T. Ulven, P. H. J. Carlsen
FULL PAPER
Table 1. ((AUTHOR: Please insert caption!))
two-phase conditions. The reaction mixtures appeared to be
homogeneous. However, if volumes were reduced too much,
two distinct phases were observed and the hydrolysis then
proceeded very slowly. The addition of co-solvents, for ex-
ample, tert-butyl alcohol, isopropyl alcohol or acetone, in
combination with ultrasound, did not noticeably improve
the rate of reaction. Adjusting the pH of the aqueous phase
of the reaction to Ͼ 12 with sodium hydroxide, and sub-
sequent continuous extraction with diethyl ether, led to the
recovery of approximately 70% of the RAMP auxiliary.
Hydrazone Reaction time Conversion (%)[a] Isolated yield (%)
1
Ͻ 60 min
7 h
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
30
Ͼ 99
Ͼ 99
Ͼ 99
94
96
50
Ϫ
2
88[b]
Ͼ 99[c]
Ϫ
3
Ͻ 16 h
Ͻ 7 h
4
5
7 ϩ 1 h[d]
48 ϩ 24 h[d]
15 d
97[c]
77[e]
6
7
8
Ͻ 3 h
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
9
Ͻ 14 h
Ͻ 15 h
Ͼ 15 h
Ͼ 220 h
Ͼ 46 d
10
11
12
13
Conclusion
[a]
[b]
[c]
Determined by GC. Ϫ
Purified by recrystallisation. Ϫ
[e]
A procedure for the hydrolysis of hydrazones containing
acid-labile acetal groups and ozone-sensitive olefin moiet-
ies, using ammonium phosphate buffers (pH ϭ 4.5) under
mild reaction conditions is reported. The method is more
suitable for acid-sensitive substrates than the known acetate
buffer method, and worked satisfactorily for a series of
N,N-dimethylhydrazones and RAMP-hydrazones, yielding
the corresponding ketones in high yields.
[d]
Crude product. Ϫ
chromatography.
Two-stage hydrolysis. Ϫ Purified by flash-
than 48 hours. However, by-products (e.g. benzaldehyde)
corresponding to the hydrolysis of the acetal moiety were
observed.
Hydrolysis of the dialkylated compound 3 proceeded
more slowly but was complete within 16 h. Hydrolysis of
the RAMP-hydrazones 5 and 6 stopped at approximately
90% conversion. However, extraction of the ketone and the
unchanged hydrazone with dichloromethane and sub-
sequent repeated hydrolysis of the concentrated extract re-
sulted in complete conversion. In neither of these cases were
products corresponding to hydrolysis of the acetal group
observed. The more substituted RAMP-hydrazone 6, re-
quired longer reaction times. Reaction at room temperature
for 48 h, extraction of the partially hydrolysed product, and
repeated hydrolysis for an additional 24 h, however, resulted
in complete conversion into the ketone. Hydrolysis of the
trisubstituted BDHA-hydrazone 7 was slow and only 30%
was converted after 15 d at room temperature. To investig-
ate the scope of this method further, the hydrolysis of a
number of other hydrazones was investigated. The RAMP-
hydrazone 8 of 3-pentanone was hydrolysed in less than 3
h, the acetophenone hydrazone 9 in 15 h, and the 4-tert-
butylcyclohexanone hydrazone 10 in less than 14 h.
The method is useful for hydrazones of enones, which
are incompatible with ozonolysis. Hydrolysis of the RAMP-
hydrazone 11 of 2-cyclohexenone, was almost complete
within 15 h, but the more substituted hydrazone 12 required
220 h for 96% conversion. Only 50% of compound 13 was
converted after 46 d at room temperature.
All experiments described above were performed under
nitrogen at room temperature. Under refluxing conditions,
the reaction proceeded faster. For example, GC analysis in-
dicated that the reaction of compound 13 was complete in
approximately 1 h. The more substituted hydrazones ap-
peared to react sluggishly. This may be due to either steric
effects or to differences in solubilities under the potential
Experimental Section
Hydrolysis of Hydrazones. ؊ General Procedure: The hydrazone
(1 mmol) was dissolved in THF (6 mL). Aqueous NH4H2PO4 (1.6
, pH ϭ 4.5, 30 mL) was added and the mixture was stirred vigor-
ously at room temperature under nitrogen. When no more hy-
drazone was detected by GLC and TLC analysis, the reaction mix-
ture was extracted with dichloromethane (5 ϫ 5 mL). The organic
phase was washed with brine and dried with anhydrous magnesium
sulfate. The solvent was removed under reduced pressure to yield
the crude product, which was further purified by recrystallisation,
flash chromatography or analysed by GLC.
Acknowledgments
The authors would like to express their gratitude to the Norwegian
National Research Council for financial support.
[1] [1a]
D. Enders, Asymmetric Synthesis (Ed.: J. D. Morrison),
[1b]
Academic Press, New York, 1984, vol. 3, chapter 4. Ϫ
D.
Enders, M. Klatt, Encyclopedia of Reagents for Organic Syn-
thesis (Ed.: L. A. Paquette), Wiley, 1995, vol. 1, pp. 178Ϫ182.
D. Enders, H. Eichenauer, U. Baus, H. Schubert, K. A. M.
Kremer, Tetrahedron 1984, 40, 1345Ϫ1359.
D. B. Collum, D. Kahne, S. A. Gut, R. T. DePue, F. Moham-
adi, R. A. Wanat, J. Clardy, G. Van Duyne, J. Am. Chem. Soc.
1984, 106, 4865Ϫ4869.
[2]
[3]
[4]
[5]
[6]
S. Bath, A. R. Ramesha, S. Chandrasekaran, Synlett 1995,
329Ϫ330.
D. Enders, V. Bhushan, Z. Naturforsch., Teil B 1987, 42,
1595Ϫ1601.
E. J. Corey, H. L. Pearce, J. Am. Chem. Soc. 1979, 101,
5841Ϫ5843.
Received December 8, 1999
[O99664]
3972
Eur. J. Org. Chem. 2000, 3971Ϫ3972
Ulven
