From ketones, aldehydes or alkyl halides to terminal 1,1-difluoroolefins using BrF3

Terminal difluoromethylenes were prepared by two different routes: (a) by treating ketones and aldehydes with bis(methylthio)methane, producing 2-alkyl-1,1-bis(methylthio)alkene (2) (b) reacting alkyl halides with tris(methylthio)methane forming 1-alkyl-1,1,1-tris(methylthio)alkane derivatives (7). The reaction of either 2 or 7 with BrF₃, followed by oxidation with HOF·CH₃CN gave the difluorosulfonyl derivatives 4. Consecutive treatment with Zn led to the target difluoroolefins (5) in overall yields of 60-75%.     

Factors controlling the regioselectivity of additions to α-enones—VI: Reactions of acetonitrile and phenylacetonitrile anions

Reaction of α-enones 1a-g with acetonitrile anion 5, in THF at ?80° gives, irreversibly, alcohols 7 or 11, resulting from carbonyl carbon attack, whatever the associated cation is (K⁺ or Li⁺). The reaction is considered to be under charge control. In THF, lithiated phenylacetonitrile 6 gives the alcohols 8 and 12 under kinetic control with benzalacetone 1b, 2-cyclohexenone 1d and 3-methyl 2-cyclohexenone 1e. Lithium alcoholate formation is reversible and ketones 10b, 14a and 14b formation, resulting from carbon 4 attack, is thermodynamically controlled. The other α-enones studied lead, under the same reaction conditions, to ketones 10a, 10c, 14c and 14d only. In a THF-HMPA mixture, reagent 6 only gives the starting α-enone, ketones 10 and 14. The lower lying the α-enone LUMO level, the faster the reaction, which indicates, in the present case, that the transition state for carbon carbon double bond attack occurs relatively early in the reaction path.     

On the electroreduction mechanism of α-haloketones

The electrolytic reduction of phenacyl chloride 3, phenacyl bromide 4, 4-(chloroacetyl)pyridine 6 and 4-(bromoacetyl) pyridine 7 was investigated and compared to that of the analogous ketones [acetophenone 5 and acetyl pyridine 8] and halides (2-chloroethyl)benene 9 and (2-bromoethyl)benzen 10]. Current-potential curves on mercury were measured and the products from preparative electrolyses were isolated and identified. The α-haloketones exhibited two reduction waves, the less negative of which corresponded to the cleavage of the CX bond while the other was due to the reduction of the resulting ketone. The α-haloketones in general were found to be more reactive than the analogous halides and this effect was even more pronounced in the pyridine derivatives. A mechanism involving addition of an electron to an orbital delocalized over the carbonyl and the halogen is suggested, to account for this phenomenon.     

An efficient synthesis of (E)-α,β-unsaturated ketones and esters with total stereoselectivity by using chromium dichloride

(E)-α,β-Unsaturated ketones 1 or esters 2 can be obtained with complete stereoselectivity by reaction of different 2-chloro-3-hydroxy ketones 3 or esters 4 and CrCl₂. A comparative study of the results of synthesis of ketones 1 with CrCl₂ or samarium is performed. A mechanism to explain both β-elimination reactions has been proposed.     

Asymmetric synthesis of new chiral long chain alcohols

Sixteen new chiral alcohols with alkyl (C₁₁–C₁₉) and aryl, substituted aryl, hetero aryl and biaryl groups 2a–2t were synthesized by three different asymmetric reduction methods from their corresponding ketones 1a–1t. Chiral NaBH₄ (method A), chiral BH₃ (method B) and chiral AIP (method C) were used as asymmetric reduction catalysts. Chiral NaBH₄ was modified by four different ligands 3a–3d, chiral BH₃ and chiral AIP by four different ligands 4a–4d. Ligand 4c was synthesized for the first time in this work. Chiral NaBH₄ generated chiral alcohols of (R)-configuration and chiral BH₃ and chiral AIP of (S)-configuration with high enantiomeric excesses, were analysed by chiral HPLC. In order to determine the ee values by chiral HPLC, sixteen corresponding racemic alcohols, synthesized by reducing their corresponding ketones via NaBH₄, were used for chiral resolution on a Daicel OD HPLC column. The sixteen starting ketones were synthesized in this study by Friedel–Craft acylation. The new chiral alcohols were characterized by IR, NMR, (¹H and ¹³C), MS, elemental analyses and specific rotation. The reduction methods A, B and C were applied to these ketones for the first time in this study and were compared with each other. The relationship between the structure of the ketone and the yield and the enantiomeric excess was discussed.     

Unsymmetrical double Wittig olefination on the syntheses of insect pheromones. Part 1: Synthesis of 5,9-dimethylpentadecane, the sexual pheromone of Leucoptera coffeella

An expeditious three-step synthesis of a mixture of stereoisomers of 5,9-dimethylpentadecane 1, the sexual pheromone of the coffee leaf miner Leucoptera coffeella, is described. The route employs an unsymmetrical double Wittig olefination to build the carbon skeleton of the molecule, as the key reaction. The bis-phosphonium salt 3, derived from 1,3-dibromopropane 2, reacted ‘one-pot’ with the ketones 2-octanone and 2-hexanone, affording the asymmetric diene 4. This was readily hydrogenated over Pd/C, furnishing pheromone 1 in 54% overall yield. Synthetic 1 showed high biological activity when tested in field experiments.     

Nucleophilic eliminative ring fission of bridgehead substituted 1,3-bishomocubyl acetates

The base induced cage fission of three different types of functionalized bridgehead substituted 1,3-bishomocubyl acetates, vizA,B and C is described. The synthesis of two 6-functionalized 1,3-bishomocubyl 4-acetates (type A), viz4-acetoxypentacyclo[5.3.0.0^2,5.0^3,9.0^4,8]decan-6-one 5 and its ethylene acetal 6 has been accomplished starting from the readily available Diels-Alder adduct 4. The synthesis of three 1,3-bishomocubyl 8-acetates (type B), viz 8-acetoxypentacyclo[5.3.0^2,5.0^3,9.0^4,8]decan-6-one 15, its ethylene acetal 16 and the parent acetate 20 has been carried out starting from the cyclopentadiene-benzoquinone adduct 7. Base induced homoketonization of 6, 16 and 20 leads regio- and stereospecifically to the thermodynamically favored half cage ketones 22,28 and 31, respectively. In contrast, the cage opening of the β-ketoacetates 5 and 15 is essentially directed by the β-ketone function. In the case of 5, regiospecific cleavage of the central C₄-C₅ bond is observed producing in a stereospecific manner diketone 25 in quantitative yield. Under similar conditions, acetate 15 gives a complex mixture of cage opened products arising from further fragmentation of the initially formed diketone 34. Deuterium labeling experiments reveal an anti-Bredt behavior of half cage ketones 28 and 31. The synthesis of a bridgehead acetate of type C has been accomplished by stereoselective reduction of ketone acetate 5 with LiAlH(t-OBu)₃ followed by mesylation. A mixture of epimers 36a and 36b (ratio 1:4) is obtained from which the predominant anti-epimer 36b could be isolated. An X-ray analysis established its structure. Base induced cage fission of 36b leads regiospecifically to tetracyclo[5.3.0.0^2,5.04,8]decenone 37. In contrast the syn-epimer 36a, under similar conditions, only affords the bridgehead alcohol 38.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

Synthesis and resolution of 2,2′-bis[di(p-tolyl)stibano]-1,1′-binaphthyl (BINASb); the first example of an optically active organoantimony ligand for asymmetric synthesis

Racemic 2,2′-bis[di(p-tolyl)stibano]-1,1′-binaphthyl (BINASb) (±)-2 has been prepared from 2,2′-dibromo-1,1′-binaphthyl 1 via 2,2′-dilithio-1,1′-binaphthyl intermediate, and has been resolved via the separation of a mixture of the diastereomeric Pd complexes 4A and 4B, derived from the reaction of (±)-2 with di-μ-chlorobis{(S)-2-[1-(dimethylamino)ethyl]phenyl-C,N}dipalladium(II) 3. The optically active BINASbs (S)-(+)-2 and (R)-(−)-2 have been shown to be effective chiral ligands for the rhodium-catalyzed asymmetric hydrosilylation of ketones.     

Functionalized enamines—XVII : Ring expansion of α,β-unsaturated cyclic ketones by reaction of pyrrolidine dienamines with dihalocarbenes; Synthesis of A-homo-steroids

Reaction of pyrrolidine dienamine 2b with carbenes 3a and 3b leads to the formation of ring expanded ketones 4a and a mixture of 4a and 4b, respectively. The ring-expansion reaction has been utilized in a two-step conversion of Δ⁴-cholestenone and testoterone acetate into the A-homo-steroids 7a-c. Structure assignments and the mechanism of formation of the reaction products are discussed.     

Reaction of diazomethane with selenoesters : Preparation of α-(alkyl- or arylseleno)methyl ketones and methyl ketones

The reaction of diazomethane with a series of selenoesters 1 in the presence of CuI, CuSePh or Cu powder produced α-(alkyl- or arylseleno)methyl ketones 2 in yields of 41–65%. Methyl ketones 3 and bis(arylseleno)methanes 9 or 14 were formed as by-products. The direct conversion of selenoesters to methyl ketones was accomplished in high yield by the usual reaction with diazomethane, followed by workup with HBr solution. The simultaneous copper-catalyzed reactions of selenoesters 1c and 1i with diazomethane resulted in crossover, with the formation of all four possible α-seleno ketones 2b, 2c, 2h and 2i. A non-concerted mechanism involving attack by the diazo compound upon the acyl carbon atom of an activated selenoester with the formation of a tetrahedral intermediate 11 has been suggested. The reaction of the selenothiocarbamate 4 with diazomethane resulted in 1,3-dipolar cycloaddition to afford 5 instead of insertion into the acyl-selenium bond.     

Isoprene functionalization : E/Z-isomerism of 1-sulfonyl substituted 2-methylbutadienes

The isomeric chlorosulfones 3, 4 and 5 are prepared by 1,4-addition of sulfonyl chlorides to isoprene, Dehydrohalogenation affords the corresponding 2- and 3-methylbutadienyl sulfones in a configuration which is dependent on the configuration of the chlorosulfone. Pure Z-2-methylbutadienyl sulfones 1 are obtained by displacement of primary halides by the Z-sulfinate anion 2. The Z-sulfones 1 are isomerized to E/Z-mixtures. The E/Z-mixtures are separated into their components and the configuration of the isomers is established by the NMR-NOE technique.     

C11H12 Hydrocarbons—II : Preparation of tricyclo[5.4.0.0]undeca-3,8,10-triene a norbornenone route from cycloheptatriene

A stereoselective 6-step synthesis of the C₁₁H₁₂ hydrocarbon cis,anti,cis-tricyclo[5.4.0.0^2,5]undeca-3,8,10-triene (2a) is described. The dichloro compound 3c was prepared by the selective reduction of 3a with chromous perchlorate-ethylenediamine complex, a general reagent for this type of transformation. Irradiation of 3c produced 6a and 7a in ∼ 7:1 ratio. Reduction of the mixture with sodium produced ketal mixture 6b and 7b. The ketals were hydrolyzed to ketones 6c and 7c and the ketones decarbonylated to 2a and an isomeric hydrocarbon tentatively assigned as homobasketene 2b′. Hydrocarbon 2a was readily obtained pure by a silver nitrate extraction procedure and 2b′ by preparative VPC. It was shown that pure 6c gives only 2a and therefore, 7c is the source of 2b′. The stereochemical assignments, based on both spectral and chemical evidence, are discussed.     

Silacyclohexadienylanionen bis- und tris-trimethylsilyl)-silacyclohexadiene

1,1-Dialkyl(1,1-diaryl)-4-R-1-silacyclohexadienyl anions (1) are available by ether cleavage of the corresponding, 1,1-dialkyl(1,1-diaryl)-4-methoxy-4-R-1-silacyclohexa-2,5-dienes (4), or by deprotonation of the 1,1-dialkyl(1,1-diaryl)-4-R-1-silacyclohexa-2,4-dienes (3) - which are available from 4 - with n-BuLi or LDA resp.The anions 1 are regioselectively silylated by trimethylchlorosilane to give the 6-trimethylsilyl-1-silacyclohexa-2,4-dienes (7,8), their alkylation or acylation occurs exclusively in 4-position to 16 or 17 resp.Deprotonation of 7, 8 with n-BuLi gives the 2-trimethylsilyl-1-silacyclohexadienyl (9), with trimethylchlorosilane they react regioselectively to give the 2,6-bis(trimethylsilyl)-1-silacyclohexa-2,4-dienes (10, 11), with alkyl halides and ketones the anion 9 reacts only in the 4-position.The 1-silacyclohexa-2,5-dienes 22, 25, 28 substituted at the silicon atom by functional groups (O-i-Prop) or by hydrogen can be transformed into 2,6-bis(trimethylsilyl)-1-silacyclohexa-2,4-dienes 24, 27, 33 resp., if LDA is used as base.The easily formed 4-R-2,6-bis(trimethylsilyl)-1-silacyclohexa-2,4-dienyl anions (by deprotonation of 10, 11, 24, 27, 33 with LDA) react with trimethylchlorosilane regioselectively to give the 4-R-2,4,6-tris(trimethylsilyl)-1-silacyclohexa-2,5-dienes 37. Accessing 37 succeeds very simply by manifold-silylation of the 1-sila-2,4-cyclohexadienes 38 with excess trimethylchlorosilane in the presence of 3 mol LDA.Owing to trimethylsilyl substitution in the 2,6-position of the 1-silacyclohexa-2,4-dienes, the ring-silicon atom is strongly sterically shielded, therefore reactions of functional groups at the silicon atom are restricted.     

Benzolactams—I : Alkylation of 1,2,4,5-tetrahydro-3-methyl-3h-3-benzazepin-2-one with sodium hydride and alkyl halide

Alkylation of 1,2,4,5-tetrahydro-3-methyl-3H-3-benzazepin-2-one 1a with various halides and sodium hydride in tetrahydrofuran-dimethylformamide solvent system was studied. Primary halides predominantly provided the 1-mono-substituted products, such as alkyl (2a-g, p, q), allyl (2j, k), propargyl (21) and benzyl (2m-o) derivatives, in satisfactory yields, and secondary halides resulted in lower yields (2h, i) than primary halides. In attempted dialkylations with ω, ω'-dibromoalkanes, 5- and 6-membered spiro products (4c, d) were obtained by this method. The Michael type addition reaction was also studied and it was found that acrylic acid esters gave the corresponding adducts (2p, q).     

Reaction of isatin with alkylating agents with acidic methylenes

The reaction of isatin (1) with different alkyl halides 2 and alkaline carbonates in aprotic polar solvents leads mainly to N-alkyl derivatives 3. The use of alkylating agents that have acidic methylenes leads to competitive formation of the corresponding epoxide 5. The formation of 5 is favored by low-polarity solvents at low temperatures and strong bases. Epoxides 5c, d obtained using NaEtOH/EtOH at 0–5 °C are transformed into the corresponding 4-quinolinones 6 at higher temperatures. The use of Ag₂CO₃ allows obtaining compounds 3 as major products, along with varying amounts of labile O-alkyl derivatives 4 and dimerization products.     

Regio- and stereoselective addition of N-p-tosyl-trichloromethylimine to vinyl dihydronaphthalenes

Imine 1 underwent regioselective addition to vinyl dihydronaphthalenes 2 and 3 to afford the cyclo-adducts 4, 5 and 6. The structures and stereochemistry of the latter adducts have been determined by PMR and X-ray analysis. Factors influencing the mode of addition are discussed. Epoxidation and bromination of 4 led to the formation of aromatizated products. Hydrolysis of 5 and 6 gave the corresponding ketones which underwent facile ringopening via a retro-Michael type of reaction.     

Quinoxalines. Part 12: Synthesis and structural study of 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines—the dehydrogenative cyclization with hydroxylamine hydrochloride

Starting with 2-acetylquinoxaline a novel class of heterocyclic compounds, the 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines 4, were prepared by following two different synthetic procedures: 2-acetylquinoxaline reacted with thiosemicarbazide to the thiosemicarbazones 1a which was (i) cyclized with α-halogeno ketones to the thiazoles 3. These compounds were dehydrogenated in acidic medium to the title compounds 4. (ii) The thiosemicarbazone 1a could be also dehydrogenated using NH₂OH·HCl to the thioamide 5a and these, finally, were cyclized with α-halogeno ketones to the title compounds 4. Only thiazole 3a was isolated, the other thiazoles 3 were dehydrogenated in a one-pot procedure. From the thioamide 5a also both the compounds 9, by reacting with dibromodiacetyl, and 10, by treatment with dimethyl acetylenedicarboxylate, were obtained. The analysis of both the ¹H and ¹³C NMR spectra was not straightforward but could be attained finally by employing the whole arsenal of 1D and 2D NMR spectroscopy.     

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodifluoromethyl ketones 2 in good yields. The reaction of 1a with electrophilic reagent ICl yielded α-iodoenone 4. The substitution reaction of the cyclic enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate yields.     

Vinylallenes—V(xf2): Reaction des magnesiens vinylalleniques avec les cetones et aldehydes conjugues et transposition d'oxy-cope de certains alcools en resultant

Vinylallenic Grignard reagents prepared from 5-halogeno alk-3-ene-1-ynes react with acyclic conjugated aldehydes and ketones leading exclusively to 4-ethynyl hexa 1,5-diene 3-ols 5; with cyclohexénone and other ketones having more extended conjugation, the same alcohol 5 is still the major product but isomeric ketones and alcohols are also obtained resulting from the intervention of the two other nucleophilic sites of the reagent. The alcohols 5 are easily isomerised to δ-ethylenic ξ-acetylenic aldehydes and ketones 6 by reflux of their solution in diglyme or by fast distillation through a column heated at 350°.