Hydrative Aminoxylation of Ynamides: One Reaction, Two Mechanisms

Abstract Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation of ynamides, a reaction which can proceed by either a polar‐radical crossover mechanism or through a rare cationic activation. Common to both processes is the versatility of the persistent radical TEMPO and its oxidised oxoammonium derivative TEMPO+. The unique mechanisms of these processes are elucidated experimentally and by in‐depth DFT‐calculations.


Introduction
The chemistry of free radicals has shaped organicc hemistry for over ah undred years, and during this time, has produced several ground-breaking innovations. [1] Oncet hought uncontrollable due to high reactivity and barely predictableb ehaviour, the last decades have broughtadeeper understanding of the role of free radicals in organic reactions [2] and have placed them at the forefront of some major developments in organic synthesis. These range from free-radical chain reactions, [3] all the way to photoredox catalysis. [4] In contrast to transient radicals generated in situ, persistentr adicals exhibitm uch greater lifetimes and therefore stability. [5] The triphenylmethyl radical, the first described member of this family, [6] is perhaps the most well-known carbon-centred radical, while the oxygen-centred persistentn itroxyl radical( 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) has also gained widespread attention sincei ts discovery in 1959. [7] TEMPO (alongsideo ther nitroxylr adicals) has found extensive application in hydrogen-abstraction reactions, [8] as well as in combination with organometallic reagents for CÀO, CÀNa nd also CÀCc oupling reactions, [7c,d] and in nitroxide-mediated living free-radical polymerisation (NMP) [7a, 9] (Scheme 1a). Additionally,i ts longevity allows TEMPO to be used as at rapping agent or radical scavenger in radical carbon-carbonb ond-formingr eactions. [7c, 10] Similarly,T EMPO itself has been employed in the aminoxylation of enolate derivatives, affording a-oxidised carbonyl products. [11] It is, however, arguably mostfamous for its ability to oxidise primary and secondary alcohols to the correspondingc arbonylc ompounds, [12] at ask which it achieves via its oxidised oxoammonium counterpart TEMPO + .C uriously,t he chemistry of oxoammonium salts is not much developed beyondt his synthetically useful reactivity manifold (Scheme 1b). [13] Herein we report the TEMPO-mediated hydrative aminoxylation of ynamides (Scheme 1c), an unusual reaction that can proceedb ye ither ap olar-radicalc rossover mechanism or a cationic hydrativep athway and which showcases the unique versatility of the chemistries of persistent radicals and keteniminium ions, as well as ad etailed mechanistic and computational study of the process.

Results and Discussion
Following our recent report on the reaction of TEMPO with activated amides, [14] our initial efforts focused on the combination of ynamides [15] with TEMPO under the action of aBrønsted acid (Scheme 2). We eventually found that it was possible to intercepta na cid-preactivatedy namide 1a with TEMPO under mild conditions. This enabled the preparation of ah ydrative oxyamination product 2a in 80 %i solated yield. [16] Further modification of the conditions, including the premixing of ynamide and TEMPO, as well as the use of fewer equivalents of TEMPO, led to no improvement in yield (details of optimisation experimentsa re compiled in the Supporting Information). The strict requirement for 2.2 equivalents of TEMPO in order to obtain high yields of product would prove to have significant mechanistic implications (vide infra).
Having identified optimal reactionc onditions, we were interested in investigating the scope and functional group tolerance of the reaction (Scheme 3).
From the outset, we were intrigued about the role of TEMPO in this reaction, and carriedo ut the mechanistic experiments depicted in Scheme4. [19][20][21] For instance, we initially suspectedt hat TEMPO + ,t he oxoammonium counterpart of TEMPO, was involvedi nt his process. However,s ubstituting TEMPO for TEMPO + in the procedure presented above yielded no traces of product (Scheme 4a). Similart houghts concerning ap ossible in situ disproportionation of TEMPO under reaction conditions led us to add TEMPO-H (the reduced, protonated form of TEMPO) instead, which also didn ot afford any product (with or without added TEMPO + ,Scheme 4b).
Similarly,t he addition of triflic acid to TEMPO (known to promote disproportionation [22] )f ollowed by subsequenti ntroduction of the ynamide into the reactionm ixture afforded only 7% NMR yield of the hydrative aminoxylation product (Scheme 4c). Surprisingly,h owever,w eo bserved that in the absence of triflic acid, ac ombinationo fT EMPO + (1.00 equiv) and water (2.00 equiv) is competent in providingt he hydrative aminoxylation product 2a in 62 %y ield (Scheme 4d). This unexpected observation hints at the ability of TEMPO + to activate ynamides as ac ationic O + -donor reagent. [23] The generality of this transformationw as briefly investigated and results are compiled in Scheme 5. As can be seen, the use of TEMPO + /water allows hydrative aminoxylation of several ynamides in yields comparable to those of the combined TfOH/TEMPO procedure (and with considerably shorter reaction times) for av ariety of substitution patterns.I na ddition to select repeated examples from Scheme 3( 2a,b,d,k,m,p,s,t), ynamides containing varying alkyl and aryl substitution (2u-x) were smoothly converted to the desired products and, pleasingly,b oth silyl ethers (2y)a nd nitriles (2z)w ere tolerated under the reaction conditions.

Mechanistic studies
The unusual observation that two sets of diametrically opposed conditions lead to the same product, raises significant mechanistic questions. While the procedure involvingT EMPO + /water appears to proceed by a" conventional" cationic activation/aqueous capturep athway (Scheme 6a), we still hadn o clear picturef or the intriguing polar-radicalc ombination of the TfOH/TEMPO protocol. In particular, the stringent requirement for 2equivalents of TEMPO in the latter set of conditions contrasts with the successful hydrativea minoxylationo bserved with only 1equivalent TEMPO + in the aqueous procedure. Furthermore, the possibility that both mechanismsw ould overlap remained open-until the isotopic labellinge xperiments of Scheme6were carried out.
As shown, when using 18 O-water in conjunction with TEMPO + ,u nambiguous incorporation of the label into the carbonyl oxygen was observed (Scheme 6a). This strongly suggests that the reactionp roceeds by cationic activation of the ynamide coupledt ohydrolysis. Unexpectedly,the use of 18 O-labelled TEMPO for the TfOH/TEMPO procedure led to significant double incorporation of the label (Scheme6b), indicating that both oxygensi nserted into the final product originate from the persistent aminoxyl radical reagent. Notably,q uenching the TfOH/TEMPO reaction with 18 O-labelledw ater did not lead to incorporationo fthe label into the final product, therebyfurther corroborating ad ifference in mechanismf or the two transformations. At this juncture, we resorted to quantum chemicalc alculations at the DFT level of theory (see the Supporting Information fort he computational details) to shed more light on the intricacies of this unusual polar-radical crossover process.

DFT studies
As shown previously, [24] the treatmento fy namide 1a with TfOH leads to the transient formation of an E/Z-mixture of the triflateds pecies A-OTf,w hich exists in equilibrium with the keteniminium ion A.F or this reason, calculations of the reaction mechanism for the formationo fp roducts 2a were performed startingf rom A (Scheme 7).
At the outseto fo ur calculations, we were mindfulo fthe labelling studies that effectively established the prerequisite for incorporation of two oxygen atoms from TEMPO in the final product;this prerequisite was reflected in the calculations.
The computed reactionp rofile is shown in Figure1.T he startingp oint (intermediate A')p resents two TEMPO radicals and the keteniminium cation A.I nt he first step, one of the TEMPO radicals attacks the cation A leading to the imidate intermediate B (Pinner-type). [25] The intermediates A' and B,a s well as the corresponding transition state TS A'-B are cationic diradicals and therefore exist both in triplet and singlet states, both of which were consideredi nt he calculations (showni n red and blue, Figure1). [26] Intersystem crossing (ISC) of the triplet and the singlet states occurs on the phase between the transition state TS A'-B and the intermediate B (Figure 1). The depicted resonance structure of B (a N,O-keteneacetal derivative) also accountsf or the stability of the cationic radical species and therebyc an be reconciled with the low amountso ft he corresponding ring-opening product detected in the case of cyclopropylp roduct 2o (vide supra).
The next steps of the reactiono ccur in the closed-shell state. Intermediate B and the second TEMPO radical recombine, formingi ntermediate C.T his explains the experimental fact that both oxygen atoms within the final product are derived from TEMPO (cf. Scheme 6b). The final step C!D is very favourable thermodynamically (À95.0 kcal mol À1 ). In this step, one of the OÀNb onds is cleaved heterolytically,l eading to the neutralf inal product 2a,a nd ac ation originating from rearrangementofthe TMP + fragment (two possiblecationsare depicted in Figure 1). [27] We have also computationally considered the reactiono f the keteniminium intermediate with TEMPOH or TEMPO À as alternative non-radical mechanismo fthes tudied processes.
The quantum chemical calculations at the DFT level of theory suggest that the necessary closed-shell( non-radical) transition state does not exist as as tationary point on the potential energy surface. This meanst hat this process has al arge kinetic barrier and therefore is highly unlikely to take place. This is consistentwith the aforementioned experimental observations (cf. Scheme 4).

Conclusions
In conclusion, we have documented an unusualh ydrativea minoxylation of ynamides that can proceed by two different mechanisms. Crucial to each pathway is the presence of either the persistent aminoxyl radicalT EMPO or its oxidised oxoammoniumv ariant TEMPO + .T he first process involves addition of ar adical species to ak eteniminiumi ntermediate, at ransformation which is underrepresented in synthesis and which was elucidated by extensive DFT calculations. The second pathway dispenses with acidic pre-activation and proceeds by ac lassical nucleophile/electrophile cooperative process. Both processes highlight the versatility of TEMPOa satruly chameleonic reagent in synthesis. DOC-fellowo ft he Austrian Academy of Sciences. A.P.a cknowledges aG rant from the Ministerio de Economía, Industria y Competitividad (BES-2013-064292 and EEBB-I-17-11898). Calculations were partially performed at the Vienna Scientific Cluster (VSC). Generous continued support of our research by the University of Viennaisg ratefully acknowledged.