Tandem reactions acetalization

Raja and Perumal reported the synthesis of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and methylamine or ammonium acetate <06CPB795>. Further elaboration of this four component reaction to a novel five component tandem Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below <06T4892>. When this five-component tandem reaction involves para-substituted benzaldehydes, the cis (193) and trans (194) diastereomers of thiazones are obtained. Alternatively, orf/zo-substituted benzaldehydes form only the trans (194) diastereomer along with an air-oxidized product 195. 

As a consequence of the complimentary electron demand of the nitroalkene and the product nitronate, there exists the possibility of a one-pot, tandem reaction. In this case, the nitroalkene will react preferentially with the electron-rich alkene to produce an intermediate nitronate. This nitronate can then react with a second alkene bearing an electron-withdrawing substituent. Therefore subjection of the nitroalkene 210 to both ethyl vinyl ether and acrylonitrile provides only the nitroso acetal 211 in moderate yield (Eq. 20) (70). Moreover, this also allows the possibility of intramolecular variants of the process. 

There is no easy and/or effective method for the preparation of 1,2,3,4-tetrasubstituted naphthalenes starting from a simple naphthalene derivative and based on classical substitution methodology. A clever new route, based on the now common concept of "tandem" reactions, is illustrated as follows. Heating of the sulfoxide 1 with acetic anhydride at 120°C in the presence of maleic anhydride gave an adduct 2, C20H16O4S, in 87% yield as a mixture of diastereomers. Reaction of the adduct 2 with PTSA in THF at 25°C gave the naphthalene derivative 3 in quantitative yield. Use of methyl propiolate in place of maleic anhydride did not result in isolation of an adduct the product was the tetralone 4 (51%). 

Double aldol reaction followed by a series of tandem reactions of a Co-complex of bis-acetal of acetylenedicarbaldehyde afforded furyl-a-pyrone. The quantity of Lewis acid was shown to affect the result greatly. As shown below, a quantitative amount of furan product was provided when 6 equivalents of FjB OEtj were used. However, a mixture of alkylation products as well as furan was provided if 2 equivalents of BF, ... 

In the presence of excess acetyl halide and a tin(II) catalyst aromatic acetals react with allyltrimethylsilane to give a-allylbenzyl halides in good yield by double substitution of the acetal alkoxy groups (Scheme 10.127) [365]. The indium-catalyzed tandem reaction using a hydrosilane-allylsilane system enables deoxygenative allylation of aromatic ketones [366]. 

Manganese(III) can oxidize carbonyl compounds and nitroalkanes to carboxy-methyl and nitromethyl radicals [186]. With Mn(III) as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [186, 187). Further Mn(III)-mediated anodic additions of 1,3-dicarbonyl and l-keto-3-nitroalkyl compounds to alkenes and alkynes are reported in [110, 111, 188). Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(III)-mediated oxidation of acetic acid acetic anhydride in the presence of butadiene [189]. Also the nitromethylation of benzene can be performed in 78% yield with Mn(III) as electrocatalyst [190]. A N03 radical, generated by oxidation of a nitrate anion, can induce the 1,4-addition of aldehydes to activated olefins. NOj abstracts a hydrogen from the aldehyde to form an acyl radical, which undergoes addition to the olefin to afford a 1,4-diketone in 34-58% yield [191]. 

A tandem hydroformylation/acetalization reaction of/r-menthenic terpenes in the absence of an acid co-catalyst was reported by Vieira et The reaction took place in ethanol solution in the presence of PPhsor P(0-o-BuPh)3. 

Typical procedure forthe tandem hydroformylation-acetalization reaction of terpene ... 

A tandem reaction using Ti +-mont and HT that comprises deprotection and aldol condensation from malononitrile and benzaldehyde dimethyl acetal as starting materials is outlined in Table 2. The product is obtained only when both Ti + mont and HT are present and it is synthesized by Ti +-mont-catalyzed deacetalization of benzaldehyde dimethyl acetal, followed by the aldol reaction of malononitrile with benzaldehyde. When either Ti +-mont or HT was replaced by a homogeneous reagent such as p-toluenesulfonic acid or piperidine, neither the deacetalization nor the aldol reactions occurred to any great extent. 

Coumarin-fused 4H-pyrans can be achieved through the tandem reaction of 4-hydroxycoumarins with chalcones mediated by iodine/acetic acid... 

They also demonstrated that inexpensive molecular iodine can be used as a cheap, nontoxic, general, and fast catalyst for one-pot tandem acetalation-esteri-fication reactions of glycosides in good to excellent yields without the need of purification after every reaction step. Further, the addition of catalytic DMAP can be used to accelerate the esterification step and thus shorten the reaction times. The method is mild and compatible with different thioglycosides and 0-glycosides, applicable to the formation of 4,6-0-benzylidene and 4,6-0-p-methoxybenzylidene acetals in tandem reaction with either 2,3-0-di-acetate or 2,3-0-di-benzoate esters and also amenable to commonly used amino-protecting groups (e.g., phthalimides and 2,2,2-trichloroethoxycarbonyl chloride). 

The intermediary aldehydes derived from the Ru-catalyzed hydroformylation can be trapped as acetals, as shown by Borner and colleagues (Scheme 1.40) [45]. Only traces of alcohols or aldehydes could be detected. The tandem reaction proceeded exclusively with diols that formed thermodynamically stable 1,3-dioxolane and 1,3-dioxane rings. Methanol as the acetalization reagent failed. As olefins, terminal aliphatic olefins as well as styrene derivatives reacted. The catalyst could be recycled and reused at least twice. 

The group of Taddei added the important observation to the hydroformyla-tion chemistry of formaldehyde that the irradiation with microwaves is of additional value [18]. The scope of the methodology has been broadened to several hydroformylation-cyclization tandem reactions, as exemplarily illustrated with a final Af,0-acetalization step (Scheme 3.7). 

The same catalytic system proved to be advantageous for the tandem hydroformylation (Wittig olefination) reaction of a more sophisticated vinyl acetate as substrate at about 10bar (Scheme 4.68) [41]. (-p)-Patulohde C, a compound exhibiting both antifungal and antibacterial activity, was obtained with 93% de (for more details and examples of stereoselective tandem reactions, see Section 5.5). 

Scheme 5.69 Types of hydroformylation-acetalization tandem reactions.

With increasing P/Rh ratio, the rate of conversion decreased. Monodentate phosphines, especially PCyg, favored hydrogenation of the olefinic substrate and the transient aldehyde to give alkane and alcohol, respectively. With bidentate phosphines, a natural bite angle of about 110°, as realized with Xantphos, was essential for the success of the tandem reaction. Variation of the composition of the syngas mixture (ratio of CO/H2) had only a marginal effect. Remarkably, in the absence of H2 and under 10 bar of CO pressure, acetalization with... 

Application of the Hydroformylation-Acetalization Tandem Reaction in Practice... 

More interesting seems to be the hydroformylation-acetalization in one pot under the same conditions as a tandem reaction. In this regard, two aspects must be differentiated undesired and desired acetalization after the hydroformylation step. 

During hydroformylation, acetalization of aldehydes can take place as an undesired side reaction when the hydroformylation is conducted in alcohols as solvent and under the influence of a hydroformylation catalyst with acidic properties. Moreover, when alcohols result in a hydroformylation-hydrogenation tandem reaction (see Section 5.2), acetalization has always been taken into consideration. 

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