Kinetics deprotonation

Kinetic deprotonation of 1-alkenyl sulfoxides produces the corresponding a-lithiosulfmyl carbanions59 which have been deuterated, alkylated, acylated (e.g., equation 19)60 and carboxylated. 

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

The effect of HMPA on the reactivity of cyclopentanone enolate has been examined.44 This enolate is primarily a dimer, even in the presence of excess HMPA, but the reactivity increases by a factor of 7500 for a tenfold excess of HMPA at -50° C. The kinetics of the reaction with CH3I are consistent with the dimer being the active nucleophile. It should be kept in mind that the reactivity of regio- and stereoisomeric enolates may be different and the alkylation product ratio may not reflect the enolate composition. This issue was studied with 2-heptanone.45 Although kinetic deprotonation in THF favors the 1-enolate, a nearly equal mixture of C(l) and C(3) alkylation was observed. The inclusion of HMPA improved the C(l) selectivity to 11 1 and also markedly accelerated the rate of the reaction. These results are presumably due to increased reactivity and less competition from enolate isomerization in the presence of HMPA. 

Hydrazones can also be deprotonated to give lithium salts that are reactive toward alkylation at the (3-carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.119 The A N-dimcthyl hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent... 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

Oxidative ring opening of isoxazolidines leads to nitrones. Thus, bicyclic isox-azolidines (50) and (51), treated with m-CPBA, afford nitrones (52), (53), (54), and (55) (Scheme 2.19). Conformational analysis has confirmed the key role of the nitrogen lone pair with respect to regioselectivity of the reaction and of the intramolecular kinetic deprotonation of the intermediate oxoammonium derivative (125). 

Enolate anion 68, which was generated by kinetic deprotonation of ketone 67, produced CF3 ketone 70 almost exclusively, while enolate anion 69, generated by thermodynamic deprotonation, gave a 3 4 mixture of 70 and 71 (Eq. 36). 

On the other hand, LHMDS is a bulky base and, more likely, the kinetic deprotonation at C(4 ) occurs selectively with carboxylate 127a Li, providing the enolate 127a 2Li, which is alkylated, while the isomeric carboxylates 131a Li and 127s Li remained unchanged (Scheme 6, path B). 

Direct metalation of 2,6-disubstituted pyridines has also been reported to occur at the 4-position under certain conditions. Thus the 2,6-bistrimeth-ylsilyl chromium tricarbonyl compound 96 gave the 4-lithio derivative 102 [91JCS(P1)501], and 2,6-dichloropyridine gave mainly the 4-lithio derivative 103 under kinetic deprotonation conditions, in contrast to the thermodynamic situation where 3-lithiation was preferred (91JOC4793). 

More direct evidence for the preferred kinetic deprotonation of the (Z)-methyl group was found when d3-14 was treated with LDA and after a-protonation only 17 was isolated33. 

Metzner reports that lithium dithioenolates, which are softer nucleophiles than the corresponding carbonyl enolates, add kinetically in a 1,4-mode exclusively to ot, 3-enones and the diastereoselectivity preferences are similar to that for ester enolate additions.l43a d Typically, kinetic deprotonation of dithioesters affords predominantly the (Z)-enethiolate (170) which is opposite to that for esters 139 thus, with ( )-enones, anti adducts (172) are obtained. In contrast, the addition of methyl dithioacetate to ot,P-disubstituted enones affords predominantly syn adducts (174 and 175) which is a consequence of intramolecular protonation of the resultant enolate (Scheme 68).143e... 

Nevertheless, diastereomeric product 26 was used to test the validity of the Claisen approach. Thus, esterification of 26 with propionic anhydride offered the requisite ester 15 along with the inseparable diastereomer 15a (1 1 ratio). Kinetic deprotonation of the mixture of 15/15a was effected with lithium N-cyclohexyl-lV-isopropylamide (LICA) and, upon warming to room temperature, Ireland-Claisen... 

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. 

If an [Os]-anisolium complex bears a proton at C4 (63, Scheme 7), exposure to DIEA at low temperature results in a kinetic deprotonation of the benzylic carbon attached to C3 generating the extended vinyl ether 64. This complex cyclizes under Lewis addic conditions to generate an anisolium ion, which can then be deprotonated at C4 to generate a tetralin complex [25]. Heating this species liberates the tetralin 65 in 39 % yield (based on 63). 

In general, this effect is sufficient to allow selective kinetic deprotonation of methyl ketones, that is, where the distinction is between Me and alkyl. In this example, unusually, MeLi is used as a base LDA was probably tried but perhaps gave poorer selectivity. The first choice for getting kinetic enolate formation should always be LDA. 

The lithium amide of (1) has also been used to perform the kinetic resolution of racemic lactams by selective kinetic deprotonation of one of the enantiomers, followed by reaction of the partially formed enolates with an electrophile. These procedures have not... 

The two main problems in the preparation of silyl enol ethers are control of regios-electivity, kinetic and thermodynamic, and stereoselectivity, (E) and (Z). Although many useful procedures are now available for the kinetic deprotonation of ketones by use of alkali metal dialkylamides, there are few practical procedures for thermodynamic deprotonation. Recently, the author and Yamamoto et al. found that the regio- and stereoselective isomerization of a kinetic silyl enol ether to a thermodynamic ether was catalyzed by LBA [138]. 

Jacobi extended this methodology for the synthesis of the novel sesquiterpene ( )-paniculide A (528) (Scheme 66) (84TL4859). Thermal cycloaddition of 518 in ethylbenzene in a similar condition afforded the methoxyfuran 520 in 94% yield through the intermediate 519. Phenylselenation of 520 with LDA and phenylselenyl chloride gave a 1 1 mixture of phenylselenides 521, which upon kinetic deprotonation-protonation afforded the a-isomer (522) in... 

Directed lithiations of a,3- and -y.b-unsaturated amides " have been extensively studied. Illustrative examples are shown in Scheme 44. Prior complexation of the alkyllithium base with the amide carbonyl oxygen directs the base to the thermodynamically less acidic -position in a,3-unsaturated amide (31), which adds to benzophenone and subsequently lactonizes. Analysis of the NMR spectrum reveals that the organolithium added the benzophenone in the equatorial position. A Afferent kinetic deprotonation is seen in y,8-unsaturated amide (32), where -lithiation to form an allylic anion predominates over a-lithiadon to form an enolate. > Addition of the lithium anion to acetone affords poor regioselectivity, but transmetalation to magnesium before carbonyl addition yields a species which adds exclusively at the 8-position. ... 

The Thermodynamic Enolate Is the Most Stable of the Possible Enolates The Kinetic Enolate Is the Result of Deprotonating the Most Accessible Acidic Hydrogen Z Enolates Are Usually Favored Sterically Ion Pairing And Kinetic Deprotonation Can Favor E Enolates. 

A number of investigations have explored the reactions of ally lie stannanes containing a y-alkoxy substituent. A direct preparation of these substances utilizes the kinetic deprotonation of an allyl ether followed by alkylation with tri-n-butylstannyl chloride. In a typical experiment, the deprotonation of 101 with 5-butyllithium leads to internal coordination of lithium cation and provides formation of the Z-allylstannane 102. The behavior of y-alkoxyallylstannanes is similar to the corresponding Z-alkylstannanes, and as a result, the reaction provides a stereoselective route for the synthesis of complex diol derivatives. In the allylation of chiral aldehyde 80 with stannane 102, /l-chelation dictates face selectivity. The expected. yyn, anti-product 104 is obtained with high diastereoselection via the antiperi-planar 103, which accommodates the sterically demanding silyl (TBS) ether (Scheme 5.2.23).23... 

In the lithiation of fluoroanisoles (15) and (16) and their derivatives, butyllithium exclusively deprotonates the less acidic protons from the position ortho to the alkoxyl group. On the other hand, deprotonation takes place at the more acidic site, i.e. the ortho-position next to the fluorine substituent on reaction of the substrates with super bases, such as BuLi— t-BuOK or BuLi—N,N,N/,N//,N//-pentamethyldiethylenetriamine, in which lithium cation is stabilized by chelation in the combined base-system (Scheme 3.5) [ 14]. The lithium cation interacts preferentially with the more Lewis basic alkoxyl oxygen to locate butyllithium close to the position ortho to the alkoxyl group, enhancing kinetic deprotonation (see 17 in Scheme 3.5). 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

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