N-acylaminophenylcyclopropanes in reaction with nitrous acid generated in situ

Article abstract of DOI:10.1007/s10593-012-0929-y

The reaction of N-acylaminophenylcyclopropanes with HNO2 proceeds regioselectively with introduction of an N=O fragment into the three-membered ring and formation of the corresponding Δ²-isoxazolines. For ortho-substituted N-acylaminophenylcyclopropanes side processes were observed, caused by the intramolecular participation of the N-acyl group in conversions of the carbenium ions formed on opening the cyclopropane ring under the action of the nitrosating reagent, and by direct insertion of the modified ortho substituent into the three-membered ring.

Full text of DOI:10.1007/s10593-012-0929-y

Chemistry of Heterocyclic Compounds, Vol. 47, No. 11, February, 2012 (Russian Original Vol. 47, No. 11, November, 2011)
N-ACYLAMINOPHENYLCYCLOPROPANES IN REACTION
WITH NITROUS ACID GENERATED in situ
S. S. Mochalov1*, R. A. Gazzaeva2, A. Z. Kadzhaeva1,
A. N. Fedotov1, and E. V. Trofimova1
The reaction of N-acylaminophenylcyclopropanes with HNO2 proceeds regioselectively with
introduction of an N=O fragment into the three-membered ring and formation of the corresponding
Δ2-isoxazolines. For ortho-substituted N-acylaminophenylcyclopropanes side processes were observed,
caused by the intramolecular participation of the N-acyl group in conversions of the carbenium ions
formed on opening the cyclopropane ring under the action of the nitrosating reagent, and by direct
insertion of the modified ortho substituent into the three-membered ring.
Keywords: N-acylaminophenylcyclopropanes, 3,1-benzoxazines, Δ2-isoxazolines, heterocyclization.
It was shown previously that phenylcyclopropanes, in which the cyclopropane fragment and the acyl
amino group are drawn close together in space, are in fact quantitatively transformed under conditions of acid
catalysis into the corresponding 4H-3,1-benzoxazines [1-3].
On the other hand phenylcyclopropanes containing no ortho substituents may be directly transformed
into Δ2-isoxazolines (or into isoxazoles), for example under the action of nitrous acid generated in situ [4-9].
Since 4H-3,1-benzoxazines and isoxazolines attract the attention of investigators up to the present time
as synthetic precursors for obtaining biologically active compounds [10-15] and as independent subjects for
biological testing [16-18], the synthesis of new heterocycles of this type seemed of practical interest. In this
connection we have attempted to clarify how far the processes of heterocyclization will proceed regioselectively
if conditions are created for arylcyclopropanes to react in two possible directions, viz. heterocyclization into
4H-3,1-benzoxazines and the formation of isoxazoline derivatives.
For this purpose we have synthesized a series of 1-[2-(N- and 4-(N-acylamino)phenyl]cyclopropanes
and their 1-methyl analogs and have studied their interaction with nitrous acid, generated in situ.
Substrates necessary for the investigation were obtained from the corresponding phenylcyclopropanes
1a-c, 2 by sequential reactions of nitration, reduction, and N-acylation (Scheme 1, Table 1).
Since the amide group may be deaminated under nitrosation conditions [19], we initially investigated
the conversion of para-substituted N-acylaminophenylcyclopropanes under the action of nitrous acid and
clarified how the presence of the acyl amino group influences the reactivity of the substrates.
_______
*To whom correspondence should be addressed, e-mail: ssmoch@org.chem.msu.ru.
1Moscow M. V. Lomonosov State University, 1 Leninskie gory, Moscow 119992, Russia.
2North-Ossetiian K. L. Khetagurov State University, 46 Vatutin St., Vladikavkaz 362040, North-Ossetiya,
Russia; e-mail: gazzaevar@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1702-1717, November, 2011.
Original article submitted December 8, 2010; revision submitted November 5, 2011.
0009-3122/12/4711-1415©2012 Springer Science+Business Media, Inc.
1415

Scheme 1
R
R
R1COCl
Fe, HCl
X
NH
R
X
NH2
3, 4, 11, 12
R1
O
HNO3
7a–h, 8a–e, 13a,b, 14
Ac2O
X
R
– 50 °C
1a–c, 2
R
R1COCl
Fe, HCl
HN
H2N
R1
5, 6
O
9a–c, 10a,b
1a–c, 3, 5, 7a–h, 9a–c, 11–14 R = H; 2, 4, 6, 8a–e, 10a,b R = Me; 1a, 2, 3, 4, 7a–h, 8a–e X = H;
1b, 11, 13a,b X = Br; 1c, 12, 14 X = Ас; 7a R1 = CH2Cl, b R1 = Ph, c R1 = 4-MeOC6H4,
d R1 = CH2OPh, e R1 = 2-BrC6H4, f R1 = 3-FC6H4, g R1 =3,4,5-(MeO)3C6H2, h R1 = 3,5-(NO2)2C6H3;
8a R1 = CH2Cl, b R1 = Bn, c R1 = 2-thienyl, d R1 = 3,4,5-(MeO)3C6H2, e R1 = 1,4-benzodioxan-6-yl;
9 a R1 = 4-MeC6H4, b R1 = 2-ClC6H4, c R1 = 3,5-(NO2)2C6H3; 10 a R1 = 4-MeOC6H4,
b R1 = 3-MeOC6H4; 13 a R1 = 4-MeOC6H4, b R1 = 4-FC6H4; 14 R1 = 4-MeOC6H4
It turned out that the interaction of para-substituted N-acylaminophenylcyclopropanes 9a-c, 10a,b with
equimolar amounts of nitrous acid formed in situ from sodium nitrite is effected with retention of the N-acyl-
amino group, and mainly with introduction of an N=O group into the cyclopropane ring with subsequent
formation of the corresponding Δ2-isoxazolines 15a-c, 16a,b (Scheme 2, Table 2).
Scheme 2
N
H
H
3
O
4
R
R
H
NaNO2
+
9a–c, 10a,b
CF3CO2H, CHCl3,
0–5 °C
O2N
NHCOR1
NHCOR1
15a–c, 16a,b
17a,b
15a–c, 17a,b R = H; 16a,b R = Me; 15, 17 a R1 = 4-MeC6H4, b R1 = 2-ClC6H4;
15c R1 = 3,5-(NO2)2C6H3; 16 a R1 = 4-MeOC6H4, b R1 = 3-MeOC6H4
The conversion of substrates 9c, 10a is effected practically without side reactions (a significantly longer
time is required for complete conversion of compound 9c), and in the case of N-acylamino derivatives 9a,b
formation was observed of small quantities of nitration products in the aromatic nucleus, viz. 4-methyl-N-(4-
cyclopropyl-2-nitrophenyl)benzamide (17a) and 2-chloro-N-(4-cyclopropyl-2-nitrophenyl)benzamide (17b).
Herewith the nitro group enters into the cyclopropyl-substituted benzene ring in an ortho position to the
N-acylamino substituent. This result shows that the N-acylamino substituent in strength of orienting effect in
electrophilic substitution reactions at the aromatic nucleus surpasses the cyclopropyl group, one of the strongest
ortho,para-orientants in the series of alkyl and cycloalkyl substituents.
1416

TABLE 1. Characteristics of Synthesized o- and p-(N-Acylamino)phenyl-
cyclopropanes
Found, %
——————
Calculated, %
Com-
pound*
Empirical
formula
Mp,°C*2
Yield, %
С
Н
N
7a
C11H12CINO
C17H17NO2
C17H17NO2
C16H14FNO
C19H21NO4
C16H13N3O5
C12H14CINO
C18H19NO
63.27
63.01
76.22
76.38
76.16
76.38
74.98
75.27
69.55
69.70
58.47
58.71
64.21
64.43
81.29
81.48
70.13
70.01
70.22
70.36
73.55
73.77
81.12
81.24
71.01
70.72
58.56
58.71
76.77
76.84
76.97
76.84
5.66
5.77
6.19
6.41
6.22
6.41
5.38
5.53
6.33
6.47
3.91
4.00
6.07
6.31
6.99
7.22
5.68
5.87
6.61
6.79
6.06
6.19
6.71
6.82
5.03
5.19
3.82
4.00
6.71
6.81
6.63
6.81
6.47
6.68
5.11
5.24
5.13
5.24
5.55
5.49
4.38
4.28
12.58
12.84
6.11
6.27
5.36
5.28
5.41
5.44
4.22
4.10
4.64
4.53
5.42
5.57
4.96
5.15
12.61
12.84
4.82
4.98
4.77
4.98
63-64
64
82
77
81
69
71
63
78
86
76
73
76
81
73
86
83
88
92
71
7c
106-107
74-75
7d
7f
105-106
122-123
181-182
Viscous oil
114-115
121-122
79-81
7g
7h
8a
8b
8c
C15H15NOS
C20H23NO4
C19H19NO3
C17H17NO
8d
8e
Viscous oil
151-152
126-127
222-223
163-164
155-156
118-119
111-112
115-116
9а
9b
9c
C16H14CINO
C16H13N3O5
C18H19NO2
C18H19NO2
C17H16BrNO2
C16H13BrFNO
C19H19NO3
10a
10b
13a
13b
14
58.82
58.98
57.31
57.51
73.59
73.77
4.41
4.66
3.76
3.92
6.03
6.19
3.93
4.05
4.01
4.19
4.31
4.53
_______
*Compounds 7b,e are described in [1].
*2Solvent for recrystallization: ethanol for compounds 7c,d,f,g, 8b,c, 9a,b,
10a,b, 13a,b, 14; EtOH-H2O, 2:3 for compounds 7a, 8d; EtOH–CHCl3,
1:1 for compounds 7h, 9e.
In principle it might have been assumed that the nitration of substrates 9a,b may be effected under the
action of the nitronium cation capable of being formed from nitrous acid according to Scheme 3 [20].
Scheme 3
.
– 2NO
H+
– 2H2O
.
+
2N2O3
N2O4
NO2 + HNO2
4HNO2
2NO2
However, considering that in these conditions only an equimolar amount of nitrous acid is used and the
conversion of the initial substrates into isoxazolines 15a,b proceeded with high yield, it seems unlikely that
nitro compounds 17a,b are formed by the way of electrophilic nitration.
1417

Since it is known that electron-donating substituents reduce the first ionizing potential of the
corresponding phenylcyclopropanes thereby enabling reaction to occur by an electron-transfer mechanism [21],
it may be assumed that the formation of nitration products 17a,b occurs by a SET mechanism (Scheme 4) with
+
participation of NO2 radicals, formed (as is seen from Scheme 3) at an earlier stage in comparison with NO2
formation.
Scheme 4
+
.
.
+
+
NO
– H
NO2
17a,b
9a,b
.
+
H
– NO
O2N
NHCOR
NHCOR
Interaction of ortho-substituted N-acylaminophenylcyclopropanes 7a-d with nitrous acid showed that in
contrast to para-substituted analogs the starting arylcyclopropanes do not completely react when using
equimolecular amounts of reactants, but at a substrate−HNO2 ratio of 1:2 the reaction of compounds 7a-d
proceeds with complete conversion and without significant changes in composition of the reaction products.
1
Analysis of the H NMR spectra of reaction mixtures obtained by interaction of ortho-substituted
phenylcyclopropanes 7a-h, 13a,b, and 14 with HNO2, shows that in all cases in fact only 5-(N-acyl-
aminophenyl)-Δ2-isoxazolines 18a-h, 20a,b, and 22 are formed, and only in the reaction of amides 7a,b and
13a, together with Δ2-isoxazolines 18a,b and 20a, are small amounts of substituted 3,1-benzoxazines 19a,b and
21 are formed (Scheme 5).
Scheme 5
N
H
H
3
OH
4
H
H
H
NaNO2
(2 equiv.)
7a–h, 13a,b, 14
N
O
CF3CO2H, CHCl3,
0–5°C
+
O
COR
X
N
R
X
N
H
18a–h, 20a,b, 22
19a,b, 21
18a–h, 19a,b Х = H; 20a,b, 21 Х = Br; 22 Х = Ac; 18 a R = CH2Cl, b R = Ph;
18c, 20a, 21a, 22 R = 4-MeOC6H4; 18 d R = CH2OPh, e R = 2-BrC6H4, f R = 3-FC6H4,
g R = 3,4,5-(MeO)3C6H2, h R = 3,5-(NO2)2C6H3; 19 a R = CH2Cl, b R = Ph; 20b R = 4-FC6H4
It must be noted that even using a twofold amount of nitrous acid in the reaction of o-(N-acyl-
amino)phenylcyclopropanes 7h, 13a,b, and 14, a significant portion (20-25%) of substrate remained unreacted.
In attempts to isolate the desired heterocycles from reaction mixtures in the pure state it turned out that
aryl-substituted Δ2-isoxazolines 18a-h were unstable and on chromatography on Al2O3 were isomerized into
2,4-disubstituted 4H-2,1-benzoxazines. The latter were also capable of being modified under the
chromatographic conditions used. An experiment with a pure sample of 5-phenyl-Δ2-isoxazoline 18b served as
additional confirmation of the fact of Δ2-isoxazolines recyclization into 3,1-benzoxazines on Al2O3. It was
found that on application of compound 18b to Al2O3 (column) with subsequent elution, recyclization does in
1
fact occur with formation of a mixture of Δ2-isoxazoline 18b and 3,1-benzoxazine 19b (according to H NMR
data of spectra of a mixture) in a percentage ratio of 82:18 respectively.
1418

We consider that the type of recyclization found for 5-[o-(N-acylamino)phenyl]-Δ2-isoxazolines into the
corresponding 4H-3,1-benzoxazines has a general character and that the presence of a nucleophilic N-acyl-
amino group directly next to it assists a benzyl type of intramolecular nucleophilic attack by the activated
oxygen atom (Scheme 6).
Scheme 6
_
N
H
H
O
N
O
NOH
+
H
~ H
O
O
+
O
N
R
N
R
N
R
H
H
A
The hypothesis expressed is confirmed indirectly by the fact that 5-aryl-Δ2-isoxazolines 15a-c, 16a,b,
formed from 4-(N-acylamino)phenylcyclopropanes 9a-c, 10a,b are not modified on Al2O3.
A similar recyclization was also observed by the authors of [22, 23] investigating the behavior of esters
of nitro-substituted carboxylic acids under nitrosation conditions.
o-(N-Acylamino)phenyl-substituted Δ2-isoxazolines 18a-h, 20a,b, and 22 may be isolated in a pure state
by crystallization from solutions of reaction mixtures dissolved in absolute ether. The Δ2-isoxazolines isolated
in this way may already be recrystallized from suitable solvents.
It turned out to be fairly unexpected that the behavior of 1-[o-(N-acylamino)phenyl]-1-methylcyclo-
propanes 8a-e in reaction with HNO2 differs significantly from the behavior of analogous phenylcyclopropanes
containing no methyl group at position 1 of the cyclopropane.
Interaction of ortho-substituted compounds 8a-e with HNO2 proceeds in two directions. One leads to
the product of the N=O fragment insertion into the cyclopropane ring and to formation of the corresponding
Δ2-isoxazolines 23a-e, as in the case of phenylcyclopropanes 7a-c, 13a,b unsubstituted in the small ring, and the
other leads to 4-methylquinoline (24) and carboxylic acids 25b-e corresponding to the acyl fragment of the
amide groups (Scheme 7). Monochloroacetic acid, unidentified in the case of reaction of compound 8a by this
route, is apparently lost in the process of processing the reaction mixture.
Scheme 7
H
3
H
H
Me
N
4
H3C
N
NaNO2, CF3CO2H
CHCl3, 0–5°C
O
8a–e
+
+
RCO2H
25b–e
N
COR
H
24
23a–e
23a R = CH2Cl; 23, 25 b R = Bn, с R = 2-thienyl, d R = 3,4,5-(MeO)3C6H2,
e R = 1,4-benzodioxan-6-yl
It is important to note that in the reaction of methyl-substituted phenylcyclopropanes 8a-e not in a single
case was the 4-methyl-substituted 4H-3,1-benzoxazine of the type 19a,b identified (Scheme 5), which might
have been formed on initiating the opening of the cyclopropane ring with nitrosyl cation.
It is known [1] that the corresponding 4H-3,1-benzoxazine structures are readily formed from
anilidocyclopropanes of the type 8a-e under conditions of acid-catalyzed opening of the cyclopropane ring in
them. Consequently it is difficult to imagine that in the course of reactions of o-substituted cyclopropane
substrates 7a-h, 8a-e, 13a,b, and 14, initiated by nitrosating reagents, cyclic intermediates responsible for the
1419

synthesis of the corresponding 4H-3,1-benzoxazines (ions of type A, Scheme 6) are either not formed at all
(from compounds 8a-e) or are formed in insignificant amounts (from compounds 7a,b, 13a). It was shown
specially that in CF3CO2H at 0-5oC in the absence of NaNO2, all the arylcyclopropanes studied by us were
unchanged. It seems extremely probable that in the early stage of reactions of all the studied o-substituted
arylcyclopropanes just cyclic ions of this type are formed. The latter, due to the fact that they have a
heterocyclic onium structure, may not be transformed into neutral reaction products (corresponding 3,1-benz-
oxazines) and are stabilized in a different way, by recyclization into the thermodynamically more favorable
Δ2-isoxazolines (Scheme 8).
Scheme 8
N
+
NO
N
O
R
R
O
+
R
– H
O
O
O
+
R1
N
R1
N
R1
N
H
H
H
It is important to note that 5-[o-(N-acylamino)phenyl]-5-methyl-Δ2-isoxazolines (for example, 23a,b),
unlike Δ2-isoxazolines 18a-h, are not recyclized during chromatography on Al2O3. This may probably be a
consequence of both steric factors, hindering nucleophilic attack of the amide group by the "charged" benzyl
type carbon atom, and electronic factors, a reduction in the electrophilicity of the benzyl carbon atom due to the
effect of the electron-donating methyl group. Concerning the found special direction of transformation of
compounds 8a-e into 4-methylquinoline (24), this evidently seems to be a new type of transformation of
cyclopropane-containing substrates under the action of the nitrosating reagent.
Scheme 9
Me
Me
HO
Me
NO+
– H+
–
H+
OX
8a–e
–
O
O
O
+
+
N
N
N
OX
R
R
N=O
N
N
R
I
HO
III
II
b
a
Me
Me
Me
RCO2X
H2O
–
OX
+
+
+
N
N
N
N
N
H
N
–
O
O
HO
HO
OH
H
R
OX
R
RCO2H
IV
VIII
VII
25b–e
+
H
– RCO2X
Me
Me
NH2OH
–
24
+
N
N
N
H
OH
N
OH
H
V
VI
X = NO, COCF3
1420

Apparently, attack of the nitrosating reagent at the amide group nitrogen atom in parallel with the
introduction of an N=O fragment into the cyclopropane ring is effected for 1-methyl-1-phenylcyclopropanones
8a-e. It is possible to suggest two routes of transformation of the N-nitroso compounds I into the quinoline
heterocycle 24 (Scheme 9), with cleavage of the amide bond at an earlier (route a) or at a later stage (route b).
Route a might be interpreted as a conversion of 1-(2-aminophenyl)-1-methylcyclopropane 4 into
4-methylquinoline (24) under the conditions of nitrosation. However, in the reaction of amine 4 with HNO2, as we
have shown specially, 4-methylquinoline (24) is not formed, but the main reaction products proved to be
2-(1-methylcyclopropyl)phenol (26) and 2-(5-methyl-Δ2-isoxazolin-5-yl)phenol (27) (Scheme 10).
Scheme 10
Me
Me
Me
N
O
NaNO2, CF3CO2H
CHCl3, 0–5°C
4
+
NH
OH
27 (16%)
OH
26 (71%)
N=O
TABLE 2. Characteristics of the Reaction Products of N-Acylamino-
substituted Phenylcyclopropanes with HNO2
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
Mp, °C*
6
С
Н
N
5
1
2
3
4
7
15а
15b
15c
16a
16b
17a
17b
18a
18b
18c
18d
18e
18f
C17H16N2O2
73.18
72.83
64.11
63.90
54.12
53.94
69.71
69.66
69.84
69.66
69.09
68.90
60.51
60.67
55.11
55.35
72.34
72.17
68.76
68.91
68.68
68.91
55.41
55.67
67.44
67.60
63.88
64.04
54.01
53.94
55.61
55.35
5.62
5.75
4.22
4.36
3.51
3.40
5.68
5.85
5.71
5.85
5.60
5.44
4.23
4.14
4.38
4.65
5.16
5.30
5.21
5.44
5.26
5.44
3.82
3.79
4.38
4.61
5.42
5.66
3.32
3.40
4.71
4.65
10.14
9.99
9.51
9.32
15.52
15.73
9.24
9.03
9.17
9.03
9.41
9.46
8.96
8.85
11.56
11.74
10.31
10.52
9.61
9.45
9.33
9.45
7.88
8.11
9.76
9.85
7.71
7.86
15.82
15.72
11.82
11.74
171-172
151-152
215-216
180-182
115-116
124-125
—
71
93
72
81
94
8
C16H13CIN2O2
C16H12N4O6
C18H18N2O3
C18H18N2O3
C17H16N2O3
C16H13CIN2O3
C11H11CIN2O2
C16H14N2O2
C17H16N2O3
C17H16N2O3
C16H13BrN2O2
C16H13FN2O2
C19H20N2O5
C16H12N4O6
C11H11CIN2O2
C16H14N2O2
5
Viscous oil
121-122
161-162
99-100
194-195
147-148
129-130
214-215
—*2
74
93
89
85
87
91
89
78
11
18
18g
18h
19a
19b
72.51
72.17
5.29
5.30
10.76
10.52
—*2
1421

TABLE 2 (continued)
1
20a
20b
21
2
3
4
5
6
7
C17H15BrN2O3
C16H12BrFN2O2
C17H15BrN2O3
54.15
54.42
53.06
52.91
54.11
54.42
67.16
67.45
56.85
57.04
73.21
73.45
62.68
62.91
64.72
64.85
4.21
4.03
3.41
3.33
4.16
4.03
5.27
5.36
5.04
5.18
6.01
6.16
4.72
4.93
5.77
5.99
7.37
7.46
7.84
7.71
7.55
7.46
8.03
8.28
11.26
11.09
9.24
9.52
9.51
9.78
7.62
7.56
125-126
167-168
—*2
65
89
21
81
59
44
54
46
52
71
16
22
C19H18N2O4
154-155
C12H13CIN2O2
Viscous oil
23a
23b
23c
23d
23e
26
C18H18N2O2
C15H14N2O2S
C20H22N2O5
C19H18N2O4
C10H12O
118-119
—
Viscous oil
146-147
Viscous oil
—
67.55
67.45
80.87
81.04
67.61
67.78
5.16
5.36
8.22
8.16
6.11
6.26
8.02
8.28
—
27
C10H11NO2
7.93
7.91
_______
*Solvent for crystallization: compounds 15b, 16a,b, 17a, 18c-e,g, 20a,b, 23e
from EtOH; compounds 15a,e, 18b,f,h from EtOH–CHCl3, 2:3; compound 22
from Et2O–CHCl31:1; compound 23b from Et2O.
*2Substances were not isolated in a pure state. Elemental analyses are given for
mixtures of compounds 18a and 19a, 18b and 19b, 20a and 21 after separation
of the corresponding Δ2-isoxazolines (18a,b, 20a) from the reaction mixtures.
It is perfectly obvious that conversion of amine 4 into compound 24 may be carried out only through the
formation of the corresponding diazonium ion, which, as testified by experiment, is incapable of intramolecular
conversion into 4-methylquinoline under the conditions used. This fact may indicate that intermediate IV is
evidently not formed in the course of the reaction of anilides 8a-e, and the process occurs by route b.
EXPERIMENTAL
The 1H NMR spectra were recorded on Bruker DRX-500 (500 MHz) (compounds 7d,h 9c, 10a,b) and
Varian VXR-400 spectrometers (400 MHz) (remaining compounds) in DMSO-d6 (internal standard TMS) or in
CDCl3 (internal standard was the signal of the residual CHCl3 protons). Mass spectra were recorded on a
Finnigan SSQ 7000 instrument (GC-MS type) using a capillary column (30 m2 mm, stationary phase DB-1),
carrier gas, helium (40 ml/min), and with temperature programming from 50 to 300oC (10 deg/min). Ionization
energy was 70 eV. Melting points were determined on an Electrothermal Digital Melting Point Apparatus
1A9100. Separation of reaction mixtures and a check of the purity of reaction products was carried out on
Silufol columns and plates or on plates of unbound Al2O3, activity grade II (according to Brockmann), using as
eluent ether–chloroform–petroleum ether (40-70oC), 1:1:3 and 1:1:2 (vol.).
1422

1423

1424

1425

1426

1427

2-Cyclopropylaniline (3) was obtained by the reduction of 2-nitrophenylcyclopropane (bp 111-112oC
(8 mm Hg); n20 1.5614 (bp 105oC (5 mm Hg); n20 1.5606 [24])) by the procedure of [25]. Yield 81%,
D
D
colorless liquid; bp 105oC (10 mm Hg); n20D 1.5812 (bp 103-104oC (9 mm Hg) [26]).
2-(1-Methylcyclopropyl)aniline (4) was synthesized from 1-methyl-1-(2-nitrophenyl)cyclopropane (bp
127-128oC (16 mm Hg); n20 1.5369 (bp 111-112oC (7 mm Hg); n20 1.5372 [27])) analogously to [25]. Yield
D
D
74%, colorless liquid; bp 115-117oC (20 mm Hg); n20D 1.5812 (bp 106-108oC (12 mm Hg) [26]).
4-Cyclopropylaniline (5) was obtained by the reduction of 4-nitrophenylcyclopropane (bp 132-133oC
(8 mm Hg), mp 29-30oC (bp 122oC (5 mm Hg), mp 31oC [24])) by the procedure of [25]. Yield 76%, colorless
1
liquid; bp 112oC (10 mm Hg) (bp 122oC (5 mm Hg) [24]). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.63
(2H, m), 0.92 (2H, m) and 1.87 (1H, m, cyclo-Pr); 3.57 (2H, br. s, NH2); 6.55 (2H, d, 3J = 8.2, H Ar); 6.95 (2H,
d, 3J = 8.2, H Ar).
4-(1-Methylcyclopropyl)aniline (6) was obtained from 1-methyl-1-(4-nitrophenyl)cyclopropane
1
(mp 56-58oC (EtOH) (mp 57-58oC [27])) by the procedure of [25]. Yield 77%, viscous oil. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 0.68 (2H, m) and 0.81 (2H, m, cyclo-Pr); 1.39 (3H, s, CH3); 3.58 (2H, br. s, NH2); 6.65
(2H, d, 3J = 8.2,H Ar); 7.11 (2H, d, 3J = 8.2, H Ar). Found, %: C 81.47; H 8.81; N 9.61. C10H13N. Calculated, %:
C 81.59; H 8.90; N 9.52.
5-Bromo-2-cyclopropylaniline (11) was obtained by the reduction of 4-bromo-2-nitrophenyl-
o
cyclopropane (mp 42 C (alcohol) (mp 42oC [28])) by the procedure of [25]. Yield 61%, colorless liquid; bp
145-146oC (8 mm Hg) (bp 152-154oC (11 mm Hg) [29]), n20D 1.6122.
Aceto-3-amino-4-cyclopropylphenone (12) was synthesized analogously [25] from aceto-4-cyclo-
1
propyl-3-nitrophenone (mp 67oC (alcohol) (mp 66-67oC [30]). Yield 64 %, viscous oil. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 0.64 (2H, m); 0.95 (2H, m) and 1.77 (1H, m, cyclo-Pr); 2.51 (3H, s, COCH3); 4.12
3
(2H, br. s, NH2); 7.08 (1H, d, J = 8.0, H Ar); 7.31 (2H, m, H Ar). Found, %: C 75.21; H 7.32; N 8.11.
C11H13NO. Calculated, %: C 75.40; H 7.48; N 8.00.
N-Acylaminophenyl- and 1-(N-acylaminophenyl)-1-methylcyclopropanes 7a-h, 8a-e, 9a-c, 10a,b,
13a,b, and 14 were synthesized by the acylation of cyclopropylanilines 3-6, 11, 12 with the corresponding acid
chlorides as described in [1]; yields and physicochemical characteristics are given in Tables 1 and 3.
Interaction of N-Acylaminophenylcyclopropanes 7a-h, 8a-e, 9a-c, 10a,b, 13a,b, 14, and 1-(2-Amino-
phenyl)-1-methylcyclopropane (4) with Nitrous Acid, Generated in situ (General Method). Sodium nitrite
(50 mmol, or 100 mmol) was added in portions at 0-5oC to a solution of the corresponding N-acyl-
aminophenylcyclopropane (50 mmol) in trifluoroacetic acid (6.5 ml) and CHCl3 (10 ml). The mixture was
stirred for 1 h at the same temperature, and while increasing the temperature to 20oC, was poured into water
(60 ml). The organic layer was separated, the aqueous layer was extracted with chloroform (210 ml). The
chloroform solutions were combined, washed with water until a neutral reaction, and dried over MgSO4. After
solvent evaporation, the reaction mixture was separated on Silufol plates, or on plates with a binder-free layer of
Al2O3, or by adding absolute ether (20-30 ml) to the reaction mixture, a crystalline reaction product was
precipitated. Yields of the 5-arylisoxazolines and other reaction products obtained and their physicochemical
properties are given in Tables 2 and 4.
REFERENCES
1.
2.
3.
S. S. Mochalov, R. A. Gazzaeva, A. N. Fedotov, Yu. S. Shabarov, and N. S. Zefirov, Khim. Geterotsikl.
Soedin., 922 (2003). [Chem. Heterocycl. Comp. 39, 794 (2003)].
A. N. Fedotov, E. V. Trofimova, V. A. Romanov, S. S. Mochalov, Yu. S. Shabarov, and N. S. Zefirov,
Khim. Geterotsikl. Soedin., 115 (2008). [Chem. Heterocycl. Comp., 44, 96 (2008)].
E. V. Trofimova, B. P. Archegov, A. N. Fedotov, R. A. Gazzaeva, S. S. Mochalov, and N. S. Zefirov,
Khim. Geterotsikl. Soedin., 1368 (2009). [Chem. Heterocycl. Comp., 45, 1095 (2009)].
1428

4.
5.
Yu. S. Shabarov, L. G. Saginova, and R. A. Gazzaeva, Khim. Geterotsikl. Soedin., 738 (1983). [Chem.
Heterocycl. Comp., 19, 589 (1983)].
R. A. Gazzaeva, Yu. S. Shabarov, and L. G. Saginova, Khim. Geterotsikl. Soedin., 309 (1984). [Chem.
Heterocycl. Comp., 20, 246 (1984)].
6.
7.
L. G. Saginova, I. L. Kukhareva, A. T. Lebedev, and Yu. S. Shabarov, Zh. Org. Khim., 27, 1852 (1991).
O. B. Bondarenko, A. Yu. Gavrilova, L. G. Saginova, N. V. Zyk, and N. S. Zefirov, Izv. Akad. Nauk,
Ser. Khim., 3, 741 (2003).
8.
9.
O. B. Bondarenko, A. Yu. Gavrilova, M. A. Kazantseva, V. N. Tikhanushkina, E. E. Nifant'ev,
L. G. Saginova, and N. V. Zyk, Zh. Org. Khim., 42, 265 (2006).
A. Z. Kadzhaeva, E. V. Trofimova, A. N. Fedotov, K. A. Potekhin, R. A. Gazzaeva, S. S. Mochalov,
and N. S. Zefirov, Khim. Geterotsikl. Soedin., 753 (2009). [Chem. Heterocycl. Comp., 45, 595 (2009)].
A. P. Kozikowski and P. D. Stein, J. Am. Chem. Soc., 104, 4023 (1982).
D. P. Curran, J. Am. Chem. Soc., 105, 5825 (1983).
S. H. Andersen, K. K. Sharma, and K. B. G. Torssell, Tetrahedron, 39, 2241 (1983).
A. P. Kozikowski, Acc. Chem. Res., 17, 410 (1984).
S. Y. Lee, B. S. Lee, C.-W. Lee, and D. Y. Oh, J. Org. Chem., 65, 256 (2000).
A. Yashiro, Y. Nishida, K. Kobayashi, and M. Ohno, Synlett, 361 (2000).
P. Conti, C. Dallanoce, M. De Amici, C. De Micheli, and K. N. Klotz, Bioorg. Med. Chem., 6, 401
(1998).
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
C. Mohan, G. S. Saharia, and H. R. Sharma, J. Indian Chem. Soc., 53, 181 (1976).
T. Ogawa, M. Inazu, K. Goton, and S. Hayashi, Agents Actions, 31, 321 (1990).
O. A. Reutov, A. L. Kurts, and K. P. Butin, Organicheskaya Khimiya, Vol. 3 [in Russian], BINOM,
Moscow (2004), p. 245.
20.
21.
S. Uemara, A. Toshimitsu, M. Okano, J. Chem. Soc., Perkin Trans. 1, 1076 (1978).
S. S. Mochalov, R. A. Gazzaeva, A. N. Fedotov, E. V. Trofimova, I. V. Trushkov, and N. S. Zefirov,
Zh. Org. Khim., 40, 1148 (2004).
22.
23.
24.
25.
26.
27.
R. Chang and K. Kim., Tetrahedron Lett., 40, 6773 (1999).
R. Chang and K. Kim., Tetrahedron Lett., 41, 8499 (2000).
Yu. S. Shabarov, V. K. Potapov, and R. Ya. Levina, Zh. Obshch. Khim., 34, 3127 (1964).
R. Ya. Levina, Yu. S. Shabarov, and V. K. Potapov, Zh. Obshch. Khim., 29, 3233 (1959).
S. S. Mochalov, A. N. Fedotov, A. I. Sizov, and Yu. S. Shabarov, Zh. Org. Khim., 15, 1425 (1979).
Yu. S. Shabarov, S. S. Mochalov, I. P. Stepanova, and G. V. Aleksakhin, Dokl. Akad. Nauk, 207, 621
(1972).
28.
29.
Yu. S. Shabarov and S. S. Mochalov, Zh. Org. Khim., 8, 293 (1972).
A. N. Fedotov, I. N. Shishkina, T. G. Kutateladze, S. S. Mochalov, and Yu. S. Shabarov, Khim.
Geterotsikl. Soedin., 1063 (1987). [Chem. Heterocycl. Comp., 23, 849 (1987)].
Yu. S. Shabarov and S. S. Mochalov, Zh. Org. Khim., 8, 2085 (1972).
30.
1429