PAPER
Synthesis of a LIMK1 Inhibitor
1095
partitioned between EtOAc (30 mL) and brine (50 mL). The layers
were then separated. The organic layer was dried (MgSO4) and the
organic layer was concentrated in vacuo to give an oil. The oil was
then subjected to column chromatography (silica gel, EtOAc–PE,
0:100 to 40:60); this gave the 3-thiazole isomer 19. Further elution
gave the 2-thiazole isomer 20.
to stir for 5 h at 90 °C. A 10% citric acid soln (20 mL) was added to
the reaction mixture. The aqueous soln was extracted with EtOAc
(2 × 10 mL). The organic layer was dried (MgSO4) and the organic
layer was concentrated in vacuo to give an oil. The oil was then sub-
jected to column chromatography (silica gel, EtOAc–PE, 0:100 to
40:60); this gave borate 22.
White solid (49%); Rf = 0.41 (EtOAc–PE, 1:1).
IR (ATR): 1554, 1521, 1323, 1156, 849, 802 cm–1.
Isomer 19
Pale yellow oil; yield: 0.9 g (19%) (19 was found to be unstable at
1H NMR (300 MHz,CDCl3): d = 9.72 (d, J = 1.5 Hz, 1 H), 8.81 (dd,
J = 1.5, 2.4 Hz, 1 H), 8.71 (d, J = 2.4 Hz, 1 H), 7.35 (s, 1 H), 6.70
(s, 2 H), 3.84 (s, 3 H), 2.16 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 162.7, 162.4, 160.0, 149.1,
146.1, 145.9, 144.5, 137.3, 129.6, 122.7, 113.6, 55.2, 20.5.
LC–MS: tR = 7.25 min; m/z (%) = 327, 329 (100 each) [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H1535ClN4O: 327.1013;
r.t. over a period of 1 month); Rf = 0.75 (EtOAc–PE, 1:5).
IR (ATR): 2953, 1708, 1248, 1157, 1060, 832 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34 (s, 1 H), 5.49 (s, 2 H), 3.69–
3.63 (m, 2 H), 1.58 (s, 9 H), 0.97–0.91 (m, 2 H), –0.02 (s, 9 H).
13C NMR: not obtained due to lack of stability of 19.
ESI-MS: m/z (%) = 410, 409 (6 each) [M + H]+, 279 (4), 192 (50).
ESI-HRMS: m/z [M + H]+ calcd for C14H2579BrN2O3SSi: 409.0617;
found: 409.0609.
found: 327.1011.
tert-Butyl {5-[6-Chloro-2-(pyrazin-2-yl)pyrimidin-4-yl)thiazol-
2-yl}{[2-(trimethylsilyl)ethoxy]methyl}carbamate (23)
Isomer 20
Colourless oil; yield: 3.35 g (73%); Rf = 0.5 (EtOAc–PE, 1:5).
IR (ATR): 2952, 1706, 1508, 1249, 1090, 833 cm–1.
1H NMR (300 MHz,CDCl3): d = 6.98 (s, 1 H), 5.43 (s, 2 H), 3.64–
3.59 (m, 2 H), 1.54 (s, 9 H), 0.98–0.93 (m, 2 H), 0.00 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 161.0, 138.5, 103.7, 84.2, 75.2,
67.0, 28.1, 18.1, –1.4.
ESI-MS: m/z (%) = 410, 409 (7 each) [M + H]+, 279 (4), 192 (38).
ESI-HRMS: m/z [M + H]+ calcd for C14H2579BrN2O3SSi: 409.0617;
A mixture of dichloropyrimidine 10 (350 mg, 1.54 mmol), thiazole
21 (704 mg, 1.54 mmol), Pd(PPh3)4 (Strem; 5 mol%), and Na2CO3
(327 mg, 3.1 mmol) in a mixture of toluene (16 mL), EtOH (2 mL),
and H2O (4 mL) was allowed to stir for 2 h at 90 °C. A 10% citric
acid soln (20 mL) was added to the reaction mixture. The aqueous
soln was extracted with EtOAc (2 × 10 mL). The organic layer was
dried (MgSO4) and the organic layer was concentrated in vacuo to
give an oil. The oil was then subjected to column chromatography
(silica gel, EtOAc–PE, 0:100 to 40:60); this gave pyrimidine 23.
White solid (74%); Rf = 0.5 (EtOAc–PE, 1:1); mp 155 °C.
IR (ATR): 2900, 1707, 1516, 1415, 1215, 1085, 832 cm–1.
found: 409.0616.
tert-Butyl [5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thia-
zol-2-yl]{[2-(trimethylsilyl)ethoxy]methyl}carbamate (21)
A 2.06 M soln of BuLi in hexanes (Fluka; 3.92 mL, 8.1 mmol) was
added slowly to a mixture of thiazole 20 (3.0 g, 7.3 mmol) in THF
(30 mL) at –78 °C under a N2 atmosphere. Isopropoxypinacolbo-
rane (i-PrOBPin; Boron Molecular; 1.91 g, 10.3 mmol) was added
and the resulting mixture was then allowed to warm to 0 °C under a
N2 atmosphere for 2 h. A 2 M NH4Cl soln (30 mL) was added to the
reaction mixture. The mixture was partitioned between EtOAc (30
mL) and brine (30 mL). The layers were then separated. The organic
layer was dried (MgSO4) and the organic layer was concentrated in
vacuo to give an oil. The oil was then subjected to column chroma-
tography (silica gel, EtOAc–PE, 0:100 to 40:60); this gave borate
21.
1H NMR (300 MHz, CDCl3): d = 9.76 (d, J = 1.5 Hz, 1 H), 8.80 (dd,
J = 1.5, 2.4 Hz, 1 H), 8.72 (d, J = 2.4 Hz, 1 H), 8.22 (s, 1 H), 7.56
(s, 1 H), 5.61 (s, 2 H), 3.74–3.69 (m, 2 H), 1.64 (s, 9 H), 1.00–0.95
(m, 2 H), 0.00 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 164.9, 162.6, 162.6, 160.3, 152.7,
148.9, 146.1, 145.8, 144.47, 140.5, 130.7, 114.7, 84.8, 75.7, 67.3,
28.2, 18.3, –1.3.
ESI-MS: m/z (%) = 521 (100) [M + H]+, 282 (95).
ESI-HRMS: m/z [M + H]+ calcd for C22H2935ClN6O3SSi: 521.1558;
found: 521.1561.
tert-Butyl {5-[6-(4-Methoxy-2,6-dimethylphenyl)-2-(pyrazin-2-
yl)pyrimidin-4-yl)thiazol-2-yl}{[2-(trimethylsilyl)ethoxy]meth-
yl}carbamate (24)
Compound 24 was obtained from 22 by one route, and from 23 by
another route, according to the two procedures outlined below.
Pale yellow oil, which solidified on standing; yield: 2.4 g (72%);
Rf = 0.6 (EtOAc–PE, 1:5); mp 59 °C.
IR (ATR): 2900, 1712, 1370, 1242, 1132, 1087, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 1 H), 5.58 (s, 2 H), 3.70–
3.64 (m, 2 H), 1.59 (s, 9 H), 1.32 (s, 12 H), 0.97–0.91 (m, 2 H), –0.02
(s, 9 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 152.7, 147.9, 137.8, 114.3,
84.0, 76.1, 66.8, 28.2, 24.7, 18.1, –1.4.
ESI-MS: m/z (%) = 457 (100) [M + H]+, 375 (50), 330 (58).
ESI-HRMS: m/z [M + H]+ calcd for C20H37BN2O5SSi: 457.2364;
From 22: A mixture of chloropyrimidine 22 (20 mg, 0.06 mmol),
thiazole 21 (28 mg, 0.06 mmol), Pd(PPh3)4 (Strem; 5 mol%), and
Na2CO3 (13 mg, 0.12 mmol) in a mixture of toluene (3 mL), EtOH
(0.3 mL), and H2O (0.3 mL) was allowed to stir for 2 h at 90 °C. A
10% citric acid soln (10 mL) was added to the reaction mixture. The
aqueous soln was extracted with EtOAc (2 × 10 mL). The organic
layer was dried (MgSO4) and the organic layer was concentrated in
vacuo to give an oil. The oil was then subjected to column chroma-
tography (silica gel, EtOAc–PE, 0:100 to 40:60); this gave pyrimi-
dine 24.
found: 457.2374.
4-Chloro-6-(4-methoxy-2,6-dimethylphenyl)-2-(pyrazin-2-
yl)pyrimidine (22)
A mixture of dichloropyrimidine 10 (790 mg, 0.035 mmol), 4-meth-
oxy-2,6-dimethylphenylboronic acid (11; Chembridge; 688 mg,
0.38 mmol), Pd(PPh3)4 (Strem; 5 mol%), and Na2CO3 (737 mg, 0.44
mmol) in a mixture of toluene (16 mL) and H2O (4 mL) was allowed
Oil, which solidified on standing; yield: 68%.
From 23: A mixture of chloropyrimidine 23 (70 mg, 0.13 mmol), 4-
methoxy-2,6-dimethylphenylboronic acid (11; 36 mg, 0.20 mmol),
Pd(PPh3)4 (Strem; 5 mol%), and Na2CO3 (30 mg, 0.28 mmol) in a
mixture of toluene (4 mL), EtOH (0.5 mL), and H2O (0.5 mL) was
allowed to stir for 2 h at 90 °C. A 10% citric acid soln (15 mL) was
Synthesis 2010, No. 7, 1091–1096 © Thieme Stuttgart · New York