Iodonitrene-Mediated Nitrogen Transfer to Alkenes for the Direct Synthesis of NH-Aziridines

Abstract

This work presents a novel and efficient method for the direct synthesis of NH-aziridines from a broad range of alkenes under mild conditions. The developed method uses aqueous ammonia and (diacetoxyiodo)­benzene (PIDA) at 0 °C, offering a straightforward and atom-economical approach. Notably, this approach addresses the common challenge of chemoselectivity, effectively preventing the overoxidation of aziridines to nitriles. Mechanistic studies support the involvement of an in situ-generated iodonitrene as the key nitrogen-transfer intermediate. Overall, this method represents a significant advancement in aziridine synthesis, combining simplicity and selectivity, and complements the existing procedures for the direct NH insertion into alkenes.

Introduction

Aziridines, highly strained analogs of epoxides, are highly versatile compounds for organic synthesis. First, their intrinsic strain renders them prone to various regio- and stereoselective transformations, such as ring openings, expansions, and rearrangements, offering a convenient way to rapidly build structural complexity and molecular diversity. − Second, the aziridine motif can impart positive physiochemical properties on lead compounds, as demonstrated by its frequent appearance in biologically active natural products (e.g., azinomycin and mitomycins), or significant enhancement of potency in the case of thailanstain A after replacement of the oxirane moiety with an aziridine (Scheme ). In drug development, particularly, NH-aziridines (i.e., unprotected aziridines) are of importance; hence, their synthesis is highly sought after.

1. (a) Examples of Biologically Active Compounds Featuring an Aziridine Ring; (b) General Approaches for the Preparation of NH-Aziridines from Alkenes; and (c) Overview of the Main Strategies for N–H Aziridination of Olefins.

Analogous to the well-established peracid-mediated Prilezhaev reaction for the epoxidation of alkenes, the synthesis of aziridines also most often relies on nitrogen transfer to olefins. Specifically, traditional alkene aziridination methods rely on high-energy electrophilic nitrogen reagents (e.g., iminoiodinanes) or nitrene precursors (e.g., organoazides), which act as both the stoichiometric oxidant and nitrogen source. − These reagents usually carry electron-withdrawing N-substituents to balance reactivity and stability and often require metal catalysis using copper, rhodium, or silver. − Most recently, contributions by Parasram and Koenigs leverage photocatalysis for the aziridination of alkenes mediated by a singlet nitrene or a nitrene radical anion as the N-transfer species. , All of these methods result in N-substituted aziridines; however, these compounds must undergo a further N-deprotection step to release the corresponding NH-aziridine. The desire for direct NH-aziridination of alkenes, alleviating the requirement for an additional deprotection step, is thus imperative.

Addressing this need, Kürti, Ess, Falck, and Powers have independently introduced electrophilic reagents capable of directly converting alkenes into N–H aziridines with high stereo- and enantiocontrol, showcasing the potential of developing more practical and general aziridination methods (Scheme ). Given their broad tolerance for densely functionalized and complex substrates, their efficiency, and practicality, these protocols are currently considered state-of-the-art. ,− Despite their wide range of advantages, these methodologies have some limitations in scope for the direct aziridination of unsubstituted styryl derivatives and electron-deficient alkenes.

A practical and general approach to directly prepare NH-aziridines from such electronically challenging olefins as a complementary approach to the aforementioned protocols, ideally from a simple, commercially available nitrogen source, is thus desirable and remains a significant challenge for synthetic chemists, as recently highlighted by Schomaker and co-workers.

Leveraging our expertise in the construction of strained aza-heterocycles, as well as in electrophilic transfer of nitrogen (as NH group) to heteroatoms, we wondered if the aforementioned challenges could be addressed using iodonitrene IN as the active nitrogen-transfer reagent (Scheme ). − Iodonitrene IN, first introduced by Luisi and Bull in 2016, , has recently gained significant traction in electrophilic nitrogen-transfer methodologies , and skeletal editing tactics. , In fact, it has been demonstrated that iodonitrene IN can participate in electrophilic addition across unsaturated carbon–carbon bonds via direct nitrogen insertion into substrates, such as indenes, indoles, and pyrroles, leading to the corresponding nitrogen-containing heterocycles, namely, isoquinolines, quinoxalines, and pyrimidines, respectively. − Most recently, Morandi and co-workers reported that the reaction of iodonitrene IN with alkenes leads to the conversion of alkenes into nitrile (Scheme ). The proposed mechanism for this reaction involves an aziridine iodonium intermediate IA that collapses into an azaallenium species IB as the precursor of the final nitrile. We thus wondered if the proposed aziridine iodonium intermediate could be converted into the corresponding aziridine and an I^III species in the presence of a suitable proton donor and a nucleophile, prior to its fate of collapsing into an azaallenium species IB. We hypothesized that the most significant challenge here is to precisely and efficiently control the proton transfer to the aziridine nitrogen and the nucleophilic addition to iodine. Our results on the successful implementation of this strategy are reported herein.

2. (a) Preparation of Nitriles or Amidines via Direct Nitrogen Atom Insertion into Carbon–Carbon Double Bonds Mediated by an Iodonitrene Intermediate and (b) This Work Unlocks the Use of Iodonitrene as an Active Nitrogen-Transfer Reagent for the Direct Synthesis of NH-Aziridines.

Results and Discussion

At the outset, we tested the proof of concept and selected styrene, a mildly nucleophilic and electronically neutral olefin, as a model compound for electrophilic nitrogen transfer. Upon optimization of the solvent, nitrogen source, hypervalent iodine precursor, and stoichiometry (see the Supporting Information), we found that treatment of 1a with PIDA (2 equiv) and aqueous ammonia (30 equiv) in aqueous trifluoroethanol (TFA) at room temperature afforded aziridine 2a in 70% yield within 40 min, although the formation of nitrile 3a could not be completely suppressed (Table , entry 1, conditions A). Notably, alternative, common nitrogen sources, such as ammonium acetate, ammonium carbonate, or ammonium carbamate, or PIFA as an alternative oxidant, proved ineffective for this transformation. The use of ammonia as a readily available and atom-economical nitrogen source under transition-metal-free conditions represents a significant advance in terms of practical metrics compared to previous routes, although care should be taken when handling concentrated (15 M) ammonia. Reduction of the equivalents of aqueous ammonia and increase of equivalents of PIDA (Table , entries 2 and 3) had detrimental effects on the yield and product ratio. In contrast, an increase in the equivalents of aqueous ammonia (Table , entries 5 and 6) had a favorable effect on the product ratio, almost completely suppressing the formation of nitrile 3a, yet with a significant reduction in yield. The reaction was tolerant to the replacement of trifluoroethanol with hexafluoroisopropanol (HFIP) or MeOH (Table , entries 7 and 8), although with a detrimental effect on the observed yield. Given the fate of aziridine iodonium intermediates IA, collapsing into azaallenium species IB, we hypothesized that for more electron-deficient alkenes, which might be less prone to convert into IB as they inefficiently stabilize the undesired azaallenium species, milder reaction conditions could be suitable to release the desired aziridines. In fact, electron-deficient para-trifluoromethylstyrene 1b underwent the desired aziridination to 2b using 3 equiv of PIDA and only 20 equiv of aqueous ammonia (Table , entry 13, conditions B). Conversely, the use of electron-rich para-methoxy styrene 1c failed to provide the corresponding aziridine 2c under different reaction conditions (Table , entries 9 and 10), and the main product was nitrile 3c.

1. Optimization of Reaction Conditions.

entry	R	oxidant (equiv)	NH3(aq) (equiv)	solvent	yield of 2	2/3 ratio
1	H	PIDA (2)	30	TFE	70%	88/12
2	H	PIDA (3)	20	TFE	55%	75/25
3	H	PIDA (3)	8	TFE	33%	39/61
4	H	PIDA (2)	15	TFE	30%	50/50
5	H	PIDA (2)	60	TFE	23%	99/1
6	H	PIDA (1)	60	TFE	47%	99/1
7	H	PIDA (2)	30	MeOH	10%	90/10
8	H	PIDA (1)	30	HFIP	34%	83/7
9	OMe	PIDA (2)	30	TFE	5%	5/95
10	OMe	PIDA (3)	20	TFE	0%	0/100
11	CF3	PIDA (2)	30	TFE	43%	99/1
12	CF3	PIDA (3)	20	TFE	86%	99/1
13	CF3	PIDA (3)	8	TFE	70%	99/1

^aTFE/H₂O ratio 1:1.7.

^b40% nitrile.

^c16% nitrile.

The optimization study revealed that different protocols were needed, depending on the electronic properties of the alkene. With this in mind, we evaluated the scope of alkenes that could be employed to grant access to various NH-aziridines (Scheme ). Using conditions A, a series of electronically neutral and mildly electronically rich styrenes gave the corresponding aziridines in moderate to excellent yields. For example, styrene derivatives bearing a slightly activating Me-group on the ortho and para positions of the aromatic ring furnished the corresponding aziridines 2d,e in 68 and 47% yields, respectively. When the Me group was placed on the α-position of the styrene, very good yields of the corresponding α,α-disubstituted NH-aziridines 2f,g were obtained. When the Me group was positioned on the β-carbon of styrene, the reaction proceeded efficiently, yielding aziridine 2h in 45% yield. However, the presence of an additional electron-donating methoxy group on the aromatic ring expectedly reduced the yield, with aziridine 2i obtained in a modest 25% yield, due to the facile decomposition of aziridine iodonium intermediates IA into azaallenium species IB, and further into the corresponding nitrile. Remarkably, both aziridines 2h and 2i retained the stereochemistry of the starting alkenes and were obtained with high trans-selectivity.

3. Scope of the Direct Aqueous Aziridination of Alkenes.

^a Reaction was performed using 24 equiv of ammonia instead of 30.

^b A reaction time of 1 h was used instead of 40 min.

^c A reaction time of 16 h was used instead of 40 min.

Next, alkenes bearing mildly electron-withdrawing groups were tested under conditions B. As expected, the reaction proceeded with high efficiency and selectivity to provide aziridines 2b and 2k–o, with yields in the range 40–86%. Interestingly, when a p-formyl-substituted styrene was employed as the starting alkene, aziridine 2p was obtained as the sole product in 48% yield. It is likely that under the reaction conditions, the formyl group undergoes the formation of an imine that is further oxidized to the corresponding nitrile in the presence of PIDA. Furthermore, α,α-disubstituted aziridines 2q,r were obtained in yields of up to 55%. Similarly, the presence of functional groups, such as a heterocycle or a sulfone group, on the α,α-disubstituted alkenes did not affect the reaction, and aziridines 2s,t could be obtained in yields of up to 80%. To our delight, aliphatic alkenes also proved to be competent substrates, furnishing aziridines 2u,v in yields of up to 51%. Next, we sought to extend the methodology to challenging substrates such as strongly electron-deficient substrates using mild conditions C. Pleasingly, NH-aziridines 2w–z were obtained in yields of up to 70%. Any attempt to use conditions B in the case of alkene 1w resulted in a lower yield of the corresponding aziridine (2w, 28%). Cognizant of the importance and need for developing simple and as general as possible methods for the direct aziridination of alkenes, we focused our attention on more challenging electron-poor alkenes, such as acrylates and acrylamides, which represent a platform for introducing/accessing N-unsubstituted aziridine-bearing amino acids and modified peptides. To our delight, the use of acrylamides 1ab-ae resulted in the formation of the corresponding NH-aziridines 2ab–ae in 41–47% yields. Remarkably, in the case of 2ab, a complete selectivity toward the inactivated double bond was observed. Gratifyingly, the use of acrylamides 1af–ai produced the corresponding aziridines 2af–ai with yields in the range of 27–45%, representing the first examples of aziridination of such inactivated double bonds. Notably, aziridine 2ai includes the functional core of the antihistaminic drug bepotastine. Last, we investigated the reactivity of more challenging aliphatic alkenes. For example, subjecting cyclohexene to conditions C furnished aziridine 2al in 45% yield. Also, cinnamyl chloride reacted to afford aziridine 2am in 41% yield. Nonetheless, we were faced with some substrate limitations during the investigation of our scope. For example, aziridination for the conjugated alkenes stilbene and some aliphatic internal alkenes (e.g., geraniol or trans-oct-4-ene) was unsuccessful under our conditions. Nevertheless, effective alternative protocols for the aziridination of these substrates have been previously reported, showcasing the complementarity of the developed procedures. ,,

With a series of NH-aziridines in hand, we sought to perform various synthetic manipulations on the key amine functionalities to test their robustness (Scheme ). Sulfonylation of aziridines 2f, 2h, and 2n under basic conditions provided N-protected aziridines 2an– 2ap in yields of up to 93% from the sulfonyl chloride. Furthermore, Boc protection afforded azirdine 2aq in a 95% yield from 2k. Next, we engaged aziridine 2f in a Buchwald–Hartwig coupling to install the pharmaceutically relevant Celecoxib core in an 89% yield. Notably, no decomposition of the starting aziridines was observed in any case.

4. Derivatization of Aziridine Products .

^a See the Supplementary Information for experimental details.

After assessing the scope of this direct NH-aziridination method and its synthetic potential, we sought to investigate more deeply the mechanism of this process in order to justify the observed chemical reactivity and the tolerance to different conditions depending on the electronic properties of the alkene. Several experimental probes were thus considered to rationalize the outcome and mechanism of the transformation (Scheme ) (see the Supporting Information for full details). Based on our design plan and other developed protocols, ,, we proposed the intermediacy of iodonitrene IN as the active nitrogen-transfer agent. According to the proposed mechanism reported in Scheme , ligand exchange between PIDA and ammonia would provide iminoiodinane 4, which, upon reaction with an additional molecule of PIDA, would form 5. The short-lived IN might derive from 5 after the loss of PhI and an acetate ion. A plausible subsequent step would be the reaction of the electrophilic iodonitrene IN into the alkene forming N-iodonium aziridine IA, which, upon reaction with a proton donor and a nucleophile, would release the NH-aziridine and an I­(III) species capable of intercepting ammonia or reacting with 4.

5. Proposed Mechanism for the Direct Metal-Free Aziridination of Olefins.

This hypothesized mechanism appears complex in terms of chemical species involved, each of which must be individually considered to explain the different protocols (i.e., conditions A, B, C) adopted with alkenes of differing reactivity. Given that the protocols differ mainly in the concentration of ammonia, we speculated that there are two different reasons for this. One plausible explanation is that a larger concentration of ammonia increases the probability of successful collapse of potentially unstable intermediate IA by substitution with ammonia to the desired aziridine, prior to rearrangement to IB. Relatively unstable IA intermediates derived from more electron-rich alkenes thus demand a higher concentration to facilitate this interception.

Another potential explanation is that the success of the reaction hinges on the rate of iminoiodinane 4 formation, which would be directly dependent on the concentration of ammonia. Hence, we tested the effect of varying the concentration of ammonia on the outcome of the reactions and chose pH as a measure of this variable (Scheme , A). Using styrene 1a as a model substrate, we found that at pH < 10, and hence lower concentrations of ammonia (15:85 NH₃:NH₄ ⁺ based on the Henderson–Hasselbach equation), the formation of nitrile 3a is favored with respect to the desired aziridine 2a. At higher pH values, and hence higher concentrations of ammonia, this trend is reversed, with the optimal yield (70%) obtained for the desired aziridine 2a at pH = 10.5. Above this value, the formation of aziridine 2a is still favored over the nitrile, although at the cost of unsatisfactory conversion (20%). We rationalized that at optimal concentrations of ammonia, sufficient iminoiodinane 4 is formed to allow complete consumption of PIDA by subsequent conversion to the active iodonitrene IN. Thus, the overoxidation to nitrile 3a is suppressed. In addition, at high concentrations of ammonia, the formation of 4 is favored, reducing the quantity of available PIDA to drive oxidation to the active nitrogen-transfer agent iodonitrene IN, leading to cessation of alkene conversion. In striking contrast, lower concentrations of ammonia, that is, slower formation of iminoiodinane 4, result in incomplete consumption of PIDA that can react with aziridine 2a, which, upon formation, leads to IA and eventually to 3a.

6. Mechanistic Investigation .

^a (a) pH effect on reactivity and selectivity; (b) reactivity rationale based on Mayr’s scale; and (c) NMR investigation of N-iodonium aziridine stability.

Next, based on the proposed mechanism, we hypothesized that the reactivity of the alkene influences the nitrogen-transfer process, necessitating different protocols. Given that iodonitrene 4 is highly electrophilic, it should preferentially react with highly nucleophilic alkenes under conditions A (i.e., higher concentration of IN). To test this hypothesis, we correlated the nucleophilicity of various alkenes, as defined by Mayr’s nucleophilicity scale, with their conversion rates (Scheme , b). This analysis revealed that more nucleophilic alkenes generally exhibited higher conversion rates under conditions A. Furthermore, Mayr’s scale helped explain the differing reactivity observed between trans- and cis-β-methylstyrenes (1h). Although this analysis provided a satisfactory rationale for the trend observed with electronically rich and electronically neutral alkenes (e.g., various styrenes), the results obtained for electronically deficient alkenes (e.g., acrylic esters and acrylamides) do not align with this correlation. In line with recent literature reports, we therefore considered that an alternative mechanism might be operative for these substrates (Scheme d): a stepwise mechanism consisting of Michael addition of intermediate 4, followed by intramolecular substitution to afford the free NH-aziridines with concomitant generation of iodobenzene as a byproduct. This alternative pathway is particularly plausible for electron-deficient alkenes, demanding protocol C, which operates at very low concentrations of ammonia.

Last, our proposed mechanism considers that in the case of successful nitrene insertion into alkenes, N-iodonium aziridine IA would be formed. To seek proof for this intermediate, we sought to test its likely fate upon generation. During our scope investigation, we regularly observed byproducts (e.g., nitriles), which we hypothesized could stem from IA under our reaction conditions. Specifically, the formation of this intermediate could either trigger collapse into an azaallenium species IB as the precursor of the observed nitrile byproducts or undergo protonation to release the desired aziridines. To test this, we generated N-iodonium aziridine intermediate IA by treatment of three electronically different aziridines (2a, 2b, and 2ae) with PIDA, and their fate was monitored over time by NMR. The N-iodonium aziridine intermediate generated from aziridine 2a expectedly and, in line with the optimization and pH-dependence studies, collapsed rapidly (<5 min) into benzonitrile and benzaldehyde, likely deriving from hydrolysis and further oxidation of the azaallenium species 2a-IB. In addition, the presence of 2a-M arising from the addition of deuterated methanol to the putative azaallenium intermediate and detected by GC-MS analysis further provided supporting evidence. In contrast, the analogous intermediate generated from aziridine 2b, containing an electron-withdrawing para-trifluoromethyl group, showed slower decomposition rates. To our delight, the desired N-iodonium aziridine intermediate 2b-IA could be observed by ¹H NMR and LC-MS analysis. Although the same decomposition products are observed, their rate of formation is significantly slower, with aziridine 2b still present after 30 min. This result further supports the proposed mechanism and justifies the higher yields observed using conditions B as a good balance between the stability of IA and the reactivity of less nucleophilic alkenes. Surprisingly, the acrylate derivative 2ae did not show any conversion into the corresponding iodonium intermediate even after 16 h (Scheme c). This result provided further indication for the operation of an alternative mechanism when electron-deficient alkenes were employed (i.e., Michael addition, followed by intramolecular substitution).

Conclusions

A key aspect of the presented work is the facile preparation of NH-aziridines from alkenes and aqueous ammonia as a simple, commercially available nitrogen source. Importantly, we demonstrate that through careful optimization of the reaction conditions, the commonly observed overoxidation to the corresponding nitriles can be successfully managed to isolate the synthetically useful NH-aziridines. The proposed reaction mechanism has been carefully investigated and supported by experimental evidence (e.g., NMR studies and pH effect). In conclusion, we foresee the use of these conditions in other high-value nitrogen-insertion reactions, expanding the repertoire of heterocycle synthesis.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c10372.

• Experimental procedures, optimization tables, characterization data (¹H, ¹³C, and ¹⁹F NMR and HRMS) for synthesized compounds, and further references provided by the authors (PDF)

§.

Y.G. and L.M. contributed equally.

The authors declare no competing financial interest.