ꢀꢀꢀꢁ
8ꢁ ꢁE.P. Kirar et al.: Synthesis of functionalized pyrazole derivatives by regioselective [3ꢁ+ꢁ2] cycloadditions
– IR (ATR): νꢀ=ꢀ3325, 2929, 1733, 1626, 1542, 1450, 1203, 1089, powder (20 mg). Yield: 80 mg (47%) of a yellow resin. –
1
837, 642 cm−1. – H NMR (500 MHz, [D6]DMSO]): δꢀ=ꢀ1.08, IR (ATR): νꢀ=ꢀ3325, 2976, 2933, 1733, 1710, 1631, 1537, 1206,
1
1.10, 1.13 and 1.14 (12H, 4s, 1:1:1:1, 4ꢀ×ꢀ7′-CH3), 1.24 and 1.25 1047, 698 cm−1. – H NMR (500 MHz, [D6]DMSO]): δꢀ=ꢀ1.09,
(6H, 2d, 1:1, Jꢀ=ꢀ7.3 Hz, 2ꢀ×ꢀCHCH3), 2.36 and 2.37 (2H, 2d, 1.11, 1.13 and 1.14 (12H, 4s, 1:1:1:1, 4ꢀ×ꢀ7′-CH3), 1.236 and 1.242
1:1, Jꢀ=ꢀ15.6 Hz, 2ꢀ×ꢀ6′-Ha), 2.83 and 2.84 (2H, 2d, 1:1, Jꢀ=ꢀ15.7, (6H, 2d, 1:1, Jꢀ=ꢀ7.3 Hz, 2ꢀ×ꢀCHCH3), 2.35 and 2.36 (2H, 2d, 1:1,
15.8 Hz, 2ꢀ×ꢀ6′-Hb), 3.53 and 3.57 (6H, 2s, 1:1, 2ꢀ×ꢀCO2CH3), Jꢀ=ꢀ15.6 Hz, 2ꢀ×ꢀ6′-Ha), 2.82 and 2.83 (2H, 2d, 1:1, Jꢀ=ꢀ15.6 Hz,
4.15 and 4.23 (2H, 2p, 1:1, Jꢀ=ꢀ7.2, 7.3 Hz, 2ꢀ×ꢀCHCH3), 5.55 and 2ꢀ×ꢀ6′-Hb), 3.52 and 3.57 (6H, 2s, 1:1, 2ꢀ×ꢀCO2CH3), 4.15 and
5.57 (2H, 2d, 1:1, Jꢀ=ꢀ1.7, 1.6 Hz, 2ꢀ×ꢀ1′-H), 7.35–7.42 (8H, 2m, 4.23 (2H, 2p, 1:1, Jꢀ=ꢀ7.2, 7.3 Hz, 2ꢀ×ꢀCHCH3), 5.52 and 5.55 (2H,
8H of Arl), 7.81 and 7.88 (2H, 2d, 1:1, Jꢀ=ꢀ1.4, 1.5 Hz, 2ꢀ×ꢀ3′-H), 2br s, 1:1, 2ꢀ×ꢀ1′-H), 7.21–7.38 (10H, m, 2ꢀ×ꢀPh), 7.78 and 7.85
8.18 and 8.20 (2H, 2d, 1:1, Jꢀ=ꢀ6.3, 6.9 Hz, 2ꢀ×ꢀNH). – 13C NMR (2H, 2d, 1:1, Jꢀ=ꢀ1.6, 1.5 Hz, 2ꢀ×ꢀ3′-H), 8.157 and 8.162 (2H, 2d,
(126 MHz, [D6]DMSO]): δꢀ=ꢀ16.6, 16.9, 18.0, 18.1, 24.09, 24.12, 1:1, Jꢀ=ꢀ6.9, 7.3 Hz, 2ꢀ×ꢀNH). – 13C NMR (126 MHz, [D6]DMSO]):
47.5, 47.6, 48.1, 48.2, 51.7, 51.8, 63.45, 63.49, 64.7, 64.8, 118.9, δꢀ=ꢀ16.7, 16.9, 18.0, 18.1, 24.1, 24.2, 47.5, 47.6, 48.1, 48.2, 51.71,
119.0, 126.4, 126.7, 127.96, 127.99, 129.5, 129.6, 131.70, 131.72, 51.74, 64.1, 64.2, 64.77, 64.83, 119.2, 119.3, 126.3, 126.7, 127.10,
142.2, 142.3, 162.5, 167.3, 167.4, 172.9, 173.1. – HRMS ((+)-ESI): 127.13, 127.6, 127.7, 127.99, 128.01, 143.05, 143.13, 162.7, 167.5,
+
m/zꢀ=ꢀ392.1371 (calcd. 392.1372 for C19H23ClN3O4, [Mꢀ+ꢀH] ).
167.6, 173.0, 173.1. – HRMS ((+)-ESI): m/zꢀ=ꢀ358.1766 (calcd.
+
358.1761 for C19H24N3O4, [Mꢀ+ꢀH] ).
4.2.3 Methyl (2S,1′S)-[7,7-dimethyl-1-(3,4,5-
trimethoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-
pyrazolo[1,2-a]pyrazole-2-carbonyl]alaninate (5c)
and its (2S,1′R)-isomer 5′c
4.2.5 Methyl (2S,1′S)-[7,7-dimethyl-1-propyl-5-oxo-6,7-
dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carbonyl]
alaninate (5e) and its (2S,1′R)-isomer 5′e
Prepared from 1 (64 mg, 0.56 mmol) and 2c (117 mg, Prepared from 1 (120 mg, 1.05 mmol) and 2e (108 μL,
0.60 mmol), 16 h; then 4a (80 mg, 0.52 mmol) and copper 1.2 mmol), 23 h; then 4a (175 mg, 1.1 mmol) and copper
powder (20 mg), 24 h. Yield: 139 mg (60%) of a yellow powder (40 mg). Yield: 93 mg (27%) of a yellow resin. – IR
residue as a mixture of diastereomers. – IR (ATR): νꢀ=ꢀ3339, (ATR): νꢀ=ꢀ3324, 2929, 1732, 1625, 1554, 1536, 1206, 1162, 1121,
1
2939, 1733, 1710, 1638, 1592, 1421, 1230, 1121, 1005, 767, 892, 641 cm−1. – H NMR (500 MHz, [D6]DMSO]): δꢀ=ꢀ0.866
1
732 cm−1. – H NMR (500 MHz, [D6]DMSO]): δꢀ=ꢀ1.13, 1.14, and 0.869 (6H, 2d, 1:1, Jꢀ=ꢀ7.2, 7.3 Hz, 2ꢀ×ꢀCH2CH2CH3); 0.94,
1.16, and 1.20 (12H, 4s, 1:1:1:1, 4ꢀ×ꢀ7′-CH3), 1.26 and 1.27 0.95, and 1.23 (12H, 3s, 1:1:2, 4ꢀ×ꢀ7′-CH3), 0.98–1.08 and
(6H, 2d, 1:1, Jꢀ=ꢀ7.0, 7.1 Hz, 2ꢀ×ꢀCHCH3), 2.35 and 2.36 (2H, 1.41–1.49 (8H, 2m, 2ꢀ×ꢀCH2CH2CH3), 1.30 (6H, br d, Jꢀ=ꢀ7.4 Hz,
2d, 1:1, Jꢀ=ꢀ15.6 Hz, 2ꢀ×ꢀ6′-Ha), 2.837 and 2.843 (2H, 2d, 1:1, 2ꢀ×ꢀCHCH3), 2.27 and 2.28 (2H, 2d, 1:1, Jꢀ=ꢀ15.4 Hz, 2ꢀ×ꢀ6′-Ha),
Jꢀ=ꢀ15.7, 15.6 Hz, 2ꢀ×ꢀ6′-Hb), 3.54, 3.58, 3.639, 3.641, 3.74 and 2.75–2.80 (2H, m, 2ꢀ×ꢀ6′-Hb), 3.617 and 3.621 (6H, 2s, 1:1,
3.75 (24H, 6s, 1:1:1:1:2:2, 2ꢀ×ꢀCO2CH3 and 6ꢀ×ꢀOCH3), 4.21 and 2ꢀ×ꢀCO2CH3), 4.27–4.34 (2H, m, 2ꢀ×ꢀCHCH3), 4.39–4.42 (2H,
4.27 (2H, 2p, 1:1, Jꢀ=ꢀ7.3 Hz, 2ꢀ×ꢀCHCH3), 5.50 and 5.53 (2H, 2d, m, 2ꢀ×ꢀ1′-H), 7.64 and 7.68 (2H, 2d, 1:1, Jꢀ=ꢀ1.4 Hz, 2ꢀ×ꢀ3′-H),
13
1:1, Jꢀ=ꢀ1.3, 1.2 Hz, 2ꢀ×ꢀ1′-H), 6.69 and 6.70 (4H, 2s, 1:1, 4H of 8.18 and 8.19 (2H, 2d, 1:1, Jꢀ=ꢀ7.1, 7.2 Hz, 2ꢀ×ꢀNH). – C NMR
Arl), 7.72 and 7.78 (2H, 2d, 1:1, Jꢀ=ꢀ1.5 Hz, 2ꢀ×ꢀ3′-H), 8.16 and (126 MHz, [D6]DMSO]): δꢀ=ꢀ13.98, 14.01, 16.7, 17.5, 17.56, 17.60,
8.23 (2H, 2d, 1:1, Jꢀ=ꢀ7.0, 7.3 Hz, 2ꢀ×ꢀNH). – 13C NMR (126 MHz, 17.63, 24.19, 24.21, 37.79, 37.81, 47.5, 47.6, 47.7, 47.79, 47.82,
[D6]DMSO]): δꢀ=ꢀ16.7, 16.8, 17.9, 18.0, 24.19, 24.22, 47.5, 47.6, 51.8, 60.4, 60.5, 64.96, 64.99, 118.8, 127.5, 127.6, 163.0, 163.1,
48.15, 48.22, 51.7, 51.8, 55.7, 55.8, 59.86, 59.87, 64.1, 64.3, 169.36, 169.41, 173.1, 173.2. – HRMS ((+)-ESI): m/zꢀ=ꢀ324.1921
+
64.8, 64.9, 104.7, 104.9, 118.9, 119.1, 126.4, 126.8, 136.5, 136.6, (calcd. 324.1918 for C16H26N3O4, [Mꢀ+ꢀH] ).
138.5, 138.7, 152.56, 152.60, 162.8, 162.9, 167.5, 167.8, 173.08,
173.10. – HRMS ((+)-ESI): m/zꢀ=ꢀ448.2079 (calcd. 448.2078
+
for C22H30N3O7, [Mꢀ+ꢀH] ).
4.3 Synthesis of (S)-3-{4-[(1-methoxy-
1-oxopropan-2-yl)carbamoyl]-5-(3,4,5-
trimethoxyphenyl)-1H-pyrazol-1-yl}-3-
4.2.4 Methyl (2S,1′S)-[7,7-dimethyl-1-phenyl-5-oxo-6,7-
dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carbonyl]
alaninate (5d) and its (2S,1′R)-isomer 5′d
methylbutanoic acid (7c)
Aldehyde 2c (1.3 mmol) and trifluoroacetic acid (one
Prepared from 1 (62 mg, 0.54 mmol) and 2d (56 μL, drop) were added to a stirred solution of pyrazolidinone 1
0.55 mmol), 3 h; then 4a (93 mg, 0.60 mmol) and copper (114 mg, 1 mmol) in anhydrous dichloromethane (5 mL) and
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