G.-P. Zeng et al. / Chinese Chemical Letters 26 (2015) 1158–1160
1159
Scheme 1. Preparation of oxazolo[5,4-d]pyrimidi-7(6H)-ones 7. (a) NaNO2/HOAc, then Na2S2O4/Ac2O, H2O, 0–5 8C, 3 h, 66%; (b) HCl, then NaHCO3, CH3COCH3, r.t., 2 h, 89%; (c)
Ph3P, C2Cl6, Et3N, CH2Cl2, r.t., 3 h, 78%; (d) ArNCO, CH2Cl2, 0–5 8C, 8–12 h; (e) HNR1R2, CH3CN, r.t., 0.5–4 h; (f) EtONa, CH3CN, r.t., 4–8 h, 72%–87%.
Instruments Co., Beijing, China) and are uncorrected. The ethyl 5-
amino-2-methyloxazole-4-carboxylate 3 were prepared according
to the reported method [27].
recrystallized from ethanol to give 2-methyl-5-amino-6-aryl-
oxazolo[5,4-d]pyrimidi-7(6H)-ones 7a–7i.
3. Results and discussion
2.1. Preparation of iminophosphorane 4
The ethyl 5-amino-2-methyloxazole-4-carboxylate 3 was easily
prepared by acid catalytic cyclization of compound 2, which was
obtained from ethyl cyanoactate 1, nitrous acid, Na2S2O4 and acetic
anhydride [27]. Further treatment of 3 with triphenylphosphine,
hexachloroethane and triethylamine produced iminophosphorane
4 in good yield (Scheme 1). The conversion of 5-amino-2-
methyloxazole-4-carboxylate 3 to iminophosphorane 4 involves
initial formation of dichlorotriphenyl phosphorane between
reaction of triphenylphosphine with hexachloroethane, and
further reaction with compound 3 to give iminophosphorane 4
in the presence of triethylamine.
To a mixture of ethyl 5-amino-2-methyloxazole-4-carboxylate
3 (1.36 g, 8 mmol), PPh3 (3.14 g, 12 mmol) and C2Cl6 (2.84 g,
12 mmol) in dry CH2Cl2 (40 mL), was added dropwise Et3N (2.42 g,
24 mmol) at room temperature. After stirred for 3 h, the solvent
was removed under reduced pressure and the residue was
recrystallized from ethanol–ether (1:3) to give iminophosphorane
4 as pale yellow crystals (2.68 g, yield 78%), mp: 121–123 8C. 1H
NMR (400 MHz, CDCl3):
d 7.82–7.27 (m, 15H, Ar–H), 4.31 (q, 2H,
J = 6.8 Hz, OCH2), 2.12 (s, 3H, CH3), 1.37 (t, 3H, J = 7.0 Hz, CH3). IR
(KBr, cmꢀ1): 1699, 1621, 1563, 1439, 1268, 1172. MS (70 eV) m/z
(%): 430 (M+, 50), 262 (100), 183 (51), 108 (13). Anal. Calcd. for
Iminophosphorane 4 had good reactivity as it reacted with
aromatic isocyanates even at low temperature (0–5 8C). The
carbodiimide intermediates 5 were produced and were then
allowed to react with secondary amines to generate guanidines 6.
In the presence of catalytic amount of sodium ethoxide, 6 were
easily converted to 5-dialkylamino oxazolo[5,4-d]pyrimidi-7(6H)-
ones 7 in satisfactory yields at room temperature under dry N2
protection. It is noteworthy that the reaction proceeds under mild
conditions to give various substituted oxazolo[5,4-d]pyrimidi-
7(6H)-ones 7, and the overall transformation is run in a simple one-
pot procedure from iminophosphorane 4 in good overall yields.
The results are listed in Table 1. As indicated in Table 1, good yields
were obtained whenever dialkylamines (compounds 7a, 7c and
7h), cyclic amines (compounds 7e, 7f, 7g and 7i) or alkylarylamines
(compound 7d) were used. The isolated yield of 7 was good even as
the bulky di-iso-propylamine was applied (compound 7b).
The structure of compounds 7 was confirmed by their spectra
data (Table 2). For example, the 1H NMR spectrum of 7a shows
C
25H23N2O3P (430.4): C, 69.76; H, 5.39; N, 6.51. Found: C, 70.01; H,
5.25; N, 6.27.
2.2. General preparation of 2-methyl-5-amino-6-aryl-oxazolo[5,4-
d]pyrimidi-7(6H)-ones 7a–7i
To a solution of iminophosphorane 4 (0.86 g, 2 mmol) in dry
methylene dichloride (15 mL) was added aromatic isocyanate
(2 mmol) under nitrogen at room temperature. After the
reaction mixture was left unstirred for 8–12 h at 0–5 8C, the
solvent was removed off under reduced pressure and Et2O/
petroleum ether (1:2, 10 mL) was added to precipitate triphe-
nylphosphine oxide. Removal of the solvent gave carbodiimide
5, which were used directly without further purification. To the
solution of carbodiimide 5 prepared above in CH3CN (15 mL)
was added an amine (2 mmol). After the mixture was stirred for
0.5–4 h, several drops of EtONa in EtOH was added. The mixture
was stirred for 4–8 h at room temperature under dry N2
protection. The solution was condensed and the residual was
doublets at
d 2.84 due to –NCH2– group. The signals of CH3 appear
at d 2.54 as singlet. The signals of CH(CH3)2 appear at
d
1.84–1.80 as
Table 1
Synthesis of 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6H)-ones 7a-7i by aza-Wittig reaction at room temperature.
Compd.
Ar
NR1R2
Time (h)
Yield (%)
Elementary analysis (%, calcd.)
C
H
N
7a
7b
7c
7d
7e
7f
Ph
N(i-Bu)2
8
8
6
8
4
4
4
5
4
80
77
75
81
75
87
83
78
72
67.51 (67.77)
66.11 (66.24)
71.02 (70.91)
68.44 (68.66)
65.96 (65.79)
61.45 (61.53)
59.44 (59.22)
62.50 (62.78)
62.08 (62.19)
7.30 (7.39)
6.94 (6.79)
7.25 (7.44)
5.01 (4.85)
5.91 (5.85)
5.20 (5.16)
5.02 (4.97)
6.30 (6.15)
5.46 (5.22)
15.98 (15.81)
17.45 (17.17)
13.58 (13.78)
16.99 (16.86)
18.30 (18.05)
18.03 (17.94)
16.38 (16.25)
16.34 (16.27)
17.28 (17.06)
Ph
N(i-Pr)2
Ph
N(c-Hex)2
N(Me)Ph
Ph
Ph
1-Piperidinyl
4-Morpholinyl
1-Piperidinyl
NPr2
Ph
7g
7h
7i
4-ClC6H4
4-FC6H4
4-FC6H4
1-Piperidinyl