3- Methylenetetrahydrofuranes

Chemoselectivity in the cycloaddition of 2-methylenecycloheptenone (174) changes on addition of In(acac)3. The allylic carbonate 175 reacts with the ketone 174 in the presence of In(acac)3 to give the methylenetetrahydrofuran 176, and the methylenecyclopentane 177 is obtained in its absence[l 13], The cycloaddition of ynones to produce the methylenetetrahydrofuran proceeds smoothly only in the presence of In(acac)3 (10 mol%)[114]. 

Aldehydes take part in the cycloaddition to give the methylenetetrahydrofuran 178 by the co-catalysis of Pd and Sn compounds[115]. A similar product 180 is obtained by the reaction of the allyl acetate 179, which has a tributyltin group instead of a TMS group, with aldehydesfl 16]. The pyrrolidine derivative 182 is formed by the addition of the tosylimine 181 to 154[117]. 

Substituted TMM complexes also cycloadd to aldehydes in the presence of a tin cocatalyst such as MesSnOAc and MesSnOTs [31]. Reaction of 2-heptenal with methyl precursor (6) gave a mixture of methylenetetrahydrofurans (68) and (69). This regioselectivity is reversed with 10-undecenal and methyl precursor (5), where adduct (70) now predominates over (71). As in the carbocyclic system, the phenylthio group also functions as a regiocontrol element in reaction with cyclohexyl aldehyde. The initially formed adduct (72) eliminates the element of thio-phenol on attempted allyl rearrangement, and the overall process becomes a cycloaddition approach to furans (Scheme 2.21) [20]. 

Benzaldehyde dimethyl acetal 121 reacts, for example, with the silylated allylic alcohol 645, in the presence of SnCl2-MeCOCl, via an intermediate analogous to 641, to the 3-methylenetetrahydrofuran 646 and methoxytrimethylsilane 13 a [182], whereas benzaldehyde dimethyl acetal 121 reacts with the silylated homoallylalco-hol 640 in the presence of TMSOTf 20 to afford exclusively the ds 4-vinyltetrahy-drofuran 647 and 13 a [183]. A related cyclization of an a-acetoxy urethane 648 containing an allyltrimethylsilane moiety gives the 3-vinylpyrrohdine 649 in 88% yield and trimethylsilyl acetate 142 [184, 185]. Likewise, methyl 2-formylamido-2-trimethylsilyloxypropionate reacts with allyltrimethylsilane 82 or other allyltri-methylsilanes to give methyl 2-formamido-2-aUyl-propionate and some d -unsatu-rated amino acid esters and HMDSO 7 [186] (Scheme 5.56). 

Chan and Li reported that conjugated 1,3-butadienes were produced in moderate yields when carbonyl compounds reacted with 1,3-dichloropropene and zinc in water (Eq. 8.29).61 The use of 3-iodo-1-chloropropene instead of 1,3-dichloropropene greatly improved the yields. When the reactions were interrupted after their initial allyla-tions, subsequent base treatment of the intermediate compounds produced vinyloxiranes in high yields. Similarly, reactions of carbonyl compounds with 3-iodo-2-chloromethyl-l-propene followed by base treatment produced 2-methylenetetrahydrofurans (Eq. 8.30).62 Thus, the 3-iodo-2-chloromethyl-l-propene served as a novel trimethylene-methane equivalent.63... 

Pentyn-l-ol has been prepared from 4-penten-l-ol3 by bromi-nation followed by dehydrobromination with alkali,7 by the reaction of 3-bromodihydropyran with w-butylsodium or w-butyl-lithium,6 8 by the reaction of 2-methylenetetrahydrofuran with w-amylsodium or w-butyllithium,8 and by the method used in this preparation.9... 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

Enantiomerically pure 2-alkylidenetetrahydrofurans were prepared by TiCl4 mediated reactions of 1,3-bis-silyl enol ethers with enantiomerically pure epichlorohydrin <06TA892>. Rhodium complexes as the one shown below reacted in solution in the presence of triethylphosphine to afford 2,2-disubstituted-5-methylenetetrahydrofurans in good yield <06JA9642>. 

Methylenetetrahydrofurans can also be realized by an intramolecular radical cyclization of bromoalkynes utilizing indium(I) iodide as a radical initiator <06TL2859>. 3-Diiodomethylenetetrahydrofurans were also prepared from l,to-diiodo-l-alkynes in the presence of l-hexynyllithium<06CC638>. 

The Cu(I)-catalyzed cyclization for the formation of ethyl ( )-tetrahydro-4-methylene-2-phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(a-substituted N-tosyIaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4-hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>. 

Cycloaddition to aldehydes. In the presence of a Pd(0) catalyst, 1 adds to electron-poor alkenes to give methylenecyclopentanes. It also adds to aldehydes to form methylenetetrahydrofurans when tributyltin acetate is used as a cocatalyst.1... 

Adenosine analogues where the furanose ring was replaced with alternative dihydro- and tetrahydrofurans were prepared from 6-chloro-9-(4-methylenetetrahydrofuran-3-yl)-9/7-purine <2002T4865>. Of particular interest was the transformation of the exocyclic alkene on the THF ring first by dihydroxylation, then elimination to yield (4-(6-aminopurin-9-yl)-2,5-dihydrofuran-3-yl)methanol after amination of the purine ring at C-6. This A-alkenylpurine was reduced (Pd/C, H2, 25 psi, 73% yield) to provide the tetrahydrofuran-3-yl derivative. 

For a similar Li/Pd-mediated approach to functionalized 3-methylenetetrahydrofurans or pyrrolidines, see References 219 and 235. 

Dihydrofurans are known to polymerize readily by cationic means but not by free radical initiation (77MI11102). 2,3-Dihydro-5-methylfuran (40), for example, has been polymerized to a stereoregular, optically active polymer (Scheme 9) by the appropriate choice of a catalyst system. Interestingly, the double bond isomer 2-methylenetetrahydrofuran (41) can be cationically polymerized (74CL499) to the isomeric polymer (42 Scheme 10). Under the polymerization conditions, no isomerization of (41) to (40) occurred, and the resultant polymer was shown to be isotactic and crystalline by NMR and X-ray analysis, respectively. 

Amongst the plant neolignans one finds some 2-methylenetetrahydrofurans of which burchellin (146) (lignan numbering) is an example. In this series the structures, stereochemistry and absolute configurations have been established by a combination of... 

In place of a Grignard reagent, several homoenolate equivalents have also been employed. Kempt 1 7 reported the titanium-mediated addition of /V-alkylmethylacrylamide dianions to N-protected a-amino aldehydes (Scheme 8). Pyrolytic cyclization affords a 3-methylenetetrahydrofuran-2-one and the side chain of C3 is appended via conjugate addition. The resulting lactone can be converted into the 1-hydroxyethylene dipeptide by hydrolysis. The stereochemistry of the C6 atom is the same as that of the a-amino aldehyde. However, the stereoselectivities of the reactions regarding the C3 and C5 atoms are unsatisfactory. 

Methylenetetrahydrofurans and 4-methylenepyrrolidines.1 The adducts formed by Lewis acid-catalyzed reaction of 1 with an aldehyde or ketone undergo cyclization to 4-methylenetetrahydrofurans in the presence of a Pd(0) catalyst prepared from Pd(OAc)2, P(C6H5)3, and BuLi, and a base, DBU or N(C2H5)3 (1.5 equiv.). 

BINAP-Ru complexes can catalyze the enantioselective hydrogenation of alkenyl ethers as shown in Scheme 1.15 [93], 2-Methyltetrahydrofuran with 91% ee and 87% ee can be synthesized by BINAP-Ru-catalyzed hydrogenation of 2-methylenetetrahydrofuran and the endo-type substrate, 2-methyl-3,4-dihydrofuran, in CH2C12 under 100 atm of hydrogen, respectively. With the same Ru complex, phenyl 1-phenylethyl ether, an acyclic alkenyl ether, is reduced in a moderate optical yield. 

B. M. Trost, S. A. King, and T. Schmidt, Palladium-catalyzed trimethylenemethane reaction to form methylenetetrahydrofurans. Aldehyde and ketone substrates and the tin effect, J. Am. Chem. Soc., Ill (1989) 5902-5915. 

Again there are numerous reports on the synthesis of methylenefurans. The reaction of acetals with 2-(trimethylsilyloxymethyl)allyltrimethylsilane 71 under the influence of tin(II)halide and acetyl halide afforded 2-suhstituted 4-methylenetetrahydrofurans in good yields. 

Cobaloxime 255 was also applied as a catalyst (6 mol%) in a cyclization of 2-bromo-l,2-diphenylethyl propargyl ether 257 or bromoindanyl propargyl ether 259 to afford 3-methylenetetrahydrofurans of type 258 or 260 in 50% and 57% yields, respectively (entry 4) [312, 313],... 

The 2-methylenetetrahydrofuran depicted in the following scheme underwent a Claisen rearrangement catalyzed by -Bu,Al to provide an inseparable mixture of cycloheptenes as well as a ring-opened product <02T10189>. 

Promoted by copper iodide, a large array of 3-methylenetetrahydrofurans were synthesized from propargylic alkoxides as nucleophiles and activated alkenes as Michael acceptors. One of these reactions is shown below <02TL2609>. 

In the synthesis of the C-14-C-26 segment of halichondrins, the chromium complex (10 mol%) was shown to catalyze the reaction between the alkenyl iodide and the aldehyde in the presence of NiCl2 (40 mol%), Mn, Me3SiCl, Et3N HCl and LiCl in THF, affording the 3-methylenetetrahydrofuran in 70-80% yield <02OL4435>. 

As shown below, a novel indium-mediated reaction of an iodoalkyne led to a 5-exo-cyclization involving radical species and as a result a 3-methylenetetrahydrofuran was obtained <02TL4585>. 

---