Imidization procedures, general

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

The procedure described here for the preparation of succinimide silver salt is a modification of one reported for the formation of the silver derivative of maleimide. The alkylation step is modeled after the procedure of Comstock and Wheeler/ who prepared 2-ethoxypyrrolin-5-one in unspecified 3deld, and is an improvement over a later procedure developed in the laboratories of the submitters/ The general scheme has been successfully applied to the preparation of a variety of 2-ethoxypyrrolin-5-ones (Table 1) as well as 6-ethoxy- and 6-propoxy-4,5-dihydro-2(3H)-pyridone from the corresponding five- and six-membered cyclic imides/... 

The modification of carboxyl groups has been carried out (1) by esterification with dry methanol and HC1, (2) by esterification with aliphatic diazo compounds, (3) by the formation of adducts with carbodi-imides, or (4) by the formation of amides through activation with carbodiimides. Both complete and, apparently specific, partial modification of the 11 free carboxyl groups have been obtained. In general, the first method suffers from the denaturing medium, the second from incomplete reaction, and the third from the uncertain nature of the products. The fourth procedure is perhaps subject to the least question. There are a total of 11 free carboxyl groups in native RNase-A l (Val), 5/ (Asp), 5y(Glu). A summary of the derivatives is given in Table V. 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

Early attempts to extend the halolactonization procedure to yield lactams gave cyclic imidates instead, but several approaches favor lactam products. These include working with silyl imidates, imidate esters or oxazolines, using sulfonylcarbamates or other acidic amides or by using hydroxyl-amine derivatives with increased nucleophilicity due to the a-effect. Lactams can also be favored as a consequence of steric requirements. In a few cases, amines can be cyclized to cyclic amines many lead references are given in a recent report on cyclic hydroxylamines such as (64). Veiy recent work has provided a fairly general iodolactamization procedure from unsaturated amides, trimethylsilyl triflate and iodine (Scheme 89). ... 

Nitta, Hatanaka and Ishimura11 started their synthesis of cephalosporin precursors from L-aspartic acid. The key intermediate is the lactone 1. The azidation resembles the general preparation procedure given for open-chain imide enolates in Section 7.1.1. The main differences are the generation of a dianion with lithium diisopropylamide and the application of tosyl azide. 

An ice-cooled solution of 0.50 mmol of the imide 2 in 2.0 mL of THF is treated ill one portion with a cold (0°C) solution of 28 mg (1.2 mmol 2.3 equiv) of LiOH in 1.0 mL of H20. The resulting two-phase mixture is stirred at 0 C until the reaction is complete. Two general procedures (Methods Al and A2, below) describe the transformation of the acids 3 into the corresponding methyl esters 41611 ... 

A general two-step method has been developed for the synthesis of 5//-5-alkyl-2-phenyloxazoM-ones 251. This procedure involves the initial condensation of a-bromo acid halides 249 with benzamide to form an imide intermediate 250 followed by microwave-mediated cyclization in the presence of NaF to give the corresponding 4(5//)-oxazolones 251 (Scheme 73) <2004JA1944>. 

The mechanism of the reaction is illustrated in Scheme 1 for the conversion of r-butanol, using sulfuric acid and acetonitrile, into A -r-butylacetamide. Three intermediates are involved. Firstly, a carbenium ion (1) is produced under strongly acidic conditions. This reacts with the nitrile to produce a resonance-stabilized nitrilium ion (2), which in turn is converted into the corresponding imidate (3). Finally, the latter is hydrolyzed to the amide. Since all three events occur in a one-pot process, frequently in high yield, the Ritter reaction is a simple, efficient and general synthetic procedure. 

As an alternative to the well established phenylacetyl group in (3-lactam chemistry, recently a biocatalyzed procedure for the removal of phthalyl imide has been described (Fig. 18-2)[45, 71 Its general usefulness remains to be demonstrated, however. 

Oxazolines are formed directly from the reaction of carboxylic acids with 2-ami-no-2-methyl-l-propanol in refluxing toluene but a two-step procedure involving reaction of 2-amino-2-methyl-l-propanol with an acid chloride followed by treatment of the resultant amide with excess thionyl chloride as a dehydrating agent is generally preferred (Scheme 2.128].2 o 26i Alternatives include reaction of dimethylaziridine with a carboxylic acid in the presence of dicyclohexylcarbo-diimide to form the N-acylaziridine followed by acid-catalysed rearrange-ment or reaction of an orthoester, or an imidate ester, with an amino alcohol as illustrated by the conversion of 129.1 to 1293 [Scheme 2.129). ... 

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