Bicyclo nonan-3-ones synthesis

Graindorge and co-workers" reported the synthesis of 2,5,7,9-tetranitro-2,5,7,9-tetraaza-bicyclo[4.3.0]nonane-8-one (113) (K-56, TNABN) from the nitration of 2,5,7,9-tetraazabi-cyclo[4.3.0]nonane-8-one dihydrochloride (112) with dinitrogen pentoxide in absolute nitric acid, the latter obtained from the condensation of urea with l,4-diformyl-2,3-dihydroxy-piperazine (111) in hydrochloric acid. Treatment of (112) with nitronium tetrafluoroborate in nitromethane results in the nitration of the piperazine ring nitrogens only and the isolation of (114) in 86 % yield (Table 5.2). 

Studies by the submitters have indicated that the procedure reported here is the preferred method for the preparation of bicyclo[3.2.1]octan-3-one. It employs readily available, inexpensive reagents, and the overall yield is good. In addition, the method can be used for the synthesis of the difficultly accessible next higher homologues of bicyclo[2.2.2]oct-2-ene as well as for derivatives of norbornene. Bicyclo[3.2.2]nonan-3-one and l-methylbicyclo[3.2.1]octan-3-one have been prepared by a similar route6 in 60% and 47% yields, respectively (based on adduct). However, the preferred procedure for the formation of the dichlorocarbene adduct of bicyclo[2.2.2]oct-2-ene is that of Seyferth using phenyltrichloromethylmercury. Even in this case the overall yield is moderate (37%). 

Barboni, L., Gabrielli, S., Pabnieri, A., Femoni, C., and Ballini, R. 2009. Diastereoselective, one-pot synthesis of polyfnnctionahzed bicyclo[3.3.1]nonanes via an anionic domino process. Chemistry-A European Journal, 32 7867-70. 

The excision of the keto bridge present in tricyclo[5.3.1.1 ]dodecan-l 1-one taken from the work of Cha et al. on synthetic studies of taxol deserves special mention. Highly functionalized derivatives of bicyclo]5.3.1]undecane are obtained using the DIB/I2 system (Eq. 11) [38]. The fragmentation of a related derivative of oxabicyclo[3.3.1]nonan-9-one is used by the same authors as a key step in the synthesis of cK-2,8-disubstituted oxocanes (Eq. 12) [39]. 

As a useful alternative to carbonylation, the Brown dichloro-methyl methyl ether (DCME) process has been effectively used for the synthesis of 9-alkylbicyclo[3.3.1]nonan-9-ols. 2 The ketone bicyclo[3.3.1]nonan-9-one (eq 29) has also been prepared from a hindered B-aryloxy-9-BBN derivative, with simple B-alkoxy-9-BBN derivatives failing to undergo this process. However, most borinate esters are smoothly converted to ketones through this process, including germa- and silaborinanes (eq 30). In these cases, 9-BBN-H provides the essential 1,5-... 

Domino reduction/aldol cydization was applied for the synthesis of ( )-fredericamydn A 44, a potent antitumor and antibiotic agent, by Kelly et al. [18] in 1988 (Scheme 9.10). DIBAL-H (diisobutylaluminum hydride) reduction of lactone 45 afforded an intermediate 46 having both enolate and aldehyde. Subsequent cychzation via aldol reaction gave a diastereomeric mixture of spiro hydroxy ketone 47, which was further converted into ( )-fredericamycin A 44 by sequential organic transformations. A similar strategy was employed by Mehta et al. [19] for the synthesis of bicyclo[3.3.1]nonan-9-one core of hyperforin, an antidepressant. 

A soln. of 2,2-bis(chloromethyl)acetophenone in acetonitrile added dropwise during 0.5 hr. to N-cyclohex-l-enylpyrrolidine, triethylamine, and acetonitrile, stirring continued 1 hr., the solvent removed, first at atmospheric pressure and finally in vacuo, water added to the resulting immonium salt, and stirred 12 hrs. at room temp. -> 3-benzoylbicyclo[3,3.1]nonan-9-one. Y 81%. F. e. s. H. Stetter, K. D. Ramsch, and K. Elfert, A. 1974, 1322 bicyclo[4.n.l]enones cf. W. C. Still, Synthesis 1976, 453 ring closure with 3-chlor-2-enamines cf. Synth. Meth. 31, 838. 

The free radical addition of a thiol to carbon-carbon double or triple bonds is a well-established reaction. It represents one of the most useful methods of synthesizing sulfides under mild conditions. Since its discovery [5] and its much later formulation as a free-radical chain reaction (Scheme 1) [6], the anti-Markovnikov addition of thiols to unsaturated compounds has been the subject of many reviews [8, 9]. These reactions were originally initiated by thermal decomposition of peroxides or azocompounds, by UV irradiation or by radiolysis [10]. (An example of addition of 1-thiosugar to alkenes initiated by 2,2 -azobisisobutyronitrile (AIBN) [11] is reported in equation (1)). More recently, organoboranes have been used as initiators and two examples (Et3B and 9-bora-bicyclo [3.3.1.] nonane) are reported in equations (2) and (3) [12,13]. Troyansky and co-workers [14a] achieved the synthesis of macrocycles like 12- and 13-membered sulfur-containing lactones by the double addition of thiyl radical to alkynes. An example is depicted in equation (4). The same approach has also been applied to the construction of 9- and 18-membered crown thioethers [14b]. The radical chain addition of thiyl radicals to differently substituted allenes has been considered in detail by Paste and co-workers [15], who found that preferential attack occurs at the central allenic carbon and gives rise to a resonance-stabilized ally radical. The addition of benzenethiol to allenic esters has been reported and the product formation has been similarly inferred (equation (5)) [16]. 

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