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261
evaporated off. Purification by flash chromatography [hexane-ethyl
acetate (1:2), hexane-ethyl acetate (1:3), then hexane-ethyl acetate
(1:4)] affords 29b. Yield: 28%, orange solid, mp 98e100 ꢀC (from
diethyl ether). IR (KBr) 1703, 1682, 1517, 1248, 1220 cmꢂ1. 1H NMR
4.1.9.1. 6,7-Bis(hydroxymethyl)-5-methyl-1H,3H-pyrrolo[1,2-c]thia-
zole (27a). Yield: 86%, white foam. IR (film) 3359, 1430, 1404,
1374, 1032, 988 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
d
2.21 (s, 3H),
2.50 (br s, 2H), 4.06 (s, 2H), 4.50 (s, 4H), 4.86 (s, 2H). 13C NMR
(400 MHz, CDCl3)
d
3.78 (s, 3H), 3.87 (s, 3H), 4.41 (dd, J ¼ 1.1 e
(100 MHz, CDCl3) d 9.9, 27.7, 46.8, 56.4, 56.6, 113.6, 122.6, 122.8,
15.0 Hz, 1H), 4.52 (dd, J ¼ 1.8 and 15.0 Hz, 1H), 6.40 (br s, 1H, CHAr),
6.89 (s, 1H), 7.36 (dd, J ¼ 4.8 and 8.1 Hz, 1H, ArH), 7.60e7.64 (m, 1H,
ArH), 8.59 (d, J ¼ 2.1 Hz, 1H, ArH), 8.66 (dd, J ¼ 1.6 and 4.8 Hz, 1H,
130.5. MS (EI) m/z 199 (Mþ, 100%), 181 (83), 164 (51), 162 (46), 152
(40), 108 (26). HRMS (EI-TOF) m/z 199.0665 (Mþ, C9H13NO2S
requires 199.0667).
ArH). 13C NMR (100 MHz, CDCl3)
d 30.8, 51.6, 51.6, 63.9, 108.0, 121.0,
121.1, 124.2, 133.7, 134.8, 142.6, 148.6, 151.2, 163.4, 163.6. MS (EI) m/z
318 (Mþ, 16%), 286 (100), 228 (10), 200 (11), 164 (30), 123 (37).
HRMS (EI-TOF) m/z 318.0678 (Mþ, C15H14N2O4S requires 318.0674).
4.1.9.2. (3R)-6,7-Bis(hydroxymethyl)-5-methyl-3-(3,4,5-trimethoxy-
phenyl)-1H,3H-pyrrolo[1,2-c]thiazole (27b). Yield: 54%, with solid,
mp 143e144 ꢀC (from diethyl ether). IR (KBr) 3505, 3423, 1599,
½
a D20
ꢃ
¼ þ40 (c 0.5, CH2Cl2).
1507, 1467, 1405, 1424, 1239, 1127, 968 cmꢂ1 1H NMR (400 MHz,
.
CDCl3) d 1.71 (br s, 1H), 1.89 (s, 3H), 2.65 (br s, 1H), 3.79 (s, 6H), 3.83
4.1.8. 6-Hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole (24)
and 7-hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole (25)
(s, 3H), 4.09 (d, J ¼ 12.8 Hz, 1H), 4.28 (d, J ¼ 12.8 Hz, 1H), 4.49 (d,
J ¼ 12.3 Hz, 1H), 4.53 (d, J ¼ 12.3 Hz, 1H), 4.58 (s, 2H), 6.16 (s, 1H),
A
solution containing
a
mixture of 22 and 23 (3.35 g,
6.27 (s, 2H, ArH). 13C NMR (100 MHz, CDCl3)
d 10.0, 27.7, 56.2, 56.4,
17.01 mmol) in dry dichloromethane (200 mL) was added drop-
wise to a suspension of lithium aluminum hydride (1.1 equiv.,
0.71 g, 18.71 mmol) in anhydrous diethyl ether (120 mL) at 0 ꢀC.
The solution was refluxed for 1.5 h after the addition was
completed and then cooled on an ice bath. The excess of hydride
was carefully decomposed by addition of ethyl acetate followed by
slow addition of water (0.8 mL), NaOH 15% (0.8 mL) and water
(2.4 mL). The mixture was filtered through celite and the inorganic
residue was washed with several portions of hot dichloromethane.
The filtrate was dried (Na2SO4) and the solvent evaporated off.
Purification of the crude product by flash chromatography
[hexane-ethyl acetate (2:1), then hexane-ethyl acetate (1:1)] gave,
in order of elution, 7-hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-
c]thiazole 25 and 6-hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-c]
thiazole 24.
56.7, 60.9, 64.7, 102.8, 113.6, 123.3, 123.6, 131.6, 136.9, 138.1, 153.7.
MS (EI) m/z 365 (Mþ, 7%), 331 (18), 212 (100), 197 (47), 181 (14), 153
(16). HRMS (EI-TOF) m/z 365.1299 (Mþ, C18H23NO5S requires
365.1297). ½a D20
¼ þ250 (c 0.5, CH2Cl2).
ꢃ
4.1.9.3. (3R)-6,7-Bis(hydroxymethyl)-3-phenyl-1H,3H-pyrrolo[1,2-c]
thiazole (30a). Yield: 38%, white solid, mp 108e109 ꢀC (from
diethyl ether). IR (KBr) 3406, 3365, 1521, 1456, 1340, 1159, 1024,
999 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d 2.69 (br s,1H), 2.83 (br s, 1H),
4.16 (d, J ¼ 13.0 Hz, 1H), 4.22 (d, J ¼ 13.0 Hz, 1H), 4.47 (d, J ¼ 12.3 Hz,
1H), 4.52 (d, J ¼ 12.3 Hz, 1H), 4.58 (s, 2H), 6.29 (s, 1H), 6.33 (s, 1H),
7.26e7.28 (m, 2H, ArH), 7.33e7.35 (m, 3H, ArH). 13C NMR (100 MHz,
CDCl3)
d 28.3, 56.5, 57.8, 65.7, 113.9, 114.1, 127.1, 128.2, 128.9, 129.1,
133.9, 139.3. MS (EI) m/z 261 (Mþ, 53%), 243 (36), 226 (24), 140 (31),
121 (100), 94 (18). HRMS (EI-TOF) m/z 261.0833 (Mþ, C14H15NO2S
6-Hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole (24).
requires 261.0824). ½a 2D0
¼ þ192 (c 0.5, CH2Cl2).
ꢃ
Yield: 28%, brown solid, mp 73e75 ꢀC (from diethyl ether). IR (KBr)
3285, 1421, 1358, 991 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
1.57 (br s,
1H), 2.22 (s, 3H), 4.04 (s, 2H), 4.45 (s, 2H), 4.86 (s, 2H), 5.84 (s, 1H).
13C NMR (100 MHz, CDCl3)
10.0 (CH3), 28.8 (C-1), 46.8 (C-3), 58.2
4.1.9.4. (3R)-6,7-Bis(hydroxymethyl)-3-(pyridin-3-yl)-1H,3H-pyrrolo
[1,2-c]thiazole (30a). Yield: 45%, colorless oil. IR (film) 3334, 1648,
d
1517, 1429, 1362, 1162, 996 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d 3.36
(CH2), 100.1 (C-7), 122.5 (C-6), 124.3 (C-5), 131.9 (C-7a). MS (EI) m/z
169 (Mþ, 100%), 151 (44), 136 (17), 106 (25). HRMS (EI-TOF) m/z
169.0558 (Mþ, C8H11NOS requires 169.0561).
(br s, 2H), 4.18 (d, J ¼ 13.0 Hz, 1H), 4.25 (d, J ¼ 13.0 Hz, 1H), 4.56 (s,
2H), 4.59 (s, 2H), 6.30 (s, 1H), 6.32 (s, 1H), 7.29e7.32 (m, 1H, ArH),
7.58 (d, J ¼ 7.9 Hz, 1H, ArH), 8.48 (s, 1H, ArH), 8.57e8.58 (m, 2H,
7-Hydroxymethyl-5-methyl-1H,3H-pyrrolo[1,2-c]thiazole (25).
ArH). 13C NMR (100 MHz, CDCl3)
d 28.39, 56.0, 57.2, 63.0, 113.5,
Yield: 9%, yellowish oil. IR (film) 3399, 1426, 1391, 1258, 984 cmꢂ1
.
114.5, 124.1, 129.0, 133.8, 135.0, 136.0, 147.9, 149.9. MS (EI) m/z 262
(Mþ, 41%), 244 (56), 227 (47),122 (100),108 (30), 94 (29). HRMS (EI-
TOF) m/z 262.0772 (Mþ, C13H14N2O2S requires 262.0776).
1H NMR (400 MHz, CDCl3)
4.43 (s, 2H), 4.85 (s, 2H), 5.94 (s, 1H). 13C NMR (100 MHz, CDCl3)
d 1.58 (br s, 1H), 2.19 (s, 3H), 4.06 (s, 2H),
d
11.9 (CH3), 28.1 (C-1), 46.8 (C-3), 58.2 (CH2), 110.4 (C-6), 114.4 (C-
½
a D20
ꢃ
¼ þ70 (c 1, CH2Cl2).
7), 124.5 (C-5), 130.8 (C-7a). MS (EI) m/z 169 (Mþ, 100%), 151 (28),
138 (31), 94 (21).
4.1.9.5. (3R)-6,7-Bis(hydroxymethyl)-3,5-diphenyl-1H,3H-pyrrolo
[1,2-c]thiazole (33a). Yield: 26%, white foam. IR (KBr) 3390, 3132,
4.1.9. General procedure for the synthesis of 6,7-bis(hydroxymethyl)-
1H,3H-pyrrolo[1,2-c]thiazoles and 6,7-bis(hydroxymethyl)-1H,3H-
pyrazolo[1,5-c]thiazole
1398, 1385, 1005 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d 2.54 (br s, 2H),
4.16 (d, J ¼ 13.1 Hz, 1H), 4.36 (d, J ¼ 13.1 Hz, 1H), 4.51 (s, 2H), 4.69 (s,
2H), 6.31 (s, 1H, CHPh), 6.74e6.76 (m, 2H, ArH), 7.00-7.03 (m, 2H,
ArH), 7.12e7.13 (m, 3H, ArH), 7.17e7.19 (m, 3H, ArH). 13C NMR
A solution containing the appropriate 1H,3H-pyrrolo[1,2-c]
thiazole or 1H,3H-pyrazolo[1,5-c]thiazole (1.66 mmol) in dry
dichloromethane (16 mL) was added dropwise to a suspension of
lithium aluminum hydride (2.2 equiv., 0.15 g, 3.65 mmol) in
anhydrous diethyl ether (23 mL) at 0 ꢀC. The solution was refluxed
for 1.5 h after the addition was completed and then cooled on an
ice bath. The excess of hydride was carefully decomposed by
addition of ethyl acetate followed by slow addition of water
(0.2 mL), NaOH 15% (0.2 mL) and water (0.6 mL). The mixture was
filtered through celite and the inorganic residue was washed with
several portions of hot dichloromethane. The filtrate was dried
(Na2SO4) and the solvent evaporated off. The crude product was
purified by flash chromatography [hexane-ethyl acetate] or
recrystallization.
(100 MHz, CDCl3)
d 27.4, 56.7, 64.7, 114.2, 125.0, 125.3, 127.4, 127.9,
128.0, 128.4, 128.8, 129.6, 130.8, 133.3, 141.8. MS (ESI) m/z 360
([M þ Na]þ, 100%), 295 (3), 227 (9). HRMS (ESI-TOF) m/z 360.1032
([M þ Na]þ, C20H19NO2SNa requires 360.1029). ½a D20
¼ þ250 (c 1,
ꢃ
CH2Cl2)
4.1.9.6. (3R)-6,7-Bis(hydroxymethyl)-(4-fluorophenyl)-3-phenyl-
1H,3H-pyrrolo[1,2-c]thiazole (33b). Yield: 73%, pale yellow foam. IR
(film) 3151, 1496, 1454, 1423, 1398, 1339, 1223 cmꢂ1 1H NMR
.
(400 MHz, CDCl3)
d
2.59 (br s, 1H), 2.78 (br s, 1H), 4.15 (d, J ¼ 13.1 Hz,
1H), 4.35 (d, J ¼ 13.1 Hz, 1H), 4.45 (s, 2H), 4.68 (s, 2H), 6.25 (s, 1H,
CHPh), 6.75e6.77(m,2H, ArH),6.84e6.88(m, 2H, ArH),6.95e6.98(m,
2H, ArH), 7.13e7.15 (m, 3H, ArH). 13C NMR (100 MHz, CDCl3)
d 27.6,