Ring-expansions

Ring expansion reactions of free radicals are useful in synthesis (equation 77) and were reported independently in 1987 by the groups of Beckwith and Dowd  

In a base-catalyzed ring expansion route to 1,2-diazocines, Sommelet-Hauser rearrangement of the A-amino derivative of nicotine (22) using sodium in ammonia afforded pyrido-l,2-diazocine 23. The reaction was regiospecific, i.e., no isomeric 24 was detected (82H1595). 

There have been three reported syntheses of 1,2-diazocines by means of ring-expansive cycloaddition reactions. In the first case, Sasaki and coworkers reacted 4,4-dimethyl-3,5-diphenylisopyrazole 25 with diphe-nylcyclopropenone to obtain diazocine 26 (73SC249). The second cycloaddition was achieved by Haddadin et al., who condensed cyclobutanone with tetrazine 27 (Ar = Ph) to afford diazocine 28 (Ar = Ph, X = O) or 29, depending on whether methanolic base or diethylamine was used as catalyst (84TL2577). A similar reaction was used to prepare a triazocine see Section IV,A,1. 

In the last case, l-oxido-3-phenylphthalazinium ion (30) underwent cycloaddition with unsaturated molecules to give 8-phenyl-3,4-benzo-l, 8-diazabicyclo[3.2.1]octane-2-ones, 8-phenyl-3,4-benzo-l,8-diazabicyclo- 

An attempted Friedel-Crafts acylation of (7t-C5H5)(C6H6)M (M = Cr, Mn) resulted in expansion of the benzene ring to give the (7t-tropylium)-(jt-cyclopentadienyl) metal complexes, equation (6-40). 

A normal Claisen condensation of methylbenzoatechromium tricarbonyl and acetone occurs in a basic solution to give benzoylacetonechromium tricarbonyl, equation (6-41). This same complex can be obtained by the 

The kinetics of 5-exo and 6-endo acyl radical cyclizations have been investigated under a variety of reaction conditions. The presence of the 6-endo product was found to arise either by a direct cyclization (2.0 x 10 s ) or by a ring expansion (4.2 X 10 s ) from the 5-exo radical product (1.6 x 10 s ). Consequently, cyclization in the presence of high concentrations of fast H-donors (e.g. BuaSnH) furnished 5-exo products whereas reactions under high dilution conditions or with poor H-donors gave rise to 6-endo products. 

The formation of ring sizes other than five- and six-membered rings has been reported, in particular the formation of three- and four-membered rings by 5-exo and 4-exo radical cyclization, respectively. High-yielding 3-exo cyclizations have been reported when the cyclized radical contains a radical-stabilizing group. The effects of 

Ab initio studies (UHF/6-31G ) have been used to investigate the 5-endo cyclization of various substituted radicals including the 5-oxapenta-2,4-dienoyl radical. The results show that the 5-endo cyclization is both kinetically and thermodynamically favoured.  

The cyclization of a range of a-heteroatom-functionalized radicals has been studied. Both a-sulfonyl and a-sulfinyl radicals can imdergo 5-exo cyclization on to alkenes.  

The chirahty of the sulfoxide led to only moderate control of stereoselectivity. a-Alkoxy radicals also undergo cyclization in a 5-exo and 6-exo mode, again with httle control of stereoselectivity.  

Reactions of Isothiazoles.—Photolytic. Whilst photoisomerization of isothiazoles to thiazoles is well documented, examples of this reaction occurring with isothiazol-3(2H)-ones have not previously been reported. Irradiation of (10 R = alkyl or Ph) gave the corresponding thiazolone (11). The isomerization probably involves homolysis to a biradical, which cyclizes to an a-lactam and subsequently undergoes ring-expansion. Support for the homolytic step comes from the isolation of a small amount of (12) from the photolysis of (10 R = Ph). 

3-Hydroxy-isothiazoles (15) undergo ring-expansion under Vilsmeier reaction conditions (using R R NCHO) to give the corresponding thiazine derivatives 

Rokach, P. Hamel, Y. Girard, and G. Reader, Tetrahedron Lett., 1979, 1281. 

TomitaandT. Murakami, Jpn. KokaiTokkyo Koho 79 20 504 (Chem. Abstr., 1979,91,157 755). 

Synthesis.—A novel method of formation of 3-methyl-1,2-benzisothiazole (17 R = Me) is by thermal decomposition of the benzothiadiazepine (18), obtained by the reaction of 2-NCSC6H4COMe with NH2CONHNH2. Oxidation of (17 R = Me) to (17 R = CHO) takes place with I2 in DMSO, and to (17 R = CO2H) using SOCI2 and alkali. 

5- lactic acid residues were easily racemized in the PPL-catalyzed ROP of 3 and/or 

These authors successfully prepared 11- and 14-membered cycloesteramides by the ring-expansion of N-(hydroxyacyl)-lactams and N-(hydroxyacyl)-2,5-diketopiperazines. The mechanism involved a nucleophilic attack of the hydroxyl 

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Ring Expansion/Contraction via Sigrnatropic Rearrangements - Cope Rearrangement... 

The thermal ring opening of l,2-bis(trimethylsiIoxy) cyclobutenes (from acyloin condensation of 1,2-dicarboxylic esters) was used in ring expansion prodecures (see p. 53f.). 

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 Pd(0)-catalyzed rearrangement of the iV-allylenamine 800 in CF3CO2H affords the (5, -unsaturated imine 801, which is hydrolyzed to give the 7, 8-unsaturated aldehyde 802[498]. The vinyloxaspirohexane 803 undergoes rearrangement-ring expansion to give the cyclopentanone 804 in the presence of 1 equiv. of p-nitrophenol[499]. 

The 2-alkylideneindanone 282 is formed by carbopalladation via ring expansion of the alkynylcyclobutenol 280 with palladium trifluoroacetate to yield an intermediate 281 and its protonolysis. 4-Oxygenated 5-alkylidenecyclopente-nones react similarly[139]. 

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]. 

In contrast to the 4-hydroxy isomers, the thermally stable 5-hydroxy-THISs add to the C=C bond of cyclopropenylidenes (4. 18, 27. 28). The adducts eliminate carbonyl sulfide, and the strained bond breaks resulting in ring-expansion with formation of pyridin-4-ones. -thiones, or -imines. or 4-alkylidenedihydropvridines (20, X = 0. S.NR. or CRR ) (Scheme 19). 

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). 

Other ring-expansion reactions have already been mentioned in regard to addition reactions leading to pyrrolothiazoles (Section III. 3), which sometimes rearrange to 1,4-thiazines (333, 497). 

With 2-methyl- and 2,4-dimethylthiazole, the methyl thiirenium ion (m/e 72) is obtained, which can easily lose a hydrogen radical to give the ml ell ion (confirmed by the metastable peak). This latter can rearrange by ring expansion to give the thietenyl cation whose structure was confirmed in certain spectra by the presence of a metastable peak corresponding to the decomposition of the m/e 71 ion to give the thioformyl cation m/e 45, probably by elimination of acetylene. 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

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. 

Synthesis From Other Ring Systems. These syntheses are further classified based on the number of atoms in the starting ring. Ring expansion of dichlorocyclopropane carbaldimine (53), where R = H and R = ryl, on pyrolysis gives 2-arylpyridines. Thermal rearrangement to substituted pyridines occurs in the presence of tungsten(VI) oxide. In most instances the nonchlorinated product is the primary product obtained (63). 

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