Cycloadditions annulation reactions

Aniinophenyl)-a,(J>-ynones react with nitrile oxides by domino [3 + 2] cycloaddition/annulation reactions, giving rise to isoxazolo[4,5-c]quinolines in satisfactory yields (434). Nitrile oxides undergo addition to allylzinc bromide to generate 5-butenylisoxazolines in good yields. The domino reaction combines 1,3-cycloaddition with Wurtz coupling (435). 

Polycyclic Carbon Skeletons by Tandem Cycloaddition/Annulation Reactions... 

Domino [3+2] cycloaddition/annulation reactions of aminophenyl-ynones 23 with nitrile oxides, generated in situ from chloro oximes 22, allowed the synthesis of isoxazolo[4,5-c]quinolines 24, in satisfactory yields <03EJO1423>. Bromine substituents on naphthoquinones activate and orient 1,3-DC with nitrile oxides. Compound 25 reacted with halo oximes 22 to give regioselectively only unsymmetrical naphthoquinones 26, as polyketide building blocks <03TL8901>. 

Cycloaddition-cyclorevcrsion reaction of 9-oxabicyclo[6.1.0]nona-2,4,6-triene (6) with 3,6-diphenyl-1,2,4,5-tetrazine followed by dehydrogenation with tetrachloro-1,2-benzoquinone (o-chloranil) yields the annulated oxonin 7.8... 

A combination of a Diels-Alder and a Fisher carbene-cyclopentannulation is described as the last example in this subgroup. Thus, Barluenga and coworkers used a [4+2] cycloaddition of 2-amino-l,3-butadienes 4-115 with a Fischer alkoxy-arylalky-nylcarbene complex 4-116 this is followed by a cyclopenta-annulation reaction with the aromatic ring in 4-116 to give 4-117 (Scheme 4.25) [36]. An extension of this domino process is the reaction of 4-118 with 2equiv. of the alkynyl carbene 4-119 containing an additional C-C-double bond (Table 4.2) [37]. The final product 4-120, which was obtained in high yield, is formed by a second [4+2] cycloaddition of the primarily obtained cyclopenta-annulated intermediate. 

Other annulation reactions using TiIV-based Lewis acids have been also reported (Scheme 27) 1,3-dipolar cycloadditions,100 [2 + 2] cycloadditions,101 the ene reaction,102 and [3 + 4] cycloadditions103 are also promoted by Tilv compounds. 

Reaction of linear conjugated dienes with la at —10 °C in hydrocarbon solvent in the presence of McsSiCl/AlCls affords stereospecific tra i-l-silyl-3-vinyl-cyclopentanes, indicating a [3 + 2] cycloaddition of the allyl group of la with a carbon arbon double bond of the diene [Eq. (9)]. In the [3 + 2] annulation reaction, of greater significance is the tram conformation of the trimethylsilyl group and vinyl groups. 

Employing ynamines, the cycloaddition-extrusion reaction can be extended to heterocondensed 1,3-oxazinones, resulting in a smooth, simple annulation of a pyridine ring to an existing heterocyclic system (87CB1427). 

Despite the obvious synthetic potential of this formal cycloaddition or annulation reaction, its application has remained little known because of the competing reaction pathways due to 1,2- versus 1,4-addition as well as C-addition versus O-addition [Scheme 4], Moreno-Manas reported a... 

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

The synthesis of polysubstituted tetrahydrofurans was also achieved in a stereoselective manner by a formal [3+2] cycloaddition of an allylsilane with a-triethylsiloxy aldehydes. An example showing the mechanism is illustrated <02JA3608>. In another approach, allylsilane was also allowed to react with a-keto esters in a [3+2] annulation reaction, providing highly substituted tetrahydrofurans in good yields as single diastereomers <02OL2945>. 

Bi- and tricyclic carbocyclic ring systems can be easily obtained from (1-alkynyl)carbene complexes in two or more reaction steps without isolation of intermediate products. For example, the bicyclic 1,3-dienone 44 has been generated from compound le in a two-step cycloaddition/annulation procedure involving [4+2] cycloaddition of a diene to the C=C bond of a (l-alkynyl)carbene complex and a subsequent Dotz reaction.68 Furthermore, a 1,4-dioxy dihydronaphthalene 45 was obtained from the silyl derivative lg in a similar reaction sequence. In contrast to the methyl derivative 44, the corresponding silyl derivative generated from lg undergoes facile... 

Ito and coworkers developed a mild and efficient procedure for generating o-quinodimethanes" as reactive intermediates in [4 -I- 2] cycloadditions. The key step in the sequence, illustrated here by the synthesis of Estrone methyl ether (146 Scheme 53) involves a fluoride-induced fragmentation of the o-[a-(trimethylsilyl)alkyl]benzyltrimethylammonium iodide (144) to give the o-quinodimethane (145), which underwent stereoselective intramolecular [4 + 2] cycloaddition to give the desired tetracyclic framework in (146). The entire process was conducted at room temperature. The annulation reaction is not limited to intramolecular cycloadditions intermolecular versions of the reaction proceed equally well. 

Pyrones can serve either as dienes (47r-component) or as dienophiles (2ff-component) in [4 + 2]-annulation reaction, depending on their reaction partner and their substituents. However, 4-pyrones, coumarins, and chro-mones react only as the 27r-component (dienophile) with electron-rich dienes. A review of the Diels-Alder cycloaddition of 2-pyrones and related compounds has appeared (92T9111). 

R.L. Danheiser and co-workers generated a key vinylketene intermediate via tandem Wolff rearrangement-ketene-alkyne cycloaddition to utilize it in a photochemical aromatic annulation reaction Danheiser benzannulation) for the total synthesis of the phenalenone diterpene salvilenone. ... 

The nitrile oxide cycloaddition has been performed on 83 under Mukaiyama conditions giving the isoxazoline 84 in about 50% yields with high stereocontrol of the annulation reaction. 

D.iii. Trimethylenemethane Equivalents. Palladium catalysts can be used to convert trimethylsilyl acetate 390 to a trimethylene methane (TMM, 391) equivalent. Reaction with alkenes via [3+2]-cycloaddition (sec. 11.11) generates cyclopentanes (this process constitutes a quinane annulation reaction).229 in this reaction, the trimethylsilyl unit is a carbanion equivalent and acetate is a carbocation equivalent. In one example, Trost reacted 390 and 392 with palladium acetate and triisopropyl phosphite [P(Oi-Pr)3] to generate 393 in... 

According to the authors , the driving force of this annulation reaction (equation 31) is the high reactivity of siloxyacetylenes with vinylketene 44, which is thermally generated by the An electrocyclic opening of cyclobutenone 43. The [2+2] cycloaddition of... 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

It has been used for stereo and/or regio selective dipolar cycloadditions, e.g. with chiral aciylamides it produces 2A-pyrazoline caiboxylic acids (azaprolines) after protio-desilylation [Mish et al. J Am Chem Soc 119 8379 7997], or with diethyl /rani -glutacoiiate where the pyrazoline ester is oxidised to the respective pyrazole [Di Rein Tetrahedron Lett 45 4703 2004], It also acts as a caibene sonrce in stereoselective [1 + 4] annulation reactions with silylvinylketenes to form a variety of cyclopent-2-enones in good to excellent yields [Moser et al. J Org Chem 71 6542 2006. ... 

Highly substituted 4/f-pyrans are obtained from [4 + 2] cycloaddition reactions of a-ester-substituted a,P-imsaturated carbonyl compounds with alkynes promoted by a nickel(0) complex (14BCSJ1058) and by annulation reactions of a-allenals with chalcones mediated by the NHC catalyst 2 (Scheme 6) (140L4742). 

Total syntheses of diterpenoid hydrokempenones have been accomplished by Paquette et al.,f using the Pd-catalyzed [3 + 2] cycloaddition methodology. One example is outlined on Scheme 43 and describes the synthesis of an isomeric compound 208 of 3/3-hydroxy-7/3-kemp-8(9)-en-6-one, a defense secretion agent of the neotropical species Nasutitermes octopilis. 3-AUcoxy-2-cyclohexenone 204 was efficiently functionalized and transformed to bicylic adduct 205 via a Robinson annulation reaction. Reduction of the double bond followed by condensation of dimethyl carbonate and oxidation gave the keto ester 206, which was treated with [2-(acetoxymethyl)-3-allyl]trimethylsilane, palladium acetate, and triisopropyl phosphite in refluxing tetrahydrofuran to afford a 98% yield of 207. Substituted methylenecyclopentane 207 was then functionalized by stereoselective reduction and protections, and final closure was done under basic conditions after an ozonolysis step. A modified Barton-McCombie reaction produced the desired tetracyclic adduct 208. 

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