Nickel-catalyzed intermolecular alkyne insertion into cyclobutanones

Cyclobutanones reacted with alkynes in the presence of nickel(0) catalysts to produce cyclohexenones. Oxidative cyclization of the carbonyl group of the cyclobutanone and the alkyne with the nickel(0) was followed by beta-carbon elimination from the resulting oxanickelacyclopentene and subsequent reductive elimination. This reaction achieves a formal alkyne insertion between the carbonyl carbon and the alpha-carbon, providing a six-membered carbocyclic skeleton.     

Determination of the pKa of cyclobutanone: Brønsted correlation of the general base-catalyzed enolization in aqueous solution and the effect of ring strain

The induction of strain in carbocycles, thereby increasing the amount of s-character in the C-H bonds and the acidity of these protons, has been probed with regard to its effect on the rate constants for the enolization of cyclobutanone. The second-order rate constants for the general base-catalyzed enolization of cyclobutanone have been determined for a series of 3-substituted quinuclidine buffers in D(2)O at 25 °C, I = 1.0 M (KCl). The rate constants for enolization were determined by following the extent of deuterium incorporation (up to ～30% of the first α-proton) into the α-position, as a function of time. The observed pseudo-first-order rate constants correlated to the [basic form] of the buffer and yielded the second-order rate constants for the general base-catalyzed enolization of cyclobutanone for four tertiary amine buffers. A Br?nsted β-value of 0.59 was determined from the second-order rate constants determined. Comparison of the results for cyclobutanone to those previously reported for acetone and a 1-phenylacetone derivative, under similar conditions, indicated that the ring strain of the carbocycle appeared to have only a small effect on the general base-catalyzed rate constants for enolization. The similarity of the rate constants for the general base-catalyzed enolization of cyclobutanone to those determined for acetone allowed for an estimation of the limits of the rate constant for protonation of the enolate intermediate of cyclobutanone by the conjugate acid of 3-quinuclidinone (k(BH) = 5 × 10(8) - 2 × 10(9) M(-1) s(-1)). Combining the rate constants for deprotonation of cyclobutanone (k(B)) and protonation of the enolate of cyclobutanone (k(BH)) by 3-quinuclidinone and its conjugate acid, the pK(a) of the α-protons of cyclobutanone has been estimated to be pK(a) = 19.7-20.2.     

A novel route to geminal dibromocyclobutanes: syntheses of 2-substituted cyclobutanone acetals and their reaction with boron tribromide

Nine 2-substituted cyclobutanone acetals, in addition to the parent cyclobutanone acetal, were synthesized from their corresponding cyclobutanones and subsequently treated with boron tribromide. The substituents were either alkyl chains or a phenyl and a benzyl group, respectively. The major compounds obtained in these reactions were, in most cases, the geminal dibromocyclobutanes which were obtained in yields between 50 and 73%. A 2-fold excess of BBr3 and a reaction time of 3 h at -78 degrees C afforded the best yields. In four cases no dibromide formation was observed at all, and the cyclobutanone acetals were hydrolyzed to the corresponding cyclobutanone. This is probably due to increased steric hindrance of the acetal and BBr3 in the transition state.     

An economical and convenient preparation of 2-(phenylthio)cyclobutanone,a synthetic equivalent of cyclobutanone

A practical procedure is given for the preparation of 2-(phenylthio)cyclobutanone ($\text{3}$) and the use of the latter as a convenient substitute for cyclobutanone is demonstrated.     

Catalyzed intramolecular olefin insertion into a carbon-carbon single bond

Intramolecular insertion of a C-C double bond into a C-C single bond was achieved by treatment of cyclobutanone bearing an o-styryl group at the 3-position with a catalytic amount of a cationic rhodium(I)-dppp complex. Initially, rhodium is inserted between the carbonyl carbon and the alpha-carbon of the cyclobutanone. Intramolecular coordination of the vinyl group results in its migratory insertion into the C-Rh linkage. Reductive elimination affords benzobicyclo[3.2.1]octan-3-one. Notably, a ring-opened alpha,beta-unsaturated ketone was obtained when dppe was used instead of dppp. In this reaction, rhodium cleaved the bond between the alpha sp3 carbon and the beta sp3 carbon of the cyclobutanone. The coordinating vinyl group directs this new regioselectivity of cleavage observed with the dppe ligand.     

An efficient route to 3-substituted cyclobutanone derivatives

An efficient route to 3-(hydroxymethyl)cyclobutanone acetals via a [2+2] cycloaddition reaction is reported. The dramatic effect of different diol acetals on benzyl deprotection is discussed. Efficient synthesis of two synthetically useful intermediates, 3-methylenecyclobutanone acetal and 3-(bromomethyl)cyclobutanone, are provided.     

Cycloaddition of keteniminium with terminal alkynes toward cyclobuteniminium and their use in Diels–Alder reactions

An efficient access to cyclobutanone derivatives has been developed via a ‘one-pot’ [2+2]/[4+2] sequence involving keteniminium and cyclobuteniminium salts as key intermediates. A broad range of novel cyclobuteniminium salts have been prepared via [2+2] cycloaddition of keteniminium salts and alkynes. The resulting [2+2] adducts were then further transformed by Diels–Alder reaction with various dienes to afford cyclobutanone derivatives in good yields. A density functional theory (DFT) based computational study has been performed to obtain insight into the nature of the cycloaddition reactions and to investigate the difference in reactivity of cyclobuteniminium salts. Finally, the usefulness of cyclobutanone derivatives has been demonstrated by ring expansion reactions affording lactone, lactame, and cyclopentanone derivatives.     

Measurement and modelling of bubble and dew points in the binary systems carbon dioxide + cyclobutanone and propane + cyclobutanone

The fluid phase behaviour for the binary systems carbon dioxide+cyclobutanone and propane+cyclobutanone has been determined experimentally, using Cailletet equipment. For both the systems bubble points have been determined for a number of isopleths covering the whole mole fraction range. Additionally, for the binary system carbon dioxide+cyclobutanone dew points and critical points could be observed for a number of overall-compositions rich in carbon dioxide. The temperature and pressure range were, respectively, from 278 to 369 K and from 0.1 to 14.0 MPa. Correlation of the experimental data of both systems has been performed using the Soave–Redlich–Kwong (SRK) equation of state. Satisfactory results have been achieved using only one binary interaction parameter.     

Water-ketones hydrogen bonding: the rotational spectrum of cyclobutanone-water

The hydrogen-bonded complex cyclobutanone-water has been studied by Fourier-transform molecular-beam microwave spectroscopy in the frequency range of 6-18.5 GHz. The rotational spectra of ten isotopomers have been assigned and measured. Five of them have been obtained from different isotopic species (or configurations) of water (H2O, D2O, DOH, HOD, and H2 18O). The remaining five correspond to the four singly substituted 13C and to the 18O species of cyclobutanone, observed in natural abundance. For all species the inertial defect is in the range from -10.44 to -10.50 uA2, showing that the cyclobutanone frame is effectively planar and that the water molecule is coplanar to this frame. The hydrogen bond, almost linear, is formed between a water proton and one of the lone pairs of the cyclobutanone oxygen.     

Acid‐Promoted Ring Opening of α‐Hydroxyl Cyclobutanones: A Novel and Facile One‐Pot Synthesis of Nitrile Derivatives

A facile one‐pot synthesis of nitriles via a ring‐opening reaction of cyclobutanone adducts with hydroxylamine hydrochloride was developed.     

Enantiomeric resolution of cyclobutanones and related derivatives by enzyme-catalyzed acylation and hydrolysis

A method for the regio- and enantioselective protection and deprotection of a number of cyclobutanone derivatives employing the isolated enzyme porcine pancreatic lipase (PPL) has been developed. PPL catalyzes the regioselective acylation or deacylation of the C-3 substituent in (2S,3R)-(+)-bis[hydroxymethyl]-1,1-dimethoxycyclobutanone and its enantiomer. Photochemical ring expansion of the corresponding cyclobutanones in methanol gave anomeric mixtures of the methyl furanosides with stereochemical retention of the ring substituents. The PPL-catalyzed hydrolysis of the acetal derived from (2S,3R)-bis[acetoxymethyl]cyclobutanone resulted in a regioselective reaction of the C-3 acetoxymethyl group. PPL exhibits no hydrolysis activity toward the acetal derived from the enantiomeric cyclobutanone diacetate.

Racemic 2-acetoxymethyl-3,3-dimethylcyclobutanone was converted to its enantiomerically enriched (S)-alcohol by PPL-catalyzed hydrolysis. The corresponding methyl furanoside obtained from the photochemical ring expansion of racemic 2-acetoxymethyl-3,3-dimethylcyclobutanone in methanol is not an effective substrate for PPL mediated hydrolysis.     

Synthesis of cyclobutanones and four-membered enol ethers by using a rearrangement reaction of enol triflates

A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the β′-position, were synthesized from the corresponding β-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.     

An unusual effect of selenium substituents on the regiochemistry of a baeyer-villiger rearrangement

The regioselectivity of a Baeyer-Villiger oxidation of a cyclobutanone is dependent upon the oxidation state of a proximal selenium substituent.     

Iron(II)-catalyzed direct CH cyanoalkylation of 2H-indazoles and coumarins via radical CC bond cleavage

An iron-catalyzed C-3 cyanoalkylation of 2H-indazole and coumarin derivates with cyclobutanone oxime esters has been accomplished, which proceeds efficiently in a high regioselective manner to construct diverse alkylated 2H-indazole and coumarin derivates in moderate to good yields. Preliminary mechanistic studies reveal that a distal cyanosubstituted alkyl radicals intermediate would be formed through radical-involved CC bond cleavage of cyclobutanone oximes ester.     

A three-carbon (n+1+2) ring expansion method for the synthesis of macrocyclic enones. Application to muscone synthesis

The three-carbon ring expansion methodology commences with the preparation of a cyclic allene (C9, C11, C13), readily available from the corresponding cycloalkene via dibromocarbene addition and subsequent treatment with methyllithium. Dichloroketene addition to the cyclic allene regioselectively provides the [2+2] cycloadduct, which is reductively dechlorinated with zinc in methanol. The resulting cyclobutanone is then catalytically hydrogenated; cyclobutanone ring opening is affected with trimethylsilyl iodide; immediate dehydroiodination of the resulting β-iodocycloalkanone with diazabicycloundecane (DBU) provides the corresponding macrocyclic enone. The 15-membered enone was converted to d,l-muscone with (CH₃)₂CuLi.     

Aldol reactions of a cyclobutanone enolate

Addition of an aldehyde and zinc chloride to a cyclobutanone enolate, prepared by the reaction of an α-chlorocyclobutanone with dimethylcopperlithium, gave an aldol adduct in good yield.     

Synthesis of an enantiomerically pure 2,2,4-trisubstituted cyclobutanone building block by zirconocene-promoted deoxygenative ring contraction of structurally modified 4-vinylfuranosides

A route to an enantiopure trisubstituted cyclobutanone has been devised. The pursuit of this building block begins with d-glucose and features a zirconocene-promoted ring contraction.     

α-Selenocyclobutyllithium as a 2-lithio-1,3-diene equivalent. regioselective (100%) synthesis of ipsenol

1-substituted cyclobutenes and 2-substituted dienes are prepared in high yield and regioselectively from a variety of electrophiles and cyclobutanone via α-lithio-α-seleno-cyclobutyllithiums.     

Palladium-catalyzed intramolecular selenocarbamoylation of alkynes with carbamoselenoates: formation of alpha-alkylidene-beta-lactam framework

Pd-catalyzed intramolecular selenocarbamoylation of alkynes leading to alpha-alkylidene-beta-lactams was developed. This reaction can be applied to thiocarbamoylation and to the synthesis of delta- and epsilon-lactams and a cyclobutanone.     

Nickel-catalysed intramolecular alkene insertion into cyclobutanones

A nickel(0) catalyst converted 3-styrylcyclobutanones into benzobicyclo[2.2.2]octenones by an intramolecular insertion of the vinyl moiety into the cyclobutanone skeleton.