-Substituted indoles undergo C-2 alkylation. Sequential C-3/C-2 gold catalyzed alkylation of the indole with dibenzylidene acetone gives a polycyclic indole b-annulated with a seven-membered cycle.

Full text of DOI:10.1055/s-2004-822903

LETTER
944
Gold-Catalyzed Conjugate Addition Type Reaction of Indoles with a,b-Enones
G
old-CatalyzedCo
n
njugate
A
dd
t
ition
T
o
ype
R
eaction
n
of Indoles io Arcadi,*a Gabriele Bianchi,a Marco Chiarini,a Gaetano D’Anniballe,b Fabio Marinellia
a
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università di L’Aquila, Via Vetoio, Coppito Due, 67010 L’Aquila, Italy
b
Dompé Research Center, Località Campo di Pile, 67100 L’Aquila, Italy
Fax +39(0862)433753; E-mail: arcadi@univaq.it
Received 17 January 2004
Dedicated to Professor Luciano Caglioti on the occasion of his 70th birthday.
1,3-dimetyluracil was characterized10 and 5,5¢-diuracilyl
Abstract: 3-Unsubstituted indoles undergo regioselective alkyla-
tion at the 3-position of the indole nucleus through gold-catalyzed
conjugated addition type reaction with a,b-enones. 3-Substituted
indoles undergo C-2 alkylation. Sequential C-3/C-2 gold catalyzed
species from uracil and [AuCl4]– were synthesized.11 Sub-
stituted electron-rich arenes underwent AuCl3/silver salts
catalyzed C-H activation to give hydroarylation reaction
alkylation of the indole with dibenzylidene acetone gives a poly- with alkynes.12 The direct electrophilic attack of a
cyclic indole b-annulated with a seven-membered cycle.
gold(III) catalyst at the furan derivatives was suggested to
form a furyl-gold species which subsequently gave 1,4-
addition to Michael systems.13 Then, both the direct aura-
tion of indoles14 at C-3, or at the 2-position if C-3 is occu-
pied, and gold-catalyzed Friedel–Crafts-type process15
promises to allow a new approach to the C-alkylation of
the title heteroaromatics through gold-catalyzed conjugat-
ed addition type reaction to a,b-enones (Scheme 1).
Key words: gold catalysis, indoles, a,b-enones, conjugated addi-
tion
The development of new efficient, clean and selective
synthetic methods of indole derivatives continues to re-
ceive considerable attention due to their central role as
versatile building bocks in the synthesis of natural prod-
ucts and in the design of therapeutic agents.1 Their prepa-
ration through direct derivatization of the heteroaromatic
ring eliminates the need for establishing a reactive func-
tionality (cf. halogenation or stoichiometric metalation)
prior to C-C coupling, enabling further elaboration and
expansion of the core motif.2 The carbon-carbon bond for-
mation at C-3 of indoles could take advantage of the elec-
tron-rich nature of this position, which can be viewed as
possessing enamine-like character.3 Therefore, the totally
atom-efficient Michael addition reactions of indoles rep-
resent one of the most important carbon-carbon bond
forming reactions at their C-3 position. There are several
different metal-based Lewis acid catalysts available for
these Michael reactions.4 Nevertheless, some drawbacks
of the reported procedures as well as the achievement of
the substitution at the 2-position of the indole nucleus (3-
substituted indoles usually fail to give Michael adducts),
are spurring on the search of more efficient catalysts.5
Recently, gold(III) catalysts6 are emerging as powerful
Lewis acids and transition metal catalysts for various
chemical transformations.7 Furthermore, activation of C-
H bonds followed by C-C bond formation points out
unique catalytic properties of gold derivatives. A highly
efficient gold-catalyzed three component-coupling of al-
dehyde, alkyne, and amine via C-H activation was
achieved in water.8 Moreover, the activation of C-H bonds
of aromatic hydrocarbons by stoichiometric anhydrous
gold(III) chloride was demonstrated to give stable
arylgold(III) complexes.9 The organogold(III) complex of
O
R3
O
R2
R2
R3
2
R1
R1
NaAuCl4·2H2O, Ethanol
N
N
H
H
1
3
R1= H, Ph, Heteroaryl, Vinyl
R2= H, Ph; R3= Me, Ph, Vinyl
R1
R1
R3
O
2
NaAuCl4·2H2O, Ethanol
R2
N
N
H
H
4
5
R1= Alkyl, Aryl
Scheme 1
Indeed, 3-unsubstituted indoles 1a–f reacted with a,b-
enones 2a–f in the presence of a catalytic amount of
NaAuCl4·2H2O in ethanol16 to give the adduct 3a–m in
good to high yield (Table 1).17 The air-stable catalyst is
commercially available and has been used as purchased,
without further purification. The procedure does not re-
quire any acidic promoters or anhydrous conditions and
occur under neutral conditions. Aqueous workup and neu-
tralization are not necessary in our protocol. Even when
only 2.5 mol% of NaAuCl4·2H2O was used as catalyst, the
yield of isolated 3f was 79% after 24 hours at ambient
temperature; the starting indole 1a was recovered in 19%
yield (Table 1, entry 7).
SYNLETT 2004, No. 6, pp 0944–0950
0
6.
0
5.
2
0
0
4
Advanced online publication: 01.04.2004
DOI: 10.1055/s-2004-822903; Art ID: G02004ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Gold-Catalyzed Conjugate Addition Type Reaction of Indoles
945
Usually, the reactions of derivatives 1 with methyl-vinyl withdrawing groups such as 4,6-dichloroindole 1b afford-
ketone 2d proceed smoothly at ambient temperature with ed the corresponding 3-(3-oxoalkyl) derivative 3e in good
high selectivity [e.g., the reaction of 2-phenylindole 1c yield (Table 1, entry 5). Formation of N-alkylated indoles
with 2d in the presence of a catalytic amount of by conjugated addition was not observed.20 This impor-
NaAuCl4·2H2O (5 mol%) in ethanol accomplished the tant result provides a remarkable contrast to similar reac-
formation the adduct 3f in 95% yield after 1.5 hours with- tions under gold catalysis, where gold(I) and gold(III)
out dimerization and polymerization side reactions18 derivatives were found to catalyze aza-Michael reac-
(Table 1, entry 6). The Au(III) salt showed better catalytic tions.21 In the case of dibenzylidene acetone 2c, by chang-
activity than the Au(I) salt AuCl (Table 1, entry 8). With- ing the 1a/2c ratio, either the formation of bis-alkylated
out the addition of any catalyst the starting 1c was re- product 3c (Table 1, entry 3) or of the mono-alkylated 3m
covered unreacted (95%) after 24 hours at ambient (Scheme 2a and Table 1, entry 15) were isolated as main
temperature]. The precipitation of gold in the form of gold reaction products. Interestingly, in this latter case the
mirror could occasionally occur but this was always ob- polycyclic indole b-annulated with a seven-membered
served after the reaction was complete. The reaction of cycle 5a was isolated as a by-product. To shed light on
functionalized 3-unsubstituted indoles with cyclic enones this point 3m was reacted in ethanol in the presence of the
and a,b-disubstituted enones resulted in better yield at gold catalyst, leading to the formation of 5a (94% yield;
30 °C.19 In general, an equimolecular ratio of indole Scheme 2, reaction (b) and Table 1, entry 16).
derivative 1 and enone 2 were reacted. With regard to
indoles 1, the procedure is compatible with a variety of
functional groups. Even indolyl ring bearing two electron-
Table 1 Gold-Catalyzed Conjugated Addition of Indoles 1 to a,b-Enones 2a
Entry
1
Indole
a,b-Enone
Time (h)
1.5c
Product (yield, %)b
Ph
Ph
O
O
Ph
N
H
Ph
N
H
1a
1a
2a
3a (88)
2
1c
O
O
N
H
2b
3b (83)
3
4
1a
1a
1.5c
Ph
Ph
O
O
N
N
Ph
Ph
H
O
H
2c
3c (92)d
1.5
O
2d
2d
N
H
3d (72)
5
4
Cl
Cl
O
N
N
H
H
Cl
Cl
1b
3e (71)
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York

946
A. Arcadi et al.
LETTER
Table 1 Gold-Catalyzed Conjugated Addition of Indoles 1 to a,b-Enones 2a (continued)
Entry
6
Indole
a,b-Enone
Time (h)
24
Product (yield, %)b
2d
O
Ph
N
H
Ph
N
1c
1c
H
3f (95)
7
2d
24
3f (79)e
8
9
1c
1c
2d
24
8c
3f (64)f
O
O
Ph
Ph
Ph
N
2e
H
3g (92)
10
11
1c
1.5
O
O
Ph
N
2f
H
3h (85)
2d
2
O
N
S
H
1d
N
S
H
3i (69)
3j (72)
3k (87)
12
13
14
2d
2e
2a
2
O
O
O
Ph
N
H
Ph
1e
1e
N
H
1c
Ph
Ph
N
H
1.5c
Ph
Ph
N
H
1f
N
H
3l (79)
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York

LETTER
Gold-Catalyzed Conjugate Addition Type Reaction of Indoles
947
Table 1 Gold-Catalyzed Conjugated Addition of Indoles 1 to a,b-Enones 2a (continued)
Entry
15
Indole
a,b-Enone
Time (h)
1.5c
Product (yield, %)b
1a
2c
Ph
O
N
Ph
H
3m (63)g
16
3m
–
3
Ph
O
N
Ph
H
5a (94)h
5a (80)
17
18
1a
4a
2c
2f
6
6
N
N
H
H
O
5b (75)i
19
2f
3.5
OCH3
OCH3
N
N
H
H
O
4b
5c (58)i
a Procedure: 1/2/NaAuCl4·2H2O = 1:1:0.05 in EtOH at r.t. (0.38–0.89 mmol scale).
b Yields refer to single runs and are given for isolated products.
c 30 °C.
d 1a/2c/NaAuCl4·2H2O = 1:0.5:0.05.
e 1c/2d/NaAuCl4·2H2O = 1:1:0.025.
f 1c/2d/AuCl = 1:1:0.05.
g 1a/2c/NaAuCl4·2H2O = 1:2:0.05.
h 3m/NaAuCl4·2H2O = 1:0.05 at 60 °C.
i 60 °C.
Interestingly, a sequential one-pot protocol22 for the con- mation of 3m (5 mol% NaAuCl4·2H2O, ethanol, 30 °C).
version of 1a to 5a was then optimized as follows: 1a (1.0 After 2.5 hours the temperature was raised to 60 °C and
equiv) and 2c (2.0 equiv) underwent conjugate addition the reaction was left to stir for 3.5 hours to afford 5a in
reaction under the conditions previously used for the for- 80% isolated yields [Scheme 2, reaction (c)]. Combined
mono- (1H NMR) and bi-dimensional (COSY, HSQC
with multiplicity editing and HMBC) experiments,
Ph
O
Ph
performed at 600 MHz, allowed the assignment of 5a
resonances (diastereomeric mixture, 2.1:1 ratio). The
extension of the C-2 alkylation of 3-substituted indoles 4
through the intermolecular conjugated addition to a,b-
enones was then explored. Satisfactory yields were ob-
tained by reacting 3-alkyl- or 3-aryl substituted indole
4a,b with the cyclic a,b-enone 2f (Table 1, entries 18,
19).23
O
catalyst
(a)
1a
2c
+
+
N
H
Ph
5a (18%)
+ 3c (14%)
N
Ph
H
3m (63%)
catalyst
(b)
(c)
3m
2c
5a (94%)
5a (80%)
Even if a Friedel–Crafts-type mechanism can not be ruled
out, an initial auration of the indole derivative could ac-
count for the conjugated-additions type reaction of 3-un-
substituted indoles to a,b-enones as depicted in Scheme 3.
catalyst
1a
+
Scheme 2
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York

948
A. Arcadi et al.
LETTER
H+
AuCl2
R1
N
H
References
(1) (a) Joule, J. A. In Science of Synthesis, Vol. 10; Thomas, E.
J., Ed.; Thieme: Stuttgart, 2000, 361–652. (b) Gribble, G.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
O
R2
R3
1
6
2
(c) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17,
75.
(2) (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274.
(b) Beccalli, E. M.; Broggini, G. Tetrahedron Lett. 2003, 44,
1919.
AuCl3
O
R3
R2
O
(3) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. Synlett 2003, 2377.
(4) (a) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi,
A. J. Org. Chem. 2003, 68, 7126. (b) Bandini, M.; Fagioli,
M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A.
Tetrahedron Lett. 2003, 44, 5843. (c) Jørgensen, K. A.
Synthesis 2003, 1117. (d) Yadav, J. S.; Reddy, B. V. S.;
Satheesh, G. Tetrahedron Lett. 2003, 44, 8331. (e) Evans,
D. A.; Scheidt, K. A.; Fandrik, K. R.; Wai Lam, H.; Wu, J.
J. Am. Chem. Soc. 2003, 125, 10780. (f) Bandini, M.;
Fagioli, M.; Melloni, A.; Umani-Ronchi, A. Synthesis 2003,
397. (g) Bandini, M.; Cozzi, P. G.; Giacobini, M.;
Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org. Chem.
2002, 67, 3700. (h) Yadav, J. S.; Reddy, B. V. S.; Abraham,
S.; Sabitha, G. Synlett 2002, 1550. (i) Harrington, P. E.;
Kerr, M. A. Synlett 1996, 1047.
(5) (a) Bartoli, G.; Bertolacci, M.; Bosco, M.; Foglia, G.;
Giuliani, A.; Marcantoni, E.; Sembri, L.; Torregiani, E. J.
Org. Chem. 2003, 68, 4594. (b) Ji, S. H.; Wang, S.-Y.
Synlett 2003, 2074. (c) Ji, S. H.; Zhou, M.-F.; Gu, D.-G.;
Wang, S.-Y.; Loh, T.-P. Synlett 2003, 2077. (d) Reddy, A.
V.; Ravinder, K.; Goud, T. V.; Krishnaiah, P.; Raju, T. V.;
Venkateswarlu, Y. Tetrahedron Lett. 2003, 44, 6257.
(e) Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett.
2003, 44, 5115.
R3
AuCl2
R1
R2
N
H
7
R1
N
H
H+
3
Scheme 3
Regioselective direct electrophilic attack of the gold at the
indole forms an indolyl-gold species 6, which subsequent-
ly undergoes addition reaction to to a,b-enones to give the
s-alkyl-gold species 7. By contrast with the behavior of
the similar s-alkyl-palladium intermediates,24 which un-
dergo a b-H elimination reaction, the organo-gold deriva-
tive 7 is prone to protonation by the proton set free during
the electrophilic aromatic substitution step. b-H-Elimina-
tion reactions are slow with gold catalysis.25 Protonolysis
reaction of 6 liberates the adduct 3 and recycles the cata-
lyst. Support for the proposed mechanistic pathway is pro-
vided by the positive ion electrospray mass spectra (ESI-
MS) of the solution derived by mixing 1 with a stoichio-
metric amount of NaAuCl4·2H2O in MeCN which shows
the ion peaks at m/z = 348 and 350 with isotope distribu-
tion that match calculated patterns for [indolyl-AuCl]+.
On the other hand C-H activation at C-2 position of 3-sub-
stituted indoles under similar conditions results in 2-alky-
lation of the indole nucleus. Electrophilic metallation of
indoles is a useful method for achieving their substitu-
tion.26
(6) For a recent review on gold catalysis, see: Dyker, G. Angew.
Chem. Int. Ed. 2000, 39, 4237.
(7) (a) Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz,
S. J. Am. Chem. Soc. 2003, 125, 11925. (b) Dyker, G.;
Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem. Int. Ed.
2003, 42, 4399. (c) Asao, N.; Nogami, T.; Lee, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.
(d) Hashmi, A. S.; Ding, L.; Bats, J. W.; Fischer, P.; Frey, W.
Chem.–Eur. J. 2003, 9, 4339. (e) Mizushima, E.; Hayashi,
T.; Tanaka, M. Org. Lett. 2003, 5, 3349. (f) Abbiati, G.;
Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.;
Rossi, E. J. Org. Chem. 2003, 68, 6959. (g) Arcadi, A.;
Bianchi, G.; Di Giuseppe, G.; Marinelli, F. Green Chem.
2003, 5, 64. (h) Arcadi, A.; Chiarini, M.; Di Giuseppe, S.;
Marinelli, F. Synlett 2003, 203. (i) Krause, N.; Hoffmann-
Röder, A.; Canisius, J. Synthesis 2002, 1759. (j) Arcadi, A.;
Di Giuseppe, S.; Marinelli, F.; Rossi, E. Tetrahedron:
Asymmetry 2001, 12, 2715. (k) Arcadi, A.; Di Giuseppe, S.;
Marinelli, F.; Rossi, E. Adv. Synth. Catal. 2001, 343, 443.
(l) Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809.
(8) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
(9) Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem. Soc.,
Dalton Trans. 2001, 2330.
In conclusion, we have shown that NaAuCl4·2H2O is an
efficient catalyst for the regioselective alkylation at the 3-
position of of 3-unsubstituted indoles through conjugated
addition type reaction with a,b-enones. 3-Substituted in-
doles undergo C-2 alkylation.
Sequential C-3/C-2 gold catalyzed alkylation can, also,
occur. Direct regioselective C-H gold catalyzed activation
of heteroaromatics prefigures future extensions of this
chemistry in organic synthesis.
(10) Zamora, F.; Zangrado, E.; Furlan, M.; Randaccio, L.;
Lippert, B. J. Organomet. Chem. 1998, 552, 127.
(11) Zamora, F.; Amo-Ochoa, P.; Fischer, B.; Scimanski, A.;
Lippert, B. Angew. Chem. Int. Ed. 1999, 38, 2274.
(12) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485.
(13) Hasmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem. Int. Ed. 2000, 39, 2285.
Acknowledgment
Work carried out in the framework of the National Project ‘La
Catalisi dei Metalli di Transizione nello Sviluppo di Strategie
Sintetiche Innovative di Eterocicli’ supported by the Ministero
dell’Università e della Ricerca Scientifica e Tecnologica, Rome,
and by the University of L’Aquila.
(14) Formation of 3-indolylaurate species by aminoauration of 2-
alkynylanilines was suggested by: Iritani, K.; Matsubara, S.;
Utimoto, K. Tetrahedron Lett. 1988, 29, 1799.
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York

LETTER
Gold-Catalyzed Conjugate Addition Type Reaction of Indoles
949
(15) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. Adv. Synth.
Catal. 2003, 345, 1247.
130.01, 128.72, 128.52, 127.89, 127.73, 126.25, 122.49,
120.59, 37.33, 32.91, 29.80. MS: m/e (relative intensity) =
269 (63) [M+], 213 (100). 3j: IR (KBr): 3400, 1710 cm–1. 1H
NMR: d = 8.13 (bs, 1 H), 7.52–7.06 (m, 9 H), 6.04 (bs, 1 H),
3.15–3.07 (m, 2 H), 2.80–2.72 (m, 2 H), 2.50–1.95 (m, 7 H),
2.13 (s, 3 H). 13C NMR: d = 209.09, 146.37, 135.97, 135.13,
129.82, 128.65, 128.44, 127.15, 126.82, 126.19, 121.83,
119.30, 118.38, 110.63, 110.51, 44.79, 39.42, 33.67, 30.02,
29.83, 28.74, 19.10. MS: m/e (relative intensity) = 343 (100)
[M+], 286 (86). 3k: IR (neat): 3440, 1730 cm–1. 1H NMR:
d = 7.92 (bs, 1 H), 7.46–7.01 (m, 14 H), 6.02 (bs, 1 H), 5.08–
5.05 (m, 1 H), 3.43–3.36 (m, 2 H), 2.62–2.46 (m, 1 H), 2.16–
2.08 (m, 4 H), 2.06 (s, 3 H), 2.04–1.96 (m, 2 H). MS: m/e
(relative intensity) = 419 (38) [M+], 362 (100). 3l: IR (neat):
3380, 1680 cm–1. 1H NMR: d = 7.92 (d, J = 7.9 Hz, 1 H),
7.54–7.04 (m, 14 H), 5.17 (t, J = 7.3 Hz, 1 H), 4.01 (dd,
J = 16.7 and 6.9 Hz, 1 H), 3.93 (dd, J = 16.7 and 6.9 Hz, 1
H), 2.87–2.75 (m, 2 H), 1.62–1.58 (m, 2 H), 1.39–1.36 (m, 2
H), 0.92 (t, J = 7.3 Hz, 3 H). 13C NMR: d = 199.08, 144.26,
137.09, 136.34, 135.54, 132.84, 128.41, 128.18, 128.01,
127.47, 125.78, 120.70, 119.36, 119.08, 113.27, 110.50,
43.84, 36.59, 31.83, 26.02, 22.52, 13.82. EI-MS: m/e
(relative intensity) = 381 (30) [M+], 263 (100).
(16) General Procedure for the Synthesis of Indoles 3. To a 1:1
mol ratio solution of indole 1 and a,b-enone 2 in EtOH was
added NaAuCl4·2H2O (5 mol%). The resulting mixture was
allotted to react under stirring at r.t. or at 30 °C and the
reaction was monitored by TLC or GC-MS. After
completion, the solvent was removed by evaporation. To the
residue, acetone (few mL) was added to precipitate the
catalyst, which was separated by filtration. The filtrate was
concentrated and the crude products were purified by
chromatography on silica gel (230-400 mesh) eluting with n-
hexane/EtOAc mixtures.
(17) Selected data for 3b: IR (neat): 3420, 1725 cm–1. 1H NMR:
d = 8.25 (bs, 1 H), 7.64–7.60 (m, 1 H), 7.24–7.03 (m, 3 H),
6.80 (d, J = 2.3 Hz, 1 H), 3.47–3.40 (m, 1 H), 2.84–2.76 (m,
2 H), 1.95 (s, 3 H), 1.73–1.63 (m, 2 H), 1.25–1.15 (m, 4 H),
0.77 (t, J = 3.9 Hz, 3 H). 13C NMR: d = 209.51, 136.39,
126.34, 121.55, 121.26, 119.02, 118.86, 118.38, 111.31,
50.07, 35.49, 32.73, 30.24, 29.63, 22.51, 13.89. MS: m/e
(relative intensity) = 244 (100) [M + 1]+, 243 (35) [M+], 186
(63). 3c: IR (KBr): 3430, 1715 cm–1. 1H NMR
(diastereomeric mixture, 2:1 ratio): d = 7.80 (bs, 2 H), 7.39–
7.03 (m, 18 H), 6.73 (bs, 2 H), 4.82 (t, J = 7.4 Hz, 2 H), 3.24
(dd, J = 16.3 and 7.4 Hz, 2 H), 3.09 (dd, J = 16.3 and 7.4 Hz,
2 H);(diastereoisomer) d = 7.78 (bs, 2 H), 7.32–7.00 (m, 18
H), 6.69 (bs, 2 H), 4.82 (t, J = 7.4 Hz, 2 H), 3.19 (dd,
J = 16.3 and 7.5 Hz, 2 H), 3.09 (dd, J = 16.3 and 7.5 Hz, 2
H). 13C NMR (diastereomeric mixture, 2:1 ratio): d = 207.79,
143.97 136.65, 128.37, 127.66, 126.59, 126.19, 122.11,
121.62, 119.54, 119.45, 118.85, 111.09, 49.77, 38.12;
(diastereoisomer) d = 207.70, 144.15, 136.62, 128.43,
127.77, 126.64, 126.26, 122.11, 121.49, 119.50, 119.40,
118.78, 111.05, 49.90, 38.18. ESI-MS: m/e (relative
intensity) = 469 (100) [M + 1+]. 3e: IR (KBr): 3360, 1720
cm–1. 1H NMR: d = 8.28 (bs, 1 H), 7.44 (s, 1 H), 7.17 (s, 1
H), 7.04 (s, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.79 (t, J = 7.2
Hz, 2 H), 2.13 (s, 3 H). 13C NMR: d = 208.03, 135.59,
132.11, 129.09, 123.61, 121.49, 116.21, 117.06, 43.73,
29.99, 19.07. MS: m/e (relative intensity) = 259 (10) [M+],
257 (63) [M+], 256 (63) [M + 1]+, 255 (100) [M+], 214 (34),
213 (49), 212 (19), 200(83), 199 (100), 198 (39). 3f: IR
(KBr): 3400, 1710 cm–1. 1H NMR: d = 8.20 (bs, 1 H), 7.57–
7.14 (m, 9 H), 3.19–3.11 (m, 2 H), 2.79–2.71 (m, 2 H), 2.05
(s, 3 H). 13C NMR: d = 208.93, 135.86, 134.44, 132.97,
128.86, 128.66, 127.89, 127.68, 122.27, 119.59, 118.82,
111.55, 110.97, 44.45, 29.90, 18.70. MS: m/e (relative
intensity) = 264 (63) [M + 1]+, 207 (100). 3g: IR (KBr):
3360, 1710 cm–1. 1H NMR: d = 8.15 (s, 1 H), 7.62–7.10 (m,
14 H), 5.09 (t, J = 7.4 Hz, 1 H), 3.46 (dd, J = 16.4 and 7.4
Hz, 1 H), 3.37 (dd, J = 16.4 and 7.4 Hz, 1 H), 1.97 (s, 3 H).
13C NMR: d = 207.51, 144.45, 136.28, 135.73, 132.98,
128.81, 128.76, 128.43, 128.14, 127.70, 127.48, 126.05,
122.08, 120.61, 119.76, 114.03, 111.21, 49.31, 37.09, 30.31.
MS: m/e (relative intensity) = 339 (23) [M+], 283 (100). 3h:
IR (KBr): 3300, 1690 cm–1. 1H NMR: d = 8.14 (s, 1 H), 7.84
(d, J = 7.9 Hz, 1 H), 7.50–7.46 (m, 4 H), 7.44–7.40 (m, 2 H),
7.24 (t, J = 7.9 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 3.46–3.40
(tt, J = 12.9 and 4.1 Hz, 1 H), 3.14 (t, J = 13.6 Hz, 2 H),
2.62–2.45 (m, 2 H), 2.21–1.66 (m, 4 H). 13C NMR: d =
211.33, 136.29, 134.52, 132.97, 128.88, 128.75, 128.16,
126.94, 122.13, 120.10, 119.55, 115.11, 111.38, 48.11,
41.39, 37.14, 31.70, 25.87. MS: m/e (relative intensity) =
289 (100) [M+], 246 (49), 232 (74), 218 (58). 3i: IR (neat):
3360, 1715 cm–1. 1H NMR: d = 8.25 (bs, 1 H), 7.57–7.10 (m,
7 H), 3.26–3.18 (m, 2 H), 2.83–275 (m, 2 H), 2.12 (s, 3 H).
13C NMR: d = 207.45, 139.58, 132.00, 131.34, 130.88,
(18) Sundberg, R. J. In Indoles; Academic Press: London, 1996.
(19) Temperatures are reported as bath temperature.
(20) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
(21) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002,
4, 1319.
(22) Sequential Procedure for the Preparation of 5a. To a
solution of the indole 1a (0.072 g, 0.612 mmol) and the
trans,trans-dibenzylidene acetone 2c (0.287 g, 1.22 mmol)
in EtOH (3 mL) was added NaAuCl4·2H2O (0.012 g, 0.0306
mmol). The resulting mixture was allotted to react under
stirring at 30 °C. After 2 h, the temperature was raised at
60 °C and the heating was continued for 3 h after which the
reaction mixture was concentrated in vacuo. The residue was
purified by column chromatography eluting with n-hexane/
EtOAc 90/10 v/v mixture to afford 4a (0.17 g, 80% yield).
IR (KBr): 3440, 1720 cm–1. 1H NMR (diastereomeric
mixture, 2.1:1 ratio): major isomer: d = 7.56 (bs, NH, 1 H),
7.50–6.90 (m, Csp2-H, 14 H), 4.82 (t, J = 4.5 Hz, 10-CH, 1
H), 4.54 (dd, J = 2.3 and 12.1 Hz, 6-CH, 1 H), 3.40 (d,
J = 4.5 Hz, 9-CH, 2 H), 3.21 (dd, J = 12.1 and 15.5 Hz, 7-
CHa, 1 H) 2.73 (dd, J = 2.3 and 15.5 Hz, 7-CHb, 1 H); minor
isomer: d = 7.68 (bs, NH, 1 H), 7.50–6.90 (m, Csp2-H, 14 H),
4.86 (dd, X part of ABX system, 6-CH, 1 H), 4.78 (dd,
J = 4.5 and 7.9 Hz, 10-CH, 1 H), 3.47 (dd, J = 8.3 and 14.0
Hz, 9-CHa, 1 H), 3.08 (dd, J = 4.5 and 14.4 Hz, 9-CHb, 1 H),
3.18–3.09 (m, AB part of ABX system 7-CH, 2 H). 13
C
NMR: (diastereomeric mixture, 2.1:1 ratio): major isomer:
d = 209.97 (8-CO), 143.43 (1-CPha), 141.78 (1-CPhb), 136.57
(5a-C), 134.88 (4a-C), 129.26, 128.62 (10b-C), 128.60,
128.05, 127.71, 127.42, 126.45 (Pha and Phb), 122.13 (3-C),
119.71 (2-C), 118.63 (1-C), 113.65 (10a-C), 110.53 (4-C),
50.37 (7-C), 49.08 (9-C), 41.13 (6-C), 36.42 (10-C); minor
isomer: d = 209.43 (8-CO), 143.66 (1-CPha), 140.01 (1-CPhb),
136.04 (5a-C), 134.76 (4a-C), 129.19, 128.47 (10b-C),
128.18, 128.05, 127.45, 126.49 (Pha and Phb), 121.97 (3-C),
119.65 (2-C), 118.65 (1-C), 112.86 (10a-C), 110.53 (4-C),
50.06 (4-C), 49.93 (7-C), 41.02 (6-C), 38.63 (10-C). MS:
m/e (relative intensity) = 351 (100) [M+], 219 (47).
(23) Selected data for 5b: IR (neat): 3400, 1710 cm–1. 1H NMR:
d = 8.19 (bs, 1 H), 7.52–7.47 (m, 1 H), 7.28–7.24 (m, 1 H),
7.17–7.05 (m, 2 H), 3.30–3.25 (m, 1 H), 2.52–2.28 (m, 4 H),
2.21 (s, 3 H), 2.13–1.73 (m, 4 H). 13C NMR: d = 210.85,
136.03, 135.11, 129.01, 121.28, 119.08, 118.25, 110.43,
106.25, 47.09, 41.07, 36.34, 30.77, 25.33, 8.37. MS: m/e
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York

950
A. Arcadi et al.
LETTER
(24) (a) Itahara, T.; Kawasaki, K.; Ouseto, F. Synthesis 1984,
236. (b) Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc.,
Perkin Trans. 1 1983, 1361.
(25) Baker, R. T.; Nguyen, P.; Marder, T. B.; Westcott, S. A.
Angew Chem., Int. Ed. Engl. 1995, 34, 1336.
(relative intensity) = 227 (100) [M+]. 5c: IR (neat): 3390,
1710 cm–1. 1H NMR: d = 8.39 (bs, 1 H), 7.57–7.09 (m, 8 H),
3.85 (s, 3 H), 3.55–3.35 (m, 1 H), 2.63–2.58 (m, 2 H), 2.41–
2.16 (m, 2 H), 2.05–1.98 (m, 4 H). 13C NMR: d = 210.28,
158.21, 136.53, 135.20, 130.77, 128.03, 127.01, 121.98,
119.98, 119.20, 114.13, 113.86, 110.64, 55.29, 47.76, 41.10,
36.26, 31.72, 25.23. MS: m/e (relative intensity) = 319 (100)
[M+].
(26) (a) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545.
(b) Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J.
Org. Chem. 2003, 68, 7625.
Synlett 2004, No. 6, 944–950 © Thieme Stuttgart · New York