Initial Michael Addition Research Articles

Nitrone Ylides: Two Possible 1,3‐Dipolar Cycloadditions but Only One Stepwise Formation of all‐cis‐5‐Aryl‐2,3,5‐trisubstituted N‐Hydroxypyrrolidines

AbstractAn efficient methodology for the synthesis of all‐cis‐N‐hydroxypyrrolidines has been developed through the formal [3+2] dipolar cycloaddition of electron‐poor alkenes and nitrone ylides generated from N‐(methoxycarbonylmethyl)nitrones. Treatment of the nitrone with a tertiary amine in the presence of either a lithium salt or butyllithium followed by addition of the alkene at low temperature provided the product in very good chemical yield and excellent diastereoselectivity. Isolation and characterization of a key intermediate demonstrated that the reaction is a stepwise process consisting of an initial Michael addition followed by an intramolecular Mannich‐type reaction.

ChemInform Abstract: One‐Pot Organocatalytic Asymmetric Synthesis of 1H‐Pyrrolo[1,2a]indol‐3(2H)‐ones via a Michael—Hemiaminalization—Oxidation Sequence.

AbstractThe initial Michael addition is achieved with very high asymmetric induction.

ChemInform Abstract: Convenient One‐Pot Synthesis of Fluorinated DHPs Derivatives and Their Further Transformations.

AbstractThe four‐component reaction proceeds via initial Michael addition and a subsequent intramolecular cyclization to give trifluoromethyl substituted piperidines, which are dehydrated to the corresponding dihydropyridine derivatives.

ChemInform Abstract: Facile Synthesis of Oxaspirobicyclic Butenolides via a Domino Michael Addition/Aldol Reaction/γ‐Lactonization Sequence.

A three-component domino reaction approach between a primary amine, a dialkyl acetylenedicarboxylate, and 1,3-dimethylalloxan that affords novel oxaspirobicyclic γ-butenolidobarbiturate derivatives is reported. The reaction sequence consists of an initial Michael-addition of primary amines to dialkyl acetylenedicarboxylates, followed by aldol-like reaction with 1,3-dimethylalloxan, and then γ-lactonization to afford the products. This cascade reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules.

ChemInform Abstract: Benzopyrans. Part 41. Reactions of 2-(2-Dimethylaminovinyl)-1-benzopyran-4-ones with Various Dienophiles.

Dienamine 1 with N-phenylmaleimide and chromenone 14 as well as 15 produces, through initial [4 + 2]cycloaddition, xanthenones 10 and 18, respectively. Initial Michael addition of 1 to chromenones 14 and 16, and dimethyl acetylenedicarboxylate (DMAD), triggers the formation of xanthenone 19, 4-azaxanthenone 26 and substituted fumarate 49, respectively. Initial [2 + 2]cycloadducts of dienamines 1–3 with electrophilic acetylenes always undergo further transformations. Thus, 1 with DMAD, dibenzoylacetylene and ethyl propiolate (EP) ultimately gives xanthenones 33, 34 and 37, respectively, the latter being admixed with flavone 43. Enamine 2, cyclisable to xanthenone 11, gives 33 and 35 with DMAD, and 37 and 44 with EP. Reaction of 3 with DMAD affords 36 exclusively.

Convenient one-pot synthesis of fluorinated DHPs derivatives and their further transformations

One-pot four-component reactions of aromatic aldehyde, Meldrum’s acid, ethyl-4,4,4-trifluoro-1,3-dioxobutanoate, and ammonium acetate afford ethyl 2-hydroxy-6-oxo-4-aryl-2-(trifluoromethyl)piperidine-3-carboxylate in good yields. The one-pot four-component process consists of an initial Michael addition, and a subsequent intramolecular cyclization. The effect of solvents on the reaction efficiency and yield is briefly investigated. The structure of product is further confirmed by XRD analysis. Meanwhile, the further transformation of hemi-aminal moiety to the corresponding dehydrated product is also achieved under the mild reaction conditions. The possible mechanism for the formation of product is presented.

Facile synthesis of oxaspirobicyclic butenolides via a domino Michael addition/aldol reaction/γ-lactonization sequence

A three-component domino reaction approach between a primary amine, a dialkyl acetylenedicarboxylate, and 1,3-dimethylalloxan that affords novel oxaspirobicyclic γ-butenolidobarbiturate derivatives is reported. The reaction sequence consists of an initial Michael-addition of primary amines to dialkyl acetylenedicarboxylates, followed by aldol-like reaction with 1,3-dimethylalloxan, and then γ-lactonization to afford the products. This cascade reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules.

Computational Study on the Cyclopropanation Reaction of Ylides Generated from α-Pyridiniumacetates

Ab initio MO calculations were performed on the cyclopropanation reaction of methylidenemalononitriles with the ylide generated from α-pyridiniumacetates. The calculations indicated that the rate-determining step was the final cyclopropane forming step for the gas phase reaction, whereas solvent effect approximations implied that it was the initial Michael addition leading to the cis intermediate for reaction in water. It was also revealed that the plausible [3+2] cycloaddition reaction to give bicyclic products is more likely to be a stepwise and not an asynchronous concerted process in DFT calculations at the B3LYP/6-31G(d) level of theory.

Three-component synthesis of novel trifluoromethyl-containing tetrahydropyran derivatives

l-Proline-catalyzed reaction of ethyl 4,4,4-trifluoroacetoacetate, cinnamaldehyde and anilines provide a novel method for preparation of ethyl-6-(arylamino)-2-hydroxy-4-phenyl-2-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate derivatives in good yields. The reaction was conducted by initial Michael addition, followed by intra-molecular cyclization under mild conditions. The structure of a typical ethyl-2-hydroxy-4-phenyl-6-( m-tolylamino)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate ( 4h) was confirmed by XRD analysis. A plausible mechanism is presented.

Formation of Three N-Acetyl-l-cysteine Monoadducts and One Diadduct by the Reaction of S-(1,2-Dichlorovinyl)-l-cysteine Sulfoxide with N-Acetyl-l-cysteine at Physiological Conditions: Chemical Mechanisms and Toxicological Implications

Previously, our laboratory has shown that S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS), a Michael acceptor produced by a flavin-containing monooxygenase 3 (FMO3)-mediated oxidation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is a more potent nephrotoxicant than DCVC. In the present study, we characterized reactions of DCVCS with nucleophilic amino acids. DCVCS incubations with N-acetyl-L-cysteine (NAC) at pH 7.4 and 37 degrees C for 1 h resulted in the formation of three monoadducts and one diadduct characterized by LC/MS, 1H NMR, and 1H-detected heteronuclear single quantum correlation. The formation of all adducts (with relative ratios of 29, 31, 24, and 12%, respectively) was rapid and time-dependent; the half-lives of the two DCVCS diastereomers in the presence of NAC were 13.8 (diastereomer I) and 9.4 min (diastereomer II). Adducts 1 and 2 were determined to be diastereomers of S-[1-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed by Michael addition of NAC to the terminal vinylic carbon of DCVCS followed by loss of HCl. Adduct 4 was determined to be S-[2-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed from the initial Michael addition product followed by a less favorable loss of HCl and/or by a rearrangement of adduct 2 through the formation of a cyclic chloronium ion. The addition of another molecule of NAC to monoadducts 1, 2, or 4 resulted in the formation of the novel diadduct, S-[2,2-( N-acetyl-L-cystein-S-yl)vinyl]-L-cysteine sulfoxide (adduct 3), whose detection in relatively large amount suggests that DCVCS could act as a cross-linking agent. DCVCS was not reactive with N-acetyl-L-lysine or L-valinamide at similar incubation conditions. Collectively, the results suggest selective reactivity of DCVCS toward protein sulfhydryl groups. Furthermore, the cross-linking properties of DCVCS may in part explain its high nephrotoxic potency.

Tandem Michael Addition and Lactonization of Silyl Enolates and α,β-Unsaturated Ketones

A highly diastereo- and enantioselective tandem reaction between silyl enolates and α,β-unsaturated ketones is presented. The initial Michael addition of the enolate to the ketone is followed by an intramolecular substitution of the aryl­oxy group by the created oxyanion, yielding the lactone. The reaction is mediated by a quaternary ammonium salt derived from cinchonidine. The authors have employed several enolates for this reaction and found both diastereo- and enantio­selectivities to be highly dependent on the steric bulk of the enolate compound. The biggest influence is exercised by the R1 group, but it was also revealed that the use of more sterically hindered aryl groups was beneficial for the selectivities. In contrast to that, changing the electronic properties of the aryl group was found to decrease the enantioselectivity.

Reaction of a stable aminoarylcarbene with 2-chloroacrylonitrile: dearomatizing cyclization rather than cyclopropanation

The reaction of a stable aminoarylcarbene with 2-chloroacrylonitrile is reported. The resulting 1/1 adduct has been spectroscopically and structurally characterized. The initial Michael addition is not followed by cyclopropane formation but by a dearomatizing cyclization affording an original bicyclic structure.

Fischer Carbene Complexes. A New Tool for Heterocyclic Synthesis

AbstractFor Abstract see ChemInform Abstract in Full Text.

Model Studies on Protein Side Chain Modification by 4-Oxo-2-nonenal

trans-4-Oxo-2-nonenal (ONE) has recently been demonstrated to be a direct product of lipid peroxidation. In earlier studies to elucidate the structure of the trans-4-hydroxy-2-nonenal (HNE)-derived fluorescent Lys-Lys cross-link, we showed that ONE was capable of both oxidative and nonoxidative cross-linking of amines. A more comprehensive study on nonoxidative modification of protein nucleophiles by ONE is described here, focusing on the initial Michael addition of imidazole, thiol, and amine groups to C2 or C3 to give 4-keto aldehydes that can then condense with amines to form nucleophile-substituted pyrroles. 2,3-Substituted pyrroles (major) and 2,4-substituted pyrroles (minor) were distinguished by 2D NMR techniques, and N(tau)-substitution is preferred over N(pi)-substitution in the Michael addition of histidine. Mechanisms of both nonoxidative and oxidative side chain reactions of ONE are discussed, as is the relative propensity (ONE > HNE) to induce cross-linking of the model proteins ribonuclease A and beta-lactoglobulin.

Unusual expressions of Michael reactivity of 1,3-bis(phenylsulfonyl)allene

An improved procedure for producing the potent cycloaddition dienophile 1,3bis(phenylsulfonyl)allene 1 is described based on ensuring removal of excess triethylamine in the work-up of the final dehydroiodination step. Triethylamine, as well as other tertiary amines, promote trimerisation of 1 to 3 (X-ray shown), and a possible mechanism involving potentiation via a Michael addition to 1 is proposed. A further expression of the potent Michael acceptor character of 1 is provided by insertion into the α-position of THF to form 5. Mechanistically, this is suggested as proceeding via an oxonium-ion ylide, also generated via initial Michael addition of THF to 1.

Fischer carbene complexes. A new tool for heterocyclic synthesis

Abstract This short review covers our contribution in the field of the application of group 6 Fischer carbene complexes toward the synthesis of heterocyclic compounds. Alkenyl and alkynyl carbene complexes are suitable partners in [2+2], [3+2], [4+2], and [4+3] cycloaddition reactions. Moreover, chiral alkenyl carbene complexes react in sequential processes involving an initial Michael addition of a ketone lithium enolate to afford lactones with up to five consecutive stereogenic centers. Based on this strategy, we have devised a new method for the enantioselective synthesis of eight-membered carbocycles.

Enaminones as Building Blocks In Heterocyclic Synthesis: A New One Pot Synthesis of Polyfunctional Substituted Pyridines

Enaminones react with a variety of active methyl and methylene reagents in presence of ammonium acetate to yield functionally substituted pyridines in good yields. The reaction proceeded via initial Michael addition across the double bond followed by cyclization. The reaction of enaminone with aromatic aldehyde in acetic acid/ammonium acetate afforded the dihydropyridine that was oxidized to the corresponding pyridine.

Unexpected reactions of α,β-unsaturated esters with hydrazine hydrate

The reactions of hydrazine hydrate with methyl acrylate and ethyl acrylate do not result in the formation of 1,5-diazabicyclo[3.3.0]octane-2,6-dione 1 at reaction temperatures below 200 °C; 1,2-bis(alkoxycarbonylethyl)pyrazolidin-3-one 8, 1-(alkoxycarbonylethyl)pyrazolidin-3-one 6, and 2-(alkoxycarbonylethyl)pyrazolidin-3-one 11 were isolated and identified. At 260–280 °C, however, 1 could be isolated in 20–28% yield; formation of 1 could also be observed by spectroscopic measurements when the reaction was carried out above 200 °C. It is concluded that the major pathway involves initial Michael addition to give a 1,1-disubstituted hydrazine that cannot yield 1 without undergoing unfavourable retro-Michael reactions. The apparently similar reaction of hydrazine with excess diethyl glutaconate to give 4,8-bis(ethoxycarbonylmethyl)-1,5-diazabicyclo[3.3.0]octane-2,6-dione 2 takes a quite different course. Initial Michael addition gives a 1,2-disubstituted adduct for steric reasons. Although double cyclisation of this adduct to 2 appears straightforward, retro-Michael reaction of the monocyclised adduct is very rapid and competes with the second cyclisation. The reaction of ethyl methacrylate and hydrazine hydrate at 80 °C results in a complex reaction mixture, which is transformed into 4-methylpyrazolidin-3-one 13 at 390 °C under reduced pressure.

Synthetic Potential of the Reaction of Allylic Phosphonium Ylides with α, β-Unsaturated Carbonyl Compounds

The reaction of triphenylphosphonium-2-propenylide (14) with mesityl oxide (9) is shown to proceed via initial Michael addition followed by trans ylidation and an intramolecular Wittig condensation to yield 1, 5, 5-trimethyl-1, 3-cyclohexadiene (10) as the reaction product.

Benzopyrans. Part 41. Reactions of 2-(2-dimethylaminovinyl)-1-benzopyran-4-ones with various dienophiles

Dienamine 1 with N-phenylmaleimide and chromenone 14 as well as 15 produces, through initial [4 + 2]cycloaddition, xanthenones 10 and 18, respectively. Initial Michael addition of 1 to chromenones 14 and 16, and dimethyl acetylenedicarboxylate (DMAD), triggers the formation of xanthenone 19, 4-azaxanthenone 26 and substituted fumarate 49, respectively. Initial [2 + 2]cycloadducts of dienamines 1–3 with electrophilic acetylenes always undergo further transformations. Thus, 1 with DMAD, dibenzoylacetylene and ethyl propiolate (EP) ultimately gives xanthenones 33, 34 and 37, respectively, the latter being admixed with flavone 43. Enamine 2, cyclisable to xanthenone 11, gives 33 and 35 with DMAD, and 37 and 44 with EP. Reaction of 3 with DMAD affords 36 exclusively.