Of 2- piperidine

It is now applied more widely to include malonic acid derivatives, such as diethyl monoethyl-malonate, ethyl cyanacetate, etc. Various amines may be used as catalysts, and usually the most effective is piperidine (hexahydro-pyridine) a mixture of piperidine and pyridine, or pyridine alone, is also often used. 

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. 

Dissolve 50 g. of piperonal and 75 g. of malonic acid in a mixture of 160 ml. of pyridine and 2-5 ml. of piperidine contained in a 500 ml. round-bottomed flask, and heat under reflux for 1 hour on a water bath. A rapid evolution of carbon dioxide takes place. Complete the reaction by boiling the solution for 5 minutes. Cool, pour into excess of water containing enough hydrochloric acid to combine with the pyridine, filter ofiFthe piperonylacrylic acid, wash with a little water, and dry. The yield is almost quantitative and the acid is practically pure. It may be recrystallised from glacial acetic acid m.p. 238°. 

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). 

With arylthioamides except for some nitrothiobenzamides (101), yields are usually higher than those obtained above, due to the increased stability of these amides under acidic conditions (3), Rj = Ph, yield 70 to 82% (264, 285, 336, 483, 578, 641). In this case, cyclizations are carried out several hours to reflux, in absolute alcohol, in the presence of melted sodium acetate and few drops of piperidine. 

When thioamides such as thiobenzamide are used directly, neither dioxane nor magnesium carbonate is necessary. Instead absolute alcohol with fused sodium acetate in the presence of piperidine is used (457). 

Piperidines. A significant use of piperidine (18) has been ia the manufacture of vulcanization accelerators, eg, thiuram disulfide [120-54-7] (115) (see Rubber chemicals). Mepiquat dichloride [24307-26-4] the dimethyl quaternary salt of (18), is used as a plant growth regulator for cotton (qv). Piperidine is used to make vasodilators such as dipyridamole [58-32-2] (116) and minoxidil [38304-91-5] (117), and diuretics such as etozoline [73-09-6] (118). 

Diaminoanthraquinone is an important intermediate for vat dyes and disperse dyes, and is prepared by oxidizing leuco-l,4-diaminoanthraquinone with nitrobenzene in the presence of piperidine. An improved process has been reported (45). 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

The use of piperidine starting materials for preparation of perhydro derivatives is also seen in the reaction of the ethoxymethyleneaminonitrile (119) with sodium hydrosulfide to give (120) (66AG(E)308). 

The succinimide derivative (234) can be used in peptide synthesis for conversion of amino acids into their succinimide esters (235 Scheme 41) (79CL1265). 3-Substituted mercapto-1,2-benzisothiazole 1,1-dioxides (236) have been recommended as an odourless means of storage of thiols. The latter are readily regenerated by the action of piperidine (81CL1457). 

Intramolecular Michael addition of acrylamides (149) in the presence of piperidine gives /3-lactams (65T449). The method requires that R must be a strongly electron withdrawing... 

Most heterocyclic anions may be considered to be derived by loss of a proton from a parent compound, which is therefore the conjugate acid. Such anions have at least one unshared pair of electrons at the anionic site. They are named by appending the suffix -ide , with elision of a terminal e (lUPAC recommendation RC-83.1.1), as in (190)-(193). The site may be specified by a locant placed immediately before the suffix, and so chosen as to be as low as possible consistent with the numbering of the skeleton of the parent compound. The locant may be omitted in order to designate an equilibrating mixture of positionally isomeric anions, which is what one usually obtains in practice. The anion of piperidine is often informally referred to as piperidide . 

A mixture of ethyl cyanoacetate (Note 1) (56.6 g., 0.5 mole), freshly distilled butyraldehyde (43.2 g., 0.6 mole), 1 g. of palladium on carbon (Note 2), and 80 ml. of glacial acetic acid is placed in a 500-ml. bottle suitable for attachment to a low-pressure reduction apparatus. A solution of piperidine (2.0 ml., 0.02 mole) in 20 ml. of glacial acetic acid is added, and the bottle is connected to the reduction apparatus. 

Many other amines are catalytic in their action. One of these, piperidine, has been in use since the early patents of Castan. 5-7 pts phr of piperidine are used to give a system with a pot life of about eight hours. A typical cure schedule is three hours at 100°C. Although it is a skin irritant it is still used for casting of larger masses than are possible with diethylenetriamine and diethylaminopropylamine. 

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. 

The results of more recent investigations by Blicke with Maxwell and with Kaplan covering a wide range of basic components and of acyl residues, do not lend themselves to a simple generalisation. The basic components were mainly dialkylamino-derivatives of aliphatic hydrocarbons from ethane to pentane, e.g.,. CHj. CHj. NMcj to. CHj. CMcj. CHj. NEtj, and similar but shorter series of derivatives of piperidine (CgHjoN), morpholine, e.g.,. CHj. CHj. NC HgO, and methylcj/clohexylamine... 

Delourme-Houd found that on conversion to quaternary derivatives the capacity of sparteine to intensify and prolong the hypertensive action of adrenaline was increased. Pratesi and Aitieri have investigated the sparteine-like activity of piperidine derivatives of the type, CjHioN. CHj. CHjX where X is NH, NMcj, NEtj, NMePh or a second... 

The striking effect of the catalyst is exemplified by the reaction of pregna-4, 16-diene-3,20-dione (10) with benzyl mercaptan. In the presence of piperidine only conjugate addition occurs to give (11) whereas with pyridine hydrochloride only the 3-benzyl thioenol ether (12) is formed. In the presence of p-toluenesulphonic acid both reactions take place to yield (13). 

Powdered potassium permanganate (94 mg) is added to an ice-cold, stirred solution of 0.1 g of the unsaturated nitrile in 3.5 ml of acetone containing 0.11 ml of piperidine. The reaction mixture is stirred at 0° for 1.5 hr, allowed to warm to room temperature (30 min) and then treated with 0.02 ml of acetic acid in 0.2 ml of acetone. After stirring at room temperature for an additional 1.5 hr the mixture is treated with chloroform, aqueous sodium bisulfite and sufficient 1 N sulfuric acid to reduce all of the manganese dioxide. 

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)... 

These base-sensitive protective groups were introduced from the chloroformate or azidoformate. They are more sensitive to base than is the Fmoc group. Cleavage times with 0.2 mL of piperidine to 0.1 mmole of urethane in 5 mL of CHCL at It occur as follows Climoc, <10 min Bimoc, <14 h Fmoc, 18 h. °... 

In the addition of piperidine to 3,4-quinolyne, the orienting effect of the nitrogen atom manifests itself in bringing the ratio of the 3- and 4-substituted derivatives formed to 49 51 (cf. 86), whereas the ratio is 69 31 in the case of 3,4-naphthalyne (cf. 87). 

The composite results of benzo-fusion on the rates and activation energies of ethoxylation and of piperidination are summarized in round numbers in Scheme VI to give a broad perspective. 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

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