Carbonyldiimidazole, reaction

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

The antiarrhythmic activity of local anesthetics has been noted several times previously. Another such agent is prepared by first alkylating isopropylamine with sulfone 199. Reaction of the ])ioduct (200) with diethylethylenediamine and carbonyldiimidazole results in transfer of the CDI carbonyl group and formation of the urea suricainide (201) [52]. The transform in all likelihood involves stepwise replacement of the imidazole groups by the basic groups in the other reactants. 

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

Photosensitive functions are in many cases also heat sensitive, so the preparation of photosensitive polyimides needs smooth conditions for the condensations and imidization reactions. Some chemical reactants, which can be used for polyamide preparation, have been patented for the synthesis of polyimides and polyimide precursors. For example, chemical imidization takes place at room temperature by using phosphonic derivative of a thiabenzothiazoline.102 A mixture of N -hydroxybenzotriazole and dicyclohexylcarbodiimide allows the room temperature condensation of diacid di(photosensitive) ester with a diamine.103 Dimethyl-2-chloro-imidazolinium chloride (Fig. 5.25) has been patented for the cyclization of a maleamic acid in toluene at 90°C.104 The chemistry of imidazolide has been recently investigated for the synthesis of polyimide precursor.105 As shown in Fig. 5.26, a secondary amine reacts with a dianhydride giving meta- and para-diamide diacid. The carbonyldiimidazole... 

First, the acid anhydride is produced by the reaction of the free acid with DCC. NucleophiUc attack by 4-pyrroUdinonepyridine on the anhydride results in the corresponding, highly reactive acylpyridinium carboxylate this leads to the formation of cellulose ester, plus a carboxylate anion. The latter imdergoes a DCC-mediated condensation with a fresh molecule of acid to produce another molecule of anhydride. N,N-carbonyldiimidazole (CDl) may substitute DCC for acid activation, the intermediate being N-acyhmidazol,... 

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. 

Urethane linkages between amino groups of a protein and PEG provide a stable attachment, more resistant to hydrolytic cleavage (13). In fact, it was demonstrated on radioactively labeled PEG-derivatives that urethane links are completely stable under a variety of physiological conditions (14). The attachment of PEG to a protein via carbamate was obtained (15,16) using carbonyldiimidazole activated PEG. However, the polymer activated in this manner is not very reactive and therefore very long reaction times (48-72 h at pH 8.5) were required to achieve sufficient modifications. 

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. 

Table 2-1 lists some examples of carboxylic acid imidazolides of various structures prepared by the use of A -carbonyldiimidazole (CDI), A -thiocarbonyldiimidazole (Im-CS-Im), and A -sulfinyldiimidazole (Im-SO-Im). Independent of the specific method applied, the data in Table 2-1 show that reasonable yields of imidazolides and diimidazolides are quite general, irrespective of various substituents and of steric factors. The rather mild reaction conditions also permit the formation of imidazolides of highly unsaturated systems. As a further advantage, it should be mentioned that almost all imidazolides are crystalline compounds, which can be conveniently handled. Melting points are therefore included for the imidazolides listed in Table 2—1. 

The broad use of A -carbonyldiimidazole (CDI) for the synthesis of amide and peptide linkages became a routine method only in the early sixties. JV-Protected amino acids were treated at room temperature with an equimolar amount of CDI to give imidazolides. Anhydrous tetrahydrofuran, dimethoxyethane, dichloromethane, pyridine, dimethylfor-mamide, and diethyl phosphite were utilized as solvents. In the second step the esters of amino acids, their hydrochlorides, or sodium salts were added to yield the peptide after several minutes or hours of reaction time. 

The scheme below shows reaction possibilities for carbonyldiimidazole activation of polyhydroxylic matrices. The formation of these activated sites depends on[117] 1. the partial disposition of hydroxyl groups accessible to the solvent, 2. the initial concentration of CDI, and 3. the chemical nature of the gel matrix. 

Another compound 9 with three heterocyclic rings linearly fused (5 5 5) with two heteroatoms has been prepared from 1,1 -carbonyl diindole 297 <2001T5199>. Palladium-mediated coupling of the 2- and 2 -positions of 297 afforded the 1,1 -carbonyl-2,2 -biindolyl 9. 1,1 -Carbonyl diindole 297 was in turn obtained in 41% yield from 1,1 -carbonyldiimidazole 296 by reaction with indole in DMSO at 125 °C. The palladium-catalyzed coupling step afforded the desired product 9 in low yield and required a stoichiometric amount of palladium acetate. Therefore, it was felt prohibitively expensive. Addition of various co-oxidants (Ac20, Mn02, and Cu(OAc)2, etc) to make the reaction catalytic in palladium did not result in any improvement of the yield of 18 (Scheme 53). 

Reaction of dipyrrinones such as 242 with A,A -carbonyldiimidazole (CDI) have been used to synthesize carbonyl-bridged dipyrrinones such as 243, which are highly fluorescent compounds (Equation 66) <2002JOC2713>. 

Figure 25.8 N,N -carbonyldiimidazole (CDI) may be used to activate the terminal hydroxyl of mPEG to an imidazole carbamate. Reaction of this intermediate with an amine-containing compound results in the formation of a stable carbamate linkage.

The activation of the hydrazines 397 (Scheme 68) with l,l -carbonyldiimidazole (CDI) and reaction with hydroxylamines gave the hydroxy semicarbazides 398, which could be treated with methyl chloroformate in the presence of TEA to give the first examples of 4-amino-substituted l,2,4-oxadiazolidin-3,5-diones 399 <2000HC055>. 

By working quickly, the imidazolium chloride may be removed by suction filtration through a Buchner funnel. However, the precipitate should not be freed of solvent completely because imidazolium chloride is extremely hygroscopic. If the moist precipitate is washed with 50-100 ml. of anhydrous tetrahydrofuran, the yield of 1,1 -carbonyldiimidazole may be slightly increased however, there is some danger of the introduction of too much moisture into the reaction solution. 

Another possibility to produce l,3-dioxoperhydropyrrolo[l,2-f]imidazoles started with the reaction of Art-butyl carbamate 143 with carbonyldiimidazole 144. The intermediate 145 was treated with L-proline in dioxane at room temperature to give the 3-aminohydantoin 146 in good yield (91%) (Scheme 20) <2000TL135>. 

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. 

A typical protocol for the DTPA-PL-NGPE synthesis and loading with Gd (to prepare contrast agent for MR imaging) is given below. NGPE (25 mg) was activated with A/,A -carbonyldiimidazole (25 mg) in the presence of N-hydroxysuccinimide (11.4 mg) for 16 h at room temperature. At this point, e, A-carbobenzoxy PL (100 mg, Mw 3,000 Da) and triethylamine (10 [jlL), were added to the initial mixture and the reaction was allowed to proceed for... 

Reaction of a-aminoketoximes 374 with l,l -carbonyldiimidazole (GDI) in THE afforded l,2,5-oxadiazin-6-ones 375 in 41-65% yields (equation 163) °. 

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