Synthesis and heterocyclization of 5-amino-4-cyano-1, 3-oxazoles

Article abstract of DOI:10.14233/ajchem.2013.14633

A convenient one-pot method for synthesis of some new oxazolo[5,4-d] pyrimidines via base catalyzed heterocyclization of 2-substituted 5-amino-4-cyano-1,3-oxazoles with various isothiocyanates is described.

Full text of DOI:10.14233/ajchem.2013.14633

Asian Journal of Chemistry; Vol. 25, No. 9 (2013), 5079-5083
http://dx.doi.org/10.14233/ajchem.2013.14633
Synthesis and Heterocyclization of 5-Amino-4-cyano-1, 3-oxazoles
1,*
2
2
2
MEHDI BAKAVOLI , AHMAD NIKSERESHT , JALIL LARI and HOOSHANG VAHEDI
1Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran
2Department of Chemistry, Payame Noor, University, 19395-4697 Tehran, Iran
*Corresponding author: Fax: +98 511 8796416; Tel: +98 511 8797022; E-mail: mbakavoli@yahoo.com
(Received: 29 September 2012;
Accepted: 20 March 2013)
AJC-13142
A convenient one-pot method for synthesis of some new oxazolo[5,4-d]pyrimidines via base catalyzed heterocyclization of 2-substituted
5-amino-4-cyano-1,3-oxazoles with various isothiocyanates is described.
Key Words: Oxazolopyrimidine, Heterocyclization, Isothiocyanate, Amino malononitrile tosylate, 1,4-Diazabicyclo[2,2,2]octane.
510 and are uncorrected. IR spectra were obtained on a Bruker
Alpha-P FTIR DiamondATR spectrophotometer 1H NMR and
13C NMR spectra were recorded with a Bruker 400 spectro-
meter, using tetrmethylsilane as internal standard. All the
assignments for proton and carbon were made via 2D COSY,
HSQC and HMBC experiments. High-resolution mass spectra
were obtained by a thermo scientific exactive high resolution
MS (ESI probe).
INTRODUCTION
Oxazoles continue to hold a center stage in organic
synthesis, although the structure of the first oxazole was
reported over a century ago. This is evidenced by the continued
growth in the number of research publications and reviews1.
1,3-Oxazole derivatives are heterocyclic ring system present
in a number of natural products, should this be medicine and
materials or synthetic products endowed with interesting
pharmacological or physical properties2. They also elicit a
variety of biological responses3, including anti-cancer and
anti-HIV/AIDS activity4. Annulated 1,3-oxazoles such as
oxazolopyrimi-dines have also been reported to exhibit a host
of biological activities such as inhibitors of receptor tyrosine
kinases (RTK)5 and A2A adenosine receptor antagonists6. In
pursuing our efforts towards the synthesis of bioactive hetero-
cycles7 in this communication we wish to present a convenient
and versatile method for the synthesis of some new 7-amino-
2,6-disubstituted-oxazolo[5,4-d]pyrimidine-5(4H)-thiones
through cyclocondensation of 1,3-oxazoles with various aryl
and alkylisothiocyanates.
Synthesis of 2-substituted-5-amino-4-cyano-1,3-
oxazoles (1-4): According to Freeman and Kim8b, to a stirred
solution of aminomalononitrile tosylate, (2.71 g, 8.60 mmol) in
1-methyl-2-pyrrolidinone (28 mL), were added 1.0-1.4 equiv
(depending on the case) of the corresponding acid chloride in
one portion. The reaction mixture was stirred at room temperature
until the reaction was complete. Then, the mixture was diluted
with a mixture of EtOAc and Et2O (1:1) and washed with water,
10 % aqueous NaHCO3 and water. The organic layer was dried,
the solvent was evaporated in vacuo and the crude product was
purified by flash silica gel chromatography (PE/EtOAc). The
1,3-oxazoles were recrystallized from Et2O/EtOAc.
5-Amino-4-cyano-2-methyl-1,3-oxazole (1): Amino-
malononitrile tosylate (1.17 g, 4.6 mmol), 1-methyl-2-pyrro-
lidinone (10 mL) and acetyl chloride 1 equiv, were reacted at
room temperature for 8 days. Work up (EtOAc: Et2O, 1:1) and
flash silica gel chromatography (1:1, hexanes: EtOAc) afforded
compound (1).Yield (57 %) as a yellow solid: m.p. 150-153 ºC;
IR νmax 3305, 3259, 2922, 2850, 2212, 1428, 1659, 1093
cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 7.51 (br s, NH2, 2 H),
2.21 (s, CH3, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 162.59
(C5), 150.14 (C2), 116.05 (CN), 82.57 (C4), 13.42 (CH3); HR
MS: m/z calcd. for C5H4N3O (M-H+) 122.0360, found
122.0349.
EXPERIMENTAL
Reactions were monitored by TLC using precoated silica
gel aluminum plates. Detection was done by UV (254 nm)
followed by dipping in either sulfuric acid in EtOH (10 %) or
0.5 % phosphomolybdic acid in 95 % EtOH solutions and
subsequent charring at 200 ºC or dipping in a 1 % aqueous
potassium permanganate solution and air drying. Anhydrous
MgSO4 was used to dry organic solutions during work up and
the removal of solvents was carried out under vacuum with a
rotary evaporator. Melting points were determined on a Buchi

5080 Bakavoli et al.
Asian J. Chem.
5-Amino-4-cyano-2-(4-nitrophenyl)-1, 3-oxazole (2).
Amino malononitrile tosylate (2.71 g, 8.60 mmol), 1-methyl-
2-pyrrolidinone (28 mL) and p-nitrophenyl benzoyl chloride
1.1 equiv, were reacted at room temperature for 7 days. Work
up and flash chromatography (PE:EtOAc, 1:1) rendered
compound (2), Yield (90 %) as yellow crystals: m.p. 274-
277 ºC; IR νmax 3285, 3227, 2221, 1668, 1597, 1514, 1319,
1057, 852 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (br s,
NH2, 2H), 8.33 (d, H2', H6', 2 H), 7.95 (d, H3', H5', 2 H); 13C
NMR (DMSO-d6, 100 MHz) δ 162.8 (C5), 147.47 (2C,C2,
C4'), 131.27 (C1'), 125.74 (2C, C2', C6'), 124.50 (2C, C3',
C5'), 114.87 (CN), 85.54 (C4); HR MS: m/z calcd. for
C10H5N4O3 (M-H+) 229.0362, found 229.0360.
131.5 (C3'), 130.5 (C4'), 130.3 (C6'), 128.4 (C5'), 115.3 (CN),
94.5 (C2'), 84.04 (C4); HR MS: m/z calcd. for C10H5N3O I(M-
H+) 309.9483, found 309.9479.
5-Amino-2-benzhydryl-4-cyano-1,3-oxazole (6):Amino
malononitrile tosylate (2.13 g, 8.6 mmol), pyridine (41 mL),
diphenylacetic acid (1.79 g, 8.34 mmol) and DCC (1.77 g, 8.6
mmol) were reacted at room temperature for 5 days. Work up
and flash chromatography (1:1, EtOAc/PE) gave compound
(6) (71 % yield). White crystals; m.p. 163-166; IR νmax 3341,
3310, 3139, 2923, 2852, 2220,1660, 1591, 1158, 696, 744
cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 7.70 (br s, NH2, 2H),
7.2-7.4 (m, 10 Harom.), 5.59 (s, CH, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 162.34 (C5), 152.65 (C2), 139.49 (2 C, 2C1'),
128.55 (4 C, 2C3', 2C5'), 128.44 (4 C, 2C2', 2C6'), 127.13 (2
C, 2C4'), 115.44 (CN), 82.52 (C4), 49.23 (CH); HR MS: m/z
calcd. for C17H12N3O (M-H+) 274.0986, found 274.0981 and
m/z calcd. for C17H14N3O (MH+) 276.1131, found 276.1131.
N-(9-(2-(5-amino-4-cyano-oxazol-2-yl)phenyl)-6-
(diethylamino)-3H-xanthen-3-ylidene)-N-ethylethana-
minium chloride (7): Amino malononitrile tosylate (1.40 g,
5.5 mmol), pyridine (25 mL), Rhodamin B (2.5 g, 5 mmol)
and DCC (1.13 g, 5.5 mmol) were reacted at room temperature
for 7 days. Work up and flash chromatography (1:3, EtOAc/
PE) gave compound (7) (47 % yield). Purple crystals; m.p.
298-300 ºC; IR νmax 3392, 3324, 2927, 2850, 2219, 1625, 1046
cm-1; 1H NMR (CDCl3, 400 MHz) δ 8.22 (q, H3', 1 H), 7.65
(m, H4', H5', H6', 3 H), 7.15 (t, H8, 1 H), 7.05 (d, H7, 1H),
7.03 (s, H5, 1 H), 7.01 (br s, NH2, 2 H), 6.72 (d, H2, 1H), 6.70
(d, H1, 1H), 6.67 (d, H4, 1H); 13C NMR (DMSO-d6 and CDCl3,
100 MHz) δ 167.8 (C5''), 159.35 (C10a), 157.71 (C6), 155.24
(C4a), 142.04 (C3), 139.84 (C9), 133.56 (C1'), 132.96 (C1),
131.71 (C5'), 131.52 (C9a), 131.15 (C4'), 130.07 (C8), 129.41
(C3'), 128.51 (C4''), 125.71 (C6'), 113.59 (CN), 113.46 (C2),
95.95 (2 C, C4, C5), 45.74 (CH2), 13.83 (CH3); HR MS: m/z
calcd. for C31H32N5O2 MH+ 506.2551, found 506.2548 and
m/z calcd. for C31H30N5O2 M-H+ 504.2400, found 504.2400.
Synthesis of oxazolo[5, 4-d]pyrimidine-5(4H)-thiones
(8-14): To a solution of 1,4-diazabicyclo[2,2,2]octane
(DABCO) (1.5 equiv) in dry DMF (5 mL) under Argon, the
corresponding aryl- and alkylisothiocyanates (1.5 equiv) and
the oxazole were added. The mixture was reacted at 120 ºC
until the reaction was complete. Then, water and a solution of
HCl (1 M) were added until PH 9. Then, the precipitate was
filtered off and purified.
5-Amino-4-cyano-2-phenyl-1,3-oxazole (3): Amino-
malononitrile tosylate (1.17 g, 4.6 mmol), 1-methyl-2-pyrro-
lidinone (10 mL) and benzoyl chloride 1.4 equiv, were
reacted at room temperature for 8 days. Work up and flash
chromatography (6:4, CH2Cl2: EtOAc) afforded compound (3),
(67 %, yield) and compound(4) (7 %, yield). 5-Amino-4-
cyano-2-phenyl-1,3-oxazole (3): Yellow solid; m.p. 240-
244 ºC; IR νmax 3314, 3273, 2207, 1650, 1600, 1052.2 cm -1;
1H NMR (DMSO-d6, 400 MHz) δ 7.95 (br s, NH2, 2H), 7.75
(dd, H2', H6', 2 H), 7.49 (m, H3', H4', H5', 3 H); 13C NMR
(DMSO-d6, 100 MHz) δ 162.42 (C5), 149.50 (C2), 130.11
(C4'), 129.24 (2C, C3', C5'), 126.08 (C1'), 125.49 (2C, C2',
C6'), 115.49 (CN), 85.34 (C4); HR MS: m/z calcd. for
C10H6N3O (M-H+) 184.0516, found 184.0509.
5-Amino-4-cyano-2-(phenylamino)-1,3-oxazole (4):
Withe crystals; m.p. 240-243 ºC; IR νmax 3220, 3062, 1687,
2240, 1599, 1490, 1063, 769 cm-1; 1H NMR (DMSO-d6, 400
MHz) δ 12.40 (br s, NH, 1 H), 8.1 (m, H2', H6', 2 H), 7.95 (m,
H2', H6', 2H), 7.70 (m, H4'', 1H), 7.60 (m, H3', H4', H5', H3'',
H5'', 5H); 13C NMR (DMSO-d6, 100 MHz) δ 164.8 (C5), 155.1
(C1'), 151.6 (C2), 133.6 (C1'), 132.1 (C4'), 129.9 (2C, C3'',
C5''), 129.2 (2C, C3', C5'), 128.8 (2C, C2', C6'), 126.5 (2C,
C2'', C6''), 113.8 (CN), 100.4 (C4), 125.6 (C4''); HR MS: m/z
calcd. for C17H10N3O2 (M-H+) 288.0779, found 288.0778.
Synthesis of 2-substituted-5-amino-4-cyano-1,3-
oxazoles (5-7): According to Freeman and Chen4, to a stirred
solution of amino malononitrile tosylate (2.66 g, 10.5 mmol)
in pyridine (50 mL) was added the corresponding carboxylic
acid (10 mmol) and 1,3-dicyclohexylcarbodiimide (DCC)
(2.16 g, 10.5 mmol) and the reaction mixture was stirred at
room temperature until the reaction was complete. The white
precipitate (dicyclohexylurea) was removed by filtration and
the filtrate was concentrated in vacuo to give a residue, which
was purified by flash silica gel chromatography (1:1, PE/
EtOAc) to give product. 1, 3-Oxazoles were crystallized from
Et2O/EtOAc.
7-Amino-2-benzhydryl-6-(4-methoxyphenyl)-oxazolo
[5,4-d]pyrimidine-5(4H)-thione (8): DABCO (266 mg, 2.3
mmol) in DMF dry (3 mL) was reacted with p-methoxy-
phenylisothiocyanate (270 µL, 1.9 mmol) and oxazole (6) (551
mg, 2 mmol). The mixture was reacted at 120 ºC for overnight.
Then, participate was filtered and was purified by flash
chromatography (3:1, PE: EtOAc) to give compound (8) (71
% yield): White crystals; m.p. 273-276 ºC; IR νmax 3392, 3330,
5-Amino-4-cyano-2-(2-iodophenyl)-1,3-oxazole (5):
Amino malononitrile tosylate (2.66 g, 10.5 mmol), pyridine
(50 mL), 2-iodobenzoic acid (2.53 g, 10 mmol) and DCC (2.16
g, 10.5 mmol) were reacted at room temperature for 4 days.
Work up and flash chromatography (1:1, EtOAc/Et2O) gave
compound (5) (56 % yield). Yellow crystals; m.p. 170-172
ºC; IR νmax 3389, 3321, 3277, 2214, 1658, 1002, 762 cm-1; 1H
NMR (DMSO-d6, 400 MHz) δ 8.03 (dd, H3, 1 H), 7.95 (br s,
NH2, 2 H), 7.50 (ddd, H4', 1H), 7.20 (ddd, H5', 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 162.4 (C5), 148.75 (C2), 140.9 (C1'),
1
2954, 2852, 1692, 1509, 1257, 693, 738 cm-1; H NMR
(DMSO-d6, 400 MHz) δ 9.90 (br s, NH2, 2 H), 7.46 (m, 2 H4',
2H), 7.31 (m, 2H3', 2H5', 4H), 7.23 (m, 2H2', 2H6', 4H), 7.15
(m, H3'', H5'', 2H), 6.73 (d, H2'', H6'', 2H), 5.06 (s, CH, 1H),
3.68 (s, CH3, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 170.27
(C5), 158.9 (C2), 154.5 (C3a), 150.5 (2 C, C7, C4''), 114 (C7a),
140.4 and 140.2 (2 C, 2C1'), 131 (2 C, C2'', C6''), 129 (4C,

Vol. 25, No. 9 (2013)
Synthesis and Heterocyclization of 5-Amino-4-cyano-1, 3-oxazoles 5081
2C3', 2C5'), 128.4 (4 C, 2 C2', 2 C6'), 128.5 (C1''), 127 (2C,
2C4'), 110.86 (2C, C3'', C5''), 55 (CH3), 50 (CH); HR MS: m/z
calcd. for C25H21N4O2S MH+ 441.1380, found 441.1379 and
m/z calcd. for C25H19N4O2S M-H+ 439.1223, found 439.1226.
7-Amino-6-(4-methoxyphenyl)-2-(4-nitrophenyl)-
oxazolo[5,4-d]pyrimidine-5(4H)-thione (9): DABCO (318
mg, 2.75 mmol) in DMF dry (5 mL) was reacted with p-
methoxyphenylisothiocyanate (468 µL, 2.75 mmol) and
oxazole (2) (575 mg, 2.5 mmol). The mixture was reacted at
120 ºC for overnight. Then, participate was filtered and
recrystallized in EtOH, provided compound (9) (69 % yield):
Yellow crystals; m.p. > 300 ºC; IR νmax 3391, 3328, 2932,
7-Amino-6-hexyl-2-(4-nitrophenyl)-oxazolo[5,4-
d]pyrimidine-5(4H)-thione(12): DABCO (290 mg, 2.5
mmol) in DMF dry (5 mL) was reacted with hexylisothio-
cyanate (330 µL, 2.4 mmol) and oxazole (2) (575 mg, 2.5
mmol). The mixture was reacted at 120 ºC under Argon for
overnight. Then, participate was filtered and recrystallized in
EtOH to give compound (12) (58 % yield ): Red crystals; m.p.
220-223 ºC; IR νmax 3379, 3297, 2925, 2854, 1622, 1551, 1336,
1275, 852 cm-1; 1H NMR(CDCl3, 400 MHz) δ 0.92 (m, 3H6'',
3H), 1.36 (m, 2H3'', 2H4'', 2H5'', 6H), 1.71 (m, 2H2'', 2H), 4
(br s, NH2, 2H), 3.93 (m, 2 H1'', 2H), 8.13-8.41 (m, 4Harom.);
13C NMR (CDCl3, 100 MHz) δ 166 (C5), 159.6 (C3a), 155.27
(C2), 149.3 (C4'), 148.4 (C7),127.8 (C1'), 126.8 (2C, C2', C6'),
124.2 (2C, C3', C5'), 52.9 (C1''), 31.7 (C4''), 31.6 (C2''), 26.7
(C3''), 22.7 (C5''), 14.1 (C6''); HR MS: m/z calcd. for
C17H20O3N5S MH+ 374.1281, found 374.1276 and m/z calcd.
for C17H18N5O3S M-H+ 372.1136, found 372.1131.
1
2834, 1622, 1599, 1292, 1040, 854 cm-1; H NMR (DMSO-
d6, 400 MHz) δ 10.0 (br s, NH2, 2H), 8.42 (m, H3', H5', 2H),
8.23-8.34 (m, H2', H6', 2H), 7.7 (m, H3'', H5'', 2 H), 6.93 (m,
H2'', H6'', 2H), 3.7 (s, CH3, 3H); 13C NMR (DMSO-d6, 100
MHz) δ 162.8 (C5), 158.5 (C2), 156.5 (C3a), 147.46 (C4''),
147.42 (C7), 132.2 (C4'), 131.3 (C1'), 127.23 (2C, C2', C6'),
126 (2C, C2', C6'), 125.6 (C1''), 124.4 (2 C, C3', C5'), 115.04
(2C, C3', C5'), 115.04 (C7a), 55.4 (CH3); HR MS: m/z calcd.
for C18H14O4N5S MH+ 396.0761 found 396.0758 and m/z calcd.
for C18H12N5O4S M-H+ 394.0616, found 394.0609.
7-Amino-6-cyclohexyl-2-(4-nitrophenyl)-oxazolo[5,4-
d]pyrimidine-5(4H)-thione (13): DABCO (290 mg, 2.5
mmol) in DMF dry (5 mL) was reacted with cyclohexylisothio-
cyanate (338 µL, 2.4 mmol) and oxazole (2) (575 mg, 2.5
mmol). The mixture was reacted at 120 ºC under argon for 2
days. Then, participate was filtered and recrystallized in EtOH
to provided compound (13) (77 % yield): Brown crystals; m.p.
239-241 ºC; IR νmax 3402, 3379, 2927, 2851, 1620, 1517, 1337,
1273, 853 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.29-1.47 (m,
2H3'', 2H5'', 4H), 1.59-1.81 (m, 1H2'', 2H4'', 1H6'', 4H), 2.04-
2.16 (m, 1H2'', 1H6'', 2H), 4.2 (br s, NH2, 2H), 8.18-8.36 (m,
4 Harom.); 13C NMR (CDCl3, 100 MHz) δ 165.2 (C5), 162.7
(C2), 159.7 (C3a), 148.3 (C7), 149.1 (C4'), 132.2 (C1'), 126.7
(2C, C2', C4'), 124.2 (2C, C3', C5'), 57.8 (C1''), 33.1 (2C, C2'',
C6''), 25.6 (C4''), 24.9 (2C, C3'', C5''); HR MS: m/z calcd. for
C17H18N5O3S MH+ 372.1125, found 372.1129 and m/z calcd.
for C17H16O3N5S M-H+ 370.0968, found 370.0974.
7-Amino-2-(2-iodophenyl)-6-(4-methoxyphenyl)-
oxazolo[5,4-d]pyrimidine-5(4H)-thione (10): DABCO (213
mg, 2 mmol) in DMF dry (5 mL) was reacted with p-
methoxyphenylisothiocyanate (270 µL, 1.9 mmol) and oxazole
(5) (622 mg, 2 mmol). The mixture was reacted at 120 ºC
under Argon for overnight. Then participate was filtered and
purified by flash chromatography (1:1, PE/EtOAc), provided
compound (10). (60 % yield): Brown crystals; m.p. 247-251
ºC; IR νmax 3390, 3301, 2930, 2833, 1616, 1580, 1242, 763
cm-1; 1H NMR (DMSO-d6, 400 MHz) δ 9.81 (br s, NH2, 2H),
8.10 (ddd, H3', 1H), 7.86 (ddd, H4', 1H), 7.57-7.70 (m, H5',
H6', 2H), 7.29-7.39 (m, H3'', H5'', 2H), 6.90-6.95 (dd, H2'',
H6'', 2H), 3.75 (s, CH3, 3H); 13C NMR (DMSO-d6, 100 MHz)
δ 166.6 (C5), 158.9 (C3a), 155.98 (C4''), 155.26 (C7), 140.62
(C1'), 140.58 (C3'), 132.26 (2C, C2'', C6''), 132.14 (C4'),
131.78 (C5'), 128.4 (C6'), 128.48 (C1''), 113.65 (2C, C3'', C5''),
113.74 (C7a), 95.6 (C2'), 55.2 (CH3); HR MS: m/z calcd. for
C18H12N4O2IS M-H+ 474.9731, found 474.9718.
7-Amino-6-[3,5-bis-(trifluoromethyl)phenyl]-2-(4-
nitrophenyl)-oxazolo[5,4-d]pyrimidine-5(4H)-thione (14):
DABCO (290 mg, 2.5 mmol) in DMF dry (5 mL) was reacted
with 3,5-bis-(trifluoromethyl)phenylisothiocyanate (424 µL,
2.3 mmol) and oxazole (2) (575 mg, 2.5 mmol). The mixture
was reacted at 120 ºC under argon for 2 days. Then, participate
was filtered and purified by flash chromatography (1:1, PE/
EtOAc) to provided compound (14) (57 % yield): m.p. >300
ºC; IR νmax 3415, 3355, 3117, 1633, 1592, 1516, 1341, 1274,
7-Amino-6-(3-chlorophenyl)-2-(4-nitrophenyl)-
oxazolo[5,4-d]pyrimidine-5(4H)-thione (11): DABCO (213
mg, 2 mmol) in DMF dry (5 mL) was reacted with m-
chlorophenylisothiocyanate (258 µL, 1.8 mmol) and oxazole
(2) (460 mg, 2 mmol). The mixture was reacted at 120 ºC
under argon for overnight. Then, participate was filtered and
recrystallized with EtOH to give compound (11) (54 % yield):
Yellow crystals; m.p. 242-244 ºC; IR νmax 3374, 3325, 1620,
1
1095, 1125, 937, 881, 854 cm-1; H NMR (DMSO-d6 and
CDCl3, 400 MHz) δ 8.53 (d, H3', H5', 2H), 8.3 (d, H2', H6',
2H), 8.2 (s, H4'', 1H), 7.84 (s, H2'', H6'', 2H), 5.47 (br s, NH2,
2H); 13C NMR (DMSO-d6, 100 MHz) δ 166.1 (C5), 164.5
(C2), 158.7 (C3a), 153.3 (C4'), 140.6 (C7), 140.1 (C1'), 132.8
(C1''), 132.7 (2C, C2'', C6''), 129.9 (C3''), 129.8 (C5''), 126.8
(2C, C2', C6'), 124.3 (2C, C3', C5'), 120 (C4''), 120.3 (2C,
CF3), 120.17 (C7a); HR MS: m/z calcd. for C19H8N5O3SF6
M-H+ 500.0258, found 500.0250.
1
1548, 1338, 1308, 1105, 853, 898,776, 679 cm-1; H NMR
(DMSO-d6, 400 MHz) δ 8.24-8.44 (m, H3', H5', 2 H), 8.02-
8.1 (m, H5'', 1H), 7.74-7.82 (m, H2', H6', 2H), 7.34-7.39 (m,
H4'', 1H), 7.10-7.12 (m, H2'', 1H), 6.67-6.71 (m, H6'', 1H),
6.03 (br s, NH2, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 179.5
(C5), 162.8 (C2), 147.4 (C3a), 147.3 (C7), 140.8 (C4'), 135.3
(C1'), 133.9 (C1'), 132.6 (C3''), 131.5 (C5''), 131.2 (2 C, C2',
C6'), 129.9 (C4''), 127.8 (2 C, C3', C5'), 122.9 (C6''), 121.8
(C2''); HR Ms: m/z calcd. for C17H9N5O3ClS M-H+ 398.0120,
found 398.0114.
RESULTS AND DISCUSSION
Two major routes for the synthesis of 1,3-oxazole deriva-
tives has been previously reported4,8. Consequently, a solution
of aminomalononitrile tosylate in 1-methyl-2-pyrrolidinone
was reacted with various aryl or alkyl acid chlorides at room
temperature (Scheme-I).

5082 Bakavoli et al.
Asian J. Chem.
the investigated reaction took around 18 h to reach completion,
under Argon and with excess of catalyst (DABCO).
The structures of these compounds have been confirmed
by spectroscopic analysis (see experimental). For example,
the IR spectrum of compound (8) was devoid of the stretching
vibration bands at 3341, 3310 and 2220 cm-1 for NH2 and CN
CN
1) R = CH3; 2) R = 4-NO2-C6H4; 3) R = C6H5
Scheme-I: Synthesis of the 2-substituted-5-amino-4-cyano-1,3-oxazoles (1-3)
H
O
DCC
N
H2N
CN
Pyridine
R
NH2
The standard procedure worked especially well in yield-
ing the desired products (1-3) in moderate yield, although long
reaction times (around 7 days) were required. In other
circumstances, we were forced to employ an excess of the
acid chloride since no reaction was observed when employing
a 1.4 equiv. of the reagent, but under these conditions,
by-products were formed which substantially lowered the yield
of the target product (3). Concerning the undesirable by-
products, we have isolated the 2-phenyl-5-(phenylamino)-
oxazole-4-carbonitrile (4) (in 7 % yield) (Scheme-II).
OH
CN
R
O
5) R = 2-I-C6H4 7) R =
6) R = CH(Ph)2
N
O
N
Scheme-III: Synthesis of the 2-substituted-5-amino-4-cyano-1,3-oxazoles
(5, 6 and7)
Scheme-II: Synthesis of the N-acylated-5-amino-4-cyano-1,3-oxazole (by
product 4)
Fig. 1. 13C NMR (DMSO-d6, 400 MHz) data of the 2-alkyl(2-aryl)oxazolo
derivatives
For the other procedure used to synthesize 5, 6 and 7, we
employed aminomalononitrile tosylate in pyridine with carbo-
xylic acids at room temperature4. The carboxyl activating
reagent, 1,3-dicyclohexylcarbodiimide, was used to synthesize
compounds 5, 6 and 7 (Scheme-III). All new compounds
communicated in this work showed good analytical and
spectroscopic data (see experimental). Furthermore, the 13C
NMR spectra (Fig. 1) have been assigned via HMBC and
HSQC experiments and are in good agreement with those
previously reported for other 1,3-oxazoles9. Cyclocondensation
was carried out with these precursors by employing 1,4-
diazabicyclo[2,2,2]octane (DABCO) under argon using aryl
and alkylisothiocyanates (Scheme-IV). Under these conditions,
the reaction with 1,3-oxazoles (2, 5 and 6) afforded the fore-
casted products (8-14) in moderate to good yields. In total,
absorption of the precursor but instead showed new absor-
ption bands at 3392, 3330 1692 and 1257 cm-1 for NH2, C=N
and C=S groups, respectively. The 1H NMR spectra in DMSO-
d6 showed two broad singlets at 9.90 and 5.06 due to NH2 and
CH groups respectively, as well as a singlet 3.68 correspon-
ding to methyl group and the characteristic signals at 7.14-7.48
for phenyl groups. High resolution mass spectra of the com-
pound (8) showed the molecular ion peak at m/z 441.1379 and
439.1226 corresponding to the MH+ and M-H+, respectively.
ACKNOWLEDGEMENTS
This work is dedicated to Professor Han Zuilhof and Dr.
Tom Wennekes of the Laboratory of Organic Chemistry at
Wageningen University for partial support of this research.
NH2
R2NCS
DMF, dry
under Ar, 120 ºC
NH2
8 R1 = (Ph)2CII,
9 R1 = 4-NO2-C6H4,
10 R1 = 2-I-C6H4,
R2 = 4-MeO-C6H4 (71 %)
R2 = 4-MeO-C6H4 (69 %)
R2 = 4-MeO-C6H4 (60 %)
R2 = 4-Meo-C6H4
3-Cl-C6H4
Cyclohexyl
2 R1 = 4-NO2-C6H4
3 R1 = 2-I-C6H4
4 R1 = (Ph)2CH
11 R1 = 4-NO2-C6H4, R2 = 3-Cl-C6H4 (54 %)
12 R1 = 4-NO2-C6H4, R2 = Hexyl (58 %)
3,5-Bis(CF)3-C6H3
Hexyl
13 R1 = 4-NO2-C6H4,
14 R1 = 4-NO2-C6H4,
R2 = Cyclohexyl (77 %)
R2 = 3,5-Bis(CF)3-C6H3 (57%)
Scheme-IV: Synthesis of the oxazolo [5,4-d]pyrimidine analogues (8-14)

Vol. 25, No. 9 (2013)
Synthesis and Heterocyclization of 5-Amino-4-cyano-1, 3-oxazoles 5083
6. a) M.H. Holschbach, D. Bier, S. Stüsgen, W. Wutz, W. Sihver, H.H.
Coenen and R.A. Olsson, Eur. J. Med. Chem., 41, 7 (2006); b) M. Bauser,
G. Delapierre, M. Hauswald, T. Flessner, D. D'Urso, A. Hermann, B.
Beyreuther, J. De Vry, P. Spreyer, E. Reissmüller and H. Meier, Bioorg.
Med. Chem. Lett., 14, 1997 (2004).
Thanks are also due to Frans Claassen and Barend van Lagen
for their technical assistance.
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