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Published in final edited form as: Tetrahedron Lett. 2025 May 29;167:155684. doi: 10.1016/j.tetlet.2025.155684

Regioretention Probes Distinguish Ring Scission Mechanisms in Nitrogen Insertion Reactions

Yahia Ali 1, Liao Chen 1, Mark D Levin 1
PMCID: PMC12165437  NIHMSID: NIHMS2087706  PMID: 40520076

Abstract

Atom insertion reactions into ring systems may occur via one of two pathways, proceeding either through initial cyclization to form a 3-membered ring intermediate followed by cleavage of the ring-fusion bond, or through initial ring-scission followed by recyclization onto the inserting atom. Herein, we demonstrate the use of regioretention probes, substrates with latent symmetry that is unveiled only in the case of ring scission and are thus able to distinguish between possible mechanisms for atom insertion. We apply these probes to a handful of previously reported nitrogen insertion methods and in each case unambiguously establish whether the reaction proceeds through aziridination or C=C cleavage. In particular, we show that recently reported cobalt- or manganese-catalyzed nitrogen insertion protocols, postulated to proceed via an aziridinyl radical intermediate, instead proceed through a ring-opened ketone-containing intermediate.

Graphical Abstract

graphic file with name nihms-2087706-f0001.jpg

Introduction

The insertion of nitrogen atoms into cyclic alkenes has garnered interest in recent years, and there are now a handful of methods to insert nitrogen atoms into a variety of cyclic alkenes and heteroarenes such as indoles, pyrroles, indenes, cyclopentenes, and cyclobutenes to form quinazolines, pyrimidines, isoquinolines, pyridines and pyrroles, respectively 1–6. Mechanistically these reactions are all proposed to proceed through the intermediacy of either an aziridinyl cation7–9 or an aziridinyl radical10 intermediate (or surrogate thereof), followed by cleavage of the aziridine C–C bond to yield the net nitrogen insertion product (Figure 1a). Another mode by which this transformation can be achieved, termed “amozonolysis” by Fields in 1964, instead proceeds via oxidative cleavage of the double bond followed by recyclization with an ammonia source to deliver the net nitrogen insertion product.11–15

Figure 1.

Figure 1.

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(a) different pathways for achieving nitrogen insertion, (b) evaluated protocols for nitrogen insertion (c) this work, substrates with built-in, latent symmetry act as mechanistic probes.

Herein, we provide a mechanistic probe (Figure 1c) to distinguish between these two modes for nitrogen insertion and apply it to three recently reported nitrogen insertion protocols: Morandi’s ammonium carbamate-hypervalent iodine protocol, as well as Wei and Zhu’s recently reported Co- and Mn-catalyzed azide/O2-based methods (Figure 1b). Our experiments reveal that these latter two reactions, postulated to proceed via an aziridinyl radical intermediate, are in fact mechanistically analogous to amozonolysis and must proceed via a ring opened intermediate. In addition to pure, scientific motivations to understand these mechanisms, this mechanistic analysis provides insight that may be practically useful for identifying failure modes, scope limitations, and approaches for optimization, all of which can guide method selection.

Main text

The design of the regioretention probes was inspired by a mechanistic analysis of Wei’s 2022 report of a cobalt-catalyzed protocol for nitrogen insertion into cyclic olefins.1 The authors propose that the transformation proceeds by an initial attack of an azide radical onto an alkene to furnish a β-azido radical I, which then cyclizes onto the adjacent N3 moiety to generate, after loss of N2, aziridinyl radical intermediate II. This species proceeds to the nitrogen insertion product through cleavage of the aziridine C-C bond followed by aerobic oxidation. β-azido radicals are commonly invoked intermediates; it therefore struck us that nitrogen insertion reactivity had not been previously observed in such reactions.16–22 However, under the aerobic reaction conditions necessary for the generation of the azide radical, one might expect that the initially formed β-azido radical could instead be trapped by O2 and following HAT form a peroxy-azide intermediate III (Figure 2a). Indeed, the Jiao group proposed exactly such a species formed putatively by addition of an azide radical to an alkene under aerobic conditions in a method for the preparation of β-azido alcohols 23 O2 trapping of β-azido radicals was also invoked by the Jiao group in their earlier report of oxidative cleavage of cyclic alkenes into oxo-nitriles.24 It is worth noting that both β-azido alcohols and oxo-nitriles were observed as side products in Wei’s report.

Figure 2.

Figure 2.

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(a) potential pathways for Wei’s nitrogen insertion, (b) latent symmetry probe allows distinguishing the operative pathway for N-Insertion.

Although the Jiao reactions were catalyzed by manganese rather than cobalt, a recent report by Zhu2 shows that MnCl2 is an effective catalyst for nitrogen insertion using TMSN3 under similar conditions as to those employed by Wei. Further, control experiments by Zhu show that a β-peroxyazide is a competent intermediate in the nitrogen insertion reaction. We thus hypothesized that the nitrogen insertion might be proceeding from the peroxy-azide intermediate through a ring-opening/recyclization sequence rather than through the intermediacy of an aziridinyl radical.

We envisioned that an appropriately designed substrate, 1 (Figure 2b), would be capable of distinguishing between these two mechanistic frameworks by acting as a regioretention probe. Ring opening would lead to a pseudo-symmetric diketone intermediate VII that would be expected to form two regioisomeric products 3 and 3’ through unselective cyclization, whereas aziridinyl radical VI, would not unveil the latent symmetry and thus would lead to the formation of a single nitrogen-insertion product 3.

In the event, subjecting substrate 1 to either Wei’s cobalt catalyzed nitrogen insertion protocol or Zhu’s manganese catalyzed protocol led to the formation of the two regioisomeric pyridine products 3 and 3’ in almost equal amounts (Figure 3). Resubjecting isolated samples of these pyridines to the reaction conditions confirmed that they do not interconvert and thus that they must be formed competitively during the reaction. Though the yields were moderate, the remainder of the mass balance in these reactions was predominantly unreacted 1. Tetrasubstituted alkenes of this kind are not optimal substrates for these reactions; none feature in the scope of Wei’s report, and a lone example (Me/Phenyl) was reported as successful in Zhu’s. Subjecting substrate 1 to a sequence of ozonolysis/NH3 recondensation leads to a similar outcome, in line with expectations based on a ring-opening first pathway.

Figure 3.

Figure 3.

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Nitrogen insertion into cyclopentenyl regioprobe 1

Experiments conducted on indenyl substrate 2a (Figure 4a) led to a similar outcome, with two isomeric isoquinoline products (which, again, do not interconvert when isolated and resubjected) observed under both the Wei and Zhu conditions, albeit in an unexpected ~2:1 ratio favoring 4 over 4’. Initially, our hypothesis for this unexpected selectivity was that perhaps there were two operative mechanisms for the nitrogen insertion reaction of indenes, one that proceeds via regioretention and leads to exclusive formation of 4, and another, regioscrambling mechanism that proceeds via ring-opening and unselectively forms a mixture of 4 and 4’. This hypothesis was ruled out by the observation that the nitrogen insertion on the flipped substrate 2b proceeds with similar selectivity favoring 4 over 4’.

Figure 4.

Figure 4.

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(a) Nitrogen insertion into indenyl regioprobes 2a/2b, (b) Mechanistic conclusions drawn from this work

Because indenes have a broader range of reported methods for nitrogen insertion, we examined additional approaches. Under the Morandi group’s ammonium-carbamate/hypervalent iodine protocol, we observed the exclusive formation of 4 from 2a, consistent with a reaction that proceeds without ring opening. Again here, the low yields are reflective of the fact that this tetrasubstituted alkene substrate is suboptimal for all three methods. However, the mass balance is once again largely unreacted starting material. We note, along these lines, that the Sharma group’s recent sulfenyl-nitrene-promoted method does not afford any observable isoquinoline products under these conditions.4,25 Finally, under the amozonolysis sequence, we observed formation of 4 and 4’ in a 1.1: 1 ratio.

The difference in selectivity between the Wei/Zhu protocol and that of the amozonolysis procedure is surprising. We tentatively attribute this divergence to the different nature of the nitrogen species involved in cyclization. Specifically, under the Wei/Zhu protocol, cyclization may be occurring directly from an iminyl radical,26 whereas under the amozonolysis sequence, cyclization is likely occurring through the NH imine. These cyclization modes may have differing electronic sensitivities which lead to the observed difference in selectivity.27 The difference in selectivity observed in the insertions of 1 and 2 may originate from the influence of benzofusion in 2, which would influence the reactivity of the ketone intermediates involved, add rigidity to the ring-opened intermediates, and obviate the need for aerobic oxidation to form the final products, all of which could affect the observed selectivity either directly or indirectly. Nonetheless, the collective results presented here conclusively demonstrate that the Wei and Zhu methods cannot proceed through the intermediacy of aziridinyl radicals and must involve ketone-containing ring-opened intermediates (Figure 4b).

Conclusions

This work demonstrates the use of mechanistic probes that can unambiguously detect ring scission during nitrogen insertion into cyclic alkenes. When applied to the recently reported aerobic nitrogen-insertion protocols reported by Wei and Zhu, these probes rule out the formation of an aziridinyl radical intermediate and rule in the involvement of a ring-opened intermediate. Regioretention probes28–34 of this kind may find use more generally for atom insertion reactions that are suspected of proceeding through ring scission.

Supplementary Material

1

Highlights.

  • Nitrogen insertion can proceed via oxidative cleavage or aziridination pathways

  • Substrates with latent symmetry can differentiate between the two pathways

  • Transition-metal-catalyzed, aerobic insertions proceed via ring opening

Footnotes

Declaration of interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Mark D. Levin reports financial support was provided by NIH National Institute of General Medical Sciences (R35 GM142768). Liao Chen reports financial support was provided by The University of Chicago Quad Scholars Grant. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Supplementary Materials

1
NIHMS2087706-supplement-1.pdf (5MB, pdf)

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