Electrophilic allylations and benzylations of indoles in neutral aqueous or alcoholic solutions

Article abstract of DOI:10.1021/ol0618555

(Chemical Equation Presented) Indoles are allylated and benzylated in moderate to quantitative yield when stirred with allyl and benzyl halides in 80% aqueous acetone in the presence of NH₄HCO₃ at room temperature.

Full text of DOI:10.1021/ol0618555

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4791-4794
Electrophilic Allylations and
Benzylations of Indoles in Neutral
Aqueous or Alcoholic Solutions‡
Martin Westermaier and Herbert Mayr*
Department Chemie und Biochemie, Ludwig Maximilians UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13 (Haus F), 81377 Mu¨nchen, Germany
herbert.mayr@cup.uni-muenchen.de
Received July 27, 2006
ABSTRACT
Indoles are allylated and benzylated in moderate to quantitative yield when stirred with allyl and benzyl halides in 80% aqueous acetone in
the presence of NH4HCO3 at room temperature.
Facile access to substituted indoles is of general interest
because indoles are building blocks of many natural products
and have applications as pharmaceuticals, as agrochemicals,
and in materials science.1,2 Among the numerous methods
to synthesize substituted indoles, substitution reactions play
an important role, among which Friedel-Crafts-type reac-
tions are relatively rare. Although the BF3‚OEt2-induced
prenylation of indole with prenyl pyrophosphate gave only
26% of 3-prenylated indoles,3a electrophilic allylations of
indoles with allyl bromides in the presence of 1.2 equiv of
zinc triflate, tetrabutylammonium iodide (1 equiv), and
Hu¨nig’s base (2.2 equiv) in toluene have been reported to
give 30-69% of 3-allylated products.3b Transition-metal-
catalyzed allylations at the 3-position have been performed
with Mo(II),4a Ni(II),4b and Pd(0) or Pd(II) complexes,4c,d
and Pd-catalyzed allylations of 3-substituted indoles have
also been used for the enantioselective synthesis of 3,3-
disubstituted 3H-indoles.4e An alternative approach employs
zinc- or gallium-mediated Barbier reactions,5 where the
initially formed allylmetal compounds deprotonate indoles
to yield N-metalated indoles, which act as nucleophiles in
the succeeding SN2 reactions to give good yields of the
3-allylated indoles.6 In contrast, Li and Na salts of indoles
are predominantly alkylated and allylated at nitrogen.7 The
(4) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
Kocˇovsky´, P. J. Org. Chem. 1999, 64, 2751-2764. (b) Wenkert, E.; Angell,
E. C.; Ferreira, V. F.; Michelotti, E. L.; Piettre, S. R.; Sheu, J.-H.; Ch.
Swindell, C. S. J. Org. Chem. 1986, 51, 2343-2351. (c) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199-3202. (d) Kimura,
M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127,
4592-4593. (e) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128,
6314-6315.
(5) (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. M.; Srinivas, C.
Tetrahedron Lett. 2002, 43, 5185-5187. (b) Prajapati, D.; Gohain, M.;
Gogoi, B. J. Tetrahedron Lett. 2006, 47, 3535-3539.
(6) For reactions of indolylmagnesium salts with allyl halides, see also:
(a) Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127-130. (b) Mirand, C.; Do¨e´
de Maindreville, M.; Le´vy, J. Tetrahedron Lett. 1985, 26, 3985-3988.
(7) (a) Bocchi, V.; Casnati, G.; Dossena, A.; Villani, F. Synthesis 1976,
414-416. (b) Guida, W. C.; Mathre, D. J. J. Org. Chem. 1980, 45, 3172-
3176. (c) Bourak, M.; Gallo, R. Heterocycles 1990, 31, 447-457.
‡ Dedicated to Professor Rolf Gleiter on the occasion of his 70th birthday.
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (b)
Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York,
1970. (c) Jones, R. A. In ComprehensiVe Heterocyclic Chemistry; Pergamon
Press: Oxford, 1984; Vol. 4, Chapter 3.05. (d) Katritzky, A. R.; Taylor, R.
AdV. Heterocycl. Chem. 1990, 47, 87-137. (e) Black, D. S. C. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Bird, C. W., Eds.; Pergamon: Oxford, 1996; Chapter
2.02.
(2) (a) Yamamoto, H. In Lewis Acids in Organic Synthesis; Wiley-
VCH: Weinheim, 2000. (b) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-
Ronchi, A. Synlett 2005, 1199-1222.
(3) (a) Araki, S.; Manabe, S.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1984,
57, 1433-1434. (b) Zhu, X.; Ganesan, A. J. Org. Chem. 2002, 67, 2705-
2708.
10.1021/ol0618555 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/22/2006

3-allylation of N-substituted indoles has also been achieved
via 3-halogenation followed by halogen-metal exchange and
consecutive treatment with allyl halides.8 The isolation of
up to 30% 3-prenylindole from indole and prenyl bromide
in buffered aqueous solutions by Casnati and co-workers9 is
of particular interest for this investigation because this
observation indicates that indole can successively compete
with the buffer system in the trapping of the intermediate
prenyl cation.
Scheme 2. Reactions of Indoles with Allyl and Benzyl
Halides 4-10
We now report a novel approach to 3-substituted indoles
which compares well with the best yields obtained previously
but considerably exceeds previous methods with respect to
its simplicity.
Previously, we have shown that the rates of the reactions
of carbocations with n-, π-, and σ-nucleophiles can be
described by eq 1.10
various conditions (Scheme 2). Acid catalysis by the liberated
HCl was excluded by performing the reactions in the
presence of a base. Bisallylation was avoided by employing
5 equiv of 1a. Table 1 shows that comparable yields of
Table 1. Product Ratios and Yields of the Reaction of Indole
(1a) with (E)-4-Chloro-pent-2-ene (2) Isolated after 1 h at
Ambient Temperature
log k ) s(N + E)
(1)
In eq 1, k is a second-order rate constant at 20 °C (M-1
s-1), s is a nucleophile-specific slope parameter, N a
nucleophile-specific parameter, and E is an electrophile-
specific parameter.
Because eq 1 also holds for the reactions of carbocations
with solvents,11 it can be employed to predict the relative
reactivities of π-nucleophiles and solvents toward carboca-
tions which are generated as intermediates of SN1 processes.
Stimulated by our reactivity scales which revealed that many
electron-rich π-systems were more nucleophilic than aqueous
acetone or aqueous acetonitrile,11,12 we have recently intro-
duced a novel protocol for Friedel-Crafts alkylations under
neutral or slightly basic conditions by trapping the intermedi-
ates of SN1 reactions in aqueous solutions with electron-
rich π-systems.13
We now report that this method can be employed for the
mild and efficient allylation and benzylation of indoles by
dissolving indoles and SN1 active allyl and benzyl halides
in aqueous acetone or acetonitrile in the presence of a base
(Scheme 1).
ratio
yield
no.
solventa
baseb
3a:3bc
3a + 3bd (%)
1
2
3
4
5
6
7
8
90AN10W
90AN10W
90AN10W
80A20W
80A20W
80A20W
80A20W
TFE
Na2CO3 (2.0)
80:20
83:17
67:33
78:22
80:20
81:19
80:20
77:23
>99
96
97
96
95
95
>99
73
NH4HCO3 (2.0)
2,6-lutidine (1.2)
Na2CO3 (2.0)
NaHCO3 (2.0)
NH4HCO3 (1.0)
NH4HCO3 (2.0)
NH4HCO3 (2.0)
a Solvent mixtures are given as (v/v). Solvents: A ) acetone, AN )
acetonitrile, TFE ) 2,2,2-trifluoroethanol, W ) water. b Equivalents of
auxiliary base relative to the electrophile are given in parentheses. c Peak
areas determined by GC-MS of the crude products. d Based on the isolated
yield of pure 3a which was obtained after column chromatography.
Scheme 1. Trapping of SN1 Intermediates by Indoles
allylation products were obtained when the reactions were
performed in 90% aqueous acetonitrile (N1 ) 4.56, s )
0.94)11 or 80% aqueous acetone (N1 ) 5.77, s ) 0.87)12 using
Na2CO3, NaHCO3, or NH4HCO3 as the auxiliary base. The
yields were less satisfactory when 2,2,2-trifluoroethanol was
(9) Bocchi, V.; Casnati, G.; Marchelli, R. Tetrahedron 1978, 34, 929-
932.
(10) Reviews: (a) Mayr, H.; Patz, M. Angew. Chem. 1994, 106, 990-
1010; Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957. (b) Mayr, H.; Bug,
T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.;
Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123,
9500-9512. (c) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66-77.
(11) Minegishi, S.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2004,
126, 5174-5181.
To optimize the reaction conditions, we examined the
reaction of indole (1a) with (E)-4-chloropent-2-ene (2) under
(12) Denegri, B.; Minegishi, S.; Kronja, O.; Mayr, H. Angew. Chem.
2004, 116, 2353-2356; Angew. Chem., Int. Ed. 2004, 43, 2302-2305.
(13) (a) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew. Chem.
2004, 116, 5518-5521; Angew. Chem., Int. Ed. 2004, 43, 5402-5405. (b)
Mayr, H.; Hofmann, M.; Minegishi, S.; Hampel, N. PCT Int. Appl. WO
2005077863, 2005; Chem. Abstr. 2005, 143, 248153.
(8) (a) Ishikura, M.; Kamada, M.; Oda, I.; Ohta, T.; Terashima, M. J.
Heterocycl. Chem. 1987, 24, 377-386. (b) Amat, M.; Hadida, S.;
Sathyanarayana, S.; Bosch, J. J. Org. Chem. 1994, 59, 10-11.
4792
Org. Lett., Vol. 8, No. 21, 2006

used as solvent. Possibly, the acidity of this solvent (pKa )
12.3)14 is responsible for the formation of some oligomers
of indole.15
The conditions of experiment no. 7 (Table 1), i.e.,
dissolving the reactants in 80% aqueous acetone in the
presence of NH4HCO3,16 were then employed for the
reactions of various SN1-reactive allyl and benzyl halides
4-10 with the indoles 1a and 1b (Scheme 2). The reactions
were monitored by GC-MS and interrupted after complete
conversion of 4-10 or after 3 days.
Because of the longer retention times of the 2-substituted
isomers (11-13)b, the predominantly formed 3-substitution
products (11-13)a could be obtained as pure isomers by
chromatography on silica gel. Generally, the allyl bromides
reacted faster and gave better yields than the corresponding
chlorides. Exclusive 3-attack was observed when indole (1a)
was treated with 3-bromocyclohexene (8) in 90% aqueous
acetonitrile (Table 2, entry 9). Surprisingly, the corresponding
reaction in 80% aqueous acetone gave only 27% of 15a along
with cyclohex-2-enol as the major product. In the case of
14a/b, 16a/b, and 17a/b, the trace amounts of the 2-isomers
were not removed by chromatography, and pure 17a was
obtained by crystallization. Although the 1,1-dialkyl-
substituted allyl cations derived from the allyl halides 4 and
5 were selectively attacked at the terminal position of the
allyl cation, the 1-phenylallyl cation arising from 6a/b was
attacked at both allylic termini, with attack at the nonsub-
stituted allylic position predominating. As previously reported
for Lewis acid-catalyzed allylations of π-nucleophiles,17 the
regioselectivity of attack is predominantly controlled by steric
effects and not by LUMO coefficients or charge distribution
in the allyl cations.18 Entries 10 and 11 of Table 2 show
that this novel type of electrophilic substitution of indoles
is not restricted to allyl halides but can also be employed
for other types of SN1 active substrates such as benzyl
halides.
The reactions with indole (1a) gave mixtures of 3- and
2-allylated indoles in moderate to very good yields, when
disubstitution was suppressed by employing 5 equiv of 1a,b
(Table 2). When indole (1a, 10 mmol), prenyl bromide (4b,
Table 2. Reactions of Indole (1a) with Allyl and Benzyl
Halides 4-10 in 80% Aqueous Acetone
Similar reactions were observed with N-methylindole (1b,
Table 3). Preferential 3-attack is generally accompanied by
Table 3. Reactions of N-Methylindole (1b) with Allyl and
Benzyl Halides 4-10 in 80% Aqueous Acetone
a Peak areas determined by GC-MS of the crude products. b Isolated
yields of the mixtures of a and b isomers. The number in parentheses is
the isolated yield of the isomers (11-17)a. c Besides 13a and 3-(1-
phenylallyl)-1H-indole (13c), a third isomer was detected by GC/MS (28%,
possibly 13b). d 8:1 mixture of 13a and 3-(1-phenylallyl)-1H-indole (13c).
e A third isomer was detected by GC/MS (26%, possibly 13b). f Reaction
performed in 90% aqueous acetonitrile. g 10:1 mixture of 16a and 16b.h 15:
1 mixture of 17a and 17b.
a Peak areas determined by GC-MS of the crude product. b Isolated yields
of the mixtures of a and b isomers; isolated yields of the isomers (18-
23)a are given in parentheses. c 10:1 mixture of 18a and 18b. d 10:1 mixture
of 19a and 19b. e Product contains traces of 21b. f Reaction performed in
90% aqueous acetonitrile.
8.3 mmol), and NH4HCO3 (10 mmol) were stirred in 80%
aqueous acetone (25 mL) for 1 h at room temperature, a
significant amount of 2,3-diprenylindole [2,3-bis(2-methyl-
propenyl)-1H-indole, 11c] was formed, and only 54% of 11a
could be isolated. Under the same conditions, disubstitution
was favored when 4b was used in excess, and compound
11c was obtained as the major product (83% by GC-MS)
from a 1:4 mixture of 1a and 4b.
some 2-attack, but 3-bromocyclohexene (8) again attacks the
3-position of 1b selectively. As before, the reaction with 8
has to be carried out in 90% aqueous acetonitrile because
cyclohex-2-enol is the major product in 80% aqueous
acetone.
(14) Das, U.; Crousse, B.; Kesavan, V.; Bonnet-Delpon, D.; Begue´, J.
P. J. Org. Chem. 2000, 65, 6749-6751.
(15) Smith, G. F. AdV. Heterocycl. Chem. 1963, 2, 287-309.
Our previously published concept of Friedel-Crafts reac-
tions under acid-free conditions13 has thus been demonstrated
Org. Lett., Vol. 8, No. 21, 2006
4793

to be applicable for an important class of compounds.
Because indoles are generally more nucleophilic than water
in acetone,11,12 the competing trapping of the intermediate
carbocation by water is usually not a problem. The method
is rather limited by the rates of ionization of the correspond-
ing allyl and benzyl halides.
aqueous acetone,19a one can expect that ionization half-lives
will exceed 1 day as the electrofugality of the carbocation
gets smaller than -7 in the case of R-Cl and smaller than
-8 in the case of R-Br. In line with the published
electrofugality parameter of the cinnamyl cation (Ef ) -8),19b
cinnamyl bromides but not chlorides have successfully been
employed in this study. Reactions via less stabilized car-
bocations will require more harsh conditions.
Because nucleofugality parameters of Nf ) 2 and 3 have
been reported for chloride and bromide, respectively, in 80%
(16) General reaction procedure: NH4HCO3 (10 mmol) was suspended
in a solution of indole 1a or 1b (25 mmol) in 80% aqueous acetone (25
mL). After the addition of the allyl or benzyl halide (5.0 mmol), the
suspension was stirred at ambient temperature for the time specified in Table
2. Water (30 mL) was added, and the organic phase was separated. The
aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic
phases were dried (MgSO4), and the solvents were removed in vacuo. Indole
(1a, bp 103-107 °C/3 × 10-3 mbar) or 1-methylindole (1b, bp 95-98
°C/3 × 10-3 mbar) was removed from the crude product by Kugelrohr
distillation. The residue was purified by flash column chromatography on
silica gel with n-hexane/ethyl acetate mixtures as eluents.
Acknowledgment. This work was financially supported
by the Deutsche Forschungsgemeinschaft.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Mayr, H.; Klein, H.; Kolberg, G. Chem. Ber. 1984, 117, 2555-
2579. (b) Klein, H.; Freyberger, G.; Mayr, H. Angew. Chem. 1983, 95,
62-63; Angew. Chem., Int. Ed. Engl. 1983, 22, 49. (c) Klein, H.; Erbe, A.;
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21, 82.
(18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: London, 1976; Chapter 3.
OL0618555
(19) (a) Denegri, B.; Streiter, A.; Juric´, S.; Ofial, A. R.; Kronja, O.; Mayr,
H. Chem.-Eur. J. 2006, 12, 1648-1656; 5415. (b) Denegri, B.; Ofial, A.
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4794
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