5218
M. Han et al. / Tetrahedron Letters 49 (2008) 5217–5219
O
O
O
N
N
H
HO
O
O
O
O
CH3
KOAc
+
O
N
H
N
H
EtOH, 50 ºC
air
H3C
Cl
OAc
4
86%
5
3
< 5 %
Scheme 1. Competitive reactions of substitution and dimerization.
atmosphere failed only to give complex mixtures including starting
material, which suggested that the molecular oxygen was essen-
tially involved in the reaction process. Sodium hydroxide delivered
nearly the same yield as potassium hydroxide. Even when mild
amine bases (triethylamine and pyridine) were used, detectable
dimerized compounds were obtained though the yields were very
low.
Though there are a few precedent papers on dimerization of
ethyl acetoacetate,7,8 it is the first finding of dimerization of
a-
chloroacetoacetanilide. The exact mechanism for this unusual
dimerization is now unclear. However, increased yields were
obtained in case the reaction was performed under oxygen atmo-
sphere. One major by-product in the reaction was
tanilide by nucleophilic substitution of chloride with hydroxide.
The starting -chloroacetoacetanilides 3a–l were readily pre-
a-hydroxyace-
a
pared through the previously reported methods, as shown in Table
2.6 Diketene and anilines in refluxing benzene afforded acetoani-
lides 7 in quantitative yields, followed by chlorination of acetoani-
lides by sulfuryl chloride in benzene at room temperature to give
the desired products. Regardless of substituents on anilines, the
manipulation of the process was very simple and overall yields
were excellent.
As shown in Table 3, dimerization reactions of
a-chloroaceto-
acetanilides with various substituents on phenyl ring were carried
out. The optimized, high-yielding procedure (EtOH/air/50 °C/7 h)
afforded the desired dimerized products (5a–l), which were iso-
lated by slow crystallization and absolutely pure enough for ele-
mental analysis without further recrystallization. By virtue of
easiness of preparation of starting materials, manipulation of reac-
tion, and isolation of products, there were few problems even in
scale-up process.
Figure 2. ORTEP plot of the structure of bicyclic
Hydrogens are excluded.
c-lactam in dimeric form.
Table 1
Optimization of reaction condition for dimerization
In summary, we have described the first finding of unusual
dimerization/oxidation of
a-chloroacetoacetanilide under basic
O
O
O
N
reaction condition to give structurally unique 6-oxa-3-azabi-
cyclo[3.1.0]hexane. The beneficial aspects of this reaction, that is,
the easiness of preparation of starting materials, manipulation of
reaction, and isolation of products allowed us to establish structur-
ally unique chemical library. Further studies on their biological
activities as well as for the scope and mechanism of the reaction
are now in progress.
N
H
HO
O
O
CH3
Reaction Conditions
O
N
H
H3C
Cl
3
5
Entry
Base
Reaction conditions
Yielda (%)
Typical procedure: Synthesis of compound 5: To a solution of
1
2
3
4
5
6
7
KOAc
KOH
KOH
KOH
NaOH
Et3N
EtOH, air, 50 °C, 7 h
EtOH, air, 50 °C, 7 h
EtOH, O2, 50 °C, 7 h
EtOH, N2, 50 °C, 7 h
EtOH, air, 50 °C, 7 h
EtOH, air, 50 °C, 7 h
EtOH, air, 50 °C, 7 h
<5
77
a-chloroacetoacetanilide 3 (42.3 g, 0.20 mol) in 95% ethanol
(300 ml) at 50 °C was added a solution of 85% potassium hydroxide
(11.2 g, 0.20 mol) in 95% ethanol dropwise over 80 min under air.
The reaction mixture was stirred for 7 h. The white solid precipi-
tates were filtered off and the solvent was removed to obtain a
brown caramel. Crystallization of the resulting mixture with benz-
ene gave a white crystal (27.8 g, 77%).
79
N.R.b
74
<10
<10
Pyridine
a
Isolated yields.
No reaction.
b
Spectroscopic and analytical data for compound 5a: 1H NMR
(CDCl3, 300 MHz) d 1.62 (s, 3H) 2.70 (s, 3H) 6.57 (s, 1H) 7.27–
7.63 (m, 10H) 8.65 (s, 1H); 13C NMR (CDCl3, 75.5 MHz) d 21.34,
29.74, 67.07, 67.45, 89.38, 120.46, 125.94, 127.33, 128.29, 129.18,
133.78, 135.50, 161.48, 165.24, 196.09. IR (KBr): 3450, 3335,
3246, 3086, 2980, 1728 (C@O), 1696 (C@O), 1594, 1542, 1480,
1400, 1310, 1144, 1048, 928, 876, 800, 760, 684 cmÀ1. Elemental
and less nucleophilic, is used under the same reaction condition,
and the chemical yields were dramatically improved (entries 2
and 3). Bubbling oxygen gave almost same yield, compared to open
to air condition. But, attempt to the same reaction under nitrogen