Isoquinoline reductive alkylation

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... 

Isopulegol, 24 517-519, 526 Isoquinoline. See also Isoquinolines reduction of, 27 201 uses for, 27 206-208 Isoquinoline derivatives. See also Isoquinolines drugs, 27 207—208t synthesis of, 27 201-206 uses for, 27 206-208 Isoquinoline TV-oxide, 27 200-201 Isoquinolines, 27 182, 200-208 alkyl, 27 205... 

Scheme 7.2. Centres of attack during reductive alkylation of quinoline and isoquinoline...

The reductive alkylation with tertiary halides40 gives no N-alkylation and another product distribution, as discussed below for the alkylation of isoquinoline. 

Radical reductive alkylation of enamines has also been utilized for the intramolecular cyclization reaction34. Enamine 38 bearing an exo-olefin moiety, on treatment with Bu3SnH in the presence of a radical initiator, generates an aryl radical 39 which undergoes exclusive 1,6-cyclization to give the isoquinoline 40 as the sole product in 51.3% yield (equation 9). 

Isoquinoline (176), as in the case of quinoline, undergoes reductive alkylation with NBH in the presence of carboxylic acids, affording the amine 184. Sodium cyanoborohydride under these conditions gave the unalkylated product 177. Under similar conditions, but at lower temperature, 5-ni-troisoquinoline affords the tetrahydroisoquinoline. ... 

Reductive alkylation of 3-(2-nitro-l-hydroxyethyl)isoquinoline over Pd/ C in the presence of hydrogen and acetone afforded a mixture of 1,1-dimethyl-4-hydroxy-23,4,4a,5,10-hexahydro-l//-pyrimido[l,6-b]-h]isoquino-line and 3-[l-hydroxy-3-(N-isopropylamino)propyl]-l,2,3,4-tetrahydroiso-quinoline (72JMC49). 

The synthesis of hydrastine (61) by Falck and Manna demonstrate that the amide product of the Passerini reaction could be used in a subsequent Bischler-Napieralski reaction as a method to produce isoquinolines. In their report, carboxybenzaldehyde derivative 62 was condensed with isonitrile 63 in 71% yield to provide amide 64. Cyclization (POCI3/CH3CN), reduction of the dihydroisoquinoline (Adam s catalyst/H2), and reductive alkylation with formaldehyde gave a diastereomeric mixture of a- and p-hydrastines in 58% overall yield from Passerini product 64. 

Isoquinoline also forms Reissert compounds when treated with benzoyl chloride and alkyl cyanide (28), especially under phase-transfer conditions (29). The W-phenylsulfonyl Reissert has been converted to 1-cyanoisoquinoline with sodium borohydride under mild conditions (154). When the AJ-benzoyl-l-alkyl derivative is used, reductive fission occurs and the 1-alkyLisoquinoline is obtained. 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

The synthesis of compound 135 (Scheme 12) includes the production of isoquinoline 132 via a Bischler-Napieralski reaction, its reduction and alkylation on the nitrogen atom followed by cyclization of N-alkyl derivatives 134 in the presence of acids (83JHC1477 Scheme 36). 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

Another methods for the electrochemical formation of the active carbanion is the cathodic reduction of iminium salts. When an iminium salt is reduced in the presence of a suitable alkylating agent, an alkyl group is introduced to the carbon atom of the imine. Some isoquinoline and indole type alkaloids are synthesized by using this substitution method as exemplified bellow by the synthesis of laudanosine 51 37>. 

N-Alkyl derivatives were prepared from 7-phenyl-2,3,4,6,7,llh-hexahy-dro-l//-pyrazino[2,l-a]isoquinoline by acylation, followed by diborane reduction (84EUP107825,84JMC995). 

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. ... 

---