Search

1-Benzylwye (8) underwent electrophilic substitution at the 7-position in the presence of phosgene and pyridine in tetrahydrofuran (THF) to afford the 1,4-dihydropyridines (11, 10, and 14) together with the carboxylic acid 6 and its methyl ester 2 after short treatment of the reaction mixture with methanol and then with water. When triethylamine was used instead of pyridine, phosgene reacted with triethylamine rather than 8, producing (E)-3-(diethylamino)propenoyl chloride (17) and diethylcarbamoyl chloride (18).

Phenyl, tolyl, anisyl, and 1-naphthyl iodides (7a-g, n) smoothly reacted with (S)-N-(benzyloxycarbonyl)-vinylglycine (6) in H2O in the presence of Pd(OAc)2, Bu4NCl, and NaHCO3 at 45°C, producing [S-(E)]-(2-arylvinyl)glycine derivatives 8a-g, n of high enantiomeric purity. The yields of the reactions of 3- (7f), 2- (7e), and 4-iodoanisoles (7g) increased in this order. This relationship between the yield and the position of substitution has been found to hold for bromophenyl iodides (7i-k), although somewhat lower chemical and optical yields were realized in these cases. Phenyl iodide 7l carrying an electron-withdrawing 4-acetyl group gave an unsatisfactory result, and more electron-deficient 4-nitrophenyl iodide (7m) did not provide the desired product. All these results suggest that the reaction is advantageous with electron-sufficient substrates 7. However, this was not the case for 4-iodophenol (7h), as well as some heterocyclic iodides.

3-Alkyl-8-hydroxyadenines (5) have been shown to undergo regioselective methylation at the 7- or 9-position depending on the reaction conditions. Thus, treatment of 5a, c with dimetyl sulfate in aqueous NaOH provided 3-alkyl-7-methyl-8-oxoadenines (6b, h) in 48-60% yields, together with 3-alkyl-8-methoxyadenines 4d, h), whereas treatment of 5a-c with MeI in AcNMe2 at 40°C for 48h and subsequent anion exchange afforded 3-alkyl-9-methyl-8-oxoadenine hydrochlorides (7d, g, h·HCl) in 50-59% yieds. However, the reactions of 5a, c with EtI or PhCH2Br took place slowly, giving complex mixtures of products.Compounds 6d, h were alternatively prepared in 51% and 31% yields, respectively, together with 3-alkyl-7, 9-dimethyl-8-oxoadenine hydrochlorides (11d, h·HCl), by treatment of 3-alkyl-8-methoxyadenines (4d, h) with MeI in AcNMe2 at room temperature for 6 h, followed by hydrolysis with boiling aqueous HCl. This method was applicable to ethylation with EtI, and 7-ethyl-3-methyl-8-oxoadenine (6e) was obtained in 70% yield from 8-ethoxy-3-methyladenine (4e). Compound 11h was shown to be obtainable through futher methylation of 6h. Thus, 11d, h were prepared in good yields by treatment of 6d, h with MeI in AcNMe2.Compounds 7, to which zwitterionic structures were assigned, were stable in 0.1 N aqueous NaOH at room temperature, whereas 11d, h were no longer stable under such conditions.

On treatment with boiling H2O for 5-6h, 1-alkoxy-7-alkyladenines (13) underwent hydrolytic cleavage at the N(1)-C(2) and the N(1)-C(6) bonds to produce the imidazole-5-carboxamidines (14) in 53-60% yields and the imidazole-5-carboxamides (18) in 5-7% yields, respectively. The Dimroth rearrangement of 13 to N6-alkoxy-7-alkyladenine (15) was found to proceed through 14 more slowly than that of the 9-alkyl analogues 1 at pH 7 and above, being accompanied by hydrolysis to give the deformylated product (16) and by deamination through 18 leading to 7-alkylhypoxanthine (12), 1-alkoxy-7-alkylhypoxanthine (19), and 1-alkyl-4-aminoimidazole-5-carboxamide (20). Interestingly, the N(1)-C(6) bond fission product 17a was obtained from 13a by treatment with 0.01N aqueous NaOH at 4°C for 35d, but in only 2% yield, or more efficiently (in 56% yield) by pyrolysis at 150°C for 1h. On the other hand, 13 underwent acid hydrolysis faster than 1, providing the deformylated product 16 in 85-96% yields on treatment with 1-2N aqueous HCl at room temperature for 2-5h. 4-amino-N'-methoxy-1-methyl-5-carboxamidine (16a) was alternatively obtained in 59% yield by treatment of 1-methoxy-7-methyladenine (13a) with boiling 2N aqueous NaOH for 10min. Efficient preparations of the rearranged products 15 (80-86%) were accomplished by treating 13 with boiling 0.1N aqueous NaOH for 20-30min.

An alternative synthesis of 3, 9-dimethyl-8-oxoadenine (N6-demethylcaissarone) hydrochloride (5a·HCl) starting from 9-methyl-8-oxoadenine (17) is described. The synthesis proceeded through N(7)-benzylation, N(1)-oxidation, and O-benzylation to afford the 1-benzyloxy derivative 25, which afforded the ring-opened formamide derivative 26 on treatment with dilute aqueous NaOH. Methylation of the monocycle 26 with MeI in the presence of K2CO3, followed by acid-catalyzed cyclization and subsequent catalytic hydrogenolysis afforded 5a·HCl. The key intermediate 25 was alternatively prepared from 17 by N-oxidation and subsequent O, N(7)-dibenzylation with PhCH2Br in the presence of K2CO3.

7-Methyladenine (6a) and 7-ethyladenine (6b) afforded the N(1)-oxides 7a, b in 78% yield each on treatment with m-chloroperoxybenzoic acid at room temperature; this is analogous to the previously reported N-oxidation of 7-benzyladenine (6c) to give the N(1)-oxide 7c. When treated with an excess of methyl iodide, ethyl iodide, or benzyl bromide in N, N-dimethylacetamide at room temperature, each of the 1-oxides 7a-c underwent alkylation almost exculsively at the oxygen atom of the N-oxide group. The products, isolated in good yields, were the salts 8d-l·HX of the nine 1-alkoxy-7-alkyladenines, in which either the O-alkyl or the N(7)-alkyl group is any one of methyl, ethyl, and benzyl. The UV and 1H-NMR spectral data for 8·HX and some of their free bases 8 are presented.

7-Alkoxy-3-alkyladenine perchlorates (9) were prepared from 3-alkyladenines (4) by N-oxidation followed by alkylation with alkyl halides in N, N-dimethylacetamide. The 7-methoxy derivatives 9d, g, j thus obtained afforded 3-methyl-8-hydroxyadenine (7a), 3-ethyl-8-hydroxyadenine (7b), and 3-benzyl-8-hydroxyadenine (7c) in 74%, 72%, and 39% yields, respectively, on treatment with boiling 0.1 N aqueous sodium hydroxide, whereas treatment of 9d, g, j with sodium methoxide in methanol at room temperature afforded 3-alkyl-8-methoxyadenines (10m, p, q) in 91%-98% yields. Similar treatment of 9d with sodium ethoxide in ethanol afforded 8-ethoxy-3-methyladenine (10n) in 89% yield. Compounds 10m, q were alternatively prepared from 9d, j in 77% and 84% yields, respectively, by treatment with 0.1 N aqueous sodium hydroxide in the presence of methanol. This method was suitable for the synthesis of the 8-benzyloxy compound 10o : it was obtained in 60% yield by treating 7-benzyloxy-3-methyladenine perchlorate (9f) with a mixture of aqueous sodium hydroxide and benzyl alcohol. Compounds 7 were alternatively prepared from 9 through 10. For example, 7c was obtained in 84% overall yield by treatment of 9j with sodium methoxide, followed by hydrolysis of the resulting 10q with boiling 1 N hydrochloric acid.On the other hand, methylation of 3-methyladenine 7-oxide (8a) with dimethyl sulfate in 0.1 N aqueous sodium hydroxide in the absence or presence of added methanol afforded N6, 3-dimethyladenine 7-oxide (14) in 13% or 14% yield, together with 7a (4% yield) or 10m (11%).

Oxidations of N6-methyladenine (8a) and N6-benzyladenine (8b) with m-chloroperoxybenzoic acid (MCPBA) in methanol have been found to afford the N(1)-oxides 7a, b in 36% and 35% yields, respectively. The structure of 7b has been established by leading it to N6-methoxyadenine (10) through O-methylation, Dimroth rearrangement, and nonreductive debenzylation. On the other hand, N6, N6-dimethyladenine (16) afforded the N(3)-oxide 17 in 40% yield on treatment with MCPBA in methanol. On the basis of these findings, together with data accumulated for N-oxidations of adenine, Nx-monosubstituted adenines, and 6-substituted purines, the formation of hydrogen bonding between the 6-amino NH and the carbonyl oxygen of a peroxycarboxylic acid may account for regioselective N(1)- and N(7)-oxidations of adenine and Nx-monosubstituted adenines.

A detailed account is given of the first unequivocal synthesis of adenine 7-oxide (8). The synthesis started with peroxycarboxylic acid oxidation of 3-benzyladenine (6), readily obtainable from adenine (1) by benzylation, and proceeded through nonreductive debenzylation of the resulting 3-benzyladenine 7-oxide (7). The location of the oxygen function in 7 and 8 was confirmed by their chemical reactions including deamination and methylation and by X-ray crystallographic analysis. A UV spectroscopic approach suggested that the neutral species of 8 exists in H2O as an equilibrated mixture of the N(7)-oxide (8) and N(7)-OH (21) tautomers. Treatment of 6 with 30% aqueous H2O2 in MeOH in the presence of MeCN and KHCO3 at 30°C produced the N(7)-oxide 7 and 7-acetamido-3-benzyladenine (15) in 12% and 1% yields, respectively.

In contrast to the N(3)-selectivity in N-alkylation, N-oxidation of 7-benzyladenine (17) with m-chloroperoxybenzoic acid in MeOH has been found to give 7-benzyladenine 1-oxide (18) in 76% yield. Alternatively, the same N-oxide (18) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile(19) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imidazole-5-carbonitrile (24), obtained in 63% yield from the corresponding 4-nitro drivative (20) by catalytic hydrogenation (Pt/H2), with formamidine acetate in boiling EtOH furnished 7-benzyladenine 3-oxyde (23) in 78% yield. A UV spectroscopic approach indicated that the neutral species of 18 exists in H2O in the N(1)-oxide form rather than the N(1)-OH form (27).

Oxidation of 1-benzyladenine (12) with m-chloroperoxybenzoic acid in MeOH or in MeOH-0.5 M phosphate buffer (pH 6.6) has been found to afford 1-benzyladenine 7-oxide (13) as the main product. Nonreductive debenzylation of 13 gave adenine 7-oxide (14) in 63% yield. The structure of 13 was unequivocally established by an X-ray crystallographic analysis.

Among N-protected and unprotected vinylglycines tested, N-(benzyloxycarbonyl)vinylglycine (1c) provided the highest yield of the coupling product 3c in the reaction with 1-iodo-4-methoxybenzene (2) in N, N-dimethylformamide in the presence of palladium acetate, sodium bicarbonate, and tetrabutylammonium chloride, whereas none of the desired product was obtained in the reaction with 4-methoxyphenyl trifluoromethanesulfonate (7). The stereoselectivity of the reaction was reversed by employing triethylamine instead of sodium bicarbonate to furnish (Z)-3c predominantly. In the presene of sodium bicarbonate, replacement of the solvent by water improved not only the chemical yield and stereoselectivity but also the optical purity : geometrically pure (E)-3c of 96% ee was formed in a good yield.

Oxalyl chloride reacts with a wide range of acyclic 1,2-glycols 1 in the presence of triethylamine to produce 1,3-dioxolan-2-ones 3 together with 1,4-dioxane-2,3-diones 2. Ethylene glycol (1d), monosubstituted ethylene glycols 1e, j—l, and erythro-1,2-disubstituted ethylene glycols 1f, m, o provide the cyclic carbonates 3 as the minor products, while the threo-compounds 1g, i, n, p, q and pinacol (1h) afford 3 as the main products. The formation of 3 may be rationalized in terms of stereoelectronically controlled cleavage of the conjugate base 17− of the tetrahedral intermediates. The rate for the conformational change of 17− into 18− and the equilibrium constant between these conformers are proposed to be the major factors affecting the reaction pattern.

(R)-[2-Carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) was converted by treatment with anion exchange resin (HCO-3) into the inner salt 13h, which gave a better yield (43%) than 1 in the Wittig reaction with benzaldehyde to afford the [S-(E)]-(2-phenylvinyl)glycine derivative 24. The inner salt 13i bearing an N-benzyloxycarbonyl group was prepared by hydrogenolysis of (R)-[3-benzyloxy-2-[(benzyloxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11e) over palladium on carbon, followed by dehydrochlorination. Hydrogenolysis of 11e over Pearlman's catalyst afforded the unprotected phosphonium chloride 12 (X=Cl). N-tert-Butoxycarbonylation of 12 followed by dehydrochlorination afforded 13j, which was more efficiently prepared through hydrogenolysis of (R)-[3-benzyloxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11f).The usefulness of 13h-j as building blocks for the synthesis of configurationally labile (2-arylvinyl)glycine derivatives was exemplified by the Wittig reactions with piperonal, which exclusively afforded the (E)-isomers 18h-j with high optical purity in 28-39% yield.

Dehydration of 5-(cyanomethylamino)-1-methyl-1H-imidazole-4-carboxamide (14a) with a combination of phosphorus oxychloride and triethylamine afforded the nitrile 17a. This compound underwent selective hydration at the cyanamide moiety to furnish the urea 18a followed by cyclization to 3, 9-dimethylisaguaninae (19a) under alkaline conditions. Similar dehydration of the nucleoside analog 14b followed by treatment with 0.1 N aqueous sodium hydroxide led to the first access to 3-methylisoguanosine (19c). Although 3-methylisoguanosine (19c) proved to undergo hydrolysis at the N-glycosidic bond most slowly among the known 3-methyl-9-β-D-ribofuranosylpurines in 0.1 N hydrochloric acid at 25°C, the rate was 650 times faster than that for the unmethylated isoguanosine (3).

Oxidation of 7-benzyladenine (9) with m-chloroperoxy-benzoic acid in MeOH has been found to yield 7-benzyladenine 1-oxide (11) as the main product. Alternatively, the same N-oxide (11) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile (12) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imida- zole-5-carbonitrile (17), prepared in 63% yield from the corresponding 4-nitro derivative (13) by catalytic reduction (Pt/H 2 ), with formamidine acetate in boiling EtOH gave 7-benzyladenine 3-oxide (16) in 83% yield

Oxalyl chloride reacts with a wide range of acyclic 1,2-glycols 1 in the presence of triethylamine to produce 1,3-dioxolan-2-ones 3 together with 1,4-dioxane-2,3-diones 2. Ethylene glycol (1d), monosubstituted ethylene glycols 1e, j—l, and erythro-1,2-disubstituted ethylene glycols 1f, m, o provide the cyclic carbonates 3 as the minor products, while the threo-compounds 1g, i, n, p, q and pinacol (1h) afford 3 as the main products. The formation of 3 may be rationalized in terms of stereoelectronically controlled cleavage of the conjugate base 17− of the tetrahedral intermediates. The rate for the conformational change of 17− into 18− and the equilibrium constant between these conformers are proposed to be the major factors affecting the reaction pattern.

(R)-[2-Carboxy-2-[(methoxycarbonyl)amino]ethyl]triphenylphosphonium chloride (1) was converted by treatment with anion exchange resin (HCO-3) into the inner salt 13h, which gave a better yield (43%) than 1 in the Wittig reaction with benzaldehyde to afford the [S-(E)]-(2-phenylvinyl)glycine derivative 24. The inner salt 13i bearing an N-benzyloxycarbonyl group was prepared by hydrogenolysis of (R)-[3-benzyloxy-2-[(benzyloxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11e) over palladium on carbon, followed by dehydrochlorination. Hydrogenolysis of 11e over Pearlman's catalyst afforded the unprotected phosphonium chloride 12 (X=Cl). N-tert-Butoxycarbonylation of 12 followed by dehydrochlorination afforded 13j, which was more efficiently prepared through hydrogenolysis of (R)-[3-benzyloxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl]triphenylphosphonium chloride (11f).The usefulness of 13h-j as building blocks for the synthesis of configurationally labile (2-arylvinyl)glycine derivatives was exemplified by the Wittig reactions with piperonal, which exclusively afforded the (E)-isomers 18h-j with high optical purity in 28-39% yield.

Among N-protected and unprotected vinylglycines tested, N-(benzyloxycarbonyl)vinylglycine (1c) provided the highest yield of the coupling product 3c in the reaction with 1-iodo-4-methoxybenzene (2) in N, N-dimethylformamide in the presence of palladium acetate, sodium bicarbonate, and tetrabutylammonium chloride, whereas none of the desired product was obtained in the reaction with 4-methoxyphenyl trifluoromethanesulfonate (7). The stereoselectivity of the reaction was reversed by employing triethylamine instead of sodium bicarbonate to furnish (Z)-3c predominantly. In the presene of sodium bicarbonate, replacement of the solvent by water improved not only the chemical yield and stereoselectivity but also the optical purity : geometrically pure (E)-3c of 96% ee was formed in a good yield.

Deoxygenation of the 1,2-glycol (±)-5 was achieved at the position adjacent to the heterocycle through the cyclic carbonate (±)-14, providing the monohydroxy compound 6. This new method of regioselective deoxygenation was employed for the first synthesis of β-hydroxywybutines [[R-(R ∗ ,S ∗ )]- and [S-(R ∗ ,R ∗ )]-2] : oxidation of the methyl butenoate 7 with osmium tetroxide, followed by deoxygenation through the cyclic carbonates (19 and 20), afforded the two diastereomers of 2.

1-Methyl-5-(methylamino)imidazole-4-carbonitrile (4a) afforded three minor ring-opened products (5a, 6a, 10a) besides its 2-oxo derivative 3a on treatment with ethyl chloroformate in aqueous sodium bicarbonate. The geometrical isomers of these trisubstituted propenenitriles (5a, 6a, 10a) can be separated from each other by means of TLC, but equilibrate rapidly in solution. Because these compounds were converted into 3a in aqueous sodium hydroxide, alkaline treatment of the reaction mixture of 4a afforded a higher yield of 3a; although 3a also rapidly changed into other compounds in 0.1 N aqueous sodium hydroxide at room temperature, it could be recovered from the solution in high yield.5-Alkylamino homologues 3b, c were also prepared in 64% and 46% yields, respectively, by similar treatment of the substrates 4b, c having the 5-alkylamino substituents. The same products 3b, c were obtainable from the positional isomers 4d, e in 83% and 51% yields, respectively. These outcomes are interpretable by supposing that the reactions proceed through common intermediates, equilibrated mixtures of (E)- and (Z)-[2-(alkylamino)-1-cyano-2-(methylamino)ethenyl]carbamic acid ethyl esters (7).

Phenyl, tolyl, anisyl, and 1-naphthyl iodides (7a-g, n) smoothly reacted with (S)-N-(benzyloxycarbonyl)-vinylglycine (6) in H2O in the presence of Pd(OAc)2, Bu4NCl, and NaHCO3 at 45°C, producing [S-(E)]-(2-arylvinyl)glycine derivatives 8a-g, n of high enantiomeric purity. The yields of the reactions of 3- (7f), 2- (7e), and 4-iodoanisoles (7g) increased in this order. This relationship between the yield and the position of substitution has been found to hold for bromophenyl iodides (7i-k), although somewhat lower chemical and optical yields were realized in these cases. Phenyl iodide 7l carrying an electron-withdrawing 4-acetyl group gave an unsatisfactory result, and more electron-deficient 4-nitrophenyl iodide (7m) did not provide the desired product. All these results suggest that the reaction is advantageous with electron-sufficient substrates 7. However, this was not the case for 4-iodophenol (7h), as well as some heterocyclic iodides.

The relationship between the product patterns and the configurations of 1,2-cycloheptane- and 1,2-cyclooctanediols 9 in the cyclocondensations with oxalyl chloride in the presence of triethylamine at 0 degrees C has been shown analogous to that obtained for 1,2-disubstituted acyclic ethylene glycols 1: cis-1,2-cyclooctanediol (9f) produced the cyclic oxalate 14f as the major product, while trans-1,2-cycloheptanediol (9e) and trans-1,2-cyclooctanediol (9g) formed the cyclic carbonates 12e, g as the major products. On the other hand, the cyclic oxalates 14a-d were formed as the major products from 1,2-cyclopentane- and 1,2-cyclohexanediols regardless of the configuration. These results can be accounted for by assuming the boat-like transition states for cyclizations of the half esters of comparatively rigid five- and six-membered diols 9a--d. The cyclic oxalates 14a, c may be directly formed through the resulting tetrahedral intermediates from cis-diols (9a,c), and the cyclic carbonates 12a,c as the minor products after ring inversion of the tetrahedral intermediates. The tetrahedral intermediates from the trans-isomers 9b, d cannot undergo ring inversion, producing no traces of the cyclic carbonates 12b, d.

Based on the mechanism postulated for the formation of the cyclic carbonates 3 in the reactions of glycols 1 with oxalyl chloride in the presence of triethylamine, we present here three efficient syntheses of the cyclic oxalates 2 of various glycols 1 by controlling the formation of 3: replacement of the base by pyridine markedly diminishes yields of 3 in all reactions, realizing dramatic reversals of the product ratios in the reactions with the (R*,R*)-compounds 1g-i,q,r and pinacol (1k); although considerable amounts of the oxalate polymers are formed in the reactions with some (R*,S*)-glycols, this drawback can be removed by the use of 2,4,6-collidine instead of pyridine; 1,1'-oxalyldiimidazole is useful for the synthesis of two selected cyclic oxalates 2e,f. The cyclic oxalates 2 other than trisubstituted and tetrasubstituted ones were found to be very reactive: kinetic studies on the hydrolysis of 1,4-dioxane-2,3-dione (2a) as well as its mono- and some selected 5,6-disubstituted derivatives 2 have revealed that they undergo hydrolysis 260-1500 times more rapidly than diethyl oxalate (12) in acetate buffer-acetonitrile (pH 5.69) at 25 degrees C. Although the cyclic oxalate 21 from cis-1,2-cyclopentanediol (11) was 1.5 times more reactive than 2a, it has been shown with other substrates that increasing number of the alkyl substituents decreases the rate of hydrolysis. On the contrary, the phenyl group was found to have somewhat accelerative effect.

Treatment of N6-benzyladenine (2) with 15% aqueous H2O2 in trifluoroacetic acid at 65-70°C for 1 h was found to give the N(3)-oxide (3) and the N(7)-oxide (4) in 4% and 4% yields, respectively. The structure of 3 was established by its identity with a sample prepared from 6-chloropurine 3-oxide (6) and benzylamine, and the structure of 4 by its identity with a sample obtained from 1-benzyladenine 7-oxide (8) by Dimroth rearrangement. The N-oxides 3 and 4, together with previously reported N6-benzyladenine 1-oxide (1), were tested for cytokinin activity in the tobacco callus bioassay. Each of the three N-oxides was active at 4 μM concentration, being less active than the parent base 2 by a factor of 40.

Based on the mechanism postulated for the formation of the cyclic carbonates 3 in the reactions of glycols 1 with oxalyl chloride in the presence of triethylamine, we present here three efficient syntheses of the cyclic oxalates 2 of various glycols 1 by controlling the formation of 3: replacement of the base by pyridine markedly diminishes yields of 3 in all reactions, realizing dramatic reversals of the product ratios in the reactions with the (R*,R*)-compounds 1g-i, q, r and pinacol (1k); although considerable amounts of the oxalate polymers are formed in the reactions with some (R*,S*)-glycols, this drawback can be removed by the use of 2,4,6-collidine instead of pyridine; 1,1′-oxalyldiimidazole is useful for the synthesis of two selected cyclic oxalates 2e, f. The cyclic oxalates 2 other than trisubstituted and tetrasubstituted ones were found to be very reactive: kinetic studies on the hydrolysis of 1,4-dioxane-2,3-dione (2a) as well as its mono- and some selected 5,6-disubstituted derivatives 2 have revealed that they undergo hydrolysis 260-1500 times more rapidly than diethyl oxalate (12) in acetate buffer-acetonitrile (pH 5.69) at 25°C. Although the cyclic oxalate 2l from cis-1,2-cyclopentanediol (1l) was 1.5 times more reactive than 2a, it has been shown with other substrates that increasing number of the alkyl substituents decreases the rate of hydrolysis. On the contrary, the phenyl group was found to have somewhat accelerative effect. © 2002 Pharmaceutical Society of Japan.

A detailed account is given of the synthesis and glycosidec cleavage of 1-ehyladenosine (2b), which established an alternative synthesis of 1-ethyladenine (3b). Ethylation of adenosine (1) with EtI in AcNMe2 at 35-38°C for 90h gave 2b·HI in 54% yield. The hydriodide 2b·HI was readily converted into the perchlorate 2b·HClO4 and into the free nucleoside 2b. Treatment of 2b·HI with 0.5N aqueous HCl at 92-94°C for 30min or that of 2b·HClO4 with boiling AcOH for 60min produced the aglycone 3b in good yield. The free base easily formed the hydrochloride 3b·HCl, and the perchlorate 3b·HClO4 as well.

The synthesis of 8-methylguanine 7-oxide (3) was accomplished via a "phenacylamine route", which started from condensation of alpha-(4-methoxybenzylamino)propiophenone (6), prepared by coupling of alpha-bromopropiophenone (4) and 4-methoxybenzylamine (5), with 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone (7) and proceeded through cyclization of the resulting phenacylaminopyrimidinone (8) and removal of the 4-methoxybenzyl group. The N-oxide 3 and its 9-arylmethyl derivatives 9 and 11 showed only very weak antileukemic activity and no antimicrobial activity.

A full account is given of the first chemical synthesis of the antitumor antibiotic guanine 7-oxide (5) and its 9-substituted derivatives (24a-k and 26). Coupling of appropriate primary amines (17a-e, g-k) with phanecyl bromide (16) produced, after treatment with HCl, the corresponding N-substituted phenacylamine hydrochlorides (18a-e, g-k). A similar phenacylation of 4-amino-1-butanol (21) failed to give the desired compound 18f, so that 21 was heated with 2-bromomethyl-2-phenyl-1, 3-dioxolane (20) at 150-155°C for 3h to furnish, after treatment with HCl, the amino ketal hydrochloride 22 in 40% yield. Deketalization of 22 with hot 2N aqueous HCl afforded 18f in 96% yield. Condensations of the free bases, generated in situ from the hydrochlorides 18a-l and 1N aqueous NaOH, with the chloropyrimidinone 6 were effected in aqueous EtOH at the boiling point for 20 min or at 25-30°C for 3-24h, giving the 6-phenacylamino-4-pyrimidinones 19a-l in 54-90% yields. On treatment with 2N aqueous NaOH at room temperature for 10-60 min, the nitropyrimidinones 19a-k cyclized to provide the 9-substituted guanine 7-oxides 24a-k in 61-98% yields. A similar alkali-treatment of 19l failed to yield guanine 7-oxide (5). However, removal of the 9-(arylmethyl) group from 24i-k was effected with conc, H2SO4 at room temperature for 1-3h in the presence of toluene, producing the target N-oxide 5 in 56-89% yields. In the in vitro bioassay of antileukemic activity against murine L5178Y cells, none of the 9-substituted guanine 7-oxides (24a-k and 26) was more effective than the parent, natural N-oxide 5. Within this series, however, the benzyl analogues 24g-k with or without alkoxy functions were more cytotoxic, with IC50's of 13.0-48.0μg/ml, than the alkyl analogues 24a-f.

An alternative synthesis of 2', 3', 5'-tri-O-benzoyl-N, N, 3-trimethyladenosine iodide (9a) was attained by the reaction of N, N, 3-trimethyladenine (11a) with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-β-D-ribofuranose (10) in the presence of SnCl4 followed by treatment with NaI. Although 3-benzyl-N, N-dimethyladenine (11c) did not react with under similar conditions, the ribosylation of 3-ethyl-N, N-dimethyladenine (11b) followed by alkaline hydrolysis led to the first synthesis of 5-(ethylamino)-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide (15b). A more general procedure for the synthesis of 5-(alkylamino)-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamides (15) was developed via a series of reactions : alkylation of N'-benzyloxy-5-formamido-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamidine (12) with alkyl halides in the presence of K2 CO3, catalytic hydrogenolysis, and alkaline hydrolysis. By means of this method, 5-(benzylamino)- (15c) and 5-(isopropylamino)-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide (15d) were synthesized for the first time.

Oxidation of 7-benzyladenine (9) with m-chloroperoxy-benzoic acid in MeOH has been found to yield 7-benzyladenine 1-oxide (11) as the main product. Alternatively, the same N-oxide (11) has been synthesized in 81% yield from 1-benzyl-4-(ethoxymethyleneamino)imidazole-5-carbonitrile (12) and hydroxylamine. Treatment of 1-benzyl-4-(hydroxyamino)imida- zole-5-carbonitrile (17), prepared in 63% yield from the corresponding 4-nitro derivative (13) by catalytic reduction (Pt/H 2 ), with formamidine acetate in boiling EtOH gave 7-benzyladenine 3-oxide (16) in 83% yield

6-Mercaptopurine 7-N-oxide (6) has been synthesized for the first time from 4,6-dichloro-5-nitropyrimidine (12) by following a «phenacylamine route» through the intermediates (8) and (9). Methylation of (9) and removal of the p-methoxybenzyl group provided 6-methylthiopurine 7-N- oxide (7)

Oxidation of N 6 -benzyladenine (2) with m-chloroperoxybenzoic acid in MeOH has been found to give N 6 -benzyladenine 1-oxide (1) as the main product. The structure of 1 has been established by leading it to N 6 -methoxyadenine (4) though O-methylation, Dimroth rearrangement, and nonreductive debenzylation

The first unequivocal synthetic route to adenine 7-oxide (7) has been established. The route started with peroxycarboxylic acid oxidation of 3-benzyladenine (5), readily obtainable from adenine (2) by benzylation, and proceeded through nonreductive debenzylation of the resulting 3-benzyladenine 7-oxide (6)

Oxidation of N, 9-dimethyladenine (IIIa) with m-chloroperbenzoic acid in ethanol or 30% aqueous hydrogen peroxide in acetic acid produced the 1-N-oxide (VIII). N-Oxide VIII underwent methylation at the oxygen atom when treated with methyl iodide in N, N-dimethylacetamide, giving 1-methoxy-N, 9-dimethyladenine hydriodide (IX·HI) in 89% yield. The Dimroth rearrangement of IX to N-methoxy-1, 9-dimethyladenine (XI) was readily effected by treating the free base (IX) with boiling water under mildly alkaline conditions. On the other hand, treatment of IX with water at room temperature furnished the ring-opened intermediate (X), which recyclized in boiling water to XI with the formation of a trace of the reversion product (IX). On treatment with 0.2N hydrochloric acid at room temperature, intermediate X gave both XI (62% yield) and IX (13% yield as the perchlorate). Catalytic hydrogenolysis of XI to 1, 9-dimethyladenine (Ia) (71% yield as the perchlorate), effected with hydrogen and Raney nickel catalyst, completed the reaction sequence which made possible a reverse Dimroth rearrangement of IIIa to Ia.

Reaction of 1-methyl-5-(methylamino) imidazole-4-carboxamide (6a) with a boiling mixture of ethyl orthoformate and acetic anhydride produced 3, 9-dimethylhypoxanthine (7a) in 60% yield and 1-methyl-5-(N-methylformamido) imidazole-4-carboxamide (5a) in 39% yield. Compound 5a was transformed into 7a by treatment with NaH in 78% yield. Compound 7a was alternatively prepared by cyclocondensation of 6a with diethoxymethane followed by oxidation with I2. The pyrimidine moiety of 7a has been shown to be reactive : 7a affords the 1, 2-dihydro derivative 9 under reductive conditions and undergoes ring opening to 5a in aqueous NaOH. 3-Ethyl-9-methyl-(7b), 3-benzyl-9-methyl-(7c), 9-ethyl-3-methyl-(7d), and 3, 9-dibenzylhypoxanthine (7e) were also prepared from the corresponding carboxamides 6b-e.

Alkylations of N, N-dimethyl-(Ia) and N, N-diethyladenine (Ib) with methyl iodide, ethyl iodide, and benzyl bromide in N, N-dimethylacetamide in the presence of potassium carbonate gave the corresponding N, N, 9-trialkyladenines (II) in 54-74% yields, as well as minor amounts of N, N, 3-trialkyladenines (III). The alkylation of I without base gave the latter compounds (III) in 76-90% yields.

The rates of the Dimroth rearrangements of 1-alkyladenosines (Ie, f) and 1-alkyl-9-methyladenines (Ia-d) at various pH's and ionic strength 1.0 at 40° have been measured. It has been shown that all reactions obey good pseudo-first-order kinetics and follow the rate law given by k(0)obsd=k(0)ionic [I·H+] [OH-]+k(0)neut [I] [OH-] where k(0)obsd is the observed limiting specific rate for zero buffer concentration ; [I·H+] is the fraction of the base protonated at each pH ; [I], the fraction present as free base. Comparison between the individual second-order rate constants thus obtained (Table III) has revealed that attack of hydroxide ion on the protonated species is faster than on the neutral species by a factor of 90-1100 and that the former is affected by the electronic property of a substituent at the 1-position, whereas the latter is influenced by a steric factor. The rate of the rearrangement is enhanced by the benzyl group at the 1-position at near neutrality and by the β-D-ribofuranosyl group at the 9-position at all pH's examined.

The reaction of adenine 1-oxide (II) with alkyl halides in N,N-dimethylacetamide resulted in O-alkylation. These 1-alkoxyadenine salts (III) were readily converted into the corresponding free bases (IV). The alkylation of IV m a similar manner gave 1-alkoxy-9-alkyladenine salts (V) in 52–71 % yield. This method was applied to the synthesis of 9-alkyladenines (VII), by transformation of the free bases (VI) of 1-alkoxy-9-alkyladenines into VII by catalytic hydrogenolysis over Raney nickel.

Treatment of 9-alkyladenines (Ia, b, c) with 30% aqueous hydrogen peroxide in acetic acid at 30° produced the corresponding 9-alkyladenine 1-oxides (II a, b, c) in 51-71% yield. The 1-N-oxides were found to undergo alkylation almost exclusively at the oxygen atoms of the N-oxide groups when treated separately with methyl iodide, ethyl iodide, and benzyl bromide in N, N-dimethylacetamide at room temperature, and the corresponding salts (III) of all the nine possible 1-alkoxy-9-alkyladenines were obtained in excellent yields. 1-Ethoxyadenosine hydriodide and 1-benzyloxyadenosine perchlorate were also prepared from adenosine 1-oxide (II d) in a similar way. The ultraviolet and nuclear magnetic resonance spectral data on the 1-alkoxyadenine derivatives obtained in the previous and present studies are collected in Tables II and III.

The rates of the Dimroth rearrangements of l-alkoxy-9-alkyladenines (I) and 1-alkyl-9-methyladenines (V) have been measured. It is shown that 1-alkoxy derivatives (I) undergo rearrangement to give isomeric 6-alkoxyamino derivatives (III) through isolable monocyclic intermediates (II) and that these intermediates also suffer hydrolysis leading to deformylated derivatives (IV) in competition with their reclosure to III. In the I-alkyl series, no intermediates have been detected and thus the observed first-order rate constants for the rearrangements may be regarded as those for the ring-opening of V. Comparison of the rate constants for 1-methoxy-9-methyladenine (Ia) and 1,9-dimethyladenine (Va) reveals that at pH 7·60 and above Va rearranges more rapidly than Ia, although the latter undergoes ring- opening ca. 30 times as fast as the former. In each of both compounds ring-opening proceeds at a rate proportional to hydroxide ion concentration below pH 8·5 and above pH 11, with a plateau between the two values. These results are consistent with attack by the hydroxide ion on both the protonated and neutral species of the adenine derivatives.

Treatment of 1-alkoxyadenine (I) with reactive alkyl halides (R2X) in N, N-dimethylacetamide yielded the 9-alkylated salts (II) in good yields. However, an alkyl halide (R2X) less reactive than that (R1X) whose alkyl group was the same as in I reacted with I to give a mixture of at most four possible 1-alkoxy-9-alkyladenine salts (II, IV, V, and VII), two 9-alkyladenine 1-oxides (III and VI), and, possibly, a more reactive alkyl halide (R1X). The intricate pattern of formation of products was due to O→N (9) alkyl migration during the reaction, and a plausible mechanism is presented. A clear O→N (9) benzyl migration was demonstrated by the reaction of 1-benzyloxyadenine (I: R1=C6H5CH2) with 0.1 equivalent of benzyl bromide to give 0.58 equivalent of 9-benzyladenine 1-oxide (VI: R1=C6H5CH2).

Alkylation of adenosine 1-oxide (I) and its 2', 3'-O-isopropylidene derivative (V) with alkyl halides in N, N-dimethylacetamide furnished the corresponding 1-alkoxy derivatives (IIa-f). The free bases, obtained from IIa-f, readily underwent rearrangement to give the isomeric N6-alkoxy derivatives (IVa-f) when heated in water. Treatment of 1-benzyloxyadenosine perchlorate (IIc : X=ClO4) with water at pH 9.5 and 39-41°for 4 hr afforded the ring-opened intermediate (IIIc)(79% yield), which was recyclized in hot water (pH 7) to IVc. In alternative synthesis of IVa, b, c, condensation of 6-chloro-6-β-D-ribofuranosylpurine (VIa) with the appropriate alkoxyamines proceeded smoothly. Removal of the isopropylidene group from IVe under acid conditions or exchange amination of adenosine with ethoxyamine at pH 5 also yielded N-ethoxyadenosine (IVb).

Alkylations of N, N-dimethyl-(Ia) and N, N-diethyladenine (Ib) with methyl iodide, ethyl iodide, and benzyl bromide in N, N-dimethylacetamide in the presence of potassium carbonate gave the corresponding N, N, 9-trialkyladenines (II) in 54-74% yields, as well as minor amounts of N, N, 3-trialkyladenines (III). The alkylation of I without base gave the latter compounds (III) in 76-90% yields.

3,9-Dimethyl- and 3-methyl-9-ethyl-adenine have been synthesized from N′-alkoxy-1-alkyl-5-formamidoimidazole-4-carboxamidine (II) by reduction with LiAIH4 followed by cyclisation with ethyl orthoformate and removal of the alkoxy-group by catalytic hydrogenolysis.

1-Benzyl- (IIIa), 1-(3-methyl-2-butenyl)-(IIIb), and 1-allyladenine (IIIc) were prepared in 77, % 44%, and 69% yield, respectively, by alkylation of adenosine (I) followed by heating the resulting 1-substituted adenosine hydrobromides (IIa, b, c) in acetic acid.