Photoredox Activation and Anion Binding Catalysis in the Dual Catalytic Enantioselective Synthesis of β-Amino Esters

Abstract

The enantioselective oxidative C-H functionalization of tetrahydroisoquinoline derivatives is achieved through the merger of photoredox and asymmetric anion-binding catalysis. This combination of two distinct catalysis concepts introduces a potentially general approach to asymmetric transformations in oxidative photocatalysis.

Introduction

Photoredox catalysis has emerged recently as a powerful tool for organic synthesis.¹ Irradiation of photoactive catalysts with visible light can be parlayed to the practical generation of synthetically useful high-energy organic intermediates such as free radicals² and radical anions and cations.^3,4 Successful efforts to induce enantioselective catalytic control in such photocatalyzed processes have relied thus far on covalent organocatalysis: photoredox aminocatalysis as introduced by MacMillan,^2a,5 and the combination of photoredox catalysis with N-heterocyclic carbene catalysis as developed by Rovis.^6,7The main text of the article should appear here.

Since many reactions initiated by visible light photocatalysis involve the reductive generation of halide anions, ⁸ we considered whether the use of chiral anion-binding catalysts⁹ in combination with photocatalysis would provide opportunities for new types of enantioselective transformations^10,11 In one specific embodiment of this idea, we envisioned that iminium ion equivalents generated under mild conditions from tertiary amines by photocatalyzed oxidation¹² might be trapped in stereoselective nucleophilic addition reactions under the influence of a chiral H-bond donor catalyst (Figure 1). We describe here the successful development of a dual catalyst strategy for the enantioselective oxidative alkylation of tetrahydroisoquinolines with silyl ketene acetals.

Fig. 1.

Merger of photoredox and anion-binding catalysis in oxidative enatioselective C-H functionalization of amines

We chose to evaluate the proposed dual catalytic reaction design in enantioselective oxidative Mannich reactions to access tetrahydroisoquinoline derived β-amino esters such as 3a (Table 1).^13,14 In this context, we reported recently a photocatalytic method for the oxidative generation of iminium ion precursors from simple N-aryltetrahydroisoquinolines such as 1a using bromotrichloromethane as the stoichiometric oxidant.¹⁵,¹⁶,¹⁷ Coupling this protocol to an enantioselective thiourea-catalyzed addition of enolate equivalents such as silyl ketene acetal 2 would require identification of the appropriate photoredox and chiral thiourea catalysts, as well as reaction conditions suitable for both transformations.

Table 1.

Thiourea catalyst optimization

entry	thiourea catalyst	T (°C)a	[1a]o (M)	yield[%]b	ee[%]c
1	-	−78	0.1	0	N/A
2	4	−78	0.1	75	10
3	5a	−78	0.1	68	50
4	5b	−78	0.1	63	20
5	5c	−78	0.1	57	80
6	5d	−78	0.1	63	29
7	5c	−60	0.05	37	93
8	epi-5c d	−60	0.05	68	44
9	5e	−60	0.05	63	87
10	5f	−60	0.05	63	85
11	ent-5g	−60	0.05	72	−97

^aReaction temperature for the alkylation step in MTBE.

^bYields determined by ¹H NMR spectroscopic analysis of the crude reaction mixture relative to 2,5-dimethylfuran as the internal standard.

^cDetermined by HPLC on commercial chiral columns.

^dPyrrolodine configuration is (R), tert-leucine configuration is (S).

Results and Discussion

In initial experiments, the proper choice of solvent systems was revealed as a key challenge. In relatively polar media (CH₃CN, CH₂Cl₂, DMF), with CCl₄ as the stoichiometric oxidant, the oxidative photocatalytic Mannich reaction of N-phenyltetrahydroisoquinoline (1a) and silyl ketene acetal 2 afforded 3a cleanly in the presence of chiral thiourea catalysts, but always in racemic form. In contrast, unreacted tetrahydroisoquinoline 1a could be recovered from attempted oxidations in non-polar solvents such as MTBE, which are optimal for attaining high enantioselectivity in anion-binding thiourea catalysis. The failure of the photoredox reaction under these conditions could be ascribed simply to the lack of solubility of the photocatalyst, even when relatively non-polar complexes such as Ru(bpy)₃(PF₆)₂ were employed. Ultimately, the enantioselective oxidative Mannich reaction could be achieved by performing the photocatalytic oxidation in CH₃CN and switching solvents to MTBE for the thiourea-catalyzed alkylation reaction. In this manner, full conversion of 1a to the corresponding iminium ion in CH₃CN was observed after irradiation with blue LEDs for 16 hours using 2 equiv of CCl₄, and tetrahydroisoquinoline 3a was obtained in 50% ee upon alkylation with 2 in the presence of chiral thiourea 5a at −78 °C.

Enantioselective oxidative Mannich reactions of 1a and silyl ketene acetal 2 were evaluated with a variety of thiourea catalysts (Table 1). Only catalysts bearing both 3,5-bis(trifluoromethyl)aniline and tertiary amide components were found to promote useful reaction rates at −78 °C.¹⁸ Constrained arylpyrrolidine-derived thiourea catalysts of the general structure 5, which have proven effective in a wide range of enantioselective transformations,^19,20 induced significantly higher ee’s than catalysts bearing a less constrained tertiary amide fragment (e.g. 4). In that context, the relative configuration of the arylpyrrolidine unit relative to the tert-leucine component had a significant impact on reaction enantioselectivity (entries 7–8), pointing to the importance of the precise disposition of the aryl group relative to the thiourea anion-binding site. No straightforward correlation between the expanse of the α-aryl substituent on the pyrrolidine and reaction enantioselectivity was observed (Table 1, entries 3–6). In contrast, substitution on the ortho-position of the arylpyrrolidine resulted in significant improvements in enantioinduction, although the electronic properties of the substituent had little impact (entries 9–11). Further reaction optimization using catalyst 5c revealed a significant improvement in enantioselectivity when the reaction was conducted at −60 °C with an initial concentration of 0.05M (entries 5 and 7). After extensive evaluation of different arylpyrrolidine-derived analogs of 5, thiourea 5g was identified as an optimal catalyst for the model transformation of 1a to 3a.

During the course of the optimization studies outlined above, we observed that the identities of both the photocatalyst counterion and the halogen atom source had significant effects on enantioselectivity in the thiourea-catalyzed silyl ketene acetal addition reaction (Table 2). Consistently lower enantioselectivity was observed when using BrCCl₃ as the stoichiometric oxidant compared with CCl₄, a result that is attributable to more favorable interactions of the chloride-bound thiourea catalyst in the enantioselectivity-determining transition structure.²¹ When Ru(bpy)₃(PF₆)₂ was used as the photocatalyst in place of Ru(bpy)₃Cl₂ together with CCl₄ as the stoichiometric oxidant, highly variable enantioselectivities were obtained (e.g. 61–97% ee with catalyst 5g). This unpredictable behavior associated with the use of the Ru(bpy)₃(PF₆)₂ photocatalyst appears to be tied to the heterogeneous nature of the alkylation reaction mixture. Although only 2 mol % of PF₆⁻ is present in the reaction medium and the iminium ion intermediate is predominantly associated with chloride (Cl⁻/PF₆⁻ = ca. 51:1), the PF₆⁻ may impart enhanced solubility properties to the iminium ion, and thereby enable the racemic, background reaction to a greater extent.

Table 2.

Counterion effects

^aDetermined by HPLC on commercial chiral columns.

^bIsolated yield after purification by chromatography on silica gel.

^cDetermined by ¹H NMR spectroscopic analysis of the crude reaction mixture relative to 2,5-dimethylfuran as the internal standard.

^dRange of enantiomeric excess achieved over >10 runs.

With optimized conditions in hand we next explored the substrate scope of the reaction (Figure 2). The time required for full conversion of the N-aryltetrahydroisoquinoline derivatives 1 in the oxidation reaction was highly dependent on the electronic nature of the substrate, with electron-rich derivatives being more readily oxidized. To ensure complete conversion to the iminium ion, the amine was treated under the photochemical oxidation conditions for 16 h in all cases. The position of substituents on the N-aryl group influenced the enantioselectivity of the oxidative alkylation addition more profoundly than did their electronic properties. Thus, ortho-substituted substrates generally provided higher ee compared to para-substituted analogs (3l vs 3b; 3j vs 3d). In contrast, reaction enantioselectivities were very sensitive to the electronic nature substituents on the tetrahydroisoquinoline ring, with electron-rich systems generally affording lower ee’s and/or yields (e.g. 3e, 3h, 3i).

Fig. 3.

Substrate scope

In order to better establish the synthetic utility of this chiral tetrahydroisoquinoline synthetic methodology, we sought to develop a protocol for N-dearylation of the products to provide access to the more useful secondary amine derivatives.²² Electron-rich anilines have favorable redox properties that render them prone to N-aryl bond cleavage under oxidative conditions.²³ Accordingly, compound 3l, which was generated with nearly perfect enantioselection in the oxidative Mannich reaction, was chosen as a model substrate for dearylation studies. Application of standard oxidative protocols for PMP or PMB removal (CAN, PhI(TFA)₂, or DDQ) led to rapid consumption of 3l but low yields of the desired secondary amine due to product decomposition via over-oxidation. We anticipated that the use of an oxidant more closely matched to the oxidation potential of the substrate would have a better chance of avoiding decomposition of the relatively sensitive secondary amine product. Evaluation of Fe(III)-based oxidants led to the identification of [Fe(bpy)₃]³⁺, formed in situ upon treatment of [Fe(bpy)₃](PF₆)₂ with CAN,²⁴ as a highly effective oxidant for this transformation, leading to clean conversion to the desired amine 6. Comparison of the optical rotation of 6 with the reported value enabled the assignment of its absolute configuration. Acylation of 6 with acetyl chloride provided 7 (95% ee, 87% yield starting from 3l) with no significant compromise of enantiomeric purity.

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Conclusions

In summary, we have developed an approach to the oxidative, enantioselective C-H functionalization of tetrahydroisoquinoline derivatives. A mild method for the selective dearylation of products bearing N-o-anisyl groups was developed, thereby enabling further derivatization of the tetrahydroisoquinoline scaffold. Further applications of photoredox /chiral anion binding dual catalysis are anticipated and are the subject of current study.