Bicyclo[2.2.2]octane-2-spirocyclohexanes, Part 4 [1] Birch Reduction of Spirodiisophor-6-ones Frederick Kurzer* and Zakir Kapadia Royal Free Hospital School of Medicine, University of London, London NW 3, England Z. Naturforsch. 47b, 579-588 (1992); received November 4, 1991 Bicyclo[2.2.2]octane-2-spirocyclohexanes, Spirodiisophoranes, Birch Reduction Birch reduction of spirodiisophorones by sodium in liquid ammonia -/-butanol reduces their normally inert 6-keto-group, producing the corresponding secondary alcohols, the 6-hydroxy- group of which assumes the endo- or exo-configuration. 3'-Oximinospirodiisophor-6-one is converted predominantly into the 6-endo-hydroxy-compound, from which the 3',6-endo-ketol is obtainable by the action of sodium bisulphite. 3'-eq(and ax)-Hydroxyspirodiisophor- 6-one each yield a pair of stereoisomeric 3',6-diols, distinguished by their spectral characteristics and derivatives. Spirodiisophora-3',6-dione yields a mixture of the same four diols, three of which are isolable in low yield. The structure of selected compounds is correlated with their assigned 13C NM R spectra. Introduction chloride or an alcohol, is a versatile method of re­ Spirodiisophora-3',6-dione (1) is the product of ducing a variety of structures. Its scope extends the controlled dimerisation of isophorone (3,5,5- from the controlled hydrogenation of unsaturated trimethylcyclohex-2-enone). Its ready synthesis molecules including aromatic compounds, mono- form this source [2-4], together with its subse­ and polyolefins, to the reductive fission of ethers, quent transformations [1-5] provide a convenient and the hydrogenolysis of groups attached to oxy­ entry to the study of the bicyclo[ 2.2.2]octane- gen, sulphur and nitrogen [7, 8]. In addition, the 2-spirocyclohexane ring system. successful reduction of steroid ketones (incorpo­ The 3'- and 6-keto functions of the spiro struc­ rating 3, 11, 12, 16 or 17a-carbonyl functions) to ture 1, located in its respective alicyclic rings, differ the corresponding secondary alcohols [9] suggest­ in their reactivity: The 6-keto group of the tri- ed its potential applicability to the present struc­ methylated bicyclo[ 2.2.2]octane moiety is unusual­ tural pattern. Our results show that the Birch re­ ly inert, so that reactions expected to affect both duction is in fact capable of attacking, in the spiro- ketonic centres, occur exclusively at C-3' of the cy- diisophorane structure, the 6-keto function which clohexanone ring. Thus, the 6-keto group of 1 fails is resistant to the action of several other reducing to react with ketonic reagents [4], does not pro­ agents, including lithium aluminium hydride, bo­ mote a-bromination [ 1] and is unaffected by sever­ ron trifluoride etherate, as well as the Huang-Min- al reducing agents [5]; all these reactions occur lon reduction and catalytic hydrogenation [5]. normally in the isolated parent bicyclo[ 2.2.2]octa- The 6-hydroxy-group arising in the Birch reduc­ none [6]. Our aim to modify this keto group of the tion may assume two spatial positions, which, extended spiro structure 1 has been realised in the though equivalent relative to the bicyclo- Birch reaction, which has been found to reduce the [2.2.2]octane ring-system, are distinct in relation to 6-ketones to 6-secondary alcohols. the extended carbon framework, illustrated for ex­ ample, by their differing distances from the spiro Results and Discussion centre C-2 (ca. 2.8 and 3.8Ä, respectively). They The Birch reaction [7], involving the action of al­ are here designated as the endo- and exo-configu­ kali metals in liquid ammonia, usually in conjunc­ rations, the former referring to the substituent sit­ tion with a proton donor such as ammonium uated more closely, and the latter more distantly from C-2 and C- 6'. There is a tendency for one of * Reprint requests to Dr. F. Kurzer. the stereoisomers to be formed preferentially as the predominating, or indeed the sole isolable Verlag der Zeitschrift für Naturforschung, D-W-7400 Tübingen product: these are regarded as the endo-isomers, 0932-0776/92/0400-0579/$ 01.00/0 for reasons given below. 580 F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes In model experiments, the action of sodium in being unaffected by conventional acid hydrolysis liquid ammonia-r-butanol on 3'-oximinospirodi- [11], and largely decomposed in the pyruvic acid isophor- 6-one 2 [4] gave exclusively the 3'-oximi- procedure [12], The attempted use of seleninic an­ no- 6-endo-hydroxy compound 3. Its reoxidation hydride, known to regenerate ketones from their with Kiliani’s chromic acid [10] proceeded directly nitrogenous derivatives in difficult cases [13], left to the 3',6-dione stage 1, with simultaneous the 3'-oximino group intact, but reoxidised the regeneration of the 3'-keto from the 3'-oximino 6-hydroxy function, affording good yields of the group. The 6-hydroxy-3'-oxime 3 was of chief in­ known [4] 3',6-dione-3'-monoxime 2. The desired terest as a potential precursor of 6-hydroxyspiro- reaction (3—>4) was finally accomplished by the diisoophor-3'-one 4, i. e. the position isomer of the use of sodium bisulphite in aqueous ethanol [14], 6,3'-ketols 5 and 6. In the present instance, how­ which provided the 3',6'-ketol 4 in good yield. Its ever, the usual methods of converting the oximino IR spectrum resembles closely those of its position into the parent keto group failed, the oxime 3 isomers 5, 6, except for insignificant displacements 4a : Semicarbazide 9a : DNB 4b : DNP 4c : DNB 9b: NB 9c :Ts BR : Birch reduction DNP : 2,4-Dinitrophenylhydrazone KO : Kiliani oxidation DNB : 3,5-Dinitrobenzoate LAH : Lithium aluminium hydride NB : p-Nitrobenzoate S e : Seleninic anhydride Ts :Toluene-p-sulphonate F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes 581 towards lower wave numbers of its intense hy­ The reduction by lithium aluminium hydride of droxy and keto absorptions (3420 and 1690 cm“1) the 3',6-diketone 1, being confined to its 3'-keto and the C-OH-stretching bands (1040, 1050 cm“1). group, yields the 6,3'-eq-ketol 6 [5]. Applied to the The ketol 4 was reconvertible into its 3'-oxime 3 position isomer 4, which retains the active 3'-keto and was further characterised as ketonic deriva­ group, LAH reduction gave the 3'-eq-6-endo-diol tives (4a, 4b) and as the 6-(3,5-dinitrobenzoate) 9, thus confirming the identical configuration of ester (4c). Kiliani oxidation regenerated the parent the 6-hydroxy group in compounds 3 ,4 and 9. 3',6-diketone 1. The data established for the 3',6-diols 7 -1 0 The model structure most relevant for examin­ helped in elucidating the Birch reduction of the ing the Birch reaction in the present context is spi- parent 3',6-dione 1. This gave a product, liquid at rodiisophor- 6-one (11), with its unreactive 6-keto ordinary temperatures, of a mixture of presumably group as the only function. This is unaffected by all four diols (7-10): it showed the expected in­ the drastic action of hydrazine and sodium of the tense broad hydroxyl absorption in the IR range Huang-Millon reduction (by which 11 is produced (3300-3400 cm“1) and was reoxidised quantita­ from 1 [5]), but responded readily to the Birch re­ tively to the starting material 1. It was separable duction, which afforded good yields of 6-endo-hy- into the two 3'-ax-diols 7 and 8 (isolated as the free droxyspirodiisophorane (11—>12). The product is alcohols) and the 3'-eq-6-endo-diol 9 (as the dini- a viscous liquid, having the correct composition trobenzoate), but the fourth isomer 10 was appar­ and appropriate IR spectral properties, but is ad­ ently retained in a substantial uncrystallisable re­ vantageously isolated as its crystalline 6-(3,5-dini- sidual fraction. The Birch reaction thus effectively trobenzoate) ester. reduces the 3'-keto group of the cyclohexanone Preliminary experiments indicated that Birch re­ ring, but the process is not stereoselective as are duction of the parent 3', 6-diketone 1 gave a mix­ the LAH reduction and catalytic hydrogenation ture of all four possible 3',6-diols (7 -1 0 ), that [5]- proved difficult to separate on the preparative scale. The reduction of the individual 3'-ax- and 3'- Mechanism and Stereoisomerism eq-hydroxyspirodiisophor- 6-ones (5, 6) was there­ The mechanism and stereochemical course of fore first examined, with the aim of isolating the the Birch reaction has been interpreted by Barton individual stereoisomeric products. Each of the ke- [15] and by House [8 c, 16, 17] and further elabo­ tols (5, 6) gave one pair of 3',6-diols (7, 8 and rated by Huffman [18]. Application of the accepted 9, 10), which were separable by fractional crystal­ scheme in its simplest form to the present case sug­ lisation and were characterised by their spectral gests that reduction is initiated by a one-electron properties and as derivatives. In each case, the transfer from the metal, by which the ketone (i) is stereoisomer arising as the major product is re­ converted into the radical anion (ii). This is pro- garded as the 6-endo-form of the respective struc­ tonated to the alkoxy free radical (iii), which after ture (see mechanism, below). The main IR spectral feature of the diols are their intense and broad hy­ droxyl peaks centred, for each stereoisomer, at slightly different but constant positions (between 3300 and 3400 cm“1); the spectra of the isomer pair 7 and 8 are readily distinguishable, but those of 9 and 10 resemble one another closely, except for the presence of additional sharp peaks (at 1150 and i ii iii 850 cm“1) in that of the latter.