Recent Developments in the Transition-metal catalyzed Transfer Hydrogenation, Hydroformylation and Hydrocyanation

MSc Chemistry

Molecular sciences

Literature Thesis

Recent Developments in the Transition-metal

catalyzed Transfer Reactions

Hydrogenation, Hydroformylation and Hydrocyanation

Sagel Cali

11946008

December 2019 - April 2020

12 EC

Supervisor:

Examiner:

Marianne Lankelma

Prof. dr. Joost Reek

2

_examiner:

dr. Chris Slootweg

2. Transfer Hydrogenation ... 7

2.1 Hydrogen donors ... 8

2.2 Mechanism ... 8

2.3 Developments in the transfer hydrogenation with transition metals ...10

2.3.1 Ir-based transfer hydrogenation catalysts...10

2.3.2 Ru-based transfer hydrogenation catalysts ...11

2.3.3 Rh based TH catalysts ...14

2.3.4 Fe based TH catalysts ...16

3. Hydroformylation ...18

3.1 Transfer Hydroformylation ...20

3.1.1 Rh catalyzed transfer hydroformylation using decarbonylation-hydroformylation mechanism ...21

3.1.2 Rh catalyzed transfer hydroformylation via the direct mechanism ...25

3.2 Other syngas substitutes ...27

3.2.1 Formic acid ...27

3.2.2 Alcohols ...28

3.2.3 Butyraldehyde ...30

4. Transfer hydrocyanation ...32

4.1 Transfer hydrocyanation ...33

4.1.1 Acetone cyanohydrin (ACH) ...33

4.1.2 Trimethylsilyl cyanide (TMS-CN) ...37 4.1.3 Heterocyclic compounds ...39 4.1.3.1 Oxazoles ...39 4.1.3.2 Hydrazones ...40 4.1.4 Isobutylcyanide ...41 4.1.5 Tosyl cyanide (TsCN) ...42 4.1.6 Zinc cyanide (Zn(CN)2) ...43 4.1.7 Cyclohexadiene (CHD) ...45

5. Conclusion and discussion ...47

Abstract

Hydrogenation is the most widely applied reaction in organic synthesis, but the use of H

has a lot

of drawbacks. The toxic and harmful nature of H

led to the development of alternative methods.

Transfer hydrogenation is an alternative method which is characterized by the use of hydrogen

donors instead of H

gas. Transfer hydrogenation became a well-established method used in the

synthesis of fine chemicals and pharmaceuticals. A more recent development is transfer

hydroformylation and hydrocyanation. Substitutes such as formaldehyde and formic acid are used

in the transfer hydroformylation of alkenes and yield the aldehyde in high yield and selectivity. Two

mechanisms have been proposed which are the decarbonylation-hydroformylation and the direct

transfer hydroformylation. Transfer hydrocyanation was performed with less toxic HCN

substitutes such as acetone cyanohydrin (ACH) and TMS-CN. Heterocyclic compounds such as

oxazoles and hydrazones have proven to be a good alternative to the toxic HCN. This literature

review gives an overview of the characteristics of transfer reactions and the limitations of these

methods.

reactions. The first one is the direct hydrogenation with H

gas and a transition metal catalyst such

as palladium (Pd), rhodium (Rh) or ruthenium (Ru).

_{The second method is known as transfer}

hydrogenation and this method uses hydrogen donors as a source of H

.

This could be a donor

which can transfer hydrogens and therefore participate in the hydrogenation reaction.

This method

is more favourable than the direct hydrogenation due to the elimination of the toxic and highly

flammable H

gas. Most of the hydrogen donors which can be employed during transfer

hydrogenation are readily available and inexpensive.

The hydrogen used in the direct hydrogenation is produced via steam reforming. Steam reforming

is responsible for the production of 95% of the bulk hydrogen produced in the world.

_Steam

reforming, also known as steam methane reforming, is the process in which high temperature steam

is used to produce hydrogen from a methane source in the presence of a metal based catalyst (Eq.

1). This reaction is endothermic and therefore a substantial amount of heat is required in order for

the reaction to proceed.

𝐶𝐻4+ 𝐻2𝑂 → 𝐶𝑂 + 3𝐻2 Eq. 1

The use of high temperatures and pressures are eliminated by the use of transfer hydrogenation.

The first transfer hydrogenation using transition metals was first discovered by Henbest and

Mitchell, who showed that iridium hydride complexes were able to catalyze the transfer

hydrogenation of unsaturated ketones

and cyclohexanones to alcohols with the use of isopropanol

as hydrogen source.

_{Sasson and Blom also showed that similar transfer hydrogenation have been}

performed using Rh complexes.

_{Due to the great success of the development of transfer}

hydrogenation a lot of research has also been conducted on asymmetric transfer hydrogenation.

Noyori contributed a substantial amount of research on asymmetric transfer hydrogenation using

propanol as hydrogen donor.

_{Transfer hydrogenation has been proven to be very powerful}

methods due to the abundant availability of hydrogen donors and the elimination of the use of

hydrogen gas.

This approach could therefore also be employed in different types of reactions such as

hydroformylation and hydrocyanation. The hydroformylation and hydrocyanation are

characterized by the interaction between a substrate and an external gaseous group.

Hydroformylation is the conversion of alkenes to aldehydes with the use of a catalyst and syngas,

which is a mixture of CO and H

. Hydroformylation, also known as the oxo process, has been

discovered by Roelen in 1938 during his research in Fischer-Tropsch reactions.

_{It is currently the}

largest homogeneously catalyzed reaction in the industry and has produced nearly 10.4 million

metric tons of product. The main products are aldehydes which can be further converted to

valuable bulk chemicals such as alcohols and amines.

hydroformylation. This has inspired Dong et al. to come up with a transfer hydroformylation

method which eliminates the use of syngas.

_{The dehydroformylation of an aldehyde was driven}

by the simultaneous hydroformylation of a strained olefin. Several studies have been inspired by

the transfer hydroformylation reported by Dong and those studies describe different methods of

transfer hydroformylation. This transfer method has also been applied to other reaction such as

hydrocyanation. Transfer hydrocyanation is a fairly new field in the hydrocyanation. Several HCN

substitutes are reported in literature and will be summarized.

The use of transfer reactions is becoming a powerful tool but there are still some concerns

regarding the nature of the substrate. For example, can these reactions still take place when the

substrate is more bulky? How can the regio- and stereoselectivity be controlled during these

transfer reactions and what is the proposed mechanism of the reaction? This literature review aims

to give an overview of the characteristics and limitations of transfer hydrogenation,

hydroformylation an hydrocyanation. The research questions of this literature review are what are

the characteristics and limitations? Which problems are solved using transfer reactions and what

are the drawbacks of transfer reactions?

addition of hydrogen via a hydrogen gas substitute also known as the hydrogen donor. The

difference between hydrogenation and transfer hydrogenation is the elimination of toxic H

gas.

The reaction scope of the transfer hydrogenation is very broad and several transition metal catalyst

are able the catalyze transfer hydrogenation. The most common hydrogen donors are formic acid,

isopropanol (IPA) and triethylamine in formic acid (TEAF). There are two main pathways of

hydrogen transfer from the hydrogen donor. The first on is the direct H

transfer which is

characterized by the cyclic transition state found in Meerwein-Ponndorf-Veley (MPV) reductions.

The second one is the hydridic pathway which is characterized by the separate interaction of the

donor and acceptor units with the metal centre. The MPV reduction is known as the first published

transfer hydrogenation on the carbonyl functionality. Meerwein and Verley developed the transfer

hydrogenation of carbonyl compounds in 1925 where an aluminium oxide promoted the formation

of an alcohol via the reduction of a ketone. The alcohol is the hydrogen donor in this case.

Scheme 2: The MPV reduction via the six-membered cyclic transition state

In recent years a substantial amount of catalysts have been published such as metal oxides, Lewis

acidic or basic catalyst as well as transition metal catalysts. The first transfer hydrogenation using

transition metals was first discovered by Henbest and Mitchell and showed that iridium hydride

complexes were responsible for the transfer hydrogenation of

unsaturated ketones

and

cyclohexanones to alcohols with the use of isopropanol as hydrogen source.

The most utilized transition metals in transfer hydrogenation are Rh, Ru and Ir. Nolan et al.

reported on the Ir-catalyzed transfer hydrogenation using 2-propanol as hydrogen donor.

[Ir(cod)(py)(NHC)] was able to catalyse a wide range of substrates including alkenes, ketones and

nitroarenes. The Ir-catalyzed hydrogenation was the most efficient when ketones were used as

substrate. The first development in the Ru-catalyzed transfer hydrogenation was reported by Peris

and Danopoulus.

_{These Ru complexes consist of N-heterocyclic carbene ligands. These catalyst}

The scope of the transfer hydrogenation was explored even further when Noyori published the

asymmetric transfer hydrogenation catalyzed by a Ru catalyst in 1995. This reaction was able to

catalyze aromatic ketones and imines and transform them into alcohols and amines. The use of

cyclopentadienyl (Cp), also known as the ‘sandwich’ ligand was responsible for the asymmetric

transformation of unsaturated bonds into hydrogenated molecules via the use of isopropyl alcohol

or formic acid as hydrogen source.

2.1 Hydrogen donors

The hydrogen donors utilized in transfer hydrogenation are characterized by the presence of two

hydrogens which are able to transfer an unsaturated functional group into a saturated one under

the presence of a suitable promoter. This implies that any compound bearing hydrogens which can

be transferred could be a potential hydrogen donor. The most common hydrogen donors in

transition metal-catalyzed transfer hydrogenation are isopropanol and formic acid, these are usually

also the solvent. The use of isopropanol requires an alkoxide which acts as a base in order for the

reaction to proceed. The alkoxide is usually in excess with ratios between 5:1 all the way to 200:1

in certain reactions. Formic acid is another common used hydrogen donor which is eventually fully

dehydrogenated to CO

which makes the reaction irreversible. Formic acid is usually activated by

triethylamine but a downside of the use of formic acid is the inhibition or decomposition of the

catalyst. This is due to the strong interaction between formic acid and the catalytic complex. This

also leads to a decreased scope of this hydrogen donor in transfer hydrogenation reactions. A

hydrogen donor which is occasionally used is the Hantzsch ester. This donor is particularly used in

reduction reactions with organocatalysis or photo-redux catalysts. The Hantzsch ester is however

not extensively reported in transition metal-catalyzed hydrogenation due to the unfavourable atom

efficiency of the reaction.

2.2 Mechanism

There are two proposed reaction pathways for the transfer hydrogenation which are the direct

hydrogen transfer and the hydridic route. The direct hydrogen transfer is characterized by

simultaneous binding of the substrate and the hydrogen donor with the catalyst to form a cyclic

intermediate where the hydrogen is transferred from the donor to the acceptor in a concerted

manner. This mechanism is commonly observed with electropositive metals such as aluminium,

lanthanum and samarium. The mechanism that is observed with transition metal catalysts is the

hydridic mechanism, which can be further divided in the mono- and dihydride route. The hydridic

route is characterized by the separate interaction of the substrate and hydrogen donor with the

metal centre.

A general catalytic cycle is depicted in Scheme 4 which starts with the coordination of the hydrogen

donor with the metal centre, thereby forming the metal alkoxy species 1. This is followed up by the

beta-hydride elimination forming the metal dihydride complex 2. The substrate 3 coordinates to

the metal centre creating a metal-oxygen bond 4. The next step is the migratory insertion of the

substrate into one of the metal-hydride bonds to yield metal alkoxy complex 5. Reductive

Scheme 4: General reaction of the inner-sphere mechanism of TH

A different pathway has been proposed for Ru-complexes by Noyori et al. and is known as the

outer-sphere mechanism (Scheme 5). The catalytic cycle shows the transfer hydrogenation of

acetophenone 10. The hydrogens are transferred from the hydrogen donor in a manner which is

depicted by the transition state 12. The hydrogens of the Ru complex 8 generate the perfect angle

for the interaction with substrate 10. The outer sphere mechanism is characterized by the transfer

of hydrogens from the donor to the Ru-hydride complex 9 which forms the Ru-hydride complex

8. The substrate does not interact with the metal centre directly and this mechanism is therefore

known as the outer-sphere mechanism.

The difference between the mono- and dihydride route can be determined via deuterium labelling

experiments. Ir-catalyzed transfer hydrogenation reactions generally proceed via the monohydride

route. Ru-catalyzed transfer hydrogenation reactions are however dependent on the nature of the

ligand.

2.3 Developments in the transfer hydrogenation with

transition metals

Since the establishment of transfer hydrogenation a lot of developments have been made regarding

the different transition metals which are able to catalyse the transfer hydrogenation. Commonly

employed transition metals are Ir, Ru and Rh. A more recent development is the use of Fe as

transfer hydrogenation catalyst due to fact that Fe is a more environmentally friendly and

inexpensive metal. This chapter will give a brief overview of the different transition metals used in

transfer hydrogenation.

2.3.1 Ir-based transfer hydrogenation catalysts

The Ir-catalyzed transfer hydrogenation of ketones was established by the group of Mestoroni in

the 1980s using various Ir complexes.

_{The Ir complexes which coordinate with N-heterocyclic}

carbenes (NHC) are mostly employed in transfer hydrogenation. The Ir-NHC complexes are

formed via transmetalation of Fe(I)-NHC complexes. The group of Gulcemal showed that

substituted NHC ligands 13 led to a higher reactivity and selectivity in the transfer hydrogenation

of benzaldehyde and acetophenone. Ester functionalized Ir-NHC led to the highest activity in the

transfer hydrogenation which is due to the stabilizing interaction between the ester and the metal

centre. The reaction was performed using acetophenone and benzaldehyde as substrates and

isopropanol as hydrogen donor. The results however showed a slight preference of the transfer

hydrogenation of benzaldehyde.

Scheme 6: The Ir-NHC catalyzed TH of ketones and aldehydes by Gulcemal 12

Different substituents on the NHC such as trimethylbenzyl also showed a high activity in the

transfer hydrogenation of ketones. This reaction was performed using microwave heating and

glycerol as hydrogen donor. The benefit of using glycerol as hydrogen donor is the biodegradable

nature of the solvent. Glycerol is also a by-product in the production of biodiesel. The use of

glycerol as hydrogen donor in transfer hydrogenation therefore uses waste streams of the biodiesel

production more efficient. This reaction has proven to tolerate a wide variety of ketones and

catalyst increased even more when two imidazole substituent were introduced in combination with

Cp (15).

Another class of active transfer hydrogenation catalysts are the triazolyl substituted Ir catalysts 16.

These chelating substituents have proven to have a high activity, high stability and are easy to

modify.

_{The triazolyl substituted catalysts were used in the transfer hydrogenation of}

nitrobenzene using isopropanol as hydrogen donor.

Scheme 7: Several Ir-based Cp catalysts

There is a wide range of Ir-based transfer hydrogenation catalysts which have not been mentioned

but this chapter only gave a brief overview of the most commonly employed ones. These Ir are

excellent catalysts for the transfer hydrogenation of substituted ketones.

2.3.2 Ru-based transfer hydrogenation catalysts

Ru-based catalysts are the most used catalysts in transfer hydrogenation with high efficiency and

selectivity. NHC substituted catalysts also show promising results when used in Ru-catalyzed

transfer hydrogenation. Catalysts based on bidentate chelating NHC ligands generally show a

higher activity compared to those based on monodentate NHCs. Hwang et al. reported on a Ru

catalyst which consist of four chelating NHC ligands which required only 0.001 mol% of the

catalyst.

_{The transfer hydrogenation of ketones using this catalyst have proven to be highly}

Another class of catalysts are Ru-arene complexes such as the Noyori catalyst (Scheme 3). Arene

ligands are usually combined with NHC ligands or phosphorus-based ligands such as phosphines

and phophites (Scheme 8). Aydemir et al reported on the asymmetric transfer hydrogenation of

ketones using isopropanol as hydrogen donor.

_{The Ru-arene complex combined with chiral}

bis-phosphine ligands showed a far greater activity then catalysts without phosphorus-based ligands.

Scheme 8: Several Ru-arene catalysts with phosphorus based ligands

Ru based catalysts with pincer scaffolds have also been applied in transfer hydrogenation of ketones

(Scheme 9). Several pincer ligands have proven to be good in transfer hydrogenation such as the

dimethoxy-bipyridine ligand 17. Espino et al reported on the transfer hydrogenation using

Ru-arene complexes which consist of pincer 17 and using formic acid as hydrogen donor.

_{The oxygen}

in dihydro-bipyridine 18 also had an positive influence on the solubility of the catalyst. Another

Ru-catalyzed transfer hydrogenation using pincer like ligands was reported by the group of Yus.

Even simple and cheap amino alcohols like 19 can acts as pincer ligands in transfer hydrogenation.

Yus et al. reported on the asymmetric transfer hydrogenation of ketones which yielded the desired

product in an excellent ee and yield. Pyridine-based Ru catalysts are also another class of catalysts

which are extensively employed in transfer hydrogenation. Pizzano et al. reported on the transfer

hydrogenation using several Ru-pyridines ligands and have shown that this catalyst was able to

convert ketones into alcohols with excellent yield and ee.

Scheme 9: Common used Pincer ligands in Ru based transfer hydrogenation catalysts

A new class of catalysts in the transfer hydrogenation of ketones are the bi- and trinuclear Ru

catalysts (Scheme 10). A couple of examples of these catalysts are reported in literature. Binuclear

pyridazine-based Ru catalyst 20 was able to catalyse the TH of aromatic ketones. The activity of

trinuclear Ru catalysts have been reported by the group of Baysal.

_{The catalyst 21 was used in the}

transfer hydrogenation of substituted ketones with isopropanol as hydrogen donor and the reaction

proceeded with an excellent yield.

Scheme 10: Bi- and tridentate Ru-based transfer hydrogenation catalysts

The versatility of the Ru based transfer hydrogenation catalysts is very broad. A substantial amount

of catalyst have proven to yield the desired product of the transfer hydrogenation reaction in high

yield. A rough overview is given of the different Ru catalyst which have contributed to the field of

transfer hydrogenation.

2.3.3 Rh based TH catalysts

The previous chapter gave a rough overview of the different Ru catalysts which have contributed

to the field of transfer hydrogenation. Rh catalysts are however also extensively reported in

literature. This chapter will provide a brief overview of these catalysts. Wilkinson’s catalyst,

[Rh(PPh3)

Cl] is the most popular homogeneous hydrogenation catalyst. This catalyst was also

observed to be active in transfer hydrogenation. Another catalyst class which is extensively used

are the [Rh(NHC)(COD)] catalysts (Scheme 11).

The group of Akinci reported on the transfer hydrogenation of several substituted ketones.

Rh-COD catalyst 22 showed low activity in the transfer hydrogenation which could be due to the weak

binding of the perimidin-2ylidene ligand. This catalyst did however show great activity in the

hydrogenation using H

gas. Gulcemal showed that the mesitylene substituted imidazole catalyst

result in the desired alcohol product with a high yield.

_{This was achieved with a relatively low}

catalyst loading. The reaction was also performed without the mesitylene substituent but the yield

decreased significantly.

Scheme 11: Various Rh(COD)(NHC) catalysts

There is an increasing interest in the Rh catalyst bearing triazolyl ligands. These ligands were already

used in the Ir and Ru transfer hydrogenation reaction and were therefore also reported in Rh

catalyzed transfer hydrogenation. Elsevier et al. synthesized several square-planar Rh triazolyl

catalysts which were combined with a NHC ligand.

_{The combination of the triazolyl and NHC}

ligands has been proven to be more active than two NHC ligands.

Half-sandwich Rh catalysts are also widely applied in transfer hydrogenation using isopropanol as

hydrogen donor (Scheme 12). The Rh-Cp complex bearing bis-phosphino amine ligand 25 was

used in the transfer hydrogenation of acetophenone and led to the desired alcohol product in a

high yield and high TOF.

_{Rh-Cp complexes based on bridged pyridinium 26 have also shown to}

be active transfer hydrogenation catalysts.

_{Not only the transfer hydrogenation of ketones was}

performed successfully but also those of imines. The amine and alcohol were obtained in moderate

yield. Next to the half sandwich Rh-catalysts there are also newer catalysts which are so called

tethered half-sandwich complexes. The tethered complexes are the combination of Cp ligands and

tosylated diphenyl ethylenediamine (TsDPEN). These catalysts were able to transform ketones into

alcohols in an asymmetric manner using formic acid as hydrogen donor.

Scheme 12: Half-sandwich Rh catalysts

Carbohydrate-based ligands 27 have also been employed in Rh-based asymmetric TH catalysts

(Scheme 13). Coll et al synthesized several Rh-Cp and Rh-arene complexes containing carbohydrate

ligands which were able to transform acetophenone to the alcohol using isopropanol as hydrogen

donor.

_{The reaction tolerates a wide variety of heteroaromatic ketones leading to the alcohol in a}

excellent yield.

Scheme 13: Carbohydrate ligand used in Rh-based asymmetric TH catalysts

Water-soluble ligands such as the surfactant-like ligand 28 developed by Deng et al. has proven to

be an excellent ligand in the transfer hydrogenation (Scheme 14).

_{The high enantioselectivity of}

the alcohols is due do a synergistic effect between the metal centre and the hydrophobic

environment of the core.

2.3.4 Fe based TH catalysts

The use of iron-based catalysts offers a lot of advantages compared to the previously mentioned

transition metals. Fe-based catalysts are usually classified as a greener substitute due to the

non-toxic nature and the large abundancy on earth. The group of Chikir reported on the first

iron-catalyzed hydrogenation.

_{These catalysts were able to transform alkenes into alkanes with low}

catalyst loading and high TOF (Scheme 15).

Scheme 15: Chikir’s Fe catalysts

In 2010 Morris et al. developed several Fe-based transfer hydrogenation catalysts which are based

on tetradentate ligands (Scheme 16).

_{This catalyst 29 is able to transform ketones into chiral}

alcohols using isopropanol as hydrogen donor. The activity of the catalysts was enhanced by

introducing larger substituents on the tetradentate ligand and the partial reduction of the ligand.

Mechanistic studies showed that Fe(0) nanoparticles with achiral tetradentate ligands are the active

species which are responsible for the catalysis. The first transfer hydrogenation of imines with

excellent results was reported by the group of Beller using a similar Fe catalyst (30).

Scheme 16: Fe-based TH catalysts by Morris et al

Due to the wide application of NHC ligands in transfer hydrogenation catalysts, a few Fe

NHC-based catalyst have been synthesized (Scheme 17). Various Fe-NHC complexes were used in the

transfer hydrogenation of ketones and imines. Fe catalyst 32 was synthesized via the reaction of

imidazolium salts with [Fe(N(SiMe

)

)

]. Fe-halide catalyst 33 was also active in the transfer

hydrogenation. Formic acid was used as an hydrogen donor and the presence of a base was not

necessary. The application of Fe-based catalysts in TH is gaining more popularity over the years

and more research is performed on broadening the substrate scope.

Scheme 17: The Fe-NHC catalysts for TH

The wide application of transfer hydrogenation has led to a great alternative to conventional

hydrogenation. There are however a number of factors which lead to a successful transfer reaction:

(i) the first one is the nature of the interchanging functional group. (ii) The stability of the donor

molecule after the reaction and (iii) the stability of the desired product. The transfer

hydroformylation and hydrocyanation are gaining more popularity over the years and could

potentially lead to a safer application in industry and academia. Hydroformylation and

hydrocyanation are reactions which could be performed using a donor molecule instead of syngas

and HCN.

3. Hydroformylation

Hydroformylation is the conversion of alkenes to aldehydes by the addition of syngas in the presence of a catalyst. The possible products are the linear and the branched aldehyde (scheme 18). The ratio between the linear and branched product is dependent on the type of metal, the bite angle of the ligand and the type of substrate.30

Scheme 18: General reaction of hydroformylation

The first hydroformylation reactions were performed with cobalt in the form of [Co(H)(CO)4]. These Co complexes are known as the first generation catalysts. The second generation catalysts are the same catalysts as the first generation but the temperature and pressure which can be tolerated is much higher. The third generation catalysts are Rh-based catalysts which have a higher efficiency compared to Co-based catalysts. Co-based catalysts have the tendency to form Co carbides which lead to deposits. Rh-based catalysts are the most common used catalysts in hydroformylation but there are several other metals which are able to catalyze the reaction such as Ir, Ru and Os. This chapter will only focus on the Rh-catalyzed transfer hydroformylation because this is the most reported transition metal in literature. Rh-based catalysts have proven to have a high catalytic activity and excellent stereoselectivity towards the aldehyde.

flammable. Transfer hydroformylation is an alternative method which eliminates the use of syngas. Traditional hydroformylation is however still the most employed in both industry and academia. The most common substitute of syngas in transfer hydroformylation is formaldehyde. Transfer hydroformylation is further divided in two types depending reaction pathway. The first one (a) is the tandem decarbonylation-hydroformylation mechanism. Formaldehyde is broken down into CO and H2 and then follows the same route as the conventional hydroformylation. The second mechanism (b) is the direct use of formaldehyde without first decomposing into CO and H2.

3.1 Transfer Hydroformylation

Conventional hydroformylation uses pressurized syngas as the hydrogen and CO donor, but due to the toxicity and flammability of syngas other methods have been explored. Transfer hydroformylation is a method which is syngas-free and instead uses simple and inexpensive aldehydes as hydrogen and CO donor. This chapter summarizes all the literature reported in the Rh-catalyzed transfer hydroformylation using formaldehyde as syngas substituent. Formaldehyde is the most common syngas substitute because it is composed of the same exact elements present in syngas.

Scheme 21: The proposed decarbonylation-hydroformylation mechanism by Makado32

The proposed catalytic cycle of the decarbonylation-hydroformylation mechanism is depicted in scheme 21.32 _{Two different Rh catalysts are independently responsible for the decarbonylation and} hydroformylation. Rh complex I undergoes oxidative addition of formaldehyde to form Rh-acyl species II. The next step is CO de-insertion forming Rh-CO complex III which reductively eliminates H2, creating complex IV. The starting complex I is regenerated by the loss of CO. It is unclear whether complex I, III or IV enters the hydroformylation cycle. The hydroformylation of the alkane is depicted in the second cycle and there are three possible Rh complexes which could participate in the hydroformylation. The alkene coordinates to the Rh complex VI and thereby forms Rh-alkyl species VII. This is followed by the migratory insertion of the CO ligand creating complex VIII. Reductive elimination of the aldehyde is driven by the addition of H2.

of 1-hexene with formaldehyde catalyzed by [RhH2(O2COH)-(PiPr3)2].33 The reaction had a moderate yield due to the formation of hexanol. Several alkene substrates were tested but the use of 1-hexene led to the highest yield.

This hydroformylation reaction has also been tested by the group of Ahn using [RhH(CO)-(PPh3)3] and they found alkenes with an alcohol or carbonyl at the beta position have higher reaction rate than alkenes without the alcohol or carbonyl.34 _{This is due to the olefin forming a metallacycle with the Rh complex and} the alcohol or carbonyl, creating a five membered ring. Rosales et al were also inspired by the Rh-catalyzed TH of Ahn et al using [RhH(CO)-(PPh3)3] (Scheme 22).35 Different commonly used transfer hydroformylation Rh catalysts such as [Rh(acac)(CO)2] were used but the yield could not compare to when [RhH(CO)-(PPh3)3] was used. Increasing the temperature did not affect the yield nor selectivity. The addition of one equivalent of dppe however substantially increased the yield. The use of [RH(acac)(CO)2/2dppe] resulted in an increased reaction rate and yield, but the selectivity towards the linear or branched aldehyde was moderate.

Scheme 22: Rh catalyzed hydroformylation of 1-hexene using formaldehyde by Rosales35

Makado et al reported in 2010 on the linear-selective transfer hydroformylation using formaldehyde as syngas substitute (Scheme 23).36 _{Two catalysts have been used during this reaction, the first one is able to} catalyze decarbonylation of formaldehyde towards CO and H2 and these components are then further employed in the consecutive hydroformylation reaction. The decarbonylation and hydroformylation reaction should be controlled in such a manner that the hydroformylation takes place after the decarbonylation. The order in which the reaction takes place is controlled by the use of two catalysts. The decarbonylation catalyst consists of a strong diphosphine ligand, BINAP, which ensures that the decarbonylation is preferred. 37 _{The ligand chosen for the hydroformylation was Xantpos. Several control} reactions were performed to look at the effect of these ligands. When only Rh-BINAP was used the aldehyde was isolated in a high yield. When only Rh-Xantphos was used only trace amount of aldehyde was formed but the selectivity was high. This indicates that Rh-BINAP is essential for the formation of H2 and CO. The combined use of Rh-BINAP and Rh-Xantphos resulted in a high yield and selectivity towards the linear aldehyde. After further optimization they found that the combination of Rh-BIPHEP and Rh-Nixantphos gave even better results. The yield increased to 95% and the selectivity remained the same.

The catalyst reported by Makado has also been used for the total synthesis of sedum alkaloids reported by Ren et al. 38 _{The desired product 40 had a yield of 46% and a large amount of by-product was formed due} to the presence of traces of methanol in formaldehyde. 1_{H NMR analysis of the crude reaction mixture} showed formation of the desired product 40 and the by-product with a ratio of 5:3 (Scheme 24).

Scheme 24: The intramolecular amido carbonylation with formaldehyde

The reaction time of the Rh catalyzed hydroformylation reported by Makado et al is 20 hours but Taddei has proven that the reaction time can be decreased to only 30 minutes via microwave heating.39 _Several substrates such as alkyl alkenes, benzylic alkenes and bulky alkenes all converted to the aldehyde product with excellent yield and a high linear selectivity. This method has also been applied to a β,γ-unsaturated amide which is known to undergo cyclization (Scheme 25). The cyclized product was obtained in a high yield and within 30 minutes. The Rh catalyzed microwave assisted hydroformylation has proven to be a successful method for simple and complex substrates.

Scheme 25: The Rh catalyzed domino hydroformylation-cyclization using formalin39

Uhlemann and co-workers also used the method published by Makado in which the transfer hydroformylation is catalysed by two Rh complexes.40 _{Uhlemann reported on the Rh-catalyzed transfer} hydroformylation with formaldehyde and additional H2 gas. The substrate was 1-octene and the reaction was catalyzed by [Rh(cod)2(Cl)2(BINAP)] with formaldehyde and 10 bar of H2 gas. The additional hydrogen gas improved the conversion and selectivity for the linear aldehyde. Trace amounts of octane have also been detected due to the increased amount of H2 in the system. Other hydrogen sources have also been tested such as formic acid and the reaction proceeded with a moderate yield. The benefit of this reaction is the increased regioselectivity towards the linear aldehyde, but the addition of gaseous H2 is still a downside. The use of Rh-BIPHEP and Rh-Nixantphos as transfer hydroformylation catalysts has become a good

remained unaffected.

Scheme 26: Asymmetric Rh-catalyzed hydroformylation of styrene using formaldehyde by Makado32

Several papers have been published on conventional asymmetric hydroformylation but recently Feuntes published a paper on asymmetric transfer hydroformylation.41–43 _{Several ligands have been tested for the} transfer hydroformylation of cis-stilbene. Commonly used ligands such as BINAP and Xantphos have been tested but these yielded racemic aldehydes as expected. Several commonly used ligands in hydroformylation such as BOBPHOS (41) Kelliphite (42) have been used. The conversion was relatively high but the aldehyde was retrieved in very low yield (Scheme 27).

Scheme 27: Common used hydroformylation ligands

The group of Fuentes published an article in 2010, the same year as Makado et al.43 _{The group of Makado} showed that two different Rh catalysts were independently responsible for the transfer hydroformylation. The group of Fuentes however showed that using [Rh(Cl(COD)2(R,R)-Ph-bpe] was able to catalyze both the decarbonylation and the hydroformylation.The catalyst was tested in the hydroformylation of cis-stilbene and the aldehyde was formed in a high yield and selectivity. These results showed that [Rh(acac)(CO)2(R,R)-Ph-bpe] could be used in the asymmetric hydroformylation of alkenes. Several substituted cis-stilbenes, such as 4-methoxybenzene and 3-methoxybenzene were hydroformylated with high enantioselectivity (Scheme 28).

All examples of Rh catalyzed transfer hydroformylation mentioned in this chapter were proposed to follow the decarbonylation-hydroformylation mechanism. Fuentes et al proposed that the pressure build up in the beginning of the reaction is due to the formation of CO and H2.

The proposed mechanism was also confirmed via deuterium labelling when carried out with cis-stilbene and deuterated formaldehyde. The reaction proceeded the same as the non-deuterated formaldehyde hydroformylation with a 5.7:1 ratio between the deuterated aldehyde and the deuterated cis-stilbene. The 1_{H isotope was also present at the beta position which is consistent with the} decarbonylation-hydroformylation mechanism (Scheme 29)

Scheme 29: The formation of aldehydes via the decarbonylation-hydroformylation mechanism

These methods have been created to rely less on the use of syngas and to eventually transition towards syngas-free hydroformylation methods. This section summarized all the reports of the transfer hydroformylation via the decarbonylation-hydroformylation mechanism. The other mechanism which has been reported is the direct transfer hydroformylation via the formation of Rh-formyl complexes. Recent developments on transfer hydroformylation via the direct transfer hydroformylation mechanism will be discussed in the coming section.

catalyzed C-C bond cleavage by transfer hydroformylation.8 _{This work has been inspired by the} monooxygenases, a class of the cytochrome P450 enzymes, which are able to convert aldehydes into olefins (the reverse of the hydroformylation reaction).

Scheme 30: The possible products of the hydroacylation, decarbonylation and dehydroformylation

This reaction is rather difficult due to the required activation of the aldehyde C-H bond. The Rh-acyl intermediate would rather proceed the reaction via the hydroacylation and decarbonylation instead of the dehydroformylation product (Scheme 30). In order for the dehydroformylation to proceed, a method has been created in which the hydroformylation of an aldehyde is driven by the simultaneous hydroformylation of a strained olefin. This method is inspired by the article of Diem et al in which the hydroacylation of cyclopropenes is reported.44 _{They speculated that the released strain energy would favour the hydroacylation} over the decarbonylation.45 _{This reaction has proven to be very versatile with a wide substrate scope and} the use of ferrocene-based phosphines resulted in a high yield and conversion.

Dong and co-workers were inspired by the hydroacylation reaction described by Diem et al and implemented it into the Rh-catalyzed transfer hydroformylation of norbornadiene (Scheme 31).8 _{Several ligands have been} used and the use of Xantphos has proven to be an excellent ligand. The addition of counterions (X) also led to an increase of the yield. Typical small counterions (X) of the Rh complex such as Cl- _{and BF4- have} been used but unfortunately led to a small amount of decarbonylation product. Larger counterions like I -resulted in a mixture of dehydroformylation and decarbonylation products but the quantity was still too low. The use of 1-methoxybenzoate substantially increased the yield (99%) and the ratio between dehydroformylation and decarbonylation (99:1).

Scheme 31: Rh catalyzed transfer hydroformylation

The choice of olefin is norbornadiene (nbd) due to the strain energy which is released in the reaction. Similar acceptors, such as norbornene (nbe) and benzonorbornadiene (bnbd) and all resulted in the aldehyde in a high yield. The ratio between the dehydroformylation and decarbonylation product was 99:1. The more strained the acceptor, the more the temperature could be decreased but this also resulted in the necessity

This reaction tolerates a large substrate scope such as aldehydes, carboxaldehydes and cyclic aldehydes. All reactions had an average yield of 80% and a high selectivity towards the dehydroformylation product 46. The transfer hydroformylation reaction was performed using nbd which eventually resulted in the formation of 5-norbornene-2-carboxaldehyde 47. This study showed that the transfer hydroformylation of a strained olefin could be driven by the reverse hydroformylation. Stochiometric quantities of aldehyde 47 have been observed during the dehydroformylation reaction.

Scheme 32: Proposed catalytic cycle of the transfer hydroformylation/dehydroformylation taken from Dong8

The cycle starts with neutral Rh-methoxy benzoate complex 48a which reacts with the aldehyde substrate

45 (Scheme 32). The aldehyde C-H bond is activated, resulting in complex 48b. The aldehyde and the

methoxy benzoate are still both present in the complex. The methoxy benzoate ligand undergoes reductive elimination, resulting in complex 48c. The CO ligand in complex 48c undergoes the reverse insertion and binds to the Rh metal centre creating complex 48d which is followed by the beta hydride elimination, forming 48e. The next step is the coordination of norbornadiene 49 with complex 48e forming complex

48f. This step is followed by the migratory insertion of CO and eventually leads to the transfer

hydroformylation product, 5-norbornene-2-carboxaldehyde 47. The proposed mechanism shows that the strained olefin acceptor and proton transfer of the methoxy benzoate are responsible for the high reactivity and selectivity. This article published by Dong has shown that transfer hydroformylation is possible when a strained olefin is used.

Scheme 33: The hydroformylation of an olefin via the decarboxylation using formic acid46

Formaldehyde is the most commonly used syngas substitute but Ren et al recently published the Pd-catalyzed hydroformylation with the use of formic acid.46 _{Formic acid is commonly used in the formation of} carboxylic acids via olefins (Scheme 33). The carboxylation of olefin 50 with formic acid goes via intermediate 51 and eventually yields carboxylic acid 52, but the reaction can also be tuned in a way that intermediate 51 losses CO2 and therefore forms Pd-hydride complex 53 and eventually yields aldehyde 54. Ren et al came up with this method in which the transfer hydroformylation is favoured over the carboxylation. The use of dppp led to the highest yield compared to other ligands, such as dppe, dppb and BINAP. The styrene substrate led to a high yield and an almost complete selectivity towards the linear product. This reaction has a large substrate scope: a wide range of styrene derivates, aliphatic olefins and cyclic olefins are converted to the desired aldehydes in good yields and selectivity.

The reaction mechanism of this hydroformylation reaction is not clear but a proposed catalytic cycle is depicted in scheme 34. The first step is the migratory insertion of olefin 50 into the Pd-hydride bond, creating Pd-alkyl complex 56 and followed by the CO de-insertion, creating complex 57. The acetate ligand is replaced by a iodide and therefore creating the Pd-iodide complex 58 and subsequently followed by the reaction of complex 58 with formic acid creating complex 59. Complex 62 is formed via the loss of CO2 and the last step is the reductive elimination creating the aldehyde 54. Intermediate 51 has can follow two different reaction pathways. The first one is the reductive elimination which forms anhydride 60. This is the pathway which eventually leads to the formation of the carboxylic acid 52. The second pathway is the desired route which starts with the loss of CO2. This pathway is favoured due to the bite angle of dppp which favours the loss of CO2 over the reductive elimination.

Scheme 34: The proposed catalytic cycle of the Pd-catalyzed hydroformylation using formic acid.

3.2.2 Alcohols

Polyols could be a great substitute of syngas during hydroformylation reactions. Verendel et al demonstrated the hydroformylation of alkenes using polyols as the source of H2 and CO.47 A dual reactor system has been created to first decompose the polyols into H2 and CO catalyzed by an Ir catalyst (A). The H2 and CO are further used in the Rh-catalyzed hydroformylation (B) (Scheme 35). The choice of catalyst was Wilkinson’s catalyst due to its efficiency under mild conditions. Several polyols have been used as a source of H2 and CO, such as primary alcohols, secondary alcohols and various naturally occurring saccharides. The use of primary alcohol 67 resulted in a high yield and linear selectivity. A structurally similar alcohol 68 also resulted in a high yield and a linear selectivity. A small amount of the hydrogenated styrene was also detected, which could be due to the accumulation of H2 in the system. Polyols 69 and 70 led to further a decrease in the yield of the aldehyde and an increase of the hydrogenated styrene. The longer the polyol, the greater the effect of the build-up of H2. Several hydrogen acceptors have been used in the Ir-catalyzed decarbonylation (Reactor A) to decrease the build-up of H2 but this also led to a decrease in the conversion of styrene because less Ir catalyst was available for the decarbonylation. This method has proven that small primary alcohols can be successful syngas substitutes in the Rh-catalyzed hydroformylation but the build-up of H2 is a downside when larger alcohols are used.

Scheme 35: The dual system of the transfer of polyols through the Ir-catalyzed dehydrogenation-decarbonylation (A) followed by the Rh-catalyzed hydroformylation (B)

In 2015 Christensen also reported on the use of alcohols as a possible syngas substitute via a two-vessel system. 48 _{The reaction is divided into two chambers. In which the first one, the dehydrogenation of an} alcohol is catalyzed by an Ir-BINAP catalyst which results into H2 and CO (Scheme 36). The second chamber is where the hydroformylation takes place which is catalyzed by Wilkinson’s catalyst. This is the same catalyst which has been used by Verendel47 _{and has proven to be good hydroformylation catalyst.} Several primary alcohols such as 1-pentanol, 1-heptanol and 1,6-hexanediol all resulted in high yield and little to no formation of hydrogenated styrene. 1,6-hexanediol has proven to be an excellent substrate which led to 100% yield. Verendel already mentioned that the more hydroxy substituents and the larger the alcohol, the more H2 in the system which eventually leads to hydrogenated substrates. 1,6-Hexanediol is a relatively small substrate and therefore eliminates the build-up of H2

3.2.3 Butyraldehyde

Recently Tan et al established the regioselective transfer hydroformylation of alkynes using n-butyraldehyde as syngas substitute (Scheme 37). 49 _{The catalyst of choice was [Rh(cod)OMe2 (Xantphos)] due to the} excellent performance in the transfer hydroformylation reported by Dong.8 _{This reaction also required the} addition of a carboxylic acid and nitrobenzoic acid has proven to be the acid which gave the highest yield. Several alkyne substrates, such as symmetric internal alkynes, cyclic alkynes and aryl alkynes, formed the α,β-unsaturated aldehydes in high yield and complete E-selectivity.

Scheme 37: The Rh catalyzed transfer hydroformylation of alkynes using butyraldehyde

The proposed catalytic cycle of the transfer hydroformylation of alkynes is depicted in scheme 38, which starts with the oxidative addition of the aldehyde and therefore activating the C-H bond to form Rh-hydride complex 72. This is followed by the reductive elimination of HX which results in Rh-acyl species 73, which undergoes de-insertion of CO forming complex 74. The next step is the β-hydride elimination which leads to the allylic coordinated alkene Rh complex 75 followed up by exchange of the alkene for the incoming alkyne. The release of propene gas is the driving force of the reaction. Rh-acyl 76 complex undergoes oxidative addition of the acid, thereby creating Rh-hydride complex 77. The last step is reductive elimination of the α,β-unsaturated aldehyde, thus completing the cycle. The carboxylic acid, nitrobenzoic acid is involved in several steps of the catalytic cycle. Nitrobenzoic acid is suggested to play a crucial role in the formation of RhLnX complex 71 where the X is the benzoic acid counterion. The acid also participates in the deprotonation of Rh-acyl species 72, promoting the reductive elimination towards Rh-acyl complex 73 and the oxidative addition towards complex 78.

Scheme 38: The proposed mechanism of the transfer hydroformylation reaction of alkynes

This chapter has described the methods which are known in the field of transfer hydroformylation. The literature shows that there are two main pathways, the tandem decarbonylation-hydroformylation method and the direct transfer hydroformylation driven by the release of strain energy. The most common syngas substitute was formaldehyde but several articles reported on the use of similar substitutes. Compared to traditional hydroformylation, transfer hydroformylation has proven to be a safer method which is versatile and offers a practical and simple route to aldehydes.

4. Transfer hydrocyanation

Recent developments in the transfer hydroformylation have proven that the transfer between a H2 and CO donor and acceptor is possible. This method could therefore also be applied to different reactions which are characterized by the catalytic transfer of a donor to an acceptor. Hydrocyanation is the addition of hydrogen cyanide (HCN) to an unsaturated bond of an alkene or alkyne to create a nitrile functionality. Nitriles are versatile intermediates which play an important role in the preparation of pharmaceuticals. Most studies focus on the synthesis of nitriles with the use of HCN and the most used transition metal is nickel.

Scheme 39: The hydrocyanation of an alkene resulting in the linear and branched aldehyde

The DuPont adiponitrile process is an example of the application of hydrocyanation. Adiponitrile is the precursor of Nylon-6,6 which is formed by reacting HCN with 1,3-butadiene. There are several drawbacks to this reaction, e.g. the toxic and explosive nature of HCN. The substrate scope is also limited because most of the research is focused on aryl alkenes and much less is reported on aliphatic alkenes due to their lower reactivity. Hydrocyanation can yield linear and branched nitriles. The low control over the regioselectivity is another drawback usually with aliphatic alkenes.

The first hydrocyanation reaction was reported by Arthur et al using Co2(CO)8 and this led to the Markovnikov addition of HCN. Co-catalyzed hydrocyanation are mostly performed at high temperatures and generally have a low TOF. Co-based hydrocyanation catalysts are currently replaced by the more efficient Ni analogues. Ni-catalyzed hydrocyanation starts with the oxidative addition of HCN, creating a Ni-hydride complex. The alkene coordinates and forms the Ni-alkyl complex via a migratory insertion. The nitrile product is finally released via reductive elimination. The reductive elimination is the slowest step in the process and is accelerated by the addition of Lewis acids. Lewis acids may also influence the regioselectivity but this is not certain.

Previous studies have established the Ni-catalyzed hydrocyanation but recently there is an increase in explorations of transfer hydrocyanation which eliminates the use of toxic HCN. Commonly used HCN substitutes are acetone cyanohydrin (ACH) and TMS-CN. The use of these substitutes allows for a safer alternative to the existing hydrocyanation. Hydrocyanation is more extensity applied in industry compared to academia due to the safety hazards concerning HCN. The use of these substitutes could lead to an increase in the hydrocyanation applied in academia. Even though these substitutes are a safer alternative there are still some drawbacks which should be mentioned. A substantial amount of HCN is required for the for the synthesis of ACH and TMS-CN, and the elimination of HCN is therefore not achieved. The use of these HCN substitutes is a good development but even safer methods should be created. Recently several promising hydrocyanation reactions involving heterocyclic compounds as HCN donor have been reported. This chapter will give an overview of all the reported HCN donors in the transfer hydrocyanation.

acrylate. Next to the production of plastic, ACH is also used in transfer hydrocyanation as an HCN substitute. ACH has proven to be a safer alternative compared to the toxic HCN. One of the advantages is the liquid state of ACH, which allows for safe handling compared to HCN.

Several articles have been published on transfer hydrocyanation with the use of ACH. One of the first reported transfer hydrocyanation using ACH was performed by Park et al.50 _{This reaction was performing} by reacting diazoacetates with ACH using a Cu catalyst (Scheme 40). The first test reaction was performed with Copper(I) chloride but the yield was low, however when switching to cationic catalyst [Cu(CH3CN)4 PF6] improved the yield substantially. The addition of TMS-CN increased the conversion due to the presence of free CN- _{in the system which accelerates the reaction rate. Several substituted phenyls were all} tolerated in the reaction and yielded the nitrile in a good yield. The methoxy group was also changed for larger substituents but this did not influence the yield negatively. The diastereoselective hydrocyanation has also been tested to further examine the scope of the reaction. Optical active alpha-aryl diazoacetates were synthesized and used as substrate in the transfer hydrocyanation. The diastereoselectivity was low but increased when the larger substituents were used but the substrate scope was not broad.

Scheme 40: The Cu-catalyzed transfer hydrocyanation using ACH and TMS-CN

Arai et al studied the Ni-catalyzed hydrocyanation of allenes using ACH.51 _{The allene functionality has the} ability to forms five different intermediates due to the various unsaturated bonds which could participate in the reaction. Aryl substituents have been proven to lead to the highest yield and regioselectivity (Scheme 41). The aryl substituent forms a trans-styryl derivate which is thermodynamically favoured over other substituents. An aryl substituent is therefore necessary in the substrate for the reaction to proceed with a high regioselectivity.

Scheme 41: The Ni-catalyzed hydroformylation of allenes by Arai

When the nitrogen protected substituent was replaced by an alkyl group, the reaction still proceeded with a good yield and regioselectivity. This also applies to cycloalkene rings and aromatic indole functionalities. The control of the regioselectivity was further examined by the introduction of an cyclopropane substituent. This substituent is known to undergo a C-C bond cleavage and the transfer hydrocyanation reaction could therefore yield different products. The reaction pathway of the Ni-catalyzed transfer hydrocyanation is depicted in Scheme 42.

Alkene 81 was not observed during the reaction. This was the main product in the transfer hydrocyanation without the cyclopropane substituent. This could be explained by the fact that beta-hydride elimination is favoured over reductive elimination. This Ni-catalyzed transfer hydrocyanation has proven to be applicable for the hydrocyanation of di-substituted allenes towards nitriles in a regioselective manner. The introduction of the cyclopropane substituent is another method of controlling the regioselectivity via a C-C bond cleavage.

Scheme 42: The proposed reaction pathway of the transfer hydrocyanation via C-C bond breakage.

The ACH transfer hydrocyanation by Arai et al was later employed in the total synthesis of Quebrachamine by the same group (Scheme 43).52 _{This compound shows biological activity in the urogenital tissue. The} transfer hydrocyanation was one of the key steps in the total synthesis.

Scheme 43: The synthesis of Quebrachamine via the stereoselective transfer hydrocyanation of arylallene

Nemoto et al have also studied Ni-catalyzed transfer hydrocyanation using ACH, aiming to easily convert simple alkenes to nitriles with a safer HCN source (Scheme 44).53 _{Ni(acac)2(H2O) was initially chosen as the} catalyst as it is a good precursor to Ni(0). The transfer hydrocyanation reaction proceeded to yield the product in only 4%. Several solvent were tested to increase the yield but unfortunately had no effect. The use of Ni halide hydrates such as NiCl2(H2O) substantially increased the yield. The solubility of the catalyst is important and polar solvents have proven to be requisite for the reaction to proceed. The use of DMF resulted in the highest yield. The use of diphosphine ligands improved the yield even more, dppp was the best ligand for this reaction. The reaction has proven to be compatible with aromatic, heterocyclic and aliphatic alkenes.

Scheme 44: The Ni-catalyzed transfer hydrocyanation of alkenes using ACH by Nemoto et al53

In 2017 Ritter et al published a study on the Rh-catalyzed hydrocyanation of terminal alkynes with anti-Markovnikov regioselectivity using ACH (Scheme 45).54 _{Several commonly Rh-catalysts have been tested} and TpRh(COD) has proven to be superior. The Tp (Tris(1-pyrazolyl)borohydride) ligand was one of the few ligands which resulted in alkenes with anti-Markovnikov selectivity. Several functionalized alkynes with e.g. esters, halides, phenols and amides have proven to be good substrates. Aliphatic functional groups were also tolerated but the anti-Markovnikov selectivity was lower than that of aromatic functional groups.

Scheme 45: The Rh-catalyzed transfer hydrocyanation of terminal alkynes by Ritter et al54

Recently Fang et al reported on the Markovnikov regioselective Ni-catalyzed transfer hydrocyanation of α-substituted styrenes without the aid of a Lewis acid.55 _{Several ligands which have proven to be efficient in} hydrocyanation reactions were used but very low yields were observed. Eventually the use of binaphthol-based diphosphite ligands substantially increased the yield. The substrate scope of this reaction is very broad: various aromatic, cyclic and complex alkenes were tolerated. Electron-rich aryls led to a high yield, and electron-withdrawing substituents led to a decrease in the yield. The elimination of Lewis acids enhanced the functional group tolerance especially for the substituent with unprotected OH and NH2 groups. This transfer hydrocyanation led to formation of nitriles with substituents bearing unprotected OH and NH2 groups.

Several HCN sources are reported in literature but ACH is known as one of the most commonly used ones for transfer hydrocyanation. The use of ACH should allow for safer handling compared to HCN, but ACH does also bear some drawbacks. ACH is labelled as lethal by inhalation and skin absorption even though it is commonly characterized as a safe HCN source in literature.

In 2010 an article appeared on a safer method for the production of ACH. This procedure starts with the production of HCN from potassium cyanide and acetic acid (Scheme 46). 56 _{Once the HCN is formed it}

transfer hydrocyanations performed with TMS-CN.

The first transfer hydrocyanation using TMS-CN was reported by Iida et al (Scheme 47).57 _{The transfer} hydrocyanation was performed with chalcone and TMS-CN without any solvent or catalyst. This was followed by the addition of TBAF to deprotect the carbonyl group. Only the 1,3-nitrile was detected and not the 1,2-nitrile. Several substituted chalcones led to the nitrile in a good yield, but the substrate scope of this reaction is very narrow. This catalyst could only be applied in the transfer hydrocyanation of substituted chalcones. This transfer hydrocyanation was performed without the use of any catalyst and which could be the reason behind the small substrate scope.

Scheme 47: The transfer hydrocyanation of chalcones using TMS-CN

Falk et al reported on the enantioselective transfer hydrocyanation of vinylarenes with TMS-CN as a HCN source (Scheme 48).58 _{The reaction was first performed with styrene and ACH as a test reaction and a} phosphite-phosphine ligand and the reaction proceeded with a moderate yield and selectivity. Varying the aryl substituent of the ligand and the addition of an isopropyl group substantially increased the ee. The reaction performed with ACH or TMS-CN both resulted in the nitrile with moderate yield. The yield was also influenced by the choice of solvent, THF increases the yield in comparison to DCM.

Scheme 48: The Ni-catalyzed transfer hydrocyanation using ACH or TMS-CN

The transfer hydrocyanation of terminal alkynes with TMS-CN was studied by the group of Arai(Scheme 49).59 _{This reaction was also performed using ACH, but the use of TMS-CN increased the yield and the} selectivity remained the same. Several proton donors have been tested but trifluoroethanol (TFE) has shown to be slightly more efficient over methanol and water. Sulfonamide alkynes were able to stabilize organonickel(II) complexes and therefore control the hydronickelation.

hydrocyanation but has great promise for the future.

4.1.3.1 Oxazoles

Schuppe and his group suggested that heterocyclic aromatic compounds could be potential HCN donors due to the nitrogen and carbon atoms which are present in the molecule (Scheme 50).60 _{Several heterocycles,} such as pyrimidines, pyrazines and oxazoles, have been proposed as possible HCN donors, because these heterocycles usually yield nitriles as by-products in cycloadditions. Oxazoles possess only one nitrogen atom and will therefore not introduce any regiochemical complications.

Scheme 50: The Pd-Cu catalyzed transfer hydrocyanation of alkenes

The transfer hydrocyanation was performed using styrene as a substrate and several substituted oxazoles which yield the nitrile via a dual Pd-Cu catalytic cycle. The reaction consist of two steps which are the Pd/Cu-catalyzed hydroarylation using the oxazole and a consecutive [4+2]/retro-[4+2] cycloaddition. The cycle starts with the alkene coordination and the migratory insertion of alkene 86 into Cu-hydride bond of catalyst species I. (Scheme 51). The Pd-catalyzed cycle starts with the oxidative addition of the halide- carbon bond of the oxazole 87 over Pd(0) species III. A consecutive transmetalation of Cu-alkyl species II with Pd-halide complex IV creates Pd-alkyl species V. The latter undergoes reductive elimination which results in the formation of oxazole 89.

The second step is a [4+2] cycloaddition between oxazole 89 and alkyne 90, to form the strained cycloheptadiene 91. Nitrile 88 is formed via the retro [4+2] cycloaddition, with the release of furan 92 (Scheme 52).

Scheme 52: The [4+2]/retro-[4+2] sequence of oxazole 89

Several halide-substituted oxazoles have been examined and bromide-substituted oxazole 87 has proven to result in the highest yield. The substrate scope of this reaction is very broad; various para- and ortho- substituted alkenes all resulted in the nitrile with a good yield and enantioselectivity. N-Heterocyclic substituted alkenes were also transformed to the nitrile product. However, this was not the case when cyclic substrates were used. The yield was low and this could be due to the steric hindrance which results in a difficult transmetalation between Cu-alkene (II) and Pd-halide species IV.

4.1.3.2 Hydrazones

The above described hydrocyanation via hydroarylation and [4+2] cycloaddition has proven to be an excellent method to yield nitriles in an enantioselective manner. This method also eliminates the need to use of HCN, which is not the case when ACH or TMS-CN are used as HCN substitutes. This is the first and only publication on the use of oxazoles as HCN substitute in transfer hydrocyanation.

In the same year Li et al reported on another two-step reaction which yields nitriles in an excellent yield (Scheme 53).61 _{The reaction starts with hydroformylation of an alkene followed by condensation and lastly} an aza cope elimination which yields the nitrile. The hydroformylation is performed using Rh(acac)(CO)2/(S,S)-Ph-bpe) which yields the branched aldehyde in an enantioselective manner. This aldehyde then undergoes condensation with hydrazine which forms the hydrazones upon loss of H2O. The condensation step was proven to be the enantioselective step when conjugated hydrazones were used, the ee of the reaction remained high, but after the condensation a racemic mixture of the nitrile was obtained. When weakly conjugated hydrazones were employed, the ee was low but after the condensation the ee remained the same in contrast with the strongly conjugated hydrazones. Weakly conjugates hydrazones were therefore used despite the low ee. Several methods have been uses to increase the ee such as the addition of an additive which is responsible for the acceleration of the condensation step which will avoid racemization. Various additives have been used such as molecular sieves and several acids, but the addition of benzoic acid has proven to be far superior.

type II (Scheme 54). The reaction starts with the hydroformylation of pyrroline 95, followed by the an aza-Cope rearrangement which yields nitrile 96.

Scheme 54: The synthesis of Anagliptin

4.1.4 Isobutylcyanide

In 2016 Morandi et al. reported on the reversible transfer hydrocyanation of substituted alkenes using isobutylcyanide 98 as HCN donor (Scheme 55).62 _{Substituted aromatic alkenes were examined using} Ni(cod)2(DPEphos) in toluene which yielded the linear nitrile with a good yield and selectivity. Several aliphatic nitriles were used as HCN donor but isobutylcyanide has proven to be far superior. The yield increased even more when the reaction was performed in the presence of air. The driving force of this reaction is the formation of gaseous alkene 100. Various functionalized aromatic and aliphatic alkenes yielded nitriles in good yield with a linear selectivity. Several medicinal compounds like Nabumetone and Pheniramine have been synthesized using this transfer hydrocyanation reaction. The reaction using styrene and isobutylcyanide was performed on a multigram scale and gave nitrile 99 in excellent yield (Scheme 55).

Scheme 55: The Ni-catalyzed transfer hydrocyanation of alkenes using isobutylcyanide62

The nitrile 99 that was formed in the hydrocyanation using isobutylcyanide was used as a substrate in the reverse transfer hydrocyanation. Norbornadiene and norbornene were both applied as HCN acceptors and the results showed that a more strained HCN acceptor led to a better yield. A wide variety of styrenes, aliphatic alkenes and terpene derivatives has been prepared via the retro transfer hydrocyanation. This is the first published reversible transfer hydrocyanation using isobutylcyanide as HCN donor and norbornadiene