Dihydrobenzofuran, formation

Scheme 4. Annulation of indole and the stereochemistry of oxidative dihydrobenzofuran formation.

An improved procedure for the rapid synthesis of aryl dihydrobenzofurans with a boron tribromide-mediated cyclization was discussed and is shown below <03HCA343>. In the second total synthesis of diazonamide A, the late key step accounting for the dihydrobenzofuran formation was a DIBAL-H mediated lactam reduction and cyclization <03AG(E)1753>. 

Benzodioxanes, rearrangement of 824, 825 Benzofurans—see also Dibenzofurans, Dihydrobenzofurans formation of 1255, 1256 Benzoic acids—see also Hydroxybenzoic acids... 

The mechanistic rationale for the dramatic Lewis acid effect on the course of the Engler indole/benzofuran synthesis involving styrenes is illustrated in Scheme 3. Whereas titanium forms a bidentate complex 11 with the C-1 carbonyl and C-alkoxy oxygens, which leads to the dihydroindole (equation 1), boron trifluoride engages in monodentate complexation 12 with the sulfonyl nitrogen, leading to dihydrobenzofuran formation (equation 2) [3, 4]. Likewise, the reaction between 11 and an enol ether derived from 4-piperidone is depicted in equation 3 [5]. 

In a recent continuation of the work on dediazoniation of 2-(2 -propenyloxy)ben-zenediazonium salts (10.55, Z = 0, n= 1, R=H) in the presence of ferrocene, Beckwith et al. (1992) found that 3-ferrocenylmethyl-2,3-dihydrobenzofuran (10.65) is formed. The results are consistent with a mechanism involving electron transfer and dediazoniation followed by homolytic attack on the ferrocenium ion. This investigation resolved a long-lasting dispute regarding the heterolytic or homolytic character of the formation of arylferrocenes from arenediazonium ions (for literature since 1955 see Beckwith et al., 1992, references 1-7). 

Photoaddhion of electron donor olefins such as vinyl ethers and stilbene to variously methyl and halogeno-substituted 1,4-benzoquinones resulted in the formation of dihydrobenzofurans via a dienone-phenol rearrangement of the primary product spirooxetanes <96H(43)619>. High-temperature water seems to be an alternative to use of acid catalysts or organic solvents by the cyclization of allyl phenyl ethers to dihydrobenzofurans <96JOC7355>. 

Cycloadduct 212 is converted into the dihydrobenzofuran 213 when treated with boron trifluoride diethyl etherate in good yield <2000JA8155>. The formation of the dihydrobenzofuran proceeds by an initial ring opening followed by a subsequent dehydration and acid-catalyzed cyclopropyl ketone rearrangement (Equation 142). 

The formation of oxygen heterocycles through carbon-oxygen bond formation was also reported. Substituted 2-(o-halophenyl)-ethanols were converted to dihydrobenzofuranes using palladium and Buchwald s bulky biaryl-type ligands (3.43.). The reaction was also efficient in the formation of six and seven membered oxygen heterocycles.53... 

The Niki reaction474 (alkylation of dimedone by l,4-dibromo-2-methyl-2-butene, with formation of compound 218), applied to phloro-acetophenone and to 3-isopentyl-2,4,6-trihydroxyisobutyrophenone, leads respectively to 2,3-dihydrobenzofurans 219a and 219b. Furan 219b with toluene- >-sulfonic acid rearranges to the benzofuran 220b.475... 

Catalytic dehydrogenation over (AI203, Fe203) at G00°-630° in the presence of moist, air converts 2,3-dihydrobenzofurans (78% yield) into benzofurans, with formation of phenolic compounds as by-products.768,769 Excellent yields are also obtained with Pd/C (reflux diphenyl oxide), Pt or Rh/C at 250°-3500,770 or Pd on norite.761 The method can be applied to the preparation of naphtho[2,l-6]furans,43e furocou-marins515,539,777 (e.g., psoralene781), furochromones,442,534 and 5H-benzofuro[4,5-c]benzopyran-5-one.441... 

To a solution of 5.2 g of 2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g anhydrous ammonium acetate. This mixture was heated for 4 h on the steam bath, and then a small amount of H20 was added to the hot solution. This instigated the formation of a copious deposition of brick-red crystals which were, after cooling, removed by filtration, and recrystallized from 50 mL boiling MeOH. After air drying there was thus obtained 2.7 g of day-glo yum-yum orange crystals of 2,2-dimethyl-5-methoxy-6-(2-nitro- l-propenyl)-2,3-dihydrobenzofuran. An additional 0.6 g of product was obtained by working the mother liquors. 

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. 

The value of Eox for BH 4 is not known, but the borohydride radical, BH4 has been characterized by e.s.r and UV spectroscopy in oxidations of the anion by hydroxyl or azide radicals under pulse-radiolysis conditions (Symons et al., 1983 Horii and Taniguchi, 1986). Most borohydride reductions seem to be straightforward hydride transfers, but stepwise processes occur in the reductions of aryl bromides or iodides under photochemical or di-t-biftyl peroxide initiation. Radical intermediates are shown by the formation of 3-methyl-2,3-dihydrobenzofuran in the reduction of o-allyloxyiodobenzene (Abeywickrama and Beckwith, 1986). 

In spite of the reduced nucleophilicity of o-CH30 by resonance interaction with the aromatic nuclei, the p electrons of the oxygen assist the participation of the aryl ring in the partial C—Cl bond cleavage in the transition state, which eventually leads to formation of the corresponding cyclic product, dihydrobenzofuran. The mechanism for the two parallel processes is given in equations 84 and 85. 

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. 

Five-membered O-heterocycIic derivatives of the type dihydrobenzofuran (352 in Fig. 137) are formed by reaction with diazomethane or analogous reagents. It is to be stressed, in partieular, that the deamination of a Mannich base may be favored by the formation of amine N-oxide, instead of the corresponding quaternary ammonium salt, as is usually required. 

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