1.3.4- Oxadiazoles Diels-Alder reactions

Hydrocarbon oxadiazoles do not readily undergo Diels-Alder reactions, but 2,5-bis(trifluoromethyl)-l, 3,4-oxadiazole reacts with a number of strained or elec-... 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

AMI semi-empirical and B3LYP/6-31G(d)/AMl density functional theory (DFT) computational studies were performed with the purpose of determining which variously substituted 1,3,4-oxadiazoles would participate in Diels-Alder reactions as dienes and under what conditions. Also, bond orders for 1,3,4-oxadiazole and its 2,5-diacetyl, 2,5-dimethyl, 2,5-di(trifluoromethyl), and 2,5-di(methoxycarbonyl) derivatives were calculated <1998JMT153>. The AMI method was also used to evaluate the electronic properties of 2,5-bis[5-(4,5,6,7-tetrahydrobenzo[A thien-2-yl)thien-2-yl]-l,3,4-oxadiazole 8. The experimentally determined redox potentials were compared with the calculated highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO) energies. The performance of the available parameters from AMI was verified with other semi-empirical calculations (PM3, MNDO) as well as by ab initio methods <1998CEJ2211>. 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

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. ... 

The ring bond order deviation from uniformity partially agreed with the order of reactivity computed on the basis of FMO energy gaps. The least aromatic was 1,2,5-oxadiazole, while 1,2,3-thiadiazole should be most aromatic (Table 36). The order of reactivity was oxadiazole, triazole, thiadiazole in all 1,2,3-, 1,2,5- and 1,3,4-series of the three heteroatom heterocycles. Except for 1,3,4-oxadiazole, the two other 1,3,4- five-membered heterocycles were predicted to be more reactive than their 1,2,3- isomers (Table 36). The prediction that 1,2,5-oxadiazole was the most reactive heterocycle as a diene for Diels-Alder reaction was unacceptable due to the fact that two C-N bonds should be formed in the course of the reaction, which usually requires an exceptionally high activation barrier. 

Transition state structures are for s3mchronous concerted mechanism of Diels Alder reactions and are very similar to each other. The two isomeric structures for the cyclopropene addition to 1,2,5-oxadiazole are presented in Figure 9. Sometimes the AMI semiempirical method can compute as3Tnmetric transition state structures that are, in energy, very close to the symmetric transition state structures presented in Figure 9. 

Here we present only activation barriers for heterocycles with heteroatoms in 1,2,5- positions in reaction with the most reactive dienophile, cyclopropene (Table 40). It demonstrates our previous postulate that the activation barriers were too high, even with very reactive dienophiles such as cyclopropene. The most reactive was 1,2,5-oxadiazole but not 1,2,5-tbiadiazole as predicted on the basis of FMO energy gap between reactants. The results indicated that the reaction should not be experimentally achievable. To the best of our knowledge, there is no experimental evidence that heterocycles with heteroatoms in 1,2,5- positions might be acceptable dienes for Diels-Alder reactions. 

Further investigation of the role of 1,3,4-oxadiazole as a diene in Diels-Alder reactions... 

As mentioned above, the cycloaddition reaction with 1,3,4-oxadiazole is predicted to be LUMO diene (heterocycle) controlled. That definitely suggests that with electron-withdrawing substituents in the two and five positions of the heterocycle ring, the heterocycle should become more reactive as a diene for Diels-Alder reactions. To study the usefulness of 1,3,4-oxadiazole and its derivatives as dienes for the Diels-Alder reaction, we are presenting the results of our theoretical study of the cyclopropene addition to 2,5-di(trifluoromethyl)-l,3,4-oxadiazole. The AMI computed FMO energy gap for this reaction pair was only 8.00266 eV in comparison to 9.64149 eV FMO energy gap between LUMO of 1,3,4-oxadiazole and HOMO of cyclopropene. Therefore, the computed activation barrier for the cyclopropene addition to 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole should be very... 

The accumulation of the cycloaddition product is related to its thermal stability in regard to nitrogen elimination. Here, elimination of nitrogen is even more pronounced because of two reasons the presence of the double C-C bond instead of a cyclopropane moiety (Scheme 11) and because it can produce corresponding furan derivatives. Furan is actually one of the rare aromatic heterocyclic compounds that easily participates in Diels-Alder reactions as a moderately active diene. Therefore, it is also reasonable to postulate that the furan derivative obtained after elimination of nitrogen is more reactive than 2,5-bis(trifluoromethyl)-l,3,4-oxadiazole. Additionally, the cycloadduct with a second molecule of cyclooctyne would be a final product of the cycloaddition reaction. To explore this possibility further, a semiempirical study of cycloadduct stability and activation barrier needed for cyclooctyne to react with furan was performed. 

The Diels-Alder cycloaddition has played an important role in the synthesis of Narcissus alkaloids and related structures. Roger has prepared anhydrolycorinone using an intramolecular hetero-Diels-Alder reaction in which a 1,3,4-oxadiazole... 

Recent developments in the retro-Diels-Alder reaction have been reviewed. 1,3-Dipolar cycloadditions of nitrile oxides to 4-aryl-2-alkyIthio-l-azetines gave oxadiazabicyclo[3.2.0]heptenes that undergo a 2 -i- 2-cycloreversion with the loss of a styrene to furnish 5-alkylthio-3-aryl-l,2,4-oxadiazoles (Scheme 1). ... 

The Diels-Alder reactivity of 1,3,4-oxadiazoles as dienes was investigated with AMI semiempirical and hybrid density-functional methods. The validity and usefulness of the inertia principle for the qualitative evaluation of reactivity in Diels-Alder reactions is presented. The reactivity of 1,1-dimenthene to Diels-Alder cycloaddition is poor as a result of the difficulty of the diene adopting a planar conformation. The Diels-Alder transition states of dienes having conjugating substituents at C(2) or C(3) have been investigated to determine the reason for the unexpected high diene reactivity. Differences in rates of Diels-Alder reactions have been used as experimental indicators of synchronous or asynchronous transition states when non-symmetrical diene 2-(trimethylsilyloxy)cyclohexa-l,3-diene reacts with symmetrical ethylenic dienophiles. ... 

Bis(trifluoromethyl)-l,2,4,5-tetrazine (1111) and its homologue 1112 are extremely reactive hetero-dienes towards Diels - Alder reaction. Compounds 1111 and 1112 were prepared by reaction of oxadiazole 1114 [675] or perfluoropropene 1116 [676], respectively, with hydrazine, followed by oxidation (Scheme 237). 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

More recently, some examples of intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloaddition reactions of especially designed 1,3,4-oxadiazole derivatives have been described (Scheme 3). The... 

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