Visible-Light-Mediated Generation of Nitrogen-Centered Radicals: Metal-Free Hydroimination and Iminohydroxylation Cyclization Reactions

The formation and use of iminyl radicals in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O-aryl oximes. Owing to their low reduction potentials, the inexpensive organic dye eosin Y could be used as the photocatalyst of the organocatalytic hydroimination reaction. Furthermore, reaction conditions for a unique iminohydroxylation were identified; visible-light-mediated electron transfer from novel electron donor–acceptor complexes of the oximes and Et3N was proposed as a key step of this process.

Nitrogen-centered radicals (NCRs) are av ersatile class of intermediates that have wide applications in the synthesis of N-containing molecules (Scheme 1A). [1] However,t he difficulties associated with their generation have significantly thwarted their use in synthetic chemistry.Infact, established methods often rely on the homolysis of difficult-to-construct N À Xb onds and require the use of toxic and hazardous reagents at elevated temperatures. [1a,2] Thed evelopment of amild, selective,and general method to catalytically generate NCRs from readily available precursors would enable the facile construction of many N-heterocycles,w hich are privileged motifs in natural products and therapeutic agents. [3] Photoredox catalysis has emerged as apowerful technique through which single electron transfer (SET) reactions can be performed under mild conditions. [4] MacMillan [5] and coworkers have developed an asymmetric visible-light-mediated amination of aldehydes by enamine catalysis,a nd the groups of Sanford, [6] Lee, [7] Yu, [8] and Luo [9] have reported the photoredox generation of phthalimidyl and saccharyl radicals and their use in Minisci-type reactions.T he groups of Zheng [10] and Knowles [11] have developed am ethod for the photoredox generation of diaryl and aryl alkyl aminium radical cations and employed them in CÀNb ond-forming reactions.
Drawing inspiration from the work of Forrester, [12] Narasaka, [13] and Walton, [14] we speculated that appropriately functionalized O-aryl oximes could serve as general, benchstable NCR precursors that could deliver iminyl radicals upon photoredox activation under mild conditions. [15] Such an approach would clearly benefit from the facile synthesis of aryl oximes,and we hoped that the high structural modularity of the O-aryl hydroxylamines would allow us to identify substrates that do not require the use of transition-metalbased photocatalysts. [16] Herein, we describe the successful implementation of this approach and the development of novel, transition-metal-free,v isible-light-mediated hydroimination and iminohydroxylation cyclization reactions (Scheme 1B).
Theg uiding principle of our photoredox NCR synthesis capitalized on the evidence that electron-poor aromatic compounds have reduction potentials compatible with SET reduction by visible-light-excited photocatalysts, [17] as shown by MacMillan and co-workers. [18] Our envisaged photoredox iminyl NCR generation was initiated by the visible-lightpromoted excitation of ap hotocatalyst (PC!*PC) [19] followed by SET reduction of the aryl unit of oxime A to give radical anion B (Scheme 2A). Af ragmentation leading to phenoxide C and the desired NCR D was anticipated to occur next owing to the low bond dissociation energy of the NÀO bond. [20] At this stage,w ed ecided to test the viability of this activation mode by combining it with an intramolecular cyclization to synthesize valuable five-membered N-heterocycles. [21] After 5-exo-trig cyclization,the C-centered radical E was expected to abstract aHatom from 1,4-cyclohexadiene (CHD) [20b] to give the desired product F and radical G,which regenerates the photocatalyst by SET,c losing the catalytic cycle.As5-exo-trig cyclizations occur rapidly (k c % 910 3 s À1 at RT), [22] we expected that the reaction yields would correlate with the efficiency of the photoredox system.
TheS ET between the visible-light-excited photocatalyst and the aryl oxime became af ocal point. As the reduction potentials of many photocatalysts are known, [4a] we started our investigations by evaluating the redox profiles of various aryl oximes with the goal of identifying the most suitable/ active substrates.Analysis of oximes 1a-1g by cyclic voltammetry revealed irreversible reduction profiles that are in accordance with the expected fragmentation process.According to our electrochemical scale (Scheme 2B), almost all of the examined oximes are expected to undergo SET reduction by *Ir III ;whereas only the nitro-substituted substrates 1a-1d have E 1/2 red potentials suitable for SET with the excited state of the organic dye eosin Y. [23] Based on these results,w es elected oximes 2a-2c as representative substrates for the evaluation of the proposed radical cyclization reaction (Table 1). To our delight, visiblelight irradiation of 2a-2c in the presence of [Ir(ppy) 3 ], cyclohexadiene,a nd K 2 CO 3 gave pyrroline 3a in good to excellent yields (entries 2, 4, and 6). As predicted by the electrochemical studies, 2aand 2bfurnished 3awhen eosin Y was used as the photocatalyst (entries 3a nd 5), thus setting the stage for af ully organocatalytic photoredox hydroimination cyclization.
Thes ubstrate scope was evaluated with af ocus on 2,4dinitro-substituted aryl oximes owing to four favorable aspects:1 )Ther equired hydroxylamine is commercially available,2 )these oximes are typically purified by crystallization, 3) their photoredox reactions do not require at ransition-metal catalyst, and 4) the products can be purified by as imple acid-base wash (no chromatographic purification needed on the way from the ketone to the final product).
Abroad range of oximes with diverse electronic and steric properties participated efficiently in the visible-light-promoted process (Scheme 3). Bicyclic heterocycles were also obtained in good yields as well as products arising from the cyclization onto di-and trisubstituted olefins.
Intrigued by the low reduction potential and LUMO energy [24] of the 2,4-dinitro-substituted aryl oxime 1a,a nd inspired by the reports of Kochi, [25] Cossy, [26] and Melchiorre [27] on SET,w ew ondered whether ac omplementary activation mode could be exploited for the generation of NCRs by visible-light irradiation. As illustrated in Scheme 4A,w especulated that asimple tertiary amine would be able to reversibly interact with 2a to give an electron donoracceptor complex H. [28] Visible-light irradiation should then initiate aS ET process to give the radical ion pair J. [29] Fragmentation to give D, 5-exo-trig cyclization, and Hatom   [30] theprocess was calculated to be exergonic (DG %À30 kcal mol À1 ), which indicates avery favorable SET.UV/Vis spectroscopy data further corroborated this proposal. When aCH 3 CN [31] solution of 2a was treated with Et 3 N, ab athochromic shift was observed, which indicates the formation of ad onor-acceptor complex (Scheme 4B). Theformation of such complexes has not been studied extensively,p rompting us to evaluate the strength of this key interaction. By using Jobs method, the 2a/Et 3 N stoichiometry in the complex was confirmed to be 1:1, and titration experiments gave an association constant of K % 22 m À1 (Scheme 4B). TD-DFT calculations [CAM-B3LYP/ 6-311 ++G(d,p) in CH 3 CN] confirmed that absorption at approximately 440 nm is due to atransition from the nitrogen lone pair to the p*orbital of the aromatic unit of the oxime. [24] Exposure of 2band 2cto Et 3 N(up to 10 equiv) did not lead to significant bathochromic shifts,w hich suggests that there is limited or no donor-acceptor complex formation. [24] Encouraged by the UV/Vis studies,w ed ecided to evaluate the ability of 2a to undergo the proposed visiblelight-and Et 3 N-mediated SET process.I rradiation of as olution of 2a,Et 3 N, and cyclohexadiene in CH 3 CN furnished the desired product 3a (47 %) together with iminoalcohol 4a (41 %; Scheme 4C). Theunforeseen formation of 4a opened the way to the development of the first visible-light-mediated iminohydroxylation cyclization reaction. By simply excluding cyclohexadiene from the reaction mixture,the yield of 4a was increased to 85 %. Other amines were evaluated, and they also selectively provided 4a,a lbeit in lower yields.A s suggested by the UV/Vis studies,s ubstrate 2b gave the desired product in low yield whereas 2c did not react. [24] Theformation of 4a raised additional questions about the underlying mechanism and the origin of the oxygen atom in the final product (Scheme 4D). Thei nvolvement of adventitious O 2 or H 2 Owas excluded by running the reaction under rigorously moisture-and oxygen-free conditions. [24] In contrast to the hydroimination cyclization, 2,4-dinitrophenol (8-H) was not formed, but we obtained 2-NO-4-NO 2 -C 6 H 3 OH (10-H). This observation indicates aunique trifunctional role of the aromatic unit of the O-aryl oximes,w hich sequentially serves as as ensitizer,a ne lectron acceptor,a nd an oxidant. Initial rate kinetics revealed the reaction to be first order in 2a and to display saturation behavior in Et 3 N (1st order at 0 < [Et 3 N] < 1equiv and zero order at [Et 3 N] > 1equiv). Based on these findings,w ep ropose the following mechanism:F ast and reversible binding of Et 3 Nand 2a gives intermediate 5,w hich undergoes SET upon visible-light excitation to give the dipolar species 6.F ragmentation and 5-exo-trig cyclization give the C-centered radical 7 and the stable phenoxide 8 (pK a % 4). Subsequent oxidation by attack of the radical onto the NO 2 group [32] leads to 9,and successive NÀObond homolysis furnishes 10 and the O-centered radical 11,which undergoes afast hydrogen atom abstraction. [24] With this very simple optimized procedure in hand, the scope of the iminohydroxylation was evaluated with the aryl oximes 2a and 2e-2y.A ll examined substrates reacted well and provided the desired iminoalcohols 4a-4uin good to high yields (Scheme 5). Bicyclic products could be obtained, and substrates containing di-and trisubstituted olefins also reacted well, giving access to products containing up to three contiguous stereogenic centers.
In conclusion, we have developed adivergent strategy for the hydroimination and iminohydroxylation cyclization of unactivated olefins.E lectrochemical studies facilitated the identification of av ery reactive class of O-aryl oximes that obviate the need for at ransition-metal photocatalyst and undergo organocatalytic hydroimination cyclizations.T he unprecedented ability of the aryl unit to sequentially act as as ensitizer,e lectron acceptor,a nd oxidant enabled the development of au nique Et 3 N-and visible-light-mediated iminohydroxylation cyclization. Future studies will focus on applying this method to other nitrogen-centered radicals and on developing asymmetric variants of the hydroimination and iminohydroxylation cyclizations.