Synthesis of Enantioenriched gem-Disubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Abstract

A variety of enantioenriched gem-disubstituted 4-imidazolidinones were prepared in up to >99% yield and 95% ee by the Pd-catalyzed decarboxylative asymmetric allylic alkylation of imidazolidinone-derived β-amidoesters. In the process of preparing these substrates, a rapid synthetic route to 4-imidazolidinone derivatives was developed, beginning from 2-thiohydantoin. The orthogonality of the benzoyl imide and tert-butyl carbamate groups used to protect these nitrogen-rich products was demonstrated, enabling potential applications in drug design.

Graphical Abstract

Nearly 75% of small-molecule drugs contain at least one nitrogen heterocycle.¹ However, despite a significant correlation between the Csp³ complexity of a drug and its clinical success,² most of the heterocycles found in marketed drugs lack stereochemical complexity. This phenomenon can largely be attributed to a lack of synthetic methods for the efficient incorporation of chiral centers into medicinally relevant heterocycles.

4-Imidazolidinones are a class of nitrogen-rich saturated lactams that have found applications in medicinal chemistry (Scheme 1a). Our attention was drawn to the fully substituted (albeit achiral) tertiary carbon atom at the 5-position of several of the drugs and drug candidates bearing this heterocyclic moiety, such as the spirocyclic drug spiperone. Given the prevalence of this substitution pattern, we reasoned that drug design would potentially benefit from a methodology for the asymmetric construction of chiral 4-imidazolidinones bearing fully substituted tertiary stereocenters. 4-Imidazolidinones have also been used as chiral auxiliaries in the preparation of artificial amino acids³ and have found applications in popular organic catalysts,⁴ but to our knowledge, preparation of these species has been largely restricted to processes involving the use of chiral pool materials or kinetic resolution.

Scheme 1.

gem-Disubstituted Diazaheterocycles by Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Our group and others have reported extensively on the palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction,⁵ including several recent publications detailing the use of these methods for the preparation of 6- and 7-membered gem-disubstituted diazaheterocycles.⁶ gem-Disubstituted tetrahydropyrimidin-4-ones, piperazin-2-ones,^6b and 1,4-diazepan-5-ones^6c are all available in high yield and enantioselectivity via our group’s allylic alkylation chemistry (Scheme 1b). We report our efforts to extend this methodology to the 5-membered imidazolidinone substrate class, enabling rapid access to stereochemically complex imidazolidinones suitable for further functionalization (Scheme 1c).

We began by developing a rapid and scalable synthetic route to imidazolidinone allylic alkylation substrates 7, which proved to be a considerable challenge. We anticipated that the use of a Boc protecting group at the 4-position would be essential for high enantioselectivity by analogy to other substrate classes.^6b Several routes to unsubstituted or carbamate-protected 4-imidazolidinones have been reported, but none of these routes were conducive to reliable material throughput in our hands.⁷ Nevertheless, we were able to develop a rapid synthesis of 7 from 2-thiohydantoin (1) (Scheme 2).

Scheme 2.

Synthesis of Allylic Alkylation Substrates 7

2-Thiohydantoin (1) was subjected to precedented Boc protection to provide carbamate 2,⁸ followed by nickel boride mediated reductive desulfurization to produce Boc-protected 4-imidazolidinone 3 in high yield.^9,10 Subsequent benzoylation furnished doubly protected imidazolidinone derivative 4. Acylation of 4 proved challenging due to the extremely rapid reactivity of the corresponding enolate toward starting material even at −108 °C, but the use of acylimidazole electrophile 5¹¹ and the precombination of 5 with LiHMDS prior to starting material addition allowed desired 1,3-dicarbonyl 6 to be prepared in 50% yield on a multigram scale. To our delight, treatment of 6 with base and various electrophiles allowed for the rapid preparation of multiple allylic alkylation substrates 7.¹²

With model substrate 7a in hand, beginning with the conditions for our group’s prior allylic alkylation of N-Boc piperazinones,^6b a brief solvent screen was conducted for the optimization of enantioselectivity (Table 1). In line with previously observed trends, ethereal solvents provided the product 8a in only modest enantioselectivity. Less polar solvents such as benzene and toluene resulted in promising levels of enantioselectivity, but the use of a nonpolar hexanes/toluene mixture led to an ee of 91%.

Table 1.

Solvent Screen^a

entry	solvent	eeb (%)
1	THFc	51
2	1,4-dioxane	68
3	benzene	89
4	PhMe	87
5	2:1 hexanes/PhMe	91

^aScreening was performed on a 0.01 mmol scale at 0.014 M concentration. Reactions proceeded to completion unless otherwise noted. For additional experimentation, see the SI.

^bValues determined by chiral SFC analysis.

^cReaction incomplete after 45 h.

Using this optimized solvent system, we examined the palladium-catalyzed decarboxylative asymmetric allylic alkylation of 4-imidazolidinone substrates 7a–k (Scheme 3). Various nonpolar side chains proved to be well-tolerated, such as benzyl (8a), p-trifluoromethylbenzyl (8b), methyl (8c), prenyl (8d), and cinnamyl (8e) groups. A propargyl group was also tolerated with high enantioselectivity (8f), albeit with a reduction in yield. We were pleased to observe that the reaction proceeded smoothly with a methyl group at the 2-position of the allyl fragment (8g). Lastly, several polar functional groups were also well-tolerated in the allylic alkylation (8h–k), including an alkenyl chloride and a carbamate. In particular, nitrile substrate 8j was obtained in quantitative yield and an excellent 95% ee.

Scheme 3.

Substrate Scope^a

^aReactions were performed on a 0.1 mmol scale at 0.014 M concentration. ee values were determined by chiral SFC analysis. ^bConducted at 40 °C. ^c1.86 mmol scale: 86% yield, 95% ee. ^dPd₂(dba)₃ was used instead of Pd₂(pmdba)₃ to facilitate product purification.

Having demonstrated the broad functional group tolerance of the reported method, we sought to explore the feasibility of further functionalization of the 4-imidazolidinone products (Scheme 4). The selective removal of either protecting group would likely prove essential for applications in medicinal chemistry. Toward this end, treatment of chiral benzyl imidazolidinone 8a with TFA led to facile Boc cleavage, affording free secondary amine 9. Similarly, treatment of 8a with lithium hydroxide readily affected benzoyl group removal, providing free lactam 10.

Scheme 4.

Product Transformations

At the outset of this research, we had planned to explore the conversion of 4-imidazolidinone allylic alkylation products 8a–k to synthetically useful derivatives of biologically relevant and synthetically challenging α,α-disubstituted α-amino acids.¹³ Imidazolidinones were envisioned as surrogates for these desirable compounds based on prior examples of imidazolidinone chiral auxiliary-based strategies to access α,α-disubstituted α-amino acids,³ as well as our own group’s preparation of quaternary substituted β-amino acids from the analogous tetrahydropyrimidinones.^6b Unfortunately, the presence of olefinic functionality hampered the feasibility of converting 8a–k into amino acid derivatives due to the harsh conditions required for ring opening. Despite extensive experimentation, the highest yielding conditions identified for the conversion of imidazolidinone 8a to amino ester 11 (H₂SO₄/MeOH) provided highly variable results, with the maximum observed yield of 11 being only 25%.

This research represents the first direct catalytic asymmetric synthesis of gem-disubstituted 4-imidazolidinones. Applying palladium-catalyzed decarboxylative asymmetric allylic alkylation to this nitrogen-rich substrate class enabled access to enantioenriched imidazolidinones bearing diverse functional groups in high yield and enantioselectivity. This methodology, in combination with the demonstrated orthogonality of the protecting groups of the products, could enable access to a novel class of medicinally relevant compounds.