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As early as the 1980s, direct alkenylation of an excess furfural with diphenylacetylenes as the reactive partner was reported under rhodium catalysis (Scheme 9). Harsh conditions, such as a high pressure of carbon monoxide and high temperatures were involved in this reaction to obtain the C5-alkenylated product in 41% yield (based on the alkyne) as a mixture of Z:E isomers in 59:41 ratio. Regarding the alkyne, the reaction is a hydroarylation since a C–H bond of the substrate is activated by the metal, and then addition on the unsaturated reaction partner (in this case, the acetylene) occurs.
Later, C5-alkenylation of C2- and C3-substituted furan substrates was performed under palladium(0)-catalysis through a similar alkenylation reaction using a Pd(dba)2/PCy3 catalytic system with a carboxylic acid additive (Scheme 10). Here, after coordination of the alkyne to the Pd(0) complex, the carboxylic acid reacts to generate an alkenylpalladium amylate complex. The regioselectivity is probably derived from the steric repulsion between bulky substituents on the alkynyl carbon and the palladium center. Then, a C–H activation of 1 (via the CMD pathway) takes place to give the corresponding single and double alkenylated products. Reductive elimination of the alkenyl-palladium-aryl complex leads to a syn-addition product, which is proposed to isomerize in the presence of amylic acid to give the anti-addition product. It should be noted that the reactive aldehyde group remains intact during this reaction.
Interestingly, when a competitive reaction between furfural (2-furancarboxaldehyde) and 3-furancarboxaldehyde was carried out under the same conditions (Scheme 11), C–H alkenylation occurred predominantly on the 3-furancarboxaldehyde regioisomer (at C2). This result suggests that an electron-deficient directing group enhances the reactivity of the C2–H bond in spite of a higher steric hindrance.
C5-fluorosulfonylvinylation of furfural 1 was carried out under oxidative conditions with silver(I) acetate as oxidant, Pd(OAc)2 and a pyridine-based ligand (L1) in HFIP to yield a β-heteroarylethenesulfonyl fluoride in moderate yield (Scheme 12). The electron-deficient 2-pyridone ligand is crucial for this transformation in accelerating the C−H cleavage step as an inner base and stabilizing the active palladium catalyst. Similar Fujiwara-Moritani-type processes were also reported by Itahara from electron-poor alkenes, but in the presence of a stoichiometric amount of Pd(OAc)2.
The alkynylation of furfural 1 with phenylacetylene was also developed. Using Pd2(dba)3 as pre-catalyst and an Ag(I)-based oxidation system, C5-alkynylated furfural was produced in 45% yield (Scheme 13). The reaction proceeds through the formation of an alkynyl-Ag(I) species, which then transmetalates with a Pd(II) species (or Ar–[Pd(II)] generated through a CMD mechanism) from which reductive elimination produces the final product; thus, Ag(I) is implied not only as oxidant of Pd(0) to Pd(II), but also takes part in the formation of the reactive alkynyl intermediate.
Besides these catalytic C–H activation processes, functionalization at C5 was also achieved through stoichiometric metalation. In 1985, Chadwick reported the C5-regioselective metalation of furfural following protection of the aldehyde unit as an imidazolidine derivative (6) and treatment with n-BuLi. (Scheme 14). The C5-lithiated intermediate 7 undergoes electrophilic substitution with an array of electrophiles, delivering C5-functionalized furfural derivatives following acidic work-up (which also induces aldehyde deprotection).
A few years after, Roschanger showed that a similar strategy could be implemented on treatment of furfural with lithium N,O-dimethylhydroxylamide. No directing effect was observed and deprotonation with n-BuLi occurred regioselectively at C5 (Scheme 15). Trapping with iodomethane and deprotection led to C5-methylfurfural. Later, Killpack demonstrated that using lithium N-methyl piperazide (instead of lithium N,O-dimethylhydroxylamide) also allowed to achieve C5-metalation regioselectively.
Finally, Zhou and co-workers reported one example of the alkylation of furfural 1 with alkyl iodides under Pd(0) catalysis. The reaction with cyclohexyl iodide in the presence of Pd(PPh3)4/dppp as catalytic system and Cs2CO3 as base, afforded predominantly the C5-alkylated product with only minor amounts of the C3-alkylated isomer in 80% combined yield (Scheme 16). Mechanistically, the authors propose a radical pathway with the formation of an alkyl radical and a Pd(I) intermediate.
Using FeCl2, a radical approach has also been developed by Nishikata to carry out the selective functionalization of furfural derivatives at the C5 position (Scheme 17). The alkylation was performed in the presence of a tertiary alkyl bromide and diisopropylethylamine. It was proposed that the alkyl radical generated by single electron transfer (SET) adds to the C5 position. The resulting radical is then oxidized by Fe(III) and the cation trapped by bromide. The presence of base was proposed to be essential for the re-aromatization of the heteroaromatic ring.
In contrast with the C5-position, direct selective C4-functionalization has received little attention. The C4-functionalized products are often achieved by the C2-formylation reaction of C4-substituted furans through the Vilsmeier-Haack reaction. In addition, they are sometimes obtained as a side product from C5-arylation under acidic media. For instance, Itahara and co-workers reported that under harsh conditions : Pd(OAc)2 (1 equiv.), furfural and benzene (in large excess) as coupling partners, in acetic acid under reflux, a mixture of the C4- and C5-arylated product was obtained, with a slight preference for the C4-position (Scheme 18). It is nonetheless important to highlight the absence of the C3-H activation was evidenced, which showed that it is a hardly accessible position. Under similar conditions in acetonitrile, it was noted that biphenyls and furfural dimer were obtained as side products of the reaction.
Later, Doucet reported the selective Pd(0)-catalyzed C4-arylation of 5-methylfurfural using electron-deficient aryl bromides. This cross-coupling was performed under low catalyst loading of dimeric (allyl)palladium chloride with KOAc as base (Scheme 19). Here, the C5 position of the substrates tested is always substituted so that competition can only occur between C4- and C3-functionalization, and reaction at C4 is favored. Note however that such innate selectivity depends on the base used. Indeed, in the presence of bases other than KOAc (e.g. K2CO3, Cs2CO3, or K3PO4) arylation at C3 was observed leading to C3-arylated or C3,C4-diarylated compounds. The authors rationalized this behavior in terms of a preferred SEAr mechanism when KOAc is used (which involves a cationic palladium complex), as opposed to an insertion mechanism (Mizoroki-Heck type), favored in the presence of the other bases. However, the yields of 5-methyl furan 2-carboxaldehyde products are significantly lower than the ketone counterpart. This behaviour can relate to the use of an excess of furan substrate, because furfural is known to undergo decarbonylative processes under certain conditions unlike the ketone derivative.
While the above-discussed results establish that C4-functionalization may be achieved through Friedel-Crafts-type reactivity, only a very limited amount of work has been accomplished towards this goal, which leaves much room for future work on this direction.
Functionalization of the C–H bond at C3 of furfural derivatives has attracted considerable attention. Given that innate selectivity is rarely in favor of this position, selective functionalization relies mostly on directed activation strategies that take advantage from the carbonyl substituent at C2.
In 1985, Chadwick and co-workers developed methodologies for the selective functionalization of five-membered heteroarenes through directed metalation using amides as directing groups, and implemented this strategy for the C3-functionalization of the furan ring. They noticed that poor yields were obtained with tertiary carboximido groups, while with secondary amides, better yields and selectivity were obtained. It was suggested that following deprotonation of the amide with one equivalent of s-BuLi, the resulting lithiated intermediate 8 directed the second deprotonation towards the C3–H, delivering 9. Subsequently, trapping of 9 with electrophiles, allowed to obtain various C3-substitued furanamides (Scheme 20).
Table of contents :
CHAPTER I: FURFURAL AND DERIVATIVES
1 BIOMASS VALORIZATION: FURFURAL AND 5-HYDROXYMETHYLFURFURAL
2 SELECTIVE FUNCTIONALIZATION OF FURFURAL DERIVATIVES
CHAPTER II: SILYLATION OF C(sp2)–H BONDS
2 OVERVIEW OF DEHYDROGENATIVE SILYLATION METHODS
2.1 ELECTROPHILIC SUBSTITUTION
2.2 RADICAL SILYLATION
2.3 TRANSITION-METAL CATALYZED SILYLATION
3 C3-SILYLATION OF FURFURAL DERIVATIVES: RESULTS AND DISCUSSION
3.1 PREPARATION OF FURFURYLIMINES
3.2 RUTHENIUM(0)-CATALYZED SILYLATION
3.3 IRIDIUM(I)-CATALYZED C3-SILYLATION
CHAPTER III: CARBON-TO-OXYGEN SILYL MIGRATION
1 C(sp2)–Si BOND FUNCTIONALIZATION THROUGH INTRAMOLECULAR ACTIVATION BY ALKOXIDES
1.2 C(sp2)–Si BOND FUNCTIONALIZATION THROUGH ENDOCYCLIC CLEAVAGE
1.3 C(sp2)–Si BOND FUNCTIONALIZATION THROUGH EXOCYCLIC CLEAVAGE
2 SILYL-MIGRATION FROM C3-SILYLATED FURFURAL DERIVATIVES: RESULTS AND DISCUSSION
2.1 SYNTHESIS OF MODEL C3-SILYLATED FURFURYL ALCOHOLS
2.2 t-BUOCu-PROMOTED SILYL MIGRATION OF ARYLSILANES
2.3 t-BUOCu-PROMOTED SILYL MIGRATION OF FURFURYLSILANES
2.4 BARBIER-TYPE CONDITIONS
CHAPTER IV: FLUORIDE-MEDIATED TRANSMETALATION
2 FLUORIDE-PROMOTED CROSS-COUPLING REACTIONS OF ORGANOBENZYLDIMETHYLSILANES AND CYCLIC SILOXANES
2.1 CASE OF ALKENYL BENZYLDIMETHYLSILANES
2.2 CASE OF CYCLIC SILOXANES
2.3 FLUORIDE-PROMOTED FUNCTIONALIZATION OF C3-SiMe2Bn-SUBSTITUTED FURFURYL ALCOHOLS
2.4 FUNCTIONALIZATION OF C3-SiMe2Bn FURFURYLIMINES AND RELATED DERIVATIVES
3 FUNCTIONALIZATION OF C3-SiMe(OSiMe3)2 FURFURALDEHYDES
3.1 C3-HALOGENATION OF FURFURALDEHYDES
3.2 C3-ALKENYLATION AND -ARYLATION OF FURFURALDEHYDES
3.3 C3-ALKYNYLATION OF FURFURALDEHYDES
3.4 C3-ALLYLATION AND ALKYLATION OF FURFURALDEHYDES
3.5 C3-TRIFLUOROMETHYLATION OF FURFURALDEHYDE
3.6 C3-AMINATION OF FURFURALDEHYDES
4 DERIVATIZATION OF C3-FUNCTIONALIZED FURFURALDEHYDES
4.2 PYRIDINIUM ZWITTERION FROM HMF
5 CONCLUSION AND OUTLOOK