Note Cite This: J. Org. Chem. 2018, 83, 14820−14826
pubs.acs.org/joc
Oxidative NHC Catalysis for the Generation of Imidoyl Azoliums: Synthesis of Benzoxazoles Atanu Patra,† Anjima James,† Tamal Kanti Das,† and Akkattu T. Biju*,‡ †
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
‡
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S Supporting Information *
ABSTRACT: N-Heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and aromatic aldehydes leading to the synthesis of 2arylbenzoxazoles under mild conditions is presented. The reaction proceeds via the generation of the aza-Breslow intermediates from imines and NHC, which under oxidative conditions form the key imidoyl azoliums and a subsequent intramolecular cyclization furnishes the product. The reaction tolerates a broad range of functional groups, and the products are formed in generally good yields.
O
Scheme 1. NHC-Catalyzed Generation of Acyl Azoliums and Imidoyl Azoliums
ne of the unconventional ways of forging carbon−carbon and carbon−heteroatom bonds and thereby constructing new or existing molecules is by using N-heterocyclic carbene (NHC) organocatalysis.1 The underlying principle behind many of these reactions is the remarkable ability of NHCs to reverse the normal mode of reactivity of electrophiles (the umpolung concept).2,3 In majority of cases, the electrophiles used are aldehydes, and the reactions proceed via the generation of nucleophilic Breslow intermediates (acyl anion equivalents).4 Two important transformations proceeding via the umpolung of aldehydes are the benzoin reaction and the Stetter reaction. Intriguingly, catalysis using this concept employing NHCs has been extended to the umpolung of Michael acceptors5 and aldimines.6,7 NHCs are also useful for catalyzing transformations, which proceed in the normal way without polarity reversal.8 One such intermediate is the activated carboxylate generated from suitably substituted aldehydes and NHCs, which can undergo redox esterification to furnish functionalized esters.9 In 2010, Studer and co-workers demonstrated the NHCcatalyzed oxidation of aldehydes to esters using the bisquinone oxidant developed by Kharasch and Joshi.10a,11 These reactions proceed via the initial generation of the Breslow intermediate from aldehyde and NHC followed by the two electron oxidation using bisquinone to form the key acyl azolium intermediate and a subsequent acylation to form the ester product (Scheme 1, eq 1). In the context of our interest in the NHC-catalyzed transformations in general12 and umpolung of aldimines triggered by NHCs in particular,6a,b we envisioned that aldimines could be converted into analogous imidoyl azoliums by the addition of NHC to imines followed by the two electron oxidation of the initially formed aza-Breslow intermediate (eq 2). Herein, we report the synthesis of 2arylbenzoxazoles by the NHC-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and © 2018 American Chemical Society
aromatic aldehydes proceeding under oxidative conditions. Notably, the benzoxazole moiety is found in various biologically active natural products and marketed drugs.13 Encouraged by our recent findings on NHC-catalyzed umpolung of imines,6a,b the present studies were initiated by treating aldimine 1a with the carbene generated from triazolium salt 3 using KOt-Bu under oxidative conditions using bisquinone 411 in DMF at 30 °C. Interestingly, under these conditions, the expected 2-aryl benzoxa-zole 2a was formed in 72% yield (Table 1, entry 1). The reactions performed using NHC generated from other commonly used triazolium salts 5−7 returned reduced yields of 2a (entries 2− 4).14 KOt-Bu was found to be the optimal base for this annulation as the reactions carried out using other organic and inorganic bases furnished low yields of 2a (entries 5−8). The Received: October 8, 2018 Published: October 29, 2018 14820
DOI: 10.1021/acs.joc.8b02598 J. Org. Chem. 2018, 83, 14820−14826
Note
The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa
entry
variation of standard conditionsa
yield of 2a (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13c,d 14c,d 15c,d 16c,d 17c 18c 19c
none 5 instead of 3 6 instead of 3 7 instead of 3 DBU instead of KOt-Bu DIPEA instead of KOt-Bu K2CO3 instead of KOt-Bu Cs2CO3 instead of KOt-Bu 1,4-dioxane instead of DMF toluene instead of DMF CH2Cl2 instead of DMF DMSO instead of DMF no 3 no 3 and KOt-Bu no 3 and KOt-Bu, run at 60 °C no 3 and 4 2.0 equiv of 4 instead of 1.5 equiv air as an oxidant 8 instead of 4
72 51 64
