Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions

Abstract

A simple procedure for the conversion of tertiary lactams to 2-monoalkylated cyclic amines is described. The reaction sequence involves conversion of a lactam to a thioiminium ion followed by reaction with an organocopper (RCu) reagent and final reduction with triacetoxyborohydride. The reaction is high yielding and shows an excellent functional group tolerance. Its utility is demonstrated by a rapid synthesis of indolizidine 167B. The excellent chemoselectivity of the process, where only monoalkylation products are formed, is rationalized by a mechanism involving the formation of a transient enamine.

Novel Benzylated (Pyrrolidin-2-one)/(Imidazolidin-2-one) Derivatives as Potential Anti-Alzheimer’s Agents: Synthesis and Pharmacological Investigations

“…11−13 The pyrrolidin-2-one derivatives (Scheme 1) were prepared by using a key intermediate 3-bromo-1-(4-methoxybenzyl)pyrrolidin-2-one (9), which in turn was synthesized by using 4methoxy benzylamine and 2,4-dibromobutanoyl chloride in stoichiometric equivalents followed by cyclization with sodium hydride (NaH) in dimethylformamide (DMF). 14,15 Compound 9 was then coupled with a few commercially available substituted piperidines (a−c) to afford target compounds 10a−c.…”

“…On the other hand, imidazolidin-2-one substituted molecules were synthesized by starting material 1-(3,4-dimethoxybenzyl)imidazolidin-2-one (14), which in turn was synthesized by reductive amination of 3,4-dimethoxy-benzaldehyde (12) with tert-butyl(2-aminoethyl)-carbamate (11) and later on cyclized with potassium t-butoxide (KOtBu) in tetrahydrofuran (THF) to give an intermediate compound 14. 16 Intermediate compound 14 was coupled with tert-butyl 4-(((methylsulfonyl)-oxy)-methyl)-piperidine-1-carboxylate (15) in the presence of NaH in DMF to afford compound 16 as per Scheme 2. The N-boc protected intermediate 16 was deprotected with 4 M HCl in dioxane to afford 17 and was further coupled with few commercial benzyl bromides (a−d) to give the corresponding 18a−d.…”

Amide activation: an emerging tool for chemoselective synthesis

“…118 Although the validity of the HSAB principle has been recently questioned, 119 such electrophiles are classically believed to have a high affinity towards the sulfur atom due to their similarities in HOMO/LUMO-properties and electrostatics. [120][121][122][123][124] Alternatively, electrophiles classically perceived as ''hard'' (such as methyl triflate, 125 or Meerwein's salt 126,127 ) can also be employed, further supporting Mayr's criticism of the HSAB-principle. The iminium sulfide salt (215), generated upon alkylation of a thioamide (214), can be engaged by several carbon nucleophiles such as organocerium species, 128 enolates, 126 cuprates, 120,121,123 or Grignard reagents 121,122 (Scheme 29).…”

One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates (KATs) from Organocuprates

“…With these revised conditions, we were able to prepare a broad range of secondary aliphatic KATs ranging from branched to cyclic products in good yields (see Scheme 4). For the synthesis of the saturated heterocyclic KATs (16,17), we observed fast decomposition of the organocuprate at 0 °C, even with CuCN. By forming the organocuprate at −78 °C under sonication, we were able to circumvent this problem and were able to obtain KATs 16 and 17 in good yields.…”

“…Selective mono-alkylation of thioiminium reagents has been deemed challenging, with little precedence in the literature . Bosch and Renaud independently reported the selective mono-alkylation of thioiminium moieties with organocuprates. , Inspired by these works, we attempted the addition of organocuprates to transfer reagent 1 , and we were pleased to observe the formation of the desired product. Encouraged by this finding, we set out to optimize the reaction conditions for the synthesis of aliphatic KATs (see Table ).…”