Hydrosulfite reduction of N-nitroso-1,2,3,4-etrahydroisoquinolines and oxidation of N-amino-l,2,3,4 tetrahydroisoquinolines

The sodium hydrosulfite reduction of N-nitroso-1,2,3,4-tetrahydroisoquinoline ( 5 ) does not result in the loss of nitrogen and leads to the corresponding hydrazine 6 which upon oxidation with mercuric oxide in ethanol at 62° gives the hexahydrotetrazine 7 in 39% yield. Treatment of the N-tosyl derivative of 6 with base affords 7 in nearly quanitative yield. Oxidation of 6 in 1-butanol at 95° results in the formation of a complex product mixture from which only one component, 1,1′-azobis-3,4-dihydroisoquinoline ( 8 ) could be isolated. Surprisingly the sodium hydrosulfite reduction of 2-nitroso-3-phenyl-1,2,3,4-tetrahydroisoquinoline ( 15 ) also failed to proceed with loss of nitrogen and yields the corresponding hydrazine 16 . However, 16 was cleanly oxidized by mercuric oxide in ethanol at 62° with concurrent elimination of nitrogen to afford 2-phenylindane in 75% yield. Possible rationalizations for these results are presented.     

Studies on the syntheses of heterocyclic compounds—DXCI : Total synthesis of (±)-cherylline and corgoine through quinonoid intermediates

Acid catalysed cyclisation of N - (4′ - benzyloxy - β - methoxyphenethyl) - 3 - benzyloxy - 4 - methoxy - N-methylbenzylamine (18) gave (±)-cherylline (1), one of the Amaryllidaceae alkaloids. Fusion of 4-hydroxybenzyl alcohol (22) with 1,2,3,4-tetrahydroisoquinoline (24) also gave corgoine (5).     

Photochemical synthesis of 1,2,3,4-tetrahydroisoquinolin-3-ones from N-chloroacetylbenzylamines

When N-chloroacetyl-3-hydroxybenzylamine (37) in aqueous acetonitrile was irradiated, both ortho and para photocyclizations with reference to the OH group occurred to give 7- and 5-hydroxy-3-oxo-1,2,3,4-tetrahydroisoquinolines (52,53). Similarly, 1-methylisoquinoline derivatives (54,55) were synthesized. N-Chloroacetyl-3,5-dihydroxybenzylamine (39) gave a single photoproduct, 5,7-dihydroxy-3-oxo-1,2,3,4-tetrahydroisoquinoline (56). These photocyclizations were smoothly extended to the synthesis of 1-benzyl, 1-(4′-methoxybenzyl)- and 1-(3′,4′,5′-trimethoxybenzyl)-isoquinoline derivatives (58～64).     

Studies on Debenzylation and Photolysis of 1-Benzyl- and 1-(β-Phenethyl)-1,2,3,4-tetrahydroisoquinolines

Debenzylation of 1-(3-benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinolines 1 , 6 , 7 with hydrochloric acid and ethanol gave the corresponding phenolic isoquinolines 2 , 8 , 9 and tetrahydroprotoberberines 4 , 12 , 13 . Compounds 2 , 8 , 9 on photolysis also gave, besides the expected noraporphines 3 , 10 , 11 , the tetrahydroprotoberberines 4 , 12 , 13 [1–4] (Schemes 1 and 2). 6-Benzyloxy-1-(5-benzyloxy-2-bromo-benzyl)-1,2,3,4-tetrahydroisoquinoline (27a) containing no methoxy or methylenedioxy groups either in ring A or C does not give protoberberine during debenzylation; but 28 , the debenzylation product of 27a , on photolysis gives both the noraporphine 29 and the tetrahydroprotoberberine 30 (Scheme 6), proving that during debenzylation of 1-(3-benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinolines containing additional methoxy or methylenedioxy groups, the necessary formaldehyde comes from the latter groups. During photolysis both the methoxy groups (methylenedioxy groups) and the C(3) atom of the tetrahydroisoquinoline moiety provide the formaldehyde. Veratrole under debenzylation and photolytic conditions and tetrahydroisoquinoline under the latter condition also give rise to formaldehyde (Schemes 8 and 10). The novel bromohomoprotoberberine 43 along with 42 was formed during debenzylation of the 1-phenethyl-1,2,3,4-tetrahydroisoquinoline 41 . Photolysis of 42 yielded the novel nor-homoaporphine 44 , in addition to 43 ; the latter was debrominated to give the homoberbine 45 .     

Eine neue Synthese von 8-Hydroxy-2-methyl-1,2,3,4-tetrahydroisochinolin

A new Synthesis of 8-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline Vilsmeier formylation of N-[2-(3,5-dimethoxyphenyl)ethyl]-trifluoroacetamide ( 5 ) yielded the aldehyde 6 , which under mild basic conditions was hydrolyzed to 7 and cyclized to 6,8-dimethoxy-3,4-dihydroisoquinoline ( 3 ). Methylation of 3 and reduction of the double bond in 10 afforded 6,8-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline ( 11 ). The methoxyl group at C(6) was selectively demethylated and the free hydroxyl group in 12 was phosphorylated to give 13 . Reduction of the latter with potassium in liquid ammonia yielded 8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline ( 2 ), which was demethylated to the title compound 1 .     

Synthesis of bridged azabicycles from isoquinolines via a tandem of allylboration and intramolecular metathesis

A method for the synthesis of bridged azabicyclic compounds from isoquinolines was developed. The method is based on a combination of allylboration and ruthenium-catalyzed intramolecular metathesis. Reductive 1,3-diallylation of bromoisoquinolines with triallylborane gave trans-1,3-diallyl-1,2,3,4-tetrahydroisoquinolines. When heated with triallylborane, these compounds yielded mixtures of cis-and trans-isomers in the ratio ∼1: 1. The structure of cis-1,3-diallyl-5-bromo-1,2,3,4-tetrahydroisoquinoline was confirmed by X-ray diffraction analysis. In a similar way, trans-3-allyl-1-vinyl-1,2,3,4-tetrahydroisoquinoline synthesized by sequential vinylation (with vinyllithium) and allylboration of isoquinoline, yielded a mixture of cis-and trans-isomers in the ratio 1.6: 1. Intramolecular metathesis reactions of N-Boc derivatives of cis-isomers in the presence of the Grubbs catalyst (2.0–2.5 mol.%) afforded 7,8-benzo-10-azabicyclo[4.3.1]dec-2-enes or 7,8-benzo-9-azabicyclo[3.3.1]non-2-ene in nearly quantitative yields. Dedicated to Academician V. A. Tartakovsky on the occasion of his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1510–1515, August, 2007.     

Mechanism of formation of doubly charged fragments from bis-benzyltetrahydroisoquinolines under electron impact

Some bis-benzyltetrahydroisoquinolines [α,α′-di-N,N-(1-benzyl-1,2,3,4-tetrahydroisoquinoline)-p-xylene and various substituted analogues] give rise to very abundant doubly charged fragment ions under electron impact, corresponding to the loss of the two benzyl groups. Substituent effects, ionization and appearance energy measurements and metastable transitions show that these doubly charged ions are formed (at least in part) from singly charged precursors by a heterolytic cleavage (charge separation).     

An effective method for the preparation of mono N-alkyl derivatives of 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline)

The condensation of 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) with alkyl, aralkyl and aryl aldehydes, but not ketones, in ethanol or chloroform provides useful cyclic aminal [8-substituted 5,6,10,11,15b,15c-hexahydro-2,3,13,14-tetramethoxy-8H-imidazo[5,1-a:4,3-a′]diisoquinoline] intermediates that when subsequently treated with sodium cyanoborohydride in ethanol, followed by the addition of 2 M hydrochloric acid, gave monosubstituted N-alkyl 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) derivatives in very high yields. The rates of the initial condensation with four different aldehydes were measured, and the entire sequence was successfully applied in one example to a ‘one-pot’ process; this signals a versatile route to differentially N-substituted 1,1′-bis(1,2,3,4-tetrahydroisoquinoline) derivatives.     

Nitrones-III: Reaction of 3,4-dihydroisoquinoline n-oxide with phosphonoylids

Reaction of 3,4-dihydroisoquinoline N-oxide 1 with diethyl cyanomethylphosphonate 2 gave the enaminonitrile 1-cyanomethylene-1,2,3,4-tetrahydroisoquinoline 3. Reaction of 1 with trialkyl phosphonoacetate 4 gave 5, the fused aziridine derivative 7 - exo - carbethoxy -1 - aza - 4,5 - benzo - bicyclo[4.1.0]heptene - 4, and the enaminoester 1-carbalkoxymethylene-1,2,3,4-tetrahydroisoquinoline 6. The ratio of 5:6 depends on the reaction conditions. While using 1,2-dimethoxyethane the aziridine 5 is the major product; using alcoholic solvents the yield of 6 increases at the expense of 5 with increasing acidity of the solvent.     

Die massenspektrometrische retro-Diels-Alder-Reaktion: 1, 2, 3, 4-Tetrahydroisochinolin und 1, 2, 3, 4-Tetrahydronaphthalin (Tetralin). 31. Mitteilung über massenspektrometrische Untersuchungen

The Mass Spectral retro-Diels-Alder-Reaction: 1,2,3,4-Tetrahydroisoquinoline and 1,2,3,4-Tetrahydronaphthaline (Tetraline) The retro-Diels-Alder reaction of 1,2,3,4-tetrahydroisoquinoline and of its N-acetyl derivative was confirmed on the basis of labelled derivatives (Scheme 2). Furthermore, the loss of ethylene was investigated with the 1,2,3,4-tetrahydronaphthalene- and 1,2,3,4-tetrahydronaphthalen-1-one-derivatives given in Schemes 4, 5 and 6. In the case of the 1,2,3,4-tetrahydronaphthalen-1-one-derivatives ethylene is lost via a retro-Diels-Alder reaction. The loss of ethylene from 1,2,3,4-tetrahydronaphthalene ( 1 ) and from its derivatives is a rather complex reaction (Scheme 8): 1/3 of ethylene is split off 1 ⁺ via a formal retro-Diels-Alder reaction, 2/3 are lost after a specific rearrangement. The ratio of these two fragmentation pathways depends very much on the substituents placed at the aliphatic and the aromatic rings, compare e.g. Table 4.     

Synthesis and Structure of Metal Complexes of 1-(1-R-3-Methylpyrazole-5-onilidene-4)-1,2,3,4-tetrahydroisoquinoline Derivatives

Twenty new complexes were synthesized by reacting Co(II), Cu(II), Zn, Cr(III), Fe(III), Cd and Ag salts with 3,3-dimethyl-1-(3-methylpyrazole-5-onilidene-4)-1,2,3,4-tetrahydroisoquinoline (L¹), spiro{cyclohexane-1,3"-[1-(1-phenyl-3-methylpyrazole-5-onilidene-4)-1,2,3,4-tetrahydroisoquinoline]} (L²), and 3,3-dimethyl-1-(1-phenyl-3-methylpyrazole-5-onilidene-4)-1,2,3,4-tetrahydroisoquinoline (L³). These compounds were studied by IR and electronic absorption spectroscopy. The type of coordination of their ligands was discussed on the basis of the results obtained and X-ray diffraction data for L³ and [CuL₂ ² Cl₂] · 2L² obtained previously.     

Benzoheterocycles via aryne C−C cyclisation: Initial approaches

The preparation of some benzo-4,5 and 6-membered mononitrogen heterocycles by cyclisation of an aryne with a side chain carbanion α to a cyanide group has been investigated: Thus 1-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline, (50%); 4-cyano-1-ethyl-1,2,3,4-tetrahydroquinoline, (11%) 2-methylisoindole, (89%) have been prepared. Attempts to prepare an N-acetyl indoline gave 2-methylbenzoxazole, and a benzazetine approach gave predominantly amination products.     

Synthesis of 3,3′-biisoxazoles from cyanogen N,N′-dioxide and trimethylsilyl enol ethers via the corresponding 5,5′-bis(trimethylsilyloxy)-3,3′-Δ2-biisoxazolines

Regioselective 1,3-dipolar cycloaddition of Cyanogen N,N′-dioxide ( 2 ) to trimethylsilyl enol ethers 3a-d, 6 and 7 gave the corresponding 5,5′-bis(trimethylsilyloxy)-3,3′-Δ²-biisoxazolines which upon short heating with 10% hydrochloric acid afforded 3,3′-biisoxazoles 5a-d , 8 and 9. Only the intermediate 5,5′-bis(trimethylsilyloxy)-derivative 4a was isolated and studied. Reaction of 2 with vinyl methyl ketone ( 10 ) gave biisoxazoline 11 which by oxidation with γ-manganese dioxide gave biisoxazole 12.     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Weinreb amide based synthetic equivalents for convenient access to 4-aryl-1,2,3,4-tetrahydroisoquinolines

New synthetic equivalents, N-methoxy-N-methyl-N′-phenylsulfonyl glycinamide and N-methoxy-N-methyl-N′-benzyl-N′-tert-butyloxy carbonyl glycinamide based on WA functionality were developed for the convenient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline framework. Two simple reactions, N-benzylation and addition of arylmagnesium halide on the WA functionality of the former afforded the key intermediate for convenient synthesis of N-phenylsulfonyl protected 4-aryl-1,2,3,4-tetrahydroisoquinoline, through reduction and acid promoted cyclization. With the latter, the addition of arylmagnesium halide on the WA functionality followed by the same protocol afforded the direct synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines in good yields. The acid promoted cyclization step enabled concomitant removal of N-Boc protection.     

Acetylenic chemistry: Part 15 [1]. Reactions of 1,2,3,4-Tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne

Reaction of 1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne gave 1-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4a ), 3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4b ), and 1,3-diprop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4c ). Subsequent boiling of 1,3-diprop-2′-ynylpyrido-[2,3-d]pyrimidine-2,4-dione ( 4c ) in formic acid afforded 1-methylimidazo[1,2-a]pyridyl-N-prop-2′-ynylamide ( 5 ) and 1-acetonyl-3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 6 ).     

Reactions of 6-hydrazino-, 6-hydroxylaminopurines and related derivatives

7H-Tetrazolo[5,1-i]purine was prepared by nitrosation of 6-hydrazinopurine and by reaction of 6-chloropurine with sodium azide; it was converted to adenine upon catalytic hydrogenation. 6-Hydroxylaminopurine was oxidized to 6-nitrosopurine with manganese dioxide, while alkaline treatment of the former gave 6,6′-azoxypurine. Nitrosation of 6-hydroxylaminopurine afforded 6-(N-nitroso)hydroxylaminopurine. Reaction of 6-chloropurine with 6-hydrazinopurine led to 6,6′-bisadenine; the corresponding ribosyl derivatives gave 6,6′-bisadenosine. Upon air oxidation, 6,6′-bisadenine was converted into 6,6′-azopurine. The related 6-thiosemicarbazino- and 6-(N-methyl)ureidopurine derivatives are also described. 6-N-(Nitroso)hydroxylaminopurine showed an inhibitory activity against several mouse tumors and leukemias.     

Reaction of N-[(α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide with alkyl isocyanates

Reaction of N-(α-acetoxy)4-pyridylmethyl]-3,5-dimethylbenzamide 3 with methyl and ethyl isocyanates afforded 1,3-dimethyl and 1,3-diethyl-4-(3,5-dimethylbenzoylamino)-2-oxoimidazolidine-5-spiro-4′-[1′,4′-dihydro-1′-acetyl]pyridine 6a,b , respectively. However, the reaction of 3 with isopropyl, t-butyl and phenyl isocyanates gave the corresponding N,N′-diurea and the dimerization compound 8 . The structure of 6a was confirmed by crystal X-ray diffraction analysis.     

Acid-Catalyzed [3,3]-Sigmatropic Rearrangements of N-Propargylanilines

The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)-, N-(1′-methylprop-2′-ynyl)-, and N-(1′-arylprop-2′-ynyl)-2,6-, 2,4,6-, 2,3,5,6-, and 2,3,4,5,6-substituted anilines in mixtures of 1N aqueous H₂SO₄ and ROH such as EtOH, PrOH, BuOH etc., or in CDCl₃ or CCl₄ in the presence of 4 to 9 mol-equiv. trifluoroacetic acid (TFA)has been investigated (cf. Scheme 12-25 and Tables 6 and 7). The rearrangement of N-(3′-X-1′,1′-dimethyl-prop-2′-ynyl)-2,6- and 2,4,6-trimethylanilines (X = Cl, Br, I) in CDCl₃/TFA occurs already at 20° with τ_1/2 of ca. 1 to 5 h to yield the corresponding 6-(1-X-3′-methylbuta-1,2′-dienyl)-2,6-dimethyl- or 2,4,6-trimethylcyclohexa-2,4-dien-1-iminium ions (cf. Scheme 13 and Footnotes 26 and 34) When the 4 position is not substituted, a consecutive [3,3]-sigmatropic rearrangement takes place to yield 2,6-dimethyl-4-(3′-X-1′,1′-dimethylprop-2′-ynyl)anilines (cf. Footnotes 26 and 34). A comparable behavior is exhibited by N-(3′-chloro-1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ( 45 ., cf. Table 7). The acid-catalyzed rearrangement of the anilines with a Cl substituent at C(3′) in 1N aqueous H₂SO₄/ROH at 85-95°, in addition, leads to the formation of 7-chlorotricyclo[3.2.1.0^2,7]oct-3-en-8-ones as the result of an intramolecular Diels-Alder reaction of the primarily formed iminium ions followed by hydrolysis of the iminium function (or vice versa; cf. Schemes 13,23, and 25 as well as Table 7). When there is no X substituent at C(1′) of the iminium-ion intermediate, a [1,2]-sigmatropic shift of the allenyl moiety at C(6) occurs in competition to the [3,3]-sigmatropic rearrangement to yield the corresponding 3-allenyl-substituted anilines (cf. Schemes 12,14–18, and 20 as well as Tables 6 and 7). The rearrangement of (?)?(S)-N-(1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 38 ; cf. Table 7) in a mixture of 1N H₂SO₄/PrOH at 86° leads to the formation of (?)-(R)-3-(3′-phenylpropa-1′,2′-dienyl)-2,6-dimethylaniline ((?)- 91 ), (+)-(E)- and (?)-(Z)-6-benzylidene-1,5-dimethyltricyclo[3.2.1.0^2′7]oct-3-en-8-one ((+)-(E)- and (?)-(Z)- 92 , respectively), and (?)-(S)-2,6-dimethyl-4-( 1′-phenylprop-2′-ynyl)aniline((?)- 93 ). Recovered starting material (10%) showed a loss of 18% of its original optical purity. On the other hand, (+)-(E)- and (?)-(Z)- 92 showed the same optical purity as (minus;)- 38 , as expected for intramolecular concerted processes. The CD of (+)-(E)- and (?)-(Z)- 92 clearly showed that their tricyclic skeletons possess enantiomorphic structures (cf. Fig. 1). Similar results were obtained from the acid-catalyzed rearrangement of (?)-(S)-N-(3′-chloro-1′phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 45 ; cf. Table 7). The recovered starting material exhibited in this case a loss of 48% of its original optical purity, showing that the Cl substituent favors the heterolytic cleavage of the N–C(1′) bond in (?)- 45. A still higher degree (78%) of loss of optical activity of the starting aniline was observed in the acid-catalyzed rearrangement of (?)-(S)-2,6-dimethyl-N-[1′-(p-tolyl)prop-2′-ynyl]aniline ((?)- 42 ; cf. Scheme 25). N-[1′-(p-anisyl)prop-2-ynyl]-2,4,6-trimethylaniline( 43 ; cf. Scheme 25) underwent no acid-catalyzed [3,3]-sigmatropic rearrangement at all. The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)aniline ( 25 ; cf. Scheme 10) in 1N H₂SO₄/BuOH at 100° led to no product formation due to the sensitivity of the expected product 53 against the reaction conditions. On the other hand, the acid-catalyzed rearrangement of the corresponding 3′-Cl derivative at 130° in aqueous H₂SO₄ in ethylene glycol led to the formation of 1,2,3,4-tetrahydro-2,2-dimethylquinolin-4-on ( 54 ; cf. Scheme 10), the hydrolysis product of the expected 4-chloro-1,2-dihydro-2,2-dimethylquinoline ( 56 ). Similarly, the acid-catalyzed rearrangement of N-(3′-bromo-1′-methylprop-2′-ynyl)-2,6-diisopropylaniline ( 37 ; cf. Scheme 21) yielded, by loss of one i-Pr group, 1,2,3,4-tetrahydro-8-isopropyl-2-methylquinolin-4-one ( 59 ).