Stereoselective double friedel-crafts alkylation of indoles with divinyl ketones

Article abstract of DOI:10.1021/ol900014a

A tandem double Friedel-Crafts reaction of indoles and nonsymmetrical divinyl ketones has been achieved. The tandem reaction forms complex [6-5-7]-tricyclic indoles in excellent yields. The reaction is completely regioselective and offers high levels of s

Full text of DOI:10.1021/ol900014a

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1175-1178
Stereoselective Double Friedel-Crafts
Alkylation of Indoles with Divinyl
Ketones
Andrew C. Silvanus,† Stephen J. Heffernan,† David J. Liptrot,†
Gabriele Kociok-Ko¨hn,† Benjamin I. Andrews,‡ and David R. Carbery*,†
Department of Chemistry, UniVersity of Bath, Bath BA2 7AY, U.K. and
GlaxoSmithKline Medicines Research Centre, SteVenage, Hertfordshire SG1 2NY, U.K.
d.carbery@bath.ac.uk
Received January 5, 2009
ABSTRACT
A tandem double Friedel-Crafts reaction of indoles and nonsymmetrical divinyl ketones has been achieved. The tandem reaction forms
complex [6-5-7]-tricyclic indoles in excellent yields. The reaction is completely regioselective and offers high levels of syn diastereoselectivity.
The reaction is also seen to be sensitive to substrate structure and catalyst.
Indoles are an important class of molecule because of their
ubiquity in nature, their structural diversity, and the wealth
Scheme 1
.
Reaction of Divinyl Ketones and Double
Nucleophiles
of biological activity they possess.1 Therefore, the indole
nucleus has become a key component of pharmaceutical
molecules and is regarded as a privileged structure.2 As a
result of the simultaneous diversity of indole structure and
biology, the organic chemist continues to search for novel
indole scaffolds. To answer this issue, the ability to modify
simpler indoles in a rapid, diverse, and controlled manner
remains an important goal.3
Divinyl ketones are largely associated with the Nazarov
reaction for the synthesis of cyclopentenones.4 However,
divinyl ketones can also be viewed as double electrophiles,
capable of participating in two conjugate addition reactions.
More specifically, the use of a nucleophile with the capacity
for two nucleophilic reactions allows for the formation of
cyclic structures via an initial intermolecular reaction and
subsequent intramolecular reaction (Scheme 1).
† The University of Bath.
‡ GlaxoSmithKline.
(1) (a) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843. (b)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216. (c) Brancale, A.;
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Chem. 2006, 4, 3291.
For example, nucleophiles such as amines,5 water or
sulfides,6 selenides,7 active methylenes,8 and primary phos-
phines9 have all been used in this manner. However, in the
majority of cases, symmetrical divinyl ketones such as
dibenzylidene acetone have been used, leading to the
formation of symmetrical products of limited synthetic value.
Indoles can also be expected to fulfill the role of a double
nucleophile.10,11 It has been demonstrated that indole reacts
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893.
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10.1021/ol900014a CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society

Table 1. Initial Screening of Tandem Indole Friedel-Crafts
Table 2. Solvent and Brønsted Acid Catalyst Screena
Alkylation
time
(h)
yield (%)b
3:4:5
entry
solvent
acid
TsOH
drc
1
2
3
4
5
6
7
8
H2O
DMSO
Et2O
168
168
96
168
8
1
3
2
5
24
48
168
168
n.r.d
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
DNsOHe
MsOH
n.r.d
15:0:0
48:0:0
80:0:4
0:40:28
0:45:26
99:0:0
74:10:6
PhCH3
CHCl3
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
4.5:1
1:1
9
2:1
1:1
10
11
12
13
(PhO)2PO2H 30:26:19
CF3CO2H
PhCO2H
none
82:0:7
47:0:0
n.r.d
a Reactions performed at 85 °C; 5 mol % catalyst used. b Isolated yields.
syn:anti; measured by H NMR analysis of crude reaction mixture. d No
c
1
reaction observed, starting material recovered. e DNsOH: 2,4-dinitroben-
zenesulfonic acid.
entry solvent temp (°C) time (h) yield (%)a3:4:5
drb
1
2
3
4
5
MeCN
MeCN
MeOH
MeOH
MeOH
40
85
20
40
85
8
3
6
4
1
90:0:3
0:45:26
0:57:20
0:43:26
0:40:28
1:1
11:1
5.5:1
4.5:1
Scheme 2. Improved Two-Step, Solvent Substitution Protocol
a Isolated yields. b Measured by 1H NMR analysis of crude reaction
mixture.
with symmetrical divinyl ketones through the consecutive
addition of two molecules of indole at the enone moieties.12
However, there has been a single report of indole reacting
with a symmetrical divinyl ketone under gold catalysis to
form a fused tricyclic structure.13 We felt that employing
nonsymmetrical divinyl ketones would offer an opportunity
to form diverse and biologically interesting fused-tricyclic
indoles.
To explore this concept, indole 1a was reacted under acid
catalysis with divinyl ketone 2a, a nonsymmetrical electro-
phile with sterically and electronically differentiated enone
termini.14
Reaction in acetonitrile at 40 °C resulted in the chemose-
lective formation of the mono adduct 3a (Table 1, entry 1)
with exclusive attack of the indole on the methyl-substituted
enone terminus.15 Performing the reaction at higher temper-
ature afforded a mixture of cyclic 4a and bis 5a products
(Table 1, entry 2). The cyclic compound was formed with
complete regioselectivity (the positions of methyl and phenyl
relative to indole),16 but no diastereoselectivity was observed
(the syn/anti relationship of the methyl and phenyl groups).17
However, with methanol as solvent, the cyclic and bis
compounds were formed at room temperature, with consider-
able diastereoselectivity in favor of the syn isomer (dr )
11:1, table 1, entry 3). Increasing the temperature of the
reaction in methanol resulted in a drop of both cyclic
compound yield and chemoselectivity (Table 1, entries 4 and
5). After this initial success, a reaction optimization was
attempted with a number of variables screened (Table 2).
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1176
Org. Lett., Vol. 11, No. 5, 2009

Table 3. Exploration of Scope between Indoles and Divinyl Ketonesa
entry
R
Ar
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-MeO-Ph (2h)
4-Me-Ph (2i)
2-Me-Phf (2j)
4-Cl-Ph (2k)
4-CF3-Phf (2l)
time (h)b
yield 3 (%)
yield 4 (%)c
yield 5 (%)c
dr 4d
1
2
3
4
5
6
7
8
H (1a)
OMe (1b)
Me (1c)
Cl (1d)
F (1e)
CN (1f)
NO2 (1g)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
2 + 6
0.5 + 4
3 + 6
1.5 + 5
3 + 6
4.5 + 48
5 + 48
2 + 7
2 + 7
2 + 6
2 + 6
2 + 6
0
0
0
0
88 (4a)
81 (4b)
88 (4c)
86 (4d)
82 (4e)
0
6
9
6
7
9
0
20:1
10:1
11:1
9:1
0
12:1
99c (3f)
33c (3g)
0
33c (5g)
0
0
0
0
0
84 (4h)
89 (4i)
71 (4j)
93 (4k)
70 (4l)
6
3
13
2
10
8:1
8:1
23:1
14:1
17:1
9
10
11
12
a See Supporting Information for full experimental details. b Reaction times depicted as intermolecular reaction + intramolecular reaction. c Isolated
yield. d Measured by 1H NMR analysis relative to 4 in crude reaction mixture. e syn:anti; measured by 1H NMR analysis of crude reaction mixture. f Divinyl
ketones 2j and 2l were used as 2:1 E,Z/E,E mixtures.
Scheme 3. Partial Mechanistic Rationale for the Formation of
Fused Tricyclic Indoles from Divinyl Ketones
Figure 1. ORTEP plot of syn-4b (ellipsoids at 30% probability).
None of the alternative solvents improved the reaction
compared to methanol or acetonitrile (Table 2, entries 1-7).
A screen of Brønsted acids showed a trend between acid
strength and reaction rates: the lower the pKa the faster the
reaction (Table 2, entries 7-13). Of particular note was the
use of 2,4-dinitrobenzenesulfonic acid, which gave only
mono adduct 3a even at elevated temperature (Table 2, entry
8). Significantly, no Nazarov products were observed, despite
the fact that the Nazarov reaction is known to be promoted
by strong Brønsted acids.18-20
These observations were combined to give a practical two-
step procedure: the first step involves reaction in acetonitrile
resulting in the high-yielding formation of mono adduct 3a.
This was followed by a solvent swap to methanol and
cyclization to give a further improvement in diastereoselec-
tivity. This protocol minimizes the formation of bis adduct
5a and ensures high yields and excellent diastereoselectivities
(Scheme 2; Table 3, entry 1).
The syn diastereoisomer formed in this reaction appears
to be the kinetic product, as subjection of syn-4a (dr )
10:1) to 5 mol % DNsOH in refluxing MeOH for 5 h led to
a drop in dr to 1.6:1
The sense of diastereoselectivity was assigned by NOE
spectroscopy with an interaction observed between the
methyl group and the phenyl ring, indicating a syn relation-
ship between these two moieties. This assignment was
confirmed by X-ray diffraction analysis of methoxy deriva-
tive 4b (Figure 1).
Org. Lett., Vol. 11, No. 5, 2009
1177

To further explore the scope of this reaction, a number of
indole and divinyl ketone substrates were examined under
the new two-step conditions (Table 3).
In conclusion, a Brønsted acid catalyzed double Friedel-
Crafts reaction of indoles and nonsymmetrical divinyl
ketones is reported. The reaction forms complex fused-
tricyclic indole products in a highly regio- and diastereose-
lective manner, displaying a clear sensitivity to substrate
substitution. Studies directed toward absolute stereochemistry
control, mechanistic understanding, and expansion of the
substrate scope are currently ongoing in our laboratories and
will be reported in due course.
First, the effect of substitution at the C-5 position of indole
was investigated (Table 3, entries 1-7). A general trend was
observed, with electron-withdrawing substituents resulting
in a slower intermolecular conjugate addition. Also, strongly
electron-withdrawing groups prevented cyclization altogether
with only mono and bis adducts observed (Table 3, entries
6 and 7). Second, the aryl substituent of the divinyl ketone
was varied (Table 3, entries 8-12). In all cases, cyclization
proceeded in good yield with only small amounts of bis
adduct formed. The diastereoselectivity of the cyclization
was seen to improve with both increasing electron-withdraw-
ing aptitude and increasing steric bulk of the aryl substituents
(Table 3, entries 10 and 12).
We postulate that 4a forms through intramolecular cy-
clization to form spiroindoleninium intermediate II (Scheme
3). This cyclization occurs via a chair transition state and
establishes the syn relationship between the methyl and
phenyl groups. The benzylic group of spiroindoleninium
intermediate II then undergoes a C-3 to C-2 suprafacial
migration with retention of configuration,21-23 followed by
rearomatization to give the fused [6-5-7] ring system.24
Therefore the syn arrangement of methyl and phenyl groups
is preserved in the fused tricyclic indole product.
Acknowledgment. The authors are grateful to the EPSRC
and GSK for a studentship (A.C.S.). Pfizer and AstraZeneca
are gratefully acknowledged for unrestricted funding (D.J.L.).
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and CIF file for
structure 4b. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL900014A
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1178
Org. Lett., Vol. 11, No. 5, 2009