Thionyl chloride with amides

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

Introduction of the C2 sulfonamide is accomplished via sulfonylation with chlorosulfonic acid, conversion to the sulfonyl chloride using thionyl chloride, and amidation using concentrated ammonium hydroxide in tetrahydrofuran. Reduction of the 4-acetamido compound using borane-tetrahydrofuran complex provides the 4-ethylamino derivative. The 45,65-frans diastereomer is selectively crystallized as its maleate salt from acetone in the presence of the unwanted 4R,6S-cis diastereomer. Neutralization of the maleate salt and extraction of the free base in ethyl acetate, followed by formation of the hydrochloride salt, yields crude dorzolamide hydrochloride. 

Treatment of the sulfinamide anhydride, prepared from anthranilic acid and thionyl chloride, with carboxamides and thiocarboxamides 1 affords quinazolin-4(3//)-ones 2. Thiocarbox-amides, being much more easily dissolved than carboxamides in nonprotic solvents such as benzene, are more suitable as starting materials. This approach has been used by Kametani et al. in the synthesis of the quinazoline alkaloids glomerine, homoglomerine, chrysoginc, and glycosminine. " ... 

Treatment of S4(NH)4 with ozone converts it into a linear polymer (—SO—NH—) the brown, insoluble material has also been made by treating thionyl chloride with ammonia in the vapour phase. Thionyl fluoride, however, reacts with ammonia to give a volatile ether-soluble amide as the initial product ... 

For acylation in pyridine by Einhorn s method it is not always necessary to start with preformed acyl chloride. Its preparation and reaction can be effected in one operation by dissolving the amine and carboxylic acid together in pyridine, adding the calculated amount of thionyl chloride with cooling, and after some time pouring the mixture into water the amide is precipitated and is washed successively with dilute acid, dilute alkali hydroxide, and water. 

The mechanism of dehydration of alcohols by hexamethylphosphortri-amide , phosphorus oxychloride and thionyl chloride in the presence of bases , and sulfur tetrafluoride have been studied. Kirk and Shaw have shown that it is unwise to assume a r/-stereospecificity in dehydration with phosphorus oxychloride or thionyl chloride with basic catalysts. The stereoselectivity is greatly dependent upon the basicity and steric environment of the base. Various steroidal alcohols undergo stereoselective iy -elimination upon treatment with methyl (carboxysulfamoyl) triethylammonium hydroxide inner salt . 

No new methods for the preparation of N-sulphinylamines, R—N==S==0, have been reported. Additional examples of the reaction of thionyl chloride with amines and amides have been reported. Oberhammer " has reported CNDO/2 calculations on HNSO and CINSO which predict the N—S—O angle to be 130 and 119°, respectively, and the charge densities for the former to be -0.20 on N and +0.02 on S. Through examination of the mass spectra of N-sulphinylamines, Grunwell and Kochan concluded that the trans configuration dominated and was more stable, as their calculations had predicted. 

By the dehydration of primary amides with phosphorus pentoxide or with thionyl chloride, for example ... 

Amino-pyridazines and -pyridazinones react with monomethyl- or iV,A-dimethyl-formamide and other aliphatic amides in the presence of phosphorus trichloride, thionyl chloride, phosgene or benzenesuUonyl chloride to give mono- or di-alkylaminomethyl-eneamino derivatives. The same compounds can be prepared conveniently with A,iV-dimethylformamide dimethyl acetal in high yield (Scheme 50). 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2-bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28]. 

The simplest method of nitrile preparation is the Sj 2 reaction of CN with a primary or secondary alkyl halide, as discussed in Section 20.5. Another method for preparing nitriles is by dehydration of a primary amide, RCONH2. Thionyl chloride is often used for the reaction, although other dehydrating agents such as POCI3 also work. 

A classical procedure for the synthesis of the A-(1-chloroalkyl)amides1 or carbamates68 involves substitution of the hydroxy group in stable A-( 1-hydroxyalkyl)amides (or carbamates) by a halogen function with reagents such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, etc. In certain cases merely heating in concentrated hydrochloric or hydrobromic acid suffices1. 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

The by-products are both gaseous and the excess of thionyl chloride (b.p. 78°) may be readily removed by distillation. Interaction of the acid chloride with ammonia solution, aniline or p-toluidiiie yields the amide, anilide or p-toluidide respectively ... 

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. 

Amide bond is an effective anchor to connect CNTs to substrate surfaces. Lan et al. [52] covalently assembled shortened multi-walled carbon nanotubes (s-MWNT) on polyelectrolyte films. The shortened MWNT is functionalized with acyl chloride in thionyl chloride (SOCl2) before self-assembling. The FTIR spectrum of self-assem-bled MWNT (SA-MWNT) adsorbed on a CaF2 plate modified with PEI/(PSS/PEI)2 shows two characteristic absorption peaks at 1646cm-1 (amide I bond) and 1524cm-1 (amide II bond) resulting from the amide bond formed between the polyelectrolyte films and s-MWNTs. 

Ester 324 is hydrolyzed to acid 325 by refluxing in 10% NaOH. In a reaction with thionyl chloride, acid 325 is converted to acid chloride 326, which is isolated as a solid in 96% yield and consecutively converted into amide 327 in 85% yield. Treatment of amide 327 with LDA extracts a proton from the methyl group. The generated anion is trapped by added benzonitrile. Subsequent cyclocondensation of the obtained imine anion with the amide group provides derivative 328 in 62% isolated yield (Scheme 50) <2003EJM983>. 

In contrast to uridine,389 cytidine does not yield a 5 -chloro-5 -deoxy derivative on reaction with N,N-dimethyl(chlorometh-animinium) chloride instead 2,2 -anhydrocytidine is formed.395 However, thionyl chloride or bromide in hexamethylphosphor-amide at room temperature achieves this selective replacement of the primary hydroxyl group of halogen in cytidine, and also in adenosine, in respective yields of 80 and 75% for the chloro compounds, and 55 and 30% for the bromo analogs.396... 

The treatment of diethyl A/-(4-carboxy-3-hydroxyphenyl)aminomethy-lenemalonate with thionyl chloride at reflux for 2 hr afforded the acid chloride (1542), which then was reacted with ammonium hydroxide or anilines in dry acetone at ambient temperature for 1 hr to give the corresponding amide (1543) (75IJC1275). 

The carboxylic functionalities inserted onto the tubes can be used as platforms to obtain further transformations (Fig. 3.5). A commonly utilized route is the reaction of carboxylic groups with thionyl chloride or oxalyl chloride to prepare the corresponding acyl chlorides, which are useful intermediates for amidation or esterification reactions. Amides can also be prepared directly from the acids by means of standard solution chemistry conditions, using carbodiimide derivatives in the presence of the selected amine. 

The cis-fagaramide (J) was synthesized as outlined below. The required acetylenic acid (c) was prepared from piperonal (a) by the Corey s procedure.Treatment of piperonal with carbon tetrabromide, triphenylphosphine and zinc gave the bromo olefin (b) as an oil in 71% yield. The bromo olefin (b) was treated with 2 equivalents of n-butyl lithium followed by quenching with dry ice to give acetylenic acid (c) in 54% yield. Treatment of (c) with excess thionyl chloride without solvent at 50 followed by addition of isobutyl amine in benzene gave the acetylenic amide (d) as a viscous oil in 96% yield. Partial reduction of (d) gave cis-fagarmide (7 ) in 89% yield. 

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