Cobalt(III)-catalyzed cross-coupling of enamides with allyl acetates/maleimides

Abstract

Cp*Co(III)-catalyzed direct allylation of enamides has been accomplished with the exclusive formation of allylated Z-enamides with high efficiency. In addition, the employment of maleimides as the reaction partner under the same catalytic conditions provides a series of succinimide-substituted Z-enamides.

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The allyl moiety is among the most synthetically useful motifs in organic synthesis, and is easily functionalized by numerous methods. Consequently, methodological studies relating to it have attracted the attention of synthetic chemists for many years, and efficient approaches for incorporating the allyl group into a molecule are of great value.¹ In recent years, in terms of atom economy and efficiency, the direct allylation of inert C–H bonds under transition metal catalysis has drawn much attention, and various allylating reagents, such as allyl acetates,² carbonates,³ phosphates,⁴ allylic halides,⁵ allylic ethers,⁶ and allylic alcohols⁷ have been successfully exploited in direct coupling reactions with C(sp²)–H bonds under transition metal catalysis. Enamides are versatile building blocks and key precursors for catalytic asymmetric C–C bond forming processes.⁸ As important synthons, enamides have been studied as key coupling partners for vinyl C–H bond activation, and their arylation,⁹ alkenylation,¹⁰ alkylation,¹¹ alkynylation,¹² acylation,¹³ and acetoxylation¹⁴ have been demonstrated. Despite these indisputable advances, the highly selective allylation of enamides through direct vinyl C–H functionalization has not been realized.

The use of inexpensive earth-abundant first-row transition metals to perform established transition metal-catalyzed C–H functionalizations has recently gained significant attention because of their low cost, nontoxicity, and novel catalytic properties.¹⁵ Among them, high-valent Cp*Co(III) catalysts have been proven to be robust, powerful, and cheap metal catalysts for C–H activation by the groups of Kanai and Matsunaga,^7b,c,16 Ackermann,^2c,17 Glorius,^3b,18 Ellman,¹⁹ Chang,²⁰ Li,²¹ Cheng,²² and others.²³ Our group has been devoted to enlarging the application of cobalt catalysis in the field of C–H activation.²⁴ Considering the practical importance of enamides, we were attracted to exploring the reaction conditions for cobalt-catalyzed C–H allylation of enamides with readily available allyl acetate. In this context it is noteworthy that the reaction proceeds efficiently with high stereoselectivity to deliver the allylated enamides as absolute Z-isomers. Additionally, succinimide, a central pharmacophore of many pharmaceuticals,²⁵ could be easily installed into enamides under cobalt catalysis when maleimides were employed as the coupling partner (Table 1).

Table 1 Optimization of the reaction conditions^a

Entry	Additive	Solvent	Yield^b (%)
a Reactions were carried out using 1a (0.1 mmol), 2a (0.15 mmol), Cp*Co(CO)I2 (10 mol%), additive (20 mol%), solvent (1.0 mL), 90 °C, air, 10 h. b Isolated yield. c  2a (0.3 mmol). d  2a (0.45 mmol). e [Cp*RhCl2]2/AgOAc (5 mol%/10 mol%) was used as the catalyst. f Cp*Co(CO)I2 was not used.
1	AgOAc	CH3CN	NR
2	AgOAc	DCE	NR
3	AgOAc	PhMe	NR
4	AgOAc	Dioxane	NR
5	AgOAc	MeOH	NR
6	AgOAc	CF3CH2OH	40
7^c	AgOAc	CF3CH2OH	63
8^d	AgOAc	CF3CH2OH	73
9^d	KOAc	CF3CH2OH	45
10^d	Zn(OAc)2	CF3CH2OH	33
11^d	Cu(OAc)2	CF3CH2OH	56
12^d^,^e	AgOAc	CF3CH2OH	60
13^f	AgOAc	CF3CH2OH	NR
14	—	CF3CH2OH	Trace

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We initiated our optimization experiments with enamide 1a and allyl acetate (2a) as model substrates for the allylation reaction. It was found that solvents had a significant influence on the reaction. Common solvents that are widely used in C–H activation reactions, including DCE, PhMe, CH₃CN, dioxane and MeOH, were all ineffective (entries 1–5). To our delight, when the reaction was conducted in CF₃CH₂OH, the desired product was obtained in 40% yield (entry 6). Increasing the amount of allyl acetate (2a) was necessary to improve the yield, which may be attributed to the volatilization loss of the allyl acetate (2a) (entries 6–8). AgOAc gave the optimal result among the acetate salts screened (entries 8–11), providing 3aa in 73% yield. Other acetate salts such as KOAc, Zn(OAc)₂, and Cu(OAc)₂ were not as effective as AgOAc. Replacing Cp*Co(CO)I₂ with [Cp*RhCl₂]₂ afforded the product 3aa in a lower yield (entry 12), indicating that Cp*Co(III) had a better catalytic activity than Cp*Rh(III) in this transformation. No reaction was observed in the absence of the cobalt catalyst or AgOAc (entries 13 and 14).

With the set of optimized reaction conditions in hand, the scope of substrates in this reaction was explored as illustrated in Scheme 1. It was observed that the reaction efficiency was dependent on electronic effects. Enamides bearing electron-donating substituents, such as methyl (3ba), methoxyl (3ca), phenyl (3da), and meta-methyl (3ia), displayed good reactivity, providing the desired products in 65–86% yields. Comparably, enamides with electron-withdrawing groups, such as fluorine (3ea), chlorine (3fa), and bromine (3ga), showed better reactivity in this reaction to deliver the corresponding products in 85–93% yields. Steric effects also had a significant impact on the reaction. Enamides with substituents at the ortho position of the phenyl ring had poor reactivity, giving the products (3ha, 3ja) in 52–60% yields. Naphthyl enamides participated in the reaction smoothly to furnish the allylation products (3ka). Notably, heteroarene-substituted enamides (3la, 3ma) were also effective substrates, generating the allylation products in moderate yields. Using allyl acetate (2a) as the reaction partner, methyl 2-acetamidoacrylate (1n) could not be successfully transformed into the corresponding allylation product under the established reaction conditions. Fortunately, the allylation product (3na) was obtained in 80% yield when the allyl acetate (2a) was replaced by allyl methyl carbonate (2a′).

Scheme 1 Scope of substrates in the allylation reaction.^{a,b a}Reaction conditions: enamide 1 (0.1 mmol), allyl acetate 2 (0.45 mmol), Cp*Co(CO)I₂ (10 mol%), AgOAc (20 mol%), CF₃CH₂OH (1 mL), 90 °C, air, 10 h. ^bIsolated yields. ^cAllyl methyl carbonate 2a′ (0.2 mmol) was used as the allylation reagent. ^dEnamide 1a (1 mmol), allyl methyl carbonate 2a′ (1.5 mmol), Cp*Co(CO)I₂ (5 mol%), AgOAc (10 mol%), CF₃CH₂OH (3 mL), 90 °C, air, 24 h. ^e The amount of allylation reagent was 2 equiv.

Different allylation reagents were also investigated under the reaction conditions. The coupling of enamide 1a with allyl methyl carbonate (2a′) proceeded smoothly to give the product (3aa) in 63% yield. Interestingly, the desired product was obtained in higher yield when the reaction was performed on a 1 mmol scale with a lower catalyst loading. The introduction of a phenyl group into the α-position of the allyl acetate (2b) was unfavorable for the reaction, and the corresponding product (3ab) was isolated in low yield. The allylation reagents were not restricted to allyl acetates. The employment of 2-vinyloxirane (2c) as the coupling partner delivered a novel allylic alcohol-substituted enamide (3ac) in good yield. In particular, vinylcyclopropane (2d) was also an effective allylation reagent,^17c providing a ζ-amino acid precursor (3ad) in moderate yield. Cinnamyl acetate and allyl alcohol were unreactive in this transformation.

Encouraged by these results, we turned our attention to studying the coupling of enamides with maleimides, which are effective coupling partners to introduce the useful succinimide motif into biomolecules in organic synthesis.²⁶ To our delight, the enamide (1a) reacted with N-methyl maleimide (4a) smoothly under the established reaction conditions to afford the desired product (5aa) in 78% yield. The structure of 5aa was further confirmed by X-ray crystal analysis. Surprisingly, when Cp*Rh(III) was employed as the catalyst in this transformation, the desired product was obtained in trace amounts, implying the unique reactivity of the Cp*Co(III) catalyst. Enamides bearing different groups on the phenyl such as methyl, methoxyl, phenyl, fluoro, chloro, bromo, and meta-methyl were all well tolerated and provided the corresponding products (5ba–5ga, 5ia) in 42–91% yields. It was found that steric effects in the enamide seemingly exerted a negligible influence on the efficiency of the reaction. The reaction of an ortho-enamide (5ha) gave the product in 70% yield. A disubstituted enamide also showed high reactivity, providing the corresponding product (5ja) in 85% yield. Enamides bearing naphthalene and heteroarene groups (5ka–5ma) also provided good results. N-Vinylacetamide (1n) was sluggish in this reaction, giving the product (5na) in low yield. Interestingly, when methyl 2-acetamidoacrylate (1o) was employed as the substrate, a mixture (5oa/5oa′ = 1.4/1), including the olefin migration product (5oa′), was obtained in moderate yield. Cyclic enamides could not react with maleimides in this reaction (Scheme 2).

Scheme 2 Cobalt-catalyzed direct coupling of various enamides and maleimide.^{a,b a}Reaction conditions: enamide 1 (0.2 mmol), maleimide 4 (0.3 mmol), Cp*Co(CO)I₂ (10 mol%), AgOAc (20 mol%), CF₃CH₂OH (1 mL), 90 °C, air, 10 h. ^bIsolated yields. ^c[Cp*RhCl₂]₂ (5 mol%)/AgOAc (10 mol%) was used as the catalyst. ^dReactions were performed on a 0.5 mmol scale with Cp*Co(III) (5 mol%) and AgOAc (10 mol%). ^eDetermined by ¹H NMR.

To further evaluate the scope of this process, a range of maleimides were investigated under the optimal reaction conditions. The N-substituents of the maleimide had an obvious influence on the coupling reaction. The unprotected maleimide was tolerated to deliver the product (5ab) in 78% yield. Maleimides bearing different N-alkyl groups such as ethyl, benzyl, cyclohexyl, and t-butyl were all effective coupling partners, affording the final products in good to excellent yields (5ac–5af). However, when N-phenyl maleimide was employed as the substrate, the corresponding product (5ag) was isolated in moderate yield. Some common olefins such as butyl acrylate, styrene, benzoquinone and norbornene were ineffective substrates in this reaction.

Although electron-deficient butyl acrylate could not provide the alkylation product under the optimal conditions, it was found that the addition of copper oxide promoted the generation of the alkenylation product (6) (eqn (1)). Furthermore, the allene as a coupling partner was tested in this reaction and no desired product was detected under the established reaction conditions. To our delight, after 20 mol% Ag₂CO₃ was added to the reaction, a mixture of pyridine (7) and pyrrole (7′) was obtained in moderate yield (eqn (2)). The structure of 7 was further characterized by X-ray crystal analysis (see ESI†). In addition, the enamide 5aa was further transformed into a γ-amino acid derivative (8) in good yield with a Pd/C catalyst under a hydrogen atmosphere (eqn (3)).

Conclusions

In conclusion, we have developed an efficient cobalt(III)-catalyzed cross-coupling of enamides with allyl acetates/maleimides. This reaction proceeds efficiently under mild conditions and displays good functional group compatibility. Besides allyl acetates, 2-vinyloxirane and even vinylcyclopropane can also serve as allyl sources. Maleimides were also effective coupling partners to introduce the useful succinimide motif into enamides under the established conditions. Notably, Cp*Co(III) exhibited a better catalytic activity than Cp*Rh(III) in this transformation.

Acknowledgements

Funding from the Natural Science Foundation of China (No. 21272205, 21472165) and the Program for Zhejiang Leading Team of S&T Innovation (2011R50007) is acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra of compounds 3aa–3na, 3ab–3ad, 5aa–5oa, 5ab–5ag, 6, 7, 7′ and 8; X-ray crystal data for compounds 5aa and 7. CCDC 1486236 and 1492223. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00479b

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