PAPER
Synthesis of cis-4-Aryl-3-chloro-2-azetidinones
197
MS: m/z (%) = M+ (not detected), 157 (3), 147 (2), 145 (2), 139/141
(100), 132 (3), 104 (19), 101 (3), 83 (3), 77 (7), 67 (1), 57 (4), 55
(6), 51 (3).
MS: m/z (%) = 237/239 (M+, 1), 152 (73), 150 (100), 130 (14), 116
(63), 114 (38), 90 (12).
Anal. Calcd for C13H16ClNO: C, 65.70; H, 6.74; N, 5.90. Found: C,
65.80; H, 6.94; H, 5.86.
Anal. Calcd for C15H18ClNO: C, 68.32; H, 6.83; N, 5.31. Found: C,
68.46; H, 6.96; N, 5.24.
cis-3-Chloro-3-ethyl-1-isopropyl-4-phenyl-2-azetidinone (11)
Yield: 40%; mp 70.9–71.1 °C (MeOH).
trans-3-Chloro-1-cyclohexyl-4-phenylazetidin-2-one (8b)
Flash chromatography: petroleum ether–EtOAc (6:4), Rf 0.65.
IR (KBr): 1769 cm–1 (C=O).
1H NMR (CDCl3): d = 0.96–2.04 [10 H, m, (CH2)5], 3.33–3.45 (1 H,
m, NCH), 4.44 and 4.54 (2 × 1 H, 2 d, J = 1.6 Hz, NCH and CHCl),
7.34–7.46 (5 H, m, C6H5).
IR (KBr): 1748 cm–1 (C=O).
1H NMR (CDCl3): d = 1.13 and 1.36 (2 × 3 H, 2 d, J = 6.6 Hz,
CH(CH3)3], 1.17 (3 H, t, J = 7.26 Hz, CH2CH3), 2.14 (2 H, m,
CH2CH3), 3.76 (1 H, septet, J = 6.93 Hz, CHMe2), 4.67 (1 H, s,
NCHC6H5), 7.30–7.44 (5 H, m, C6H5).
13C NMR (CDCl3): d = 24.95, 25.01, 30.21, 31.15 and 32.80
[(CH2)5], 53.75 (NCH), 62.85 and 65.15 (NCH and CHCl), 126.95,
129.20 and 129.31 (Co, Cm, Cp), 136.71 (Cq), 163.82 (C=O).
MS: m/z (%) = M+ (not detected), 175 (2), 153 (3), 151 (4), 138/140
(100), 135 (3), 131 (3), 105 (4), 103 (20), 91 (31), 86 (18), 84 (28),
77 (7), 74 (8), 59 (13), 55 (4), 51 (3), 49 (5), 47 (6).
13C NMR (CDCl3): d = 9.07 (CH2CH3), 20.31 and 21.06
[CH(CH3)3], 30.64 (CH2CH3), 45.59 (CHMe2), 65.91 (NCHC6H5),
77.43 [CqCl(CH2CH3)], 128.10 and 128.26 (Co, Cm), 128.82 (Cp),
135.40 (Cq), 166.95 (C=O).
MS: m/z (%) = 251/253 (M+, 1), 216 (M+ – Cl, 2), 166/168 (100),
151 (6), 131 (41), 115 (10), 91 (6).
Anal. Calcd for C15H18ClNO: C, 68.32; H, 6.83; N, 5.31. Found: C,
68.22; H, 6.94; N, 5.26.
Anal. Calcd for C14H18ClNO: C, 66.81; H, 7.16; N, 5.57. Found: C,
66.95; H, 7.32; N, 5.52.
cis-1-Benzyl-3-chloro-4-phenyl-2-azetidinone (9a)
Flash chromatography: petroleum ether–EtOAc (8:2), Rf 0.34.
IR (neat): 1770 cm–1 (C=O).
1H NMR (CDCl3): d = 3.89 [1 H, d, J = 15 Hz, CH(H)C6H5], 4.77
(1 H, d, J = 5 Hz, NCHC6H5), 4.88 [1 H, d, J = 15 Hz, CH(H)C6H5],
5.05 (1 H, d, J = 5 Hz, CHCl), 7.13–7.39 (10 H, m, 2 × C6H5).
13C NMR (CDCl3): d = 44.92 (NCH2), 60.23 (NCH), 61.11 (CHCl),
128.07, 128.19, 128.48, 128.53, 128.86 and 129.04 (2 Co, 2 Cm, 2
Cp), 132.95 and 134.32 (2 Cq), 163.95 (C=O).
cis-1-Benzyl-3-chloro-4-phenyl-3-propyl-2-azetidinone (12)
Flash chromatography: petroleum ether–EtOAc (8:2); Rf 0.52;
yield: 23%.
IR (neat): 1781 cm–1 (C = O).
1H NMR (CDCl3): d = 0.95 (3 H, t, J = 7.6 Hz, CH3), 1.41–1.72 (2
H, m, CH2CH3), 1.89–2.17 (2 H, m, CH2CH2CH3), 3.86 [1 H, d,
J = 14.5 Hz, NCH(H)C6H5], 4.44 (1 H, s, NCHC6H5), 4.93 [1 H, d,
J = 14.5 Hz, NCH(H)C6H5], 7.10–7.45 (10 H, m, 2 C6H5).
13C NMR (CDCl3): d = 13.93 (CH2CH3), 17.99 (CH2CH3), 39.21
(CH2CH2CH3), 44.49 (NCH2), 66.38 (NCHC6H5), 77.99 (CqCl),
127.57, 127.99, 128.10, 128.34, 128.46 and 128.67 (2 Co, 2 Cm, 2
Cp), 133.82 and 134.63 (2 Cq), 166.88 (C=O).
MS: m/z (%) = 271/273 (M+, 0.4), 138/140 (100), 132 (2), 104 (4),
103 (25), 91 (40), 77 (10), 65 (7), 51 (10).
Anal. Calcd for C16H14ClNO: C, 70.73; H, 5.16; N, 5.16. Found: C,
70.89; H, 5.40; N, 5.11.
MS: m/z (%) = 278 (M+ – Cl, 2), 145 (13), 103 (7), 91 (100), 77 (11),
65 (10), 51 (3).
trans-1-Benzyl-3-chloro-4-phenylazetidin-2-one (9b)
Flash chromatography: petroleum ether–EtOAc (8:2), Rf 0.36.
Anal. Calcd for C19H20ClNO: C, 72.74; H, 6.38; N, 4.47. Found: C,
72.94; H, 6.68; N, 4.45.
IR (neat): 1774 cm–1 (C=O).
Halogen–Lithium Exchange Experiments Confirming the Pro-
posed Reaction Mechanism
1H NMR (CDCl3): d = 3.82 [1 H, d, J = 15 Hz, CH(H)C6H5], 4.38
(1 H, d, J = 1.7 Hz, NCHC6H5), 4.56 (1 H, d, J = 1.7 Hz, CHCl),
4.88 [1 H, d, J = 15 Hz, CH(H)C6H5], 7.13–7.38 (10 H, m, 2 ×
C6H5).
13C NMR (CDCl3): d = 44.90 (NCH2), 63.18 (NCH), 65.25 (CHCl),
126.61, 128.03, 128.41, 128.88, 129.22 and 129.40 (2 Co, 2 Cm, 2
Cp), 134.66 and 137.30 (2 Cq), 163.63 (C=O).
The first experiment (vide supra) conducted to confirm some mech-
anistic aspects of the results obtained from the previously described
halogen–lithium exchange reactions, was concerned with the
isomerization of cis-3-chloro-1-isopropyl-4-phenyl-2-azetidinone
(6a) to the corresponding trans-derivative 6b. cis-3-Chloro-1-iso-
propyl-4-phenyl-2-azetidinone (6a; 0.10 g, 0.4 mmol) was dis-
solved in a H2O–THF solvent mixture (1:4, 2 mL). Subsequently,
LiOH·H2O (0.06 g, 0.5 mmol) was added and the resulting mixture
was stirred during 40 h. Afterwards, H2O was added and the aque-
ous layer was extracted with Et2O. Drying (MgSO4), filtration and
evaporation of the solvent yielded the crude reaction product, i.e. a
mixture of cis- and trans-3-chloro-1-isopropyl-4-phenyl-2-azetidi-
nones (6a and 6b), which was used to determine the ratio of both
MS: m/z = M+ (not detected), 194/196 (M+ – C6H5, 2), 103 (20), 91
(21), 77 (7), 65 (5), 51 (3).
Anal. Calcd for C16H14ClNO: C, 70.73; H, 5.16; N, 5.16. Found: C,
70.50; H, 5.28; N, 5.06.
cis-3-Chloro-1-isopropyl-3-methyl-4-phenyl-2-azetidinone (10)
Yield: 57%; mp 106.6–106.8 °C (MeOH).
1
products by H NMR spectroscopy. The cis:trans ratio obtained
turned out to be 1:2.63.
IR (KBr): 1747 cm–1 (C=O).
In a second experiment, the conventional procedure was followed.
A solution of 3,3-dichloro-1-isopropyl-4-phenyl-2-azetidinone (4a;
R1 = i-Pr, R2 = H; 1.00 g, 3.9 mmol) in THF (10 mL) was placed un-
der N2 and kept at –78 °C. With a syringe, a 2.5 M solution of n-
BuLi in hexanes (1.90 mL, 4.7 mmol) was added through the sep-
tum. The mixture was kept at –78 °C for 1 h. Afterwards, H2O (0.14
g, 7.8 mmol) in THF (10 mL) was added. The reaction mixture was
stirred for only 1 min and subsequently poured into 10% citric acid
1H NMR (CDCl3): d = 1.14 and 1.35 [2 × 3 H, 2 d, J = 6.9 Hz,
CH(CH3)3], 1.87 [3 H, s, C(O)CH3], 3.76 (1 H, septet, J = 6.9 Hz,
CHMe2), 4.62 (1 H, s, NCHC6H5), 7.31–7.45 (5 H, m, C6H5).
13C NMR (CDCl3): d = 20.22 and 21.02 [CH(CH3)3], 24.55
[C(O)CH3], 45.59 (CHMe2), 68.01 (NCHC6H5), 72.69
[CqCl(CH3)], 128.05 and 128.28 (Co, Cm), 128.95 (Cp), 135.27 (Cq),
167.13 (C=O).
Synthesis 2005, No. 2, 193–198 © Thieme Stuttgart · New York