Bases non-nucleophilic

Amines are weak acids, and are deprotonated only in the presence of a strong base. Treatment of a secondary amine with a strong base will generate a strong conjugate base (R2NH -1- base R2N M ), the amide 

Collum and co-worker studied the solution structure of lithium diethylamide (16) in THF and in ether. Not only dimers and trimers, but also four-, five-, and six-rung ladder structures such as 22 were detected. 

Collum also investigated the aggregation state of LDA in solution during the metalation of Af,Af-dimethyl-hydrazones (sec. 9.4.F.ii) using Li and N NMR. The NMR data also suggested a solvated, dimeric 

There are many cases when formation of an enolate anion from a ketones is accompanied by formation of ( ) and (Z) isomers. Treatment of 2-methyl-3-pentanone with LDA (THF, -78°C), for example, gave a 60 40 mixture of the (Z) and (E) enolates (24 and 25) Subsequent reaction of 24 and 25 with a carbonyl 

Only moderate variations in kinetic ElZ) ratios are observed except for LHDS, which favored the thermodynamically more stable (Z) enolate. The sterically demanding LTMP favored formation of the kinetic E enolate.22 An equilibration process is clearly occurring, possibly by an aldol addition — retro-aldol process that was suggested by Rathke and co-workers (via 26). The aldol condensation will be discussed in Section 9.4.A. Addition of HMPT (hexamethylphosphorus triamide) destabilizes and deaggregates aldolate 26, promoting equilibration. 

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Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)... 

The conversion of a thiolactone to a cyclic ether can also be used as a key step in the synthesis of functionalized, stereochemically complex oxacycles (see 64—>66, Scheme 13). Nucleophilic addition of the indicated higher order cuprate reagent to the C-S double bond in thiolactone 64 furnishes a tetrahedral thiolate ion which undergoes smooth conversion to didehydrooxepane 65 upon treatment with 1,4-diiodobutane and the non-nucleophilic base 1,2,2,6,6-pentamethylpiperidine (pempidine).27 Regio- and diastereoselective hydroboration of 65 then gives alcohol 66 in 89 % yield after oxidative workup. Versatile vinylstannanes can also be accessed from thiolactones.28 For example, treatment of bis(thiolactone) 67 with... 

Water, which can be taken to a minimum by the use of molecular sieves, can produce a lactamide either through direct reaction with the aziridinone intermediate, or upon hydrolysis of oxazolidinone self-condensation products, previously obtained also in the presence of a strong non-nucleophilic base (H ) (ref. 17). The recently reported 0-self-alkylation compound H bears the (S,S)-configurations at the unreacted C-Br and newly formed C-0 bonds. The presence of bromine was expedient for the x-ray assessment of configuration at the two chiral centers of 11 which forms in high diastereoisomeric excess (ref. 5). 

The analogous dimerization of alkynes over Fe(C0)5 is not applicable, so clearly a different route towards alkynylated derivatives of 25 was needed. Comparison of 25 to cymantrene suggests that metallation of the hydrocarbon ligand should be the route of choice for the synthesis of novel substituted cyclobutadienes. In the literature, addition of organolithium bases (MeLi, BuLi) to the CO ligands with concomitant rearrangement had been observed [25]. But the utilization of LiTMP (lithium tetramethylpiperidide, Hafner [26]) or sec-BuLi as effectively non-nucleophilic bases led to clean deprotonation of the cyclobuta-... 

Steric factors and especially hindered rotations may change the pATa of an acid by up to two pAfa units as has been found for 2,6-disubstituted pyridines 2,6-di-t-butylpyridine [70k] is an unusual (Kanner, 1982) non-nucleophilic base which has a surprisingly low pKa value. When [70k] is compared to other 2,6-dialkylsubstituted pyridines [70] it is found to be the only disubstituted pyridine with a smaller pKa than pyridine itself (see Table 29). The exceptional behaviour of [70k] has been investigated intensively... 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

Ring transformations were conducted with a variety of organic and inorganic bases <1997T4611>. The results are summarized in Equation (7) and Table 4. Treatment of cycloadduct 30a with strong and non-nucleophilic bases such... 

Nitrobenzofurazan 240 and 4-chloro-7-nitrobenzofurazan 232 also condense with isocyanoacetates in the presence of the non-nucleophilic base l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give tricyclic pyrrole derivatives 241 in excellent yields (Scheme 60) <2005T11615>. 

A number of cationic (diene)metal complexes undergo a-deprotonation. Treatment of (cyclodiene)Mo(CO)2Cp+ cations (e.g. 44) with NEt3 or other non-nucleophilic bases... 

Nitriles will direct lithiation with non-nucleophilic bases such as LiTMP, particularly in conjuction with another nitrile group . The nitriles presumably act by an acidifying effect alone—no intramolecular N-Li coordination is possible in the intermediate (Scheme 60). 

HNu nucleophilic base B non-nucleophilic base ACT polyaromatic hydrocarbon Ar substituted aryl moiety... 

Treatment of pyridine with NaOD/D20 at elevated temperatures results in eventual replacement of all hydrogen atoms by deuterium. This process presumably involves deprotonation followed by rapid deuteration of the intermediate negatively charged species (cf. equation 21) in a sequential manner. Azine N- oxides are deuterated in a similar way, positions adjacent to the N- oxide exchanging particularly rapidly. Controlled deprotonation of ring carbon atoms a and y to the heteroatom can be accomplished by the use of strong, non-nucleophilic bases and the intermediate carbanions may be trapped by electrophiles (equation 27). The yields in these reactions are in most cases only moderate, however. As expected, deprotonation occurs more easily if the heteroatom is positively charged. 

As will be seen in the following section the most widespread use of the alkylation of lactones is that of y-lactones. Clearly the need for a-substitution of y-lactones was present before the advent of Creger s non-nucleophilic base. The most versatile method was the reaction of a-substitutcd malonic or acetoacetic esters with epoxyethane or 2-chloroethanol, followed by hydrolysis and decarboxylation or ketonic cleavage5. Another common approach was the condensation of butyrolactones (y-lactones) with aldehydes and subsequent hydrogenation5,s. It should be mentioned at this point that these older methods still have their merits, especially for large scale production. 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

Vinyl triflates. Use of this hindered, non-nucleophilic base (1) allows direct conversion of aldehydes to vinyl triflates (equation 1). The method is also applicable to Conversion of ketones to 1-alkenyl triflates. 

Section V contains specific examples of procedures for Inflate synthesis some general comment about these procedures is worthwhile. Triflic anhydride is the reagent of choice for preparing triflates derived from sugars, whereas triflyl chloride is used more often when uucleosides are involved. Triflate formation with triflic anhydride requires addition of a base (usually pyridine) to the reaction mixture to neutralize the triflic acid produced [Eq. (4) 7]. Some triflates are reactive enough that pyridine can function as a nucleophile in the substitution process. In these instances, replacement of pyridine with a non-nucleophilic base, such as 2,6-di-r-butyl-4-methylpyridine, avoids this undesired reaction (Scheme 1) [7]. 

There are no known de novo preparations of unfunctionalized thiabenzenes, and in fact of the two methods claimed.only one has any real scope. The earliest approaches used the addition of an aryllithium species to a thiopyrylium salt in the expectation of achieving reaction at sulfur. There is evidence for the transient formation of some sulfur-arylated materials, but as addition at positions 2, 4 and 6 also takes place, interpretation of results is hazardous. With the recognition of the ylidic nature of thiabenzenes , the preferred route of synthesis becomes more obviously deprotonation of a thiinium salt (equation 117) (75JA2718). Non-nucleophilic bases may be used to avoid competing addition reactions. The lability of the products is ameliorated if electron-withdrawing substituents are present on the a- and y-carbons, which also permits the use of milder bases for the proton removal. This method has been used in the preparation of both the monocyclic materials and their benzannelated counterparts, which may in certain cases be isolated, e.g. 9-cyano-10-methyl-10-thiaanthracene (80JOC2468). As yet there are no reports of substituents other than aryl and alkyl having been introduced into simple thiabenzenes . 

Many of the most elegant syntheses of complex natural products are based on mechanistic speculation, as illustrated by the following postulated entry to stiychnine-based alkaloids. Thus, it was reasoned that treatment of the indole 1 with methyl chloroformate and a non-nucleophilic base followed by acid catalysed rearrangement would lead to the tetracycle 2. In practice, the first step worked well when Hiinig s base was used, but the second step, the acid catalysed rearrangement, failed to give 2. The only product, isolated in good yield, was the carbazole 3. 

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