cas 5147-80-8, 2-[DI(METHYLTHIO)METHYLIDENE]MALONONITRILE

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Synthesis of Polysubstituted Pyrimidines from Ketene Dithioacetals Using KF/Al2O3 Catalyst
KF/Al2O3 was first used to catalyze the synthesis of 2-alkylthio-4-amino-5-cyano-6-methylthiopyrimidines 3a-f via the reaction of the ketene dithioacetals 1 (prepared from malononitrile) with isothiuronium salts 2a-f. Six pyrimidine compounds were prepared and all of their structures were confirmed by elemental analysis, 1H NMR, and IR. The reaction conditions (solvents, catalyst amounts, and temperature) were investigated for the first time. The separation yield reached 89%.
Yu, Shen-Yi,Cai, Ya-Xian
p. 3989 - 3995
(2003)
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Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity
Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.
Chen, Rui,Gong, Guowei,Han, Yufei,Lei, Qiancheng,Liao, Weike,Liu, Jiaan,Qi, Yinliang,Sun, Ming,Tang, Lei,Tian, Ye,Wang, Zhongyuan,Xie, Juan,Zhao, Yanfang
supporting information

(2020/05/05)

Preparation method and use of thiophene compound
The invention belongs to the technical field of pharmaceutical chemistry, and relates to thiophene compounds shown by general formula I, pharmaceutically acceptable salts, solvates or prodrugs and preparation methods thereof. In which substituents L, Ar, R have the meanings given in the specification. The invention also relates to a strong PI3K inhibitory effect of a compound of the general formula I, and also relates to the use of such compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in the preparation of drugs for the treatment and/or prevention of diseases caused by abnormally high expression of PI3K, in particular in the preparation of drugs for the treatment and/or prevention of cancer.
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(2020/02/17)

Discovery and optimization of pyrazolopyrimidine sulfamates as ATG7 inhibitors
Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.
Adhikari, Sharmila,Brownell, James E.,Calderwood, Emily F.,Chouitar, Jouhara,D'Amore, Natalie Roy,England, Dylan B.,Foley, Klaudia,Gould, Alexandra E.,Harrison, Sean J.,Huang, Shih-Chung,LeRoy, Patrick J.,Lok, David,Lublinsky, Anna,Ma, Li-Ting,Menon, Saurabh,Yang, Yu,Zhang, Ji
(2020/08/13)

Tailored-design Synthesis of Sulfapyrimidine Derivatives
In this paper, we report an efficient and convenient approach for the synthesis of tailored-design target sulfapyrimidine derivatives expected to show remarkable antimicrobial activities. The approach is based on reacting arylsulfonyl guanidine with α,β-unsaturated carbonyl compounds to afford N-(4,6-diarylpyrimidin-2-yl)arylsulfonamide or with ylidene derivatives to afford N-(6-aryl-5-cyanopyrimidin-2-yl)arylsulfonamide, N-(4-amino-5-cyano-6-(methylthio)-pyrimidin-2-yl)-arylsulfonamide, and N-(5-cyanopyrimidin-2-yl)arylsulfonamide compounds through Michael addition reaction. The structure of the newly synthesized compounds was confirmed from spectral data and elemental analysis.
Azzam, Rasha A.
p. 619 - 627
(2019/01/04)

Reactions of ketene dithioacetal for a new versatile synthesis of 4,5-substituted 3-aminothiophene-2-carboxylate derivatives
ABSTRACT: Poly substituted 3-aminothiophenes were successfully synthesized in good yields by using a one-pot protocol via ketene S,S-acetal as an intermediate in basic medium (K2CO3/N,N-dimethylformamide) followed by Dieckmann condensation with ethyl bromoacetate. Further, chemistry of thiophenes was explored using active functional groups such as C3–NH2, C4–CN and C5–SCH3 on the thiophene nucleus. Synthesis of ethyl 3-acetamido-4-cyano-5-(methylthio)thiophene-2-carboxylate derivatives and ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate derivatives.
Chavan, Satish M.,Toche, Raghunath B.,Patil, Vasant M.,Aware, Pankaj B.,Patil, Poonam S.
p. 426 - 437
(2016/07/23)

Tin tetrachloride-catalyzed regiospecific allylic substitution of quinone monoketals: An easy entry to benzofurans and coumestans
A highly regioselective allylic substitution of quinone monoketals with a-oxoketene dithioacetals is achieved under the catalysis of only tin tetrachloride (1 mol%). The advantages of the reaction, including its simplicity, rapidity, low catalyst loading of inexpensive tin tetrachloride, mild conditions and; in particular, the regiospecificity, is proposed to be due to a pseudo-intramolecular process. This new synthetic method provides a facile [3+2] cycloaddition route to benzofurans and is highlighted by the synthesis of coumestans.
Liu, Yingjie,Liu, Jingxin,Wang, Mang,Liu, Jun,Liu, Qun
supporting information
p. 2678 - 2682
(2013/01/15)

Synthesis, structural characterization of some pyrazolo [3,4-d] pyrimidine derivatives as anti-inflammatory agents
A SERIES of pyrimidine and fused triazolopyrimidine derivatives were newly synthesized using aminopyrazole carbonitrile 1 as a had starting material and compounds 14 and 16 are intermediates. Initially, the acute toxicity of the compounds was assayed via the determination of their LD50, and all compounds were interestingly less toxic and had lower ulcerogenic activities than Diclophenac as a reference drug. Regarding the protection against Carrageenan induced edema; the pharmacological screening showed that compounds 17, 11, 13 and 5 have good anti-inflammatory activities comparable to the reference drug. On the other hand, in searching for COX-2 inhibitor, the inhibition of plasma prostaglandine (PGE2) for the compounds was determined and the same four compounds were found the more potent agents. The detailed synthesis, spectroscopic data, pharmacological screening and acute toxicity LD50 for the synthesized compounds were reported.
Abd El-Salam,Zaki,Said,Abdulla
p. 529 - 547
(2014/04/03)

SNAr and palladium-catalyzed reactions of deactivated thiophene: Application to the synthesis of protein farnesyltransferase inhibitors
To investigate the influence of the 5-thioether moiety of our previously identified hit thiophene compound upon protein farnesyltransferase inhibition, we synthesized a new library of 3-(4-chlorophenyl)-4-cyanothiophene-2-carboxylic derivatives through the application of aromatic nucleophilic substitutions benefiting from a sulfone-based leaving group and by direct palladium-catalyzed reactions on a thioalkylthiophene. This small library of ester derivatives and their corresponding acids was then evaluated for protein farnesyltransferase inhibitory activity; some library members exhibited promising submicromolar activities. Copyright
Lethu, Sebastien,Dubois, Joelle
experimental part
p. 3920 - 3931
(2011/09/14)

Development of scalable syntheses of selective PI3K inhibitors
On the basis of a more practical and scalable route to an iodothiophene, an efficient and reliable synthesis has been developed for three selective PI3K inhibitors. From this advanced intermediate, the three title compounds were each prepared in five additional steps. Key learnings also include: high throughput experimentation (HTE) screening toward a more robust Suzuki coupling, a more efficient triazole synthesis, and an acid/base cleanup developed to purify the final compounds. The final enabled synthesis required no column chromatography.
Huang, Qinhua,Richardson, Paul F.,Sach, Neal W.,Zhu, Jinjiang,Liu, Kevin K.-C.,Smith, Graham L.,Bowles, Daniel M.
experimental part
p. 556 - 564
(2011/12/02)

Facile method for the synthesis of pyrazolo[3,4-b]-pyrido[4,3-d]- pyrimidine-4-ones via a tandem aza-wittig reaction
Fifteen novel pyrazolo[3,4-b]-pyrido[4,3-d]-pyrimidine-4-ones (7a-o) were designed and have been successfully synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 5, phenylisocyanate, and substituted phenols in 60-77% isolated yields. Their structures were clearly verified by infrared (IR), 1H NMR, electron impact-mass spectrometry (EI-MS), and elemental analysis. The results of a preliminary bioassay indicated that some compounds possess inhibition activities against the root of Brassica napus (rape) and Echinochloa crusgalli (barnyard grass) at a dosage of 100mg/L and 10mg/L.
Wang, Tao,Zheng, Cai Hua,Liu, Shu,He, Hong Wu
scheme or table
p. 3386 - 3398
(2009/12/09)

One-pot synthesis of new tetrasubstituted thiophenes and selenophenes
In this work, we described the synthesis of new tetrasubstituted thiophenes and selenophenes achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from ketene dithioacetals.
Thomae, David,Perspicace, Enrico,Henryon, Dorothée,Xu, Zhanjie,Schneider, Serge,Hesse, Stéphanie,Kirsch, Gilbert,Seck, Pierre
experimental part
p. 10453 - 10458
(2010/02/28)

Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines
9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)2C=C(SMe) 2]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines. Georg Thieme Verlag Stuttgart.
Crawford, Julia A.,Fraser, William,Ramsden, Christopher A.
body text
p. 1271 - 1278
(2009/12/07)

Facile synthesis of pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d] pyrimidin-4-one derivatives
Pyrazolopyrimidine and pyrimidopyrimidine derivatives have shown a wide range of biological activities such as acting as A1 adenosine receptors, kinase insert domain receptor (KDR), Rous sarcoma oncogene (Src), epidermal growth factor receptor (EGFR), antiproliferative, dihydrofolate reductase (DHFR), antimicrobial, antifungal, and lipid peroxidation. Because of this wide range of activities, we have synthesized pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d]pyrimidin-4-one derivatives. Copyright Taylor & Francis Group, LLC.
Katiyar, Sanjay Babu,Kumar, Arun,Chauhan, Prem M. S.
p. 2963 - 2973
(2007/10/03)

An easy access to variously substituted pyrroles starting from ketene dithioacetals
Variously substituted pyrroles 4 can easily be synthesized in two steps by reacting a primary or secondary amine and a ketene dithioacetal in a basic medium in moderate to good yield. Ketene dithioacetals 2 are readily prepared from acetylaceton or malononitrile, carbon disulfide, and methyl iodide.
Sommen, Geoffroy L.,Cornel, Alain,Kirsch, Gilbert
p. 693 - 699
(2007/10/03)

Ketene aminal-based lactam derivatives as a novel class of orally active FXa inhibitors
N,N′-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
Shi, Yan,Zhang, Jing,Stein, Philip D.,Shi, Mengxiao,O'Connor, Stephen P.,Bisaha, Sharon N.,Li, Chi,Atwal, Karnail S.,Bisacchi, Gregory S.,Sitkoff, Doree,Pudzianowski, Andrew T.,Liu, Eddie C.,Hartl, Karen S.,Seiler, Steven M.,Youssef, Sonia,Steinbacher, Thomas E.,Schumacher, William A.,Rendina, Alan R.,Bozarth, Jeffrey M.,Peterson, Tara L.,Zhang, Ge,Zahler, Robert
p. 5453 - 5458
(2007/10/03)

Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists
In the past few years, our group has been involved in the development of A2A and A3 adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine, 61), potent and very selective at the A2A receptor subtype, and N8-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines-N5-urea or amide (MRE series, b), very selective at the human A3 adenosine receptor subtype. We now describe a large series of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N8-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidines-N5-urea or -amide. The substitution of the furanyl moiety of compound 61, necessary for receptor binding, with a phenyl or a substituted aromatic ring (compounds 5a-d, 6-8), caused a complete loss of the affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface. The introduction of an ethoxy group at the ortho position of the aromatic ring to mimic the oxygen of the furan (compound 5c, 5-amino-7-(2-phenylethyl)-2-(2-ethoxyphenyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine) did not enhance affinity. The introduction of the cycloaminomethyl function by Mannich reaction at the 5′ position of the furanyl ring of 61 and the C9-substituted compound 41 (5-amino-8-methyl-9-methylsulfanyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine) resulted in complete water solubility but a loss of receptor affinity. We can conclude that modifications or substitutions at the furanyl ring are not allowed and the introduction of a substituent at the 9-position of the core pyrazolo-triazolo-pyrimidine structure caused a severe loss of selectivity, probably due to an increased steric hindrance of the radical introduced.
Baraldi, Pier Giovanni,Fruttarolo, Francesca,Tabrizi, Mojgan Aghazadeh,Preti, Delia,Romagnoli, Romeo,El-Kashef, Hussein,Moorman, Allan,Varani, Katia,Gessi, Stefania,Merighi, Stefania,Borea, Pier Andrea
p. 1229 - 1241
(2007/10/03)

PHARMACEUTICALLY ACTIVE COMPOUNDS HAVING A TRICYCLIC PYRAZOLOTRIAZOLOPYRIMIDINE RING STRUCTURE AND METHODS OF USE
New compounds having a tricyclic pyrazolotriazolopyrimidine ring structure are provided and methods of using those compounds for a variety of therapeutic indications.
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Page 35-36

(2010/11/30)

Novel intramolecular cyclization of pyrazolone ketene S,N-acetals for the construction of methylsulfanylpyrazolo-[4,3-b]pyridines
A novel and efficient method for the synthesis of 6-substituted-7,7a-dihydro-1,7a-dimethyl-7-imino-2-phenyl-1H-pyrazolo[4, 3-b]pyridin-3(2H)-ones via the reaction of 4-amino-2,3-dimethyl-1-phenylpyrazolin-5-one with ketene dithioacetals and ethoxy-methylenemalononitrile or ethyl ethoxymethylene-cyanoacetate followed by intramolecular cyclization of the products has been investigated.
Elgemeie, Galal H.,Elzanate, Ali M.,Elghandour, Ahmed H.,Ahmed, Sayed A.
p. 3509 - 3517
(2007/10/03)

Application of commercially available anhydrous potassium fluoride for a convenient synthesis of ketene dithioacetals
Commercially available anhydrous KF without activation or solid support promotes condensation between active methylene compounds, carbon disulfide and an alkylating agent in dry DMF to allow the preparation of a variety of ketene dithioacetals in fair to good yields under ambient conditions.
Mashraqui, Sabir H.,Hariharasubrahmanian, Harini
p. 492 - 493
(2007/10/03)

SYNTHESIS OF SOME NEW FUSED HETEROCYCLES CONTAINING A BRIDGEHEAD NITROGEN ATOM UNDER PTC CONDITIONS. A NEW APPLICATION OF CYANOKETENE S,S-ACETALS
A novel synthesis of some fused heterocyclic compounds containing a bridgehead nitrogen atom was achieved using PTC conditions.Suitable ketene S,S-acetals were thus prepared and allowed to react with some o-substituted anilines to give (2,3-dihydrobenzothiazol-2-ylidenyl)malonodinitrile, 2a, ethyl (2,3-dihydrobenzothiazol-2-ylidenyl)cyanoacetate, 2b, (2,3-dihydrobenzoxazol-2-ylidenyl)malonodinitrile, 2c, ethyl (2,3-dihydrobenzoxazol-2-ylidenyl)cyanoacetate, 2d, (2,3-dihydrobenzimidazol-2-ylidenyl)malonodinitrile, 2e, and ethyl (2,3-dihydrobenzimidazol-2-ylidenyl)cyanoacetate, 2f.These afforded the desired products on reaction with a variety of halo compounds.
El-Shafei, Ahmed Kamal,Soliman, Ahmed Mohamed,Sultan, Adel Abdel-Rahim,El-Saghier, Ahmed Mohamed Mohamed
p. 115 - 118
(2007/10/02)

The Reaction of Methyl 3-Amino-4-cyano-5-methylthiothiophene-2-carboxylate with DMAD. A New Synthesis of Polyfunctionalized Quinolines
The reaction of methyl 3-amino-4-cyano-5-methylthiothiophene-2-carboxylate (2), which was prepared by the reaction of bis(methylthio)methylenepropanedinitrile (1) with methyl thioglycolate followed by dimethyl acetylenedicarboxylate (DMAD) in the presence of potassium carbonate in dimethyl sulfoxide gave the polyfunctionalized quinoline pentamethyl 4-amino-5-mercaptoquinoline-2,3,6,7,8-pentacarboxylate (3).The oxidation of 3 with iodine in DMSO provided the novel ring system in the form of the derivative, pentamethyl-2H-isothiazoloquinoline-3,4,6,7,8-pentacarboxylate (4).
Tominaga, Yoshinori,Luo, Jiann-Kuan,Castle, Raymond N.
p. 771 - 774
(2007/10/02)

6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
Novel 6-heterocyclyl-pyrazolo[3,4-d]pyrimidin-4-ones, useful in treating cardiovascular disease, are prepared by reacting a 5-amino-1H-pyrazole-4-carboxamide with heterocyclylcarboxaldehyde or by reacting a 5-amino-1H-pyrazole-4-carbonitrile with a heterocyclylcarboxamidine, followed by diazotization and hydrolysis of the resulting 4-amino-6-heterocyclyl-pyrazolo[3,4-d]pyrimidine.
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(2008/06/13)

Synthesis, Reactions, and Tautomerism of Ketene N,S-Acetals with Benzothiazoline Ring
Ketene dithioacetals 2 react with 2-aminothiophenol to afford the corresponding substituted 2(3H)-methylenebenzothiazoles 3.Some compounds 3 react with α,β-unsaturated esters to give 1H-pyridobenzothiazole derivatives 4 and 5 by an electrophilic addition and cyclocondensation sequence.
Huang, Zhi-Tang,Shi, Xian
p. 541 - 547
(2007/10/02)

SYNTHESIS OF NUCLEOSIDES USING KETENE DITHIOACETALS
Several unnatural pyrazole and 1,2,4-triazole nucleosides are synthesized in a regio- and stereoselective manner by the reaction of readily available ketene dithioacetals with 1-ribofuranosylhydrazine.
Yokoyama, Masataka,Kumata, Katsushi,Yamada, Naoyuki,Noro, Hidehiko,Sudo, Yuka
p. 2309 - 2314
(2007/10/02)

HETEROCYCLIC AND RELATED COMPOUNDS DERIVED FROM DIPOTASSIUM 1,1-DIMERCAPTO-2,2-DICYANOETHYLENE AND SODIUM 2-MERCAPTOPYRIDINE N-OXIDE
The reaction of dipotassium 1,1-dimercapto-2,2-dicyanoethylene with certain halogen compounds furnished the expected dialkylation products (1)-(4).Replacing the halogen compound with 4-chloro-3,5-dinitrobenzotrifluoride afforded a novel heterocycle (5).The reaction of the potassium salt with phenyl or p-chlorophenylchlorothioformate gave 2,2-diphenyl or di-p-chlorophenylthio-2,2-dicyanoethylene (6) and (7).The reaction of 1 or 2 with excess hydrogen peroxide afforded substituted oxiranes (8) and (9).Depending on reaction conditions, the reaction of sodium 2-mercaptopyridine N-oxide with 4-chloro-3,5-dinitrobenzotrifluoride afforded either the expected sulfide (11) or the unexpected heterocycle (12).Possible mechanisms and supporting NMR, Ir and mass spectral data are discussed.
D'Amico, J. J.,Ruminski, P. G.,Suba, L. A.,Freeman, J. J.,Dahl, W. E.
p. 307 - 314
(2007/10/02)

Quantitative structure activity relationships of S,S'-dialkyldithiomethylenmalonodinitrilen with regard to antimicrobial activity (author's transl)
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Rehn,Nolte,Zerling,Rehn
p. 817 - 823
(2007/10/02)

3-Aminoisothiazole derivatives as herbicides
A new class of herbicidal compounds consisting of 1-alkyl- and 1,1-dialkyl-3-(4-substituted-3-amino-5-isothiazolyl)ureas and N-(4-substituted-3-amino-5-isothiazolyl)-alkanamides, in which the 4-substituent consists of cyano and carbamoyl, exhibits preemergence and postemergence herbicidal activity, controlling effectively the growth of a wide spectrum of grassy and broad-leaved plant species. The synthesis of members of this class is described in detail, and the utility of representative compounds is exemplified.
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(2008/06/13)

PYRIDYL-ALKYLAMINOETHYLENE COMPOUNDS
The compounds are ethylene derivatives which are inhibitors of histamine activity, in particular, inhibitors of H-2 histamine receptors. A compound of this invention is 1-nitro-2-2-((4-methyl-5-imidazolyl) methylthio)ethylamino!-2-2-((3-chloro-2-pyridyl)methylthio) ethylamino!ethylene.
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(2008/06/13)

IMIDAZOLE ALKYLAMINOETHYLENE COMPOUNDS
The compounds are ethylene derivatives which are inhibitors of histamine activity, in particular, inhibitors of H-2 histamine receptors. A compound of this invention is 1-nitro-2-methylamino-2-2-((4-methyl-5-imidazolyl)methylthio)-ethylamino!ethylene.
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(2008/06/13)

3-Alkylthio-, 3-alkylsulfinyl-, and 3-alkylsulfonylisothiazole derivatives as herbicides
A new class of herbicidal compounds consisting of 1-alkyl- and 1,1-dialkyl-3-(3,4-substituted-5-isothiazolyl)ureas and N-(3,4-substituted-5-isothiazolyl)-alkanamides in which the 3-substituent consists of alkylthio, alkylsulfinyl, and alkylsulfonyl, and the 4-substituent consists of cyano, and carbamoyl, exhibits preemergence and postemergence herbicidal activity, controlling effectively the growth of a wide spectrum of grassy and broad-leaved plant species. The synthesis of members of this class is described in detail, and the utility of representative compounds is exemplified.
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(2008/06/13)