Synthesis of new 1,2,4-oxadiazolidin-5-ylthiophenes and thienopyrimidine derivatives by aza-Wittig reaction using a thienyl carbodiimide

Article abstract of DOI:10.1016/j.cclet.2011.12.017

Azidation of aminothiophene derivative 1 afforded the corresponding azido derivative 2. The latter reacted with triphenylphosphine to afford iminophosphorane derivatives 3. Reacting 3 with phenylisocyanate gave the highly reactive carbodiimide intermediat

Full text of DOI:10.1016/j.cclet.2011.12.017

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 411–414
www.elsevier.com/locate/cclet
Synthesis of new 1,2,4-oxadiazolidin-5-ylthiophenes and
thienopyrimidine derivatives by aza-Wittig reaction using
a thienyl carbodiimide
Afaf M. Abdel Hameed
Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
Received 28 October 2011
Available online 3 March 2012
Abstract
Azidation of aminothiophene derivative 1 afforded the corresponding azido derivative 2. The latter reacted with triphenylpho-
sphine to afford iminophosphorane derivatives 3. Reacting 3 with phenylisocyanate gave the highly reactive carbodiimide
intermediate 4, which was reacted with different nitrones to afford new 1,2,4-oxadiazolidin-5-ylidene-aminothiophenes 5a–c.
Treatment of 4 with absolute EtOH at room temperature gave methyleneamino-5-(methylthio)thiophene 7, (methylthio)-3-(3-
phenylureidothiophene)-2-carboxylate 8 or thienopyrimidine 9 and 10 at refluxing temperature. Finally reaction of carbodiimide
intermediate 4 with different secondary amines gave the new thienopyrimidines 11a–c.
# 2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Carbodiimide; Cycloaddition; 1,2,4-Oxadiazolidin-5-ylideneaminothiophene derivatives; Thienopyrimidine; Aza-Wittig reaction
Recently, the use of iminophosphoranes [1] has become a powerful tool in organic synthetic strategies directed
towards the construction of nitrogen-containing heterocycles [2,3]. The aza-Wittig reaction of iminophosphoranes
with isocyanates provides a valuable method for the synthesis of 5–7 membered nitrogen heterocycles such as
oxazoles [4], pyridines [4,5], pyrimidine derivatives [6], and thienopyrimidine derivatives [7–9].
This work aims to develop new synthetic method of nitrogen heterocycles based on the 1,3-dipolar cycloaddition
reaction of nitrones to thienyl carbodiimide intermediate. Consequently, we examined the dipolarophilic behavior of
thienyl carbodiimide towards some C-aryl-N-phenyl nitrones. Moreover, the reactivity of thienyl carbodiimide
towards alcohols and secondary amines was investigated.
Interestingly, and to the best of our knowledge, new 1,2,4-oxadiazolidin-5-ylthiophene derivatives have been
synthesized for the first time by this route under the reaction conditions. Furthermore, new thienopyrimidine
derivatives, which are an important class of heterocycles for their expected biological importance, were obtained [10].
We have been engaged in a program to investigate the reactivity of carbodiimide towards nitrones, alcohols and
secondary amines with the aim of synthesizing new nitrogen heterocyclic compounds using aminothiophene ester 1.
The latter was prepared from ketene di(methylthio)acetal with ethyl thioglycolate [11]. Azidothiophene ester 2 was
prepared by reacting aminothiophene 1 with sodium nitrite and sodium azide. Refluxing compound 2 with one
E-mail address: afafabdelhamid1@yahoo.com.
1001-8417/$ – see front matter # 2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2011.12.017

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A.M.A. Hameed / Chinese Chemical Letters 23 (2012) 411–414
SH
NC
H3CS
NH2
CO2Et
NC
H3CS
N
PPh3
NC
H3CS
N3
CO2Et
NC
CN
NaNO2
NaN3
CO2Et
abs. EtOH
pip.
PPh3
dry tol.
CO2Et
MeS
SMe
S
1
S
S
2
3
dry benzene
PhNCO
Ph
Ph
N
H
N
O
Ar
O
Ar C N Ph
O
NC
MeS
N C
Ar
NC
N C NPh
CO2Et
N
Ph
NC
H3CS
N C NPh
CO2Et
H3CS
ref.2-6h
S
CO2Et
S
S
4
5a-c
Ar
5
a
P-OCH3-C6H4
P-CH3-C6H4
p-Cl-C6H4
b
c
Scheme 1.
equivalent of triphenylphosphine in dry toluene for 30 min yields ethyl 4-cyano-5-(methylthio)-3-triphenylpho-
sphinimino-thiophene-2-carboxylate (3) (Scheme 1).
Iminophosphorane derivative 3 underwent aza-Wittig type reaction with phenyl isocyanate to give highly reactive
carbodiimide intermediate 4, which underwent 1,3-dipolar cycloaddition reaction with nitrones in dry benzene at
refluxing temperature to afford new 1,2,4-oxadiazolidin-5-ylideneamino-5-(methylthio)thiophene derivatives 5a–c in
good yields (Scheme 1). The structures of 5a–c were identified by mass spectroscopy fragmentation pattern, which
showed a 1-(4-substituted phenyl)-N,N0-diphenylmethanediamine as the base peak. Elemental analysis and spectral
data provide further confirmation for the structure of 5a–c. The IR of the reaction products showed aromatic CH at n
3072–3100 cmꢀ1 and an ester CO group at n 1702–1704 cmꢀ1. The 1H NMR showed a singlet signal for the methine
protons at d 6.13–6.39 in addition to the aromatic protons. Furthermore, their structures were supported by 13C NMR
(see Section 1).
In order to extend the investigation of carbodiimide 4 reactivity, it was treated with ethyl alcohol, which afforded
several products depending on the reaction conditions. (Methylthio)thiophene 7 and ureidothiophene 8 were isolated
by treatment of 4 with absolute ethyl alcohol at room temperature. Reaction of 4 with absolute EtOH under refluxing
conditions gave 4-oxothienopyrimidine 9 and 2,4-dioxothienopyimidine 10 via intramolecular heterocyclization of 7
and 8 (Scheme 2). Moreover, the reaction of carbodiimide 4 with secondary amines in sodium ethoxide afforded 2-
aminothienopyrimdine derivatives 11a–c via intramolecular heterocyclization reaction in good yields (Scheme 2).
In conclusion we have developed an efficient and simple route for the synthesis of new 1,2,4-oxadiazolidin-5-
ylthiophene derivatives via a 1,3-dipolar cycloaddition reaction of nitrones with thienyl carbodiimide. To the best of
our knowledge, this is the first reported synthesis of 1,2,4-oxadiazolidin-5-ylthiophene derivatives via cycloaddition
reaction. Moreover, the reactivity of carbodiimide with alcohols and secondary amines interestingly afforded
thienopyrimidine derivatives.
1. Experimental
General procedure for the synthesis of compounds 5a–c: To a solution of 3 (0.250 g, 0.50 mmol), in dry benzene,
was added phenylisocyanate (0.600 g, 0.50 mmol). The reaction mixture was heated under reflux for 1 h. After cooling
the reaction mixture, nitrones (0.50 mmol) were added. The reaction mixture was heated under reflux for 2–6 h. After
concentration and cooling to room temperature, the resulting solid product was collected by filtration, washed well
with petroleum ether, dried and recrystallized from ethanol to give 5a–c. Ethyl 4-cyano-3-(3-(4-methoxyphenyl)-2,4-
diphenyl-1,2,4-oxadiazolidin-5-ylideneamino)-5(methylthio)thiophene-2-carboxylate (5a). Yellow crystals 0.255 g,
90% yield; mp 156–158 8C. IR (KBr): 3072 (arom. CH), 2976 (aliph. CH), 2224 (CN), 1702 (CO) cmꢀ1. 1H NMR

A.M.A. Hameed / Chinese Chemical Letters 23 (2012) 411–414
413
O
OEt
NC HN C
NC
N C
NHPh
NHPh
+
abs.EtOH
R.T.
H CS
C OEt
O
H CS
COOEt
3
3
S
S
7
8
NC
NC
H
N
N
O
OEt
O
PhNCO
abs. EtOH
reflux 1h
3
4
H CS
3
+
H CS
3
N
dry benzene
N
S
S
Ph
Ph
O
10
1
R
9
NC
R
1
HN
2
N
N
R
2
R
H CS
3
1
2
N
11
a
b
c
abs. EtOH
R
R
S
Ph
EtONa
morpholino
piperidino
4-methylpiperidino
O
11a-c
Scheme 2.
(DMSO-d6): d 0.98 (t, 3H, J = 6.9 Hz, CH3), 2.73 (s, 3H, SCH3), 3.74 (s, 3H, OCH3), 3.95 (q, 2H, J = 7.2 Hz, CH2),
6.39 (s, 1H, CH), 6.92 (d, 2H, ArH, J = 8.4 Hz), 7.05 (d, 2H, ArH, J = 8.4 Hz), 7.13 (m, 2H, ArH), 7.33-7.43 (m, 6H,
ArH), 7.64 (d, 2H, ArH, J = 8.4 Hz). 13C NMR (DMSO-d6): d 14.05 (CH3), 16.75 (SCH3), 54.77 (OCH3), 60.29
(OCH2), 100.25 (C-4), 101.38 (C-aryl) 105.43(C-2), 114.33 (CN), 120.63, 120.72, 122.04, 123.54, 124.44, 128.36,
128.92, 130.45, 138.04, 140.12, 143.51, 144.38 (Ar–C) 152.78 (C-3), 153.72 (C-5), 156.39(C N), 159.86 (CO). MS
(EI) m/z (%): 570 (M+, 96), 540 (39), 524 (2), 462 (2), 403 (2), 358 (19), 344 (1), 330 (15), 314 (4), 302 (90), 301 (100),
274 (1), 267 (24), 239 (10), 209 (75), 195 (23), 167 (6), 107 (2), 100 (1), 77 (2), 73 (16). Elem. Anal. Calcd. for
C30H26N4O4S2 (570.68): C, 63.14; H, 4.59; N, 9.82; S, 11.24. Found: C, 63.35; H, 4.72; N, 9.96; S, 11.47.
General procedure for the synthesis of compounds 7 and 8: To a solution of iminophosphorane 3 (0.250 g,
0.50 mmol), in dry benzene, was added phenylisocyanate (0.060 g, 0.50 mmol). The reaction mixture was heated
under reflux for 1 h. The solvent was removed under reduced pressure and absolute ethanol (10 mL) was added. The
reaction mixture was stirred for 15 min at room temperature. After concentration, the reaction mixture was dissolved
in acetone and then separated via preparative layer chromatography (PLC) using a suitable solvent mixture as eluent
(toluene: ethyl acetate = 10:1) to afford 7 and 8. Ethyl 4-cyano-3-(ethoxy(phenylamino)-methyleneamino)-5-
(methylthio)thiophene (7). Colourless crystals 0.105 g, 54% yield; mp 190–192 8C. IR (KBr): 3300 (NH), 3100 (arom.
1
CH), 2990–2930 (aliph. CH), 2228 (CN), 1702 (CO), 1635 (C N) cmꢀ1. H NMR (DMSO-d6): d 1.17 (t, 3H,
J = 6.9 Hz, CH3), 1.33 (t, 3H, J = 7.2 Hz, CH3), 2.84 (s, 3H, SCH3), 4.38 (q, 2H, J = 7.2 Hz, CH2), 4.44 (q, 2H,
J = 7.2 Hz, CH2), 7.35–7.52 (m, 5H, ArH), 7.54 (s, 1H, NH). 13C NMR (DMSO-d6): d 13.76 (CH3), 14.05 (CH3), 16.88
(SCH3), 54.73 (CH2), 60.28 (CH2), 100.25 (C-2), 105.43 (C-4), 113.35 (CN), 120.22. 120.62. 122.04, 123.54, 128.36,
138.04 (Ar-C), 152.98 (C-3), 153.70 (C-5), 159.86 (CO). MS (EI): m/z (%): 389 (M+, 8), 360 (30), 344 (2), 312 (3), 298
(15), 297 (5), 256 (12), 240 (9), 225 (16), 223 (61), 214 (5), 197 (12), 164 (5), 135 (25), 119 (97), 104 (11), 92 (28), 77
(100), 72 (8), 58 (18). Elem. Anal. Calcd. for C18H19N3O3S2 (389.49): C, 55.51; H, 4.92; N, 10.79; S, 16.47. Found: C,
55.32; H, 5.12; N, 10.94; S, 16.21. Ethyl 4-cyano-(methylthio)-3-(3-phenylureidothiophene)-2-carboxylate (8).
Colourless crystals 0.050 g, 28% yield; mp 210–212 8C. IR (KBr): 3340 (NH), 3100 (arom. CH), 2990–2930 (aliph.
CH), 2228 (CN), 1702 (CO), 1680 (CO) 1635 (C N) cmꢀ1. 1H NMR (DMSO-d6): d 1.18 (t, 3H, J = 6.9 Hz, CH3),
2.71 (s, 3H, SCH3), 4.13 (q, 2H, J = 7.2 Hz, CH2), 6.99–7.26 (m, 5H, ArH), 8.71 (s, 1H, NH), 10.70 (s, 1H, NH). 13
C
NMR (DMSO-d6): d 14.08 (CH3), 16.74 (SCH3), 54.70 (OCH2), 98.13 (C-4), 104.52 (C-2), 115.35 (CN), 120.22,
122.04, 123.54, 128.36, 138.04 (arom. C), 150.58 (C-3), 151.64 (C-5), 158.49 (CO), 160.89 (CO). MS (EI): m/z (%):
361 (M+, 85), 316 (5), 288 (15), 269 (20), 225 (45), 209 (11), 164 (15), 135 (45), 119 (30), 104 (5), 92 (10), 77 (100), 72
(4). Elem. Anal. Calcd. for C16H15N3O3S2 (361.44): C, 53.17; H, 4.18; N, 11.63; S, 17.74. Found: C, 53.29; H, 4.31; N,
11.43; S, 17.92.
General procedure for the synthesis of compounds 9 and 10: To a solution of iminophosphorane 3 (0.250 g,
0.50 mmol), in dry benzene, was added phenylisocyanate (0.060 g, 0.50 mmol). The reaction mixture was heated

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A.M.A. Hameed / Chinese Chemical Letters 23 (2012) 411–414
under reflux for 1 h. The solvent was removed under reduced pressure and absolute ethanol (10 mL) was added. The
reaction mixture was heated for 1 h. After cooling and concentration, the reaction mixture was dissolved in acetone
and then separated via preparative layer chromatography (PLC) using a suitable solvent mixture as eluent
(toluene:ethyl acetate = 10:2) to afford 9 and 10. 2-Ethoxy-6-(methylthio)-4-oxo-3-phenyl-3,4-dihydrothieno[3,2-
d]pyrimidine-7-carbonitrile (9). Colourless crystals 0.094 g, 55% yield; mp 200–202 8C. IR (KBr): (arom. CH),
2990–2930 (aliph. CH), 2228 (CN), 1690 (CO) cmꢀ1. 1H NMR (DMSO-d6): d 1.28 (t, 3H, J = 6.9 Hz, CH3), 2.68 (s,
3H, SCH3), 4.45 (q, 2H, J = 7.2 Hz, CH2), 7.23–8.12 (m, 5H, ArH). 13C NMR (DMSO-d6): d 13.66 (CH3), 17.31
(SCH3), 65.45 (CH2), 101.83 (C-7), 112.18 (C4-a), 114.01 (CN), 128.22, 128.70, 128.91, 134.32 (arom. C), 154.98 (C-
7a), 155.70 (C-2), 156.08 (C-6), 162.91 (CO). MS (EI): m/z (%): 343 (M+, 66), 328 (4), 315 (45), 382 (4) 276 (11), 262
(14), 231 (12), 183 (100), 177 (71). Elem. Anal. Calcd. for C16H13N3O2S2 (343.42): C, 55.96; H, 3.82; N. 12.24; S,
18.67. Found: C, 55.74; H, 3.69; N, 12.45; S, 18.87. 6-(Methylthio)-2,4-dioxo-3-phenyl-1,2,3,4-tetra-hydrothieno[3,2-
d]pyrimidine-7-carbonitrile (10). Colourless crystals 0.055 g, 35% yield; mp 180–182 8C. IR (KBr): (arom. CH),
2990–2930 (aliph. CH), 2224 (CN), 1690 (CO), 1645 (CO) cmꢀ1. 1H NMR (DMSO-d6): d 2.83 (s, 3H, SCH3), 7.35–
7.54 (m, 5H, ArH), 11.35 (s, 1H, NH). 13C NMR (DMSO-d6): d 17.35 (SCH3), 102.92 (C-7), 107.21 (C-4a), 116.01
(CN), 128.45. 128.56, 128.93, 138.05 (arom. C), 151.92 (C-7a), 156.39 (C-6), 159.75 (CO), 162.91 (CO). MS (EI): m/z
(%): 315 (M+, 78), 237 (15), 223 (20), 162 (78), 77 (15), 56 (100), 55 (78). Elem. Anal. Calcd. for C14H9N3O2S2
(315.37): C, 53.32; H, 2.88; N, 13.32; S, 20.33. Found: C, 55.74; H, 3.01; N, 12.74; S, 20.59.
General procedure for the synthesis of compounds 11a–c: To a solution of 3 (0.250 g, 0.50 mmol), in dry benzene
(10 mL), was added phenylisocyanate (60 mg, 0.50 mmol). The reaction mixture was heated under reflux for 1 h.
After cooling the reaction mixture, secondary amines (0.50 mmol) were added. The reaction mixture was heated under
reflux for 1 h. The solvent was removed under reduced pressure and sodium ethoxide (0.012 g, 0.50 mmol of Na in
10 mL abs. EtOH) was added. The reaction mixture was stirred for 5–10 min at room temperature. The resulting solid
products was collected by filtration, washed from methanol, dried and recrystallized from ethanol to afford 11a–c. 6-
(Methylthio)-2-morpholino-4-oxo-3-phenyl-3,4-dihydrothieno[3,2-d]pyrimidine-7-carbonitrile (11a). Colourless
1
crystals 0.165 g, 86% yield; mp 200–202 8C, IR (KBr): 2990, 2850 (aliph. CH), 2228 (CN), 1676 (CO) cmꢀ1. H
NMR (DMSO-d6): d 2.83 (s, 3H, SCH3), 3.06-3.09 (m, 4H, NCH2), 3.29–3.31 (m, 4H, OCH2), 7.45–7.56 (m, 5H,
arom. H). MS (EI) m/z (%): 383 (MꢀH)+ (9), 384 (M+, 17), 307 (18), 300 (14), 293 (18), 281 (2), 267 (14), 263 (10),
197 (68), 183 (3), 171 (8), 162 (12), 131 (6), 122 (2), 91 (21), 84 (7), 77 (100), 72 (3). Elem. Anal. Calcd. for
C18H16N4O2S2 (384.48): C, 56.23; H, 4.19; N, 14.57; S, 16.68. Found: C, 56.54; H, 4.43; N, 14.74; S, 16.82.
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