Ring fission

The rings of cyclic ethers are opened more readily than in the acyclic series e.g. tetrahydropyran with aqueous hydrochloric acid at 100°C gives C1(CH2)5C1. 

4-Tetrahydroisoquinoline undergoes a thermal retro-Diels-Alder reaction to give o-quinodi-methane (Equation 13). 

Ring Fission. The kinetics of the hydrolytic ring-scission of 2-methylthio-4,5-diphenyl-l,3,4-thiadiazolium iodide (111) to A -benzoyl-A -phenyldithiocarbamate (113) have been studied spectrophotometrically. Above pH 4, the reaction is of the first order and is almost independent of pH, in accord with the rate-determining formation of a neutral intermediate, e.g. (112), via a cationic transition state. 

The partial inhibition of the hydrolysis observed at pH 4, and the negative salt effect, may be attributed to a specific cation-anion interaction. The proposed mechanism receives further support from the observed effects on the hydrolysis rates of increased viscosity of the medium and of added inorganic nucleophiles. Hydrazine or alkylhydrazines cleave and recyclize 1,3,4-thiadiazolium salts (114) to 1,2- or l,4-dihydro-l,2,4,5-tetrazines (115) in high yield. The action of arylhydrazine results in the alternative recyclization of the probable intermediate ArNHN=CR2NR N=CR SH, to 4-amino-1,2,4-triazolium salts (116). 5-Amino-2-imino-3-phenacyl-l,3,4-thiadiazolines (117) isomerize in boiling ethanol to 5-amino-3-mercapto-l-phenacyl-l,2,4-triazoles (118). This example 

The rates of decarboxylation of substituted indoxazene-3-carboxylic acids correlate well with their pK values, which in turn reflect the electron-withdrawing effects of the substituent groups.8 5,6-Dinitroindoxazene-3-carboxylic acid is particularly labile and decarboxylates during recrystallization or on storage. 

The rate of decarboxylation of 6-nitroindoxazene-3-carboxylic acid is subject to dramatic solvent effects which support the anionic nature of the transition state (38).8,53 The marked acceleration on going from water (rate 7.3 x 10-6sec-1) to a dipolar aprotic solvent (e.g., dimethylformamide, rate 3.7 x 10 sec- ) is interpreted in terms of the different solvation requirements of the carboxylate anion (40), with its comparatively localized charge, and the transition state (38) with its delocalized charge. In protic solvents intermolecular hydrogen bonding with the carboxylate ion inhibits decarboxylation by selectively stabilizing the acid, whereas dipolar aprotic solvents stabilize the transition state (38) and hence accelerate loss of carbon dioxide. 

As anticipated, the strong intramolecular hydrogen bonding present in the 4-hydroxy-3-carboxylic acid (40 R = 4-OH) inhibits conversion to the salicylonitrile in all solvent systems.8 A similar but less marked effect is noticed with the zwitterionic 4-pyridinium derivative (41) in which there is electrostatic stabilization.54, 

Bunton and his co-workers55 have shown that the decarboxylative ring opening of 6-nitroindoxazene-3-carboxylic acid is strongly catalyzed by cationic micelles and by micelles of zwitterionic surfactants such as N,N-dimethyl-JV-dodecylglycine. Later studies by other workers indicate that the decarboxylation is also catalyzed by polysoaps,56 modified polyethylene-imines,57 cycloheptaamylose,9 and by poly(vinylbenzo-18-crown-6).58 The 

Photolysis of indoxazene in 96% sulfuric acid produces a mixture of 2,5-dihydroxy- (64%) and 2,3-dihydroxybenzaldehyde (17%) 3-methyl- 

Pyrazolidines (172) can be transformed into diamines (173) by Raney Ni the d,l stereochemistry is preserved. 

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The ring fission of pyrimidinium gives good results when this salt is condensed with 2-methylbenzothiazolium the yield obtained is very poor with 2-methylthiazolium (method D) (545). 

The nitration of the 2-anilino-4-phenylselenazole (103) is much more complicated. Even careful nitration using the nitrate-sulfuric acid method leads to the formation of a mixture of variously nitrated compounds in an almost violent reaction. By the use of column chromatography as well as thin-layer chromatography a separation could be made, and the compounds could be partly identified by an independent synthesis. Scheme 33 shows a general view of the substances prepared. Ring fission was not obser ed under mild conditions. 

Active Raney nickel induces desulfurization of many sulfur-containing heterocycles thiazoles are fairly labile toward this ring cleavage agent. The reaction occurs apparently by two competing mechanisms (481) in the first, favored by alkaline conditions, ring fission occurs before desul-, furization, whereas in the second, favored by the use of neutral catalyst, the initial desulfurization is followed by fission of a C-N bond and formation of carbonyl derivatives by hydrolysis (Scheme 95). 

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

Compounds of type (42) are widely used in the dye industry (see Azo dyes). The Mannich reaction also takes place at C, as does halogenation and nitration. The important analgesic aminoantipyrine [83-07-8] (43) on photolysis in methanol undergoes ring fission to yield (44) (27). 

Oxidation to an azolone is an expected reaction for a pseudo base, but little appears to be known of such reactions. Most commonly, pseudo bases suffer ring fission. Estimated rates of ring-opening of (169) are in the ratio 10 10" 1 for X = O, S and NMe, respectively (79AHC(25)1). 

Isoxazotes are readily reduced, usually with concomitant ring fission (e.g. 262 — 263). They behave as masked 1,3-diketones 79AHC(25)147). 1,2-Benzisoxazoles are easily reduced to various products (Scheme 28) (67AHC(8)277). Chemical or catalytic reduction of oxazoles invariably cleaves the heterocyclic ring (Scheme 29) <74AHQ 17)99). For similar reactions of thiazoles, see Section 4.02.1.5.1. 

However, in some cases carboxylic acid-derived groups can participate in ring fission-reclosure reactions. Thus photolysis of 1,5-disubstituted tetrazole (399) gives nitrogen and appears to involve the amino-nitrene intermediate (400), which reacts further to give (401) (77AHC(21)323). 

When an azole carbene is formed, spontaneous ring fission can occur. The prototypes for these reactions are shown (409) (410), (411) (412). 

Ring fission occurs readily in many of these compounds. For example, azlactones, i.e. 4JT-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydrolyzed to a-benzamido-a,/3-unsaturated acids (509), further hydrolysis of which gives a-keto acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis of a-amino acids e.g. 508 -> 507). 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

The catalytic reduction of 2-methyl-3-phenyl-3-isoxazoline (159) produced /3-hydroxypropiophenone (160) (74CPB70). Ring fission also occurred on base treatment of the 3,5-diaryl-3-isoxazoline (161) to give the a,/3-unsaturated oxime (162) (70CI(L)624). 

In contrast to the 3-amino derivatives, 3-hydroxy-2,l-benzisoxazoles are relatively labile. With nitrous acid they undergo ring fission to anthranilic add. Its 3-acetoxy derivative (258) reacts with primary amines to form the quinazolone (259) (67AHC(8)277, p. 297). 

The reaction of vinylogous amides, or ketoaldehydes, with hydroxylamine produced 4,5,6,7-tetrahydro-l,2-benzisoxazole. A side product is the 2,1-benzisoxazole (Scheme 173) (67AHC(8)277). The ring system can also be prepared by the reaction of cyclohexanone enamines with nitrile oxides (Scheme 173) (78S43, 74KGS901). Base treatment produced ring fission products and photolysis resulted in isomerization to benzoxazoles (76JOC13). 

IsoxazoIidine-3,3-dicarboxylic acid, 2-methoxy-dimethyl ester reaction with bases, 6, 47 Isoxazolidine-3,5-diones synthesis, 6, 112, 113 Isoxazoli dines conformation, 6, 10 3,5-disubstituted synthesis, 6, 109 oxidation, 6, 45-46 PE spectra, 6, 5 photolysis, 6, 46 pyrolysis, 6, 46 reactions, 6, 45-47 with acetone, 6, 47 with bases, 6, 47 reduction, 6, 45 ring fission, S, 80 spectroscopy, 6, 6 synthesis, 6, 3, 108-112 thermochemistry, 6, 10 Isoxazolidin-3-ol synthesis, 6, 111 Isoxazolidin-5-oI synthesis, 6, 111... 

Thiazolidine-2,4-dione, 2-dialkylamino-bisimide synthesis, 5, 129 Thiazolidine-2,4-diones IR spectroscopy, 6, 242 tautomerism, 6, 270 Thiazolidine-2,5-diones synthesis, 5, 138 Thiazolidine-4,5-diones synthesis, 5, 129 6, 316-317 Thiazolidine-2,4-dithiones tautomerism, 6, 270 Thiazolidines "C NMR, 6, 243 conformation, 6, 242, 247 dihydrothiazines from, 2, 93 hydrolysis, 6, 273 IR spectra, 6, 242 ring fission, 5, 80 synthesis, 5, 118 6, 316-321 Thiazolidines, imino-tautomerism, 6, 273 Thiazolidines, methyl-conformation, 6, 242 Thiazolidine-2-thione, 3-acyl-reduction, 1, 469 Thiazolidine-2-thione, 4-alkyl-synthesis, 6, 318... 

Degradation Decarboxylation, deamination, dehalogenation, dehydroxylation, ring fission, demethoxylation, deacetylation... 

The A -oxide reactions in quinazoline 3-oxide are, however, modified to a certain extent by the aforementioned properties. Thus, whereas it can be reduced to quinazoline with phosphorus trichloride or iron and ferrous sulfate in ethanol, reactions with alkali, acetic anhydride, and benzoyl chloride in the presence of cyanide result in ring fission (Scheme 4). 

It has also been stated that the 5-position of selenazoles is more reactive toward electrophilic substitution than that of thiazoles. Such reactivity is still further increased by substituents in the 2-position of the selenazole ring, which can have an —E-effect. Simultaneously, however, an increasing tendency toward ring fission was observed by Haginiwa. Reactions of the selenazole ring are thus limited mainly to the 5-position which, specially in the 2-amino-and the 2-hydrazino-selenazoles, is easily substituted by electrophilic reagents. However, all attempts to synthesize selenazole derivatives by the Gattermann and by the Friedel-Crafts methods... 

The direct nitration of 2-amino-4-methylselenazole leads to a ring fission. However, if the amino group is previously acetylated, the corresponding 5-nitro compound is formed in good yield 2-acetamido-4-methyl-5-nitroselenazole, mp 185°C. ... 

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