Dipolar Cycloadditions of Furans

In 1982, Vasella and Voeffray [196] presented a synthesis of (-f)-nojirimycin (5-amino-5-deoxy-D-glucose) using the 1,3-dipolar cycloaddition of a D-mannose-derived nitrone to furan. The chiral source in that synthesis (D-mannose) is not recovered. Jager and Muller used 

SCHEME 13.99 Applications of the naked sugars of the second generation to the synthesis of branched-chain sugar derivatives. 

With LiAlH4, both the aldehyde and isoxazoline moieties of (+)-422 are reduced with formation of aminotriol (—)-424. Treatment of (—)-424 with acid generates the l,6-anhydro-/Jo-piperidinose (+)-425, the hydrogenation of which provides (—)-L-l-deoxyidonojirimycin. The same sequence of reactions applied to (—)-422 gives (+)-D-l-deoxyidonojirimycin [200]. 

SCHEME 13.101 Total syntheses of (—)- and (+)-l-deoxynojirimycin and of (+)- and (—)-l-deoxy-idonojirimycin starting from furan. 

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Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Few solid-phase syntheses of furans have been reported. Most of these have been limited to furans with a specific substitution pattern and lack general applicability. Furans can be obtained by thermolysis of support-bound 7-oxa-2-azanorbornenes, which are prepared by 1,3-dipolar cycloaddition of electron-poor alkynes to iso-miinchnones (Figure 15.4). 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

The 1,3-dipolar cycloadditions of ethyl 4//-furo[3,2-/>]pyrrole-5-carboxylate (8a) or its 4-methyl derivative (8f) (Equation (2)) with C-benzoyl-A-phenylnitrone and ACV-diphenylnitrone proceeded regiospecifically at positions 2 and 3 of the furan ring. During these reactions, exclusively endo cycloadducts were formed, because their transition states are stabilized by secondary orbital interactions <81CCC2421>. 

The cycloaddition of isomiinchnones with acetylenic dipolarophiles followed by the extrusion of an alkyl or aryl isocyanate (RNCO) has proven to be an effective method for the synthesis of substituted furans. The Ibata group investigated the bimolecular 1,3-dipolar-cycloaddition of aryl-substituted isomiinchnones with a number of acetylenic dipolarophiles [50]. Aryl diazoimides of type 1 were heated in the presence of a catalytic amount of Cu(acac)2 and the appropriate acetylenic dipolarophile. Formation of the substituted furan was found to be temperature-dependent higher temperatures (ca. 120°C) were needed for complete conversion to the furan. It was reasoned that the extrusion of methyl isocyanate was not as facile as the loss of carbon dioxide from sydnones and miinchnones [50]. 

Intermolecular [3+2] 1,3-dipolar cycloaddition of a D-glyceraldehyde-derived nitrile oxide to the 4,5-double bond of 2-methylfuran gave a 60 40 diastereomeric ratio of the two furoisozaxoline isomers. This chemistry was employed in the synthesis of L-furanomycin <2005EJ03450>. As depicted in Scheme 43, an intramolecular cycloaddition of a furan with a carbonyl ylide dipole proceeded under rhodium-catalyzed microwave-promoted conditions to provide the cycloadduct in a modest yield <20040L3241>. 

In an alternative process, an apparent [3 + 2]-dipolar cycloaddition of ring-opened cyclopropenes to alkenes has been reported, e.g. cycloaddition of 2 to furan. ... 

The dipolar cycloaddition of 2-oxyallyl cations is also a process that has been exploited for the synthesis of substituted furans and polycyclic materials, for example it can be made the means for the introduction of acylmethyl groups at the furan 2-position." ... 

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). 

Cycloaddition reactions, [3 + 2] or [2 + 2] depending on L, of TpRe(CO)(L) (f/ -furan) complexes have been reported. The electrophilic alkene tetracyano-ethylene (TCNE) and the alkyne dimethylacetylenedicarboxylate (DMAD) were used as dienophiles. For L = PMcs and BuNC, 1,3-dipolar cycloaddition of TCNE to / -furan gives [3 + 2] products via a carbonyl ylide (Scheme 47). Addition of... 

The cationic, goid(I)-catalysed tandem heterocyclization/3 + 2-cycloaddition of 2-(l-alkynyl)-2-alken-l-ones (1) with 3-styrylindoles (2) yielded highly substituted cyclopenta[c]furans (3) in a one-pot reaction under mild conditions. The expected cyclohepta[c]furans (4) were not isolated (Scheme 1). The 1,3-dipolar cycloaddition of 3-oxidopyridinium betaines with pentafulvenes produced a variety of bicyclo[6.3.0]undecanes and bicyclo[5.3.0]decanes via 3 + 2- and 6 + 3-cycloadditions. ... 

Gowravaram and Gallop have developed a traceless synthesis of substituted furans using 1,3-dipolar cycloadditions of isomunchones [72]. Zaragoza published the synthesis of 1,2,3-triazoles [73] and aminothiophenes [74] wherein the final targets were monoamides of piperazine. Hydantoins continue to be a favorite target for combinatorial chemists. Matthews and Rivero [75] have described a modification of... 

One recent example of applying this process was reported by Johnson et al. for the preparation of furan derivatives (Scheme 16.12) [19]. This reaction involved the rhodium(II)-catalyzed intermolecular generation of carbonyl ylides A or B from diazosulfone (18) and aldehydes 19 or 21, respectively. The 1,3-dipolar cycloaddition of the resulting carbonyl ylides with an intramolecular tethered alkyne moiety or dimethyl acetylenedicarboxylate (DMAD, an intermolecular process), followed by elimination of phenylsulfinic acid, could access furan derivatives. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brpnsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated a-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2-dihydrobenzo /j]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. 

The meso-ionic l,3-oxathiol-4-ones (498) are a new class of meso-ionic heterocycle which appear to be too unstable to be isolated at room temperature. They can be generated by cyclodehydration of the acids 499, R = NR2 R — Ph, using acetic aiihydride, and trapped in situ by 1,3-dipolar cycloaddition with acetylenes the product is a furan (500) formed via the bicyclic adduct (501). ... 

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