The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the Generation and Solvent-Dependent Trapping of 3-Phosphonyl Benzynes

Abstract

Synthetic methodology utilizing two aryne intermediates (i.e., a formal benzdiyne) enables the rapid generation of structurally complex molecules with diverse functionality. This report describes the sequential generation of two ortho-benzyne intermediates for the synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates have proven useful in medicinal chemistry and materials science, and the reported methodology provides a two-step route to functionally dense variants by way of 3-phosphonyl benzyne intermediates. The process begins with regioselective trapping of a 3-trifloxybenzyne intermediate by an O-silyl phosphite in an Abramov-like reaction to bond the strained Csp carbons with phosphorus and silicon. Standard aryne-generating conditions follow to convert the resulting 2-silylphenyl triflate into a 3-phosphonyl benzyne, which readily reacts with numerous aryne trapping reactants to form a variety of 2,3-difunctionalized aryl phosphonate products. DFT computational studies shed light on important mechanistic details and revealed that 3-phosphonyl benzynes are highly polarizable. Specifically, the distortion in the internal bond angles at each of the Csp atoms was strongly influenced by both the electronegativity of the phosphonate ester groups as well as the dielectric of the computational solvation model. These effects were verified experimentally as the regioselectivity of benzyl azide trapping increased with more electronegative esters and/or increasingly polar solvents. Conversely, replacing the conventional solvent, acetonitrile, with nonpolar alternatives provided attenuated or even inverted selectivities. Overall, these studies showcase new reactivity of benzyne intermediates and extend the aryne relay methodology to include organophosphonates. Furthermore, this work demonstrates that the regioselectivity of aryne trapping reactions could be tuned by simply changing the solvent.

Regioselective transformation of 3-phosphoryl benzyne intermediates to diverse phosphorus-substituted arenes

“…1), so that superior regioselectivity was observed in PO1 , MePO1 and PO2 , which is different from that of phosphonate type benzynes with potentially flexible alkoxyl groups reported by the group of Willoughby. 35 Meanwhile, the NPA charges at the C1 positions of PO1 , MePO1 and PO2 are more positive than those at the C2 positions (Fig. S2, ESI†), further illustrating that the C1 positions are preferred.…”

“…36 Then treatment with triflic acid anhydride and suitable bases successfully produced target agents 5 (73%) as a white solid and 6 (72%) as a viscous oil, which cannot be achieved via an aryne relay process as illustrated by Willoughby's report. 35 This concise and straightforward approach can easily prepare new 3-phosphoryl benzyne precursors in three steps on gram scales. Furthermore, the structure of compound 5 was unambiguously verified by single-crystal X-ray diffractometry (Scheme 2).…”

“…Nevertheless, 3-phosphabenzynes have remained largely unexplored due to the limited synthetic methods, until very recently Willoughby and co-workers reported a unique aryne relay process to synthesize a family of 3-phosphonyl benzyne precursors bearing phosphonates. 35 Herein, we develop a phospho-Fries rearrangement reaction from easily available phenol derivatives, affording o -silylaryl triflate-type 3-phosphoryl benzyne precursors 5 and 6 on gram scales in three steps. Furthermore, they can readily be used to construct a series of arylated organophosphorus molecules in high selectivity under mild conditions without transition metal catalysts.…”

The Aryne Phosphate Reaction**

“…[ 24 , 25 ] Between 2013 and 2021 Mhaske, Chen, Zhang and Willoughby applied phosphites, H‐phosphonates and silylphosphates ( 11 ) to generate arylphosphonates ( 12 ). [ 26 , 27 , 28 ] Moreover, He and Guo presented a σ‐P‐O‐bond insertion of arynes into organophosphinic acids ( 9 ). [29] In summary, the broad spectrum of aryne reactivity can be exploited with phosphorous functionalities towards diversely arylated products enabling C‐P‐bond formation.…”

The Aryne Phosphate Reaction

“…[24,25] Between 2013 and 2021 Mhaske, Chen and Willoughby applied phosphites, H-phosphonates and silylphosphates (11) to generate arylphosphonates (12). [26][27][28] Moreover, He presented a σ-P-O-bond insertion of arynes into organophosphinic acids (9). [29] In summary, the broad spectrum of aryne reactivity can be exploited with phosphorous functionalities towards diversely arylated products enabling C-P -bond formation.…”