Substituent effects on the stereochemistry of substituted cyclohexanone dimethylhydrazone alkylations. An x-ray crystal structure of lithiated cyclohexanone dimethylhydrazone

N,N-Dialkylhydrazones in Organic Synthesis. From Simple N,N-Dimethylhydrazones to Supported Chiral Auxiliaries

“…However, simple lithio-N,N-dimethylhydrazones show aggregation in solution (suggested as high as tetramer for lithiated cyclohexanone DMH-hydrazone). 29 Fast aggregate dissociation may precede slow alkylation reaction. In general, complex homonuclear and heteronuclear (with a lithium amide such as LDA) aggregation and metal coordination may be expected for metalo-N,N-dimethylhydrazones and related simple hydrazones.…”

1-Azaallylic Anions in Heterocyclic Chemistry

“…1-Azaallylic anions 525 upon treatment with electrophiles (alkyl halides, carbonyl compounds, ...) produce the regioselective (Z)-C-N hydrazone 526 that reequilibrates to the more stabilized E products 527 (according to the steric hindrance of the electrophiles used). 144,147,152,155 The use of N,N-dimethylhydrazone 528 derived from 4-tert-butylcyclohexanone led to selective axially monoalkylated products at the R-carbon atom 145,148,156 (Scheme 98), a clear advantage as compared to analogous enolates, which exhibit mediocre selectivity toward axial alkylation. [157][158][159] Moreover, an electronegative substituent (SR, OR, ...) at C-2 drove the deprotonation toward the more substituted carbon atom, without affecting the axial alkylation preference.…”

“…Further studies showed how the substituent(s) on the cyclohexanone imine could influence the stereochemistry, the axial position still remaining more favored. 148,149 X-ray and theoretical studies on hydrazone lithioanions were done to try to explain the often >98% axial selectivity. Earlier hypotheses reported chelation 147,156 and orbital symmetry to explain the strong preference for the substituent on the imine nitrogen atom to orient Z to the carbanionic carbon.…”

Lithium Diisopropylamide: Solution Kinetics and Implications for Organic Synthesis

“…During a natural product synthesis in 1980, we noted that alkylations of hydrazones displayed odd stereoselectivities when compared to alkylations of their ketone counterparts 1. 2 Lacking a satisfactory explanation and inspired by Seebach's contemporaneous crystallographic studies of lithium enolates,3, 4 we obtained two crystal structures of lithiated hydrazones displaying curious structural features that posed more questions than answers 2. Subsequent rate studies led to mechanistic and stereochemical models5 and, more important, left us captivated by organolithium aggregation and solvation.…”