Sulfonylative and Azidosulfonylative Cyclizations by Visible‐Light‐Photosensitization of Sulfonyl Azides in THF

Abstract The generation of sulfonyl radicals from sulfonyl azides using visible light and a photoactive iridium complex in THF is described. This process was used to promote sulfonylative and azidosulfonylative cyclizations of enynes to give several classes of highly functionalized heterocycles. The use of THF as the solvent is critical for successful reactions. The proposed mechanism of radical initiation involves the photosensitized formation of a triplet sulfonyl nitrene, which abstracts a hydrogen atom from THF to give a tetrahydrofuran‐2‐yl radical, which then reacts with the sulfonyl azide to generate the sulfonyl radical.


Introduction
Azides are highly versatile functional groups because they undergo many different reactions. [1,2] The recent, dramatic increase in the use of visible light photocatalysis in synthesis [3] has led to its application in reactions of organic azides, resulting in several interesting new processes. [4] Aryl, [4a-c,i] alkyl, [4a] alkenyl, [4c] and acyl [4d,j] azides, as well as azidoformates [4f] have been employed in reductions, [4a] radicala dditionst on itriles, [4a] nitrenei nsertions, [4b,d] rearrangements, [4c] aziridinations, [4c,f] enantioselective enolate aminations, [4i] and cascade cyclizations. [4j] Azidoiodanes have also been used in radical azidations. [4e,g,h] However,s ulfonyl azides have hardly been explored in visible light photocatalysis. To our knowledge, the only example reported used as ulfonyla zide as ap recursor to as ulfonyl nitrene, which, in the presence of acid,r eactedw ith N-methylpyrrole in aC ÀHa midation (Scheme 1A). [4d] Given the versatility of sulfonyl azides, [1,2] their application in other classes of photocatalytic reactions could lead to valuable new synthetic opportunities.H erein, we describer adical cyclizationso f enynes which use sulfonyl azides,v isible light, and ap hotoactive iridium complex to give several classes of highlyf unctionalized oxacycles and azacycles (Scheme 1B). In contrast to the aforementioned example, [4d] the overall net outcome is not cleavageo fan itrogen-nitrogen bond of the sulfonyl azide, but cleavage of the sulfur-nitrogen bond to give as ulfonyl radical, whichi si ncorporatedi nto the products. Depending upon the enyne, the products can also contain the azide group,au seful handle for further derivatizations. [1,2] Results and Discussion

Initial mechanistic considerations
Given that the only reportede xample of av isible light photocatalytic reaction of as ulfonyl azide proceeds through as ulfonyl nitrene (Scheme 1A), [4d] the generation of sulfonyl radicals in the reactions described herein was intriguing from am echa-  nistic standpoint. The observation that THF is au niquely effective solvents uggestst he reaction medium plays ak ey role in radicali nitiation. The reactions shown in Ta ble 2r esult from overall addition of as ulfonyl group and ah ydrogen atom to the substrate. We therefore assumed that, in addition to its suspected role in radicali nitiation, the effectiveness of THF in the sulfonylative cyclizationsa rises from its ability to act as a hydrogen atom donor. [9] To shed light on this latter issue, 1a was reacted with paratoluenesulfonyl azide (2a)i n[ D 8 ]-THF with Ir 2 as the photocatalyst [Eq. (3)].W ith the standard quantity of 2a (1.2 equiv), this reaction was much slower than the corresponding reaction using non-deuterated THF ( Table 1, entry 4). However,i ncreasing the quantity of 2a to 10.0 equivalents and raising the temperature to 50 8Cg ave, after 96 h, a4 5% yield of am ixture of isotopologues 3a,[ D]-3a,a nd [D 2 ]-3a,w hich contain different numberso fd euterium atoms at the methylene carbon adjacent to the carbonyl group. [10] The major component was the monodeuterated compound [D]-3a (likely am ixture of diastereomers), while the non-deuterated compound 3a was a minor component. Mass spectrometry suggested at race (ca. < 5%)o ft he di-deuteratedc ompound [D 2 ]-3a was present. This result is consistent with the final product-forming step being hydrogen/deuteriuma bstraction from THF,w hich may be rate-limiting.T he presenceo fa ll three isotopologues may be explained by reversible, acid-catalyzed hydrogen-deuterium exchange through enol intermediates.

Proposedradical chain mechanisms
We consider it likely that the sulfonylativec yclizationso perate throughr adical chain mechanisms (Scheme 2). [11] First, irradiation of the sulfonyl azide 2a in the presence of the iridium complex and THF produces the sulfonyl radical 12.P ossible pathways for this initiation are discussed below.A ddition of 12 to the alkyne of the substrate 1a gives an alkenylr adical 13, which cyclizeso nto one of the alkenes to give an ew radical 14.I ti sw ell-known that electrophilice nolate radicals such as 14 do not reactw ith sulfonyl azides to give azidation products. [2d] However,ahydrogen abstraction from THF,a ss uggestedb yt he resultso fE quation (3), would give product 3a along with the nucleophilic tetrahydrofuran-2-yl radical 15. [9] In ac hain propagation step, 15 could react with the sulfonyl azide to give azide 16 and regenerate the sulfonyl radical 12. The beneficial effect of TsOH·H 2 Oi sn ot currently known.
Scheme3.Proposed mechanism for azidosulfonylative cyclization. tion, the sulfonyl radical 12 adds to the alkyneo f7a to give alkenyl radical 17,w hich undergoes 6-exo-trig cyclization onto the alkene to give tertiary radical 18.A zidation of 18 with the sulfonyl azide 2 in ac hain propagation step gives the product 8 and regenerates the sulfonyl radical 12.
[2d] The formation of the non-azidated byproduct 9 (Table 3) can be explained by radical 18 undergoing competitive hydrogen atom abstraction with the solvent THF.

The role of THF in radical initiation
Although both the sulfonylative and azidosulfonylative cyclizations are readily explained by radical chain mechanisms (Schemes 2a nd 3), the questionr emains of how the combination of visible light, photoactive iridium complex, THF,a nd the sulfonyl azide leads to the generation of sulfonyl radicals.
In principle, single-electron-transfer from the photoexcited iridium complex to the electrophilics ulfonyl azide, followed by fragmentation of the resulting radical anion would give an azide anion and the requisite sulfonyl radical 12.S ingle-electron-transfer to organic azides hasbeen postulated in photocatalytic reactions. [4a,i] However,t he reduction potential E 1/2 red of para-toluenesulfonyl azide (2a)w as measured by cyclic voltammetry to be À1.22 Vv ersus SCE in MeCN, [12] and it would appear that the photoexcited states of the iridium complexes Ir 1-3 are insufficiently reducing to promote this electron transfer efficiently( Ir 1, E* III/IV = À0.96 Vv s. SCE; [3e] Ir 2, E* III/IV = À0.85 Vv s. SCE, [13] and Ir 3, E* III/IV = À0.89 Vv s. SCE [3e] ). The superiority of THF over other solvents is also not readily explained by an electron transfer mechanism.
As econd mechanism that we considerm ore likely begins with irradiation of Ir 1 (depicted as Ir III )t og ive the photoexcited * Ir III species 19 (Scheme 4). Triplet sensitization of the sulfonyl azide by an energy transfer mechanism gives 20,w hich then loses dinitrogen to give at riplet nitrene 21.T his pathway is consistent with the only reported example of av isible light photocatalytic reactiono fasulfonyl azide (Scheme1A), which also proceeds through as ulfonyl nitrene. [4d] The formation of a sulfonyl nitrenef rom UV irradiationo fasulfonyl azide with benzophenonea satriplet sensitizer is also known. [14] Furthermore, other electron-deficient azides such as acyl azides and azidoformates are knownt op roduce nitrenes by triplet sensitization with photoactive metal complexes. [4b-d,f] The triplet nitrene 21 could then abstract ah ydrogen atom from THF to give tetrahydrofuran-2-yl radical 15 and sulfonamidylr adical 22.I nr elevant precedent, it is known that triplet sulfonyl nitrenes can abstract ah ydrogen atom from the methine carbon of i-PrOH. [14] Azidation of 15 with the sulfonyl azide would then provide the sulfonyl radical 12 to enter the chain mechanisms shown in Schemes 2a nd 3. The sulfonamidyl radical 22 could then undergo as econd hydrogen abstraction with THF to give para-toluenesulfonamide (23). It should be noted that we did observe the formation of small quantities of 23 in all of the reactions reported in Ta bles 2a nd 4, which lends some support for the participation of triplet nitrene intermediates.
Furthermore, reaction of 1,6-enyne 7a with 2a in DCE ratherthan THFgave aziridine 24 in 42 %y ield [Eq. (4)]. Evidently, in thea bsence of THF,t he putative tripletn itrene 21 reacts with thea lkene of 7a to give 24,p resumably by as tepwise radical addition and ring closure as describedb yY oon and co-workers. [4f] Implications for other reactions As discussed above, our collective results point to the formation of tetrahydrofuran-2-yl radical 15 from the reactionofT HF with at riplet sulfonyl nitrene 21 derived from as ulfonyl azide 2 (Scheme 4). Although this process leads to the generation of sulfonyl radicals by subsequent reactionof15 with the sulfonyl azide 2,w eq uestioned whether 15 could be formed by the reaction of THF with tripletn itrenes derived from azides that are unreactivetoward 15.I fs o, it might be possible to utilize 15 in ac arbon-carbon bond-formingr eaction.

Conclusions
We have described sulfonylative and azidosulfonylative cyclizations of enynes that give several classes of highly functionalized heterocycles. These reactions operate through radical chain mechanisms,w ith the combination of sulfonyl azide, THF,v isible light, and ap hotoactive iridiumc omplex serving as a" smart initiation" [11a] system for the generation of sulfonyl radicals. Radical initiationb egins with the photosensitized formation of at riplet nitrene from the sulfonyl azide, followed by hydrogen atom transfer from THF to the nitrenet og ive at etrahydrofuran-2-ylr adical, which then reacts with the sulfonyl azide to produce the sulfonyl radical. By using an azidoformate insteado ft he sulfonyl azide, the tetrahydrofuran-2-yl radical can be intercepted by electron-deficient alkenes. This work further demonstrates that spin-selective formation of triplet nitrenes from organic azides using visible light photocatalysis can serve as ap owerful platform for new reactiond evelopment. [15]