Unsaturated 5 -oxazolones reaction with

Urea, thiourea, and 5-alkylisothiouronium halides have also been used as bis(nucleophiles) in reactions with unsaturated oxazolones. Reaction with urea and thiourea leads to the corresponding imidazolones. The use of... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

Alkyl(aryl)-2-(trifluoromethyl)-5(277)-oxazolones have been used as intermediates to prepare 2-(trifluoromethyl)pyrroles interesting compounds frequently used as insecticides and acaricides. The oxazolones react with electron-dehcient unsaturated compounds in the presence of a base. Reaction of 5(277)-oxazolones, usually with a substituted aryl ring at C-4, with a wide variety of alkynes and alkenes has given rise to numerous 2-(trifluoromethyl)pyrroles 56. For example,... 

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. 

Reaction of methyl 3-(dimethylamino)-2-isocyanoacrylate (Ri = Me) with acyl chlorides gave 2-acyl-4-(dimethylaminomethylene)-5(477)-oxazolones 375. ° The same reaction with arenesulfenyl chlorides gave either 2-arylthio-4-(dimethylami-nomethylene)-5(477)-oxazolones 376 or an unsaturated 5(477)-oxazolone 377 containing an imidazole at C-2 depending on the substitution present in the arenesulfenyl chloride. Nitroarenesulfenyl chlorides favored 376. ° ° Selected examples of 372, 375, and 376 are shown in Table 7.33 (Fig. 7.44 Scheme 7.121). 

Reaction of unsaturated 5(4//)-oxazolones with appropriate nucleophiles affords new unsaturated 5(4//)-oxazolone analogues used as intermediates to prepare a variety of interesting compounds. 4-(Chloromethylene)-5(4/i/)-oxazolones react with a variety of nucleophiles. For example, 4-(chloromethylene)-2-phenyl-5(4F/)-oxazolone 395 reacts with imidazole to afford 4-[(imidazol-l-yl)methyl-ene]-2-phenyl-5(4F/)-oxazolone 396. The authors found no evidence for the product derived from carbon-carbon bond formation, that is, 4-[(imidazol-4-yl)methylene]-2-phenyl-5(4//)-oxazolone (Scheme 7.126). 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

There are a number of comprehensive studies reported of the reactions of a particular unsaturated oxazolone with nitrogen nucleophiles. On the other hand, unsaturated 5(4/f)-oxazolones react with a variety of amines to yield acylamino amides with interesting agrochemical properties. ... 

The direct condensation of unsaturated oxazolones with tryptamine in hydrochloric acid is an important and interesting case that deserves special attention. The reaction occurs via in situ hydrolysis of the oxazolone to a keto acid followed by a Pictet-Spengler-like reaction with tryptamine. This protocol affords a tetrahydro-p-carboline wherein the oxazolone is the synthetic equivalent of an arylacetalde-hyde. The reaction has been extended to substituted tryptamines 500 thus, allowing access to 1,3,4-trisubstituted tetrahydro-p-carbolines 501 as shown in Scheme 7.159. Some of these compounds have shown promising central nervous system activity. 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

Reaction of unsaturated 5(4//)-oxazolones with bis(nucleophiles) opens the way for the preparation of diverse heterocyclic compounds depending on the nucleophilic atoms of the reagent. First, if we consider nitrogen-containing bis(nucleo-philes), the reaction of anthranilic acid with unsaturated oxazolones 550 gives rise to substituted 3,l-benzoxazin-4-ones 551 (Scheme 7.174). " °... 

In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,0-bis(nucleophile) when reacted with unsaturated 5(4//)-oxazolones 584 with a leaving group at the exocyclic p-carbon. In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabihzed ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2//-pyran-2-ones (Scheme 7.185). 

Unsaturated 5(4H)-oxazolones undergo a Friedel-Crafts reaction with aromatic hydrocarbons in the presence of a Lewis acid. In particular, a 2-aryl-4-benzylidene-5(4H)-oxazolone 598 reacts with o- or p-xylene in the presence of aluminum chloride via ring opening and subsequent dearylation to yield 599 as indicated in Scheme 7.191. ... 

Some examples of the Michael reaction on the exocyclic double bond of an unsaturated oxazolone have been discussed in previous sections. The synthesis of unsaturated 5(4//)-oxazolones from unsaturated 5(4/l/)-oxazolones via an addition-elimination sequence and the sequential reaction of unsaturated 5(4/i/)-oxazolones with a l,3-bis(nucleophile) have already been considered. This section will review Michael additions exclusively and, in this respect, a wide array of nucleophiles has been studied. 

Although it is well known that sulfur nucleophiles are excellent candidates for Michael reactions, they have scarcely been examined with unsaturated oxazolones. Nevertheless, 4-methyltoluene-a-thiol reacts with 4-benzylidene-2-methyl-5 (4//)-oxazolone 614 to give 615 as a mixture of erythro and threo isomers (Scheme 7.197). ° ... 

Organophosphorous compounds have also been used as nucleophiles with unsaturated oxazolones. Initially, Michael reaction of a trialkyl- or dialkylphosphite gives 617 or 619 that undergo subsequent ring opening to yield a 2-acylamino-3-phosphonyl-618 or 2-acylammo-3-phosphinyl-620 derivative of the corresponding carboxylic acid, respectively (Scheme 7.198). ° ... 

Sulfur ylides are among the most interesting carbon nucleophiles and their synthetic importance has been recently reviewed.One especially interesting use of these ylides is their application to the synthesis of cyclopropane derivatives using unsaturated oxazolones. For example, stabilized sulfur yhdes react with unsaturated oxazolones 629 via a Michael reaction to give oxazolone spirocyclopropanes 630 as shown in Scheme 7.202 and Table 7.46 (Fig. 7.57), whereas the less stabilized sulfur ylides give ring-opened products 631 as the major compounds (Scheme 7.202). ... 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

Unsaturated 5(4//)-oxazolones have an additional exocylic double bond which has been exploited in various reactions. Chiral oxazolone 120 undergoes diastereoselective reaction with diazomethane to give cyclopropane adduct 121, which can be transformed into various cyclopropylamino acids 122 (Scheme 29) <1996T5881>. 

The difference is interestingly exemplified in the differing modes of reaction of hydrazoic acid with some alkylidene (and arylidene) oxazolone derivativesThe alkylidene compound 174 behaves as an a, -unsaturated carbonyl compound with the hydrazoic acid adding to the exocyclic double bond. A subsequent ring opening with further addition leads to the formation of the diazide 175 (equation 75). In contrast the exocyclic double bond of the arylidene compound 176 is unreactive, and nucleophilic attack occurs at the... 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

The isolation of several pairs of geometric isomers of 4-unsaturated-5-oxazolones has been described. Generally, only one isomer is obtained when an aldehyde reacts with hippuric acid in the presence of acetic anhydride. Occasionally, mixtures have been separated in base-catalyzed reactions. In acetic anhydride-sulfuric acid or in 100% sulfuric acid, a mixture is obtained, and it has been suggested that sulfuric acid inhibits mutarotation of the intermediate addition product 53, which is a mixture of diastereomers (see, e.g., compound... 

TABLE 7.10. 2-(TRIFLUOROMETHYL)PYRROLES FROM REACTION OF 5(2/7)-OXAZOLONES WITH ELECTRON-DEFICIENT UNSATURATED COMPOUNDS... 

The behavior of 2-substituted- or 2-unsubstituted-5(4//)-oxazolones is completely different. Reaction of electrophiles with 2-substimted-5(47/)-oxazolones usually occurs at C-4, whereas reaction of electrophiles with 2-unsubstituted-5(47/)-oxazolones affords the corresponding 5(2//)-oxazolones. The best example of the behavior of 2-unsubstituted-5(47/)-oxazolones involves 4-isopropyl-5(47/)-oxazolone 143, the anion of which can be considered as a formyl anion equiva-lent. ° ° Thus, reaction of 143 with a catalytic amount of triethylamine gives 144 that reacts with a,p-unsaturated carbonyl compounds to afford Michael adducts or with aldehydes to produce the corresponding aldol adducts. Mild acid hydrolysis of 145 yields the corresponding aldehydes (Scheme 7.42). 

Michael Reaction. 5(47/)-Oxazolones undergo base-catalyzed conjugate addition to activated unsaturated compounds to afford the corresponding C-4 Michael adducts. For example, base-catalyzed addition of a 4-monosubstituted-5(4//)-oxazolone 157 to methyl propiolate yields a mixture of diastereomeric methyl 3-(5-oxo-2-phenyl-2-oxazolin-4-yl)acrylates 158. Hydrolytic ring opening of 158 and subsequent oxidation with lead tetraacetate affords 3-acylacrylates 160... 

Synthesis oe Heterocyclic Compounds. In some cases, dehydroamino acids obtained from unsaturated 5(477)-oxazolones have been used as intermediates to prepare other heterocyclic compounds. For example, reaction of 2-benzoylamino-3-substituted-2-alkenoic acids 485 with alkyl or arylisothiocyanates affords 4-aryl-methylene-l,2-disubstituted-5-oxo-4,5-dihydroimidazoles 486 (Scheme 7.155). ... 

TABLE 7.43. 2-STYRYL-l-SUBSTITUTED IMIDAZOLONES FROM REACTION OF UNSATURATED 5(4ff)-OXAZOLONES WITH SCHIFF BASES... 

TABLE 7.44. BENZIMIDAZOLES AND BENZOTHIAZOLES EROM REACTION OF UNSATURATED 5(4i7)-OXAZOLONES WITH 2-SUBSTITUTED ANILINES... 

Reaction of suitably functionahzed phosphonium ylides with unsaturated 5(47/)-oxazolones 579 has opened the way for the use of new C,C-bis(nucleophiles). Of particular interest is ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate used to prepare dihydrobenzoxazoles 582 and diastereoisomeric 1,3-cyclohexanedione ylides 583 (Scheme 7.184). ... 

TABLE 7.46. OXAZOLONE SPIROCYCLOPROPANES EROM REACTION OF UNSATURATED 5(4//)-OXAZOLONES WITH A STABILIZED SULFUR YLIDE ... 

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