Lithium amides synthesis

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Tantalum Nitrides. Tantalum nitride [12033-62-4] TaN, is produced by direct synthesis of the elements at 1100°C. Very pure TaN has been produced by spontaneous reaction of lithium amide, L1NH2, and TaCl ( )- The compound is often added to cermets in 3—18 wt %. Ta N [12033-94-2] is used as a red pigment in plastics and paints (78). 

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

Before the emergence in the mid-1980s of the asymmetric deprotonation of cA-dimethyl cyclohexanone using enantiomerically pure lithium amide bases, few reports pertaining to the chemistry of these chiral reagents appeared. Although it is not the focus of this chapter, the optically active metal amide bases are still considered to be useful tools in organic synthesis. Readers are advised to consult the appropriate literature on the application of enantiomerically pure lithium amides in asymmetric synthesis.6... 

Hodgson DM, Stent MAH (2003) Overview of Organolithium-Ligand Combinations and Lithium Amides for Enantioselective Processes. 5 1-20 Hodgson DM, Tomooka K, Gras E (2003) Enantioselective Synthesis by Lithiation Adjacent to Oxygen and Subsequent Rearrangement. 5 217-250... 

Diastereoselective 1,4- and 1,6-addition reactions of lithium amides to chiral naph-thyloxazolines were used by Shimano and Meyers108-110 for the synthesis of novel amino acids. For example, treatment of (S )-2-(l-naphthyl)-4-t-butyloxazoline with lithi-ated l,4-dioxa-8-azaspiro[4.5]decane and iodomethane provided the diastereomerically pure 1,4-addition product with excellent yield cleavage of the heterocyclic rings then gave the desired /3-amino acid (>99% ee/ds equation 32)108,109. In contrast to this, most acyclic lithium amides reacted with these oxazolines under 1,6-addition the products were transformed smoothly to 5-amino acid derivatives (equation 33)110. 

FIGURE 12. Synthesis of the lithium amides 14-16 produced by the hthiation of A, A -di-tert-butylethylenediamine. Reprinted with permission from Reference 16b. Copyright 1996 American Chemical Society... 

Pridefine (80) is a somewhat structurally related antidepressant. It is a centrally active neurotransmitter blocking agent. It blocks norepinephrine in the hypothalamus but does not affect dopamine or 5-hydroxytryptamine. Its synthesis be-(jins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78. Heating in the presence of ethylamine gives N-ethylsuccinimide 79. Lithium aluminum hydride reduction completes the synthesis of pridefine (80)... 

Lithium amide is used in synthesis of histamine and analgesic drugs. The compound also is used in many organic synthetic reactions including alkylation of ketones and nitriles, Claisen condensation, and in synthesis of antioxidants and acetylenic compounds. 

The most versatile lithium amides in regard to accessibility and asymmetric induction in deprotonation and elimination reactions arc lithium bis(l-phenylethyl)amide, lithium 2,2-dimethyl-A -[1 -pheny 1-2-0-piperidinyliethyljpropylamide and lithium 2,2-dimethyl-A-[2-(4-methyl-l-piperazinyl)-l-phenylethyl]propylamide. 1-Phenylethylamine and phenylglycine, which serve as educts for the synthesis of these bases, are commercially available at modest prices in both enantiomeric forms. Relevant preparative procedures can be found in the Appendix. 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

The Diels-Alder reaction is an important and widely used reaction in organic synthesis (Sauer and Sustmann, 1980), and in the chemical industry (Griffiths and Previdoli, 1993). Rate enhancement of this reaction has been achieved by the use of solvents such as water, surfactants, very high pressure, lithium amides, alkylammonium nitrate salts, and macrocyclic hosts (Sherman et ak, 1998). Diels-Alder reactions can be ran in neutral ionic liquids (such as 1-butyl-3-methylimidazolium trifluoromethanesulfo-nate, l-butyl-3-methylimidazolium hexafluorophophate, l-butyl-3-methylimidazolium tetrafluoroborate, and l-butyl-3-methylimidazolium lactate). Rate enhancements and selectivities are similar to those of reactions performed in lithium perchlorate-diethyl ether mixtures. 

DL-cordycepose it was obtained in two steps, namely, epoxidation to 55 and mild, acid hydrolysis of the epoxide 55. For the synthesis of 53, substrate 54 was first brominated to the 2-bromo compound 57, which was dehydrobrominated with lithium amide, to afford the unsaturated acetal 58. cis-Hydroxylation of 58 under typical conditions then afforded 53. 

The reactions of lithium amides with pnictogen halides have also been used in the synthesis of heavy cyclopnict(III)azanes. For example, the combination of one equivalent of LiNH Bu and two equivalents of DippNHLi in reactions with ECI3 produces the series of bis(amido)dipnict(III)azanes [DippN(H)E... 

Fieser, M., Reagents for Organic Synthesis, Vol. 15. Wiley (Interscience), New York, 1990. Vol. 15 and earlier volumes give specific uses of lithium amides arranged according to individual N—Li compounds. 

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