Enaminonitrile as building block in heterocyclic synthesis: Synthesis of novel 4H -Furo[2,3- d ][1,3]oxazin-4-one and Furo[2,3- d ]pyrimidin-4 (3H) -one Derivatives

Article abstract of DOI:10.1155/2017/5610707

2-Amino-4,5-diphenylfuran-3-carbonitrile 1 was utilized as building block for the construction of new furo[2,3-d]pyrimidin-4(3H)-one derivative 2 and 4H-furo[2,3-d][1,3]oxazin-4-one derivative 3 via treatment with acetic anhydride and benzoyl chloride, re

Full text of DOI:10.1155/2017/5610707

Hindawi
Journal of Chemistry
Volume 2017, Article ID 5610707, 6 pages
https://doi.org/10.1155/2017/5610707
Research Article
Enaminonitrile as Building Block in
Heterocyclic Synthesis: Synthesis of Novel
4H-Furo[2,3-d][1,3]oxazin-4-one and
Furo[2,3-d]pyrimidin-4(3H)-one Derivatives
Manal M. El-Shahawi and Ahmed K. El-Ziaty
Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo 11566, Egypt
Correspondence should be addressed to Manal M. El-Shahawi; elshahawi31@yahoo.com
Received 24 January 2017; Accepted 28 March 2017; Published 20 April 2017
Academic Editor: Xinyong Liu
Copyright © 2017 Manal M. El-Shahawi and Ahmed K. El-Ziaty. is is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
2-Amino-4,5-diphenylfuran-3-carbonitrile 1 was utilized as building block for the construction of new furo[2,3-d]pyrimidin-
4(3H)-one derivative 2 and 4H-furo[2,3-d][1,3]oxazin-4-one derivative 3 via treatment with acetic anhydride and benzoyl chloride,
respectively. e 4H-furo[2,3-d][1,3]oxazin-4-one derivative 3 was transformed into novel furo[2,3-d]pyrimidin-4(3H)-ones 4–8,
tetrazolylfuran derivative 10, and furo[3,2-d]imadazolone derivative 11 via reaction with various nitrogen nucleophiles. e
structure features of the synthesized compounds were established from their spectral and elemental analyses.
1. Introduction
furo[2,3-d][1,3]oxazin-4-one and its transformation into dif-
ferent furo[2,3-d]pyrimidines and other heterocyclic systems
via reactions with different nitrogen nucleophiles.
Substituted and fused furans are one of the most impor-
tant scaffolds in medicinal chemistry due to owning vari-
ous biological activities including antimicrobial, antitumor,
antiviral, antidepressant, and antihistaminic effects [1]. On
the other hand, pyrimidines and fused pyrimidines represent
an important class of heterocyclic compounds due to their
biological activities [2–7]. Among the fused pyrimidines,
the furopyrimidines attract the attention of the chemists
due to possessing broad scope of pharmaceutical activities
such as anticancer [8, 9], antiviral [10, 11], and antimicrobial
[12] activities. ere are great numbers of synthetic strate-
gies for the preparation of furo[2,3-d]pyrimidines [10, 13–
20]. Substituted 2-aminofuran-3-carbonitriles are known as
easily obtainable starting material for synthesis of furo[2,3-
d]pyrimidines using different reagents [13–16]. In the context
of our sustained efforts to construct fused oxazine systems
[21–23] and other heterocycles with potent antimicrobial
activities [24–27], herein we reported the utility of 2-
amino-4,5-diphenylfuran-3-carbonitrile [28] in synthesis of
2. Experimental
Melting points were recorded on a Gallenkamp melting point
apparatus. e FTIR spectra were run on a Pye Unicam
1
SP 3-300 spectrometer. H-NMR spectra were recorded on
a JEOL ECA-500 (300 MHz) spectrometer; chemical shifs
were expressed in part per million 훿 (ppm) against TMS as an
internal standard. 13C-NMR spectra were run at 75.46 MHz.
e MS spectra were measured on Agilent 5977A/MSD
mass spectrometers (Agilent Technologies, USA) at 70 eV.
Elemental analysis was performed by Vario EL-III elemental
analysis.
2.1. 2,5,6-Triphenylfuro[2,3-d]pyrimidin-4(3H)-one 2. A mix-
ture of amino carbonitrile 1 (3 g, 10 mmol) and benzoyl
chloride (30 mL) was refluxed for 24 hrs. e excess solvent
was distilled off and the remaining solid was crystallized from

2
Journal of Chemistry
benzene to give 2 as brown crystals, m.p. 122–124∘C, yield
ice/HCl. e obtained solid was filtered off, dried, and crys-
tallized from benzene to give 6 as pale yellow crystals, m.p.
70–72∘C, yield 77%. Anal. Calcd. for C H N O (318.316):
49%. Anal. Calcd. for C H N O (364.388): C, 79.11; H,
24 16
2
2
4.42; N, 7.69. Found: C, 79.07; H, 4.45; N, 7.65. IR (KBr, ]
19 14
2
3
cm−1): 3169 (NH), 1687 (CO). 1H-NMR (DMSO-d ) 훿 (ppm):
C, 71.69; H, 4.43; N, 8.80. Found: C, 71.65; H, 4.40; N, 8.83. IR
6
12.93 (s, 1H NH, exchangeable by D O), 7.92–7.44 (m, 15H,
(KBr, ] cm−1): 3412, (br, OH), 1670 (CO). 1H-NMR (DMSO-
2
Ar-H); 13C-NMR (DMSO-d ) 훿 (ppm): 167.87, 133.50, 130.99,
d ) 훿 (ppm): 8.02–7.20 (m, 10H, Ar-H), 7.36 (s, 1H, OH,
6
6
exchangeable by D O), 2.46 (s, 3H, CH ); 13C-NMR (DMSO-
129.78, 129.12. MS m/z (%): 364 (M+∙, 100), 345 (10), 204 (9),
2
3
d ) 훿 (ppm): 167.19, 137.99, 134.21, 129.74, 129.40, 129.25, 128.54,
128 (15), 122 (18), 105 (42), 77 (40).
6
128.27, 49.91, 22.40. MS m/z (%): 318 (M+∙, 3), 317 (13), 286
(19), 271 (21), 236 (38), 231 (20), 189 (11), 105 (100), 77 (51).
2.2. 2-Methyl-5,6-diphenyl-4H-furo[2,3-d][1,3]oxazin-4-one
3. A solution of amino carbonitrile 1 (3 g, 10 mmol) and
freshly distilled acetic anhydride (30 mL) was heated under
reflux for 24 hrs. e excess of acetic anhydride was removed
and the remaining solid was crystallized from benzene to give
3 as gray crystals, m.p. 196–198∘C, yield 55%. Anal. Calcd. for
C H NO (303.303): C, 75.24; H, 4.32; N, 4.62. Found: C,
2.6. 1-(2-Methyl-4-oxo-5,6-diphenylfuro[2,3-d]pyrimidin-
3(4H)-yl)thiourea 7. A mixture of furo[2,3-d][1,3]oxazinone
3 (1.5 g, 5 mmol), thiosemicarbazide (0.45 g, 5 mmol), and
acetic acid (15 mL) was heated under reflux for 4 hrs. e
reaction mixture was concentrated and poured into ice/cold
water. e formed solid was filtered off, washed with water,
dried, and then crystallized from toluene to give 7 as
violet crystals, m.p. 168–170∘C, yield 50%. Anal. Calcd. for
C H N O S (376.420): C, 63.82; H, 4.28; N, 14.88; S, 8.52.
19 13
3
75.20; H, 4.30; N, 4.65. IR (KBr, ] cm−1): 1773 (CO). 1H-NMR
(DMSO-d ) 훿 (ppm): 7.70–7.00 (m, 10H, Ar-H), 2.4 (s, 3H,
6
CH ); 13C- NMR (DMSO-d ) 훿 (ppm): 167.68, 163.56, 156.18,
3
6
146.88, 145.68, 130.27, 129.44, 129.26, 129.16, 129.03, 128.83,
126.82, 21.90. MS m/z (%): 303 (M+∙, 100), 261 (96), 204 (18),
178 (14), 128 (28), 105 (31), 77 (33).
20 16
4
2
Found: C, 63.78; H, 4.32; N, 14.85; S, 8.55. IR (KBr, ] cm−1):
1
3377, 3360, 3290 (NH, NH ), 1672 (CO), 1179 (C=S). H-
2
NMR (DMSO-d ) 훿 (ppm): 10.63 (s, 1H, NH, exchangeable
6
2.3. 3-Amino-2-methyl-5,6-diphenylfuro[2,3-d]pyrimidin-4-
one 4. A mixture of furo[2,3-d][1,3]oxazinone 3 (1.5 g,
5 mmol) and hydrazine hydrate (0.25 mL, 5 mmol) was
stirred at room temperature in absolute ethanol (30 mL) for
30 min. e solid produced was filtered off, dried, and then
crystallized from dioxane to afford 4 as pale yellow crystals,
m.p. 212–214∘C, yield 87%. Anal. Calcd. for C H N O
by D O), 9.50 (s, 2H, NH , exchangeable by D O), 7.60–7.29
2
2
2
(m, 10H, Ar-H), 2.25 (s, 3H, CH ). MS m/z (%): 376 (M+∙, 1),
3
304 (22), 303 (100), 261 (94), 204 (16), 178 (14), 128 (27), 105
(44), 77 (39).
2.7. 2-Methyl-5,6-diphenyl-3-p-tolylfuro[2,3-d]pyrimidin-
4(3H)-one 8. A mixture of furo[2,3-d][1,3]oxazinone 3
(1.5 g, 5 mmol), p-toluidine (0.53 g, 10 mmol), and n-butanol
(15 mL) was heated under reflux for 3 hrs. e reaction
mixture was concentrated and the solid formed afer cooling
was filtered off, dried, and then crystallized from ethanol to
afford 8 as brown crystals, m.p. 160–162∘C, yield 50%. Anal.
Calcd. for C H N O (392.436): C, 79.58; H, 5.13; N, 7.14.
19 15
3
2
(317.330): C, 71.92; H, 4.76; N, 13.24. Found: C, 71.95; H, 4.80;
N, 13.27. IR (KBr, ] cm−1): 3308, 3256 (NH ), 1691 (CO).
2
1H-NMR (DMSO-d ) 훿 (ppm): 7.75–7.30 (m, 10H, Ar-H),
6
5.79 (s, 2H, NH , exchangeable by D O), 2.4 (s, 3H, CH ).
2
2
3
13C-NMR (DMSO-d ) 훿 (ppm): 161.76, 157.64, 157.48, 146.27,
6
131.10, 130.50, 129.50, 129.31, 128.92, 128.66, 126.72, 104.95,
22.45. MS m/z (%): 317 (M+∙, 100), 260 (9), 184 (15), 178 (4),
128 (4), 105 (13), 77 (12).
26 20
2
2
Found: C, 79.53; H, 5.16; N, 7.14. IR (KBr, ] cm−1): 1698 (CO).
1H-NMR (DMSO-d ) 훿 (ppm): 7.67–7.04 (m, 14H, Ar-H),
6
2.46 (s, 3H, CH ). MS m/z (%): 392 (M+∙, 8), 373 (12), 368
3
2.4. 2-Methyl-5,6-diphenylfuro[2,3-d]pyrimidin-4-one 5. A
mixture of furo[2,3-d][1,3]oxazinone 3 (1.5 g, 5 mmol) in
formamide (15 mL) was refluxed for 3 hrs. e reaction
mixture, afer cooling, was poured into ice/cold water and the
separated solid was filtered off, dried, and crystallized from
benzene to give 5, as pale yellow crystals, m.p. 225-226∘C,
yield 75%. Anal. Calcd. for C H N O (302.317): C, 75.53;
(22), 337 (21), 302 (100), 261 (30), 206 (14), 178 (15), 128, (27),
105 (71), 77 (47).
2.8. 2-Acetamido-N-(4-aminophenyl)-4,5-diphenylfuran-3-
carboxamide 9. A mixture of furo[2,3-d][1,3]oxazinone 3
(1.5 g, 5 mmol), p-phenylenediamine (0.54 g, 5 mmol), and
dioxane (15 mL) was heated under reflux for 3 hrs. e
reaction mixture was concentrated and the solid formed afer
cooling was filtered off, dried, and then crystallized from
ethanol to afford 9 as yellow crystals, m.p. 200–202∘C, yield
60%. Anal. Calcd. for C H N O (411.437): C, 72.98; H,
19 14
2
2
H, 4.67; N, 9.27. Found: C, 75.51; H, 4.64; N, 9.30. IR (KBr,
] cm−1): 3474, (NH), 1676 (CO). H-NMR (DMSO-d ) 훿
1
6
(ppm): 12.63 (s, 1H, NH, exchangeable by D O), 7.50–7.29 (m,
2
10H, Ar-H), 2.4 (s, 3H, CH ); 13C-NMR (DMSO-d ) 훿 (ppm):
3
6
25 21
3
3
161.40, 151.96, 148.31, 129.95, 129.43, 129.25, 128.86, 74.51, 22.45.
MS m/z (%): 302 (M+∙, 3), 288 (9), 271 (100), 256 (14), 216 (9),
189 (13), 105 (3), 77 (6).
5.14; N, 10.21. Found: C, 73.02; H, 5.16; N, 10.17. IR (KBr, ]
cm−1): 3401, 3324 (2NH), 1699 (br, CO). 1H-NMR (DMSO-
d ) 훿 (ppm): 12.07 (s, 1H, NH, exchangeable by D O), 9.77
6
2
(s, 1H, NH, exchangeable by D O), 7.33–7.14 (m, 14H, Ar-H),
2
2.5. 3-Hydroxy-2-methyl-5,6-diphenylfuro[2,3-d]pyrimidin-
4-one 6. A solution of furo[2,3-d][1,3]oxazin-4-one 3 (1.5 g,
5 mmol) and hydroxylamine hydrochloride (0.34 g, 5 mmol)
in pyridine (10 mL) was heated under reflux for 3 hrs. e
reaction mixture was allowed to cool and then poured into
5.09 (s, 2H, NH exchangeable by D O), 2.46 (s, 3H, CH ).
2
2
3
13C-NMR (DMSO-d ) 훿 (ppm): 163.55, 159.53, 146.92, 141.72,
6
133.84, 130.60, 130.46, 128.97, 128.66, 127.89, 127.32, 125.10,
124.65, 123.23, 114.36, 101.78, 66.89, 21.28. MS m/z (%): 411

Journal of Chemistry
3
O
O
Ph
Ph
Ph
CN
．（2
∙∙
1,6-Exo-trig
cyclization
NH
PhCOCl
Ph
Ph
Ph
Ph
Ph
O
．（2
O
O
HN
N
H
OH
O
1
−（2O
！＝2O
O
O
Ph
O
O
N
Ph
Ph
OH
(1) 1,6-Exo-trig
cyclization
NH
Ph
∙∙
OH
Ph
(2) −（2O
O
Ph
O
N
Ph
O
N
3
2
Scheme 1
(M+∙, 2), 337 (14), 302 (100), 261 (10), 189 (13), 178 (10), 128,
(21), 105 (74), 77 (42).
afforded 2,5,6-triphenylfuro[2,3-d]pyrimidin-4(3H)-one 2 as
a sole product. e IR spectrum of 2 showed strong
absorption bands at 3169 and 1687 cm−1 corresponding to
2.9. Procedure for Preparation of 10 and 11. A mixture of
furo[2,3-d][1,3]oxazinone 3 (1.5 g, 5 mmol) and sodium azide
(0.65 g, 5 mmol) in glacial acetic acid (15 mL) was heated
under reflux for 3 hrs. e reaction mixture was allowed to
cool and then poured onto ice/cold water and the separated
solid was filtered, washed with water, and dried. Fractional
crystallization from ethanol gave tetrazole derivative 10 and
the insoluble fraction was crystallized from dioxane to yield
the imidazolone derivative 11.
1
NH and CO groups, respectively. Moreover, the H-NMR
spectrum of 2 exhibited a singlet (exchangeable by D O) at
2
훿 12.93 attributed to NH group. 13C-NMR spectrum of 2
displayed signals at 훿 of 167.87 ppm corresponding to CO
of pyrimidinone ring. Formation of furo[2,3-d]pyrimidinone
2 is believed to proceed via benzoylation of the amino
group and conversion of cyano group to the amide group,
followed by 1,6-exo-trig cyclization of the amino group to
the carbonyl group as formulated in Scheme 1. On the
other hand, by treatment of 2-amino-4,5-diphenylfuran-3-
carbonitrile 1 with freshly distilled acetic anhydride for 24
hours, the desired furo[2,3-d][1,3]oxazin-4-one 3 was formed
via acetylation of the amino group and complete hydrolysis
of cyano group to the acid group, followed by 1,6-exo-
trig cyclization of enolated carbonyl group to acid group
(Scheme 1). IR spectrum of 3 displayed absorption band
at 1773 cm−1 characteristic for CO group of oxazine ring;
additionally, 13C-NMR spectrum of 3 showed signals at 훿
167.68 and 21.90 ppm corresponding to CO of oxazine ring
2.9.1. 2-(5-Methyl-1H-tetrazol-1-yl)-4,5-diphenylfuran-3-car-
boxylic acid 10. White crystals; m.p. > 300∘C, yield 35%. Anal.
Calcd. for C H N O (346.328): C, 65.89; H, 4.07; N, 16.18.
19 14
4
3
Found: C, 65.92; H, 4.05; N, 16.14. IR (KBr, ] cm−1): 3431 (br,
OH, acid), 1669 (CO, acid). 1H NMR (DMSO-d ) 훿 (ppm):
6
11.25 (s, 1H, COOH, exchangeable by D O), 8.20–7.35 (m,
2
10H, Ar-H), 2.14 (s, 3H, CH ). MS m/z (%): 346 (M+∙, 30),
3
301 (100), 273 (25), 128 (13), 105 (65), 77 (50).
2.9.2. 3-Acetyl-5,6-diphenyl-1H-furo[3,2-d]imidazol-2(3H)-
one 11. Pale yellow crystals; m.p. > 300∘C, yield 65%. Anal.
Calcd. for C H N O (318.316): C, 71.69; H, 4.43; N, 8.80.
and CH , respectively.
3
19 14
2
3
Oxazinone ring is very reactive semiacid anhydride
ring and can be transformed into pyrimidinone ring via
reaction with various nitrogen nucleophiles. us, stir-
ring furo[2,3-d][1,3]oxazin-4-one 3 with hydrazine hydrate
in ethanol yielded 3-amino-2-methyl-5,6-diphenylfuro[2,3-
d]pyrimidin-4-one 4 (Scheme 2). IR spectrum of 4 exhibited
Found: C, 71.66; H, 4.46; N, 8.84. IR(KBr, ] cm−1): 3262 (NH),
1746, 1668 (2CO). 1H NMR (DMSO-d ) 훿 (ppm): 11.98 (s, 1H,
6
NH, exchangeable by D O), 7.95–7.06 (m, 10H, Ar-H), 2.45 (s,
2
3H, CH ). MS m/z (%): 318 (M+∙, 26), 303 (70), 275 (100), 128
3
(30), 105 (78), 77 (45).
absorption bands at 3308, 3256, and 1691 cm−1 due to NH
2
3. Results and Discussion
1
and CO groups and H-NMR (DMSO-d ) showed signal
6
at 훿 5.79 ppm which disappeared by D O, confirming the
2-Amino-4,5-diphenylfuran-3-carbonitrile 1 [28] was used
as precursor for the preparation of the target heterocyclic
compounds. us, benzoylation of 1 using benzoyl chloride
2
presence of NH group; also 13C-NMR spectrum of 4
2
revealed signal at 훿 161.76 ppm due to CO of pyrimidinone

4
Journal of Chemistry
O
N
Ph
NH
Ph
O
5
HCOꢀꢁ2
O
N
O
O
Ph
Ph
Ph
ꢀꢁ2
OH
ꢁ2NOH·HCl
N
N
N2H4·H2O
O
Ph
Ph
Ph
py.
EtOH
O
O
O
N
N
4
3
AcOH
6
Nꢁ2NHCSNꢁ2
O
Ph
NHCSNꢁ2
N
Ph
O
N
7
Scheme 2
O
Ph
．（2
O
Ph
O
Ph
N
N（2＃6（4．（2:4
O
Ph
N（2＃6（4＃（3:4
Ph
N
H
Dioxane
Ph
O
N
n-Butanol
O
N
O
NH
8
3
9
O
Na．3
AcOH
Ph
Ph
H
COOH
N
Ph
O
Ph
+
N
N
O
O
N
N
CO＃（3
11
10
N
Scheme 3
ring. On the other hand, boiling furo[2,3-d][1,3]oxazin-4-
one 3 with formamide afforded furo[2,3-d]pyrimidin-4-one
derivative 5 (Scheme 2). Furthermore, furo[2,3-d]pyrimidin-
4-one derivative 6 was obtained on reacting hydroxy-
lamine hydrochloride and furo[2,3-d][1,3]oxazin-4-one 3
(Scheme 2). Spectral data supported the proposed structure
6 as IR spectrum exhibited bands at 3412 cm−1 (br, OH)
D O, indicating the presence of OH group. Additionally,
2
13C-NMR spectrum of 6 exhibited signal at 훿 167.19 ppm
due to CO of pyrimidinone ring. Refluxing compound 3
with thiosemicarbazide in acetic acid for 4 hours yielded the
thiourea derivative 7 (Scheme 2).
On the other hand, when furo[2,3-d][1,3]oxazin-4-one 3
was allowed to react with p-toluidine in refluxing n-butanol
the corresponding furo[2,3-d]pyrimidin-4-one derivative 8
was produced (Scheme 3). On the contrary, the reaction of
and 1670 cm−1 (CO); also 1H-NMR (DMSO-d ) showed the
6
appearance of band at 훿 7.36 ppm which disappeared by

Journal of Chemistry
5
−
+
N=N=N
O
N
B
O
N
Ph
1,5-Endo-trig
cyclization
COOH
Route A
O
OH
Ph
N
N
O
A
N
N
+
−
+
N
3
N=N=N
10
N
N
Route B
Ph
H
N
O
+
N
1,5-Exo-dig
cyclization
N
O
N
−
−．2
C
Ph
O
N
Curtius’s rearrangement
∙∙
CO＃（3
O
N
CO＃（3
N
H
N
H
CO＃（3
Isocyanate
11
Scheme 4
3 with p-phenylenediamine in boiling dioxane yielded the
furancarboxamide derivative 9, whose structure was deduced
from spectral and analytical data (Scheme 3). 1H-NMR
spectrum revealed signals at 훿 12.07 (s, 1H, NH, exchangeable
by D O), 9.77 (s, 1H, NH, exchangeable by D O), 7.33–7.14 (m,
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2
2
14H, Ar-H), 5.09 (s, 2H, NH exchangeable by D O), and 2.46
2
2
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3
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3
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by Curtius’s rearrangement to isocyanate intermediate and
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as summarized at Scheme 4.
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Conflicts of Interest
e authors declare that there are no conflicts of interest
regarding the publication of this paper.

6
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ꢀ
(E) 2-cyano-3-(3ꢀ
,4 - dimethoxyphenyl)-2-propenoylamide

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