Synthesis of novel spiro cyclic 2-oxindole derivatives of 6-amino-4H-pyridazine via [3+3] atom combination utilizing chitosan as a catalyst

Article abstract of DOI:10.1055/s-0028-1087558

Azaenamines were reacted with 3-cyanomethylidene-2-oxindoles using chitosan catalyst to yield spirocyclic 2-oxindole derivatives of 6-amino-4H-pyridazine and fused pyridazinoquinazolines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087558

LETTER
625
Synthesis of Novel Spiro Cyclic 2-Oxindole Derivatives of 6-Amino-4H-Pyrida-
zine via [3+3] Atom Combination Utilizing Chitosan as a Catalyst
S
ynthesi
s
s
of
N
ove
m
l
Spiro Cyclic 2-O
x
a
indole Deri
i
vatives
l
of 6-Amino-4
A
H
-Pyridazine bdelshafy Abdelhamid*a,b
a
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Fax 002(02)35727556; E-mail: ismail_shafy@yahoo.com
b
Institut für Organische Chemie der Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Received 5 November 2008
2-oxindoles 3, where only further cyclization occurred in
the case of 6-aminopyridazines, while in the case of 4-
aminopyridazines no further cyclization occurred. Thus
the reaction of 4c with 3a results in the formation of prod-
uct of cyclization with methanol elimination to give com-
pound 9.16 The formation of 9 rather than 8 also excludes
the initial addition of NH to the double bond in 2 to give
6. The structure of compound 9 was confirmed based on
MS and NMR spectra that revealed the absence of the
OMe group.17 Also reacting 4d with 3a has resulted in the
formation of a product that can be formulated as 10. It is
believed that initially 8 is formed and cyclized into 10 (cf.
Scheme 2).
Abstract: Azaenamines were reacted with 3-cyanomethylidene-2-
oxindoles using chitosan catalyst to yield spirocyclic 2-oxindole de-
rivatives of 6-amino-4H-pyridazine and fused pyridazinoquinazo-
lines.
Key words: aza-enamine, chitosan, Michael addition, 3-spiro-
pyridazines-2-oxindoles
The heterocyclic spirooxindole ring system is a widely
distributed structural framework present in a number of
pharmaceuticals and natural products,1,2 The unique struc-
tural array and the highly pronounced pharmacological
activity displayed by the class of spirooxindole com-
pounds have made them attractive synthetic targets.3–6
Azaspiro derivatives are well known,3–8 but the prepara-
tion of the corresponding oxa analogues has evolved at a
relatively slow pace.9
R
O
R
CN
O
O
CN
2
Me
N
O
+
NH
Ar
In conjunction to our interest in developing syntheses for
biologically interesting pyridazines,10–12 the possibility of
[3+3] atom combination of pyruvaldehyde-1-arylhydra-
zones 4a–d with 3-cyanomethylidene-2-oxindoles 3a,b
through Michael addition reaction was studied. Com-
pound 3 was prepared by reacting isatin 1 with 2 in the
presence of chitosan as a catalyst (as shown in Scheme 1)
or in the presence of triethyamine as described in the liter-
ature.13 Chitosan, which is an amino polysaccharide, was
also used as a substitute to the carcinogenic piperidine and
pyridine catalysts and the yield (%) was found to be high-
er in the case of chitosan (cf. Table 1). Compounds 4a,b
reacted with compound 3a in the presence of chitosan to
yield spiropyridazines that may be formulated as 6 or 8.14
If the initial addition involves the NH of aza-enamine to
the activated double bond in 3a, Michael adduct 6 would
be formed. On the other hand, if the initial addition in-
volves the hydrazone CH to the activated double bond in
3a, Michael adduct 8 would be formed. The NOE differ-
ence experiment revealed enhancement of aryl protons on
irradiating the NH2 group at d = 6.14 ppm, and this is in
agreement with structure 8 (cf. Scheme 1).15 The structure
of compounds 8 was also simply elucidated chemically by
reacting pyruvaldehyde-1-arylhydrazones 4c,d (carrying
substituent on ortho position) with 3-cyanomethylidene-
N
chitosan
N
H
H
1
4a Ar = Ph
4b Ar = 2-ClC6H4
4c Ar = 2-MeO2CC6H4
4d Ar = 2-NCC6H4
3a R = CN
3b R = CO2Et
O
CN
4a,b
R = CN
X
NC
O
NH
Me
N
Me
O
NH
O
CN
N
Ar
N
CN
NH
Ar
5
7
O
NH2
N
NH
CN
O
Me
O
O
CN
Me
N
NH
N
N
NH2
Ar
Ar
6
8a Ar = Ph 89%
8b Ar = 2-ClC6H4 84%
Scheme 1
On the other hand, it was found that heating 3-cyano
methylidene-2-oxindole (3b) with pyruvaldehyde-1-aryl-
hydrazone (4a) in ethanol–piperidine solution resulted in
the formation of a mixture of 12 and another product 13
SYNLETT 2009, No. 4, pp 0625–0627
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087558; Art ID: G34608ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

626
I. A. Abdelhamid
LETTER
Table 1 Synthesis of Compounds 8–10 and 12 Using Different Cat-
alysts
EtO2C
CN
O
Compound
Yield (%)
O
NH
N
Using piperidine
Using chitosan
H
3b
Me
O
O
CO2Et
Me
8a
8b
9
78
76
74
75
52
89
84
79
77
55
N
NH
Ph
N
CN
NH
Ph
11
4a
10
12
NH
Me
O
O
O
NH2
R
O
NC
CN
COOEt
another product
+
Me
N
N
NH2
O
N
NH
O
X
N
X
Ph
12
N
H
Me
13
35%
55%
3a
N
NH
Scheme 3
6
X
NH
O
O–
Me
O
O
O
CN
–
4c X = CO2Me
4d X = CN
Me
Me
Me
N
+
N
N
+
NH
N
NH2
X
NH
N
NH
X
X
X
8
4(II)
4
4(I)
X = CO2Me
X = CN
Figure 1
Acknowledgment
NH
O
NH
The author is deeply indebted to the Alexander von Humboldt
Foundation, Germany, for granting him a postdoctoral fellowship
(AGY1129032STP). He is also very thankful to Prof. Dr. Holger
Butenschön, Institut für Organische Chemie, Leibniz Universität
Hannover, for kind hospitality.
Me
Me
O
O
CN
CN
O
N
N
N
N
N
NH
NH2
O
References and Notes
10
9
77%
79%
(1) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127.
(2) Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem.
Soc. 2001, 273.
Scheme 2
(3) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta
that results most likely via addition of 3b to 4a followed
by elimination of water. Spectral data of compound 12 are
in complete agreement with the proposed structures (cf.
Scheme 3)18 while the structure of the side product 13 is
still under investigation.19
2000, 83, 1175.
(4) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
Carreira, E. M. Angew. Chem. Int. Ed. 1999, 38, 3186; and
references cited therein.
(5) Ashimori, A.; Bachand, B.; Overmann, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6477.
Finally, the regioselectivity of the addition can be easily
explained on the basis that the delocalization of the nitro-
gen lone pair make hydrazone CH more nucleophlilic than
NH (as shown in Figure 1), so the hydrazone CH adds first
on the activated double bond in 3 to give the acyclic inter-
mediate 7 that readily cyclizes into Michael adduct 8.
(6) Matsuura, T.; Overmann, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6500.
(7) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.;
Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita,
Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem.
Soc. 2005, 127, 10130.
(8) Chen, C.; Li, X.; Neumann, C. S.; Lo, M. M.-C.; Schreiber,
S. L. Angew. Chem. Int. Ed. 2005, 44, 2249.
Synlett 2009, No. 4, 625–627 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Spiro Cyclic 2-Oxindole Derivatives of 6-Amino-4H-Pyridazine
627
(9) Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org.
Chem. 2006, 71, 2346; and references cited therein.
(10) Abdelhamid, I. A.; Ghozlan, S. A. S.; Kolshorn, H.; Meier,
H.; Elnagdi, M. H. Heterocycles 2007, 71, 2627.
(11) Ghozlan, S. A. S.; Abdelhamid, I. A.; Hassaneen, H. M.;
Elnagdi, M. H. J. Heterocycl. Chem. 2007, 44, 105.
(12) Ghozlan, S. A. S.; Abdelhamid, I. A.; Elnagdi, M. H.
ARKIVOC 2006, (xiii), 147.
(13) Redkin, R. G.; Shemchuk, L. A.; Chernykh, V. P.; Shishkin,
O. V.; Shishkin, S. V. Tetrahedron 2007, 63, 11444.
(14) General Procedures for Compounds 8a,b and 12
Method A: A mixture of aza-enamine 4 (10 mmol) and 3-
cyanomethylidene-2-oxindoles 3 was refluxed in EtOH (20
mL) in the presence of piperidine (0.1 mL) for 3 h. The
solvent was evaporated under vacuum, and the crude product
was collected and crystallized from EtOH or EtOH–dioxane.
Method B: A mixture of arylhydrazone 4 (10 mmol) and 3-
cyanomethylidene-2-oxindoles 3 was refluxed in EtOH (20
mL) in the presence of chitosan (0.2 g) for 3 h. The solvent
was evaporated under vacuum, and the crude product was
collected and crystallized from EtOH or EtOH–dioxane. The
catalyst chitosan was removed by filtration prior or during
the crystallization process.
compound 3a (10 mmol) in pyridine (10 mL). The solution
was refluxed for 5 h, then poured onto H2O and acidified
with dilute HCl. The solid product obtained was crystallized
from EtOH or EtOH–dioxane.
(17) 4,3¢-Spiro{2-acetyl-6-oxo-3-phenyl-3,5,6,11-
tetrahydropyridazino[1,6-a]quinazoline-4-carbonitrile}-
2¢-oxindole (9)
Mp >300 °C. IR (KBr): n = 3376, 3189 (2 NH), 2196 (CN),
1735, 1693, 1633 (3CO) cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 2.46 (s, 3 H, CH3CO), 6.86–8.00 (m, 8 H, Ar H),
10.78 (br s, 1 H, indole NH), 11.79 (br s, 1 H, pyrimidine
NH). 13C NMR (100 MHz, DMSO-d6): d = 25.5 (CH3), 49.6
(spiro C), 66.4 (CCN), 109.7, 114.4, 114.9, 115.7 (CN),
122.3, 124.8, 126.8, 127.3, 129.9, 133.5, 139.7, 141.2,
142,5, (Ar CH), 141.3 (CCOCH3), 149.7 (CNH2), 162, 176.2
(2 CONH), 194.0 (CO). MS (EI): m/z (%) = 383 [M+].
(18) 4,3¢-Spiro(ethyl 3-acetyl-6-amino-1-phenyl-1H,4H-
pyridazine-5-carboxylate)-2¢-oxindole (12)
Mp 244–246 °C. IR (KBr): n = 3496, 3428, 3237 (NH2 and
NH), 1720, 1644, 1608 (3 CO) cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 0.87 (t, 3 H, CH3, J = 7.2 Hz), 2.11 (s, 3 H,
CH3CO), 4.2 (q, 2 H, CH2, J = 7.2 Hz), 6.71 (br s, 2 H, NH2),
6.86–7.89 (m, 9 H, Ar H), 10.31 (br s, 1 H, indole NH).
13C NMR (100 MHz, DMSO-d6): d = 13.2 (CH3), 25.4
(CH3), 48.6 (CH2), 56.9 (spiro C), 76.5 (CCN), 108.5, 119.3,
126.9, 128.7, 129.9, 132.8, 136,9, 141.1, 142.9, 143.1 (Ar
CH), 144.5 (CCOCH3), 149.4 (CNH2), 167.9 (CONH),
179.1 (CO2Et), 194.8 (CO). MS (EI): m/z (%) = 404 [M+].
(19) Spectral Data of Compound 13
(15) 4,3¢-Spiro(3-acetyl-6-amino-1-phenyl-1H,4H-
pyridazine-5-carbonitrile)-2¢-oxindole (8a)
Mp 262–264 °C. IR (KBr): n = 3444, 3359, 3220 (NH2 and
NH), 2190 (CN), 1724, 1623 (2 CO) cm–1. 1H NMR (400
MHz, DMSO-d6): d = 2.18 (s, 3 H, CH3-CO), 6.14 (br s, 2 H,
NH2), 6.83–7.58 (m, 9 H, Ar H), 10.57 (br s, 1 H, indole
NH). 13C NMR (100 MHz, DMSO-d6): d = 24.7 (CH3), 48.5
(spiro C), 59.7 (CCN), 109.5, 118.0 (CN), 122.1, 123.8,
126.6, 128.7, 129, 129.7, 134.4, 139.9, 140.6 (Ar CH), 141.3
(CCOCH3), 149.7 (CNH2), 177 (CONH), 194.8 (CO). MS
(EI): m/z (%) = 357 [M+].
Mp 285 –287 °C. IR (KBr): n = 3120, 3245, 1646 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.21 (t, 3 H, CH3,
J = 7.2 Hz), 2.62 (s, 3 H, CH3CO), 4.25 (q, 2 H, CH2, J = 7.2
Hz) 6.84–7.84 (m, 9 H, Ar H), 9.00 (s, 1 H), 13.40 (br s,
1 H). 13C NMR (100 MHz, DMSO-d6): d = 14.1, 15.5, 63.8,
73, 116.8, 118.6, 119.6, 120.9, 121, 123.3, 123.9, 124.5,
125.5, 128.1, 128.8, 136.3, 139.8, 145.6, 155.7, 165.8. MS
(EI): m/z (%) = 386 [M+].
(16) General Method for the Synthesis of Compounds 9 and
10
A solution of each of 4c or 4d (10 mmol) was treated with
Synlett 2009, No. 4, 625–627 © Thieme Stuttgart · New York

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