Michael Initiated Ring Closure Research Articles

ChemInform Abstract: Catalytic One‐Pot Diastereoselective Michael‐Initiated Ring‐Closure of Methyl Ketones with 3‐Bromochromones: Synthesis of Cyclopropa[b]chromanones.

A one-pot diastereoselective base-catalyzed Michael-initiated ring-closure (MIRC) of activated methyl ketones with 3-bromochromones to give cyclopropa[b]chromanones is described. Three asymmetric centres are generated in the new cyclopropa[b]chromanone skeleton. Stereochemistry studies based on NMR spectroscopy and single-crystal X-ray diffraction analysis revealed the trans configuration of the cyclopropane ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as was further confirmed by chiral HPLC. The use of acetone in our reaction produced a 1-acetyl-substituted cyclopropa[b]chromanone that can undergo a subsequent MIRC reaction with a second molecule of 3-bromochromone to give the first described 1,1′-carbonylbis(cyclopropa[b]chromanone) dimers as a meso form.

Synthesis and Applications of Fluorocyclopropanes

The combination of a fluorine atom and a cyclopropane ring, which both possess unique structural and chemical features, can generate new relevant scaffolds with potential interest for the synthesis of new bioactive compounds. In this review, we report the impressive progress recently devoted to the synthesis of fluorocyclopropanes especially using asymmetric methods and highlight some recent reported applications. 1 Introduction 2 Addition of Carbenes to Fluoroalkenes 3 Addition of Fluorocarbenes to Alkenes 4 Michael Initiated Ring Closure 5 Nucleophilic Fluorination 6 Applications to the Synthesis of Biorelevant Compounds 7 Conclusion

Catalytic One‐Pot Diastereoselective Michael‐Initiated Ring‐Closure of Methyl Ketones with 3‐Bromochromones: Synthesis of Cyclopropa[b]chromanones

A one‐pot diastereoselective base‐catalyzed Michael‐initiated ring‐closure (MIRC) of activated methyl ketones with 3‐bromochromones to give cyclopropa[b]chromanones is described. Three asymmetric centres are generated in the new cyclopropa[b]chromanone skeleton. Stereochemistry studies based on NMR spectroscopy and single‐crystal X‐ray diffraction analysis revealed the trans configuration of the cyclopropane ring, with the (1R,1aS,7aR)/(1S,1aR,7aS) pair of enantiomers, as was further confirmed by chiral HPLC. The use of acetone in our reaction produced a 1‐acetyl‐substituted cyclopropa[b]chromanone that can undergo a subsequent MIRC reaction with a second molecule of 3‐bromochromone to give the first described 1,1′‐carbonylbis(cyclopropa[b]chromanone) dimers as a meso form.

Cyclopropanation of Various Substrates via Simmons-Smith and Michael-Initiated Ring Closure (MIRC) Reactions

Cyclopropanation of various electron rich and electron deficient olefins via Simmons-Smith and Michael-initiated ring closure reactions was studied in our research. Cinnamyl alcohol 18 was succesfully cyclopropanated in a good to excellent yield using Simmons-Smith reactions. Methyl and benzyl crotonate 14 and 16 were labile in MIRC reaction condition indicated by the detection of starting material degradation in the NMR spectra of the crude reactions, and allowed a low to moderate product yield. The other starting materials, i.e., cinnamaldehyde 19 , methyl cinnamate 20 , mono- and di-protected cross-coupled product (4 R ,5 R , E )-methyl 5-( tert -butyldimethylsilyloxy)-4-hydroxyhepta-2,6-dienoate 25 and (4 R ,5 R , E )-methyl 5-( tert -butyldimethylsilyloxy)-4-(methoxymethoxy)hepta-2,6-dienoate 26 , were apparently incompatible to the reaction condition set in our study.

Orthoamides and iminium salts, LXXXIX. Reactions of N,N,N′,N′,N″,N″,N′″,N′″-octamethyl-acetylene-bis(carboxamidinium) tetrafluoroborate with nucleophilic reagents – new methods for the preparation of amidinium salts and ketene aminalsa

Abstract The acetylene-bis(carboxamidinium) salt 4 dehydrates carboxylic acids to the corresponding anhydrides, as the byproduct 2-oxo-but-2-en-amidinium salt 6b was isolated. Aromatic hydroxy compounds and 2-furyl-methylmercaptan add to the triple bond of the salt 4 to give 2-aryloxy- and 2-alkylmercapto-but-2-ene-bis(amidinium) salts 7–9. According to this reaction principle, 2-organoamino-buten-2-ene-bis(amidinium) salts 10 and 11 were prepared from 4 and primary and secondary amines, whereas 4-chlorobenzhydrazide reacted with 4 to give the imidazole-3-carboxamidinium salt 13. The reaction of CH2-acidic compounds as malononitrile or ethyl cyanoacetate with the bis(amidinium) salt 4 affords 2-cyanomethylene-but-3-enamidinium salts 15. With the CH-acidic diethyl 2-bromomalonate, compound 4 undergoes a Michael-initiated ring closure cyclopropenation reaction with further ring opening by the released Br– to the corresponding 2-diethoxycarbonylmethylene-3-bromo-but-3-enamidinium salt 18. Unlike cyclopentadiene and furane, the reaction of N-methylpyrrole and bis(amidinium) salt 4 does not lead to Diels–Alder [4 + 2] cycloadduct but to the Michael-type 1:1 adduct 20. Pyrrole- and thiophene-2-carboxamidinium salts 23–25 can be prepared from compound 4 and esters of glycine, N-methylglycine (sarcosine), and mercaptoacetic acid, respectively. The derivatives of quinoxaline-2-carboxamidinium salts 29 are accessible from aromatic 1,2-diamines and compound 4. The reaction of the CH2/NH-acidic cyanoacetamide with the bis(amidinium) salt 4 produced the 3-pyrroline-2-on derivatives 33.

Bifunctional Squaramide Catalysts with the Same Absolute Chirality for the Diastereodivergent Access to Densely Functionalised Cyclohexanes through Enantioselective Domino Reactions. Synthesis and Mechanistic Studies

AbstractWe have developed a procedure for the stereoselective and diastereodivergent synthesis of densely functionalised cyclohexanes containing four stereocentres through an asymmetric Michael‐initiated ring closure (MIRC) cascade reaction employing hydrogen‐bond catalysis, which is able to prepare adducts with different absolute configurations starting from the same starting materials. The overall process involves a highly diastereo‐ and enantioselective Michael/Henry cascade reaction between a wide range of nitroalkenes and α‐nitro‐δ‐oxo esters, allowing access to different diastereoisomers of the final adduct by introducing subtle changes in the general (R,R)‐configured bifunctional tertiary amine/squaramide catalyst structure. Moreover, this methodology is also amenable to a three‐component one‐pot procedure, leading to the formation of the same adducts with very good results directly from commercially available reagents, on a multigram scale, and employing a very low catalyst loading. Furthermore, a detailed experimental and computational study is described which shows the origin of the diastereodivergent behaviour of these structurally similar catalysts and the nature of the substrate–catalyst interaction.magnified image

ChemInform Abstract: Asymmetric Cyclopropanation Reactions

AbstractReview: [198 refs.

Asymmetric Cyclopropanation Reactions

Both physical and organic chemists are interested in the cyclopropane ring, the former owing to the strain inherent to the small ring structure, the latter prompted by the importance of this ring in naturally occurring compounds. In recent years, the increasing interest in enantioselective organic synthesis has led to a large number of papers on the preparation of cyclopropane compounds in enantioenriched form. The last review on asymmetric cyclopropanation reactions is dated 2008, thus an update is necessary with critical comparison of preparations using chiral auxiliaries, chiral metal complexes and organocatalysts. The aim of this review is an overview of these topics from 2008 to mid-2013. 1 Introduction 2 Simmons–Smith Cyclopropanation 2.1 Chiral Auxiliaries 2.2 Chiral Catalysts 3 Transition-Metal-Catalyzed Decomposition of Diazoalkanes 3.1 Cobalt 3.2 Copper 3.3 Rhodium 3.4 Ruthenium 3.5 Other Metals 4 Michael-Initiated Ring Closure (MIRC) 4.1 Chiral Auxiliaries 4.2 Organocatalysis 4.3 Metal Catalysis 5 Miscellaneous 5.1 C–H Insertion 5.2 Nucleophilic Ring Closure 5.3 Cycloisomerization of 1,<i>n</i>-Enynes 5.4 Other Methods 6 Conclusion 7 Abbreviations

ChemInform Abstract: A Straightforward and Highly Diastereoselective Access to Functionalized Monofluorinated Cyclopropanes via a Michael Initiated Ring Closure Reaction.

AbstractA tandem Michael addition/ring closure sequence is developed to yield fluorinated cyclopropanes from a reaction of ammonium salts (I) derived from bromofluoroacetate and DABCO with electron deficient alkenes.

Regio- and Stereocontrol in the Michael-Initiated Ring-Closure Reactions of γ,δ-Epoxy-α,β-unsaturated Esters, Ketones, Sulfones, and Amides

Organozincates or Grignard reagents in the presence of zinc catalysts undergo Michael initiated ring closure (MIRC) reactions with γ,δ-epoxy-α,β-enoates, enones, enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of diastereoselectivity is solvent dependent for alkyl Grignard reagents reacting with epoxy enoates, ensulfones, and enamides but solvent independent for the enones. Excellent diastereoselectivity can be achieved for the epoxy enoates, enones, and ensulfones, while the enamides afford modest diastereoselectivity under optimal conditions. The MIRC reaction can be achieved with phenylmagnesium chloride and these substrates under reaction conditions designed to minimize biphenyl formation.

A Straightforward and Highly Diastereoselective Access to Functionalized Monofluorinated Cyclopropanes via a Michael Initiated Ring Closure Reaction

The synthesis of highly functionalized monofluorinated cyclopropanes based on a Michael Initiated Ring Closure (MIRC) reaction has been developed. The addition of quaternary ammonium salts derived from ethyl bromofluoroacetate on a panel of electron deficient alkenes followed by cyclization gave rise to an efficient access to monofluorinated cyclopropanes with good yields and remarkable diastereoselectivity.

ChemInform Abstract: Stereoselective Cyclopropanation of α‐Bromochalcone with Diethyl Malonate Promoted by K2CO3.

AbstractBesides good yields for the exclusive formation of the trans‐isomers (III), this Michael‐initiated ring closure reaction also provides the first access to the cis‐isomers (IV) of the depicted densely substituted cyclopropanes.

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This chapter will present an overview of the most effective catalytic enantioselective syntheses of functionalized cyclopropanes. The following transformations will be discussed: the metal catalyzed asymmetric cyclopropanations using rhodium, ruthenium, cobalt, iron, gold, scandium, zinc and copper chiral catalysts; the Michael Initiated Ring Closure and the biocatalytic synthesis from engineered enzymes, to access enantiopure cyclopropanes scaffolds.

Stereoselective cyclopropanation of α-bromochalcone with diethyl malonate promoted by K2CO3

A new Michael-initiated cyclopropanation reaction using α-bromochalcones as Michael acceptor was developed. Compared to previous works using arylidenemalonates as Michael acceptor, this novel protocol could improve the synthesis of trans-isomers of diethyl 2-benzoyl-3-phenyl-cyclopropane-1,1-dicarboxylates. More importantly, this method also provided the first access to the cis-isomers of these densely substituted cyclopropanes with the Michael-initiated ring closure (MIRC) strategy, albeit with a poor diastereoselectivity.

Catalyst-free stereoselective cyclopropanation of electron deficient alkenes with ethyl diazoacetate

Doubly activated electron deficient alkenes react with ethyl diazoacetate in a Michael Initiated Ring Closure (MIRC) fashion to yield highly diastereoselective cyclopropanes even without any added base or metal catalyst. Following the strategy, a one-pot, two-step, three-component reaction of aldehydes, malononitrile/ethyl cyanoacetate, and ethyl diazoacetate was successfully developed.

Asymmetric Synthesis of Cyclopropanes with a Monofluorinated Quaternary Stereocenter

New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer.

ChemInform Abstract: Michael Initiated Ring Closure (MIRC) Reaction on in situ Generated Benzylidenecyclohexane‐1,3‐diones for the Construction of Chromeno[3,4‐b]quinoline Derivatives.

Abstract One-pot synthesis of chromeno[3,4-b]quinoline derivatives have been achieved in good yields through Michael Initiated Ring Closure (MIRC) by employing three-component condensation of aromatic aldehydes, 3-aminocoumarins, and cyclic 1,3-diketones in the presence of catalytic amount of p-toluenesulfonic (p-TSA) acid in ethanol under reflux condition. The salient features of this protocol are: simple reaction procedure, shorter reaction time, good yields, avoidance of aqueous work-up, and column-chromatographic separation. The merit of this process is highlighted by its high bond efficiency of producing three new bonds and one stereocenter in a single operation.

Michael Initiated Ring Closure (MIRC) reaction on in situ generated benzylidenecyclohexane-1,3-diones for the construction of chromeno[3,4-b]quinoline derivatives

One-pot synthesis of chromeno[3,4-b]quinoline derivatives have been achieved in good yields through Michael Initiated Ring Closure (MIRC) by employing three-component condensation of aromatic aldehydes, 3-aminocoumarins, and cyclic 1,3-diketones in the presence of catalytic amount of p-toluenesulfonic (p-TSA) acid in ethanol under reflux condition. The salient features of this protocol are: simple reaction procedure, shorter reaction time, good yields, avoidance of aqueous work-up, and column-chromatographic separation. The merit of this process is highlighted by its high bond efficiency of producing three new bonds and one stereocenter in a single operation.

Electrocatalysis in MIRC reaction strategy: facile stereoselective approach to medicinally relevant spirocyclopropylbarbiturates from barbituric acids and activated olefins

The combined electrolysis of barbituric acids and benzylidenemalononitriles or benzylidenecyanoacetates in methanol in an undivided cell in the presence of sodium bromide results in efficient MIRC (Michael-initiated ring-closure) formation of the corresponding spirocyclopropylbarbiturates in 45–93% yield. The electrocatalytic reaction proceeds smoothly under neutral and mild conditions with benzylidenemalononitriles or benzylidenecyanoacetates bearing both electron-donating and electron-withdrawing groups. NMR and single X-ray diffraction studies indicate that the electrocatalytic MIRC transformation of barbituric acids and benzylidenecyanoacetates results in the stereoselective formation of spirocyclopropanes with an (E)-configuration of aryl and alkoxycarboxylate substituents. The implication of electrocatalysis in the MIRC reaction strategy allows the combination of the synthetic virtues of both methods and accounts for an efficient approach to medicinally relevant spirocyclopropylbarbiturates avoiding inconvenient direct use of molecular halogen or halogenated substrates in accordance with the concepts of modern green chemistry.

Base promoted synthesis of activated cyclopropanes bearing homologated carbonyl groups via tandem Michael addition–intramolecular enolate trapping

A simple base promoted intramolecular Michael initiated ring closure reaction of γ-hydroxyenone derived diphenyl phosphinates with 1,3-indandione, enabled the synthesis of novel activated cyclopropanes with homologated carbonyl moiety in good yield. Promising levels of enantioselectivity are achieved when using cinchona derivatives as promoters.