Ring-contractions

Ring Contraction. The cycloaddition of azidobenzenes (237) to malonic acid esters gave triazolines (238 R = OMe or OEt), which on thermolysis 

The stereochemistry of cycloaddition of phenyl azide to hexamethyl Dewar benzene has been established by an X-ray diffraction structural analysis of the cjco-isomer of a )z-bromo-derivative of triazoline (240). The exo-triazoline thus formed was converted into the ejro-aziridine (241) by u.v. light. The addition of cyanogen azide to hydrocarbon olefins yields 1- 

Photodecomposition of A2-1,2,3-triazolines gives aziridines. In cyclohexane the cis derivative (434) gives the cis product (435), whereas photolysis in benzene in the presence of benzophenone as sensitizer gives the same ratio of cis- and /ran.y-aziridines from both triazolines which is accounted for in terms of a triplet excited state (70AHC(il)l). A2-Tetrazolines are photolyzed to diaziridines. 

Dihydro compounds show reactions which parallel those of their aliphatic analogues provided that the aromatization or ring-contraction reactions just discussed do not interfere. 

A2-Imidazolines (416 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A2-Oxazolines (416 Z = O) are cyclic imino ethers, and A2-thiazolines (416 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

2-Imidazolines (437) are readily iV-alkylated or X-acylated to form 1-alkyl- (438) or 1-acyl derivatives or 1,3-disubstituted salts (439). Improved alkylations involve pre-generation of the imidazoline anions. With excess alkyl halide the quaternary salt is formed, but suitable 2-substituents allow deprotonation by sodium hydride to give 2-alkylideneimidazolidines (440) (87CB2053). 

Reactivity of Five-membered Rings with Two or More Heteroatoms 

Chiral Aziridines.—The optically active aziridines [224 R = H, Me, Ph, 4-MeOC6H4, or 3,4-(MeO)2C6H3] were prepared by heating (223) with NaOEt. Each asymmetric carbon was of S configuration, and H n.m.r. spectra indicated that compounds (224) exist predominantly as the fra .s-conformers. 

The reaction of R COCH CHR (R = Ph or Me, R = Ph or COPh) with (-l-)-(225) in MeOH gave chiral 2-acyl-aziridines (226). Thus trans-l-benzoy -2-phenylethene, after reaction with (-l-)-(225) in MeOH at room temperature for 6days,gave(-)-(2R,3i )-rran.9-(226 R = R = Ph) (55%) with 30.4% optical yield. 

Studies of the circular dichroism of (S)-pyrazinoyl-aziridines (227 R = H, Me, Pr , or PhCH2) revealed similar spectra, and indicated that all have similar conformational equilibria. These equilibria are associated with rapid inversion of nitrogen and rapid rotation around the N—CO bond, this being supported by H n.m.r. studies. 

The invertomers of (228) have been separated by gas chromatography on a column coated with optically active nickel(ii) bis-3-heptafluorobutanyl-(l/ )-camphorate in squalene. The chiral invertomers gave two distinct peaks, of intensity 1 1. 

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Ester Enolate Claisen- 4 carbon ring contractions... 

Within the cubane synthesis the initially produced cyclobutadiene moiety (see p. 329) is only stable as an iron(O) complex (M. Avram, 1964 G.F. Emerson, 1965 M.P. Cava, 1967). When this complex is destroyed by oxidation with cerium(lV) in the presence of a dienophilic quinone derivative, the cycloaddition takes place immediately. Irradiation leads to a further cyclobutane ring closure. The cubane synthesis also exemplifies another general approach to cyclobutane derivatives. This starts with cyclopentanone or cyclohexane-dione derivatives which are brominated and treated with strong base. A Favorskii rearrangement then leads to ring contraction (J.C. Barborak, 1966). 

Cyclopentene-l-carboxaldehydes are obtained from cyclohexene precursors by the sequence cyclohexene - cyclohexane-1,2-diol -> open-chain dialdehyde - cyclopentane aldol. The main advantage of this ring contraction procedure is, that the regio-and stereoselectivity of the Diels-Alder synthesis of cyclohexene derivatives can be transferred to cyclopentane synthesis (G. Stork, 1953 G. BUchi, 1968). 

Another useful route to cyciopentanes is the ring contraction of 2-bromo-cydohexanones by a Favorskii rearrangement to give csrdopcntanecarboxylic acids. If a 0 dibromoketones are used, ring opening of the intermediate cydopropanone leads selectively to, y-unsaturated carboxylic acids (S.A, Achmad, 1963, 1965 J. Wolinsky, 1965). 

The reaction sequence is successful because reverse, ring-contraction reactions are unlikely and because only the final product contains a secondary lactam group, which is depro-tonated under the reaction conditions. 

Oxidative rearrangement takes place in the oxidation of the 1-vinyl-l-cyclo-butanol 31, yielding the cyclopentenone derivative 32[84], Ring contraction to cyclopropyl methyl ketone (34) is observed by the oxidation of 1-methylcyclo-butene (33)[85], and ring expansion to cyclopentanone takes place by the reaction of the methylenecyclobutane 35. [86,87]... 

Ring contraction of 2-thiocephems has also been examined as a route to penems. Desulfurization of (82, n = 0) using triphenylphosphine gave mixtures of 5(R)- and 5(5)-penems (121). The stereochemical problem was neatiy overcome by regioselective oxidation to the thiosulfonate (82, n = 2) which underwent stereospecific thermal extmsion of sulfur dioxide (122) to give the S(R)-penem (83). 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

Hydroxy-6-methyl-2-phenylpyridazin-3(2Fr)-one and 4-hydroxy-5-nitropyridazin-3(2FT)-one rearrange in acidic medium to 3-methyl-l-phenylpyrazole-5-carboxylic acid and 4-nitropyrazole-5-carboxylic acid. 4-Hydroxypyridazin-3(2FT)-ones with a hydroxy group or other group at positions 5 or 6, which is easily replaced in alkaline medium, are transformed into 5-(or 3-)pyrazolones with hot alkali. An interesting example is ring contraction of 5-chloro-4-(methylthio)-l-phenylpyridazin-6(lFT)-one which gives, besides pyrazole derivative (127), 4-hydroxy-5-methylthio-l-phenylpyridazin-6(lFf)-one (128 Scheme 41). 

In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

There are several examples of the formation of pyridazines from other heterocycles, such as azirines, furans, pyrroles, isoxazoles, pyrazoles or pyrans and by ring contraction of 1,2-diazepines. Their formation is mentioned in Section 2.12.6.3.2. 

In a series of reactions with potassium amide in liquid ammonia, 6-chloropyrido[2,3-f)]pyrazine gave reduction and ring contraction (Section 2.15.13.3), the 6-bromo analogue underwent only reduction, whilst the 6-fluoro derivative gave only the 6-amino substitution product (79JHC305). 

The base-promoted ring contraction of 3-bromo-2-pyrones to 2-furoic acids cf. Scheme llOd) is a well exemplified reaction 01CB1992,69JCS(C)1950,73JCS(P1)1130> which has also been applied to the obtention of benzofuran-2-carboxylic acids frorn 3-bromocoumarins 08CB830,70KGS(S2)166), Similar base treatment of 3-amino-2-pyrones provides pyrrole-2-carboxylic acids (Scheme IlOe) 75JHC129). 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

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