Dihydrobenzofurane derivative

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). 

Research in this area was developed further by Li et at. using 1,3-dienes 64 for the gold-catalyzed annulation of phenols and naphtols [58, 59]. These generated various dihydrobenzofuran derivatives. The best yields were achieved when the catalytic system included enough AuCl3 and silver salt to remove halogen atoms and deliver cationic gold. 

Another simplified nomenclature adopted here relates to natural spiro-2,3-dihydrobenzofuran derivatives, such as griseofulvin. The fundamental heterocycle, named grisan, being spirobenzofuran-2(3ff)-l -cyclohexane (5), griseofulvin (7-chloro-4,6,2 -trimethoxy-6 -methyl-spirobenzofuran-2(3//)-l -[2]cyclohexene-3,4 -dione) (6) becomes 7-chloro-4,6,2 -trimethoxy-6 -methyl-2 -grisene-3,4 -dione. 

Several systems of nomenclature have been used for rotenoids, some of which have been synthesized from dihydrobenzofuran derivatives. 

Finally, condensation of phenols with various aliphatic compounds in the presence of a catalyst or a dehydrating compound, such as KHS04, H3P04, PPA, leads to 2,3-dihydrobenzofuran derivatives. It has been the subject of many investigations303-309 in the field of chemical technology. 

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). 

Transition from a chromenoid skeleton to a benzofuran has also been achieved by other means. We may mention the photooxidation of rotenone814 and the preparation of 5,6-dirnethoxybenzofuran by electronic impact on 6,7-dimethoxycoumarin.815 The Koelsch reaction is kindred it converts couinarine into 2,3-dihydrobenzofuran derivatives.816... 

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. 

Several oxidations of this kind were performed inter- and intramolecularly. In the first case with 4-methoxyphenols and electron-rich styrenes or propenylbenzenes, dihydrobenzofuran derivatives were formed [19] ... 

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... 

Looking for a suitable preparation of dihydrobenzofuran derivatives by carbolithiation reactions, we have recently described how allyl 2-bromophenyl ethers 358 with a substituent at the a-position afford, after treatment with r-BuLi, addition of TMEDA and further quenching with electrophiles, functionalized fraws-2,3-dihydrobenzofuran derivatives 359 in a totally diastereoselective manner (Scheme 94)155. The key for the success of this reaction is the fact that intermediate organolithium 360 is not prone to undergo the 1,3-elimination process, probably due to the steric effect of the R substituent. The high diastereoselectivity of the ring closure could be explained by a transition state that accommodates the R group in a pseudoequatorial position. Moreover, simple allyl... 

An enantioselective method for the synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives via an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers uses (—)-sparteine as a chiral inductor. A variety of electrophiles can be reacted with the cyclized organolithium intermediate. With certain substrates, however, /3-elimination occurs instead (Equation 140) <2005CEJ5397>. 

Anodic fluorination of ethyl (3-benzofuranyl)acetate was applied to the syntheses of 2,3-difluoro-2,3-dihydrobenzofuran derivatives, togedier with 2-fluoro-3-hydroxy derivatives as minor products <03SL1631>. 

By using a stoichiometric amount of the chiral titanium reagent prepared by mixing chiral diol, Titanium IV) Chloride, and titanium tetraisopropoxide, the asymmetric [2 + 2] cycloaddition reaction of 1,4-benzoquinones and styrenes gives the corresponding cyclobutane derivatives with high optical purity. These rearrange to 2,3-dihydrobenzofuran derivatives on mild acid treatment (eq 13). ... 

Pd/C in AcOH or on Pd/BaS04 in AcOH, the reaction proceeds through to the 2,3-dihydrobenzofuran stage. Some catalysts (Raney nickel at 60° 50 kg/cm ) lead directly from 237 to 2,3-dihydrobenzofuran derivatives, without going through the acetoxy derivatives. The corresponding benzofuran derivative is obtained under normal pressure. ... 

Titanium Lewis acids effect formal [2 + 2] cycloaddition as shown in Eqs (158) [401] and (159) [402,403]. Subtly changing the reaction conditions and substrates alters the product of Eq. (159) from the cyclobutane to a dihydrobenzofuran derivative, as will be described below. The analogous hetero [2 + 2] addition of a chiral aldehyde to a silylketene proceeded stereoselectively in the presence of titanium tetrachloride to give the propiolactone, as shown in Eq. (160) [404]. The silyl group was removed by the treatment with KF. 

On treatment with Mn(acac)3 in MeCN, 2-aUyl-4-(tert-butyl)phenol (675) undergoes one-electron oxidation to afford a phenoxy radical. The radical is expected to react with the ort/io-allyl group to yield a dihydrobenzofuran derivative 676. However, Mn(acac)3-promoted oxidation of 675 provided a spiro compound 677 (25%) (Scheme 132) . 

The group have also developed an analogous process for direct C-H functionalization of electron rich aromatic rings and cyclization with unactivated alkenes to access substituted benzofuran and dihydrobenzofuran derivatives (Scheme 43) [71]. 

The carbene mechanism is to be highly preferred over the anionic mechanism proposed earlier for the formation of the dihydrobenzofuran derivative. Further study revealed that the preferred mode of cyclization in most of the cases is the one which leads to five rather than six-membered rings. Thus o-propylbenzoyl- and o-phenoxybenzoyl phospho-nates give the five-membered ring products 13 and 14 In the latter case, the reaction involves expansion of the aromatic ring. 

Other cycloadditions. A [3+2]-cycloaddition involving a benzoquinone and an alkene to give 2,3-dihydrobenzofuran derivatives, and an intramolecular [4+3]-cycloaddition to provide functionalized polycyclic compounds, are further demonstrations of the utility of LiClQj-OEtj. The reaction of aromatic or a,p-unsaturated aldehydes with acid chlorides proceeds via ketenes and then 2-oxetanones. ... 

---