Cyclizations Producing Hydrindanones with Two Methyl Groups at the Juncture Positions Mediated by Samarium Diiodide and Electrolysis

One-electron reductive intramolecular cyclization of enones with ketones or aldehydes mediated by samarium diiodide and electrolysis to afford cis-trimethyl- hydrindanolones. The reactions gave selectivities ranging from 1:1 to 100:0 depending on the conditions.


Introduction
Samarium diiodide has been used for many synthetic reactions [1][2][3][4] and the mechanism of its reactions has also been studied [5,6]. We are interested in preparing bicyclic compounds such as perhydroindenes [7,8], perhydronaphthalenes [9], and guaianes [10] and have published some results in this area. Compounds bearing methyl groups at the juncture positions are interesting from the synthetic point of view. For example deoxopinguisone (1) [11,12] and -pinguisene (2) [13,14] ( Figure 1) have four methyl groups in the bicyclo [4.3.0]nonane framework, all in a -orientation; two of them are at the ring juncture positions, and have been synthetic targets [15,16]. We now planned to construct hydrindanone systems by 5-exo mode cyclization, although such a case involving a cascade cyclization giving one substituent at the ring-juncture position was described by Procter and his group [17,18]. Electrolysis is easy to carry out using water as a solvent, which is environmentally OPEN ACCESS benign [19,20]. We now describe the carbon-carbon bond formation reactions leading from B to A mediated by SmI 2 as well as electrolysis for the synthesis of hydrindanones ( Figure 1).

Results and Discussion
For the synthetic work we chose compounds 9 and 10 (Scheme 1), which were prepared starting from ketone 3. Several routine reactions afforded aldehyde 9 and ketone 10. This route can also be used in chiral form, because compound 3 is now commercially available and easy to prepare [21]. Scheme 1. Preparation of compounds 9 and 10.
Aldehyde 9 was subjected to reaction with SmI 2 (3 equiv.) in THF with or without additives. The results are shown in Table 1. The products were isomeric keto-alcohols 11 and 12, whose stereochemistries were established from the NOESY spectra. Without an additive, the reactions proceeded smoothly and both compounds were obtained in a ratio of 87:13 in favor of compound 11 at 0 °C (entry 1). When the reaction temperature was raised to rt (entry 2), the ratio of compound 12 increased to 31%. The yields were always good. When MeOH was added as a proton source, the ratio was about 7:3 in favor of compound 11 (entries 3 and 4). The yield varied from 47% to 58%. The reason why the yields were not so high is presumably due to the simple reduction of the double bond to give the corresponding dihydro derivatives, which were not isolated but detected in GC-MS. The ratio of 11 and 12 did not change very much when using HMPA (entries 7 and 8), however, when NiI 2 was added (entries 9 and 10) the ratio of 12 was slightly increased [22]. We next studied the reaction of ketone 10 under various conditions ( Table 2). The products were isomeric keto-alcohols 13 and 14, and a mixture of bicyclic compounds 15, whose structures were determined by spectroscopic analyses. When ketone 10 was subjected to reaction with SmI 2 without additive at 0 °C (entry 1), the products were 13 and 14 in a ratio of 84:16. In this case the major product had the hydroxy group in a -orientation as determined by the NOESY spectrum (Table 2). When the temperature was raised to rt (entry 2), the ratio of compound 14 increased. This tendency was the same as that of the aldehyde mentioned above. However, when HMPA was added, a third product 15 was also obtained (entries 5 and 6). The ratio of 15 was 40% of the products at rt from a total yield of 71% (entry 6). This product was formed by an aldol type condensation of the samarium enolate of the α,β-unsaturated enone. When NiI 2 was added, the yield was high and the ratio of compound 12 was slightly increased (entries 7 and 8) [22].
Electrolysis does not use organic solvents and expensive reagents, but rather water and electric power. In order to compare the selectivity, compounds 9 and 10 were subjected to electrolysis conditions as shown in Table 3. The yields were moderate and the ratio was 11:12 = 62:38 in the case of aldehyde 9. The results were not very different from those of samarium iodide reduction. However, in the case of ketone 10, only -alcohol 13 was formed selectively (entry 2). Comparison of the half-wave potentials of α,β-unsaturated carbonyls with those of corresponding saturated carbonyl compounds has been extensively studied in electrochemistry [23]. The first waves of carbonyl groups, referred to as SCE., are −2.45 V (cyclohexanone), −2.25 V (methyl ethyl ketone), −1.8 V (propionaldehyde), −1.55 V (cyclohex-2-en-1-one), −1.50 V (acrolein), and −1.42 V (methyl vinyl ketone), respectively [23]. Therefore, the reduction of ,-unsaturated carbonyl moiety seems easier than that of the isolated ketone carbonyl group with electrochemistry, but the selectivity of the one-electron reduction of the carbonyl moiety using SmI 2 depends on the stereoelectronic properties of the substrate [6]. Samarium transfers one-electron to the carbonyl group of the enone moiety to form a radical anion (C to D) (Figure 2). Then one more samarium atom reduces the ketone carbonyl group and the carbon-carbon bond is formed as shown by arrow a to afford E (alkene first mechanism [2]). The hydroxy group is outside the bicyclic ring formed, because the samarium ion radical is large and the outside position is more energetically favored than inside of the ring. Thus, this configuration is more or less predominant. However, with HMPA as the additive, the reducing power must be higher than that with samarium alone [24], and the enone moiety is susceptible to reduction to afford a samarium enolate D. Then the aldol-type cyclization occurs to afford bicyclic anion radical F from D (shown by arrow b in Figure 2). Further reduction of this anion radical F and protonation afford product 15. Electrolysis also creates a similar transition state leading to similar results. The reason why compound 10 produces 13 much more selectively is not clear at this stage. However, it is assumed that solvent molecules surround the methyl ketone carbonyl group resulting in the bulkier CO (solvent) moiety with consequent protrusion outside of the ring leading to the -alcohol 13 [24].

General
IR spectra were measured on a JASCO FT/IR-5300 spectrophotometer. The 1 H and 13 C-NMR spectra were taken using a Varian Unity 600 (at 600 MHz and 150 MHz, respectively) and a Varian Unity 200 (200 MHz and 50 MHz, respectively) spectrometer. Mass spectra including high-resolution mass spectra were recorded on a JEOL JMS-700 MStation. A Chemcopak Nucleosil 50-5 column (4.8 × 250 mm) was used for HPLC (JASCO pump system). For GC-MS an Agilent GC 6890 system equipped with a MS detector 5973 was used and the product ratios were determined by the area %. Silica gel 60 (70-230 mesh, Fuji Silysia) was used for column chromatography and silica gel 60 F 254 plates (Merck) were used for TLC.

General Procedure for Smi 2 Reduction
A solution of substrate in dry THF was introduced into a solution of SmI 2 at a certain temperature. Saturated solution of sodium potassium tartrate was added and the solvent was evaporated. The mixture was extracted with ether and worked up as usual. The residue was purified by silica-gel column chromatography.

General Procedure for Electrolysis
Zn and Pt were used for the cathode and anode, respectively, with Et 4 NOTs in tBuOH-H 2 O (2:3) (20 mL), CCE at 100 mA (from −1.5 to −2.0 V vs. SCE) at rt. Work-up: benzene was added and most of the water was removed under reduced pressure. The residue was extracted with EtOAc and the organic layer was washed with Sat. NaCl solution. The organic layer was dried (MgSO 4 ), and the filtrate was evaporated to give a residue, which was purified by silica-gel column chromatography or HPLC.

Conclusions
We have developed methods to create cis-fused trimethylated hydrindanones in excellent-to high-yields by intra-molecular 5-exo cyclization mediated by SmI 2 and electrolysis.