Pyrans Knoevenagel reaction

The Knoevenagel reaction of aromatic and heteroaromatic aldehydes with cyanothioacetamides affords a-cyanothioacrylamides (126), which easily undergo thermal dimerization to 3,4-dihydro-2//-thio-pyrans (127). a-Keto-substituted acrylonitriles are synthesized by condensation of p-keto nitriles with aldehydes or ketones. - Benzoylacetonitrile self-condenses to afford (128), which can be transformed... 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

In a one-pot three-component reaction, aromatic aldehydes, malononitrile and 1,3-dicarbonyl compounds react to form 2-amino-5-carboxy-4-aryl-47/-pyran-3-carbonitriles 87. The reaction proceeds by an initial Knoevenagel condensation of malononitrile with the aromatic aldehyde to afford the 2-benzylidenemalononitrile intermediate 88. Michael addition of the activated methylene group forms the 1,5-dicarbonyl equivalent 89, which upon ring closure affords 477-pyrans (Scheme 29) <2004SL871, 1999H(51)1101 >. 

Radi M, Bernardo V, Bechi B et al (2009) Microwave-assisted organocatalytic multi-component Knoevenagel/hetero Diels-Alder reaction for the synthesis of 2, 3-dihydro-pyran[2, 3-c]pyrazoles. Tetrahedron Lett 50 6572-6575... 

Furaldehyde is a colourless, poisonous, water-soluble liquid, bp 162°C, which slowly turns brown in air. Like benzaldehyde, it undergoes the Cannizzaro reaction, the Perkin reaction, the Knoevenagel condensation and the acyloin condensation. The catalytic hydrogenation of 2-furaldehyde yields 2-(hydroxymethyl)oxolane 23 (tetrahydro-2-furfuryl alcohol). This compound undergoes a nucleophilic 1,2-rearrangement to give 3,4-dihydro-2/7-pyran 24 by the action of acid catalysts ... 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

In a review on the intramolecular DA reaction as a key step in tandem or sequential processes, versatile syntheses of tetrahydro-2H-pyrans, chro-mans, heterocycle-fused 2H-benzopyrans and related compounds were considered (14T2857). Although many examples of the synthetic methods of O- and S-6-membered heterocycles are based on the tandem use of the Knoevenagel condensation and a hDA reaction, a review described only domino reactions with Knoevenagel condensation as a step and without the DA step in the synthesis of several types of chromones and coumarins (14T551) and of only coumarins (14SC2756). 

Nanoparticulate ZnO was used as an efficient catalyst for the synthesis of cou-marins (84) by the reaction of o-hydroxy benzaldehydes (82) and 1,3-dicarbonyl compounds (83) via Knoevenagel condensation under microwaves and thermal conditions (Scheme 9.24) in moderate to excellent yields (Kumar et al. 2011). This protocol differs from the previous methods for the synthesis of coumarins (84) in terms of simplicity and effectiveness. The application of ZnO/MgO in ionic liquid [bmim] [BF4] was carried out successfully for the synthesis of 4//-pyrans (85) and coumarins (88) at ambient temperature via Knoevenagel condensation reaction of aldehydes (8) or 2-hydroxybenzaldehyde derivatives (86) with active methylene compounds (16, 43, 87) (Schemes 9.25 and 9.26) (Valizadeha and Azimib 2011). The method has several advantages in terms of mild reaction conditions, reusability of the catalyst, high yields of the products, and short reaction times. In comparison with methods mentioned in the literature for the synthesis of 4F(-pyrans (85) and coumarins (88), this protocol has better yield and eco-friendly advantages. 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

Yuan and coworkers have reported an enantioselective three-component domino Knoevenagel/Michael/cyclization sequence using 226, a 1,3-dicarbonyl compound 228, and malononitrile 227 catalyzed by cinchona alkaloid cupreine 229 (Scheme 6.32). The spirocychc oxindole pyrans 231 were obtained in high yields (85-99%) and enantioselectivi-ties (up to 96% ee) [63]. Inconveniently, the reaction requires high dilutions (0.1-0.005 M) resulting in a large amount of used solvents. Macaev and coworkers have used chiral catalyst (-)-(S)-brevicolline 230 for the obtainment of the same... 

Domino Knoevenagel/Hetero-Diels-Alder Reaction and Pyran Syntheses... 

The use of special enamines in the three-component Knoevenagel-Michael addition/cyclization sequence directly led to Af-alkyl- or Af-aryl-substituted 2-amino-4//-pyrans. Perumal et al. therefore applied catalytic amounts of piperidine in ethanol at ambient temperature to add ( )-Al-methyl-l-(methylthio)-2-nitroethenamine 49 to the previously formed Michael acceptor in a one-pot fashion (Scheme 13.16) [7]. This protocol provides the desired lV-methyl-2-amino-4//-pyrans 50/51 in good yields. The methylthio substituent serves as a good leaving group facilitating the cyclization subsequent to the Michael addition reaction by nucleophilic substitution. 

Dihydro-2H-pyrans and the KnoevenageU lEDHDA Reaction In 2006, Prajapati and Gohain reported the reaction of 1,3-dimethylbarbituric acid 61 with various aromatic aldehydes 62 and two types of vinyl ethers (ethyl vinyl ether 63 and 2,3-dihydrofuran) to give a racemic cis-ltrans-mijXme, of the corresponding Knoevenagel/ hetero-Diels-Alder products 64 (Scheme 13.19) [30]. In the case of 2,3-dihydrofuran as the dienophile, the product showed to be exclusively cis. 

In 2012, Rueping et al. reported the proline-mediated reaction of 1,3-diketones with aldehydes to provide 2-hydroxy-3,4-dihydro-2//-pyran derivatives in good to excellent yields [46]. The reaction mechanism involves a Knoevenagel-Michael addition sequence with subsequent hemiacetalization. The haniacetal was oxidized with TPAP/ NMO or PCC to give the corresponding lactones 96. An enantioselective variant utilizing stoichiometric amounts of an... 

A similar reaction was published by Song et al. in 2013 (Scheme 13.29) [47]. 2-Hydroxynaphthoquinone 75 was reacted with aromatic aldehydes 97 and ethyl 4,4,4-lrifluoro-3-oxobutanoate 98 catalyzed by a mixture of ammonium acetate and acetic acid (25mol% each). A Knoevenagel-Michael addition sequence was followed by hemiketal formation to give the desired product 99 in moderate to good yields. Dehydration of the product yielded the 4 f-pyran derivatives. 

A series of 2-amino-4 /-thiopyrans 268 has been synthesized by one-pot Knoevenagel condensation/Michael addition/cyclization of several p-oxodithioesters 265, active methylene compounds 267, and various aldehydes 266 (Scheme 13.62) [102], The products could be isolated in good to excellent yields (70-93%), after stirring for a few hours in refluxing dichloromethane. Analogous 4-spirothio-pyrans 272 have been prepared by Majumdar et al. [103]. These reactions were conducted without any catalyst in refluxing ethanol, and the products could also be isolated in excellent yields (89-99%). 

Keywords Aldehydes, malononitrile, C-H activated acids, urea, organocatalyst, ethanol-water (1 1), room temperature, tandem Knoevenagel-cyclocondensation, one-pot three-component reaction, chemoselectivity, functionalized 2-amino-3-cyano-4//-pyrans and pyran annulated heterocycles... 

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