An efficient and simple route to prospective biologically active isoindoloquinazoline, pyrimidine and thiazine derivatives using 2-amino-N'-arylbenzamidine and related compounds as starting materials

Article abstract of DOI:10.1515/znb-2011-0916

The reaction of (Z)-2-amino-N'-arylbenzamidines 1, 2-amino-4,5,6,7- tetrahydrobenzo[b]-thiophene-3-carboxamide (4) and 4-amino-5-substituted-2- (phenylamino)thiophene-3-carboxamides 12 with o-phthalaldehyde (2), terephthalaldehyde (9), and 4-formyl[2.2]paracyclophane (16) in ethanol under reflux conditions afforded isoindoloquinazoline, thienopyrimidine, pyrimidine and thiazine derivatives, respectively. The products were characterized based on their spectroscopic data and elemental analysis.

Full text of DOI:10.1515/znb-2011-0916

An Efficient and Simple Route to Prospective Biologically Active
Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives Using
2-Amino-Nꢀ-Arylbenzamidine and Related Compounds as Starting
Materials
Fathy F. Abdel-Latif, Kamal M. El-Shaieb, and Ahmed G. El-Deen
Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt
Reprint requests to Dr. Kamal M. El-Shaieb. Fax: +2-086-2342601. E-mail: kmelshaieb@yahoo.com
Z. Naturforsch. 2011, 66b, 965 – 971; received April 21, 2011
The reaction of (Z)-2-amino-Nꢀ-arylbenzamidines 1, 2-amino-4,5,6,7-tetrahydrobenzo[b]-thio-
phene-3-carboxamide (4) and 4-amino-5-substituted-2-(phenylamino)thiophene-3-carboxamides 12
with o-phthalaldehyde (2), terephthalaldehyde (9), and 4-formyl[2.2]paracyclophane (16) in ethanol
under reflux conditions afforded isoindoloquinazoline, thienopyrimidine, pyrimidine and thiazine
derivatives, respectively. The products were characterized based on their spectroscopic data and ele-
mental analysis.
Key words: Amidines, Aldehydes, Quinazolines, Thienopyrimidines, Thiazines
Introduction
Results and Discussion
We have found that on warming amidines 1a, b and
the thiophenecarboxamide derivative 4 with o-phthal-
aldehyde (2) reactions proceed with the formation of
isoindoloquinazoline derivatives 3 and the thienopy-
rimidinone derivative 5 (Scheme 1).
Quinazolines are undoubtedly of interest as topics
of study because they are heterocyclic systems with
multiple reactive centers. Among them are found a se-
ries of highly effective compounds used in agriculture,
such as fungicides, bactericides, defoliants, and plant
growth stimulants [1 – 3]. Compounds of this class are
also used as medicinal drugs with various pharma-
cological activities [4 – 6]. Very recently quinazoline
derivatives have been obtained by the reaction of (Z)-
2-amino-Nꢀ-arylbenzamidines with tetracyanoethylene
(TCNE) [7], isatoic anhydride [8], 4-formyl[2.2]para-
cyclophane [9], p-tolualdehyde [10], 2,3-dichloro-1,4-
naphthoquinone (DCHNQ) [11], 7,7,8,8-tetracyano-
quinodimethane (TCNQ) [12], and 2-di-cyanomethyl-
eneindane-1,3-dione (CNIND) [13].
Fused pyrimidines continue to attract considerable
attention of researchers because of their great practical
usefulness due to a very wide spectrum of their bio-
logical activities. Thienopyrimidines occupy a special
position among these compounds. Along with some
other pyrimidine systems containing an annelated five-
membered heteroaromatic ring, thienopyrimidines are
structural analogs of biogenic purines and can be con-
sidered as potential nucleic acid antimetabolites. Ear-
lier, various aspects of the chemistry and biology
of isomeric thienopyrimidines have been reviewed
[14 – 17].
The structure of the products 3 was deduced
from their spectral data and elemental analysis. The
1H NMR spectrum of compound 3a revealed, beside
signals of the aromatic protons in their expected po-
sitions, a singlet at δ = 6.09 ppm for the methylene
protons. This peak existed in the lower field due to the
inductive effect of both the adjacent nitrogen atom and
the aromatic unit. The IR spectrum revealed no absorp-
tion maxima for either NH or C=O groups, but the C=N
absorption was observed at 1621 cm−1. On the other
hand, both the mass spectrum and the elemental analy-
sis confirm the molecular formula of the product 3a as
C21H15N3. The formation of compounds 3a could be
explained as shown in Scheme 2.
We suggest that the aniline amino group of the reac-
tant 1 adds one of the formyl carbon atoms of the alde-
hyde 2 losing a molecule of water to give the azome-
thine 6. The lone pair of electrons of the azomethine
nitrogen of 6 attacks the carbon atom of the second
formyl group to give the intermediate 7 which under-
goes rearrangement through 1,3-hydride shift to give
the cycloadduct 8 which is suitable for an attack by the
c
0932–0776 / 11 / 0900–0965 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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F. F. Abdel-Latif et al. · Prospective Biologically Active Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives
Scheme 1. Condensation
of amidines 1a, b and thio-
phenecarboxamide 4 with
o-phthalaldehyde (2).
second amino group to form the end product 3 by los- a plane of symmetry. This was further confirmed by
ing a second molecule of water.
the appearance of half of the number of lines for the
Mass spectrometry and elemental analysis con- product carbon atoms in the 13C NMR spectra. Mass
firm the molecular formula of the product 5 as spectrometry revealed the molecular ion peak of 10b
at m/z = 588.
C17H14N2OS. However, the IR spectrum showed two
absorption maxima at ν = 1632 and 1600 as a result of
Heating a mixture of thiophenecarboxamide deriva-
(C=O) and (C=N) groups, respectively. The 1H NMR tive 4 and terephthalaldehyde (9) in molar ratio 2 : 1
spectrum of 5 revealed, beside the protons of both the in ethanol in the presence of a catalytic amount of
p-toluenesulfonic acid for several hours under re-
aromatic and cyclohexyl groups which resonated as
multiplets in their expected positions, a singlet at δ = flux conditions yielded the thienopyrimidinone deriva-
5.24 ppm due to the N-CH2-aryl protons.
tive 11 (Scheme 3). The product was identified by its
1H NMR spectrum where two singlets resonated at
δ = 10.06 and 8.59 ppm attributed to the two different
NH groups. Furthermore, the presence of a singlet at
δ = 7.41 ppm for the pyrimidine C-2 protons strongly
supports that idea. The IR spectrum showed two ab-
sorption bands at ν = 3390 and 1629 cm−1 for NH and
C=O groups, respectively. Both mass spectrum and el-
emental analysis confirm the molecular formula of the
product 11 as C26H26N4O2S2.
On the other hand, the reaction of amidines 1a, b
and terephthalaldehyde (9) in the molar ratio 2 : 1 in
ethanol in presence of p-toluenesulfonic acid yielded
quinazoline derivatives 10a, b (Scheme 3).
The 1H NMR spectrum of the product 10b an-
nounced two exchangeable protons at δ = 7.93
and 10.02 ppm related to the NH groups. The ap-
pearance of half the number of expected signals in
1
the H NMR data indicates that the product 10b has
Scheme 2. A suggested
mechanism for the forma-
tion of compounds 3.
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967
Scheme 3. Condensation
of terephthalaldehyde (9)
with aminoderivatives 1, 4
and 12.
The novel carboxamide reactants 12a, b were ob- of novel heterocycles with prospective biological
tained by heating a mixture of the acrylamide deriva- activity. We have found that on warming carboxamide
tive 14 with either ethyl chloroacetate (15a) or ω- derivatives 12a, b with terephthalaldehyde (9) leads to
chloroacetophenone (15b) in the presence of triethy- the formation of the 2 : 1 adducts 13a, b as shown in
lamine as a catalyst (Scheme 4). The compound 12a Scheme 3. The 1H NMR spectrum of 13a revealed, in
1
as an example showed in its H NMR spectrum the addition to the peaks of the aromatic protons at their
peaks of three exchangeable protons at δ = 10.12, 7.33 characteristic positions, three singlets at δ = 10.42,
and 6.73 ppm for an -NH and two -NH2 groups, re- 8.57 and 7.65 ppm for three different NH groups.
spectively. Moreover, there are a quartet and a triplet Their appearance at lower field may be the result of the
at δ = 4.10 and 1.20 ppm, characteristic for both CH2 presence of intramolecular hydrogen bonds. Further-
and CH3 groups of the -COOEt group, respectively.
more, a triplet at δ = 5.83 ppm is related to pyrimidine
The functional groups (NH, NH2 and C=O) of C2 protons. The pyrimidine C2 protons appeared in
1
the product 12a absorbed in the IR spectrum at ν = the H NMR spectrum as a triplet due to the splitting
3373, 3329, 3197, and 1655 cm−1, respectively. Mass by the two adjacent NH groups. Moreover, the ester
spectrometry of compound 12a revealed the molecular ethyl group resonated as a quartet and a triplet at δ =
ion peak at m/z = 305. The products 12a, b were 4.15 and 1.21 ppm. The IR spectrum of this compound
used to complete our study dealing with the synthesis showed five characteristic bands at ν = 3387, 3273,
Scheme 4. Synthesis of thiophene-
carboxamide derivatives 12.
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F. F. Abdel-Latif et al. · Prospective Biologically Active Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives
Scheme 5. Reaction of 4-
formyl[2.2]paracyclophane
(16) with 14 and 12a, b.
3172, 3050, and 1646 cm−1 for NH and C=O ical shift value due to the presence of intramolecu-
groups, respectively. The molecular ion peak of the lar hydrogen bonding as shown in Scheme 5. Further-
compound 13a appeared in the mass spectrum at more, the 1H NMR of 18a revealed, in addition to sig-
m/z = 708. However, we have found that the acryl- nals for the ester-ethyl group, two multiplets at δ =
amide derivative 14 and the thiophenecarboxamide 3.10– 2.84 ppm for the protons of the paracyclophane
derivatives 12a, b react with 4-formyl[2.2]paracyclo- ethylene bridges. The mass spectrum revealed a peak
phane (16) under reflux conditions to give the thiazi- at m/z = 523 with intensity = 100% representing the
none derivative 17 and the thienopyrimidinone deriva- molecular ion peak.
tives 18a, b, respectively (Scheme 5).
The 1H NMR spectrum of the product 17 revealed, Experimental Section
in addition to the signals of the aromatic protons,
two singlets at δ = 10.01 and 8.59 ppm related to
the two different NH groups, and a doublet at δ =
5.99 ppm characteristic for the thiazinone-C2 proton.
sor 27 instrument and a Jasco FT/IR-450 Plus infrared spec-
Melting points were measured in capillary tubes using
a Bu¨chi 530 melting point apparatus and are uncorrected.
The infrared spectra were measured using a Bruker Ten-
The paracyclophane ethylene bridges appeared in the
1H NMR as three multiplets at δ = 3.27 – 2.92 ppm.
The NH groups absorbed in the IR spectrum at ν =
3211 and 3179 cm−1, and the cyano and carbonyl
groups at ν = 2196 and 1678 cm−1, respectively.
Both mass spectrometry and elemental analysis have
confirmed the molecular formula of compound 17 as
C27H23N3OS.
trophotometer. 1H NMR (300 MHz) spectra were recorded in
[D6]DMSO on a Bruker AM 300 MHz spectrometer. Chem-
ical shifts are quoted in δ and are referenced to TMS on
measurements carried out in the Assiut Microanalysis Cen-
ter at Assiut University and at the Microanalytical Center of
Cairo University. Mass spectra were obtained with a Finni-
gan MAT 8430 instrument at 70 eV. Elemental analyses were
performed on a Perkin-Elmer CHN-2400C analyzer model.
Precoated silica gel plates (silica gel 0.25 mm, 60 GF254
;
1
The H NMR spectrum of 18a showed one singlet
Merck) were used for thin layer chromatography.
for an exchangeable proton at δ = 10.36 ppm related
to the Ph-NH proton and two doublets at δ = 8.21
and 6.75 ppm for the two pyrimidine NH protons (two
doublets due to coupling with the adjacent pyrimidine-
C2 proton registered at δ = 5.97 ppm as a triplet).
Starting materials
All reagents were purchased from Alfa Aesar, Fluka and
Aldrich companies and were used without further purifica-
tion. (Z)-2-Amino-Nꢀ-arylbenzamidines 1a and 1b were pre-
1
From the H NMR spectrum we noticed that one of
the pyrimidine NH groups resonated at a higher chem- pared as reported in ref. [7].
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Reaction of 2-amino-Nꢀ-arylbenzimidamides 1a, b with o- (6), 69 (2). – C17H14N2OS (294.37): calcd. C 69.36, H 4.79,
phthalaldehyde (2)
N 9.52, S 10.89; found C 69.23, H 4.73, N 9.37, S 10.71.
Equimolar amounts of (Z)-2-amino-Nꢀ-arylbenzamid-
ines 1a, b and o-phthalaldehyde (2) were boiled in ethanol
under reflux conditions for 4 – 6 h. After completion of the
reaction (monitored by TLC), the resulting precipitate was
Reaction of (Z)-2-amino-Nꢀ-phenylbenzimidamides (1a, b)
with terephthalaldehyde (9)
Equimolar amounts of 1a, b and 9 were allowed to react
filtered off and recrystallized from DMF/EtOH to yield 3a, b. in boiling ethanol in the presence of a catalytic amount of
p-toluenesulfonic acid (p-TSA) for 2 – 3 h. After comple-
tion of the reaction (monitored by TLC), the resulting pre-
cipitate was filtered off and recrystallized using a mixture of
DMF/EtOH to give the products 10a, b.
(Z)-N-(Isoindolo[2,1-a]quinazolin-5(11H)-ylidene)anil-
ine (3a) was obtained as◦ a yellow solid; yield (176 mg,
57 %); m. p. = 284 – 285 C. – IR (film): ν = 2928, 1621,
155◦1, 1474 cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 C, TMS): δ = 6.09 (s, 2 H, N-CH2), 7.14 – 7.24 (m,
6 H), 7.25 – 7.27 (m, 2 H), 7.32 (t, 2 H, J = 5.7 Hz), 7.48
(t, 1 H, J = 8.1 Hz), 8.06 – 8.16 (m, 2 H, Ar-H). – MS (EI,
70 eV): m/z (%) = 310 (28) [M+1]+, 309 (100) [M]+, 308
(89), 293 (13), 291 (14), 279 (18), 246 (13), 228 (14), 204
(19), 190 (16), 179 (19), 165 (16), 158 (14), 153 (20), 134
(12), 119 (17), 115 (19), 102 (29), 99 (14), 95 (16), 92 (24),
89 (31), 82 (20), 77 (78), 68 (20). – C21H15N3 (309.36):
calcd. C 81.53, H 4.89, N 13.58; found C 81.44, H 4.75,
N 13.66.
(Z)-4-Chloro-N-(isoindolo[2,1-a]quinazolin-5(11H)-yl-
idene)aniline (3b) was obtained as a yellow solid; yield
(189 mg, 55 %); m. p. = 273 – 275 ◦C. – IR (film): ν = 3068,
292◦2, 1604, 1549 cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 C, TMS): δ = 6.09 (s, 2 H, N-CH2), 7.14 – 7.24 (m,
5 H), 7.25 – 7.27 (m, 2 H), 7.32 (t, 2 H, J = 5.7 Hz), 7.48
(t, 1 H, J = 8.1 Hz), 8.06 – 8.16 (m, 2 H, Ar-H). – MS (EI,
70 eV): m/z (%) = 345 (20) [M+2]+, 344 (12) [M+1]+, 343
(38) [M]+, 342 (43), 340 (25), 335 (30), 329 (34), 317 (25),
288 (30), 257 (29), 233 (33), 226 (28), 218 (25), 208 (32),
201 (37), 195 (41), 177 (47), 164 (28), 143 (38), 130 (10),
103 (20), 91 (29), 84 (36), 79 (47), 68 (38). – C21H14ClN3
(343.81): calcd. C 73.36, H 4.10, Cl 10.31, N 12.22; found
C 73.18, H 4.11, Cl 10.15, N 12.06.
N,Nꢀ-(2,2ꢀ-(1,4-Phenylene)bis(2,3-dihydroquinazoline-
2(1H)-yl-4(1H)-ylidene))dianiline (10a) was obtained as
a yellow powder; yield (203 mg, 39 %); m. p. = 211 –
213 ◦C. – IR (film): ν = 3273, 3159, 1587 cm−1. – 1H NMR
◦
(300 MHz, [D6]DMSO, 25 C, TMS): δ = 5.07 (s, 2 H, 2
CH), 6.91 – 7.47 (m, 5 H, Ar-H), 7.55 – 7.63 (m, 4 H, Ar-H),
7.64 – 7.67 (m, 5 H, Ar-H), 7.91 (s, 2 H, 2 NH), 7.69 – 7.93
(m, 5 H, Ar-H), 8.27 – 8.45 (m, 3 H, Ar-H), 10.04 (s, 2 H, 2
NH). – MS (EI, 70 eV): m/z (%) = 520 (64) [M]+, 456 (7),
353 (17), 338 (20), 335 (6), 285 (15), 222 (21), 206 (5), 151
(4), 120 (9), 109 (8), 83 (11), 69 (18). – C34H28N6 (520.63):
calcd. C 78.44, H 5.42, N 16.14; found C 78.25, H 5.46,
N 15.89.
N,Nꢀ-(2,2ꢀ-(1,4-Phenylene)bis(2,3-dihydroquinazoline-
2(1H)-yl-4(1H)-ylidene))bis(4-chloro-aniline) (10b) was
obtained as a pale-yellow solid; yield (295 mg, 61 %); m. p.
> 300 ◦C. – IR (film): ν = 3224, 3052,◦1563, 1506 cm−1. –
1H NMR (300 MHz, [D6]DMSO, 25 C, TMS): δ = 5.02
(s, 2 H, CH), 7.55 – 7.63 (m, 4 H, Ar-H), 7.64 – 7.67 (m,
4 H, Ar-H), 7.93 (s, 2 H, 2 NH), 7.91 – 8.09 (m, 4 H, Ar-H),
8.37 – 8.58 (m, 8 H, Ar-H), 10.02 (s, 2 H, 2 NH). – MS (EI,
70 eV): m/z (%) = 592 (25) [M+4]+, 590 (55) [M+2]+, 588
(80) [M]+, 583 (40), 297 (30), 296 (25), 293 (30), 291 (45),
201 (30), 192 (25), 137 (25), 118 (55), 102 (100), 85 (25),
76 (60). – C34H26Cl2N6 (589.53): calcd. C 69.27, H 4.45,
N 14.26; found C 69.33, H 4.37, N 14.09.
Reaction of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (4) with o-phthalaldehyde (2)
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
amide (4) and o-phthalaldehyde (2) in absolute ethanol
were heated under reflux conditions for 2 h. A precipitate
was formed and filtered off, washed with hot ethanol and
Reaction of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (4) with terephthalaldehyde (9)
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
recrystallized from DMF/EtOH to give 7,8,9,10-tetra- amide (4) and 9 were heated in absolute ethanol for 3 – 4 h.
hydrobenzo[4ꢀ,5ꢀ]thieno[3ꢀ,2ꢀ:5,6]pyrimido[2,1-a]isoindol-
A precipitate was formed. It was filtered off, washed with
6(13H)-one (5) as a violet solid; yield (159 mg, 54 %); m. p. ethanol, dried and recrystallized from DMF/EtOH to give
> 304 ◦C. – IR (film): ν = 2927, 1632, 1600, 1443 cm−1. – 2,2ꢀ-(1,4-phenylene)bis(2,3,5,6,7,8-hexahydrobenzo[4,5]-
1H NMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ = 1.03 (t, thieno[2,3-d]pyrimidin-4(1H)-one) (11). This compound
2 H, CH2), 1.78 (t, 2 H, CH2), 2.67 – 2.94 (m, 4 H, 2 CH2), was obtained as an orange solid; yield (179 mg, 73 %);
◦
5.24 (s, 2 H, N-CH2), 7.59 – 7.96 (m, 4 H, Ar-H). – MS (EI, m. p. > 300 C. – IR (film): ν = 3390, 2926, 2859, 1629,
70 eV): m/z (%) = 295 (10) [M+1]+, 294 (39) [M]+, 293 1415 cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
(100), 291 (7), 278 (22), 266 (33), 252 (4), 237 (4), 216 (7), TMS): δ = 1.72 – 1.76 (m, 12 H), 2.51 – 2.70 (m, 4 H ), 7.4
186 (7), 179 (5), 160 (4), 133 (5), 115 (28), 99 (3), 82 (9), 73 (s, 2 H, 2CH), 7.95 – 8.08 (m, 4 H, Ar-H), 8.59 (s, 2 H, 2
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F. F. Abdel-Latif et al. · Prospective Biologically Active Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives
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NH), 10.06 (s, 2 H, 2 NH). – MS (EI, 70 eV): m/z (%) = 490 57 %); m. p. > 300 C. – IR (film): ν = 3387, 3273, 3172,
(48) [M]+, 489 (50), 468 (48), 427 (50), 383 (71), 359 (58), 3050, 1646, 1589 cm−1. – 1H NMR (300 MHz, [D6]DMSO,
342 (36), 306 (38), 294 (54), 253 (70), 244 (35), 238 (35), 25 ◦C, TMS): δ = 1.21 (t, 6 H, 2 CH3, J = 7.2 Hz), 4.15 (q,
226 (45), 214 (42), 193 (53), 189 (37), 171 (44), 152 (94), 4 H, 2 CH2, J = 5.7 Hz), 5.83 (t, 2 H, 2 pyrimidine C2, J =
149 (57), 136 (93), 100 (100), 91 (92), 80 (62), 77 (85). – 3.9 Hz), 7.13 – 7.25 (m, 2 H, Ar-H), 7.29 (s, 4 H, Ar-H),
C26H26N4O2S2 (490.64): calcd. C 63.65, H 5.34, N 11.42, 7.31 – 7.39 (m, 6 H, Ar-H), 7.40 – 7.44 (m, 2 H, Ar-H),
S 13.07; found C 63.49, H 5.31, N 11.28, S 12.92.
7.65 (s, 2 H, 2 NH), 8.57 (s, 2 H, 2 NH), 10.42 (s, 2 H, 2
Ph-NH). – MS (EI, 70 eV): m/z (%) = 708 (18) [M]+, 354
(12), 333 (16), 331 (47), 330 (33), 305 (49), 288 (12), 259
(29), 242 (31), 214 (45), 200 (14), 189 (12), 171 (35), 148
(14), 130 (13), 119 (29), 104 (33), 94 (18), 93 (49), 91 (26),
77 (98). – C36H32N6O6S2 (708.81): calcd. C 61.00, H 4.55,
N 11.86, S 9.05; found C 60.87, H 4.53, N 11.73, S 8.92.
Reaction of 2-cyano-3-mercapto-3-(phenylamino)acryl-
amide (14) with α-chloroketones 15a, b
A mixture of (Z)-2-cyano-3-mercapto-3-(phenylamino)-
acrylamide (14) (219 mg, 1 mmol) and 1.1 mmol of the α-
chlorocarbonyl compound (ethyl chloroacetate or ω-chloro-
acetophenone) in the presence of five drops of triethylamine
was refluxed in 20 mL ethanol for 2 h. The precipitate that
was formed after cooling the reaction mixture was filtered
off, dried, and recrystallized from ethanol to give 12a, b.
2,2ꢀ-(1,4-Phenylene)bis(7-benzoyl-5-(phenylamino)-
2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-one) (13b) was
obtaine◦d as a pale-yellow solid; yield (356 mg, 54 %); m. p.
> 300 C. – IR (film): ν = 3274, 3181, 3048, 2907, 1649,
1581 cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 6.01 (t, 2 H, 2 pyrimidine C2, J = 2.5 Hz), 7.15
(s, 4 H, Ar-H ), 7.33 – 7.47 (m, 10 H, Ar-H), 7.49 – 7.52
(m, 2 H, Ar-H), 7.64 – 7.67 (m, 8 H, Ar-H), 8.63 (s, 2 H,
2 NH), 8.92 (s, 2 H, 2 NH), 10.50 (s, 2 H, 2 Ph-NH). –
MS (EI, 70 eV): m/z (%) = 774 (17) [M+2]+, 772 (24)
[M]+, 544 (8), 386 (10), 337 (32), 319 (100), 294 (20),
216 (9), 162 (12), 128 (11), 99 (22), 89 (6), 73 (40). –
C44H32N6O4S2(772.89): calcd. C 68.38, H 4.17, N 10.87,
S 8.30; found C 68.21, H 4.11, N 10.67, S 8.12.
Ethyl 3-amino-4-carbamoyl-5-(phenylamino)thiophene-
2-carboxylate (12a) was obtained as colorless crystals; yield
(253 mg, 80 %), m. p. = 202 – 203 ◦C. – IR (film): ν = 3373,
3329, 3197 (NH, NH2), 165◦5 (CO), 1559 cm−1. – 1H NMR
(300 MHz, [D6]DMSO, 25 C, TMS): δ = 1.20 (t, 3 H, J =
6.9 Hz), 4.1 (q, 2 H, J = 7.2 Hz), 6.73 (s, 2 H, NH2), 7.12 –
7.29 (m, 3 H, Ar-H), 7.33 (s, 2 H, NH2), 7.35 – 7.40 (m,
2 H, Ar-H), 10.12 (s, 1 H, Ph-NH). – MS (EI, 70 eV): m/z
(%) = 306 (11) [M+1]+, 305 (51) [M]+, 304 (22), 288 (24),
242 (100), 241 (41), 215 (26), 214 (34), 171 (11), 170 (14),
143 (36), 89 (18), 77 (24). – C14H15N3O3S (305.08): calcd.
C 55.07, H 4.95, N 13.76, S 10.50; found C 54.91, H 4.88,
N 13.63, S 10.32.
Reaction of both acrylamide 14 and carboxamides 12a and
12b with 4-formyl[2.2]paracyclophane (16)
General procedure
A mixture of either (Z)-2-cyano-3-mercapto-3-(phenyl-
amino)acrylamide (14) or 4-amino-5-substituted-2-(phenyl-
amino)thiophene-3-carboxamide 12a or 12b with 4-formyl-
[2.2]paracyclophane (17) in dry EtOH (15 mL) was kept at
70 – 80 ◦C for 1 – 3 h. After completion of the reaction (mon-
itored by TLC), the precipitate was collected by filtration,
washed and recrystallized from DMF/EtOH to give the prod-
ucts 17 and 18a, b.
4-Amino-5-benzoyl-2-(phenylamino)thiophene-3-carbox-
amide (12b) was obtained◦as orange crystals; yield (183 mg,
52 %); m. p. = 222 – 224 C. – IR (film): ν = 3312, 3267,
3153, 1661, 1572 cm−1. – 1H NMR (300 MHz, [D6]DMSO,
25 ◦C, TMS): δ = 7.07 (t, 1 H, J = 6.80 Hz), 7.28 – 7.35 (m,
3 H, Ar-H), 7.40 – 7.44 (m, 4 H, Ar-H), 7.50 (s, 2 H, NH2),
7.56 (d, 2 H, J = 7.59 Hz), 8.02 (s, 2 H, NH2), 10.20 (s,
1 H, Ph-NH). – MS (EI, 70 eV): m/z (%) = 339 (4) [M+2]+,
338 (16) [M+1]+, 337 (57) [M]+, 319 (100), 264 (3), 243
(4), 216 (3), 143 (12), 99 (16), 73 (34). – C18H15N3O2S
(337.09): calcd. C 64.08, H 4.48, N 12.45, S 9.50; found
C 63.89, H 4.41, N 12.28, S 9.29.
4-Oxo-2-paracyclophan-4-yl-6-(phenylamino)-3,4-di-
hydro-2H-1,3-thiazine-5-carbonitrile (17) was obtained as a
colorless solid; yield (191 mg, 87 %); m. p. = 189 – 192 ◦C. –
IR (film): ν = 3211, 3179, 2196, 1678 cm−1. – 1H NMR
◦
(300 MHz, [D6]DMSO, 25 C, TMS): δ = 2.78 – 2.92 (m,
Reaction of 12a, b with terephthalaldehyde (9)
2 H), 2.94 – 3.01 (m, 4 H), 3.11 – 3.27 (m, 2 H), 5.99 (d, 1 H,
thiazine C2, J = 4.00 Hz), 6.42 – 6.61 (m, 5 H), 7.03 (d, 1 H,
J = 8.40 Hz), 7.18 (t, 2 H, J = 7.40 Hz), 7.27 – 7.31 (m, 3 H,
Ar-H), 7.42 (s, 1 H, Ar-H), 8.59 (d, 1 H, NH, J = 2.80 Hz),
10.01 (s, 1 H, Ph-NH). – MS (EI, 70 eV): m/z (%) = 437
Refluxing of the thiophene-3-carboxamides 12a or 12b
with 9 in the presence of a catalytic amount of p-TSA in
boiling ethanol led to the formation of 13a or 13b.
Diethyl 2,2ꢀ-(1,4-phenylene)bis(4-oxo-5-(phenylamino)- (28) [M]+, 410 (8), 352 (28), 333 (36), 329 (44), 272 (16),
1,2,3,4-tetrahydrothieno[3,4-d]-pyrimidine-7-carboxylate)
238 (32), 207 (28), 186 (20), 139 (12), 131 (44), 121 (24),
(13a) was obtained as a colorless solid; yield (343 mg, 99 (56), 84 (48), 73 (100), 69 (40), 65 (24). – C27H23N3OS
Unauthenticated
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F. F. Abdel-Latif et al. · Prospective Biologically Active Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives
971
(437.56): calcd. C 74.11, H 5.30, N 9.60, S 7.33; found
C 73.92, H 5.21, N 9.47, S 7.17.
7-Benzoyl-2-(paracyclophan-4-yl)-5-(phenylamino)-
2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-one (18b) was
obtained as a yellow solid; yield (205 mg, 74 %); m. p. =
246 – 247 ◦C. – IR (film): ν = 3291, 3187, 1680, 1604,
1577 cm−1. – 1H NMR (300 MHz, [D6]DMSO, 25 ◦C,
TMS): δ = 2.84 – 2.93 (m, 2 H), 2.96 – 3.10 (m, 6 H), 6.18
(t, 1 H, pyrimidine C-2, J = 13.40 Hz), 6.49 – 6.57 (m, 6 H),
6.75 (d, 1 H, NH, J = 7.59 Hz), 7.14 (t, 2 H, J = 7.20 Hz),
7.25 – 7.58 (m, 7 H), 7.72 – 7.81 (m, 2 H), 8.30 (d, 1 H,
CONH, J = 7.20 Hz), 10.45 (s, 1 H, Ph-NH). – MS (EI,
70 eV): m/z (%) = 557 (5) [M+2]+, 555 (7) [M]+, 523 (4),
546 (58), 509 (9), 465 (4), 440 (50), 402 (13), 379 (5), 348
(15), 321 (51), 319 (100), 291 (14), 278 (10), 239 (17), 209
(8), 201 (12), 186 (46), 178 (22), 143 (17), 129 (31), 104 (4),
98 (77), 86 (60), 73 (77). – C35H29N3O2S (555.69): calcd.
C 75.65, H 5.26, N 7.56, S 5.77; found C 75.48, H 5.24,
N 7.42, S 5.64.
Ethyl
2-(paracyclophan-4-yl)-4-oxo-5-(phenylamino)-
1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-7-carboxylate
(18a) was obtained as a pale-yellow solid; yield (217 mg,
◦
83 %); m. p. = 206 – 208 C. – IR (film): ν = 3237, 3154,
1711, 1663, 1600, 1554 cm−1. – 1H NMR (300 MHz,
◦
[D6]DMSO, 25 C, TMS): δ = 1.29 (t, 3 H, CH3), 2.84 –
2.93 (m, 2 H), 2,96 – 3.10 (m, 6 H), 4.27 (q, 2 H, CH2, J =
6.40 Hz), 5.97 (t, 1 H, CH, J = 10.80 Hz, pyrimidine C2),
6.41 – 6.57 (m, 4 H), 6.75 (d, 1 H, NH, J = 7.59 Hz), 7.14 (t,
2 H, J = 7.20 Hz), 7.25 – 7.54 (m, 6 H), 8.21 (d, 1 H, NH,
J = 8.40 Hz), 10.36 (s, 1 H, Ph-NH). – MS (EI, 70 eV): m/z
(%) = 525 (11) [M+2]+, 523 (7) [M]+, 509 (100), 466 (34),
425 (30), 412 (39), 365 (26), 311 (17), 273 (39), 238 (30),
207 (30), 195 (21), 170 (31), 142 (26), 114 (13), 104 (22),
99 (56), 84 (52), 73 (26). – C31H29N3O3S (523.65): calcd.
C 71.10, H 5.58, N 8.02, S 6.12; found C 70.87, H 5.53,
N 7.89, S 5.97.
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