Reductive alkylation of indoles with alkynes and hydrosilanes under indium catalysis

Article abstract of DOI:10.1021/ol1029673

Under Indium catalysis, diverse alkylindoles were successfully prepared with a flexible combination of indoles and alkynes in the presence of hydrosilanes. In addition to the hydrosilane, carbon nucleophiles are also available. This new method generates alkylindoles in yields over 70% with a broad scope of functional group compatibility.(Figure Presented)

Full text of DOI:10.1021/ol1029673

ORGANIC
LETTERS
2011
Vol. 13, No. 5
912–915
Reductive Alkylation of Indoles with Alkynes
and Hydrosilanes under Indium Catalysis
Teruhisa Tsuchimoto* and Mitsutaka Kanbara
Department of Applied Chemistry, School of Science and Technology, Meiji University,
Higashimita, Tama-ku, Kawasaki 214-8571, Japan
tsuchimo@isc.meiji.ac.jp
Received December 8, 2010
ABSTRACT
Under Indium catalysis, diverse alkylindoles were successfully prepared with a flexible combination of indoles and alkynes in the presence of
hydrosilanes. In addition to the hydrosilane, carbon nucleophiles are also available. This new method generates alkylindoles in yields over 70%
with a broad scope of functional group compatibility.
Indoles having alkyl units at the C2 and/or C3 positions
are widely recognized as structural motifs, especially in
natural products and pharmaceuticals.1 Due to this rea-
son, Friedel-Crafts (F.C.) alkylation of indoles, which
features easy accessibility, has been broadly studied in
organic synthesis, where addition or substitution has been
the reaction mode of choice.2 From atom economical and
environmental viewpoints, the addition mode is appar-
ently more useful. However, it is rather surprising that
alkenes successfully accepting indoles intermolecularly have
been restricted to the following two types:2-4 highly electro-
philic alkenes with electron-withdrawing groups,5 and aryl-
and multi-substituted alkenes with the ability to stabilize
intermediary positive charges.6 These thus appear to have
narrowed the applicability of the F.C. alkylation of indoles.
Alkynes also have been well-established as platforms to
accept addition of a variety of molecules.7 We envisaged
that achievement of reductive F.C. alkylation of indoles
using alkynes with broad substrate generality including
(1) d’Ischia, M.; Napolitano, A.; Pezzella, A. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven,
E. F. V., Taylor, R. J. K., Jones, G., Eds.; Elsevier: Oxford, 2008; Vol. 3,
pp 353-388.
(2) (a) Trofimov, B. A.; Nedolya, N. A. In Comprehensive Hetero-
cyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Jones, G., Eds.; Elsevier: Oxford, 2008; Vol. 3, pp 110-133.
(b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608–
9644.
(3) Use of simple aliphatic terminal alkenes causes some undesired
reactions on the alkene, i.e., isomerization of the CdC bond, formation
of regioisomers, and rearrangement of alkyl groups: (a) Zhang, Z.;
Wang, X.; Widenhoefer, R. A. Chem. Commun. 2006, 3717–3719.
(b) Wang, M.-Z.; Wong, M.-K.; Che, C.-M. Chem.;Eur. J. 2008, 14,
8353–8364.
(4) Although Terada and Sorimachi have reported addition of
indoles to enamines as electron-rich alkenes, the mechanistic study
indicates that imines produced in situ by isomerization of the enamine
are actual acceptors of the indole: Terada, M.; Sorimachi, K. J. Am.
Chem. Soc. 2007, 129, 292–293.
(5) For selected recent examples, see: (a) Itoh, J.; Fuchibe, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016–4018. (b) Ganesh,
M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464–16465. (c) Angelini,
E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J. Org.
Chem. 2008, 73, 5654–5657. See also recent reviews: (d) Bandini, M.;
Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199–1222.
(e) Bandini, M.; Eichholzer, A.; Umani-Ronchi, A. Mini-Rev. Org.
Chem. 2007, 4, 115–124.
(6) For selected recent examples, see: (a) Rozenman, M. M.; Kanan,
M. W.; Liu, D. R. J. Am. Chem. Soc. 2007, 129, 14933–14938. (b) Chao,
C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet, J.-P.; Michelet, V. Chem.;
Eur. J. 2009, 15, 1319–1323. See also ref 3b.
(7) For selected recent reviews, see: (a) Willis, M. C. Chem. Rev. 2010,
ꢀ ꢁ
ꢀ
110, 725–748. (b) Denes, F.; Perez-Luna, A.; Chemla, F. Chem. Rev.
2010, 110, 2366–2447. (c) Kondoh, A.; Yorimitsu, H.; Oshima, K. Chem.
Asian J. 2010, 5, 398–409. (d) Wang, X.; Zhou, L.; Lu, W. Curr. Org.
Chem. 2010, 14, 289–307. (e) de Mendoza, P.; Echavarren, A. M. Pure
Appl. Chem. 2010, 82, 801–820.
r
10.1021/ol1029673
Published on Web 01/26/2011
2011 American Chemical Society

contrast to other metal triflates, In(NTf2)3 greatly im-
proved the reaction rate, while significant amounts of by-
products, mainly 5a and 6a, were formed (entries 2-6).
Lowering the temperature made the reaction sluggish, but
favorably affected to suppress the side reaction (entry 7). The
higher conversion of 2a was achieved by the prolonged
reaction time with In(NTf2)3 (30 mol %) (entry 8).12 Under
the conditions, screening of hydrosilanes 3 showed that those
having phenyl group(s) are more promising (entries 9-11).
With HSiMePh2 (3a), the fine-tuning of the solvent volume
and temperature finally raised the yield to 86% (entry 12).
Under the suitable conditions, 15-30 mol % of In(NTf2)3
was found to affect effectively the present reaction with a
broad substrate scope on both indoles 1and alkynes 2(Table2).
Besides 1a, substituted indoles 1b-1f were thus alkylated
successfully, in the presence of 3a, by 2a as well as aliphatic
terminal alkynes 2b-2e with a range of functional groups
(entries1-11). Importantly, with alkynol 2e, oxygen-silylated
or -unsilylated alkylindole 4j [R6 = (CH2)4OSiMePh2] or 4j0
[R6 = (CH2)4OH] was obtained exclusively in each case,
by performing the reaction without or with H2O (entries 10
and 11). Worthy of note is that no troublesome reaction was
observed in the use of 2f and 2g, in contrast to the variants
with the corresponding alkenes (entries 12 and 13).3 Terminal
aryl- and heteroarylalkynes 2h-2k with different electronic
natures also participated well in this strategy (entries 14-20).
In these cases, adding H2O greatly accelerated the reaction
(e.g., entries 14 vs 15, and also see Scheme 2). The source of the
alkyl group can be further extended to aliphatic and aromatic
internal alkynes (entries 21 and 22). The less nucleophilic C2,
compared to C3, also worked well as a reaction site, giving 4u
and 4v (entries 23 and 24). As shown thus far, the outstand-
ing compatibility of the functional groups, OMe, Br, Cl,
CN, phthalimidoyl, OH, t-Bu, B(pinacolate), I and NO2, is
noteworthy. Among them, the carbon-OMe,13 -boron14
and -halogen14 bonds should be useful for further elongation
of a carbon-carbon bond. The achievement of perfect
regioselection on both 1 and 215 and of yields of 4 over 70%
in all cases represent high validity and reliability of this strategy.
Moreover, a practical advantage can be demonstrated by
synthesis on a preparative-scale. For example, 4m was synthe-
sized on 10 mmol scale using 10 mol % of In(NTf2)3 at 70 °C
for 2 h, and thus obtained in 97% yield (2.48 g).
Table 1. Lewis Acid-Catalyzed Reductive Octylation of Indolea
conv of
Lewis acid
(mol %)
temp time
2a
(%)b
4a
(%)b
entry
Si in 3
(°C)
(h)
1
2
3
4
5
6
7
8
9
In(OTf)3 (20) SiEt3
Cu(OTf)2 (20) SiEt3
100
100
100
100
100
100
40
12
12
12
12
12
12
12
24
24
24
24
24
27
16
7
8
<1
<1
<1
2
AgOTf (20)
SiEt3
Zn(OTf)2 (20) SiEt3
Bi(OTf)3 (20) SiEt3
In(NTf2)3 (20) SiEt3
In(NTf2)3 (20) SiEt3
In(NTf2)3 (30) SiEt3
In(NTf2)3 (30) SiMe2Ph
14
18
97
45
86
84
94
89
>99
43
32
61
78
82
65
86
40
40
10 In(NTf2)3 (30) SiMePh2
11 In(NTf2)3 (30) SiPh3
12 In(NTf2)3 (30) SiMePh2
40
40
45
a Reagents: 1a (0.6 mmol), 2a (0.4 mmol), 3 (0.6 mmol), PhCl (0.6 mL
for entries 1-11 or 0.4 mL for entry 12). b Determined by GC.
high functional group tolerance would open up promising
perspectives to construct alkylindoles toward a variety of
situations.8 This study with an indium catalyst, which is
the first example of reductive alkylation of indoles with
alkynes and hydrosilanes, proves to be the case.9-11
We first examined suitable conditions in the reductive
alkylation of indole (1a) with 1-octyne (2a) (Table 1).
Thus, treating 1a, 2a and HSiEt3 with In(OTf)3 (20 mol
%, Tf = SO2CF3) in PhCl at 100 °C for 12 h gave
3-(2-octyl)indole (4a), albeit in a low yield (entry 1). In
(8) (a) Tsuchimoto, T.; Wagatsuma, T.; Aoki, K.; Shimotori, J. Org.
Lett. 2009, 11, 2129–2132. See also a Concept article: (b) Tsuchimoto, T.
Chem.-Eur. J. 2011, accepted.
(9) A part of this research was presented at the 89th annual meeting of
the Chemical Society of Japan on March 29, 2009 (presentation
#3F2-53). During the course of this research, two research groups
reported alkylation of indoles with alkynes. However, their research
Instead of hydride nucleophiles, carbon nucleophiles
[Nu(C)] 3, such as Me3SiCN (3b) and 2-methoxythiophene
(3c), can be adopted to install a quaternary carbon center
into the product, where the stepwise procedure in one-pot
as shown in Scheme 1 is effective. The assembly of indole
1a, alkyne 2n and thiophene 3c for 7c can be regarded as a
substrate-selective double addition of two different hetero-
arenes to a CtC bond.
ꢀ
profiles are different from ours. (a) Barluenga, J.; Fernandez, A.;
~ ꢀ
Rodrıguez, F.; Fananas, F. J. Chem.;Eur. J. 2009, 15, 8121–8123.
´
(b) Cadierno, V.; Francos, J.; Gimeno, J. Chem. Commun. 2010, 46,
4175–4177.
(10) For variants with carbonyl compounds as alkyl group suppliers,
but always requiring more than a stoichiometric amount of acid
promoters, see: (a) Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele,
J. Tetrahedron Lett. 1993, 34, 1529–1532. (b) Mahadevan, A.; Sard, H.;
Gonzalez, M.; McKew, J. C. Tetrahedron Lett. 2003, 44, 4589–4591.
(c) Campbell, J. A.; Bordunov, V.; Broka, C. A.; Dankwaedt, J.;
Hendricks, R. T.; Kress, J. M.; Walker, K. A. M.; Wang, J.-H. Tetra-
hedron Lett. 2004, 45, 3793–3796. (d) Rizzo, J. R.; Alt, C. A.; Zhang,
T. Y. Tetrahedron Lett. 2008, 49, 6749–6751.
(11) For our recent reports on indium-catalyzed carbon-carbon
bond-forming reaction with indoles as nucleophiles, see: (a) Tsuchimoto,
T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.; Miyamura, T.; Shirakawa,
E. J. Am. Chem. Soc. 2008, 130, 15823–15835. (b) Tsuchimoto, T.;
Iwabuchi, M.; Nagase, Y.; Oki, K.; Takahashi, H. Angew. Chem., Int.
Ed. 2011, DOI: 10.1002/anie.201005750.
(12) Effect of other solvents also was examined under the conditions
shown in entry 8: PhH (55%), PhMe (48%), ClCH2CH2Cl (46%),
CH2Cl2 (35%), CHCl3 (46%), Bu2O (40%), n-decane (9%).
(13) For a leading example, see: Tobisu, M.; Shimasaki, T.; Chatani,
N. Angew. Chem., Int. Ed. 2008, 47, 4866–4869 and references therein.
(14) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(15) Ratios of 4 and other possible regioisomers were assessed to
be >99:<1 by GC and GC-MS analyses.
Org. Lett., Vol. 13, No. 5, 2011
913

Table 2. Indium-Catalyzed Reductive Alkylation of Indolesa
Scheme 1. Indium-Catalyzed Alkylation of Indoles with Al-
kynes and Carbon Nucleophilesa
a Reagents (unless otherwise specified): 1 (0.48-1.2 mmol), 2 (0.40 mmol),
3 (0.80-2.4 mmol), In(NTf2)3 (0.12 mmol), PhCl (0.4 mL). Isolated
yields of 7 based on 2 are shown here. See Supporting Information
for further details. b Obtained with 1c, 2a and 3b. c Obtained with 1e, 2h
and 3b. d H2O (0.40 mmol) was added successively after the addition
of 3b. e Obtained with 1a, 2n and 3c.
indole
alkyne In(NTf2)3 temp time product,
entry
1
2
(mol %)
(°C)
(h)
yield (%)d
1
2
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2f
30
30
30
30
30
30
30
30
15
30
30
30
30
30
15
15
30
20
30
20
30
30
30
15
45
45
45
45
45
45
45
70
85
70
70
85
85
70
70
70
rt
24
24
24
24
24
24
30
5
4a, 84
4b, 93
4c, 87
4d, 82
4e, 92
4f, 80
4g, 70
4h, 72
4i, 81
4j, 85
4j’, 86
4k, 81
4l, 78
4m, 98
4m, 98
4n, 97
4o, 80
4p, 75
4q, 77
4r, 99
4s, 90
4t, 98
4u, 75
4v, 71
yield, whereas the absence of H2O resulted in the much
slower reaction (30 h), even with the higher loading of
In(NTf2)3 (30 mol %). Interestingly, in contrast to the
single addition using C2-substituted indole 1g, the double
addition was exclusive for C2-free indole 1c to give 9a,
which was then readily converted to alkylindole 4n. Here
again, H2O actively worked to hasten the hydride reduc-
tion. These results suggest that the single and double
additions depending on the structure of indoles are crucial
as the first steps and that H2O would act as an activator,
enhancing nucleophilicity of 3a by its coordination.16 The
exclusive double addition should be due mainly to little or
no steric congestion in 9a, compared to steric stress that
would arise between the two methyl groups at the C2, in
case of further addition of 1g to 8a.
Two plausible routes, which are paths A and B for
C2-substituted and -unsubstituted indoles, respectively,
are depicted in Scheme 3 that exemplify the reaction with
H-SiR3 as a nucleophile. In path A, the first step is the
single addition of indoles 1 (R2 ¼ H) to alkynes 2 activated
by the indium (In),17 which successively activates the CdC
bond of 8 to induce the hydride reduction from H-SiR3
coordinated by H2O. Finally, protonation of the C-In
bond affords alkylindoles 4 and HOSiR3,18 and regener-
ates the In catalyst. On the other hand, path B starts with
the double addition of 1 (R2 = H) to 2 via CtC and CdC
3
4
5
6
7
1c
1c
1c
1c
1c
1g
1c
1g
1g
1c
1h
1i
8
9
30
6
10
11e
12
13f
14
15g
16g
17h
18g
19g
20g
21i
22
23
24g
1
9
2g
2h
2h
2h
2h
2i
48
12
1
0.5
7
4
8
45
70
70
1c
1g
1c
1c
1j
2j
2k
2l
0.7
i
i
-
-
2m
2a
2h
70
70
70
120
7
1j
4
a Reagents (unless otherwise specified): 1 (0.48-0.60 mmol), 2 (0.40
mmol), 3a (0.60 mmol), In(NTf2)3 (0.060-0.12 mmol), PhCl (0.4 mL).
See Supporting Information for further details. b pin = pinacolate.
c PI = phthalimidoyl. d Isolated yield based on 2. e Performed in the
presence of H2O (0.80 mmol). f HSiPh3 instead of 3a was used. g Per-
formed in the presence of H2O (0.20 mmol). h Performed in the presence
of MgSO4 (1.2 mmol). i Procedure, reagents and conditions: After
treatment of 1c (2.0 mmol) and 2l (0.40 mmol) with In(NTf2)3 (0.12
mmol) in o-Cl2C6H4 at 135 °C for 24 h, HSiPh3 (0.60 mmol) was added
and then the mixture was stirred at 70 °C for 12 h.
(16) H2O reportedly coordinates to a silicon center. For example, see:
Kobayashi, J.; Kawaguchi, K.; Kawashima, T. J. Am. Chem. Soc. 2004,
126, 16318–16319.
(17) We have also previously observed that indoles with a (hetero)-
aryl group at the C2 position add to phenylacetylene under indium
catalysis to give alkenylindoles such as 8. See ref 11a.
(18) All of the reactions shown in Table 2 produced the silanol and/or
its self-condensation compounds, disiloxanes, both of which can be
confirmed by GC-MS analysis. Since substrates other than solvent
PhCl were used without any special care, H2O that would be present in
each substrate should contribute to the activation of hydrosilanes and
thus to the formation of the silanol in the reaction carried out without
adding external H2O.
We next performed some reactions to get insight into the
reaction mechanism (Scheme 2). Thus, the indium-cata-
lyzed reaction of 1g with 2h, but without 3a, was completed
in only 10 min to give alkenylindole 8a in 97% yield.
Subsequently, the treatment of isolated 8a with 3a, H2O
and In(NTf2)3 (15 mol %) for 30 min provided 4m in 98%
914
Org. Lett., Vol. 13, No. 5, 2011

Scheme 2. Indium-Catalyzed Reaction for Mechanistic Studies
Scheme 3. Plausible Reaction Mechanismsa
a Substituents other than R1 and R2 on indoles 1 are omitted for
clarity.
bond activations giving diindolylalkanes 9,19 one indolyl
group of which coordinates to the In and then eliminates
to provide cationic species 10 by way of the C(sp3)-
C(indolyl) bond cleavage.8,20 The hydride transfer to 10
gives products 4. These considerations imply that indium
Lewis acids have unique characteristics to activate carbon
functional groups, CtC, CdC and C-C,21 while typical
Lewis acids consisting of B, Ti or a rare earth metal prefer
activating heteroatom-containing functional groups, e.g.,
CdO, CdNR and C-halogens.22
proved to be highly effective at catalyzing this transforma-
tion with high levels of reaction efficiency and perfect
regioselection on both indoles and alkynes. A further
salient feature herein is a wide range of substrate coverages
with excellent functional group compatibility. From a
mechanistic point of view, the operation of the two differ-
ent pathways in this single transformation is a unique
aspect.
In closing, we disclosed the first reductive alkylation of
indoles with alkynes and hydrosilanes, where In(NTf2)3
Acknowledgment. We greatly appreciate Dr. Go Hirai
as well as Dr. Mikiko Sodeoka at RIKEN, Japan, for their
help in HRMS measurements.
(19) For indium-catalyzed double addition of heteroarenes to
alkynes, see: Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 2454–2455.
(20) For a precedent with respect to C(sp3)-C(indolyl) bond cleavage,
see: Deb, M. L.; Bhuyan, P. J. Synlett 2008, 325–328.
(21) For an account, see: Tsuchimoto, T. J. Synth. Org. Chem., Jpn.
2006, 64, 752–765.
Supporting Information Available. Experimental pro-
1
cedures, characterization data and H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Yamamoto, H.; Ishihara, K. Acid Catalysis in Modern Organic
Synthesis; Wiley-VCH: Weinheim, 2008.
Org. Lett., Vol. 13, No. 5, 2011
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