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PRACTICAL SYNTHETIC PROCEDURES
IR (KBr): 3091 (m, CarH), 2954 (s, CH), 1603 (m, ar C=C), 1585 (s,
ar C=C), 1504 (s, ar C=C), 1450 (s, ar C=C), 1138 (s), 895 cm–1 (s).
moved and the residue was purified by flash chromatography over
silica gel (pentane–Et2O, 50:1–4:1), yielding bithiazoles 3a–g.
1H NMR (200 MHz, CDCl3): d = 1.35 [s, 9 H, C(CH3)3], 3.40 (s, 3
Representative analytical data for bithiazole 3a20 are provided be-
low. Data for compounds 3b–g20 can be found in the corresponding
reference.
H, OCH3), 5.24 (s, 2 H, OCH2O), 7.04–8.34 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 31.8 [q, C(CH3)3], 34.8 [s,
C(CH3)3], 56.7 (q, OCH3), 94.6 (t, OCH2O), 114.3 (d, CarH), 117.9
(d, CarH), 121.6 (s, Car), 125.6 (d, CarH), 128.6 (d, CarH), 128.7 (s,
CarBr), 145.3 (s, Car), 152.5 (s, Car), 164.1 (s, Car).
MS (EI, 70 eV): m/z (%) = 357 (21, [M (81Br)+]), 355 (20, [M
(79Br)+]), 312 (41, [(M (81Br) – C2H4O)+]), 310 (40, [(M (79Br) –
C2H4O)+]), 45 (100, [C2H5O+]).
4-Bromo-2¢-butyl-2,4¢-bithiazole (3a)
Yield: 183 mg (0.60 mmol, 96%).
1H NMR (360 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H, CH3),
1.44 (virt. sext, J ≈ 7.4 Hz, 2 H, CH2), 1.78 (virt. quint, J ≈ 7.7 Hz,
2 H, CH2), 3.01 (t, J = 7.7 Hz, 2 H, ArCH2), 7.19 (s, 1 H, ArH), 7.85
(s, 1 H, ArH).
13C NMR (90 MHz, CDCl3): d = 13.7 (q, CH3), 22.2 (t, CH2), 31.9
(t, CH2), 33.1 (t, CH2), 116.0 (d, CarH), 117.1 (d, CarH), 125.9 (s,
CarBr), 147.7 (s, Car), 167.7 (s, Car), 172.6 (s, Car).
Anal. Calcd for C15H18BrNO2S: C, 50.57; H, 5.09; N, 3.93. Found:
C, 50.31; H, 4.82, N, 4.02.
4-Bromo-2-[5-chloro-2-(methoxymethoxy)phenyl]thiazole (2c)
The reaction was carried out on a 3.00 mmol scale; yield: 620 mg
(1.85 mmol, 62%); Rf = 0.37 (pentane–t-BuOMe, 3:1, UV); mp
82 °C.
Procedure 1b (Table 3)
By Direct Zincation of Commercially Available Organolithium Re-
agents:20 A solution of the commercially available organolithium
compound (5.00 mmol) was added at –78 °C to a solution of ZnCl2
(15.0 mL, 7.50 mmol, 0.5 M in THF). The resulting mixture was
stirred at r.t. for 30 min and was then added via a syringe to a solu-
tion of 2,4-dibromothiazole (1; 486 mg, 2.00 mmol), Pd2(dba)3
(46.0 mg, 0.10 mmol), and dppf (56.0 mg, 0.10 mmol) in THF
(10 mL). After stirring for 16 h at r.t., the reaction was quenched
with sat. aq NH4Cl (10 mL), and the aqueous layer was extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with brine (20 mL). After drying (Na2SO4) and filtration, the sol-
vent was removed and the residue was purified by flash chromatog-
raphy over silica gel (pentane–Et2O, 30:1–20:1), yielding 4-
bromothiazoles 4a, 4f, and 4g.
By Lithiation of Alkyl Iodides and Subsequent Zincation:20 A solu-
tion of t-BuLi (6.90 mL, 10.4 mmol, 1.5 M in pentane) was added
at –78 °C to a solution of the corresponding primary alkyl iodide
(5.00 mmol) in Et2O (8 mL). After stirring the mixture at –78 °C for
1 h, ZnCl2 (15.0 mL, 7.50 mmol, 0.5 M in THF) was added. The re-
sulting mixture was stirred at r.t. for 30 min and was then added via
a syringe to a solution of 2,4-dibromothiazole (1; 486 mg,
2.00 mmol), Pd2(dba)3 (46.0 mg, 0.10 mmol), and dppf (56.0 mg,
0.10 mmol) in THF (10 mL). After stirring for 16 h at r.t., the reac-
tion was quenched with sat. aq NH4Cl (10 mL), and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with brine (20 mL). After drying (Na2SO4) and
filtration, the solvent was removed and the residue was purified by
flash chromatography over silica gel (pentane–Et2O, 30:1–20:1),
yielding 4-bromothiazoles 4b–e and 4h.
IR (KBr): 3120 (m, CarH), 2959 (m, CH), 1594 (m, ar C=C), 1575
(s, ar C=C), 1489 (s, ar C=C), 1450 (s, ar C=C), 1260 (s), 984 cm–1
(s).
1H NMR (200 MHz, CDCl3): d = 3.52 (s, 3 H, OCH3), 5.37 (s, 2 H,
OCH2O), 7.15–8.39 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 57.1 (q, OCH3), 94.9 (t, OCH2O),
116.1 (d, CarH), 118.9 (d, CarH), 123.4 (s, Car), 125.9 (s, CarBr),
127.9 (s, CarCl), 128.3 (d, CarH), 131.2 (d, CarH), 152.9 (s, Car),
162.3 (s, Car).
MS (EI, 70 eV): m/z (%) = 337 (9, [M (81Br37Cl)+]), 335 (31, [M
(81Br35Cl)+]), 335 (31, [M (79Br37Cl)+]), 333 (14, [M (79Br35Cl)+]),
45 (100, [C2H5O+]).
Anal. Calcd for C11H9BrClNO2S: C, 39.48; H, 2.71; N, 4.19. Found:
C, 39.29; H, 2.69, N, 4.22.
4-Bromo-2-[4-(tert-butyl)-2-(methoxymethoxy)phenyl]thiazole
(2d)
Yield: 987 mg (2.77 mmol, 55%); Rf = 0.67 (pentane–t-BuOMe,
3:1, UV); yellow oil.
IR (NaCl): 3121 (m, CarH), 2964 (s, CH), 1608 (m, ar C=C), 1570
(s, ar C=C), 1506 (s, ar C=C), 1456 (s, ar C=C), 993 cm–1 (s).
1H NMR (200 MHz, CDCl3): d = 1.23 [s, 9 H, C(CH3)3], 3.42 (s, 3
H, OCH3), 5.27 (s, 2 H, OCH2O), 7.00–8.21 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 34.1 [s,
C(CH3)3], 55.6 (q, OCH3), 93.3 (t, OCH2O), 110.3 (d, CarH), 116.2
(d, CarH), 118.1 (s, Car), 118.3 (d, CarH), 124.0 (s, CarBr), 126.9 (d,
CarH), 153.1 (s, Car), 154.2 (s, Car), 162.4 (s, Car).
Representative analytical data for 4-bromothiazole 4a20 are provid-
ed below. Data for compounds 4b–g20 and 4h21 can be found in the
corresponding references.
MS (EI, 70 eV): m/z (%) = 357 (7, [M (81Br)+]), 355 (8, [M (79Br)+]),
45 (100, [C2H5O+]).
4-Bromo-2-butylthiazole (4a)
Yield: 375 mg (1.70 mmol, 85%).
Anal. Calcd for C15H18BrNO2S: C, 50.57; H, 5.09; N, 3.93. Found:
C, 50.24; H, 4.21, N, 5.14.
1H NMR (360 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H, CH3),
1.38 (virt. sext, J ≈ 7.5 Hz, 2 H, CH2), 1.73 (virt. quint, J ≈ 7.6 Hz,
2 H, CH2), 2.96 (t, J = 7.7 Hz, 2 H, ArCH2), 7.03 (s, 1 H, ArH).
13C NMR (90 MHz, CDCl3): d = 13.6 (q, CH3), 22.1 (t, CH2), 31.8
(t, CH2), 33.2 (t, CH2), 115.5 (d, CarH), 124.1 (s, CarBr), 172.7 (s,
Car).
Procedure 1a (Table 2)20
A solution of t-BuLi (1.15 mL, 1.73 mmol, 1.5 M in pentane) was
added at –78 °C to a solution of the corresponding 4-bromothiazole
(0.82 mmol) in THF (4 mL). After stirring the mixture at –78 °C for
10 min, ZnCl2 (2.40 mL, 1.20 mmol, 0.5 M in THF) was added.
The resulting mixture was stirred at r.t. for 30 min and a mixture of
2,4-dibromothiazole (1; 153 mg, 0.63 mmol) and PdCl2(PPh3)2
(22.0 mg, 32.0 mmol) in THF (4 mL) was added via a syringe. After
refluxing for 16 h, the reaction was quenched with sat. aq NH4Cl
(10 mL), and the aqueous layer was extracted with Et2O
(3 × 20 mL). The combined organic layers were washed with brine
(20 mL). After drying (Na2SO4) and filtration, the solvent was re-
Procedure 1c (Table 4)
A solution of t-BuLi (0.60 mL, 0.90 mmol, 1.5 M in pentane) was
added at –78 °C to a solution of the corresponding 4-bromothiazole
(0.43 mmol) in Et2O (2 mL). After stirring the mixture at –78 °C for
10 min, Me3SnCl (0.43 mL, 0.43 mmol, 1.0 M in THF) was added.
The resulting mixture was stirred at r.t. for 2 h, then Et2O (8 mL)
Synthesis 2011, No. 2, 199–206 © Thieme Stuttgart · New York