Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain energy accommodated in the small ring, (ca. 27 kcal/mol), aziridines undergo ring-opening reactions with a variety of nucleophiles. Therefore, among the synthetic reactions utilizing aziridines, regioselective ring-opening substitutions of aziridines with nucleophiles, such as heteroatomic nucleophiles (e.g., amines, alcohols, and thiols) and carbonaceous nucleophiles (e.g., carbanions, organometallic reagents, and electron-rich arenes), constitute a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. However, the regioselection in such traditional ring-opening substitutions of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging to achieve, especially in the case of Lewis acid-promoted variants. Therefore, the development of robust catalytic ring-opening functionalization methods that enable precise prediction of regioselectivity and stereochemistry is desirable. In this direction, our group focused on the highly regioselective and stereospecific nature of the stoichiometric oxidative addition elementary step of 2-substituted aziridines into Pd(0) complexes in an S N 2 fashion. In conjunction with the recent advancements in transition-metal-catalyzed cross-coupling reactions of alkyl pseudohalides containing a C(sp 3 )−Q (Q = O, N, S, etc.) bond, aziridines can be used as nonclassical alkyl pseudohalides in regioselective and stereospecific cross-couplings.In this Account, starting from the background of transition-metal-catalyzed ring-opening functionalization of aziridines, our contributions to the palladium-catalyzed regioselective and stereoinvertive cross-couplings of aziridines with organoboron reagents to form C(sp 3 )−C, C(sp 3 )−B, and C(sp 3 )−Si bonds have been compiled. The developed methods allow the syntheses of medicinally important amine compounds, e.g., enantioenriched β-phenethylamines, β-amino acids, and their boron and silyl surrogates, from readily available enantiopure aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst (i.e., Pd/NHC vs Pd/PR 3 systems). Computational studies rationalized the detailed mechanisms of the full catalytic cycle and the regioselectivity and stereospecificity of the reactions. The computational results suggested that the interactions operating between the Pd catalyst and aziridine substrate play important roles in determining the regioselection of the aziridine ring-opening event (i.e., oxidative addition). Also, the computational results rationalized the role of water molecules in promoting the transmetalation step through the formation of a Pd−hydroxide active intermediate. This Account evidences the benefits of synergistic collaborations between experimental and computational met...

Emerging computational approaches for the study of regio- and stereoselectivity in organic synthesis

“…Aziridine is a three-membered azaheterocycle, which is a versatile building block in organic synthesis, especially as a precursor for the ring opening reaction of N-containing natural products. 94 Transition metal complexes have been used as reactive catalysts for C-N bond cleavage in an S N 2 fashion to form azametallabutanes. [94][95][96] The regio-selective ring opening C-B cross-coupling reaction of 2-arylaziridines via a Pd(P(t-Bu) 2 Me/bpy) catalyst was shown to give β-amino-alkylboronates.…”

“…94 Transition metal complexes have been used as reactive catalysts for C-N bond cleavage in an S N 2 fashion to form azametallabutanes. [94][95][96] The regio-selective ring opening C-B cross-coupling reaction of 2-arylaziridines via a Pd(P(t-Bu) 2 Me/bpy) catalyst was shown to give β-amino-alkylboronates. This reaction is useful in natural product synthesis and amino-functionalization.…”

Catalyst and Additive‐Free Selective Ring‐Opening Selenocyanation of Heterocycles with Elemental Selenium and TMSCN

“…In particular, ring‐opening reactions of small saturated heterocycles [1] and bridged heterocycles [2,3] have been extensively investigated, mainly because their huge ring strain can significantly derive ring‐opening to proceed. The most successful small heterocycles employed in ring‐opening reactions have been the epoxides [1a,b,c,d,4] and aziridines, [1a,h,i,5] which can be subjected to the attack from a series of nucleophilic reagents to furnish aliphatic alcohols and amines respectively. Nevertheless, C‐heteroatom bond cleavage in five‐ or six‐membered rings is usually a rather challenging task due to their negligible ring strain [6]…”

Boron Reagents and Catalysts for the Functionalization of Strained Heterocycles

“…The ring opening of aziridines with carbon nucleophiles constitutes an important class of synthetic method to access biologically relevant β‐functionalized amines. Even if an isolated example of arylative cross‐coupling of a terminal sulfonyl‐protected aziridine has been reported with a copper catalyst, [43] more interesting results have been obtained using palladium catalysis [50] . In particular, Takeda and Minakata found that catalyst [SIPr−Pd(cinnamyl)Cl] has a pivotal role in a C‐2‐selective and enantiospecific arylative ring opening of 2‐arylaziridines occurring in very mild reaction conditions (Scheme 13, eq.…”