Condensation piperidine

Ethyl E7E -2,4-dienoutes.1 These diunsaturaled esters can be prepared by Knoevenagel condensation (piperidine catalyzed) of ethyl 2-phenylsulfinylacetate with aldehydes and thermolysis of the product in the presence of potassium carbonate (equation I). 

EDDA is the best catalyst for the condensation. Piperidine acetate gives side products. 

Ootonic acid may be prepared by condensing acetaldehyde with malonic acid in pyridine solution in the presence of a trace of piperidine (Doebner reaction see discussion following Section IV,123). 

Mix together in a 250 ml. flask carrying a reflux condenser and a calcium chloride drying tube 25 g. (32 ml.) of freshly-distilled acetaldehyde with a solution of 59-5 g. of dry, powdered malonic acid (Section 111,157) in 67 g. (68-5 ml.) of dry pyridine to which 0-5 ml. of piperidine has been added. Leave in an ice chest or refrigerator for 24 hours. Warm the mixture on a steam bath until the evolution of carbon dioxide ceases. Cool in ice, add 60 ml. of 1 1 sulphuric acid (by volume) and leave in the ice bath for 3-4 hours. Collect the crude crotonic acid (ca. 27 g.) which has separated by suction filtration. Extract the mother liquor with three 25 ml. portions of ether, dry the ethereal extract, and evaporate the ether the residual crude acid weighs 6 g. Recrystallise from light petroleum, b.p. 60-80° the yield of erude crotonic acid, m.p. 72°, is 20 g. 

Into a 500 nil. round-bottomed flask, provided with a double surface condenser, place 50 g. (63 ml.) of pure, dry acetone, 50 g. (47 ml.) of ethyl cyanoacetate (Section 111,131) and 0 -5 g. of piperidine. Allow to stand for 60 hours and heat on a water bath for 2 hours. Treat the cold reaction mixture with 100 ml. of ether, wash with dilute hydrochloric acid, then with water, and dry over anhydrous sodium or magnesium sulphate. Distil under diminished pressure and collect the ethyl fsopropylidene cyanoacetate (ethyl a-cyano-pp-dimethylacrylate) at 114-116°/14mm.(l). The yield is 39 g. 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

An alkyi group occupying the 4-position of the thiazole ring may condense if the 5-position is substituted. 2-Acetamido-4-methy]-5-nitrothiazole (80) and p-cyanobenzaldehyde when refluxed with small amounts of piperidine yield the 4-styryl derivative (81) (Scheme 57) (238, 239). 

Succinic esters condense with aldehydes and ketones in the presence of bases, eg, sodium alkoxide or piperidine, to form monoesters of alkybdenesuccinic acids, eg, condensation of diethyl succinate with acetone yields ethyl 2-isopropyhdenesuccinate (eq. 3). This reaction, known as Stobbe condensation, is specific for succinic esters and substituted succinic esters (98,99). 

Epoxy cross-linking is cataly2ed by TYZOR TPT and TYZOR TBT, alone or with piperidine, and by TYZOR TE. The soHd condensation product from 3 TPT 4 TEA (triethanolamine) has also been appHed to epoxy curing (490). Titanate curing is accelerated by selected phenoHc ethers and esters at 150°C the mixtures have along pot life at 50°C (491) (see Epoxyresins). 

A dry 1-1. three-necked round-bottomed flask is fitted in the center neck with a sweep-blade stirrer whose shaft passes through an airtight bearing (Note 1). One side neck is fitted with a condenser topped by a soda-lime drying tube, and the other is fitted with a solid stopper. In the flask are placed 75 ml. of piperidine (Note 2) and 15.6 g. (0.4 mole) of sodium amide (Note 3), and the mixture is heated at reflux (Note 4) for 15 minutes with good stirring. The mixture is cooled just below reflux temperature, and 46 g. (0.2 mole) of sodium -naphtha-lenesulfonate (Note 5) is added, followed by an additional 75 ml. of piperidine. The mixture is then heated at reflux for 12 hours with stirring. 

N-d-Nai)hthylpipcridine has been preimrcd l)y the condensation of /3-br<)monai)hthaleno or of /3-na])hthol with piperidine... 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Trifluoromethyl alkyl ketones also undergo directed aldol condensations under thermodynamic conditions in the presence of piperidine and acetic acid [2, d] Under these reaction conditions, the product suffers a facile dehydration to form the unsaturated trifluoromethyl ketones (equations 2 and 3)... 

The synthetic utility of enamines presupposes their general accessibility. In most cases, ketones are readily converted to enamines by condensation of the carbonyl compound with a secondary amine such as pyrrolidine, morpholine, or piperidine and azeotropic removal of water with a solvent such as benzene (3-19). 

The reactions of enamines with aldehydes (329,350) are noteworthy in that they provide a route to the monobenzylidene derivatives of five- to seven-membered eyclic ketones as well as a method for the formation of other a, 9-unsaturated carbonyl compounds, in fair to good yields. The condensation of benzaldehyde with enamines is also involved in the formation of 3,5-dibenzylpyridine from piperidine and benzaldehyde (191-193). 

According to the Friedlander method, the condensation of the readily available 2-aminoiiicotinic aldehyde (20a) (74JOC726) or its 6-phenyl derivative (20b) [66JCS(C)315] with nitroacetic acid (21) in boiling ethanol with piperidine as catalyst is another example of this method, which affords in fair yields the corresponding 3-nitro-l,8-naphthyridin-2(lFI)-ones (22a, 74%) and (22b, 47%), respectively [66JCS(C)315]. 

Aliphatic and aromatic aldehydes condensed with 2-amino-(62BRP898414), 5-amino- (80AJC1147), or 8-amino-l,2,4-triazolo[l,5-cjpyrimidines (68JOC530) to give the related Schiff bases. Treatment of the 2-amino-5-methyl-l,2,4-triazolo[l,5-c]quinazoline 11 with formaldehyde and piperidine in the presence of acetic acid gave the 2-hydroxymethyl-amino-5-(2-piperidinoethyl) derivative 172. Utilization of aromatic aldehydes and piperidine in this reaction gave the 2-arylideneamino-5-styryl derivatives 173 (68CB2106) (Scheme 67). 

Aminobutenones of Z-configuration having at least one hydrogen atom attached to the amino group (80MI1) condense with aldehydes (EtOH, piperidine acetate, 25°C, 12 h) in 2 1 ratio to form 1,4-dihydropyiidine derivatives 290 (50NKZ1061). 

Base catalyzed condensation of 2-azidobenzaldehyde 796 with cyano-carbanions in piperidine or NaOEt in ethanol afforded tetrazoloquinolines... 

Reaction of 2-oxo-2,3-dihydropyrido[l,2,3- /e]-l,4-benzoxazinium chloride (253) with 1 and 2 mol of the appropriate heterocyclic quaternary salt 254 in the presence of a few drops of piperidine gave mono and bis condensation products 255 and 256, respectively (98MI45). Similar reactions of 2-arylpyrido[l,2,3- /e]-l,4-benzoxazinium bromides and 254 [R = R =-(CH=CH)2-] yielded condensation products 257 (X = 0). 

Treatment of piperidine with nitrous acid affords the N-nitroso derivative (190) reduction gives the corresponding hydrazine (191). Condensation of this intermediate with the carbamate (192) obtained from p-toluenesulfonamide leads to the oral hypoglycemic agent tolazemide (193). In a similar vein, reaction of the hydrazine obtained by the same sequence from azepine (194) with the carbamate, 188, gives azepinamide (195). ... 

Conversion of m-bromobenzonitrile to the tetrazole and addition of the elements of acrylic acid gives 7S, starting material for the patented synthesis of the antiinflammatory agent, bropera-mole (76). The synthesis concludes by activation with thionyl chloride and a Schotten-Baumann condensation with piperidine. 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

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