3-Pentanone deprotonation

Many enolates can exist as both E- and Z-isomers.11 The synthetic importance of LDA and HMDS deprotonation has led to studies of enolate stereochemistry under various conditions. In particular, the stereochemistry of some enolate reactions depends on whether the E- or Z-isomer is involved. Deprotonation of 2-pentanone was examined with LDA in THF, with and without HMPA. C(l) deprotonation is favored under both conditions, but the Z.E ratio for C(3) deprotonation is sensitive to the presence of HMPA.12 More Z-enolate is formed when HMPA is present. 

In the case of 3-pentanone, evidence has been presented27-28 for thermodynamic control during formation of the (Z)-enolates and for kinetic control during formation of the ( )-eno-lates in the presence or absence of HMPA. Ester enolates are preferentially ( ), when prepared with LDA (THF), and (Z) when prepared with LDA in the presence of HMPA. In contrast, dialkylamides are deprotonated (LDA/THF) preferentially to give the (Z)-enolates. The role of HMPA in the above case is still not quite clear6-29. 

SCHEME 15. Effect of salts on the stereoselectivity of the deprotonation of 3-pentanone by LiTMP82... 

The stereoselective enolization of 3-pentanone by LiTMP mixed aggregates with butyl-lithium was studied by Pratt and coworkers. The mixed aggregate resulted in a slightly higher stereoselectivity, which increased with decreasing amount of the lithium base. Semiempirical PM3 calculations were used in an attempt to determine the mechanism of ketone deprotonation by the mixed aggregate. Equations 20 and 21 show two alternative mechanisms for the formation of lithium acetone enolate in thf solution, involving... 

Reaction of 3-pentanone with the commercially available hydrazine (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) affords the corresponding chiral hydrazone. Deprotonation with LDA followed by alkylation and hydrolysis furnishes (S)-4-methyl-3-heptanone in greater than 99% enantiomeric excess. Using the corresponding (R)-hydrazine (RAMP) provides (R)-4-methyl-3-heptanone. 

Formation of an imine from a symmetrical ketone effects a desymmetrization of the two a-carbons. The deprotonation of such imines has been extensively investigated by Bergbreiter and Newcomb. In general, there is little observed selectivity for deprotonation by lithium dialkylamide bases, as, for example, with the 3-pentanone imine in equation (38). 

Bergbreiter and Newcomb have shown that the benzylamine imine of 3-pentanone is deprotonated by lithium diisopropylamide selectively at the benzylic position of a 2-azaallyllithium system that slowly isomerizes by a protonation-deprotonation sequence to afford the 1-azaallyl system (equation 46). ... 

Kuwajima and coworkers used very hindered bases such as (2) to deprotonate methyl alkyl ketones regioselectively in the presence of enolizahle aldehydes.One example of this amazing process is shown in equation (11) the reaction is reported to work equally well with other methyl ketones, including 2-pentanone. The process was also demonstrated with other bases in the reaction of 3-methyl-2-buta-none with dihydrocinnamaldehyde (equation 12). Among the bases that are effective are LDA, lithium hexamethyidisilazane, lithium r-butoxide and even lithium ethoxide. However, base (2) is superior, giving the aldol in 83% yield. 

Masamune and coworkers studied the deprotonation of 3-pentanone and ethyl cyclohexyl ketone with various bases. These workers confirmed that lithium hexamethyldisilazane gives more ( -isomer than... 

The 1,2-addition of simple azaallyllithium reagents derived from ketone and aldehyde dimethylhydra-zones to aldehydes and ketones was also first described by Corey and Enders.Regioselective deprotonation of 2-pentanone dimethylhydrazone with Bu"Li followed by addition of an aldehyde or... 

In the presence of coordinating additives such as HMPA, DMPU or TMEDA, the trend outlined in Scheme 3.4 may not hold [36,41-43]. For example, in the presence of HMPA, LDA deprotonation of 3-pentanone affords a 5 95 mixture of E(0)- and Zf 0)-enoiates under conditions of thermodynamic control (equilibration by reversible aldol addition) [39,41], but a 50 50 mixture under kinetic control [41,42]. 

For a simple protocol for the preparation of LTMP/LiBr solutions by deprotonation of TMP HBr with butyllithium, which affords a 50 1 ratio of the E(0) and Z(0) enolates of 3-pentanone, see ref. [38]. 

These techniques will be discussed in Section 9.2, but an example is conversion of 3-pentanone to a 77 23 mixture of ( )- and (Z)-enolates by reaction with lithium diisopropylamide. When the enolate was formed by treatment with lithium 2,2,6,6-tetramethylpiperidide (LTMP), only slightly greater amounts of the ( ) -enolate were observed (86 14 E/Z). Addition of HMPA) to this reaction medium, however, led to a reversal of selectivity, favoring the (Z)-enolate (8 92). Under the best conditions, this ( /Z)-mixture will lead to a similar mixture of diastereomers in the products formed by reaction of the enolates. Some isomerization can occur in the deprotonation or condensation steps, and the product may isomerize under the reaction conditions. ... 

A complicating factor in the analysis is the observation that aldolates can undergo syn/anti equilibration by enolization or by reverse aldolization. Aldols such as 407 can be deprotonated to the dianion (408) and this undergoes alkylation with iodomethane to give the anti product (409), as shown.230 This equilibration is clearly the basis of the aldol-transfer reaction discussed in 143 to 145 in Section 9.4.A.i. If 409 forms a new enolate, equilibration can lead to a mixture of syn and anti products. The primary mechanism for syn/anti equilibration appears to be reverse aldolization.23 A retro-aldol will convert the syn diastereomer (410) into the aldehyde and enolate components, which can regenerate 410 or form the anti diastereomer 411. Syn/anti equilibration can be much slower than reverse aldolization, as with the (Z) enolate of 2,2-dimethyl-3-pentanone).227 Aldolates derived from the more basic ketone enolates are more likely to suffer reverse aldolization than aldolates derived from the less basic enolates of esters, amides, or carboxylate salts. Steric crowding in an aldolate promotes reverse aldolization. The metal is very important, and some metals form... 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

Another issue is the ratio of enolate E and Z isomers that can form in appropriate systems. In general, Z-enolates are more stable than -enolates due to lower steric interactions with the R group on the carbonyl carbon. For example, in the deprotonation of 3-pentanone with lithium tetramethylpiperidide (LTMP) at low temperature, the -enolate is formed preferentially (Eq. 11.7). In contrast, the use of LTMP with added HMPA (hexamethyl-phosphoramide, which binds cations) at ambient temperature preferentially gives the thermodynamic enolate (Eq. 11.8). The HMPA assists in breaking up the aggregates mentioned above, and in the exchange of enolate deprotonation sites. 

Enders synthesises this simple compound, the defence secretion of the daddy longlegs insect, Leiobunum vittatum and L. calcar, to illustrate the use of his RAMP and SAMP chiral auxiliaries (see section 5.3.2). The imine of 3-pentanone and SAMP is deprotonated with LDA, and the anion alkylated with -l-bromo-2-methylbut-2-... 

Kinetically controlled deprotonation also leads to the lower substituted alkali enolates of acyclic ketones, as illustrated by selected examples in Scheme 2.5 2-heptanone [27], 3-methyl-2-butanone [26a], and 2-methyl-3-pentanone [23]. Under the conditions of kinetic deprotonation with LDA, a-alkoxy-substituted ketones behave similar to their alkyl-substituted counterparts giving predominantly the less substituted enolate, as illustrated for 2-methoxycyclohexanone [28] in Scheme 2.5. a-Dialkylamino ketones also follow this tendency. In M-carbamato-substituted ketones, however, regioselectivity is reversed, and enolization predominantly occurs toward the nitrogen atom - a result that might be caused by the electron-withdrawing nature of the urethane moiety this effect becomes even more dominant when the enolate is formed under thermodynamic control (LiHMDS, equilibrating conditions) [29]. 

Lithium Enolate trans-30 [X = CHiMejj, M = Li] by Deprotonation of 2-Methyl-3-pentanone with LiHMDS/triethyiamine [41]... 

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