Hindered base, nucleophilicity

An attempt to generate an amino-aryl carbene 154 from the alkylated phenanthridinium salt 153 (Equation 78) <2006TL531> was unsuccessful due to steric interactions. The actual reaction with a variety of strong, sterically hindered bases/nucleophiles is shown (Equations 79-81). The mesityllithium products proved that a carbene intermediate is not possible. Unlike /-butyl alcohol and hexamethyldisilazane, trimethylbenzene, the conjugate acid of mesityllithium, is not prone to carbene insertion reactions. Electronically this is explained by the planar nature of 153 which serves to lower the lowest unoccupied molecular orbital (LUMO) energy of the iminium moiety. 

Strong hindered base/nucleophile leads to E2 Low temperature (Sn2) / high temperature (E2)... 

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 formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Tertiary alkyl halides are so sterically hindered to nucleophilic attack that the pres ence of any anionic Lewis base favors elimination Usually substitution predominates over elimination m tertiary alkyl halides only when anionic Lewis bases are absent In the solvolysis of the tertiary bromide 2 bromo 2 methylbutane for example the ratio of substitution to elimination is 64 36 m pure ethanol but falls to 1 99 m the presence of 2 M sodium ethoxide... 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Secondary alkyl halides may undergo substitution or elimination under basic conditions, but with the strong hindered base and lousy nucleophile LDA, elimination is certain to occur. The product is CH3CH=CH2. 

A sterically hindered, non-nucleophilic strong base, useful for carbanion generation. ... 

This acidity means that even iodopyrimidines and iodopyrazines may be lithiated because hindered, non-nucleophilic lithium amide bases will deprotonate them. For example, the base 244, which is easily made by BuLi attack on the imine, deprotonates 243 a to N rather than ortho to and the lithiation of 245 with LiTMP is also successful (Scheme 121). ... 

With heterocycles containing an sp--nitrogen atom, a totally different problem can occur, namely nucleophilic addition of the base to the azo-methine (C=N) bond. The use of very sterically hindered bases such as lithium tetramethylpiperidide (LiTMP) can prevent this type of addition in certain cases, but bases of this sort tend to be expensive and not suitable for general use. However, two different approaches to overcoming the problem of azomethine addition have been developed over the years, both relying on the fact that the addition is temperature dependent, and that by enabling metalation reactions to be performed at low temperatures, the desired carbanion formation can often be achieved. 

Derivatives of trifluoroethanethiol have limited though interesting chemistry. Unfortunately, metallated difluorothioenol chemistry has not been reported, because rapid nucleophilic attack occurs even by hindered bases such as LDA. Nakai et al. exploited this high electrophilicity in a tandem addition/elimina-tion-rearrangement sequence [146], but more recent applications have concerned free radical chemistry (Eq. 46). Chlorination of trifluoroethyl phenyl sulfide followed by exposure to tin hydride in the presence of an allylstannane resulted in C-C bond formation with a reasonable level of stereocontrol [147]. 

Trifluoroacetyl triflate is probably the most powerful trifluoro-acetylating agent known, as evidenced by its reactivity toward several types of nucleophiles under mild conditions. A sterically hindered base, 2,6-di-... 

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. 

Notes Hindered base with low nucleophilicity. Is stable with TMS-C1 thus reactions can be carried out under equilibrium-controlled conditions, where substrate, TMS-C1 and LTMP are present at the same time. 

Notes Strong, sterically-hindered base, soluble in THF, ether, and toluene. The Li and K analogs are also available. The reagent also can act as a nucleophile under certain conditions. 

A regioselective and highly syn-stereoselective catalyst-free intermolecular alkylation of aryl borates with aryl epoxides under mild, neutral conditions has been reported.27 The reaction of /ra .s-stilbene oxide with tri(3,5-dimethylphenyl)borate gave a 38% yield (>95% syn) of the C-alkylated product (13), easily separated from (g) the O-alkylated product(s). Triflic anhydride has been used to activate enones to nucleophilic attack by electron-rich arenes in the presence of a sterically hindered base.28 Resorcinol dimethyl ether, for example, reacted with cyclohex-2-en-l-one to... 

The absence of scatter in a Bronsted plot for a general base-catalysed reaction can imply that the reaction mechanism involves a rate-limiting proton transfer step. This is because proton transfer to the base in the reaction is closely similar to the equilibrium proton transfer to the base in the reaction which defines the p Ka of the conjugate acid of that base. The observation of scatter, especially for sterically hindered bases (such as 2,6-dimethylpyridine), is evidence that nucleophilic catalysis is operating as opposed to general base catalysis. 

The rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, 6), rather than simple tertiary amines were used. Further improvements were observed when 3-quinuclidinole (3-QDL, 7) was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [14f ]. The rate of the reaction was decreased by the presence of substituents in the a-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [15]. 

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