Dihydrobenzofurans 3-functionalized

A convenient preparation of dihydrobenzofurans has been achieved from the appropriately functionalized ort/ o-halophenol derivatives. Treatment of the aryl iodide (5)-33 with (TMS)3SiH and EtsB in the presence of air at room temperature, gave the aryl radical which cyclized in a 5-exo-trig mode and provided the bicyclic derivatives 34/35 as a 29 1 mixture of diastereoisomers in favour of 34 (Reaction 7.40) [51]. 

Dihydrobenzofuran (327) reacted with lithium and a catalytic amount (5%) of DTBB in TFIF at 0°C to give mainly or exclusively the corresponding intermediate 328, which by treatment with an electrophile at the same temperature and final hydrolysis yielded functionalized phenols 329 (Scheme 96) . ... 

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>. 

More recently, elegant mechanistic studies on intramolecular Meer-wein reactions by Beckwith et al. considerably extended the utility of diazonium salts. They showed that many electron donors could convert an arenediazonium cation into an aryl radical which cyclized in good yield to form dihydrobenzofurans and indolines. The final radical was functionalized as a halide, sulfide, or ferrocene. Thus, the credentials of diazonium salts as electron acceptors were well established, and the stage was set to investigate the interaction between diazonium salts and TTF. 

The radical nucleophilic substitution is perfectly suited for tandem reactions [180]. Recent examples have been reported by the Rossi group (Scheme 66). Dihydrobenzofuranes and dihydroindoles substituted at the 3-position were prepared from ortho-functionalized haloaromatic compounds in high yields [181]. The nucleophiles involved in the initial electron transfer and subsequent coupling are varied. In particular, starting form naphthyl derivative 210, phosphinyl anions lead to tricyclic phosphine oxide 211 (after oxidation) in 98% yield. 

Although the tosylguanidine bond is cleaved by HF, for the protection of the guanidino function the Tos group has been replaced by more efficiently cleaved sulfonyl derivatives such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr, 98),f l 4-methoxy-2,6-dimethyl-phenylsulfonyl (Mds, 99), mesitylsulfonyl (Mts, 100),2,3,4,5,6-pentamethylphe-nylsulfonyl (Pme, 101),f l 2,2,5,7,8-pentamethylchroman-6-ylsulfonyl (Pmc, lOl), ] and 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonyl (Pbf, 103),f l as described in Section 2.6.1.4. 

Cyclic alkyl aryl ethers lead also to functionalized organolithium compounds by reductive carbon-oxygen bond cleavage in arene-catalyzed lithiation process. Thus, the treatment of 2,3-dihydrobenzofuran (47) with an excess of lithium in the presence of a catalytic amount of DTBB in THF at 0°C gives the dianion (48) which after reaction with different carbonyl compounds and final hydrolysis with water leads to... 

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]. 

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. ... 

A different approach for the synthesis of racemic /rans-pterocarpans was also developed. A frans-fused 2-3-disubstituted dihydrobenzofuran was produced by AgBF,-promoted intramolecular cyclization, and after reduction of an ester function the six-membered oxygen ring was formed by Mitsunobu cyclization <01T7113>. 

A novel synthetic approach was established in which the Wilkinson s catalyst activated the C-H bond of aromatic imines to generate functionalized dihydrobenzofurans. The characteristic feature of this annulation procedure was the cross-coupling reaction proceeded selectively at the more hindered ortho site, providing functionalized bicyclic ring systems that would be otherwise difficult to access <01JA9692>. 

Zhang, H., Ferreira, E.M. and Stoltz, B.M. (2004) Direct oxidative Heck cyclizations intramolecular Fujiwara-Moritani arylations for the synthesis of functionalized benzofurans and dihydrobenzofurans. Angew. Chem. Int. Ed., 43, 6144-8. 

If the allyl group of the aryl allyl ether featured a tri- or tetra-substituted alkene, then the thermodynamic isomerization to the aromatic benzofuran could not occur, and dihydroben-zofurans were consequently produced in good to excellent yields (Figure 9.8). As in the benzofuran systems, a host of aryl and alkyl substitution patterns were tolerated in this oxidative cyclization. A number of polycyclic and highly functionalized dihydrobenzofurans were obtained via this palladium(II)-catalysed oxidation. 

Similar substituent effects have been determined in the reaction of complexes 10 to form palladacycles 11 (Scheme 11.3) [31]. The opposite process-the intramolecular palladium-catalyzed arylation of alkanes to form dihydrobenzofuranes-has also been examined [32]. For this transformation, a mechanism based on a C—H bond-activation process by the aryl-Pd(II) involving a three-center transition state was found to be more consistent with the experimental kinetic isotope effect (3.6 at 115 °C), as well as with density functional theory (DFT) calculations. 

Under the optimized conditions, allyl 2-bromophenyl ethers were treated with 2.0 equiv. of tert-butyllithium in diethyl ether at —78 °C to afford allyl 2-lithiophenyl ethers 166, which were stable at low temperature. Addition of TMEDA to the reaction mixture, followed by warming to 0°C, and subsequent treatment with various electrophiles led to the functionalized dihydrobenzofuran derivatives 165 in moderate to good yields (Scheme 10.53, path A). It is interesting to note that the 1,3-elimination pathway (Scheme 10.53, path B) could be avoided. Furthermore, this intramolecular carbolithiation reaction was completely diastereoselective, and only the trans diastereomers were obtained. This stereochemistry was explained considering the chairlike transition state 166 in which the a-substituent predominantly occupies a pseudoequatorial position resulting in high levels of... 

The effect of substitution on the aromatic ring was also investigated, and 2-propenyl aryl ethers 169, bearing substituents at the 4,6-positions of the aromatic ring, when treated under the optimized conditions, also led to the corresponding functionalized 2,3-dihydrobenzofurans 171 in moderate to good yields (Scheme 10.55a). 

Note here that, as shown in Scheme 9, the methyl carbon of 2-butenyl or 2-pentenyl moiety of the starting 2-alkenylphenols can be functionalized via the resulting 2-vinyl-2,3-dihydrobenzofuran or 2-vinylchroman with nucleophiles in the presence of palladium(O) catalyst. ... 

More recently, a palladium-catalyzed tandem protocol for the synthesis of cyclopentene fused heterocycles from diazabicyclic alkenes and ortho-functionalized atyl iodides was elaborated. A number of cyclopentene fused dihydrobenzofurans and indolines were prepared by this procedure (Scheme 2.50). The reaction can he tuned toward the formation of either... 

Figure 6 Polymerization of bioactive functionalized monomers using polar mixed reaction solvents, (a) Polymerization of unprotected carbohydrate-functionalized oxanorbornene monomers, (b) Poiymerization of cyclooctene monomers bearing sulfated carbohydrates using highly active catalyst 9. (c) Peptide-functionalized norbornene monomers were polymerized using defined cataiyst 10. DCE, 1,2-dichloroethane Pbf, 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyi.

Furan formation through 5-exo-dig type of cyclization involving functionalization of the alkyne moiety was observed by Luo et al. during their study of PdCb-catalyzed stereocontrolled syntheses of ( )-2-arylidene-2,3-dihydrobenzofurans 265 (Table 19.1) [130], The reaction of 2-propargylphenol 264 with BuLi followed by aryl iodides in the presence of 10 mol % PdCb produced a small amount of the benzofuran 266, formed by double-bond isomerization under basic conditions. The reaction using Pd(PPh3)4 gave only the benzofuran 266 in low yield (28%). 

Later, Yu and Davies further elaborated this fascinating reaction in the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans (Scheme 3.31) [60]. Through a rhodium-catalyzed enantioselective intermolec-ular C-H insertion and following palladium-catalyzed C-H activation/C-O cyclization sequence, a variety of 2,3-dihydrobenzofurans were synthesized with a high regio-, diastereo-, and enantioselectivity. 

Scheme 3.31 Enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans.

More recently, Cramer and coworkers reported an asymmetric version of this chemistry to access functionalized chiral dihydrobenzofurans that possess a quaternary stereocenter using chiral rhodium catalyst (Scheme 6.13) [23]. They found that O-tethered substrate 54 was deuterated more quickly than meta-methyl-substituted derivative 55. Furthermore, the reaction will take more time for both substrates when the chiral complex with a 1,2-disubstituted cyclopen-tadienyl ligand was replaced with achiral complex with a more hindered Cp ligand. These differences between substrate 54 and 55 emphasize the significance of the alkoxy substituent as a secondary directing group for rhodium-catalyzed reactions. 

In 2011, the second total synthesis of (-F)-lithospermic acid was achieved by Yu and coworkers (Scheme 16.22) [43]. They employed two types of C-H functionalization an intramolecular C-H insertion and an intermolecular C-H alkenylation to construct the dihydrobenzofuran unit and to connect the side chain. Treatment of diazo compound 106 withRh2(5 -DOSP)4 (tetralds[l-[[4-alkylphenyl]sulfonyl]-(2S)-pyrrolidinecarboxylate) (Davies catalyst) [44] at room temperature achieved... 

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