A New Approach to Prepare 2-Acetyl-Mono (5,6,7,8)-Nitro-1,2,3,4-Tetrahydroisoquinolines

N-Acetyl-p, m or o-nitro-phenylethylamines and (HCHO)n were treated in 60% H2SO4/HOAc, via α-amidoalkylation to give 2-acetyl-mono(5, 6, 7 or 8)-nitro-1,2,3,4-tetrahydro-isoquinolines.Additionally, some interesting phenomena were observed when the comparison between 2-acetyl-5, 6, 7 or 8-nitro-1,2,3,4-tetrahydroisoquinolines and 2-alkylsulfonyl-5 , 6 or 7- nitro-1,2,3,4-tetrahydroisoquinolines was made.     

Synthesis of 5-amino-6-nitro-1,2,3,4-tetrazine 1,3-dioxide

5-Amino-(tert-butyl-NNO-azoxy)-1,2,3,4-tetrazine 1,3-dioxide reacts with nitronium tetra-fluoroborate to give 5-amino-6-nitro-1,2,3,4-tetrazine 1,3-dioxide. This compound is of interest as a new energetic material. A plausible reaction mechanism involves electrophilic substitution of the tert-butyl-NNO-azoxy group by the nitro group.

     

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 .     

Synthese einiger 8-substituierter 2-Methyl-1,2,3,4-tetrahydroisochinoline

Synthesis of Some 8-Substituted 2-Methyl-1,2,3,4-tetrahydroisoquinolines A general route to 8-substituted tetrahydroisoquinolines is exemplified by the preparation of the 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol ( 11 ), the -8-carbaldehyde oxime ( 12 ) and the -8-carbonitrile ( 13 ). It involves the conversion of isoquinoline ( 1 ) by partially modified Steps 1, 2, 3, and 5 (see the Scheme) into the 5-bromo-8-nitro derivative 5 , reduction of the latter to the 8-amino derivative 8 and replacement of the NH₂-group with an appropriate substituent by a Sandmeyer-like reaction. The selective reductions of the N-containing ring in 6 (Steps 5, 6, and 8) and of the NO₂-group in 5 (Steps 4 and 7) were also studied.     

Synthesis of enantiomers of 6-nitro- and 6-amino-2-methyl-1,2,3,4-tetrahydroquinolines

Enantiomers of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline have been obtained by kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline in acylation with acyl chlorides of N-protected amino acids followed by regioselective nitration of the diastereoisomeric amides and acidic hydrolysis. The introduction of a trifluoroacetyl protecting group into the position 1 of the enantio pure nitro compound followed by the reduction led to (S)-6-amino-2-methyl-1-trifluoroacetyl-1,2,3,4-tetra-hydroquinoline in a high yield.     

PREPARATION OF 1,7-DISUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES

ABSTRACT

A simple procedure for the preparation of 1,7-disubstituted-1,2,3,4-tetrahydroisoquinolines from 3,4-dihydroisoquinoline (2) is presented. This strategy overcomes the limitation of cyclisation approaches which generally require electron rich ring systems. A variety of 1-substituents has been incorporated using the appropriate organometallic or activated methylene nucleophile to prepare both electron rich (7a–f) and electron deficient 1,7-disubstituted-1,2,3,4-tetrahydroisoquinolines (16, 17).     

Alkylation of N-boc-1,2,3,4-tetrahydroisoquinolines in the 1-position and its application to the synthesis of isoquinoline alkaloids

Boc-protected 1,2,3,4-tetrahydroisoquinolines 2 can be lithiated with t-butyllithium in the presence of N,N,N',N',-tetramethylethylenediamine. Reaction of the anion with alkyl halides provides 1-alkyl N-Boc-1,2,3,4-tetrahydroisoquinolines in 67–71% yield. The protecting group is easily removed in high yield with trifluoroacetic acid. The alkaloids salsolidine ( 8 ) and laudanosine ( 11 ) were synthesized in racemic form using this method.     

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).     

1-Phenyl-6,7-disubstituted-aminopropyl)-1,2,3,4-tetrahydroisoquinolines as possible antituberculer agents

The Condensation of 3,4-disubstituted phenylethylamine and benzaldehyde furnished l-phenyl-6,7-disubstituted-1,2,3,4-tetrahydroisoquinolines l. which on reaction with 1,3-dibromopropane gave l-phenyl-6,7-disubstituted-2-(3-bromoprophyl)-1,2,3,4-tetrahydroisoquinolines 2. The reaction of 2 with different secondary amines resulted in the synthesis of 3. The compounds 3 were screened for their in vitro antituberculer activity against Mycobacterium smegmatis, and some of them have been found to be total inhibitors of M. Smegmatis     

Conformational analysis of 1,2,3,4-tetrahydroisoquinolines

Ring and nitrogen inversion account for the conformational equilibria of 3-phenyl-1, 2,3, 4-tetrahydroiso-quinolines. In order to quantitate the relative contribution of each conformer to the equilibrium, we undertook a molecular mechanics study on several substituted 3-phenyl-1, 2, 3, 4-tetrahydroisoquinolines. Predictions from calculations were checked against cmr chemical shift data. No boat conformation contributed significantly to the equilibrium. A general result of our calculations is that in all cases the 3-phenyl group in the equatorial position is strongly favored (by at least 2.50 kcal/mole). For 3-phenyl-1, 2, 3, 4-tetrahydroisoquinolines without substitution at nitrogen, N-H in equatorial position is preferred over the axial conformer, although the energy difference between both is always small (0.30–1.10 kcal/mole). For the cis-1,3-disubstituted compounds the le'3e conformers are the only species present (at least 99.8%). The calculated energy differences between the la′3a conformer and the le′3e conformer are always large (3.80–6.10 kcal/mole for the NHe conformers and 3.60–3.80 kcal/mole for the NHa conformers). The lack of a γ_1a upfield shift at C3 also points to the preference for the pseudoequatorial-equatorial conformer. For N-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline a preference for the NMe group in the equatorial position is predicted (0.60–2.00 kcal/mole). The small downfield shift at C4 (γ_Na = 0.5 ppm) is consistent with the equatorial NMe preference. For the cis-1,2,3-trisubstituted compounds no significant γ_1a effect at C3 (γ_1a = -0.2 and 1.0 ppm) or γ_Na effect at C4 (γ_Na = 0.1 and 0.4 ppm) is observed. For these compounds, deformations due to steric congestion are evidenced by the deviation from the values of the C4a-C8a-Cl-N and C4a-C4-C3-N torsional angles, as compared to less crowded 3-phenyl-1,2,3,4-tetrahydroisoquinolines. Here the heterocyclic ring adopts a distorted half-chair conformation.     

Beiträge zur Chemie des Phosphors. 66. Kristall- und Molekülstrukturen von 1,2,3,4-Tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphan, (PC6H5)4CH2, und 1,4-Dithio-1,2,3,4-tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphan, (PC6H5)4CH2S2

Contributions to the Chemistry of Phosphorus. 66. Crystal and Molecular Structure of 1,2,3,4-Tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphane, (PC₆H₅)₄CH₂, and 1,4-Dithio-1,2,3,4-tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphane, (PC₆H₅)₄CH₂S₂ The following results were achieved by X-ray structure analyses of 1,2,3,4-Tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphane 1 and 1,4-Dithio-1,2,3,4-tetraphenyl-cyclo-5-carba-1,2,3,4-tetraphosphane 2 :

• crystallises in the monoclinic space group Cc with a = 22.272, b = 13.726, c = 7.492 Å, β = 96.82° and Z = 4. The P₄C-ring has an envelope conformation. The phenyl groups are arranged alternately on both sides of the ring.
• forms triclinic crystals, space group P1 , with a = 10.900, b = 10.663, c = 12.233 Å, α = 106.26, β = 100.04, γ = 70.65°, Z = 2. The P₄C-ring has twist conformation, the carbon atom lies almost in the mean plane of the ring. The sulfur atoms are bonded in exo position to the phosphorus atoms neighbouring the carbon atom and in trans position to each other.

     

Synthesis and some conversions of 6-methyl- and 1,6-dimethyl-5-nitro-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidines

Using a modification of the Biginelli reaction, we have synthesized 6-methyl- and 1,6-dimethyl-5-nitro-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidines. We have studied some of their chemical conversions involving the methyl group on the C₍₆₎ atom, the nitrogen atoms of the pyrimidine ring, and the phenyl substituent.Translated from Khimiya Geterosiklicheskikh Soedinenii, No. 3, pp. 388–392, March, 1993.     

The Benzoylation of 6-Methyluracil and 5-Nitro-6-methyluracil

6-Methyluracil and 5-nitro-6-methyluracil react with variable molar quantities of benzoyl chloride in acetonitrile-pyridine at room temperature to give I-N, 3-N-dibenzoyl-6-methyluracil 3b and l-N-benzoyl-5-nitro-6-methyluracil 4b. The reactive rates of debenzoylation of 3b and 4b were investigated.     

Mannich and eschweiler-clarke reaction of 1-benzyl-1,2,3,4-tetrahydroisoquinolines. Studies on the syntheses of heterocyclic compounds. Part CCCXVIII

Modified Mannich reactions of a number of 1-benzyl-1,2,3,4-tetrahydroisoquinolines (Ia-Ie) were attempted to afford the corresponding protoberberine derivatives (IIa-IIe) in good yield. Treatment of both If and Ig with formalin under a variety of Mannich or Eschweiler-Clarke conditions did not give the expected protoberberine derivatives IIf and IIg, but afforded the N-methyl derivatives (VIIa) and (VIIb), respectively.     

3-芳基-1,2,3,4-噁三唑-5-亚胺与阿司匹林偶联物的合成和抗血栓活性研究

取代苯胺经重氮化、还原得苯肼盐酸盐, 与硫氰酸钾作用得苯基取代的氨基硫脲, 再在亚硝酸异戊酯、盐酸的作用下环合、成盐, 加碱中和后生成3-芳基-1,2,3,4-噁三唑-5-亚胺, 最后与乙酰水杨酰氯反应得目标物6a～6l, 其结构经MS, IR, ¹H NMR和元素分析确证. 体外血小板聚集试验和小鼠肺血栓生成试验结果表明, 部分目标物在体内、外均显示出较好的抗血栓活性, 值得深入进行研究.     

The dramatic effect of thiophenol on the reaction pathway of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with thiophenolates: ring expansion versus nucleophilic substitution

Ethyl 4-methyl-2-oxo-7-phenylthio-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylate and/or ethyl 6-methyl-2-oxo-4-(phenylthiomethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained in the reaction of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with PhSNa or PhSK with or without PhSH, depending on the reagent ratio, reaction time, or temperature, as a result of ring expansion and/or nucleophilic substitution. The reaction pathway was affected strongly by the basicity-nucleophilicity of the reaction media. The results obtained were confirmed by reactions of 4-mesyloxymethyl-6-methyl-5-tosyltetrahydropyrimidin-2-one with PhSNa/PhSH and ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with NaCN/HCN or NaCH(COOEt)₂/CH₂(COOEt)₂.     

Preparation and reactions of some 1,2,3,4-Tetrahydro-2,3-disubstituted 7(or 8)hydroxy-1,4-dioxopyrazino[1,2-a] indoles

1,2,3,4-Tetrahydro-2,3-disubstituted 7(or 8) hydroxy-1,4-dioxopyrazino[1,2-a]indoles have been prepared by the condensation of 6(or 5)benzyloxyindole-2-carbonyl chloride with d1-N- alkylamino acid ethyl esters in the presence of triethyl amine followed by the hydrogenolysis over palladium-carbon. Methylation and alkaline hydrolysis of 1,2,3,4-tetrahydro-2-benzy1-1,4-dioxopyrazino[1,2-a]indole are discussed.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

3-Nitro-1,2,4-triazol-5-one derivatives

3-Nitro-1,2,4-triazol-5-one and its monomethyl derivatives react with methyl vinyl ketone to give products of addition to the ring N₁ and N₄ atoms. The reaction with formaldehyde and N-methylolacetamide proceeds only at the N₁ atom. The keto derivatives of 3-nitro-1,2,4-triazol-5-one undergo the Schmidt reaction to give the corresponding acetamides. A number of compounds that include functional groups in the N₁-alkyl substituent of the 3-nitro ring were obtained by treatment of the bases of N₁-substituted 3,5-dinitro-1,2,4-triazoles in aprotic media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552–558, April, 1981.     

5-Substituted 3-Nitro-1-vinyl-1,2,4-triazoles

A series of 5-substituted 3-nitro-1-vinyl-1,2,4-triazoles were synthesized by alkaline treatment of the corresponding 1-(2-haloethyl- or 2-nitroxyethyl)-3-nitro-1,2,4-triazoles and by transvinylation of NH acids of the same series with vinyl acetate. The scope of applicability of the transvinylation procedure was established with respect to the azole pK _a value. The vinylic double bond on the nitrogen was shown to be inactive toward both nucleophilic and electrophilic reagents, whereas the halogen atom in position 5 exhibits enhanced reactivity. The latter factor provides the possibility for versatile structural modification via nucleophilic replacement of the 5-halogen atom by various groups, including triazolate ion.