Catalytic Amide Reductions under Hydrosilylation Conditions Alexey Volkov
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Catalytic Amide Reductions under Hydrosilylation Conditions Alexey Volkov
Catalytic Amide Reductions under Hydrosilylation Conditions Alexey Volkov © Alexey Volkov, Stockholm 2016 Cover picture: Photo of the tube by Tove Slagbrand Edited by Alexey Volkov ISBN: 978-91-7649-406-6 Printed in Sweden by Holmbergs, Malmö 2016 Distributor: Department of Organic Chemistry, Stockholm University ii “Somewhere, something incredible is waiting to be known.” ― Carl Sagan iii iv Abstract This thesis covers the development of catalytic methodologies for the mild and chemoselective reductions of amides. The first part of the thesis describes the use of a Fe(II)/NHC catalyst for the deoxygenation of aromatic tertiary amides to corresponding amines. The protocol is characterized by low catalyst loading, mild reaction conditions and the use of air and mois‐ ture stable polymethylhydrosilaxane (PMHS) as the hydride source. The second part concerns the development of a protocol for the room temperature deoxygenation of a wide range of tertiary amides to amines using catalytic amounts of Et2Zn and LiCl together with PMHS. The system displayed high levels of chemoselectivity tolerating various reducible groups such as nitro, nitrile, and olefin functionalities, and was shown to be applicable for the reduction of aromatic, heteroaromatic and aliphatic ter‐ tiary amides. The attempts to expand the scope of the Fe‐based protocol to accom‐ modate benzylic tertiary amides led to the development of a transition metal‐free catalytic system based on KOtBu for the formation of enamines. The final products constitute an important class of precursors for a wide range of valuable compounds in organic chemistry. Moreover, avoiding the use of transition metals in the protocol allowed the desired products to be obtained without the hazardous metal contaminants. The last chapter of the thesis describes the Mo(CO)6‐catalyzed hydrosi‐ lylation of amides. The Mo‐based catalyst was proven to mediate the deox‐ ygenation of α,β‐unsaturated tertiary and secondary amides to the corre‐ sponding allylamines without reduction of the olefinic bonds. Further de‐ velopment of the catalytic system revealed an unprecedented chemoselec‐ tivity in the hydrosilylation of aromatic and certain aliphatic tertiary amides in the presence of a variety of reducible groups along with aldehydes and imines that were tolerated for the first time. Moreover, it was possible to control the reaction outcome by variation of the reaction temperature to obtain either amines or aldehydes as the major products. The synthetic utility of the developed Mo(CO)6‐catalyzed protocols was further demon‐ strated in the synthesis of the pharmaceuticals Naftifine and Donepezil. v Populärvetenskapligsammanfattningpå svenska De flesta kemiska processer inom industrin samt flertalet viktiga transformationer inom biokemi är katalyserade. Katalytiska system tillåter reaktioner att ske under milda förhållanden med minskad mängd genererat avfall, i motsats till reaktioner baserade på stökiometriska reagens där betydligt fler biprodukter bildas. De ovan nämnda fördelarna med katalys resulterar i mer kostnadseffektiva, milda och miljövänliga processer. Reduktion av amider är en transformation som kan leda till en rad viktiga föreningar som aminer, iminer, enaminer, aldehyder och alkoholer. Amidbindningen, även känd som peptidbindning, förekommer naturligt i proteiner och enzymer och är mycket stabil i jämförelse med andra karbonyl föreningar som karboxylsyror, estrar, ketoner och aldehyder. De flesta publicerade katalytiska system för amidreduktion är i överlag baserade på dyra ädelmetaller som iridium, rodium och platinum. Ett delmål med denna avhandling var att utveckla katalytiska system baserade på rikligt förekommande och ogiftiga metaller som järn och zink. Resultatet av dessa studier presenteras i kapitel två och tre. Att helt undvika användandet av metaller och istället applicera en organisk molekyl som katalysator är ett annat sätt att närma sig en miljövänlig process. En effektiv organokatalytisk metod för reduktion av amider till enaminer utvecklades och behandlas i kapitel fyra. Eftersom amider generellt är minst reaktiva bland karbonylföreningarna är det en svår uppgift att selektivt reducera denna i närvaro av andra funktionella grupper. Kemoselektiva reduktioner av amider är viktigt då det kan möjliggöra nya syntesvägar samt förkorta kemiska processer. I den sista delen i avhandlingen beskrivs två protokoll där reduktion av amider har utförts med en mycket hög kemoselektivitet. Den syntetiska användbarheten av de sistnämda protokollen demonstrerades i nya syntesvägar för två läkemedel, Naftifin och Donepezil. vi Listofpublications This thesis is based on the following papers, which will be referred to by their Roman numerals I‐V. Reprints were made with the kind permission from the publishers. The contribution by the author to each publication is clarified in Appendix A. I. II. III. IV. V. Direct Hydrosilylation of Tertiary Amides to Amines by an In Situ Formed Iron/N‐Heterocyclic Carbene Catalyst Alexey Volkov, Elina Buitrago,* Hans Adolfsson* European Journal of Organic Chemistry, 2013, 11, 2066‐2070 Mild and Selective Et2Zn‐Catalyzed Reduction of Tertiary Amides under Hydrosilylation Conditions Oleksandr O. Kovalenko, Alexey Volkov, Hans Adolfsson* Organic Letters, 2015, 17, 446‐449 Catalytic Reductive Dehydration of Tertiary Amides to Enamines under Hydrosilylation Conditions Alexey Volkov, Fredrik Tinnis, Hans Adolfsson* Organic Letters, 2014, 16, 680‐683 Mo(CO)6 Catalyzed Chemoselective Hydrosilylation of α,β‐ Unsaturated Amides for the Formation of Allylamines Alexey Volkov, Fredrik Tinnis,* Tove Slagbrand, Ida Pershagen, Hans Adolfsson* Chemical Communications, 2014, 50, 14508‐14511 Chemoselective Reduction of Tertiary Amides under Thermal Control for the Formation of Aldehydes or Amines Fredrik Tinnis,* Alexey Volkov, Tove Slagbrand, Hans Adolfsson* Angewandte Chemie International Edition, 2016, 55, 4562‐4566 vii Papers not included as part of this thesis: Mild Deoxygenation of Aromatic Ketones and Aldehydes over Pd/C Using Polymethylhydrosiloxane as the Reducing Agent Alexey Volkov, Karl P. J. Gustafson, Cheuk‐Wai Tai, Oscar Verho,* Jan‐E. Bäckvall,* Hans Adolfsson* Angewandte Chemie International Edition, 2015, 54, 5122‐5126 viii Contents Abstract ................................................................................................................................ v Populärvetenskaplig sammanfattning på svenska ........................................ vi List of publications........................................................................................................ vii Contents ............................................................................................................................. ix Abbreviations ................................................................................................................... xi 1 Introduction ..................................................................................... 1 1.1 Catalysis...................................................................................................................2 1.2 Reduction of amides...........................................................................................3 1.2.1 Non‐catalytic reduction protocols..........................................................................4 1.2.2 Catalytic hydrogenation protocols.........................................................................6 Heterogeneous catalysts for hydrogenation of amides .................................................... 7 Homogeneous catalysis in hydrogenation of amides ....................................................... 8 1.2.3 Catalytic hydrosilylation of amides.....................................................................10 Hydrosilylation of amides proceeding via C‐O bond scission .......................................... 13 a) Precious metal‐catalyzed deoxygenation ................................................................13 b) First row and non‐precious transition metal‐catalyzed protocols ..............................16 c) Transition metal‐free systems ................................................................................19 Hydrosilylation of amides to aldehydes and precursors thereof ..................................... 21 1.3 Objectives of the thesis...................................................................................22 2 Direct Hydrosilylation of Tertiary Amides by an In Situ Formed Iron/N‐Heterocyclic Carbene Catalyst (Paper I) ................................. 23 2.1 Introduction........................................................................................................23 2.2 Results and discussion.....................................................................................24 2.3 Conclusions.........................................................................................................28 3 Mild and Selective Et2Zn‐Catalyzed Reduction of Tertiary Amides under Hydrosilylation Conditions (Paper II) ....................................... 29 3.1 Introduction........................................................................................................29 ix 3.2 Results and discussion.....................................................................................29 3.3 Conclusions.........................................................................................................32 4 Catalytic Reductive Dehydration of Tertiary Amides to Enamines under Hydrosilylation Conditions (Paper III) ...................................... 35 4.1 Introduction........................................................................................................35 4.2 Results and discussion.....................................................................................36 4.3 Conclusions.........................................................................................................41 5 Mo(CO)6 Catalyzed Chemoselective Hydrosilylation of Tertiary Amides (Paper IV and V) ..................................................................... 43 5.1 Introduction........................................................................................................43 5.2 Hydrosilylation of α,β‐unsaturated tertiary amides (Paper IV)..........44 5.3 Chemoselective hydrosilylation of tertiary benzamides (Paper V)...47 5.4 Application of the Mo‐catalyzed protocols in the synthesis of pharmaceuticals (Papers IV and V).....................................................................55 5.5 Conclusions.........................................................................................................56 Concluding remarks ............................................................................ 58 Appendix A: Contribution list ............................................................. 60 Appendix B: Reprint permissions ....................................................... 61 Acknowledgements ............................................................................ 62 References .......................................................................................... 65 x Abbreviations Abbreviations and acronyms are used in agreement with the standard of the subject.1 Only nonstandard and unconventional abbreviations that ap‐ pear in the thesis are listed here. BDSB [DMHEMIM][I] 1,2‐bis(dimethylsilyl)benzene 1‐(1‐hydroxy‐2‐methylpropan‐2‐yl)‐3‐methyl‐1H‐imidazol‐3‐ ium iodide Ea activation energy 1,4‐dihydropyridine dicarboxylate (Hantzsch ester) HEH [HEMIM][OTf] 1‐(2‐hydroxyethyl)‐3‐methyl‐1H‐imidazol‐3‐ium triflate LDBIPA lithium diisobutyl‐iso‐propoxyaluminum hydride NHC N‐heterocyclic carbene [Ph‐HEMIM][OTf] 1‐(2‐hydroxy‐1‐phenylethyl)‐3‐methyl‐1H‐imidazol‐3‐ium triflate PMHS poly(methylhydrosiloxane) TMDS 1,1,3,3‐tetramethyldisiloxane TON turnover number TOF turnover frequency Ph 1,1,1‐tris(diphenylphosphino‐methyl)ethane Triphos xi 1 Introduction In our continuously growing society the design and implementation of effi‐ cient and environmentally benign technologies and processes are playing the key role for the preservation of the fragile balance in Nature. The field of chemistry provides a number of different essential products like novel materials, pharmaceuticals, fuels and food additives. Taking into account the vast amount of generated products in chemical industries it is of great importance to circumvent negative impact on the environment. In 1998 Anastas and Warner implemented the important concept guiding the de‐ sign of sustainable processes, “green chemistry” (Figure 1).3 The term is based on twelve principles with catalysis being one of the most important aspects. The use of catalysts opens up the possibility for the adoption of less harmful reagents and cut down on generated waste products, resulting in more atom economic transformations which are more chemoselective or even unattainable without catalysts. Figure 1. Twelve principles of Green Chemistry. 1 1.1 Catalysis Most of the industrial chemical processes, as well as transformations within the biochemical field are catalyzed.4 Each year a lot of effort is put into the field of catalysis in applied science, since catalytic systems allow reactions to be performed under milder conditions with reduced amount of generat‐ ed waste, as opposed to stoichiometric reactions in which significantly more side products are formed. All of the above mentioned advantages of catalysis result in more cost‐effective, mild and environmentally friendly processes. A catalyst mediates a certain transformation and unlike other compo‐ nents of a reaction, it is regenerated after each catalytic cycle, and can therefore be used in less than stoichiometric amounts. Upon the use of the catalyst the energy profile of the reaction is changed since new pathways became feasible with lower activation energy (Ea) (Figure 2) increasing the reaction rate. Catalysts are characterized by different parameters such as selectivity, stability, activity, and efficiency which can be measured in terms of turnover number (TON) and turnover frequency (TOF). Figure 2. A Simplified Gibbs free energy diagram showing the influence of the cata‐ lyst (∆G – the Gibbs free energy change). Depending on the active species, catalysts can be divided into different categories: transition metal, Lewis or Brønsted acid/base, organocatalyst, and biocatalyst. Among them transition metal catalysis is of particular im‐ portance and has made a tremendous impact on the progress in organic chemistry. Fine tuning of the electronic properties of the metal center ena‐ bles previously unattainable transformations to take place in high efficiency and selectivity. 2 Catalysts are classified into two major groups: homogeneous and heter‐ ogeneous depending on whether the active species is in the same or differ‐ ent phases as the reactants (gas/solid, liquid/solid or two immiscible liq‐ uids).5 Having their advantages and disadvantages these systems are com‐ plimentary to each other. Generally homogeneous catalysis shows supreme activity due to a greater degree of interactions with the substrates6 and exhibits higher selectivity than the heterogeneous counterparts.7 Moreo‐ ver, modifications of the catalyst properties such as solubility, activity, and selectivity are more straightforward through rational ligand design, where‐ as for heterogeneous catalysts these modifications are limited and chal‐ lenging. However, it is difficult to separate homogeneous catalysts from the reaction mixture and they are seldom recycled, therefore the final com‐ pound can contain metal impurities. In the pharmaceutical industry it is of high importance to keep the content of hazardous metals below the ac‐ ceptable amounts and additional purification procedures are then required. Heterogeneous catalysts can easily be recovered by simple filtration or through phase separation allowing for minor metal contaminant in the product. Furthermore, they usually exhibit higher stability in comparison to homogeneous catalysts and can often be recycled, reducing cost and the environmental impact of a process. Taking into account the above men‐ tioned properties, heterogeneous catalysts are very attractive in industrial applications.8 1.2 Reductionofamides Reduction of the amide functionality is an important transformation that allows access to valuable building blocks for fine and bulk chemicals as well as for polymers and dyes. Depending on the reaction conditions and rea‐ gents used the reduction can lead to a formal deoxygenation and yield amines, imines or enamines, whereas in many cases it is possible to change the reaction outcome to promote C‐N bond cleavage and subsequently to obtain a variety of products like deacylated amine, alcohols, and aldehydes (Scheme 1). Amides are generally the least reactive and thus the most challenging class of carbonyl compounds, due to the conjugation between the lone pair 3 of the nitrogen and the π‐orbital of the carbonyl group, resulting in a de‐ creased carbonyl electrophilicity.9 Scheme 1. Different pathways for the amide reduction. 1.2.1 Non‐catalytic reduction protocols Despite the growing number of selective catalytic methods for amide re‐ duction stoichiometric protocols based on the main group metal hydrides LiAlH4 and NaBH4 are currently widely applied both on industrial and labor‐ atory scale in organic synthesis.10 The use of NaBH4 often requires activa‐ tion of the hydride or the carbonyl group, and for this purpose organic compounds such as acetic acid,11 ethaneditiol, and dimethoxyethane12; or inorganic compounds e.g. transition metals (CuCl2, CoCl2)13 or Lewis acids (TiCl4, B(OPh)3)14 can be used. LiAlH4 being very reactive is susceptible for tuning of its activity by substituting hydrides for alkyl‐ and alkoxy‐groups (diisobutylaluminium hydride (DIBALH),15 lithium diisobutyl‐iso‐ propoxyaluminum hydride (LDBIPA),16 and di‐ and triethoxyaluminohy‐ drides17). It allows for conversion of amides not only to amines but also through partial reduction to aldehydes. In spite of the utility of main group metal hydrides, there are several major drawbacks associated with their use. The protocols display poor functional group tolerance; moreover, be‐ ing air and moisture sensitive, metal hydrides react violently with water to give rise to rapid hydrogen gas evolution. Generation of stoichiometric amounts of hazardous waste during the reaction leads to tedious product isolation and purification procedures. 4 Boranes (BH3, etc.) provide a better alternative to the stoichiometric metal hydride reagents in the reduction of amides to amines.18 Being a milder reagent it was possible to perform selective reductions of amides in the presence of ester‐ and nitro‐groups.19 Moreover, several methods for an in situ generation of different borane reagents were developed using sodium or lithiumborohydride in combination with iodine, trimethylsilyl chloride, alkyl selenides, or methanesulfonic acid.20 Stoichiometric reductions of secondary and primary amides to the cor‐ responding aldehydes using zirconocene hydrochloride (Schwartz reagent) were reported by several groups.21 The protocols are characterized by mild reaction conditions and outstanding chemoselectivity, tolerating nitro‐, nitrile‐, ester‐group and are applicable for both aromatic and aliphatic am‐ ides. Unfortunately, this reagent suffers from certain drawbacks: it has low solubility in common solvents, and its sensitivity to air, light and moisture makes it problematic for long‐term storage and requires two fold excess to ensure good product yields. The use of stoichiometric amounts of Ti(OiPr)4 as a mediator in the hy‐ drosilylation of secondary and tertiary amides to enamines followed by subsequent hydrolysis to aldehydes was reported.22 The group of Buchwald used Ph2SiH2 as the hydride source under mild conditions that enabled for good functional group tolerance in the formation of aldehydes. Lemaire and co‐workers took advantage of the cost‐effective, air and moist stable silane 1,1,3,3‐tetramethyldisiloxane (TMDS) at elevated temperatures, however, no chemoselectivity could be obtained under these conditions. The same group adopted a stoichiometric protocol with Ti(OiPr)4 for the reduction of primary amides to the corresponding amine hydrochlorides. Performing the reaction at elevated temperatures with an excess of poly(methylhydrosiloxane) (PMHS) it was possible to get quantitative con‐ version of the starting compounds to deoxygenated disilyl‐substituted amines and with the subsequent hydrolysis by hydrochloric acid the target products were obtained.23 Another important non‐catalytic reduction method based on trifluoro‐ methanesulfonic anhydride (Tf2O) as an electrophilic activating agent of the amide was recently reported. Charette and co‐workers demonstrated two significant metal‐free chemoselective reductions of tertiary and secondary amides.24,25 Charette showed that when 1,4‐dihydropyridine dicarboxylate (Hantzsch ester, HEH) was used as mild reductant the tertiary amides were 5 converted to amines in good isolated yields (Scheme 2).24 Secondary am‐ ides could be deoxygenated employing triethylsilane (Et3SiH) instead of the Hantzsch ester yielding the corresponding secondary amines.25 By the addi‐ tion of the weak base 2‐fluoropyridine it was possible to promote the for‐ mation of imines and aldehydes in good yields. The latter system repre‐ sented a state of the art process allowing for the first time conversion of the amide moiety in the presence of aldehydes. Later on the concept of pre‐activation of the amide functionality for mild reduction was further explored in the group of Huang.26 By employing sodium borohydride as reductant it was possible to convert various tertiary and secondary amides to amines in high yield. Nevertheless it was not possible to achieve the ex‐ cellent chemoselectivity previously demonstrated by the group of Charette. Scheme 2. Protocol for deoxygenation of amides developed by Charette. In 2014 the group of Nikonov reported a semi‐catalytic approach for the reduction of secondary amides to imines.27 The starting compounds were reacted with SOCl2 or PCl5 to yield iminoyl chlorides, prior to the Ru‐ catalyzed hydrosilylation to obtain corresponding imines. The protocol was intolerant to nitrile and nitro‐substituents; however ketone and ester func‐ tionality remained unreacted under the reaction conditions. 1.2.2 Catalytic hydrogenation protocols The use of hydrogen gas as the reductant constitutes the most atom effi‐ cient and environmentally friendly approach, in particular for the reduction of amides, since the only by‐product of the reaction is water. Formally, it requires two equivalents of hydrogen to reduce the amide functionality, one of which is involved in the final deoxygenation of carbonyl with the release of water. Instead of hydrogenolysis of the C‐O bond, alternatively a less desired cleavage of the C‐N bond can occur yielding deacylated amine and alcohol as the main products (Scheme 1). Furthermore, depending on the parameters of the reaction, such as temperature, pressure, solvent, 6 catalyst and degree of N‐substitution of the starting compound, a number of side reactions were identified that are responsible for the loss of selec‐ tivity in the reduction.28 As a result, the reaction mixtures of amide hydro‐ genations often contain primary, secondary and tertiary amines together with various hydrocarbons formed through hydrogenolysis of carbon‐ nitrogen bonds. Heterogeneous catalysts for hydrogenation of amides Due to the importance and the environmental perspective, substantial ef‐ forts are focused on the development of protocols for heterogeneously catalyzed hydrogenation of amides. The first report was published by Maihle in 1908 where acetamide and propionamide were reduced in the vapor phase over a Ni‐based catalyst resulting in the formation of mixtures of primary and secondary amines.29 In other early reports cop‐ per/chromite,30 ReO3,31 or Raney nickel32 catalysts have shown activity for this transformation. However, due to harsh reaction conditions (100–1000 bar of H2 at 175–400 °C) the selectivity of these systems was poor and products of cross amination constituted the major fraction of the reaction outcome. Recent examples of hydrogenation of amides using heterogeneous cata‐ lysts are associated with the use of bifunctional, bimetallic or even polymetallic catalysts. A significant activity improvement was achieved by Dobson, using a Pd/Re catalyst supported on high surface area graph‐ ite/zeolite.33 The combination of different metal species was shown to be beneficial for the activity of the catalyst due to synergistic behavior, leading to a surge in the research field. A vast amount of bi‐metallic (Rh/Re, Rh/Mo, Ru/Re, Ru/Mo)34 and tri‐metallic systems (Pt/Re/In)35 were devel‐ oped, which demonstrated superior reactivity and selectivity in the hydro‐ genation of amides to amines. Moreover, these systems allowed for reac‐ tions at lower temperatures and hydrogen pressure (120–160 °C, 10–100 bar H2).28 More recently, robust bimetallic TiO2‐supported Pt/Re (120 °C, 20 bar H2) and graphite‐supported Pd/Re (160 °C, 30 bar H2) based catalysts were developed by the groups of Hardacre36 and Breit.37 These catalytic systems showed remarkable reactivity in the reduction of amides to amines without scrambling of N‐substituents occurring. Only limited amount of comparative experimental information is available for the hydrogenation of 7 amides to amines, however, the reactivity trend is known to be the follow‐ ing: primary > tertiary >> secondary with primary amides being the easiest to reduce.38 Apart from potentially being more easily recycled, the use of heteroge‐ neous catalysts is also advantageous in continuous‐flow set up. The flow system allows for a facile separation of the product, process scale up, and suppressing mechanical degradation processes of the catalyst, thus mini‐ mizing metal leaching contaminating the product. Cole‐Hamilton and co‐ workers were the first to report on the successful application of TiO2‐ supported bimetallic Pt/Re catalyst in a continuous flow reaction for the conversion of amides to amines (120 °C, 20 bar H2).39 Despite of the recent advances in the field of heterogeneous hydrogena‐ tion of amides, the systems suffer from poor chemoselectivity with even aromatic rings being hydrogenated, which limits the scope of the reaction to pure aliphatic amides. Homogeneous catalysis in hydrogenation of amides Methods reported on homogeneous hydrogenation of amides are mainly limited to the use of Ru catalysts and are suitable for the hydrogenolysis of the C‐O bond to yield the corresponding amines, and the C‐N bond with the generation of amines and alcohols as the main products. The first example of homogeneous hydrogenation of amides proceeding through C‐N bond scission was reported by Crabtree and co‐workers where they observed the conversion of propanamide at 160 °C to a mixture of compounds.40 Employing Ru(acac)3 in combination with 1,1,1‐ tris(diphenylphosphino‐metyl)ethane (TriphosPh) it was possible to obtain a mixture of secondary amine, propanol, alkylated amide and ester (Figure 3, a). Later on the group of Ikariya improved the selectivity of the process and widened the substrate scope of the reaction using Ru in combination with various PN and NN ligands (Figure 3, b).41 The breakthrough in the area was made with the introduction of ruthenium pincer complexes with so‐called non‐innocent ligands42 which were reported by Milstein and co‐workers (Figure 3, c).43 The protocol was suitable for the hydrogenation of second‐ ary and tertiary amides containing ether functionality in close proximity. The corresponding amines and alcohols were obtained in good yields and excellent selectivity at relatively mild reaction conditions (10 bar H2, 8 110 °C). The group of Bergens reported on a π‐allyl ruthenium complex for the catalytic hydrogenation of amides and lactams that did not require the presence of activating groups (Figure 3, d).44 In 2016 Beller and co‐workers reported on a novel homogeneous Ru‐based catalyst for the hydrogenation of amides proceeding with C‐N bond scission (Figure 3, e).45 Taking ad‐ vantage of the imidazolylaminophosphino pincer ligand they were able to convert a wide range of primary, secondary and tertiary amides to the cor‐ responding alcohols and amines in good to excellent yields at 120 °C and 30 bars of H2. The only non‐Ru‐based homogeneous system for the hydro‐ genation of amides to amines and alcohols was reported by Milstein.46 Highly activated secondary amides derived mainly from trifluoroacetic acid were hydrogenated using a Fe/PNP‐ligand catalyst under harsh reaction conditions (60 bars H2, 140 °C). Figure 3. Catalysts and ligands for homogeneous hydrogenation developed by Crab‐ tree (a), Ikaria (b), Milstein (c), Bergens (d), Beller (e). The first protocol which enabled for the selective C‐O bond cleavage un‐ der hydrogenation conditions leading to the formation of the correspond‐ ing amines was reported by Cole‐Hamilton47. The system was based on Crabtree’s original work employing Ru(acac)3 and TriphosPh and enabled for the reduction of primary and secondary amides with good selectivity. Addi‐ tion of substoichiometric amounts of water was necessary in order to stabi‐ lize the catalyst. The protocol was initially proven to be irreproducible and was subsequently corrected.48 The purity of the ligand was found to be crucial for the reaction outcome and the temperature was elevated to 200– 220 °C maintaining 40 bar of H2 pressure. The group of Cole‐Hamilton re‐ ported on another protocol based on a homogeneous Ru system49 which constitutes an improvement of the previous results.50 Using 1 mol% of [Ru(acac)3], 2 mol% of TriphosPh and 1 mol% of methanesulfonic acid at 210 °C under 10 bars of H2, the authors were able to reduce a wide range of primary and secondary amides to the corresponding amines as a sole prod‐ uct. The protocol was mainly suitable for aniline‐derived amides, while re‐ 9 actions involving tertiary and N‐alkyl amides displayed low conversions and selectivity. Recently the group of Beller reported on the improved Crabtree system employing different Lewis acids as additives.51 The use of catalytic amounts of Yb(OTf)3∙H2O proved to be beneficial for the selectivity of the reaction allowing for lower reaction temperature (150 °C) and performing the transformation only with 5 bars of H2. Studies on the reaction mecha‐ nism revealed that the initial reduction of the amide proceeded via C‐N bond cleavage resulting in the formation of alcohol and amine which was suggested to undergo reaction with each other through a borrowing hydro‐ gen pathway to form the final product. It is important to point out that the field of homogeneous hydrogena‐ tion of amides currently is restricted to the use of Ru‐based complexes un‐ der rather harsh reaction conditions. Reports on C‐N bond cleavage are prevailing over the deoxygenation pathway and the functional group toler‐ ance of the transformation is still limited. 1.2.3 Catalytic hydrosilylation of amides Alternatively to H2 various hydrosilanes52 can be used as hydride donors in catalytic reductions of amides. The addition of the Si‐H bond across an un‐ saturation is denoted as hydrosilylation, which in comparison to other methods allows for the reduction to occur under milder conditions and with superior chemoselectivity. There are a number of commercially avail‐ able silanes, such as Cl3SiH, Ph2SiH2, BDSB (1,2‐bis(dimethylsilyl)benzene), (MeO)3SiH, (EtO)2MeSiH, Et3SiH, TMDS (1,1,3,3‐tetramethyl‐disiloxane), and PMHS (polymethylhydrosiloxane) that can be employed as reducing agents (Figure 4). The hydridic nature of the hydrogen attached to the silicon, as well as the stability of the silanes varies significantly depending on the na‐ ture and amounts of substituents. Figure 4. Structures of various silanes employed in hydrosilylation reactions. The use of PMHS as hydride source is the most attractive alternative, as it is one of the most stable and cost‐effective silane.53 Employing this silane 10 allows for facile isolation of amines from Pd‐, Ru‐ and Pt‐catalyzed deoxy‐ genation of amides.70c,d,f,g The O‐crosslinking of PMHS occurring during the reduction process, produces an insoluble siloxane resin that encapsulates almost all metal‐species present. In general, due to the stability of organosilanes, the hydride needs to be activated in order to perform the reaction. Such activation can be facilitat‐ ed by the use of a proper catalyst and can occur by σ‐bond metathesis or oxidative addition of the Si‐H bond to the transition metal‐center. In the case of nucleophilic catalysis, the reaction proceeds through a pentavalent silicon intermediate, whereas Lewis acids are believed to directly activate the hydride to perform the transformation.54,55,56 Scheme 3. Classic and modified Chalk‐Harrod mechanisms for the hydrosilylation of carbonyl‐containing compounds. In the case of groups 8‐10 transition metals the catalytic cycle usually in‐ cludes oxidative addition of the silane to the metal center forming a metal‐ hydride species.55 In 1965 Chalk and Harrod proposed such a mechanism for the Pt‐catalyzed hydrosilylation of olefins, where the oxidative addition of the Si‐H bond to the metal center was followed by the addition of the M‐ H bond over the alkene with subsequent reductive elimination of the si‐ lylated product (Scheme 3).57 Later on a modified Chalk‐Harrod mechanism was discussed and proposed for Co and Rh catalysis, where the insertion occurs into M‐Si bond instead (Scheme 3).58 Even though silicon affinity for oxygen plays an important role in the case of hydrosilylation of carbonyl compounds both mechanisms can be plausible. Mechanistic investigations proposed that Ir and Rh‐catalyzed reductions of carbonyl‐containing sub‐ strates proceed through a modified Chalk‐Harrod catalytic cycle,59,76,105 whereas the Pt‐promoted hydrosilylation was found to progress through the original one (Scheme 3).77 11 When oxidative addition is not possible or disfavored due to the elec‐ tronic nature of the metal (for early transition metals like titanium or zirco‐ nium, group 11 or 12 metals) σ‐bond metathesis of the Si‐H becomes the major pathway of hydride transfer from silane to the catalyst (Scheme 4).55 Scheme 4. Proposed mechanism for the hydrosilylation of carbonyl‐containing compounds proceeding through σ‐bond metathesis. Silicon is a weak Lewis acid and will readily interact with a Lewis base, generating a pentacoordinated intermediate (Scheme 5).54,55 This interme‐ diate is characterized by a higher Lewis acidity and can expand its coordina‐ tion sphere by coordination to an oxygen atom of a carbonyl compound. This results in a weakening of the Si‐H bond in the hypercoordinated silicon compound and facilitates the hydride‐transfer step to the substrate. Scheme 5. Proposed mechanism for Lewis base (to the left) and Lewis acid (to the right) catalyzed hydrosilylation of carbonyl‐containing compounds. Today there are reported examples of Lewis acid promoted hydrosilyla‐ tion of carbonyl containing compounds.60 In case of protocols based on BF3∙OEt2 the reductions are not catalytic and they are postulated to pro‐ ceed through the carbonyl activation,61 whereas reactions involving B(C6F5)3 are catalytic and studies proposed a different reaction pathway (Scheme 12 5).62,63 After thorough investigations it was established that the reaction proceeds with Lewis acid hydride activation forming silylium‐hydrideborate ion‐pair species followed by the attack of the carbonyl on the silicon center with subsequent reduction step. Interestingly, an increased concentration of the reagents had a strong negative effect on the rates of the reactions suggesting competing and unproductive coordination of the catalyst to the substrate. A somewhat similar outer sphere mechanism was proposed for cationic iridium complexes for the hydrosilylation of ketones.64 In the area of catalytic hydrosilylation of amides a general trend has been observed for the reactivity of different amides towards reduction comprising tertiary > secondary > primary amide, where the latter proved to be the most problematic and often lead to nitrile formation65 or silyla‐ tion of nitrogen.66 Hydrosilylation of amides proceeding via C‐O bond scission a) Precious metal‐catalyzed deoxygenation Selective hydrosilylation of amides has attracted significant attention dur‐ ing the last decades, leading to the development of large amounts of reduc‐ tion methods. One of the first examples (1982) was performed in the labor‐ atory of Pataud‐Sat.67 Employing the Wilkinson catalyst (RhH(CO)(PPh3)3) together with 1,2‐bis(dimethylsilyl)benzene as the hydride source, it was possible to convert N,N‐dimethylphenylacetamide to the corresponding enamine. Later the group of Ito reported on the deoxygenation of a range of tertiary amides to the corresponding amines using the Wilkinson catalyst and Ph2SiH2.68 The protocol was mild and selective and tolerated esters and epoxides, showing superior chemoselectivity in comparison to other meth‐ ods existing at that time. However, primary and secondary amides proved to be unreactive under the developed conditions. Later Igarashi and Fuchikami performed an extensive study on the hydrosilylation of tertiary, and for the first time, secondary and primary amides catalyzed by Mn, Re, Ru, Os, Ir, Pd and Pt.69 It was found that the catalysts were substrate specif‐ ic and for some catalytic systems the addition of a co‐catalyst was central to achieve full conversion of the starting material. In the study, various additives such as secondary amine, pyridine, iodine, iodomethane, and iodoethane, and a number of different hydrosilanes were examined. Unfor‐ 13 tunately, the substrate scope used in the work was limited and no investi‐ gation to determine the chemoselectivity of the protocols was performed. Essential developments in the field of hydrosilylation of amides came from the group of Nagashima.70 They first reported on a catalytic system based on a triruthenium carbonyl cluster and ethyldimethylsilane (Scheme 6, a).70a The protocol was further improved when PMHS was used as the hydride source.70c Moreover it was found that the catalyst was almost fully encapsulated in the cross‐linked silicon polymer by the end of the reaction. This enabled a facile separation of the metal species and only 15 ppm of ruthenium remained in the extracted amine product. The same self‐ encapsulation approach was shown on a Pt‐catalyzed amide reduction sys‐ tem in which olefin, nitro and ester functionalities were tolerated using either PMHS or TMDS as the hydride sources.70d,g A significant improvement in chemoselectivity was later demonstrated using the Ru‐based protocol in combination with PhMe2SiH and stoichiometric amounts of trimethylamine. This protocol showed for the first time the preference for selective reduc‐ tion of tertiary amide to amine in the presence of a ketone.70e O R N R2 (CO)2 Ru Ru(CO)2 Ru (CO)2 a CO R1 cat,silane, solvent, N Pt N b R Si O Si N R2 R1 N - 3 N N N N SbF6 N Rh nBu nBu c Scheme 6. Catalysts developed by Nagashima (a), Beller (b) and Kobayashi (c) for hydrosilylation of tertiary amides to amines. In 2014 the group of Beller reported on a mild hydrosilylation of tertiary amides by a platinum NHC (N‐heterocyclic carbene) catalyst (Scheme 6, b).71 Using 1 mol% of the Pt‐catalyst together with diphenylsilane it was possible to deoxygenate amides at 40 °C to the corresponding amines. Un‐ fortunately, secondary and primary amides were proved to be challenging to reduce under these reaction conditions. The same group also reported on several protocols based on the Rh(cod2)BF4 catalyst for the hydrosilyla‐ tion of tertiary amides.72 The latter system is of significant importance since 14 it allowed for the selective reduction of the amide functionality in N‐ acetylamino acid esters substrates and more importantly peptides. The protocol was demonstrated to tolerate esters, amines, and phenols while secondary and primary amides remained unreacted. The group of Koba‐ yashi reported on a versatile Rh‐NHC system that could mediate a number of reactions, such as reductive methylation of amines using CO2, deoxygen‐ ation of carboxylic acids, tertiary and secondary amides and reductive al‐ kylation of amines using carboxylic acids under hydrosilylation conditions (Scheme 6, c).73 As mentioned above, hydrosilylation of secondary and primary amides is more challenging and the conversion to the amine is less chemoselective due to more active catalysts and harsher reaction conditions employed. A hydrosilylation system based on [RuCl2(mesitylene)]2 as the catalyst for the reduction of primary amides yielding secondary amines as the major prod‐ ucts was developed by Darcel and co‐workers.74 Using catalytic amounts of [RhCl(cod)]2/4PPh3 or RhCl(PPh3)3, Furukawa showed the possibility to re‐ duce secondary amides; however, the outcome of the reaction was not selective leading to a mixture of secondary amines and imines.75 Even though a great number of transition metal‐catalyzed amide hy‐ drosilylation protocols have been developed, only a limited amount of thorough mechanistic investigations have been performed. The group of Brookhart reported on the Ir‐catalyzed deoxygenation of tertiary amides including the study of the reaction mechanism.76 During their investigation it was possible to determine the catalytically active species using various NMR techniques. Interestingly, it was possible to significantly improve the activity of the system allowing for very high turnover numbers (TON 103 s‐1) and the reduction of sterically congested amides such as N,N‐ diisopropylbenzamide. In 2015, the group of Nagashima published results on mechanistic inves‐ tigation of a Pt‐based hydrosilylation system for the deoxygenation of ter‐ tiary amides.77 The computational studies were performed using data from previously reported protocols70d,g and were focused on the determination of the mechanism involving hydrosilanes bearing dual Si‐H groups. Based on DFT (density functional theory) calculations of the reaction pathway they were able to establish that the catalysis proceeds through the double oxidative addition of two Si‐H bonds to Pt‐species (Scheme 7). The adduct was found to be highly activated for the insertion into the C=O bond. 15 Moreover, the proximity effect of the two Si‐H bonds was observed to en‐ hance the rate of the reaction. Finally, the conventional Chalk‐Harrod mechanism was adopted which proceeds through coordination of the sub‐ strate to the platinum‐dihydride followed by the insertion to the Pt‐H bond and subsequent Si‐O reductive elimination to afford a silylhemiaminal A (Scheme 7). O Si Si Si L H H Si Pt(H2)(L) Si O H R1 H NR2R3 NR2R3 R1 NR2R3 Si O H Pt H Si L Pt(0)L2 Si R 1 R1 NR2R3 O H Pt H Si L A Si Scheme 7. Simplified reaction mechanism proposed by Nagashima for Pt‐catalyzed hydrosilylation of amides with silanes bearing dual Si‐H groups. Kaneda and co‐workers discovered that the hydrosilylation of amides al‐ so can be performed with a heterogeneous catalyst, utilizing hydroxyap‐ atite‐supported gold nanoparticles.78 It was possible to efficiently deoxy‐ genate secondary and tertiary amides using dimethylphenylsilane as the hydride source in the presence of ester, nitrile and olefin functionality un‐ der the developed reaction conditions. b) First row and non‐precious transition metal‐catalyzed protocols There are several examples of systems employing catalytic amounts of non‐ precious transition metals such as Mo79, In80 and Ti81 for the deoxygenation of tertiary and secondary amides under hydrosilylation conditions. These protocols can be characterized by high reaction temperatures and limited substrate scope due to low functional group tolerance. The use of first row transition metals is advantageous from environmen‐ tal and economical points of view in comparison to precious metals. The group of Beller reported on a highly chemoselective hydrosilylation method 16 based on Zn(OAc)2 catalyst with triethoxysilane ((EtO)3SiH) as the hydride source.82 The catalytic system demonstrated such a high level of group tol‐ erance that it was possible to reduce tertiary amides in presence of nitrile, nitro, ester and ketone functionalities. Later on they improved the catalytic protocol83 switching from (EtO)3SiH to the more stable diethoxyme‐ thylsilane ((EtO)2MeSiH) and TMDS due to the safety hazards associated with trialkoxysilanes.84 Even though it was not possible to fully preserve the chemoselectivity of the reaction and keto‐groups were no longer tolerated, it was shown that the catalytic system was active in the deoxygenation of secondary amides to amines. Recently the same system was used by Gómez‐Campillos for the synthesis of functionalized chiral azetidines from β‐lactams that previously was proven to be challenging target compounds (Scheme 8).85 Scheme 8. Selected example of application of Zn‐catalyzed protocol by the group of Gómez‐Campillos. A general protocol for deoxygenation of secondary amides using copper catalysis was reported by Beller.86 After thorough screening of bi‐ and tri‐ dentate ligands, pyridinebisoxazolines were established as the most active ones and in combination with Cu(OTf)2 and TMDS it was possible to reduce amides to corresponding secondary amines in good yields. In 2013, Sortais developed a catalytic method based on Co2(CO)8 for the hydrosilylation of tertiary amides.87 The reaction proceeded either with conventional heating at 100 °C or under UV irradiation (350 nm). The system was evaluated on a number of substrates and was proven to tolerate esters, nitro‐group, ni‐ triles as well as olefins. Iron represents an attractive metal for catalysts preparation, due to the natural abundance, non‐toxicity and low cost. Beller reported on an Fe‐ based catalytic system for the reduction of tertiary amides using Fe3(CO)12 as the catalyst and polymeric siloxane (PMHS) as the hydride source.88 With a catalyst loading up to 10 mol% at 100 °C and a reaction time of 24 h, they were able to reduce aromatic, heteroaromatic and even aliphatic amides in good to excellent yields. High conversion of a secondary amide to the cor‐ responding amine was shown when Ph2SiH2 was used instead of PMHS. The 17 group of Nagashima, following their own work on the reduction of carbox‐ amides using Pt and Rh catalysts with PMHS,70 reported on two iron car‐ bonyl catalytic systems (Fe(CO)5, Fe3(CO)12) which could be employed for the same transformation.89 It was found that the reaction could be per‐ formed either at elevated temperature (100 °C, 24 h) or under irradiation (rt, 9 h) using TMDS as the hydride source in the reduction of tertiary and secondary amides. Furthermore, the protocol was successfully extended to the selective reduction of nitroarenes to anilines in the presence of an am‐ ide functionality. Later the same group reported on an enhanced system using a heptanuclear iron carbonyl cluster as a precursor for the active catalyst.90 Furthermore, by employing 1,2‐bis(dimethylsilyl)benzene (BDSB) they were able to reduce the catalyst loading to 0.5 mol% and the reaction time to 0.5 h. The same year (2011), Darcel published a well‐defined piano‐ stool iron complex that could be used in catalytic hydrosilylation of tertiary amides together with PhSiH3.91 During the investigation of suitable condi‐ tions it was found that the catalyst performed better under solvent‐free conditions. It was possible to reach good conversion of the starting com‐ pound at 100 °C after 24 h reaction time using 6 hydride equivalents. The results from the extensive substrate scope screening demonstrated that aliphatic, aromatic, and heteroaromatic tertiary amides and aromatic sec‐ ondary amides could be reduced to the amines in high yields. If a primary amide was used as a substrate the corresponding nitrile derivative was formed instead in good yield. The same iron complex was shown to be ac‐ tive in the hydrosilylation of imines to amines.92 In 2012, the group of Beller reported on a general and efficient catalytic system, comprising two iron‐based complexes for the reduction of aromatic and aliphatic primary amides to amines, as a tandem process with two sub‐ sequent catalytic reactions (Scheme 9).93 Initially, the amide is reduced to the corresponding nitrile catalyzed by [Et3NH][HFe3(CO)11] (2‐5 mol%), and the cyano‐derivative is then reduced to the target amine by an in situ formed iron complex from Fe(OAc)2 (10 mol%) and the bidentate phenan‐ throline ligand (20 mol%). 18 Scheme 9. Proposed mechanism by Beller for the reduction of primary amides to amines using two different iron complexes in a consecutive manner. Nagashima published results on studies of an iron complex that was ra‐ tionally designed to perform hydrosilylation of chosen tertiary amides at room temperature using 1,2‐bis(dimetylsilyl)benzene (BDSB) as the hydride source.94 c) Transition metal‐free systems As previously mentioned, catalytic activation of silanes can be accom‐ plished not only employing transition‐metals but also with Lewis acids or through nucleophilic activation. An efficient protocol was reported by Cui showing that 1 mol% of Cs2CO3 could catalyze the deoxygenation of tertiary aromatic and aliphatic amides at rt to 80 °C with PhSiH3 as the hydride source.95 The authors proposed a nucleophilic activation pathway by the carbonate anion as the most plausible one based on the observed for‐ mation of formic acid as the by‐product of the reaction. The group of Crab‐ tree published a protocol for the catalytic reduction of various carbonyl containing compounds to alcohols including two examples of tertiary aro‐ matic amides to the corresponding amines using 5 mol% of LiHBEt3 and 19 PhSiH3.96 The mechanism for the reduction of an aldehyde substrate was investigated using computational techniques. It was postulated that the initial reduction of the carbonyl by the borohydride reagent was followed by the activation of the silane through a pentavalent silicon species, and the catalyst is regenerated through a hydride transfer to the boron. Recent‐ ly a straightforward and efficient methodology based on catalytic amounts of potassium hydroxide was developed by Nolan.97 Employing only 4 mol% of KOH it was possible to reduce esters to alcohols and deoxygenate ter‐ tiary amides to amines using PhSiH3 under neat conditions at rt. In the re‐ port from Xie another base‐catalyzed system was presented for the reduc‐ tion of N‐substituted cyclic imides to ω‐hydroxylactams and lactams.98 Us‐ ing catalytic amounts of KOH (2.5 mol%) together with Ph2SiH2 as the hy‐ dride source, they were able to perform hydrosilylation of the starting compounds in the presence of aliphatic nitrile, ester and tertiary amide groups. An example of TBAF (tetra‐n‐butylammonium fluoride) catalyzed deoxygenation was reported by Beller.99 Selective monoreduction of phta‐ limides was performed using PMHS, and the mild reaction conditions al‐ lowed for the reduction of substrates containing epoxides, aliphatic halides and alkynes. The results of in situ spectroscopic measurements suggested that the reaction preceded through a fluorine adduct of pentavalent silicon as an active reducing agent. In general, the above mentioned transition metal‐free protocols, alt‐ hough being simple to operate, have a limited substrate scope and reduci‐ ble groups such as nitrile and nitro groups, etc. were not tolerated. The first example of boron‐based Lewis acid‐catalyzed deoxygenation of amides was presented by Zhang.100 Employing tris(pentafluorophenyl) bo‐ rane (B(C6F5)3) in catalytic amounts (2 mol%) at elevated temperature N‐phenylacetamide was deoxygenated to the secondary amine using the air sensitive diphenylsilane. Later on the limitation of using air sensitive silanes was overcome by two groups of Cantat and Adronov. 101 They independent‐ ly reported on the successful application of the same Lewis acid in deoxy‐ genation of various secondary and tertiary amides with TMDS and PMHS as the hydride sources. In the case of the Cantat method, attempts for deoxy‐ genation of primary amides were unsuccessful and additional derivatization (silylation using TMSCl) of the nitrogen amide group atom was required. Recently the group of Chang reported on orthogonal reactivity of B(C6F5)3 where catalytic α‐silylation of α,β‐conjugated sterically hindered tertiary 20 amides occurred chemoselectively leaving the carbonyl group intact.102 Another example of a boron‐catalyzed hydrosilylation of primary, second‐ ary and tertiary amides to the corresponding amines was reported by Bel‐ ler.103 After an extensive screening of boronic acid derivatives they identi‐ fied benzothiophene‐derived boronic acid as the most active catalyst for deoxygenation of amides. The reactions were performed at elevated tem‐ peratures (>100 °C) and in the case of tertiary amides it was possible to perform selective reduction in presence of nitro, nitrile and ester function‐ alities. Overall transition metal‐free catalytic deoxygenation of amides can be characterized by high reaction temperatures, often in combination with air sensitive silanes in large excess. Moreover, the chemoselectivity of the transformations are inferior to the metal‐catalyzed protocols where there are many systems exhibiting high chemoselectivity even though only a few allows for the presence of more reactive carbonyl functionalities. Hydrosilylation of amides to aldehydes and precursors thereof Limited examples of catalytic hydrosilylation of amides to the correspond‐ ing aldehydes and their precursors have been reported. Nagashima pub‐ lished an efficient Ir‐based protocol for the synthesis of enamines from tertiary amides at room temperature.104 Employing 0.01–0.05 mol% of IrCl(CO)(PPh3)2 together with TMDS or PMHS as the hydride sources it was possible to convert highly functionalized tertiary amides to enamines with excellent selectivity. The protocol was shown to be compatible with sub‐ strates bearing aliphatic halides, olefins, esters and even ketones. Later on the same group published results on the synthesis of sterically congested π‐ conjugated enamines through the catalytic hydrosilylation of the corre‐ sponding amides with an improved Ir‐catalyst.105 Another Ir‐based catalytic protocol reported by Brookhart enabled for the reduction of secondary amides to imines.106 Employing [Ir(cod)Cl]2 in combination with Et2SiH2 at room temperature allowed for the isolation of a limited number of imines after short reaction times. 21 1.3 Objectivesofthethesis The aim of this thesis has been to develop efficient catalytic systems for the mild and selective hydrosilylation of amides. The use of hydrosilanes repre‐ sents a good alternative among other hydride sources generally allowing for the reaction to occur under mild reaction conditions with high function‐ al group tolerance. The majority of the existing amide hydrosilylation pro‐ tocols are based on precious metals as catalysts. These metal‐precursors are expensive and display high toxicity; therefore, it is advantageous to employ readily abundant and relatively non‐toxic metals like iron and zinc for the development of more environmentally friendly catalytic protocols. Thus, the first two parts of the thesis is devoted to the catalytic methods based on these metals for the selective deoxygenation of tertiary amides to the corresponding amines. Moreover in these procedures it was possible to use cost‐effective, air, and moisture stable polymeric silane (PMHS) as the hydride source. From the pharmaceutical industry’s point of view the major improve‐ ment in catalytic hydrosilylation of amides would be the development of a transition metal‐free protocol avoiding hazardous metal contamination of the products. By the time we started to work on our KOtBu‐based catalytic system only a few methods were reported for the use of non‐metal‐based catalysts for deoxygenation of amides and none of them could yield syn‐ thetically useful enamines as the final product of the reaction. The last chapter of this doctoral thesis was devoted to the development of a highly chemoselective Mo‐based catalytic system. In the field of amide reduction few protocols are available tolerating the ketone group among others in the course of the reaction while selectivity over aldehyde and imine groups remained unattainable until now. The creation of a protocol with such level of chemoselectivity is of high synthetic value, both for aca‐ demic and industrial chemists. 22 2 DirectHydrosilylationofTertiary AmidesbyanInSituFormedIron/N‐ HeterocyclicCarbeneCatalyst(PaperI)2 2.1 Introduction Amines are valuable intermediates in organic synthesis, constitute a vital class of compounds for bulk and pharmaceutical chemistry. As was men‐ tioned in Section 1.2, new efficient and environmentally friendly catalytic methods for the synthesis of amines are of great importance. Iron, having high natural abundance and therefore low cost, represents an attractive precursor for catalytic reactions. Previously in our group a highly active Fe(II)/NHC catalyst was developed for the hydrosilylation of aldehydes and ketones to the corresponding alcohols (Scheme 10).107 The developed in situ formed complex allowed for the use of the air and mois‐ ture stable, cost‐effective silane PMHS as the hydride source. An extensive ligand screening showed that bifunctional NHC‐based precursor ([HEMIM][OTf]) in combination with Fe(OAc)2 led to high yields of alcohol after very short reaction time (up to 10 min). Later it was discovered that the developed catalytic system also was suitable for the reduction of ter‐ tiary amides to amines. Scheme 10. Hydrosilylation of aldehydes and ketones by an in situ formed Fe(II)/NHC catalyst. 23 2.2 Resultsanddiscussion N,N‐Dimethylbenzamide (1a) was chosen as a model substrate and was subjected to the reaction conditions previously optimized for the reduction of ketones (Scheme 10). Gratifyingly, full conversion of the tertiary amide was observed after prolonged reaction time (16 h); however, two by‐ products (alcohol 1c and aldehyde 1d) were identified along with target amine 1b as determined by 1H NMR analysis (Table 1). Table 1. Screening of the conditions for the reduction of tertiary amides.a) Entry Fe(OAc)2 Ligand mol % precursor Silane Solvent Conversion (%) b) Products (%) 1b 1c 1d 1 1 [HEMIM][OTf] PMHS THF >95 53 20 27 2 2.5 [HEMIM][OTf] PMHS THF >95 65 11 24 3 1 [Ph‐HEMIM][OTf] PMHS THF >95 74 11 15 4 1 [Ph‐HEMIM][OTf] TMDS THF >95 48 14 38 5 1 [Ph‐HEMIM][OTf] (EtO)2 MeSiH THF >95 75 15 10 6 1 [Ph‐HEMIM][OTf] (EtO)3 SiH THF >95 82 10 8 7 1 [Ph‐HEMIM][OTf] PMHS Dioxane 0 ‐ ‐ ‐ 8 1 [Ph‐HEMIM][OTf] PMHS Toluene >95 54 19 27 9 0 [Ph‐HEMIM][OTf] PMHS THF 0 ‐ ‐ ‐ 10 5 ‐ PMHS THF 0 ‐ ‐ ‐ a) General reaction conditions: N,N‐dimethylbenzamide (1 mmol), Fe(OAc)2 (x mol%), NHC precursor ‐ (1.1x mol%), nBuLi (2.2x mol%), dry solvent (3 mL), silane (3 [H ] equiv), 65 °C, 16–18 h. b) Conversion 1 and product ratio were determined by H NMR spectroscopy. Varying the catalyst loading from 1 mol% to 2.5 mol% and employing different NHC‐precursors ([Ph‐HEMIM][OTf]) resulted in a slight increase in the selectivity of the reaction (Table 1, entries 1‐3). Optimization of the reaction conditions proceeded with the screening of various hydride sources and solvents, unfortunately, unsatisfactory selectivity of the reduc‐ tion was observed in these cases as well (Table 1, entries 4‐8). A selectivity of 82% towards amine was obtained when trimethoxysilane was employed, however, owing to the high price and previous reports on the formation of volatile hazardous compounds;108 it was decided to continue the optimiza‐ tion of the reaction conditions using PMHS as the hydride source. Interest‐ ingly, among the evaluated silanes TMDS stood out and the C‐N bond 24 cleavage reaction almost prevailed over the deoxygenation pathway (Table 1, entry 4). Further change of the catalyst loading, ratio of the Fe(OAc)2 towards the ligand, equivalents of silane, and concentration of the reaction did not lead to higher selectivity of the process. It is important to point out that the iron precursor was used in high purity (99.995%) excluding the possibility of other trace metal catalysis and no reaction was observed if one of the components of the reaction was omitted. From the initial screening of the conditions it can be observed that, a significant amount of benzyl alcohol 1d and some benzaldehyde 1c could be detected in all of the experiments (Table 1). In order to increase the selectivity of the process we hypothesized regarding the possible pathways of the by‐product formation (Scheme 11). The reduction of the amide 1a to amine 1b is a two‐step process proceeding through tetrahedral intermedi‐ ate I that collapses to iminium ion II which is known to undergo very fast reduction yielding the desired amine 1b. Alternatively, intermediate II could lead to the formation of aldehyde 1c via hydrolysis by any water present in the reaction or to the oxo‐carbenium ion III. Both pathways (through 1c or III) would ultimately result in the formation of alcohol 1d under the reduc‐ tion conditions. Since all of the reactions were run in dry solvent under inert atmosphere the amount of by‐product 1d formed could not be ac‐ counted for the hydrolysis of the intermediate II to aldehyde 1c by water. According to the possible pathways of the reaction it was assumed that, since the selectivity is set by the collapse of the tetrahedral intermediate I, the addition of an oxophilic Lewis acid should promote cleavage of species I following the desired pathway. Scheme 11. Plausible pathway for the reduction of tertiary amide and by‐products formation. 25 Further optimizations of the reaction conditions were performed using piperidinebenzamide 2a as the standard compound since the attempts to isolate dimethyl amine 1b led to significantly lower yields than could be anticipated from the 1H NMR analysis of the crude reaction mixtures. Lithi‐ um chloride was previously reported as an achiral promoter in catalytic reductions109 and was evaluated as an additive in the current protocol. To our delight addition of 1 mol% increased the selectivity of the reduction to >95% towards the formation of target amine 2b according to 1H NMR analysis and decreased the reaction time from 16 h to 5 h to reach full con‐ version of the starting tertiary amide 2a. Furthermore, it was shown that LiCl could not catalyze the reduction of 2a in absence of the in situ formed iron complex under the optimized reaction conditions. a) General reaction conditions: amide (1 mmol), Fe(OAc)2 (1 mol%), NHC precursor (1.1 mol%), nBuLi ‐ (2.2 mol%), THF (3 mL), PMHS (3 [H ] equiv), 65 °C, 5–14 h, isolated yields. Scheme 12. Substrate scope evaluation for iron‐catalyzed hydrosilylation of amides. 26 With the optimized reaction conditions at hand we proceeded with sub‐ strate scope investigation (Scheme 12). The evaluation of a number of ar‐ omatic and heteroaromatic amides resulted in the formation of the corre‐ sponding amines in good isolated yields. Noteworthy, halogen containing amides 7b, 8b, 9b were reduced to the target compounds without occur‐ ring dehalogenations. A prolonged reaction time was required for sterically hindered azepane 3b and N,N‐dibenzyl‐derived 6b amides to reach full con‐ version of the starting compound. The developed Fe‐catalyzed protocol showed a limitation in functional group tolerance, where easily reducible groups such as esters, ketones, nitro‐ and nitrile‐functionalities underwent competing hydrosilylation reac‐ tions. Also pyridine containing amides were not reduced, most probably due to a competing coordination with the metal center. Moreover, deoxy‐ genation of tertiary aliphatic, secondary and primary amides did not lead to the desired amines. The importance of the alcohol moiety of the NHC‐ligand was investigat‐ ed in the previous protocol designed for the reduction of ketones and alde‐ hydes and it was proven to be significant for the reactivity of the catalyst. Tosylation of the free hydroxyl group of the NHC‐precursor led to a catalyst which showed no conversion of the starting compound under optimized reaction conditions. Moreover, the introduction of chirality to the handle of the NHC did not result in any chirality transfer to the produced alcohol in the reaction. The investigation suggests that at some point in the catalytic cycle the handle is not attached to the metal center but it still plays a cru‐ cial role in the overall process. It can be envisioned that the activation of the silane proceeds through a σ‐bond metathesis step IV involving the alkoxy‐group of the ligand forming metal‐hydride and alkoxysilane V (Scheme 13). Presumably, after the hydride and silane transfer to the sub‐ strate the catalyst is regenerated and the tetrahedral intermediate is re‐ leased. Subsequently, after the Lewis acid‐catalyzed collapse of the inter‐ mediate to iminium ion the second reduction step yields the target amine. Scheme 13. Proposed in situ catalyst formation and activation of the silane. 27 2.3 Conclusions The developed in situ formed Fe(II)/NHC catalyst for deoxygenation of ter‐ tiary amides to amines is of particular importance due to the use of non‐ toxic and environmentally benign iron as the metal center and low catalyst loading (1 mol%). Polymeric silane (PMHS), characterized by air and mois‐ ture stability, was used as the hydride source. The analysis of the possible pathways for by‐products formation led to the conclusion that, most prob‐ ably, the collapse of the tetrahedral intermediate is the step determining the selectivity of the process. It was assumed that catalytic amounts of an oxophilic Lewis acid might positively affect the selectivity and rate of the collapse of the tetrahedral intermediate to iminium ion species. Fortunate‐ ly, addition of 1 mol% of LiCl increased the conversion and improved the selectivity of the amine formation to >95% according to 1H NMR analysis and decreased the reaction time from 16 h to 5 h. A number of aromatic and heteroaromatic tertiary amides were evaluated using the developed catalytic protocol resulting in the formation of amines in good isolated yields. 28 3 MildandSelectiveEt2Zn‐Catalyzed ReductionofTertiaryAmidesunder HydrosilylationConditions(PaperII) 3.1 Introduction The catalytic system described in chapter two was based on a cost‐effective iron catalyst and an air and water stable polymeric silane (PMHS), however, elevated temperature was required to reach full conversion of the starting compounds (Chapter 2). Furthermore, the system showed limited function‐ al group tolerance and important functionalities such as nitro, nitrile or olefins were partially reduced under the optimized reaction conditions. Consequently, during the development of a new catalytic protocol we were aiming for milder reaction conditions with higher chemoselectivity while still maintaining low toxicity of the catalyst and stability of the hydride source. We started with a screening of the first row transition metals for the ability to catalyze the reduction of tertiary amides to amines. Previous‐ ly, Beller and co‐workers identified Zn‐salts to be active in selective hydrosi‐ lylations of amides to amines using either (MeO)3SiH at room temperature or the safer (EtO)2MeSiH at elevated temperature. It was envisioned that by tuning the Zn‐metal center using previously developed NHC ligands it would be possible to employ PMHS as hydride source while maintaining high chemoselectivity of the transformation of amides to amines. 3.2 Resultsanddiscussion Keeping in mind the intended goals for the project to develop a mild and selective reduction of amides using PMHS as the hydride source we per‐ formed an initial evaluation of the ZnCl2/[Ph‐HEMIM][OTf] system. Fortu‐ nately, it was possible to fully convert N‐piperidinebenzamide 2a to amine 2b at 65 °C in 24 h (Table 2, entry 1). Later on it was decided to use Et2Zn 29 instead of ZnCl2 in order to avoid the addition of base for the deprotonation of the ligand, but blank experiments without the NHC showed activity of the organozinc reagent at room temperature on its own (Table 2, entry 2). Gratifyingly, the addition of 10 mol% LiCl to the reaction increased the con‐ version of starting amide to amine from 9% to >95% in THF (Table 2, entry 3). Subsequently, it was shown that omitting the diethyl zinc from the reac‐ tion mixture resulted in no conversion of starting material, thus it was de‐ cided to continue the investigation of the Et2Zn‐catalyzed protocol (Table 2, entry 4). Table 2. Optimization of the conditions for Zn‐catalyzed reduction of amides.a) Entry 1 Zn LiCl precursor mol % ZnCl 2 /[Ph‐HEMIM][OTf] Temperature Silane Solvent Conversion (%) b) 0 65 C o PMHS THF >95 2 Et2 Zn 0 rt PMHS THF 9 3 Et2 Zn 10 rt PMHS THF >95 4 0 10 rt PMHS THF 0 5 Et2 Zn 10 rt PMHS Et2O 61 6 Et2 Zn 10 rt PMHS Toluene 41 7 Et2 Zn 10 rt (EtO)3SiH THF >95 8 Et2 Zn 10 rt TMDS THF 24 9 Et2 Zn 10 rt (EtO)2 MeSiH THF >95 a) General reaction conditions: N,N‐piperidinebenzamide (1 mmol), [Zn] (5 mol%), LiCl (x mol%), dry ‐ solvent (2 mL), silane (3 [H ] equiv), 24 h, rt. b) Conversion of the starting compound to amine 2b was 1 determined by H NMR spectroscopy. During the screening of the reaction conditions various amounts and ra‐ tios of organozinc reagent and lithium additive were evaluated. The best activity was achieved using 5 mol% Et2Zn and 10 mol% of LiCl giving 90% conversion of amide 2a to amine 2b already after 7 h. Evaluation of the reaction in Et2O and toluene showed only moderate activity of the catalytic system resulting in 61% and 41% conversion respectively after 24 h reaction time (Table 2, entries 5, 6). When Zn(OAc)2 was employed as the catalyst under optimized reaction conditions no target amine could be observed. While screening different silanes TMDS was found to give the lowest con‐ 30 version of the starting amide to amine whereas (MeO)3SiH, Me(EtO)2SiH, and PMHS were superior resulting in quantitative reductions (Table 2, en‐ tries 3, 7‐9). During our investigations of the catalysts we also identified Et2Zn to have catalytic activity in the reduction of other carbonyl com‐ pounds.110 a) General reaction conditions: amide (1.0 mmol), Et2Zn (5 mol%), LiCl (10 mol%), PMHS (3 [H ] equiv), THF (2 mL), 24 h, rt, isolated yields. b) The reactions were carried out for 24 h at 40 °C. ‐ Scheme 14. Substrate scope for the Zn‐catalyzed reduction of tertiary amides. With the optimized catalytic protocol in hand (Table 2, entry 3) we set to investigate the scope of the reaction (Scheme 14). A wide range of elec‐ tron‐rich and electron‐poor tertiary amides were successfully deoxygenat‐ ed to the corresponding amines under mild reaction conditions. In general, 31 aliphatic amides showed lower reactivity resulting in decreased yields of amines (19b, 20b); fortunately, this could be overcome by using slightly elevated reaction temperature (40 °C). Pyridine and other heteroaromatic substituted amides were shown to undergo reduction to the target tertiary amines 21b, 11b, 12b in good to excellent yields. The amide containing a chiral center was converted to amine 26b with almost full retention of the ee. More importantly, it was possible to perform the chemoselective hy‐ drosilylation of amides to the target compounds in presence of a variety of reducible groups. Thus, nitro, nitrile, carbamate moieties, double and triple C‐C bonds were tolerated under the developed reaction conditions (23b, 24b, 25b, 22b, 27b). In contrast, amides containing a conjugated alkyne functionality proved to be inactive in the catalytic protocol. The tertiary amide containing an acidic proton (28a) was successfully reduced to amine 28b. It is possible that the ortho‐phenol functionality is deprotonated prior to the reduction and in combination with the neighboring amide group the substrate acts as a bidentate ligand to the zinc, forming an active complex for further reduction of the remaining starting material. Unfortunately the protocol was incompatible with certain functionalities such as Boc‐protected primary amines and primary and secondary amides; where unreacted starting materials were fully recovered. The above com‐ pounds contain labile protons that could react with the catalyst inhibiting the activity. Moreover, tertiary amides containing ketone or ester groups gave mixtures of products as a result of partial reduction of the carbonyl functionalities. An aniline based tertiary amide was evaluated in the proto‐ col yielding the target amine and the product of a competing C‐N bond cleavage. It was impossible to determine the catalytic species of zinc‐lithium sys‐ tem in the reduction of tertiary amide to amine; however, there are reports on use of LiCl to enhance the reactivity of organozinc reagents.111 In the developed protocol presented above it is possible that Lewis acid activation of carbonyl is central in order for the zinc‐hydride to perform the reduction. 3.3 Conclusions A Zn/Li‐based catalytic system for the deoxygenation of tertiary amides to amines was developed with enhanced chemoselectivity in comparison to 32 the previously reported Fe(II)/NHC system. Using commercially available Et2Zn and LiCl in catalytic amounts it was possible to convert a wide range of tertiary amides to the corresponding amines in high isolated yields. The reactions were performed under mild reaction conditions (rt) and the air and moisture stable polymeric silane PMHS was used as the hydride source. The system is characterized with high chemoselectivity and allowed for the reduction of the amide functionality in the presence of other reducible groups such as nitro, nitrile, olefins and carbamate. 33 34 4 CatalyticReductiveDehydrationof TertiaryAmidestoEnaminesunder HydrosilylationConditions(PaperIII)2 4.1 Introduction Development of transition metal‐free procedures is of high interest for the synthesis of pharmaceuticals since it results in no contamination of the product with toxic metal impurities, which decreases the number of purifi‐ cation steps. The previously developed Fe‐ and Zn‐based catalytic systems were effective in the reduction of aromatic, heteroaromatic tertiary am‐ ides, whereas benzylic derivatives proved to be either unreactive or leading to a mixture of products (Chapter 2, 3). In the case of the iron‐catalyzed protocol, the formation of enamine 29b was observed instead of the corre‐ sponding amine when the reaction was performed at elevated tempera‐ tures (120 °C) (Scheme 15). As mentioned previously (Section 1.2.3) very few catalytic protocols have been reported on the synthesis of enamines from amides, thus it was decided to continue the investigation of this trans‐ formation. Scheme 15. Reduction of benzylic amide to the corresponding enamine. 35 4.2 Resultsanddiscussion Performing blank experiments in order to determine the necessity of all components of the catalytic system it was found that 20 mol% LiCl at 120 °C or 10 mol% nBuLi at 65 °C catalyzed the transformation using (EtO)3SiH as the hydride source (Table 3, entries 1,2). Evaluation of various bases showed that potassium tert‐butoxide (10 mol%) was most active in the reduction of amide 29a to corresponding enamine 29b (Table 3, entries 3‐ 5). The reaction could be performed in either THF or toluene, whereas DCM or acetonitrile were incompatible with the protocol (Table 3, entries 5‐8). Table 3. Optimization of the conditions for the base‐catalyzed hydrosilylation. Entry catalyst Temperature 1 20 mol% LiCl 120 C 2 3 4 5 10 mol% n BuLi 5 mol% NaOMe 10 mol% KOH 10 mol% KOt Bu 6 10 mol% KOt Bu 7 10 mol% KOt Bu 8 10 mol% KOt Bu o (EtO)3 SiH THF 56 (EtO)3 SiH THF 37 o (EtO)3 SiH THF 43 o (EtO)3 SiH THF 57 o (EtO)3 SiH THF >95 o (EtO)3 SiH Toluene 80 o (EtO)3 SiH DCM 0 o (EtO)3 SiH MeCN 0 o PMHS THF 0 o TMDS THF 0 o 0 65 C 65 C 65 C 65 C 65 C 65 C 65 C 9 5 mol% KOt Bu 5 mol% KOt Bu 65 C 11 5 mol% KOt Bu 65 C 65 C Et3 SiH THF o Ph2 SiH2 THF 0 o (EtO)2 MeSiH THF 0 o (EtO)3 SiH THF 43 o (MeO)3 SiH THF 63 o (MeO)3 SiH THF 12 5 mol% KOt Bu 13 5 mol% KOt Bu 65 C 14 5 mol% KOt Bu 65 C 16 b) 5 mol% KOt Bu 5 mol% KOt Bu Solvent Conversion (%) a) o 10 15 Silane 65 C 65 C 65 C >95 1 a) Conversion of the starting compound to enamine 29b was determined by H NMR spectroscopy. b) 99.99% purity KOtBu, THF (2 mL), (MeO)3SiH (4 equiv). 36 While screening different silanes it was found that only trialkoxysilanes were suitable for the reduction (Table 3, entries 9‐15). To rule out the in‐ volvement of transition metal impurities in the catalysis, 99.99% grade KOtBu (5 mol%) was used for the reaction yielding 74% conversion of the starting amide 29a to enamine 29b. Performing the reaction in 2 mL of solvent and increasing the hydride equivalents to 4 it was possible to achieve >95% yield of the target compound 29b as determined with 1 H NMR analysis (Table 3, entry 16). A possible reaction mechanism for the reduction of tertiary amides to enamines is shown in Scheme 16. Most likely, the base activates the silane through the nucleophilic pathway via a pentacoordinated silicon intermedi‐ ate VI (Scheme 16). This makes the hydride active enough to be transferred to the amide carbonyl and to produce the tetrahedral intermediate VII. An aromatic moiety in the β‐position to the amide carbonyl would stabilize the formed enamine with π‐conjugation, and also decrease the pKa of the α‐ proton, therefore, facilitate the deprotonation step. Thus, instead of the nitrogen lone pair promoting the collapse of the tetrahedral intermediate to yield the iminium ion, it is assumed that an α‐deprotonation occurs fol‐ lowed by a deoxygenation step to form the enamine compound. Scheme 16. Proposed mechanism for the base‐catalyzed reduction of tertiary am‐ ides to enamines. A number of amides were reduced to the corresponding enamines un‐ der the optimized reaction conditions (Scheme 18). Different aromatic, 37 heteroaromatic, and aliphatic enamines could be obtained in good yields and selectivity from tertiary amides. Amides containing aromatic chlorine and fluorine substituent readily underwent reduction to corresponding target compounds 35b, 36b whereas a p‐bromo‐substituted amide resulted in only 36% enamine. The sterically demanding amide 33a was successfully converted to target compound 33b. The reductions of the tertiary amides were trans‐selective except for the substrate 40b where a mixture of E and Z isomers in a 9:1 ratio was obtained. Aliphatic amides that are not branched at the α‐carbon were converted to the corresponding enamines 41b, 42b in good yields. Unfortunately, the reductions of compounds 41a and 42a were characterized with lower selectivity in comparison to benzylic tertiary amides and the corresponding amines products were formed in substantial amounts. In the case of cyclohexanecarboxylic acid derived am‐ ide 20a only amine formation was observed (Scheme 17). The observed selectivity in these reactions can most likely be explained by steric hin‐ drance of the α‐position and higher pKa of the α‐proton in the starting compounds compared to benzylic amides. These factors would slow down the deprotonation step, diverting the reaction pathway to the iminium ion formation, followed by the rapid reduction step, yielding the corresponding amine. Scheme 17. Transition metal‐free reduction of cyclohexanecarboxylic acid derived amide. Under optimized reaction conditions and lower concentration of the components (Scheme 19), it was possible to reduce amide 44a to the target enamine 44b in 75% yield according to 1H NMR using 1,3,5‐ trimethoxybenzene as internal standard. Along with the formed enamine 44b, amino amide 44c was identified as a byproduct. Most probably, the enamine (44b) attacks the starting compound (44a) and a subsequent elim‐ ination of the stabilized diphenylmethanide generates the iminium com‐ pound VIII which can undergo reduction to yield 44c. The amide group of this compound is probably too sterically hindered for the reduction to occur under the reported hydrosilylation conditions. When the more bulky silane 38 ((EtO)3SiH) was used compound 44c was obtained in 82% yield. The results could be explained by the rate of enamine formation, where the ethoxy‐ substituted silane gave rise to a slower reaction than that with trimethox‐ ysilane. A 78% isolated yield of diphenylmethane when (EtO)3SiH was used as the hydride source, further supports the suggested mechanism for the formation of the compound 44c (Scheme 19). a) General reaction conditions: amide (1.0 mmol), Mo(CO)6 (5 mol%), (MeO)3SiH (4 equiv), THF (2.0 mL), 1 65 °C, 14–24 h, Isolated yields. b) H NMR yield using 1,3,5‐trimethoxybenzene as internal standard. c) Obtained as a 9:1 mixture of E and Z isomers. Scheme 18. Substrate scope for the base‐catalyzed conversion of tertiary amides to enamines. 39 Scheme 19. Unexpected in situ trapping of the formed enamine. The developed methodology was further extended to generate more complex compounds. Employing the site‐selective alkylation of the enamine 29b generated using optimized reaction conditions it was possible to isolate aldehyde 45 in good yield after two steps (Scheme 20). Scheme 20. Site‐selective alkylation of the formed enamine. Several of the enamines were possible to isolate by a quick filtration of the reaction mixture through Et3N deactivated silica gel; however, aliphatic enamines were rapidly decomposed during the isolation. Nevertheless, we were able to use the formed aliphatic enamine 46b in situ, avoiding purifi‐ cation procedures (Scheme 21). β‐Amino alcohol 47 was isolated in 75% yield after direct hydroboration reaction of 46b followed by oxidative cleavage. Scheme 21. Synthesis of amino alcohol via hydroboration of enamine with subse‐ quent oxidative cleavage. 40 4.3 Conclusions A transition metal‐free protocol was developed for the conversion of ben‐ zylic and aliphatic tertiary amides to the corresponding enamines. The methodology makes use of trialkoxysilanes as the hydride source and cata‐ lytic amounts of KOtBu, resulting in E‐selective and generally high yielding formation of the target enamines. A method for purification of stabilized aromatic enamines was developed using deactivated silica gel flash chro‐ matography, whereas the aliphatic products were proven to be unstable and decomposed rapidly. In order to circumvent this problem and avoid purification step of the enamines in situ trapping experiments of the final compounds were performed including site‐selective alkylation and hydrob‐ oration reaction with subsequent oxidative cleavage. It was shown that using the extended methodology it was possible to generate a number of different synthetically useful multifunctional compounds. Alkoxides have previously been reported as the catalysts for the hydrosilylation of alde‐ hydes, ketones, amides and imines,54,97,112 however, to the best of our knowledge, this protocol represents a sole example of the alkoxide‐ catalyzed conversion of amides to enamines. 41 42 5 Mo(CO)6CatalyzedChemoselective HydrosilylationofTertiaryAmides (PaperIVandV) 5.1 Introduction In the field of carbonyl reductions, deoxygenation of amide represents the most challenging transformation and only a limited number of protocols allows for this reaction to occur in the presence of ester or ketone groups. Today, the catalytic methods developed by Nagashima and Beller based on Ru70e and Zn(OAc)2,82 are the only examples of deoxygenation of amides to amines in the presence of ketones. Molybdenum, an abundant metal, represents a valuable alternative to precious metals for the development of catalytic protocols. Various dioxo‐ molybdenum complexes were reported by Royo and Romão for the hydros‐ ilylation of aldehydes, ketones, imines and esters.113 Moreover, the same research group developed a hydrosilylation method using MoO2Cl2 catalyst and PhSiH3 for the deoxygenation of tertiary amides in toluene under reflux reaction conditions.79 Mo(CO)6 is a less expensive metal complex which rarely have been explored as a catalyst for hydrosilylation. The group of Pannell performed mechanistic investigation on the hydrosilylation of DMF using catalytic amounts of Mo(CO)6 with the main focus on the formation of silicon adducts.114 Keinan and Perez developed a protocol based on the same complex for the hydrosilylation of olefins in the presence of ketones, esters, carboxylic acids, and amides.115 We found that it was possible to achieve orthogonal reactivity using the Mo(CO)6 complex in the chemose‐ lective deoxygenation of the amide functionality in α,β‐unsaturated am‐ ides. The product of the reaction, an allylamine, is a common functionality in polymerization chemistry for the synthesis of various membranes and constitutes a core structure for many pharmaceutical compounds.116 43 5.2 Hydrosilylationofα,β‐unsaturatedtertiaryamides (PaperIV) Initial experiments on the Mo(CO)6‐catalyzed reduction of the α,β‐ unsaturated amide 48a were performed using TMDS as the hydride source yielding the target allylamine 48b with perfect selectivity towards the de‐ oxygenation of the carbonyl moiety (Table 4, entry 1). Performing the reac‐ tion with PhSiH3 resulted in the same level of selectivity, and stands in con‐ trast to the results obtained by Keinan and Perez (Table 4, entry 2). Howev‐ er, in their work on α,β‐unsaturated tertiary amides, only amides contain‐ ing terminal alkenes were evaluated which could be more susceptible for olefin reduction. From economical and stability perspectives TMDS was chosen as the hydride source for further screening of the reaction condi‐ tions. The investigation of suitable solvents for the selective deoxygenation of tertiary amide 48a, revealed that the reaction could be performed in toluene or acetonitrile whereas the use of THF resulted in the highest con‐ version of the starting compound even with lower amounts of TMDS (Table 4, entries 5‐7). Table 4. Conditions optimization for the deoxygenation of α,β‐unsaturated amides. Entry a s Silane Silane equiv 1 TMDS 2 s s Solvent Conversion (%) 2 THF >95 PhSiH3 2 THF >95 3 (MeO)3 SiH 2 THF 61% 4 PMHS 2 THF 20% 5 TMDS 2 toluene 84% 6 TMDS 2 MeCN 95 7 TMDS 1.5 THF >95% a) a) General reaction conditions: amide (1.0 mmol), Mo(CO)6 (5.0 mol%), silane (1.5–2.0 equiv.), solvent 1 (2 mL), 65 °C, 24 h, conversion of the starting compound was determined by H NMR spectroscopy 44 a) General reaction conditions: amide (1.0 mmol), Mo(CO)6 (5 mol%), TMDS (1.5 equiv), THF (2.0 mL), 65 °C, 24 h, isolated yields Scheme 22. Substrate scope for the reduction of α,β‐unsaturated tertiary amides. Using the optimized reaction conditions (Table 4, entry 7) we began the evaluation of the substrate scope for the Mo‐catalyzed deoxygenation of α,β‐unsaturated amides (Scheme 22). It was observed that the substitution pattern of the nitrogen played a crucial role for the yields of the target al‐ lylamines. N,N‐dimethylamine 49a and N,N‐dibenzylamine 52a derived amides gave lower yields of the target compounds, in comparison to piper‐ idine 48a, pyrrolidine 50a, and morpholine 51a containing carboxamides which resulted in the formation of allylamines in 87%, 89% and 89% isolat‐ ed yields respectively. 1H NMR analysis of the reaction mixtures showed no detectible amounts of the reduction of the double bonds. Next, substrates containing different aromatic moieties in the β‐positions were submitted to the optimized reaction conditions. Heteroaryl‐derived tertiary amides 54a and 55a were smoothly reduced to the corresponding target amines 54b and 55b in good yields. The protocol proved to tolerate aromatic halides without any competing dehalogenation occurring and p‐Br aryl allylamine 45 56b was obtained with excellent selectivity and yield. Phenol and tertiary amine groups containing tertiary amides 57a and 53a were successfully deoxygenated to the corresponding target compounds in 90% and 82% yields. When the more sterically demanding α‐methyl‐β‐phenyl‐substituted allylamide 58a with E‐configuration of the double bond was subjected to the reaction conditions a mixture of Z/E‐isomers (1:5) of the target amine 58b was isolated. The configuration of the major isomer was determined using 1H NMR NOE experiments. In a pursuit to expand the scope of the reaction, and to obtain a homoallylamine, amide 59a was subjected to the reaction conditions (Scheme 23). Surprisingly, enamine compound 59b was observed as the major product. Most likely the formation of the continuous conjugated π‐ system was the main driving force resulting in more energetically favored pathway proceeding through abstraction of an α‐proton of the correspond‐ ing tetrahedral intermediate. Scheme 23. Formation of enamine compound under Mo(CO)6‐catalyzed hydrosilyla‐ tion conditions. The amide reactivity trend (tertiary>secondary>primary) could also be observed in the developed Mo(CO)6 protocol, since the reduction of the secondary amide 60a required a higher loading (10 mol%) of the catalyst and longer reaction time (48 h) to achieve good conversion of the starting compound to the target secondary allylamine 60b (Scheme 24). This result is contradictive to the report of Keinan and Perez where selective reduction of the olefin in N‐methylcinnamamide was performed. The most probable explanation might be the choice of silane in the two protocols. Nagashima and co‐workers previously reported that the synergistic effect of dual Si‐H promoted higher activity and efficiency in their catalytic protocol for the reduction of carboxamides.70g Thus, it can be envisioned that the use of TMDS instead of PhSiH3 might alter the general selectivity of the reaction. In an attempt to deoxygenate cinnamamide an even higher catalyst loading 30 mol% was required to achieve full conversion of the starting material, 46 however, this lead to a mixture of saturated primary amide and target al‐ lylamine. Scheme 24. Hydrosilylation of α,β‐unsaturated secondary amide. During the development of the next protocol (Section 5.3) for the hy‐ drosilylation of benzamides it was determined that it is possible to preacti‐ vate the catalyst at 80 °C and then run the reaction for 24 h at rt to achieve full conversion of the starting α,β‐unsaturated amide 48a to the corre‐ sponding allylamine 48b. 5.3 Chemoselectivehydrosilylationoftertiary benzamides(PaperV) Continuing the investigation of the Mo(CO)6‐catalyzed protocol for the de‐ oxygenation of amides, benzamide 2a was subjected to the previously op‐ timized reaction conditions, which resulted in the formation of amine 2b (Scheme 25). Full conversion of the starting compound was observed only at a temperature of 80 °C, while performing the catalysis at lower tempera‐ tures, silylhemiaminal 2c’ was identified as the major product in the reac‐ tion mixture. Scheme 25. Tuning the reaction outcome by the temperature of the reaction. As mentioned previously (Section 1.2), the reduction of the amide func‐ tionality is a two‐step process, presumably proceeding through a tetrahe‐ dral intermediate. The silylated form of this species was previously charac‐ terized by the group of Pannell while performing mechanistic investigations 47 on the Mo(CO)6‐catalyzed hydrosilylation of DMF and N,N‐diethylamide.114 The group of Brookhart also identified a silylhemiaminal in Ir‐catalyzed hy‐ drosilylations of tertiary amides.76 The collapse of the tetrahedral interme‐ diate to the iminium ion followed by the reduction into amine is usually a fast process in the catalytic protocols and it is rarely possible to detect this species or isolate the corresponding hydrolysis products. However, in the Mo‐catalyzed protocol, high concentration of silylhemiaminal was ob‐ served, which could lead to the formation of an aldehyde after aqueous work‐up (Scheme 25). As mentioned above (Section 1.2.1), Georg developed a highly chemose‐ lective stoichiometric protocol for the transformation of amides to alde‐ hydes employing over‐stoichiometric amounts of the Schwartz reagent as reductant.21 The protocol displayed high chemoselectivity tolerating nitrile, nitro and ester functionalities. Apart from this method there are reports on the conversion of secondary amides to imines (which will lead to aldehydes upon hydrolysis) by Charette25 and tertiary benzylic amides to aldehydes by Buchwald and Lemaire.22 In the field of catalytic hydrosilylation of amides, only a limited number of systems were found to render the reduction of amides to the aldehyde precursors such as imines106 or enamines.104 In the latter transformation, developed by Nagashima, it was possible to tolerate ketones during the conversion of tertiary carboxamides to enamines (Sec‐ tion 1.2.3). As a result our protocol under development would be the only reported catalytic protocol for the conversion of tertiary benzamides to aldehydes, and we continued working on this interesting transformation. p‐Metoxy benzamide 5a was chosen as the benchmark substrate to simplify the isola‐ tion of the corresponding aldehyde 5c. It was found to be essential to pre‐ activate the catalyst at 80 ˚C, if the reaction was performed at lower tem‐ peratures than 65 ˚C, and TMDS was added when the desired temperature was reached. Aldehyde 5c was obtained in 80% yield after running the re‐ duction of amide 5a at 0 °C for 2 h (Scheme 26). In general, the work‐up procedure for the reaction included column chromatography, during which silylhemiaminal was efficiently hydrolyzed to the target compound. By vary‐ ing the temperature and time of the reaction, N,N‐dibenzyl 75a and mor‐ pholine 76a derived p‐methoxy‐substituted amides were readily reduced to the corresponding aldehyde 5c in high yields. 48 a) General reaction conditions: piperidine derived amide (1.0 mmol), Mo(CO)6 (5 mol%), TMDS (4 equiv), THF (2.0 mL), isolated yields. b) N,N‐Dibenzyl derived amide (75a), 3 h, rt. c) Morpholine derived amide (76a), 13 h, rt. d) Mo(CO)6 (10 mol%), TMDS (6 equiv). e) N,N‐dimethyl derived amide (77a), 2 h, rt. f) 1 Mo(CO)6 (10 mol%). g) TMDS (8 equiv). h) 0.5 mmol scale. i) H NMR yield. Scheme 26. Substrate scope for the formation of aldehydes. 49 The catalytic protocol proved to be sensitive towards electronic proper‐ ties of the aromatic ring, and substrates bearing electron‐withdrawing groups generally required higher reaction temperature and longer reaction time to achieve full conversion of the starting material. For instance, p‐ trifluoromethyl‐substituted amide 17a was converted to the aldehyde 17c in moderate yield after 6 h at 65 °C. Halogen containing aldehyde 61c was obtained in good yield without dehalogenation reaction occurring under mild reaction conditions. The protocol was compatible with the aliphatic 70a and heteroaromatic 11a, 12a substrates delivering aldehydes 70c, 11c, 12c in good yields (Scheme 26). It was determined that only α‐branched aliphatic tertiary am‐ ides resulted in the selective formation of silylhemiaminal, whereas, ben‐ zylic tertiary amide 29a gave enamine 29b, and the reaction with amide 42a resulted in a mixture of amine 42c and enamine 42b (Scheme 27). O N THF, T, t 29a O N 42a Mo(CO)6 5 mol% TMDS 4 equiv Mo(CO)6 5 mol% TMDS 4 equiv N 29b N 42c THF, T, t N 42b Scheme 27. Reduction of non α‐branched aliphatic tertiary amides. In the cases of furyl 11a and thiophenyl 12a amides 1H NMR yields were reported using 1,3,5‐trimethoxybenzene as the internal standard due to the volatility of the aldehyde products (Scheme 26). Amides bearing reducible functional groups were successfully converted to the corresponding nitro 62c, nitrile 64c, olefin 63c and carboxylic acid 72c substituted aldehydes in high isolated yields. The evaluation of a p‐nitro‐substituted benzamide re‐ sulted in a nonselective reduction process due to the harsh conditions re‐ quired for this highly electron withdrawing substrate. By employing the p‐ methoxy‐m‐nitro‐substituted tertiary amide 62a as the starting compound and thereby increasing the electron density of the aromatic ring, the reac‐ tion could be performed under milder conditions with a preference for the amide reduction. The ester functionality remained untouched and piperi‐ 50 dine and N,N‐dimethyl derived amides were selectively reduced to target methyl 4‐formylbenzoate 65c. We were delighted to observe that ketones were readily tolerated under the developed catalytic conditions, resulting in the formation of the corresponding amines 66c and 67c in good isolated yields. The influence of electronic properties of the benzene ring on the efficiency of the catalytic protocol could further be illustrated with these substituted amides 66a and 67a, where depending on the position of the keto‐group the reaction was performed either at rt (67c) or at 65 °C (66c) to ensure full conversion of the starting material. More importantly, the cata‐ lytic procedure could tolerate the presence of aldehydes (68c, 69c) and imines (73c, 74c) in the starting compounds, and excellent chemoselectivity of the process was achieved yielding the corresponding aldehydes in high yields (Scheme 26). We continued our investigation with exploration of the high tempera‐ ture reduction of tertiary amides for the formation of the corresponding amines (Scheme 28). Generally, the starting compounds were fully reduced within 5 h except for the electron‐deficient p‐CF3 (17a), ester (65a, 77a, 78a) and carboxylic acid (72a) substituted tertiary amides, where prolonged reaction times were required in order to ensure good yields of the corre‐ sponding amines. Piperidine, morpholine, N,N‐dibenzyl, and N,N‐dimethyl derived amides were smoothly reduced to the target compounds in high yields (Scheme 28). Furyl and thiophene‐containing amides were readily deoxygenated to the corresponding amine compounds 11b and 12b. The developed catalytic system tolerated a chiral center in the amide 80a and no racemization occurred during the reaction. Various reducible groups remained unreacted under the optimized reduction conditions and the corresponding nitro (62b), olefin (63b, 79b), and carbamate (71b) substi‐ tuted amines were isolated in good yields. Ketimine (73a) and aldimine (74a) substituted tertiary amides were deoxygenated with excellent chemoselectivity without any observed reduction of the imine functionali‐ ties. Unfortunately, the developed hydrosilylation protocol for the reduction of carboxamides to amines was intolerant towards nitrile, terminal alkyne and p‐nitro functionalities, resulting in the formation of complex mixture of products. 51 a) General reaction conditions: amide (1.0 mmol), Mo(CO)6 (5 mol%), TMDS (4 equiv), THF (2.0 mL), isolated yields. b) Mo(CO)6 (10 mol%), TMDS (2 equiv). c) TMDS (2 equiv) 9 h, 80 °C. d) 24 h, 65 °C. e) THF (3.0 mL). f) 99% ee. g) 0.5 mmol scale. Scheme 28. Substrate scope for the formation of amines. 52 The chemoselectivity of the catalytic procedure was further evaluated by the competitive reduction of tertiary amide 5a in the presence of equimolar amounts of ketone 81 and aldehyde 5c (Scheme 29). Following the optimized reaction conditions for the p‐methoxy amide 5a full conver‐ sion to the corresponding amine 5b was observed leaving compounds 81 and 5c untouched. Scheme 29. Competitive reduction of amide in presence of ketone and aldehyde. Due to the elevated temperature needed for the deoxygenation of am‐ ides to amines, the first attempts for the reduction of ketone (66a) and aldehyde (68a) containing tertiary amides, unfortunately, led to the over‐ reduction of the carbonyl functionalities. In order to increase the activity of the catalyst, the reaction vessel was purged with N2 after the catalyst acti‐ vation to remove CO which was found to slow down the reaction and de‐ crease the chemoselectivity of the process. These new conditions allowed us to perform the reduction of p‐acetyl‐substituted amide 66a to the corre‐ sponding silylhemiaminal at 50 °C in 2 h, with 94% yield according to 1H NMR analysis of the reaction mixture. Following the previously obtained results in the Fe‐catalyzed protocol (Paper I), where the addition of a Lewis acid was found to increase the rate of the collapse of the tetrahedral intermediate, catalytic amounts of LiCl was added to the reaction. Gratifyingly, the reduction to amine 66b took place at lower temperature, but the presence of the Lewis acid also facili‐ tated the reduction of the keto‐group and a mixture of target keto‐amine and amino‐alcohol was observed. Lowering the reaction temperature for the second step to 30 °C and prolonging the reaction time increased the chemoselectivity of the process and allowed for the isolation of compound 66b in 73% yield (Scheme 30). The same approach was implemented in the synthesis of amino‐aldehyde compound 68b, allowing for the first time a selective deoxygenation of an amide to amine in the presence of aldehyde functionality (Scheme 30). 53 Scheme 30. Highly chemoselective reduction of amides into amines. The use of the inexpensive TMDS as the hydride source could in princi‐ ple permit the application of the method on an industrial scale, therefore, it is important to determine the scalability of the protocol. Thus, it was decid‐ ed to evaluate the reduction of 61a on a larger scale (10 mmol) in the more environmentally benign 2‐methyl THF as a solvent (Scheme 31).117 Gratify‐ ingly, p‐Iodo‐derived amide 61a was readily reduced at room temperature to the corresponding carbonyl compound 61c in 90% isolated yield. The amine 61b was obtained in 91% yield after running the reaction at 80 °C for 1.5 h. Scheme 31. Large scale hydrosilylation experiments. The mechanistic investigations explaining high chemoselectivity of the Mo‐catalyzed reduction of tertiary amides are currently under investiga‐ tion. 54 5.4 ApplicationoftheMo‐catalyzedprotocolsinthe synthesisofpharmaceuticals(PapersIVandV) To assess the synthetic utility of the developed Mo‐catalyzed hydrosilyla‐ tion protocols for the chemoselective reduction of α,β‐unsaturated, ali‐ phatic and aromatic tertiary amides two pharmaceutical compounds, Naftifine 86 and Donepezil 96, were targeted. Recently a catalytic protocol for direct amide formation was developed in our group118 and it was decided to combine this amidation method with the Mo(CO)6‐catalyzed hydrosilylation of α,β‐unsaturated tertiary amides in the synthesis of the antifungal drug Naftifine (Scheme 32). Amide 84 was obtained in 91% yield through the direct amidation protocol of cinnamic acid 83 with 1‐naphtylmethylamine 82 using 10 mol% of ZrCl4. The second‐ ary amide 84 was then methylated with methyliodide to furnish compound 85 in 93% yield. Using the optimized Mo‐catalyzed reduction conditions, tertiary amide 85 was deoxygenated to give the target Naftifine (86) in an overall (three steps) yield of 78%. Scheme 32. Synthesis of antifungal pharmaceutical compound Naftifine. The Mo‐catalyzed protocol for chemoselective reduction of tertiary am‐ ides was evaluated in the synthesis of Donepezil (94), a drug used in the treatment of Alzheimer’s disease (Scheme 33). This pharmaceutical con‐ tains both keto‐ and benzylic amine functionalities and a late stage reduc‐ tion of the corresponding amide group in the presence of a reducible ke‐ tone would lead to the target compound 94. The synthesis of precursor 93 was performed in a similar fashion to the route described by Charette and Barde.24 By employing the developed Mo(CO)6‐based catalytic hydrosilyla‐ tion method, amide 93 was selectively deoxygenated in 4 h reaction time 55 yielding target compound 94 in 82% yield. The key reduction step to obtain Donepezil proceeded without detectable reduction of the ketone group and could be performed without addition of Lewis acid co‐catalyst since the keto‐functionality does not inflict an electron‐withdrawing effect on the tertiary amide. Scheme 33. Synthesis of Donepezil with late stage chemoselective deoxygenation of amide functionality. 5.5 Conclusions Chemoselective and efficient catalytic systems were developed using Mo(CO)6 as the catalyst and the cost‐effective TMDS as the hydride source. In the first protocol, an orthogonal chemoselectivity of the catalyst with regards to previous findings was achieved allowing for chemoselective de‐ oxygenation of tertiary and secondary amide functionalities in α,β‐ unsaturated substrates without reduction of the double bonds. The re‐ versed chemoselectivity could be explained by the different choice of silanes (TMDS vs PhSiH3). Furthermore, a method allowing for selective catalytic reduction of ter‐ tiary aliphatic and aromatic amides to the corresponding aldehydes and amines was developed. It was found that the reaction could be controlled by variation of the temperature and it was possible to obtain products of 56 either C‐N or C‐O bond cleavage with unprecedented chemoselectivity. A number of easily reducible groups were tolerated for both transformations including nitrile‐, nitro‐, ester‐, olefin‐, and imine groups. Tertiary amides containing ketone and aldehyde functionalities were readily reduced at lower reaction temperatures to keto‐aldehyde and bisaldehyde compounds with high yields and selectivity, whereas an additional catalytic amount of Lewis acid was necessary for smooth deoxygenation of the amide function‐ ality at higher temperatures yielding the corresponding amino‐aldehyde and keto‐amine compounds. Moreover, the synthetic utility of chemoselective reductions was demonstrated in the synthesis of pharmaceutical compounds Naftifine and Donepezil. 57 Concludingremarks In this thesis, novel catalytic systems for the hydrosilylation of amides are discussed. The first part is devoted to a protocol employing a cost‐effective Fe‐based catalyst in combination with an NHC‐ligand and the air and mois‐ ture stable PMHS as the hydride source. Addition of catalytic amounts of LiCl was found to be beneficial, decreasing the reaction times and increas‐ ing the selectivity of the deoxygenation of aromatic amides. In the next chapter an efficient and selective Zn‐catalyzed protocol is described. Using commercially available Et2Zn and LiCl as the catalysts, and PMHS as the reductant, it was possible to reduce a wide range of tertiary amides with good chemoselectivity under mild reaction conditions. The protocol was demonstrated to tolerate nitro‐, nitrile‐, olefins and Boc‐ protection group under the developed reaction conditions. During the further development of the iron‐based method from the first part it was found that various bases were able to catalyze the conversion of benzylic tertiary amides to enamines when trialkoxysilanes were used. Em‐ ploying the developed transition metal‐free protocol based on catalytic amounts of KOtBu, various tertiary amides were converted to enamines in good‐to‐excellent yields and in situ trapping of the formed compounds were evaluated. This protocol constitutes the only example in the litera‐ ture, where a catalytic transition metal‐free method is used for the conver‐ sion of tertiary amides to enamines. In the last part of the thesis highly chemoselective catalytic systems are discussed. Previously it was reported that Mo(CO)6 catalyzed the hydrosi‐ lylation of the olefins in α,β‐unsaturated amides, whereas performing the reaction with TMDS as the hydride source we demonstrated that it was possible to achieve orthogonal reactivity and instead to reduce the amide functionality leaving the double bond untouched. A number of tertiary am‐ ides and one example of a secondary amide, were deoxygenated yielding the corresponding allylamines. The synthetic utility of the developed cata‐ 58 lytic system was further demonstrated in the synthesis of the pharmaceuti‐ cal compound Naftifine. The Mo‐catalyzed protocol for the chemoselective hydrosilylation of am‐ ides was further investigated and it was found that it is possible to tune the reaction outcome when aromatic and aliphatic amides were used as the starting compounds. Adjusting of the reaction temperature allowed for the isolation either amines or aldehydes as the major products in good‐to‐ excellent yields. Moreover the catalytic system showed unprecedented chemoselectivity and tolerated a number of reducible functional groups including ketones, aldehydes, and imines during the course of the reac‐ tions. In the deoxygenation of the ketone and aldehyde substituted tertiary amides to amines, catalytic amounts of LiCl allowed us to perform the reac‐ tions under milder reaction conditions enhancing the selectivity of the re‐ duction. The synthesis of the pharmaceutical compound Donepezil was performed through a late stage reduction of a tertiary amide functionality to the corresponding amine in the presence of an aromatic ketone group. 59 AppendixA:Contributionlist The author’s contribution to publications I‐V: I. Performed the major part of the experimental work. Took part in the preparation of the manuscript. II. Performed half of the experimental work. Took part in the prepara‐ tion of the manuscript. III. Initiated the project. Performed the major part of the experimental work. Wrote the manuscript. IV. Took part in the design of the experiments and performed a third part of experimental work, including the full synthesis of Naftifine. Participated in the preparation of the manuscript. V. Took part in the design of the experiments and performed a third part of experimental work, including the full synthesis of Donepezil. Participated in the preparation of the manuscript. 60 AppendixB:Reprintpermissions Reprint permissions were kindly granted for each publication by the follow‐ ing publishers: I. A. Volkov, E. Buitrago,* H. Adolfsson* Eur. J. Org. Chem., 2013, 11, 2066‐2070 Copyright © 2013 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim II. O. O. Kovalenko, A. Volkov, H. Adolfsson* Org. Lett., 2015, 17, 446‐449 Copyright © 2015 American Chemical Society III. A. Volkov, F. Tinnis, H. Adolfsson* Org. Lett., 2014, 16, 680‐683 Copyright © 2014 American Chemical Society IV. A. Volkov, F. Tinnis,* T. Slagbrand, I. Pershagen, H. Adolfsson* Chem. Commun., 2014, 50, 14508‐14511 Copyright © 2014 The Royal Society of Chemistry V. F. Tinnis,* A. Volkov, T. Slagbrand, H. Adolfsson* Angew. Chem. Int. Ed., 2016, 55, 4562‐4566 Copyright © 2016 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim 61 Acknowledgements I would like to express my sincerest gratitude to the following people: My supervisor professor Hans Adolfsson. Thank you for taking a leap of faith and accepting me as a PhD student in your group, for your continuous support, sharing your knowledge and showing the way out when I was lost. Thank you for interesting and fruitful discussions about chemistry and life. Professor Pher Andersson for showing interest in this thesis. Professor Jan‐Erling Bäckvall for the rewarding collaboration resulting in the successful project and valuable publication. Professor Amir Hoveyda for accepting me as a three months exchange scholar in your laboratory at Boston College and giving me the opportunity to work with exciting transformation extending my theoretical knowledge and practical skills in synthetic and asymmetric chemistry. Fredrik, Toffy, Maximka for proof‐reading the thesis and providing valuable comments on how to improve it. Past and present members of the HA group who have created amazing working atmosphere and whom I had the pleasure to share the lab with: Fredrik Tinnis, Tove Slagbrand, Helena Lundberg, Tove Kivijärvi, Gabriella Kervefors, Paz Trillo Alarcón, Andrey Shatskiy, Oleksandr Kovalenko, Elina Buitrago, Ida Pershagen, Nils Schultz, Dennis Hübner and Jéssica Margalef. Collaborators and colleagues whom I had the pleasure of working with on interesting projects: Jan‐Erling Bäckvall, Karl Gustafson, Oscar Verho, Fred‐ rik Tinnis, Tove Slagbrand, Oleksandr Kovalenko, Ida Pershagen, Elina Bui‐ trago, Cheuk‐Wai Tai. 62 Fredrik Tinnis, hard to put everything in words, I am very happy that I’ve met you when I came to Sweden. You’ve made my transition from new‐ comer to PhD student easy and hard at the same time. With all your sup‐ port and friendship it was so easy to feel at home here but still I had to keep up with your knowledge, skills and ideas. Thanks! Oscar Verho for being the awesome person to work and party with. Big thanks for allowing me to crash in your apartment in Boston for three months during my exchange! Markus Kärkäs for the nice and productive time at the gym, advices on the projects and fun party‐times! Karl Gus‐ tafson for being a very good man and awesome collaborator on the fin‐ ished project and all never‐ending ones. Eric Johnston for all your help, nice chemistry and life discussions! Tove Slagbrand, I am not grumpy, I am thinking! All past and present people in my office (The Broffice) for enjoyable and interesting times of serious scientific discussions and tons of laughs. The BO‐ and NS‐groups members for interesting meetings and tasty fika. All the technical and administrative staff at the Department of Organic Chemistry: Martin Roxengren, Kristina Romare, Carin Larsson and Ola An‐ dersson for continuous support with the problems occurring with naughty equipment and other things; Sigrid Mattson, Louise Lehto, Jenny Karlsson and Christina Wolf for the help in fighting bureaucracy. Eric Johnston and Joel Malmgren, thank you for introducing me to the gym, your advices and spotting when I was too weak to continue! That was amazing and rewarding time! All friends at the department for nice and friendly atmosphere, small and long talks, and coffee‐breaks! My friends in Boston College, especially great supervisor Kyung A Lee (Stel‐ la), for awesome and productive time in USA! Good luck with your chemis‐ try and hope to see you again. The foundation and agencies for the generous financial support during my scientific exchange, conferences and work at the department: Olle Engkvist 63 Byggmästare, Helge Ax:son Johnsons, C F Liljevalch J:ors travel grant, Längmanska kulturfonden, the Foundation Sigurd and Elsa Goljes memory, Ångpanneföreningens scholarship, Stockholm university’s donation stipen‐ dium, Kungliga Vetenskapsakademien, Knut & Alice Wallenberg Founda‐ tion. Maximka, who inspired me with his example to apply for PhD abroad, and for being my friend. All my friends in Russia for all the study‐together and fun times. There were several people in the beginning of my passion for chemistry. Georgiy G. Klimov, I am forever grateful to you for unraveling chemistry to me. Vladimir I. Terenin for being my mentor during my studies in MSU, sharing your knowledge and expertise. My family, mother, sister and Pasha, for always supporting and believing in me! 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