Enantioselective Direct α-Amination of Aldehydes via a Photoredox Mechanism: A Strategy for Asymmetric Amine Fragment Coupling

Abstract

The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated, nitrogen-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require post-reaction manipulation.

A central goal in organic synthesis is the development of methods to enantioselectively build C–N bonds within complex molecular structures. In particular, aldehydes, acids, and alcohols bearing α-amine substitution are widely distributed among pharmaceutically active compounds, and their broad representation has prompted the invention of a number of catalysis strategies for stereogenic nitrogen installation.^1,2 In this context, α-amino aldehydes represent a valuable class of structural motif, mainly due to their capacity to serve as versatile synthetic handles en route to a diverse range of complex nitrogen-containing synthons.³ However, the development of robust methods for the asymmetric α-amination of aldehydes has been complicated by the requirement for electrophilic sources of nitrogen, along with the need to circumvent post-reaction racemization with relatively acid- or base-sensitive products. As a consequence, traditional α-carbonyl amination reactions often involve π-electrophile addition pathways that culminate in the installation of hydrazinyl or oxy-amino substituents,⁴ a class of N-stereogenicity that must be chemically modified (e.g. N–N or N–O reduction) prior to synthetic elaboration (Eq 1). In 2008, our lab introduced a versatile platform for catalytic activation, termed photoredox organocatalysis. In a common embodiment, electron-rich chiral enamines, derived from the condensation of aldehydes and secondary amine catalysts, undergo rapid and enantioselective coupling with electrophilic radical systems (e.g. CF₃ •, ArCH₂ •, etc; Eq 2).⁵ In this manuscript, we demonstrate that this “borrowed electron” catalysis strategy can be readily translated to the enantioselective α-amination of aldehydes using nitrogen-centered radicals. As a critical design element, this open shell coupling mechanism allows for the direct generation of α-amino aldehyde products of broad diversity that do not require post-reaction manipulation yet are stable to racemization.

Design Plan

A detailed catalytic cycle for our proposed asymmetric aldehyde amination is presented in Scheme 1. We postulated that an electrophilic nitrogen-based radical 1 might be generated under mild conditions from an amine substrate 3 that incorporates a photolabile leaving group. While recent literature suggests that nitrogen-centered radicals might be formed using photoredox-active metal complexes,⁶ we envisioned that direct access to such open shell reaction partners might be best accomplished using a traceless activation handle such as the dinitrophenylsulfonyloxy group (a subunit that can be chemoselectively triggered using a simple household lightbulb). From the outset, it seemed plausible that an electrophilic nitrogen radical (such as 1) would rapidly undergo coupling with a transiently generated π-rich enamine 2 (derived from the condensation of an imidazolidinone catalyst with the aldehyde coupling partner). Oxidation of the resulting 3π-electron α-amino radical species 4 would then occur via single-electron transfer (SET) to a second equivalent of the photoexcited amine reagent 3^*, a critical propagation step that would simultaneously deliver the iminium ion 5, while releasing the next round of the nitrogen radical coupling partner.⁷ Hydrolysis of iminium 5 would then reconstitute the imidazolidinone catalyst and, at the same time, deliver the enantioenriched α-amino aldehyde product. Notably, despite a growing interest in nitrogen-centered radicals as a source of electrophilic nitrogen,⁸ few intermolecular amine coupling processes have been reported,⁹ and indeed, no enantioselective applications have been described to date.

Scheme 1.

Proposed Mechanism for Aldehyde α-Amination.

Our evaluation of the proposed aldehyde–amine coupling began with exposure of 3-phenylpropionaldehyde to a series of chiral amine catalysts and a large collection of nitrogen-based coupling partners. As revealed in Table 1, we were delighted to find that carbamate 3, incorporating a photolabile dinitrophenylsulfonyloxy (ODNs) residue, is competent at producing the requisite heteroatom-centered radical upon exposure to household light and in the presence of catalyst 6 (entry 1, 30% yield, 91% ee).¹⁰ Presumably, upon photonic excitation, amine 3^*readily undergoes single-electron reduction and mesolysis of the weak N–O bond to yield the desired amine-centered radical and the ODNs anion. Initial experiments using catalyst 6 confirmed that the reaction does indeed require the use of light (cf. entries 1 and 2), and that a continuous source of photons is required for reaction propagation.¹¹ Moreover, use of a monochromatic light source tuned to 300 nm (λ_max absorption band of sulfonyloxyamine 3 = 292 nm)¹⁰ resulted in increased conversion and efficiency (entry 4, 38% yield, 90% ee, 6 h).¹² These experiments provide additional evidence for the participation of the amine reagent 3^* excited state in the photoredox process as described in Scheme 1.

Table 1.

Initial Studies towards α-Amination of Aldehydes.

entry	catalyst	temp (°C)	light	yielda	% eeb
1	6	rt	26W CFL	30%	91%
2	6	rt	none	0%	--
3c	6	rt	26W CFL	0%	--
4d	6	rt	LZC (300 nm)	38%	90%
5	7	rt	26W CFL	40%	75%
6	6	−15	26W CFL	47%	92%
7	7	−15	26W CFL	65%	78%
8	8	−15	26W CFL	82%	88%
9	9	−15	26W CFL	77%	86%
10	10	−15	26W CFL	72%	86%
11	11	−15	26W CFL	76%	91%

^aObtained by ¹H NMR analysis using methyl benzoate as internal standard.

^bDetermined by chiral HPLC analysis of the corresponding alcohol.

^cPerformed without 2,6-lutidine.

^dReaction carried out in a photobox equipped with 10 × Luzchem LZC-UVB. DNs = 2,4-dinitrobenzenesulfonyl. CFL = compact fluorescent light.

We next evaluated amine catalysts of varying steric demand, with the supposition that higher enamine content¹³ and increased exposure of the reactive π-system would facilitate the critical radical addition step. Indeed, experiments performed in the presence of imidazolidinone catalyst 7, a system that generally provides higher enamine content, exhibited improved overall efficiency (entry 5, 40% yield) albeit with lower levels of stereocontrol (75% ee). Next, the effect of temperature on this α-amination protocol was evaluated. A significant improvement in reaction yield was observed at subambient temperatures, presumably due to the capacity to circumvent deleterious reduction of the carbamyl radical (cf. entries 1 and 6, 30 vs. 47% yield), a pathway that would consume amine reagent without productive C–N bond formation.¹⁴ Finally, during the course of our optimization studies, we determined that the aminal C(2)- position on the imidazolidinone framework was susceptible to hydrogen atom abstraction by the N-centered radical, leading to diminished levels of reaction efficiency. This catalyst decomposition pathway was suppressed via the design of a novel organocatalyst framework, wherein the C(2)-position incorporates a fully substituted carbon stereocenter (catalysts 8– 11, entries 8–11).¹⁵ In particular, the use of imidazolidinone 11 provided the desired α-amino aldehyde adduct with optimal levels of efficiency and enantiocontrol (entry 11, 76% yield, 91% ee).

It is notable that amine catalyst 11 was identified as the optimal organocatalyst for this transformation, given that it has not previously been utilized in enamine- or iminium-based transformations. The high levels of enantiocontrol observed in this study can be rationalized on the basis of enamine olefin geometry and π-facial selectivity. More specifically, DFT studies¹⁶ of the corresponding enamine intermediate (DFT-12, Figure 1) reveal that the (E)-configuration of the 4π-olefin system is preferred as it positions the electron-rich reaction site away from the fully substituted carbon center on the imidazolidinone framework. This preferred enamine geometry along with the meta-ethyl arene orientation (as shown) has further been confirmed by 2D NMR (NOESY) studies.¹⁷

Figure 1.

DFT structure of catalyst-derived enamine (DFT-12).

Reaction Scope

With our optimal conditions in hand, we examined the scope of this new enantioselective C–N bond-forming protocol. As shown in Table 2, this radical-based coupling is compatible with a variety of amine reaction partners adorned with an array of alkyl motifs and carbamate protecting groups (entries 1–8, 71–79% yield, 86–94% ee). It is important to note that many of these novel amine reagents are readily accessed in two steps from N-methyl hydroxylamine and are uniformly bench-stable, crystalline solids.¹⁸ Moreover, the bis- protected N-Moc, N-MOM amine reagent can be effectively used for α-amination of aldehydes with excellent enantiocontrol (entry 6, 75% yield, 94% ee). This specific example represents an important expansion of the scope of this method, offering a means to enantioselectively access orthogonally N ,N-protected α-amino aldehydes.

Table 2.

Enantioselective α-Amination: Scope of the Amine.

^aStereochemistry assigned by chemical correlation or by analogy.

^bEnantiomeric excess determined by chiral HPLC analysis of the corresponding alcohol. DNs = 2,4-dinitrobenzenesulfonyl.

We next sought to establish the scope of the aldehyde coupling partner in this transformation. As shown in Table 3, we were pleased to find that these mild redox conditions accommodate a wide range of substituents on the aldehyde component, including ethers, amines, alkenes, and aromatic rings (entries 2–6, 71–79% yield, 88–91% ee). Moreover, excellent levels of enantiocontrol are achieved with sterically demanding formyl substrates (entries 7–8, 67–72% yield, 91–94% ee). It should be noted that α-dialkyl aldehyde systems are not useful substrates in this transformation as the imidizolidinone family of catalysts do not readily condense with α-branched aldehydes. This is an important catalyst design feature as it prevents post-reaction racemization with the products generated in Tables 2 and 3. Moreover, this protocol provides direct asymmetric access to synthetically valuable, configurationally stable α-amino aldehyde adducts which may be readily isolated and purified via column chromatography without further derivatization.

Table 3.

Enantioselective α-Amination: Scope of the Aldehyde.

^aStereochemistry assigned by chemical correlation or by analogy.

^bEnantiomeric excess determined by chiral HPLC analysis of the corresponding alcohol or 2-naphthoyl ester. DNs = 2,4-dinitrobenzenesulfonyl.

As a further demonstration of the synthetic utility of this method, we illustrate representative procedures for the conversion of these enantioenriched α-amino aldehyde adducts to either β-amino alcohol or α-amino acid motifs. As shown in Scheme 2, the crude product of the α-amination reaction (see Table 2, entry 2) may be directly converted to the corresponding β-amino alcohol in good yield and with complete stereofidelity. Alternatively, direct oxidation with buffered KMnO₄ affords the Cbz-protected N-methyl phenylalanine with useful reaction efficiency and with retention of optical purity. We anticipate that this α-amination/aldehyde derivatization strategy will find broad application in the synthetic community, as a facile means by which to gain rapid access to high value non-proteogenic α-amino acids and N-alkyl α-amino acids.^19–22

Scheme 2.

Telescoped synthesis of β-amino alcohols and α-amino acids from hydrocinnamaldehyde.

In summary, we have developed an organocatalytic photoredox-based approach to the asymmetric α-amination of aldehydes via the direct coupling of functionalized nitrogen and formyl precursors. This operationally facile process provides ready access to complex, N-substituted α-amino aldehyde architecture and at the same time offers a useful alternative to standard π-electron addition approaches to carbonyl α- amination. Moreover, this disclosure marks, to the best of our knowledge, the first demonstration of the use of nitrogen-based radicals as viable reagents in a catalytic enantioselective transformation. We anticipate that this α-amination method will prove widely useful in the synthesis of complex target structures bearing chiral amine fragments.