Recent Developments in the “Cation Pool” Method 1 1 2 3 Jun ─ ichi Yoshida, ＊ Yosuke Ashikari, Kouichi Matsumoto, and Toshiki Nokami 1 Department of Synthetic Chemistry & Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo ku, Kyoto 615 8510, Japan 2 ─ ─ Faculty of Science and Engineering, Kinki University 3 4 1 Kowakae, Higashi osaka, Osaka 577 8502, Japan 3 ─ ─ ─ ─ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University 4 ─ 101 Koyamacho minami, Tottori 680 ─ 8552, Japan (Received July 1, 2013; E ─ mail: [email protected]) Abstract: The “cation pool” method involves the generation and accumulation of highly reactive organic cati- ons in solution. These can serve as powerful carbon and heteroatom electrophiles in organic synthesis. Recent developments in the cation pool method including the indirect cation pool method, cation chain reactions, and integrated electrochemical ─ chemical reactions are described. react with the organic cation. The counteranions of the organic 1． Introduction cations are derived from the supporting electrolyte that is used Organic cations such as carbenium ions and onium ions for electrolysis (usually tetraalkylammonium salts). To avoid serve as useful electrophiles in a variety of reactions in organic nucleophilic attack on the cationic center, anions which are synthesis. Usually, organic cations are generated in the pres- normally considered to be very weak nucleophiles such as - - ence of nucleophiles, because the former are often very unsta- BF 4 and B(C 6F 5) 4 are used as the counter anion. Dichloro- ble, and to be utilized efciently should be trapped by the latter methane (CH 2Cl 2) seems to be the best solvent of those exami- immediately after generation. Therefore, reactions of organic ned, presumably because of its low viscosity even at low tem- cations suffer from limitations in the variety of usable nucleo- peratures. After electrolysis is complete, a nucleophile is added 3 philes. Nucleophiles that do not survive under the conditions to obtain the desired product (Scheme 1). Use of the LiClO 4/ of cation generation cannot be used. In contrast, organic CH 3NO 2 system also enables the generation and accumulation anions such as organolithium reagents and Grignard reagents of N ─ acyliminium ions by electrolysis in an undivided cell at are generated and accumulated in solution in the absence of 0 ℃. 4 Furthermore, an ionic liquid can be used as the reaction electrophiles. After the generation process is complete, an elec- media for electrochemical generation and accumulation of an 5 trophile is added to the solution of the pre ─ formed carbanion N ─ acyliminium ion pool at room temperature. to achieve a desired transformation. Thus, development of a new method that enables genera- Scheme 1. tion of organic cations in the absence of nucleophiles was strongly needed for expanding the scope of cation chemistry in organic synthesis. In this vein, we developed the “cation pool” method, 1 whereby organic cations are generated by the electro- chemical method 2 and are accumulated in solution in the absence of nucleophiles, and are then used in subsequent reac- tions with nucleophiles. This paper will provide a brief outline The “cation pool” method enables easy manipulation of of this “cation pool” method, with special emphasis on recent organic cation intermediates to achieve reactions with various developments which develop new aspects of the approach. nucleophiles, but its applicability strongly depends on the sta- bility of the cation that is generated and accumulated. To solve 2． Electrochemical Methods for Generating Organic Cations this problem, the cation ow method whereby an organic in the Absence of Nucleophiles “ ” cation is generated continuously by low temperature electroly- 2.1 Direct Cation Pool Method sis using an electrochemical ow microreactor was developed. 6 The “cation pool” method is based on the irreversible oxi- The resulting cation is immediately allowed to react with a dative generation of organic cations. In the direct cation pool nucleophile in the ow system. The use of parallel laminar ow method a cation precursor is oxidized by direct electron trans- in a ow microelectrochemical reactor enables the effective fer on the surface of the electrode. The cation precursor such generation of an N ─ acyliminium ion followed by trapping with as a carbamate is electrolyzed using an H ─ type divided cell a nucleophile. 7 The laminar ow prevents the oxidation of an equipped with an anode consisting of ne bers made from easily oxidizable nucleophile at the anode. carbon felt and a platinum plate cathode. To avoid thermal 2.2 Indirect Cation Pool Method decomposition of the cation, electrolysis should be carried out Because electrochemical reactions take place only on the at low temperatures such as -78 ℃. The resulting organic cati- surface of the electrode, the efciency of cation generation in on such as an N ─ acyliminium ion is accumulated in the solu- the “cation pool” method and the “cation ow” method is not tion in the absence of a nucleophile that we want to allow to high. To solve this problem, the indirect “cation pool” method 1 136 （ 28 ） J. Synth. Org. Chem., Jpn. 有機合成化学71-11＿06論文_Yoshida.indd 28 2013/10/21 14:52:09 was developed. 8 In the indirect “cation pool” method, as shown dialkylation products due to disguised chemical selectivity. 12 in Scheme 2, an active reagent such as ArS(ArSSAr) + is gene- Supramolecular coordination with the chiral N ─ acyliminium rated from diaryldisulde (ArSSAr) and accumulated electro- ion pool allows stereoselective addition of a cyanide ion. 13 This chemically at -78 ℃ (step 1). In the next step (step 2), it is protocol was applied to an asymmetric synthesis of ropiva- allowed to react with a precursor of a cation, such as thioace- caine and its analogues. tal, to generate a “cation pool” (-78 ℃). The resulting “cation pool” is allowed to react with a nucleophile (step 3). Because Scheme 4. the cation ─ generating reactions take place in homogeneous solution, they are complete within a few minutes even at low temperatures. Scheme 2. N ─ Acyliminium ion pools add to a C ─ C double bond Steps 2 and 3 can also be done in ow to avoid the decom- (Scheme 5). For example, their reactions with aliphatic olens position of highly unstable organic cations. The indirect “cati- and styrene derivatives followed by treatment with triethyl- on ow” method which involves the ash generation of unstable amine give [4+2] cycloaddition products. 14 Reactions with organic cations using electrochemically generated electron ─ rich olens such as enecarbamates followed by trap- ArS(ArSSAr) + in the absence of nucleophiles and their subse- ping with carbon nucleophiles such as allyltrimethylsilane give 15 quent reactions with nucleophiles in a ow system has also three ─ component coupling products. Trapping with water been developed (Scheme 3). 9 The method can be applied to the leads to carbohydroxylation of alkenes. 16 The reactions with generation and reactions of alkoxycarbenium ions at higher vinyl ethers give polymers. The use of a ow microreactor sys- temperatures. tem enables high ─ level control of the molecular weight and molecular weight distribution without using a capping agent. 17 Scheme 3. Scheme 5. The electrochemical reduction of an N ─ acyliminium ion 3． Generation and Reactions of Cation Pools as Carbon pool gives rise to the formation of the corresponding homo ─ Electrophiles coupling product, presumably via a radical intermediate. 18 3.1 N Acyliminium Ions However, a mechanism involving two ─ electron reduction to It is─ well known that oxidation of carbamates leads to the give the anion followed by reaction of this with the cation can- formation of N ─ acyliminium ions via dissociation of the C ─ H not be ruled out. 10 bond at the α position of nitrogen. Low ─ temperature electro- The electrochemical reduction of “cation pools” in the chemical oxidation of a carbamate gives a pool of the corre- presence of radical acceptors such as methyl acrylate leads to 18 sponding N ─ acyliminium ion, which can be characterized by formation of the corresponding addition products. A mecha- NMR and IR. The resulting N ─ acyliminium ion pool reacts nism involving radical formation by one ─ electron reduction of 3,11 with various nucleophiles as shown in Scheme 4. The “cation the cation followed by addition to a C ─ C double bond, reduc- pool” method serves as a powerful tool for parallel combinato- tion of the resulting radical to give the carbanion, and subse- rial synthesis, because organic cations generated by this quent protonation seems to be reasonable (Scheme 6). method are usually so highly reactive as to couple with a wide Radical addition to an N ─ acyliminium ion is also an inter- 19 range of nucleophiles. For Friedel ─ Crafts type reactions, esting feature of “cation pool” chemistry. Alkyl iodides react micromixing is quite effective for avoiding the formation of with an N ─ acyliminium ion pool in the presence of hexabutyl- Vol.71 No.11 2013 （ 29 ） 1137 有機合成化学71-11＿06論文_Yoshida.indd 29 2013/10/21 14:52:10 Scheme 6. applied to the synthesis of cephalotaxine, which is the parent compound of the antileukemic harringtonines, a group of pentacyclic alkaloids of unique structure having a nitrogen ─ containing spiro system (Scheme 9). Scheme 9. distannane to give the coupling products. A chain mechanism shown in Scheme 7, which involves the addition of the alkyl radical