LETTER
LiCl-Mediated Mg Insertion into Polysubstituted Aryl Chlorides
2067
1925. (d) Rieke, R. D. Top. Curr. Chem. 1975, 59, 1.
(e) Rieke, R. D. Acc. Chem. Res. 1977, 10, 301. (f) Rieke,
R. D. Aldrichimica Acta 2000, 33, 52.
(45 min, 0.75 M, 72%), was transmetalated with ZnCl2 (1 M
in THF, 1.1 mL, 1.1 mmol) at 25 °C. After addition of 2-
iodothiophene (168 mg, 0.8 mmol), Pd(dba)2 (17 mg, 3
mol%) and P(o-furyl)3 (14 mg, 6 mol%) the resulting
solution was stirred for 1 h at 25 °C. The reaction mixture
was then quenched with sat. aq NH4Cl solution (10 mL) and
the resulting mixture was extracted with Et2O (3 × 10 mL).
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude residue was purified by
flash column chromatography(isohexane) to give 12 as a
colorless solid (165 mg, 85%); mp 25 °C. IR (ATR): 3104,
3066, 3035, 1932, 1856, 1794, 1658, 1589, 1563, 1529,
1479, 1466, 1419, 1256, 1215, 1172, 1078, 1056, 979, 874,
856, 826, 774, 763, 752, 734, 693, 680 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.57–7.58 (m, 1 H), 7.44–7.48 (m, 1 H),
7.28–7.30 (m, 3 H), 7.20–7.24 (m, 1 H), 7.06 (dd, J = 5.0, 3.6
Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 142.7, 136.1,
134.8, 130.1, 128.1, 127.3, 125.9, 125.5, 124.0, 123.8. MS
(70 eV, EI): m/z (%) = 196 (36), 195 (12), 194 (100) [M+],
159 (13), 149 (16), 115 (32). HRMS (EI): m/z calcd for
C10H7ClS: 193.9957; found: 193.9952.
(6) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802;
Angew. Chem. 2008, 120, 6907. (b) Piller, F. M.; Metzger,
A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P.
Chem. Eur. J. 2009, 15, 7192.
(7) The yields of the Grignard reagents were determined by
titration using I2: Krasovskiy, A.; Knochel, P. Synthesis
2006, 890.
(8) Preparation of the Grignard Reagents (TP1): A dry and
argon-flushed Schlenk flask equipped with a magnetic
stirring bar and a septum was charged with LiCl (530 mg,
12.5 mmol) and heated with a heat gun under high vacuum
for 10 min. Magnesium turnings (608 mg, 25 mmol) and
THF (10 mL) were added and the magnesium was activated
with 1,2-dibromoethane (1 drop per mmol). After 5 min of
stirring, the aryl chloride (10 mmol) was added and the
reaction mixture was stirred for the indicated time at 25 °C.
GC analysis of a quenched reaction aliquot showed complete
conversion. Then, the supernatant solution was cannulated
to a new, dry and argon-flushed Schlenk flask and the yield
was determined by iodometric titration.
(13) Preparation of 4-(3-Fluorophenyl)-2,6-dimethoxy-
pyrimidine (13): The freshly prepared and titrated (3-
fluorophenyl)magnesium chloride (6b; 1.56 mL, 1 mmol)
prepared according to TP1 (4 h, 0.64 M, 60%), was
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
transmetalated with ZnCl2 (1 M in THF, 1.1 mL, 1.1 mmol)
at 25 °C. After addition of 4-iodo-2,6-dimethoxypyrimidine
(213 mg, 0.8 mmol), Pd(dba)2 (17 mg, 3 mol%) and P(o-
furyl)3 (14 mg, 6 mol%) the resulting solution was stirred for
3 h at 25 °C. The reaction mixture was then quenched with
sat. aq NH4Cl solution (10 mL) and the resulting mixture
was extracted with Et2O (3 × 10 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
The crude residue was purified by flash column chromatog-
raphy (isohexane–Et2O, 10:1) to give 13 as a light yellow
solid (173 mg, 74%); mp 53.1–54.4 °C. IR (ATR): 3080,
2954, 2361, 1567, 1481, 1462, 1352, 1258, 1242, 1199,
1160, 1099, 1018, 982, 922, 886, 825, 802, 784, 777, 706,
662 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.75–7.79 (m, 2
H), 7.37–7.44 (m, 1 H), 7.11–7.17 (m, 1 H), 6.74 (s, 1 H),
4.07 (s, 3 H), 4.00 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
172.7, 165.5, 164.5 (d, J = 2.8 Hz), 163.1 (d, J = 246 Hz),
139.1 (d, J = 7.8 Hz), 130.1 (d, J = 8.1 Hz), 122.5 (d, J = 2.8
Hz), 117.4 (d, J = 21.6 Hz), 114.0 (d, J = 23.0 Hz), 97.4,
54.8, 53.9. MS (70 eV, EI): m/z (%) = 235 (18), 234 (100)
[M+], 233 (74), 219 (18), 205 (23), 204 (56), 203 (13), 189
(24), 163 (16), 146 (15). HRMS (EI): m/z calcd for
(10) (a) Preparation of (4-Fluorophenyl)(thiophen-2-yl)-
methanone (10): The freshly prepared and titrated (4-
fluorophenyl)magnesium chloride (4b; 1.59 mL, 1 mmol)
prepared according to TP1 (2 h, 0.63 M, 65%), was trans-
metalated with CuCN·2LiCl (1 M in THF, 1.1 mL, 1.1
mmol) at –20 °C and the mixture was stirred for 30 min.
After addition of thiophene-2-carbonyl chloride (117 mg,
0.8 mmol) the resulting solution was stirred for 30 min at this
temperature. The reaction was then quenched with sat. aq
NH4Cl solution (10 mL) and the resulting mixture was
extracted with Et2O (3 × 10 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
The crude residue was purified by flash column chromatog-
raphy (isohexane–Et2O, 50:1) to give 10 as a white solid
(151 mg, 73%). (b) Analytical data matches the literature:
Zhao, W.; Carreira, E. M. Chem. Eur. J. 2007, 13, 2671.
(11) Preparation of N,N-Dimethyl-4-[(triisopropylsilyl)-
oxy]benzamide (11): To the freshly prepared and titrated
{4-[(triisopropylsilyl)oxy]phenyl}magnesium chloride (4c;
1.56 mL, 1 mmol) prepared according to TP 1 (4 h, 0.64 M,
64%), was added dimethylcarbamoyl chloride (86 mg, 0.8
mmol) at –20 °C and the mixture was stirred for 30 min. The
reaction was then quenched with sat. aq NH4Cl solution (10
mL) and the resulting mixture was extracted with Et2O (3 ×
10 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude residue was
purified by flash column chromatography (isohexane–Et2O,
10:1) to give 11 as a colorless oil (260 mg, 81%). IR (ATR):
2944, 2867, 1634, 1604, 1514, 1490, 1463, 1387, 1261,
1168, 1102, 1078, 1013, 997, 908, 882, 845, 766, 752, 709,
684, 675 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.29–7.33
(m, 2 H), 6.84–6.88 (m, 2 H), 3.03 (s, 6 H), 1.20–1.31 (m, 3
H), 1.08 (d, J = 7.2 Hz, 18 H). 13C NMR (100 MHz, CDCl3):
d = 171.6, 157.3, 129.0, 128.7, 119.5, 36.4 (br), 17.8, 12.6.
MS (70 eV, EI): m/z (%) = 321 (22) [M+], 279 (18), 278
(100), 277 (12), 250 (39), 223 (11), 222 (57), 208 (18), 111
(11), 110 (25), 103 (19), 72 (88). HRMS (EI): m/z calcd for
C18H31NO2Si: 321.2124; found: 321.2118.
C12H11FN2O2: 234.0805; found: 234.0808.
(14) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P.
Angew. Chem. Int. Ed. 2010, 49, 4665.
(15) (a) Preparation of 3-[(Triisopropylsilyl)oxy]benz-
aldehyde (14): To the freshly prepared and titrated {3-
[(triisopropylsilyl)oxy]phenyl}magnesium chloride (6c;
1.45 mL, 1 mmol) prepared according to TP1 (3 h, 0.69 M,
74%), was added N,N-dimethylformamide (80 mg, 1.1
mmol) at –20 °C and the mixture was stirred for 30 min. The
reaction was then quenched with sat. aq NH4Cl solution (10
mL) and the resulting mixture was extracted with Et2O (3 ×
10 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude residue was
purified by flash column chromatography (isohexane–Et2O,
20:1) to give 14 as a yellow oil (267 mg, 96%).
(b) Analytical data matches the literature: Joncour, A.; Liu,
J. M.; Décor, A.; Thoret, S.; Wdzieczak-Bakala, J.; Bignon,
J.; Baudoin, O. ChemMedChem 2008, 3, 1731.
(12) Preparation of 2-(3-Chlorophenyl)thiophene (12): The
freshly prepared and titrated (3-chlorophenyl)magnesium
chloride (6a; 1.33 mL, 1 mmol) prepared according to TP1
(16) (a) Preparation of 3,5-Dichlorobenzoic Acid (15): The
freshly prepared and titrated (3,5-dichlorophenyl)-
Synlett 2011, No. 14, 2064–2068 © Thieme Stuttgart · New York