Carboxylic acids phosgene

The electrophilic one-carbon species can be an aldehyde, ketone, carboxylic acid, phosgene, thiophosgene, carbonyl diimidazole (CDI), etc., and the reaction essentially involves condensation with a 1,5-dinucleophile. The 1,5-dinucleophile invariably contains at least one heteroatom at a terminus, and more often than not two, so that the cyclization always involves the formation of at least one bond between carbon and a heteroatom. 

This reaction is commercially important because it serves as a basis for the manufacture of polycarbonate. Carboxyhc acids react with phosgene to give acid chlorides (26) (see Carboxylic acids). 

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. 

A carboxylic acid (not the salt) can be the nucleophile if F is present. Mesylates are readily displaced, for example, by benzoic acid/CsF. Dihalides have been converted to diesters by this method. A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH2Br). The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see 10-21) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO3 and K2C03- ... 

Anhydrides can be formed from certain carboxylic acid salts for example, by treatment of trimethylammonium carboxylates with phosgene ... 

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

AyV -Carbonyl-2,2 -biimidazole (A V7-carbonyl-2,2 -biimidazyl) prepared from 2,2 -biimidazole and phosgene is relatively unreactive on hydrolysis, and shows reduced reactivity in reactions with carboxylic acids.[19],[2]... 

However, because CDI reacts with HC1 to give phosgene (COCl2), reaction of the carboxylic acid with CDI must be complete before treatment with hydrochloric acid is undertaken. The yield of an acid chloride prepared by this one-pot reaction is comparable to those reported in Table 13-2. In general, acid chlorides are formed at room temperature within a few minutes. 

Anthanthrone is synthesized from naphthostyril (105), which is saponified to form l-aminonaphthalene-8-carboxylic acid (106). Naphthostyril itself is prepared from 1-naphthylamine with phosgene in the presence of dry aluminum chloride. 

When a nonproteinogenic unsaturated amino acid was subjected to the Sharpless asymmetric epoxidation, 49 was formed (87TL3605). It is known that AAs are converted with phosgene into A-carboxy-a-amino acid anhydride (NCA) derivatives. Unexpectedly, A-protected dehydroaspartic acid gave l,3-oxazine-2,6-dione-4-carboxylic acid under such conditions (88CL1473). 

Phosgene is highly toxic gas (caution ). Phosgene is a suitable reagent for this method since it can simultaneously activate several functional groups such as amines, carboxylic acids, hydroxyl, etc. Twenty percent of COCl in toluene, almost saturated solution, is commercial available from Aldrich ( 681776). 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

The kinetics and mechanism of the reaction of carboxylic acids with phosgene COCI2 in DMF in benzene were zero-order in substrate and proceeded via rapid formation of... 

The decomposition of mandelic acid (70),62 the elimination of CO2 from the intermediate in the reaction of phosgene with carboxylic acids,64 the thermal decomposition of haloacetic acids (74),65 and the hydrolysis of aryl carbazates (140)119 were discussed earlier. 

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