Recyclable NaHSO4 catalyzed alkylation of tert-enamides with indoles or amines in water: Facile construction of pharmaceutically analogous bis-alkaloid scaffolds

Article abstract of DOI:10.1039/c3ra40833g

An efficient sodium hydrogen sulfate catalyzed alkylation of indoles or amines with tertiary enamides has been accomplished in water, affording the pharmacologically and biologically active 2-oxo-1-pyrrolidine derivatives in moderate to excellent yields. The key to our success is the use of NaHSO ₄ as a low loading, inexpensive, green and recyclable catalyst and the reactions could be scaled up to gram level.

Full text of DOI:10.1039/c3ra40833g

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Recyclable NaHSO4 catalyzed alkylation of tert-
enamides with indoles or amines in water: facile
construction of pharmaceutically analogous bis-alkaloid
scaffolds 3
Cite this: RSC Advances, 2013, 3,
8380
Xue-Qiang Chu, Shun-Yi Wang* and Shun-Jun Ji*
Received 19th February 2013,
Accepted 19th March 2013
An efficient sodium hydrogen sulfate catalyzed alkylation of indoles or amines with tertiary enamides has
been accomplished in water, affording the pharmacologically and biologically active 2-oxo-1-pyrrolidine
derivatives in moderate to excellent yields. The key to our success is the use of NaHSO4 as a low loading,
inexpensive, green and recyclable catalyst and the reactions could be scaled up to gram level.
DOI: 10.1039/c3ra40833g
www.rsc.org/advances
use of iodine9a and AcOH9b in these transformations.
However, catalytic amount of Brønsted acids delivered no or
Introduction
The c-butyrolactam ring is currently explored as a privileged
structure for drug design and discovery due to the broad scope
of numerous pharmacologically active agents and natural
products.1 For example, some of them are used as cerebro-
vascular disease drugs (Nefiracetam),1a protective agents of
hypoxic and ischemic type aggressions of the central nervous
system, as well as therapeutic compounds for epilepsy
(Levetiracetam).1b Therefore, much attention has been paid
to the synthesis and modification of above 2-oxo-1-pyrrolidine
pharmaceutically derivatives. Other alkaloid scaffolds such as
indole and (heterocyclic) aromatic amines are also implanted
as subunit structures, and their typical structures can be
depicted as I1c and II1d (Fig. 1).
relatively low reactivity. What’s more, existing methods for the
synthesis of pharmaceutical analogues of compound I often
suffer from limitations such as metal residue, medium
detriment, narrow substrate scopes and catalyst non-recycl-
ability. To the best of our knowledge, using enamide as
alkylation reagent in the presence of inorganic salt catalysis in
water is still unknown. As a continuation of our interests in
green chemistry,10 herein, we report the development of a
simple procedure utilizing NaHSO4?H2O11 as a transition
metal-free, green, efficient and recyclable catalyst for alkyla-
tion of tert-enamides with indoles or amines in water.
Organic reactions in aqueous media are undergoing an
unprecedented explosion of interest,2 not only because water
offers practical advantages over organic solvents from eco-
nomical, environmental and safety standpoints, but also
reactions in aqueous media display unique selectivity and
reactivity, especially the alkylation reactions.3 Despite various
alkylation reagents (e.g., alcohols, esters, and olefins) have
been successfully employed in water,4 most of these investiga-
tions focus on the electron-deficient alkenes.5 Enamides, as
good candidates in the realms of electron-rich olefins, are
seldomly considered for the alkylation probably due to the
poor electrophilicity.6 Previously, Zhang et al.7 and our group8
have described an efficient Fe(III)-catalyzed alkylation of
indoles with enamides. More recently, we also reported the
Results and discussion
Initially, the reaction of indole 2a with 1-vinylpyrrolidin-2-one
1a was carried out under aqueous conditions without catalyst
(Scheme 1). It was found that no desired product was formed
(Table 1, entry 1). Then, the feasibility of Brønsted acid
catalysis was investigated. Treatment of 1a and 2a with 5 mol%
p-toluenesulfonic acid failed to give any product even with
prolonged reaction time for 24 h (Table 1, entry 2). It should be
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123,
P. R. China. E-mail: shunyi@suda.edu.cn; shunyi@suda.edu.cn;
Fax: +86 512 65880307; Tel: +86-512-65880307
Fig. 1 The typical structures of pharmaceutically active 2-oxo-1-pyrrolidine
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
analogues.
c3ra40833g
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system (Table 2, entry 2), although it failed under other
Brønsted acid catalyzed conditions.13 It was noteworthy that
steric hindered 2d with phenyl substituent at 2-position also
could give the product 3ad in 75% yield when 5 mol%
NaHSO4?H2O was used (Table 2, entry 4). Moreover, the yield
decreased slightly with 4-methyl indole 2e, possibly as a result
of steric effects (Table 2, entry 5). Meanwhile, indoles with
electron-withdrawing groups (Br and NO2) also worked
smoothly to furnish the corresponding alkylated products in
89% and 45% yields, respectively (Table 2, entries 7–8).
Furthermore, 1-vinylazepan-2-one 1b, the derivatives of struc-
turally-related fused ring having important pharmacologically
activities,14 was selected to synthesize the corresponding
pharmaceutical analogous. It was found that the reactivity of
1-vinylazepan-2-one 1b was apparently lower than that of
1-vinylpyrrolidin-2-one 1a (Table 2, entries 12–14), which may
due to the steric hindrance arising from the bigger ring
system. Another acyclic enamide 1c was also proven as a good
candidate in undergoing alkylation with indole, affording the
desired products in 55% yield (Table 2, entry 15). Additionally,
further expansion of this protocol to other N-vinyl compounds
was limited, 1d and N-vinylcarbazole 1e were almost inert
under the standard conditions, respectively (Table 2, entries
16–17).
Scheme 1
noted that the desired product 3aa was obtained in 81% yield
when acetic acid was applied (Table 1, entry 3). This result is
different with previous reports in organic medias.7,9b To our
12
surprise, acidic-functionalized ionic liquid [PMIm]HSO4 was
sufficient to promote the reaction, and 3aa could be obtained
in 90% yield (Table 1, entry 4). When NaHSO4?H2O and H2SO4
were applied to the reaction instead of [PMIm]HSO4, similar
results were found, respectively (Table 1, entries 5–6). This
result suggested that the presence of HSO4 groups was crucial
to the high catalytic performance of the catalysts. To validate
this hypothesis, other sodium salts such as NaHSO3, Na2HPO4,
Na2SO4 etc. were examined subsequently (Table 1, entries 7–
11). As anticipated, no better results were obtained in these
cases. Based on the above results, NaHSO4?H2O is the
preferred catalyst for this reaction. Further exploration led to
a discovery that the yield of product could be increased to 97%
then slowly decreased with the reaction time decreasing from
12 h to 3 h (Table 1, entries 5 and 12–13). Moreover, with an
attempt to decrease the catalyst loading to 1 mol%, 3aa also
could be observed in 96% yield (Table 1, entry 14).
With the optimal reaction conditions in hand, we explored
the scope of the reaction by using various indoles and the
results are summarized in Table 2. Similar to the case of 2a,
the alkylation of indoles with electron-donating groups, such
as methyl, phenyl, and methoxyl could be accomplished with
good generality in water, provided the desired addition
products in good to excellent yields (Table 2, entries 2–6 and
9–11). N-methylindole 2b presented high efficiency in this
Inspired by the above results, we were eager to know
whether the present protocol was still general enough to
construct the bio-active compound II with wider structural
diversity under aqueous conditions. Thus, we turned our
attention to investigate the scope and limitations of this
alkylation reaction with a wide range of substituted anilines,
moderate to good yields were achieved in the corresponding
products, as shown in Table 3.
The substrates with strong electron-withdrawing groups on
aryl ring, such as CN, COOEt, NO2, exhibited good reactivity
(Table 3, entries 1–3). In addition, the steric hindered 3-nitro-
phenylamine 4d and 2-nitro-phenylamine 4e were well
tolerated (Table 3, entries 4–5). Notably, the presence of a
weak electron-withdrawing group such as halogens at the para
or ortho position of anilines obviously reduced the reactivity
presumably owing to the electronic effect and sometimes
steric effect (Table 3, entries 4–5). However, aniline 4h and
aniline with an electron-donating group (Me) 4i, furnished the
desired products 5ah and 5ai with yields of just 41% and 40%
respectively, albeit with an elevated reaction temperature
(Table 3, entries 8–9). Unfortunately, the reaction of 1a with
4j only afforded the product 5aj in 35% yield (Table 3, entry
10). What’s more, aliphatic amine 4k, which shows stronger
basicity than anilines, was inert to the alkylation reaction
(Table 3, entry 11). Nevertheless, 1H-benzotriazole 4l demon-
strated high efficiency to give the target product in good yield
(Table 3, entry 12). Another N-containing substrate, sulfona-
mide 4m proceeded smoothly and 62% yield of addition
product 5am was obtained (Table 3, entry 13). When
1-vinylpyrrolidin-2-one 1a was replaced with 1-vinylazepan-2-
one 1b, satisfying results were obtained (Table 3, entries 14–
15).
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Time (h)
Yield (%)b
1
2
3
4
—
12
24
12
12
12
12
12
12
12
12
12
7
0 (0c)
0
PTSAd
HOAc
[PMIm]HSO4
NaHSO4?H2O
H2SO4
NaHSO3
Na2HPO4
Na2SO4
NaCl
NaOAc
81
90
91
90
e
5
6f
7
Trace
Trace
46
,10%
0
8
9
10
11
12
13
14
NaHSO4?H2O
NaHSO4?H2O
1 mol% NaHSO4?H2O
97
88
96
3
7
a
Reaction conditions: 2a (0.5 mmol), 1a (1.0 mmol), catalyst (5
b
c
mol%), H2O (1.5 mL), at room temperature. Isolated yield. At 60
d
e
uC. PTSA = p-toluenesulfonic acid. [PMIm]HSO4 = 3-methyl-1-
f
pentyl-3H-imidazol-1-ium hydrogen sulfate. Concentrated sulfuric
acid (wt%: 98%) was used.
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Table 2 Alkylation of indoles with enamidesa
Table 2 (Continued)
Entry Enamide
17
Indole
Product Time (h) Yield (%)b
—
24
NRf
Entry Enamide
1
Indole
Product Time (h) Yield (%)b
3aa
7
96
a
Reaction conditions: indoles 2a–k (0.5 mmol), enamide 1a–e (1.0
mmol), NaHSO4c(1 mol%), H2O (1.5 mL), at room temperature.
b
d
Isolated yield. 5 mol% of catalyst was used, at 100 uC. 3 equiv.
e
f
2
3ab
5
99
1a was used at 60 uC for 24 h. At 60 uC for 23 h. NR = No
reaction.
3
3ac
3ad
3ae
16
19
15
85
This mild and green methodology would be potentially
useful for the synthesis of pharmaceutically active c-butyr-
olactam analogues in industrial process. Therefore, a large-
scaled reaction of indole 2a (10.0 mmol) with 1.2 equiv. of 1a
(12.0 mmol) was carried out under little modified conditions
(Scheme 2). To our delight, the reaction was completed in 5 h
to give the pure product of 3aa in 95% yield only after the
removal of excessive 1a under the reduced pressure without
further purification and was washed with water.
In addition, to test the catalyst reusability, a series of
relatively large-scaled experiments of 1a and 2a with 1 mol%
NaHSO4?H2O were carried out in water. The results are
summarized in Fig. 2. The reaction could also give 3aa in
60% yield after three cycles.
4
75c/80d
56
5e
6
7
3af
14
23
92
3ag
62/89e
8
3ah
19
32c/45d
9
3ai
3aj
19
23
95
90
Conclusions
In summary, we have explored the efficient alkylation of
indoles or amines with tert-enamides catalyzed by inexpensive
NaHSO4 with low loading under aqueous conditions, the
desired product could up to 99% yield. The reactions could be
scaled up to gram level and the catalyst was reusable for three
times. Thus, this catalytic system serves as an environmentally
benign tool for the efficient synthesis of pharmaceutically
active 2-oxo-1-pyrrolidine derivatives and would lead to a
potential application in industrial processes.
10
11
12
3ak
3ba
15
25
87
87
13
3bi
23
23
91
24
Experimental
14e
3bg
General
Melting points were recorded on an Electrothermal digital
melting point apparatus. IR spectra were recorded on a Varian
FT-1000 spectrophotome-ter using KBr optics. 1H NMR spectra
were recorded on a Varian INOVA 400 and and 13C NMR were
recorded on a Varian INOVA 75 or 100 MHz spectrometer
using CDCl3 as solvent and TMS as internal standard. High
resolution mass spectra were obtained using Microma GCT-
TOF instrument.
15
16
3ca
3da
25
24
34/55e
Trace
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Table 3 Alkylation of amino compounds with enamidesa
Table 3 (Continued)
Entry Enamide Amine
14
Product Time (h) Yield (%)b
5ba
12
90
Entry Enamide Amine
1
Product Time (h) Yield (%)b
15
5bd
12
91
5aa
12
92
2
5ab
12
90
a
Reaction conditions: enamide 1a–b (1.0 mmol), amino compound
4 (0.5 mmol), NaHSO4 (1 mol%), H2O (1.5 mL), at room
b
c
d
temperature. Isolated yield. At 100 uC for 24 h. NR = No
reaction.
3
4
5ac
5ad
12
12
96
90
Typical procedure for the alkylation of indoles, anilines with
enamides
Nucleophile (0.5 mmol), NaHSO4?H2O (1 mol%), enamide (1
mmol) and water (1.5 mL) were added into a tube. Then the
mixture was vigorously stirred at room temperature, until
nucleophile was completely consumed as indicated by TLC
analysis. Then the mixture was poured into H2O and extracted
with ethyl acetate (3 6 5 mL). The combined organic layer was
washed with brine (2 6 3 mL), dried with anhydrous MgSO4,
and evaporated under the reduced pressure. Finally, the
residue was purified by flash column chromatography with
EtOAc and PE as eluents to afford pure product.
5
5ae
12
62
6
5af
24
24
73
29
7c
5ag
Typical procedure for reuse of NaHSO4 in water
Indole 2a (10 mmol), NaHSO4?H2O (5 mol%), 1-vinylpyrrolidin-
2-one 1a (12 mmol) and water (3 mL) were added into a flask.
Then the mixture was vigorously stirred at room temperature
and and the progress of the reaction was monitored by TLC
analysis. After completion of the reaction, 10 mL of deionized
water was added into the reaction, the mixture was extracted
with CH2Cl2 (3 6 10 mL), and the combined organic layer
washed with deionized water (3 6 5 mL), the water layer was
collected. Organic layers were dried with anhydrous MgSO4,
filtered, and concentrated under reduced pressure and the
residue was purified by flash column chromatography.
NaHSO4 left in water was concentrated to 1 mL under reduced
pressure at 80 uC for another cycle.
8
5ah
5ai
5aj
12
24
24
36/41c
40
9c
10c
35
11
12
—
24
24
NRd
80
1-(1-(1H-Indol-3-yl)ethyl)pyrrolidin-2-one (3aa). White solid;
m.p. 165–167 uC. IR (KBr): 3243, 3165, 3107, 2972, 2876, 1659,
1
1490, 1440, 1288, 1198, 751 cm21. H NMR (400 MHz, DMSO-
5al
d6): d = 1.52 (d, J = 7.0 Hz, 3H), 1.62–1.73 (m, 1H), 1.78–1.88 (m,
13
5am
24
63
Scheme 2 A large-scaled reaction under neat conditions.
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7.08 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 12.7 Hz, 2H), 8.41 (br, s, 1H).
13C NMR (75 MHz, CDCl3): d = 174.1, 137.2, 131.2, 125.5, 123.2,
122.4, 121.6, 115.9, 109.3, 44.4, 43.4, 32.4, 20.2, 17.9, 17.5.
HRMS (EI): m/z calcd for C15H18N2O: 242.1419; found:
242.1420.
1-(1-(5-Methoxy-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3af).
White solid; m.p. 134.5–135.4 uC. IR (KBr): 3433, 3235, 3050,
2935, 2826, 1647, 1489, 1440, 1289, 1216, 1028, 926, 800, 666
1
cm21. H NMR (300 MHz, CDCl3): d = 1.57 (d, J = 6.9 Hz, 3H),
1.70–2.01 (m, 2H), 2.30–2.55 (m, 2H), 2.86 (dd, J = 8.9, 14.9 Hz,
1H), 3.26 (dd, J = 8.9, 14.5 Hz, 1H), 3.80 (s, 3H), 5.75 (q, J = 6.8
Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 7.10 (s, 2H), 7.24 (d, J = 8.8 Hz,
1H), 8.61 (br, s, 1H). 13C NMR (100 MHz, CDCl3): d = 174.5,
154.1, 146.4, 131.8, 126.9, 123.0, 115.5, 112.7, 112.2, 100.8,
55.9, 42.8, 42.3, 31.9, 17.8. HRMS (EI): m/z calcd for
Fig. 2 Recyclability of catalyst.
1H), 2.18–2.34 (m, 2H), 2.67–2.73 (m, 1H), 3.22–3.27 (m, 1H),
5.53 (q, J = 6.9 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.5
Hz, 1H), 7.32 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 7.9 Hz,
1H). 13C NMR (100 MHz, CDCl3): d = 174.8, 137.0, 126.9, 122.8,
122.6, 120.3, 119.9, 116.4, 111.6, 43.1, 42.7, 32.2, 18.2, 17.1.
HRMS (EI): m/z calcd for C14H16N2O: 228.1263; found:
228.1266.
1-(1-(1-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ab).
Yellow oil. IR (KBr): 3056, 2971, 2890, 1673, 1468, 1280,
1213, 1095, 745 cm21. 1H NMR (300 MHz, CDCl3): d = 1.58 (d, J
= 7.2 Hz, 3H), 1.78–1.93 (m, 2H), 2.40–2.46 (m, 2H), 2.85–2.93
(m, 1H), 3.23–3.31 (m, 1H), 3.77 (s, 3H), 5.73–5.80 (q, J = 6.9
Hz, 1H, CH), 6.97 (s, 1H), 7.07–7.12 (m, 1H), 7.21–7.30 (m, 2H),
7.61 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 174.4,
137.4, 127.1, 127.0, 122.3, 119.9, 114.7, 109.5, 42.8, 42.5, 33.1,
32.0, 18.0, 17.0. HRMS (EI): m/z calcd for C15H18N2O: 242.1419;
found: 242.1418.
C
15H18N2O2: 258.1368; found: 258.1364.
1-(1-(5-Bromo-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ag).
White solid; m.p. 154–156 uC. IR (KBr): 3157, 3080, 2982,
1650, 1439, 1288, 1194, 885, 790 cm21 1H NMR (300 MHz,
.
CDCl3): d = 1.58 (d, J = 7.2 Hz, 3H), 1.79–1.98 (m, 2H), 2.45 (t, J
= 8.1 Hz, 2H), 2.82–2.90 (m, 1H), 3.24–3.31 (m, 1H), 5.70 (q, J =
6.9 Hz, 1H), 7.14–7.31 (m, 3H), 7.74 (s, 1H), 8.25 (br, s, 1H). 13
C
NMR (100 MHz, CDCl3): d = 174.9, 135.7, 128.6, 125.7, 123.9,
122.3, 116.1, 113.6, 113.2, 43.0, 42.7, 32.2, 18.2, 17.2. HRMS
(EI): m/z calcd for C14H15BrN2O: 308.0347(81Br); found:
308.0343.
1-(1-(5-Nitro-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ah).
Yellow solid; m.p. 241–242 uC. IR (KBr): 3379, 2968, 1660,
1522, 1295 cm21. 1H NMR (400 MHz, DMSO-d6): d = 1.54 (d, J =
6.8 Hz, 3H), 1.70–1.74 (m, 1H), 1.86–1.90 (m, 1H), 2.20–2.36
(m, 2H), 2.70–2.76 (m, 1H), 3.27–3.34 (m, 1H), 5.56–5.61 (m,
1H), 7.54 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H), 8.00 (d, J = 8.4 Hz,
1H), 8.45 (s, 1H). 13C NMR (100 MHz, DMSO-d6): d = 173.1,
140.5, 139.6, 127.2, 125.4, 117.6, 116.8, 115.7, 112.0, 41.4, 41.3,
31.0, 17.3, 16.7. HRMS (EI): m/z calcd for C14H15N3O3:
273.1113; found: 273.1112.
1-(1-(5-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ai).
White solid; m.p. 173–174 uC. IR (KBr): 3154, 2928, 2890,
1652, 1490, 1441, 1290, 792 cm21. 1H NMR (300 MHz, CDCl3):
d = 1.58 (d, J = 6.9 Hz, 3H), 1.77–1.91 (m, 2H), 2.42–2.46 (m, 5H,
CH2), 2.88–2.90 (m, 1H), 3.27–3.28 (m, 1H), 5.75 (q, J = 6.6 Hz,
1H), 7.03 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 7.24–7.27 (m, 1H),
7.39 (s, 1H), 8.26 (br, s, 1H). 13C NMR (100 MHz, CDCl3): d =
174.7, 135.3, 129.5, 127.1, 124.4, 122.8, 119.3, 115.8, 111.3,
43.2, 42.8, 32.2, 22.0, 18.2, 17.2. HRMS (EI): m/z calcd for
C15H18N2O: 242.1419; found: 242.1420.
1-(1-(2-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ac).
White solid; m.p. 176–177 uC. IR (KBr): 3317, 2974, 2933,
2876, 1656, 1491, 1435, 1287, 1198, 1051, 749 cm21. H NMR
1
(300 MHz, CDCl3): d = 1.72 (d, J = 6.9 Hz, 3H), 1.82–2.00 (m,
2H), 2.32–2.41 (m, 2H), 2.48 (s, 3H), 3.11–3.19 (m, 1H), 3.53–
3.61 (m, 1H), 5.75 (q, J = 7.2 Hz, 1H), 7.05–7.12 (m, 2H), 7.27 (t,
J = 1.8 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 8.07 (br, s, 1H). 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.
1-(1-(2-Phenyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ad).
White solid; m.p. 166–167 uC. IR (KBr): 3398, 3165, 2930,
2895, 1660, 1442, 1288, 1204, 778 cm21 1H NMR (300 MHz,
.
CDCl3): d = 1.62 (d, J = 6.9 Hz, 3H), 1.79–2.00 (m, 2H), 2.36–2.43
(m, 2H), 3.24–3.31 (m, 1H), 3.58–3.66 (m, 1H), 5.62 (q, J = 7.2
Hz, 1H), 7.16–7.23 (m, 2H), 7.39–7.49 (m, 6H), 7.84 (d, J = 7.8
Hz, 1H), 8.21 (br, s, 1H). 13C NMR (100 MHz, CDCl3): d = 174.3,
737.3, 136.3, 133.0, 129.5, 129.1, 128.8, 128.3, 122.5, 121.0,
120.3, 111.7, 111.5, 45.3, 44.9, 32.0, 18.7, 18.3. HRMS (EI): m/z
calcd for C20H20N2O: 304.1576; found: 304.1577.
1-(1-(6-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3aj).
White solid; m.p. 135–136 uC. IR (KBr): 3213, 3100, 2980,
1
2879, 1662, 1610, 1493, 1440, 1289, 1119 cm21. H NMR (400
MHz, CDCl3): d = 1.57 (d, J = 7.0 Hz, 3H), 1.74–1.81 (m, 1H),
1.87–1.93 (m, 1H), 2.41–2.46 (m, 5H), 2.84–2.89 (m, 1H), 3.23–
3.29 (m, 1H), 5.73–5.78 (q, J = 7.0 Hz, 1H), 6.93 (d, J = 8.0 Hz,
1H), 7.04 (s, 1H), 7.16 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 8.36 (br,
s, 1H). 13C NMR (75 MHz, CDCl3): d = 174.50, 137.19, 132.19,
124.40, 121.84, 121.59, 119.07, 115.64, 111.38, 42.91, 42.39,
31.94, 21.80, 17.83, 16.80. HRMS (EI): m/z calcd for C15H18N2O:
242.1419; found: 242.1416.
1-(1-(4-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ae).
Yellow solid; m.p. 184–185 uC. IR (KBr): 3158, 3109, 3041,
2942, 2878, 1661, 1493, 1439, 1290, 750 cm21. H NMR (300
1
MHz, CDCl3): d = 1.58 (d, J = 6.4 Hz, 3H), 1.82–1.93 (m, 2H),
2.43 (t, J = 7.9 Hz, 2H), 2.60 (s, 3H), 2.85–2.92 (m, 1H), 3.17–
3.25 (m, 1H), 5.85 (q, J = 6.4 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H),
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7.4 Hz, 1H), 7.22–7.19 (m, 2H), 7.31–7.26 (m, 5H), 7.36 (d, J =
8.1 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d = 174.7, 138.2, 138.6, 129.1, 128.6, 126.7,
122.8, 122.6, 120.1, 119.8, 114.7, 111.5, 48.1, 42.8, 37.1, 31.7,
18.0 ppm. HRMS (EI): m/z calcd for C20H20N2ONa: [M+Na]+
327.1473; found, 327.1468.
4-(1-(2-Oxopyrrolidin-1-yl)ethylamino)benzonitrile (5aa).
White solid; m.p. 185–186 uC. IR (KBr): 3305, 2983, 2218,
1664, 1612, 1531, 1285, 1161 cm21. 1H NMR (400 MHz, CDCl3):
d = 1.48 (d, J = 6.4 Hz, 3H), 1.88–2.05 (m, 2H), 2.39–2.44 (m,
2H), 3.15–3.21 (m, 1H), 3.30–3.36 (m, 1H), 4.51 (br s, 1H, NH),
5.70–5.75 (m, 1H), 6.67 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz,
2H) ppm. 13C NMR (100 MHz, CDCl3): d = 174.97, 148.93,
133.83, 120.30, 113.17, 99.97, 56.39, 40.86, 31.60, 19.08, 17.82
ppm. HRMS (EI): m/z Calcd for C13H15N3O: 229.1215; found,
229.1213.
Ethyl 4-(1-(2-oxopyrrolidin-1-yl)ethylamino)benzoate (5ab).
White solid; m.p. 91–92 uC. IR (KBr): 3503, 2977, 1708, 1439,
1281, 1103, 844, 770 cm21. 1H NMR (400 MHz, CDCl3): d = 1.36
(t, J = 7.1 Hz, 3H), 1.47 (d, J = 6.3 Hz, 3H), 1.86–1.99 (m, 2H),
2.40 (t, J = 8.0 Hz, 2H), 3.14–3.20 (m, 1H), 3.29–3.34 (m, 1H),
4.31 (q, J = 7.1 Hz, 2H), 5.75 (q, J = 6.2 Hz, 1H), 6.64 (d, J = 8.5
Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H) ppm. 13C NMR (75 MHz,
DMSO-d6): d = 173.6, 165.7, 150.4, 130.9, 117.7, 111.8, 59.7,
55.6, 40.3, 18.5, 17.4, 14.3 ppm. HRMS (EI): m/z Calcd for
C15H20N2O3: 276.1474; found, 276.1473.
1-(1-(4-Nitrophenylamino)ethyl)pyrrolidin-2-one (5ac).
Yellow solid; m.p. 204–205 uC. IR (KBr): 3271, 3072, 2928,
1665, 1484, 1323, 1161, 832 cm21. 1H NMR (400 MHz, CDCl3):
d = 1.51 (d, J = 6.4 Hz, 3H), 1.90–2.05 (m, 2H), 2.40–2.45 (m,
2H), 3.16–3.22 (m, 1H), 3.32–3.38 (m, 1H), 4.77 (d, J = 6.9 Hz,
1H), 5.75–5.81 (m, 1H, CH), 6.67 (d, J = 9.0 Hz, 2H), 8.09 (d, J =
9.0 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): d = 175.15,
150.75, 126.53, 112.45, 56.69, 41.02, 31.62, 19.31, 17.98 ppm.
HRMS (EI): m/z Calcd for C12H15N3O3: 249.1113; found,
249.1108.
1-(1-(7-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one (3ak).
White solid; m.p. 166–168 uC. IR (KBr): 3222, 3113, 2971,
2933, 2873, 1650, 1614, 1498, 1444, 1298, 1201, 1123, 788
1
cm21. H NMR (300 MHz, CDCl3): d = 1.59 (d, J = 6.9 Hz, 3H),
1.78–1.91 (m, 2H), 2.40–2.46 (m, 2H), 2.49 (s, 3H), 2.83–2.91
(m, 1H), 3.23–3.31 (m, 1H), 5.77 (q, J = 6.6 Hz, 1H), 7.02–7.06
(m, 2H), 7.13(s, 1H), 7.46–7.49 (m, 1H), 8.11 (br, s, 1H). 13C
NMR (100 MHz, CDCl3): d = 174.7, 136.6, 126.4, 123.2, 122.4,
120.9, 120.4, 117.5, 116.7, 43.2, 42.7, 32.2, 18.2, 17.1, 17.1.
HRMS (EI): m/z calcd for C15H18N2O: 242.1419; found:
242.1417.
1-(1-(1H-Indol-3-yl)ethyl)azepan-2-one (3ba). White solid;
m.p. 125–126 uC. IR (KBr): 3482, 3182, 2930, 1607, 1483,
1
1178, 744 cm21. H NMR (300 MHz, CDCl3): d = 1.12–1.32 (m,
3H), 1.52 (d, J = 6.9 Hz, 3H), 1.57–1.70 (m, 3H), 2.59–2.62 (m,
2H), 3.01–3.19 (m, 2H), 6.29 (q, J = 6.9 Hz, 1H), 7.07–7.22 (m,
3H), 7.36 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 8.26 (br, s,
1H). 13C NMR (100 MHz, DMSO-d6): d = 173.8, 136.4, 126.4,
123.5, 121.2, 118.7, 118.5, 115.2, 111.4, 43.9, 41.8, 37.0, 29.2,
28.6, 23.0, 17.0. HRMS (EI): m/z calcd for C16H20N2O: 256.1576;
found: 256.1577.
1-(1-(5-Methyl-1H-indol-3-yl)ethyl)azepan-2-one (3bi). White
solid; m.p. 75–76 uC. IR (KBr): 3464, 3184, 3159, 2932, 1585,
1
1486, 1446, 1174 cm21. H NMR (300 MHz, CDCl3): d = 1.12–
1.30 (m, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.57–1.72 (m, 3H), 2.42 (s,
3H), 2.59–2.63 (m, 2H), 3.01–3.19 (m, 2H), 6.24 (q, J = 6.9 Hz,
1H), 7.01–7.10 (m, 2H), 7.23–7.26 (m, 1H), 7.35 (s, 1H), 8.13
(br, s, 1H). 13C NMR (100 MHz, CDCl3): d = 176.0, 135.3, 129.2,
127.3, 124.3, 123.3, 119.6, 116.3, 111.2, 45.6, 43.3, 38.2, 30.5,
29.3, 23.8, 21.9, 17.6. HRMS (EI): m/z calcd for C17H22N2O:
270.1732; found: 270.1732.
1-(1-(5-Bromo-1H-indol-3-yl)ethyl)azepan-2-one (3bg). White
solid; m.p. 73–74 uC. IR (KBr): 3484, 3006, 2973, 2934, 1584,
1
1486, 1377, 1113 cm21. H NMR (300 MHz, CDCl3): d = 1.07–
1.35 (m, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.57–1.71 (m, 3H), 2.60–
2.64 (m, 2H), 3.00–3.17 (m, 2H), 6.22 (q, J = 6.9 Hz, 1H), 7.14 (s,
1H), 7.21–7.37 (m, 2H), 7.71 (s, 1H), 8.32 (br, s, 1H). 13C NMR
(75 MHz, CDCl3): d = 176.0, 136.9, 127.1, 123.1, 123.0, 122.7,
120.1, 117.1, 117.1, 111.6, 45.4, 43.4, 38.2, 30.5, 29.4, 23.9,
17.5. HRMS (EI): m/z calcd for C16H19BrN2O: 336.0660 (81Br);
found: 336.0645.
1-(1-(3-Nitrophenylamino)ethyl)pyrrolidin-2-one (5ad).
Yellow solid; m.p. 89–90 uC. IR (KBr): 3297, 3094, 2979, 1663,
1
1572, 1339, 1156, 735 cm21. H NMR (400 MHz, CDCl3): d =
1.50 (d, J = 6.3 Hz, 3H), 1.90–2.20 (m, 2H), 2.39–2.44 (m, 2H),
3.20–3.24 (m, 1H), 3.32–3.38 (m, 1H), 4.44 (br s, 1H), 5.74 (q, J
= 6.2 Hz, 1H), 6.99 (d, J = 6.2 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H),
7.56 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d = 175.2, 149.3, 146.3, 130.3, 118.6, 112.8, 108.2, 56.9,
41.0, 31.7, 19.2, 17.9 ppm. HRMS (EI): m/z Calcd for
C12H15N3O3: 249.1113; found, 249.1108.
N-(1-(1H-Indol-3-yl)ethyl)-N-methylacetamide (3ca). White
solid; m.p. 95–98 uC. IR (KBr): 3243, 3050, 2957, 1650, 1497,
1
1456 cm21. H NMR (300 MHz, CDCl3, d = 1.51 (d, J = 6.9 Hz,
3H), 1.65 (d, J = 6.5 Hz, 1H), 2.15 (s, 3H), 2.40 (s, 1H), 2.62 (s,
3H), 2.64 (s, 1H), 5.33 (q, J = 6.6 Hz, 0.35 H), 6.33 (q, J = 6.9 Hz,
1H), 7.05–7.19 (m, 4H), 7.35–7.44 (m, 1.7H), 7.57 (d, J = 7.9 Hz,
1H), 8.17 (s, 1H), 8.90 (s, 0.35H) ppm. 13C NMR (75 MHz,
DMSO-d6): d = 169.2, 169.0, 136.6, 136.5, 126.3, 126.0, 123.6,
123.6, 121.4, 121.3, 118.9, 118.7, 118.6, 118.4, 114.9, 114.6,
111.7, 111.5, 49.8, 43.5, 29.1, 26.7, 22.2, 21.8, 17.9, 16.5 ppm.
HRMS (EI): m/z Calcd for C13H16N2O: 216.1263; found,
216.1268.
1-(1-(2-Nitrophenylamino)ethyl)pyrrolidin-2-one (5ae).
Yellow solid; m.p. 89–91 uC. IR (KBr): 3361, 3091, 2976, 1687,
1
1504, 1421, 1041, 753 cm21. H NMR (400 MHz, CDCl3): d =
1.57 (d, J = 6.3 Hz, 3H), 1.91–2.04 (m, 2H), 2.40–2.46 (m, 2H),
3.17–3.23 (m, 1H), 3.36–3.42 (m, 1H), 5.86–5.92 (m, 1H), 6.67
(t, J = 7.7 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 7.6 Hz,
1H), 8.09–8.19 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): d =
174.8, 142.8, 136.7, 132.5, 126.6, 117.0, 115.3, 55.9, 40.7, 39.5,
19.3, 17.8 ppm. HRMS (EI): m/z Calcd for C12H15N3O3:
249.1113; found, 249.1108.
1-(1-(1H-Indol-3-yl)-2-phenylethyl)pyrrolidin-2-one (3ad).
White solid; m.p. 190.8–191.7 uC. IR (KBr): 3280, 2942, 2359,
1
1655, 1438, 1283, 741 cm21. H NMR (400 MHz, CDCl3): d =
1.82–1.72 (m, 2H), 2.29–2.19 (m, 2H), 2.97–2.91 (m, 1H), 3.39–
3.27 (m, 2H), 3.44–3.40 (m, 1H), 6.02–5.98 (m, 1H), 7.11 (t, J =
1-(1-((4-Chlorophenyl)amino)ethyl)pyrrolidin-2-one (5af).
White solid; m.p. 162–164 uC. IR (KBr): 3302, 3105, 2981,
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1602, 1493, 1428, 1258, 1160, 820 cm21
.
1H NMR (300 MHz,
3087, 1662, 1446, 1322, 1147, 1023, 878, 664 cm21 1H NMR
.
CDCl3): d = 1.44 (d, J = 6.4 Hz, 3H), 1.85–2.06 (m, 2H), 2.39 (t, J
= 8.2 Hz, 2H), 3.12–3.20 (m, 1H), 3.25–3.33 (m, 1H), 5.65 (q, J =
6.3 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H)
ppm. 13C NMR (100 MHz, CDCl3): d = 175.1, 143.7, 129.4,
123.2, 114.5, 57.1, 40.9, 31.8, 19.5, 17.9 ppm. HRMS (EI): m/z
Calcd for C12H15ClN2O: 238.0873; found, 238.0874.
(400 MHz, DMSO-d6): d = 1.17 (d, J = 6.6 Hz, 3H), 1.59–2.03 (m,
2H), 1.95–2.03 (m, 1H), 2.38 (s, 3H), 2.74–2.78 (m, 1H), 2.97–
3.03 (m, 1H), 3.34–3.37 (m, 1H), 5.39–5.42 (m, 1H), 7.37 (d, J =
7.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 172.6, 142.8, 138.1, 129.3, 126.4, 56.4, 56.3, 30.4,
21.0, 18.9, 16.6 ppm. HRMS (EI): m/z Calcd for C13H18N2O3S:
282.1038; found, 282.1039.
4-(1-(2-Oxoazepan-1-yl)ethylamino)benzonitrile (5ba). White
solid; m.p. 196–197 uC. IR (KBr): 3294, 3163, 2931, 2215, 1612,
1536, 1340, 1164, 1142, 817 cm21. 1H NMR (400 MHz, CDCl3):
d = 1.40 (d, J = 6.4 Hz, 3H), 1.54–1.70 (m, 6H), 2.46–2.59 (m,
2H), 3.16–3.28 (m, 2H), 4.58 (br s, 1H), 6.15–6.20 (m, 1H), 6.63
(d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H) ppm. 13C NMR (100
MHz, CDCl3): d = 176.10, 149.14, 133.86, 120.39, 113.27, 99.98,
58.38, 41.57, 37.96, 30.07, 29.04, 23.47, 19.51 ppm. HRMS (EI):
m/z Calcd for C15H19N3O: 257.1528; found, 257.1512.
1-(1-(2-Iodophenylamino)ethyl)pyrrolidin-2-one (5ag). Pale
yellow oil. IR (KBr): 3231, 3067, 2978, 1680, 1498, 1418, 1121
1
cm21. H NMR (400 MHz, CDCl3): d = 1.51 (d, J = 6.4 Hz, 3H),
1.83–1.98 (m, 2H), 2.36–2.41 (m, 2H), 3.08–3.13 (m, 1H), 3.29–
3.35 (m, 1H), 4.41 (br s, 1H), 5.75–5.79 (m, 1H, CH), 6.50 (t, J =
8.0 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.65
(d, J = 7.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d = 174.93,
144.24, 139.00, 129.90, 120.06, 112.43, 85.17, 56.96, 40.66,
31.69, 19.40, 17.78 ppm. HRMS (EI): m/z Calcd for C12H15IN2O:
330.0229; found: 330.0232.
1-(1-(Phenylamino)ethyl)pyrrolidin-2-one (5ah). White solid;
m.p.124–125 uC. IR (KBr): 3311, 3053, 2934, 1661, 1496, 1280,
1168 cm21. 1H NMR (400 MHz, CDCl3): d = 1.44 (d, J = 6.4 Hz,
3H), 1.84–1.91 (m, 2H), 2.39 (t, J = 8.1 Hz, 2H), 3.17–3.23 (m,
1H), 3.27–3.33 (m, 1H), 3.95 (s, 1H, NH), 5.69 (q, J = 6.0 Hz,
1H), 6.64 (d, J = 8.2 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 7.18 (d, J =
7.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): d = 175.0, 145.1,
129.6, 118.5, 113.3, 57.1, 41.0, 31.9, 19.5, 17.9 ppm. HRMS (EI):
m/z Calcd for C12H16N2O: 204.1263; found, 204.1262.
1-(1-(p-Tolylamino)ethyl)pyrrolidin-2-one (5ai). White solid;
m.p. 147–148 uC. IR (KBr): 3317, 3054, 2937, 1661, 1497, 1280,
1160 cm21. 1H NMR (400 MHz, CDCl3): d = 1.43 (d, J = 6.4 Hz,
3H), 1.82–1.96 (m, 2H), 2.23 (s, 3H), 2.38 (t, J = 8.0 Hz, 2H),
3.16–3.22 (m, 1H), 3.26–3.31 (m, 1H), 3.87 (br s, 1H), 5.66 (q, J
= 6.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H)
ppm. 13C NMR (100 MHz, CDCl3): d = 174.9, 142.8, 130.0,
127.6, 113.3, 57.3, 41.0, 31.9, 20.5, 19.5, 17.9 ppm. HRMS (EI):
m/z Calcd for C13H18N2O: 218.1419; found, 218.1417.
1-(1-(3, 4-Dihydroquinolin-1(2H)-yl)ethyl)pyrrolidin-2-one
(5aj). Colorless oil; IR (KBr): 2981, 2939, 1677, 1499, 1316,
1186 cm21. 1H NMR (300 MHz, CDCl3): d = 1.49 (d, J = 6.7 Hz,
3H), 1.91–1.98 (m, 4H), 2.35–2.40 (m, 2H), 2.78 (t, J = 5.8 Hz,
2H), 3.13–3.18 (m, 1H), 3.34–3.38 (m, 2H), 3.44–3.47 (m, 1H),
6.87 (q, J = 6.6 Hz, 1H), 6.63–6.68 (m, 2H), 6.98 (d, J = 6.9 Hz,
1H), 7.08 (t, J = 7.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d
= 174.5, 143.8, 129.3, 127.8, 122.7, 117.1, 111.6, 61.3, 43.2, 42.4,
31.2, 28.5, 22.4, 18.0, 16.8 ppm. HRMS (EI): m/z Calcd for
C15H21N2O: [M+H]+ 245.1654; found, 245.1660.
1-(1-(1H-Benzo[d][1,2,3]triazol-1-yl)ethyl)pyrrolidin-2-one
(5al). White solid; m.p. 57–58 uC. IR (KBr): 3451, 2972, 1685,
1422, 1268, 1241, 1049, 752 cm21. 1H NMR (400 MHz, CDCl3):
d = 1.84–1.87 (m, 1H), 1.99–2.04 (m, 1H), 2.12 (d, J = 6.7 Hz,
3H), 2.27–2.36 (m, 1H), 2.42–2.48 (m, 1H), 3.08–3.14 (m, 1H),
3.60–3.66 (m, 1H), 7.00 (q, J = 6.6 Hz, 1H), 7.39 (t, J = 7.3 Hz,
1H), 7.54–7.47 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 8.1
Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d = 175.2, 145.9,
132.5, 127.9, 124.5, 119.7, 110.5, 60.0, 41.9, 31.0, 17.7, 17.1
ppm. HRMS (EI): m/z Calcd for C12H14N4O: 230.1168; found,
230.1168.
1-(1-(3-Nitrophenylamino)ethyl)azepan-2-one (5bd). Yellow
solid; m.p. 115–117 uC. IR (KBr): 3288, 3063, 2936, 1623, 1530,
1339, 1151, 982cm21. 1H NMR (400 MHz, CDCl3): d = 1.25–1.26
(m, 1H), 1.41 (d, J = 6.2 Hz, 3H), 1.54–1.68 (m, 5H), 2.49–2.56
(m, 2H), 3.20–3.30 (m, 2H), 4.64 (br s, 1H), 6.16–6.18 (m, 1H),
6.49 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.46 (s, 1H), 7.55
(d, J = 7.6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): d = 176.3,
149.3, 146.6, 130.2, 118.7, 112.7, 108.1, 59.0, 41.6, 38.0, 30.1,
29.1, 23.5, 19.6 ppm. HRMS (EI): m/z Calcd for C14H19N3O3:
277.1426; found, 277.1426.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
China (No. 21042007, 21172162), the Young National Natural
Science Foundation of China (No. 21202111), the Young
Natural Science Foundation of Jiangsu Province (BK2012174),
Key Laboratory of Organic Synthesis of Jiangsu Province
(KJS1211), PAPD, and Soochow University for financial
support.
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mide (5am). White solid; m.p. 113–115 uC. IR (KBr): 3466,
8386 | RSC Adv., 2013, 3, 8380–8387
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