Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal-Controlled, Regioselective, Direct Intermolecular α- or γ‑Amination with Azodicarboxylates Xin Fu,†,‡ He-Yuan Bai,‡ Guo-Dong Zhu,‡ Yan Huang,*,† and Shu-Yu Zhang*,‡ †
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China ‡ Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs & School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China S Supporting Information *
ABSTRACT: A metal-controlled, regioselective intermolecular amination of unsaturated N-acylpyrazoles with azodicarboxylates is described. Under zinc catalysis, the N-acylpyrazole substrates undergo amination at the α-position of the Nacylpyrazole moiety. Conversely, with silver as the catalyst, the reaction gave γ-amination products. Both catalytic protocols provided alternative, convenient, and simple strategies for efficiently and regioselectively accessing structurally unique C−N-bond containing compounds. The synthetic utility of this method was illustrated by a gram-scale experiment and subsequent efficient synthesis of the γ-amino acid analogue.
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difficult and sufficiently challenging.10 Herein, we report our investigation of a metal-controlled regioselective intermolecular α- or γ-amination of unsaturated N-acylpyrazoles11 with azodicarboxylates. These protocols provided an alternative, convenient, and simple strategy for efficiently and regioselectively accessing structurally unique α- or γ-C−N compounds. Our initial attempt involved the reaction of β, γ-unsaturated Nacylpyrazole 1a with DIAD (diisopropyl azodicarboxylate) 2a to test this C−N bond-forming reaction (Table 1). After an initial screening of metal catalysts, the feasibility of this reaction was confirmed. Desired γ-amination product 4a was isolated in 11% yield when 20 mol % Zn(OAc)2 was used as the catalyst. This reaction also produced α-amination product 3a in 21% yield (Table 1, entry 1, α/γ = 2/1). Interestingly, when 20 mol % of AgOAc was used as the catalyst, the amination reaction gave γamination product 4a in 22% yield and α-amination product 3a in 10% yield (Table 1, entry 2, α/γ = 1/2). These results suggests a potential method for selectively accessing α- or γ-amination products from N-acylpyrazoles, and the selectivity can be controlled by varying the metal catalyst. Based on this assumption, we surveyed a series of zinc catalysts and additives to promote the α-amination reaction (Table 1, entries 3−6). We were delighted to find that the conversion and α-C−N selectivity of the reaction could be notably improved when an organic base was used as the additive. A 72% isolated yield of 3a (α/γ > 14:1) was obtained under the optimized reaction conditions: Zn(OAc)2 (20 mol %) and DIPEA (20 mol %) at room temperature in TBME under air for 48 h (entry 4). To our surprise, in the silver-catalyzed system, the γ-selective
itrogen-containing molecules are very important and widely present in alkaloids, peptides, and pharmaceutical compounds. 1 The development of efficient and highly regioselective C−N bond-forming methods is an intensely investigated field and has been a focus of synthetic chemistry.2 While many classic transformations have been established for the formation of C−N bonds at the α-position of a carbonyl,3 the direct selective formation of remote C−N bonds remains a great challenge, and the development of such approaches is an attractive target in synthetic chemistry. In our ongoing efforts to develop efficient and selective C−N bond-forming methods and apply these techniques in the synthesis of natural products,4 azodicarboxylates have recently attracted our interest as a special amino source.5 In 2017, our laboratory reported the first example of a palladium-catalyzed, bidentate chelation-assisted, unactivated methylene-directed intermolecular C(sp3)−H β-amination protocol using azodicarboxylates as the amino source (Scheme 1a).4e This reaction provided a convenient and straightforward method for the efficient preparation of β-amino acid analogues. Encouraged by these results, we decided to investigate and develop an amination of more remote γ-positions with azodicarboxylates to access γamino acid analogues, which are common in a variety of alkaloids and biologically active pharmaceutical agents (Figure 1).6 Although azodicarboxylates have been exploited in various αamination reactions,7 use of azodicarboxylates as aminating reagents in γ-amination reactions is still very rare (Scheme 1b).5f,8 Among these reactions, the direct and selective amination of β,γ-unsaturated carbonyl compounds via a dienolate system is one of the most attractive synthetic approaches due to its high efficiency and atom-efficiency.9 However, controlling the regioselectivity of the α-adduct and γ-adduct proved to be © XXXX American Chemical Society
Received: April 13, 2018
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DOI: 10.1021/acs.orglett.8b01183 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Approaches for Regioselective Aminations with Azodicarboxylates
Table 1. Optimization of the Reaction Conditions for the Selective Intermolecular α- or γ-Amination with DIADa
yieldb (%) entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
cat. (0.2 equiv) Zn(OAc)2 AgOAc Zn(OAc)2 Zn(OAc)2 ZnBr2 Zn(OTf)2
AgOAc AgOAc AgOAc AgCOOCF3 Ag2SO4 AgF AgNO3
base (0.2 equiv)
3a
4a
TEA DIPEA DIPEA DIPEA TEA DIPEA DIPEA TEA TMG TMG TMG TMG TMG
21 10 59 72 39 14 16 21 5 4
