Carbon-nitrogen bond formation via catalytic alcohol activation
Yan, Tao
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via Catalytic Alcohol Activation
The work described in this thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, The Netherlands.
This work was financially supported by University of Groningen.
Cover design by Tao Yan.
Printed by Ipskamp Printing, Enschede, The Netherlands.
ISBN: 978-94-034-0047-1 (printed version) ISBN: 978-94-034-0046-4 (digital version)
faculty of science and
Carbon-Nitrogen Bond Formation
via Catalytic Alcohol Activation
PhD thesis
to obtain the degree of PhD at the
University of Groningen
on the authority of the
Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Monday 18 September 2017 at 12.45 hours
by
Tao Yan
Prof. K. Barta
Assessment Committee Prof. J. G. de Vries
Prof. B. de Bruin Prof. M. Beller
Chapter 1
Borrowing hydrogen meets metal-ligand bifunctional
catalysis, an introduction to the thesis
1
Chapter 2
Iron catalyzed direct alkylation of amines with alcohols
21
Chapter 3
Benzylamines via iron catalyzed direct amination of
benzyl alcohols
49
Chapter 4
Pyrroles via Iron-Catalyzed N-Heterocyclization from
Unsaturated Diols and Primary Amines
75
Chapter 5
Direct N-alkylation of unprotected amino acids with
alcohols
93
Chapter 6
Ruthenium catalyzed N-alkylation of amino acid esters
with
121
Nederlandse samenvatting
141
English summary
143
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
1.1 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
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
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].
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 18-16-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]-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
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 5-3-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.
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).
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
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.
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.
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.
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
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.
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.
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Chapter 2
Iron catalyzed direct alkylation of amines with alcohols
The selective conversion of carbon-oxygen bonds into carbon-nitrogen bonds to form amines is one of the most important chemical transformations for the production of bulk and fine chemicals and pharma intermediates. An attractive atom economic way of carrying out such C-N bond formations is the direct N-alkylation of simple amines with alcohols through the so-called borrowing hydrogen strategy. Recently, transition metal complexes based on precious noble metals have emerged as suitable catalysts for this transformation; however, the crucial change towards highly selective methodologies, which use abundant, inexpensive and environmentally friendly metals, in particular iron, has not yet been accomplished. In this chapter, the homogeneous, iron-catalyzed, direct alkylation of amines with alcohols is described. The scope of this new methodology includes the selective monoalkylation of anilines and benzyl amines with a wide range of alcohols as well as the use of diols in the formation of five-, six- and seven- membered nitrogen heterocycles, which are privileged structures in numerous pharmaceuticals.
Part of this chapter was published:
Introduction
Amines are among the most valuable classes of compounds in chemistry, omnipresent in natural products, in particular alkaloids[2a], and widely used as pharmaceuticals, agrochemicals, lubricants and surfactants[1,2,3]. Therefore the development of efficient catalytic methodologies for C-N bond formation is a paramount goal in organic chemistry.
The choice of an alcohol[4,5] as substrate for direct C-N bond formation is highly desirable in order to produce secondary and tertiary amines and N-heterocyclic compounds (Figure 1).
Figure 1: Catalytic, direct N-alkylation of amines with alcohols. a Conventional conversion
of alcohol into amine via installing a leaving group before nucleophilic substitution with an amine donor or oxidizing alcohols to carbonyl compounds followed by reductive amination.
b The direct C–N bond formation via coupling of primary alcohols and amines forms
secondary amine products R1–NH–R2. R1–OH is a short- or long-chain aliphatic alcohol and
may contain aromatic functionality. R2–NH2 is an aromatic or aliphatic amine. c Using diols
of various chain lengths the products are 5- (n=1), 6- (n=2) or 7- (n=3) membered N-heterocycles.
Alcohols are readily available through a variety of industrial processes and are highly relevant starting materials in view of recent developments in the field of renewables as they can be obtained via fermentation or catalytic conversion of lignocellulosic biomass.[6,7] Conventional non-catalytic transformations of an amine with an alcohol take place via installing a suitable leaving group instead of the alcohol functionality followed by nucleophilic substitution, or oxidizing alcohols to carbonyl compounds followed by reductive amination; these multistep pathways suffer from low atom economy[8] or limited selectivity and the production of stoichiometric amounts of waste (Figure 1a).[9]
A privileged catalytic methodology for the direct coupling of alcohols with amines is based on the so-called borrowing hydrogen strategy (Figure 1b, 1c and Figure 2). During the catalytic cycle an alcohol is dehydrogenated to the corresponding carbonyl compound, which reacts with the amine to form an imine. The imine is in
situ reduced to the alkylated amine and the metal complex facilitates the required hydrogen shuttling. In fact the hydrogen delivered by the alcohol is temporarily stored in 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. A number of transition metal complexes have proven effective in this catalytic C-N bond formation, in particular those based on ruthenium[10-12] and iridium[13]. These and related methodologies have been extensively reviewed[1,3,4,14-16]. Despite recent progress, the key challenge is the development of catalysts that rely on the use of widely abundant, inexpensive metals[3,17]. Iron is considered to be the ultimate, sustainable alternative for ruthenium[18], however, no unequivocal reductive amination via a borrowing hydrogen mechanism has been reported[19]. Direct N-alkylation of amines with alcohols is limited to iron-halogenides under rather harsh reaction conditions (160-200 °C), not proceeding via a hydrogen autotransfer pathway[20].
This work shows that a well-defined homogenous Fe-based catalyst can be successfully used in this atom-economic process, with a broad substrate scope. These direct, Fe-catalyzed transformations are highly modular, and provide water, as the only stoichiometric byproduct. The products are valuable secondary and tertiary amines or heterocycles, which contain diverse moieties R1 (from the alcohol substrate) and R2 (from the amine substrate) (Figure 1).
The presented direct waste-free alcohol to amine functional group interconversions are important toward the development of sustainable iron based catalysis and will enable the valorization of biomass-derived alcohols in environment-benign reaction media.
Results and discussion
We reasoned that direct C-N bond formation with an iron catalyst is possible provided by the catalytic complex which shows high activity both in alcohol dehydrogenation (Figure 2a, Step 1) and imine hydrogenation (Figure 2a, Step 3). The realization of this concept for direct alkylation of amines with alcohols using cyclopentadieneone iron tricarbonyl complex Cat 3, the precurse to form Knölker’s complex[21] Cat 3-H, is presented here (Figure 2). Iron cyclopentadienone complex Cat 3 (Figure 2b), has been recently employed in catalysis including hydrogenation of ketones[22], reductive amination[23], transfer hydrogenation of carbonyl compounds and imines[24a], Oppenauer-type oxidation of alcohols[24b] as well as cooperative dual catalysis[25]. Given its unique reactivity, we considered Cat 3 a promising candidate for the development of the desired iron-catalyzed hydrogen borrowing methodology. To achieve the direct amination of alcohols, the key challenge is to match alcohol dehydrogenation and imine hydrogenation steps by establishing conditions under which the formed Fe-H species (Cat 3-H) from the initial alcohol dehydrogenation step is able to reduce the imine at a sufficient rate, not requiring the use of dihydrogen.
Catalytic N-alkylation with alcohols Preliminary experiments using 4-methoxyaniline (1a) and a simple aliphatic alcohol, 1-pentanol (2a), with 5 mol% pre-catalyst Cat 3 and 10 mol% Me3NO oxidant (to form active Cat 3-O) at 110 °C in toluene showed the formation of 4-methoxy-n-pentylaniline (3aa), albeit with only 30% selectivity at 48% substrate conversion (Table 1, entry 1). Although promising, the initial results using common organic solvents indicated low conversion of 1a or low selectivity towards 3aa and analysis of the reaction mixtures identified insufficient imine reduction as the key problem. We reasoned that most probably a weakly coordinating ethereal solvent is needed to stabilize the key iron intermediates Cat 3-O[27]. In addition, imine formation might be facilitated in solvents, which have limited miscibility with water. The major breakthrough came when the green solvent cyclopentyl methyl ether (CPME), one that uniquely combines such properties, was selected as reaction medium. CPME recently emerged as a low-toxicity, sustainable solvent alternative for tetrahydrofuran[28].
Figure 2 Individual reaction steps in the iron-catalyzed N-alkylation of amines using iron
cyclopentadienone complexes. a The overall transformation is the direct coupling of an alcohol (R1–OH) with an amine (R2–NH2) to form the product amine (R1–NH–R2). The
sequence of reaction steps starts with the dehydrogenation of R1–OH to the corresponding
aldehyde with iron complex Cat 3-O (Step 1). Thereby one ‘hydrogen equivalent’ is temporarily stored at the bifunctional iron complex Cat 3-O, which is converted to its reduced, hydride form Cat 3-H. In Step 2, the carbonyl intermediate reacts with amine R2–NH2 to form an imine intermediate and water. In Step 3, the hydrogen equivalent
“borrowed” from alcohol R1–OH are used in the reduction of the imine intermediate to
obtain the desired product R1–NH–R2. The reduction is accompanied by conversion of iron
hydride Cat 3-H to Cat 3-O, thereby a vacant coordination site is regenerated and the catalytic cycle closed. b Reactivity of Fe cyclopentadienone complexes: Cat 3 is an air- and moisture-stable iron tricarbonyl precatalyst. The active Cat 3-O complex is in situ generated from Cat 3 by the addition of Me3NO to remove one CO. Cat 3-O is readily
Table 1: Optimization of reaction conditions for N-alkylation of p-methoxyaniline (1a) with 1-pentanol (2a).
Entry 2a
[eq.] Sol. T [°C] Conv. 1a[%]a Sel. 3aa [%]a Sel. 4aa [%]a
1 1 Toluene 110 48 30 10 2 2 Toluene 110 71 50 20 3 2 DCE 110 75 15 41 4 2 CH3CN 110 10 <2 <2 5 2 DMF 110 18 10 2 6 2 THF 110 42 22 19 7 2 Dioxane 110 50 34 15 8 2 CPME 110 88 74 13 9b 2 CPME 110 77 67 9 10c 2 CPME 110 8 0 0 11 2 CPME 130 97 94 (91) 2 12 1 CPME 130 99 95 <1 13 6 CPME 130 99 90 <1
General reaction conditions: General Procedure A, 110 or 130 °C, 2 ml solvent, 18 h, isolated yield in parenthesis. aConversion and selectivity were determined by GC-FID; bCat
3b was used without Me3NO; cCat 3 was used, Me3NO was replaced by 10 mol% NaOH.
In CPME at 110 °C, amine 1a is alkylated with pentanol to provide 3aa in 74% selectivity at 88% conversion of 1a. Full conversion of 1a and an excellent (91%) isolated yield of 3aa were obtained at slightly higher temperature (130 °C) (Table 1, entry 11). Product formation profiles (Table 2) show that the reaction is highly selective and essentially complete within 7 h. The concentration of the imine intermediate stays constantly low, and exclusive mono-N-alkylation to 3aa with increasing 1a conversion is observed. Although multiple N-alkylation is often a notorious side reaction[1], it should be noted that the use of 1 equiv of alcohol 2a is sufficient to form 3aa selectively and even a larger excess (6 equiv) of 2a did not result in further alkylation of the secondary amine product (Table 1, entry 12 and 13).
Table 2: Product formation profiles for products 3aa, 4aa and substrate 1a.
Entry Time [h] Remain 1a
[%]a Sel. [%]b 3aa Sel. [%]b 4aa
1 1 92 11 6
2 2 59 31 8
3 3 48 40 8
4 5 21 70 4
5 7 1 92 1
General reaction conditions: General Procedure A, 1a (0.5 mmol), 2a (1 mmol), 130 °C, CPME (2 ml). Reactions were set up in parallel and runs were stopped at given time.
aConversion determined based on GC-FID using octadecane as internal standard. bSelectivitydetermined based on GC-FID and corresponding conversion.
Next, an in situ NMR study (Figure 3) was conducted, using d-8 toluene at 100 °C that allowed the detection of all key reaction intermediates (as depicted in Figure 2a), that is, 1-pentanol (2a), 1-pentanal, amine 3aa and the corresponding imine, in support of the borrowing hydrogen mechanism.
Selective monoalkylation of anilines The general applicability of this method for the selective monoalkylation of substituted anilines was examined using 1- pentanol 2a and 17 anilines 1a–1q with diverse electron density and steric hindrance on the amino group. The isolated yields under optimized conditions are shown in Table 3.
Figure 3: In situ 1H NMR study of the N-alkylation of p-methoxyaniline (1a) with
1-pentanol (2a) in toluene-d8 at 100 °C. Full ppm range, showing 2 small absorptions at 9.41 and 7.65 ppm, which can be attributed to HA (pentane-1-al)[26a] and HI (imine 4aa)[26b].
Table 3: Selective monoalkylation of anilines with alcohols.
General reaction conditions: General Procedure A, 0.5 mmol 1, 1 mmol 2, 2 ml CPME, 130 °C, 18 h, isolated yields, unless otherwise specified. For details see Table 4 and Table 5. a120 °C; bselectivity determined by GC-FID; c2 mmol 2 was used.
Monoalkylation of various anilines with 1-pentanol The reactivity of substrates 1a–1q was also compared under standard reaction conditions (reaction time 18 h) to assess substituent effects (Table 4). Selective monoalkylation was observed in each case; however, the differences in reactivity were significant. Para-substituted anilines were more reactive than ortho- or metasubstituted analogues (Table 4, entry 1-2), wheras the reactivity of toluidines increased in the order ortho (1c) < meta (1d) < para (1e) probably owing to a combination of basicity and steric effects (Table 4, entry 4, 6 and 8). It was further more established that anilines comprising electron-withdrawing substituents were less reactive and that the reactivity of para-halogenated anilines decreased in the order: fluoro (1h), chloro (1i) > iodo (1k) (Table 4, entry 13, 15 and 19). Whereas para-substituted anilines bearing strong withdrawing groups including –COOCH3, -NO2, -CN do not give desired products (Table 4, entry 20-22).
Table 4: Assessment of reactivity of functionalized anilines (1a-1q) in N-alkylation with 1-pentanol (2a).
Entry 1 / R T [h] Temp. [°C] Conv. 1 [%]a Sel. 3 [%]b 1 1a p-OCH3 18 130 97 3aa 94 (91) 2 1b o-OCH3 18 130 28 3ba 27 3 1b o-OCH3 38 120 63 3ba 51 (42) 4 1c o-CH3 18 130 23 3ca 12 5 1c o-CH3 39 120 83 3ca 71(49) 6 1d m-CH3 18 130 50 3da 40 7 1d m-CH3 62 130 >99 3da >95 (84) 8 1e p-CH3 18 130 88 3ea 75 (63) 9 1e p-CH3 22 130 >99 3ea 90 (91) 10 1f p-OH 18 130 >99 3fa 84 (69) 11 1f p-OH 4 130 96 3fa 92 (94) 12 1g o-F 18 130 25 3ga 13 13 1h p-F 18 130 84 3ha 60 14 1h p-F 42 120 >95 3ha 84(77) 15 1i p-Cl 18 130 73 3ia 54 16 1i p-Cl 63 120 87 3ia 77(76) 17 1j p-Br, m-CH3 18 130 33 3ja 18 18 1j p-Br, m-CH3 39 120 80 3ja 62(58) 19 1k p-I 18 130 16 3ka 8 20 1l p-COOCH3 18 130 <5 3la 0 21 1m p-NO2 18 130 <10 3ma 0 22 1n p-CN 18 130 <5 3na 0 23 1o H 18 130 75 3oa 54 24 1o H 25 130 97 3oa 86(90) 25 1p o-NH2 18 130 85 3pa 52 26 1q p-Me, m-NH2 15 130 92 3qa 60 (58)
General reaction conditions: General Procedure A, 0.5 mmol 1a-q, 1 mmol 2a, 130 °C, 2 ml CPME, isolated yield in parenthesis. aConversion determined by GC-FID; bSelectivity
Accordingly, the best result was obtained with p-hydroxyaniline, which was converted to 3fa in excellent 94% isolated yield already after 4 h (Table 4, entry 11). This increased reactivity might be attributed to the enhanced nucleophilicity of 1f or the presence of the relatively acidic phenol moiety, which likely catalyzes the imine formation step. p-Methoxyaniline was converted to 3aa within 7 h (Table 2), and para-methylaniline (1e), being less reactive, gave 3ea in 91% isolated yield after 22h (Table 4, entry 9). Unsubstituted aniline (1o) gave 3oa 90% isolated yield after 25 h (Table 4, entry 24).
Other substrates required further optimization, which was initially conducted using one of the least reactive substrates 1b. It was shown that prolonged reaction times and the addition of molecular sieves (to accelerate the imine formation step) lead to satisfactory results and products 3ba (Table 4, entry 3), as well as 3ca, 3da, 3ia and 3ja were isolated in moderate-to-high yields (42–84%) (Table 4, entry 5, 7, 16 and 18). Taking advantage of the distinct difference in reactivity between substituted anilines, the selective monoalkylation of 1-methyl-2,4-diamino-benzene (1q) resulted in preferential formation of 3qa in 58% isolated yield (Table 4, entry 26).
Table 5: N-alkylation of p-methoxyaniline (1a) with various alcohols (2b-2l).
Entry 2 Time [h] Conv.
1a [%]a
Sel. 3 [%]b Sel. 4 [%]b
1 2b n-Octanol 18 85 3ab 79 (69) 4ab 6 2 2c Ethanol 18 94 3ac 90 (85) 4ac 2
3 2d Methanol 18 8 3ad 0 4ad 0
4c 2e Propane-2-ol 24 42 3ae 12 4ae 24
5c 2f Cyclohexanol 24 50 3af 14 4af 32
6 2g Benzyl-alcohol 18 79 3ag 12 4ag 66 7 2h Phenylethanol 18 93 3ah 87 (75) 4ah 5 8 2i Ethane-1,2-diol 22 82 3ai 70 (74) 4ai 0 9 2k Hexane-1,6-diol 22 83 3ak 65 (43) 4ak 0 10d 2i Ethane-1,2-diol 24 80 3pi 40 4pi 0
11d 2i Ethane-1,2-diol 42 90 3pi 60 (45) 4pi 0
General reaction conditions: General Procedure A, 0.5 mmol 1a, 1 mmol 2a, 130 oC, 2 ml
CPME, isolated yield in parenthesis. aConversion determined by GC-FID; bSelectivity
determined by GC-FID; c2 mmol alcohol 2 was used; d3 mmol 2i was used and
2-aminoaniline (1p) was used instead of 1a. Main products also see Table 3.
Monoalkylation of p-methoxyaniline with various alcohols Having established the reactivity pattern of anilines, we found that the selective monoalkylation of p-methoxyaniline (1a) proceeds with a variety of alcohols (2b-2l) with excellent results (Table 5). For instance, octanol (2b), ethanol (2c) as well as 2-phenyl-ethane-1-ol (2h) were readily converted to the corresponding amines 3ab, 3ac and 3ah in 69–85% isolated yields (Table 5, entry 1, 2 and 7).
Alkylations using methanol were not successful (Table 5, entry 3), probably because the dehydrogenation of MeOH with employed catalytic system is unfavored. Interestingly, selective mono-alkylation with ethane-1,2-diol (2i) and hexane-1,6-diol (2k) delivered valuable amino-alcohols 3ai (74%) and 3ak (43%) (Table 5, entry 8-9). Notably, 2,3-dihydro-quinoxaline (3pi) containing a heterocyclic structure could also be constructed directly from inexpensive ethylene glycol (Table 3; Table 5, entry 10-11).
N-alkylation of aliphatic amines with aliphatic alcohols It is important that
aliphatic amines could also be successfully used as reaction partners with various alcohols (Figure 4). For instance, pentane-1-amine (5a) was alkylated with benzylalcohol (2g), providing 6ag in 67% yield. The same monoalkylated amine was obtained in 62% yield by a reverse route from benzylamine (7a) and 1-pentanol (2a), showing the flexibility and versatility of the new catalytic transformation. The reaction of piperidine (5b) with 2-phenylethylamine (2h) afforded tertiary amine 6bh in 53% isolated yield. Interestingly, furfuryl-amine (5c), which can be derived from lignocellulosic biomass through furfural, displayed an interesting reactivity towards bis-N-alkylation. In the reaction of 5c with 3 equiv of 2a, preferentially the corresponding tertiary amine (6caa) was formed.
Figure 4: N-Alkylation of various aliphatic amines with alcohols. a Modular synthesis with
aliphatic amines and alcohols. Pentyl-1-amine (5a) can be coupled with benzyl-alcohol (2g) or benzyl amine (7a) is coupled with 1-pentanol (2a) to afford the same amine product. b The methodology can be extended to secondary amines, piperidine (5b) is alkylated with 2-phenyl-1-ethanol (2h). c The reaction of furfuryl-amine (5c) with 1-pentanol (2a) results in bis-N-alkylation product 6caa. aMolecular sieves were added.
N-alkylation of benzylamines N-alkylated benzyl amines are particularly
important targets, as these moieties are present in a variety of drug molecules[29].
Figure 5: Reactivity of various benzylamines (7) with 1-pentanol (2a) based on
conversion in 6 h. General reaction conditions: General Procedure A, 0.5 mmol 7, 1 mmol
2a, 130 oC, 2 ml CPME, conversion was determined by GC-FID using octadecane as internal
standard.
Again a distinct substituent effect was observed in the benzylamine reaction partner (Table 6). Para-methyl substituted 7g and unsubstituted 7a showed lower reactivity than meta-halogen substituted benzylamines (7b–7f), which reacted much faster with 1-pentanol (2a). This is probably due to the increased rate of reduction of the corresponding imines.[30] Substituted N-alkylated benzylamines 8ba, 8ca, 8da and 8ea were obtained in excellent, 80–95% isolated yield. Following the alkylation over 6 h confirmed that the reactivity of benzyl amines 7a–7e, increases in the order 7a<7b<7c<7d<7e, reflecting the increasing electronegativity of the substituents (Figure 5).
Table 6: N-Alkylation of benzylamines with 1-pentanol and diols.
General reaction conditions: General procedure A, 0.5 mmol 7, 1 mmol 2, 130 oC, 18-50
h, isolated yields after purification. aSelectivity determined by GC-FID.
Heterocycle formation with various benzylamines and diols Building on the excellent reactivity of benzyl amines 7c–7e, we attempted the formation of nitrogen-containing heterocycles of various sizes using diols of different chain lengths (butane-1,4-diol 2m, pentane-1,5-diol 2l or hexane- 1,6-diol 2k) (Table 6). An additional advantage of the use of benzylamines is that the free N-heterocycles can be readily obtained by common debenzylation procedures. Despite the fact that a sequential catalytic N,N-dialkylation at the same nitrogen has to occur involving each of the hydroxyl groups of the diol, we reasoned that the first intermolecular alkylation is followed by an iminium ion-based alkylation, likely facilitated by the intramolecular nature of the second alkylation step. To our delight, pyrrolidine 9cm, containing a key five-membered heterocycle, was obtained in 60% yield from 7c and butane-1,4-ol (2m). Six-membered piperidine derivative 9cl was constructed using pentane-1,5 diol (2l) and 7c. As seven-membered ring formation is generally challenging in organic synthesis, it is a notable feature of our new Fe-based catalytic procedure that various azepane type
N-heterocyclic compounds were readily obtained using benzyl amines 7b–7e and
hexane-1,6-diol (2k). It is remarkable that in all these reactions, full conversion and perfect product selectivity was observed. Among all derivatives, the chloro-substituted 9bk was obtained with the highest isolated yield (85%). In contrast,
