AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. V. SOME 3-(β-KETO-sec-AMINOALKYL)-4-QUINAZOLONES

Baker, B. R.; Querry, Merle V.; Kadish, Arthur F.; Williams, James H.

doi:10.1021/jo01135a006

Cited by 14 publications

(7 citation statements)

References 2 publications

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“…Since, in contrast, the amine salt formed in acid solution seems to destroy this resonance, it might be expected that the double bond would hydrogenate normally under these conditions. This has been found to be the case using Adams catalyst, the desired compound, XI, being obtained which was identical with that described previously (1).…”

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confidence: 83%

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

Baker¹,

Querry²,

Schaub³

et al. 1952

J. Org. Chem.

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A synthesis of 3-[jS-keto-7-(2-piperidyl)propyl]-4-quinazolone (XI) was de-scribed in an earlier publication (1). This compound was the first of some sixty 3-alkyl-4-quinazolones (2) tested to show antimalarial activity, being about 1% as active as the Hydrangea alkaloid or about equal to quinine.1 Since this compound also duplicated all of the reactions of the natural alkaloid except those due to the hydroxyl function (3), a second type of synthesis was devised which would be applicable to the introduction of an hydroxyl group on certain positions of the piperidine moiety.The key reaction (4) was cyclization of a properly substituted 5-aminoketone to a tetrahydropyridine (X), followed by hydrogenation of the resultant double bond. The necessary diketone, IX, was obtained by an ester-ketone Claisen condensation. Attempted Claisen condensation between 3-acetonyl-4-quinazo-

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confidence: 83%

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

Baker¹,

Querry²,

Schaub³

et al. 1952

J. Org. Chem.

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“…The solvent was evaporated under reduced pressure, and subsequent vacuum distillation gave dibenzyl malonate (249.3 g; 87%) as a colorless oil: bp 180-185 °C/0.2 Torr (lit. 62 bp 188 °C/0.2 mmHg); 1 H NMR (CDCl3) δ 3.22 (2H, s), 4.98 (4H, s), 7.2 (10H, s).…”

Section: Experimental Section 61mentioning

confidence: 99%

Normal and Abnormal Heme Biosynthesis. 2.¹ Synthesis and Metabolism of Type-III Pentacarboxylic Porphyrinogens: Further Experimental Evidence for the Enzymic Clockwise Decarboxylation of Uroporphyrinogen-III

et al. 1998

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Uroporphyrinogen decarboxylase catalyses the sequential decarboxylation of uroporphyrinogen-III (1) to give coproporphyrinogen-III (2), a precursor to the hemes and chlorophylls. This involves the decarboxylation of four nonequivalent acetate side chains to produce methyl units and in principle could take place by 24 different pathways involving up to 14 intermediary porphyrinogens. In the past, seemingly contradictory data have been presented that either support an ordered "clockwise" decarboxylation pathway or a random decarboxylation process. Four pentacarboxylate porphyrinogens might be involved immediately before the formation of 2, and these compounds have been synthesized as the corresponding porphyrin pentamethyl esters via tripyrrene and a,cbiladiene intermediates. Hydrolysis of the methyl esters and reduction with 3% sodium amalgam gave the required porphyrinogens, and these were incubated with crude enzyme preparations derived from chicken red cell hemolysates. One of these pentacarboxylate porphyrinogens (5dab) consistently proved to be a much better substrate than the other three, providing new support for the "clockwise" pathway for coproporphyrinogen-III formation.

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“…A 92% yield of l-earbethoxy-2-(7-bromoacetonyl)-4-methoxymethylpyrrolidine was obtained from XLIIIb as described for 1-benzoyl-2-(7-bromoacetonyl)piperidine (10). Condensation with 4-quinazolone (10) gave 4.3 g. (49%) of crystalline product (from benzeneheptane), m.p.…”

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confidence: 99%

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

Baker¹,

Schaub²,

Williams³

1952

J. Org. Chem.

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The two possible hydroxymethylpyrrolidine structures (XLV and XLVI) for the Hydrangea alkaloid (1) have now been synthesized via the requisite 2-pyrrolidineacetic acids, XLIII. It was found that neither of these two compounds . . BAKER, R. . SCHAUB, AND J. H. WILLIAMS tion. Cyclization to the pyrrolinone, XIa, by a one to two day treatment with 40 volumes of aqueous alcoholic ammonia was reported to give an over-all yield of 85%. Duplication of this procedure gave only a 45% yield which could be increased to 61% if the intermediate imine was not distilled.A more rapid and convenient procedure has now been devised. The imine, Xa, was prepared in 30 minutes by constant removal of water from the components in boiling benzene. Cyclization was effected by treating this benzene solution with alcoholic sodium ethoxide for ten minutes. The over-all yield was 91% of crystalline material.Treatment of the pyrrolinone, XIa, with lithium aluminum hydride caused reduction at three sites, the lactam, ester, and pseudo imine double bond with the formation of 1 -benzylpyrrolidine-2-ethanol, b.p. 115°( 0.1 mm.) in 47% yield. The N-benzyl group was readily removed by hydrogenolysis. The resultant pyrrolidine, XHIa, was oxidized with chromic acid in dilute sulfuric acid to the amino acid, XlVa, characterized as its benzoyl derivative, XVa.The same sequence of reactions proceeded smoothly from Vb to XVb with R = CH3. The pyrrolidine acid, XVb, was converted to the bromo ketone, XVI, via the acid chloride and diazoketone, then condensed with 4-quinazolone to give the crystalline carbethoxylated 4-quinazolone, XVII, in 76% over-all yield from XVb. Short 48% hydrobromic acid hydrolysis of the latter gave the desired model compound, XVIII, isolated as the dihydrochloride in 80% yield.Another method for the preparation of the pyrrolidone, XXVI, was also investigated. In this synthesis a ß-amino adipic ester was desired which could be cyclized to XXVI rather than form XXVI by the hydrogenation of the pyrrolinone, XI, which takes place with difficulty (6). In addition methanol might be added to the double bond of the ester of XX in order to obtain an intermediate of the methoxymethyl series. Reaction of methylaniline with itaconic anhydride, XIX, rapidly took place to give an 81% yield of a pure anilide, XX, which was hydrogenated to XXI in 92% yield. The structures of the monoanilides, XX and

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AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. V. SOME 3-(β-KETO-sec-AMINOALKYL)-4-QUINAZOLONES

Abstract: The Hydrangea alkaloid (I) has been observed to form an N-carbamyl derivative (II) with potassium cyanate which cyclized to III when heated with acid (1). In order for this cyclization to take place the NH group would have to be 0Similar hydrolyses are listed in Table III under method B.

Cited by 14 publications

References 2 publications

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

Normal and Abnormal Heme Biosynthesis. 2.¹ Synthesis and Metabolism of Type-III Pentacarboxylic Porphyrinogens: Further Experimental Evidence for the Enzymic Clockwise Decarboxylation of Uroporphyrinogen-III

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

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AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. V. SOME 3-(β-KETO-sec-AMINOALKYL)-4-QUINAZOLONES

Abstract: The Hydrangea alkaloid (I) has been observed to form an N-carbamyl derivative (II) with potassium cyanate which cyclized to III when heated with acid (1). In order for this cyclization to take place the NH group would have to be 0Similar hydrolyses are listed in Table III under method B.

Cited by 14 publications

References 2 publications

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VI. A SECOND SYNTHESIS OF 3-[Β-Keto-Γ-(2-Piperidyl)-Propyl]-4-Quinazolone

Normal and Abnormal Heme Biosynthesis. 2.1 Synthesis and Metabolism of Type-III Pentacarboxylic Porphyrinogens: Further Experimental Evidence for the Enzymic Clockwise Decarboxylation of Uroporphyrinogen-III

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. XI. SYNTHESIS OF 3-[Β-Keto-Γ-(3- AND 4-Hydroxymethyl-2-Pyrrolidyl)propyl]- 4-Quinazolones

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Normal and Abnormal Heme Biosynthesis. 2.¹ Synthesis and Metabolism of Type-III Pentacarboxylic Porphyrinogens: Further Experimental Evidence for the Enzymic Clockwise Decarboxylation of Uroporphyrinogen-III