Synthesis of 2′-bromo-8-methylspiro(4H-3,1-benzooxazine-4,1′-cyclopentan)-2(1H)-o ne and 2-amino-2′-bromo-8-methylspiro(4H-3,1-benzooxazine-4,1′-cyclopentane ) from 6-(cyclopent-1-enyl)-2-methylaniline

Article abstract of DOI:10.1023/A:1015020604764

The reaction of 6-(cyclopent-1-enyl)-N-ethoxycarbonyl-2-methylaniline with Br₂ or its reaction with NH₃ followed by the reaction with Br₂ afforded 2′-bromo-8-methyl-spiro(4H-3,1-benzooxazine-4,1′-cyclopentan)-2(1H)- one and 2-amino-2′-bromo-8-methyl-spiro(4H-3,1-benzooxazine-4,1′-cyclopentan e), respectively.

Full text of DOI:10.1023/A:1015020604764

2
466
Russian Chemical Bulletin, International Edition, Vol. 50, No. 12, pp. 2466—2467, December, 2001
Brief Communications
Synthesis of 2´-bromo-8-methylspiro(4H-3,1-benzooxazine-4,1´-
cyclopentan)-2(1H )-one and 2-amino-2´-bromo-8-methylspiro(4H-3,1-
benzooxazine-4,1´-cyclopentane) from 6-(cyclopent-1-enyl)-2-methylaniline
«
R. R. Gataullin, I. S. Afon´kin, A. A. Fatykhov, L. V. Spirikhin, and I. B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
7
1 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6066. E-mail: chemorg@anrb.ru
The reaction of 6-(cyclopent-1-enyl)-N-ethoxycarbonyl-2-methylaniline with Br2 or its
reaction with NH3 followed by the reaction with Br2 afforded 2´-bromo-8-methyl-
spiro(4H-3,1-benzooxazine-4,1´-cyclopentan)-2(1H)-one and 2-amino-2´-bromo-8-methyl-
spiro(4H-3,1-benzooxazine-4,1´-cyclopentane), respectively.
Key words: alkenylanilines, ureas, halocyclization, 3,1-benzooxazines.
Some compounds of the 3,1-benzooxazine series
exhibit high activities in inhibition of chymase or HIV-1
reverse transcriptase.2 As a continuation of our studies
on the synthesis of 3,1-benzooxazines,3—5 we examined
emental analysis. The 13C NMR spectra of benzooxazines
1
4—6 have a signal of the spiro-C(4) atom at δ 91—97,
which is virtually identical with the values obtained by
us previously for analogous structures.3—5
the reactions of Br with N-substituted urethane (1) and
2
urea (2) with the aim of preparing their 2-oxo and
Experimental
2
-amino analogs.
Results and Discussion
The 1H and 13C NMR spectra were recorded on a Bruker
AM-300 instrument (300.13 MHz for 1H; 75.47 MHz for 13C;
Me Si as the internal standard). The IR spectra were measured
4
on a UR-20 spectrometer (Nujol mulls). The purities of the
products were monitored by chromatography on Silufol UV-254
plates (CH Cl as the eluent).
The reaction of amine 3 3 with ethyl chloroformate
in CH Cl in the presence of K CO afforded urethane
2
2
2
3
2
2
1
in 95% yield (Scheme 1). Heating of the latter in a
methanolic solution of ammonia in an autoclave at
00 °C gave rise to arylurea 2 in 65% yield. The reaction
6
-(Cyclopent-1-enyl)-N-ethoxycarbonyl-2-methylaniline
(1). Potassium carbonate (10 g) was added to a solution of
amine 3 (1.75 g, 10 mmol) in CH2Cl2 (20 mL). Then a
solution of EtCO Cl (1.6 g, 15 mmol) in CH Cl (15 mL) was
1
of compound 1 with Br2 in CCl4 produced benzo-
oxazinone 4 in high yield. The reaction of urea 2 with
Br2 in MeOH at 20 °C afforded hydrobromide 5,
which yielded aminobenzooxazine 6 upon treatment
2
2
2
added dropwise with stirring at 20 °C. The reaction mixture
was stirred for 2 h and kept at 20 °C for 18 h. The inorganic
precipitate that formed was filtered off and washed with
CH Cl (2½10 mL). The filtrate was successively washed with
2
2
with Na CO .
2
3
a 10% aqueous solution of NaHCO3 until liberation of CO2
The structures of the resulting compounds were es-
tablished based on the data from spectroscopy and el-
ceased and then with water and dried with MgSO . The solvent
was evaporated and the residue was extracted with hot hexane.
4
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2355—2356, December, 2001.
066-5285/01/5012-2466 $25.00 © 2001 Plenum Publishing Corporation
1

Brominative spirocyclization
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 12, December, 2001 2467
Scheme 1
Benzooxazinone 4 was obtained in a yield of 0.42 g (87%),
m.p. 171—173 °C. Found (%): C, 52.38; H, 4.41; Br, 26.54;
N, 4.32. C13H14BrNO . Calculated (%): C, 52.72; H, 4.77;
2
1
Br, 26.98; N, 4.73. H NMR (CDCl ), δ: 1.10—2.90 (m, 6 H,
3
3
CH ); 2.30 (s, 3 H, CH ); 4.60 (s, 1 H, H(2´)); 6.90—7.40
2 3
EtCO Cl
2
13
(
m, 3 H, Ar); 9.10 (s, 1 H, NH). C NMR (CDCl ), δ: 16.9
3
2
K CO3
(CH ); 20.0 (C(4´)); 33.0 (C(5´)); 34.4 (C(3´)); 55.8 (C(2´));
3
9
NH2
NHCOEt
O
3.9 (C(4)); 120.2 (C(7)); 122.2 (C(8)); 122.7 (C(5)); 124.1
Me
Me
(
C(6)); 131.1 (C(8a)); 133.0 (C(4a)); 152.3 (C(2)).
2-Amino-2´-bromo-8-methylspiro(4H-3,1-benzooxazine-
1
3
4
,1´-cyclopentane) hydrobromide (5). A solution of Br2
NH /MeOH 100 °C
Br2
3
(0.05 mL, 1 mmol) in MeOH (1 mL) was added dropwise with
CCl4
stirring to a solution of urea 2 (0.22 g, 1 mmol) in MeOH
(
5 mL) at 20 °C. The solvent was evaporated in vacuo.
Br
Hydrobromide 5 was obtained in a yield of 0.37 g (100%),
m.p. 113—115 °C (CH Cl ). Found (%): C, 41.28; H, 4.11;
Br, 42.04; N, 7.02. C13H16Br N O. Calculated (%): C, 41.51;
H, 4.30; Br, 42.49; N, 7.44. H NMR (CDCl ), δ: 1.10—2.90
(
2
2
O
2
1
2
NHCNH2
3
N
H
O
m, 6 H, 3 CH ); 2.40 (s, 3 H, CH ); 4.50 (s, 1 H, H(2´));
2 3
Me
O
Me
6.90—7.30 (m, 3 H, Ar); 9.00 (br.s, 2 H, NH ); 11.00 (s, 1 H,
2
HBr). C NMR (CDCl ), δ: 18.4 (CH ); 20.3 (C(4´)); 33.5
2
1
3
4
3
3
Br2 MeOH
(C(5´)); 34.7 (C(3´)); 54.7 (C(2´)); 97.2 (C(4)); 120.3 (C(4a);
24.6 (C(5)); 125.1 (C(8)); 125.2 (C(6)); 128.6 (C(7)); 132.3
C(8a)); 157.3 (C(2)).
-Amino-2´-bromo-8-methylspiro(4H-3,1-benzooxazine-
,1´-cyclopentane) (6). A solution of compound 5 (0.38 g,
1
(
Br
Br
2
4
O
Na CO3
O
2
1 mmol) in CH Cl (10 mL) was stirred with a 10% aqueous
2 2
CH Cl
solution of Na CO (10 mL) at 20 °C for 30 min. The organic
phase was separated, washed with water (5 mL), dried with
2
2
2 3
N
NH2
N
NH2
•
HBr
MgSO , and filtered. The solvent was evaporated in vacuo.
Me
Me
4
Benzooxazine 6 was obtained as an amorphous compound in a
6
5
yield of 0.27 g (93%), R 0.4 (CH Cl ). Found (%): C, 52.58;
f
2
2
H, 4.81; Br, 26.64; N, 9.12. C13H15BrN O. Calculated (%):
2
After evaporation of the hexane, carbamate 1 was obtained in a
yield of 2.34 g (95%), m.p. 51—53 °C. Found (%): C, 73.19;
1
C, 52.89; H, 5.13; Br, 27.07; N, 9.49. H NMR (CDCl ), δ:
3
1
.10—2.90 (m, 6 H, 3 CH ); 2.20 (s, 3 H, CH ); 4.50 (s, 1 H,
2 3
H, 7.15; N, 5.43. C15H19NO . Calculated (%): C, 73.47;
2
H(2´)); 5.00 (br.s, 2 H, NH ); 6.90—7.30 (m, 3 H, Ar).
–
1
1
2
H, 7.76; N, 5.71. IR, ν/cm : 3290 (NH). H NMR (CDCl ),
13
3
C NMR (CDCl ), δ: 17.9 (CH ); 20.2 (C(4´)); 33.0 (C(5´));
3
3
δ: 1.30 (t, 3 H, CH , J = 7.31 Hz); 1.90—2.70 (m, 6 H,
3
3
(
1
4.5 (C(3´)); 55.7 (C(2´)); 91.7 (C(4)); 121.4 (C(6)); 122.7
C(8)); 123.5 (C(7)); 129.3 (C(4a)); 130.7 (C(7)); 140.1 (C(8a));
53.8 (C(2)).
3
CH ); 2.30 (s, 3 H, CH ); 4.15 (m, 2 H, CH ); 5.90 (s, 1 H,
2 3 2
1
3
CH); 6.35 (s, 1 H, NH); 7.10 (m, 3 H, Ar).
C NMR
(
CDCl ), δ: 14.7 (Me); 18.3 (Me); 23.7 (C(4´)); 33.5 (C(3´));
3
3
5.9 (C(5´)); 61.1 ((OCH ); 126.1 (C(5)); 126.7 ((C(4)); 129.2
2
References
(
(
C(2)); 130.9 (C(3)); 133.8 ((C(6)); 136.4 (C(2´)); 138.4
C(1)); 141.3 (C(1´)); 154.6 (C=O).
N-[6-(Cyclopent-1-enyl)-2-methylphenyl]urea (2). A so-
1. M. Gütschow, Sci. Pharm., 1999, 67, 524.
lution of urethane 1 (2.4 g, 10 mmol) in a saturated methanolic
solution of ammonia (17 mL) was heated in a metallic auto-
clave at 100 °C for 25 h. Then the reaction mixture was cooled
and the precipitate that formed was filtered off, washed with a
methanolic solution of ammonia (3 mL), and dried in vacuo.
Urea 2 was obtained in a yield of 1.37 g (65%), m.p. 218 °C
2. M. E. Pierce, R. L. Parsons, L. A. Radesca, Y. S. Lo,
St. Silverman, J. R. Moore, Q. Islam, A. Choudhury,
J. M. D. Fortunak, D. Nguyen, C. Luo, S. G. Morgan,
W. P. Davis, P. N. Confalone, C. Chen, R. D. Tillyer,
L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thomson, E. G.
Corley, E. G. G. Grabowski, R. Robert, and P. P. Reider,
J. Org. Chem., 1998, 63, 8536.
(
MeOH/NH ). Found (%): C, 72.07; H, 7.15; N, 12.85.
3
C13
H
N O. Calculated (%): C, 72.22; H, 7.41; N, 12.96. IR,
3. R. R. Gataullin, I. S. Afon´kin, I. V. Pavlova, A. A.
Fatykhov, I. B. Abdrakhmanov, and G. A. Tolstikov, Izv.
Akad. Nauk, Ser. Khim., 1999, 398 [Russ. Chem. Bull., 1999,
48, 396 (Engl. Transl.)].
4. R. R. Gataullin, I. S. Afon´kin, A. A. Fatykhov, L. V.
Spirikhin, and I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser.
Khim., 2000, 118 [Russ. Chem. Bull., Int. Ed., 2000, 49, 122].
5. R. R. Gataullin, I. S. Afon´kin, A. A. Fatykhov, L. V.
Spirikhin, E. V. Tal´vinskii, and I. B. Abdrakhmanov, Izv.
Akad. Nauk, Ser. Khim., 2001, 633 [Russ. Chem. Bull., Int.
Ed., 2001, 50, 659].
16
2
–
1
1
ν/cm : 3392, 3440 (NH, NH ). H NMR (DMSO-d ), δ:
2
6
1
2
1
3
.90—2.70 (m, 6 H, 3 CH ); 2.20 (s, 3 H, Me); 5.70 (br.s,
H, NH ); 5.90 (s, 1 H, CH); 7.10 (m, 3 H, Ar); 8.50 (br.s,
H, NH). 1 C NMR (DMSO-d ), δ: 18.4 (Me); 23.3, 33.2,
2
2
3
6
5.3 (C(3´), C(4´), C(5´)); 125.8 (C(5)); 125.9 (C(4)); 128.8
(
1
C(2)); 129.0 (C(3)); 134.6 (C(6)); 135.9 (C(2´)); 137.1 (C(1));
41.8 (C(1´)); 157.0 (C=O).
´-Bromo-8-methylspiro(4H-3,1-benzooxazine-4,1´-cyclo-
2
pentan)-2(1H)-one (4). A solution of Br2 (0.5 g, 3.12 mmol)
in CCl4 (3 mL) was added dropwise with stirring to a solution
of urethane 1 (0.4 g, 1.63 mmol) in CCl4 (10 mL). The
reaction mixture was kept at 20 °C for 1 h, the solvent was
evaporated, and the residue was recrystallized from hexane.
Received February 15, 2001;
in revised form July 24, 2001