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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Hagan, Ann A
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Cornell University
Schools of Arts and Sciences
United States
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Ma, Yun; Algera, Russell F; Collum, David B (2016) Sodium Diisopropylamide in N,N-Dimethylethylamine: Reactivity, Selectivity, and Synthetic Utility. J Org Chem 81:11312-11315
Ma, Yun; Mack, Kyle A; Liang, Jun et al. (2016) Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies. Angew Chem Int Ed Engl 55:10093-7
Liang, Jun; Hoepker, Alexander C; Algera, Russell F et al. (2015) Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition. J Am Chem Soc 137:6292-303
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
Liang, Jun; Hoepker, Alexander C; Bruneau, Angela M et al. (2014) Lithium diisopropylamide-mediated lithiation of 1,4-difluorobenzene under nonequilibrium conditions: role of monomer-, dimer-, and tetramer-based intermediates and lessons about rate limitation. J Org Chem 79:11885-902
Ma, Yun; Stivala, Craig E; Wright, Ashley M et al. (2013) Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model. J Am Chem Soc 135:16853-64
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
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

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