Ketones 1a Research Articles

Novel Synthesis of Vinylcyclopropyl Ketones and Vinylcyclopropanecarboxylic Acids: Application to the Stereoselective Synthesis of trans-Chrysanthemic Acid

Some years ago, we designed1a a stereoselective synthesis of (1RS)-cis-chrysanthemic acid 1a (R1, R2 ) Me)2 from dimethyldimedone 2a (R1, R2 ) Me) which uses cheap reagents compatible with industrial requirements. The key steps of this process are (i) the cyclopropanation of 2a, which produced the bicyclo[3.1.0]hexa-2,4-dione1a,3 3a, and (ii) the Grob fragmentation4 on the mesylate 5a derived from â-hydroxy ketone 4a, itself resulting from the mono-reduction of 3a. The stereochemical outcome of each individual step that is important for the success of the whole process is depicted in Scheme 1.1 Most of the reducing agents used, including sodium borohydride (methanol, -78 °C), efficiently achieved5 monoreduction of the bicyclic dione 3a but delivered, exclusively or mainly, the endo alcohol 4aendo. This alcohol, which results from the attack of the hydride from the least hindered exo face of 3a,1a,b is unsuitable, however, for the synthesis of 1a. This synthesis has been nevertheless successfully achieved from the exo stereoisomer 4aexo, readily available from the reduction of 3a1a,b with sodium borohydride-cerium trichloride (methanol, -78 °C, Luche’s reagent).6 This synthetic approach has been successfully extended to homologous derivatives of 1 bearing one methyl group and one hydrogen or even two hydrogens on the cyclopropane ring. This approach is unsuitable, however, for the synthesis (for example) of derivatives 1 bearing one or two hydrogens on the terminal sp2 carbon, due to competing metalation at the position R to the carbonyl group of 2 and 4 (R1 or/and R2 ) H).

Preparation, Properties, and Reactions, of Metal‐Containing Heterocycles, XCVI. Mono‐, Di‐ and Trinuclear Metallacycloalkanes of the Iron‐Triad

AbstractThe reaction of the bis(triflates) [F3CSO3‐(CH)m‐O3SCF3] [m = 5–10, 12, 14, 16 (1a–i) with Na2[Os(CO)4] in dimethyl either affords the osmacycloalkanes 2a, 2b and 2f–i (m = 5, 6, 10, 12, 14, 16), diosmacycloalkanes 3a–i (m = 5‐10, 12, 14, 16), and triosmacycloalkanes 4a–i (m = 5–10, 12, 14, 16). The structure of 3f was investigated by an X‐ray structural analysis. This 22‐membered disomacycle crystallizes in the space group Pā with Z = 1. If the unsaturated cis‐4‐octen‐1,8‐diyl bis(trifluoromethanesulfonate) (5) is treated with Na2[Os(CO)4] the diosmacyclooctadeca‐5,14‐diene 6 is obtained. By treating the bis(triflates) 1a, b with Na2[Fe(CO)4] the corresponding ferracycloalkanes are formed only in situ. Insertion of carbon monoxide into the M–C σ bonds leads to the cyclic ketones 7a, d and to the diketone 8d.

Synthesis of 6,7‐dihydrobenzo[4,5]cyclohept‐[1,2‐b]indol‐12(5H)‐one and related compounds

AbstractThe synthetic routes of 6,7‐dihydrobenzo[4,5]cyclohept[1,2‐b]indol‐12(5H)‐one 5 from either 1‐methyl or 1‐sulfonylindole‐2‐carboxaldehyde 1 or ethyl 1,2‐dimethylindole‐3‐carboxylate 6 are reported. The structure of the ketone 5a was confirmed by X‐ray crystallography. Several indole derivatives have been prepared with potential antitumor activity.

An Efficient Stereocontrolled Strategy in the Cyclopropanation Reactions of α,β-Unsaturated Ketones with Semistabilized Ylides: Highly Selective Synthesis of Two Geometrical Isomers of Vinyl-Substituted Cyclopropane Derivatives

The semistabilized telluronium ylides 2a−e, generated in situ from the corresponding telluronium salts 1a−e, reacted with α,β-unsaturated ketones 6a−d to afford cis-2-vinyl-trans-3-substituted cyclopropyl ketones with high stereoselectivity and in high to excellent yields. Conversely, these enones gave trans-2-vinyl-trans-3-substituted cyclopropyl ketones, when the corresponding arsonium ylides 10a−e were employed. Other factors such as solvent and amount of base also influenced the stereochemistry of this reaction. A mechanistic rationale is discussed briefly.

New reaction mode of the Horner–Wadsworth–Emmons reaction using Sn(OSO2CF3)2 and N-ethylpiperidine

Excellent Z or E selectivity is observed in the Horner–Wadsworth–Emmons reactions of methyl bis(trifluoroethyl)phosphonoacetate 2 with aryl alkyl ketones 3a–d or aldehydes 3f,g using Sn(OSO 2 CF 3 ) 2 in the presence of N-ethylpiperidine, which should have a different reaction mode to those using sodium hydride.

On Some Italicene Derivatives

AbstractOxidation of the tricyclic sesquiterpene hydrocarbon italicene (1a) or its 10‐epimer 1b (isolated previously from Helichrysum oil) with SeO2 yielded mixtures of italicene‐5‐one (3a), italicen‐15‐al (4a), italicen‐5‐ol (9a) and italicen‐15‐ol (10a) or their 10‐epimers 3b, 4b, 9b, 10b, whereas commercial α‐copaene (6) reacted only to give a mixture of α‐copaen‐15‐al (7) and α‐copaen‐15‐ol (8). Jones oxidation of the allyl alcohols 9a or 9b afforded the pure ketones 3a or 3b MnO2 oxidation of the alcohols 10a or 10b furnished the aldehydes 4a or 4b. – Surprisingly, the italicene epoxides 2a or 2b rearranged with diluted HCl to the italicene ethers (epoxyacorenes) 5a or 5b, which previously were isolated from Lantana and Helichrysum oil. – The odor of 3a, 3b, 4a, 4b and 5a was evaluated.

2‐Alkynylcyclopent‐2‐enols from 2‐Alkynylcyclohex‐2‐enones via 1‐Alkynyl‐7‐oxabicyclo[4.1.0]heptan‐2‐ones

Abstract2‐Alkynylcyclohex‐2‐enones 1a–c and 2a–c react with H2O2/NaOH in MeOH to afford 1‐alkynyl‐7‐oxabicyclo[4.1.0]heptan‐2‐ones 3a–c and 4a–c, respectively. The 3‐unsubstituted bicyclic epoxy ketones 3a, 3b, and 4a, 4b react further with H2O2/NaOH, undergoing ring contraction and (formal) decarbonylation to give 2‐alkynylcy‐clopent‐2‐enols 5a, 5b, and 6a, 6b, respectively. Epoxy ketones 3 are also obtained under neutral conditions on irradiation (λ = 350 nm) of cyclohexenones 1 in air‐saturated benzene solution. Similarly, under neutral conditions oxo‐cycloalkenecarbonitriles 8 react (thermally) with H2O2 in MeCN to give the oxabicyclic carbonitriles 9.

Synthesis and reactivity of oxopyrrolidinothieno[2]azepinones: [3]Benzazepine antidepressant analogs

AbstractA synthesis of oxopyrrolidino[2]azepinones annelated to a thiophene ring 3a,b,c is described starting from succinimide and halogenomethylthiophenes 6a,b,c. Stereoselective reduction, Schmidt reaction and the Beckmann rearrangement of the oximes of the ketones 3a,b,c are studied.

Preparation, Properties, and Reactions of Metal‐Containing Heterocycles, XCIII. Diosma[5.n.5.n]ortho‐, ‐meta‐, and ‐paracyclophanes (n = 0–2)

AbstractThe reaction of the ortho‐, meta‐, and para‐bis(triflates) [(F3CSO2OCH2CH2C6H4)2(CH2)n] with n = 0 (ortho: 1a), n = 0, 1 (meta: 1b, d), and n = 0–2 (para: 1c, e, g) with [Os(CO)4]2– results in the formation of the diosma[5.n.5.n]‐ortho‐, ‐meta‐, and ‐paracyclophanes with n = 0 (ortho: 2a), n = 0, 1 (meta: 2b, d), and n = 0–2 (para: 2c, e, g). On reaction of the bis(triflates) 1a, b with the dianionic [Fe(CO)4]2– the corresponding ferracyclophanes are formed only in situ. Carbon monoxide insertion into the Fe–C s̀ bonds of the ferracycles affords the ketones 6a, b. The structures of 2a and 2e were investigated by X‐ray structural analysis. Compounds 2a and 2e crystallize in the space group P21/c with Z = 8 and P1 with Z = 2, respectively.

A Versatile Domino Synthesis Affording Novel S‐ and U‐Shaped Terpyridines. – Synthesis, Properties and Crystal Structure

The development of a simple and general method for the preparation of multifunctional terpyridines is described. The treatment of the ketones 1a–g with ternary iminium salts results in the formation of the isomeric terpyridines 6 and 8 (according to a domino reaction). A possible reaction mechanism is discussed. In some cases the isolation of the postulated dihydropyridine intermediates was successful. The isolation of the 1,4‐dihydropyridines 5e, 5j, and 5r (donor‐substituted) is surprising, because most of the stable dihydropyridines are acceptor‐substituted. In several cases the yields of such domino reactions are very high (>80%). Whether Sor U‐shaped terpyridines are formed is immediately recognized by NMR spectroscopy. Some special cases (8c, 8e, 6h) were investigated by means of single‐crystal X‐ray analysis.

Allylated ketosulphides of benzothiazole as intermediates for stereoselective synthesis of allyl ketones, allyl thiiranes and dienes

α-Ketosulphides of benzothiazole 1 react with allylic carbonates in the presence of palladium acetate in dichloromethane under mild conditions affording α- and α,α-diallylated ketosulphides 2 in high yields. Reductive desulphurization of 2a–d with tributyltin hydride gives diallylated ketones 3a–d, whereas reduction of mono-allylated 2e–k with sodium borohydride in isopropanol affords allyl episulphides 4e–k prevalently as (Z)-isomers which can be transformed stereoselectively into dienes.

Synthesis of (1S,5S)‐4,5‐Dihydro‐1,5‐epoxy‐1H‐2‐benzoxocin‐6(3H)‐one from (S)‐Malic Acid Derivatives

AbstractThe homochiral 1,3‐dioxanes 8a–e with a 2‐bromophenyl substituent in position 2 and an electrophilic group in position 4 were stereo‐ and regioselectively prepared from the (S)‐malic acid derivatives 6a, 6b, 11, and 14. Attempts to prepare the tricycles 5a–c by connecting the 2‐phenyl substituent with the electrophilic groups in position 4 of 8a–e in a Parham cyclization across the 1,3‐dioxane ring failed. The synthesis of the tricyclic title ketone 5a succeeded, however, by addition of the lithiated benzaldehyde acetal 7c to the protected α‐hydroxylactone 10b and subsequent treatment of the intermediate ketone 23 with acid. The acid hydrolysis of the alcohol 26, which was obtained by addition of 7c to the protected dihydroxy aldehyde 25b, followed by oxidation of the resulting alcohols 27a and b represent a second possibility for the preparation of the tricyclic ketone 5a.

Sterically Crowded Heterocycles. VIII. Preparative Photoisomerization of Some Imidazo[1,2-a]pyridines

UV-Illumination of (Z)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)-1,3-diphenylprop-2-en-1-one (1a) or its 6-methyl and 6-iodo derivatives 1c and 1g resulted in minor (E)-isomers 2a, 2c, and 2g and prevailing (E,Z)-mixtures of N-(pyridin-2-yl)-[(3,5-diphenylfuran-2-yl)phenylmethylidene]amines 3a, 3c, and 3g while only corresponding furanoic derivatives 3b and 3d-3f were obtained from 5-methyl (1b), 7-methyl (1d), 8-methyl (1e), and 5-phenyl (1f) derivatives of the (Z)-ketone 1a. VIS-Illumination of (Z)-1,3-diphenyl-3-(2-phenylimidazo[1,2-a]benzo[I]quinolin-3-yl)prop-2-en-1-one (4) led to N-(benzo[h]quinolin-2-yl)-[(3,5-diphenylfuran-2-yl)phenylmethylidene]amine (5). Photoisomers 2a, 2c, 2g, 3a-3g, and 5 were isolated and the molecular structure of 3c was X-ray determined. Mechanism of the photoisomerization is discussed using semiempirical quantum chemical calculations and compared with mass spectra of compounds 1a, 2a, 3a, 1g, 2g, and 3g.

Reaction of small-size cycloalkane rings with RuO 4. Oxidative scission of ethyl 2,2-dimethoxycyclopropane-1-carboxylates and methyl 2,2,6,6-tetramethoxybicyclo[2.2.0]hexane-1-carboxylates

The reaction of ethyl 2,2-dimethoxycyclopropane-1-carboxylates 1a-d and methyl 2,2,6,6-tetramethoxybicyclo[2.2.0]hexane-1-carboxylates 5a and 5b with RuO 4 in CCl 4 at room temperature leads in both cases to the oxidative ring opening by regioselective scission of the electron-rich C1C2 bond for 1a-d, and both C1C2 and C1C6 bonds for 5a and 5b. Methyl ethyl oxobutanedioates 2a-d were obtained in the first case while the 3-substituted ethyl methyl 2-oxopentanedioates 6a and 6b in the second one. In the same reaction conditions, cyclopropanes substituted with electron withdrawing groups, namely cyclopropyl methyl ketone ( 3a) and cyclopropane-1,1-dicarboxylic acid ( 3b) are unreactive; methyl 2,2-dimethoxycyclobutane-1-carboxylate 4 is unreactive as well.

Regioselective Enolization and Alkylation of 4-Oxo-N-(9-phenylfluoren-9-yl)proline: Synthesis of Enantiopure Proline−Valine and Hydroxyproline−Valine Chimeras

The regioselective enolization of 4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (5) followed by alkylation with different alkyl halides has been used to synthesize a variety of β-alkylproline derivatives. In particular, enolization of 5 with 400 mol % of KN(SiMe3)2 and alkylation with iodomethane provided 3,3-dimethyl-4-oxo-N-(9-phenylfluoren-9-yl)proline benzyl ester (7a) in excellent yield. Subsequent hydride reduction of ketone 7a and protecting group exchange by hydrogenation in the presence of di-tert-butyl dicarbonate provided enantiopure (2S,4R)- and (2S,4S)-3,3-dimethyl-4-hydroxy-N-(BOC)prolines 2. Hydroxyproline−valine chimeras (2S,4R)- and (2S,4S)-2 are each synthesized from hydroxyproline in six steps and 27% respective overall yield. Deoxygenation of 3,3-dimethyl-4-hydroxy-N-(9-phenylfluoren-9-yl)proline benzyl esters 9 via their conversion to xanthates 10 followed by tributylstannane-mediated reduction provided 3,3-dimethyl-N-(9-phenylfluoren-9-yl)proline benzyl ester (11) in excellent y...

Reduction of 2-Substituted Cyclohexanones by Saccharomyces Cerevisiae

An enzymatic reduction of 2-substituted cyclohexanones mediated by Saccharomyces cerevisiae was studied with respect to the stereochemical course and optical purity of the products. Reduction of ketones 1b-1f resulted in separable diastereoisomeric mixtures of cis- and trans-stereoisomers of 2-substituted cyclohexanols (2b-2f and 3b-3f) having the (S) absolute configuration at the chiral center bearing the hydroxyl functionality with high enantiomeric purity. Reduction of ketone 1a yielded mixture of cis-(1S, 2R)- and trans-(1R, 2R)-stereoisomers (2a and 3a) with lower enantiomeric purity. Changes in the nature of the C(2)-substituent affect the stereochemical course of the biotransformation. However, they significantly influenced the enantiomeric purity of the products. The diastereoselectivity of the process was studied as well; high diastereoselectivity was observed with the substrates 1a, 1e and 1f.

Asymmetric [2 + 1] Cycloaddition Reactions of 1-Seleno-2-silylethene.

The reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene (1) and vinyl ketones 2a-d in the presence of a chiral Lewis acid prepared from TiCl(4), Ti(O(i)Pr)(4), (R)- or (S)-1,1'-binaphthol (BINOL), and MS4A gave enantiomerically enriched cis cyclopropane products 3a-d. The enantiomeric excess and chemical yield varied depending on the ratio of TiCl(4) and Ti(O(i)Pr)(4) to 1. Reproducible results (43-47% ee/33-41% yields) for cis-1-acetyl-2-[(phenylseleno)(trimethylsilyl)methyl]cyclopropane (3a) were obtained using 1.1 equiv of TiCl(4), 0.54-0.65 equiv of Ti(O(i)Pr)(4), and 1.65 equiv of BINOL. The observed enantioselectivity was explained by consideration of the structure of the postulated intermediates, alkoxy titanium-carbonyl complexes, via ab initio MO calculations.

Implementation of the Dakin-West reaction for the preparation of an α-amino-pentafluoroethyl ketone

We have successfully implemented the Dakin-West reaction to prepare 4-(carbamoyl- or benzoylamino)-5-methyl-1,1,1,2,2-pentaffuorohexan-3-one ( 3, 7a and 7b). We also isolated and characterized the impurities obtained from this Dakin-West reaction. Although we were successful in the literature-described conversion of 3 to 4, we have been unsuccessful at benzamide cleavage of 7a or 7b under a variety of conditions, presumably owing to the presence of an electrophilic pentafluoroethyl ketone moiety. We illustrated that 5-pentafluoroethyl oxazole 15 can be derived from N-benzoyl-pentafluoroethyl ketone 7a and that oxazole 15 is also resistant to ring opening.

A new synthesis of (±)‐phoracantholide, (±)‐dihydrorecifeiolide, and (±)‐muscone via α‐nitro ketones

AbstractCα′ alkylation of α‐nitro cycloalkanones 1a–c with methyl iodide at −35 to −70°C in THF/heptane/DMPU/TMDA in the presence of LDA as a base furnished the methylated α‐nitro ketones 2a–c. Denitration of 2a, b with Bu3SnH/AIBN in dry benzene afforded the α′‐methylated ketones 3a, b, which were converted to (±)‐phoracantholide (4a) and (±)‐dihydrorecifeiolide (4b), respectively, by the Baeyer‐Villiger oxidation. Reduction of 2c with NaBH4 and dehydration of the obtained nitro alkanol 5 with Al2O3/DMAP furnished the corresponding nitro alkene 6. Nef conversion of 6 with sodium hypophosphite and Raney nickel afforded (±)‐muscone (7) in good yields.

Chiral polymethine dyes, V. syntheses, absolute configuration, spectroscopic, and chiroptical properties of chiral dinuclear tri‐ and pentamethinium as well as trinuclear [2.2.2]heptamethinediium cyanine dyes with 3‐sec‐butyl‐1,3‐dimethylindolyl end groups

AbstractStarting with natural monochiral (−)‐(S)‐2‐methyl‐1‐butanol (1a) generated by alcoholic fermentations, we have synthesized the new monochiral heterocyclic iminium salt (+)‐(3R,15S)‐3‐sec‐butyl‐1,2,3‐trimethylindoleninium tetrafluoroborate (11) in an eight‐step reaction sequence. Important steps of this sequence are the zeolite‐catalyzed Fischer synthesis of the monochiral indole 6a from the phenylhydrazone of ketone 5a and the separation of the diastereomeric salts 9 and 10 by fourfold fractional recrystallization from ethanol. With the new quaternary iminium salt 11, new monochiral dinuclear tri‐ (13) and pentamethinium cyanine dyes (14) as well as the trinuclear [2.2.2]heptamethinediium 17 and [1.1.1]tetramethinium cyanine dyes 18 have been synthesized. The absolute configuration of the four stereogenic centers in the cyanine dye 14 has been confirmed by means of an X‐ray structural analysis. Spectroscopical and chiroptical properties of all new cyanine dyes have been determined.