Titanium Lewis Acids for Asymmetric Catalysis: Synthesis and Structural Characterization of Dichloro[diolato(2−)‐κO,κO′]bis(solvent)titanium ([TiCl2(diolato)(solvent)2]) Complexes

The complexes [TiCl₂{(R,R)‐TADDOLato}(DME)]⋅MeCN ( 3 ), and [TiCl₂{(R,R)‐1‐Nph‐TADDOLato}(MeCN)₂]⋅CH₂Cl₂ ( 4b ) (DME=1,2‐dimethoxyethane; (R,R)‐TADDOLato=(4R,5R)‐2,2‐dimethyl‐α,α,α′,α′‐tetraphenyl‐1,3‐dioxolane‐4,5‐dimethanolato(2−)‐κO,κO′; (R,R)‐1‐Nph‐TADDOLato=(4R,5R)‐2,2‐dimethyl‐α,α,α′,α′‐tetra(naphthalen‐1‐yl)‐1,3‐dioxolane‐4,5‐dimethanolato(2−)‐κO,κO′) were prepared and isolated in high yield as stable crystalline materials (Scheme 1). They constitute ideally suited and easy‐to‐handle catalyst precursors for a large number of Ti‐catalyzed asymmetric reactions, for which they have been previously generated in situ. The X‐ray crystal structures of 3 and 4b show a distorted octahedral geometry around Ti with the chloro ligands in mutual trans positions (Figs. 5 and 6). The new chiral diols α‐(1S,3R)‐3‐hydroxy‐2,2,3‐trimethylcyclopentyl]‐α‐phenylbenzenemethanol ( 13a ), derived from camphoric acid ( 5 ), and (M)‐6,6′‐dimethyl‐α,α,α′,α′‐tetraphenyl[1,1′‐biphenyl]‐2,2′‐dimethanol ( 15 ) were prepared (Schemes 3 and 4). These new ligands are able to form mononuclear complexes with the Ti^IVCl₂ fragment. The corresponding complex 14 derived from 13a was characterized by X‐ray as a mixed THF/MeCN adduct.     

Asymmetric Catalytic Synthesis of Hexahydropyrrolo-isoquinolines via Three-Component 1,3-Dipolar-Cycloaddition

An asymmetric three-component 1,3-dipolar cycloaddition of 3,4-dihydroisoquinolines, bromoacetates and α,β-unsaturated pyrazole amide is realized by using a chiral N,N’-dioxide-Y(OTf)₃ complex as the catalyst. The process includes a base-promoted formation of dihydroisoquinolium ylides in situ, and a chiral Lewis acid-catalyzed asymmetric [3+2] cycloaddition with α,β-unsaturated pyrazole amides. A series of hexahydropyrrolo-isoquinolines are obtained in moderate to good yields with excellent diastereo- and enantioselectivities.     

Solid-phase based synthesis of biologically promising triazolyl aminoacyl (peptidyl) penicillins

An efficient and versatile methodology for the preparation of valuable triazolyl aminoacyl (peptidyl) penicillins is described. Solid-phase Cu(I)-catalyzed Hüisgen 1,3-dipolar cycloaddition was used as the key step showing general applicability and excellent regioselectivity either with CuI or [Cu(CH₃CN)₄]PF₆ as Cu(I) source.     

Acetals of γ-oxo-α,β-unsaturated esters in nitrone cycloadditions. Regio- and stereochemical implications

Several acetals of γ-oxo-α,β-unsaturated esters have been prepared, mainly from enantiopure C₂-symmetric diols, and their 1,3-dipolar cycloaddition to 2,3,4,5-tetrahydropyridine 1-oxide has been studied. All the reactions showed complete regioselectivity and a high preference for the endo approach of the reactants in the transition state. The enantiopure acetals derived from (cis,cis)-spiro[4.4]nonane-1,6-diol gave the highest diastereofacial selectivity.     

Synthesis and characterization of some heterocyclic derivatives from 1,2:3,4-Di-o-isopropylidene-α-d-galacto-1,6-hexadialdo-1,5-pyranose oxime

We report the synthesis of 5-[5′-(1′,2′:3′,4′-di-O-isopropylidene-β-L-arabinopyranosyl)]tetrazole, from 1,2:3,4-di-O-isopropylidene-α-D-galacto-1,6-hexodialdo-1,5-pyranose oxime via 1,2:3,4-di-O-isopropylidene-α-D-galcturononitrile as intermediate by 1,3-dipolar cycloaddition. We also report the synthesis of 5-methyl- and 5-phenyl-2-[5′-(1′,2′:3′,4′-di-O-isopropylidene-β-L-arabinopyranosyl)]-1,3,4-oxadiazole from the tetrazole derivative. The physical and spectroscopic characterizations of the heterocyclic derivatives as well as the intermedi ate nitrile and the principal by product are described and we discuss its possible formation pathway. We present the preferential conformation in solution using computational calculation and spectroscopic data.     

[2+3] Cycloadditions of ‘Thiocarbonyl Ylides’ (= (Alkylidenesulfonio)methanides) and diazoalkanes with N,N′-(thiocarbonyl)diimidazole (= 1,1′-(carbonothioyl)bis[1H-imidazole])

Heating of a mixture of N,N′-(thiocarbonyl)diimidazole (= 1,1′-(carbonothioyl)bis[1H-imidazole]; 1 ) and 2,5-dihydro-1,3,4-thiadiazole 2a or 2b gave the 1,3-dithiolanes 4a and 4b , respectively, via a regiospecific 1,3-dipolar cycloaddition of the corresponding ‘thiocarbonyl methanides’ 3a , b onto the C?S group of 1 (Schemes 1 and 2). The adamantane derivative 4b was not stable in the presence of 1H-imidazole and during chromatographic workup. The isolated 1,3-dithiole 5 is the product of a base-catalyzed elimination of 1H-imidazole from the initial cycloadduct 4b . The formation of the S,N-acetal 6 can be rationalized by a protonation of the ‘thiocarbonyl ylide’ 3b followed by a nucleophilic addition of 1H-imidazole. With the diazo compounds 8a–e (Scheme 3) 1 underwent a regiospecific 1,3-dipolar cycloaddition to give the corresponding 2,5-dihydro-1,3,4-thiadiazole derivatives 9 , which spontaneously eliminated 1H-imidazole to yield (1H-imidazol-1-yl)-1,3,4-thiadiazoles 10 . The structures of 10a and 10d were established by X-ray crystallography. In the case of diazodiphenylmethane ( 8f ), the initial cycloadduct 9f decomposed via a ‘twofold extrusion’ of N₂ and S to give 1,1′-(2,2-diphenylethenylidene)bis[1H-imidazole] ( 11 ; Scheme 3).     

Catalytic asymmetric synthesis of descurainin via 1,3-dipolar cycloaddition of a carbonyl ylide using Rh2(R-TCPTTL)4

A catalytic asymmetric synthesis of descurainin has been achieved by incorporating an enantioselective 1,3-dipolar cycloaddition, a stereoselective alkene hydrogenation, an oxidation with Fremy’s salt and a regioselective demethylation with NbCl₅ as the key step. The 1,3-dipolar cycloaddition of a carbonyl ylide derived from tert-butyl 2-diazo-5-formyl-3-oxopetanoate with 4-hydroxy-3-methoxyphenylacetylene in the presence of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(R)-tert-leucinate], Rh₂(R-TCPTTL)₄, provided an 8-oxabicyclo[3.2.1]octane skeleton in 95% ee.     

Catalytic opening of the diaziridine fragment in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes

Treatment of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with Lewis acids [BF₃·Et₂O or In(OTf)₃] promotes opening of the diaziridine ring, followed by formation of 1,3-dipolar cycloaddition products with N-arylmaleimides. The conversion of the initial diaziridine depends on the nature of the 6-aryl group. Diazabicyclohexanes with donor substituents react quantitatively to give (in the absence of dipolarophiles) the corresponding azomethine imine dimers, 1,2,4,5-tetrazine derivatives. The conversion of diazabicyclohexanes having acceptor substituents is poor; simultaneously, the fraction of the hydrolysis products increases. The stereoselectivity in the 1,3-dipolar cycloaddition, i.e. the ratio of the cis-and trans-adducts, depends on the catalyst and solvent. Azomethine imine dimers react with N-arylmaleimides in the presence of indium(III) trifluoromethanesulfonate to give the same 1,3-dipolar cycloaddition products as those obtained from parent 1,5-diazabicyclohexanes.     

A facile stereoselective synthesis of 2-perfluoroalkyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles

Methyl 2-perfluoroalkynoates 2 reacted readily with cyclic nitrones 1 via 1,3-dipolar cycloaddition at room temperature to give 2-perfluoroalkyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 3 in good to excellent yields with high diastereoselectivity and regioselectivity.     

Synthesis of 1,3-benzothiazol-2(3<Emphasis Type="Italic">H</Emphasis>)-one and some its derivatives

Acylation of 2-aminobenzenethiol with methyl chloroformate in pyridine gave dimethyl 2,2′-disulfanediylbis(2,1-phenylene)dicarbamate instead of expected methyl 2-suylfanylphenylcarbamate. Heating of the product with zinc dust in glacial acetic acid led to the formation of 1,3-benzothiazol-2(3H)-one. Alkylation of the latter with 1,2-dibromoethane and allyl bromide, as well as acylation with chloroacetyl chloride, afforded the corresponding 3-substituted derivatives. 3-[3-(Pyridin-2-yl)-4,5-dihydroisoxazol-5-ylmethyl]-1,3-benzothiazol-2(3H)-one was synthesized with high regioselectivity by 1,3-dipolar cycloaddition of 3-allyl-1,3-benzothiazol-2(3H)-one to pyridine-2-carbonitrile oxide generated fromN-hydroxypyridine-2-carboximidoyl chloride hydrochloride by the action of triethylamine.     

氧化腈与丙炔1,3-偶极环加成反应中区域选择性的理论研究

用密度泛函(DFT)B3LYP/6-311＋＋G**方法研究了氧化腈(RCNO, R＝F, NO₂, OCH₃, OH, COOCH₃, CHO, CONH₂, H, CH₃)与丙炔的1,3-偶极环加成反应, 并且计算了不同温度下的反应速率常数, 讨论了氧化腈上不同取代基R的取代效应和温度对反应区域选择性的影响. 结果显示, 氧化腈与富电子亲偶极体——炔烃反应, 5-取代反应占优势; 氧化腈上取代基R为强吸电子基团时或在较高温度下, 有利于4-取代反应的进行.     

Clay-Supported Cu(II) Catalyst: An Efficient,Heterogeneous, and Recyclable Catalyst for Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Alloxan-Derived Terminal Alkyne and Substituted Azides Using Click Chemistry

A novel series of alloxan-derived 1,4-disubstituted 1,2,3-triazoles was synthesized in excellent yields under catalytic conditions using a click reaction strategy through 1,3-dipolar cycloaddition. Their structures have been ascertained on the basis of spectroanalytical and elemental analysis data. Synthesis of hybrid compounds with varying substitutions in the triazole ring was achieved by reaction between alloxan-derived terminal alkyne and a pertinent azide derivative in the presence of clay-Cu(II) as the catalyst in methanolic medium. Also, comparative evaluation of various catalytic systems [viz., CuI, CuSO₄, CuI-zeolite, K10Ti, and clay-Cu(II)] was investigated. Of these catalytic systems, clay-Cu(II) was observed to be the best. The catalyst was recyclable for several runs without showing significant loss in its activity. The good selectivity, cost-efficiency, short reaction time, milder reaction conditions, and simple workup procedure are the added salient features of this synthetic protocol.     

A novel Fe(II)/diaryl prolinol catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with alkenes

A novel Fe(II)/diaryl prolinol catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with alkenes has been developed. In the presence of FeCl₂ (10 mol %) and α,α-bis(3,5-bistrifluoromethylphenyl)prolinol L1 (10 mol %), [3+2] cycloaddition of azomethine ylides with electronic-deficient olefins underwent smoothly in CH₃CN at room temperature to generate the desired endo-adducts in moderate to good yields and enantioselectivities. This is the first example of Fe(II)/N,O-ligand (L1) catalyzed 1,3-dipolar enantioselective cycloaddition reaction of azomethine ylides.     

Mechanistic Intricacies of Gold‐Catalyzed Intermolecular Cycloadditions between Allenamides and Dienes

The mechanism of the gold‐catalyzed intermolecular cycloaddition between allenamides and 1,3‐dienes has been explored by means of a combined experimental and computational approach. The formation of the major [4+2] cycloaddition products can be explained by invoking different pathways, the preferred ones being determined by the nature of the diene (electron neutral vs. electron rich) and the type of the gold catalyst (AuCl vs. [IPrAu]⁺, IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazole‐2‐ylidene). Therefore, in reactions catalyzed by AuCl, electron‐neutral dienes favor a concerted [4+3] cycloaddition followed by a ring contraction event, whereas electron‐rich dienes prefer a stepwise cationic pathway to give the same type of formal [4+2] products. On the other hand, the theoretical data suggest that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF₆, the mechanism involves a direct [4+2] cycloaddition between the diene and the gold‐activated allenamide. The theoretical data are also consistent with the observed regioselectivity as well as with the high selectivity towards the formation of the enamide products with a Z configuration. Finally, our data also explain the formation of the minor [2+2] products that are obtained in certain cases.     

Catalytic Asymmetric Chlorination of β‐Keto Esters with Hypervalent Iodine Compounds

(Dichloroiodo)toluene (=dichloro(4‐methylphenyl)iodine; 2 ) was found to be a suitable chlorinating agent in the catalytic asymmetric chlorination of β‐keto esters 3 catalyzed by the [Ti(TADDOLato)] complex 1 (=bis(acetonitrile)dichloro[(4R,5R)‐2,2‐dimethyl‐α,α,α′,α′‐tetra(naphthalen‐1‐yl)‐1,3‐dioxolane‐4,5‐dimethanolato(2?)‐κO,κO′]titanium), whereby α‐chlorinated products were obtained in moderate to good yields and enantioselectivities of up to 71% (Scheme 2, Table 2). The enantioselectivity of the reaction shows a remarkable temperature dependence, the maximum selectivity being obtained at ca. 50°.     

Cycloaddition Reactions and Dendritic Polymer Architectures – A Perfect Match

Summery: The potential of cycloaddition (CA) reactions for the synthesis of dendritic polymers is pointed out. The [4 + 2] Diels Alder cycloaddition as well as 1,3-dipolar CA reactions including “click chemistry” are addressed, and the advantages of these reactions like high selectivity, thus high tolerance towards additional functionalities, high yields and synthesis under mild reaction conditions are highlighted. New perfectly branched dendrimers as well as hyperbranched polymers have been prepared and modified using the 1,3-dipolar cycloaddition reaction of azines with alkynes. The 1,3-dipolar CA reaction of bisazine with maleimides results in hyperbranched and thus, irregular and broadly distributed polymers though with a degree of branching of 100% due to special intermediate formation. The [4 + 2] Diels Alder cycloaddition was successfully applied for the synthesis of highly branched polyphenylene structures using the AB₂ + AB and the A₂ + B₃ approach. CA reactions are also very suitable for highly efficient polymer analogous reactions and thus, they can also be used to prepare complex polymer architectures like dendronized polymers.     

Organometallic gold(III) and gold(I) complexes as catalysts for the 1,3-dipolar cycloaddition to nitrones: synthesis of novel gold-nitrone derivatives

Gold(III) and gold(I) anionic salts mediate the 1,3-dipolar cycloaddition of N-benzyl-C(2-pyridyl)nitrone (2-PyBN) (1) and methyl acrylate (2) (gold 5-10 mol% with respect to the nitrone) decreasing the reaction time and favouring the formation of the exo (cis) isomer. The best catalyst found was Na[AuCl₄] (7) able to perform the addition reaction in 56 h (instead of the 96 h required for the control experiment) and giving an endo/exo relation between isomers of 44/56 (as opposed to 73/27, blank reaction). The catalytic activity of several organometallic gold complexes with the radicals pentafluorophenyl (C₆F₅) or mesityl (2,4,6-(CH₃)₃C₆H₂) has been also investigated. In some cases the activity is very similar to that obtained with inorganic salts. With the aim of identifying possible metallic intermediates in the cycloaddition reaction, novel gold(III) and gold(I) nitrone derivatives such as [Au(C₆F₅)Cl₂(2-PyBN)] (21), [Au(C₆F₅)₂Cl(2-PyBN)] (22) and [Au(C₆F₅)(2-PyBN)] (23) have been prepared and characterized. The reaction between [AuCl₃(tht)] and 2-PyBN unexpectedly affords the ionic compound [2-PyBN-H][AuCl₄] (5) which also displays catalytic activity and moderate regioselectivity and whose crystal structure has been confirmed by X-ray studies.     

Heteropolyacid–silica mediated [3+2] cycloaddition of azomethine ylides—a facile multicomponent one-pot synthesis of novel dispiroheterocycles

An efficient synthesis of dispiroindenoquinoxaline pyrrolizidine derivatives has been expediently accomplished by a one-pot four component 1,3-dipolar cycloaddition reaction. High regioselectivity was achieved using heteropolyacid H₄[Si(W₃O₁₀)₃]–silica as a catalyst. X-ray diffraction studies of one of the cycloadducts proved the structure and regiochemistry of the cycloadduct.     

A convenient and versatile synthesis of 4-trifluoromethyl-substituted pyrazoles

Trifluoromethyl-substituted pyrazoles were synthesized via 1,3-dipolar cycloaddition from sydnones 2a-j and 1-aryl-3,3,3-trifluoro-propynes 5a-f. The regioselectivity of the reaction and the spectroscopic characteristics of the products are discussed.     

Cerium(IV) oxide as a neutral catalyst for aldehyde-induced decarboxylative coupling of l-proline with triethyl phosphite and nitromethane

The application of cerium(IV) oxide (CeO₂) as a neutral and heterogeneous catalyst for aldehyde-induced decarboxylative coupling of l-proline with triethyl phosphite and nitromethane is described. In addition, a [3+2] cycloaddition reaction of the in situ generated 1,3-dipolar intermediate with benzaldehyde in the absence of a nucleophile is also reported.