[31509-80-5]  · C2H2Li2O2  · Dilithioacetate  · (MW 71.92)

(metalated species used to elaborate or functionally substitute the a-carbon of carboxylic acids;3 useful for highly substituted examples;4 possible alternatives for the malonic ester synthesis and the Haller-Bauer, Reformatsky,23 and Wittig28 reactions)

Physical Data: colorless solid.

Solubility: slightly sol THF; reacts with H2O, air (O2, CO2), and protic solvents. Ethylene glycol-based solvents may react with lithium amides from which the dianions are formed. Dianions derived from disubstituted acetic acids are soluble in THF; less sol other ether solvents. Most carboxylate dianions are stable up to the boiling point of THF.

Formation and Reactivity.

The metalation of carboxylic acids is a general phenomenon and many aliphatic, alicyclic, araliphatic, and functionally substituted acetic acids have been used in various applications.1 The intermediate carboxylate dianions are commonly generated by one of four methods: (1) a carboxylic acid and 2 equiv of lithium (sodium) naphthalenide2 or preferably (2) 2 equiv of LDA;3 (3) a carboxylate salt and 1 equiv of LDA;4 (4) a metathetical reaction of a dilithium carboxylate dianion and a metal halide. The more traditional method of reacting 2 equiv of a Grignard reagent with carboxylic acids (Ivanov reagents1e) is restricted to examples in which the carboxylate a-protons are relatively acidic, principally arylacetates (pKa <= 22).5

Accordingly, carboxylate dianions have been formed (method 3) from Lithium Diisopropylamide and Li, Na, K, Ca, Mg, and Zn carboxylates. Metathesis of dilithium dianions with Copper(I) Iodide, Zinc Chloride, and several other metal halides produced carboxylate dianions with more selective reactivity.6-8 Monosubstituted acetic acids yield dilithium or lithium-sodium dianions with limited solubilities, presumably due to polymeric aggregation of the metalated species.9,10 HMPA has been recommended as cosolvent.9 Monosubstituted acetic acids with bulky substituents (Ph, t-Bu) and disubstituted acetic acids form soluble (THF) dianions. Glycol ether solvents may react with LDA and THF is preferred.11,12 LDA is preferred as base1c and, although more hindered bases13 may be necessary for special applications, amines from less hindered lithium amides can react competitively with some electrophiles (TMSCl).11 The lithium amide of hexamethyldisilazane is not sufficiently basic (pKa &egt; 26 (THF))14 for general use (LDA, pKa &egt; 36 (THF)).15 In examples where the carboxylate dianion is soluble, as little as 3 mol % of the amine can be used for metalation (eq 1).1c The latter is a useful variation for reactions with highly reactive electrophiles where diisopropylamine might compete for electrophiles (acylation).16

Unsaturated carboxylic acids as their Cu dianions react selectively at the g-rather than the a-position with allyl bromide and vinylic epoxides6,7 The reaction occurs by an SN2 process and the yields and selectivity are impaired with substituted allyl bromides. Other electrophiles react poorly; however, unsaturated ketones react with the Cu dianion of acetic acid8 predominantly by 1,2-addition.

LDA or LTBA metalation of Zn or Mg carboxylates offers considerable promise because they are soluble.17,18 Small, aliphatic carboxylic acids, aromatic, and arylacetic acids form crystalline zinc carboxylates as their TMEDA complexes which are soluble in THF and hot toluene (eq 2). Butyric acid and larger aliphatic zinc carboxylates are soluble in hot toluene without TMEDA. The lithium amide displaces TMEDA as ligand on metalation and an additional equivalent abstracts the a-protons (eq 3). Reaction with carbonyl compounds provides adducts in yields equivalent to the Reformatsky reaction (eq 4). This metalated species is especially useful for acetic and propionic acids. Unlike alkali metal dianions, alkylation is not selective and disubstituted products are formed except when activating substituents are present (R = Ph). Like t-butylacetate anion,19,20 alkylation of acetic acid dianion (1) (R = H) fails in the absence of dipolar solvents.

Reactions with Electrophiles.

Carboxylate dianions have been treated with many electrophiles,1 but reactions with alkyl halides and carbonyl compounds have been used most widely. Most common carboxylate dianions have been reported to react successfully except acetic acid and cyclopropanecarboxylic acids where carboxyl derivatives must be used with few exceptions.21 Carboxylate dianions are especially useful where forcing conditions are required, as in reactions with epoxides,22 or in reactions with carbonyl substrates where hydrolysis of a carboxyl derivative causes product degradation.23 Carbonyl addition is sensitive to steric effects, but steric hindrance must be severe to prevent adduct formation (eq 5).23 The adduct may cyclize spontaneously on isolation, forming a b-lactone in highly constrained examples.23b

A C-silylated analog, the trimethylsilylacetic acid dianion (2), forms carbonyl adducts which undergo spontaneous Peterson elimination (eq 6).24 Mixtures of (E) and (Z) products are obtained. The limited accessibility of (2) has been overcome by use of a softer, C-silylating reagent (eq 7)25

Unsaturated carboxylate dianions have been used to demonstrate the reversibility of carbonyl addition. The a:g ratio of adducts depends on the metal ion, temperature, solvent polarity, time, and steric effects (eqs 8 and 9).26 Reaction with aldehydes gives threo products predominantly, and the threo:erythro ratio can reach 49:1 if the substituents are sufficiently large and thermodynamic conditions are used (eq 10).27 The major threo isomer (5) can produce either trans (8) or cis (9) alkene in many cases (eqs 11 and 12). Formation of b-lactone (7) is a general reaction28 and cis elimination of carbon dioxide makes this sequence a useful alternative to the Wittig reaction.28 Use of DMF acetals or DEAD effects an anti elimination through a charged intermediate and produces (Z)-alkene (9).29 Lactones (7) can be alkylated stereospecifically (eq 13) if the lactone is sufficiently stable.30,31 Combination of these procedures allows substantial control to be exercised over syntheses of di- and trisubstituted alkenes.

Alkylation of carboxylate dianions in which one cation is lithium and the other an alkali metal is a simple synthetic operation.1 Many primary and secondary halides (tosylates) have been used and success is independent of the leaving group and the order of introduction of the substituents.1c Further, successful reaction does not depend on obtaining a homogeneous solution of the dianion. Simple functionally substituted (ethers, double bonds, acetals, carboxylates) alkylating agents can be accommodated. Alkyl halides sensitive to elimination proceed normally unless steric hindrance in the dianion is extreme.4 The stability of carboxylate dianions is important in uses with epoxides22 or acylaziridines32 where extended reaction times or forcing conditions may be necessary (eq 14). The scale and low temperatures are not important requirements. The production of the hypolipidemic agent gemfibrozil uses typical reaction conditions (eq 15).1 7,33

Chiral Syntheses.

Asymmetric syntheses with carboxylate dianions requires a chiral amide that can also act as a chiral auxiliary by remaining associated with the dianion without being covalently bonded to it. Carbonyl addition gave as much as 85% ee in a carefully chosen model (eq 16).34 Alkylation is much less stereospecific than carbonyl addition and it proved to be much less selective in the formation of a chiral product (eq 17).35

Related Reagents.

t-Butyl a-Lithiobis(trimethylsilyl)acetate; t-Butyl a-Lithioisobutyrate; t-Butyl Trimethylsilylacetate; 2,6-Dimethylphenyl Propionate; Ethyl Bromozincacetate; Ethyl Lithioacetate; Ethyl Lithio(trimethylsilyl)acetate; Ethyl Trimethylsilylacetate; 2-Methyl-2-(trimethylsilyloxy)-3-pentanone; Trimethylsilylacetic Acid.

1. (a) Thompson, C. M.; Green, D. L. C. T 1991, 47, 4223. (b) Petragnani, N.; Yonashiro, M. S 1982, 521. (c) Creger, P. L. Annu. Rep. Med. Chem. 1977, 12, 278. (d) Ivanov, D.; Vassilev, G.; Panayotov, I. S 1975, 83. (e) Blagoev, B.; Ivanov, D. S 1970, 615. (f) Ebel, H. F. in MOC 1970, 13/1, 445. (g) Morton, A. A. Solid Organoalkali Metal Reagents; Gordon & Breach: New York, 1964; p 47ff.
2. (a) Angelo, B. CR(C) 1973, 276, 293. (b) Angelo, B. BSF(2) 1970, 1848.
3. Creger, P. L. JACS 1967, 89, 2500.
4. Creger, P. L. OSC 1988, 6, 517.
5. Gronert, S.; Streitweiser, A. JACS 1988, 110, 4418.
6. Savu, P. M.; Katzenellenbogen, J. A. JOC 1981, 46, 239.
7. Pitzele, B. S.; Baran, J. S.; Steinman, D. H. T 1976, 32, 1347.
8. Mulzer, J.; Brüntrup, G.; Hartz, G.; Kühl, U.; Blaschek, U.; Böhrer, G. CB 1981, 14, 3701.
9. Pfeffer, P. E.; Silbert, L. S. JOC 1971, 36, 3290.
10. Bauer, W.; Seebach, D. HCA 1984, 67, 1972.
11. House, H. O.; Liang, W. C.; Weeks, P. D. JOC 1974, 39, 3102.
12. Gall, M.; House, H. O. OSC 1988, 6, 121.
13. (a) Olofson, R. A.; Dougherty, C. M. JACS 1973, 95, 582. (b) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. JOC 1987, 52, 448. (c) Prieto, J. A.; Suarez, J.; Larson, G. L. SC 1988, 18, 253.
14. Fraser, R. R.; Mansour, T. S.; Savard, S. JOC 1985, 50, 3232.
15. Fraser, R. R.; Bresse, M.; Mansour, T. S. CC 1983, 620.
16. (a) Krapcho, A. P.; Kashdan, D. S.; Jahngen, Jr., E. G. E.; Lovey, A. J. JOC 1977, 42, 1189. (b) Krapcho, A. P.; Stephens, W. P. JOC 1980, 45, 1106.
17. Creger, P. L. U.S. Patent 3 674 836, 1972 (CA 1970, 72, 43 167p).
18. Creger, P. L. U.S. Patent 5 041 640, 1991 (CA 1991, 115, 255 632t).
19. Rathke, M. W.; Lindert, A. JACS 1971, 93, 2318.
20. Bos, W.; Pabon, H. J. J. RTC 1980, 99, 141.
21. (a) Häner, R.; Maertzke, T.; Seebach, D. HCA 1986, 69, 1655. (b) Jahngen, E. G. E.; Phillips, D.; Kobelski, R. J.; Demko, D. M. JOC 1983, 48, 2472. (c) Warner, P. M.; Le, D. JOC 1982, 47, 893.
22. Creger, P. L. JOC 1972, 37, 1907.
23. (a) Moersch, G. W.; Burkett, A. R. JOC 1971, 36, 1149. (b) Krapcho, A. P.; Jahngen, Jr., E. G. E. JOC 1974, 39, 1650.
24. Grieco, P. A.; Wang, C.-L. J.; Burke, S. D. CC 1975, 537.
25. Larson, G. L.; Cruz de Maldonado, V.; Berrios, R. R. SC 1986, 16, 1347.
26. (a) Johnson, P. R.; White, J. D. JOC 1984, 49, 4424. (b) Ballester, P.; García-Raso, A.; Mestres, R. S 1985, 802.
27. Mulzer, J.; Zippel, M.; Brüntrup, G.; Segner, J.; Finke, J. LA 1980, 1108.
28. Adam, W.; Baeza, J.; Liu, J.-C. JACS 1972, 94, 2000.
29. (a) Rüttimann, A.; Wick, A.; Eschenmoser, A. HCA 1975, 58, 1450. (b) Mulzer, J.; Brüntrup, G. CB 1982, 115, 2057. (c) Hara, S.; Taguchi, H.; Yamamoto, H.; Nozaki, H. TL 1975, 1545. (d) Mulzer, J.; Lammer, O. AG(E) 1983, 22, 628.
30. (a) Mulzer, J.; Zippel, M. AG(E) 1981, 20, 399. (b) Mulzer, J.; Kerkmann, T. JACS 1980, 102, 3620.
31. (a) Mulzer, J.; Brüntrup, G. AG(E) 1979, 18, 793. (b) Black, T. H.; Hall, J. A.; Shen, R. G. JOC 1988, 53, 2371. Not cited in text.
32. Stamm, H.; Weiss, R. S 1986, 395.
33. Anderson, R. CI(L) 1984, 205.
34. Mulzer, J.; deLasalle, P.; Chucholowski, A.; Blaschek, U.; Brüntrup, G.; Jibril, I.; Huttner, G. T 1984, 40, 2211.
35. Ando, A.; Shiori, T. CC 1987, 656.

Paul L. Creger

Ann Arbor, MI, USA

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