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 in liquid -/-butanol reduces their normally inert 6-keto-group, producing the corresponding secondary , 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 , 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 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 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 [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 (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. Each of the diols (7 -1 0 ) gave a distinct 3',6-bis(3,5-dinitroben- zoate) ester; the most readily accessible isomer 9 M- was further characterised as the 3',6-bis-/?-ni- trobenzoate (9 b), and a monotoluene-/?-sulpho- nate (9c). Oxidation by chromic acid reconverted each of the four diols into the parent dione 1. 582 F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes further metal reduction to the alkoxide (iv) and and the 3'-ax-ketol 5, and on further correlations final protonation from the least hindered side gives within this ring system, involving groups of com­ the individual stereoisomers of the product (v). pounds varying in the structure of their cyclohexa­ The stereochemical aspects of this mechanism none moiety [1, 5]. are founded on extensive classical data on the steric 13C NMR spectral data are also available [23] course of reactions in the comparable for ketones, alcohols and monoolefms (including bicyclo[ 2.2.1]heptane (norbornane) ring system methylated examples) of the isolated bicy- [19, 20], especially the analogous reduction of ke­ clo[2.2.2]octane ring-system. They provide limited tones: Thus, nor-camphor A, the exo-side of which guidance in identifying the doublet of the hydrox- is more accessible to reagent attack [19], is reduced ylated C -6 centre in the spirodiisophorones (see to endo-norborneol B [21], while camphor C, with below), but being otherwise not comparable, are its exo-face screened by the 7-dimethyl group, not helpful in the allocation of the signals of the bi- yields by endo-approach predominantly exobor- cyclo-octane moiety once this forms part of the ex­ neol D [19, 22], tended spirane structure. However, the obvious close correspondence of the present numerical data with those of the mapped spectra of the mod­ el ketols 5, 6 and the diketone 1 [1,4,5] and its 3'- monoxime [4] provide an acceptable basis for the assignment and correlation of the new spectra. The interpretation of the 13C NMR spectra is ex­ A b emplified by reference to the two diols 7 and 8 de­ rived from the model 3'-ax-ketol 5 [4, 5], The near­ constancy of the signals of their skeletal carbon at­ oms except those in the immediate proximity of the structural change is evident, and resonances are particularly close for the centres more remote from C -6 (i.e. C-3,4,8 and C-2',5',6'). The replace­ ment of the strongly electron-attracting 6-keto by the hydroxyl group results in the expected shield­ ing of the adjacent carbon atoms (C-1,5), with consequent upfield displacement of their signals. In the present spiro structure, the -keto group 6 The same tendencies are apparent in the 3'-eq- set is screened from both faces (of the C -1,4,5,6- of compounds (6 vs 9 and 10). plane). Molecular models suggest that the ap­ In assigning the three doublets of the diols proach of reagent is, on balance, hindered less by (7 -1 0 ), the signal of the 3'-hydroxy-group is first the proximate 10-methyl group than by the larger identified by comparison with the reliably estab­ 5'-gem-dimethylcyclohexane moiety on the oppo­ lished resonances of the 3'-ax- and 3'-eq-hydroxy site side. Accordingly, the major (or sole isolable) groups in the reference compounds 5 and 6 (63.5 isomers are regarded to arise by protonation from and 68 ppm respectively), the structural environ­ the former direction, and formulated as the ment of which is identical with that in the present 6-endo-alcohols. The concept also accounts for the examples (7 -1 0 ). This leaves, in each case, a dou­ formation of both configurations side by side. blet in the 65-70 ppm and one in the 48-55 ppm range. Since the corresponding signals in I3C N M R Spectra bicyclo[2.2.2]octan-2-ols [23] and (nor)borneols The ,3C NMR spectra of the spirodiisophoranes [24, 25] appear consistently in the higher of these now described are displayed in the usual manner two ranges (viz. 65-80 ppm), we assign these (Table I) in accordance with their proposed assign­ doublets (at 65-69 ppm) to the C -6 centre of the ments. These are ultimately based on the unequi­ bicyclo[ 2.2.2]octane moiety; their resonances dif­ vocal identification by the INADEQUATE tech­ fer only slightly for the endo- and exo-configura- nique [4] of the signals of the parent 3', 6-diketone 1 tion of the 6-hydroxy group (in 7 and 8; 9 and 10). F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spiroeyclohexanes 583

Table I. I3C-NM R Spectra of bicyclo[2.2.2]octane-2-spirocyclohexanes and their assignment3.

C om p oun d 6 C -l C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9

5° 60.2 d 36.9 s 50.41 33.5 s 46.9 t 215.8s 32.0 s 50.3 t 26.8 q 7 55.1 d 39.6 s 50.41 33.6 s 43.1 t 69.0 d 33.1 s 50.1 t 28.0 q 8 47.3 d 38.8 s 50.6 1 34.3 s 4 1 .8 1 69.4 d 33.1 s 49.7 t 27.9 q 6C 64.3 d 37.5 s *49.5 t 33.9 s +46.7 t 215.8s 31.8 s *49.2 t 26.9 q 9 55.3 d 39.2 s *49.6 1 34.3 s 42.0 t 65.8 d 32.8 s *49.3 t 28.1 q 10 47.3 d 38.8 s *49.5 t 34.2 s 41.8 t 65.0 d 33.0 s 50.6 t 28.0 q lc 67.6 d 40.5 s * 46.01 33.5 s *46.2 t 212.6 s 31.5s 49.0 t 26.5 q 3 54.0 d 41.2s 45.9 t *34.3 s 41.6 1 69.1 d 32.6 s 49.5 t 27.9 q 4 54.6 d 42.8 s 44.5 t 34.0 s 41.7 t 68.9 d 32.5 s 49.41 27.7 q

C om p oun d 6 C-10 C -l 1 C-2' C-3' C-4' C-5' C -6' C-7' C-8 ' eq ax

5C -32.6 q +34.6 q 52.3 t 63.5 d 47.6 t 32.5 s 49.2 t 34.7 q 29.7 q 7 33.0 q 35.2 q 52.1 t 65.3 d 48.7 t 32.2 s 49.2 t 37.8 q 30.0 q 8 33.0 q 35.8 q 53.1 t 65.0 d 48.2 t 32.8 s 49.5 t 33.5 q 29.5 q 6C -33.0 q +34.4 q 51.3 t 68.3 d +46.6 t 33.1 s 47.5 t +34.6 q 28.0 q 9 33.3 q 34.4 q 51.9 t 69.5 d 47.6 t 32.7 s 44.9 t 36.5 q 28.8 q 10 33.1 q +35.5 q 53.2 t 69.5 d *49.2 t 32.6 s 48.2 t + 35.8 q 29.5 q r 33.4 q 34.1 q 54.0 t 209.6 s 53.5 t 36.7 s 50.9 t 32.8 q 28.0 q 3 •33.1 q 36.3 q 37.8 t 160.7 s 43.8 t *34.7 s 52.6 t +33.0 q 29.1 q 4 33.5 q 36.3 q *55.7 t 214.3 s *54.3 t 36.4 s 51.9 t 33.1 q 29.1 q

* + Signals may be exchanged horizontally. a The figures refer to the proton noise-decoupled chemical shifts and first order multiplicities of the individual sig­ nals. Shieldings are given in <5 (ppm) downfield from SiMe4. - The solvent was deuteriochloroform. b The numbering of the carbon atoms is given in structure 1. c The spectra of the parent 3', 6-diketone 1, and of the 3'-ax- (5) and 3'-eq-ketol (6) have been reported before [4, 5] and are here included for direct comparison with the new spectra. Those of 1 and 5 were assigned by the INADEQUATE technique [4],

In contrast, the chemical shifts of the remaining In the interpretation of the spectra of the higher-field doublets, allotted by exclusion to C-l, 6-hydroxy-3'-ketone 4 and its 3'-oxime 3, the are influenced significantly by the spatial position 3',6-dione 1 (and its 3'-monoxime) [4] serve as of the adjacent 6-hydroxyl group (ca. 55 and 47 models for identifying the signals of their cyclo- ppm for endo- and exo-, respectively). Attention is hexanone carbons, and the present diols for those drawn, however, to the fact, that the same configu­ of their bicyclo[2.2.2]octane-moiety. Correspond­ rational differences in the detached bicy- ing chemical shifts match closely and require little clo[2.2.2]octane structure (E, F) are conversely as­ further comment. The resonances of the high-field sociated with signal shifts at the hydroxyl-bearing C-l doublets (at ca. 54 ppm) correspond to the en- carbon (C-2) rather than the adjacent bridgehead do-configuration of the 6-hydroxy group, in ac­ position (C-l). The necessity of an interchange of cord with the favoured steric course of this reduc­ the C-l and C-6 doublets (of compounds 3, 4, tion. The apparently deviating chemical shifts of 7 -1 0 ) is therefore not entirely discounted. C-2',3' and 4' of 3 are in fact characteristic of ox- imes and nearly coincident with those of the model 3'-oxime 2 [4],

Conclusion The keto function of bicyclo[2.2.2]octanes un­ dergoes the normal reactions of alicyclic ketones [6], but is remarkably unreactive, once the bicy- C-1 C-2 E : 2-trans OH 40.1 65.0 ppm clooctane framework forms part of the extended F : 2-cisOH 39.1 71.4 ppm methylated spirodiisophorane structure (e.g. 1, 2, 584 F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes

5, 6). This inertness may possibly be ascribed to monia (250 ml), followed by sodium (6.9 g, obstruction to the approach of reagents by the 0.3 g.atom), introduced in small pieces over a proximate 7-dimethyl group as well as the screen­ period of 6 h. Initially the deep-blue colour of the ing cyclohexane-moiety, especially its 3'-ax-methyl liquid faded and disappeared rapidly, but later substituent. persisted and was finally discharged within 4 -6 h. On spontaneous evaporation of the ammonia, The Birch reduction now described provides the there remained a suspension of a granular white first general method of modifying this otherwise material. This was extracted with ether, the ex­ inert 6-keto function: the readiness with which it tracts washed with M hydrochloric acid, then wa­ responds to this reaction may therefore be trace­ ter, to neutrality, and the solvent removed under able to the smaller steric requirement of the one- reduced pressure. The residue gave on crystallisa­ electron transfer that initiates the reduction proc­ tion from light petroleum, microprisms (4.4 g, ess (see mechanism, above). The significance of 38%) o f3, m.p. 210-212 °C. steric factors in this context could be assessed by IR (KBr): 3300 vs br (OH), 2960-2880 vs br, parallel experiments involving “nor”-spirodiiso- 1460 s, 1435-1425 ms (CH3,CH-,), 1655 ms phorones (e.g. G, the dimer of 3-methylcyclohex- (C = N), 1390 ms, 1370 s (CMe2), 1290 ms, 1040 s, 990 s, 970 s, 940 m, 865 m cm“1. 2-enone [2]); the fact that in contrast to the 3', 6-di- ketone 1 [4], this yields a 3',6-bis-hydrazone [2], C,8H3IN 02 (293.45) holds out some promise for the utility of such an Calcd C 73.7 H 10.65 N 4.8, approach. Found C 73.8 H 10.8 N 4.8. (b) Reoxidation to 3'-oximinospirodiisophor-6- one (2): A solution of 3 (0.9 g, 3 mmol) in anhy­ drous tetrahydrofuran (100 ml) was treated with benzeneseleninic anhydride [13] (1.09 g, 3 mmol), and the pale-yellow liquid boiled under reflux for 2.5 h. After the removal of most of the solvent un­ der reduced pressure, the residual liquid was stirred into ice-water (100 ml). The resulting yel­

G low gum which failed to solidify was isolated by ether extraction, and the extracts washed with 25% lead acetate solution, then water, to neutrali­ ty. The nearly colourless oil remaining on removal Experimental of the solvent was dissolved in light petroleum The equipment used in determining the spectral (8 ml); the solution slowly deposited prisms characteristics of the compounds is specified in (0.43 g, 48%) of 2, identified by mixed m.p. 177— Part 1 [4], This also gives details concerning sol­ 179 °C and IR spectrum [4], vents, reagents and general procedures, and lists (c) Reoxidation to spirodiisophora-3',6-dione (1): abbreviations that continue to be used. A solution of 3 (0.29 g, 1 mmol) in glacial acetic The reductions requiring the use of liquid am­ acid (10 ml) was treated dropwise with Kiliani’s monia were performed in a three-neck flask fitted 10% chromic acid [10] (3 ml, 2.5 mmol), and stir­ with a solid carbon dioxide condenser. When reac­ ring at room temperature continued for 1 h. The tion was complete and the deep-blue colour of the reddish-brown liquid was treated with water (50 mixture had faded and permanently disappeared, ml) and 10% aqueous sodium sulphite (10 ml), the ammonia was allowed to volatalise sponta­ and the resulting dark-green liquid extracted with neously from the stirred reaction mixture at room ether. The washed neutral extracts gave, on temperature. removal of the solvent, a pale-yellow oil; its solu­ tion in light petroleum deposited prisms (70%) of 1, identified by mixed m.p. 114-115 °C, and IR 6-endo-Hydroxy-3'-oximinospirodiisophorane spectrum [4], [ 6-endo-Hydroxy-4,5' ,5' ,7,7-pent amethy 1-3'-oximi- nobicyclof 2.2.2]octane-2-spirocyclohexane] (3) (a) Preparation: To a stirred solution of 3'-oxi- 6-endo-Hydroxyspirodiisophor-3'-one (4) minospirodiisophor- 6-one (2 [4], 11.64 g, 40 A stirred solution of 3 (2.1 g, 7 mmol) in ethanol mmol) in /-butanol (100 ml) was added liquid am­ (35 ml), treated with aqueous sodium bisulphite F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes 585

(40% w/v, 10 ml) was boiled under reflux for 5 h, deep-orange prisms, m.p. 208-211 °C (from the precipitated solid (sodium bisulphite) filtered ethanol). off and rinsed with a little ethanol; the combined C24H34N40 5 (458.57) filtrate was evaporated under reduced pressure to Calcd C 62.9 H 7.5 N 12.2, small volume, and stirred into ice-water (300 ml). Found C 62.8 H 7.5 N 12.2. The precipitated white gum (which solidified im­ perfectly) was collected, rinsed with water, air- (c) 6-(3,5-Dinitrobenzoate)ester (4c): A solution dried and dissolved in light petroleum (15 ml). The of 4 (1 mmol) in pyridine (10 ml), treated with 3,5- separating product (m.p. 95-105 °C, 1.33 g, 67%) dinitrobenzoyl chloride (0.35 g, 1.5 mmol) gave, by gave, on further crystallisation from methanol- the procedure described for the 3',6-diols (see be­ light petroleum (5 ml each, recovery 70%), mas­ low), a buff solid (0.5 g), which gave on crystallisa­ sive plates of 4, m.p. 115-119 °C. tion from acetone (15 ml), yellow platelets (0.36 g, IR: 3420 vs (OH), 2950-2910 vs, 2860 s sh, 1460 77%) of 4c, m.p. 206-208 °C. ms, 1425 ms (CH3,CH,), 1690 vs (CO), 1390 m, IR: 3100 m (Ar), 2950-2910 s, 2860 ms sh, 1465 1370 ms (CMe2), 1050^ 1040 s d (C -O of OH), s (CH3,CH2), 1720 vs, 1710 vs (CO, ring and acyl), 1350 ms, 1295 s, 1250 m, 1140 m, 980 m, 940 m 1630 s (C = C), 1550 vs, 1350 vs (N -O ), 1275 vs cm-1. (C -O , ester), 1165 s (C -N ), 730, 720 s (1,3,5-tri­ sub. Ar) cm-1. C I8H30O2 (278.4) Calcd C 77.65 H 10.9, C,5Hr N20 7 (472.55) Found C 77.2 H 10.9. Calcd C 63.5 H 6.8 N 5.9, Found C 63.7 H 6.9 N 5.9. Reconversion into spirodiisophora-3',6-dione (1): The 3',6-ketol 4 (0.28 g, 1 mmol) gave on chromic acid oxidation [ 10] by the procedure specified for Spirodiisophora-3',6-diols (7—10) the oxime 3 (see above), prisms of 1 (0.18 g, 64%), Birch reduction of 3'-ax (and eq) -hydroxyspirodi- identified by mixed m.p. 114-115 °C and IR spec­ isophor-6-ones (5,6 [5]) trum [4], Reconversion into the oximino-alcohol 3: A solu­ 3'-ax-6-endo (and exo)-Dihydroxyspirodiiso- tion of 4 (0.28 g, 1 mmol) in pyridine (10 ml), treat­ phoranes (7 ,8) ed with hydroxylamine hydrochloride (0.21 g, 3 To a stirred solution of 3'-ax-hydroxyspiro- mmol) gave, by the standard procedure [4], prisms diisophor- -one (5 [5]) (8.34 g, 30 mmol) in (72%) of 3, m.p. 210-212 °C (from light petrole­ 6 /-butanol (50 ml) was added successively liquid um). ammonia (250 ml) and sodium (5 g, 0.22 g-atom), introduced in small pieces over a period of 3 h. The 6-endo-Hydroxyspirodiisophor-3'-one (4): derivatives deep-blue colour of the liquid faded and disap­ peared within 1 h. On spontaneous evaporation of (a) Semicarbazone (4a): A solution of 4 (0.28 g, the ammonia, a suspension of a white gelatinous 1 mmol) and semicarbazide hydrochloride ( 0.35 g, material remained. This was extracted with ether, 3 mmol) in ethanol (10 ml) - pyridine (2 ml) was the extracts washed with M hydrochloric acid and refluxed for 3 h, distilled to half volume under re­ water to neutrality, and the solvent removed under duced pressure, and added to ice-water (80 ml) - reduced pressure. The residual pale yellow oil was concentrated hydrochloric acid (2 ml). The result­ dissolved in light petroleum (25 ml); the successive ing precipitate gave microprisms (0.25 g, 72%) of crops of solid gave, on further recrystallisation, the 4a, m.p. 215 °C (decomp.) (from ethanol - light following products: petroleum). (i) The initial less soluble fractions gave, on crys­ C l9H33N30 7 (335.50) tallisation from ethanol, rhombic prisms of 3'- Calcd C 68.0 H 9.9 N 12.5, ax-6-endo-dihydroxyspirodiisophorane 7, m.p. Found C 67.8 H 9.9 N 12.1. 156-159 °C (3.82 g, 45%). IR: 3380 vs vbr (OH), 2965-2850 vs, 1470 s br (b) 2,4-Dinitrophenylhydrazone (4b): A solution of 4 (1 mmol) and 2,4-dinitrophenylhydrazine (CH3,CH2), 1390 ms, 1365 s (CMe2), 1055 vs (C -O of OH), 1030 vs, 985 vs, 900 w, 840 w cm-1. (0.20 g, 1 mmol) in ethanol (15 ml) - concentrated hydrochloric acid (1 ml) was boiled under reflux CI8Hr O2 (280.45) for 30 min, then distilled to half-volume. The Calcd C 77.1 H 11.5, separated derivative 4b (0.41 g, 89%) formed Found C 76.8 H 11.4 M 280. 586 F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes

(ii) The more soluble later and final fractions Spirodiisophora-3',6-diols (7—10): 3',6-Bis(3,5-di- gave the 6-exo-isomer 8, forming needles, m.p. nitrobenzoate) esters 171-174 °C (from light petroleum) (1.89 g, 23%). A solution of the respective 3',6-diol (7-10) IR: 3350 vs vbr (OH), 2980-2860 vs, 1475 — (0.28 g, 1 mmol) in pyridine (10 ml), treated with 1460 vs (CH3,CH2), 1385 ms, 1365 s (CMe2), 1050 3,5-dinitrobenzoyl chloride (0.58 g, 2.5 mmol), vs (C -O of OH), 1320 s, 1290 s, 1245 s, 1225 m, was kept at 100 °C for 30 min, then stirred into ice- 1175 s, 1140 ms, 1080 s, 1040-1020 vs, 990 vs, 950 water (100 ml) containing concentrated hydro­ m, 840 m, 680 mw cm-1. chloric acid (10 ml). The precipitate was crystal­ Found C 76.7 H I 1.4 M 280. lised from acetone-light petroleum, giving pale- buff to yellow microprisms of the derivative (of 7-10). The data for that of 9 are as follows: m.p. 153-155 °C (decomp., sintering from 125 °C); yield 64%. 3'-eq-6-endo (and exo)-Dihydroxyspirodiiso- IR (identical for all four derivatives): 3100 m phoranes (9,10) (Ar), 2980-2880 s, 1465 s (CH 3CH2), 1720 vs, The foregoing Birch reduction procedure was 1285 vs br (C O -O ester), 1635 m (C = C), 1550 vs, applied to 3'-eq-hydroxyspirodiisophor-6-one (6 1350 vs (N-O), 1170 vs (C-N), 730-720 vs d [5], 8.34 g, 30 mmol) in liquid ammonia - (1,3,5-trisub.Ar), 1075 m, 960 m, 925 m, 775 w /-butanol, but with addition of less sodium (3.5 g, cm-1. 0.15 g-atom) over a longer period (5 h), the deep- C32H36N40 I2 (668.67) blue colour fading more slowly (6 h). The standard Calcd C 57.5 H 5.4 N 8.4, work-up gave a pale-yellow viscous oil, which was Found C 57.7 H 5.5 N 8.3. dissolved in light petroleum and gave the following products: The data for the other three derivatives are as (i) The less soluble initial fractions gave mi­ follows: croprisms (4.75 g, 57%) of the 3'-eq- 6-endo-isomer Deriv.of m.p. Found Yield 9, m.p. 142-145 °C (from ethanol). 10 200-203 °C C 57.9 H 5.7 N 8.2 90% IR: 3400 vs vbr (OH), 2960-2850 vs, 1470 s br 7 234-237 °C C 57.4 H 5.5 N 8.2 48% 8 243-244 °C C 57.7 H 5.4 N 8.3 80% (CH3,CH2), 1390 m, 1370 s (CM e2), 1050 vs (C -O of OH), 1290 ms, 1170 ms, 1030 s, 985 s, 935 m, 905 mw, 870 w em -1. Found C 77.1 H 11.7 M 280. 3'-eq-6-endo-Dihydroxyspirodiisophorane (9): Further derivatives (ii) The filtrates and motherliquors from the 3',6-Bis(p-nitrobenzoate) ester. The use, in the above gave, on spontaneous evaporation, a soft re­ foregoing procedure, of 9 (0.28 g, 1 mmol) and sidue: its solution in acetone (20 ml) slowly de­ /7-nitrobenzoyl chloride (0.56 g, 3 mmol), gave a posited crystalline solid at 0 °C, which gave on re­ crude product (0.73 g), which formed lemon-yel- crystallisation from light petroleum, microprisms low prisms (0.48 g, 83%) of the derivative, m.p. (2.31 g, 28%) of the 3'-eq-6-exo-isomer 10, m.p. 185-186 °C (from acetone - light petroleum). 150-152 °C. IR: 2950-2870 vs, 1470 ms (CH 3,CH2), 1720 vs IR: 3300 vs vbr (OH), 2960-2850 vs, 1460 s br (CO, acyl), 1610 ms (C = C), 1535 vs, 1360-1350 s (CH3,CH2), 1390 m, 1365 s (CMe2), 1050 vs (C -O br (N -O ), 1285 vs br (C -O , ester), 1120-1100 vs of OH), 1285 m, 1180-1170 m, 1150 ms, 1130 w, d (C -N ), 720 vs (1,4-disub.Ar) cm "1. 1030 vs, 1015 s, 985 s, 935 w, 905 w, 870 w, 850 w c m '1. C 2H38N2O s (578.67) Calcd C 66.4 H 6.6 N 4.8, Found C 77.2 H 11.6 M 280. Found C 66.2 H 6.6 N 4.8. Reoxidation to spirodiisophora-3',6-dione (1): Monotoluene-p-sulphonate ester: A solution of 9 Each of the foregoing diols (7-10) was subjected (0.21 g, 0.75 mmol) in pyridine (8 ml), treated with to Kiliani oxidation [10] as described for 3 (see toluene-/?-sulphonyl chloride (0.48 g, 2.5 mmol) above), which gave, in each case, prisms of 1 (from was kept at room temperature for 12 h, then light petroleum), identified by mixed m.p. 114- stirred into ice-water (80 ml) containing concen­ 115 °C and IR spectrum. The yields ranged from trated hydrochloric acid (8 ml). The precipitated 70 to 80%. white gum, which failed to solidify, was isolated by F. Kurzer-Z. Kapadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes 587

ether-extraction and crystallised from light petro­ Birch Reduction of Spirodiisophor-6-one 11 [5] leum. On storage at 0 °C, the solution slowly de­ The 6-monoketone 11 ([5] 2.62 g, 10 mmol) was posited massive prisms (0.24 g, 73%) of the deriva­ subjected, by the standard procedure, to the action tive, m.p. 128-130 °C. of sodium (2.3 g, 0.1 g.atom) in liquid ammonia IR: 3620 s (OH), 2970-2870 vs, 1465 s (CH3, (250 ml) - /-butanol (10 ml). The crude product CH2), 1600 ms (C=C), 1365 vs, 1190 vs, 1175 vs was a yellow oil that failed to solidify, or crystallise (R S 02), 855 s, 840 s, 815 vs ( 1,4-disub.Ar) cm“'. from the usual solvents, even at 0 °C. Its solution C25H380 4S (434.65) in light petroleum (b.p. 40-60 °C) was filtered Calcd C 69.1 H 8.8, through alumina (2.5x30 cm) and the eluate col­ Found C 68.9 H 9.0. lected in three fractions. Removal of the solvent from each gave 6-endo-hydroxyspirodiisophorane 3'-eq-6-endo-Dihydroxyspirodiisophorane (9). 12, again as uncrystallisable faintly yellow liquids, Alternative synthesis by LAH reduction of 4 identical in their IR spectra (total, 2.4 g, 90%). A solution of 4 (0.70 g, 2.5 mmol) in anhydrous IR (NaCl plates): 3450 vs br (OH), 2960-2860 ether (75 ml) was added to a stirred suspension of vs, 1465, 1455 s d (CH3,CH2), 1720, 1710 w d (ves­ lithium aluminium hydride (0.38 g, 10 mmol) in tigial CO?), 1390 m, 1370 ms (CMe2), 1040-1020 s the same solvent at such a rate that the reaction cm-1. mixture effervesced gently. It was boiled under re­ Cl8H320 (264.45) flux for 2.5 h, the excess of the reducing agent de­ Calcd C 81.75 H 12.2, stroyed by the slow addition of water and 3 M hy­ Found C 81.5 H 12.6. drochloric acid. The product was isolated by ether extraction, and crystallised from ethanol-light pe­ The 6-hydroxyspirane was reoxidised by the troleum, giving elongated prisms (75%) of 9, iden­ standard procedure using Kiliani’s 10% chromic tified by mixed m.p. 140-143 °C, IR spectrum, acid [10] to the 6-ketone 11 (65%), identified by and its bis(3,5-dinitrobenzoate) ester. mixed m.p. 62-63 °C and IR spectrum [5], The crude product of an identical experiment (10 mmol), dissolved in anhydrous pyridine (40 ml) and treated with 3,5-dinitrobenzoyl chloride Birch Reduction of Spirodiisophora-3' ,6-dione (1) (2.8 g, 12 mmol), was kept at 100 °C for 1 h, then stirred into ice-water containing concentrated hy­ To a solution of the parent diketone 1 (11.04 g, drochloric acid (40 ml). The soft precipitate (which 40 mmol) in anhydrous ether (25 ml) - liquid am­ failed to solidify) was isolated by ether extraction. monia (250 ml), /-butanol (10 ml, 110 mmol) was Crystallisation from acetone - light petroleum added, followed by sodium (6.9 g, 0.30 g.atom), gave colourless platelets (3.7 g, 80%) of the 6-(3,5- added in small portions over 4 h. Stirring of the dinitrobenzoate) ester of 12, m.p. 154-155 °C. liquid was continued for a further 4 h; the usual IR: 3100 m (Ar), 2970-2890 vs, 1465 s br isolation procedure by ether extraction gave a (CH3,CH2), 1720 vs, 1280 vs (C O -O ester), 1630 pale-yellow viscous oil. Its solution in light petro­ ms (C = C), 1555, 1540 vs d, 1345 vs (N -O ), 1170 leum (20 ml) deposited successively the following vs (C -N ), 730, 720 vs d (1,3,5-trisub. Ar), 1075 m, fractions: (i) prisms of the 3'-ax-6-endo-diol 7, m.p. 975 m, 925 m cm-1. 157-159 °C (1.34 g, 12%); (ii) needles of the 3'-ax-6-exo-diol 8, m.p. 170-172 °C (0.42 g, 4%), C,5H34N20 6 (458.56) both epimers identified by mixed m.p. and IR Calcd C 65.5 H 7.5 N 6.1, spectrum. Complete evaporation of the filtrates re­ Found C 65.5 H 7.5 N 6.2. sulted in an uncrystallisable oil. This oil showed only vestigial keto-absorption Recovery o f the 3' ,6-dione 1 from its 3'-mono-oxime 2 (at 1740-1700 [4,5]), showing that both 3'-and {model experiment for reaction 3 —■* 4) 6-keto-functions had been reduced. - It was To a stirred solution of the oxime 2 (1.45 g, re-oxidisable to the 3',6-dione 1 in 56% yield by 5 mmol) in ethanol (50 ml), 40% aqueous sodium Kiliani oxidation [10] by the standard procedure. bisulphite (50 ml) was gradually added at room - It was convertible, by the action of 2.5 moles of temperature. The reaction mixture, containing 3,5-dinitrobenzoyl chloride, under the standard separated white solid, was boiled under reflux for conditions, into prisms (35%) of the 3',6-bis(3,5- 3 h, cooled, and the inorganic solid filtered off. dinitrobenzoate) ester of 9, m.p. 155 °C (after sin­ The filtrate was evaporated to ca. half-volume and tering from 118 °C) (from acetone). the residual turbid liquid added to water. The re­ 588______F. K u rze r-Z . K apadia • Bicyclo(2.2.2)octane-2-spirocyclohexanes suiting resinous precipitate solidified at 0 °C and We are again indebted to Mrs. J. E. Hawkes and gave, on crystallisation from ethanol - light petro­ Mr. J. Cobb, of the University of London NMR leum, prisms (1.15 g, 85%) of the 3',6-dione 1, Spectroscopy Service at King’s College, London, identified by mixed m.p. 112—113 °C and IR spec­ for the production of the 13C NMR spectra. trum [4].

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