Aminomethylation reactions

Mannich Reaction. Aminomethylation of polyacrylamide with formaldehyde [50-00-0] and a secondary amine to produce a Mannich polyacrjiamide has been extensively studied (40). 

Keywords /V-arylmcthylcniminc, cascade reaction, solid-solid reaction, gas-solid reaction, aminomethylation, cyclization, Troeger base... 

Ferrocene is an aromatic compound similar to benzene. As the aromatic rings of ferrocene are coordinated by iron, ferrocene shows a higher basicity than that of benzene. Then an electrophilic reaction is liable to proceed. For example, Friedel-Crafts acylation, Mannich reaction (aminomethylation) and lithiation easily proceeds as shown in eqs. (15.12)-(15.14) [26]. 

Ferrocenes are aromatic compounds similar to benzene, as they have a high basicity, electrophilic substitution reactions such as Friedel-Crafts acylation (eq. (15.12)), metalation (eqs. (15.14) and (15.16), Scheme 15.1), Mannich reaction (aminomethylation, eq. (15.13)) and formylation (Scheme 15.1) are liable to proceed as described above. These products also have a high reactivity and they are used as raw materials for other ferrocene derivatives as shown in Schemes 15.1 and 15.2. For example, if one bridged ferrocene is obtained from Scheme 15.1 to form another bridge, lithium diisopropylamide (EDA) is reacted, oxidized with CuCl2, and reduced with LiAlH4 to afford a two bridged ferrocenophane as shown in eq. (15.23) [50,69]. 

Without additional reagents Mannich reaction — Aminomethylation... 

Mannich reaction — Aminomethylation Nitramines from aliphatic nitro compounds... 

Without additional reagents Modified Mannidi reaction Aminomethylation with methyleneammonium chlorides... 

Thiazolidine-2,4-dione and its derivatives undergo the Mannich reaction aminomethylation occurs at the hetero-nitrogen atom, yielding products of type (237) and (238). SeIenazolidine-2,4-diones react analogously. ... 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

The yields of this reaction are typically 40—80%. C-nmr studies (41) indicate that the reaction is a second-order process between polyacrylamide and dim ethyl am in om eth an ol, which is one of the equiUbrium products formed in the reaction between formaldehyde and dimethylamine [124-40-3] C2H2N. The Mannich reaction is reversible. Extensive dialysis of Mannich polyacrylamides removes all of the dimethyl aminomethyl substituents (42). 

The A/-carboxyl group is lost duting the reaction, and no additional deprotection step is requited (104). Benzene reacts with A/-carboxyglyciae anhydride to give aminomethyl phenyl ketone however, it does not react with other A/-carboxy-a-amino acid anhydrides (105). 

Other reactions that show preference for the acidic N-3—H group include Mannich aminomethylation by treatment with formaldehyde and an amine (38) to yield compound (8), reaction with ethyleneimine (39) to give (9), and Michael-type additions (40) such as the one with acrylonitrile to give (10) ... 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

There is a scattered body of data in the literature on ordinary photochemical reactions in the pyrimidine and quinazoline series in most cases the mechanisms are unclear. For example, UV irradiation of 4-aminopyrimidine-5-carbonitrile (109 R=H) in methanolic hydrogen chloride gives the 2,6-dimethyl derivative (109 R = Me) in good yield the 5-aminomethyl analogue is made similarly (68T5861). Another random example is the irradiation of 4,6-diphenylpyrimidine 1-oxide in methanol to give 2-methoxy-4,6-diphenyl-pyrimidine, probably by addition of methanol to an intermediate oxaziridine (110) followed by dehydration (76JCS(P1)1202). 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Halogenomethyl, hydroxymethyl and aminomethyl groups readily undergo displacement reactions with nucleophilic reagents. Both side-chain and nuclear substitution products have been obtained (Scheme 57). These two possibilities are exemplified by the reaction of furfuryl chloride with sodium cyanide (Scheme 58). 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

In systems of proper geometry, nucleophiles within a side chain may be well connected for attack on ring atoms. For example, an aminomethyl group at the 5-position of a dibenzazepine-2-one was found to attack the carbonyl group (Section 5.16.3.5.2). Such reactions should be possible in rings of any size. 

Jap-KIingermarm reactions, 4, 301 oxidation, 4, 299 reactions, 4, 299 synthesis, 4, 362 tautomerism, 4, 38, 200 Indole, 5-amino-synthesis, 4, 341 Indole, C-amino-oxidation, 4, 299 tautomerism, 4, 298 Indole, 3-(2-aminobutyl)-as antidepressant, 4, 371 Indole, (2-aminoethyl)-synthesis, 4, 278 Indole, 3-(2-aminoethyl)-synthesis, 4, 337 Indole, aminomethyl-reactions, 4, 71 Indole, 4-aminomethyl-synthesis, 4, 150 Indole, (aminovinyl)-synthesis, 4, 286 Indole, 1-aroyl-oxidation, 4, 57 oxidative dimerization catalysis by Pd(II) salts, 4, 252 Indole, 1-aroyloxy-rearrangement, 4, 244 Indole, 2-aryl-nitration, 4, 211 nitrosation, 4, 210 synthesis, 4, 324 Indole, 3-(arylazo)-rearrangement, 4, 301 Indole, 3-(arylthio)-synthesis, 4, 368 Indole, 3-azophenyl-nitration, 4, 49 Indole, 1-benzenesulfonyl-by lithiation, 4, 238 Indole, 1-benzoyl photosensitized reactions with methyl acrylate, 4, 268 Indole, 3-benzoyl-l,2-dimethyl-reactions... 

The side-chain cyanoethylation of alkyl thienyl ketones with acrylonitrile has been studied " and used for the preparation of 8-oxonitriles and S-oxoacids. Aminomethylation (Mannich reaction) of 2-acetylthiophene followed by steam distillation yielded 50% of 2-thienyl vinyl ketone, and has also been used for the synthesis of compounds of biological interest. ... 

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. ... 

Similar isomerization reactions were observed in CDCI3 solutions of N-( -aminomethyl)-l,2,4-triazoles and -tetrazoles (90T633). As for the analogous benzotriazoles, these reactions are-intermolecular and slow at 20°C in the NMR time scale. 

Synthesis of 3-aminomethyl-6-chloropyridine by combining microbial and chemical reactions 99YGK466. 

Another example of the preparation of functionalized pyrazoles is the reaction of aminomethylated methoxyenynes 116 with hydrazine and alkylhydrazines, which leads to aminoethylpyrazoles 117 (80% yield) and vinylpyrazoles 118 via EtaNH elimination. 

Reaction of 2-amino-4/f-pyrido[l,2-n]pyrimidin-4-ones 143 with HNMei -HCl and paraformaldehyde in Dowtherm A afforded a mixture of 3-(A,A-dimethylamino)methyl derivatives 144 and bis-compounds 145 (93FES1225). Mannich reaction of 9-hydroxy-2-methyl-4//-pyri-dor],2-nlpyrimidin-4-one (146) yielded 8-aminomethyl derivatives 147 (94KFZ(10)23). 

Chloro-2,3,4,4fl,5,6-hexahydro-l //-pyrazino[l, 2-fl]quinolin-2-one (407) was prepared when 6-chloro-2-[A -(2-bromoacetyl),-A -(rerf-butoxycarbonyl) aminomethyl]-l,2,3,4-tetrahydroquinoline (406) was first treated with TFA, then the evaporated reaction mixture was heated in DMF in the presence of powdered K2CO3 (96USP5576319). 

---