MSc Chemistry
Molecular Sciences
Literature Thesis
Transition metal catalyzed electrochemical
functionalization of hydrocarbon bonds
by
Vera Cornelia Deij
10624139
November 2017
12 EC
Period 1
Supervisor/Examiner:
Examiner:
Prof. dr. Bas de Bruin
Dr. Moniek Tromp
Van ’t Hoff Institute of Molecular Sciences
/
Homogeneous, Supramolecular and
Bio-Inspired catalysis
2
Abstract
In this study, research on transition metal catalyzed electrochemical functionalization reactions of carbon-hydrogen and carbon-carbon double bonds is summarized. Electrochemical functionalization methods are examined because these reactions can potentially replace conventional redox reagents by electrodes. By changing the redox reagent to electrons, less organic byproducts are formed and this results in an easier separation and less waste, making the reaction more sustainable. The atom economy will be improved as well as the redox economy since the synthesis of the redox reagents is no longer required, which reduces the amount of oxidation and reduction steps. Also the required amount of energy can be reduced as the applied voltage can be tuned, resulting in mild(er) reaction conditions. However, in an electrochemical cell electrolyte is required and the other electrode may give an unwanted byproduct, therefore product separation is still needed.
This study shows that methods are present in which C-H halogenation, C-H phosphorylation, conversion of C-H into C-O bonds, C-H olefination, C-H fluoroalkylation, diazidation of alkenes and fluoroalkylation of alkenes can be performed electrochemically. These methods give the desired products in comparable or higher yields than non-electrochemical ones, but without the presence of additional oxidants. In general, expanding the substrate scope expansion is desirable for these methods to obtain a method that tolerates (more) substrates. In C-H bond functionalization reactions, substrates with a nitrogen based directing group are used to facilitate the C-H activation, but this limits the substrate scope to these compounds. Therefore, it would be promising to examine the possibility of using substrates without a directing group, to obtain an even broader implementation of the method. In addition, further research is desirable to understand the mechanisms of the reactions and to examine the reactions at the other electrode because the byproduct might be useful such as hydrogen gas. It can be concluded that these electrochemical methods are promising additions to functionalization reactions in general and that they show advantages in making the reactions more sustainable.
3
Content
Abstract ... 2
Introduction ... 4
Methods and techniques ... 6
C-H functionalization reactions ... 8
C-H halogenation ... 8
C-H phosphonation ... 20
Conversion of C-H to C-O bond ... 29
C-H olefination and fluoroalkylation ... 35
C=C bond functionalization reactions ... 40
Diazidation of alkenes ... 40
Fluoroalkylation of alkenes ... 43
Conclusion and outlook ... 45
4
Introduction
An important aspect in chemistry is the formation of carbon, heteroatom and carbon-halogen bonds and possible routes towards these bonds are carbon-hydrogen or C=C bond functionalization. The functionalization of C-H bonds catalyzed by transition metals has gained lots of attention in the last decades since functionalizing the C-H bonds has become an important and promising tool in making carbon-carbon, carbon-heteroatom and carbon-halogen bonds.1,2 Due to
direct molecule transformation, multiple initial functionalization reactions of the substrate have become avoidable, which decreases the amount of steps in the reaction and this results in less waste and higher atom economy. In most C-H functionalization reactions stoichiometric oxidants or co-oxidizing agents, such as silver or other metal salts, are needed to promote the reductive elimination of the product or to recycle or activate the transition-metals used as catalysts.3–5 The disadvantages of
using such stoichiometric oxidants can be waste formation, the difficult separation of the oxidants or derived byproducts from the reaction mixture, the use of expensive oxidants which might be toxic or the insufficient selectivity resulting in low yields and poor atom economy.6,7 Another aspect is the
redox economy which means that it is tried to reduce the oxidation or reduction steps in the overall synthesis and to select an oxidant that is not stronger than required.8 The oxidant has to be
synthesized, which requires energy and if the oxidant has a higher potential than the substrate, it can oxidize the substrate but the extra energy is lost since it is not used in the reaction. The amount of reduction and oxidation steps in the synthesis are also influenced by synthesizing oxidants, for example the synthesis of a hypervalent iodide includes an oxidation with sodium perioidate.9 The same
disadvantages apply to functionalization reactions of C=C bonds, for example azidation potentially followed by reduction for amination and fluoroalkylation, both of which may require oxidizing or reducing agents.10,11
A potential and promising solution to these disadvantages is the use of electrochemistry for redox transformations. Utilizing electrodes instead of oxidizing or reducing agents can result in an easier separation due to the absence of stoichiometric redox agents, which reduces the costs and improves the sustainability. Additional energy and reagents are needed to synthesize the redox agents so by circumventing the use of these reagents, less energy is required and less waste is generated, resulting in a better redox economy and making it more sustainable.8,12 Furthermore, the absence of
the reagents in the reaction reduces the amount of needed chemicals and therefore the amount of waste. Replacing stoichiometric redox agents by electrodes can prevent the use of toxic reagents as the unstable and dangerous reagents can be formed in situ using clean reagents, making the reaction safer.6,12 Due to the controllability of the energy of the electrons by the applied voltage, the reactions
can be performed under mild(er) conditions so energy usage could be reduced.12 The transfer of
electrons is potentially specific for an electroactive group and that results in a controllable and selective electrolysis as the amount of reactive intermediates and chemoselectivity can be tuned by changing the applied voltage.13,14 This control also allows other functional groups that are labile to
reduction or oxidation to be present in the substrate. No additional steps are therefore required to protect and deprotect these groups, improving the sustainability of the reaction and by shortening the synthetic route and reducing the amount of energy and waste. This may result in a better redox economy if oxidation and reduction steps are used in the protection and because the applied energy is tuned and specific, no energy is lost due to a stronger oxidizing agent.
5 The advantages of using electrodes instead of redox agents are thus promising to make the reactions more sustainable and perhaps more selective. This report will therefore summarize research on C-H and C=C functionalization using electrochemical methods to examine what kind of reactions can be replaced by transition metal catalyzed electrochemical reactions. Different methods will be compared in order to form an answer to the following questions: Which C-H or C=C bond functionalization reactions can be performed using electrodes instead of conventional oxidizing or reducing agents? Is it possible to synthesize the desired products in yields comparable to methods using redox agents? Which specific redox agents are replaced and could this be extrapolated to similar reactions using the same reagent?
6
Methods and techniques
Implementation of electrolysis in reactions can occur through the use of a divided cell (two compartments and a separator) or an undivided cell (one compartment) as shown in Figure 1.12,15 In
general, an electrochemical cell consist of a working electrode, an auxiliary (or counter) electrode, electrolyte, solvent and an electroactive reagent. Depending on whether the reaction is an oxidation or a reduction, the working electrode is the anode or the cathode respectively, and the anode is connected to the positive pole and the cathode to the negative. Furthermore, the electrolyte is mostly a salt which improves the conductivity of the solution by dissociating in ions and it should be chosen such that it will not oxidize or reduce under the reaction conditions. In an undivided cell, the anode and the cathode are present in the same compartment and are linked via a potentiostat that closes the system.15 It should be taken into account that, when this cell is chosen, the substrates and the
products of both electrodes are present in the same solution which can lead to interference of the reaction at the other electrode. This potential problem can be solved by using a divided cell in which, ideally, the separator allows good conductivity by transport of the ions but exchange of substrate or product molecules is low.12
Figure 1. Schematics of a divided (left) and an undivided (right) electrochemical cell.15
Another aspect of electrocatalysis is the use of a controlled potential or a constant current in the reaction.15 The controlled potential can be chosen to selectively oxidize or reduce species in the
mixture under a specific potential resulting in less byproducts. In addition to the working and the counter electrode, a reference electrode is needed to measure the applied potential and to set a chosen potential in a controlled potential reaction. In a constant potential oxidation or reduction reaction, the resistance increases as the substrate is consumed and because the potential is kept constant, the current will drop. This is shown in Equation (1) in which V is the potential, i is the current and R is the resistance of the cell.15 The drop in current will result in a longer reaction time because
the oxidation or reduction will take longer as the transfer of electrons becomes more difficult with higher resistance. Another option is performing the reaction with a constant current. The potential will increase and stay constant whilst the substrate is oxidized and after full oxidation the potential will increase further where it can oxidize other species of the reaction mixture.15 Under this condition the
potential of the substrate should be known to selectively oxidize or reduce the substrate and not the solvent, byproducts or the product.
V = 𝑖R (1)
The redox potential of the substrate can be determined by cyclic voltammetry (CV). This method measures the current response of an electrode immersed in an unstirred solution to a linear
7 potential scan with a triangular waveform.15,16 As the potential increases the molecule at the electrode
will be oxidized, resulting in a positive current, and if the molecules are all oxidized the current will decrease.15 When the potential is decreased, the molecules get reduced, resulting in a negative
current. As the potential reaches its starting value the measurement is finished and plots such as Figure
2 can be obtained. Next, for a reversible redox couple the redox potential can be determined by
calculating the potential that lies exactly between the potentials of the oxidation and reduction peaks.16
Figure 2. Cyclic voltammogram of a reversible redox couple with current (mA) on the y-axis and potential (V) on the x-axis.15
The transfer of electrons to the substrate can either occur via direct or indirect (mediated) electrolysis. In direct electrolysis the electron transfer occurs at the surface of the electrode and that can be seen as a heterogeneous process.12,17 It is possible that direct electrolysis does not yield the
desired selectivity and this can be solved by using indirect electrolysis utilizing a redox catalyst which is an electron carrier and is also called a mediator as shown in Figure 3.12,13 To acts as the mediator, a
few requirements must be met, such as the capability of transferring the electrons fast and easy and of being recycled, good stability in both oxidation states and easily separable from the reaction mixture.12 Only catalytic amounts are needed of the mediator as a result of the electron transfer from
the electrode to the substrate or vice versa in which the mediator is recycled. In addition, attention must be paid to the chosen potential since the mediator should be oxidized or reduced by the electrodes as it should react indirect with the substrate. This results in a mediator with a redox potential which is higher than the substrate redox potential for indirect reduction and lower for indirect oxidation of the substrate.17 The same reasoning applies to the functional groups in the
substrate so by choosing the right potential, the reaction could be tolerable for many functional groups.18 As a result the reaction can be performed under milder conditions and there will be less side
reactions with the substrate since the potential is lower and the reaction proceeds via the mediator. This will make the reaction more sustainable because the energy use is decreased and formation byproducts that are considered as waste are reduced.12
8
C-H functionalization reactions
An important and promising tool in synthesizing molecules is C-H functionalization since there are often many C-H bonds present in molecules. The C-H bonds are often unreactive but the reaction can occur if the bond is activated by for example transition metals.2 With the direct transformation of C-H
bonds to C-X, C-P or C-C bonds, prefunctionalization such as protecting and deprotecting other functional groups has become unnecessary which reduces the amount of steps in the synthesis and therefore also the waste. These reactions still produce waste as the catalyst is re-oxidized to recycle the catalyst by using stoichiometric amounts of oxidants. This waste may be avoided when electrolysis is used to recycle the catalyst as the used electrons do not generate waste. In this chapter, the transformation of C-H to C-X, C-P, C-O and C-C with the use of transition metal and electrolysis will be discussed.
C-H halogenation
A useful functionalization is the transformation of C-H bonds into C-X bonds since halogenated molecules can be used as reagents in synthesis in, for example, arylation and for some molecules there is pharmaceutical interest.19,20 One common way to introduce halogens to arenes is by means of
electrophilic aromatic substitution in which an arene-H bond can be transformed to an arene-X bond using reagents such as N-halosuccinimides.21 It is also possible to use a transition metal catalyst for
C-H activation which can be used in direct oxidation of the C-C-H bond. This is shown in research on palladium catalyzed oxidative functionalization of benzo[h]quinoline resulting in chlorination and bromination conducted by Sanford et al as shown in Scheme 1.22 This research shows a halogenation
reaction in which first iodobenzene diacetate was used in stoichiometric amounts as oxidant in combination with Pd(OAc)2 and oxidation in the presence of excess LiCl or LiBr gives only traces of the
desired halogenated product. Then, it was found that the yield could be improved if N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) is used in stoichiometric amounts instead of iodobenzene resulting in an isolated yield of 95% and 93% after 1-3 days, respectively.
Scheme 1. General halogenation reaction of benzo[h]quinoline by Sanford et al.22
However, research conducted by Kakiuchi et al states that separation of product, byproducts and remaining oxidant is unavoidable in the above mentioned reactions.23 Therefore, the use of
aqueous HCl an HBr as halogenation reagent for aromatic C-H halogenation was examined in an electrochemical cell considering organic byproducts will not be formed.23 The reaction is performed in
a divided cell with platinum electrodes and an anion-exchange membrane under constant current with the halogen source, the arene and PdCl2 or PdBr2 as catalyst at 90 °C as shown in Scheme 2. Depending
on the halogen source being either HCl or HBr the temperature changes and depending on the substrate the time changes. It is expected that the halogen ions originate from HX that diffuse through the anion-exchange membrane. The first examined arene was benzo[h]quinoline and then halogenation of 2-phenylpyridine and substituted arylpyridines were studied.
9 Substrates with electron-donating and electron-withdrawing groups were tested and the reaction proceeded for all substituents, which shows that the reaction tolerates for both kinds of substituents. The chlorination method gives the products in yields between 87 and 100% and the bromination gives the products with R= 2-Me or R= 3-CF3 in 83 and 94% yield. Furthermore, using the same method it
also possible to chlorinated arylpyrimidine, 2-(2-methylphenyl)pyrimidine, naphthylpyridine and naphthylpyrimidine giving the products in 91, 94, 100 and 95%, respectively.
Scheme 2. The general reactions of the palladium catalyzed chlorination (a) and bromination (b) by electrochemical oxidation by Kakiuchi et al.23
The mechanism of the halogenation includes most likely the Pd(II) and Pd(IV) species as shown in Scheme 3. First, it is expected that the nitrogen atom in the substrate coordinates to the PdX2
followed by C-H activation resulting in a palladacycle and the loss of HX. Then a halonium ion is generated by anodic oxidation which will react with the palladacycle leading to a Pd(IV) species. After reductive elimination and dissociation the ortho-halogenated product and the catalyst are obtained. The reductive elimination of the product can take place under milder conditions as the reduction from Pd(IV) is easier than that from Pd(II).3 The proposed mechanism includes the anodic oxidation but not
the reaction at the cathode. However, Scheme 2 shows the reaction conditions and it can be seen that at the cathode HXaq is present which may result in a transformation of H+ into H2 at the cathode. An
advantage of the performed reaction is the absence of supporting electrolyte because HCl and HBr can act as electrolyte and therefore the amount of used chemicals can be reduced. Furthermore, the separation of this process is rather simple as all the arene is converted resulting in a mixture with only the solvent and product that have to be separated. Another advantage is the use of electrolysis which allows control over the reactive ions by changing the applied current resulting in a suppression of side reactions. Furthermore, tuning the electric current can control the regioselectivity and this in combination with the suppression of the side reactions makes the reaction more selective.
10
Scheme 3. Generalized mechanism of palladium catalyzed halogenation by Kakiuchi et al (adjusted from Jiao et al).3,23
The substrate scope of the halogenation method by Kakiuchi et al covers arylpyridine and arylpyrimidines and this scope was expanded with benzamide derivatives with a bidentate directing group by the same group by Kakiuchi et al.20 Prior to expansion of the scope, research had been
conducted by several groups into C-H chlorination of arenes containing bidentate directing groups as shown in Scheme 4. Research conducted by Stahl et al showed that the ortho C-H chlorination of N-(8-quinolinyl)- benzamide can be performed using CuCl2 as catalyst, 20 mol% LiOAc, 2 equivalents LiCl
under 1 atm O2 at 100 °C with a yield of 88%.24 In a study by Shi et al the halogenation of benzamides
is performed with a removable auxiliary using a Co(II)-catalyst, 1.4 equivalent N-halosuccinimide (NXS) and a zinc additive which may participate in activating the NXS reagent.25 The reaction showed
tolerance for a broad substrate scope including electron-donating and electron-withdrawing groups resulting in moderate to good yield, but poor regioselectivity was found for meta-methoxy- and bromo substituted benzamides. Another study by Shi et al examined the halogenation of similar substrates but using Ni(OTf)2 catalyst in combination with a removable directing group for benzamides, three
equivalents LiX as halogen source and two equivalents KMnO4 as oxidant.26 It was found that
bromination and iodination of benzamide proceeded in moderate to good yield for both electron-withdrawing and electron-donating substituents on the phenylring. Chlorination was performed with yields of 62, 71 and 82% with the substituents being R= Br, OMe or Cl, respectively. A disadvantage of these studies is the amount of reagents used in the halogenation such as two or three equivalents instead of one equivalent LiX and stoichiometric KMnO4 making a reduction of the chemicals desirable.
11
Scheme 4. Halogenation reactions by Stahl et al and by Shi et al.24–26
Kakiuchi et al uses an electrochemical method for the chlorination of the benzamide derivatives to replace stoichiometric reagents or oxidants by anodic oxidation making the reaction more clean and possibly less expensive.20 Initially aromatic carbonyl compounds were tested but the
reaction does not proceed with the substrates. According to the researchers, this may be due to low coordination ability which results in inefficient C-H bond cleavage. Therefore, benzamides with a bidentate directing group as shown in Scheme 5 were chosen as the coordination ability is higher resulting in a more efficient C-H bond cleavage. The mechanism was determined by reacting a benzamide derivative with PdOAc2 making a palladacycle that can react with the generated Cl+ to form
the desired products according to the mechanism shown in Scheme 3. The formed palladacycle is most likely the result of a directed C-H bond cleavage of the benzamide derivative which is also found in literature.27 The reaction at the cathode is not mentioned but a solution of 2M HCl is present at the
cathode, which could result in a reduction of H+ to H
2. The initial reaction conditions were changed to
10 mol% PdCl2, 5 mA because it was found that a lower electric current increases the yield as product
decomposition is suppressed and acetonitrile because DMF did not give high yield. In addition, substrates containing a 5,7-dichloro-8-quinolinyl group are chosen as it is preferred to avoid complicated mixtures and this choice results in a mixture of the mono- and di-chlorinated product as shown in Scheme 5.
12
Scheme 5. The halogenation of benzamide derivatives by Kakiuchi et al.20
The reaction of the o-methylbenzamide derivative was performed by lowering the electric current to 2.5 mA and increasing the reaction time to 12 hours instead of 6 hours, which increases the yield to 86%. Next, meta- and para-substituted benzamide derivatives were examined using the same electric current but changing reaction times depending on the substituted group. It was found that electron-withdrawing groups give a higher selectivity for the monochlorination products, providing the product in 71 and 77% yield for Br- and CF3-substituents but longer reaction times are required.
Furthermore, electron-donating groups are showing higher reactivity and a mixture of mono- and dichlorination products and for meta-substituted substrates the mixture can consist of 62-84% monochlorination product and 10% dichlorination product. Although several substituents are tolerated, the examined scope is limited to benzamide with the specific bidentate directing group so perhaps additional research can look into other bidentate directing groups to further expand the substrate scope. The advantage of this method compared to the previous methods is the absence of the zinc additive and excess of halogen source resulting in a better atom economy.
In the same group, Kakiuchi et al examined the catalytic electrochemical C-H iodination for an one pot halogenation/ arylation reaction.19 Previous research on the iodination of substituted arenes
was found by Glorius et al using a cationic Rh(III) catalyst.28 This method can both perform bromination
and iodination reactions. The iodination reaction is performed using [RhCp*Cl2]2 as catalyst, 1.1
equivalent NIS as iodine source, AgSbF6, 1.1 equivalent pivalic acid in 1,2-DCE as shown in Scheme 6.
The time and temperature are dependent on the substituent with times of 16-52 hours and temperatures of 60, 90 or 120 °C. First, diisopropyl-, dimethyl- and n-butyl- benzamide were tested giving the ortho-iodinated products in 98, 75 and 78% yield, respectively. Then acetanilide was tested but instead of the ortho-iodinated product the para-substituted product was formed in 82% yield. This presumably occurs via electrophilic aromatic substitution since the same product is obtained when no catalyst is used. Phenylpyridine can also be used as substrate and upon addition of 2.2 equivalent of NIS, the dihalogenated product is formed in 88% yield. For the iodination of tert-butyl phenyl ketone the NIS should be added in portions and for acetophenone and isopropylphenone the pivalic acid should be changed in Cu(OAc)2 with higher catalyst loading resulting in the products up to 62% yield.
Looking into the mechanism shows that C-H activation of the substrates is the rate determining step. It is suggested that C-H activation leads to a rhodacycle and then the halogenation can proceed via an oxidative addition of NIS forming a Rh(V) species followed by reductive elimination of the product or via a kind of nucleophilic addition of iodine to the rhodacycle giving directly the product and Rh(III). An advantage is the versatile substrate scope and the high yields but using NIS gives an organic byproduct which could be prevented by using I2.
13
Scheme 6. The iodination reaction of substituted arenes, adjusted from Glorius et al.28
Research conducted by Yu et al shows the use of I2 as sole oxidant in the iodination of arenes
containing an amide substituent acting as a directing group.29 In this study the reaction is performed
using Pd(OAc)2 as catalyst, I2, CsOAc and NaHCO3 as coadditive in a mixture of DMF and t-AmylOH at
65 °C for 20 hours as shown in Scheme 7. The reaction was also tested with PdCl2 and PdI2 as catalyst.
This shows that the presence of CsOAc is required as absence of CsOAc result in loss of reactivity. It is suggested that formation of Pd(OAc)2 or PdI(OAc) via anionic ligand exchange is essential.
Furthermore, the role of CsOAc is to improve the catalytic turnover by regenerating the Pd(OAc)2
catalyst. Previous research by the same group shows that the first step is C-H activation which is easier as the amide directing group can coordinate to the Pd(II) center. The C-H activation results in AcOH and the Pd(II) complex which is oxidized by I2. Then after the reductive elimination the product and
Pd(II)-I is obtained. Since it is suggested that CsOAc regenerates the catalyst, Pd(OAc)2 and CsI are most
likely formed. The method shows tolerance for naphthalene and methyl-, methoxy-, chloro-, fluoro- and trifluoromethyl substituents on the phenylacetic amides giving the products in yields of 87-96%. Increasing the catalyst loading was required for the strong electron-withdrawing groups. This also applies to the di-iodination which can even occur for a meta-substituted aryl giving the products in 85-95% yield. The reaction can also be performed at gram-scale for methoxy-, methyl- and trifluoromethyl substituents with a catalyst loading of 0.5 mol% giving the product in 71, 75 and 50% yield. If the solvent is changed to DMSO and 0.2 equivalents of K2S2O8 instead of NaHCO3, ortho-substituted
benzamides with methoxy-, methyl-, chloro- or trifluoro substituents are also allowed obtaining the products in 89-97% yield. Using the new conditions for the iodination of unsubstituted benzamide results in the product in 41% yield opposed to the conditions shown in Scheme 7 which results in the homocoupling product in 48%. The reaction is also performed using pyrazoles, oxazoles, thiazoles and pyridine substituted isonicotinic amide and 2-methyl-nicotinic amide as substrates using 10 mol% Pd(OAc)2 and for some substrates K2S2O8 instead of NaHCO3 resulting in the iodinated products in
52-91% yield. This method shows a broad range of substrates, the products are obtained in moderate to good yields and I2 is used as iodine source which can result in an easier separation. However, the
reaction requires additives in stoichiometric amounts and this can lead to more waste and a lower atom economy.
14 In the research by Kakiuchi et al shown in Scheme 8, the chlorination method was tried for iodination.19 The chlorination method uses no electrolyte and therefore the separate addition of
electrolyte and an iodine source was examined. If the reaction uses HI as iodine source, the product is not observed. Using KI and H2SO4 gives the desired product but it was observed that there is an
induction period before the iodination reaction. It is expected that the iodide ion is converted to I2 in
the induction period which is supported by the relation between a longer induction period when more equivalents KI are used. When I2 is used as iodine source, no induction period is observed and the
researchers suggest that the active species is the iodonium ion generated by electrochemical oxidation from I2. It is considered that the iodination occurs via the same mechanism as the chlorination depicted
in Scheme 3. Different arylpyridines can be halogenated in a divided electrochemical cell using 2 equivalents I2 at 90 °C and either an electric current of 5 or 10 mA depending on the substrate.
Arylpyridines can be substituted with m- or p-Me, CF3 and p-F giving the product in 61-85% yield.
Furthermore, it is found that to obtain a higher yield a substituent is needed at the 3-position of the pyridine ring or the ortho-position on the benzene ring. After formation of the iodinated product, the electric current is switched off in order to stop the formation of the reactive oxidant and then base and phenyl boronic acid are added to perform the Suzuki−Miyaura coupling. The method allows both electron-donating as electron-withdrawing substituents on the phenyl boronic acid and gives the product in yields between 53-84%. The disadvantage of this method is the use of two equivalents I2
which is not preferred as it is an excess. Compared to the aforementioned method no organic byproduct is formed which may indicate an easier separation and no additives are required. The substrate scope is limited to arylpyridines so additional research to expand the scope is desirable and perhaps the amount of used I2 could be reduced to improve atom economy.
Scheme 8. The iodination of pyridine derivatives by Kakiuchi et al.19
Research by Kakiuchi et al on the homocoupling of arenes uses the same iodination method to some extent with the difference being the amount of I2 that is used.30 In this method the coupling can
be performed in a similar fashion as shown in Scheme 8, using one equivalent I2 and different
substituted phenylpyridines with substituents such as methoxycarbonyl, phenyl, trifluoromethyl, bromine and methyl giving the product in 56-80% yield. The homocoupling of para-methyl substituted phenylpyridine gives the product in 66%, but without applying electric current the product is also formed but less effective and the same applies to phenylpyridine which gives the product in 62% when electric current is applied. The reaction is also performed for the coupling of 2-(3-(trifluoromethyl)phenyl)pyridine using I2 in catalytic amounts for 9 hours and this gives the product in
59% yield. Looking at the formal changes in the molecules, no incorporation of I2 occurs and this shows
that I2 probably acts as a redox mediator. The precise mechanism is not mentioned, only that the
ortho-C-H bond of two phenylpyridines are activated and will form a complex with the Pd(II) catalyst. This complex will be oxidized by I+ which is generated in situ by anodic oxidation of I
15 elimination occurs of the coupled phenylpyridines as shown in Scheme 9. A possible explanation of the iodide mediated reaction is that after the reductive elimination in which the product and I-Pd(II)-L are formed, the catalyst activates an ortho-C-H bond forming HI that is present in ionized form. The proton will be present at the cathode after a transfer through the membrane. The iodide is present at the anode and can be oxidized to I+ which subsequently will oxidize the complex. This will be followed by reductive elimination which closes the catalytic cycle. The transferred proton is reduced at the cathode resulting in the formation of H2. The formation of H2 is confirmed in this reaction but also in the
chlorination and bromination when the method by Kakiuchi et al is used. The homocoupling using catalytic I2 is promising since no prefunctionalization is needed but additional research is required to
further examine the scope of this method.
Scheme 9. Suggested mechanism for the iodination with the method of Kakiuchi et al.30 I+ is generated electrochemically
from I2 or I- at the anode.
Another halogenation reaction that has been studied is the fluorination of pyridine and pyridine derivatives. The fluorination of pyridines commonly occurs via nucleophilic substitution at the 2-position with a suitable leaving group for fluoride resulting in fluoroarenes which are more reactive, making an intermediate that can be used for synthesizing a broad range of 2-pyridyl compounds.31,32
Fluorination can also occur directly at C(sp2)-H bonds replacing a hydrogen by fluorine which is shown
in research conducted by Daugulis et al as shown in Scheme 10.33 This research shows the use of a
Cu(I)-catalyst for the mono- and difluorination of benzamides. The monofluorination is performed using 10-25% CuI depending on the substituents on the benzylgroup, 3.5-4 equivalents AgF and 4.5-5 equivalents NMO as oxidant at temperatures of 50-125 °C which results in yields between 54 and 80%. The reaction time varies from 30 to 120 minutes with pyridine added for longer reaction times to prevent substrate decomposition. The difluorination is performed using 18-30% CuI, two equivalents pyridine, 5-6 equivalents AgF, 7-8 equivalents NMO at temperatures of 75-105 °C with times varying from 1.5 to 2 hours obtaining the product in yields of 61-77%. Both reactions tolerate electron-withdrawing and electron-donating groups and heterocyclic benzyl substituents.
16
Scheme 10. Fluorination of benzamides by Daugulis et al.33
Another method is the electrochemical monofluorination of pyridine found in 1985 by Teare
et al as shown in Scheme 11.34 This research shows the oxidation of pyridine to a cation at a potential
of 2.5 V which is lower than the potential of the used fluoride source to perform controlled fluorination. Next, the cation reacts with MeNF.2HF in acetonitrile that acts as both electrolyte and fluoride source to get 2-fluoropyridine. However, a 70-fold excess of dry fluoride is needed to obtain the product in 22% yield because if water is added the yield decreases to 11%. Over time the current efficiency decreases as the anode is coated and if an undivided cell is used it is possible that the yield is low due to reduction of the product at the cathode but this can potentially be solved by placing a diaphragm in the cell.34 The method allows the fluorination of dilute pyridine, pyridine derivatives and
compounds that are solid under the reaction temperature due to the presence of acetonitrile, but the fluorination of nicotine was not possible.
Scheme 11. Fluorination of pyridine by Teare et al.34
A disadvantage of these methods is the large amount of chemicals needed to perform the reactions. Therefore, a new method is desirable and this has been studied for pyridine and 4-ethylpyridine by Budnikova et al.31 This research shows a monofluorination method using a nickel,
cobalt or silver nitrate catalyst in a divided electrochemical cell in which the catalyst can be regenerated for the selective fluorination as shown in Scheme 12. The reaction is performed using K2NiF6 as catalyst, pyridine and two equivalents cesium fluoride (CsF) as fluoride source in acetonitrile
at room temperature, providing 3-fluoropyridine in 43% yield. Furthermore, it can also be performed using CoF3 both as catalyst and as fluoride ion source in acetonitrile but it suspected that a pyridinium
salt is formed and upon addition of triethylamine 2-fluoropyridine can be obtained in 49% yield. In addition, the reaction can also be performed using AgNO3 as catalyst, 2 equivalents CsF as fluoride
source in acetonitrile and this gives 2-fluoropyridine in 48% yield. It is also possible to perform the reaction using 4-ethylpyridine which result in 3-fluoro-4-ethylpyridine and 2-fluoro-4-ethylprydine in 45, 57 and 20% yield, respectively. This research found that the source of fluorine influences the yield and not the position of the fluorination. It is stated that pyridine does not oxidize at the applied potentials and it assumed that the fluoride ions oxidize but the mechanism is not elucidated so clarification is needed. Furthermore, the position of the fluorine by the different catalysts is only mentioned and no reason for this difference is given.
17 This method is an improvement of the aforementioned methods as the product are obtained in higher yield and the amount of fluorine source is reduced. However, further research is desirable to expand the scope of the reaction, to elucidate the mechanism of the different catalyst to potentially explain the difference in products and to examine further optimization to improve the yields coming closer to the yields of the method by Daugulis et al. A potential method could be a method that combines the fluorination of aromatic C-H bonds by Daugulis et al with the electrochemical halogenation by Kakiuchi et al as both methods are applicable to the halogenation of benzamide. Furthermore, it is possible for pyridine to coordinate to the palladium center to facilitate C-H activation. If this can be combined, the fluoride source might be 1 equivalent and no excess of oxidants is needed. However, this can only happen if a non-dangerous fluoride source can be used and not HF.
Scheme 12. The monofluorination of pyridine catalyzed by (a) nickel, (b) cobalt and (c) silver nitrate by Budnikova et al.31
Not only arenes and pyridines can be halogenated also halogenation of 1,3-dicarbonyl compounds is performed. A study by Ibrahim et al shows the α-chlorination of 1,3-dicarbonyl compounds using 0.25 equivalents TiCl4 as catalyst and chlorine source and 1.2 equivalents
(diacetoxyiodo)benzene (DIB) in acetonitrile at room temperature.35 According to the authors, the DIB
is used as oxidant that generates Cl+ by umpolung which reacts with the substrate that formed a complex with TiCl4 as shown in Scheme 13. Furthermore, the authors argue that the use of 0.25
equivalent TiCl4 indicates that under the conditions TiCl4 can contribute four equivalents of Cl+. Various
1,3-diketones, β-ketoesters, β-ketoamides and a β-ketophosphonate were tested and the mono-chlorinated products are obtained in high yields in the range 71 to 98%. The reaction time is mostly two to four minutes with some exceptions of 20, 25 or 50 minutes for substrates containing a phenyl or NBn2 substituent. Furthermore, the dichlorination of benzyl-3-oxobutanoate is performed in two
minutes with 0.6 equivalents TiCl4 and 2.2 equivalents DIB and this gives the product in 93% yield. A
disadvantage of this method is use of stoichiometric amounts of DIB which result in stoichiometric amounts of waste as iodobenzene is formed when Cl+ is generated. The waste could be reduced by replacing the oxidants by an anode to remove electrons directly to generate Cl+ by anodic oxidation.
18
Scheme 13. Mechanism of chlorination of 1,3-dicaronyl compounds by Ibrahim et al.35
Research conducted by Kakiuchi et al continues on the chlorination of aromatic C-H bonds in which HCl is used as chlorine source as shown in Scheme 2.36 The reaction is performed in a divided
cell with Cu(II) as catalyst, β-keto esters, HCl as chlorine source and acetonitrile as solvent at room temperature as shown in Scheme 14. No electrolyte is separately added but it is required so it is most likely that HCl acts as electrolyte as shown in previous research.23 The reaction can give both the mono-
and dichlorination product after extraction but in the optimized reaction gives the dichlorination product in 6% yield and the monochlorination product in 83% isolated yield. Furthermore, copper(II) triflate is used as catalyst because it shows good catalytic activity and is easier to handle than copper(II) tetrafluoroborate hexahydrate. The method tolerates benzoylacetate derivatives with electron-withdrawing groups such as NO2 and CF3 which gives moderate yields of 56 and 57% and an o- or
p-methoxy substituent gives higher yields of 70 and 82%. Fluoro- and bromobenzoylacete are also allowed giving the products in 73-84% yield. In addition, the reaction is performed with a β-diketone and that gives the monochlorination product in 66% yield. The reaction is also performed with a β-ketoamide and by reducing the reaction time with 1 hour, the monochlorination product is obtained in 68% and the dichlorination product in 15%. This shows that the method is applicable for multiple substrates. The mechanism is not clarified but it is believed that a copper enolate reacts with generated Cl+. This method does not form iodobenzene as byproduct and thus reduces the amount of waste. However, the products are obtained in lower yields so if further optimization could be examined as it would improve the potential of the method. Additional research may also lead to broadening of the substrate scope to more β-diketones and β-ketoamides and possible clarification of the mechanism.
19 In summary, C-H activation can be used in electrochemical halogenation reactions for pyridines, pyridines derivatives, benzamides and 1,3-dicarbonyl compounds in moderate to good yields. In the discussed methods, divided cells are used because it can occur that the product is reduced at the cathode in an undivided cell as found in fluorination of pyridine by Teare et al. The chlorination and bromination of substituted arylpyridines and arylpyrimidines and the chlorination of benzamides containing a bidentate directing group tolerates both electron-withdrawing and electron-donating groups. Iodination of pyridines derivatives with various substituents can also be performed electrochemically. These new methods replace N-halosuccinimide or LiX as halogen source by aqueous HX or I2. Therefore, no organic byproducts are formed which results in an easier separation and a better
atom economy. In addition, the aqueous HX can act as electrolyte which reduces the amount of chemicals since no additional electrolyte is added. Expansion of the substrate scope for all the methods and tolerance for more bidentate groups is desirable and for some methods further optimizing is preferable if it is possible. In addition, the iodination method ca be used for arylation of the iodinated phenyl derivatives and for the homocoupling of arenes with various substituents. In the homocoupling, I2 may even react as a redox mediator which is promising for coupling reactions since no
prefunctionalizations are required, but additional research is required to determine the scope of this method. It is also confirmed that the reactions with aqueous HX produce H2 at the cathode as a result
of the reduction of protons and this may potentially be used in other reactions.
Electrochemical fluorination of pyridine and 4-ethylpyridine is possible which are obtained in moderate yields. The new method reduces the amount of required chemicals, improving the atom economy. Direct fluorination of benzamide derivatives is known with oxidants and since the reactions use similar substrates it could be promising to look into another electrochemical fluorination that uses a similar method as shown for the chlorination of benzamides. However, it can only contribute to a more sustainable method if a non-dangerous fluoride source is used.
Moreover, a method shows that 1,3-dicarbonyl compounds with various substrates and substituents can be chlorinated electrochemically. This method replaces the use of (diacetoxyiodo)benzene by electrons which result in less byproducts since iodobenzene is not formed. The method is promising but the yield is lower than in a previous method, so additional research is desirable to examine if further optimization is feasible. This can be combined with elucidation of the mechanism and broadening of the substrate scope to increase the possible applications of the method.
20
C-H phosphonation
Another useful functionalization is the formation of C-P bonds as these are present in natural molecules, pesticides and potential drugs and since phosphorus can coordinate to metals molecules with C-P bonds can act as ligands.37,38 A problem in the formation of C-P bonds is the influence of the
strong coordinating phosphorus reagents which may result in inhibition of the C-H activation.39,40 To
suppress this coordination, the phosphorus reagent is added dropwise to keep the concentration as low as possible. Furthermore, minimizing the concentration can result in the C-H activation of a less coordination bond that would not coordinate in the presence of strong coordinating phosphorus reagents.
In 2013 Yu et al conducted a research on phosphorylation of phenylpyridine derivatives using Pd(II) as catalyst, H-phosphonates as phosphorus sources, AgOAc as oxidant to recycle the catalyst as shown in Scheme 15.39 The study shows that NaOAc is used as base to promote the reaction and that
the stronger base K3PO4 inhibits the reaction. In addition, the reaction requires 1,4-benzoquinone (BQ)
because it likely has a promoting role in the reductive elimination of the product. The phosphorylated 2-phenylpyridine was obtained 84% yield when the reaction is performed at 120 °C in tert-amyl alcohol for 13 hours with Pd(OAc)2 as catalyst, 1 equivalent BQ, 2 equivalents NaOAc as base, 2 equivalents
AgOAc as oxidant and diisopropyl H-phosphonate as phosphorus source. Methyl and methoxy substituents on both the pyridine and arene ring are tolerated giving the products in moderate to good yields, 61 to 80%. Chlorine as substituent at the para position at the arene gives the product in 67% yield and at the meta position the yield reduces to 58%. Furthermore, different strong electron-withdrawing groups at the para position give lower yields ranging from 58 to 15%. The method also allows 2-napthalene or phenylpyrimidines as substrates and directed phosphorylation of quinoline and isoquinoline. It is also possible to change the phosphorus source from H-phosphonate to diaryl phosphine oxides and this give the product in moderate yield.
Scheme 15. The phosphorylation of arylpyridines by Yu et al.39
The suggested mechanism is depicted in Scheme 16 and shows the forming a palladacycle by C-H activation of 2-phenylpyridine followed by anionic ligand exchange which results in a complex containing both the phosphonate and 2-phenylpyridine. Then reductive elimination promoted by 1,4-benzoquinone gives the product and AgOAc oxidizes the formed Pd(0) to Pd(II) to recycle the catalyst. The promoting role of BQ could come from oxidation of Pd(II) leading to an easier reductive elimination or from the stabilization of Pd(0) by BQ.41 Since AgOAc is used to oxidize Pd(0) to Pd(II) it is presumed
that due to stabilization of Pd(0), the reductive elimination occurs more easily. A disadvantage is the use of both AgOAc and BQ to make the reaction catalytic for palladium.
21
Scheme 16. Proposed mechanism for phosphorylation of 2-pheylpyridine [adjusted from Yu et al].39
Around the same period is Murakami et al performed similar research on phosphonation of 2-arylpyridines using a palladium catalyst as shown in Scheme 17.40 This study tested both
H-phosphonate and α-hydroxyH-phosphonate as phosphate source with the latter being a masked phosphorus source to prevent catalyst deactivation. It was found that α-hydroxyphosphonate gives the product in 70% yield compared to the 12% yield when H-phosphonate is used. It is suggested that α-hydroxyphosphonate gives a better result due to gradually supply of H-phosphonate that is generated when acetone is released from α-hydroxyphosphonate. The reaction is performed using Pd(OAc)2 as catalyst, 40 mol% N-methylmaleimide (NMMI) to promote reductive elimination, 2.5
equivalents AgOAc as oxidant and 4.5 equivalents K2HPO4 as base in tBuOH at 120 °C for 48 hours. The
method tolerates both ortho- and meta-tolyl pyridine, methoxy and chloro substituents on the phenyl ring, benzothiophene as well as pyrimidine and quinoline as directing groups giving the products in good yields between 66 and 84%. Also mechanistic studies are performed with dimeric palladium complexes and this shows the formation of the phosphorylation palladium complex after a reaction of α-hydroxyphosphonate and the dimeric complex containing acetate with K2PO4 in dioxane at 120 °C
showing that a ligand exchange occurs prior to the reductive elimination of the product. The suggested mechanism shows a good resemblance with the mechanism of Yu et al as shown in Scheme 16 with the difference being the formation of dibutyl H-phosphonate and acetone from an α-hydroxyphosphonate instead of adding the H-phosphonate directly.
22 Both methods use the expensive oxidant AgOAc and elevated temperatures. The reaction may be performed under milder conditions without expensive oxidants using an electrochemical cell. This is shown in research conducted by the group of Budnikova et al in which the phosphorylation of 2-phenylpyridine is studied similar to Scheme 15.6,37 The reaction is performed using Pd(OAc)
2 as catalyst,
2 equivalents NaOAc as base, 2 equivalents BQ in MeCN at 20 °C with a constant potential. The phosphorus source is diethyl phosphite and is added dropwise and afterwards the mixture is heated at 80 °C for 1 hour and that gives the product in 68% yield.37 By changing the amount of NaOAc to 4
equivalents the product can be obtained in 78% yield which the same group published concerning the same research.6 It is speculated by the authors that the role of AgOAc depicted in Scheme 16 is not the
oxidation of Pd(0) to Pd(II) but rather the oxidation of the palladacycle to release the desired product. The mechanism is examined using dimeric palladium complexes and the proposed mechanism of the phosphorylation by Budnikova et al is depicted in Scheme 18. It shows that there are two complexes present which can both be oxidized at the anode giving either the acetoxylated or phosphorylated product. Two oxidation steps are possible in both complexes and oxidation of complex B occurs at higher potentials than that of complex A showing that oxidation of complex B is more difficult. However, complex B can be electrochemically oxidized at room temperature giving the desired product at the first oxidation potential which may show that electrochemical oxidation is more effective for complex B than for complex A. After the oxidation of complex B either Pd(III) or Pd(IV) is formed depending on the number of electrons that are transferred to the anode, but it is not mentioned if one specific species is present in the intermediate or that both species are present in the dimer and participate in the reaction. The use of BQ increases the yield and it is suggested that this is due to a shift of the oxidation potential leading to the preferred oxidation of complex B resulting in a more facile reductive elimination of the product. At the cathode a saturated solution of pyridinium tetrafluoroborate is present but is not mentioned what might occur at the cathode so it is expected that the reaction is not known. An advantage of this method is the absence of 2-2.5 equivalents AgOAc as oxidants since this would reduce the amount of waste. However, the disadvantage is the use of stoichiometric amounts of BQ but it is known in literature that BQ can be recycled by electrons.42 Thus,
a potential improvement of the method is recycling BQ (i.e. use BQ as a redox mediator) to generate less waste but the applied potential should be thoroughly studied as it can interfere with the reaction so additional research is required.
23
Scheme 18. The proposed mechanism of the phosphorylation of 2-phenylpyridine, adjusted from Budnikova et al.6
Benzene is also a potential substrate for oxidative phosphorylation although it does not contain substituents that can facilitate C-H activation.43 In 1985 the electrochemical phosphorylation
of benzene was studied by Effenberger and Kottmann.44 The reaction was performed using triethyl
phosphite as phosphorus source, Bu4NClO4 in acetonitrile at 20 °C giving the product in 38% yield. Also,
chemical oxidation was studied using Na2S2O8 and AgNO3 giving the phosphorylated benzene in 48%
yield. These methods use dangerous reagents and give moderate yield and therefore a catalytic method was studied by Ishii et al as shown in Scheme 19.38 This research conducted by Ishii et al on
benzene phosphorylation continues on alkene phosphorylation under mild conditions by the same group.45 The reaction was performed using a Mn(II)/Co(II) catalytic system under O
2 (0.5 atm) and N2
(0.5 atm) with diethyl phosphite as phosphorus source and after 5 hours at 45 °C a 62% conversion with 81% selectivity for the desired product can be obtained.
Scheme 19. Phosphonation of benzene by Ishii et al.38
A reaction with dimethyl phosphite under the same conditions gives 68% conversion and 87% selectivity but using diisopropyl phosphite gives 30% conversion and 83% selectivity showing that the phosphorus source influences the conversion. The study shows that upon addition of AcOK the reaction rate increases and it can be performed at 25 °C but a conversion of 25% and selectivity of 92% are observed. Then different substituents were tested and this showed a conversion ranging from 56-71% and p-xylene and mesitylene gave a selectivity of 90 and 82%, respectively. Reaction with electron-withdrawing substituents as –Cl and –CF3 required longer reaction times (15 hours) giving 89%
24 radical mechanism as the reaction does not run upon addition of 2,6-di-tert-butyl-4-methylphenol and as the reaction is accelerated by base a hydrogen abstraction is expected. Generation of Mn(III) by Co and O2 was proposed leading to a one-electron oxidation of diethyl phosphite by in situ generated
Mn(III) which forms a radical cationic phosphite. This is deprotonated by base and can react with benzene giving the desired product as shown in Scheme 20.
Scheme 20. Phosphonation of benzene by a Mn(II)/Co(II)/O2 system by Ishii et al.38
The conversion of the reagents was low and therefore Budnikova et al examined benzene phosphorylation.43 This study tried the phosphorylation of benzene using different catalytic systems
containing two metals that can be electrochemically oxidized from M(II) to M(III) such as manganese, cobalt or nickel. The reaction is performed in with controlled potential in a divided cell under argon using one equivalent diethyl phosphite as phosphorus source at 20 °C in a mixture of acetonitrile and acetic acid as the solubility of the manganese salts is increased by acetic acid. It is found that complexes [MnSO4/CoCl2dmphen] and [MnCl2/CoCl2bipy] are the most efficient with 100% conversion of diethyl
phosphite after passing 2 F electricity and 90% yield of phosphorylated benzene. To examine the metal complexes cyclic voltammetry was used and this showed that for CoCl2dmphen and CoCl2bipy upon
addition of a mixture of benzene and diethyl phosphite the reaction can be performed catalytically. Furthermore, a quasi-reversible peak is observed at lower potentials which presumably is a result of the coordination of diethyl phosphite to the metal forming a metal phosphonate that could be oxidized at a lower potential than the starting metal complex. It is supposed that in the mechanism a metal phosphonate is formed after which anodic oxidation of the metals occurs followed by rearrangement resulting in the metal complex and a phosphonate radical that reacts with benzene as shown in Scheme
21. An advantage of this method is the use of reagents only and no additional additives are used and
25
Scheme 21. Proposed mechanism of phosphorylation of benzene under oxidative conditions by Budnikova et al.46
Based on this research the same group performed the phosphorylation of coumarins using a bimetallic complex as catalyst.47 The phosphorylation of coumarins has been studied by Wu et al
shortly after the research on aryl C-H phosphorylation by Yu et al and Murakami et al.48 The reaction
is performed using PdCl2 as catalyst, 2,2’-bipyridine (bipy) as ligand, 3 equivalents K2S2O8 as oxidant
and diethyl phosphite in acetonitrile at 100 °C for 24 hours and this gives the product in 46% yield as shown in Scheme 22. The yield can be improved using diisopropyl phosphite or di-sec-butyl phosphite giving the phosphorylated coumarin in 56 and 59%, respectively. For C-6 methyl substituted coumarin the yield is 46 or 52% using either diethyl phosphite or diisopropyl phosphite. The method was also tested for coumarin derivatives giving the products in moderate to good yield with high regioselectivity. In general, higher yields were obtained with electron-donating groups than with electron-withdrawing groups. With an electron-donating substituent on C-7 and either diethyl phosphite or diisopropyl phosphite the product can be obtained in yields ranging from 57 to 74%. Furthermore, the method also tolerates an OH-group and CHO-group giving the product in 34 and 27% yield and 1-methyl-2-quinolinone was phosphorylated in 47% yield when diisopropyl phosphite was used. To investigate if the reaction proceeds via a radical mechanism TEMPO was added but it did not influence the reaction. Furthermore, the addition of BQ and tert-butyl hydroperoxide instead of K2S2O8
resulted in no reaction, which could be an indication that a radical mechanism is not followed. The formation of a cationic complex was found and this may be Pd(bipy) connected with one diethyl phosphite and coordinated to diethyl phosphite giving the positive charge. Then the catalyst is oxidized by the K2S2O8 to Pd(IV) after which reductive elimination can occur.
26
Scheme 22. Palladium catalyzed phosphorylation of coumarins by Wu et al.48
The phosphorylation of coumarins by Budnikova et al is performed in a divided cell using 1 equivalent diethyl phosphite, 1% [MnCl2bipy/CoCl2bipy] or [MnCl2bipy/Ni(BF4)2bipy] as catalyst in
acetonitrile in at room temperature as shown in Scheme 23.47 When the complex containing nickel is
used the products are obtained in 30-37% yield and when the cobalt complex is used in 50-70%. The higher yield is obtained when a methyl substituent is present in the coumarin and efficiency is decreased when a monometallic system is used leading to an inseparable suspension. The electrolysis in the reaction proceeds at the potential of the metal phosphonate which supports the formation of the metal phosphonates in the proposed mechanism as shown in Scheme 21. It is also expected that the high regioselectivity in the coumarin phosphorylation comes from coordination of Mn cations to the carbonyl group and participation of the cations in the radical generation in directing the reaction to the C-H next to carbonyl. The advantage of this method is the absence of K2S2O8 as oxidant and the
lower reaction temperature.
Scheme 23. Phosphorylation of coumarins catalyzed by a bimetallic complex by Dudkina et al.47
Further expansion of the substrate scope was performed by the same group using [MnCl2bipy/Ni(BF4)2bipy] as catalyst and the same method as shown in Scheme 23.46 This study tested
diethyl phosphite, diisopropyl phosphite and dibutyl phosphite as phosphorus source for phosphorylation of benzene, coumarins and benzene substituted with -CN, -NMe2 and -NO2 at the
meta and para position. When diethyl phosphite is used the products are obtained in 50-71% yield,
with diisopropyl phosphite 46-68% yield and with dibutyl phosphite 48-71% yield. This shows that the phosphorus source does not greatly influence the yield and both donating and electron-withdrawing groups are tolerated in this method. The study states that base on the research on benzene it is shown that higher yields can be obtained for all substrates including benzene and coumarins if the electrosynthesis is performed a day after mixing the substrates. This can be attributed to the formation of metal phosphonates which are oxidized at lower potentials than the bimetallic complexes and corresponds to the used potential for phosphorylation coumarins in which the reaction proceeds at the metal phosphonate potential. Using cyclic voltammetry, it is observed that the best catalytic efficiency occurs when a bimetallic complex is used, which is supported by a higher yield for a bimetallic complex in comparison with a monometallic complex. These findings support the proposed mechanism of the benzene phosphorylation as shown in Scheme 21. In addition, it is suggested that the reaction at the cathode is the reduction of protons forming H2 in the process. However, further
27 Budnikova et al also performed a direct phosphorylation on pyridine using the metal complexes Ni(BF4)2bipy and CoCl2bipy and diethyl phosphite at 20 °C in acetonitrile and this gives the
pyridyl-2-phosphonate in 85-90% yield.49 Prior to this research, different methods for phosphorylation
of pyridine were found as shown in Scheme 24. One method is the reaction of a N-methoxypyridinium salt with an alkali metal derivative of diethyl phosphonate giving the pyridine-2-phosphonates in 35-67% yield.50,51 The formation of the N-methoxypyridinium requires dimethyl sulfate and either H
2O2
and pyridine or pyridine N-oxide. In another method a pyridine cation is refluxed in benzene followed by oxidation with tetrachloro-1,4-benzoquinone (chloranil) resulting in pyridine-2-phosphonate, in unknown yields, which can be converted to phosphonic acid upon heating with HCl.51 Comparing these
methods to the one used by Budnikova et al shows the absence of H2O2 and n-butyl lithium, higher
yield of the desired product, the use of less energy as the reaction is performed at 20 °C instead of reflux and the replacement of benzene by acetonitrile, making the method more sustainable.
Scheme 24. Different methods for the phosphorylation of pyridine.51
Additional research in the same group shows the phosphorylation of hetaryl-azoles such as benzoxazoles using Ni(BF4)2bipy as catalyst in acetonitrile at 20 °C in a divided cell as shown in Scheme
25.52 It is found that diethyl phosphite coupling with benzoxazoles gives 67% yield and diethyl
phosphite is the best phosphorus source in this method but no additional information on other phosphorus sources were given. The reactions are performed in the presence of Ni(BF4)2bipy or
CoCl2bipy as catalyst. However, this seems counterintuitive since a bimetallic system in which the
catalyst is combined with MnCl2bipy is used in similar work by the group on which this research is
based. Furthermore, the authors stated that for coumarins the use of a monometallic system reduces the efficiency and gives a non-separable suspension. The reason for the formation of this suspension is not mentioned but according to the proposed catalytic cycle in Scheme 21 the reaction proceeds via the conversion of a Mn(II)-Mn(II) dimer in a dimer containing Mn(II) and Ni(II). A possible explanation is the requirement of different metal centers to create asymmetry to form the phosphorus radical. No reasoning for the low efficiency in coumarin phosphorylation is given so the possible explanation is not supported. Thus, additional research is needed to determine the role of the different metal centers in the phosphorylation of coumarins, benzene and its derivatives. Furthermore, it is advised to look into the mechanism of the phosphorylation of pyridine and hetaryl-azoles to understand why one metal center is needed instead of two centers and this could be combined with expansion of the substrate scope of both substituted pyridines as hetaryl-azoles.
28
Scheme 25. The phosphorylation of hetaryl-azoles by Budnikova et al.52
In summary, an electrochemical method for the phosphorylation of 2-phenylpyridine is found which produces the product in comparable yield to a non-electrochemical method. The reaction time at elevated temperatures is shortened and the AgOAc as oxidant is absent because it is replaced with electrodes. This decreases the required amount of energy and improves the atom economy, making it more sustainable. Nevertheless, benzoquinone is still needed in excess in the reaction to facilitate the reductive elimination. A potential solution may be the recycling of benzoquinone which could be done by electrons but this could interfere with the phosphorylation so additional research is required.
In addition, a method is found for the oxidative phosphorylation of benzene and different substituted benzenes with different phosphite sources. This method reaches higher conversion than previous ones and a higher yield is obtained. The use of Na2S2O8 as oxidant is prevented by the use of
electrodes which result in a better atom economy. A similar method is used for the phosphorylation of non-substituted and methyl-substituted coumarins with different phosphite sources. The products can be obtained in comparable yields with non-electrochemical methods and the reaction temperature is lower, thus the required amount of energy is reduced. However, the scope is limited compared to the method that uses K2S2O8 as oxidant. For both new methods, broadening of the scope
is desirable to examine whether they can be made more applicable to obtain a sustainable method while maintain the functional group tolerance.
The phosphorylation of pyridine and benzoxazoles can be performed electrochemically in high and moderate yield, respectively. The mechanisms of these reactions are not mentioned and additional research is desirable since a similar method by the same group uses bimetallic complexes instead of monometallic complexes as catalyst. In addition to understanding the mechanism, additional research could broaden the scope of the method to substituted pyridines for example.
