Crystalline Ketones

The utility of the solid-state photodecarbonylation of crystalline ketones was recently demonstrated in the total syntheses of two natural products, where the key step is the solid-state reaction. The first example involves the synthesis of the sesquiterpene ( )-herbertenolide [80] by the solid-state decarbonylation of cyclohexanone 189, followed by cyclization of the photoproduct 190 (Scheme 2.46). With precursor 189 obtained by simple methods and a solid-state reaction carried out to 76% conversion, herbertenolide was obtained in good overall yield in a record number of steps from commercial starting materials. With a similar synthetic strategy, samples of the natural product (i)-a-cuparenone were obtained in about 60% overall yield from 191 by a very succinct procedure that included four simple steps and a solid-state reaction at — 20 °C [81]. 

Ng, D., Yang, Z., and Garcia-Garibay, M.A. (2004) Total synthesis of ( )-herber-tenolide by stereospecific formation of vicinal quaternary centers in a crystalline ketone. Organic Letters, 6, 645-647. 

Mortko, C.J. and Garcia-Garibay, M.A. (2006) Engineering stereospecific reactions in crystals synthesis of compounds with adjacent stereogenic quaternary centers by photodecarbonylation of crystalline ketones, in Topics in Stereochemistry, Vol. 25 (eds S.E. Denmark and J.S. Siegel), John Wiley Sons, Hoboken, NJ, pp. 205—253. 

The pioneer in phenolate radical coupling was Pummerer. In 1925 he showed1 that one electron oxidation of />-cresol using potassium ferricyanide afforded a nicely crystalline ketonic dimer of the radical in up to 25 % yield. Pummerer s ketone, as it became known, was considered to result from the coupling of two p-cresol radicals to give the dienone 1. This then underwent spontaneous cyclization to furnish 2. As proof of the structure... 

Speyer and Rosenfeld on reduction of 14-bromocodeinone [xxn] with sodium hydrosulphite obtained an amorphous halogen-free base that was converted by hot alkali to a crystalline, ketonic, tertiary base Cx8H2i03N that they suggested was dihydro-i/ -codeinone [40], but its properties do not agree with those of the latter [7] and its nature remains obscure. 

The last examples demonstrated that the solid-to-solid photoinduced decarbonylation of crystalline ketones can have an important role in natural product synthesis and in green chemistry due to the high yield, the fewer steps involved and the easy scale-up of such reactions. 

Experimental details solid-state photolysis 957 A crushed crystalline ketone (279a or 279b) ( 5 mg), suspended in hexane (3 ml), was placed between Pyrex microscope slides, sealed in a polyethylene bag under nitrogen and irradiated with a medium-pressure mercury lamp (450 W) at a distance of 10 cm from a water-cooled Pyrex immersion well (Figure 3.9) at either 20 or — 20 °C (cryostat ethanol bath). The product, a chiral organic salt, was derivatized to the corresponding methyl ester by treatment with excess diazomethane and purified by column chromatography. 

S)-Diester E prepared from (.S )-citronellal was cyclized under the Dieckmann conditions to give (S)-F. Its hydrolysis and decarboxylation were followed by methylation to furnish (S)-G, whose Robinson annu-lation yielded (-)-A (= 81 ). The structure of the crystalline ketone (-)-A was solved by X-ray analysis, and then (-)-A was further converted to (-)-B, (-)-C and (—)-D. Although C (= 83 ) and D (= 84 ) possess the absolute configuration given to the dextrorotatory natural pheromone components, our synthetic C and D were levorotatory in hexane. In addition, none of them showed pheromone activity.48... 

The natural 104 must therefore be either (35,115)- or (35,ll/ )-104. All the stereoisomers of 104 showed IR spectra (as chloroform solutions) identical to each other. When their IR spectra were measured as nujol mulls, the stereoisomeric and crystalline ketones showed small differences in the spectra due to the differences in their crystal structures. Thus, the natural 104 showed a IR spectrum identical to those of... 

The cinchona ketones resemble o-diketones in that they enolize very readily. For this reason, freshly prepared solutions of the crystalline ketones exhibit the phenomenon of mutarotation, as the ketone of one configuration is converted, through the enol, to an equilibrium mixture of C.8 epimers. Enol derivatives, such as the benzoyl (LXVI, R = C HiCO) and toluenesulfonyl (LXVI, R = CtHtSO ) esters are readily prepared. The cleavage the ketones by sodium ethoxide and alkyl nitrites (95) has already been mentioned (Section I) here we may point out that the reaction involves the attack of the anion of the enol (LXVI, R = H) on the nitrite, followed by a cleavage reaction (LXVII — LXXI) similar to that which is familiar in the cases of -diketones and /3-keto esters. 

It might be expected that oxidation of cinchonine and of cinchonidine would furnish epimeric Q-keto compounds. Both substances, however, yield the same crystalline ketone, cinchonidinone (CXXIII) (75, 153). 

The JNr,0(3)-diacetyl derivative of compound 152 has been synthesized independently from solafloridine (41) by Nagai and Sato (279). They obtained the crystalline ketone 144 via 143. Reduction of the C=N bond in 144 was effected with zinc and acetic add. Subsequent acetylation gave the 22,26-acetylepimino compound 158. Treatment of 158 with base and reacetylation afforded Ar-acetyl-3-deamino-3j3-acetoxysolanocapsine (159) (279). 

The decision to develop pyrifenox meant a challenge to establish an economical synthesis suited for large scale production. The crystalline ketone 5 was considered a key intermediate in a synthesis of the oily end product Its lab synthesis described earlier in Scheme 2 was tmsatisfactory becatise a very variable yield of only 30-50% could not be surpassed in the phase transfer coupling of 3 with 3-chloromethyl-pyridine. Attention was therefore given to alternative procedures to produce 5 as illustrated in Figure 8. 

Concentrations of the benzene-ether washings at 30 should yield 1.6 g (49% based on 5 g of the crystalline ketone) of chromatographically pure material as a colorless, slightly viscous liquid. 

Suppression of ot-Cleavage by P-Phenyl Quenching in Crystalline Ketones... 

Choi, T, Peterfy, K., Khan, S. I. and Garcia-Garibay, M. A., Molecular Control of Solid State Reactivity and Biradical Formation in Crystalline Ketones, /. Am. Chem. Soc., 118, 12477, 1996. 

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