PAPER
One-Step Synthesis of b-Lactams with Retro-Amide Side Chain
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HRMS (ESI–): m/z [M – H+]– calcd for C13H12ClNO5: 297.0404;
H), 7.09 (t, J = 7.32 Hz, 1 H), 7.28 (t, J = 8.3 Hz, 2 H), 7.37 (d,
found: 269.0426.
J = 8.8 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 2 H), 8.45 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 28.4, 55.6, 55.6, 56.8, 63.0, 114.6,
5-[(Cyclohexylamino)(hydroxy)methylene]-2,2-dimethyl-1,3-
dioxane-4,6-dione (1c); Typical Procedure
120.0, 124.6, 128.2, 129.1, 131.2, 137.8, 160.1, 163.9, 165.5.
HRMS (ESI): m/z [M + Na]+ calcd for C21H24N2NaO3: 352.1787;
found: 352.1867.
To a soln of Meldrum’s acid (0.72 g, 5 mmol) in anhyd DMF (5 mL)
in a glass ampoule was added Et3N (1.4 mL, 10 mmol). Cyclohexyl
isocyanate (0.751 g, 6 mmol) was added, and the ampoule was
sealed. The ampoule was placed in the bath at 40 °C for 20 h. The
mixture was poured into ice-cold 2 M HCl (30 mL). The solid pre-
cipitate was filtered and washed with cold H2O. The precipitate was
dissolved in EtOAc (30 mL) and dried (MgSO4), after cooling the
soln the precipitate of DCU was removed by filtration. The solvent
was removed under reduced pressure and the residue crystallized
(EtOAc–hexane); yield: 0.795 g (60%); mp 103–104.5 °C.
1H NMR (500 MHz, CDCl3): d = 1.28 (m, 1 H), 1.40 (m, 4 H), 1.64
(m, 1 H), 1.73 (m, 6 H), 1.78 (m, 2 H), 1.98 (m, 2 H), 3.81 (m, 1 H),
9.22 (s, 1 H), 14.91 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 24.59, 25.42, 26.51, 32.73, 50.09,
73.02, 104.77, 164.60, 169.42, 170.65.
1-tert-Butyl-4-(3-chlorophenyl)-2-oxo-N-phenylazetidine-3-
carboxamide (3ac)
Purification by flash column chromatography (EtOAc–toluene,
1:12); mp 207–208 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.22 (s, 9 H), 3.85 (d, J = 2.4
Hz, 1 H), 4.96 (d, J = 2.4 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.32 (t,
J = 7.8 Hz, 2 H), 7.43–7.50 (m, 3 H), 7.51–7.60 (m, 2 H), 10.14 (s,
1 H).
13C NMR (50 MHz, DMSO-d6): d = 27.7, 54.4, 54.6, 63.6, 119.0,
123.6, 125.2, 126.6, 128.3, 128.7, 130.7, 133.4, 138.5, 142.7, 163.3,
164.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21ClN2NaO2: 356.1291;
found: 356.1286.
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NNaO5: 269.1262;
found: 269.1266.
1-tert-Butyl-4-(4-nitrophenyl)-2-oxo-N-phenylazetidine-3-car-
boxamide (3ad)
Purification by flash column chromatography (EtOAc–toluene,
5-[(Ethylamino)(hydroxy)methylene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1d)
Following the typical procedure for 1c using Meldrum’s acid (0.72
g, 5 mmol), anhyd DMF(5 mL), Et3N (1.4 mL, 10 mmol) and ethyl
isocyanate (0.426 g, 6 mmol), at 40 °C for 10 h; yield: 0.706 g
(65%); mp 72–74 °C.
1H NMR (500 MHz, CDCl3): d = 1.30 (t, J = 7.3 Hz, 3 H), 1.74 (s,
6 H), 3.49 (m, 2 H), 9.25 (br s, 1 H), 14.98 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.7, 26.4, 35.8, 104.2, 164.1.
HRMS (ESI): m/z [M + Na]+ calcd for C9H13NNaO5: 215.0794;
1:8); mp 183–185 °C.
1H NMR (500 MHz, CDCl3): d = 1.32 (s, 9 H), 3.77 (d, J = 1.9 Hz,
1 H), 5.13 (d, J = 1.9 Hz, 1 H), 7.14–7.21 (m, 1 H), 7.35 (t, J = 8.3
Hz, 2 H), 7.56 (d, J = 7.8 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 2 H), 8.10
(br s, 1 H), 8.30 (d, J = 8.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 28.2, 55.8, 62.7, 119.8, 124.3,
124.7, 127.4, 128.2, 129.0, 137.2, 146.7, 162.7, 164.9.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21N3NaO4: 367.1532;
found: 367.1528.
found: 215.0792.
1-Ethyl-2-oxo-N,4-diphenylazetidine-3-carboxamide (3ae)
Purification by flash column chromatography (EtOAc–hexane,
1:3); mp 114–116 °C.
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.32 Hz, 3 H), 3.03
(hept, J = 7.32, 6.83 Hz, 1 H), 3.53 (hept, J = 7.32, 6.83 Hz, 1 H),
3.98 (d, J = 2.4 Hz, 1 H), 5.09 (d, J = 2.4 Hz, 1 H), 7.07 (t, J = 7.32
Hz, 1 H), 7.25 (m, 2 H), 7.40 (m, 5 H), 7.53 (d, J = 8.3 Hz, 2 H),
8.78 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.2, 36.7, 57.5, 64.5, 120.4,
124.9, 127.1, 129.4, 129.6, 137.3, 138.1, 164.0, 165.5.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18N2NaO2: 294.1367;
found: 294.1351.
1,4-Disubstituted 2-Oxoazetidine-3-carboxylic Acid Amides 3;
General Procedure
Cooled (0 °C) soln of 1 (2 mmol) and aldimine 2 (2 mmol) in tolu-
ene (10 mL) was saturated with HCl over 20 min. The resulting
mixture was stirred and heated to reflux for the time specified in
Table 1. After completion of the reaction, the solvent was removed
under vacuum, and the residue was purified.
1-Isopropyl-2-oxo-N,4-diphenylazetidine-3-carboxamide (3aa)
Purification by flash column chromatography (EtOAc–hexane,
1:3); mp 144–146 °C.
1H NMR (500 MHz, CDCl3): d = 1.11 (d, J = 6.8 Hz, 3 H), 1.34 (d,
J = 6.8 Hz, 3 H), 3.78 (hept, J = 6.8 Hz, 1 H), 3.90 (d, J = 2.4 Hz, 1
H), 5.02 (d, J = 2.4 Hz, 1 H), 7.10 (t, J = 7.32 Hz, 1 H), 7.28–7.37
(m, 2 H), 7.38–7.76 (m, 5 H), 7.55 (d, J = 7.8 Hz, 2 H), 8.35 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.3, 21.2, 46.0, 56.8, 63.0, 119.9,
124.5, 126.7, 128.8, 128.9, 129.0, 137.4, 137.9, 163.5, 165.0.
HRMS (ESI): m/z [M + Na]+ calcd for C19H20N2NaO2: 308.1525;
found: 308.1501.
1-Butyl-4-tert-butyl-2-oxo-N-phenylazetidine-3-carboxamide
(3ag)
Purification by flash column chromatography (EtOAc–toluene,
1:6); mp 109–111 °C.
1H NMR (500 MHz, CDCl3): d = 0.95 (t, J = 7.3 Hz, 2 H), 1.08 (s,
9 H), 1.33–1.38 (m, 2 H), 1.58–1.65 (m, 2 H), 3.01–3.06 (m, 1 H),
3.58–3.64 (m, 1 H), 3.72 (s, 1 H), 3.84 (d, J = 1.9 Hz, 1 H), 7.12 (t,
J = 7.3 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 2 H), 7.56 (d, J = 7.8 Hz, 2 H),
8.32 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.5, 19.9, 26.0, 29.4, 32.5, 42.4,
55.2, 64.3, 119.7, 124.3, 128.8, 137.5, 164.0, 165.9.
1-tert-Butyl-4-(4-methoxyphenyl)-2-oxo-N-phenylazetidine-3-
carboxamide (3ab)
Purification by flash column chromatography (EtOAc–hexane,
1:3); mp 164–166 °C.
1H NMR (500 MHz, CDCl3): d = = 1.29 (s, 9 H), 3.80 (d, J = 2.4 Hz,
1 H), 3.83 (s, 3 H), 5.00 (d, J = 2.4 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 2
HRMS (ESI): m/z [M + Na]+ calcd for C18H26N2NaO2: 302.1993;
found: 302.2015.
Synthesis 2011, No. 1, 69–72 © Thieme Stuttgart · New York