Tetrahydrofurans, alkylidene

The Williamson ether synthesis remains the most practical method for the preparation of tetrahydrofurans, as can be exemplified by the two examples shown in the following schemes. A simple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles 84 is achieved by generating the alkoxide under a phase transfer condition via reaction between 4-chlorobutyronitrile and non-enolizable aldehydes <00SL1773>. A synthesis of 2-alkylidene-tetrahydrofuran 85 was recorded, in which a dianion can be generated through treatment of the amide shown below with an excess of LDA, and is followed by addition of l-bromo-2-chloroethane. In this way, the more basic y-carbon is alkylated and leads eventually to the nucleophilic cyclization <00SL743>. 

Ojima has reported a rhodium-catalyzed protocol for the disilylative cyclization of diynes with hydrosilanes to form alkylidene cyclopentanes and/or cyclopentenes. As an example, reaction of dipropargylhexylamine with triethyl-silane catalyzed by Rh(acac)(GO)2 under an atmosphere of CO at 65 °G for 10 h gave an 83 17 mixture of the disilylated alkylidene pyrrolidine derivative 92b (X = N-//-hexyl) and the disilylated dihydro-1/ -pyrrole 92c (X = N-//-hexyl) in 76% combined yield (Equation (60)). Compounds 92b and 92c were presumably formed via hydrosilyla-tion and hydrosilylation/isomerization, respectively, of the initially formed silylated dialkylidene cyclopentane 92a (Equation (60)). The 92b 92c ratio was substrate dependent. Rhodium-catalyzed disilylative cyclization of dipro-pargyl ether formed the disilylated alkylidene tetrahydrofuran 92b (X = O) as the exclusive product in low yield, whereas the reaction of dimethyl dipropargylmalonate formed cyclopentene 92c [X = C(C02Et)2] as the exclusive product in 74% isolated yield (Equation (60)). 

More recently, a zinc-catalyzed tandem 1,4-addition/carbocychzation, involving propar-gyl alcohol and 2-alkylidene-l,3-dicarbonyl compounds of type 400 as partners, was reported257. These compounds were stirred in the presence of Zn(OTf)2 and Et3N and afforded the 3-methylene tetrahydrofurans 401 in excellent yields (equation 175)258. 

In a similar manner, Lu and Liu have more recently utilized the hetero-Michael addition of lithium propargylic alkoxides to alkylidene malonates in a synthesis of stereodefined allylidene tetrahydrofurans, based on the use of allylic chloride as coupling partner [98]. In this case, the cydization reaction is initiated by a catalytic amount of palladium salt [Pd(OAc)2] rather than by an organopalladium species as mentioned above. 

Dialkyl allyl telluronium bromides and dibutyl ethoxycarbonylmethyl (cyanomethyl, benzoylmethyl) telluronium bromide generated dialkyl alkylidene telluriums on treatment with potassium ferf-butoxide in tetrahydrofuran at low temperatures (s. p.837). The tellurium ylides were not isolated but were trapped with aldehydes and ketones4-6. 

Similar reactions with dibutyl cyanomethyl telluronium bromide and dibutyl benzoylmeth-yl telluronium bromide gave the expected dibutyl alkylidene telluriums however, their reactions with benzaldehydes in tetrahydrofuran yielded cyanoethenes and conjugated enones but no epoxides1. 

We reported that the palladium catalyzed hetero [3 + 2] cycloaddition of the alkylidenecyclopropanes 31 with the aldehydes 32 gave the 3-methylene-tetrahydrofurans 33 in good yields (Scheme 13) [48]. The reaction initiated by oxidative addition of palladium(O) to a distal bond of the alkylidene-... 

However, this intriguing catalyst system is capable of performing a subsequent reductive amination in the same pot and under the same conditions if secondary amines are added and if an atmosphere of hydrogen is introduced. Therefore, alkyne allyl alcohols 200 are readily transformed in moderate to good yields into /J-amino ethyl alkylidene tetrahydrofurans 203... 

A Pd(0)-catalyzed three-component coupling of propargylic alcohols and aryl halides with a suitable Michael-acceptor to yield alkylidene tetrahydrofuran derivatives has been developed. Upon decarboethoxylation of these compounds with potassium fet7-butoxide, 3-benzylfurans are eventually formed (Scheme 22) <2001JOC4069>. The reaction sequence can be carried out as a one-pot procedure with acceptable yields. 

It is well known that enolates act as O-nucleophiles in Sisr -type cyclizations to furnish alkylidene tetrahydrofurans (Equation 72) <2004JOC6715>. A double intramolecular Sn reaction with O-nucleophiles to yield bis-tetrahydro-furan cores of acetogenins has been achieved <1999JOC2259>. 

Stereospecific reductive ring opening of bis-epoxides separated by two methylene groups to 2-alkylidene tetrahydrofurans has been brought about by elimination-cyclization of l-iodomethyl-l,5-bis-epoxides with zinc dust (Equation 76) <20030L1931>. 

When propargyl allyl ethers are subjected to transition metal-catalyzed enyne cyclization reactions, 3-alkylidene-substituted tetrahydrofurans are usually formed. A useful variation of this scheme is the Pd(0)-catalyzed tandem enyne cyclization/Suzuki coupling reaction with various arylboronic acids (Equation 90) <2005JOC1712>. The stereoselectivity of this reaction is explained by invoking a chairlike transition state. 

TL 30 57 (1989) (3-alkylidene tetrahydrofuran, 4-alkylidene tetrahy-dropyran) 31 3745 (1990) (bicyclic ketones) 33 7857... 

In a later study, bis-NHC ruthenium-alkylidene complex was activated under compressive strain [87] (Fig. 16). In order to initiate Ru-mediated polymerisation of norbomene in solid state, polymer catalyst (34 kg mol ) and a norbomene monomer were incorporated in a high molecular weight poly(tetrahydrofuran) (pTHF) matrix (Mn=170 kDa, PDI=1.3) which provided the physical cross-linking through the crystalline domains and allowed macroscopic forces to be transferred to the metal-ligand bonds. Consecutive compressions showed that up to 25% of norbomene monomer was polymerised after five loading cycles. 

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