Diastereoselective alkylation of 8-phenylmenthyl 2- methylacetoacetate. Preparation of enantiomerically pure 4,4-disubstituted 2-pyrazolin-5-ones

Article abstract of DOI:10.1016/S0957-4166(97)00131-6

Alkylation of (1R,3R,4S)-8-phenylmenthyl 2-methylacetoacetate with alkyl halides affords 2-alkyl-2-methylacetoacetates in diastereomeric ratios 72:28 to 85:15. The major R (at C-α) diastereoisomers are converted into enantiopure 4,4-disubstituted 2-pyrazolin-5-ones with recovery of the chiral inductor.

Full text of DOI:10.1016/S0957-4166(97)00131-6

Tetrahedron As)mmetr?. Vol 8. No. 10. pp. 1525-1527. 1997
Pergamon
@
1997 Elsevier Science Ltd All rights reserved.
Printed in Great Britain
PII: S0957-4166(97)00131-6
0957-4166/97 $ 1 7 0 0 + 0.00
Diastereoselective alkylation of 8-phenylmenthyl 2-
methylacetoacetate. Preparation of enantiomerically pure 4,4-
disubstituted 2-pyrazolin-5-ones
Marcial Moreno-Mafias, ~'* Rosa M. Sebasti~in,a Adelina Vailribera? Elies Molins b and
Enrique Espinosab
Department of Chemistry, Universitat Aut6noma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
t, CSIC, Institut de Cibncia de Materials, Campus de [a UAB, E-08193 Cerdanyola, Spain
Abstract: Alkylation of (lR,3R,4S)-8-phenylmenthyl 2-methylacetoacetate with alkyl
halides affords 2-alkyl-2-methylacetoacetates in diastereomeric ratios 72:28 to 85:15. The
major R (at C-cx) diastereoisomers are converted into enantiopure 4,4-disubstituted 2-
pyrazolin-5-ones with recovery of the chiral inductor. @ 1997 Elsevier Science Ltd
4,4-Disubstituted 2-pyrazolin-5-ones are prepared by reaction of hydrazine with ~x,cx-disubstituted
13-ketoesters.l Alternatively, 4-unsubstituted pyrazolones are selectively allylated at C-4 under Pd(0)-
catalysis.2 However, to the best of our knowledge methods to prepare enantiomerically pure 4,4-
disubstituted 2-pyrazolin-5-ones have not been described. Their preparation requires either cyclization
of enantiomerically pure cx,~x-disubstituted 13-ketoesters featuring different substituents at C-~ or
the enantioselective alkylation of a pyrazolinone already monosubstituted at C-4. We present here a
solution based on the first strategy.
Diastereoselective monoalkylations of chiral acetoacetyl derivatives (CH3COCH2CO-Xc) are
known in spite of the lability of the stereogenic center formed at C-o~.3 Diastereoselective dialkylations
in open chain [3-ketoesters or ketoamides present a more difficult problem. However, diastereoselective
dialkylations of the relatively unencumbered c~-cyanoacetamides (NC-CH2~20-Xc) have been
reported.4 Concerning open-chain 13-ketoesters the most general approach consists of the alkylation
of chiral enamines formed from monoalkylated 13-ketoesters and t-butyl ester of (S)-valine,5'6 each
enantiomer (after hydrolysis) of the final product being predominantly produced depending on the
solvent. However, the enantiomeric purity of the final product depends only on the diastereoselectivity
of the alkylation step, since no diastereoisomers are isolated, direct hydrolysis of the initially formed
imines being carried out.
Since we are interested in enantiomerically pure 2-pyrazolin-5-ones, we looked for methods pro-
viding separable diastereoisomers before the cyclization step. Experiments with menthyl acetoacetate
showed low diastereoselectivity. Much better results were obtained using (1R,3R,4S)-8-phenylmenthyl
acetoacetate, 1,7,8 (Scheme 1). Methylation of 1 afforded 2 (92%, oil, bp 130°C/0.2 mmHg) as
a diastereoisomeric mixture (69:31). Alkylation of 2 as indicated furnished compounds 3a-d (see
Table 1) in reasonable diastereoisomeric excesses. The major diastereoisomers were isolated in pure
form. X-Ray diffraction of 3a and 3c showed their configurations at C-o( to be R and we assume this
is the case for the major diastereoisomers 3b and 3d.
Reaction of 3a-d with hydrazine hydrate affords (4R)-4-alkyl-3,4-dimethyl-2-pyrazolin-5-ones,
4a--d, the recovery of the chiral inductor 5 by column chromatography being nearly quantitative.
* Corresponding author. Email: iqorb@cc.uab.es
1525

1526
M. MORENO-MA~AS et al.
o
o v v
O~'"
CH3I/K2CO3
,~ CH3
1) HNa/THF
2) R-X
CH3
O~,.'
Acetone/40°C
CH3
Ph
Ph
1
2
.-7
H
oo@
N-"~tx
2
6
5
NH2NH2-H20
CH3
J ~ . O~'"
EtOH/140oc CH3
O
HO~"
CH3
R
.
~
CH3
R
Ph
Ph
5
3a: R = Ph-CH2-
4a-d
3b: R = PhCH=CHCH2-
3c: R = 4-C1-PhCH2-
3d: R = PhCH2CH2-
Scheme 1.
Table 1. Compounds 3 and 4
Yield (%) (a) dr (R:S) (b) mp (°C)
[ot]589(c)
Yield (%) mp (°C)
4a 95 99-101
[~]589(c)
- 186
3a 62 (27)
3b 57 (24)
83:17
82:18
72:28
85:15
91-93
70-72
112-113
oil
ca. 0 (d)
+ 14
ca. 0 (e)
- 13
4b 70 (f)
4c 88
127-128 - 201
3c
--- (29)
87-88
71-72
- 87
-95
3d 41 (35)
4d 80
Acknowledgements
Financial support from DGICYT (Ministry of Education and Science of Spain: Project PB-0896)
and DGR (Generalitat de Catalunya: SGR96-30 and a predoctoral scholarship to R.M.S.) is gratefully
acknowledged.
References
1. (a) Elguero, J. Pyrazoles and Their Benzo Derivatives. In Comprehensive Heterocyclic Chemistry;
Potts, K. T., Ed.; Pergamon Press: New York, 1984; Vol 5, Chapter 4.04. (b) Elguero, J.; Jacquier,
R.; Tarrago, G. Bull. Soc. Chim. Fr. 1967, 3772-3779. (c) Elguero, J.; Guiraud, G.; Jacquier, R.;
Tarrago, G. Bull. Soc. Chim. Ft. 1968, 5019-5029. (d) Dagli, D. J.; Gorski, R. A.; Wemple, J. J.
Org. Chem. 1975, 40, 1741-1745.
2. Moreno-Mafias, M.; P6rez, M.; Pleixats, R. Tetrahedron 1994, 50, 515-528.
3. (a) Bram, G.; Cabaret, D.; Welvart, Z.; Geraghty, N. W. A.; Garvey, J. Tetrahedron Lett. 1988,
29, 4615-4618. (b) Marco, J. L.; Martin, N.; Martfnez-Grau, A.; Seoane, C.; Albert, A.; Cano,
E H. Tetrahedron 1994, 50, 3509-3528. (c) Moreno-Mafias, M.; Sebasti~in, R. M.; Vallribera, A.;
Molins, E. Tetrahedron 1995, 51, 10795-10800. (d) G~ilvez, N.; Moreno-Mafias, M.; Vallribera,
A.; Molins, E.; Cabrero, A. Tetrahedron Lett. 1996, 37, 6197-6200.
4. Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 2463-2464.
5. (a) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 1579-1588. (b) Ando,
K.; Yasuda, K., Tomioka, K.; Koga, K. J. Chem. Soc. Perkin Trans. 1 1994, 277-282. (c) Ando,
K.; Seo, W.; Tomioka, K.; Koga, K. Tetrahedron 1994, 50, 13081-13088.
6. Georg, G. I.; Guan, X.; Kant, J. Tetrahedron Lett. 1988, 29, 403-406.

1527
Alkylation of 8-phenyLmenthyl 2-methylacetoacetate
7. Oil, bp 165-175°C/0.2-0.3 mmHg, [cx]589=+ 16 (in HCCI3) prepared by reaction of (1R,3R,4S)-8-
phenylmenthol, 5, with 2,2,6-trimethyl-4H- 1,3-dioxin-4-one (diketene-acetone adduct) according
to a general method, see Clemens, R. J.; Hyatt, J. J. Org. Chem. 1985, 50, 2431-2435.
8. We use the stereochemical descriptor (1R,3R,4S) for 8-phenylmenthol according to the IUPAC
authorized trivial names nomenclature and contrary to the numbering found in some catalogues
(Received in UK 4 March 1997)