Spiro cycloadducts

Addition reactions of 2-substituted N- methylpyrroles with C- acetyl-TV- phenylnitrilimine gave double cycloaddition products, spiro-cycloadducts and noncyclic bis-adducts (78JHC293). 

A combination of lithium bromide (LiBr) and DBU (1) catalyses regio- and stereospe-cific cycloaddition [54]. Imines of aminopyradazino[l,2-a][l,2]diazepine react with a range of achiral and chiral dipolarophiles in the presence of LiBr and DBU (1) in MeCN to afford enantiopure spiro-cycloadducts in excellent yield via lithio azomethine ylides [54b] (Scheme 3.34). 

The 1,3-dipolar cycloaddition reaction of pyridinium ylides (40) with 3-alkenyl oxindoles (41) yielded spiro-cycloadducts (42) related to oxindole alkaloids, such as strychnofoline (Scheme 12). The one-pot 1,3-dipolar cycloaddition of 3-arylsydnones with a,/ -unsaturated ketones formed 1,3,4-trisubstituted pyrazoles in refluxing dry dimethylbenzene. ... 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

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). 

Treatment of the cycloadduct 22d with a variety of bases afforded the spirocyclopentene derivative 25 and the spiro-1,2-dioxolane derivative 26 (see Equation (5) and Table 2) <1996J(P1)2227>. 

On the other hand, deprotonation of cycloadduct 76 with sodium hydride in acetonitrile at 0°C afforded cyclic sulfilimine 78, the so-called 1,2-azathiabenzene derivative, together with a spiro compound 79 (see Equation (21) and Table 11) <1999TL1505>. 

Reactions of arylsulfonylallenes with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide (227) proceed in a manner similar to that of the above-mentioned sulfides. Probably, both 4- and 5-alkylidene-4,5-dihydroisoxazole cycloadducts are initially formed which then undergo different transformations. 4-Alkylidene isomers give spiro adducts such as 60 with an additional molecule of nitrile oxide, while 5-isomers convert to isoxazoles 61, products of their prototropic rearrangement. 

Formation of a spiro-fused triazolooxadiaine 103 was described by Butler et al. <1997J(P1)1047>. The transformation of 102 to 103 is a 1,3-dipolar cycloaddition carried out by AMd-NOT/I I/ )bcnzonitrilimine (generated from Ar-(4-nitrophenyllbenzohydrazonoyl bromide with triethylamine) to yield the cycloadduct 103 in 85% yield. 

Scheme 61) [2b, 150], but can give rise to a variety of products. With unsym-metrically substituted alkenes of type 266, two regioisomeric products were obtained, but the isomer 268 bearing the ester group near the spiro atom was the minor component in all cases. Norbornadiene and norbornene react with 1 by the same mode to give formal [3 -F 2] cycloadducts 269 and 270, respectively, the latter as a 9 1 mixture of exo- and endo-isomers. 

The intramolecular cycloadditions of cyclic nitronates have received much more attention. The cyclic nitronate structure provides three basic modes of intramolecular cycloaddition (Fig. 2.15). Attachment of the tether to the C(3) position of the nitronate results in the formation of a spiro system (spiro mode). However, if the tether is appended to the C(4) position of the nitronate, the dipolar cycloaddition yields a fused ring system (fused mode). Finally, if the tether is attached at any other point of the cyclic nitronate, the cycloadducts obtained will consist of bicyclic structures (bridged mode). 

In contrast to all investigated a,/J-unsaturated ketones, cyclopentadienones like 497 react with 149 and 473 exclusively to give the spiro compounds 498 i.e. the nominal [2 + 2] cycloadduct, in 61 and 63% yield (equation 164)243. 

Meijere et al. [117] group have investigated the direct synthesis of 3-spiro-cyclopropanated p-lactams 184 (Scheme 43) using novel three-component cascade reaction. Earlier, Alberto Brandi and coworkers [118-120] have applied nitrones 181 and bicyclopropylidene 182 to obtain cylcoadducts 183, which were further fragmented under acidic conditions to afford spiro-p-lactams 184. However, this reaction required longer reaction time for the formation of cycloadducts 183. 

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 spiro compound 106 underwent a Diels-Alder cycloaddition with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate to give the condensed 1,2-diazocine 107, presumably via retrograde deazatization of the initial [4+2] cycloadduct with cleavage of the cyclobutane ring (Scheme 22) <20040L1313>. 

A spiro adduct is the result of the reaction of diazofluorene and perflu-oro-2-butyne (72AG(E)224, 72TL3479 74CB2027). With diazomethane and ethyl diazoacetate the above-mentioned trifluoromethyl-substituted alkynylamino and alkynyl hydroxy acid esters give a single [3 -t- 2] cycloadduct, namely the 2-(3-pyrazolyl)-3,3,3-trifluoroalanine and the 2-(3-pyrazolyl)-3,3,3-trifluorolactic acid derivatives, respectively (92LA947) (Scheme 71). 

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 of 4-methyl-3//-l,2,4-triazole-3,5(4/f)-dione to spiro[fluorenyl-l,3,5-cyclo-heptatriene] at — 10°C gives the norcaradiene-type cycloadduct, monitored by NMR spectroscopy, which by warming at room temperature is converted to an isomeric triazolidinedione, whose structure is confirmed by X-ray analysis22. 

Heterocyclic spirans are prepared by [Ni(CO)4]-promoted tandem cycloaddition of diphenylcyclopio-panone (100) to isothiocyanates (101 equation 43) or to carbon disulfide (105 equation 44). When an equimolar mixture of (100), (101) and [Ni(CO)4] is allowed to react in DMF at 65-70 C, two heterocyclic spirans, pyrrolin-2-one-5-spiro-5 -thiolen-4 -one (102), and (103), are formed in addition to the pyrroline derivative (104). Similarly, carbon disulfide (105), reacts with (100) to give thiolen-2-one-5-spiro-5 -thiolen-4 -one (106) along with a small amount of 1 1 cycloadduct (107). ... 

The cycloadducts obtained in the oximinosulfonate Diels-Alder reaction are best converted directly to pyridines without purification. Exposure of the spiro-fused cycloadducts to a combination of NCS and sodium methoxide brings about cleavage of the dioxanedione ring with concomitant elimination of acetone and carbon dioxide. Elimination of tosylate from the resulting ester enolate then generates a dihydropyridine, and subsequent chlorination by NCS and elimination of HCl finally provides the desired aromatic pyridine product. 

Bischof and Mattay have shown that radical anion cyclization leading to spirocyclic products compete effectively with intramolecular [2 -f 2]-cycloaddition on photoexcitation of olefinic enones in the presence of triethylamine [332, 333]. The [2 -f 2] cycloadducts could be converted to the corresponding spiro compounds under PET conditions (Scheme 75) [307]. 

The chiral moiety of the nitrone can also be located at the carbon atom. Yokoyama et al. [50] used this approach in the asymmetric synthesis of spiro isoxazohdines (Scheme 10.21). The ribose-derived nitrone 62 is obtained from the corresponding oxime by Michael addition to methyl acrylate. With a second equivalent of methyl acrylate, the sugar nitrone 62 gave a single cycloadduct 63, which was converted into the corresponding pyrrolidine by reduction. 

Among the known [4 + 3] cycloaddition protocols examined, only the Schmid2 and Fohlisch4-10 procedures were found to afford the [4 + 3] cycloadducts in synthetically useful yields. Schmid s rarely-used "aminoallyi" reaction appears to be most effective, particularly when sterically demanding 1,3-dienes [e.g., spiro[2.4]hepta-4,6-diene] or otherwise recalcitrant N-acylpyrroles are required for the cycloadditions. On the other hand, with sterically unencumbered 1,3-dienes and also with furans, the Fohlisch reaction has emerged as the method of choice in view of the practical aspects of simple and convenient execution. 

The method described here is the direct adaptation of the original procedure developed by the late Professor Hans Schmid- As summarized in Scheme 1, the Schmid reaction has been successfully applied to [4 + 3] cycloadditions with cyclopentadiene, spiro[2.4]hepta-4,6-diene, and N-Boc-pyrrole. Additional examples can be found in references 8 and 9. Use of functionalized six-membered oxyallyls and synthetic applications of the [4 + 3] cycloadducts have also been described.8... 

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. 

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