Quinoxalines, fluorinated

Indirect fluorination of quinoxaline gave a separable mixture of 2-fluoro- and 2,3-difluoroquinoxaline (I2, Et3N, CIP2CCP2CI, P2 -f N2i, 5°C, min 48%... 

Reaction of quinoxaline with the fluorine-iodine-triethylamine system gives 2-fluoroquinoxaline 40 and 2,3-difluoroquinoxaline 41, whose yields depend on the fluorine usage (Equation 6) <1999J(P1)803>. Using 6-chloro-quinoxaline or 6,7-dichloroquinoxaline as the substrate, the monofluoro product is predominantly formed regardless of the amount of fluorine used. It is suggested that the reaction proceeds via attack of the fluoride ion on the a-carbon of an intermediate A -iodo quinoxalinium species followed by elimination of hydrogen iodide with triethylamine. 

Chambers and co-workers reported similar results fiom the fluorination of disubstituted quinoxalines 220 <99JCS(P1)803>. Chemoselectivity could be controlled simply throu the use of 1.5 equivalents (for 221) or 2 equivalents (for 222) of fluorine. 

Our approach was based on the observation that it is possible to perform SwAr reactions on solid support with amino acids using a solvent system comprised, in equal parts, of acetone and an aqueous 0.5 M NaHC03 solution at temperatures around 70-75°C. Application of this solvent system to the synthesis of quinoxalin-2-ones 6 from la and a-amino acids is described in Section 3.3.2. With respect to the synthesis of 1,5-ben-zodiazepin-2-ones 4, more than 40 examples of aliphatic and aromatic P-amino acids 35 were found to furnish the desired o-nitro anilines 36, about 80% of which were successfully carried on to eventually afford the ben-zodiazepinone products 4 (Scheme 6). In general, the anthranilic acids required slightly harsher conditions to drive the fluorine displacement to completion (75-80°C, 72 h vs. 70-75°C, 24 h for aliphatic P-amino acids). 

The fluorine chemical shifts for fluoropyrimidines, 2-fluoropyrazine, 2-fluoro quinoxaline, 4-fluoroquinazaline, 5-fluorouracil, 5-fluoro-cytosine, and cyanuric fluoride are provided in Scheme 3.82. The fluorine of 2-fluoropyrimidine is considerably deshielded relative to... 

G. J. Dear, I. M. Ismail, P. J. Mutch, R. S. Plumb, L. H. Davies, and B. C. Sweatman, Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in rabbit, mouse and human Identification of fluorine NIH shift metabolites using NMR and tandem Xenobiotica 30 (2000), 407 26. 

Four-membered heterocydes are easily formed via [2+2] cycloaddition reac tions [63] These cycloaddition reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [77d] Via this route, p lactones are formed on addition of ketene derivatives to hexafluoroacetone [777, 77S] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, l,4-benzoxazin-2-ones, l,2,4-tnazin-5-ones, and l,2,4-tnazm-3,5-diones accelerates [2+2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluorinated oxetanes are formed thermally and photochemically [779, 720] The reaction of 577-1,2-azaphospholes with fluonnated ketones leads to [2+2] cycloadducts [727] (equation 27)... 

Perfluorobutane-2,3-dione (76.15), a reactive compound which sometimes shows unexpected properties, behaved predictably with o-phenylenediamine to give quinoxalines. The cyclizations proceeded at or below room temperature in good yields [3165]. Transmolecular covalent hydrates were isolated from the reaction of diaminouracils (76.16) with the fluorinated diketones [3166]. 3-Phenyl-l,l,I-trifluoropropane-2,3-dione also behaves normally to give 3-(4-tolyl)-2-trifluoromethylquinoxaline in 63% yield [3409]. 

Fluorine-containing 2-oximino-l,3-oxo ethers 49 react with o/7/w-phenylenedia-mine in methanol, benzene, or toluene, giving substituted quinoxalines 50 and 51 rather than the expected 1,5-benzodiazepinones or benzimidazoles (98ZOR405) (Scheme 49). 

Heteroaromatic fluorination. Fluorination of pyridine, quinoline, and quinoxaline systems occurs with fluorine-iodine mixtures. Pyridine is alkoxylated when an appropriate alcohol is present. 

Under the same conditions, quinolines and quinoxalines also undergo regiose-lective fluorination and give monofluorinated products 7a-7g in high yields (Scheme 6.4, Table 6.3). 

Chambers, R.D. Parsons, M. Sandford, G. Skinner, C.J. Atherton, M.J. Moilhet, J.S. Elemental fluorine. Part 10. Selective fluorination of pyridine, quinohne and quinoxaline derivatives with fluorine-iodine mixtures. J. Chem. Soc., Perkin. Trans. 1 1999, 803-810. 

Recently, Kamitori reported a new procedure to synthesize fluorine-containing heterocycles including pyrazines and imidazoles <01JHC773>. Aldehyde-derived dialkylhydrazones 199 were treated with trifluoroacetic anhydride to give 200, which was then hydrolyzed with H2SO4 to afford 201, a-Diketohydrates 201 reacted readily with diamines such as diamino succinonitrile to afford pyrazines 202, or with 1,2-phenylencdiamine to yield quinoxalines 203 in good yields. 

Charushin and co-workers prepared the first example of fluorine-containing quinoxaline derivatives, pyrimido[4,5-b]quinoxalincs 265. in two steps <01MC54>. First, orlho-aminonitriles 263 were converted into carboxamides 264 upon treatment with concentrated sulfuric acid, followed by cyclization of the cvr/to-aminocarboxamides 264 with triethyl orthoformate to give 265 in excellent yield. 

Similar selectivity issues can be found in triflamide-directed reactions (Scheme 23.48) [153]. Using a modified fluorinating reagent 26, mono- and difluorinated products can be obtained. A more recent development focuses on addressing this selectivity issue with an auxihary-based approach [ 154]. Finally, quinoxaline-based directing groups are also able to promote mono-selective C-H bond fluorinations in combination with N-fluorobenzenesulfonimide as F+ source [151],... 

Khaksar S, Rostamnezhad F (2012) A novel one pot synthesis of quinoxaline derivatives in fluorinated alcohols. Bull Korean Chem Soc 33 2581-2585... 

Reaction of 3,4-difluoropyrrole 391 with oxalyl chloride 460 led to the corresponding 1,2-diketone 461, which was transformed into quinoxaline 463 in high yield by the reaction with 1,2-phenylenediamine 462 [150], Using reaction of 1,3-diketone 464 with hydrazine, fluorinated dipyrrolylpyrazole 465 was prepared in good yield [151]. 

Excluding pyrimidine derivatives electrophilic fluorination of other diazines was almost not studied. To the best of our knowledge there is no examples of electrophilic fluorination of pyridazines and only 1 paper and 1 patent devoted to fluorination of pyrazines and quinoxaline. Chambers and co-workers described fluorination of quinoxalines 29 in good yields using elemental fluorine-iodine mixtures at room temperature (Scheme 8). Mono- (30) and difluorinated products 31 were formed in different ratio depending on amount of fluorine used in the reaction. It should be noted that pyrazine, pyrimidine and pyridazine were recovered unchanged using similar condition [42]. 

Chain-fluorinated diazines is another family of organofluorine compounds which is of great importance for synthetic, medicinal and agricultural chemistry [12, 13], The first representatives of this class, namely, chain-fiuorinated pyrimidines and quinoxalines were obtained in late 1950s. Since then, over a thousand papers dealing with synthesis and chemistry of chain-fluorinated diazines were published. 

A common method for the preparation of chain-fluorinated pyrazines relies on reaction of NCCN binucleophiles (i.e. 1,2-diamines) and fluorinated CC bis-electrophiles. This approach is especially valuable for the synthesis of quinoxalines and their hetero-analogues, since aromatic system is formed directly under reaction conditions. Therefore, most of the literature data concern heterocyclization with o-phenylenediamines, as well as the corresponding heterocyclic 1,2-diamines. 

An interesting method for preparation of fluorinated quinoxaline AA -dioxides 1094 relies on reaction of benzofuroxanes 1093 with flnorinated p-dicarbonyl componnds - a fluoro version of the so-called Beirut reaction (named after the city where it was discovered) (Scheme 232). The reaction has attracted some attention due to the products 1094 revealed high antitumor and anti-trypanosomatid activity [665-667], The method gave satisfactory results when at least one of the starting components was symmetric otherwise, the reaction was not always regioselective. The approach was also used for simple fluorinated ketones in this case, the corresponding products 1095 were obtained in low to moderate yields (16-48 %) [668]. 

The same group of Japanese authors studied the photochemical reaction of fluorinated quinoxalines. Photochemical cycloadditions with quinoxaline derivative 1294 occurred and C=N double of the diazine ring, leading to the formation of azetidine derivatives (Scheme 299). The presence of trifluoromethyl group in the molecule of 1294 activated the substrate towards cycloaddion, so that even electron-deficient methyl methacrylate was introdnced in the reaction [797], In the case of ethyl vinyl ether as the alkene, the addnct 1296 also as in a case with 1289 was not stable and underwent azetidine ring-opening npon action of the solvent. Ketene was also successfully introduced in [2+2] cycloaddition with trifiuoromethyl-substituted quinoxaline derivatives [797]... 

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