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Мета роботи – розробка ефективного методу синтезу 3-арил-3-трифторометил-2,3-дигідро-1Н-піролізин-1-онів як перспективних скафолдів для дизайну біоактивних сполук.Результати та їх обговорення. Показано, що конденсація метилових естерів 3-аміно-3-арил-4,4,4-трифторобутанової кислоти з 2,5-диметокситетрагідрофураном є зручним синтетичним підходом до синтезу метилових естерів 4,4,4-трифторо-3-арил-3-(1Н-пірол-1-іл)бутанової кислоти, які за схемою внутрішньомолекулярної реакції Фріделя-Крафтса перетворені на 3-арил-3-трифторометил-2,3-дигідро-1Н-піролізин-1-они.Експериментальна частина. Взаємодією метилових естерів 3-аміно-4,4,4-трифторо-3-арилбутанової кислоти із 2,5-диметокситетрагідрофураном в оцтовій кислоті при 70 оС отримані метилові естери 4,4,4-трифторо-3-арил-3-(1Н-пірол-1-іл)бутанової кислоти, які при дії броміду бору в дихлорометані при кімнатній температурі циклізуються в 3-арил-3-трифторометил-2,3-дигідро-1Н-піролізин-1-они. Структура всіх синтезованих сполук доведена методами хроматомас-спектрометрії та ІЧ-, ЯМР (1Н, 13С, 19F)спектроскопії.Висновки. Розроблено ефективний двостадійний варіант синтезу 3-арил-3-трифторометил-2,3-дигідро-1Н-піролізин-1-онів, який включає перетворення метилових естерів 3-аміно-4,4,4-трифторо-3-арилбутанової кислоти на відповідні 3-(1Н-пірол-1-іл)похідні та їх подальшу селективну внутрішньомолекулярну циклізацію в присутності надлишку броміду бору., Цель работы – разработка эффективного метода синтеза 3-арил-3-трифторметил-2,3-дигидро-1Н-пирролизин-1-онов как перспективных скаффолдов для дизайна биоактивных веществ.Результаты и их обсуждение. Показано, что конденсация метиловых эфиров 3-амино-3-арил-4,4,4-трифторбутановой кислоты с 2,5-диметокситетрагидрофураном является удобным синтетическим подходом к метиловым эфирам 4,4,4-трифтор-3-арил-3-(1Н-пиррол-1-ил)бутановой кислоты, которые по схеме внутримолекулярной реакции Фриделя-Крафтса превращены в 3-арил-3-трифторметил-2,3-дигидро-1Н-пирролизин-1-оны.Экспериментальная часть. Взаимодействием метиловых эфиров 3-амино-3-арил-4,4,4-трифторбутановой кислоты с 2,5-диметокситетрагидрофураном в уксусной кислоте при 70 оС получены метиловые эфиры 4,4,4-трифтор-3-арил-3-(1Н-пиррол-1-ил)бутановой кислоты, которые при действии бромида бора в дихлорметане при комнатной температуре циклизуются в 3-арил-3-трифторметил-2,3-дигидро-1Н-пирролизин-1-оны. Структура всех синтезированных соединений доказана методами хроматомасс-спектрометрии и ИК-, ЯМР (1Н, 13С, 19F)спектроскопии.Выводы. Разработан эффективный двустадийный вариант синтеза 3-арил-3-трифторметил-2,3-дигидро-1Н-пирролизин-1-онов, который включает превращение эфиров 3-амино-3-арил-4,4,4-трифторбутановой кислоты в соответствующие 3-(1Н-пиррол-1-ил)производные и их дальнейшую селективную внутримолекулярную циклизацию в присутствии избытка бромида бора., Aim. To develop the efficient method for the synthesis of 3-aryl-3-trifluoromethyl-2,3-dihydro-1H-pyrrolizin-1-ones as promising scaffolds in design of bioactive compounds.Results and discussion. It has been shown that condensation of 3-amino-3-aryl-4,4,4-trifluorobutanoic acid methyl esters with 2,5-dimethoxytetrahydrofuran is a convenient synthetic approach to 4,4,4-trifluoro-3-aryl-3-(1H-pyrrol-1-yl)methylbutanoic acid methyl esters converted to 3-aryl-3-trifluoromethyl-2,3-dihydro-1H-pyrrolizin-1-ones by the intramolecular Friedel-Crafts reaction.Experimental part. By the interaction of 3-amino-3-aryl-4,4,4-trifluorobutanoic acid methyl esters with 2,5-dimethoxytetrahydrofuranin acetic acid at 70 оC 4,4,4-trifluoro-3-aryl-3-(1H-pyrrol-1-yl)methylbutanoic acid methyl esters were obtained and subsequently cyclized into 3-aryl-3-trifluoromethyl-2,3-dihydro-1H-pyrrolizin-1-ones upon treatment with boron tribromide in dichloromethane at room temperature. The structures of the compounds synthesized were confirmed by LCMS, IR and NMR (1H, 13C, 19F) spectroscopic methods.Conclusions. An efficient two step protocol for the synthesis of 3-aryl-3-trifluoromethyl-2,3-dihydro-1H-pyrrolizin-1-ones has been developed. It includes transformation of 3-amino-3-aryl-4,4,4-trifluorobutanoic acid methyl esters into the corresponding 3-(1H-pyrrol-1-yl) derivatives and their further intramolecular cyclization.

Cyanoacetic acid reacted selectively with 4-(trifluoromethyl)pyrimidin-2(1Н)-ones with the formation of Michael addition–decarboxylation products in DMSO solution at 85°С and Mannich reaction products when the reagents were fused together under solventfree conditions.

The information related to the methods of the synthesis of 4- and 6-trifluoromethyl-3,4-dihydropyrimidine- 2-ones and their condensed analogs as potent molecular platforms for the synthesis of bioactive compounds has been analyzed and systematized. The role of inter- and intramolecular cyclocondensations of CF3-containing substrates, as well as nucleophilic addition to C=N bond as key steps for construction of 4-trifluorinated derivatives has been emphasized. The major part of this article is devoted to the construction of trifluoromethyldihydropirimidones of a high optical purity and their thioanalogs based on the condensation of the chiral ureas and thioureas. A special attention is paid to asymmetric reactions, which are used for the synthesis of chiral analogs of the anti-HIV drug Efavirenz. It has been noted that Biginelly reaction of the corresponding fluorinated ketoesters is the common way for obtaining 6-trifluoromethylpyrimidones. The method allows obtaining the target products in one stage although it has limitations due to the need to isolate intermediate cyclic products, which in the future should be subjected to dehydration. The effect of the catalyst nature on the course of Biginelly reaction of trifluoromethylated substrates has been analyzed. It has been shown that nucleophilic 3,6-addition to 4-CF3- dihydropyrimidones is effective method for the synthesis of dihydroorotic acid derivatives.

Background: Due to the high reactivity towards various C-nucleophiles, trifluoromethylketimines are known to be useful reagents for the synthesis of α-trifluoromethylated amine derivatives. However, decarboxylative reactions with malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues.Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones, unique heterocyclic ketimines, react with malonic acid under organic base catalysis to regioselectively provide either Michael- or Mannich-type decarboxylative addition products depending on solvent polarity. Malonic mono(thio)esters give exclusively Michael-type products. The two regioisomeric products can be converted into saturated (2-oxohexahydropyrimidin-4-yl)acetic acid derivatives by mild hydrogenation of the endocyclic C=C double bond in the presence of Pd/C as catalyst. The cis-stereoisomers selectively formed upon reduction of the Michael-type products were structurally determined by X-ray diffraction. As a result of this study, a number of novel acetic acid derivatives containing trifluoromethylated, partially or fully saturated 2-oxopyrimidine cores were prepared and characterized as promising building blocks.Conclusions: Regio- and stereoselective protocols have been developed for the synthesis of novel isomeric 4(6)-trifluoromethylated 1,2,3,4-tetrahydro- and perhydro-(2-oxopyrimidin-4-yl)acetic acid derivatives.

β-Ketoacids reacted with 4-(trifluoromethyl)pyrimidin-2(1Н)-ones according to the mechanism of Michael addition–decarboxylation, forming 4-(2-oxoalkyl)-6-(trifluoromethyl)-3,4-dihydropyrimidin-2-ones.

International audience; Unprotected -(het)aryl--fluoroalkyl -amino acids and their -hydroxy derivatives can be readily obtained using a decarboxylative Mannich-type reaction without protection/deprotection steps. This protocol utilizes lithium hexamethyldisilazide and (het)arylfluoroalkyl ketones to generate NH-ketimine intermediates. The mild reaction conditions allow the preparation of original fluorinated -amino acids as useful building blocks in a practical and scalable manner.

4-(Trifluoromethyl)pyrimidin-2(1H)-ones react with trimethylsilyl cyanide in the presence of a tertiary amine catalyst to give Michael-like 1,4-conjugate hydrocyanation adducts exclusively at the 3,6-positions. The resulting 2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carbonitriles have been used to synthesize new trifluoromethylated 4,5-dihydroorotic acid analogues and their esters in racemic as well as enantiopure forms by a chiral auxiliary approach. The orthogonal intramolecular C–F···C=O interaction between the fluorine atom of the CF3 group and the carbon atom of the ester group observed in the crystal state may stabilize the sterically unfavourable conformation of the methyl 2-oxo-6-(trifluoromethyl)hexahydropyrimidine-4-carboxylate molecule with axially oriented substituents.

Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Here we demonstrate that novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b, designed with molecular modeling approach, inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7. Acidification to 5.0 decreases the inhibition efficacy by up to 3 orders of magnitude. The 5b molecule not only shifts pH dependence of ASIC1a activation but also inhibits its maximal evoked response. These findings suggest that compound 5b binds to pH sensor of ASIC1a acting as orthosteric noncompetitive antagonist. At 100 nM, compound 5b completely inhibits induction of long-term potentiation (LTP) in CA3-CA1 but not in MF-CA3 synapses. These findings support the knockout data indicating the crucial modulatory role of ASIC1a channels in the NMDAR-dependent LTP and introduce a novel type of ASIC1a antagonists.

Робота присвячена отриманню та дослідженню перетворень нових поліфункціональних фторовмісних синтез-блоків – алкіл N-(3-нітро-1,1,1-трифторопропан-2-іл)карбаматів. Для їх одержання запропонована каталізована триетиламіном реакція аза-Генрі 2,2,2-трифтороетиліденкарбаматів із нітрометаном. Структура синтезованих сполук надійно доведена комплексом спектральних методів, серед яких найбільш доказовими є спектри ЯМР 13С, в яких новоутворений стереогенний атом вуглецю фіксується у вигляді квартету при 63 м.ч. Показано, що при дії на алкіл N-(3-нітро-1,1,1-трифторопропан- 2-іл)карбамати борогідриду натрію в присутності еквімолярної кількості NiCl2.6H2O відбувається селективне відновлення нітрогрупи і утворення відповідних алкіл N-(3-амінопропан-2-іл)карбаматів. Наявність в їх структурі аміногрупи суттєво позначається на хімічних зсувах діастереотопних метиленових протонів, які в спектрах ЯМР 1Н зміщені в область сильного поля приблизно на 2 м.ч. порівняно з нітропохідними. Алкіл N-(3-амінопропан-2-іл)карбамати при кип’ятінні в толуолі в присутності ДБУ піддаються внутрішньомолекулярній циклоконденсації в 4-трифторометилімідазолідин-2-они. В свою чергу, при обробці трет-бутил N-(3-амінопропан-2-іл)карбаматів хлороводнем у діоксані спостерігається легке зняття захисної Boc-групи і утворення 3,3,3-трифторопропан-1,2-діамінів., The paper is devoted to preparation and study of the transformations of novel multifunctional fluorinated synthetic building blocks – alkyl N-(3-nitro-1,1,1-trifluoropropan-2-yl) carbamates. In order to obtain them in high yields the aza-Henry reaction of 2,2,2-trifluoroethylidencarbamates with nitromethane catalyzed by triethylamine has been proposed. The structure of the compounds obtained has been confirmed by spectral methods. Essential elements of the structure corroboration are 13C NMR spectra, in which a signal of the newly formed stereogenic carbon atom is found as a quartet at 63 ppm. It has been shown that the interaction of sodium borohydride with alkyl N-(3-nitro-1,1,1-trifluoropropan-2-yl)carbamates in the presence of the equimolar amount of NiCl2.6H2O leads to selective reduction of the nitro group and formation of the corresponding alkyl N-(3-aminopropan-2-yl)carbamates. The presence of amino group in their structure considerably affects the chemical shifts of diastereotopic methylene protons. Their signals in the 1H NMR spectra are upfield (about 2 ppm difference in comparison with nitro derivatives). Alkyl N-(3-aminopropan-2-yl)carbamates in refluxing toluene in the presence of DBU were easily transformed into 4-trifluorometylimidazolidyn-2-ones by intramolecular cyclization. In its turn, tert-butyl N-(3-aminopropan-2-yl)carbamates when treating with hydrogen chloride in dioxane readily gave 3,3,3-trifluoropropan-1,2-diamines through Boc protecting group cleavage., Работа посвящена получению и исследованию преобразований новых полифункциональных фторсодержащих синтез-блоков – алкил N-(3-нитро-1,1,1-трифторопропан-2-ил)карбаматов. Для их получения предложена катализируемая триэтиламином реакция аза-Генри 2,2,2-трифтороэтилиденкарбаматов с нитрометаном. Строение синтезированных соединений надежно подтверждено комплексом спектральных методов, среди которых наиболее доказательными являются спектры ЯМР 13С, в которых новообразованный стереогенный атом углерода фиксируется в виде квартета при 63 м.д. Показано, что при воздействии на алкил N-(3-нитро-1,1,1-трифторопропан-2-ил)карбаматы боргидрида натрия в присутствии эквимолярного количества NiCl2.6H2O происходит селективное восстановление нитрогруппы и образование соответствующих алкил N-(3-аминопропан-2-ил)карбаматов. Наличие в их структуре аминогруппы существенно сказывается на химических сдвигах диастереотопных метиленовых протонов, которые в спектрах ЯМР 1Н смещены в область сильного поля примерно на 2 м.д. по сравнению с нитропроизводными. N-(3-Аминопропан-2-ил)карбаматы при кипячении в толуоле в присутствии ДБУ подвергаются внутримолекулярной циклизации в 4-трифторометилимидазолидин-2-оны. В свою очередь, при обработке трет-бутил (3-аминопропан-2-ил)карбаматов хлористым водородом в диоксане происходит легкое снятие защитной Boc-группы и образование 3,3,3-трифторопропан-1,2-диаминов.

The reactions of variously substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones with acetone in the presence of L-proline or chiral secondary amine organocatalysts were studied. As demonstrated, 4-(trifluoromethyl)pyrimidin-2(1H)-ones unsubstituted at the 6-position of the heterocyclic ring react with acetone at the endocyclic C=N or C=C bond depending on whether thermodynamic or kinetic control is operative in the addition reaction and also depending on the catalyst used. Racemic kinetically preferred regioisomers, 6-(2-oxopropyl)-4-(trifluoromethyl)-3,4-dihydropyrimidin-2(1H)-ones, were found to undergo intermolecular organocatalytic rearrangement into enantioenriched thermodynamically stable products, 4-(2-oxopropyl)-4-(trifluoromethyl)-3,4-dihydropyrimidin-2(1H)-ones, with enantiomeric ratios up to 83:17.

N-Benzyloxycarbonyl-2,2,2-trifluoroacetimidoyl chloride reacted with pyridin-2-amine derivatives to form substituted 2-trifluoromethyl-4H-pyrido[1,2-a][1,3,5]triazin-4-ones.

The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.

A novel synthetic strategy to 4-trifluoromethyl substituted 2-oxo-1,2-dihydropyrimidine-5-carboxylates has been developed based on the cyclocondensation of β-enaminoesters with N-(1-chloro-2,2,2-trifluoroethylidene)carbamates.

Mannich reactions of ethyl 1-aryl-2,2,2-trifluoroethylidenecarbamates and ureas with acetone in the presence of L-proline gave 1-aryl-3-oxo-1-(trifluoromethyl)butylcarbamates and ureas with an enantiomeric excess of 24–54%.

(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-one reacted with aryl isothiocyanates containing electron-withdrawing substituents to give (S)-(−)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4-dihydropyrimidine-2(1H)-thiones.

(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-ones reacted with ethyl acetoacetate and ethyl trifluoroacetoacetate to give (S)-(+)-6-aryl-3-acetyl(or trifluoroacetyl)-6-trifluoromethyl-5,6-dihydropyridin-2(1H)-ones.

1-Chlorobenzyl isocyanates react with N-arylfumarates with the formation of dialkyl 2-oxo-3,6-diaryl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates that on alkaline hydrolysis are converted into 6-alkoxycarbonyl-1,4-diaryl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids. The condensation of 1-chloro-1-phenyl-2,2,2-trifluoroethyl isocyanate with N-arylfumarates results in dialkyl 6-oxo-2,3-diaryl-2-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates.

Acylation of (S)-(−)-4-amino-4-aryl-5,5,5-trifluoropentan-2-ones with chloroacetyl chloride gave the corresponding chloroacetamides which were treated with sodium azide and then with triphenylphosphine to obtain triphenyl-λ5-phosphanylideneaminoacetic acid amides. The latter underwent thermal (boiling toluene) or base-catalyzed (NaOH/MeOH) intramolecular cyclization with elimination of triphenylphosphine oxide and formation of (7S)-(−)-7-aryl-5-methyl-7-trifluoromethyl-1,3,6,7-tetrahydro-2H-1,4-diazepin-2-ones.

S(−)-4-Aryl-4-(N-acylamino)-5,5,5-trifluoropentan-2-ones have been reacted with phosphorus pentachloride and pentasulfide to yield S(−)-4-aryl-4-trifluoromethyl-4H-1,3-oxazines and S(+)-4-aryl-4-trifluoromethyl-4H-1,3-thiazines, respectively.

A cyclocondensation of disubstituted (thio)ureas and isocyanates derived from enantiomerically enriched 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones affords a novel synthetic access to chiral 4-trifluoromethyl-substituted 3,4-dihydropyrimidin-2(1H)-(thi)ones and 3,4-dihydro-1,3-oxazin-2-ones, respectively.

The l -proline-catalyzed asymmetric Mannich reaction has been performed between aryl trifluoromethyl ketimines and acetone to provide, for the first time, chiral β-aryl-β-trifluoromethyl-β-aminoketones in high yields and with 74–92% enantiomeric excesses.

The condensation of binucleophilic 3-amino-1-arylimino-1H-isoindoles with bifunctional 1-chloro-benzylisocyanates occurs regioselectively resulting in 3,4-dihydro-1,3,5-triazino[2,1-a]isoindol-2-one derivatives. The structures of the synthesized compounds were unambiguously established by NOE experiments.

1-Chlorobenzyl isocyanates react with 4-hydroxy-6-methylpyran-2-one and 4-hydroxycoumarin forming 4-aryl-3,4-dihydro-2H,5H-pyrano(chromeno)[3,4-e][1,3]oxazine-2,5-diones. The reaction of 1-aryl-2,2,2-trifluoro-1-chloroethyl isocyanates with the above substrates gives rise to structurally isomeric 2-aryl-2-trifluoromethyl-2,3-dihydro-2H,5H-pyrano(chromeno)[3,4-e][1,3]-oxazine-4,5-diones.

Reactions of α-chlorobenzyl isocyanates and 1-aryl-2,2,2-trifluoro-1-chloroethyl isocyanates with N,N-disubstituted cyanothioacetamides gave 3,4-dihydro-2H-1,3-thiazin-4-ones and 3-aryl-2-cyano-4,4,4-trifluorobut-2-enethioamides. The effect of substituents in the reactant molecules on the reaction course and product ratio was studied.

The cyclocondensation of 1-chlorobenzyl isocyanates with S, N- and N, N-nitroketeneacetals has been employed to synthesize hitherto-unknown 6-methylthio-5-nitro-3,4-dihydropyrimidin-2(1 H)-ones, 8-nitro-2,3,6,7-tetrahydroimidazo[1,2-c]pyrimidin-5(1 H)-ones and 9-nitro-1,2,3,4,7,8-hexahydro-6 H-pyrimido[1,6-a]pyrimidin-6(1 H)-ones. Substitution of the methylthio group in 6-methylthio-5-nitro-3,4-dihydropyrimidin-2(1 H)-ones provided 6-amino-5-nitro-3,4-dihydropyrimidin-2(1 H)-ones, which exist in tautomeric equilibrium with 4-imino-5-nitro-3,4,5,6-tetrahydropyrimidin-2(1 H)-ones. The compounds obtained, if boiled in dioxane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), eliminate the nitro groups to give substituted 4-imino-3,4-dihydropyrimidin-2(1 H)-ones.

Condensations of 1-phenyl-2,2,2-trifluoro-1-chloroethyl isocyanate and 1-chlorobenzyl isocyanate with cyclic 1,3-diketones yield respectively carbofused 2,3-dihydro-1,3-oxazin-4-ones and 3,4-dihydro-1,3-oxazin-2-ones.

The regioselective base-catalyzed addition of nitromethane to 2-oxo-4-trifluoromethyl-1,2-dihydropyrimidine-5-carboxylates is reported. It was found that the Michael-like pathway is highly reversible and substantially dominating under conditions of kinetic control (0–5 °C, 10 h) whereas the aza-Henry reaction leads to thermodynamically stable adducts after 8–24 h exposure at room temperature. The adjacent nitro and alkoxycarbonyl groups were exploited to demonstrate the synthetic potential of the obtained products by converting to the isomeric trifluoromethylated pyrrolo[3,4-d]pyrimidine-2,5-diones. With this aim an efficient protocol for selective reduction of nitro-derivatives to the corresponding 4- or 6-aminomethyl-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates and their subsequent thermal cyclocondensations was applied.

The regioselective base-catalyzed addition of nitromethane to 2-oxo-4-trifluoromethyl-1,2-dihydropyrimidine-5-carboxylates is reported. It was found that the Michael-like pathway is highly reversible and substantially dominating under conditions of kinetic control (0–5 °C, 10 h) whereas the aza-Henry reaction leads to thermodynamically stable adducts after 8–24 h exposure at room temperature. The adjacent nitro and alkoxycarbonyl groups were exploited to demonstrate the synthetic potential of the obtained products by converting to the isomeric trifluoromethylated pyrrolo[3,4-d]pyrimidine-2,5-diones. With this aim an efficient protocol for selective reduction of nitro-derivatives to the corresponding 4- or 6-aminomethyl-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates and their subsequent thermal cyclocondensations was applied.

Functionalized 2,3-dihydro-1,3-thiazin-4(1H)-one derivatives have been synthesized by cyclocondensation of 3-alkyl(aryl)amino-2-cyano-3-mercaptoacrylamides with aldehydes and ketones under acidic catalysis. 6-Alkyl(aryl)amino-5-cyano-2,3-dihy- dro-1,3-thiazin-4(1H)-ones, when treated with a dilute solution of potassium hydroxide, are converted into the potassium salts of isomeric compounds, 1-alkyl- (aryl)-5-cyano-6-mercapto-2,3-dihydropyrimidin- 4(1H)-ones. Alkylation of the latter with dimethyl sulfate in situ furnishes 1-alkyl(aryl)-6-alkylthio-5- cyano-2,3-dihydropyrimidin-4(1H)-ones, whereas boiling them in ethanol with an excess of hydrochloric acid leads to starting 2,3-dihydro-1,3-thiazin-4(1H)-ones. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:426–436, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20129

1-Chloroalkyl isocyanates react with imidazole, 4(5)-phenylimidazole, and 4,5-dimethyl(phenyl)-imidazoles to give 5-aryl-5-trifluoromethyl-5,6-dihydro-7H-imidazo[1,5-a]imidazole-7-ones, and with benzimidazole affording 1-aryl-1-trifluoromethyl-1,2-dihydro-3H-imidazo-[1,5-a]benzimidazole-3-ones.

1-Chloroalkyl isocyanates react with 2-R-methylbenzothiazoles [R = CN, C(O)OAlk, 2-benzothiazolyl] in the presence of triethylamine to give 4-R-2,3-dihydro-1H-pyrimido[6,1-b][1,3]benzothiazol-1-ones. The same reaction at elevated temperature in the absence of a base yields isomeric 4-R-2,3-dihydro-1H-pyrimido[6,1-b][1,3]benzothiazol-3-ones. 4-R-1H-Pyrimido[6,1-b][1,3]benzothiazol-1-ones are formed in the reaction of 1,1-dichloroalkyl isocyanates or methyl 1-chloroalkylidenecarbamates with 2-benzothiazolylacetonitrile or bis(2-benzothiazolyl)methane.

N-Benzyloxycarbonyl-2,2,2-trifluoroacetimidoyl chloride reacted with pyridin-2-amine derivatives to form substituted 2-trifluoromethyl-4H-pyrido[1,2-a][1,3,5]triazin-4-ones.

Mannich reactions of ethyl 1-aryl-2,2,2-trifluoroethylidenecarbamates and ureas with acetone in the presence of L-proline gave 1-aryl-3-oxo-1-(trifluoromethyl)butylcarbamates and ureas with an enantiomeric excess of 24–54%.

Cyclization of N-(1-aryl-1-chloro-2,2,2-trifluoroethyl)-N -arylcarbodiimides with 3-substituted 1-phenylpyrazol-5-ones yields 6-aryl-4-arylimino-1-phenyl-6-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[4,3-e][1,3]oxazines. N-(1-Chloroalkyl)carbodiimides are used as 1,3-dielectrophilic components in the synthesis of various nitrogen-containing heterocyclic compounds [2, 3]. In particular, we previously showed that condensation of these reagents with 1,3-diketones (which act as O,Cdinucleophiles) yields 1,3-oxazine derivatives [4]. With the goal of synthesizing relatively difficultly accessible fused pyrazolo[4,3-e][1,3]oxazine systems [5], in the present work we examined reactions of N-(1-aryl-1-chloro-2,2,2-trifluoroethyl)-N -arylcarbodiimides Ia Ic with such O,C-dinucleophiles as 3-substituted 1-phenylpyrazol-5-ones IIa IIc. We have found that N-(1-chloroalkyl)carbodiimides Ia Ic react with 1-phenylpyrazol-5-ones IIa IIc containing an electron-acceptor substituent R in position 3 to afford 3-R-4-aryl-6-arylimino-1-phenyl-4-trifluoromethyl-1,4,5,6-tetrahydropyrazolo[4,3-e][1,3]oxazines IIIa IIIe (Scheme 1). The reactions occur in benzene in the presence of triethylamine at room temperature and take 3 days.

Selective saponification of diester (IIId) succeeds under well-defined conditions; the hydrolysis leads otherwise to a complex mixture of mono- and diacids as well as decarboxylation products.