A facile synthesis of polysubstituted furo[2,3-d]pyrimidinones and 1,2,4-triazole-fused derivatives

Article abstract of DOI:10.1177/1747519820925264

In this paper, a series of polysubstituted furo[2,3-d]pyrimidinones, including 1,2,4-triazole-fused derivatives, are synthesized via aza-Wittig reactions of iminophosphoranes, under mild conditions.

Full text of DOI:10.1177/1747519820925264

925264CHL0010.1177/1747519820925264Journal of Chemical ResearchGao et al.
research-article2020
Research Paper
Journal of Chemical Research
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A facile synthesis of polysubstituted
furo[2,3-d]pyrimidinones and
1,2,4-triazole-fused derivatives
https://doi.org/10.1177/1747519820925264
DOI: 10.1177/1747519820925264
journals.sagepub.com/home/chl
Hai-Tao Gao1,2, Jun-Kai Ma1,2, Yang-Gen Hu1,2
and Hong-Mei Wang1,2
Abstract
In this paper, a series of polysubstituted furo[2,3-d]pyrimidinones, including 1,2,4-triazole-fused derivatives, are
synthesized via aza-Wittig reactions of iminophosphoranes, under mild conditions.
Keywords
carbodiimide, iminophosphorane, aza-Wittig reaction, furo[2,3-d]pyrimidin-4(3H)-ones, 1,2,4-triazole
Date received: 3 March 2020; accepted: 18 April 2020
O
O
N
O
O
NH2
NH
C2H5O
C2H5O
OC2H5
N
(1) ArNCO, CH2Cl2
(2) NH2NH2.H2O, C2H5OH
H3C
O
H3C
O
N PPh3
3a-3b
2
R1
75% PPh3, C2Cl6, NEt3
O
O
O
O
N PPh3
C2H5O
C2H5O
R2
N
N
R2NCO
N
N
N
H
H3C
O
N
NH
H3C
O
N
R1
R1
4a-4b
5a-5e
rings with N-heterocycles by means of an aza-Wittig reac-
Introduction
tion has been widely utilized.11,12 In the course of our work
Heterocycles containing the furopyrimidinone system are
considered templates for drug design and discovery because
of their remarkable biological activities. Thus, some of them
have shown anti-inflammatory,1 antiviral,2 analgesic,3 anti-
proliferative,4 and antimicrobial5 activities. Heterocycles
containing the 1,2,4-triazole nucleus also possess diverse
biological activities such as fungicidal, bactericidal, insecti-
cidal, antitumor and as anti-inflammatory agents.6–10 We
1School of Pharmaceutical Sciences, Hubei University University of
Medicine, Shiyan, China
2Hubei Key Laboratory of Wudang Local Chinese Medicine Research
and Institute of Medicinal Chemistry, Hubei University of Medicine,
Shiyan, China
Corresponding authors:
expected therefore, that the combination of a 1,2,4-triazole Yang-Gen Hu, Hubei Key Laboratory of Wudang Local Chinese
Medicine Research and Institute of Medicinal Chemistry, Hubei
University of Medicine, Shiyan 442000, China.
Email: huyg@hbmu.edu.cn
Hong-Mei Wang, School of Pharmaceutical Sciences, Hubei University of
and a furo[3,2-d]pyrimidin-4(3H)-one would produce com-
pounds that might have significant biological activity.
The aza-Wittig reactions of iminophosphoranes have
received considersble attention in view of their utility in the
Medicine, Shiyan 442000, China.
synthesis of N-heterocyclic compounds. Annelation of Email: wanghm01@hbmu.edu.cn

2
Journal of Chemical Research 00(0)
aimed at drug discovery, we recently became interested in the separation of products 5 from the reaction mixture can
the synthesis of a series of new heterocyclic compounds via be easily carried out by simple filtration.
1
aza-Wittig reactions.13,14
The structures of 5a-5e were confirmed based on H
Based on our background in poly-substituted furo[2,3-d] NMR, 13C NMR, mass spectrometry, infrared and elemen-
1
pyrimidin-4(3H)-ones, we decided to add a fused 1,2,4-tri- tal analyses. For example, the H NMR spectrum of 5e
azole ring, hoping for biologically active compounds. showed the signals of -OCH2 at 4.38 ppm as quartets, sig-
Herein, we report the results of that investigation.
nals of CH3 at 1.28, 1.45 and 2.60 ppm as doublet, triplet or
singlet. The signal attributable to the NCH was found at
4.19–4.25 ppm as a multiplet. The aromatic signals are
found at 7.29–7.52 ppm as a multiplet. The IR spectra of 5e
revealed N-H and C=O absorption bands at 3240 and 1698
cm-1 respectively. The mass spectrum of 5e shows a strong
molecular ion peak at m/z 413 with 52% abundance.
In conclusion, we have developed an efficient synthe-
sis of ethyl 6-methyl-8-oxo-3-phenyl-2-(phenylamino/
alkylamino)-3,8-dihydrofuro[2,3-d]-1,2,4-triazolo-[1,5-
a]pyrimidine-7-carboxylates 5, having a furo[2,3-d]
pyrimidinone fused to a 1,2,4-triazole, via aza-Wittig
reactions. The method utilizes easily accessible starting
materials, needs only mild reaction conditions, and fea-
tures straightforward product isolation and good yields.
Further optimization and bioassay and structure–activity
relationship studies of the title compounds are underway.
Results and discussion
Diethyl 2-amino-5-methylfuran-3,4-dicarboxylate (1),
obtained by combination of ethyl 2-chloro-3-oxobu-
tanoate and ethyl 2-cyanoacetate under basic conditions,15
was converted into diethyl 2-methyl-5-[(triphenyl
phosphoranylidene)amino]-furan-3,4- dicarboxylate (2)
(an iminophosphorane) via reaction with triphenylphos-
phine, hexachloroethane and triethylamine (Scheme 1).
Iminophosphorane 2 was reacted successively with aro-
matic isocyanates and then with hydrazine hydrate, at room
temperature, to give 3-amino-5-ethoxycarbonyl-6-methyl-
2-arylamino)-furo[2,3-d]pyrimidin-4(3H)-ones 3 in 85%–
88% yields. Compounds 3 were further converted via
non-isolated iminophosphorane intermediates 4, produced
by reaction with triphenylphosphine, hexachloroethane and
triethylamine. To these, without isolation, phenylisocy-
anate or alkyl isocyanates were added. The synthetic
Experimental section
sequence proceeded well at room temperature producing General
polysubstituted tricycles 5 as crystalline solids in excellent
yields (80%–86%, Scheme 2, Table 1). It is noteworthy that
Analytical grade reagents were purchased from standard
suppliers and used without further purification. Solvents
were dried and purified using standard techniques.
Reactions were monitored by thin layer chromatography on
silica gel GF254 pre-coated plates. Melting points were
determined with an uncorrected X-4 digital melting point
apparatus. Mass spectra were measured on a Finnigan
Trace MS spectrometer. NMR spectra were recorded on a
Bruker UltrashiedTM 400 MHz Plus spectrometer. IR were
recorded on a PE-983 infrared spectrometer as KBr pellets
with absorptions in cm−1. Elementary analysis was carried
out on a PerkinElmer CHN 2400 instrument.
O
O
O
O
C2H5O
OC2H5
C2H5O
OC2H5
PPh3
PPh3, C2Cl6
NEt3, 75%
H3C
O
NH2
H3C
O
N
1
2
Scheme 1. Synthesis of diethyl 2-methyl-5-
[(triphenylphosphoranylidene)amino]-furan- 3,4-dicarboxylate.
O
O
N
O
O
NH2
NH
C2H5O
C2H5O
OC2H5
N
(1) ArNCO, CH2Cl2
(2) NH2NH2.H2O, C2H5OH
H3C
O
H3C
O
N PPh3
3a-3b
2
R1
75% PPh3, C2Cl6, NEt3
O
O
O
O
N
PPh3
R1
C2H5O
C2H5O
R2
N
N
R2NCO
N
N
N
H
H3C
O
N
NH
H3C
O
N
R1
4a-4b
5a-5e
Scheme 2. Synthesis of ethyl 3-amino-6-methyl-4-oxo-2-(aryl)-3,4-dihydrofuro[2,3-d]- pyrimidine-5-carboxylates.

Gao et al.
3
Table 1. Yields of compounds 3 and 5.
added under nitrogen at room temperature. After stirring
for 2–3 h, the solution was concentrated under reduced
pressure and the residue was recrystallized from methylene
chloride/petroleum ether to produce the product, 5a-5e.
R1
R2
Yield
3a
3b
5a
5b
5c
5d
5e
H
p-F
H
H
H
88
85
84
82
80
86
84
Ph
Ethyl 6-methyl-8-oxo-3-phenyl-2-(phenylamino)-3,8-dihydrofuro
[2,3-d]-1,2,4-triazolo- [1,5-a]pyrimidine-7-carboxylate (5a).
White crystals; mp >300 °C. 1H NMR (400 MHz, CDCl3):
δ =1.41 (t, J = 7.2 Hz, 3H, CH3), 2.51 (s, 3H, CH3), 4.38 (q,
J = 7.2 Hz, 2H, OCH2), 6.74 (s, 1H, NH), 6.98–7.64 (m,
10H, Ar-H). 13C NMR (100 MHz, CDCl3): δ = 162.8,
162.4, 154.8, 150.0, 148.5, 146.6, 138.8, 131.3, 128.7,
126.6, 122.6, 119.0, 117.0, 116.7, 110.0, 97.2, 60.3, 14.0,
13.2. IR (KBr) 3238 (N-H), 1722 (C=O), 1588, 1376, 1230
cm-1. MS (70 eV) m/z (%): 429 (M+, 39), 383 (22), 355
(27), 278 (75), 235 (12), 118 (41), 77 (100). Anal. Calcd for
C23H19N5O4 (429.4): C, 64.33; H, 4. 46; N, 16.31; Found:
C, 64.50; H, 4.58; N, 16.48.
n-Bu
i-Pr
n-Bu
i-Pr
p-F
p-F
General procedure for the preparation
of ethyl 3-amino-6-methyl-4-oxo-2-
(2-arylamino)-3,4-dihydrofuro[2,3-d]
pyrimidine-5-carboxylates 3a-3b
A general synthetic approach to 2 had been reported
previously.16 To a solution of iminophosphorane 2 (10
mmol) in anhydrous dichloromethane (25 mL) was added
an aromatic isocyanate under N2 at rt. After the mixture was
kept for 24–30 h at 0–5 °C, the solvent was removed under
reduced pressure and diethyl ether/petroleum ether (1:2, 20
mL) was added to precipitate the Ph3PO. After filtration,
the solvent was removed to give the key intermediate,
which was used directly without further purification by
adding to a stirring solution of hydrazine hydrate (15 mmol)
in EtOH (50 mL). After 5–6 h, the solution was concen-
trated under reduced pressure and the residue was recrystal-
lized from methylene chloride/petroleum ether to give ethyl
3-amino-6-methyl-4-oxo-2-(2-arylamino)-3,4-
dihydrofuro[2,3-d]pyrimidine-5-carboxylate 3a-3b.
Ethyl 6-methyl-8-oxo-2-(n-butylamino)-3-phenyl-3,8-dihydrofuro
[2,3-d]-1,2,4-triazolo- [1,5-a]pyrimidine-7-carboxylate (5b).
1
White crystals; mp 195–197 °C; H NMR (400 MHz,
CDCl3): δ = 0.90 (t, J = 7.2 Hz, 3H, CH3), 1.34 (t, J = 7.2
Hz, 3H, CH3), 1.44-1.64 (m, 4H, 2×CH2), 2.60 (s, 3H, CH3),
3.45-3.52 (m, 2H, CH2), 4.25 (s, 1H, NH), 4.39 (q, J = 7.2
Hz, 2H, OCH2), 7.28–7.64 (m, 5H, Ar-H). 13C NMR (100
MHz, CDCl3): δ =163.8, 162.4, 161.4, 154.5, 151.6, 150.1,
146.9, 130.8, 126.6, 117.0, 116.7, 110.2, 97.1, 60.2, 41.8,
30.4, 19.5, 14.0, 13.2. IR (KBr) 3243(N-H), 1724(C=O),
1588, 1376, 1230, 1093 cm-1. MS (70 eV) m/z (%): 409 (M+,
100), 363 (91), 335 (85), 257 (97), 214 (25), 91 (28), 77 (29).
Anal. Calcd for C21H23N5O4 (409.4): C, 61.60; H, 5.66; N,
17.10; Found: C, 61.53; H, 5.57; N, 17.01.
Ethyl 3-amino-6-methyl-4-oxo-2-(phenylamino)-3,4-dihydrofuro
[2,3-d]pyrimidine- 5-carboxylate (3a). White crystals; mp
198-200 °C. 1H NMR (400 MHz, CDCl3): δ = 1.36 (t, J =
7.2 Hz, 3H, CH3), 2.60 (s, 3H, CH3), 4.38 (q, J = 7.2 Hz, 2H,
OCH2), 4.65 (s, 2H, NH2), 7.49–7.63 (m, 5H, Ar-H), 8.61 (s,
1H, NH). IR (KBr) 3236(N-H), 1701(C=O), 1596, 1556,
1288. Ms (70 eV) m/z (%): 328 (M+, 82), 282 (100), 254
(28), 145 (22), 134 (27), 118 (45), 104 (30), 92 (86), 77 (44).
Ethyl 6-methyl-8-oxo-2-(i-propylamino)-3-phenyl-3,8-dihydrofuro
[2,3-d]-1,2,4-triazolo- [1,5-a]pyrimidine-7-carboxylate (5c).
1
White crystals; mp 245-246 °C; H NMR (400 MHz,
CDCl3): δ = 1.27 (d, J = 6.4 Hz, 6H, 2×CH3), 1.46 (t, J =
7.2 Hz, 3H, CH3), 2.60 (s, 3H, CH3), 3.83-3.85 (m, 1H,
CH), 4.24 (s, 1H, NH), 4.39 (q, J = 7.2 Hz, 2H, OCH2),
7.48-7.66 (m, 5H, Ar-H). 13C NMR (100 MHz, CDCl3): δ
= 162.4 (2), 154.5, 150.8, 150.1, 146.7, 130.5, 129.8(2),
128.1, 110.2, 97.1, 60.2, 44.5, 21.8, 14.0, 13.2. IR (KBr)
3245 (N-H), 1720 (C=O), 1558, 1376 cm-1. MS (70 eV) m/z
(%): 395 (M+, 100), 349 (75), 321 (74), 243 (91), 201 (36),
118 (19), 91 (14), 77 (16). Anal. Calcd for C20H21N5O4
(395.4): C, 60.75; H, 5.35; N, 17.71; Found: C, 60.71, H,
5.28, N, 17.64.
Ethyl 3-amino-6-methyl-4-oxo-2-(4-fluorophenylamino)-3,4-di-
hydro-furo[2,3-d] pyrimidine-5-carboxylate (3b). White crys-
1
tals; mp 226-228 °C. H NMR (400 MHz, CDCl3): δ =
1.40(t, J = 7.2 Hz, 3H, CH3), 2.55(s, 3H, CH3), 4.37(q, J =
7.2 Hz, 2H, OCH2), 4.68(s, 2H, NH2), 7.08–7.58(m, 4H,
Ar-H), 8.65(s, 1H, NH). Ms (70 eV) m/z (%): 346 (M+, 48),
329 (9), 300 (100), 284 (22), 272 (34), 163 (30), 136 (80),
110 (93), 95 (48), 83 (45).
Ethyl 6-methyl-8-oxo-2-(n-butylamino)-3-(p-fluro-phenyl)-3,8-di-
hydrofuro[2,3-d]- 1,2,4-triazolo-[1,5-a]pyrimidine-7-carboxyl-
ate (5d). White crystals; mp 234–236 °C. H NMR (400
General method for the preparation of ethyl
6-methyl-8-oxo-3-phenyl-2-(phenylamino/
alkylamino)-3,8-dihydrofuro[2,3-d]-1,2,4-
triazolo[1,5-a]pyrimidine-7-carboxylates 5a-5e
1
MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3H, CH3), 1.33–1.37
(m, 2H, CH2), 1.44 (t, J = 7.2 Hz, 3H, CH3), 1.58–1.65 (m,
2H, CH2), 2.60 (s, 3H, CH3), 3.48 (t, J = 6.0 Hz, 2H, CH2),
4.55 (s, 1H, NH), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 7.30–
7.53 (m, 4H, Ar-H). 13C NMR (100 MHz, CDCl3): δ =
162.4 (2), 154.4, 151.4, 150.1, 146.7, 130.4, 129.9, 129.8,
128.0, 110.2, 97.1, 60.2, 41.8, 30.4, 19.5, 14.0, 13.7, 13.2.
IR (KBr) 3250 (N-H), 1730 (C=O), 1555, 1376, 1221, 1082
cm-1. MS (70 eV) m/z (%): 427 (M+, 34), 381 (69), 353
To a mixture of 3 (3 mmol), triphenylphosphine (1.57 g, 6
mmol) and hexachloroethane (1.42 g, 6 mmol) in dry ace-
tonitrile (15 mL), was added dropwise triethylamine
(2.00 mL, 15 mmol) at room temperature. After the reaction
mixture was stirred for 6–8 h, completion of the reaction
was verified by TLC, and then an isocyanate (2 mmol) was

4
Journal of Chemical Research 00(0)
and the Scientific and Technological Project of Shiyan City of
Hubei Province (Grant Nos. 18K79 and 18Y01).
(66), 275 (100), 232 (27), 134 (32), 109 (32), 83 (13). Anal.
Calcd for C21H22FN5O4 (427.4): C, 59.01; H, 5.19; N,
16.38; Found: C, 59.15; H, 5.32; N, 16.51.
ORCID iD
Ethyl 6-methyl-8-oxo-2-(i-propylamino)-3-(p-fluro-phenyl)-3,8-
dihydrofuro[2,3-d]- 1,2,4- triazolo-[1,5-a]pyrimidine-7-carbox-
ylate (5e). White crystals; mp 229–230 °C. 1H NMR (400
MHz, CDCl3): δ = 1.28 (d, J = 6.4 Hz, 6H, 2×CH3), 1.45
(t, J = 7.2 Hz, 3H, CH3), 2.60 (s, 3H, CH3), 4.08 (s, 1H,
NH), 4.19–4.25 (m, 1H, CH), 4.38 (q, J = 7.2 Hz, 2H,
OCH2), 7.29–7.52 (m, 4H, Ar-H). 13C NMR (100 MHz,
CDCl3): δ =162.4 (2), 154.5, 151.3, 150.1, 146.7, 130.4,
129.9, 129.8, 128.0, 110.1, 97.0, 60.2, 44.5, 21.8, 14.0,
13.2. IR (KBr) 3240 (N-H), 1698 (C=O), 1548, 1375, 1285,
1130, 1075cm-1. MS (70 eV) m/z (%): 413 (M+, 52), 367
(100), 340 (44), 261 (72), 219 (45), 136 (14), 95 (10). Anal.
Calcd for C20H20FN5O4 (413.4): C, 58.11; H, 4.88; N,
16.94; Found: C, 58.01; H, 4.94; N, 16.78.
Yang-Gen Hu
https://orcid.org/0000-0001-7704-4632
References
1. Li Q, Chen YM, Hu YG, et al. Res Chem Intermed 2016;
42: 939.
2. Chen W, Jia ZJ, Thomas W, et al. WO PCT Int Appl 2017;
2017205762 A1 20171130.
3. Sambavekar PP, Aitawade MM, Kolekar GB, et al. Indian J
Chem Sect B Org Chem 2014; 53B: 1454.
4. Devambatla RK, Choudhary S, Ihnat ML, et al. Bioorg Med
Chem Lett 2018; 28: 3085.
5. Raval K, Patel K, Patel S, et al. J Pharm Res 2012; 1: 1.
6. Jones M, Mathieu E, Dyrager C, et al. Chem Sci 2017; 8: 5636.
7. Gao F, Wang T, Xiao J, et al. Eur J Med Chem 2019; 173: 274.
8. Kumar J, Meena P, Singh A, et al. Eur J Med Chem 2016;
119: 260.
Declaration of conflicting interests
9. Chu CM, Wang C, Wang WL, et al. Eur J Med Chem 2019;
166: 206.
10. Yadav N, Agarwal D, Kumar S, et al. Eur J Med Chem 2018;
145: 735.
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
11. Hu YG, Liu MG and Ding MW Helv Chim Acta 2008; 91: 862.
12. Hu YG, Wang Y, Du SM, et al. Bioorg Med Chem Lett 2010;
20: 6188.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti- 13. Hou N, Man JH, Wang XY, et al. ChemistrySelect 2019;
cle: We gratefully acknowledge financial support from the Open
4: 4901.
Project of Hubei Key Laboratory of Wudang Local Chinese 14. Wang HM, Wang TS, He SJ, et al. J Chem Res 2019; 43: 201.
Medicine Research (Hubei University of Medicine) (Grant No. 15. Hu YG, Li GH and Ding MW Arkivoc 2008; xiii: 151.
WDCM2018001), the Natural Science Foundation of Hubei 16. Hu YG, Gao HT, Wang G, et al. Chin J Org Chem 2012,
Provincial Department of Education (Grant No. D20192102)
32: 1468.