4H-3,1-benzoxazines from benzyl cyclopropanes. First example of acid catalyzed rearrangement in ortho-substituted benzylcyclo-propanes

Article abstract of DOI:10.1007/s10593-009-0400-x

The synthesis of 2-N-acylamino-substituted benzylcyclopropanes has been carried out. It was established that under the action of acids 2-N-acylamino-substituted benzylcyclopropanes are rearranged into the corresponding 4H-3,1-benzoxazines and not into the

Full text of DOI:10.1007/s10593-009-0400-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
4H-3,1-BENZOXAZINES FROM BENZYL
CYCLOPROPANES. FIRST EXAMPLE OF
ACID CATALYZED REARRANGEMENT
IN ortho-SUBSTITUTED BENZYLCYCLO-
PROPANES
E. V. Trofimova1, B. P. Archegov1, A. N. Fedotov1*,
R. A. Gazzaeva1, S. S. Mochalov1, and N. S. Zefirov1
The synthesis of 2-N-acylamino-substituted benzylcyclopropanes has been carried out. It was
established that under the action of acids 2-N-acylamino-substituted benzylcyclopropanes are
rearranged into the corresponding 4H-3,1-benzoxazines and not into the expected 3,1-benzoxazepines.
It was shown that a similar type of rearrangement is also characteristic for 2-N-acylamino-substituted
allylbenzenes.
Keywords: 4-alkyl-4H-3,1-benzoxazines, 6-allyl-7-amino-1,4-benzodioxane, 2-aminobenzylcyclo-
propanes, 2-N-acylaminoallylbenzenes, 2-N-acylaminobenzylcyclopropanes, 6-butyroyl-7-nitro-1,4-benzo-
dioxane, 1-(2-N-p-methoxybenzoylamino)-4,5-ethylenedioxyphenylbutan-1-ol, 2-nitrobenzylcyclo-
propanes, rearrangements.
Benzylcyclopropanes belong to a little-studied class of compounds, although formally they are homologs
of phenylcyclopropanes, the chemistry of which has been studied extremely thoroughly, especially in the region
of synthesis of heterocyclic compounds of various classes [1-14]. In addition the available data on the chemical
conversion of benzylcyclopropanes indicate that the introduction of a methylene group into phenylcyclopropane
in the benzene ring–three-carbon ring bond leads to a significant difference in the behavior of the indicated
cyclopropyl-containing substrates in identical reactions, although in certain cases phenyl- and
benzylcyclopropanes behave in a similar manner [15-21].
In the present work the problem was set of comparing the behavior of ortho functionally-substituted
benzylcyclopropanes with analogous phenylcyclopropanes under conditions of acid-catalyzed conversion. With
this aim we synthesized a series of o-acylaminobenzylcyclopropanes and studied the probability of rearranging
them under conditions in which the phenylcyclopropane analogs are converted into the corresponding 3,1-benz-
oxazines [3].
_______
* To whom correspondence should be addressed, e-mail: fed@org.chem.msu.ru.
1Moscow M. V. Lomonosov State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1368-1379, September, 2009.
Original article submitted September 23, 2008.
0009-3122/09/4509-1095©2009 Springer Science+Business Media, Inc.
1095

The o-acylaminobenzylcyclopropanes 7-16 needed for the investigation were obtained from nitro
compounds 1-3 by sequential reduction and acylation.
R1
R2
R1
R2
R1
R2
.
R3COCl
NH2NH2 H2O
NH–C–R3
O
NO2
Ni / Ra,
60°C
NH2
4–6
1–3
7–16
1, 4, 7–9 R1 = R2 = H; 2, 5, 10–15 R1 = R2 = O(CH2)2O; 3, 6, 16 R1 = R2 = OMe;
7, 11 R3 = Ph; 8, 13 R3 = p-MeC6H4; 9, 14 R3 = p-BrC6H4; 10 R3 = i-Pr;
12, 16 R3 = p-MeOC6H4; 15 R3 = p-NO2C6H4
In view of the result of converting o-acylaminophenylcyclopropanes and the route of carrying it out [3]
in acidic media, for acylaminobenzylcyclopropanes 7-16 under the same conditions we have a right to expect the
formation of heterocyclic compounds of the 3,1-benzoxazepine series (type B), products of the rearrangement of
amides corresponding to the formation of heterocyclic ions A in the course of the conversion.
R1
R2
NHCOR3
7–16
CF3CO2H
or H2SO4
Me
R1
R2
R1
R2
Me
+
O
+
NHCOR3
N
R3
H
A1
A
+
+
–H
H
Me
R1
R1
R2
Me
O
NHCOR3
R2
N
C
R3
B
+
Me
+
H
–H
R1
R2
+
R1
R2
O
Me
+
N
H
R3
NHCOR3
D1
D
Me
R1
R2
O
N
R3
17–26
1096

However it turned out that on treating ortho-substituted benzylcyclopropanes 7-16 with trifluoroacetic acid
under standard conditions there was formed in high yield not the 4-ethyl-3,1-benzoxazepines of type B but the
corresponding 4-propyl-3,1-benzoxazines 17-26* (Table 2). Rearrangement of compounds 7-16 under the action
of conc. H2SO4 at -20oC also leads to the same result.
The rearrangement products, the corresponding 4-propyl-4H-3,1-benzoxazines 17-26, may not be
formed directly from 2-acylaminobenzylcyclopropanes 7-16 and, as is evident from the Scheme, are the result of
secondary processes the substance of which includes the isomeric transition of ions of the homobenzyl type A
into ions of the benzyl type D. It must be assumed that the cyclic 3,1-benzoxazepinium ions (type A1) formed in
the initial stage of the rearrangement are rapidly isomerized, being thermodynamically significantly less stable,
into ions of the six-membered structure D1. The time interval of isomerization of ions A1 into D1 is so small that
we were unsuccessful in establishing the signals of protons of the cyclic ions (type A1) in the 1H NMR spectrum.
For example in a solution of 2-(4-methylbenzoyl)aminobenzylcyclopropane 8 in fluorosulfonic acid, only
signals of protons belonging to the structure of the corresponding 4H-3,1-benzoxazinium ion were identified
directly after mixing the reactants. It is interesting to note that a similar rapid transition of cyclic intermediates
of seven-membered structure (type A1) into ions of a six-membered structure (type D1) were also observed in the
acid-catalyzed reaction of p-nitrobenzylideneiminobenzylcyclopropane N-oxide [19]. In difference to the
1
present case the authors of [19] successfully established by H NMR the formation in predominant amount of
cyclic ions of a seven-membered structure, which after a short time interval (~2 h) were quantitatively
isomerized into ions of a six-membered structure. We propose that isomerization of ions of type A1 into ions of
the six-membered structure D1 was effected through a reversible stage of forming ions of an open structure (type
A and D). In view of the data of [10, 14, 19], it may be considered that the isomeric transition of ions A into D is
effected through intermediate C.
O
O
O
O
O
O
Me
Fe / H2O
benzene
Me
NH2
NO2
27
28
O
HO
H
O
MeO
COCl
O
NaBH4
Me
CF3CO2H
Me
H
N
H
N
–
O
OMe
O
OMe
OH
30
O
O
29
Me
H
+
O
O
O
O
O
Me
22
+
N
H
OMe
N
H
OMe
D1
O
D
_______
*The meaning of R1, R2, and R3 for compounds 17-26 is the same as for compounds 7-16 respectively.
1097

Support for the proposed scheme of converting acylaminobenzylcyclopropanes 7-16 is also indicated by
the alternate synthesis of 4-propyl-4H-3,1-benzoxazine (22) from o-amidophenylbutan-1-ol 30, the compound
from which under the reaction conditions the carbene ion D or the cyclic intermediate D1 is formed directly and
not indirectly as in the case of the corresponding benzylcyclopropane 12.
We have therefore succeeded in showing for the first time that ortho functionally-substituted
benzylcyclopropanes, although indirectly, are capable of being rearranged into stable isomeric structures.
O
O
O
O
O
[ H ]
RCOCl
O
NH2
NO2
NHCOR
32
31
33, 34
33 R = i-Pr, 34 R = p-BrC6H4
TABLE 1. Characteristics of Compounds 7-16, 29, 33, 34
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula*
mp, °C
IR spectrum,
ν, cm–1
Yield,
(alcohol)
%
С
Н
N
94
7
C17H17NO
C18H19NO
C17H16NBrO
C16H21NO3
C19H19NO3
C20H21NO4
C20H21NO3
81.14
81.24
6.59
6.86
5.32
5.57
118-119 3210-3340 (NH),
1640 (C=O)
8
81.12
81.47
6.93
7.22
5.43
5.28
120-121 3220-3380 (NH),
1645 (C=O)
92
89
88
89
91
84
93
87
83
9
61.23
61.83
4.53
4.88
4.19
4.24
147-148 3330-3460 (NH),
1650 (C=O)
10
11
12
13
14
15
16
69.36
69.79
7.41
7.69
4.83
5.09
—
3210-3360 (NH),
1660 (C=O)
73.49
73.77
5.87
6.19
4.38
4.53
—
3190-3330 (NH),
1640 (C=O)
69.89
70.78
5.95
6.24
4.09
4.13
146–147 3220-3350 (NH),
1650 (C=O)
74.39
74.28
6.31
6.55
4.09
4.33
—
3200-3310 (NH),
1650 (C=O)
C19H18NBrO3 58.63
58.78
4.45
4.67
3.54
3.61
199–200 3220-3340 (NH),
1650 (C=O)
C19H18N2O5
64.13
64.40
4.92
5.12
7.56
7.90
—
3230-3370 (NH),
1640 (C=O)
C20H23NO4
70.45
70.36
6.48
6.79
3.83
4.10
141-142 3220-3350 (NH),
1650 (C=O)
29
33
C20H21NO5
C15H19NO3
67.31
67.59
68.79
68.94
5.82
5.96
7.47
7.33
3.79
3.94
5.21
5.36
201-202
—
88
91
—
3210-3320 (NH),
1650 (C=O)
34
C18H16NBrO3 57.63
57.77
3.47
4.31
3.53
3.74
—
3200-3360 (NH),
1640 (C=O)
82
_______
*Mass spectrum, m/z (Irel, %): compound 7 – 251 [M]+ (22.1); 222 (8.2);
146 (34.8); 131 (21.9); 118 (16.9); 105 (100); 77 (62.3); 51 (7.9);
compound 8 –265 [M]+ (12.1); 172 (5.1); 146 (24.8); 136 (8.1); 130 (23.5);
119 (100); 91 (47.9); 77 (5.2); 65 (14.3); compound 9 –330 [M]+ (11.3);
185 (100); 172 (8.1); 157 (37.9); 146 (91.5); 130 (61.8); 118 (27.1); 91
(5.1); 76 (16.2); compound 16 – 341 [M]+ (29.3); 326 (5.2); 206 (33.8); 190
(24.8); 175 (7.9); 135 (100); 107 (8.1); 92 (7.3); 77 (12.1).
1098

TABLE 2. 1H NMR Spectra of Compounds 7-16, 29, 33, and 34
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
7
0.39 (2H, m, H c-Pr); 0.58 (2H, m, H c-Pr); 1.19 (1H, m, H c-Pr);
2.48 (2H, d, J = 5.4, CH2-benzyl); 7.01 (2H, m, Н arom);
7.19 (1H, t, J = 8.0, Н arom); 7.25-7.35 (3H, m, Н arom);
7.48 (2H, d, J = 8.0, Н arom); 7.91(1H, m, Н arom); 9.19 (1H, s, NH)
8
9
0.19 (2H, m, H c-Pr); 0.61 (2H, m, H c-Pr); 1.01 (1H, m, H c-Pr);
2.42 (3H, s, CH3); 2.62 (2H, d, J = 4.8, CH2-benzyl); 7.11-7.33 (5H, m, Н arom);
7.76 (2H, d, J = 8.1, Н arom); 7.91 (1H, m, Н arom); 8.93 (1H, s, NH)
0.21 (2H, m, H c-Pr); 0.59 (2H, m, H c-Pr); 0.95 (1H, m, H c-Pr);
2.61 (2H, d, J = 5.2, CH2-benzyl); 7.18 (1H, m, Н arom); 7.23 (1H, m, Н arom);
7.38 (1H, m, Н arom); 7.63 (2H, d, J = 8.2, Н arom); 7.68 (2H, d, J = 8.2, Н arom);
7.89 (1H, m, Н arom); 9.41 (1H, s, NH)
10
11
12
13
14
15
16
29
0.17 (2H, m, H c-Pr); 0.48 (2H, m, H c-Pr); 0.94 (1H, m, H c-Pr);
1.17 (6H, d, J = 6.4, CH(CH3)2); 2.38 (2H, d, J = 5.2, CH2-benzyl);
2.59 (1H, m, CH(CH3)2); 4.22 (4H, m, OCH2CH2O); 6.78 (1H, s, Н arom) and
6.82 (1H, s, Н arom); 8.81 (1H, s, NH)
0.12 (2H, m, H c-Pr); 0.39 (2H, m, H c-Pr); 0.91 (1H, m, H c-Pr);
2.38 (2H, d, J = 5.4, CH2-benzyl); 4.25 (4H, m, OCH2CH2O);
6.77 (1H, s, Н arom); 6.91 (1H, s, Н arom); 7.48-7.59 (3H, m, Н arom);
7.95 (2H, m, Н arom); 9.71 (1H, s, NH)
0.19 (2H, m, H c-Pr); 0.54 (2H, m, H c-Pr); 0.92 (1H, m, H c-Pr);
2.24 (2H, d, J = 5.6, CH2-benzyl); 3.85 (3H, s, OCH3);
4.31 (4H, m, OCH2CH2O); 6.91 (2H, d, J = 8.2, Н arom); 7.06 (1H, s, Н arom);
7.08 (2H, d, J = 8.2, Н arom); 7.12 (1H, s, Н arom); 9.29 (1H, s, NH)
0.16 (2H, m, H c-Pr); 0.47 (2H, m, H c-Pr); 0.97 (1H, m, H c-Pr);
2.42 (3H, s, CH3); 2.48 (2H, d, J = 5.4, CH2-benzyl); 4.26 (4H, m, OCH2CH2O);
6.84 (1H, m, Н arom); 6.86 (1H, s, Н arom); 7.25 (2H, d, J = 8.2, Н arom);
7.86 (2H, d, J = 8.2, Н arom); 9.17 (1H, s, NH)
0.12 (2H, m, H c-Pr); 0.41 (2H, m, H c-Pr); 0.91 (1H, m, H c-Pr);
2.44 (2H, d, J = 5.6, CH2-benzyl); 4.21 (4H, m, OCH2CH2O); 6.81 (1H, s, Н arom);
6.92 (1H, s, Н arom); 7.69 (2H, d, J = 8.4, Н arom); 7.92 (2H, d, J = 8.4, Н arom);
9.54 (1H, s, NH)
0.11 (2H, m, H c-Pr); 0.42 (2H, m, H c-Pr); 0.87 (1H, m, H c-Pr);
2.35 (2H, d, J = 5.6, CH2-benzyl); 4.27 (4H, m, OCH2CH2O); 6.79 (1H, s, Н arom);
6.93 (1H, s, Н arom); 7.34 (2H, d, J = 8.4, Н arom); 8.13 (2H, d, J = 8.4, Н arom);
10.05 (1H, s, NH)
0.21 (2H, m, H c-Pr); 0.56 (2H, m, H c-Pr); 0.93 (1H, m, H c-Pr);
2.14 (2H, d, J = 5.6, CH2-benzyl); 3.78 (3H, s, OCH3); 3.89 (3H, s, OCH3);
3.97 (3H, s, OCH3); 6.91 (2H, d, J = 8.0, Н arom); 7.06 (1H, s, Н arom);
7.08 (2H, d, J = 8.0, Н arom); 7.12 (1H, s, Н arom); 9.31 (1H, c, NH)
1.01 (3H, t, J = 7.2, CH3CH2CH2); 1.76 (2H, m, CH3CH2CH2);
2.97 (2H, t, J = 7.2, CH3CH2CH2); 3.88 (3H, c, CH3O); 4.29 (2H, m, OCH2CH2O);
4.38 (2H, m, OCH2CH2O); 7.02 (2H, d, J = 8.2, Н arom); 7.48 (1H, s, Н arom);
7.92 (2H, d, J = 8.2, Н arom); 8.39 (1H, s, Н arom); 12.04 (1H, c, NH)
33
34
1.15 (6H, d, J = 6.2, CH(CH3)2); 2.58 (1H, m, CH(CH3)2);
3.22 (2H, d, J = 6.4, CH2CH=CH2); 4.21 (4H, m, OCH2CH2O); 5.03 (2H, m, CH2=CH);
5.89 (1H, m, CH2CH=CH2); 6.59 (1H, s, Н arom); 6.85 (1H, s, Н arom); 8.55 (1H, s, NH)
3.27 (2H, d, J = 6.4, CH2CH=CH2); 4.25 (4H, m, OCH2CH2O); 5.11 (2H, m, CH2=CH);
5.88 (1H, m, CH2CH=CH2); 6.65 (1H, s, Н arom); 6.85 (1H, s, Н arom);
7.61 (2H, d, J = 8.2, Н arom); 7.89 (2H, d, J = 8.2, Н arom); 9.45 (1H, s, NH)
H
Me
R
Me
O
O
O
O
+
+
H
H
O
33, 34
O
N
N
R
35, 36
37, 38
33, 35 R = i-Pr, 34, 36 R = p-BrC6H4
1099

With the aim of clarifying whether this type of rearrangement, anomalous at first glance, is of a general
character, or this special conversion applies only to acylaminobenzylcyclopropanes, we studied the reaction of
alkenyl analogs of the latter, the hydrocarbon fragment of which under acid catalysis conditions is also capable
of generating a carbene ion of the homobenzyl type.
The required model 2-acylaminoalkenylbenzenes 33, 34 were synthesized analogously to 2-acyl-
aminobenzylcyclopropanes 7-16.
It turned out that acylaminoallylbenzenes 33, 34 under the conditions used are also converted into
4H-3,1-benzoxazines 35, 36 and not into 3,1-benzoxazepines 37, 38, i.e. it is evident that in this case the
rearrangement is effected by the scheme assumed for the rearrangement of acylaminobenzylcyclopropanes 7-16.
Consequently, unlike 2-acylaminophenylcyclopropanes directly undergoing acid-catalyzed rearrange-
ment into 4H-3,1-benzoxazines, the 2-acylaminobenzylcyclopropanes, at least those containing no electron-
withdrawing substituents in the benzene ring, are not able to be transformed under the same conditions into
stable products corresponding to the direct interaction of the ion of the homobenzyl type, formed with an
internal nucleophile. In spite of that, in the route of transformation of ortho-acylaminobenzylcyclopropanes to
the final products of the reaction, the 4-propyl-4H-3,1-benzoxazines 17-26, the cyclic ions (A1) bearing a
positive charge, corresponding to the direct interaction of a carbene ion of the homobenzyl type with an internal
nucleophile, are evidently formed nevertheless. The anomalous rearrangement found for 2-acylamino-
benzylcyclopropanes to all appearances may be extended not only to the corresponding allylbenzenes, but also
to ortho-substituted benzenes, which contain substituents displaying nucleophilic properties and substituents
capable under the reaction conditions of generating a carbene center of the homobenzyl type.
TABLE 3. Characteristics of 4-Alkyl-4H-3,1-benzoxazines 17-26, 35, 36*
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
С
Н
N
17*2
18
19
20
21
22
23
24
25
26
35
36
C17H17NO
81.07
81.24
81.13
81.48
61.53
61.83
69.43
69.79
73.48
73.77
70.47
70.78
74.45
74.28
58.91
58.78
64.19
64.40
70.11
70.36
68.51
68.94
57.52
57.77
7.12
6.82
6.97
7.22
4.61
4.88
7.42
7.69
5.92
6.19
6.11
6.24
6.21
6.55
4.32
4.67
4.82
5.12
6.53
6.79
7.59
7.33
4.18
4.31
5.33
5.57
5.07
5.28
3.98
4.24
4.81
5.09
4.21
4.53
3.89
4.13
4.12
4.33
3.39
3.61
7.51
7.91
4.41
4.10
5.51
5.36
3.49
3.74
69
76
72
63
67
65
72
71
57
76
65
79
C18H19NO
C17H16BrNO
C16H21NO3
C19H19NO3
C20H21N4O4
C20H21NO3
С19Н18BrNО3
С19Н18N2О5
C20H23NO4
C15H19NO3
C18H16BrNO3
_______
* Compounds 17, 19-26, 35, 36 were viscous oils. Compound 18 had
mp 115oC (alcohol).
*2 Mass spectrum, m/z (Irel, %): compound 17, 251 [M] (21.9); 208 (100);
152 (10.1); 105 (12.3), 77 (22.4); 51 (8.3).
1100

TABLE 4. 1H NMR Spectra of Compounds 17-26, 35, 36
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
17
18
19
20
0.95 (3Н, t, J = 6.2, СH3СH2СH2); 1.52 (2Н, m, СH3СH2СH2);
1.82 (2H, m, СH3СH2СH2); 5.56 (1Н, m, H-4 benzoxazine);
7.12-7.65 (7H, m, H arom); 8.07 (2H, d, J = 8.0, H arom)
1.04 (3Н, t, J = 6.6, СH3СH2СH2); 1.62 (2Н, m, СH3СH2СH2);
1.95 (2Н, m, СH3СH2СH2); 2.45 (3Н, s, CH3); 5.47 (1Н, t, J = 6.5, H-4 benzoxazine);
7.17 (3Н, m, H arom); 7.28 (3Н, m, H arom); 7.94 (2Н, d, J = 8.0, H arom)
1.05 (3Н, t, J = 6.4, СH3СH2СH2); 1.57 (2Н, m, СH3СH2СH2);
1.89 (2H, m, СH3СH2СH2); 5.65 (1Н, m, H-4 benzoxazine); 7.21-7.43 (4Н, m, H arom);
7.79 (2Н, d, J = 8.2, H arom); 8.09 (2Н, d, J = 8.2, H arom)
0.94 (3Н, t, J = 6.2, СH3СH2СH2); 1.21 (6H, d, J = 6.4, (СH3)2СH);
1.45 (2Н, m, СH3СH2СH2); 1.65 (2Н, m, СH3СH2СH2); 2.55 (1Н, m, (СH3)2СH);
4.21 (4H, m, OСH2СH2O); 5.10 (1Н, m, H-4 benzoxazine); 6.38 (1Н, s, H arom);
6.65 (1Н, s, H arom)
21
22
23
24
25
26
0.96 (3H, t, J = 6.4, СH3СH2СH2); 1.57 (2H, m, СH3СH2СH2); 1.77 (1H, m, СH3СH2СH2);
1.89 (1H, m, СH3СH2СH2); 4.24 (4H, m, OСH2СH2O); 5.31 (1Н, m, H-4 benzoxazine);
6.48 (1H, s, H arom); 6.82 (1H, s, H arom); 7.30–7.46 (3Н, m, H arom);
8.08 (2Н, d, J = 8.0, H arom)
1.02 (3H, t, J = 6.4, СH3СH2СH2); 1.62 (2H, m, СH3СH2СH2); 1.78 (1H, m, СH3СH2СH2);
1.91 (1H, m, СH3СH2СH2); 3.85 (3H, s, CH3O); 4.24 (4H, m, OСH2СH2O);
5.28 (1Н, m, H-4 benzoxazine); 6.51 (1H, s, H arom); 6.81 (1H, s, H arom);
6.93 (2Н, d, J = 8.2, H arom); 8.06 (2Н, d, J = 8.2, H arom)
1.02 (3H, t, J = 6.2, СH3СH2СH2); 1.58 (2H, m, СH3СH2СH2); 1.78 (1H, m, СH3СH2СH2);
1.94 (1H, m, СH3СH2СH2); 2.46 (3H, s, CH3); 4.26 (4H, m, OСH2СH2O);
5.34 (1Н, m, H-4 benzoxazine); 6.25 (1H, s, H arom); 6.82 (1H, s, H arom);
7.22 (2Н, d, J = 7.8, H arom); 8.02 (2Н, d, J = 7.8, H arom)
0.97 (3H, t, J = 6.4, СH3СH2СH2); 1.52 (2H, m, СH3СH2СH2); 1.76 (1H, m, СH3СH2СH2);
1.88 (1H, m, СH3СH2СH2); 4.24 (4H, m, OСH2СH2O); 5.24 (1Н, m, H-4 benzoxazine);
6.49 (1H, s, H arom); 6.78 (1H, s, H arom); 7.51 (2Н, d, J = 8.2, H arom);
7.92 (2Н, d, J = 8.2, H arom)
0.91 (3Н, t, J = 6.2, СH3СH2СH2); 1. 49 (2H, m, СH3СH2СH2);
1.77 (2H, m, СH3СH2СH2); 4.22 (4H, m, OСH2СH2O); 5.52 (1Н, m, H-4 benzoxazine);
6.71 (1H, s, H arom); 6.75 (1H, s, H arom); 8.12 (2Н, d, J = 8.4, H arom);
8.31 (2Н, d, J = 8.4, H arom)
1.02 (3Н, t, J = 6.2, СH3СH2СH2); 1.62 (2H, m, СH3СH2СH2); 1.77 (1H, m, СH3СH2СH2);
1.92 (1H, m, СH3СH2СH2); 3.79 (3H, s, СH3O); 3.85 (3H, s, СH3O); 3.94 (3H, s, СH3O);
5.28 (1Н, m, H-4 benzoxazine); 6.51 (1H, s, H arom); 6.80 (1H, s, H arom);
6.93 (2Н, d, J = 8.1, H arom); 8.06 (2Н, d, J = 8.1, H arom)
35
36
0.97 (3Н, t, J = 6.3, СH3СH2); 1.21 (6H, d, J = 6.4, СH(СH3)2); 1.76 (2H, m, СH3СH2);
2.56 (1H, m, СH(СH3)2); 4.19 (4H, m, OСH2СH2O); 5.05 (1Н, m, H-4 benzoxazine);
6.37 (1H, s, H arom); 6.65 (1H, s, H arom)
1.04 (3Н, t, J = 6.6, СH3СH2); 1.85 (2H, m, СH3СH2); 4.22 (4H, s, OСH2СH2O);
5.23 (1Н, m, H-4 benzoxazine); 6.45 (1H, s, H arom); 6.78 (1H, s, H arom);
7.51 (2Н, d, J = 8.2, H arom); 7.96 (2Н, d, J = 8.2, H arom)
EXPERIMENTAL
1
The H NMR spectra were obtained on Varian VXR-400 (400 MHz) and Bruker DRX-500 (500 MHz)
spectrometers in CDCl3, the residual protons of the deuterated solvent acted as standard. The IR spectra were
recorded on a UR-20 spectrometer in nujol and hexachlorobutadiene. The mass spectra were obtained on a
Finnigan SSQ-7000 instrument, GC-MS type using a capillary column (30 m, DV-1 stationary phase, carrier gas
helium) and temperature programing from 50 to 300oC (10 deg/min). Ionization energy was 70 eV. A check on
the purity of the obtained compounds was carried out on Silufol plates and on Al2O3 of Brockmann grade II activity
in the system ether–chloroform–petroleum ether (40-70oC), 1:1:3. Preparative separation of reaction mixtures was
carried out on plates of Al2O3 of Brockmann grade II activity in the system benzene–ethyl acetate, 5:1.
1101

2-Nitrobenzylcyclopropane (1) was obtained by the nitration of benzylcyclopropane as described in
[15], yield 37.5%; bp 106-107oC (3 mm Hg), n20D 1.5447 [15].
4,5-Ethylenedioxy-2-nitrobenzylcyclopropane (2) was obtained analogously from 3,4-ethylene-
1
dioxybenzylcyclopropane, (bp 144-146oC (14 mm Hg), n20 1.5503), yield 83%; mp 87-88oC (alcohol). H
D
NMR spectrum, δ, ppm (J, Hz): 0.21 (2H, m, H c-Pr); 0.49 (2H, m, H c-Pr); 1.01 (1H, m, H c-Pr); 2.71 (2H, d,
J = 7.6, CH2 benzyl); 4.46 (4H, m, OCH2CH2O); 7.08 (1H, s, H arom); 7.53 (1H, s, H arom). Found, %:
C 61.01; H 5.41; N 5.71. C12H13NO4. Calculated, %: C 61.27; H 5.57; N 5.95.
4,5-Dimethoxy-2-nitrobenzylcyclopropane (3) was obtained by the nitration of 3,4-dimethoxy-
benzylcyclopropane (bp 162-164oC (19 mm Hg), n20 1.5354) as described in [15], yield 72%; mp 75-76oC
D
(alcohol). 1H NMR spectrum, δ, ppm (J, Hz): 0.24 (2H, m, H c-Pr); 0.56 (2H, m, H c-Pr); 1.11 (1H, m, H c-Pr);
2.89 (2H, d, J = 6.8, CH2 benzyl); 3.92 (3H, s, CH3O); 3.99 (3H, s, CH3O); 6.98 (1H, s, H arom); 7.62 (1H, s,
H arom). Found, %: C 60.46; H 6.21; N 5.71. C12H15NO4. Calculated, %: C 60.75; H 6.37; N 5.90.
6-Butyroyl-7-nitro-1,4-benzodioxane (27) was synthesized analogously from 6-butyroyl-1,4-benzo-
1
dioxane, yield 78%; mp 90-91oC (alcohol). H NMR spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.3,
CH3CH2CH2); 1.76 (2H, m, CH3CH2CH2); 2.68 (2H, t, J = 7.3, CH3CH2CH2); 4.35 (4H, m, OCH2CH2O); 6.80
(1H, s, H arom); 7.66 (1H, s, H arom). Found, %: C 57.12; H 5.03; N 5.31. C12H13NO5. Calculated, %: C 57.37;
H 5.21; N 5.57.
6-Allyl-7-nitro-1,4-benzodioxane (31) was obtained by the nitration of 6-allyl-1,4-benzodioxane under
1
the action of N2O4, as described in [22]. Yield 71%; mp 40-41oC (alcohol). H NMR spectrum, δ, ppm (J, Hz):
3.59 (2H, d, J = 7.6, CH2CH=CH2); 4.33 (4H, m, OCH2CH2O); 5.06 (2H, m, CH2CH=CH2); 5.91 (1H, m,
CH2CH=CH2); 6.88 (1H, s, H arom); 7.52 (1H, s, H arom). Found, %: C 59.41; H 4.88; N 6.12. C11H11NO4.
Calculated, %: C 59.72; H 5.01; N 6.33.
2-Aminobenzylcyclopropane (4). Raney nickel (2 g, 33 mmol) and hydrazine hydrate (3.2 g,
100 mmol) were added in portions to a solution of 2-nitrobenzylcyclopropane (1) (5.3 g, 30 mmol) in ethanol
(30 ml). The reaction mixture was stirred for 1 h at 20oC, poured into water (150 ml), extracted with ether (2×50
ml), and the extract dried over MgSO4. After evaporating the solvent the residue was chromatographed on a
1
column of Al2O3. Compound 4 (3.8 g, 86%) was obtained as a viscous oil. H NMR spectrum, δ, ppm (J, Hz):
0.19 (2H, m, H c-Pr); 0.58 (2H, m, H c-Pr); 1.02 (1H, m, H c-Pr); 2.42 (2H, m, CH2 benzyl); 3.52 (2H, br. s,
NH2); 6.68 (1H, dd, Jo = 8.0, Jm = 1.8, H arom); 6.75 (1H, m, H arom); 7.04 (1H, m, H arom); 7.21 (1H, dd,
Jo = 8.0, Jm = 1.8, H arom). Found, %: C 81.38; H 8.67; N 9.31. C10H13N. Calculated, %: C 81.59; H 8.90;
N 9.51.
2-Amino-4,5-ethylenedioxybenzylcyclopropane (5) was obtained analogously, yield 76%, viscous oil.
1H NMR spectrum, δ, ppm (J, Hz): 0.18 (2H, m, H c-Pr); 0.59 (2H, m, H c-Pr), and 0.98 (1H, m, H c-Pr); 2.38
(2H, m, J = 7.6, CH2 benzyl); 3.28 (2H, br. s, NH2); 4.21 (4H, m, OCH2CH2O); 6.22 (1H, s, H arom); 6.73 (1H,
s, H arom). Found, %: C 69.91; H 7.22; N 6.62. C12H15NO2. Calculated, %: C 70.22; H 7.37; N 6.82.
2-Amino-4,5-dimethoxybenzylcyclopropane (6) was obtained analogously by the reduction of nitro
1
compound 3, yield 72%, viscous oil. H NMR spectrum, δ, ppm (J, Hz): 0.17 (2H, m, H c-Pr); 0.56 (2H, m,
H c-Pr); 0.97 (1H, m, H c-Pr); 2.43 (2H, m, CH2 benzyl); 3.42 (2H. br. s, NH2); 3.81 (3H, s, CH3O); 3.83 (3H, s,
CH3O); 6.28 (1H, s, H arom); 6.78 (1H, s, H arom). Found, %: C 69.32; H 8.07; N 6.38. C12H17NO2. Calculated,
%: C 69.54; H 8.26; N 6.76.
6-Amino-7-butyroyl-1,4-benzodioxane (28) was obtained from 1,4-benzodioxane 27 by the procedure
1
described in [23]. Yield 81%; mp 65-66oC (alcohol). H NMR spectrum, δ, ppm, (J, Hz): 1.01 (3H, t, J = 6.8,
CH3CH2CH2); 1.71 (2H, m, CH3CH2CH2); 2.79 (2H, t, J = 6.8, CH3CH2CH2); 4.17 (2H, m, OCH2CH2O); 4.27
(2H, m, OCH2CH2O); 5.86 (2H, br. s, NH2); 6.09 (1H, s, H arom); 7.21 (1H, s, H arom). Found, %: C 64.78;
H 6.69; N 6.12. C12H15NO3. Calculated, %: C 65.14; H 6.83; N 6.33.
6-Allyl-7-amino-1,4-benzodioxane (32). Disodium disulfinate (12.2 g) and Na2CO3 (7.3 g) were added
gradually to a suspension of nitro compound 31 (4.4 g, 20 mmol) in aqueous ethanol (1:1, 100 ml). The reaction
1102

mixture was stirred for 1 h at 20oC, diluted with water, extracted with CHCl3 (3×40 ml), and the extract dried
over MgSO4. The solvent was evaporated and the residue chromatographed on a column of Al2O3. Amino
1
compound 32 (2.14 g, 56%) was obtained as a viscous oil. H NMR spectrum, δ, ppm (J, Hz): 3.14 (2H, d,
J = 7.2, CH2CH=CH2); 3.38 (2H, br. s, NH2); 4.14 (4H, m, OCH2CH2O); 5.06 (2H, m, CH2=CHCH2); 5.89 (1H,
m, CH2=CHCH2); 6.17 (1H, s, H arom); 7.42 (1H, s, H arom). Found, %: C 68.87; H 6.71; N 7.18. C11H13NO2.
Calculated, %: C 69.09; H 6.85; N 7.32.
2-N-Acylaminobenzylcyclopropanes 7-16, 6-N-(p-Methoxybenzoylamino)-7-butyroyl-1,4-benzo-
dioxane (29), and 2-N-Acylaminoallylbenzenes 33, 34 (Tables 1 and 2) were obtained by the acylation of
amino compounds 4-6, 28, 32 with acid chlorides of the appropriate acids as described in [24].
1-[2-N-(4-Methoxybenzoylamino)-4,5-ethylenedioxy]phenylbutan-1-ol (30) was obtained by the
reduction of o-acylaminobutyrophenone 29 with NaBH4 as described in [20], yield 78%; mp 150-151oC
(aqueous alcohol 1:1 mixture). 1H NMR spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 6.8, CH3CH2CH2CH2); 1.26 (1H,
m, CH3CH2CH2CH); 1.43 (1H, m, CH3CH2CH2CH); 1.74 (1H, m, CH3CH2CH2CH); 1.85 (1H, m, CH3CH2CH2CH);
3.37 (1H, br. s, OH); 3.83 (3H, s, CH3O); 4.19 (4H, m, OCH2CH2O); 4.66 (1H, t, J = 6.6, CHOH); 6.56 (1H, s,
H arom); 6.92 (2H, d, J = 8.2, H arom); 7.85 (2H, d, J = 8.2, H arom); 7.88 (1H, s, H arom); 9.85 (1H, s, NH).
Found, %: C 66.93; H 6.22; N 3.71. C20H23NO5. Calculated, %: C 67.21; H 6.49; N 3.92.
Isomerization of N-Acylaminobenzylcyclopropanes 7-16 and N-Acylaminoallylbenzenes 33, 34
under the Action of Trifluoroacetic Acid (General Method). The appropriate amidobenzylcyclopropane 7-16
or the corresponding amidoallylbenzene 33, 34 (2 mmol) was added gradually to trifluoroacetic acid (6 ml).
After 15-30 min the temperature of the reaction mixture was raised to 30-33oC. The reaction mixture was cooled
to 20oC, poured into a mixture of water (30 ml) and ice (30 g) and carefully neutralized with NaOH. The
reaction products were extracted with CHCl3 (3×30 ml), the extract dried over MgSO4, and the solvent
evaporated. The residue was chromatographed on plates of Al2O3 (eluent was benzene–ethyl acetate, 5:1).
Yields and physicochemical characteristics of the products of isomerization are given in Tables 3 and 4.
Isomerization of 2-Benzoylamino-4,5-ethylenedioxybenzylcyclopropane (11) under the Action of
Conc. H2SO4. Amide 11 (0.62 g, 2 mmol) was added gradually with stirring to conc. H2SO4 (5 ml) cooled to
-20oC. The reaction mixture was stirred for 1 h at -20oC, poured into a mixture of ice (50 g) and water (50 ml),
neutralized with NaOH, and the isomerization product isolated as described above. 2-Phenyl-4-propyl-
1
4H-3,1-benzoxazine (21) (0.43 g, 69%) was obtained as a viscous oil. The H NMR spectrum was identical to
that of a sample obtained by isomerization of amide 11 by the action of trifluoroacetic acid.
Reverse Synthesis of 6,7-Ethylenedioxy-2-(4-methoxyphenyl)-4-propyl-4H-3,1-benzoxazine (22)
from Amidoarylpropan-1-ol 30. 3,1-Benzoxazine 22 (0.48 g, 71%) was obtained from alcohol 30 (0.71 g,
1
2 mmol) by the procedure for isomerizing acylaminobenzylcyclopropanes 7-16. The H NMR spectrum of
compound 22 obtained by this method was identical to the spectrum of 3,1-benzoxazine 22 obtained from the
corresponding acylaminobenzylcyclopropane 12.
The work was carried out with the financial support of the grant "Advanced Scientific School of
Academician N. S. Zefirov".
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