Kinetic Studies on the Stability and Reactivity of β-Amino Alkylzinc Iodides Derived from Amino Acids

Abstract

Beta-amino alkylzinc iodides are intrinsically unstable toward beta-elimination and protonation. The aim of this study was to determine the rates of these processes and also to understand how the reactivity of a range of beta-amino alkylzinc iodides in Negishi cross-coupling reactions is influenced by the presence of functional groups within the zinc reagent. Decomposition of beta-benzamido alkylzinc iodides occurs by protonation, and the first-order rate constant for the self-protonation of the carbon-zinc bond in reagent 4b was determined to be 5.2 x 10(-6) s(-1) (at 291 K). In contrast, the carbamate derivative 2 decomposes by a first-order elimination process. The homologous reagent 3, derived from glutamic acid, decomposes more quickly by beta-elimination, with a first-order rate constant of 24 x 10(-6) s(-1) (at 291 K). Reagents 23 and 25, in which the Boc group has been replaced with a trifluoroacetyl group, are more stable toward beta-elimination than the corresponding reagents 2 and 3, a striking outcome given that the trifluoroacetamido group is a better leaving group. Moreover, this replacement also changes the mechanism of the elimination to a second order process. Pseudo-second-order rate constants for the Negishi cross-coupling of reagents 2, 3, 23, and 25 with iodobenzene have been determined, revealing the higher reactivity of the glutamic acid-derived reagents 3 and 25. The main factor influencing reactivity, therefore, is determined to be the proximity of the ester group, rather than the nature of the nitrogen protecting group. Finally, beta-amino alkylzinc iodides 46-48 containing Weinreb amides have been prepared, rate constants for their decomposition through elimination determined, and their synthetic potential for the preparation of beta-amino ketones established.

Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners

“…The issues include but are not limited to: (1) the spontaneous decomposition of alkyl organometallics via β-elimination or by proto-demetalation,12 (2) the necessity to pre-form the organometallic reagents without purification as they are not air stable, making the use of superstoichiometric (3–4 equiv.) amounts necessary to achieve satisfactory conversions, and (3) often slow transmetalation (vide infra), thereby requiring various additives 13.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…The development of cross-coupling strategies to take advantage of halo-amino acid precursors has allowed access to a wide variety of fluorinated unnatural amino acids. Negishi cross-coupling of halo-serine derivatives is a mainstay in this area and was pioneered by the Jackson group [ [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] ]. The Negishi cross-coupling reaction allows two, often readily available, halogen containing building blocks to be coupled together through a halo-zinc intermediate in the presence of palladium.…”

Negishi cross-couplings in the synthesis of amino acids

“…Jackson's group built upon the observation that SPhos improved the yields of Negishi cross-couplings. By taking inspiration from their work on the kinetics of β-elimination, the Boc protecting group (see mechanistic studies) 42 was replaced with a trifluoro-acyl (TFA) group (Scheme 10). 43 The TFA protecting group had been shown previously to perturb the alkyl zinc halide from undergoing β-elimination, (see later section on mechanistic studies for further information) so it was hoped that the combination of SPhos and a TFA protecting group on the zinc halide would lead to improved reaction conditions for the synthesis of phenylethylamine derivatives.…”

“…87 Jackson and Rilatt further studied this kinetic stability and reactivity of β-amino alkyl zinc iodides in 2008. 88 They found that the N-protecting group on the zinc iodide was critical in determining the rate of β-elimination. Boc protecting groups were found to increase the rate of elimination, and from this it was theorised that the carbonyl group (within the carbamate) was competing with the ester for coordination with zinc, leading to increased elimination.…”