Synthesis of quinolin-2-ones by an intramolecular Knoevenagel condensation and by tandem Michael-Knoevenagel heterocyclization

Article abstract of DOI:10.1007/s10593-011-0881-2

The synthesis of 2-(N-R-amino)- and 2-(N-vinylcarbonylamino)acylbenzenes has been carried out and their heterocyclization into quinolin-2-ones under the action of sodium ethylate has been studied.

Full text of DOI:10.1007/s10593-011-0881-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 9, December, 2011 (Russian Original Vol. 47, No. 9, September, 2011)
SYNTHESIS OF QUINOLIN-2-ONES BY AN INTRAMOLECULAR
KNOEVENAGEL CONDENSATION AND BY TANDEM MICHAEL-
KNOEVENAGEL HETEROCYCLIZATION
S. S. Mochalov1*, M. I. Chasanov1, A. N. Fedotov1, and N. S. Zefirov1
The synthesis of 2-(N-R-amino)- and 2-(N-vinylcarbonylamino)acylbenzenes has been carried out and
their heterocyclization into quinolin-2-ones under the action of sodium ethylate has been studied.
Keywords: acyl-2-(N-acylamino)benzenes, acyl-2-vinylcarbonylaminobenzenes, quinolin-2-ones, intra-
molecular Knoevenagel condensation, tandem heterocyclization.
Compounds containing the quinolin-2-one fragment have already been studied systematically as subjects
of medicobiological investigations for more than 50 years. Since then it was discovered that quinolin-2-ones as
structural units, form part of the composition of a series of natural alkaloids [1]. The investigations led to a
remarkable result, but only in practically the last 10-12 years, when new biological targets were discovered and
test systems based on them were designed and in practice highly coeffective screening was embodied in the
search for new medicinals. It was established that derivatives of quinolin-2-ones may display properties of
nonsteroidal selective androgen modulators [2-4] and may show effective action against hepatitis B [5], act as
inhibitors of acyl coenzyme A and cholesterol acyltransferase and increase the permeability of calcium activated
K+ channels [6, 7], display high antiproliferative activity [8-11] and the ability to bind to 5-HT3 receptors [12],
to receptors of antibiotics [13], and are inhibitors of various types of kinase [14-17], of farnesyl transferase [18],
and affect erectile dysfunction [19]. The established broad spectrum of biological activity of quinolin-2-ones
derivatives studied up to the present time, on the one hand, stimulated the search of new medicinals of various
profile based on them, and on the other, made urgent the problem of synthesizing new representatives of this
class with the prospect of developing for them characteristic forms of biological activity and the potential of
using them for practical purposes.
For the synthesis of new derivatives of quinolin-2-ones, we turned to the Knoevenagel intramolecular
condensation using as precursor the corresponding derivatives of ortho-aminoacylbenzenes. This route to the
synthesis of quinolin-2-one, comprising the heterocyclization of 2-(acetylamino)acetophenone under the action
of aqueous alcoholic alkaline solution, was used for the first time in [20]. However, many years passed before a
series of quinolin-2-ones was synthesized in a similar manner [21, 22]. In all probability, insufficient attention to
this method of synthesis was linked with the difficulties of obtaining the starting ortho-aminoacylbenzenes.
_______
*To whom correspondence should be addressed, e-mail: ssmoch@org. chem.msu.ru.
1 M. V. Lomonosov Moscow State University, 1, bld. 3 Leninskie gory, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1345-1363, September, 2011.
Original article submitted January 18, 2011.
0009-3122/11/4709-1105©2011 Springer Science+Business Media, Inc.
1105

This was confirmed, for example, by the fact that with the development of new approaches to the synthesis of
ortho-aminoacylbenzenes, the intramolecular Knoevenagel condensation as a method of heterocyclization in
quinolin-2-ones became used more intensively [5, 15, 18, 19].
Previously, in a brief communication [23], we showed that by the Knoevenagel reaction it was possible
to synthesize the corresponding quinolin-2-ones from ortho-amino ketones of the 1,4-benzodioxane series. The
condensation occurs in alcohol at 20oC in the presence of an equimolecular quantity of sodium ethylate. In the
present work we have studied the behavior of a series of ortho-(R-acetylamino)acylbenzenes under the action of
the same reagent to obtain functionalized quinolin-2-ones.
The starting ortho-(R3-acetylamino)acylbenzenes 20-49 were obtained by the acylation of ortho-
acylanilines 1-19 with acid chlorides of substituted acetic acids. Most of the ortho-acylanilines 1-5, 7-14, 17-19
used were synthesized as described in [23-28], but 6-amino-7-butyroyl-1,4-benzodioxane (6), 6-amino-7-(2-iodo-
benzoyl)-1,4-benzodioxane (15), and 2-amino-4,5-dimethoxyacetophenone (16), were obtained by the reduction
of the corresponding nitro compounds (see EXPERIMENTAL).
O
O
R
R
R2
NH2
R2
NHCOCH2R3
R3CH2COCl , 3N NaOH
dioxane, 20°С
R1
R1
1–17
20–47
13 R = H, 1 R1 = t-Bu, R2 = Me; 2 R1 = H, R2 = Et; 3 R1 = Br, R2 = Et; 415 R + R1 = OCH2CH2O,
4 R2 = Me, 5 R2 = Et, 6 R2 = Pr, 7 R2 = cyclo-Pr, 8 R2 = Ph, 9 R2 = p-MeC6H4, 10 R2 = m-FC6H4,
11 R2 = p-FC6H4, 12 R2 = o-ClC6H4, 13 R2 = p-ClC6H4, 14 R2 = o-BrC6H4, 15 R2 = o-IC6H4;
16, 17 R = R1 = OMe, 16 R2 = Me; 17 R2 = cyclo-Pr; 2023 R = H, 20 R1 = t-Bu, R2 = Me, R3 = o-MeOC6H4;
21 R1 = H, R2 = Et, R3 = Ph; 22 R1 = Br, R2 = Et, R3 = Ph; 23 R1 = Br, R2 = Et, R3 = o-MeOC6H4;
2445 R + R1 = OCH2CH2O, 24 R2 = Me, R3 = Ph; 25 R2 = Me, R3 = o-MeOC6H4; 26 R2 = Et, R3 = Ph;
27 R2 = Pr, R3 = Me; 28 R2 = Pr, R3 = Ph; 29 R2 = Pr, R3 = o-MeOC6H4; 30 R2 = cyclo-Pr, R3 = Ph;
31 R2 = cyclo-Pr, R3 = p-NO2C6H4; 32 R2 = R3 = Ph; 33 R2 = p-MeC6H4, R3 = p-ClC6H4O;
34 R2 = p-MeC6H4, R3 = CH2Br; 35 R2 = p-MeC6H4, R3 = p-NO2C6H4; 36 R2 = m-FC6H4, R3 = Ph;
37 R2 = p-FC6H4, R3 = CH2Br; 38 R2 = o-ClC6H4, R3 = p-NO2C6H4; 39 R2 = p-ClC6H4, R3 = Pr;
40 R2 = p-ClC6H4, R3 = Ph; 41 R2 = p-ClC6H4, R3 = o-MeOC6H4; 42 R2 = p-ClC6H4, R3 = p-NO2C6H4;
43 R2 = o-BrC6H4, R3 = Ph; 44 R2 = o-IC6H4, R3 = Ph; 45 R2 = o-IC6H4, R3 = o-MeOC6H4;
46, 47 R = R1 = OMe, 46 R2 = Me, R3 = Ph; 47 R2 = cyclo-Pr, R3 = Ph
Ph
NH2
O
O
O
NH
O
O
O
PhCH2COCl
R
R
dioxane, NaOH, 20oC
O
48, 49
18, 19
18, 48 R = Me; 19, 49 R = i-Pr
All the R-acylaminobenzenes 20-49 had not been obtained previously, their yields and physicochemical
characteristics are given in Tables 1-3.
We found further, that if the reaction of ortho-arylacetylaminoacylbenzenes 20-26, 28-32, 35, 36, 38,
40-47 was carried out under the conditions described in [23] (equivalent quantity of sodium ethylate, in alcohol,
20oC), the heterocyclization, irrespective of the nature of the substituents in the aromatic ring of the starting
anilides, was effected practically regioselectively and the corresponding quinolin-2-ones 50-72 were formed in
high yield (see Tables 2, 4-6). The substituents R, R1, R2, and R3 are identical with the substituents of these in
the starting anilides respectively.
1106

R2
R
R 3
O
EtONa (1 equiv.)
EtOH, 20oC
20–26, 28–32, 35, 36, 38, 40–47
R1
N
H
50–72
TABLE 1. Characteristics of Compounds 20-49
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C*
Yield, %
С
Н
N
5
1
2
3
4
6
7
20
C21H25NO3
74.01
74.31
7.31
7.42
3.92
4.13
90-91
83
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
C17H17NO2
76.11
76.38
6.94
6.41
5.03
5.24
67-68
88
85
76
86
79
87
81
77
68
91
87
94
76
79
82
85
84
91
83
89
91
C17H16BrNO2
C18H18BrNO3
C18H17NO4
59.12
58.97
4.51
4.66
3.88
4.05
92-93
57.16
57.46
4.65
4.82
3.51
3.72
100-101
132-133
167-168
151-152
128-129
91-92
69.31
69.44
5.32
5.50
4.47
4.50
C19H19NO5
66.72
66.85
5.41
5.61
4.01
4.10
C19H19NO4
70.02
70.14
5.72
5.89
4.26
4.31
C15H19NO4
64.71
64.96
6.81
6.91
4.97
5.05
C20H21NO4
70.43
70.78
6.02
6.24
3.98
4.13
C21H23NO5
67.95
68.28
6.11
6.28
3.64
3.79
126-127
137-138
122-123
167-168
199-201
135-136
137-138
157-158
94-95
C20H19NO4
71.01
71.20
5.47
5.68
3.91
4.15
C20H18N2O6
C23H19NO4
62.61
62.82
4.56
4.74
7.23
7.33
73.65
73.98
5.01
5.13
3.69
3.75
C24H20ClNO5
C19H18BrNO4
C24H20N2O6
C23H18FNO4
C18H15BrFNO4
C23H17ClN2O6
C20H20ClNO4
C23H18ClNO4
C24H20ClNO5
65.61
65.83
4.48
4.60
3.12
3.20
56.21
56.45
4.38
4.49
3.41
3.47
66.31
66.66
4.51
4.66
6.33
6.48
70.26
70.58
4.51
4.63
3.52
3.58
52.71
52.96
3.62
3.70
3.24
3.43
60.78
61.00
3.61
3.78
6.01
6.19
191-192
114-115
138-139
156-157
64.01
64.26
5.16
5.39
3.71
3.75
67.51
67.73
4.31
4.45
3.35
3.44
65.71
65.83
4.44
4.60
3.11
3.20
1107

TABLE 1 (continued)
1
2
3
4
5
6
7
C23H17ClN2O6
60.74
61.00
3.51
3.78
6.04
6.19
140-141
77
42
C23H18BrNO4
C23H18INO4
60.95
61.08
3.91
4.01
2.93
3.10
147-148
158-159
76
81
43
44
54.96
55.33
3.41
3.63
2.62
2.81
C24H20INO5
C18H19NO4
C20H21NO4
C18H17NO4
54.21
54.46
3.64
3.81
2.41
2.65
144-145
137-138
121-122
91-92
71
90
77
79
45
46
47
48
68.78
68.99
5.93
6.11
4.21
4.47
70.62
70.78
6.09
6.24
4.07
4.13
69.22
69.44
5.32
5.51
4.38
4.50
C20H21NO4
70.51
70.78
6.14
6.24
3.98
4.13
114-115
81
49
_______
*Solvents for recrystallization: EtOH (compounds 20-27, 29, 30, 34, 35, 37,
39, 40, 45, 47-49) and EtOH–CHCl3, 1:1 mixture (compounds 28, 31-33,
36, 38, 41-44, 46).
TABLE 2. Mass Spectra of Compounds 20, 26, 32, 36, 40, 59, 64, 67
Com-
pound
m/z (Irel, %)
339 [M]+ (4), 218 (46), 191 (26), 176 (8), 148 (23), 132 (10), 121(38), 91 (100), 77 (16),
20
65 (24), 57 (13), 43 (61)
325 [M]+ (69), 296 (35), 234 (78), 207 (65), 188 (20), 178 (83), 91 (100), 77 (8), 65 (41),
26
57 (44), 51 (13), 39 (27)
373 [M]+ (56), 282 (100), 255 (98), 204 (26), 178 (9), 171 (11), 143 (19), 105 (60),
32
91 (65), 77 (59), 65 (34), 51 (24), 39 (20)
391 [M]+ (30), 300 (48), 273 (65), 204 (9), 161 (14), 123 (65), 91 (100), 75 (11), 65 (42),
36
51 (13), 39 (26)
407 [M]+ (41), 318 (35), 316 (100), 290 (55), 289 (98), 204 (9), 141 (16), 139 (21),
40
98 (14), 91 (43), 59 (26), 43 (36)
319 [M]+ (100), 304 (15), 291 (35), 262 (12), 235 (24), 206 (21), 178 (17), 152 (31),
59
139 (26), 115 (25), 102 (24), 89 (26), 77 (36), 68 (36), 51 (37), 39 (55)
434 [M]+ (56), 399 (36), 353 (26), 297 (36), 269 (30), 256 (21), 240 (99), 226 (36),
64
213 (79), 200 (60), 187 (38), 176 (52), 163 (37), 149 (72), 141 (46), 126 (46), 107 (82),
94 (100), 87 (35), 75 (55), 68 (85), 55 (65), 41 (95)
434 [M]+ (100), 386 (6), 240 (29), 214 (12), 200 (10), 187 (25), 176 (16), 163 (10),
67
140 (10), 120 (21), 106 (58), 99 (28), 87 (26), 75 (41), 68 (84), 50 (42), 44 (61)
5-Phenacetylamino-substituted 6-acyl-1,4-benzodioxanes 48, 49 were cyclized in a similar manner
under the same conditions.
1108

O
Ph
R
HN
O
O
EtONa (1 equiv.)
EtOH, 20oC
48, 49
73, 74
73 R = Me; 74 R = i-Pr
TABLE 3. 1H NMR Spectra of Compounds 20-49
Com-
pound
Chemical shifts*, δ, ppm (J, Hz)
1
2
1.35 (9H, s, C(CH3)3); 2.61 (3H, s, CH3CO); 3.79 (2H, s, CH2Ar);
20
3.87 (3H, s, CH3O); 6.94 (1H, d, J = 7.6, H Ar); 6.99 (1H, t, J = 7.6, H Ar);
7.12 (1H, dd, J = 7.8, J = 2.0, H Ar); 7.33 (2H, m, H Ar);
7.78 (1H, d, J = 7.8, H Ar); 8.91 (1H, d, J = 2.0, H Ar); 11.67 (1H, s, NH)
21
1.21 (3Н, t, J = 6.6, СН2СН3); 3.02 (2Н, q, J = 6.6, СН2СН3);
3.77 (2H, s, CH2Ph); 7.11 (1Н, dt, J = 7.8, J = 1.4, H Ar);
7.31 (1Н, m, H Ar); 7.41 (4Н, m, H Ar); 7.52 (1Н, dt, J = 7.8, J = 1.4, H Ar);
7.89 (1Н, dd, J = 7.8, J = 1.4, H Ar); 8.75 (1Н, dd, J = 7.8, J = 1.4, H Ar);
11.81 (1H, s, NH)
22
23
1.22 (3Н, t, J = 7.2, СН2СН3); 2.98 (2Н, q, J = 7.2, СН2СН3);
3.77 (2H, s, CH2Ph); 7.23 (1Н, dd, J = 7.8, J = 1.9, H Ar);
7.33 (1Н, m, H Ar); 7.39 (4Н, m, H Ar); 7.73 (1Н, d, J = 7.8, H Ar);
9.02 (1Н, s, H Ar); 11.85 (1H, s, NH)
1.19 (3Н, t, J = 6.4, СН2СН3); 2.97 (2Н, q, J = 6.4, СН2СН3);
3.79 (2H, s, CH2Ar); 3.88 (3H, s, CH3O); 6.94 (1Н, d, J = 7.6, H Ar);
6.99 (1Н, dt, J = 7.8, J = 1.2, H Ar); 7.21 (1Н, dd, J = 8.4, J = 2.0, H Ar);
7.32 (2H, m, H Ar); 7.71 (1Н, d, J = 8.4, H Ar); 9.03 (1Н, s, H Ar); 11.68 (1H, s, NH)
2.51 (3Н, s, СН3CO); 3.75 (2H, s, CH2Ph); 4.24 (2Н, m) and 4.31 (2Н, m, ОСН2СН2О);
7.31 (1Н, m, H Ar); 7.33 (1Н, s, H Ar); 7.41 (4Н, m, H Ar); 8.35 (1Н, s, H Ar);
11.65 (1H, s, NH)
24
25
2.51 (3Н, s, СН3CO); 3.71 (2H, s, CH2Ph); 3.85 (3H, s, CH3O);
4.24 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 6.87 (1Н, d, J = 7.8, H Ar);
6.98 (1Н, t, J = 7.8, H Ar); 7.31 (3Н, m, H Ar); 8.36 (1Н, s, H Ar); 11.52 (1H, s, NH)
26
27
1.01 (3Н, t, J = 7.2, СН2СН3); 2.98 (2Н, q, J = 7.2, СН2СН3); 3.71 (2H, s, CH2Рh);
4.23 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 7.24 (1H, m, H Ar); 7.33 (4H, m, H Ar);
7.62 (1H, s, H Ar); 8.01 (1H, s, H Ar); 11.51 (1H, s, NH)
0.91 (3Н, t, J = 6.8, СН2СН2СН3); 1.11 (3Н, t, J = 6.4, СН2СН3);
1.61 (2Н, m, СН2СН2СН3); 2.38 (2Н, q, J = 6.4, СН2СН3);
2.96 (2Н, t, J = 6.7, СН2СН2СН3); 4.25 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О);
7.54 (1H, s, H Ar); 8.07 (1H, s, H Ar); 11.48 (1H, s, NH)
28
29
0.99 (3Н, t, J = 7.0, СН2СН2СН3); 1.73 (2Н, m, СН2СН2СН3);
2.84 (2Н, t, J = 6.7, СН2СН2СН3); 3.75 (2H, s, CH2Рh);
4.22 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 7.27 (1H, m, H Ar);
7.35 (4H, m, H Ar); 7.38 (1Н, s, H Ar); 8.62 (1Н, s, H Ar); 11.81 (1H, s, NH)
0.98 (3Н, t, J = 7.2, СН2СН2СН3); 1.74 (2Н, m, СН2СН2СН3);
2.85 (2Н, t, J = 6.9, СН2СН2СН3); 3.75 (2H, s, CH2Ar); 3.86 (3H, s, CH3O);
4.24 (2Н, m) and 4.30 (2Н, m, ОСН2СН2О); 6.92 (1Н, d, J = 8.2, H Ar);
6.97 (1Н, t, J = 8.2, H Ar); 7.28 (2H, m, H Ar); 7.36 (1Н, s, H Ar);
8.33 (1Н, s, H Ar); 11.62 (1H, s, NH)
30
1.01 (2Н, m, cyclo-Pr); 1.17 (2Н, m, cyclo-Pr); 2.51 (1Н, m, cyclo-Pr);
3.70 (2H, s, CH2Рh); 4.26 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О);
7.29 (1H, m, H Ar); 7.37 (4H, m, H Ar); 7.59 (1Н, s, H Ar);
1109

TABLE 3 (continued)
1
2
31
32
1.03 (2Н, m, c-Pr); 1.17 (2Н, m, c-Pr); 2.54 (1Н, m, c-Pr); 3.81 (2H, s, CH2Рh);
4.26 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 7.53 (2Н, d, J = 8.4, H Ar);
7.62 (1Н, s, H Ar); 8.20 (1Н, s, H Ar); 8.24 (2Н, d, J = 8.4, H Ar); 11.84 (1H, s, NH)
3.34 (2H, s, CH2Рh); 4.25 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.88 (1Н, s, H Ar);
7.15 (2Н, d, J = 7.8, H Ar); 7.22 (1Н, t, J = 7.8, H Ar); 7.28 (2Н, m, H Ar);
7.42 (1Н, s, H Ar); 7.49 (2Н, m, H Ar); 7.62 (3Н, m, H Ar); 10.35 (1H, s, NH)
33
33
34
2.45 (3Н, s, СН3); 4.26 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 4.59 (2H, s, CH2OAr);
7.05 (2Н, d, J = 8.3, H Ar); 7.14 (1H, s, H Ar); 7.28 (4H, m, H Ar); 7.61 (2Н, d, J = 8.0,
H Ar); 8.31 (1Н, s, H Ar); 11.92 (1H, s, NH)
2.45 (3Н, s, СН3); 4.26 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 4.59 (2H, s, CH2OAr);
7.05 (2Н, d, J = 8.3, H Ar); 7.14 (1H, s, H Ar); 7.28 (4H, m, H Ar); 7.61 (2Н, d, J = 8.0,
H Ar); 8.31 (1Н, s, H Ar); 11.92 (1H, s, NH)
2.45 (3Н, s, СН3); 3.02 (2Н, t, J = 6.8, СН2СН2Br); 3.73 (2Н, t, J = 6.8, СН2СН2Br);
4.25 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 7.12 (1H, s, H Ar); 7.29 (2Н, d, J = 8.1,
H Ar); 7.59 (2Н, d, J = 8.1, H Ar); 8.28 (1Н, s, H Ar); 11.19 (1H, s, NH)
35
36
2.45 (3Н, s, СН3); 3.85 (2H, s, CH2Ar); 4.25 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О);
7.15 (1Н, s, H Ar); 7.29 (2Н, d, J = 7.4, H Ar); 7.54 (2Н, d, J = 8.1, H Ar);
7.58 (2Н, d, J = 7.4, H Ar); 8.18 (1Н, s, H Ar); 8.22 (2Н, d, J = 8.1, H Ar);
11.26 (1H, s, NH)
3.33 (2H, s, CH2Ph); 4.26 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.89 (1Н, s, H Ar);
7.12 (2Н, d, J = 7.2, H Ar); 7.22 (1Н, t, J = 7.2, H Ar); 7.26 (2Н, m, H Ar);
7.31 (1Н, s, H Ar); 7.34 (1Н, m, H Ar); 7.40 (1Н, m, H Ar); 7.44 (1Н, m, H Ar);
7.51 (1Н, m, H Ar); 10.31 (1H, s, NH)
37
38
3.02 (2Н, t, J = 7.2, СН2СН2Br); 3.71 (2Н, t, J = 7.2, СН2СН2Br); 4.25 (2Н, m) and
4.35 (2Н, m, ОСН2СН2О); 7.06 (1H, s, H Ar); 7.17 (2Н, m, H Ar); 7.71 (2Н, m, H Ar);
8.26 (1Н, s, H Ar); 11.11 (1H, s, NH)
3.92 (2H, s, CH2Ar); 4.21 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 6.85 (1Н, s, H Ar);
7.26 (1H, m, H Ar); 7.37 (1Н, m, H Ar); 7.45 (2Н, m, H Ar); 7.59 (2Н, d, J = 8.6, H Ar);
8.25 (2Н, d, J = 8.6, H Ar); 8.36 (1Н, s, H Ar); 11.81 (1H, s, NH)
39
40
41
0.82 (3Н, t, J = 6.4, СН2СН2СН2СН3); 1.12 (2Н, m, СН2СН2СН2СН3);
1.28 (2Н, m, СН2СН2СН2СН3); 2.02 (2Н, t, J = 6.2, СН2СН2СН2СН3);
4.26 (2Н, m) and 4.34 (2Н, m, ОСН2СН2О); 6.91 (1H, s, H Ar); 7.19 (1H, s, H Ar);
7.54 (2Н, d, J = 8.0, H Ar); 7.62 (2Н, d, J = 8.0, H Ar); 9.95 (1H, s, NH)
3.41 (2H, s, CH2Ph); 4.23 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.88 (1Н, s, H Ar);
7.10 (2Н, d, J = 7.5, H Ar); 7.21 (1Н, t, J = 7.5, H Ar); 7.25 (2Н, m, H Ar);
7.28 (1Н, s, H Ar); 7.51 (2Н, d, J = 8.4, H Ar); 7.59 (2Н, d, J = 8.4, H Ar);
10.22 (1H, s, NH)
3.74 (2H, s, CH2Ar); 3.83 (3Н, s, СН3О); 4.23 (2Н, m) and
4.33 (2Н, m, ОСН2СН2О); 6.90 (1Н, d, J = 8.1, H Ar); 6.97 (1Н, s, H Ar);
6.98 (1Н, t, J = 8.1, H Ar); 7.32 (2Н, m, H Ar); 7.44 (2Н, d, J = 8.4, H Ar);
7.60 (2Н, d, J = 8.4, H Ar); 8.21 (1Н, s, H Ar); 10.73 (1H, s, NH)
42
43
3.85 (2H, s, CH2Ar); 4.22 (2Н, m) and 4.31 (2Н, m, ОСН2СН2О);
7.05 (1Н, s, H Ar); 7.46 (2Н, d, J = 8.4, H Ar); 7.57 (4Н, m, H Ar);
8.21 (1Н, s, H Ar); 8.22 (2Н, d, J = 8.6, H Ar); 11.21 (1H, s, NH)
3.78 (2H, s, CH2Ph); 4.21 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.62 (1Н, s, H Ar);
7.28 (1Н, m, H Ar); 7.36 (4Н, m, H Ar); 7.43 (1Н, dd, J = 7.4, J = 1.9, H Ar);
7.47 (1Н, dt, J = 7.8, J = 1.9, H Ar); 7.52 (1Н, dt, J = 7.4, J = 1.3, H Ar);
7.74 (1Н, dd, J = 7.8, J = 1.1, H Ar); 8.11 (1Н, s, H Ar); 11.23 (1H, s, NH)
44
3.79 (2H, s, CH2Ph); 4.21 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 6.60 (1Н, s, H Ar);
7.28 (1Н, m, H Ar); 7.36 (6Н, m, H Ar); 7.52 (1Н, dt, J = 7.6, J = 1.0, H Ar);
7.95 (1Н, d, J = 7.8, H Ar); 8.12 (1Н, s, H Ar); 11.27 (1H, s, NH)
1110

TABLE 3 (continued)
1
2
45
3.69 (2H, s, CH2Ar); 3.82 (3H, s, OCH3); 4.17 (2H, m) and 4.32 (2H, m, OCH2CH2O);
6.57 (1H, s, H Ar); 6.95 (1H, t, J = 8.0, H Ar); 7.03 (1Н, d, J = 8.0, H Ar);
7.39 (5Н, m, H Ar); 7.52 (1Н, t, J = 8.0, H Ar); 7.94 (1Н, d, J = 8.0, H Ar);
11.29 (1Н, s, NH)
46
47
2.59 (3Н, s, COСН3); 3.75 (2H, s, CH2Ph); 3.90 (3Н, s, СН3О); 3.96 (3Н, s, СН3О);
7.25 (1Н, s, H Ar); 7.32 (1Н, m, H Ar); 7.39 (4Н, m, H Ar);
8.54 (1Н, s, H Ar); 12.06 (1H, s, NH)
1.06 (2Н, m, cyclo-Pr); 1.22 (2Н, m, cyclo-Pr); 2.57 (1Н, m, cyclo-Pr);
3.73 (2H, s, CH2Рh); 3.93 (3Н, s, СН3О); 3.96 (3Н, s, СН3О);
7.28 (1H, m, H Ar); 7.37 (4H, m, H Ar); 7.51 (1Н, s, H Ar); 8.51 (1Н, s, H Ar);
12.01 (1H, s, NH)
48
49
2.51 (3Н, s, COСН3); 3.52 (2H, s, CH2Ph);
4.26 (2Н, m) and 4.35 (2Н, m, ОСН2СН2О); 6.75 (1Н, d, J = 8.8, H Ar);
7.30 (1Н, d, J = 8.8, H Ar); 7.35 (1Н, m, H Ar); 7.40 (4Н, m, H Ar); 9.02 (1H, s, NH)
1.11 (6Н, d, J = 7.0, СH(СН3)2); 3.35 (1Н, sept, J = 7.0, СH(СН3)2);
3.75 (2H, s, CH2Ph); 4.26 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О);
6.74 (1Н, d, J = 8.9, H Ar); 7.24 (1Н, d, J = 8.9, H Ar); 7.31 (1Н, m, H Ar);
7.38 (4Н, m, H Ar); 9.01 (1H, s, NH)
_______
*The 1H NMR spectra of compounds 20, 21, 24, 25, 28-31, 33-35, 37, 38, 41, 42,
46-49 were recorded in CHCl3, and of compounds 22, 23, 26, 27, 32, 36, 39, 40,
43-45 in DMSO-d6.
In contrast to this, derivatives of alkyl (compounds 27, 39) or aryloxy (compound 33) substituted acetic
acids did not react, but derivatives of β-bromopropionic (bromomethylacetic) acid 34, 37 were converted into
the products of hydrogen bromide elimination (compounds 75, 76) and nucleophilic substitution of the halogen
atom (compounds 77, 78), and not into quinolin-2-ones of type A.
R
O
EtONa (1 equiv.)
EtOH, 20oC
O
O
R
O
O
CH2Br
O
NH
N
H
A
Br
O
34, 37
O
O
O
O
R
O
O
R
EtONa (1 equiv.)
EtOH, 20oC
+
NH
NH
OEt
O
O
75, 77 R = Me; 76, 78 R = F
1111

It turned out that if the alkoxy derivatives 77, 78 were treated repeatedly with 2 equiv. sodium ethylate,
and β-bromomethylacetylamines 34, 37 were reacted with 3 equiv. alcoholate and the reaction was carried out
with heating, then in both cases alkoxy-substituted quinolin-2-ones 79, 80 were formed in high yield.
R
O
O
CH2OEt
O
EtONa (2 equiv.)
EtOH, 78oC
EtONa (3 equiv.)
EtOH, 78oC
34, 37
77, 78
N
H
79, 80
34, 77, 79 R = Me; 37, 78, 80 R = F
When transforming β-haloethylcarbonylamino-substituted acylbenzenes 34, 37 into alkoxy-substituted
quinolin-2-ones 79, 80, two separate and subsequent processes are undergoing. 1) Conversion of the starting
anilides 34, 37 into alkoxyethylcarbonylamino-1,4-benzodioxanes 77, 78, in all probability, occurs in an excess
of alcoholate by way of both the direct substitution reaction of the halogen atom by an alkoxy group, and
addition of ethanol to the α,β-vinyl group of compounds 75, 76, catalyzed by alcoholate, and 2) subsequent
condensation into quinolin-2-ones 79, 80.
O
O
O
O
R
O
O
R
EtONa (2 equiv.)
EtOH, 78oC
–
NH
N
CHCH2OEt
H
O
O
I
R
75, 76, 81
O
–
EtO–
(– EtOH )
O
+ H+
– H+
O
O
R
H
O
CH2OEt
O
O
N
H
O
N
EtOH
H
CH2CH2OEt
(– EtO–)
R
II
77, 78, 82
R
HO
EtO–
(– EtOH )
EtOH
H
O
O
(–EtO–)
O
O
CH2OEt
CH2OEt
– OH–
EtO–
(– EtOH )
N
O
N
O
H
H
79, 80, 83
81, 82, 83 R = Cl
Indirect confirmation of the fact that the β-alkoxyethylcarbonyl fragment in compounds 77, 78 may be
formed from the vinylcarbonyl substituent in the process of base-catalyzed addition of alcohol according to
Michael, is the conversion of 6-acyl-7-vinylcarbonylamino-1,4-benzodioxanes 75, 76, 81 into the corresponding
alkoxy-substituted quinolin-2-ones 79, 80, 83 under heterocyclization conditions.
1112

It is seen from the scheme that the formation of quinolinones 79, 80, 83 may occur both through the
stage of forming addition products of ethanol to the vinylcarbonyl group according to Michael 77, 78, 82 and
through the stage of forming the cyclic ion II, obtained in the process of adding alcohol according to a pseudo-
Michael reaction involving the carbonyl group in the ortho-position to the vinyl-containing substituent. It is
interesting that if the reaction of vinylcarbonylamino-substituted acylbenzenes 75, 76, 81 is completed with the
formation of the corresponding quinolinones, analogously substituted benzodioxane 84 containing a 2-chloro-
benzoyl group in the ortho-position is mainly converted into the product of Michael addition 85. In this way, a
partial cleavage of the amide bond is observed with the formation of 7-acyl-6-amino-1,4-benzodioxane 12.
The obtained result shows that alkoxy-substituted acylaminobenzenes, the immediate precursors of the
corresponding quinolinones, may in reality be formed from the vinylcarbonyl fragments by a Michael reaction.
Regarding the impossibility of compound 85 to give products of heterocyclization, it is evident that the
heterocyclization stage to the corresponding quinolinone is inhibited due to steric factors.
On the whole, irrespective of the fact that whether products of addition according to Michael are formed
or heterocyclization into the corresponding quinolin-2-ones is effected through anions of types I, II (see scheme
on p. 1112), arising at the stage of adding ethylate anion to the double bond of the vinylcarbonyl group, the
process of forming alkoxy-substituted quinolin-2-ones (of type 79, 80, 83) from ortho-acylanilides of acrylic
acid (of type 75, 76, 81) under the action of sodium ethylate may be considered as a tandem heterocyclization.
O
Cl
O
Cl
O
Cl
O
O
O
O
O
O
EtO– , EtOH
78oC
NH
+
NH
NH2
O
OEt
O
84
85
12
It is interesting to note that if 3 equiv. alcoholate and heating are necessary for complete conversion of
β-haloethylcarbonylamino-substituted benzodioxanes 34, 37 into the corresponding quinolin-2-ones 79, 80, then
compounds 27, 33, and 39 were practically unchanged by the action of 1 equiv. sodium ethylate at 20oC, but
underwent complete conversion into the corresponding quinolin-2-ones 86-88 at a substrate–sodium ethylate
ratio of 1:2 in boiling alcohol.
EtONa (1 equiv.)
R
EtOH, 20oC
O
O
R1
O
27, 33, 39
N
EtONa (2 equiv.)
EtOH, 78oC
H
86–88
27, 86 R = Pr, R1 = Me; 33, 87 R = p-MeC6H4, R1 = p-ClC6H4O;
39, 88 R = p-ClC6H4, R1 = Pr
According to the scheme of the intramolecular variant of the Knoevenagel condensation of
N-acylamino-substituted acylbenzenes 20-49, 77, 78 studied by us, this conversion may be effected under the
action of even catalytic quantities of alcoholate, moreover, this reaction may be initiated by released hydroxide
anion [21, 22].
1113

Probably, since the positive charge on the carbon atom of the carbonyl group in the present case is lower
than in the classical variant of the Knoevenagel condensation, the process is conducted significantly more
slowly. In our case, it is therefore necessary to use a larger quantity of alcoholate to achieve complete
conversion of the starting substrates into quinolin-2-ones. In reality, we have established that under the action of
catalytic amounts of sodium ethylate chromatographically appreciable quantities of condensation products are
formed only after 10-12 h.
TABLE 4. Characteristics of Quinolin-2-ones 50-74, 79, 80, 83, 86-88
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp., °C*
6
Yield, %
7
С
Н
N
5
1
2
3
4
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
C21H23NO2
C17H15NO
78.12
78.47
7.03
7.21
4.11
4.36
238–239
224–225
232–233
237–238
323–324
293–294
311–312
297–298
269–271
301–302
402–404
353–354
392–394
354–355
250–270
398–400
328–329
405–407
382–383
400–401
322–323
76
69
86
83
92
93
88
87
81
91
89
92
82
95
86
93
92
79
81
88
74
81.54
81.91
6.23
6.06
5.66
5.62
C17H14BrNO
C18H16BrNO2
C18H15NO3
C19H17NO4
C19H17NO3
C20H19NO3
C21H21NO4
C20H17NO3
C20H16N2O5
C23H17NO3
C24H18N2O5
C23H16FNO3
C23H15ClN2O5
C23H16ClNO3
C24H18ClNO4
C23H15ClN2O5
C23H16BrNO3
C23H16INO3
C24H18INO4
62.30
62.21
4.31
4.30
4.28
4.27
60.15
60.35
4.66
4.50
4.15
3.91
73.61
73.71
4.96
5.15
4.63
4.78
70.32
70.58
5.17
5.30
4.21
4.33
74.02
74.25
5.50
5.58
4.38
4.56
74.38
74.75
5.78
5.96
4.18
4.36
71.52
71.78
5.88
6.02
4.11
3.99
74.92
75.22
5.28
5.37
4.24
4.39
65.69
65.93
4.54
4.43
7.78
7.69
77.69
77.73
4.65
4.82
4.05
3.94
69.23
69.56
4.21
4.38
6.62
6.76
73.82
73.99
4.24
4.32
3.73
3.75
62.96
63.53
3.57
3.48
6.22
6.44
70.52
70.86
3.96
4.14
3.71
3.59
68.41
68.66
4.19
4.32
3.31
3.34
63.32
63.53
3.33
3.48
6.38
6.44
63.36
63.61
3.51
3.71
3.25
3.23
56.94
57.40
3.17
3.35
2.83
2.91
56.48
56.38
3.57
3.55
2.59
2.74
1114

TABLE 4 (continued)
1
2
3
4
5
6
7
72
C20H19NO3
C18H15NO3
C20H19NO3
C21H21NO4
C20H18FNO4
C20H18ClNO4
C15H17NO3
C24H18ClNO4
C20H18ClNO3
74.52
74.74
5.54
5.96
4.31
4.36
281-282
225-226
232-233
268-269
244-245
264-265
269-270
321-322
325-326
84
71
65
86
95
93
52
78
75
73
74.00
73.71
5.35
5.15
4.94
4.78
74
74.61
74.75
5.93
5.96
4.20
4.36
79
71.59
71.78
5.87
6.02
3.91
3.99
80
67.45
67.60
5.16
5.10
3.76
3.94
83
64.70
64.61
4.95
4.88
3.64
3.77
86
69.27
69.48
6.48
6.61
5.26
5.41
87
68.41
68.66
4.19
4.32
3.21
3.34
88
67.42
67.51
4.96
5.10
3.88
3.94
_______
*Solvents for recrystallization: EtOH (compounds 50-55, 58, 70, 73, 74, 79,
80, 83, 86, 88) and EtOH–CHCl3, 1:1 mixture (compounds 56, 57, 59-69, 71,
72, 87).
The lower proton mobility of hydrogen atoms in the methylene component of the starting substrates 27,
33, 39, 77, 78 (in comparison with classical substrates) leads to the fact that their heterocyclization into the
corresponding quinolin-2-ones succeeds not only because of the increase in alcoholate concentration, but also as
a result of an increase in times of the reaction and heating.
It is important to emphasize that under conditions of heterocyclization not only is the Knoevenagel
intermolecular condensation not observed but also there is no formation of the isomeric quinolones (quinolin-
4-ones) from substrates for which this is possible (compounds 20-29, 46, 48).
EXPERIMENTAL
The IR spectra were recorded on a UR 20 instrument in nujol (compounds 51, 56, 60, 61, 64, 65, 70, 83)
1
13
or hexachlorobutadiene (compounds 59, 80). The H and C NMR spectra were obtained on a Bruker Avance
400 instrument (at 400 MHz and 100 MHz respectively), internal standard was TMS. Mass spectra were
recorded on a Finnigan SSQ 7000 (GC-MS type) instrument using a capillary column (30 m  2 mm, stationary
phase DB-1), carrier gas was helium (40 ml/min) with temperature programing from 50 to 300oC (10 deg/min).
Ionization energy was 70 eV. Elemental analysis was carried out on a Vario-II CHN analyzer. A check on the
purity of compounds obtained and the separation of certain reaction mixtures was effected by TLC on Al2O3,
activity grade II (according to Brockmann) in the systems ether–petroleum ether (40-70oC), 1:3, or ether–
CH2Cl2–petroleum ether (40-70oC), 1:1:3 by volume.
1-(7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl)butan-1-one was obtained by the nitration of 1-(2,3-di-
hydro-1,4-benzodioxin-6-yl)butan-1-one with acetyl nitrate in Ac2O as described in [29]. Yield 84%; mp 90-
1
91oC (EtOH). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.02 (3H, t, J = 6.7 CH2CH2CH3); 1.79 (2H, m,
CH2CH2CH3); 2.78 (2H, t, J = 6.8, CH2CH2CH3); 4.19 (4H, m, OCH2CH2O); 6.82 (1H, s, H-5); 7.71 (1H, s,
H-8).
1115

TABLE 5. 1H NMR Spectra of Quinolin-2-ones 74, 79, 80, 83, 86-88
Com-
Chemical shifts*, δ, ppm. (J, Hz)
pound
1
2
50
1.34 (9H, s, C(CH3)3); 2.55 (3H, s, CH3); 3.78 (3H, s, CH3O);
7.03 (1H, d, J = 7.8, H Ar); 7.08 (1H, t, J = 7.8, H Ar); 7.25 (1H, dd, J = 7.8, J = 1.4, H Ar);
7.29 (2H, m, H Ar); 7.41 (1H, dt, J = 7.8, J = 1.4, H Ar); 7.69 (1H, d, J = 9.1, H Ar);
11.85 (1H, s, NH)
51
1.07 (3Н, t, J = 7.1, СН2СН3); 2.62 (2Н, q, J = 7.1, СН2СН3); 7.22 (3Н, m, H Ar);
7.37 (2Н, t, J = 8.0, H Ar); 7.44 (2Н, t, J = 7.6, H Ar); 7.51 (1Н, t, J = 7.6, H Ar);
7.81 (1Н, d, J = 8.0, H Ar); 11.82 (1H, s, NH)
52*2
53
1.04 (3Н, t, J = 6.6, СН2СН3); 2.61 (2Н, q, J = 6.6, СН2СН3);
7.21 (2Н, d, J = 7.4, H Ar); 7.37 (2Н, m, H Ar); 7.43 (2Н, t, J = 7.4, H Ar);
7.52 (1Н, d, J = 1.3, H Ar); 7.74 (1Н, d, J = 8.4, H Ar); 11.91 (1H, s, NH)
0.99 (3Н, t, J = 6.6, СН2СН3); 2.45 (1Н, m) and 2.59 (1Н, m, СН2СН3);
3.68 (3H, s, CH3O); 7.01 (1Н, t, J = 8.2, H Ar); 7.07 (2Н, m, H Ar); 7.37 (2Н, m, H Ar);
7.51 (1Н, d, J = 1.9, H Ar); 7.72 (1Н, d, J = 8.8, H Ar); 11.80 (1H, s, NH)
54
2.15 (3Н, s, СН3); 4.26 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 6.80 (1Н, s, H Ar);
7.21 (3Н, m, H Ar); 7.33 (1Н, t, J = 7.8, H Ar); 7.40 (2Н, t, J = 7.8, H Ar);
11.49 (1H, s, NH)
55
2.04 (3Н, s, СН3); 3.68 (3H, s, CH3O); 4.27 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О);
6.79 (1Н, s, H Ar); 6.98 (1Н, t, J = 7.8, H Ar); 7.04 (2Н, m, H Ar); 7.17 (1Н, s, H Ar);
7.34 (1Н, dt, J = 7.8, J = 1.2, H Ar); 11.40 (1H, s, NH)
56
1.02 (3Н, t, J = 7.4, СН2СН3); 2.54 (2Н, q, J = 7.4, СН2СН3);
4.27 (2Н, m) and 4.31 (2Н, m, ОСН2СН2О); 6.82 (1Н, s, H Ar);
7.17 (2H, d, J = 7.4, H Ar); 7.21 (1H, s, H Ar); 7.34 (1H, m, H Ar); 7.41 (2H, m, H Ar);
11.55 (1H, s, NH)
57
58
0.77 (3Н, t, J = 7.3, СН2СН2СН3); 1.46 (2Н, m, СН2СН2СН3);
2.50 (2Н, m, СН2СН2СН3); 4.27 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О);
6.82 (1H, s, H Ar); 7.16 (2H, m, H Ar); 7.19 (1Н, s, H Ar); 7.34 (1Н, m, H Ar);
7.40 (2Н, m, H Ar); 11.51 (1H, s, NH)
0.71 (3Н, t, J = 7.2, СН2СН2СН3); 1.49 (2Н, m, СН2СН2СН3);
2.51 (2Н, m, СН2СН2СН3); 3.76 (3H, s, CH3O);
4.19 (2Н, m) and 4.29 (2Н, m, ОСН2СН2О); 6.30 (1Н, s, H Ar); 6.75 (1Н, s, H Ar);
7.02 (1H, d, J = 8.4, H Ar); 7.03 (1Н, t, J = 8.4, H Ar); 7.14 (1H, dd, J = 8.4, J = 1.3, H Ar);
7.37 (1Н, m, H Ar); 11.21 (1H, s, NH)
59
60
0.05 (2Н, m, сyclo-Pr); 0.73 (2Н, m, сyclo-Pr); 2.02 (1Н, m, сyclo-Pr);
4.27 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.79 (1H, s, H Ar); 7.31 (3H, m, H Ar);
7.36 (2Н, m, H Ar); 7.58 (1Н, s, H Ar); 11.55 (1H, s, NH)
0.05 (2Н, m, сyclo-Pr); 0.71 (2Н, m, сyclo-Pr); 1.99 (1Н, m, сyclo-Pr);
4.22 (2Н, m) and 4.25 (2Н, m, ОСН2СН2О); 6.61 (1Н, s, H Ar); 7.43 (1Н, s, H Ar);
7.61 (2Н, d, J = 8.4, H Ar); 8.14 (2Н, d, J = 8.4, H Ar); 11.62 (1H, s, NH)
61
62
4.18 (2Н, m) and 4.28 (2Н, m, ОСН2СН2О); 6.36 (1Н, s, H Ar); 6.88 (1Н, s, H Ar);
7.06 (7Н, m, H Ar); 7.28 (3Н, m, H Ar); 11.70 (1H, s, NH)
2.26 (3Н, s, СН3); 4.19 (2Н, m) and 4.30 (2Н, m, ОСН2СН2О); 6.42 (1Н, s, H Ar);
6.88 (1Н, s, H Ar); 7.02 (2Н, d, J = 8.0, H Ar); 7.13 (2Н, d, J = 8.0, H Ar);
7.34 (2Н, d, J = 8.5, H Ar); 8.01 (2Н, d, J = 8.5, H Ar); 11.95 (1H, s, NH)
4.20 (2Н, m) and 4.29 (2Н, m, ОСН2СН2О); 6.35 (1Н, s, H Ar); 6.88 (1Н, s, H Ar);
6.96 (1Н, d, J = 8.0, H Ar); 6.98 (1Н, d, J = 8.5, H Ar); 7.06 (2Н, m, H Ar);
7.10 (2Н, m, H Ar); 7.15 (2Н, m, H Ar); 7.33 (1Н, m, H Ar); 11.80 (1H, s, NH)
63
64
4.21 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 6.19 (1Н, s, H Ar);
6.91 (1Н, s, H Ar); 7.31 (2H, m, H Ar); 7.36 (1Н, m, H Ar);
7.38 (2Н, d, J = 8.8, H Ar); 7.47 (1Н, d, J = 8.0, H Ar); 8.03 (2Н, d, J = 8.8, H Ar);
12.05 (1H, s, NH)
1116

TABLE 5 (continued)
1
2
65
66
4.21 (2Н, m) and 4.31 (2Н, m, ОСН2СН2О); 6.34 (1Н, s, H Ar);
6.88 (1Н, s, H Ar); 7.04 (2Н, d, J = 8.2, H Ar); 7.15 (5Н, m, H Ar);
7.36 (2Н, d, J = 8.2, H Ar); 11.81 (1H, s, NH)
3.58 (3Н, s, СН3О); 4.19 (2Н, m) and 4.29 (2Н, m, ОСН2СН2О);
6.33 (1Н, s, H Ar); 6.75 (1Н, t, J = 8.0, H Ar); 6.82 (1Н, d, J = 8.0, H Ar);
6.87 (1Н, s, H Ar); 6.89 (1Н, dd, J = 8.0, J = 1.4, H Ar); 7.03 (1Н, m, H Ar);
7.14 (2Н, m, H Ar); 7.32 (2Н, d, J = 8.5, H Ar); 11.69 (1H, s, NH)
67
68
69
4.21 (2Н, m) and 4.33 (2Н, m, ОСН2СН2О); 6.38 (1Н, s, H Ar);
6.89 (1Н, s, H Ar); 7.20 (2Н, d, J = 8.1, H Ar); 7.36 (2Н, d, J = 8.2, H Ar);
7.40 (2Н, d, J = 8.1, H Ar); 8.13 (2Н, d, J = 8.2, H Ar); 11.91 (1H, s, NH)
4.19 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 6.15 (1Н, s, H Ar);
6.91 (1Н, s, H Ar); 7.14 (5Н, m, H Ar); 7.22 (2Н, m, H Ar);
7.31 (1Н, t, J = 8.0, H Ar); 7.60 (1Н, d, J = 8.0, H Ar); 11.51 (1H, s, NH)
4.20 (2Н, m) and 4.32 (2Н, m, ОСН2СН2О); 6.12 (1Н, s, H Ar);
6.89 (1Н, s, H Ar); 7.02 (1Н, dt, J = 7.7, J = 1.6, H Ar); 7.11 (1Н, m, H Ar);
7.15 (4Н, m, H Ar); 7.20 (1Н, dd, J = 7.7, J = 1.6, H Ar);
7.34 (1Н, dt, J = 7.5, J = 1.0, H Ar); 7.82 (1Н, d, J = 7.5, H Ar);
11.82 (1H, s, NH)
70
3.66 (3H, s, OCH3); 4.25 (4H, m, OCH2CH2O); 6.10 (1H, s, H Ar);
6.82 (1H, m, H Ar); 6.84 (1H, m, H Ar); 6.88 (1H, s, H Ar);
7.04 (4H, m, H Ar); 7.29 (1H, m, H Ar); 7.81 (1H, d, J = 8.1, H Ar);
11.71 (1H, br. s, NH)
71
2.23 (3Н, s, СН3); 3.83 (6Н, s, 2СН3О); 6.89 (1Н, s, H Ar); 7.15 (1Н, s, H Ar);
7.22 (2Н, d, J = 7.6, H Ar); 7.33 (1Н, m, H Ar); 7.41 (2Н, t, J = 7.6, H Ar);
11.60 (1H, s, NH)
72
0.05 (2Н, m, сyclo-Pr); 0.76 (2Н, m, сyclo-Pr); 2.05 (1Н, m, сyclo-Pr);
3.86 (6Н, s, 2СН3О); 6.89 (1Н, s, H Ar); 7.35 (5H, m, H Ar);
7.59 (1Н, s, H Ar); 11.61 (1H, s, NH)
73*2
74*2
79
2.19 (3Н, s, СН3); 4.36 (4Н, s, ОСН2СН2О); 6.78 (1Н, d, J = 8.6, H Ar);
7.22 (2Н, d, J = 8.0, H Ar); 7.26 (1Н, d, J = 8.6, H Ar); 7.35 (1Н, t, J = 8.0, H Ar);
7.42 (2Н, t, J = 8.0, H Ar); 10.77 (1H, s, NH)
1.26 (6H, d, J = 5.4, CH(CH3)2); 3.09 (1H, sept, CH(CH3)2); 4.35 (4H, m, OCH2CH2O);
6.77 (1H, d, J = 8.9, H Ar); 7.16 (2H, m, H Ar); 7.39 (1H, m, H Ar); 7.41 (2H, m, H Ar);
7.51 (1H, m, H Ar); 10.68 (1H, br.s, NH)
1.16 (3Н, t, J = 6.8, ОСН2СН3); 2.44 (3Н, s, СН3); 3.48 (2Н, q, J = 6.8, ОСН2СН3);
4.20 (2Н, s, СН2ОEt); 4.27 (4Н, m, ОСН2СН2О); 6.63 (1H, s, H Ar);
6.94 (1H, s, H Ar); 7.21 (2Н, d, J = 7.4, H Ar); 7.27 (2Н, d, J = 7.4, H Ar);
12.12 (1H, s, NH)
80
83
86
1.18 (3H, t, Ј = 6.2, OCH2CH3); 3.49 (2H, q, Ј = 6.2, OCH2CH3);
4.23 (2H, m) and 4.31 (2H, m, OCH2CH2O); 4.26 (2H, s, CH2OEt);
6.58 (1H, s, H Ar); 6.97 (1H, s, H Ar); 7.19 (2H, m, H Ar); 7.34 (2H, m, H Ar);
12.25 (1H, br. s, NH)
1.19 (3H, t, Ј = 6.2, OCH2CH3); 3.50 (2H, q, Ј = 6.2, OCH2CH3);
4.23 (2H, m) and 4.31 (2H, m, OCH2CH2O); 4.26 (2H, s, CH2OEt); 6.57 (1H, s, H Ar);
6.95 (1H, s, H Ar); 7.31 (2H, d, J = 8.0, H Ar); 7.48 (2H, d, J = 8.0, H Ar);
12.11 (1H, br. s, NH)
0.99 (3Н, t, J = 7.1, СН2СН2СН3); 1.49 (2Н, m, СН2СН2СН3); 2.05 (3Н, s, СН3);
2.73 (2Н, t, J = 6.9, СН2СН2СН3); 4.25 (2Н, m) and 4.29 (2Н, m, ОСН2СН2О);
6.75 (1H, s, H Ar); 7.14 (1H, s, H Ar); 11.36 (1H, s, NH)
1117

TABLE 5 (continued)
1
2
2.32 (3Н, s, СН3); 4.21 (2Н, m) and 4.29 (2Н, m, ОСН2СН2О); 6.48 (1Н, s, H Ar);
6.85 (2Н, d, J = 8.4, H Ar); 6.89 (1H, s, H Ar); 7.17 (2Н, d, J = 8.0, H Ar);
7.25 (4Н, m, H Ar); 11.94 (1H, s, NH)
87
88
0.72 (3Н, t, J = 7.3, СН2СН2СН3); 1.36 (2Н, m, СН2СН2СН3);
2.18 (2Н, m, СН2СН2СН3); 4.17 (2Н, m) and 4.26 (2Н, m, ОСН2СН2О);
6.15 (1H, s, H Ar); 6.83 (1H, s, H Ar); 7.26 (2Н, d, J = 8.4, H Ar);
7.59 (2Н, d, J = 8.4, H Ar); 11.65 (1H, s, NH)
_______
* Spectra of quinolinones 50, 74, 79, 80, 83 were recorded in CDCl3, and of
51-73, 86-88 in DMSO-d6.
*
2 13C NMR spectra, δ, ppm, compound 52: 14.1, 23.1, 55.7, 111.6, 118.0, 120.7, 123.2,
125.0, 125.3, 127.5, 129.6, 129.6, 131.2, 140.0, 149.3, 157.3, 161.2; compound 73: 17.2,
64.7, 64.9, 111.9, 114.9, 117.9, 127.5, 128.3, 130.9, 137.0, 143.9, 161.3; compound 74:
21.7, 31.8, 64.7, 64.9, 111.3, 112.6, 119.3, 127.5, 128.5, 129.6, 130.2, 137.9, 143.34,
152.62, 161.50.
TABLE 6. IR Spectra of Compounds 51, 56, 59, 60, 61, 64, 65, 70, 80, 83
Com-
pound
ν, cm–1
3200–2800 (NH); 1645 (С=О)
51
56
59
60
61
64
65
70
80
83
3000–2400 (NH); 1660 (C=O)
3000–2600 (NH); 1640 (С=О)
3050–2600 (NH); 1650 (С=О); 1520, 1360 (NO2)
3000–2600 (NH); 1650 (С=О)
3000–2400 (NH); 1650 (С=О); 1520, 1370 (NO2)
3000–2400 (NH); 1645 (С=О)
3100–2700 (NH), 1650 (C=O)
3180–2800 (NH); 1660(C=O)
3200–2760 (NH); 1645(C=O)
1-(7-Amino-2,3-dihydro-1,4-benzodioxin-6-yl)butan-1-one (6) was synthesized by the reduction of
1-(7-nitro-2,3-dihydro-1,4-benzodioxin-6-yl)butan-1-one by the procedure of [28]. Yield 77%; mp 65-66oC
1
(EtOH). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.01 (3H, t, J = 6.8, CH2CH2CH3); 1.71 (2H, m,
CH2CH2CH3); 2.79 (2H, t, J = 6.8, COCH2CH2CH3); 4.18 (2H, m) and 4.28 (2H, m, OCH2CH2O); 5.88 (2H,
br. s, NH2); 6.11 (1H, s, H-5); 7.22 (1H, s, H-8). Found, %: C 64.78; H 6.69; N 6.12. C12H15NO3. Calculated, %:
C 65.14; H 6.83; N 6.33.
7-Nitro-2,3-dihydro-1,4-benzodioxin-6-yl 2-iodophenyl ketone was obtained by the nitration of
(2,3-dihydro-1,4-benzodioxin-6-yl) 2-iodophenyl ketone by the procedure of [27]. Yield 86%; mp 167-168oC
1
(EtOH). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 4.41 (4H, m, OCH2CH2O); 7.03 (1H, s, H Ar); 7.15 (1H,
m, H Ar); 7.31 (2H, m, H Ar); 7.67 (1H, s, H-8); 8.04 (1H, d, J = 8.0, H Ar). Found, %: C 43.61; H 2.31;
N 3.26. C15H10INO5. Calculated, %: C 43.82; H 2.45; N 3.41.
7-Amino-2,3-dihydro-1,4-benzodioxin-6-yl 2-iodophenyl ketone (15) was synthesized analogously to
compound 6 by the reduction of 2-iodophenyl 7-nitro-2,3-dihydro-1,4-benzodioxin-6-yl ketone, yield
1118

1
79%, mp 168-169oC (EtOH). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 4.11 (2H, m) and 4.27 (2H, m,
OCH2CH2O); 6.32 (1H, s, H-5); 6.65 (1H, s, H-8); 6.96 (2H, br. s, NH2); 7.43 (1H, d, J = 8.1, H Ar); 7.52 (2H,
m, H Ar); 7.63 (1H, d, J = 8.1, H Ar). Found, %: C 47.12; H 3.01; N 3.51. C15H12INO3. Calculated, %: C 47.27;
H 3.17; N 3.68.
4,5-Dimethoxy-2-nitroacetophenone was obtained by the nitration of 3,4-dimethoxyacetophenone, as
1
described in [29]. Yield 64%; mp 121-122oC (EtOH). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.51 (3H, s,
COCH3); 3.90 (3H, s, OCH3); 3.95 (3H, s, OCH3); 7.21 (1H, s, H Ar); 7.62 (1H, s, H Ar).
2-Amino-4,5-dimethoxyacetophenone (16) was syhthesized analogously to compound 6 by the
1
reduction of 4,5-dimethoxy-2-nitroacetophenone. Yield 55%. H NMR spectrum (CDCl3), δ, ppm: 2.48 (3H, s,
COCH3); 3.82 (3H, s, OCH3); 3.87 (3H, s, OCH3); 6.09 (1H, s, H Ar); 6.25 (2H, br. s, NH2); 7.07 (1H, s, H Ar).
Found, %: C 61.28; H 6.52; N 6.96. C10H13NO3. Calculated, %: C 61.53; H 6.71; N 7.18.
(o-Acylamino)acylbenzenes 20-49 (General Method). The acid chloride of the corresponding acid
(10 mmol) and 3 N NaOH solution (10 mmol) were added gradually and at the same time, with stirring to a
solution of the corresponding ortho-aminoacylbenzene 1-19 in dioxane (25 ml). The reaction mixture was stirred
for 30 min and poured into water (250 ml). The precipitated solid was filtered off, washed with water, air-dried,
and recrystallized from a suitable solvent. The yields and physicochemical characteristics of the obtained
anilides 20-49 are given in Tables 1 and 2.
Interaction of o-Acylaminoacylbenzenes 20-49 with Equimolecular Quantities of Sodium Ethylate
(General Method). The corresponding acylanilide (2 mmol) was added to a solution of sodium ethylate,
prepared from sodium (46 mg, 2 mmol) and ethanol (25 ml). The mixture was stirred at 20oC for 2 h, poured
into water (120 ml) and neutralized with 2 N HCl. The precipitated solid was filtered off, washed with alcohol,
air-dried, and recrystallized from a suitable solvent. In the case of o-acylaminoacylbenzenes 20-26, 28-32, 35,
36, 38, and 40-49 the corresponding quinolin-2-ones 50-74 were obtained. Yields, physicochemical
characteristics, and data of elemental analysis of the obtained heterocycles are given in Tables 3 and 4.
N-[7-(4-Methylbenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acrylamide (75) and 3-Ethoxy-N-[7-(4-
methylbenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]propionamide (77). A mixture (0.74 g) was obtained from
3-bromo-N-[7-(4-methylbenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]propionamide (34) (0.81 g, 2 mmol),
chromatography of which on preparative plates of Al2O3 gave the starting anilide 34 (0.36 g, 44%), compound
75 (0.21 g, 58%), and compound 77 (0.17 g, 42%). The yields of compounds 75 and 77 were calculated on the
1
anilide consumed in the reaction. Compound 75: mp 116-117oC. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.44 (3H, s, CH3); 4.24 (2H, m) and 4.35 (2H, m, OCH2CH2O); 5.76 (1H, d, J = 10.1, COCH=CH2, H-cis); 6.30
(1H, dd, J = 10.1, J = 17.0, COCH=CH2); 6.42 (1H, d, J = 17.0, COCH=CH2, H-trans); 7.14 (1H, s) and 8.36
(1H, s, H-5,8); 7.28 (2H, d, J = 7.9, H-3',5'); 7.57 (2H, d, J = 7.9, H-2',6'); 11.34 (1H, s, NH). Found, %:
C 70.65; H 5.13; N 4.22. C19H17NO4. Calculated, %: C 70.58; H 5.30; N 4.33. Compound 77: viscous oil.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.19 (3H, t, J = 6.9, OCH2CH3); 2.43 (3H, s, CH3); 2.66 (2H, t, J = 6.1,
COCH2CH2O); 3.55 (2H, q, J = 6.9, CH3CH2O); 3.77 (2H, t, J = 6.1, COCH2CH2O); 4.23 (2H, m) and 4.32 (2H,
m, OCH2CH2O); 7.08 (1H, s) and 8.22 (1H, s, H-5,8); 7.26 (2H, d, J = 8.2, H-3',5'); 7.56 (2H, d, J = 8.2, H-2',6');
11.01 (1H, s, NH). Found, %: C 68.45; H 5.98; N 3.65. C21H23NO5. Calculated, %: C 68.28; H 6.21; N 3.79.
N-[7-(4-Fluorobenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acrylamide (76) and 3-ethoxy-N-[7-(4-fluo-
robenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]propionamide (78) were obtained from 3-bromo-N-[7-(4-fluoro-
benzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]propionamide (37) (0.82 g, 2 mmol) analogously to compound 75.
From the mixture (0.79 g) of reaction products the starting compound 37 (0.43 g, 52%), compound 76 (0.18 g,
52%), and compound 78 (0.19 g, 48%) were separated chromatographically. The yields of compounds 76 and 78
were calculated on the anilide 37 consumed in the reaction. Compound 76: mp 141-142oC. 1H NMR spectrum, δ,
ppm (J, Hz): 4.32 (4H, m, OCH2CH2O); 5.77 (1H, d, J = 10.1, COCH=CH2-cis); 6.29 (1H, dd, J = 10.1, J = 16.9,
COCH=CH2); 6.42 (1H, d, J = 16.9, COCH=CH2-trans); 7.08 (1H, s) and 8.36 (1H, s, H-5,8); 7.16 (2H, m, H Ar);
7.69 (2H, m, H Ar); 11.24 (1H, s, NH). Found, %: C 66.32; H 4.36; N 4.09. C18H14FNO4. Calculated, %:
1
C 66.05; H 4.31; N 4.28. Compound 78: viscous oil. H NMR spectrum, δ, ppm (J, Hz): 1.18 (3H, t, J = 7.0,
1119

CH3CH2O); 2.66 (2H, t, J = 6.1, COCH2CH2O); 3.55 (2H, q, J = 7.0, CH3CH2O); 3.77 (2H, t, J = 6.1,
COCH2CH2O); 4.28 (4H, m, OCH2CH2O); 7.02 (1H, s) and 8.21 (1H, s, H-5,8); 7.15 (2H, m, H Ar); 7.71 (2H,
m, H Ar); 10.58 (1H, s, NH). Found, %: C 64.18; H 5.29; N 3.71. C20H20FNO5. Calculated, %: C 64.34; H 5.40;
N 3.75
Cyclization of (o-Acylamino)acylbenzenes 27, 33, 39, 77, 78 was carried out by the general method
using sodium ethylate (2 equiv.) in boiling ethanol for 5 h. The corresponding quinolin-2-ones 79, 80, 86-88
were obtained. Yields and physicochemical characteristics are given in Tables 4 and 5.
Cyclization of (o-Acylamino)acylbenzenes 34 and 37. Analogously, but at a substrate–sodium ethylate
ratio of 1:3, quinolinone 79 (0.31 g, 88%) was obtained from compound 34 (0.4 g, 1 mmol) and also the
corresponding quinolin-2-ones 79 and 80 were obtained from compound 37 (0.41 g, 1 mmol).
Interaction of N-(7-Aroyl-2,3-dihydro-1,4-benzodioxin-6-yl)acrylamides 75, 76, 81, 84 with
Sodium Ethylate. The corresponding anilide (1 mmol) was added to a solution of sodium ethylate prepared
from sodium (46 mg, 2 mmol) and ethanol (10 ml). The mixture was refluxed for 2 h, the ethanol was
evaporated, the residue was treated with water (30 ml), the resulting solid filtered off, and air-dried. (In the case
of compound 84, after evaporation of the ethanol the reaction products were extracted with CHCl3.) The
corresponding quinolin-2-ones 79, 80, and 83 were obtained from vinylcarbonylaminobenzodioxanes 75, 76, and
81. From compound 84, after chromatography of the reaction mixture on Al2O3, N-[7-(2-chlorobenzoyl)-2,3-di-
hydro-1,4-benzodioxin-6-yl]-3-ethoxypropionamide (85) (0.24 g, 72%) and 7-amino-2,3-dihydro-1,4-benzo-
1
dioxin-6-yl 2-chlorophenyl ketone (12) (60 mg, 22%) were obtained. Compound 85: viscous oil. H NMR
spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.2, OCH2CH3); 2.74 (2H, t, J = 6.0, COCH2CH2O); 3.58 (2H, q,
J = 7.2, CH3CH2O); 3.84 (2H, t, J = 6.0, COCH2CH2O); 4.21 (2H, m) and 4.32 (2H, m, OCH2CH2O); 6.85 (1H,
s, H Ar); 7.29-7.48 (4H, m, H Ar); 8.42 (1H, s, H Ar); 11.65 (1H, br. s, NH). Found, %: C 61.41; H 5.01;
N 3.42. C20H20ClNO5. Calculated, %: C 61.62; H 5.17; N 3.59.
The work was carried out with the financial support of a grant "Academician N. S. Zefirov Leading
Scientific School".
REFERENCES
1.
2.
E. A. Clarke and M. F. Grundon, J. Chem. Soc., 438 (1964).
A. van Oeveren, M. Motamedi, N. S. Mani, K. B. Marschke, F. J. Lopez, W. T. Schrader, A. Negro-
Vilar, and L. Zhi, J. Med. Chem., 49, 6143 (2006).
3.
4.
R. I. Higuchi, A. W. Thompson, J. H. Chen, T. R. Caferro, M. L. Cummings, C. P. Deckhut,
M. E. Adams, C. M. Tegley, J. P. Edwards, F. J. Lopez, E. A. Kallel, D. S. Karanewsky, W. T. Schrader,
K. B. Marschke, and L. Zhi, Bioorg. Med. Chem. Lett., 17, 5442 (2007).
E. Martinborough, Y. Shen, A. van Oeveren, Y. O. Long, T. L. S. Lau, K. B. Marschke, W. Y. Chang,
F. J. Lopez, E.G. Vajda, P. J. Rix, O. H. Viveros, A. Negro-Vilar, and L. Zhi, J. Med. Chem., 50, 5049
(2007).
5.
6.
P. Cheng, Q. Zhang, Y. B. Ma, Z. Y. Jiang, X. M. Zhang, F. X. Zhang, and J. J. Chen, Bioorg. Med.
Chem. Lett., 18, 3787 (2008).
J. Wang, R. P. Discordia, G. A. Crispino, J. Li, J. A. Grosso, R. Polniaszek, and V. C. Truc,
Tetrahedron. Lett., 44, 4271 (2003).
7.
8.
P. Hewawasam, J. E. Starrett, and S. G. Swartz, US Patent Appl. 5972961.
A. Chilin, C. Marzano, A. Guiotto, F. Baccichetti, F. Carlassare, and F. Bordin, J. Med. Chem., 45, 1146
(2002).
9.
B. Joseph, F. Darro, A. Behard, B. Lesur, F. Collignon, C. Decaestecker, A. Frydman, G. Guillaumet,
and R. Kiss, J. Med. Chem., 45, 2543 (2002).
1120

10.
11.
B. Batanero and F. Barba, J. Org. Chem., 68, 3706 (2003).
L. Xie, X. Qian, J. Cui, Y. Xiao, K. Wang, P. Wu, and L. Cong, Bioorg. Med. Chem. Lett., 16, 8713
(2008).
12.
H. Hatashi, Y. Miwa, I. Miki, S. Ichikawa, N. Yoda, A. Ishii, M. Kono, and F. Suzuki, J. Med. Chem.,
35, 4893 (1992).
13.
14.
B. I. Usachev and V. Ya. Sosnovskikh, J. Fluorine Chem., 125, 1393 (2004).
J. T. Kuethe, A. Wong, Ch. Qu, J. Smitrovich, I. W. Davies, and D. L. Hughes, J. Org. Chem., 70, 2555
(2005).
15.
16.
17.
C. Peifer, K. Kinkel, M. Abadleh, D. Schollmeyer, and S. Lanfer, J. Med. Chem., 50, 1213 (2007).
Y.-Q. Fang, R. Karisch, and M. Lautens, J. Org. Chem., 72, 1341 (2007).
M. J. Wall, J. Chen, S. Meegalla, S. K. Ballentine, K. J. Wilson, R. L. DesJarlais, C. Schubert,
M. A. Chaikin, C. Crysler, I. P. Petrounia, R. R. Donatelli, E. J. Yurkow, L. Boczon, M. Mazulla,
M. R. Player, R. J. Patch, C. L. Manthey, C. Molloy, B. Tomczuk, and C. R. Illig, Bioorg. Med. Chem.
Lett., 18, 2097 (2008).
18.
19.
Q. Li, K. W. Woods, W. Wang, N.-H. Lin, A. Claiborne, W. Gu, J. Cohen, V. S. Stoll, C. Hutchins,
D. Frost, S. H. Rosenberg, and H. L. Sham, Bioorg. Med. Chem. Lett., 15, 2033 (2005).
P. Hewawasam, W. Fan, M. Ding, K. Flint, D. Cook, G. D. Goggins, R. A. Myers, V. K. Gribkoff,
C. G. Boissard, S. I. Dworetzky, J. E. Starrett, Jr., and N. J. Lodge, J. Med. Chem., 46, 2819 (2003).
R. Camps, Chem. Ber., 32, 3228 (1899).
P. Shanmugam, P. Lakshminarayana, and R. Palaniappan, Monatsh. Chem., 104, 633 (1973).
T. P. Blakburn, B. Cox, A. J. Guildford, D. J. Le Count, D. N. Middlemiss, R. J. Pearce, and
C. W. Thornber, J. Med. Chem., 30, 2252 (1987).
20.
21.
22.
23.
24.
S. S. Mochalov and M. I. Khasanov, Khim. Geterotsikl. Soedin., 788 (2008). [Chem. Heterocycl. Comp.,
44, 628 (2008)].
R. A. Gazzaeva, M. I. Khasanov, S. S. Mochalov, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 941
(2007). [Chem. Heterocycl. Comp., 43, 799 (2007)].
25.
26.
27.
Yu. S. Shabarov and S. S. Mochalov, Zh. Org. Khim., 8, 293 (1972).
A. N. Fedotov, S. S. Mochalov, and Yu. S. Shabarov, Zh. Prikl. Khim., 50, 1860 (1977).
S. S. Mochalov, D. V. Kosynkin, I. D. Yudin, V. I. Atanov, Yu. S. Shabarov, and N. S. Zefirov, Khim.
Geterotsikl. Soedin., 601 (1994). [Chem. Heterocycl. Comp., 30, 527 (1994)].
S. S. Mochalov, M. I. Khasanov, E. V. Trofimova, A. N. Fedotov, and N. S. Zefirov, Khim. Geterotsikl.
Soedin., 1507 (2009). [Chem. Heterocycl. Comp., 45, 1208 (2009).
28.
29.
R. A. Gazzaeva, A. N. Fedotov, E. V. Trofimova, O. A. Popova, S. S. Mochalov, and N. S. Zefirov, Zh.
Org. Khim., 42, 94 (2006).
1121