Acyl chlorides formation with thionyl

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Mechanism of Acyl Chloride Formation with Thionyl Chloride... 

This method is usually used for producing small will nonetheless also catalyse acyl chloride amounts of valuable acyl chlorides—oxalyl chloride formation with thionyl chloride, though on a large... 

The common synthetic route3 to N,N-dimethylhomoveratrylamine involves acyl chloride formation from (3,4-dimethoxyphenyl)acetic acid with thionyl chloride (84%),7 followed by amide formation with dimethylamine (99%),8 and reduction with lithium aluminum hydride (71%).9 The procedure provides N.N-dimethylhomoveratrylamine in 59% overall yield, requires three steps and more expensive substrates and reagents. 

The HCl salt of A-butyl-iV-(cyclohexylethyl)amine (2 HC1) was synfiiesized firom commercially available cyclohexylacetic acid (11). Acid chloride formation using thionyl chloride in toluene with catalytic DMF was followed by amine acylation under Schotten-Baumann conditions to give the amide (8). After workup, the resulting toluene solution was azeotropically dried and the amide was reduced with BH3 SMe2. The crude reaction mixture was quenched with HCl in MeOH and the resulting salt was crystallized from toluene/MTBE. The salt was isolated in 80% yield for the 3 steps. 

Sahcyhc acid can be converted to sahcyloyl chloride [1441 -87-8] hy reaction with thionyl chloride in boiling ben2ene. The formation of acyl haUde may also extend to reaction with the phenoHc hydroxyl. The reaction with phosphoms tri- and pentachlorides is not restricted to the formation of the acid chloride. Further interaction of the phosphoms haUde and the phenoHc hydroxyl results in the formation of the phosphoric or phosphorous esters. 

Synthesis of the remaining half of the molecule starts with the formation of the monomethyl ether (9) from orcinol (8). The carbon atom that is to serve as the bridge is introduced as an aldehyde by formylation with zinc cyanide and hydrochloric acid (10). The phenol is then protected as the acetate. Successive oxidation and treatment with thionyl chloride affords the protected acid chloride (11). Acylation of the free phenol group in 7 by means of 11 affords the ester, 12. The ester is then rearranged by an ortho-Fries reaction (catalyzed by either titanium... 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

Another example has been provided by Ito et al., who described the use of methanofullerene derivatives as powerful and stable precursors for glycofullerenes.217 Their study was based on the use of [60]fullerenoacetyl chloride (227), obtained from the ferf-butyl [60]fullerenoacetate derivative 226, which had been prepared in 56% yield by treatment of corresponding stabilized sulfonium ylides 225 with C6o-218 Subsequent transformation with p-TsOH in toluene gave [60]full-erenoacetic acid, which was directly converted into the corresponding acyl chloride 227 by using thionyl chloride. Standard ester formation with methyl 2,3,4-tetra-O-benzyI -/<-d-gl ucopyranoside (228) and 4-(dimethylamino)pyridine (DMAP) afforded the desired hybrid derivative 229 in 66% yield. 

In one synthesis of this drug, L-proline (11-2) is acylated with the acid chloride (11-1) obtained from the addition of hydrogen chloride to the double bond in methacrylic acid followed by reaction with thionyl chloride to give amide (11-3) as a mixture of diastereomers. The pure 2S isomer is then isolated from the mixture by fractionation as the dicyclohexylamine salt. Treatment of that compound with ammonium hydrosulfide leads to the displacement of chlorine by a thiol group and the formation of captopril (11-4) [13]. 

The incorporation of complex side chains at the 7 position based on alkyloximes of 2-amino-thiazole-5-gyloxylamides has provided drugs with very wide antibacterial activity that extend to hitherto resistant species such as pseudomonas. The preparation of one of the simpler side chains involves, first, the formation of the methyl ether from the oxime obtained by the nitrosation of methyl acetoacetate. Chlorination of the product, for example with sulfuryl chloride, gives the intermediate (21-1). The aminothiazole ring is then formed by reaction of that with thiourea to give (21-2). The free acid (21-3) is obtained by saponification of the product. The protected acid chloride (21-5) is obtained by sequential acylation of the amino group with chloroacetyl chloride and then reaction with thionyl chloride. 

Thionyl chloride can be viewed as the di(acid chloride) of sulfurous acid. It is even more reactive than the acyl halide. Its reactivity, along with the formation of gaseous products (S02 and HC1), serves to drive the equilibrium to the acyl chloride. The mechanism for this reaction is shown in Figure 19.2. It is interesting to note that thionyl chlo-... 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

N-Acylsaccharins (13) possess a certain potential as acylating agents. They will acylate amines, but will react with water or alcohols only when acid or base is present.167 The method was used to acylate a-amino-penicillanic acid.170 Micheel162-165 has based a peptide (38) synthesis on the acyl transfer from 31 [Z = carbobenzoxy, obtained through reaction with DCC or with pseudosaccharin chloride (6) or with thionyl chloride and imidazole] to amino acids. Pseudosaccharin anhydride 323, lee js thg product of a condensation between 6 and 1, mostly from hydrolysis of 6. Formation of 32 tends to occur in nonprotic solvents with base catalysis, even when practical precautions are taken to exclude moisture. Water and protic solvents seem to shield the anion 19 and prevent attack on 6. 

Thionyl chloride forms a fairly stable primary adduct (15) with DMF, which has been isolated. On heating it decomposes to SO2 and NA -dimethylformamide chloride (equation 4). Treatment of the adduct (15) with carboxylic acids affords iminium salts (16 equation S) in which the carboxylic acid function is strongly activated, e.g. for amide formation. With imines -lactams are formed, sodium azide is converted to acyl azides. ... 

Treatment of alkanoic acids with thionyl chloride and a catalytic amount of pyridine causes oxidation at the a-methylene group and the formation of an a-chloro-a-(chlorosulphenyl)acyl chloride, RCHiQSCOCICOCl. This usually reacts further and when R contains a benzene ring, this may be attacked with consequent formation of a fused ring system.. Unsaturated aralkanoic acids behave similarly. Extension of this work to related compounds suggests that a concerted elimination-cyciization operates. 

Formation of acyl chloride by the reaction of carboxylic acid with thionyl chloride. 

Surface oxides on graphite undergo the reactions typical of carboxylic acids, phenols and alcohols. Methylation with diazomethane or dimethylsulfate, silanization of—OH groups by reaction with halosilanes, formation of acyl chlorides by reaction with thionyl chloride, further reactions of these acyl chlorides, neutralization of acidic surface groups with different bases, ion exchange and more special reactions are used to characterize surface oxides on carbon and to modify their properties for technical applications . 

Formation of acyi chiorides (Section 12.7) Thionyl chloride reacts with carboxylic acids to yield acyl chlorides. 

The mechanism is similar to that for the formation of chlorides from alcohols and thionyl chloride. The hydroxyl group is converted to a good leaving group by thionyl chloride, followed by a nucleophilic acyl substitution in which chloride is the nucleophile (compare with Sec. 7.10). Phosphorus pentachloride and other reagents can also be used to prepare acyl chlorides from carboxylic acids. 

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