α-Amination of keto-nitrones via Multihetero-Cope rearrangement employing an imidoyl chloride reagent

Abstract

α-Aminations of ketone-derived nitrones have been developed via [3,3]-rearrangement of the intermediates generated upon condensation with imidoyl chlorides. Careful reagent selection provides synthetically attractive amino protecting groups. The enediamide or α′-carbamoyl enamide products can be hydrolyzed to the desired carbonyl, or exposed to electrophiles for further α-functionalization.

α-Amino carbonyls are ubiquitous in organic chemistry. Creation of this functional group via C_α–N bond construction is a central challenge in organic synthesis that has received considerable attention in the literature.¹ The electrophilic α-amination of enolates and their equivalents is in principle a direct, efficient method for α-amino carbonyl synthesis and significant work on this problem has been reported. Azodicarboxylates are especially prominent N(+)-sources that have been widely and effectively applied to this reaction, including asymmetric variants,² but come with several drawbacks. Atom inefficiency, explosion hazard,³ and typically harsh or multistep deprotection protocols to reveal the amine somewhat counterbalance the favourable reactivity profile. Thus, an argument can be made that an important but often-overlooked component of the electrophilic α-amination problem lies in the “packaging” of the amine product. Previous studies by our group made use of a weak N–O bond for electrophilic amination methodology,⁴ and we questioned whether this tactic could be harnessed to provide convenient nitrogen protecting groups (e.g. Boc, Fmoc, Cbz) concomitantly upon α-amination. The purpose of this communication is to report a [3,3]-rearrangement of imidoyl nitrones providing α-amination products with synthetically-attractive amino protecting groups.

[3,3]-Sigmatropic rearrangements are important reactions for the reliable introduction of various functionality in complex settings.⁵ Multihetero-[3,3]-rearrangements, such as those of N-alkyl-N-acetoxyenamines, are an important subclass.⁶ Coates and Cummins were the first to develop this rearrangement as a method for α-functionalization: treatment of N-^tBu nitrones with acyl chlorides provide α-acyloxy carbonyls (eqn (1)).^6b Extension of this strategy to achieve α-amination has been scarcely pursued. The use of an imidoyl chloride rather than an acyl chloride in the condensation with a keto-nitrone afforded α-amido ketone products in two preliminary investigations.⁷ The imidoyl electrophiles used (Y, Z = Ph or Y = Ph, Z = Me (Scheme 1)) provided N-Ph/Me-benzoylamino products that would be difficult to convert to the free α-amino ketones.

(1)

Scheme 1.

α-Amination via multiheteroatom [3,3]-rearrangement.

In formulating a reaction design for an α-amination that proceeds with concurrent generation of synthetically-attractive protecting groups, we envisioned that a [3,3]-rearrangement involving an appropriately functionalized imidoyl chloride reagent could be useful (Scheme 1). Herein, we disclose an α-amination protocol for keto-nitrone substrates via [3,3]-rearrangement. The α-amino products obtained are conveniently configured as benzyl carbamates (NH–Cbz). An unexpected deprotonation event occurs with acyl migration to furnish enediamide or α′-carbamoyl enamide products dependent on the α-proton availability on the nitrone substrate (vide infra).

The requisite keto-nitrones were prepared via hydroxylamine/ketone condensation.⁸ A variety of enolizable ketones were employed with aryl, alkyl, and cyclic substrates providing varied yields (13–88%) of nitrone product.⁹ These compounds are stable to SiO₂ chromatography and can be stored in a freezer indefinitely. The Cbz-protected trifluoromethyl imidoyl chloride 1 was synthesized via the published two step route.¹⁰

The reaction of cyclopentanone-derived nitrone 2 and the imidoyl chloride 1 in the presence of Et₃N at 0 °C led to rapid and complete reagent consumption. Analysis of the crude reaction mixture showed formation of an α′-carbamoyl enamide product (3), rather than the anticipated α-amino imine or ketone (Scheme 2). This was rationalized ex post facto by a 1,4-trifluoroacetyl migration/proton transfer^6a of the initial [3,3]-imine product (5 → 3, Scheme 2). At this time it is unclear whether the system is under kinetic or thermodynamic control, although the formation of α′-carbamoyl enamide products (deprotonation at the less-hindered site) suggests a kinetic scenario. Equimolar quantities of nitrone and reagent 1 treated with 2.0 equiv. triethylamine provided the optimal results for this transformation when run in CH₂Cl₂ at 0 °C. The reaction was usually complete within 30 min.

Scheme 2.

Initial result and proposed mechanism.

A divergence in reactivity was observed when acetophenone-derived nitrone 6 was subjected to identical conditions. In the absence of an α′-enolizable proton, terminal deprotonation occurred at the α-site furnishing the enediamide product (9 → 7, Scheme 3).

Scheme 3.

Divergent reactivity with aryl nitrone.

With optimized conditions in hand and two product classes identified, we explored the scope of the [3,3]-rearrangement/α-amination. Nitrones derived from acetophenone derivatives provided moderate yields ranging from 49–66% (7, 10–12, Table 1). The enediamide moiety was formed exclusively in the (Z)-configuration. When a propiophenone-derived nitrone was used, the product geometry was reversed (12), presumably due to increased A^1,3-strain introduced by the methyl substituent (vs. −H). Cyclic nitrones also performed well in the [3,3]-rearrangement (Table 2). Cyclopentyl and cyclohexyl substrates provided α′-carbamoyl enamides in 64–78% yields (3, 13–16). The use of a 4-^tBu-cyclohexanone derived nitrone decreased the yield and provided minimal diastereoselectivity (17).

Table 1.

Aryl nitrone scope^a,^b,^c

^aAll reactions: [1]₀ = 0.1 M.

^bYields of isolated products.

^cSee Supporting Information for more details.

Table 2.

Cyclic/alkyl nitrone scope^a,^b,^c

^aAll reactions: [1]₀ = 0.1 M.

^bYields of isolated products; dr determined by ¹H NMR spectroscopy.

^cSee Supporting Information for more details.

The nitrone N-benzyl protecting group was varied, using the cyclopentyl core as a model. Several substituted benzyl nitrones were examined, with the tolyl group providing the highest yield (14). A chiral nitrone derived from (S)-α-methyl benzylamine was synthesized and tested,¹¹ but chirality transfer was poor (18).

The acetone-derived nitrone provided the enediamide 19 rather than the isomeric α′-carbamoyl enamide. In this case and other examples reported with diminished yields, competing reactions producing unknown byproducts account for the mass balance. The cyclohexenone-derived nitrone displayed unique reactivity wherein the chloride byproduct was incorporated yielding cis-β′-chloro-α′-carbamoyl enamide 20.

Both the enediamide and α′-carbamoyl enamide products are resistant to hydrolysis and survive acidic or basic aqueous workup; however, after extensive screening of conditions, basic hydrolysis was realized upon treatment with freshly prepared sodium benzylthiolate in MeOH. Subjecting the enamide 3 to these conditions cleanly provided the Cbz-protected α-amino ketone 21 in 85% yield (A, Scheme 4). Enediamide product 7 was also hydrolyzed upon thiolate exposure and subsequent acidic workup. In this case, partial tranesterification occurred providing the methoxy-carbamyl protected α-amino ketone as a minor product (B, Scheme 4). A one-pot procedure taking nitrone starting material directly to the Cbz-protected α-amino ketone 21 was also realized by treating the crude reaction product from the [3,3]-α-amination with NaSBn/MeOH. This sequence resulted in a yield of 69%, significantly higher than the analogous two-step process (C, Scheme 4).

Scheme 4.

Secondary transformations.

The enamide in both product classes provides opportunities for further α-functionalization. Exposure of enamide 3 to Br₂ provided hemiaminal oxazolidinone 23 from bromination-debenzylation (D, Scheme 4).

In conclusion, we have developed an α-amination of keto-nitrones via multiheteroatom-[3,3]-rearrangement. This reaction provides enediamide or α′-carbamoyl enamide products based on the enolizable sites on the substrates employed. Upon basic hydrolysis, carbonyl functionality may be revealed providing a new method for carbonyl α-amination. Ongoing studies in our laboratory are focused on extending this method to aldo-nitrones and development of an asymmetric variant.