Cycloheptane-1,3-dione

Typical cyclic diketones such as dimedone, cyclopentane-1,3-dione, cycloheptane-1,3-dione or cyclic 3-oxocarboxylic acid derivatives such as 4-hydroxycoumarin, 4-hydroxyquinolone, 4-hydroxypyrone, 4-hydroxypyridone or tetronic acid are aminocyclopropylated directly. 

This reaction was also successfully applied in the production of smaller (six-membered) and larger ring cycloalkenones 1,6-bis(trimethylsiloxy)bicyclo[4.1.0]heptane (17) was cleaved under similar conditions to give cycloheptane-1,3-dione (18). ... 

Preparation of cycloheptane-1,3-dione. Indian chemists19 have prepared this dione from dihydroresorcinol (1) by conversion into the monoethylene ketal (2) followed by reaction with ethyl diazoacetate catalyzed by anhydrous zinc chloride. They note that the quality of zinc chloride is important consistently good yields were obtained with material supplied by Riedel-de Haen. The product (3) is converted into the dione (4) by hydrolysis and decarboxylation with aqueous potassium hydroxide. 

Lithiated bis(methylthio)(trimethylsilyl)methane undergoes a Michael addition with cyclohept-2-enone to give (309) after hydrolysis. 4-Chloro-2,6-bis(methylthio) thiopyrylium perchlorate condenses with P-diketones in the presence of triethylamine to give thiopyranylidene derivatives, e.g. cycloheptane-1,3-dione gave (310). ... 

A variety of synthetic studies focused on clinical CNS candidate 1 are described. The original medicinal chemistry route (Scheme 1) is described, and issues which precluded its scale-up are discussed. An Ullman route to 2-fluoro-4-methoxyaniline (Scheme 4) was developed to avoid a non-selective nitration reaction. The first GMP bulk canpaign utilized a ring expansion strategy via a dichloroketene [2+2] cycloaddition (Scheme 6) to prepare cycloheptane-1,3-dione. While effective on laboratory scale, several issues arose upon scale-up the mechanistic basis for these issues was determined to be competition between desilylation and dechlorination of dichlorocyclobutanone 22 (Scheme 11). These issues led us to develop a third synthesis of 1, in which c3reloheptane-1,3-dione is avoided. Two variants of this Friedel-Crafts strategy are described (Schemes 13 and 14). 

With the requisite aniline in hand, we turned our efforts to developing a scaleable route to fiiran acid 9 (Scheme 1). As discussed previously, concerns with the oxymercuration reaction motivated us to seek an alternative route to cycloheptane-1,3-dione, which we knew was a viable precursor to the requisite furan acid (Scheme 2). Of the known syntheses of cycloheptane-1,3-dione, 4) one which intrigued us was Noyori s report 4d) of a palladium-mediated... 

In seeking a new route to furan acid 9, we felt that it would be advantageous to avoid cycloheptane-1,3-dione as an intermediate. The reasons for this were varied, but included ... 

Modest stability of the diketone. Cycloheptane-1,3-dione is a colorless oil. We foimd that crude san5>les of this material tended to discolor upon storage above 0 °C. This color could be removed by distillation or filtration through silica gel, but with associated loss of material (distillation was particularly inefficient, 60-65% recoveries were typical). This is in marked contrast to cyclohexane-1,3-dione, which is a stable, crystalline, white solid. Interestingly, the NMR spectra of these two materials in CDCI3 are also quite different the 6-meiribered diketone is completely enolized, whereas the 7-membered diketone exists exclusively in the diketo form. Transannular interactions or some other form of ring strain are presumably responsible for this difference in enolization propensity, and this correlates with the greater reactivity/instability of the 7-... 

Few options to significantly improve the current synthesis. The three step synthesis of cycloheptane-1,3-dione outlined in Scheme 6 is quite short, and we felt it was unlikely that we would be able to significantly shorten this sequence, or add crystalline intermediates. To the latter end, the dibromo and tert-butyldimethylsilyl analogs of 22 were prepared, but were not crystalline, and offered no significant advantage over the dichloro/TMS ether 22. 

Bicyclo[3.2.0]heptane-l,5-diols are oxidized by Jead(IV) acetate35,36 or sodium periodate35 to give cycloheptane-1,4-diones. With lead(IV) acetate in acetic acid at 100 C substrates with a hydroxy group in -position to one of the newly formed carbonyl groups eliminate water to afford a,/ -unsaturated cycloheptanediones,36 and / ,y-double bonds migrate to the apposition.35... 

The reaction of 1,2-dicarbonyl compounds with amidrazones, semicarbazide, thiosemicarbazide and aminoguanidine has also been used for the synthesis of condensed 1,2,4-triazines. Cyclohexane-, cycloheptane- and cyclooctane-1,2-diones (489) with amidrazones (453) afford the cycloalkatriazines (490) (78HC(33)189, p.66l). 

The synthesis of 3,3,7,7-tetramethylcycloheptyne (64), a carbocyclic analogue of 55, has also been performed. The bishydrazone (63) derived from tetramethyl-cycloheptane-l,2-dione (62) was oxidized with lead tetraacetate and 64 was obtained together with 65, 66, 67 and 68. The last compound (68) is a dimer of 64 with... 

The generation of alkoxides in large-ring cycloalkanones results in the formation of relatively stable bicyclic hemiacetals. Thus, treatment of 70 with sodium borohydride results in the generation of 71 a, in equilibrium with its hydroxyoctanone tautomer, while treatment with phenyllithium gave the stable hemiacetal 71b (Scheme 3). Similar reactions were observed with cycloheptane- 1,4-dione and cyclooctane-1,5-dione however, no transannular hemiacetal formation was observed for hydroxycydohexanones [83]. 

In 2007, an interesting strategy for the generation of the enolate in a decarboxylative allylation was demonstrated by Schulz and Blechert. The enolate as well as the 7t-allylpalladium complex were formed in a decarboxylative de Mayo ring expansion reaction from 85 [107] and could be trapped in an asymmetric allylic alkylation (AAA) (Scheme 12.45). This allowed for the first time the preparation of enantioenriched substituted cycloheptane-1,4-dione and cyclooctane-l,5-dione derivatives 86 [108]. 

Cycloheptane-1,2-dione dioxime (heptoxime) (CyH2 202N2)... 

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