Pyrolysis of 3-hydroxy-2-arylhydrazonoalkanoic acid derivatives

Article abstract of DOI:10.1016/j.tet.2010.11.074

1,2-Diaza-1,3-butadienes have been obtained from readily available 3-hydroxy-2-arylhydrazonopropanoates under various reaction conditions including pyrolysis, dehydration under Mitsunobu conditions or with acetic anhydride or acetic acid. According to their method of synthesis these 1,2-diaza-1,3- butadienes underwent subsequent reactions to give interesting products, and in the presence of proper dienophiles gave the corresponding cycloaddition products. Also, a new approach to pyrazole-3-carboxylic acid derivatives was discovered during an attempt to dehydrate 3-hydroxy-2-arylhydrazonobutanoic esters.

Full text of DOI:10.1016/j.tet.2010.11.074

Tetrahedron 67 (2011) 1298e1307
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pyrolysis of 3-hydroxy-2-arylhydrazonoalkanoic acid derivatives
*
Nouria A. Al-Awadi , Yehia A. Ibrahim, Elizabeth John, Aneesha Parveen
Chemistry Department, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2010
Received in revised form 1 November 2010
Accepted 23 November 2010
Available online 27 November 2010
1,2-Diaza-1,3-butadienes have been obtained from readily available 3-hydroxy-2-arylhydrazonopropano
ates under various reaction conditions including pyrolysis, dehydration under Mitsunobu conditions or with
acetic anhydride or acetic acid. According to their method of synthesis these 1,2-diaza-1,3-butadienes un-
derwent subsequent reactions to give interesting products, and in the presence of proper dienophiles gave
the corresponding cycloaddition products. Also, a new approach to pyrazole-3-carboxylic acid derivatives
was discovered during an attempt to dehydrate 3-hydroxy-2-arylhydrazonobutanoic esters.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrolysis
1,2-Diaza-1,3-butadienes
Pyrazole-3-carboxylic acid derivatives
1. Introduction
chromatographically as two diastereoisomers (racemic and meso
compound) in the case of 8a, and identified by their 1H and 13C NMR
The chemistry of 1,2-diaza-1,3-butadienes 1 has been widely
reported, however, the number of synthetic procedures is limited.1
These compounds, whether isolated or trapped, undergo a variety
of reactions including addition of nucleophiles2 and cycloaddition
with structurally diverse groups of electron-rich and electron
deficient olefins, as well as 1,3-dipolar cycloadditions affording a va-
riety of heterocyclic systems.3 Synthetic procedures for these 1,2-
spectra in the cases of 8bed. Each of these two isomers showed
a singlet for the OCH at
d
¼5.01e5.07 and 5.18e5.25. On the other
hand, pyrolysis of 6eei (R¼CH3) yielded ethyl glyoxalate arylhy-
drazones 7aed, 1,2-bis-(2-ethoxycarbonylindol-3-yl)ethane 9a,b,
and 6-(ethoxycarbonyl-arylhydrazono-methyl)-4-methyl-1-aryl-
1,4,5,6-tetrahydropyridazine-3-carboxylates 10eei (Scheme 2)
(Table 1).
The structures of the diastereomeric ethers 8, bis-indolyle-
thenes 9 and pyridazines 10 were established by their NMR spec-
troscopic data. 1H NMR spectra of each of the diastereomers 8
diazadienes include dehydrohalogenationof
a
-halohydrazones,4 and
oxidation of hydrazones with I2 or HgO.5 Pyrolysis of 2,5-dihydro-
1,2,3-thiadiazole-1,1-dioxides 2, 3,6-dihydro-1-oxa-3,4-diazin-2-
ones 3 and their sulfur analogues readily takes place affording good
access to derivatives of 1, which have been trapped with N-phe-
nylmaleimide togive the corresponding cycloadducts 46 (Scheme 1).
showed different methine proton and NH signals at
CH), 11.96 (s, 2H, NH) for one diastereomer, and at
CH), 12.05 (s, 2H, NH) for the other diastereomer. The methylene
protons signals (of the COOC2H5) appeared as two signals as
expected for nonidentical diastereotopic proton signals.
d
¼5.22 (s, 2H,
d¼5.06 (s, 2H,
2. Results and discussion
The structures of compounds 9a and 10e were readily confirmed
by 2D NMR experiments. Fig. 1 shows 1H and 13C signal assign-
ments and the HeC correlations in the HMBC 2-D experiment.
In the present work, we report an easy access to these 1,2-diaza-
1,3-butadienes starting with b-ketoesters. Treatment of ethyl ace-
toacetate, ethyl benzoylacetate or acetoacetanilide with different
arenediazonium salts yielded the corresponding hydrazones 5aei,
which, upon reduction with sodium borohydride, gave the corre-
sponding 3-hydroxy-2-arylhydrazonoalkanoic acids 6aei. Pyrolysis
of 6aed (R¼Ph) at 200 ꢀC for 30 min yielded benzaldehyde, ethyl
glyoxalate arylhydrazones 7aed, and ethyl 3-(2-ethoxycarbonyl-1-
phenyl-2-phenylhydrazono-ethoxy)-3-phenyl-2-phenylhydrazono
propionate 8aed. Interestingly, the latter were readily isolated
3. Mechanism
Formation of 7aed and benzaldehyde from each of 6aed can be
explained as a retro Baylis Hillman reaction as shown in Scheme 3.
Compounds 7 were also isolated from the pyrolysis of 6eeh; how-
ever, the expected acetaldehyde yield was so much diminished most
probably due to polymerization under the reaction conditions.
The formation of 9 and 10 can be explained by first dehydration
of 6 to intermediate 1,2-diaza-1,3-butadienes 11, which can then
undergo further reaction depending on the R group. When R¼Ph,
* Corresponding author. E-mail address: n.alawadi@ku.edu.kw (N.A. Al-Awadi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.074

N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
1299
Ph
O
N
O
N
Pyrolysis
S
O
Ph
N
-SO
Ph
N
N
Ph
2
O
R'
R"
N
2
N
O
N
Ph
Ph
N
R'
R'
O
Y
R"
R"
Pyrolysis
-CXY
N
4
1
X
R'
Y
X
R"
3
O
O
S
S
O
S
O
S
Scheme 1.
Ar
NH
N
R
CHO
X
Ph Ph
O
Ph Ph
O
X
R = Ph
X
X
X
X
O
5
N
+
+
HN
+
N
N
N
N
NH
Ar
7
NH
Ar
HN
NH
NaBH /EtOH
4
Ar
Ar
Ar
Static Pyrolysis
200 oC/30 min
8-Syn
8-Anti
Ar
Y
NH
N
X
X
H
N
R
X
N
X
R = CH
N
OH
3
+
+
7
N
Ar
6
N
H
NH
X
9
Ar
10
R
Ar
X
Y
Y
5-8a
5-8b
5-8c
5-8d
Ph Ph
CO Et
2
Ph p-ClC H
CO Et
6
4
2
Ph p-CH OC H CO Et
3
6
4
2
Ph p-O NC H CO Et
2
6
4
2
5e, 6e, 10e CH Ph
CO Et
3
2
5f, 6f, 10f
CH p-ClC H
CO Et
3
6
4
2
5g, 6g, 10g CH p-CH OC H CO Et
3
3
6
4
2
5-7h, 10h
5i, 6i, 10i
CH p-CH C H CO Et
3 3 6 4 2
CH p-ClC H
4
CONHPh
3
6
6j
Ph Ph
Ph
9a
CO Et
H
2
9b
CO Et
Cl
2
Scheme 2.
compound 11 reacts with the starting hydroxyl compound to give
the bis-ether 8. When R¼CH3, compounds 11 undergo a 1,5-H shift
to give the corresponding vinylhydrazones 12, which undergo
[4þ2] cycloaddition with 11 to give the corresponding cycloadduct
pyridazines 10 (Scheme 4).
The formation of the bis-indole derivatives 9 presumably starts by
dimerisation of two molecules of 12 to give 13, which undergo ther-
mal Fischer indolization to give 14. The latter undergoes two suc-
cessive 1,5-H-shift to give 15, which finally undergo another thermal
Fischer indolization to give the isolated products 9 (Scheme 5).
Attempted acetylation of compound 6 with acetic anhydride led
to identifiable isolated products only with 6eei after refluxing for
5 h, and yielded mainly 1-arylpyrazole-3-carboxylates 16, in addi-
tion to their 4-acetyl derivatives 17 and the pyridazine derivatives
10 as a minor by-product. This method offers an easy access to this
class of pyrazole derivative, which are important intermediates in
the synthesis of agrochemicals, herbicides, microbicides,7 plant
growth and protectants.8 Different methods have been reported in
the literature for the synthesis of pyrazole-3(5)-alkyl esters:9
compound 16a was prepared from the reaction of phenyl-
hydrazine with
mation of pyrazole derivatives 16 involves dehydration of 6 to give
intermediates 12, which undergo 6 -electrocyclization followed by
b
-alkoxyvinyl trichloromethyl ketones.9a The for-
p
1,2-hydrogen shift to give 18, this will then oxidize in a similar
fashion to the recently reported fused pyrazolo[3,4-b]pyrazines and
pyrazolo[4,3-c]pyridazines.10 Interestingly, compounds 16f,i have
been obtained as the only product in good yield upon heating 6f,i in
acetic acid (Scheme 6) (Table 2).
The structure of the acetyl derivative 17 has been established
by preparing the isomeric 5-acetyl derivative 20. Thus, treatment

1300
N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
8.21
8.36
121.9
H
H
122.9
8
C=)
H
1.45
14.4
H
C=)
2
2
123.8
4
3
7.24
3a
124.3
120.8 H
5
H
H
O
O
H 4.46
60.8
H
2
161.7
H
9
H
6
1
N
120.1
7.37
137.0 N
H
O
O
125.6 H
7a
7
H
11.91
H
15N 136.3
H
7.54
113.1
9a
1.08 (20.1)
7
CH
CH
O
O
3
3
H
2.92 (23.5)
2.29 (28.0)
H
H
4
O
O
C H O
5
C H O
(135.1)
2 5
5
3
2
6
5.31 (51.1)
1
2N
N
OC H
2
OC H
5
N
N
8
(122.6)
H
5
2
N
H
N
H11.96
N
N
10e
Fig. 1. NMR assignment of compounds 9a and 10e, arrows indicates the HMBC HeC correlation.
of ethyl 2-p-chlorophenylhyradono-3-oxopropionate 19 with
chloroacetone in ethanol in the presence of K2CO3 following
reported procedure11 for the synthesis of 2-acetylpyrazole de-
rivatives gave good yield of 5-acetylpyrazole derivative 20
(Scheme 7).
Dehydration of compounds 6 using Mitsunobu conditions (Ph3P
and DEAD) yielded different products depending on the substrate 6.
Thus, treating 6b,j with Ph3P (1.2 equiv) and DEAD (1.2 equiv) led to
the formation of the corresponding diazadienes 11b,j in good yields
(these two compounds exist as two stereoisomeric forms most
probably around the C]C as indicated by their 13C NMR spectra,
which show double the expected number of 13C signals). On the
other hand, similar treatment of 6e gave the corresponding
R
X
X
X
_
O
H
- H+
R
H
+
+
:N
N
N
+ H+
NH
Ar
H
NH
Ar
NH
O
Ar
7
6
Scheme 3.
X
Ph
Ph
O
O
OH
O
NH
R
N
C H O
2
OC H
2 5
O
5
OC H
2
R
O
R
5
OC H
2
N
N
5
:O
R = Ph
N
HN
NH
O
NH
H
EtO
N
N
Ar
X
8
X
11
X
6
R = CH
3
O
1,5-H shift
O
O
C H O
2
5
N
O
OEt
4 + 2 Cycloaddition
OC H
2
N
5
N
N
EtO
N
NH
N
Ar
NH
X
Ar
12
X
10
12
Scheme 4.

N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
1301
Ar
N
H
H
N
H
N
X
O
O
OEt
OEt
OEt
EtO
O
O
N
N
H
O
O
Thermal Fischer
Indolization
HN
Ar
Dimerization
N
Ar
EtO
EtO
12
-NH
12
12
3
N
N
N
N
Ar
Ar
13
14
Two successive
1,5-H shift
H
N
H
N
X
X
OEt
OEt
Thermal Fischer
Indolization
O
O
O
O
-NH
3
EtO
EtO
X
HN
N
H
NH
Ar
9
15
X = H, Cl
Scheme 5.
AcOH/ Reflux 24 hrs
O
X
X
X
X
OH
H
Ac O/ Reflux 5 hrs
N
X
2
N
N
N
N
+
N
+
N
N
N
Ar
NH
Ar
Ar
16
Ar
6
Ar
17
-H O
10
2
-H
2
X
X
6 π−electrocyclization
N
H
NH
N
followed by 1,2 H shift
N
Ar
12
Ar
18
Scheme 6.
acetic acid. Interestingly, compound 6b reacts with 3-dimethyla-
mino-1-arylpropenones 24a,b in acetic acid to give the corre-
sponding pyridazine derivatives 25a,b (Scheme 8) (Table 3).
The structure of compound 21e was readily confirmed by 2D-
NMR experiments. Fig. 2 shows 1H and 13C important signal as-
signments and the HeC correlations in the HMBC 2-D experiment.
O
O
OC H
2
CHO
5
O
N
N
N
ClCH COCH
2
3
HN
O
EtOH/K CO
2
3
4. Conclusion
Cl
Cl
19
20 (80%)
This work presents a new approach to the 1,2-diaza-1,3-buta-
diene system, which provides versatile intermediates for the syn-
thesis of important heterocyclic compounds. Some of these
diazadienes were successfully isolated and used in cycloaddition
reactions. Also, a new interesting bis-indole derivative was seren-
dipously obtained although in low yield but certainly will open
a new route to the synthesis of this interesting class of compound.
An interesting approach to pyrazole-3-carboxylic acid derivatives
was discovered during the dehydration of 3-hydroxy-2-arylhy-
drazonobutanoic esters.
Scheme 7.
cycloadduct tetrazine derivative 21. Diazadiene 11b readily un-
dergoes cycloaddition with N-phenylmaleimide (22) in refluxing
xylene to give the corresponding pyridazine derivative 23b. Py-
rolysis of 6bef,i,j in the presence of 22 also yielded the corre-
sponding cycloaddition pyridazine derivatives 23bef,i,j. Improved
yields of 23b,e,f,j were obtained upon heating 6b,e,f,j with 22 in

1302
N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
R
O
Pyrolysis, 200 oC
or reflux in AcOH
X
N
Ph
O
N
N
N
Ph
O
Ar
23
O
R = Ph
22
22
OH
CH
3
R
CH
3
X
CO C H
5
X
2
2
R
CO C H
5
X
X
2
2
N
R = CH
-H O
N
3
2
N
NH
Ar
6
HN
N
N
[4 + 2] Cycloaddition
N
N
CO C H
5
N
2
2
N
CO C H
5
N
2
2
Ar
Ar
11
Ar
21
COAr'
R
(CH ) N
3 2
COAr'
X
24a,b
24a, 25a Ar' = Ph
24b, 25b Ar' = p-ClC H
N
6
4
AcOH/Reflux
N
Ar
25a,b (60-72%)
Scheme 8.
2.37
12.2
4.26
64.7
O
O
CH
3
O
O
CH
3
118.6
135.0
O
O
N
O
158.6
62.6
63.6
150.6
155.4
O
O
N
O
4.22
4.40
N
N
N
N
6.01
7.44
H
H
N
H
H
N
142.0
O
O
124.2
128.4
7.32 H
125.6
H
7.17
H
H
Fig. 2. NMR assignment of compounds 21e, arrows indicates the HMBC HeC correlation.
5. Experimental
5.1. General
temperature. Ethanol was evaporated in vacuo and the residue was
extracted with ether, washed several times with water, and dried
over anhydrous sodium sulfate. The solvent was then removed
in vacuo and remaining product was recrystallised from ethanol.
All melting points are uncorrected. IR spectra were recorded in
KBr disks on Perkin Elmer System 2000 FT-IR spectrophotometer.
1H, 13C, and 15N NMR spectra were recorded on Bruker DPX 400,
400 MHz, AvanceII 600, 600 MHz super-conducting NMR spec-
trometers. Mass spectra were measured on a GCMSDFS-Thermo
and with LCMS using Agilent 1100 series LC/MSD with an API-ES/
APCI ionization mode. Microanalyses were performed on a LECO
CHNS-932 Elemental Analyzer. The starting compounds 5a,12
5b,c,13 5d,14 5eeg,15 5h,16 5i,17 6e,18 6j,19 24,23 were prepared by
5.2.1. Ethyl 3-hydroxy-3-phenyl-2-phenylhydrazonopropionate 6a.
Yellow crystals, yield 2.44 g (82%), mp 140 ꢀC. IR: 3417, 3293, 3063,
3015, 2958, 2920, 2851,1696,1563,1235,1097, 755.1H NMR (CDCl3):
d
10.14 (s,1H, NH), 7.48 (d, 2H, J 7.2), 7.37 (t, 2H, J 7.2), 7.31 (t,1H, J 7.2),
7.27 (t, 2H, J 8.4), 7.10 (dd, 2H, J 8.4, 0.6), 6.96 (tt,1H, J 8.4, 0.6), 6.27 (d,
1H, J 3.6), 4.31 (q, 2H, J 7.2), 3.23 (d, 1H, J 3.6), 1.38 (t, 3H, J 7.2). 13C
NMR (CDCl3):
d 165.1, 142.9, 138.7, 131.8, 129.2, 128.8, 128.2, 126.1,
122.2, 113.9, 71.8, 61.4, 14.3. HRMS: m/z¼298.1311 (calcd for
the reported methods. The products 7a,22 7b,
,
20 21 7c,24 7d,22 were
C17H18N2O3: 298.1310).
characterized by comparison with reported data.
5.2.2. Ethyl 2-p-chlorophenylhydrazono-3-hydroxy-3-phenylpropio
nate 6b. Yellow crystals, yield 3.09 g (93%), mp 149 ꢀC. MS: m/
z¼332 (Mþ,100%), 334 (Mþ2, 32%). IR: 3378, 3291,1695,1596,1566,
1513, 1487, 1370, 1329, 1238, 1170, 1088, 1034, 835, 809. 1H NMR
5.2. Synthesis of compounds 6. General procedure
To a solution of 5aei (10 mmol) in ethanol (10 mL), sodium bo-
rohydride (0.57 g,15 mmol, dissolved in 0.5 mL of 2 M NaOH, diluted
with 2 mL of water) was added and stirred overnight at room
(CDCl3):
d 10.18 (s, 1H, NH), 7.48 (d, 2H, J 7.6), 7.40 (t, 2H, J 7.6), 7.33
(t, 1H, J 7.2), 7.25 (d, 2H, J 8.8), 7.06 (d, 2H, J 8.8), 6.30 (d, 1H, J 4.0),

N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
1303
4.32 (m, 2H), 2.94 (d, 1H, J 4.0), 1.39 (t, 3H, J 7.0). 13C NMR (CDCl3):
164.8, 141.6, 138.6, 132.4, 129.2, 128.9, 128.4, 127.0, 126.1, 115.1,
72.3, 61.5, 14.3. Anal. Calcd for C17H17N2O3Cl (332.8): C 61.36, H 5.15,
N 8.42. Found C 61.11, H 5.42, N 8.40.
6.8). 13C NMR (CDCl3):
d
162.6, 142.1, 137.0, 130.8, 129.3, 129.2, 126.5,
d
124.9, 120.5, 114.7, 71.6, 21.3. HRMS¼317.0924 (C16H16N3O2Cl re-
quires 317.0924).
5.3. Action of acetic anhydride on 6eei. General procedure
5.2.3. Ethyl 3-hydroxy-2-p-methoxyphenylhydrazono-3-phenylprop
ionate 6c. Yellow crystals, yield 2.96 g (90%), mp 150 ꢀC. IR: 3338,
3282, 1687,1566, 1517, 1309, 1228,1209,1187,1118,1093,1028, 827,
A mixture of compounds 6eei (1 mmol) and acetic anhydride
(1 mL) was refluxed for 5 h. The reaction mixture was poured over
crushed ice, extracted with DCM, washed with water and dried over
anhydrous sodium sulfate. The solvent was then removed in vacuo
and the product was separated by column chromatography using
pet. ether (60e80)/ethyl acetate as an eluent to give the corre-
sponding compounds 10eeh, 16f,g,i, and 17f,h (Table 2).
578. 1H NMR (CDCl3):
d 9.99 (s, 1H, NH), 7.49 (d, 2H, J 7.6), 7.38 (t,
2H, J 7.2), 7.32 (t, 1H, J 7.2), 7.06 (d, 2H, J 6.8), 6.85 (d, 2H, J 7.2), 6.29
(d, 1H, J 4.0), 4.33 (m, 2H), 3.79 (s, 3H), 3.01 (d, 1H, J 4.0), 1.39 (t, 3H,
J 7.2). 13C NMR (CDCl3):
d 165.2, 155.3, 138.8, 136.9, 130.6, 128.8,
128.2, 126.1, 115.2, 114.6, 71.8, 61.2, 55.6, 14.3. Anal. Calcd for
C18H20N2O4 (328.4): C 65.84, H 6.14, N 8.53. Found C 65.41, H 6.23,
N 8.51.
5.4. Static pyrolysis of 6aei. General procedure
5.2.4. Ethyl 3-hydroxy-2-p-nitrophenylhydrazono-3-phenylpropiona
te 6d. Yellow crystals, yield 2.92 g (85%), mp 151 ꢀC. IR: 3375, 3271,
1701, 1602, 1574, 1508, 1484, 1335, 1242, 1191, 1167, 1111, 1090, 1009,
Compounds 6aei (0.5 mmol) were introduced in a reaction tube
(1.5ꢁ12 cm Pyrex), cooled in liquid nitrogen, sealed under vacuum
(0.045 Torr) and placed in the pyrolyzer for 30 min at 200 ꢀC. The
products obtained 7e10 (Table 1) were isolated by column chro-
matography using pet. ether (60e80)/ethyl acetate as an eluent.
852. 1H NMR (CDCl3):
d
10.79 (s, 1H, NH), 8.21 (d, 2H, J 10.4), 7.47 (d,
2H, J 7.6), 7.42 (m, 3H), 7.21 (d, 2H, J 10.4), 6.35 (d, 1H, J 4.0), 4.33 (m,
2H), 3.03 (d, 1H, J 4.0), 1.40 (t, 3H, J 6.0). 13C NMR (CDCl3):
164.2,
d
148.1, 142.0, 138.2, 135.9, 129.1, 128.8, 126.9, 125.8, 113.3, 73.4, 61.8,
14.3. Anal. Calcd for C17H17N3O5 (343.3): C 59.47; H 4.99, N 12.24.
Found C 59.19, H 5.08, N 12.17.
Table 1
Static pyrolysis of compounds 6aeia
Entry
Substrate
Products (yield%b)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
PhCHO (31), 7a (38), 8a (32, 19)
PhCHO (15), 7b (15), 8b (25, 13)
PhCHO (6), 7c (6), 8c (10, 7)
PhCHO (8), 7d (7), 8d (5, 4)
AcH (3), 7a (20), 9a (2), 10e (4)
AcH (4), 7b (20), 9b (2), 10f (8)
AcH (3), 7c (18), 10g (8)
5.2.5. Ethyl 3-hydroxy-2-phenylhydrazonobutyrate 6e. Yellow crys-
tals, yield 4.6 g (50%), mp 83e84 ꢀC (lit.18 mp 93 ꢀC). LCMS: m/
z¼237 (Mþ1). IR: 3416, 3274, 2980, 1696, 1600, 1566, 1500, 1286,
1234, 1169, 1110, 1069, 752. 1H NMR (CDCl3):
d 10.35 (s, 1H), 7.19 (t,
2H, J 8.0), 7.01 (d, 2H, J 8.4), 6.87 (t, 1H, J 7.4), 5.14 (q, 1H, J 7.2), 4.16
(m, 2H), 3.08 (s, 1H), 1.40 (d, 3H, J 7.2), 1.27 (t, 3H, J 7.2). 13C NMR
AcH (3), 7h (20), 10h (5)
10i (30)
(CDCl3): d 164.6, 143.1, 133.6, 129.2, 121.9, 113.7, 67.3, 61.2, 18.5, 14.2.
HRMS¼236.1155 (C12H16N2O3 requires 236.1155).
a
The substrate (0.5 mmol) was pyrolyzed at 200 ꢀC for 30 min.
Conversion yield.
b
5.2.6. Ethyl 2-p-chlorophenylhydrazono-3-hydroxybutyrate 6f.
Colorless crystals, yield 0.7 g (26%), mp 99e100 ꢀC. LCMS: m/
z¼271 (Mþ1). IR: 3398, 3252, 2982, 1703, 1577, 1490, 1282, 1240,
Table 2
Products of heating 6eei in acetic anhydride and acetic acid
1164, 1120, 1093, 833, 819. 1H NMR (CDCl3):
d 10.49 (s, 1H), 7.18 (d,
Entry
Substrate
Products (yield%)
1a
2a
3b
4a
5a
6a
7b
6e
6f
6f
6g
6h
6i
10e (4)
10f (8), 16f (24), 17f (10)
16f (97)
10g (8), 16g (40)
10h (5), 17h (25)
16i (12)
2H, J 9.2), 6.97 (d, 2H, J 9.2), 5.19 (dq, 1H, J 7.2, 3.2), 4.23 (m, 2H),
3.52 (d, 1H, J 3.2), 1.46 (d, 3H, J 7.2), 1.34 (t, 3H, J 7.2). 13C NMR
(CDCl3):
d 164.5, 141.7, 134.4, 129.2, 126.7, 114.8, 67.3, 61.4, 18.4,
14.2. HRMS¼270.0765 (C12H15N2O3Cl requires 270.0765).
5.2.7. Ethyl 3-hydroxy-2-p-methoxyphenylhydrazonobutyrate 6g.
Red oil, yield 0.9 g (35%). LCMS: m/z¼267 (Mþ1). IR: 3264, 2981,
2933, 2836, 1678, 1545, 1515, 1228, 1171, 1037, 909, 733. 1H NMR
6i
16i (30)
a
Refluxing in acetic anhydride for 5 h.
Refluxing in acetic acid for 24 h.
b
(CDCl3):
(q, 2H, J 7.2), 4.25 (m, 2H), 3.81 (s, 3H), 1.50 (d, 3H, J 7.2), 1.37 (t,
3H, J 7.2). 13C NMR (CDCl3):
164.9, 155.3, 137.4, 132.6, 115.1,
d 10.33 (s, 1H), 7.07 (d, 2H, J 9.2), 6.87 (d, 2H, J 9.2), 5.26
Table 3
Cycloaddition products of dehydration of compounds 6 under various conditions
d
114.8, 67.5, 61.2, 55.8, 18.7, 14.5. HRMS¼266.1263 (C13H18N2O4
Entry
Substrate
Products (yield)
requires 266.1261).
1a
6b
6b
6b
11b
6e
6e
6e
6f
6f
6i
6j
6j
11b (53%)
23b (10%)
23b (44%)
23b (21%)
21e (26%)
23e (15%)
23e (51%)
23f (10%)
23f (48%)
23i (20%)
11j (90%)
23j (20%)
23j (49%)
2b
3c
5.2.8. Ethyl 3-hydroxy-2-p-tolylhydrazonobutyrate 6h. Yellow crys-
tals, yield 0.75 g (30%), mp 73e74 ꢀC. LCMS: m/z¼251 (Mþ1).1H NMR
4d
5a
(CDCl3): d 10.30 (s,1H), 7.05 (m, 4H), 5.25 (dq,1H, J 6.8, 3.6), 4.29 (m,
6b
2H), 2.82 (d,1H, J 3.6), 2.28 (s, 3H),1.49 (d, 3H, J 6.8),1.37 (t, 3H, J 7.2).
7c
13C NMR (CDCl3):
d
164.6, 140.9, 132.9, 131.4, 129.8, 113.7, 67.3, 61.1,
8b
9c
20.7, 18.6, 14.3. HRMS¼250.1311 (C13H18N2O3 requires 250.1311).
10b
11a
12b
13c
5.2.9. 2-p-Chlorophenylhydrazono-3-hydroxybutyranilide
6i. Yellow oil, yield 3.10 g (98%). LCMS: m/z¼318 (Mþ1). IR: 3375,
3289, 3060, 2979, 2927, 1652, 1597, 1532, 1495, 1441, 1315, 1239,
6j
a
DEAD, Ph3P, THF, rt 24 h.
1155, 1085, 915, 823, 753. 1H NMR (CDCl3):
d 12.76 (s, 1H), 9.60 (s,
b
c
Pyrolysis with NPMA, 200 ꢀC, 30 min.
NPMA in acetic acid, reflux 2 h.
NPMAþ11b, in xylene, reflux 2 h.
1H), 7.55 (d, 2H, J 8.4), 7.37 (t, 2H, J 8.4), 7.23 (d, 2H, J 8.8), 7.16 (t, 1H,
J 7.4), 7.08 (d, 2H, J 8.9), 4.83 (m, 1H), 2.39 (d, 1H, J 5.2), 1.60 (d, 3H, J
d

1304
N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
5.4.1. Ethyl glyoxalate phenylhydrazone 7a. Yellow crystals, mp
130 ꢀC (lit.22 mp 130 ꢀC). 1H NMR (CDCl3):
12.32 (s, 1H), 7.32 (t, 2H,
m/z¼647 (Mþ1). IR: 3239, 3202, 2972, 2929, 1677, 1539, 1496, 1207,
1162, 1128, 1095, 952, 824, 708. 1H NMR (CDCl3):
12.05 (s, 2H, NH),
d
d
J 7.6), 7.21 (d, 2H, J 7.2), 7.03 (t, 1H, J 7.2), 6.67 (s, 1H, J 8.8), 4.27
(q, 2H, J 7.2), 1.37 (t, 3H, J 7.2). HRMS¼192.0893 (C10H12N2O2
requires 192.0893).
7.24 (d, 4H, J 8.0), 7.13e7.01 (m, 14H), 5.01 (s, 2H), 4.25 (m, 4H), 1.35
(t, 6H, J 7.2). Anal. Calcd for C34H32Cl2N4O5 (647.6): C 63.06, H 4.98,
N 8.65. Found C 63.35, H 5.23, N 8.62.
5.4.2. Ethyl glyoxalate p-chlorophenylhydrazone 7b. Colorless crys-
tals, mp 68 ꢀC. MS: m/z¼226 (Mþ, 100%), 228 (Mþ2, 31%). IR: 2981,
1713, 1551, 1493, 1458, 1320, 1215, 1149, 1096, 824. 1H NMR (CDCl3):
5.4.10. Ethyl 2-p-methoxyphenylhydrazono-3-(2-p-methoxyphenylh
ydrazono-2-ethoxycarbonyl-1-phenylethoxy)-3-phenylpropionate 8c
(isomer 1). Yellow crystals, yield 0.03 g (10%), mp 197 ꢀC. FAB-
MS: m/z¼639 (Mþ1). IR: 3026, 2980, 2958, 2928, 2832, 1674,
d
12.47 (s, 1H), 7.29 (d, 2H, J 8.8), 7.14 (d, 2H, J 8.8), 6.68 (s, 1H), 4.27
(q, 2H, J 7.2), 1.37 (t, 3H, J 7.2). HRMS¼226.0503 (C10H11ClN2O2
1537, 1513, 1455, 1221, 1204, 1155, 1029. 1H NMR (CDCl3):
d 11.94
requires 226.0503).
(s, 2H, NH), 7.43 (d, 4H, J 8.0), 7.19 (t, 4H, J 7.6), 7.11 (m, 6H), 6.90
(d, 4H, J 8.8), 5.18 (s, 2H), 4.13 (m, 4H), 3.82 (s, 6H), 1.32 (t, 6H, J
5.4.3. Ethyl glyoxalate p-methoxyphenylhydrazone 7c. Yellow crys-
7.2). 13C NMR (CDCl3):
d 163.4, 154.9, 142.1, 137.7, 129.2, 127.94,
tals, mp 152 ꢀC. IR: 2986, 2937, 2908, 2837, 1721, 1696, 1550, 1506,
127.86, 126.1, 114.9, 114.7, 60.4, 55.7, 50.1, 14.1. Anal. Calcd for
C36H38N4O7 (638.7): C 67.70, H 6.00, N 8.77. Found C 67.41, H
6.29, N 8.61.
1248,1145,1030, 830, 742.1H NMR (CDCl3):
d 12.30 (s,1H), 7.13 (d, 2H,
J 8.8), 6.87 (d, 2H, J 9.2), 6.59 (s,1H), 4.23 (q, 2H, J 7.2), 3.79 (s, 3H),1.34
(t, 3H, J 7.2). HRMS¼222.0998 (C11H14N2O3 requires 222.0998).
5.4.11. Ethyl 2-p-methoxyphenylhydrazono-3-(2-p-methoxyphenylh
ydrazono-2-ethoxycarbonyl-1-phenylethoxy)-3-phenylpropionate 8c
(isomer 2). Yellow crystals, yield 0.02 g (7%), mp 204 ꢀC. FAB-MS:
m/z¼639 (Mþ1). IR: 3060, 3027, 2982, 2958, 2928, 1674, 1544, 1514,
1228, 1208, 1164, 1136, 1106, 1033, 826, 756, 701. 1H NMR (CDCl3):
5.4.4. Ethyl glyoxalate p-nitrophenylhydrazone 7d. Yellow crystals,
mp 165 ꢀC (lit.22 mp 130 ꢀC). 1H NMR (CDCl3):
d 12.54 (s, 1H), 8.22
(d, 2H, J 7.6), 7.23 (d, 2H, J 7.6), 6.81 (s, 1H), 4.23 (q, 2H, J 7.2), 1.36
(t, 3H, J 4.4). HRMS¼237.0744 (C10H11N3O4 requires 237.0744).
d
12.03 (s, 2H, NH), 7.17 (d, 4H, J 9.2), 7.11 (m,10H), 6.87 (d, 4H, J 9.2),
5.4.5. Ethyl glyoxalate p-tolylhydrazone 7h. Colorless oil. IR: 2981,
5.03 (s, 2H), 4.13 (m, 4H), 3.81 (s, 6H), 1.33 (t, 6H, J 7.2). Anal. Calcd
for C36H38N4O7 (638.7): C 67.70, H 6.00, N 8.77. Found C 67.45, H
6.21, N 8.55.
2927, 1683, 1544, 1517, 1229, 1203, 1171, 1137, 1105, 816. 1H NMR
(CDCl3): d 12.30 (s, 1H), 7.25e7.26 (m, 4H), 6.64 (s, 1H), 4.29 (q, 2H, J
7.2), 2.33 (s, 3H), 1.36 (t, 3H, J 7.2). HRMS¼206.1049 (C11H14N2O2
requires 206.1049).
5.4.12. Bis-1,2-(2-ethoxycarbonylindol-3-yl)ethene 9a. Yellow crys-
tals, yield 0.004 g (2%), mp 331 ꢀC. MS: m/z¼402 (Mþ). IR: 3435,
3322, 2926, 1666, 1456, 1380, 1333, 1255, 740. 1H NMR (DMSO-d6):
5.4.6. Ethyl 3-(2-ethoxycarbonyl-1-phenyl-2-phenylhydrazonoethoxy)-
3-phenyl-2-phenylhydraz-onopropionate 8a (isomer 1). Yellow crys-
tals, yield 0.09 g (32%), mp 188e190 ꢀC. FAB-MS: m/z¼579 (Mþ1). IR:
3251, 1678, 1598, 1544, 1499, 1447, 1365, 1209, 1165, 1130, 1071, 1026,
d
11.91 (s, 2H), 8.36 (s, 2H), 8.21 (d, 2H, J 8.4), 7.54 (d, 2H, J 8.4), 7.37
(t, 2H, J 7.6), 7.24 (t, 2H, J 7.6), 4.46 (q, 4H, J 7.2), 1.45 (t, 6H, J 7.2). 13C
NMR (DMSO-d6):
d 161.7, 137.0, 125.3, 124.3, 123.8, 122.9, 121.8,
697, 628. 1H NMR (CDCl3):
d
12.05 (s, 2H, NH), 7.30 (t, 4H, J 8.4), 7.21 (d,
120.9, 120.1, 113.1, 60.8, 14.4. HSQC 13N NMR (DMSO-d6):
HRMS¼402.1574 (C24H22N2O4 requires 402.1574).
d 136.3.
4H, J 7.6), 7.12 (d, 4H, J 8.4), 7.07 (t, 4H, J 7.2), 7.01 (m, 2H), 6.96 (tt, 2H,
J 7.2, 1.2), 5.06 (s, 2H), 4.19 (m, 4H), 1.36 (t, 6H, J 7.2). 13C NMR (CDCl3):
d
163.4,143.9,140.7,129.9,129.24,129.22,127.7,126.1,121.6,113.4, 60.7,
5.4.13. Bis-1,2-(5-chloro-2-ethoxycarbonylindol-3-yl)ethene
9b. Yellow crystals, yield 0.005 g (2%), mp >360 ꢀC. MS: m/z¼470
(Mþ, 100%), 472 (Mþ2, 65%), 474 (Mþ4, 11%). IR: 3439, 3311, 2923,
50.9, 14.1. 15N NMR (CDCl3):
d
352.7, 155.5. Anal. Calcd for C34H34N4O5
(578.6): C 70.57, H 5.92, N 9.68. Found C 70.30, H 6.02, N 9.49.
1674, 1465, 1252. 1H NMR (DMSO-d6):
d 12.20 (s, 2H), 8.18 (s, 2H),
5.4.7. Ethyl 3-(2-ethoxycarbonyl-1-phenyl-2-phenylhydrazonoethoxy)-
3-phenyl-2-phenylhydraz-onopropionate 8a (isomer 2). Yellow crys-
tals, yield 0.06 g (19%), mp 214 ꢀC. FAB-MS: m/z¼579 (Mþ1). IR: 3258,
1678, 1601, 1550, 1502, 1449, 1368, 1244, 1210, 1164, 1134, 1074, 1024,
8.17 (d, 2H, J 2.0), 7.56 (d, 2H, J 8.8), 7.40 (dd, 2H, J 8.8, 2.0), 4.49 (q,
4H, J 7.2), 1.46 (t, 6H, J 7.2). HRMS¼470.0795 (C24H20Cl2N2O4 re-
quires 470.0795).
911, 746, 695, 630. 1H NMR (CDCl3):
d
11.96 (s, 2H, NH), 7.44 (d, 4H, J
7.2), 7.34 (t, 4H, J 8.0), 7.20 (m, 8H), 7.09 (t, 2H, J 7.2), 6.98 (t, 2H, J 7.2),
5.22 (s, 2H), 4.13 (m, 4H), 1.33 (t, 6H, J 7.2). 13C NMR (CDCl3):
163.2,
5.5. Action of acetic anhydride on 6eei. General procedure
d
A mixture of compounds 6eei (1 mmol) and acetic anhydride
(1 mL) was refluxed for 5 h. The reaction mixture was poured over
crushed ice extracted with DCM, washed with water, and dried over
anhydrous sodium sulfate. The solvent was then removed in vacuo
and the product was separated by column chromatography using
pet. ether (60e80)/ethyl acetate as an eluent to give the corre-
sponding compounds 10eeh, 16f,g,i, and 17f,h (Table 2).
143.7, 141.8, 129.3, 129.2, 129.1, 128.0, 126.2, 121.7, 113.8, 60.6, 50.2,
14.1. Anal. Calcd for C34H34N4O5 (578.7): C 70.57, H 5.92, N 9.68.
Found C 70.28, H 6.00, N 9.51.
5.4.8. Ethyl 2-p-chlorophenylhydrazono-3-(2-p-chlorophenylhydrazono-
2-ethoxycarbonyl-1-phenylethoxy)-3-phenylpropionate 8b
(isomer
1). Yellow crystals, yield 0.08 g (25%), mp 207 ꢀC. FAB-MS: m/z¼647
(Mþ1). IR: 3237, 3203, 2920, 1676, 1539, 1496, 1206, 1162, 1126, 1093,
5.6. Action of acetic acid on 6f,i. General procedure
824, 707. 1H NMR (CDCl3):
d 11.95 (s, 2H, NH), 7.40 (d, 4H, J 7.2), 7.28 (d,
4H, J 7.2), 7.21 (t, 4H, J 7.6), 7.10 (t, 6H, J 7.2), 5.18 (s, 2H), 4.14 (m, 4H),
Compounds 6f,i (1 mmol) were refluxed in acetic acid (1 mL) for
24 h. The solvent was removed in vacuo and the products 16f,i were
isolated by column chromatography using pet. ether (60e80)/DCM/
ethyl acetate as an eluent.
1.32 (t, 6H, J 7.2). 13C NMR (CDCl3):
d
163.1, 142.3, 141.5, 129.7,
129.3, 129.1, 128.1, 126.5, 126.4, 114.9, 60.8, 50.2, 14.1. Anal. Calcd
for C34H32Cl2N4O5 (647.6): C 63.06, H 4.98, N 8.65. Found C 63.40, H
5.31, N 8.52.
5.6.1. Ethyl 6-[ethoxycarbonyl-(phenylhydrazono)-methyl]-4-methyl-
1-phenyl-1,4,5,6-tetrahydro-pyridazine-3-carboxylate 10e. Colorless
oil. LCMS¼437 (Mþ1). IR: 2923, 2855, 1693, 1596, 1554, 1498,
5.4.9. Ethyl 2-p-chlorophenylhydrazono-3-(2-p-chlorophenylhydrazo
no-2-ethoxycarbonyl-1-phenylethoxy)-3-phenylpropionate 8b (iso-
mer 2). Yellow crystals, yield 0.042 g (13%), mp 204 ꢀC. FAB-MS:
1275, 1230, 1169, 1077, 751. 1H NMR (CDCl3):
d 11.96 (s, 1H,

N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
1305
NH), 7.38 (d, 2H, J 7.8), 7.29 (t, 2H, J 7.2), 7.20 (t, 2H, J 8.4),
6.97 (d, 2H, J 9.0), 6.96 (t, 1H, J 7.2), 6.92 (t, 1H, J 7.2), 5.33 (t,
1H, J 3.6), 4.45 (q, 1H, J 7.2), 4.36 (m, 3H), 2.93 (m, 1H), 2.30 (t,
1H, J 7.2), 2.29 (q, 1H, J 7.2), 1.45 (t, 3H, J 7.2), 1.41 (t, 3H, J 7.2),
(s, 3H), 1.42 (t, 3H, J 7.2). 13C NMR (CDCl3):
d
162.4, 159.1, 144.8,
140.5, 128.4, 121.8, 114.5, 110.1, 61.1, 55.6, 14.4. HRMS¼246.0998
(C13H14N2O3 requires 246.0998).
1.08 (d, 3H, J 7.2). 13C NMR (CDCl3):
d
165.2, 162.4, 145.9, 142.8,
5.6.8. 1-p-Chlorophenylpyrazole-3-carboxylanilide 16i. Yellow oil.
MS: m/z¼297 (Mþ, 100%), 299 (Mþ2, 32%). IR: 2922, 2852, 1684,
1600, 1542, 1499, 1439, 1380, 1312, 1256, 825, 771, 749, 688, 602,
135.1, 129.2, 128.9, 122.6, 122.5, 121.8, 115.3, 114.0, 61.1, 60.6,
51.5, 29.0, 23.5, 20.1, 14.5, 14.3. HRMS¼436.2105 (C24H28N4O4
requires 436.2105).
503. 1H NMR (CDCl3):
d
8.77 (s, 1H), 7.95 (d, 1H, J 2.8), 7.71 (t, 4H, J
8.8), 7.49 (d, 2H, J 8.8), 7.39 (t, 2H, J 8.0), 7.15 (t,1H, J 7.2), 7.11 (d,1H, J
2.4). 13C NMR (CDCl3):
159.3, 148.5, 138.1, 137.7, 133.2, 129.8, 129.1,
5.6.2. Ethyl 6-[ethoxycarbonyl-(p-chlorohydrazono)-methyl]-4-meth
yl-1-p-chlorophenyl-1,4,5,6-tetrahydro-pyridazine-3-carboxylate
10f. Colorless oil. LCMS¼506 (Mþ1). IR: 2978, 2930, 1699, 1557,
d
129.0, 124.3, 120.9, 119.8, 109.1. HRMS¼297.0663 (C16H12ClN3O re-
quires 297.0663).
1495, 1266, 1234, 1167, 1139, 1092, 827. 1H NMR (CDCl3):
d 11.95 (s,
1H), 7.16e7.19 (m, 4H), 7.17 (d, 2H, J 9.2), 6.88 (d, 2H, J 9.2), 5.27 (m,
1H), 4.49e4.33 (m, 4H), 2.94 (m,1H), 2.39e2.29 (m, 2H),1.46 (d, 3H,
J 7.3), 1.41 (d, 3H, J 7.2), 1.06 (d, 3H, J 10.4). HRMS¼504.1325
(C24H26Cl2N4O4 requires 504.1325).
5.6.9. Ethyl 4-acetyl-1-p-chlorophenylpyrazole-3-carboxylate 17f.
Colorless oil. MS: m/z¼292 (Mþ). IR: 2922, 1734, 1709, 1591, 1305,
1214, 1196, 1136, 771. 1H NMR (CDCl3):
d 7.53 (d, 2H, J 9.2), 7.05 (d,
2H, J 9.2), 6.61 (s, 1H), 4.29 (q, 2H, J 7.2), 2.61 (s, 3H), 1.32 (t, 3H,
7.2). 13C NMR (CDCl3):
173.3, 162.9, 136.1, 133.4, 131.7,
129.9, 128.8, 61.6, 21.8, 14.1(two sp2 overlap). 15N NMR
(CDCl3):
362.4, 191.8. HRMS¼292.0609 (C14H13ClN2O3 requires
292.0609).
J
d
5.6.3. Ethyl 6-[ethoxycarbonyl-(p-methoxyphenylhydrazono)-meth
yl]-1-p-methoxyphenyl-4-methyl-1,4,5,6-tetrahydropyridazine-3-
carboxylate 10g. Colorless oil. LCMS¼497 (Mþ1). IR: 2921, 2851,
C
d
1691,1512,1244,1169, 909, 733. 1H NMR (CDCl3):
d 11.99 (s,1H, NH),
7.29 (d, 2H, J 6.8), 6.96 (d, 2H, J 6.8), 6.81 (m, 4H), 5.24 (t, 1H, J 3.6),
4.35 (m, 4H), 3.77 (m, 6H), 2.92 (t, 1H, J 7.2), 2.27 (m, 2H), 1.42 (m,
5.6.10. Ethyl 4-acetyl-1-p-tolylpyrazole-3-cþarboxylate 17h. Color
less crystals, mp 83e84 ꢀC. MS: m/z¼272 (M ). IR: 2983, 2932,1740,
1709, 1586, 1512, 1371, 1308, 1193, 1135, 1044, 614. 1H NMR (CDCl3):
6H), 1.07 (d, 3H, J 7.2). 13C NMR (CDCl3):
d 165.3, 162.5, 155.5, 155.0,
140.2, 136.8, 134.1, 121.5, 117.3, 115.1, 114.6, 114.2, 60.8, 60.4, 55.6,
55.5, 52.2, 29.3, 23.5, 20.1, 14.5, 14.3. HRMS¼496.2315 (C26H32N4O6
requires 496.2316).
d
7.30 (d, 2H, J 8.0), 6.94 (d, 2H, J 8.0), 6.60 (s, 1H), 4.25 (q, 2H, J 7.2),
2.56 (s, 3H), 2.38 (s, 3H), 1.29 (t, 3H, J 7.2). 13C NMR (CDCl3):
d
173.5,
163.2, 140.1, 132.3 (2C), 131.5 (CH-5, C), 131.2 (ArCH), 128.1 (ArCH),
61.5, 21.8, 21.3, 14.1. 15N NMR (CDCl3):
d
364.1, 194.4.
5.6.4. Ethyl 6-[ethoxycarbonyl-(p-tolylhydrazono)-methyl]-4-methyl-
1-p-tolyl-1,4,5,6-tetrahydro-pyridazine-3-carboxylate 10h. Colorless
oil. LCMS¼465 (Mþ1). IR: 2925, 2854, 1680, 1542, 1521, 1463, 1203,
HRMS¼272.1155 (C15H16N2O3 requires 272.1155).
5.7. Static pyrolysis of 6bef,i,j with N-phenylmaleimide.
General procedure
1132,1107, 909, 817, 735. 1H NMR (CDCl3):
d
11.98 (s,1H, NH), 7.26 (d,
2H, J 9.2), 7.05 (m, 4H), 6.91 (d, 2H, J 9.2), 5.29 (m, 1H), 4.38 (m, 4H),
2.92 (m,1H), 2.28 (s, 3H), 2.26 (s, 3H), 2.27 (m, 2H),1.41 (m, 6H),1.06
A mixture of compounds 6bef,i,j (0.5 mmol) and N-phenyl-
maleimide (1.5 mmol) was introduced into a reaction tube
(d, 3H, J 7.6). 13C NMR (CDCl3):
d
163.9 (2CO), 140.7, 139.2, 132.2,
129.9, 128.4, 117.7, 116.2, 113.9, 112.5, 112.4, 60.3 (2CH2), 58.9, 58.8,
29.7, 28.3, 20.7, 19.2, 14.2, 12.7. HRMS¼464.2418 (C26H32N4O4
requires 464. 2418).
(1.5ꢁ12 cm Pyrex), cooled in liquid nitrogen, sealed under vacuum
(0.045 Torr) and placed in the pyrolyzer for 30 min at 200 ꢀC. The
products 23bef,i,j were isolated by column chromatography using
pet. ether (60e80)/DCM/ethyl acetate as an eluent.
5.6.5. 1-p-Chlorophenyl-6-[(p-chlorophenylhydrazono)-phenyl-
carbamoylmethyl]-4-methyl-1,4,5,6-tetrahydro-pyridazine-3-carbox-
anilide 10i. Colorless oil. LCMS¼599 (Mþ1). IR: 3380, 3296, 3060,
2967, 2931, 2871, 1667, 1596, 1522, 1495, 1442, 1310, 1251, 1216,
5.8. Cycloaddition of 6bef,i with N-phenylmaleimide in acetic
acid. General procedure
1170, 1091, 908, 825, 750, 734. 1H NMR (CDCl3):
d
8.87 (s, 1H, NH),
A mixture of compounds 6bef, 6i (1 mmol) and N-phenyl-
maleimide (1.5 mmol) in acetic acid (1 mL) was heated under reflux
for 2 h. The solvent was removed in vacuo and the products 23bef,i
were isolated by column chromatography using pet. ether (60e80)/
DCM/ethyl acetate as an eluent.
8.69 (s, 1H, NH), 8.64 (s, 1H, NH), 7.63 (t, 4H, J 8.8), 7.41e7.31 (m,
5H), 7.21e7.26 (m, 4H), 7.18e7.11 (m, 3H), 6.90 (d, 2H, J 8.8), 5.62
(dd, 1H, H-6, J 12.2, 4.6), 3.36 (m, 1H, H-4), 2.36 (dt, 1H, H-5, J 13.4,
5.0), 2.07 (ddd, 1H, H-5, J 13.4, 4.4, 1.2), 1.38 (d, 3H, J 7.2). 13C NMR
(CDCl3):
d 161.2, 160.9, 144.9, 143.4, 141.0, 137.5, 137.4, 133.5, 130.3,
129.5, 129.4, 129.2, 129.1, 127.8, 124.5, 124.3, 119.9, 119.63, 119.56,
115.0, 46.2, 25.0, 23.2, 20.2. HRMS¼598.1645 (C32H28Cl2N6O2 re-
quires 598.1645).
5.9. Procedure for synthesis of compound 23b from 11b
A mixture of compound 11b (1 mmol) and N-phenylmaleimide
(1.5 mmol) in xylene (1 mL) was refluxed for 2 h. The solvent was
removed in vacuo and the product 23b was isolated by column
chromatography using pet. ether (60e80)/DCM/ethyl acetate as an
eluent.
5.6.6. Ethyl 1-p-chlorophenylpyrazole-3-carboxylate 16f. Colorless
oil. MS: m/z¼250 (Mþ, 100%), 252 (Mþ2, 33%). IR: 2926, 2854, 1721,
1493, 1462, 1380, 1264, 1178, 909, 735. 1H NMR (CDCl3):
d 7.93 (d,
1H, J 2.4), 7.73 (d, 2H, J 8.8), 7.47 (d, 2H, J 8.8), 7.02 (d, 1H, J 2.4), 4.47
(q, 2H, J 7.2), 1.45 (t, 3H, J 7.2). 13C NMR (CDCl3):
133.3, 129.6, 128.3, 121.3, 110.7, 61.3, 14.4. HRMS250.0506
(C12H11ClN2O2 requires 250.0506).
d
162.1, 145.5, 138.2,
5.9.1. Ethyl 1-p-chlorophenyl-5,7-dioxo-4,6-diphenyl-4,4a,5,6,7,7a,-
hexahydro-1H-pyrrolo[3,4-c]pyridazine-3-carboxylate
23b. Colorless crystals, yield 0.03 g (10%). Mp 265e266 ꢀC.
LCMS¼488 (Mþ1). IR: 2926, 2853, 1727, 1493, 1378, 908, 734. 1H
5.6.7. Ethyl 1-p-methoxyphenylpyrazole-3-carboxylate 16g. Color
less oil. MS: m/z¼246 (Mþ). IR: 2922, 2852, 1722, 1519, 1461, 1378,
NMR (CDCl3): d 7.68 (d, 2H, J 9.2), 7.37 (d, 2H, J 9.2), 7.29 (m, 6H),
7.09 (m, 2H), 6.39 (dd, 2H, J 8.0, 2.0), 5.02 (d, 1H, J 8.4), 4.79 (d, 1H, J
1255, 1176, 909, 734. 1H NMR (CDCl3):
d 7.83 (d, 1H, J 2.8), 7.64 (d,
7.2), 4.26 (m, 2H), 3.53 (dd, 1H, J 8.4, 7.2), 1.31 (t, 3H, J 7.2). 13C/DEPT
2H, J 9.2), 6.97 (d, 1H, J 2.4), 6.97 (d, 2H, J 9.2), 4.44 (q, 2H, J 7.2), 3.85
13C NMR (CDCl3):
d 172.4 (C), 172.2 (C), 163.2 (C), 145.5 (C), 133.9 (C),

1306
N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
133.87 (C), 130.1 (C), 129.4 (CH), 129.3 (C), 129.1 (CH), 128.9 (CH),
128.7 (CH), 126.0 (CH), 118.0 (CH), 61.7 (CH2), 55.8 (CH), 39.4 (CH),
36.3 (CH), 14.2 (CH3) (two ArCH’s overlap). HRMS¼487.1293
(C27H22ClN3O4 requires 487.1293).
2H, J 7.2), 1.34 (t, 3H, J 7.2). 13C NMR (CDCl3):
d 166.7, 164.9, 151.2,
150.7, 149.3, 144.7, 140.7, 137.7, 137.1, 135.9, 133.7, 133.1, 132.6,
130.3, 130.1, 129.54, 129.47, 129.3, 129.0, 128.6, 124.4, 124.1,
61.1, 61.4, 14.3, 14.1. HRMS¼314.0816 (C17H15ClN2O2 requires
314.0816).
5.9.2. Ethyl 4-methyl-5,7-dioxo-1,6-diphenyl-4,4a,5,6,7,7a,-hexahy-
dro-1H-pyrrolo[3,4-c]pyridazine-3-carboxylate 23e. Colorless crys-
tals, yield 0.03 g (15%), mp 154e155 ꢀC. LCMS¼392 (Mþ1). IR:
2966, 2929, 2857, 1723, 1592, 1496, 1376, 1258, 1200, 1146, 752,
5.10.2. Triethyl 6-methyl-3-phenyl-1,2,3,4-tetrahydro-1,2,3,4-tetra-
zine-1,2,5-tricarboxylate 21e. Colorless crystals, yield 0.1 g (26%).
MS: m/z¼392 (Mþ). IR: 3316, 2982, 2933, 2361, 2335, 1727, 1531,
1449, 1397, 1378, 1340, 1311, 1233, 1093, 1068, 793, 753. 1H NMR
691. 1H NMR (CDCl3):
d 7.65 (dd, 2H, J 8.8, 1.2), 7.51 (t, 2H, J 7.6),
7.44 (d, 1H, J 7.6), 7.37 (m, 4H), 7.14 (dt, 1H, J 7.6), 5.02 (d, 1H, J 8.4),
4.36 (m, 2H), 3.74 (quint, 1H, J 7.2), 3.30 (dd, 1H, J 8.4, 6.4), 1.42 (t,
(CDCl3):
6.01 (s, 1H), 4.40 (q, 2H, J 7.2), 4.26 (q, 2H, J 7.2), 4.22 (q, 2H, J 7.2),
2.37 (s, 3H), 1.39 (t, 3H, J 7.2), 1.25 (q, 6H, J 7.2). 13C (CDCl3):
158.6,
d 7.44 (d, 2H, J 7.6), 7.32 (t, 2H, J 8.4), 7.17 (tt, 1H, J 7.6, 0.8),
3H, J 7.2), 1.15 (d, 3H, J 7.2). 13C NMR (CDCl3):
d
173.7, 172.7, 163.5,
d
146.8, 135.0, 130.8, 129.4, 129.13, 129.07, 126.0, 123.8, 116.6, 61.6,
55.3, 38.2, 25.7, 14.4, 13.1. HRMS¼391.1526 (C22H21N3O4 requires
391.1526).
155.4, 150.6, 142.0, 135.0, 128.4 (CH), 125.6 (CH), 124.2 (CH), 118.6,
64.7, 63.6, 62.6, 14.6, 14.5, 14.47, 12.2. HRMS¼392.1659 (C18H24N4O6
requires 392.1659).
5.9.3. Ethyl 1-p-chlorophenyl-4-methyl-5,7-dioxo-6-phenyl-4,4a,5,6,
7,7a,-hexahydro-1H-pyrrolo[3,4-c]pyridazine-3-carboxylate
23f. Colorless oil, yield 0.07 g (34%). MS: m/z¼425 (Mþ, 100%), 427
(Mþ2, 31%). IR: 2979, 2926, 1723, 1495, 1377, 1258, 1200, 1147, 911,
5.10.3. 1,3,4-Triphenyl-1,2-diaza-1,3-butadiene 11j. Red oil, yield
0.26 g (90%). MS: m/z¼284 (Mþ). IR: 3059, 3030, 2924, 2853, 1598,
1496, 1451, 1070, 1022, 920, 793. 1H NMR (CDCl3):
d
7.75e7.65 (m,
4H), 7.34 (m, 8H), 7.11 (m, 4H). 13C NMR (CDCl3):
d 155.9, 153.5,
745. 1H NMR (CDCl3):
d
7.60 (d, 2H, J 9.2), 7.53 (t, 2H, J 8.0), 7.47 (t,
153.2, 152.9, 141.7, 137.1, 135.8, 135.4, 135.1, 134.6, 132.2, 130.9, 130.4,
130.3, 130.1, 129.5, 129.1, 128.9, 128.8, 128.56, 128.51, 128.3, 128.24,
128.13, 128.0, 127.9, 123.2, 122.6. HRMS¼284.1307 (C20H16N2 re-
quires 284.1308).
2H, J 7.2), 7.35 (m, 4H), 4.98 (d, 1H, J 8.4), 4.39 (q, 1H, J 7.2), 3.75
(quint, 1H, J 7.2), 3.32 (dd, 1H, J 8.4, 6.4), 1.42 (t, 3H, J 7.2), 1.15
(d, 3H, J 7.2). 13C NMR (CDCl3):
d 173.5, 172.6, 163.3, 145.5, 135.7,
130.7, 129.4, 129.2, 129.1, 126.0, 117.9, 61.7, 55.3, 38.2, 25.7, 14.4,
13.1 (one sp2 C overlaps). HRMS¼425.1136 (C22H20N3O4Cl requires
425.1136).
5.11. Cycloaddition of 6 with 24a,b. General procedure
A mixture of 6b (0.33 g, 1 mmol) and 24a,b (1 mmol) in acetic
acid (2 mL) was heated under reflux for 1 h. The solvent was
then removed in vacuo and the remaining residue was crystal-
lized from ethanol to give the corresponding products 25a,b,
respectively.
5.9.4. 1-p-Chlorophenyl-4-methyl-5,7-dioxo-6-phenyl-4,4a,5,6,7,7a,-
hexahydro-1H-pyrrolo[3,4-c]pyridazine-3-carboxylanilide
23i. Colorless oil, yield 0.08 g (34%). LCMS¼473 (Mþ1). IR: 2921,
2852, 1724, 1671, 1597, 1525, 1495, 1444, 1378, 1196, 908, 734. 1H
NMR (CDCl3):
d 8.71 (s, 1H), 7.64 (d, 2H, J 7.6), 7.53 (m, 4H), 7.45
(m, 1H), 7.39 (m, 6H), 7.15 (t, 1H, J 7.6), 4.97 (d, 1H, J 8.0), 3.99
5.11.1. Ethyl 5-benzoyl-1-p-chlorophenyl-4-phenyl-1,4-dihydropyr-
idazine-3-carboxylate 25a. Yellow crystals, yield 0.27 g (60%), mp
178 ꢀC. MS: m/z¼444 (Mþ, 100%), 446 (Mþ2, 34%). IR: 3058, 3030,
2980, 2931, 1732, 1619, 1595, 1568, 1493, 1447, 1366, 1307, 1255,
(quint, 1H, J 7.2), 3.33 (dd, 1H, J 8.0, 6.8), 1.18 (d, 3H, J 7.2). 13C
NMR (CDCl3):
d 173.3, 172.9, 160.2, 145.5, 139.4, 137.4, 130.7,
129.44, 129.4, 129.3, 129.2 (2 overlapped CH), 126.0, 124.5, 119.7,
118.3, 55.9, 38.3, 24.0, 13.1. HRMS¼472.1297 (C26H21ClN4O3 re-
quires 472.1297).
1189, 1142, 1099, 1046, 954, 717, 702. 1H NMR (CDCl3):
d
7.55 (m,
4H), 7.42 (m, 6H), 7.33 (m, 4H), 7.25 (m, 1H), 5.56 (s, 1H), 4.33 (m,
2H), 1.35 (t, 3H, J 7.2). 13C NMR (CDCl3):
193.5, 163.2, 141.8, 141.6,
d
5.9.5. 1,3,4,6-Tetraphenyl-1,4,4a,7a-tetrahydropyrrol[3,4-c]pyr-
idazine-5,7-dione 23j. Colorless crystals, yield 0.05 g (20%), mp
216e217 ꢀC. MS: m/z¼457 (Mþ). IR: 3019, 2921, 2852, 1714,
141.5, 138.5, 135.7, 131.6, 131.2, 129.6, 128.9, 128.6, 128.5, 128.0,
127.6, 119.4, 116.1, 62.0, 36.4, 14.1. HRMS¼444.1235 (C26H21N2O3Cl
requires 444.1235).
1496, 1386, 1212, 756. 1H NMR (CDCl3):
d 7.76 (d, 4H, J 8.4),
7.40e7.28 (m, 13H), 7.10 (t, 1H, J 8.0), 6.47 (m, 2H), 5.03 (dd, 1H,
5.11.2. Ethyl 5-p-chlorobenzoyl-1-p-chlorophenyl-4-phenyl-1,4-di-
hydropyridazine-3-carboxylate 25b. Yellþow crystals, yield 0.34 g
(72%), mp 162e3 ꢀC. MS: m/z¼478 (M , 100%), 480 (Mþ2, 69%),
482 (Mþ4, 13%). IR: 3439, 2984, 1730, 1623, 1594, 1491, 1255, 1192,
J 8.8, 1.2), 4.73 (dd, 1H, J 6.8, 0.8), 3.60 (dd, 1H, J 7.6, 6.8). 13C
NMR (CDCl3):
d 173.4, 173.2, 148.3, 140.6, 136.6, 134.2, 130.5,
129.5, 129.3, 129.1, 128.9, 128.8, 128.7, 128.6, 128.0, 126.2, 125.4,
122.4, 115.7, 55.6, 40.5, 38.2. HRMS¼457.1785 (C30H23N3O2 re-
quires 457.1785).
1093, 833, 751. 1H NMR (CDCl3):
d 7.48 (m, 3H), 7.37 (m, 6H), 7.27
(m, 4H), 7.21 (m, 1H), 5.48 (s, 1H), 4.28 (m, 2H), 1.30 (t, 3H, J 7.2). 13C
NMR (CDCl3): 192.3, 163.1, 141.7, 141.4, 137.9, 136.7, 135.6, 131.4,
d
5.10. Reaction of 6b, 6e, and 6j under Mitsunobu conditions.
General procedure
129.9, 129.7, 129.0, 128.9, 128.0, 127.7, 119.4, 115.8, 62.1, 36.3, 14.1
(one sp2 C overlaps). HRMS¼478.0845 (C26H20N2O3Cl2 requires
478.0845).
A mixture of compounds 6b, 6e, and 6j (1 mmol), triphenyl-
phosphine (1.2 mmol), and diethylazodicarboxylate (1.2 mmol) in
THF (2 mL) was stirred for 24 h at room temperature. The reaction
mixture was purified using column chromatography to give the
corresponding compounds 11 and 21.
5.11.3. Ethyl 5-acetyl-1-p-chlorophenylpyrazole-3-carboxylate 20. A
mixture of 19 (0.24 g, 1 mmol), anhydrous K2CO3 (0.21 g, 1.5 mmol),
and chloroacetone (0.13 mL, 1 mmol) was heated under reflux for
3 h. The solvent was then removed in vacuo and the remaining
residue was crystallized from ethanol to give colorless crystals,
yield 0.23 g (80%), mp 158e9 ꢀC. MS: m/z¼292 (Mþ, 100%), 294
(Mþ2, 33%). IR: 3439, 3130, 2978, 2927, 1720, 1692, 1495, 1367,
5.10.1. Ethyl 2-p-chlorophenylazo-3-phenylacrylate 11b. Yellow oil,
yield 0.17 g (53%). MS: m/z¼314 (Mþ, 100%), 316 (Mþ2, 29%). IR:
3062, 2963, 2926, 2856, 1730, 1622, 1577, 1481, 1452, 1391, 1373,
1252, 1203, 1124, 1093, 1016, 836, 753, 691. 1H NMR (CDCl3):
1280, 1236, 1125, 1092, 1025, 839. 1H NMR (CDCl3):
d
7.43 (s,
1H), 7.35 (d, 2H, J 3.2), 7.26 (d, 2H, J 4.4), 4.37 (q, 2H, J 7.2), 2.48
(s, 3H),1.34 (t, 3H, J 7.2). 13C NMR (CDCl3):
187.1,161.4, 144.0, 140.6,
d
7.75 (d, 2H, J 8.4), 7.68 (s, 1H), 7.57 (m, 2H), 7.43 (m, 5H), 4.41 (q,
d

N.A. Al-Awadi et al. / Tetrahedron 67 (2011) 1298e1307
1307
6. Boeckman, R. K., Jr.; Ge, P.; Reed, J. E. Org. Lett. 2001, 3, 3647e3650 and refer-
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138.5, 135.2, 128.9, 127.4, 115.1, 61.7, 28.7, 14.4. HRMS¼292.0609
(C14H13ClN2O3 requires 292.0609).
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Acknowledgements
The support of the University of Kuwait received through re-
search grantno. SC10/07and thefacilities of ANALABand SAF(grants
no. GS01/01, GS01/03, GS03/01) are gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.11.074.
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