Oxazoles diene reactivity

The rate of Diels-Alder reactions of oxazoles with electron-deficient olefins and acetylenes depends on the electron-donating ability of the oxazole substituent Rates decrease in the order OR > NR1R2 > alkyl > 4-phenyl > COCH3 > CO2CH3 3> 2-,5-phenyl 5-aIkoxy oxazoles have reactivity roughly equivalent to an all-carbon diene. 

Oxazole A is often used as a diene in Diels-Alder reactions. However, isoxazole B appears to be inert. Their different reactivities are surprising, considering that their MOs are similar. Propose an explanation. Bond lengths and strengths CC 1.54 A and 82.6 kcalmoU1 C=C 1.34 A and 144 5 kcalmoU1 CN 1.47 A and 72.8 kcalmol-1 C=N 1.27 A and 147 kcal/mol-1 NO 1.40 A and 48 kcalmol-1.86... 

The instability of 1-azabuta-1,3-dienes arising from the imine moiety and the low reactivity as dienes in the Diels-Alder reaction are sometimes problems. Benzylidene(cyano)methyl-l,3-benzothia/oxazoles, featuring a stabilized imine moiety in the form of a heteroaromatic ring... 

Electron-releasing substituents on the oxazoles increase the rate of reaction 5-alkoxy-oxazoles are comparable in reactivity to typical all-carbon dienes. 4-(Trimethylsilyloxy)-oxazoles react smoothly to produce furans at modest temperatures. ... 

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 reactivity of five membered heterocycles with two heteroatoms as dienes with at least one nitrogen for Diels-Alder reactions is also very low. In fact, there is not much experimental data in this area of research, except for addition of dienophiles to oxazole, better known as the Kondrateva reaction [57]. The main reason for their low reactivity is high heterocycle aromaticity delocalization of molecular x-orbitals that should be part of the cycloaddition reaction. That can be explained from FMO energy difierences between aromatic heterocycles as well as by bond order uniformity of heterocycles with two heteroatoms... 

Thionyl chloride is one of the most common and effective reagents to effect cyclodehydration of 2-acylamino ketones. For example, Litak and Kauffman refluxed 446 in SOCI2 and isolated 4-[2-(3,4-dihydro-2//-l-benzopyran-6-yl)oxazol-5-ylpyridine 447 in excellent yield (Scheme 1.123). Both 447 and 441 were starting materials for reactive fluorescent stains to be used in fluorescence microscopy. Reck and Friedrichsen refluxed 448 in SOCl2/chloroform and prepared 4-(methoxy-carbonyl)-2-methyl-5-oxazoleacetic acid methyl ester 449 (Scheme 1.123). This material was a precursor of the novel diene 4-methoxy-2-methyl-furo[3,4-ti]ox-azole-6-carboxylic acid methyl ester 450. 

Thiazole does not have a relative diene character possessed by other heterocycles, unlike other heterocyclic structures such as 1,3-oxazole and furan. So 1,3-thiazoIe does not undergo Diels-AIder reactions very easily due to the its low reactivity on accoimt of greater aromaticity than oxazoles as well as due to highly nucleophilic thiazole. However, there are exceptions where an intramolecular Diels-AIder reaction of thiazole with alkyne activated by a methoxyl group is facilitated to produce a thiophene, albeit in a rather low yield of 48%, after three days at reflux in degassed mesitylene. This happens through the extrusion of acetonitrile. 

Considerable attention has been paid to the reactions of oxazoles with typical Diels-Alder alkene dienophiles much of the early work is relatively inaccessible, being described in Russian and patent literature. The adducts are transformed into pyridines by different routes (section 5.15.1.4). Electronreleasing substituents on the oxazoles increase the rate of reaction 5-alkoxyoxazoles are comparable in reactivity to typical all-carbon dienes. Particularly useful dienophiles are the N-acyl-oxazolones these are synthons for cis-1,2-amino-alcohols. ... 

A domino sequence comprising a cycloaddition and subsequent cycloreversion step can often find a more general application in organic synthesis, especially in the formation of aromatic compounds such as furans or pyrroles. Oxazole moieties as electron-deficient dienes often serve as the crucial reactive centers which cycloadd to a triple bond and eliminate a nitrile upon cycloreversion. If the first step is intramolecular, the impelling enthalpy preserved in the stability of the formed CN function is additionally accompanied by a positive entropy when the nitrile, sometimes volatile, leaves the substrate. In an older example from 1984 [10], Jacobi and coworkers devised a scheme for the preparation of a highly substituted furan on their synthetic way to paniculide A. An intramolecular Diels-Alder reaction was followed by the critical extrusion of volatile acetonitrile, furnishing the bicycle 8 in 94% yield (Scheme 6.2). 

Four-Component Synthesis of Pyrrolopyridines If a primary amine were used as an input, the three-component reaction shown in Scheme 15.10 would produce an oxazole bearing a secondary amine. In other words, the so-produced adduct 24 would contain both a diene (oxazole) and a nucleophilic site (amine). Therefore, a dienophile bearing an electrophihc center would pair perfectly with the dual reactivity of 24. In practice, if an activated a,P-unsaturated carboxylic acid derivative were introduced after the three-component reaction, a sequence of N-acylation/intramolecular Diels-Alder reaction (IMDA) might occur to produce the four-component adducts. 

If a reactive dienophile was incorporated into one of the following inputs, namely, amine, aldehyde, and a-isocyanoacetamide, then the resulting oxazoles 61-63 having both the diene and dienophile functions could undergo directly the IMDA reaction. Depending on the coimectivity and the nature of the dienophile (double bond or triple bond), different products would then be produced after a sequence of three-component reaction/DA reaction/fragmentation (Figure 15.4). 

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. 

It was shown that the electron-rich oxazolium anions decrease the rate of reaction for NEDDA, and increase the activation barrier however, electron-poor oxazolium cations have low activation barriers for lEDDA and reactivity can be promoted by adding alkyl, Lewis, and Br0nsted acids to the oxazole nitrogen atom. The dehydration of cationic Diels-Alder cycloadducts was also found to be a highly exothermic process, favoring formation of pyridinium cations. Therefore, the best strategy to harness the potential of oxazole as a diene in lEDDA reaction is to use a proton-assisted process (i.e., to exploit the electron-poor oxazolium cation). 

The heterocyclic 1,3-dienes such as pyrroles, thiazoles, ° and oxazoles are also reactive and afford endoperoxides on photooxygenation. Most of these ozonide-type cycloadducts have neither been isolated nor detected but have been postulated as plausible reaction intermediates. 

The reaction of vinylfurans with DAD usually affords intractable mixtures however, furan itself undergoes cycloaddition readily, provided suitable reaction conditions are employed to avoid decomposition of the reactive products. Oxazole derivatives readily participate in [4 + 2] cycloadditions with DAD. 7 asymmetric Diels-Alder reaction between DAD and pyridazin-3-ones facilitated by Baker s Yeast has been reported with ee s in the range of 9.1-62.7%. The reactions of a number of acyclic heterodienes with DAD have also been reported recently, including 2-aza-l,3-dienes, a,p-unsaturated thioketones, and l-thia-3-aza-1,3-dienes. The quinodimethane derivatives of a number of heterocycles have been used in cycloadditions with DAD (eq 9). ... 

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