1,3-Dipolar cycloaddition reactions of 1-methyl- and 1,3-dimethylindol-2-yl nitrile oxides

Reactions of the in situ prepared 1-methylindol-2-yl nitrile oxide ( 2a ) with dipolarophiles lead to isoxazolines 5 and isoxazoles 8 and to their chloro-derivatives 6 and 9 in good yields. Analogous reactions of the 1,3-dimethylindol-2-yl nitrile oxide ( 2b ) give the isoxazolines 10 and the isoxazoles 12 as main products as well as their oxidation products 11 and 13 in low yields. The mechanism of the reactions and the spectral elucidation of the cycloadducts are discussed.     

Magtrieve™ (CrO2) and MnO2 mediated oxidation of aldoximes: studying the reaction course

Magtrieve™ (CrO₂) and MnO₂ mediated oxidation of aldoximes to nitrile oxides were studied in details. In presence of external radical source, TEMPO, these reagents did not furnish nitrile oxides, instead favoured deoximation to aldehydes. A common trend of deoximation was established from electronically tuned aldoximes, which is: aliphatic>aromatic>aldoximes with strong electron-withdrawing group, though the extent of deoximation was less in case of CrO₂. Above effects were not observed with chloramine-T and diacetoxyiodobenzene, reagents known to produce nitrile oxides via hydroximoyl halide or equivalent ionic intermediates. A putative reaction mechanism is proposed for MO₂ (M=Cr, Mn) mediated oxidation of aldoximes through formation of a nitroso-oxime tautomeric pair. Formation of nitrile oxide is possibly occurred from the oxime tautomer via a σ-type iminoxy radical intermediate. The deoximation process, dominating in presence of external radical environment, is explained following decomposition of the nitroso tautomer.     

Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles

A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3-functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile.     

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.     

A modular approach to polyketide building blocks: cycloadditions of nitrile oxides and homoallylic alcohols

A general approach to the diastereoselective synthesis of Delta(2)-isoxazolines via magnesium-mediated, hydroxyl-directed diastereoselective nitrile oxide cycloadditions of homoallylic alcohols and monoprotected homoallylic diols is disclosed. A broad spectrum of aliphatic and aromatic nitrile oxides and a variety of homoallylic alcohols participate in the cycloaddition, thus expanding the scope of polyketide building blocks that can be accessed using this strategy.     

Stereocontrolled intramolecular nitrile oxide cycloaddition reaction using a gauche-gauche interaction

A gauche-gauche interaction is proposed as a powerful controlling factor for the stereochemistry in the intramolecular nitrile oxide cycloaddition reaction derived from N-protected 3-(N-allylamino)propionaldehyde and 2-(N-homoallylamino)acetaldehyde oximes. High levels of stereoselectivity (76% de to perfect) were obtained from the reaction involving nitrile oxides with substituents at the adjacent carbon atom to the tether nitrogen.     

Role of conformational effects on the regioselectivity of macrocyclic INOC reactions: two new asymmetric total syntheses of (+)-brefeldin A

We have gained some insight into the role of conformational effects on the regioselectivity of the macrocyclic intramolecular nitrile oxide cycloaddition observed in our (+)-brefeldin A synthesis. During the course of this regiochemical study, we have developed two novel stereoselective and regioselective schemes for total synthesis of (+)-brefeldin A (i.e. intramolecular nitrile oxide cycloaddition-isomerization and intermolecular nitrile oxide cycloaddition-ring closing metathesis strategies).     

N-heterocyclic carbene-catalyzed 1,3-dipolar cycloaddition reactions: a facile synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles

A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with alkynes was developed for the regioselective synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles. Triethylamine (Et(3)N) was employed as an effective base to generate both nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety of substituents, including other biologically active fragments, onto the isoxazole ring to selectively design multinucleus structures. Further, we have also optimized the conditions for Cu(I)-free Sonogashira cross-coupling to obtain internal alkynes in high yields, which were subsequently used in cycloaddition. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of isoxazoles was ascribed to a beneficial zwitterion intermediate developed by the interaction of the strongly nucleophilic organo-NHC catalyst with alkyne followed by nitrile oxide.     

Intramolecular 1,3-dipolar ene reactions of nitrile oxides occur by stepwise 1,1-cycloaddition/retro-ene mechanisms

Density functional theory studies of intramolecular ene-like (or the so-called 1,3-dipolar ene) reactions between nitrile oxides and alkenes (Ishikawa, T.; Urano, J.; Ikeda, S.; Kobayashi, Y.; Saito, S. Angew. Chem., Int. Ed. 2002, 41, 1586) show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular (3+2) reactions between nitrile oxides and alkenes or the intermolecular dimerizations of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reactions when the tether joining the nitrile oxide and alkene is elongated or some substituents such as trimethylsilyl are absent.     

Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes

The effective generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides can be achieved with powdered molecular sieves 3 Å and 4 Å as mild solid bases. Rate of nitrile oxide generation depends upon the choice of reaction solvents, among which alcohols are the best media. A catalytic process is achieved by use of a catalytic amount of amine in the presence of MS 4 Å leading to the amine-catalytic generation of nitrile oxides. This new synthetic method can be applied to the catalytic enantioselective nitrile oxide 1,3-dipolar cycloaddition reactions with monosubstituted alkenes.     

Fast RNA conjugations on solid phase by strain-promoted cycloadditions

Strain promoted cycloaddition is presented as a tool for RNA conjugation on the solid phase; RNA-cyclooctyne conjugates are prepared by cycloaddition to both azide (strain-promoted azide-alkyne cycloaddition, SPAAC) and nitrile oxide dipoles (strain-promoted nitrile oxide-alkyne cycloaddition, SPNOAC). The conjugation is compatible with 2'-OMe blocks and with 2'-O-TBDMS protection on the ribose moieties of the sugar. Nitrile oxide dipoles are found to be more reactive click partners than azides. The conjugation proceeds within 10 min in aqueous solvents, at room temperature without any metal catalyst and tolerates dipoles of varying steric bulk and electronic demands, including pyrenyl, coumarin and dabcyl derivatives.     

氧化锰晶体作为催化材料调控氨氧化反应产物选择性

有机腈类化合物作为一类重要的化工原料,被广泛应用于医药/农药制造、精细化学品合成和高性能纤维/橡胶生产中.传统合成有机腈类化合物一般使用剧毒的氰化物作为腈化试剂,这类氰化物在危害人体健康的同时,也会严重污染生态环境.针对无氰化物的腈化过程,发展了很多新的反应路线,其中,采用氨气作为氮源的直接氨氧化引起了广泛关注.在该反应中,高温气固相氨氧化反应容易发生过氧化等副反应.与之相比,液相体系中的氨氧化过程反应条件则相对温和,可以有效抑制过氧化.但是,在液相反应中,腈类产物很容易被水合成酰胺类化合物,从而导致该反应的产物选择性大幅降低.本文研究发现,通过改变氧化锰晶体结构可以有效地调控醇类分子氨氧化反应中腈和酰胺产物的选择性.MnO2(包括α,β,γ和δ相)催化的氨氧化过程中,主要得到了酰胺(选择性>99.0％),而在相同反应条件下,α-Mn2O3却可以高选择性地催化醇氨氧化到腈类产物(选择性>99.0％),在该体系中,即使额外增加反应体系中水和催化剂的用量,腈类产物依然不会转化为酰胺产物.动力学研究结果表明,α-Mn2O3催化腈水合到酰胺的反应速率几乎为零,这说明该类催化剂可以有效抑制腈水合反应.原位红外光谱结果表明,α-Mn2O3表面无法有效活化水分子,并且对腈类分子的吸附较弱,这些因素都导致了腈水合反应难以进行,从而可以高选择性地形成腈类化合物.与之相反,MnO2催化材料则可以高效地活化水分子,并且对腈类分子吸附较强,从而有效促进了水合反应并获得了酰胺产物.综上,通过调控氧化锰的晶体类型就可以简单、有效地改变氨氧化反应中的产物选择性.即使在苛刻的反应条件下,例如较大量的水存在下,α-Mn2O3催化的反应体系中依然可以高选择性地获得腈类化合物.本文为高效调控氨氧化反应的产物选择性提供了一个可靠方案.     

Preparation of 1,3-Disubstituted-5-cyano-4,5-dihydropyrazoles via 1,3-Dipolar Cycloaddition of Nitrile Imine with Acrylonitrile

Ｉｎｔｒｏｄｕｃｔｉｏｎ4 ,5 Ｄｉｈｙｄｒｏｐｙｒａｚｏｌｅｄｅｒｉｖａｔｉｖｅｓｈａｖｅｂｅｅｎｓｔｕｄｉｅｄｅｘｔｅｎｓｉｖｅｌｙｄｕｅｔｏｔｈｅｉｒｄｉｖｅｒｓｅｃｈｅｍｉｃａｌｒｅａｃｔｉｖｉｔｙ ,ｂｒｏａｄｓｐｅｃｔｒｕｍｏｆｂｉｏｌｏｇｉｃａｌａｃｔｉｖｉｔｙａｎｄｖａｒｉｅｔｙｏｆｉｎｄｕｓｔｒｉａｌａｐ ｐｌｉｃａｔｉｏｎ .1Ｉｎａｄｄｉｔｉｏｎ ,ｉｔｉｓｋｎｏｗｎｔｈａｔ 4 ,5 ｄｉｈｙｄｒｏｐｙｒａ ｚｏｌｅｄｅｒｉｖａｔｉｖｅｓｗｅｒｅｕｓｅｆｕｌｃｏｍｐｏｕｎｄｓｎｏｔｏｎｌ…     

A new route to 2-substituted perimidines based on nitrile oxide chemistry

A new route to perimidines has been developed which involves reaction of a nitrile oxide with 1,8-diaminonaphthalene. Benzonitrile oxide, generated by dehydrochlorination of benzohydroximoyl chloride, and 1,8-diaminonaphthalene afforded 2-phenylperimidine. 2-Pyranosylperimidines were prepared by the same approach from pyranosyl hydroximoyl chlorides.     

Dimerizations of nitrile oxides to furoxans are stepwise via dinitrosoalkene diradicals: a density functional theory study

Density functional theory calculations at the B3LYP/6-31G* level on the dimerization reactions of acetonitrile oxide and para-chlorobenzonitrile oxide to form furoxans indicate that these processes are stepwise involving dinitrosoalkene intermediates that have considerable diradical character. The rate-determining steps for these two reactions correspond to C-C bond formation. The retardation of dimerization in aromatic nitrile oxides arises from the interruption of conjugation between the nitrile oxide and aryl groups in the C-C bond formation step. The present study also suggests that the isomerization of single-ring furoxans occurs via a diradical intermediate mechanism.     

Synthesis of 2-(12-aryldodecanoyl)cyclohexane-1,3-diones

Synthesis was developed of 2-(10-undecenoyl)cyclohexane-1,3-diones containing in the side chain keto and hydroxy groups and a phenyl substituent. The synthesis is underlain by a nitrile oxide approach. The scheme included isoxazole synthesis for the protection of the β,β′-tricarbonyl fragment, building up of a heterocycle by 1,3-dipolar cycloaddition of nitrile oxide in situ to the terminal double bond, cycle opening (of isoxazole and isoxazoline), and alkaline hydrolysis.     

Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5‐Disubstituted Isoxazoles

An efficient procedure for the synthesis of 3,5‐disubstituted isoxazoles via [3 + 2] cycloaddition reaction of in situ generated nitrile oxides with acetylenes employing readily preparable copper(0) nanoparticles is described. A variety of in situ generated nitrile oxide and acetylenic substrates were engaged in the study and found to undergo cyclization in short duration affording respective isoxazoles in excellent yield. Several amino acid‐derived isoxazoles were also prepared in high yield. Consistent activity of the recovered catalyst was found to be almost same up to three cycles.     

Quantum-chemical study of the Lewis acid influence on the cycloaddition of benzonitrile oxide to acetonitrile, propyne and propene

Quantum chemical methods (MP2 and B3LYP) together with a topological analysis of the charge density have been used to study the BH₃- or BF₃-mediated reaction of benzonitrile oxide with acetonitrile, propyne and propene. In the reaction with propene or propyne, addition of Lewis acids has only little influence on the outcome of the reactions. The cycloaddition of nitrile oxides with nitriles, however, is generally promoted by strong Lewis acids. When the Lewis acid coordination takes place at the nitrile oxide the reactant is activated and the product binds weakly to the Lewis acid so that the reaction is expected to be catalytic. In the case of coordination to the nitrile the reaction is Lewis acid mediated. Here the reactant is not much influenced by addition of Lewis acid, but the transition state and the product are stabilised and consequently such processes require a stoichiometric amount of Lewis acid and form a stable Lewis acid-product complex.It has also been demonstrated that the different activation routes for these reactions involve different reaction mechanisms. Whereas the reaction of a Lewis acid coordinated nitrile oxide is of ‘inverse electron demand’, the Lewis acid coordinated nitrile reacts through a ‘normal electron demand’ cycloaddition.     

An efficient preparation of β‐dimethylaminovinyl sulfone and sulfoximide,and investigation of their reactivity as dipolarophiles

A simple reaction affording (E)‐1‐dimethylamino‐2‐phenylsulfonylethylene, and S‐((E)‐2‐(N',N'‐dimethylamino)ethenyl)‐S‐phenyl‐N‐(p‐tolylsulfonyl) sulfoximide in high yields is described. A reversal in regioselectivity was observed when the β‐dimethylaminovinyl sulfone was employed as a dipolarophile in cycloadditions with nitrile oxides. The sulfone gives rise mainly to 4‐substituted isoxazoles, after elimination of dimethyl amine. In comparison, phenyl vinyl sulfone cycloadds to give 5‐substituted isoxazolines. Although not showing comparable dipolarophilic activity in reactions with nitrile oxides and nitrile imides, the β‐dimethylaminovinyl sulfoximide was easily converted to S‐((E)‐(3‐ethoxycarbonyl)prop‐2‐enyl)‐S‐phenyl‐N‐(p‐tolylsulfonyl) sulfoximide. This allylic sulfoximide cycloadds in good yield to both benzonitrile oxide and diphenylnitrile imide, but no stereoselectivity was observed in the process; and only modest regioselectivity was detected in the case of benzonitrile oxide.     

Multicomponent cascade reactions: sequential [1 + 4] and [2 + 3] cycloadditions for the generation of heterocyclic ring systems

[reaction: see text]. A novel intermolecular nitrile oxide cycloaddition sequence has been developed for the formation of highly substituted heterocyclic rings. Reaction of trimethylsilyl cyanide with epoxides generates isonitriles which can react with nitroalkenes to form N-(isoxazolylidene)alkylamines. After fragmentation to nitrile oxides, the dipoles can undergo intermolecular 1,3-dipolar cycloadditions with electron deficient dipolarophiles to generate substituted isoxazolines in one synthetic operation.