Cyclodehydrating agents/cyclodehydration

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. 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

Trepipam (69) is a sedative agent apparendy acting via dopaminergic mechanisms. It can be synthesized by attack on the less hindered terminus of styrene oxide (66) by 4,5-dimethoxyphe-nethylamine (65) to give 67. Cyclodehydration catalyzed by strong acid then leads to 68 and N-... 

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... 

A related antiinflammatory agent prepared via a more traditional route is fluproquazone (65). Heating with urea in acetic acid results in transamidation by synthon and subsequent cyclodehydration completes the synthesis. 

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

The most versatile syntheses of 3-unsubstituted-2,4-oxazolidinediones involve either cyclization of a-hydroxy esters with urea or cyclization of a-hydroxy amides with a carbonate or phosgene. A third very useful approach is cyclodehydration of 0-carbamoyloxy acetic acids. Normally, this method affords 3-substituted analogues in which the 3-substitutent is derived from an isocyanate. However, examples in which an a-O-carbamoyloxy ester has been prepared via chlorosulfo-nyl isocyanate or an equivalent will also be described in this section. Extensions of these methodologies together with new approaches to 2,4-oxazolidinediones follow. Many of the analogues prepared, particularly as potential antidiabetic agents, employ a-hydroxy esters or a-hydroxy amides as precursors, which provides clear evidence of the versatility and generality of these classical approaches. A selection of recent examples will illustrate this point. 

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. 

Hydrazides have also been used as nucleophiles for ring opening to give the corresponding bis(acylhydrazides) 540. ° Subsequent cyclodehydration of 540 leads to the 4-alkylidene(arylidene)imidazolones 541 that have been evaluated as anticonvulsant, antihelmintic, antibacterial, antifungal, antiviral, and antitubercular agents (Scheme... 

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... 

The key to acetylene terminated polyimides is the availability of the end-capper which carries the acetylene group. Hergenrother (130) published a series of ATI resins based on 4-ethynylphthalic anhydride as endcapping agent. This approach first requires the synthesis of an amine-terminated amide acid prepolymer, by reacting 1 mole of tetracarboxylic dianhydride with 2 moles of diamine, which subsequently is endcapped with 4-ethynylphthalic anhydride. The imide oligomer is finally obtained via chemical cyclodehydration. The properties of the ATI resin prepared via this route are not too different from those prepared from 3-ethynylaniline as an endcapper. When l,3-bis(3-aminophenox)benzene was used as diamine, the prepolymer is completely soluble in DMAc or NMP at room temperature, whereas 4,4 -methylene dianiline and 4,4 -oxydianiline based ATIs were only partially soluble. The chemical structure of ATIs based on 4-ethynylphthalic anhydride endcapper is shown in Fig. 45. 

Similar cyclodehydrations of simple 1,5-diketones may require more reactive agents. Thus 24 undergoes dehydration with P4O10 to 2,4,4,6-tetraph-enyl- 4//-pyran (25, 68%).58... 

AHC(18)337>. The 3-alkylbenzo[6 ]furans result from cyclodehydration of aryloxyacetones the most common dehydrating agents are sulfuric acid, phosphorus oxychloride and poly-phosphoric acid. The allyl ethers of phenols can be converted to 2-alkyl-2,3-dihydro-benzo[6]furan by heating with polyphosphoric acid, pyridine hydrochloride or magnesium chloride at 180 °C the intermediate o-allylphenol is not isolated. 

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