By -toluenesulfonic acid

A solution of about 0.19 gram of p-toluenesulfonic acid monohydrate and 3.14 grams of crystalline cannabidiol in 100 cc. of dry benzene was refluxed for one and one-half hours. At the end of that time the alkaline beam test was negative. The benzene solution-was extracted twice with about 5% aqueous bicarbonate solution and twice with water. The benzene was then evaporated and the residue distilled under reduced pressure. Four fractions were collected. B.P. 169-172° (0.03 mm.), having essentially the same rotation, [a]29 D-264° to -270° 

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The first step in one synthesis of the antipsychotic dmg clozapine (37-5) involves UUman coupling of anthranUic acid (37-1) with 2,4-dichloronitrobenzene (30-1) to give the substituted anthranilate (37-2). The carboxyl group is then converted to the A-methylpiperazinamide (37-3) via a suitably activated intermediate as, for example, the imidazohde obtained by reaction with carbonyidiimidazole (CDl). The nitro group is then reduced to amine (37-4) by means of catalytic hydrogenation. Intramolecular Schiff base formation catalyzed by toluenesulfonic acid then completes the synthesis of clozapine (37-5) [38]. 

An unsuccessful attempt was next made to simplify the problem of purifying the product by using dioxane as the extracting solvent with only enough benzaldehyde for solvolysis. Finally, on the assumption that an acetal should be as effective in transacetalization as an aldehyde or ketone, the benzaldehyde was replaced by 2,2-dimethoxypropane. In several experiments the hydrogen chloride was replaced by -toluenesulfonic acid also, dimethyl sulfoxide was tried instead of dioxane. All these experiments are summarized in Table I, and they lead to the following conclusions ... 

The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation-dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product (Scheme 70) <2005TL6847>. 

Steroidal O-tetrahydropyran 2-yl derivatives. Ott et at prepared the O-tetra-hydropyran-2-yl derivative of testosterone by the reaction of testosterone with 2,3-dihydropyrane catalyzed by //-toluenesulfonic acid monohydrate. The reaction required three weeks and the yield was 59 %. Use of boron trifluoride etherate as catalyst raises the yield to 67% and lowers the reaction time to 10 hr.9... 

The oxygen in the enol form of the aldehyde attacks intramolecularly the epoxide, which is previously activated by protonation by / -toluenesulfonic acid. 

Although the acid-catalyzed side-reaction of EDOT to EDOT-dimers and -trimers,i induced by toluenesulfonic acid, is no dead end in the reaction route, because these intermediates are also leading to doped PEDOT at the end of the reaction (see Chapter 8), detrimental effects cannot be excluded and may be one of the reasons for improvements by the addition of bases. Additionally, catalytic effects on EDOT polymerization by protic acids— reducing pot life—are suppressed, and premature precipitation of doped PEDOT is diminished. 

Aqueous caprolactam is polymerized alone and in the presence of sebacic acid (S) or hexamethylenediamine (H).t After a 24-hr reaction time, the polymer is isolated and the end groups are analyzed by titrating the carboxyl groups with KOH in benzyl alcohol and the amino groups with p-toluenesulfonic acid in trifluoroethanol. The number of milliequivalents of carboxyl group per mole caprolactam converted to polymer, [A ], and the number of milliequivalents of amino groups per mole caprolactam converted to polymer, [B ], are given below for three different runs ... 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

Direct, acid catalyzed esterification of acryhc acid is the main route for the manufacture of higher alkyl esters. The most important higher alkyl acrylate is 2-ethyIhexyi acrylate prepared from the available 0x0 alcohol 2-ethyl-1-hexanol (see Alcohols, higher aliphatic). The most common catalysts are sulfuric or toluenesulfonic acid and sulfonic acid functional cation-exchange resins. Solvents are used as entraining agents for the removal of water of reaction. The product is washed with base to remove unreacted acryhc acid and catalyst and then purified by distillation. The esters are obtained in 80—90% yield and in exceUent purity. 

Polyhydric alcohol mercaptoalkanoate esters are prepared by reaction of the appropriate alcohols and thioester using -toluenesulfonic acid catalyst under nitrogen and subsequent heating (16,17). Organotin mercapto esters are similarly produced by reaction of the esters with dibutyltin oxide (18). Pentaerythritol can be oxidized to 2,2-bis(hydroxymethyl)hydracryhc acid [2831-90-5] C H qO, ... 

H2SnClg 6H20, CISO H + CH OH, CH COOH, as well as ben2ene-, naphthalene-, and -toluenesulfonic acids (44). Zinc chloride is probably the most frequentiy used catalyst. Its activity is sometimes increased by fusion with a small amount of aluminum chloride. In other instances, however, sufficient catalytic effect is obtained with a mineral acid alone. 

Isophorone usually contains 2—5% of the isomer P-isophorone [471-01-2] (3,5,5-trimethyl-3-cyclohexen-l-one). The term a-isophorone is sometimes used ia referring to the a,P-unsaturated ketone, whereas P-isophorone connotes the unconjugated derivative. P-lsophorone (bp 186°C) is lower boiling than isophorone and can be converted to isophorone by distilling at reduced pressure ia the presence of -toluenesulfonic acid (188). Isophorone can be converted to P-isophorone by treatment with adipic acid (189) or H on(Ill) acetylacetoate (190). P-lsophorone can also be prepared from 4-bromoisophorone by reduction with chromous acetate (191). P-lsophorone can be used as an iatermediate ia the synthesis of carotenoids (192). 

Mixtures of /V-alkylanilines can usually be separated by fractional distillation. Mixtures of the methyl or ethyl derivatives have also reportedly been separated by converting the V/-ethyl or the /V-methyl derivative to the nonvolatile salt with -toluenesulfonic acid (12) or phthaUc anhydride (13), followed by distillation. 

These precursors are prepared by reaction of fuming nitric acid in excess acetic anhydride at low temperatures with 2-furancarboxaldehyde [98-01-1] (furfural) or its diacetate (16) followed by treatment of an intermediate 2-acetoxy-2,5-dihydrofuran [63848-92-0] with pyridine (17). This process has been improved by the use of concentrated nitric acid (18,19), as well as catalytic amounts of phosphoms pentoxide, trichloride, and oxychloride (20), and sulfuric acid (21). Orthophosphoric acid, -toluenesulfonic acid, arsenic acid, boric acid, and stibonic acid, among others are useful additives for the nitration of furfural with acetyl nitrate. Hydrolysis of 5-nitro-2-furancarboxyaldehyde diacetate [92-55-7] with aqueous mineral acids provides the aldehyde which is suitable for use without additional purification. 

Toluenesulfonic Acid. Toluene reacts readily with fuming sulfuric acid to yield toluene—sulfonic acid. By proper control of conditions, /)i7n7-toluenesulfonic acid is obtained. The primary use is for conversion, by fusion with NaOH, to i ra-cresol. The resulting high purity i7n -cresol is then alkylated with isobutylene to produce 2 (i-dii-tert-huty -para-cmso (BHT), which is used as an antioxidant in foods, gasoline, and mbber. Mixed cresols can be obtained by alkylation of phenol and by isolation from certain petroleum and coal-tar process streams. 

The starting materials of the aldehyde method may be sulfonated. For example. Cl Acid Blue 9 [2650-18-2] Cl Food Blue 2 (Cl 42090), is manufactured by condensing a-(A/-ethylanilino)-y -toluenesulfonic acid with o-sulfobenzaldehyde. The leuco base is oxidized with sodium dichromate to the dye, which is usually isolated as the ammonium salt. In this case, the removal of the excess amine is not necessary. However, this color caimot be used in the food sector because separation of the chromium compounds from the dye is difficult. An alternative method which gives food-grade Cl Acid Blue 9 (14) and dispenses with the use of sodium dichromate employs oxidative electrolysis of the leuco base (49). 

Fig. 5. Direct red dyes, (a) Direct Red 81 described ia text (68) (b) Direct Red 2 (o-toLidiae coupled to two moles of naphthionic acid) (69) (c) Direct Red 23 (aniline coupled to 6,6 -ureylenebis-l-naplitliol-3-sulfonic acid with a second coupling with j aminoacetanilide) (70) and Direct Red 80 (2 mol 6-amino-3,4 -azobenzenedisulfonic acid coupled twice to 6,6 -ureylenebis-l-naphthol-3-sulfonic acid) (73). Direct Red 24 (4-aniino-y -toluenesulfonic acid coupled under acidic conditions to 6,6 -ureylenebis-l-naphthol-3-sulfonic acid followed by an alkaline coupling of o-anisidine) (71) (d) Direct Red 72 (Broenner s acid, ie, 6-artiino-2-naphthalenesulfonic acid coupled under acidic conditions to 6,6 -ureylenebis-l-naphthol-3-sulfonic acid followed by an...

ButylatedPhenols and Cresols. Butylated phenols and cresols, used primarily as oxidation inhibitors and chain terrninators, are manufactured by direct alkylation of the phenol using a wide variety of conditions and acid catalysts, including sulfuric acid, -toluenesulfonic acid, and sulfonic acid ion-exchange resins (110,111). By use of a small amount of catalyst and short residence times, the first-formed, ortho-alkylated products can be made to predominate. Eor the preparation of the 2,6-substituted products, aluminum phenoxides generated in situ from the phenol being alkylated are used as catalyst. Reaction conditions are controlled to minimise formation of the thermodynamically favored 4-substituted products (see Alkylphenols). The most commonly used is -/ fZ-butylphenol [98-54-4] for manufacture of phenoHc resins. The tert-huty group leaves only two rather than three active sites for condensation with formaldehyde and thus modifies the characteristics of the resin. 

Acrylic Esters. A procedure has been described for preparation of higher esters from methyl acrylate that illustrates the use of an acid catalyst together with the removal of one of the products by azeotropic distillation (112). Another procedure for the preparation of butyl acrylate, secondary alkyl acrylates, and hydroxyalkyl acrylates using -toluenesulfonic acid as a catalyst has been described (113). Alurninumisopropoxide catalyzes the reaction of amino alcohols with methyl acrylate and methyl methacrylate. A review of the synthesis of acryhc esters by transesterification is given in Reference 114 (see... 

Of the alkyl esters, methyl esters are the most useful because of their rapid hydrolysis. The acid is refluxed with one or two equivalents of methanol in excess alcohol-free chloroform (or dichloromethane) containing about O.lg of p-toluenesulfonic acid (as catalyst), using a Dean-Stark apparatus. (The water formed by the... 

Acetyl p-toluenesulfonate [26908-82-7] M 214.2, m 54-56°. The most likely impurity is p-toluenesulfonic acid (could be up to 10%). This can be removed by dissolving in dry Et20 and cooling until the anhydride crystallises out. It decomp on heating below -130° it gives the disulfonic anhydride and above -130° polymers are formed. It is used for cleaving ethers [Prep, IR, NMR Karger and Mazur J Org Chem 36 528, 532 1971]. 

Cinnamaldehyde dimethylacetal is prepared by the method used to prepare the corresponding diethylacetal. A mixture of 66.0 g. (0.5 mole) of Aldrich Chemical Company, Inc.), 100 g. (1.06 mole) of trimethyl orthoformate (Eastman Organic Chemicals), 450 ml. of anhydrous methanol (J. T. Baker Chemical Company), and 0.5 g. ofp-toluenesulfonic acid monohydrate (Fisher Scientific Company) is stirred at room temperature for 24 hours. At the end of this time the alcohol is removed with a rotary evaporator and the residue is distilled to give 81-83 g. (91-93%) of cinnamaldehyde dimethylacetal, b.p. 93—96° (0.2 mm.). 

Toluenesulfonic anhydride has been prepared from the acid by the use of thionyl chloride and phosphorus pentoxide. It has also been obtained by heating oxime -toluenesulfonates, by reaction of -toluenesulfonic acid with di- -tolylcarbodiimide, and by the interaction of methoxyacetylene and -toluenesul-fonic acid. ... 

The change of mechanism with tertiary alkyl esters is valuable in synthetic methodology because it permits certain esters to be hydrolyzed very selectively. The usual situation involves the use of t-butyl esters, which can be cleaved to carboxylic acids by action of acids such as p-toluenesulfonic acid or trifluoroacetic acid under anhydrous conditions where other esters are stable. 

Smid and coworkers have developed a straightforward and effective method for the synthesis of 4 -vinylbenzo-15-crown-5. In this method, 3,4-dihydroxybenzaldehyde is converted into the crown in the usual fashion and then the side chain is transformed by successive treatment with methylmagnesium bromide and then toluenesulfonic acid to effect dehydration. The overall yield is about 20%. 

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