Acid chlorides conversion

One example of an a -chloro acid chloride conversion to a diazetidinone has been reported (Scheme 74) (63JCS674). Similarly, oxalyl chloride and di-f-butylhydrazine give 1,2-di-f-butyl-l,2-diazetidine-3,4-dione which is moderately stable in absence of air. The corresponding diisopropyl is much less stable (67JOC2360). 

The conversion of aliphatic acids Into their acid chlorides is usually accomplished with —... 

Place 125 ml. of concentrated ammonia solution (sp. gr. 0-88) in a 600 ml. beaker and surround the latter with crushed ice. Stir the ammonia solution mechanically, and introduce the n-caproyl chloride slowly by means of a suitably supported separatory funnel with bent stem. The rate of addition must be adjusted so that no white fumes are lost. The amide separates immediately. Allow to stand in the ice water for 15 minutes after all the acid chloride has been introduced. Filter oflF the amide at the pump use the flltrate to assist the transfer of any amide remaining in the beaker to the Alter (2). Spread the amide on sheets of Alter or drying paper to dry in the air. The crude n-capro-amide (30 g.) has m.p. 98-99° and is sufficiently pure for conversion into the nitrile (Section 111,112) (3). Recrystallise a small quantity of the amide by dissolving it in the minimum volume of hot water and allowing the solution to cool dry on filter paper in the air. Pure n-caproamide has m.p. 100°. 

Ethyl a-bromopropionate. This preparation illustrates the facile bromination of an acid chloride (propionyl chloride) in the presence of red phosphorus, and the subsequent conversion of the bromoacid chloride into the ethyl ester by direct interaction with ethanol. 

Uses. A principal use of thionyl chloride is in the conversion of acids to acid chlorides, which are employed in many syntheses of herbicides (qv), surfactants (qv), dmgs, vitamins (qv), and dyestuffs. Possible larger-scale appHcations are in the preparation of engineering thermoplastics of the polyarylate type made from iso- and terephthaloyl chlorides, which can be made from the corresponding acids plus thionyl chloride (186) (see Engineering plastics). 

Because of the presence of an extended polyene chain, the chemical and physical properties of the retinoids and carotenoids are dominated by this feature. Vitamin A and related substances are yellow compounds which are unstable in the presence of oxygen and light. This decay can be accelerated by heat and trace metals. Retinol is stable to base but is subject to acid-cataly2ed dehydration in the presence of dilute acids to yield anhydrovitamin A [1224-18-8] (16). Retro-vitamin A [16729-22-9] (17) is obtained by treatment of retinol in the presence of concentrated hydrobromic acid. In the case of retinoic acid and retinal, reisomerization is possible after conversion to appropriate derivatives such as the acid chloride or the hydroquinone adduct. Table 1 Hsts the physical properties of -carotene [7235-40-7] and vitamin A. 

Conversion of CA into cyanuric chloride [108-77-0] (C1CN)3 by PCl is another example of reaction at carbon (78). Cyanuric chloride as an imidoyl chloride reacts as an acid chloride, unlike chloroisocyanurates. 

Orotic acid undergoes 5-nitration, 5-bromination in hydrobromic acid with peroxide, 5,5-dibromination following decarboxylation in bromine water, esterification, methylation (rather complicated), conversion into its acid chloride (containing some anhydride) by treatment with thionyl chloride, and conversion into 2,6-dichloropyrimidine-4-carboxylic acid by phosphoryl chloride (62HC(16)422). 

The chemical inertness of the three-membered ring permitted many conversions of functional groups in diazirines. Esterifications, cleavage of esters and acetals, synthesis of acid chlorides, oxidation of hydroxy groups to carboxyl groups as well as Hofmann alkenation all left the three-membered ring intact (79AHC(24)63). 

Chlorophenylacetic acid has been prepared from mandeloni-trile and hydrochloric acid in a sealed tube, from mandelic acid and hydrochloric acid in a sealed tube/ from a-nitrostyrene and hydrochloric acid in a sealed tube, from phenylglycine, hydrochloric acid, and sodium nitrite, from mandelic acid and phosphorus pentachloride (to give the acid chloride which is then hydrolyzed), and, in poor yield, from mandelic acid and thionyl chloride. In the method described, ethyl mandelate is prepared according to Fischer and Speier. The conversion to the chloroester and the acid hydrolysis step are modifications of a preparation described by McKenzie and Barrow. ... 

Section 19.13 Among the reactions of carboxylic acids, their conversions to acyl chlorides, primary alcohols, and esters were introduced in earlier chapters and were reviewed in Table 19.5. 

From an acid chloride t-BuOH, AgCN, benzene, 20-80°, 60-100% yield.Alumina also promotes the conversion of an acid chloride to a t-Bu ester in 79-96% yield. ... 

This is one of the few methods available for the direct and efficient conversion of an acid, via the acid chloride, to an ortho ester. The preparation of the oxetane is straightforward, and a large number of oxetanes have been prepared [triol, (EtO)2CO, KOH]." In addition, the -butyl analogue has been used for the protection of acids. During the course of a borane reduction, the ortho ester was reduced to form a ketal. This was attributed to an intramolecular delivery of the hydride. ... 

The conversion of a nitrile R —CN into a ketone R —CO—R demonstrates that polarized multiple bonds other than C=0 also react with Grignard reagents, and that such reactions are synthetically useful. Esters 22 and acid chlorides can react subsequently with two equivalents of RMgX the initially formed tetravalent product from the first addition reaction can decompose to a ketone that is still reactive, and reacts with a second RMgX. The final product 23 then contains two substituents R, coming from the Grignard reagent ... 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

A related agent, g1 icetanile sodium (42), is made b / a variant of this process. Methyl phenyl acetate is reacted with chlorosulfonic acid to give 38, which itself readily reacts with aminopyrimidine derivative 39 to give sulfonamide Saponification to acid 4 is followed by conversion to the acid chloride and amide formation with 5-chloro-2-methoxyaniline to complete the synthesis of the hypoglycemic agent glicetanile (42). ... 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Phthalic anhydride is reacted with phenylacetic acid to form 3-benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d] cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(7-dimethylaminopropylidene)-5H-dibenzo[a,d] cycloheptene. 

Conversion of Carboxylic Acids into Acid Chlorides... 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

Conversion of Acid Halides into Esters Alcoholysis Acid chlorides react with alcohols to yield esters in a process analogous to their reaction with water to yield acids. In fact, this reaction is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HC1 formed. 

Conversion of Acid Halides into Amides Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride plus alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines (R3N). 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Conversion of Esters into Amides Aminolysis Esters react with ammonia and amines to yield amides. The reaction is not often used, however, because it s usually easier to start with an acid chloride (Section 21.4). 

Reactions of carboxylic acids (Section 21.3) (a) Conversion into acid chlorides... 

Curtius rearrangement (Section 24.6) The conversion of an acid chloride into an amine by reaction with azide ion, followed by heating with water. 

Calcium carbonate as support for palladium catalyst, 46, 90 Calcium hydride, 46, 58 D,L-Camphor, sulfonation to d,l-10-camphorsulfonic acid, 46,12 10-Camphorchlorosulfoxide, 46, 56 d,l-10-Camphorsulfonic acid, 46,12 conversion to acid chloride, 45,14 10-Camphorsulfonyl chloride, 45, 56 d,l-10-Camphorsulfonyl chloride,... 

Acid chloride 5 is readily available from the known benzylic alcohol 6,4e but intermediate 4 is still rather complex. It was recognized that compound 4 could conceivably be formed in one step from 2-methoxyfuran (9)10 and iodotriflate 10. The latter compound was designed with the expectation that it could be converted to benzyne 8," a highly reactive species that could be intercepted in an intermolecular Diels-Alder reaction with 2-methoxyfuran (9) to give 7. The intermediacy of 7 is expected to be brief, for it should undergo facile conversion to the aromatized isomer 4 either in situ or during workup. 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

A further variant of Method B is the acylation of a 2-aminobenzophenone with a protected a-amino acid chloride, followed by conversion of the product 11 into the 2-(aminoacet-amido)benzophenone 12 by reaction with hydrobromic acid in acetic acid.196... 

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

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