Dihydrobenzofuran synthesis

Little attention has been paid to the capture of aryl radicals but an example of dihydrobenzofuran synthesis published this year uses just this reaction. Thus the aryl halides (62) cyclize in the... 

Chiba K, Fukuda M, Kim S, Kitano Y, Tada M (1999) Dihydrobenzofuran synthesis by an anodic [3 -l- 2] cycloaddition of phenols and unactivated alkenes. J Org Chem 64 7654-7656... 

Secoquettamine (234) and dihydrosecoquettamine (235) together with their probable biogenetic precursor quettamine (236) form a small group of alkaloids. They were isolated by Shamma et at. (179) from Berberis baluchista-nica in yields of 0.00036,0.00017, and 0.0012%, respectively. These alkaloids incorporate either a benzofuran or a dihydrobenzofuran ring within the molecular framework, and the seco ones possess the /V,W-dimethylaminoethyl substituent. The structures of these bases were determined on the grounds of spectral data as well as by total synthesis. There is one chiral center at C in dihydrosecoquettamine (235) however, the base was isolated in the form of a racemic mixture (179). 

The intramolecular G-H insertion of aryldiazoacetates is a very powerful strategy for synthesizing heterocyclic rings such as dihydrobenzofurans and dihydrobenzopyrans. The first effective asymmetric copper-catalyzed C-H activation reaction was reported by the group of Sulikowski in the synthesis of the anti-tumor antibiotic FR-66979 93 (Scheme 7)123 219 The G-H insertion of the aryldiazoacetate 90 formed four diastereomeric products 91a, 91b, 92a,... 

A very impressive application of this chemistry is the total synthesis of (—)-ephedradine A 102.222 The key intermediate /rcarboxylic acid ester 101 was synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh2(Y-DOSP)4, aryl diazo ester 100 possessing a chiral auxiliary underwent a C-H insertion reaction to give 101 in 63% yield and 86% de (Equation (83)). 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

Other examples of the iodonium ylide-based syntheses of furan derivatives involve cycloaddition reactions with alkenes or alkynes. Although the majority of these syntheses involve stable iodonium ylides (86JOC3453 94T11541) (e.g., Eqs. 16 and 17), in some cases the ylides are unstable and are generated in situ (92JOC2135) (e.g., Eq. 18). In the case of alkenes, dihydrofuran derivatives are obtained (Eqs. 16-18). This synthetic route is especially useful for the synthesis of dihydrobenzofuran derivatives that are related to the neolignan family of natural products (Eq. 18). 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

The Bz-hydroxylated 2,3-dihydrobenzofuran derivatives required for the synthesis of several natural substances have been obtained by this method 4-allyl-l,3-dimethoxybenzene gives (HBr/HOAc with de-methylation) 6-hydroxy-2-methyl-2,3-dihydrobenzofuran.427 2-Allyl-4-methoxyphenol and 2-allyl-3,5-dimethoxyphenoI lead, respectively, to 5-methoxy-2-methyl-2,3-dihydrobenzofuran and 4,6-dimethoxy-2-methyl-2,3-dihydrobenzofuran (without demethylation). 

The same intermediate occurs in the Lehmann method463 for converting the methiodides of phenolic Mannich bases into 2,3-dihydrobenzo-furans, through reaction with dimethyloxosulfonium methylide. Thus, o-benzoquinone methide (207) leads to 2,3-dihydrobenzofuran according to Scheme 4. Similarly, 2-naphtholgives l,2-dihydronaphtho[2,l-6]furan through 208 and 209, formed and rearranged in situ.i6i The reaction has been applied to the synthesis of polycyclic benzofurans.483,485... 

Numerous examples of natural products with the benzo[6]furan nucleus have been identified. It occurs under many guises dibenzofurans, /3-coumaranones, a-pyranobenzo[6]furans, y-pyranobenzo[6]furans, and the spiro-2,3-dihydrobenzofurans such as griseofulvin. Many of the natural benzo[6]furans have physiological, pharmacological and toxic properties and as a result an active interest exists in their chemical synthesis. 

Benzofurans and dihydrobenzofurans have been prepared on polymeric supports by the palladium-mediated reaction of 2-iodophenols with dienes or alkynes (Entries 1 and 2, Table 15.9). This reaction is closely related to the synthesis of indoles from 2-iodoanilines, and probably proceeds via an intermediate palladacycle (Figure 15.3). Benzofuran and isobenzofuran derivatives have also been prepared on cross-linked polystyrene by intramolecular addition of aryl radicals to C=C double bonds and by intramolecular Heck reaction. 

Dihapto 7>ligands, in copper complexes, 2, 174 Dihydride iridium complexes, preparation, 7, 396 Dihydrido clusters, with decarutheniums, 6, 1036 Dihydrobenzofuran, carbene C-H insertions, 10, 193 Dihydrobenzopyran, carbene C-H insertions, 10, 193 ring-closing diene metathesis,... 

On the other hand, PIFA-induced oxidation of p-methoxy-substituted phenols (15) in the presence of electron-rich styrene derivatives (16) resulted in new carbon-carbon bond formation via an intermolecular 1,3-cycloaddition to afford frazzs-dihydrobenzofurans (17) stereoselectively [35,36] [Eq. (4)]. A formal synthesis of neolignans such as kadsurenone (18) and denudatin B (19) was achieved by this methodology. 

An effective and general method for the synthesis of 2,3-dihydrobenzofuran derivatives has been developed via an intramolecular carbolithiation reaction of o-lithioaryl ethers (Scheme 16).89 This process was the first example in which the carbolithiation reaction has been stopped at the 2,3-dihydrobenzofuran stage by appropriate selection of the ether moiety. 

More recently, the catalyst that was prepared from AgOTf and Tol-BINAP was applied to the synthesis of 2,3-dihydrobenzofnrans. The reaction of 2,3-dihydroben-zoxasilepine and an aromatic aldehyde was carried out in the presence of the silver catalyst, KF, and 18-crown-6 to give tra s-2,3-disubstituted 2,3-dihydrobenzofuran... 

The synthesis of a variety of dihydrobenzofuranes can be accomplished via the Aryl SN1 mechanism. The acetone-sensitized irradiation of various o-chlorophenyl allyl ethers in polar solvents affords the aryl cation, which adds onto the tethered double bond following the 5-exo-trig mode leading to (dihydro)benzofurans. The reaction is solvent-dependent, and byproducts are also generally obtained. The best results are found when ethyl acetate is used. Depending on the substrate employed, the cation intermediate can yield products as a result of proton elimination or trapping by chloride ions (Scheme 10.54) [70],... 

Another intramolecular substitution has been used for the synthesis of an intermediate in a proposed route to 3-substituted benzofurans. A / -methylene-dihydrobenzofuran complex was obtained upon fluoride-induced removal of the SiR3 protecting group from complex 37 (Scheme 16) in an ipso SnAr process. Desilylation resulted in spontaneous cyclization to the stable methylene complex 38 in 89 % yield. No isomerization occurred and the 3-methyl benzofuran complex was not detected [21]. 

On the other hand, Wacker-type oxidative cyclization is a versatile approach for the construction of oxygenated stereocenters [213,214]. The synthesis of a number of dihydrobenzofurans catalyzed by an in situ-formed carbene-palladium complex has been reported by Muniz [215]. When Pd(TFA)2 in combination with IMes were employed, high yields in pure cyclized products were obtained after simple work-up (Table 9). However, palladium salts containing chlorine or acetate groups led to the formation of mixtures containing the desired product and its six-membered ring isomer. 

The BF3-catalyzed reaction of a-aminoaldehydes with 10 is valuable for highly stereoselective synthesis of 2,3,5-trisubstituted pyrrolidines with all -cis configurations (Equation (50)).197 The stereochemical outcome like chelation-controlled stereochemistry might result from the inherent conformational arrangement of the aldehyde-BF3 complex. />-Quinoneimines, o-quinones, and a-alkoxyhydroperoxides undergo similar types of [3 + 2]-cycloadditions with allylsilanes to afford dihydro indoles, dihydrobenzofurans, and 1,2-dioxolanes, respectively.164,175,198... 

Although the synthesis of dihydrobenzofuran derivatives seems to be not possible by this anionic cyclization methodology, there are some particular examples in which these heterocycles are prepared by an intramolecular carbolithiation reaction. In this respect Baldwin and coworkers described in 1980 the preparation of 350 by rearrangement of 349 when it was treated with BuLi in THF/TMEDA (Scheme 91)151. The most likely explanation starts with an orf/zo-lithiation giving a dilithium intermediate, which undergoes an intramolecular 5-exo carbolithiation reaction affording a 3-lithiomethyldihydrobenzofuran... 

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