Ketene Precursors Research Articles

Stereo- and regiocontrol in intermolecular [2+2] cycloadditions between diarylketenes and allenamides to access substituted α-methylenecyclobutanones.

The development of intermolecular [2+2] cycloadditions between allenamides and diarylketenes is described. α-Aryldiazo arylketones are employed as ketene precursors that react smoothly with allenamides in the presence of a P(C6F5)3 promoter. High diastereoselectivity (dr > 20 : 1) with endo-regioselectivity can be achieved when two aryl groups of ketenes have opposite electronic properties. The role of P(C6F5)3 is to increase the reaction yields, but also enhancing stereoselectivity.

Continuous Flow Generation of Acylketene Intermediates via Nitrogen Extrusion.

A flow chemistry process for the generation and use of acylketene precursors through extrusion of nitrogen gas is reported. Key to the development of a suitable continuous protocol is the balance of reaction concentration against pressure in the flow reactor. The resulting process enables access to intercepted acylketene scaffolds using volatile amine nucleophiles and has been demonstrated on the gram scale. Thermal gravimetric analysis was used to guide the temperature set point of the reactor coils for a variety of acyl ketene precursors. The simultaneous generation and reaction of two reactive intermediates (both derived from nitrogen extrusion) is demonstrated.

Synthesis of functionalized γ-lactams by a lewis acid catalyzed ketene formation/cyclization/claisen rearrangement sequence of 5,5-disubstituted Meldrum’s acid

A series of γ-lactams were synthesized by intramolecular aza-claisen rearrangement of ketenes using Meldrum’s acid as ketene precursor. Derivatives of Meldrum’s acid with tertiary ammonia structure were used as raw material, and the reaction was catalyzed by Lewis acid at high-temperature conditions under microwave. Ketene formation by losing acetone and CO2, cyclization and claisen rearrangement occurred in sequence to form the γ-lactams.

Stereoselective synthesis of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted β-lactams: Potential synthons for diverse biologically active agents

An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate tethered β-lactam conjugates 8a–j from novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f is reported here. The reaction between various ketene precursors and novel Schiff’s bases 6a–f afforded exclusive formation of trans-β-lactams 8a–j. The substrate scope of this approach was investigated extensively by varying different groups (R, Z). All the novel compounds were characterized using various spectroscopic techniques, such as FT-IR, 1H NMR, 13C NMR, elemental analysis, 13C NMR (DEPT-135), and mass spectrometry in representative cases. Single crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular structure and the stereochemical outcome. To the best of our knowledge, the synthesis of such types of Schiff’s bases and β-lactam conjugates has not been reported so far.

Synthesis of Eight‐Membered Lactams through Formal [6+2] Cyclization of Siloxy Alkynes and Vinylazetidines

AbstractA new approach for the efficient synthesis of eight‐membered lactams through formal [6+2] cyclization of siloxy alkynes and vinylazetidines has been developed. Evidence from a chirality transfer experiment suggests that the reaction proceeds via a [3,3]‐sigmatropic rearrangement from a ketene intermediate. This insight led to the development of alternative conditions and use of acyl chlorides as ketene precursors for the [6+2] reaction with vinylazetidines.

Synthesis of Eight-Membered Lactams through Formal [6+2] Cyclization of Siloxy Alkynes and Vinylazetidines.

A new approach for the efficient synthesis of eight-membered lactams through formal [6+2] cyclization of siloxy alkynes and vinylazetidines has been developed. Evidence from a chirality transfer experiment suggests that the reaction proceeds via a [3,3]-sigmatropic rearrangement from a ketene intermediate. This insight led to the development of alternative conditions and use of acyl chlorides as ketene precursors for the [6+2] reaction with vinylazetidines.

Effect of ketene additive and Si/Al ratio on the reaction of methanol over HZSM‐5 catalysts

The influence of ketene as possible intermediate for the reaction of methanol to aromatics was investigated over HZSM‐5 catalysts (Si/Al ratio of 15 and 9) using diketene‐acetone (2,2,6‐trimethyl‐4H‐1,3‐dioxin‐4‐one) as ketene precursor under atmospheric pressure at 300 °C. The physicochemical properties of HZSM‐5 catalysts were investigated by NH3‐TPD, BET, XRD and ICP analysis. The distribution of products was measured by GC‐Mass spectrometer. These catalysts exhibit high reactivity and selectivity for the conversion of methanol and/or ketene to hydrocarbons (mostly high octane number xylenes, trimethylbenzenes, tetramethylbenzenes and ≤1.5% benzene). The conversion of neat diketene‐acetone over these catalysts produced aromatics compounds and significant amounts of oxygenated compounds (ketone, carboxylic acid, phenol, furan, pyran and others) depending on Si:Al ratio. These catalysts with high acid content produced small amount of saturated and unsaturated hydrocarbons without releasing significant amount of gas. The ketene and produced oxygenates from ketene appears to act as intermediates for the formation of aromatic compounds.

Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetyl Meldrum's acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and their synthetic usefulness as (trifluoroacetyl)ketene precursors

A simple and reliable method for the preparation of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one on a multigram scale was developed. These (trifluoroacetyl)ketene precursors were used in the hetero-Diels-Alder reaction with dialkylcyanamides and 1-ethoxyprop-1-yne, as well as in some reactions with nucleophiles.

Synthesis and time resolved infrared analysis of photochemical oxiranyl carbene and diphenyl ketene precursors

Synthesis of a nonnitrogenous phenanthrene-based precursor of oxiranyl carbene yielded a photochemical source for diphenyl ketene after an in situ intramolecular rearrangement. The initial carbene precursor targeted rearranged from a putative spiro-oxiranyl intermediate to a cyclobutanone. Photolysis of the phenanthrene–cyclobutanone generated an infrared signal centered at 2100cm−1 consistent with diphenyl ketene formation. Time-resolved infrared spectroscopy followed the reaction progress and measured bimolecular rate constants (kobs=9.1×106M−1s−1; butyl amine) consistent with diphenyl ketene formation. Quenching experiments combined with Stern–Volmer kinetics suggests a radical pathway is likely involved in the formation of diphenyl ketene from the phenanthrene-based precursor. The generality of the rearrangement is also discussed.

Chemoselective halogenation of 2-hydroperfluoroalkyl aldehydes

2-Hydroaldehydes, RfCH(R)CHO, where Rf=CF3, C2F5, n-C3F7 and R=CF3, C2F5, n-C3F7, Ph, H, were prepared via acid hydrolysis of the corresponding vinyl ethers, RfC(R)=CHOCH3, which can be readily prepared by reaction of [Ph3P+C¯HOCH3] with the corresponding ketone. The 2-hydroaldehydes can be chemoselectively converted to the acyl halide, RfCH(R)C(O)X (X=Cl, Br), via free-radical halogenation. The perfluoroalkyl group deactivates the 2-position toward radical abstraction of the 2-hydrogen, and halogenation occurs exclusively at the formyl hydrogen. However, halogenations of the 2-hydroaldehydes in glacial acetic acid chemoselectively gives the 2-haloaldehydes, RfCX(R)CHO, X=Cl, Br. Hydrolysis of the 2-hydroperfluoroacyl halides provides a useful route to 2-hydroperfluoroalkyl branched carboxylic acids, useful ketene precursors. This route avoids the use of toxic fluoroolefins, such as perfluoroisobutylene.

Synthesis of 3-Alkoxy/Aryloxy-β-lactams Using Diazoacetate Esters as Ketene Precursors Under Photoirradiation

3-Alkoxy/aryloxy-β-lactams are synthesized in satisfactory to good yields from the reaction of imines and alkyl/aryl di­azoacetates under photoirradiation conditions. Typically, trans-β-lactams are obtained as the major products from linear imines using the current method. By contrast, the corresponding thermal reaction of imines and alkoxy/aryloxyacetyl chlorides, or their equivalents, in the presence of triethylamine affords cis-β-lactams as the major or exclusive products. The formation of trans-β-lactams from linear imines is attributed to isomerization of the imines from their trans-isomers into syn-isomers under UV irradiation. The reported method represents a metal-free and neutral approach for the synthesis of 3-alkoxy/aryloxy-β-lactams.

ChemInform Abstract: Laser Flash Photolysis of 2-Diazo-1,3-diphenyl-1,3-propanedione: An Unusual Long-Lived Triplet as a Reaction Intermediate.

Laser flash photolysis of 2-diazo-1,3-diphenyl-1,3-propanedione (DBD) is presumed to involve a short-lived carbene, followed by Wolff rearrangement to a long-lived ketene. We have detected ketene ylides following photolysis of DBD in the presence of amines but not with pyridine. The triplet state of DBD lives several microseconds, an unusual observation for a diazo compound; however, the triplet is not a ketene precursor, which must result from excited singlet state fragmentation of DBD.

Laser flash photolysis of 2-diazo-1,3-diphenyl-1,3-propanedione: An unusual long-lived triplet as a reaction intermediate

Laser flash photolysis of 2-diazo-1,3-diphenyl-1,3-propanedione (DBD) is presumed to involve a short-lived carbene, followed by Wolff rearrangement to a long-lived ketene. We have detected ketene ylides following photolysis of DBD in the presence of amines but not with pyridine. The triplet state of DBD lives several microseconds, an unusual observation for a diazo compound; however, the triplet is not a ketene precursor, which must result from excited singlet state fragmentation of DBD.

Product Branching Ratio of the HCCO + NO Reaction

The reaction of HCCO radicals with NO was studied at room temperature by excimer laser photolysis of ketene precursor molecules followed by infrared absorption spectroscopic detection of CO and CO{sub 2} product molecules. After quantification of product yields and consideration of secondary chemistry, the authors obtain the following product branching ratios (1{sigma} error bars) at 296 K: 0.12 {+-} 0.04 for CO{sub 2} + (HCN) and 0.88 {+-} 0.04 for CO + (HCNO). In addition, they estimate a relative quantum yield for HCCO production in the 193 nm photolysis of CH{sub 2}CO to be 0.17 {+-} 0.02.

Scavenging of Intermediates Formed in Photolysis of α-Diazocarbonyl Compounds and Hydroxycyclopropenones. Implication on the Mechanism of the Photo-Wolff Reaction

The question of whether α-carbonylcarbene intermediates are formed as ketene precursors in the photo-Wolff reaction of α-diazocarbonyl compounds was addressed by comparing pyridine scavenging of transients generated by laser flash photolysis of benzoyldiazomethane and 1-naphthoyldiazomethane with pyridine scavenging of transients formed by flash photolysis of the corresponding arylhydroxycyclopropenones. The rate laws for the scavenging process in the two different photoreactions in aqueous solution were found to be exactly the same, and since ketene intermediates are common to both reactions but α-carbonylcarbenes are not, the transients were thus identified as ketenes. Formation of these ketene intermediates in the photo-Wolff reaction took place within the duration of the laser pulse (ca. 20 ns), and α-carbonylcarbene intermediates, if formed at all, must have lifetimes shorter than this.

A Three-Step General Synthesis of 2-Azetidinones BearingN-Dehydroamino Acid Side Chains

An efficient, three-step synthesis of N-vinyl-2-azetidinones 7 starting from α- or β-amino ester imines 3 has been developed. Staudinger reaction between imines 3 and a ketene precursor gave 2-azetidinones 4. Enolate formation on the amino ester moiety of the 2-azetidinone 4, selenation, and finally m-CPBA treatment, afforded N-vinyl-2-azetidinones 7 in fair to excellent yields, with total retention of the stereochemistry of the starting material. Two examples of the use of compounds 7 in preparing bi- and tricyclic 2-azetidinones are presented.

Synthesis of Optically Pure 2-Azetidinones Having N-Dehydroamino Acid Side-Chains

An efficient, three step synthesis of optically pure N-vinyl-2-azetidinones 1 starting from α- or β-amino ester imines has been developed. Staudinger reaction between amino ester derived imines and ketene precursors gave 2-azetidinones 2. Enolate formation on the amino ester moiety of the optically pure 2-azetidinones 2, selenylation and, finally, MCPBA treatment afforded N-vinyl-2-azetidinones 1 in good to excellent yields, with total retention of the stereochemistry of the starting material. Compounds 2 bear the functionality needed to place a carboxy group contiguous to the lactam nitrogen, a structural feature common to all the active β-lactam antibiotics.

An efficient use of Oppolzer sultam for Diastereospecific Synthesis of cis-β-Lactams

Diastereospecific Synthesis of cis-β-Lactams ( 6a-g) has been achieved in ketene-imine cycloaddition reaction (Staudinger reaction) by using homochiral ketene precursors 3 and 4 derived from Oppolzer sultam, in very good yields.

An efficient synthesis of cis-3-hydroxy-4-phenyl-β-lactams: Precursor for taxol side chain

Chiral ketene precursors derived from naturally occurring (+)-3-carene have been used for the synthesis of β-lactams via the Staudinger reaction. The major diastereomer 5a was separated by crystallization and converted in very good yield into (3 R, 4 S)-3-hydroxy-4-phenyl- β-lactam, an advanced intermediate towards the taxol side chain.

Reactions of transition-metal η1-ally and propargyl complexes with ketenes and some new nonoxidative transition-metal-carbon bond cleaving reactions of the ketene cycloadducts which yield cyclopentenones

Reactions of cyclopentadienyl iron 2-alkynyl and allyl complexes with ketenes or ketene precursors yield transition-metal substituted cyclopentenones in some cases and new transition-metal substituted allyl complexes in others. The transition metals can subsequently be cleaved from the cyclopentenone containing complexes under a variety of oxidative and nonoxidative reaction conditions.