Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes

Intramolecular cyclization of nitrogen-containing molecules onto pendant alkenes is an efficient strategy for the construction of N-heterocycles, which are of paramount importance in, for example, pharmaceuticals and materials. Similar intermolecular cyclization reactions, however, are scarcer for nitrogen building blocks, including N-centred radicals, and divergent and modular versions are not established. Here we report the use of sulfilimines as bifunctional N-radical precursors for cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis. Structurally diverse sulfilimines can be synthesized in a single step, and subsequently engage with alkenes to afford synthetically valuable five-, six- and seven-membered heterocycles. The broad and diverse scope is achievable by a radical-polar crossover annulation enabled by the bifunctional character of the reagents, which distinguishes itself from all other N-centred-radical-based reactions. The modular synthesis of the sulfilimines allows for larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods.


Results and discussion
Our goal was to generate a stable reagent that could be transformed into an electrophilic NCR under conditions that would tolerate the presence and reactivity of a pendant nucleophile for subsequent ring closure. While, a priori, several NCR precursors could meet such a goal, one reason why such a compound class has not yet been disclosed may be the synthetic challenge to make these reagents due to undesired cross-reactivity of the pendant nucleophile or undesired reactivity of the nitrogen-activating group. For example, the chloride released upon NCR formation from N-chloroamonium salts may outcompete a pendant hydroxyl group for addition 38 . Here we report the use of sulfilimines, a substrate class that has previously been used in other transformations 39 , to address this synthetic challenge. The bifunctional sulfilimine 1 was obtained directly from commercially available reagents in a reaction of aminoethanol and dibenzothiophene-S-oxide activated by triflic anhydride (Fig. 2a). Irradiation of a photoredox catalyst in the presence of sulfilimine 1, acid and styrene results in phenylmorpholine formation (Fig. 2a). Light and photoredox catalyst are essential for the reactivity (Supplementary Tables 1-6). Both Brønsted acids and Lewis acids accelerate cyclization, possibly due to more efficient single electron transfer (SET) from the excited photoredox catalyst to the sulfilimine coordinated to acid ( Fig. 2b and Supplementary Table 1). According to the recorded cyclic voltammogram of sulfilimine 1 ( Supplementary Fig. 7), no reduction peak was observed within the evaluated potential, which indicates that mesolytic cleavage of the S=N bond in sulfilimine 1 by initial SET to 1 to the corresponding NCR is slow with standard photocatalysts. In contrast, Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes Qiang Cheng 1 , Zibo Bai 1 , Srija Tewari 1,2 and Tobias Ritter 1,2 ✉ Intramolecular cyclization of nitrogen-containing molecules onto pendant alkenes is an efficient strategy for the construction of N-heterocycles, which are of paramount importance in, for example, pharmaceuticals and materials. Similar intermolecular cyclization reactions, however, are scarcer for nitrogen building blocks, including N-centred radicals, and divergent and modular versions are not established. Here we report the use of sulfilimines as bifunctional N-radical precursors for cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis. Structurally diverse sulfilimines can be synthesized in a single step, and subsequently engage with alkenes to afford synthetically valuable five-, sixand seven-membered heterocycles. The broad and diverse scope is achievable by a radical-polar crossover annulation enabled by the bifunctional character of the reagents, which distinguishes itself from all other N-centred-radical-based reactions. The modular synthesis of the sulfilimines allows for larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods.
the Bi(OTf) 3 -coordinated sulfilimine 1 (A) exhibits a high reduction potential (E p = −0.4 V versus Ag/AgCl, Supplementary Fig. 7), so that fast SET with the excited iridium photocatalyst (E 1/2 (Ir III */ Ir IV ) = −1.28 V vs saturated calomel electrode) 40 can be observed, to form B (Fig. 2b). Bi(OTf) 3 was identified as optimal because Brønsted acids could result in cationic polymerization of activated olefins such as electron-rich styrenes (Supplementary Table 2) 41 . In addition, both Lewis and Brønsted acids could be responsible for rendering the amine radical electrophilic for polarity-matched addition to the electron-rich π system of the olefin [42][43][44] . A stoichiometric amount of Bi(OTf) 3 is required due to the basicity of the products. A conceptual advantage of the sulfilimines over other NCR precursors is their ability to enable easy introduction of pendant nucleophilic functional groups on NCRs, and directly afford unprotected N-H nitrogen heterocycles in a single step without the need for covalent activating groups or a deprotection step. Upon addition to the π system, the oxidized photoredox catalyst can oxidize the resulting carbon radical C for subsequent intramolecular nucleophilic attack (D) of the pendant nucleophile and regeneration of the photoredox catalyst resting state (Fig. 2b).
Various bifunctional sulfilimine reagents can be synthesized in a single step (Tables 1 and 2). Primary amines including aminoalcohols, diamines and aminopyridines react to produce iminodibenzothiophenes with pendant hydroxyl (3-6), amide (7,8) or pyridinyl groups (9,10). The diversity of the suitable sulfilimines for heterocycle synthesis was extended by reaction of the parent iminodibenzothiophene (11) with acylating reagents, which gives access to other classes of sulfilimines, such as those derived from amides, pyrimidines and triazines from acid chlorides (12)(13)(14)(15), chloropyrimidines (16) and chlorotriazines (17), respectively. All sulfilimines shown, with the exception of 6, are easily handled solids and are stable in ambient atmosphere without detectable decomposition for at least three months; while also stable, 6 was isolated as an oil.
Cyclization of a variety of sulfilimines with a variety of electron-rich olefins gives access to a large family of diverse, synthetically valuable heterocycles in a single step (Table 3 and Fig. 3). The products can be isolated without protecting groups on nitrogen, but in situ protection of nitrogen with a tert-butyloxycarbonyl (Boc) group is facile, if desired, as shown for 18. Styrene derivatives that are prone to cationic polymerization under acidic conditions 45 such as 19 and 22 can selectively react with the bifunctional sulfilimine 1 to produce morpholines in 78% and 55% yield, respectively. Olefins with heteroaryl substituents, such as indoles (24), pyridines (25) and benzothiophenes (28), are well tolerated. The putative bismuth(III)-coordinated amine radicals undergo addition reactions chemoselectively to alkenes in the presence of electron-rich arenes (19), allylic hydrogens (23, 27, 30-33, 35) and even ether (DME) as solvent. Such functional groups are often reactive with other NCRs either via radical addition 46,47 or via hydrogen-atom transfer processes [48][49][50] . In addition to α-styrenes, 1,1-disubstituted alkenes (37) can also undergo cyclization with sulfilimine 1 to produce morpholine heterocycles with a quaternary centre, although for most other investigated alkyl-substituted alkenes that feature allylic hydrogen atoms, allylic amination was observed 44 . For 1,2-disubstituted alkenes that bear a group that can stabilize a positive charge, high diastereoselectivity is observed for cyclization (26,27), providing 2,3-disubsituted morpholines. Both trans-and cis-propenylbenzenes produce the same product with the same diastereoselectivity, which supports the proposed intermediacy of NCRs. High regioselectivity is also obtained in reactions with dienes, such as 34 and 35, as cyclization reaction only occurs at the terminal alkene of the diene, producing alkenyl-substituted morpholines. When alkyl-substituted dienes are used, the thermodynamically more stable trans-olefin is obtained as major product (35). In the case of styrene-derived dienes (34), a known photocatalysed isomerization 51 occurs to produce cis-and trans-styrenylmorpholines. Cyclic alkenes afford bicyclic and tricyclic morpholines. Highly diastereoselective formation of morpholine derivatives with fused rings is achieved when endocyclic olefins such as norbornene (29), 1-phenyl-1-cyclohexene (30) and indenes (31, 32) are used. Exocyclic olefins such as 7-methyl-4-methylenechromane (33) and camphene (37) are also suitable reaction partners, producing spirocyclic morpholines. These polycyclic heterocycles can be constructed selectively in a single step from the corresponding alkenes, and are not readily accessible via other synthetic methods. Olefins that would afford cations upon radical addition and oxidation that are not sufficiently stabilized, such as in α olefins and 1,2-disubstituted alkenes without stabilizing groups, such as an aryl or vinyl substituent, cannot participate in the reaction   ( Supplementary Fig. 1), whereas styrene-like, 1,1-disubstituted and diene-based olefins participate successfully. The method can be used for late-stage diversification (38,39). To further demonstrate the synthetic value of the method, we accomplished a concise synthesis of H1 receptor antagonist 41 (Fig. 3). The modular approach allows us to construct the key morpholine structure directly from alkene 40, which substantially increased the total yield and reduced the step count compared to the previously published procedure 52 . The reaction requires the use of a stoichiometric amount of dibenzothiophene heterocycle, which, however, can be recycled after successful cyclization; for example, 92% of dibenzothiophene was reisolated after formation of 2.
The modular approach and the accessibility of various bifunctional sulfilimines enables the synthesis of other types of N-heterocycles under the same reaction conditions by simply changing the substituents on the sulfilimines (Fig. 3). Disubstituted morpholines are obtained when sulfilimines such as 3 or 4 react with alkenes. Although low diastereoselectivity (2:1) was observed when the stereocentre is α to the hydroxy substituent, high diastereoselectivity (>20:1) is obtained when the stereocentre is α to the nitrogen substituent. Other sulfilimine reagents (5-8) enable the construction of oxazepanes (44,45) and piperazines (46,47) in synthetically useful yields. We subsequently explored the generality of our modular approach to N-heterocycles with sulfilimines derived from amines other than alkyl amines. Acyl-amine-derived sulfilimines (12)(13)(14) can also function as bifunctional reagents, which undergo cyclization with alkenes under the same reaction conditions to produce dihydrooxazoles (50-52) 53,54 . An intriguing reactivity was discovered when using sulfilimine 15 as substrate, providing tetrahydrobenzofuran 53 exclusively in 89% yield instead of an N-heterocycle. A plausible rationale is that the generated enamine NCR reacts to the more stable carbon-centred radical, which is then involved in annulation with 1,1-diphenylethylene ( Supplementary  Fig. 13). The photocatalytic annulation strategy can also be applied to heteroaryl-amine-derived sulfilimines (9, 10, 16, 17), generating electrophilic arylamine radicals that are reactive for cyclization with alkenes to form dihydroimidazole derivatives (48, 49, 54, 55    same photocatalytic method, which is difficult to achieve with other NCR precursors 55,56 . The scope of heterocycles presented herein exceeds that of other reported single methods 12 . Preliminary mechanistic experiments are in agreement with the proposed strategy shown in Fig. 2b (Supplementary Figs. 2-12).
A 1:1 mixture of sulfilimine 1 and Bi(OTf) 3 results in a new peak potential that is absent in both 1 and Bi(OTf) 3 alone, which we assign to the 1-Bi(OTf) 3 adduct A as observed in the cyclic voltammogram (Fig. 4a). The high reduction potential (E p = −0.4 V versus Ag/AgCl) may be responsible for a fast SET from the excited iridium     photocatalyst, while reduction of 1 by itself was not observed. The existence of adduct A is further substantiated by ultraviolet-visible spectroscopy through a new absorption maximum at 326 nm (Fig. 4b). Radical clock experiments with 2-vinylcyclopropylbenzene and a 1,6-diene under optimized reaction conditions with sulfilimine 1 produce ring-opened product 56 and cyclization product 57, respectively, in agreement with NCRs (Fig. 4c).

Conclusion
Photocatalysed modular synthesis has enabled the construction of various N-heterocycles with different ring types, ring sizes and substituents on the skeleton in a single step by reaction of easily available bifunctional sulfilimines and alkenes. The scope of heterocycles provided here is broader than that of other reported single methods for N-heterocycle synthesis from olefins.

Online content
Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41557-022-00997-y.