Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

Synthesis of a novel tetrahydroisoquinoline pentacyclic framework

N-Acyliminium cyclization of 6-substituted (3R^∗,6R^∗,11aS^∗)-3-arylmethyl-pyrazino[1,2-b]isoquinoline-1,4-diones gave with very good yields a novel tetrahydroisoquinoline pentacyclic core framework (29), while this reaction failed in all-cis-isomers to give instead conjugated enamines by deprotonation. Electronic and steric factors that govern the approach to both diastereomers from 6-substituted pyrazino[1,2-b]isoquinoline-1,4-diones have been studied.     

Pictet Spengler-type reactions in 3-arylmethylpiperazine-2,5-diones. Synthesis of pyrazinotetrahydroisoquinolines

The behavior of aldehydes and acetals as N-alkylating agents of 1-acetyl-3-arylmethylpiperazine-2,5-diones and the subsequent cyclization of the N-alkylated products was studied. Use of paraformaldehyde in different reaction conditions gave 6-unsubstituted 3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-diones and, in some cases, benzo[f]pyrazino[1,2-c]1,3-oxazepine-1,4-diones. Succesful reactions with benzaldehyde required a first activation of the lactam function and a catalyzed N-alkylation with the aldehyde dimethyl acetal. The isolated O,N-amidoacetals thus obtained were submitted to a diastereoselective Pictet Spengler-type reaction that worked with arenes at several degrees of ring activation and with thiophene to give 6-phenylpyrazinoisoquinolinediones and the corresponding thieno analog.     

From cyclic dehydrodipeptides to uncommon acyclic peptide mimetics

1-Acetyl-3-arylmethylene-2,5-piperazinediones gave N-3-arylpyruvylamino esters by acid-promoted alcoholysis under thermal conditions or microwave irradiation. Compounds obtained from 1-acetyl-3-(o-nitro)arylmethylene-2,5-piperazinediones gave, after reduction of the nitro group and spontaneous cyclization, N-2-indolylcarbonylamino acid derivatives. A similar alcoholysis/reduction sequence applied to dehydrodipeptides bearing a 3(4)-nitroaryl substituent gave N-3(4)-aminophenyl-α-ketopropionylamino acid derivatives. Coupling of the free amino group with Boc-protected amino acids gave tripeptide mimetics with a 6-aminoindole-2-carboxylic or a 3(4)-aminophenyl-α-ketopropionic acid as the second residue.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Halogenation of N-substituted p-quinone monoimines and p-quinone monooxime esters: X. Halogenation of N-aroyl-2,5(2,3)-dialkyl-1,4-benzoquinone monoimines and their reduction products

Introduction of a strong electron-withdrawing substituent to the nitrogen atom of 2,5(2,3)-dialkyl-1,4-benzoquinone imines makes their halogenation products, the corresponding cyclohexene derivatives, very unstable and favors halogenation of methyl groups in the quinoid ring. Bromination of 4-amino-N-aroyl-2,5-dialkyl-6-bromophenols gave 2,5-dialkyl-6-benzoyloxy-3,5-dibromocyclohex-2-ene-1,4-diones.     

Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Azines and azoles: CXXVI. First example of a novel heterocyclic system: Pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>][1,5]benzodiazepines

4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones readily undergo acylation at the N¹ atom of the benzodiazepine system by the action of acetic anhydride. Heating of the acetylated products in boiling dimethylformamide leads to the formation of 75–93% of the corresponding 7-acetyl-6-R-6,7-dihydropyrimido[1,6-a][1,5]benzodiazepine-1,3-diones that are derivatives of hitherto unknown fused heterocyclic system, pyrimido[1,6-a][1,5]benzodiazepine. 4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones are converted into 1-(2-aminophenyl)-6-(2-R-vinyl)uracils on heating in boiling DMF.     

Synthesis of phthalascidin analogs

We report a new approach to obtain phthalascidin analogs. 6-Phthalimidomethylpyrazino[1,2-b]isoquinoline-1,4-dione (5a) was obtained in a one-pot N-alkylation/cyclization of the corresponding 1-acetyl-3-arylmethyl-2,5-piperazinedione with N-phthalylacetaldehyde dimethyl acetal. Chemoselective reduction of the C(1)-carbonyl group in the 3-arylmethyl-11,11a-dehydroderivative 9a was followed by cyclization of an acyliminium intermediate, to give the 6,15-imino-7-oxo-14,14a-dehydroisoquino[3,2-b]3-benzazocin 11a. Alternatively, the octacyclic compound 13a was obtained through a novel double cyclization of a precursor in which the C(1)-carbonyl and one phthalimide carbonyl group were reduced.     

A convenient procedure for the synthesis of chiral 6,7-dihydroxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones

The cyclocondensation reactions between l-α-amino acid phenylhydrazides and 2,3-O-isopropylidene-l-erythruronolactone in the presence of a catalytic amount of p-toluenesulfonic acid afforded diastereomerically pure (3S,6R,7R,7aS)-3-substituted-6,7-isopropylidenedioxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, which were converted by acidic hydrolysis with MeOH–HCl into their corresponding optically active (3S,6R,7R,7aS)-3-substituted-6,7-dihydroxy-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones in good yields.     

Studies on ketene and its derivatives. CXI . Photoreaction of diketene with 2(1H)-quinolone derivatives

Photoreaction of diketene with 4-methyl-2(1H)-quinolone and 1,4-dimethyl-2(1H)-quinolone gave 2R*,2aR*,SbR*- and 2R*,2aS*8bS*-8b-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-2-spiro-2′-(oxetan)-4′-one ( 6a and 6b ), and their 4-methyl derivatives 7a and 7b , respectively. Thermolysis of compounds 6 and 7 afforded 2aR*,8bS*-8b-methyl-2-methylene-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline ( 8 ) and its 4-methyl derivatives 9 , respectively. Similarly, photolysis of diketene and 4-acetoxy-2(1H)-quinolone gave 1R*,2aS*,8bS*- and 1R*,2aR*,8bR*-8b-acetoxy-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]-quinoline ( 11a and 11b ). Alcoholysis of compounds 11a and 11b with hydrogen chloride in methanol gave 1-hydroxy-1-(methoxycarbonyl)methylcyclobuta[c]quinoline derivative 12 and 13 which were transformed to 4-acetyl-3-methyl-2(1H)-quinolone ( 15 ) by further alcoholysis. Photoreaction of diketene with 2(1H)-quinolone derivatives gave the corresponding cyclobuta[c]quinoline spirooxetanone derivatives 18 and 23 , which, by thermolysis, were transformed to 2-methylenecyclobuta[c]quinoline 23 and 25 , respectively.     

Condensation of 1,4-diacetylpiperazine-2,5-dione with aldehydes

Condensation of 1,4-diacetylpiperazine-2,5-dione with aldehydes has been applied to the synthesis of albonoursin and unsymmetrical 3,6-diarylidenepiperazine-2,5-diones. The reaction has been extended to 1,4-diacetyl-3,6-dimethylpiperazine-2,5-dione, which gives derivatives of 2-methyl-3- phenylserine. The mechanism and stereochemistry are discussed; cis 1-acetyl-3-isobutylidene- piperazine-2,5-dione has been isolated.     

6,8-Dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione: new heterocyclizations based on SN-methodology. Unexpected formation of the first iso-π-electronic analogue of the still unknown dibenzo[a,o]pycene

N₍₂₎-Oxide and 3-amino derivatives of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione have been shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines or imidazoles. Both conversions based on S_N^H-strategy represent a new approach to imidazoline-(imidazole-)ring annulation. Heterocyclic analogues of the still unknown dibenzo[a,o]pycene were obtained as a by-products of the above transformations upon using of cyclohexylamine.     

One pot conversion of azido arenes to N-arylacetamides and N-arylformamides: synthesis of 1,4-benzodiazepine-2,5-diones and fused [2,1-b]quinazolinones

Sodium iodide in acidic media has been employed for the synthesis of N-arylformamides and N-arylacetamides. The NaI/acetic acid reagent system has also been extended for the synthesis of 1,4-benzodiazepine-2,5-diones, pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones, and fused [2,1-b]quinazolinones.     

The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine-2,5-diones

Alkoxycarbonylpiperazine-2,5-diones are versatile precursors for the α-functionalisation of piperazine-2,5-diones. The alkoxycarbonyl group activates the α-carbon position to alkylation reactions and this provides a mild and selective method for the extension of the carbon framework of piperazine-2,5-diones. In addition, the alkoxycarbonyl group can be converted to the carboxy group, which in turn can be ‘deleted’ or manipulated for the installation of carbon and/or heteroatom substituents where desired, the latter via N-acyliminium chemistry. We also demonstrate that hydroxymethylpiperazine-2,5-diones complement carboxypiperazinediones as precursors for the generation of N-acyliminium ions.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

Ionic liquid-catalyzed and microwave-assisted syntheses of pyrrolizine- and indolizinedione derivatives

3H-Pyrrolo[2,1-a]isoindole-2,5-diones and isoindolo[2,1-a]quinoline-5,11-diones were synthesized by intramolecular cyclization of N-[2-oxo-3-(triphenyl-??⁵-phosphanylidene)propyl]- and N-[2-(triphenyl-??⁵-phosphanylidene)acetyl]phthalimides, respectively, in the presence of ionic liquid ([bmim][BF₄], 10 mol %) as catalyst or under microwave irradiation.     

Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5,10(2H)-triones

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily available 1,4-dihydroxy-2-naphthoic acid, β-ketoesters and primary amines. Finally, a short synthesis of substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.