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DOI:10.15227/orgsyn.070.0256

Organic Syntheses, Coll. Vol. 9, p.619 (1998); Vol. 70, p.256 (1992).

SYNTHESIS OF β-KETO ESTERS BY C-ACYLATION OF
PREFORMED ENOLATES WITH METHYL CYANOFORMATE:
PREPARATION OF METHYL (1α,4aβ,8aα)-2-OXODECAHYDRO-1NAPHTHOATE

Submitted by Simon R. Crabtree, Lewis N. Mander, and S. Paul Sethi1.
Checked by Thierry Vandenheste and Leo A. Paquette.

1. Procedure
CAUTION! Cyanide salts are formed in this procedure. All procedures should be conducted in awell-ventilated hood and rubber gloves should be worn.
Liquid ammonia (350 mL) is dried over sodium amide for 20 min (Note 1), then distilled under apositive pressure of dry nitrogen into a flame-dried, 1-L, three-necked, round-bottomed flask equippedwith a dry ice condenser, rubber septum and magnetic stirring bar. The flask is cooled to −78°C andsmall pieces of lithium (1.11 g, 0.16 mol) (Note 2) are added over 10 min to afford a deep blue solution.
A solution of enone 1 (10.08 g, 0.07 mol) (Note 3) in tert-butyl alcohol (5.10 g, 0.07 mol) (Note 4) andether (40 mL) (Note 5) is added dropwise over a 15-min period at −78°C, and then sufficient isoprene(Note 6) is added dropwise to discharge the residual blue color of the reaction mixture. The ammonia isallowed to evaporate under a stream of dry nitrogen and the ether is removed under reduced pressure toleave a white foam. After a further 5 min under high vacuum, the nitrogen atmosphere is restored, thelithium enolate 2 is suspended in dry ether (80 mL) at −78°C by vigorous stirring, and methyl
cyanoformate (6.73 g, 0.08 mol) (Note 7) is added over a 5-min period. Stirring is maintained at thistemperature for a further 40 min and then the mixture is allowed to warm to 0°C. Water (500 mL) andether (200 mL) are added and the mixture is stirred vigorously until the precipitate has dissolved. After
separation of the organic layer, the aqueous phase is extracted with ether (2 × 300 mL), the combined
extracts are washed with water (200 mL) and brine (200 mL) (Note 8), and then dried over anhydrous
magnesium sulfate. Removal of solvent under reduced pressure furnishes a pale yellow oil which isdissolved in hexane (200 mL); the solution is kept in the freezer (−28°C) for approximately 1.5 hr, after
which time very pale yellow crystals of the β-keto ester 3 are deposited. These are collected by filtration
at low temperature and after concentration of the mother liquors, two further crops are collected. Flashchromatography (ethyl acetate/hexane, 13:87) on silica gel (140 g) (Note 9) of the residue (3.5 g) fromthe remaining mother liquor followed by two recrystallizations affords further 3. The total quantity of 3
obtained is 11.5–11.8 g (81–84% yield) (Note 10).

2. Notes
1. Sodium amide is generated in situ from sodium metal and a crystal of ferric nitrate. Sodium metal byitself is not an effective drying agent.
2. Lithium wire was purchased from Merck Schuchardt.
3. Enone 1 was prepared according to the procedure of Augustine, R. L.; Caputo, J. A. Org. Synth., Coll.
Vol. V 1973, 869.
4. tert-Butyl alcohol was purchased from Ajax Chemicals and was freshly distilled from calcium
hydride.
5. Diethyl ether was purchased from Ajax Chemicals and was freshly distilled from sodium andbenzophenone.
6. Isoprene was purchased from Eastman Kodak, Ltd.
7. Methyl cyanoformate was purchased from the Aldrich Chemical Company, Inc. The ethyl and benzyl
analogues are also available. Small quantities up to 30 g are conveniently prepared by the method ofChilds and Weber,2 but several workers have found it to be unsatisfactory on a larger scale because of
the generation of inseparable impurities.
8. The aqueous washings contain toxic lithium cyanide and should be treated with a strong oxidizing
agent (e.g., potassium permanganate) before disposal.
9. Merck Kieselgel 60 silica gel was used.
10. A sample recrystallized twice from hexane had mp 48–49°C (Anal. Calcd for C12H18O3: C, 68.53; H.
8.63%; Found C, 68.59; H, 8.93). The spectroscopic properties of this product are as follows: IR(CHCl3) cm−1: 3026, 2931, 2859, 1744, 1710, 1454, 1447, 1437, 1364, 1348, 1340, 1155, 1112; 1H
NMR (CDCl3) δ: 1.00–1.50 (m, 6 H), 1.65–1.8 (m, 5 H), 1.9–2.0 (m, 1 H CH), 2.30–2.50 (m, 2 H, CH2),
3.12 (d, 1 H, J = 12), 3.76 (s, 3 H, OMe). 13C NMR (CDCl3) δ: 25.4, 25.9, 32.6, 32.9, 33.3, 40.5, 41.4,45.5, 51.8, 53.8, 170.2, 205.6; MS (m/z): 210 (M+, 34.6%), 192 (72), 122 (66), 108 (59), 95 (68), 94(94), 81 (100), 79 (53), 67 (77), 51 (61).

Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory";
National Academy Press; Washington, DC, 1995. See (Note 8).

3. Discussion
The present procedure provides an example of the regiospecific synthesis of β-keto esters by the Cacylation of preformed lithium enolates with cyanoformate esters.3 The enolates can be generated in avariety of ways, including direct enolization of ketones with suitable bases, liberation from silyl enolethers and acetates, conjugate additions of cuprates to α,β-unsaturated enones and by the reduction ofenones by lithium in liquid ammonia, as in the example described above. The more traditional acylating
agents (acyl halides and anhydrides) afford variable amounts of O-acylated products4 and although theuse of reaction temperatures of −100°C is reported to obviate this problem with some substrates,5 themethod does not appear to be general. The classical solution has been to use carbon dioxide followed byesterification,6 but yields rarely exceed 50%, indicating, inter alia, that the formation of enol carbonates
probably occurs to a significant extent and that these unstable intermediates decompose to ketones onwork up.7 There is also the problem of handling thermally unstable β-keto acids. Carbon disulfide8 andcarbon oxysulfide9 have been used instead of carbon dioxide, and the products methylated in situ toform dithio and thio esters, respectively. These can subsequently be converted into methyl esters bymercury(II) diacetate-catalyzed transesterification in methanol, but the methods are elaborate and do notappear to have found general use. Diethyl dicarbonate and its analogues show promise as possible
alternatives to cyanoformates, but the reported yields to date are inferior.10
In the early investigations of this reaction it was found that in one comparative study of lithium,sodium and potassium enolates, only the lithium derivatives reacted satisfactorily,3 although sodium
enolates have subsequently been used successfully.11 A range of cyanoformates can be employed, butthe tert-butyl derivatives have been reported to be too unreactive. However, a satisfactory substitutewhich affords esters that can be de-alkylated with comparable facility is the p-methoxybenzyl
analogue,12 13 although it is prepared with some difficulty. In general, benzyl derivatives seem to giveslightly better yields, possibly due to the more efficient isolation of products from substrates with lower
molecular weights. Optically active cyanoformates derived from (+)-menthol, (−)-borneol, and theOppolzer alcohol were reported to furnish good chemical yields, but the level of stereoselectivity wasdisappointingly low.14
For more conformationally-constrained chiral substrates, however, diastereoselectivity can beexpected to be good to excellent. Lithium enolates derived from sterically unencumbered
cyclohexanones undergo preferential axial acylation as illustrated by the reductive acylation of (R)-(−)carvone 4 to afford a 3:1 mixture of esters 5 and 6, whereas equatorial acylation is favored incompounds that possess an alkyl substituent in a 1,3-syn-axial relationship to the reacting center, as inthe conversion of tricyclic enone 7 to ester 8 (epimeric with the product from the more traditionalsequence of acylation followed by alkylation).15 (In substrates of this kind it is assumed that thetransition state structure is based on a twist-boat conformation which permits the reagent to approach
along an axial-like trajectory on the less encumbered, lower face of the substrate.)16

For compounds in which the β-carbon of the enolate is sterically hindered, this problem cannormally be eliminated by the use of diethyl ether as the solvent. In several cases a switch fromexclusive O-acylation in tetrahydrofuran to complete C-acylation in ether has been observed, and theconversion of 7 into 8 provides a typical illustration. When 3-methyl-2-cyclohexen-1-one 9 is converted
into 10 by the addition of lithium dimethyl cuprate followed by in situ reaction with methyl
cyanoformate, however, enol carbonate 11 accounts for 6% of the products. This can be avoided if theintermediate enolate is trapped as the enol trimethylsilyl ether and the enolate reliberated by treatment
with butyllithium (note that the traditional reagent, methyllithium, is ineffective in ether as a solvent),
but the overall yield is reduced.

Quite apart from the issue of regioselectivity, the present method is exceptionally reliable andmakes it possible to prepare β-keto esters from ketones under especially mild conditions. It is not only
the method of choice with sensitive substrates, but will often ensure superior results with more stableintermediates as well.8,17 A wide range of examples is provided in the Table, while further examples
have been reported elsewhere.18 19 20 The methodology has also been applied to esters,12,13 lactones,21
phosphonates,22 23 imines24 and the N-acylation of lactams.25 The formation of β-diketones by thetreatment of lithium enolates with alkanoyl and aroyl nitriles has also been described.26TABLE
PREPARATION OF β-KETO-ESTERS BY THE KINETICALLY CONTROLLED C-ACYLATION OF
LITHIUM ENOLATES WITH METHYL CYANOFORMATE
Entry

Substrate

Procedure‡

1A

3A

ProductYield(%)
84868686

2A

96

4A

857175

A

57268
67

A

8A

84

9A

92

10A

92

11C85

B
65

Procedures: A: Reference; B: Lithium enolates generatedby addition of methyllithium in THF at −78°C; C: As
described for the conversation of enone 1 into β-keto ester
3.
‡References and Notes
1. Research School of Chemistry, Australian National University, G.P.O. Box 4, Canberra, A.C.T.,
2601, Australia.
2. Childs, M. E.; Weber, W. P. J. Org. Chem. 1976, 41, 3486.
3. Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
4. Caine, D. In "Carbon-Carbon Bond Formation"; Augustine, R. L., Ed.; Marcel Dekker: 1979;
Vol. 1, pp 250–258.
5. Seebach, D.; Weller, T.; Protschuk, G.; Beck, A. K.; Hoekstra, M. S. Helv. Chim. Acta 1981, 64,716.
6. Caine, D. Org. React. 1976, 23, 1–258.
7. Caine, D. In "Carbon-Carbon Bond Formation"; Augustine, R. L., Ed.; Marcel Dekker: 1979;
Vol. 1, p 258, footnote 69.
8. Kende, A. S.; Becker, D. A. Synth. Commun. 1982, 12, 829.
9. Vedejs, E.; Nader, B. J. Org. Chem. 1982, 47, 3193.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.

Hellou, J.; Kingston, J. F.; Fallis, A. G. Synthesis 1984, 1014.
Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. J. Am. Chem. Soc. 1985, 107, 2730.
Winkler, J. D.; Henegar, K. E.; Williard, P. G. J. Am. Chem. Soc. 1987, 109, 2850;
Henegar, K. E.; Winkler, J. D. Tetrahedron Lett. 1987, 28, 1051.
Kunisch, F.; Hobert, K.; Welzel, P. Tetrahedron Lett. 1985, 26, 5433.
Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett. 1990, 169
Evans, D. A. In "Asymmetric Synthesis"; Morrison, J. D., Ed.; Academic Press: Orlando, FL,1984; Vol. 3, pp 1–110.
Mori, K.; Ikunaka, M. Tetrahedron 1987, 43, 45.
Miyata, O.; Hirata, Y.; Naito, T.; Ninomiya, I. Heterocycles 1984, 22, 1041;
Schuda, P. F.; Phillips, J. L.; Morgan, T. M. J. Org. Chem. 1986, 51, 2742;
Haynes, R. K.; Katsifis, A. G. J. Chem. Soc., Chem. Commun. 1987, 340.
Ziegler, F. E.; Cain, W. T.; Kneisley, A.; Stirchak, E. P.; Wester, R. T. J. Am. Chem. Soc. 1988,110, 5442.
Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Tetrahedron Lett. 1986, 27,4799;
Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Heterocycles 1987, 26, 75.
McLure, C. K.; Jung, K.-Y. J. Org. Chem. 1991, 56, 2326.
Bennet, R. B.; Cha, J. K. Tetrahedron Lett. 1990, 31, 5437.
Howard, A. S.; Meerholz, C. A.; Michael, J. P. Tetrahedron Lett. 1979, 1339.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)silica gel
carbon oxysulfidebrine(R)-(−)-carvone(−)-borneol
lithium dimethyl cuprateammonia (7664-41-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
potassium permanganate (7722-64-7)
nitrogen (7727-37-9)
mercury(II) diacetate (1600-27-7)

carbon dioxide (124-38-9)
Benzophenone (119-61-9)
sodium (13966-32-0)
carbon disulfide (75-15-0)(+)-menthol (15356-60-2)
lithium (7439-93-2)
magnesium sulfate (7487-88-9)
sodium amide (7782-92-5)butyllithium (109-72-8)
Tetrahydrofuran,
THF (109-99-9)
ferric nitrate
ISOPRENE (78-79-5)
hexane (110-54-3)
Methyllithium (917-54-4)
tert-butyl alcohol (75-65-0)
calcium hydride (7789-78-8)
3-methyl-2-cyclohexen-1-one
lithium cyanide
METHYL CYANOFORMATE (17640-15-2)
Methyl (1α,4aβ,8aα)-2-oxodecahydro-1-naphthoate (147086-16-6)
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