Electron-deficient Amines Research Articles

The direct reductive amination of electron-deficient amines with aldehydes: the unique reactivity of the Re2O7 catalyst

An unprecedented direct reductive amination of electron-deficient amines such as Cbz-, Boc-, EtOCO-, Fmoc-, Bz-, ArSO(2)-, Ar(2)PO-, etc. protected amines with aldehydes is achieved using the Re(2)O(7) catalyst and silanes as the hydride source. Excellent regioselective mono-alkylation and chemoselective reductive-amination were observed.

Scope and Mechanism of Tandem Aza‐Michael Reaction/Enantioselective Protonation Using a Pd–μ‐Hydroxo Complex under Mild Conditions Buffered with Amine Salts

The tandem aza-Michael reaction/enantioselective protonation of α-substituted α,β-unsaturated carbonyl compounds is described in detail. The key to success is the combined use of a Brønsted basic palladium-μ-hydroxo complex and amine salts, which allows for the controlled generation of active catalyst and nucleophilic free amines. This catalytic system was applicable to various acceptors and aromatic amines, and the desired β-amino acid derivatives with a chiral center at the α position were produced in good yield with excellent enantioselectivity (up to 98% ee). For electron-deficient amines, the introduction of free amine as an additive was effective in promoting the reaction. The results of mechanistic studies, including determination of the absolute configuration of the product, are discussed.

Enantioselective Protonation in the Aza-Michael Reaction Using a Combination of Chiral Pd-µ-Hydroxo Complex with an Amine Salt

A highly enantioselective protonation of enolate intermediates in aza-Michael reaction was achieved by using the combination of a bifunctional chiral Pd-µ-hydroxo complex with aromatic amine salts. The reaction proceeded smoothly to give the desired β-amino carbonyl compounds bearing a stereogenic carbon center at the α-position in good yield with excellent enantioselectivity (up to 97% ee). Although reactions with salts of electron-deficient amines were slow, the introduction of free amine as an additive promoted the reaction to a synthetically useful level.

Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide- p-aminobenzyl-amine linker system

Cytotoxic agents streptonigrin and 17-amino-geldanamycin were linked to monoclonal antibodies (mAbs), forming antibody–drug conjugates (ADCs) for antigen-mediated targeting to cancer cells. The drugs were conjugated with a linker construct that is labile to lysosomal proteases and incorporates a valine-alanine- p-aminobenzyl (PAB)-amino linkage for direct attachment to the electron-deficient amine functional groups present in both drugs. The resulting ADCs release drug following internalization into antigen-positive cancer cells. The drug linkers were conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) via alkylation of reduced interchain disulfides to give ADCs loaded with 4 drugs/mAb. The streptonigrin ADCs were potent and immunologically specific on a panel of cancer cell lines in vitro and in a Hodgkin lymphoma xenograft model. We conclude that streptonigrin ADCs are candidates for further research, and that the novel linker system used to make them is well-suited for the conjugation of cytotoxic agents containing electron-deficient amine functional groups.

Environmentally Benign N‐Boc Protection under Solvent‐ and Catalyst‐Free Conditions.

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N-Boc Protection of Amines with Di-tert-butyldicarbonate in Water under Neutral Conditions in the Presence of β-Cyclodextrin

A new protocol for protection of aryl and aliphatic amines was developed with (Boc) 2 O in the presence of -cyclodextrin in water. A catalytic amount of β-cyclodextrin is specific for activation of amines. This procedure works well on a wide variety of both electron-rich and electron-deficient amines.

TiCl(OiPr)3 and NaBH(OAc)3: An Efficient Reagent Combination for the Reductive Amination of Aldehydes by Electron‐Deficient Amines.

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TiCl(O iPr) 3 and NaBH(OAc) 3: an efficient reagent combination for the reductive amination of aldehydes by electron-deficient amines

Sodium triacetoxyborohydride, NaBH(OAc) 3 with tri-isopropoxytitanium chloride, TiCl(O i Pr) 3 is a useful reagent combination for reductive amination. Electron-deficient amines and heteroaromatic amines such as 2-aminopyrimidine and 2-aminothiazole can be reductively alkylated at room temperature to afford the corresponding secondary amines in good yields.

N‐(Benzoyloxy)amines: An Investigation of Their Thermal Stability, Synthesis, and Incorporation into Novel Peptide Constructs.

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N-(Benzoyloxy)amines: an investigation of their thermal stability, synthesis, and incorporation into novel peptide constructs

A series of N-benzoyloxyamines were pyrolyzed and their decomposition temperatures correlated well with the amine architecture's ability to stabilize a N-centered radical. A variety of amine substrates were treated with a biphasic mixture of benzoyl peroxide (BPO), CH 2Cl 2 and an aqueous carbonate buffer (at pH 10.5). Primary and secondary amines were successfully N-benzoyloxylated in good yield. Tertiary amines and BPO gave low yields of the corresponding N-oxide and complex product mixtures, presumably via radical decomposition. Electron deficient amines (such as fluorinated aliphatic amines, α-aminoacids, α-aminoesters, and α-aminoamides) were not N-benzoyloxylated under these conditions. Instead, N-benzoylation was observed with the fluorinated amines and the reaction was sensitive to temperature and the pH of the aqueous medium. A one-pot-two-step synthesis of N α-FMOC- l-Leu- N β-(benzoyloxy)-β-alanine ethyl ester, a peptide containing both an α- and a novel β-amino acid framework, was also developed.

AN IMPROVED SYNTHESIS OF N-BOC PROTECTED ARYL AMINES

There are several known methods of protecting amines as their Boc derivatives. For less nucleophilic amines such as aryl amines these methods often give poor yields and are generally not satisfactory. Here, Boc aryl amines are obtained by first introducing two Boc groups followed by selective removal of one of them. This procedure works well for a number highly sterically hindered substrates as well as electron deficient and electron rich aryl amines.

Preparation of N,N′-bis(aryl)guanidines from electron deficient amines via masked carbodiimides

Preparation of N,N′-bis(aryl)guanidines by alkylation of electron deficient amines with trityl protected carbodiimides is described. Also reported is a method for the dehydration of N-trityl- N′-aryl ureas to the corresponding carbodiimides using the Burgess reagent.