Hemiacetals Hemiaminals

Racemization via a reversible addition/elimination process under mild conditions can be used, with for example cyanohydrins, hemiacetals, hemiaminals and hemithioacetals. SiUca-supported benzyltrimethylammonium hydroxide (BTAH) was used to racemize cyanohydrins and effected an efficient DKR process in tandem with porous ceramic-immobilized lipase (lipase PS-C II) (Scheme 4.22) [57]. 

A rather complex microwave-assisted ring-opening of chiral difluorinated epoxy-cyclooctenones has been studied by Percy and coworkers (Scheme 6.131) [265]. The epoxide resisted conventional hydrolysis, but reacted smoothly in basic aqueous media (ammonia or N-methylimidazole) under microwave irradiation at 100 °C for 10 min to afford unique hemiacetals and hemiaminals in good yields. Other nitrogen nucleophiles, such as sodium azide or imidazole, failed to trigger the reaction. The reaction with sodium hydroxide led to much poorer conversion of the starting material. 

Halocarbons, ketone-alcohol reduction, 84 Halogenation, 4-methylbenzyl chloride [reductive halogenation of aldehyde to benzyl chloride], 124 Hemiacetals, reduction of, 97-99 Hemiaminals, reduction of, 99-100 Hemiketals, reduction of, 97-99 Heptene derivatives, alkene to alkane reductions, disubstituted alkenes, 36-38... 

Oxidative biotransformation provides a commonly reported means of removing alkyl groups from substituted oxygen and nitrogen atoms. These reactions are believed to proceed via monooxygenase-mediated a-hydroxylation of the alkyl group to an unstable hemiacetal or hemiaminal, as outlined in Fig. 4 for an 0-alkyl substituted compound. 

When the hemiaminals A (Figure 9.12, Nu = NR3R4) are formed in a neutral or weakly basic solution, they also have the possibility to react further by an SN1 reaction albeit in a different manner than just described for the corresponding hemiacetals (Nu = OR3) and hemithioacetals (Nu = SR3). The OH group of hemiaminals A is then ejected without prior protonation (i.e., simply as an OH ion). This is possible because an especially well-stabilized carbocation is produced at the same time, that is, the iminium ion C (Nu = NR3R4). It reacts with the second equivalent of the N nucleophile. Proton loss affords the jVW-acetal B (Nu = NR3R4). 

This has been nicely demonstrated and exploited by Woodward s syntheses of bicyclic systems of the penem type. They are typically formed in moderate to good yields upon refluxing the requisite substituted starting -lactams in toluene or xylene for extended periods. The key step is the introduction of the ylidic moiety into the 1-position of a 4-functionalized azetidin-2-one which itself can be obtained as a relay substance by degradation of natural penicillins or from easily available 4-acetoxyazetidin-2-one. The ester ylide function is built up by reaction first with alkyl hemiacetals of glyoxylates to give a hemiaminal and then successive replacement of the OH-group of the latter by Cl with thionyl chloride and finally of the chlorine atom by triphenylphosphane under basic conditions. 

The tautomeric composition in solution of 4-(arylmethyl)isoxazol-5-one derivatives has been determined on the basis of H NMR and infrared (IR) data. The CH form was predominant in chloroform solution, while the NH and OH forms are more common in polar solvents and in the solid state <1996T1443>. 5-Hydroxy- and 5-amino-2-isoxazo-lines show different tautomeric forms in solution. The presence of cyclic hemiacetal or hemiaminal moieties in such molecules allows the easy cleavage of the C-5-0 bond to form linear structures. Subsequent intramolecular addition of nucleophiles to the C=N bond gives rise to cyclic structures. Compounds 20 exist, in the crystalline state, as the isoxazoline form A. In solution, a ring-ring tautomeric equilibrium was observed between the isoxazoline form A and the pyrazoline form C. The tautomeric ratio depended on steric factors and on the solvent used. The tautomeric equilibrium was established after several days (Scheme 2) <2000CHE722>. 

When 1-ethoxycyclopropanol (10) was employed as a cyclopropanone source, the addition of aniline led to a mixture of hemiaminal 11 and aminal 12/ The conversion of hemiacetal 10 into dimer 7 at — 78 °C was quantitative when an excess of aniline was employed. However, at 25 °C, only the aminal 12 was obtained. -... 

Aliphatic hydrazines react with cyclopropanone or cyclopropanone hemiacetals, providing good access to carbinol-type adducts which are versatile sources for the synthesis of cyclo-propylidenehydrazines. Upon reacting hemiacetal 10 with A,A-dimethylhydrazine, without solvent, the distillable but sensitive hemiaminal 39 was formed in 64% yield. ... 

We have shown that heterogeneous catalysis can be applied to reductive alkylation with success in reactions such as ether synthesis or N-alkylation of amides and anilines. Concerning the mechanism, several pathways are in competition depending on the structure of the substrate and of the alkylating agent. The important point is that both the product of addition (the hemiacetal or hemiaminal) and the product of elimination (imine, enamine or enolether)... 

In 2004 Percy and coworkers observed unexpected selective formation and reactions of epoxycyclooctenones under microwave-mediated conditions [83]. Topologically mobile difluorinated cyclooctenones undergo epoxidations with methyl(tri-fluoromethyl)dioxirane. The epoxides resist conventional hydrolysis but react smoothly in basic media under microwave irradiation to afford unique hemiacetals and hemiaminals in good yields (Scheme 10.39). 

Dehydration of the hemiaminal gives the imine. Now there is some need for catalysis acid must be added so that the OH group can become a good leaving group. This step resembles the conversion of hemiacetals to acetals. The difference is that the iminium ion can lose a proton... 

Up to this point, the two mechanisms follow a very similar path, with clear analogy between the hemiaminal and hemiacetal intermediates, and between the iminium and oxonium ions. Here, though, they diverge, because the iminium ion carries a proton, which the oxonium ion doesn t have. The iminium ion therefore acts as an acid, losing a proton to become the imine. The oxonium ion, on the other hand, acts as an electrophile, adding another molecule of alcohol to become the acetal. 

Notably, the potentially competing polyester formation [19] by dehydrogenative selfcoupling of diols was not observed under these conditions. This is probably because the intermediate aldehyde reacts preferentially with the amine, which is a better nucleophile than the alcohol, forming a hemiaminal intermediate [14] (rather than a hemiacetal [11]) followed hy its dehydrogenation to the amide (Schemes 1.6 and 1.11). In addition, it should he noted that complex 8 also catalyzes the formation of amides by coupling of esters with amines (Section 1.4.2) [15] hence, even if some ester (or oligoester) were to be initially formed, it would be converted to the polyamide. 

When ammonia or a primary amine is used, there are two possible pathways to the product via an amino alcohol that is similar to a hemiacetal and is called a hemiaminal or via an imine (Section 16.8A). When secondary amines are used, an imine cannot form, and, therefore, the pathway is through the hemiaminal or through an iminium ion ... 

As a special case, the formation of hemiacetals 2 (lactolization) during the hydroformylation of hydroxy-functionalized olefins, such as allyl or homoallyl alcohols, has to be mentioned (1, Y= O, Scheme 5.70). With these substrates, the reaction occurs in an intramolecular manner. In the presence of an external alcohol, the cyclic hemiacetal can further react to give a nonsymmetric cyclic acetal 3. Hemiacetals can be subjected to hydrogenation to afford diols 4. Under reducing conditions and in the presence of amines, amino alcohols 5 are formed both are valuable building blocks in fine chemistry. Alternatively, oxidation gives lactones 6 [5]. By dehydration of hemiacetals, cychc vinyl ethers 7 are formed. The same transformation with allylamines (Y=NR) gives cyclic hemiaminals, A/ ,0-acetals, lactames, or vinyl amines. 

Scheme 5-70 Hydroformylation-intramolecular cyclization to hemiacetals and hemiaminals and some subsequent transformations.

The imine (Formula 4.52) formed by the reaction of glucose with the amine is easily converted to the cyclic hemiaminal, a- and P-glucosylamine. However, N-glycosides of this type are relatively instable because they very easily mutarotate, i. e., they are easily hydrolyzed via the open-chain imine or are converted to the respective a- and P-anomer. However, the Amadori rearrangement leads to furanose, which as a hemiacetal, has a stability to mutarotation comparable with that of carbohydrates. 

Upon exposure to an amine, aldehydes and ketones initially form hemiaminals, the nitrogen analogs of hemiacetals. In a subsequent, slower step, hemiaminals of primary amines lose water to form a carbon-nitrogen double bond. This function is called an imine (an older name is Schiff base) and is the nitrogen analog of a carbonyl group. 

The mechanism of the elimination of water from the hemiaminal is the same as that for the decomposition of a hemiacetal to the carbonyl compound and alcohol. It begins with protonation of the hydroxy group. (Protonation of the more basic nitrogen jnst leads back to the original carbonyl compound.) Dehydration follows to the intermediate iminium ion, which is then deprotonated to furnish the imine. 

Ammonia and amines of the general formula RNH2 are nitrogen analogs of water and alcohols. They are more nucleophilic than water and alcohols and react faster with carbonyl groups of aldehydes and ketones. In these reactions, a nitrogen analog of a hemiacetal, called a hemiaminal, forms. 

Mechanistic studies revealed that the reaction does not involve ester intermediacy and proceed via a hemiaminal-type mechanism (Scheme 5). When the benzyl benzoate and benzylamine were reacted under similar experimental conditions of the amidation reactions, either in the presence or absence of catalyst 5, no amide formation took place and the starting materials were recovered. These studies preclude the involvement of a hemiacetal pathway in the reactions. Further, the dehydrogenation of hemiaminal prevails over the anticipated water elimination to result in an imine, which upon H2 addition would provide the secmidary amine. Secondary amines were observed only in trace amounts when linear alcohols were used. 

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