Aminomethylation reaction conditions

A generally applicable reaction scheme naturally cannot be given. The reaction mechanism of one particular carbinolamine with a particular reagent can depend on the reaction conditions in nonpolar solvents, the nondissociated carbinolamine obviously reacts (Sj 2 mechanism). In polar solvents, on the other hand, the mesomeric cation reacts (S l mechanism). Formally all these reactions belong to the general class of aminomethylation. The reaction products can be considered to be Mannich bases. ... 

Vainilavicius and co-workers studied the Mannich reaction of oxadiazolethiones in detail and reported several examples pointing to the importance of starting reagent stmctures and the reaction conditions on the course of the reaction <2002M 173, 2003CHE1364>. For example, aminomethylation and acylation of 5-(4,6-diphenyl-2-pyrimidinyl)-... 

The reaction of 2,5-dimercapto-l,3,4-thiadiazolidine 34 with dialkylamines under Mannich reaction conditions gave N,S-aminomethylated thiadiazoles in 69-70% yields (Equation 24) <1998CHE1431>. With urea, thiourea, semicarbi-zide, or thiosemicarbazide, thiadiazolidine 34 gave N,N-aminomethylated thiadiazoles in 89-98% yields (Equation 25). 

In a similar manner, polymers with unsaturated chains or side chains can be converted to polyamines [66-69]. Conjugated diolefins usually undergo hydroformylation with low selectivities [70]. Mostly hydrogenation of at least one double bond occurs and mixtures of various saturated and unsaturated amines and diamines are obtained [71]. Similar to alkenes also alkynes may serve as unsaturated compounds in hydro aminomethylation reaction sequences. Although synthetically attractive, only a few investigations towards hydroformylation and hydroaminomethylation of alkynes in the presence of N-nuclcophilcs are known. Usually a preferred transformation to furanonic derivatives is observed under hydroformylation conditions [27]. 

Alkyl-3-hydroxy-4-pyridinones can be converted into analogues containing, e.g., anilino-, phenylthio-, or 2-hydroxyethylthio-substitu-ents by silver(I) oxidation (Ag20 in ethanol) followed by Michael addition (71). In aminomethylation of 3-hydroxy-4- and -2-pyridinones under Mannich conditions the position of substitution can be tailored, by reaction conditions to position C4 or C6, or by converting the OH into OMe, which directs substitution to C5 (72). 

A The Mannich reaction proceeds through the intervention of the N,A dimethylmethyleniininium cation [Me N =CHJ, This is insufficiently electrophilic to react with the benzene ring under the mild reaction conditions. Similarly, were the electrophile to react with the carbonyl oxygen atom of the heterocycle, this reaction would be reversible, as an aminomethyl ether is relatively unstable in acidic media. Thus, it seems plausible that the chromone utilizes enol or enolate character to trap the electrophile at C-3, followed by deprotonation of the adduct to reform the chromone ring system ( heme 5.9). 

When the carbonyl groups are removed further apart, as in ketoesters 65, the reaction product derives from aminomethylation on the less alkyl-substituted carbon atom in the a position with respect to the keto group. The carboxyl is in fact unable to activate the adjacent carbon atom under the usual reaction conditions. 

The reaction mechanism schematically depicted in Fig. 62, involves the methyleneimmonium ion as aminomethylating agent. This is generated by acidic reaction conditions (usually acetic acid is used as solvent). Attack by this reagent on the substrate leads to an intermediate carbocation, which then can follow various reaction... 

The reaction conditions reported in Table 6 become increasingly mild on going from A (the most severe, particularly for pH, temperature, and reaction time) to E these last, however, are characterized by the high concentration of the aminomethylating agent. 

Among terpenoid substrates bearing the alkyl ketone moiety, 4-caranone" and 2-pincne-4-one," in addition to camphor, are worth mentioning. The stereoselectivity of aminomethylation" is remarkably affected by the reaction conditions moreover, the tendency of 2-pinene-4-one, like steroid substrates, to give the vinylogous Mannich base (Table 8, Chap. I, C. 1) is important. 

Cyclopropanols can be converted to various cyclopropyloxy derivatives (esters, e.g. acetates, ethers, e.g. methyl and ethyl ethers, and acetals, e.g. tetrahydropyran-2-yloxy derivatives) under the appropriate reaction conditions. In most cases the synthesis of cyclopropyl esters by the reaction between a cyclopropanol and an acid chloride (e.g. formation of 1 ) or acetic anhydride (e.g. formation of 2 ) have been reported. The yields were particularly good (84-95%) when acetic anhydride was used, although a drawback of the reaction can be byproduct formation. When a reactive moiety is attached to the cyclopropane ring in addition to the hydroxy group, other reactions can also occur m-l-(aminomethyl)-2,2-dimethyl-3-(2-methylprop-l-enyl)cyclopropanol (3) reacted with phosgene in benzene to give the corresponding carbamate l,l-dimethyl-2-(2-methylprop-l-enyl)-4-oxa-6-azaspiro[2.4]heptan-5-one (4) in 31% yield. ... 

The first of these alternative approaches started with commercially available indanone-3-carboxylic acid 23 (derived from phenylsuccinic anhydride via Friedel-Crafts chemistry). This indanone was a viable precursor to 6 through an aminomethyl homologation with cyanide or nitromethane (Scheme 3.10). Our intent was to obtain ester 25, which after reduction would afford methylamine 28, which in turn would cyclize to generate lactam 29, giving benzazepine 6 upon reduction. Stereocontrol in the homologation was unnecessary, as lactam 29 would theoretically provide a thermodynamic sink under epimerizing reaction conditions, capturing the desired di-indane isomer. 

Ohba and co-workers developed a general synthesis of chiral iV-protected 5-(aminomethyl)oxazoles from a-lithiated isocyanides and Af-protected amino acid esters (Scheme 1.101). Metalation of an alkyl or benzyl isocyanide with n-BuLi or LDA and acylation with an A-Boc-ot-amino acid methyl ester afforded an iV-Boc-a-amino acid acyl isocyanide 369, which cyclized to a chiral A-Boc-5-(aminomethyl) oxazole 370. The products were obtained in > 98% ee based on chiral HPLC analysis. The yields of 370 were somewhat variable, ranging from 45 to 91%. A-Boc-protected glycine, alanine, phenylalanine, proline, serine, and (9-benzyl serine were all compatible with these reaction conditions. 

Some interesting reactions of thioamides not primarily involving the thiocarbonyl function of the latter deserve notice. Mohrle and Spillmann have investigated the behaviour of thioamides under Mannich reaction conditions, and they found that a successful iV-aminomethylation is critically dependent on steric conditions. Salts of the type (180), generated by the action of acetic acid on the corresponding 7ST-(hydroxymethyl)-thiobenzamides, were found to be reactive towards simple olefins, yielding... 

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