1.2- Dihydroisoquinolines reduction

Various Reactions in the Side-Chains of Thiophens. - The preparation of various iV-substituted thieno[3,2-/]morphans from 2,5-dimethylthieno[3,2-/Jmorphan has been described. Several thiophen isosteres of proto-berberine alkaloids have been prepared, starting from amides between 3-thienylacetic acid and substituted )3-phenylethylamine or 3-(3-thienyl)ethyl-amine, followed by classical cyclization to dihydroisoquinolines, reduction to the tetrahydro system, and Mannich-type reaction with formaldehyde. 

Reductions of imines can also be carried out under aqueous conditions. The aqueous process appears to be readily applicable to dihydroisoquinoline reduction and also for dihydro-jS-carbolines (discussed in more detail later), but can be significantly enhanced by the addition of a silver salt and Ln(OTf)3 or a closely related salt (Sc, Y, Ce, Yb, Bi salts were tested), and thus applied to more challenging substrates than would otherwise be possible (Fig. 11) [38]. The use of a combined methanol/water solvent also provides some advantages in the most difficult cases. The acceleration of the reduction through an open-TS hydride... 

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... 

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... 

The cyclization reaction of some substituted 1,2-dihydroisoquinolines is of interest (255). The reduction of papaverine with tin and hydrochloric acid affords the 1,2-dihydro compound in the form of immonium salt 172, which then undergoes a cyclization reaction in the acidic medium to give compound 173, called pavine (257). 

A common modification of the Bischler-Napieralski reaction involves reduction of the dihydroisoquinoline product 2 to provide a tetrahydroisoquinoline derivative 19. A variety of different reducing agents have been employed, with NaBHi used with the greatest frequency. In many cases the reduction is carried out on the crude product of the Bischler-Napieralski reaction purification of the dihydroisoquinoline prior to reduction is usually not necessary. 

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

The Bischler-Napieralski reaction was employed by Bonjoch in the synthesis of melinonine-E and strychnoxanthine. The preparation of polycyclic compound 57 was achieved in 53% yield by treating 56 with POCI3 followed by reduction of the dihydroisoquinoline with NaBIii. 

Bischler-Napieralski reaction of 139 to a 3,4-dihydroisoquinoline, oxidation, dehydrogenation and reduction of the nitro to the amino function gave 140 which was subjected to a Pschorr reaction (Scheme 49). Quaternization was accomplished by methyl iodide to furnish the isoquinolininium salt 141 which underwent an ether cleavage on heating a solid sample or benzene or DMF solution to Corunnine (127) (73TL3617). 

The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

The synthetic process leading to pavine formation can now be illustrated as in Scheme 1. It includes quatemization and selective reduction of the iminium bond to afford a 1,2-dihydroisoquinoline (36), which is the key intermediate in the synthesis of pavine bases. Acid-catalyzed cyclization of this enamine furnishes the pavinane framework 38 via the 1,4-dihydroisoquinolinium ion 37. Langhals... 

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. 

Other synthetic routes to benzazepines involving ring expansion of six-membered heterocycles include the action of diazomethane (77CPB321), sulfonium ylides (77H(7)37> or acyl halides (75T1991) on quaternary 3,4-dihydroisoquinolines that of sulfoxonium ylides on quaternary quinolines (74IJC(B)1238) and the zinc-acetic acid reduction of quaternary 1-acyltetrahydroisoquinolines (77BSF893). Photoaddition of acyl- or aryl-nitrenes to the exocyclic alkene bond of 2-methylene-1,2-dihydroquinolines results in ring expansion to... 

A mixture of isomers was, however, obtained if the a,a -dibromoxylene was not symmetrical. This difficulty was overcome by using a reductive coupling of a substituted 3,4-dihydroisoquinoline (71) as its salt with an o-methoxycarbonyl-substituted benzyl bromide (73)129 [Eq. (60)]. 

The radical may attack either the anion-radical or isoquinoline in the latter case, a second electron is transferred from an A7. The reductive rert-butyl-ation of 3-methylisoquinoline gives mainly 162 and 163 together with small amounts of 4-, 5-, or 8-substituted dihydroisoquinolines. Imine 163 was oxidized to 164 during workup40 [Eq. (102)]. 

Reduction of dihydro compounds to the tetra- or hexa-hydro derivatives is usually possible. For example, dihydroisoquinolines of type (484) form the corresponding tetrahydroisoquinolines with H2/Pd or with Na/Hg-EtOH. 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

An alternative approach to synthesis of this ring system involves insertion of CO into the brominated secondary base (43), by treatment with carbon monoxide, lead tetra-acetate, and triphenylphosphine in tributylamine, the product being the amide (44), reduction of which affords the amine.81 Govadine (42 R1 = R4 = OMe, R2 = R5 = OH, R3 = H) has been synthesized by the conventional ring-closure, with formaldehyde, of the diphenolic base (45), or of its dibenzyl ether, in acid solution.82 Tetrahydroberberines, together with N-benzyltetrahydroisoquinolines, have also been obtained by the electrolytic reduction of 3,4-dihydroisoquinolines of structure (46).83... 

These structures were confirmed by syntheses. The amide 3 prepared from known compounds was reacted with phosphorus oxychloride in acetonitrile to generate a dihydroisoquinoline which on reduction, diazotization, and treatment with activated copper gave dihydro-imeluteine. Dehydrogenation to the natural alkaloid was effected by... 

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. 

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... 

The reduction of isoquinolinium salts to 1,2-dihydroisoquinolines was first reported by Schmid and Karrer78,79 and has been exploited many times.80-82 The novel and practical application of this inter-... 

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... 

Dihydroisoquinolines are easily reduced to 1,2,3,4-tetrahydro-isoquinoline derivatives catalytically,55 or by means of NaBH4 in the presence of a proton source. Gensler25 ascribes to Robinson and Shinoda79 a report that the reduction of 37a with stannous chloride gives 37b, but the reduction actually described79 is of 38 and is entirely unexceptional. 

A closely related reaction with berberines has been known80 for some time. Palmatine [(41) R = OMe] condenses with acetone to yield the 1,2-dihydroisoquinoline derivative [(55) R = OMe] which, with methyl iodide, followed by acid-catalyzed removal of the acetone residue, yields 56. Reduction then gives corydaline [(57) R = OMe]. Dihydroberberine (34) is alkylated by methanol in a similar reaction... 

In 1964 Grewe et al.bb reported that when a mixture of isoquinoline methiodide and benzaldehyde is hydrogenated in the presence of alkali, a 64% yield of 4-benzyl-2-methyl-1,2,3,4-tetrahydroiso-quinoline can be isolated. It was postulated that reduction of isoquinoline methiodide occurs to form the 1,2-dihydroisoquinoline, which then condenses with the benzaldehyde to form 81 and this is immediately further reduced. With isoquinoline itself and a variety... 

The tetrahydroisoquinolone (1), iV-methylcorydaldine, has been isolated from Papaver bracteatum,6 and it is apparently a true constituent, not an artefact. The (+)-(i )- and (-)-(5)-forms of salsolidine (2) have been prepared by the reduction with sodium borohydride of the dihydroisoquinolines [3 R = (+)-(i )-PhCHMe, (-MS)-PhCHMe, (—)-(S)-PhCHEt, or (-)-(S)-C10H7CHMe] (which were prepared in three steps from 3,4-dimethoxyphenylacetaldehyde and RNH2) followed by hydrogenolysis over 10% Pd(OH)2 on carbon.7... 

Chiral sodium acyloxy borohydride 554 prepared from NaBH4 and AyV-phthaloyl amino acid reduced cyclic imines in good enantioselectivity. Thiazazincolidine complex 555 was shown to be an excellent catalyst for the catalytic reduction of dihydroisoquinolines with BH3-THF (Equation (265)).1132-1134... 

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