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N. Boyer et al. / Tetrahedron 63 (2007) 12352–12366
4.2.21. (S)-3,3-Difluoro-4-(4-fluorophenyl)-1-((R)-2-me-
thoxy-1-phenylethyl)azetidin-2-one (12e). This compound
was prepared by the above General Procedure A, using 4-flu-
orobenzaldehyde (0.30 g, 2.4 mmol), (R)-2-methoxy-1-phe-
nylethanamine (0.36 g, 2.4 mmol), zinc (0.47 g, 7.2 mmol),
ethyl bromodifluoroacetate (0.97 g, 4.8 mmol), and THF
(9 mL). The crude product was purified by silica gel column
chromatography with cyclohexane/EtOAc (95:5–90:10) to
give the product as a pale yellow oil, yield 63% (510 mg);
[a]2D5 +44.4 (c 1.58, CHCl3); TLC: silica gel, 7:3 cyclohex-
ane/EtOAc, Rf 0.54; IR (KBr) 1785, 1608, 1513, 1455,
8:2 cyclohexane/EtOAc, Rf 0.34; IR (KBr) 1785, 1614,
1517, 1455, 1305, 1254, 1202, 1123, 1032, 840, 702 cmꢁ1
;
1H NMR (CDCl3, 300.3 MHz) 7.35–7.30 (m, 3H), 7.25–
7.15 (m, 4H), 6.87 (d, 2H, J¼9 Hz), 4.87 (dd, 1H, J¼5
and 9.5 Hz), 4.72 (dd, 1H, J¼2.5 and 8 Hz), 3.80 (s, 3H),
3.75 (t, 1H, J¼10 Hz), 3.44 (dd, 1H, J¼5 and 10 Hz), 3.29
(s, 3H); 13C NMR (CDCl3, 75.4 MHz) 161.8 (t,
J¼30.5 Hz), 160.8, 135.0, 1129.9, 129.1, 128.8, 128.1,
123.4, 120.1 (dd, J¼288.5 and 291.5 Hz), 114.2, 72.2,
69.5 (dd, J¼24 and 26.5 Hz), 58.9, 58.0, 55.4; 19F NMR
(CDCl3, 288.3 MHz) ꢁ115.7 (dd, J¼8.5 and 224.5 Hz),
ꢁ122.2 (d, J¼224.5 Hz); MS (CI+) 348 ([M+H]+).
1303, 1232, 1201, 1120, 701 cmꢁ1 1H NMR (CDCl3,
;
300.3 MHz) 7.40–7.35 (m, 2H), 7.3–7.2 (m, 4H), 7.05 (t,
2H, J¼8.5 Hz), 4.88 (dd, 1H, J¼4.5 and 9.5 Hz), 4.82 (dd,
1H, J¼2 and 8 Hz), 3.81 (t, 1H, J¼9.5 Hz), 3.49 (dd, 1H,
J¼4.5 and 10 Hz), 3.31 (s, 3H); 13C NMR (CDCl3,
75.4 MHz) 163.5 (d, J¼248.5 Hz), 161.5 (t, J¼30.5 Hz),
134.9, 130.3 (d, J¼8.5 Hz), 129.1, 128.8, 127.8, 127.3 (d,
J¼3 Hz), 119.9 (dd, J¼288.5 and 292 Hz), 115.8 (d, J¼
22 Hz), 71.9, 69.1 (dd, J¼23.5 and 26.5 Hz), 58.7, 58.3; 19F
NMR (CDCl3, 288.3 MHz) (major diastereomer of b-lactam)
ꢁ111.6, ꢁ115.6 (dd, J¼8.5 and 225 Hz), ꢁ122.0 (d, J¼
225 Hz); (minor diastereomer of b-lactam) ꢁ111.6, ꢁ115.3
(dd, J¼7.5 and 229.5 Hz), ꢁ123.0 (d, J¼229.5 Hz); MS
(CI+) 336 ([M+H]+). Anal. Calcd for C18H16F3NO2: C,
64.47; H, 4.81; N, 4.18. Found: C, 64.41; H, 4.67; N, 4.06.
4.2.24. (S)-3,3-Difluoro-1-((R)-2-methoxy-1-phenyl-
ethyl)-4-(2,4,6-trimethoxyphenyl) azetidin-2-one (12h).
This compound was prepared by the above General Proce-
dure A, using 2,4,6-trimethoxybenzaldehyde (0.26 g,
1.3 mmol), (R)-2-methoxy-1-phenylethanamine (0.20 g,
1.3 mmol), zinc (0.26 g, 4 mmol), ethyl bromodifluoroace-
tate (0.53 g, 2.6 mmol), and THF (4.5 mL). The crude prod-
uct was purified by silica gel column chromatography with
cyclohexane/EtOAc (8:2–6:4) to give the product as a pale
yellow oil, yield 79% (415 mg); [a]2D5 ꢁ79.7 (c 1.13,
CHCl3); TLC: silica gel, 7:3 cyclohexane/EtOAc, Rf 0.42;
IR (KBr) 1778, 1610, 1592, 1457, 1307, 1230, 1207, 1157,
1140, 1071, 817, 702 cmꢁ1
;
1H NMR (CDCl3,
300.3 MHz) 7.30–7.25 (m, 3H), 7.25–7.15 (m, 2H), 6.03
(s, 2H), 5.45 (dd, 1H, J¼2 and 9.5 Hz), 4.67 (t, 1H,
J¼7 Hz), 3.84 (dd, 1H, J¼7.5 and 9.5 Hz), 3.79 (s, 3H),
3.61 (s, 6H), 3.50 (dd, 1H, J¼6.5 and 9.5 Hz), 3.21 (s,
3H); 13C NMR (CDCl3, 75.4 MHz) 162.6, 161.6 (t,
J¼30.5 Hz), 160.8, 136.2, 128.6, 128.2, 128.1, 121.1 (dd,
J¼281 and 297 Hz), 99.3, 90.4, 72.1, 61.7 (dd, J¼24 and
28.5 Hz), 58.9, 57.8, 55.5, 55.4; 19F NMR (CDCl3,
288.3 MHz) ꢁ115.1 (dd, J¼9.5 and 219 Hz), ꢁ119.5 (dd,
J¼2 and 219 Hz); MS (CI+) 408 ([M+H]+); MS (ESI+)
408.00 ([M+H]+). Anal. Calcd for C21H23F2NO5: C, 61.91;
H, 5.69; N, 3.44. Found: C, 61.55; H, 5.71; N, 3.21.
4.2.22. (S)-3,3-Difluoro-1-((R)-2-methoxy-1-phenyl-
ethyl)-4-(2-methoxyphenyl)azetidin-2-one (12f). This
compound was prepared by the above General Procedure
A, using 2-methoxybenzaldehyde (0.18 g, 1.3 mmol), (R)-
2-methoxy-1-phenylethanamine (0.20 g, 1.3 mmol), zinc
(0.26 g, 4 mmol), ethyl bromodifluoroacetate (0.53 g,
2.6 mmol), and THF (4.5 mL). The crude product was puri-
fied by silica gel column chromatography with cyclohexane/
EtOAc (9:1–8:2) to give the product as a white solid, yield
60% (270 mg); mp¼116 ꢀC; [a]D25 +85.3 (c 0.80, CHCl3);
TLC: silica gel, 7:3 cyclohexane/EtOAc, Rf 0.55; IR (KBr)
1783, 1607, 1498, 1472, 1297, 1251, 1206, 1113, 1022,
1
762, 702 cmꢁ1; H NMR (CDCl3, 300.3 MHz) 7.40–7.25
4.2.25. Benzyl 4-((S)-3,3-difluoro-1-((R)-2-methoxy-1-
phenylethyl)-4-oxoazetidin-2-yl) benzyl carbamate (12i)
and benzyl 4-((S)-1-((R)-2-methoxy-1-phenylethyl-
amino)-2-(ethoxy carbonyl)-2,2-difluoroethyl)benzyl-
carbamate (13i). These compounds were prepared by the
above General Procedure A, using benzyl 4-formylbenzyl-
carbamate (0.27 g, 1 mmol), (R)-2-methoxy-1-phenylethan-
amine (0.15 g, 1 mmol), zinc (0.32 g, 5 mmol), ethyl
bromodifluoroacetate (0.61 g, 3 mmol), and THF (4.5 mL).
The crude product was purified by silica gel column chroma-
tography with cyclohexane/EtOAc (9:1–6:4) to give the
product as a colorless oil, yield 77% (390 mg); TLC: silica
gel, 6:4 cyclohexane/EtOAc, Rf 0.51.
(m, 6H), 7.10 (d, 1H, J¼7.5 Hz), 6.88 (d, 1H, J¼8.5 Hz),
6.86 (t, 1H, J¼7.5 Hz), 5.38 (dd, 1H, J¼2 and 8.5 Hz),
4.72 (dd, 1H, J¼4.5 and 9.5 Hz), 3.93 (t, 1H, J¼10 Hz),
3.79 (s, 3H), 3.50 (dd, 1H, J¼4.5 and 10 Hz), 3.31 (s, 3H);
13C NMR (CDCl3, 75.4 MHz) 162.4 (t, J¼30.5 Hz), 157.9,
135.8, 130.5, 129.1, 128.7, 128.2, 120.6, 120.2 (dd,
J¼287.5 and 292 Hz), 110.7, 72.6, 65.2 (dd, J¼24 and
27 Hz), 59.6, 58.9, 55.7; 19F NMR (CDCl3, 288.3 MHz)
ꢁ115.9 (dd, J¼8.5 and 223.5 Hz), ꢁ122.2 (d,
J¼223.5 Hz); MS (CI+) 348 ([M+H]+); MS (ESI+) 348.02
([M+H]+). Anal. Calcd for C19H19F2NO3: C, 65.70; H,
5.51; N, 3.95. Found: C, 65.71; H, 5.48; N, 3.95.
4.2.23. (S)-3,3-Difluoro-1-((R)-2-methoxy-1-phenyl-
ethyl)-4-(4-methoxyphenyl)azetidin-2-one (12g). This
compound was prepared by the above General Procedure
A, using 4-methoxybenzaldehyde (0.25 g, 1.85 mmol),
(R)-2-methoxy-1-phenylethanamine (0.28 g, 1.85 mmol),
zinc (0.33 g, 5 mmol), ethyl bromodifluoroacetate (0.67 g,
3.3 mmol), and THF (4.5 mL). The crude product was puri-
fied by silica gel column chromatography with cyclohexane/
EtOAc (9:1–8:2) to give the product as a colorless oil, yield
42% (275 mg); [a]2D5 +59.0 (c 1.34, CHCl3); TLC: silica gel,
Mixture of two products: IR (KBr) 3341, 1774, 1702, 1519,
1
1455, 1410, 1306, 1259, 1203, 1115, 756, 701 cmꢁ1; H
NMR (CDCl3, 300.3 MHz) 7.4–7.1 (m, 28H), 5.15–5.00 (br
d, 6H), 4.80 (dd, 1H, J¼4.5 and 9.5 Hz), 4.71 (dd, 1H, J¼2
and 8 Hz), 4.40 (dd, 1H, J¼10 and 19.5 Hz), 4.35–4.25 (m,
6H), 3.94 (dd, 1H, J¼4.5 and 7.5 Hz), 3.71 (t, 1H, J¼
10 Hz), 3.5–3.3 (m, 3H), 3.25 (s, 3H), 3.22 (m, 3H), 1.30 (t,
3H, J¼7 Hz); 19F NMR (CDCl3, 288.3 MHz) ꢁ110.7 (dd,
J¼8.5 and 255 Hz), ꢁ115.4 (dd, J¼8.5 and 224 Hz),
ꢁ116.9 (dd, J¼17 and 255 Hz), ꢁ121.8 (d, J¼224 Hz).