Cyclodehydrating agents

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Cyclobuxine-D, 2 104 P-Cyclocitral, 24 570 Cyclocitronellene acetate, 24 488 a-Cyclocitrylidenebutanone, 24 565 Cyclodehydrating agents, 20 276 Cyclodemol, 24 488 P-Cyclodextrin, 4 715 Cyclodextrin glucanotransferase, 24 48 Cyclodextrin glycosyltransferase, 4 715 Cyclodextrin inclusions, 74 183 Cyclodextrin inclusion compounds, 74 166-167... 

Ph R = H). Other cyclodehydrating agents used to prepare meso-ionic l,3-oxazol-5-ones (66) include oxalyl chloride or dicyclohexyl-carbodiimide. ... 

It was shown previously that saturated 5(4//)-oxazolones or 2-oxazolm-5-ones with only one substituent at C-4 can be considered as the tautomeric form of saturated 5(2//)-oxazolones or 3-oxazolin-5-ones. These compounds can also be considered as amino acid derivatives and, indeed, cyclization procedures are the most commonly used to prepare these compounds. The cyclization reaction employs a variety of cyclodehydrating agents and the general method is shown in Scheme 7.23, with an A-acyl-a-amino acid being the most typical starting material used. In this way, 5(4//)-oxazolones derived from most natural amino acids 99 (R3 = H) have been obtained by heating the corresponding A-acyl derivatives in the presence of acetic anhydride. 

In addition to the typical cyclization procedures described above, methods involving the use of other mild, cyclodehydrating agents have been published. For example, cyanuric chloride in the presence of triethylamine, 2-ethoxy-A-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ) or 2-isobutoxy-A-isobutoxy-carbonyl-1,2-dihydroquinoline (IIDQ), ° A,A-dimethylchlorosulfitemethanimi-... 

The first procedure to prepare unsaturated 5(4//)-oxazolones was the Erlenmeyer synthesis" " that was described more than one hundred years ago and is still used extensively with some variations in the experimental conditions. In general, the reaction employs an acylamino acid, for example, A-acetyl- or A-benzoylglycine are the most common, and a carbonyl compound, usually an aldehyde, in the presence of a cyclodehydrating agent such as acetic anhydride (Scheme 7.114). Hundreds of unsaturated oxazolones 363 have been obtained via this procedure and these compounds are valuable intermediates for the synthesis of many interesting organic compounds. 

Condensation of A -acylglycines with carbonyl compounds, the Erlenmeyer synthesis, continues to be exploited to prepare of a wide variety of unsaturated-5(47/)-oxazolones. The reaction is performed in the presence of a cyclodehydrating agent and recently bismuth(lll) acetate has been evaluated in this capacity. Alternatively, unsaturated 5(47/)-oxazolones can be obtained from hippuric acid and a carbonyl compound or from the appropriate dehydroamino acid derivative using 3-(aIkoxycarbonyl)benzotriazole-l-oxides as the cyclodehydrating agent. 

The various side reactions of the chemical cyclodehydration and because of the high cost for solvents, catalyst and cyclodehydration agent, researchers have been looking at more economic ways to manufacture bismaleimides. Efforts have been directed towards a catalytic cyclodehydration process via azeotropic distillation to avoid undesirable byproducts and to achieve improved yield of pure bismaleimide. The use of Lewis add/base salts based on p-toluene sulfonic acid, sulfuric add or trifluoroacetic add and dimethylformamide (DMF), N-methylpyrrolidone (NMP) and acetone as bases provided high yields of high purity bismaleimide (24). In another patent dimethyldialkylammoniummethane... 

As described previously, thiazohnes are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. In the total synthesis of cyclopeptide YM-216391, (diethylamino)sulfur trifluoride (DAST) is used as the cyclodehydrating agent for the conversion of P-hydroxy thioamide 76 to thiazoline 13 <05CC797>. A similar strategy has been used in the construction of the thiazoline moiety in two independent total syntheses of hahpeptin A (77 to 78 79 to 80)... 

The tris(trifluoromethyl)-l,3,2,5-dioxathiazine 2,2-dioxide (228), obtained by the action of SO3 on Ar-[bis(trifluoromethyl)hydroxyniethyl]trifluoroacetaniide, on treatment with trifluoroacetamide undergoes ring scission accompanied by loss of SO3, which acts as a cyclodehydrating agent on the bis-amide (229) so-formed, to yield 2,4,4,6-tetrakis(trifluoromethyl)-4//-l,3,5-oxadiazine (230) (Scheme 38) <84JOU1213, 89JOU578>. 

The chemistry of 1,3,4-thiadiazole has been recently reviewed <04MI405>. The 2-substituted 1,3,4-thiadiazoles 258 are formed by the reactions of thiohydrazides 257 with DMF and diethyl chlorophosphate. This cyclodehydrating agent is superior to several commonly used ones such as ethyl orthoformate, ethyl formate or even phosphorus oxychloride for this type of cyclization <04817>. Reaction of/ -tolualdehyde hydrazone 259 with disulfur dichloride in the presence of DBU gives 2,5-di(p-tolyl)-1,3,4-thiadiazole 260 <04S1929>. 

This mechanism, however, does not explain the exact nature of participation of the cyclodehydrating agents. It is also uncertain which of the two oxygen atoms is expelled on cyclization. 

Subsequent developments, including cyclizations by means of benzene-sulfonyl chloride or silver benzenesulfonate in pyridine, and by phosphoryl or thionyl chloride have already been reviewed by Cornforth.2 4 Of the above cyclodehydrating agents, phosphorus pentoxide is generally preferred to effect cyclizations smoothly 40 for example, phosphorus pentachloride tends to give oxazoles chlorinated in the side chain,60 as shown in Eq. (4). 

A wide range of polyoxadiazole polymers with hexafluoropropylidene linkages have been synthesized in Cambridge (3. As illustrated in Scheme 5, aromatic oxadiazole polymers 18 and 20 have been synthesized by a one pot reaction of the diacid 15 with tiie dicarboxylic hydrazide 16 and hydrazine sulphate 17 respectively at 100 °C in the presence of P2O5/CH3SO3H which serves both as solvent and cyclodehydration agent. 

More recently, the synthesis of 1,3,4-oxadiazoles 73, including fluorinated derivatives, from 1,2-diacylhydrazines was reported by using [Et2NSF2]BF4 as a convenient cyclodehydration agent (Scheme 21) [40]. 

Scheme 21 Synthesis of 1,3,4-oxadiazoles 73 by using [Et2NSp2]BF4 as a cyclodehydration agent...

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