University of Groningen

Carbon-nitrogen bond formation via catalytic alcohol activationYan, Tao

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1

Chapter 1

Borrowing hydrogen meets metal-ligand bifunctional catalysis,

an introduction to the thesis

1.1 Introduction

1.1.1 Catalysis: key to a sustainable future

1.1.2 Catalytic carbon-nitrogen bond formation: the focus of this thesis

1.2 Metal-ligand bifunctional catalysis

1.2.1 Background

1.2.2 The Shvo catalyst

1.2.3 The Knölker complex

1.2.4 Recent progress in bifunctional catalysis

1.3 Catalysis based on the borrowing hydrogen strategy

1.3.1 Alkylation of amines with alcohols through borrowing hydrogen

1.3.2 Challenges and recent discoveries

1.4 Conclusion

1.5 Outline of the thesis

Chapter 1

2

1.1 Introduction

1.1.1 Catalysis: the key to a sustainable future

Catalysis is the tool to tune the kinetics of a chemical transformation, that allows

desired reactions to be conducted selectively, under mild reaction conditions.[1]

Catalysis is one of the few areas with a direct influence on our daily life.[2] It

contributes directly and indirectly to 35% of the global GDP.[3]

Currently, a variety of chemical transformations still rely on the use of

stoichiometric reagents and low atom economy processes.[1,2,4] These include the

use of protecting groups or harsh reaction conditions, mainly due to high activation

energy of the desired transformations. During these processes, stoichiometric

amount of side-products are produced and frequently discarded. Also, the

increasing demand for a more environmental benign society and the changing

landscape of accessible chemical feedstocks and energy sources, indicate we are

facing a transition period of energy and chemical production.[5]

Catalysis, beyond accelerating chemical transformations, allows the use of

renewable carbon sources through converting bio-based molecules and CO2 to

more valuable chemicals, as well as accessing alternative energy such as

converting and storing solar energy in chemicals.[5,6] Consequently, the new

advances in catalysis will not only lead to considerable economic benefit, but more

importantly, are key to build a sustainable society.[7]

1.1.2 Catalytic carbon-nitrogen bond formation: the focus of this thesis

This thesis discusses an alternative methodology to construct carbon-nitrogen

bonds[8], using widely abundant alcohols as substrates instead of the traditional

alkyl halides or aldehydes, promoted by metal-ligand bifunctional catalytic systems.

As an introduction to this thesis, this chapter gives background to the field of

ligand-metal bifunctional catalysis which is dramatically changing the face of

chemistry, in particular redox chemistry.[9] The introduction will include catalysis

based on the borrowing hydrogen strategy which will be also extensively involved

in the following chapters. Further, literature background to the Shvo catalyst[10a]

and the Knölker complex[10b] which are important catalysts employed in this thesis

will also be discussed.

1.2 Metal-ligand bifunctional catalysis

1.2.1 Background

Transition metal catalyzed chemical transformations promote the efficient and

environmentally benign synthesis of molecular targets[11]. In conventional

transition metal based catalysis, the coordination and further transformation of the

substrate is performed at the metal center and the role of the ligand is to keep the

metal complex in solution as well as regulate the electronic and steric properties

of the transition metal complex[12]. However, there is a class of catalysts, in that

the coordination and chemical transformation occurs on both the metal center as

well as the ligand. An early example from the Noyori group described the

Introduction to the thesis

3

asymmetric hydrogenation of ketones using a ruthenium diphosphine-diamine

complex.[13] The diamine ligand acts as the proton donor that stabilizes the alkoxy

before forming an alcohol by reduction of a simple ketone (Scheme 1, intermediate

1). It was proposed that the substrate is in the second coordination sphere of the

catalyst complex, not directly coordinated to the metal center[14] (Scheme 1, A).

The original halogen contained BINAP-Ru(II) complexes were only found to be

active for hydrogenation of functionalized ketones with nitrogen, oxygen or

halogen atoms near the carbonyl group (Scheme 1, B)[15]. In the latter case, the

additional heteroatom is required to form a metallacycle (Scheme 1, intermediate

2) to stabilize the alkoxy ligand before protonation. The type of catalysis described

in Scheme 1A was coined as ‘metal-ligand bifunctional catalysis’ by Noyori in

2001.[9a,16]

Scheme 1: A Asymmetric hydrogenation of acetophenone with a ruthenium BINAP

diamine complex; B asymmetric hydrogenation of activated carbonyls with

ruthenium BINAP complex.

1.2.2 The Shvo catalyst

In 1984, it was reported by the Shvo group that the reactivity of transfer

hydrogenation reactions catalyzed by triruthenium dodecacarbonyl was

significantly improved by adding diphenylacetylene (Scheme 2, A).[17] Later on, it

was proven that a ruthenium complex bearing cyclopentadienone was formed and

played an essential role.[18] The structure of the complex was determined by X ray

spectroscopic analysis (Scheme 2, B) by the Shvo group.[10a] The initial synthetic

approach to obtain this complex took 2 steps (Scheme 2, C, a) during which

Ru3(CO)12 (3) and tetraphenylcyclopentadienone (4) were heated to reflux in

benzene, forming [Ph4(4-C4CO)]-Ru(CO)3 (Cat 2)[19]. Subsequently, Cat 2 was

refluxed in isopropanol to give Shvo’s catalyst (Cat 1)[10a]. An alternative synthetic

Chapter 1

4

approach to Cat 1 was reported by Bäckvall and coworkers through sequentially

treating Cat 2 with an aqueous Na2CO3 in acetone, and an aqueous NH4Cl (Scheme

2, C, b)[20]. Finally, a concise, one-step synthesis of Cat 1 was reported by Casey

through heating 3 and 4 in methanol (Scheme 2, C, c)[21].

Scheme 2: A Crystal structure of Cat 1; B approaches of preparation of Cat 1.

Shvo’s catalyst was mainly applied in hydrogen transfer reactions (Scheme 3, A),

for example, oxidative coupling of primary alcohols to esters[22a], oxidation of

alcohols to ketones[22b] or to form imines with amines[22c], and the hydrogenation

of ketones, alkenes[22d] and imines[23]. The complex was also successfully used in

the dynamic kinetic resolution of secondary alcohols through the coupling of

enzyme catalyzed acetylation of one of the alcohol enantiomers and Cat 1

catalyzed racemization of the remaining alcohols[24]. Recently, several hydrogen

auto-transfer reactions were also reported using Shvo’s catalyst, including N-

alkylation of amines with aliphatic amines[25a], C-3-alkylation of indoles[25b] and tri-

alkylation of ammonium salts with alcohols[25c].

Scheme 3: Selected reactions catalyzed by Cat 1.

Introduction to the thesis

5

The bench-stable diruthenium complex Cat 1 actually is still a pre-catalyst which

is activated by heat and dissociates into two mono-ruthenium complexes, a 16-

electron species Cat 2-O, and an 18-electron complex Cat 2-H (Scheme 4, A).

Cat 2-H was the first reported well-defined metal-ligand bifunctional catalyst. The

formed Cat 2-O can then participate in, for example, dehydrogenation of

isopropanol to form acetone and Cat 2-H, and subsequent hydrogenation of

acetophenone reforms Cat 2-O through intermediate 3 (Scheme 4, B).

The reactivity and application of this complex has been extensively reviewed in

2005[26a], 2009[26b], 2010[26c] and 2011[26d].

Scheme 4: A Activation of Cat 1; B catalytic properties of Cat 2-H and Cat 2-O.

1.2.3 The Knölker complex

One of the first iron complexes used in organic synthesis was Fe(CO)5.[27] Back in

the 1950s, the reaction of Fe(CO)5 with alkynes was reported to be a [2+2+1]-

cycloaddition[28ab] (Scheme 5, A) resulting in the formation of tricarbonyl(4-

Chapter 1

6

cyclopentadienone)iron complex. The cyclopentadienone ligands obtained through

demetallation of the complexes had drawn considerable interest.[28c] However, the

reactivity of the complexes was not explored.

Scheme 5: A [2+2+1]-cycloaddition between Fe(CO)5 and 2 alkynes; B synthesis

of Cat 3 and Cat 3-H.

Until 1999, Knölker and coworkers reported key reactivity studies of tricarbonyl

cyclopentadienone complexes[10b]. It was observed, that especially when treating

iron complex Cat 3 that bears two trimethylsilane (TMS) substituents, sequentially

with aqueous NaOH in tetrahydrofuran (THF) and H3PO4, the mono-iron hydride

complex Cat 3-H (Knölker complex) can be obtained (Scheme 5, B). Cat 3-H was

fully characterized also by X ray analysis (Scheme 6, A)[10b].

Scheme 6: A Crystal structure of Cat 3-H; B mechanistic illustration of Cat 3-H

catalyzed hydrogenation of acetophenone; C Relative activity for stoichiometric

acetophenone reduction in toluene-d8 at 5 °C.

In 2007, the first catalytic reactivity of the Knölker complex (Cat 3-H) was

discovered by Casey and Guan[29] (Scheme 6, B). It was established, that the iron

hydride complex Cat 3-H, acts as a metal-ligand bifunctional catalyst in the

Introduction to the thesis

7

hydrogenation of ketones. In this case, the non-innocent[30] cyclopentadienone

backbone acts as a proton donor, while the metal center bears the hydride. In this

way, selective reduction of polar unsaturated bonds such as C=O and C=N[31]

becomes possible through an appropriate intermediate (such as intermediate 4).

The formed Cat 3-O can be reduced to Cat 3-H with molecular hydrogen (Scheme

6, B). Later, in 2012 Casey and Guan reported that iron hydride complexes Cat 3-

H and Cat 5-H give comparable activity to the ruthenium hydride complex Cat 4-

H in stoichiometric acetophenone reduction. This suggests that these more

economical iron catalysts are attractive alternatives to ruthenium catalysts

(Scheme 6, C)[32]. The dimerization of Cat 3-H or Cat 4-H for providing binuclear

species as Cat 1 has not been detected, suggesting that the bulky TMS groups

prevent such formation of the hydride bridged dimeric complexes.

Scheme 7: Tricarbonyl(4-cyclopentadinenone)iron complexes in catalysis: (A)

hydrogen transfer reactions and (B) dual catalysis.

Chapter 1

8

After Casey and Guan’s initial discovery on the catalytic behaviour of the Knölker

complex, several studies involving this complex have been reported. These

included reductive amination[31], hydrogenation of carbonyl compounds and imines

in water[33], transfer hydrogenation of carbonyl compounds and imines[34],

Oppenauer-type oxidation of alcohols[35] (Scheme 7, A). Furthermore, catalytic

systems involving dual catalysis were described, in which the Knölker complex

catalyzed hydrogen transfer reactions were coupled with organo-catalysis[36] or

enzyme promoted transformations[37] (Scheme 7, B). Moisture and air stable

complex Cat 3 is frequently used as a pre-catalyst. One CO ligand in Cat 3 can be

easily removed by Me3NO, generating Me3N, CO2 and active species Cat 3-O

(Scheme 6A).

Several analogues of the original complex have been reported through steric and

electronic modifications[38] of Cat 3 (Scheme 8). Modifications of the proton donor

site on the non-innocent ligand were reported by Nakazawa[39] and Guan[40], and

chirality was introduced to the metal complex by Wills[41], Berkessel[42] and

Gennari[43]. The field has been reviewed by Knölker[44], Guan[45], as well as

Quintard and Rodriguez[46] recently.

Scheme 8: Analogues of Knölker’s complex.

1.2.4 Recent progress in metal-ligand bifunctional catalysis

Since Noyori’s ruthenium diphosphine-diamine system was reported in 1995,

besides the development of the Shvo and Knölker complexes, considerable

progress has been established in this area[47,59]. For example, Morris and coworkers

reported well-defined iron complexes bearing PNNP ligands (such as Cat 8, shown

in Scheme 9) for the asymmetric transfer hydrogenation of carbonyl compounds

and imines. The reactions were completed within minutes in most cases, and the

ee reached 99% when imines were employed as the substrates[48]. Related to these

excellent results established by the Morris group, Bullock highlighted the potential

of iron-based catalysts to reach reactivity comparable to that obtained with noble

metal catalysts[49] (Scheme 9).

Introduction to the thesis

9

Scheme 9: Comparison of bifunctional catalyst systems developed by Noyori and

Morris.

In 2004, Milstein and coworkers reported a new type of ruthenium pincer complex,

that operates via the aromatization-rearomatization of a pyridine based

heteroaromatic ligand. This complex catalyzed the acceptorless dehydrogenation

of alcohols to ketones[50] and esters[51]. Subsequently the acceptorless

dehydrogenation and coupling between alcohols and amines to form amides was

reported[52] (Scheme 10, A). Comparing to classical metal-ligand bifunctional

catalysts that bear N-donors to activate H2 or alcohols and subsequently reducing

polar unsaturated bonds, the Milstein-type pincer complex has a C-donor (Scheme

10, B), and is able to activate a wider variety of bonds, including N-H bonds[53],

CO2[54], nitriles[55] and O2

[56].

Scheme 10: A Milstein pincer complex catalyzed acceptorless dehydrogenative

coupling for the synthesis of esters and amides; B activation of H2 by the Milstein

pincer complex Cat 9.

Recently, a number of new metal-ligand bifunctional catalysts have been

reported[57]. Selected examples are shown in Scheme 11, in which the structures

shown are after dihydrogen activation. In these complexes, the p- or π electron on

the ligand offers a proton acceptor site that is involved in the heterolytic splitting

of dihydrogen which results in the formation of the corresponding metal hydride.

Interestingly, Harman and Peters recently reported a nickel complex featuring a

borane moiety in the supporting ligand scafford (Scheme 11)[57e]. The property of

this complex is more comparable to a heterobimetallic complex (boron mimics a

second metal)[58] instead of a Noyori-type bifunctional complex. The catalytic

Chapter 1

10

applications of metal-ligand bifunctional complexes were reviewed by

Khusnutdinova and Milstein recently[59].

Scheme 11: Metal-ligand bifunctional complexes.

Starting from the reduction of polar unsaturated bonds, through the activation of

diverse bonds, to the recent application in the ‘borrowing hydrogen’ chemistry,

metal-ligand bifunctional complexes that operate based on metal-ligand

cooperation, have opened the gate to more efficient catalysis.

1.3 Catalysis based on borrowing hydrogen strategy

1.3.1 Alkylation of amines with alcohols through borrowing hydrogen

Selective C-N bond formation is a challenging task for synthetic chemists[8]. The

traditional methodologies include reductive amination of carbonyl compounds[60],

or nucleophilic substitution of amines with alkyl halides[61]. These methods,

however, suffer from either unstable and limited accessible substrates or the

formation of stoichiometric amounts of side products as waste. In the chemical

industry, alcohols are preferred reaction partners for alkylation of ammonia or

various amines, they however require harsher reaction conditions[62].

Scheme 12: First examples on transition metal catalyzed alkylation of amines

with alcohols by (A) Grigg and (B) Watanabe.

Introduction to the thesis

11

In 1981, Grigg and coworkers reported the first example of alkylation of amines

with alcohols under significantly milder conditions using transition metal

catalysts[63] (Scheme 12, A). They proposed that the reactivity of the alcohol was

improved by the formation of the corresponding carbonyl compound, which

subsequently underwent imine formation with the amine reaction partner.

Reduction of this imine intermediate resulted in the alkylated amine. At around the

same time, Watanabe and coworkers also reported the alkylation of anilines with

various alcohols catalyzed by a ruthenium complex[64] (Scheme 12, B).

Following these studies, during the past 3 decades, various catalytic systems have

been developed for direct alkylation of amines with alcohols, mostly using

ruthenium or iridium based catalysts[65] (Scheme 13). This field has been

extensively reviewed[66].

Scheme 13: Alkylation of amines with alcohols catalyzed by ruthenium or iridium

based catalytic systems.

Chapter 1

12

To characterize these types of reactions, Williams et al. coined the term ‘borrowing

hydrogen’[67] in 2004. During the catalytic cycle, an alcohol is dehydrogenated to

the corresponding carbonyl compound, which reacts with the amine to form an

imine (Scheme 14, A). The hydrogen delivered from the alcohol is temporarily

stored at the metal complex. The imine is reduced in situ to the alkylated amine

by the hydrogen stored on the metal complex. Key features are that the process

is hydrogen neutral, no other reagents are needed and the only stoichiometric by-

product is water. Variations of this reaction have also been reported, for instance,

C-C bond formation through alcohol activation[68,69] (Scheme 14, B) and alkane

metathesis through dehydrogenation of alkane to alkene, alkene metathesis and

hydrogenation of alkene to alkane[70] (Scheme 14, C).

Scheme 14: A Proposed mechanism of alkylation of amines with alcohols through

borrowing hydrogen; B C-C bond formation through alcohol activation; C alkane

metathesis through borrowing hydrogen.

Alkylation of amines with alcohols through borrowing hydrogen has been applied

in the pharmaceutical industry due to its significant economic benefit compared to

traditional methodologies of N-alkylations[66]. For example, Pfizer recently

developed a new pathway for synthetizing a GlyT1 inhibitor (9) (Scheme 15)[65h].

Comparing to conventional pathway, the key optimization was a direct amination

of alcohol 6 with amine 7 to provide the key intermediate 8 through the borrowing

hydrogen strategy. It is a redox-neutral process that avoids the use of

stoichiometric amount of oxidant and reductant.

Introduction to the thesis

13

Scheme 15: Conventional and Pfizer’s pathway for the synthesis of a GlyT1

Inhibitor.

1.3.2 Challenges and recent discoveries

The borrowing hydrogen strategy has been recognized as a key concept in catalysis

and sustainable chemistry, as it is a highly atom economic process[71]. Since the

first examples reported by the groups of Grigg[63] and Watanabe[64], and till recent

discoveries[65,66], most reactions were promoted by ruthenium or iridium based

catalytic systems. After three decades of discovery, the scientific community

realized that the main challenge was to developa non-precious metal based

catalyst for promoting this transformation[66d,72]. Iron with its high Earth-

abundance[73a], low cost[73b] and toxicity[73c], has been identified as an attractive

candidate.

In 2014, our group reported the first example of alkylation of amines with alcohols

with the well-defined bifunctional iron complex (Knölker complex)[74] (Scheme 16,

A). Subsequently, Wills and coworkers[75a] reported the same transformation with

an analogue complex Cat 16. Zhao and coworkers[75d] showed that with the

assistance of Lewis acids, the yields of alkylated amines could be significantly

improved when secondary alcohols were employed. The synthesis of allylic

amines[75c] and pyrroles[76], and -alkylation of ketones with alcohols[75d] were

further explored using the same catalytic system. In 2016, Kirchner and

coworkers[77] reported a PNP pincer type iron complex Cat 17 catalyzed alkylation

of amines with alcohols.

Besides iron, cobalt pincer complexes were successfully applied in the same

transformation by the groups of Kempe[78a], Zhang[78b] and Kirchner[78c] (Scheme

16). Also, novel catalytic systems based on manganese pincer complexes were

reported by the groups of Beller[79ab] and Sortais[79c] (Scheme 16, B). Several types

Chapter 1

14

of hetero-aromatics were also synthetized employing Co[80] and Mn[81] based

catalysts.

Scheme 16: (A) Iron, (B) Cobalt and manganese catalyzed alkylation of anilines

with alcohols.

1.4 Conclusion

In the past decades, tremendous progress has been made in the development of

metal-ligand bifunctional catalysis and the borrowing hydrogen strategy, mainly

with noble metal complexes. Recently, there is a clear interest in moving towards

non-precious metals based catalytic systems. In particular, iron based systems are

desired due to their lower toxicity, abundance and lower price as more sustainable

alternatives to noble metal catalysts.[73] Recent literature suggests that iron

catalysis is potentially able to cover the entire range of catalysis for organic

synthesis[44,82]. Carefully designed ligands which are capable of stabilizing as well

as cooperating with the metal center, are key for promoting desired chemical

transformations.

Introduction to the thesis

15

1.5 Outline of the thesis

This thesis describes the development of novel catalytic methods for the selective

alkylation of amines with alcohols through the borrowing hydrogen methodology,

using metal-ligand bifunctional complexes, in particular the Knölker complex and

the Shvo catalyst.

In Chapter 2, the discovery of the first well-defined iron complex catalyzed

alkylation of amines with alcohol is described. Chapter 3 describes the application

of the discovered method for transformations involving benzyl alcohols in order to

obtain benzylamines. In Chapter 4, iron catalyzed pyrrole synthesis is described

by N-heterocyclization of amines with unsaturated diols. Chapter 5 describes the

direct N-alkylation of unprotected amino acids with alcohols using the Knölker

complex and the Shvo catalyst with retention of stereochemistry. Chapter 6

describes the use of the Shvo catalyst in alkylation of amino acids esters with

alcohols, without racemization.

Chapter 1

16

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