The synthesis of new spiro β-lactam and thiazolidinone compounds incorporating quinones and their biological activity

Article abstract of DOI:10.1080/10426500600754760

A series of some fused and spiro heterocyclic compounds such as pyrazolines, isoxazolines, pyrimidines, β-lactams, and thiazolidinone derivatives incorporating compounds 3, 6a-d, 7a-d, 9a-c, 10a-c, 11a-c, 12a-c, and 13a-c have been synthesized by a cycloa

Full text of DOI:10.1080/10426500600754760

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The Synthesis of New Spiro
β-Lactam and Thiazolidinone
Compounds Incorporating
Quinones and Their Biological
Activity
A. K. Khalafallah a , N. A. A. El-Kanzi a , H. A.
Soleiman a & M. Younis b
a Chemistry Department, South Valley University,
Aswan, Egypt
b Botany Department, South Valley University,
Aswan, Egypt
Version of record first published: 01 Feb 2007.
To cite this article: A. K. Khalafallah, N. A. A. El-Kanzi, H. A. Soleiman & M.
Younis (2006): The Synthesis of New Spiro β-Lactam and Thiazolidinone Compounds
Incorporating Quinones and Their Biological Activity, Phosphorus, Sulfur, and Silicon
and the Related Elements, 181:11, 2483-2503
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Phosphorus, Sulfur, and Silicon, 181:2483–2503, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600754760
The Synthesis of New Spiro β-Lactam and
Thiazolidinone Compounds Incorporating
Quinones and Their Biological Activity
A. K. Khalafallah
N. A. A. El-Kanzi
H. A. Soleiman
Chemistry Department, South Valley University, Aswan, Egypt
M. Younis
Botany Department, South Valley University, Aswan, Egypt
A series of some fused and spiro heterocyclic compounds such as pyrazolines, isoxa-
zolines, pyrimidines, β-lactams, and thiazolidinone derivatives incorporating com-
pounds 3, 6a–d, 7a–d, 9a–c, 10a–c, 11a–c, 12a–c, and 13a–c have been synthesized by
a cycloaddition and cyclocondensation reaction of monochloroacetyl chloride, mer-
captoacetic acid, hydrazines, hydroxylamine, urea, and thiourea with the prepared
5a–d and 8a–c.
Keywords Spiro β-lactam; thiazolidinone
INTRODUCTION
A wide range of thiazole containing metabolites have been isolated
and characterized from marine organisms;1,2 thiazole derivatives such
as pencillins, which have fused thiazolidine and β-Lactam rings, are
potent antibiotics.3 The addition quinones possess widespread ap-
plication in various fields, including use as fungicides,4−9 antibacte-
rial10−13 drugs,14−17 and vat dyes,18−21 and have biological activity,22−28
antioxidant.29,30 The goal of this project was to investigate and develop
newer approaches for the synthesis of new heterocyclic quinones incor-
porating sulfur. We synthesized new heterocyclic by a cyclocondensation
reaction of compound 2 with chloroketene to give the new compound 3,
which was used for the synthesis of β-Lactams 6a–d, thiazolidinones
Received October 23, 2005; accepted April 6, 2006.
Address correspondence to H. A. Soleiman, South Valley University, Chemistry De-
partment, Faculty of Science, Aswan, Egypt. E-mail: hsoleiman2001@yahoo.com
2483

2484
A. K. Khalafallah et al.
7a–d, pyrazolines 9a–c, l0a–c, Isoxazolines lla–c, and pyrimidines l2a–
c and 13a–c.
RESULTS AND DISCUSSION
The new compound 2 was synthesised by the reaction of benz[g]-1,2,3,4-
tetrahydroquinoline-4,5,10-trione 1, which was prepared in our labora-
tory, as it has been reported in an earlier publication,31 with equimolar
ratios of sulfur in ethanol containing piperidine as a catalyst. In the
presence of a piperidine catalyst, compound 1 transformed into a tau-
tomeric form. The dihydroxynaphthopyrido is the more likely tautomer;
thus, the reaction of the pyridone with elemental S8 could conceivably
result in the proposed product. Thus compound 2 was prepared accord-
ing to Equation (1).
EQUATION 1
The structure of compound 2 was confirmed by elemental analysis,
1
and an IR and H NMR spectrum, which revealed the presence of a
broad singlet signal at δ 10.2 for NH, broad signals at δ 11.8 for 2OH,
and a multiplet signal at δ 8–6 for Ar H+ at δ 5.7 (s, CH) and δ 1.8
(br, SH), and mass spectral data showed the molecular ion peak at m/z
(259).
The reaction of compound 2 with chloroacetyl chloride in the pres-
ence of an excess triethylamine catalyst is considered chloroketene

2485

2486

SCHEME 3
2487

2488
A. K. Khalafallah et al.
chemistry.32 The reaction of the more likely tautomeric structure of
compound 2 with chloroketene gives the opportunity for a [3 + 2] cy-
cloaddition because triethylamine is really only strong enough to de-
protonate the thiolbarely strong enough to deprotonate the NH.32 Thus
compound 3 was prepared according to Equation (2).
EQUATION 2
There is, of course, also the opportunity for the coupling to occur in
the opposite manner with the chloroketene; this would give an inter-
mediate that would not easily lose chlorine. Therefore, the combustion
analysis rules this option out. The structure of compound 3 was con-
1
firmed by elemental analysis and an IR and H NMR spectrum of the
product in DMSO showed at δ 10.5(br, NH), δ 8–7(m, 4H), δ 2.1(d, 2H),
δ 1.6(d, 1H), and at δ 1.1 (q, 1H) supporting the structure of compound
3, and mass spectral data showed the molecular ion peak at m/z (299).
According to the spectral analysis, the formation of compound 4 ap-
pears to be unlikely because there are no singlet signals assigned for
the CH2 group at δ 2.54 and singlet signals for the CH group at δ 1.65,
thus, the reaction of compound 2 with chloroacetyl chloride leads to the
formation of compound 3.
Our approach to the synthesis of the desired spiro compounds started
with compounds 5a–d, which were prepared by the condensation of
nitroso compounds such as α-nitroso β-naphthol, β-nitroso α-naphthol,

Spiro β-Lactam and Thiazolidinone Compounds
2489
p-nitrosophenol, and p-nitroso-N-dimethylaniline with compounds 3 in
ethanol using a piperidine catalyst, which afforded the new Schiff bases
compounds.
The structure of these newly synthesised Schiff bases compounds
5a–d were confirmed by elemental analysis and infrared spectra, which
showed absorption bands at 1620–1580 cm−1 attributed to C N and a
characteristic band attributed to C O at 1700–1696 cm−1 and 3310
attributed to NH.33
The formation of Schiff bases 5a–d is expected to owing suggested
mechanism, (c.f. Equation (3)).
EQUATION 3
The first step in the previous mechanism involves the formation of
carboanion (a) using piperidine as a catalyst, which abstracted a proton
from the active hydrogen center; accordingly, it was added itself on

2490
A. K. Khalafallah et al.
the polarized aromatic nitroso compounds forming the intermediate
compound (b) to uptake a proton from the piperidinium ion forming
compound (c). The latter compound (c) lost a mole of water to produce
the Schiff base compound 5a–d.
Compound 3 underwent cycloaddition with chloroketene to give
spiro lactam 6a–d. The cycloaddition proceeded smoothly in dimethyl-
formamide in the presence of a triethyl amine catalyst34,35 to afford
6a–d. The reaction of compound 2 with chloroacetyl chloride proceeded
through a [2 + 2] cycloaddition; the reaction is presented as follows (c.f.
Equation (4)).
EQUATION 4
Structure (a) was preferred over possible (b) based on 1H NMR, which
revealed proton β-lactam nuclei that appeared at δ = 4ppm. If the prod-
uct of the reaction β-lactam nuclei to appear at lower field Ca = 5 ppm
as it is deohielded by lone pair anisotropy.
The more stable product formed according to the following mecha-
nisms (c.f. Equation (5)).
Thus, I would fully expect a farther rearrangement to a more stable
product. The structure of spiro lactams 6a–d confirmed by analytical
data and infrared spectra, which showed the disapperance of the ab-
sorption band of C N at 1580 cm−1, also showed a C N absorption band
1
at 1222 cm−1 and C O of a β-Lactam ring 1760 cm−1 and a H NMR
spectrum, which showed signals at δ 10.2(br, NH), multiplet signals at
δ 8–6 for aromatic protons at δ 4, a singlet for β-lactam carbon proton
at δ 1.6, a doublet singlet for a saturated carbon proton, and at δ 1.1 for
another saturated carbon proton.

Spiro β-Lactam and Thiazolidinone Compounds
2491
EQUATION 5
Spiro thiazolidinone 7a–d was prepared by the cycloaddition of thio-
glycolic acid (1:1 molar ratios) in boiling benzene using a water separa-
tor system for five days36,37 and afforded the corresponding compound
7a–d, the cycloaddition proceeded as follows (c.f. Equation (6)).
The cycloaddition reaction was assumed to go through the following
suggested mechanism (c.f., Equation (7)).
The structure of thiazolidinone derivatives 7a–d was identified from
the correct elemental analysis and infrared spectra, which showed an
1
absorption band at 1685–1645 cm−1 attributed to C O group and H
NMR spectrum, which showed singlet a signal at 2.39 for CH2 of the
thiazolidinone ring.
The activity of the methylene group in compound 3 lead compound
3 was easily condensed with different aromatic aldehydes in ethanol
and dimethyl formamide (5 mL) as a solvent using a piperidene cata-
lyst to give 8a–c. The structure of compound 8a–c was confirmed by
elemental analysis and IR, which revealed the presence of peak NH

2492
A. K. Khalafallah et al.
EQUATION 6
EQUATION 7
at 3400–3100 cm−1, C O 1730–1660 cm−1, and C C 1610–1580 cm−1
;
also, its structures were confirmed by 1H NMR and mass spectral data
(c.f. Tables I and II).
The activity of the exocyclic group C C in compound 8a–c in conjuga-
tion with the carbonyl group was demonstrated by a reaction with hy-
drazines, hydroxylamine hydrochloride, urea, and thiourea. The nature
of the structure of the products for the previously mentioned reaction,
according to the different methods of analysis, elemental analysis, IR,
and mass spectra, gave us the agreements that the reaction is carried
out by a condensation addition reaction through the α, β-unsaturated
ketonic system. Thus, the chemical work covers the implementation

Spiro β-Lactam and Thiazolidinone Compounds
2493
TABLE I The Yield, m.p., and Elemental Analysis of Compounds
(1–13)
Elemental Analysis (Found)
Compound Yield (%)
C
H
N
S
Cl
1
2
3
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
9a
75
65
70
73
69
67
65
75
68
67
70
65
67
65
70
70
68
69
72
71
73
70
69
67
65
60
77
76
77
75
65
68
69
68.72 (68.70) 3.99 (3.97) 6.16 (6.15)
60.22 (60.21) 3.49 (3.47) 5.43 (5.42) 12.34 (12.33)
60.19 (60.18) 3.03 (3.02) 4.60 (4.59) 10.69 (10.68)
—
—
—
—
—
—
—
—
66.06 (66.05) 3.10 (3.05) 6.19 (6.17)
66.06 (66.03) 3.10 (3.00) 6.19 (6.14)
62.35 (62.34) 2.98 (2.97) 6.95 (6.94)
64.00 (64.00) 3.97 (3.96) 9.78 (9.76)
61.07 (61.06) 2.85 (2.84) 5.29 (5.27)
61.07 (61.05) 2.85 (2.83) 5.29 (5.28)
57.55 (57.54) 2.52 (2.51) 5.86 (5.85)
59.09 (59.08) 4.57 (4.56) 8.31 (8.30)
61.34 (61.33) 3.05 (3.04) 5.32 (5.31) 12.13 (12.12)
61.34 (61.32) 3.05 (3.03) 5.32 (5.30) 12.13 (12.11)
57.84 (57.83) 2.74 (2.73) 5.89 (5.87) 13.43 (13.42)
59.37 (59.36) 3.79 (3.77) 8.34 (8.33) 12.68 (12.67)
68.19 (68.18) 3.38 (3.37) 3.63 (3.61)
61.09 (61.08) 2.79 (2.77) 6.50 (6.49)
65.49 (65.48) 3.25 (3.24) 3.49 (3.48)
64.98 (64.97) 3.86 (3.85) 9.51 (9.50)
58.98 (58.97) 3.29 (3.27) 11.51 (11.50) 6.56 (6.55)
62.71 (62.70) 3.73 (3.72) 9.18 (9.17)
70.39 (70.38) 4.01 (4.00) 8.83 (8.82)
7.05 (7.03)
7.05 (7.00)
7.93 (7.92)
7.43 (7.42)
6.04 (6.03) 6.68 (6.67)
6.04 (6.02) 6.68 (6.66)
6.68 (6.67) 7.39 (7.38)
6.31 (6.30) 6.98 (6.97)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8.27 (8.26)
7.41 (7.40)
7.95 (7.94)
7.39 (7.38)
9b
9c
6.98 (6.97)
6.71 (6.70)
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
64.33 (64.32) 3.47 (3.46) 12.49 (12.47) 6.31 (6.12)
68.12 (68.11) 3.88 (3.86) 8.55 (8.54)
65.64 (65.63) 3.51 (3.50) 6.99 (6.98)
59.04 (59.03) 2.93 (2.91) 9.43 (9.42)
63.13 (63.12) 3.37 (3.36) 6.72 (6.72)
64.30 (64.29) 3.52 (3.51) 9.82 (9.80)
56.30 (56.28) 2.97 (2.96) 11.86 (11.85) 6.76 (6.75)
61.99 (61.98) 3.39 (3.38) 9.47 (9.45)
67.73 (67.72) 3.55 (3.53) 9.92 (9.91)
6.49 (6.47)
7.96 (7.95)
7.16 (7.15)
7.66 (7.65)
7.46 (7.45)
7.19 (7.17)
7.53 (7.51)
56.29 (56.28) 2.88 (2.87) 11.47 (11.45) 13.07 (13.06)
59.84 (59.82) 3.28 (3.27) 9.14 (9.13) 13.89 (13.87)
All compounds were crystallized from DMF. All m.p. (except for 1, m.p., 178, 2, m.p.,
280◦) are above 300◦ and occur decomposition.
of the following fused heterocyclic compounds and the details are as
follows (c.f. Equation (8)).
N-acetyl (phenyl) derivatives of compounds 9a–c and 10a–c were
synthesised by the interaction of 8a–c with equimolecular ratios of
hydrazine hydrate or phenyl hydrazine in the presence of acetic acid
(piperidine) as a catalyst, respectively.

2494
A. K. Khalafallah et al.
TABLE II Spectral Data of Compounds (1–13)
Compound
IR (cm−1
)
1H-NMR δ
MS (m+)
227
1
3400–3150 (NH, OH), 1645 10.2 (br, NH), 8–7 (m, 4ArH+), 1.4 (t,
(C O)
CH2), 1.6 (t, CH2)
2
3350–3200 (NH), 1640
(C O)
3450–3150 (NH), 1660
(C O)
3400–3100 (NH, OH), 1695 11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 10
(C O)
11.8 (s, 2OH), 10.2 (br, NH), 8–6 (m,
4ArH+), 5.3 (s, CH), 3.4 (br, s)
10.2 (br, NH), 8–7 (m, 4 ArH+), 2.1 (d,
2H), 1.6 (d, 1H), 1.1 (q, 1H)
259
299
454
3
5a
ArH+), 4 (s, CH), 1.6 (d, CH), 1.1 (d,
CH)
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
3400–3100 (NH, OH), 1695 11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 10
(C O), 1620 (C N)
454
403
431
531
531
479
508
528
528
477
505
ArH+), 4 (s, OH), 1.6 (d, CH), 1.1 (d,
CH)
3400–3100 (NH, OH), 1680 11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 8
(C O), 1624 (C N)
ArH+), 4 (s, CH), 1.6 (d, CH), 1.1 (d,
CH)
3400–3100 (NH), 1685
(C O), 1625 (C N)
11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 8
ArH+), 4 (s, CH), 2.3 (s, 6H), 1.6 (d,
CH), 1.1 (d, CH)
3450–3100 (NH, OH), 1688 11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 10
(C O)
ArH+), 4 (s, CH), 1.6 (d, CH), 1.1 (d,
CH)
3400–3100 (NH, OH), 1685 11.5 (s, OH), 10.5 (br, NH), 8–7 (m, 10
(C O)
ArH+), 4 (s, CH), 1.6 (d, CH), 1.1 (d,
CH)
3400–3100 (NH, OH), 1687 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C O)
8ArH+), 4 (s, CH), 1.6 (d, CH), 1.1
(d, CH)
3450–3150 (NH), 1689
(C O)
11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
8ArH+), 4 (s, CH), 2.3 (s, 6H), 1.6
(d, CH), 1.1 (d, CH)
3400–3100 (NH, OH), 1697 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C O)
10Ar+H+), 2.1 (s, CH2), 1.6 (d, CH),
1.1 (d, CH)
3400–3100 (NH, OH), 1696 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C O)
10ArH+), 2.1 (s, CH2), 1.6 (d, CH),
1.1 (d, CH)
3400–3100 (NH, OH), 1685 11.5 (s, 2OH), 10.5 (br, NH), 8–7 (m,
(C O)
8ArH+), 2.1 (s, CH2), 1.6 (d, CH),
1.1 (d, CH)
3400–3100 (NH), 1692
(C O)
11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
8ArH+), 2.3 (s, 6H), 2.1 (s, CH2),
1.6 (d, CH), 1.1 (d, CH)
8a
8b
3400–3100 (NH), 1647
(C O), 1580 (C C)
3450–3100 (NH), 1665
(C O), 1580 (C C)
10.5 (br, NH), 8–7 (m, 9ArH+), 6 (s,
CH), 1.6 (d, CH), 1.1 (d, CH)
10.5 (br, NH), 8–7 (m, 8ArH+), 6 (s,
CH), 1.6 (d, CH), 1.1 (d, CH)
387
432
(Continued on next page)

Spiro β-Lactam and Thiazolidinone Compounds
2495
TABLE II Spectral Data of Compounds (1–13) (Continued)
Compound IR (cm−1
)
1H-NMR δ
MS (m+)
403
8c
3400–3100 (NH, OH), 1668 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C O), 1610–1580 (C C)
8ArH+), 6 (s, CH), 1.6 (d, CH), 1.1
(d, CH)
9a
3400–3100 (NH), 1630
(C N), 1725 (C O)
10.5 (br, NH), 8–7 (m, 9ArH+), 2.5 (s,
CH3) 2.2 (d, CH), 1.6 (d, CH), 1.4 (t,
CH), 1.1 (d, CH)
443
488
459
477
522
493
402
447
418
429
474
445
425
490
461
9b
3450–3150 (NH), 1625
(C N), 1715 (C O)
10.5 (br, NH), 8–7 (m, 8ArH+), 2.5 (s,
CH3) 2.2 (d, CH), 1.6 (d, CH), 1.4 (t,
CH), 1.1 (d, CH)
9c
3400–3100 (NH, OH), 1620 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C N), 1715 (C O)
8ArH+), 2.5 (s, CH3) 2.2 (d, CH),
1.6 (d, CH), 1.4 (t, CH), 1.1 (d, CH)
10.5 (br, NH), 8–7 (m, 14ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
3400–3100 (NH), 1615
(C N), 1665 (C O)
3400–3100 (NH), 1610
(C N), 1680 (C O)
10.5 (br, NH), 8–7 (m, 13ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
3450–3150 (NH, OH), 1625 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C N), 1680 (C O)
13ArH+), 2.2 (d, CH), 1.6 (d, CH),
1.4 (t, CH), 1.1 (d, CH)
3400–3100 (NH), 1636
(C O), 1585 (C N)
10.5 (br, NH), 8–7 (m, 9ArH+), 2.2 (d,
CH), 1.6 (d, CH), 1.4 (t, CH), 1.1 (d,
CH)
3400–3100 (NH), 1635
(C O), 1590 (C N)
10.5 (br, NH), 8–7 (m, 8ArH+), 2.2 (d,
CH), 1.6 (d, CH), 1.4 (t, CH), 1.1 (d,
CH)
3450–3150 (NH, OH), 1625 11.5 (s, OH), 10.5 (br, NH), 8–7 (m,
(C N), 1596 (C O)
8ArH+), 2.2 (d, CH), 1.6 (d, CH), 1.4
(t, CH), 1.1 (d, CH)
3400–3100 (NH), 1615
(C O), 1590 (C N)
10.5 (bs, 2NH), 8–7 (m, 9ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
3400–3100 (NH), 1660
(C O), 1635 (C N)
10.5 (bs, 2NH), 8–7 (m, 8ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
34500–3150 (NH, OH),
1554 (C N), 1625 (C O)
11.5 (s, OH), 10.5 (bs, 2NH), 8–7 (m,
8ArH+), 2.2 (d, CH), 1.6 (d, CH), 1.4
(t, CH), 1.1 (d, CH)
3400–3100 (NH), 1670
(C O), 1619 (C N)
10.5 (bs, 2NH), 8–7 (m, 9ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
3400–3100 (NH), 1675
(C O), 1617 (C N)
10.5 (bs, 2NH), 8–7 (m, 8ArH+), 2.2
(d, CH), 1.6 (d, CH), 1.4 (t, CH), 1.1
(d, CH)
3400–3100 (NH, OH), 1697 11.5 (s, OH), 10.5 (bs, 2NH), 8–7 (m,
(C O), 1630 (C N)
8ArH+), 2.2 (d, CH), 1.6 (d, CH), 1.4
(t, CH), 1.1 (d, CH)

2496
A. K. Khalafallah et al.
EQUATION 8
The structures of 9a–c and 10a–c were confirmed by elemental anal-
ysis, IR, 1H NMR, and mass spectra (c.f. Tables I and II). The structure
1
of compound 9a was confirmed by elemental analysis, IR, and an H
HNR spectrum, which revealed the presence of broad singlet signal at
δ 10.5 for NH and a multiplet signal at δ 8–7 for 9 ArH+ at δ 2.5(s,
CH3), δ 2.2(d, CH), δ 1.6(d, CH), δ 1.4(t, CH), and δ 1.1(d, CH), and
mass spectral data showed the molecular ion peak at m/z(443). Also,
the structure of compound 10a was confirmed by elemental anlysis, IR,
and an 1H NMR spectrum, which revealed the presence of a broad sin-
glet signal at δ 10.5 for NH and a multiplet signal at δ 8–6 for 14 ArH+
at δ 2.2(d, CH), δ 1.6(d, CH), δ 1.4(t, CH), and δ 1.1(d, CH), and mass
spectral data showed the molecular ion peak at m/z(477).
Isoxazolino derivatives of compounds 11a–c were synthesised by the
reaction of 8a–c with equimolecular ratios of hydroxylamine hydrochlo-
ride in the presence of sodium hydroxide (c.f. Equation (9)). The struc-
tures of 11a–c were confirmed by elemental analysis, IR, 1H NMR, and
mass spectra (c.f. Tables I and II).
Pyrimidino and pyrimidine thiono derivatives of compounds 12a–c
and 13a–c were synthesized by the reaction of 8a–c with equimolecu-
lar ratios of urea and/or thiourea in ethanol containing 20 mL of hy-
drochloric acid and/or in the presence of sodium hydroxide, respectively
(c.f. Equation (10)). The structures of compounds 12a–c and 13a–c were
confirmed by analytical and spectral analysis (c.f. Tables I and II).
Many antimicrobial agents have been introduced into therapy;37,38
thus, we selected some compounds and tested the biological activity
of the prepared compounds. The biological activity of some selected

Spiro β-Lactam and Thiazolidinone Compounds
2497
EQUATION 9
EQUATION 10
prepared compounds determined using the filter paper disk method.39
The data of the disc susceptibility tests for the used 2, 3, 5a, 6a, 7a
compounds clearly showed significant and potent antibacterial activity
(bactericidal) against all the gram positive tested bacteria; the gram
negative organisms revealed weak susceptibility for most of the tested
compounds. The compound also tested against fungi; the results showed
as follows (see Table III).
EXPERIMENTAL SECTION
Melting points were obtained uncorrected. IR spectra were obtained
1
as KBr pellets on a pye-unican Sp 1000 spectrophotometer. H NMR
spectra were recorded in DMSO-d6 at 200 MHz on a Varian Gemini

2498

Spiro β-Lactam and Thiazolidinone Compounds
2499
NMR spectrometer using TMS as a internal reference. Mass spectra
were obtained on a Shimadzu GCMS QP 1000 EX mass spectrometer
at 70 eV. Elemental analysis were carried out at the Microanalytical
Center of Cairo University (Cairo, Egypt).
The Synthesis of Benz[g]1,2,3,4-tetrahydroquinoline-
4,5,10-trione (1)
A solution of 1,4 naphthoquinone (0.02 mol, 2 × 1.58 g) ethanol 30 mL
was treated with β-alanine (0.01 mol, 0.89 g). The reaction mixture was
heated under reflux on a water bath for 8 h. The mixture was filtered
hot, and the filtrate was added to ice water and stirred until red brown
ppt. Separate the solid product so formed was collected by filtration and
crystallized from ethanol (c.f. Tables I and II).
The Synthesis of Compound 2
A solution of compound 1 (0.01 mol, 2.27 gm) in ethanol (20 mL) con-
taining 5 mL of piperidine was treated with sulfur (0.01 mol, 0.32 g).
The reaction mixture was heated under reflux for 10–12 h. The solvent
was then evaporated under reduced pressure and poured on to ice water
acidified by HC1; the solid product so formed was collected by filtration
and crystallized from ethanol (c.f. Tables I and II).
The Synthesis of Compound 3
A solution of 2 (0.01 mol, 2.59 g) in ethanol (30 mL) was treated with
chloroacetylchloride (0.01 mol, 1.13 g) and 5 mL of triethyl amine cata-
lyst. The reaction mixture was heated under reflux for 12 h. The solvent
was then evaporated under reduced pressure. The solid product was col-
lected by filtration and crystallized from dimethylformamide (c.f. Tables
I and II).
The Synthesis of the New Schiff Bases Derivatives 5a–d
A solution of 3 (0.01 mol, 2.99 g) in ethanol (30 mL) was treated with
aromatic nitroso compounds (0.01 mole) in the presence of a catalytic
amount of piperidine (0.5 mL). The reaction mixture was heated under
reflux for 7–6 h. The solvent was then evaporated under reduced pres-
sure, and the residue was treated with ice water. The solid product was
collected and crystallized from dimethylformamide (c.f. Tables I and II).

2500
A. K. Khalafallah et al.
The Synthesis of Spiro Lactam Derivatives 6a–d
A solution of 5a–d (0.01 mole) was treated with chloroacetyl chloride
(0.01 mol, 1.13 g) in dry DMF (30 mL) in the presence of a catalytic
amount of triethylamine (0.01 mL); the reaction mixture was heated
under reflux for l0 h. (monitored by TLC). The solvent was then evap-
orated under reduced pressure and the residue was treated with ice
water. The solid product formed collected by filtration and crystallized
from dimethylformamide (c.f. Tables I and II).
The Synthesis of Spiro Thiazolidinone Derivatives 7a–d
A solution of Schiff bases 5a–d (0.01 mole) was treated with mercap-
toacetic acid (0.01 mol, 0.92 g) in benzene (50 mL) and refluxed on a
water bath for about 5 days. The mixture was then separated using a
separator funnel. The solid product was collected and crystallized from
dimethylformamide (c.f. Tables I and II).
The Synthesis of Arylidene Compound Derivatives 8a–c
A solution of compound 3 (0.01 mol, 2.99 g) in absolute ethanol
(30 mL) and DMF was treated with different aromatic aldehydes
(0.01 mol) in the presence of a piperidine catalyst. The reaction mix-
ture was heated under reflux for 4–6 h (monitored by TLC). The sol-
vent was then evaporated under reduced pressure, and the residue
was treated with ice water acidified by HC1. The solid product
was collected and crystallized from dimethylformamide (c.f. Tables I
and II).
The Reaction of Compound 8a–c with Hydrazine Hydrate
to Give N-Acetyl-pyrazolo Derivatives 9a–c
A solution of 8a–c (0.01 mol) in absolute ethanol (30 mL) was treated
with hydrazine hydrate (0.01 mol, 0.50 g) in the presence of glacial
acetic acid as a catalyst. The reaction mixture was heated under
reflux for 10–12 h. (monitored by TLC). The reaction mixture was
filtered hot; the solvent was then evaporated under reduced pres-
sure, and the remaining resin was boiled with petroleum ether (60–
80◦C). The residue was treated with ice water, and the solid obtained
was collected and crystallized from dimethylformamide (c.f. Tables I
and II).

Spiro β-Lactam and Thiazolidinone Compounds
2501
The Reaction of Compound 8a–c with Phenylhydrazine
to Give N-phenyl-pyrazolo Derivatives 10a–c
A solution of 8a–c (0.01 mol) in dimethylformamide (30 mL) was treated
with phenylhydrazine (0.01 mol, 1.08 g) in the presence of a catalytic
amount of piperidine (0.1 mL). The reaction mixture was heated un-
der reflux for 11 h. (monitored by TLC). The solvent was then evapo-
rated under reduced pressure, and the residue was treated with cold
water. The solid product was collected and crystallized from dimethyl-
formamide (c.f. Tables I and II).
The Reaction of Compound 8a–c with Hydroxylamine
Hydrochloride to Give Isoxazolo Derivatives 11a–c
A solution of 8a–c (0.01 mole) in absolute ethanol (30 mL) was treated
with hydroxylamine hydrochloride (0.01 mol, 6.95 g) in the presence of
sodium hydroxide as a catalyst. The reaction mixture was heated under
reflux for 10–12 h (monitored by TLC). The reaction mixture was fil-
tered hot. The solvent was then evaporated under reduced pressure, and
the remaining resin was boiled with petroleum ether (60–80◦C). The
solid product was collected and crystallized from dimethylfomiamide
(c.f. Tables I and II).
The Reaction of Compound 8a–c with Urea to give Pyrimidino
Derivatives 12a–c
A solution of 8a–c (0.01 mol) in ethanol (20 mL) was treated with urea
(0.01 mol, 0.60 g) in the presence of conc. HC1. The reaction mixture
was heated under reflux for 13–15 h (monitored by TLC). It was then
filtered hot and allowed to cool; the solvent evaporated under reduced
pressure, and the residue was treated with crushed ice and neutralized
with 5N NaOH. The solid product was collected and crystallized from
dimethylformamide (c.f. Tables I and II)
The Reaction of Compound 8a–c with Thiourea to Give
Thiopyrimidino Derivatives 13a–c
A solution of 8a–c (0.01 mol) in ethanol was treated with thiourea (0.01
mol, 0.76 g) in the presence of sodium hydroxide as a catalyst. The
reaction mixture was heated under reflux for 10–12 h (monitored by
TLC). It was then filtered hot; the solvent evaporated under reduced
pressure to dryness, and the residue treated with petroleum ether (60–
80◦). The excess of petroleum ether was removed, and the residue was

2502
A. K. Khalafallah et al.
treated with cold water. The solid product was collected and crystallized
from dimethylformamide (c.f. Tables I and II).
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