Cation Pool Method and Cation Flow Method - ACS Symposium Series

Chapter 10

Cation Pool Method and Cation Flow Method Jun-ichi Yoshida

Downloaded by UNIV OF PITTSBURGH on May 3, 2015 | http://pubs.acs.org Publication Date: July 7, 2007 | doi: 10.1021/bk-2007-0965.ch010

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan

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 thusgenerated 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.

Introduction Reactions of Organic Cations in Synthesis Organic cations (carbocations and onium ions) are important reactive intermediates in organic synthesis. From an experimental point of view, it is noteworthy that the manner in which we carry out reactions of organic cations is different from that for carbanions (Scheme 1). Usually, carbanions are generated and accumulated in a solution in the absence of electrophiles. After the generation process is complete, an electrophile is added to the solution of the pre-formed carbanion to achieve a desired transformation. In contrast, organic cations are usually generated in the presence of nucleophiles. This is probably

184

© 2007 American Chemical Society

In Recent Developments in Carbocation and Onium Ion Chemistry; Laali, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.


185 because organic cations that are often used in organic synthesis are unstable and transient in conventional reaction media and should be trapped in situ by nucleophiles immediately after their generation. Therefore, reactions of organic cations suffer from the limitation of variation of nucleophiles. Nucleophiles that do not survive under the generation conditions cannot be used. This comparison is, however, probably unfair, because we usually regard organometallic compounds as carbanions. Organometallic compounds have carbon-metal covalent bonds, although magnitude of the ionic character of the bond depends on the nature of the metal and substituents on the carbon. Organometallic compounds are widely utilized as carbanions equivalents, but ionic carbanions are rarely used in organic synthesis. On the other hand, we do not regard a species that has a covalent bond between carbon and a leaving group as an organic cation. We only regard ionic species that do not have such a covalent bond as carbocations or onium ions. Apart from such arguments, development of a new method that enables generation of organic cations in the absence of nucleophiles is strongly needed for expanding the scope of cation chemistry in organic synthesis. In this vein, we initiated our project on the "cation pool" method and the "cation flow" method, whereby organic cations are generated in the absence of nucleophiles and are used for the subsequent reactions.

Reactions of Carbocations

generation in the presence of nucleophiles Reactions of Carbanions

generation in the absence of electrophiles

I —C-M I Organometallic Compounds

Scheme 1.

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


186 Two methods are popular in organic synthesis; the acid promoted method and the oxidative method. Acid promoted reactions are most commonly used for the generation of organic cations in organic synthesis. In this method, a proton or a Lewis acid is used to activate a leaving group that is covalently bound to a carbon. In the next step, heterolysis of the bond occurs to generate a carbon having a positive charge. These steps are reversible. The equilibrium usually lies toward the starting material. Then, a nucleophile, which is present in the solution, attacks the cationic carbon to give the final product. In the oxidative generation, a neutral organic molecule is oxidized to generate the corresponding radical cation species. There are several possibilities for the fate of the radical cation. In some cases, elimination o f a proton takes place to give a carbon radical. Such a radical species can also be generated via dissociation of a carbon-heteroatom bond or a carbon-carbon bond in the radical cation. Such carbon radical species are often further oxidized under the reaction conditions to give the corresponding cations. These steps are essentially irreversible. Then, a nucleophile attacks the cation to give the final product. The oxidative cation generation is also usually carried out in the presence o f nucleophiles because of the instability o f organic cations. Therefore, only a nucleophile that has a higher oxidation potential relative to the cation precursor could be used for this type of transformation.


1

Oxidative generation I —C-Y

I

-e

Ç-YI

Y = H, SiR SR, C R 3i

-e

—Ο

-Y

—C I ^Nu

—C-Nu I

+

3

Acid promoted generation A —C-X reversible

I i —c—Χ

+

«

-

χ

-

Α

,

* reversible

l —C I ^ +

_— Nu

I —C-Nu |

Χ = heteroatom A =acid +

Scheme 2.


187

Principle of the "Cation Pool" Method


Outline of the "Cation Pool" Method 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. A n 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 I. Schematic Diagram for the "Cation Pool" Method.

Low Temperature Electrolysis When we initiated our study on the "cation pool" method, it was generally considered to be very difficult to carry out preparative electrochemical reactions at such a low temperature because of high viscosity of the solution, which renders the movement of ions in solution to carry charges unfavorable. Conductivity typically decreases when electrolysis temperature is lowered. However, we found that by tuning the reaction conditions such as the solvent and the supporting electrolyte, electrolyses can be accomplished at such low temperature in a preparative scale. The low temperature electrolysis is the key technology for the success of the "cation pool" method. Dichloromethane (CH C1 ) seems to be the best solvent among the solvents examined, presumably because o f its low viscosity even at low temperatures. Tetrabutylammonium 2

2


188 tetrafluoroborate ( B i ^ N ^ B F / ) is usually used as a supporting electrolyte because of its high solubility, which ensures sufficient conductivity at low temperatures. Therefore, the counter anion of organic cations generated by the "cation pool" method is usually B F \ which is considered to be a very weak nucleophile to cationic carbons.


4

Figure 2. Apparatus for Low Temperature Electrolysis

Methods for the Oxidative Generation of Cations for Use in "Cation Pools" We focused on two types of organic cations, JV-acyliminium ions and alkoxycarbenium ions, because they are very popular in organic synthesis. A number of reactions involving such onium ions have been developed and widely utilized for the construction of organic molecules. Four methods are used for generating "pools" of these onium ions; oxidative C - H bond dissociation, oxidative C-Si bond dissociation, oxidative C S bond dissociation, and oxidative C - C bond dissociation (Scheme 3). In the following sections, we will discuss the principles and synthetic applications of these methods. 2


189 (1) Oxidative C - H bond dissociation R'

R' Ν C0 Me

C0 Me

C0 Me 2

2

2

(2) Oxidative C - S i bond dissociation R' R

R

Nu

X

^N^SiMe C0 Me

Ν

3

2


2

R N

R' JL cr^SiMe

Nu

C0 Me

R'

Nu Ο

Nu

3

(3) Oxidative C-S bond dissociation R R

R'

R'

Nu

^ S A r

R

\ A N U

(4) Oxidative C - C bond dissociation Ar R.

CT

T

a

Ar

R

Nu

Ar

f R

V^Nu

Scheme 3.

/V-Acyliminium Ions Generation of TV-Acyliminium Ion Pools by C - H Bond Dissociation It is well known that oxidation of carbamates leads to the formation of Nacyliminium ions via dissociation of the C - H bond a. to nitrogen. The electrochemical, metal-catalyzed, and chemical methods have been reported in the literature to accomplish this transformation. The transformation serves as a useful tool for organic synthesis, although only compounds of high oxidation potentials such as methanol and cyanide ion can be used as nucleophile. It 4

5

6


190 should be noted that N-acyliminium ions, which do not have a stabilizing group, have not been detected spectroscopically and that they have been considered to be transient intermediates. Thus, we first chose to apply the "cation pool" method to generate and accumulate N-acyliminium ions. For example, low-temperature electrolysis o f pyrrolidine carbamate 1 gave the corresponding N-acyliminium ion 2 as a single species, which was indicated by N M R analysis (*H N M R : 9.38 ppm due the methine proton; C N M R : 193.36 ppm due to the methine carbon) (Scheme 4). These chemical shifts indicated that there was a strong positive charge at the carbon and that the /V-acyliminium ion was formed as an ionic species. The addition of allyltrimethylsilane to the solution afforded the corresponding allylated product 3 in 82% yield. It should be noted that the oxidation potential of allyltrimethylsilane is lower than the starting carbamate 1. Therefore, it should be very difficult to carry out the electrochemical oxidation o f 1 in the presence of the more easily oxidized allyltrimethylsilane to obtain 3 selectively. 7


1 3

ο

-2e 2.5 F/mol

Ν

C0 Me 2

1

8

Bu NBF 4

CH2CI2

4

SiMe

3

(2eq)

9

C0 Me 2

Ν C0 Me

-72 ° C - r.t. 30 min

2

3

-72 ° C

82%

"cation pool" (ca. 0.05 M)

Scheme 4. 9

The JV-acyliminium ion can be characterized by FTIR spectroscopy as well. The starting carbamate 1 exhibited an absorption at 1694 cm" due to the carbonyl stretching, while the N-acyliminium ion 2 generated by the "cation pool" method exhibited an absorption at 1814 cm" . 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. 1

1

Generation of /V-Acyliminium Ion Pools by C-Si Bond Dissociation 10

We have proposed the concept of electroauxiliary, which activates substrate molecules toward electron transfer and controls a reaction pathway that would favor the formation of the desired products. For example, preintroduction of an electroauxiliary such as a silyl group to a carbon α to nitrogen gives rise to selective introduction of a nucleophile on the carbon to which the auxiliary has been attached. The use o f a silyl group as electroauxiliary was


191 11

found to be quite effective for the "cation pool" method (Scheme 3). The introduction of a silyl group decreases the oxidation potentials of carbamates. Therefore, the electrolysis can be carried out more easily. Control of the regiochemistry by the silyl group is also advantages if we use unsymmetrical carbamates.


Reactions of yV-Acyliminium Ion Pools W-Acyliminium ion pools were found to react with various carbon nucleophiles. Scheme 5 summarizes reactions of the N-acyliminium ion pools with allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds. 12

Scheme 5.

Friedel-Crafts Type Reactions of JV-Acyliminium Ion N-Acyliminium ion pools were also found to react with aromatic and heteroaromatic compounds to give Friedel-Crafts type alkylation products (Scheme 6). The reaction of iV-acyliminium ion pool 4 with electron-rich aromatic compounds such as 1,3,5-trimethoxybenzene is interesting. The reaction was extremely fast and a macroscale batch reaction led to the formation of a significant amount of the dialkylation product 6 together with the monoalkylation product 5, although it was revealed that the second alkylation was slower than the first reaction. Therefore, the observed selectivity can be ascribed to the problem of "disguised chemical selectivity" because of faster reaction relative to mixing rate. The problem was solved by using micromixing, which enables extremely fast mixing by virtue of short diffusion path in the microstructure. 13

14


192 OMe C0 Me 2

Bu

MeO

OMe OMe

OMe k l

X0 Me 2

Bu

MeO*

MeOoC^, h Bu

OMe


2

Bu

MeO

5

batch reactor micromixer

X0 Me OMe 6

32% 4%

37% 92%

Scheme 6.

[4+2] Cycloaddition of /V-Acyliminium Ion with Alkenes ΛΓ-Acyliminium ions are known to serve as electron-deficient 4π components and undergo [4+2] cycloaddition with alkenes and alkynes. The reaction has been utilized as a usefiil 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. ΛΓ-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. 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. 15

16

Scheme 7.


193 Three Component Coupling based on the "Cation Pool" Method Because of the increasing demand for producing a large number of compounds in a highly time-efficient fashion, integration of chemical transformation is one of the central issues in current organic synthesis. We have developed sequential one-pot multi-component coupling reactions based on the "cation pool" method. The basic concept of the present coupling reaction is as follows: The addition of a "cation pool" with an electron-rich carbon-carbon double bond generates a new "cation pool", which is allowed to react with a carbon nucleophile. This approach is the umpolung of the addition of a carbon nucleophile to an electron-deficient carbon-carbon double bond followed by the trapping of the resulting carbanion with a carbon electrophile. Thus, an N-acyliminium ion pool 4 was allowed to react with an enamine derivative 8 (Scheme 8). The addition of the cation to the carbon-carbon double bond generated the second cation 9, which seemed to exist either as the open form or the cyclic form. In the next step, cation 9 was treated with allyltrimethylsilane to give the final three component coupling product 10. 17

18


19

C0 Me 2

R. .C0 Me N

^

2

Bu^C0 Me 2

N C0 Me

Ν C0 Me

+

2

2

9

C0 Me 2

(R = Bu)

I

^rv^SiMe3 - J

8

C0 Me 10 66% 2

Scheme 8.

Various carbon nucleophiles, such as allylsilanes, allylstannanes, silyl enol ethers, ketene silyl acetals, organoaluminum compounds, and Grignard reagents were effective as carbon nucleophiles. Cationic Carbohydroxylation of Alkenes Carbo-oxylation (carbohydroxylation and carboalkoxylation), whereby an organic group and an oxy (hydroxyl or alkoxy) group add across a carboncarbon 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


194


formation of the corresponding carbohydroxylation product (Scheme 9). When vinyltrimethylsilane was used as an alkene for the reaction of cation 11, the reaction was highly diastereoselective, allowing access to an enantiomerically pure a-silyl-y-amino alcohol 12.

11

quant.

Scheme 9.

Carbocationic Polymerization Using a "Cation Pool" as an Initiator "Cation pools" were found to serve as effective initiators in cationic polymerization of vinyl ethers. In conjunction with a microsystem, this method effects cationic polymerization in a highly controlled manner without the deceleration inherent in the dynamic equilibrium between active and dormant species, which is essential for conventional living cationic polymerization. The molecular weight distribution (Mw/Mn = 1.14) can be controlled by extremely fast micromixing, and the polymer end can be used as living reactive species for the follow-up reaction. Extremely fast initiation reaction together with extremely fast mixing by the microsystem seem to be responsible for the high level of molecular weight distribution control. 21

22

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


195 Radical Chemistry Using the "Cation Pool" Method 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. The electrochemical reduction of Af-acyliminium ion pool 2 gave rise to the formation of the corresponding homo-coupling product 13 (Scheme 8). Presumably, a radical intermediate 14 was generated by one electron reduction of 2 and homo-coupling of the radical led to the formation o f the dimer 13. However, a mechanism involving two-electron reduction to give anion 15 followed by the reaction with cation 2 cannot be ruled out. Downloaded by UNIV OF PITTSBURGH on May 3, 2015 | http://pubs.acs.org Publication Date: July 7, 2007 | doi: 10.1021/bk-2007-0965.ch010

23

COOMe COOMe 13

Scheme 10.

Next, we examined the reduction of "cation pools" in the presence of radical acceptors. The radical that is formed by one-electron reduction o f 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 o f the "cation pool" chemistry. We found that an alkyl iodide reacted with an Nacyliminium ion pool in the presence of hexabutyldistannane to give coupling product 19. 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. 24


196

COOMe

COOMe

2

14

v.

Cation Pool Method and Cation Flow Method - ACS Symposium Series

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