Facile synthesis of 3-spiroindolines

Article abstract of DOI:10.1002/hc.10020

Cyanoacetyldiazoindol-2-one (3), the condensation product of cyanoacetohydrazide with isatin (1), could be cyclized in acidic medium via its C=N group and its enolic OH to give cyanomethyloxadiazole-spiroindoline (4). The presence of the methylcyano side

Full text of DOI:10.1002/hc.10020

Heteroatom Chemistry
Volume 13, Number 3, 2002
Facile Synthesis of 3-Spiroindolines
Yehia A. Allam and Galal A. M. Nawwar
Pesticides Laboratory, National Research Center, Cairo, Egypt
Received 16 April 2001; revised 9 July 2001
3-cyanoacetyldiazoindol-2-one (3). It showed the 1H
ABSTRACT: Cyanoacetyldiazoindol-2-one (3), the
condensation product of cyanoacetohydrazide with
isatin (1), could be cyclized in acidic medium
via its C N group and its enolic OH to give
cyanomethyloxadiazole-spiroindoline (4). The pres-
ence of the methylcyano side chain could be invested—
through oximation, diazotization, or condensation
with aldehydes—to form polyfunctional spiroindo-
lines 5, 8–10. Also, a second route for preparing
the title compound could be achieved through a nu-
cleophilic attack on position 3 in the isatin deriva-
tives, followed by subsequent ring closure to give 6
NMR methylene signal and the IR CN absorption
already detected in 2, while its mass spectral data
was compatible with C11H8N4O2 (m/z = 228).
When the indoline (3) was refluxed in acetic acid,
a new compound having the same molecular for-
mula as the parent was obtained. It had similar spec-
tral characteristics of 3, but showed only one IR CO
1
absorption, and the H NMR methylene singlet ap-
peared at lower field = 4.4 compared to the sin-
glet observed in 3 at = 4.2; the product also had
a lower melting point and was detected at a differ-
ent RF value. According to this information and that
contained in a previous report [6], the oxadiazolo-2-
spiroindoline structure (4) was assigned to this prod-
uct. It was probably formed through an intracycliza-
tion involving the enolic OH and the C N group.
Starting with 4, a number of spiro compounds
could be obtained via simple procedures. Thus, when
it was treated with nitrous acid, the oximino deriva-
tive (5a) was obtained, which showed a molecular
ion peak at m/z = 257 and an additional (D2O ex-
changeable) singlet at = 13.85 with the absence of
the methylene one.
C
and 7. 2002 Wiley Periodicals, Inc. Heteroatom Chem
13:207–210, 2002; Published online in Wiley Interscience
(www.interscience.wiley.com). DOI 10.1002/hc.10020
INTRODUCTION
The reactivity and ease of preparation of cyanoaceto-
hydrazide (2) can be utilized in heterocyclic synthe-
sis. Previously, we have reported its utility in prepar-
ing pyridines [1] and pyrazoles [2]. In continuation,
the present work is concerned with the preparation
of 3-spiroindolines starting with 2, because of the
biological importance of this class of compounds
[3–5] (Scheme 1).
On the other hand, when the same reaction was
repeated with 3 instead of 4, the reported 3-hydrazo-
2-oxoindole was formed [7] through decyanoacety-
lation, a result which gave further confirmation of
stucture 4.
Furthermore, diazotization of 4, using phenyl-
diazonium chloride, afforded the corresponding
phenylhydrazone (5b). This structure was deduced
from element analyses, spectral data and its mass
spectrum, which showed the molecular ion peak at
m/z = 332. Compound 4 condensed also with sali-
cylaldehyde with the formation of the correspond-
ing coumarin derivative (8) in which the coumarin
RESULTS AND DISCUSSION
Cyanoacetohydrazide condensed readily with isatin
(1) in acetic acid, affording the corresponding
Correspondence to: Galal A. M. Nawwar; e-mail: g.nawwar@link.
net.
c
2002 Wiley Periodicals, Inc.
207

208 Allam and Nawwar
via the direct Michael addition to the C N group
in 3.
Furthermore, 2-aminothiophenol reacted with
1 to afford a single compound having one IR CO
absorption, and two (D2O exchangeable 1H each)
1H NMR signals in addition to those of the aro-
matic protons. From these data, the benzothiazolo-
spiroindoline structure (7) was assigned to this
product. Although compound 7 had previously
been obtained via the deoxygenation of 3-(2-
nitrophenylthio)indole with triethyl phosphite, to-
gether with other products [11], the present method
offers a simple route for its preparation as a sole
product in a very good yield.
EXPERIMENTAL
Melting points are uncorrected and were taken on
an Electrothermal 9100 apparatus. IR spectra were
recorded with a Carl Zeiss spectrophotometer model
1
UR10 in KBr pellets. H NMR spectra were deter-
mined with a Jeol 270 MHz (internal TMS). Mass
spectra were recorded with a Finigan SSQ 7000 mass
spectrometer. Microanalyses were performed by the
Central Service Laboratory at Cairo University and
the Microanalytical Unit at the National Research
Center.
SCHEME 1
1
4-H appeared at = 9.10 in its H NMR spectrum
1
and the coumarinyl CO at 1720 cm in its IR
spectrum.
3-Cyanoacetyldiazo-indol-2-(1H)-one (3) and
Benzothiazol-(3H)-2-spiro-3-indol-2-(1H)-one
(7)
The reactions of 4 with each of 2-nitrobenz-
aldehyde, thiophen-2-aldehyde, and 2-furaldehyde
were carried out to give the corresponding benzyli-
denes (9a-c) in which the ylidene H was detected
A mixture of 1 (10 mmol) with 2 (10 mmol) or 1
(10 mmol) with 2-aminothiophenol (10 mmol) was
refluxed in ethanol (30 ml) for 1 h. A precipitate was
formed in the hot solution, filtered off, and crystal-
lized.
at
8.9 [8]. Compound 9a was reduced with Zn
dust in acetic acid, and the product lacked both
the IR CN absorption and the ylidene signal. In-
stead, a new (D2O exchangeable) one was found at
= 6.80–7.00 (2H) together with a singlet (1H) at
= 8.45; its mass spectral data gave a molecular ion
peak at m/z = 331. From these data and previous re-
sults [2], the aminoquinolino structure (10) was as-
signed to this product. When compound 3 was re-
fluxed with malononitrile in ethanol/triethylamine,
a new product with a molecular formula com-
patible with C14H10N6O2 (m/z = 294) was obtained.
It showed a twin CN absorption besides the in-
doline CO one and four (D2O exchangeable) sin-
glets at = 3.75 (1H), 4.60 (2H), 5.95 (2H), and
9.90 (1H). Based on these data as well as previ-
ous reports [9], the indolin-3-spiropyridine struc-
ture (6) was indicated. It is assumed that an intra-
ylidene exchange occurred under the experimental
conditions used [10], followed by spontaneous attack
by malononitrile in a Michael-type addition to give
6, as the spectral data excluded a product formation
3-Cyanoacetyldiazo-indol-2-(1H)-one (3)
M.p. 230–232 C; yield 90% (ethanol). 1H NMR (D2O,
DMSO-d6, TMS) 4.20 (s, 2H, CH2), 6.90–7.10 (m,
2H, indole 5-H, 6-H), 7.45–8.10 (m, 2H, indole 4-H,
7-H), 10.85 (s, 1H, indole NH), 11.60 (s, 1H, NH).
IR (KBr) 3250, 3200 (NH), 2250 (CN), 1730, 1700
(2CO). MS: m/z (M+ 228). Anal. Calcd. for C11H8N4O2
(228.204): C, 57.89; H, 3.53; N, 24.55. Found: C,
57.70; H, 3.40; N, 24.30.
Benzothiazol-(3H)-2-spiro-3-indol-2-(1H)-one
(7)
1
M.p. 228 C; yield 85% (acetic acid). H NMR (D2O,
DMSO-d6, TMS) 6.50–6.65 (m, 2H, indole 5-H, 6-H),
6.85–7.35 (m, 6H, indole 4-H, 7-H and benzothia-
zole H), 7.55 (s, 1H, benzothiazole NH), 10.40 (s, 1H,

Facile Synthesis of 3-Spiroindolines 209
indole NH). IR (KBr) 3200 (NH), 1700 (CO). Anal.
Calcd. for C14H10N2O S (254.304): C, 66.12; H, 3.96;
N, 11.02; S, 12.61. Found: C, 66.00; H, 3.70; N, 10.80;
S, 12.30.
Reactions of 4 with Aldehydes or 3
with Malononitrile
General Procedure. A mixture of 4 (10 mmol)
with an equimolecular amount of the proper alde-
hyde, or 3 (10 mmol) with malononitrile (10 mmol)
was refluxed in ethanol (30 ml) in the presence of
triethylamine (3–4 drops) for 1–2 h. A precipitate
formed in the hot solution; it was collected by fil-
tration and finally crystallized from acetic acid.
5-Cyanomethyl-1,3,4-oxadiazol-(3H)-2-spiro-3-
indol-2-(1H)-one (4)
Compound 3 (10 mmol) was refluxed in acetic acid
(25 ml) for 2 h. The solution was partially con-
centrated, cooled, the precipitate that had formed
was filtered off and crystallized from acetic acid:
M.p. 207–209 C, yield 80%. 1H NMR (D2O, DMSO-d6,
TMS) 4.40 (s, 2H, CH2), 6.90–7.05 (m, 2H , indole
5-H, 6-H), 7.35–7.45 (m, 2H , indole 4-H, 7-H), 11.25
(s, 1H, indole NH), 12.60 (s, 1H, oxadiazole NH). IR
(KBr) 3200 (NH), 2260 (CN), 1720 (CO). MS: m/z
(M+ 228). Anal. Calcd. for C11H8N4O2 (228.204): C,
57.89; H, 3.53; N, 24.55. Found: C, 57.60; H, 3.40; N,
24.30.
1,2-Diamino-3,5-dicyano-6-hydroxypyridin-4-
spiro-3-indol-2-(1H)-one (6)
1
M.p. 222–224 C; yield 40%. H NMR (D2O, DMSO-
d6, TMS) 3.75 (br s, 1H, OH), 4.60 (s, 2H, NH2),
5.95 (s, 2H, NH2), 6.60–7.15 (m, 4H, indole H), 9.90
(br s, 1H, indole NH). IR (KBr) 3290–3100 (OH,
NH2, NH), 2220, 2200 (2CN), 1710 (CO). MS: m/z
(M+ 294). Anal. Calcd. for C14H10N6O2 (294.27): C,
57.14; H, 3.43; N, 28.56. Found: C, 57.00; H, 3.20; N,
28.30.
5-(1-Hydroxyimino)cyanomethyl-1,3,4-
oxadiazol-(3H)-2-spiro-3-indol-2-(1H)-one (5a)
5-(3-Coumarinyl)-1,3,4-oxadiazol-2-spiro-3-
indol-2-(1H)-one (8)
To a solution of 4 (10 mmol) in acetic acid (25 ml),
a solution of sodium nitrite (20 mmol in 2 ml H2O)
was added dropwise with stirring and the solution
was allowed to stand for 3 h. Water was then added to
the reaction mixture until precipitation commenced;
the solid, thus formed, was filtered off and crystal-
1
M.p. > 300 C; yield 70%. H NMR (D2O, DMSO-d6,
TMS) 6.85–7.65 (m, 8H, indole H and coumarin
5-H to 8-H), 8.60 (s, 1H, oxadiazole NH), 9.10 (s,
1H, coumarin 4-H), 11.00 (s, 1H, indole NH). IR
(KBr) 3200 (NH) , 1720, 1700 (CO). Anal. Calcd.
for C18H11N3O4 (333.29): C, 64.86; H, 3.33; N, 12.61.
Found: C, 64.70; H, 3.10; N, 12.30.
1
lized from acetic acid: M.p. > 300 C; yield 45%. H
NMR (D2O, DMSO-d6, TMS) 6.95–7.10 (m, 2H, in-
dole 5-H, 6-H), 7.40–7.60 (m, 3H, indole 4-H, 7-H
and oxadiazole NH), 11.35 (s, 1H, indole NH), 13.85
(s, 1H, OH). IR (KBr) 3280–3200 (OH, NH), 2220
(CN), 1700 (CO). MS: m/z (M+ 257). Anal. Calcd.
for C11H7N5O3 (257.206): C, 51.36; H, 2.74; N, 27.23.
Found: C, 51.20; H, 2.60; N, 27.00.
5-(2-Nitro-cinnamonitril-2-yl)-1,3,4-oxadiazol-
2-spiro-3-indol-2-(1H)-one (9a)
1
M.p. 245–247 C; yield 85%. H NMR (D2O, DMSO-
d6, TMS) 6.95–7.10 (m, 2H, indole 5-H, 6-H), 7.40–
7.60 (m, 2H, indol 4-H, 7-H), 7.85–8.25 (m, 4H,
2-NO2 Ph), 8.90 (s, 1H, ylidene H), 11.45 (s, 1H, in-
dole NH), 13.95 (br s, 1H, oxadiazole NH). IR (KBr)
3250 (NH), 2200 (CN), 1710 (CO). Anal. Calcd.
for C18H11N5O4 (361.31): C, 59.83; H, 3.07; N, 19.39.
Found: C, 59.70; H, 2.90; N, 19.10.
5-(1-Phenyldiazo)cyanomethyl-1,3,4-oxadiazol-
(3H)-2-spiro-3-indol-2-(1H)-one (5b)
Phenyldiazonium chloride was added to an ice-
cooled solution of 4 (10 mmol) in DMF (25 ml) in
the presence of Na acetate trihydrate (5 g) with stir-
ring for 10 min, then the ice bath was removed and
stirring was continued at room temperature. After
3 h, water was added to the solution and the precipi-
tate obtained was filtered off and crystallized from
acetic acid: M.p. 291–293 C; yield 80%. 1H NMR
(D2O, DMSO-d6, TMS) 6.95–7.70 (m, 9H, indole H
and Ph), 11.40 (s, 1H, indole NH), 12.45 (s, 2H, oxa-
diazole NH and diazo NH). IR (KBr) 3250–3200
(NH), 2220 (CN), 1700 (CO). MS: m/z (M+ 332). Anal.
Calcd. for C17H12N6O2 (332.32): C, 61.44; H, 3.64; N,
25.29. Found: C, 61.20; H, 3.40; N, 25.00.
5-[1-(2-Thienyl)acrylonitril-2-yl]-1,3,4-oxadiazol-
2-spiro-3-indol-2-(1H)-one (9b)
M.p. 297–299 C; yield 80%. 1H NMR (D2O, DMSO-d6,
TMS) 6.95–7.15 (m, 2H, indole 5-H, 6-H), 7.35–7.45
(m, 2H, indole 4-H, 7-H), 7.60 (dd, J = 8 Hz, 1H, thio-
phene 3-H), 8.10 (dd, J = 8 Hz , 1H, thiophene 4-H),
8.25 (dd, J = 8Hz, 1H, thiophene 5-H), 8.75 (s, 1H,
ylidene CH), 11.20 (s, 1H, indole NH), 13.40 (s, 1H,

210 Allam and Nawwar
NH). IR (KBr) 3200, (NH), 2220 (CN), 1705 (CO).
Anal. Calcd. for C16H10N4O2S (322.334): C, 59.62; H,
3.13; N, 17.38; S, 9.95. Found: C, 59.30; H, 3.00; N,
17.10; S, 9.60.
8.45 (s, 1H, quinoline 4-H), 9.50 (br s, 1H, oxadia-
zole NH), 10.85 (s, 1H, indole NH). IR (KBr) 3250–
3200 (NH2, NH), 1710 (CO). MS: m/z (M+ 331). Anal.
Calcd. for C18H13N5O2 (331.32): C, 65.25; H, 3.95; N,
21.14. Found: C, 65.10; H, 3.80; N, 21.00.
5-[1-(2-Furyl)acrylonitril-2-yl]-1,3,4-oxadiazol-
2-spiro-3-indol-2-(1H)-one (9c)
REFERENCES
1
M.p. 292–294 C; yield 85%. H NMR (D2O, DMSO-
[1] Haggag, B. M.; Chabaka, L. M.; Allam, Y. A.; Nawwar,
G. A. M. Polish J Chem 1997, 71, 52.
[2] Nawwar, G. A. M.; Allam, Y. A. J Chem Res Synop
1993, 1, 456.
[3] Robertson, D. W. Eur Pat 178876, 1986; Chem Abstr
1986, 105, 66459z.
[4] Dandia, A.; Upreti, M.; Rani, B.; Pant, U. C. J Chem
Res Synop 1998, 752; J Chem Res Miniprint 1998,
3348.
d6, TMS) 6.85–6.95 (m, 2H, furan 3-H, 4-H), 7.05–
7.15 (m, 1H, indole 5-H), 7.35–7.65 (m, 3H, indole
6-H, 4-H, 7-H), 8.25 (s, 2H, furan 5-H and ylidene
CH), 11.35 (s, 1H, indole NH), 13.90 (br s, 1H, NH).
IR (KBr) 3200 (NH), 2220 (CN), 1710 (CO). Anal.
Calcd. for C16H10N4O3 (306.27): C, 62.74; H, 3.29; N,
18.29. Found: C, 62.60; H, 3.10; N, 18.00.
[5] Schwartz, R. C.; Hirsch, C. F.; Sigmuna, J. M;
Pettibone, D. J. US Patent 4 803 217, 1989; Chem
Abstr 1989, 111, 132572h.
[6] Dopp, D.; Gomaa, M. A. M.; Henkel, G.; Nour El-Din,
A. M. J Chem Soc, Perkin Trans 2 1996, 573.
[7] Diesbach, H.; Heppner, E. Helv Chim Acta 1949, 32,
687.
[8] Nawwar, G. A. M.; Shafik, N. A. Collect Czech Chem
Commun 1995, 60, 2200.
[9] Nawwar, G. A. M. Quatar Univ Sci J 1994, 14(2),
252.
5-(2-Aminoquinolin-3-yl)-1,3,4-oxadiazol-2-
spiro-3-indol-2-(1H)-one (10)
To a solution of 9a (10 mmol) in acetic acid (20 ml)
maintained at 60 C, Zn dust (0.5 g) was added por-
tionwise with stirring and this was continued for 2 h.
Afterwards, the mixture was filtered, the filtrate con-
centrated, and the precipitate that had been collected
was crystallized from acetic acid: M.p. < 300 C;
[10] Hammad, M. A.; Nawwar, G. A. M.; Gemeie, G. E.;
EL-nagdi, M. H. Heterocycles 1985, 23, 2177.
[11] Jackson, A. H.; Johnson, D. N.; Shannon, P. V. R.
J Chem Res Synop 1988, 9, 272.
1
yield 35%. H NMR (D2O, DMSO-d6, TMS) 6.80–
7.00 (m, 4H, indole 5-H, 6-H and NH2), 7.15–7.70
(m, 6H, indole 4-H, 7-H and quinoline 5-H to 8-H),