Electrophilic intramolecular cyclization of functional derivatives of unsaturated compounds: V. Cyclization of anilides of styrylacetic acids in polyphosphoric acid

Article abstract of DOI:10.1134/S1070428013080137

Anilides of styrylacetic acids at heating in polyphosphoric acid undergo an intramolecular cyclization giving 1,5-diarylpyrrolidin-2-ones, 5-aryl-1,3,4,5-tetrahydro-2H-benzazepin-2-ones, and 5-(3-fluorophenyl) dihydrofuran-2(3H)-one, where the ratio of th

Full text of DOI:10.1134/S1070428013080137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 8, pp. 1175−1181. © Pleiades Publishing, Ltd., 2013.
Original English Text © R.I. Vas’kevich, A.I. Vas’kevich, I.Yu. Daniluk, M.V. Vovk, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 8,
pp. 1192−1198.
Electrophilic Intramolecular Cyclization
of Functional Derivatives of Unsaturated Compounds: V.*
Cyclization of Anilides of Styrylacetic Acids
in Polyphosphoric Acid
R. I. Vas’kevich, A. I. Vas’kevich, I. Yu. Daniluk, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine
Kiev, 02094 Ukraine
e-mail: vaskevich@ioch.kiev.ua
Received April 15, 2013
Abstract—Anilides of styrylacetic acids at heating in polyphosphoric acid undergo an intramolecular cyclization
giving 1,5-diarylpyrrolidin-2-ones, 5-aryl-1,3,4,5-tetrahydro-2Н-benzazepin-2-ones, and 5-(3-fluorophenyl)
dihydrofuran-2(3Н)-one, where the ratio of the products depends on the character of the aromatic substituents in
the amide and styrene fragments of the substrate.
DOI: 10.1134/S1070428013080137
In the series of styrylacetic acids an important place systems we investigated in this study their proton-
initialed cyclization under the action of polyphosphoric
acid (PPA). PPA is an efficient cyclizing reagent and
simultaneously a good polar solvent and proton donor [8].
Formerly PPA was successfully applied to lactonization
[9] and lactamization [10] of amides of unsaturated
carboxylic acids.
belongs to amides whose biologic properties are governed
as a rule by the chemical versatility of the amide fragment.
The efforts of researchers directed to its structural
modification made it possible to develop the methods
of the synthesis of inhibitors of histone deacetylase [2],
monoamine oxidase [3], and also substances stimulating
the cardiovascular system [4] and exhibiting antitumor
[5] activity. However the styrylacetamides as original
polyfunctional systems containing several nucleophilic
sites remain poorly studied. In particular, the literature
contains only information on the reaction of N-arylamides
of styrylacetic acids with sulfenyl chlorides that
depending on the conditions proceeds either as addition
As the principal objects of the study we selected amides
Іа–Ik containing diverse by the nature aryl substituents in
the styrene and the amide fragments. It was established
experimentally that their virtually 100% conversion in
the reaction products occurred within 1 h at heating in
PPA at 105–110°С. Analysis of the reaction products by
the GC-MS method after the treatment of the reaction
[6] or as electrophilic cyclization [7]. In the latter case mixture with water and extraction with dichloromethane
along with the intramolecular transformation involving (see the table) showed that from amides Іа, Ib, Id–Ig, Ii,
Ij a mixture formed containing pyrrolidin-2-ones ІIа, IIb,
IId–IIg, IIi, IIj and benzazepin-2-ones ІIIа, IIIb, IIId–
IIIg, IIIi, IIIj.Amides Іc, Ih along with pyrrolidin-2-ones
ІIc, IIh and benzazepin-2-ones ІIIc, IIIh furnished also
furan-2-one IV (see the scheme).
the oxygen atom of the amide group a cyclization reaction
also occurs with the participation of the ortho-carbon
atom of N-arylamide.
With the goal to extend the synthetic potential of the
styrylacetic acid anilides and to search for convenient
paths to synthesize on their basis important heterocyclic
–––––––––––––––
* For Communication IV, see [1].
The versatility of the transformation products
originates from operation of three possible cyclization
routes of the carbocation А primary formed by the
1175

VAS’KEVICH et al.
1176
Scheme.
H
N
R2
Ar
O
Iа_Ik
R1
PPA
b
б
a
а
H2PO_4
H
N
+
R2
Ar
c
в
O
R1
А
b
a
c
Ar
F
Ar
H
R1
R2
O
N
N+
H2PO_4
O
N
R1
H
O
R1
R2
IIа_IIk
IIIа_IIIk
R2
B
F
O
O
IV
R1 = R2 = H, Ar = Ph (a), 2-FC6H4 (b), 3-FC6H4 (c), 4-FC6H4 (d), 4-MeC6H4 (e); R1 = R2 = MeO, Ar = Ph (f), 2-FC6H4 (g), 3-FC6H4
(h), 4-FC6H4 (i), 4-MeC6H4 (j); R1 = H, R2 = EtOC(O), Ar = Ph (k).
Composition (%) of products of amides Iа–Ik cyclization in
PPA according to GC-MS data
protonation of the multiple bond. The dominant among
these paths is the attack of С+ on the amide nitrogen atom
(path а) or on the ortho-position of the N-aryl substituent
(path b). The attack on the amide oxygen atom (path
c) is less favorable probably because of its additional
protonation, and it leads to the formation of an easily
hydrolysable iminium salt B (see the scheme).
Initial Pyrrolidin-2-ones Benzazepin-2- Furan-2-ones
amide
IIа–IIk
ones IIIа–IIIk
IV
Iа
37
60
–
Ib
Ic
Id
Ie
If
18
53
53
92
15
13
23
33
56
90
80
29
44
7
–
17
–
As seen from the table, the ratio of the reaction
products depends on the character of the aryl substitu-
ents in the amide and styrene fragments of compounds
I. From the unsubstituted anilide Ia pyrrolidinone IIа
and benzazepinone IIIа formed in the ratio 37:60. The
increased electron density in the ortho-position of the
N-aryl substituent in compound If originating from the
donor effect of the methoxy groups results in the growth
–
83
75
55
66
42
5
–
Ig
Ih
Ii
–
21
–
Ij
–
Ik
–
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ELECTROPHILIC INTRAMOLECULAR CYCLIZATION OF FUNCTIONAL... : V..
1177
of the fraction of benzazepine IIIf in the reaction mixture
to 83%, and vice versa, in the presence of the electron-
acceptor ethoxycarbonyl substituent in compound Ik
the fraction of pyrrolidinone IIk reaches 90%. The
comparison of compounds Ia and Ie, and also If and Ik
shows that at the same N-aryl substituent the growth of
the donor effect of the styrene substituent of the amides
Ie, Ik (Ar = 4-MeC6H4) also results in the increased yield
of pyrrolidinones IIe, IIk by 55 and 41% respectively.
acids under the action of PPA can be regarded as a con-
venient one-stage method of the synthesis of 1,5-diaryl-
substituted pyrrolidin-2-ones and of derivatives of
5-arylbenzazepin-2-one. It has significant advantage com-
pared to the methods of preparation of 1,5-disubstituted
lactams [11, 14–17] as well as of 5-arylbenzazepinones
[12, 13, 18, 19].
EXPERIMENTAL
In its turn the introduction of a fluorine atom in the
ortho-position of the aryl fragment in the styrene part
of the molecule of compound Ib results in the increased
by 20% yield of benzazepine IIIb as compared to а
benzazepine ІІІа. However in the case of compound
Ig with more electron-donor N-aryl substituent the
fraction of benzazepine IIIg is by 8% less than that of
benzazepine ІІІf. The presence of the fluorine atom in
the para-position (compounds Id, Ii) independent of the
character of the N-aryl substituent leads to the increased
fraction of pyrrolidines IId, IIi by 16–17% and to the
analogous decrease in the fraction of benzazepines IIId,
IIIi. meta-Fluoroaryl substituents of compounds Ic, Ih
direct the cyclization both to the increase in the fraction
of pyrrolidines IIc, IIh and to the formation of a consid-
erable amount of furanone IV.
IR spectra were recorded on a spectrophotometer UR-
20 from pellets with KBr. 1Н and 13С NMR spectra were
registered on a spectrometer Varian VXR-400 (399.97
and 125.74 MHz respectively), internal reference TMS.
GC-MS measurements were carried out on an instrument
Agilent110\DAD\HSD\VLG 119562.
Cyclization of anilides Iа–Ik. In 45 g of PPA5 mmol
of anilide Iа–Ik was heated for 1 h on an oil bath at
105–110°С. The reaction mixture was slowly cooled and
poured on ice. The formed solid reaction product was
extracted with dichloromethane, the solvent was distilled
off, and the residue was chromatographed on silica gel,
eluent chloroform–methanol, 25:1.
1,5-Diphenylpyrrolidin-2-one (IIа). Yield 0.43 g
(36%), mp 108–110 °С (110–112°С [11]). IR spectrum,
cm–1: 1720, 1600, 1510, 1360, 1330, 1240, 1160. 1H NMR
spectrum (DMSO-d6), δ, ppm: 1.82–1.88 m (1H, CH),
2.51–2.67 m (3H, CH, CH2), 5.45–5.48 m (1H, C5H),
7.04 t (1Harom, J 7.0 Hz), 7.20–7.30 m (7Harom), 7.46 d
(2Harom, J 9.0 Hz). 13С NMR spectrum (DMSO-d6), δ,
ppm: 29.02 (C4), 31.33 (С3), 62.85 (С5), 122.80 (2Сarom),
124.89 (Сarom), 126.66 (2Сarom), 127.86 (Сarom), 128.87
(2Сarom), 129.19 (2Сarom), 138.76 (Сarom), 142.41 (Сarom),
174.58 (С2). Mass spectrum: m/z 238 [M + 1]+. Found,
%: C 80.76; H 6.25; N 5.67. C16H15NО. Calculated, %:
C 80.98; H 6.37; N 5.90. M 237.296.
The column chromatography proved to be an efficient
method of preparative separation of the reaction mixture,
and it was sufficient for isolation and identification of all
cyclization products except for benzazepine IIIk whose
amount reached 5% (according to GC-MS data).
The structure of pyrrolidin-2-ones ІІа–IIk, benzazepin-
2-ones ІІІа–IIIj, and furan-2-one (IV) was proved by
their spectral evaluation as well as by the agreement of
the physicochemical characteristics of formerly known
compounds IIa and IIIa to the published data [11] and
1
[12, 13] respectively. In the Н NMR spectra of com-
5-(2-Fluorophenyl)-1-phenylpyrrolidin-2-one (IIb).
Yield 0.20 g (16%), mp 95–97 °С. IR spectrum,
pounds ІІа–IIk alongside the typical signals of aromatic
substituents multiplets of the protons of the methylene
(1.79–2.79 ppm) and methine (5.08–5.72 ppm) groups are
observed, and in the 13С NMR spectra the signals appear
belonging to the pyrrolidinone ring, δ, ppm: 27–29 (С4),
cm–1: 1690, 1590, 1490, 1460, 1390, 1350, 1300, 1240,
1230, 1180, 1100, 1050. 1H NMR spectrum (DMSO-d6),
δ, ppm: 1.89–1.97 m (1H, CH), 2.53–2.69 m (3H, СН,
CH2), 5.67–5.72 m (1H, C5H), 7.05–7.12 m (2Harom),
7.15–7.20 m (1Harom), 7.23–7.30 m (4Harom), 7.43 d
(2Harom, J 8.4 Hz). 13С NMR spectrum (DMSO-d6), δ,
ppm: 27.18 (C4), 31.26 (С3), 57.33 (С5), 116.23 d (Сarom–F,
J 21.25 Hz), 122.67 (2Сarom), 125.16 (Сarom), 125.20
(Сarom), 128.49 d (Сarom–F, J 3.75 Hz), 128.79 d (Сarom–F,
J 12.50 Hz), 129.00 (2Сarom), 130.01 d (Сarom–F, J 8.75 Hz),
138.49 (Сarom), 160.32 d (Сarom–F, J 243.75 Hz), 174.40
1
30–32 (С3), 57–63 (С5), 174–175 (С2). The Н NMR
spectra of diazepinones ІІІа–IIIj are characterized by
the multiplets of methylene (2.18–2.57 ppm) and methine
(4.09–4.50 ppm) protons, and the 13С NMR spectra con-
tain characteristic carbon atoms of the azepine ring, δ,
ppm: 30–33 (С3), 33–34 (С4), 37–45 (С5), 173–175 (С2).
Therefore the cyclization of anilides of styrylacetic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

VAS’KEVICH et al.
1178
(С2). Mass spectrum: m/z 256 [M + 1]+. Found, %: C 75.14;
H 5.48; N 5.41. C16H14FNО. Calculated, %: C 75.28;
H 5.53; N 5.49. M 255.287.
5-(3-Fluorophenyl)-1-phenylpyrrolidin-2-one (IIc).
Yield0.54g(42%), mp78–80°С. IRspectrum, cm–1:3080,
2970, 1710, 1600, 1500, 1450, 1360, 1320, 1290, 1250,
1220, 1150, 1120, 1060, 960. 1H NMR spectrum (CDCl3),
δ, ppm: 1.94–2.01 m (1H, CH), 2.56–2.66 m (2H, CH2),
2.71–2.79 m (1H, CH), 5.21–5.25 m (1H, C5H), 6.89–
C 81.24; H 6.82; N 5.57. M 251.323.
1-(3,4-Dimethoxyphenyl)-5-phenylpyrrolidin-2-
one (IIf). Yield 0.19 g (13%), oily substance. IR spectrum,
cm–1: 2950, 1700, 1610, 1520, 1460, 1400, 1320, 1250,
1
1180, 1150, 1110, 1080, 1030. H NMR spectrum
(CDCl3), δ, ppm: 1.96–2.04 m (1H, CH), 2.55–2.61 m
(2H, CH2), 2.71–2.78 m (1H, CH), 3.74 s, 3.76 s (6H,
2OCH3), 5.12–5.17 m (1H, C5H), 6.65–6.72 m (2Harom),
7.13–7.29 m (6Harom). 13С NMR spectrum (CDCl3),
δ, ppm: 28.98 (C4), 31.20 (С3), 55.84 (OCH3), 55.91
(OCH3), 64.55 (С5), 107.26 (Сarom), 110.93 (Сarom),
114.75 (Сarom), 126.08 (2Сarom), 127.82 (Сarom), 128.95
(2Сarom), 131.63 (Сarom), 141.51 (Сarom), 146.37 (Сarom),
148.72 (Сarom), 174.77 (С2). Mass spectrum: m/z 298 [M
+ 1]+. Found, %: C 72.67; H 6.33; N 4.66. C18H19NО3.
Calculated, %: C 72.71; H 6.44; N 4.71. M 297.348.
1-(3,4-Dimethoxyphenyl)-5-(2-fluorophenyl)-
pyrrolidin-2-one (IIg). Yield 0.17 g (11%), mp 75–77
°С. IR spectrum, cm–1: 1690, 1530, 1460, 1410, 1320,
1230, 1180, 1120, 1040. 1H NMR spectrum (CDCl3), δ,
ppm: 2.00–2.08 m (1H, CH), 2.58–2.63 m (2H, CH2),
2.71–2.77 m (1H, CH), 3.76 s, 3.78 s (6H, 2OCH3),
5.49–5.54 m (1H, C5H), 6.67–6.77 m (2Harom), 7.00–
7.06 m (2Harom), 7.12–7.16 m (1Harom), 7.19–7.23 m
(2Harom). 13С NMR spectrum (CDCl3), δ, ppm: 27.31
(C4), 31.15 (С3), 55.82 (OCH3), 55.90 (OCH3), 57.99 d
(С5–F, J 5.00 Hz), 106.83 (Сarom), 111.00 (Сarom),
114.34 (Сarom), 115.80 d (Сarom–F, J 21.25 Hz), 124.53 d
(Сarom–F, J 3.75 Hz), 127.39 d (Сarom–F, J 3.75 Hz),
128.19 d (Сarom–F, J 13.75 Hz), 129.44 d (Сarom–F,
J 7.50 Hz), 131.37 (Сarom), 146.44 (Сarom), 148.81 (Сarom),
160.20 d (Сarom–F, J 245.00 Hz), 174.57 (С2). Mass
spectrum: m/z 316 [M + 1]+. Found, %: C 68.52; H 5.63;
N 4.36. C18H18FNО3. Calculated, %: C 68.56; H 5.75;
N 4.44. M 315.339.
6.91 m (2Harom), 6.99 d (2Harom, J 7.6 Hz), 7.06 t (1Harom
,
J 7.6 Hz), 7.23–7.26 m (3Harom), 7.39 d (2Harom, J 7.6 Hz).
13С NMR spectrum (CDCl3), δ, ppm: 29.00 (C4), 31.09
(С3), 63.33 (С5), 113.01 d (Сarom–F, J 21.25 Hz), 114.77 d
(Сarom–F, J 21.25 Hz), 121.59 d (Сarom–F, J 2.50 Hz),
122.12 (2Сarom), 125.07 (Сarom), 128.78 (2Сarom), 130.66 d
(Сarom–F, J 8.75 Hz), 138.04 (Сarom), 144.18 d (Сarom–F,
J 6.25 Hz), 163.20 d (Сarom–F, J 246.25 Hz), 174.65
(С2). Mass spectrum: m/z 256 [M + 1]+. Found, %:
C 75.11; H 5.46; N 5.44. C16H14FNО. Calculated, %:
C 75.28; H 5.53; N 5.49. M 255.287.
5-(4-Fluorophenyl)-1-phenylpyrrolidin-2-one (IId).
Yield 0.61 g (48%), mp 67–69 °С. IR spectrum, cm–1:
1
1700, 1610, 1520, 1430, 1380, 1240, 1150. H NMR
spectrum (DMSO-d6), δ, ppm: 1.80–1.89 m (1H, CH),
2.51–2.69 m (3H, СН, CH2), 5.44–5.52 m (1H, C5H),
7.03–7.07 m (1Harom), 7.11 t (2Harom, J 8.0 Hz), 7.26 t
(2Harom, J 8.0 Hz), 7.31–7.34 m (2Harom), 7.41 d (2Harom
,
J 8.4 Hz). 13С NMR spectrum (DMSO-d6), δ, ppm:
28.99 (C4), 31.30 (С3), 62.16 (С5), 115.95 d (2Сarom–F,
J 21.25 Hz), 123.00 (2Сarom), 125.0 (Сarom), 128.81 d
(2Сarom–F, J 8.70 Hz), 128.88 (2Сarom), 138.50 (Сarom),
138.57 (Сarom), 161.81 d (Сarom–F, J 242.50 Hz), 174.48
(С2). Mass spectrum: m/z 256 [M + 1]+. Found, %:
C 75.17; H 5.49; N 5.48. C16H14FNО. Calculated, %:
C 75.28; H 5.53; N 5.49. M 255.287.
5-(4-Methylphenyl)-1-phenylpyrrolidin-2-one
(IIe). Yield 0.89 g (71%), mp 119–120 °С. IR spectrum,
cm–1: 1690, 1600, 1510, 1390, 1360, 1240, 1160, 1120.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.80–1.86 m
(1H, CH), 2.23 с (3H, CH3), 2.53–2.66 m (3H,
1-(3,4-Dimethoxyphenyl)-5-(3-fluorophenyl)-
pyrrolidin-2-one (IIh). Yield 0.33 g (21%), oily
substance. IR spectrum, cm–1: 2950, 1700, 1590, 1520,
1450, 1390, 1320, 1260, 1220, 1140, 1120, 1030.
1H NMR spectrum (CDCl3), δ, ppm: 1.96–2.00 m (1H,
CH), 2.56–2.65 m (2H, CH2), 2.70–2.77 m (1H, CH),
3.76 s (6H, 2OCH3), 5.14–5.17 m (1H, C5H), 6.68–6.71 m
(2Harom), 6.91–6.92 m (2Harom), 6.99–7.00 m (1Harom),
7.15–7.17 m (1Harom), 7.23–7.26 m (1Harom). 13С NMR
spectrum (CDCl3), δ, ppm: 28.66 (C4), 30.93 (С3), 55.85
(OCH3), 55.90 (OCH3), 63.94 (С5), 107.20 (Сarom),
110.98 (Сarom), 113.07 d (Сarom–F, J 22.50 Hz), 114.64
(Сarom), 114.80 d (Сarom–F, J 21.25 Hz), 121.70 d (Сarom–F,
J 2.50 Hz), 130.61 d (Сarom–F, J 8.75 Hz), 131.34 (Сarom),
CH, CH2), 5.39–5.43 m (1H, C5H), 7.04 t (1Harom
J 7.6 Hz), 7.09 d (2Harom, J 7.6 Hz), 7.15 d (2Harom
J 8.0 Hz), 7.25 t (2Harom, J 8.0 Hz), 7.42 d (2Harom
,
,
,
J 8.0 Hz). 13С NMR spectrum (DMSO-d6), δ, ppm: 21.09
(СН3), 29.08 (C4), 31.35 (С3), 62.66 (С5), 122.78 (2Сarom),
124.83 (Сarom), 126.58 (2Сarom), 128.84 (2Сarom), 129.76
(2Сarom), 137.02 (Сarom), 138.79 (Сarom), 139.36 (Сarom),
174.53 (С2). Mass spectrum: m/z 252 [M + 1]+. Found,
%: C 81.16; H 6.74; N 5.48. C17H17NО. Calculated, %:
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ELECTROPHILIC INTRAMOLECULAR CYCLIZATION OF FUNCTIONAL... : V..
1179
144.27 d (Сarom–F, J 7.50 Hz), 146.51 (Сarom), 148.80
(Сarom), 163.14 d (Сarom–F, J 246.25 Hz), 174.61 (С2).
Mass spectrum: m/z 316 [M + 1]+. Found, %: C 68.53;
H 5.69; N 4.37. C18H18FNО3. Calculated, %: C 68.56;
H 5.75; N 4.44. M 315.339.
1-(3,4-Dimethoxyphenyl)-5-(4-fluorophenyl)-
pyrrolidin-2-one (IIi). Yield 0.30 g (19%), oily
substance. IR spectrum, cm–1: 2980, 1710, 1610, 1520,
1450, 1330, 1270, 1240, 1180, 1120, 1040, 920. 1H NMR
spectrum (CDCl3), δ, ppm: 1.84–1.92 m (1H, CH),
2.48–2.56 m (2H, CH2), 2.60–2.68 m (1H, CH), 3.68 s,
3.69 s (6H, 2OCH3), 5.08–5.11 m (1H, C5H), 6.61–6.65 m
(1Harom), 6.90 t (2Harom, J 8.5 Hz), 7.04–7.06 m (1Harom),
7.11–7.13 m (2Harom). 13С NMR spectrum (CDCl3),
δ, ppm: 28.92 (C4), 31.05 (С3), 55.79 (OCH3), 55.82
(OCH3), 63.94 (С5), 107.46 (Сarom), 110.98 (Сarom),
125.68 (Сarom), 126.52 (2Сarom), 127.95 (Сarom), 129.26
(2Сarom), 130.03 (2Сarom), 141.92 Сarom), 142.93 (Сarom),
165.64 (Сэфирн.=О), 175.13 (С2). Mass spectrum: m/z 310
[M + 1]+. Found, %: C 73.66; H 6.09; N 4.47. C19H19NО3.
Calculated, %: C 73.77; H 6.19; N 4.53. M 309.359.
5-Phenyl-1,3,4,5-tetrahydro-2ꢀ-1-benzazepin-2-
one (IIIа). Yield 0.69 g (58%), mp 179–181 °С (179–180
°С [13]). IR spectrum, cm–1: 3200, 3090, 1690, 1490,
1
1390, 1250, 1170. H NMR spectrum (DMSO-d6), δ,
ppm: 2.18–2.44 m (4H, 2CH2), 4.22–4.28 m (1H, C5H),
6.67 d (1Harom, J 7.8 Hz), 6.97–7.03 m (2Harom), 7.19 t
(1Harom, J 7.8 Hz), 7.30–7.41 m (5Harom), 9.65 s (1H,
NH). 13С NMR spectrum (DMSO-d6), δ, ppm: 30.30 (C3),
33.78 (С4), 45.35 (С5), 122.26 (С9), 124.93 (С7), 127.32
(С8), 127.39 (Сarom), 128.59 (С6), 128.97 (2Сarom), 129.30
(2Сarom), 136.50 (С5а), 138.84 (С9а), 141.87 (Carom),
173.58 (С2). Mass spectrum: m/z 238 [M + 1]+. Found,
%: C 80.87; H 6.34; N 5.86. C16H15NО. Calculated, %:
C 80.98; H 6.37; N 5.90. M 237.296.
114.95 (Сarom), 115.77 d (2Сarom–F, J 21.25 Hz), 127.79 d
(2Сarom–F, J 8.75 Hz), 131.33 (Сarom), 137.23 d (Сarom–F,
J 2.50 Hz), 146.47 (Сarom), 148.74 (Сarom), 162.07 d
(Сarom–F, J 245.00 Hz), 174.57 (С2). Mass spectrum:
m/z 316 [M + 1]+. Found, %: C 68.51; H 5.66; N 4.33.
C18H18FNО3. Calculated, %: C 68.56; H 5.75; N 4.44.
M 315.339.
5-(2-Fluorophenyl)-1,3,4,5-tetrahydro-2ꢀ-1-
benzazepin-2-one (IIIb). Yield 0.96 g (75%), mp
203–205 °С. IR spectrum, cm–1: 3210, 3080, 2980, 1690,
1590, 1490, 1390, 1330, 1230, 1210, 1110, 1040, 960.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.20–2.48 m
1-(3,4-Dimethoxyphenyl)-5-(4-methylphenyl)-
pyrrolidin-2-one (IIj). Yield 0.83 g (53%), mp 109–111
°С. IR spectrum, cm–1: 2950, 1690, 1610, 1530, 1450,
1390, 1360, 1250, 1180, 1140, 1110, 1030, 990. 1H NMR
spectrum (DMSO-d6), δ, ppm: 1.79–1.86 m (1H, CH),
2.23 s (3H, CH3), 2.51–2.67 m (3H, СН, CH2), 3.65 s,
3.66 s (6H, 2OCH3), 5.33–5.36 m (1H, C5H), 6.80 s
(2Harom), 7.09–7.17 m (5Harom). 13С NMR spectrum
(DMSO-d6), δ, ppm: 21.09 (СН3), 28.90 (C4), 31.33
(С3), 55.98 (2OCH3), 63.17 (С5), 108.29 (Сarom), 111.87
(Сarom), 115.58 (Сarom), 126.75 (2Сarom), 129.68 (2Сarom),
132.04 (Сarom), 137.00 (Сarom), 139.58 (Сarom), 146.29
(Сarom), 148.68 (Сarom), 174.24 (С2). Mass spectrum:
m/z 312 [M + 1]+. Found, %: C 73.14; H 6.75; N 4.47.
C19H21NО3. Calculated, %: C 73.29; H 6.80; N 4.50.
M 311.375.
Ethyl 4-(2-oxo-5-phenylpyrrolidin-1-yl)-benzoate
(IIk). Yield 1.26 g (83%), mp 108–110 °С. IR spectrum,
cm–1: 1720, 1690, 1610, 1520, 1460, 1390, 1360, 1280,
1240, 1180, 1110, 1030. 1H NMR spectrum (DMSO-d6),
δ, ppm: 1.26 t (3H, CH3, J 6.9 Hz), 1.83–1.91 m (1H,
CH), 2.53–2.73 m (3H, CH, CH2), 4.24 q (2H, CH2,
J 6.9 Hz), 5.51–5.55 m (1H, C5H), 7.19–7.32 m (5Harom),
7.60 d (2Harom, J 9.3 Hz), 7.82 d (2Harom, J 9.3 Hz).
13С NMR spectrum, δ, ppm: 14.61 (CН3), 28.89 (C4),
31.41 (С3), 60.98 (CН2), 62.58 (С5), 121.71 (2Сarom),
(4H, 2CH2), 4.46–4.50 m (1H, C5H), 6.61 d (2Harom
,
J 7.6 Hz), 6.99–7.05 m (2Harom), 7.19–7.28 m (2Harom),
7.30 t (2Harom, J 7.6 Hz), 7.37–7.42 m (1Harom), 7.58 t
(2Harom, J 7.6 Hz), 9.70 s (1H, NH). 13С NMR spectrum
(DMSO-d6), δ, ppm: 32.74 (C3), 33.21 (С4), 38.28 d
(С5F, J 2.50 Hz), 116.07 d (Сarom–F, J 21.25 Hz),
122.38 (С9), 125.00 d (Сarom–F, J 3.75 Hz), 125.15
(С7), 127.51 (С8), 127.64 (С6), 128.55 d (Сarom–F,
J 15.00 Hz), 129.48 d (Сarom–F, J 8.75 Hz), 130.43 d
(Сarom–F, J 3.75 Hz), 135.21 (С5a), 138.78 (С9а), 160.73 d
(Сarom–F, J 243.75 Hz), 173.44 (С2). Mass spectrum:
m/z 256 [M + 1]+. Found, %: C 75.22; H 5.45; N 5.39.
C16H14FNО. Calculated, %: C 75.28; H 5.53; N 5.49.
M 255.287.
5-(3-Fluorophenyl)-1,3,4,5-tetrahydro-2ꢀ-1-
benzazepin-2-one (IIIc). Yield 0.34 g (27%), mp
191–192 °С. IR spectrum, cm–1: 3200, 3120, 2970,
1690, 1590, 1490, 1460, 1400, 1270, 1220, 1150, 970.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.20–2.48 m
(4H, 2CH2), 4.28–4.33 m (1H, C5H), 6.69 d (1Harom
,
J 8.0 Hz), 7.01–7.04 m (2Harom), 7.12–7.24 m (4Harom),
7.40–7.45 m (1Harom), 9.64 s (1H, NH). 13С NMR spec-
trum (DMSO-d6), δ, ppm: 33.21 (C3), 33.49 (С4), 45.01
(С5), 114.10 d (Сarom–F, J 21.25 Hz), 116.08 d (Сarom–F,
J 21.25 Hz), 122.35 (С9), 125.02 (С7), 125.44 d (Сarom–F,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

VAS’KEVICH et al.
1180
J 2.50 Hz), 127.58 (С8), 128.52 (С6), 130.78 d (Сarom–F,
J 8.75 Hz), 135.95 (С5a), 138.82 (С9а), 144.96 d (Сarom–F,
J 7.50 Hz), 162.81 d (Сarom–F, J 241.25 Hz), 173.46 (С2).
Mass spectrum: m/z 256 [M + 1]+. Found, %: C 75.23;
H 5.51; N 5.47. C16H14FNО. Calculated, %: C 75.28;
H 5.53; N 5.49. M 255.287.
spectrum: m/z 298 [M + 1]+. Found, %: C 72.68; H 6.37;
N 4.76. C18H19NО3. Calculated, %: C 72.71; H 6.44;
N 4.71. M 297.348.
7,8-Dimethoxy-5-(2-fluorophenyl)-1,3,4,5-
tetrahydro-2ꢀ-1-benzazepin-2-one (IIIg). Yield 1.06 g
(67%), mp 179–181 °С. IR spectrum, cm–1: 3290, 2950,
1
5-(4-Fluorophenyl)-1,3,4,5-tetrahydro-2ꢀ-1-
benzazepin-2-one (IIId). Yield 0.46 g (36%), mp 203–
205 °С. IR spectrum, cm–1: 3210, 3080, 1700, 1610, 1520,
1690, 1530, 1380, 1270, 1230, 1190, 1020. H NMR
spectrum (DMSO-d6), δ, ppm: 2.19–2.50 m (4H, 2CH2),
3.46 s, 3.73 s (6H, 2OCH3), 4.40–4.45 m (1H, C5H),
1
1490, 1400, 1310, 1240, 1170, 1110, 1030. H NMR
6.16 s (1H, C6H), 6.68 s (1H, C9H), 7.21 t (1Harom
,
spectrum (DMSO-d6), δ, ppm: 2.19–2.49 m (4H, 2CH2),
4.22–4.36 m (1H, C5H), 6.66 d (1Harom, J 7.2 Hz),
7.02 t (2Harom, J 7.8 Hz), 7.19–7.24 m (3Harom), 7.38 t
(2Harom, J 7.8 Hz), 9.66 s (1H, NH). 13С NMR spectrum
(DMSO-d6), δ, ppm: 33.23 (C3), 33.92 (С4), 44.53 (С5),
115.64 d (2Сarom–F, J 21.25 Hz), 122.32 (С9), 125.03
(С7), 127.48 (С8), 128.46 (С6), 131.09 d (2Сarom–F,
J 7.50 Hz), 136.38 (С5a), 137.94 (Сarom), 138.75 (С9а),
161.55 d (Сarom–F, J 241.25 Hz), 173.66 (С2). Mass
spectrum: m/z 256 [M + 1]+. Found, %: C 75.26; H 5.44;
N 5.48. C16H14FNО. Calculated, %: C 75.28; H 5.53;
N 5.49. M 255.287.
J 8.4 Hz), 7.29 t (1Harom, J 8.0 Hz), 7.37–7.42 m (1Harom),
7.55 t (1Harom, J 8.0 Hz), 9.44 s (1H, NH). 13С NMR
spectrum (DMSO-d6), δ, ppm: 33.01 (C3), 33.23 (С4),
37.99 (С5), 56.09 (OCH3), 56.13 (OCH3), 107.33 (С9),
111.92 (С6), 116.01 d (Сarom–F, J 22.50 Hz), 124.96 d
(Сarom–F, J 1.25 Hz), 126.92 (С5a), 128.92 d (Сarom–F,
J 7.50 Hz), 129.42 d (Сarom–F, J 7.50 Hz), 130.22 d
(Сarom–F, J 3.75 Hz), 131.82 (С9а), 146.08 (С7), 148.22
(C8), 160.71 d (Сarom–F, J 242.50 Hz), 173.56 (С2). Mass
spectrum: m/z 316 [M + 1]+. Found, %: C 68.51; H 5.69;
N 4.40. C18H18FNО3. Calculated, %: C 68.56; H 5.75;
N 4.44. M 315.339.
5-(4-Methylphenyl)-1,3,4,5-tetrahydro-2ꢀ-1-
benzazepin-2-one (IIId). Yield 0.08 g (6%), mp
189–190 °С. IR spectrum, cm–1: 3180, 2970, 1685,
1520, 1490, 1400, 1330, 1240, 1210, 1170, 1030, 930.
1H NMR spectrum (CDCl3), δ, ppm: 2.37 s (3H, CH3),
2.43–2.57 m (4H, 2CH2), 4.33–4.41 m (1H, C5H), 6.81 d
(1Harom, J 6.9 Hz), 6.98–7.06 m (2Harom), 7.15–7.23 m
(5Harom), 7.61 br.s (1H, NH). 13С NMR spectrum, δ,
ppm: 21.09 (СН3), 32.85 (C3), 33.88 (С4), 44.72 (С5),
121.85 (С9), 125.61 (С7), 127.23 (С8), 128.75 (С6),
128.80 (2Сarom), 129.32 (2Сarom), 136.66 (С5а), 137.06
(Сarom), 137.32 (Сarom), 137.96 (С9а), 175.22 (С2). Mass
spectrum: m/z 252 [M + 1]+. Found, %: C 81.17; H 6.78;
N 5.56. C17H17NО. Calculated, %: C 81.24; H 6.82;
N 5.57. M 251.323.
7,8-Dimethoxy-5-phenyl-1,3,4,5-tetrahydro-2ꢀ-
1-benzazepin-2-one (IIIf). Yield 0.94 g (63%), mp
155–158 °С. IR spectrum, cm–1: 3270, 2950, 1680, 1530,
1460, 1390, 1270, 1230, 1130, 1020. 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.18–2.43 m (4H, 2CH2), 3.48 s,
3.72 s (6H, 2OCH3), 4.17–4.21 m (1H, C5H), 6.26 s (1H,
C6H), 6.66 s (1H, C9H), 7.28–7.40 m (5Harom), 9.35 s (1H,
NH). 13С NMR spectrum (DMSO-d6), δ, ppm: 33.32 (C3),
33.95 (С4), 45.08 (С5), 56.10 (OCH3), 56.14 (OCH3),
107.26 (С9), 113.04 (С6), 127.23 (Сarom), 128.28 (С5а),
128.92 (2Сarom), 129.09 (2Сarom), 131.79 (С9а), 142.29
(Сarom), 145.93 (С7), 148.04 (C8), 173.72 (С2). Mass
7,8-Dimethoxy-5-(3-fluorophenyl)-1,3,4,5-
tetrahydro-2ꢀ-1-benzazepin-2-one (IIIh). Yield 0.76
g (48%), mp 139–141 °С. IR spectrum, cm–1: 3210, 3100,
2980, 1685, 1620, 1590, 1530, 1450, 1390, 1270, 1230,
1130, 1040, 1020, 920. 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.20–2.48 m (4H, 2CH2), 3.52 s, 3.72 s (6H,
2OCH3), 4.22–4.26 m (1H, C5H), 6.30 s (1H, C6H), 6.66 s
(1H, C9H), 7.10–7.19 m (3Harom), 7.39–7.44 m (1Harom),
9.36 s (1H, NH). 13С NMR spectrum (DMSO-d6), δ,
ppm: 32.66 (C3), 33.84 (С4), 44.44 (С5), 56.05 (OCH3),
56.17 (OCH3), 106.38 (С9), 111.75 (С6), 113.97 d
(Сarom–F, J 21.25 Hz), 115.65 d (Сarom–F, J 21.25 Hz),
124.46 d (Сarom–F, J 2.50 Hz), 128.25 (С5a), 130.05 d
(Сarom–F, J 8.75 Hz), 130.15 (С9а), 143.98 d (Сarom–F,
J 7.50 Hz), 146.73 (С7), 148.15 (C8), 162.99 d (Сarom–F,
J 245.00 Hz), 175.34 (С2). Mass spectrum: m/z 316 [M +
1]+. Found, %: C 68.50; H 5.74; N 4.43. C18H18FNО3.
Calculated, %: C 68.56; H 5.75; N 4.44. M 315.339.
7,8-Dimethoxy-5-(4-fluorophenyl)-1,3,4,5-
tetrahydro-2ꢀ-1-benzazepin-2-one (IIIi). Yield
0.96 g (61%), mp 151–153 °С. IR spectrum, cm–1: 3210,
3110, 1680, 1520, 1390, 1270, 1230, 1170, 1130, 1020.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.18–2.43 m
(4H, 2CH2), 3.50 s, 3.72 s (6H, 2OCH3), 4.18–4.24 m
(1H, C5H), 6.24 s (1H, C6H), 6.66 s (1H, C9H), 7.20 t
(2Harom, J 8.8 Hz), 7.37 t (2Harom, J 6.8 Hz), 9.36 s (1H,
NH). 13С NMR spectrum (DMSO-d6), δ, ppm: 33.24 (C3),
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ELECTROPHILIC INTRAMOLECULAR CYCLIZATION OF FUNCTIONAL... : V..
1181
34.06 (С4), 44.27 (С5), 56.10 (OCH3), 56.11 (OCH3),
107.25 (С9), 112.79 (С6), 115.60 d (2Сarom–F, J 21.25 Hz),
128.10 (С5a), 130.90 d (2Сarom–F, J 7.50 Hz), 131.68
(С9а), 138.43 (Сarom), 145.95 (С7), 148.03 (C8), 161.45 d
(Сarom–F, J 241.25 Hz), 173.71 (С2). Mass spectrum:
m/z 316 [M + 1]+. Found, %: C 68.52; H 5.71; N 4.44.
C18H18FNО3. Calculated, %: C 68.56; H 5.75; N 4.44.
M 315.339.
REFERENCES
1. Vas’kevich, A.I., Tsizorik, N.M., Staninets, V.I., and
VovkM.V., Zh. Org. Khim., 2013, vol. 49, p. 1185.
2. Andrianov, V., Gulite, V., Lola D., Loza, E., Seme-
nikhina, V., Kalvinsh, I., Petersen, K.D., Ritchie, J.W.A.,
Khan, N., Tumber,A., Collins, L.S., Vadlomudi, S.M., and
Bjokling, F., Sehested N. Eur. J. Med. Chem. 2009, vol. 44,
p. 1067.
7,8-Dimethoxy-5-(4-methylphenyl)-1,3,4,5-
tetrahydro-2ꢀ-1-benzazepin-2-one (IIIj). Yield 0.53 g
(34%), mp 167–169 °С. IR spectrum, cm–1: 3200, 3090,
2980, 1680, 1520, 1460, 1390, 1350, 1270, 1230, 1160,
1120, 1040, 1020, 920. 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.20–2.42 m (7H, СН3, 2CH2), 3.48 s, 3.72 s
(6H, 2OCH3), 4.09–4.19 m (1H, C5H), 6.29 s (1H, C6H),
6.66 s (1H, C9H), 7.18 m (4Harom), 9.35 s (1H, NH).
13С NMR spectrum (DMSO-d6), δ, ppm: 21.11 (СН3),
33.33 (C3), 34.13 (С4), 44.69 (С5), 56.09 (OCH3), 56.23
(OCH3), 107.24 (С9), 113.08 (С6), 128.44 (С5а), 128.95
(2Сarom), 129.50 (2Сarom), 131.77 (С9а), 136.19 (Сarom),
139.18 (Сarom), 145.91 (С7), 148.02 (C8), 173.72 (С2).
Mass spectrum: m/z 312 [M + 1]+. Found, %: C 73.16;
H 6.79; N 4.47. C19H21NО3. Calculated, %: C 73.29;
H 6.80; N 4.50. M 311.375.
3. Legoabe, L., Kruger, J., Petzer,A., Petzer, J.P. Eur. J. Med.
Chem., 2011, vol. 46, p. 5162.
4. Ozaki, F., Matsukura, M., Kabasawa, Y., Ishibashi, K.,
Ikemori, M., Hamano, S., and Minami, N. Chem. Pharm.
Bull., 1992, vol. 40, p. 2735.
5. Dothager, R.S., Putt, K.S., Allen, B.J., Leslie, B.I., Nest-
erenko, V., and Hergenrother, P.J. J. Am. Chem. Soc., 2005,
vol. 127, p. 8686.
6. Potsyute, N.K., Rateikane, L.P., and Knunyants, I.L., Byul.
Akad. Nauk SSSR, Ser. Khim., 1980, p. 2363.
7. Vas’kevich, A.I., Tsizorik, N.M., Rusanov, E.B., Stani-
nets, V.I., and Vovk, M.V., Zh. Org. Khim., 2012, vol. 48,
p. 1565.
8. Krongauz, E.S., Rusanov, A.L., and Renard, T.L., Usp.
Khim., 1970, vol. 39, p. 1591.
9. Wittekind, R.R. and Weissman, C. J. Heterocycl. Chem.,
1972, vol. 9, p. 111.
10. Hill, R.K,. J. Org. Chem., 1957, vol. 22, p. 830.
11. Meyer, W.L. and Vaughar, W.R., J. Org. Chem., 1957,
vol. 22, p. 1554.
12. Sato, T., Ishida, S., Ishibashi, H., and Ikeda, M., J. Chem.
Soc., Perkin, Trans. I, 1991, p. 353.
5-(3-Fluorophenyl)dihydrofuran-2(3Н)-one (IV).
Yield 0.14 g (16%) from compound (Ic), 0.17 g (19%)
from compound (Ih), oily substance. IR spectrum,
cm–1: 1790, 1610, 1500, 1450, 1330, 1230, 1190, 1090,
1
1040, 990, 920. H NMR spectrum (CDCl3), δ, ppm:
13. Barsky, L.I. and Bencze, W.L. J. Med. Chem., 1971, vol. 14,
p. 40.
14. Takahata, H., Wang, E.-C., and Yamazaki, T. Synth. Com-
mun., 1988, vol. 18, p. 1159.
15. Dugar, S., Crouse, J.R., and Das, P.R. J. Org. Chem., 1992,
vol. 57, p. 5706.
16. Machrouki, F. and Namy, J.-L. Tetrahedron, 1998, vol. 54,
p. 11111.
2.13–2.19 m (1H, CH), 2.61–2.71 m (3H, СН, 2CH2),
5.46–5.50 m (1H, C5H), 6.99–7.04 m (2Harom), 7.09 d
(1Harom, J 7.2 Hz), 7.31–7.37 m (1Harom). 13С NMR
spectrum (CDCl3), δ, ppm: 28.75 (C4), 30.84 (С3), 80.30
(С5), 112.34 d (Сarom–F, J 22.50 Hz), 115.29 d (Сarom–F,
J 21.25 Hz), 120.87 d (Сarom–F, J 3.75 Hz), 130.50 d
(Сarom–F, J 8.75 Hz), 142.12 d (Сarom–F, J 7.50 Hz),
162.95 d (Сarom–F, J 245.00 Hz), 176.58 (С2). Mass
spectrum: m/z 181 [M + 1]+. Found, %: C 66.63; H 5.01.
C10H9FО2. Calculated, %: C 66.66; H 5.03. M 180.176.
17. Bertho, A., Chem. Ber., 1957, vol. 90, p. 29.
18. Love, B., Greenwald, R.B., Goodman, M.M., and Zirkle,
C.L., J. Med. Chem., 1971, vol. 14, p. 849.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013