Cation pool

As C-C bond formation is an important step in organic synthesis, particularly for pharmaceutical applications, it is useful to look for operation modes of chemical micro processing that allow one to carry out combinatorial chemistry investigations. As such, the serial introduction of multiple reactant streams by flow switching was identified [66,67]. The wide availability of precursors for acyiiminium cations has led to the expression cation pool [66, 67]. 

OS 30] [R 30] [P 22] The feasibility of generating a cation pool, i.e. of performing multiple reactions with various reactants, by means of electrooxidative micro flow processing was demonstrated [66,67]. The micro reaction system was consequently termed cation flow . By this means, various C-C bonded products were made from carbamates, having pyrrolidine, piperidine, diethylamine and trihydroisoquinoline moieties. These carbamates were combined with various silyl enol ethers, yielding nine products. 

Figure 4.46 Schematic of serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers [66. ...

OS 30] [R 30] [P 22] By simple flow switching, serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers was accomplished (Figure 4.46) [66, 67]. The conversions and selectivities were comparable to continuous processing using three feed streams only (see Conversion/yield/selec-tivity, above). 

Cation Pool Method and Cation Flow Method... 

In the cation pool method organic cations are generated by electrochemical oxidation and are accumulated in a solution. In the next step, a suitable nucleophile is added to the thus-generated solution of the cation. In the cation flow method organic cations are generated by electrochemical oxidation using a microflow cell. The cation thus generated is allowed to react with a nucleophile in the flow system. 

Before discussing the concepts of the cation pool method and the cation flow method, let us briefly touch on generation methods of organic cations. 

The cation pool method is based on the irreversible oxidative generation of organic cations. In the first step, the cation precursor is oxidized via an electrochemical method. An organic cation thus generated is accumulated in the solution in the absence of a nucleophile that we want to introduce onto the cationic carbon. Counter anions which are normally considered to be very weak nucleophiles are used to avoid the nucleophilic attack on the cationic center. In order to avoid thermal decomposition of the cation, electrolysis should be carried out at low temperatures such as -78 °C. After electrolysis is complete, the nucleophile is then added to obtain the desired product. The use of a carbon nucleophile results the direct carbon-carbon bond formation. 

Figure 1. Schematic Diagram for the Cation Pool Method.

Methods for the Oxidative Generation of Cations for Use in Cation Pools ... 

The W-acyliminium ion can be characterized by FTIR spectroscopy as well.9 The starting carbamate 1 exhibited an absorption at 1694 cm 1 due to the carbonyl stretching, while the V-acyliminium ion 2 generated by the cation pool method exhibited an absorption at 1814 cm 1. The higher wave number observed for the cation is consistent with the existence of a positive charge at the nitrogen atom adjacent to the carbonyl carbon. The shift to higher wave number is also supported by DFT (density functional theory) calculations. 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

Carbo-oxylation (carbohydroxylation and carboalkoxylation), whereby an organic group and an oxy (hydroxyl or alkoxy) group add across a carbon-carbon double bond or a triple bond, is an important transformation in organic synthesis. We found that the reaction of a cation pool with an alkene or alkyne followed by the trapping of the resulting carbocation by water led to the... 

Carbocationic Polymerization Using a Cation Pool" as an Initiator... 

Figure 3. Microsystem for the "cation pool initiated polymerization of...

Carbocations, carbon radicals, and carbanions are important reactive carbon intermediates in organic chemistry and their interconversions could be effected, in principle, by redox processes. With the cation pool method at hand, we next examined the redox-mediated interconversions of such reactive carbon species. 

Next, we examined the reduction of cation pools in the presence of radical acceptors. The radical that is formed by one-electron reduction of the cation is expected to add to a carbon-carbon double bond. The electrochemical reduction of 2 in the presence of methyl acrylate gave the expected addition product 16 (Scheme 9). A mechanism involving addition of radical 14 to the acrylate to generate radical 17 followed by subsequent reduction of anion 18, which is protonated to give 16 has been suggested. 

Radical addition to an Af-acyliminium ion is also an interesting feature of the cation pool chemistry. We found that an alkyl iodide reacted with an N-acyliminium ion pool in the presence of hexabutyldistannane to give coupling product 19.24 A chain mechanism shown in Scheme 10, which involves the addition of the alkyl radical to the N-acyliminium ion to form the corresponding radical cation, seems to be reasonable. The present reaction opens a new possibility for radical-cation crossover mediated carbon-carbon bond formation. 

Sequential Generation of Cation Pools Using Two Siiyi Groups... 

The cation pool method serves as a powerful tool for parallel combinatorial synthesis.25 Required for successful combinatorial synthesis are reactions of high generality to couple any desired combination of molecules we want. The cation pool method seems to be suitable for this purpose, because organic cations generated by this method are usually so highly reactive as to couple with a wide range of nucleophiles. 

A typical example of the parallel synthesis based on the cation pool method is shown in Fig 4. A solution of a cation generated by low-temperature electrolysis is divided into several portions. To each portion, different nucleophiles are added to obtain products of different coupling combinations. 

Figure 4. Parallel combinatorial synthesis based on the cation pool" method.

The cation pool method enables easy manipulation of organic cation intermediates to achieve reactions with various nucleophiles, but its applicability strongly depends on the stability of the cation that is generated and accumulated. In order to solve this problem, the cation flow method using a microflow electrochemical system has been developed.9,27... 

Lewis acid-acetal complexes in NMR studies, but never detected alkoxycarbenium ions.29 The absence of alkoxycarbenium ions in the spectra, however, does not necessarily rule out their intermediacy in the reactions with nucleophiles. Therefore, it was imperative to accomplish the reactions of spectroscopically characterized, nonstabilized alkoxycarbenium ions with carbon nucleophiles. The cation pool method made it possible and opened a new chapter in the chemistry of alkoxycarbenium ions. 

The concept of electroauxiiiaiy is quite powerful to solve these problems. The pre-introduction of a silyl group as an electroauxiliary decreases the oxidation potential of dialkyl ethers by virtue of the orbital interaction. As a matter of fact, we demonstrated that the anodic oxidation of a-silyl ether took place smoothly in methanol.30 Selective dissociation of the C-Si bond occured and the methoxy group was introduced on the carbon to which the silyl group was attached. Therefore, a-silyl ethers seemed to serve as suitable precursors for alkoxycarbenium ions in the cation pool method. 

The thermal stability of the alkoxycarbenium ion is noteworthy. When the electrolysis was complete, the cation pool of 26 was allowed to warm up to a second temperature. After being kept there for 30 min, the cation was allowed to react with allyltrimethylsilane. The yield of allylated product 27 was plotted against the temperature. It can be seen from Fig. 7 that alkoxycarbenium ion 26 is stable at temperatures approximately below -50 °C. Above this temperature, the yield of 27 decreased significantly. Intramolecular coordination of ether functionality seems to be effective for the stabilization of alkoxycarbenium ions.33... 

The alkoxycarbenium ions generated by the cation pool method react with various carbon nucleophiles such as substituted allylsilanes and enol silyl ethers to give the corresponding coupling products in good yields. It should be noted that the reactions of alkoxycarbenium ion pools with such nucleophiles are much faster than the Lewis acid promoted reactions of acetals with similar nucleophiles. A higher concentration of the cationic species in the cation pool method seems to be responsible. 

The a-phenylthioether 28 was oxidized in the absence of a nucleophile by low temperature electrolysis (Scheme 15). The corresponding alkoxycarbenium ion pool 26 was formed, which exhibited a single set of signals in H and l3C NMR spectroscopy. The chemical shifts were quite similar to those obtained by the oxidative C-Si bond dissociation described in the previous section. Subsequently, the cation pool was allowed to react with allyltrimethylsilane to obtain the allylated product 27. 

We chose to study the generation of alkoxycarbenium ion 26 from thioacetal 28. The electrochemically generated ArS(ArSSAr)+, 37 which was well characterized by CSI-MS, was found to be quite effective for the generation of alkoxycarbenium ions, presumably because of its high thiophilicity (Scheme 17). The conversion of 28 to 26 requires 5 min at -78 °C. The alkoxycarbenium ion pool 26 thus obtained exhibited similar stability and reactivity to that obtained with the direct electrochemical method. The indirect cation pool method serves a powerful tool not only for mechanistic studies on highly reactive cations but also for rapid parallel synthesis. 

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