Enantioselective α-Benzylation of Aldehydes via Photoredox Organocatalysis

Abstract

The first enantioselective aldehyde α-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a chiral imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst in the presence of household fluorescent light directly affords the desired homobenzylic stereogenicity in good to excellent yield and enantioselectivity. The utility of this methodology has been demonstrated via rapid access to an enantioen-riched drug target for angiogenesis suppression.

The benzylic alkylation of chiral enolates has become a mainstay transformation in chemical synthesis, mainly due to the seminal research efforts of Evans, Oppolzer, Seebach, and Myers.¹ Surprisingly, however, catalytic enantioselective variants of this venerable reaction remain confined to a small but valuable group of substrate types. Phase transfer benzylation of glycine-derived imines,² chiral triamine ligation of ketone-derived lithium enolates,³ and the use of Jacobsen’s Cr(salen) complex with preformed stannous enolates⁴ are among the most successful examples.⁵ Direct organocatalytic methods to form α-benzylated aldehydes have also been reported wherein the electrophilic partner requires multiple and/or electron-rich aryl rings (to enable the intermediate formation of stabilized benzylic carbocations).⁶ Recently, our laboratory introduced a new mode of activation termed photoredox organocatalysis,^7,8 the mechanistic foundation of which relies on the propensity of electrophilic radicals (derived from photocatalytic reduction of alkyl halides) to combine with facially biased enamines (derived from aldehydes and a chiral amine catalyst). Inspired by this strategy, we hypothesized that the enantioselective α-benzylation of aldehydes might also be possible via the marriage of these activation pathways. Herein, we present a new direct and enantioselective catalytic protocol for the α-alkylation of aldehydes, a transformation that is successful with a wide array of simple monoaryl⁹ and monoheteroaryl methylene halides.

Design Plan

As detailed in Figure 1, it has been established that commercially available fac-Ir(ppy)₃ (1) (ppy = 2-phenylpyridine), commonly used as a green triplet emitter in OLEDs, can readily accept a photon from weak fluorescent light to generate the strong reductant excited state fac-*Ir(ppy)₃ (2) (E_1/2 = −1.73 V vs saturated calomel electrode (SCE) in CH₃CN).¹⁰ We hoped that single electron transfer (SET) from fac-*Ir(ppy)₃ to a suitable benzylic bromide might render an aromatic radical anion that would rapidly undergo σ-bond cleavage to afford the bromide anion and an electrophilic benzyl radical 3. Within the same time frame, condensation of an aldehyde substrate with imidazolidinone catalyst 4 should form a highly π-nucleophilic enamine 5 which should then combine with the electron-deficient radical 3 to enantioselectively forge the crucial homobenzylic center. Rapid oxidation of the resultant α-amino radical¹¹ 6 by fac-Ir(ppy)₃⁺ (7) (E_1/2 = 0.77 V vs SCE in CH₃CN)¹⁰ would then close the redox cycle while regenerating the photocatalyst fac-Ir(ppy)₃ (1). Moreover, subsequent hydrolysis of iminium 8 would reconstitute the organocatalyst 4 while liberating the enantioenriched α-benzyl aldehyde adduct.

Figure 1.

Proposed catalytic cycle for aldehyde α-benzylation.

Evaluation of this tandem catalysis strategy was first examined with octanal, imidazolidinone catalyst 9, fac-Ir(ppy)₃ (1), a 26 W compact fluorescent lamp, and 2,4-dinitrobenzyl bromide, benzyl bromide, or 4-(bromomethyl)pyridine as the alkylating reagent. As shown in Table 1, initial experiments revealed that the proposed benzylation was indeed possible; however, the coupling component was restricted to the most electron-deficient dinitro-aryl system (entry 2). Intriguingly, the use of benzyl bromide resulted in the complete recovery of starting materials¹² while 4-(bromomethyl)-pyridine rapidly decomposed under photoredox conditions (entries 1, 5). These data suggest that electron-neutral benzylic halides do not readily undergo the initial reduction step, while the pyridinium radical is formed but does not couple with the enamine derived from amine 9. To address this latter limitation, we next examined amine catalysts of diminished steric demand with the presumption that a higher concentration and increased spatial exposure of the enamine intermediate should increase the rate of the critical radical-olefin addition step. Indeed, the pseudo-C₂-symmetric catalyst 10 (wherein the tert-butyl substituent has been replaced by a methyl group) does enable the pyridinium methylene bromide to become a viable coupling partner, albeit with low selectivities (entry 6, 81% yield, 78% ee). Enantiocontrol is regained, however, when the benzyl, methyl disubstituted amine 4 is employed (entry 7, 90% ee), a catalyst that likely operates via the preferred E-enamine geometry with shielding of the π-nucleophilic Re-face by the benzylic moiety on the catalyst framework (DFT-5).¹³ The superior levels of scope, induction, and efficiency exhibited by the combination of catalysts 4 and fac-Ir(ppy)₃ (1) in DMSO at 23 °C prompted us to select these conditions for further exploration.

Table 1.

Evaluation of Amine Catalyst for Benzylation

entry	Ar	catalyst	% yielda	% eeb
1	Phenyl	9	0	ND
2	2,4-(NO2)2C6H3	9	74	97
3	2,4-(NO2)2C6H3	10	93	82
4	2,4-(NO2)2C6H3	4	94	92
5c	4-Pyridinyl	9	0	ND
6c	4-Pyridinyl	10	81	78
7c	4-Pyridinyl	4	86	90

^aIsolated yields.

^bEnantiomeric excess determined by chiral HPLC.

^c4-(Bromomethyl)pyridine added as the hydrobromic acid salt with an additional equivalent of 2,6-lutidine.

We next performed a series of experiments to determine the scope of the aldehydic component in this asymmetric benzylation protocol. As revealed in Table 2, these mild redox conditions are compatible with a wide range of functional groups, including ethers, amines, imides, carbamates, and aromatic rings (72–91% yield, 87–90% ee). Moreover, significant variation in the steric demand of the aldehyde substituent can be accommodated without loss in enantiocontrol (entries 4 and 5, ≥73% yield, 90% ee).

Table 2.

Asymmetric Aldehyde α-Benzylation: Aldehyde Scope

entry	producta	yield, eeb	entry	producta	yield, eeb
1		86% yieldc 90% ee	4		73% yield 90% ee
2		91%yieldc,d 90% ee	5		75% yield 90% ee
3		78% yieldc 87% ee	6		72% yieldd 90% ee

^aStereochemistry assigned by chemical correlation or by analogy.

^bEnantiomeric excess determined by chiral SFC or HPLC.

^cSubstrate added as the hydrobromic acid salt with an additional equivalent of 2,6-lutidine. The free base organocatalyst was used.

^dIsolated yield of the corresponding alcohol.

We have found that a broad range of electron-deficient aryl and heteroaryl methylene bromides also participate in this enantioselective benzylation reaction (Table 3). For example, benzyl systems that incorporate a nitro-substituent with other electron-withdrawing groups such as nitriles and esters (Table 3, entries 1–3) are well-tolerated. Moreover the 1,2-nitro-fluoro aryl ring can serve to produce a suitably electrophilic radical without the intervention of S_NAr byproducts (entry 3). Perhaps more notable with respect to medicinal agent synthesis, a large range of heteroaryl rings can be successfully employed such as pyridines, quinolines, benzimidazoles, pyrimidines, and triazines. As highlighted in entries 4 and 5, bromomethyl pyridines that have electron-donating substitution (entry 5, 2-methyl, 91% ee) or electron-withdrawing groups (entry 4, 5-nitro, 90% ee) are both competent in this enantioselective coupling. Moreover, fused bicycles such as 4-quinolinyl and 2-benzimidazolyl also perform well (81–90% yield, 82–88% ee, entries 6, 10). We postulate that, for substrates with a basic nitrogen (4-pyridinyl, and entries 5–6, 10),¹⁶ substrate protonation facilitates the initial reduction step¹⁷ and thereafter enhances the electrophilicity of the resulting radical intermediate. However, heterocycles containing two nitrogens, such as 2-pyrazinyl and 4-pyrimidinyl, and three nitrogens, such as 2-triazinyl—which all lack a basic nitrogen—also react with good efficiency and excellent enantioselectivity (68–78%, 87–91% ee, entries 7–9).¹⁸

Table 3.

Asymmetric Aldehyde α-Benzylation: Bromide Scope

entry	producta	yield, eeb	entry	producta	yield, eeb
1		76% yield 93% ee	6		90% yielde 82% ee
2		83% yield 90% ee	7		73% yieldf 90% ee
3		74%yieldc 90% ee	8		78% yield 87% ee
4		74% yieldd 90% ee	9		68% yieldg 91% ee
5		75%yielde 91% ee	10		81% yielde,h 88% ee

^aStereochemistry assigned by chemical correlation or by analogy.

^bEnantiomeric excess determined by chiral SFC or HPLC.

^c30 mol% organocatalyst used.

^dPerformed at 15 °C using Ru(bpy)₃Cl₂ as the photoredox catalyst; ref 14.

^eSubstrate added as the hydrobromic acid salt with an additional equivalent of 2,6-lutidine. The free base organocatalyst was used.

^fYield determined by ¹H NMR.

^gIr(dF(CF₃)ppy)₂(dtbbpy)PF₆ was employed

as the photoredox catalyst; ref 15.

^hIsolated yield of the corresponding alcohol.

We fully expect that the α-heteroarylmethyl aldehyde products generated in this study will be of value for the generation and testing of medicinal agents. To highlight this possibility, we have applied our new catalytic enantioselective benzylation strategy to the synthesis of the angiogenesis inhibitor 12,¹⁹ a drug candidate that was developed for the treatment of diseases such as diabetic retinopathy and tumor proliferation. As illustrated above, exposure of propionaldehyde and 4-(bromomethyl)pyridine to our photoredox coupling protocol followed by in situ oxime formation yields the α-methylene pyridyl intermediate in 82% yield and 93% ee. Subsequent oxime reduction followed by urea coupling with amine 11 (available in two chemical steps) allows the rapid construction of angiogenesis inhibitor 12 in only three linear steps (34% overall yield, 93% ee).

In an effort to provide insight into the mechanistic details of this tandem catalysis coupling, we have performed several fluorescence quenching experiments (Stern–Volmer studies) with our fac-Ir(ppy)₃ photoredox catalyst (Figure 2). Notably, fac-*Ir(ppy)₃ oxidation of enamine 5 is not observed and, as such, cannot be the first step in the photocatalytic cycle (in contrast to previous studies from our laboratory that centered upon Ru(bpy)₃Cl₂).⁷ Instead, both aryl and heteroaryl methylene bromides display efficient quenching of the fac-*Ir(ppy)₃ excited state, strongly suggesting that the electron transfer event occurs directly between fac-*Ir(ppy)₃ and the aryl coupling partner. This is in accord with the catalytic cycle set out in Figure 1.

Figure 2.

Fluorescence quenching by reaction substrates.

In conclusion, the first enantioselective aldehyde α-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a novel imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst directly allows the stereocontrolled formation of homobenzylic stereogenicity in good to excellent yield. This new alkylation reaction, which exhibits broad scope and wide functional group tolerance, has been successfully utilized for the rapid and enantioselective construction of a previously developed angiogenesis inhibitor in only three linear chemical steps.