Heterocyclization of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl N-[2-(cyclopent-1-enyl)phenyl]carbamates under the action of hydrogen peroxide

Article abstract of DOI:10.1070/MC2001v011n05ABEH001489

The oxidation of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl N-[6-methyl-2-(cyclopent-1-enyl)phenyl]carbamate with hydrogen peroxide in methanolic NaOH gave spiro[4H-3,1-benzoxazine-4,1′-cyclopentanes]. On the other hand, ethyl [2-(cyclopent-1-enyl

Full text of DOI:10.1070/MC2001v011n05ABEH001489

, 2001, 11(5), 200–201
Heterocyclization of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl
N-[2-(cyclopent-1-enyl)phenyl]carbamates under the action of hydrogen peroxide
Rail R. Gataullin,* Marat F. Nasyrov, Ol’ga V. Shitikova, Leonid V. Spirikhin and Il’dus B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa, Russian Federation.
Fax: +7 3472 35 6066; e-mail: chemorg@anrb.ru
10.1070/MC2001v011n05ABEH001489
The oxidation of N-[2-(cyclopent-1-enyl)phenyl]acetamides and ethyl N-[6-methyl-2-(cyclopent-1-enyl)phenyl]carbamate with
hydrogen peroxide in methanolic NaOH gave spiro[4H-3,1-benzoxazine-4,1'-cyclopentanes]. On the other hand, ethyl [2-(cyclo-
pent-1-enyl)phenyl]carbamate reacted with hydrogen peroxide in the presence of acetonitrile and NaOH to give ethyl 3a-hydroxy-
2,3,3a,8b-tetrahydrocyclopenta[b]indole-4(1H)-carboxylate, which was dehydrated with polyphosphoric acid to ethyl 2,3-dihydro-
cyclopenta[b]indole-4(1H)-carboxylate.
Benzoxazine derivatives exhibit considerable activity in the in-
hibition1 of chymase or reverse transcriptase of HIV-1.2 Recently,
we have reported a convenient synthesis of 3,1-benzoxazines from
ortho-(alk-1-enyl)anilides under the action of hydrogen chlo-
ride or bromine.3,4 At present, the cyclization of these anilides
under the effect of oxidising agents as hydrogen peroxide has
not been studied. In order to search for new methods of con-
trollable heterocyclization of ortho-alkenylanilines, the effect of
hydrogen peroxide on acetamides 1a,b and carbamates 1c,d† has
been studied. Therefore, the reaction of 1a3 or 1c with hydrogen
peroxide in the presence of sodium hydroxide in acetonitrile
and methanol as solvents gave 8-methylspiro[4H-3,1-benzoxazine-
4,1'-cyclopentanes] 2a or 2c.‡ Under the same reaction condi-
tions, carbamate 1d gave ethyl 3a-hydroxy-2,3,3a,8b-tetrahydro-
cyclopenta[b]indole-4(1H)-carboxylate 4, the effect of poly-
phosphoric acid on which caused dehydration and gave ethyl
2,3-dihydrocyclopenta[b]indole-4(1H)-carboxylate 5.§ Compounds
1a–d were found to be sensitive to oxidation conditions. The
interaction of 1d with H2O2 in the presence of Na2WO4 and
H3PO4 resulted in 3,1-benzoxazinone 3. Under these conditions,
amide 1b gives benzoxazine 2b in 85% yield.¶ Under the same
conditions, anilides 1a and 1c did not react.
with hydrogen peroxide, which leads to arylcycloalkylketones
should be taken into account.5 Probably, 4 is formed by the
intramolecular cyclization of intermediate A (Scheme 1), which
was not detected in the reaction mixture most probably because
of its high reactivity under alkaline conditions.
The structure of compounds 1b–d, 2a–c, 3–5 was determined
using spectral methods and elemental analyses.
‡
General procedure for the synthesis of spirobenzoxazinecyclopentanes
2a and 2c and tetrahydrocyclopentaindole 4. Acetamide 1a or carbamate
1c or 1d was added to a stirred solution of sodium hydroxide (0.2 g) in
methanol (5 ml) and acetonitrile (5 ml). To the resulting mixture, an excess
of a 50% hydrogen peroxide solution (1 g, 29.4 mmol) was added drop-
wise. Evolution of oxygen and an increase of the reaction temperature
were observed upon standing for 2 h. A saturated sodium thiosulfate
solution (10 ml) was added, extracted with dichloromethane and dried
(MgSO4). The solvent was evaporated in vacuo, and the yellowish oily
residue was purified by column chromatography using silica gel (5 g,
eluent: hexane–EtOAc, 2:1) to give spirobenzoxazinecyclopentane 2a,
which was recrystallised from ethyl acetate or spirobenzoxazinecyclo-
pentane 2c, which crystallised upon standing or tetrahydrocyclopenta-
indole 4, which was obtained as an amorphous substance.
2a: yield 80%, mp 103 °C. 1H NMR (CDCl3) d: 1.7–2.0 (m, 2H, CH2),
2.1 (s, 3H, Me), 2.1–2.2 (m, 2H, CH2), 2.3 (s, 3H, Me), 2.4–2.5 (m, 2H,
CH2), 2.9 (br. s, 1H, OH), 4.0 (d, 1H, CH, J 5.9 Hz), 7.0–7.3 (m, 3H,
ArH). 13C NMR (CDCl3) d: 17.3, 21.8 (2Me), 20.6, 31.5, 34.4 (3CH2),
75.5 (CHOH), 90.2 [C(4)], 122.6 [C(6)], 123.5 [C(4a)], 125.4 [C(5)],
130.8 [C(7)], 132.4 [C(8)], 137.5 [C(8a)], 159.6 (C=N). MS, m/z: 231
(M+). Found (%): C, 72.45; H, 7.42; N, 6.30. Calc. for C14H17NO2 (%):
C, 72.70; H, 7.41; N, 6.06.
To clarify the mechanism of the formation of 4, the well-
known reaction of aryl(cycloalk-1-enes) bearing no amine moiety
†
General methods. 1H and 13C NMR spectra were recorded using a
Bruker AM-300 spectrometer at 300.13 and 75.47 MHz (with Me4Si
as an internal standard). IR spectra were recorded on a Specord M-80
spectrophotometer. The purity of initial compounds and reaction pro-
ducts was controlled with a Chrom 5 instrument and Silufol UV 25 plates.
Mass spectra were recorded using an MH 1320 spectrometer (70 eV).
Acetamide 1b was obtained according to the published method3 by the
reaction of ortho-(cyclopent-1-enyl)aniline6 with acetic anhydride.
General procedure for the synthesis of carbamates 1c and 1d. Ethyl
chloroformate (1.3 g, 12 mmol) was added dropwise to a vigorously
stirred mixture of ortho-(cyclopent-1-enyl)aniline6 or 2-methyl-6-(cyclo-
pent-1-enyl)aniline3 (10 mmol) and potassium carbonate (2.76 g, 20 mmol)
in dichloromethane (20 ml) at 20 °C. After 1 h, water (2 ml) was added,
the mixture was stirred, the precipitate was filtered off, and the filtrate
was washed with water and dried (MgSO4). The solvent was evaporated
in a vacuum, the products were isolated as a yellowish oil.
2c: yield 63%, mp 105 °C. 1H NMR (CDCl3) d: 1.4 (t, 1H, Me, J
7.2 Hz), 1.7–2.2 (m, 6H, 3CH2), 2.3 (s, 3H, Me), 4.1 (br. s, 1H, CH–O),
4.4 (m, 2H, CH2), 5.0 (br. s, 1H, OH), 6.9–7.0 (m, 2H, ArH), 7.1 (d, 1H,
ArH, J 8.1 Hz). 13C NMR (CDCl3) d: 14.2, 17.0 (2Me), 20.6, 31.4, 34.2
(3CH2), 64.3 (OCH2), 75.4 (CHOH), 93.5 [C(4)], 122.3 [C(4a)], 122.6
[C(6)], 123.2 [C(5)], 130.7 [C(7)], 131.7 [C(8)], 140.0 [C(8a)], 154.8
(C=O). Found (%): C, 68.42; H, 7.21; N, 5.40. Calc. for C15H19NO3 (%):
C, 68.94; H, 7.33; N, 5.36.
4: yield 70%. 1H NMR (CDCl3) d: 1.3 (t, 3H, Me, J 7.6 Hz), 1.5–1.7
(m, 2H, CH2), 1.7–1.9 (m, 2H, CH2), 2.2–2.4 (m, 2H, CH2), 3.5–3.6 (m,
1H, CH), 4.3 (q, 2H, CH2, J 6.9 Hz), 7.0 (t, 1H, ArH, J 7.4 Hz), 7.1–7.3
(m, 3H, ArH), 7.6 (br. s, 1H, OH). 13C NMR (CDCl3) d: 14.6 (Me), 25.4
[C(2)], 34.0 [C(1)], 42.2 [C(3)], 53.2 [C(8b)], 61.9 (OCH2), 103.6 [C(3a)],
114.4 [C(5)], 123.2 [C(7)], 124.4 [C(8)], 129.0 [C(6)], 132.7 [C(8a)],
141.5 [C(4a)], 153.5 (C=O). Found (%): C, 67.83; H, 6.71; N, 5.78.
Calc. for C14H17NO3 (%): C, 68.00; H, 6.93; N, 5.66.
1
1c: yield 95%, mp 51–53 °C. H NMR (CDCl3) d: 1.30 (t, 3H, Me, J
7.31 Hz), 1.90–2.70 (m, 6H, 3CH2), 2.30 (s, 3H, Me), 4.15 (m, 2H,
CH2), 5.90 (s, 1H, CH), 6.35 (s, 1H, NH), 7.10 (m, 3H, Ar). 13C NMR
(CDCl3) d: 14.65 (Me), 18.34 (Me), 23.66 [C(4')], 33.51 [C(3')], 35.91
[C(5')], 61.14 (OCH2), 126.14 [C(5)], 126.73 [C(4)], 129.24 [C(2)],
130.91 [C(3)], 133.80 [C(6)], 136.37 [C(2')], 138.35 [C(1)], 141.33
[C(1')], 154.60 (C=O). Found (%): C, 73.19; H, 7.15; N, 5.43. Calc. for
C15H19NO2 (%): C, 73.47; H, 7.76; N, 5.71.
§
Synthesis of tetrahydrocyclopentaindole 5. A mixture of tetrahydro-
cyclopentaindoline 4 (0.5 g, 2.02 mmol), phosphoric acid (85%) (3 g)
and phosphorus pentoxide (2 g) was vigorously stirred and then left to
stand for 10 h. The acid solution was neutralised with aqueous sodium
hydroxide, extracted with benzene, and the organic extract was dried
(NaOH). The solvent was evaporated to give crystalline tetrahydrocyclo-
pentaindole 5. Yield 97%, mp 67 °C. 1H NMR (CDCl3) d: 1.4 (t, 3H,
Me, J 6.2 Hz), 2.4 (q, 2H, CH2, J 7.0 Hz), 2.7 (t, 2H, CH2, J 6.8 Hz), 3.0
(t, 2H, CH2, J 6.6 Hz), 4.4 (q, 2H, CH2), 7.1–7.3 (m, 2H, ArH), 7.3 (d,
1H, J 7.4 Hz, H-8), 8.1 (d, 1H, H-5, J 6.2 Hz). 13C NMR (CDCl3) d:
14.5 (Me), 24.2, 27.5, 29.0 (3CH2), 62.8 (OCH2), 115.9 [C(5)], 118.7
[C(8)], 124.8 [C(6)], 125.1 [C(7)], 127.0 [C(8a)], 128.0 [C(8b)], 140.3
[C(3a)], 144.0 [C(4a)], 151.5 (C=O). Found (%): C, 74.01; H, 6.67; N,
6.00. Calc. for C14H15NO2 (%): C, 73.34; H, 6.59; N, 6.11.
1
1d: yield 95%, Rf 0.6 (hexane–EtOAc, 4:1). H NMR (CDCl3) d: 1.3
(t, 3H, Me, J 7.3 Hz), 2.0 (quint, 2H, CH2, J 7.8 Hz), 2.6 (br. s, 2H,
CH2), 2.7 (br. s, 2H, CH2), 4.2 (q, 2H, CH2O, J 7.2 Hz), 5.9 (br. s, 1H,
=CH), 7.0 (m, 1H, ArH), 7.1 (br. s, 1H, NH), 7.1–7.3 (m, 2H, ArH), 8.1
(d, 1H, ArH, J 8.1 Hz). 13C NMR (CDCl3) d: 14.3 (Me), 23.0, 33.5, 36.4
(3CH2), 61.0 (CH2O), 119.5 [C(6)], 122.7 [C(2')], 127.3 [C(4)], 127.5
[C(3)], 127.6 [C(2)], 129.9 [C(5)], 134.6 [C(1')], 140.3 [C(1)], 153.4
(C=O). Found (%): C, 72.68; H, 7.45; N, 5.99. Calc. for C14H17NO2 (%):
C, 72.70; H, 7.41; N, 6.06.
– 200 –

, 2001, 11(5), 200–201
Finally, it must be concluded that the structure of products
obtained (benzoxazine or indoline type) is dependent on the
nature of protecting group and the type of catalysts used (tung-
state–phosphoric acid or acetonitrile–alkali) despite that both of
these systems are epoxydising.
HO
O
i, 1a–c
N
R
R1
References
2a–c
1 M. Gütschow, Sci. Pharm., 1999, 67, 524.
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.
3 R. R. Gataullin, I. S. Afonkin, 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).
HO
O
1d
ii,
NHC(O)R
1a–d
N
H
O
R1
3
4 R. R. Gataullin, I. S. Afonkin, A. A. Fatykhov, L. V. Spirikhin and I. B.
Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000, 118 (Russ. Chem.
Bull., 2000, 49, 122).
5 E. N. Prilezhaeva, Reaktsiya Prilezhaeva. Elektrofil’noe okislenie (Prile-
zhaev Reaction. Electrophilic Oxidation), Nauka, Moscow, 1974, p. 332
(in Russian).
6 R. R. Gataullin, T. V. Kazhanova, A. A. Fatykhov, L. V. Spirikhin and
I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000, 171 (Russ.
Chem. Bull., 2000, 49, 174).
a
b
1 = Me
R = R
R = Me, R
1 = H
c R = OEt, R1 = Me
d R = OEt, R1 = H
1d
i,
O
NHCO2Et
A
H
iii
N
N
OH
CO2Et
CO2Et
5
4
Scheme 1 Reagents and conditions: i, H2O2, NaOH, MeCN+MeOH (1:1);
ii, H2O2, Na2WO4, H3PO4; iii, PPA, 20 °C.
Received: 28th June 2001; Com. 01/1815
¶
General procedure for the synthesis of spirobenzoxazinecyclopentane
1H, OH), 4.1 (d, 1H, CH, J 4.62 Hz), 7.0 (d, 1H, J 7.59 Hz), 7.1–7.3 (m,
3H, ArH). 13C NMR (CDCl3) d: 21.5 (Me), 20.5, 31.6, 34.7 (3CH2), 75.9
(CHOH), 90.0 [C(4)], 123.5 [C(4a)], 123.6 [C(6)], 125.1 [C(7)], 125.8
[C(8)], 129.1 [C(5)], 139.1 [C(8a)], 160.3 (C=N). Found (%): C, 71.03;
H, 6.82; N, 6.76. Calc. for C13H15NO2 (%): C, 71.87; H, 6.96; N, 6.45.
2b and 3. A solution of sodium tungstate (50 mg, 0.17 mmol) in water
(0.2 ml), one drop of conc. phosphoric acid and a solution of 50% of
hydrogen peroxide (0.34 g, 4.98 mmol) were added to a solution of acet-
amide 1b or carbamate 1d (2.48 mmol) in methanol (5 ml). The reaction
mixture was allowed to stand for 48 h at 30 °C, and then dichloromethane
(50 ml) was added, washed with a saturated sodium thiosulfate solution
followed by water and then the organic extracts were dried (MgSO4).
The solvent was evaporated in vacuo to give an oil of spirobenzoxazine-
cyclopentanes 2b or 3, which crystallised on standing.
1
3: yield 85%, mp 216 °C. H NMR ([2H6]DMSO) d: 1.6–2.4 (m, 6H,
3CH2), 4.0 (m, 1H, CH–O), 4.9 (br. s, 1H, OH), 6.9 (d, 1H, H-5, J
8.2 Hz), 7.0 (t, 1H, ArH, J 7.6 Hz), 7.2 (t, 2H, ArH, J 7.4 Hz), 10.1 (s, 1H,
NH). 13C NMR ([2H6]DMSO) d: 19.5, 32.1, 33.2 (3CH2), 74.6 (CHOH),
92.8 [C(4)], 113.5 [C(8)], 120.7 [C(4a)], 121.7 [C(6)], 126.5 [C(5)],
128.6 [C(7)], 136.0 [C(8a)], 150.7 (C=O). Found (%): C, 65.30; H, 6.02;
N, 6.36. Calc. for C12H13NO3 (%): C, 65.74; H, 5.98; N, 6.39.
2b: yield 80%, mp 143 °C. 1H NMR (CDCl3) d: 1.7–2.0 (m, 2H, CH2),
2.0 (s, 3H, Me), 2.1–2.2 (m, 2H, CH2), 2.4–2.5 (m, 2H, CH2), 2.7 (br. s,
– 201 –