Direct alkylation of indoles and amines by tert-enamides: Facile access to pharmaceutically active 2-oxo-1-pyrrolidine analogues

Article abstract of DOI:10.1039/c1ob05546a

Direct alkylation of indoles and amines by tertiary enamides for the synthesis of pharmaceutically active 2-oxo-1-pyrrolidine analogues was described. With only a 0.5 mol% catalyst loading, molecular iodine was demonstrated to be efficiently enough to promote the reaction under neat condition. Only Markovnikov addition product was obtained indicating that the reactions proceeded with excellent regioselectivity.

Full text of DOI:10.1039/c1ob05546a

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PAPER
Direct alkylation of indoles and amines by tert-enamides: facile access to
pharmaceutically active 2-oxo-1-pyrrolidine analogues†
Ran Jiang, Hai-Yan Xu, Xiao-Ping Xu,* Xue-Qiang Chu and Shun-Jun Ji*
Received 7th April 2011, Accepted 13th May 2011
DOI: 10.1039/c1ob05546a
Direct alkylation of indoles and amines by tertiary enamides for the synthesis of pharmaceutically
active 2-oxo-1-pyrrolidine analogues was described. With only a 0.5 mol% catalyst loading, molecular
iodine was demonstrated to be efficiently enough to promote the reaction under neat condition. Only
Markovnikov addition product was obtained indicating that the reactions proceeded with excellent
regioselectivity.
Introduction
2-Oxo-1-pyrrolidine fragment is featured in a wide variety of phar-
macologically and biologically active compounds. For example, N-
(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide, which is
known as Nefiracetam, is a commonly used drug for the treatment
of cerebrovascular disease; Levetiracetam, bearing a 2-oxo-1-
pyrrolidine moiety, is also disclosed as a protective agent for the
treatment and prevention of hypoxic and ischemic type aggressions
of the central nervous system, as well as an effective compound in
the treatment of epilepsy (the structures of two drugs were shown
in Fig. 1).1 The analogues of above pharmaceuticals, especially in
which another biologically active alkaloid motif incorporated, has
been discovered as well to exhibit good activities in the therapy of
common diseases such as attention deficit hyperactivity disorder
(ADHD), cardiac arrhythmia, asthmatic syndrome, and so on
(typical structures can be depicted as A1e and B,1d Fig. 1). However,
existing synthetic methods for these compounds significantly lack
efficiency. Taking these facts into account, the development of a
more convenient protocol for preparing compounds containing 2-
oxo-1-pyrrolidine moiety as well as other alkaloid scaffolds such as
indole and (heterocyclic) aromatic amine become highly desirable.
In recent years, enamide, as a good alternative in the family
of electron-rich olefins, have attracted considerable attention in
organic synthesis.2 Despite extensive application of enamide as
a nucleophile in organic synthesis,3 the utilization of enamide as
electrophile were relatively rare. Although electron-rich alkenes
have been successfully employed in acid-catalyzed Friedel–Crafts
(F–C) alkylation for industrial purpose, enamide has not been
examined until chiral phosphoric acid-induced enantioselective
F–C alkylations were reported.4 Even so, organic transformation
using enamide as alkylation reagent in the presence of Lewis acid
Fig.
1
Pharmaceuticals
and
their
analogues
containing
2-oxo-1-pyrrolidine fragment.
catalysis was still unknown. More recently, we have described
an efficient Fe(III)-catalyzed F–C alkylation between indoles
and enamides in water.5 Almost at the same time, Zhang and
coworkers also reported the same reaction carried out in organic
solvent.6 Both cases provided efficient methods for the synthesis of
pharmaceutical analogue of compound A. In view of the fact that
compound A is an oral drug, if metallic catalysis is used during
its preparation, metal residue will pose an inevitable problem
for above processes. Thus, a metal-free approach to realize this
transformation is highly anticipated. Quite recently, we fortunately
found that molecular iodine,7 which has been demonstrated to be
a versatile catalyst in organic synthesis, could effectively promote
the synthesis of pharmaceutical analogues of A and B under neat
condition. Moderate to high yields of the desired products could
be obtained with simple work-up. Herein, we report these results.
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chem-
istry, Chemical Engineering and Materials Science, Soochow University,
Suzhou, 215123, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05546a
Results and discussion
Our initial attempt focused on the feasibility of reaction of indole
(2a) with 1-vinylpyrrolidin-2-one (1a) under neat condition at
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Table 1 Catalyst screening for the model reactiona
reactivity with respect to that of indoles, leading to the adduct
3al in 90% yield (Table 2, entry 12). Although pharmaceuticals
containing azepan-2-one key structural unit has not been reported
yet, the derivatives of structural-related fused ring 4,5-dihydro-1H-
benzo[b]azepin-2(3H)-one have been discovered to be modulator
of ghrelin receptor (GHSR) activity and often be used in treating
and preventing conditions associated with obesity, obesity-related
disorders or eating disorders.8 Thus, 1-vinylazepan-2-one (1b) as
another candidate of cyclic enamide was selected to synthesize the
corresponding pharmaceutical analogous. It was observed that
seven-membered cyclic enamide 1b showed similar reactivity with
that of 1a, affording the desired products in moderate to high
yields (Table 2, entries 13–16). Furthermore, acyclic enamide 1c
was also proven as a good candidate in undergoing alkylation with
indole, and a 62% yield of the final product 3ca was generated after
workup (Table 2, entry 17).
Entry
Catalyst (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
—
I2 (0.5)
24
2
4
4
4
0
91
76
74
45
42
0
Fe(NO3)3·9H2O (0.5)
In(OTf)3 (0.5)
Cu(OTf)2 (0.5)
PTSA (0.5)
KI (0.5)
PhI(OAc)2 (0.5)
I2 (0.1)
4
24
24
4
0
54
Encouraged by the above successful access to the pharma-
ceutical analogous of compound A via alkylation of indoles by
enamides, we were eager to know if the present protocol was
general enough to construct the bio-active compounds with wider
structural diversity. Thus, we turned our attention to the synthesis
of compound B and its derivatives. The details of results were
listed in Table 3. One of the pharmaceutical analogs containing a
1,2,3,4-tetrahydroquinoline skeleton was firstly considered to be
the target for synthesis. It was a bit regret that the reaction of
1a and 4a was out of our expectation, and the yield of desired
product was very poor, which probably due to the steric reason
of 1,2,3,4-tetrahydroquinoline (Table 3, entry 1). Heterocyclic
arene of 1H-benzo[d][1,2,3]triazole(4b) can be employed as a
suitable substrate as well, affording the adduct in an acceptable
yield of 53% (Table 3, entry 2). Especially noteworthy is that
aniline was also active in the catalytic process (Table 3, entry
3), and hitherto few systematic studies have been achieved upon
alkylation of anilines by enamides. Therefore, the scope and
limitations of this alkylation reaction was next examined with
a wide range of substituted anilines. As is shown, the presence
of a strong electron-withdrawing group (CN, Ac, COOEt, and
NO2) at the ortho, meta and para position of aniline are well
tolerated (Table 3, entries 4–9). The presence of a weak electron-
withdrawing group such as halogens at the para or ortho position
of aniline obviously reduced the reactivity presumably owing to
the electronic effect and sometimes steric effect (Table 3, entries
10–11). Significant decrease of yield of desired adduct was also
detected in the example of aniline with an electron-donating group
(Me), albeit with a prolonged reaction time (Table 3, entry 12).
What’s more, aliphatic amine 4m, which shows stronger basicity
than anilines, was inert to the alkylation reaction (Table 3, entry
13). Nevertheless, sulfonamide 4n demonstrated high efficiency to
give the product 5an in good yield (Table 3, entry 14). Based
on these results, 1-vinylazepan-2-one (1b) was introduced to
couple with active anilines, a comparable efficiency of 1b was also
observed, providing the target products in high yields (Table 3,
entries 15–16). Furthermore, the structure of the representative
compound 5aj was confirmed by X-ray single crystal diffraction
(Fig. 2).9
a Reaction conditions: indole (0.5 mmol), 1-vinyl-2-pyrrolidinone
(1.25 mmol), catalyst (0.0025 mmol). b Isolated yield based on indole as
limiting reagent.
room temperature. As expected, the model reaction did not occur
in the absence of catalyst under neat condition (Table 1, entry 1).
But it was fortunately found that 0.5 mol% amount of iodine was
sufficient to promote the reaction, high yield (91%) of product 3aa
was isolated after a short reaction time of 2 h. It should be noted
that the reaction was regiospecific because only Markovnikov
addition (from 1a) and C3-alkylated (from 2a) product was
observed. Fe(III) catalyst, previously used in the similar system,5
was also employed in the model reaction in order to compare
its reactivity with iodine. The result apparently indicated that the
catalytic activity of iodine was superior to that of Fe(III) catalyst
(Table 1, entry 3). We also screened other commonly utilized Lewis
or Brønsted acid catalysts, no better result was obtained in these
cases (Table 1, entries 4–6). The effect of the source of iodine on
the template reaction was subsequently examined. It seemed that
both I- and I3+ were inactive in mediating the reaction (Table 1,
entries 7–8). Attempt to decrease the catalyst loading from 0.5 to
0.1 mol% was unsuccessful because the yield of desired product
decreased even after a prolonged reaction time (Table 1, entry 9).
With the optimal reaction conditions in hand, we continued
to examine the scope of the reaction by using various indoles
and related electron-rich arenes. As illustrated in Table 2, the
alkylation of indoles under neat condition could be accomplished
with good generality. Indoles with electron-donating groups,
such as methyl, phenyl, and benzyloxyl, provided the desired
addition products within several hours in good to excellent yields
(Table 2, entries 2–6, 9–10). Noteworthy, indoles with steric
hindered substituents at 2-position has no detrimental effect on
the reactions (Table 2, entries 3–4). Meanwhile, 5-nitro-1H-indole
containing a strong electron-withdrawing group also worked well
to furnish the desired product 3ah in 65% yield (Table 2, entry
8). These results prompted us to investigate the use of other
related electron-rich arenes. Pyrrole was firstly introduced and
reacted with 1-vinylpyrrolidin-2-one (2a). Interestingly, a double
alkylation of pyrrole by enamide was achieved giving rise to
2,5-dialkylated pyrrole 3ak in 63% yield (Table 2, entry 11).
Besides the heterocyclic arenes used above, other electron-rich
arenes such as 1, 3, 5-trimethoxybenzene exhibited comparable
Further expansion of this protocol to thiol compound as
nucleophile was also explored. It was found that the reaction
of naphthalene-2-thiol with enamides 1a and 1b also proceeded
smoothly to give S-alkylated products, majorly belonging to
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Table 2 Alkylation of indoles and other electron-rich arenes with enamidesa
Entry
1
Enamide
ArH
Product
Time (h)
2
Yield (%)b
91
2
2
94
3
4
1
94
95
0.75
5
6
0.5
89
92
1
7
8
2
1
87
65
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Table 2 (Contd.)
Entry
9
Enamide
ArH
Product
Time (h)
3
Yield (%)b
96
10
11
1
1
96
63
12
13
5
90
95
1.5
14
15
1
1
66
88
16
5
65
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Table 2 (Contd.)
Entry
17
Enamide
ArH
Product
Time (h)
1
Yield (%)b
62
a Reaction conditions: aromatic ring 2a–l (1.0 mmol), enamide 1a–c (2.5 mmol), iodine (0.5 mol%). b Isolated yield based on indole as limiting reagent.
Fig. 2 Crystal structure of compound 5aj.
Markovnikov addition adducts, in 70% and 85% yields, respec-
tively (Scheme 1).
Scheme 2
charge was trapped and coordinated by the carbonyl group,
thus a relatively stable six-membered intermediate was formed.
Scheme 1
Under this circumstance, the C C bond, which was polarized
Considering the low catalyst loading, solvent-free conditions
simultaneously by iodine, was attacked by a nucleophile, after a
and a relatively wide generality of this protocol, it would be
hydrogen transfer step, as well as leaving of catalyst, the final
potentially useful in industrial process if the reactions could be
product was thus produced.
scaled up. Thus, a large-scaled reaction of indole (25.0 mmol)
with one equiv. of 1a (25.0 mmol) was carried out under optimized
conditions (Scheme 2). It was gratifying to find that the reaction
was completed within 30 min and the pure product of 3a could
Conclusion
be obtained in 90% yield without need of excessive enamide and
further purification by column chromatography.
Based on the reported results,5 we suppose this iodine-catalyzed
direct alkylation reaction would be carried out as follows (in
Scheme 3): with the interaction of b-C (from C C bond) and
the molecular iodine, the polarized iodine atom with positive
In summary, we have developed a simple and highly efficient ap-
proach to synthesize pharmaceutically active 2-oxo-1-pyrrolidine
analogues through Markonikov additions of indoles, anilines, and
thiols to tertiary enamides. The reactions proceeded efficiently in
the presence of 0.5 mol% molecular iodine to afford the desired
2-oxo-1-pyrrolidine derivatives in moderate to good yields. In
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Table 3 Alkylation of amino compounds with enamidesa
Entry
1
Enamide
Amine
Product
Time (h)
12
Yield (%)b
21
2
5
53
3
4
10
1
44
93
5
6
87
6
7
12
95
96
0.5
8
9
1
1
81
81
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Table 3 (Contd.)
Entry
10
Enamide
Amine
Product
Time (h)
12
Yield (%)b
65
11
12
7
47
37
20
13
14
—
24
1
—
87
15
16
1
1
95
69
a Reaction conditions: amino compound 4 (1.0 mmol), enamide 1a–b (2.5 mmol), iodine (0.5 mol%). b Isolated yield based on amino compound 4 as
limiting reagent.
Scheme 3
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addition, the reactions could be scaled up to gram level without
the need of excessive substrate or any organic solvent, which would
lead to a potential application in industrial process.
18.0, 13.0 ppm. HRMS: Calcd for C15H18N2O: [M]+ 242.1419;
Found, 242.1420.
1-(1-(2-Phenyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3ad)5.
(288 mg, 95%). White solid. m.p. 166–167 ◦C. IR (KBr): n = 3398,
1
3165, 2930, 2895, 1660, 1442, 1288, 1204, 778 cm-1. H NMR
Experimental
(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),
5.68–5.75 (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) ppm. 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 ppm. HRMS: Calcd for C20H20N2O: [M]+ 304.1576; Found,
304.1577.
General
Melting points were recorded on an Electrothermal digital melting
point apparatus and were uncorrected. IR spectra were recorded
on a Varian FT-1000 spectrophotometer using KBr optics. H
1
NMR and 13C NMR spectra were recorded on a Varian INOVA
300 or 400 MHz (1H NMR) and 75 or 100 MHz (13C NMR)
spectrometer using CDCl3 or DMSO-d6 as solvent and TMS as
internal standard. High resolution mass spectra were obtained
using GCT-TOF instrument with EI or ESI source. X-ray
diffraction data were recorded on a Rigaku Mercury CCD area
detector with graphite monochromated Mo-Ka radiation.
1-(1-(4-Phenoxy-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3ae)5.
(297 mg, 89%). White solid. m.p. 215–216 ◦C. IR (KBr): n =
3160, 2930, 2870, 1650, 1510, 1443, 1352, 1288, 1230, 1099, 737
1
cm-1. H NMR (300 MHz, CDCl3): d = 1.58 (d, J = 6.9 Hz,
3H), 1.77–1.89 (m, 2H), 2.21–2.38 (m, 2H), 3.00–3.08 (m, 1H),
3.19–3.27 (m, 1H), 5.25 (s, 2H), 5.84–5.89 (q, J = 6.6 Hz, 1H),
6.45 (d, J = 7.5 Hz, 1H), 6.92–7.04 (m, 3H), 7.23–7.42 (m, 5H),
8.29 (br s, 1H) ppm. 13C NMR (75 MHz, DMSO-d6): d = 173.4,
153.2, 138.9, 138.5, 129.0, 128.1, 127.8, 122.7, 122.4, 117.1, 116.0,
105.6, 101.2, 69.3, 44.8, 43.9, 32.0, 19.3, 18.3 ppm. HRMS: Calcd
for C21H22N2O2: [M]+ 334.1681; Found, 334.1678.
General procedure for the alkylation of indoles, anilines and
thiols with enamide. Nucleophile (1.0 mmol), I2 (0.5 mol%) and
enamide (2.5 mmol) were added into a flask. Then the mixture
was vigorously stirred at room temperature, until nucleophile was
completely consumed as indicated by TLC analysis. After the
completion of reaction, the residue was directly purified by flash
column chromatography with ethyl acetate and petroleum ether
as eluents to afford pure product.
1-(1-(5-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3af)5.
(222 mg, 92%). White solid. m.p. 173–174 ◦C. IR (KBr): n =
1-(1-(1H-Indol-3-yl)ethyl)pyrrolidin-2-one (3aa)5. (207 mg,
91%). White solid. m.p. 165–167 ◦C. IR (KBr): n = 3243, 3165,
3107, 2972, 2876, 1659, 1490, 1440, 1288, 1198, 751 cm-1. 1H NMR
(400 MHz, DMSO-d6): d = 1.52 (d, J = 7.0 Hz, 3H), 1.62–1.73 (m,
1H), 1.78–1.88 (m, 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) ppm. 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 ppm. HRMS: Calcd for C14H16N2O: [M]+
228.1263; Found, 228.1266.
3154, 2928, 2890, 1652, 1490, 1441, 1290, 792 cm-1. H NMR
1
(300 MHz, CDCl3): d = 1.58 (d, J = 6.9 Hz, 3H), 1.77–1.91 (m,
2H), 2.42–2.46 (m, 5H), 2.88–2.90 (m, 1H), 3.27–3.28 (m, 1H),
5.71–5.79 (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) ppm. 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 ppm.
HRMS: Calcd for C15H18N2O: [M]+ 242.1419; Found, 242.1420.
1-(1-(5-Bromo-1H-indol-3-yl) ethyl)pyrrolidin-2-one (3ag)5.
(266 mg, 87%). White solid. m.p. 154–156 ◦C. IR (KBr): n =
3157, 3080, 2982, 1650, 1439, 1288, 1194, 885, 790 cm-1. 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), 5.76–5.74 (q, J = 6.9 Hz, 1H), 7.14–7.31 (m, 3H), 7.74 (s,
1H), 8.25 (br s, 1H) ppm. 13C 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 ppm. HRMS: Calcd for C14H15BrN2O: [M]+
308.0347(81Br); Found, 308.0343.
1-(1-(1-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3ab)5.
(227 mg, 94%). Yellow oil. IR (KBr): n = 3056, 2971, 2890,
1
1673, 1468, 1280, 1213, 1095, 745 cm-1. H NMR (300 MHz,
CDCl3): d = 1.58 (d, J = 7.2 Hz, 3H), 1.78–193 (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) ppm. 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 ppm. HRMS: Calcd
for C15H18N2O: [M]+ 242.1419; Found, 242.1418.
1-(1-(5-Nitro-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3ah).
(177 mg, 65%). Yellow solid. m.p. 241–242 ◦C. IR (KBr): n =
3379, 2968, 1660, 1522, 1295 cm-1. 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) ppm. 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 ppm. HRMS: Calcd for
C14H15N3O3: [M]+ 273.1113; Found, 273.1112.
1-(1-(2-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3ac)5.
(227 mg, 94%). White solid. m.p. 176–177 ◦C. IR (KBr): n =
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, 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), 5.71–5.78 (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) ppm. 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,
1-(1-(6-Methyl-1H-indol-3-yl)ethyl)azepan-2-one
(3ai).
(232 mg, 96%). White solid. m.p. 135–136 ◦C. IR (KBr): n = 3213,
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1
3100, 2980, 2879, 1662,1610, 1493, 1440, 1289, 1119 cm-1. H
110.9, 110.9, 47.3, 44.6, 38.1, 30.4, 29.5, 24.0, 18.5, 13.3 ppm.
HRMS: Calcd for C17H22N2O: [M]+ 270.1732; Found, 270.1732.
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) ppm. 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 ppm. HRMS: Calcd for
C15H18N2O: [M]+ 242.1419; Found, 242.1416.
1-(1-(5-Methyl-1H-indol-3-yl)ethyl)azepan-2-one
(3bf)5.
◦
(237 mg, 88%). White solid. m.p. 75–76 C. IR (KBr): n = 3464,
1
3184, 3159, 2932, 1585, 1486, 1446, 1174 cm-1. 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), 6.21–6.28 (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) ppm. 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 ppm. HRMS:
Calcd for C17H22N2O; [M]+ 270.1732: Found, 270.1732.
1-(1-(7-Methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-one
(3aj)5.
(232 mg, 96%). White solid. m.p. 166–168 ◦C. IR (KBr): n =
3222, 3113, 2971, 2933, 2873, 1650, 1614, 1498, 1444, 1298, 1201,
1
1123, 788 cm-1. H NMR (300 MHz, CDCl3): d = 1.59 (d, J =
1-(1-(5-Bromo-1H-indol-3-yl)ethyl)az◦epan-2-one
(3bg)5.
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), 5.74–5.80 (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) ppm. 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 ppm. HRMS: Calcd for C15H18N2O: [M]+ 242.1419;
found, 242.1417.
(217 mg, 65%). White solid. m.p. 73–74 C. IR (KBr): n = 3484,
1
3006, 2973, 2934, 1584, 1486, 1377, 1113 cm-1. 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),
6.19–6.26 (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) ppm. 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 ppm HRMS: Calcd
for C16H19BrN2O: [M]+ 336.0660(81Br); Found, 336.0645.
1,1¢-(1,1¢-(1H-Pyrrole-2,5-diyl)bis(ethane-1,1-diyl))dipyrro-
lidin-2-one (3ak). (187 mg, 63%). Gray powder. m.p. 136–139 ◦C.
1
IR (KBr): n = 3197, 2975, 1689, 1664, 1439, 1289, 844 cm-1. H
N-(1-(1H-Indol-3-yl)ethyl)-N-methylacetamide
(3ca)6.
(134 mg, 62%). White solid. m.p. 95–98 ◦C. IR (KBr): n =
NMR (400 MHz, DMSO-d6): d = 1.34 (d, J = 7.0 Hz, 6H), 1.79–
1.88 (m, 4H), 2.22 (t, J = 8.0 Hz, 4H), 2.80–2.86 (m, 2H), 3.18–3.24
(m, 2H), 5.12 (q, J = 6.9 Hz, 2H), 5.83 (d, J = 2.2 Hz, 2H), 10.58
(br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6) d = 173.0,
131.0, 105.1, 43.5, 42.1, 31.1, 17.5, 16.6 ppm. HRMS: Calcd for
C16H23N3O2: [M]+ 289.1790; Found, 289.1795.
1
3243, 3050, 2957, 1650, 1497, 1456 cm-1. H NMR (300 MHz,
CDCl3, including isomer): 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,
including isomer): 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: Calcd for C13H16N2O: [M]+ 216.1263; Found, 216.1268.
1-(1-(2,4,6-Trimethoxyphenyl)ethyl)pyr◦rolidin-2-one
(3al)5.
(251 mg, 90%). White solid. m.p. 94–96 C. IR (KBr): n = 3063,
1
2968, 2890, 1673, 1468, 1280, 1220, 1095 cm-1. H NMR (400
MHz, CDCl3): d = 1.50 (d, J = 7.3 Hz, 3H), 1.84–1.96 (m, 2H),
2.30–2.35 (m, 2H), 3.23–3.28 (m, 1H), 3.51–3.56 (m, 1H), 3.81 (s,
9H), 5.84 (q, J = 7.3 Hz, 1H), 6.12 (s, 2H) ppm. 13C NMR (100
MHz, CDCl3): d = 174.2, 160.5, 160.0, 109.8, 91.1, 55.9, 55.4,
44.6, 42.6, 31.7, 18.3, 17.4 ppm. HRMS: Calcd for C15H21NO4:
[M]+ 279.1471; Found, 279.1476.
1-(1-(3,4-Dihydroquinolin-1(2H )-yl)ethyl)pyrrolidin-2-one
(5aa). (51 mg, 21%). Colorless oil. IR (KBr): n = 2981, 2939,
1
1677, 1499, 1316, 1186 cm-1. H 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:
Calcd for C15H21N2O: [M+H]+ 245.1654; Foud, 245.1660.
1-(1-(1H-Indol-3-yl)ethyl)azepan-2-one (3ba)5. (243 mg, 95%).
White solid. m.p. 125–126 ◦C. IR (KBr): n = 3482, 3182, 2930,
1
1607, 1483, 1178, 744 cm-1. 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), 6.26–6.33 (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) ppm. 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 ppm. HRMS: Calcd. for
C16H20N2O: [M]+ 256.1576; Found, 256.1577.
1 - (1 - (1H-Benzo[d][1,2,3]triazol - 1 - yl)ethyl)pyrrolidin - 2 - one
(5ab). (122 mg, 53%). White solid. m.p. 57–58 ◦C. IR (KBr): n =
3451, 2972, 1685, 1422, 1268, 1241, 1049, 752 cm-1. 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: Calcd for C12H14N4O: [M]+ 230.1168; Found, 230.1168.
1-(1-(2-Methyl-1H-indol-3-yl)ethyl)azepan-2-one
(3bc)5.
(178 mg, 66%). White solid. m.p. 151–153 ◦C. IR (KBr): n =
3261, 2970, 2934, 2855, 1610, 1442, 1183, 745 cm-1. H NMR
1
(300 MHz, CDCl3): d = 1.05–1.41 (m, 4H), 1.58 (s, 2H), 1.70 (d,
J = 7.2 Hz, 3H), 2.46 (s, 3H), 2.54–2.57 (m, 2H), 3.18–3.36 (m,
2H), 6.18–6.26 (q, J = 6.9 Hz, 1H), 7.05–7.14 (m, 2H), 7.29 (s,
1H), 7.70 (d, J = 7.5 Hz, 1H), 8.03 (br s, 1H) ppm. 13C NMR (100
MHz, CDCl3): d = 175.3, 135.5, 134.2, 129.0, 121.2, 120.0, 119.4,
1-(1-(Phenylamino)ethyl)pyrrolidin-2-one (5ac). (90 mg, 44%).
White solid; m.p.124–125 ◦C. IR (KBr): n = 3311, 3053, 2934,
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1
1661, 1496, 1280, 1168 cm-1. H NMR (400 MHz, CDCl3): d =
1-(1-(2-Nitrophenylamino)ethyl)pyrrolidin-2-one
(5ai).
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: Calcd for C12H16N2O: [M]+ 204.1263; Found, 204.1262.
(202 mg, 81%). Yellow solid; m.p. 89–91 ◦C. IR (KBr): n =
3361, 3091, 2976, 1687, 1504, 1421, 1041, 753 cm-1. H NMR
1
(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: Calcd for
C12H15N3O3: [M]+ 249.1113; Found, 249.1108.
4-(1-(2-Oxopyrrolidin-1-yl)ethylamino)benzonitrile
(5ad).
(213 mg, 93%). White solid; m.p. 185–186 ◦C. IR (KBr): n = 3305,
2983, 2218, 1664, 1612, 1531, 1285, 1161 cm-1. H NMR (400
1
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: Calcd for C13H15N3O: [M]+ 229.1215; Found,
229.1213.
1-(1-((4-Chlorophenyl)amino)ethyl)pyrrolidin-2-one
(5aj).
(155 mg, 65%). White solid; m. p. 162–164 ◦C. IR (KBr): n = 3302,
3105, 2981, 1602, 1493, 1428, 1258, 1160, 820 cm-1. 1H NMR (300
MHz, 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:
Calcd for C12H15ClN2O: [M]+ 238.0873; Found, 238.0874.
Ethyl 4-(1-(2-oxopyrrolidin-1-yl)ethylamino)benzoate (5ae).
◦
(240 mg, 87%). White solid; m.p. 91–92 C. IR (KBr): n = 3503,
2977, 1708, 1439, 1281, 1103, 844, 770 cm-1. 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,
1-(1-(2-Iodophenylamino)ethyl)pyrrolidin-2-one
(5ak).
(155 mg, 47%). Pale yellow oil. IR (KBr): n = 3231, 3067,
2978, 1680, 1498, 1418, 1121 cm-1. 1H 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:
Calcd for C12H15IN2O: [M]+ 330.0229; Found: 330.0232.
1H), 6.64 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H) ppm. 13
C
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: Calcd for
C15H20N2O3: [M]+ 276.1474; Found, 276.1473.
1-(1-(4-Acetylphenylamino)
ethyl)pyrrolidin-2-one
(5af).
(233 mg, 95%). White solid; m.p. 152–153 ◦C. IR (KBr): n = 3221,
2968, 1746, 1678, 1445, 1162 cm-1. 1H NMR (400 MHz, CDCl3):
d = 1.48 (d, J = 6.4 Hz, 3H), 1.90–1.95 (m, 2H), 2.39–2.43 (m,
2H), 2.50 (s, 3H), 3.51–3.21(m, 1H), 3.30–3.36 (m, 1H), 4.49 (br s,
1H, NH), 5.75–5.78 (m, 1H), 6.65 (d, J = 8.7 Hz, 2H), 7.83 (d, J =
8.7 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 196.8, 175.1,
149.3, 131.0, 128.2, 112.6, 56.7, 41.0, 31.8, 26.3, 19.5, 18.0 ppm.
HRMS: Calcd for C14H18N2O2: [M]+ 246.1368; Found, 246.1385.
1-(1-(p-Tolylamino)ethyl)pyrrolidin-2-one (5al). (81 mg, 37%).
White solid; m.p. 147–148 ◦C. IR (KBr): n = 3317, 3054, 2937,
1
1661, 1497, 1280, 1160 cm-1. H 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:
Calcd for C13H18N2O: [M]+ 218.1419; Found, 218.1417.
1-(1-(4-Nitrophenylamino)ethyl)pyrrolidin-2-one
(5ag).
(239 mg, 96%). Yellow solid; m.p. 204–205 ◦C. IR (KBr):
n = 3271, 3072, 2928, 1665, 1484, 1323, 1161, 832 cm-1. 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: Calcd for C12H15N3O3: [M]+ 249.1113;
Found, 249.1108.
4-Methyl-N-(1-(2-oxopyrrolidin-1-yl)ethyl)benzenesulfonamide
(5an). (245 mg, 87%). White solid. m.p. 113–115 ◦C. IR (KBr):
n = 3466, 3087, 1662, 1446, 1322, 1147, 1023, 878, 664 cm-1.
1H NMR (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: Calcd for C13H18N2O3S:
[M]+ 282.1038; Found, 282.1039.
1-(1-(3-Nitrophenylamino)ethyl)pyrrolidin-2-one
(5ah).
(201 mg, 81%). Yellow solid; m.p. 89–90 ◦C. IR (KBr): n =
3297, 3094, 2979, 1663, 1572, 1339, 1156, 735 cm-1.1H 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: Calcd for
C12H15N3O3: [M]+ 249.1113; Found, 249.1108.
4-(1-(2-Oxoazepan-1-yl)ethylamino)benzonitrile
(5bd).
(244 mg, 95%). White solid; m.p. 196–197 ◦C. IR (KBr):
n = 3294, 3163, 2931, 2215, 1612, 1536, 1340, 1164, 1142, 817
cm-1. 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 = 176.1,
149.1, 133.9, 120.4, 113.3, 100.0, 58.4, 41.6, 38.0, 30.1, 29.0, 23.5,
5668 | Org. Biomol. Chem., 2011, 9, 5659–5669
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19.5 ppm. HRMS: Calcd for C15H19N3O: [M]+ 257.1528; Found,
257.1512.
Y. Quesnel, A. Ates, P. Michel, L. Turet and J. Mercier, WO2006128693,
2006; (e) J. Gobert, J.-P. Geerts and G. Bodson, EP0162036, 1985; (f) R.
J. Schmiesing and R. J. Murray, US5334720, 1994.
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7, 2628–2634.
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1-(1-(3-Nitrophenylamino)ethyl)azepan-2-one (5bh). (191 mg,
◦
69%). Yellow solid; m.p. 115–117 C. IR (KBr): n = 3288, 3063,
1
2936, 1623, 1530, 1339, 1151, 982 cm-1. H 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: Calcd
for C14H19N3O3: [M]+ 277.1426; Found, 277.1426.
1-(1-(Naphthalen-2-ylthio)ethyl)pyrrolidin-2-one
(6a).
(190 mg, 70%). White solid. 62–63 ◦C. IR (KBr): n = 2961,
1
1681, 1399, 1266, 1047, 644 cm-1. H NMR (400 MHz, CDCl3):
d = 1.54 (d, J = 6.9 Hz, 3H), 1.72–1.80 (m, 1H), 1.86–1.94 (m,
1H), 1.98–2.06 (m, 1H), 2.21–2.39 (m, 1H), 3.32–3.38 (m, 1H),
3,56–3.62 (m, 1H), 6.31 (q, J = 6.9 Hz, 1H), 7.44–7.49 (m, 3H),
7.74–7.79 (m, 3H), 7.85 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d = 170, 129.1, 127.8, 126.0, 124.0, 123.0, 122.0, 121.7, 49.6,
37.0, 26.7, 17.7, 13.3 ppm. HRMS: Calcd for C16H17NOS: [M]+
271.1031; Found, 271.1029.
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Iskra, Org. Lett., 2006, 8, 2491–2494; (l) J. Wu, H.-G. Xia and K. Gao,
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2-(1-(Naphthalen-2-ylthio)ethyl)cycloheptanone (6b). (254 mg,
85%). Colorless oil. IR (KBr): n = 2854, 1640, 1448, 1131, 1023,
1
823, 739 cm-1. H NMR (400 MHz, CDCl3): d = 1.35–1.40 (m,
1H), 1.47–1.58 (m, 8H), 2.33–2.43 (m, 2H), 3.32–3.36 (m, 1H),
3.44–3.50 (m, 1H), 6.65 (q, J = 6.8 Hz, 1H), 7.41–7.47 (m, 3H),
7.72–7.78 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): d = 176.0,
133.8, 132.0, 131.9, 128.5, 128.3, 127.8, 127.7, 127.5, 126.6, 125.9,
55.8, 42.9, 37.6, 30.0, 29.2, 23.3, 19.4, 19.2 ppm. HRMS: Calcd
for C18H21NOS: [M]+ 299.1344; Found, 299.1344.
Acknowledgements
The work was partially supported by the National Natural Science
Foundation of China (No. 20672079, 21042007), 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), and Key
Project in Science & Technology Innovation Cultivation Program
of Soochow University.
8 X. Chen, X. Chen, R. V. Connors, K. Dai, Y. Fu, J. C. Jaen, Y.-J.
Kim, L. Li, M. E. Lizara-Aburu, J. T. Mihalic and S. J. Shuttleworth,
WO2006020959, 2006.
9 Structural parameters for product 5aj: data collection: Rigaku Mercury
CCD area detector; crystal size: 0.10 ¥ 0.60 ¥ 0.15 mm3; C12H15ClN2O,
Mr = 238.71, monoclinic, space group P 21/c, a = 11.180 (3), b = 9.4995
Notes and references
1 (a) S. Akiyama, T. Niki, T. Utsunomiya, J. Watanabe, M. Nishioka,
H. Suzuki, F. Hayasaka and K. Yamagishi, EP1020447, 2000; (b) J.
Gobert, C. Giurgea, J.-P. Geerts and G. Bodson, EP172096, 1985; (c) B.
Kenda, P. Michel and Y. Quesnel, WO2005054188, 2005; (d) B. Kenda,
˚
(18), c = 12.049(3) A, a = 90.00, b = 111.894 (5), g = 90.00, V = 1187.4(5)
3
-3
˚
A , Z = 4, Dc = 1.335 g cm , R[I > 2s(I)] = 0.0529, wR[I > 2s(I)] =
0.1404.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5659–5669 | 5669
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