Seven-membered ketone

These steric factors are also indicated by the relative basicity of enamines derived from five-, six-, and seven-membered ketones. The five- and seven-membered enamines are considerably stronger bases, indicating better conjugation between the amine lone pair and the double bond. The reduced basicity of the cyclohexanone enamines is related to the preference for exo and endo double bonds in six-membered rings (see Section 3.10). 

Cycloadditions. Silver perchlorate converts the l,l-dimcthyl-2-(tri-methylsiloxy)allyl chloride (1) and related allylic chlorides into an oxyallyl cation (a), which reacts with 1,3-dienes to form seven-membered ketones, often in high yield, particularly in reactions conducted in nitromethane. 

Intramolecular acylations of pyrroles and indoles are useful synthetically, for example, A-glutamyl-substituted pyrrole 94 gives 95, regioselectively, with retention of configuration, on brief treatment with methanolic hydrogen chloride or boron tribromide. A seven-membered ketone 97 was produced from 96 no cyclization onto the indole 4-position was observed <1999T4341>. 

The first total synthesis of the marine polycyclic ether toxin (-)-gambierol was accomplished in the laboratory of M. Sasaki. The introduction of the a,(3-unsaturation into the seven-membered H ring of the FGH tricyclic subunit proved to be problematic, because both the conventional selenium-based method and the Nicolaou oxidation with IBX failed. However, when the seven-membered ketone was treated with LiHMDS in the presence of TMSCI and EtsN, the corresponding silyl enol ether was formed, which was oxidized under Saegusa conditions to give the desired cyclic enone in high yield. Because of the small scale of the reaction, a large excess of Pd(OAc)2 was used in acetonitrile so the presence of a co-oxidant was not necessary. 

The stereoselectivity seen in the reduction of the seven-membered ketone above has proved to be general. This particular result, rationalized by the propensity for pseudoaxial hydride addition under Luche conditions, proved useful in the convergent total synthesis of Gymnocin-A, a polycyclic ether toxin isolated from the red tide dinoflagellate—Karenia mikimotoi.u The Luche reduction was used for the production of allylic alcohol 9 from ketone 8 in 84% yield. Luche conditions were similarly applied to the synthesis of the related polycyclic ether toxin gambierol.12... 

These steric factors are also indicated by the relative basicity of enamines derived from five-, six-, and seven-membered ketones. The five- and seven-membered enamines... 

The feasibility of such a sequential process was accidentally discovered in 1989 in an unsuccessful attempt to achieve cyclic acylpalladation (Sect. VI.4) of la (Scheme 1) with 40 atm of CO, 1.5 equiv of NEtj, and 4 equiv of MeOH in the presence of 3 mol % of Pd(PPh3)4 at 100 °C. Whereas none of the desired cyclic acylpalladation product 2a was formed, the reaction gave an unexpected carbopalladation product 3a in 42% yield along with an uncyclized premature esterification product 4a formed in 28% yield. Similarly, lb provided 3b and 4b in 18% and 42% yields, respectively, rather than the desired 2b (Scheme 1). Since formation of seven-membered ketones via cyclic acylpalladation has never been observed, the results are perhaps not surprising. Later optimization of the reaction conditions including the use of 1 atm pressure of CO has... 

Clardy carried out the Baeyer-Villiger oxidation of the seven-membered ketone... 

When the rhodium-catalyzed reaction of bicyclopropyl 56 was performed under latm of CO, carbonylative annulation occurred, producing a seven-membered ketone ring (Scheme 2.45) [65]. 

An equatorial attack of TMS-diazomethane is the first step of the Bp3-promoted ring-expansion reaction of six-membered ketones to give frani -seven-membered ketones (Scheme 60)... 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

Preparation of spirooxaziridines from cyclic ketones poses no problems nor does oxaziridine synthesis from cyclic Schiff bases, which was preferably carried out with pyrro-lines to give, for example (245) (59JCS2102) and, in connection with tranquilizer synthesis, with heterocyclic seven-membered rings to give, for example, (246) (63JOC2459). 

The reactions of enamines with aldehydes (329,350) are noteworthy in that they provide a route to the monobenzylidene derivatives of five- to seven-membered eyclic ketones as well as a method for the formation of other a, 9-unsaturated carbonyl compounds, in fair to good yields. The condensation of benzaldehyde with enamines is also involved in the formation of 3,5-dibenzylpyridine from piperidine and benzaldehyde (191-193). 

The formation of a-acetoxyketones by oxidation of enamines with thallic acetate has been studied in detail (27) and found to be of preparative value (80 % yields) particularly in five- and six-membered-ring ketone derivatives. Enamines of linear or seven-membered-ring ketones were oxidized also, but at very much slower rates. Enamines of aldehydes with a-hydrogen substituents underwent self-eondensations during the oxidation reactions. Lead tetraacetate was less satisfactory as an oxidizing agent. 

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

Seven-membered carbocycles are also available from the reaction of alkenylcarbene complexes of chromium and lithium enolates derived from methyl vinyl ketones [79b] (Scheme 65). In this case, the reaction is initiated by the 1,2-addition of the enolate to the carbene complex. Cyclisation induced by a [1,2]-migration of the pentacarbonylchromium group and subsequent elimination of the metal fragment followed by hydrolysis leads to the final cyclo-heptenone derivatives (Scheme 65). 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

This process, called Ruzicka cyclization, is good for the preparation of rings of six and seven members and, with lower yields, of Cg and Cio to C30 cyclic ketones. Not much work has been done on the mechanism of this reaction. However, a free-radical mechanism has been suggested on the basis of a thorough study of all the side products. ° ... 

Bisulfite addition products are formed from aldehydes, methyl ketones, cyclic ketones (generally seven-membered and smaller rings), a-keto esters, and isocyanates, upon treatment with sodium bisulfite. Most other ketones do not undergo the reaction, probably for steric reasons. The reaction is reversible (by treatment of the addition product with either acid or base ) and is useful for the purification of the starting compounds, since the addition products are soluble in water and many of the impurities are not. ... 

A regio-and stereoselective rearrangement of N-phenylspirooxaziridines 274 was reported by Suda [51e]. A Mn(III) tetraphenylporphyrin complex [Mn(tpp)Cl] served as activating reagent. Six- to eight-membered ketones 273 (n = 1,2,3) were converted into the corresponding seven- to nine-membered lactams 275 and... 

In order to construct the thiepin conjugation, the seven-membered cyclic ketones containing sulfur could be converted to either their enol ethers or enol acetates. The resulting thiepins should have a number of substituents. The first stable 3,5-diacetoxy-4-phenylbenzo[6]thiepin (15) has been obtained by Hofmann et al. from the diketone (14) by acetylation with acetic anhydride in pyridine in good yield 13). By this methodo-... 

In connection with studies on anthnalarial compounds, simpler mimics of artemisinin based on substituted 1,2,4-trioxepanes were examined. Examples include the 1,2,4-trioxepanes 152, 153 and 154, with the seven-membered ring being made by acid catalysed condensation of the appropriate ketone with the hydroxy hydroperoxide 151. Unfortunately the 1,2,5-trioxepanes were not active as antimalarials in vitro (up to 1000 nM) probably due to their resistance to Fe(II)-mediated degradation <06BMCL6124>. 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

Palladium-catalyzed bis-silylation of a,/ -unsaturated ketones using bis(disilanyl)dithiane affords seven-membered ring silyl enol ethers in high yields via 1,4-addition (Equation (48)).8,97 Application of this reaction to a,/ -unsaturated esters and nitriles gives five-membered ring 1,2-addition products in good yields (Equation (49)). 

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