Synthesis of some new heterocyclic compounds from benzopyrano[2,3-c]pyrazol-3-one derivatives

Article abstract of DOI:10.1081/SCC-100105398

The reaction of benzopyrano[2,3-c]pyrazol-3-one (1) with some active halo compounds, afforded compounds 4, 8 and 12, respectively. The cyanoethyl derivative 19 was synthesized and treated with active methylenes and sulfur or benzoylisothiocyanate and phenacyl bromide, to give compounds 24_a,b and 27. Compounds 25_a,b and 28 were obtained through the reaction of compounds 24_a,b with acrylonitrile or compound 27 with maleic anhydride. Thiation of compound 1 afforded the corresponding thio derivative 29. The reaction of 4-benzylidene-2-methyloxazolin-5-one with compounds 1 or 29 gave products 30_a,b, respectively.

Full text of DOI:10.1081/SCC-100105398

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SYNTHESIS OF SOME NEW HETEROCYCLIC
COMPOUNDS FROM BENZOPYRANO[2,3-c]PYRAZOL-3-
ONE DERIVATIVES
A. Khodairy
Published online: 09 Nov 2006.
To cite this article: A. Khodairy (2001): SYNTHESIS OF SOME NEW HETEROCYCLIC COMPOUNDS FROM BENZOPYRANO[2,3-
c]PYRAZOL-3-ONE DERIVATIVES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:17, 2697-2712
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SYNTHETIC COMMUNICATIONS, 31(17), 2697–2712 (2001)
SYNTHESIS OF SOME NEW
HETEROCYCLIC COMPOUNDS FROM
BENZOPYRANO[2,3-c]PYRAZOL-3-ONE
DERIVATIVES
A. Khodairy
Department of Chemistry, Faculty of Science, Sohag, Egypt
ABSTRACT
The reaction of benzopyrano[2,3-c]pyrazol-3-one (1) with
some active halo compounds, afforded compounds 4, 8 and
12, respectively. The cyanoethyl derivative 19 was synthesized
and treated with active methylenes and sulfur or benzoyli-
sothiocyanate and phenacyl bromide, to give compounds
24a,b and 27. Compounds 25a,b and 28 were obtained through
the reaction of compounds 24a,b with acrylonitrile or com-
pound 27 with maleic anhydride. Thiation of compound 1
afforded the corresponding thio derivative 29. The reaction
of 4-benzylidene-2-methyloxazolin-5-one with compounds 1
or 29 gave products 30a,b, respectively.
It has been found that coumarin is one of the most interesting
molecules since it shows a wide spectrum of chemical reactivity.1–3
The reported antibacterial3 and the antibiotic novobiocin4,5 of many hetero-
cyclic compounds containing coumarin moiety has prompted us to use a
*Corresponding author.
2697
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
2698
KHODAIRY
benzopyrano[2,3-c]pyrazol-3-one (1) as a building block for the synthesis of
poly fused heterocycles containing pyran, oxazine, pyrazole, thienyl, thio-
phene and substituted benzene derivatives.
RESULTS AND DISCUSSIONS
Bezopyrano[2,3-c]pyrazol-3-one 11 was prepared from the reaction of
3-carbethoxy-benzopyran-2-thione1 with hydrazine hydrate in a good yield.
IR spectrum of compound 1 showed an absorption bands corresponding to
NH and C¼O group at 3213 and 1679 cm–1.
On reacting compound 1 with a mixture of formaldehyde and mor-
pholine or piperidine gave Mannich’s bases 2. IR spectra showed the
absence of the absorption band corresponding to NH group (cf. Table 1).
When compound 1 was allowed to react with ethyl chloroacetate in the
presence of potassium carbonate it gave the corresponding ethyl ester deri-
vative 3. The reaction of compound 3 with hydrazine hydrate afforded the
hydrazide derivative 4, which reacted with carbon disulfide, acetylacetone
and benzylidenemalononitrile to give oxazole and pyrazole derivatives 5–7,
1
respectively. IR and H NMR spectra are in agreement with the proposed
Structures (cf. Table 1, Scheme 1).
When compound 1 was reacted with diethyl bromomalonate, the cor-
responding malonic acid ester derivative 8 was obtained, which was treated
with hydrazine hydrate, phenylhydrazine or hydoxylamine to afford pyra-
zoledione and isoxazoledione derivatives 9–11, respectively (cf. Table 1).
Acetylation of compound 1 using acetyl chloride in pyridine afforded
N-acetyl derivative 12. A one-pot synthesis of fused pyrazolobenzopyrane
attached to heterocyclic rings and spiro systems 13–15 were obtained

ORDER
REPRINTS
HETEROCYCLIC COMPOUNDS
2699
Table 1. Analytical and Spectral Data of the New Compounds
Analytical Data (Cal./Found)b
Product M.P (ꢀC)a Yield
Mol. Form.
(Mol. Wt)
No.
Cryst. Solvent (%)
C
H
N
S
1
217–220
(EtOH)
210
(EtOH)
240
(EtOH)
200
(EtOH)
222
(EtOH)
210
(Benzene)
120
(EtOH)
222
(EtOH)
270
(Dioxan)
310
(Benzene)
305
(Benzene)
295
(Dioxan)
341
(Dioxan)
300
(EtOH)
311
(EtOH)
281
(EtOH)
175
60
55
67
71
68
64
69
44
77
50
80
77
68
56
60
56
C10H6N2O2
(186.16)
C15H15N3O3
(285)
C16H17N3O2
(288.31)
C14H12N2O4
(272.25)
C12H10N4O3
(258.24)
C13H8N4O3S
(300.3)
C17H14N4O3
(322.33)
C22H14N6O3
(410.4)
C17H16N2O6
(344.31)
C13H8N4O4
(284.23)
C19H12N4O4
(360.33)
C13H7N3O5
(285.22)
C12H8N2O3
(228.19)
C22H13ClN4O3
(416.87)
C22H12ClN3O4
(417.78)
C22H15ClN4O4
(432.86)
64.51
64.43
63.21
63.43
67.82
67.63
61.76
61.43
55.81
55.64
51.99
51.64
63.34
63.43
64.38
64.63
59.3
59.43
54.93
54.64
63.33
63.52
54.74
54.63
63.16
63.32
63.38
63.66
63.24
63.55
60.76
60.59
3.24
3.00
5.30
5.43
6.04
6.32
4.44
4.60
3.90
3.73
2.68
2.90
4.37
4.61
3.43
3.12
4.68
4.55
2.83
2.63
3.35
3.66
2.47
2.30
3.53
3.68
3.14
3.44
2.89
2.76
3.47
3.56
2.57
2.66
4.84
4.66
3.09
3.26
15.04
15.22
14.74
14.61
14.84
14.69
10.29
10.48
21.69
21.51
18.65
18.49
17.38
17.51
20.47
20.51
8.13
2a
2b
3
4
5
10.67
10.43
6
7
8
8.34
9
19.71
19.48
15.55
15.48
14.73
14.44
12.27
12.54
13.44
13.23
10.05
10.57
12.88
12.75
13.00
13.32
14.96
14.76
16.54
16.80
10
11
12
13a
13b
13c
14
15a
15b
85 C22H11ClN4O4S 61.33
7.44
7.29
(EtOH)
181
(EtOH)
215
(Dioxan)
(430.84)
C21H18N4O3
(374.38)
C23H13N5O4
(423.36)
61.55
67.37
67.56
65.25
65.00
75
65
(continued)

ORDER
REPRINTS
2700
KHODAIRY
Table 1. Continued
Analytical Data (Cal./Found)b
Product
No.
M.P (ꢀC)a
Cryst. Solvent (%)
Yield Mol. Form.
(Mol. Wt)
C
H
N
S
15c
15d
16
285
(EtOH)
301
(Benzene)
295
(EtOH)
285
(EtOH)
301
(Benzene)
295
(DMF)
301
(Benzene)
295
(EtOH)
285
(EtOH)
285
(EtOH)
301
(Benzene)
295
(EtOH)
285
(Dioxan)
301
(Dioxan)
295
(Dioxan)
285
(Dioxan)
301
57
66
58
57
80
55
81
45
70
49
C23H12N4O5
(424.35)
C21H20N4O4
(392.39)
C18H17N3O3
(323.35)
C24H22N4O2
(398)
C23H15N3O4
(397.37)
C13H7N3O3
(253.22)
C13H9N5O2
(267.27)
C20H11N5O2
(353.34)
65.10
65.34
64.28
64.44
66.86
66.76
72.36
72.65
59.52
59.44
61.66
61.76
58.47
58.64
67.98
67.76
2.85
2.67
5.13
5.22
5.29
5.56
5.52
5.67
3.80
3.55
2.78
2.56
3.39
3.22
3.13
3.46
2.76
2.67
2.96
2.67
3.48
3.52
3.80
3.66
3.65
3.77
3.87
3.52
2.90
2.76
3.27
3.43
2.84
2.76
2.99
2.75
3.78
3.55
3.38
3.43
13.20
13.44
14.28
14.47
12.99
12.66
14.07
14.44
10.57
10.67
16.56
16.66
26.20
26.47
19.82
19.66
12.83
12.66
13.71
13.44
11.16
11.27
10.57
10.42
14.50
14.44
13.44
13.77
13.45
13.66
13.01
13.24
11.28
11.47
13.85
13.76
12.89
12.69
10.84
10.69
17
18
19
20
21
22
C15H9N3O4S 55.00
9.78
9.55
(327.54)
C23H12N4O4
(408.38)
55.24
67.64
67.34
23
24a
24b
25a
25b
26
44 C18H13N3O3S 57.43
(376.39) 57.64
65 C19H15N3O5S 57.42
8.51
8.33
8.06
8.15
(397.41)
C21H14N4O4
(386.37)
C22H16N4O5
(416.63)
59.76
65.28
65.34
63.42
63.44
70
81
55 C21H12N4O4S 60.57
(416.42) 60.76
57 C22H14N4O4S 61.38
7.70
7.60
7.44
7.22
27
(430.45)
C26H14N4O7
(496.44)
C10H6N2OS
(202.23)
61.44
62.90
62.87
39.39
39.75
67.73
67.98
28
67
64
53
(EtOH)
165
(EtOH)
195
(Benzene)
210
(EtOH)
29
15.85
15.69
30a
30b
C21H13N3O4
(372.36)
67 C21H14N3O3S 65.10
(387.42) 65.26
8.27
8.22
(continued)

ORDER
REPRINTS
HETEROCYCLIC COMPOUNDS
2701
Table 1. Continued
Product
No.
I.R (cm–1)c
1H NMR (d, ppm)d
1
3339 (NH), 1690 (CO).
10.4(s,1H,NH), 9.4 (s,1H,¼ CH),
8.3–7.7 (m,4H, arom.).
2a
2989–2760 (CHaliph.),
1676 (CO)
9.1(s,1H,¼CH), 8.1–7.4(m,4H,arom.),
4.2(s, 2H, NCH2N), 3.8–3.4
{m,4H, O(CH2)2}, 2.9–2.3
{m, 4H, N(CH2)2}
9.3 (s,1H,¼CH), 8.2–7.6 (m,4H,arom.),
2b
3
2980–2790 (CHaliph.),
1680 (CO).
4.0 (s,2H,NCH2N), 2.8–2.4
{m,4H,N(CH2)2}, 1.8–1.4 (m,6H,(CH2)3}.
1710 (COester), 1688 (CO). 9.0 (s,1H,¼CH), 8.7–7.9 (m,4H,arom.),
4.2–4.0(q, 2H,OCH2 ester),
3.2(s,2H,NCH2),1.3–1.0 (t,3H,CH3).
4
3323–3130 (NH, NH2),
1689–1667 (CO).
10.2 (s,1H,CONH), 9.0 (s,1H,¼CH),
8.3–7.7 (m,4H,arom.), 4.2–4.0 (br,2H,NH2),
3.5 (s,2H,CH2).
5
6
3160 (OH), 1699 (CO)
9.0 (s,1H,¼CH), 8.3–7.7
(m,5H,arom.þNH), 4 (s,2H,NCH2).
9.3 (s,1H,¼CH), 8.0–7.5 (m,4H,arom.),
4.8 (s,1H,CHpyrazole), 3.7 (s,2H,NCH2),
2.4 (s,6H,2CH3).
1690–1676 (CO),
1580 (C¼N).
7
3210, 3122 (NH2), 2210
(CN), 1690–1667 (CO).
9.4 (s,1H,¼CH), 8.7–7.9 (m,9H,arom.),
5.4–5.2 (br,2H,NH2), 3.6 (s,2H,NCH2.
8
1720 (COester), 1687 (CO). 8.0–7.6 (m,4H,arom.), 4.4–4.1 (q,4H,2CH2),
3.5 (s,1H,CH), 1.3–1.1 (t,6H,2CH3).
9
3350, 3212 (2NH),
1690–1660 (3CO).
3217 (NH),
690–1660 (3CO).
3320 (2NH),
1698–1665 (3CO)
2980 (CHaliph.),
1690–1662 (CO)
3210, 3120 (NH2),
2210 (CN), 1690 (CO).
3345 (OH), 2168
(CN), 1687 (CO)
9.0 (s,1H,¼CH), 8.3–7.7 (m,4H,arom.),
6.4 (s,1H,CHexo), 4.4 (s,2H,2NH).
9.9 (s,1H,¼CH), 8.4–7.9
10
11
12
13a
13b
(m,10H,arom.þNH), 5.8 (s,1H,CHexo).
9.0 (s,1H,¼CH), 8.0–7.5
(m,5H,arom.þNH), 5.5 (s,1H,CHexo).
9.4 (s,1H,¼CH), 7.7–7.2 (m,4H,arom.),
2.1 (s,3H, CH3)
9.0 (s,1H,¼CH), 7.8–7.2 CH), 5.4
(s,1H,¼CHb).
9.2 (s,1H,¼CH), 7.8–7.2
(m,9H,arom.þCH), 5.1 (s,1H,¼CHb)
2.4 (s,1H,OH).
(continued)

ORDER
REPRINTS
2702
KHODAIRY
Table 1. Continued
Product
No.
I.R (cm–1)c
1H NMR (d, ppm)d
13c
3340–3121 (NH2),
1690–1675 (CO)
9.2 (s,1H,¼CH), 7.6–7.0
(m,9H,arom.þCH), 6.6 (s,2H,NH2),
5.5–5.2 (br,2H,CONH2), 4.9
(s,1H,¼CHb).
14
3230 (NH), 2189
(CN), 1668 (CO)
3210, 3121 (NH2),
2210 (CN), 1680 (CO).
10 (s,1H,NH), 9.0 (s,1H,¼CH),
7.8–7.2 (m,8H, arom.), 5.1 (s,1H,¼CHb).
9.0 (s,1H,¼CH), 7.9–7.5 (m,4H,arom.),
6.3 (s,2H,NH2), 4.4 (s,1H,CHb),
3.1–2.9 (m,4H,2CH2), 2.2–1.7 (m,6H,3CH2).
10.1 (s,1H,NHisatine), 9.0 (s,1H,¼CH),
15a
15b
15c
15d
3340–3120 (NH, NH2),
1711 (COisatine), 1669 (CO) 8.1–7.5 (m,8H,arom.), 6.0–5.6 (br,2H,NH2),
4.8 (s,1H,CHb).
3480, 3210 (OH, NH),
10.0 (s,1H,NHisatine), 9.1
2200 (CN) 1707 (COisatine), (s,1H,¼CH), 8.0–7.3 (m,8H, arom.),
1663 (CO).
3330–3120 (NH2),
1697–1668 (CO).
6.0–4.8 (s,1H,CHb), 3.0 (s,1H,OH).
9.2 (s,1H,¼CH), 7.6–7.0 (m,8H,arom.),
6.1 (s,2H,NH2), 4.8–4.4 (br,2H,CONH2),
4.1 (s,1H,CHb), 3.1–2.7 (m,4H,2CH2),
2.1–1.6 (m,6H, 3CH2).
16
17
18
310 (NH),
1680–1670 (CO).
10.0 (s,1H,¼CH), 8.3–7.9
(m,5H,arom.þNH), 4.9 (s,1H,CHb),
3.1–2.9 (m,4H,2CH2), 2.2–1.7 (m,6H,3CH2).
9.2 (s,1H,¼CH), 8.3–7.9
3230 (NH), 1677 (CO).
(m,10H,arom.þNH), 4.9 (s,1H,CHb),
3.0–2.6 (m,4H,2CH2), 2.1–1.3 (m,6H,3CH2).
8.5 (s,1H,¼CH), 8.0–7.5 (m,9H,arom.),
5.4 (s,1H,¼CHb),4.4 (s,1H,CH(),
2.2 (s,3H,CH3).
2980 (CHaliph.),
1690 (CO).
19
20
2100 (CN),
9.0 (s,1H,¼CH), 8.1–7.4 (m,4H,arom.),
1690–1970 (CO).
3310–3140 (NH, NH2),
1690 (CO).
4.0 (s,2H,CH2).
10.0 (s,1H,NH), 8.5 (s,1H,¼CH), 8.1–7.6
(m,4H, arom.), 7.0 (s,1H,¼CHb),
6.2–6.0 (br,2H,NH2).
21
22
3321 (NH), 2214
(CN), 1686 (CO).
3340 (NH),
9.0 (s,1H,NH), 8.3 (s,1H,¼CH),
8.8–8.2 (m,9H,arom.).
9.9 (s,1H,NH), 8.9 (s,1H,¼CH), 8.0–7.6
nbsb;(m,4H,arom.), 6.4–6.2 (br,1H,CHCO),
3.9 (s,2H,CH2)
1690–1676 (3CO).
(continued)

ORDER
REPRINTS
HETEROCYCLIC COMPOUNDS
2703
Table 1. Continued
Product
No.
I.R (cm–1)c
1H NMR (d, ppm)d
23
3420 (OH), 2218 (CN),
1675 (CO).
9.5 (s,1H,¼CH), 8.0–7.5 (m,9H,arom.),
4.4 (s,1H,CH), 2.3 (s,1H,OH).
24a
3310, 3220 (NH2), 1710
(COacetyl), 1680–1668 (CO).
9.4 (s,1H,¼CH), 8.3–7.9 (m,4H,arom.),
6.4–6.2 (br,2H,NH2), 2.5 (s,3H,CH3CO),
2.1 (s,3H,CH3).
24b
25a
25b
3210, 3140 (NH2), 1730
(COester), 1695–1680 (CO).
8.5 (s,1H,¼CH), 8.0–7.3 (m,4H, arom.),
6.6–6.3 (br,2H,NH2), 4.2–3.8 (q,2H,CH2),
2.2 (s,3H, CH3), 1.3–1.0 (t,3H,CH3).
9.0 (s,1H,¼CH), 8.1–7.6 (m,5H,arom.),
4.5–4.3 (br,2H,NH2), 2.7 (s,3H,CH3CO),
2.1 (s,3H,CH3).
8.9 (s,1H,¼CH), 8.0–7.5 (m,5H,arom.),
6.6–6.3 (br,2H,NH2), 4.0–3.8 (q,2H,CH2),
2.2 (s,3H,CH3), 1.3–1.0 (t,3H,CH3 ester).
10.0 (s,1H,NH), 9.2 (s,1H,¼CH), 8.2–7.7
3321, 3214 (NH2),
2190 (CN), 1704 (COacetyl),
1680–1670 (CO).
3215, 3133 (NH2),
2119 (CN), 1730 (COester),
1690–1670 (CO).
3321 (NH), 2779 (SH),
26
2200 (CN), 1690–1677 (CO). (m,9H,arom.), 2.2–2.0 (br,1H,SH).
27
3310-3110 (NH2),
1700–1666 (CO)
3310, 3220 (NH2),
1695 1668 (CO)
3180 (NH), 1180 (CS).
9.2 (s,1H,¼CH), 8.2–7.8 (m,9H,arom.),
5.5–5.1 (br,4H,2NH2).
9.0 (s,1H,¼CH), 7.8–7.3 (m,9H, arom.),
7.1–6.8 (br,4H,2NH2).
28
29
11.5 (s,1H,NH), 9.2 (s,1H,¼CH),
8.0–7.5 (m,4H,arom.).
9.4 (s,1H,¼CH), 7.8–7.2 (m,9H,arom.),
2.3 (s,3H,CH3).
30a
30b
2879 (CHaliph.),
1700 (COester).
2870 (CHaliph.),
1715 (COester).
9.7 (s,1H,¼CH), 8.0–7.7
(m,9H,arom.), 2.7 (s,3H,CH3).
aUncorrected bSatisfactory microanalyses obtained; C, Æ 0.3%, H, Æ 0.3%,
N, Æ 0.45%, S, Æ 0.21.
cMeasured on Nicolet 710 FT-IR spectrophotometer d) Measured with a Varian EM
360 L using TMS as internal standard.
through the reaction of compound 12 with ylidenenitriles. The postulated
mechanism was suggested to proceed via addition of the carbanion to the
activated double bond to give the intermediate Michael adduct which was
cyclized through the addition of the enolised OH group to CN or C¼O with
elimination of ethanol, in case of product 14 elimination of water takes place
(cf. Table 1, Scheme 2).
Similarly, treating compound 12 with cyclohexylidenoxime, cyclohex-
ylidenephenylhydrazone and 4-benzylidene-2-methyloxazolin-2-one gave

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KHODAIRY
oxazine, pyrazine and g-pyran derivatives 16–18, respectively. We assume
the reaction to proceed via the addition of the carbanion to the activated
CꢁN or C¼C followed by elimination of water (cf. Table 1, Scheme 2).
The reaction of compound 1 with ethyl cyanoacetate in the presence of
sodium t-butoxide afforded the N-cyanoacetyl derivative 19 in 43% yield via
the elimination of ethanol. Reacting compound 19 with hydrazine hydrate,
benzoylhydrazine, mercaptoacetic acid and ethyl benzylidencyanoacetate
gave the corresponding pyrazole, 4-thiazolidinone and g-pyran derivatives
20–23 respectively (cf. Table 1, Scheme 3).
Scheme 1.
It was shown that the cyanomethyl functions are active toward elec-
trophilic reagents which enable synthesis of several condensed systems.6
Compound 19 reacted with acetylacetone and/or ethyl acetoacetate in the
presence of sulfur in ethanolic triethylamine solution to give thienyl deriva-
tives 24a,b, which reacted with acrylonitrile7 in DMF to yield a products
25a,b through initial formation of cycloadduct (A) which is rearranged to (B)
followed by a proton transfer (C) and subsequent elimination H2S and
aromatization6 to give 25a,b (Table 1, Scheme 4).
El-nagdi et al.7,8 have recently shown that electron rich strained con-
densed thienopyridazines acts as excellent dienes in 4 þ2 cycloaddition reac-
tion. Treatment of compound 19 with benzoylisothiocyanate, yielded the

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HETEROCYCLIC COMPOUNDS
2705
Scheme 2.
adduct 26. Compound 26 reacted with phenacyl bromide to give substituted
thiophenoylpyrazolobenzopyran derivative 27. Compound 27 reacted with
maleic anhydride to yield addition product which subsequent looses hydro-
gen sulphide6–8 giving compound 28. The mechanism6,7 of the formation of
compound 28 is indicated in Scheme 5. MS of the product 28 showed the
molecular ion peak at m/z 496 (cf. Table 1, Scheme 5).
Thiation of compound 1 afforded the corresponding thio derivative 29.
IR spectrum of compound 29 showed the absence of the absorption band

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KHODAIRY
Scheme 3.
corresponding to C¼O group (cf. Table 1). It was found that compound 1
and/or 29 reacted with 4-benzylidene-2-methyloxazolin-5-one in the
presence of sodium ethoxide to yield the corresponding ester and thioester
derivatives 30a,b, respectively. The reaction is thought to proceed through a
mechanism9 illustrated in Scheme 6.
EXPERIMENTAL
The MS were recorded on a Micromass 7070 E spectrometer operating
70 eV, using direct inlet.
Synthesis of Compound 1
To a solution compound 3-carbethoxybenzopyran-2-thione (2.34 g,
0.01 mol) in ethanol (20 mL), hydrazine hydrate (0.5 mL, 0.01 mol) was
added. The reaction mixture was treated with few drops of triethylamine,

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2707
Scheme 4.
Scheme 5.
refluxed for 10–15 h., evaporated in vacuo and the residual solid was crystal-
lized from ethanol.
Synthesis of Compounds 2a,b
A mixture of compound 1 (3.72 g, 0.02 mol), formaldehyde (2 mL) and
the appropriate amine (0.02 mol) [morpholine (1.74 mL), piperidine
(1.72 mL)] in ethanol (40 mL) was refluxed for 3 h. The solvent was concen-
trated and the residual product was filtered off, washed with water and
crystallized from ethanol (cf. Table 1).

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KHODAIRY
Scheme 6.
Synthesis of Compounds 3,8
General Procedure
To a stirred solution of compound 1 (5.58 g, 0.03 mol) in DMF
(50 mL), the suitable haloester (0.03 mol) [ethyl acetate (3.21 mL), diethyl
bromomalonate (7.2 mL)] and potassium carbonate (6 gm) were added. The
reaction mixture was refluxed for 2 h, evaporated in vacuo and the remaining
product was triturated with water and the residual solid was collected by
filtration and crystallized from the suitable solvent (cf. Table 1, Scheme 1,2).
Synthesis of Compounds 4,9-11
General Procedure
An equimolar amount (0.02 mol) of compounds 3 (5.4 g) and/or 8
(6.8 g) and the proper bidentate (0.02 mol) [hydrazine (1 mL), phenylhydra-
zine (2.16 mL) or hydroxylamine. HCl (0.69 g) were dissolved in dioxan
(30 mL). The reaction mixture was treated with few drops of triethylamine,
refluxed for 6 h and concentrated. The precipitate was filtered off and crys-
tallized from the suitable solvent (cf. Table 1, Scheme 1).
Synthesis of Compound 5
A mixture of compound 4 (1.29 g, 0.005 mol) and carbon disulfide
(0.38 mL, 0.005 mol) in pyridine (20 mL) was refluxed until the evolution
of H2S ceased (20 h), the solvent was evaporated in vacuo and the remaining

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2709
product was triturated with water and the residual solid was collected by
filtration and crystallized from benzene (cf. Table 1, Scheme 1).
Synthesis of Compounds 6 and 7
General Procedure
To a solution of compound 4 (0.77 g, 0.003 mol) in dioxane (20 mL),
0.003 mol of acetylacetone (0.31 mL) or benzylidenemalononitrile (0.46 g)
was added. The reaction mixture was treated with few drops of triethyla-
mine, refluxed for 5 h, evaporated in vacuo and the residual solid was crystal-
lized from ethanol.
Synthesis of Compound 12
To a stirred solution of compound 1 (0.93 g, 0.005 mol) in pyridine
(20 mL), acetyl chloride (0.39 mL, 0.005 mol) was added. The reaction mix-
ture was refluxed for 12 h, evaporated in vacuo and the remaining product
was triturated with water and the residual solid was collected by filtration
and crystallized from dioxan (cf. Table 1, Scheme 2).
Synthesis of Compounds 13–18
General Procedure
To a solution of compound 12 (2.28 g, 0.01 mol) in dioxane (20 mL),
ylidenenitrile, oxime, hydrazone and/or oxazolone (0.01 mol) was added.
The reaction mixture was treated with few drops of triethylamine, refluxed
for 5 h., evaporated in vacuo and the residual solid was crystallized from
suitable solvent (cf. Table 1, Scheme 2).
Synthesis of Compound 19
A mixture of compound 1 (0.93 g, 0.005 mol), ethyl cyanoacetate
(0.56 mL, 0.005 mol) and sodium t-butoxide [Na, (0.12 g, 0.005 mol) in
20 mL t-butanol] was refluxed for 3 h, evaporated in vacuo and the separated
solid was collected by filtration, washed with water and crystallized from
DMF (cf. Table 1, Scheme 3).

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Synthesis of Compounds 20–23
General Procedure
To a solution of compound 19 (0.94 g, 0.004 mol) in dioxan (20 mL),
0.004 mol of hydrazine hydrate (0.2 mL), benzoyl hydrazine (0.54 g), mer-
captoacetic acid (0.37 mL), and/or ethyl benzylidenecyanoacetate (0.8 g) was
added. The reaction mixture was treated with few drops of piperidine,
refluxed for 5 h., evaporated in vacuo and the residual solid was crystallized
from suitable solvent (cf. Table 1, Scheme 3).
Synthesis of Compounds 24a,b
To a solution of compound 19 (0.47 g, 0.002 mol) in ethanol (20 mL),
0.002 mol of acetylacetone (0.2 mL) and/or ethyl acetoacetate (0.26 mL) and
sulfur (0.07 g, 0.002 mol) were added. The reaction mixture was treated with
catalytic amount of triethylamine (0.5 mL), refluxed for 5 h., evaporated in
vacuo and the residual solid was collected by filtration, washed with water
and crystallized from suitable solvent (cf. Table 1, Scheme 4).
Synthesis of Compounds 25a,b
To a stirred solution of compound 24a (3.7 g, 0.01 mol) or 24b (3.9 g,
0.01 mol) in DMF (30 mL), acrylonitrile (0.5 mL, 0.01 mol) was added. The
reaction mixture was refluxed until the evolution of H2S ceased (12 h), eva-
porated in vacuo and the remaining product was triturated with water and
the residual solid was collected by filtration and crystallized from dioxane
(cf. Table 1, Scheme 4).
Synthesis of Compound 26
A mixture of compound 19 (1.17 g, 0.005 mol) and benzoylisothiocya-
nate (0.67 mL, 0.005 mol) in DMF (30 mL) was refluxed for 3 h, evaporated
in vacuo and the separated solid was collected by filtration, and crystallized
from dioxane (cf. Table 1, Scheme 5).
Synthesis of Compound 27
To a stirred solution of compound 26 (1.25 g, 0.003 mol) in DMF
(20 mL), phenacyl bromide (0.59 g, 0.01 mol) and potassium carbonate

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2711
(5 gm) were added. The reaction mixture was refluxed for 5 h, evaporated in
vacuo and the remaining product was triturated with water and the residual
solid was collected by filtration and crystallized from dioxane (cf. Table 1,
Scheme 5).
Synthesis of Compound 28
To a solution of compound 27 (1.72 g, 0.004 mol) in DMF (20 mL),
malice anhydride (0.39 g, 0.004 mol) was added. The reaction mixture was
refluxed until the evolution of H2S ceased (5 h), evaporated in vacuo and the
residual solid was crystallized from ethanol (cf. Table 1, Scheme 5).
M.S of compound 28: m/z (relative intensity): 496 (11.19), 489 (6.27),
450 (11.02), 397 (0.57), 364 (1.35), 320 (9.77), 268 (2.3), 207 (2.1), 105 (3.1),
77 (30.2).
Synthesis of Compound 29
To a stirred solution of compound 1 (0.56 g, 0.003 mol) in pyridine
(20 mL), phosphorous pentasufide (0.66 g, 0.003 mol) was added. The reac-
tion mixture was refluxed for 10 h, filtered while hot. The filtrate was eva-
porated in vacuo and the residual solid was crystallized from ethanol
(cf. Table 1, Scheme 6).
Synthesis of Compounds 30a,b
A mixture of compound 1 (0.93 g, 0.005 mol) or 29 (1.01 g, 0.005 mol),
4-benzylidene-2-methyl-2-oxazolin-5-one (0.93 g, 0.005 mol) and sodium
ethoxide [Na, (0.14 g, 0.006 mol) in 30 mL ethanol] was refluxed for 3 h,
evaporated in vacuo and the residual separated solid was collected by
filtration, washed with water and crystallized from appropriate solvent
(cf. Table 1, Scheme 6).
REFERENCES
1. Tadao, S.; Hisashi, O. (Jpn. Kokai Kokkyo Koho JP 02,172,916). C.A.
1991, 114, 101980.
2. Keiichi, I.; Junko, M. J. Heterocycl. Chem. 1988, 25(6), 1681.

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3. Gingolani, G.M.; Gavltrieri, F.; Pigini, M. J. Med. Chem. 1969, 12,
531.
4. El-Naggar, A.M.; Ahmed, F.S.; Abd El-Salam, A.M.; Rady, M.A.;
Latif, M.S. A. J. Heterocycl. Chem. 1981, 18, 1203.
5. Sadek, K.U. Mourad, A.E. Abdelhafeez, A.E.; El-nagdi, M.H.
Synthesis 1983, 739.
6. Al-Awadhi, H.; Al-Omran, F.; El-nagdi, M.H. Infantes, L. Foces-
Foces, C.; Jagerovic, N.; Elguero, J. Tetrahedron 1995, 51, 12745.
7. Al-Omran, F.; Abdel Kalik, M.M.; Al-Awadhi, H.; El-nagdi, M.H.
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8. El-nagdi, M.H.; Negm, A.M.; Erian, A.W. Liebigs Ann. Chem. 1989,
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Received in the USA November 21, 2000

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