Li Enolates Research Articles

ChemInform Abstract: A Systematic Study of the Effects of Relative Configuration, Protecting Group, and Enolate Type on the Diastereoselectivities of Aldol Reactions of a Chiral Ethyl Ketone with 2‐Methylpropanal.

The diastereoselectivities of aldol reactions of 2-methylpropanal with various enolates of 5-O-methoxymethyl and 5-O-triethylsilyl derivatives of the four racemic diastereomers of 6-(2-ethyl-1,3-dioxolan-2-yl)-5-hydroxy-4-methylheptan-3-one are reported. Reactions of the (E)-enol dicyclohexylborinates, (Z)-enol 9-BBN borinates (i.e., 9-((Z)-enoxy)-9-borabicyclo[3.3.1]nonanes), Li (E)-enolates, Li (Z)-enolates, and Ti(IV) (Z)-enolates were examined. Boron and Li enolates were prepared by standard methods, but Ti(IV) enolates were obtained via transmetalation of the Li (Z)-enolates by reaction with TiCln(Oi-Pr)4–n (n = 0–2). Aldol relative topicity (simple diastereoselectivity) was strongly correlated to the enolate geometry: anti aldols from (E)-enolates and syn aldols from (Z)-enolates. However, for each enolate type, the diastereoface selectivities varied widely (by factors of 5–400) with the relative configuration and nature of the C5 protecting group in the 8 starting ketones. Plausible transition stat...

A systematic study of the effects of relative configuration, protecting group, and enolate type on the diastereoselectivities of aldol reactions of a chiral ethyl ketone with 2-methylpropanal.

The diastereoselectivities of aldol reactions of 2-methylpropanal with various enolates of 5-O-methoxymethyl and 5-O-triethylsilyl derivatives of the four racemic diastereomers of 6-(2-ethyl-1,3-dioxolan-2-yl)-5-hydroxy-4-methylheptan-3-one are reported. Reactions of the (E)-enol dicyclohexylborinates, (Z)-enol 9-BBN borinates (i.e., 9-((Z)-enoxy)-9-borabicyclo[3.3.1]nonanes), Li (E)-enolates, Li (Z)-enolates, and Ti(IV) (Z)-enolates were examined. Boron and Li enolates were prepared by standard methods, but Ti(IV) enolates were obtained via transmetalation of the Li (Z)-enolates by reaction with TiCln(Oi-Pr)(4-n) (n = 0-2). Aldol relative topicity (simple diastereoselectivity) was strongly correlated to the enolate geometry: anti aldols from (E)-enolates and syn aldols from (Z)-enolates. However, for each enolate type, the diastereoface selectivities varied widely (by factors of 5-400) with the relative configuration and nature of the C5 protecting group in the 8 starting ketones. Plausible transition state models are postulated to rationalize some of these observations. The relative configurations for the complete set of 16 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy-3-(methoxymethoxy)-4,6,8-trimethylnonan-5-one aldol adducts were confirmed by NMR analysis of 12 acetonide derivatives prepared from the corresponding 5,7-syn diols. Examination of the NMR data for the above set of aldol adducts revealed consistent trends that were exploited to assign the relative configurations of 13 diastereomeric 2-(2-ethyl-1,3-dioxolan-2-yl)-7-hydroxy-3-(triethylsilyloxy)-4,6,8-trimethylnonan-5-one aldol adducts.

ChemInform Abstract: Factors that Cause Contrasteric Alkylation of a Cyclopentane-1,2- dicarboxylic Acid Monoester.

Abstract The stereochemical outcome in the alkylation of the enolate generated from a cyclopentane-1,2-dicarboxylic acid monoester is described. The alkylation of the Li enolate with an alkylating reagent having a hard leaving group such as Cl gave a contrasteric alkylation (alkylation from the more hindered side of the enolate) product, predominantly. An important factor effecting contrasteric alkylation was found to be complexation of the hard leaving group of the alkylating reagent to the carboxylate Li counterion in the enolate.

Effect of solvent molecules on negative charge development on α-carbon of Li–enolate from acetaldehyde: A computational study

Tetrameric Li–enolate (TLE) molecules from acetaldehyde are studied by attaching solvent (guest) molecules like benzene, trimethylamine (TMA), tetrahydrofuran (THF), dimethyl ether (DME), ethanol and water to one of the Li atoms in order to examine the development of negative charge on the α-carbon of the enolate and stabilization of the TLE–guest complex. The density functional calculations at the B3LYP/6-311++G** level suggest that the charge on the α-carbon (−0.5 a.u.) is almost the same for most solvents that form σ-bonded TLE–guest complex, and is larger for a π-bonded TLE–benzene complex (−0.7 a.u.). Interestingly, each enolate unit in the TLE-complex has primarily a CC double bond and a CO single bond, and contradicts what one expects from a valence bond resonance structure that has a negative charge on the α-carbon.

Experimental and Theoretical Studies on Radical Trifluoromethylation of Titanium Ate and Lithium Enolates

The radical trifluoromethylation of Ti ate and Li enolates has been investigated by both experiments and density functional (UB3LYP/6-311+G//UB3LYP/6-31+G*) calculations. Radical CF3 addition to the enolates proceeds in a highly exothermic manner without significant reaction barriers in both Ti ate and Li enolates. There are two possible reaction paths after the addition of CF3 radical in the case of Ti ate enolate; one is the elimination of Ti(III) from the ketyl radical intermediate and the other is the direct reaction of the ketyl radical intermediate with CF3I. However, in the case of Li enolate, only the latter path is possible due to the high energy barrier of the elimination of the Li radical. This analysis provides an explanation of the experimental observation that the Li enolate could form the radical cycle efficiently but the Ti ate enolate could not. To make the radical cycle complete, I- has to be extracted from CF3I itself or the radical anion of CF3I. In the case of Li, formation of Li-I bond could be the driving force for the extraction of I- and regeneration of CF3 radical. However, Ti does not give exothermic Ti-I formation and thus regeneration of CF3 radical is less likely.

Radical Trifluoromethylation of Ketone Li Enolates.

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Radical trifluoromethylation of ketone Li enolates

It has generally been believed that highly basic Li enolates cannot be applied as substrates for radical trifluoromethylation due to defluorination of the α-CF3 product. However, Li enolates can be in fact employed for radical trifluoromethylation. Moreover, the reaction is extremely fast and the minimum reaction time is only ∼1 s.

Addition of Organolithium Reagents to Double Bonds

AbstractFor Abstract see ChemInform Abstract in Full Text.

Versatile One‐Step One‐Pot Direct Aldol Condensation Promoted by MgI2.

A true one-step one-pot aldol-reaction procedure has been developed for the synthesis of -hydroxy ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH2Cl2, with medium-to-high yields of aldol products obtained after regular workup. Mechanistically, the process probably proceeds via Mg-enolate formation of the ketone or ester component, followed by addition to the electrophilic aldehyde. Introduction. ± The development of new multicomponent-coupling processes for the construction of complex target molecules from simple starting materials has attracted much attention in recent years. Aldol reactions, i.e., the condensation of a nucleophilic enolate with an electrophilic carbonyl compound, are considered to be among the most-powerful C,C-bond-forming reactions. The development of direct aldol reactions from unmodified ketones and aldehydes does not require the pre- conversion of a ketone or an ester to a more-reactive species (e.g., an enol silyl ether or a ketene silyl acetal) and has, thus, attracted considerable attention. Generally, direct aldol reactions fall into one out of two categories: 1) the carbonyl compound is first converted to its Li (or other metal) enolate by treatment with a strong base, typically lithium diisopropylamide (LDA) or a metal hexamethyldisilazide (MHMDS), followed by the addition of a carbonyl acceptor; or 2) the carbonyl compound is converted to its metal enolate under relatively mild conditions by treatment with a Lewis acid and a tertiary amine, followed by the reaction with the carbonyl acceptor. Both methods are two-step one-pot reactions, since the enolate needs to be formed before the addition of the carbonyl acceptor (1) (2). Recently, we found that MgI2 is an excellent Lewis acid for C,C-bond-forming reactions in the synthesis of -iodo BaylisHillman adducts (3). We think that, in this process, MgI2 serves both as a Lewis acid and an iodine source for a Michael-type addition in which an ,-ethynyl ketone (or ester) is converted to an active −-iodo- allenolate× intermediate, which, in turn, reacts with aldehydes to yield -iodo BaylisHillman adducts. Consequently, we were interested in testing whether MgI2, in the presence of a tertiary amine, would be a suitable reagent for the mild in situ formation of Mg enolates.

Versatile One‐Step One‐Pot Direct Aldol Condensation Promoted by MgI2

AbstractA true one‐step one‐pot aldol‐reaction procedure has been developed for the synthesis of β‐hydroxy ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH2Cl2, with medium‐to‐high yields of aldol products obtained after regular workup. Mechanistically, the process probably proceeds via Mg‐enolate formation of the ketone or ester component, followed by addition to the electrophilic aldehyde.

Synthesis of (7‐Polyfluoroalkyl)pyrazolo[1,5‐a]pyrimidines Based on Lithium Fluorine‐Containing β‐Diketonates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Influence of the beta-alkoxy group on the diastereoselectivity of Aldol reactions of tetrahydro-4H-thiopyran-4-one with 4-Alkoxytetrahydro-2H-thiopyran-3-carboxaldehydes.

The diastereoselectivity of the aldol reaction of tetrahydro-4H-thiopyran-4-one (3) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (9a) under a variety of conditions is examined. Under optimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained selectively (3-16:1). Reactions of 9a with the Li, B, Mg(II), and Ti(IV) enolates of 3 and with the corresponding trimethylsilyl enol ether 4b in the presence of BF(3) x OEt(2), SnCl(4), or TiCl(4) as promoters gave the Felkin adducts exclusively (>95%) as mixtures of syn (11a) and anti (12a) diastereomers. Use of the "amine-free" Li enolate of 3 gave 12a with a much higher diastereoselectivity (9:1) and yield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of 3 (2-3:1; 15-40%). The TiCl(4)-promoted reaction of 4b with 9a gave 11a with excellent selectivity (16:1). In contrast, the MgBr(2) x OEt(2)-promoted reaction of 4b with 9a gave the anti-Felkin adducts exclusively as a 3:1 mixture of syn (13a)/anti (14a) diastereomers. Similar aldol reactions of 3 with the cis and trans isomers of 4-(methoxy)methoxytetrahydro-2H-thiopyran-3-carboxaldehyde (9b and 9c) were examined to probe the influence of the ketal protecting group in 9a on the observed aldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model for merged 1,2- and 1,3-asymmetric induction (non-chelation), with the exception of the MgBr(2) x OEt(2)-promoted reactions of 4b with 9a, 9b, and 9c, which are accommodated by assuming chelation control. Comparison of the reactions of 9a, 9b, and 9c suggests that the ketal group in 9a uniquely allows high levels of either Felkin or anti-Felkin selectivity to be achieved.

Synthesis of (7-polyfluoroalkyl)pyrazolo[1,5-a]pyrimidines based on lithium fluorine-containing β-diketonates

The reactions of Li enolates of fluorine-containing β-diketones with 3-aminopyrazoles afforded (7-polyfluoroalkyl)pyrazolo[1,5-a]pyrimidines. The structure of 3-bromo-2-methyl-5-phenyl-7-trifluoromethylpyrazolo[1,5-a]pyrimidine was established by X-ray diffraction analysis.

Preparation and Use in Amino Acid Synthesis of a New Chiral Glycine Derivative – (R)- and (S)-tert-Butyl 2-tert-Butyl-4-methoxy-2,5-dihydroimidazole-1-carboxylate (BDI)⋆

The title compound BDI is prepared on multigram scale, either by resolution of the precursor 2-tert-butylimidazolidin-4-one (from glycine amide and pivalaldehyde) through diastereomeric salts (Scheme 2) or by preparative chromatographic enantiomer separation on a chiral column. Lithiated BDI derivatives are highly nucleophilic species, combining the structural elements of a Li enaminate, of an enolether and of an N-Boc-enaminate (E, G). They react with complete diastereoselectivity (NMR analysis) from the face trans to the tert-butyl group. The electrophiles employed are primary and secondary alkyl, allyl, benzyl, and propargyl halides (Schemes 3 and 5), enoates (in Michael additions, Scheme 7), as well as aliphatic and aromatic aldehydes (in aldol additions, Scheme 8). When a third, exocyclic, stereocenter is formed in these reactions, there is a high degree of enantiomer differentiation (with rac.sec. halides, products 10-12) and of enantiotopic face differentiation (with enoates and aldehydes, products 40-50). The reactions are so clean that highly efficient in-situ double alkylations are feasible, in which the sequence of addition of the two different electrophiles determines the configuration at the newly formed stereogenic center (Scheme 5). In contrast to derivatives of previously reported chiral glycine reagents, the products from BDI are converted to methyl esters of amino acids under mild conditions and without concomitant formation (… and the need for recovery or removal) of a chiral auxiliary; the method is compatible with acid-sensitive side chains in the α-amino acids and α-branched α-amino acids to be synthesized (Schemes 4 and 6). The addition of Li-BDI to aldehydes furnishes, after hydrolysis, α-amino-β-hydroxy acids of erythro configuration (allo-threonine analogs, Scheme 8); a model for the stereochemical course of this reaction (rel. topicity unlike) is proposed, and compared with the corresponding conversions of analogous oxazolidinone and imidazolidinone Li enolates which occur with rel. topicity like.

The thiopyran route to polypropionates revisited: Selective syn and anti aldol reactions via 3,6-dihydro-4-trimethylsilyloxy-2 H-thiopyran

Aldol reaction of the amine free Li enolate of tetrahydro-4 H-thiopyran-4-one with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde gives mainly the 2,3- anti-3,4- syn aldol (7:1) in good yield; reaction of the LDA generated lithium enolate proceeds poorly. Using the trimethylsilyl enol ether and TiCl 4 gives the 2,3- syn-3,4- syn aldol (> 10:1). The adducts can be used for polypropionate synthesis.

Chele‐ und Anticheleselektivität, V [1] . Über die Struktur und Chemoselektivität einiger Übergangsmetall‐Derivate von Carbonsäureestern

Chele- and Anti-cheleselectivity, V[1]. - On the Structure and Chemoselectivity of Some Transition Metal Derivatives of Carboxylic Acid Esters On account of the IR spectra of EtO2CCH2FeCl (2a), EtO2CCH2CoCl (3a), and EtO2CCH(Et)CoCl (3b), prepared in situ by transmetalation of the corresponding Li enolates, and EtO2CCH(Et)CrCl2 (5b), obtained in situ by one-electron oxidative addition of EtO2CCH(Et)Br to CrCl2, it is assumed that these and similar complexes (2b, 2c, 3c) form 8-membered cyclic dimers of type 11 in THF in analogy to the Reformatzky reagents. Representatives of these complexes and of corresponding Ti complexes were treated (THF, mol ratio 1:1:1) with substrate pairs, consisting of a normal ketone and a s-functionalized ketone (Table 2) or alternatively of a normal ketone and an α-functionalized ketone (Table 3). In the first case high anti-cheleselectivity was observed, but in the second case high cheleselectivity. The reasons for this different behaviour are discussed.

Stereoselective conjugate addition of propionate Ti ate enolate to unsaturated chiral ketones: A new insight in the reaction mechanism

The reactions of the Ti ate enolate 1 and the Li enolate 2 with the chiral enone 3 were studied. Both reactions are moderately stereoselective, leading to the synthesis of the 2,3-anti-3,4-anti and the 2,3syn-3,4anti isomers with 78% and 82% selectivity, respectively. The addition of 1 appears to take place via an inverse demand Diels-Alder reaction, rather than a conjugate addition. This finding can explain the different stereochemical behavior of lithium and titanium enolates in the addition to enones.

Peptide Enolates. C‐Alkylation of Glycine Residues in linear tri‐, tetra‐, and pentapeptides via dilithium azadienediolates

AbstractThe Boc‐protected tripeptides Boc‐Val‐Gly‐Leu‐OH (1), Boc‐Leu‐Sar‐Leu‐OH (2), Boc‐Leu‐Gly‐MeLeu‐OH (3), and Boc‐Val‐BzlGly‐Leu‐OMe (64), tetrapeptide Boc‐Leu‐Gly‐Pro‐Leu‐OH (9), and pentapeptides Boc‐Val‐Leu‐Gly‐Abu‐Ile‐OH (4), Boc‐Val‐Leu‐Sar‐MeAbu‐Ile‐OH (5), Boc‐Val‐Leu‐Gly‐MeAbu‐Ile‐OH (6), Boc‐Val‐Leu‐BzlGly‐BzlAbu‐Ile‐OH (7), and Boc‐Val‐Leu‐Gly‐BzlAbu‐Ile‐OH (8) are prepared by conventional methods (Schemes 4–7) or by direct benzylation of the corresponding precursors (Scheme 8). Polylithiations in THF give up to Li6 derivatives containing glycine, sarcosine or N‐benzylglycine Li enolate moieties (A–H). The polylithiated systems with a dilithium azadienediolate unit (C, F–H) are best generated by treatment with t‐BuLi. The yields of alkylation of the glycine or sarcosine residues are up to 90%, with diastereoselectivities from nil to 9:1. Normally, the newly formed stereogenic center has (R)‐configuration (i.e. a D‐amino‐acid residue is incorporated in the peptide chain). Electrophiles which can be employed with the highly reactive azadienediolate moiety are: MeI, EtI, i‐PrI, allyl and benzyl bromide, ethyl bromoacetate, CO2, and Me2S2 (Schemes 11–13). No epimerizations of the starting materials (racemization of the amino‐acid residues) are observed under the strongly basic conditions. Selected conformations of the peptide precursors, generated by shock‐freezing or by very slow cooling from room temperature to −75° before lithiation, give rise to different stereoselectivities (Scheme 11). The latter and the yields can also be influenced by tempering the lithiated species before (Scheme 9) or after addition of the electrophiles (Scheme 12). Besides the desired products, starting peptides are recovered in the chromatographic purification and isolation procedures (material balance 80–95%). The results described are yet another demonstration that peptides may be backbone‐modified through Li enolates, and that whole series of analogous peptide derivatives with various side chains may thus be produced from a given precursor.

ChemInform Abstract: Enantioselective Aldol and Michael Additions of Achiral Enolates in the Presence of Chiral Lithium Amides and Amines

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Alkyleisen‐ und Alkylcobalt‐Reagenzien, IX. Umlagerung aliphatischer terminaler Epoxide zu Methylketonen durch Eisenalkyl‐Reagenzien statt durch Co2(CO)8 oder Edelmetallkatalysatoren

Alkyliron and Alkylcobalt Reagents, IX[1]. — Rearrangement of Aliphatic Terminal Epoxides to Methyl Ketones by Iron Alkyl Reagents instead of Co2(CO)8 or Noble Metal CatalystsThe highly selective rearrangement of aliphatic terminal epoxides to methyl ketones, hitherto possible only with Co2(CO)8 or noble metal catalysts, occurs smoothly with Me4‐FeLi2, Me3FeLi, or the catalytic systems [RLi + 2.5 mol% FeCl3] (R = Me, Bu). This was demonstrated by the rearrangement of 1‐decene oxide (1) to 2‐decanone (2) (yield 80–81%; Table 1) and 6‐bromo‐1‐hexene oxide (5) to 6‐bromo‐2‐hexanone (6) (yield 78%, Me4FeLi2 applied only). The competition reaction of Me4FeLi2 with 1 and 2‐octanone (8) (mole ratio 0.5:1:1) led to 87% 2‐methyl‐2‐octanol (9) and not to the rearrangement 1 → 2. This indicates that Me4FeLi2 ‐ in contrast to the opposite behavior of organo cuprates ‐ reacts faster with ketones than with the aliphatic terminal epoxides. By treatment of 1 with methyl derivatives of MnII, CoII, and NiII or with Bu4FeLi2 (Table 2) other products (3, 4) besides 2 were formed. The rearrangement of 1 with Me4FeLi2 is assumed to start with an oxidative addition and yields 2 as its Li or Fe enolate (trapped with acetanhydride to give 64% of 20) after reductive elimination of CH4. The catalytic rearrangement of 1 with [MeLi + 0.25 mol% FeCl3] very probably occurs in an analogous manner with an super‐ate complex Me4FeLi2(MeLi)n as the active species and the Li enolate of 2 as end product (Scheme 4). The aromatic terminal epoxides styrene oxide and α‐methylstyrene oxide give various products in the reaction with Me4FeLi2 or Me3FeLi, including the deoxygenation products styrene and α‐methylstyrene. These products are exclusively formed on treatment of the epoxides with Me4MnLi2. (Prepared, hitherto in the literature not described compounds: 7 and 10–15.)