5-Aminomethyl-3-hydroxy

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. 

Imidazo[4,5-6]pyridine, 1,2-dimethyl-methylation, 5, 618 Imidazo[4,5-6]pyridine, 2,3-diphenyl-synthesis, 5, 636 Imidazo[4,5-6]pyridine, 6-halo-alkylation, 5, 616 aminomethylation, 5, 616 Imidazo[4,5-6]pyridine, 2-(4-hydroxy-6-methylpyrimidin-2-ylamino)-synthesis, 5, 637... 

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). 

A solution of 192 g of 1 -phenethyl-4-hydroxy-4-aminomethyl piperidine in BOO cc of diethyi-carbonate is heated for 1 /i hours to refiux at about B0°C in the presence of sodium methylate (prepared for immediate use from 2 g of sodium). After this time, the ethyl alcohol formed during the reaction is slowly distilled while the maximum temperature is reached. The excess ethyl carbonate is distilled under reduced pressure. A crystallized residue Is then obtained, which is stirred with 400 cc of water and 400 cc of ether. The solution is filtered and 125 g (77.6%) of practically pure product melting at 232°C to 233°C, are obtained. 

Iron, cyclopentadienyl[(dimethyl-aminomethyl)cyclopenta-dienyl]-, methiodide j, 40,31 (Iron, cyclopentadienyl[(hydroxy-methyl)cyclopentadienyl]- [,... 

Hydroxy-phenyl) -dthylamin 5 2-Aminomethyl-1, l-diphenyl-butanol ... 

The direct bromination of 2-hydroxypyridine is regioselective at C-3 whereas chlorination is not. Qu6guiner has developed a halide exchange reaction. Heating 3-bromo-2-hydroxypyridine in pyridine hydrochloride at reflux gives 3-chloro-2-hydroxypyridine in good yield <96TL(37)6695>. The directed aminomethylation of 3-hydroxy-2(lH)-pyridones and 3-hydroxy-4(lfl)-pyridones has been studied <96T(52)1835>. 

As already mentioned, Lippard and co-workers have also studied the -hydroxy dizinc unit found in metallohydrolases in a model system [Zn2L(/x-OI I)(/x-02PPh2)]2+, L = 2,7-bis [2-(2-pyridylethyl)-aminomethyl]-l,8-naphthyridine) 454 Hydrolysis of phosphodiesters and beta-lactams was studied and related to the PI nuclease and beta-lactamase enzymes. The dinuclear complex... 

Bis(aminomethyl)cyclohexane, c349 l,2-Bis(benzylamino)ethane, d74 Bis(3-tert-butyl-4-hydroxy-5-ethylplienyl) sulfide, tl40... 

The allylic HYCRAM derivative was subsequently modified by insertion of a standard amino acid between the aminomethyl resin and the hydroxy butenoic acid moiety. Using this allylic anchor, the resin-linked, glycosylated HIV peptide T-derivative 164 was synthesized by application of Fmoc amino protection and sidechain protection with lert-butyl groups. The lac-tosamine peptide T (165) could be released from the resin by application of the palladium(0)-catalyzed allyl-transfer reaction to V-methyl aniline as the allyl acceptor. 

Fig. 20 Reversible hydration/dehydration of diphenylselenoxide (47), di-4-hydroxy-phenyltelluroxide, di-4-aminophenyltelluroxide, and A, A -dimethyl-2-aminomethyl)phenyl benzylselenoxide (50) and the corresponding dihydroxy selenanes/telluranes.

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). 

Pliotolytic. Bussacchini et al. (1985) studied the photolysis (7, = 254 nm) of phenmedipham in ethanol, ethanol/water, and hexane as solvents. In their proposed free radical mechanism, homolysis of the carbon-oxygen bond of the carbamate linkage gave the following photoproducts 3-(hydroxylphenyl)carbamic acid methyl ester, m-toluidine, 2-hydroxy-4-aminomethyl benzoate, 3-hydroxy-5-aminomethyl benzoate, 2-amino-4-hydroxymethyl benzoate, and 2-amino-6-hydroxymethyl benzoate. 

Fig. 6. Biotransformation of 7-methoxy-4-(aminomethyl) coumarin (MAMC, emission 396 nm) to 7-hydroxy-4-(aminomethyl) coumarin (HAMC, emission 470 nm) by cytochrome P450 enzyme CYP2D6...

The observation that fram-2-hydroxy-l-cyclopentanecarboxamide does not react with aldehydes or ketones was used in the synthesis of stereohomo-geneous cis cyclopentane-fused oxazinones and c -2-aminomethyl-l-cyclo-pentanol derivatives. The cumbersome separation of the cis- and tram-2-hydroxy-l-cyclopentanecarboxamides can be avoided, because only the cis isomer forms the oxazinone ring (81S628 83T1829). 

There are cases in which appropriate modification of one unsaturated oxazolone yields a new unsaturated oxazolone analogue. Most of the examples described in the literature involve modification of the substituent on the exocyclic double bond. For example, a series of 4-[2-hydroxy-3-(aminomethyl)benzylidene]-5(4//)-oxazo-lones 382 that were evaluated for bactericidal and fungicidal activities were obtained from Mannich reaction of 4-(2-hydroxybenzylidene)-5(4//)-oxazolones 381 (Scheme 7.123). ... 

Hydroxypyridine reacts with formaldehyde and base to give the 2-hydroxymethyl derivative which reacts further, ultimately to yield the 2,6-disubstituted product. No 4-substitution is detected in this case or with 3-hydroxy-2,6-dimethylpyridine when it is treated under the same conditions (75RCR823). 3-Hydroxypyridine readily undergoes bis-aminomethylation at the 2- and 6-positions. 

Ebenfalls unter intramolekularer Beteiligung der Hydroxy-Gruppe verlauft die Umsetzung von 4(5)-(2-Hydroxy-ethyl)-imidazol mit 2- Amino-1,1-diethoxy-ethan zu4-Aminomethyl-1,4,6,7-te-trahydro-(j)yrano[3,4-d imidazoT) (60%)767 ... 

---