Assuming a mechanistic manifold similar to pyrrole formation with azobenzene as the nitrene source 7a, 7d the 2 nd order dependence of 3-hexyne indicates that 2 nd insertion of 2a into the azatitanacyclobutene intermediate II is the rate-determining step of catalysis.Ĭomparison of the mechanisms of pyrrole formation with azide or azobenzene reveal different mechanisms of reoxidation. Kinetic analysis of the (THF) 3TiI 2(Ntol)-catalyzed reaction of 1b with 2a through variable time normalization analysis 15 yields the rate law in Figure 3 (top). By moving to a more Lewis acidic catalyst (THF) 3TiI 2(Ntol), which more indiscriminately binds ligands, the desired pyrrole product 3ba was formed in 80% yield with no detectable azide decomposition side-products ( eq 2). Reaction of adamantyl azide ( 1b) with 2a catalyzed by 10% py 3TiCl 2(N tBu) in C 6D 5Br at 115 ☌ resulted in low conversion, presumably due to inhibition of alkyne binding by azide ( eq 1).
Alkyl azides are significantly more thermally robust than aryl azides and undergo addition more slowly, and are thus less likely to undergo competitive decomposition under catalytic conditions.
14Īttempts to improve the selectivity and yield of this reaction through reaction optimization only marginally improved catalysis, and as a result alkyl azides were explored.
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All of the sideproducts in this reaction can be ascribed to thermal azide decomposition- 6a from the uncatalyzed Huisgen condensation of 1a with 2a 7a from the Ti-catalyzed hydroamination of 2a with aniline, which is formed during azide decomposition to the free nitrene and 8a from thermal azide coupling. However, this reaction is marred by significant side-product formation: 4,5-diethyl-1-( p-tolyl)-1 H-1,2,3-triazole, ( 6a), N-( p-tolyl)hexan-3-imine, ( 7a), and 4,4’-azotoluene ( 8a). Initial coupling attempts of p-tolyl azide ( 1a) with 3-hexyne ( 2a) catalyzed by 10% py 3TiCl 2(N tBu) in C 6D 5Br at 115 ☌ yielded 16% of the desired pyrrole product, 2,3,4,5-tetraethyl-N-( p-tolyl) pyrrole ( 3aa). These reactions provide access to N-alkyl functionalized products, in contrast to previously-described methods which were limited to N-arylated products. 13 Herein, we report that organic azides are competent reaction partners for Ti-catalyzed formal pyrrole synthesis and related oxidative multicomponent alkyne aminations. A wide variety of organic azides are also easily accessed through simple substitution chemistry, providing a more straightforward method for synthesizing complex N-substituted pyrroles. 11 Additionally, many diazenes are made from azides, 5b, 12 so direct use of azides could streamline precursor synthesis. 10 This would also give access to pentaalkyl pyrroles, which are extremely rare structures due to their oxidative instability and difficulty of synthesis. For example, alkyl azides-unlike alkyl diazenes-are typically stable above 130 ☌ and thus could allow access to N-alkyl pyrroles, allowing for installation of N-protecting groups on the pyrrole. Further, organic azides offer several advantages over diazenes. Inspired by the successes of Wolczanski and Heyduk in RNI-promoted catalytic oxidative nitrene transfer from azides with group 4 metals, we sought to investigate the use of azides in pyrrole synthesis in the absence of an engineered RNI ligand.Īlthough organic azides are well-known to undergo Huisgen cycloadditions with alkynes to form triazoles-either thermally 8 or with myriad metal catalysts 9-we hypothesized that Ti II intermediates generated in the reaction would be sufficiently reactive to reduce the azide and turn over the catalytic cycle at rates competitive with this potential background reaction. 7 In the absence of ancillary RNI ligands, we hypothesize that the success of this reaction is predicated on the ability of Ti to backbond into the substrates and/or the products, either of which can act as a π-acceptor to mask the Ti II species. Recently, we reported the Ti-catalyzed formal multicomponent coupling of alkynes and aryl diazenes for the synthesis of penta- and trisubstituted pyrroles, which at the time was the first example of catalytic nitrene transfer from Ti. Nitrene transfer reactions catalyzed by early transition metal/redox noninnnocent ligand systems.
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