Recent advance in transition-metal-mediated trifluoromethylation for the construction of C(sp)–CF3 bonds

In the past 5 years, transition-metal-mediated trifluoromethylation for the construction of various CF₃-containing building blocks has been the focus of recent research in both industrial and academic communities. Progresses in the construction of C(sp²)–CF₃ bonds and C(sp)–CF₃ have been well reviewed. This Letter will focus on the cases of transition-metal-mediated C(sp³)–CF₃ bond formation, which involves the trifluoromethylation of sp³-hybridized C–X bonds, alkyl organometallic reagents, sp³-hybridized C–H bonds, and alkene derivatives.     

Synthese und Konfiguration einiger Spiro [indan-2,2′-pyrrolidin]- und Spiro [pyrrolidin-2,2′-tetralin]-Derivate,

Synthesis and configuration of some spiro [indan-2,2′-pyrrolidine] and spiro [pyrrolidine-2,2′-tetraline] derivatives Catalytic hydrogenation of the nitrosoindan and nitrosotetralin derivatives 8 yielded trans-1-hydroxy-spiro [indan-2,2′-pyrrolidin]-5′-one ( 9 ) and trans-1′-hydroxy-spiro [pyrrolidine-2,2′-tetralin]-5-one ( 10 ) respectively, whilst the corresponding cis compounds 12 and 15 were prepared via the chlorides 11 and 14 . The configurations of 10 and 13 were determined by X-Ray analysis.     

Studies on the biological activity of gem-difluorinated 3,3-spirocyclic indole derivatives

The biological activities of a series of 3,3-spirocyclic indole derivatives containing CF₂, phosphine oxide,indole, and cyano functional groups were evaluated, and these derivatives were found to exhibit antiTMV, fungicidal, and insecticidal activities.     

Highly Enantioselective Tandem Michael Addition of Tryptamine‐Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos Alkaloids

A highly enantioselective tandem Michael addition of tryptamine‐derived oxindoles to alkynones was developed by taking advantage of a chiral N,N′‐dioxide Sc(OTf)₃ catalyst. The reaction enables the facile preparation of enantioenriched spiro[pyrrolidine‐3,3′‐oxindole] compounds, which provides a novel strategy for the synthesis of monoterpenoid indole alkaloids. As a demonstration, the asymmetric synthesis of strychnos alkaloids [(?)‐tubifoline, (?)‐tubifolidine, (?)‐dehydrotubifoline] was achieved in 10–11 steps.     

Facile Chemoselective synthesis of 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids and 3H,3’H‐Spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives

Oxidation of some derivatives of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐one have been investigated in detail using lead(IV) acetate in acetic acid under reflux conditions and periodic acid in aqueous ethanol at room temperature. We realized that during the first 5–15 minutes of the oxidation reactions in lead(IV) acetate/acetic acid system, 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives have been synthesized chemo selectively, while, if the reaction mixtures stirred for additional 3 hours, the main products would be 2‐(2‐(Methoxycarbonyl)‐3‐oxo‐2,3‐dihydrobenzofuran‐2‐yl)benzoic acids. Moreover, room temperature oxidation of 4b,9b–dihydroxyindeno[1,2‐b]benzofuran‐10‐ones by periodic acid (H₅IO₆), leads to the formation of 3H,3’H‐spiro[benzofuran‐2,1′‐isobenzofuran]‐3,3′‐dione derivatives in good to excellent yields.     

Reactivity of spiroanthraceneoxazolidines with cyclopropanes: An approach to the oxindole alkaloid scaffold

The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3′-indolin]-2-ones in the presence of MgI₂ formed the corresponding spiro[pyrrolidine-3,3′-indolin]-2-ones in 42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.     

Synthesis of spiro[indoline‐3,3′‐pyrrolizines] by 1,3‐dipolar reactions between isatins,l‐proline and electron‐deficient alkenes

Two spiro[indoline‐3,3′‐pyrrolizine] derivatives have been synthesized in good yield with high regio‐ and stereospecificity using one‐pot reactions between readily available starting materials, namely l ‐proline, substituted 1H‐indole‐2,3‐diones and electron‐deficient alkenes. The products have been fully characterized by elemental analysis, IR and NMR spectroscopy, mass spectrometry and crystal structure analysis. In (1′RS ,2′RS ,3SR ,7a′SR )‐2′‐benzoyl‐1‐hexyl‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine]‐1′‐carboxylic acid, C₂₈H₃₂N₂O₄, (I), the unsubstituted pyrrole ring and the reduced spiro‐fused pyrrole ring adopt half‐chair and envelope conformations, respectively, while in (1′RS ,2′RS ,3SR ,7a′SR )‐1′,2′‐bis(4‐chlorobenzoyl)‐5,7‐dichloro‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine], which crystallizes as a partial dichloromethane solvate, C₂₈H₂₀Cl₄N₂O₃·0.981CH₂Cl₂, (II), where the solvent component is disordered over three sets of atomic sites, these two rings adopt envelope and half‐chair conformations, respectively. Molecules of (I) are linked by an O—H…·O hydrogen bond to form cyclic R ₆⁶(48) hexamers of (S ₆) symmetry, which are further linked by two C—H…O hydrogen bonds to form a three‐dimensional framework structure. In compound (II), inversion‐related pairs of N—H…O hydrogen bonds link the spiro[indoline‐3,3′‐pyrrolizine] molecules into simple R ₂²(8) dimers.     

Synthesis of spiro[furan-3,3′-indolin]-2′-ones by PET-catalyzed [3+2] reactions of spiro[indoline-3,2′-oxiran]-2-ones with electron-rich olefins

An efficient procedure for the synthesis of spiro[furan-3,3′-indolin]-2-ones and dispiro[cycloalkane-1,2′-furan-3′,3″-indolin]-2″-ones has been achieved in high yields and stereoselectivity by photoinduced electron transfer-catalyzed [3+2] reactions of substituted spiro[indoline-3,2′-oxiran]-2-ones with olefins. The reactions proceed by ring opening of spiro[indoline-3,2′-oxiran]-2-ones via C_β–O bond cleavage and subsequent cycloaddition with olefins by using 2,4,6-triphenylpyrylium tetarfluoroborate (TPT) as a sensitizer.     

Copper‐Catalyzed Difunctionalization of Activated Alkynes by Radical Oxidation–Tandem Cyclization/Dearomatization to Synthesize 3‐Trifluoromethyl Spiro[4.5]trienones

A copper‐catalyzed difunctionalizing trifluoromethylation of activated alkynes with the cheap reagent sodium trifluoromethanesulfinate (NaSO₂CF₃ or Langlois’ reagent) has been developed incorporating a tandem cyclization/dearomatization process. This strategy affords a straightforward route to synthesis of 3‐(trifluoromethyl)‐spiro[4.5]trienones, and presents an example of difunctionalization of alkynes for simultaneous formation of two carbon–carbon single bonds and one carbon–oxygen double bond.     

Facile synthesis of spiro[benzo[e]indole-2,2′-piperidine] derivatives and their transformation to novel fluorescent scaffolds

The reaction of azaheterocyclic enamines with acrylamide was employed for the preparation of novel fluorescent scaffolds possessing a benzo[e]indoline moiety. Reaction of 3-substituted 2-methylidene-1H-benzo[e]indole with acrylamide gave rise to spiro[benzo[e]indole-2,2′-piperidin]-6′-ones. Ring opening reactions of the latter spiro compounds were investigated. Benzo[e]indoline derivatives possessing 2-(3-carbamoylpropyl), 2-[3-(ethoxycarbonyl)propyl] and 2-(4-aminobutyl) side chains were synthesised. The optical properties of the benzo[e]indoline derivatives were studied by UV-vis and fluorescence spectroscopy.     

Highly diastereoselective synthesis of spiro[tetrahydrothiophene-3,3′-pyrazol] with an all-carbon quaternary stereocenter via [3 + 2] cascade Michael/Michael cyclization catalyzed by DABCO

The diastereoselective formation of spiro[tetrahydro thiophene-3,3′-pyrazol] derivatives has been achieved via a Michael/Michael cyclization reaction. The reaction was performed using trans-ethyl 4-mercapto-2-butenoate 1 with various 4-benzylidene-5-methyl-2-phenylpyrazolones 2 catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) in toluene at 0 °C. The reaction proceeds rapidly and affords the corresponding spiro[tetrahydrothiophene-3,3′-pyrazol] derivatives in excellent yields and moderate to excellent diastereoselectivities (up to 98% yield and >20:1 dr).     

Spirans XVIII . gem-Dialkyl and spirotetrahydrocarbazoles

The reactions of 4,4-dialkylcyclohexanones, spiro[4.5]decan-8-one and various spiro[5.5]-undecanones with phenylhydrazines to produce corresponding 3,3-dialkyltetrahydro and spiro (cycloalkyl 1,n′)-1′,2′,3′,4′-tetrahydrocarbazoles (n = 1, 2 or 3) by the Fischer indole synthesis were examined. Structural assignment of the one isomeric product derived from spiro[5.5]-undecan-2-one was obtained on the basis of pmr spectra.     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

Synthesis of nitrogen-containing heterocycles. 8. Preparation and ring-opening of spiro[cycloalkane-[1′,2′,4′]triazolo[1′,5′-c]pyrimidine] derivatives

Diaminomethylene- and aminomethylthiomethylenehydrazones [2] of cyclic ketones 1–8 readily reacted with ethoxymethylenemalononitrile to give spiro[cycloalkane-1,2′-[1,2′,4′]triazolo[1,5′-c]pyrimidine-8′-carbonitrile] derivatives 12–19 through the electrocyclic reaction of the initially formed condensation products 26 in moderate to high yields. The spiro[cyclopentanetriazolopyrimidine] derivatives underwent ring-opening at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-substituted-[1,2,4]triazolo[1,5-c]pyrimidine-8′-carbonitriles 20–23 . When an alkyl substituent was introduced into the cyclopentane ring, cleavage of the spiro compounds occurred preferentially at the cyclopentane moiety between the spiro carbon and the more branched one. In contrast, the cyclohexane ring, especially of spiro-5-amino-triazolopyrimidines 17 and 18 strongly resisted to ring-opening under similar conditions, but those of 5-methylthiotriazolopyrimidines 14 gave up to 17 percent of cleavage after prolonged heating in hot ethanol. 2-t-Butyl-5-methylthio-2,3-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile 25 [R³ = C(CH₃)₃] was highly susceptible to the cleavage even at room temperature and produced the corresponding 2-unsubstituted triazolopyrimidine 24 with loss of the t-butyl group.     

Pd-catalyzed intramolecular amidation of 2-(buta-1,3-dienyl)phenylcarbamoyl chloride: a concise synthesis of spiro[indoline-3,3′-pyrrolidine]

A palladium-catalyzed intramolecular amidation of arylcarbamic acid derivatives bearing 1,3-diene moiety with or without external nucleophiles is described. The tandem cycloamidation and nucleophilic allylic substitution are successfully applied to the construction of the spiro[indoline-3,3′-pyrrolidine] skeleton as well as contiguous stereogenic centers with an aim of synthesizing spirocyclic oxindole alkaloids.     

Three‐Component Reaction for Construction of Spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and Spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines]

The three‐component reaction of thiazole (benzothiazole), dialkyl but‐2‐ynedioate, and isatinylidene malononitriles in toluene at 110–120°C in a sealed tube afforded a mixture of cis/trans‐isomers of functionalized diastereoisomeric spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines] in good yields. Both cis‐isomers and trans‐isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three‐component reaction containing 2‐(1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene)malononitrile resulted in spiro[indene‐2,7′‐thiazolo[3,2‐a]pyridine] derivatives.     

Investigation of the reactions of fluorine containing 3-hydrazino-5H-1, 2, 4-triazino[5, 6-b]indoles with ethyl acetoacetate. Synthesis of some novel tetracyclic ring systems

Novel tetracyclic ring systems viz. 3-methyl-1-oxo-12H-1, 2, 4-triazepino[3′,4′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 4a ) and 3-methyl-5-oxo-12H-1, 2, 4-triazepino[4′,3′:2, 3][1, 2, 4]triazino[5, 6-b]indole ( 5a ), having angular and linear structures respectively, were synthesized by the cyclization of 3-oxobutanoic acid [5H-1, 2, 4-triazino-[5, 6-b]indole-3-yl]hydrazone ( 3a ). However, cyclization of 3b (R = CH_a, R¹ = R² = H) afforded the angular product 4b exclusively. Moreover, cyclization of 3c (R = R³ = H, R¹ = F) yielded 7-fluoro-1-0xo-10H-1, 3-imidazo[2′,3′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 6c ) and 7-fluoro-3-oxo-10H-1, 3-imidazo[3′,2′:2, 3][1, 2, 4]triazino-[5, 6-b]indole ( 7c ) instead of the expected triazepinone derivatives. Compound 3d (R = R¹ = H, R² = CF₃) also gave an imidazole derivative but only one angular product was obtained. In all these reactions, formation of the angular product involving cyclization at N-4 is favoured. Characterization of these products have been done by elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral studies.     

Stereoselective [4+2] cycloadditions of tetrazines to 3-oxo- and 3-arylimino-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furans]

Stereoselective inverse-demand [4+2] cycloadditions of 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine and dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate to 4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furans] and 4′-methylene-1′-(4-nitrophenyl)spiro[bicyclo[2.2.1]heptane-3,2′-pyrrolidine] were studied. Cycloadditions took place stereoselectively at the exocyclic CC double bonds to give novel 11:14-isopropylidene-14-methyl-2,3-diaza-8-oxadispiro[5.1.5.2]pentadecane and 11:14-isopropylidene-11-methyl-2,3,8-triazadispiro[5.1.5.2]pentadecane derivatives in 50–98% de. The structures of the novel dispiro compounds were determined by NMR techniques, NOESY spectroscopy and X-ray diffraction.     

Reactivity of sugar α-aminonitrile derivatives under titanium-mediated cyclopropanation conditions

The reactivity of different sugar α-aminonitriles has been studied under titanium-mediated cyclopropanation conditions. This study has been performed on amide, lactam, and imide derivatives. It has been possible to obtain spiro[furanose-3,3′-(3′,5′,6′,7′-tetrahydrospiro[cyclopropane-1,2′-pyrrolo[1,2-a]imidazole])] derivatives.     

Syntheses of spiro[indazole-3,3′-indolin]-2′-ones and spiro[indazole-3,3′-indolin]-2′-imines via 1,3-dipolar cycloadditions of arynes and studies on their isomerization reactions

A 1,3-dipolar cycloaddition reaction of arynes with 3-diazoindolin-2-ones under mild conditions in excellent yields has been developed, which allows facile access to a library of labile spiro[indazole-3,3′-indolin]-2′-ones. Spiro[indazole-3,3′-indolin]-2′-imines could be obtained as well following the same protocol. The isomerization reaction of spiro[indazole-3,3′-indolin]-2′-ones under thermal or acidic conditions has been efficiently achieved to afford a wide range of indazolo-[2,3-c]quinazolin-6(5H)-ones and the one-pot synthesis of indazolo-[2,3-c]quinazolin-6(5H)-ones from arynes and 3-diazoindolin-2-ones is also described. Whereas, spiro[indazole-3,3′-indolin]-2′-imines could not undergo the same rearrangement.