Tetrahydroisoquinolines hydride reduction

The reduction of 2-substituted-isoquinolinium salts has been reported by Torossian65 with potassium borohydride in water, by Mirza,68 and by Durmand et al.,87,68 using sodium borohydride in aqueous methanol to yield 1,2,3,4-tetrahydroisoquinolines. The reduction of the second double bond appears to arise from a mechanism similar to that leading to tetrahydropyridines from pyridinium ions (see Section I). Mirza66 (see also Bose60) found that the reduction of berberine (60) with sodium borohydride could be stopped at the 1,2-dihydro-intermediate (61), and Karrer and Brook70 showed that the 1,2-dihydroisoquinoline formed by the lithium aluminum hydride reduction of l-phenyl-2-methylisoquinolinium iodide (62) could be further reduced to the 1,2,3,4-tetrahydroisoquinoline (63) with sodium borohydride in methanol. Awe et al.71,72 and Huffman73... 

As a result of their potent pharmacological activity, 4-aryl-1,2,3,4- tetrahydroisoquinolines have attracted numerous synthetic efforts. Treatment of ( S)-1 with acetone under acid catalysis generates ( S)-( + )-2,2-dimethyl-5-phenyl-l,3-dioxolan-4-one (55) in 80% yield. Reaction of 55 with methylamine followed by lithium aluminum hydride reduction of the resultant amide provides ( S)-(+ )-A-methylamino-l-phenylethanol [(5)-( + )-halostachine] (56). N-... 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Nucleophilic addition takes place at C-1, and this is considerably enhanced if the reaction is carried out upon an isoquinolinium salt. Reduction with lithium aluminium hydride [tetrahydroaluminate(III)] in THF (tetrahydrofuran), for example, gives a 1,2-dihydroisoquinoline (Scheme 3.15). These products behave as cyclic enamines and if isoquinolinium salts are reacted with sodium borohydride [tetrahy-droboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected through protonation at C-4 and then hydride transfer from the reagent to C-3. 

The reduction of isoquinolinium ions has been extensively investigated with borohydride and aluminum hydride ions. The use of boro-hydride ion in a protonic solvent normally leads to the formation of 1,2,3,4-tetrahydroisoquinolines, whereas the reduction with aluminum hydride ion in an aprotic medium generally gives a 1,2-dihydroiso-quinoline. This 1,2-dihydroisoquinoline contains an enamine system and may undergo further reaction on treatment with acid. The 1,2-and 3,4-dihydroisoquinolines as well as isoquinolinium ions are reduced by the borohydride ion in a protonic medium to the 1,2,3,4-tetrahydroisoquinolines. 

Quinolines generally produce 1,2-dihydroqulnolines with aluminum hydrides. Diisobutylaluminum hydride and Red-Al have been used to reduce quinolines and quinoline-A -boranes (42 Scheme 9). The reactions are believed to proceed via aminoalanes or boranes and the dihydroquinolines produced are quenched and trapped as the carbamates by the addition of chloroformate esters. Minor amounts of 1,4-dihydro- and 1,2,3,4-tetrahydro-quinolines are also formed. The possession of a 2-substituent hinders reaction. At low temperatures the kinetic product, i.e. (43), is favored, but at higher temperatures reduction at the 4-position predominates which subsequently produces the tetrahydro derivative (44). A similar approach has been employed with isoquinoline, generating 1,2-disubstituted tetrahydroisoquinolines (45 Scheme 9). ... 

Thiazoles are deactivated towards electrophilic substitution, and thus direct reaction with hydride re-ductants to give thiazolines should be facilitated. There are indeed some examples of this type of reaction, but it is more common to reduce N-alkylated thiazolium salts (209). These compounds are converted first by reaction with sodium borohydride into 4-thiazolines (210), which in protic solvents become protonated and undergo further reduction to yield thiazolidines (211). Similarly the isoquinoli-nium salt (213), formed by the acid-promoted cyclization of the isoquinoline (212), is converted into the tetrahydroisoquinoline (214) (presumably via an intermediate 1,2-dihydroisoquinoline) by reaction with sodium borohydride. ... 

When treated with diethylaluminium hydride, isoquinoline yields its 1,2-dihydro derivative, as does quinoline. Metal reductions, e.g. with sodium in liquid NH3 or with tin/HCl, afford the tetrahydroisoquinoline 26. Isoquinolinium ions are reduced to 1,2,3,4-tetrahydroisoquinolines by NaBH4. This reaction is important for establishing the structure of alkaloids. Since the reduction of the... 

Chiral 1,2,3,4-tetrahydroisoquinolines are accessible from 0-carbamyl lactates via N-oxaacyliminium cyclization (Scheme 31). The precursor for the generation of the chiral N-oxaacyliminium ion 220 is prepared by reaction of (5)-methyl lactate (97) with azide 217 followed by partial reduction of 218 with diisobutylaluminum hydride. Cyclization of 219 with formic acid at room temperature for 14 h gives the oxazolo[4,3- 2]isoquinoline (221) without racemization [78]. Reductive cleavage of the oxazoline ring with lithium aluminum hydride furnishes the corresponding l-hydroxyalkyl-l,2,3,4-tetrahydroisoquinoline in 98% yield. 

Treatment of 106 or 107 with formic acid at room temperature leads to the corresponding 1-substituted oxazolo[4,3- ]isoquinoline 108 or 109, where the absolute configuration of the a-substitutent of the intermediate iminium carbon does not suffer racemization during the cyclization. Reduction of the isoquinoline with lithium aluminum hydride yields the appropriate l-(a-hydroxy-a-phenyl)-l,2,3,4-tetrahydroisoquinoline (110 or 111) (Scheme 23) [34]. 

Deuterium-labelling experiments have shown that a stereoselective intermolecular hydride-shift mechanism operates in the novel reduction of the benzylic hydroxy group of 4-hydroxy-4-phenyl-l,2,3,4-tetrahydroisoquinoline to the corresponding alkane with 10m HCl-EtOH.326... 

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