Pyrrolo[2,1-b]thiazole derivatives by asymmetric 1,3-dipolar reactions of thiazolium azomethine ylides to activated vinyl sulfoxides

1,3-Dipolar reactions of thiazolium azomethine ylides to enantiopure cyclic and acyclic vinyl sulfoxides provide an efficient access to polyfunctionalized pyrrolo[2,1-b][1,3]thiazoles in a highly regio- and stereoselective manner. Regioselectivity can be inverted by modifying the position of the sulfinyl group at the double bond of the sulfinylfuranones. The sulfoxide is the main controller of the endo selectivity of these processes as well as of the pi-facial selectivity in reactions of (Z)-3-p-tolylsulfinylacrylonitriles. In contrast, the pi-facial selectivity in reactions of 5-alkoxy-3-p-tolylsulfinyl furan-2(5H)-ones is mainly controlled by the configuration at C-5, affording the anti adducts with respect to the alkoxy group as the major or exclusive adducts.     

Formal asymmetric 1,3-dipolar cycloaddition of azomethine ylides to (S)-2-p-tolylsulfinyl-2-cyclopentenone

Azomethine ylides, derived from iminoesters 1 and DBU in the presence of silver salts, react with (S)-2-p-tolylsulfinyl-2-cyclopentenone 2 in a completely regio- and endoselective manner but with a low facial selectivity, affording a mixture of two cycloadducts 3 and 4. When the ylides were prepared with LHMDS, only one diastereoisomer 3 was obtained in an almost quantitative yield. A nucleophilic addition/ring closure process easily accounts for the stereochemical results. Compounds 3 were transformed into optically pure 4-oxocyclopenta[c]dihydropyrroles and tetrahydropyrroles by elimination of the sulfinyl group.     

The role of steric and electronic interactions in the stereocontrol of the asymmetric 1,3-dipolar reactions of 5-ethoxy-3-p-(S)-tolylsulfinylfuran-2(5H)-ones with diazoalkanes: theoretical calculations and experimental evidences

The addition of diazomethane and diazoethane to (5S,SS)- and (5R,SS)-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (1a and 1b) and their 4-methylderivatives (2a and 2b) proceeded in almost quantitative yields and complete regioselectivity. The observed pi-facial selectivity is determined by the configurations at both C-5 and the sulfinyl group, the later being the most important. The syn adducts were almost exclusively obtained from 1a and 2a in apolar solvents but the pi-facial selectivity was strongly decreased in more polar solvents. On the other hand, the major adducts from 1b and 2b were the anti ones and such predominance was slightly increased with solvent polarity. The exo-selectivity was complete in all the cases except for the anti approach to compounds 2a (in polar solvents) and 2b. The role of the sulfinyl group in this behavior was inferred by comparison of these results with those obtained in reactions of diazoalkanes with 5-methoxyfuran-2(5H)-one (3). Steric interactions seem to be the main ones responsible for the observed exo selectivity of reactions with diazoethane, but electronic factors, which can be modulated by the solvent, are also significant in the pi-facial selectivity control. DFT computational methods are able to correctly predict the reactivity, regioselectivity, and pi-facial selectivity exhibited by 5-alkoxyfuranones as well as their changes with the solvent polarity. A C-H.O hydrogen bond, involving the oxygen atom of the 5-alkoxy group at dipolarophiles and the endo-hydrogen atom at dipoles, seems to play a key role in the electronic interactions influencing the stereochemical course of these reactions.     

4-Methylpyrimidinium ylides. Part 7: 3+2 Dipolar cycloadditions to non-symmetrical substituted alkenes and alkynes

The ability of 4-methylpyrimidinium ylides (as 1,3-dipoles) to react with activated non-symmetrical substituted dipolarophiles (alkenes and alkynes) is presented. 4-Methylpyrimidinium ylides did not react with alkenes. With alkynes the reactions are regiospecific, a single regioisomer being obtained. A possible mechanism for the reaction pathway is proposed. For the first time in the pyrimidinium ylides series both isomers resulting from bonding to the 2-and 6-positions of the heterocycle ring were obtained. The appropriate conditions in order to increase the selectivity of one of the isomers were determined.     

Asymmetric 1,3-dipolar cycloadditions of a chiral nonracemic glyoxylic azomethine imine

The reactivity of a chiral nonracemic glyoxylic azomethine imine has been investigated. This species reacts with a wide range of dipolarophiles, with a complete regio- and facial stereoselectivity. The introduction of an electron-withdrawing substituent on the ylide leads to a lower endo selectivity with electron-withdrawing dipolarophiles, but to an improved exo selectivity with styrene derivatives when compared to the reactivity of aliphatic- or aromatic-substituted ylides.     

The role of the sulfinyl group on the course of the reactions of 3-p-tolylsulfinylfuran-2(5H)-ones with nitrones. synthetic uses of cycloreversion processes

[reaction: see text] The reaction of enantiopure 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) with cyclic (4) and acyclic (6) nitrones afforded furoisoxazolidines (5 and 7) in high yields under mild conditions. The reactivity of the dipolarophile was dramatically enhanced by the sulfinyl group, which modulated the pi-facial selectivity (it was complete for reactions from 2b, yielding only the anti adducts) and was the main controller of the endo/exo selectivity. Cycloreversion processes from the resulting sulfinyl furoisoxazolidines proceeded readily and were to be considered to account for an improvement in the selectivity (facial and endo/exo) and even for an inversion of it when the composition of the reaction mixtures obtained under kinetic and thermodynamic conditions were quite different.     

亚甲胺叶立德参与的不对称1,3-偶极环加成构建含连续季碳中心的螺四氢吡咯衍生物

Cu(I)催化的亚甲胺叶立德和亚环丙基乙酸乙酯参与的不对称endo-1,3-偶极环加成反应,高效构建了多官能化、含有多个连续季碳中心的5-氮杂-[2,4]庚烷化合物.此反应具有广泛的底物适用性,α-取代的和α-非取代的亚甲胺叶立德和亚环丙基乙酸乙酯都能很好的参与反应,并以很高的产率、优秀的非对映选择性(95:5–98:2 d.r)和对映选择性(87%–98%ee)生成相应的在2,3,4位上含有连续季碳中心的螺四氢吡咯化合物.     

An efficient,one-pot,three-component procedure for the synthesis of chiral spirooxindolopyrrolizidines via catalytic highly enantioselective 1,3-dipolar cycloaddition

The catalytic, highly regio-, diastereo-, and enantioselective synthesis of a small library of chiral spirooxindolopyrrolizidines via a three-component 1,3-dipolar cycloaddition reaction of azomethine ylides, derived from isatin, with electron-deficient dipolarophiles, 3-(2-alkenoyl)-1,3-oxazolidin-2-ones, is described. A chiral copper(II) complex of cyclohexane-1,2-bis(arylmethyleneamine) catalyzed this process at room temperature. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts.     

Thermolysis of 1-phthalimidoaziridine-2-carbonitriles in the presence of dipolarophiles

Thermolysis of trans-3-phenyl-1-phthalimidoaziridine-2-carbonitrile and trans-1-phthalimidoaziridine-2,3-dicarbonitrile in the presence of several dipolarophiles involves 1,3-dipolar cycloaddition to intermediate azomethine ylides and leads to 1-phthalimidopyrrolidine derivatives with good yields and high stereoselectivity. Thermally induced opening of the three-membered ring in trans-2,3-disubstituted 1-phthalimidoaziridines occurs in conrotatory mode to produce the corresponding cis-azomethine ylides in keeping with the orbital symmetry conservation rules. The relative configuration of substituents in the dipolarophiles is retained, which implies concerted mechanism of the addition.     

Cu-Fesulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar cycloaddition of azomethine ylides

The Cu^I-Fesulphos catalyst system (≤3 mol %) shows an excellent performance in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. High to very high levels of reactivity, endo/exo selectivity, and enantioselectivity (69->99% ee) are generally achieved with a very wide range of azomethine ylides and dipolarophiles. Based on experimental and computational studies data, a model that accounts for this high enantiocontrol is proposed.     

On the origin of high E selectivity in the Wittig reaction of stabilized ylides: importance of dipole-dipole interactions

The salt-free Wittig reaction of stabilized ylides Ph3PCHCO2Me 1 and (MeO)3PCHCO2Me 2 has been investigated using DFT method including solvation. This analysis shows that TS structures and E/Z selectivity in the phosphine stabilized ylide 1, which gives high E selectivity with PhCHO, are predominantly controlled by a dipole-dipole interaction between the two reactants at the TS (as well as the well-known 1,2 and 1,3 steric interactions). The surprisingly different behavior of the phosphite ylide 2, which gives only 69:31 E/Z ratio with PhCHO, is accounted for by its much smaller overall dipole. The introduction of this new parameter (dipole-dipole interactions), which has not previously been invoked in discussions of this important reaction, accommodates all the experimental observations relating to selectivity in the Wittig reaction of stabilized ylides under salt-free conditions.     

A three-component, one-pot synthesis of indolizidines and related heterocycles via the [3+2] cycloaddition of nonstabilized azomethine ylides

Nonstabilized azomethine ylides (i.e. those bearing only hydrogens or alkyl groups) can be generated from (2-azaallyl)stannanes and (2-azaallyl)silanes through an intramolecular N-alkylation/demetalation cascade. The resulting ylides undergo [3+2] cycloaddition with electron-poor or electron-rich dipolarophiles yielding indolizidines and related 1-aza[m.3.0]bicycloalkane systems in good yield. An in situ protocol allows for a one-pot, three-component synthesis of indolizidines. The (2-azaallyl)stannanes tolerate enolizable hydrogens in these cycloadditions, while (2-azaallyl)silanes do not. The mechanism of the cycloaddition cascade is clarified by a series of control experiments. The same (2-azaallyl)stannanes may be transmetalated by n-butyllithium to generate 2-azaallyllithiums, which also may undergo a [3+2] cycloaddition/N-alkylation cascade to form indolizidines.     

Search for ideal sulfinyl dienophile and dipolarophile

By analysis, the advantages and drawbacks of the differently substituted vinyl sulfoxides so far reported, (Z)‐3‐p‐tolylsulfinyl acrylonitriles are proposed as the best sulfinyl dienophiles. The stereoselective synthesis of these compounds was optimized by hydrocyanation of sulfinyl alkynes with Et₂AlCN. Their behavior as chiral dienophiles and dipolarophiles is responsible for the high stereocontrol of Diels–Alder and 1,3‐dipolar reactions, respectively. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:453–462, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10066     

Reaction of chromone-3-carbaldehyde with α-amino acids—syntheses of 3- and 4-(2-hydroxybenzoyl)pyrroles

Azomethine ylides generated from the reaction of chromone-3-carbaldehyde with α-amino acids undergo 1,5-electrocyclization reactions to afford 3- and 4-(2-hydroxybenzoyl)pyrroles. These ylides can be trapped with dipolarophiles in 1,3-dipolar cycloaddition reactions to yield chromonyl pyrrolidines. The reaction of chromone-3-carbaldehyde with methyl glycinate gives a mixture of pyrrole, pyridine, and 3-aza-9-xanthenone derivatives.     

Theoretical studies on the stereochemical course of 1,3‐dipolar cycloaddition of azomethine ylides derived from indol‐2,3‐dione and thiazolidine‐4‐carboxylic acid

1,3‐Dipolar cycloadditon of azomethine ylides with different dipolarophiles leads to the formation of novel heterocyclic spiro compounds having two or more chiral centers. The theoretical studies (HF/3–21G) on the 1,3‐dipolar cycloaddition reaction between ethene and azomethine ylide A4 derived from isatin and thaizolidine‐4‐carboxylic acid, indicates that the energy barrier for this addition is about ～ 8 kcal/mol higher than that in simplest azomethine ylide A1 . HF/3–21G studies on a series of azomethine ylides A2 and A3 suggested that the increased barrier is mainly due to stabilization of azomethine ylides arising from aromatic indol nucleus. Semi‐empirical studies indicate that the cycloaddition is streocontrolled as the transition states corresponding to only the stericlly allowed paths could be located on the potential energy surface.     

Stereoselective synthesis of functional derivatives of 2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid

Azomethine ylides generated from dimethyl 2-(arylmethylideneamino)pentanedioates by the action of AgOAc and Et₃N reacted with dipolarophiles in regio-and stereoselective fashion to form 5-aryl-2-(2-carboxyethyl)pyrrolidine-2-carboxylic acid derivatives. 1,3-Dipolar cycloaddition of divinyl sulfone to the azomethine ylide generated from the Schiff base derived from methyl (S)-2-phthalimido-4-oxobutanoate and dimethyl glutamate gave chiral simplified kaitocephalin analogs.     

Studies of Diastereoselectivity in Diels-Alder Reactions of (S)S-4a,5,8,8a-Tetrahydro-5,8-methane-2-(p-tolylsulfinyl)-1,4-naphtho- quinones with Cyclopentadiene

The title compounds 6 and 7 have proved to be adequate rigid models to evaluate the ability of the sulfinyl group to control the diastereoselectivity of the [4 + 2] cycloadditions of cyclopentadiene on the ene-dione moiety. The results of thermal and Lewis acid-catalyzed reactions allowed us to establish that both reactivity and endo/exo selectivity were modulated by the presence of the sulfinyl group, the endo-anti-endo or the exo-anti-endo bisadducts being obtained as major products depending on experimental conditions. The role of the association between the SOTol group and several Lewis acids (BF(3).OEt(2), Eu(fod)(3), ZnBr(2)), which shifted the conformational equilibrium around the C-S bond, was used to explain the stereochemical course of the cycloadditions mainly controlled by steric factors. The synthesis of the exo-anti-endo bisadduct 5 was described for the first time.     

Reactivity and selectivity in the Wittig reaction: a computational study

The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using density functional theory (DFT) calculations, including continuum solvation. Our results provide unequivocal support for the generally accepted mechanism and are in very good agreement with experimental selectivities. This study shows that E/Z selectivity of non- and semi-stabilized ylides cannot be fully understood without considering the energy of the elimination TS. The influence of ylide stabilization and the nature of phosphorus substituents on reversibility of oxaphosphetane formation is clarified. Unexpectedly, the puckering ability of addition TSs is shown not to depend on ylide stabilization, but the geometry of the TS is decided by an interplay of 1,2; 1,3; and C-H...O interactions in the case of non- and semi-stabilized ylides, whereas a dipole-dipole interaction governs the addition TS structures for stabilized ylides. The well-known influence of ylide stabilization on selectivity of PPh(3) derivatives is explained as follows: in non- and semi-stabilized ylides reactions, cis and trans addition TSs have, respectively, puckered and planar geometries, and selectivity is governed by an interplay of 1,2 and 1,3 interactions. For stabilized ylides, the high E selectivity is due to a strong dipole-dipole interaction at the addition TS. The influence of the nature of phosphorus substituents on selectivity is also detailed, the different behavior of (MeO)(3)PCHCO(2)Me ylides being explained by their lower dipole. This novel picture of the factors determining TS structures and selectivity provides a sound basis for the design of new ylides.     

Asymmetric 1,3-dipolar cycloaddition of N-metalated azomethine ylides to methyl (S)-2-(p-tolylsulfinyl)acrylate. Synthesis of optically pure 2,4,5-trisubstituted 2,5-dihydro-1H-pyrroles

The first 1,3-dipolar reaction of azomethine ylides with optically pure vinyl sulfoxide are reported. The presence of the sulfinyl group increase the reactivity of the acrylate moiety as a dipolarophile, and the reactions evolve with complete regio- and endo-selectivities. Nevertheless, mixtures of the two diastereoisomers 4 and 5 (75-88% de) resulting from the anti dipole/s-cis dipolarophile and syn dipole/s-trans dipolarophile approaches, respectively, are obtained. The stereoselectivity can be controlled by using THF or MeCN as solvents or by changing the reaction temperature in MeCN. After separation of the cycloadducts, optically pure 2,5-dihydro-1H-pyrroles are easily obtained by pyrolytic desulfinylation.     

Photo- and thermoinduced generation of 1,3-diaryl carbonyl ylides from 2,3-diaryloxiranes 1,3-dipolar cycloadditions to dipolarophiles

A group of symmetrically substituted 2,3-diaryloxiranes have been studied as photoprecursors for carbonyl ylides. The stereochemistry of the adducts obtained upon interception of these 4n pi-transient systems with a variety of dipolarophiles provides information on the mode(s) of electrocyclic opening of the oxiranes to carbonyl ylides, as well as the mechanism of the 4n + 2 cycloaddition process. The stereochemistry of the dipolarophiles is preserved in the cycloadducts, which is consistent with a concerted addition process; however, solvent effects, steric hindrance, and possibly secondary orbital overlap factors all may play a role in determining the product distribution.