Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives via radical pathways

Copper(II)-salt-promoted oxidative ring-opening reactions of bicyclic cyclopropanol derivatives were investigated. The regioselectivities of these processes were found to be influenced by the structure of cyclopropanols as well as the counter anion of the copper(II) salts. A mechanism involving rearrangement reactions of radical intermediates and their competitive trapping by copper ions is proposed.


Introduction
Radical ions are key intermediates in electron-transfer (ET) reactions of organic molecules [1][2][3][4][5] and they often undergo fragmentations to yield free radicals and ions [6][7][8][9][10]. The ensuing reaction pathways followed by the resulting radicals are governed not only by their intrinsic nature but also by the nature of co-existing redox reagents. In principle, radical intermediates in ET-promoted reactions have a tendency to participate in further ET processes to generate ionic species when stoichiometric amounts of redox reagents are used (Scheme 1) [1][2][3][4][5][6][7][8][9][10]. In contrast, radical intermediates formed by a photoinduced ET (PET) are less likely to undergo these secondary reactions, because steady-state concentrations of PET-generated redox Scheme 1: Comparison of fragmentation reaction pathways of organic radical ions generated under the redox-reagent-promoted ET and PET conditions. Scheme 2: Using rearrangements of radicals and ions to distinguish mechanistic pathways for ET-reactions. reagents are low [11][12][13][14][15][16][17][18][19]. When radical intermediates and ions derived from their precursor radical ions undergo different rearrangement reactions, it is often possible to distinguish respective reaction pathways of radicals and ions by examining the product distributions of the reactions of substrates that contain appropriate probe moieties (Scheme 2).
Careful examination of the reaction of probe II with FeCl 3 revealed that a small quantity of the spirocyclic ketone was also formed [23,28]. This observation prompted us to explore the possibility that the free radical rearrangement route becomes more predominant when oxidizing reagents weaker than Fe(III) are used to promote the reaction. Based on a consideration of the redox potentials of Fe and Cu ions (Eº in H 2 O, V versus NHE), +0.77 for Fe(III)/Fe(II), +0.17 for copper(II)/copper(I) [31], we chose to explore the use of copper(II) reagents in this effort. Although various ET reagents have been employed to promote reactions of cyclopropanol derivatives [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], the employment of copper(II) reagents to induce reactions has not been extensively studied [36,39]. In the investigation described below, we have explored copper(II)-salt-promoted oxidative ring-opening reactions of selected bicyclic cyclopropanol derivatives.

Results and Discussion
In the initial phase of this effort, we examined the reaction of cyclopropyl silyl ether 1a (0.40 mmol) with copper(II) acetate, Cu(OAc) 2 , (1.1 equiv) for 1 h at room temperature (Scheme 4). Under these conditions no reaction takes place, which we attribute to the steric bulk of the silyl substituent causing interference in the reaction of the substrate with Cu(OAc) 2 . In accordance with this reasoning, we found that inclusion of n-Bu 4 NF (1.2 equiv) in the reaction mixture led to a reaction that completely consumes 1a and produced the expected spirocyclic ketone 2, albeit in low yield, and spirocyclic ketone 3 possessing an exo-methylene moiety as the major product. Interestingly, ketone 3 was previously observed as a product of the DCA-BP-sensitized PET reaction of 1a in the presence of Cu(OAc) 2 [25]. Only a trace amount of ring-expanded enone 4 along with small amounts of desilylated alcohol 1b (ca. 8%) and ketone 5 were detected in the product mixture by using 1 H NMR analysis. Treatment of 1a (0.19 mmol) with n-Bu 4 NF (2.0 equiv) in THF for 1 h followed by hydrolysis gave a mixture of 1b and 5 (12:88). Therefore, 5 may not result from the copper(II)-oxidation reaction.
Based on the above observations, we anticipated that sterically less hindered cyclopropanols would more efficiently undergo copper(II)-induced oxidation reactions than the corresponding silyl ethers. To probe this prediction, cyclopropanols 1, prepared by SmI 2 -promoted intramolecular Barbier reaction of the corresponding α-bromomethyl cycloalkanones 6 [28], were subjected to reactions promoted by various copper(II) salts, CuX 2 (Scheme 5). The results of the reaction of 1b with Cu(OAc) 2 (Scheme 6) are summarized in Table 1. As expected, this process produces ketone 3 as the major product along with both 2 and ringexpanded enone 4 as minor products. Moreover, the order of addition of 1b and Cu(OAc) 2 does not significantly affect the product distribution (compare Table 1, entry 1 to entry 2). An exploration of solvent effects revealed that MeCN is more suitable than DMF while the solubility of Cu(OAc) 2 is higher in the latter solvent (compare Table 1, entry 1 to entry 5). In entry 5 (Table 1), ring-opened ketone 5 was obtained. In other experiments (see below), the formations of 5 (see Table 2), and other ring-opened ketones 22 (see Table 3) and 25 (see Scheme 11) are also observed. These products might be formed by deprotonation of the corresponding cyclopropanols 1. It should be noted that THF is not an appropriate solvent for this reaction ( Table 1, entry 8), a finding that is in contrast to the previous observation that ether is a better solvent than MeCN and DMF in Cu(BF 4 ) 2 -promoted ring-opening reactions of cyclopropylsilyl ethers [39]. When CH 2 Cl 2 is employed as solvent, formation of 2 becomes more efficient while the yield of 3 remains moderate (Table 1, entry 7). Although the effect of the quantity of Cu(OAc) 2 on the reaction is not great, a decrease in the amount of Cu(OAc) 2 causes a small increase in the yield of 2 and a decrease in the yield of 3 (compare Table 1, entry 3 to entry 1). By using more Cu(OAc) 2 , the yield of 3 is increased in DMF (compare Table 1, entry 6 to entry 5) while it is decreased in MeCN (compare Table 1, entry 4 to entry 2).
Studies of the effect of the counter ion on copper(II)-promoted reactions of 1b (Scheme 8) gave the results summarized in Table 2. While no reaction occurred when copper(II) acetylacetonate, Cu(acac) 2 , is used, ( Table 2, entry 1), copper(II) 2-ethylhexanoate, Cu(ehex) 2 , serves as an effective oxidant in transforming 1b to 3 in a yield that is comparable to the process promoted by Cu(OAc) 2 (compare Table 2, entry 2 to entry 3). Noticeable amounts of 2 are also generated in this reaction. When CuCl 2 is employed to oxidize 1b, only ring-expanded ketones 4 and 14 are produced along with a lesser amount of chloro ketone 15, and competitive formation of 2 and 3 does not occur ( Table 2, entry 4). An increase in the amount of CuCl 2 causes a slight increase in the conversion of 1b and the total yield of ring-expanded products 4 and 14 (compare Table 2, entry 5 to entry 4). Interestingly, CuCl 2 (1.1 equiv) could also promote the reaction of silyl ether 1a to produce 4 (23%), 14 (4%) and 15 (3%) at 89% conversion of 1a. Although the origin  of 15 is uncertain, one possibility is that it is formed by halogen substitution of unconverted bromide 6b to 1b by SmI 2 . The formation of chloro ketone 23 (see Table 3) may be similarly explained. Finally, reaction of 1b with Cu(OTf) 2 leads to formation of ring-expanded products 4 and 16 and a negligible amount of 2 ( Table 2, entry 6). Acetamide 16 is probably produced in this process through a Ritter reaction between cation 13 and the solvent acetonitrile (Scheme 9).
Hypothetically, both the Lewis acidity and oxidizing ability of CuX 2 should depend on the basicity of the counter ion (X − : conjugate base of HX). Based on the acidity order HX, TfOH > HCl > AcOH ~ 2-ethyl hexanoic acid > acetylacetone [53,54], it is possible to assign Cu(acac) 2, which is ineffective in promoting the reaction, as the weakest oxidant. On the other hand, CuCl 2 and Cu(OTf) 2 induce reactions that follow a different pathway from those promoted by copper(II) carboxylates. These observations suggest that a rapid equilibrium does indeed exist between isomeric radical intermediates 9 and 10 (Scheme 7) and that the thermodynamically less stable isomer 9 undergoes fast hexenyl-radical cyclization leading to the formation of 11 in reactions promoted by copper(II) carboxylates. On the other hand, a fast oxidation of the more stable isomer 10 by stronger oxidants such as CuCl 2 or Cu(OTf) 2 occurs to give the stable tertiary carbocation 13, which is then captured by Cl − or MeCN.
In order to explore the generality of the proposed counteranion-dependent reactivity switch in the nature of copper(II)promoted reactions of 1, the pentenyl-substituted cyclo- propanol 1c was employed as the substrate (Scheme 10 and Table 3). A major product of the reaction of 1c promoted by Cu(OAc) 2 was observed to be the exo-methylene containing spirocyclic ketone 19 (Table 3, entry 1), which is produced in the DCA-BP sensitized PET reaction of silyl ether of 1c in the presence of Cu(OAc) 2 [25]. Contrary to the expectation that a base could assist the deprotonation of the complex between copper and 1c (similar to 7 in Scheme 7), the addition of pyridine was found to decelerate the reaction (Table 3, entry 2). This observation suggests that coordination of pyridine to copper reduces the oxidizing ability of Cu(OAc) 2 . Cu(ehex) 2 was also effective to give 19 although the yield was relatively low (  Table 3, entry 5).
As described above, observation of the occurrence of hexenylradical cyclization processes serves as good evidence for the involvement of radical intermediates in mechanistic pathways for reactions of 1b and 1c. In order to gain more information about these processes, we explored an oxidation reaction of substrate 1d, which does not contain an alkene tether and whose reaction pathway, thus, cannot involve radical intermediates that undergo hexenyl-radical cyclization. We observed that reaction of the methyl-substituted cyclopropanol 1d with Cu(OAc) 2 leads to formation of the ring-expanded enone 25 as a major product along with a trace amount of ketone 26 (Scheme 11).
The Cu(OAc) 2 -promoted reactions of 1c and 1d are compared in Scheme 12. The ring-expanded tertiary alkyl radical 27, formed as an intermediate in the reaction of 8 (R = (CH 2 ) 3 CH=CH 2 ), undergoes rapid 5-exo hexenyl cyclization along the route for the production of spirocyclic ketone 19.
Thus, oxidation of 27 followed by deprotonation to give enone 20 is a minor contributor. If an external bond cleavage of 8 occurs, cyclization of heptenyl-radical moiety in the resulting primary alkyl radical (not shown in Scheme 12) is expected. However, the exo-cyclization of heptenyl radical is two orders of magnitude slower than that of the hexenyl radical [55]. In contrast, because no competitive radical-rearrangement process exists, the corresponding radical intermediate 28 formed from 8 (R = Me) undergoes sequential oxidation and deprotonation to give enone 25 as a major product.

Conclusion
Various copper(II) salts promote ring-opening reactions of bicyclic cyclopropanol derivatives. Using substrates that possess hexenyl moieties, we observed that the nature of the counter anion of copper(II) salts has a significant impact on the product distributions. The results suggest that reaction pathways followed by radical intermediates derived from these substrates are strongly influenced by post ring-opening steps.
Thus, cyclopropane bond cleavage, which is reversible, does not serve as a product-determining step if a rapid follow-up reaction like hexenyl-radical cyclization does not exist. The results show that by using a proper choice of copper(II) salts it is possible to control the reaction pathways followed by radical and ionic intermediates derived from the initially formed Lewis base-acid complexes if the radicals and ions are capable of undergoing different rearrangement reactions.
Preparation of cyclopropanols 1: Cyclopropanol derivatives 1 were prepared from the corresponding bromo ketones 6 by using SmI 2 following previously reported procedures [25,28]. Silyl ether 1a was prepared by the treatment of alcohol 1b with TMSCl and Et 3 N. The synthesized alcohols 1b, 1c and 1d were directly used for the reactions owing to their instabilities during silica-gel chromatography.  Table 1 and Table 3). The resulting mixture was stirred under N 2 at room temperature for 1 h, diluted with water and extracted with Et 2 O. The extract was washed with water, saturated aqueous Na 2 S 2 O 3 , saturated aqueous NaHCO 3 , and brine, dried over anhydrous MgSO 4 , and concentrated in vacuo giving a residue that was subjected to TLC (AcOEt:n-hexane 20/1), and 3 (59.3 mg, 0.28 mmol, 70%) and 4 (~5 mg, ~0.02 mmol, ~5%) were obtained. Other reactions were performed in a similar manner. Because cyclopropanols 1 have a tendency to partially decompose during silica-gel chromatography, their conversion in reactions was determined by using 1 H NMR analysis of the crude reaction mixtures. When product isolations were not performed, yields were also determined by 1 H NMR, and crude yields are reported in some cases.