A series of three (E)-2-alkylidene-1,4-di-p-tosyl-1,2,3,4-tetrahydroquinoxaline compounds.

The three title quinoxaline derivatives, (E)-2-(4-methylbenzylidene)-1,4-di-p-tosyl-1,2,3,4-tetrahydroquinoxaline, C30H28N2O4S2, (II), (E)-2-(4-methoxybenzylidene)-1,4-di-p-tosyl-1,2,3,4-tetrahydroquinoxaline, C30H28N2O5S2, (III), and (E)-2-(3-chlorobenzylidene)-1,4-di-p-tosyl-1,2,3,4-tetrahydroquinoxaline, C29H25ClN2O4S2, (IV), were synthesized by palladium-catalyzed hetero-annulation. The E configuration of the exocyclic double bond in the three compounds has been established by the present X-ray study. The saturated part of the quinoxaline moiety in all three compounds assumes a distorted chair conformation. The numerical descriptors indicate a high degree of isostructurality between compounds (II) and (III), but no isostructurality with compound (IV).

Palladium-catalyzed heteroannulation leading to heterocyclic structures with two heteroatoms: a highly regio- and stereoselective synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines.

A highly convenient method has been developed for the synthesis of (Z)-4-alkyl-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzoxazines 9 and (Z)-3-alkyl(aryl)idene-4-tosyl-3,4-dihydro-2H-1,4-benzoxazines 34-38 through palladium-copper-catalyzed reactions. Aryl halides 7 reacted with 2-[N-alkyl(benzyl)-N-prop-2'-ynyl]aminophenyl tosylate 6 in the presence of (PPh3)2PdCl2 (3 mol %), CuI(5 mol %) in triethylamine at room temperature to yield 2-[N-alkyl(benzyl)-N-(3-aryl-prop-2'-ynyl)]-aminophenyl tosylates 8 in extremely good yields (72-96%). The latter could then be cyclized with KOH in ethanol-water to Z-9 in a highly regio- and stereoselective manner. Similarly, palladium-copper-catalyzed reaction of 2-(prop-2'-ynyloxy)aniline (21) with aryl iodides 7 led to 22-26 which after tosylation and cyclization with cuprous iodide in CH3CN in the presence of K2CO3 and Bu4-NBr led to the (Z)-3-alkyl(aryl)idene-4-tosyl 3,4-dihydro-2H-1,4-benzoxazines 34-38 in good overall yields. The Z-stereochemistry of the products was established from 1H NMR spectra, 3JCH values (between vinylic proton and methylenic carbon of the heterocyclic ring), NOE experiments, and X-ray analysis. The method was also found to be suitable for the synthesis of bis(benzoxazinylated) derivatives 17, 39, and 2-alkyl-3,4-dihydro-2H-1,4-benzoxazines 18. Our method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines is highly efficacious, using easily available starting materials under very mild conditions. Also the synthesis of some novel 5-substituted uracil derivatives 40 and 41 containing the benzoxazinyl moiety and of potential biological interest is being reported.

Palladium-copper catalyzed synthesis of benzofused heterocycles with two heteroatoms: novel and highly regio- and stereoselective syntheses of (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles and (E)-2-alkyl(aryl)idene-3,4-dihydro-2H-1,4-benzothiazines.

A highly novel, general, and convenient palladium and copper-catalyzed procedure has been developed for the synthesis of (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 28-40. 3-(2-Aminophenylthio)prop-1-yne 1 reacts with aryl iodides 2-14 under palladium-copper catalysis to yield the disubstituted alkynes 15-27 which after tosylation undergo a novel cyclization with CuI in the presence of triethylamine in THF to (E)-2-(2-arylvinyl)-3-tosyl-2,3-dihydro-1,3-benzothiazoles 28-40 rather than to the expected 3-alkylidene-4-tosyl-3,4-dihydro-2H-1,4-benzothiazines 41. The reaction is highly regio- and stereoselective. The synthesis of 2-(2-arylethyl)-3-tosylbenzothiazolines 42-47, 2-(2-arylvinyl)benzothiazoles 48-54, and a novel 5-substituted uracil derivative 55 of potential biological importance is also being reported. Similarly, the palladium-copper-catalyzed arylation of S-[2-(N-prop-2'-ynyl)aminophenyl]-N,N-dimethylthiocarbamate 58 with aryl iodides yields the disubstituted alkynes 59 which on cyclization with KOH in methanol leads to (E)-2-(2-aryl)methylidene-3,4-dihydro-2H-1,4-benzothiazines 61. The reaction of the diiodo compounds 12-14a, however, with 58 under palladium-copper-catalyzed reactions involves the participation of only one of the iodo groups in the heteroannulation process giving compounds 61i and 61j. These are amenable to further palladium-catalyzed reactions and afford polyunsaturated heteroaromatic compounds 62 and 63.

(Z)-7-Chloro-3-[(3-chlorophenyl)-methylidene]-4-p-tosyl-3,4-dihydro-2H-1,4-benzoxazine.

In the title compound, C22H17Cl2NO3S, the molecule is a substituted 3,4-dihydro-2H-1,4-benzoxazine compound which has three phenyl rings which are essentially planar. The 3,4-dihydro-2H-oxazine part of the molecule is fused to the benzo ring and has a half-boat conformation; the dihedral angle between the planar part of the oxazine ring and the benzo ring is 10.2 (2) degrees. The (3-chlorophenyl)methylidene substituent has a Z configuration in relation to the ring N atom of the oxazine moiety. Interestingly, the p-toluenesulfonyl (p-tosyl) substituent on the ring N atom protrudes away from the 3-chlorophenyl substituent thus avoiding any steric interaction.

(E)-2-[2-(1-Naphthyl)vinyl]-3-tosyl-2,3-dihydro-1,3-benzothiazole.

The title compound, C(26)H(21)NO(2)S(2), which consists of a benzothiazole skeleton with alpha-naphthylvinyl and tosyl groups at positions 2 and 3, respectively, was prepared by palladium-copper-catalyzed heteroannulation. The E configuration of the molecule about the vinyl C=C bond is established by the benzothiazole-naphthyl C-C-C-C torsion angle of 177.5 (4) degrees. The five-membered heterocyclic ring adopts an envelope conformation with the Csp(3) atom 0.380 (6) A from the C(2)NS plane. The two S-C [1.751 (4) and 1.838 (4) A] and two N-C [1.426 (5) and 1.482 (5) A] bond lengths in the thiazole ring differ significantly.

Palladium-catalyzed synthesis of [E]-6-(2-acylvinyl)uracils and [E]-6-(2-acylvinyl)-1-[(2-hydroxyethoxy)methyl]uracils--their antiviral and cytotoxic activities.

[E]-6-(2-Acylvinyl)uracils and their corresponding 1-(2-hydroxyethoxy)methyl derivatives were synthesized through palladium-catalyzed reactions which involved an interesting rearrangement. Some of the acylvinyl uracils (3, 4, and 5) and the acyclonucleosides (8 and 10) showed pronounced activity against human T-lymphocyte Molt 4/C8 and CEM cells. However, they were less toxic to murine L1210 and FM3A cells. The compounds did not have any marked antiviral activity.

Synthesis and biological activities of novel 5-(2-acylethynyl)uracils.

5-(2-Acylethynyl)-2,4-dimethoxypyrimidines (3-6) were synthesized in excellent yields from 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine (2) by treatment with acid chlorides in the presence of anhydrous aluminum chloride. Compounds 3-6 were deblocked with chlorotrimethylsilane and sodium iodide in acetonitrile to the corresponding 5-[(2-acyl-1-iodo)vinyl]uracils (7-10), which on treatment with potassium hydroxide in dioxane yielded the corresponding 5-(2-acylethynyl)uracils (11-14). The 5-(2-acylethynyl)uracils were found to be active against Ehrlich ascites carcinoma (EAC) cells in vivo, the most active compounds being 5-(2-benzoylethynyl)uracil (11) and 5-(2-p-toluoylethynyl)uracil (12). The T/C values of 281 and 300 were obtained for compounds 11 and 12, respectively, in the case of mice bearing EAC cells. The 5-(2-acylethynyl)uracils have also shown in vitro activity against CCRF-CEM and L1210/0 tumor cell lines. The lead compound 5-(2-p-toluoylethynyl)uracil effectively inhibited thymidylate synthetase.

N-Alkylated derivatives of 5-fluorouracil.

Some N-alkyl derivatives of 5-fluorouracil were designed to act as latent depot forms of 5-fluorouracil. A general and efficient method for the syntheses of the alkylated derivatives is described. As expected, the alkylated derivatives of 5-fluorouracil did not show any cytotoxicity in cell culture systems even up to 10(-4) M concentration. The synthesis of 1,3-dimethyl-5-fluoro-5,6-dihydrouracil is also described.

Interaction of 5-ethynyl-2'-deoxyuridylate with thymidylate synthetase.

The interaction of 5-ethynyl-2'-deoxyuridylate (5-ethynyl-dUMP; 1) with thymidylate (dTMP) synthetase has been investigated. The compound was an inhibitor of the enzyme, competitive with 2'-deoxyuridylate (dUMP) when the reaction was initiated by addition of enzyme (Ki = 2.7 X 10(-6) M). However, upon preincubation of 1 with dTMP synthetase, the inhibition pattern became noncompetitive. The time course of the enzyme reaction in the presence of 1 was nonlinear, indicating an increase in binding with time. Irreversible inactivation of the enzyme did not occur. The compound did not appear to become altered structurally as a result of interaction with the enzyme. A ternary complex was formed among dTMP synthetase, compound 1, and 5,10-methylenetetrahydrofolate, which was stable enough to survive Sephadex G-25 filtration but dissociated upon denaturation of the enzyme.

New cyclopenta[a]naphthalene derivatives. Synthesis of 2-(carbamylmethyl)-8-hydroxy-3H-cyclopental[a]naphthalene as a possible deoxyribonucleic acid binding agent.

8-Methoxy-1-oxo-2,3-dihydro-1H-cyclopenta]a]naphthalene (4) was converted to the oxalyl derivative (7) by treatment with diethyl oxalate in the presence of sodium ethoxide. Compound 7 in the form of the sodium salt was alkylated with ethyl bromoacetate in DMF to 2-(carbethoxymethyl)-8-methoxy-1-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalene (8). Treatment of 8 with methanolic ammonia yielded the corresponding amide (9). Dealkylation of 8 with 48% HBr and subsequent esterification gave compound 10. Ammonolysis of 10 led to the amide 11, which after reduction and subsequent dehydration of the reduced product afforded the desired compound, 2-(carbamylmethyl)-8-hydroxy-3H-cyclopenta[a]naphthalene (2). Compound 2 was found to be mildly growth inhibitory to L1210 and CCRF--CEM leukemic cells in culture. From thermal transition temperature studies, compound 2 was found to bind to calf thymus DNA and the poly(deoxyribonucleotides), e.g., poly(dG).poly(dC), poly(dG-dC), poly(dA).poly(dT), and poly(dA-dT).

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline.

By the use of space-filling models, a novel compound, 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3-(2H)-one was devised which would be expected to hydrogen bond specifically to GC pairs in the major groove of the double helix such that (i) the amino group of the cytosine molecule donates a hydrogen bond to the C-3 carbonyl of the isoquinoline moiety and (ii) the amide proton of the side chain donates a hydrogen bond to the N-7 of guanine. 3-Ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4) which constitutes the basic ring system of 1 was synthesized in a multistep procedure starting from m-methyl-N-acetylbenzylamine (5). Friedel-Crafts reaction of 5 led to 2,4-bis(chloromethyl)-5-methyl-N-acetylbenzylamine (6) which on treatment with KCN, hydrolysis of the resultant nitrile, and subsequent esterification afforded 6-carbethoxymethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-3-one (9). Treatment of 9 with triethyloxonium fluoborate followed by dehydrogenation of the product gave 6-carbethoxy-methyl-3-ethoxy-7-methylisoquinoline (14). Chain extension of 14 followed by cyclization led to 3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (19) which on reduction and subsequent dehydration yielded 3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (4).

Cyclopenta[f]isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7(5)H-cyclopenta[f]isoquinolin-3(2H)-one and its interaction with deoxyribonucleic acids and poly(deoxyribonucleotides).

3-Ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (2) was converted to 6-carbethoxymethyl-3-ethoxy-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinolin-5-one (6) through an oxalyl derivative. Treatment of 6 with ammonia gave the corresponding amide 7 which on sodium borohydride reduction and subsequent dehydration yielded 6-carbamylmethyl-3-ethoxy-8-methyl-7(5)H-cyclopenta[f]isoquinoline (9). The analogous ester 10 was similarly obtained from 6. Numerous attempts to dealkylate the 3-ethoxy group of 9 or 10 failed. However, 6 coould easily be dealkylated on heating with 25% hydrochloric acid in a sealed tube.The ester, 6-carbethoxymethyl-8-methyl-5,6-dihydro-7H-cyclopenta[f]isoquinoline-3(2H),5-dione (11), so obtained was converted to the corresponding amide 12 which on reduction with sodium borohydride and subsequent dehydration afforded the desired compound, 6-car-bamylmethyl-8-methyl-7(5)H-cyclopental[f]isoquinolin-3-(2H)-one (1). 1 was found to be mildly cytotoxic againstL5178Y mouse leukemia cells in culture.1 was also found to bind to native calf thymus DNA. 1 inhibited RNA synthesis by a DNA-dependent RNA polymerase and a higher inhibition of RNA synthesis was observed when poly(dG-dC) was used as a template than when poly(dA-dT) was used. A significant increase of thermal transition temperature of calf thymus DNA and poly(dG)-poly(dC) was observed in the presence of 1. The accumulated evidence demonstrates that 1 interacts weakly with calf thymus DNA and interacts preferentially with poly(deoxyribonucleotides)-containing GC pairs.