N‑Tosyl-3-Azacyclohexyne. Synthesis and Chemistry of a Strained Cyclic Ynamide Sami F. Tlais and Rick L. Danheiser* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States * S Supporting Information ABSTRACT: The first synthesis of a strained six- membered cyclic ynamide is described. N-Tosyl-3- azacyclohexyne is generated via fluoride-promoted 1,2 elimination under conditions that allow trapping of the strained heterocyclic alkyne in a variety of addition, insertion, and [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions. T he role of o-benzyne as the key intermediate in the reaction of chlorobenzene with KNH 2 was established through a series of groundbreaking experiments reported by J. D. Roberts et al. in 1953. 1 Today arynes 2 and hetarynes 3 rank among the most extensively studied reactive intermediates in organic chemistry. The electronic structure of these highly strained alkynes continues to attract great interest, and these remarkable species also have found an important place as building blocks in organic synthesis. 4 Cyclohexynes, on the other hand, are considerably less stable than benzynes, and to date these more exotic species have found very limited use in synthesis. 5,6 Even less attention has been focused on heterocyclic variants of cyclohexyne, and the application of these species in synthesis has not previously been explored. Our interest in the application of ynamides as synthetic building blocks 7,8 led us to consider whether the preparation of strained cyclic ynamides such as 1 might be feasible and whether such species might engage in transformations with utility for the construction of complex molecules. Herein we report the first synthesis of N- tosyl-3-azacyclohexyne (1) as well as its participation in highly regioselective transformations leading to a diverse range of heterocyclic compounds. To our knowledge, only a single report of the generation of an azacyclohexyne has appeared previously. In 1988, Wentrup et al. reported that flash vacuum pyrolysis of isoxazolone 2 provides access to azacyclohexyne 4 which was identified through the use of low-temperature IR spectroscopy. 9 Decomposition of the unstable heterocyclic alkyne was observed to take place upon warming above -150 °C. The formation of azacyclohexyne in this reaction is believed to proceed via the rearrangement of the intermediate carbene 3 (eq 1). For our initial studies on the chemistry of azacyclohexynes, we focused our attention on the N-tosyl derivative 1 and targeted the cyclic enamide 5 as a potential intermediate for its synthesis (Scheme 1). 10 Several considerations motivated our choice of 5 as an attractive precursor to the strained cyclic alkyne. First, several alternate routes could be envisioned for the preparation of 5 beginning with readily available derivatives of δ-valerolactam. Exposure of 5 to the action of fluoride ion was then expected to provide access to the azacyclohexyne under mild conditions that would be compatible with the presence of a wide range of interesting reaction partners capable of trapping the strained alkyne. Note that the elimination process proposed for the generation of 1 from 5 (Scheme 1, pathway a) constitutes a variant of the well established Kobayashi method for the preparation of arynes from o-(trialkylsilyl)aryl triflates. 11 It is relevant to note that 1,2-eliminations of this type have previously been employed for the generation of cyclohexyne 6c,f as well as 1,2,3-cyclo- hexatriene. 12 As depicted in Scheme 1, the formation of azacyclohexyne 1 via pathway a would involve a syn mode of elimination with triflate as leaving group. It did not escape our notice that the Received: September 9, 2014 Scheme 1. Strategy for the Generation of N-Tosyl-3- azacyclohexyne Communication pubs.acs.org/JACS © XXXX American Chemical Society A dx.doi.org/10.1021/ja509055r | J. Am. Chem. Soc. XXXX, XXX, XXX-XXX