Active Methylene Ketones Research Articles

ChemInform Abstract: Preparation of Optically Active (4aα,8aβ)‐Octahydro‐4a‐methyl‐8‐methylene‐2(1H)‐naphthalenone, a Key Intermediate for the Enantioselective Synthesis of Eudesmane Sesquiterpenes.

AbstractAusgehend von 2‐Methylcyclohexanon (I) wird die im Titel genannte Verbindung (XI) auf dem im Schema angegebenen Weg synthetisiert.

Purines. VI. Reactions of 2-chloro- and 2-(methylsulfonyl)-9-phenyl-9H-purines with nucleophiles.

The reactions of 2-chloro-9-phenyl-9H-purine (1) with sodium methoxide, ethoxide, and phenoxide as O-nucleophiles, with butylamine and piperidine as N-nucleophiles, and with sodium methylsulfide as an S-nucleophile, afforded 2-methoxy- (3a), 2-ethoxy- (3b), 2-phenoxy- (3c), 2-butylamino- (4a), 2-piperidino- (4b), and 2-methylthio-9-phenyl-9H-purine (5), respectively. Compound 1 also reacted with ethyl cyanoacetate and phenylacetonitrile as C-nucleophiles in the presence of sodium hydroxide in dimethyl sulfoxide to give ethyl H-cyano-9-phenyl-9H-purine-2-acetate (6a) and α, 9-diphenyl-9H-purine-2-acetonitrile (6b). However, 1 did not react with other active methylene compounds, ketones or potassium cyanide.On the other hand, 2- (methylsulfonyl) -9-phenyl-9H-purine (2), prepared easily from 1, smoothly reacted not only with active methylene compounds but also with ketones and potassium cyanide. When active methylene compounds, such as ethyl cyanoacetate and phenylacetonitrile, were used, 2 gave 6a and 6b in good yields. In the cases of ketones and potassium cyanide, the substitution reactions of 2 proceeded to give the corresponding 2-substituted 9H-purines (7 and 8a-d), as expected.

Preparation of Optically Active (4aα,8aβ)-Octahydro-4a-methyl-8-methylene-2(1H)-naphthalenone, a Key Intermediate for the Enantioselective Synthesis of Eudesmane Sesquiterpenes

Abstract The titled optically active methylene ketone was prepared in 45% ee from 3-methyl-1,2-cyclohexanedione by use of a novel asymmetric Michael addition with (R,R)-(−)-2,3-butanediol as chiral auxiliary.

Polarized ketene dithioacetals. Part 42. Studies on the reactions of alkyl and aryl Grignard reagents with α-oxoketene dithioacetals

The oxoketene dithioacetals (2a–k) derived from a variety of cyclic and acyclic active methylene ketones undergo 1,2-addition with methylmagnesium iodide to give the alcohol acetals (3a–k) which, on subsequent boron trifluoride—ether catalysed methanolysis, yield methyl β-methyl-α,β-unsaturated esters (6a–k) in 51–70% overall yields. Also the alcohols (3a) and (3i–k) underwent partial hydrolysis in the presence of boron trifluoride–ether and water to yield β-methyl-α,β-unsaturated S-methyl esters (7a–d) in 41–60% yield. Under similar conditions however, the oxoketene dithioacetals (21–q) derived from higher homologues of acetophenone yielded the corresponding 2-alkyl-3-methylinden-1-ones (8a–f) in 50–62% overall yields. The reactions of cyclic oxoketene dithioacetals (2g), (2h), and (2j) with higher alkyl Grignard reagents afforded the alcohols (13a–f), formed by sequential 1,4 and 1,2 addition, which on subsequent methanolysis yielded the corresponding 1-(2-alkylcycloalk-1-enyl)alkan-1-ones (14a–f) in 48–58% overall yields. Similarly the phenylmagnesium bromide underwent sequential 1,4 and 1,2 addition to the oxoketene dithioacetals (2a–c), (2h) and (2j) to yield the alcohols (13g–k), which upon subsequent methanolysis yielded either 1,3,3-triarylprop-2-en-1-ones (14g–i) or phenyl (2-phenylcycloalk-1-enyl) ketones (14j–k) in 53–71% yield.

Triazolo[4,5-d]pyrimidines. VI. 3-Phenyl-3H-1,2,3-triazolo[4,5-d]-pyrimidine-7-carbonitrile and related compounds.

Nucleophilic reagents were found to react with 3-phenyl-3H-1, 2, 3-triazolo [4, 5-d]-pyrimidine-7-carbonitrile (1) in two ways, depending on the nature of the reagent. One is substitution by attack of the reagent of the carbon at the 7-position, to which the cyano group is bonded. The other is addition to the cyano group by attack of the reagent at the carbon of the cyano group. The substitution reaction occurs with amines, alkoxide ions, carbanions (active methylene compounds or ketones in the presence of sodium hydride), and the Grignard reagents, resulting in the formation of 4-alkylamino-(2), 4-alkoxy-(3), 4-substituted (4), and 4-alkyl-3-phenyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidines (5), respectively. The addition reaction occurs in the reactions with 98% sulfuric acid and with hydroxylamine, resulting in the formation of amide (6a) and amidoxime (7), respectively. The amide (6a) forms esters (8) with alcohols, in the presence of acid. The ethyl ester (8b) is hydrolyzed by ethanolic potassium hydroxide to give the acid (9). Moreover, 8b reacts with amines, hydroxylamine, and hydrazines to form amides (6b and 6c), hydroxamic acid (10), and hydrazides (11a and 11b), respectively.

ChemInform Abstract: THE TRANSFORMATION OF PYRIDO(2,3‐D)PYRIMIDINE INTO 1,8‐NAPHTHYRIDINE

AbstractDas Pyridopyrimidin (I) liefert mit CH‐aktiven Verbindungen (II) die Pyridopyridine (III).

Studies on pyrazolo(3,4-d)pyrimidine derivatives. XI. On 1-phenyl-1H-pyrazolo(3,4-d)pyrimidine-4-carbonitrile (author's transl)

1-Phenyl-1H-pyrazolo [3, 4-d] pyrimidine-4-carbonitrile (I) is synthesized by the application of potassium cyanide to 4-(p-tolysulfonyl)- (II) or 4-chloro-1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine (III) in dimethyl sulfoxide. Application of a nucleophilic reagent to I results in two kinds of reaction according to the kind of the reagent used. One (A) is the substitution of the -CN group by the attack of the reagent on carbon at 4-position to which -CN is bonded. The other (B) is the addition reaction to -CN group by the attack of the reagent on the carbon atom of -CN group. The reaction (A) occurs with hydroxide ion, alkoxide ion, amines, hydrazines, and carbanions (active methylene compound or ketone in the presence of sodium amide). Reaction (B) occurs in acid hydrolysis and in the reaction with hydrogen peroxide in alkalinity, hydroxylamine, and hydrogen sulfide, resulting in the formation of carboxylic acid, carboxamide, carboxamidoxime, and thiocarboxamide, respectively. Reduction with Raney nickel in formic acid results in two-way reactions ; reduction of -CN group to -CH2NH2 group (B) or replacement of -CN group with a hydride ion (A).

The transformation of 3,4-dihydro-4-quinazolinylmethyl alkyl ketones into quinolines.

Both the reactions of 3, 4-dihydro-4-quinazolinylmethyl alkyl ketones (4) with active methylene compounds or ketones (NuH) without a catalyst and in the presence of alumina as a catalyst were carried out, and resulted in the transformation of 4 into quinolines (3). Thus 2-(3, 4-dihydro-4-quinazolinyl) acetophenone (4a), 2-(3, 4-dihydro-4-quinazolinyl)-cyclohexanone (4b), and 1-(3, 4-dihydro-4-quinazolinyl)-2-propanone (4c) reacted with diethyl malonate (NuH-2), phenylacetonitrile (NuH-3), acetophenone (NuH-4), cyclopentanone (NuH-5), and cyclohexanone (NuH-6) without catalyst to give 2-phenylquinoline (3b), 1, 2, 3, 4-tetrahydroacridine (3c), and 2-methylquinoline (3d), respectively, together with the dissociation product, quinazoline (1a), although the yield of 3 was very poor. Alumina as a catalyst accelerated these reactions to give 3 in moderate yield. Even the reaction with chloroform (NuH-7) and ethyl orthoformate (NuH-8) gave 3 in good yield. The phenyl and methyl groups substituted at the 2-position prevented 4 from transforming into 3 in both the reactions without a catalyst and in the presence of alumina. A similar transformation was also found between 4, 5-dihydro-5-hydroxy-1-methyl-1H-pyrazolo [3, 4-d] pyrimidine-4-malononitrile (5) and NuH in the presence of alumina, and resulted in the formation of 6-amino-1-methyl-1H-pyrazolo [3, 4-b] pyridine-5-carbonitrile (8). The possible mechanism of the reaction was discussed.

The transformation of pyrido[2,3-d]pyrimidine into 1,8-naphthyridine.

The reaction of pyrido [2, 3-d] pyrimidine (1) with active methylene compounds and ketones (NuH) were carried out, and resulted in the formation of 1, 8-naphthyridines. Thus, the reaction with acetophenone (NuH-1), propiophenone (NuH-2), butyrophenone (NuH-3), cyclopentanone (NuH-4), cyclohexanone (NuH-5), malononitrile (NuH-6), and ethyl cyanoacetate (NuH-7) gave 2-phenyl-(2-1), 3-methyl-2-phenyl-(2-2), 3-ethyl-2-phenyl-1, 8-naphthyridine (2-3), 7, 8-dihydro-6H-cyclopenta [b] [1, 8] naphthyridine (2-4), 6, 7, 8, 9-tetrahydrobenzo [b] [1, 8] naphthyridine (2-5), 2-amino-1, 8-naphthyridine-3-carbonitrile (2-6), and ethyl 2-amino-1, 8-naphthyridine-3-carboxylate (2-7), respectively. And the possible reaction mechanism was proposed.

ChemInform Abstract: STUDIES ON PYRAZOLO(3,4‐D)PYRIMIDINE DERIVATIVES. IV. ON 1‐METHYL‐ AND 1‐PHENYL‐1H‐PYRAZOLO(3,4‐D)PYRIMIDINE 5‐OXIDE

AbstractVerschiedene Reaktionen der durch Kondensation der Pyrazole (I) mit Orthoameisensäureester in 38 ‐ 39%iger Ausbeute erhältlichen Pyrazolopyrimidin‐S‐oxide (II) wurden untersucht.

ChemInform Abstract: Reactions of 1‐Substituted‐1H‐Pyrazolo(3,4‐d)pyrimidines with Active Methylene Compounds and Ketone in the Presence of Sulfuric Acid.

Abstract1‐Methyl‐ und l‐Phenylpyrazolo(3,4‐d)pyrimidin (I) werden mit aktiven Methylenverbindungen und Ketonen wie Malodinitril, Acetessigester, Aceton, Cyclopentanon, Cyclohexanon oder Acetophenon in Gegenwart von Schwefelsäure zu zahlreichen Pyrazolo(3,4‐b)pyridinen wie (II) umgesetzt.

Studies on pyrazolo[3,4-d]pyrimidine derivatives. IV. On 1-methyl- and 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 5-oxide.

Various reactions usually carried out on heterocyclic N-oxides were examined on 1-methyl-(IIm-0) and 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine 5-oxide (IIp-0) prepared from the condensation-cyclization of 1-methyl-(IIIm-1) or 1-phenyl-5-amino-4-hydroxyiminomethyl-1H-pyrazole (IIIp-1) and ethyl orthoformate. The reaction of IIp-0 with alkaline solution gave the ring fission product between the 5- and 6-position such as 5-formamido- (IIIp-5) and 5-amino-4-hydroxyiminomethyl-1-phenyl-1H-pyrazole (IIIp-1). Application of the Reissert reaction to II-0 resulted in the formation of the ring fission products such as O-benzoyl derivative of IIIp-1 (IIIp-6) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (IIIm-3). Acetic anhydride and IIm-0 gave 1-methyl-1H-pyrazolo [3, 4-d] pyrimidin-4-ol-(Im-4). But the reaction with IIp-0 gave both 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine-4-ol (Ip-4) and 5-acetamido-1-phenyl-1H-pyrazole-4-carbonitrile (IIIp-8). Ip-4 was also obtained from the reaction of IIp-0 with tosyl chloride. The thermal decomposition of II-0 afforded 4, 4'-bis [1-methyl-1H-pyrazolo [3, 4-d] pyrimidine] (IXm) and 4, 4'-bis [1-phenyl-1H-pyrazolo [3, 4-d] pyrinidime] (IXp) together with 1-methyl-(Im-0) and 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine (Ip-0). The Grignard reaction of II-0 gave 1-Methyl-(IIm-7-9) and 1-phenyl-4-alkyl-1H-pyrazolo-[3, 4-d] pyrimidine 5-oxide (IIp-5-9). Im-0 and II-0 were transformed into 1-methyl-(XIXm) and 1-phenyl-1H-pyrazolo [3, 4-b] pyridines (XIXp) by the reaction with some active methylene compounds or ketone such as malononitrile (A-1), ethyl cyanoacetate (A-2), ethyl acetoacetate (A-3), acetylacetone (A-4) and cyclohexanone (A-5). Thus, in the presence of ethoxide ion Im-0 reacted with A-1 to give 6-amino-1-methyl-1H-pyrazolo [3, 4-d] pyridine-5-carbonitrile (XIXm-1). The direct reaction of IIm-0 with A-1 and A-2 gave 4, 5-dihydro-5-hydroxy-1-methyl-1H-pyrazolo [3, 4-d] pyrimidine-4-malononitrile (XXm) and ethyl α-cyano-4, 5-dihydro-5-hydroxy-1-methyl-1H-pyrazolo [3, 4-d] pyrimidine-4-acetate (XXm-2). But the direct reaction with A-3, 4 and 5 afforded the corresponding XIXm (XIXm-3, 4, and 5), respectively. The reaction of IIp-0 with A-1, 3, and 4 formed the corresponding XIXp (XIXp-1, 3, and 4) together with IXp (in the case of A-3 and 4), Ip-0 (in the case of A-4) and the ring fission product such as ethyl 2-(4-cyano-1-phenyl-1H-pyrazol-5-ylaminomethylene)-3-oxobutyrate (XXIp-3) and ethyl 2-(4-hydroxy-iminomethyl-1-phenyl-1H-pyrazol-5-ylaminomethylene)-3-oxobutyrate (XXIp-3') (in the case of (A-3).

Reactions of 1-Substituted-1H-pyrazolo[3,4-d]pyrimidines with Active Methylene Compounds and Ketone in the Presence of Sulfuric Acid

Reactions of 1-Substituted-1H-pyrazolo[3,4-d]pyrimidines with Active Methylene Compounds and Ketone in the Presence of Sulfuric Acid