Lithium amides are some of the most important reagents in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium amides with the goal of improve existing synthetic methods and developing new ones. We continue to focus on the three most important amides: lithium hexamethyldisilazide, lithium diisopropyiamide, and lithium tetramethylpiperidide. The case studies to be investigated include: (1) ketone and ester enolizations;(2) imine lithiations;(3) epoxide eliminations;(4) ortholithiations;(5) N-alkylations;(6) N-arylations;and (7) N-acylations. These case studies touch on the preponderance of the chemistry of lithium amides. Each poses unique questions and offers unique opportunities. Through an understanding of the mechanistic principleswe learn to control reactivity and selectivity. We use a uniquely integrated approach allows a combination of NMR spectroscopy, solution kinetics, and computational chemistry are brought to bear on the problems. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of soIvation and aggregation with an unprecedented clarity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Lees, Robert G
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Cornell University
Schools of Arts and Sciences
United States
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Han, Yifeng; Ma, Yun; Keresztes, Ivan et al. (2014) Preferential geminal bis-silylation of 3,4-benzothiophane is caused by the dominance of electron withdrawal by R3Si over steric shielding effects. Org Lett 16:4678-9
Gupta, Lekha; Hoepker, Alexander C; Ma, Yun et al. (2013) Lithium diisopropylamide-mediated ortholithiation of 2-fluoropyridines: rates, mechanisms, and the role of autocatalysis. J Org Chem 78:4214-30
Hoepker, Alexander C; Collum, David B (2011) Computational studies of lithium diisopropylamide deaggregation. J Org Chem 76:7985-93
Hoepker, Alexander C; Gupta, Lekha; Ma, Yun et al. (2011) Regioselective lithium diisopropylamide-mediated ortholithiation of 1-chloro-3-(trifluoromethyl)benzene: role of autocatalysis, lithium chloride catalysis, and reversibility. J Am Chem Soc 133:7135-51
Ma, Yun; Hoepker, Alexander C; Gupta, Lekha et al. (2010) 1,4-addition of lithium diisopropylamide to unsaturated esters: role of rate-limiting deaggregation, autocatalysis, lithium chloride catalysis, and other mixed aggregation effects. J Am Chem Soc 132:15610-23
Gruver, Jocelyn M; West, Scott P; Collum, David B et al. (2010) Experimental characterization and computational study of unique C,N-chelated lithium dianions. J Am Chem Soc 132:13212-3
Viciu, Mihai S; Gupta, Lekha; Collum, David B (2010) Mechanism of lithium diisopropylamide-mediated substitution of 2,6-difluoropyridine. J Am Chem Soc 132:6361-5
Gupta, Lekha; Hoepker, Alexander C; Singh, Kanwal J et al. (2009) Lithium diisopropylamide-mediated ortholithiations: lithium chloride catalysis. J Org Chem 74:2231-3
Riggs, Jason C; Singh, Kanwal J; Yun, Ma et al. (2008) Anionic Snieckus-Fries rearrangement: solvent effects and role of mixed aggregates. J Am Chem Soc 130:13709-17
Ma, Yun; Breslin, Sean; Keresztes, Ivan et al. (2008) Synthesis of a 7-azaindole by chichibabin cyclization: reversible base-mediated dimerization of 3-picolines. J Org Chem 73:9610-8

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