Understanding the interplay of weak forces in [3,3]-sigmatropic rearrangement for stereospecific synthesis of diamines.

Chiral diamines are important building blocks for constructing stereoselective catalysts, including transition metal based catalysts and organocatalysts that facilitate oxidation, reduction, hydrolysis, and C-C bond forming reactions. These molecules are also critical components in the synthesis of drugs, including antiviral agents such as Tamiflu and Relenza and anticancer agents such as oxaliplatin and nutlin-3. The diaza-Cope rearrangement reaction provides one of the most versatile methods for rapidly generating a wide variety of chiral diamines stereospecifically and under mild conditions. Weak forces such as hydrogen bonding, electronic, steric, oxyanionic, and conjugation effects can drive this equilibrium process to completion. In this Account, we examine the effect of these individual weak forces on the value of the equilibrium constant for the diaza-Cope rearrangement reaction using both computational and experimental methods. The availability of a wide variety of aldehydes and diamines allows for the facile synthesis of the diimines needed to study the weak forces. Furthermore, because the reaction generally takes place cleanly at ambient temperature, we can easily measure equilibrium constants for rearrangement of the diimines. We use the Hammett equation to further examine the electronic and oxyanionic effects. In addition, computations and experiments provide us with new insights into the origin and extent of stereospecificity for this rearrangement reaction. The diaza-Cope rearrangement, with its unusual interplay between weak forces and the equilibrium constant of the reaction, provides a rare opportunity to study the effects of the fundamental weak forces on a chemical reaction. Among these many weak forces that affect the diaza-Cope rearrangement, the anion effect is the strongest (10.9 kcal/mol) followed by the resonance-assisted hydrogen-bond effect (7.1 kcal/mol), the steric effect (5.7 kcal/mol), the conjugation effect (5.5 kcal/mol), and the electronic effect (3.2 kcal/mol). Based on both computation and experimental data, the effects of these weak forces are additive. Understanding the interplay of the weak forces in the [3,3]-sigmatropic reaction is interesting in its own right and also provides valuable insights for the synthesis of chiral diamine based drugs and catalysts in excellent yield and enantiopurity.

Investigation of substituent effects on the selectivity of 4pi-electrocyclization of 1,3-diarylallylic cations for the formation of highly substituted indenes.

Differentially substituted 1,3-diaryl-substituted allylic cations generated by ionization of the corresponding allylic alcohols in the presence of a Lewis acid undergo chemoselective and regioselective electrocyclization reactions to generate 1-aryl-1H-indenes. Electrocyclization only occurs for allylic cations bearing a 2-substituent, with 2-ester and 2-alkyl substituents both tolerated. In general, the presence of electron-withdrawing substituents deactivates the ring and disfavors cyclization. In contrast, the selectivity of cyclization of systems containing electron-donating substituents depends on the nature and position of the electron-donating group. Electron-donating substituents at the meta position particularly favor cyclization. There was no obvious correlation of cyclization selectivity with calculated electron densities as has been suggested for electrophilic aromatic substitution reactions. However, the calculated selectivities determined by a gas-phase (B3LYP/6-31G* + ZPVE) comparison of the relative rates of cyclization were in remarkably good agreement with the observed selectivities. Calculated transition-state structures for cyclization are consistent with a cationic pi4(a) conrotatory electrocyclization mechanism. In some cases involving more electron-deficient systems, the initially formed 1H-indene underwent subsequent alkene isomerization to the 3H-indene. In one example, an unusual dimerization reaction occurred to give a cyclopenta[a]indene via an unusual formal cationic 2pi+2pi cycloaddition of the allylic cation with the intermediate indene.

Electronic effect on the kinetics of the diaza-cope rearrangement.

Hammett plot reveals that there is a significant electronic effect on the rate of resonance assisted hydrogen bond (RAHB) directed diaza-Cope rearrangement reaction with a rho value of 1.6. DFT computation shows that the rearrangement reaction becomes thermodynamically more favorable for the substrates with electron withdrawing substituents. A substrate with the nitro substituent (1a) reacts about 50-fold faster than that with the methoxy substituent (1g).