Tetrahydroquinoline hydroxylation

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

The procedure has also been applied for the hydroxylation of aromatic amines. Aniline and its /V-alkyl-substimted derivatives show similar behavior under similar conditions to afford the meta-substi tuted aminophenols as the major hydroxylated product.627 Product formation was interpreted by the attack of protonated hydrogen peroxide on the anilinium ion protected by /V-protonation from oxidation or degradation. Indoles, indolines, and tetrahydroquinoline have also been successfully hydroxylated with H202 in HF-SbF5 with the hydroxyl group meta to the nitrogen function.559,628 Hydroxylation of tryptophane and tryptamine derivatives affords pretonine and serotonine derivatives in 42% and 38% yields, respectively.629... 

On the other hand, the pyridine ring portion of quinolines and isoquinolines can be oxidized to various hydroxyl-derivatives by enzymes. 1,2,3,4-Tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline derivatives are easily aromatized to quinolines and isoquinolines, respectively, by using hypervalent iodine reagents or DDQ. ... 

They are easily prepared from dithiocarbamate and nickel(ll) salts, and examples including those derived from simple amines (587,1472) fluorinated amines (76) amines with (O-hydroxyl groups (1473) indole (341) indoline, carbazole, and imidazole (342) (72) together with those with heterocyclic (72,1116,1126,1424,1474) benzyl (346,1475) and aryl (95,1423,1425,1476, 1477) substituents. Others include examples prepared from Schiff bases (1121), 2-aryldecahydroquinolin-4-ones (1478), tetrahydroquinoline and tetrahydroiso-quinoline (1479), succinimide and phthalimide (49), l,4,7,10-tetraoxa-13-aza-cyclopetadecane (50), 1,3,4-thiazolyl (1426), and 3-dithiocarboxy-3-aza-5-aminopentanoate (343) (1480,1481). A wide range of amino acid derivatives have also been prepared (122,133-137), as have derivatives of glycine, DL-alanine and DL-valine peptide bonded to ethyl esters of a-amino acids (134). 

In addition to quinoline-based SARMs, tetrahydroquinoline-derived drug candidates were reported to possess tissue-selective androgen receptor agonist activity. Two representatives are S-40503 and 2-methyl-2-(8-nitro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]chinolin-4-yl)propan-l-ol (Fig. 4.9,12 and 13), and the mass spectrometric behavior was studied for both compounds. The protonated molecule of 13 at m/z 289 dissociates under CID conditions by the loss of a hydroxyl radical (-17 Da) originating from the nitro function. The proton affinity of 1,2,3,4-tetrahydroquinoline was determined as 225 kcal/mol and... 

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