10.1002/ejoc.202000536
European Journal of Organic Chemistry
FULL PAPER
purifications were carried out on silica gel (200-300 mesh) using petroleum
ether (PE) and ethyl acetate (EA) as eluents. All 1H NMR and 13C NMR
spectra were recorded using a Bruker AV-600 instrument. Chemical shifts
(δ) were expressed in parts per million (ppm) with TMS used as an internal
standard. Coupling constants (J) were quoted in hertz (Hz). 1H NMR
splitting patterns were designated as singlet (s), doublet (d), triplet (t),
quartet (q), and broad (brs). Splitting patterns that could not be interpreted
or easily visualized were designated as multiplet (m). High resolution
electro-spray ionization mass spectra (HRMS-ESI) were obtained using a
Waters SYNAPT Q-TOF instrument.
52.98, 43.72.(minor diastereomer) HRMS (ESI): calcd. for C18H11F6N4O5S
[M-H]- 509.0354, found 509.0361.
Typical experimental procedure of 5,5-disubstituted 4,5-
dihydropyrazolo[1,5-a]quinazolines (5b-5s). To a solution of 5-amino-
1H-phenylpyrazole (1k-1s, 5.0 mmol, 1.0 equiv.) and dialkyl 2-
butenedioate (2a-2j, 1.1 equiv.) in acetonitrile (35 mL) was added K2CO3
(2.5 equiv.) under air. The reaction mixture was then heated to 50 °C for 3
h. After completion of the reaction, acetonitrile was removed in vacuo and
the resulting residue was purified via flash column chromatography to
afford the 5,5-disubstituted 4,5-dihydropyrazolo[1,5-a]quinazolines (5b-
5s). The characterization data for representative compounds 5b, 5g, 5k
and 5r are shown below.
Typical experimental procedure of 5,5-disubstituted 4,5-
dihydropyrazolo[1,5-a]quinazolines (4b-4j). To a solution of 5-amino-
1H-phenylpyrazole (1a-1j, 1.0 mmol, 1.0 equiv) and dialkyl 2-butenedioate
(2a or 2f, 1.1 equiv) in acetonitrile (35 mL) was added K2CO3 (2.5 equiv)
under air. The reaction mixture was then heated to 50 °C. After completion
of the reaction, acetonitrile was removed in vacuo and the resulting residue
was purified via flash column chromatography to afford the 5,5-
Methyl-6-chloro-2-cyano-5-(2-methoxy-2-oxoethyl)-8-
(trifluoromethyl)-3-[(trifluoromethyl)sulfinyl]-4,5-
dihydropyrazolo[1,5-a]quinazoline-5-carboxylate (5aa or 5b): 50:50
d.r.; Rf : 0.3 (EA:PE = 1:6, v/v); white solid; 2.33 g, 86% yield; 1H NMR (600
MHz, CDCl3) δ 8.14 (d, J = 1.8 Hz, 0.5H), 8.13 (d, J = 1.8 Hz, 0.5H), 7.57
(d, J = 1.7 Hz, 1H), 7.28 (brs, 0.5H), 6.83 (brs, 0.5H), 3.82 (s, 1.5H), 3.81
(s, 1.5H), 3.66 (s, 1.5H), 3.62 (s, 1.5H), 3.57 – 3.25 (m, 2H). 13C NMR (151
MHz, CDCl3) δ 169.48, 168.05, 144.64, 134.50, 133.72 (q, J = 34.9 Hz),
133.19, 126.39 (q, J = 3.9 Hz), 125.72, 125.58 (q, J = 336.2 Hz), 123.69,
122.38 (q, J = 273.4 Hz), 111.66 (q, J = 3.8 Hz), 110.39, 93.69, 61.75,
54.46, 52.51, 41.85. (A diastereomer) 13C NMR (151 MHz, CDCl3) δ
169.75, 168.21, 144.69, 134.36, 133.62 (q, J = 34.6 Hz), 133.03, 126.46
(q, J = 3.9 Hz), 125.57, 125.52 (q, J = 336.5 Hz), 123.71, 122.41 (q, J =
273.2 Hz), 111.80 (q, J = 3.8 Hz), 110.39, 94.05, 61.70, 54.38, 52.27,
41.14. (B diastereomer) HRMS (ESI): calcd. for C18H11ClF6N4NaO5S
[M+Na]+ 566.9941, found 566.9918.
disubstituted
4,5-dihydropyrazolo[1,5-a]quinazolines
(4b-4j).
The
characterization data for representative compounds 4b, 4e and 4h are
shown below.
Methyl-7,9-dichloro-2-cyano-5-(2-methoxy-2-oxoethyl)-3-
[(trifluoromethyl)sulfinyl]-4,5-dihydropyrazolo[1,5-a]quinazoline-5-
carboxylate (4b): 75:25 d.r.; Rf: 0.3 (EA:PE = 1:7, v/v); white solid; 368
mg, 72% yield; 1H NMR (600 MHz, CDCl3) δ 7.86 (brs, 0.75H), 7.84 (brs,
0.25H), 7.58 (d, J = 2.2 Hz, 0.75H), 7.57 (d, J = 2.1 Hz, 0.25H), 7.33 (d, J
= 2.2 Hz, 0.75H), 7.32 (d, J = 2.2 Hz, 0.25H), 3.80 (s, 2.25H), 3.79 (s,
0.75H), 3.77 (s, 0.75H), 3.73 (s, 2.25H), 3.68 (dd, J = 32.0, 17.1 Hz, 1H),
3.00 (dd, J = 32.4, 17.1 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 170.14,
170.10, 148.29, 134.02, 133.57, 127.83, 127.21, 125.45 (q, J = 336.2 Hz),
125.27, 124.85, 124.14, 110.81, 94.41, 60.98, 54.48, 53.09, 42.82. (major
diastereomer) 13C NMR (151 MHz, CDCl3) δ 170.41, 170.01, 147.26,
134.39, 134.15, 127.69, 126.62, 125.33 (q, J = 336.2 Hz), 125.20, 124.76,
124.43, 110.75, 94.71, 61.02, 54.68, 53.27, 42.97. (minor diastereomer)
HRMS (ESI): calcd. for C17H10Cl2F3N4O5S [M-H]- 508.9701, found
508.9692.
Allyl-5-[2-(allyloxy)-2-oxoethyl]-6-chloro-2-cyano-8-(trifluoromethyl)-
3-[(trifluoromethyl)sulfinyl]-4,5-dihydropyrazolo[1,5-a]quinazoline-5-
carboxylate (5g): 85:15 d.r.; Rf : 0.3 (EA:PE = 1:12, v/v); white solid; 2.16
g, 72% yield; 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 1.8 Hz, 1H), 7.57
(d, J = 1.9 Hz, 1H), 7.23 (s, 0.85H), 6.85 (s, 0.15H), 5.88 – 5.74 (m, 2H),
5.33 – 5.19 (m, 4H), 4.70 (ddd, J = 75.0, 12.8, 6.1 Hz, 2H), 4.56 – 4.47 (m,
2H), 3.56 – 3.35 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 168.90, 167.28,
144.66, 134.36, 133.74 (q, J = 34.8 Hz), 133.27, 131.28, 130.43, 126.42
(q, J = 3.8 Hz), 125.80 (q, J = 336.2 Hz), 125.74, 123.58, 122.39 (q, J =
273.2 Hz), 120.46, 119.50, 111.80 (q, J = 3.7 Hz), 110.39, 94.01, 68.16,
66.31, 61.96, 41.54. (major diastereomer) 13C NMR (151 MHz, CDCl3) δ
168.63, 167.16, 144.60, 134.52, 133.66 (q, J = 34.8 Hz), 133.13, 131.14,
130.43, 126.38 (q, J = 3.2 Hz), 125.59, 125.53 (q, J = 336.7 Hz), 123.64,
122.41 (q, J = 273.1 Hz), 120.55, 119.64, 111.67 (q, J = 3.8 Hz), 110.39,
93.71, 68.29, 66.21, 61.92, 42.09. (minor diastereomer) HRMS (ESI):
calcd. for C22H14ClF6N4O5S [M-H]- 595.0278, found 595.0259.
Methyl-6-chloro-2-cyano-5-(2-methoxy-2-oxoethyl)-3-
[(trifluoromethyl)sulfinyl]-4,5-dihydropyrazolo[1,5-a]quinazoline-5-
carboxylate (4e): 55:45 d.r.; Rf : 0.3 (EA:PE = 1:4, v/v); white solid; 196
mg, 41% yield; 1H NMR (600 MHz, CDCl3) δ 7.91 (dd, J = 8.2, 1.3 Hz,
0.55H), 7.90 (dd, J = 8.2, 1.3 Hz, 0.45H), 7.45 (t, J = 8.2 Hz, 0.45H), 7.44
(t, J = 8.2 Hz, 0.55H), 7.42 (brs, 0.45H), 7.36 (dd, J = 2.0, 1.3 Hz, 0.55H),
7.34 (dd, J = 2.0, 1.3 Hz, 0.45H), 6.93 (brs, 0.55H), 3.82 (s, 1.35H), 3.81
(s, 1.65H), 3.68 (s, 1.35H), 3.63 (s, 1.65H), 3.56 – 3.21 (m, 2H). 13C NMR
(151 MHz, CDCl3) δ 169.75, 168.73, 144.33, 133.70, 132.20, 131.02,
129.99, 125.51 (q, J = 336.6 Hz), 124.92, 120.22, 114.46, 110.75, 93.49,
61.56, 54.23, 52.14, 41.91. (major diastereomer) 13C NMR (151 MHz,
CDCl3) δ 170.14, 168.87, 144.38, 133.53, 132.33, 131.10, 130.07, 125.52
(q, J = 336.6 Hz), 125.08, 120.24, 114.59, 109.73, 93.93, 61.62, 54.15,
52.40, 41.23. (minor diastereomer) HRMS (ESI): calcd. for
C17H11ClF3N4O5S [M-H]- 475.0091, found 475.0093.
Methyl-6-chloro-2-cyano-5-(2-methoxy-2-oxoethyl)-8-
(trifluoromethyl)-3-[(trifluoromethyl)thio]-4,5-dihydropyrazolo[1,5-
a]quinazoline-5-carboxylate (5k): Rf : 0.35 (EA:PE = 1:6, v/v); white solid,
1
2.22 g, 84% yield; H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 1.8 Hz, 1H),
7.56 (d, J = 0.3 Hz, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.51 (d, J
= 16.9 Hz, 1H), 3.10 (d, J = 16.9 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
170.42, 168.68, 145.37, 134.71, 133.90 (q, J = 34.7 Hz), 133.44, 133.24,
128.57 (q, J = 312.4 Hz), 126.09 (q, J = 3.6 Hz), 123.71, 122.43 (q, J =
273.3 Hz), 111.73 (q, J = 3.8 Hz), 111.30, 84.06 (d, J = 2.6 Hz), 62.19,
54.34, 52.51, 40.55. HRMS (ESI): calcd. for C18H10ClF6N4O5S [M-H]-
527.0015, found 527.0002.
Methyl-2-cyano-5-(2-methoxy-2-oxoethyl)-8-(trifluoromethyl)-3-
[(trifluoromethyl)sulfinyl]-4,5-dihydropyrazolo[1,5-a]quinazoline-5-
carboxylate (4h): 55:45 d.r.; Rf : 0.35 (EA:PE = 1:3, v/v); white solid; 265
mg, 52% yield; 1H NMR (600 MHz, CDCl3) δ 8.12 (dd, J = 4.0, 1.7 Hz, 1H),
7.66 (brs, 0.55H), 7.62 – 7.58 (m, 1H), 7.58 (brs, 0.45H), 7.56 (s, 0.55H),
7.55 (s, 0.45H), 3.80 (s, 1.65H), 3.79 (s, 1.35H), 3.77 (s, 1.35H), 3.76 (s,
1.65H), 3.73 (d, J = 1.1 Hz, 1H), 3.09 (dd, J = 20.9, 17.2 Hz, 1H). 13C NMR
(151 MHz, CDCl3) δ 170.65, 170.26, 146.13, 133.46 (q, J = 34.0 Hz),
132.06, 126.98, 125.57 (q, J = 336.1 Hz), 125.29, 124.76 (q, J = 3.4 Hz),
124.70, 122.97 (q, J = 273.0 Hz), 113.39 (q, J = 3.9 Hz), 110.63, 94.86,
60.89, 54.48, 53.05, 43.53. (major diastereomer) 13C NMR (151 MHz,
CDCl3) δ 170.26, 170.21, 145.71, 133.49 (q, J = 34.0 Hz), 131.99, 126.98,
125.55, 125.36 (q, J = 336.0 Hz), 124.76 (q, J = 3.4 Hz), 124.42, 122.95
(q, J = 272.9 Hz), 113.31 (q, J = 3.9 Hz), 110.60, 94.60, 60.85, 54.34,
Methyl-6-chloro-2-cyano-3-(cyclohexylsulfinyl)-5-(2-methoxy-2-
oxoethyl)-8-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-
5-carboxylate (5r): 80:20 d.r.; Rf : 0.3 (EA:PE = 1:5, v/v); white solid; 1.99
g, 71% yield; 1H NMR (600 MHz, CDCl3) δ 8.16 – 8.10 (m, 0.8H), 8.12 (d,
J = 1.6 Hz, 0.2H), 7.53 (d, J = 3.6 Hz, 0.2H), 7.52 (s, 0.8H), 7.43 (s, 0.2H),
6.90 (s, 0.8H), 3.82 (s, 0.6H), 3.79 (s, 2.4H), 3.63 (s, 0.6H), 3.58 (s, 2.4H),
3.56 – 3.37 (m, 2H), 2.92 (tt, J = 11.8, 3.4 Hz, 1H), 2.07 – 1.98 (m, 2H),
1.97 – 1.86 (m, 2H), 1.77 – 1.69 (m, 1H), 1.52 – 1.43 (m, 2H), 1.44 – 1.34
(m, 3H). 13C NMR (151 MHz, CDCl3) δ 169.71, 168.21, 143.32, 134.75,
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