Propargyl alkoxide

Some single examples of this type of reaction were discussed in earlier sections, but due to the importance of these transformations, an additional overview will be provided here. One of the first transformations based on this strategy was published by Inoue and coworkers [134] using propargylic alkoxide, an arylhalide or vinyl bromide and C02 to give cyclic carbonates. The Balme group used this ap-... 

Interestingly, this strategy was applied to the more reactive propargyl alkoxides allowing for the simultaneously introduction of the three partners at the start of the reaction. In fact, in this case, no side reactions occurred [95]. This process is remarkably versatile, giving good yields of stereodefined 3-arylidene (and alkenyli-dene) tetrahydrofurans 105 with a variety of propargyl alcohols (primary, secondary, and tertiary) and unsaturated halides (aryl iodides, vinyl bromides, and tri-flates) (Scheme 8.45). 

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. 

An equimolar mixture of 3,4,5-trimethoxy phenyl iodide 157, lithium propargyl alkoxide 158, and diethyl ethoxymethylene malonate 159 was stirred at room temperature in the presence of a palladium catalyst. Then, to the resulting intermediate 161 potassium t-butoxide was added, and the ensuing base-promoted decarboxylative aromatization afforded tetrahydrofuran MCR adduct 162 in good yield. The ester was first reduced and the furan ring was hydrogenated with Raney nickel to furnish a diastereomeric mixture of products 163 in high yield. Further synthetic manipulations then provided a known precursor to the natural product. 

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>. 

On the other hand, treatment of the benzenesulfonate depicted below with 3 equivalents of LDA gave an intermediate propargyl alkoxide through a double elimination. Then a concomitant intramolecular nucleophilic substitution led to the formation of the tetrahydrofuran ring <03TA1363>. 

An impressive alternate approach to the synthesis of furans beginning with alkynols was developed by Balme [160, 161] and subsequently applied in a total synthesis by Morimoto [162]. Balme discovered that a three-component coupling reaction between a propargylic alkoxide, a conjugate addition acceptor, and an unsaturated halide yields a variety of di- and trisubstituted furans. In one example, propargyl alcohol, diethyl ethoxymethylene malonate (193), and iodobenzene combine to furnish disubstituted furan 194 in... 

The key transformation was next effected by exposnre of 161 to 3 equiv of LDA, which resulted in the generation of propargyl alkoxide throngh donble elimination... 

Vinylidenecarbene or allenylidene3 (R)2C=C=C has a lance-shaped, unsubstituted and sp-hybridized carbene center and, therefore, will not be easily subject to steric hindrance in its insertion reactions. On this assumption, (2-methyljpropenylidenecarbene or its carbenoid was chosen as a prototype of typical vinylidenecarbenes and its insertion reaction with several different types of alkoxides was investigated by employing two methods (A and B, Scheme 10) for carbene generation.20 The insertion products 20 were obtained almost exclusively except lithium allyloxide (Table 4, entry 10).21 By-products such as propargyl ether and allenyl ether were not formed at all. To be noted here, in... 

If the addition involves an alkynyllithium such as 34, the first-formed alkoxide intermediate 35 isomerizes into the propargylic-allenic lithium reagent. Reactions with electrophiles lead to either 36a or the allenol silyl ethers 36b (equation 13). ... 

The procedure described in this experiment exemplifies a general method [225] for the reduction of propargylic alcohols to -allylic alcohols. The first step in the reaction is the formation of the aluminium alkoxide -C=C-C-OAlH3. Subsequently one of the three hydrogen atoms attached to aluminum is transferred to the triple bond with formation of a 5-membered cyclic aluminum compound. Hydrolysis affords the -allylic alcohol. In the present case an -enyne alcohol is formed. 

When the alcohol adduct from the allenylzinc reagent and diisopropyl ketone was treated with 80 mol% of allenylzinc bromide in HMPA, a mixture containing 12% of diisopropyl ketone and 88% of recovered alcohol was obtained after 7 days at ambient temperatures (equation 1). Thus, it may be deduced that the allenylzinc additions are reversible. Presumably, the propargyl adducts are intrinsically favored, but steric interactions between the R1 and R2 substituents in the propargyl product favors an increased proportion of allenyl adducts in a reversible process (see Table 1). HMPA would expectedly facilitate reversal of the addition by decreasing the ion pairing between the alkoxide anion and ZnBr cation of the adducts. This expectation was subsequently confirmed by a study of solvent effects. 

When 303 was directly treated with Me2Cu(CN)Li2, the transmetallation failed to discriminate between the two carbon-metal bonds. By contrast, the allylzincation of the alkynyllithium derived from the propargylic alcohol 309 produced the alkenyl 1,1-dimetallic species 310, in which the two carbon-metal bonds exhibit different reactivities due to the presence of a metal-alkoxide. Indeed, transmetallation with Me2Cu(CN)Li2 led to the alkenyl copper-zinc species 311, which was relatively poorly reactive towards electrophiles but underwent successful 1,4-addition to ethyl propiolate leading to 312 in satisfactory overall yield (equation 145)180. 

The transformation termed propargylic rearrangement attracted much attention, and detailed discussions are available in review papers.134-141 Suitable reagents to bring about this rearrangement are metal alkoxides and metal amides in alcohols and dipolar aprotic solvents (DMSO, HMPT), and metal amides in ammonia. Reactivities are strongly dependent on the base employed, the solvent, and the reaction conditions. 

The TBS protecting group is selectively cleaved in the first step. The released propargylic alcohol is then reduced with Red-AI to an allylic alcohol. Reduction of the propargylic alcohol occurs selectively trims. Since during this reaction a five-membered ring system 41 is created through coordination of aluminum with the alkox-ide, it is assured that aluminum is located m the 3-position relative to the alkoxide. 

Isomerization of chiral propargyl alcohols.1 The isomerization of chiral alcohols of the type RCHOHC,=C(CH2)nCH3 to terminal acetylenic alcohols, RCHOH(CH2)n + 1C=CH, in the presence of KAPA occurs with no significant loss of enantiomeric purity. Evidently, formation of the alkoxide suppresses racemization. Retention of configuration is observed even when the triple bond moves through several methylene groups. 

ROC==CCH -> ROCHjC CH. Propynyl ethers can be obtained from secondary alkoxides by reaction with trichloroethylene followed by dehydrochlorination and methylation. These can be rearranged to propargyl ethers by KAPA. This sequence is applicable to highly hindered secondary alcohols.1... 

Metalatlon of 2-alkynyl and 1,2-alkadienyl tetrahydropyranyl ethers furane synthesis. /-Butyllithium metalates the lithium alkoxide 1 to afford the allenyllithium compound a quantitatively. This anion reacts with alkyl halides or CH3OH to afford 2. Another metalation-alkylation protonation sequence proceeds via b to afford 3. Hydrolysis of the latter intermediate affords furanes directly. The overall sequence can be performed in one pot from a propargyl tetrahydropyranyl ether, r-butyl-lithium, and an aldehyde. ... 

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