A highly regioselective C-3 benzylation reaction of indoles with alcohols catalysed by an N-heterocyclic carbene

Article abstract of DOI:10.3184/174751915X14376593652711

The direct C-3 alkylation of indoles with primary and secondary alcohols through the combination of KOH and an N-heterocyclic carbene is described. The KOH/NHC-catalysed system can give desired C-3 alkylated indoles with high selectivity in moderate to excellent yields. Moreover, this process has obvious advantages such as high atom economy and the absence of a metal source.

Full text of DOI:10.3184/174751915X14376593652711

438 RESEARCH PAPER
VOL. 39 AUGUST, 438–441
JOURNAL OF CHEMICAL RESEARCH 2015
A highly regioselective C-3 benzylation reaction of indoles with alcohols
catalysed by an N-heterocyclic carbene
Yan-fang Zhu, Guo-ping Lu and Chun Cai*
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaoling Wei, Nanjing 210094, P.R. China
The direct C-3 alkylation of indoles with primary and secondary alcohols through the combination of KOH and an N-heterocyclic carbene
is described. The KOH/NHC-catalysed system can give desired C-3 alkylated indoles with high selectivity in moderate to excellent yields.
Moreover, this process has obvious advantages such as high atom economy and the absence of a metal source.
Keywords: N-heterocyclic carbene, benzylation, indole, alcohol, base, 3-benzyl indoles, 3-substituted indoles
Owing to the prevalence of the indole framework in natural
products, pharmaceuticals and functional materials,1-3 the
development of efficient and environmentally benign synthetic
protocols for the formation of indoles has been an important
objective in organic synthesis over the years.4,5 Among the
numerous known bioactive indole derivatives, C-3 alkylated
derivatives such as serotonin and melatonin (Fig.1) are of major
importance.
Alkylation with alcohols directly is thought to be difficult
due to the poor leaving ability of the hydroxy group in the
alkylation reactions; alcohols generally require preactivation
by transformation into the corresponding halides, carboxylates,
esters or related compounds with good leaving groups.
Nevertheless, these transformations have serious drawbacks
such as poor atom economy and large quantities of unwanted
byproducts.6-9 In view of the demand for efficient and atom-
economic processes, the direct alkylation of indoles with
alcohols ROH is highly desirable because the only byproduct
would be water (Scheme 1).
reaction, and finally, re-hydrogenated.19-22Remarkable examples
are the [Cp*IrCl2]2-catalysed system,23 the Ru-catalysed
system24 and the alumina-supported Pt nanocluster25 catalysed
system. Amongst these, the alumina-supported Pt nanocluster
catalysed system is noteworthy, because this catalytic system
can afford C-3 alkylated indoles with primary alcohols.
However, this methodology could only be readily accomplished
with primary alcohols and the preparation process of the
alumina-supported Pt nanocluster catalyst needed complex
handling and harsh conditions. In addition to the above two
methodologies, Yus and co-workers26 have recently reported
non-catalytic C-3 alkylation by alcohol sthrough a hydrogen-
autotransfer strategy with a stoichiometric amount of base.
This new methodology not only readily succeeds with primary
alcohols but is also successful with secondary alcohols.
However, the main limitation of this strategy is that this system
suffers from harsh reaction conditions (150 oC). Therefore,
developing a new methodology C-3 alkylation of indoles with
alcohols remains a challenge.
Two kinds of methodologies have been reported for the direct
catalytic substitution of indoles with alcohols. One is a Lewis
acid or Brønsted acid promoted Friedel–Crafts reaction.10-18
The synthesis of C-3 alkylated indoles can be accomplished
under mild reaction conditions. However, most of the synthetic
approaches reported so far could only be readily accomplished
with secondary alcohols. Primary alcohols are not suitable
becauseofsidereactions. Anothermethodologyiswellknownas
‘a hydrogen autotransfer process. In this procedure, the alcohol
is initially dehydrogenated, then undergoes a functionalisation
In recent years, N-heterocyclic carbenes (NHCs) have
attracted considerable attention as an important type of
organocatalyst.27-29 Particularly, the inversion of the classical
reactivity (umpolung) opens up new synthetic pathways.
Furthermore, due to their strong basicity, some reports of
31
aldol30 and Michael reactions
catalysed by NHCs have
been developed. Building on these, we became interested
in exploring the organocatalytic activity of NHCs in this
direct C-3 alkylation of indoles (Scheme 2) using a few
commercially available N-heterocyclic carbene precursors
A–D (Fig. 2). It was found that the NHCs exhibited
significant facilitation for the C-3 alkylation of indoles.
HN
NH2
CH2CH2
O
HO
Ar
H
3CO
R3
N
H
O
H
N
H
R2
R1
R1
R2
+
precursor
R3
Ar
N
N
base, solvent
Serotonin
Melatonin
H
H
Scheme 2 NHCs-mediated C-3 alkylation of indoles with alcohols.
Fig. 1 Examples of biologically active indole derivatives.
R1
N
N
N
N
N
N
l
C
N
N
ideal
R3
r
r
B
R1
H
O
R2
+ H
2O
R2
R3
+
Ph
Ph
r
B
B
Ph
Ph
reaction
N
N
H
H
A
B
D
C
Scheme 1 Ideal reaction for the direct C-3 alkylation of indoles.
* Correspondent. E-mail: c.cai@mail.njust.edu.cn
Fig. 2 N-heterocyclic carbene precursors used in the reaction.

JOURNAL OF CHEMICAL RESEARCH 2015 439
Results and discussion
(Table 1, entry 8). Optimisation of solvents for the synthesis of
3a employing the precatalyst D was also undertaken and it was
found that among toluene, p-xylene, DMF, CH3CN and water
(Table 1, entries 4 and 9–12), the best solvent in terms of yield
was toluene (Table 1, entry 4). This direct C-3 alkylation of
indoles was also markedly influenced by the base used (Table 1,
entries 4, 13–18). Among the screened bases, KOH was found
to be the most effective (Table 1, entry 4). NaOEt and NaOH
were less effective, giving 3-benzyl-1H-indole 3a in only 20%
and 23% yields, respectively (Table 1, entries 13 and 14). When
other bases including pyridine, DBU, K2CO3 and CH3COONa
were used, none of the desired product was observed (Table 1,
entries 15–18). Finally, the optimal amount of benzyl alcohol
2a was found to be 3 equiv. (Table 1, entry 20). 3a was isolated
in 85% yield when indole 1a reacted with 3 equiv. of benzyl
alcohol 2a in the presence of NHC precursor A (5 mol%) under
air in toluene at 110 oC for 24 h (Table 1, entry 21).
Having obtained the optimised reaction conditions, we
turned our attention to the examination of reactant limitation
of this catalytic system. The reactions of various substituted
indoles with several alcohols were explored, and the results
are summarised in Table 2. In order to get a high yield of the
product, the reaction time is not a priority. Benzyl alcohols with
electron-donating and electron-withdrawing groups at para-
position gave excellent yields of products (3b and 3d). However,
steric hindrance at the ortho-position of a benzyl alcohol
seems to have a depressing effect on yield. The ortho-position
halogen substituted benzyl alcohols gave the desired products
in a lower yield than the corresponding benzyl alcohol (3c and
3e). Furthermore, indoles with electron-donating or electron-
withdrawing groups all furnished the desired products 3f–l in
good to excellent yields. Note that the system also could be
applied to secondary alcohols (3m and 3n), albeit in moderate
For the reaction of free (N–H) indoles with alcohols, the
selective formation of the C-3 alkylated products is usually a
challenging task. In order to explore this process, the direct
substitution between indole 1a and benzyl alcohol 2a was
chosen as the model reaction and a brief screening of the
reaction conditions was undertaken. As we expected, 3-benzyl-
1H-indole 3a was isolated in 74% yield when indole 1a
reacted with 2 equiv. of benzyl alcohol 2a in the presence of
o
NHC precatalyst A (5 mol% ) under air in toluene at 110 C
for 24 h (Table 1, entry 1). Different types of N-heterocyclic
carbene precursors A–D were tested and D was found to be
the most effective for the preparation of 3a under the present
reaction conditions (Table 1, entries 1–4). Next, the reaction
temperature was screened and it was found that the best result
o
was obtained at 110 C with a yield of 87% (Table 1, entries
4–6). With the amount of precatalyst D decreased to 2 mol%,
the yield dropped to 74% and could not be improved even after
prolonging the reaction time to 48 h (Table 1, entry 7). When
no precatalyst D was used, only a low yield could be obtained
Table 1 Optimisation of the reaction conditions for the synthesis of
3-benzyl-1H-indolea
OH
precursor
+
N
base solvent
H
N
H
3a
1a
2a
Precursor/
mol%
2a/
equiv.
Entry
T/oC
Base/equiv.
Solvent
Yield/%b
1
2
A (5)
B (5)
C (5)
D (5)
D (5)
D (5)
D (2)
–
110
110
110
110
90
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1.2
3
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
KOH (1)
NaOEt (1)
NaOH (1)
DBU (1)
Pyridine (1)
K2CO3 (1)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-Xylene
CH3CN
74
29
45
87
76
47
74
23
83
nr
Table 2 C-3 benzylation of indoles with alcohols catalysed by NHCsa
3
and some realted reactions
4
R3
Ar
5
O
R2
R1
+
D
precursor
R2
N
6
7c
130
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
120
120
R3
KOH toluene
R1
Ar
H
N
H
8
3
1
2
9
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
D (5)
A (5)
D (5)
–
Isolated
yield/%b
Entry
3
R1 R2
R3 Ar
Time/h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DMF
nr
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h Ph
3i Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
24
24
24
24
24
24
24
24
24
24
24
24
48
48
24
24
95
89
67
90
62
88
90
85
87
80
83
86
42
67
88
79
4-CH3OC6H4
2-BrC6H4
4-BrC6H4
2- ClC6H4
Ph
Water
nr
Toluene
Toluene
Toluene
Toluene
Toluene
20
23
nr
H
5-Me
4-MeO
H
H
5-F
5-Cl
5-Br
H
H
H
nr
Ph
4-BrC6H4
4-BrC6H4
Ph
Ph
Ph
nr
CH3COONa (1) Toluene
nr
10
11 3k
12 3l
13 3m
14 3n
15 3o
16 3p
3j
H
H
H
H
H
H
H
KOH (1)
KOH (1)
Toluene
Toluene
Toluene
Toluene
Toluene
57
95
85
78
36
3
3
3
KOH (1)
KOH (1)
KOH (1)
Me Ph
Ph Ph
H
2-thienyl
3-pyridyl
H
H
aReaction conditions: 1a (1.0 mmol), 2a and precursor were mixed together in toluene (2
aThe reaction was carried out with indole (1 mmol), alcohol (3 mmol), precursor D
(0.05mmol), and KOH (1 equiv.) in toluene (2 mL) at 110 °C.
bIsolated yield.
mL) under air and finally base was added, 24 h.
bIsolated yield.
c Reaction time is 48h.

440 JOURNAL OF CHEMICAL RESEARCH 2015
3-Benzyl-5-bromo-1H-indole (3l): Yellow oil.39
3-(1-Phenylethyl)-1H-indole (3m): Pale pink solid; m.p. 69–71 ºC
(lit.25 70–73 ºC).
3-Benzhydryl-1H-indole (3n): White solid; m.p. 122–124 ºC (lit.26
122–123 ºC).
OH
Ph
2a
base+NHC
dehydrogenation
3-Thiophen-2-ylmethyl)-1H-indole (3o): White solid; m.p. 61–64 ºC
(lit.25 60–63 ºC).
N
Ph
3-Pyridin-3-ylmethyl)-1H-indole (3p): Colourless microneedles;
m.p. 159–163 ºC (lit.20 159–160 ºC).
O
NHC-H
base+NHC
New compounds
nucleophilic
attack
1
3-Benzyl-4- methoxy-1H-indole (3g): Colourless oil; H NMR (500
H2O
MHz, CDCl3) δ 7.73 (s, 1H), 7.43–7.33 (m, 4H), 7.28 (t, J = 6.8 Hz, 1H),
7.16 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 6.56 (d,
J = 7.8 Hz, 1H), 4.38 (s, 2H), 3.92 (s, 3H);13C NMR (126 MHz, CDCl3)
δ 154.1, 141.7, 137.1, 128.1, 127.3, 124.7, 121.9, 120.3, 116.5, 115.6,
103.6, 98.7, 54.2, 32.2; MS (M+H)+, 238. Anal. calcd for C16H15NO: C,
80.98; H, 6.37; N, 5.90; found: C, 80.92; H, 6.31; N, 5.84%.
3-(4-Bromobenzyl)-2-phenyl-1H-indole (3h): Colourless oil;1H NMR
(500 MHz, CDCl3) δ 8.12 (s, 1H), 7.57–7.48 (m, 5H), 7.48–7.42 (m, 4H),
7.36–7.30 (m, 1H), 7.23–7.15 (m, 3H), 4.30 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 139.6, 135.1, 134.7, 131.8, 130.6, 129.1, 128.4, 128.1, 127.0, 121.6,
119.1, 118.7, 118.5, 110.1, 109.6, 29.0; MS (M+H)+ 362 (79Br), 364 (81Br).
Anal. calcd for C21H16BrN: C, 69.63; H, 4.45; N, 3.87; found: C, 69.58; H,
4.40; N, 3.81%.
3-(4-Bromobenzyl)-2-methyl-1H-indole (3i): Colourless oil;1H NMR
(500 MHz, DMSO) δ 10.80 (s, 1H), 7.45–7.36 (m, 2H), 7.32–7.27
(m, 1H), 7.26–7.21 (m, 1H), 7.20–7.10 (m, 2H), 7.00–6.93 (m, 1H),
6.91–6.83 (m, 1H), 4.02–3.87 (m, 2H), 2.43–2.31 (m, 3H); 13C NMR
(126 MHz, DMSO) δ 141.1, 134.8, 131.7, 130.5, 129.8, 127.6, 119.6,
117.9, 117.7, 117.0, 109.9, 108.2, 28.4, 10.8; MS (M+H)+, 300 (79Br), 302
(81Br). Anal. calcd for C16H14BrN: C, 64.02; H, 4.70; N,4.67; found: C,
63.96; H, 4.65; N,4.60%.
N
H
1a
Ph
N
Ph
base+NHC-H
hydrogenation
N
H
3a
Scheme 3 Proposed mechanism for the C-3 benzylation of indole
with benzyl alcohol catalysed by KOH/NHCs.
yields. However, when indole (1a) and heptan-1-ol were used,
no reaction occurred. The reaction also could be performed
with the hydroxymethyl heteroaromatics in good yields (3o and
3p). However, when simple aliphatic alcohols or ally alcohols
were used instead of benzyl alcohols, no reaction occurred.
The proposed mechanism for the C-3 benzylation of indoles
with benzyl alcohol catalysed by KOH/NHC is presented in
Scheme 3. The base and NHC seem to play three different roles,
the first one is the deprotonation of the alcohol, favouring the
first dehydrogenation step, the second is the deprotonation of
indole increasing the nucleophilicity at the C3-position and the
third is the reduction of the C–C double bond.
Conclusions
NHCs belong to the most investigated reactive species in
the field of organic chemistry, and are formed in situ by
deprotonation of NHC precursors with the assistance of a
base. The NHCs exhibited significant utility for the direct
C-3 alkylation reaction of indoles with alcohols under suitable
reaction conditions. This methodology for the generation of
C-3 alkylated is indoles not only readily accomplished with
primary alcohols in excellent yields, but is also accomplished
with secondary alcohols in moderate yields. This methodology
is of high atom economy, employing an air stable precatalyst
and producing water as the only side product.
Experimental
All of the reagents and solvents were commercially available and
used without further purification. GC analyses were performed on
an Agilent 7890A instrument. H NMR and 13C NMR spectra were
recorded on Bruker DRX 500 instrument and TMS was used as a
reference. The 1H NMR spectroscopic data of these precatalysts are in
agreement with those reported in the literature.29-35
1
Reaction of C-3 benzylation of indoles with alcohols; general
procedure
KOH (0.056 g, 1 mmol) was added to a solution of catalyst precursor D
(0.05 mmol), indole (1 mmol) and alcohol (3 mmol) in toluene (2 mL),
then the mixture was stirred and heated at 110 °C for an appropriate
time. The mixture was then quenched by the addition of a saturated
NH4Cl solution (20 mL) and extracted with ethyl acetate (3×15 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered and the solvent removed under reduced pressure. The resulting
residue was usually purified by chromatography on silica gel (hexane/
ethyl acetate) to give the corresponding product.
Electronic Supplementary Information
The NMR spectra of 3g, 3h and 3i have been deposited in
the ESI available through stl.publisher.ingentaconnect.com/
content/stl/jcr/supp-data
We are grateful for financial support from the Province Natural
Science Foundation of Jiangsu (BK20131346).
3-Benzyl-1H-indole (3a): White solid; m.p. 101–102 ºC (lit.35
100–102 ºC).
Received 14 April 2015; accepted 2 July 2015
Paper 1503312 doi: 10.3184/174751915X14376593652711
Published online: 7 August 2015
3-(4-Methoxybenzyl)-1H-indole (3b): White solid; m.p. 82–83 ºC
(lit.35 81–83 ºC).
3-(2-Bromobenzyl)-1H-indole (3c): Light yellow oil.36
3-(4-Bromobenzyl)-1H-indole (3d): Pink solid; m.p. 120–121 ºC
(lit.37 119–120 ºC).
3-(2-Chlorobenzyl)-1H-indole (3e): Light yellow oil.39
3-Benzyl-5-methyl-1H-indole (3f): Yellow oil.35
3-Benzyl-5-fluoro-1H-indole (3j): White solid; m.p. 128-130 ºC
3-Benzyl-5-chloro-1H-indole (3k): Colourless micro-needles; m.p.
81–84 °C (lit.38 82–84 ºC).
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