Carbonyldiimidazole with carboxylic acids

Crystalline l,r-carbonyldiimidazole 16, prepared from phosgene and imidazole, is particularly reactive. Even at room temperature, it reacts vigorously with water to give imidazole and carbon dioxide. With carboxylic acids in aprotic solvents, 1-acyloxycarbonylimidazole 17 is formed, which is capable of an intermolecular transacylation ... 

PROBLEM 17.37 In Section 17.7b, we saw how dicyclohexyl-carbodiimide (DCC) could be used as a dehydrating agent for the formation of amides from carboxylic acids and amines. Another reagent that can be used to good effect is the phosgene derivative A(A -carbonyldiimidazole (CDI). Carboxylic acids and CDI react under mild conditions to form imidazolides, 1, which then easily react with amines to give amides. Propose mechanisms for the formation of 1 from carboxylic acids and CDI, and for the formation of amides from 1 and amines. 

A-Acylimidazolides. A,iV -Thionylimidazole reacts with carboxylic acids to form A-acylimidazolides (eq 1) that readily acylate amines, amino acids, or alcohols. The products are readily purified since the byproducts, imidazole and SO2, are easily removed. N,N -Carbonyldiimidazole (GDI) is another useful reagent for formation of A-acylimidazolides. TDI is used less frequently for formation of A-acylimidazolides because of its high reactivity also, GDI is commercially available and easier to handle. Most reported transformations from A-acylimidazolides involve GDI however, TDI should give similar results. 

Carboxyl group of (-)-9-fluoro-3-methyl-7-oxo-10-[(3S)-3-(tert-butoxy-carbonylamino)pyrrolidino]-2,3-dihydro-7//-pyrido[l,2,3- 7e]-l,4-benzoxa-zine-6-carboxylic acid was converted into l-nitro-2-oxoethyl group in 45% yield by treatment with l,l -carbonyldiimidazole in boiling CFICI3 for 18h, then with MeN02 in the presence of KOr-Bu for another 18 h (96MI12). 6-(2,2-Diethoxycarbonyl)acetyl derivative formed from the aforementioned 6-carboxylic acid, when it was treated with l,l -carbonyldiimidazole in... 

In addition to acyl halides and acid anhydrides, there are a number of milder and more selective acylating agents that can be readily prepared from carboxylic acids. Imidazolides, the (V-acyl derivatives of imidazole, are examples.115 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with carbonyldiimidazole. 

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. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

FIGURE 6.10 The side chain of histidine is readily acylated (A) by activated residues. The imidazolide produced is an activated species similar to the intermediate generated by reaction (B) of a carboxylic acid with coupling reagent carbonyldiimidazole. (Staab, 1956). Imida-zolides acylate amino and hydroxyl groups. Isomerization of histidyl during activation results from abstraction (C) of the a-proton by the 7t-nitrogen. 

EtjN,663 and N,N -carbonyldiimidazole (100).664 In the latter case easily alcoholyzed im-idazolides (101) are intermediates. BF3 promotes the esterification by converting the acid to RCO+ BF3OH, so the reaction proceeds by an AacI type of mechanism. The use of BF etherate is simple and gives high yields.665 Carboxylic esters can also be prepared by treating carboxylic acids with /-butyl ethers and acid catalysts.666... 

Carbonyldiimidazole does certainly stand out as one of the most remarkable reagents for peptide coupling. Carboxylic acids react readily with this reagent to yield acyl imidazoles which in turn couple with the amino group of a peptide to produce a new acyl-nitrogen linkage with very little racemization. Reaction of the acylimidazolide with other nucleophiles can lead to a variety of carbonyl derivatives (62AG(E)35l). 

Treatment of ethyl l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylates with ammonia in methanol and hydrazine hydrate in ethanol at ambient temperature afforded 2-carboxamides and 2-carbohydrazides, respectively (74MIP1 79MIP2). Reaction of l-oxo-l//-pyrimido[l,2,-a]quinoline-2-carboxylic acids (169) with A-. /V-carbonyldiimidazole in dimethyl-formamide, then with 5-aminotetrazole gave 7V-(5-tetrazolyl)-1 -oxo-1H-pyrimido[l,2-a]quinoline-2-carboxamides (170) (77GEP2630469 77USP 4017625). 

A-(l//-5-Tetrazolyl)-10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxamide was prepared on treatment of the 3-carboxylic acid with l,l -carbonyldiimidazole in dimethyl-formamide at ambient temperature under nitrogen, then with 5-amino-lH-tetrazole at 100°C for 1 h (85EUP143001). Treatment of lO-(acylamido)-... 

Y/ .v-(3-Lactains have also been obtained by the Staudinger reaction carried out between divinylimine and /V-acylimidazoles possessing an electron-withdrawing group (EWG) in a position [111]. This latter were prepared by treatment of a-EWG substituted carboxylic acids with 1,1-carbonyldiimidazole. 

Methyl esters may be prepared by reaction of the aromatic carboxylic acid with diazomethane (cf. Section 4.2.25, p. 433) or, more conveniently, by reaction with a boron trifluoride-methanol reagent. The latter procedure is illustrated by the preparation of methyl m-chlorobenzoate and dimethyl terephthalate (Expt 6.164). t-Butyl esters may be prepared by conversion of the acid into an N-acylimidazole by reaction with N,N -carbonyldiimidazole, followed by reaction with t-butyl alcohol in the presence of DBU62 (Expt 6.165). 

Another carboxylic acid activation in a neutral environment together with all mechanistic details is shown in Figure 6.13 carboxylic acids and carbonyldiimidazole (A) react to form the reactive carboxylic acid imidazolide B. 

In the second route to l,20 acid chloride 23, prepared by treatment of 5-chlorothiophene-2-carboxylic acid 28 with SOCl2 is coupled with (5)-3-amino-1,2-propanediol hydrochloride 29 in the presence of NaHCCh to furnish the dihydroxy amide 30 (Scheme 3). The primary alcohol in 30 is then brominated by a solution of HBr in HOAc to produce the bromohydrin 31, which is then condensed with the morpholinoaniline derivative 18 to yield 32. Finally, the ring closure with N,N -carbonyldiimidazole (CDI) afforded 1. 

Cyclization of methyl 4-(c/s-3,5-H-2-oxomorpholin-5-yl)butyrate in boiling toluene provided c/s-4,9a-H-4-phenylperhydropyrido[2,l-c][l,4]ox-azine-3,6-dione [95H(41)1931], Heating l,4-oxazin-2-one 163 afforded [l,4]oxazino[4,3-a]quinoline-4,6-dione 164 (94IZV299, 94JFC119). The reaction of carboxylic acid 165 with l.l -carbonyldiimidazole in the presence of 4-methylmorpholine afforded pyrido[2,l-c][l,4]oxazin-4-one (61)... 

Recently, Melillo et al.t applied this Meldrum s acid method with some modifications to the synthesis of thienamycin. A carboxylic acid was treated with carbonyldiimidazole, followed by treatment with Meldrum s acid to give an acyl Meldrum s acid, which was converted to a 0-keto p-nitrobenzyl ester by refluxing in acetonitrile containing p-nitrobenzyl alcohol. ... 

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