TiCl₄‐Mediated [2+2] Cycloaddition for Synthesis of Isolable CF₃‐Substituted 2‐Azetines

Abstract

We demonstrate the catalytic intermolecular [2 + 2] cycloaddition of electron-rich alkynes and a trifluoroiminopyruvate, affording the corresponding CF 3 -substituted isolable 2-azetines. Whereas [4 + 2] interaction affording acyclic imidates was predominant in the absence of a Lewis acid catalyst, using a catalytic amount of titanium(IV) tetrachloride was quite effective in promoting the desired [2 + 2] cycloaddition providing 2-azetines. Electron-rich arylsubstituted inner alkynes provided complete regioselectivity, and using a silyl group was effective for inducing the dominant [2 + 2] cycloaddition pathway. Both [2 + 2] cycloaddition and formation of γ-butenolides via a "5-exo-dig type" cyclization pathway were confirmed. Hydride reduction of a 2-azetine provided the azetine-substituted primary alcohol, and treatment with potassium t-butoxide promoted ring expansion, affording the 6-membered cyclic sulfonamide.

New Strategies for the Synthesis of 1- and 2-Azetines and Their Applications as Value-Added Building Blocks

“…Their method shows the formation of 6-membered cyclic sulfonamide 105 upon treating N-mesylated 2-azetine 104 with three equivalents of potassium tert-butoxide. 9 The authors hypothesized the reaction proceeded via a [2,3]-rearrangement following deprotonation of the mesyl group.…”

“…1,2 While development of methods to access azetines has been more limited, the field has seen a recent rise in popularity with the development of five new synthetic methods since 2018. [7][8][9][10][11][12] Azetidines and azetines share desirable physical properties including high ring-strain and the potential to serve as bioisosteres; however, these fourmembered heterocycles have important differences in their inherent reactivity, making azetines highly desirable synthetic targets.…”

“…Methods to access azetines through [2+2]-cycloadditions (Fig. 2A) fall into two categories, [2+2]-cycloadditions of imines (9) and alkynes (10) to access 2-azetines (11) [24][25][26] and [2+2]cycloadditions of nitriles (12) and alkenes (13) to access 1azetines (14). [27][28][29] Cycloadditions relying on imines (9) and alkynes (10) have been shown to proceed either under UV light irradiation 24 or metal-mediated conditions.…”

1- and 2-Azetines via Visible Light-Mediated [2+2]-Cycloadditions of Alkynes and Oximes

“…Moreover, aryl alkynes incorporating electron-donating groups in the para position resulted in up to 34% yield (39,40) while an electron-withdrawing substituent proved superior (38) and resulted in 55% yield. Importantly, an alkyne lacking an aryl activating group but incorporating two ester groups allowed formation of the product in an excellent yield of 88% (37) demonstrating that aryl alkynes are not required if the resulting intermediates can be sensitized through TTEnT. With respect to the 2-isoxazole coupling partner, both unsubstituted (41) and monosubstituted (42,43) substrates were tolerated, albeit proceeding with overall decreased yields.…”

“…Synthesis of 2-azetines is similarly limited, relying on eliminations [27][28][29][30][31][32][33] (7), and metal mediated cycloadditions via ring expansion of diazoaziridines (8). Arguably, [2+2]-cycloadditions between alkenes and nitriles 34,35 or alkynes and imines [36][37][38] represent the most efficient strategies to access 1-and 2-azetines, however they suffer from a limited scope and the competing formation of azadiene byproducts 39 (12 and 16, Fig. 1C).…”