Visible light photoredox catalysis: regioselective radical addition of aminoalkyl radicals to 2,3-allenoates

Abstract

The regioselective addition of α-aminoalkyl radicals to 2,3-allenoates by visible-light-mediated electron transfer using 1 mol% of Ru(bpy)₃(BF₄)₂ as a photocatalyst was successfully established. This photoredox protocol is a simple and effective method for the synthesis of unsaturated γ-aminobutyric ester derivatives.

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Allenes are a class of compounds containing the unique cumulative diene structural.¹ Affected by substituent groups and the chemical environment, the cumulated three-carbon atoms have different electron density distributions, which gives its distinctive reactivity. As versatile synthons, allenes have been widely used in synthetic chemistry.² Similar to olefins and other unsaturated hydrocarbons, allenes can participate in electrophilic addition, nucleophilic addition, and free radical addition reactions. In the reported radical additions of allenes, the in situ formed radical species can attack either the sp² hybridized carbon atom or the sp hybridized carbon atom, which generates a variety of isomer mixtures.³ Due to its low regioselectivity and poor controllability, the radical reactions of allene were less examined up to date. And at the same time, the reaction conditions and structure of substrates also have a strong impact on the selectivity. In general, carbon-centered radicals tend to attack its end sp² hybridized carbon atoms, while heteroatom-centered radicals tend to attack the sp hybridized carbon atom.

Recently visible-light photoredox catalysis has been paid much attention due to its particular characteristics.⁴ Compared with the traditional ionic and radical reactions, visible-light photoredox catalysis, which follows the “ion radical” reaction path, provides a new view for studying the reactions of allenes. According to visible light photoredox reaction path, it may proceed either by oxidative or by reductive quenching, and the in situ formed radicals have to lose or obtain an electron to complete the catalytic cycle.⁵ Compared with vinyl radical B and C, the allylic radical A is more easily oxidized or reduced. However, from the stability of the radical intermediates, A should be more stable than B and C. Therefore, we hypothesize that radical reaction of allenes may occur in the middle sp hybridized carbon atom under visible light photoredox catalysis (Scheme 1).

Scheme 1 Possible pathways of allenes under photoredox catalysis.

Generally, tertiary amines are popular electron donors which can readily undergo single-electron oxidation, and thus have been widely used in visible light catalysis.^6–8 There are two paths for the photoredox oxidation of tertiary amine, which give the reactive intermediates electrophilic iminium ion or nucleophilic α-aminoalkyl radical according to the reaction system. The routes of addition of various nucleophiles to iminium ion, for example Strecker reaction, Mannich reaction, aza-Henry reactions, etc. have been successfully realized and extensively studied.⁷ Comparatively the research of α-aminoalkyl radical is less investigated due to its easily oxidation to form the iminium ions,⁹ and currently electron-deficient olefins, isocyanates, azodicarboxylates, alkynes (intramolecular reaction) function as appropriate coupling partners.⁸ Recently we reported the photoredox coupling of tertiary amines with acrylate derivatives including Baylis–Hillman adducts under visible light irradiation (Scheme 2a).¹⁰ Based on the similarity of allenoates and electron-deficient olefins, the photoredox coupling reaction with tertiary amine, mediated by visible light photoredox, was examined (Scheme 2b).

Scheme 2 Visible-light photoredox synthesis of unsaturated γ-aminobutyric ester.

At first, the reaction of ethyl buta-2,3-dienoate (1a) with 1.2 equiv. of N,N-dimethylaniline (2a) was carried out (Table 1). When a solution of 1a and 2a in the presence of 1 mol% of Ru(bpy)₃(BF₄)₂ and 1 equiv. of NaOAc in N-methylpyrrolidone (NMP) was illuminated with a 45 W compact fluorescent lamp at room temperature for 24 h, ethyl 3-((methyl(phenyl)amino)methyl)but-3-enoate (3a) and (E)-ethyl 3-methyl-4-(methyl(phenyl)amino)but-2-enoate (4a) were obtained in 52% yield (entry 1, 3a/4a = 6.0/1). Next, the control experiment showed that no formation of 3a or 4a was observed in the absence of a photocatalyst or light (entries 2–3), and switch on-off experiment also revealed that the light was essential. Notably, without base the reaction afforded the products with diminished yield (entry 4). Examination of a range of photocatalysts showed Ru(bpy)₃(BF₄)₂ was the most effective catalyst (entries 5–9). Solvents affected the reaction greatly, and polar aprotic solvents facilitated the reaction (entries 10–12). The reaction was difficult to proceed in MeOH (entry 13). A survey of base demonstrated that K₂HPO₄·3H₂O was the best choice (entries 14–19). Curiously, the use of K₂HPO₄ gave the worse result than the one containing crystal water. However, the use of the mixture of NMP and H₂O as the solvent did not improve the yield (entry 20). Finally, 1 mol% of Ru(bpy)₃(BF₄)₂ as photocatalyst, K₂HPO₄·3H₂O as a base and NMP as a solvent were shown to be optimal to provide the isomer mixtures of 3a and 4a in 67% yield. The product of N,N-dimethylaniline coupling with the sp² hybridized carbon atom of ethyl buta-2,3-dienoate was not found in all of these reactions, indicating the high regioselectivity of the reaction.

Table 1 Oxidative coupling optimization of ethyl buta-2,3-dienoate with N,N-dimethylaniline^a

Entry	Cat.	Solvent	Base	Yield^b (%)	3a : 4a^c
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), photocatalyst (0.005 mmol), base (0.5 mmol), solvent (2 mL), 24 h, 45 W compact fluorescent lamp irradiation under N2 and room temperature until otherwise noted.b Isolated yield of 3a and 4a based on 1a.c the ratio of 3a : 4a was measured by GC.d In the dark.e 2 mL NMP and 2 mL H2O as the solvents.
1	Ru(bpy)3(BF4)2	NMP	NaOAc	52	6.0 : 1
2^d	Ru(bpy)3(BF4)2	NMP	NaOAc	0
3	—	NMP	NaOAc	0
4	Ru(bpy)3(BF4)2	NMP	—	35	6.7 : 1
5	Ru(bpy)3Cl2	NMP	NaOAc	42	5.6 : 1
6	Ru(phen)3(BF4)2	NMP	NaOAc	12	9.0 : 1
7	Ir(ppy)3	NMP	NaOAc	Trace
8	[Ir(ppy)2bpy]BF4	NMP	NaOAc	46	5.6 : 1
9	Eosin Y	NMP	NaOAc	Trace
10	Ru(bpy)3(BF4)2	DMSO	NaOAc	38	4.2 : 1
11	Ru(bpy)3(BF4)2	MeCN	NaOAc	27	2.8 : 1
12	Ru(bpy)3(BF4)2	DCM	NaOAc	31	3.0 : 1
13	Ru(bpy)3(BF4)2	MeOH	K2HPO4·3H2O	Trace
14	Ru(bpy)3(BF4)2	NMP	Cs2CO3	Trace
15	Ru(bpy)3(BF4)2	NMP	DABCO	Trace
16	Ru(bpy)3(BF4)2	NMP	2,6-Lutidine	28	1.3 : 1
17	Ru(bpy)3(BF4)2	NMP	NaF	27	3.5 : 1
18	Ru(bpy)3(BF4)2	NMP	K2HPO4·3H2O	67	5.9 : 1
19	Ru(bpy)3(BF4)2	NMP	K2HPO4	60	6.1 : 1
20^e	Ru(bpy)3(BF4)2	NMP/H2O	K2HPO4·3H2O	54	12.8 : 1

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Other reactions of a variety of 2,3-allenoates 1 and tertiary amines 2 were investigated under the optimized reaction conditions (Table 2). When the fourth position of 2,3-allenoates with substituent groups were reacted with N,N-dimethylaniline, only isomer 3 was obtained and the regional isomer 4 was not found. The reactions of 1b–1d bearing an aryl group at the 4-position proceeded smoothly to give the corresponding products (3b–3d) in moderate yields (entries 2–4). Ethyl penta-2,3-dienoate was also applicable to this reaction system, giving the product 3e in 47% isolated yield (entry 5). Due to the steric effect, 4,4-disubstituted 2,3-dienoates gave the desired products in low yield (entries 6–7). The yield of methyl ester was slightly lower than the yield of ethyl ester (entry 8). On the other hand, a variety of tertiary amines 2 was examined as well. When methyldiphenylamine 2b and N,N-diethylaniline 2c reacted with ethyl buta-2,3-dienoate 1a, it afforded the desired products 3i/4i and 3j/4j in low isolated yield (entries 9–10). N,N-Dimethylaniline with an electron-donating group on the benzene ring, afforded 3k/4k and 3l in reasonable yields (entries 11–12). The substrates with weak electron-withdrawing groups, such as F, Cl and Br, successfully afforded the desired products in moderate yields (entries 13–15). Cyclic amine N-phenylpyrrolidine (2i) was transformed into 3p in 12% yield (entry 16). However, aromatic tertiary amines with a strong electron-withdrawing group such as 4-(dimethylamino)benzonitrile and 4-dimethylaminopyridine deter the reaction. Unfortunately, aliphatic tertiary amines could not give the desired products.

Table 2 Scope of 2,3-allenoates and tertiary amines^a

Entry	R^1, R^2, R^3	R^4, R^5, R^6	Yield^b (%)
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), photocatalyst (0.005 mmol), K2HPO4·3H2O (0.5 mmol), NMP (2 mL), 24 h, 45 W compact fluorescent lamp irradiation under N2 and room temperature.b Isolated yield based on 1.c The configuration of E/Z was determined by NOESY spectra, please see ESI.d Only E configuration product was obtained.
1	H, H, Et (1a)	Ph, Me, H (2a)	67 (3a/4a = 85/15)
2	Ph, H, Et (1b)	2a	52 (3b), E/Z = 1/1^c
3	4-ClC6H4, H, Et (1c)	2a	33 (3c), E/Z = 1/1
4	4-MeOC6H4, H, Et (1d)	2a	40 (3d), E/Z = 1/1
5	Me, H, Et (1e)	2a	47 (3e), E/Z = 77/23
6	Ph, Ph, Et (1f)	2a	29 (3f)
7	Me, Me, Et (1g)	2a	32 (3g)
8	Me, Me, Me (1h)	2a	20 (3h)
9	1a	Ph, Ph, H (2b)	23 (3i/4i = 91/9)
10	1a	Ph, Et, Me (2c)	14 (3j/4j = 88/12)
11	1a	4-MeOC6H4, Me, H (2d)	38 (3k/4k = 95/5)
12	1b	4-MeC6H4, Me, H (2e)	41 (3l), E/Z = 48/52
13	1b	4-FC6H4, Me, H (2f)	38 (3m), E/Z = 51/49
14	1b	4-ClC6H4, Me, H (2g)	34 (3n), E/Z = 40/60
15	1b	4-BrC6H4, Me, H (2h)	38 (3o), E/Z = 46/54
16	1b	N-Phenylpyrrolidine (2i)	12 (3p)^d

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Based on experimental results and related literatures,⁹ a plausible mechanism is proposed in Scheme 3. First tertiary amine 2 is oxidized by visible light excited Ru*²⁺ to give amino radical cation 5 and Ru⁺. In the presence of base, 5 loses a proton to afford α-aminoalkyl radical 6, which undergoes nucleophilic radical addition to 2,3-allenoate 1 to form a new C–C bond and afford the alkyl radical 7. When R⁴ is hydrogen atom, a part of 7 can be converted into 8. Then, a single electron transfer from the Ru⁺ to the alkyl radical 7 and 8 completes the photoredox cycle and generates the corresponding alkyl anion 9 and 10. Subsequent protonation of 9 leads to the product 3, and the same with 10 to 4.

Scheme 3 Possible mechanism.

Conclusions

In summary, we have developed a new visible light driven photocatalytic C–C coupling between tertiary amines and 2,3-allenoates. It's an efficient method for the synthesis of unsaturated γ-aminobutyric ester derivatives. Further work is in progress to broaden the synthetic applicability of the α-aminoalkyl radicals in visible-light photoredox catalysis.

Acknowledgements

The authors are grateful acknowledge the Zhejiang Provincial Natural Science Foundation of China (no. LY15B020004) and National Basic Research Program of China (973 Program) (no. 2011CB710800).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data. See DOI: 10.1039/c5ra10491b

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