Brønsted Acid‐Catalyzed Synthesis of Pyrans via a Formal [3+3] Cycloaddition

Abstract

Brønsted acids catalyze the addition of enolizable b-keto esters to a,b-unsaturated aldehydes leading to substituted 2H-pyrans in good yields under mild conditions via a formal [3 + 3] cycloaddition.Keywords: cycloaddition; electrocyclic reactions; organocatalysis; oxygen heterocycles; a,b-unsaturated carbonyl compounds 1,3-Dicarbonyl derivatives constitute important synthetic intermediates as they incorporate electrophilic or nucleophilic functionalities.[1] Rodriguez and colleagues developed anionic methodologies based on the reactivity of stabilized carbanions for the stereoselective synthesis of bicycloA C H T U N G T R E N N U N G [3.2.1]octanols, [2a] arylidenecycloalkanones, [2b] cycloheptanols, [2c] and cyclooctane derivatives [2d] as well as functionalized cyclic enol ethers.[2e] These 1,3-dicarbonyl compounds, in the presence of a,b-unsaturated aldehydes, can also lead to pyrans and oxodecalins via a formal [3 + 3] cycloaddition (Scheme 1).[3] Such derivatives are common motives and are present in numerous natural products.[4] Elegant approaches to these intermediates, and their use in synthesis, were described by several groups using either a,b-unsaturated iminium salts as activated electrophiles, [5] Lewis acids as catalysts, [6] and tandem Stille-oxo-electrocyclization reaction. [7][8][9][10] Electrophilic activation by small-molecule chiral Hbond donors has emerged as an important tool for enantioselective catalysis, with new applications and developments appearing at a rapidly increasing pace.[11] Such organocatalysts do not contain any metals and, therefore, are advantageous from environmental perspectives. Compared to Lewis acid, they are less expensive, stable and moisture insensitive. Among the known carbonyl activators, Brønsted acids have recently demonstrated their potential to serve as active catalysts for a variety of synthetically useful reactions in organic chemistry. [12] We report here our preliminary results on the synthesis of pyran compounds by a cascade reaction involving diketones 2 and conjugated enals in the presence of a catalytic amount of a Brønsted acid under mild conditions. For this work, the phosphoric acids 4 and 5 were prepared following known procedures, [13] and isolated in good yields (69 % and quantitatively, respectively, Scheme 2). [14] 3,3-Dimethyl-1,5-cyclohexanedione 2a has been used as the starting material to synthesize substituted pyrans. A blank reaction carried out at room temperScheme 1. Scheme 2.

The [3 + 3]-Cycloaddition Alternative for Heterocycle Syntheses: Catalytically Generated Metalloenolcarbenes as Dipolar Adducts

“…11 In this pathway, a heteroatom (Z, mainly nitrogen, but also oxygen) activates 1,2-addition onto the iminium ion, and reversible β-elimination occurs to form a heterotriene that undergoes pericyclic rearrangement to form the formal [3 + 3]-cycloaddition product. Often the enamine (Z = NR 2 ) and the iminium ion are derived from the same unsaturated aldehyde or ketone.…”

Iodine-Catalyzed One-Pot Synthesis of 2H-Pyrans by Domino Knoevenagel/6π-Electrocylization

“…The best yield (94%) was obtained in refluxing methylene chloride for 24 h. Other solvents included in toluene (reflux, 24 h, 75%), DMF (100 o C, 24 h, 47%), and acetonitrile (reflux, 24 h, 40%). In this reaction, we found that iodine (94%) was the much superior catalyst for this cyclization than indium (III) chloride (53%), 5 phosphoric acid (73%), 8 and PPTS (59%). 8 The formation of 2 was readily confirmed by the observation of a carbonyl absorption of enone in the IR spectrum at 1651 cm -1 and the expected chemical shifts associated with two vinylic protons on 2H-pyranyl ring at 6.40 (10.0 Hz) and 5.24 (10.0 Hz) ppm in the 1 H NMR spectrum.…”

“…In this reaction, we found that iodine (94%) was the much superior catalyst for this cyclization than indium (III) chloride (53%), 5 phosphoric acid (73%), 8 and PPTS (59%). 8 The formation of 2 was readily confirmed by the observation of a carbonyl absorption of enone in the IR spectrum at 1651 cm -1 and the expected chemical shifts associated with two vinylic protons on 2H-pyranyl ring at 6.40 (10.0 Hz) and 5.24 (10.0 Hz) ppm in the 1 H NMR spectrum. Next, additional reactions of cyclic 1,3-dicarbonyls with 3-metyl-2-butenal and 1-cyclohexene-1-carboxaldehyde were attempted.…”

“…6 Later, novel approaches for the synthesis of 2H-pyrans were also developed by other groups using TiCl4, and In(OTf)3 Lewis acids as a catalyst 7 and phosphoric acid as a Brønsted acid catalyst. 8 Although several synthetic approaches for constructing 2H-pyrans derivatives have been reported by us 5,6 and other groups, 7,8 more simple and cost-effective approaches are still demand because of their importance.…”

Efficient synthesis of tetrahydroquinolinones by acetic acid-mediated formal [3+3] cycloaddition

“…Later, novel approaches were also designed by other groups using BF 3 ÁEt 2 O, TiCl 4 , and In(OTf) 3 Lewis acids as catalysts [13], phosphoric acids as Brønsted acid catalysts [14], and EDDA/ZnCl 2 as co-catalysts [15].…”