Oxalyl chloride reaction with amides

The pyrazino[l,2-i>][l,2]oxazine (313) was formed in excellent yield by acylating the amide (312) with oxalyl chloride (Scheme 23). Reaction with chloroacetyl chloride gave only the monocyclic (314). Neither (314) nor its saturated analogue (315) could be cyclized. (317) was obtained through the ester (316) <79JOC2487>. 

Specialty Isocyanates. Acyl isocyanates, extensively used in synthetic appHcations, caimot be direcdy synthesized from amides and phosgene. Reactions of acid haUdes with cyanates have been suggested. However, the dominant commercial process utilizes the reaction of carboxamides with oxalyl chloride [79-37-8]. CycHc intermediates have been observed in these reactions which generally give a high yield of the desired products (86). 

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

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. 

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

Antibacterial activity is retained when the relatively complex amide side chains are replaced by a simple heterocycle amidine. The required reagent (7-2) is prepared by reaction of azepine formamide (7-1) with oxalyl chloride. Condensation of the product with 6-APA (2-4) leads to the formation of the amidine and thus amdinocillin (7-3) [11]. 

EXTENSIONS AND COMMENTARY N-Methyltryptamine (monomethyltryptamine, NMT) is an alkaloid that has been found in the bark, shoots and leaves of several species of Virola, Acacia and Mimosa. However, the major snuffs associated with these plant have been shown to also contain 5-MeO-DMT and are discussed there. NMT has been synthesized in a number of ways. One can react 3-(2-bromoethyl)indole with methylamine. NMT can be isolated as the benzoyl derivative from the methylation of tryptamine with methyl iodide followed by reaction with benzoyl chloride, with the hydrolysis of this amide with alcoholic KOH. It can also be synthesized from indole with oxalyl chloride, with the resulting glyoxyl chloride reacting with methylamine in ether to give indol-3-yl N-methylglyoxalylamide (mp 223-224 °C from IPA) which is obtained in a 68% yield, which is reduced to NMT to give the amine hydrochloride (mp 175-177 °C from ) in a 75% yield. The most simple and direct synthesis is the formamide reduction given above. 

Activation of 13 with oxalyl chloride, followed by addition of methylamine, afforded amide 45 in 86 % yield. Except for a concentration step after the first reaction to remove excess oxalyl chloride, both reactions were performed in one pot. 

Acylation of the C3 position can also be accomplished with acid chlorides, as illustrated in the synthesis of indole 7.34, a drug for the treatment of depression. Reaction of indole 7.31 with oxalyl chloride affords C3-substituted product 7.32 even though the benzene ring is very electron-rich. Conversion to amide 7.33 is followed by reduction with lithium aluminium hydride which removes both carbonyl groups, affording the target indole 7.34. 

Similar reactions are employed for the synthesis of chlorimines from amides (191) and N-fluorosulfonylimines (192, 193). Acylation of SF5NH2 with oxalyl chloride produces the corresponding diamide SF5NHC(0)C(0)NHSF5, in 78% yield, whereas acylation by fluorosuc-cinyl chloride yields both the diamide, [SF5NHC(0)CF2]2, and the cyclic... 

So far, we have considered protocols that result in chiral centres in the C and position (actnally always with the same substiment). Let us now turn to satnrated carbenes that have only one chiral centre in the backbone. Figure 5.15 shows a procedure that utilises a chiral diamine derived from proline, a naturally occurring a-amino acid. Reaction with aniline to the corresponding amide and reduction with LiAlH yields the diamine used [60]. The actual synthesis of the chiral carbene then calls for reaction of the proUne derived diamine with thiophosgene and subsequent S/Cl exchange with oxalyl chloride [50]. The... 

Scheme 160 Reactions of oxalyl chloride and phosgene with primary amides.

This postulate was confirmed by synthesis. Reaction of 2-ethyIindole with oxalyl chloride gave 262, which reacted with 3-ethylpiperidine to afford the amide 263. Lithium aluminum hydride reduction gave the amine 260, identical with the natural material. The correct name for this compound, based on secodine nomenclature (117), is 16-decarbomethoxy-14,15,16,17-tetrahydrosecodine. 

Aryl 3,4-dihydroisoquinolinesJ Isoquinolines are generally prepared by the Bis-chler-Napieralski reaction, but this classical route is not useful in the case of 3-aryl-isoquinolines. In a modified procedure, the precursor, (phenylethyl)amide (I), is treated with oxalyl chloride to form a, which on treatment with FeCl.i forms an N-acy-liminium ion b. This ion cyclizes to 2, which is converted into 3,4-dihydroisoquinoline 3 by treatment with sulfuric acid in methanol. Overall yields of 3 are in the range 55-90%. 

Carboxylic acids can be converted to the corresponding acyl chlorides, which react with an amine containing chromophore. A few methods have been developed for conversion of acids to acyl chlorides. Hoffman and Liao [107] used a mixture of triphenylphosphine and carbon tetrachloride or polystyryldiphenylphosphine to prepare acyl chlorides of fatty acids. The reaction was carried out at 80 °C for 5 min. The intermediate acyl chlorides were then converted to amides with p-nitroaniline or p-melhoxyaniline. Thionyl chloride [108] and oxalyl chloride [109] were also applied to prepare acyl chloride. The conversion with oxalyl chloride was quantitative in 30 min at 70 °C. The commonly used amines were 1-naphthylamine [109] and p-chloroaniline [110]. The final derivatives were separated by RP-HPLC with either gradient [108] or isocratic elution [109,110]. 

---