Synthesis of functionalized furans

Recently, Gagosz et al. extended the methodology to other substrates for the synthesis of functionalized furans via Claisen-type rearrangement. The future asymmetric version of the process could be a very useful tool for the synthesis of natural products [101]. 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

Previous works have shown that metallic iodide activated bismuth(lll) chloride efficiently catalyzes the Mukaiyama aldol and Michael reactions. Moreover, it has been shown that ultrasound activates significantly the catalytic power of these metallic halide systems [32a]. Interestingly, the use of these catalytic systems proved to be particularly remarkable in the case of the synthesis of functional furan derivatives [24c, 32b]. The use of Bi(OTf)3 xH20 has also been reported for these reactions [32c-e]. The Mukaiyama aldol reaction in an ionic liquid such as [Bmim][BF4] proceeds smoothly with silyl enolates and a catalytic amount of Bi(0Tf)3 %H20 [32d,e]. Various silyl enolates and aldehydes were tested. Moderate to very good yields of P-hydroxy ketones were obtained. 

A general method for producing bicyclic heterocycles by dipolar cycloaddition to dipolarophiles possessing additional functionality is demonstrated by the synthesis of the furan (292) from the aroylaziridine (293) and the imine (294) (Scheme 76) (74CJC798). 

Several recent reviews have included specific types of electrophilic cyclofunctionalization reactions.1 Important areas covered in these reviews are halolactonization u cyclofunctionalization of unsaturated hydroxy compounds to form tetrahydrofurans and tetrahydropyrans lb cyclofunctionalization of unsaturated amino compounds lc cyclofunctionalization of unsaturated sulfur and phosphorus compounds ld lf electrophilic heterocyclization of unconjugated dienes 1 synthesis of y-butyrolactones 1 h synthesis of functionalized dihydro- and tetrahydro-furans lj cyclofunctionalization using selenium reagents lk lm stereocontrol in synthesis of acyclic systems 1" stereoselectivity in cyclofunctionalizations lP and cyclofunctionalizations in the synthesis of a-methylenelactones.lq Previous reference works have also addressed this topic.2... 

The ring-opened dipolar intermediate suggests reactivity towards nucleophiles and electrophiles. The latter occurs in the TiCl4 promoted addition of methyl 2-siloxycyclo-propanecarboxylates to carbonyl compounds and to an iminium salt (equation 99). The products of both processes are very versatile intermediates allowing synthesis of different furan derivatives and other compounds Concerning the liberated carbonyl function, both reactions can be classified as homoenolate additions, thus putting further emphasis on the cyclopropane homoalkene equivalence. 

A number of partial syntheses have been described in the bicyclic series. The synthesis of methyl (12S)- and (12i )-hydroxylabda-8(17)-en-19-oate utilized the aldehyde (10) as an intermediate. This was obtained from podocarpic acid. The synthesis of the furan methyl lambertianate (11) from dimethyl agathate has been described. Examination of the n.m.r. spectra of the levantenolides (12) has led to a revision of their C-12 stereochemistry. a-Levantenolide has the (12i ) configuration whereas jS-levantenolide has the (125) configuration. The functionalization at C-12 of labdanes by oxidation of C-15 alcohols with iodine and lead tetra-acetate has been described. ... 

The intramolecular Fujiwara-Moritani/oxidative Heck reaction was applied to the synthesis of functionalized benzo[fe]furans and dihydrobenzo[h]furans in 50-80% yields, and 15 examples are given in the article <04AG(E)6144->. Ionic liquid ([bmimJBF4) was found to be an effective solvent for the PdCl -catalyzed intramolecular Heck reaction to realize benzofurans <04TL6235>. Another palladium-catalyzed intramolecular Heck reaction between vinyl triflate and benzo[(j]furan was utilized to construct the seven-membered ring based (-)-frondosin B <04T9675>. 

The Diels-Alder reaction of oxazoles with alkynes has become a preferred method for the synthesis of substituted furans with diverse applications. A large number of early examples of this reaction have been tabulated. Activated dienophiles such as acetylenic ketones and esters can be used, although unactivated alkyl, aryl, and silyl alkynes have been used as well. In particular, the reaction of 4-phenyloxazole with substituted acetylenes is frequently used for preparing 3,4-disubstimted furans. Cycloadducts derived from 4-phenyloxazole typically decompose under milder conditions than 4-alkyloxazoles, allowing the synthesis of a wider range of functionalized furans. Several examples are shown below. 

Halogenated furans are important intermediates for the synthesis of a number of functionalized furan derivatives through metal-halogen exchange and transition metal-catalyzed cross-coupling reactions, as will be demonstrated throughout this chapter. 

HMF is a suitable precursor for the synthesis of bifunctional furan monomers as summarized in Scheme 4. All these monomers can be used to prepare polycondensates by step-growth reactions with the other corresponding bifunc-tional monomers derived either from petrochemical precursors or from renewable resources. The polycondensates obtained, such as polyesters, polyamides, and polyurethanes, etc. have been characterized [107-113]. Scheme 5 shows another approach for the synthesis of bifunctional monomers through acid-catalyzed condensation of the corresponding mono-functional furan derivatives with an aldehyde... 

One-pot reactions involving acyl chlorides, phosphorus ylides, and o-iodophenols with copper catalysis were established for the rapid synthesis of functionalized benzo[ft]furans (14JOC10599). 

Later, Pirrung investigated the employment of cyclic diazo-1,3-dicarbonyl compounds for the Rh(II)-catalyzed synthesis of fused furans (Scheme 8.69) [208]. Diazocyclohexane-1,3-dione 180 underwent a formal [3 + 2] cycloaddition with a variety of terminal alkynes 181 bearing sensitive functional groups in the presence of... 

The parallel synthesis of furans from a-hydroxycarbonyl compounds is frequently conducted using aldoses or ketoses as readily available sources of this functional grouping, especially as the resulting polyhydroxyalkyl side-chain can be removed easily by oxidative degradation (Schemes 67d and 67e) 56MI30300). 

The construction of the five contiguous stereocenters required for a synthesis of compound 3 is now complete you will note that all of the substituents in compound 5 are positioned correctly with respect to the carbon backbone. From intermediate 5, the completion of the synthesis of the left-wing sector 3 requires only a few functional group manipulations. Selective protection of the primary hydroxyl group in 5 as the corresponding methoxymethyl (MOM) ether, followed by benzylation of the remaining secondary hydroxyl, provides intermediate 30 in 68 % overall yield. It was anticipated all along that the furan nucleus could serve as a stable substi-... 

In the same area, a (5)-tryptophan-derived oxazaborolidine including a p-tolylsulfonylamide function has been used by Corey et al. to catalyse the enantioselective Diels-Alder reaction between 2-bromoacrolein and cyclo-pentadiene to form the corresponding chiral product with an unprecedented high (> 99% ee) enantioselectivity (Scheme 5.27)." This highly efficient methodology was extended to various 2-substituted acroleins and dienes such as isoprene and furan. In addition, it was applied to develop a highly efficient total synthesis of the potent antiulcer substance, cassiol, as depicted in Scheme 5.21... 

Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brpnsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated a-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2-dihydrobenzo /j]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

As mentioned in the Introduction, this chapter focuses on reactions that deliver allenes as the product. The principles discussed in Sections 1.2.1-1.2.9, of course, also allow the synthesis of allenes as reactive intermediates, which due to other functional groups that are present, undergo further reactions in situ. The most important examples here are base-catalyzed isomerizations to furans [347, 348] ring transfer reactions of propargylic ethers or amines [216, 349-371] and enyneallene cycliza-tion reactions starting from propargylic sulfones [372-375] and related substrates [376, 377]. Details are discussed, for example, in Chapters 16 and 20. 

---