Synthesis of 3,1-benzoxazines from N-substituted ortho-(cycloalk-1-enyl or alk-2-en-2-yl)anilines

Article abstract of DOI:10.1023/A:1015643505772

New derivatives of 3,1-benzoxazine have been synthesized by the cyclization of RCO-substituted at the nitrogen atom (R = OEt, Me, NH₂) ortho-(cycloak-1-enyl or alken-l-yl)anilines under mild conditions.

Full text of DOI:10.1023/A:1015643505772

Chemistry of Heterocyclic Compounds, Vol. 38, No. 3, 2002
SYNTHESIS OF 3,1-BENZOXAZINES
ortho
FROM N-SUBSTITUTED
-(CYCLOALK-1-ENYL
OR ALK-2-EN-2-YL)ANILINES*
R. R. Gataullin, I. S. Afon'kin, A. A. Fatykhov, and I. B. Abdrakhmanov
New derivatives of 3,1-benzoxazine have been synthesized by the cyclization of RCO-substituted at the
nitrogen atom (R = OEt, Me, NH2) ortho-(cycloalk-1-enyl or alken-1-yl)anilines under mild conditions.
Keywords: ortho-alkenylanilines, arylureas, arylurethanes, 3,1-benzoxazines, cyclization.
The high biological activity of certain compounds of the benzoxazine series stimulates investigation in this
area. The synthesis of highly effective cardiostimulants [1] or oxytocin antagonists from anthranilic acid [2] has
been described. 2-Aminoalkyl-3,1-benzoxazines, which potentially are active inhibitors of chymase, have been
obtained from phthalimide [3]. An inhibitor of reverse transcriptase HIV-1 belonging to this series has been
synthesized [4].
On continuation of our investigations on the heterocyclization of 2-(alkenyl)-N-acylanilines under mild
conditions [5-7] new examples of this reaction are given, carried out with such substrates as
N-ethoxycarbonylanilines 1 and 2a,b, acetanilide 3, and N-carbamoylaniline 4.
Urethanes (Z)-1, (E)-1 and 2a,b were synthesized by the ethoxycarbonylation of the (Z)- and
(E)-isomers of 4-methyl-2-(pent-2-en-2-yl)aniline (5) and also of the 2-R-6-(cycloalk-1-enyl)anilines 6a [5] and
6b obtained from cycloalk-2-enyl-substituted isomers 7a and 7b respectively. Anilide 3 was obtained by the
acetylation of aniline 6b, and arylurea 4 was obtained by the ammonolysis of urethane 2a [8].
Compounds 1-4 were subjected to heterocyclization under various conditions. The action of Br2 in CCl4
on the (Z)- and (E)-isomers of 4-methyl-2-(pent-2-en-2-yl)urethane (1) gave diastereomers (A and B) of
4,4-dimethyl-4-(1-bromopropyl)-(4H)-3,1-benzoxazin-2-one (8). Isomer A is (4R,1'R+4S,1'S) and B –
(4R,1'S+4S,1'R). The formation of enantiomer A from isomer (Z)-1 is more probable since on cyclization of
similar olefins by the action of halogens it is generally accepted that the reaction proceeds through the stage of
an onium complex [9]. Under the conditions indicated anilide 3 was converted into 2'-bromo-2-methyl-8-
methoxyspiro[4H-3,1-benzoxazine-4,1'-cyclohexane] hydrobromide (9). Treatment of urethanes 2a,b and urea 4
with HCl in EtOH or C2H4Cl2 led to the hydrochlorides 10a,b and 11 respectively. The desired derivatives of
2-substituted 3,1-benzoxazine 12 and 13 were obtained from hydrohalides 9 and 11 respectively by the action of
aqueous Na2CO3 or K2CO3 solution, and 3,1-benzoxazine derivative 14 was obtained similarly from
hydrochloride 10a,b.
_______
* Dedicated to Academician of the Russian Academy of Sciences M. G. Voronkov on his 80th Birthday.
__________________________________________________________________________________________
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa 450054,
Russia; e-mail: chemorg@anrb.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3,
pp. 367-371, March, 2002. Original article submitted June 27, 2001.
0009-3122/02/3803-0331$27.00©2002 Plenum Publishing Corporation
331

Br
H
Et
Br2, CCl4
20 °C
EtOCOCl
O
Et
Et
NH2
NHCOOEt
N
H
O
(Z)-1
(Z)-5
8-(4R, 1'R + 4S, 1'S) A
Br
Et
H
Et
Et
O
Br2, CCl4
20 °C
EtOCOCl
NHCOOEt
N
H
O
NH2
(E)-1
8-(4R, 1'S + 4S, 1'R) B
(E)-5
(CH2)
(CH )
(CH2)
n
2
n
n
KOH
EtOCOCl
300 °C
NH2
NHCOOEt
NH2
7a,b
R
2a,b
6a,b
(CH2)
n
O
Na2CO3
HCl
O
2a,b
20 °C
N
H
O
(10b)
N
HCl
OH
.
OMe
14
10a,b
Br
Br
O
O
Ac2O
Br2, CCl4
20 °C
Na2CO3
6b
N
Me
N
Me
.
NHAc
HBr
OMe
3
9
12
NH3 / CH3OH
100 °C
O
O
HCl
K2CO3
20 °C
2a
20 °C
NHCONH2
N
HCl
NH2
N
NH2
.
Me
11
4
13
2, 6, 7, 10a n = 1, R = Me; b n = 2, R = OMe; 3, 9 R = OMe; 4, 11 R = Me
The composition and structures of the compounds synthesized were confirmed by the results of
elemental analysis, and by data of 1H and 13C NMR spectra and of IR spectra (see Experimental).
332

EXPERIMENTAL
1
13
The H and C NMR spectra were taken on a Bruker AM 300 instrument with an operating frequency
of 300.13 and 75.47 MHz for solutions in CDCl3, internal standard was Me4Si. The IR spectra were obtained on
a UR 20 instrument. A check on the purity of products was effected on a Chrom 4 chromatograph and on Silufol
UV 254 plates.
6-(Cyclohex-1-enyl)-2-methoxyaniline (6b). A mixture of amine 7b (10 g) and KOH (10 g) was kept
for 1 h at 300°C. After cooling, benzene (50 ml) was added to the reaction mixture, stirred, and decanted. After
evaporation of benzene the residue was distilled in vacuum. Product 6b (8.7 g) was obtained; bp 125-128°C
1
(3 mm Hg), mp 41-43°C (pentane). IR spectrum, ν, cm-1: 3260, 3320 (NH2). H NMR spectrum, δ, ppm:
1.52-1.63 (4H, m, 2CH2); 2.18 (2H, m, CH2); 2.21 (2H, m, CH2); 3.64 (3H, s, OCH3); 4.58 (2H, br s, NH2); 5,77
13
(1H, m, =CH); 6.50-6.67 (3H, m, HAr). C NMR spectrum, δ, ppm: 20.1 (C(4')); 24.4 (C(5')); 25.1 (C(3')); 28.2
(C(6')); 55.0 (CH3O); 108.3 (C(4)); 110.4 (C(3)); 120.5 (C(5)); 126.3 (C(2')); 126.4 (C(6)); 133.5 (C(1)); 136.5 (C(1'));
145.7 (C(2)). Found, %: C 76.18; H 8.03; N 6.55. C13H17NO. Calculated, %: C 76.81; H 8.43; N 6.89.
Z
E
Ethoxycarbonylation of Compounds ( )-5, ( )-5, and 6a,b (General Method).
Potassium carbonate
(10 g) was introduced into solution of compound (Z)-5, (E)-5, or 6a,b (10 mmol) in CH2Cl2 (20 ml). Solution of
ethyl chloroformate (15 mmol) in CH2Cl2 (15 ml) was added dropwise with stirring at 20°C. The reaction
mixture was stirred for 2 h and kept for 16 h at the same temperature. The inorganic solid was filtered off,
washed with CH2Cl2 (2 × 10 ml), and the filtrate was washed with 10% aqueous NaHCO3 solution until
cessation of CO2 evolution, then with water, and dried over MgSO4. The solvent was distilled off, and the
product purified by distillation in vacuum.
6-(Cyclohex-1'-enyl)-N-(ethoxycarbonyl)-2-methoxyaniline (2b). Yield 83%; bp 180-183°C
(3 mm Hg); mp 58-61°C (CCl4). IR spectrum, ν, cm-1: 3270 (NH). 1H NMR spectrum, δ, ppm, J (Hz): 1.07 (3H,
t, J = 7.0, CH3CH2); 1.47-1.61 (4H, m, 2CH2); 2.04 (2H, m, CH2); 2.19 (2H, m, CH2); 3.60 (3H, s, OCH3); 4.04
(2H, q, J = 7.0, CH2CH3); 6.53 (1H, br. s, NH); 5.82 (1H, m, =CH); 6.60-6.72 (3H, m, HAr). 13C NMR spectrum,
δ, ppm: 14.4 (CH3); 20.2 (C(4')); 24.9 (C(5')); 25.2 (C(3')); 28.3 (C(6')); 55.0 (CH3O); 60.3 (CH2O); 108.8 (C(4));
114.4 (C(3)); 120.3 (C(5)); 122.3 (C(1)); 126.3 (C(2')); 126.4 (C(6)); 136.1 (C(1')); 142.5 (C(2)); 154.1 (C(1)). Found, %:
C 67.42; H 7.29; N 4.82. C16H21NO3. Calculated, %: C 69.79; H 7.69; N 5.09.
Z
Z
N-(Ethoxycarbonyl)-4-methyl-2-[( )-pent-2'-en-1'-yl]aniline [( )-1].
Yield 95%, oil; bp 146-148°C
(3 mm Hg). IR spectrum, ν, cm-1: 3270 (NH). 1H NMR spectrum, δ, ppm, J (Hz): 0.92 (3H, t, J = 7.5, CH3); 1.34
(3H, t, J = 7.0, CH3); 1.78 (2H, q, J = 7.0, CH2); 2.05 (3H, s, CH3); 2.30 (3H, s, CH3); 4.16 (2H, q, J = 7.5,
CH2); 5.71 (1H, dt, J = 1.0, J = 7.0, =CH); 6.65 (1H, d, J = 8.4, 6-H); 6.79 (1H, s, 3-H); 7.14 (1H, d, J = 8.4,
13
5-H); 8.02 (1H, s, NH). C NMR spectrum, δ, ppm: 13.8, 14.4, 20.6, 22.4 (4CH3); 24.9 (C(3')); 60.9 (CH2O);
118.4 (C(6)); 128.1 (C(2')); 128.5 (C(5)); 130.7 (C(1)); 131.7 (C(2)); 131.8 (C(4)); 132.1 (C(1')); 132.4 (C(3)); 153.6
(O–C=O). Found, %: C 72.42; H 8.29; N 5.21. C15H21NO2. Calculated, %: C 72.83; H 8.57; N 5.66.
E
E
Yield 95%, oil;
N-(Ethoxycarbonyl)-4-methyl-2-[( )-1'-methylbut-1'-enyl]aniline [( )-1].
bp 140-142°C (3 mm Hg). IR spectrum, ν, cm-1: 3290 (NH). H NMR spectrum, δ, ppm, J (Hz): 1.04 (3H, t,
J = 7.3, CH3); 1.31 (3H, t, J = 7.1, CH3); 1.94 (3H, s, CH3); 2.22 (2H, m, CH2); 2.33 (3H, s, CH3); 4.18 (2H, m,
CH2); 5.43 (1H, t, J = 6.9, =CH); 6.74 (1H, d, J = 8.4, 6-H); 6.82 (1H, s, 3-H); 6.95 (1H, d, J = 8.4, 5-H); 7.76
1
13
(1H, s, NH). C NMR spectrum, δ, ppm: 13.8, 14.4, 17.5, 20.5 (4CH3); 21.5 (C(3')); 60.8 (CH2O); 119.3 (C(6));
127.5 (C(2')); 128.6 (C(5)); 131.6 (C(1)); 132.0 (C(2)); 132.1 (C(4)); 133.4 (C(3)); 140.1 (C(1')); 153.5 (O–C=O).
Found, %: C 72.42; H 8.29; N 5.21. C15H21NO2. Calculated, %: C 72.83; H 8.57; N 5.66.
N-Acetyl-6-(cyclohex-1-enyl)-2-methoxyaniline (3). Acetic anhydride (1.5 ml, 15 mmol) was added to
solution of aniline 6b (2.3 g, 10 mmol) in CH2Cl2 (20 ml) and the mixture was kept for 2 h at room temperature.
The reaction mixture was treated with 10% Na2CO3, the organic portion was separated, dried over MgSO4, and
the solvent evaporated. Anilide 3 (2.25 g, 91%) was obtained; mp 99-101°C (CCl4). 1H NMR spectrum, δ, ppm:
1.51-1.68 (4H, m, 2CH2); 2.14 (2H, m, CH2); 2.23 (3H, s, CH3–CO); 2.24 (2H, m, CH2); 3.72 (3H, s, CH3–O);
333

13
6.77 (1H, m, =CH); 6.88-7.47 (3H, m, HAr); 8.25 (1H, s, NH). C NMR spectrum. δ, ppm: 20.3 (C(4')); 23.5
(CH3); 24.8 (C(5')); 25.5 (C(3')); 28.4 (C(6')); 55.1 (C–O); 109.0 (C(3)); 114.7 (C(4)); 122.0 (C(5)); 124.3 (C(1)); 126.4
(C(2')); 127.5 (C(6)); 136.0 (C(1')); 148.3 (C(2)); 168.3 (C=O). Found, %: C 72.70; H 7.30; N 5.04. C15H19NO2.
Calculated, %: C 73.44; H 7.81; N 5.71.
Z
E
Cyclization of Compounds 3, ( )-1, and ( )-1 under the Action of Br2.
Solution of Br2 (0.1 ml,
1.9 mmol) in CCl4 (5 ml) was added dropwise to solution of compound 3, (Z)-1, or (E)-1 (1.86 mmol) in dry
CCl4 (20 ml). The solid hydrobromide 9 was filtered off and washed with CCl4 (10 ml). (R,S) and (R,R)
benzoxazinones 8 were isolated by evaporating the solvent.
2'-Bromo-8-methoxy-2-methylspiro[4H-3,1-benzoxazine-4,1'-cyclohexane] Hydrobromide (9).
1
Yield 86%; mp 132-134°C (CHCl3). H NMR spectrum, δ, ppm, J (Hz): 1.61-2.82 (8H, m, 4CH2); 3.11 (3H, s,
CH3); 4.05 (3H, s, OCH3); 4.51 (1H, m, CHBr); 6.92 (1H, d, J = 7.9, 5-H); 7.02 (1H, d, J = 8.4, 7-H); 7.41 (1H,
13
dd, J = 7.9, J = 8.4, 6-H); 14.90 (1H, br. s, HBr). C NMR spectrum, δ, ppm: 19.6 (CH3); 20.0 (C(5')); 20.3
(C(4')); 30.5 (C(6')); 31.4 (C(3')); 52.5 (C(2')); 56.3 (OCH3); 88.6 (C(4)); 112.9 (C(7)); 116.9 (C(4a)); 118.2 (C(5)); 124.3
(C(8a)); 130.1 (C(6)); 149.3 (C(8)); 171.5 (C(2)). Found, %: C 44.03; H 4.03; Br 39.17; N 3.01. C15H18BrNO2·HBr.
Calculated, %: C 44.47; H 4.73; Br 39.45; N 3.46.
R
R
Yield 88%;
(4 *),(1' *)-4-(1-Bromopropyl)-4,6-dimethyl-4H-3,1-benzoxazin-2-one (8A).
1
mp 149-151°C (CCl4). H NMR spectrum, δ, ppm, J (Hz): 1.14 (3H, t, J = 7.2, CH3); 1.83 (3H, s, CH3); 2.14
(2H, m, CH2); 2.26 (3H, s, CH3); 4.11 (1H, d d, J = 2.0, J = 11.4, CHBr); 6.78 (1H, d, J = 8.0, 8-H); 6.91 (1H, s,
13
5-H); 7.13 (1H, d, J = 8.0, 7-H); 9.85 (1H, s, NH). C NMR spectrum, δ, ppm: 13.1, 20.9, 25.0 (3CH3); 26.0
(C(3')); 64.0 (C(2')); 86.3 (C(4)); 114.7 (C(5)); 122.0 (C(6)); 126.0 (C(7)); 130.1 (C(8)); 131.7 (C(4a)); 132.7 (C(8a));
152.3 (C(2)). Found, %: C 51.83; H 5.22; Br 26.06; N 4.14. C13H16BrNO2. Calculated, %: C 52.37; H 5.41;
Br 26.80; N 4.70.
R
S
Yield 85%;
(4 *),(1' *)-4-(1-Bromopropyl)-4,6-dimethyl-4H-3,1-benzoxazin-2-one (8B).
1
mp 134-136°C (CCl4). H NMR spectrum, δ, ppm, J (Hz): 1.12 (3H, t, J = 7.0, CH3); 1.74 (2H, m, CH2); 1.85
(3H, s, CH3); 2.32 (3H, s, CH3); 4.28 (1H, dd, J = 2.4, J = 11.2, CHBr); 6.81 (1H, d, J = 8.0, 8-H); 6.98 (1H, s,
5-H); 7.08 (1H, dd, J = 1.1, J = 8.0, 7-H); 9.55 (1H, s, NH). 13C NMR spectrum, δ, ppm: 13.5, 20.3, 24.8
(3CH3); 22.0 (C(3')); 64.3 (C(2')); 85.4 (C(4)); 117.4 (C(5)); 121.4 (C(6)); 125.0 (C(7)); 128.9 (C(8)); 131.3 (C(4a));
131.9 (C(8a)); 151.8 (C(2)). Found, %: C 51.94; H 5.17; Br 26.30; N 4.45. C13H16BrNO2. Calculated, %: C 52.37;
H 5.41; Br 26.80; N 4.70.
Cyclization of Urethanes 2a,b and Urea 4 under the Action of HCl. Hydrogen chloride was passed
for 5 min into solution of urethane 2a,b or urea 4 (1 mmol) in ethyl alcohol or dichloroethane (20 ml). The
reaction mixture was then left for 1 h at room temperature. The solvent was evaporated in vacuum.
Hydrochlorides 10a,b and 11 were obtained. Benzoxazine hydrochloride 10b was treated with Na2CO3 solution
without isolation.
2-Hydroxy-8-methylspiro[4H-3,1-benzoxazine-4,1'-cyclopentane] Hydrochloride (10a). Yield 98%;
mp 128-131°C. Rf 0.37 (CH2Cl2–MeOH, 9:1). 1H NMR spectrum, δ, ppm: 1.11-2.58 (8H, m, 4CH2); 2.40 (3H, s,
13
CH3); 6.78-7.23 (3H, m, HAr); 9.36 (1H, s, NH); 10.22 (1H, s, HCl). C NMR spectrum, δ, ppm: 16.7 (CH3);
23.2 (C(3'), C(4')); 38.8 (C(2'), C(5')); 92.0 (C(4)); 120.0 (C(7)); 122.4 (C(8)); 122.8 (C(5)); 124.2 (C(6)); 129.8 (C(8a));
132.7 (C(4a)); 152.8 (C(2)). Found, %: C 61.12; H 6.37; Cl 14.03; N 5.07. C13H15NO2.HCl. Calculated, %: C
61.54; H 6.31; Cl 14.00; N 5.52.
2-Amino-8-methylspiro[4H-3,1-benzoxazine-4,1'-cyclopentane] Hydrochloride (11). Yield 95%;
mp 122-124°C. 1H NMR spectrum, δ, ppm; 1.67-2.58 (8H, m, 4CH2); 2.44 (3H, s, CH3); 6.89 (1H, m, 6-H); 7.05
(2H, m, 7-H, 5-H); 8.77 (1H, s, =NH); 9.21 (1H, s, NH); 11.45 (1H, s, HCl). 13C NMR spectrum, δ, ppm: 18.6
(CH3); 23.5 (C(3'), C(4')); 39.2 (C(2'), C(5')); 96.5 (C(4)); 120.2 (C(4a)); 124.0 (C(5)); 125.3 (C(6)); 126.5 (C(8)); 128.8
(C(7)); 131.2 (C(8a)); 157.7 (C(2)). Found, %: C 61.47; H 6.72; Cl 14.15; N 10.77. C13H16N2O·HCl. Calculated, %:
C 61.78; H 6.73; Cl 14.06; N 11.09.
334

Preparation of 3,1-Benzoxazines 12 and 14 as Bases. Hydrohalides 9 or 10b (5 mmol) were dissolved
in CH2Cl2 (50 ml) and treated with 10% Na2CO3 solution (10 ml). The organic phase was washed with water
(10 ml), dried over MgSO4, evaporated at reduced pressure, and bases 12 and 14 respectively were obtained.
8-Methoxyspiro[3,1-benzoxazine-4,1'-cyclohexan]-2-one (14). Yield 87%; mp 158-160°C (CCl4),
1
Rf 0.47 (benzene–AcOEt, 6:1). H NMR spectrum, δ, ppm, J (Hz): 1.46-1.75 (10H, m, 5CH2); 3.74 (3H, s,
13
OCH3); 6.45 (1H, d, J = 7.0, 7-H); 7.02 (1H, d, J = 7.0, 5-H); 7.63 (1H, t, J = 7.0, 6-H). C NMR spectrum,
δ, ppm: 22.6 (C(3'), C(5')); 24.4 (C(4')); 34.9 (C(2'), C(6')); 55.1 (OCH3); 82.6 (C(4)); 109.7 (C(7)); 122.5 (C(5)); 122.8
(C(8a)); 125.4 (C(6)); 128.3(C(4a)); 144.7 (C(8)); 154.5 (C(2)). Found, %: C 67.33; H 6.09; N 5.07. C15H17NO2.
Calculated, %: C 68.00; H 6.93; N 5.66.
2'-Bromo-8-methoxy-2-methylspiro[3,1-benzoxazine-4,1'-cyclohexane] (12). Yield 90%;
1
mp 82-85°C (CCl4). Rf 0.75 (benzene–AcOEt, 9:1). H NMR spectrum, δ, ppm, J (Hz): 1.47-2.68 (8H, m,
4CH2); 2.22 (3H, s, CH3); 3.87 (3H, s, OCH3); 4.40 (1H, m, CHBr); 6.77 (1H, d, J = 9.0, 7-H); 6.85 (1H, d,
13
J = 9.0, 5-H); 7.06 (1H, t, J = 9.0, 6-H). C NMR spectrum, δ, ppm: 19.1 (CH3); 19.5 (C(5')); 20.2 (C(4')); 29.4
(C(6')); 29.9 (C(3')); 53.5 (C(2')); 55.8 (OCH3); 78.6 (C(4)); 110.9 (C(7)); 118.3 (C(5)); 125.8 (C(6)); 127.0 (C(8a));
127.9 (C(4a)); 151.8 (C(8)); 158.8 (C(2)). Found, %: C 55.33; H 5.43; Br 24.07; N 4.07. C15H18BrNO2.
Calculated, %: C 55.57; H 5.60; Br 24.65; N 4.32.
2-Amino-8-methylspiro[3,1-benzoxazine-4,1'-cyclopentane] (13). Solution of hydrochloride 11
(50 mg, 0.2 mmol) in CHCl3 (20 ml) was stirred with K2CO3 (0.5 g) at 20°C for 2 h. The precipitate was filtered
off, the filtrate was evaporated in vacuum, and base 13 (42 mg, 97.6%) was obtained as an amorphous powder.
1H NMR spectrum, δ, ppm, J (Hz): 1.57-2.31 (8H, m, 4CH2); 2.32 (3H, s, CH3); 5.30 (2H, br. s, NH2); 6.67 (1H,
13
t, J = 7.4, 6-H); 6.44 (1H, d, J = 7.4, 7-H); 7.08 (1H, d, J = 7.4, 5-H). C NMR spectrum, δ, ppm: 17.4 (CH3);
23.3 (C(2'), C(5')); 38.8 (C(3'), C(4')); 89.8 (C(4)); 119.1 (C(5)); 121.5 (C(6)); 129.3 (C(7)); 126.8 (C(4a)); 130.0 (C(8));
140.0 (C(8a)); 154.1 (C(2)). Found, %: C 71.85; H 7.07; N 12.52. C13H16N2O. Calculated, %: C 72.19; H 7.46;
N 12.95.
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