Concerning the potential reversibility of carbometalation in alkoxide-directed Ti(Oi-Pr)4-mediated reductive cross-coupling of homoallylic alcohols with aromatic imines

Abstract

In an attempt to understand the nature of selectivity in Ti-mediated reductive cross-coupling between homoallylic alcohols and imines, we investigated whether thermodynamic equilibration of the presumed organometallic intermediate plays a role in selectivity. No evidence could be found for olefin exchange in preformed azatitanacyclopentanes -an observation that is consistent with a model based on kinetically controlled selective carbometalation.Reductive cross-coupling is emerging as a powerful strategy for bimolecular C-C bond formation.1 This mode of reactivity has historically been limited to a relatively small substrate scope as a result of firmly established barriers associated with the control of reactivity and selectivity in the bimolecular C-C bond forming event.2 In a program aimed at advancing a suite of methods for reductive cross-coupling that overcome these limitations, we recently described highly regio-and stereoselective coupling reactions of substituted homoallylic alcohols with aromatic imines (Figure 1).3 This process, proceeding with stoichiometric use of an inexpensive and non-toxic metallic species (Ti(Oi-Pr) 4 ), was accomplished by: 1) initial conversion of an aromatic imine to an azatitanacyclopropane, 2) introduction of a homoallylic alkoxide, and 3) protonation of the presumed bicyclic azametallacyclopentane intermediate. A mechanistic proposal to account for the enhanced reactivity and high selectivity observed was put forth based on: 1) rapid and reversible ligand exchange at titanium, and 2) site-and stereoselective intramolecular carbometalation under kinetic control.During the course of these studies, we observed a stereoconvergence in reductive crosscoupling between disubstituted alkenes and aromatic imines. As illustrated in Figure 2, coupling of the homoallylic alcohol 7 or 8 with a simple aromatic imine provided the anti-1,5-amino alcohol 11 in 68 and 73% yield with very high levels of stereoselection (dr ≥ 95:5).3 This observation was consistent with a mechanistic proposal whereby each alkene underwent selective carbometalation by way of distinct geometries (I and II). While the number of ligands on Ti in the transition state for these coupling reactions remains unclear, we expected that the development of a cis-fused bicyclo-[3.3.0] system would be favoured.4 Further, minimization of eclipsing 1,2-interactions about the developing C-C bond was thought to be important for the control of stereochemistry en route to intermediates 9 and 10. Subsequent protonation would then furnish the 1,5-amino alcohol 11. Overall, the high anti-selectivity and stereoconvergence was consistent with this mechanistic proposal based on kinetic control. (Figure 3).5 , 6 These observations led us to speculate whether the selectivity of our alkene-imine coupling was a result of thermodynamic, rather than kinetic, control.Our studies aimed at addressing this question began with an analysis of the basic reaction process -we accepted that: 1) Ligand exchange at Ti was readily reversible and fas...

Metallacycle-mediated cross-coupling with substituted and electronically unactivated alkenes

“…In the coupling reaction of 1,1-disubstituted alkenes, stereoselection is thought to derive from the preferred orientation of While it is well-established that saturated metallacyclopentanes can be in a rapid equilibrium with their corresponding metallacyclopropane and alkene, 42 recent investigations have provided support for the proposition that the coupling reactions illustrated in Table 1 proceed under reaction conditions that do not promote such fragmentation. 43 These observations are consistent with the assumed underlying principles that govern the empirical model depicted in Fig. 18 and are based on kinetic control in the C-C bond forming event.…”

“…While it is well-established that saturated metallacyclopentanes can be in rapid equilibrium with expulsion of an alkene and generation of a metallacyclopropane,42 recent investigations have provided support for the proposition that the coupling reactions depicted in Table 1 proceed under reaction conditions that do not promote such fragmentation 43. These observations are consistent with the assumed underlying principles that govern the empirical model depicted in Figure 17.…”

Imines in the Titanium Coordination Sphere: Highly Reactive Titanaaziridines and Larger Titanacycles Formed by Subsequent C–C Coupling Reactions

“…[1,10,[18][19][20][21][22][23]36] In such a way, the titanoceneaziridine 5 undergoes insertion with carbonyl derivatives, whereas insertion reactions with olefins, acetylenes, nitriles, ketones, and aldehydes are found for the (methyleneaniline)titanium complex 6. [1,10] For these reasons, we were interested in the relationship between the substitution pattern of the imine ligand as well as the nature of the titanium fragment and the reactivity of the corresponding titanaaziridine.…”

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

“…131 Overall, these studies of hydroxyl-directed Ti-mediated cross-coupling between aromatic imines and terminal alkenes support the conclusion that the coupling process proceeds under kinetic control (i.e., no evidence was found to support the reversibility of C-C bond formation under the reaction conditions).…”