PRACTICAL SYNTHETIC PROCEDURES Large-Scale Preparation of Polyfunctional Benzylic Zinc Reagents
889
mixture was quenched with sat. aq NH4Cl (50 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). Evaporation of the solvents and purification by flash
chromatography (silica gel, pentane–Et2O, 3:1) afforded 3h
(441 mg, 86%) as a yellow oil.
IR (Diamond-ATR, neat): 2982 (w), 1715 (vs), 1589 (w), 1446 (m),
1367 (m), 1278 (vs), 1251 (s), 1192 (s), 1156 (s), 1104 (s), 1081 (s),
1025 (s), 902 (w), 863 (w), 741 (s), 725 (m), 685 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96–7.91 (m, 2 H), 7.49–7.45 (m,
1 H), 7.41–7.35 (m, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.14 (q,
J = 7.1 Hz, 2 H), 3.65 (s, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.1, 166.3, 134.4, 133.7, 130.8,
130.3, 128.5, 128.3, 61.0 (double), 41.1, 14.3, 14.1.
MS (EI, 70 eV): m/z (%) = 236 (M+, 99), 208 (33), 192 (18), 191
(87), 164 (100), 136 (54), 135 (89), 119 (95), 77 (16), 59 (11).
IR (Diamond-ATR, neat): 2970 (w), 2919 (w), 1739 (m), 1450 (m),
1428 (m), 1365 (m), 1326 (s), 1217 (m), 1201 (m), 1160 (s), 1118
(vs), 1098 (s), 1072 (s), 797 (m), 761 (s), 732 (s), 701 (s), 657 (s)
cm–1.
1H NMR (400 MHz, C6D6): d = 7.68–7.64 (m, 1 H), 7.59–7.55 (m,
1 H), 7.39 (s, 1 H), 7.25 (d, J = 7.4 Hz, 1 H), 7.20–7.15 (m, 1 H),
7.12–7.07 (m, 1 H), 6.92–6.88 (m, 1 H), 6.86 (t, J = 7.7 Hz, 1 H),
6.78–6.76 (m 1 H), 4.68 (t, J = 6.3 Hz, 1 H), 2.79 (d, J = 6.2 Hz, 2
H), 1.24 (s, 1 H).
13C NMR (100 MHz, C6D6): d = 141.3, 139.7, 139.2, 137.5, 133.2
(q, J = 1.5 Hz), 130.6 (q, J = 248 Hz), 128.7, 126.5 (q, J = 4 Hz),
125.0 (q, J = 272 Hz), 124.7, 124.2, 123.4 (q, J = 4 Hz), 123.2,
122.6, 122.6, 70.5, 43.4.
HRMS: m/z calcd for C13H16O4 (M+): 236.1049; found: 236.1033.
Ethyl 3-[2-Hydroxy-2-(3-thienyl)ethyl]benzoate (3k)
According to P2, 3-ethoxycarbonylbenzylzinc chloride (2g;
3.07 mL, 3.90 mmol, 1.27 M in THF) was reacted with 3-thiophene-
carbaldehyde (337 mg, 3.00 mmol, in 1.5 mL THF) at 0 °C. After
22 h at 25 °C, the reaction mixture was quenched with sat. aq
NH4Cl (50 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). Evaporation of the solvents
and purification by flash chromatography (silica gel, pentane–
Et2O, 3:1) afforded the benzylic alcohol 3k (730 mg, 88%) as a pale
yellow solid; mp 44–46 °C.
MS (EI, 70 eV): m/z (%) = 322 (M+, 2), 240 (2), 164 (100), 135 (21),
91 (8).
HRMS: m/z calcd for C17H13F3OS (M+): 322.0639; found:
322.0630.
1-(4-Chlorophenyl)-2-(2-methoxyphenyl)ethanone (3i)
IR (Diamond-ATR, neat): 3350 (w), 3267 (w), 3100 (w), 2980 (w),
2924 (w), 1711 (vs), 1605 (w), 1587 (w), 1472 (w), 1443 (m), 1363
(m), 1279 (s), 1261 (s), 1196 (s), 1106 (s), 1060 (s), 1029 (s), 922
(m), 853 (s), 792 (s), 757 (s), 727 (vs), 673 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94–7.82 (m, 2 H), 7.37–7.26 (m,
3 H), 7.14–7.08 (m, 1 H), 7.09–7.03 (m, 1 H), 4.99 (dd, J = 6.9,
6.4 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.16–3.00 (m, 2 H), 2.22 (s,
1 H), 1.37 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.6, 145.0, 138.2, 134.0, 130.5,
130.4, 128.3, 127.7, 126.1, 125.5, 120.9, 71.2, 60.9, 44.8, 14.3.
MS (EI, 70 eV): m/z (%) = 276 (M+, 1), 231 (13), 164 (100), 136
(42), 118 (12), 113 (35), 91 (18), 85 (22).
According to P3, 4-chlorobenzoyl chloride (411 mg, 2.35 mmol)
was added dropwise to a mixture of CuCN·2LiCl (3.29 mL,
3.29 mmol, 1.00 M in THF) and 2-methoxybenzylzinc chloride (2f;
2.19 mL, 3.29 mmol, 1.50 M in THF) at –40 °C. The reaction mix-
ture was allowed to reach 25 °C within 21 h and was quenched with
a mixture of sat. aq NH4Cl–NH3 (25% in H2O) (2:1, 100 mL). The
phases were separated and the aqueous layer was extracted with
Et2O (3 × 100 mL). Evaporation of the solvents and purification by
flash chromatography (silica gel, pentane–Et2O, 14:1) afforded the
ketone 3i (605 mg, 99%) as a white solid; mp 56–57 °C.
IR (Diamond-ATR, neat): 2988 (w), 2954 (w), 2940 (w), 2912 (w),
2832 (w), 1692 (vs), 1590 (s), 1494 (s), 1466 (m), 1398 (m), 1334
(s), 1288 (m), 1238 (vs), 1208 (s), 1196 (s), 1174 (m), 1110 (s),
1086 (s), 1026 (s), 992 (s), 816 (vs), 766 (vs), 758 (vs), 568 (m)
cm–1.
HRMS: m/z calcd for C15H16O3S (M+): 276.0820; found: 276.0817.
Ethyl 3-[(Methylthio)methyl]benzoate (3l)
1H NMR (300 MHz, CDCl3): d = 7.99–7.94 (m, 2 H), 7.44–7.38 (m,
2 H), 7.29–7.22 (m, 1 H), 7.16 (dd, J = 7.8, 1.7 Hz, 1 H), 6.95–6.85
(m, 2 H), 4.23 (s, 2 H), 3.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.8, 157.0, 139.2, 135.2, 130.9,
129.8, 128.8, 128.5, 123.4, 120.7, 110.6, 55.4, 39.9.
MS (EI, 70 eV): m/z (%) = 260 (M+, 19), 141 (31), 139 (100), 121
(22), 111 (14), 91 (24).
HRMS :m/z calcd for C15H13ClO2 (M+): 260.0604; found: 260.0599.
3-Ethoxycarbonylbenzylzinc chloride (2g; 1.82 mL, 2.40 mmol,
1.32 M in THF) was added dropwise to S-methyl methanethiosul-
fonate (254 mg, 2.01 mmol) at 25 °C. After 25 h, the reaction mix-
ture was quenched with sat. aq NH4Cl (25 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2
(3 × 25 mL) and the combined extracts were dried (MgSO4). Evap-
oration of the solvents in vacuo and purification by flash chroma-
tography (silica gel, pentane) afforded the thioether 3l (370 mg,
88%) as a yellow liquid.
IR (Diamond-ATR, neat): 2979 (w), 2914 (w), 1713 (vs), 1605 (w),
1587 (w), 1442 (m), 1366 (m), 1303 (m), 1277 (vs), 1236 (s), 1190
(s), 1102 (s), 1078 (s), 1021 (m), 912 (w), 863 (w), 818 (w), 761
(m), 730 (s), 714 (m), 699 (s), 682 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.98–7.88 (m, 2 H), 7.50 (d,
J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H),
3.69 (s, 2 H), 1.98 (s, 3 H), 1.38 (q, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 138.7, 133.2, 130.7, 129.8,
128.5, 128.2, 61.0, 38.0, 14.9, 14.3.
MS (EI, 70 eV): m/z (%) = 210 (M+, 28), 181 (11), 163 (100), 135
(18), 119 (39), 91 (12), 77 (6).
Ethyl 3-(2-Ethoxy-2-oxoethyl)benzoate (3j)
The preparation of the title compound was carried out by following
P6. Ethyl chloroformate (1.09 g, 10.0 mmol) was dissolved in THF
(5 mL) at –30 °C. Then, Pd(PPh3)4 (290 mg, 0.25 mmol, 2.5 mol%)
was added and the mixture was stirred for 10 min. 3-Ethoxycarbo-
nylbenzylzinc chloride (2g; 9.09 mL, 12.0 mmol, 1.32 M in THF)
was added dropwise. The reaction mixture was stirred for 6 h at
25 °C. Then, sat. aq NH4Cl–NH3 (25% in H2O) (9:1, 100 mL) was
added. The layers were separated and the aqueous layer was extract-
ed with CH2Cl2 (3 × 150 mL) and the combined extracts were dried
(MgSO4): Evaporation of the solvents in vacuo and purification by
flash chromatography (silica gel, pentane–Et2O, 9:1) afforded the
ester 3j (1.79 g, 76%) as a colorless liquid.
HRMS: m/z calcd for C11H14O2S (M+): 210.0715; found: 210.0711.
Synthesis 2010, No. 5, 882–891 © Thieme Stuttgart · New York