Decan-2,4-dione

Syntheses of hydantoin compounds from 1,3,5-triaza-7,7,9,9-tetramethylspiro[4.5]decane-2,4-dione (61) were also planned, since derivatives of this type showed high activity compared to oxazoli-dones and 4-oxoimidazolidines. Further, three different types of... 

Triethoxysilyl propyl)-7,7,9,9-tetramethyl-l,3,8-triazaspiro[4.5]-decane-2 4-dione Figure 9.10 Structure of previously synthesised N-halamine compounds [79]... 

Bipyirolidine]-2,2 -dione, B-70125 Cyclo(prolylalanyl), C-80194 > l,3-Diazaspiro[4.5]decane-2,4-dione, D-60056... 

For example, full-scan mass spectra of buspirone contain an abundant [M+H]+ ion signal with little detectable fragmentation. The product ion spectrum reveals product ions and neutral losses associated with diagnostic substructures of buspirone (Figure 6.25). The product ion at mlz 122, for example, is indicative of the pyrimidine substructure. The presence of this ion in the product ion spectrum of a metabolite indicates a structure that contains the pyrimidine substructure. Similarly, the mlz 180 product ion is diagnostic of the azaspirone decane substructure, and the neutral loss of 164 (producing the mlz 222 product ion) is diagnostic of the butyl azaspirone decane dione substructure. 

To assist with the MS/MS structure identification, the gross substructure of buspirone is categorized into profile groups (Kerns et al., 1995). Profile groups directly correlate specific product ions and neutral losses with the presence, absence, substitution, and molecular connectivity (Lee et al., 1996) of specific buspirone substructures and their modifications. The profile groups of buspirone are identified with abbreviations that correspond to the three specific substructures azaspirone decane dione (A), butyl piperazine (B), and pyrimidine (P). Substituted substructures are designated with a subscript ( ), and a dash (-) denotes substructure connectivity. Thus, the buspirone molecule is represented by A-B-P. The As-B-P designation... 

Table 6.11 illustrates a representative buspirone metabolite structure database. Information on the structure, molecular weight, UV characteristics, RRT, and product ions of metabolites obtained from rat bile, urine, and liver S9 samples are compiled. Using this format, the predominant buspirone metabolite profile groups, As-B-P, A-B-Ps, and As-B-Ps are easily recognized. These profile groups indicate azaspirone decane dione and pyrimidine as metabolically active sites of attack and the presence of multiple substitution sites on each of these substructures. In many cases, the profile groups indicate the occurrence of metabolic reactions on more than one substructure. 

The concept can be illustrated by the identification of the metabolites of the anxiolytic drag buspirone [1, 12]. Buspirone (Figure 10.2b) is considered as a combination of three subgroups the azaspirone decane dione (A), the butyl piperazine (B), and pyrimidine (P). Whereas buspirone itself is annotated at A-B-P, a metabolite with a substitution in the pyrimidine ring can be indicated as A-B-P. It was found that in buspirone the azaspirone decane dione and the pyrimidine part of the molecule are prone to (multiple) substitution, such as hydroxylation, hydroxylation and methoxylation, and glucuronidation. The loss of the complete substructure is also observed. In this way, a total number of 26 buspirone metabolites were identified and categorized. 

Intramolecular H-abstraction from Saturated Carbon. Urry and coworkers i83,i64> have reported reactions of 2,3-pentanedione, 3,4-hexanedione, 4,5-octanedione, 2,7-dimethyl-4,5-octanedione, 5,6-decane-dione, and 1,2-cyclodecanedione. Intramolecular H-abstraction from a gamma carbon atom, followed by intramolecular radical coupling produced cyclobutanolones (65, 98) in high yield. The cyclization product 98... 

Spiro[4.5]decane-l,4-dione and Ethyl 4-Cyclohexyl-4-oxobutanoate... 

CN 8-[4-[4-(2-pyrimidinyl)-1 -piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride... 

Bis [N-(3-Dimethylcarbamoxy-o -picolyl)-N,N-dimethylammonio]decane-2,9-dione Dibromide... 

Nonan-2-ol Decanoic acid Decane-2,5-dione 3-Methylphenol... 

MDL 73005 = 8,2 (2,3-dihydro-l,4-benzodioxin-2yl) methylamino-ethyl-8-azaspirol (4,5) decan-7,9-dione NAN 190 = l-(2-methoxyphenyl) 4-(4(2-phthalimido)entyl-piperazine)... 

Marchand and co-workers ° synthesis of 5,5,9,9-tetranitropentacyclo[5.3.0.0 .0 °.0 ] decane (52) reqnired the dioxime of pentacyclo[5.3.0.0 .0 °.0 ]decane-5,9-dione (49) for the incorporation of the four nitro groups. Synthesis of the diketone precursor (48) was achieved in only five steps from cyclopentanone. Thus, acetal protection of cyclopentanone with ethylene glycol, followed by a-bromination, and dehydrobromination with sodium in methanol, yielded the reactive intermediate (45), which underwent a spontaneous Diels-Alder cycloaddition to give (46). Selective acetal deprotection of (46) was followed by a photo-initiated intramolecular cyclization and final acetal deprotection with aqueous mineral acid to give the diketone (48). Derivatization of the diketone (48) to the corresponding dioxime (49) was followed by conversion of the oxime groups to gem-dinitro functionality using standard literature procedures. 

Buspirone Buspirone, 8-[4-[4-(2-pyrimidyl)-l-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of l-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of l-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-l-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51-55]. 

A few other oxidations involve no C=C bond cleavage. Cti-9-octadecene gave 9.10-diketo-octadecane with RuO /aq. Na(C10)/( Bu N)Br/CHjCl2 [324], while cyclo-octene was oxidised by RnCyaq. Na(10 )/DCE to 8-oxo-octanal [325]. Oxidation of A -, and A - steroids using RuO /aq. Na(10 )/acetone gave cis-diols, diones and acids [303] while RuO /aq. Na(10 )/CHjCyCH3CN oxidised 2,3-dichlorodecene to decane-2,3-dione [326]. 

Since the advent of multipulse-NMR techniques, more detailed 1H-NMR studies on methylcyclo-hexanes547, phenylcyclohexanes548, neomenthyl halides549 and bicydo[4.4.0]decanes 550 551 have been undertaken. The two diastereomeric 4-fm-butyl-7,ll-diphenylspiro[5.5]undecane-1,9-diones (3) and (4) could be identified unambiguously552, and substituted spirodioxane cyclohexanes such as, 9- m-butyl-2-methyl-1.3-dioxaspiro[5.5]undecane (5), have also been investigated553,554. 

Better yields of cyclobutanones were obtained with steroidal ketones.85 86 In the reaction of 5a-cholestan-3-one (5) with diazocyclopropane, spiroannulation to give 6 (30%) dominated insertion to give 7 (24%), and with 3/ -acetoxy-5a-pregnane-l 1,20-dione (8) only spiroannulation to give 9 (60%) was observed.85 A comparable high yield (78%) of a spiroannulation product 11 was obtained with trispiro[2.0.2.0.2.1]decan-10-one (10).84 It is apparent that efficient formation of oxaspiropentanes as direct precursors of cyclobutanones only takes place with sterically hindered ketones. 

Preference for the cleavage of the C3-C4 bond was observed for the hydrogenolysis of bishomocubanes.40-43 In an effort to synthesize barettane and dihydrobarettane, the hydrogenation of the bishomocubane bis(dimethyl acetal) 12 a over 10% palladium on charcoal at 119 atmospheres in methanol produced in quantitative yield tetracyclo[5.2.1.02-6.04,8]decane-5,10-dione bisfdimethyl acetal) (13a). Similar hydrogenation of bishomocubane bis(ethylene acetal) 12b in ethanol afforded tetracyclo[5.2.1.02-6.04,8]decane-5,10-dione bis(ethylene acetal) (13b), also in quantitative yield.42... 

On heating above 200 °C, 2,5-bis(trimethylsiloxy)tricyclo[4.4.0.02 5]decan-7-ones undergo a [2 4- 2] cycloreversion to form either 1,2-divinylcyclohexanes or 1,5-bis(trimethylsiloxy)cyclodeca-1,5-dienes. These are not stable at elevated temperatures and rearrange. After aqueous acidic workup, bicyclo[5.3.0]decene-2,5-diones 13 are isolated.45... 

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