Letter pubs.acs.org/OrgLett
Single Reactant Replacement Approach of Passerini Reaction: OnePot Synthesis of β‑Acyloxyamides and Phthalides Yangyong Shen, Bo Huang, Linwei Zeng, and Sunliang Cui* Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China S Supporting Information *
ABSTRACT: The Passerini reaction is a classical and well-known multicomponent reaction for accessing α-acyloxy amides. A single reactant replacement (SRR) approach of Passerini reaction is described, which involves aldehydes, carboxylic acids, and ynamides to constitute a one-pot synthesis of β-acyloxy amides in a convergent manner. When this method was subject to intramolecular reaction, the process would produce phthalide products. The scalability was demonstrated, and a crossover reaction was conducted to elucidate a plausible mechanism.
T
Scheme 1. Single Reactant Replacement Approach in MCRs Design
he one-pot multicomponent reactions (MCRs) have been extensively developed as powerful tools for rapid assembly of complex and druglike molecules with the achievement of atom economy and molecular diversity and, therefore, are widely applied in drug discovery and natural products synthesis.1 Due to their value and utility, much effort has been devoted to the development of MCRs. Recently, the discovery and development of MCRs mainly relied on logicbased approaches, such as the single reactant replacement (SRR) approach which is first coined by Ganem.2 The SRR approach involves the replacement of one reactant with a different reactant which exhibits the same essential reactivity mode required for the MCR, thus representing an efficient way both to improve known MCRs and to design new routes toward bioactive molecules (Scheme 1A). For example, the Passerini three-component reaction for accessing α-acyloxy amides is one of the oldest and well-known MCRs (Scheme 1B).3 In recent decades, many innovative variations and asymmetric versions of this reaction have been uncovered by Wang, Zhu, Denmark, Dömling, Schreiber, and Tan.4 The first SRR approach of the Passerini reaction was probably the Ugi reaction, in which the carbonyl component was replaced with imines for leading to the formation of α-acylamino amides.5 This demonstrated that the SRR approach is indeed an efficient strategy and would continue to inspire the discovery of new MCRs. Ynamides display unique chemical profiles of intrinsic dual nucleophilic and electrophilic properties and, thus, have been widely explored as versatile synthons in organic synthesis.6 For example, the ynamides could convert to iminium ions in the presence of strong acids and metal catalysts and then undergo addition and cyclization for accessing heterocycles. Popik, Hsung, Evano, Liu, Ye, Sun, and many other groups have made great progress in this area.7 More recently, Zhao and coworkers revealed that ynamides could be used as racemizationfree coupling reagents for amide and peptide synthesis.8 These indicated the potential for the multiple reactivities of ynamides to serve as flexible building blocks in MCRs. © 2017 American Chemical Society
Recently, we reported a one-pot multicomponent synthesis of β-amino amides from aryl aldehydes and anilines, in which the ynamides acted as a two-carbon component.9a Continuing our investigations in MCRs and small molecules synthesis,9 we hypothesized that the ynamides were suitable to apply in the SRR approach of the Passerini reaction for discovering new MCRs. Herein, we report a new one-pot multicomponent reaction of aldehyde, carboxylic acids, and ynamides for facile synthesis of β-acyloxy amides and phthalides, with the feature of broad substrate scope and sufficient molecular diversity (Scheme 1C). Received: July 20, 2017 Published: August 16, 2017 4616
DOI: 10.1021/acs.orglett.7b02232 Org. Lett. 2017, 19, 4616−4619
Letter
Organic Letters We commenced our study by investigating benzaldehyde 1a, 4-nitrobenzoic acid 2a, and N-ethynyl-N,4-dimethylbenzenesulfonamide 3a. Initially we added these three reagents in DCM at the same time with a 20 mol % amount of BF3−Et2O as an additive and found complex product formation (Table 1, entry Table 1. Reaction Optimizations
entrya
solvent
catalystb
t (°C)
yield (%)c
d
DCM DCM THF CH3CN toluene DCM DCM DCM DCM DCM DCM DCM DCM DCM
BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O Ti(OEt)4 Mg(ClO4)2 Cu(OTf)2 Tf2NH BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O none
25 25 25 25 25 25 25 25 25 0 40 0 0 0
