Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Oxy-aminomethylation of Diazo Compounds with N,O‑Acetals Jianliang Yu,† Long Chen,† and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P.R. China
Org. Lett. Downloaded from pubs.acs.org by WEBSTER UNIV on 02/28/19. For personal use only.
S Supporting Information *
ABSTRACT: A novel oxy-aminomethylation reaction of diazo compounds has been developed, providing the α-hydroxy-β2-amino acid derivatives with quaternary carbon centers in moderate to excellent yields. Importantly, the readily available N,O-acetals have been employed as efficient bifunctionalization reagents to react with copper carbene intermediates, leading to the concurrent incorporation of an alkoxy and an iminium group into one molecule. Moreover, a water-involved three-component reaction occurs to deliver the free-hydroxy amino acid derivatives. β-Amino acids are key motifs found in numerous natural products and biologically active pharmaceuticals,1 and they are also key building blocks in organic synthesis, especially in preparing peptidic foldamers.2,3 Among various β-amino acids, the α-hydroxy-β2-amino acids, especially those containing a quaternary carbon center, are very hard to achieve. Although such types of amino acids have been widely used in drug molecules and leading compounds with diverse pharmaceutical activities (Figure 1),4 methods toward such compounds remain scarce. Thus, we decided to develop a novel protocol to accomplish their synthesis.
Scheme 1. Previous Reports and Our Strategy
Figure 1. Examples of α-hydroxy-β2-amino acid derivatives.
It is well-known that metal carbene species exhibit umpolung reactivity on the single carbon atom through ylide formation (reaction with a nucleophile) followed by exposure to an exogenous electrophile (Scheme 1a).5 Typically, this amphiphilic reactivity enables the possibility of incorporating two functional groups into one molecule with high atom economy.6 Recently, Huang and co-workers reported an elegant aminomethylation reaction to prepare α,β-diamino acid esters via palladium-catalyzed reaction of diazoacetates with tetrabenzylmethanediamine, in which the amine reagent split into both the nucleophilic and the electrophilic moieties in situ (Scheme 1b).7 Later, our group developed a gold-catalyzed formal [4 + 1]cycloaddition by using hexahydro-1,3,5-triazines as the amphiphilic reagents.8 Inspired by the former reports, and in © XXXX American Chemical Society
continuation with our ongoing research interest,9 we want to report the development of N,O-acetals as the amphiphilic reagents to react with diazo compounds to deliver the αhydroxy-β2-amino acid derivatives in good yields. It should be noted that, just recently, Xu co-workers reported an excellent asymmetric counteranion-directed aminomethylation to prepare chiral β-diamino acid esters, in which the N,O-acetals were employed as aminomethylation reagents in their strategy Received: January 17, 2019
A
DOI: 10.1021/acs.orglett.9b00203 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (Scheme 1c).10 Notably, different from previous reports on the use of N,O-acetals as single aminomethylation reagents,11 we herein employed these compounds as bifunctionalization reagents to incorporate concurrently an oxygen group and an aminomethylation group into one molecule. Initially, N,O-acetal 1a and diazoacetate 2a were selected as model substrates to optimize the reaction conditions (Table 1).
With the established optimal conditions in hand, we next started to investigate the scope of this oxy-aminomethylation reaction (Scheme 2). First, the scope of diazo compounds was Scheme 2. Substrate Scopea−c
Table 1. Optimization of the Reaction Conditionsa
entry
cat.
solvent
time (h)
yield of 3b (%)
yield of 4b (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c
(ArO)3PAuNTf2 BuXPhosAuCl CuCl Cu(OAc)2 Cu(MeCN)4PF6 CuOTf Cu(OTf)2 Rh2(OAc)4 Rh2(esp)2 AgOTf AgPF6 Sc(OTf)3 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene DCE MeCN THF dioxane DMSO DMSO
18 18 6 6 6 6 6 6 6 1 1 6 6 6 6 6 6 6 1.5
54 39
14 17
38 72 88 11 34 29 45 37 65 81
