2-Methylfuran, Diels-Alder reactions

An interesting mechanistic issue was raised by Firestone on the aqueous Diels-Alder reaction between 2-methylfuran and maleic acid in water, which is found to be 99.9% stereospecific.80 By adding heavy atom (defined as any below the first complete row of the periodic table) salts to the aqueous media, it was found that addition of heavy but not light atom salts reduced the degree of stereospecificity significantly in the retrodiene reaction. The results suggest that a large portion of the Diels-Alder reaction occurs via diradical intermediates (Scheme 12.2). 

Similarly, ab initio calculations on the thermal reaction of propene forming methyl-cyclopentane suggested a three-step biradical reaction with 1,4-biradical and 1,5-biradical as intermediates. Quantum-chemical calculations have been carried out for the cyclization of the neocarzinostatin chromophore cyclonona-l,2,3,5-tetraen-7-yne to 1,5-didehydroindene biradical. The degree of stereoselectivity of the Diels-Alder reaction of 2-methylfuran and maleic acid in water has been found to reduce significantly in the presence of heavy atoms. Taking into account the relatively low concentration (3.5-7 m) of heavy-atoms, and the rapid fall off of the heavy-atom effect with distance, these results show that a large portion of the Diels-Alder reaction occurs via diradical intermediates. " ... 

The competition between Michael addition of a,(3-unsaturated ketones and Diels-Alder reactions involving furan and 2-methylfuran is affected by the catalyst used. Methyl vinyl ketone gives the alkylation product with furan and 2-methylfuran in the presence of silica gel (88TL175). Bis(alkylated) products have also been obtained in reactions of 2-methylene-1,3-dicarbonyl compounds (90H(31)1699). An intramolecular proton catalyzed alkylation reaction of an a,(3-unsaturated ketone provided a straightforward synthesis of norpinguisone (90TL4343) and in the example shown in Equation (4) the cyclization reaction involved an a,(3-y,8-dienone (94TL4887). 

Mechanism of the Diels-Alder Reaction. Studies of the Addition of Maleic Anhydride to Furan and Methylfurans. 

It is well known that simple furans, e.g., furan and 2-methylfuran, do not react with a,)3-unsaturated aldehydes and ketones under Diels-Alder reaction conditions. If the reaction is catalyzed by... 

Best and Wege59have reported the first total synthesis of Mansonone F and this is described in Scheme 10. Phenol (111)60 was made to react with 2-chloroacetyl-5-methylfuran (112) in dimethylsulfoxide and sodium methoxide to yield (113). Ketalization of (113) followed by catalytic reduction and basic hydrolysis afforded anthranilic acid (114). Diazotization followed by pyrolysis with propene oxide in 1,2-dichloroethane probably yielded aryne (115), which undergoes intramolecular Diels-Alder reaction producing the adduct (116). Deoxygenation and then acid hydrolysis afforded the product (117). This was subjected to Grignard reaction. The resulting tertiary alcohol on nitration yielded the nitro compound (118) which was subjected to reduction and oxidation respectively to obtain (119). It yielded Mansonone F (120) on dehydration. 

Diels-Alder reactions with furans can be very problematic due to the thermal sensitivity of the cycloadduct and their tendency for cycloreversion, which is due to the strain inherent to the 7-oxabicycloheptane cycloadduct (128) as well as the aromatic character of the furan. As shown in Table 11.9, high pressure significantly increases the yield of Diels-Alder adduct with furan derivatives. 2-Methylfuran is more reactive than furan but substituents on the alkene (dienophile) lower the... 

A reverse Diels-Alder reaction, the decomposition of 2-methylfuran-maleic anhydride ejro-adduct (in iso-octane) was the object of an extensive study of isotope effects . Here rehybridisation is from ip to sp and therefore a ratio knlko > 1 is to be anticipated. This has, in fact, been found (/ h/ d)50 c = 108 per D atom, both for all possible deuterations on the maleic anhydride moiety (see below), either at X or at Y or at X and at Y, and for deuteration of the furan moiety at Z. 

The enantioselective synthesis of (-i-)-shikimic acid and (-i-)-5-ep/-shikimic acid by an asymmetric Diels-Alder reaction of (5)-a-sulfmylacrylates with furan was reported. In the Diels-Alder reaction between acryloyloxazolidinone and furan catalyzed by a chiral cationic Cu(II) complex a high enantioselectivity was observed <97TL57>. The synthesis of ubiquinones-3 specifically labelled with C at the C(5)- or C(6)-positions starting with 2,5-bis(trimethylsilyloxy)-3-methylfuran and (2- C)-2-bromo-l,2-dichloroethene was reported <97T2505>. Diels-Alder reactions of 5-triisopropylsilyl-2-vinylfuran and 2-triethylsilyl-4-vinylfuran with acetylenic and olefinic dienophiles occur with high site specificity in the extraannular mode to produce trialkylsilylbenzofuran derivatives <97H(45)1795>. 

The genesis of the fumaric acid formed in the Diels-Alder reaction of 2-methylfuran with maleic acid has been re-investigated. Kinetic measurements indicate that fumaric acid is formed in a very minor side reaction, its rate of formation being very much less than the rates of cycloaddition between the furan and maleic acid and the cyclo-reversion of the exo-cis- and cndo-cis-Diels-Alder adducts. It therefore appears that the fumaric acid is obtained as a product of a very minor side reaction, a non-concerted reverse cycloaddition pathway, that is superimposed on the lower activation-energy concerted pathway. 

Diels-Alder reaction/retro-Diels-Alder sequence can be applied to the synthesis of furans with unusual substitution pattern. For example, the reaction of furan 69 and 2-methylfuran 83 with hexafluorobut-2-yne 84 afforded 7-oxanorbomadienes 85, which were further transformed into 3,4-bis(trifluoromethyl)furans 87 through the intermediate 86 [72-75], Temperature of retro-Diels-Alder reaction should be relatively high in this case. However, this drawback can be circumvented by the addition of tetrazine 88. It was shown that reaction of 85a with this reagent proceeds at room temperature giving rise to 3,4-bis(trifluoromethyl)furan 87a through the Diels-Alder cycloaddition and double retro-Diels-Alder reaction [76]. 

S5mthesis of CD-ring of paclitaxel was accomplished by Schereen [26]. In model studies, 2-methylfuran was used as diene in the high-pressure promoted Diels-Alder reaction with citraconic anhydride 31 (Scheme 12). The reaction... 

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