Imidazolides with alcohols

Imidazolides can also be activated by N-alkylation with methyl triflate.116 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. 

Imidazolides of aromatic sulfonic acids react much more slowly in alcoholysis reactions than the carboxylic acid imidazolides. Although the reaction with phenols is quantitative when a melt is heated to 100 °C for several hours, with alcohols under these conditions only very slight alcoholysis is observed. In the presence of 0.05 equivalents (catalytic amount) of sodium ethoxide, imidazole sodium, of NaNH2, however, imidazolides of sulfonic acids react with alcohols almost quantitatively and exothermically at room temperature in a very short time to form sulfonic acid esters (sulfonates). (If the ratio of sulfonic acid imidazolide to alcoholate is 1 2, ethers are formed see Chapter 17). The mechanism of catalysis by base corresponds to that operative in the synthesis of carboxylic esters by the imidazolide method. Because of the more pronounced nucleophilic character of alkoxide ions, sulfonates can also be prepared in good yield by alcoholysis of their imidazolides in the presence of hydroxide ions i.e., with alcoholic sodium hydroxide. 45 Examples of syntheses of sulfonates are presented below. 

In a way analogous to sulfonic esters, sulfinic esters are available quite readily and in very good yield. As usually the first step is the activation of sulfinic acid by CDI to the corresponding imidazolide which then reacts with alcohols [12H14]... 

The effect upon the transphosphorylation reaction with alcohols and amines of electron-releasing (CH3) and electron-withdrawing (Cl, N02) groups in the benzene ring of phosphoric imidazolides has been studied as well.[191]... 

The preparation of ketones proceeds conveniently by reaction of imidazolides with organomagnesium reagents, as shown in Table 14-6 for several examples of purely aromatic, aromatic-aliphatic, and purely aliphatic ketones. The yields are very satisfactory even for purely aliphatic ketones, since in this case, too, alcohol formation is completely suppressed.t851,t861... 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

A rapid method for esterification using a mild agent was described by Ko and Royer [37], A substrate containing a carboxyl group reacts with N,N -carbonyldiimidazole, and the acyl imidazolide produced in this way is decomposed with alcohol and the appropriate ester is produced (Scheme 4.9). The reaction proceeds very rapidly even at room temperature and is completed within several minutes. In the course of this procedure no transesterification of the esters occurs, e.g., triglycerides or cholesteryl esters. The method... 

There are limitations to the use of DCC yields are variable and A -acylureas are side products. Many other dehydrating agents " have been used, including DCC and an aminopyridine, Amberlyst-15, chlorosilanes, MeS02Cl-Et3N, and AA -carbonyldiimidazole(99). In the latter case, imidazolides (100) are intermediates that readily react with alcohols. 

Succinic esters of dextran have been prepared and transformed into the corresponding imidazolides, which react smoothly with alcohols or amines to yield the corresponding polymeric esters or amides. These activated amides may be of value for the preparation of polymer-drug adducts with a main backbone degradable to safe metabolites in the body fluids. 

All the polymers listed in Table 1 are able to enter into exchange reactions with alcohols and amines, giving ester or amidic bonds. The order of reactivity is succinimides < benzotriazolides < imidazolides. ... 

The reagent reacts with carboxylic acids to form imidazolides which give esters with alcohols under basic catalysis H. A. Staab and A. Mannschreck, Chem. Ber., 95, 1284 (1962). 

Sulfonic peracids (66) have also been applied recently to the preparation of acid sensitive oxiranes and for the epoxidation of allylic and homoallylic alcohols, as well as relatively unreactive a, p - unsaturated ketones. These reagents, prepared in situ from the corresponding sulfonyl imidazolides 65, promote the same sense of diastereoselectivity as the conventional peracids, but often to a higher degree. In particular, the epoxidation of certain A -3-ketosteroids (e.g., 67) with sulfonic peracids 66 resulted in the formation of oxirane products (e.g., 68) in remarkably high diastereomeric excess. This increased selectivity is most likely the result of the considerable steric requirements about the sulfur atom, which enhances non-bonded interactions believed to be operative in the diastereoselection mechanism <96TET2957>. 

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. 

The reaction of a carboxylic acid with N,Af -carbonyldiimidazolellH33 (abbreviated as CDI), forming an imidazolide as the first step followed by alcoholysis or phenolysis of the imidazolide (second step), constitutes a synthesis of esters that differs from most other methods by virtue of its particularly mild reaction conditions.t41,[5] It may be conducted in two separate steps with isolation of the carboxylic acid imidazolide, but more frequently the synthesis is carried out as a one-pot reaction without isolation of the intermediate. Equimolar amounts of carboxylic acid, alcohol, and CDI are allowed to react in anhydrous tetrahydrofuran, benzene, trichloromethane, dichloromethane, dimethylformamide, or nitromethane to give the ester in high yield. The solvents should be anhydrous because of the moisture sensitivity of CDI (see Chapter 2). Even such unusual solvent as supercritical carbon dioxide at a pressure of 3000 psi and a temperature of 36-68 °C has been used for esterification with azolides.[6]... 

The second step, nucleophilic attack of an alcohol or phenol on the activated carboxylic acid RCOIm (carboxylic acid imidazolide), is usually slow (several hours), but it can be accelerated by heating[7] or by adding a base[8] [9] such as NaH, NaNH2, imidazole sodium (ImNa), NaOR, triethylamine, diazabicyclononene (DBN), diazabicycloimdecene (DBU), or /7-dimethylaminopyridine to the reaction mixture (see Tables 3—1 and 3—2). This causes the alcohol to become more nucleophilic. Sodium alcoholate applied in catalytic amounts accelerates the ester synthesis to such an extent that even at room temperature esterification is complete after a short time, usually within a few minutes.[7H9] This catalysis is a result of the fact that alcoholate reacts with the imidazolide very rapidly, forming the ester and imidazole sodium. 

Similarly applicable for ester syntheses as CDI is A AT -oxalyldiimidazole, which was first described in reference [109]. It has been used to convert not only carboxylic acids but also metal carboxylates into the corresponding imidazolides.[110] Typical reaction conditions for the reactions with oxalyldiimidazole are for the first step 1-2 h, 25-45 °C, and for the second step 4 h, room temperature if X = H if X = Li or Na, if 60 °C and DMF as solvent. In the latter case the resulting Lilm or Naim function as catalysts in the conversion of alcohol into the alcoholate. Results are given in Table 3— 3 [no]... 

By adding one equivalent of alcohol to CDI at room temperature with or without base it is possible to isolate the imidazole-iV-carboxylate, which then reacts with a second mole of ROH to yield the carbonate. As in the case of alcoholysis of imidazolides, the reaction can be accelerated so effectively with catalytic amounts of NaOC2H5 or ImNa that it takes place in most cases exothermically, even at room temperature. However, tert-butyl alcohol, even when in excess, affords with CDI and base catalysis at room temperature only the imidazole-N-tert-butylcarboxylate, obviously for steric reasons. At higher temperature the carbonic ester is formed. Mixed carbonates such as ethyl benzyl carbonate or ethyl terf-butyl carbonate can be prepared with two different alcohols added sequentially.C9],[229]... 

Another way to obtain a carbamate via an isocyanate intermediate is the conversion of an imidazolide RCOIm into the azide RCON3, followed by the Curtius-Schmidt rearrangement and treatment with an alcohol [2241... 

Alcohols can be phosphorylated to phosphoric diesters by ionic phosphoric monoimidazolides in acetone at temperatures of about 50-60 °C over the course of several hours. These imidazolides are generally prepared by reaction of the appropriate phosphate with CDI (see Section 2.2). Reactions with ethyl, -butyl, w-pentyl, -octyl benzyl alcohol and various other alcohols have also been described.[1]... 

Analogously to the phosphorylation of alcohols with phosphoric azolides the phos-phinylation is carried out by means of phosphinic azolides (CH2CI2/C2H5OC2H5). In the following case a I2/C2H5OC2H5) protonated diphenylphosphinic imidazolide is used to give the allylic diphenylphosphinic esters in good yields ... 

In this procedure a diacylglyceryl phosphate is first converted with CDI into a reactive phosphoric imidazolide, which is then treated with a labeled alcohol to give a labeled phosphoric acid diester 123... 

A labeled phosphoric acid triester is formed by phosphorylation of an alcohol with a labeled phosphoric diester imidazolide [187],[188]... 

The inductive effect of the imidazole substituents on the transphosphorylation of alcohols and amines with the following spin-labeled phosphoric imidazolides is discussed in reference [190]. 

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