References and Notes
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Hudnall PM.
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6a
Piller FM.
Appukkuttan P.
Gavryushin A.
Helm M.
Knochel P.
Angew. Chem. Int. Ed.
2008,
47:
6802 ; Angew. Chem. 2008, 120, 6907
6b
Piller FM.
Metzger A.
Schade MA.
Haag BA.
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.
9
Knochel P.
Yeh MCP.
Berk SC.
Talbert J.
J. Org. Chem.
1988,
53:
2390
10a
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%).
10b Analytical data matches
the literature: Zhao W.
Carreira EM.
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): δ = 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): δ = 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.
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 (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): δ = 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): δ = 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.
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 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): δ = 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): δ = 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 C12H11FN2O2: 234.0805;
found: 234.0808.
14
Metzger A.
Bernhardt S.
Manolikakes G.
Knochel P.
Angew. Chem. Int. Ed.
2010,
49:
4665
15a
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%).
15b Analytical data matches
the literature: Joncour A.
Liu JM.
Décor A.
Thoret S.
Wdzieczak-Bakala J.
Bignon J.
Baudoin O.
ChemMedChem
2008,
3:
1731
16a
Preparation of 3,5-Dichlorobenzoic Acid (15):
The freshly prepared and titrated (3,5-dichlorophenyl)-magnesium
chloride (8a; 1.54 mL, 1 mmol) prepared according
to TP1 (30 min, 0.65 M, 73%), was added to a flask filled
with anhyd CO2 (g). Then, anhyd CO2 (g)was bubbled
through the reaction mixture (ca. 5 min) until a balloon attached
to the reaction flask by a short length rubber tubing and a needle
adapter was inflated. The reaction mixture was stirred for 1 h at
25 ˚C and then diluted with Et2O (15 mL) and
extracted with sat. aq NaHCO3 (3 × 20 mL). The
combined aq phases were carefully acidified with HCl (5 mL) until
pH <5 and extracted with Et2O (3 × 30
mL). The combined organic layers were dried over MgSO4 and concentrated
in vacuo to give 15 as a yellow solid (189
mg, 99%).
16b Analytical data matches
the literature: Heiss C.
Marzi E.
Schlosser M.
Eur. J. Org. Chem.
2003,
4625
17
Preparation of
3′-Chloro-5′-fluoro-(1,1′-biphenyl)-3-carbonitrile
(16): The freshly prepared and titrated (3-chloro-5-fluorophenyl)magnesium
chloride (8b; 1.49 mL, 1 mmol) prepared
according to TP1 (45 min, 0.67 M, 67%), was transmetalated
with ZnCl2 (1 M in THF, 1.1 mL, 1.1 mmol) at 25 ˚C.
After addition of 3-iodobenzonitrile (183 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 2 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 chroma-tography (isohexane-Et2O,
10:1) to give 16 as a colorless solid (211
mg, 91%); mp 118.7-120.2 ˚C. IR (ATR):
307, 2362, 2338, 2231, 1588, 1574, 1444, 1396, 1324, 1308, 1276,
1202, 1175, 1164, 10094, 1069, 945, 916, 890, 866, 837, 791, 748,
694, 680 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 7.74-7.81
(m, 2 H), 7.66-7.70 (m, 1 H), 7.54-7.60 (m, 1 H),
7.33-7.34 (m, 1 H), 7.11-7.17 (m, 2 H). ¹³C
NMR (75 MHz, CDCl3): δ = 162.9 (d, J = 250 Hz), 141.9 (d, J = 8.7 Hz), 139.9, 135.8 (d, J = 11.0 Hz), 131.8, 131.3,
130.5, 129.9, 123.2, 118.2, 116.0 (d, J = 25.0
Hz), 113.4, 112.6 (d, J = 23.0
Hz). MS (70 eV, EI): m/z (%) = 233 (32), 232
(14), 231 (100) [M+], 196
(17), 195 (22), 169 (13), 58 (11), 43 (28). HRMS (EI): m/z calcd
for C13H7ClFN: 231.0251; found: 231.0245.
18
Preparation of {3-chloro-5-[(triisopropylsilyl)-oxy]phenyl}(2,4-dichlorophenyl)methanone
(17): The freshly prepared and titrated {3-chloro-5-[(triisopropylsilyl)-
oxy]phenyl}magnesium
chloride (8c; 1.43 mL, 1 mmol) prepared
according to TP1 (45 min, 0.70 M, 80%), was transmetalated
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 2,4-dichlorobenzoyl
chloride (168 mg, 0.8 mmol) the resulting solution was stirred for
30 min at this temperature. 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, 50:1) to give 17 as a colorless oil (366 mg, 80%).
IR (ATR): 2946, 2867, 1718, 1606, 1595, 1566, 1501, 1453, 1433,
1398, 1318, 1254, 1199, 1137, 1112, 1065, 1025, 999, 964, 921, 880,
854, 799, 762, 738, 688 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 7.48 (d, J = 1.7 Hz, 1 H), 7.35-7.38
(m, 1 H), 7.27-7.32 (m, 2 H), 7.09-7.14 (m, 2
H), 1.16-1.28 (m, 3 H), 1.07 (d, J = 7.2
Hz, 18 H). ¹³C NMR (75 MHz, CDCl3): δ = 192.8,
157.2, 138.5, 137.0, 136.3, 135.3, 132.5, 130.1, 130.1, 127.2, 125.5,
122.6, 119.2, 17.8, 12.5. MS (70 eV, EI): m/z (%) = 458 (8) [M+], 417
(43), 416 (23), 415 (98), 414 (43), 413 (100), 389 (17), 388 (11),
387 (53), 386 (16), 385 (51), 357 (16), 356 (38), 354 (41), 279
(13), 251 (25), 249 (37), 179 (15), 178 (17), 177 (11), 174 (58),
173 (84), 145 (16), 95 (44), 94 (10), 79 (14), 75 (10), 44 (15),
43 (11), 41 (17). HRMS (EI):
m/z calcd for C22H27Cl3O2Si:
456.0846; found: 458.0842.
19a
Negishi E.
Valente LF.
Kobayashi M.
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Manolikakes G.
Muñoz Hernandez C.
Schade MA.
Metzger A.
Knochel P.
J. Org.
Chem.
2008,
73:
8422
20b
Manolikakes G.
Schade MA.
Muñoz Hernandez C.
Mayr H.
Knochel P.
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2008,
10:
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21
Preparation of
4′-Chloro-(1,1′-biphenyl)-2-amine (2):¹b The
freshly prepared and titrated (4-chlorophenyl)-magnesium chloride
(4a; 25 mL, 19.3 mmol) prepared according
to TP1 (30 min, 0.77 M, 70%), was transmetalated with ZnCl2 (1
M in THF, 19.3 mL, 19.3 mmol) and then slowly added to a 1 M premixed
solution of 2-bromoaniline (3.15 g, 18.3 mmol), Pd(OAc)2 (45
mg, 1 mol%), SPhos (164 mg, 1 mol%) in THF (19
mL). The resulting solution was stirred for 3 h at 25 ˚C.
The reaction mixture was then quenched with sat. aq NH4Cl
solution (150 mL) and the resulting mixture was extracted with Et2O
(3 × 150 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude residue was
purified by flash column chromatography (CH2Cl2)
to give 2 as a yellow solid (2.75 g, 70%).
22
Walker SD.
Barder TE.
Martinelli JR.
Buchwald
SL.
Angew.
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2004,
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