Piperidine as solvent

Ravish and Kirkiacharian (60) reported on a new and effective condensation procedure which employs a mixture of acetic acid and piperidine as solvents. This combination is known to possess mild acid as well as base-catalytic properties. 

Monosubstitution of acetylene itself is not easy. Therefore, trimethylsilyl-acetylene (297)[ 202-206] is used as a protected acetylene. The coupling reaction of trimethylsilylacetylene (297) proceeds most efficiently in piperidine as a solvent[207]. After the coupling, the silyl group is removed by treatment with fluoride anion. Hexabromobenzene undergoes complete hexasubstitution with trimethylsilylacetylene to form hexaethynylbenzene (298) after desilylation in total yield of 28% for the six reactions[208,209]. The product was converted into tris(benzocyclobutadieno)benzene (299). Similarly, hexabutadiynylben-zene was prepared[210j. 

Both piperidine (18) and AZ-formylpiperidine [2591-86-8] are used as solvents. /V-Formylpiperidine is a dipolar, aprotic solvent that has considerably better hydrocarbon solubiUty than other dipolar, aprotic solvents having form amide or acetamide functionahty. 

To the cooled reaction mixture, 200 ml. of water is added carefully with stirring. Potassium carbonate is added with continued stirring until the water layer is saturated the mixture is now transferred to a separatory funnel and extracted three times with 60-ml. portions of ether. The combined ether extracts are dried over solid sodium hydroxide and are then transferred to a simple distillation apparatus. Distillation is commenced with a steam bath as source of heat when most of the ether has been removed, the steam bath is replaced by a flame. Distillation is continued until most of the piperidine (b.p. 106°) has been removed. The cooled residue in the distillation flask is recrystallized from petroleum ether (boiling range 30-60°) with the use of charcoal. There is obtained 30.0 g. (71%) of N-/3-naphthyl-piperidine as tan crystals, m.p. 52-56°. An additional recrystallization from the same solvent gives crystals, m.p. 56-58°, with about 10% loss in weight (Note 6). 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

This approach may find application in peptide bond formation that would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine as has been demonstrated recently for the deprotection of N-boc groups (Scheme 6.7) a solvent-free deprotection of N-tert-butoxycarbonyl group occurs upon exposure to microwave irradiation in the presence of neutral alumina doped with aluminum chloride (Scheme 6.7) [41]. 

Starting from glyoxal monohydrazones and active methylene compounds, N-anilino-pyrroles were prepared under solvent-free conditions by use of piperidine as catalyst [79] (Scheme 8.55). 

The thermochemistry of the ligand replacement reaction 10.10, where pip indicates piperidine, was investigated by Adamson s group, using cyclohexane as solvent [183]. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Iron(II) bis(acetylacetonate) has been prepared by reaction of iron(II) sulfate in aqueous solution with 2,4-pentanedione in the presence of bases such as pyridine and ammonia1 and by reaction of iron (II) chloride tetrahydrate in aqueous solution with the stoichiometric amounts of 2,4-pentanedione and piperidine.2 Neither publication reports yields and the lack of complete experimental details makes duplication difficult. The following procedure is a modification of that reported by Buckingham et al.2 and employs either anhydrous iron(II) chloride or the corresponding adduct with THF. The reaction is carried out in diethyl ether as solvent instead of water. 

This kind of comparison has been made only for the diastereoselective version of this reaction.13 Water was still used as solvent for the conversion of phenylacetylene, 2-benzyloxyheptanal, and piperidine (Scheme 12.3), but the reaction temperature was lowered to 60°C, room temperature, or even 0°C. As shown in Table 12.1, neither with copper halides (entry 1) nor with silver halides (entry 2) could any satisfactory results be obtained. Only gold halides were still reactive enough at these temperatures. With AuCl at 60°C, the diastereomeric ratio (dr) was still low (entry 3) lowering the temperature to room temperature led to a slight increase of the dr (entry 4) and going to 0°C further increased the dr, but at the same time diminished the yield. With Aul at room temperature (entry 5) and 0°C (entry 6), only marginally better results were obtained. 

It is known that an aroylacetylene undergoes cyclotrimerization in the presence of diethylamine or when refluxed in DMF [101-103]. Supposedly, a small amount of DMF solvent has decomposed at the high temperature (i.e., the boiling point of DMF) to release dimethylamine, which served as the catalytic species [103]. Our attempted polymerization carried out in the presence of diethylamine, however, produced polymers in very low yields (7-21%) [105]. Good to excellent polymer yields were achieved when the bis(aroylacetylene)s were refluxed in DMF/tetralin mixtures for 72 h. Our attempts to shorten the reaction time and to increase the polymer yield by using diphenylamine as the catalyst failed. Use of piperidine as the cata-... 

However, when bis[l -naphthoyl] tellurium was reacted with piperidine at 25° in the dark with dry toluene as solvent, only tellurium and 1 -naphthoyl piperidide were isolated. When this reaction was carried out in the presence of 4-bromobenzoylmethyl bromide, 4-bromoacetophenone, 1-naphthoyl piperidide, and tellurium were obtained1. 

Nonapeptides are constructed using DCC and N-hydroxybenzodiazole, this method is also used in the synthesis of prothimosin o (pro Ta), a polypeptide consisting of 109 amino acids. In the latter reaction the coupling is conducted using DMSO as solvent. Similarly, glycoproteins are synthesized, but in this case piperidine/DMF is used as solvent. " The synthesis of cyclosporin, a cyclopeptide formed from 11 amino acids also uses DCC in the formation of the heptapeptide intermediate. ... 

Addition of amines to carbonyl-activated diynes occurs with great ease, and often the initial adducts react further to give cyclic products. Syn addition occurs in the reaction of piperidine with l-phenyl-2,4-pentadiyne-l-one (151) in either ethanol or ether as solvent giving 152... 

Tsuda used zinc activated by method 1 above for reductive rearrangement of the steroid (1) to (2). Pyridine, piperidine, or dimethylformamide containing a little water can be used as solvent. 

The reaction of triarylsulfonium halides with piperidine, used as solvent, in the presence of potassium amide at 100-110°C afforded a mixture of the derived AT-arylpiperidine (25) in high yield, together with the diarylsulfide and/or arylthiol derived from the reagent by ligand exchange.39... 

Figure 4. Logarithm of the rate constant for quenching of 02( Ag) by piperidine as a function of solvent a-values. From [80] with permission. Copyright 1989, American Chemical Society.

The synthesis of 281 (X = CN) from the same reactants was achieved by ultrasonic irradiation without catalyst (03MI488, 04MI562), and under MW irradiation in the presence of sodium bromide or piperidine under solvent-free conditions (04TL8625, 01MI742) as well as heterogeneous amines grafted on silica such as N,N-diethylamino-propylated silica (06H889). 

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