A highly efficient route to C-3 alkyl-substituted indoles via a metal-free transfer hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2014.05.064

A highly efficient route to C-3 alkyl-substituted indoles via completely metal-free catalytic transfer hydrogenation of 3-indolemethanols was developed. This process proceeds via vinylogous iminium intermediates formed in situ in the presence of Br?nsted

Full text of DOI:10.1016/j.tetlet.2014.05.064

Tetrahedron Letters 55 (2014) 3774–3776
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A highly efficient route to C-3 alkyl-substituted indoles
via a metal-free transfer hydrogenation
a
a,
Cai Chen a, Huan-Xi Feng b, Zhi-Long Li a, Pin-Wen Cai a, Yan-Kai Liu a, , Lian-Hai Shan , Xian-Li Zhou
⇑
⇑
a School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, PR China
b School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient route to C-3 alkyl-substituted indoles via completely metal-free catalytic transfer
hydrogenation of 3-indolemethanols was developed. This process proceeds via vinylogous iminium inter-
mediates formed in situ in the presence of Brønsted acids, and Hantzsch ester is used as the reductant. The
reduction works extremely well with a large substrate scope, and the yields exceed 90% in almost all cases.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 12 March 2014
Revised 10 May 2014
Accepted 15 May 2014
Available online 23 May 2014
Keywords:
Highly efficient
Substituted indoles
Reductive alkylation
Hantzsch dihydropyridine
Substituted indoles, especially bearing substitutes at N-1, C-2, or
C-3 positions, are important compounds which are the key units of
many promising therapeutic agents.1 Among them, C-3 alkylindoles
are venerable pharmacophores for medicinal chemists, especially in
the neuroscience arena. Although C-3 substituted indoles could be
prepared by Fisher indole synthesis2 or Friedel–Crafts alkylation
reaction3 from simple and commercially available materials, these
methodologies have some certain drawbacks, very few of them
allow the use of both N-alkylated and N–H indole skeletons in the
same method.4 Despite these prominent works, considering
the significance of continual emergence of novel biologically active
indole-containing natural products, there is a high demand of a syn-
thetically versatile access to a range of C-3 functionalized indoles,
which could be performed with the indole nitrogen substituted or
unsubstituted.
Previous Work:
a) Acid/Et3SiH
or
R3
OH
R4
R4
R4
R3
R3
H+
b) Pd/C, H2
- H2O
This work:
c) Acid/Hantzsch ester
N
N
N
H
H
H
Vinylogous iminium
Figure 1. General approach to functionalized 3-substituted indoles.
limitations stated in the published works, (1) when triethylsilane
is applied as the reductant, an equal or excess Brønsted acids (such
as TFA, 1.0–3.0 equiv) and reductant (Et3SiH, 2.0–3.0 equiv) are
generally required in the reduction process,4a,6 while the use of a
catalytic amount of Brønsted acid as catalyst has not been reported
yet; (2) when transition metal is used to catalyze or mediate reac-
tions including Pd-catalyzed hydrogenation, additional functional
groups that are sensitive to hydrogenation conditions, such as
the halogen, nitro, and nitrile groups, are usually not tolerated;7
and (3) it could not always afford satisfactory results in the same
method when indole nitrogen is substituted or unsubstituted.6a,8
Recently, organocatalytic transfer hydrogenation using Hantzsch
ester as the reductant emerged as a powerful method in the
hydrogenation of aromatic and heteroaromatic compounds.9 We
reasoned that this catalytic strategy might be applicable to the
The traditional methods for the synthesis of C-3 substituted
indoles are mainly focused on the direct alkylation of indole by Fri-
edel–Crafts reaction. However, these methods suffer from low effi-
ciency and lack of regioselectivity (C-3 vs N-1). 3-(a-Hydroxyalkyl)
indoles, which could be easily synthesized from the reaction of
aldehyde or ketone with indole,5 can readily dehydrate to form
vinylogous iminium intermediates in situ in the presence of
Brønsted acids, and an subsequential step of reduction provides
3-alkyl substituted indoles (Fig. 1).6 Despite much work on
the synthesis of C-3 reductive alkylation of indoles, there are
reduction of 3-(a-hydroxyalkyl) indoles which can generate vinylo-
gous iminium intermediates in situ in the presence of Brønsted
acids. Herein we disclose a highly efficient and remarkably broad
substrate scope but completely metal-free catalytic transfer
⇑
Corresponding authors. Tel./fax: +86 28 87603202.
E-mail address: liuyankai@ouc.edu.cn (Y.-K. Liu).
http://dx.doi.org/10.1016/j.tetlet.2014.05.064
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

C. Chen et al. / Tetrahedron Letters 55 (2014) 3774–3776
3775
Table 1
tested (entries 2–4). In addition to TsOHÁH2O, a survey of other
Brønsted acids revealed that diphenyl phosphate showed better
efficiency while it is much more expensive than the TsOHÁH2O
(entries 5–7). Thus, the optimized conditions were established as
follows: TsOHÁH2O/CHCl3/25 °C.
Optimization of reaction conditions of reductive alkylationa
H
H
EtOOC
COOEt
HO
N
H
3
With the established conditions, we continued to study the sub-
Brønsted acid (10 mol%)
Solvent, RT, 15 min
strate scope by using a variety of substituted 3-(a-hydroxyalkyl)
N
N
H
2a
indoles 1.11 The results are listed in Table 2. As expected, the
reductions work extremely well with the alcohols bearing benzylic
or aliphatic fragments (Table 2, entries 1–12), and the yields
exceed 90% in almost all cases. Remarkably, the hydrogenation is
also tolerant of ortho-substitution in the benzyl group (entry 9),
indicating the steric hindrance has no effect on the reaction. The
effect of the electronic properties of the substituents on the phenyl
ring of the benzyl group was also investigated. Generally, when
electron-donating or weak electron-withdrawing groups on the
benzylic fragments were employed (entries 2–5), good to excellent
yields of the expected products were obtained; whereas strong
electron-withdrawing groups decreased the efficiencies (entries 6
and 7), requiring longer reaction time but still affording the
products in high yields. A variety of functional groups that are sen-
sitive to standard hydrogenation conditions, including the nitro,
nitrile, bromo, and even thienyl functional groups, are well toler-
ated in the process (entries 5–7 and 10).
H
1a (1.2 equiv)
Entry
Acidb
Solvent
Yieldc (%)
1
2
3
TsOHÁH2O
TsOHÁH2O
TsOHÁH2O
TsOHÁH2O
PhCOOH
CF3COOH
DPP
Toluene
EA
CHCl3
THF
CHCl3
CHCl3
CHCl3
70
82
91
94
65
86
93
4d
5e
6
7
a
Conditions: 1a (0.12 mmol), 3 (0.1 mmol), acid (10% mmol), solvent (0.25 ml),
at room temperature, for 15 min.
b
TsOHÁH2O: p-toluenesulfonic acid monohydrate; DPP: diphenyl phosphate.
c
Isolated yields based on 3.
d
The reaction was carried out for 5 h.
The reaction was carried out for 24 h.
e
hydrogenation10 of 3-(
ated indole derivatives.
a-hydroxyalkyl) indoles to provide C-3 alkyl-
Interestingly, when N-tosyl-indole was used instead of the ben-
zyl group, the reaction process was extremely effective for the syn-
thesis of bis-indolylmethane compound 2l in excellent yield (entry
12). It is particularly noteworthy that 1-(1-benzyl-1H-indol-3-yl)-
1-phenylethanol even showed higher reactivity, providing
branched 3-substituted indole 2m in high yield (entry 13). In addi-
tion, similar good results were attained for 3-indolemethanols
with various substituents on the indole ring (entries 14–16). To
further test the developed reaction concept, N-substituted indoles
were also explored under the optimized reaction conditions, the
Initially, (1H-indol-3-yl)(phenyl) methanol 1a (1.2 equiv) was
selected as the model substrate in toluene, using Hantzsch ester
3 as the reductant in the presence of TsOHÁH2O at room tempera-
ture. To our delight, the hydrogenation reaction was proceeded
smoothly to give the desired product 2a with 70% yield only after
being stirred for 15 min (Table 1, entry 1). Encouraged by this
result, we have examined the effect of solvent on the reactivity,
CHCl3 was found to be the most effective among the solvents
Table 2
Scope of the transfer hydrogenation reactiona
R3
R4
R4
R3
H
H
OH
3
R5
R5
EtOOC
Me
COOEt
Me
R2
R2
TsOH•H2O (10 mol%)
N
N
N
H
3
CHCl3, 25oC
R1
R1
1
2
Entry
R1
R2
R3
R4
R5
t
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Bn
H
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Ph
4-MeC6H5
4-FC6H5
4-ClC6H5
4-BrC6H5
4-NO2C6H5
4-CNC6H5
3-MeC6H5
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
15 min
5 min
5 min
5 min
15 min
10 h
91 (2a)
92 (2b)
84 (2c)
89 (2d)
90 (2e)
86 (2f)
90 (2g)
88 (2h)
89 (2i)
95 (2j)
94 (2k)
99 (2l)
99 (2m)
84 (2n)
94 (2o)
91 (2p)
91 (2q)
96 (2r)
97 (2s)
85 (2a)
8 h
5 min
22 min
7 min
10 min
15 min
15 min
10 min
1 h
30 min
15 min
10 min
15 min
15 min
9
2-MeOC6H5
2-Thienyl
n-Pr
10
11
12c
13c
14
15
16
17
18
19
20d
3-(N-Tosyl)-indolyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Cl
H
H
H
Me
Bn
–CH2COOEt
H
H
H
a
b
c
Reaction conditions: 1 (0.36 mmol), 3 (0.3 mmol), TsOHÁH2O (10 mol %), CHCl3 (0.75 ml), at room temperature.
Yield of isolated product after chromatographic purification.
The reaction was carried out using 0.45 mmol 1.
d
The reaction was carried out on 5 mmol scale.

3776
C. Chen et al. / Tetrahedron Letters 55 (2014) 3774–3776
(c) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances,
4th ed.; Thieme: New York, 2001.
corresponding products were obtained in high yield (entries 17–
19). To our delight, the catalytic system also maintained its effi-
ciency when applied on a synthetically useful scale (5.0 mmol),
leading to the formation of the product 2a with comparable yield
(entry 20).
In conclusion, we have developed a highly efficient approach to
C-3 alkyl-substituted indoles via completely metal-free catalytic
transfer hydrogenation of 3-indolemethanols. It should be noted
that both N-alkylated and N–H indole substrates were quite
reactive in this reductive alkylation reaction process. It tolerates
various functional groups that are sensitive to the conditions of
standard hydrogenations. The main advantages of this route are
excellent yields and simple operations. Current work in our labora-
tory focuses on developing an efficient catalytic asymmetric
variant to explore further derivatives.
2. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.
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Acknowledgment
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We are grateful to the financial support from the National
Nature Science Foundation of China (21302156).
Supplementary data
9. For recent reviews on transfer hydrogenation mediated by Hantzsch esters,
see: (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 2007, 40,
1327; (b) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407; (c) You, S.-L. Chem.
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J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004, 43,
6660.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
05.064.
References and notes
11. General procedure from 3-(a-hydroxyalkyl) indoles 1 to C-3 alkyl substituted
indoles 2: Catalyst TsOHÁH2O (10 mol %) was added to a solution of compound 1
(0.36 mmol) and Hantzsch ester 2 (0.3 mmol) in CHCl3 (0.5 ml), the mixture
was stirred at room temperature and monitored by TLC until completion. After
removing the solvent under reduced pressure, the product was purified by
flash chromatography on silica gel using EtOAc/petroleum ether as eluent.
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V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt,
J. J. Med. Chem. 1988, 31, 2235; (b) Faulkner, D. J. Nat. Prod. Rep. 2002, 1;