Friedel-crafts alkylation of indoles by tert-enamides in acetic acid

Article abstract of DOI:10.1055/s-0031-1290605

In acetic acid, Friedel-Crafts alkylation of indoles by tert-enamides proceeded effectively in the absence of any catalyst to afford the pharmacologically and biologically active 2-oxo-1-pyrrolidine derivatives in moderate to good yields. The mechanistic

Full text of DOI:10.1055/s-0031-1290605

LETTER
751
Friedel–Crafts Alkylation of Indoles by tert-Enamides in Acetic Acid
F
riedel–Crafts Alk
i
ylation
n
of Indoles g Zhang, Jing Jiang, Xue-Qiang Chu, Ran Jiang, Xiao-Ping Xu,* Dan-Hua Li, Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. of China
Fax +86(512)65880307; E-mail: xuxp@suda.edu.cn; E-mail: chemjsj@suda.edu.cn
Received 14 November 2011
substrate scope.10,11 Thus, a more convenient and environ-
mentally benign protocol is highly desirable. We recently
found that the synthesis of oral drugs formulated as Id
could be achieved by the Friedel–Crafts reaction of in-
Abstract: In acetic acid, Friedel–Crafts alkylation of indoles by
tert-enamides proceeded effectively in the absence of any catalyst
to afford the pharmacologically and biologically active 2-oxo-1-
pyrrolidine derivatives in moderate to good yields. The mechanistic
study based on the NMR and HRMS analysis shows that the reac- doles and tert-enamides under catalyst-free conditions,
tion was promoted by acid catalysis. The hydrogen-bond interaction
and acetic acid was confirmed to be the appropriate medi-
between tert-enamides and AcOH may also be responsible for the
reaction.
um for this reaction. Here, we report these results.
Key words: acetic acid, Friedel–Crafts alkylation, tert-enamide,
indole
N
O
O
N
S
H
N
Indole and its derivatives occur in nature and possess a va-
riety of important biological activities.1 Therefore, a lot of
attention has been paid to the modification of the indole
motif. To date, a number of methods have been developed
for C3-functionalization of indole,2 due to the fact that the
3-position of indole is the preferred site for electrophilic
substitution, and meanwhile C3-functionalized indoles
are often featured as pharmaceuticals, such as migraine
drug almotriptan and melatonin (Ia and Ib, Figure 1).3 In
this regard, Friedel–Crafts reaction is one of the most
commonly used syntheses for the C3-alkylation of in-
doles.4 Among various alkylation reagents, such as alco-
hols, esters, and olefins, the olefins are always considered
to be the best choice because they provide atom-economic
processes. It is worthwhile to note that electron-rich alk-
enes such as enamides, which has been proved to be use-
ful reagents and widely utilized in organic synthesis,5
were seldomly considered to be convenient candidates for
alkylation probably due to their weak electrophilicity.6
N
O
N
H
O
almotriptan (1a)
nefiracetam (1c)
H
N
O
R2
MeO
O
N
R1
N
H
R3
N
melatonin (1b)
H
Id
Figure 1
Zhang and co-workers have demonstrated that acetic acid
had no catalytic activity for this reaction.11 However, re-
search work on a multicomponent reaction showed that
acetic acid served as a solvent instead of a catalyst in pro-
moting the reaction effectively.12 Based on these results,
we also carefully conducted the similar examination on
the present reaction. 1-Vinylpyrrolidin-2-one (1a) and in-
dole (2a) were employed as the template substrates to test
the reaction in 2.0 mL ethanol at room temperature in the
presence of 10 mol% acetic acid (Table 1, entry 1). Just as
reported, no desired product was detected. Under the same
conditions, increasing the acetic acid loading from 50
mol% to 150 mol% also gave disappointing results
(Table 1, entries 2–4). However, to our surprise, the de-
sired reaction could run well in the presence of 50 mol%
acetic acid under the solvent-free conditions. After opti-
mization of the reaction conditions by varying the amount
of acetic acid, finally 1 mL acetic acid was proved to be
the best suitable condition for the model reaction (Table 1,
entries 5–7). On the basis of the above observations, we
suppose that acetic acid may act as both reaction catalyst
and solvent. In comparison, a sole use of the aprotic sol-
vent N,N-dimethylformamide was detected to be inert for
the reaction (Table 1, entry 8).
Amide fragment is also widely featured in pharmacologi-
cally and biologically active compounds.7 For example,
melatonin (Ib, Figure 1) is a naturally existing compound
found in animals, plants, and microbes.3b While nefirace-
tam (Ic, Figure 1) has been explored for the treatment of
cerebrovascular disease.8 Compounds possessing both es-
sential units (Id, Figure 1) have been discovered to dem-
onstrate good activities for the therapy of common
diseases such as attention deficit hyperactivity disorder
(ADHD), cardiac arrhythmia, asthmatic syndrome, etc.9
However, existing methods for the synthesis of these
pharmaceutical molecules often suffered from limitations
such as metal residue, medium detrimental and narrow
SYNLETT 2012, 23, 751–754
x
x.
x
x.
2
0
1
2
Advanced online publication: 28.02.2012
DOI: 10.1055/s-0031-1290605; Art ID: W66711ST
© Georg Thieme Verlag Stuttgart · New York

752
Y. Zhang et al.
LETTER
Table 1 The Synthesis of 1-[1-(1H-Indol-3-yl)ethyl]pyrrolidin-2-
one (3a) – Optimization Studiesa
acid (Scheme 1). Monoalkylated products 3an and 3bn
could be obtained in moderate to good yields with high se-
lectivity.
N
After we successfully accomplished the Friedel–Crafts re-
action between electron-rich aromatic rings and tert-en-
amides, we turned our attention to the reaction
mechanism. In order to make the relationship between
substrate and solvent clear, we compared the 1H NMR and
13C NMR of 1-vinylpyrrolidin-2-one (1a) in deuterated
+
O
N
O
N
N
H
H
1a
2a
3a
Entry Conditions
Time (h) Yield (%)b
Table 2 Reaction of tert-Enamides and Various Indolesa
1
2
3
4
5
6
7
8
AcOH (10 mol%), EtOH (2 mL)
AcOH (50 mol%), EtOH (2 mL)
AcOH (100 mol%), EtOH (2 mL)
AcOH (150 mol%), EtOH (2 mL)
AcOH (50 mol%)
24
24
24
24
24
7
0
0
AcOH
n
N
(1 mL)
n
R1
R1
0
+
O
r.t.
N
N
N
O
0
R2
R2
2a–m
3aa–am
3ba–bk
1a, b
72
85
83
0
AcOH (1 mL)
Entry
1
n
R1
R2
Product Time (h) Yield (%)b
AcOH (2 mL)
7
1a 1 2a H
2b 2-Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
3aa
3ab
3ac
3ad
3ae
3af
7
7
85
89
84
–
DMF (2 mL)
24
2
a Reactions were performed with 1a (1.0 mmol), 2a (1.0 mmol) at r.t.
3
2c 2-Ph
2d 3-Ac
2e 4-Me
2f 5-Me
2g 5-Br
2h 5-MeO
2i 5-NO2
2j 6-Me
2k 7-Me
2l H
7
b Isolated yields.
4
24
17
7
With the optimal conditions established, the scope of in-
doles to the protocol was explored, and the results are
summarized in Table 2. As for the reaction with 1-vi-
nylpyrrolidin-2-one (1a), various substituted indoles,
bearing either electron-donating or electron-withdrawing
substituents, reacted efficiently to give the desired prod-
ucts in good to excellent yields. The position of a substit-
uent at the p-system of indole negligibly affected the
reaction except at 3-position (Table 2, entries 2, 5, 6, 10–
12). In the indole p-system, C3 was well known to display
the strongest nucleophilic ability among all the atoms.14
So, in our investigation, the reaction using 3-acetyl indole
did not take place at all (Table 2, entry 4), while the use of
3-methyl indole led to an alkylation at its 2-position with
moderate efficiency (Table 2, entry 13). 1-Vinylazepan-
2-one (1b), another tert-enamide possessing a similar
framework to 1-vinylpyrrolidin-2-one, was also intro-
5
83
89
78
83
81
72
83
>99
41c
88
43
66
40
73
75
86
61
72
82
6
7
3ag
3ah
3ai
9
8
18
12
12
12
24
24
17
18
19
19
24
18
9
9
10
11
12
13
14
15
3aj
3ak
3al
2m 3-Me
3am
3ba
3bb
3bc
3be
3bf
3bg
3bh
3bi
1b 3 2a H
2b 2-Me
2c 2-Ph
duced. From the results shown in Table 2, we can see that 16
the reactivity of 1-vinylazepan-2-one (1b) was apparently
lower than that of 1-vinylpyrrolidin-2-one (1a), which
17
2e 4-Me
2f 5-Me
2g 5-Br
may be due to the steric hindrance arising from the bigger
ring system of 1b. The behavior also can be seen from the
facts that 2-Me, 2-Ph, and 4-Me indoles gave relatively
low yields of the corresponding products (Table 2, entries
15–17). In addition, it was found that the electronic effect
had a slight influence on the reactions of 1a and 1b. For
example, 5-Me indole afforded a higher yield of the ex-
pected product than 5-nitro indole under identical condi-
tions (Table 2, entries 6, 9, 18 and 21).
18
19
20
21
22
23
2h 5-MeO
2i 5-NO2
2j 6-Me
2k 7-Me
24
24
17
3bj
3bk
With the success of the above protocol using indoles, next
we investigated other electron-rich p-systems such as
1,3,5-trimethoxyl benzene (2n). It was fortunately found
that the reactions could also proceed smoothly in acetic
a Reactions were performed with N-vinyl compounds (1.0 mmol) and
indoles (1.0 mmol) in AcOH (1.0 mL) at room temperature.13
b Isolated yields.
c 2-Alkylated product was obtained.
Synlett 2012, 23, 751–754
© Thieme Stuttgart · New York

LETTER
Friedel–Crafts Alkylation of Indoles
753
tion). It may be due to the existence of a fast equilibrium
between 1a and its protonated iminium species
(Scheme 2). So we supposed that the reaction mainly pro-
ceeded via an acid-catalysis way. Nevertheless, we could
not rule out the possible involvement of a hydrogen-bond
interaction.
n
OMe
n
O
N
OMe
AcOH (1 mL)
r.t.
O
N
+
MeO
OMe
1a,b
2n
MeO
OMe
3an n = 1, 83% (24 h)
3bn n = 3, 61% (17 h)
In summary, we disclosed an efficient way for a useful
Friedel–Crafts reaction of electron-rich aromatic rings
with tert-enamides. The protocol has advantages such as
wider substrate scope, mild reaction conditions, and no
catalyst participation. By employing this method, a series
of analogues of pharmaceuticals were facilely synthe-
sized. A mechanistic study shows the reactions may occur
via an acid-catalysis process.
Scheme 1 The reactions between tert-enamides and electron-rich
benzene systems
chloroform (red) and acetic acid (blue, Figure 2). It was
found that peaks for H(c) and C(c) shifted downfield ob-
viously. However, we did not detect the typical signal of
sp3 carbon as previously described.15 Thus, a deuterium-
exchange experiment was carried out as well to examine
if there is a possibility that the reaction proceeded via a
classic acid-catalysis process. After treatment of 1a with
excessive CD3COOD, partial deuteration of 1a was ob-
served from HRMS analysis (see Supporting Informa-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The work was partially supported by the National Natural Science
Foundation of China (No. 21042007, 21172162), Natural Science
Basic Research of Jiangsu Province for Higher Education (No.
10KJB150016), a Research Grant from the Innovation Project for
Graduate Student of Jiangsu Province (CX10B-033Z), Innovation
project for undergraduate student-state level (No. 101028514), and
Key Project in Science & Technology Innovation Cultivation Pro-
gram of Soochow University.
References and Notes
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O
D
N
CD3COO–
+
O
N
CD3COOD
O
N
– CD3COOH
+
N
D
O
D
CD3COO–
Scheme 2 The possible status of 1a in CD3COOD
© Thieme Stuttgart · New York
Synlett 2012, 23, 751–754

754
Y. Zhang et al.
LETTER
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1-[1-(2-Methyl-1H-indol-3-yl)ethyl]pyrrolidin-2-one
(3ab)
White solid; mp 176–177 °C. IR (KBr): 3317, 2974, 2933,
2876, 1656, 1491, 1435, 1287, 1198, 1051, 749 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.72 (d, J = 6.9 Hz, 3 H),
1.82–2.00 (m, 2 H), 2.32–2.41 (m, 2 H), 2.48 (s, 3 H), 3.11–
3.19 (m, 1 H), 3.53–3.61 (m, 1 H), 5.75 (q, J = 7.2 Hz, 1 H),
7.05–7.12 (m, 2 H), 7.27 (t, J = 1.8 Hz, 1 H), 7.70 (d, J = 7.5
Hz, 1 H), 8.07 (br s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 174.3, 135.6, 133.9, 128.3, 121.3, 119.9, 119.6, 111.0,
110.8, 44.0, 44.0, 31.9, 18.1, 18.0, 13.0. HRMS (EI):
m/z calcd for C15H18N2O: 242.1419; found: 242.1420.
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Synlett 2012, 23, 751–754
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