Lithium a-Lithiomethanenitronate1

[-]  · CHLi2NO2  · Lithium a-Lithiomethanenitronate  · (MW 72.91)

(highly nucleophilic derivatives of nitromethane and of other primary nitroalkanes2 for alkylation,2-6 hydroxyalkylation,2,5,7-12 and acylation2,5,8,13)

Preparative Methods: the reagent may be generated in THF solution.4,10,12 A solution of the nitroalkane in THF is treated with ~2 equiv n-Butyllithium or Lithium Diisopropylamide at temperatures between -75 and -95 °C; the yields of the subsequent reactions are higher when the double lithiation is carried out in the presence of the cosolvent HMPA or, preferably, of the nonmutagenic N,N-Dimethylpropyleneurea (DMPU).14 The solutions are usually bright yellow and are stable for a few hours at temperatures below about -50 °C; evaporation of the solvents at low temperature leads to residues which decompose spontaneously.

Reactivity of Doubly Lithiated Nitroalkanes (1).

While nitronates (2) are readily generated from nitroalkanes (3) (pKa &AApprox; 10), their C-nucleophilicity is generally poor.1,15,16 Alkylations of (2) with alkyl halides occur preferentially on oxygen, but the addition to aldehydes and ketones is highly reversible; the acylation is only possible with acylimidazolines or other special reagents.1,17 The most useful reaction of (2) is their Michael addition to a,b-unsaturated carbonyl compounds. There have been several preparative improvements in recent decades: the use of silyl nitronates (see Trimethylsilyl Methanenitronate), employment of new catalyst systems such as Al2O3 and Potassium Fluoride,15 application of high pressure,18 and the use of dilithio derivatives (1). They are highly nucleophilic and react at carbon irreversibly with all electrophiles tested, including alkyl halides,2-6 aldehydes and ketones,2,5,7-12 acid chlorides,2,5,8,13 and halogens such as bromine:19 with a,b-enals5 and a,b-enones8 they add in a 1,2- not in a 1,4-fashion. The structure of reagents (1) is unknown; thus in the formulae used here they are shown with the lithium at carbon, since this is where reactions with electrophiles occur.

Applications of Simple Dilithionitronates (1) in Synthesis.

Some products from reactions of the lithiated lithionitronates with electrophiles are shown in the accompaning equations. Thus nitropropane can be hexylated to give 3-nitrononane (4) in 50% yield (eq 1).3,4 Nitropropane was also added to cyclohexenone to yield (52%) the unsaturated nitro alcohol (5), a type of compound not available by any other nitroaldol-forming method (eq 2).8

The 1,4-adduct of BuLi to 1-nitro-1-butene can be further lithiated in situ to form a doubly lithiated reagent (6) which is acylated by methyl 2-methylpropanoate, with formation after aqueous workup of the nitro ketone (7) in an overall yield of 30% (eq 3).8 An application of nitroalkane C-acylation2,5,8,13 to the synthesis of rac-amino acids is exemplified with the aminoheptanoic ester (8), prepared in two steps (50% yield)13 from nitrohexane and methyl chlorocarbonate (eq 4).

Dilithionitronates Bearing Additional Functional Groups.

The doubly lithiated nitroalkanes can also be generated from precursors containing additional functional groups. For instance, 1-nitro-2-propene gives a reagent (9), which was added to benzophenone to give the otherwise not accessible nitroaldol adduct (10) in 53% yield (eq 5).8 More surprising is the fact that nitroalkanes with b-leaving groups, such as trifluoronitroethane,11,12 can also be doubly lithiated to give rather stable reagents of type (11). These may be used for the reactions with various electrophiles mentioned above. Thus the trifluoromethyl-substituted nitroaldol (12) with a tertiary hydroxy group could be prepared in 60% yield (eq 6).12 Retro-nitroaldol cleavage occurs readily during bulb-to-bulb distillation (90 °C/10 mmHg).

Nitroaldol additions of doubly lithiated alkoxyl-substituted nitroalkanes can be highly diastereoselective, as demonstrated by the addition of THP-protected 2-nitroethanol to cyclohexanecarbaldehyde to form (13) (64%) (eq 7).5 Another example is the preferential formation of the (S,S)-diastereoisomer (14) in the allylation of a glyceraldehyde-derived nitro compound (68% yield; dr = 82:18) (eq 8).6

Related Reagents.

O,O-Dilithio-1-nitropropene; Nitroethane; Nitromethane.


1. (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. C 1979, 33, 1. (b) Döpp, D.; Döpp, H. MOC 1990, E14b, 780.
2. Seebach, D.; Lehr, F. AG(E) 1976, 15, 505.
3. Seebach, D.; Henning, R.; Lehr, F.; Gonnermann, J. TL 1977, 1161.
4. Seebach, D.; Lehr, F. HCA 1979, 62, 2239 (CA 1980, 92, 75 654z).
5. Eyer, M.; Seebach, D. JACS 1985, 107, 3601.
6. Williams, T. M.; Mosher, H. S. TL 1985, 26, 6269.
7. Seebach, D.; Henning, R.; Lehr, F. AG(E) 1978, 17, 458.
8. Lehr, F.; Gonnermann, J.; Seebach, D. HCA 1979, 62, 2258 (CA 1980, 92, 110 465n).
9. Colvin, E. W.; Beck, A. K.; Seebach, D. HCA 1981, 64, 2264.
10. Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HCA 1982, 65, 1101.
11. Seebach, D.; Beck, A. K.; Renaud, P. AG(E) 1986, 25, 98.
12. Beck, A. K.; Seebach, D. CB 1991, 124, 2897 (CA 1992, 116, 40 553c).
13. Ram, S.; Ehrenkaufer, R. E. S 1986, 133.
14. Mukhopadhyay, T.; Seebach, D. HCA 1982, 65, 385.
15. (a) Rosini, G.; Ballini, R.; Petrini, M.; Marotta, E.; Righi, P. OPP 1990, 22, 707. (b) Rosini, G.; Ballini, R. S 1988, 833.
16. Ono, N.; Kaji, A. S 1986, 693.
17. Crumbie, R. L.; Nimitz, J. S.; Mosher, H. S. JOC 1982, 47, 4040.
18. Matsumoto, K. AG(E) 1984, 23, 617.
19. Nekrasova, G. V.; Lipina, E. S.; Boldysh, E. E.; Perekalin, V. V. ZOR 1988, 24, 1144 (CA 1989, 110, 212 060j).

Roger E. Marti & Dieter Seebach

Eidgenössische Technische Hochschule, Zürich, Switzerland



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