Reaction of 2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)acetic acids esters with phenylhydrazine

Article abstract of DOI:10.1134/S107042800710017X

2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)acetic acids esters reacted with phenylhydrazine yielding products of the regioselective addition of the latter in the α-(C²)-position of the exo ethylene bond, (2-oxo-2,3-dihydro-1H-indol-3-yl)(2-phenylhydrazino)acetic acids esters.

Full text of DOI:10.1134/S107042800710017X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1508−1511. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © E.N. Koz’minykh, V.I. Goncharov, V.O. Kozminykh, K.Sh. Lomidze, A.N. Berezin, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 10, pp. 1514−1517.
Reaction of 2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)acetic Acids
Esters with Phenylhydrazine
E. N. Koz’minykha, V. I. Goncharovb, V. O. Koz’minykhc,
K. Sh. Lomidzec, and A. N. Berezinc
aMoscow State University of Technology and Management, Perm Division, Perm,614065 Russia
e-mail: kvoncstu@yahoo.com
bStavropol State Medical Academy, Stavropol, Russia
cPerm State Pedagogical University, Perm, Russia
Received June 28, 2006
Abstract—2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)acetic acids esters reacted with phenylhydrazine yielding
products of the regioselective addition of the latter in the α-(C2)-position of the exo ethylene bond, (2-oxo-2,3-
dihydro-1H-indol-3-yl)(2-phenylhydrazino)acetic acids esters.
DOI: 10.1134/S107042800710017X
esters of 2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetic
acids (I, X = OAlk) differently reacted with hydrazine.
Thus in acetic acid formed a mixture of products of
α-addition to the exo ethylene bond with respect to the
ester group (followed by recyclization), 3,3a,5,9b-tetra-
hydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione (V)
and of β-addition, 1-acetyl-5'H-spiro[indole-3,3'-pyr-
azolidine]-2,5'(1H)-dione (VI) [9, 10]. The addition of
aromatic amines to the exocyclic multiple bond of
substrates (I, X = OAlk) in contrast to hydrazine occurred
regioselectively into the α-position leading to the forma-
tion of 2-arylamino-2-(2-oxo-2,3-dihydro-1H-indol-3-
yl)acetic acid esters VII [11, 12] (Scheme 1). According
to our findings the attack of mono- and binucleophiles is
directed prevailingly on the electrophilic site α-(C2) of
oxindolylideneacetates (I, X = OAlk) [9, 12–14].
A reaction of 3-(2-oxo-2-X-ethylidene)-1H-indol-2-
ones (I, X = Alk, Ar, Ht) with hydrazines under mild
conditions is known to provide 2',4'-dihydrospiro-[indol-
3,3'-pyrazol]-2(1H)-ones II [1–7] (Scheme 1). Com-
pounds II form apparently as a result of an intramolecular
spiroheterocyclization of intermediate 3-(2-hydrazono-
2-X-ethylidene)-1H-indol-2-ones III at the 3-exo ethyl-
ene bond into the β-position (C3) of the indole ring. In
some cases stable hydrazones (III, X =Ar) were isolated
and identified [5, 8] (Scheme 1).
At treating 3-(2-aryl-2-oxoethylidene)-1H-indol-2-
ones (I, X = Ar) with 2-hydrazino-1H-benzimidazole
formed both the corresponding hydrazones (III, R1 =
Me,Ac) and products of cyclization at the carbonyl group
of lactam, 3-aryl-1-(1H-benzimidazol-2-yl)-1H-pyrid-
azino[3,4-b]indoles (IV, R1 = H) [8] (Scheme 1). It was
reported that the heating of phenacylideneoxindole (I,
R1 = R2 = H, X = Ph) with hydrazine resulted in reduction
to oxindole and elimination of phenylglyoxal hydrazone
[1, 2]. The hydrazine attack occurred here evidently at
the electron-deficient site α-(C1') of indolinone I. Note
that some spiroheterocycles II exhibited antimicrobial
activity [7], and compounds III and IV, insecticidal action
[8]; these facts demonstrated the practical importance
of products of N-nucleophilic transformations of
ylideneoxindoles I.
Thus the published data show that to the attack of
hydrazines (and amines) are subjected four electrophilic
sites of ylideneoxindoles (I, X = Alk, Ar, Ht, OAlk): at
the atioms C2 (NC2=O), C3 (β-position of 3-exo ethylene
bond), C1' (α-position), and C2' (XC2'=O); it is difficult
a priori predict the direction of the nucleophilic attack.
We established that by treating with phenylhydrazine
2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-acetic acids
esters Ia–If at boiling the mixture in ethanol esters of
(2-oxo-2,3-dihydro-1H-indol-3-yl)-(2-phenylhydrazino)-
acetic acids VIIIa–VIIIf were obtained in a prepara-
tive yield (Scheme 2). Compounds VIII result from
We recently showed that unlike X-acyl derivatives of
ylideneoxindoles (I, X =Alk, Ar, Ht) similar in structure
1508

REACTION OF 2-(2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)ACETIC ACIDS
1509
a regioselective addition of the primary amino group of
phenylhydrazine to the exo ethylene bond of substrate I
not in the β-(C3')-position as might be expected by
analogy with the similar reactions of acylmethyl-
eneoxindoles (I, X = Alk, Ar, Ht) but in the α-(C2)-
position with respect to the ester moiety. Compounds
obtained VIIIa–VIIIf are colorless or off-yellow crystal-
line substances insoluble in water, sparingly soluble in
the common organic solvents, and readily soluble in DMF
and DMSO.
Scheme 1.
O
X
R2
O
N
R1
I
R3
H
N
R2
N
H
X
N
N
R3
N
N
X
N
R3 NHNH2
_H2O
N
N
N
R2
R2
O
O
N
R1
Ar
R1
II
IV
III
R1 = H, Alk, All, Ac; R2 = H, Alk, All, AlkO, Ac, Hlg; X = Alk, Ar, Ht; R3 = H, Ph, Ht, Ac.
O
N
O
H
N
H
O
O
AlkO
X
H
NHAr
O
N
N
R2
N
R2
H
Ar NH2
N2H4 H2O, AcOH
+
O
O
_ AlkOH
R1 = H, Ac; R2 = H
R1 = H, Ac;
R2 = H, Br
N
R1
I (X = OAlk)
N
N
O
R1
Ac
Ac
V
VII
VI
Scheme 2.
O H
O
OAlk
O
N Ph
H
AlkO
H
N
AlkO
N
O
Ph
R2
R2
R2
N
Ph NHNH2
O
H
O
N
N
R1
N
R1
R1
IX
_
_
Iа If
VIIIа VIIIf
I, VIII, Alk = Me: R1 = H, R2 = H (a), Br (b); R1 = Ac, R2 = H (c); Alk = Et: R1 = H, R2 = H (d), Br (e); R1 = Ac, R2 = H (f).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

KOZ’MINYKH et al.
1510
In the IR spectra of compounds VIII are present well
(2-Oxo-2,3-dihydro-1H-indol-3-yl)-(2-phenyl-
hydrazino)acetic acids esters VIIIa–VIIIf. To a solu-
tion of 10 mmol of esters Ia–If in 70–100 ml of ethanol
was added at stirring 1.08 g (10 mmol) of phenyl-
hydrazine, and the mixture was boiled for 0.5–2 h (TLC
monitoring). The separated precipitate was filtered off
and recrystallized from ethanol.
consistent with the structure wide bands of the stretching
vibrations of amino groups from the phenylhydrazine
fragment and of the amide group of lactam at 3130–
3293 cm–1, and also absorption bands of carbonyl groups
of ester (1720–1732 cm–1) and lactam (1673–1696 cm–1).
1
The proton signals in the H NMR spectra of indo-
linones VIIIa–VIIIf appear in a double set, in particular,
pairs of signals are present from two vicinal methine
protons of the fragment C2H–C3'H at δ 4.11–4.38 and
4.35–4.73 ppm. The character of these signals indicates
the presence of at least two diastereomers, and the
findings obtained are in agreement with the spectral
characteristics of 2-arylamino-2-(2-oxo-2,3-dihydro-1H-
indol-3-yl)acetic acids esters VII [12]. The presence of
a pair of coupled methine protons permits a rejection of
the regioisomeric structure of 2-oxo-3-(2-phenylhy-
drazino)-2,3-dihydro-1H-indol-3-ylacetic acids esters IX
containing a methylene group CH2 (Scheme 2). It was
not possible to exclude preliminary the formation of the
latter taking into account published data, in particular,
on the β-addition of amines to the exo ethylene bond of
ylideneoxindoles I [15].
Methyl (2-oxo-2,3-dihydro-1H-indol-3-yl)(2-phenyl-
hydrazino)acetate (VIIIa). Yield 2.46 g (79%), mp 148–
149°C. IR spectrum, ν, cm–1: 3287 (C6H5NHNH), 3130–
3185 (N1HCO, C6H5NHNH), 1728 (C=Oester), 1696
(N1HCO), 1618, 1597, 1466. 1H NMR spectrum, δ, ppm:
3.65 s (3H, COOCH3), 3.82 s (3H, COOCH3), 4.18 d,
4.32 d (2H, C3'H, C2H, J 4.3 Hz), 4.47 d, 4.65 d (2H,
C3'H, C2H, J 5.6 Hz), 5.22 br.s (2H, 2C6H5NHNH),
6.62 s (1H, C6H5NHNH), 6.77–7.36 group of signals
(18H, 2 C6H4, 2C6H5), 7.38 s (1H, C6H5NHNH), 10.26 s
(1H, N1'H), 10.64 s (1H, N1'H). Mass spectrum, m/z (Irel,
%): 311 (14) [M]+, 252 (3) [M – COOCH3]+ or
[C15H14N3O]+, 203 (37) [M – C6H5NHNH2]+ or
[C11H9NO3]+, 172 (35) [M – C6H5NHNH2 – OCH3]+ or
[C9H6NO2]+, 147 (40) [C9H9NO]+ or [C8H5NO2]+, 144
(34) [M – C6H5NHNH2 – COOCH3]+ or [C9H6NO]+, 133
(100) [oxindole = C8H7NO]+, 108 (38) [C6H5NHNH2]+,
92 (72) [C6H5NH]+, 77 (61) [C6H5]+. Found, %: C 65.29;
H 5.72; N 13.34. C17H17N3O3. Calculated, %: C 65.58;
H 5.50; N 13.50. M 311.33.
Thus the reaction of compounds Ia–If with hydrazine
proceeds as a regioselective addition of the latter to the
exo ethylene bond into the α-position with respect to the
ester group. The changed nucleophiles addition direction,
in particular, that of phenylhydrazine, into the α-C2-
position of oxindolylideneacetates (I, X = OAlk) [11–
14] unlike the usual β-C3'-attack of 3-acylmethylene-1H-
indol-2-ones (I, X = Alk, Ar, Ht), probably is caused by
stronger electron-acceptor effect of the ester group in
the former substrates compared to the het(aroyl) moiety
of the latter.
Methyl (5-bromo-2-oxo-2,3-dihydro-1H-indol-3-
yl)(2-phenylhydrazino)acetate (VIIIb). Yield 2.50 g
(64%), mp 166–167°C. IR spectrum, ν, cm–1: 3275
(C6H5NHNH), 3140–3192 (N1HCO, C6H5NHNH), 1722
1
(C=Oester), 1688 (N1HCO), 1623, 1605, 1470. H NMR
spectrum, δ, ppm: 3.72 s (3H, COOCH3), 3.86 s (3H,
COOCH3), 4.23 d, 4.38 d (2H, C3'H, C2H, J 4.6 Hz),
4.54 d, 4.73 d (2H, C3'H, C2H, J 5.8 Hz), 5.48 br.s (2H,
2C6H5NHNH), 6.55 s (1H, C6H5NHNH), 6.75–7.48
group of signals (16H, 2C6H3, 2C6H5), 7.52 s (1H,
C6H5NHNH), 10.15 s (1H, N1'H), 10.47 s (1H, N1'H).
Found, %: C 52.12; H 3.97; Br 20.23; N 10.59.
C17H16BrN3O3. Calculated, %: C 52.32; H 4.13; Br 20.48;
N 10.77.
EXPERIMENTAL
IR spectra of compounds VIII were recorded on
a spectrophotometer Specord M-80 from mulls in mineral
oil. 1H NMR spectra of indolinones VIII were registered
on a spectrometer Bruker DRX-500 (500.13 MHz) in
DMSO-d6, internal reference TMS. Mass spectrum of
compound VIIIa was measured on a Finnigan MAT
INCOS-50 instrumen at the direct admission mode
(electron impact). The reactions progress was monitored
and the homogeneity of compounds VIIIa–VIIIf was
checke by TLC on Silufol UV-254 plates in a system
benzene–ether–acetone, 10:9:1, development in iodine
vapor. Initial esters Ia–If were obtained by procedures
[16–18].
Methyl (1-acetyl-2-oxo-2,3-dihydroO-1H-indol-3-
yl)(2-phenylhydrazino)acetate (VIIIc). Yield 2.60 g
(73%), mp 137–138°C. IR spectrum, ν, cm–1: 3265
(C6H5NHNH), 3135–3172 (N1CO, C6H5NHNH), 1720
(C=Oester), 1685, 1673 (N1CO), 1610, 1590, 1455. 1H NMR
spectrum, δ, ppm: 2.62 s (3H, CH3CO), 2.66 s (3H,
CH3CO), 3.60 s (3H, COOCH3), 3.73 s (3H, COOCH3),
4.12 d, 4.24 d (2H, C3'H, C2H, J 4.0 Hz), 4.35 d, 4.56 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

REACTION OF 2-(2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)ACETIC ACIDS
1511
(2H, C3'H, C2H, J 5.2 Hz), 5.40 br.s (2H, 2C6H5NHNH),
REFERENCES
6.80 s (1H, C6H5NHNH), 6.84–7.48 group of signals
(18H, 2C6H4, 2C6H5), 7.58 s (1H, C6H5NHNH). Found,
%: C 64.70; H 5.58; N 11.77. C19H19N3O4. Calculated,
%: C 64.58; H 5.42; N 11.89.
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Its Derivatives), Kishinev: Shtiintsa, 1973, p. 129.
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Khim. Geterotsikl. Soedin., 1973, p. 40.
Ethyl (2-oxo-2,3-dihydro-1H-indol-3-yl)(2-phenyl-
hydrazino)acetate (VIIId). Yield 2.63 g (81%), mp 150–
151°C. IR spectrum, ν, cm–1: 3293 (C6H5NHNH), 3135–
3182 (N1HCO, C6H5NHNH), 1732 (C=Oester), 1692
(N1HCO), 1615, 1604, 1470. 1H NMR spectrum, δ, ppm:
1.20 t (3H, COOCH2CH3), 1.26 t (3H, COOCH2CH3),
3.82 q (2H, COOCH2CH3), 3.88 q (2H, COOCH2CH3),
4.16 d, 4.27 d (2H, C3'H, C2H, J 4.5 Hz), 4.50 d, 4.66 d
(2H, C3'H, C2H, J 5.7 Hz), 5.44 br.s (2H, 2C6H5NHNH),
6.57 s (1H, C6H5NHNH), 6.75–7.32 group of signals
(18H, 2C6H4, 2C6H5), 7.32 s (1H, C6H5NHNH), 10.47 s
(1H, N1'H), 10.65 s (1H, N1'H). Found, %: C 66.52;
H 5.67; N 13.11. C18H19N3O3. Calculated, %: C 66.45;
H 5.89; N 12.91.
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Ethyl (5-bromo-2-oxo-2,3-dihydro-1H-indol-3-
yl)(2-phenylhydrazino)acetate (VIIIe). Yield 2.63 g
1
(68%), mp 158–159°C. H NMR spectrum, δ, ppm:
1.18 t (3H, COOCH2CH3), 1.23 t (3H, COOCH2CH3),
3.77 q (2H, COOCH2CH3), 3.84 q (2H, COOCH2CH3),
4.11 d, 4.23 d (2H, C3'H, C2H, J 4.9 Hz), 4.46 d, 4.61 d
(2H, C3'H, C2H, J 6.2 Hz), 5.72 br.s (2H, 2C6H5NHNH),
6.43 s (1H, C6H5NHNH), 6.65–7.33 group of signals
(16H, 2 C6H3, 2C6H5), 7.69 s (1H, C6H5NHNH), 10.73 s
(1H, N1'H), 10.90 s (1H, N1'H). Found, %: C 53.61;
H 4.58; Br 19.87; N 10.52. C18H18BrN3O3. Calculated,
%: C 53.48; H 4.49; Br 19.77; N 10.39.
Ethyl (1-acetyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-
(2-phenylhydrazino)acetate (VIIIf). Yield 2.60 g
1
(70%), mp 144–145°C. H NMR spectrum, δ, ppm:
2.55 s (3H, CH3CO), 2.63 s (3H, CH3CO), 1.22 t (3H,
COOCH2CH3), 1.28 t (3H, COOCH2CH3), 3.78 q (2H,
COOCH2CH3), 3.83 q (2H, COOCH2CH3), 4.15 d, 4.28
d (2H, C3'H, C2H, J 4.2 Hz), 4.38 d, 4.61 d (2H, C3'H,
C2H, J 5.6 Hz), 5.53 br.s (2H, 2C6H5NHNH), 6.85 s (1H,
C6H5NHNH), 6.90–7.57 group of signals (18H, 2C6H4,
2C6H5), 7.71 s (1H, C6H5NHNH). Found, %: C 65.09;
H 5.71; N 11.27. C20H21N3O4. Calculated, %: C 65.38;
H 5.76; N 11.44.
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Zh. Obshch. Khim., 1996, vol. 66, p. 1128.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007