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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM039764-24
Application #
8244503
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
1989-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
24
Fiscal Year
2012
Total Cost
$358,423
Indirect Cost
$133,000
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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
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
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
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
Gupta, Lekha; Ramírez, Antonio; Collum, David B (2010) Reaction of lithium diethylamide with an alkyl bromide and alkyl benzenesulfonate: origins of alkylation, elimination, and sulfonation. J Org Chem 75:8392-9

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