Phosgene reactions with carboxylic acids

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]... 

Phosgene reacts with carboxylic acids, usually in the presence of an amine base, to give the acid chloride. All by-products are gases (the HCl is trapped by an amine as the ammonium salt) and the reaction is very efficient. Most carboxylic acids react with phosgene, but, once again, the toxicity of phosgene makes it an unattractive reagent in most cases. 

Reactions with Carboxylic Acids, Alcohols, and Amines. Phosgene reacts with carboxylic acids to give anhydrides, with liberation of carbon dioxide. This has been used to activate acids to attack from nucleophiles, e.g. in esterification, lactonization, and thiolation. For example, acids can be protected as 3-butenyl esters using phosgene and Pyridine, followed by addition of 3-buten-l-ol (eq 1). 

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. 

This classification is illustrated in Scheme 300. The annelation of o-phenylenediamines with carboxylic acid derivatives is the most common method for the syntheses of benzimidazoles. As discussed in CHEC(1984) and CHEC-II(1996), either Br0nsted or Lewis acids can be used to promote the cyclization (e.g.. Scheme 301 also see Section 4.02.9.1(i)) <1998TA2245>. Carboxylic acids and their derivatives, such as acid chlorides, imidates, and phosgene iminium chloride, have been used in these reactions <2005JME8289, 2006BML4994>. 

We introduced these guanidinium salts in a 1985 patent (Ref. 6) on the conversion of carboxylic acids to acid chlorides with phosgene. In this process, only 0.02 mol. % of HBGCI was required, two orders of magnitude less than the quantities of other catalysts typically used. Many new other applications including phosgene reactions with phenols, thiols, aldehydes, epoxides or O-demethyla-tion methods have been developed later and are discussed in this book. 

Another example is the Friedel-Crafts phosgene reaction with 0.xylene giving 3,3, 4,4 -tetramethylbenzophenone in high yield and free of isomers (Ref. 14). This substituted benzophenone is easily oxidized into benzophenone tetra-carboxylic acid dianhydride (BTDA) widely used for the manufacture of polyimides [Scheme 18] ... 

Only a limited amount of work has been published concerning the reactions of phosgene with carboxylic acid anhydrides, despite the fact that the product acid chlorides, formed as illustrated in Equation (10.23), are generated without concomitant formation of co-product hydrogen chloride, as in the case for the corresponding reaction of the carboxylic acids. 

Reactions. As with other tertiary alcohols, esterification with carboxylic acids is difficult and esters are prepared with anhydrides (181), acid chlorides (182), or ketene (183). Ca.rba.mic esters may be prepared by treatment with an isocyanate (184) or with phosgene followed by ammonia or an amine (185). 

The yields of carboxylic acid chlorides, obtained in the reaction of carboxylic acids with phosgene using 1-10 % of DMF as the catalyst, are between 83-93 % (107,211 a,jS-Unsaturated carboxylic acids afford j -chloro-carboxylic acid chlorides XCII ( 07.247 ... 

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- ... 

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. 

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. 

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 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. 

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