Isomerization base-induced

As indicated in the general scheme below, butatrienes are the first products from base-induced 1,4-elinination of hydrogen and a suitable leaving group. The butatriene in general very readily undergoes isomerization into enynes, if sufficiently "acidic" protons are available (see Chapter 11 in Ref. 3a). In aprotic media cumulenic ethers are fixed as their lithio derivatives if an excess of alkyllithium is applied... 

The elegant biomimetic synthesis of carpanone by Chapman and coworkers commences with the base-induced isomerization of 2-allyl-4,5-methylenedioxyphenol (4)3 to 2-(/ran.y-l-propenyl)-4,5-methylenedioxyphenol (3) (see Scheme 2). Compound 3, as simple as it is, is actually the key intermediate in this synthesis oxidative dimerization of 3 could result in the formation of carpanone (1) through the intermediacy of the C2-symmetric and highly reactive bis(quinodimethide) 2. 

It is appropriate at this juncture to address some of the more useful transformations of 2,3-epoxy alcohols.913 A 2,3-epoxy alcohol such as compound 14 possesses two obvious electrophilic sites one at C-2, and the other at C-3. But in addition, C-l of a 2,3-epoxy alcohol also has latent electrophilic reactivity. For example, exposure of 14 to aqueous sodium hydroxide solution results in the formation of triol 19 in 79% yield (see Scheme 5). In this interesting transformation, hydroxide ion induces the establishment of an equilibrium between 2,3-epoxy-l-ol 14 and the isomeric 1,2-epoxy-3-ol 18. This reversible, base-induced epoxide migration reaction is a process known as the Payne rearrangement.14... 

THF/liq. NH3, followed sequentially by oxidation and base-induced double bond isomerization, provides butenolide 33, a compound that possesses the lactone system of the steroidal cardiac aglycones. 

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

Azepine-3,6-dicarboxvlates, e. g. 14, formed by solvolysis of 4-(chloromethyl)-l, 4-dihydro-pyridine-3,5-dicarboxylates(see Section 3.1.1.4.1.5.), readily undergo thermal and base-induced isomerizations to 3//-azepines, e.g. 15.29... 

The procedure described here 1 is a convenient two-step reaction that relics on the base-induced elimination-isomerization reactions of gem-dichlorooyclopropanes.8-15 The reaction mechanism has been studied.16 The principal advantage of this method is the ready availability of necessary reagents. 

T6036>. It should also be mentioned that an isomeric series of thieno[2,3- >]pyridines has been prepared by base induced annulations involving for instance 2-mercaptopyridine-3-carbonitrile precursors and ethyl chloroacetate <06SC97>. 

It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3 OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also found to give minor amounts of lactone or dithiolactone side products <06TL6067>. Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,5-diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction <06TL8087>. 

This system was described in one report and has been synthesized by a copper-assisted cycloisomerization of alkynyl imines. The authors proposed the following mechanism at first, 372 could undergo a base-induced propargyl-allenyl isomerization to form 373 next, coordination of copper to the terminal double bond of the allene (intermediate 374) would make it subjected to intramolecular nucleophilic attack to produce a zwitterion 375. The latter would isomerize into the more stable zwitterionic intermediate 376, which would be transformed to the thiazole 377 (Scheme 55) <2001JA2074>. 

The first investigations in the 1960s [11,12] established the base-induced isomerization of alkyne precursors as the most practical and general route for the synthesis of alkoxy-and aryloxyallenes. In the meantime, a number of monosubstituted allenes 8 bearing an achiral or a chiral group R is smoothly accessible by this efficient procedure (Scheme 8.5) [1, 2,13-19]. Beside the most commonly used base potassium tert-butoxide, other bases, e.g. n-butyllithium, are also applicable for this isomerization. Recently, the yields of alkyne-allene isomerizations could be significantly increased, in particular with aryloxy-substituted allenes, by using microwave irradiation (Eq. 8.1) [20]. 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

In general, sulfur-substituted allenes are accessible starting from alkyne precursors by a variety of transformations such as isomerization, rearrangement or addition reactions. The standard method for the synthesis of donor-substituted allenes is again the base-induced isomerization of alkynes. This very first method was applied for the preparation of achiral [11, 162, 163] and chiral [164] S-functionalized 1,2-dienes (Scheme 8.78). 

Some interesting modifications with respect to the base-induced isomerization have recently been developed. For example, conversion of 4-hydroxy-l-thiophenyl-2-alkynes 299 into the corresponding 4-hydroxy-substituted thiophenylallenes 300 was achieved by treatment with potassium hexamethyldisilazide at low temperature (Scheme 8.79) [165], If the hydroxyl group is protected as the THP ether an elimination reaction occurred, resulting in the formation of an enyne instead of allene 300. 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

Building on Inoue s pioneering work and using Andersson s versatile diamine, Kozmin and coworkers have described a catalytic base-induced isomerization of silacyclopentene oxide 139 [Eq. (10.41)] as a potential route to acyclic polyol domains, important components of a number of natural products. Epoxida-tion of 140, epoxide ring opening, and oxidation of the C—Si bonds provides tetra-ols in good overall yield and selectivity ... 

The reaction conditions (80 °C) used for the addition of 33 and 34 to the o-quinodimethane 32 are incompatible with the presence of 1,2-bromochlorocy-clopropene (27), thus the potential of this approach was for quite a while not further exploited. However o-quinodimethanes may be synthesized under much milder conditions, and trapped as reactive intermediates with 27. Thus base-induced isomerization of cw-oct-4-ene-2,7-diyne (38) at -78 °C leads to bis-allene (39). Upon warming of 39, rearrangement to o-quinodimethane (40) occurs between -20 and -10 °C this adds smoothly to 27 and furnishes the adduct 41. Conversion of... 

Base-induced isomerization of propargyl amide 29a gives chiral ynamide 30a, which is subjected to ring-closure metathesis to afford cyclic enamide 31a. Diels-Alder reaction of 31a with dimethyl acetylene dicarboxylate (DMAD) gives quinoline derivative 32. In a similar manner, propargyl amide 29b is converted into ynamide 30b, RCM of which gives bicyclic compounds 31b and 31b in a ratio of 1 to 1 (Scheme 10). 

The powerful 7V,7V-diethylcarbamate DMG serves admirably for the synthesis of substituted oxygenated pyridines. Thus, metalation of all isomeric pyridyl O-carbamates 317 with sec-BuLi/TMEDA followed by quench with numerous electrophiles affords diversely substituted products 318 in good to excellent yields (Scheme 96) (85JOC5436). Base-induced hydrolysis provides access to pyridones and hydroxypyridines. 

Photochemical decomposition of ethyl azidoformate in cyclohexene gives 7-carbethoxy-7-azabicyclo[4.1.0]heptane (108) as main product (56% at 38° and 75% at —75°) together with the three isomeric cyclohexenylurethans.82>83M>8 A nitrene mechanism for the reaction is supported by the fact that the same products in almost the same ratio are obtained in the base-induced cleavage of N-p-nitrobenzenesulfonoxyurethan (107). All evidence indicates that the second reaction yields the carbethoxynitrene by an a-elimination mechanism. The aziridine isomerizes at 140° into 2-ethoxy-4,5-cy clo hexano-A2-oxazoline (109). 

The action of triethylamine may cause base-induced reactions, such as a-epimerization of carbonyl compounds isomerization of alkenes into conjugation with carbonyl groups and, elimination in carbonyl compounds posssessing a good-leaving group at the (3-position... 

The Swern oxidation of homoallylic alcohols leads to a (3,y-unsaturated carbonyl compound, which sometimes suffers an in situ base-induced isomerization of the alkene into conjugation with the carbonyl group.239... 

It should be noted that addition of DBU (or HMPT) has often - particularly for the catalytic procedures - proven beneficial in terms of enantioselectivity. This effect has been attributed to the breaking-up of active but less enantioselective base aggregates [50, 56, 62-64]. Interestingly, when solid-phase-bound stoichiometric (achiral) bases were used instead of LDA, no addition of DBU was necessary [58, 59]. (An example of the stoichiometric use of a chiral solid-phase bound base is given elsewhere [52].) Both experimental and theoretical investigations [66-68] indicate that the base-induced isomerization of epoxides proceeds as a syn elimination, with the lithium ion of the base acting as a Lewis acid (Scheme 13.31). 

Further studies described the interconversion of stegane diastereoisomers via thermal (for the biaryl axis) or acid/base-induced (for the a-lactone position) processes, Fig. (18) [110,111,112], These isomerization possibilities were largely exploited in the different total syntheses discussed in the following pages. 

The gas-phase base-induced elimination reaction of halonium ions was thoroughly investigated in radiolytic experiments22. Radiolytically generated acids C/JH5+ (n = 1,2) were allowed to react at 760 Torr with selected 2,3-dihalobutanes to form the halonium intermediates which, in the presence of trimethylamine, undergo base-induced bimolecu-lar elimination as shown in Scheme 6. This elimination reaction occurs in competition with unimolecular nucleophilic displacement to the cyclic halonium ion and subsequent rearrangement. Isolation and identification of the neutral haloalkenes formed and kinetic treatment of the experimental results indicated that 3-halo-1 -butene is formed preferentially with respect to the isomeric 2-halo-2-butenes and that the bimolecular elimination process occurs predominantly via a transition state with an anti configuration22. 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

Mixtures of Z and E stereoisomers have been obtained in most syntheses. This undoubtedly holds in the presence of an acid catalyst. The tendency of the E-enamine to isomerize to the Z-enamine was readily observed on numerous occasions under unexpectedly mild conditions. Munk and Kim357 summarized the requirements for the stereospecific synthesis of enamines. First, if the introduction of the double bond is to be the final step of the synthesis, it must be stereospecific in character. Second, once the enamine is formed it must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. The base-induced bimolecular -elimination reaction fulfills both these requirements. Indeed, treatment of the mesitoate esters of ( )-threo- (99) and ( )-erythro- (100) l-(4-morpholino)-l,2-diphenylethanol with... 

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