Synthesis of benzofurans

An analogous synthesis of benzofurans from O-aryloximes has been exemplified, but not investigated in any detail (Scheme 39e) (66TL5225,67TL2867,73KGS31). 

Scheme 66 Phase-transfer catalyzed synthesis of benzofuran carboxylates...

NHC-Pd(ll) complexes have also been used in tandem reactions involving a Sonogashira couphng and hydroalkoxylation of the resulting alkyne for the synthesis of benzofurans [131] as well as sequential Heck-Sonogashira couphngs [132] (Scheme 6.44). 

Tethered alkenes feature in the synthesis of benzofuran-fused chromans 48 <00JCS(P1)1387> through intramolecular cycloadditions. 

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

Lu K, Luo TP, Xiang Z, You ZJ, Eathi R, Chen JH, Yang Z (2005) A concise and diversity-oriented strategy for the synthesis of benzofurans and indoles via Ugi and Diels-Alder reactions. J Comb Chem 7 958-967... 

Larock, R. C. Stinn, D. E. Synthesis of Benzofurans via Palladium-Promoted Cyclization of Ortho-Substituted Aryl Allyl Ethers, Tetrahedron Lett. 1988,29,4687-4690. 

An analogous synthesis of benzofurans from o-aryloximes is exemplified by (49 —< 50) (67TL2867, 73KGS31). 

The present chapter represents the first part of this study and is devoted to the natural occurrence and to the general methods of synthesis of benzofuran and its derivatives. Structural and spectrographic properties as well as the chemical reactivity of these compounds will be covered in a later chapter. 

Synthesis of benzofuran derivatives with physiological, pharmacological, therapeutic, or toxic properties. 

These methods utilize molecules of type B (p. 362) (=104) a. Synthesis of Benzofurans by Thermal Ring Closure and Cyclodehydrogenation (Thermal, Catalytic or Photochemical) of o-Substituted Phenols. The Hansch Reaction. o-Alkylhydroxy-compounds on heating with a suitable catalyst give either a benzofuran or a 2,3-dihydrobenzo-furan with the same number of carbon atoms.285-292 Side products are formed by decomposition of the starting material. The initial phenol can be o-alkylated and ring-closed in one stage. 

While the synthesis of benzofuran derivatives from suitable furan derivatives has been comparatively little investigated, the synthesis of fused two-ring and three-ring compounds containing a pyridine nucleus from furan derivatives has been more successful furo[3,2-c]pyridines (345),752>753 2,3-dihydrofuro[2,3-a ]quinolines (from 4,5-dihydro-3-furoic acid),754 acrophyllin (346), and 7-hydroxydictamnine (347) (from ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate),755 are examples of compounds in this class which have been prepared. 

The Fischer indole synthesis has been extended to the synthesis of benzofurans as shown in a recent synthesis of 4,5, 8-trimethylpsoralen (Scheme 60) (79JOC2176). The availability of methods for the synthesis of the precursor O-aryloximes limits its application. 

The analysis depicted for (64) reveals that the synthesis of benzofuran involves the conversion of salicylaldehyde into the corresponding aryloxyacetic acid by reaction with sodium chloroacetate in the presence of alkali, followed by heating with a mixture of acetic anhydride, acetic acid and sodium acetate (Expt 8.24). The ensuing cyclisation may be regarded as an internal Perkin reaction (Section 6.12.3, p. 1036) accompanied by a decarboxylative dehydration step. 

Coupling of aryl bromides with diethyl sodiomalonate. CuBr is the most effective Cu(I) catalyst for effecting coupling of aryl iodides or bromides with the sodium salts of active methylene compounds such as diethyl sodiomalonate. Coupling is facilitated by ori/io-substituents in the halide, particularly nitro, carbomethoxy, and methoxy groups.1 This reaction has been adapted to synthesis of benzofurane-2-ones.2... 

One synthesis of benzofurans is based on cyclofragmentation. An appropriately substituted sulfone is used as a nucleophile in intramolecular ring opening of an epoxide. The resulting molecule loses a sulfinate and formaldehyde. By immobilization of the sulfinate on a resin this sequence can be used for the cleavage of benzofurans from solid supports [112] (Scheme 6.1.31). 

In 1979, an interesting effect on the dioxetane/diendoperoxide product ratio was observed upon the addition of methanol to acetone. The addition of methanol increased the dioxetane/diendoperoxide ratio. The photooxidation of 2,3-dipheny-lindene 15 afforded its dioxetane 31 in methanol at —78 °C [26]. On the basis ofliquid chromatography (LC) analysis and NMR spectroscopy, dioxetane 31 formed in high yields in methanol or methanol-acetone (3 7) mixtures. However, the formation also occurred of a diendoperoxide with the solvents Freon-11 and acetone-d6 (the topic of bisperoxides will be discussed in Section 11.5.2.1). The synthesis of benzofuran dioxetanes has also been accomplished from a TPP-sensitized photooxidation of benzofurans [27, 28]. 

A clever synthesis of benzofurans, benzothiophenes and indoles starts with the trifluoroethyl ethers 425 and uses a 5-endo-dig cyclisation. Four equivalents of rc-BuLi perform two eliminations, one substitution, and one lithiation to generate aryllithium 426, which undergoes 5-endo-dig cyclisation. 3-Butylbenzofuran is generated in 40% yield.186... 

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