New versatile Pd-catalyzed alkylation of indoles via nucleophilic allylic substitution: Controlling the regioselectivity

Article abstract of DOI:10.1021/ol048663z

(Chemical Equation Presented) A systematic study addressed toward the optimization of the Pd-catalyzed alkylation of indoles by allylic carbonates is presented. The protocol uses a catalytic amount of [PdCl(π-allyl)] ₂/phosphine as a promoting

Full text of DOI:10.1021/ol048663z

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3199-3202
New Versatile Pd-Catalyzed Alkylation of
Indoles via Nucleophilic Allylic
Substitution: Controlling the
Regioselectivity
Marco Bandini,* Alfonso Melloni, and Achille Umani-Ronchi*
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126, Bologna, Italy
marco.bandini@unibo.it; achille.umanironchi@unibo.it
Received July 12, 2004
ABSTRACT
A systematic study addressed toward the optimization of the Pd-catalyzed alkylation of indoles by allylic carbonates is presented. The protocol
uses a catalytic amount of [PdCl(π-allyl)]2/phosphine as a promoting agent, providing allylindoles in excellent yields. The regioselectivity of
the reaction can be controlled by a proper choice of the base and the reaction media. The method proved to be effective also for intramolecular
allylic alkylations of indolyl carbonates, providing a flexible route to fused indole alkaloids.
Indole is widely recognized as a key motif in the synthesis
of complex molecules with numerous applications in material
science, pharmaceuticals, and agrochemicals.1 For this
reason, the functionalization of such a compound via low
cost, selective, and ecofriendly strategies has captured the
attention of the chemical community over the past decades.
Among them, Lewis acid promoted Friedel-Crafts reactions2
and metal-catalyzed arylation processes3 proved to be
remarkably effective in the alkylation/arylation of indole
under homogeneous as well as heterogeneous conditions. In
this context, a related straightforward approach could involve
the nucleophilic allylic alkylation4 of the heteroaromatic
system via π-allylmetallo intermediates (Tsuji-Trost reac-
tion).5
amounts of Lewis acids.4d As a matter of fact, the discrimi-
nation between the N-alkylated product (kinetic control) and
the C3-alkylated product (thermodynamic control) with
unsubstituted indoles is usually a challenging task.6
In this scenario, Kocˇovsky´ and co-workers recently
reported on the Mo(II)-catalyzed alkylation of electron-rich
aromatics, but only a few examples of indole alkylations with
unsymmetrical allyl acetates were described.7
In this paper, we intend to describe our systematic study
in the regioselective alkylation of indoles with cyclic and
(4) (a) Billups, W. E.; Erkes, R. S.; Reed, L. E. Synth. Commun. 1980,
10, 147-151. (b) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981,
103, 5969-5972. (c) Bourak, M.; Gallo, R. Heterocycles 1990, 31, 447-
457. (d) Zhu, X.; Ganesan, A. J. Org. Chem. 2002, 67, 2705-2708. (e)
Yadav, J. S.; Reddy, B. V. S.; Muralikrishna Reddy, P.; Srinivas, Ch.
Tetrahedron Lett. 2002, 43, 5185-5187. (f) Trost, B. M.; Krische, M. J.;
Berl, V.; Grenzer, E. M. Org. Lett. 2002, 4, 2005-2008.
(5) (a) Moreno-Man˜as, M.; Pleixats, R. AdV. Heteroycl. Chem. 1996,
66, 73-129 and references therein. (b) Trost, B. M.; Van Vraken, D. L.
Chem. ReV. 1996, 96, 395-422. (c) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921-2944.
Despite the high potential of this approach, only a few
examples of alkylation of indoles via mild allylic substitution
have been reported to date, and most of them generally
exhibit scarce regioselectivity or require stoichiometric
(1) Sundberg, R. J. In Indoles; Academic Press: San Diego, 1996.
(2) Yamamoto, H. In Lewis Acids in Organic Synthesis; Wiley-VCH:
Weinheim, 2000.
(3) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684-11688 and references therein.
(6) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.; Eguchi,
S. J. Chem. Soc., Perkin Trans. 1 1990, 111-114.
(7) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
Kocˇovsky´, P. J. Org. Chem. 1999, 64, 2751-2764.
10.1021/ol048663z CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/11/2004

acyclic carbonates in the presence of a catalytic amount of
[PdCl(π-allyl)]2/phosphine complexes. The protocol allowed
the regioselectivity of the reaction to be effectively con-
trolled.
The allylic substitution between indole 1a and rac-1,3-
diphenylprop-2-enyl methyl carbonate (2a) was taken into
account as the model reaction and a brief screening of
reaction conditions were undertaken.
Then the generality of the reaction was taken into account;
excellent tolerance toward sterically demanding indoles (1b
and 1c), which smoothly reacted with 2a to give 3b and 3c
in high yields (78%, 92% respectively) and in excellent
regioselectivity (Table 2). Moreover, in the presence of both
Table 2. Screening of Indoles in the Pd-catalyzed Allylic
Alkylation with 2aa
The data collected in Table 1 clearly proved that, in the
presence of 5 mol % of [PdCl(π-allyl)]2/dppe8 as the catalytic
Table 1. Pd-Catalyzed Alkylation of Indole 1a by Allylic
Substitutiona
entry
indole
product
yieldb (%)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
3b
3c
3d
3e
3f
78 (72)
92 (87)
62 (60)
87 (82)
68 (62)
15 (8)
entry
solvent/base
allylic compd convnb (%) yieldc (%)
1
2
3
4
5
6
DMF/Cs2CO3
THF/K2CO3
THF/Li2CO3
CH2Cl2/Li2CO3
CH2Cl2/Li2CO3
CH2Cl2/Li2CO3
2a
2a
2a
2a
2b
2a
62
75
25
70
<10
58
55 (7)
61 (19)
19 (-)
65 (8)
1g
1h
3g
3h
a All the reactions were carried out under nitrogen atmosphere in CH2Cl2
at reflux. Reaction time 24 h. Indole/carbonate/[Pd]/dppe/Li2CO3 ratio: 1/2/
0.05/0.11/2. b Determined by HPLC analysis of the crude material. Isolated
yields are given in parentheses.
52 (31)d
a All the reactions were carried out under nitrogen atmosphere in CH2Cl2
at reflux unless otherwise specified. Reaction time 24 h. Indole/carbonate/
[Pd]/dppe/base ratio: 1/2/0.05/0.11/2. b Determined by HPLC analysis of
the crude material and related to the 3a formation. c Isolated yields. Isolated
yields of the N/C-dialkylated product are given in parentheses. d The reaction
was carried out without base.
indoles bearing electron-releasing (1d) and electron-with-
drawing groups (1e,f) the reaction with 2a proceeded
effectively yielding the C-alkylated adduct (62-87%) in high
regioselectivity (entries 3-5). Finally, the disappointing
results obtained with N-Me- (1g) and N-SO2Ph-indole (1h)
(entries 6 and 7, Table 2) suggest the pivotal role played by
N-metalloindole species as active nucleophiles in the present
allylic alkylation.
system, indole 1a (1 equiv) coupled smoothly with allyl
carbonate 2a9 (2 equiv), and the combined use of a low-
coordinating solvent (DCM) and Li2CO3 as the base drove
the reaction course toward the exclusive formation of the
thermodynamic C-attack (70%) with the double-alkylated
adduct being the only side product (8%, entry 4). Interest-
ingly, no kinetic N-allylic indole was observed under these
conditions. On the other hand, the use of strongest bases
(i.e., Cs2CO3, K2CO3) and more coordinating solvents (i.e.,
DMF, THF) also promotes the alkylation of 1a in satisfactory
yields (entries 1 and 2). However, the reaction conversion
as well as the regioselectivity of the process were inferior
respect to the use of Li2CO3 in DMC.
Allyl carbonates as alkylating precursors as well as the
base proved to be essential in order to guarantee optimal
chemical outcomes. In fact, while the use of allylic acetate
(2b) afforded 3a just in traces (<10%, entry 5), the absence
of base drops the regioselection by enhancing the formation
of the side N/C-dialkylated product (entry 6).10
Then, we turned our attention to the alkylation of 1a (1
equiv) in the presence of less reactive pent-2-enyl methyl
carbonate 2c (2 equiv). However, under the previously
utilized conditions (CH2Cl2, dppe, Li2CO3), a mixture of
C-alkylated 4 and N-alkylated product 5 (3.7:1) was isolated
in moderate yield (62%, Scheme 1). In accord with our
intention to optimize a metallo-catalyzed allylic alkylation
protocol that allows allylindoles to be prepared regioselec-
tively,11 we investigated the influence of the reaction
(9) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem., Int. Ed. 2002,
41, 1059-1061.
(10) As a peculiarity of carbonate 2a, we observed that mild acidic
conditions (solvent, silica, etc.) also significantly promote the allylic
alkylation of 1a predominantly at the C3 position (i.e., CH2Cl2 in the
presence of silica, reflux 24 h, convn >90%). On the other hand, carbonates
2c-e and 12 (vide infra), less prone to originate carbocationic species respect
to 2a, did not undergo the present indole alkylation in any extent under the
above-mentioned conditions. For a related study, see: Bisaro, F.; Prestat,
G.; Vitale M.; Poli, G. Synlett 2002, 1823-1826.
(8) Several commercially available Pd complexes were tested in the
model reaction, however the use of [PdCl(π-allyl)]2 provided the highest
yields and selectivity. For instance, by using [Pd2dba3]‚CHCl3, a significant
amount of 1,4-addition of indole to the dba (dibenzylidenacetone) was
detected. For a related case, see: Bandini, M.; Cozzi, P. G.; Giacomini,
M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67,
3700-3704.
(11) For a related study concerning the synthesis of 3-allylindoles by
Pd-catalyzed cyclization of alkynyltrifluoroacetanilidenes, see: Cacchi, S.;
Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001-1011.
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Org. Lett., Vol. 6, No. 18, 2004

%) and K2CO3 (2 equiv), the regiochemistry was completely
switched toward the formation of the N-alkylated compound
5 (90% yield, 4/5 > 1:50).13 Interestingly, monitoring the
reaction course of the present protocol by gas chromatog-
raphy revealed that, when the BSA/Li2CO3 base system was
utilized, N-TMS-indole was initially formed in situ followed
by subsequent C-alkylation. Therefore, the initial fast sily-
lation of the indole might be responsible for preventing the
formation of the charged species via the equilibrium depicted
in Scheme 2.
Scheme 1. Effect of Base and Solvent in Controlling the
Regioselectivity of the Pd-Catalyzed Coupling of 1a with 2ca
This strategy has also proven successful for controlling
the regiochemistry in the indole alkylation with cyclohex-
2-enyl methyl carbonate 2d and more challenging asym-
metric 4-phenylbut-3-enyl methyl carbonate 2e (Table 3).
a Reagents and conditions: 1a/2c/[PdCl(π-allyl)]2/phosphine/
base, 1/2/0.05/0.22(0.11)/2.
Table 3. Pd-Catalyzed Alkylation of Indole 1a by Allylic
Substitution with 2d and 2ea
parameters on the outcome of the process.12 In particular,
we supposed that while low coordinating solvents (i.e., CH2-
Cl2) would favor the formation in solution of a contact
indolyl-metal ion pair A (predominant thermodynamic
alkylation), the use of highly coordinating solvents in
combination with bases bearing larger cationic radius
(K2CO3, Cs2CO3) would drive the regiochemistry toward the
formation of the kinetic N-product through the intermediate
solvent-separated ion pair B (Scheme 2).
overall yieldb
entry carbonate
conditions
(%)
C/N ratioc
Scheme 2. Influence of the Solvent and Base in the
1
2
3
4
2d
2d
2e
2e
CH2Cl2 BSA/Li2CO3
DMF/Cs2CO3
CH2Cl2 BSA/Li2CO3
DMF/Cs2CO3
99
99
91
84
6/7 (8:1)
Regioselective Alkylation of Indoles
6/7 (1:12)
8/9 (10:1)
8/9 (1:50)
a All the reactions were carried out under nitrogen atmosphere (reflux
with CH2Cl2 and rt with DMF). Reaction time 12-24 h. Indole/carbonate/
[Pd]/PPh3/base ratio: 1/2/0.05/0.22/2. b Combined overall yields of the two
isomers after flash chromatography separation. c The C/N ratio was
1
determined by H NMR analysis of the crude material.
In the case of cyclic carbonate 2d, the alternative employ-
ment of BSA/Li2CO3 in CH2Cl2 or Cs2CO3 in DMF afforded
the 6/7 mixture in 8:1 (6: 89% isolated yield, entry 1) and
1:12 ratios (7: 91% isolated yield, entry 2), respectively.
Analogously with the asymmetric carbonate 2e, while the
use of Li2CO3/BSA as the base system led to the C-3 adduct
8 in 82% isolated yield (8/9 10:1, entry 3), the reaction
between 1a with 2e in the presence of Cs2CO3 in DMF at
actual temperature provided the N-alkylated compound 9 in
84% yield (8/9 1:50, entry 4). Noteworthy, in both cases
only attack at the less hindered position of the asymmetric
carbonate 2e was detected.14
In fact, while the combined use of low-coordinating
solvent (CH2Cl2, reflux, PPh3) and BSA/Li2CO3 as the base
system provided the desired C-alkylated product in 80% yield
after flash chromatography (4/5 16:1), by running the allylic
substitution in THF with a catalytic amount of dppe (11 mol
Finally, the synthetic utility of the present catalytic strategy
was proven by applying a Pd-catalyzed intramolecular
(12) (a) Hogen-Esch, T. E.; Smid, J. J. Am. Chem. Soc. 1965, 87, 669-
670. (b) Zaugg, H. E.; Schaefer, A. D. J. Am. Chem. Soc. 1965, 87, 1857-
1866. (c) Hogen-Esch, T. E.; Smid, J. J. Am. Chem. Soc. 1966, 88, 307-
318. (d) Powers, J. C.; Meyer, W. P.; Parsons, T. G. J. Am. Chem. Soc.
1967, 89, 5812-5820. (e) Buncel, E.; Menon, B. J. Org. Chem. 1979, 44,
317-320.
(13) In some cases, with carbonate 2c the product of N/C-dialkylation
was also isolated from the crude mixture (5-10%).
Org. Lett., Vol. 6, No. 18, 2004
3201

version15 of the protocol for the synthesis of polycyclic
indolyl alkaloids such as 4-substituted 1,2,3,4-tetrahydro-â-
carbolines 1416a and pyrazino[1,2-a]indoles 15.16b
the primary alcohol obtained with ClCO2Me/py/Et2O, af-
forded the desired indolyl precursor 12 in 37% yield (three
steps).
The synthesis of the key intermediate 12 was readily
accomplished starting from 2-carboxy aldehyde 1017 in five
steps (Scheme 3). In particular, the reductive amination of
Initial attempts of cyclization were performed by treatment
of the intermediate 12 (0.1 mM) with [PdCl(π-allyl)]2/PPh3
in the presence of Li2CO2/BSA as the base (Scheme 3).
Noteworthy, the desired cyclized tetrahydro-â-carboline 14
was isolated, by selective C-alkylation, in 91% yield (99%
conversion, 14/15 > 50:1) after 4 h at room temperature.18
Notably, compound 12 underwent Pd-cyclization with ex-
clusive formation of the six-membered ring, stressing the
regioselective attack to the internal more hindered position
of the η3-Pd intermediate 13. One the other hand, by using
inorganic bases bearing less covalently coordinating metals
(Cs2CO3, 2 h) in DMF at 50 °C, the regioselectivity of the
reaction was remarkably switched toward the kinetic N-
alkylated product 15 (85% yield, 14:15 1:8).
Scheme 3
In summary, a general and mild palladium-catalyzed
alkylation of indoles through nucleophilic substitution with
allylic carbonates is reported. The protocol, besides affording
the desired products in excellent yields, provides a rationale
to unambiguously predict and control the regioselectivity of
the reaction. Moreover, the synthetic usefulness of the
method was also demonstrated in the preparation of func-
tionalized polycyclic alkaloids by Pd-catalyzed intramolecu-
lar cyclization. Studies addressed toward the development
of an asymmetric version of the present strategy are
underway in our laboratories.
10 with benzylamine afforded the secondary amine 11 in
89% yield. Then, the treatment of 11 with ethyl 4-bromo-
crotonate in TEA with subsequent reduction of the carboxylic
moiety with DIBAL/toluene/-78 °C and derivatization of
Acknowledgment. This work was supported by MIUR
(Rome), National project “Stereoselezione in Sintesi Or-
ganica: Metodologie and Applicazioni”, FIRB Project (Pro-
gettazione, preparazione e valutazione biologica e farmaco-
logica di nuove molecole organiche quali potenziali farmaci
innovativi), and the University of Bologna (funds for selected
research topics).
(14) Under thermodynamic conditions (CH2Cl2, Li2CO3), the reaction
between prenyl methyl carbonate and 1a afforded exclusively (62% yield)
the C-alkylated indole as a mixture of the isomers C/D (5:1). However,
kinetic conditions (DMF, Cs2CO3) furnished a complex mixture of N- and
C-products in low yield and poor regioselectivity.
Supporting Information Available: Typical experimen-
tal procedures for the catalytic allylic substitution and
analytical data for the isolated unknown compounds. This
material is available free of charge from the Internet at
http://pubs.acs.org.
(15) For recent reports of Pd- and Pt-catalyzed intramolecular alkylation
of indoles with unactivated olefins, see: (a) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 9578-9579. (b) Abbiati, G.; Beccalli, E.
M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003, 68, 7625-7628. (c)
Xiaoqing, C. L.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 3700-3701. (d) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 10250-10251.
(16) (a) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797-1842 (b)
Chang-Fong, J.; Tyacke, R. J.; Lau, A.; Westaway, J.; Hudson, A. L.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2004, 14, 1003-1005.
OL048663Z
(17) Suzuki, H.; Unemoto, M.; Hagiwara, M.; Ohyama, T.; Yokoyama,
Y.; Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1999, 1717-1724.
(18) For a related Lewis acid mediated cyclization procedure see:
Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A. J. Org. Chem.
2003, 68, 7126-7129.
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