Ring expansion derivatives

Klemm (16) and Lee and coworkers (17) have examined the effect of various solvents on the photochemistry of cyclobutanone. By monitoring the quantum yields for formation of ethylene (B-cleavage product) and cyclopropane (decarbonylation product) in different solvents, they were able to demonstrate a significant reduction in the quantum yields for product formation in methanol as compared to other hydrocarbon solvents. Whereas the quantum yield of ethylene formation was found to be essentially solvent insensitive, that for cyclopropane formation was found to be somewhat solvent sensitive. This suggested that B-cleavage and decarbonylation do not result from the same immediate precursor. Since ring-expansion derivatives have not been isolated from photolyses carried out in saturated hydrocarbon solvents, the importance of this process under these conditions remains to be determined. Irradiation of cyclobutanone in the presence of 1,3-penta-diene (17,59) or 1,3-cyclohexadiene (16) did not appear to affect the quantum yields for ketone disappearance or product appearance. 

V. Currently ca. 70001 penicillin G are used per year of which over 90% originate from Escherichia coli immobilized on polymer carriers. It is released with penicillin amidase. A. is the precursor for all semisynthetic penicillins that arise through acylation of A. at the amino group. By chemical or enzymatic ring expansion, derivatives of 7-aminocephalosporanic acid (parent compound of the cephalosporins) are also accessible from A. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

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]... 

The thiepin system 31 is formed quantitatively by ring expansion of the diazoacetate derivative 30 via carbene formation catalyzed by 7r-allylpalladium chloride and its intramolecular insertion[31], The 4-diazomethyl-4//-pyrane 32 is expanded to the oxepine 33 in quantitative yield with the same catalyst[32]. 

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

Takamizawa et al. developed a general ring-expansion reaction of heterocycles that, applied to thiazolium salts, yields 1,4-thiazines (496, 497) thiamine (220) reacts with dialkyl acylphosphonates (221) to give the tricyclic 1,4-thiazine (222) (498), which is easily hydrolyzed to dihydro-1,4-thiazinone (223) (499) (Scheme 106). In the case of thiazolium slats containing no functional groups (224), 1,4-thiazine derivatives (226) were directly obtained in fairly good yields (Scheme 107). 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

Ring expansion of ftve-membered ring heterocycHc compounds has been accompHshed to form pyridine derivatives. Reaction of tetrahydrofurfuryl alcohol with ammonia gives pyridine (1) under dehydrogenating conditions, and gives piperidine (18) under reductive conditions. 

Biochemical studies showed that the a-aminoadipoyl analogue derived from (2,3)-P-methylenepenam was not a substrate for expandase activity but rather, it was a potent reversible inhibitor of the ring expansion of (7.-aminoadipoy1-penici11in into deacetoxycephalosporanic acid by the expandase enzyme... 

Photolysis of pyridazine IV-ethoxycarbonylimide results in the formation of the pyrrole derivative (56). The rearrangement is postulated to proceed via a diaziridine, followed by ring expansion to the corresponding 1,2,3-triazepine derivative and rearrangement to a triazabicycloheptadiene, from which finally a molecule of nitrogen is eliminated (Scheme 19) (80CPB2676). 

A similar regiospecific [2 -I- 2] cycloaddition across a C=S group occurred when benzoyl isothiocyanate (436) and 2,3-diphenyl-1-azirine were heated in refiuxing benzene for 12 hours. The product obtained was shown to be (438) and an intermediate such as (437) could also be involved in this cycloaddition (74JOC3763). In contrast, thiobenzoyl isocyanate added in a [4-1-2] fashion, and after ring expansion gave a thiadiazepine derivative. 

Ring expansion of five- to six-membered rings such as oxazole —> pyridine derivatives via a Diels-Alder reaction is a well-established procedure. However, the conversion of a six-membered heterocycle into a five-membered ring system has not been exploited to any great extent, and those systems that have been studied usually involve a cationic species. 

A number of 2-acylazetidines have been prepared by reaction of 1,3-dihaloacyl compounds with amino derivatives (Section 5.09.2.3.l(m)). This is illustrated for azetidine 2-carboxylic acid (56), the only known naturally occurring azetidine. Ring expansion of activated aziridines (43) and contraction of 4-oxazolines (55) has also found limited use (Section 5.09.2.3.2(f) and Hi)). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Perfluorotetramethylthiadiphosphanorbornadiene and bis(trifluoromethyl) thiadiphosphole can be prepared by thermolysis of an adduct of methanol and hexakis(trifluoromethyl)-l,4-diphosphabarrelene with sulfur [113] (equation 23) Pyrolysis of the adduct of hexafluorinated Dewar benzene and phenyl azide results in ring expansion giving azepine, which photochemically yields an intramolecular 2-1-2 adduct, a good dienophile for the Diels-Alder reaction [114, //5] (equation 24) Thermolysis of fluonnated derivatives of 1,5-diazabicyclo-... 

Difluoro-l -vinylcyclopropane undergoes a free radical 1,3 rearrangement with ring expansion yielding difluorocyclopentene derivatives [131 132] (equation 29) Similar, but more complex rearrangement occurs with l,l-difluoro-4-meth ylenespiro[3 2]hexane (equation 30)... 

Carbonylation ot 1-adamantyl triflate in the presence of tnflic acid also gives a derivative of homoadamantane as the result of a similar rearrangement with ring expansion [55] (equation 36)... 

The lifetime of the diazomethane adduct is not known, but it must be of sufficient length that carbon can compete with nitrogen in participation as a nitrogen molecule leaves (24,109). The reaction of 66 with diazoethane yields 72, the normal adduct, and 73, the product from ring expansion. The structure of 73 was determined by hydrolysis to 2-methylcyclo-heptanone. In a similar reaction 74 yields 67 directly without isolation of 66. A similar ring expansion has been observed for cyclooctanone derivatives (16). 

The addition of diphenylcyclopropenone to pyrrolidinocyclohexene and ring expansion of the adduct gave an aminocyclononadicnone (330,331), A hereas the corresponding cyclopentanone derived enamine yielded a bieyclic enone. 

A two-carbon ring expansion of cyclic ketones was achieved by the addition of acetylenic esters and diesters to the enamine derivatives of the ketones, and reported almost simultaneously from several laboratories (337-343). The intermediate bicyclic adduct could be isolated in some cases. 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

Highly selective synthesis of polyfunctionalized heterocycles based on ring expansion of squaric acid derivatives 97YGK785, 98SL1167. 

Thianaphtheneqiiinone - (109) and diazomethane give a different reaction from that found with isatin, A -methylisatin and coumarandione. In as far as crystalline products could be isolated, the ring expansion occurs here between the sulfur and the carbonyl group in the 2-position. Depending on the solvent, there are formed 3-hydroxy-thiochromone (110), its 0-methyl derivative (111), or (presumably by attack on the 3-keto group of the tautomeric 3,4-diketo form of 110), 3,3 -epoxy-3-methylthiochromone (108). 

Adducts derived from cyclopropyl-TMM reactions are versatile synthetic intermediates. Alkylidenecyclopropanes have been proven useful in further Pd-cata-lyzed transformations [4], On the other hand, vinylcyclopropanes can undergo smooth thermal ring-expansion to cyclopentenes. Thus, a total synthesis of 11-hy-droxyjasionone (27) was achieved with the cyclopropyl-TMM cycloaddition as the crucial step, and the thermal rearrangement of the initial adduct (28) as an entry to the bicyclo[6.3.0]undecyl compound (29), a key intermediate in the synthetic sequence (Scheme 2.9) [19]. 

The well-known reaction leading to ring expansion of cyclic ketones has been applied to derivatives of oxo sugars in an attempt to develop a new route to novel deoxy sugars. By treatment with diazomethane both a five-membered (42) and a six-membered (26) sugar ring have been expanded by insertion of a methylene group. 

The ring expansions of cydohexadiene derivatives to azepines is of historical significance, as the first example of a monocyclic 1//-azepine was obtained by cyanide ion attack on 2-acetoxy-2,4,6-trimethyl-iV-(phenylsulfonyl)cyclohexa-3,5-dien-l-imine (4) 17 however, it was almost twenty years before the product was correctly formulated as the l//-azepine 5.24... 

An elegant extension of these intramolecular acylnitrene-induced ring expansions has been used for the synthesis of cyclopent[h]azepines.2 2-Haloindan-l-yl azidoformates 14 (X = Cl, Br), when subjected to pyrolysis at 300 °C in a hot tube packed with calcium oxide and copper turnings, produce cyclopent[6]azepine (15), as a dark turquoise oil, in excellent yield. Lesser yields (30 and 50%, respectively) of the 4-bromo and 3-methoxy derivatives can be similarly obtained. 

Likewise, diamides, e. g. 90, formed by bis(2-azidobenzoylation) of diamines, suffer ring expansion of both aryl rings to yield the bis(aminocarbonyl) derivatives, e. g. 91. 

The first preparation of a tribcnz[7>,d,/jazepine was achieved by decomposition of the diazonium salt 29 (R = N2 + X" X = Cl or HSOJ derived from A,7V-diphenyl-2,2 -(l,3-phenylene)diani-line (29. R = NH2).105 9-Phenyl-9//-tribenz[M,/]azepine (30) is obtained along with several other products, and is thought to be formed by ring expansion of the TV.TV-diphenylcarbazolium ion. 

---