J.-Q. Zhao et al. / Tetrahedron xxx (2015) 1e6
5
(ESI-TOF) calcd for C10H10N2O2 [MþNa]þ: 213.0634; found:
temperature, and the resulting mixture was directly purified using
flash chromatography (hexanes/ethyl acetate¼30:1) to afford the
desired product 4. Colorless oil (47.6 mg, 99% yield); 1H NMR
213.0641.
4.2.8. 3-Methyl-4-p-tolyl-1,2,5-oxadiazole 2-oxide (3h). White solid
(31.0 mg, 82% yield), mp 80.4e81.1 ꢀC; 1H NMR (300 MHz, CDCl3),
(300 MHz, CDCl3),
d
(ppm): 2.57 (s, 3H), 7.51e7.53 (m, 3H),
(ppm): 9.6, 126.1,
7.70e7.73 (m, 2H); 13C NMR (75 MHz, CDCl3),
d
d
(ppm): 2.33 (d, J¼4.2 Hz, 3H), 2.44 (s, 3H), 7.34 (d, J¼7.8 Hz, 2H),
128.0, 129.1, 130.4, 149.5, 153.8; HRMS (ESI-TOF) calcd for C9H8N2O
7.57 (d, J¼8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3),
d
(ppm): 9.1, 21.4,
[MþH]þ: 161.0709; found: 161.0710.
112.2, 123.8, 127.2, 129.4, 129.9, 141.4, 156.8; HRMS (ESI-TOF) calcd
for C10H10N2O2 [MþNa]þ: 213.0634; found: 213.0645.
4.4. Procedure for the synthesis of compound 5
4.2.9. 4-(3-Methoxyphenyl)-3-methyl-1,2,5-oxadiazole 2-oxide
Compound 3a (176.2 mg, 1 mmol) was suspended in CCl4
(10 mL), then NBS (356 mg, 2 mmol) was added, followed by
benzoyl peroxide (242 mg, 1 mmol). The reaction mixture was
stirred at reflux temperature under N2 for 20 h. After cooling, water
was added to quench the reaction. The solution was extracted with
CCl4 (three times), and the combined organic extracts were washed
with brine, dried over sodium sulfate, and concentrated using ro-
tary evaporation in vacuo. Purification using flash chromatography
(hexanes/ethyl acetate¼25:1) afforded the desired product 5.15
Colorless oil (187 mg, 83% yield); 1H NMR (300 MHz, CDCl3),
(3i). White solid (36.7 mg, 89% yield), mp 109.3e110.1 ꢀC; 1H
NMR (300 MHz, CDCl3),
d (ppm): 2.34 (s, 3H), 3.86 (s, 3H), 7.06e7.10
(m, 1H), 7.19e7.22 (m, 2H), 7.41e7.46 (m, 1H); 13C NMR (75 MHz,
CDCl3),
d (ppm): 9.2, 55.4, 112.1, 112.8, 116.7, 119.6, 127.8, 130.3,
156.7, 160.1; HRMS (ESI-TOF) calcd for C10H10N2O3 [MþNa]þ:
229.0584; found: 229.0588.
4.2.10. 4-(4-Methoxyphenyl)-3-methyl-1,2,5-oxadiazole 2-oxide
(3j). White solid (35.6 mg, 86% yield), mp 99.8e100.3 ꢀC; 1H
NMR (300 MHz, CDCl3),
d
(ppm): 2.33 (s, 3H), 3.88 (d, J¼12.6 Hz,
d
(ppm): 4.40 (s, 2H), 7.56e7.63 (m, 3H), 7.78e7.81 (m, 2H); 13C
3H), 7.02 (d, J¼8.7 Hz, 2H), 7.61 (d, J¼8.7 Hz, 2H); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3),
155.6.
d (ppm): 17.3, 113.3, 125.8, 127.5, 129.5, 131.5,
CDCl3),
d (ppm): 9.2, 55.4, 112.1, 114.6, 118.9, 128.8, 156.5, 161.6;
HRMS (ESI-TOF) calcd for C10H10N2O3 [MþNa]þ: 229.0584; found:
229.0589.
4.5. Procedure for the synthesis of compound 6
4.2.11. 4-(4-tert-Butylphenyl)-3-methyl-1,2,5-oxadiazole 2-oxide
To a solution of 73 mg (0.28 mmol, 1 equiv) compound 5 in 4 mL
acetone were added 29 mg (0.45 mmol, 1.5 equiv) NaN3 and 1 mL
H2O. The reaction mixture was stirred at room temperature for 1 h.
The solution was extracted with CH2Cl2 (three times), and the
combined organic extracts dried over sodium sulfate, and concen-
trated using rotary evaporation in vacuo. Purification using flash
chromatography (hexanes/ethyl acetate¼10:1) afforded the desired
product 6. Yellow solid (57.8 mg, 95% yield); mp 59.7e60.4 ꢀC; 1H
(3k). White solid (38.3 mg, 82% yield), mp 74.5e75.1 ꢀC; 1H NMR
(300 MHz, CDCl3),
d
(ppm): 1.36 (s, 9H), 2.36 (s, 3H), 7.54e7.57 (m,
(ppm): 9.2, 31.1,
2H), 7.61e7.64 (m, 2H); 13C NMR (75 MHz, CDCl3),
d
34.9, 112.2, 123.8, 126.2, 127.1, 154.5, 156.8; HRMS (ESI-TOF) calcd
for C13H16N2O2 [MþNa]þ: 255.1104; found: 255.1112.
4.2.12. 3-Methyl-4-(3,4,5-trimethoxyphenyl)-1,2,5-oxadiazole 2-
oxide (3l). White solid (44.2 mg, 83% yield), mp 104.9e105.4 ꢀC;
NMR (300 MHz, DMSO-d6),
d
(ppm): 4.70 (s, 2H), 7.58e7.68 (m, 3H),
(ppm): 42.4,
1H NMR (300 MHz, CDCl3),
d
(ppm): 2.35 (s, 3H), 3.90 (s, 9H), 6.86
7.75e7.78 (m, 2H); 13C NMR (75 MHz, DMSO-d6),
d
(s, 2H); 13C NMR (75 MHz, CDCl3),
d
(ppm): 9.2, 56.3, 60.9, 104.7,
112.7, 125.6, 127.7, 129.4, 131.5, 156.8; HRMS (ESI-TOF) calcd for
104.8, 112.0, 112.1, 121.8, 140.5, 153.8, 156.7; HRMS (ESI) calcd for
C9H7N5O2 [MþNa]þ: 240.0492; found: 240.0491.
C
12H14N2O5 [MþNa]þ: 289.0795; found: 289.0808.
4.6. Procedure for the synthesis of compound 7
4.2.13. 3-Methyl-4-(naphthalen-2-yl)-1,2,5-oxadiazole 2-oxide
(3m). White solid (42.0 mg, 93% yield), mp 140.1e140.8 ꢀC; 1H
A mixture of compound 5 (91.8 mg, 0.36 mmol), K2CO3
(103.5 mg, 0.75 mmol), and 6-chloro-9H-purin-2-amine (50.9 mg,
0.3 mmol) in DMF (3 mL) was stirred at room temperature for
10 min. Then water was added to quench the reaction, and the
solution was extracted with CH2Cl2 (three times). The combined
organic extracts were washed with water, brine, dried over sodium
sulfate, and concentrated using rotary evaporation in vacuo. Puri-
fication using flash chromatography (hexanes/ethyl acetate¼2:1)
afforded the desired product 7. White solid (90.0 mg, 87% yield);
NMR (300 MHz, CDCl3),
7.76e7.79 (m, 1H), 7.90e8.00 (m, 3H), 8.10 (s, 1H); 13C NMR
(75 MHz, CDCl3), (ppm): 9.3, 112.2, 123.6, 124.0, 127.1, 127.6, 127.8,
d (ppm): 2.42 (s, 3H), 7.58e7.63 (m, 2H),
d
128.5, 129.2, 132.8, 134.1, 156.8; HRMS (ESI-TOF) calcd for
C
13H10N2O2 [MþNa]þ: 249.0634; found: 249.0641.
4.2.14. 3-Ethyl-4-phenyl-1,2,5-oxadiazole 2-oxide (3n). Yellow oil
(30.0 mg, 79% yield), 1H NMR (300 MHz, CDCl3),
(ppm): 1.24 (t,
J¼7.5 Hz, 3H), 2.74 (q, J¼7.5 Hz, 2H), 7.52e7.55 (m, 3H), 7.63e7.66
(m, 2H); 13C NMR (75 MHz, CDCl3),
(ppm): 9.8, 16.7, 116.5, 126.7,
d
mp 210.5e211.2 ꢀC; 1H NMR (300 MHz, DMSO-d6),
2H), 6.87 (s, 2H), 7.53e7.55 (m, 3H), 7.75e7.78 (m, 2H), 8.11 (s, 1H);
13C NMR (75 MHz, DMSO-d6),
(ppm): 36.3, 112.1, 122.8, 125.4,
d (ppm): 5.44 (s,
d
127.4, 129.2, 130.9, 156.7; HRMS (ESI-TOF) calcd for C10H10N2O2
d
[MþNa]þ: 213.0634; found: 213.0644.
128.0, 129.1, 131.1, 143.1, 149.4, 153.8, 157.0, 159.7; HRMS (ESI-TOF)
calcd for C14H10ClN7O2 [MþNa]þ: 366.0477; found: 366.0489.
4.2.15. 4-Benzyl-3-methyl-1,2,5-oxadiazole 2-oxide (3o). White
solid (31.1 mg, 82% yield), mp 67.5e68.4 ꢀC; 1H NMR (300 MHz,
4.7. Procedure for the synthesis of compound 815b
CDCl3),
d
(ppm): 1.93 (s, 3H), 4.03 (s, 2H), 7.22e7.29 (m, 2H),
(ppm): 7.6, 32.1,
7.32e7.37 (m, 3H); 13C NMR (75 MHz, CDCl3),
d
Compound 5 (104 mg, 0.4 mmol) dissolved in 1,4-dioxane
(2 mL), then H2O (2 mL) and CaCO3 (200 mg, 2 mmol) were
added. The reaction mixture was refluxed under stirring for over-
night. After cooling, the reaction mixture was treated with 10% HCl
until CO2 ceased evolving. The solution was extracted with ethyl
acetate (three times), and the combined organic extracts were
washed with brine, dried over sodium sulfate, and concentrated
using rotary evaporation in vacuo. Purification using flash
112.8, 127.6, 128.6, 129.0, 133.9, 156.9; HRMS (ESI-TOF) calcd for
C
10H10N2O2 [MþNa]þ: 213.0634; found: 213.0632.
4.3. Procedure for the synthesis of compound 44k
A solution of 3a (52.9 mg, 0.3 mmol) in 2 mL P(OEt)3 was heated
at reflux for 3 h. The mixture was allowed to reach room