Synthesis and chemical reactivity of new azaenamines incorporated the 4,5,6,7-tetrahydrobenzo[ b ]thiophene moiety: 3+3 atom combination

Article abstract of DOI:10.1055/s-0029-1219235

Novel azaenamines incorporating a tetrahydrothiophene moiety were prepared. Michael addition of an azaenamine with ,-unsaturated nitriles took place to give [1]benzothieno[3,2:5,6]pyrimido[1,2-b]pyridazine (thia-triaza-benzo[a] fluorene) derivatives. The condensation with malononitrile resulted in the formation of a [1]benzothieno[3,2:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile. The azaenamine also reacted with aldehydes and piperidine to give Mannich products. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219235

PAPER
1107
Synthesis and Chemical Reactivity of New Azaenamines Incorporated the
4,5,6,7-Tetrahydrobenzo[b]thiophene Moiety: 3+3 Atom Combination
S
ynthesi
s
s
andChe
m
mical Reactivityof
a
NewAzaen
i
aminesl Abdelshafy Abdelhamid,*a,b Elham Sayed Darwish,a Miead Adel Nasra,a Fathy Mohamed Abdel-Gallil,a
Daisy Hanna Fleitac
a
Chemistry Department, Faculty of Science, Cairo University, Giza, A. R. Egypt
Fax +20(2)35727556; E-mail: ismail_shafy@yahoo.com
Institut für Organische Chemie der Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Chemistry Department, American University in Cairo, Egypt
b
c
Received 17 November 2009; revised 25 November 2009
report an efficient route for the Michael addition reaction
of azaenamines 5 to a,b-unsaturated nitriles. As stated
above, the CH group of the azaenamine is quite nucleo-
philic as a result of the hydrazone lone pair delocalization.
Abstract: Novel azaenamines incorporating a tetrahydrothiophene
moiety were prepared. Michael addition of an azaenamine with a,b-
unsaturated nitriles took place to give [1]benzothieno[3¢,2¢:5,6]py-
rimido[1,2-b]pyridazine (thia-triaza-benzo[a]fluorene) derivatives.
The condensation with malononitrile resulted in the formation of a Thus, in a preliminary study, we found that reacting com-
[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile.
The azaenamine also reacted with aldehydes and piperidine to give
Mannich products.
pound 5a with ethyl 2-cyano-3-phenylacrylate (7a) af-
forded a product for which several isomeric structures
seemed possible. Structures involving addition on the acyl
methyl group was readily ruled out on the basis of the 1H
NMR spectrum, which revealed a methyl signal at d =
2.36. Acyclic structures were also excluded based on 1H
NMR spectra analysis, which showed in addition to the
methyl signal, a singlet signal at d = 5.09 for H4 of the py-
ridazine and a broad signal at d = 11.19 for the NH group.
The resulting product was assigned the tetracyclic struc-
ture 10 based on mass spectroscopy and NMR analysis,
which revealed the absence of an OEt group on the
thiophene ring. IR and 13C NMR also indicated the ab-
sence of the CN signal and band. Compound 10a is most
likely formed via intermediacy of 8 and 9, which could
not be isolated (Scheme 2).
Key words: azaenamine, tetrahydrobenzo[b]thiophene, Michael
addition, condensation, Mannich alkylation
Compounds containing the tetrahydrobenzothiophene
(THBT) moiety are selective HCV polymerase inhibi-
tors,1 selective versus human DNA polymerase and calf
thymus.1 These compounds also have diverse pharmaco-
logical activities including antibacterial,2 immunodulato-
ry,3 anti-inflammatory,4 antidiabetic, antiplatelet
activating factor,5 and antiviral activity.6,7
In continuation of our interest in azaenamine chemistry,8–12
we report here a new synthesis of azaenamines containing
the 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
and -carboxamide moieties. Also we report the chemical
reactivity of the synthesized azaenamines. Thus, it has
been found that coupling acetoacetic acid with the 3-
(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-
2-diazonium chloride (3a) and the 3-carboxamide 3b af-
forded the corresponding pyruvaldehyde-1-arylhydra-
zones 5a and 5b in 73% and 68% yields, respectively.
Although, the appearance of NH at very low field implies
the presence of an azaenamine in the syn-form 6, in related
work we obtained an X-ray crystal structure for an azae-
namine analogue that indicated that it exists in the anti-
form 5.10 The low field hydrazone NH at d = 12 is not,
thus, due to deshielding by hydrogen bonding as we be-
lieved, but most likely results from the delocalization of
the nitrogen lone pair [cf. Scheme 1 structure 5(II)]. It is
clear that azaenamines can be seen as bidentate ligands
since they have two nucleophilic and two electrophilic
centers. Due to an interest in developing syntheses for bi-
ologically interesting fused pyridazines8,12,13 herein, we
Formation of such tetracyclic product supports our sug-
gestion that the reaction proceeds via initial addition of
the hydrazone CH in compound 5a to the activated double
bond in 7 followed by cyclization rather that initial addi-
tion of NH in 5a to the double bond in 7. Repeating these
reactions with carboxamide 5b gave the same results. In
an extension of our study we also found that ethyl 3-(4-
chlorophenyl)-2-cyanoacrylate (7b) and ethyl 2-cyano-3-
(4-methoxyphenyl)acrylate (7c) also added to 5a to yield
products 10b and 10c,respectively. The structure of 10c
was established based on spectral data. The IR spectra in-
1
dicated the absence of the CN band; the H NMR spec-
trum of 10c indicated the presence of one ester group with
a characteristic triplet at d = 1.14 (J = 7.2 Hz) for CH3 and
quartet at d = 4.07 (J = 7.2 Hz) for CH2. It also featured
characteristic set of multiplets at d ~ 1.77 and 2.71 for the
cyclohexene ring. It indicated two singlets at d ~ 2.36 and
3.69 for (MeCO) and OMe, respectively. In addition it in-
dicated a singlet at d = 5.05 for H4 of the pyridazine. It
also revealed aromatic protons as two doublets at d = 6.80
and 7.11. Finally the broad singlet at d = 11.16 was as-
signed to NH. Furthermore, full assignment of the 13C
NMR data confirmed the structure of 10c, where the key
signal at d = 13.7 was assigned to CH3CH2 and signals at
SYNTHESIS 2010, No. 7, pp 1107–1112
x
x
.
x
x
.2
0
1
0
Advanced online publication: 20.01.2010
DOI: 10.1055/s-0029-1219235; Art ID: Z24509SS
© Georg Thieme Verlag Stuttgart · New York

1108
I. A. Abdelhamid et al.
PAPER
signal. Full spectral data for all new compounds are pre-
sented in the experimental section. Also aryl-
idenemalononitriles added to azaenamine 5a and gave
compounds 10d,e. The structure of the products was also
established based on spectral data. Moreover, 2-cyano-3-
phenylacrylamide (7f) and 3-(4-chlorophenyl)-2-cyano-
acryamide (7g) were added to 5a to yield 10f and 10g. The
reactivity of azaenamine 5a was also tested with 2-(4-
chlorobenzoyl)-3-phenylacrylonitrile (7h) and the prod-
uct was found to be, as expected, 10h. These syntheses
have been conducted in a much shorter time by heating the
reaction mixture in a microwave oven, leading also to
much better yields (Table 1).
Y
+
N
Cl–
N
O
O
i) KOH
S
CO2H
CO2Et
ii) H+
3a, Y = CO2Et
3b, Y = CONH2
2
1
O
O
CO2H
NH
E+
O
H
N
N
N
N
S
68–73%
NH
Nu–
Y
Y
Y
S
S
Compound 5a was condensed with malononitrile (13a) in
dioxane–piperidine to yield the tetracyclic compound 16
(Scheme 3). Compound 16 is believed to be formed via
the acyclic intermediate 14, which cyclized into 15 fol-
6
5a, Y = CO2Et
5b, Y = CONH2
4
Table 1 Reaction of 5a with Various Acrylonitriles 7a–h by Con-
ventional Heating and Microwave Irradiation (MWI)
O
E+
Acrylonitrile R
Ar
Product Yield (%)
Thermal MWI
N
S
Nu–
NH
Y
7a
7b
7c
7d
7e
7f
CO2Et
Ph
10a
10b
67
71
66
70
68
78
80
72
81
85
79
92
87
94
92
86
CO2Et
CO2Et
CN
4-ClC6H4
5(II)
4-MeOC6H4 10c
Scheme 1
Ph
10d
10e
10f
CN
4-MeC6H4
Ph
d = 21.2, 22.2, 23.6, and 24.5 were assigned to CH2 of the
cyclohexene; the following signals were also assigned:
24.6 (CH3CO), 33.5 (CH pyridazine), 54.8 (OMe), 59.9
(MeCH2), 78.2 (CCO2Et), 167.1 (CO2Et), and 194.5
(CO). 13C NMR also indicated the absence of the CN
CONH2
CONH2
COPh
7g
7h
4-ClC6H4
4-ClC6H4
10g
10h
O
Ar
N
O
Ar
O
Ar
N
R
R
R
N
S
N
CN
N
S
O
67–94%
NH
NH
NH2
Ar
CN
R
CO2Et
CO2Et
O
S
N
S
NH
7
CO2Et
8
9
10
X
5a
O
O
NH2
NC
N
R
R
N
N
S
Ar
N
Ar
no further
cyclization
CO2Et
CO2Et
S
11
12
Scheme 2
Synthesis 2010, No. 7, 1107–1112 © Thieme Stuttgart · New York

PAPER
Synthesis and Chemical Reactivity of New Azaenamines
1109
lowed by ethanol elimination. The structure of 16 was elu-
cidated based on mass spectroscopy and 1H and 13C NMR,
which revealed the absence of the OEt group. Thus the IR
spectrum showed two bands at 2223.8 and 1682.4 cm–1 for
CN and CO, respectively. The 1H NMR spectrum showed
a singlet at d = 2.58 (CH3), a singlet at d = 8.69 (H2 of the
pyridazine), and multiplets at d = 1.78 and 2.91–2.93
(Hc-hexene). Furthermore, full assignment of the 13C NMR
data confirmed the structure 16; the following key signals
at d = 18.3, 21.3, 22.1, 24.4 (Cc-hexene), 24.9 (CH3), and
112.2 (CN) were assigned while the signals at 112.7,
123.8, 132.5, 134.6, 142.9, 144.3, 146.1, 146.8 were as-
signed to olefinic and aromatic carbons. The signal at
162.7 was assigned to (CO).
R
CN
O
CN
N
S
N
S
NH
R
NH
13a, R = CN
13b, R = CONH2
CO2Et
CO2Et
5a
14a, R = CN
14b, R = CONH2
CN
N
CN
N
N
N
S
On the other hand attempts to react compound 5a with cy-
anoacetamide (13b) resulted in the formation of acyclic
product 14b; attempts to cyclize compound 14b failed.
The structure of compound 14b was established based on
its mass spectrum, which indicated molecular ion peak as
base peak at m/z 360. 1H NMR revealed the presence of an
ester group with a characteristic triplet at d = 1.12 (J = 7.2
Hz, CH3) and a quartet at d = 4.23 (J = 7.2 Hz, CH2). It
featured a characteristic set of multiplets at d ~ 1.69 and
2.65 (Hc-hexene), in addition it showed a singlet at d = 8.61
(Hvinyl) and a singlet at 7.91 (NH2); the NH signal ap-
peared at d = 11.62.
N
NH
R = CN
– EtOH
63%
CO2Et
O
S
15
16
Scheme 3
O
O
R
N
O
N
N
R
H
19
N
NH
The reactivity of the CH group in the azaenamine could be
also examined via the Mannich reaction, which is one of
the most widely used reactions for the formation of car-
bon–carbon bonds.14–16 In its initial form, it utilizes the ad-
dition of an aldehyde to a ketone in the presence of an
amine. Herein, the scope of the Mannich reaction was ex-
tended to the addition of azaenamine 5a to different alde-
hydes in presence of piperidine. The CH group of
compound 5a can be easily deprotonated under basic con-
ditions. The resulting salt can be viewed as an aza-substi-
tuted carbanion and, as such, may react in the Mannich
reaction leading to C–C bond formation (Scheme 4).
Thus, the reaction of 5a with formaldehyde and piperidine
resulted in the formation of Mannich product 21a. The IR
spectrum of 21a showed two bands at 1668.1 and 1532.2
cm–1 for two CO groups and a broad band at 3450.9 cm–1
CO2Et
NH
CO2Et
S
S
5a
18
O
R
N
O
R
N
N
N
S
N
84–93%
NH
CO2Et
CO2Et
S
20
21a, R = H
21b, R = Ph
1
for NH. The H NMR spectrum showed a triplet at d =
21c, R = 4-ClC6H4
21d, R = 4-MeOC6H4
1.25 (CH3CH2), multiplets at d = 1.3, 2.32 (Hpiperidine),
multiplets at d = 1.55 and 2.56 (Hc-hexene), and a singlet sig-
nal at d = 3.53 (CH2). In addition it indicated a quartet at
Scheme 4
O
O
N
N
S
CHO
CHO
HN
N
N
piperidine
NH
O
N
S
+
O
OEt
NH
reflux, 5 h
67%
O
O
S
OEt
OEt
5a
22
Scheme 5
Synthesis 2010, No. 7, 1107–1112 © Thieme Stuttgart · New York

1110
I. A. Abdelhamid et al.
PAPER
[1]Benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazines 10a–h;
d = 4.24 (CH2, ester). In a similar fashion, benzaldehyde,
4-chlorobenzaldehyde, and 4-methoxybenzaldehyde re-
acted with azaenamine 5a to give compounds 21b–d.
General Procedures
Method A: A mixture of azaenamine 5a or 5b (10 mmol) and a,b-
unsaturated nitrile 7a–h was refluxed in dioxane (20 mL) in pres-
ence of piperidine (0.5 mL) for 5 h. The solvent was evaporated un-
der vacuum and the crude product was collected and crystallized
(dioxane).
In an extension of this reaction we found that terephthal-
aldehyde reacted with 5a to give bis-Mannich product 22
(Scheme 5). The structure was confirmed based on spec-
tral data.
Method B: A soln of 5a or 5b (10 mmol) was treated with a,b-un-
saturated nitriles 7a–h (10 mmol) in pyridine (2 mL) and irradiated
in a microwave oven for 2 min, then poured onto H2O and acidified
with dil HCl. The solid product obtained was crystallized (dioxane).
We report a new simple and efficient route to new aza-
enamines incorporated the tetrahydrobenzothiophene
moiety. The prepared azaenamines are valuable precur-
sors for synthesis of fused pyridazine derivatives via 3+3
atom combination reaction of azaenamines with unsatur-
ated nitriles.
Ethyl 2-Acetyl-6-oxo-3-phenyl-5,6,7,8,9,10-hexahydro-3H-
[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carboxy-
late (10a)
Yield: 67% (thermal), 81% (microwave); mp 220–222 °C.
IR (KBr): 3452.9 (NH), 1690.3, 1667.1, 1624.7 cm–1 (3 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.13 (t, J = 7.2 Hz, 3 H, CH3),
1.79 (m, 4 H, Hc-hexene), 2.36 (s, 3 H, CH3CO), 2.71–2.79 (m, 4 H,
Melting points were determined on a Stuart melting point apparatus
and are uncorrected. The IR spectra were recorded as KBr pellets
using a Bruker-vector 22 spectrophotometer FTIR. The 1H and 13
C
Hc-hexene), 4.07 (q, J = 7.2 Hz, 2 H, CH2), 5.09 (s, 1 H, H3), 7.21–
NMR spectra were recorded in DMSO-d6 as solvent at 300 MHz
and 75 MHz, respectively, on a Varian Gemini NMR spectrometer
using TMS as internal standard. Mass spectra were measured on a
Shimadzu GMSS-QP-1000 EX mass spectrometer at 70 eV. Micro-
wave experiments were conducted in domestic microwave. The re-
actants were placed in a glass conical container and the oven was
placed in an efficient hood. No special precautions were used as we
did not experience any bumping during our experiments.
7.27 (m, 5 H, HAr), 11.19 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.7, 21.3, 22.2, 23.7, 24.5,
34.5, 59.9, 66.2, 78.1, 113.1, 120.5, 127.1, 127.7, 128.4, 132.0,
141.1, 141.9, 149.1, 150.2, 154.7, 167.1, 194.5.
MS: m/z = 449 (M+).
Anal. Calcd for C24H23N3O4S (449.53): C, 64.13; H, 5.16; N, 9.35;
S, 7.13. Found: C, 64.00; H, 5.03; N, 9.11; S, 6.97.
2-[2-(2-Oxopropylidene)hydrazino]benzo[b]thiophenes 5a,b;
General Procedure
Ethyl 2-Acetyl-3-(4-chlorophenyl)-6-oxo-5,6,7,8,9,10-hexahy-
dro-3H-[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-
carboxylate (10b)
Yield: 71% (thermal), 85% (microwave); mp 202–204 °C.
IR (KBr): 3453.3 (NH), 1690.6, 1669.1, 1632.3 cm–1 (3 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.11 (t, J = 7.2 Hz, 3 H, CH3),
1.77 (m, 4 H, Hc-hexene), 2.35 (s, 3 H, CH3CO), 2.68–2.77 (m, 4 H,
A mixture of KOH (3.5 g) in H2O (100 mL) and ethyl acetoacetate
(1, 6.5 mL) was allowed to stir at r.t. for 24 h. This soln was then
cooled to 0 °C and acidified with concd HCl (4.5 mL) in ice water
(15 mL). The resulting soln was treated with aryldiazonium chlo-
ride [prepared from the corresponding aromatic amine (0.05 mol)
and the appropriate quantities of both HCl and NaNO2]. The mix-
ture was made basic by addition of NaOAc (8.0 g). The solid prod-
uct, so formed was collected by filtration.
Hc-hexene), 5.06 (q, J = 7.2 Hz, 2 H, CH2), 5.06 (s, 1 H, H3), 7.25–
7.33 (m, 4 H, HAr), 11.17 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 13.7, 21.2, 22.2, 23.6, 24.4,
24.6, 34.2, 59.9, 66.1, 77.7, 113.1, 120.4, 128.4, 129.7, 131.8,
132.0, 140.8, 141.1, 148.6, 154.6, 167.0, 194.4.
Ethyl 2-[2-(2-Oxopropylidene)hydrazino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylate (5a)
Yellow solid (from EtOH); yield: 73%; mp 116–118 °C.
IR (KBr): 3445.4 (NH), 1664.7, 1659.1 cm–1 (2 CO).
MS: m/z = 483 (M+).
1H NMR (300 MHz, DMSO-d6): d = 1.28 (t, J = 7.2 Hz, 3 H, CH3),
1.35–1.70 (m, 4 H, Hc-hexene), 2.24 (s, 3 H, CH3CO), 2.54–2.66 (m,
4 H, Hc-hexene), 4.24 (q, J = 7.2 Hz, 2 H, CH2), 7.65 (s, 1 H, Hvinyl),
11.48 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 22.0, 22.4, 23.9, 25.9,
59.7, 66.3, 106.8, 123.2, 132.4, 139.0, 156.3, 163.7, 196.4.
Anal. Calcd for C24H22ClN3O4S (483.98): C, 59.56; H, 4.58; N,
8.68; S, 6.63. Found: C, 59.53; H; 4.46; N, 8.62; S, 6.44.
Ethyl 2-Acetyl-3-(4-methoxyphenyl)-6-oxo-5,6,7,8,9,10-hexahy-
dro-3H-[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-
carboxylate (10c)
Yield: 66% (thermal), 79% (microwave); mp 216–218 °C.
IR (KBr): 3442.2 (NH), 1685.1 1669.0, 1632.7 cm–1 (3 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.14 (t, J = 7.2 Hz, 3 H, CH3),
1.77–1.79 (m, 4 H, Hc-hexene), 2.36 (s, 3 H, CH3CO), 2.71–2.79 (m,
4 H, Hc-hexene), 3.69 (s, 3 H, OCH3), 4.07 (q, J = 7.2 Hz, 2 H, CH2),
5.05 (s, 1 H, H3), 6.80 (d, J = 9 Hz, 2 H, HAr), 7.11 (d, J = 9 Hz, 2
H, HAr), 11.16 (s, 1 H, NH).
MS: m/z = 294 (M+).
Anal. Calcd for C14H18N2O3S (294.38): C, 57.12; H, 6.16; N, 9.52;
S, 10.89. Found: C, 57.02; H, 5.98; N, 9.43; S, 10.78.
2-[2-(2-Oxopropylidene)hydrazino]-4,5,6,7-tetrahydroben-
zo[b]thiophene-3-carboxamide (5b)
Green solid (from EtOH); yield: 68%; mp 150–152 °C.
13C NMR (75 MHz, DMSO-d6): d = 13.7, 21.2, 22.2, 23.6, 24.5,
24.6, 33.5, 43.2, 54.8, 59.9, 66.1, 78.2, 113.4, 128.8, 132.0, 134.1,
140.9, 149.3, 150.2, 154.6, 158.3, 167.1, 194.5.
IR (KBr): 3441.2 (NH), 1659.4, 1630.7 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.72 (m, 4 H, Hc-hexene), 2.23 (s,
3 H, CH3CO), 2.58–2.73 (m, 4 H, Hc-hexene), 7.06 (br s, 2 H, NH2),
7.5 (s, 1 H, Hvinyl), 11.52 (s, 1 H, NH).
MS: m/z = 479 (M+).
MS: m/z = 265 (M+).
Anal. Calcd for C25H25N3O5S (479.56): C, 62.62; H, 5.25; N, 8.76;
S, 6.69. Found: C, 62.57; H, 5.12; N, 8.66; S, 6.63.
Anal. Calcd for C12H15N3O2S (265.34): C, 54.32; H, 5.70; N, 15.84;
S, 12.08. Found: C, 54.19; H, 5.61; N, 15.82; S, 11.86.
Synthesis 2010, No. 7, 1107–1112 © Thieme Stuttgart · New York

PAPER
Synthesis and Chemical Reactivity of New Azaenamines
1111
2-Acetyl-6-oxo-3-phenyl-5,6,7,8,9,10-hexahydro-3H-[1]ben-
zothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile
(10d)
1H NMR (300 MHz, DMSO-d6): d = 1.78 (m, 4 H, Hc-hexene), 2.37 (s,
3 H, CH3CO), 2.74–2.84 (m, 4 H, Hc-hexene), 5.24 (s, 1 H, H3), 6.80–
7.49 (m, 9 H, HAr), 11.17 (s, 1 H, NH).
Yield: 70% (thermal), 92% (microwave); mp 238–240 °C.
IR (KBr): 3445.8 (NH), 2223.7 (CN), 1668.9, 1634.2 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.81–1.93 (m, 4 H, Hc-hexene),
2.12 (s, 3 H, CH3CO), 2.82–2.94 (m, 4 H, Hc-hexene), 5.11 (s, 1 H,
H3), 7.66–8.06 (m, 5 H, HAr), 11.78 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 21.4, 22.4, 23.9, 24.7, 24.8,
53.8, 86, 120.5, 120.7, 126.1, 128.3, 128.6, 129.6, 130.2, 132.1,
132.3, 139.4, 140.3, 143.1, 145.5, 150.5, 155.1, 194.4, 194.6.
MS: m/z = 515 (M+).
Anal. Calcd for C28H22ClN3O3S (516.02): C, 65.17; H, 4.30; N,
8.14; S, 6.21. Found: C, 64.97; H, 4.26; N, 8.09; S, 5.95.
MS: m/z = 402 (M+).
Anal. Calcd for C22H18N4O2S (402.48): C, 65.65; H, 4.51; N, 13.92;
S, 7.97. Found: C, 65.60; H, 4.39; N, 13.86; S, 7.91.
2-(2-But-2-enylidenehydrazino)benzo[b]thiophenes14band16;
General Procedure
A mixture of azaenamine 5a (10 mmol), and active methylene com-
pound 7a,b was refluxed in dioxane (20 mL) in presence of piperi-
dine (0.5 mL) for 5 h (10 min for 16). The solvent was evaporated
under vacuum and the crude product was collected and crystallized
(dioxane).
2-Acetyl-3-(4-methylphenyl)-6-oxo-5,6,7,8,9,10-hexahydro-3H-
[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carboni-
trile (10e)
Yield: 68% (thermal), 87% (microwave); mp 172–174 °C.
IR (KBr): 3442.5 (NH), 2221.2 (CN), 1664.1, 1624.2 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.81–1.93 (m, 4 H, Hc-hexene),
2.12 (s, 3 H, CH3CO), 2.38 (s, 3 H, CH3), 2.82–2.94 (m, 4 H, Hc-hexene),
4.81 (s, 1 H, H3), 7.37–7.47 (m, 4 H, HAr), 14.02 (s, 1 H, NH).
Ethyl 2-[2-(4-Amino-3-cyano-2-methyl-4-oxobut-2-
enylidene)hydrazino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (14b)
Yield: 65%; mp 120–122 °C.
MS: m/z = 416 (M+).
IR (KBr): 3423.3, 3341.2, 3184.8 (NH, NH2), 2259.2 (CN), 1673.9,
1624.7 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.12 (t, J = 7.2 Hz, 3 H, CH3),
1.69 (m, 4 H, Hc-hexene), 1.90 (s, 3 H, CH3), 2.65 (m, 4 H, Hc-hexene),
4.23 (q, 2 H, CH2), 8.61 (s, 1 H, Hvinyl), 7.91 (s, 2 H, NH2), 11.62 (s,
1 H, NH).
Anal. Calcd for C23H20N4O2S (416.51): C, 66.33; H, 4.84; N, 13.45;
S, 7.70. Found: C, 66.20; H, 4.78; N, 13.31; S, 7. 59.
2-Acetyl-6-oxo-3-phenyl-5,6,7,8,9,10-hexahydro-3H-[1]ben-
zothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carboxamide
(10f)
MS: m/z = 360 (M+).
Yield: 78% (thermal), 94% (microwave); mp 280–282 °C.
IR (KBr): 3466.4, 3344.9, 3143.4 (NH, NH2), 1664.2, 1567.8 cm–1
(3 CO).
Anal. Calcd for C17H20N4O3S (360.44): C, 56.65; H, 5.59; N, 15.54;
S, 8.90. Found: C, 56.29; H, 5.34; N, 15.31; S, 8.69.
1H NMR (300 MHz, DMSO-d6): d = 1.76–1.77 (m, 4 H, Hc-hexene),
2.36 (s, 3 H, CH3CO), 2.68–2.78 (m, 4 H, Hc-hexene), 5.35 (s, 1 H,
H3), 7.19–7.35 (m, 7 H, HAr, NH2), 12.98 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 21.4, 22.4, 23.8, 24.7, 33.7,
79.4, 109.2, 113.1, 120.6, 127.2, 127.7, 128.5, 132.2, 139.9, 141.4,
147.8, 155.1, 155.9, 169.6, 194.7.
3-Methyl-6-oxo-7,8,9,10-tetrahydro-6H-[1]benzo-
thieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile (16)
Yield: 63%; mp 292–294 °C.
IR (KBr): 2223.8 (CN), 1682.4 cm–1 (CO).
1H NMR (300 MHz, DMSO-d6): d = 1.78 (m, 4 H, Hc-hexene), 2.58 (s,
3 H, CH3), 2.91–2.93 (m, 4 H, Hc-hexene), 8.69 (s, 1 H, H2).
MS: m/z = 420 (M+).
13C NMR (75 MHz, DMSO-d6): d = 18.3, 21.3, 22.1, 24.4, 24.9,
Anal. Calcd for C22H20N4O3S (420.49): C, 62.84; H, 4.79; N, 13.32;
S, 7.63. Found: C, 62.52; H, 4.63; N, 13.12; S, 7.60.
112.2, 112.7, 123.8, 132.5, 134.6, 142.9, 144.3, 146.1, 146.8, 162.8.
MS: m/z = 296 (M+).
2-Acetyl-3-(4-chlorophenyl)-6-oxo-5,6,7,8,9,10-hexahydro-3H-
[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazine-4-carbox-
amide (10g)
Anal. Calcd for C15H12N4OS (296.35): C, 60.79; H, 4.08; N, 18.91;
S, 10.82. Found: C, 60.43; H, 3.82; N, 18.66; S, 10.65.
Yield: 80% (thermal), 92% (microwave); mp 264–266 °C.
IR (KBr): 3467.1, 3346.3, 3143.9 (NH, NH2), 1664.3, 1571.2 cm–1
(CO).
1H NMR (300 MHz, DMSO-d6): d = 1.75 (m, 4 H, Hc-hexene), 2.35 (s,
3 H, CH3CO), 2.67–2.77 (m, 4 H, Hc-hexene), 5.36 (s, 1 H, H3), 7.26–
7.39 (m, 6 H, HAr, NH2), 13.01 (s, 1 H, NH).
Mannich Products 21a–d; General Procedure
To a soln of hydrazone 5 (1 mmol) in piperidine (5 mL) was added
aldehyde (1 mmol) and the mixture refluxed for 3–4 h. Evaporation
of the solvent afforded the crude product which was crystallized
(EtOH) in a good yield.
Ethyl 2-{2-[2-Oxo-1-(piperidin-1-ylmethyl)propylidene]hy-
drazino}-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
(21a)
MS: m/z = 454 (M+).
Anal. Calcd for C22H19ClN4O3S (454.94): C, 58.08; H, 4.21; N,
12.32; S, 7.05. Found: C, 57.92; H, 4.03; N, 12.17; S, 6.88.
Yield: 84%; mp 140–142 °C.
IR (KBr): 3450.9 (NH), 1668.1, 1532.2 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.2 Hz, 3 H, CH3),
1.30 (m, 4 H, Hpiperidine), 1.55–1.57 (m, 4 H, Hc-hexene), 2.32 (m, 6 H,
2-Acetyl-4-benzoyl-3-(4-chlorophenyl)-3,5,7,8,9,10-hexahydro-
6H-[1]benzothieno[3¢,2¢:5,6]pyrimido[1,2-b]pyridazin-6-one
(10h)
Yield: 72% (thermal), 86% (microwave); mp 180–182 °C.
IR (KBr): 3452.9 (NH), 1692.2, 1626.7 cm–1 (3 CO).
Hpiperidine), 2.48 (s, 3 H, CH3), 2.56–2.68 (m, 4 H, Hc-hexene), 3.53 (s,
2 H, CH2), 4.24 (q, J = 7.2 Hz, 2 H, CH2), 13.25 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.1, 22.2, 22.5, 23.6, 23.7,
24.1, 24.4, 26.0, 52.6, 53.5, 59.6, 107.2, 123.0, 132.2, 141.7, 163.9,
195.3.
Synthesis 2010, No. 7, 1107–1112 © Thieme Stuttgart · New York

1112
I. A. Abdelhamid et al.
PAPER
MS: m/z = 391 (M+).
3–4 h. Evaporation of the solvent afforded the crude product which
was crystallized (EtOH); yield: 67%; mp 248–250 °C.
IR (KBr): 1723.3, 1667.6 cm–1 (4 CO).
Anal. Calcd for C20H29N3O3S (391.54): C, 61.35; H, 7.47; N, 10.73;
S, 8.19. Found: C, 61.13; H, 7.17; N, 10.49; S, 7.95.
1H NMR (300 MHz, DMSO-d6): d = 1.25–142 (t, J = 7.2 Hz, 6 H,
2CH3), 1.42–1.58 (m, 12 H, Hpiperidine), 1.60 (m, 8 H, Hc-hexene), 2.59–
2.78 (m, 8 H, Hc-hexene), 2.33 (s, 6 H, 2 CH3CO), 3.12–3.30 (m, 8 H,
Hpiperidine), 4.34 (q, J = 7.2 Hz, 4 H, 2 CH2), 4.80 (s, 2 H, CH), 7.14
(m, 4 H, HAr).
13C NMR (75 MHz, DMSO-d6): d = 14.4, 22.7, 23.0, 24.7, 25.1,
26.6, 44.0, 52.9, 59.8, 68.1, 107.9, 123.4, 125.9, 128.5, 132.9,
136.9, 142.2, 157.7, 164.5, 196.6.
Ethyl 2-(2-{2-Oxo-1-[phenyl(piperidin-1-yl)methyl]propy-
lidene}hydrazino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxylate (21b)
Yield: 93%; mp 152–154 °C.
IR (KBr): 3441.5 (NH), 1667.9, 1623.1 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.2 Hz, 3 H, CH3),
1.39 (m, 4 H, Hpiperidine), 1.69 (m, 4 H, Hc-hexene), 2.31 (m, 6 H,
H
piperidine), 2.48 (s, 3 H, CH3CO), 2.67–2.72 (m, 4 H, Hc-hexene), 4.23
MS: m/z = 857 (M+).
(q, J = 7.2 Hz, 2 H, CH2), 4.76 (s, 1 H, CH), 7.35–7.43 (m, 5 H,
Anal. Calcd for C46H60N6O6S2 (857.14): C, 64.46; H, 7.06; N, 9.80;
S, 7.48. Found: C, 64.33; H, 6.87; N, 9.71; S, 7.34.
HAr), 12.62, (s, 1 H, NH).
MS: m/z = 467 (M+).
Anal. Calcd for C26H33N3O3S (467.64): C, 66.78; H, 7.11; N, 8.99;
S, 6.86. Found: C, 66.23; H, 6.75; N, 8.57; S, 6.61.
Acknowledgment
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 Butenschön,
Institut für Organische Chemie, Leibniz Universität Hannover, for
his kind hospitality.
Ethyl 2-(2-{1-[(4-Chlorophenyl)(piperidine-1-yl)methyl]-2-oxo-
propylidene}hydrazino)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxylate (21c)
Yield: 93%; mp 176–178 °C.
IR (KBr): 1673.9 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.28 (t, J = 7.2 Hz, 3 H, CH3),
1.32 (m, 6 H, Hpiperidine), 1.71 (m, 4 H, Hc-hexene), 2.24 (s, 3 H,
CH3CO), 2.32 (m, 4 H, Hpiperidine), 2.70–2.75 (m, 4 H, Hc-hexene), 4.28
(q, J = 7.2 Hz, 2 H, CH2), 4.81 (s, 1 H, CH), 7.37–7.47 (m, 4 H,
HAr), 13.46 (s, 1 H, NH).
References
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Ghozlan, S. A. S. Tetrahedron 2009, 65, 10069.
(9) Ghozlan, S. A. S.; Mohamed, M. H.; Abdelmoniem, A. M.;
Abdelhamid, I. A. ARKIVOC 2009, (x), 302.
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Elnagdi, M. H. J. Heterocycl. Chem. 2007, 44, 105.
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MS: m/z = 502 (M+).
Anal. Calcd for C26H32ClN3O3S (502.08): C, 62.20; H, 6.42; N,
8.37; S, 6.39. Found: C, 61.92; H, 6.11; N, 8.12; S, 6.15.
Ethyl 2-(2-{1-[(4-Methoxyphenyl)(piperidine-1-yl)methyl]-2-
oxopropylidene}hydrazino)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (21d)
Yield: 87%; mp 120–122 °C.
IR (KBr): 3438.5 (NH), 1666.2, 1609.3 cm–1 (2 CO).
1H NMR (300 MHz, DMSO-d6): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3),
1.40–149 (m, 4 H, Hpiperidine), 1.72 (m, 4 H, Hc-hexene), 2.24 (s, 3 H,
CH3CO), 2.55 (m, 2 H, Hc-hexene), 2.70 (m, 2 H, Hc-hexene), 3.12–3.30
(m, 6 H, Hpiperidine), 3.7 (s, 3 H, OCH3), 4.26 (q, J = 7.2 Hz, 2 H,
CH2), 4.74 (s, 1 H, CH), 6.87 (d, J = 8.8 Hz, 2 H, HAr), 7.36 (d,
J = 8.8 Hz, 2 H, HAr), 13.32 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.6, 22.6, 22.9, 24.4, 24.6,
24.7, 24.6, 25.0, 26.6, 52.6, 55.4, 60.3, 67.5, 107.7, 114.8, 123.7,
129.5, 132.9, 143.2, 157.4, 159.2, 164.6, 195.8.
MS: m/z = 497 (M+).
(12) Ghozlan, S. A. S.; Abdelhamid, I. A.; Elnagdi, M. H.
Anal. Calcd for C27H35N3O4S (497.66): C, 65.16; H, 7.09; N, 8.44;
S, 6.44. Found: C, 64.94; H, 6.86; N, 8. 21; S, 6.20.
ARKIVOC 2006, (xiii), 147.
(13) Sayed, G. H.; Hamed, A. A.; Meligi, G. A.; Boraie, W. E.;
Shafik, M. Molecules 2003, 8, 322.
(14) Kabalka, G. W.; Zhou, L.-L.; Wang, L.; Pagni, R. M.
Tetrahedron 2006, 62, 857.
(15) Wu, H.; Shen, Y.; Fan, L.-Y.; Wan, Y.; Zhang, P.; Chen, C.-
F.; Wang, W.-X. Tetrahedron 2007, 63, 2404.
Ethyl 2-[2-(1-{[4-(2-{[3-(Ethoxycarbonyl)-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl]hydrazono}-3-oxo-1-(piperidin-1-yl)bu-
tyl)phenyl](piperidin-1-yl)methyl}-2-oxopropylidene)hydrazi-
no]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (22)
To a soln of hydrazone 5a (1 mmol) in piperidine (2 mL) was added
benzene-1,4-dicarbaldehyde (2 mmol) and the mixture refluxed for
(16) Shi, M.; Cui, S.-C.; Liu, Y.-H. Tetrahedron 2005, 61, 4965.
Synthesis 2010, No. 7, 1107–1112 © Thieme Stuttgart · New York