Acetaldehyde, lithium enolates

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

Lithiated enol carbamates 559 have been reported as complementary acyl anion equivalents of MVL (524) and EVL (525). Non-fluorinated enol carbamates have been prepared by O-carbamoylation of acetaldehyde lithium enolate (80-87% yield) or by quantitative addition of trimethylsilylamides to vinyl chloroformate837. 

SCHEME 44. Acetaldehyde lithium enolate obtained by deprotonation of THF190... 

Calculated reaction pathway for addition of acetaldehyde lithium enolate to formaldehyde. 

Even if a particular enolate vith a distinct geometry is reacted vith an aldehyde, the question vhether the transition state is closed or open cannot be ans vered by simple either-or . More recent discussions have, instead, led to an as vell as , because the role of the counter-ion becomes more evident. Thus, ab-initio calculations of Houk and co vorkers [92] predict an open-transition-state structure for metal-free, naked enoiates and closed transition states for lithium enoiates. For addition of acetaldehyde lithium enolate to formaldehyde, the lo vest-energy reaction path vay (sho vn in Scheme 1.13) has been studied on the basis of on ab-initio (3-21 G) calculations [93]. 

Scheme 8.37 Use of the lithium enolate of acetaldehyde DMH in an epoxide ring-opening reaction.

In contrast, transmetalation of the lithium enolate at —40 C by treatment with one equivalent of copper cyanide generated a species 10b (M = Cu ) that reacted with acetaldehyde to selectively provide a 25 75 mixture of diastereomers 11 and 12 (R = CH3) which are separable by chromatography on alumina. Other diastereomers were not observed. Similar transmetalation of 10a (M = Li0) with excess diethylaluminum chloride, followed by reaction with acetaldehyde, produced a mixture of the same two diastereomers, but with a reversed ratio (80 20). Similar results were obtained upon aldol additions to other aldehydes (see the following table)49. 

A facile preparation of 4-(heptafluoropropyl)quinoline 53 occurred on treatment of ortho-(nonafluorobutyl)aniline with the lithium enolate of acetaldehyde <96TL(37)4655>. 

In an attempt to generate convenient routes to organofunctional phosphazenes which could undergo homopolymerization reactions, we explored the reactions of lithium enolates, particularly that of acetaldehyde, with halophosphazenes which leads to the series of organofunctional monomers N3P3ci6 n(0CH=CH2)n15 16... 

The medicinally important )3-lactam antibiotic thienamycin (34) has stimulated several investigations into the application of the aldol reaction for the introduction of the hydroxyethyl moiety with the indicated Cg and Cg stereochemistry (29,30). Low-temperature enolization (LDA, THF) of either 35 (29a,b) or 36 (30) and subsequent condensation with excess acetaldehyde afforded the illustrated kinetic aldol adducts (eqs. [22] and [23]). In both examples the modest levels of threo diastereoselection are comparable to related data for unhindered cyclic ketone lithium enolates. Related condensations on the penam nucleus have also been reported (31). 

The excellent agreement with the experimental and calculated isotope effect (calculated for formaldehyde, 3.22, and for acetaldehyde, 3.3 experimental value 2.9) supports the computational approach. This suggests that the computed transition structure for hydride transfer in the reaction of the lithium enolate of acetone with acetaldehyde (Figure 30) is realistic. 

Wen and Grutzner used, among other NMR parameters, the QSC of the lithium enolate of acetaldehyde to deduce that it exists as tetramers of different solvation in THF and THF/n-hexane solvent systems . However, the most thorough study of Li QSC and the most interesting in the present context was reported by Jackman and coworkers in 1987167 -pjjg effects on the QSC values of both aggregation and solvation in a number of organolithium systems was studied in this paper, i.e. different arylamides, phenolates, enolates, substituted phenyllithium complexes and lithium phenylacetylide. 

An unexpected result was obtained when DTBB-catalyzed lithiation was applied to the vinyl-oxetane 313 . After work-up, lactone 314 was isolated, the process being explained by an elimination reaction via a radical pathway more than by reduction of the benzyl radical into the anion. Thus, this hypothetical intennediate reacted with the lithium enolate of acetaldehyde, generated in situ by reductive decomposition of THF (Scheme 92). 

Cyclohexylamine gives a reasonably stable imine even with acetaldehyde and this can be isolated and lithiated with LDA to give the aza-enolate. The mechanism is similar to the formation of lithium enolates and the lithium atom binds the nitrogen atom of the aza-enolate, just as it binds the oxygen atom of an enolate. 

SCHEME 86. Trajectory of the approach403 and transition state models for the reaction of monomeric and dimeric lithium enolate of acetaldehyde with MeCl405... 

SCHEME 107. Relative energies and geometries for the O- and C-addition transition state calculated for the addition of formaldehyde to the lithium enolate of acetaldehyde and the preferred conformations of aldol535... 

SCHEME 108. Transition states models for the reaction of the Z(O) lithium enolate of 1,1,1-triflu-oropropan-2-one with acetaldehyde and trifluoroethanal538... 

Abbotto, Streitwieser and Schleyer performed an exhaustive study, using the B3LYP /6-31-bG //PM3 calculation level, on the effect of dimethyl ether solvation on aggregated forms of the lithium enolate of acetaldehyde (CH2=CH0Li) (Me20) c. 

Pratt and Streitwieser performed ab initio (HF/6-31G and HF/6-311-FG ) calculations to examine the formation of mixed dimer and trimer aggregates between the lithium enolate of acetaldehyde (lithium vinyloxide, LiOVi) and lithium chloride, lithium bromide and lithium amides. Gas-phase calculations showed that in the absence of solvation effects, the mixed trimer (LiOVi)2 LiX (20) was the most favored species. 

TABLE 12. Comparison of AE and AG calculated at two levels of theory, for intermediates derived from the lithium enolates of acetaldehyde in three reactions carried out at 298.15 K... 

The epoxide is opened with the lithium enolate of the aza acetaldehyde A/, V-dimethylhydrazone (27), which is derived from 27 via deprotonation of the methyl group. 

The only sensible place to lithiate the starting material (which is, of course, the popular solver. THE) is next to the oxygen atom. A reverse cycloaddition then eliminates ethylene (ethene) arc gives the lithium enolate of acetaldehyde. It is easier to see the reverse cycloaddition if we write the lithium derivative as an anion. 

H This chemistry was used to make The intermediate A is the lithium enolate of acetaldehyde formed in the absence of an -a new protecting group (A. J. Duggan acetaldehyde (see p. 707 for the importance of this). It acylates on oxygen with the acid chloride i ... 

Therefore, our first idea was to 0-acylate simple enolates with phosgene. In a first course of attempts, we investigated the reaction of phosgene with alkaline metals enolates. For example we prepared lithium enolate of acetaldehyde through cleavage of tetrahydrofuran by n- butylllthium (Ref. 116) and reacted with phosgene under various conditions. Unfortunately, no trace of vinyl chloroformate was found in all experiments performed [Scheme 90]. 

Ando, K. A Mechanistic Study of the Horner-Wadsworth-Emmons Reaction Computational Investigation on the Reaction Pass and the Stereochemistry in the Reaction of Lithium Enolate Derived from Trimethyl Phosphonoacetate with Acetaldehyde. J. Org. Chem. 1999, 64, 6815-6821. 

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