Regioselectivity of nitrilimines 1,3-dipolar cycloaddition: Novel synthesis of spiro[4,4]nona-2,8-dien-6-one derivatives

Article abstract of DOI:10.1002/hc.20666

Regioselective 1,3-dipolar cycloaddition of nitrilimines (generated in situ from dehydrohalogenation of the corresponding hydrazonoyl halides by the action of triethylamine) with 4-arylidene-1-aryl-2-phenyl-1H-imidazol-5(4H)-one 3 afforded the correspondi

Full text of DOI:10.1002/hc.20666

Heteroatom Chemistry
Volume 22, Number 2, 2011
Regioselectivity of Nitrilimines 1,3-Dipolar
Cycloaddition: Novel Synthesis of
Spiro[4,4]nona-2,8-dien-6-one Derivatives
Omar A. Miqdad,1 Nada M. Abunada,1 and Hamdi M. Hassaneen2
1Department of Chemistry, Faculty of Applied Sciences, Al-Aqsa University, 76888 Gaza, Palestine
2Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Received 22 September 2010; revised 25 November 2010
anti-inflammatory [13], antibacterial [8,14], and an-
ABSTRACT: Regioselective 1,3-dipolar cycloaddition
titumor [15] activities. Furthermore, many spiro-
of nitrilimines (generated in situ from dehydrohalo-
compounds were found to possess antimicrobial
genation of the corresponding hydrazonoyl halides
[16], antitumor [17] activities and display mod-
by the action of triethylamine) with 4-arylidene-1-
est inhibition of human peptidyl prolyl cis/trans
aryl-2-phenyl-1H-imidazol-5(4H)-one 3 afforded the
isomerase Pin1 [18]. Moreover, spirocompounds
corresponding spiro[4,4]nona-2,8-dien-6-one 4. The
were found to exhibit vasodilation activities [19].
reaction was carried out in dry benzene under
The most developed procedure for construction of
reflux temperature. Refluxing in acetic acid, 4a
spirocompounds depends mainly on 1,3-dipolar cy-
was converted to its respective N-phenylpyrazole-5-
cloadditions to exocyclic double bonds [20–22]. On
carboxamide 8. The structures of prepared compounds
continuation of our research on the chemistry of
were established by elemental analyses and spec-
hydrazonoyl halides, which are the major precur-
tral data (IR, MS, 1H, and 13C NMR).
2011 Wi-
ꢀ
C
sors for nitrilimines [8,21,23], it is intended to
explore the 1,3-dipolar cycloaddition reaction of
nitrilimines with exocyclic double bond of 2-phenyl-
4-arylmethylene-2-imidazolin-5-one that have been
unreported hitherto, on the one hand, to synthesize
the corresponding novel spiro-heterocyclic ring sys-
tems with anticipated biological activities and, on
the other hand, to study the regioselectivity of the
reaction.
ley Periodicals, Inc. Heteroatom Chem 22:131–136, 2011;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20666
INTRODUCTION
The imidazolinone derivatives are associated with
a wide range of therapeutic activities such as an-
ticonvulsant [1] and potent CNS depressant [2,3].
Recently, some new imidazolinone derivatives have
been reported as antimicrobial [4,5] and L-DOPA
prodrugs in the treatment of Parkinson’s disease
[6]. Some workers have recognized 5-imidazolone
as having anticancer activity [5]. Also, pyrazoline
derivatives have been found to possess antifungal
[7,8], antidepressant [9–12], anticonvulsant [11,12],
RESULTS AND DISCUSSION
The reaction of the nitrilimines 2, generated in
situ by the action of triethylamine on hydrazonoyl
halides 1a,b in dry benzene at reflux tempera-
ture, with 4-arylidene-1-aryl-2-phenyl-1H-imidazol-
5(4H)-one 3, gave in each case, one regioisomer
whose elemental analysis and mass spectral data
were compatible with the molecular formula of
1,3,4,7,8-pentaryl-1,2,7,9-tetrazaspiro[4,4]nona-2,8-
dien-6-one 4 or 1,3,4,7,8-pentaryl-2,3,7,9-tetrazas-
piro[4,4]nona-1,8-dien-6-one 5 (Scheme 1).
131
Correspondence to: Nada M. Abunada; e-mail: nadanadannrs@
yahoo.com.
c
ꢀ
2011 Wiley Periodicals, Inc.

132 Miqdad, Abunada, and Hassaneen
–
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Regioselectivity of Nitrilimines 1,3-Dipolar Cycloaddition 133
H
H
O
Ph
O
Ph
Ph
Ph
Ph
N
[a]
Ph
Ph
N
N
N
N
H
N
N
N
Ph
4a
Ph
Ph
O
H
O
Ph
Ph
Ph
Ph
Ph
N
N
N
[b]
Ph
FIGURE 1
N
N
Ph
N
N
N
Ph
Ph
5a
Ph
The structural assignment of the isolated
spiropyrazoline was achieved on the basis of their
spectral data and chemical transformation. The IR
spectra of the products isolated showed carbonyl ab-
sorption bands in the region 1751.2–1759.0 cm−1.
The 1H NMR spectra showed the pyrazoline ring
proton resonates at δ 5.46–5.60 ppm. Comparison
of this chemical shift of the 4-CH proton of the pyra-
zoline ring residue of 4 with those of the related
compounds 6 and 7 showed similarity between the
proton chemical shifts for the 4-CH group of 4 with
those reported for compounds 6 (δ 5.20–5.30) and 7
(δ 5.46–5.77) (Fig. 1) [24,25], such similarity of the
chemical shifts give a good evidence that the isolated
regioisomer for the cycloadducts studied is 4.
If the cycloaddition took place in the opposite di-
rection to give 5, the chemical shift of 5-CH proton
would shift downfield due to the deshielding effect
of the more electronegative nitrogen atom attached
directly to the carbon atom bearing the hydrogen
one. It has been shown that the chemical shift of the
5-CH proton of pyrazoline is about δ 5.9–6.0 ppm
[21,26]. The 13C NMR spectra of 4 add further evi-
dence for the proposed structure, revealing the pres-
ence of 4-CH and spiro-C atoms at δ 62.747–64.082
and 90.961–91.140 ppm, respectively. The observed
regioselectivity can be explained on the basis of FMO
theory. It is fully in agreement with the prediction
[27,28] that dipole–HOMO/dipolarophile–LUMO in-
teraction would be favored since the dipolarophilic
exocyclic double bond of 3 is electron deficient, as it
conjugated with two electron-withdrawing groups,
the C O and C N groups of the imidazolinone ring
moiety, which cause its LUMO to be relatively low
in energy. Since the coefficient of nitrogen atom in
HOMO of dipole is much larger than that of carbon
atom, the 5 isomer will be favored (Fig. 2). But on
the basis of ab initio molecular orbital calculations,
it is argued that in the nonplanar most stable con-
formation of H C ≡ N+ N− H the biggest HOMO
coefficient is to be found on the carbon atom [29]
FIGURE 2 (a) Magnitude of the coefficients is estimated
from the calculation based on ab initio molecular orbital
method [29,30]. (b) Magnitude of the coefficients is esti-
mated from the calculation based on CNDO/2 molecular or-
bital method [28].
and this is also the case in diphenylnitrilimine [30].
Therefore, the formation of 4 can be explained on
the basis of dipole–HOMO control by assuming that
the coefficient of carbon atom in HOMO of diphenyl-
nitrilimine is much larger than that of nitrogen atom
(Fig. 2).
An unequivocal evidence for the production of
4 was achieved on the basis of their chemical
transformations. Thus, when the spiropyrazole 4a,
taken as a typical example of the series studied,
was refluxed in acetic acid it gave the respective
N,1,3,4-tetraphenyl-1H-pyrazole-5-carboxamide 8a
with elimination of benzonitrile (Scheme 1). The
structure of compound 8a was established on the
basis of elemental and spectral data. Its IR spectrum
reveals absorption bands at ν 3313.5 and 1651.0 cm−1
corresponding to NH and C O of the amide moi-
1
ety. H NMR spectrum exhibits broad characteris-
tic signal at δ 10.76 ppm for NH and was D2O-
exchangeable. Fortunately, compound 8a was pre-
viously synthesized through a different route [31]
and is found to be identical in all respects with our
compound.
It is worthy to mention that all attempts to isolate
products from the reaction of N-phenyl-2-oxopropa-
nehydrazonoyl chloride 9 [32], ethyl N-(phenylhy-
drazono)chloroacetate 10 [33], N-phenyl-C-phenyl-
aminocarbonylmethanohydrazonoyl chloride 11
[34], and N,Nꢁ-diphenylethane(bis-hydrazonoyl
chloride) 12 [35] (Fig. 3) with 3 failed. This finding
can be attributed to the presence of electron-
withdrawing group in the nitrilimines of 9–12,
which will lower both dipole orbitals in energy,
Heteroatom Chemistry DOI 10.1002/hc

134 Miqdad, Abunada, and Hassaneen
Cl
84%; mp 196–198◦C (dioxane); IR (KBr) νmax/cm−1
1751.2 (C O), 1596.9 (C N); H NMR (DMSO-d6) δ
5.556 (s, 1H, 4-CH), 6.840–7.681 (m, 25H, ArHs); MS
m/z (%): 519 (M+ + 1, 97.8), 491 (55%), 399 (100),
193 (30), 180 (60), 104 (24), 90 (70), 77 (60). Anal.
Calcd for C35H26N4O: C, 81.06; H, 5.05; N, 10.80.
Found: C, 81.10; H, 5.08; N, 10.81%.
Cl
1
H
H
C2H5O
CH3
N
N
N
Ph
Ph
Ph
N
10
9
O
O
O
Cl
Cl
H
N
N
NHPh
NHPh
PhHN
N
N
7 - (4 - Methylphenyl) - 1, 3, 4, 8 - tetraphenyl - 1, 2,
7,9-tetrazaspiro[4,4]nona-2,8-dien-6-one 4b. Pale
yellow crystals, yield 81%; mp 239–241◦C (tetrahy-
drofuran); IR (KBr) νmax/cm−1 1755.1 (C O), 1596.9
Cl
12
11
FIGURE 3 Unreacted hydrazonoyl halides.
1
(C N); H NMR (DMSO-d6) δ 2.295 (s, 3H, CH3),
5.557 (s, 1H, 4-CH), 6.841–7.626 (m, 24H, ArHs);
13C NMR (DMSO-d6) δ 179.818, 160.657, 149.479,
143.410, 138.367, 132.534, 131.657, 131.582,
131.355, 130.871, 130.816, 130.231, 129.948,
129.246, 128.937, 128.372, 128.105, 127.964,
127.747, 126.923, 126.774, 121.334, 114.807, 91.140,
64.082, 20.602; MS m/z (%): 533 (M+ + 1, 46), 505
(32), 399 (100), 194 (70), 104 (30), 91 (82), 77 (22);
Anal. Calcd for C36H28N4O: C, 81.18; H, 5.30; N,
10.52. Found: C, 81.18; H, 5.29; N, 10.52%.
thought to cause higher energy barrier between
HOMO of nitrilimine and LUMO of dienophile to
the extent of preventing their interaction to give
product.
EXPERIMENTAL
Melting points were measured on electrothermal
melting point apparatus and are uncorrected. The
infrared spectra were recorded in potassium bro-
mide disks on a Pye Unicam SP 3-300 and Shimadzu
7-(4-Chlorophenyl)-1,3,4,8-tetraphenyl-1,2,7,9-
tetraazaspiro[4, 4]nona - 2, 8 - dien - 6 - one 4c. Pale
1
FT-IR 8101 PC infrared spectrophotometer. The H
◦
yellow crystals, yield 84%; mp 221–223 C (tetrahy-
NMR (200 MHz) and 13C NMR (50 MHz) spectra
were recorded in DMSO-d6 on a Varian Mercury
VX 200 NMR using TMS as the internal reference.
Mass spectra were measured on a GCMS-QP 1000
EX spectrometer at 70 eV. Elemental analyses were
carried out at the Microanalytical Centre of Cairo
University, Giza, Egypt. Hydrazonoyl halides 1a
[36], 1b [37], and the imidazolinone 3 [38,39] were
prepared according to the method reported in the
literature.
drofuran); IR (KBr) νmax/cm−1 1759.0 (C O), 1600.8
1
(C N); H NMR (DMSO-d6) δ 5.560 (s, 1H, 4-CH),
6.842–7.625 (m, 24H, ArHs); MS m/z (%): 554 (M+
+ 1, 100), 525 (34), 399 (95), 214 (35), 193 (19), 104
(29), 90 (45), 77 (18); Anal. Calcd for C35H25ClN4O:
C, 76.01; H, 4.56; N, 10.13; Cl, 6.41. Found: C, 76.01;
H, 4.59; N, 10.11; Cl, 6.39%.
7-(4-Bromophenyl)-1,3,4,8-tetraphenyl-1,2,7,9-
tetraazaspiro[4,4]nona-2,8-dien-6-one 4d. Yellow
crystals, yield 81%; mp 226–228◦C (benzene); IR
(KBr) νmax/cm−1 1755.1 (C O), 1596.9 (C N); 1H
NMR (DMSO-d6) δ 5.492 (s, 1H, 4-CH), 6.839–7.633
(m, 24H, ArHs); MS m/z (%): 598 (M+ + 1, 100), 571
(26), 399 (81), 260 (22), 193 (16), 104 (16), 90 (40),
76 (20); Anal. Calcd. for C35H25BrN4O: C, 70.36; H,
4.22; N, 9.38; Br, 13.37. Found: C, 70.39; H, 4.21; N,
9.38; Br, 13.38%.
Reaction of 3a-l with Hydrazonoyl Halides
1a,b(General Procedure)
To a solution of the appropriate imidazolinone 3a-l
(5 mmol) and hydrazonoyl chloride 1a and hydra-
zonoyl bromide 1b (5 mmol) in dry benzene (50 mL),
triethylamine (0.7 mL, 5 mmol) was added and the
mixture was refluxed for 6 h. The reaction mixture
was filtered while hot to remove triethylamine hy-
drochloride and evaporated under reduced pressure
till dryness, and the remaining residue was triturated
with boiled methanol (10 mL). The separated solid
material was filtered and crystallized from a suitable
solvent.
4-(4-Methylphenyl)-1,3,7,8-tetraphenyl-1,2,7,9-
tetraazaspiro[4, 4]nona - 2, 8 - dien - 6 - one 4e. Pale
yellow crystals, yield 67%; mp 234–236◦C (benzene);
1
IR (KBr) νmax/cm−1 1755.1 (C O), 1596.9 (C N); H
NMR (DMSO-d6) δ 2.291 (s, 3H, CH3), 5.558 (s, 1H,
4-CH), 6.839–7.624 (m, 24H, ArHs); MS m/z (%): 533
(M+ + 1, 100), 505 (61), 413 (99), 192 (15), 180 (75),
104 (14), 91 (42), 77 (45); Anal. Calcd for C36H28N4O:
1,3,4,7,8-Pentaphenyl-1,2,7,9-tetrazaspiro[4,4]
nona-2,8-dien-6-one 4a. Pale yellow crystals, yield
Heteroatom Chemistry DOI 10.1002/hc

Regioselectivity of Nitrilimines 1,3-Dipolar Cycloaddition 135
C, 81.18; H, 5.30; N, 10.52. Found: C, 81.20; H, 5.28;
N, 10.52%.
yellow crystals, yield 72%; mp 186–188 ◦C (benzene);
1
IR (KBr) νmax/cm−1 1755.1 (C O), 1596.9 (C N); H
NMR (DMSO-d6) δ 5.532 (s, 1H, 4-CH), 6.867–7.689
(m, 24H, ArHs); MS m/z (%): 553 (M+, 100), 525 (56),
433 (88), 397 (39), 180 (93), 104 (35), 91 (88), 77 (97);
Anal. Calcd for C35H25ClN4O: C, 76.01; H, 4.56; N,
10.13; Cl, 6.41. Found: C, 76.02; H, 4.58; N, 10.12;
Cl, 6.39%.
7-(4-Chlorophenyl)-4-(4-methylphenyl)-1,3,8-tri-
phenyl-1,2,7,9-tetraazaspiro[4,4]nona-2,8-dien-6-one
4f. Pale yellow crystals, yield 85%; mp 240–242◦C
(benzene); IR (KBr) νmax/cm−1 1755.1 (C O), 1600.8
1
(C N); H NMR (DMSO-d6) δ 3.254 (s, 3H, CH3),
5.493 (s, 1H, 4-CH), 6.853–7.558 (m, 23H, ArHs);
13C NMR (DMSO-d6) δ 179.467, 160.038, 149.640,
143.387, 137.264, 133.244, 132.523, 131.523,
130.856, 129.841, 129.536, 129.253, 128.914,
128.693, 128.662, 128.357, 128.235, 128.193,
128.056, 127.461, 126.766, 121.342, 114.841, 91.274,
63.838, 20.659; MS m/z (%): 567 (M+, 39), 539 (22),
413 (100), 214 (78), 193 (28), 104 (63), 91 (91), 77
(58); Anal. Calcd for C36H27ClN4O: C, 76.25; H, 4.80;
N, 9.88; Cl, 6.25. Found: C, 76.19; H, 4.80; N, 9.89;
Cl, 6.26%.
4-(4-Chlorophenyl)-7-(4-methylphenyl)-1,3,8-tri-
phenyl-1,2,7,9-tetraazaspiro[4,4]nona-2,8-dien-6-one
4k. Yellow crystals, yield 74%; mp 228–230◦C (diox-
ane); IR (KBr) νmax/cm−1 1755.1 (C O), 1596.9
1
(C N); H NMR (DMSO-d6) δ 2.321 (s, 3H, CH3),
5.601 (s, 1H, 4-CH), 6.856–7.599 (m, 23H, ArHs);
13C NMR (DMSO-d6) δ 179.635, 161.057, 149.365,
143.364, 138.504, 132.645, 131.864, 131.790,
131.561, 130.806, 130.631, 130.032, 129.284,
129.089, 128.510, 128.250, 128.159, 127.976,
127.682, 126.907, 126.785, 121.559, 115.028, 90.961,
62.747, 20.640; MS m/z (%): 567 (M+, 36), 539 (27),
433 (62), 194 (70), 104 (32), 91 (100), 77 (22); Anal.
Calcd. for C36H27ClN4O: C, 76.25; H, 4.80; N, 9.88; Cl,
6.25. Found: C, 76.23; H, 4.81; N, 9.90; Cl, 6.26%.
4-(4-Methoxylphenyl)-1,3,7,8-tetraphenyl-1,2,7,9-
tetraazaspiro[4, 4]nona - 2, 8 - dien - 6 - one 4g. Pale
yellow crystals, yield 52%; mp 236–238◦C (benzene);
1
IR (KBr) νmax/cm−1 1755.1(C O), 1596.9 (C N); H
NMR (DMSO-d6) δ 3.717 (s, 3H, OCH3), 5.466 (s, 1H,
4-CH), 6.863–7.679 (m, 24H, ArHs); MS m/z (%):
549 (M+ + 1, 88), 521 (48), 429 (62), 180 (96), 104
(32), 91 (95), 77 (100); Anal. Calcd for C36H28N4O2:
C, 78.81; H, 5.14; N, 10.21. Found: C, 78.82; H, 5.12;
N, 10.20%.
4,7-Di-(4-chlorophenyl)-1,3,8-triphenyl-1,2,7,9-
tetraazaspiro[4, 4]nona-2, 8-dien-6-one 4l. Yellow
crystals, yield 76%; mp 224–226◦C (dioxane); IR
(KBr) νmax/cm−1 1759.0 (C O), 1596.9 (C N); 1H
NMR (DMSO-d6) δ 5.594 (s, 1H, 4-CH), 6.865–7.627
(m, 23H, ArHs); MS m/z (%): 587 (M+, 65), 559 (28),
434 (61), 193 (68), 104 (35), 91 (100), 77 (31); Anal.
Calcd for C35H24Cl2N4O: C, 71.55; H, 4.12; N, 9.54; Cl,
12.07. Found: C, 71.58; H, 4.11; N, 9.52; Cl, 12.09%.
7-(4-Chlorophenyl)-4-(4-methoxylphenyl)-1,3,8-
triphenyl-1,2,7,9-tetraazaspiro[4,4]nona-2,8-dien-6-
one 4h. Pale yellow crystals, yield 78%; mp 254–
256◦C (dioxane); IR (KBr) νmax/cm−1 1759.0 (C O),
1
1600.8 (C N); H NMR (DMSO-d6) δ 3.714 (s, 3H,
OCH3), 5.465 (s, 1H, 4-CH), 6.868–7.688 (m, 23H,
ArHs); MS m/z (%): 583 (M+, 99), 555 (51), 429 (100),
214 (84), 193 (22), 104 (29), 91 (80), 77 (32); Anal.
Calcd for C36H27ClN4O2: C, 74.16; H, 4.67; N, 9.61;
Cl, 6.08. Found: C, 74.18; H, 4.69; N, 9.61; Cl, 6.09%.
3-(2,4-Dichlorophenyl)-1-(4-nitrophenyl)-4,7,8-
triphenyl-1,2,7,9-tetraazaspiro[4,4]nona-2,8-dien-6-
one 4m. Yellow crystals, yield 66%; mp 214–216◦C
(dioxane); IR (KBr) νmax/cm−1 1751.2 (C O), 1581.5
1
(C N); H NMR (DMSO-d6) δ 5.600 (s, 1H, 4-CH),
6.866–7.821 (m, 22H, ArHs); MS m/z (%): 633 (M+ +
1, 37), 605 (56), 513 (30), 191 (15), 180 (81), 105 (24),
89 (37), 77 (100); Anal. Calcd for C35H23Cl2N5O3: C,
66.46; H, 3.67; N, 11.07; Cl, 11.21. Found: C, 66.45;
H, 3.69; N, 11.09; Cl, 11.23%.
7-(4-Bromophenyl)-4-(4-methoxylphenyl)-1,3,8-
triphenyl-1,2,7,9-tetraazaspiro[4,4]nona-2,8-dien-6-
one 4i. Pale yellow crystals, yield 65%; mp 241–
243◦C (benzene); IR (KBr) νmax/cm−1 1751.2 (C O),
1
1600.8 (C N); H NMR (DMSO-d6) δ 3.715 (s, 3H,
OCH3), 5.464 (s, 1H, 4-CH), 6.868–7.697 (m, 23H,
ArHs); MS m/z (%): 628 (M+ + 1, 47), 600 (29), 429
(54), 260 (41), 104 (50), 91 (100), 76 (83); Anal. Calcd
for C36H27BrN4O2: C, 68.90; H, 4.34; N, 8.93; Br,
12.73. Found: C, 68.87; H, 4.33; N, 8.91; Br, 12.71%.
Synthesis of N,1,3,4-Tetraphenyl-1H-pyrazole-5-
carboxamide 8a
A mixture of compound 4a (0.5 g) and acetic acid
(20 mL) was refluxed for 2 h. The mixture was left to
cool, and then the precipitated solid was filtered off
and recrystallized from ethanol.
4-(4-Chlorophenyl)-1,3,7,8-tetraphenyl-1,2,7,9-
tetraazaspiro[4, 4]nona - 2, 8 - dien - 6 - one 4j. Pale
Heteroatom Chemistry DOI 10.1002/hc

136 Miqdad, Abunada, and Hassaneen
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N,1,3,4-tetraphenyl-1H-pyrazole-5-carboxamide
8a. White, yield 83%; mp 243–244oC (lit. mp 240–
242◦C) [31]; IR (KBr) νmax/cm−1 3313.5 (NH), 1651.0
1
(C O amide), 1596.9 (C N); H NMR (DMSO-d6) δ
7.06–7.72 (m, 21H, ArH), 10.76 (br, s, 1H, NH, D2O-
exchangeable); 13C NMR (DMSO-d6) δ 119.1, 119.8,
122.8, 124.4, 124.5, 127.7, 127.9, 128.0, 128.3, 128.6,
128.7, 128.9, 129.2, 130.1, 131.2, 131.9, 132.5, 137.8,
138.0, 139.1, 149.0, 158.9, 187.1; MS m/z (%): 416 (M
+ 1+, 56), 323 (100), 190 (14), 165 (16), 89 (69), 77
(31); Anal. Calcd. for C28H21N3O: C, 80.94; H, 5.09;
N, 10.11. Found: C, 80.92; H, 5.10; N, 10.12%.
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Heteroatom Chemistry DOI 10.1002/hc