Isoquinoline lithium aluminum hydride reduction

The synthesis of 13-hydroxylated tetrahydroprotoberberines from norphthalideisoquinolines has been achieved. Catalytic reduction of the phthalide-isoquinoline 32, derived from papaverine (see Sec. 24.2.3), afforded a separable mixture or erythro- and /Areo-norphthalideisoquinolines. Base-catalyzed lacta-mization followed by lithium aluminum hydride reduction of the threo-nov and rj fAro-norphthalides yielded the 13 - and 13a-hydroxytetrahydroprotober-berines, respectively. The hydroxylactam derived from the / r o-norphthalide tends to dehydrate readily to the oxoprotoberberine system (see Scheme 19.4). ... 

Hydroisoquinolines. In addition to the ring-closure reactions previously cited, a variety of reduction methods are available for the synthesis of these important ring systems. Lithium aluminum hydride or sodium in Hquid ammonia convert isoquinoline to 1,2-dihydroisoquinoline (175). Further reduction of this intermediate or reduction of isoquinoline with tin and hydrochloric acid, sodium and alcohol, or catalyticaHy using platinum produces... 

Cyclic enamines can also be obtained by the reduction of pyridine and isoquinoline with lithium aluminum hydride (163-165), and the latter reduction has also been accomplished with sodium in liquid ammonia (166). 

R" = CH20H). The use of sodium borohydride in place of lithium aluminum hydride did not lead to ring closure but to 3-[j8-(A-l,2,3,4-tetrahydroisoquinolyl)ethyl]indole derivatives (53). Reductive cyclization by means of lithium aluminum hydride of the j8-(3-indolyl)ethyl-l-isoquinoline (52) to the pentacyclic tetrahydro-j8-carboline 49 (R = R = R" = H) has been reported. Strong acid alone sufficed to convert 52 into 54, the 0x0 derivative of 49. ... 

C. Reduction of Isoquinoline with Lithium Aluminum Hydride or Dialkyl Aluminum Hydride... 

The isoquinoline ring undergoes attack by the nucleophilic aluminum hydride anion in much the same manner as the pyridine ring to produce 1,2-dihydroisoquinolines,91,92 although tetrahydroisoquino-lines have been reported as products even though no proton source was apparently present.92 (For a probable mechanism see Section IV,B.) The reduction of isoquinoline A-oxide by lithium aluminum hydride was also reported to yield the 1,2-dihydroisoquinoline.93... 

The condensation of 3-acetylindole (XXXII) with isoquinoline in the presence of iodine generates a quaternary ketonic compound (XXXIII), and this upon reduction with lithium aluminum hydride furnishes the unstable enamine XXXIV which finally, in an acid medium, cyclizes to XXXI (21, 22). 

In contrast to the quinoline and isoquinoline series, thienopyridines are apparently resistant to reduction by tin-hydrochloric acid, since the parent systems can be obtained by reductive dehalogenation or chloro-derivatives. Quaternary salts are reduced to the JV-alkyl-4,5,6,7-tetra-hydrothienopyridine by sodium borohydride,45,48,89-91 and the azo-methine bond in dihydro derivatives (e.g. 69) is reduced by lithium aluminum hydride.47... 

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]. 

A variation of the synthesis of racemic codamine described by Burger 126) has been developed by Billek 127) who transformed the dihydro-isoquinoline (LXX[ into A -norcodamine (LXXI[ (mp 88°-90°[. The nor base was forraylated and the formyl derivative (LXXII[, on reduction with lithium aluminum hydride, gave codamine as an oil. 

The synthesis of 8-aza-D-homoestrogens has also been carried out from compound (432) (Scheme 42) [551, 552]. Compound (432) was converted via (435) in four stages into the isoquinoline derivative (438). The action of thionyl chloride led to the chloride (439), which, on reaction with 2,4-dim ethoxy-.1,4-cyclohexadiene, gave the tricyclic compound (440). Acid hydrolysis of this compound was accompanied by cyclization to the D-homo derivative (443). Reduction of the latter with lithium aluminum hydride gave a mixture of equal amounts of the cis-C/D ketone (441) and the trans-C/D ketone (442) the first was isomerized into the second on treatment with sodium methoxide. The configuration of compounds (441)-(443) at Cg has remained undetermined. 

---