By Cycloaddition

4 By Reaction of Hydrazines with Cyciic Equivaients of 1,4-Diketo and Reiated Compounds 

6-dicarboxylate undergoes cycloaddition with naphthalenes but yields of benzo[/]phthalazines are generally poor. With 1-methoxy and 1-dimethylaminonaphthalenes loss of methanol (or dimethyl-amine) to give the unsubstituted benzo[/]phthalazine competes with oxidation of the intermediate, and in toluene 1-dimethylaminonaphthalene reacts with two moles of the tetrazine to give the bis(4-pyridazinyl)benzene derivative (140) in 47% yield. With 2-dimethylaminonaphthalene there is still 

5-tetrazines. The use of 3,6-bismethylthio-l,2,4,5-tetrazine in cycloaddition reactions for the preparation of pyridazines offers greater scope for substituent modification in the products than is the case with the dicarboxylates the methylthio substituents can be removed or oxidised and used for nucleophilic displacement reactions. This approach forms the basis of a synthesis of substituted indoles and indolines (see Section 6.01.5.1.1) 88J0C1415 . 

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Indoles by cycloaddition with pyrrole-2,3-quinodimethane equivalents... 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

The Af-chlorosulfonyl-4-alkenyl-/3-lactams (119), formed by cycloaddition of CSI with the corresponding dienes, undergo a thermal rearrangement to give the formal [4 + 2]... 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

A series of 3-imino-2-aryl-l-azetines has been prepared by cycloaddition of nitrile ylides to isocyanides. Thus generation of the nitrile ylides (215) in the presence of cyclohexyl isocyanide gives the 3-cycIohexyIimino-2-aryI-l-azetines (205). Similar 1-azetines are formed by interception of nitrile ylides with a-methylbenzyl isocyanide (72AG(E)47) cf. Section 5.09.4.2.2). 

The only stannole complex 290 was found by cycloaddition of species 289 to 2-butyne [98ICA(281)53],... 

The 3//-azepines obtained by cycloaddition of azirines to cyclopentadienones (see Section 3.1.1.1.2.) are thought to arise from the initially formed 2/7-azepines by [1,5]-H suprafacial sigmatropic shifts.31-108 In contrast, 1/Z-azepine 9 results from the thermal rearrangement of the nonisolable 2//-azepine-2-carboxylate 8.13 Presumably, the 1 //-azepine is stabilized, relative to the 3//-isomer, by intramolecular hydrogen bonding between the NH and the adjacent ester group. 

Similarly, 4//-azepinc-2-carboxylates 16, obtained by cycloaddition of 1,2,4-triazines with cyclopropenes (see Section 3.1.1.1.2.), isomerize in practicable yields to 3//-azepines 17 in refluxing pyridine,84-85 or with sodium methoxide in refluxing methanol.28-83... 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

By analogy with the formation of3//-azepines by cycloaddition of 2//-azirines withcyclopenta-dienones, l,3-diphenyl-2//-inden-2-one (58) and its dibenzo analog 60 enter into [4 + 2] cycloadditions with 27/-azirines to give 3//-2-benzazepines 59 and phenanthro[9,10-e]azepincs 61, respectively.96... 

The diazepines 13 react with dimethyl acetylenedicarboxylate to yield mixtures of the pyrazole 19 and the benzene derivatives 18. The reaction proceeds by cycloaddition to yield 14, followed by valence isomerization to the 1,2-diazonines 15, a further valence isomerization to 16, a Second cycloaddition to give 17 and, finally, fragmentation."... 

In contrast, C,V-diphenylnitrone in the presence of boron trifluoride-diethyl ether gives 35 by cycloaddition at the 3,4-bond of the tautomer 34.305... 

The bicyclic system 5 can also be used to prepare annulated systems by cycloaddition-cycloreversion processes. With 2//-pyran-2-one (6) a mixture of cycloadducts is formed on... 

Trifluoromethyl-l,2,4-triazines and 1,2,4-triazin-5-ones are versatile precursors for azetidines and pyridines by cycloaddition reactions. Enhancement of reactivity was observed through the presence of the trifluor-omethyl group (88CPB3354). 

Thiazolotriazines 636 (R = CO,Me) were prepared [84JCS(P1)2707] by cycloaddition of dimethyl acetylenedicarboxylate with triazine derivative 632. Derivatives of thiazolo[3,2-b][l,2,4]triazin-3,7-diones 637 have been formed (74JPR163) on reaction with aromatic aldehydes and diazonium salts to give 636 (R = Ar) and 638, respectively. Regioselective catalyzed... 

The unsubstituted benzyne (8.26) from 2-diazoniobenzenecarboxylate can be trapped in the absence of a Bronsted acid as biphenylene, i.e., dimeric benzyne (8.30 Ford, 1971), or by cycloaddition to a 4-71 donor such as furan to give 8.31 (Stiles et al., 1963). 

Heterocyclic sulphoxides of general structure 185,186 and 187 have been prepared by cycloaddition of diarylsulphines 173b to nitrile oxides 188226, nitrile ylides 189227 and nitrones 190228, respectively (equation 100). 

In a more recent and improved approach to cyclopropa-radicicol (228) [ 110], also outlined in Scheme 48, the synthesis was achieved via ynolide 231 which was transformed to the stable cobalt complex 232. RCM of 232 mediated by catalyst C led to cyclization product 233 as a 2 1 mixture of isomers in 57% yield. Oxidative removal of cobalt from this mixture followed by cycloaddition of the resulting cycloalkyne 234 with the cyclic diene 235 led to the benzofused macrolactone 236, which was converted to cyclopropa-radicicol (228). 

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