H. Kawanami, Y. Ikushima / Tetrahedron Letters 45 (2004) 5147–5150
5149
in one-pot, which consists of some elemental reactions
of the Michaelreaction and the adl olcondensation and
dehydration.
increasing yield of 5a with decreasing the yield of 3a.
However, the by-product 6a, which is formed by the
hetero-Diels–Alder cycloaddition (Scheme 1),11 is
known to proceed favorably under supercritical and
pressurized condition,12 and this formation of 6a inter-
feres the Michaelreaction of 1a and 2a, leading to the
decrease in selectivity of 3a at higher pressures above
10 MPa.
To elucidate what is responsible for the effect of one-pot
Robinson annelation by the pressure and temperature
manipulation, the pressure dependence of selectivities at
100 and 180 °C was investigated, and the results were
shown in Figures 1 and 2. One can see the interesting
pressure dependence at each temperature. In the case of
100 °C (Fig. 1), the selectivities of 5a, and by-product 6a
decrease with increasing pressure up to 10 MPa, whereas
the selectivity of 3a increases, reaching maximum
selectivity of 95% at 10 MPa near the critical pressure.
In the case of 180 °C (Fig. 2), the selectivity of 5a was
improved and was much higher than 3a, with maximum
selectivity of 65% at 20 MPa (density is 0.281 g cmꢀ3).
However, the both selectivities of 3a and 5a were de-
creased with increasing pressure above 20 MPa, because
of formation of the by-product 6a, which interferes the
production of 3a and 5a. Therefore, acceleration only
the Robinson annelation in one-pot to obtain 5a in good
yield and good selectivity can be achieved by the simply
gradualpressure and temperature manipualtion, and
this method would be apply for other reactions.
It is considered that in the near criticaldensity
(0.189 g cmꢀ3) at 10 MPa, the local concentration of 2a
with 1a would be large than that at lower pressure,10 and
the product 3a would be less soluble into CO2 phase as
compared to 1a and 2a, resulting promotion of the
Michaelreaction of 2a with 1a. On the other hand, at
the higher pressure than 10 MPa, the aldol condensation
from 3a to 5a was accelerated under supercritical con-
dition in the presence of MgO catalyst,5 giving the
In conclusion, we demonstrated that the gradual pres-
sure and temperature manipulation under supercritical
conditions is available for the one-pot Robinson anne-
lation in high yield. By adjusting the pressure and tem-
perature, 5a was obtained in very high yield of 95%.
Furthermore, under supercriticalcondition, this reac-
tion was found to be much faster compared to that in
100
80
60
40
20
0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
3a;b;c
conventionalorganic sovl ent.
3a
5a
Acknowledgements
6a
This work was supported in part by CREST from Japan
Science and Technology Corporation, and Industrial
Technology Research Grant Program in 2003 from
NEDO of Japan.
0
5
10
15
20
25
Pressure / MPa
References and notes
Figure 1. Pressure dependence of the selectivity of each product (3a,
5a, and 6a) under scCO2 at 100 °C.
1. (a) Ikushima, Y.; Arai, M. In Chemical Synthesis Using
Supercritical Fluids; Jessop, P. G., Leitner, W., Eds.;
Wiley–VCH: Weinheim, 1999; pp 259–279; (b) High
€
Pressure Chemistry; Eldik, R., Klarner, F.-G., Eds.;
Wiley–VCH: Weinheim, 2002.
70
60
50
40
30
20
10
0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2. (a) Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935,
1285–1288; (b) Rapson, W. S. J. Chem. Soc. 1936, 1626–
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F., III. Tetrahedron Lett. 2000, 41, 6951–6954; (c)
Dutcher, J. S.; Macmillian, J. G.; Heathcock, C. H.
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5a
3a
6a
0
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10
15
20
25
30
35
4. (a) Kawanami, H.; Sasaki, A.; Matsui, K.; Ikushima, Y.
Chem. Commun. 2003, 896–897; (b) Kawanami, H.;
Ikushima, Y. J. Jpn. Pet. Inst. 2002, 45, 321–323; (c)
Kawanami, H.; Ikushima, Y. Tetrahedron Lett. 2002, 43,
Pressure / MPa
Figure 2. Pressure dependence of the selectivity of each product (3a,
5a, and 6a) under scCO2 at 180 °C.