Synthetic studies on the synthesis of pyridine, α-pyran, α-thiopyran, and Thienothiopyranopyrrol derivatives using PTC technique

Article abstract of DOI:10.1081/SCC-100000573

The reaction of p-chlorophenylmethylenemalononitrile 1 with some reactive halo compounds under phase-transfer catalysis conditions (PTC) afforded the corresponding alkylated or cyclized products 2-9 Thienothiopyranopyrrol 12_a-c were synthesized from the reaction of compound 1 or 4 with CS₂ and ethyl chloroacetate in 1:1:2 molar ratio via the formation of the intermediates thiopyrans 10_a-c and theinothiopyrans 11_a-c. Also, compound 1 or 4 reacted with phenylisocyanate or phenylisothiocyanate to give α-pyran, α-thiopyran pyridinone, and pyridine-2-thione derivatives 13-16, respectively. The sequence of the reactions was studied.

Full text of DOI:10.1081/SCC-100000573

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SYNTHETIC STUDIES ON THE SYNTHESIS OF
PYRIDINE, α-PYRAN, α-THIOPYRAN, AND
THIENOTHIOPYRANOPYRROL DERIVATIVES USING PTC
TECHNIQUE
A. Khodairy & A. M. El-Sayed
Version of record first published: 16 Aug 2006.
To cite this article: A. Khodairy & A. M. El-Sayed (2001): SYNTHETIC STUDIES ON THE SYNTHESIS OF PYRIDINE, α-PYRAN,
α-THIOPYRAN, AND THIENOTHIOPYRANOPYRROL DERIVATIVES USING PTC TECHNIQUE, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:4, 475-486
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SYNTHETIC COMMUNICATIONS, 31(4), 475–486 (2001)
SYNTHETIC STUDIES ON THE SYNTHESIS
OF PYRIDINE, α-PYRAN, α-THIOPYRAN,
AND THIENOTHIOPYRANOPYRROL
DERIVATIVES USING PTC TECHNIQUE
A. Khodairy and A. M. El-Sayed*
Chemistry Department, Faculty of Science, Sohag, Egypt
ABSTRACT
The reaction of p-chlorophenylmethylenemalononitrile 1
with some reactive halo compounds under phase-transfer cataly-
sis conditions (PTC) afforded the corresponding alkylated or cy-
clized products 2–9 Thienothiopyranopyrrol 12a−c were synthe-
sized from the reaction of compound 1 or 4 with CS2 and ethyl
chloroacetate in 1:1:2 molar ratio via the formation of the inter-
mediates thiopyrans 10a−c and theinothiopyrans 11a−c. Also, com-
pound1or4reactedwithphenylisocyanateorphenylisothiocyanate
to give α-pyran, α-thiopyran pyridinone, and pyridine-2-thione
derivatives 13–16, respectively. The sequence of the reactions was
studied.
In connection with our research program on the synthesis of pyridinone,
pyridines, triazines (1), and thiopyrans (2) starting with arylmethylenemalononi-
triles, we report here the synthesis of some α-pyran, cyclopentadienone,
∗Corresponding author.
475
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

ORDER
REPRINTS
476
KHODAIRY AND EL-SAYED
pyridinethione, thienothiopyran, thienothiopyranopyrrol, and pyridinone deriva-
tivesthroughconsecutivereactionsof p-chlorophenylmethylenemalononitrilewith
some reactive halo compounds followed by reacting the yielded intermediates with
CS2, PhNCO, or PhNCS.
The reaction of p-chlorophenylmethylenemalononitrile 1 with chloroaceto-
nitrile (1) benzyl chloride, or bromomalononitrile under PTC conditions [dioxan/
K2CO3/tetrabutylammonium bromide (TBAB)], afforded the corresponding poly-
functional compounds 2a−c, respectively. The IR and 1H-NMR spectra are consis-
tent with their structures (cf. Scheme 1, Table I). MS of compound 2a showed the
molecular ion peak at m/e 278.
R
CN
CN
CN
CN
PTC
+
Cl
CH
C
X
CH
Cl
C
C
R
CH(RR)
=
X
Cl, Br
2a-c
1
Comp.
No
R
R
2a
2b
2c
CN
Ph
CN
H
H
CN
Equation 1.
The study was extended to the reaction of ylidenenitrile 1 or 3 with chloroac-
etaldehyde or phenacyl bromide under PTC conditions (DMF/ K2CO3/ tetrabuty-
◦
lammonium bromide TBAB) at 120 C for 3 h to afford the corresponding α-
pyran derivatives 6a−c in a one-pot procedure. The control of time, temperature,
and using different solvents gave the chance to follow up the sequence of the
reaction. Thus, by the reaction of compound 1 or 3 with the same reactants un-
der the PTC conditions [dioxan/K2CO3/ tetrabutylammonium bromide (TBAB)]
◦
at 60◦–70 C for 3–5 h, the corresponding alkylated derivatives 4a−c were sep-
arated. The IR spectra showed absorption bands at 1709 cm−1 and1715 cm−1
indicative of CHO and COketone groups. 1H-NMR spectra showed singlet signals
at 9.5, 3.4, and 2.9 ppm for CHO, CH2CHO, and CH2CO groups, respectively.
MS ofcompound 4a showed the molecular ion peak at m/e 229. However, when
the reaction was carried out at higher temperature 100 ◦–110 ◦C for a period of

ORDER
REPRINTS
p-CHLOROPHENYLMETHYLENEMALONONITRILE
477
CN
Cl
CH
C
X
1 & 3
1, X = CN,
3, X = COOEt
A
A
PTC
PTC
A = YCH2COR, Y = Cl or Br
CN
X
Cl
Cl
C
C
CN
Z
CH2COR
4a-c
O
6a-c
R
4a, X = CN,
b, X = CN,
R = H
6a, R = H,
b, R = Ph,
Z = NH
Z = NH
Z = O
R = Ph
PTC
CN
X = COOEt, R = H
c,
R = H,
c,
Cl
C
C
X
CH
C
OH
R
5a-c
NH2NH2
Cl
CN
NH
NH2
N
7a
Scheme 1.
time 10–13 h using the same last conditions, the corresponding α-pyran deriva-
tives 6a−c were obtained. The cyclization step proceeded through formation of the
enol form, which either added at the cyano group to form the imino derivatives
6a,b or attacked the carbonyl ester group with elimination of ethanol molecule to
give 6c. We were able to separate the intermediate enol form 5a [R = H, Y = CN]
from the reaction of compound 1 with chloroacetaldehyde under PTC conditions
[benzene/K2CO3/tetrabutylammonium bromide (TBAB)], which in turn cyclized
to compound 6a in [dioxan/K2CO3/tetrabutylammonium bromide (TBAB)]. The
IR spectrum of compound 5a showed an absorption band at 3390 cm−1 indica-
1
–
tive of OH group. H-NMR spectra showed a broad peak at 6.00–5.80 ppm for
==
CH CH and singlet peak at 2.3 ppm for OH group. Also, compound 5a reacted
with hydrazine hydrate in ethanol to afford the corresponding pyridine derivative 7a
(Scheme 1, Table I).

ORDER
REPRINTS
478
KHODAIRY AND EL-SAYED
Table I. Analytical and Spectral Data of the Prepared Compounds
React. Time (h)
Analytical Datab
Cal./(Found)
Prod. React. Temp. ◦C
No.
M.P.a
Yield
%
Mol. Form.
(Mol. wt.)
React. Solvent (Cryst. Solv.)
C
H
N
S
2b
5/70
(dioxan)
6/65
(dioxan)
3/65
(benzene)
4/65
(dioxan)
4.5/60
(dioxan)
2.5/100
(DMF)
4/110
(DMF)
4/110
(DMF)
6/65
(benzene)
2/79
(ethanol)
3/80
(benzene)
6.5/80
(benzene)
3/50
(dioxan)
4.5/75
(dioxan)
3/75
(dioxan)
4/75
(dioxan)
4/75
(dioxan)
5.5/77
230
(benzene)
300–302
(ethanol)
271–273
(ethanol)
218–220
(ethanol)
210
(benzene)
311–313
(ethanol)
238–240
(ethanol)
288
(dioxan)
192–194
(ethanol)
302–304
(dioxan)
305
(benzene)
140
(ethanol)
265
(ethanol)
320
(ethanol)
162
(ethanol)
271
(ethanol)
219
(ethanol)
295
(dioxan)
297
(ethanol)
315
(dioxan)
221
65
50
75
52
45
65
62
60
77
87
90
70
65
60
55
35
68
75
45
80
85
75
C17H11ClN2
(278.74)
C13H5ClN4
(252.66)
C12H7ClN2O
(230.65)
C18H11ClN2O
(306.75)
C14H11ClN2O2
(274.71)
C12H7ClN2O
(230.64)
C18H11ClN2O
(306.75)
C12H6NCIO2
(231.64)
73.33 3.97 10.05
73.02 3.76 10.29
61.80 1.99 22.17
61.95 1.76 22.09
62.49 3.06 12.15
62.74 3.23 12.39
2c
4a
4b
70.48 3.61
70.60 3.43
9.13
9.48
4c
61.21 4.04 10.20
61.00 4.23 10.27
62.49 3.06 12.15
62.64 3.23 12.39
6a
6b
70.48 3.61
70.70 3.83
62.22 2.61
62.50 2.41
9.13
9.28
6.05
6.30
6c
5a
C12H7ClN2O
(230.65)
C13H9ClN2
(228.68)
62.49 3.06 12.15
62.20 3.23 12.42
86.28 3.97 12.57
86.50 3.73 12.32
63.93 2.68 11.18
63.61 2.59 11.42
63.92 2.68 11.18
63.60 2.43 11.38
7a
8
C
20H10ClN3O3
(375.77)
9
C20H10ClN3O3
(375.75)
C13H6ClN3S2
(303.79)
C13H7ClN2OS2 50.90 2.30
(306.79) 50.60 2.25
C19H11ClN2OS2 59.60 2.90
(382.89) 59.90 2.61
C17H12ClN3O2S2 52.37 3.11 10.78 16.45
(389.88) 52.19 3.35 10.75 16.75
C17H11ClN2O2S 59.56 3.23
(342.81) 59.79 3.50
C23H15ClN2O2S2 61.26 3.35
(450.97) 61.56 3.51
C21H18ClN3O4S2 52.99 3.81
(475.98) 52.72 3.60
C21H17ClN2O4S2 54.72 3.72
(460.96) 54.51 3.90
C27H21ClN2O4S2 60.38 4.96
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
51.38 1.99 13.83 21.11
51.10 1.70 13.67 21.35
9.13 20.90
9.27 20.68
7.32 16.75
7.50 16.56
8.17
8.37
9.35
9.60
6.21 14.22
6.40 14.54
8.83 13.47
8.65 13.21
6.07 13.91
6.31 13.77
5.21 11.94
5.46 11.70
(dioxan)
6/75
(dioxan)
6/75
(dioxan)
5/75
(dioxan)
5/35
(benzene)
341
(benzene)
(537.10)
C19H11ClN4O
(346.77)
60.55 4.83
65.79 3.19 16.15
65.91 3.30 16.45
(acetonitrile)

ORDER
REPRINTS
p-CHLOROPHENYLMETHYLENEMALONONITRILE
479
Table I. Continued
React. Time (h)
Analytical Datab
Cal./(Found)
Prod. React. Temp. ◦C
No.
M.P.a
(Cryst. Solv.)
Yield
%
Mol. Form.
(Mol. wt.)
React. Solvent
C
H
N
S
13b
3/35
(acetonitrile)
4/35
(acetonitrile)
5/35
(acetonitrile)
10/40
(acetonitrile)
4/40
(acetonitrile)
2/38
(acetonitrile)
2/40
(acetonitrile)
2/40
(acetonitrile)
5/35
265
(dioxan)
305
(ethanol)
>350
(ethanol)
310
(ethanol)
>350
(ethanol)
138
(benzene)
195
(ethanol)
188
(dioxan)
340
71
75
35
40
40
75
75
80
77
66
90
C24H16ClN3O 72.44 4.05 16.56
(397.86) 72.16 4.30 16.31
C25H16ClN3O2 70.49 3.79 9.87
70.10 3.53 10.00
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
(425.86)
C19H11ClN4S
(362.84)
62.88 3.05 15.44 8.83
63.00 2.90 15.61 9.00
70.20 3.89 10.15 7.74
70.00 4.60 10.40 7.55
C24H16ClN3S
(413.93)
C25H16ClN3OS 67.93 3.64
(441.94) 67.73 3.84
9.50 7.25
9.30 7.01
C19H11ClN4O 65.79 3.19 16.15
(346.77) 65.51 3.30 16.45
C24H16ClN3O 72.44 4.05 16.56
(397.86) 72.66 4.30 16.31
C25H16ClN3O2 70.49 3.79
9.87
9.69
(425.87)
19H11ClN4S
(362.84)
24H16ClN3S
(413.93)
70.10 3.93
C
C
62.88 3.05 15.44 8.83
62.60 3.20 15.61 8.76
70.20 3.89 10.15 7.74
70.40 3.99 10.00 7.95
(acetonitrile)
5/40
(acetonitrile)
5/40
(ethanol)
320
(ethanol)
250
C
25H16ClN3OS 67.93 3.64
9.50 7.25
9.70 7.41
(acetonitrile)
(ethanol)
(441.94)
67.70 3.44
c
Com. No.
I.R. (cm−1
)
1H-NMRd (δ ppm)
≡
2b
2979–2865 (CHaliph), 2140 (C N)
7.7–7.3 (s, 9H, aromatic), 3.4–3.2
(br, 2H, CH2)
≡
2c
4a
2950 (CHaliph), 2190 (C N)
7.7–7.4 (m, 4H, aromatic), 6.0 (s, 1H, CH)
10.0 (s, 1H, CHO), 7.5–7.0 (m, 4H, aromatic),
3.3 (s, 2H, CH2)
≡
2990–2895 (CHaliph), 2250 (C N)
==
1709 (C O)
≡
4b
4c
2980–2890 (CHaliph), 2195 (C N)
==
7.6–7.3 (m, 9H, aromatic), 3.3 (s, 2H, CH2)
1720 (C O)
2970–2850 (CHaliph), 2189 (C N), 9.9 (s, 1H, CHO),7.5–7.2 (m, 4H, aromatic),
≡
==
1755 (C Oester), 1710
4.4–4.2 (q, 2H, CH2), 3.4 (s, 2H, CH2 CO),
1.3–1.0 (t, 3H, CH3)
==
(C Oaldehyde
)
5a
6a
6b
6c
3440 (OH), 2900 (CHaliph), 2190
7.7–7.2 (m, 4H, aromatic), 6.6–6.4
(br, 2H, CH CH), 2.3 (s, 1H, OH)
≡
–
==
(C N), 1090 (C O)
≡
3310 (NH), 2171 (C N), 1100
9.0 (s, 1H, NH), 7.7–7.3 (m, 4H, aromatic),
–
–
==
(C O C)
6.0–5.6 (m, 2H, CH CH)
≡
3321 (NH), 2180 (C N), 1155
(C O C)
8.8 (s, IH, NH), 7.8–7.5 (m, 9H, aromatic),
–
–
==
5.6 (s, IH, CH)
≡
==
2190 (C N), 1700 (C O), 1149
7.9–7 (m, 4H, aromatic), 6.4–6.1
==
(br, 2H, CH CH)
–
–
(C O C)
(continued)

ORDER
REPRINTS
480
KHODAIRY AND EL-SAYED
Table I. Continued
7a
3340, 3296, 3245 (NH, NH2), 2187
10.0 (s, 1H, NH), 8.4–7.9 (m, 4H, aromatic),
≡
==
(C N)
6.8 (s, 1H, NH2), 6.4–6.1 (br, 2H, CH CH)
≡
8
2970–2810 (CHaliph), 2184 (C N),
7.7–7.3 (m, 8H, aromatic), 2.9 (s, 2H,CH2)
==
==
1720 (C O), 1677 (C Oamidie
)
≡
8
3368, 3290 (NH2), 2189 (C N),
7.9–7.2 (m, 8H, aromtic), 6.3–6.1
(br, 2H, NH2)
==
==
1714 (C O), 1687 (C Oamidie
)
≡
10a
10b
10c
11a
3390, 3285 (NH2), 2210, 2200 (2C N),
7.7–7.2 (m, 4H, aromatic), 6.2–6.0
(s, 2H, NH2)
9.6 (s, 1H, CHO), 7.7–7.0 (m, 4H, aromatic),
6.0 (s, 2H, NH2).
7.9–7.0 (m, 9H, aromatic), 6.2–6.0
(s, 2H, NH2)
9.2 (s, 1H, NH), 7.7–6.9 (m, 4H,
aromatic), 6.6 (s, 2H, NH2), 4.3–4.0
(q, 2H, CH2), 1.3–1.0 (t, 3H, CH3)
9.2 (s, 1H, NH), 8.3–7.9 (m, 4H,
==
– –
1095 (C S), 679 (C S C)
≡
3230, 3150 (NH2), 2190 (C N), 1730
(C O), 1134 (C S), 690 (C S C)
3260, 3150 (NH2), 2190 (C N), 1700
(C O), 1150 (C S), 689 (C S C)
3343, 3290, 3160 (NH, NH2),
==
==
– –
≡
==
==
– –
≡
2970–2810 (CHaliph), 2178 (C N),
==
1740 (C
Oester).
11b
11c
12a
12b
12c
3283 (NH), 2910–2880 (CHaliph), 2182
==
≡
==
(C N), 1740 (C Oester
)
aromatic), 5.8 (s, 1H, CH), 4.4–4.1
(q, 2H, CH2), 1.3–1.0 (t, 3H, CH3)
9.3 (s, 1H, NH), 8.4–7.7 (m, 9H,
3160 (NH), 2940–2870 (CHaliph), 2200
==
≡
==
(C N), 1740 (C Oester
)
aromatic), 6.1 (s, 1H, CH), 4.4–4.0
(q, 2H, CH2), 1.4–1.2 (t, 3H, CH3)
7.7–6.9 (m, 4H, aromatic), 6.6–6.36
(br, 4H, 2NH2), 4.5–4.1 (q, 4H, 2CH2),
1.4–1.0 (t, 6H, CH3)
3283, 3290, 3270, 3160 (2NH2), 2970–
==
2810 (CHaliph), 1740 (C O)
3290, 3180 (NH2), 2970–2810
7.7–6.9 (m, 4H, aromatic), 6.6 (s, 2H,
==
==
(CHaliph), 1740 (C O)
NH2), 5.9 (s, 1H, CH), 4.3–4.1
(q, 4H, 2CH2), 1.3–1.0 (t, 6H, 2CH3)
7.7–6.8 (m, 9H, aromatic), 6.6 (s, 2H,
3343, 3250 (NH2), 2970–2810
≡
==
==
(CHaliph) 2178 (C N), 1740 (C O)
NH2), 5.5 (s, 1H, CH), 4.4–4.1
(q, 4H, 2CH2), 1.5–1.2 (t, 6H, 2CH3)
13a
13b
13c
14a
14b
14c
15a
15b
15c
3280, 3170 (NH2), 2209, 2200
8.0–7.6(m, 9H, aromatic), 6.4 (s, 2H, NH2),
≡
– –
(2C N) 1060 (C O C)
≡
3210, 3170 (NH2), 2175 (C N), 1106
8.2–7.8 (m, 14H, aromatic), 6.0
(s, 2H, NH2)
8.0–7.2 (m, 14H, aromatic), 6.4–6.0 (br, NH2)
–
–
(C O C)
3200, 3150 (NH2), 2170 (C N), 1705
==
≡
–
–
(C O) 1110 (C O C)
3280, 3170 (NH2), 2200, 2180 (2C N),
– –
≡
7.5–7.0 (m, 9H, aromatic), 6.4–6.0
(br, 2H, NH2)
8.2–7.5 (m, 14H, aromatic), 6.0 (s, 2H, NH2)
679 (C S C)
3210, 3170 (NH2), 2175 (C N), 686
– –
≡
(C S C)
3200, 3150 (NH2), 2170 (C N), 1700
== – –
≡
8.0–7.4 (m, 14H, aromatic), 6.4–6.0
(br, 2H, NH2)
8.4–7.9 (m, 9H, aromatic), 6.0 (s, 2H,
NH2)
7.9–7.1 (m, 14H, aromatic), 5.5 (s, 2H,
NH2)
8.2–7.9 (m, 14H, aromatic), 6.3 (s, 2H,
NH2)
(C O), 690 (C S C)
3280, 3170 (NH2), 2200, 2180 (2C N),
==
≡
1680 (C O)
3210, 3170 (NH2), 2175 (C N), 1696
==
≡
(C O)
3210, 3170 (NH2), 2175 (C N), 1699
==
≡
(C O)

ORDER
REPRINTS
p-CHLOROPHENYLMETHYLENEMALONONITRILE
481
Table I. Continued
≡
16a
16b
16c
3321, 3210 (NH2), 2200, 2195 (2C N),
8.4–8.0 (m, 9H, aromatic), 6.9 (s, 2H,
NH2)
8.0–7.6 (m, 14H, aromatic), 6.5 (s, 2H,
NH2)
8.2–7.8 (m, 14H, aromatic), 6.6 (s, 2H,
NH2)
==
1140 (C S)
≡
3321, 3210 (NH2), 2195 (C N), 1140
==
(C S)
3321, 3210 (NH2), 2200 (C N), 1718
== ==
≡
(C O), 1140 (C S)
aUncorrected.
bSatisfactory microanalysis obtained C; 0.35; H; 0.40, N; 0.30.
cMeasured by Nicolet FT-IR 710 spectrophotometer.
d Measured by a varian EM 360 L spectrometer at 60 MHz using TMS as internal standard
and DMSO as a solvent.
Moreover, 4-amino-3-cyano-2-p-chlorophenylcyclopentadiene-4-one (9)
was synthesized through the reaction of compound 1 with phthalylglycinyl chlo-
ride and triethylamine in 1:1:1 molar ratio in refluxing benzene for 6 h. On re-
ducing the reaction time to 3 h, it is possible to separate the acylated compound
8, which cyclized to compound 9 with an additional 3 h refluxing (Scheme 2,
Table I).
5-Amino-2, 6-diethylcarboxy-3-substituted-4-p-chlorophenyl-6-iminothi-
eno- [3,2:5,6]thiopyrano[2,3-b]pyrrols 12a−c were synthesized in a one-pot proce-
dure via the reaction of compound 2a, 4a, or 4b with CS2 and ethyl chloroacetate
in 1:1:2 molar ratio under PTC conditions (dioxan/K2CO3/tetrabutylammonium
bromide TBAB) in good yield. The formation sequence of compounds 12a−c was
followed up by using stepwise reactions through the reaction of compound 2a, 4a,
CN
Cl
CH
C
CN
O
1a
B
TEA
N
CH2COCl
B
B =
TEA
ref. 3h
O
ref. 6h
CN
CN
O
Cl
C
C
NH2
Cl
CN
N
O
COCH2
N
O
O
8
O
9
TEA
ref. 3h
Scheme 2.

ORDER
REPRINTS
482
KHODAIRY AND EL-SAYED
CN
Cl
C
C
CN
CH2R
2a, 4a and 4b
2a, R = CN
CS2 + 2C
CS2
PTC
PTC
4a, R = CHO
R = COPh
4b,
Cl
CN
H2N
COOEt
NH2
Cl
2C
C = Cl CH2COOEt
N
PTC
S
Z
S
S
Y
10a-c
S
10a, Z = CN
b, Z = CHO
c, Z = COPh
EtOOC
12a-c
Cl
C
C
CN
PTC
PTC
12a, Y = NH2
b, Y = H
c, Y = Ph
NH
S
Y
S
EtOOC
11a-c
11a, Y = NH2
Y = H
Y = Ph
b,
c,
Scheme 3.
or 4b with CS2 under the same PTC conditions, in which thiopyran derivatives
10a−c were separated. IR spectra showed absorption bands at 3300, 3215 cm−1 for
NH2 group, and at 1160 cm−1 for C S group. MS of compound 10c showed the
==
molecular ion peak at m/e 382.
The compounds 10a−c were reacted with ethyl chloroacetate in 1:1 or 1:2
molar ratio using the current PTC conditions to afford thienothiopyrans 11a−c or
thienothiopyranopyrrols 12a−e, respectively. Moreover, when compounds 11a−c
were treated with another mole of ethyl chloroacetate using the same PTC condi-
tions, compounds 12a−c were obtained with fair yields (Scheme 3, Table I). Their
stepwise reactions study revealed the priority of S-alkylation to N-alkylation ac-
cording to the role of reactivity (3) (S > N > O).
In analogy, compound 2a, 2b, or 4b was treated with phenylisocyanate
or phenylisothiocyanate under PTC conditions [CH3CN/K2CO3/tetrabutylamm-
onium bromide (TBAB)] to afford α-pyran, α-thiopyran, pyridinone, and pyridine-
2-thione derivatives 13a−c-16a−c, respectively. The reaction pathway is thus
assumed to proceed via anucleophilic addition of the active methylene group at
==
the N C followed by the attack of the SH, NH or OH to the cyano group to give

ORDER
REPRINTS
p-CHLOROPHENYLMETHYLENEMALONONITRILE
483
CN
CN
C
CN
CN
CH3CN
PTC
Cl
C
C
+
PhNCX
Cl
C
C
CN
Cl
C
CN
+
CH2R
2a, 2b and 4b
XH
NPh
R
NHPh
R
X = O or S
X
Cl
Cl
CN
CN
NH2
NH2
N-Ph
+
X
R
R
NPh
13a-c & 14a-c
X
15a-c & 16a-c
13-16 a,
13 & 15, X = O
14 & 16, X = S
R = CN
b, R = Ph
c, R = PhCO
Scheme 4.
compounds 13–16 (Scheme 4, Table I). This is in accordance with the sequence
of reactivity of anionic poles S > N > O ≈ C.
EXPERIMENTAL
The MS were recorded on a Micromass 7070 E spectrometer operating at
70 eV, using direct inlet.
Synthesis of Compounds 2b,c, 4a−c, and 6a−c General Procedure
To a mixture of anhydrous potassium carbonate (3 g), dry benzene, dioxan,
or DMF (40 mL), compound 1 (1.88 g, 0.01 mol) or 3 (2.35 g, 0.01 mol) and
catalytic amount of tetrabutylammonium bromide (TBAB) was added to an equi-
molar amount 0.01 mol of benzyl chloride (1.15 mL), bromomalononitrile,
(1.44 gm), chloroacetaldehyde (0.64 mL), or phenacyl bromide (1.99 g). The
reaction mixtures were vigorously stirred over different periods of time at the
appropriate temperatures (Table I), until completion of the reaction (TLC). The re-
action mixtures were filtered off and the filtrate was evaporated in vacuo.
The residual solid was washed with water and crystallized from the appropriate
solvent, where compounds 2b,c, 4a,c, and 6a−c were obtained, respectively.
The solid potassium carbonate was dissolved in distilled water (50 mL). The
separated solid was collected by filtration and crystallized from the proper solvent,

ORDER
REPRINTS
484
KHODAIRY AND EL-SAYED
where compounds 4b and 5a were obtained (Tab. 1). MS of compound 2b : m/z.
(relative intensity): 278 (18.23), 188 (3.64), 138 (8.9), 125 (100), 91 (59.24). MS
of product 4a: m/z (relative intensity): 230 (6.4), 184 (0.01), 163 (0.1), 124 (100),
86 (4.8), 63 (7.88).
Synthesis of 4-p-Chlorophenyl-3-substituted-2-
imino(oxo)-2H-3-pyrancarbonitrile 6a−c from the
Intermediates 4a−c or 5a
A mixture of compound 4a−c (0.01 mol) or 5a (2.3 g, 0.01 mol) in dry
dioxan (20 mL) and anhydrous potassium carbonate (3 g) was treated
with catalytic amount of tetrabutylammonium bromide (TBAB), and was vig-
orously stirred over different periods of time at the appropriate temperatures
(Tab. I). The separation of the products was completed using the same previous
procedure.
Synthesis of 1-Amino-4-p-chlorophenyl-2-
imino-1,2-dihydro-3-pyridinecarbonitrile 7a
An equimolar mixture of compound 5a (0.69 g, 0.003 mol) and hydrazine
hydrate (0.15 mL, 0.003 mol) in 30 mL of ethanol was refluxed for 2 h. The
reaction mixture was evaporated in vacuo, and the residual solid was crystallized
for ethanol (Tab. I).
Synthesis of 4(1,3-Dioxo-2,3-dihydro-1H-2-isoindolyl)5-amino-2-p
Chlorophenyl-3-oxo-1,4-cyclopentadiene-1-carbonitrile 8 and
2-[3(1,2-Dioxo-2,3-dihydro-H-2-isoindolyl)-2-oxo-1-
phenylpropylidene]malononitrile 9
An equimolar mixture (0.01 mol) of compound 1 (1.88 g), phthalylglycinyl
chloride (2.23 g) and triethylamine (1 mL) in 50 mL of dry benzene was re-
fluxed for 3 h. The solvent was evaporated under reduced pressure and the residual
solid was filtered off, washed with water, and crystallized from ethanol to give
product 8. Product 9 was obtained using the same procedure with 6-h reflux or
by refluxing a benzene solution of compound 8 in presence of catalytic amount
of triethylamine for 3 h. The desired product 9 was crystallized from ethanol
(Tab. I).

ORDER
REPRINTS
p-CHLOROPHENYLMETHYLENEMALONONITRILE
485
Synthesis of 6-Amino-3-Substituted-4-p-Chlorophenyl-
2-thioxo-2H-5-thiopyran Carbonitrile 10a−c
General Procedure
To a mixture of compound 2a (2.27 g, 0.01 mol), 4a (2.30 g, 0.01 mol), or
4b (3.06 g, 0.01 mol) and 3 g potassium carbonate in dry dioxan (40 mL), CS2
(0.76 mL, 0.01 mol) was added. The reaction mixture was treated with a cat-
alytic amount of TBAB and vigorously stirred over different periods of time at
the appropriate temperature until completion of the reaction (TLC). The reaction
mixtures were filtered off and the filtrate was evaporated in vacuo. The residual
solid was washed with water and crystallized from the appropriate solvent, where
compounds 10a−c were obtained (Tab. I). MS of compound 10c : m/z (relative
intensity): 383 (25), 349 (16.66), 333 (21.75), 188 (7.47), 142 (9.73), 105 (100).
Synthesis of 2-Ethylcarboxy-3-substituted-4-p-chlorophenyl-6-
imino-6H-thieno-[2,3-c]thiopyran-5-carbonitrile 11a−c
Compounds 11a−c were prepared from the reaction of compound 2a, 4a, or
4b (0.01 mol) in dioxan (20 mL) and ethyl chloroacetate (1.06 mL, 0.01 mol) using
the same previous procedure.
Synthesis of 5-Amino-2,6-diethylcarboxy-3-substituted-4-p-chlorophenyl
6-iminothieno[3,2:5,6]thiopyrano[2,3-b]pyrrols 12a−c
Method A: General Procedure
To a mixture of anhydrous potassium carbonate (3 g) in dry dioxan (20 mL),
compound 10a−c or 11a−c (0.01 mol) and ethy1 chloroacetate (1.06 mL, 0.01 mol)
or (2.12 mL, 0.02 mol) were added. The reaction mixture was treated with a
catalytic amount of TBAB and vigorously stirred over different periods of time at
the appropriate termperatures until completion of the reaction (TLC). The reaction
mixture was filtered off and the filtrate was evaporated in vacuo. The residual
solid was washed with water and crystallized from the appropriate solvent, where
compounds 12a−c were obtained (Tab. I).
Method B
Ethyl chloroacetate (0.02 mol) (2.12 mL) was added to a stirred mixture of
compound 2a (2.27 g, 0.01 mol), 4a(2.30 g, 0.01 mol), or 4b (3.06 g, 0.01 mol), CS2

ORDER
REPRINTS
486
KHODAIRY AND EL-SAYED
(0.76 mL, 0.01 mol), anhydrous potassium carbonate (3 g), and catalytic amount
of TBAB in dry dioxan (40 mL). The reaction mixture was treated as previously
described in Method A.
Synthesis of 6-Amino-3-substituted-2-iminophenyl-4-p-
chlorophenyl-2H-5-pyrano(thiopyrano)carbonitrile 13&15 and
6-Amino-3-substituted-4-p chloro-phenyl-1-
phenyl-2-oxo(thioxo)-1,2-dihydro-5-pyridinecarbonitrile 15&16
General Procedure
To a mixture of compound 2a(2.27 g, 0.01 mol), 2b (2.78 g, 0.01 mol),
or 4b (3.06 g, 0.01 mol) and 3 g potassium carbonate in acetonitrile (40 mL),
phenylisocyanate(1.19mL, 0.01mol)orphenylisothiocyanate(1.35mL, 0.01mol)
was added. The reaction mixture was treated with a catalytic amount of TBAB and
vigorously stirred at the appropriate temperature untill completion of the reaction
(TLC). The reaction mixture was filtered. The filtrate was evaporated in vacuo.
The residual solid was crystallized from the appropriate solvent, where compounds
13a−c and 14a−c were obtained, respectively.
The solid potassium carbonate was dissolved in distilled water (50 mL). The
separated solid was collected by filtration and crystallized from the proper solvent,
where compounds 15a−c and 16a−c were obtained.(Tab. I, Scheme 4).
REFERENCES
1. El-Sayed, A.M.; Khodairy, A. Synth. Comm. 1998, 28 (18), 3331.
2. El-Shafei, A.K.; El-Sayed, A.M.; El-Saghier, A.M. Phosphorus, Sulfur and
Silicon, 1994, 90, 213.
3. Abdel-Ghany, H., Phosphorus, Sulfur and Silicon 1997, 122, 173.

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