Communications
J . Org. Chem., Vol. 62, No. 9, 1997 2677
condensation of iodoaniline 1c with 2-methylcyclohex-
anone gave 2-methyltetrahydrocarbazole 6 in 68% yield
(entry 4). Reaction of 3-methylcyclohexanone with iodo-
aniline formed carbazole 7 predominantly (7/8; 8:1) (entry
5).
The reaction tolerates a variety of functional groups,
especially the acid-sensitive acetal (entry 6), carbamate
(entry 7), or benzyl triazole6a (entries 1, 3, and 4). These
intermediates, which would be unstable under the condi-
tions of the traditional Fischer indole reaction, were
conveniently synthesized using this method. The struc-
turally interesting indole 11 was prepared from 3-qui-
nuclidinone hydrochloride (1.0 equiv) in 55% yield (entry
8). The coupling of the indole nucleus onto a steroid was
also achieved with 5R-cholestanone (1.0 equiv), affording
12 exclusively in 79% yield (entry 9).
In order to obtain a reaction free of amine-derived
byproducts, an amine that would not be oxidized by
palladium was required. Applying Bredt’s rule,8 quinu-
clidine or DABCO should resist oxidation to the imine.
Direct coupling of o-iodoaniline (1a ) with cyclohexanone
in the presence of 5 mol % Pd(OAc)2 and 3 equiv of
DABCO as base successfully afforded the tetrahydrocar-
bazole 4a in 77% yield with no other major impurities
(Table 1). The use of DMF as solvent is crucial to the
success of the reaction; other solvents, such as acetonitrile
and toluene were ineffective.
The coupling of acyclic ketones is not as effective. For
example, only a 30% yield of 2 with excess acetone was
obtained. However, the coupling was quite successful
with pyruvic acid and acetylsilane (entries 10 and 11).
With pyruvic acid, 1a coupled efficiently to give 2-indole-
carboxylic acid (13) in 82% yield. Coupling of acetylsilane
gave a 2:1 mixture of 2-(trimethylsilyl)indole 14 and
indole (15) in a combined 64% yield. Evidently, the
reaction conditions cause some desilylation. Either the
carboxy12 or silyl group6a can be removed providing an
entry into 2-unsubstituted indoles.
Though most reactions proceeded efficiently in DMF
at 105 °C, the additive MgSO4 (1.5 equiv), presumably
acting as a dehydrating agent, was found to promote the
annulation in the more sluggish cases (entries 1, 2b, 4,
8, and 11).
In summary, we have discovered and demonstrated a
new and efficient method for the synthesis of indoles from
carbonyl compounds. In conjunction with the use of
alkynes in the palladium-catalyzed indolization,5,6a the
coupling of cyclic ketones widens the spectrum of indoles
that can be prepared by this means. The simple proce-
dure, mild reaction conditions, and availability of the
starting materials render this method a valuable addition
to indole chemistry.
This is the first example of a palladium-catalyzed
coupling of a simple ketone and an iodoaniline to prepare
an indole. Although 1,3-dicarbonyl systems have been
coupled to indoles,4 the reported reaction conditions did
not provide any coupling with cyclohexanone. In addi-
tion, it was necessary to preform the â-enaminone.
The generality of this reaction was investigated.9 The
desired indoles were readily prepared in 52-82% yields
from iodoanilines 1a -c10 and cyclic ketones (Table 1). In
addition to the coupling of cyclohexanones (entries 2, 4,
and 5), the reaction is also compatible with cyclopen-
tanone11 and cycloheptanone (entries 1 and 3). The
coupling reaction is highly regioselective. For instance,
W. B.; Guiblin, A. R.; J elley, R.; Reeve, A. J .; Routledge, H.; Sternfeld,
F.; Watt, A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A. J .; Stanton,
J . A.; Scholey, K.; Hargreaves, R. J .; Sohal, B.; Graham, M. I.; Matassa,
V. G. J . Med. Chem. 1995, 38, 1799.
(7) For the oxidation of amines with Pd(OAc)2, see: (a) McCrindle,
R.; Ferguson, G.; Arsenault, G. J .; McAlees, A. J .; Stephenson, D. K.
J . Chem. Res. Synop. 1984, 360. (b) Guram, A. S.; Rennels, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348. (c) Clark,
F. R. S.; Norman, R. O. C.; Thomas, C. B. J . Chem. Soc., Perkin Trans.
1 1975, 121.
(8) For a review of Bredt’s rule, see: Shea, K. J . Tetrahedron 1980,
36, 1683.
(9) A typical procedure follows: A mixture of iodoaniline (1a ) (2.19
g, 10 mmol), cyclohexanone (2.94 g, 30 mmol, 3 equiv), DABCO (3.36
g, 30 mmol, 3 equiv), and Pd(OAc)2 (112 mg, 0.5 mmol, 5 mol %) in
dry DMF (30 mL) was degassed via vacuum/nitrogen purges and
heated to 105 °C. The mixture was heated at 105 °C for 3 h or until
the reaction was complete (usually <12 h). The reaction mixture was
cooled to room temperature and partitioned between isopropyl acetate
(150 mL) and water (50 mL). The organic layer was separated, washed
with brine (50 mL), and concentrated under vacuum to dryness. The
residue was chromatographed and crystallized from isopropyl acetate-
heptane to give 1.32 g of tetrahydrocarbazole 4 (77%) as an off-white
solid: mp 119-120 °C (lit. mp 118-120 °C: Rogers, C. U.; Corson, B.
B Organic Synthesis; Wiley: New York, 1967; Collect. Vol. IV, p 884).
The ketone charge ranged from 1 to 3 equiv.
Ack n ow led gm en t. The authors wish to thank Pro-
fessors David A. Evans and Barry M. Trost for their
helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for the annulation of iodoaniline 1a and cyclohexanone,
and spectral data for compounds 3-12 (3 pages).
J O970278I
(10) Iodoaniline 1a is commercially available from Aldrich. Iodo-
anilines 1b and 1c were prepared from the corresponding anilines
using ICl-CaCO3 in methanol following the procedure in ref 6 in 86%
and 92% yield, respectively.
(11) The coupling reaction reported by Kibayashi4a failed with
cyclopentanedione.
(12) J ones, G. B.; Chapman, B. J . J . Org. Chem. 1993, 58, 5558.
Chen
