Benzaldehyde equilibration

Even when the retroaldol reaction is fairly facile, stereoisomer equilibration can be slow. This phenomenon is illustrated in Scheme 16. A solution of the lithium aldolate (243) and benzaldehyde equilibrates to (244) and p-anisaldehyde with a half-life of 15 min at 0 °C. However, the syn lithium aldolate (244) equilibrates with its anti diastereomer (246) with a half-life of approximately 8 h at room temperature. The reason for this apparent dichotomy is that enolate (245) is so stereoselective in its reactions with aldehydes. Since the kinetic syn.anti ratio is 98.7 1.3, the syn aldolate must dissociate approximately 75 times in order for one syn aldolate molecule to be converted into one anti aldolate molecule. Of course, for less stereoselective enolates, such as the cyclohexanone enolate referred to above, stereochemical isomerization will more nearly parallel the rate of actual aldol reversal. 

The rate-determining step in the formation of the x-lithio ethers is the formation of a carbon radical as a precursor to the anion. The intermediate radical in the tetrahydropyranyl system is expected to be nonplanar, to be capable of rapid equilibration between the quasiequatorial and quasiaxial epimers, and to exist largely or entirely in the axial configuration at — 78 °C. However, treatment of the a-phenylthio ether 4 with LDMAN at higher temperature in the presence of A, A, lV, ./V -tetramethylethylenediamine leads to the more stable equatorial epimer of the lithio ether 5 and, after addition to benzaldehyde, the axial- and equatorial-substituted products were obtained in a ratio of 13 87. 

An interesting case of product-controlled simple diastereoselectivity has been reported103. [l-[Methyl(nitrosoamino)]-2-propenyl]lithium adds to benzaldehyde at — 78°C to give the amino alcohol with an anti/syn ratio of 65 35, but equilibration of the reversible reaction at room temperature leads exclusively to the more stable, vv -product. 

An important feature of saturated oxazolo[3,4- ]pyridines is their easy epimerization at the aminal C-l stereocenter. A quite explicit example has been reported by Moloney et al. and is depicted in Scheme 46. The reaction between lactam 157 and benzaldehyde produces a mixture of hexahydro-oxazolo[3,4- ]pyridines, the kinetic product 158 being the major one. Equilibration of the mixture with boric acid allows the ratio of diasteroisomers to be reversed since /rarcr-oxazolidine 159 is now the major product <1998TL1025> the equilibration of epimeric oxazolidines via ring-chain tautomerism has been investigated in detail and explains the epimerization observed for some hexahydro-oxazolo[3,4-4]pyridines <1993JOC1967>. 

An additional important observation that (Z)-enolates exhibit erythro diastereoselection was made by Dubois and Fellmann (5b). Their investigation demonstrated that the magnesium enolate 24a (20°C, Et2 0) condensed with benzaldehyde under kinetic conditions to give exclusively the erythro diastereomer 25E (R3 = Ph, E T>95 5), and upon prolonged equilibration afforded the isomeric threo adduct (T E > 95 5) (eq. [ 15]). Heathcock has reported... 

Similarly, the authors also examined the stabilization effect of dynamic modification of a U-NH -appended RNA aptamer that forms a kissing complex with the HIVl transactivation-responsive RNA element TAR. In this dynamic library, 2-chloro-6-methoxy-3-quinofinecarboxaldehyde (Rd) was incorporated in place of benzaldehyde (Ra). After equilibration of the U-NHj-substituted aptamer and aldehydes Rb-Rd in the presence of the TAR RNA target, it was found that the nalidixic aldehyde Rc-appended RNA was amplified 20%, and accompanied by an increased (Fig. 3.17). Interestingly, the nalidixic aldehyde Rc was selected in both DNA and RNA complexation experiments. 

Although catalytic amounts of base proved sufficient for library generation, 10 equivalents were used in order to achieve a reasonable equilibration rate for the slightly different ratio between the quantities of aldehydes and nihoalkane (5 1). Furthermore, these benzaldehydes were chosen in view of their similar individual reactivity in the nitroaldol reaction, resulting in close to isoenergefic behavior in the produced DCL. 

Figure 6.13 displays H-NMR analysis of the resulting (3-nitroalcohol DCL. Aher mixing benzaldehydes (24, 26, 27, 36, and 37) with 2-nitropropane (38), equilibration was initiated by the addition of triethyl-amine. To allow faster equilibration, the exchange took place at 40°C, and all adducts were clearly present at equilibrium that was established afier 18 hours. Equilibration also worked well at ambient temperature, albeit showing slower rates. Temperatures above 40°C, however, had a negative influence on the enantioselectivity of the subsequent enzymatic reaction and also caused slow decomposition of the (3-nitroalcohol substrates. 

Because the aldol reaction is reversible, it is possible to adjust reaction conditions so that the two stereoisomeric aldol products equilibrate. This can be done in the case of lithium enolates by keeping the reaction mixture at room temperature until the product composition reaches equilibrium. This has been done, for example, for the product from the reaction of the enolate of ethyl /-butyl ketone and benzaldehyde. 

By this process phenylglycine derivatives have been resolved by crystallization of the tartaric acid ammonium salts. The equilibration is induced at the amino ester stage by forming the configurationally labile imines with a catalytic amount of benzaldehyde or acetone (Table 11). 

Racemic colchiceine was obtained by Corrodi and Hardegger by a base-catalyzed equilibration of the Schiff base obtained by reacting deacetyl-colchiceine with benzaldehyde (34). Aldimine-ketimine isomerization was found to be the mechanism by which the racemization had occurred (35). The optical resolution of deacetylcolchiceine was accomplished with cam-phorsulfonic acids, affording, after O-methylation with diazomethane, separation of the enolate isomers and after N-acetylation, unnatural (+)-and natural (-)- colchicine (Fig. 1). Racemization of colchicine in refluxing acetic anhydride followed by mild hydrolysis of the intermediate triacetate represents a much improved method of preparing ( )-colchicine (36). The Blade-Font procedure was later extended to the preparation of ( )-3-demethylcolchicine and other racemic analogs (5). 

Toluene, durene, hexamethylbenzene, 1- and 2-methylnaphthalenes are oxidized to the corresponding benzaldehydes by irradiation in oxygen-equilibrated acetonitrile sensitized by 1,4-dicyanonaphthalene, 9-cyano-, 9,10-dicyano-, and 3,7,9,10-tetracyanoanthracene. The reaction involves proton transfer from the radical cation of the donor to the sensitizer radical anion or the superoxide anion, to yield the benzyl radical which is trapped by oxygen. In the case of durene, some tetramethylphthalide is also formed with this hydrocarbon it is noteworthy that the same photosensitization, when carried out in an nonpolar medium, yields the well-known singlet oxygen adduct, not the aldehyde [227,228] (Sch. 20). 

In 1987, Sonoda and co-workers reported that the tellurium-lithium exchange reaction of l-(phenyltelluro)-2-phenylethene with -butyllithium, followed by capture with benzaldehyde, gave the corresponding allylic alcohol with retention of the double-bond configuration.243 It was observed that, depending on the length of time the reaction mixture of the aryl vinyl telluride and -butyllithium was allowed to equilibrate prior to addition of the electrophile, a complex mixtures of products could be formed (Scheme 97).256... 

The double aldol product from acetone and benzaldehyde, known as dibenzylidene acetone (dba), is a constituent of some sun-protection materials and is used in organometallic chemistry as a metal ligand. It is easily made geometrically pure by a simple aldol reaction—again, reversible Michael addition equilibrates any Zproduct to E... 

The reaction of benzaldehyde with phenylacetic acid to produce a mixture of the a-carboxylic acid derivatives of Z- and -stilbene a form of aldol condensation known as the Perkin reaction, is effected by heating a mixture of the components with acetic anhydride and triethylamine. In the course of the reaction the phenylacetic acid is probably present both as anion and as the mixed anhydride resulting from equilibration with acetic anhydride. A reflux period of 5 h specified in an early procedure has been shortened by a factor of 10 by restriction of the amount of the volatile acetic anhydride, use of an excess of the less expensive, high-boiling aldehyde component, and use of a condenser that permits some evaporation and consequent elevation of the reflux temperature. 

Dropwise addition of butyllithium to a solution of ( )-l,3-dithiane 5,5 -dioxide (110) in pyridine-THF (1.5 1) generates an anion (111), which reacts with an aldehyde to give an adduct (112) as a 1 1 diastereomeric mixture. The reaction is extremely rapid at -78 °C, but the kinetic selectivity is moderate. In the reaction with benzaldehyde or pivalaldehyde, equilibration is attained at 0 C to give predominantly a single diastereomer in good yield (Scheme 31). ... 

Electrophilic catalysis of the departure of halogens in the century-old Koenigs-Knorr reaction is implicit in the use of heavy metal bases such as silver oxide and mercuric cyanide, but the first demonstration of electrophilic catalysis in water (in the hydrolysis of the p-glucoside of 8-hydroxyquinoline by first-row transition metals (Cu Np > C")) was by Clark and Hay in 1973. The observations were expanded to the more conveniently followed (because more labile) benzaldehyde methylacetals or tetrahydropyranyl derivatives of 8-hydroxyquinoline, whose hydrolysis is now known to give solvent-equilibrated oxocarbenium ions (Figure 3.19). Surprisingly, however, the observation of electrophilic catalysis of glycoside hydrolysis itself was not picked up by paper... 

Diamine 263 is made by the radical (pinacol style) dimerisation of the benzaldehyde imine 268. This gives a diastereomeric mixture equilibrated in favour of the syn isomer with lithium in isoprene and separated (51% yield) from the meso isomer by crystallisation with racemic tartaric acid.47 Finally, ( )-263 is resolved with a single enantiomer of tartaric acid giving 90% yield of either (S,S)-263 or (R,R)-263, depending on which enantiomer of tartaric acid is used, in 99% ee. The isomer remaining in solution can be isolated with only slightly worse ee 96%. 

A similar phenomenon has been reported by Sugiyama and coworkers, who found that the vinylogous amide (23) reacts with benzaldehyde to give (24) as the sole product (equation 90). When (23) is treated with two equivalents of sodium amide in ammonia, followed by treatment with benzaldehyde, aldol (25) is formed in 25% yield. Although the authors invoke a dianion in the latter reaction, it is unlikely that one could be formed under the reaction conditions used. Instead, it is likely that deprotonation at the endocyclic a-position is preferred kinetically, and that this leads to the product observed with NaNH2/NH3 (irreversible enolate formation). Reaction of this enolate must be slow, for steric reasons, as witnessed by the low yield in the aldol reaction. Under conditions of enolate equilibration, the more stable extended dienolate is produced. 

Stotter has reported a study that suggests that the low stereoselectivity sometimes observed in aldol reactions of cyclohexanones results from significant aldolate equilibration. As shown in equation (63), the lithium enolate of l-azabicyclo[2.2.2]octan-3-one reacts with benzaldehyde to give, after normal... 

In most cases, aldolate equilibration is to be avoided, since the result is usually to degrade the kinetically established stereoisomer ratio. A good example is seen in the reaction of the lithium enolate of cyclohexanone with benzaldehyde (Scheme 1, vide supra). If this reaction is carried out at -50 °C and worked up after 3 s, the diastereomer ratio is 82 18. If the reaction mixture is worked up after 5 min, however, the ratio is only 60 40. 

Chelated structures analogous to (19) and (20) were first proposed by House and coworkers to explain the increased anti selectivity observed for lithium ketone enolates following addition of ZnCh (equation 30). Heathcock and coworkers determined the rate of equilibration as well as the equilibrium composition for a number of aldolates derived from benzaldehyde and zinc ketone enolates (equation 31). Again, the preference for anti aldolates is in accord with zinc-chelated structures. 

Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and co-workers have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn.anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. 

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