Sodium dithionite initiated addition of 1-bromo-1-chloro-2,2,2-trifluoroethane to β-pinene: Synthesis of CF3-substituted terpenoids

Sodium dithionite effectively promotes the addition of 1-bromo-1-chloro-2,2,2-trifluoroethane to the exocyclic double bond of β-pinene. The reaction proceeded in an MeCN/H₂O system to give almost quantitatively a 1:1 mixture of diastereoisomers of 4-(2-bromoisopropyl)-1-(2-chloro-3,3,3-trifluoropropyl)-cyclohexene (1). Dehydrobromination of 1 with pyridine gave a mixture of regioisomeric dienes 2 and 3, while treatment with DBU at elevated temperature resulted in total dehydrohalogenation to give trienes 4 and 5. Reduction of 1 with Bu₃SnH gave 1-(2-chloro-3,3,3-trifluoropropyl)-4-(isopropyl)cyclohexene (6) which on dehydrochlorination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) afforded conjugated diene, 4-isopropyl-1-(trans-3,3,3-trifluoropropenyl)-cyclohexene (7), with 50% overall yield. All the transformations proceeded with the retention of configuration at the carbon atom C-4 and the final compound 7 exhibited high optical activity.     

An easy preparation of per- and poly-fluoroalkyl propenyl sulfones

Sodium tridecafluorohexanesulfinate (1a) and sodium 1-chloro-2,2,2-trifluoroethanesulfinate (1b) were prepared by the treatment of 1-iodo-tridecafluorohexane and 1-bromo-1-chloro-2,2,2-trifluoroethane with sodium dithionite in a water-acetonitrile solution. Prolonged reaction of 1a with allyl bromide in DMF afforded tridecafluorohexane 1-propenyl sulfone 2 as the only product in good yield. A similar treatment of 1b gave exclusively 1-chloro-2,2,2-trifluoroethane 3-propenyl sulfone 4. Bromination of 4 followed by dehydrobromination with Et₃N resulted in a mixture of 1-chloro-2,2,2-trifluoroethane 3-bromo-1-propenyl sulfone 6 and 1-chloro-2,2,2-trifluoroethane 2-bromo-3-propenyl sulfone 7, while dehydrobromination with pyridine gave sulfone 6 practically as the only product. α,β-Unsaturated sulfones 2 and 6 were shown to be active dienophiles.     

Reaction of halothane with carbonyl compounds in the presence of bases

The reaction of halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane (1), with aldehydes and ketones in the presence of bases was found to give 1-alkyl- or 1-aryl-2-bromo-2-chloro-3,3,3-trifluoropropanols (2) or 2-chloro-3,3-difluoro-2-propenols (3) selectively in good to moderate yields depending on the bases and reaction conditions.     

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane with enol ethers of cyclic ketones

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane (1) with methyl and trimethylsilyl ethers of cyclopentanone and cyclohexanone enols (2a-d) in a MeCN/H₂O system were investigated. 2-(2,2,2-Trifluoroethylidene)cyclopentanone (4a) and 2-(2,2,2-trifluoroethylidene)-cyclohexanone (4b), respectively, were obtained as the main products and isolated in reasonable yields. The reaction with a 1:1 mixture of 5- and 3-methyl substituted 1-methoxycyclohexenes, 2e and 2f, revealed strong influence of steric hindrance on the reaction rate; a mixture of 2-(2,2,2-trifluoroethylidene)-5-methylcyclohexanone (6) and 2-(2,2,2-trifluoroethylidene)-3-methylcyclohexanone (7) in a 9:1 ratio was formed. Ketones 4a and 4b were reduced to the corresponding alcohols 8 and 9 and the reaction of 4b with hydrazine gave an indazole derivative 10.     

First cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides

The halogenated 1H-1,2,4-triazole glycosides 6-10 were synthesized by BF₃-activated glycosylation of 3(5)-chloro-1,2,4-triazole (2), 3,5-dichloro-1,2,4-triazole (3), 3,5-dibromo-1,2,4-triazole (4), and 3(5)-bromo-5(3)-chloro-1,2,4-triazole (5) with 1,2,3,4-tetra-O-pivaloyl-β-d-xylopyranose (1). The β-anomeric major products 3-chloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (6β), 3,5-dichloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (7β), and 3,5-dibromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (8β) were used as starting materials for transition metal catalyzed C-C-coupling reactions. Arylations of the triazole ring of 7β, and 8β were successful in 5-position with phenylboronic acid, 4-vinylphenylboronic acid, and 4-methoxyphenylboronic acid, respectively, under Suzuki cross-coupling conditions (products 11-17). Moreover, a Cu-catalyzed perfluoroalkylation of 8β is reported with 1-iodo-perfluorohexane yielding 3-perfluorohexyl-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (18). Compound 18 was depivaloylated to the trihydroxy derivative 19. The copper-mediated reaction of 8β with Rupert's reagent gave the bis(3-bromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazol-5-yl) (20).     

Comparison of the electrophilic and free-radical addition of halogens with hexafluoro-1,3-butadiene and 1,3-butadiene

Ionic and photochemical reaction of chlorine (Cl₂), bromine (Br₂) and iodine monochloride (ICl) to hexafluoro-1,3-butadiene (1) and 1,3-butadiene (2) were carried out under conditions that would provide product distributions under controlled ionic or free-radical conditions. Product distributions for ionic reaction of Cl₂ and Br₂ with 1 are similar and suggest a weakly-bridged halonium ion species. Theoretical calculations support weakly-bridged chloronium and bromonium ions for both dienes 1 and 2. There are more of the 1,4-dihalo-2-butene products from ionic halogenation of 1 than 2 which correlates with the greater charge density on carbon-4 of halonium ions from 1. Ionic and free-radical reactions of ICl with 1 give 8 and 2% of 3-chloro-4-iodohexafluoro-1-butene and 4-chloro-3-iodohexafluoro-1-butene, respectively. The minor cis-1,4-dihalo-2-butene products from 1 and 2 are reported when formed.     

Rearrangement during halogenation of 2-hydroxy-1,2-diphenylpropan-1-one (α-methylbenzoin)

The reaction of 2-hydroxy-1,2-diphenylpropan-1-one 1 with SOCl₂ or PBr₃ gives, respectively, the 3-chloro- and 3-bromo-1,2-diphenylpropan-1-ones 4 and 6. The expected 2-chloro- and 2-bromo-1,2-diphenylpropan-1-ones 2 and 5 can, however, be formed by treatment of 1,2-diphenylpropan-1-one 8 with Cl₂ or Br₂/AlCl₃. The four halogenated products are characterised by ¹H and ¹³C NMR spectroscopy for the first time.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

Sodium dithionite initiated fluoroalkylation of trimethoxybenzenes, mesitylene and pyrroles with BrCF2CF2Br

Sodium dithionite initiated reaction of 1,2-dibromotetrafluoroethane with 1,3,5-trimethoxybenzene (1a) in an acetonitrile-water mixture proceeded efficiently at ambient temperature to give 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) almost quantitatively. Similar reaction with 1,2,3-trimethoxybenzene (1b) gave only reasonable yield of regioisomers of (2-bromotetrafluoroethyl)-trimethoxybenzenes 3 and 4 and small amount of a substitution product of the central trimethoxy group, 1-(2-bromotetrafluoroethyl)-2,6-dimethoxybenzene (5). The reaction with mesitylene (6) gave complex mixtures from which, depending on the temperature and a mesitylene/BrCF₂CF₂Br ratio, the expected (2-bromotetrafluoroethyl)mesitylene (8) or a dimeric product, 4,4′-bis(2-bromo-1,1,2,2-tetrafluoroethyl)-1,3,5,1′,3′,5′-hexamethylbicyclohexyl-2,5,2′,5′-tetraene (7), were isolated in a yield of 18 and 13%, respectively. The reactions of BrCF₂CF₂Br with pyrrole (9) and 1-methylpyrrole (11) gave the respective alkylated compounds, 2-(2-bromotetrafluoroethyl)pyrrole (10) and 2-(2-bromotetrafluoroethyl)-1-methylpyrrole (12) in over 70% yields; the former was found to be fairly unstable. The reactivity of the terminal bromine atom in 1-(2-bromotetrafluoroethyl)-2,4,6-trimethoxybenzene (2) was also investigated.     

Pentamethylcyclopentadienyl rhodium(III) trifluorovinyl phosphine complexes and attempted intramolecular dehydrofluorinative coupling of pentamethylcyclopentadienyl and trifluorovinyl phosphine ligands

The trifluorovinyl phosphine complexes [Cp*RhCl₂{PR_3−x(CFCF₂)_x}] (1x = 1, a R = Ph, b Prⁱ, c Et; 2x = 2, R = Ph) have been prepared by treatment of [Cp*RhCl(μ-Cl)]₂ with the relevant phosphine. The salt [Cp*RhCl(CNBu^t){PPh₂(CFCF₂)}]BF₄, 3, was prepared by addition of Bu^tNC to 1a in the presence of NaBF₄. The salt [Cp*RhCl{κP,κS-(CF₂CF)PPh(C₆H₄SMe-2)}]BF₄ was prepared as a mixture of cis (5a) and trans (5b) isomers by treatment of [Cp*RhCl(μ-Cl)]₂ with the phosphine-thioether (CF₂CF)PPh(C₆H₄SMe-2), 4, in the presence of NaBF₄. The structures of 1a-c and 5a have been determined by single-crystal X-ray diffraction. Intramolecular dehydrofluorinative carbon-carbon coupling between pentamethylcyclopentadienyl and trifluorovinylphosphine ligands of 1a, 3 and 5 has been attempted. No reaction was observed on treatment of the neutral complex [Cp*RhCl₂{PPh₂(CFCF₂)}], 1a, with proton sponge, however, 5a underwent dehydrofluorinative coupling to yield [{η⁵,κP,κS-(C₅Me₄CH₂CFCF)PPh(C₆H₄SMe-2)}RhCl]BF₄, 6. Other reactions, in particular addition of HF across the vinyl bonds of 5, occurred leading to a mixture of products. The cation of 3 underwent similar reactions.     

Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P₂S₅ (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P₂S₅ gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol %) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P₂S₅ (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization.     

The conversion of isothiazoles into pyrazoles using hydrazine

The conversion of isothiazoles into pyrazoles on treatment with hydrazine is investigated. The influence of various C-3, C-4 and C-5 isothiazole substituents and some limitations of this ring transformation are examined. When the isothiazole C-3 substituent is a good nucleofuge, 3-aminopyrazoles are obtained. However, when the 3-substituent is not a leaving group it is retained in the pyrazole product. Treatment of 4-bromo-3-chloro-5-phenylisothiazole 56 or 3-chloro-4,5-diphenylisothiazole 57 with anhydrous hydrazine at ca. 200 °C for a few minutes gives the corresponding 3-hydrazinoisothiazoles 61 and 64 respectively in high yields; the stability of these new hydrazines is investigated. 5,5′-Diphenyl-3,3′-biisothiazole-4,4′-dicarbonitrile 78 reacts with hydrazine to give 5,5′-diphenyl-3,3′-bi(1H-pyrazole)-4,4′-dicarbonitrile 79. Methylhydrazine reacts with 3-chloro-5-phenylisothiazole-4-carbonitrile 1 to give 3-(1-methylhydrazino)-5-phenylisothiazole-4-carbonitrile 83 and 3-amino-1-methyl-5-phenylpyrazole-4-carbonitrile 84. All products are fully characterised and rational mechanisms for the isothiazole into pyrazole transformation are proposed.     

The peculiar reaction of 2-arylazo-1-vinylpyrroles with trifluoroacetic acid: a novel synthesis of 2-methylquinolines

2-Arylazo-1-vinylpyrroles 1-6 react with CF₃CO₂H (benzene, reflux, 5 h) in a peculiar way: instead of expected electrophilic addition of CF₃CO₂H to the N-vinyl group, the latter is transferred to the azo group followed by NN bond cleavage to afford substituted 2-methylquinolines 10-12 in up to 56% yields. The reaction was shown (¹H, ¹³C, and ¹⁵N NMR) to start with the protonation of the azo group with further inter- and intramolecular involving of two protonated N-vinyl groups to finally build up the quinoline cycle over the aryl moiety.     

Synthesis of 2-aryl-1,2,3,4-tetrahydroquinazolin-1-ols and their conversion to 7-aryl-9H-6-oxa-5,8-diaza-benzocycloheptenes

2-Aminobenzylamine was reacted with corresponding aromatic or heteroaromatic aldehydes to give 1,2,3,4-tetrahydroquinazolines 1 the oxidation of which with H₂O₂-tungstate in methanol led to the formation of the corresponding 1,2,3,4-tetrahydroquinazolin-1-ols 2. A one-pot procedure involving the treatment of the in situ formed quinazoline 1 with H₂O₂-tungstate again led to the formation of 2. Compounds 2 react with 2 equiv of aryl isocyanate in toluene at room temperature to produce compounds 3. The probable mechanism of the ring-expanding carbamoylation of quinazolin-1-ols 2 to 6-oxa-5,8-diaza-benzocycloheptenes 3 is discussed.     

Selective lithiation of 1,6-dihalohex-1-enes and 1,6-dihalohex-1-ynes

The lithiation of 1-choro- and 1-bromo-6-chlorohex-1-yne (2, 3) with lithium naphthalene in the presence of benzaldehyde in THF at −78 °C leads after hydrolysis with water to the corresponding chloroalkynol (5) resulting from a regioselective lithiation at the alkynylic position. However, the lithiation of 1-chloro-6-iodohex-1-yne (4) under the same reaction conditions and using pentan-3-one as electrophile leads to the corresponding chloroalcohol (6) from the exclusive lithiation at the aliphatic carbon-iodine bond. Double lithiation of compounds 2 and 3 under Barbier conditions allows the isolation of diols (9), whereas the two-step process leads to differently substituted diols 13. The monolithiation of (E)-1-bromo-6-chlorohex-1-ene (14) under the above conditions and using pentan-3-one as electrophile affords a mixture of chloroalcohols 15 and 16, the process being not stereospecific. However, the lithiation of the same starting material with t-BuLi leads exclusively to a bromine-lithium exchange with retention of the configuration, so after treatment with pentan-3-one only compound 16 was isolated. Finally, whereas double lithiation of compound 14 under the conditions for compounds 9 gives the mixture of compounds 18 and 19, the tandem process involving the t-BuLi-promoted bromine-lithium exchange as the first step followed by lithiation under DTBB-catalysed conditions allows the isolation of (E)-diols 19 as the only reaction products isolated.     

Claisen rearrangements based on vinyl fluorides

2-Fluoroalk-1-en-3-ols (4), available from terminal alkenes (1) by bromofluorination, subsequent dehydrobromination of the 1-bromo-2-fluoroalkanes (2) to form 2-fluoroalkenes (3) and selenium dioxide mediated allylic oxidation with tert-butylhydroperoxide, undergo Johnson-Claisen rearrangement on treatment with trimethyl orthoacetate to give methyl 4-fluoroalk-4-enoates (7) in high yields. In contrast Ireland-Claisen rearrangement of 3-acetoxy-2-fluorodec-1-ene (9b) with triethylamine and TMSOTf in ether failed. Instead of the expected formation of a carboxylic acid, selective C-silylation of the α-position to the carboxyl group to form 14 occurred. However, Ireland-Claisen rearrangement was successful with corresponding chloroacetates 10 and propionates 11 of four 2-fluoroalk-1-en-3-ols (4) to give 2-chloro-4-fluoroalk-4-enecarboxylic acids (15) or its 2-methyl derivatives 16, respectively, in moderate yields. These [3,3]-sigmatropic rearrangements are diastereoselective giving trans-configured double bonds, exclusively. Corresponding esters derived from (Z)-2-fluorocyclododec-2-enol (22), did rearrange to yield mixtures of diastereomers much less selectively. Also 2-fluorodec-2-enol (6), which was prepared by rearrangement of 2-fluoro-2-octyloxirane (5) with TMSOTf and triethylamine, was successfully applied as a starting material for [3,3]-sigmatropic rearrangements. The corresponding 3-(1-fluoroethenyl)alkanoic acid derivatives 17 and 18 were formed in moderate yield.     

Stereoselective cycloaddition of 1-glucosyl-1,3-butadienes with tert-butyl 2H-azirine-3-carboxylate, glyoxylates and imines

Glucosyl dienes 1 have been reacted with the achiral 2H-azirine 4 and with glyoxylates, forming fused structures of type 5 and disaccharide-like compounds 7 with good to excellent selectivity. Glucosyl dienes 1 participated as dienophiles in reactions with Schiff bases derived from anilines forming isoquinolines 10 and 11. The diastereoselectivity of this reaction is poor.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

An efficient method for the synthesis of 1-chlorophenazines based on the selective cathodic reduction of 3,3,6,6-tetrachloro-1,2-cyclohexanedione

An efficient method for the synthesis of 1-chlorophenazines has been established. It is based on the use of 3,6,6-trichloro-2-hydroxy-2-cyclohexen-1-one 4 as a synthetic equivalent of 3-chloro-1,2-benzoquinone 3. The intermediate 4 was prepared in near quantitative yield by electroreductive monodechlorination of 3,3,6,6-tetrachloro-1,2-cyclohexanedione 1, which is an inexpensive and easily available starting material. Efficient reactions of 4 with primary 1,2-phenylenediamines provided the corresponding 1,1,4-trichloro-1,2,3,4-tetrahydrophenazines 6, which were directly aromatized by treatment with 2,6-lutidine to give the title compounds in high yields. X-ray crystallographic structures for 1,1,4-trichloro-1,2,3,4-tetrahydro-6-methylphenazine 6f, 8-benzoyl-1,1,4-trichloro-1,2,3,4-tetrahydro-phenazine 6ea, and 1,7-dichlorophenazine 10db have been determined.     

Efficient and selective synthesis of quinoline derivatives

The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination of 1,2,3,4-tetrahydroquinoline (7) in efficient yields (75 and 90%, respectively). 6-Bromo- (4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (6) were converted to 6-bromo- (1) and 6,8-dibromo quinolines (2), respectively, by aromatization with DDQ in 83 and 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared via lithium-halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi followed by quenching with electrophiles [Si(CH₃)₃Cl, S₂(CH₃)₂, I₂] regioselectively proceeded at C-4 and C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation of tribromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield. Copper-induced nucleophilic substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxyquinoline (17) in 60% yield.