Direct access to 2-imidazolines from unactivated alkenes

Abstract

The formation of carbon–nitrogen bonds is crucial for the discovery of pharmaceuticals, materials, and agrochemicals. Nitrogen-containing functional groups, especially heterocycles, are common motifs in biologically active compounds. Among these, 2-imidazolines have emerged as important scaffolds with their own class of biological targets. Herein, we report the development of an oxidative amination process to directly convert unactivated alkenes into 2-imidazolines. The combination of ammonia and a commercially available hypervalent iodine reagent achieves the cleavage of the carbon–carbon double bond. Subsequent interception of the resulting imine by ethylenediamine and oxidation furnishes 2-imidazolines in high yields. The reaction is rapid and tolerates a wide range of functional groups, showcasing its potential for late-stage diversification of complex molecules.

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Introduction

Nitrogen-containing heterocycles are prevalent scaffolds in biologically active molecules and functional materials.^1,2 Among these, imidazolines represent an important class, with 2-imidazoline being the most frequently occurring isomer.³ 2-Imidazolines interact with a distinct set of biological targets^4–7 and function as more lipophilic bioisosteres of amidines.⁸ They also serve as synthetic intermediates for accessing imidazoles, which rank among the most prevalent nitrogen heterocycles in U.S. FDA-approved drugs.⁹ Besides their biological application, 2-imidazolines have also been widely used as ligands for transition metal catalysts.¹⁰ Over the past years, numerous strategies for the synthesis of 2-imidazolines have been developed. Most approaches rely on the reaction of carbonyl derivatives, such as carboxylic acids, esters, or aldehydes, with diamines, followed by oxidation,^10,11 or the use of nitriles^12–16 (Fig. 1Ai). However, these methods mostly require harsh conditions or include transition metal catalysis. Synthetically, an interesting alternative approach to the use of those classical carbonyl derivatives would be to directly employ easily accessible alkenes as starting materials in an oxidative diamination process.

Fig. 1 (A) Literature precedents for the synthesis of 2-imidazolines. (B) Oxidative amination of alkenes, recently developed by our group. (C) The reaction design for the direct transformation of alkenes to 2-imidazolines.

Alkenes are valuable precursors for nitrogen-containing molecules due to their prevalence in petrochemical feedstocks, natural products, and wide use as synthetic intermediates.^17,18 To date, however, there is a dearth of methods realizing the desired direct transformation of alkenes into 2-imidazolines (Fig. 1Aii).^19–23 The first example converts electron-deficient alkenes to 2-imidazolines using ethylenediamine via carbon–carbon bond cleavage, yet it is limited to activated substrates.²⁰ Another method is the iridium-catalyzed photoredox functionalization using N-Ts-protected 1-aminopyridinium and acetonitrile as nitrogen sources.²¹ However, this operationally complex procedure furnishes N-tosylated products, which are challenging to deprotect; additionally, the method produces substituted 2-imidazolines. Thus, the development of a simple method that would directly convert unactivated alkenes to unprotected 2-imidazolines to expedite the incorporation of this motif in biologically relevant molecules is needed.

In our design, we aimed to use commercially available reagents to develop an operationally simple transformation of unactivated alkenes to 2-imidazolines to maximize the reaction's applicability. Our group recently reported an oxidative amination strategy via nitrogen atom insertion into unactivated carbon–carbon double bonds, yielding either nitriles or amidines, depending on the initial alkene substitution pattern (Fig. 1B).²⁴ Key to this reactivity is the combination of an ammonia source and a hypervalent iodine reagent, forming an electrophilic nitrogen species in situ,²⁵ which engages with unsaturated bonds to achieve various transformations, such as atom swaps or nitrogen atom insertions.^26–29 For the oxidative amination of alkenes, the electrophilic nitrogen reagent undergoes a formal [2 + 1]-cycloaddition with the alkene, furnishing an activated aziridine I1. This subsequently undergoes a concerted electrocyclic ring-opening, forming an aza-allenium species I2. Aminolysis by ammonia generates an imine I3 after proton transfer and extrusion of formaldimine. Imine I3 then undergoes rapid oxidation events to the final nitrile or amidine. We hypothesized that the imine intermediate I3 might be intercepted by a suitable diamine nucleophile, followed by oxidation to the desired 2-imidazoline (Fig. 1C). However, challenges arise from the highly oxidative reaction conditions leading to compatibility issues with several oxidation-sensitive species, including the diamine reagent itself as well as the desired product of the reaction. Moreover, the proposed diamine attack onto the imine intermediate needs to outcompete the rapid oxidation to the nitrile.

Herein, we describe the successful realization of this concept in which unactivated alkenes are directly converted to unsubstituted 2-imidazolines via a carbon–carbon double bond cleavage using inexpensive, commercially available reagents. The high functional group compatibility was demonstrated on a wide range of alkenes and drug-like molecules, highlighting its potential use for immediate applications in late-stage diversification.

Results and discussion

We initially focused on the use of ammonium carbamate as the nitrogen source and (bis(trifluoroacetoxy)iodo) benzene (PIFA) as the hypervalent iodine reagent.²⁴ The primary challenge of the reaction development was to find conditions that favor the interception of the proposed imine intermediate I3 by a diamine over its oxidation to the nitrile 3a. We selected alkene 1a and ethylenediamine as our model system. We were delighted to find that 2-imidazoline 2a (Fig. 2, entry 1) was obtained in moderate yield with only small amounts of nitrile 3a as byproduct. PIFA was generally demonstrated to be the most efficient oxidant for the targeted transformation, with other iodine(III) reagents such as (diacetoxyiodo)benzene (PIDA) providing significantly lower yields of the desired product 2a (Fig. 2, entry 3). Moreover, the reaction was found to proceed only in the presence of fluorinated, protic solvents, among which hexafluoroisopropanol (HFIP) proved to be the most efficient for the formation of 2-imidazoline 2a (Fig. 2, entries 4, 7, and 8). Achieving high yields of the desired product 2a and favoring its formation over nitrile 3a required 4 equivalents of ethylenediamine, likely due to the undesired oxidation of the diamine under the reaction conditions (Fig. 2, entries 1 and 6). After careful adjustments of the ratio of ammonium carbamate, PIFA, and ethylenediamine, we found reaction conditions that gave access to 2-imidazoline 2a in high yield with, remarkably, no detected formation of nitrile 3a (Fig. 2, entry 4).

Fig. 2 Selected optimization data for the transformation of alkenes to 2-imidazolines. ^aRefers to ¹H NMR yield determined with dibromomethane as internal standard.

With the optimized conditions in hand, we set out to explore the functional group tolerance and synthetic utility of this transformation (Fig. 3). Aliphatic, unactivated alkenes cleanly afforded 2-imidazolines 2a to 2j in good yields, while halogens, TBS-protected, as well as unprotected alcohols remained untouched. Esters, acetamides, and Boc-protected amines were well tolerated (2g to 2i). Styrene derivatives (2l and 2n) could be obtained in high yield. Electron-deficient heterocycles such as 4-vinylpyridine resulted in a decrease in yield (35% for 2m versus 99% for 2l). Next, we investigated internal alkenes. Symmetrical trans-4-octene furnished two equivalents of 2-imidazoline 2o by cleavage of the carbon–carbon double bond, whereas cyclohexene underwent ring-opening to give bis-imidazoline 2p in good yield. The conjugated diene, cinnamylideneacetophenone (1q), also reacted under our conditions to give both imidazoline fragments 2l and 2q in moderate yield. Moreover, we demonstrated the synthesis of tolazoline 2k, an adrenoblocking drug,³⁰ in one step from allylbenzene in good yield by applying our reaction conditions. Next, we investigated whether our reaction was amenable to more complex substrates. Hexenyl esters from ambrisentan, ataluren, telmisartan, artesunate, and lumacaftor all afforded 2-imidazolines 2r to 2v in good to high yields, showcasing the potential of our method for late-stage diversification of drug-like molecules.

Fig. 3 Scope of the reaction of alkenes to 2-imidazolines. The yields are given as isolated yields on 0.5 mmol scale.

Next, different derivatizations of the obtained 2-imidazolines were tested. Simple oxidation with PIDA under basic conditions afforded imidazole 3l, another valuable heterocycle. The oxidative ring-opening of 2-imidazoline 2l to 4l could be achieved under basic conditions and elevated temperatures (Fig. 4A). Interestingly, we found that exposing bromo-substituted 2-imidazoline 2d to basic conditions led to a nucleophilic substitution reaction by the imidazoline's NH on the bromide, forming fused amidine 2w (Fig. 4B). We then tested different leaving groups and chain lengths. Tosyl worked similarly to bromide (2x), as well as longer alkyl chains performed well, giving six- and seven-membered fused amidines (2y and 2z).

Fig. 4 (A) and (B) Scope diversification. The yields are given as isolated yields on 0.5 mmol scale. ^aOxidation of 2-imidazoline 2l to imidazole 3l: K₂CO₃ (1.1 equiv.), PIDA (1.1 equiv.), DMSO (0.1 M), r.t., 48 h. ^bOxidative ring-opening of 2-imidazoline 2l: KOH (0.2 equiv.), iPrOH/H₂O (1/1, 0.25 M), 95 °C, 48 h. ^cCyclization to fused amidines: aqueous 1 M NaOH (10 equiv.), DCM (0.1 M), r.t., 16 h. (C) Proposed mechanism of the reaction of alkenes to 2-imidazolines.

To better understand the underlying mechanism (Fig. 4C) and gain evidence for imine I3 being a possible intermediate in our reaction, we performed several control experiments (see SI for more details). Using ¹⁵NH₄OAc in the presence of an equivalent amount of K₃PO₄ instead of ammonium carbamate as the ammonia source yielded the desired product without any ¹⁵N incorporation. This suggests that both nitrogen atoms in the product arise from ethylendiamine, supporting a mechanism in which imine I3 was intercepted by the diamine, consequently releasing any ¹⁵N-labelled species. However, we cannot rule out that the imine first hydrolyzes to a short-lived aldehyde intermediate, given that an aldehyde was chemically competent when used as the substrate in the reaction. Finally, an alternative mechanism through attack of the diamine onto a nitrile intermediate could be ruled out, given the lack of reactivity of the latter under the reaction conditions, showing that it is not a chemically competent species.

Conclusions

In summary, we have developed a method for the direct conversion of unactivated alkenes into unsubstituted 2-imidazolines using commercially available reagents. The key to this reactivity is the successful trapping, by a diamine, of a short-lived imine species generated in situ from the reaction between an alkene and a combination of ammonia with a hypervalent iodine reagent. Given the operationally simple and rapid reaction, together with the broad functional group tolerance, we believe that this reaction will find immediate applicability in the synthesis of heterocyclic building blocks and the late-stage diversification of complex compounds.

Author contributions

S. S. and A.-S. K. P. conceived the project. S. S., A.-S. K. P., G. R. conducted the experimental work and analysed the data. B. M. supervised the research. S. S., A.-S. K. P., and B. M. wrote the manuscript with input from all authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2529027–2529029 contain the supplementary crystallographic data for this paper.^31a–c

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d6sc03337g.

Acknowledgements

We thank the Molecular and Biomolecular Analysis Service (Mo-BiAS), the X-ray structure service (SMoCC), and the LOC NMR Service at ETH Zurich for technical assistance. We further thank the whole Morandi group for critical proofreading of the manuscript. This project was financially supported by ETH Zurich and the Swiss National Science Foundation (10002372). S. S. acknowledges a fellowship from the Fonds der Chemischen Industrie (FCI). X-ray data were recorded on a rotating anode diffractometer co-funded by SNF (R'EquipProject No. 206021_213224).

Notes and references

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