Spiro cycloaddition reactions

Spiro-(indoline-isoxazolidines) 137, exhibiting interesting biological activities, were prepared in modest yields, by the cycloaddition reaction between ethyl (3-indolylidene)-acetate 135 and various substituted a,N-diphenylnitrones 136 under solvent-free conditions (Scheme 48). The reaction conducted under conventional heating in an oil bath did not proceed even after 20 h, especially when it was carried out without solvent [87]. 

Recently, [2+3] cycloaddition reaction of 2-acetyl-[l,2,3]diazaphosphole (6) with 9-diazofluorenes (96) has been reported [105, 106], From the reaction in cyclohexane at rt, bicyclic phosphirane 97 was obtained as a result of the loss of nitrogen from the initial cycloadduct (Scheme 30). The cycloadduct, 3-spiro substituted 3H-[l,2,4]diazaphospholo-fused [l,2,3]diazaphosphole (98) could be isolated in good yield at room temperature in one case (R=/Bu) its stability was assigned to the presence of bulky fert-butyl group at 7-position. Use of polar solvent like dichloromethane led to the cyclic trimeric compound 99 (Scheme 30). 

The cycloaddition reactions of [(thioacyl)methylene]thiadiazoles 83 with dimethyl acetylenedicarboxylate (DMAD) under UV irradiation at room temperature gave the spiro[3/7-l,3,4-thiadiazoline-2,4 -477-thiopyrans] 84 in 50-60% yields (Equation 23) <2003EJ02480>. 

Cyclic imidate esters, 2-ethoxypyrrolin-5-one and 2-ethoxy-1II -indol-3-one, undergo 1,3-dipolar cycloaddition reactions with nitrile oxides, the reaction site being at the pyrroline C=N bond (317). Rigid and sterically congested pyrroline spiro compounds 148 demonstrate complete diastereofacial selection in site and regiospecific cycloaddition reactions with nitrile oxides to give products 149 (318). 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

Liebscher and Anklam [100] have introduced a facile access to novel optically active spiro-(5-lactams 112-113,115-116 through cycloaddition reaction of diazomethane to a-alkylidene-p-lactams (Scheme 29). Diazomethane gave a clean reaction to 7-methylene-(5-lactam 111 affording spiroazetidin-2-ones 112, 113 (d.r. 87 13, 93%) with preference of anti-addition with respect to the CH2OTBS substituent. The 7-ethylene-(5-lactam 114 reacted slowly with diazomethane and... 

Santillian et al. [102] have investigated the synthesis of N-aryl substituted spiro-(3-lactams 125 (Scheme 31) using [2 + 2] cycloaddition of isomaleimides to acid chlorides. The arylamines 121 were treated with maleic anhydride 122 to afford arylmaleamic acids 123 in excellent yields, which on reaction with dicyclohexy-lcarbodiimide provided isomaleimides 124. Further these underwent [2 + 2] cycloaddition reaction with acid chlorides in the presence of triethylamine and resulted in the regioselective formation of spiro-(3-lactams 125. The trans stereochemistry of... 

Gonzalez et al. [105] have further investigated the diastereoselective [2+2] cycloaddition reaction of unsymmetrical cyclic ketenes with imines for the synthesis of a variety of spiro-(3-lactams (Scheme 34). 

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

Scheme 33 Synthesis of spiro-P-lactams by [2+2] cycloaddition reaction...

A cycloreversion mechanism is suggested for the transformation of the nonisolable cycloadduct 90 to the aldehyde 91 and isothiocyanate 92 <1996BCJ719> and for the spiro-1,4,2-oxathiazole intermediates 94 to the dioxothiazoline 95 and the aryl isothiocyanate 92 <2001MOL510>. Both cycloadducts are obtained by cycloaddition reactions of nitrile oxides 88 to thiocarbonyl compounds (Scheme 12). 

The cycloaddition reactions of captodative olefins all are considered to proceed through the intermediacy of a 1,4-diradical, due to the captodative stabilization of the terminal radicals. In cross-cycloadditions captodative olefins easily give cyclobutanes when heated with fluoroolefins [141]. They also react with allenes to give methylenecyclobutanes [142], and with methylenecyclopropane to give spiro[2.3]hexanes [143]. 

Cycloaddition Reactions. Carbodiimides also react as dipolarophiles in [2+3] cycloaddition reactions. For example, generation of diphenylnitryl imine 292 in the presence of diphenylcarbodiimide affords a spiro compound 293 as the result of the reaction of the initially formed [2+3] cycloadduct with a second equivalent of the nitrile imine. ... 

The cycloaddition reaction of o-thioquinones with acyclic 1,3-dienes is a finely tuned process that can involve either reagent behaving as the diene component. It has now been established that formation of a 2-spiro-linked thiopyran by a [2-1-4] reaction is kinetically controlled and that the [4-1-2] alternative leads to the thermodynamic product, a 1,4-benzoxathiin (Scheme 31). Cyclic dienes yield only the oxathiin <03T5523>. Incorporation of the thionocarbonyl diene unit into fiiran and pyran rings and reaction with carbohydrate glycols leads to tricyclic oxathianes, desulfurisation of which yields 2-deoxydisaccharides <03T4249>. 

Adamantane-2-thione undergoes a concerted regioselective cycloaddition reaction with alkynoic acids to give 2-spiro-linked l,3-oxathiin-6-ones (Scheme 32). When applied to thiofenchone, the reaction also appears to be stereospecific <03EJO3727>. 

The [3+2] cycloaddition reactions of equimolar quantities of DMAD and 4,4-dimethyM,5 d>hydto-l,2-dithiolo[3,4-f]quinoline-l-thiones 121 led at room temperature after prolonged reaction time (20-30h) to the 1,3-dithioles 122 in good yields (72-86%) <1999CHE587>. In the presence of excess DMAD (2/1 molar ratio of DMAD/ thione 121), or upon a treatment of the resulting 1,3-dithioles 122 with an additional equivalent of DMAD, the products of multiple additions afforded the bright yellow spiro-type 1,3-dithioles 123. 

Monocyclic and some bicyclic l,2-dithiole-3-thiones are known that readily undergo 1,3-dipolar cycloaddition reactions to give cyclic 1,3-dithiole and spiro[l,3]dithiole systems. Due to a great variety of applications, the chemistry of this class of compounds still remains a subject of active research. 

The Diels-Alder reaction of methylenecyclopropane with cyclohexa-1,3-diene at 120°C gave the spirocyclopropanebicyclooctene in 50% yield.When cyclopentadiene and spiro[2.4]hepta-4,6-diene were used as dienes the respective spirocyclopropanenorbornenes were obtained. At 190°C, (chloromethylene)cyclopropane underwent [2 + 4] cycloaddition reactions with cyclopentadiene, furan and cyclohexa-1,3-diene to give the respective Diels-Alder adducts. The reaction of buta-1,3-diene and cyclohexa-1,3-diene with bicyclopropylidene as dienophile gave predominantly the [2 + 2] cycloadduct in addition to a small quantity of the Diels-Alder product. Cyclopentadiene, however, formed exclusively the dispirocyclo-propanenorbomene as result of a formal [2 + 4] cycloaddition. 

When bicyclopropylidene was treated in the same way only trimers of the initially formed 8,9-diazadispiro[2.0.2.4]deca-7,9-diene were isolated.The cycloaddition reaction of the unsym-metrical dimethyl 3-cyano-l, 2,4-triazine-5,6-dicarboxylate with methylenecyclopropane was re-gioselective. The primary product was the 2-cyanospiro-3,4-dihydropyridine system (with C3 as spirocenter) which hydrolyzed readily upon chromatography. Dimethyl 4-oxo-5-aza-spiro[2.5]oct-5-ene-6,7-dicarboxylate was isolated as a stable product in 8%> yield. ... 

Table 4. [27r + 27i] and Formal [27t + 2(T + 2ti] Products from the Cycloaddition Reactions of Spiro-fused Vinylcyclopropanes with Dienophiles... 

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