Azaenolates addition reactions

The mechanism of organolithium addition to naphthyl oxazolines is believed to occur via initial complexation of the alkyllithium reagent to the oxazoline nitrogen atom and the methyl ether to form chelated intermediate 17. Addition of the alkyl group to the arena 7t-system affords azaenolate 18, which undergoes reaction with an electrophile on the opposite face of the alkyl group to provide the observed product 4. The chelating methyl... 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

The obviously low electrophilicity of the C=N double bonds of aldimines precludes the addition of the azaenolate to remaining aldimine in the course of aldimine deprotonation. The aldimine enolate is obtained quantitatively and then reacted with the alkylating reagent. This step results cleanly in the desired product, again because of the low electrophilicity of imines as the alkylation progresses, azaenolate and the alkylation product coexist without reacting with each other, no aldol-type reaction, no proton transfer. All the azaenolate is thus converted... 

Reactions of the Bislactim Ether Cuprate. The lithiated bislactim ether can be converted to an azaenolate cuprate by treatment with CuBr SMe2 (see Copper(I) Bromide)fi Conjugate addition of the cuprate to enones (eq 3) and dienones, or alkylation with base labile electrophiles like ethyl 3-bromopropionate, proceeds with high trans diastereoselectivity. Hydrolysis of the Michael... 

The diastereoselectivity observed during the addition of (61c) to isobutyraldehyde stands in marked contrast to the significantly lower selectivity (1.5 1) that was previously observed when the chiral 2-methyloxazoline (59) was used as the nucleophilic partner (vide supra). The enhanced diastereoselection in the reaction involving (61c) is presumably a consequence of internal lithium chelation, which enhances both the selectivity in the deprotonation step as well as the diastereofacial selectivity in the nucleophilic addition to the aldehyde. For example, in separate experiments it was determined that metallation of (61c) proceeded with a (Z) ( ) diastereoselectivity of >9 1. Subsequent reaction of this (Z)-azaenol-ate with isobutyraldehyde via the chelated, chair-like transition state depicted in (64 R = Me), in which steric interactions between the reacting residues are minimized, would lead preferentially to the anti isomer (62c). For the additions involving (59), examination of the related transition state (64 R = H) clearly reveals that the facial selectivity should be somewhat less. 

The early (1975) contributions from the Meyers laboratory (Scheme 4.13a) paved the way for a number of related methods in subsequent years. Figure 4.24 illustrates a number of conceptually related conjugate additions. In several of these examples, there is a crucial difference from the examples in Scheme 4.13 in all except Figure 4.24e the a-carbon is prochiral, and two stereocenters are formed in the reaction. Fortunately, it is possible to either alkylate or protonate the azaenolate stereoselectively, such that two new stereocenters are produced in a single... 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

These 0,A-dialkylated amino alcohols are used as the lithium salts for enantioselective deprotonation and elimination reactions (Section C.), and for the formation of enamines used in Michael-type additions of azaenolates (Section D.1.5.2.4.). 

The asymmetric a-sulfenylation of ketones is a particularly challenging reaction, as demonstrated by the poor success reported in the stereoselective variants via classical enolate/azaenolate reaction with an electrophilic sulfur reagent [71]. An umpolung approach has been devised by Coltart and co-workers [72] to effect the first asymmetric a-sulfenylation of ketones with arene thiols. Nitroso alkene derivatives, in i/tM-generated under basic conditions from a-chloro oximes, reacted with arene thiols in the presence of cinchona thiourea 27, which promoted the conjugate addition of thiophenol (Scheme 14.25). The chiral nonracemic a-sulfenylated oximes were directly hydrolyzed by IBX to ketones in high yield and good enantioselectivity. 

These observations can be rationalized by a model in which an addition-elimination pathway is operative, with the overall stereoselectivity determined by the two steps (Scheme 8.4). The first step presumably involves initial complexation of organomagnesium 9 with oxazoline 8. The nitrogen lone pair would lie in the plane of the oxazoline and coordinate Mg. Furthermore, Mg is also coordinated to the methoxy leaving group. Although the mechanism of the Meyers reaction has not yet been elucidated computationally [20], it is assumed that chelate B is favored sterically over chelate A. The bulky isopropyl substituent favors attack of the nucleophile from the opposite face, leading to azaenolate 12. The oxazoline moiety not only induces chirality but also favors addition of the... 

The new hydrazones were first tested in simple a-alkylation reactions. As is shown in scheme 14, metalation with Lochmann-Schlosser base in THF at low temperature yielded highly reactive azaenolates, which were alkylated by a number of alkyl halides at -100°C in good yields and with high diastereomeric excess (de = 85 - > 95%). It is noteworthy that, besides the usual oxidative cleavage with ozone, the SAMP-hydrazones could be converted without racemization to the final 3-substituted 2-oxoesters under very mild conditions with boron trifluoride-ether in acetone/water with the addition of paraformaldehyde. Thus, this method permitted for the first time the highly enantioselective transfer of a homologous pyruvate unit to electrophiles (scheme 14) [41]. 

Other reports deal with a pyrrolidine-catalysed homo-aldol condensation of aliphatic aldehydes (further accelerated by benzoic acid), a diastereoselective aldol-type addition of chiral boron azaenolates to ketones,the use of TMS chloride as a catalyst for TiCU-mediated aldol and Claisen condensations, a boron-mediated double aldol reaction of carboxylic esters, gas-phase condensation of acetone and formaldehyde to give methyl vinyl ketone, and ab initio calculations on the borane-catalysed reaction between formaldehyde and silyl ketene acetal [H2C=C(OH)OSiH3]. ... 

Carbon-carbon bond-forming reactions comprise the most important general class of synthetic transformations. Among the various methods used for the construction of these bonds, those based on electrophilic addition to eno-lates (and their analogs silyl ketene acetals, silyl enol ethers, enamines, azaenolates, etc.) are especially pervasive. Indeed, enolate chemistry has provided much of the foundation for the advancement of synthetic organic chemistry to its present state. Over the years, an enormous amount of effort has gone into the study of enolate chemistry. Much of this work has focused on the development of strategies for the asymmetric a-alkylation of monocarbonyl compounds. 

The C-methoxycarbonylation of lithium ester and amide enolates can be effectively accomplished using MCF. Addition of n-BuLi to a chiral 1-oxazolinylnaphthalene followed by trapping the resulting azaenolate with MCF affords the C-acylation product with high diastereoselectivity (eq 11). In contrast, reaction of copper and potassium ketone enolates with MCF typically results in O-acylation to afford the corresponding enol carbonates (eq 12). The weak nucleophilicity of enol carbonates (they are stable to peroxy acids and Ozone) makes them useful masked enolate equivalents. 

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