1,2-dihydroisoquinoline derivative

Isoquinolinium salts are reduced to 2-alkyl-1,2-dihydroisoquinoline derivatives by sodium dithionite,6 lithium aluminum hydride7,8 (LAH), or dialkyl aluminum hydrides.9 LAH is preferred7 to dithionite since it leads to purer products, and will reduce those salts that are inert to dithionite (e.g., papaverine methiodide). Isoquinoline itself10,11 and 3-methyl-6,7-methylenedioxyisoquinolinelz (5) can be reduced to the 1,2-dihydroisoquinoline with LAH, as can isoquinoline... 

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 an additional report, Shaabani el al. described a novel environmentally friendly three-component reaction of isoquinoline and isocyanides in the presence of activated CH-acids in water to provide 1,2-dihydroisoquinoline derivatives 145 <07TL4743>. The desired products were synthesized in good to high yields without the need for a catalyst. 

The shortest synthesis of papaverine was achieved in the laboratory of R. Hirsenkom starting from racemic stilbene oxide and using a modified Pomeranz-Fritsch reaction The aminolysis of the stilbene oxide led to the formation of the cyclization precursor, which upon treatment with excess benzoyl chloride, underwent cyclization to give the N-benzoyl 1,2-dihydroisoquinoline derivative. Reduction under Wolff-Kishner conditions afforded papaverine. 

B. Pavine Alkaloids.—Eschscholtzine (70 R = Me) has been isolated from Eschscholtzia californica.89a The structure of ( )-bis-norargemonine (70 R = H) has been confirmed by synthesis.90 The key intermediate (69), prepared by two unexceptional methods, was converted into (70 R = H) in three steps. Interestingly, 1,2-dihydroisoquinoline derivatives do not give this type of product but rather undergo a variety of other reactions if excess acid is avoided [see reactions of compound (58)]. 

Nitrogen heterocycles can also b e prepared by silver(I)-catalyzed cyclization reaction. Asao, Yamamoto, and their colleagues have shown synthesis of 1,2-dihydro-isoquinoline derivatives by addition of pronucleophiles to ortho-alkynylaryl ald-imines employing AgOTf as a catalyst [29]. For example, treatment of imine (19) with 2 equiv of nitromethane (20) in the presence of 3 mol% of the catalyst at 80 °C, 1,2-dihydroisoquinoline derivative (21) is produced in 85% yield (Scheme 18.7). Terminal alkynes and carbonyl compounds possessing activated methylene groups are also usable as the pronucleophiles [29]. 2-Alkoxyazetidines are efficiently synthesized by Ag(fod)-catalyzed [2-F2] cycloadditions of imines to (alkoxymethylene)... 

In 2007, Ding and Wn reported a cascade reaction combining enamine and Ag catalysis for the synthesis of 1,2-dihydroisoquinoline derivatives [42]. Initially, the nncleophilic enamine derived from the ketone and proUne attacked the imine that arose from the aldehyde and the amine, forming the Mannich base 140, which then participated in a hydroamination reaction toward pendant alkyne to build the final prodnct (Scheme 9.46). 

An example of a cascade reaction combining enamine and silver catalysis for synthesis of 1,2-dihydroisoquinoline derivatives is shown in Fig. 8.26. In the first step, nucleophilic enamine formed from the ketone and proline reacts with the imine, which is generated from the aldehyde and the amine. As a result, the Mannich base is formed, which then undergoes a hydroamination reaction in the presence of silver catalyst. 

Leptopinine 82 possesses the 3,4-dihydro-isoquinolin-7-ol moiety without further conjugation and was isolated as yellow powder from Hypecoum leptocarpum after several extractions with hydrochloric acid so that this alkaloid was finally isolated as a chloride (Scheme 29). The formation of a mesomeric betaine from this dihydroisoquinoline derivative is unlikely because on addition of base no significant changes of the UV spectra were observed (99P339). A similar structure is Pycnarrhine Pycnarrhena longifolia), which was isolated as a hydroxide (81P323). 

Scheme 5.44 Ring closure reaction of dihydroisoquinoline derivative catalysed by a NHC-Pd system...

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ 1126 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

Eventually, the same method was applied to the dihydroisoquinoline derivative 135 g, and the hexahydropyrroloisoquinoline 141 was isolated in 78% yield (with a 1.8 1 ratio of cis- and frans-diastereomers) (Scheme 45) [60b]. 

This reagent has been used to reduce several 3,4-dihydroisoquinoline derivatives to optically active alkaloids in 60-85% ee. 

This powerful quaternization method enabled the catalytic asymmetric synthesis of quaternary isoquinoline derivatives with 42 (R1 = Me) as a substrate. When 42 (R1 = Me) was treated with a,a -dibromo-o-xylene, CsOHH20 and (S,S)-le (1 mol%) in toluene at 0 °C, the transient monoalkylation product was rapidly produced, and subsequently transformed into the desired 44 (64%, 88% ee) during the work-up procedure. Catalytic asymmetric alkylation of 42 (R1 = Me) with functionalized benzyl bromide 45, followed by the sequential treatment with 1 M HC1 and then excess NaHC03, furnished the corresponding dihydroisoquinoline derivative 46 in 87% with 94% ee (Scheme 5.23) [25]. 

Photo-NOCAS reactions of p-dicyanobenzene with 2-methylpropene in acetonitrile afforded novel 3,4-dihydroisoquinoline derivatives, as shown in Scheme 132 [482], This photoreaction is initiated by a single electron transfer from olefin to p-dicyanobenzene. Acetonitrile as a nucleophile combined with the alkene radical cation and the resulting radical cation adds to the radical anion of 1,4-di-cyanobenzene. Cyclization to the ortho position of phenyl group followed by loss... 

Agbalyan et al 9 recently employed this reaction in the synthesis of several 3,4-dihydroisoquinoline derivatives with unsaturated substituents in the 1-position. The Madrid group50 has shown that (with the exception of benzyl thiocyanate) aliphatic and aromatic thiocyanates yield 1-alkylthio- and l-arvlthio-3,4-dihydroisoquinolines as expected (cf. Table V). 

Reported Yields (%) of 3,4-Dihydroisoquinoline Derivatives Obtained from jS-Halogenoalkylbenzenes and Tin Tetrachloride-Nitrile Complexes... 

A total synthesis of a mixture of diastereoisomers having the constitution of magnolamine was reported recently by Kametani and Yagi 26). Arndt-Eistert reaction of 3-methoxy-4-benzyloxyphenethylamine with the diazoketone prepared from the acid chloride XLVII furnished the diamide LI. Bischler-Napieralski cyclization of the latter afforded the dihydroisoquinoline derivative XLIX, whose methiodide was reduced with sodium borohydride to the stereoisomers of constitution XLV. Debenzylation of the latter mixture gave a noncrystalline product which behaved similarly on paper chromatography to magnolamine and had IR- and UV-spectra which were superimposable on those of the alkaloid. 

A synthetic route to ( )-0,f>-dimethyltubocurarine iodide (CXXV), via the racemate of 0,0-dimethylbebeerine (CXXIII), was announced in 1959 by Tolkachev and his collaborators (94). It started by the condensation of 3-methoxy-4-hydroxyphenethylamine with 4-benzyloxy-phenylacetic acid to give the amide CXXVI. Reaction of the potassium salt of the latter with the methyl ester of 3-bromo-4-methoxyphenyl-acetic acid in the presence of copper powder gave compound CXXVII. This on condensation with 3-methoxy-4-hydroxy-5-bromophenethyl-amine afforded compound CXXVIII, which was methylated to CXXIX. The latter compound was cyclized with phosphorous oxychloride to the dihydroisoquinoline derivative CXXX. Debenzylation of CXXX followed by intramolecular Ullmann condensation yielded compound CXXXI. The latter was converted to racemic dimethylbebeerine (CXXIII) by reduction with zinc dust in acetic acid followed by methyla-tion. Finally, treatment of ( + )-CXXIII with methyl iodide furnished the dimethyl ether of ( + )-tubocurarine iodide, identified by comparison of its UV-spectrum with that of the dimethyl ether of natural tubo-curarine iodide and by melting-point determination of a mixture of the two specimens. 

The dihydroisoquinoline derivative 11, which was formed as an intermediate upon reaction of benzophenone imine (9) with methyl 2-chloro-2-cyclopropylideneacetate (10) in carbon tetrachloride, can be regarded as an acceptor-substituted spirocyclopropane derivative. Under the conditions of its formation, it rearranges with attack of chloride ion on the spirocyclopropane group to give the ) -chloroethyl-substituted isoquinoline derivative 12. ... 

Napieralski cyclization of (79) in the presence of the very effective reagent polyphosphate ester, to yield the dihydroisoquinoline derivative (80). Two successive oxidation stages led to the fully aromatic system (81) which, upon reduction and Pschorr cyclization, gave cassameridine (82).112... 

A shorter and neater synthesis of (+ )-dihydrogambirtannine involved the multiple-phase reduction of the isoquinolinium salt 78 with sodium borohydride in a methanol-ether—water system in the presence of a high concentration of cyanide ion. The intermediate, presumably the cyanide (79) formed by trapping of the initially generated dihydroisoquinoline derivative by nucleophilic cyanide ion, was not isolated but was converted directly into ( )-dihydrogambirtannine (67) by heating in dilute hydrochloric acid. Dehydrogenation of the stable hydrochloride of 67 by means of iodine and sodium acetate afforded an improved route... 

Azomethane imines undergo an analogous photoinduced cyclization to give diaziridines. The dihydroisoquinoline derivative (99), for example, is converted on irradiation in cyclohexane or benzene into the diaziridine (100) the transformation is thermally reversible. In contrast, the pyrazolidinone azomethine imines (101) undergo photoreversible conversion into the diaziridines (102), providing in this way a useful reversible photochromic system. The analogous photoisomerization of a pyrene-substituted pyrazolidinone azomethinimine has... 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

DL-Dimethylcoclaurine was synthesized by the Bischler-Napieralski method starting with homoveratrylamine and p-methox3q)henylacetyl chloride. The 3,4-dihydroisoquinoline derivative first obtained was hydrogenated in the presence of palladium. The necessary comparison with material from the optically active alkaloid was achieved by subjecting the synthetic dimethylcoclaurine to exhaustive methylation, which robs Ci of the tetrahydroisoquinoline system of its asymmetric character. The meth-... 

Asymmetric reduction of prochiral imines, ketoximes, and several dihydroisoquinoline derivatives was successfully performed with chiral rhodium and ruthenium catalysts (Table 7). 

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