Kinetic Analysis of Copper(I)/Feringa-Phosphoramidite Catalyzed AlEt₃ 1,4-Addition to Cyclohex-2-en-1-one

Abstract

ReactIR studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one (CX) in Et2O indicate immediate formation of the Lewis acid–base complex CX·A at −40 °C (K = 12.0 M–1, ΔG°react = −1.1 kcal mol–1). Copper­(I) catalysts, derived from precatalytic Cu­(OAc)2 (up to 5 mol %) and (R,S,S)-P­(binaphtholate)­{N­(CHMePh)2} (Feringa’s ligand (L), up to 5 mol %) convert CX·A (0.04–0.3 M) into its 1,4-addition product enolate (E) within 2000 s at −40 °C. Kinetic studies (ReactIR and chiral GC) of CX·A, CX, and (R)-3-ethylcyclohexanone (P, the H+ quenching product of enolate E) show that the true catalyst is formed in the first 300 s and this subsequently provides P in 82% ee. This true catalyst converts CX·A to E with the rate law [Cu]1.5[L]0.66[CX·A]1 when [L]/[Cu] ≤ 3.5. Above this ligand ratio inhibition by added ligand with order [L]−2.5 is observed. A rate-determining step (rds) of Cu3 L 2(CX·A)2 stoichiometry is shown to be most consistent with the rate law. The presence of the enolate in the active catalyst best accounts for the reaction’s induction period and molecularity as [E] ≡ [CX·A]. Catalysis proceeds through a “shuttling mechanism” between two C 2 symmetry related ground state intermediates. Each turnover consumes 1 equiv of CX·A, expels one molecule of E, and forms the new Cu–Et bond needed for the next cycle. The observed ligand (L) inhibition and a nonlinear ligand L ee effect on the ee of P are well simulated by the kinetic model. DFT studies (ωB97X-D/SRSC) support coordination of CX·A to the groundstate Cu trimer and its rapid conversion to E.

Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones

“…However, there is strong indirect evidence that Zn(CX)2 ( 13) is vital in the transmetalation. Attempted use of well characterised Et3Al(CX) 6 as a terminal ethyl source in the 7/L A catalytic system leads to only background reactions at low rate strongly implying that 13 is vital for the transmetalation. 13) would also be in agreement with the observed rate law, and this could not be explicitly discounted on kinetic data alone.…”

“…We have previously shown in related aluminum chemistry that enolate product E can play such an acceleration role. 6 The observed rate law [Zn] 0.217 [CX] 0.272 [Cu] 0.123 [L A ] 0.175 p r ov i d e s a n e st i mat e d st oi c h i o me t ri c r a t io o f Zn 3.5 CX 4.4 Cu 2.0 L A2.9 (coefficients ±0.3) for events closely related to the transition state. One model consistent with this result is shown in Scheme 7.…”

“…The former concluded 4 was the transition state for copper­(I) sulphonamide catalyzed additions of ZnEt 2 ( Zn ) to cyclohex-2-en-1-one ( CX ), and the latter concluded 5 was the transition state for the same transformation catalyzed by Cu­(OTf) 2 in the presence of chiral phosphoramide ligands (Scheme ). As induction periods − and poor rate reproducibility have frequently complicated kinetic studies of copper-based ACA reactions, other approaches to arriving at catalytic cycle proposals have been sought. Transition state 6 has been proposed based on NMR studies of model complexes .…”

Conjugate Addition Routes to 2‐Alkyl‐2,3‐dihydroquinolin‐4(1H)‐ones and 2‐Alkyl‐4‐hydroxy‐1,2‐dihydroquinoline‐3‐carboxylates

“…As no general ligand providing > 90 % ee over a range of 4(1H)-quinolone-3-carboxylates was identified it is likely that individual substrate optimisation will be required. Rather than ad hoc screening we propose in silico ligand screening of a test transition state, modelled out of our own mechanistic studies, [20] but using the substrates employed here may be an attractive alternative strategy to the discovery of such systems. Such investigations are our next target.…”

Use of Standard Addition to Quantify In Situ FTIR Reaction Data

“…Consequently, the reaction must be sampled at least once, often at the end of the reaction, to quantify the concentration of the analyte using an offline technique. 4 The need for sampling and offline analysis lessens the intrinsic benefits of in situ FTIR spectroscopy. Alternatively, standard addition can determine the concentration of an analyte without sampling and offline analysis.…”