Imidazolidin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations onto (E)-Narylideneanilines

Abstract

In the course of our studies on the chemistry of oxyallyl species we uncovered a new (3+2) cycloaddition of aza-oxyallyl systems, generated in situ from N-benzyloxy-2-chloroamides in the presence of NEt₃, onto N-arylimines yielding imidazolidin-4-ones in moderate to good yields. The cycloadditions are regioselective. Computational modelling using DFT at the M062×/6–311+G** level is in support the observed regioselectivities. Although the path to the trans imidazolin-4-one is favored, the cis product is preferred by almost 8 kcal/mol and could be formed by base-catalyzed epimerization. All products were isolated by chromatography and characterized by means of their FTIR, NMR and HRMS data.

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1. Introduction

The aza-oxyallyl cation has been implicated in the nucleophilic ring opening reactions of α-lactams (nitrogen analogs of cyclopropanones).¹ The valence isomerization of an alkylidene oxazirine (the nitrogen analog of an allene oxide) to an α-lactam was proposed to proceed through an aza-oxyallyl cation which was supported by computation.² An aza-oxyallyl cation was also suggested in the solvolysis of N-chloro-Nalkoxyphenylacetamides.³ Definitive proof of the intermediacy of aza-oxyally cations via trapping with unsaturated systems failed until Jeffrey et al. succeeded in intercepting these elusive species through intermolecular (4+3) cycloaddition reactions with cyclopentadiene and furan.⁴ In a follow-up report on the synthetic applications of aza-oxyallyl cations, Jeffrey and co-workers extended the (4+3) cycloadditions to the diaza-oxyallyl cation and several other cyclic dienes, including 6,6-dimethylfulvene.⁵

They were also able to exploit the aza-oxyallyl-cyclic diene cycloadditions in intramolecular cycloadditions.⁶ Since these ground-breaking studies by Jeffrey et. al., synthetic activity in this area increased, and several intermolecular (3+2) cycloadditions leading to heterocycles have been reported.⁷

In the course of our own studies on the thermal isomerizations of saturated fulvene endoperoxides (e.g., 6), we disclosed the first method for the generation of the allene oxide-cyclopropanone-oxyallyl triad under neutral conditions⁸.

We also reported the first examples of intramolecular 1,3-dipolar cycloadditions of oxyallyl cations onto carbonyl groups (Scheme 1), as well as inter-and intramolecular trapping reactions of oxy-allyl species derived from these reactive intermediates.⁹ Moreover, we unveiled the first aliphatic [3.4] sigmatropic shifts involving an oxy-allyl cation (13→14).¹⁰ A survey of our results from these efforts are summarized in Schemes 2 and 3.

Scheme 1.

Aza-oxyallyl intervonversions and trapping with dienes.

Scheme 2.

Oxy-allyl cation generation from saturated fulvene peroxides and first example of intramolecular 1,3-dioplar cycloaddition with a carbonyl group.

Scheme 3.

Inter-and intramolecular trapping, as well as sigmatropic shifts of oxy-allyl cations derived from saturated fulvene endoperoxides

We have now extended our synthetic effort toward the aza analogs of oxy-allyl cations and discovered that these species are at least as reactive and versatile in terms of their reactivity toward a variety of cycloaddends. Herein, we disclose in a collaborative effort our results from the (3+2) cycloadditions of aza-oxyallyl cations onto imines.

2. Results and Discussion

α-Lactams, valence isomers of aza-oxyally cations have first been proposed by Leuchs as reactive intermediates. He observed that α-amino acid N-carboxyanhydrides (“Leuchs-anhydrides”) lose CO₂ upon heating to give α-lactams that polymerize to form polypeptides.¹¹ We recently developed a method for the synthesis of imidazolidin-4-ones by the condensation of Leuchs anhydrides with imines under loss of CO₂ with DBU in MeOH (Scheme 4).¹²

Scheme 4.

Synthesis of imidazolidin-4-ones from Leuchs anhydride and imines.

We then explored the possibility for establishing a more versatile method for imidazolidin-4-ones by employing an azaoxyallyl cation as the key reactant, since our previous method suffered from limited availability of diversely substituted Leuchs anhydrides. We are pleased to report that aza-oxyallyl cations, generated in situ from N-benzyloxy-2-chloroamides^4,5 and NEt₃ (or Na₂CO₃) as base in trifluoroethanol (TFE) solutions, reacted smoothly with (E)-N-arylimines¹² to give imidazolidin-4-ones 22 in good yields (Scheme 5). N-Aryl imines derived from aromatic aldehydes were chosen due to their greater stability and ease of isolation.

Scheme 5.

(3+2) Cycloadditions of aza-oxyallyl cations with imines.

Table 1 shows that in some cases only trans isomers are formed, and in a few cases mixtures of cis/trans isomers are isolated. The transition state leading to the products may favor one or the other isomer; the presence of base during the cycloadditions may also affect the cis/trans ratios by way of base-catalyzed epimerization, especially at higher temperatures. These issues are addressed below in computational work. Also the reaction conditions in several cases needs some comment. The method for generating the aza-oxyallyl cation in each case (either with NEt₃ as base at 0 ^oC in TFE or Na₂CO₃ at 80 ^oC in the same solvent) was chosen based on which method furnished the best yields.

Table 1.

Imidazolin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations with imines

2-Chloroa mide	Imine	Conditions	Product(s)	Yiel d %
19a[a]		TFE,0 °C NEt3		61
19a		TFE, 0 °C NEt3		43
19a		TFE, 80 °C Na2CO3		64
19a		TFE, 80 °C Na2CO3		55
19b[b]	21a	TFE,0 °C NEt3		66
19b	21b	TFE,0 °C NEt3		54
19b		TFE, 0 °C NEt3		66
19b		TFE, 80 °C Na2CO3		71
19b		TFE, 80 °C Na2CO3		68

^[a]a:R=Ph

^[b]b: R=Me

To gain greater insight, the reaction was computationally modeled using DFT at the M062×/6–311+G** level. As a model, the reaction of N-phenylbenzylimine with an N-methoxyphenyl aza-oxyallyl intermediate was used. The computed enthalpic barrier is 6.7 kcal/mol on the path (Figure 1) to the trans imidazolin-4-one (8.3 kcal/mol to the cis stereoisomer). The structure suggested asynchronicity in the cycloaddition and shows advanced bond formation with the imine nitrogen relative to the imine carbon. This transition state is over 25 kcal/mol lower than the alternatives paths to imidazolidin-4-one regioisomers (Table S1 in supplementary material). Although the path to the trans imidazolin-4-one is favored, the cis product is preferred by almost 8 kcal/mol and could be formed by basecatalyzed epimerization.

Figure 1.

Transition state for trans imidazolin-4-one formation modeled at the M062×/6–311+G** level (carbon: grey, hydrogen: white, nitrogen: blue, and oxygen: red).

3. Conclusions

Aza-oxyallyl species are reactive intermediates that may serve as important building blocks for various heterocycles, providing that the right cycloaddends are found that exhibit considerable reactivity in a (3+2) cycloaddition process. We uncovered a new regioselective cycloaddition of the aza-oxyallyl species onto Narylimines giving rise to imidazolidin-4-ones. The present method is superior to our method via the Leuchs anhydrides because the latter are difficult to obtain in in diverse substitution patterns, thus rendering the method of limited value. Moreover, the reductive removal of N-OCH₂Ph groups to give the 3hydroxyimidazolidin-4-one derivatives, which, to the best of our knowledge, are not accessible by other methods. Computational modeling correctly predicts the observed regioselectivities with an asynchronous pathway, favoring trans stereoselectivity, though the cis product in the model system should be favored by 8 kcal/mol and is indeed the dominant product in several cases due to base-catalyzed epimerization. Further studies are under way exploring cycloadditions of other C=N containing cycloaddends and will be reported in due course.

General procedure for the cycloadditions.

To a solution of imine (0.25 mmol) in TFE (2 mL), α-haloamide (0.5 mmol) and Na₂CO₃ or Et₃N (1 mmol) was added. The reaction was stirred at 0 ^oC or refluxed at 80 ^oC. Once the reaction was complete, as judged by TLC analysis, the reaction mixture was diluted with ethyl acetate, filtered through Celite, the filtered cake washed with ethyl acetate. The filtrate was then concentrated under rotary evaporation. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to afford the cycloadducts.