New Journey to Synthesis of Multiple N-Heterocycles

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Partially and fully saturated N-heterocycles are ubiquitous moieties in functional molecules of pharmaceuticals and materials. It’s a long pursuing journey for concise synthesis of multiple N-heterocycles from simple and easily accessible reagents in synthetic chemistry. Excellent examples include the vinyl sulfonium reagents1 and SnAP reagents2, yet reagents for single-step cyclization with widely accessible alkenes has not been established. In our report, we use sulfilimines as bifunctional N-radical precursors for various cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis (Figure 1). The sulfilimine reagents can be synthesized in a single step from amines with modular manner. Structural diverse morpholines, piperazines, dihydrooxazoles, dihydroimidazoles, and oxazepanes are all achievable by a radical polar crossover annulation enabled by the bifunctional character of the reagents.

Figure 1. Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes

The initial results were derived from our previous publication of iminothianthrene enabled allylic amination reactions3. The proposed mechanism in the previous work has shown that nitrogen-centered radicals (NCR) generated from iminothianthrenes under acidic conditions favor the addition to alkenes, and a possible aminothianthrenation intermediate was proposed before formation of allylic amines. Considering thianthrene as a good leaving group in alkyl thianthrenium salts, we hypothesize that a pendant nucleophilic group on NCRs could potentially lead to subsequent ring closing process to form N-heterocycles. Thus, a new bifunctional sulfilimine 1 was designed to address the synthetic purpose, which was obtained directly from commercially available reagents in a reaction of aminoethanol and dibenzothiophene-S-oxide activated by triflic anhydride (Figure 2a). Irradiation of a photoredox catalyst in the presence of sulfilimine 1, HBF4, and styrene results in phenylmorpholine formation. Everything works perfect until the exploration of substrate scope. For example, no product was obtained when using 4-methoxystyrene instead of styrene. With further experiments, we found that the major problem here is that strong Brønsted acids such as HBF4 could result in cationic polymerization of electron rich styrenes4. Luckily, by investigation of different Lewis acids, Bi(OTf)3 was discovered as optimal one that fits a broad substrate scope (Figure 2a). The reaction mechanism was also proposed as shown in Figure 2b. Notably, various polycyclic heterocycles can be constructed selectively in a single step from the corresponding alkenes, which are not readily accessible via other synthetic methods (Figure 3). We also accomplished a concise synthesis of H1 receptor antagonist 4. The modular approach allows us to construct the key morpholine structure directly from alkene 3, which substantially increased the total yield and reduced the synthetic steps compared to the reported procedure5 (Figure 3). The full scope can be found in the published paper.

Figure 2. Synthesis of sulfilimine 1, reaction optimization, and proposed mechanism of the cyclization reaction.

Figure 3. Scope of alkenes for synthesis of morpholine derivatives.

More intriguingly, the developed method is not limited to the synthesis of morpholines. It is also one of the conceptual advantages of our sulfilimine reagents that they are prone to enable easy introduction of pendant nucleophilic functional groups on NCRs. Thus, other types of N-heterocycles, such as piperazines, dihydrooxazoles, dihydroimidazoles, and oxazepanes, can be constructed under the same reaction conditions by simply changing the substituents on the sulfilimines (Figure 4a). An intriguing reactivity was discovered when applying sulfilimine 5 as substrate, providing tetrahydrobenzofuran 6 exclusively instead of an N-heterocycle. A plausible rationale is that the generated enamine NCR E reacts to the more stable carbon-centered radical F, which is then involved in annulation with 1,1-diphenylethylene (Figure 4b). Such reactivity may provide new opportunities for synthesis of other ring systems.

Figure 4. Scope of bifunctional sulfilimines.

We believe the features making this work attractive include novel bifunctional sulfilimine reagents that can be synthesized modularly, new pathway for construction of N-heterocycles from alkenes, and larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods. We hope this work will inspire discovery of more interesting cyclization methods and NCR related reactions.

For more details, see our paper: " Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes". Link:


  1. Yar, M., McGarrigle, E. M. & Aggarwal, V. K. An Annulation Reaction for the Synthesis of Morpholines, Thiomorpholines, and Piperazines from β-Heteroatom Amino Compounds and Vinyl Sulfonium Salts. Chem. Int. Ed. 47, 3784–3786 (2008).
  2. Vo, C.-V. T., Mikutis, G. & Bode, J. W. SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines—An Alternative to Cross-Coupling with Saturated Heterocycles. Chem. Int. Ed. 52, 1705–1708 (2013).
  3. Cheng, Q., Chen, J., Lin, S. & Ritter, T. Allylic Amination of Alkenes with Iminothianthrenes to Afford Alkyl Allylamines. Am. Chem. Soc. 142, 17287−17293 (2020).
  4. Throssell, J. J., Sood, S. P., Szwarc, M. & Stannett, V. The Instantaneous Polymerization of Styrene by Trifluoroacetic Acid. Am. Chem. Soc. 78, 1122–1125 (1956).
  5. Botta, M., Castiglioni, E., Di Fabio, R., Spinosa, R. & Togninelli, A. Spiro compounds useful as antagonists of the H1 receptor and their asymmetric preparation, pharmaceutical compositions and use in the treatment of sleep disorders. WO patent 2009016085 (2009).

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