Synthesis of new spiro compounds containing a carbamate group

Article abstract of DOI:10.1134/S1070428010120092

1,3-Dipolar cycloaddition to methyl 4-[2-(2-oxo-2,3-dihydro-1H-indol-3- ylidene)-1-oxoethyl]-phenylcarbamate of diazomethane in chloroform-diethyl ether and of 3,4-dimethoxybenzonitrile oxide generated from the corresponding aldehyde oxime by the action of N-chlorobenzenesulfonamide sodium salt (Chloramine B) in boiling ethanol gave, respectively, methyl 4-(2-oxo-1′,5′-dihydro-1H-spiro[indole-3,4′-pyrazol] -3′-ylcarbonyl)phenylcarbamate and methyl 4-[3′-(3,4- dimethoxyphenyl)-2-oxo-1H,4′H-spiro[indole-3,5′-isoxazol] -4′-ylcarbonyl]phenylcarbamate. The condensation of methyl 4-[2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)-1-oxoethyl]phenylcarbamate with hydrazine hydrate in ethanol afforded methyl 4-(2-oxo-1,2,2′,4′- tetrahydrospiro[indole-3,3′-pyrazol]-5′-yl)phenylcarbamate. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010120092

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 12, pp. 1826–1829. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Velikorodov, O.Yu. Poddubnyi, A.K. Kuanchalieva, O.O. Krivosheev, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 12, pp. 1816–1819.
Synthesis of New Spiro Compounds Containing
a Carbamate Group
A. V. Velikorodov, O. Yu. Poddubnyi, A. K. Kuanchalieva, and O. O. Krivosheev
Astrakhan State University, pl. Shaumyana 1, Astrakhan, 414000 Russia
e-mail: avelikorodov@mail.ru
Received March 20, 2010
Abstract—1,3-Dipolar cycloaddition to methyl 4-[2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)-1-oxoethyl]-
phenylcarbamate of diazomethane in chloroform–diethyl ether and of 3,4-dimethoxybenzonitrile oxide
generated from the corresponding aldehyde oxime by the action of N-chlorobenzenesulfonamide sodium salt
(Chloramine B) in boiling ethanol gave, respectively, methyl 4-(2-oxo-1′,5′-dihydro-1H-spiro[indole-3,4′-pyra-
zol]-3′-ylcarbonyl)phenylcarbamate and methyl 4-[3′-(3,4-dimethoxyphenyl)-2-oxo-1H,4′H-spiro[indole-3,5′-
isoxazol]-4′-ylcarbonyl]phenylcarbamate. The condensation of methyl 4-[2-(2-oxo-2,3-dihydro-1H-indol-
3-ylidene)-1-oxoethyl]phenylcarbamate with hydrazine hydrate in ethanol afforded methyl 4-(2-oxo-1,2,2′,4′-
tetrahydrospiro[indole-3,3′-pyrazol]-5′-yl)phenylcarbamate.
DOI: 10.1134/S1070428010120092
Unsaturated ketones are widely used in the syn-
thesis of various heterocyclic compounds [1]. With
a view to obtain new biologically active compounds
possessing a carbamate functionality in the present
work we examined reactions of methyl 4-[2-(2-oxo-
2,3-dihydro-1H-indol-3-ylidene)-1-oxoethyl]phenyl-
carbamate (I) with diazomethane, 3,4-dimethoxyben-
zonitrile oxide, and hydrazine hydrate. Compound I
was prepared by the Knoevenagel condensation of
indole-2,3-dione with methyl (4-acetylphenyl)carba-
mate in the presence of diethylamine in anhydrous
ethanol, followed by dehydration of the condensation
product on heating in glacial acetic acid in the pres-
ence of concentrated hydrochloric acid.
conformational isomerization s-cis→s-trans is 20–
40 kJ/mol [4].
Condensations of chalcones with various 1,2-binu-
cleophiles (such as hydrazine and hydroxylamine
derivatives) underlie an important synthetic approach
to five-membered heterocyclic compounds [5–9]. The
condensation of compound I with hydrazine hydrate
was carried out by heating equimolar amounts of the
reactants in boiling anhydrous ethanol over a period of
1 h. The product structure was determined on the basis
of its IR and 1H and 13C NMR spectra; it was identified
as methyl 4-(2-oxo-1,2,2′,4′-tetrahydrospiro[indole-
3,3′-pyrazol]-5′-yl)phenylcarbamate (II) (Scheme 1).
The yield of II was 93%. The 1H NMR spectrum of II,
apart from other signals, contained two doublets be-
longing to two diastereotopic methylene protons 4-HA
and 4-HB (δ 3.65 and 4.03 ppm, respectively). In the
13C NMR spectrum of II we observed a signal from the
pyrazole C=N carbon atom at δC 153.80 ppm, and the
cis Isomers of chalcones are generally less stable
than their trans isomers, and they readily undergo
isomerization, e.g., by the action of nucleophiles [2, 3].
Unlike α,β-unsaturated aldehydes, s-cis conformer of
chalcones predominates, and the energy barrier to the
Scheme 1.
H
3''
6''
2'
MeO
O
N
OMe
4''
3'
4'
2''
1'
6'
4
NH2NH2 ·H2O, EtOH, Δ
5''
O
3
NH
1''
5'
5
1
HN
N2
HN
HN
O
O
O
I
II
1826

SYNTHESIS OF NEW SPIRO COMPOUNDS
1827
Scheme 2.
MeO
O
O
CH2N2, CHCl3–Et2O
NH
O
NH
OMe
HN
HN
N
O
O
N
H
O
I
III
O
NH
O
OMe
HN
N
N
O
A
signal at δC 68.96 ppm was assigned to the spiro car-
bon atom, in keeping with published data [10]. Spiro
compound II displayed a strong molecular ion peak in
the mass spectrum (m/z 336). Obviously, the first step
in the reaction of I with hydrazine is condensation at
the chalcone carbonyl group, and the second step is
intramolecular cyclization via addition of the second
nucleophilic center at the C=C bond [11].
tion of spiro-fused pyrazole A which undergoes tau-
tomerization into compound III.
Cycloaddition of benzonitrile oxides to α,β-unsatu-
rated ketones was studied fairly poorly. Azizian et al.
[20] reported on regioselective cycloaddition of
ethoxycarbonylformonitrile oxide to 3-(2-aryl-2-oxo-
ethylidene)indol-2-ones with formation of spiro oxy-
indoles, the fraction of one regioisomer not exceeding
3%. Highly regioselective cycloaddition of 3,4-dime-
thoxybenzonitrile oxide (generated from 3,4-dimethox-
ybenzaldehyde oxime by the action of Chloramine T)
to 3[(E)-2-oxophenylethylidene]indol-2-one was also
described [21].
Chalcones having a strongly polarized double C=C
bond are capable of participating in 1,3-dipolar cyclo-
addition reactions. Reactions of various chalcone
derivatives with diazomethane were studied previously
[12–17], but the available data concerning the product
structure still remain contradictory [18, 19].
We performed 1,3-dipolar cycloaddition of 3,4-di-
methoxybenzonitrile oxide (generated in situ from
3,4-dimethoxybenzaldehyde oxime by the action of
N-chlorobenzenesulfonamide sodium salt trihydrate) to
compound I on heating in boiling ethanol over a period
of 3 h. The reaction was completely regioselective, and
the product was methyl 4-[3′-(3,4-dimethoxyphenyl)-
2-oxo-1H,4′H-spiro[indole-3,5′-isoxazol]-4′-ylcar-
bonyl]phenylcarbamate (IV) which was isolated in
35% yield (Scheme 3).
We examined the reaction of compound I with
diazomethane in chloroform–diethyl ether, and the
1
product structure was studied by IR and H and
13C NMR spectroscopy. The results showed that 1,3-di-
polar cycloaddition of diazomethane to compound I
leads to the formation of methyl 4-(2-oxo-1′,5′-dihy-
dro-1H-spiro[indole-3,4′-pyrazol]-3′-ylcarbonyl)phen-
ylcarbamate (III) (Scheme 2). In the 13C NMR spec-
trum of III, the spiro carbon atom (C4′) resonated at
δC 81.10 ppm), and the signal from the sp3-hybridized
C5 atom in the pyrazole ring appeared at δC 45.22 ppm.
Presumably, the process involves intermediate forma-
The structure of compound IV was confirmed by
1
the IR, H NMR, and mass spectra. The position of
1
signals in the H NMR spectrum of IV is consistent
Scheme 3.
H
O
N
MeO
MeO
OH
OMe
PhSO2NCl Na+, Et2O, Δ
N
I
+
O
HN
OMe
O
N
O
OMe
IV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

VELIKORODOV et al.
1828
with the data reported in [20, 21]. Our attempts to
perform reactions of compound I with oximes having
electron-withdrawing substituents, as well as with
p-methoxybenzaldehyde oxime, were unsuccessful,
presumably because of reduced reactivity of the corre-
sponding benzonitrile oxides generated in situ.
A solution of diazomethane (prepared from 2 g of ni-
trosomethylurea and 6 ml of 40% potassium hydrox-
ide) in 40 ml of diethyl ether was added to a cold
solution of 1.61 g (5 mmol) of compound I in 35 ml of
chloroform [20]. The mixture was kept for 8 h at 0°C,
and the precipitate was filtered off, washed on a filter
with diethyl ether (15 ml), dried in air, and purified by
column chromatography on silica gel (100–400 μm)
using methylene chloride as eluent. Yield 1.7 g (95%),
colorless crystals, mp 152–154°C. IR spectrum, ν,
cm–1: 3330–3410 (NH); 1720, 1680 (C=O); 1620,
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
VXR-500 spectrometer (500.13 MHz) from solutions
in DMSO-d6 using tetramethylsilane as internal refer-
1
1575, 1560 (C=Carom). H NMR spectrum (DMSO-d6),
13
ence. The C NMR spectra were measured with com-
δ, ppm: 3.71 s (3H, OMe), 4.84 d and 4.97 d (1H each,
CH2, J = 10.0 Hz), 7.07–7.47 m (6H, Harom), 8.31 d
(2H, Harom, J = 8.5 Hz), 9.54 br.s (1H, NHCO), 10.75 s
(1H, NH, pyrazole), 11.53 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 45.22 (C5), 51.86 (OMe), 81.10
(C4), 109.57 (C4′), 117.55 (C3″, C5″), 119.95 (C2′),
121.29 (C1′), 126.38 (C6′), 127.39 (C1′), 130.10 (C3′),
132.51 (C2″, C6″), 135.70 (C1″), 142.29 (C5′), 145.25
(C=N), 153.77 (NHCO), 175.35 (C=O), 196.20
(3′-C=O). Found, %: C 62.45; H 4.46; N 15.27.
C19H16N4O4. Calculated, %: C 62.64; H 4.40; N 15.39.
plete decoupling from protons on a Bruker DRX 500
spectrometer at 126 MHz from solutions in the same
solvent. The IR spectra (4000–400 cm–1) were record-
ed in KBr on a Specord M82 instrument. The mass
spectra (electron impact, 70 eV) were obtained on
a Finnigan MAT INCOS 50 spectrometer. The purity
of the isolated compounds was checked by TLC on
Silufol UV-254 plates.
Methyl 4-(2-oxo-1,2,2′,4′-tetrahydrospiro[indole-
3,3′-pyrazol]-5′-yl)phenylcarbamate (II). A mixture
of 3.22 g (10 mmol) of compound I and 0.356 g
(11 mmol) of 99% hydrazine hydrate in 20 ml of
anhydrous ethanol was heated for 1 h under reflux. The
mixture was cooled, and the precipitate was filtered
off, washed on a filter with 10 ml of cold anhydrous
ethanol and 5 ml of diethyl ether, and recrystallized
from dioxane. Yield 3.2 g (95%), colorless crystals,
mp 255–257°C. IR spectrum, ν, cm–1: 3340–3400
(NH); 1740, 1680 (C=O); 1620, 1580, 1565 (C=Carom).
1H NMR spectrum, δ, ppm: 3.65 d (4-HA, J = 11.0 Hz),
3.71 s (3H, OMe), 4.03 d (4-HB, J = 11.0 Hz), 7.03–
7.17 m (3H, Harom), 7.24 d (2H, Harom, J = 8.2 Hz),
7.42 d (1H, Harom, J = 7.6 Hz), 7.93 d (2H, Harom, J =
8.2 Hz), 8.820 s (1H, NH, pyrazole), 9.54 br.s (1H,
Methyl 4-[3′-(3,4-dimethoxyphenyl)-2-oxo-
1H,4′H-spiro[indole-3,5′-isoxazol]-4′-ylcarbonyl]-
phenylcarbamate (IV). A mixture of 1.13 g
(3.5 mmol) of compound I, 0.63 g (3.5 mmol) of
3,4-dimethoxybenzaldehyde oxime, and 1.2 g
(4.5 mmol) of Chloramine B trihydrate in 25 ml of
ethanol was heated for 3 h under reflux. The precip-
itate was filtered off, the solvent was distilled off from
the filtrate under reduced pressure, the residue was
treated with diethyl ether (3×15 ml), the ether solution
was washed with a 1 N solution of sodium hydroxide
(50 ml) and water (50 ml), and dried over anhydrous
sodium sulfate. The solvent was removed, and the
residue was recrystallized from methanol to obtain
0.6 g (35%) of spiro compound IV. Colorless crystals,
mp 199–201°C. IR spectrum, ν, cm–1: 3340–3410
(NH); 1720, 1690 (C=O); 1610, 1575, 1560 (C=Carom).
1H NMR spectrum (DMSO-d6), δ, ppm: 3.70 s (3H,
NHCOOMe), 3.78 s (3H, OMe), 3.79 s (3H, OMe),
6.21 s (1H, 4-H), 6.73 d (1H, 6′′′-H, J = 7.9 Hz), 6.97 s
(1H, 2′′′-H), 7.12 t (2H, 5′-H, 6′-H, J = 7.4 Hz), 7.32 d
(1H, 5″-H, J = 8.6 Hz), 7.42 d (1H, Harom, J = 7.6 Hz),
7.44 d (1H, 4′-H, J = 7.6 Hz), 7.66 d (1H, 7′-H, J =
7.8 Hz), 7.95 d (1H, 2″-H, J = 7.9 Hz), 8.06 d (2H,
2″-H, 6″-H, J = 8.6 Hz), 10.03 br.s (1H, NHCO),
10.78 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 501
(3.3) [M]+, 322 (38.3), 294 (100), 262 (30), 234 (24.7),
13
NHCO), 10.72 br.s (1H, NH). C NMR spectrum, δC,
ppm: 43.75 (C4), 51.60 (OMe), 68.96 (C5), 109.50
(C5′), 117.84 (C3″, C5″), 122.05 (C3′), 123.50 (C2′),
126.27 (C4′), 126.74 (C1″), 128.97 (C1′), 132.24 (C2″,
C6″), 139.24 (C4″), 141.36 (C6′), 147.23 (CO2Me),
153.80 (C=N), 178.61 (C=O). Mass spectrum, m/z
(Irel, %): 336 (66.7) [M]+, 308 (100) [M – N2]+, 276
(51.9), 247 (51.5), 204 (18.5), 192 (7.4), 178 (7.8), 157
(14.8), 146 (22.2), 130 (31.0), 117 (19.3), 104 (16.7),
90 (22.2), 77 (23.7). Found, %: C 64.09; H 4.77;
N 16.48. C18H16N4O3. Calculated, %: C 64.29; H 4.76;
N 16.67.
Methyl 4-(2-oxo-1′,5′-dihydro-1H-spiro[indole-
3,4′-pyrazol]-3′-ylcarbonyl)phenylcarbamate (III).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

SYNTHESIS OF NEW SPIRO COMPOUNDS
1829
10. Azizian, J., Shaabanzadeh, M., Hatamjafari, F., and
Mohammadizadeh, M.R., Arkivoc, 2006, part (xi), p. 47.
11. Weissberger, A., Chemistry of Heterocyclic compounds,
207 (4.2), 178 (70), 146 (66.7), 116 (28.3), 90 (15.0),
77 (18.3). Found, %: C 64.58; H 4.63; N 8.30.
C27H23N3O7. Calculated, %: C 64.67; H 4.59; N 8.38.
New York: Wiley, 1967, p. 180.
12. Azarello, J., Gazz. Chim. Ital., 1906, vol. 36, p. 50.
REFERENCES
13. Smith, L.T. and Pings, W.B., J. Org. Chem., 1937,
vol. 2, p. 23.
1. Desenko, S.M. and Orlov, V.D., Azageterotsikly na
osnove aromaticheskikh nepredel’nykh ketonov (Aza
Heterocycles Based on Aromatic Unsaturated Ketones),
Khar’kov: Folio, 1998.
14. Ghate, S.G., Kaushal, R., and Deshapande, S.S.,
J. Indian Chem. Soc., 1950, vol. 27, p. 633.
15. Mustafa, A. and Freifel, A.M., J. Org. Chem., 1959,
2. Menger, F.M. and Smith, J.H., J. Am. Chem. Soc., 1969,
vol. 24, p. 1470.
vol. 91, p. 4211.
3. Grunbaum, Z., Patai, S., and Rappoport, Z., J. Chem.
Soc., 1966, p. 1133.
16. Aleksandrova, I.D., Dorofeeva, N.A., Chernova, A.V.,
and Khairullin, V.K., Zh. Org. Khim., 1978, vol. 14,
p. 1974.
4. Aston, J.G., Szasz, O., Wolley, H.W., and Brick-
17. Sayed, G.H. and Kjosen, N., Indian J. Chem., Sect. B,
wedde, F.G., J. Chem. Phys., 1946, vol. 14, p. 67.
1980, vol. 19, p. 980.
5. Dhar, D.N., The Chemistry of Chalcones and Related
Compounds, New York: Wiley, 1981.
18. Levai, A., Cziaky, Z., Jeko, J., and Szabo, Z., Indian J.
Chem., Sect. B, 1996, vol. 35, p. 1091.
6. Raiford, L.C. and Zutrikin, J.B., J. Am. Chem. Soc., 1933,
19. Pijewska, L., Kamecki, J., and Perka-Karolezak, W.,
vol. 55, p. 1125.
Pharmazie, 1993, vol. 48, p. 254.
7. Wiley, R.H., Jarboc, C.H., and Hayes, F.N., J. Org.
Chem., 1958, vol. 23, p. 732.
20. Azizian, J., Morady, A.V., and Jadidi, K., Synth.
Commun., 2000, vol. 30, p. 537.
8. Pereyaslova, D.G., Bondarenko, V.E., and Krasovits-
kii, B.M., Khim. Geterotsikl. Soedin., 1969, p. 114.
9. Suchehar, S.P. and Singh, A.K., J. Indian Chem. Soc.,
21. Izbrannye metody sinteza i modifikatsii geterotsiklov
(Selected Methods for the Synthesis and Modification
of Heterocycles), Kartsev, V.G., Ed., Moscow: IBS,
2004, vol. 3.
1985, vol. 62, p. 142.
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