Alkenes Diels-Alder reactions, oxazole

An oxazole-alkene Diels-Alder reaction has also been used to synthesize a tri-fluoromethylated pyridine related to pyridoxol. 5-Ethoxy-4-(trifluoromethyl)-2-oxazolecarboxylic acid 41 decarboxylated and then reacted with acrylic acid to give the expected 3-hydroxy-2-(trifluoromethyl)pyridine-4-carboxylic acid 42 in 63% yield (Fig. 3.13)." The electron-withdrawing trifluoromethyl group of 41 strongly modulates its reactivity, however, and it does not react with ethyl acrylate or A-phenyl maleimide. 

Since 1985, the major application of intramolecular oxazole-alkene Diels-Alder reactions has been in the held of natural product synthesis, in which readily available oxazole-olehns can provide access to highly substituted pyridines. All of the intramolecular reactions described here have four-atom linkers between the oxazole and olehn, found by Turchi to be optimal for these cycloadditions. 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

The bicyclic intermediate arising from Diels-Alder reaction of oxazoles with alkynes extrudes nitriles (comprised of the nitrogen atom and C4 of the oxazole) to form furans as the ultimate product of the cycloaddition. The same regioselectivity seen in alkene Diels-Alder reactions is noted here. 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

Oxazoles represent the most widely recognized heteroaromatic azadiene capable of [4 + 2] cycloaddition reactions. The course of the oxazole Diels-Alder reaction and the facility with which it proceeds are dependent upon the dienophile structure (alkene, alkyne), the oxazole and dienophile substitution, and the reaction conditions. Alkene dienophiles provide pyridine products derived from fragmentation of the [4 + 2] cycloadducts which subsequently aromatize through a variety of reaction pathways to provide the substituted pyridines (Scheme 14). In comparison, alkyne dienophiles provide substituted fiirans that arise from the retro Diels-Alder reaction with loss of R CN from the initial [4 + 2] cycloadduct (Scheme 15,206 Representative applications of the [4 + 2] cycloaddition reactions of oxazoles are summarized in Table 14. Selected examples of additional five-membered heteroaromatic azadienes participatiitg in [4 + 2] cycloaddition reactions have been detailed and include the Diels-Alder reactions of thiazoles, - 1,3,4-oxadiazoles, isoxazoles, pyrroles and imidazoles. ... 

Examples of cycloadditions with oxazole substrates that lead to products other than furans are also known. 4-Substituted oxazole 73 has been used in an intramolecular Diels-Alder reaction <2004TL6471> with an alkene to afford a pyridyl cycloadduct 74 in good yields en route to the synthesis of a Rauwolfm alkaloid, (—)-suaveoline. This reaction required refluxing xylene with l,5-diazabicyclo[4.3.0]non-5-ene (DBN) as an additive (Scheme 13). 

An intramolecular Diels-Alder reaction of oxazoles with alkenes has not been investigated (83T2869). Recently, Levin and Weinreb (83JA1397 84JOC4325) applied an intramolecular Kondrat va pyridine synthesis (74AHC(17)99 81MI1) to the total synthesis of azaphenanthrene alkaloids eupolauramine (506). Independently, some examples of intramolecular... 

Since their discovery in 1957, Diels-Alder reactions of oxazoles have proven useful for the synthesis of a variety of compounds and consequently have been a constant focus of attention <57MI 304-01 >. Reaction fundamentals and generalities were discussed in <84CHEC-I(6)177>. Alkynes and alkenes are the usual dienophiles. 

The ring enlargement of pyrroles providing 3-chloropyridines has already been described (see p 93). Oxazoles react as masked 2-azadienes with alkenes yielding pyridine derivatives of various types (see p 131). With enamines and ynamines, diazines and triazines undergo Diels-Alder reactions with inverse electron demand (see p 441). This leads to pyridines (e.g. 201) by the enamine cycloaddition of the 1,2,4-triazine, as shown below ... 

The Diels-Alder reaction of oxazoles with alkenes, alkynes, and heterodieno-philes has become a valuable tool for the construction of highly substituted pyridines, furans, and other heterocycles and has now been exploited for the synthesis of diverse compounds from pharmaceuticals to complex natural products. These reactions have been extensively reviewed. The purpose of this chapter is to provide an introduction to the use of oxazoles in Diels-Alder cycloadditions and an update on these reactions since 1985. 

Although the regiochemistry of oxazole-olefin cycloadditions has not been extensively studied, some generalizations can be made. The major product is the 4-substituted pyridine in those instances when the alkene dienophile bears an electron-withdrawing substituent. This regioselectivity is exemplified by the Diels-Alder reaction used in a synthesis of the natural product ellipticine by Kozikowski and Hasan," starting from the reaction of oxazole 21 with acrylonitrile to give 4-cyanopyridine 22 (Fig. 3.6). 

On occasion, oxazole-alkene Diels-Alder adducts such as 29, and more generally 15, fragment to provide products other than pyridines, depending on the reaction conditions used (Fig. 3.9). The reaction of 5-isopropoxy-4-methyloxazole 28 with nitroethylene therefore gave 31, rather than the expected nitropyridine." " Compound 31 was presumed to form via acid-catalyzed decomposition of the initial Diels-Alder adduct 29 to provide amino-diketone 30, which then cyclized to give 2-acetyl-3-nitropyrrole 31. 

The use of oxazole-alkene Diels-Alder cycloadditions to form biologically relevant molecules has recently been applied to the synthesis of isoindoles, useful intermediates for the preparation of substance P antagonists. Thus 5-ethoxy-4-methyloxazole 8 reacted with 4,4-dimethyl-2-cyclopentenone 78 in refluxing benzene in the presence of catalytic zinc bromide to give the (l//)-cyclopenta(c)-pyrrole 80 as a separable 3 1 mixture of cis and trans isomers in 53% yield (Fig. 3.22). The reaction is presumed to proceed via the intermediacy of cycloadduct 79. When cyclohexenone 81 was used as the dienophile, the product was the hydro-(l//)-isoindole 82, obtained via dehydroformylation of the cycloadduct, in 85% yield after only 30 min in refluxing benzene. 

Oxazoles are competent dienes for Diels-Alder reactions with alkenes, alkynes, and singlet oxygen however, the initial cycloadduct is unstable and decomposes to yield different products depending on the nature of the dienophile. 

In the oxazole system, the structural element of a bridged 2-aza-l,3-diene is present. Therefore, oxazoles are enabled to undergo Diels-Alder reactions with activated alkenes and alkynes. For example, acryhc acid (as an unsymmetrical activated dienophile) adds to the oxazole 13 to give the product 14 of a (4 + 2)-cycloaddition regioselectively. The Diels-Alder adduct 14 can be transformed to the pyridine derivative 15 by acid-catalyzed dehydration. 

Diels-Alder reaction between oxazole and alkenes and subsequent rearomatization of the cycloadducts provides access to substituted p3nidines and other natural products that can be difficult to obtain via other synthetic means. Oxazole can participate in both inverse electron-demand Diels-Alder (lEDDA) reactions as an electron-poor diene and in normal electron-demand Diels-Alder reactions (NEDDA) as an electron-rich diene. NEDDA reactions often involve harsh conditions and high temperatures, whereas lEDDA reactions require substitution with electron-withdrawing groups onto the oxazole moiety or Brpnsted/Lewis acid catalysis to promote reactivity. 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

Benzoxazolo[3,4-a]pyridinium salts (116) are known to give cycloadditions of the [4-1-2] and [3 -I- 2] type with alkenes and alkynes. The primary adducts were readily converted to alternative heterocyclic systems (121) and (122) which were usually the isolated major products (Scheme 24) <79JOCill, 82JOC3098>. The formation of oxazoles from the reaction of alkynic aldehydes with (116) was claimed to result from the Diels-Alder pathway with the carbonyl group acting as the dienophile <93JCS(P1)1839>. 

Considerable attention has been paid to the reactions of oxazoles with typical Diels-Alder alkene dienophiles. The adducts can be transformed into pyridines by different routes (section 5.15.1.4). Electron-releasing substituents on the oxazoles increase the rate of reaction 5-alkoxyoxazoles are comparable in reactivity to typical all-carbon dienes. Particularly useful dienophiles are AT-acyl-oxazolones - synthons for c/j-l,2-amino-alcohols. ... 

Pyridines can be achieved by the [4 + 2] hetero Diels-Alder cycloaddition of i) an alkene dienophile and an 3-azadiene such as 1,2,4-triazine (the Boger reaction), oxazole (Kondrat eva pyridine synthesis), oxazinone, pyrimidine, or ii) an alkene and a 4-azadiene or iii) a butadiene and an azadienophile. 

Thioamide vinylogues (100) have been reported to yield Diels-Alder adducts on treatment with substituted alkenes and sulphenes/ In the former case, the heterocyclic compounds (107) and/or (108) were produced, depending on the substituents. In the latter case, the unsubstituted sulphene afforded merely (109), whereas solely the de-aminated products (110) were formed in reactions with benzylsulphene. 3-Alkylthio-l-aryl-3-arylamino-2-propene-l-thiones (41) have been converted into 3-arylamino-1,2-oxazoles, 3-arylaminopyrazoles, and the quinoline derivatives (111) by treatment with hydroxylamine, hydrazine, and sulphuric acid, respectively. " The formation of 2-imino-2H-thiopyrans by spontaneous ring-closure of -mercaptovinyl-acrylonitriles (112) has been reported recently. ... 

---