Timothy J. Barker

Umpolung Amination: Nickel-Catalyzed Coupling Reactions of N,N-Dialkyl-N-chloroamines with Diorganozinc Reagents

N,N-dialkyl-N-chloroamines are an effective source of electrophilic nitrogen for nickel-catalyzed coupling with diarylzinc reagents. A variety of N-chloroamines as well as organozinc reagents react smoothly under the reaction conditions. A one-pot procedure that circumvents the need to isolate the N-chloroamines is described.

Titanium‐Mediated Amination of Grignard Reagents Using Primary and Secondary Amines

The synthesis of anilines through the formation of an aryl– nitrogen bond is a powerful method for the preparation of natural products and pharmaceutical targets. Although palladium catalysis has proven to be an expedient and practical method for this type of bond construction, the use of electrophilic aminating reagents with nucleophilic organometallic reagents presents an alternative strategy. This approach typically requires synthesis and isolation of the electrophilic nitrogen source; methods that use amines directly increase the appeal of this strategy. Transitionmetal-catalyzed amination of organometallic reagents with N-chloroamines has been demonstrated by a number of research groups. Although several of these methods were amenable to generation of the N-chloroamines in situ, none of these reports utilized the nonisolable primary N-chloroamines; thus establishing the need for a new method to address these challenging substrates. Herein, we report the one-pot chlorination and titanium-mediated coupling of Grignard reagents with amines, including primary amines. Our investigations began with examination of the reaction between N-chlorocyclohexylamine and Grignard or arylzinc reagents in the presence of a series of catalysts or promoters (Table 1). A one-pot procedure to prepare the electrophilic N-chloroamines in situ was utilized. In the absence of additive, no desired aniline was formed (Table 1, entry 1). Notably, in the presence of either nickel catalyst or diamine ligand, negligible to modest yields of desired product were observed (Table 1, entries 2 and 3). We hypothesized that an aryltitanium intermediate may provide a suitably nucleophilic reaction partner that could best decomposition of the Nchloroamine (Scheme 1). Use of [Ti(OiPr)4] with Grignard reagent provided the best yield of the desired product (Table 1, entry 6). A series of primary amines reacted smoothly under the one-pot procedure (Table 2). Steric bulk on the adjacent carbon atom is well-tolerated, with a,a-disubstituted amines providing some of the best yields (Table 2, entries 5–7). Configuration is conserved when starting with a chiral amine (Table 2, entry 10). The reaction conditions tolerate protected alcohols and amines as well as a terminal alkyne (Table 2, entries 9–12). Use of unbranched primary amines generally resulted in lower yields. Next we turned our attention to functionalized secondary amines, including the synthesis of the biologically active biarylpiperazine substructure (Table 3). Functionalized cyclic and acyclic secondary amines were found to be very effective substrates under the reaction conditions. Diallylamine, a substrate that shows potential for being part of a protecting group strategy, gave the desired aniline in good yield (Table 3, entry 2). Primary nitriles were well tolerated (Table 3, entry 3), as were ethyl and benzyl carbamates (Table 3, entries 5 and 9). Arylpiperazines that incorporate functional groups including pyridine, nitrile, and 2-furanyl underwent smooth cross-coupling under the reaction conditions and provided biarylpiperazines (Table 3, entries 6–8). These types of structures are of particular interest because of the myriad of biological activities associated with the biarylpiperazine pharmacophore. The synthesis of an N-aryl homopiperazine was also examined (Table 3, entry 9), thus demonstrating Table 1: Optimization with Cyclohexylamine.

Diene-ligated iridium catalyst for allylation reactions of ketones and imines.

[Ir(cod)Cl](2) is a highly reactive catalyst for allylation reactions of ketones using allylboronic ester. Mechanistic experiments are consistent with formation of a nucleophilic allyliridium(I) complex that is activated by the diene ligand toward attack of a ketone. Aryl and alkyl ketones react smoothly at room temperature. Aldimines also undergo allylation under these reaction conditions, requiring increased reaction times relative to the corresponding ketones.

Total Synthesis of (−)-Vindoline and (+)-4-epi-Vindoline Based on a 1,3,4-Oxadiazole Tandem Intramolecular [4 + 2]/[3 + 2] Cycloaddition Cascade Initiated by an Allene Dienophile

It is reported that an allene dienophile can initiate a tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles, that the intermediate cross-conjugated 1,3-dipole (a carbonyl ylide) can participate in an ensuing [3 + 2] dipolar cycloaddition in a remarkably effective manner, and that the reaction can be implemented to provide the core pentacyclic ring system of vindoline. Its discovery improves a previous total synthesis of (-)-vindoline and was used in a total synthesis of (+)-4-epi-vindoline and (+)-4-epi-vinblastine that additionally enlists an alternative series of late-stage transformations.

B(C6F5)3-catalyzed synthesis of benzylic azides

ABSTRACT B(C6F5)3 was found to catalyze the reaction between trimethylsilyl azide and benzylic acetates. Secondary and tertiary benzylic acetates were competent substrates in this reaction providing the azide products in moderate to high yields. Mechanistic experiments are consistent with the possible formation of a Lewis acid-base pair between the B(C6F5)3 and trimethylsilyl azide. GRAPHICAL ABSTRACT