DBU-Catalyzed, facile and efficient method for synthesis of spirocyclic 2-oxindole derivatives with incorporated 6-amino-4H-pyridazines and fused derivatives via [3+3] atom combination

Article abstract of DOI:10.1016/j.tet.2009.09.081

3-Cyanomethylidene oxindole derivatives were prepared in excellent yields utilizing DBU-promoted Knoevenagel condensation of isatin derivatives with active methylene reagents. The isolated products were then reacted with azaenamines via a DBU-promoted Mic

Full text of DOI:10.1016/j.tet.2009.09.081

Tetrahedron 65 (2009) 10069–10073
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
DBU-Catalyzed, facile and efficient method for synthesis of spirocyclic
2-oxindole derivatives with incorporated 6-amino-4H-pyridazines
and fused derivatives via [3þ3] atom combination
,
b
,
a
a
a,
*
Ismail A. Abdelhamid a , Mona H. Mohamed , Amr M. Abdelmoniem , Said A.S. Ghozlan
*
a Chemistry Department, Faculty of Science, Cairo university Giza, Egypt
b Institut fu¨r Organische Chemie der Universita¨t Hannover, Schneiderberg 1B, 30167 Hannover, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Received in revised form
16 September 2009
Accepted 18 September 2009
Available online 22 September 2009
3-Cyanomethylidene oxindole derivatives were prepared in excellent yields utilizing DBU-promoted
Knoevenagel condensation of isatin derivatives with active methylene reagents. The isolated products
were then reacted with azaenamines via a DBU-promoted Michael addition to yield spirocyclic 2-ox-
indole derivatives with incorporated 6-amino-4H-pyridazines and their fused derivatives.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
3-Cyanomethylidene oxindole
DBU
Azaenamines
Michael addition
Spiropyridazines
1. Introduction
based on cycloaddition or condensation reactions.16–22 Considering
these reports, the development of new and simple synthetic
Spirocyclic systems containing one sp3 carbon atom common to
two rings are structurally interesting.1 The asymmetric structure of
the molecule due to the chiral spiro carbon atom is one of the
important criteria of the biological activities.2,3 The presence of the
sterically constrained spiro structure in various natural products
also adds to the interest in the investigations of spiro compounds.4
Similarly, functionalized spiro cycloalkyloxindoles are found in
a variety of natural products and bioactive molecules.5,6 Due to the
biological activity of pyridazines7–9 and our interest in the syn-
thesis of heterocyclic compounds,10–15 herein, we report a simple
and efficient method for the preparation of new 4,30-spiro(pyr-
idazine)-2-oxindole derivatives. To the best of our knowledge, this
is the first report on this synthesis.
methods for the efficient preparation of spiro heterocycles contain-
ing pyridazine ring fragments is therefore an interesting challenge.
So, in continuation of our interest in azaenamine chemistry10,23–25
and also of our interest in utilizing green methodologies,24,26,27
herein, we report an efficient route for the synthesis of spiropyr-
idazines containing 2-oxindole nucleus using DBU as a basic catalyst.
Recently, DBU has received considerable attention as an inexpensive
and readily available catalyst for Knoevenagel condensations28 and
Michael additions29 under mild and convenient conditions, affording
the corresponding products in excellent yields. Thus, in our initial
attempt, 3-cyanomethylidene-2-oxindoles 3a–f were obtained in
80–90% yields by Knoevenagel condensation of isatin derivatives
1a,b with active methylene compounds 2a–c. In the next step, the
isolated 3-cyanomethylidene-2-oxindoles 3 were reacted with
azaenamine 4, in the presence of DBU via Michael addition reaction
to yield products, which can be formulated as 6 or 8. Compounds 6
result from Michael addition of CH of azaenamine 4 to the double
bond in 3, followed by cyclization (pathway A), while compounds 8
result from initial addition of NH of compound 4 to the exocyclic
double bond in 3, followed by cyclization (pathway B) (cf. Scheme 1).
Itis clear that simple spectral tools cannot differentiate betweenboth
structures 6 and 8. So, to establish the structure of the product with
certainty, the X-ray crystal structure of product 6f was determined 30
2. Results and discussion
Many synthetic methodologies have been developed for con-
structing spirocycles containing 2-oxindole, most of which were
* Corresponding authors.
E-mail addresses: ismail_shafy@yahoo.com (I.A. Abdelhamid), s_ghozlan@
yahoo.com (S.A.S. Ghozlan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.081

10070
I.A. Abdelhamid et al. / Tetrahedron 65 (2009) 10069–10073
X
N
O
CN
O
X
CN
O
N
2a, X=CN
b, X=COOC2H5
c, X=benzthiazol-2-yl
R
R
3a-f
1a, R = H
b, R = CH3
O
Me
DBU or piperidine
N
NH
Ph
4
Pathway
Pathway
A
X
B
O
Ph
Me
HN
CN
N
CN
X
N
X
O
N
Ph
O
Me
O
N
R
N
R
7
5
52-84%
Figure 1. X-ray crystal structure of compound 6f.
H2N
X
Ph
N
NH2
O
X
Table 1
Selected bond angles and bond lengths of compound 6f
N
Me
N
Bond lengths (Å)
Atoms
Bond angles (degrees)
Me
N
O
N
N
R
O
Ph
Found
Atoms
Found
O
R
N4dC13
N5dC13
C8dC11
C8dC16
C8dC9
1.337
1.382
1.535
1.517
1.526
1.382
C9dC8dC16
C9dC8dC20
C11dC8dC16
C9dC8dC11
C16dC8dC20
C8dC11dC15
C13dC11dC15
N5dC13dC11
111.2
100.8
109.1
113.8
108.3
120.7
119.4
120.8
6a-f
8a-f
R
Compound
X
3 and 5-8 a
CN
H
b
c
d
e
f
COOEt
C11dC13
H
Benzthiazol-2-yl
H
CN
Me
Me
Me
COOEt
Benzthiazol-2-yl
Scheme 1. Synthesis of compounds 6a–f.
Table 2
Comparison of the % yields of 6a–f in cases of piperidine and DBU catalysts
(cf. Fig. 1 and Table 1) (R]CH3 and X¼benzthiazol-2-yl) that in-
dicates that the reaction proceeds through pathway A not B. The
structure of the formed products was also supported based on the
elemental analysis and spectral data. IR spectra of compounds 6a–f
Entry
R
X
% Yield
Piperidine
DBU
6a
6b
6c
6d
6e
6f
H
H
H
CH3
CH3
CH3
CN
77
48
79
75
78
80
80
52
83
79
81
84
COOC2H5
Benzthiazol-2-yl
CN
COOC2H5
Benzthiazol-2-yl
revealed broad absorption bands at n
w3168–3496 cmꢀ1 assigned to
the NH2 group. It also indicated the absence of CN bands in case of 6b,
c, e, andf.1H NMR spectra indicated thepresence ofNH2 bya signal at
d
w6.14–6.91 ppm. The structure was also supported by the 13C NMR
spectrum, which indicated the absence of CN for compounds 6b, c, e,
and f. In addition it featured a signal at w50 ppm assigned for the
spiro carbon atom. The other carbon atoms appeared at their
expected positions (as shown in Experimental part).
d
compounds 11 are well established based on mass and NMR
spectral tools, which indicated the absence of the OEt group
attached to thiophene ring. Thus, 1H NMR spectra of 11a–f com-
These syntheses have been also conducted using a dioxane so-
lution containing piperidine as the catalyst and the yields in every
case are compared in Table 2.
pounds revealed characteristic set of multiplets at
2.275 ppm for cyclohexene ring. It also indicated singlet signals at
w2.30 for (CH3CO). In addition it indicated singlet signals at 3.12–
dw1.76–
d
In an extension of the program to confirm the proposed path-
way we carried out the reaction using azaenamine 931 containing
carboxylic ester on thiophene ring, where only further cyclization
occurred if the reaction followed pathway A, while in case of
pathway B no further cyclization would be occurred (Scheme 2).
Thus, reacting 9 with 3-cyanomethylidene-2-oxindoles 3 has
resulted in formation of compounds 10 that then directly cyclized
into 11 under the reaction conditions. The chemical structures of
3.15 for the methyl attached to indole ring in compounds 11d–f. It
also featured aromatic protons at 6.8–7.5 ppm, a broad singlet at
dw11–13.8 ppm for NH. The corresponding non-alkylated com-
pounds 11a–c (R]H) also revealed a proton singlet from the NH
group of the 2-oxindole ring in a higher field at 10.4–11 ppm.
Furthermore, full assignment of the 13C NMR data confirmed the
structures 11, where the key signal at
d 167–168 ppm was assigned
to the 2-oxindolic carbonyl group; at 174–177 ppm was assigned for

I.A. Abdelhamid et al. / Tetrahedron 65 (2009) 10069–10073
10071
R
R
4. Experimental
4.1. General
N
N
O
O
O
O
O
X
X
Me
Me
Melting points were determined on a Stuart melting point ap-
paratus and are uncorrected. The IR spectra were recorded as KBr
pellets using a Bruker–vector 22 spectrophotometer FTIR. The 1H
and 13C NMR spectra were recorded in DMSO-d6 as solvent at
300 MHz and 75 MHz, respectively on Varian Gemini NMR spec-
trometer using TMS as internal standard. Chemical shifts are
Me
N
S
N
3a-f
NH2
N
N
NH
N
S
NH
Pathway A
73-80%
CO2Et
O
S
CO2Et
reported in
d units (ppm). Mass spectra were measured on a Shi-
10
11a-f
madzu GMSS-QP-1000 EX mass spectrometer at 70 eV. The crystal
structure was determined by the X-ray unit at the National Re-
search Center, Dokki, Cairo.
9
NH2
O
X
Me
no further cyclization
X
N
3a-f
X
CO2Et
N
4.2. General method for preparation of compounds 3a–f
N
Pathway B
O
Me
S
4.2.1. General procedure. A mixture of isatin or N-methylisatin 1a
or b (10 mmol) and active methylenes 2a–c (10 mmol) was dis-
solved in absolute ethanol (10 ml) in presence of piperidine (0.2 ml)
or DBU (0.2 ml). The reaction mixture was heated in water bath for
about 15 min to ensure complete reaction. The precipitate formed
was filtered. The crude products are pure enough to be directly
used in the next step without need to further crystallization.
However, they may be crystallized from ethanol or ethanol/dioxan.
12a-f
Scheme 2. Synthesis of compounds 11a–f.
CONH; at
(spiro carbon); at
matic carbons. The signal at
d
50–55 ppm was assigned to the quaternary sp3 carbon
80–145 ppm was assigned to the sp2 and aro-
118 ppm was assigned to the nitrile
d
d
carbon in the pyridazine ring for compounds 11a,d. Full spectral
data for all new compounds are presented in Experimental section.
Also, the reactions were carried out in both conditions of DBU
and piperidine catalysts and the % yields were compared each time
(Table 3).
4.2.1.1. 2-(2-Oxo-1,2-dihydro-indol-3-ylidene)-malononitrile
3a. Yield: (84% piperidine, 88% DBU), Mp: 236–238 ꢁC (reported:
143–145 ꢁC).32
Table 3
4.2.1.2. Ethyl cyano-(2-oxo-1,2-dihydro-indol-3-ylidene)-acetate
3b. Yield: (82% piperidine, 83% DBU), Mp: 180–182 ꢁC (reported:
173–175 ꢁC).32
Comparison of the % yields of 11a–f in case of piperidine and DBU catalysts
Entry
R
X
% Yield
Piperidine
DBU
4.2.1.3. Benzothiazol-2-yl-(2-oxo-1,2-dihydro-indol-3-ylidene)-
11a
11b
11c
11d
11e
11f
H
H
H
CH3
CH3
CH3
CN
74
73
76
74
69
77
78
76
80
78
75
79
acetonitrile 3c. Yield: (86% piperidine, 89% DBU), Mp: 204–206 ꢁC;
COOC2H5
Benzthiazol-2-yl
CN
COOC2H5
Benzthiazol-2-yl
IR (KBr):
n
3233 (NH), 2195 (CN), 1617 (CO) cmꢀ1; MS (EI)¼303.
Anal. Calcd for C17H9N3OS (303.34): C, 67.31; H, 2.99; N, 13.85; S,
10.57. Found: C, 67.19; H, 2.78; N, 13.66; S, 10.43.
4.2.1.4. 2-(1-Methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-malono-
nitrile 3d. Yield: (83% piperidine, 87% DBU), Mp: 234–236 ꢁC
(reported: 148–150 ꢁC).32
Similarly azaenamine 13 reacted with 3-cyanomethylidene-2-
oxindole 3e to yield the spiro compound 15 through the in-
termediate 14. The structure of this compound was also established
based on elemental analysis and spectral data that indicated the
absence of OMe (Scheme 3).
4.2.1.5. Ethyl cyano-(1-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-
acetate 3e. Yield: (81% piperidine, 85% DBU), Mp: 156–158 ꢁC
(reported: 190–193 ꢁC).32
Me
Me
N
N
4.2.1.6. Benzothiazol-2-yl-(1-methyl-2-oxo-1,2-dihydro-indol-3-
O
O
O
ylidene)-acetonitrile 3f. Yield: (83% piperidine, 88% DBU), Mp: 184–
COOEt
O
O
186 ꢁC; IR (KBr):
n
2207 (CN), 1606 (CO) cmꢀ1; MS (EI)¼317. Anal.
Me
COOEt
Me
3e
N
Me
N
N
NH
O
Calcd for C18H11N3OS (317.36): C, 68.12; H, 3.49; N, 13.24; S, 10.10.
Found: C, 68.06; H, 3.22; N, 13.31; S, 10.18.
N
NH
79%
N
NH2
COOMe
COOMe
4.3. General method for preparation of compounds 6a–f
15
13
14
Scheme 3. Synthesis of compound 15.
4.3.1. General procedure. A mixture of azaenamine 4 (10 mmol)
and cyanomethylidine oxindoles 3a–f (10 mmol) was refluxed in
dioxan (20 ml) in the presence of piperidine (0.2 ml) or DBU
(0.2 ml) for 3–5 h. The solvent was evaporated under vacuum and
the crude product was crystallized from ethanol/dioxan.
3. Conclusion
In the present article we could manage to report a new simple
and efficient route to new spirocyclic 2-oxindole derivatives of 6-
amino-4H-pyridazine and fused derivatives via the first reported
[3þ3] atom combination reaction of azaenamines with 2-methyl-
idene oxindole derivatives.
4.3.1.1. 4,30-Spiro(3-acetyl-6-amino-1-phenyl-1,4-dihydropyr-
idazine-5-carbonitrile)-20-oxindole 6a. Yield: (77% piperidine, 80%
DBU), Mp: 262–264 ꢁC; IR (KBr):
n
3444, 3359, 3220 (NH2 and NH),
2190 (CN), 1724, 1623 (2 CO) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):

10072
I.A. Abdelhamid et al. / Tetrahedron 65 (2009) 10069–10073
d
¼2.18 (s, 3H, CH3CO), 6.14 (br s, 2H, NH2), 6.83–7.58 (m, 9H, Ar H),
50.9 (spiro C), 81.9 (C-benzthiazol-2-yl), 108.8, 120.5, 121.3, 123.3,
10.57 (br s, 1H, indole NH); 13C NMR (100 MHz, DMSO-d6):
d
¼24.7
123.7, 124.5, 126.5, 127.3, 129.2, 130.0, 130.3, 131.3, 132.0, 140.6, 140.9,
144.6 (Ar CH), 145.0 (C–NH2), 151.5 (C–COCH3), 166.6 (benzthiazole
C-2), 175.8 (CONH), 195.2 (CO); MS (EI): m/z (%)¼481 (Mþþ2, 6.9),
480 (Mþþ1, 5.9), 478 (Mþ–1, 6.9), 436 (28.7), 345 (54.5). Anal. Calcd
for C27H21N5O2S (479.55): C, 67.62; H, 4.41; N, 14.60; S, 6.69. Found:
C, 67.42; H, 4.18; N, 14.25; S, 6.51.
(CH3), 48.5 (spiro C), 59.7 (CCN), 109.5, 118.0 (CN), 122.1, 123.8,
126.6, 128.7,129.0,129.7,134.4, 139.9,140.6 (Ar CH),141.3 (CCOCH3),
149.7 (CNH2), 177 (CONH2), 194.8 (CO); MS (EI): m/z (%)¼357. Anal.
Calcd for C20H15N5O2 (357.12): C, 67.22; H, 4.23; N, 19.60. Found: C,
67.48; H, 4.37; N, 19.78.
4.3.1.2. 4,30-Spiro(ethyl 3-acetyl-6-amino-1-phenyl-1,4-dihydro-
4.4. General method for preparation of compounds 11a–f
pyridazine-5-carboxylate)-20-oxindole 6b. Yield: (48% piperidine,
52% DBU), Mp: 244–246 ꢁC; IR (KBr):
n
3496, 3428, 3237 (NH2 and
NH), 1720, 1644, 1608 (3 CO) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
¼0.87 (t, 3H, CH3, J¼7.2 Hz), 2.11 (s, 3H, CH3CO), 4.2 (q, 2H, CH2,
J¼7.2 Hz), 6.71 (br s, 2H, NH2), 6.86–7.89 (m, 9H, Ar H), 10.31 (br s,
1H, indole NH); 13C NMR (100 MHz, DMSO-d6):
4.4.1. General procedure. A mixture of azaenamine 9 (10 mmol)
and cyanomethylidine oxindoles 3a–f (10 mmol) was refluxed in
dioxan (20 ml) in the presence of piperidine (0.2 ml) or DBU
(0.2 ml) for 3–5 h. The solvent was evaporated under vacuum and
the crude product was crystallized from ethanol/dioxan.
d
d
¼13.2 (CH3), 25.4
(NCH3), 48.6 (CH2), 56.9 (spiro C), 76.5 (CCOOEt), 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 (COOEt), 194.8 (CO); MS (EI)¼404
(Mþ). Anal. Calcd for C22H20N4O4 (404.15): C, 65.34; H, 4.98; N,
13.85. Found: C, 65.22; H, 4.79; N, 13.68.
4.4.1.1. 3,30-Spiro(2-acetyl-6-oxo-3,5,6,7,10-pentahydro-11-thia-
1,5,11b-triaza-benzo[a]fluorene-4-carbonitrile)-20-oxindole
11a. Yield: (74% piperidine, 78% DBU), Mp: 256–258 ꢁC; IR (KBr):
n
3446 (NH), 3283 (NH), 2204 (CN), 1730, 1690, 1641 (3 CO) cmꢀ1; 1H
NMR (300 MHz, DMSO-d6):
d¼1.76 (m, 4H, cyclohexene H), 2.30 (s,
4.3.1.3. 4,30-Spiro(3-acetyl-6-amino-5-benzthiazol-2-yl-1-phenyl-
1,4-dihydropyridazine)-20-oxindole 6c. Yield: (79% piperidine, 83%
3H, CH3CO), 2.69 (m, 2H, cyclohexene H), 2.75 (m, 2H, cyclohexene
H), 6.86–7.36 (m, 4H, Ar H), 10.70 (s, 1H, CONH), 11.41 (s, 1H, oxin-
dole NH); MS (EI): m/z (%)¼443 (Mþ, 6.1), 417 (0.9), 400 (100), 374
(27.1). Anal. Calcd for C23H17N5O3S (443.48): C, 62.29; H, 3.86; N,
15.79; S, 7.23. Found: C, 62.11; H, 3.57; N, 15.57; S, 7.11.
DBU), Mp: 244–246 ꢁC; IR (KBr):
n
3455, 3558, 3168 (NH2 and NH),
1700, 1617 (2 CO) cmꢀ1; 1H NMR (300 MHz, DMSO-d6):
¼2.16 (s, 3H,
CH3CO), 6.90–7.75 (m, 13H, Ar H), 8.05 (br s, 2H, NH2), 10.8 (br s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6):
d
d
¼25.5 (CH3), 50.9 (spiro C), 81.8
(C-benzthiazol-2-yl), 109.6, 119.6, 120.6, 122.0, 123.1, 124.3, 125.8,
126.7, 128.5, 129.4, 129.7, 131.7, 131.8, 140.3, 140.9, 143.6 (Ar CH), 144.0
(C–NH2), 150.9 (C–COCH3), 166.4 (benzthiazole C-2), 176.7 (CONH),
194.6 (CO); MS (EI)¼465 (Mþ). Anal. Calcd for C26H19N5O2S (465.53):
C, 67.08; H, 4.11; N, 15.04; S, 6.89. Found: C, 66.98; H, 4.03; N, 14.96; S,
6.77.
4.4.1.2. 3,30-Spiro(ethyl 2-acetyl-6-oxo-3,5,6,7,10-pentahydro-11-
thia-1,5,11b-triaza-benzo[a]fluorene-4-carboxylate)-2‘-oxindole
11b. Yield: (73% piperidine, 76% DBU), Mp: 290–294 ꢁC; IR (KBr):
n
1711 (COOC2H5), 1663, 1621, 1562 (3 CO) cmꢀ1; 1H NMR (300 MHz,
DMSO-d6):
d
¼0.85 (t, 3H, CH3, J¼7.2), 1.79 (m, 4H, cyclohexene H),
2.27 (s, 3H, CH3CO), 2.71 (m, 2H, cyclohexene H), 2.79 (m, 2H,
cyclohexene H), 3.85 (q, 2H, CH2, J¼7.2), 6.76–7.30 (m, 4H, Ar H),
10.44 (s, 1H, CONH), 11.70 (s, 1H, oxindole NH); 13C NMR (75 MHz,
4.3.1.4. 4,30-Spiro(3-acetyl-6-amino-1-phenyl-1,4-dihydropyr-
idazine-5-carbonitrile)-10-methyl-20-oxindole 6d. Yield: (75% piper-
DMSO-d6):
d
¼12.7, 21.3, 22.2, 23.7, 24.6, 25.4, 48.8, 60.0, 66.2, 78.6,
idine, 79% DBU), Mp: 248–250 ꢁC; IR (KBr):
n
3469, 3335 (NH2),
2190 (CN), 1725, 1684 (2 CO) cmꢀ1; 1H NMR (300 MHz, DMSO-d6):
¼2.17 (s, 3H, CH3CO), 3.20 (s, 3H, NCH3), 6.18 (br s, 2H, NH2), 7.02–
7.59 (m, 9H, Ar H); 13C NMR (75 MHz, DMSO-d6):
108.6, 113.0, 120.6, 121.2, 124.0, 128.7, 132.0, 134.3, 141.2, 146.3,
149.8, 154.7, 166.9, 177.1, 193.6; MS (EI): m/z (%)¼491 (Mþþ1, 5.6),
490 (Mþ, 15.3), 447 (72.9), 417 (100). Anal. Calcd for C25H22N4O5S
(490.53): C, 61.21; H, 4.52; N, 11.42; S, 6.54. Found: C, 61.05; H, 4.14;
N, 11.25; S, 6.44.
d
d
¼25.1 (CH3), 27.3
(CH3), 48.6 (spiro C), 58.7 (CCN), 109.2, 118.3 (CN), 123.3, 124.1,
127.3,129.1,129.6,130.2,130.9,140.3,140.8 (Ar CH),143.2 (CCOCH3),
149.2 (CNH2), 175.9 (CONH2), 195.2 (CO); MS (EI): m/z (%)¼371 (Mþ,
0.8), 328 (67.9), 345.2 (0.7). Anal. Calcd for C21H17N5O2 (371.39): C,
67.91; H, 4.61; N, 18.86. Found: C, 67.45; H, 4.22; N, 18.50.
4.4.1.3. 3,30-Spiro(2-acetyl-6-oxo-4-benzthiazol-2-yl-3,5,6,7,10-
pentahydro-11-thia-1,5,11b-triaza-benzo[a]fluorene)-20-oxindole
11c. Yield: (76% piperidine, 80% DBU), Mp: 280–282 ꢁC; IR (KBr):
n
3444 (NH), 3194 (NH oxindole), 1711, 1681, 1619 (3 CO) cmꢀ1
;
1H
¼1.76 (m, 4H, cyclohexene H), 2.66 (s,
4.3.1.5. 4,30-Spiro(ethyl 3-acetyl-6-amino-1-phenyl-1,4-dihydro-
pyridazine-5-carboxylate)-10-methyl-20-oxindole 6e. Yield: (78% pi-
NMR (300 MHz, DMSO-d6):
d
3H, CH3CO), 2.65 (m, 2H, cyclohexene H), 2.79 (m, 2H, cyclohexene
H), 6.97–7.81 (m, 8H, Ar H),11.07 (s,1H, CONH),13.85 (s,1H, oxindole
NH); MS (EI): m/z (%)¼552 (Mþþ1, 5.2), 551 (Mþ, 16.9), 508 (100),
417 (53.5). Anal. Calcd for C29H21N5O3S2 (551.64): C, 63.14; H, 3.84;
N, 12.70; S, 11.63. Found: C, 63.02; H, 3.45; N, 12.38; S, 11.44.
peridine, 81% DBU), Mp: 198–200 ꢁC; IR (KBr):
n
3402, 3281 (NH2),
1H NMR (300 MHz,
¼0.79 (t, 3H, CH3, J¼7.2 Hz), 2.11 (s, 3H, CH3CO), 3.18 (s,
3H, NCH3), 3.73 (q, 2H, CH2, J¼7.2 Hz), 6.91–7.65 (m, 11H, Ar H and
NH2); 13C NMR (75 MHz, DMSO-d6):
1715 (COOC5H5), 1654, 1613 (2 CO) cmꢀ1
DMSO-d6):
;
d
d¼14.0 (CH3), 25.8 (CH3CO),
26.7 (NCH3), 56 (spiro C), 59.2 (CH2), 76.7 (CCN), 107.7, 122.3, 123.6,
127.4, 128.9, 130.3, 134.7, 140.2, 143.0, 144.7 (Ar CH), 149.9
(CCOCH3), 149.9 (CNH2), 168.2 (CONH), 177.8 (COOEt), 195.2 (CO);
MS (EI): m/z (%)¼418 (Mþ, 1.6), 375 (29.3), 345 (31.3). Anal. Calcd for
C23H22N4O4 (418.45): C, 66.02; H, 5.30; N, 13.39. Found: C, 65.99; H,
5.44; N, 13.11.
4.4.1.4. 3,30-Spiro(2-acetyl-6-oxo-3,5,6,7,10-pentahydro-11-thia-
1,5,11b-triaza-benzo[a]fluorene-4-carbonitrile)-10-methyl-20-ox-
indole 11d. Yield: (74% piperidine, 78% DBU), Mp: 258–260 ꢁC; IR
(KBr):
NMR (300 MHz, DMSO-d6):
3H, CH3CO), 2.70 (m, 2H, cyclohexene H), 2.76 (m, 2H, cyclohexene
H), 3.19 (s, 3H, NCH3), 7.03–7.46 (m, 4H, Ar H), 11.49 (s, 1H, NH); 13
NMR (75 MHz, DMSO-d6):
n
3442 (NH), 2199 (CN), 1729, 1689, 1639 (3 CO) cmꢀ1
;
1H
d¼1.76 (m, 4H, cyclohexene H), 2.29 (s,
C
4.3.1.6. 4,30-Spiro(3-acetyl-6-amino-5-benzthiazol-2-yl-1-phenyl-
1,4-dihydropyridazine)-10-methyl-20-oxindole 6f. Yield: (80% piperi-
d
¼21.3, 22.3, 23.8, 24.6, 24.7, 26.4, 62.2,
108.5, 113.6, 114.5, 120.7, 122.9, 124.4, 128.5, 129.7, 132.2, 132.5,
141.2, 142.4, 142.7, 149.4, 155.9, 174.4, 193.7; MS (EI): m/z (%)¼458
(Mþþ1, 3.8), 457 (Mþ, 8.1), 414 (100), 388 (20). Anal. Calcd for
C24H19N5O3S (457.50): C, 63.01; H, 4.19; N, 15.31; S, 7.01. Found: C,
62.98; H, 4.21; N, 15.18; S, 6.89.
dine, 84% DBU), Mp: 270–272 ꢁC; IR (KBr):
n
3409, 3296 (NH2), 1709
1H NMR (300 MHz, DMSO-d6):
¼2.11 (CH3CO), 2.17 (NCH3), 7.01–7.80 (m, 13H, Ar H), 8.20 (br s, 2H,
NH2); 13C NMR (75 MHz, DMSO-d6):
¼25.9 (CH3CO), 27.1 (NCH3),
(CH3CO), 1610 (CO oxindole) cmꢀ1
;
d
d

I.A. Abdelhamid et al. / Tetrahedron 65 (2009) 10069–10073
10073
4.4.1.5. 3,30-Spiro(ethyl 2-acetyl-6-oxo-3,5,6,7,10-pentahydro-11-
Acknowledgements
thia-1,5,11b-triaza-benzo[a]fluorene-4-carboxylate)-10-methyl-20-ox-
indole 11e. Yield: (83% piperidine, 79% DBU), Mp: 290–292 ꢁC; IR
Ismail A. Abdelhamid is deeply indebted to the Alexander von
Humboldt Foundation, Germany, for granting him a postdoctoral
fellowship. He is also very thankful to Prof. Dr. Holger Butenscho¨n,
Institut fu¨r Organische Chemie, Leibniz Universita¨t Hannover, for
his kind hospitality.
(KBr):
n ;
3516 (NH), 1704 (COOC2H5), 1662, 1604, 1565 (3 CO) cmꢀ1
1H NMR (300 MHz, DMSO-d6):
d¼0.78 (t, 3H, CH3, J¼7.2), 1.79 (m,
4H, cyclohexene H), 2.27 (s, 3H, CH3CO), 2.73 (m, 2H, cyclohexene
H), 2.80 (s, 2H, cyclohexene H), 3.18 (s, 3H, NCH3) 3.81 (q, 2H, CH2),
6.93–7.38 (m, 4H, Ar H), 11.70 (s, 1H, NH); 13C NMR (75 MHz, DMSO-
d6):
d
¼13.1, 21.3, 22.2, 23.7, 24.6, 25.3, 26.1, 48.0, 60.0, 78.2, 107.4,
References and notes
113.2, 122.0, 124.0, 128.8, 129.0, 132.0, 133.3, 141.4, 143.7, 145.8,
149.8, 154.7, 166.7, 175.7, 193.7; MS (EI): m/z (%)¼506 (Mþþ2, 5.7),
505 (Mþþ1, 5.2), 504 (Mþ, 5.2), 461 (12.3). Anal. Calcd for
C26H24N4O5S (504.56): C, 61.89; H, 4.79; N, 11.10; S, 6.36. Found: C,
61.66; H, 4.61; N, 10.98; S, 6.19.
1. Sannigrahi, M. Tetrahedron 1999, 55, 9007.
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3. Kobayashi, J.; Tsuda, M.; Agemi, K.; Shigemiri, H.; Ishibashi, M.; Sasaki, T.;
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10. Ghozlan, S. A. S.; Mohamed, M. H.; Abdelmoniem, A. M.; Abdelhamid, I. A.
ARKIVOC 2009, x, 302–311.
11. Abdelhamid, I. A.; Ghozlan, S. A. S.; Kolshorn, H.; Meier, H.; Elnagdi, M. H.
Heterocycles 2007, 71, 2627–2637.
12. Al-Awadi, N. A.; Ibrahim, M. I.; Abdelhamid, I. A.; Elnagdi, M. H. Tetrahedron
2008, 64, 8202–8205.
13. Ghozlan, S. A. S.; Abdelhamid, I. A.; Gaber, H.; Elnagdi, M. H. J. Chem. Res. 2004,
12, 789–793.
14. Ghozlan, S. A. S.; Abdelhamid, I. A.; Elnagdi, M. H. J. Heterocycl. Chem. 2005, 42,
1185–1189.
15. Ghozlan, S. A. S.; Abdelhamid, I. A.; Al-Dib, H. I.; Elnagdi, M. H. ARKIVOC 2006,
xv, 53–60.
4.4.1.6. 3,30-Spiro(2-acetyl-6-oxo-4-benzthiazol-2-yl-3,5,6,7,10-
pentahydro-11-thia-1,5,11b-triaza-benzo[a]fluorene)-10-methyl-20-
oxindole 11f. Yield: (77% piperidine, 79% DBU), Mp: 286–288 ꢁC; IR
(KBr):
DMSO-d6):
(m, 2H, cyclohexene H), 2.85 (m, 2H, cyclohexene H), 3.2 (s, 3H,
NCH3), 7.01–7.85 (m, 8H, Ar H), 13.85 (s, 1H, NH); MS (EI): m/z
(%)¼568 (Mþþ3, 1.5), 567 (Mþþ2, 4.5), 566 (Mþþ1, 7.7), 565 (Mþ,
22.4), 522 (100), 431 (55.1). Anal. Calcd for C30H23N5O3S2 (565.67):
C, 63.70; H, 4.10; N,12.38; S,11.34. Found: C, 63.62; H, 3.98; N,12.17;
S, 11.39.
n
3429 (NH),1717,1618,1586 (3 CO) cmꢀ1; 1H NMR (300 MHz,
d¼1.80 (m, 4H, cyclohexene H), 2.31 (s, 3H, CH3CO), 2.74
16. Yong, S. R.; Ung, A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 2007,
63, 1191.
17. Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505.
18. Robertson, D. W.; Krushinski, J. H.; Pollock, G. D.; Wilson, H.; Kauffman, R. F.;
Hayes, J. S. J. Med. Chem. 1987, 30, 824.
19. Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White, A. H.;
Turner, P. Tetrahedron 2005, 61, 8120.
20. Feldman, K. S.; Vidulova, D. B.; Karatjas, A. G. J. Org. Chem. 2005, 70, 6429.
21. Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425.
4.5. Preparation of compound (15)
A mixture of azaenamine 13 (10 mmol) and cyanomethylidine
oxindole 3e (10 mmol) was refluxed in dioxan (20 ml) in the
presence of piperidine (0.2 ml) or DBU (0.2 ml) for 5 h. The solvent
was evaporated under vacuum and the crude product was crys-
tallized from ethanol/dioxan.
22. Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137.
23. Ghozlan, S. A. S.; Abdelhamid, I. A.; Hassaneen, H. M.; Elnagdi, M. H. J. Heterocycl.
Chem. 2007, 44, 105–108.
4.5.1. 2,30-Spiro(ethyl 3-acetyl-9-oxo-2,9,10-trihydro-4,4a,10-triaza-
24. Abdelhamid, I. A. Synlett 2009, 625.
phenanthrene-1-carboxylate)-10-methyl-20-oxindole 15. Yield: (77%
25. Ghozlan, S. A. S.; Abdelhamid, I. A.; Elnagdi, M. H. ARKIVOC 2006, xiii, 147–157.
26. Al-Awadi, N.; Abdelhamid, I. A.; Al-Etaibi, A.; Elnagdi, M. H. Synlett 2007,
2205–2208.
27. Al-Awadi, N. A.; Abdelkhalik, M. M.; Abdelhamid, I. A.; Elnagdi, M. H. Synlett
2007, 2979–2982.
piperidine, 79% DBU), Mp: 256–258 ꢁC; IR (KBr):
n
3389 (NH), 1702,
1660,1614,1598 (4 CO) cmꢀ1; 1H NMR (300 MHz, DMSO-d6):
d¼0.78
(t, 3H, CH3 J¼7.2), 2.40 (s, 3H, CH3CO), 3.19 (s, 3H, NCH3), 3.82 (q, 2H,
CH2, J¼7.2), 6.94–8.06 (m, 8H, Ar H), 12.24 (s, 1H, NH); 13C NMR
28. Warea, M.; Madjeb, B.; Pokalwara, R.; Kakadea, G.; Shingarea, M. Bull. Cat. Soc.
Ind. 2007, 6, 104–106.
(75 MHz, DMSO-d6):
d
¼13.1, 25.9, 26.1, 60.1, 79.6, 107.3, 114.6, 115.3,
29. Yeom, C.-E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904–909.
30. Further details of the crystal structure of 8b will be available in the Cambridge
Crystallographic Data centre under deposit numbers CCDC 739769.
31. Darwish, E.S.; Abdelhamid, I.A.; Nasra, M.A.; Abdel-Gallil, F.M.; Fleita, D.H.,
submitted for publication.
120.4,121.9, 123.8, 124.9,127.0,128.9,133.2,135.6,140.0,141.9,143.9,
145.0, 157.1, 167.2, 175.9, 194.4; MS (EI): m/z (%)¼446 (Mþþ2, 0.8),
445 (Mþþ1, 3.7), 444 (Mþ, 9.5), 401 (100), 371 (80.2). Anal. Calcd for
C24H20N4O5 (444.44): C, 64.86; H, 4.54; N, 12.61. Found: C, 64.44; H,
4.17; N, 12.44.
32. Redkin, R. G.; Shemchuk, L. A.; Chernykh, V. P.; Shishkin, O. V.; Shishkina, S. V.
Tetrahedron 2007, 63, 11444–11450.