Piperidinium acetate

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

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]. 

The intramolecular formal [3+3] cycloaddition reaction of l- [l-phenyl-2-(4-oxobut-2-enyloxy)ethyl]amino cyclo-hexen-3-one at 150°C in the presence of piperidinium acetate afforded /ra 3--l,4a-77-l-phenyl-l,2,4,4a,7,8,9,10-octahydro[l,4]oxazino[4,3- ]quinolin-7-one <2002JA10435>. At 85°C, the 6-(l-piperidnyl)-l,2,4,4a,5,6,7,8,9,10-dec-ahydro derivative formed, which could be converted into the l,2,4,4a,7,8,9,10-octahydro derivative by heating at 150 °C. Cyclization of iV-[(2-butyl-2-oxoethoxy)acetyl]-3,4-dimethoxyphenylethylamine on the action of TFA gave llb-butyl-1,3,4,6,7,1 lb-hexahydro[l,4]oxazino[3,4- ]isoquinolin-4-one <1997JOC2080>. 

We attempted the key intramolecular oxa-[3 + 3] annulation reaction of diketo-enal 8 under high-dilution conditions at room temperature using piperidinium acetate salt in THF. We were delighted upon the discovery of the formation of the desired... 

Ogawa and co-workers37 have reported the synthesis of 6,7-benzo-4,9-epoxy[ 11]-annulenone 60. Manganese dioxide oxidation of the bis(hydroxymethylene)benzo-xepin 57 gave the dialdehyde 58 which on condensation with dimethyl acetonedicarb-oxylate 23 in chloroform in presence of piperidinium acetate gave the diester 59. This on hydrolysis followed by decarboxylation gave the annulenone 60. The NMR spec-... 

As discussed in Section 7.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [33], For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. In general, enolization can be initiated with a variety of catalysts (for example, piperidine, piperidinium acetate, ethylenediamine diacetate), but for the microwave-assisted procedure piperidinium acetate was found to be the catalyst of choice, provided that the temperature was kept below 130 °C. At higher reaction temperatures, there is significant cleavage of material from the resin. 

GToh O 0 rvAA 1,2-dichlorobenzene 0 vs 0 1,2-dichlorobenzene piperidinium acetate... 

The formation of 1-aryl-l,3-diketones (381) from the reaction of the corresponding 1-aryl-1,5-diketones (379) with piperidinium acetate has been explained ° as outlined in Scheme 113 and involves a retroaldol-type reaction in intermediate... 

Putilova ES, Troitskii NA, Zlotin SG (2005) Reaction of aromatic aldehydes with beta-dicarbonyl compounds in a catalytic system piperidinium acetate - l-butyl-3-methylimida-zolium tetrafluoroborate ionic liquid. Russ Chem Bull 54 1233-1238... 

As seen in many of the above examples, acetic anhydride and zinc chloride each make effective condensation catalysts for the free bases, presumably by efficient coordination with the ring nitrogen. The quaternary salts condense readily in the presence of piperidine. Potassium hydroxide, methoxide or piperidinium acetate are suitable for condensations with 2- and 4-methylpyridine AAoxides. For example, the Claisen condensation is effective with these Af-oxides using ethoxide catalyst (Scheme 45) but the reaction fails with the parent picolines unless activated by nitro substitution (69JHC775). 

DBU, MeCN, rtthen reflux or piperidinium acetate, reflux... 

Pyridinophanes (96) can be constructed from bis-(/3-chlorovinyl ketonic) intermediates upon treatment with ammonia. Wolff-Kishner reduction of (96) gives the parent (3,5)pyridinophane (68HCA2027). Some /3-aminovinyl carbonyls have been condensed with cycloalkanones in the presence of triethylamine and piperidinium acetate to give the (2,3)pyridinophane series (97) (70TL3291). 

Transmetalation of the vinylmercurial derivative with n-BuLi, followed by reaction with 2-lithium thienylcyanocuprate and subsequent addition of BF3-OEt2 and 167, leads to lactone 168 in 86% yield. Cationic biscyclization of vinylsilane 168 with TiCL and Ti(Oi-Pr)4 (at a proportion of 5 1), followed by the cleavage of the remaining acetal (oxidization of the hydroxypropyl ether side chain and subsequent 15-elimination of piperidinium acetate) leads to secondary alcohol 169. 

This process represents a Knoevencigel condensation,3 a reaction in which a compound with an acidic methylene group, such as dimethyl malonate (8). condenses with a carbonyl compound like citronellal (9) to give an alkene. Reaction occurs in a weakly basic or neutral medium. Catalytic amounts of piperidinium acetate suffice to deprotonate malonic ester 8. The resulting anion 15 adds to the aldehyde citronellal (9) to give alkoxide 16. 

Keto-aldehyde 55 proved to be suitable for constructing the pentacycle 10.55 The iminium salt intermediate 56 was generated from 55 using 0.5-1.0 equiv of piperidinium acetate in the presence of Na2S04 at 80 °C for 1... 

Finally, we isolated hexacycle 79 from reaction of enal 77 with pyrone 12 using piperidinium acetate salt [Scheme 18]. Although hexacycle 79 was found as a minor product initially when the reaction was terminated in 2 h, the yield of 79 could be as high as 60-70% if the reaction time for was extended to 18-24 h. 

The first results which indicate that stereoelectronic effects play an important role in the aldol condensation were reported by Hajos and Parrish (6) who found that (a) triketone J8 cyclizes to the bicyclo[3.2.1]octane ketol on treatment with piperidinium acetate in water and (b) ketol 19 undergoes an epimerization at C-4 yielding the more stable isomeric ketol 20 on treatment with piperidine. The authors concluded that the formation of ketol 19 from 18 under kinetically controlled conditions is the result of... 

Intramolecular cyclization. Knoevenagel condensation of diphenylacetaldehyde with diethyl malonate (piperidinium acetate catalysis) results in only a trace of the expected product when molecular sieves are present, the a-naphthol 1 is formed in 52% yield.2 A similar reaction is observed with ethyl acetoacetate and ethyl benzoylacetate. 

Intramolecular aldo condensation.1 The opposite regioselectivity of this system (1) as compared to that of piperidinium acetate (1, 888-889) is also observed with dialdehydes of the general structure 2. 

Scheme 17. Domino hydroformylation-Knoevenagel condensation-hydrogenation. Reagents and conditions 1.1 Equiv. CH2EWG2, 1.2 equiv. piperidinium acetate, 0.7 mol% [Rh(CO)2acac], 2.8 mol%...

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