Carbonyldiimidazole with alcohols

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. 

Instead, as illustrated in Fig. 14.14, PEG is treated with propargyl bromide and with l,l -carbonyldiimidazole-propargyl alcohol to link the triple bond to its terminal hydroxyl groups. 

N-Alkoxycarbonyl)- and (N-aryloxycarbonyl)imidazoles (carbamates) were unambiguously proven to be the products of the reaction of JV,JV -carbonyldiimidazole (CDI) with alcohols [448]. Reaction of CDI with 2,6-dimethylphenol or 1-indanol gave (on the basis of IR and NMR evidence) the corresponding carbamate in yields of 91% and 42%, respectively. 

Consider the Merrifield method described above and the use of an N-protected serine (Ser, S) reactant that is to be reacted by coupling the carboxylate of this N-protected serine (Ser, S) at the amine of an amino acid with a protected ester group. It should be clear, based on the chemistry discussed in Chapter 8 (Alcohols) that both of the coupling agents discussed in conjunction with the Merrifield method above, viz., dicyclohexylcarbodiimide (DCCD) and carbonyldiimidazole (CDI) (Scheme 12.76) cannot be used because they both are known to react with alcohols. Of course, in principle, the alcohol can be protected too, but a separate step is then required and the standard Merrifield system as outlined above will need modification. 

In 1995, Pirrung and Bradley " reported the use of dimethoxybenzoin (DMB) carbonate to protect various alcohols, including the 5 -hydroxyl group of nucleosides. The DMB carbonate was synthesized in three steps, starting with methylation of carbonyldiimidazole with methyl triflate followed by addition of 2-(3,5-dimethoxyphenyl)-2-hydroxy-l-phenylethanone to form a relatively stable activated acylating agent. Treatment with an alcohol under basic conditions in nitromethane furnished the protected alcohol 72 in yields that ranged from 42 to 95%. 

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-... 

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. 

Macor has developed what appears to be a quite general method for the acylation (protection) of the indole nitrogen using l,r-carbonyldiimidazole (CDI) in the presence of DMAP. Reaction of substituted indoles 98 with CDI presumably occurs to form the imidazolyl amide of indole 99 which upon treatment in situ with either amines, alcohols or thiols affords the desired indole-1-carboxamides, -1-carboxylates, or 1-thiocarboxylates derivatives 100, respectively. 

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). 

N,N -Carbonyldiimidazole (1.65 g, 10 mmol) was added to a solution of o-chlorobenzoic acid (1.57g, lOmmol) in dimethylformamide (10ml) held under nitrogen, and the mixture was stirred for 1 hour at 40 °C. t-Butyl alcohol (1.48 g, 20mmol) and DBU (l,8-diazabicyclo[5.4.0]undec-7-ene, 1.52 g, 10 mmol) were added and the mixture stood for 24 hours at 40 °C. Ether (100 ml) was then added, and the solution was washed with 10 per cent hydrochloric acid (20 ml), water (20 ml), aqueous potassium hydrogen carbonate (20 ml) and dried over anhydrous sodium sulphate. The solvent... 

Amino acylations.1 This salt is far more reactive, particularly for O-acylation, than N,N -carbonyldiimidazole. Thus it effects esterification of N-Cbz protected amino acids with even hindered alcohols such as /-menthol in 98% yield without need of a base and, consequently, free from racemization. It also can effect coupling of amino acids in high yields and without racemization. 

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. 

In the scale-up synthesis of linezolid21 (Pharmacia/Upjohn), the inexpensive (S)-epichlorohydrin was used as the chiral source and was used to prepare key intermediate 34, a crystalline material (Scheme 4). Treatment of carbamate 33 with BuOLi in alcohol-DMF, followed by addition of chloride 34, gave linezolid 14 in 73% isolated yield. In contrast, the Bayer team applied a much simpler method for the formation of oxazolidinone by directly heating the mixture of amino alcohol 35 with N.N1-carbonyldiimidazole (CDI) in refluxing THF, using catalytic amounts of DMAP, to provide oxazolidinone 36 (or 21) in 87% isolated yield. 

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. ... 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Carbonyldiimidazole 820 can be used to convert alcohols into alkyl halides by a one-step reaction using an excess of such reactive halides as allyl bromide or methyl iodide, and 820 can be made even more reactive by quaternization. The disadvantages of 820 are its cost and the fact that phosgene must be used in its preparation. An alternative is 1,1-oxalyldiimidazole 821 (made from 1-trimethylsilylimidazole and oxalyl chloride). Transacylation reactions occur very readily with this reagent (Scheme 176). 

When intermediate 81 is formed from indole 80 and l,l -carbonyldiimidazole (GDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with GDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with GDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1-carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics. 

Alkyl halides.1 Alcohols can be converted into alkyl bromides or iodides by reaction with N,N -carbonyldiimidazole and an activated halide. Any halide more reactive than the resultant halide can be used, but in practice allyl bromide and methyl iodide are preferred because they are effective and are easily removed after reaction. At least 3 equivalents are necessary for satisfactory yields. Acetonitrile is preferred as solvent. The yields are generally >80%. 

Imidazole and benzimidazole esters are quite reactive towards lithium enolates of ketones. Kinetic studies show that the reaction involves primarily monomers of the enolates <19990L145>. This is in contrast to reactions of aryl esters where both monomers and aggregates of the enolates participate in the reaction. Although (thio)carbonylimidazole esters are normally formed between alcohols and Kl -carbonyldiimidazole or l,l -(thiocarbonyl)diimidazole 1039, transfer of the imidazole group has been reported in reactions with activated alcohols to give, for example, 1040 (Scheme 250) <1997JOC7319>. 

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