Mandelic acid derived α-aziridinyl alcohols as highly efficient ligands for asymmetric additions of zinc organyls to aldehydes

A straightforward synthesis of a series of new catalysts containing secondary hydroxyl and aziridine moieties as nucleophilic centers built on the chiral scaffold of (S)-(+)-mandelic acid is described. The new compounds have been tested for the enantioselective addition of diethylzinc and phenylethynylzinc to aryl and alkyl aldehydes, which yielded the corresponding chiral alcohols in high chemical yields (up to 95%) and with excellent ee’s of ca. 90%. The strong influence of the stereogenic center located at the aziridine subunit on the stereochemical outcome is also reported on.     

Stereoselective synthesis of cis- and trans-2′,5′-disubstituted N-arylpyrrolo[3′,4′:1,9](C60-I h )[5,6]fullerenes by the 1,3-dipolar cycloaddition of azomethine ylides from dialkyl aziridinedicarboxylates to fullerene C60

A stereoselective method for the synthesis of 2′,5′-disubstituted N-arylpyrrolofullerenes from anilines, alkyl glyoxylates, alkyl diazoacetates, and fullerene C₆₀ was proposed. The key step of the synthesis is the 1,3-dipolar cycloaddition reaction of fullerene with azomethine ylides generated by heating of dialkyl aziridinedicarboxylates. The thermal opening of the aziridine ring to azomethine ylide and the cycloaddition of the latter to C₆₀ at 100 °C are nearly completely stereoselective: only trans-adducts are formed from cis-aziridines, whereas trans-aziridines give exclusively cis-adducts.     

Lactic acid derived aziridinyl alcohols as highly effective catalysts for asymmetric additions of an organozinc species to aldehydes

A straightforward synthetic route to a series of new catalysts bearing secondary hydroxyl and aziridine moieties as nucleophilic centers built on the chiral skeleton of (S)-(+)-lactic acid is described. All of the new compounds have been tested in the enantioselective addition of diethyl- and phenylethynylzinc to aryl and alkyl aldehydes, yielding the corresponding chiral alcohols in high chemical yields (up to 85%) and good ee’s of approximately 85%. The influence of the stereogenic center located at the aziridine subunit on the stereochemical outcome is also discussed.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Lewis acid mediated SN2-type nucleophilic ring opening followed by [4+2] cycloaddition of N-tosylazetidines with aldehydes and ketones: synthesis of chiral 1,3-oxazinanes and 1,3-amino alcohols

A highly efficient strategy for Cu(OTf)₂ mediated S_N2-type nucleophilic ring opening followed by [4+2] cycloaddition reactions of enantiopure 2-phenyl-N-tosylazetidines with various aldehydes and ketones afforded a variety of substituted 1,3-oxazinanes and 1,3-amino alcohols in excellent yields, excellent de and good to excellent ee. The proposed S_N2-type mechanism of the cycloaddition reaction is supported by experimental evidence.     

Iodine-Mediated One-Pot Synthesis of 1,4,5-Substituted Pyrazoles from MBH Acetates via Allyl Hydrazone Intermediate

Herein, we report the regioselective one-pot synthesis of 1,4,5-trisubstituted pyrazoles by reacting Morita-Baylis-Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential S_N2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I₂-catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating-induced intramolecular aza-Michael reaction and cyclization, and oxidative aromatization. The key intermediate, the s-trans allyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd-catalyzed benzoylation of the N-aryl ring, and metal-free tetrazole synthesis has been demonstrated.     

α-Methylserinals as an access to α-methyl-β-hydroxyamino acids: application in the synthesis of all stereoisomers of α-methylthreonine

The asymmetric synthesis of all stereoisomers of α-methylthreonine using a stereodivergent synthetic route starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals is reported. The key step involves the asymmetric addition of methylmagnesium bromide to these aldehydes with a high level of asymmetric induction being observed. This methodology represents a powerful tool for the synthesis of different β-substituted α-methylserines.     

Asymmetric synthesis of 3-hetero-substituted 2,3-dihydro-1H-isoindol-1-ones

An efficient asymmetric synthesis of highly enantioenriched 3-hetero-substituted 2,3-dihydro-1H-isoindolinones is reported. The key step is a diastereoselective nucleophilic addition on N-acylhydrazonium intermediates generated by acidic treatment of hemiaminal precursors bearing an (S)-2-alkoxymethyl-pyrrolidin-1-yl type auxiliary. The auxiliary is removed by an oxidative N,N-bond cleavage with magnesium monoperoxyphthalate.     

Synthetic studies on 3-arylquinazolin-4-ones: intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-ones and its application to the synthesis of secondary aryl amines

The general synthesis and a novel intramolecular nucleophilic aromatic substitution (S_NAr) reaction of 2-carboxamido-3-arylquinazolin-4-ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utility of the S_NAr reaction as a tool for the synthesis of secondary aryl amines, including diaryl amines, is also demonstrated.     

Application of novel sulfonamides in enantioselective organocatalyzed cyclopropanation

Three novel aryl sulfonamides derived from (2S)-indoline-2-carboxylic acid have been obtained and used as organocatalysts. The catalysts incorporate diverse functionality on the phenyl ring, enabling steric, and electronic fine tuning of the catalysts. The catalysts facilitate the reaction between a range of α,β-unsaturated aldehydes and sulfur ylides, thus providing cyclopropane products in enantiomeric excesses of up to 99%.     

Asymmetric synthesis of all isomers of α-methyl-β-phenylserine

This report describes the synthesis of enantiomerically pure (2R,3R)-, (2R,3S)-, (2S,3S)- and (2S,3R)-2-amino-3-hydroxy-2-methyl-3-phenylpropanoic acids, four quaternary α-amino acids, using a stereodivergent synthetic route and starting from (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals. The key step involves the asymmetric Grignard additions to the above chiral aldehydes, in which high levels of asymmetric induction are observed.     

Guanidine chemistry

Guanidines are categorized as strong organobases; however, their catalytic utility in organic synthesis has not been discussed thoroughly. The author's group has extensively and systematically studied their potential ability focusing on: 1) modified guanidines as chiral auxiliaries; 2) guanidinium ylides for aziridine formation; 3) the affinity of bisguanidine for proton and metal salts; and 4) the potential chirality of bisguanidine. Under the first topic, a variety of chiral guanidines was designed by the introduction of chirality on the three guanidinyl nitrogens, and the modified guanidines prepared using our original methods were found to be effective not only in catalytic but also in stoichiometric asymmetric syntheses. Under the second topic, the reaction of guanidinium salts carrying a glycinate function with aromatic or unsaturated aldehydes under basic conditions unexpectedly afforded aziridine-2-carboxylates, which were available as useful building blocks in organic synthesis due to their convertibility to functionalized amino acid derivatives in the ring-opening reaction, together with urea compounds recyclable to the starting guanidinium salts. The introduction of a chiral template to the guanidinium salt allowed us to expand the cyclic aziridination reaction to an asymmetric version. Under the third topic, effective complexabilty of bisguanidines with either proton or metal ions in water was observed, suggesting their possible application to the removal of toxic substances from polluted water and recovery of rare elements as material sources. Under the final topic, monomethylation or monoethylation of bisguanidine afforded a chiral product via asymmetric crystallization, indicating that bisguanidines have a potential chiral character due to the plane asymmetry.     

Rh(II)-catalyzed [2,3]-sigmatropic rearrangement of sulfur ylides derived from N-tosylhydrazones and sulfides

In this paper, Rh₂(OAc)₄-catalyzed [2,3]-sigmatropic rearrangement of sulfur ylides derived from N-tosylhydrazones and sulfides is reported. A series of tosylhydrazones derived from aldehydes were successfully used for [2,3]-sigmatropic rearrangement by reaction with either allylic phenyl sulfides or propargyl phenyl sulfides. The reaction conditions were optimized and afforded the products in moderate to good yields. In addition, a novel and convenient approach for the synthesis of cyclobutenones and cyclopropanes has been developed through direct oxidation of the rearrangement products.     

Synthesis of allenylzinc reagents by 1,2-rearrangement of alkynyl(disilyl)zincates derived from acetylenic epoxides and acetylenic aziridines

Lithium alkynyl(disilyl)zincates obtained from metalated ethynyloxiranes, as well as from N-tert-butanesulfinyl(ethynyl)aziridines or N-tert-butanesulfonyl(ethynyl)aziridines, undergo 1,2-migration of the organosilyl group with ring opening of the oxirane or aziridine ring by S_Ni displacement. A developed protocol that involves nBuLi for the metalation step offers a straightforward approach to the corresponding δ-oxy- and δ-amino α-silyl allenylzinc intermediates. The reagents derived from the epoxides are amenable to subsequent in situ condensation with aldehydes or ketones to provide 1,3-diols but not those derived from aziridines that only react sluggishly in similar condensations.     

Synthesis of 1-thio-phytosphingolipid analogs by microwave promoted reactions of thiols and aziridine derivatives

A practical and versatile method for the synthesis of 1-thio-phytosphingolipid analogs through regioselective nucleophilic ring-opening reactions of phytosphingosine aziridine derivatives with thiols is described. The reactions were carried out with N-acylaziridines and a variety of thiol compounds. Microwave irradiation highly improved the yield of the ring-opening reaction and the intermediate N-acyl adducts were converted into 1-S-phytosphingolipid analogs, such as phytoceramide and phytosphingosine derivatives.     

Synthesis of enantiomerically pure 2-(N-aryl,N-alkyl-aminomethyl)aziridines: a new class of ligands for highly enantioselective asymmetric synthesis

A simple and effective synthesis of enantiomerically pure 2-(N-aryl-, N-alkyl-aminomethyl)aziridines from (2S)-N-tritylaziridine-2-carboxylic acid methyl ester has been developed. Treating of this key ester with several primary and secondary amines in the presence of AlMe₃ provided the corresponding chiral N-trityl-2-carboxamides, and their reduction performed with different reagents resulted in the formation of the expected 2-(aminomethyl)aziridines. The choice of reaction conditions allows to either keep or leave the trityl substituent in the product. Such 2-(aminoalkyl)aziridines have shown very high catalytic efficiency in the asymmetric arylation of aldehydes and in other testing asymmetric reactions. On the other hand, homochiral N-trityl-2-carboxamides are interesting building blocks for the synthesis of various biologically active compounds.     

Mechanism of the reaction of N-p-tosylsulphilimine and related compounds with thiophenolate ion

The reaction of alkyl aryl N-p-tosylsulphilimines with thiophenolate ion was found to afford quantitatively the sulphide that arises by an S_N2 like reaction on the carbon atom adjacent to the tri-valent sulphur atom. This reaction was also found to proceed smoothly with such compounds as sulphoxides and sulphones and sulphoxmanes. The kinetic study on the reaction between aryl methyl N-p-tosylsulphilimine with thiophenolate ion in DMF reveals that the reaction is of second order, namely, first order with respect to each thiophenolate ion and the sulphilimine. The enthalpy and entropy of activation for the reaction are ΔH^≠ = ?17· kcal/mol and ΔS^≠ = ?5·7 eu respectively. The effect of substituents in the reaction, p-XC₆H₄⁺(^?SO₂C₆H₄Y-p)CH₃ + p-ZC₆H₄SK is nicely correl with Hammett σ values giving ?_x = + 2·4, ?_y = + 1·2 and ?_z = ?1·8 respectively. Meanwhile, a marked steric retardation by a bulky alkyl group in alkyl phenyl N-p-tosylsulphilimine is observed. Furthermore, from the stereochemical study of the reaction using an optically active sec-octyl phenyl N-p-tosylsulphilimine with thiophenolate ion it is concluded that the reaction proceeds via a typical S_N2 process on α-carbon atom attached to the tri-valent sulphur atom.     

Thermal transformations of alk-1-enyl-N-phthalimidoaziridines

Thermolysis of alk-1-enyl-N-phthalimidoaziridines leads to products of 1,5-electrocyclization of intermediate azomethine ylides with participation of C=C bonds. If acyl or alkoxycarbonyl substituent is present in the aziridine ring, the C=O bond is also involved. Thermolysis of the title compounds in the presence of N-phenylmaleimide or dimethyl acetylenedicarboxylate under analogous conditions gives products of 1,3-dipolar cycloaddition of azomethine ylides to the double or triple bond of the dipolarophile.     

Dimerization of aldehydes to carboxylic esters catalyzed by K2[Fe(CO)4]–crown ether system

K₂[Fe(CO)₄] (1) with a crown ether was found to be an efficient catalyst for the dimerization of aldehydes to carboxylic esters. Several aromatic aldehydes including furfural gave the corresponding esters in good yields. This reaction also proceeded intramolecularly to give phthalide from phthalaldehyde. However, aliphatic aldehydes gave aldol-condensation products instead of the corresponding esters. In the reactions of p-substituted benzaldehydes with 1, the reactivity decreased with increase of the electron-releasing ability of the substituents. On the basis of these results, the reaction mechanism including the nucleophilic attack of tetracarbonylferrate dianion to the carbonyl carbon is discussed.     

Transition-metal-free approach to synthesis of indolines from N-(ortho-chloromethyl)aryl amides and iodonium ylides

A transition-metal-free method for the synthesis of indolines has been developed. In the presence of K₂CO₃, the cyclization reaction of N-(ortho-chloromethyl)aryl amides and iodonium ylides proceeded smoothly at room temperature in moderate to good yields.