Lithium Diisopropylamide-Mediated Lithiations of Imines: Insights into Highly Structure-Dependent Rates and Selectivities

Journal of the American Chemical Society

Volumn 125, Issue 49, 2003, Pages 15114-15127

  Liao, Songping ^a   Collum, David B ^a  

^a Department of Obstetrics Gynecology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DENSITY FUNCTIONAL THEORY;

CHELATION; MONOMERS; PROTONS; SUBSTITUTION REACTIONS;

LITHIUM COMPOUNDS;

CYCLOHEXANONE DERIVATIVE; IMINE; LITHIUM DERIVATIVE; LITHIUM DIISOPROPYLAMIDE; MONOMER; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; CHELATION; COMPARATIVE STUDY; DENSITY FUNCTIONAL THEORY; ISOMERISM; LITHIATION; MATHEMATICAL ANALYSIS; NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; STRUCTURE ANALYSIS; TEMPERATURE DEPENDENCE;

CYCLOHEXANONES; IMINES; KINETICS; LITHIUM; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROPYLAMINES; STRUCTURE-ACTIVITY RELATIONSHIP; THERMODYNAMICS;

EID: 0344667434     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja030409z     Document Type: Article

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79. The concentration of the lithium amide, although expressed in units of molarity, refers to the concentration of the monomer unit (normality).
80. Espenson, J. H. Chemical Kinetics and Reaction Mechanisms; McGraw-Hill: New York. 1995; p 15.
81. The small isotope effects for 11 and 12 could be interpreted as evidence of a rate-limiting syn-anti isomerism as suggested previously.10 The LDA-concentration-dependent rate constants argue against such a mechanism due to the dependence of regioselectivity on syn/anti orientation in the substrate. Moreover, we have noted surprisingly low isotope effects in the LDA-mediated lithiation of the dimethylhydrazone of cyclohexanone, in which symmetry renders syn-anti isomerism irrelevant. Collum, D. B.; Romesberg, F. E., unpublished.
82. Edwards, J. O.; Greene, E. F.; Ross, J. J. Chem. Educ. 1968, 45, 381.
83. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Gill, A.; Nanayakkara, C.; Gonzalez, M.; Challacombe, P. M. W.; Johnson, B.; Chen, W. ; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh, PA, 1998.
84. Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1992, 114, 2112. Ramirez, A.; Collum, D. B., unpublished.
85. Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1992, 114, 2112. Ramirez, A.; Collum, D. B., unpublished.
86. For excellent references and discussions of kinetic resolutions, see: Acc. Chem. Res. 2000, issue No. 6.
87. The calculated relative energies of two isomers corresponding to 7 and 8 with the tert-butyl group omitted show a 0.2 kcal/mol preference for 8. (Without the tert-butyl group, there are still two isomers.)
88. For examples and leading references, see: Ramírez, A.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 11114.
89. ≠ for imine 1 bearing an n-butyl group is 21.9 kcal/mol.
90. ≠ due to the distal methyl.
91. The 0.9 kcal/mol is an estimate from the value derived for the chair-chair flip of N,2-dimethylcyclohexanone imine. The cost of the chair-chair flip must be included because the anti-axial form is not the lowest energy conformer.
92. Imine hydrolyses without epimerization have been reported: Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 6362.
93. The small isotope effects for 11 and 12 could be interpreted as evidence of a rate-limiting syn-anti isomerism as suggested previously.10 The LDA-concentration-dependent rate constants argue against such a mechanism due to the dependence of regioselectivity on syn/anti orientation in the substrate. Moreover, we have noted surprisingly low isotope effects in the LDA-mediated lithiation of the dimethylhydrazone of cyclohexanone, in which symmetry renders syn-anti isomerism irrelevant. Collum, D. B.; Romesberg, F. E., unpublished.
94. Edwards, J. O.; Greene, E. F.; Ross, J. J. Chem. Educ. 1968, 45, 381.
95. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Gill, A.; Nanayakkara, C.; Gonzalez, M.; Challacombe, P. M. W.; Johnson, B.; Chen, W. ; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh, PA, 1998.
96. Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1992, 114, 2112. Ramirez, A.; Collum, D. B., unpublished.
97. Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1992, 114, 2112. Ramirez, A.; Collum, D. B., unpublished.
98. For excellent references and discussions of kinetic resolutions, see: Acc. Chem. Res. 2000, issue No. 6.
99. The calculated relative energies of two isomers corresponding to 7 and 8 with the tert-butyl group omitted show a 0.2 kcal/mol preference for 8. (Without the tert-butyl group, there are still two isomers.)
100. For examples and leading references, see: Ramírez, A.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 11114.
101. ≠ for imine 1 bearing an n-butyl group is 21.9 kcal/mol.
102. ≠ due to the distal methyl.
103. The 0.9 kcal/mol is an estimate from the value derived for the chair-chair flip of N,2-dimethylcyclohexanone imine. The cost of the chair-chair flip must be included because the anti-axial form is not the lowest energy conformer.
104. Imine hydrolyses without epimerization have been reported: Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 6362.