1,3-Dipolar cycloadditions 4- dihydrofuran

In a more recent work the same research group has applied cyclic and acyclic vinyl ethers in the oxazaborolidinone-catalyzed 1,3-dipolar cycloaddition reaction with nitrones [30]. The reaction between nitrone 5 and 2,3-dihydrofuran 6 with 20 mol% of the phenyl glycine-derived catalyst 3c, gave the product 7 in 56% yield as the sole diastereomer, however, with a low ee of 38% (Scheme 6.9). 

The rhodium-mediated reaction of 69 with 2,3-dihydrofuran (a formal dipolar cycloaddition of a cyclic diazo dicarbonyl compound with a vinyl ether) yields 70. Corrqiound 70 can be transformed in a number of steps to 71 a,b <96TL2391>. 

Besides isocyanides, Nair and coworkers also used carbenes to add to alkynes such as DMAD (9-90) leading to 1,3-dipoles, which can be trapped in a formal 1,3-dipolar cycloaddition (Scheme 9.21) [61]. Thus, the dimethoxycarbene 9-99, generated in situ through thermolysis of 9-98, reacts with DMAD (9-90) to give the dipole 9-100, which adds to an aldehyde 9-97 or a ketone. As the final product, dihydrofurans 9-101 are obtained in good yields. 

Dipolar cycloaddition reactions of 2,6-dichlorobenzonitrile oxide with 2/,3/-didehydro-2/,3/-dideoxythymidine 91 (R = H, Me3CMe2Si), at its 2,5-dihydrofuran double bond, gave nucleosides 92 and 93 in 67% yield and 3 2 ratio and 96% yield and 3 1 ratio, respectively (260). 

The 1,3-dipolar cycloaddition of nitrile oxides and 2-methylfuran provides suitable precursors for a-amino acids such as L-furanomycin 448 that contains a dihydrofuran ring (495). By using a chiral nitrile oxide derived from mannitol bis(acetonide), the enantiomerically pure furoisoxazoline 449 has been obtained. Hydroboration-oxidation of the latter leads to the hydroxy-substituted annulated THF derivative 450, which is converted via dihydrofuran 451 to furanomycin 448 in enantiomerically pure form (Scheme 1.55). 

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

An example of enantioselective 1,3-dipolar cycloaddition of ethyl diazopyruvate to 2,3-dihydrofuran, catalyzed by a chiral ruthenium-PyBox complex, to provide a tetrahydrofurofuran was reported (Equation 125). However, the adduct 240 was only obtained in 74% ee, and its absolute configuration not determined <2004SL2573, 2005HCA1010>. As shown in Equation (126), 2,3-dihydrofuran also participated in 1,3-dipolar cycloaddition with dipoles derived from aziridines under Sc(OTf)3-catalyzed conditions, forming rfr-fused furopyrrolidines <2001TL9089>. 

Dihydrofuran derivatives 319 are formed as major products in Rh2(OAc)4-catalyzed reactions of a-diazoacetophenone with 2-methoxy-propene or a-methoxystyrene (84MI1). Copper chelate or rhodium(II) acetate-catalyzed 1,3-dipolar cycloaddition of metal carbenoids, generated from ethyl formyldiazoacetate (90JOC4975), ethyl diazopyruvate... 

A full account of the Ru(PyBox)-catalyzed enantioselective 13-dipolar cycloaddition between 2,3-dihydrofuran and diazopyruvates, first described in 2004, was reported <05HCA101Q>. 2,3-Dihydrofurans having a 3-acetyl group, e.g. benzocycloalla[l,2-fojfurans and spiro[furan-2(37/),r-benzocycloalkane], underwent benzannulation via photo-induced cleavage of the dihydrofuran ring <05rL7303>. An example that produced a helicene-type compound is shown below. 

Diazo-5,5-dimethylcyclohexan-l,3-dione (140) with an excess of acrylate esters serving as both reactant and solvent in the presence of rhodium acetate afforded benzofuran 141 (98SC865). The formation of the dihydrofurans probably proceeded via a 1,3-dipolar cycloaddition of a metal carbenoid to the x,/)-unsa titrated ester (98SC865). Similarly, the reaction can take place with dihydrofuran, furan, and 1-acetyl indole to give 109,142, and 143, respectively (91JOC6269) (Scheme 24). 

Full details are now availableof the synthesis of (i)-iso-retronecanol [diastereoisomer of (26)] utilising the 1,3-dipolar cycloaddition of a cyclic nitrone to dihydrofuran (cf. Vol. 11, p. 45). ... 

These dihydrofuran syntheses may be considered as 1,3-dipolar cycloadditions because the ketocarbene (8.117 a) formed in the reaction of diazocarbonyl compounds (8.116), like 8.110, with metal complexes has dipolar character (8.117 b). 

There is no doubt that such a ketocarbene is expected to be a 1,3-dipole, as discussed in Section 6.2, but the process 8-52 is not a carbeno/rf reaction, as shown in Doyle s general scheme 8-46. The dihydrofuran syntheses are, therefore, only apparently dipolar cycloadditions. Doyle et al. (1984 b) suggested a mechanism for these cycloadditions that is closely related to his explanation of the preferential trans-stereoselectivity in cyclopropanation by a-carbonylcarbenes. One argument of Doyle for this conclusion is the close analogy between the results of dihydrofuran formation of 1- and 2-methoxybuta-l,3-diene with ethyl 3-diazo-2-oxopropionate (8.110) and the cyclopropanation of these butadiene derivatives with ethyl diazoacetate (Doyle et al., 1981, and other papers see Maas, 1986, p. 97). We return, therefore, to the transition state of cyclopropanation (8.105) here in order to investigate whether it is consistent with the mechanism of formation of dihydrofuran. 

Carbonyl ylides undergo 1,3-dipolar cycloaddition with alkenes and al-kynes to yield tetrahydrofuran and 2,5-dihydrofuran derivatives, respectively (Scheme 5.14). 

V. Nair, S. Bindu, V. Sreekumar, L. Balagopal, Synthesis 2003, 1446-1456. Novel dipolar cycloaddition reactions of zwitterionic species generated from dimethoxycarbene and dimethyl acetylenedicarhoxylate with carhonyl compounds facile synthesis of dihydrofuran derivatives. 

Dipolar cycloaddition of ethyl 2-diazo-4,4,4-trifluoroacetoacetate 201 with isobutyl vinyl ether produced dihydrofuran 202 which underwent elimination affording 2-trifluoromethylfuran 203 [130], A related reaction with alkynes directly... 

Murphy and Neville found that dihydrofuran undergoes Me2AlCl-promoted [2 + 2] cycloaddition with benzo- and naphthoquinone [55]. It was proposed that this cycloaddition occurs by initial Lewis acid coordination to the quinone, then Michael addition to dihydrofuran, followed by rapid ring closure of the intermediate dipolar ion, as shown in Sch. 31. 

Dihydrofuran (21) reacted with nitrostyrene (15a) and methyl acrylate yielding the tricyclic nitroso acetal (23) in 88 % yield as a mixture of three diastereomers (15 kbar, RT, 16 h. Scheme 9.7). The use of methyl-substituted nitrostyrene (15b) resulted in the formation of nitroso acetal (24) as a mixture of five diastereomers in 84 % yield (15 kbar, 50 °C, 18 h). The formation of five diaster-eomeric products indicated a non-selective [4 - - 2] cycloaddition exo and mdo). The loss of endo-selectivity in the [4 -I- 2] cycloaddition was also observed when 3,4-dihydropyran (22) was used. Tricyclic nitroso acetal (25) was produced in 37 % yield (15 kbar, 50 °C, 92 h) as a mixture of diastereomers resulting from exo and mdo [4 -h 2] cydoadditions and syn/anti exo and endo 1,3-dipolar cydoadditions [7]. It is known that 3,4-dihydropyran (22) reacts much more slowly than the five-membered 2,3-dihydrofuran (21), mainly due to the lower ring strain. This is reflected in the moderate yield of 25 and the lack of reactivity of 3,4-dihydropyran... 

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