Aryne approach towards 2,3-difluoro-10-(1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indoles (original) (raw)
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Journal of the Brazilian Chemical Society, 2008
Este trabalho descreve a versatilidade sintética dos derivados N-Acil-3,3-diflúor-2-oxoindóis, obtidos a partir da reação de N-acilisatinas com dietilaminotrifluoreto de enxofre (DAST) que, através da reação com diferentes nucleófilos, promovem a abertura do anel heterocíclico, levando à formação de vários produtos. A reação de N-Acil-3,3-diflúor-2-oxoindóis com água fornece os ácidos 2-(2-N-acilfenil)-2,2-difluoracéticos e com álcoóis fornece os ésteres correspondentes. Reações com aminas e glicina levam à formação das correspondentes amidas 2-(2-N-acilfenil)-2,2-difluoracetamidas. Na reação com tiossemicarbazidas os derivados difluortiossemicarbazidas são obtidos. Estes últimos sofrem uma ciclização catalisada por ácido para fornecer N-(2-((5aminoaril-1,3,4-tiadiazol-2-il)difluormetil)-4-(R)-fenil)acetamida. A estrutura de N-(2-((5-amino-1,3,4-tiadiazol-2-il)difluormetil)-4-metilfenil)acetamida foi determinada por raio-X. This paper describes the versatility of N-Acyl-3,3-difluoro-2-oxoindoles, obtained from the the reaction of N-acylisatins with (diethylamino)sulphur trifluoride (DAST) which, on opening of the heterocyclic ring by reactions with nucleophiles, lead to the formation of a variety of products: reaction with water yields 2-(2-amidoacyl)-2,2-difluoroacetic acids, with alcohols yields alkyl 2-(2-amidoacyl)-2,2-difluoroacetates, with amines and glycine yields 2-(2-amidoacyl)-2,2difluoroacetamides and with thiosemicarbazides yields difluorothiosemicarbazide derivatives. The latter undergo acid-catalysed cyclizations to yield N- (2-((5-aminoaryl-1,3,4-thiadiazol-2-yl) difluoromethyl)-4-(R)-phenyl)acetamide. The X-ray structure of N- (2-((5-amino-1,3,4-thiadiazol-2-yl)difluoromethyl)-4-methylphenyl)acetamide has been determined.
ChemInform, 2010
This review covers the trifluoroacetylation reaction in organic synthesis and its importance for the construction of trifluoromethylated compounds. Developed reagents for trifluoroacetylation are described, as well as their characteristics and preparation, giving emphasis on their applications and limitations in organic synthesis. Trifluoroacetylation, although commonly employed for the protection of functional groups (amines, alcohols, thiols), may be a useful tool for the further introduction of a trifluoromethyl group into an organic molecule. Its application, mainly in the synthesis of trifluoromethyl-heterocycles such as benzothiadiazines, pyrazoles, benzodiazepines, thieno-thiazines, isoxazoles and pyrimidines, is also covered.
Current Organic Synthesis, 2010
This review covers the trifluoroacetylation reaction in organic synthesis and its importance for the construction of trifluoromethylated compounds. Developed reagents for trifluoroacetylation are described, as well as their characteristics and preparation, giving emphasis on their applications and limitations in organic synthesis. Trifluoroacetylation, although commonly employed for the protection of functional groups (amines, alcohols, thiols), may be a useful tool for the further introduction of a trifluoromethyl group into an organic molecule. Its application, mainly in the synthesis of trifluoromethyl-heterocycles such as benzothiadiazines, pyrazoles, benzodiazepines, thieno-thiazines, isoxazoles and pyrimidines, is also covered.
ChemInform Abstract: Convenient One-Pot Synthesis of N-Substituted 3-Trifluoroacetyl Pyrroles
Cheminform, 2009
Preparation of 2-oxazoline, a versatile intermediate in synthetic chemistry, from carboxylic acids is a classical and useful method. Since 2-oxazolines can be readily re-converted into carboxylic acids, they can be used as a protecting group for carboxylic acids. 3,6) Among various methods employed to convert derivatives of carboxylic acids to the oxazolines, intramolecular dehydrohalogenation of N-(bhaloethyl)amides to give 2-oxazolines is well established. Although the reaction readily takes place by treatment with either base or silver ion, such reactions have not adapted well to the preparation of 2-oxazolines, presumably because of the cumbersome method used to prepare N-(b-haloethyl)amides. For example, they have been prepared by Ritter reaction of nitriles with halohydrins or haloalkenes, 8) chlorination of N-(b-hydroxyethyl)amides with thionyl chloride, 9) and coupling of 2-haloethylammonium salts with acid chlorides 10,11) or acid anhydrides. We report here a simple and general one-pot method to prepare 2-oxazolines from carboxylic acids; the reaction involves dehydrocondensation of carboxylic acids and 2haloethylammonium salts leading to the formation of N-(bhaloethyl)amides, which then can be readily converted into 2-oxazolines by base treatment.
Tetrahedron Letters, 1999
Readily accessible fluorinated N-arylenaminones 3 were reacted with N,Ndimethylformamide dimethylacetal to produce functionalized hexadienones 4. Ring closure of 4 with ammonium acetate afforded selectively N-aryl-2-(trifluoromethyl)-4-pyridinamines 5 in good to excellent yields. N-Aryl-4-pyridinamines have recently acquired great importance as adrenergic agents, ~ CNS drugs, z antihypertensives 3 and anticonvulsant agents, 4 while the diuretic Torasemide and the cardiovascular agent MCI-154 have shown useful clinical activities. ~ Introduction of a trifluoromethyl group into bioactive molecules sometimes results in significant enhancement, not only of the potency, but also of the duration of action because of increased lipophilicity: 6 development of efficient methodologies for the synthesis of trifluoromethylated analogues has attracted great attention. 7 Synthetic procedures for access to N-aryl-4pyridinamines involve the reaction of arylamines with 4-chloropyridine s or its hydrochloride 9 or with 4chloro-l-pyridiniopyridinium salts ~° or the reaction of an active aryl chloride with 4-aminopyridine. H Nevertheless, these methods require vigorous reaction conditions and do not always give satisfactory yields. On the other hand, direct trifluoromethylation ~z and the construction of trifluoromethylated precursors L3 are widely employed for the synthesis of trifluoromethylated organic compounds. Previously, ~4 we have been Sugiura, M.; et al. Pessolano, A. A.; Shen, T.-Y.; Jacobus, D. P.; Jones, H.; Lotti, J. V.; Flataker, L. M. MedChem. 1978, 21,965-978. (b) Bailey, D. M.; DeGrazia, C. G.; Hoff, S. J.; Schulenberg, P. L.; O'Connor, J. R.; Paris, D. A.; McKenzie Slee, A. J. Med.Chem. 1984, 27, 1457-1464. 9. Sarges, R.; Howard, H. R.; Donahue, K. M.; Welch, W. M.; Dominy, B. W.; Weissman, A.; Kennet Koe, B.; Bordner, J. J. MedChem. 1986, 29, 8-19. 10. Sammes, M. P.; Ho, K.-W.; Tam, M.-L.; Katritzky, A. R. J. Chem. Soc., Perkin Trans.1 1983, 973-978.
N-Difluoromethylation of monosubstituted polydentate azoles
Chemistry of Heterocyclic Compounds, 2019
Compounds containing a difluoromethyl group are very common in the pharmaceutical industry and among chemicals used for crop protection, as well as other products with practical importance. 1,2 The difluoromethyl group has significant lipophilicity and at the same time is capable of hydrogen bonding. 3 Drug molecules containing difluoromethoxy-or difluoromethylsulfanyl groups often have low toxicity. This is a major factor enabling the use of such compounds in medicinal chemistry. Some of the compounds containing difluoromethyl group have been approved for pharmaceutical use, for example, the anaesthetic agent desflurane, the antihypertensive drug foridone (riosidine, riodipine), antiulcer medication pantoprazole, and the anti-psoriasis drug diftorant. A specific antagonist of neuropeptide Y that contains an NCHF 2 moiety is currently in clinical trial phase. 4 Some derivatives of N-(difluoromethyl)pyridin-2(1Н)-one have been characterized as enzyme inhibitors and thus have attracted the attention of researchers as potential drug molecules. 5 In agrochemical industry, herbicides sulfentrazone and carfentrazone-ethyl have been used for a long time. These herbicides are N-difluoromethyl derivatives of 1,2,4-triazol-5-one. Strong herbicidal activity has been also observed for some other N-difluoromethylazole derivatives. 6-8 Difluoromethylation of organic compounds can be performed on multikilogram scale by using such affordable reagents as chlorodifluoromethane (Freon 22) or fluoroform. 9 The difluoromethylation reactions of phenols, thiophenols, azoles, and other heterocyclic compounds have been considered in several review articles. 10-12 Difluoromethylation of ambidentate (polydentate) heterocyclic systems, as a rule, produces a mixture of isomers. 13-16 The separation of such mixtures is a key task