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A new approach to 2-substituted-4-furanmethanol compounds

F. Reyna Díaz-Cortés, P. Ana Luisa Silva and G. Luis Angel Maldonado

División de Estudios de Posgrado, Facultad de Química, UNAM,

Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México D.F., México


A two step synthesis of the title compounds from readily available starting materials is reported. The method involves a Hörner-Wadsworth-Emmons reaction between b-ketophosphonates anions and 1,3-diacetoxy-2-propanone, followed by mild acid treatment of the g,g'-diacetoxyenones thus obtained.

Background: the total synthesis of racemic bilobanone

In 1980 a total synthesis of the sesquiterpene bilobanone 5 from 2-isobutyl-4-furanmethanol 4a was reported (Escalona, H.; Maldonado, L.A., Synth. Commun., 1980,10, 857) from our laboratory. The synthesis of 4a involved a new method for the preparation of 2-substituted-4-functionalized furans in which the heterocyclic ring was formed by acid hydrolysis of nitroketal diol 1, followed by base treatment of the nitroketone diol 2 intermediate.

Scheme 1

Proposed reaction mechanism for the conversion

2 TO 4a

Although the reaction mechanism for the conversion 2 -> 4a is unknown. In our 1980 paper a completely different reaction mechanism was proposed for this conversion. However, with the recent isolation of 2 as intermediate in this transformation, we have changed our original proposal., from our point of view it was reasonable to assume that HNO2 elimination in nitroketone diol 2 would afford an undetected intermediate g,g'-dihydroxyenone 3 which cyclizes very rapidly to the furan ring.

Scheme 2

Working hypothesis: g,g'-dihydroxyenones as precursors of 2-substituted 4-furanmethanol compounds

Accordingly with the proposed reaction mechanism, we reasoned that if undetected intermediate g,g'-dihydroxyenone 3 (or a conveniently protected derivative) could be prepared by a direct method, a simple synthesis of furans such as 4 would be at hand.

Scheme 3

The experimental demonstration of this working hypothesis strongly suggests (although does not prove) that our proposed reaction mechanism is correct.

Synthesis of g,g'-diacetoxyenones through the HÖrner-Wadsworth-Emmons reaction

For its convergency, simplicity and generality, the method of enone formation we choose, was the Hörner-Wadsworth-Emmons reaction between b-ketophosphonate anions and 1,3-diacetoxypropan-2-one (Bentley, P.H.; McCrae, W., J. Org. Chem., 1970, 35, 2082.) as the carbonyl acceptor.

Scheme 4

R= (CH3)2CHCH2 77%

R= C6H5 65%

R=2,5-(OCH3)2C6H3, 80%

Although we have found that 1,3-diacetoxypropan-2-one is a highly convenient (easily obtained, stable crystalline solid) substrate for the Hörner-Wadsworth-Emmons reaction many other OH-protected 1,3-dihydroxyacetone derivatives are also conceivable candidates.

Synthesis of 2-substituted-4-furanmethanol compounds

Our first attempts to convert the g,g'-bisacetoxyenones to the title furans under basic conditions failed. However, in acidic medium (catalytic aqueous HCL in EtOH, 65 oC, 4-5 h) they were obtained in good to moderate yields (52-85%). In some experiments, small amounts of the corresponding acetates have been isolated.

Scheme 5

4a, R= (CH3)2CHCH2 76%

4b, R= C6H5 85%

4c, R=2,5-(OCH3)2C6H3, 52%

Conclusion (I)

2-Isobutyl-4-furanmethanol 4a, an intermediate in our bilobanone synthesis, has now been obtained in two simple steps and in 59% overall yield. This is a considerable improvement over our original procedure (~ 23% overall yield through seven steps).

Scheme 6

Conclusion (II)

2-(2,5-dimethoxyphenyl)-4-furanmethanol 4c is an easily available, potential intermediate for shikonofuran and echinofuran syntheses. (Inovye, H.; Matsumara, H.; Kawasaki, M.;Inove, K.; Tsukada, M.; Tabata, M. Phytochemistry, 1981,20,1701; Yoshizaki, F.; Hisamichi, S.; Kondo, Y.; Sato, Y.; Nozoe, S., Chem. Pharm. Bull., 1982,30,4407.

Scheme 6