Nonnucleophilic bases

After the initial claim of the synthesis of an oxirene (by the oxidation of propyne Section 5.05.6.3.1) this system reappeared with the claim 31LA(490)20l) that 2-chloro-l,2-diphenyl-ethanone (110) reacted with sodium methoxide to give diphenyloxirene (111), but it was later shown (52JA2082) that the product was the prosaic methoxy ketone (112 Scheme 97) (the formation of 111 from 110 would be an a-elimination carbene-type reaction). Even with strong, nonnucleophilic bases, (110) failed to provide evidence of diphenyloxirene formation (64JA4866). 

Nitriles can also be converted to anions and alkylated. Acetonitrile (p DMso = 31.3) can be deprotonated, provided a strong nonnucleophilic base such as LDA is used. 

Hindered nonnucleophilic bases are typically added to sulfoxide glycosylations to buffer the acidic by-products. Classically, the 2,6-di-tert-butylpyridines have been employed for this purpose [86], but the more highly crystalline and easily handled 2,4,6-tri-fert-butylpyrimidine is finding increasing favor in this regard [356]. 

The sulfoxide method was introduced by Kahne and coworkers,1 and was heralded as a new method for rapid glycosylation of unreactive substrates in high yield under mild conditions. The reaction involves the sulfoxide donor [sulfoxide (I)], an activating agent (usually triflic anhydride), a hindered, nonnucleophilic base (2,6-di-tert-butyl-4-mcthylpyridine, DTBMP) and a nucleophilic acceptor (most often an alcohol) (Scheme 3.1). The glycosylation of sterically hindered steroidal alcohols, phenols and the /V-glycosylation of an acetamide was reported (Table 3.1). 

DBU = l,8-diazabicyclo[5.4.0]undec-7-ene (15) is a nonnucleophilic base employed in conjunction with piperidine in dimethylformamide (1 1 48) for removal of fluorenylmethyl-based protectors. The piperidine is necessary as a nucleophile to trap the expelled moiety that does not react with DBU. DBU has no effect on phthalimido [Pth-NH of -Lys(Pht)-], dialky-lphosphoryl [-Tyr(P03R2)-], or Dde-NH [-Lys(Dde)- see Section 6.4], but it promotes aspartimide formation at the pertinent residues of susceptible sequences (see Section 6.13). In dichloromethane, it promotes a reaction between two molecules of urethane-protected amino acid /V-carboxyanhy-dride with release of carbon dioxide (see Section 7.14). 

Metallation of 3,4-dimethyl-l,2,5-thiadiazole (55) to the anion (56) was accomplished with the use of a nonnucleophilic base, lithium diisopropylamide <82JHC1247>. Nucleophilic attack at sulfur resulted in an alkyllithium reagent <70CJC2006>. The lithiomethyl derivative (56) was carboxylated to (57) with carbon dioxide and converted to the vinyl derivative (58) via an esterification, reduction, mesylation, and base elimination sequence (Scheme 12). 

C. Synthesis of a Reactive Triflate Ester in the Presence of a Nonnucleophilic Base, 2,6-Di-ferf-butyl-4-methylpyridine [7] ... 

Isomerization can also be effected under the influence of a base (Scheme 114)233 the quaternary ammonium salt of an aminoalkyltriazoline isomerizes in an analogous manner (Scheme 115).179 5-Amino-l-aryl-4-methylenetriazolines also isomerize to 5-amino-l-aryl-4-methyltriazoles on reaction with nonnucleophilic bases.179,391... 

Today reactions of etiolates are usually carried out much differently by utilizing very strong, nonnucleophilic bases for generating the enolate nucleophile. Instead of having only small equilibrium concentrations of an enolate produced in solution, the use of strong, nonnucleophilic bases like LDA, KHMDS, and KH that have pAYs >35 permits carbonyl compounds, whose a protons have pA"a s of 20-25, to be converted completely to enolate anions. Doing so completely converts the carbonyl compound into a nucleophile which cannot condense with itself and is stable in solution. This enolate can then be reacted with a second carbonyl compound in a subsequent step to give product ... 

The enol phosphate 191 (R / H) has been widely used in the preparation of a large number of carbapenems having a 2-allyl- or aryl-thio substituents. The reaction is promoted by the presence of base and the choice of solvent is important. Diisopropylamine or dicyclohexylamine tend to give better results than tertiary amines and nonnucleophilic bases such as... 

Removal of the sterically more accessible protons at C-5 was required and hence it was reasoned that kinetic deprotonation conditions were required, namely, strong, nonnucleophilic base and low temperature. Model reactions were carried out initially on 4-keto-L-proline ester 47, in the hope of optimizing the triflation conditions before moving to C-3-alkylated derivatives 53 and 54. 

Chemoselective E2 eliminations can be carried out with sterically hindered, sufficiently strong bases. Their bulkiness causes them to react with an H atom at the periphery of the molecule rather than at a C atom deep within the molecule. These bases are therefore called nonnucleo-philic bases. The weaker nonnucleophilic bases include the bicyclic amidines DBN (diazabi-cyclononene) and DBU (diazabicycloundecene). These can be used to carry out chemoselective E2 eliminations even starting from primary and secondary alkyl halides and sulfonates (Figure 4.17). 

Fig. 4.17. Relatively weak nonnucleophilic bases use in a chemoselective E2 elimination from a primary altyl halide.

While there are no extensive reports on the relative aromaticity of the heterocycles covered in this chapter, the general reactivity of these systems can be predicted based on first principles. By assuming that these fused systems are comprised of a five-membered rc-excessive heterocyclic system and a five-membered -deficient heterocyclic system, electrophilic agents are expected to react on the n-excessive subunit. Ab initio calculations on the thienothiazoles and furothiazoles predicted that electrophilic substitutions should occur exclusively on the furan or thiophene subunit with the regioselectivity being a function of the resonance-stabilization of the reactive intermediates <76KGS1202>. A priori, C-H deprotonation by a nonnucleophilic base should occur preferentially on the -deficient heterocyclic component. 

In Chapter 12 pyridine was often used as a catalyst in carbonyl substitution reactions. It can act in two ways. In making esters from acid chlorides or anhydrides pyridine can act as a nucleophile as well as a convenient solvent. It is a better nucleophile than the alcohol and this nucleophilic catalysis is discussed in Chapter 12 (p. 282). But nonnucleophilic bases also catalyse these reactions. For example, acetate ion catalyses ester formation from acetic anhydride and alcohols. 

In our initial investigations,4,22 syn and anti 2-butyry 1-2-alkyl-1,3-dithiane 1-oxides were prepared by our standard means and were enolized using a suitable nonnucleophilic base (LHMDS) in THF at low temperature. The resulting enolate was subjected to alkylation with iodomethane, and the diastereoselectivities were determined by H NMR analysis of the crude product mixture. Our results are summarized in Scheme 5 and Table 4. Interestingly, the enolates were trapped as the corresponding silyl enol ethers, and NMR analysis revealed exclusive formation of one geometrical isomer, presumed to be the thermodynamically more favorable Z isomer.23... 

Based on this report, an attempt was made to generate the enamine quantitatively from 2-alkyl and 2-a-alkoxyalkyl-3,4-dimethylthiazolium salts (1) in aprotic solvents employing nonnucleophilic bases, according to equation 3. In fact, this could be achieved in either pyridine or DMSO21. In typical experiments performed in an NMR tube f-BuOK or (TMS)2NNa were added to the salts, the spectrum being recorded before and after addition of the base. As a control, after each set of NMR experiments, acid quench was performed in deuterated solvent and it was thus demonstrated that D was specifically incorporated at the C2a position. 

A subsequent study ° from the Arnold group showed an intriguing stereoelectronic effect in oxidative benzylic carbon-hydrogen bond cleavage reactions of substrates 8 and 9 (Scheme 3.7). In this study, electron transfer reactions were conducted in the presence of a nonnucleophilic base. Radical cation formation also weakens benzylic carbon-hydrogen bonds, thereby enhancing their acidity. Deprotonation of benzylic hydrogens yields benzylic radicals that can be reduced by the radical anion of dicyanobenzene to form benzylic anions that will be protonated by solvent. This sequence of oxidation, deprotonation, reduction, and protonation provides a sequence by which epimerization can be effected at the benzylic center. In this study, tram isomer 10 showed no propensity to isomerize to cis isomer 11 (equation 1 in Scheme 3.7), but 11 readily converted to 10 (equation 2 in Scheme 3.7). The reactions were repeated in deuterated solvents to assure that these observations resulted from kinetic rather than thermodynamic factors. Trans isomer 9 showed no incorporation of deuterium (equation 3 in Scheme 3.7) whereas cis isomer 11 showed complete deuterium incorporation. The authors attributed this difference in reactivity to... 

The term amidolithium is the unambiguous name for the compounds RR NLi (R, R = alkyl, aryl, silyl, etc.) more often termed lithium amides. They derive their importance from the near-ubiquity of their bulkier members lithium diisopropy-lamide (LDA), lithium tetramethylpiperidide (LTMP), and lithium hexamethyldisilazide (LHMDS) in organic synthesis. Using such powerful but nonnucleophilic bases, many useful reactions may be performed, notably the enolization of ketones and esters, which can proceed both regio- and stereoselectively under kinetic control at low temperatures. ... 

For example, addition of 2 equivalents of a nonnucleophilic base, 2,6-di-tert-butylpyridine, to the reaction system almost totally suppressed the reaction (Table 9). This proposes that acid catalyzed enolization is important for the a-Umpolung. In support of mechanism 1 the yields of the a-methoxylated products increased with decreasing oxidation strength of the oxidant (Table 10), since endergonic oxidation of the ketone 70 is slowed down (Fig. 2). On the other hand, in the presence of stronger aminium salts the ketone tautomer is oxidized which however does not lead to deprotonation in the benzylic position... 

The use of a nonnucleophilic base affects the dehydrobromination and the corresponding diene lactone 6 may be formally considered a [2 + 2] cycloadduct of a substituted benzene and carbon dioxide that, through the extrusion of carbon dioxide affords the aromatic compound 7. Heating the olefinic bromo-/ -Iactone 5 in a Kugelrohr apparatus leads to a stereoselective 1,2 bromide migration with concomitant expansion of the lactone to its thermodynamically more stable y-isomer 8. 

Sterically hindered bases that are poor nucleophiles are called nonnucleophilic bases. Potassium fert-butoxide [K OC(CH3)3] is a strong, nonnucleophilic base. 

The most common bases used in elimination reactions are negatively charged oxygen compounds such as OH and its alkyl derivatives, OR, called alkoxides, listed in Table 8.1. Potassium tert-butoxide, OC(CH3)3, a bulky nonnucleophilic base, is especially useful (Section 7.8B). 

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