Substituted furan rings, synthesis

The Feist-Benary furan synthesis, first described in 1902, is especially useful for the synthesis of substituted furan rings. This reaction occurs... 

Furans are even reactive enough to be substituted by some diazonium salts or diazopyrazoles, though other reactions are usual (Section V,A),135 and catalysts are used in response to difficulty in producing an electrophilic species not because the furan ring is unreactive. Scheme 27 shows the synthesis of an interesting a-amino acid derivative136 by electrophilic substitution. 

Individual substitutions may not necessarily be true electrophilic aromatic substitution reactions. Usually it is assumed that they are, however, and with this assumption the furan nucleus can be compared with others. For tri-fluoroacetylation by trifluoroacetic anhydride at 75 C relative rates have been established, by means of competition experiments 149 thiophene, 1 selenophene, 6.5 furan, 1.4 x 102 2-methylfuran, 1.2 x 105 pyrrole, 5.3 x 107. While nitrogen is usually a better source of electrons for an incoming electrophile (as in pyrrole versus furan) there are exceptions. For example, the enamine 63 reacts with Eschenmoser s salt at the 5-position and not at the enamine grouping.150 Also amusing is an attempted Fischer indole synthesis in which a furan ring is near the reaction site and diverted the reaction into a pyrazole synthesis.151... 

The cycloaddition-isomerization strategy has also been applied to the synthesis of hydrindanone. Thus, by using a modified Kanematsu s procedure, the keto aldehyde 40, a hydrindanone of the steroid C-D ring type, can be synthesized from a substituted furan via a cycloaddition-isomerization procedure and is followed by subsequent transformations . 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

The development of schemes for the total synthesis of the carbon skeleton of morphine revealed that the fused furan ring was not necessary for biological activity. More recently it has been found that substitution of a pyran ring for the terminal ali cyclic is also consistent with... 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

Substituted furan can be prepared by using the Feist-Binary synthesis, which is similar to the Hantszch synthesis of the pyrrole ring. In this reaction, a-haloketones react with 1,3-dicarbonyl compounds in the presence of pyridine to yield substituted furan. 

Alkylfurans are readily prepared by ring synthesis. The cyclization of substituted 1,4-diketones in the presence of acid to yield alkylfurans is a particularly useful reaction (see Section 3.12.2.2). Appropriately substituted oxiranes behave as masked 1,4-diketones and on acid catalysis cyclize to yield the substituted furan. 

Azole approach. An important route for the synthesis of 3-hydroxypyridines is the reaction between a substituted furan and ammonia, or a primary amine. If the amino acid cysteine is used, the corresponding fused dihydrothiazole (479) can be obtained. Starting from optically active cysteine the corresponding cyclic enantiomer is obtained provided the fused product carries a 5-substituent, which for steric reasons prevents the otherwise ready racemization. A number of steps are involved in the overall reaction which may perhaps be rationalized by thiazolidine intermediates. The desired oxidation level in the substituted furan can either be reached by a-oxidation in an alkyl side-chain (499) or more generally by raising the furan ring itself to a higher oxidation level as in (500) (81H(15)1349). 

Electrophilic substitution of the appropriately functionalized arylamine and subsequent iron-mediated oxidative cyclization with aromatization generates the carbazole skeleton. Annulation of the furan ring by treatment with catalytic amounts of amberlyst 15 affords furostifoline directly. Comparison of the six total syntheses reported so far for furostifoline demonstrates the superiority of the iron-mediated synthesis (Table 1 in ref. [43a]). Starting from the 2-methoxy-substituted tricarbonyliron-coordinated cyclohexadienylium salt this sequence has been applied to the synthesis of furoclausine-A (Scheme 15.12) [45]. 

Double cyclizations to butenolides and furanes. Radicals can undergo intramolecular addition to triple bonds when separated by three carbons. This strategy can be used for synthesis of butenolides (equation 1) and -substituted furanes (equation II). Cyclization of vinyl bromides." Fused and bridged ring systems can be prepared... 

Multisubstituted five-membered aromatic heterocycles are synthesized via this cascade protocol (equation 34). The cycloadditions of a-acyloxyketones 78a with lithium ynolates afford /3-lactone lithium enolates 79a, which spontaneously cyclize to give bicyclic compounds 80a. These intermediates, which are stable enough to be isolated, are treated with TsOH under heating to provide substituted furans 81a via decarboxylation and dehydration. Thiophenes (e.g. 81b) are also synthesized by the analogous scheme via intermediate 80b using a-acylthioketones (78b) as a substrate. In the synthesis of pyrroles using a-acylaminoketones as a substrate, the cyclization proceeded at —20 °C, and the -lactone was subsequently ring-opened via /3-elimination to furnish pyrroles in one-pot (equation 35). ... 

Ring-closing metathesis (R(, one of the most powerful tools for ring-formation, has been employed to the synthesis of substituted furans. As shown below, a range of... 

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