G. Jenner / Tetrahedron Letters 42 (2001) 243–245
Table 2. High pressure synthesis of hindered functionalized alkenesa
245
R
R%
Pressure (MPa)
T (°C)
Time (h)
Yield (%)
Isomer ratio
Et
Et
nPr
600
600
850
850
900
600
900
60
60
65
65
65
50
65
16.5
16.5
24
24
24
51.9
45.7
47.5
2.3b
85.6
12.7
32.6b
50:50
50:50
67:33
Nd
50:50
–
nBu
sec-Bu
tBu
iPr
nPr
nPr
Me
Me
Et
nPr
nPr
3
24
–
a Ethyl cyanoacetate (1.9 mmol), piperidine (0.35 mmol), ketone (1 mL). There was no reaction at ambient pressure.
b We suspect a possible solidification of the medium.
dered alkenes are difficult to prepare.12 In addition,
the Knoevenagel reaction reported here is an example
of a reaction of a similar type, which is diversely
affected by pressure. To our knowledge this finding
has precedence only in the elimination reactions stud-
ied by Brower referring to alternate or mixed mecha-
nisms.9
References
1. Jones, G. Org. React. 1967, 15, 204–599.
2. Prout, F. S. J. Org. Chem. 1953, 18, 928–933.
3. Jenner, G. J. Chem. Soc., Faraday Trans. 1 1985, 81,
2437–2460.
4. Patai, S.; Israeli, Y. J. Chem. Soc. 1960, 2020–2024.
5. Tietze, L. F.; Beifuss, U. In Comprehensive Organic Syn-
thesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p. 341.
For dissymmetrical ketones, two isomers may be pro-
duced. Interestingly, the isomer ratio is not altered by
pressure.
6. Newitt, D. M.; Linstead, R. P.; Sapiro, R. H.; Boorman,
E. J. J. Chem. Soc. 1937, 876–883.
7. Jenner, G. New J. Chem. 1999, 23, 525–529.
8. Hamann, S. D.; Teplitzky, D. R. Disc. Faraday Soc.
1956, 22, 114–121.
At the present stage it is difficult to venture a rational
explanation for these results. The yields seem to de-
pend on: (i) the pressure effect on equilibria shifts
shown in Scheme 1 toward a privileged direction13
and (ii) the general pressure effect in sterically hin-
dered reaction.3
9. Brower, K. R.; Muhsin, M.; Brower, H. E. J. Am. Chem.
Soc. 1976, 98, 779–782.
10. Agafonov, N. E.; Sedishev, I. P.; Dudin, A. V.; Kutin, A.
A.; Stashina, G. A.; Zhulin, V. M. Izv. Akad. Nauk SSR,
Ser. Khim. 1991, 426–427.
11. Standard runs (Table 1): Ester (1.9 mmol), piperidine (0.2
mmol) and 1,2,3-trimethoxybenzene (internal standard
about 0.12 mmol) were placed in a flexible 2.5 mL PTFE
tube. The volume was adjusted with the keto compound.
The tube was shaken and rapidly introduced into the
high pressure vessel. After release of pressure the volatile
compounds were removed in vacuo. The residue was
Despite the beneficial effect of a 300 MPa pressure,
hindered ketones such as pinacolone (entry 13) did
not react (at variance we observed a nearly quantita-
tive yield in the condensation of pinacolone with mal-
ononitrile at that pressure). In order to synthesize
olefins which could not be prepared at low pressures,
we carried out experiments at higher pressures. How-
ever, as neat conditions were required,14 it was not
possible to secure liquid state of the medium at the
experiment pressure (the freezing point of liquids is
raised by pressure).15 It was, therefore, necessary to
simultaneously limit pressure and increase tempera-
ture. Operating under such conditions, we were
gratified by the fair to good results listed in Table 2.
Clearly, application of pressure is of high value for
the preparation of sterically hindered olefins via Kno-
evenagel condensations. We are pursuing such studies
highlighting the correlation between pressure and
steric congestion on both theoretical and synthetic
levels.
1
directly analyzed by H NMR and the yield determined
from relative intensities of characteristic protons versus
methoxy groups of the internal standard.
12. Lenoir, D. Nachr. Chem. Tech. Lab. 1979, 27, 762–764;
Lenoir, D. Synthesis, 1989, 883–897.
13. We tested possible reversal of step 4 in Scheme 1 by
submitting the alkenes synthesized in entries 6 and 11 in
the presence of water (1.5 equiv.) and piperidine (0.1
equiv.) at 23°C (2 h) at 0.1 and 300 MPa, respectively.
No hydrolysis was however observed and the alkenes
were recovered quantitatively.
14. Operation in dichloromethane solution drastically re-
duced the yield of alkenes.
15. Babb, S. E. Rev. Mod. Phys. 1963, 35, 400–413.
.