Article pubs.acs.org/joc
Regioselective Synthesis of 2,4,5-Trisubstituted Oxazoles and Ketene Aminals via Hydroamidation and Iodo-Imidation of Ynamides Rajendra K. Mallick, B. Prabagar, and Akhila K. Sahoo* School of Chemistry, University of Hyderabad, Hyderabad 500046, India S Supporting Information *
ABSTRACT: A novel and straightforward protocol is demonstrated for the synthesis of highly substituted oxazoles from readily accessible ynamides in the presence of ytterbium(III) trifluoromethanesulfonate [Yb(OTf)3], N-iodosuccinimide (NIS), and acetonitrile. Multiple oxazole skeletons in the aryl periphery are constructed in a single operation for the first time. The hydroamidation and iodo-imidation of ynamides to trisubstituted and tetrasubstituted ketene aminals is exemplified. An isotope labeling experiment is used to identify the oxygen source in this transformation. The reactions are scalable to the gram scale, testifying the robustness of the transformations.
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INTRODUCTION Ynamides, the nitrogen-substituted alkynes, have extensively been used in the conceptual development of novel synthetic transformations.1 The polarized triple bond of ynamide under Brønsted/Lewis acid catalysis coherently allows in situ formation of reactive keteniminium species (A). The trapping of the reactive keteniminium species with nucleophiles offers novel pathways for the construction of complex N-heterocycles.2 Eventually, the regioselective α-attack of the O- and Nbearing nucleophiles to the activated ynamide 1 directly accesses ketene N,O-/N,N-acetal (B/B′; Scheme 1).3 Thus,
(II), pyrrolidone (III), and cyclobutene-fused-azepine (IV) derivatives (Scheme 1).4 Intrigued by these results, we envisage the Lewis acidmediated regioselective attack of nitrile at the α-position of ynamide to yield a reactive nitrilium intermediate C, which eventually undergoes hydration to provide ketene-aminal 3 (Scheme 2a). Next, the intramolecular cyclization of keteneaminal 3 (formed in situ) in the presence of an activator possibly constructs the peripherally decorated and highly selective 4-amino-2,5-disubstituted oxazole (2) (Scheme 2a). This is possible when the nucleophilic β-position of the aminal becomes electrophilic (i.e., “β-umpolung”), which remains challenging. In this regard, NIS is found helpful; as it facilitates the intramolecular 5-endo-trig cyclization of the ketene aminal (3/D) with the pendant amide to yield oxazole 2 (Scheme 2a). As such, the Au(I)-catalyzed [2+2+1] annulation of a terminal alkyne, nitrile, and oxygen has been successfully used for the synthesis of 2,5-disubstituted oxazole.5 The fabrication of 2,4,5trisubstituted oxazoles from ynamides involving the Au(I)catalyzed [3+2] cycloaddition with nitrene transfer reagents is reliably deliberated (Scheme 2b); the transformation involves α-imino-β-Au-carbene making the β-position of ynamide electrophilic.6 The oxazole motifs are potential building blocks that are widely present in various natural products and bioactive molecules (Figure 1)7 and are useful in many synthetic transformations.8 Of course, a modular paradigm to build a highly substituted oxazole skeleton is exceedingly desirable.9,10 Despite the progress, we herein discussed the development of a modular synthetic protocol for 4-amino-2,5-disubstituted oxazole from readily accessible ynamides in the presence of a Yb(OTf)3 catalyst, NIS promoter, and H2O in acetonitrile
Scheme 1. Significance of Ketene N,O-/N,N-Acetal from Ynamides
the intramolecular cyclization and cycloisomerization of πtethered acetals fabricate diverse molecular scaffolds.3b We have recently showcased the use of ketene N,O- and N,N-acetal, obtained from yne-tethered-ynamides by the attack of ptoluenesulfonic acid, dimethyl sulfoxide, or amide moieties to construct dihydropyridine (I), benzo[f ]dihydroisoquinolone © 2017 American Chemical Society
Received: August 22, 2017 Published: September 18, 2017 10583
DOI: 10.1021/acs.joc.7b02124 J. Org. Chem. 2017, 82, 10583−10594
Article
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
Scheme 2. Previous Work and Current Hypothesis
entry 1 2b 3 4b 5c 6d 7 8 9 10e 11e 12f 13b 14 15 16 17g 18g 19b,g 20f 21f 22f
catalyst (20 mol %)
additive (equiv)
solvent (1.5 mL)
time (h)
yield (%) 2a/3a/4a
Cu(OTf)2 Sc(OTf)3 Yb(OTf)3 Fe(OTf)3 HOTf Yb(OTf)3
NIS (2.2) NIS (2.2) NIS (2.2) NIS (2.2) NIS (2.2) I2 (2.2) NIS (2.2) NBS (2.2) NCS (2.2) NIS (2.2) NIS (1.2) NIS (2.2)
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN ClCH2CH2Cl toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
8 8 8 8 8 8 8 8 8 8 8 8 8 18 18 18 8 8 8 8 8 8
38 (2a) 65 (2a) 88 (2a) 10 (2a) complex
Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3
4 Å MS NIS NIS NIS NIS NIS NIS
(2.2) (2.2) (2.2) (2.2) (1.2) (1.2)
31 (2a) complex complex 62 (2a)
