Cycloaddition of oxazoles

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

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. 

Cycloaddition of oxazoles with arynes provides a route to substituted polycyclic ethers and hydrocarbons (80TL3627). Oxazole (354), for example, reacted with anthranilic acid and isoamyl nitrite to provide the cyclic ether (357) by way of the benzofuran (356). The ether was then treated with zinc in glacial acetic acid to furnish hydrocarbon (358) in 70% yield based on the starting oxazole (Scheme 77). 

Since the initial report that alkyloxazoles participate in Diels-Alder reactions with maleic anhydride,2 extensive efforts have defined the scope and synthetic utility of the [4 + 2] cycloadditions of oxazole derivatives. This work has been the subject of several reviews.3 9... 

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

The presence of 1,3-heteroatoms renders the C(2) position of oxazoles electron deficient. As such, this facilitates nucleophilic additions at C(2) and subsequent transformation of oxazoles into a variety of other heterocycles. Formal [3 + 2] cycloadditions of oxazoles with dipolarophiles also effects similar transformations. 

TABLE 1.57. 2-OXAZOLINE-4,5,5-TRICARBOXYLATES AND 3-OXAZOLINE-2,5,5-TRlCARBOXYLATES FROM [3 + 2] CYCLOADDITION OF OXAZOLES AND DIETHYLOXOMALONATE ... 

Examples of intermolecular cycloadditions of oxazoles with alkenes since 1985 include approaches to the ubiquitous analogs of the 3-hydroxypyridine pyridoxol, several applications in medicinal chemistry, and the first demonstrations of oxazole acting as a dienophile in [4 + 2] cycloadditions. 

A major driving force in the early study of Diels-Alder cycloadditions of oxazoles was the enormous annual commercial demand for pyridoxol, a form of vitamin Bs. The numerous studies, beginning in the 1960s, describing the utility of oxazoles for the construction of pyridoxol and its analogs have been detailed (Fig. 3.11). ... 

A variety of substituents—including alkyl, alkenyl, cyano, acetyl, and alkoxy— is tolerated at the 2 and 5 positions of the oxazole ring for these cycloadditions. Acetylenic dienophiles with alkyl, trialkylsilyl, phenyl, ester, ketone, and acetal substituents, as well as terminal alkynes, are precedented. Ab initio calculations predict a slightly higher activation energy for the cycloaddition of oxazole with acetylene compared to the oxazole-ethylene reaction. ... 

Kondrat eva reported the first example of a cycloaddition of oxazoles 224 and alkenes to afford pyridine derivatives 225. However, the reaction is... 

Cycloaddition of oxazole 229 with maleic anhydride initially gave the oxabicyclooctane system 230. Upon exposure to acidic ethanol, 230 fragmented to afford pyridine 231. Reduction of the ester 231 with LiAlH4 generated vitamin 65, pyridoxine (3). °... 

Five-Component Synthesis of Hexasubstituted Benzene Cycloaddition of oxazole with olefin afforded functionalized pyridine after fragmentation of the oxa-bridged cycloadduct (Eq. (1), Scheme 15.19). Logically, if an alkyne were used as a partner of oxazole, the cycloaddition would give an oxa-bridged cyclohexadiene that could undergo the retro-DA reaction to provide a substituted furan (Eq. (2), Scheme 15.19). 

While the cycloaddition of oxazole with acetylene is a well-established method for furan synthesis [36], the corresponding reaction of 5-amino oxazole was unknown at the outset of this work. As shown in Eq. (3) of Scheme 15.19, the reaction of 24b with 3-phenyl-2-propynoyl chloridephenylpropioloyl chloride (55a) proceeded smoothly to provide the 5,6-dihydro-furo[2,3-c]pyrrol-4-one (56) in greater than 95% yield. A triple domino sequence involving acylation/intramolecular DA cycloaddition/retro DA could explain the reaction outcome. That the domino process was initiated by acylation was evidenced by the fact that 24b failed to react with dimethyl acetylenedicarboxylate (DMAD) under the identical conditions. 

Pyrrohn-2-ones can be reached via cycloadditions of oxazoles. Bonne and colleagues employed a one-pot multicomponent cycloaddition using morpholine, cyclohexanecarboxaldehyde, and methyl p-nitrophenylisocya-noacetate to provide 5-methoxyoxazole which upon further heating in toluene and triethylamine with 3-phenylprop-2-ynoyl afforded the corresponding 3-pyrrolin-2-one (2007ACIE2485). 

Cydoadditions. Lewis acid-mediated [3 + 2] cycloadditions of oxazoles and aldehydes or diethyl ketomalonate have been observed using organoaluminum and Sn" Lewis acids. The reactions are highly regioselective, with stereoselectivity extremely dependent upon Lewis acid (eq 32). For example, the (BINOL)AlMe-promoted reaction between benzaldehyde and the oxazole (12) provides the oxazoline with a cisitrans ratio of 98 2. The selectivity is reversed with SnCU which provides a cisitrans ratio of 15 85. frans-5-Substituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes. ... 

In contrast to oxazole, thiazole does not undergo the Diels-Alder cycloaddition reaction (331). This behavior can be correlated with the more dienic character of oxazole, relative to thiazole, as shown by quantochemical calculations (184). 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

Cycloaddition of 3-methylenephthalide with ot./V-diphenylnitrone gave two diastereoisomers of 2,3-diphenyl-2,3-dihydrospiro 1,3-oxazole-5(47/ )l (3 H)-2-benzoluran]-3 -one (805). The 1,3-dipolar cycloaddition reaction of /V-benzyl-C-(2-furyl)nitrones with electron-rich alkenes gave preferentially trans-3,5-disubstituted isoxazolidines (endo approach). These experimental results are in good qualitative agreement with those predicted from semiempirical (AMI and PM3) and ab initio (HF/3-21G) calculations (806). 

A more elaborate approach was taken by Kaffy et al. [94], The goal of the research was a series of compounds with greater stability and a higher affinity for endothelial cells within tumor vessels than CA-4, 7 however, the paper described a method that was purely synthetic. The synthetic strategy involved a 1,3-dipolar cycloaddition of a nitrile oxide 186 with a substituted aryl alkyne 187 to form the oxazole 188. 

The weak aromaticity of oxazole is reflected by its chemical behavior, demonstrating a high degree of bond localization (illustrated by the propensity for cycloaddition reactions),137 and is supported by theoretical calculations (ring current indices, i.e., the bond... 

Two synthetic routes to meso-ionic l,3-diazol-4-ones (91) have recently been reported. 1,3-Cycloaddition of phenyl isocyanate to the meso-ionic l,3-oxazol-5-one (94) yields the intermediate (95 or 96) from which carbon dioxide was extruded in boiling xylene, giving the meso-ionic l,3-diazoi-4-one (97). 

Meso-ionic l,3-diazole-4-thiones (103, R = Ph) have been prepared by 1,3-dipolar cycloaddition of phenylisothiocyanate to meso-ionic 1,3-oxazol-5-ones (66) and l,3-thiazol-5-ones (105). Another route to l,3-diazole-4-thiones is exemplified by the formation of the derivative (103, R = R = Me, R = R = Ph) from the methiodide (104) and methylamine. ... 

The reaction of a-diazocarbonyl compounds with nitriles produces 1,3-oxazoles under thermal (362,363) and photochemical (363) conditions. Catalysis by Lewis acids (364,365), or copper salts (366), and rhodium complexes (367) is usually much more effective. This latter transformation can be regarded as a formal [3 + 2] cycloaddition of the ketocarbene dipole across the C=N bond. More than likely, the reaction occurs in a stepwise manner. A nitrilium ylide (319) (Scheme 8.79) that undergoes 1,5-cyclization to form the 1,3-oxazole ring has been proposed as the key intermediate. 

The facile proton abstraction of activated oxazolines offers a convenient method to convert cis oxazolines to the thermodynamically more stable trans isomer. Suga, Ibata, and co-workers took advantage of this property to correctly determine the stereochemistry for the oxazoline obtained from the [3 + 2] cycloaddition of 5-methoxy-2-(p-methoxyphenyl)oxazole with benzaldehyde (Scheme 8.122). 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

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