Copper-Catalyzed Amination of Vinyl Azides to α-Ketoamides

Abstract

An efficient approach for the amination of vinyl azides with N,N-dialkylacylamides has been developed. By using this protocol, structurally important α-ketoamides can be easily synthesized. The key to success is not only the introduction of a Cu(I)/oxygen catalytic system but also the utilization of t-BuOCl and benzoic acid as additives. The reaction is operationally simple, scalable, and displays broad scope and functional group tolerance. A possible mechanism involving copper-catalyzed oxidative generation of peroxide radicals is proposed.

Key words

amination - α-ketoamide - vinyl azide - copper-catalysis - N,N-dialkylacylamides

Vinyl azides are a class of unique functionalized alkenes with high intrinsic reactivity.[1] The numerous transformations of vinyl azides provide reliable synthetic approaches to diverse, structurally distinct molecular frameworks, including hetero/carbocycles,[2] amides,[3] ketones,[4] and 2H-azirines.[5] Recently, Wu and Liu[6] described an efficient and mild method for the synthesis of various α-fluoroketones from the corresponding vinyl azides by using Selectfluor^® as the fluorine source (Scheme [1a]). Additionally Chiba[7] and Liu,[4a] respectively, disclosed radical trifluoromethylation of vinyl azides with Me₃SiCF₃, to allow construction of α-trifluoromethyl azines, which could be further converted into α-trifluoromethyl ketones (Scheme [1b]). Bi and co-workers presented a radical-induced enamination of vinyl azides that proceeded with electron-withdrawing substrates, and a variety of β-functionalized primary enamines, including β-nitro, acyl, and sulfonyl derivatives, could be prepared, which were successfully transformed into a series of α-functionalized ketones (Scheme [1c]).[8] However, with respect to the construction of α-functionalized ketones, these methods usually suffer from disadvantages such as tedious multistep operations or harsh conditions. In a continuation of our efforts on the construction of C–N bond reactions,[9] we herein report a novel radical amination of vinyl azides using a copper catalyst, to afford a series of α-ketoamides (Scheme [1]). To our knowledge, this is the first example of the conversion of vinyl azides into α-ketoamides, which are important units in biologically active molecules, synthetic drugs, and drug candidates.[10]

Scheme 1 Transformations of vinyl azides

For the optimization of the reaction conditions, we carried out the reaction of vinyl azide 1a and N,N-dimethylformamide (DMF; 2a), as model substrates for the amination reaction, to screen different catalysts, solvents and additives (Table [1]). Firstly, when CuI was used as the catalyst in DMF as the solvent at 100 °C for 5 h under an oxygen atmosphere, the corresponding α-ketoamide 3a was obtained in 67% yield (entry 1). Using CuBr as the catalyst also gave a comparable yield under similar conditions (entry 2). Other metal catalysts, such as CuCl₂, NiCl₂, or Ag₂CO₃, gave either low yields or trace amounts of the desired product 3a (entries 3–5). Subsequent solvent screening demonstrated that DMF was the best choice; solvents, such as toluene, ethylene glycol, and nitromethane resulted in no desired product (entries 6–8). The use of additives, such as m-CPBA, TBHP or BPO, did not improve the efficiency of the reaction (entries 9–11). However, the addition of acids (HBF₄ or benzoic acid) did improve the efficiency of the reaction, affording 3a in 70% and 88% yields, respectively (entries 12 and 13). The reaction failed to occur in the absence of either the catalyst or additive (entries 14 and 15).

Table 1 Optimization of the Reaction Conditions^a

Entry	Catalyst	Solvent	Additive	Yield (%)b
1	CuI	DMF	t-BuOCl	67
2	CuBr	DMF	t-BuOCl	56
3	CuCl2	DMF	t-BuOCl	trace
4	NiCl2	DMF	t-BuOCl	19
5	Ag2CO3	DMF	t-BuOCl	20
6	CuI	toluene	t-BuOCl	0
7	CuI	EG	t-BuOCl	0
8	CuI	MeNO2	t-BuOCl	0
9	CuI	DMF	m-CPBA	26
10	CuI	DMF	TBHP	53
11	CuI	DMF	BPO	38
12	CuI	DMF	t-BuOCl + HBF4 c	70
13	CuI	DMF	t-BuOCl + PhCO2Hc	88
14	–	DMF	t-BuOCl + PhCO2Hc	0
15	CuI	DMF	–	0

^a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst (0.15 mmol), solvent (1.0 mL), additive (1.0 mmol), O₂ atmosphere, 100 °C, 5 h.

^b Isolated yield.

^c Acid (1.0 mmol).

With the optimized reaction conditions in hand (Table [1], entry 13), the generality of this α-ketoamide synthesis was examined by using a series of vinyl azides to react with DMF (Scheme [2]). α-Aryl-substituted vinyl azides were readily transformed into the corresponding α-ketoamides 3a–n in moderate to excellent yields. Electron-donating groups in the para-position of the aromatic ring were well tolerated, leading to the corresponding products 3a–e in good to excellent yields. Likewise, vinyl azides possessing aryl substituents bearing electron-withdrawing groups, such as -F, -Cl, -Br, -CHO, and -CO₂Me, afforded the desired α-ketoamides 3f–j in 79–90% yield. Note that vinyl azides bearing heteroaromatic substituents such as thienyl could be smoothly incorporated onto α-ketoamide 3k in 88% yield. Moreover, vinyl azide derivatives bearing a variety of substitutions in the meta-position of the aryl ring, including both electron-donating and electron-withdrawing groups, were well tolerated; thereby affording the functionalized α-ketoamides 3l–n in 69−87% yields.

Scheme 2 Substrate scope for the reaction of vinyl azides with DMF (used as both solvent and reactant)

To investigate the applicability of this protocol further, N,N-diethyl-α-ketoamide products 4a–f were prepared using vinyl azides 1 and N,N-diethylformamide (2b) as the substrates under the optimized conditions (Scheme [3]). Vinyl­ azides 1a–f with aromatic substituents, including aryl and heteroaryl groups, underwent the reaction smoothly to give the desired products 4a–f in 77−93% yield.

Scheme 3 Substrate scope for the reaction of vinyl azides with N,N-diethylformamide. Reaction conditions: 1 (0.5 mmol), 2 (1.0 mL), CuI (0.15 mmol), PhCO₂H (1.0 mmol), t-BuOCl (1.0 mmol), O₂ atmosphere, 100 °C, 5 h.

Encouraged by these results, we next turned our attention to other representative nitrogen sources (Table [2]). Indeed, not only DMF (2a) and N,N-diethylformamide (2b) but also N,N-dimethylacetamide (DMA) and N,N-dimethylpropylamide (DMP) were tolerated under the standard conditions, with the resultant α-ketoamide products being obtained in slightly lower yields (entries 1–4). In addition, the long chain N,N-dimethylbutylamide (DMB) was also examined, although no desired product was detected (entry 5).

Table 2 Substrate Scope for the Reaction of Vinyl Azides with N,N-Dimethyl Substrates^a

Entry	Substrate	Product		Yield (%)b
1			3a	51
2			3b	44
3			3g	55
4	DMPA		3a	20
5	DMB		3a	0

^a Reaction conditions: 1 (0.5 mmol), 2 (1.0 mL), CuI (0.15 mmol), PhCO₂H (1.0 mmol), t-BuOCl (1.0 mmol), O₂ atmosphere, 100 °C, 5 h.

^b Isolated yield.

To elucidate a plausible reaction mechanism for this transformation, some potential intermediates were prepared and tested under the standard conditions (Table [1], entry 13). Vinyl azide 1a′ did not afford benzamide 3a under the standard conditions (Scheme [4a]), although 3-phenyl-2H-azirine (1b′), N-(1-phenylvinyl)acetamide (1c′), and 2-chloro-1-phenylethan-1-one (1d′) all afforded 3a in good yields (Scheme [4b–d]). 2-(Diethylamino)-1-phenylethan-1-one (1e′) did not react under the standard conditions (Scheme [4e]),[11] nor did dimethylamine (2a′; Scheme [4f]). Interestingly, the addition of the radical scavengers 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or 2,6-di-tert-butyl-p-cresol (BHT) suppressed the reaction, which indicates that free radical intermediates could be involved in this transformation (Scheme [4g]). Notably, only 20% yield of 3a was observed under an argon atmosphere, suggesting that oxygen is required to oxidize the catalyst in preparation for another cycle (Scheme [4g]). These control experiments indicate that the vinyl azide substrate possibly reacts with the t-BuOCl as the electrophile and then undergoes oxidation catalyzed by the Cu/O₂ system.

Scheme 4 Control experiments

According to previous reports and considering the above results,[2e] [12] a possible mechanism for this amination reaction is proposed in Scheme [5]. Initially, the vinyl azide 1a undergoes thermal decomposition into a highly strained three-membered cyclic imine (2H-azirine A) that reacts with the Cu(I) catalyst and t-BuOCl to form Cu(II) imine B, which is then converted into Cu(II) imine C.[2e] [13] Radical intermediate E would be formed via Cu(III) peroxide radical D, which could be generated by a combination of molecular oxygen with Cu(II) imine C. Subsequent reductive elimination of radical intermediate E gives intermediate F and regenerates the active Cu(I) species. Finally, α-ketoamide 3a is obtained through acid hydrolysis of intermediate F.

Scheme 5 Proposed mechanism

The potential synthetic applicability of this method was investigated on a gram scale by using the model reaction. As shown in Scheme [6, 1].54 g of α-ketoamide 3a was isolated in 87% yield without any significant loss of efficiency, demonstrating the potential of this methodology for large-scale synthesis of α-ketoamide derivatives.

Scheme 6 Gram-scale experiment

In conclusion, we have developed a general and efficient method for the synthesis of α-ketoamides from vinyl azides with N,N-dialkylacylamide as the nitrogen source.[14] The key to success is not only the introduction of a Cu/O₂ catalytic system but also the use of t-BuOCl and benzoic acid as additives. This method features readily accessible substrates, commercially available and inexpensive reagents, and mild conditions. This mild catalytic reaction demonstrates a broad substrate scope and high functional group tolerance. A possible mechanism involving copper-catalyzed oxidative generation of peroxide radicals is proposed. The reaction can be effectively scaled up and the product conveniently obtained in a one-pot process. Efforts to further clarify the mechanism and to expand the application of vinyl azides are under way in our laboratory.

• References and Notes


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• 14 Synthesis of 4a; Typical Procedure: To a solution of α-azido styrene (1a; 72.5 mg, 0.5 mmol), tert-butyl hypochlorite (113.1 μL, 1.0 mmol), and benzoic acid (122.1 mg, 1.0 mmol) in N,N-diethylformamide (2b; 1 mL) at room temperature, CuI (28.6 mg, 0.15 mmol) was added. The reaction mixture was heated at 100 °C and stirred for 5 h under an oxygen atmosphere, when TLC analysis confirmed that substrate 1a had been consumed. The resulting reaction mixture was cooled to room temperature and K₂CO₃ was added. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic extracts were washed with brine (3 × 40 mL), dried over MgSO₄, filtered and concentrated. Purification of the crude product by flash column chromatography (silica gel; petroleum ether) afforded 4a (77% yield) as a yellow oil. N,N-Diethyl-2-oxo-2-phenylacetamide (4a): ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (d, J = 7.1 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 3.61–3.53 (m, 2 H), 3.29–3.20 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.16 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 191.5, 166.7, 134.5, 133.2, 129.6, 128.9, 42.0, 38.7, 14.0, 12.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₅NO₂: 206.1181; found: 206.1142.