University of Groningen Asymmetric Hydrogenation of Imines, Enamines

University of Groningen

Asymmetric hydrogenation of imines, enamines and N-heterocycles using phosphoramidite ligands Mrsic, Natasa

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RIJKSUNIVERSITEIT GRONINGEN

Asymmetric Hydrogenation of Imines, Enamines and N- Heterocycles Using Phosphoramidite Ligands

Proefschrift

ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op vrijdag 12 februari 2010 om 14.45 uur

door

Nataša Mršić

geboren op 14 maart 1974 te Zagreb, Kroatië

Promotores: Prof. dr. J. G. de Vries Prof. dr. B. L. Feringa Prof. dr. A. J. Minnaard

Beoordelingscommissie: Prof. dr. S. Gladiali Prof. dr. D. Vogt Prof. dr. K. Hummelen

ISBN: 978-90-367-4193-4 (digital version) 978-90-367-4192-7 (printed version)

“It is the mark of an educated mind to be able to entertain a thought without accepting it”, Aristotle

Chapter 1

Asymmetric hydrogenation using monodentate phosphoramidite ligands

1.1 Rhodium catalyzed asymmetric hydrogenation - a historical overview 2 1.1.1 Mechanism of the rhodium catalyzed enantioselective hydrogenation 4 1.2 Iridium catalyzed asymmetric hydrogenation - a historical overview 7 1.2.1 Mechanism of the iridium catalyzed enantioselective hydrogenation 10 1.3 Monodentate phosphoramidite ligands in asymmetric hydrogenation 12 1.3.1 Rhodium catalysts 14 1.3.1.1 Asymmetric hydrogenation of α-dehydroamino acids, enamides and itaconic acid derivatives 14 1.3.1.2 Asymmetric hydrogenation of β-dehydroamino acid derivatives 17 1.3.1.3 Asymmetric hydrogenation of enol acetates and carbamates 19 1.3.1.4 Asymmetric hydrogenation of α,β-unsaturated carboxylic acids using mixed ligand approach 20 1.3.1.5 Asymmetric hydrogenation of β-dehydroamino acids using mixed ligand approach 22 1.3.2 Iridium catalysts 24 1.4 Synthesis of phosphoramidite ligands 25 1.5 Aim and outline of this thesis 26 1.6 References 27

Chapter 2

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines 2.1 Introduction 36 2.2 Goal of the research 40 2.3 Initial screening and ligand optimization 41

2.4 High throughput experiments 49 2.5 Asymmetric hydrogenation of quinolines using mixed ligand approach 55 2.6 Additives in the asymmetric hydrogenation of 2-methylquinoline 62 2.6.1 Salts as additives 62 2.6.2 Iodine as additive 65 2.6.3 Amines as additives 66 2.6.4 Tetrahydroquinoline as additive 67 2.7 Synthesis of substrates 67 2.8 Scope 68 2.9 Kinetics 70 2.10 Mechanistic discussion 71 2.11 Conclusion 74 2.12 Experimental section 74 2.13 References 83

Chapter 3

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines 3.1 Introduction 90 3.2 Goal of the research 93 3.3 Results and Discussion 93 3.4 Conclusion 97 3.5 Experimental section 97 3.6 References 107

Chapter 4

Preparation of chiral amines via asymmetric hydrogenation of imines 4.1 Introduction 112 4.1.1 Asymmetric hydrogenation of N-Aryl imines 114 4.1.2 Asymmetric hydrogenation of N-alkyl imines 118 4.1.3 Asymmetric hydrogenation of cyclic imines 120 4.1.4 Asymmetric hydrogenation of C=N−X substrates 122 4.2 Goal of the research 123

4.3 Results 123 4.3.1 N-aryl imines 123 4.3.1.1 Protective group screening 129 4.3.1.2 Scope 131 4.3.1.3 Deprotection of the N-o-methoxy-phenyl amines 132 4.3.2 N-alkyl imines 136 4.3.3 Cyclic imines 137 4.4 Methylaluminoxane as counterion in asymmetric hydrogenation of imines 139 4.5 Conclusion 144 4.6 Experimental section 145 4.7 References 168

Chapter 5

Asymmetric hydrogenation of 2-substituted N-protected-indoles 5.1 Introduction 176 5.2 Goal of the research 180 5.3 Initial screening and ligand optimization 181 5.4 Scope 186 5.5 Mechanistic considerations 187 5.6 Conclusion 188 5.7 Experimental section 188 5.8 References 192

Chapter 6

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation 6.1 Introduction 196 6.1.1 Asymmetric hydrogenation of enamines 196 6.1.2 Asymmetric hydrogenation of β-dehydroamino acids 199 6.2 Goal of the research 204 6.3 Substrate synthesis 205 6.4 Results 205 6.5 Conclusion 219 6.6 Experimental section 220

6.7 References 227 Samenvatting 231 Summary 233 Acknowledgements 235

Chapter 1 Asymmetric hydrogenation using monodentate phosphoramidite ligands

In this chapter an overview of the asymmetric hydrogenation using monodentate phosphoramidite ligands is given. Recent developments are discussed.

Chapter 1

1.1 Rhodium catalyzed asymmetric hydrogenation - a historical overview

Asymmetric hydrogenation represents one of the most powerful catalytic methods for the preparation of enantiomerically pure compounds.1,2 High enantioselectivity, low catalyst loadings, essentially quantitative yields, perfect atom economy, and mild conditions are attractive features of this transformation. The first homogenous rhodium catalyzed hydrogenation was reported in 1939 by Iguchi.3 A range of organic and inorganic substrates were hydrogenated by aqueous solution

of RhCl3, [Rh(NH3)5(H2O)]Cl3 or [Rh(NH3)4Cl2]Cl. The most important advances in homogenous hydrogenation in the next period were the successful use of rhodium-phosphine complexes. Wilkinson and co- workers studied intensively a complex of rhodium with triphenylphosphine

(Rh(PPh3)3Cl), which has remarkable catalytic properties and is now known as Wilkinson’s catalyst. It was the first practical hydrogenation catalyst applicable under mild conditions, e.g. room temperature and atmospheric pressure of hydrogen. Wilkinson’s catalyst was employed in the selective hydrogenation of alkenes in the presence of other easily reduced groups

such as NO2 or CHO, and the hydrogenation of terminal alkenes in the presence of internal alkenes.4,5 The remarkable performance of this catalyst opened the field of catalytic enantioselective hydrogenation using chiral phosphines, pioneered by the groups of Knowles and Horner.6-8 After Wilkinson’s discovery and the development of the synthesis of chiral phosphines by Mislow9 and Horner,10 both Knowles6,7 and Horner8 showed that it is possible to hydrogenate C=C double bonds using rhodium catalysts with chiral phosphine ligands in an asymmetric fashion. The ee values were initially modest (up to 15%), the results however represented a proof of principle. An important breakthrough was accomplished by Kagan and Dang, with the use of a rhodium complex with the ligand DIOP. Using DIOP which has chirality in the backbone, in the reduction of unsaturated acids and amino acids, up to 72% ee was obtained (Scheme 1.1).11

Asymmetric hydrogenation using monodentate phosphoramidite ligands

COOH COOH 3.3 mol% [RhCl((-)-DIOP)S] ∗

R1 NHR2 10 mol % Et3N R1 NHR2 benzene/ethanol (1/2) rt, 1 atm H2 R1 = Ph, R2 = Ac, 72% ee 1 2 R = H, R = COCH2Ph, 68% ee H O PPh2 O PPh2 H

(-)-DIOP

Scheme 1.1 Kagan’s asymmetric hydrogenation of dehydroamino acids

At the same time the group of Knowles focused on the use of phosphine ligands with chirality at the phosphorus atom in the asymmetric hydrogenation of N-acyl aminoacrylic acids. Enantioselectivities of up to 88% were accomplished using P-chiral ligands (Figure 1.1).12

Ph Ph Cy P Me P Me P Me n-Pr o-Anisyl o-Anisyl

PAMP CAMP 28% ee 50-60% ee 80-88% ee

Figure 1.1 Ligands applied by Knowles et al. in the asymmetric hydrogenation of N-acyl aminoacrylic acids

A crucial achievement was accomplished by Knowles et al. in the process of the preparation of L-DOPA, a drug used for the treatment of Parkinson disease. The synthetic route included the key step of a prochiral enamide hydrogenation by an air stable rhodium complex with CAMP as ligand. This example represents the first application of homogenous hydrogenation on an industrial scale. The monodentate ligand CAMP was soon replaced by the bidentate bisphosphine ligand DIPAMP which led to an increase in ee of the hydrogenation products to 95% (Scheme 1.2).6,13,14

Chapter 1

COOH COOH 0.05 mol% [Rh(COD)DIPAMP]BF NHAc 4 NHAc 0.95 eq. NaOH 27 bar H2, rt, MeOH AcO OMe AcO OMe

Ph o-Anisyl 95% ee o-Anisyl P P Ph (-)-DIPAMP COOH

NH2

HO OH

L-DOPA

Scheme 1.2 Synthesis of L-DOPA

Rhodium complexes play an important role in the area of homogenous catalysis and especially homogenous hydrogenation, due to their remarkable reactivity and selectivity. Although the field expanded over the last 40 years, it is still continuously growing.15,16

1.1.1 Mechanism of the rhodium catalyzed enantioselective hydrogenation

The mechanism of the asymmetric rhodium catalyzed hydrogenation has been examined extensively.17-20 Studies have mostly focused on cationic rhodium complexes with bisphosphine ligands, and enamides as substrates. Early mechanistic studies were done on the asymmetric hydrogenation of alkenes using Wilkinson’s catalyst.5,21 The most often encountered mechanism in asymmetric Rh-catalyzed hydrogenation was proposed by Halpern.20,22 Halpern studied Rh-CHIRAPHOS-catalyzed hydrogenation of enamides (Scheme 1.3).20,23

Asymmetric hydrogenation using monodentate phosphoramidite ligands

Me Me H H

Ph2P PPh2 CHIRAPHOS

COOMe + MeOOC + COOMe NH Ph NHCOMe HN P H H2 P Ph Ph 2 * Rh Rh * P O O P

+ MeOOC + COOMe NH + HN * P "major" P S "minor" P * H Ph * Ph H Rh manifold P Rh S manifold Rh P O O P H H

+ + O S S O S P S NH HN S P S Rh Rh H COOMe MeOOC H * P P * Ph Ph

H H N COOMe MeOOC N

O O

(R) (S) minor product major product

Scheme 1.3 Halpern’s mechanism for the rhodium catalyzed hydrogenation of enamides

The mono-hydrido-alkyl intermediate is formed by addition of dihydrogen to the enamide complex, followed by transfer of a single hydride. Reductive elimination of the product regenerates the active catalysts and restarts the cycle. The rate determining step is the oxidative addition of hydrogen to the rhodium-substrate complex. The two diastereoisomers of the catalyst-substrate complex interconvert inter- and intramolecularly. The reactivity of the minor diastereoisomer

toward H2 is higher than that of the major diastereoisomer. As a consequence, the stereochemical outcome of the reaction is determined by this reactivity, instead of the thermodynamic stability of the diastereomeric substrate complexes (Scheme 1.4).

Chapter 1

COOMe H MeOOC NHAc 2 MeOOC NHAc HN Ph P addition is slow P S Rh * Rh + * P S O P Ph Ph B (S)-enantiomer Major complex minor enantiomer

MeOOC NH A P Ph * Rh Minor complex P O

H2 addition is fast

MeOOC P Ph reductive * H NH migration P MeOOC NHAc Ph * H elimination Rh COOMe P O + S Rh -L RhS H P 2 2 O S NH Ph (R)-enantiomer major enantiomer

Scheme 1.4 The Curtin-Hammett principle in asymmetric hydrogenation

Halpern and Landis were studying the influence of temperature and pressure on the interconversion of the substrate-catalyst complexes in the hydrogenation of methyl-(Z)-α-acetamidocinnamate.22 The oxidative addition is the step that determines absolute configuration and turnover- limiting step, and it was concluded that the increase of the ee with increase of the temperature is because the concentration of the minor diastereoisomer increased, whereas the ee decreased with increasing the pressure because the hydrogenation of the major diastereoisomer became significant. Another relevant mechanism of rhodium catalyzed hydrogenation is the dihydride mechanism, proposed by Imamoto and Gridnev (Scheme 1.5).17,24,25 Mechanistic studies were performed on the hydrogenation of α- dehydroamino acids and other unsaturated substrates such as enamides, (E)-β-dehydroamino acids and dimethyl-1-benzoyloxyethenephosphonate using the rhodium complexes [Rh(diene)(t-Bu-BisP*)]+ (the diene is COD or NBD) as catalyst precursors.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

P + X Rh * P X * H H H2 P + S Rh * P S

P + X Rh * P S H H P + H H Rh * P S S H H P + X P + H Rh Rh * P * P S X H

Scheme 1.5 Dihydride mechanism by Imamoto and Gridnev

The catalytic cycle of the dihydride mechanism starts with the diastereoselective oxidative addition of hydrogen to the rhodium solvate complex. The major diastereomeric complex provides the major product. The following step is the addition of the substrate, followed by irreversible migratory insertion (rate determining step). The last step is the reductive elimination of the product to give the rhodium solvent complex, which can continue the catalytic cycle.

1.2 Iridium catalyzed asymmetric hydrogenation - a historical overview

Iridium made its major entrance into the field of organometallic chemistry in 1965 with the discovery of the weakly catalytically active 26 Vaska’s complex ([IrCl(CO)(PPh3)2]). At the present time, iridium is a widely applied metal in modern homogenous catalysis. It tends to form stronger metal-ligand bonds, and consequently the compounds that represent reactive intermediates for rhodium, sometimes can be isolated in + the case of iridium. Since [Ir(PPh3)2] in non-coordinating solvents was

Chapter 1

found to be much more reactive than the rhodium analogue, it becomes clear that the dissociation of solvent or ligand molecules is much slower for iridium than for rhodium and this can lead to lower reaction rates with

[IrCl(PPh3)3]/MeOH. The other steps in the catalytic cycle with iridium are usually very fast, so if the dissociation step can be avoided, a highly active catalyst can be formed.

R2 - - PF6 PF6

O R2 Cy3P N Ir 1 P N (R )2 Ir

12 Crabtree´s catalyst 1 R = Ph, Cy, C6F5 R2 = H, Me Pfaltz´s catalyst

Figure 1.2 Crabtree’s and Pfaltz’s iridium catalysts

Compared to rhodium- and ruthenium-based counterparts, iridium catalysts are rather new in the field of asymmetric hydrogenation of olefins. Using an achiral catalyst, Crabtree and co-workers established the ability of iridium compounds to rapidly hydrogenate olefins.27,28 Crabtree’s catalyst (Figure 1.2), catalyzes the hydrogenation of 1-hexene 100 times faster than Wilkinson’s catalyst. It also hydrogenates tri- and even tetrasubstituted olefins while Wilkinson’s catalyst is inactive towards the latter.27 Crabtree’s catalyst also stands out in the diastereoselective, functional-group-directed hydrogenation of cyclic alkenes, consistently controlling the stereochemistry of the new stereocenter relative to the directing group better than the related rhodium catalysts.29 In the late 1990s, Lightfoot, Pfaltz and co-workers recognized that a chiral analogue of Crabtree’s catalyst would have significant potential for asymmetric hydrogenation. They replaced the phosphine and pyridine ligands of Crabtree’s catalyst with phosphinooxazoline (PHOX) ligands30 to form a series of chiral, cationic iridium complexes (2, Figure 1.2) that

Asymmetric hydrogenation using monodentate phosphoramidite ligands

hydrogenated prochiral imines to amines in a broad range of ee values (up to 89% ee).31 Although the Ir/PHOX complexes 2 also catalyzed the hydrogenation of olefins with impressive ee values (75 - 97%), they formed inactive tri- iridium species over the course of the reaction.32 This tendency to trimerize, a reaction also observed with Crabtree’s catalyst 1,27 meant that high catalyst loadings of catalysts 2 (4 mol%) were necessary for complete conversion of the olefin.33 To increase catalyst stability, Pfaltz and co- workers screened a range of reaction conditions, but found little improvement.

O F3C CF3

F3C CF3 1 P N R 2 Ir 2 R B

F3C CF3 R1 = Ph, o-tolyl F3C CF3 2 R = i-Pr, i-Bu, CH2t-Bu 3

Figure 1.3 Pfaltz’s and Lightfoot’s chiral catalysts for the asymmetric hydrogenation of olefins

However, upon changing the counterion to the weakly coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ([BArF]−), they obtained a highly active and selective olefin hydrogenation catalyst 3 (Figure 1.3) that was stable under the reaction conditions, and even to air and moisture.33 Using kinetic34 and pulsed gradient spin echo NMR spectroscopic diffusion data,35 Pfaltz, Pregosin and co-workers have examined the effect of the anion in (PHOX)Ir-catalyzed hydrogenation, and found that large, weakly coordinating anions are crucial for activity. Furthermore, Pfaltz showed that the anion in the catalytic complex does not impact the stereoselectivity of hydrogenation.34 Almost all of the numerous iridium catalysts of the form [L*Ir(COD)]+[X]− for asymmetric olefin hydrogenation

Chapter 1

that appeared after 3 featured modifications of the cation; [BArF]− is the anion of choice.36 Though Pfaltz and co-workers showed that catalysts 3 were active toward some functionalized olefins, several unfunctionalized olefins were as well hydrogenated with excellent stereoselectivity (≥94% ee) using low catalyst loadings (0.l - 4 mol%). Prior to the development of 3, there had been few reports of highly enantioselective (≥94% ee) hydrogenations of unfunctionalized olefins,37 and these either had low turnover frequencies or required very low temperature (≤−75 °C) to be selective. The success of 3 in the stereoselective hydrogenation of unfunctionalized olefins triggered therefore intense efforts to design other chiral iridium complexes for this purpose. Developments in this field have been the subject of several reviews.36,38,39 Highly stereoselective hydrogenation of functionalized olefins by rhodium and ruthenium catalysts is well-developed, while most of the research on chiral iridium hydrogenation catalysts is based on the reduction of unfunctionalized olefins. Rhodium- and ruthenium-based catalysts are extremely selective for substrates with coordinating functionality; substrates with functional groups that do not coordinate well to the metal remain challenging for these catalysts. Iridium catalysts, on the contrary, achieve very high selectivity for unfunctionalized substrates. Therefore, they have potential for the asymmetric hydrogenation of olefins with poorly coordinating functional substituents, such as electrophilic groups. Promising results have been obtained in the asymmetric iridium- catalyzed hydrogenation of unfunctionalized olefins as well as imines,38,40 therefore continued development of this field could provide useful methods for the asymmetric hydrogenation of a range of compounds while broadening the substrate scope of iridium catalysts for the asymmetric hydrogenation.

1.2.1 Mechanism of the iridium catalyzed enantioselective hydrogenation

In a combined experimental and theoretical study by Brandt and co- workers, an IrIII-IrV catalytic cycle has been proposed (Scheme 1.6).41 The catalytic cycle starts with solvated iridium - dihydride complex; then the

Asymmetric hydrogenation using monodentate phosphoramidite ligands

two solvent molecules are replaced by an olefin and molecular hydrogen. The rate - determining step is the migratory insertion of the olefin into an Ir-hydride bond, a step that is energetically favored by the simultaneously oxidative addition of the coordinated hydrogen molecule. Subsequently, the reductive elimination of the saturated hydrocarbon completes the catalytic cycle.

H * H 2S * H N P 2 N P Ir H H Ir S S H H H

S S H* H N * P * P Ir IrI/IrIII N P IrIII/IrV N Ir H Ir H H S S H H H

H2 + HH S * * N P N P Ir S Ir H H 2S H H S

Scheme 1.6 Two possible catalytic cycles for olefin hydrogenation by chiral iridium complexes

Alternatively, the groups of Buriak42 and Chen43 have published data in support of catalytic cycles with IrI and IrIII intermediates. Buriak and co- workers used para-hydrogen induced polarization (PHIP) NMR spectroscopy to study the hydrogenation of [D8]-styrene by an achiral N-

heterocyclic carbene-phosphine iridium complex in CD2Cl2. Dietiker and Chen used gas-phase MS to study the hydrogenation of styrene by the Pfaltz’s catalyst 3 (R1 = Ph, R2 = i-Pr). The proposed catalytic cycle starts with solvated iridium - dihydride complex, followed by a solvent molecule being replaced by the olefin. The olefin dihydride complex is the resting state of the catalyst. The next step is insertion of the olefin into the iridium

Chapter 1

hydride bond together with coordination of a molecule of solvent, and the reductive elimination of the alkane. The cycle is completed with the addition of the dihydrogen molecule to the solvated iridium complex.

1.3 Monodentate phosphoramidite ligands in asymmetric hydrogenation

Bidentate chiral ligands were considered superior over monodentate ones in metal-catalyzed asymmetric hydrogenation for more than 30 years, as chelation was believed to be necessary to impart the rigidity to the metal complex for an efficient transfer of chirality.1,13,19,44

R4 R3

O R1 O R P N P N O R2 O R

R4 R3

L1a R1 = R2 = Me, R3 = R4 = H (Monophos) L2a, R = Me L1b R1 = R2 = Et, R3 = R4 = H L2b, R = Et L1c R1 = R2 = i-Pr, R3 = R4 = H 1 2 3 4 L1d R = R = -(CH2)5-, R = R = H (PipPhos) 1 2 3 4 L1e R = R = -(CH2)2-O-(CH2)2-, R = R = H (MorfPhos) 1 2 3 4 L1f R = Me, R = CH2Ph, R = R = H 1 2 3 4 L1g R = R = (R)-CH(CH3)Ph, R = R = H 1 2 3 4 L1h R = R = (S)-CH(CH3)Ph, R = R = H 1 2 3 4 L1i R = H, R = (R)-CH(CH3)Ph, R = R = H L1j R1 = R2 = Me, R3 = Me, R4 = H L1k R1 = R2 = Me, R3 = H, R4 = Br 1 2 3 4 L1l R = R = -(CH2)5-, R = Me, R = H L1m R1 = H, R2 = i-Pr, R3 = R4 = H 1 2 3 4 L1n R = R = -(CH2)2-O-(CH2)2-, R = Me, R = H L1o R1 = R2 = Me, R3 = Ph, R4 = H 1 2 3 4 L1p R = R = CH2Ph, R = R = H

Figure 1.4 Reported successful BINOL and H8-BINOL-derived monodentate phosphoramidite ligands

Over the last decade chiral monodentate phosphines, phosphonites, phosphoramidites and phosphites were reported to lead to excellent results

Asymmetric hydrogenation using monodentate phosphoramidite ligands

in the asymmetric hydrogenation of α- and β-dehydroamino acids, itaconic acid derivatives, and enamides.16,45 Monodentate phosphoramidite ligands have the advantage of being readily accessible, structurally highly diverse, air stable and inexpensive compared to most bidentate ligands. In addition, they are amenable to parallel synthesis alowing rapid access to libraries of chiral phosphoramidite ligands.46 An overview of frequently used monodentate phosphoramidite ligands is shown in Figures 1.4 and 1.5.

R O

O O O P N P N O O P O N O R Fe SIPhos L3a R = H FAPhos L3b R = Br L4 L5 L3c R = Ph L3d R = OMe

Ph R1 3 O N O R O P N O P N P N O N O R2 O Ph R1

DpenPhos L6 L8 1 2 3 L7a R = PhCH2, R , R = Me 1 2 3 L7b R = 3,5-(t-Bu)2C6H3CH2, R , R = Me 1 2 3 L7c R = C6H5CH2, R = C6H5CH2, R = H

Figure 1.5 Reported successful monodentate phosphoramidite ligands

Chapter 1

1.3.1 Rhodium catalysts

1.3.1.1 Asymmetric hydrogenation of α-dehydroamino acids, enamides and itaconic acid derivatives

Since in our group monodentate phosphoramidite ligands have already successfully been applied in the copper-catalyzed 1,4-addition of dialkylzincs to olefins,47 it was decided to test the suitability of phosphoramidites in Rh-catalyzed asymmetric olefin hydrogenation. Disappointingly, a range of bidentate phosphoramidite ligands based on BINOL or TADDOL and bridged by C1 - C3 diamines led to slow hydrogenations and low enantioselectivities. Surprisingly, the use of the monodentate ligand MonoPhos L1a in the Rh-catalyzed asymmetric hydrogenation of methyl 2-acetamido-cinnamate led to an enantiomeric excess of 97% in aprotic dichloromethane and ethyl acetate (Scheme 1.7).48

COOMe COOMe 5 mol% [Rh(COD)2]BF4, 11 mol% L1a

NHAc rt, 1bar H2, solvent NHAc

up to 97% ee

Scheme 1.7 Rh-catalyzed asymmetric hydrogenation of methyl 2- acetamido-cinnamate

In that same year, Pringle and co-workers49 and Reetz and co-workers50 reported the use of BINOL-based monodentate phosphonites and phosphites, respectively, in Rh-catalyzed asymmetric hydrogenation. The best results with the catalysts based on these ligands were also obtained in aprotic solvents.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

2 mol% [Rh(COD)2]BF4 HN O 4.2 mol% L1a HN O R1 solvent, 15 bar H2, 20h R1 R2 R2

HN O HN O HN O HN O

Cl 90% ee 92% ee 89% ee 26% ee

HN O HN O HN O HN O

O S

43% ee 92% ee 94% ee 35% ee

Scheme 1.8 Asymmetric hydrogenation of enamides

Using L1a as a ligand, a large range of olefins, such as substituted 2- acetamido-cinnamic acids and esters (up to 99% ee), 2-acetamido acrylic acid and methyl ester (up to 99% ee), itaconic acid (97% ee) and its methyl ester (94% ee) were hydrogenated with excellent ee’s.51 Catalytic hydrogenation of N-acetyl-α-arylenamides using [Rh(COD)2]BF4 and MonoPhos L1a results in full conversions and high ee’s (Scheme 1.8).52 Slightly better results were obtained by Chan using the rather similar ligand L1b.53 In the same period Chan reported the use of Monophos54 and 55 H8-BINOL-derived phosphoramidite L2a in the hydrogenation of enamides with excellent ee. In collaboration with the Reetz group, we developed the use of the ligands PipPhos L1d and MorfPhos L1e, which led to even better results in most applications than L1a. Excellent and in some cases unprecedented enantioselectivities were obtained in the hydrogenation of N- acyldehydroamino acid esters, dimethyl itaconate, acyclic and cyclic N-

Chapter 1

acylenamides.56 PipPhos L1d was also the ligand of choice in the asymmetric hydrogenation of β-alkyl itaconates (up to 99% ee).57

In 2003, Jiang and Chan and co-workers reported the use of H8- Monophos L2a in the hydrogenation of α-dehydroamino acids with up to 99.9% ee.58 Zhou published the use of spiro phosphoramidite ligand L3 (SIPHOS), which also leads to excellent results in asymmetric hydrogenation59 but takes seven steps plus a resolution to prepare.60 Zhang reported synthesis of monodentate spiro phosphoramidite ligand L4 and its application in rhodium catalyzed asymmetric hydrogenation of α- dehydroamino acid derivatives and itaconic acid with up to 99% ee.61 Reetz recently reported the use of nonsymmetrical BINOL-based phosphoramidites containing only a single substituent in the 3 (and not the 3’) position in the hydrogenation of itaconates and enamides with excellent ee.62 The first Rh-catalyzed enantioselective hydrogenation of dimethyl 2- methyleneglutarate and its derivatives has been reported by Zheng and Hu.63 Chiral ferrocene based monodentate phosphoramidite ligand L5 (FAPhos) was employed, high enantioselectivity (92% ee) with full conversion was achieved. A new class of dendritic monodentate phosphoramidite ligands was reported by the group of Fan in the asymmetric hydrogenation of α- dehydroamino acid esters and dimethyl itaconate.64 High enantioselectivities (up to 98% ee) and catalytic activities (up to 4850 h-1 TOF) were achieved, which are better or comparable to those obtained from MonoPhos. Recently, the groups of Zhou and Fan demonstrated the importance of the dendritic wedges on enantioselectivity in the Rh- catalyzed asymmetric hydrogenation of functionalized olefins, such as α- dehydroamino acid derivatives and enamides. Higher enantioselectivities were achieved as the dendritic wedges on the N-atom of the phosphoramidite ligand became bigger. 65 With respect to the development of the hydrogenation methodologies in “green solvents” Lyubimov reported Rh-catalyzed asymmetric hydrogenation of itaconates and 2-acetamidoacrylate using monodentate phosphoramidite and phosphite ligands in supercritical carbon dioxide. Using phosphoramidites L1d and L1e enantioselectivities of up to 99%

Asymmetric hydrogenation using monodentate phosphoramidite ligands

were obtained.66 The high reaction rates are attributed to the higher miscibility and higher diffusivity of gaseous hydrogen in the supercritical medium when compared to that in dichloromethane. The advantage of this method is low price of both phosphoramidite ligands and carbon dioxide. It is not strictly necessary to have BINOL-based ligands for good results. Using ligand L6 based on catechol and a chiral amine also resulted in ee’s up to 99% in the rhodium catalyzed asymmetric hydrogenation of dehydroamino acids and enamides.67 Ding reported in 2005 preliminary results on the design, synthesis, and application of a new class of monodentate phosphoramidite ligands (DpenPhos L7a and L7b). Excellent ee’s (up to 99.9%) and conversions were obtained in the hydrogenation of dehydroamino acid methyl esters and acetyl enamides.68 Ding also found that monodentate phosphoramidite ligands having a primary amine moiety (L7c) lead to excellent results in the hydrogenation of (Z)-methyl α-(acetoxy)acrylates and (E)-β-aryl itaconate derivatives. This high reactivity may be attributed to the existence of intermolecular hydrogen bonding between adjacent monophosphoramidite ligands around the Rh metal center.69

1.3.1.2 Asymmetric hydrogenation of β-dehydroamino acid derivatives

Another class of substrates that required the development of new ligands was the β-dehydroamino acid derivatives. From published results with bidentate phosphines,25,70 it was clear that hydrogenation of the E isomers is rather easy, and in fact, in our group we were able to develop the rhodium-catalyzed asymmetric hydrogenation of (E)-4 using MonoPhos L1a as a ligand with 95% ee.71 Slight modification of the ligand structure led to the ligand L1f that induced up to 99% ee in the hydrogenation of the E isomers (Scheme 1.9). However, the commonly used synthesis of these substrates from the acetoacetates via amination and acetylation leads mainly to the Z precursors. Most probably, this is related to the strong internal hydrogen bond between the ester carbonyl and the NH of the amide.

Chapter 1

1 mol% [Rh(COD) ]BF 2 4 NHAc NHAc 2 mol% (S, R)-Li COOR2 10 bar H i-PrOH, rt R1 R1 2, COOR2

(Z)-4-9 4a, R1 = R2 = Me, 95% ee 5a, R1 = Et, R2 = Me, 94% ee 6a, R1 = Me, R2 = Et, 94% ee 7a, R1 = i-Pr, R2 = Et, 92% ee 8a, R1 = Ph, R2 = Et, 92% ee 9a, R1 = p-F-Ph, R2 = Me, 94% ee

NHAc 1 mol% [Rh(COD)2]BF4 NHAc 2 mol% (S)-L1f R1 R1 10 bar H DCM, rt COOR2 2, COOR2

(E)-4-7 4a, R1 = R2 = Me, 99% ee 5a, R1 = Et, R2 = Me, 99% ee 6a, R1 = Me, R2 = Et, 99% ee 7a, R1 = i-Pr, R2 = Et, 99% ee

Scheme 1.9 Asymmetric hydrogenation of β-dehydroamino acid derivatives

Minor modification of the ligand structure led to an excellent ligand, L1i, that induced up to 95% ee in the hydrogenation of (Z)-4 in i-propanol. This solvent is capable of breaking the hydrogen bond in the substrate, thus enabling its bidentate binding to the metal. The rate of this catalyst was compared with catalysts based on a number of well known bidentate ligands and the phosphite analogue of L1i (NH replaced by O), showing that the catalyst is only surpassed by DUPHOS in rate but surpasses all tested ligands in terms of ee.72 The acetyl protecting group is not a requirement for high enantioselectivity. Hydrogenations of N-formyl-dehydroamino esters also proceed with excellent enantioselectivities, with PipPhos L1d as the best ligand (Scheme 1.10).73 Excellent enantioselectivities (up to >99% ee) were obtained for the Z isomers. Very high enantioselectivities can also be achieved (up to 97% ee) for the E isomers of substrates with alkyl substituents. The formyl group can be removed or modified easily after the hydrogenation, under mild conditions.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

R2 O 5 mol% [Rh(COD)2]BF4 R2 O 10 mol% L1d R1 O R1 O 5 bar H2, DCM, rt HN H HN H

O O

O O O

O O O HN H O HN H HN H

O O O 99% ee 94% ee >99% ee

O O O

O O O HN H HN H

O O >99% ee 61 % ee

Scheme 1.10 Asymmetric hydrogenation of N-formyl-dehydroamino esters

1.3.1.3 Asymmetric hydrogenation of enol acetates and carbamates

Asymmetric hydrogenation of enol acetates, gives access to chiral alcohols after hydrolysis of the acetate ester. Since enol acetates are structurally very similar to enamides, the asymmetric hydrogenation of this class of substrates was also examined in our group. Surprisingly, using MonoPhos L1a as a ligand, the saturated acetate and carbamate was obtained with an ee of only 10% and 19%, respectively. However, replacing MonoPhos L1a by PipPhos L1d greatly improved the hydrogenation results with both aromatic enol acetates and enol carbamates (Scheme 1.11).74

Chapter 1

R2 R2 R2 R2 N 1 mol% [Rh(COD)2]BF4 N 2 mol% L1d O O O O 5 bar H2, DCM, rt R1 R1

10-16 1 2 10a, R = NO2-Ph, R = Et, 98% ee 1 2 11a, R = butyl, R = Et, 63% ee (25 bar H2) 12a, R1 = benzyl, R2 = Et, 73% ee 1 2 13a, R = SiMe3, R = Et, 43% ee 14a, R1 = Ph, R2 = Me, 94% ee 15a, R1 = Ph, R2 = Et, 96% ee 16a, R1 = Ph, R2 = i-Pr, 95% ee

O O 1 mol% [Rh(COD)2]BF4 O O 2 mol% L1d

5 bar H2, DCM, rt R R

17-19 17a, R = H, 90% ee 18a, R = Cl, 90% ee (20 bar H2) 19a, R = NO2, 98% ee

Scheme 1.11 Asymmetric hydrogenation of enol acetates and enol carbamates

1.3.1.4 Asymmetric hydrogenation of α,β-unsaturated carboxylic acids using mixed ligand approach

Both the group of Reetz75 and our group76,77 have shown that the use of mixtures of chiral monodentate ligands can improve enantioselectivity and reactivity. It is also possible to use mixed complexes based on a monodentate chiral ligand and a non-chiral phosphorus ligand.78-81 In our group the mixed ligand approach has been employed in rhodium catalyzed asymmetric hydrogenations76,78,80 and additions of boronic acids.77,81 The fact that the structure of monodentate ligands can be varied easily enables us to screen a very large number of different complexes in the asymmetric hydrogenation.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

L1 M Homo-complex 1 L1

L1 M+ L1 + L2 M Hetero-complex L2

L2 M Homo-complex 2 L2

Scheme 1.12 The monodentate ligand combination approach

Since the catalytically active species most likely contains two 1 2 monodentate ligands, two homo-complexes, Ir(L )2 and Ir(L )2, and the hetero-complex Ir(L1L2) will be formed simultaneously (Scheme 1.12). The hetero-complex represents a new catalyst, and if it is endowed with higher activity and selectivity than the two homocomplexes, it will lead to better results. At DSM where, in the course of finding an active and enantioselective catalyst for the hydrogenation of an α-alkyl-cinnamic acid, it was found that addition of a non-chiral phosphine ligand to the rhodium phosphoramidite catalyst led to greatly enhanced rate and enantioselectivity (up to 99% ee, Scheme 1.13). In this research, it was determined that triarylphosphines induce the highest increase in rate and enantioselectivity. Trialkylphosphines had much less effect than triarylphosphines. The asymmetric hydrogenation of 2-methyl-cinnamic acid was examined using eight different BINOL-based phosphoramidite ligands with and without added triphenylphosphine. In every single case, the added triphenylphosphine improved the rate and the enantioselectivity.80 A number of different α,β-disubstituted unsaturated acids were hydrogenated using the same catalytic system. Good to excellent ee’s were obtained in all cases.

Chapter 1

O O 1 mol% [Rh(COD)2]BF4, 2 mol% L* 1 mol% Ar P R1 OH 3 R1 OH 25 bar H 30 oC, 16h R2 2, R2 IPA/H2O

20-24 20a, R1 = Me, R2 = Me, 87% ee 21a, R1 = Ph, R2 = i-Pr, 99% ee 22a, R1 = 3,4-MeOPh, R2 = i-Pr, 92% ee 1 2 23a, R = 4-CF3Ph, R = i-Pr, 95% ee 1 2 O 24a, R = Ph, R = Ph, 95% ee P N X O

L1l, X = CH2 L1n, X = O

Scheme 1.13 Asymmetric hydrogenation of unsaturated carboxylic acids using a mixed ligand approach

1.3.1.5 Asymmetric hydrogenation of β-dehydroamino acids using mixed ligand approach

As mentioned earlier, the use of mixtures of ligands can also be applied to two different chiral monodentate ligands. In our group, this approach was tested in the asymmetric hydrogenation of acetylated β3-dehydroamino acid esters (Scheme 1.14).76

O R O R 1 mol% [Rh(COD)2]BF4, 2 mol% L* N 10 bar H DCM N H 2, H COOEt COOEt up to 99% ee

25, 26 25a, R = Me 26a, R = Ph L* = L1* + L2*

Scheme 1.14 Asymmetric hydrogenation of Z-β3-dehydroamino acid esters

Mixtures of two phosphoramidite ligands were examined, using L1a, L1f, L1i, L1j, L1k, and L2a in the Rh-catalyzed asymmetric hydrogenation of an aliphatic and aromatic Z-β3-dehydroamino acid ester (Scheme 1.14).

Asymmetric hydrogenation using monodentate phosphoramidite ligands

Most combinations of two different ligands induced lower enantioselectivities. However, there was one exception: all combinations that included the NH ligand L1i led to better results. Particularly striking was the combination with ligand L1j, which was the worst performer in the homo series in combination with L1i. After having established the asymmetric hydrogenation of β3- dehydroamino acids with excellent results, β2-dehydroamino acids were also examined (Scheme 1.15).78 Initial screening suggested that these substrates behaved very similarly to the α-alkylated cinnamic acids.

O O 1 mol% [Rh(COD)2]BF4, 2 mol% L1l OH 1 mol% Ar3P OH o 25 bar H2, 30 C, MeOH R NH R NH O O

27-31 27a, R = H, up to 91% ee 28a, R = o-Me, up to 90% ee 29a, m-Me, up to 91% ee 30a, p-Me, up to 91% ee 31a, p-Cl, up to 85% ee

Scheme 1.15 β2-Amino acids via mixed ligand asymmetric hydrogenation

In order to screen a large number of ligands/catalysts in a short period of time, a parallel synthesis of ligands can be performed. This is possible with a high-throughput experimentation (HTE) approach. This methodology can be applied in the cases where ligands can be readily synthesized using a robot. Prepared ligand library can then be tested in a catalytic reaction which significantly speeds the ligand/catalyst optimization process.46,82 Therefore, a ligand library containing 96 ligands was screened in the hydrogenation of β2-dehydroamino acids, in the presence of 1 equiv of

PPh3. Since ligands based on 3,3′-dimethyl-BINOL gave the best results, a library of 16 phosphoramidites and 6 triarylphosphines was screened. Ligand L1l again emerged as the best ligand, but in this case, several triarylphosphines gave good results. Hydrogenation of 27 using Rh/L1l without added triarylphosphine resulted in very low ee.

Chapter 1

Finally, Reek, van Leeuwen and co-workers have developed a strategy for the formation of supramolecular catalysts based on the self-assembly of monodentate P ligands. This approach has been successfully applied in rhodium catalyzed hydroformylation83 and asymmetric hydrogenation.84 Mixtures of monodentate BINOL-derived phosphoramidites or phosphites were used in combination with phosphines and were assembled together via hydrogen bonding or metal-ligand interactions.

1.3.2 Iridium catalysts

Apart from rhodium, iridium is reported as well to lead to excellent results in the asymmetric hydrogenation using monodentate phosphoramidite ligands. An important breakthrough was achieved by the DSM group, where an active but also highly enantioselective catalyst for the iridium-catalyzed asymmetric hydrogenation of α-dehydroamino acids was developed.85 The catalyst was containing the bulky phosphoramidites L8 based on a biphenol backbone with substituents in the 3,3’ position, derived from the neutral catalyst precursor [Ir(COD)(L)Cl] containing only one phosphoramidite ligand per metal. The catalyst was relatively fast (TOF = 150 h-1) and induced an enantioselectivity of up to 98%. Beller reported recently a synthesis of a ligand library of monodentate

H8-BINOL-based phosphoramidites bearing aryl substituents in the 3,3’ - position of the BINOL core. Synthesized ligands were applied in the Ir- catalyzed asymmetric hydrogenation of 2-amidocinnamates to obtain different α-amino acid derivatives in up to 99 % ee.86 Same group reported Ir-catalyzed asymmetric hydrogenation of β- 87 dehydroamino acid precursors in the presence of chiral monodentate H8- BINOL-based phosphoramidites. Separate studies for the E and Z isomers showed crucial differences between the two hydrogenation reactions. After optimization of the reaction conditions, enantioselectivities of up to 94% ee were achieved for the E isomers. Importantly, to obtain high enantioselectivity, substitution at the 3,3’-position of the ligands was found to be necessary. Same catalyst was employed successfully in the hydrogenation of enamides.88 Using non-coordinating salts as additives

(NaBF4, NaClO4) enantioselectivity of up to 93% was obtained.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

In 2006, Faller reported the use of combination of Monophos L1a and pyridines in the iridium-catalyzed asymmetric hydrogenation of cyclic imines.89 Enantioselectivities of only up to 58% were achieved.

1.4 Synthesis of phosphoramidite ligands

Phosphoramidites can be synthesized via three different routes (Scheme 1.16). In the first one, BINOL is heated at 80 °C in neat phosphorus trichloride in order to obtain the chlorophosphite, which is then reacted with the desired amine, in the presence of triethylamine (route A).56 In the case of sterically demanding phosphoramidites, the lithium amide, instead of the amine, is reacted with the chlorophosphite. The second method consists of the preparation of MonoPhos by stirring BINOL with hexamethylphosphoramide.51,90

R1 OH PCl O HNR1R2 O A 3 P Cl P N OH O base O R2

(S)-BINOL

R1 OH HMPT O HNR1R2 O B P N P N OH O 1H-tetrazole O R2

MonophosTM

OH OH R1 R1 R1 PCl3 O C NH N PCl2 P N R2 base R2 base O R2

Scheme 1.16 Synthesis of phosphoramidite ligands

Different phosphoramidites are subsequently prepared by amine exchange with MonoPhos (Route B).71 The third method consists of stirring

Chapter 1

the secondary amine with phosphorus trichloride. The resulting phosphoramidous dichloride thus prepared is reacted with BINOL in the presence of a base, giving the desired phosphoramidite ligand (Route C).91

1.5 Aim and outline of this thesis

As mentioned earlier, asymmetric hydrogenation represents a versatile, clean and atom economic method for the production of enantiopure compounds. Since in our group phosphoramidite ligands were successfully employed in the asymmetric hydrogenation of various benchmark substrates, we were interested in extending the scope of these reactions to more challenging classes of compounds. We were particularly interested in the asymmetric hydrogenation of heteroaromatic compounds such as quinolines, quinoxalines and indoles, due to the fact that chiral heterocyclic compounds are often found as part of the structures of pharmaceuticals and physiologically active natural products. Imines and enamines in general represent challenging substrates for the asymmetric hydrogenation, since most of the reported hydrogenation catalysts are still not acceptable for industrial applications. Ligands employed are often expensive and demand tedious synthetic routes for their preparation. There are several reasons why imines are difficult substrates for the hydrogenation.92 One is a smaller thermodynamic gain from the reduction of C=N bond relative to the C=C bond of an olefin. There is also a less effective orbital overlap and lower affinity of the C=N for the metal center due to the η1-binding mode of the imine bond compared to the η2-bonding of the olefin. In addition, competitive coordination of the hydrogenated product may lead to “catalyst poisoning”. Finally, increased steric hindrance at the unsaturated moiety of imine may also retard the hydrogenation, which is well established with olefinic substrates. Since phosphoramidites are low-cost, easy to synthesize and highly modular, the aim of this thesis was the development of efficient catalysts for the hydrogenation of imines and enamines. In Chapter 2 the asymmetric hydrogenation of 2,6-substituted quinolines is described, using mixtures of phosphoramidite and phosphine ligands. Different additives were examined and a rationale for their effect is given. Chapter 3 focuses on the hydrogenation of quinoxalines. The

Asymmetric hydrogenation using monodentate phosphoramidite ligands

preparation of primary chiral amines via asymmetric hydrogenation of N- aryl imines and their subsequent deprotection is described in Chapter 4, while Chapter 5 focuses on the hydrogenation of indoles. Finally in Chapter 6 a route to N-aryl β-amino acid derivatives via asymmetric hydrogenation is shown.

1.6 References

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Chapter 1

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Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic Asymmetric Synthesis, Ed. Ojima, I. Wiley-VCH: Weinheim, 2000, 1. (45) a) Erre, G.; Enthaler, S.; Junge, K.; Gladiali, S.; Beller, M. Coord. Chem. Rev. 2008, 252, 471; b) van den Berg, M.; Feringa, B. L.; Minnaard, A. J. The Handbook of Homogenous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. Wiley -VCH: Weinheim, 2007; Vol. 2, Chapter 28, 995; c) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267; d) Ager, D. J.; de Vries, A. H. M.; de Vries, J. G. Platinum Met. Rev. 2006, 50, 54; e) de Vries, J. G. Handbook of Chiral Chemicals, 2nd edn., Ed. Ager, D. J. CRC Press: Boca Raton, 2005, 269; f) Komarov, I. V.; Börner, A. Angew. Chem. Int. Ed. 2001, 40, 1197. (46) a) de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006, 12, 4722; b) Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org. Lett. 2004, 6, 1733. (47) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (48) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. (49) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (50) Reetz, M. T.; Mehler, G. Angew. Chem. Int. Ed. 2000, 39, 3889. (51) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G. Adv. Synth. Catal. 2003, 345, 308. (52) van den Berg, M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Adv. Synth. Catal. 2002, 344, 1003. (53) Jia, X.; Li, X.; Xu, L.; Shi, Q.; Yao, X.; Chan, A. S. C. J. Org. Chem. 2003, 68, 4539. (54) Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 5541. (55) Li, X.; Jia, X.; Lu, G.; Au-Yeung, T. T.-L.; Lam, K.-H.; Lo, T. W. H.; Chan, A. S. C. Tetrahedron: Asymmetry 2003, 14, 2687. (56) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

(57) Hekking, K. F. W.; Lefort, L.; de Vries, A. H. M.; van Delft, F. L.; Schoemaker, H. E.; de Vries, J. G.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2008, 350, 85. (58) Zeng, Q.; Liu, H.; Cui, X.; Mi, A.; Jiang, Y.; Li, X.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2002, 13, 115. (59) a) Fu, Y.; Guo, X.-X.; Zhu, S.-F.; Hu, A.-G.; Xie, J.-H.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 4648; b) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2002, 41, 2348; c) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun. 2002, 480. (60) a) Zhu, S.-F.; Fu, Y.; Xie, J.-H.; Liu, B.; Xing, L.; Zhou, Q.-L. Tetrahedron: Asymmetry 2003, 14, 3219; b) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron: Asymmetry 1999, 10, 125. (61) Wu, S.; Zhang, W.; Zhang, Z.; Zhang, X. Org. Lett. 2004, 6, 3565. (62) Reetz, M. T.; Ma, J.-A.; Goddard, R. Angew. Chem. Int. Ed. 2005, 44, 412. (63) Duan, Z.-C.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Wang, D.-Y.; Zheng, Z. Tetrahedron: Asymmetry 2009, 20, 588. (64) Tang, W.-J.; Huang, Y.-Y.; He, Y.-M.; Fan, Q.-H. Tetrahedron: Asymmetry 2006, 17, 536. (65) Zhang, F.; Li, Y.; Li, Z.-W.; He, Y.-M.; Zhu, S.-F.; Fan, Q.-H.; Zhou, Q.- L. Chem. Commun. 2008, 6048. (66) a) Lyubimov, S. E.; Said-Galiev, E. E.; Khokhlov, A. R.; Loim, N. M.; Popova, L. N.; Petrovskii, P. V.; Davankov, V. A. J. Supercrit. Fluids 2008, 45, 70; b) Lyubimov, S. E.; Davankov, V. A.; Said-Galiev, E. E.; Khokhlov, A. R. Catal. Commun. 2008, 9, 1851. (67) Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433. (68) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488. (69) Liu, Y.; Sandoval, C. A.; Yamaguchi, Y.; Zhang, X.; Wang, Z.; Kato, K.; Ding, K. J. Am. Chem. Soc. 2006, 128, 14212. (70) a) Wu, H.-P.; Hoge, G. Org. Lett. 2004, 6, 3645; b) Hoge, G.; Samas, B. Tetrahedron: Asymmetry 2004, 15, 2155; c) Lee, S.-G.; Zhang, Y.-J. Org. Lett. 2002, 4, 2429; d) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952; e) Heller, D.; Holz, J.; Drexler, H.-

Chapter 1

J.; Lang, J.; Drauz, K.; Krimmer, H.-P.; Börner, A. J. Org. Chem. 2001, 66, 6816; f) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907; g) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543; h) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 19, 1119. (71) Peña, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552. (72) Peña, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2003, 5, 475. (73) Panella, L.; Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.; Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. J. Org. Chem. 2006, 71, 2026. (74) Panella, L.; Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. Org. Lett. 2005, 7, 4177. (75) a) Reetz, M. T. Angew. Chem. Int. Ed. 2008, 47, 2556; b) Reetz, M. T.; Surowiec, M. Heterocycles 2006, 67, 567; c) Reetz, M. T.; Li, X. Angew. Chem. 2005, 117, 3019; d) Reetz, M. T.; Li, X. Tetrahedron 2004, 60, 9709; e) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron: Asymmetry 2004, 15, 2165; f) Reetz, M. T. Comprehensive Coordination Chemistry II, Eds. Ward, M. D.; McCleverty, J. A.; Meyer, T. J. Elsevier: Amsterdam, 2004; Vol. 9, 509; g) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem. Int. Ed. 2003, 42, 790; h) Reetz, M. T. Chim. Oggi 2003, 21, 5. (76) Peña, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087. (77) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 3111. (78) Hoen, R.; Tiemersma-Wegman, T. D.; Procuranti, B.; Lefort, L.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2007, 5, 267. (79) a) Reetz, M. T.; Bondarev, O. Angew. Chem. Int. Ed. 2007, 46, 4523; b) Duursma, A.; Boiteau, J.-G.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045; c) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593. (80) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem. Int. Ed. 2005, 44, 4209.

Asymmetric hydrogenation using monodentate phosphoramidite ligands

(81) Duursma, A.; Peña, D.; Minnaard, A. J.; Feringa, B. L. Tetrahedron: Asymmetry 2005, 16, 1901. (82) a) de Vries, J. G.; Lefort, L. Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. 2007; Vol. 3, Chapter 36, 1245; b) Boogers, J. A. F.; Felfer, U.; Kotthaus, M.; Lefort, L.; Steinbauer, G.; de Vries, A. H. M.; de Vries, J. G. Org. Process Res. Dev. 2007, 11, 585; c) Jagt, R. B. C.; Toullec, P. Y.; Schudde, E. P.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. J. Comb. Chem. 2007, 9, 407; d) Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Top. Catal. 2006, 40, 185; e) van den Berg, M.; Peña, D.; Minnaard, A. J.; Feringa, B. L.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Chim. Oggi 2004, 18; f) de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799; g) Gennari, C.; Piarulli, U. Chem. Rev. 2003, 103, 3071; h) Archibald, B.; Brümmer, O.; Devenney, M.; Gorer, S.; Jandeleit, B.; Uno, T.; Weinberg, W. H.; Weskamp., T. Handbook of Combinatorial Chemistry, Eds. Nicolaou, K. C.; Hanko, R.; Hartwig, W. Wiley-VCH: Weinheim, 2002; Vol. 2, 885; i) Hoveyda, A. Handbook of Combinatorial Chemistry, Eds. Nicolaou, K. C.; Hanko, R.; Hartwig, W. Wiley-VCH:: Weinheim, 2002; Vol. 2, 991. (83) a) Goudriaan, P. E.; Jang, X.-B.; Kuil, M.; Lemmens, R.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Eur. J. Org. Chem. 2008, 6079; b) Kuil, M.; Goudriaan, P. E.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Commun. 2006, 4679; c) Slagt, V. F.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Commun. 2003, 2474. (84) a) Breuil, P.-A. R.; Patureau, F. W.; Reek, J. N. H. Angew. Chem. Int. Ed. 2009, 48, 2162; b) Patureau, F. W.; Kuil, M.; Sandee, A. J.; Reek, J. N. H. Angew. Chem. Int. Ed. 2008, 47, 3180; c) Jiang, X.-B.; Lefort, L.; Goudriaan, P. E.; de Vries, A. H. M.; van Leeuwen, P. W. N. M.; de Vries, J. G.; Reek, J. N. H. Angew. Chem. Int. Ed. 2006, 45, 1223. (85) Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries, J. G. Angew. Chem. Int. Ed. 2007, 46, 1497. (86) Erre, G.; Junge, K.; Enthaler, S.; Addis, D.; Michalik, D.; Spannenberg, A.; Beller, M. Chem. Asian J. 2008, 3, 887. (87) Enthaler, S.; Erre, G.; Junge, K.; Schröder, K.; Addis, D.; Michalik, D.; Hapke, M.; Redkin, D.; Beller, M. Eur. J. Org. Chem. 2008, 3352.

Chapter 1

(88) Erre, G.; Enthaler, S.; Junge, K.; Addis, D.; Beller, M. Adv. Synth. Catal. 2009, 351, 1437. (89) Faller, J. W.; Milheiro, S. C.; Parr, J. J. Organomet. Chem. 2006, 691, 4945. (90) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry 1994, 5, 699. (91) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A. Synthesis 2004, 2586. (92) James, B. R. Catal. Today 1997, 37, 209.

Chapter 2 Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

In this chapter the asymmetric hydrogenation of 2- and 2,6-substituted quinolines catalyzed by iridium complexes of BINOL-derived phosphoramidites is described. Enantioselectivities of up to 89% were obtained using a mixed ligand system.

Part of this chapter has been published:

N. Mršić, L. Lefort, J. A. F. Boogers, A. J. Minnaard, B. L. Feringa, J. G. de Vries, Adv. Synth. Catal. 2008, 350, 1081. Chapter 2

2.1 Introduction

Asymmetric hydrogenation of unsaturated prochiral compounds represents an attractive and versatile method for the preparation of enantiopure building blocks.1 Although significant effort has been made in the area of asymmetric hydrogenation of aromatic and heteroaromatic compounds,2 many challenges remain. Enantiopure tetrahydroquinolines represent important synthetic intermediates, as they are present in numerous alkaloids and biologically active compounds.3,4 In the past, an ethanolic extract of Galipea officinalis was used against fever and inflammation. This extract contained four alkaloids depicted in Figure 2.15 and they all show activity against Mycobacterium tuberculosis.6

O N N O (R)-(-)-Angustureine (S)-(-)-Galipinine

OMe OH N N

OMe OMe

(S)-(-)-Cuspareine (S)-(-)-Galipeine

Figure 2.1 Alkaloids isolated from Galipea officinalis

2-Methyl-1,2,3,4-tetrahydroquinoline is present in the human brain as an endogenous alkaloid.7 Discorhabdin C, a polycyclic system based on tetrahydroquinoline, is a marine alkaloid.8 Dynemycin, a natural antitumor antibiotic, has a complex structure built on the tetrahydroquinoline scaffold.9 Many relatively simple synthetic 1,2,3,4- tetrahydroquinolines are already used or have been tested as potential drugs (Figure 2.2). Among them, Oxamniquine, a schistosomicide (Schistosomiasis is a parasitic disease),10 Nicainoprol, an antiarrhytmic drug,11 and Virantmycin, a novel antibiotic,12 are the best known. Tetrahydroquinoline L-689,560 is one of the most potent NMDAR (N-

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

methyl d-aspartate receptor) antagonists yet described.13 Besides pharmaceutical applications, tetrahydroquinoline derivatives are useful as pesticides, antioxidants, and corrosion inhibitors.4

HOOC OH N H H N N O O2N N H O N Oxamniquine Nicainoprol

HOOC Cl Cl HN N H N H OMe Cl N COOH H Virantmycin L-689,560

Figure 2.2 1,2,3,4-tetrahydroquinolines as potential drugs

Chiral enantiopure tetrahydroquinolines are usually prepared via asymmetric synthesis.5,14 Transition metal-catalyzed asymmetric hydrogenation of quinolines is among the most effective methods for their preparation, as many substituted quinolines are commercially available. In recent years, a number of bidentate chiral ligands were successfully used in the asymmetric hydrogenation of quinolines with high enantioselectivities (Scheme 2.1).15-27 In 2003 Zhou et al. reported the use of Ir complexes generated in situ 27 from [Ir(COD)Cl]2 and (R)-MeO-Biphep and in 2004 the application of ferrocenyloxazoline-derived N,P ligands26 for the asymmetric hydrogenation of quinolines. Using iodine as additive in both cases, excellent ee was obtained. The approach using (R)-MeO-Biphep ligand was applied in the synthesis of Galipeine.28 Same group described synthesis of (S)-MeO- Biphep-derived supported ligands and their use in the asymmetric hydrogenation of quinolines with up to 92% ee.19 The catalyst is air-stable and recyclable.

Chapter 2

metal precursor R2 R2 bidentate ligand H solvent * N R1 2, N R1 H

MeO PPh2 N OPPh2 OPPh2 Fe MeO PPh2 PPh2 OPPh2 OPPh2

(R)-MeO-Biphep Ferrocenyl N,P-ligand (S)-H8-BINAPO (R)-Spiropo up to 96% ee up to 92% ee up to 97% ee up to 94% ee Zhou et al., 2003, 2004 Chan et al., 2005, 2007

O Ph P P O O O O P

up to 96% ee Reetz et al., 2006

- O BArF S N PAr Ph Ir 2 Ts R X Ru N (COD) H2N Ph Ar = C6H5, 4-MeC6H4, 4-MeOC6H4, Ph 3,5-Me2C6H3, 4-CF3C6H4 X = OTf, Cl R = Me, Et, i-Bu, Ph(CH2)2 up to 96% ee up to 92% ee Chan et al., 2008 Bolm et al., 2008

Scheme 2.1 Efficient ligands/catalysts reported for the catalytic asymmetric hydrogenation of 2,6-substituted quinolines

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

High enantioselectivities were also reported by Chan et al. using a 25 catalyst based on the diphosphinite ligand H8-BINAPO. In addition, same group reported highly effective bisphosphinite ligand Spiropo in the Ir- catalyzed hydrogenation of quinolines with high substrate/catalyst ratio (5000).20 Recently, the first phosphine free cationic Ru/Ts-dpen catalyst was described by same authors to lead to high reactivity and enantioselectivity in the hydrogenation of quinolines in neat ionic liquid.18 The use of ionic liquid not only facilitated the recyclability, but also enhanced the stability and selectivity of the catalyst. The iridium equivalent of Ts-dpen catalyst was also shown to be efficient in the hydrogenation of quinolines.16 In 2006 Reetz reported the use of a combination of bis-phosphonites and monodentate achiral phosphorus ligands (up to 96% ee).22 The group of Bolm described a series of naphthalene-bridged P,N-type sulfoximine ligands, which were applied in the Ir-catalyzed hydrogenation of quinolines with up to 92% ee.17 Dendritic catalysts derived from BINAP are also shown to lead to high enantioselectivities (up to 93%), and excellent catalytic activities (TOF up to 3450 h-1) in the hydrogenation of quinoline derivatives.21 In addition, the catalyst could be recovered by precipitation and filtration and reused at least six times with similar enantioselectivity. Transfer hydrogenation is a valuable and versatile reaction which is emerging as one of the best methods for achieving asymmetric transformations. The combination of practical simplicity, mild reaction conditions, relatively non-hazardous reagents and high selectivities distinghishes it from other processes in synthetic organic chemistry.29-31 The first asymmetric organocatalytic transfer hydrogenation of heteroaromatic compounds was reported by Rueping in 2006 (Scheme 2.2).31 The catalysts are bulky BINOL-derived phosphoric acids while Hantzsch esters were used as stoichiometric hydrogen source (up to 99% ee).

Chapter 2

Rueping et al., 2006 H H EtOOC COOEt

N H

o N R benzene, 60 C N R H Ar

O O up to 99% ee 2 mol% P O OH

Zhou et al., 2007 H H ROOC COOR

2 N R2 R H

1 N R1 [Ir(COD)Cl]2, (S)-Segphos N R I2, solvent, rt H

up to 91% ee O 1 2 O for R = Me, R = H: PPh2 O PPh2 R ee (%) O Me up to 91 Et 79 (S)-Segphos i-Pr 59 t-Bu 23

Scheme 2.2 Asymmetric transfer hydrogenation of quinolines

In 2007, Zhou et al. reported the use of (S)-Segphos as chiral ligand in the iridium catalyzed transfer hydrogenation of quinolines with Hantzsch esters (Scheme 2.2, up to 91% ee).30 The ee is strongly determined by the nature of the ester groups of the Hantzsch ester.

2.2 Goal of the research

Asymmetric hydrogenation of quinolines is still not suitable for industrial applications due to the fact that the ligands employed are

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

usually prepared through a multi-step synthesis. Moreover, reported TOF’s are often low and higher pressures are usually necessary due to the high stability of heteroaromatic substrates. Despite all the excellent examples in literature, the substrate scope is mainly focused on 2-alkyl, 2-aryl- substituted, and 3-substituted quinoline derivatives. Highly enantioselective hydrogenation of other quinoline substrates remains a challenging task. Therefore, the asymmetric hydrogenation of quinolines is still an underdeveloped area. From earlier results in our group, it was evident that monodentate phosphoramidites give excellent results in asymmetric hydrogenation,32 conjugate addition,33-38 [3+2] cycloaddition,39 Heck reaction,40 allylic alkylation,34,41 asymmetric arylation of aldehydes,42 ketones43 and substituted imines.44 In this chapter asymmetric hydrogenation of quinolines catalyzed by iridium complexes based on monodentate BINOL-derived phosphoramidites is described. Libraries of different phosphoramidites and phosphites as well as different metal precursors were tested. The effect of additives on the enantioselectivity of the reaction was examined. Some additional kinetic experiments were performed, as well as mass analysis and high pressure 31P NMR studies of the catalyst, in order to obtain information on the metal complexes involved.

2.3 Initial screening and ligand optimization

Asymmetric hydrogenation of a benchmark substrate 2-methylquinoline 1 was chosen as a model reaction (Table 2.1). Initial hydrogenation experiments were performed at 25 bar of hydrogen pressure and 60 oC, using 1 mol% of iridium precursor (L*/Ir = 2/1). The catalyst was prepared in situ. Using (S)-PipPhos L1a as ligand and [Ir(COD)Cl]2 as iridium source, 96% conversion and ee up to 36% was obtained in 24h (Table 2.1). Only 4% conversion and 17% ee was achieved at rt using 70 bar of hydrogen pressure. Initial solvent screening showed that the enantioselectivity of the reaction is solvent dependent.

Chapter 2

Table 2.1 Solvent variation in the asymmetric hydrogenation of 2- methylquinoline 1a

1 mol% Ir precursor, (S)-PipPhos solvent, 25 bar H 60 °C, 24h N 2, N H 11a

O P N O

L1a, (S)-PipPhos

Entry Ir precursor Solvent Conversionb (%) eec (%)

1 [Ir(COD)Cl]2 HOAc 32 5

2 [Ir(COD)Cl]2 i-PrOH 91 9

3 [Ir(COD)Cl]2 MeOH 47 11

4 [Ir(COD)Cl]2 THF 97 21

5 [Ir(COD)Cl]2 acetone 97 18

6 [Ir(COD)Cl]2 EtOAc 96 28

7 [Ir(COD)Cl]2 CH2Cl2 96 18

8 [Ir(COD)Cl]2 toluene 96 36 d 9 [Ir(COD)2]BArF CH2Cl2 100 3 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 4 mL of solvent, 60 °C 25 bar H2, 24h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column. d 1 mmol quinoline 1, 0.01 mmol [Ir(COD)2]BArF, 0.02 mmol (S)-PipPhos. e(S) configuration of the product was observed in all solvents. Absolute configuration of the product is assigned by measuring optical rotation and comparing it with literature data.

The best result was obtained in the non polar solvent toluene (Entry 8), whereas the use of protic solvents such as i-PrOH and MeOH resulted in low enantioselectivity and somewhat lower conversions (Entries 2, 3). Use of acetic acid as solvent leads to only 32% conversion and 5% ee (Entry 1).

The use of cationic [Ir(COD)2]BArF resulted with full conversion but only 3% ee (Entry 9). In aprotic polar solvents like THF, acetone and ethyl acetate, excellent conversions and ee’s up to 28% were obtained (Entries 4- 6).

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

O O P R P R O O

(S)-L1 (S)-L2 Amine moieties R:

N NS N O N N N

(R,S) a bdec f Ph N N N N N Ph O NH O Ph (S, S) (R) gih j kl

Figure 2.3 Monodentate phosphoramidite ligands screened in the asymmetric hydrogenation of 2-methylquinoline 1

After screening of the solvents for the model reaction of the asymmetric hydrogenation of 2-methylquinoline 1, different monodentate phosphoramidite ligands were tested (Figure 2.3). The screening was done using 5 mol% of iridium precursor and 20 mol% of ligand, at 70 bar of H2 pressure and temperature of 60 oC. Results are presented in Table 2.2. Simple monodentate BINOL-derived phosphoramidites, derived from cyclic amines (L1a, L1c-i, L2a and L2f) gave the best result (up to 70% ee,

Entries 1, 2, 4-11). Ligands L2a and L2f that were derived form H8-BINOL induced excellent conversion and 56% and 48% ee, respectively (Entries 2, 8).

Chapter 2

Table 2.2 Screening of monodentate phosphoramidite ligands in the asymmetric hydrogenation of 2-methylquinoline 1a

5 mol% [Ir(COD)Cl]2, 20 mol% L*

N toluene, 70 bar H2, 60 °C, 20h N H 11a

Entry Ligand Conversionb (%) eec (%) 1 L1a 100 36 2 L2a 97 56 3 L1b 0 - 4 L1c 89 48 5 L1d 90 34 6 L1e 84 40 7 L1f 61 70 8 L2f 97 48 9 L1g 84 0 10 L1h 47 21 11 L1i 98 21 12 L1j 19 0 13 L1k 38 4 14 L1l 57 16 aReaction conditions: 0.12 mmol quinoline 1, 6 µmol [Ir(COD)Cl2]2, 24 µmol L*, 4 mL of toluene, 60 °C 70 bar H2, 20h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Using the ligands derived from cyclic amines, lower enantioselectivities were obtained with those synthesized from pyrrole and tetrahydroisoquinoline (L1h, L1i, 21% ee, Entries 10, 11) The catalyst synthesized from phosphoramidite L1b, which is derived from thiomorpholine, led to no conversion (Entry 3). As sulfur compounds are known to be a catalyst poison, this could be the reason for the failure of the hydrogenation.45 When ligands L1g, L1k were used, which were derived from chiral (S)-pyrrolidine-2-carboxylic acid methyl ester and (S,S)- bis-(1-phenyl-ethyl)-amine, the reaction was nonselective (Entries 9, 13). With ligand L1l, which was synthesized from the primary chiral (R)-1- Phenyl-ethylamine 57% conversion and 16% ee were obtained (Entry 14).

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

5 mol% [Ir(COD)Cl]2, L*

N toluene, 70 bar H2, 60 °C, 20h N H 11a

PPh2

O O P N P N O O

PPh2 L3, 90% conv., 37% ee L4, 3% conv., 4% ee

O O P N N P O O

L5, 95% conv., 2% ee

O O P N N P N N O O

L6, 92% conv. L7, 95% conv. 34% ee 34% ee

Scheme 2.3 Screening of phosphoramidite ligands in the asymmetric hydrogenation of 2-methylquinoline 1

With substituted BINOL-derived phosphoramidites low ee’s were invariably obtained (Scheme 2.3). The highest ee was accomplished with the use of 3,3’-dimethyl-PipPhos (L3, 37% ee). Disappointingly, 3,3’- diphenylphosphine-substituted BINOL based ligand L4 led to only 3% conversion. When bidentate phosphoramidite ligand L5 was employed 95% conversion and only 2% ee was achieved. We envisioned that ligands with an additional nitrogen atom in the structure would coordinate to the metal in a bidentate fashion and provide

Chapter 2

the product with higher ee. Unfortunately with both ligands L6 and L7 ee’s up to 34% were obtained. Phosphoramidite ligands synthesized from different diol backbones were also examined in the asymmetric hydrogenation of 2-methylquinoline 1. Results obtained with bulky biphenol-, TADDOL- and catechol-derived phosphoramidites are depicted in Scheme 2.4. Using the biphenol-derived phosphoramidite L8 87% conversion and 14% ee was obtained. With the TADDOL-derived ligand L9 no product was formed. In the case of the catechol-derived phosphoramidite L10, where the chirality comes from the (2S,5S)-2,5-diphenylpyrrolidine moiety, no enantioselectivity was observed in the hydrogenation reaction.

5 mol% [Ir(COD)Cl]2, 20 mol% L*

N toluene, 70 bar H2, 60 °C, 20h N H 11a

Ph Ph Ph O O O O P N P N P N O O O O Ph Ph Ph

L8,87% conv. (S,S)-L9, 0% conv. (S,S)-L10, 98% conv. 14% ee 3% ee

Scheme 2.4 Ligand screening in the asymmetric hydrogenation of 2- methylquinoline 1

Several commercial bisphosphine ligands were also examined in the same model reaction, using 1 mol% of iridium precursor and 2 mol% of ligand at 60 °C and 70 bar of hydrogen pressure (Table 2.3). Good conversions, however modest enantioselectivity was obtained using bidentate BINAP and tolyl-BINAP ligands (43% and 39% ee, respectively (Entries 1, 2). The us of Me-DUPHOS led to 57% conversion and 39% ee (Entry 3), while with Josiphos ligand only 64% conversion and 13% ee was accomplished (Entry 4).

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

Table 2.3 Commercial bidentate ligands examined in the asymmetric hydrogenation of 2-methylquinoline 1a

1 mol% [Ir(COD)Cl]2, 2 mol% L*

N toluene, 70 bar H2, 60 °C, 20h N H 11a

PPh2 P(o-tolyl)3

(S)-BINAP (S)-tolyl-BINAP

PCy2 P P Fe PPh2

(S,S)-Me-Duphos (RC,SFe)-Josiphos

Entry Ligand Conversionb (%) eec (%) 1 (S)-BINAP 73 43 2 (S)-Tolyl-BINAP 67 39 3 (S,S)-Me-Duphos 57 39 4 (RC,SFe)-Josiphos 64 13 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.02 mmol L*, 2 mL of toluene, 60 °C 70 bar H2, 20h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

From the results obtained so far it was evident that phosphoramidite ligands synthesized from the cyclic amines represent the best candidates for further optimisation of the asymmetric hydrogenation of 2- methylquinoline 1. In 2006 Zhou et al. reported the use of chloroformates as activating agents in the Ir/Segphos catalyzed asymmetric hydrogenation of quinolines and isoquinolines with up to 90% and 83% ee, respectively.23 Without the use of the activating agent, the hydrogenation of isoquinolines

Chapter 2

did not proceed, while by activating isoquinolines with chloroformates, the hydrogenation to dihydroisoquinolines proceeded with high yields and ee’s. This was rationalized as follows: 1) the aromaticity should be partially reduced by the formation of quinolinium salts; 2) bonding of the activating reagent to the N atom may prevent poisoning of the catalyst; and 3) Zhou et al. assumed that the attached CO2R group is probably important for coordination between the substrate and the catalyst, and thus is beneficial to the control of enantioselectivity. 2-Methylquinoline 1 was therefore in situ derivatized with benzyl-chloroformate and subjected to the iridium catalyzed hydrogenation reaction using (S)-PipPhos L1a as a ligand (Scheme 2.5).

1.1 eq ClCO2Bn toluene, rt N N Cl- CO Bn 1 2

5 mol% [Ir(COD)Cl]2, 20 mol%(S)-PipPhos 1.2 eq Li CO N 2 3, N - o Cl toluene, 70 bar H2, 60 C, 17h CO2Bn CO2Bn 2, 92% conversion, 29% ee

Pd/C, 25 bar H2 4h, THF

N H 1a

Scheme 2.5 Hydrogenation of activated quinoline substrate and subsequent deprotection

The iridium precursor and ligand were stirred under Schlenk conditions. In another Schlenk the substrate was stirred with benzylchloroformate in the presence of lithium carbonate. The solution of

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

the in situ prepared catalyst was then added to the derivatized substrate and the reaction mixture was placed in the autoclave. The mixture was hydrogenated with 5 mol% of iridium precursor and 20 mol% of PipPhos L1a at 60 °C and 70 bar of hydrogen pressure. Unfortunately following this approach only 29% ee was obtained.

2.4 High throughput experiments

Based on these results, the screening of additional phosphoramidite ligands in toluene was performed. High Throughput Experimentation (HTE) is a methodology in which a large number of ligands are quickly synthesized and tested in parallel.46 HTE is an efficient method for finding enantioselective transition-metal catalysts, especially in an industrial environment where time-to-market constraints are severe. Automation has been used in the synthesis of libraries of ligands on solid phase. However, the presence of the polymer can have an unfavourable effect on the rate and the selectivity when screening is performed on the bead.47 Until recently, most ligand libraries have been synthesized one ligand at a time, especially those made by multistep synthesis which requires purification. Phosphoramidite ligands represent perfect candidates for parallel synthesis since they are easy to make, stable, cheap and highly modular. In the HTE experiment both the BINOL backbone and the amine part of the ligand can be varied, as well as the metal, solvents and reaction conditions. In this chapter, a protocol for the automated solution-phase synthesis of a library of chiral phosphoramidites and phosphites and the screening of this library in the enantioselective hydrogenation of 2-methylquinoline 1 is described. As mentioned earlier, phosphoramidites are easily obtained by reaction between a chlorophosphite and a primary or secondary amine in the presence of a base.48 Chlorophosphites are prepared in a one step reaction

by refluxing the diol in neat PCl3. After removal of the excess PCl3 the chlorophosphite is obtained in essentially pure form. To obtain a pure phosphoramidite ligand, column chromatography and/or recrystallization were typically performed prior to its use in

Chapter 2

catalysis. This tedious workup represented a serious obstacle toward a fully automated preparation of a large ligand library.

O PCl Crude ligands O 96-well oleophobic filterplate R R NH 1 2 Orbital Shaker

Et3N Parallel Filtration Stock Ready-to-use ligands 96-well microplate Solutions Storage plate

Metal Reaction Mixture Precursor Array of 96 vials (10 mL)

Substrate #1 Substrate #2

O 2 O R2 R Et3N(1eq) . PCl + HN PN + Et3N HCl O R1 O R1

Figure 2.4 Protocol for the parallel synthesis of the ligand library49

It is assumed that as long as stoichiometric amounts of reagents are used and the reaction goes to completion, the main impurity present is the hydrochloride salt of the base (Figure 2.4). Thus, performing the reaction in a suitable solvent followed by simple filtration of the precipitated hydrochloride salt should lead to sufficiently clean phosphoramidite ligands. The simplified synthetic protocol could then be easily automated by using a 96-well oleophobic filter plate. Parallel filtration is performed upon application of vacuum, and the filtrates are collected in a second 96- well micro-plate that can be used for storage. This protocol was developed by Laurent Lefort at DSM.49 The ligand library (Scheme 2.6) was prepared by reacting (S)-2,2’- binaphthol-, (S)-H8-2,2’-binaphthol- and (S)-3,3’-dimethyl-2,2’-binaphthol-

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

based chlorophosphite with 10 different amines (6 primary and 4 secondary) and 6 alcohols in the presence of triethylamine as a base, thus generating 48 ligands (30 phosphoramidites and 18 phosphites) with a wide diversity in their amino or alcohol moiety. Two different metal precursors were used, neutral [Ir(COD)Cl]2 and cationic [Ir(COD)2]BF4. This initial set of amines and alcohols was randomly assembled to obtain diversity. Phosphoramidites derived from primary amines and BINOL have not been used extensively in catalysis in general as they partially decompose during chromatographic purification. The absence of the purification step in the automated procedure makes these primary amine based phosphoramidites readily available. Stock solutions of all the reagents were prepared in toluene and dispensed directly into the 96-well micro-plate with a liquid handling robot. The 48 reaction mixtures were vortexed using an orbital shaker for 2 h followed by parallel filtration giving 48 ligand solutions. A fraction of each solution was transferred to two sets of 48 vials, which contained iridium precursor (L*/Ir = 2/1) and the substrate 2-methylquinoline 1 in toluene (substrate/[Ir(COD)Cl]2 =

40/1, substrate/[Ir(COD)2]BF4 = 20/1). The 96 hydrogenation reactions were performed in parallel in a Premex 96-Multi Reactor at 60 °C and 25

bar of H2 for 16 h (Figure 2.5). The results are presented in Figure 2.6.

Figure 2.5 Premex 96-Multi Reactor

Chapter 2

Although 48 different phosphoramidites and phosphites based on

BINOL, H8-BINOL, and 3,3’-dimethyl-BINOL were tested, as well as two iridium precursors, high enantioselectivities were not reached. In general, the highest ee’s were obtained using ligands derived from primary amines. Although conversions were not high, the best enantioselectivity was

obtained using [Ir(COD)Cl]2 and ligand synthesized from amines A2 (aniline) and A9 (3-amino-propionitrile) with BINOL-derived chlorophosphite PCl-1 (up to 62% conv. and 51% and 52% ee, respectively). With the same iridium precursor and ligands synthesized from primary amines; 2-amino-benzoic acid ethyl ester A1, 1-propylamine A13 and i-propylamine A15 with chlorophosphite PCl-1 ee’s up to 44% were achieved (conv. 85%, 79% and 24%, respectively).

Ligand obtained from A2 (aniline) and H8-BINOL (PCl-3) led to 42% ee and only 39% conversion. Enantioselectivities of 37% and 32% were accomplished with the ligand synthesized from PCl-3 and amines (4- methoxy-phenyl)-methyl-amine A4 and 3-amino-propionitrile A9 (56% and 51% conv.) Very low enantioselectivities were obtained when ligands synthesized from 3,3’-dimethyl-BINOL were used, with both iridium precursors. When [Ir(COD)2]BF4 was used as a metal precursor, poor enantioselectivities were obtained in general, except when the ligand synthesized from 2-amino-benzoic acid ethyl ester A1 and chlorophosphite PCl-1 or PCl-3 were used (45% conv., 45% ee and 58% conv., 36% ee).

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

5 mol% Ir, 10 mol% L*

N toluene, 25 bar H2, 60 °C, 16h N H 11a

COOEt NH2 HN O NH NH2

A1 A2 A3 A4

OH H N H2N HO N

A5 A6 A7 A8

Cl CN H N HO O HN 2 HO

A9 A10 A11 A12

O OH

H2N CH3OH H2N

A13 A14 A15 A16

OH OH OH OH OH OH

PCl-1 PCl-2 PCl-3

Scheme 2.6 Setup of library of ligands for the asymmetric hydrogenation of 2-methylquinoline 1

Chapter 2

Conversion (%)

[Ir(COD)Cl]2 Ir(COD)2BF4

PCl-1 PCl-2 PCl-3 PCl-1 PCl-2 PCl-3

A1 A2

A3 A4

A5 A6

A7 A8

A9 A10

A11 A12

A13 A14

A15 A16

Ee (%)

[Ir(COD)Cl]2 Ir(COD)2BF4

PCl-1 PCl-2 PCl-3 PCl-1 PCl-2 PCl-3

A1 A2

A3 A4

A5 A6

A7 A8

A9 A10

A11 A12

A13 A14

A15 A16

100 90 80 70 60 50 40 30 20 10 0

aReaction conditions: 58 µmol quinoline 1, 1.45 µmol [Ir(COD)Cl2]2, 5.8 µmol L*, 2.45 mL of toluene, 60 °C 25 bar H2, 16h. b58 µmol quinoline 1, 1.45 µmol [Ir(COD)2]BF4, 2.9 µmol L*, 2.45 mL of toluene, 60 °C 25 bar H2, 16h. cConversion was determined by GC. dEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Figure 2.6 Results of the parallel screening of a ligand library in the asymmetric hydrogenation of 2-methylquinoline 1

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

Surprisingly, it was observed that upon addition of 10 mol% of piperidine hydrochloride to the standard hydrogenation reaction based on in situ formed complex of (S)-PipPhos L1a and [Ir(COD]Cl]2 in toluene, the enantioselectivity increased from 36% to 63%. This finding will be discussed in more detail further on in this chapter. In most hydrogenations described hereafter this additive was used.

2.5 Asymmetric hydrogenation of quinolines using mixed ligand approach

As mentioned in Chapter 1, both the group of Reetz50 and our group37,51 have shown that the use of mixtures of chiral monodentate ligands can improve enantioselectivity and reactivity. It is also possible to use mixed complexes based on a monodentate chiral ligand and a non-chiral phosphorus ligand.35,36,52,53 In our group the mixed ligand approach has been employed in rhodium catalyzed asymmetric hydrogenations51,52 and additions of boronic acids.35,37 Mixtures of (S)-PipPhos L1a and 17 different achiral phosphine ligands, 2 phosphites (L27 and L29) and 1 phosphinine (L28) were therefore screened in the asymmetric hydrogenation of 2-methylquinoline 1 (Figures

2.7 and 2.8). Reactions were performed using 1 mol% of [Ir(COD)Cl]2, 4 mol% of (S)-PipPhos L1a and 10 mol% of piperidine hydrochloride, under

50 bar of H2 pressure over 24h. Results are presented in Table 2.4. It was observed that ortho-substituted phosphines L12, L15, L16, L22, L23 as well as bulky tri-tert-butylphosphine L17 and adamantyl-phosphine L30 led to good to excellent conversions and high enantioselectivities (Table 2.4, Entries 3, 6, 7, 8, 13, 14, 21). The best result was obtained using PipPhos L1a and tri-o-tolylphosphine L12, giving full conversion and 83% ee (Entry 3). Surprisingly, the catalyst prepared from the mixture of PipPhos L1a and triphenylphosphine L11 leads to very low conversion (Entry 2).

Chapter 2

P P P P

L11 L12 L13 L14

F F F FF F

F F P P P F F P F F

F F F

L15 L16 L17 L18

F F Cl O O

P P P P Cl

F Cl O

L19 L20 L21 L22

O OO P P P P O O O O O O

L23 L24 L25 L26

Figure 2.7 Achiral phosphines tested in the asymmetric hydrogenation of 2-methylquinoline 1

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

Apart from phosphines, other type of P-ligands were tested in combination with PipPhos L1a (Figure 2.8). Non-bulky phosphite L27 and bulky phosphite L29 led to only 3% and 11% conversion, respectively (Entries 18, 20). With the use of phosphinine ligand L28 excellent conversion and high ee was achieved (Entry 19).

O O P P O

L27 L28

C(CH3)3

(H3C)3C C(CH3)3 O O P P O C(CH3)3

(H3C)3C C(CH3)3

L29 L30

Figure 2.8 Achiral ligands tested in the asymmetric hydrogenation of 2- methylquinoline 1

Chapter 2

Table 2.4 Achiral P-ligands screened in the asymmetric hydrogenation of 2-methylquinoline 1a

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos N 2 mol% achiral ligand N 10 mol% piperidine hydrochloride H toluene, 50 bar H 60 °C, 24h 11a2,

Entry Achiral phosphine Conversionb (%) eec (%) 1 - 100 63 2 L11 2 nd 3 L12 100 83 4 L13 2 0 5 L14 1 0 6 L15 41 81 7 L16 94 78 8 L17 54 82 9 L18 2 0 10 L19 1 0 11 L20 1 0 12 L21 2 0 13 L22 99 70 14 L23 18 77 15 L24 21 66 16 L25 9 5 17 L26 74 12 18 L27 3 62 19 L28 99 77 20 L29 11 77 21 L30 28 83 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol achiral ligand, 0.1 mmol piperidine hydrochloride, 4 mL toluene, 24h. bConversion is determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Since the best result was obtained with a mixture of (S)-PipPhos L1a and tri-o-tolylphosphine L12 (full conversion and 83% ee), the ratio of those two ligands was optimized. Results are presented in Table 2.5. The amount of iridium precursor was kept constant, while changing the amount of PipPhos L1a and tri-o-tolylphosphine L12. The best results

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

were obtained in cases when the amount of PipPhos L1a was higher than the amount of tri-o-tolylphosphine L12 (Entries 3-7). The highest ee was obtained with an Iridium/PipPhos/phosphine ratio of 1/2/1 (83%).

Table 2.5 Optimisation of the metal/ligands ratio in the asymmetric hydrogenation of 2-methylquinoline 1a

1 mol% [Ir(COD)Cl]2, (S)-PipPhos tri-o-tolylphosphine, N N 10 mol% piperidine hydrochloride H toluene, 50 bar H2, 60 °C, 18h 1 1a

Entry Ir/PipPhos/phosphine Conversionb (%) eec (%) 1 1/0.8/1 94 59 2 1/1/1 83 64 3 1/1.5/1 96 78 4 1/2/1 90 83 5 1/2/0.5 93 76 6 1/2/0.8 81 81 7 1/2/1.5 89 77 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 4 mL of solvent, 60 °C 50 bar H2, 18h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Different phosphoramidite ligands were tested in combination with tri- o-tolylphosphine L12, under the same conditions. Table 2.6 presents results for 4 different phosphoramidites with and without the presence of tri-o-tolylphosphine L12. In the case of the ligands L1f and L8 the reaction was slowed down by the addition of achiral phosphine, while the ee stayed the same (Entry 1, 3). With H8-PipPhos L2a the same result was obtained in the reaction with or without the addition of achiral phosphine (Entry 2). No conversion was obtained in the hydrogenation reaction using ligand L9, while with addition of achiral phosphine L12 9% of product was formed with almost no selectivity (Entry 4).

Chapter 2

Table 2.6 Different phosphoramidite ligands tested in the combination with tri-o-tolylphosphine L12a

1 mol% [Ir(COD)Cl]2, 4 mol% L* 2 mol% tri-o-tolylphosphine, N N 10 mol% piperidine hydrochloride H toluene, 50 bar H2, 60 °C, 20h 1 1a

Entry Ligands Conversionb (%) eec (%) L1f 61 70 1 L1f + L12 29 69 L2a 97 56 2 L2a+ L12 97 57 L8 87 14 3 L8+ L12 49 16 L9 0 - 4 L9 + L12 9 4 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol phosphoramidite, 0.02 mmol achiral phosphine, 4 mL of toluene, 60 °C, 50 bar H2, 20h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

The effects of solvent, pressure and temperature on the conversion and enantioselectivity were also investigated using the

[Ir(COD]Cl]2/PipPhos/phosphine/piperidine hydrochloride catalytic

system. 1 mol% of [Ir(COD)Cl]2 was used with 4 mol% of (S)-PipPhos and 10 mol% of piperidine hydrochloride as additive. The results are summarized in Table 2.7. It was observed that the rate of the reaction strongly depends on the temperature. Conversions greater than 97% were achieved in all aprotic solvents at 60 °C and 25 bar H2 pressure or higher, when 1% of iridium precursor was used. At lower temperatures the reaction is much slower (Entries 3, 6 and 14). The rate of the reaction depends on the hydrogen pressure, but importantly, the enantioselectivity stays the same for pressures above 10 bar, in keeping with earlier findings in olefin hydrogenation.48 The dependence of the rate on the hydrogen pressure confirms that oxidative addition of hydrogen is the rate- determining step in the reaction mechanism.

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

Table 2.7 Asymmetric hydrogenation of 2-methylquinoline 1a

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos 2 mol% tri-o-tolylphosphine 10 mol% piperidine hydrochloride N N solvent, H2, 24h H 1 1a

Entry Solvent H2 (bar) T (°C) Conv.b (%) eec (%) 1 toluene 100 80 97 77 2 toluene 100 60 100 83 3 toluene 100 40 24 77 4 toluene 70 80 97 78 5 toluene 70 60 98 82 6 toluene 70 40 11 79 7 toluene 50 60 100 83 8 toluene 25 60 100 83 9d toluene 25 60 30 84 10e toluene 25 60 4 nd

11 CH2Cl2 50 60 100 89

12 CH2Cl2 25 60 100 87

13 CH2Cl2 10 60 40 87

14 CH2Cl2 50 40 7 nd 15 MeOAc 50 60 100 88 16 EtOAc 50 60 100 87 17 i-PrOAc 50 60 100 87

18 ClCH2CH2Cl 50 60 100 87 19 acetone 50 60 100 80 20 i-PrOH 50 60 91 65 21 HOAc 25 60 19 28 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol tri-o-tolylphosphine, 0.1 mmol piperidine hydrochloride, 4 mL solvent, 24h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column. d 1 mmol quinoline 1, 0.005 mmol [Ir(COD)Cl2]2, 0.02 mmol (S)-PipPhos L1a, 0.01 mmol tri-o-tolylphosphine, 0.1 mmol piperidine hydrochloride.e 1 mmol quinoline 1, 0.001 mmol [Ir(COD)Cl2]2, 0.004 mmol (S)-PipPhos, 0.002 mmol tri-o- tolylphosphine, 0.1 mmol piperidine hydrochloride.

The best result (quantitative conversion and 89% ee) was achieved in dichloromethane at 50 bar of pressure and 60 °C. When only 0.5% of metal precursor was used, the reaction slowed down, however the ee stayed high (84%, Entry 9). Further decrease of the catalyst loading led to no

Chapter 2

conversion (Entry 10). In the protic solvent i-PrOH 91% conversion and 65% ee was obtained (Entry 20), while the use of acetic acid as a solvent resulted with low conversion and 28% ee (Entry 21). It was even possible to hydrogenate the hydrochloride salt of 2- methylquinoline 1 in toluene without loss in enantioselectivity, however a longer reaction time (87% in 24h) was necessary, perhaps due to the poor solubility of the substrate (Table 2.8).

Table 2.8 Asymmetric hydrogenation of 2-Me-quinoline-hydrochloride 3a

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos 2 mol% tri-o-tolylphosphine N o N HCl solvent, 60 C, 70 bar H2 H2Cl 3 40h

Entry Solvent Conversionb (%) eec (%)

1 CH2Cl2 100 71 2 EtOAc 99 83 3 toluene 100 82 aReaction conditions: 1 mmol quinoline hydrochloride 3, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol tri-o-tolylphosphine, 4 mL solvent, 40h. bConversion was determined by GC. c Enantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Hydrogenation was performed at 70 bar of hydrogen pressure in three different solvents. The best result was obtained in ethyl-acetate, giving 99% conversion and 83% ee (Entry 2). The reaction proceeds with similar selectivity as when 2-methylquinoline 1 was hydrogenated in the presence of piperidine hydrochloride.

2.6 Additives in the asymmetric hydrogenation of 2- methylquinoline

2.6.1 Salts as additives

Since the [Ir(COD]Cl]2/tri-o-tolylphosphine/PipPhos/piperidine hydrochloride catalytic system gave the best result in the asymmetric hydrogenation of 2-methylquinoline 1, further studies on the effect of addition of different salts with this system were performed (Table 2.9).

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

Table 2.9 Effect of the addition of salts on the enantioselectivity of the asymmetric hydrogenation of 2-methylquinoline 1a

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos 2 mol% tri-o-tolylphosphine 10 mol% salt N N toluene, 50 bar H2, 60 °C, 24h H 11a

Entry Salt Conversionb (%) eec (%) 1 - 100 63 2 Piperidine·HCl 100 83 3 KCl 100 83

4 Et3N·HCl 98 81 5 CsF 0 - 6 KBr 100 69 7 KI 98 30

8 KBF4 98 77 d 9 (CH3)4NI 97 74 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos, 0.02 mmol tri-o-tolylphosphine, 0.1 mmol salt, 4 mL toluene, 60 °C, 50 bar H2, 24h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.d1 mol% (CH3)4NI added.

It was observed that all tested chloride salts induced high enantioselectivities. The presence of cesium fluoride completely inhibited the reaction (Entry 5), whereas potassium bromide and tetrafluoroborate (Entries 6, 8) led to high conversions although the enantioselectivities were somewhat lower. The addition of potassium iodide also had a negative effect on the enantioselectivity (Entry 7). Since with potassium chloride irreproducible results were obtained, piperidine hydrochloride was chosen as the additive for further screenings. Under the same conditions tetramethylammonium iodide was tested as additive. Excellent conversions and high ee was obtained (74%, Entry 9). This was an interesting finding, since tetraalkylammonium salts are known to stabilize metal nanoparticles.54 To obtain more information on the relative effect of the additional ligand and the salt, all possible combinations in toluene and in dichloromethane

Chapter 2

were screened in the asymmetric hydrogenation of 2-methylquinoline 1 (Table 2.10).

Table 2.10 Effect of the addition of piperidine hydrochloride on the ee in the asymmetric hydrogenation of 1a

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos 2 mol% tri-o-tolylphosphine

N 10 mol% Piperidine hydrochloride N toluene, 50 bar H2, 60 °C, 24h H 11a

Conv.b eec Entry Solvent L* L Additive (%) (%)

1 CH2Cl2 PipPhos - - 100 18 . 2 CH2Cl2 PipPhos - Piperidine HCl 100 83

3 CH2Cl2 PipPhos P(o-tol)3 - 100 69 . 4 CH2Cl2 PipPhos P(o-tol)3 Piperidine HCl 100 89 5 toluene PipPhos - - 100 36 6 toluene PipPhos - Piperidine.HCl 100 63

7 toluene PipPhos P(o-tol)3 - 100 67 . 8 toluene PipPhos P(o-tol)3 Piperidine HCl 100 83 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol tri-o-tolylphosphine, 0.1 mmol piperidine hydrochloride, 4 mL solvent, 60 °C, 50 bar H2, 24h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

The use of 10 mol% of piperidine hydrochloride as the sole additive in dichloromethane led to an increase in enantioselectivity from 18 to 83% (Entries 1, 2). In the mixed ligand system, the addition of chloride improved the enantioselectivity from 69 to 89% (Entries 3, 4). A similar effect is observed in toluene where using piperidine hydrochloride as the sole additive led to an increase in the enantioselectivity from 36 to 63% (Entries 5, 6), whereas adding the hydrochloride salt to the mixed ligand system led to an increase in ee from 67 to 83% (Entries 7, 8). The effect of the amount of added piperidine salt on the conversion and enantioselectivity was also studied (Table 2.11). It turned out that as long as the amount of the piperidine.HCl is higher then 2 mol%, results stayed in the same range, with the best enantioselectivity still being 83% (Entry

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

1). However, we decided to always use 10 mol% because of easier handling and more precise weighing of the salt.

Table 2.11 Effect of the amount of piperidine hydrochloride on the ee in the asymmetric hydrogenation of 1a

Amount of Entry Conv.b (%) eec (%) Piperidine.HCl (%) 1 2 97 83 2 4 90 79 3 8 97 80 4 20 98 81 5 100 98 81 6 200 96 81 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol tri-o-tolylphosphine, 4 mL toluene, 60 °C, 50 bar H2, 24h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

2.6.2 Iodine as additive

Osborn reported in 1990 that iridium-iodo-hydride species are observed in the hydrogenation of imines (Figure 2.9).55

I H H H P I P P I P Ir Ir Ir Ir P I P P I P H I I I

transoid cisoid

Figure 2.9 and cisoid iodo-iridium active species observed in the hydrogenation of imines

Over the last decade it has been reported in the literature that iodine increases the enantioselectivity in the iridium catalyzed asymmetric hydrogenation.15,24-28,30,56 Presumably iodine oxidizes Ir(I) species to more catalytically active Ir(III) species. In some cases it has been shown that no conversion was obtained in the reactions without iodine.15,30,56 Zhang described recently ruthenium catalyzed hydrogenation of sulfonyl ketones, where addition of iodine improves the enantioselectivity of the reaction.57

Chapter 2

We were inspired by these findings and therefore decided to test the effect of iodine on the hydrogenation of 2-methylquinoline 1 using Ir/PipPhos catalytic system. When 10% of iodine was added to the hydrogenation of 2- methylquinoline 1 (1 mmol scale, 1% [Ir(COD)Cl]2, 60 °C, 70 bar H2) product with 79% conversion and 7% ee was obtained after 24h. A similar result was obtained when the mixture of PipPhos L1a and tri-o- tolylphosphine L12 was used (78% conversion and 10% ee). 31P NMR showed no signal of the phosphoramidite ligand after the reaction (146 ppm). A new signal appeared at 13 ppm. It is likely that iodine oxidizes the phosphoramidite ligand during the reaction and therefore no high ee can be obtained.

2.6.3 Amines as additives

Using an achiral catalyst, Crabtree and co-workers developed an iridium catalyst that was able to rapidly hydrogenate olefins.58,59 Crabtree’s catalyst (Figure 2.10), catalyzes the hydrogenation of 1-hexene 100 times faster than Wilkinson’s catalyst. It also hydrogenates tri- and even tetrasubstituted olefins; Wilkinson’s catalyst is inactive towards the latter.58 Crabtree’s catalyst also stands out in the diastereoselective, functional-group-directed hydrogenation of cyclic alkenes, consistently controlling the stereochemistry of the new stereocenter relative to the directing group better than the related rhodium catalysts.60

- PF6 PCy3 Ir N

Figure 2.10 Crabtree’s catalyst

Therefore, we decided to examine a possibility to use a mixture of a phosphoramidite ligand with an amine in the asymmetric hydrogenation of 2-methyl quinoline 1 (in situ formation of Crabtree-like catalyst). Unfortunately, triethylamine in combination with PipPhos L1a led to poor

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

conversion and 28% ee, while use of pyridine with PipPhos L1a gave 44% of racemic product.

2.6.4 Tetrahydroquinoline as additive

It was also examined whether the product of the hydrogenation also behaves as a ligand coordinating to iridium possibly even stronger than the phosphoramidite and in this way causes autocatalytic reaction (Scheme 2.7). In this experiment 2 mol% of the enantioenriched tetrahydroquinoline (80% ee) was added to the reaction mixture. The result of the hydrogenation did not improve, as full conversion overnight and 81% ee was obtained (83% ee is obtained without addition of tetrahydroquinoline).

1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos

N N 2 mol% H N H 11a, 81% ee 10 mol% Piperidine hydrochloride toluene, 50 bar H2, 60 °C, 24h

Scheme 2.7 Asymmetric hydrogenation of 2-methylquinoline 1 with addition of the enantioenriched product of the hydrogenation

2.7 Synthesis of substrates

In order to test the scope of the hydrogenation, several 2-substituted quinoline substrates were synthesized (Scheme 2.8). Reactions were performed starting from 2-methylquinoline 1, by deprotonation with butyllithium and subsequent trapping with the alkyl iodide. Products were isolated in 63-88% yield after purification, with the exception of benzylquinoline that was isolated in only 23% yield.

Chapter 2

1 n-BuLi, R I n-BuLi, R2I THF, -60 oC R1 o R1 N N THF, -60 C N R2

1 4, R1 = Me 5, R1 = Me, R2= Me 6, R1 = i-Pr 7, R1 = Bu 8, R1 = Pentyl 9, R1 = Ph

Scheme 2.8 Synthesis of 2-substituted quinolines

2.8 Scope

Under the optimized conditions, a variety of substituted quinolines was hydrogenated using the [Ir(COD]Cl]2/PipPhos/phosphine/piperidine hydrochloride catalytic system in toluene or dichloromethane. Six different achiral phosphines were tested on the selected substrates (Figure 2.11). The phosphines applied were the ones giving the best result in the hydrogenation of 2-methylquinoline 1. The best results are summarized in Table 2.12

F F F FF F

P F P F P F F F F

F F F

L12 L15 L16

O P P P O O

L17 L22 L23

Figure 2.11 Phosphines used in the testing of the scope of the reaction

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

All quinolines studied were hydrogenated with high conversions and enantioselectivities. The best results were accomplished with 2-methyl and i-Pr substituted quinoline (1, 5, 89% ee, Entries 1, 3), while the lowest enantioselectivity was obtained with benzyl-quinoline 9 (76% ee, Entry 7). Introduction of electron donating or withdrawing substituents in the 6- position did not affect the enantioselectivity significantly (Entries 9-11), whilst introduction of longer alkyl chains resulted in a small drop of ee (Entries 5 and 6).

Table 2.12 Asymmetric hydrogenation of 2- and 2,6-substituted quinolines using (S)-PipPhos and achiral phosphinesa

R2 R2 1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos 2 mol% Achiral phosphine N R1 N R1 10 mol% piperidine hydrochloride H o solvent, 60 C, 50 bar H2, 24h 1, 4-13 1a, 4a-13a

Conv.b eec Entry Solvent R1/R2 Phosphine Config.d (%) (%)

1 CH2Cl2 Me/H (1a) L12 100 89 (S)

2 CH2Cl2 Et/ H (4a) L12 100 88 (S) 3 toluene i-Pr/H (5a) L12 100 89 (R) 4 toluene i-Bu/H (6a) L12 98 86 nd

5 CH2Cl2 n-Pentyl/H (7a) L12 100 83 (S)

6 CH2Cl2 n-Hexyl/H (8a) L12 100 78 nd

7 CH2Cl2 Benzyl/H (9a) L12 100 76 nd 8 toluene Ph/H (10a) L16 88 88 (S)

9 CH2Cl2 Me/Me (11a) L12 100 85 (S)

10 CH2Cl2 Me/MeO (12a) L12 73 82 (S)

11 CH2Cl2 Me/F (13a) L24 100 88 (S) aReaction conditions: 1 mmol quinoline, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol achiral phosphine, 0.1 mmol piperidine hydrochloride, 4 mL solvent, 60 °C, 50 bar H2, 24h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by GC and HPLC. dAbsolute configuration of the products are assigned by measuring optical rotation and comparing it with literature data.

Chapter 2

2.9 Kinetics

In order to examine the stability of the catalyst during the reaction, the conversion and enantioselectivity were monitored over time (Figure 2.12). An increase of the enantioselectivity over 24h was observed. The low ee at the beginning of the reaction may be explained by the slow formation of the catalytically active species during the first hour (10% of conversion). This is also confirmed by the induction time that is observed in the hydrogenation (Figure 2.12).

Enantioselectivity over time

100 80 60 40 e.e. [%] e.e. 20 0 0 102030405060 Time [min]

Conversion over time

10 8 6 4 2 Conversion [%] Conversion 0 0 102030405060 Time [min]

aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl]2, 0.04 mmol (S)-PipPhos L1a, 0.02 mmol tri-o-tolylphosphine, 0.1 mmol piperidine hydrochloride, 4 mL toluene, 24 h. bConversion was determined by GC and enantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Figure 2.12 Rate and enantioselectivity as a function of time in the asymmetric hydrogenation of 2-methylquinoline 1a

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

To overcome this drawback the iridium precursor was pre-stirred in the presence of the ligands and piperidine hydrochloride under the reaction conditions during 1h, followed by the addition of the substrate. Unfortunately, this did not improve the enantioselectivity or change the conversion of the reaction.

2.10 Mechanistic discussion

In order to gain insight into the mechanism of the reaction, high pressure 31P NMR experiments were performed on the asymmetric hydrogenation of 1 using a mixture of PipPhos L1a and achiral phosphine as ligands (2:1) at 60 °C and 25 bar of H2 pressure. Surprisingly, no mixed ligand iridium species were observed when tri-o-tolylphosphine L12 was used as achiral phosphine. A large tri-ortho-tolylphosphine absorption was visible in the 31P-NMR prior to and throughout the hydrogenation reaction. In the case of triphenylphosphine L11 and PipPhos, mixed ligand species were observed, however, this catalyst gave only 2% conversion in the hydrogenation of 1. This result suggests that o-substituted achiral phosphines are perhaps sterically too demanding for coordination to the iridium together with PipPhos L1a, making it impossible to form a mixed ligand complex. In addition, no difference was observed between the 31P NMR spectra of the reactions with and without added piperidine hydrochloride. Despite the significant improvement of the selectivity, the role of the achiral phosphine and chloride salt has not been elucidated until now. However, it is known that iridium catalysts tend to decompose to inactive hydride-bridged clusters in the absence of substrate.61 If the substrate is a weak ligand, this decomposition can be competitive with hydrogenation. It is conceivable that the chloride salt prevents the formation of poorly active iridium clusters. The role of the added phosphine ligand is even more obscure. It may just serve as a scavenger of traces of oxygen. It is also possible that mixed ligand species are formed in one or more intermediates of the catalytic cycle but not in the resting state, thus making them unobservable. Mass spectral studies into the nature of the catalyst were hampered by the fact that these catalysts are neutral species and thus lead to feeble signals in ES-MS. To try to solve this problem an analogous catalyst which

Chapter 2

carries a positive charge in the ligand was developed. This approach has been used with great success by Chen in his MS study of metathesis catalysts.62 Thus, quaternized ligand L31 was prepared (Scheme 2.9). The synthesis starts with Boc-protection of 1-Methyl-piperazine 14, followed by methylation with methyl triflate in dichloromethane at rt, and deprotection with triflic acid. Prepared quaternized amine 17 was isolated in 76% yield.

(S)-BINOL was refluxed in neat PCl3 in order to obtain chlorophosphite 18. The solution of prepared chlorophosphite was stirred with 17 in the presence of triethylamine in THF to give the phosphoramidite L31 in overall 27% yield.

Boc2O, K2CO3 MeOTf HN N Boc-N N dioxane, rt DCM, 1h, rt 14 15

TfO TfO HOTf Boc-N N HN N DCM, rt 16 17

OH PCl3 O 17 P Cl OH reflux O Et3N, THF, rt

O TfO P N N O

L31

Scheme 2.9 Preparation of quaternized phosphoramidite ligand 34

Unfortunately, the results in the iridium-catalyzed hydrogenation of 2- methylquinoline 1 with ligand L31 were dramatically different from the results obtained with PipPhos L1a (Table 2.13). Thus, this ligand cannot

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

be assumed to be a good model compound for PipPhos L1a. In spite of this, an ESI-MS analysis of the hydrogenation reactions of 2- methylquinoline was done. In all MS very minor peaks of iridium complexes were observed, none of which could be associated with L31. In addition, the spectra showed only very small peaks of the molecular ion of L31. No satisfactory explanation for these results was obtained. One possibility is that the majority of the iridium is present in the form of nanoparticles, stabilized by L31.

Table 2.13 Asymmetric hydrogenation of 2-methylquinoline 1 using quaternized ligand L31a

1 mol% [Ir(COD)Cl]2, L1a, L31 N 10 mol% piperidine hydrochloride N tri-o-tolylphosphine H toluene, 70 bar H 60 °C, 24h 11a2,

Entry L31 / L1a / P(o-tol)3 / Cl- / Ir Conv.b (%) eec (%) 1 1 / 1 / 0 / 0 / 1 31 3 2 1 / 1 / 1 / 0 / 1 0 - 3 1 / 1 / 1 / 5 / 1 4 44 4 1 / 1 / 0 / 5 / 1 19 12 5 2 / 0 / 0 / 0 / 1 41 6 6 2 / 0 / 1 / 0 / 1 6 7 7 2 / 0 / 1 / 5 / 1 2 18 aReaction conditions: 1 mmol quinoline 1, 0.01 mmol [Ir(COD)Cl]2, 4 mL of dichloromethane, 60 °C, 25 bar H2, 2h. bConversion was determined by GC. cEnantiomeric excess was determined by GC analysis with Chiralsil DEX CB column.

Although low enantioselectivities were obtained in the asymmetric hydrogenation of 2-methylquinoline 1 using quaternized ligand L31, it was observed that using 2 equivalents of L31 per iridium atom, hydrogenation is much faster than with PipPhos, giving 41% conversion within 2h (Entry 5). Moreover, using a mixture of L31 and PipPhos (1:1), the reaction is still significantly faster (Entry 1).

Chapter 2

2.11 Conclusion

Various phosphoramidite ligands were tested in the catalytic asymmetric hydrogenation of quinolines. The best result was obtained using monodentate phosphoramidites derived from cyclic amines. When achiral ligands were screened in combination with PipPhos L1a in the mixed ligand approach, highest activity was obtained using bulky phosphines and phosphines with substituent in ortho position (up to 89%).

The combination [Ir(COD)Cl]2/PipPhos/tri-o-tolylphosphine/piperidine hydrochloride is a good catalyst for the asymmetric hydrogenation of 2- and 2,6-substituted quinolines. Full conversions and enantioselectivities up to 89% were obtained at 60 °C and 50 bar of hydrogen pressure within 24h. We still don’t have an answer about the role of a chloride salt. It is plausible that the chloride salt prevents the formation of poorly active iridium clusters. Although we did not observe mixed ligand species, it is possible that they are formed in one or more intermediates of the catalytic cycle but not in the resting state, thus making them unobservable.

2.12 Experimental section

General remarks

All solvents were reagent grade and were dried and distilled, if necessary, following standard procedures. Reagents were purchased from Aldrich, Acros, Merck or Fluka and used as received. Metal precursor

[Ir(COD)Cl]2 was purchased from Strem. High throughput experiment was performed in a Premex 96 autoclave. NMR spectra were obtained on Varian Gemini-200 and Varian AMX400 spectrometers. GC analysis was carried out on an HP6890 using a flame ionization detector, while HPLC analysis was performed on Shimadzu LC- 10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector. The enantiomeric excess was determined by HPLC with chiral columns (Chiralcel AS, AS-H, OJ-H, OD-H,) or by GC with Chiralsil DEX CB, in comparison with racemic products. High resolution mass spectra were recorded on an AEI-MS-902 mass spectrometer. Optical rotations

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). The catalysts were prepared in situ. Reaction vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. When the metal precursor and the ligand were pre-stirred over 3h under nitrogen, same result was obtained in the hydrogenation reaction. Ligands L1a,38 L1b,38 L1c,38 L1d,38 L1e,63 L1f,63 L1g,63 L1h,64 L1i,63 L1j,38 L1k,38 L1l,65 L2a,63 L2f,63 L3,66 L5,38 L6,63 L7,63 L8,67 L9,68 L1069 were prepared according to the literature procedure. Ligand L4 is commercially available.

Preparation of 2-quinolines

A solution of 2-methylquinoline (3.78 mL, 27.9 mmol) in 50 mL of dry THF was cooled to 60 oC. n-Butyl-lithium (11.2 mL, 2.5 M in hexane, 27.9 mmol) was added dropwise. The reaction mixture was stirred at 60 oC over 1.5h. The alkyl-iodide (27.9 mmol) was added dropwise over 5 min and the reaction mixture stirred overnight at room temperature. The reaction was quenched with water, and the product was extracted with ethyl acetate (2x100 mL). The organic layer was dried over sodium sulphate and filtered. The solvent was removed in vacuo and the product purified by column chromatography on silica.

2-ethyl-quinoline (4)

1 Yellow liquid, 88% yield; H NMR (400 MHz, CDCl3) 1.38 (t, J = 7.6 Hz, 3H), 2.99 (q, J = 7.6 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.42 – 7.46 (m, 1H), 7.63 – 7.67 (m, 1H), 7.71 – 7.73 (m, 1H), 8.00– 8.05 (m, 2H) ppm; 13C NMR

(100 MHz, CDCl3) 14.9, 33.2, 121.7, 126.5, 127.6, 128.3, 129.7, 130.2, 137.1, 148.8, 164.8 ppm.

Chapter 2

2-i-propyl-quinoline (5)70

1 Yellow liquid, 81% yield; H NMR (400 MHz, CDCl3) 1.39 (d, J = 7.0 Hz, 6H), 3.27 (heptet, J = 6.9 Hz, 1H), 7.29 – 7.31 (m, 1H), 7.43 – 7.47 (m, 1H), 7.64 – 7.68 (m, 1H), 7.72 – 7.75 (m, 1H), 8.03 – 8.08 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 23.4, 38.2, 120.0, 126.5, 127.8, 128.3, 129.9, 130.1, 137.2, 148.6, 168.5 ppm.

2-i-butyl-quinoline (6)71

1 Yellow liquid, 70% yield; H NMR (400 MHz, CDCl3) 0.97 (d, J = 6.6 Hz, 6H), 2.21 (nonet, J = 6.7 Hz, 1H), 2.84 (d, J = 7.37 Hz, 2H), 7.22 – 7.24, (m, 1H), 7.43 – 7.47 (m, 1H), 7.64 – 7.68 (m, 1H), 7.74 – 7.76 (m, 1H), 8.01 – 13 8.07 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 23.5, 30.3, 49.3, 122.9, 126.5, 127.6, 128.4, 129.8, 130.2, 136.8, 148.9, 163.1 ppm.

2-n-pentyl-quinoline (7)70

1 Yellow liquid, 81% yield; H NMR (400 MHz, CDCl3) 0.90 (t, J = 7.0 Hz, 3H), 1.33 – 1.44 (m, 4H), 1.78 – 1.85 (m, 2H), 2.94 – 2.98 (m, 2H), 7.27 – 7.29 (m, 1H), 7.44 – 7.48 (m, 1H), 7.64 – 7.67 (m, 1H), 7.74 – 7.76 (m, 1H), 8.03 13 – 8.06 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 15.0, 23.5, 30.7, 32.7, 40.3, 122.3, 126.5, 127.6, 128.4, 129.8, 130.2, 137.1, 148.9, 164.1 ppm.

2-n-hexyl-quinoline (8)71

1 Yellow liquid, 63% yield; H NMR (400 MHz, CDCl3) 0.88 (t, J = 7.0 Hz, 3H), 1.26 – 1.45 (m, 6H), 1.77 – 1.84 (m, 2H), 2.94 – 2.98 (m, 2H), 7.27 – 7.29 (m, 1H), 7.44 – 7.48 (m, 1H), 7.65 – 7.69 (m, 1H), 7.74 – 7.76 (m, 1H), 8.03

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

13 – 8.06 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 15.0, 23.5, 30.2, 31.0, 32.7, 40.3, 122.3, 126.5, 127.6, 128.4, 129.8, 130.2, 137.1, 148.9, 164.1 ppm.

2-benzylquinoline (9)72

1 Yellow liquid, 23% yield; H NMR (400 MHz, CDCl3) 4.34 (s, 2H), 7.22 – 7.26 (m, 2H), 7.29 – 7.33 (m, 4H), 7.50 (t, J = 7.98 Hz, 1H), 7.71 (t, J = 8.44 Hz, 1H), 7.76 (d, J = 8.08 Hz, 1H), 8.02 (d, J = 8.46 Hz, 1H), 8.11 (d, J 13 = 8.50 Hz, 1H) ppm, C NMR (100 MHz, CDCl3) 46.5, 122.5, 127.0, 127.5, 127.7, 128.5, 129.6, 129.9, 130.2, 130.5, 137.5, 140.1, 148.7, 162.2 ppm.

General Experimental Procedure for Hydrogenation

A mixture of [Ir(COD)Cl]2 (6.72 mg, 0.01 mmol), (S)-PipPhos (15.98 mg, 0.04 mmol), achiral phosphine (0.02 mmol), substrate (1 mmol) and piperidine hydrochloride (12.16 mg, 0.1 mmol) were dissolved in 4 mL of solvent in a glass vial. The vial was placed in a stainless steel autoclave. Hydrogenation was performed at 60 °C under 50 bar of hydrogen pressure for 24h. After cooling the autoclave, hydrogen pressure was carefully released. The reaction mixture was flushed over a short silica column. Solvent was removed in vacuo and conversion was determined by GC or NMR. The crude product was purified by chromatography (Silica gel, heptane/EtOAc = 4/1).

(S)-2-Methyl-1,2,3,4-tetrahydroquinoline (1a)27

N H

1 94% yield, 89% ee, [α]D = -84.3 (c 1.19, CHCl3); H NMR (200 MHz, CDCl3) 1.31 (d, J = 6.4 Hz, 3H), 1.66 – 1.80 (m, 1H), 1.97 – 2.08 (m, 1H), 2.85 – 2.97 (m, 2H), 3.45 – 3.54 (m, 1H), 3.73 (br, 1H), 6.55 – 6.70 (m, 1H), 6.70 – 13 6.77 (m, 1H), 7.06 – 7.12 (m, 2H) ppm; C NMR (50 MHz, CDCl3) 22.5, 26.5, 30.0, 47.0, 113.9, 116.8, 121.0, 127.0, 129.2, 144.7 ppm; HRMS + Calcd. for C10H13N (M ) 147.1048, found 147.1051; GC Chiralsil DEX CB

Chapter 2

(initial temp. 95 °C for 15 min, then 5 °C/min to 180 °C, 180 °C for 10 min), t1 = 25.9 min, t2 = 26.0 min.

(S)-2-Ethyl-1,2,3,4-tetrahydroquinoline (4a)27

N H

1 88% ee, [α]D = -76.9 (c 1.01, CHCl3); H NMR (200 MHz, CDCl3) 1.00 (t, J = 7.6 Hz, 3H), 1.48 – 1.70 (m, 3H), 1.93 – 2.06 (m, 1H), 2.67 – 2.92 (m, 2H), 3.12 – 3.25 (m, 1H), 3.94 (br, 1H), 6.49 – 6.66 (m, 2H), 6.94 – 7.01 (m, 2H) 13 ppm; C NMR (50 MHz, CDCl3) 10.0, 26.4, 27.5, 29.4, 53.0, 113.9, 116.8, + 121.3, 126.7, 129.2, 144.7 ppm; HRMS Calcd. for C11H15N (M ) 161.1204, found 161.1213; HPLC (OJ-H, eluent:heptane/i-PrOH = 95/5, detector:

254 nm, flow rate: 0.5 mL/min), t1 = 17.6 min, t2 = 19.1 min.

(R)-2-Isopropyl-1,2,3,4-tetrahydroquinoline (5a)27

N H

1 89% ee, [α]D = -54.1 (c 0.84, CHCl3); H NMR (200 MHz, CDCl3) 1.03 (d, J = 4.9 Hz, 3H), 1.07 (d, J = 4.9 Hz, 3H), 1.67 – 1.82 (m, 2H), 1.91 – 2.02 (m, 1H), 2.79 – 2.88 (m, 2H), 3.05 – 3.14 (m, 1H), 3.82 (br, 1H), 6.52 – 6.69 (m, 13 2H), 6.99 – 7.06 (m, 2H) ppm; C NMR (50 MHz, CDCl3) 18.2, 18.5, 24.4, 26.6, 32.4, 57.2, 113.9, 116.6, 121.3, 126.6, 129.1, 144.9 ppm; HRMS + Calcd. for C12H17N (M ) 175.1361, found 175.1363; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 254 nm, flow rate: 0.5 mL/min),

t1 = 14.7 min, t2 = 17.4 min.

(-)-2-Isobutyl-1,2,3,4-tetrahydroquinoline (6a)27

∗ N H

1 86% ee, [α]D = -73.4 (c 1.23, CHCl3); H NMR (200 MHz, CDCl3) 1.01 (d, J = 6.4 Hz, 6H), 1.38 – 2.04 (m, 5H), 2.79 – 2.90 (m, 2H), 3.35 – 3.41 (m, 1H), 3.8 (br, 1H), 6.50 – 6.62 (m, 1H), 6.63 – 6.70 (m, 1H), 6.99 – 7.06 (m, 2H) 13 ppm; C NMR (50 MHz, CDCl3) 22.4, 23.1, 24.4, 26.4, 28.5, 45.8, 49.1,

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

114.0, 116.8, 121.3, 126.6, 129.2, 144.6 ppm; HRMS Calcd. for C13H19N (M+) 189.1517, found 189.1519; HPLC (OJ-H, eluent:heptane/i-PrOH =

95/5, detector: 254 nm, flow rate: 0.5 mL/min), t1 = 12.8 min, t2 = 16.9 min.

(S)-2-Pentyl-1,2,3,4-tetrahydroquinoline (7a)27

N H

1 83% ee, [α]D = -68.9 (c 1.08, CHCl3); H NMR (200 MHz, CDCl3) 0.97 (t, J = 6.8 Hz, 3H), 1.39 – 1.75 (m, 9H), 1.95 – 2.08 (m, 1H), 2.78 – 2.88 (m, 2H), 3.22 – 3.33 (m, 1H), 3.80 (br, 1H), 6.50 – 6.61 (m, 1H), 6.61 – 6.69 (m, 1H), 13 6.98 – 7.05 (m, 2H) ppm; C NMR (50 MHz, CDCl3) 14.0, 22.6, 25.3, 26.4, 28.0, 31.9, 36.6, 51.5, 113.9, 116.8, 121.3, 126.6, 129.2, 144.7 ppm; + HRMS Calcd. for C14H21N (M ) 203.1674, found 203.1682; HPLC (AS, eluent:100% heptane, detector: 254 nm, flow rate: 1 mL/min) t1 = 6.9 min,

t2 = 11.0 min.

(-)-2-Hexyl-1,2,3,4-tetrahydroquinoline (8a)

∗ N H

1 78% ee, [α]D = -56.6 (c 0.99, CHCl3); H NMR (200 MHz, CDCl3) 0.96 (t, J = 6.6 Hz, 3H), 1.36 – 1.74 (m, 11H), 1.95 – 2.05 (m, 1H), 2.78 – 2.88 (m, 2H), 3.23 – 3.31 (m, 1H), 3.80 (br, 1H), 6.50 – 6.61 (m, 1H), 6.61 – 6.68 (m, 1H), 13 6.97 – 7.05 (m, 2H) ppm; C NMR (50 MHz, CDCl3) 14.1, 22.6, 25.6, 26.4, 28.0, 29.4, 31.8, 36.7, 51.5, 113.9, 116.8, 121.3, 126.6, 129.2, 144.7 + ppm; HRMS Calcd for C15H23N (M ) 217.1830, found 217.1830; HPLC (OD, eluent:heptane/i-PrOH = 99/1, detector: 254 nm, flow rate: 0.5 mL/min),

t1 = 12.1 min, t2 = 13.4 min.

Chapter 2

(-)-2-Benzyl-1,2,3,4-tetrahydroquinoline (9a)

∗ N H

1 76% ee, [α]D = -99.2 (c 1.01, CHCl3); H NMR (200 MHz, CDCl3) 1.75 – 1.90 (m, 1H), 2.04 – 2.17 (m, 1H), 2.73 – 2.99 (m, 4H), 3.52 – 3.65 (m, 1H), 3.81 (br, 1H), 6.46 – 6.66 (m, 1H), 6.66 – 6.74 (m, 1H), 7.00 – 7.07 (m, 2H), 7.31 13 – 7.48 (m, 5H) ppm; C NMR (50 MHz, CDCl3) 26.1, 28.1, 42.9, 52.5, 114.1, 117.1, 121.1, 126.4, 126.6, 128.5, 129.2, 138.4, 144.3 ppm; HRMS + Calcd for C16H17N (M ) 223.1361, found 223.1361; HPLC (OJ-H, eluent:heptane/i-PrOH = 95/5, detector: 254 nm, flow rate: 0.5 mL/min),

t1 = 23.5 min, t2 = 25.6 min.

(S)-2-Phenyl-1,2,3,4-tetrahydroquinoline (10a)27

N H

1 88% ee, [α]D = +69.9 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) 2.04 – 2.16 (m, 2H), 2.72 – 2.97 (m, 2H), 4.06 (br, 1H), 4.45 (dd, J = 3.6 Hz, 1H), 6.54 – 6.65 (m, 1H), 6.65 – 6.72 (m, 1H), 7.02 – 7.09 (m, 2H), 7.31 – 7.45 (m, 5H) 13 ppm; C NMR (50 MHz, CDCl3) 26.3, 30.9, 56.29, 113.9, 117.1, 120.8, 126.5, 126.9, 127.4, 128.5, 129.3, 144.7, 144.7 ppm; HRMS Calcd. for + C15H15N (M ) 209.1204, found 209.1202; HPLC (AS-H, eluent:heptane/i-

PrOH = 95/5, detector: 254 nm, flow rate: 0.5 mL/min), t1 = 9.0 min, t2 = 13.9 min.

(S)-2,6-Dimethyl-1,2,3,4-tetrahydroquinoline (11a)27

N H

1 88% ee, [α]D = -87.2 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3) 1.21 (d, J = 6.2 Hz, 3H), 1.49 – 1.69 (m, 1H), 1.89 – 1.99 (m, 1H), 2.22 (s, 3H), 2.63 – 2.89 (m, 2H), 3.29 – 3.45 (m, 1H), 3.56 (br, 1H), 6.40 – 6.44 (m, 1H), 6.78 – 13 6.81 (m, 2H) ppm; C NMR (50 MHz, CDCl3) 20.3, 22.5, 26.5, 30.3, 47.2,

114.2, 121.1, 126.1, 127.1, 129.7, 142.4 ppm; HRMS Calcd. for C11H15N

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

(M+) 161.1204, found 161.1213; GC Chiralsil DEX CB (initial temp. 95 °C for 15 min, then 5 °C/min to 180 °C, 180 °C for 10 min), t1 = 27.6 min, t2 = 27.9 min.

(S)-6-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (12a)27 O

N H

1 82% ee, [α]D = -80.4 (c 1.01, CHCl3); H NMR (200 MHz, CDCl3) 1.20 (d, J = 6.0 Hz, 3H), 1.50 – 1.67 (m, 1H), 1.86 – 1.98 (m, 1H), 2.64 – 2.86 (m, 2H), 3.25 – 3.38 (m, 1H), 3.73 (s, 3H), 6.43 – 6.57 (m, 1H) 6.57 – 6.63 (m, 2H) 13 ppm; C NMR (50 MHz, CDCl3) 22.5, 26.8, 30.2, 47.4, 55.7, 112.7, 114.5, + 115.2, 122.4, 138.8, 151.7 ppm; HRMS Calcd. for C11H15NO (M ) 177.1154, found 177.1161; GC Chiralsil DEX CB (initial temp. 95 °C for

15 min, then 5 °C/min to 180 °C, 180 °C for 10 min), t1 = 31.5 min, t2 = 31.7 min.

(S)-6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (13a)27

N H

1 88% ee, [α]D = -37.3 (c 0.53, CHCl3); H NMR (200 MHz, CDCl3) 1.21 (d, J = 6.4 Hz, 3H), 1.46 – 1.66 (m, 1H), 1.86 – 1.98 (m, 1H), 2.63 – 2.92 (m, 2H), 3.27 – 3.43 (m, 1H), 3.54 (br, 1H), 6.36 – 6.43 (m, 1H), 6.63 – 6.72 (m, 2H) 13 ppm; C NMR (50 MHz, CDCl3) 22.4, 26.6, 29.8, 47.2, 112.9, 113.2, + 114.6, 114.7, 115.1, 115.4 ppm; HRMS Calcd. for C10H12FN (M ) 165.0954, found 165.0950; GC Chiralsil DEX CB (initial temp. 95 °C for 15 min, then

5 °C/min to 180 °C, 180 °C for 10 min), t1 = 26.9 min, t2 = 27.1 min.

2,2-Dimethyl-propionic acid 4-methyl-piperazin-1-yl ester (15)

Boc N N

To a solution of 1-methyl-piperazine (5 g, 50 mmol) in dioxane (100 mL) di- tert-butyl dicarbonate (11.98 g, 55 mmol) and potassium carbonate (7.59 g, 55 mmol) were added and reaction mixture was stirred overnight at rt. The resulting mixture was washed with water (100 mL) and the water layer

Chapter 2

was extracted with ethyl acetate (100 mL). The combined organic layers were dried on anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo, and 15 was isolated as yellow oil in 92% yield (9.1 g). 1 H NMR (400 MHz, CDCl3) 1.32 (s, 9H), 2.15 (s, 3H), 2.20 (t, J = 3.8 Hz, 13 4H), 3.29 (t, J = 1.3 Hz, 4H) ppm; C NMR (100 MHz, CDCl3) 28.5, 46.3, + 54.9, 79.6, 154.8 ppm; HRMS Calcd. for C6H15N2 (M ) 200.1525, found 200.1518.

Trifluoro-methanesulfonate 1,1-dimethyl-piperazin-1-ium (17)

TfO

HN N

To a solution of 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (7.1g, 35.4 mmol) in dry dichloromethane (50 mL), methyl triflate was added dropwise (4 mL, 35.4 mmol). The reaction mixture was stirred at rt over 1h, followed by addition of triflic acid (4.97 mL, 56.2 mmol). After 1h, the solvent was decanted and 50 mL of methanol was added. After stirring for 15 min the precipitated white solid was filtered off and dried. Quaternized amine 17 was isolated in 82% yield (7.63 g). 1 H NMR (400 MHz, D2O) 3.20 (s, 6H), 3.59 (br, 4H), 3.64 (br, 4H), 4.63 (br, 13 19 1H) ppm; C NMR (100 MHz, D2O) 38.0, 52.2, 58.2, 123.0 ppm; F (376 + - MHz, D2O) -79.3 ppm; HRMS Calcd. for C6H15N2 (M -OTf ) 115.12298, found 115.12302.

(S)-Trifluoro-methanesulfonate 4-(3,5-dioxa-4-phospha-cyclohepta[2,1- a;3,4-a']dinaphthalen-4-yl)-1,1-dimethyl-piperazin-1-ium (L31)

TfO O P N N O

In a Schlenk tube (S)-BINOL (1.5 g, 5.24 mmol) was refluxed in neat phosphorus trichloride (5 mL) overnight. After cooling the reaction mixture, the excess of phosphorus trichloride was distilled off and the resulting phosphorus chloride 18 was washed with dry toluene (3 x 5 mL), and dissolved in dry THF (5 mL). In another Schlenk tube quaternized

Asymmetric hydrogenation of 2- and 2,6-substituted quinolines

amine 17 (1.38 g, 5.24 mmol) and triethylamine (726 µL, 5.24 mmol) were dissolved in 5 mL of THF. The solution of 18 was then added to the solution of 17 and triethylamine at 0 °C. After 10 min, the reaction mixture was warmed to rt and stirred overnight. The precipitated crystals were filtered off and ether was added (10 mL). Newly formed white precipitate was filtered off and washed with dichloromethane. Pure phosphoramidite L31 was isolated in 36% yield (1.09 g). 1 [α]D = -75.3 (c 1.0, EtOH); H NMR (400 MHz, CDCl3) 3.18 – 3.28 (m, 14H), 13 7.25 – 7.49 (m, 8H), 7.86 – 7.96 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 38.1, 38.3, 51.8, 62.4 (d, J = 3.8 Hz), 121.0, 121.4, 122.7, 123.6, 125.2, 126.4, 126.6, 126.7, 126.8, 128.4, 128.6, 130.7, 130.9, 131.0, 131.5, 132.3, 132.6, 148.4 ppm; 31P NMR (162 MHz) 142.9 ppm; 19F NMR (376 + - MHz, CDCl3) -78.9 ppm. HRMS Calcd. for C26H26O2N2P (M -OTf ) 429.17264, found 429.17215.

2.13 References

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Chapter 2

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Chapter 2

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(56) a) Wang, X.-B.; Wang, D.-W.; Lu, S.-M.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron: Asymmetry 2009, 20, 1040; b) Moessner, C.; Bolm, C. Angew. Chem. Int. Ed. 2005, 44, 7564. (57) Wan, X.; Meng, Q.; Zhang, H.; Sun, Y.; Fan, W.; Zhang, Z. Org. Lett. 2007, 9, 5613. (58) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331. (59) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977, 141, 205. (60) a) Bueno, J. M.; Coterón, J. M.; Chiara, J. L.; Fernández-Mayoralas, A.; Fiandor, J. M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379; b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655; c) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072. (61) Crabtree, R. H. Platinum Met. Rev. 1978, 22, 126. (62) Adlhart, C.; Hinderling, C.; Baumann, H.; Chen, P. J. Am. Chem. Soc. 2000, 122, 8204. (63) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (64) Ljungdahl, N.; Parera Pera, N.; Andersson, K. H. O.; Kann, N. Synlett 2008, 3, 394. (65) Peña, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552. (66) Hoen, R., PhD Thesis, Groningen 2006, Chapter 5, 138. (67) Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries, J. G. Angew. Chem. Int. Ed. 2007, 46, 1497. (68) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.; Levęque, J.-M.; Mazé, F.; Rosset, S. Eur. J. Org. Chem. 2000, 2000, 4011. (69) Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433. (70) Cho, C. S.; Kim, B. T.; Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetrahedron 2003, 59, 7997. (71) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332. (72) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171.

Chapter 3 Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

In this chapter the asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines catalyzed by iridium complexes of BINOL-derived phosphoramidites is described. Enantioselectivities of up to 96% were obtained.

Part of this chapter has been published:

N. Mršić, T. Jerphagnon, A. J. Minnaard, B. L. Feringa, J. G. de Vries, Adv. Synth. Catal. 2009, 351, 2549.

Chapter 3

3.1 Introduction

Enantiopure heterocyclic compounds represent valuable synthons in the synthesis of numerous natural products as well as pharmaceuticals. Numerous chiral heterocyclic compounds, including quinoxalines are prominent among various classes of physiologically active compounds.1-9

R3 R2 O R4 N O R1 N CN

5 R N N 2 R N NH2 N O O R1

1 2 2, R1=Cl, R2=H 1, R = COCH3, R = C6H7 R3 = H, R4 = Cl, R5 = H

O NH HN * N O

Figure 3.1 Quinoxaline derivatives with biological activity

A number of quinoxaline derivatives show antiallergic properties.8 For instance, 1,4-dihydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones 1 are potent antiallergic agents as judged by their ability to inhibit antigen- induced histamine release (Figure 3.1). Several quinoxaline derivatives possess anticancer activities. Hypoxic cells, which are a common feature of solid tumors, but not of normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. Quinoxaline 1,4-di-N- oxides are shown to be potent hypoxia-selective therapeutic agents. The 3- Amino-7-chloro-2-quinoxalinecarbonitrile-1,4-di-N-oxide 2 has been shown to be an efficient and selective cytotoxin for hypoxic cells.3

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

A number of quinoxalines show antidiabetic properties.7 Imidazolidinedione 3 is an inhibitor of aldose reductase and it is expected to offer a therapeutical access to the late complications of diabetes mellitus. In addition, some of the quinoxaline derivatives possess antifungal,2 angiotensin II receptor antagonistic6 as well as benzodiazepine receptor binding5 and adenosine-binding properties.4 Substituted tetrahydroquinoxalines are of interest as models for tetrahydrofolic acid9 as well as a potent CETP (cholesteryl ester transfer protein) inhibitors for the treatment of atherosclerosis and obesity.1

O OH

O O 2 OH 1 R O N R n H H 4 N O R N N N H 3 5 R H N N N R N 2 H H O O

Tetrahydrofolic acid CETP inhibitors

Figure 3.2 Tetrahydrofolic acid and CETP inhibitors

Tetrahydrofolic acid (Figure 3.2) is a coenzyme in several reactions, including the metabolism of amino acids and nucleic acids.10 It acts as a donor of a one-carbon unit. It gets this carbon by sequestering formaldehyde produced in other processes. A shortage in tetrahydrofolic acid can cause megaloblastic anemia. New approach to chiral tetrahydroquinoxalines comprising catalytic asymmetric hydrogenation would be highly useful. The first asymmetric hydrogenation of 2-methylquinoxaline 4 was reported in 1987 using Rh- DIOP catalyst, however, only 3% ee was reached (Scheme 3.1).11 In 1998 however, Bianchini reported an iridium-catalyzed asymmetric hydrogenation of the same substrate with high enantioselectivity using an ortho-metalated bidentate dihydride complex (up to 90% ee).12

Chapter 3

H N N cat. H2 Solvent ∗ N N H 44a

H O O N P Ir P H Ph2P PPh2 H DIOP

up to 3% ee up to 90% ee

Matsuura et al., 1987 Bianchini et al., 1998

O PXyl2 PPh2 n PXyl2 O PPh2

(S)-Xyl-hexaPHEMP (S,R,R), n=1

up to 73% ee up to 80% ee

Henschke et al., 2003 Chan et al., 2006

Scheme 3.1 Ligands/catalysts reported in the asymmetric hydrogenation of 2-methylquinoxaline 4

In 2003, Henschke et al. reported the use of a diverse library of Noyori- type ruthenium precatalysts in the enantioselective hydrogenation of imines.13 The highest enantioselectivity in the hydrogenation of 2- methylquinoxaline 4 (73% ee) was however obtained using (S)-Xyl- HexaPHEMP as ligand with the addition of cyclohexyldiamine and potassium tert-butoxide as base. Chan described the use of atropisomeric chiral-bridged bisphosphine ligands in the hydrogenation of 2- methylquinoxaline 4, reaching up to 80% ee.14

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

So far, only bidentate ligands were reported in the asymmetric hydrogenation of prochiral substituted quinoxalines. As mentioned in the previous chapter, in the last decade chiral monodentate phosphines, phosphonites, phosphoramidites and phosphites were reported to provide excellent results in rhodium catalyzed asymmetric hydrogenations.15-17 Notably, compared to bidentate ligands, monodentate phosphoramidites are readily accessible, structurally highly diverse, air stable and inexpensive. In addition, they are amenable to parallel synthesis.17-19 In this chapter we report the highly enantioselective hydrogenation of 2- and 2,6-substituted quinoxalines using an iridium catalyst with monodentate phosphoramidites and piperidine hydrochloride as additive.

3.2 Goal of the research

Currently, only a few efficient chiral catalytic systems are available for the asymmetric hydrogenation of quinoxalines. From our earlier work, it was evident that monodentate phosphoramidites give excellent results in asymmetric hydrogenation.16 As can be seen from previous chapter, phosphoramidites give excellent results in the hydrogenation of the C=N functional group of quinolines. The goal of this research was to develop an efficient catalyst for the asymmetric hydrogenation of quinoxalines.

3.3 Results and Discussion

Optimisation of reaction conditions was achieved using the asymmetric hydrogenation of 2-methylquinoxaline 4 as a model reaction. The results are presented in Table 3.1. Employing 1 mol% of iridium precursor, 4 mol% of phosphoramidite ligand (S)-PipPhos L1 and 10 mol% of piperidine o hydrochloride at 60 C and 25 bar of H2 pressure, low enantioselectivity was obtained in a protic solvent such as methanol (Entry 1). It should be noted that the opposite configuration of the product, although with low ee, was obtained in 2,2,2-trifluoroethanol as a solvent (Entry 2). The use of aprotic solvents such as toluene and ethylacetate led to higher enantioselectivities (55% and 70% ee, respectively), with a complete conversion within 6h (Entries 3-4).

Chapter 3

Table 3.1 Asymmetric hydrogenation of 2-methylquinoxaline 4a

H N N 1 mol% [Ir(COD)Cl]2, 4 mol% L* Solvent, 25 bar H , 60 oC, 24h N 2 N H 44a

Amine moiety R:

O P R N N N O

(R,S)

L1 L2 L3 10 mol% Phosphine Timeb eec Entry Solvent L* Piperidine Config.d (L*/L = 2/1) (h) (%) . HCl 1 MeOH L1 + - <24 17 S 2 TFE L1 + - <24 10 R 3 toluene L1 + - 4 55 S 4 EtOAc L1 + - 6 70 S 5 THF L1 + - 14 73 S

6 CH2Cl2 L1 - - 3 77 S

7 CH2Cl2 L1 + - 8 96 S e 8 CH2Cl2 L1 + - 15 91 S Tri-o- 9 CH Cl L1 + <24 89 S 2 2 tolylphosphine 10 CH2Cl2 L2 + - <24 61 S 11 CH2Cl2 L3 + - <24 64 S a Reaction conditions: 1 mmol quinoxaline 4, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol L*, 0.1 mmol piperidine hydrochloride, 4 mL of solvent, 60 °C, 25 bar H2, 24h. b Time to achieve full conversion. Conversion was determined by 1H NMR. c Enantiomeric excess was determined by HPLC. d The absolute configuration was determined by measuring the optical rotation and comparing it with literature data. e0.005 mmol [Ir(COD)Cl]2, 0.02 mmol (S)-PipPhos L1, 0.1 mmol piperidine hydrochloride used.

The use of tetrahydrofuran increased the enantioselectivity to 73%, yet the reaction was slower (Entry 5). Finally, the best results were obtained in dichloromethane with ee’s up to 96% (Entries 6-8). Lowering the catalyst loading to 0.5 mol% influenced the reaction time but only a small effect was observed with respect to the enantioselectivity (Entry 8).

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

With the use of ligand L2 which was derived from azepane, 61% ee was obtained (Entry 10). Similarly, when ligand L3 derived from (R,S)-2,6- dimethyl-piperidine was used, 64% ee was obtained (Entry 11). It is clear that the presence of piperidine hydrochloride affects the enantioselectivity of this reaction in dichloromethane (Entries 6-7). The addition of 10 mol% of the hydrochloride salt in the reaction with (S)-PipPhos, increased the ee by 19%, however the reaction was slower. We have shown in chapter 2 that applying mixture of ligands in the asymmetric hydrogenation led to higher enantioselectivities.21 When tri-o- tolylphosphine was added to the hydrogenation reaction of 4, the enantioselectivity dropped 7% compared to the reaction without achiral ligand (96% and 89% ee, respectively, Etnries 7 and 9). Therefore, optimal conditions for the hydrogenation of 2-methylquinoxaline 4 were acomplished in dichloromethane using PipPhos L1 as a ligand and piperidine hydrochloride as an additive. Various 2- and 2,6-disubstituted quinoxalines (4-15) were hydrogenated in order to examine the scope of the reaction. The substrates were synthesized according to a known method of the iron-catalyzed Kumada reaction on the 2-chloroquinoxaline.22 Prochiral quinoxalines were tested in the asymmetric hydrogenation reaction using the optimised reaction conditions with (S)-PipPhos. The results are presented in Table 3.2. All substrates were hydrogenated with high to excellent enantioselectivity, with 2- methyl-quinoxaline 4 providing the product with the highest ee (96% ee, Entry 1). Changing from the methyl to the ethyl- substituted quinoxaline substrate resulted in the decrease of selectivity in the hydrogenation of 2-ethylquinoxaline 5 (80% ee, Entry 2). Similar enantioselectivities (80-85% ee) were obtained with all 2-alkylquinoxaline substrates (Entries 3-7). 2-Phenyl-1,2,3,4-tetrahydro-quinoxaline was obtained with 86% ee (Entry 8). Low enantioselectivity was accomplished with phenethyl-substituted substrate 12 (75% ee, Entry 9). The presence of a heteroatom in the structure such as oxygen did not disturb the enantioselectivity significantly (80% ee, Entry 10).

Chapter 3

Table 3.2 Asymmetric hydrogenation of 2,6-substituted quinoxalines using (S)-PipPhos as ligand and piperidine hydrochloride as additivea

H R2 N R2 N 1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos

N R1 10 mol% piperidine hydrochloride, N R1 o H DCM, 25 bar H2, 60 C 4a-15a

4a R1 = Me, R2 = H 11a R1 = Ph, R2 = H 1 2 1 2 5a R = Et, R = H 12a R = CH2CH2Ph, R = H 1 2 1 2 6a R = i-Bu, R = H 13a R = O R = H 7a R1 = n-butyl, R2 = H O 8a R1 = n-pentyl, R2 = H 9a R1 = 2-ethylhexyl, R2 = H 14a R1 = Me, R2 = Cl 10a R1 = dodecyl, R2 = H 15a R1 = COOMe, R2 = H

Entry R1 R2 Timeb (h) eec (%) 1 Me (4a) H 11 96 2 Et (5a) H 5 80 3 i-Bu (6a) H 10 80 4 n-Bu (7a) H 8 82 5 n-pentyl (8a) H 9 85 6 2-ethylhexyl (9a) H 12 80 7 dodecyl (10a) H 7 81 8 Ph (11a) H 9 86

9 CH2CH2Ph (12a) H 8 75

O 10 H 14d 80 O (13a) 11 Me (14a) Cl 7 88 12 COOMe (15a) H - - a Reaction conditions: 1 mmol quinoxaline 4, 0.01 mmol [Ir(COD)Cl2]2, 0.04 mmol (S)-PipPhos L1, 0.1 mmol piperidine hydrochloride, 4 mL of DCM, 60 °C, 25 bar H2. b Time to achieve full conversion. Conversion was determined by 1H NMR. cEnantiomeric excess was determined by HPLC. d 83% conversion.

A chloride substituent in the 6- position didn’t influence the selectivity either (Entry 11). Tolerance for chloride in the 6- position opens a possibility of preparation of 6-substituted chiral tetrahydroquinoxalines via asymmetric hydrogenation and Suzuki or Sonogashira coupling.

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

Unfortunately, the hydrogenation reaction of the methyl ester of the quinoxaline-2-carboxylic acid 15 resulted in no conversion, which might perhaps be a result of a strong bidentate coordination of the substrate to the metal (Entry 12).

3.4 Conclusion

Using a catalytic combination of an iridium(I) precursor, PipPhos as a ligand and piperidine hydrochloride as additive in the asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines, full conversion and ee’s ranging from 75 to 96% were obtained. These results comprise the highest selectivity reached for the hydrogenation of this class of heterocyclic compounds reported up to now. The highly enantioselective hydrogenation of imines and quinolines using the phosphoramidite-based catalytic system has now been extended to an additional class of heterocycles, i. e. quinoxalines, providing high yields and ee’s.

3.5 Experimental section

General remarks (see Chapter 2)

The catalyst was prepared in situ by mixing the iridium precursor, ligand and piperidine hydrochloride in 4 mL of solvent. The enantiomeric excess values were determined by HPLC with an OD-H chiral column. Ligands L1,23 L2,19 L3,23 were prepared according to literature procedures.

Preparation of 2-quinoxalines22 (except 2-phenyl-quinoxaline 11, 14 and 15)

To a flame dried 3-necked flask, 2-chloroquinoxaline (1.15 g, 6.99 mmol) and iron(II)-acetylacetonate (125 mg, 0.35 mmol) were added. The mixture was dissolved in dry THF (50 mL) and N-methyl-2-pyrrolidone was added (4 mL). Grignard solution (8.39 mmol) was added dropwise over 10 min. The resulting reaction mixture was stirred over 20 min, diluted with ether (50 mL) and quenched with 1M (aq) HCl solution (15 mL). After 10 min water was added (50 mL). The ether layer was separated, washed with brine (50 mL), dried and the solvent was removed in vacuo. The crude

Chapter 3

product was purified by column chromatography on neutral aluminum oxide (EtOAc/heptane = 1/6). 2-Methylquinoxaline was purchased from Aldrich and used directly in the hydrogenation reactions. Although several other 2-substituted quinoxalines were synthesized, they were not obtained pure. Therefore they were not included in this study.

General Experimental Procedure for Hydrogenation

A mixture of [Ir(COD)Cl]2 (6.72 mg, 0.01 mmol), (S)-PipPhos (15.98 mg, 0.04 mmol), substrate (1 mmol) and piperidine hydrochloride (12.16 mg, 0.1 mmol) were dissolved in 4 mL of solvent, in a glass vial. The vial was placed in a stainless steel autoclave. Reaction vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. Hydrogenation was performed at 60 °C under 25 bar of hydrogen pressure for the indicated time. After cooling the autoclave, the hydrogen pressure was carefully released. Solvent was removed in vacuo and the conversion was determined by 1H-NMR. The crude product was purified by chromatography (silica gel, heptane/EtOAc = 4/1). Although no side products were observed by 1H NMR, yields were ranging from 80 to 99%. It is assumed that in some cases the yield is lower due to the loss of product on the silica column.

2-ethyl-quinoxaline (5)24

1 Yellow liquid, 69% yield; H NMR (400 MHz, CDCl3) 1.44 (t, J = 7.61 Hz, 3H), 3.05 (q, J = 7.60 Hz, 2H), 7.67 – 7.75 (m, 2H), 8.02 – 8.08 (m, 2H), 13 8.75 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 14.4, 30.6, 129.82, 129.83,

130.1, 130.8, 142.2, 143.1, 146.5, 159.4 ppm; HRMS Calcd. for C10H10N2 (M+1) 159.08440, found 159.09167.

2-Isobutyl-quinoxaline (6)

1 Orange liquid, 77% yield; H NMR (400 MHz, CDCl3) 0.95 (d, J = 6.65 Hz, 6H), 2.20 (nonet, J = 6.87 Hz, 1H), 2.83 (d, J = 7.29 Hz, 2H), 7.63 – 7.70

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

13 (m, 2H), 7.99 – 8.04 (m, 2H), 8.66 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 23.4, 30.2, 46.3, 129.78, 129.80, 130.1, 130.7, 142.1, 143.1, 147.1, 157.8

ppm; HRMS Calcd. for C12H14N2 (M+1) 187.11570, found 187.12209.

2-butylquinoxaline (7)25

1 Orange liquid, 90% yield; H NMR (400 MHz, CDCl3) 0.98 (t, J = 7.37 Hz, 3H), 1.46 (sextet, J = 7.53 Hz, 2H), 1.83 (quintet, J = 7.84 Hz, 2H), 3.02 (t, J = 7.95 Hz, 2H), 7.68 – 7.76 (m, 2H), 8.03 – 8.08 (m, 2H), 8.74 (s, 1H) 13 ppm; C NMR (100 MHz, CDCl3) 13.7, 22.5, 31.5, 36.1, 128.7, 129.0,

129.7, 141.1, 142.1, 145.7, 157.5 ppm; HRMS Calcd. for C12H14N2 (M+1) 187.11570, found 187.12093.

2-pentylquinoxaline (8)26

1 Orange liquid, 50% yield; H NMR (400 MHz, CDCl3) 0.88 (t, J = 7.10 Hz, 3H), 1.32 – 1.42 (m, 4H), 1.82 (quintet, J = 8.03 Hz, 2H), 2.97 (t, J = 7.78 Hz, 2H), 7.64 – 7.72 (m, 2H), 8.00 – 8.05 (m, 2H), 8.71 (s, 1H) ppm; 13C

NMR (100 MHz, CDCl3) 14.9, 23.4, 30.2, 32.5, 37.4, 129.77, 129.78,

130.1, 130.8, 142.1, 143.1, 146.7, 158.6 ppm; HRMS Calcd. for C13H16N2 (M+1) 201.13135, found 201.13782.

2-(2-ethylhexyl)quinoxaline (9)

1 Orange liquid, 96% yield; H NMR (400 MHz, CDCl3) 0.86 (t, J = 6.87 Hz, 3H), 0.91 (t, J = 7.46 Hz, 3H), 1.26 – 1.42 (m, 8H), 1.98 (septet, J = 6.27 Hz, 1H), 2.95 (d, J = 7.22 Hz, 2H), 7.69 – 7.76 (m, 2H), 8.06 (t, J = 8.90 Hz, 13 2H), 8.71 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 11.6, 15.0, 23.9, 26.7, 29.6, 33.4, 40.8, 41.6, 129.7, 129.9, 130.1, 130.7, 142.0, 143.2, 147.2,

158.3 ppm; HRMS Calcd. for C16H22N2 (M+1) 243.17830, found 243.18295.

Chapter 3

2-dodecylquinoxaline (10)

1 Orange oil, 98% yield; H NMR (400 MHz, CDCl3) 0.86 (t, J = 7.06 Hz, 3H), 1.23 – 1.41 (m, 18H), 1.83 (quintet, J = 7.41 Hz, 2H), 3.00 (t, J = 7.71 Hz, 2H), 7.67 – 7.74 (m, 2H), 8.02 – 8.07 (m, 2H), 8.73 (s, 1H) ppm; 13C NMR

(100 MHz, CDCl3) 14.3, 22.9, 29.55, 29.57, 29.64, 29.66, 29.7, 29.83, 29.85, 29.9, 32.1, 36.7, 128.9, 129.1, 129.4, 130.0, 141.4, 142.4, 146.0,

157.8 ppm; HRMS Calcd. for C20H30N2 (M+1) 299.24090, found 299.24515.

2-phenylquinoxaline (11)27

A solution of 1.65 g (12.3 mmol) of phenyl glyoxal was heated with phenylenediamine (1.17 g, 10.8 mmol) in 20 mL of ethanol for 16h. After cooling the reaction mixture as filtered. The solid was dissolved in DCM, charcoal was added and solution was filtered. After evaporation of the solvent the product was isolated as white solid in 35% yield (790 mg).

1 White solid, 35% yield, Mp = 77.9 – 78.5 °C; H NMR (400 MHz, CDCl3) 7.53 – 7.60 (m, 3H), 7.73 – 7.81 (m, 2H), 8.12 – 8.22 (m, 4H), 9.34 (s, 1H) 13 ppm; C NMR (100 MHz, CDCl3) 128.4, 129.9, 130.3, 130.4, 130.99,

131.06, 137.6, 142.4, 143.1, 144.1, 152.6 ppm; HRMS Calcd. for C14H10N2 (M+) 206.0844, found 206.0838.

2-Phenethyl-quinoxaline (12)

1 Orange oil, 90% yield; H NMR (400 MHz, CDCl3) 3.19 (t, J = 8.72 Hz, 2H), 3.34 (t, J = 7.45 Hz, 2H), 7.19 – 7.29 (m, 5H), 7.72 – 7.77 (m, 2H), 8.06 – 13 8.09 (m, 2H), 8.63 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 36.1, 38.9, 127.1, 129.3, 129.4, 129.7, 129.9, 130.1, 130.8, 141.6, 142.1, 143.1,

100

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

146.6, 157.2 ppm; HRMS Calcd. for C16H14N2 (M+1) 235.11570, found 235.12202.

2-(benzo[d][1,3]dioxol-5-yl)quinoxaline (13)

N O O

1 White solid, 17% yield, Mp = 161.1 – 162.4 °C; H NMR (400 MHz, CD2Cl2) 6.08 (s, 2H), 7.00 (d, J = 8.12 Hz, 1H), 7.71 – 7.80 (m, 4H), 8.07 – 8.11 (m, 13 2H), 9.27 (s, 1H) ppm; C NMR (100 MHz, CD2Cl2) 102.0, 107.6, 108.8, 122.1, 129.2, 129.3, 129.5, 130.4, 131.3, 141.6, 142.3, 143.2, 149.0,

149.9, 151.16 ppm; HRMS Calcd. for C15H10N2O2 (M+1) 251.07423, found 251.07846.

6-Chloro-2-methylquinoxaline (14)

Cl N

N A mixture of 2g (10.0 mmol) of 2,6-dichloro-quinoxaline and 179 mg (0.70 mmol) of iron acetylacetonate was placed in a three-necked round bottom flask that was previously flame-dried. The mixture was dissolved in 70 mL of dry THF and 5.7 mL of N-methyl-2-pyrrolidone. Methylmagnesium bromide solution (1.4 M, 7.14 mL, 10.0 mmol) was added dropwise over 10 min. The reaction mixture was stirred overnight at rt, and then diluted with 100 mL of ether. After quenching with 20 mL of 1M (aq) HCl solution water was added (30 mL). The organic layer was separated, washed with brine (100 mL), and dried on sodium sulphate. The solvent was removed in vacuo and product was isolated as a light brown solid (75% yield, 1.34 g).

1 Brown solid, 75% yield, Mp = 134.7 – 134.8 °C; H NMR (400 MHz, CDCl3)

2.66 (s, 3H), 7.54 (dd, J1 = 2.33 Hz, J2 = 8.94 Hz, 1H), 7.81 (d, J = 8.94 Hz, 1H), 7.92 (d, J = 2.34 Hz, 1H), 8.61 (s, 1H) ppm; 13C NMR (100 MHz,

CDCl3) 23.4, 128.9, 130.7, 131.7, 135.3, 141.3, 142.0, 147.6, 154.8 ppm;

HRMS Calcd. for C9H7ClN2 (M+1) 179.02978, found 179.03709.

101

Chapter 3

Quinoxaline-2-carboxylic acid methyl ester (15)

N COOMe The compound prepared by stirring of quinoxaline carboxylic acid with trimethylsilyl diazomethane in methanol.

1 Orange solid, 95% yield, Mp = 107.1 – 108.2 °C; H NMR (400 MHz, CDCl3) 4.04 (s, 3H), 7.76 – 7.83 (m, 2H), 8.07 (d, J = 7.93 Hz, 1H), 8.20 (d, J = 13 8.06, 1H), 9.45 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 54.2, 130.2, 131.3, 131.8, 133.2, 142.2, 143.1, 144.5, 145.8, 165.4 ppm; HRMS Calcd. for C10H8N2O2 (M+1) 189.05858, found 189.06377.

(S)-2-methyl-1,2,3,4-tetrahydroquinoxaline (4a)20

H N

N H

Light brown solid, Mp = 88.1 – 88.4 °C, 96% ee, [α]D = -75.2 (c 0.98, 1 CHCl3); H NMR (400 MHz, CDCl3) 1.21 (d, J = 6.27 Hz, 3H), 3.05 (dd, J1 =

8.19 Hz, J2 = 10.70 Hz, 1H), 3.32 (dd, J1 = 2.92 Hz, J2 = 10.71 Hz, 1H), 3.50 – 3.57 (m, 1H), 3.63 (br, 2H), 6.53 – 6.56 (m, 2H), 6.63 – 6.66 (m, 2H) 13 ppm; C NMR (100 MHz, CDCl3) 20.7, 46.4, 49.0, 115.2, 115.3, 119.4, 134.0, 134.4 ppm; HPLC (OD-H, eluent: 80% heptane, 20% i-PrOH,

detector: 210 nm, flow rate: 0.5 mL/min) t1 = 16.5 min, t2 = 19.0 min.

(–)-2-Ethyl-1,2,3,4-tetrahydro-quinoxaline (5a)

H N

∗ N H

1 Yellow solid, Mp = 67.6 – 67.9 °C, 80% ee, [α]D = -28.3 (c 0.98, CHCl3); H

NMR (400 MHz, CDCl3) 1.02 (t, J = 7.92 Hz, 3H), 1.54 (quintet, J = 7.40 Hz,

2H), 3.07 (dd, J1 = 8.13 Hz, J2 = 10.46 Hz, 1H), 3.26 – 3.32 (m, 1H), 3.38

(dd, J1 = 2.22 Hz, J2 = 10.63 Hz, 1H), 3.63 (br, 2H), 6.51 – 6.53 (m, 2H), 13 6.59 – 6.61 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 10.9, 28.0, 47.1,

52.6, 115.3, 119.5, 119.6, 134.3, 134.4 ppm; HRMS Calcd. for C10H14N2

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Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

(M+1) 163.11570, found 163.12227; HPLC (OD-H, eluent: 80% heptane,

20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 = 17.3 min, t2 = 20.5 min.

(–)-2-Isobutyl-1,2,3,4-tetrahydro-quinoxaline (6a)

H N

∗ N H

1 Yellow solid, Mp = 69.3 – 69.6 °C, 80% ee, [α]D = -38.5 (c 0.97, CHCl3); H

NMR (400 MHz, CDCl3) 0.97 (d, J = 5.89 Hz, 6H), 1.29 – 1.43 (m, 2H), 1.75

(nonet, J = 6.69 Hz, 1H), 3.05 (dd, J1 = 8.04, J2 = 10.58 Hz, 1H), 3.34 – 3.45 (m, 2H), 3.65 (br, 2H), 6.51 – 6.60 (m, 4H) ppm; 13C NMR (100 MHz,

CDCl3) 23.4, 24.1, 25.4, 44.2, 47.9, 49.0, 115.4, 115.5, 119.55, 119.62,

134.3, 134.4 ppm; HRMS Calcd. for C12H18N2 (M+1) 191.14700, found 191.153372; HPLC (OD-H, eluent: 80% heptane, 20% i-PrOH, detector:

210 nm, flow rate: 0.5 mL/min) t1 = 15.5 min, t2 = 20.1 min.

(–)-2-butyl-1,2,3,4-tetrahydroquinoxaline (7a)

H N

∗ N H

1 Light brown solid, 83% yield, 82% ee, [α]D = -30.7 (c 1.02, CHCl3); H NMR

(400 MHz, CDCl3) 0.93 (t, J = 6.82 Hz, 3H), 1.37 – 1.49 (m, 6H), 3.06 (dd,

J1 = 11.00 Hz, J2 = 8.60 Hz, 1H), 3.32 – 3.38 (m, 2H), 3.35 (br, 2H), 6.49 – 13 6.59 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 14.9, 23.7, 28.7, 34.9, 47.5, 51.1, 115.2, 115.3, 119.4, 119.5, 134.3, 134.4 ppm; HRMS Calcd. for

C12H18N2 (M+1) 191.14700, found 191.15198; HPLC (OD-H, eluent: 80%

heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 = 13.5

min, t2 = 16.8 min; Compound decomposed during the melting point measurement.

103

Chapter 3

(–)-2-pentyl-1,2,3,4-tetrahydroquinoxaline (8a)

H N

∗ N H

1 White solid, Mp = 79.0 – 79.5 °C, 85% ee, [α]D = -32.7 (c 1.07, CHCl3); H

NMR (400 MHz, CDCl3) 0.94 (t, J = 6.75 Hz, 3H), 1.36 – 1.48 (m, 8H), 3.04 – 3.08 (m, 1H), 3.36 (d, J = 8.17 Hz, 2H), 3.89 (br, 2H), 6.51 – 6.53 (m, 13 2H), 6.60 – 6.62 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 14.9, 23.5, 26.2, 32.8, 35.1, 47.5, 51.1, 115.3, 115.3, 119.4, 119.6, 134.2, 134.3 ppm;

HRMS Calcd. for C13H20N2 (M+1) 205.16265, found 205.16766; HPLC (OD- H, eluent: 80% heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5

mL/min) t1 = 12.9 min, t2 = 16.0 min.

2-(2-ethylhexyl)quinoxaline (9a)

H N

∗ N H

1 Yellow oil, 89% yield, 88% ee, 0% de, [α]D = -29.4 (c 1.04, CHCl3); H NMR

(400 MHz, CDCl3) 0.86 – 0.82 (m, 6H), 1.28 – 1.40 (m, 11H), 3.05 (dd, J1

= 8.06 Hz, J2 = 10.59 Hz, 1H), 3.35 (dd, J1 = 2.74 Hz, J2 = 10.70 Hz, 1H),

3.43 (dd, J1 = 2.15 Hz, J2 = 5.20 Hz, 1H), 3.58 (br, 2H), 6.50 – 6.60 (m, 4H) 13 ppm; C NMR (100 MHz, CDCl3) 10.8, 10.9, 14.4, 23.4, 26.1, 26.6, 28.9, 29.0, 33.0, 33.4, 35.4, 35.5, 114.7, 114.8, 118.88, 118.91, 133.7, 133.8 ppm; HRMS Calcd. for C16H26N2 (M+1) 247.20960, found 247.21385; HPLC (OD-H, eluent: 90% heptane, 10% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1(diastereoisomers 1 and 2) = 13.2 min, t2 (diastereoisomer 3) =

16.2 min, t3 (diastereoisomer 4) = 17.0 min.

2-dodecyl-1,2,3,4-tetrahydroquinoxaline (10a)

H N

∗ N H

1 Light red solid, 81% ee, [α]D = -10.2 (c 1.02, CHCl3); H NMR (400 MHz,

CDCl3) 0.86 (t, J = 6.52 Hz, 3H), 1.25 – 1.47 (m, 22H), 3.04 (dd, J1 = 8.31

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Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

Hz, J2 = 10.96 Hz, 1H), 3.32 – 3.36 (m, 2H), 3.61 (br, 2H), 6.47 – 6.57 (m, 13 4H) ppm; C NMR (100 MHz, CDCl3) 14.4, 23.0, 26.0, 29.7, 29.94, 29.99, 30.04, 32.2, 34.6, 47.0, 50.5, 114.66, 114.72, 118.8, 118.9, 133.7, 133.8

ppm; HRMS Calcd. for C20H34N2 (M+1) 303.27220, found 303.27582; HPLC (OD-H, eluent: 80% heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 = 11.0 min, t2 = 14.1 min; Compound decomposed during the melting point measurement.

(+)-2-phenyl-1,2,3,4-tetrahydroquinoxaline (11a)

H N

∗ N H

Light brown solid, Mp = 124.6 – 126 °C, 92% yield, 86% ee, [α]D = +95.3 (c 1 0.96, CHCl3); H NMR (400 MHz, CDCl3) 3.33 (dd, J1 = 8.22 Hz, J2 = 11.03

Hz, 1H), 3.46 (dd, J1 = 3.11 Hz, J2 = 11.06 Hz, 1H), 3.82 (br, 2H), 4.49 (dd,

J1 = 3.06 Hz, J2 = 8.20 Hz, 1H), 6.57 – 6.66 (m, 4H), 7.31 – 7.40 (m, 5H) 13 ppm; C NMR (100 MHz, CDCl3) 49.9, 55.4, 115.2, 115.4, 119.48, 119.55, 127.8, 128.6, 129.4, 133.6, 134.9, 142.7 ppm; HRMS Calcd. for

C14H14N2 (M+1) 211.11570, found 211.12044; HPLC (OD-H, eluent: 80%

heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 = 21.9

min, t2 = 27.5 min.

(–)-2-Phenethyl-1,2,3,4-tetrahydro-quinoxaline (12a)

H N

∗ N H

Yellow solid, Mp = 67.6 – 68.5 °C, 81% yield, 75% ee, [α]D = -30.5 (c 0.98, 1 CHCl3); H NMR (400 MHz, CDCl3) 1.86 (quartet, J = 7.80 Hz, 2H), 2.78 (t,

J = 7.24 Hz, 2H), 3.14 (dd, J1 = 7.16 Hz, J2 = 10.36 Hz, 1H), 3.39 – 3.44 (m, 2H), 3.58 (br, 2H), 6.50 – 6.65 (m, 4H), 7.25 – 7.36 (m, 5H) ppm; 13C

NMR (100 MHz, CDCl3) 33.0, 36.7, 47.3, 50.7, 115.3, 115.5, 119.57, 119.65, 127.0, 129.2, 129.4, 134.18, 134.23, 142.4 ppm; HRMS Calcd. for

105

Chapter 3

C16H18N2 (M+1) 239.14700, found 239.15334; HPLC (OD-H, eluent: 80%

heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 = 24.6

min, t2 = 31.7 min.

(+)-2-Benzo[1,3]dioxol-5-yl-1,2,3,4-tetrahydro-quinoxaline (13a)

H N

∗ N O H O

Light yellow solid, Mp = 84.5 – 85.8 °C, 83% yield, 80% ee, [α]D = +66.8 (c 1 1.02, CHCl3); H NMR (400 MHz, CDCl3) 3.25 – 3.30 (m, 1H), 3.39 – 3.43 (m, 1H), 3.76 (br, 2H), 4.38 – 4.40 (m, 1H), 5.97 (s, 2H), 6.57 – 6.69 (m, 13 4H), 6.81 – 6.91 (m, 3H) ppm; C NMR (100 MHz, CDCl3) 50.1, 55.2, 101.9, 108.2, 109.0, 115.3, 115.5, 119.6, 119.7, 121.0, 133.6, 134.9,

136.7, 147.9, 148.7 ppm; HRMS Calcd. for C15H14N2O2 (M+1) 255.10553, found 255.10985; HPLC (OD-H, eluent: 80% heptane, 20% i-PrOH,

detector: 210 nm, flow rate: 0.5 mL/min) t1 = 33.8 min, t2 = 52.3 min.

(–)-6-Chloro-2-methyl-1,2,3,4-tetrahydro-quinoxaline (14a)

H Cl N

∗ N H

1 Light yellow solid, 99% yield, 88% ee, [α]D = -12.9 (c 1.00, CHCl3); H NMR

(400 MHz, CDCl3) 1.16 (d, J = 6.28 Hz, 3H), 2.97 (dd, J1 = 8.14 Hz, J2 =

10.77, 1H), 3.26 (dd, J1 = 2.95 Hz, J2 = 10.80 Hz, 1H), 3.40 – 3.44 (m, 1H),

3.61 (br, 2H), 6.36 (d, J = 8.24 Hz, 1H), 6.43 (d, J = 2.24 Hz, 1H), 6.51 (dd, 13 J1 = 2.26 Hz, J2 = 8.24 Hz, 1H) ppm; C NMR (100 MHz, CDCl3) 20.6, 46.2, 48.7, 114.4, 115.8, 118.5, 123.8, 132.8, 135.2 ppm; HRMS Calcd.

for C9H11ClN2 (M+1) 183.06107, found 183.06612; HPLC (OD-H, eluent:

80% heptane, 20% i-PrOH, detector: 210 nm, flow rate: 0.5 mL/min) t1 =

15.9 min, t2 = 18.5 min; compound decomposes during the melting point determination.

106

Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

3.6 References

(1) a) Eary, C. T.; Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.; Mareska, D. A.; Drew, M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.; O’Sullivan, M.; Allen, A.; Marsh, V. Bioorg. Med. Chem. Lett. 2007, 17, 2608; b) Chang, G.; Didiuk, M. T.; Finneman, J. I.; Garigipati, R. S.; Kelley, R. M.; Perry, D. A.; Ruggeri, R. B.; Bechle, B. M. WO2004085401 to Pfizer Prod. Inc., 2004. (2) Forlani, L.; Medici, A.; Ricci, M.; Todesco, P. E. Synthesis 1997, 230. (3) Monge, A.; Palop, J. A.; López de Ceráin, A.; Senador, V.; Martínez- Crespo, F. J.; Sainz, Y.; Narro, S.; Garcia, E.; de Miguel, C.; González, M.; Hamilton, E.; Barker, A. J.; Clarke, E. D.; Greenhow, D. T. J. Med. Chem. 1995, 38, 1786. (4) Catarzi, D.; Cecchi, L.; Colotta, V.; Filacchioni, G.; Martini, C.; Tacchi, P.; Lucacchini, A. J. Med. Chem. 1995, 38, 1330. (5) Catarzi, D.; Cecchi, L.; Colotta, V.; Melani, F.; Filacchioni, G.; Martini, C.; Giusti, L.; Lucacchini, A. J. Med. Chem. 1994, 37, 2846. (6) Kim, K. S.; Qian, L.; Bird, J. E.; Dickinson, K. E. J.; Moreland, S.; Schaeffer, T. R.; Waldron, T. L.; Delaney, C. L.; Weller, H. N.; Miller, A. V. J. Med. Chem. 1993, 36, 2335. (7) a) Glombik, H. Tetrahedron 1990, 46, 7745; b) Glombik, H. DE3826603 (A1) to Hoechst AG, 1990. (8) Loev, B.; Musser, J. H.; Brown, R. E.; Jones, H.; Kahen, R.; Huang, F.- C.; Khandwala, A.; Sonnino-Goldman, P.; Leibowitz, M. J. J. Med. Chem. 1985, 28, 363. (9) a) Mertes, M. P.; Lin, A. J. J. Med. Chem. 1970, 13, 77; b) Benkovic, S. J.; Benkovic, P. A.; Comfort, D. R. J. Am. Chem. Soc. 1969, 91, 5270. (10) Blakley, R. L. The Biochemistry of Folic Acid and Related Pteridines, North-Holland Publishing Co.: Amsterdam, 1969. (11) Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26, 763. (12) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M. Organometallics 1998, 17, 3308. (13) a) Henschke, J. P.; Burk, M. J.; Malan, C. G.; Herzberg, D.; Peterson, J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G. Adv. Synth. Catal. 2003, 345, 300; b) Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195.

107

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(14)Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.- M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955. (15) a) Erre, G.; Enthaler, S.; Junge, K.; Gladiali, S.; Beller, M. Coord. Chem. Rev. 2008, 252, 471; b) van den Berg, M.; Feringa, B. L.; Minnaard, A. J. The Handbook of Homogenous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. Wiley -VCH: Weinheim, 2007; Vol. 2, Chapter 28, 995; c) Ager, D. J.; de Vries, A. H. M.; de Vries, J. G. Platinum Met. Rev. 2006, 50, 54; d) de Vries, J. G. Handbook of Chiral Chemicals, 2nd edn., Ed. Ager, D. J. CRC Press: Boca Raton, 2005, 269; e) Komarov, I. V.; Börner, A. Angew. Chem. Int. Ed. 2001, 40, 1197. (16) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (17) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C. Tetrahedron: Asymmetry 2004, 15, 2101. (18) a) Hoen, R.; Tiemersma-Wegman, T. D.; Procuranti, B.; Lefort, L.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2007, 5, 267; b) de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006, 12, 4722; c) Duursma, A.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2004, 2, 1682. (19) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (20) Fisher, G. H.; Schultz, H. P. J. Org. Chem. 1974, 39, 635. (21) Mršić, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2008, 350, 1081. (22) Jones, Z.; Groneberg, R.; Drew, M.; Eary, T. US 2005/0282812 A1 to Hogan & Hartson LLP, 2005. (23) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (24) Battistini, M.; Erba, E.; Pocar, D. J. Chem. Soc. Perkin Trans. 1 1993, 339. (25) Cho, C. S.; Oh, S. G. J. Mol. Catal. A: Chem. 2007, 276, 205. (26) Wallace, J. M.; Söderberg, B. C. G.; Tamariz, J.; Akhmedov, N. G.; Hurley, M. T. Tetrahedron 2008, 64, 9675.

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Asymmetric hydrogenation of 2- and 2,6-substituted quinoxalines

(27) Darabantu, M.; Boully, L.; Turck, A.; Plé, N. Tetrahedron 2005, 61, 2897.

109

Chapter 3

110

Chapter 4 Preparation of chiral amines via asymmetric hydrogenation of imines

In this chapter asymmetric hydrogenation of imines catalyzed by iridium complexes of BINOL-derived phosphoramidites is described. Enantioselectivities up to >99% were obtained in the hydrogenation of N-aryl imines. The corresponding amines were successfully deprotected with preservation of their stereochemical integrity. N-alkyl imines were hydrogenated using the same catalytic system with up to 40% ee, while in case of cyclic imines up to 62% ee was obtained.

Part of this chapter has been published:

N. Mršić, A. J. Minnaard, B. L. Feringa, J. G. de Vries, J. Am. Chem. Soc., 2009, 131, 8358. Chapter 4

4.1 Introduction

Chiral amines are important synthetic intermediates in the preparation of many physiologically active compounds. One of the methods for their preparation is the asymmetric hydrogenation of C=N containing functional groups (imines, oximes, hydrazones, etc.). The catalytic properties of the enantioselective homogenous hydrogenation catalysts are determined by the choice of the metal, the chiral ligand and the anion. Over the last two decades, iridium, rhodium, ruthenium, palladium and titanium have been reported to be effective in the hydrogenation of C=N functionalities.1-4 Despite significant progress in the field, asymmetric hydrogenation of imines still represents major challenges. Although many highly efficient catalysts have been developed for the asymmetric hydrogenation of ketones and alkenes, much less examples have been reported for the metal catalyzed asymmetric hydrogenation of imines with both high enantioselectivities and acceptable turnover frequencies.1-3 As mentioned in Chapter 1 there are several reasons why imines are difficult substrates for the hydrogenation.5 One is a smaller thermodynamic gain from the reduction of C=N bond relative to the C=C bond of an olefin. There is also a less effective orbital overlap and lower affinity of the C=N for the metal center due to the η1-binding mode of the imine bond compared to the η2- bonding of the olefin. Since imines are poorly active towards hydrogen, often higher pressures are necessary. In addition, imines are sensitive to hydrolysis, which results in formation of an amine. Traces of amine (including the product of hydrogenation) and oligomers can behave as a catalyst poison, due to the fact that they can coordinate strongly to the metal, and in this way prevent the coordination of the ligand.6 Finally, increased steric hindrance at the unsaturated moiety may also retard the hydrogenation, which is well established with olefinic substrates. The fact that imines are often isolated as mixture of syn/anti isomers (as well as enamine isomers) can influence the outcome of the hydrogenation reaction.7 Initially, only heterogenous catalysts like Pd/C, Pt black or Raney nickel were applied in the hydrogenation of C=N functions.8 These were modified with chiral auxiliaries anticipating that the transfer of chirality from the auxiliary to the reactant might take place. However, the

112

Preparation of chiral amines via asymmetric hydrogenation of imines

enantioselectivities obtained were low and not reproducible. The first homogenous Ru9 and Rh10 catalysts for imine hydrogenation were reported in 1975. The first significant enantioselectivities in the hydrogenation of the C=N bond were subsequently reported by Marko et al. in 1984, using a rhodium complex with the bidentate (2S,4S)-bis-(diphenylphosphino) pentane ligand (BDPP) in the hydrogenation of N-benzylacetophenone imine (up to 72% opt. yield, Scheme 4.1).11

Marko et al., 1984

N HN [Rh(P-P)*]-cat ∗

rt, 70 bar H2

72% opt. yield

Ph2P PPh2

BDPP

Scheme 4.1 First efficient homogenous catalyst reported for the hydrogenation of C=N function

A new development emerged when Bakos and Sinou working on water- soluble catalysts, used a partially sulphonated BDPP ligand for the rhodium catalyzed hydrogenation of N-benzylacetophenoneimine in a two phase system (water, ethyl acetate).12 They found that the obtained enantioselectivity depended strongly on the degree of the sulphonation of the bisphosphine ligand (up to 96% ee). Following these results, de Vries et al. isolated monosulfonated, the di-, the tri- and the tetrasulfonated ligand and tested them in the hydrogenation. Use of the monosulfonated ligand allowed hydrogenation of the imine with 95% ee.13 The monosulfonated ligand is a mixture of a 50%/50% of epimers. Surprisingly, use of the disulfonated ligand gave racemic product. The first example of an efficient hydrogenation of unprotected imines was reported by Zhang et al. in 2009, using iridium catalyst based on (S,S)-f-Binaphane ligand (up to 95% ee,

113

Chapter 4

Scheme 4.2).14 This method allows the enantioselective synthesis of chiral amines without the use of protecting groups.

Zhang et al., 2009

NH2Cl [Ir(COD)Cl]2, (S,S)-f-Binaphane NH3Cl ∗ R1 R2 10 bar H2, rt, 18h R1 R2

up to 95% ee

P Fe P

(S,S)-f-Binaphane

Scheme 4.2 The first asymmetric hydrogenation of unprotected imines

4.1.1 Asymmetric hydrogenation of N-Aryl imines

A great deal of effort was devoted to the development of a catalyst for the asymmetric hydrogenation of N-aryl imines, since N-alkyl-2,6- disubstituted anilines with a stereogenic center at the α-position are intermediates in the synthesis of acylanilide pesticides, the most important example being (S)-Metolachlor 3 (Scheme 4.3).15 Since not all the stereoisomers are biologically active, the stereoselective synthesis of the most active one is of great industrial importance. In 1993 a Novartis group developed a new class of iridium-ferrocenyl bisphosphines, which in the presence of both acetic acid and iodide, provided a stable effective catalyst for the asymmetric hydrogenation of the imine 1. An extensive ligand optimisation led to the choice of Ir-Xyliphos as the optimal catalyst. The production of the herbicide Metolachlor is the only commercialized asymmetric C=N bond hydrogenation. One of the important features of Metolachlor process is the influence of iodide on enantioselectivity. It is reported that catalytic additives play a crucial role in improving the reactivity and enantioselectivity of many asymmetric reactions.16-19 As mentioned in Chapter 2, Osborn reported in

114

Preparation of chiral amines via asymmetric hydrogenation of imines

1990 that iridium - iodo species are observed in the hydrogenation of imines.19

O OMe OMe Cl OMe N 0.01 mol% Ir-2 HN N - I /HOAc ClCH2COCl o 80 bar H2, 50 C 4h

1 80% ee 3 (S)-Metolachlor 10 000 tons/year

P 2 = Fe PPh2 2

(R)-Xyliphos

Scheme 4.3 Synthesis of (S)-Metolachlor 3

Since then, the influence of halide additives on the asymmetric hydrogenation was reported by several groups.16 We have also observed an increase in enantioselectivity with the addition of chloride salts in the asymmetric hydrogenation of quinolines (Chapter 2).20 Another interesting feature of the Metolachlor process is the addition of acetic acid, which dramatically increases the rate of the hydrogenation. This effect may be explained with the fact that acid can protonate the product of the hydrogenation, and in this way prevent the “catalyst poisoning” with the resulting amine. It is well known that the addition of the acid often increases the enantioselectivity21 or rate22 of the asymmetric hydrogenation. It has been described as well that Brönsted acid promotes ruthenium catalyzed ionic hydrogenations of ketones and imines.23 In these cases acid protonates and therefore activates the substrate, while the following step is the hydride transfer from the metal center. Optimal ligand in the Metolachlor process is ferrocene derived Xyliphos, which has 3,5-di-methylphenyl group attached to phosphorus. Pregosin has shown in several studies that introducing 3,5-di-tert- butylphenyl or 3,5-di-methylphenyl groups onto the MeO-Biphep ligand

115

Chapter 4

(instead of the phenyl substituent) enhances the ee’s in Heck reaction, allylic alkylation, as well as palladium catalyzed hydrosilylation and ring opening chemistry (Figure 4.1).24

P Pd R R = t-Bu, Me

Figure 4.1 Restricted rotaion around the P-C bond of the ligand

Pregosin explains this effect with the fact that there is a restricted rotation around the P-C(ipso) bonds of the P(3,5-di-methyl-phenyl) groups. This decrease in molecular freedom derives from the restricted rotation due to the interaction of the P-aryl substituent with the ligand backbone and results in a more rigid chiral pocket and thus improved correlation between substrate and catalyst. Metal catalyzed asymmetric hydrogenation of N-aryl imines was investigated by several research groups over the last decade. Most of the reported catalysts that give medium to high enantioselectivities are based on iridium catalysts with bidentate bisphosphine ligands, or phosphinooxazoline ligands as developed by Pfaltz.3,25-29 There are a few examples of efficient rhodium30 and palladium31 derived catalysts (91-94% ee). Some of the most efficient ligands/catalysts reported for the asymmetric hydrogenation of N-aryl imines are depicted in Figure 4.2. In 2001 Zhang et al. reported the use of an iridium catalyst with the ferrocenyl bidentate bisphosphine ligand (R,R)-f-Binaphane in the asymmetric hydrogenation of N-aryl imines, with excellent enantioselectivity (up to >99% ee).18 Another ferrocenyl ligand was shown to be efficient in the iridium catalyzed hydrogenation of PMP-protected N-aryl imines as was applied in the synthesis of chiral lactams with excellent enantioselectivity (Knochel et al., up to 97% ee).25 Andersson et al.27 and Zhou et al.28 independently reported the use of iridium catalysts with phosphinooxazoline ligands, while Bolm et al. described the use of iridium catalysts with diphenylphosphanylsulfoximine ligands with up to 98% ee.32 In 2002

116

Preparation of chiral amines via asymmetric hydrogenation of imines

Henschke et al. reported the use of ruthenium “Noyori-type” catalyst with (R,R)-Et-DUPHOS and (R,R)-diaminocyclohexane as ligands in the asymmetric hydrogenation of N-aryl imines.33 The first successful example of iridium catalyzed hydrogenation of N-aryl imines with catalyst bearing an achiral ligand and a chiral counterion, with excellent enantioselectivity was recently reported by Xiao et al (up to 99% ee).34

Cl H2 P N Ru **P N Cl H2

H N 2 O P P Ph S N PPh2 H2N

(R,R)-Et-DUPHOS up to 92% ee up to 98% ee Henschke et al., 2003 Bolm et al., 2005

+ BArF- + - BArF O Ar Ar Ph P Ir N Ir PAr N 2 P P O

Ar = 3,5-diMePh up to 92% ee up to 99% ee up to 97% ee Andersson et al., 2006 Imamoto et al., 2006 Zhou, 2006

Ar + - BArF O S O N O X = O Ir Ir P X O O Ph P N 2 OMe H N Fe Ar = 2,4,6-(2-C3H7)3C6H2 up to 99% ee up to 98% ee Knochel et al., 2007 Xiao et al., 2008 Figure 4.2 Efficient ligands/catalysts in the asymmetric hydrogenation of N-aryl imines

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In more recent studies in organocatalysis,35 the groups of Rueping, List, and MacMillan reported highly enantioselective transfer hydrogenation of imines36 or imines in situ generated from ketones and amines37 with Hantzsch esters as reducing agents. The reduction is catalyzed by chiral phosphoric acids, which protonate the imines while the anion directs the facial attack of the hydride (Scheme 4.4).

H H EtOOC COOEt O O N N H HN ∗ o Ar benzene, 60 C Ar Ar

O O up to 84% ee 20 mol% P O OH

Ar = 3,5-(CF3)-phenyl

Scheme 4.4 Rueping’s organocatalytic reduction of N-aryl imines with Hantzsch esters

As mentioned in Chapter 2, transfer hydrogenation is a valuable and versatile reaction which is emerging as one of the very best methods for achieving asymmetric transformations.38

4.1.2 Asymmetric hydrogenation of N-alkyl imines

There are not many examples in the literature of the asymmetric hydrogenation of N-alkyl imines.1,3 Most of the results are obtained on model substrates, especially N-benzyl imines (Scheme 4.5). With the exception of N-benzyl group which can be removed easily by hydrogenolysis, there is no known method for the deprotection of N-alkyl amines, leading to chiral primary amines. However, secondary amines are an interesting class of products in their own right.

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Preparation of chiral amines via asymmetric hydrogenation of imines

N Ph cat. HN Ph ∗ R H2 R R = Cyclohexyl, Aryl

Ph P PhP SO -Na+ 2 3 Ti X X O X = X O Ph2P PPh2

up to 91% ee up to 94% ee up to 92% ee Bakos et al. 1991 James et al., 1991 de Vries et al., 1992 Buchwald et al., 1994

Cl H2 P N Ru **P N Cl H2 O P OH +PPh3 O

HN NH H2N NH2 Ph2P PPh2

up to 92% ee up to 92% ee Morris et al., 2001 Reetz et al., 2007

Scheme 4.5 Efficient ligands/catalysts in the asymmetric hydrogenation of N-alkyl imines

The highest enantioselectivity was obtained with mono-sulphonated BDPP ligand (94% ee).12,13 Enantioselectivities exceeding 90% were reported using Buchwald’s titanocene catalyst7 and James’ rhodium catalysts with bisphosphine ligands.39 With a “Noyori-type” ruthenium catalyst, reported by Morris et al., enantioselectivity of 92% was obtained in the hydrogenation of N-benzylacetophenoneimine, with good TOF (23/h).40 In 2007 Reetz reported the use of an iridium catalyst based on a mixture of monodentate ligands in the hydrogenation of N-alkyl imines, with up to 92% ee.41 In 2003 Börner reported the in situ reductive amination of α-keto acids with N-benzylamine, catalyzed by a rhodium complex based on the

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Deguphos ligand (Scheme 4.6). Often conversions were incomplete, however, ee’s up to 98% were obtained.42

O [Rh(P-P)*]-cat HN Ph + BnNH2 R COOH rt, 60 bar H2 R COOH

PPh2 BnN up to 98% ee

PPh2 R = a: PhCH2, b: Me, (R,R)-Deguphos c: Ph, d: HOOCCH2CH2, e: HOOCCH2, f: PhCH2CH2, g: Me2CHCH2, h: Me3CCH2

Scheme 4.6 Direct reductive amination of α-keto acids with N- benzylamine

4.1.3 Asymmetric hydrogenation of cyclic imines

Cyclic imines do not have the issue of syn/anti isomerism, therefore higher enantioselectivities in the asymmetric hydrogenation could be expected. Some of the corresponding amines are of significant pharmaceutical importance (Figure 4.3). 1-Substituted 1,2,3,4- tetrahydroisoquinoline alkaloids, specifically Salsolidine, have been of great interest to synthetic chemists because of their important physiological activities, especially those related to the pathogenesis of Parkinson’s disease.43 Tetrahydroisoquinoline YH 1885 is, on the other hand, a proton pump inhibitor.44

O H N N N NH O N F

(S)-Salsolidine YH1885

Figure 4.3 Tetrahydroisoquinolines of pharmaceutical importance

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Preparation of chiral amines via asymmetric hydrogenation of imines

Buchwald’s titanocene catalyst gave enantioselectivities up to 99% in the hydrogenation of cyclic imines, although with low substrate/catalyst ratios and low TOF’s (Figure 4.4).45

O n R N N N O n = 1-3 R = alkyl 465

X X O = Ti O X X

up to 99% ee Buchwald, 1993

Figure 4.4 Buchwald’s catalyst in the asymmetric hydrogenation of cyclic imines 4-6

With respect to the activity, iridium catalysts bearing bisphosphine ligands are more promising (Figure 4.5). Achiwa showed in 1998 that imides can improve enantioselectivity of the Ir-catalyzed hydrogenation of imines.46 Zhang et al. reported in 1998 the use of iridium-BICP complex in the asymmetric hydrogenation of cyclic imines in the presence of additives like phthalimide, with up to 95% ee.47 The rate of the reaction was as well influenced (full conversion in 96h without additive, 65h with 4% of phtalimide). The iridium catalysts with ferrocenyl (R,S)-Xyliphos ligand in the combination with acid or iodide as promoters gave excellent enantioselectivity in the asymmetric hydrogenation of 2,3,3-trimethyl-3H- indole 7.48 The role of additives in the hydrogenation of imines is not fully understood. There are also examples of efficient rhodium and ruthenium catalysts for the hydrogenation of cyclic imines. Xiao reported the use of the Rh-Ts-dpen catalyst in the hydrogenation of imine 8 with up to 99% ee,49 while Noyori described the use of the same ligand in the ruthenium catalyzed transfer hydrogenation of imines 8 and 9 with up to 97% ee.50 In 2006 Zhu reported the first asymmetric transfer hydrogenation of cyclic

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imines and iminium substrates in water, catalyzed by a water-soluble and recyclable ruthenium(II) complex.51

N N N O N H R R 7 8 9

ArSO 2 Ph2P H N R H PR´2 Ru Fe PR2 N Cl H H2 PPh2

(R,R)-BICP Xylyphos, R = Ph, R´ = Xyl

up to 95% ee up to 95% ee up to 93% ee Noyori et al., 1996 Zhang et al., 1998 Blaser et al., 2001

+ SbF6 Ts N Rh Solvent N NaO S SO Na H2 3 3 TsHN NHTs

up to 99% ee up to 99% ee Xiao et al., 2008 Zhu et al., 2006

Figure 4.5 Efficient ligands/catalysts in the asymmetric hydrogenation of cyclic imines 7-9

4.1.4 Asymmetric hydrogenation of C=N−X substrates

Using Pd(OCOCF3)2/(S,S)-f-Binaphane as the catalyst, Zhou and co- workers developed an efficient enantioselective synthesis of sultams via asymmetric hydrogenation of the corresponding cyclic imines with high enantioselectivities (up to 98% ee).52 Zhang described recently an efficient Pd-catalyzed asymmetric hydrogenation of N-tosylimines, in the presence of bisphosphine ligand TangPhos, with full conversion and enantioselectivity of up to 99% ee.53

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Preparation of chiral amines via asymmetric hydrogenation of imines

However, a relatively high hydrogen pressure and catalytic loading are important limitations of that work. Spindler and Blaser reported the development of Rh-Josiphos catalysts for the highly effective hydrogenation of several N-diphenylphosphinyl imines with ee's up to 99%.54 Zhou as well reported the hydrogenation of a variety of substituted N-diphenylphosphinyl imines using

Pd(OCOCF3)2/(S)-SegPhos as a catalyst with high enantioselectivities (up to 99% ee).55

4.2 Goal of the research

Currently, only a few efficient chiral catalytic systems are available for the asymmetric hydrogenation of imines. Apart from the Metolachlor process, there are no examples of catalysts suitable for industrial applications. From earlier results in our group, it was evident that monodentate phosphoramidites give excellent results in asymmetric hydrogenation.56 As can be seen from previous chapters, phosphoramidites give excellent results in the hydrogenation of the C=N functional groups present in quinolines and quinoxalines. The goal of this research was to develop an efficient catalyst for the asymmetric hydrogenation of N-aryl, N- alkyl and cyclic imines. In addition, we were interested in developing an efficient deprotection method for corresponding N-aryl amines, in order to enable access to chiral primary amines of high enantiomeric purity.

4.3 Results

4.3.1 N-aryl imines

The asymmetric hydrogenation of N-phenyl-(1-phenyl-ethylidene)-amine 10 was chosen as a model reaction. Since by using the combination of

[Ir(COD)Cl]2 and PipPhos L1 we obtained excellent results in the hydrogenation of quinolines and quinoxalines at 60 oC, this catalytic system and the conditions were chosen for the initial screening in the hydrogenation of 10. The reactions were performed using 1 mol% of

iridium precursor in dichloromethane over 24h (50 bar H2, 60 °C). There are several additives reported in the literature to have an effect on the

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conversion and enantioselectivity of the hydrogenation of imines. We examined the effect of some of these additives on the hydrogenation of imine 10. The results are presented in Table 4.1.

Table 4.1 Testing of the [Ir(COD)Cl]2/PipPhos catalytic system and additives in the asymmetric hydrogenation of imine 10a

N 1 mol% [Ir(COD)Cl]2, 4 mol% (S)-PipPhos HN 10 mol% additive o CH2Cl2, 60 C, 50 bar H2 24h 10 10a

O P N O

(S)-PipPhos L1

Entry Additive Conversionb (%) eec (%) Config.d 1 - 89 5 R 2 Piperidine·HCl 100 39 R 3 KI 58 37 R

4 (CH3)4NI 58 34 R 5 Phthalimide 52 22 R 6 HOAc 83 28 R aReaction conditions: 1 mmol of imine 10, 0.01 mmol of [Ir(COD)Cl]2, 0.04 mmol of (S)- PipPhos L1, 0.1 mmol additive, 4 mL of CH2Cl2 at 50 bar H2 and 60 °C, 24h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by GC using a Chiralsil DEX CB column. dAbsolute configuration of the product was assigned by measuring the optical rotation and comparing it with literature data.

Without the additives the reaction proceeds with 89% conversion, however, with only 5% ee (Entry 1). In analogy with our previous findings with quinolines and quinoxalines, addition of piperidine hydrochloride improves the enantioselectivity of the reaction from 5% to 39% (Entry 2). A similar effect was obtained by addition of potassium iodide or tetramethylammonium iodide, although the reaction was significantly slower (Entries 3-4). Addition of phthalimide and organic acid increased

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Preparation of chiral amines via asymmetric hydrogenation of imines

the enantioselectivity to 22 and 28%, respectively (Entries 5-6). In the case of phthalimide the reaction was slowed down, while upon addition of acetic acid the rate of the reaction remained unchanged. In 2006 Faller et al. reported the use of a mixture of monodentate phosphoramidite MonophosTM and pyridine as ligands in the asymmetric hydrogenation of cyclic imines with up to 58% ee.57 We tested the combination of PipPhos L1 and two different amines in the model reaction i. e. hydrogenation of imine 10 (Scheme 4.7). Unfortunately, in both cases racemic product was obtained. In addition, when triphenylphosphine was used in combination with PipPhos L1 (Ir/L*/L = 1/2/1) only 2% conversion was obtained.

N 1 mol% [Ir(COD)Cl]2, 2 mol% (S)-PipPhos HN 2 mol% amine o CH2Cl2, 60 C, 50 bar H2 24h 10 10a

Amine Conversion (%) ee (%) Pyridine 88 0 Aniline 100 0

Scheme 4.7 Testing of the combination of (S)-PipPhos L1 and amines as ligands in the asymmetric hydrogenation of 10

When different iridium precursors were tested it turned out that

cationic precursors such as [Ir(COD)2]PF6, [Ir(COD)2]BF4 or [Ir(COD)2]BArF gave significantly higher enantioselectivity and conversions compared to

neutral [Ir(COD)Cl]2 in the hydrogenation of the model compound 10 (Table 4.2).

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Table 4.2 Screening of the iridium precursors in the asymmetric hydrogenation of 10a,b

N HN 1 mol% iridium precursor, (S)-PipPhos o CH2Cl2, 60 C, 50 bar H2 24h 10 10a

Iridium c d Entry precursor Conversion (%) ee (%)

1 [Ir(COD)2]PF6 100 61 2 [Ir(COD)2]BF4 100 56 3 [Ir(COD)2]BArF 100 61 4 [Ir(COD)Cl]2 89 5 aReaction conditions: 1 mmol of imine 10, 0.01 mmol of [Ir(COD)2]X, 0.02 mmol of (S)-PipPhos L1, 4 mL of CH2Cl2 at 50 bar and 60 °C, 24h. b0.01 mmol of [Ir(COD)Cl]2, 0.04 mmol of PipPhos L1. cConversion was determined by 1H NMR. dEnantiomeric excess was determined by GC using a Chiralsil DEX CB column.

Since [Ir(COD)2]PF6 and [Ir(COD)2]BArF gave the same enantioselectivity in the hydrogenation of 10 (61% ee), different monodentate phosphoramidites were tested in this reaction using less expensive

[Ir(COD)2]PF6, under the same reaction conditions (Scheme 4.8, Table 4.3). Full conversions were obtained in all cases except for ligands L1f and L2d, where only 28 and 63% conversion was obtained, respectively

(Entries 6 and 9). PipPhos L1 and H8-PipPhos L2d ligands induced the highest selectivities, however, the reaction with PipPhos L1 was significantly faster (61% and 62% ee, Entries 1 and 9). Similar results were achieved using Monophos L1a, and ligands L1b, L1e and L1g (Entries 2, 3, 5 and 7). The use of ligand L3d, with a 3,3’-substituted BINOL- backbone led to full conversion, however, the product was obtained with low ee (Entry 10). Similar results were obtained with the catechol derived ligand L4h (Entry 11).

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Preparation of chiral amines via asymmetric hydrogenation of imines

N HN 1 mol% [Ir(COD)2]PF6, 2 mol% L* o CH2Cl2, 60 C, 50 bar H2 24h 10 10a

O O O O P R P R P R P R O O O O

(S)-L1 (S)-L2 (S)-L3 (S)-L4

Amine moieties R:

N N N N N O

a bdec Ph

N N N N

Ph (S, S) fgh

Scheme 4.8 Phosphoramidite ligands examined in the in the asymmetric hydrogenation of N-phenyl-(1-phenyl-ethylidene)-amine 10

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Table 4.3 Screening of monodentate phosphoramidite ligands in the asymmetric hydrogenation of N-phenyl-(1-phenyl-ethylidene)-amine 10a

Entry Ligand Conversionb (%) eec (%) 1 L1 100 61 2 L1a 100 52 3 L1b 100 55 4 L1c 100 12 5 L1e 100 52 6 L1f 28 5 7 L1g 100 51 8 L1h 100 35 9 L2d 63 62 10 L3d 100 6 11 L4h 100 15 aReaction conditions: 1 mmol imine 10, 0.01 mmol of [Ir(COD)2]PF6, 0.02 mmol of (S)-PipPhos L1, 4 mL of CH2Cl2 at 50 bar and 60 °C, 24h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by GC using a Chiralsil DEX CB column.

Further hydrogenation experiments were performed in order to determine the optimal reaction conditions using (S)-PipPhos ligand (Table

4.4). While at 60 °C and under 50 bar of hydrogen pressure [Ir(COD)2]PF6

and [Ir(COD)2]BArF gave the same result in the hydrogenation of 10, at room temperature and lower pressures better result was obtained with

[Ir(COD)2]BArF (up to 87% ee, Entry 6). The reaction with [Ir(COD)2]BArF is strongly solvent dependent: in protic solvents such as methanol no reaction was observed (Entry 12). One reason for that could be the fact that the imine partially hydrolyses which leads to the formation of an amine. Formed amine can coordinate to the iridium preventing the coordination of the PipPhos ligand. Another reason could lie in the fact that phosphoramidites are good Π-acceptors, so the methanol could coordinate too strongly to the iridium atom and cause the push-pull effect, preventing the coordination of the substrate. Excellent conversions and high enantioselectivities (ee’s up to 87%) were obtained both in toluene and dichloromethane (Entries 7, 11). It was also observed that pressures above 5 bar caused a slight decrease in

enantioselectivity in the reaction with [Ir(COD)2]BArF, however, the reaction was faster (19h at 1 bar, 2h at 25 bar, Entries 6-8). No conversion

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Preparation of chiral amines via asymmetric hydrogenation of imines

was observed using neutral [Ir(COD)Cl]2 as catalyst precursor at rt and 5 bar, however, as mentioned earlier, at 50 bar and 60 °C 89% conversion was obtained albeit only with 5% ee (Entries 4 and 5).

Table 4.4 Screening of the reaction conditions in the asymmetric hydrogenation of N-phenyl-(1-phenyl-ethylidene)-amine 10a,b

N 1 mol% iridium precursor HN (S)-PipPhos

solvent, H2, 24h 10 10a

Entry Solvent Metal precursor P (bar) Conv.c (%) eed (%)

1 CH2Cl2 [Ir(COD)2]PF6 1 100 64

2 CH2Cl2 [Ir(COD)2]PF6 5 100 65 e 3 CH2Cl2 [Ir(COD)2]PF6 50 100 61

4 CH2Cl2 [Ir(COD)Cl]2 5 0 - e 5 CH2Cl2 [Ir(COD)Cl]2 50 89 5

6 CH2Cl2 [Ir(COD)2]BArF 1 100 87

7 CH2Cl2 [Ir(COD)2]BArF 5 100 80

8 CH2Cl2 [Ir(COD)2]BArF 25 100 73

9 EtOAc [Ir(COD)2]BArF 5 14 77

10 acetone [Ir(COD)2]BArF 5 12 80

11 toluene [Ir(COD)2]BArF 5 99 87

12 MeOH [Ir(COD)2]BArF 5 0 -

13 THF [Ir(COD)2]BArF 5 18 60 aReaction conditions: 1 mmol imine 10, 0.01 mmol of [Ir(COD)2]X, 0.02 mmol of (S)-PipPhos L1, 4 mL of solvent, 24h. b0.01 mmol of [Ir(COD)Cl]2, 0.04 mmol of PipPhos L1, 4 mL of CH2Cl2, 24h. cConversion was determined by 1H NMR. dEnantiomeric excess was determined by GC using a Chiralsil DEX CB column. eReaction performed at 60 °C.

4.3.1.1 Protective group screening

It is known that the nature of the substituent attached to nitrogen influences the properties of the C=N bond in terms of basicity, reduction potential, etc. Therefore, various N-aryl imines were hydrogenated using 1

mol% of [Ir(COD)2]BArF and 2 mol% of PipPhos L1, at room temperature and up to 5 bar of hydrogen pressure (Table 4.5).

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As mentioned in introduction, Pregosin has shown in several studies that introducing 3,5-di-tert-butylphenyl or 3,5-di-methylphenyl groups onto the MeO-Biphep ligand (instead of the phenyl substituent) enhances the ee’s in Heck reaction, allylic alkylation, as well as palladium catalyzed hydrosilylation and ring opening chemistry.24 In our case, the introduction of 3,5-dimethyl groups on the aryl ring of the substrate led to excellent enantioselectivities upon hydrogenation of the imine (Entries 4, 5). We assume that the reason for the excellent enantioselectivity also lies it the fact that there is a restricted rotation around the N-C bond of the N(3,5-dimethyl-phenyl) group. This decrease in molecular freedom perhaps derives from the restricted rotation due to the interaction of the N-aryl substituent with the ligand backbone and results in a more rigid chiral pocket and thus improved correlation between substrate and catalyst.

Table 4.5 Asymmetric hydrogenation of different N-substituted phenyl iminesa

Ar Ar N 1 mol% [Ir(COD)2]BArF HN 2 mol% (S)-PipPhos

CH2Cl2, rt, H2

10-15 10a-15a

b c Pressure Time ee d Entry Amine Ar (bar) (h) (%) Config. 1 10a Ph 1 19 87 R 2 11a p-MeO-Ph 5 3 71 R 3 12a o-MeO-Ph 5 10 97 R

4 13a 3,5-(CH3)2-Ph 1 26 >99 R

5 13a 3,5-(CH3)2-Ph 5 4 >99 R

6 14a 3,4,5-(OMe)3-Ph 1 6 99 -

7 14a 3,4,5-(OMe)3-Ph 5 1.5 99 - 3,5-(CH ) ,4-MeO- 8 15a 3 2 5 10 99 - Ph aReaction conditions: 1 mmol imine, 0.01 mmol of [Ir(COD)2]BArF, 0.02 mmol of (S)-PipPhos L1, 4 mL of CH2Cl2 at rt. bTime to achieve full conversion. cEnantiomeric excess was determined by GC or HPLC. dAbsolute configuration of the product is assigned by measuring the optical rotation and comparing it with literature data.

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Preparation of chiral amines via asymmetric hydrogenation of imines

As we considered it essential to have an aryl group which can be easily removed to afford the primary amines, we examined the additional introduction of a methoxy group at the 2- and 4-positions of the N-aryl group. Indeed substrates 14 and 15 could be hydrogenated with 99% ee (Entries 6-8). Although the rate of hydrogenation of trimethoxy-phenyl imine 14 was very high, the imine was shown to be susceptible to hydrolysis thus giving reproducibility problems. Since amines behave as catalyst poison we assume that the presence of aniline was the cause of the irreproducibility.6 As 3,5-dimethyl-4-methoxyaniline is fairly expensive we decided to test simple 2-and 4-anisidine based imines (Entries 2, 3). Although the 4-methoxy-group had a remarkable negative influence on the enantioselectivity (11a, Entry 2), hydrogenation of the imine, based on 2- anisidine gave the product 12a with 97% ee (Entry 3).

4.3.1.2 Scope

The scope of the reaction was examined on the series of imines based on 2-anisidine. A range of imines with electron-donating and -withdrawing substituents on the phenyl ring were studied (Table 4.6). All tested substrates (except 22) could be hydrogenated with excellent enantioselectivities (up to 99% ee, Entry 2) and turnover frequencies. Electron-donating or -withdrawing substituents in the 4-position gave comparable results (Entries 4-7). The NMR of all imines, except 23-26, showed the presence of only one isomer. Substrates 23 and 24 were hydrogenated with excellent ee, although those imines were isolated as a mixture of isomers (Entries 10, 11). Aliphatic imines 25 and 26 were hydrogenated with full conversions, however, with much lower enantioselectivity (up to 17% ee, Entries 12, 13).

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Table 4.6 Asymmetric hydrogenation of different N-o-MeO-phenyl iminesa

O O 1 mol% [Ir(COD)2]BArF, 2 mol% (S)-PipPhos N HN * CH2Cl2, rt, H2 R1 R2 R1 R2

12, 12a, 16-26 16a-26a

Entry Amine R1 R2 P (bar) Timeb (h) eec (%) 1 12a Ph Me 5 10 97 2 16a 2-Naphthyl Me 1 11 99 3 16a 2-Naphthyl Me 5 6 97 4 17a 4-Me-Ph Me 5 10 98 5 18a 4-Cl-Ph Me 5 3 97

6 19a 4-CF3-Ph Me 5 6 97 7 20a 4-F-Ph Me 5 6 97 8 21a 3-Me-Ph Me 5 30 93

9 22a 3-NO2-Ph Me 5 0.2 61 10 23a Ph Et 5 19 94d 11 24a Ph Pr 5 20 96d 12 25a n-butyl Me 5 <16 16d 13 26a n-pentyl Me 5 11 17d aReaction conditions: 1 mmol imine, 0.01 mmol of [Ir(COD)2]BArF, 0.02 mmol of (S)-PipPhos L1, 4 mL of dichloromethane at rt. bTime to achieve full conversion. cEnantiomeric excess was determined by HPLC. dImines prepared as mixture of E/Z isomers.

4.3.1.3 Deprotection of the N-o-methoxy-phenyl amines

Since chiral primary amines are important building blocks in the synthesis of various pharmaceutical intermediates and physiologically active compounds, efficient deprotection of chiral secondary amines is of major importance. Up to date, most reports describe oxidative removal of the N-p-methoxy- phenyl (PMP) and N-o-methoxyphenyl group with ceric ammonium nitrate (CAN) at low pH.18,58 Disadvantages of that procedure are that usually a large excess of CAN (4-5 equiv) is required and CAN is expensive and highly toxic. Some of these disadvantages also apply to phenyl iodoacetate, which has also been reported as a deprotecting agent.59,60 In recognition of these drawbacks, the Mioskowski group recently reported an

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Preparation of chiral amines via asymmetric hydrogenation of imines

electrochemical procedure for the oxidative removal of the PMP substituent.61 However, electrochemical reactions are poorly amenable to scale up, requiring special production equipment. In 2006, Rutjes reported deprotection of various N-PMP amines using different oxidation agents.62 Among the various PMP-protected amines, (4- methoxy-phenyl)-(1-phenyl-ethyl)-amine 11a was deprotected with 99% yield using trichloroisocyanuric acid (TCCA, Scheme 4.9). TCCA reacts with water, yielding hypochloric acid which oxidizes the amine.

Rutjes et al., 2006

O OMe O

HN - HN HN -2e +H2O +H2O 2 2 R R2 -MeOH R -H+

O HN NH2 OH2 -H+ R2 R2 +

O Cl H O N O O N O TCCA = + H O +HOCl NN 2 NN Cl Cl Cl Cl O O +2e- + 2HOCl (aq) + 2H Cl2 (g) + 2H2O

Scheme 4.9 Deprotection of the PMP-protected secondary amines by TCCA

In our case, the deprotection of the N-o-methoxy-phenyl amines proceeded using trichloroisocyanuric acid as the oxidant (Table 4.7). Reactions were performed in a mixture of acetonitrile and water in the presence of sulfuric acid, giving the desired primary amine in acceptable yield (up to 71%) and preserving the stereochemical integrity. Optimal yield

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was obtained using 1 equivalent of TCCA and 1 equivalent of sulfuric acid, at 90 °C (Entry 8). This yield is comparable with the known CAN (cerium ammonium nitrate) removal of the o-methoxy substituted N-phenyl group.18 When the reaction was performed in the microwave, yields were somewhat lower (up to 61%).

Table 4.7 Deprotection of o-methoxy-phenyl amines with TCCAa

. HN NH2 HCl TCCA, H2SO4 Ar Ar o CH3CN/H2O, 90 C 12a, Ar = Ph, 97% ee (R)-12b, 97% ee 16a, Ar = naphthyl, 99% ee (R)-16b, 99% ee 17a, Ar = 4-Me-Ph, 98% ee 17b, 98% ee Equiv. Equiv. Temperature Yield Entry Amine Time (h) TCCA H2SO4 (°C) (%) 1 12a 1 2 0 20 54 2 12a 0.33 1 25 20 49 3 12a 1 1 25 48 66 4 12a 1 2 25 20 55 5 12a 1 1 90 20 70 6 12a 1 2 90 20 57 7 16a 1 1 90 20 68 8 17a 1 1 90 20 71 a 0.5 mmol amine, CH3CN/H2O = 1/1, 10 mL, 1M H2SO4.

Various oxidants were also examined in the deprotection of (2-methoxy- phenyl)-(1-phenyl-ethyl)-amine 12a in order to improve the yield of the deprotection step (Table 4.8). When ceric ammonium nitrate was employed, only 25% yield was obtained (Entry 1). With a solution of sodium hypochlorite (commercial bleach) up to 51% yield was accomplished (Entries 2-4). Periodic acid gave product with 35% yield, while the use of Fremy’s salt and various iron(III) complexes with bipyridine ligand provided only traces of product (Entries 6-9). Finally, enzyme mediated deprotection gave no product (Entry 10).63

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Preparation of chiral amines via asymmetric hydrogenation of imines

Table 4.8 Various oxidants examined in the deprotection of (2-Methoxy- phenyl)-(1-phenyl-ethyl)-amine 12aa

. HN NH2 HCl Oxidant, H2SO4 Ph Ph CH3CN/H2O, rt 12a, 97% ee (R)-12b, 97% ee

Mol. equiv. Yield Entry Oxidant Temp. (°C) H2SO4 (%)

1 (NH4)2Ce(NO3)6 (3 eq.) 1 25 25 2 NaOCl (aq.) (2 eq.) 1 25 51 3 NaOCl (aq.) (2 eq.) 2 25 48 4 NaOCl (aq.) (2 eq.) 2 0 31

5 H5IO6 (1 eq.) 1 25 35 c 6 O-N(SO3K)2 (3 eq.) 1 25 0 FeCl + 2,2’-bipyridine 7 3 1 25 0 (2 eq.) K [Fe(CN) ] + 8 3 6 1 25 0 2,2’-bipyridine (2 eq.) Fe(NO ) x 9H O + 2,2’- 9 3 3 2 1 25 0 bipyridine (2 eq.) 10 Laccase 1 25 0b aOxidant was added to the solution of the amine 12a and H2SO4. bReaction was performed in THF with addition of phosphate buffer (pH = 3). cH2SO4 added after 16h. dOxidation potentials: E(Ce4+) = 1.38 V,64 E(NaOCl) = 1.12 V,65 E(HOCl) = 1.44 V,65 E(Fe(bipy)3+) = 0.66 V.64

The best result in the deprotection of (2-Methoxy-phenyl)-(1-phenyl- ethyl)-amine 12a was still accomplished with the use of trichloroisocyanuric acid, although we were not succeeding in further improving the yield. One of the possible reasons for that is that the oxidized amine is in equilibrium with it’s tautomeric form, which can get hydrolysed to acetophenone and aniline (Scheme 4.10). Signals of acetophenone were observed by 1H NMR of the organic layer after reaction. It is also possible that under the reaction conditions polymerization occurs, in that way lowering the yield of the deprotection.

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+ O MeO O

HN - N N * -2e * H2O

1 R R1 R1

O NH2 O +

+2e- + 2HOCl (aq) + 2H Cl2 (g) + 2H2O

Scheme 4.10 Possible side reaction in the deprotection of N-o-methoxy- phenyl amines

4.3.2 N-alkyl imines

We were also interested in the effect of an alkyl substituent on the nitrogen atom on enantioselectivity and conversion of the hydrogenation of imines. We were especially interested in N-benzyl imines, due to the possibility of the deprotection of the corresponding amines by hydrogenolysis. Therefore we hydrogenated benzyl-(1-phenyl-ethylidene)- amine 27, butyl-(1-phenyl-ethylidene)-amine 28 and butyl-indan-1- ylidene-amine 29 (Table 4.9). Reactions were performed using 1 mol% of

[Ir(COD)2]BArF and 2 mol% of (S)-PipPhos L1 in dichloromethane. Imine 27 was hydrogenated at room temperature and up to 25 bar of hydrogen pressure, however, only with up to 52% conversion and 8% ee (Entries 1, 2). In the hydrogenation of 28, conversion was achieved only at 25 bar of pressure, however, no enantioselectivity was observed even when the reaction mixture was heated (Entries 3, 5, 7). Indanone-derived imine 29 was hydrogenated with modest conversions and enantioselectivities up to 40%, at 25 bar of pressure (Entries 4, 6, 8). As mentioned earlier, Reetz reported the use of an iridium catalyst based on a mixture of monodentate ligands in the hydrogenation of N-alkyl imines, which significantly improved the enantioselectivity (up to 92% ee).41 In view of future improvements of our results, mixture of phosphoramidites with achiral

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Preparation of chiral amines via asymmetric hydrogenation of imines

phosphines should be examined in the asymmetric hydrogenation of N- alkyl imines.

Table 4.9 Asymmetric hydrogenation of N-alkyl iminesa

R R N HN *

1 mol% [Ir(COD)2]BArF, 27, 28 2 mol% (S)-PipPhos 27a, R = Bn 28a, R = butyl CH2Cl2, H2, 20h N HN *

29 29a

Entry Product P (bar) Temp (oC) Conv.b (%) eec (%) 1 27a 5 25 26 8 2 27a 25 25 52 7 3 28a 5 25 0 - 4 29a 5 25 0 - 5 28a 25 25 74 0 6 29a 25 25 29 29 7 28a 25 50 63 0 8 29a 25 50 47 40 aReaction conditions: 1 mmol imine, 0.01 mmol of [Ir(COD)2]BArF, 0.02 mmol of (S)-PipPhos L1, 4 mL of CH2Cl2, 20h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by HPLC.

4.3.3 Cyclic imines

Finally, we decided to test our catalyst in the hydrogenation of cyclic imines (Table 4.10). Prochiral dihydro-isoquinolines 30-32 were hydrogenated using 1 mol% of iridium precursor and 2 mol% of (S)- PipPhos L1. Different iridium precursors and conditions were tested in the hydrogenation of 30 (Entries 1-9). The best conversions were obtained using [Ir(COD)2]BArF in dichloromethane at 40 °C, however, the highest enantioselectivity was obtained in toluene at room temperature and 5 bar

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of pressure (62% ee, Entry 7). Under the same conditions dihydroisoquinoline 31 was hydrogenated with full conversion and 51% ee (Entry 10), while phenyl substituted imine 32 gave no conversion (Entry 11).

Table 4.10 Asymmetric hydrogenation of dihydroisoquinolinesa

1 mol% [Ir(COD) ]BArF R2 2 R2 2 mol% (S)-PipPhos N NH R2 solvent, H2, 16h R2 * R1 R1

30-32 30a, R1 = Me, R2 = MeO 31a, R1 = Me, R2 = EtO 32a, R1 = Ph, R2 = MeO

P Timeb Conv.c eed Entry Amine Ir precursor Solvent (bar) (h) (%) (%)

1 30a [Ir(COD)2]BArF CH2Cl2 5 25 93 43 2 30a [Ir(COD)2]BArF CH2Cl2 25 25 100 20

3 30a [Ir(COD)2]BArF CH2Cl2 5 40 100 42

4 30a [Ir(COD)2]BArF CH2Cl2 25 40 100 33

5 30a [Ir(COD)2]PF6 CH2Cl2 5 25 88 50

6 30a [Ir(COD)2]PF6 CH2Cl2 25 25 98 25

7 30a [Ir(COD)2]BArF toluene 5 25 62 62

8 30a [Ir(COD)2]BArF toluene 25 25 100 36

9 30a [Ir(COD)2]BArF MeOH 5 25 83 56

10 31a [Ir(COD)2]BArF toluene 5 25 100 51

11 32a [Ir(COD)2]BArF toluene 5 25 0 - aReaction conditions: 1 mmol imine, 0.01 mmol of [Ir(COD)2]X, 0.02 mmol of (S)-PipPhos L1, 4 mL of solvent at rt, 16h. bReaction time. cConversion was determined by 1H NMR. dEnantiomeric excess was determined by HPLC.

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Preparation of chiral amines via asymmetric hydrogenation of imines

In the hydrogenation of cyclic imine 33 using the same catalyst at room temperature and 5 bar of hydrogen pressure only 38% conversion and 10% ee was obtained (Scheme 4.11).

1 mol% [Ir(COD)2]BArF 2 mol% (S)-PipPhos * N CH2Cl2, rt, 5 bar H2, 42h N H 33 33a 38% conversion, 10% ee

Scheme 4.11 Asymmetric hydrogenation of 2,3,3-trimethyl-3H-indole 33

4.4 Methylaluminoxane as counterion in asymmetric hydrogenation of imines

As mentioned earlier, phosphoramidites are cheap ligands that are easy to make in only two synthetic steps. However, [Ir(COD)2]BArF precursor is very expensive (600 euros per 100 mg), which is making the hydrogenation of imines by using Ir/PipPhos not suitable for industrial applications. In many hydrogeantions BArF counterion outperformed PF6 counterion, which is attributed to its steric bulk.66 For these reasons the oligomeric methylaluminoxane (MAO) seemed as a good candidate for the replacement of BArF counterion.

MAO (Al(CH3)xOy)n is a poorly-defined oligomeric material, as a number of structures are present in solution. It is best known as a co-catalyst for olefin polymerizations using metallocenes or other homogenous transition metal catalysts.67 MAO alkylates and then activates the metal-chloride pre- catalyst species, forming an ion pair. It is prepared by a (controlled) hydrolysis of trimethylaluminium (TMA) and it always contains small amounts of TMA. TMA is a methylating agent and it can be removed by

reaction with phenol, in which it forms AlMe(OPh)2. We decided to examine the possibility to use MAO as a substitute for the expensive BArF counterion in imine hydrogenation (Scheme 4.12). Two imine substrates were chosen, N-aryl imine 13 and cyclic imine 30. The

reaction was performed using 2.5 mol% of [Ir(COD)Cl]2 at room

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temperature and 5 bar of hydrogen pressure. Two different ligands were used, phosphoramidite (S)-PipPhos L1 and phosphinooxazoline ligand L1i. In order to remove traces of TMA from MAO, bulky phenol 34 was used.

N HN ∗

1 mol% [Ir(COD)Cl] , L*, MAO, 33 132 13a CH2Cl2, rt, 5 bar H2 O 16h O

N ∗ NH O O

30 30a

O O P N O Ph2P N

L1d L1i

Scheme 4.12 Iridium catalyzed asymmetric hydrogenation of 13 and 30 using MAO as a counterion

Two different concentrations of the MAO solution were employed and three different amounts were screened (5, 50 and 500 equivalents with

respect to [Ir(COD)Cl]2). Catalysts were prepared in the glovebox and the hydrogenation was performed in the Premex 96-Multi Reactor with 96 reaction vessels. Solutions of MAO were dispersed by automatic dispenser into the vials, following by the addition of a phenol 34 solution. The substrate solution was then added, followed by addition of the catalyst

(pre-mixed solution of [Ir(COD)Cl]2 and ligand). Hydrogenation was carried out over 16h. Results obtained with 5, 50 and 500 equivalents of MAO are presented in Tables 4.11, 4.12 and 4.13.

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Preparation of chiral amines via asymmetric hydrogenation of imines

Table 4.11 Asymmetric hydrogenation of imines using 5 equivalents of MAOa,b

5 equivalents Conversionc (%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 0 2 17 10 CH2Cl2 30 38 18 61 66 With Toluene 13 6 0 12 2 Toluene 30 9 8 22 9 CH2Cl2 13 95 2 3 4 CH2Cl2 30 27 8 46 17 Without Toluene 13 48 0 14 2 Toluene 30 13 0 26 4 5 equivalents Eed(%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 - - 54 45 CH2Cl2 30 43 13 33 7 With Toluene 13 - - - - Toluene 30 14 26 -11 29 CH2Cl2 13 0 - - - CH2Cl2 30 28 40 27 1 Without Toluene 13 17 - - - Toluene 30 15 - -7 79 aReaction conditions: 100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 10 µmol (S)-PipPhos L1, 12.5 µmol MAO, 25 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. b100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 5 µmol L1i, 12.5 µmol MAO, 25 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. cConversion was determined by GC and HPLC. dEnantiomeric excess was determined by HPLC. eMAO A = 1.5 M in toluene, MAO B = 2.3 M in heptane.

Using 5 equivalents of MAO, with respect to the metal precursor, modest conversions were achieved. In the hydrogenation of cyclic substrate 30 the highest enantioselectivity was obtained using phosphinooxazoline ligand L1i in toluene, without use of phenol (79% ee), however, conversion was very low (4%). In the hydrogenation of N-aryl imine 13 the highest enantioselectivity was obtained using PipPhos L1 in dichloromethane, in the presence of phenol (17% conversion, 54% ee).

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Table 4.12 Asymmetric hydrogenation of imines using iridium catalyst and 50 equivalents of MAOa,b

5 equivalents Conversionc (%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 98 98 99 99 CH2Cl2 30 85 20 95 19 With Toluene 13 98 98 98 98 Toluene 30 74 12 87 9 CH2Cl2 13 98 98 99 5 CH2Cl2 30 95 15 97 12 Without Toluene 13 - 98 81 99 Toluene 30 11 5 94 12 5 equivalents Eed(%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 40 60 40 66 CH2Cl2 30 30 12 26 16 With Toluene 13 38 48 45 57 Toluene 30 6 14 32 -10 CH2Cl2 13 18 76 37 - CH2Cl2 30 15 -10 14 15 Without Toluene 13 - 59 42 70 Toluene 30 -27 12 4 24 aReaction conditions: 100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 10 µmol (S)-PipPhos L1, 125 mmol MAO, 250 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. b100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 5 µmol L1i, 125 µmol MAO, 250 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. cConversion was determined by GC and HPLC. dEnantiomeric excess was determined by HPLC. eMAO A = 1.5 M in toluene, MAO B = 2.3 M in heptane.

When 50 equivalents of MAO were used, high conversions were achieved with both substrates. High enantioselectivity was obtained in the hydrogenation of N-aryl imine 13 using phosphinooxazoline L1i in dichloromethane, without the use of phenol (98% conversion, 76% ee). Dihydroisoquinoline 30 was hydrogenated with up to 32% ee (87% conversion) in toluene, using PipPhos L1.

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Preparation of chiral amines via asymmetric hydrogenation of imines

Table 4.13 Asymmetric hydrogenation of imines using iridium catalyst and 500 equivalents of MAOa,b

500 equivalents Conversionc (%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 82 81 94 95 CH2Cl2 30 0 0 47 70 With Toluene 13 82 83 95 94 Toluene 30 0 0 0 32 CH2Cl2 13 3 2 13 40 CH2Cl2 30 0 0 0 0 Without Toluene 13 5 3 17 48 Toluene 30 0 0 0 0 500 equivalents Eed(%) MAO A MAO B Phenol Solvent Substrate Ir/L1 Ir/L1i Ir/L1 Ir/L1i CH2Cl2 13 35 15 30 60 CH2Cl2 30 - - 47 84 With Toluene 13 11 21 5 51 Toluene 30 - - - 66 CH2Cl2 13 - - - 89 CH2Cl2 30 - - - - Without Toluene 13 - - - 65 Toluene 30 - - - - aReaction conditions: 100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 10 µmol (S)-PipPhos L1, 1250 µmol MAO, 2500 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. b100 µmol imine, 2.5 µmol [Ir(COD)Cl]2, 5 µmol L1i, 1250 µmol MAO, 2500 µmol phenol 34, 2.45 mL of solvent, rt, 5 bar H2, 16h. cConversion was determined by GC and HPLC. dEnantiomeric excess was determined by HPLC. eMAO A = 1.5 M in toluene, MAO B = 2.3 M in heptane.

When 500 equivalents of MAO were used, conversions to desired product were mostly very low, especially of the cyclic imine 30. In the cases where there was no product observed, the starting material was also decomposed. The highest enantioselectivity was obtained in the hydrogenation of N-aryl imine 13 using phosphinooxazoline ligand L1i in dichloromethane, without presence of phenol (89% ee, 40% conversion). Dihydroisoquinoline 30 was hydrogenated with up to 84% ee (70% conversion) in dichloromethane with phosphinooxazoline ligand L1i, with addition of phenol. It seems that in most of the cases slightly better results are obtained when phenol was used as additive, however this effect needs to be further investigated.

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These results show that MAO is a good potential substitute for an expensive BArF counterion in the asymmetric hydrogenation of imines. For the good evaluation of the reactions with MAO, it is essential to perform additional experiments. Oxazoline ligand L1i should be examined in the hydrogenation of imines with BArF as counterion so that the result could be compared with the results obtained with MAO as a counterion. Different phenols could also be tested, as well as solvents, temperatures and equivalents of MAO. The disadvantage of this method is the fact that a large excess of MAO is needed. Enantioselectivities are modest in most of the cases. In addition, phenol is added to the reaction mixture, making the product less easy to purify.

4.5 Conclusion

In conclusion, we have developed a new hydrogenation method for a range of acyclic N-aryl imines with excellent enantioselectivities and high TOF’s, using an in situ prepared iridium catalyst based on the monodentate phosphoramidite ligand PipPhos. The advantage of the method described in this chapter compared to the previously reported results in the imine hydrogenation field is that PipPhos ligand is cheap and easily accessible. It can be synthesized in two steps starting from cheap BINOL, in high yield. In addition, the hydrogenations are perforemed at low pressure and room temperature. We have proven that aryl imines isolated as mixtures of isomers can also be hydrogenated with excellent enantioselectivity. Full conversions were obtained and ee’s up to >99% were reached. Products were deprotected smoothly with preservation of stereochemical integrity. On the contrary, aliphatic N-o-methoxy-phenyl imines were hydrogenated with low enantioselectivity using the iridium/PipPhos catalytic system. The same catalytic system was not successful in the hydrogenation of N-alkyl imines, where low conversions and enantioselectivities only up to 40% were obtained. Cyclic imines were hydrogenated with full conversions and ee’s up to 62%. Methylaluminoxane was shown to be an efficient potential substitute for the expensive BArF counterion in the imine hydrogenation. Further

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Preparation of chiral amines via asymmetric hydrogenation of imines

experiments have to be carried out in order to compare performance of the catalyst with BArF and MAO as counterions, in more detail.

4.6 Experimental section

General remarks (see Chapter 2)

The metal precursor [Ir(COD)2BArF]2 was obtained from Umicore. The catalyst was prepared in situ. Reactions were performed in stainless steal autoclave containing 7 glass vessels (8 mL volume). The vessels were closed with caps containing septa. Magnetic stirrers were placed inside each vessel and needles were placed through the septa in order to enable entrance of hydrogen. Vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. The enantiomeric excess was determined by HPLC with chiral columns (Chiralcel AD, OD-H, AS-H, OJ-H) or by GC with Chiralsil DEX CB, in comparison with racemic products. Racemic amines were prepared by reduction of the imines with sodium borohydride in ethanol. Ligands L1,68 L1a-L1e,68 L1f, L1g,69 L1h,68 L2d,69 L3d,70 L4h,71 were prepared according to the literature procedure. Imines 30-33 were purchased and used in hydrogenation without purification.

General experimental procedure for the preparation of the imines

A 100 mL round-bottom flask was filled with ketone (50 mmol) and amine (60 mmol) and molecular sieves (4Å, 20 g) in toluene (30 mL). The reaction mixture was stirred at room temperature overnight, filtered and the solvent was evaporated. The crude product was purified by Kugelrohr distillation. Solid imines were recrystallized from dry pentane or ether.

General experimental procedure for hydrogenation

A mixture of iridium precursor (0.01 mmol), chiral ligand (Ir/L* = 1/2), and substrate (1 mmol) was dissolved in solvent, in a glass vial and provided with a stirring bar. The vial was placed in a stainless steel autoclave. After the reaction, hydrogen pressure was carefully released. Solvent was removed in vacuo and conversion was determined by 1H NMR. Product was purified by chromatography column over silica gel

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(heptane/EtOAc). Absolute configurations were determined by measuring optical rotation and comparison with literature data.

General procedure for the deprotection of the hydrogenation products 12a and 16a

In 10 mL of a mixture of acetonitrile and water (1/1), 0.50 mmol of secondary amine was dissolved. Then 500 µL of 1M sulphuric acid and 118 mg (0.50 mmol) of trichloroisocyanuric acid were added to the solution. The reaction was heated at 90 °C for 18h. The cooled reaction mixture was extracted with dichloromethane (3 x 100 mL). The resulting aqueous phase was subsequently brought to pH 10.5 through the addition of 2M aqueous KOH and extracted with ethyl acetate (3 x 100 mL). The organic layer was acidified with conc. HCl, dried and concentrated. The product was isolated as its hydrochloride salt.

General procedure for the hydrogenation experiments with the use of MAO as a counterion

Reactions were performed using 2.5 mol% of [Ir(COD)Cl]2 (2.5 µmol, 1.67 mg) at room temperature and 5 bar of hydrogen pressure.

PipPhos L1 (10 µmol, 3.99 mg) and [Ir(COD)Cl]2 (2.5 µmol, 1.67 mg) were dissolved in 200 µmol of solvent was pipetted per each vial.

Phosphinooxazoline ligand L1i (5 µmol, 1.86 mg) and [Ir(COD)Cl]2 (2.5 µmol, 1.67 mg) were dissolved in 200 µmol of solvent was pipetted per each vial.

For 5 eq. of MAO:

Phenol 34 (25 µmol, 5.51 mg, per reaction vial), added as a solution in DCM or toluene (100 µL, 0.055 M). MAO A (1.5 M in toluene), for 5 eq. of MAO: 300 µL of MAO B diluted with 3.60 mL of heptane. 100 µL of solution was pipetted per each reaction vial. MAO B (2.3 M in heptane), for 5 eq. of MAO: 200 µL of MAO B diluted with 3.68 mL of heptane. 100 µL of solution was pipetted per each reaction vial.

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Preparation of chiral amines via asymmetric hydrogenation of imines

For 50 eq of MAO:

Phenol 34 (250 µmol, 55.1 mg per reaction vial), added as a solution in DCM or toluene (100 µL, 0.055 M). MAO A (1.5 M in toluene), for 50 eq. of MAO: 83 µL of solution was pipetted per each reaction vial. MAO B (2.3 M in heptane), for 50 eq. of MAO: 54 µL of solution was pipetted per each reaction vial.

For 500 eq of MAO:

Phenol 34 (2.5 mmol, 551 mg per reaction vial), added as a solid. MAO A (1.5 M in toluene), for 500 eq. of MAO: 833 µL of solution was pipetted per each reaction vial. MAO B (2.3 M in heptane), for 500 eq. of MAO: 544 µL of solution was pipetted per each reaction vial. Substrates were added as a solution in DCM or toluene (100 µmol of substrate, 2.25 mL of solvent).

Solutions were pipetted in the glovebox and the hydrogenation was performed in the Premex 96-Multi Reactor with 96 reaction vessels. Solutions of MAO were dispersed by automatic dispenser into the vials, following by the addition of phenol 34 solution. Substrate solution was then added, followed by addition of catalyst (pre-mixed solution of

[Ir(COD)Cl]2 and ligand). Hydrogenation was carried out over 16h.

N-Phenyl-(1-phenyl-ethylidene)-amine (10)25

Light yellow solid, 80% yield, Mp = 40.1 – 40.5 °C; 1H NMR (400 MHz,

CDCl3) 2.27 (s, 3H), 6.84 – 6.86 (m, 2H), 7.11 – 7.15 (m, 1H), 7.37 – 7.41 (m, 2H), 7.48 – 7.51 (m, 3H), 8.01 – 8.04 (m, 2H) ppm; 13C NMR (100 MHz,

CDCl3) 18.3, 120.3, 124.2, 128.1, 129.3, 129.9, 131.4, 140.4, 152.7, 166.4

ppm; HRMS Calcd. for C14H13N (M+1) 195.1048, found 195.1056.

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Chapter 4

N-(4-Methoxy-phenyl)-(1-phenyl-ethylidene)-amine (11)25,72

1 Yellow solid, 46% yield, Mp = 86.5 – 86.7 °C; H NMR (400 MHz, CDCl3) 2.26 (s, 3H), 3.82, (s, 3H), 6.75 – 6.78 (m, 2H), 6.90 – 6.93 (m, 2H), 7.44 – 13 7.46 (m, 3H), 7.95 – 7.99 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 18.2, 56.4, 115.2, 121.7, 128.0, 129.3, 131.2, 140.7, 145.8, 156.9, 166.6 ppm;

HRMS Calcd. for C15H15NO (M+1) 225.1154, found 225.1143.

N-(2-Methoxy-phenyl)-(1-phenyl-ethylidene)-amine (12)72

1 Yellow solid, 60% yield, Mp = 48 – 48.5 °C; H NMR (400 MHz, CDCl3) 2.20 (s, 3H), 3.80 (s, 3H), 6.78 – 6.82 (m, 1H), 6.93 – 7.10 (m, 3H), 7.44 – 7.50 13 (m, 3H), 8.01 – 8.06 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 18.7, 56.6, 112.5, 121.5, 121.8, 125.1, 128.2, 129.2, 131.3, 140.4, 141.6, 149.9,

168.0 ppm; HRMS Calcd. for C15H15NO (M+1) 225.1154, found 225.1145.

N-(3,5-Dimethyl-phenyl)-(1-phenyl-ethylidene)-amine (13)25

1 Yellow oil, 75% yield; H NMR (400 MHz, CDCl3) 2.25 (s, 3H), 2.34 (s, 6H), 6.44 (s, 2H), 6.75 (s, 1H), 7.44 – 7.48 (m, 3H), 7.96 – 8.0 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 18.3, 22.3, 117.9, 125.8, 128.1, 129.3, 131.3,

139.5, 140.6, 152.7, 165.9 ppm; HRMS Calcd. for C16H17N (M+1) 223.1361, found 223.1359.

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Preparation of chiral amines via asymmetric hydrogenation of imines

N-(1-Phenyl–ethylidene)-(3,4,5-trimethoxy-phenyl)-amine (14)

O O

N O

Light yellow solid, 34% yield, Mp = 101.6 – 103 °C; 1H NMR (400 MHz,

CDCl3) 2.26 (s, 3H), 3.81 (m, 9H), 6.02 (s, 2H), 7.42 – 7.43 (m, 3H), 7.94 – 13 7.96 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 18.3, 56.9, 61.8, 97.4, 128.0, 129.2, 131.4, 134.6, 140.1, 148.8, 154.4, 166.8 ppm, HRMS Calcd. for C17H19NO3 (M+1) 285.1365, found 285.1371.

N-(4-Methoxy-3,5-dimethyl-phenyl)-(1-phenyl-ethylidene)-amine (15)25

Light yellow solid, 79% yield, Mp = 65.7 – 66.2 °C; 1H NMR (400 MHz,

CDCl3) 2.26 (s, 3H), 2.29 (s, 6H), 3.73 (s, 3H), 6.45(s, 2H), 7.43 – 7.46 (m, 13 3H), 7.93 – 7.98 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 16.4, 17.6, 60.1, 119.7, 127.3, 128.5, 130.5, 131.4, 139.9, 147.5, 153.2, 165.4 ppm; HRMS

Calcd. for C17H19NO (M+1) 253.1467, found 253.1457.

N-(2-Methoxy-phenyl)-(1-naphthalen-2-yl-ethylidene)-amine (16)

Light yellow solid, 76% yield, Mp = 103.8 – 103.9 °C; 1H NMR (400 MHz,

CDCl3) 2.32 (s, 3H), 3.82 (s, 3H), 6.82 – 6.87 (m, 1H), 6.95 – 7.12 (m, 3H), 7.51 – 7.56 (m, 2H), 7.86 – 7.97 (m, 3H), 8.26 – 8.32 (m, 1H), 8.39 (s, 1H)

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Chapter 4

13 ppm; C NMR (100 MHz, CDCl3) 18.7, 56.6, 112.5, 121.6, 121.9, 125.2, 125.4, 127.2, 128.0, 128.6, 128.9, 129.9, 133.9, 135.4, 137.7, 141.6,

149.9, 167.8 ppm; HRMS Calcd. for C19H17NO (M+1) 275.1310, found 275.1309.

N-(2-Methoxy-phenyl)-(1-p-tolyl-ethylidene)-amine (17)

1 Yellow oil, 60% yield; H NMR (400 MHz, CDCl3) 2.17 (s, 3H), 2.42 (s, 3H), 3.79 (s, 3H), 6.78 – 6.80 (m, 1H), 6.93 – 7.10 (m, 3H), 7.25 – 7.27 (m, 2H), 13 7.92 – 7.94 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 18.6, 22.3, 56.6, 112.6, 121.6, 121.8, 124.9, 128.2, 129.9, 137.7, 141.5, 141.7, 150.0,

167.7 ppm; HRMS Calcd. for C19H17NO (M+1) 239.1310, found 239.1309.

N-[1-(4-Chloro-phenyl)-ethylidene]-(2-methoxy-phenyl)-amine (18)

Cl Light yellow solid, 46% yield, Mp = 62.8 – 62.9 °C; 1H NMR (400 MHz,

CDCl3) 2.16 (s, 3H), 3.79 (s, 3H), 6.76 – 6.78, (m, 1H), 6.93 – 6.99 (m, 2H), 7.07 – 7.11 (m, 1H) 7.40 – 7.42 (m, 2H), 7.95 – 7.97 (m, 2H) ppm; 13C NMR

(100 MHz, CDCl3) 18.6, 56.5, 112.5, 121.4, 121.8, 125.3, 129.4, 129.6,

137.4, 138.7, 141.2, 149.8, 166.8 ppm; HRMS Calcd. for C15H14ClNO (M+1) 259.0764, found 259.0772.

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Preparation of chiral amines via asymmetric hydrogenation of imines

N-(2-Methoxy-phenyl)-[1-(4-trifluoromethyl-phenyl)-ethylidene]-amine (19)

F3C Light yellow solid, 34% yield, Mp = 87.1 – 87.3 °C; 1H NMR (400 MHz,

CDCl3) 2.20 (s, 3H), 3.80 (s, 3H), 6.76 – 6.80 (m, 1H), 6.94 – 7.15 (m, 3H), 13 7.68 – 7.72 (m, 2H), 8.10 – 8.14 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 18.8, 56.5, 112.5, 121.3, 121.9, 125.0 (q, J = 272.2 Hz), 125.5 (q, J = 3.7 Hz), 125.5, 128.6, 132.9 (q, J = 32.6 Hz), 141.0, 143.5, 149.6, 166.9 ppm; 19 F (376 MHz, CDCl3) -63.1 ppm HRMS Calcd. for C16H14F3NO (M+1) 293.1028, found 293.1014.

N-[1-(4-Fluoro-phenyl)-ethylidene]-(2-methoxy-phenyl)-amine (20)

F Light yellow solid, 55% yield, Mp = 65.7 – 65.9 °C; 1H NMR (400 MHz,

CDCl3) 2.17 (s, 3H), 3.80 (s, 3H), 6.77 – 6.80 (m, 1H), 6.94 – 7.0 (m, 2H), 13 7.07 – 7.14 (m, 3H), 8.01 – 8.05 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 17.9, 55.8, 111.8, 115.4 (d, J = 21.5 Hz), 120.8, 121.2, 124.5, 129.6, 129.7, 135.8, 140.6, 149.2, 164.5 (d, J = 250.36 Hz), 166.0 ppm; 19F (376

MHz, CDCl3) -111.0 ppm; HRMS Calcd. for C15H14FNO (M+1) 243.1059, found 243.1048.

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Chapter 4

N-(2-Methoxy-phenyl)-(1-m-tolyl-ethylidene)-amine (21)

Light yellow solid, 61% yield, Mp = 64.8 – 64.9 °C; 1H NMR (400 MHz,

CDCl3) 2.17 (s, 3H), 2.42 (s, 3H), 3.79 (s, 3H), 6.76 – 6.79 (m, 1H), 6.92 – 6.98 (m, 2H), 7.05 – 7.09 (m, 1H), 7.26 – 7.35 (m, 2H), 7.75 – 7.77 (m, 1H), 13 7.88 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 18.8, 22.4, 56.5, 112.4, 121.5, 121.8, 125.0, 125.4, 128.7, 129.1, 132.1, 138.9, 140.3, 141.6,

149.8, 168.2 ppm; HRMS Calcd. for C16H17NO (M+1) 239.1310, found 239.1297.

N-(2-Methoxy-phenyl)-[1-(3-nitro-phenyl)-ethylidene]-amine (22)

O2N

1 Yellow solid, 76% yield, Mp = 89.7 – 90.1 °C; H NMR (400 MHz, CDCl3) 2.23 (s, 3H), 3.80 (s, 3H), 6.77 – 6.80 (m, 1H), 6.95 – 7.00 (m, 2H), 7.09 – 7.12 (m, 1H), 7.59 – 7.64 (m, 1H), 8.28 – 8.31 (m, 1H), 8.36 – 8.39 (m, 1H), 13 8.81 – 8.83 (m, 1H) ppm; C NMR (100 MHz, CDCl3) 18.7, 56.5, 112.4, 121.3, 121.8, 123.2, 125.7, 125.8, 130.2, 134.1, 140.5, 141.9, 149.3,

149.5, 165.8 ppm; HRMS Calcd. for C15H14N2O3 (M+1) 271.10772, found 271.10760.

N-(2-Methoxy-phenyl)-(1-phenyl-propylidene)-amine (23)

Light yellow solid, 47% yield, Mp = 55.7 – 57.0 °C, mixture of isomers 1 (6.7/1); H NMR (400 MHz, CDCl3) 1.05 (t, J = 7.68 Hz, 3H (major isomer)),

152

Preparation of chiral amines via asymmetric hydrogenation of imines

1.25 (t, J = 7.42 Hz, 3H (minor isomer)), 2.60 (q, J = 7.67 Hz, 2H (major isomer)), 2.84 (q, J = 7.42 Hz, 2H (minor isomer)), 3.70 (s, 3H (minor isomer)), 3.79 (s, 3H (major isomer)), 6.75 – 6.77 (m, 1H), 6.93 – 6.98 (m, 2H), 7.05 – 7.09 (m, 1H), 7.44 – 7.46 (m, 3H), 7.95 – 7.98 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 13.1, 25.1, 56.5, 112.4, 121.1, 121.8, 124.8, 128.7, 129.3, 131.2, 139.0, 141.6, 149.7, 173.1 ppm; HRMS Calcd. for

C16H17NO (M+1) 239.1310, found 239.1314.

N-(2-Methoxy-phenyl)-(1-phenyl-butylidene)-amine (24)

Yellow oil, 27% yield, 7% of enamine present, mixture of isomers 3.9:1; 1H

NMR (400 MHz, CDCl3) 0.81 (t, J = 7.41 Hz, 3H (major isomer)), 1.06 (t, J = 7.39 Hz, 3H (minor isomer)), 1.44 – 1.54 (m, 2H (major isomer)), 1.66–1.72 (m, 2H (minor isomer)), 2.22 (t, J = 7.35 Hz, 2H (minor isomer)), 2.54 – 2.58 (m, 2H (major isomer)), 3.78 (s, 3H, (major isomer)), 3.93 (s, 3H (minor isomer)), 6.74 – 6.76 (m, 1H), 6.92 – 6.98 (m, 2H), 7.04 – 7.09 (m, 1H), 7.43 – 7.45 (m, 3H), 7.92 – 7.95 (m, 2H) ppm; 13C NMR (100 MHz,

CDCl3) 14.6, 15.0, 20.9, 21.8, 33.8, 44.0, 56.5, 111.8, 112.3, 121.1, 121.4, 121.7, 122.1, 124.8, 127.1, 127.8, 128.6, 129.2, 131.1, 139.4, 141.5,

149.7, 172.1 ppm; HRMS Calcd. for C17H19NO (M+1) 254.15394, found 254.15384.

N-(hexan-2-ylidene)-2-methoxyaniline (25)

Yellow liquid, 35% yield, mixture of isomers 3.9:1; 1H NMR (400 MHz,

CDCl3) 0.79 (minor isomer, t, J = 7.24 Hz, 3H), 0.96 (major isomer, t, J = 7.21 Hz, 3H), 1.19 (minor isomer, sextet, J = 7.20 Hz, 2H), 1.43 (major isomer, sextet, J = 7.37 Hz, 2H), 1.67 (major isomer, quintet, J = 7.37 Hz, 2H), 1.72 (s, 3H), 2.06 (minor isomer, t, J = 8.09 Hz, 2H), 2.19 (minor

153

Chapter 4

isomer, s, 3H), 2.45 (t, J = 7.30 Hz, 2H), 3.76 (s, 3H), 6.61 – 6.67 (m, 1H), 13 6.84 – 7.05 (m, 3H) ppm; C NMR (100 MHz, CDCl3) 14.7, 14.9, 20.6, 23.3, 23.5, 26.8, 29.6, 35.3, 42.4, 56.3, 56.4, 111.9, 112.3, 121.5, 121.6, 121.7, 124.7, 140.9, 141.4, 150.1, 174.8, 175.2 ppm; HRMS Calcd. for

C13H19NO (M+1) 205.1467, found 205.1464.

2-methoxy-N-(octan-2-ylidene)aniline (26)

Light yellow liquid, 40% yield, mixture of isomers 3.3:1; 1H NMR (400 MHz,

CDCl3) 0.82 (minor isomer, t, J = 7.11 Hz, 3H), 0.89 (major isomer, t, J = 6.90 Hz, 3H), 1.12 – 1.23 (major isomer, m, 2H), 1.30 – 1.42 (major isomer, m, 6H), 1.63 – 1.68 (minor isomer, m, 2H), 1.71 (s, 3H), 2.05 (minor isomer, t, J = 8.04 Hz, 2H), 2.18 (minor isomer, s, 3H), 2.44 (major isomer, t, J = 7.85 Hz, 2H), 3.75 (s, 3H), 6.62 – 6.66 (m, 1H), 6.85 – 6.90 (m, 2H), 13 6.97 – 7.03 (m, 1H) ppm; C NMR (100 MHz, CDCl3) 14.9, 15.0, 20.5, 23.3, 23.5, 26.7, 27.3, 27.4, 29.8, 30.0, 32.3, 32.6, 35.5, 42.6, 56.4, 111.9, 112.2, 121.4, 121.5, 121.6, 124.6, 124.7, 140.9, 141.4, 150.1, 174.7, 175.2 ppm.

Benzyl-(1-phenyl-ethylidene)-amine (27)7,73

1 Colourless oil, solidifies slowly, 58% yield; H NMR (400 MHz, CDCl3) 2.35 (s, 3H), 4.76 (s, 2H), 7.26 – 7.45 (m, 8H), 7.85 – 7.95 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 15.8, 55.6, 126.5, 126.6, 127.7, 128.2, 128.3, 129.5, 140.5, 141.1, 165.9 ppm.

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Preparation of chiral amines via asymmetric hydrogenation of imines

N-(1-phenylethylidene)butan-1-amine (28)72

Colourless oil, 69% yield, mixture of isomers 3.3:1; 1H NMR (400 MHz,

CDCl3) 0.88 (minor isomer, t, J = 7.31 Hz, 3H), 1.01 (major isomer, t, J = 7.31 Hz, 3H), 1.3 (minor isomer, sextet, J = 7.71 Hz, 2H), 1.49 (major isomer, sextet, J = 7.60 Hz, 2H), 1.75 (major isomer, quintet, J = 7.36 Hz, 2H), 2.24 (s, 3H), 3.49 (t, J = 7.12 Hz, 2H), 7.37 – 7.39 (m, 3H), 7.77 – 7.81 13 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 15.0, 21.7, 34.0, 52.9, 127.4, 129.1, 130.1, 142.4, 165.6 ppm.

N-(2,3-dihydro-1H-inden-1-ylidene)butan-1-amine (29)

1 Colourless oil, 31% yield; H NMR (400 MHz, CDCl3) 0.97 (t, J = 7.35 Hz, 3H), 1.44 (sextet, J = 6.44 Hz, 2H), 1.72 (quintet, J = 7.20 Hz, 2H), 2.69 (t, J = 6.45 Hz, 2H), 3.06 (t, J = 6.07 Hz, 2H), 3.46 (t, J = 7.24 Hz, 2H), 7.25 – 13 7.38 (m, 3H), 7.82 (d, J = 7.56 Hz, 1H) ppm; C NMR (100 MHz, CDCl3) 15.0, 21.8, 28.8, 29.0, 54.6, 123.1, 126.4, 127.7, 131.7, 140.8, 150.3,

174.5 ppm; HRMS Calcd. for C13H17N (M+1) 188.14338, found 188.14279.

(R)-N-Phenyl-1-phenyl-ethylamine (10a)25,29,74

25 Yellow oil, 95% yield, 87% ee, [α]D = -4.5 (c 1.05, CHCl3), lit. value 84% 1 ee, [α]D = –3.9 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) 1.53 (d, J = 6.7 Hz, 3H), 3.98 (br, 1H), 4.50 (q, J = 6.7, 1H), 6.52 (d, J = 7.6 Hz, 2H), 6.66 (t, J = 7.33 Hz, 1H), 7.09 – 7.13 (m, 2H), 7.22 – 7.26 (m, 1H), 7.31 – 7.40 13 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 25.9, 54.4, 114.2, 118.1, 126.8,

127.8, 129.6, 130.0, 146.2, 148.2 ppm; HRMS Calcd. for C14H15N (M+1)

155

Chapter 4

197.1204, found 197.1196, GC Chiralsil DEX CB, (initial temp. 100 °C for 5 min, then 5 °C/min to 160 °C, then 10 °C/min to 170 °C, then 10

°C/min to 100 °C), t1 = 31.5 min, t2 = 34.3 min.

(R)-N-(4-Methoxy-phenyl)-1-phenyl-ethylamine (11a)25,29,34

Yellow solid, 92% yield, Mp = 63.8 – 63.9 °C, 71% ee, [α]D = +1.4 (c 1.00, 25 1 CHCl3), lit. value 88% ee, [α]D = +1.3 (c 1.00, CHCl3); H NMR (400 MHz,

CDCl3) 1.50 (d, J = 6.7 Hz, 3H), 3.86 (br, 1H), 3.70 (s, 3H), 4.42 (q, J = 6.7 Hz, 1H), 6.47 – 6.49 (m, 2H), 6.69 – 6.71 (m, 2H), 7.22 – 7.24 (m, 1H), 13 7.30 – 7.38 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 26.0, 55.1, 56. 6, 115.4, 115.6, 126.8, 127.7, 129.5, 142.5, 146.4, 152.8 ppm; HRMS Calcd. for C15H17NO (M+1) 227.1310, found 227.1300; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 26.2 min, t2 = 28.5 min.

(R)-N-(2-Methoxy-phenyl)-1-phenyl-ethylamine (12a)75

Light brown solid, 93% yield, Mp = 71.4 °C, 97% ee, [α]D = -32.3 (c 1.03,

CHCl3), absolute configuration was determined by measuring the optical rotation of deprotected derivatized product 12c and comparing it with 76 1 literature data ; H NMR (400 MHz, CDCl3) 1.71 (d, J = 6.7 Hz, 3H), 4.02 (s, 3H), 4.65 (q, J = 6.7 Hz, 1H), 4.83 (br, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.78 – 6.81 (m, 1H), 6.87 – 6.94 (m, 2H), 7.36 – 7.40 (m, 1H), 7.46 – 7.50 13 (m, 2H), 7.54 – 7.56 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 26.0, 54.1, 56.2, 110.1, 111.9, 117.2, 122.0, 126.7, 127.6, 129.4, 138.0, 146.3, 147.4 ppm; HRMS Calcd. for C15H17NO (M+1) 227.1310, found 227.1302; HPLC

156

Preparation of chiral amines via asymmetric hydrogenation of imines

(OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5

mL/min), t1 = 14.6 min, t2 = 19.0 min.

(R)-N-1-Phenyl-ethylamine hydrochloride (12b)

. NH2 HCl

Light brown solid, 70% yield, Mp = 142.5 – 142.7 °C; 1H NMR (400 MHz,

D2O) 1.64 (d, J = 6.91 Hz, 3H), 4.53 (q, J = 6.86 Hz, 1H), 7.47 – 7.52 (m, 13 5H) ppm; C NMR (100 MHz, D2O) 19.5, 51.2, 126.7, 129.3, 129.4, 137.9

ppm; HRMS Calcd. for C8H12ClN (M+1–HCl) 122.09643, found 122.09645; product was derivatized with acetic anhydride in the presence of triethylamine and the ee of the N-Ac derivative 12c was determined by GC.

(R)-N-(1-Phenyl-ethyl)-acetamide (12c)76

NHAc

1 Light brown solid, 97% ee; H NMR (400 MHz, CDCl3) 1.47 (d, J = 6.91, 3H), 1.97 (s, 3H), 5.13 (q, J = 7.20 Hz, 1H), 5.88 (br, 1H), 7.26 – 7.34 (m, 13 5H) ppm; C NMR (100 MHz, CDCl3) 22.6, 24.4, 49.7, 127.2, 128.3, 129.6, 144.1, 170.1 ppm; GC Chiralsil DEX CB, initial temp. 125 °C for 4 min, then 3 °C/min to 140 °C, then 10 °C/min to 180 °C, then 10 °C/min to

125 °C), t1 = 13.0 min, t2 = 13.25 min.

(R)-N-(3,5-Dimethyl-phenyl)-(1-phenyl-ethyl)-amine (13a)77

1 Yellow oil, 97% yield, >99% ee, [α]D = +12.3 (c 1.02, CHCl3); H NMR (400

MHz, CDCl3) 1.62 (d, J = 6.7 Hz, 3H), 2.32 (s, 6H), 4.02 (br, 1H), 4.61 (q, J = 6.7 Hz, 1H), 6.31 (s, 2H), 6.47(s, 1H), 7.34 – 7.37 (m, 1H), 7.43 – 7.47 (m, 13 2H), 7.50 – 7.52 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 22.4, 25.8, 54.2,

157

Chapter 4

112.2, 120.2, 126.8, 127.7, 129.5, 139.6, 146.4, 148.3 ppm; HRMS Calcd. for C16H19N (M+1) 225.1517, found 225.1504. HPLC (OD-H, eluent:heptane/i-PrOH = 90/10, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 8.5 min, t2 = 9.0 min.

In a HTE experiment with MAO conversion was determined by GC:

Agilent HP-5, initial temp. 80°C for 2min, then 15°C/min to 280°C, hold 4 min, retention times: starting imine t = 11.9 min, product t = 11.5 min.

(–)-N-(1-Phenyl-ethyl)-3,4,5-trimethoxy-phenyl-amine (14a)

O O

HN O *

1 Yellow oil, 94% yield, 99% ee, [α]D = -21.0 (c 1.09, CHCl3); H NMR (400

MHz, CDCl3) 1.51 (d, J = 6.7 Hz, 3H), 3.68 (s, 6H), 3.74 (s, 3H), 4.09 (br, 1H), 4.44 (q, J = 6.7 Hz, 1H), 5.77 (s, 2H), 7.21 – 7.25 (m, 1H), 7.31 – 7.35 13 (m, 2H), 7.38 – 7.40 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 25.7, 54.8, 56.4, 61.7, 91.7, 126.5, 127.6, 129.4, 130.4, 144.9, 146.2, 154.4 ppm;

HRMS Calcd. for C17H21NO3 (M+1) 287.1521, found 287.1516; HPLC (AD, eluent:heptane/i-PrOH = 90/10, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 11.1 min, t2 = 23.8 min.

(+)-N-(4-Methoxy-3,5-dimethyl-phenyl)-1-phenyl-ethylamine (15a)25

HN *

Light yellow solid, 96% yield, Mp = 90.2 – 90.9 °C, 99% ee, [α]D = +9.0 (c 1 1.02, CHCl3); H NMR (400 MHz, CDCl3) 1.52 (d, J = 6.7 Hz, 3H), 2.20 (s, 6H), 3.66 (s, 3H), 3.81 (br, 1H), 4.46 (q, J = 6.7 Hz, 1H), 6.23 (s, 2H), 7.25 – 13 7.29 (m, 1H), 7.34 – 7.43 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 17.1, 25.8, 54.6, 60.7, 114.2, 126.7, 127.6, 129.4, 132.0, 144.3, 146.4, 149.6

158

Preparation of chiral amines via asymmetric hydrogenation of imines

ppm; HRMS Calcd. for C17H21NO (M+1) 255.1623, found 255.1630; HPLC (OD-H, eluent:heptane/i-PrOH = 80/20, detector: 215 nm, flow rate: 0.5

mL/min), t1 = 9.2 min, t2 = 9.9 min.

(R)-N-(2-Methoxy-phenyl)-1-naphthalen-2-yl-ethylamine (16a)

White solid, 93% yield, Mp = 110.5 – 111.2 °C, 99% ee, [α]D = -76.8 (c 1.04,

CHCl3), absolute configuration was determined by measuring the optical rotation of deprotected derivatized product 16c and comparing it with 76 1 literature data ; H NMR (400 MHz, CDCl3) 1.70 (d, J = 6.7 Hz, 3H), 3.97 (s, 3H), 4.70 (q, J = 6.7 Hz, 1H), 4.82 (br, 1H), 6.45–6.50 (m, 1H), 6.64 – 6.88 (m, 3H), 7.48 – 7.61 (m, 3H), 7.89 – 7.91 (m, 4H) ppm; 13C NMR (100

MHz, CDCl3) 26.1, 54.6, 56.4, 110.2, 112.1, 117.3, 122.1, 125.2, 125.4, 126.4, 126.9, 128.6, 128.8, 129.4, 133.7, 134.5, 138.2, 143.9, 147.5 ppm;

HRMS Calcd. for C19H19NO (M+1) 277.1467, found 277.1476. HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 19.5 min, t2 = 24.7 min.

(R)-1-Naphthalen-2-yl-ethylamine hydrochloride (16b)

. NH2 HCl

Light brown solid, 68% yield, Mp = 214.6 – 214.7 °C; 1H NMR (400 MHz,

D2O) 1.47 (d, J = 6.49 Hz, 3H), 4.41 (q, J = 6.44 Hz, 1H), 7.28 – 7.30 (m, 13 3H), 7.57 – 7.65 (m, 4H) ppm; C NMR (100 MHz, D2O) 19.4, 51.2, 123.9, 125.9, 127.0, 127.1, 127.8, 128.1, 129.2, 132.9, 133.1, 135.2 ppm; HRMS

Calcd. for C12H14ClN (M+1–HCl) 172.11208, found 172.11195; the product was derivatized with acetic anhydride in the presence of triethylamine and the ee of the N-Ac derivative 16c was determined by GC:

159

Chapter 4

(R)-N-(1-Naphthalen-2-yl-ethyl)-acetamide (16c)76

NHAc

White solid, Mp = 119.2 – 119.3 °C, >99% ee, [α]D = +23.6 (c 1.00, CHCl3); 1 H NMR (400 MHz, CDCl3) 1.54 (d, J = 6.93 Hz, 3H), 1.97 (s, 3H), 5.26 (q, J = 7.24 Hz, 1H), 6.21 (br, 1H), 7.40 – 7.47 (m, 3H), 7.74 – 7.80 (m, 4H) 13 ppm; C NMR (100 MHz, CDCl3) 22.6, 24.4, 49.8, 125.5, 125.7, 126.8, 127.2, 128.6, 128.8, 129.4, 133.7, 134.3, 141.5, 170.1 ppm; HRMS Calcd.

for C14H15NO (M+1) 214.12264, found 214.12283; GC Chiralsil DEX CB, initial temp. 125 °C for 4 min, then 3 °C/min to 140 °C, then 10 °C/min to

180 °C, then 10 °C/min to 125 °C, t1 = 37.8 min, t2 = 38.57 min.

(–)-N-(2-Methoxy-phenyl)-1-p-tolyl-ethylamine (17a)

HN *

Light yellow solid, 95% yield, Mp = 88.6 – 88.8 °C, 98% ee, [α]D = -19.1 (c 1 1.00, CHCl3); H NMR (400 MHz, CDCl3) 1.54 (d, J = 6.7 Hz, 3H), 2.32 (s, 3H), 3.88 (s, 3H), 4.45 (q, J = 6.5 Hz, 1H), 4.60 (br, 1H), 6.33 – 6.38 (m, 1H), 6.55 – 6.79 (m, 3H), 7.10 – 7.14 (m, 2H), 7.24 – 7.28 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 22.0, 26.1, 53.9, 56.3, 110.1, 111.9, 117.1, 122.1,

126.7, 130.2, 137.2, 138.2, 143.4, 147.4 ppm; HRMS Calcd. for C16H19NO (M+1) 241.1467, found 241.1458; HPLC (OD-H, eluent:heptane/i-PrOH =

99/1, detector: 215 nm, flow rate: 0.5 mL/min), t1 = 12.9 min, t2 = 15.4 min.

1-p-Tolyl-ethylamine hydrochloride (17b)

. NH2 HCl *

1 Light brown solid, 71% yield; H NMR (400 MHz, D2O) 1.47 (d, J = 6.85 Hz, 3H), 2.19 (s, 3H), 4.35 (q, J = 6.74 Hz, 1H), 7.15 – 7.22 (m, 4H) ppm; 13C

160

Preparation of chiral amines via asymmetric hydrogenation of imines

NMR (100 MHz, D2O) 19.5, 20.4, 51.0, 126.7, 130.0, 134.9, 139.7 ppm;

HRMS Calcd. for C9H14ClN (M+1–HCl) 136.11208, found 136.11205; the product was derivatized (in the GC vial) with acetic anhydride in the presence of triethylamine and the ee of the N-Ac derivative 17c was determined by GC.

(1-p-Tolyl–ethyl)-acetamide (17c)78

NHAc *

98% ee, GC Chiralsil DEX CB, initial temp. 125 °C for 4 min, then 3

°C/min to 140 °C, then 10 °C/min to 180 °C, then 10 °C/min to 125 °C, t1

= 14.7 min, t2 = 15.0 min.

(–)-N-[1-(4-Chloro-phenyl)-ethyl]-(2-methoxy-phenyl)-amine (18a)

HN *

Light brown solid, 95% yield, Mp = 113.3 – 114.1 °C, 96% ee, [α]D = -34.8 1 (c 1.01, CHCl3); H NMR (400 MHz, CDCl3) 1.53 (d, J = 6.7 Hz, 3H), 3.89 (s, 3H), 4.45 (q, 1H), 4.61 (br, 1H), 6.26 – 6.28 (m, 1H), 6.60 – 6.79 (m, 3H), 13 7.26 – 7.32 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 25.4, 53.1, 55.6, 109.5, 111.2, 116.8, 121.3, 127.5, 129.0, 132.5, 137.2, 144.3, 146.8 ppm;

HRMS Calcd. for C15H16ClNO (M+1) 261.0920, found 261.0915; HPLC (OD- H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5

mL/min), t1 = 16.4 min, t2 = 22.7 min.

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(–)-N-(2-Methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-ethylamine (19a)

HN *

F3C

White solid, 97% yield, Mp = 93.7 – 93.8 °C, 97% ee, [α]D = -40.8 (c 1.01, 1 CHCl3); H NMR (400 MHz, CDCl3) 1.56 (d, J = 6.7 Hz, 3H), 3.91 (s, 3H), 4.53, (q, J = 6.2 Hz, 1H), 4.66 (br, 1H), 6.24 – 6.26 (m, 1H), 6.63 – 6.72 (m, 2H), 6.78 – 6.80 (m, 1H), 7.48–7.50 (m, 2H), 7.57 – 7.59 (m, 2H), ppm; 13C

NMR (100 MHz, CDCl3) 26.0, 54.1, 56.3, 110.3, 111.9, 117.7, 122.0, 125.3 (q, J = 271.9 Hz), 126.5 (q, J = 3.8 Hz), 127.1, 130.0 (q, J = 32.2 Hz), 19 137.7, 147.5, 150.7 ppm; F (376 MHz, CDCl3) -62.7 ppm; HRMS Calcd. for C16H16F3NO (M+1) 295.1184, found 295.1171; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 16.2 min, t2 = 24.2 min.

(–)-N-[1-(4-Fluoro-phenyl)-ethyl]-(2-methoxy-phenyl)-amine (20a)

HN *

White solid, 94% yield, Mp = 71.0 – 72.1 °C, 97% ee, [α]D = -56.0 (c 1.00, 1 CHCl3); H NMR (400 MHz, CDCl3) 1.68 (d, J = 6.7 Hz, 3H), 4.01 (s, 3H), 4.62 (q, J = 6.7 Hz, 1H), 4.82 (br, 1H), 6.50 – 6.52 (m, 1H), 6.79 – 6.84 (m, 1H), 6.88 – 6.95 (m, 2H), 7.13 – 7.17 (m, 2H), 7.47 – 7.50 (m, 2H) ppm; 13C

NMR (100 MHz, CDCl3) 25.6, 53.0, 55.7, 109.5, 111.3, 115.6 (d, J = 21.3 Hz), 116.8, 121.4, 127.5 (d, J = 7.9 Hz), 137.3, 141.3 (d, J = 3.0 Hz), 146.8, 19 162.0 (d, J = 244.1 Hz) ppm; F (376 MHz, CDCl3) -116.9 ppm; HRMS

Calcd. for C15H16FNO (M+1) 243.1059, found 243.1048; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 15.3 min, t2 = 20.3 min.

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Preparation of chiral amines via asymmetric hydrogenation of imines

(–)-N-(2-Methoxy-phenyl)-1-m-tolyl-ethylamine (21a)

HN *

1 Colourless oil, 88% yield, 93% ee, [α]D = -16.9 (c 1.00, CHCl3); H NMR

(400 MHz, CDCl3) 1.54 (d, J = 6.7 Hz, 3H), 2.34 (s, 3H), 3.89 (s, 3H), 4.43 (q, J = 6.7 Hz, 1H), 4.61 (br, 1H), 6.34 – 6.39 (m, 1H), 6.57 – 6.80 (m, 3H), 13 7.02 – 7.05 (m, 1H), 7.18 – 7.26 (m, 3H) ppm; C NMR (100 MHz, CDCl3) 22.4, 26.1, 54.3, 56.2, 110.1, 111.9, 117.1, 122.1, 123.8, 127.4, 128.5,

129.4, 138.2, 139.0, 146.4, 147.4 ppm; HRMS Calcd. for C16H19NO (M+1) 241.1467, found 241.1452; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1,

detector: 215 nm, flow rate: 0.5 mL/min), t1 = 12.8 min, t2 = 15.8 min.

(–)-N-2-Methoxy-phenyl-1-(3-nitro-phenyl)-ethylamine (22a)

HN * O2N

Yellow solid, 95% yield, 61% ee, Mp = 78.9 – 79.6 °C, [α]D = -41.7 (c 1.02, 1 CHCl3); H NMR (400 MHz, CDCl3) 1.61 (d, J = 6.75 Hz, 3H), 3.93 (s, 3H), 4.59 (q, J = 6.70 Hz, 1H), 4.76 (br, 1H), 6.25 – 6.28 (m, 1H), 6.65 – 6.75 (m, 2H), 6.81 – 6.84 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.73 – 7.76 (m, 1H), 13 8.08 – 8.11 (m, 1H), 8.28 – 8.29 (m, 1H) ppm; C NMR (100 MHz, CDCl3) 26.0, 53.9, 56.3, 110.3, 111.7, 117.9, 121.8, 121.9, 122.9, 130.5, 133.0,

137.4, 147.5, 149.0, 149.5 ppm; HRMS Calcd. for C15H16N2O3 (M+1) 273.12337, found 273.12329; HPLC (OD-H, eluent:heptane/i-PrOH =

80/20, detector: 215 nm, flow rate: 0.5 mL/min), t1 = 12.6 min, t2 = 16.8 min.

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Chapter 4

(–)-N-(2-Methoxy-phenyl)-1-phenyl-propylamine (23a)60

HN *

1 Yellow oil, 96% yield, 94% ee, [α]D = -13.7 (c 1.00, CHCl3); H NMR (400

MHz, CDCl3) 1.06 (t, J = 7.44 Hz, 3H), 1.94 (quint, J = 7.05 Hz, 2H), 3.95 (s, 3H), 4.30 (br, 1H), 4.78 (br, 1H), 6.43 – 6.45 (m, 1H), 6.67 – 6.69 (m, 1H), 6.76 – 6.84 (m, 2H), 7.29 – 7.31 (m, 1H), 7.38 – 7.42 (m, 4H) ppm; 13C

NMR (100 MHz, CDCl3) 11.7, 32.6, 56.2, 60.4, 110.1, 111.7, 117.0, 122.0,

127.3, 127.6, 129.3, 138.3, 145.0, 147.5 ppm; HRMS Calcd. for C16H19NO (M+1) 241.1467, found 241.1469; HPLC (OD-H, eluent:heptane/i-PrOH =

99/1, detector: 215 nm, flow rate: 0.5 mL/min), t1 = 13.0 min, t2 = 15.1 min.

(–)-N-(2-Methoxy-phenyl)-(1-phenyl-butyl)-amine (24a)

HN *

1 Colourless oil, 96% yield, 97% ee, [α]D = -23.6 (c 1.03, CHCl3); H NMR

(400 MHz, CDCl3) 0.96 (t, J = 7.35 Hz, 3H), 1.35 – 1.53 (m, 2H), 1.78 – 1.88 (m, 2H), 3.90 (s, 3H), 4.31 (t, J = 6.86 Hz, 1H), 4.70 (br, 1H), 6.35 – 6.37 (m, 1H), 6.58 – 6.62 (m, 1H) 6.68 – 6.78 (m, 2H), 7.20 – 7.26 (m, 1H), 13 7.30 – 7.37 (m, 4H) ppm; C NMR (100 MHz, CDCl3) 15.0, 20.6, 42.2, 56.4, 58.8, 110.29, 111.8, 117.0, 122.1, 127.3, 127.7, 129.4, 138.4,

145.5, 147.5 ppm; HRMS Calcd. for C17H21NO (M+1) 256.16959, found 256.16949; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215

nm, flow rate: 0.5 mL/min), t1 = 12.1 min, t2 = 17.9 min.

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Preparation of chiral amines via asymmetric hydrogenation of imines

N-(hexan-2-yl)-2-methoxyaniline (25a)

HN *

1 Light yellow liquid, 96% yield, 16% ee; H NMR (400 MHz, CDCl3) 0.93 (t, J = 6.72 Hz, 3H), 1.20 – 1.70 (m, 9H), 3.48 (q, J = 6.03 Hz, 1H), 3.86 (s, 3H), 4.06 (br, 1H), 6.60 – 6.68 (m, 2H), 6.77 – 6.89 (m, 2H) ppm; 13C NMR (100

MHz, CDCl3) 15.1, 21.8, 23.8, 29.4, 37.9, 49.0, 56.3, 110.4, 110.9, 116.5,

122.2, 138.6, 147.6 ppm; HRMS Calcd. for C13H21NO (M+1) 207.1623, found 207.1620; HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector:

215 nm, flow rate: 0.5 mL/min), t1 = 10.2 min, t2 = 12.1 min.

2-methoxy-N-(octan-2-yl)aniline (26a)

HN *

1 Light yellow liquid, 95% yield, 17% ee; H NMR (400 MHz, CDCl3) 1.01 (t, J = 6.80 Hz, 3H), 1.30 (d, J = 6.28 Hz, 3H), 1.41 – 1.60 (m, 9H), 1.68 – 1.76 (m, 1H), 3.56 (q, J = 6.02 Hz, 1H), 3.92 (s, 3H), 4.18 (br, 1H), 6.69 – 6.76 (m, 2H), 6.85 – 6.87 (m, 1H), 6.94 – 7.0 (m, 1H) ppm; 13C NMR (100 MHz,

CDCl3) 15.01, 21.7, 23.6, 27.1, 30.3, 32.8, 38.1, 49.0, 56.2, 110.3, 110.9, 116.5, 122.2, 138.5, 147.6 ppm; HPLC (OD-H, eluent:heptane/i-PrOH =

99/1, detector: 215 nm, flow rate: 0.5 mL/min), t1 = 10.4 min, t2 = 13.6 min.

Benzyl-(1-phenyl-ethyl)-amine (27a)73

HN ∗

1 Pale yellow oil; H NMR (400 MHz, CDCl3) 1.37 (d, J = 6.60 Hz, 3H), 1.63 (br, 1H), 3.60 (d, J = 13.10 Hz, 1H), 3.67 (d, J = 13.10 Hz, 1H), 3.82 (q, J = 13 6.60 Hz, 1H), 7.26 – 7.37 (m, 10H) ppm; C NMR (100 MHz, CDCl3) 24.5, 51.6, 57.5, 126.7, 126.8, 126.9, 128.1, 128.3, 128.5, 140.6, 145.5 ppm;

165

Chapter 4

HPLC (OD-H, eluent:heptane/i-PrOH = 99/1, detector: 215 nm, flow rate:

0.5 mL/min), t1 = 11.1 min, t2 = 12.3 min.

N-(1-phenylethyl)butan-1-amine (28a)79

HN *

1 Colourless oil; H NMR (400 MHz, CDCl3) 0.89 (t, J = 7.30 Hz, 3H), 1.29 – 1.37 (m, 5H), 1.43 – 1.50 (m, 2H), 2.40 – 2.55 (m, 2H), 3.76 (q, J = 6.45 13 Hz, 1H), 7.22 – 7.33 (m, 5H) ppm; C NMR (100 MHz, CDCl3) 14.9, 21.4, 25.3, 33.4, 48.5, 59.3, 127.4, 127.7, 129.3, 146.8 ppm; HPLC (AS-H, eluent:heptane/i-PrOH = 99.7/0.3, detector: 215 nm, flow rate: 0.5

mL/min), t1 = 9.3 min, t2 = 10.1 min.

N-butyl-2,3-dihydro-1H-inden-1-amine (29a)80

HN *

1 Orange oil; H NMR (400 MHz, CDCl3) 0.98 (t, J = 7.37 Hz, 3H), 1.39 (sextet, J = 7.37 Hz, 2H), 1.52 (quintet, J = 6.95 Hz, 2H), 1.80 – 1.89 (m, 2H), 2.38 – 2.46 (m, 1H), 2.74 (t, J = 7.37 Hz, 2H), 2.78 – 2.86 (m, 1H), 2.98 – 3.05 (m, 1H), 4.26 (t, J = 6.57 Hz, 1H), 7.19 – 7.26 (m, 3H), 7.35 – 13 7.37 (m, 1H) ppm; C NMR (100 MHz, CDCl3) 15.0, 21.5, 31.3, 33.6, 34.6, 48.1, 64.3, 125.0, 125.7, 127.1, 128.2, 144.5, 146.4 ppm; HRMS Calcd.

for C13H19N (M+1) 190.15903, found 190.15839; HPLC (AS-H, eluent:heptane/i-PrOH = 99.7/0.3, detector: 210 nm, flow rate: 0.5

mL/min), t1 = 8.7 min, t2 = 9.7 min.

6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (30a)81

* NH O

o 1 White solid, 98% yield, Mp = 97.3 – 97.9 C; H NMR (400 MHz, CDCl3) 1.41 (d, J = 6.28 Hz, 3H), 2.61 – 2.65 (m, 1H), 2.75 – 2.80 (m, 2H), 2.94 – 2.99 (m, 1H), 3.21 – 3.24 (m, 1H), 3.81 (s, 6H), 4.03 (br, 1H), 6.53 (s, 1H),

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Preparation of chiral amines via asymmetric hydrogenation of imines

13 6.58 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 23.6, 30.2, 42.5, 52.0, 56.7, 56.9, 109.9, 112.6, 127.5, 133.0, 148.2, 148.3 ppm; HPLC (OD-H, eluent:heptane/i-PrOH = 88/12, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 23.5 min, t2 = 28.3 min.

In a HTE experiment with MAO conversion was determined by HPLC:

Response factor was calculated: starting amine: Rf (Area/mg)= 40586, product: Rf (Area/mg)= 3407, column: Chiralpak OD-H, eluent: 95% n- heptane/5% IPA/0.05% DEA, flow: 1.3 mL/min, temperature: 50°C, wavelength: 254 nm, inject. Volume: 5µl, run time: 20 min, retention time:

Starting imine t = 7.3 min, product t1 = 10.4 and t2 = 12.0 min.

6,7-diethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (31a)

* NH O

Light yellow solid, 97% yield, Mp = 63.9 – 64.0 oC; 1H NMR (400 MHz,

CDCl3) 1.38 – 1.44 (m, 9H), 1.68 (br, 1H), 2.58 – 2.65 (m, 1H), 2.72 – 2.80 (m, 1H), 2.95 – 3.01 (m, 1H), 3.20 – 3.26 (m, 1H), 3.77 (br, 1H), 4.05 (q, J = 13 6.99 Hz, 1H), 6.57 (s, 1H), 6.64 (s, 1H) ppm; C NMR (100 MHz, CDCl3) 15.4, 15.5, 23.3, 30.0, 42.5, 51.7, 65.0, 65.4, 112.4, 114.6, 127.7, 133.2, 147.4, 147.8 ppm; HPLC (OD-H, eluent:heptane/i-PrOH = 88/12, detector:

215 nm, flow rate: 0.5 mL/min), t1 = 18.0 min, t2 = 25.4 min.

2,3,3-trimethylindoline (33a)82

* N H

1 H NMR (400 MHz, CDCl3) 1.05 (s, 3H), 1.19 (d, J = 6.56 Hz, 3H), 1.29 (s, 3H), 3.52 (q, J = 6.55 Hz, 1H), 6.62 – 6.64 (m, 1H), 6.73 – 6.77 (m, 1H), 13 7.01 – 7.05 (m, 2H) ppm; C NMR (100 MHz, CDCl3) 16.1, 23.3, 27.1, 44.3, 66.1, 110.3, 119.8, 123.2, 128.1, 140.1, 150.2 ppm; HPLC (OJ-H, eluent:heptane/i-PrOH = 90/10, detector: 215 nm, flow rate: 0.5 mL/min),

t1 = 19.2 min, t2 = 31.9 min.

167

Chapter 4

4.7 References

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(38) a) Roszkowski, P.; Czarnocki, Z. Mini-Rev. Org. Chem. 2007, 4, 190; b) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226; c) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045; d) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (39) Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kang, G.- J.; Rettig, S. J. Inorg. Chem. 1991, 30, 5002. (40) Abdur-Rashid, K.; Lough, A. J.; Morris, R. H. Organometallics 2001, 20, 1047. (41) Reetz, M. T.; Bondarev, O. Angew. Chem. Int. Ed. 2007, 46, 4523. (42) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Börner, A. J. Org. Chem. 2003, 68, 4067. (43) Kaufman, T. S. Tetrahedron: Asymmetry 2004, 15, 1203. (44) Lee, J. W.; Chae, J. S.; Kim, C. S.; Kim, J. K.; Lim, D. S.; Shon, M. K.; Choi, Y. S.; Lee, S. H. WO9605177 to Yuhan Corp., 1996. (45) Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1993, 58, 7627. (46) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183. (47) Zhu, G.; Zhang, X. Tetrahedron: Asymmetry 1998, 9, 2415. (48) Blaser, H.-U.; Buser, H.-P.; Häusel, R.; Jalett, H.-P.; Spindler, F. J. Organomet. Chem. 2001, 621, 34. (49) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208. (50) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (51) Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766. (52) Yu, C.-B.; Wang, D.-W.; Zhou, Y.-G. J. Org. Chem. 2009, 74, 5633. (53) Yang, Q.; Shang, G.; Gao, W.; Deng, J.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 3832. (54) Spindler, F.; Blaser, H. U. Adv. Synth. Catal. 2001, 343, 68. (55) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 8, 1189. (56) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (57) Faller, J. W.; Milheiro, S. C.; Parr, J. J. Organomet. Chem. 2006, 691, 4945.

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(58) a) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami, S.; Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001; b) Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K.-I.; Tomioka, K. Org. Lett. 2004, 6, 1721; c) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J. Org. Lett. 2003, 5, 1809; d) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120; e) Fustero, S.; Garcia Soler, J.; Bartolomé, A.; Sanchez Rosello, M. Org. Lett. 2003, 5, 2707; f) Fustero, S.; Bartolomé, A.; Sanz-Cervera, J. F.; Sanchez Rosello, M.; Soler, J. G.; Ramirez de Arellano, C.; Fuentes, A. S. Org. Lett. 2003, 5, 2523; g) Córdova, A. Synlett 2003, 1651. (59) a) Janey, J. M.; Hsiao, Y.; Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390; b) Ibrahem, I.; Casas, J.; Córdova, A. Angew. Chem. Int. Ed. 2004, 43, 6528; c) Córdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (60) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409. (61) De Lamo Marin, S.; Martens, T.; Mioskowski, C.; Royer, J. J. Org. Chem. 2005, 70, 10592. (62) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47, 8109. (63) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Schoemaker, H. E.; Schürmann, M.; van Delft, F. L.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2007, 349, 1332. (64) Connelly, N. G.; Geiger, W. E. Chem. Rev. 1996, 96, 877. (65) Ness, R. C.; Duncan, B. L.; Mendiratta, S. K.; Leonard, D. R. US5120452 to Olin Corp., 1992. (66) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem. Int. Ed. 1998, 37, 2897. (67) Fink, G. Handbook of Heterogeneous Catalysis (2nd Edition), Eds. Ertl, G.; Knözinger, H.; Schüth, F.; Weitkamp, J. Wiley-VCH: Weinheim, 2008; Vol. 8, 3792. (68) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (69) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943.

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(70) Maciá, B.; Fernández-Ibáñez, M. Á.; Mršić, N.; Minnaard, A. J.; Feringa, B. L. Tetrahedron Lett. 2008, 49, 1877. (71) Hoen, R.; van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2004, 6, 1433. (72) Barluenga, J.; Fernández, M. A.; Aznar, F.; Valdés, C. Chem. Eur. J. 2004, 10, 494. (73) Samec, J. S. M.; Bäckvall, J.-E. Chem. Eur. J. 2002, 8, 2955. (74) Schnider, P.; Koch, G.; Prétôt, R.; Wang, G.; Bohnen, F. M.; Krüger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887. (75) Kizirian, J.-C.; Cabello, N.; Pinchard, L.; Caille, J.-C.; Alexakis, A. Tetrahedron 2005, 61, 8939. (76) Paetzold, J.; Bäckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620. (77) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (78) Guilong, L.; Antilla, J. C. Org. Lett. 2009, 11, 1075. (79) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kočovský, P. Org. Lett. 2004, 6, 2253. (80) Pearson, W. H.; Fang, W.-K. J. Org. Chem. 1995, 60, 4960. (81) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725. (82) Byung Tae, C.; Kang, S. K. Tetrahedron 2005, 61 5725.

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174

Chapter 5 Asymmetric hydrogenation of 2- substituted N-protected-indoles

In this chapter the asymmetric hydrogenation of indoles catalyzed by rhodium complexes of BINOL-derived phosphoramidites is described. Full conversions and enantioselectivities up to 74% were obtained in the hydrogenation of N-protected indoles.

Part of this chapter has been published:

N. Mršić, A. J. Minnaard, B. L. Feringa, J. G. de Vries, Tetrahedron:Asymmetry 2009, accepted. Chapter 5

5.1 Introduction

Highly enantioselective asymmetric hydrogenation of heteroaromatics could be a valuable and straightforward method for the preparation of enantiopure heterocyclic compounds, if it could be performed successfully on a routine basis. Heterocyclic compounds represent important building blocks in the synthesis of pharmaceutical intermediates and biologically active compounds.1 As mentioned in previous chapters, asymmetric hydrogenation of heteroaromatics is still not suitable for industrial application due to the fact that the ligands employed are usually prepared through a multi-step synthesis which makes them rather expensive. Moreover, reported TOF’s are still in general low and high pressures are usually necessary due to the high stability of heteroaromatic compounds. Therefore, despite considerable progress in the field, effective hydrogenation of aromatic and heteroaromatic compounds with high enantioselectivity still remains a great challenge.2

HS O COOH N N H COOH

Figure 5.1 (S)-indoline-2-carboxylic acid and the first ACE inhibitor Captopril

Enantiomerically enriched indoline-2-carboxylic acids are important intermediates for pharmaceutical products, in particular in the preparation of angiotensin I converting enzyme inhibitors (ACE). ACE inhibitors are useful for the treatment of hypertension. Since the discovery3 of the ACE inhibitor Captopril and its use as an effective antihypertensive agent for primary and renal hypertension, a new field of drug discovery and development emerged.

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Asymmetric hydrogenation of 2-substituted N-protected-indoles

H H

COOH COOH COOH N N N H H O O O

NH NH

O O O O O O

Perindopril Pentopril Indolapril

Figure 5.2 (S)-Indoline-2-carboxylic acid-derived ACE inhibitors

Enantiopure (S)-indoline-2-carboxylic acid is used as an intermediate in the preparation of Perindopril, that is an antihypertensive or cardiotonic active ingredient.4 Other useful applications of (S)-indoline-2-carboxylic acid are, for example, in the synthesis of ACE inhibitors Pentopril and Indolapril (Figure 5.2).5

N COOH H COOH COOH H O NaBH4 OH NO2 NO2

DMF, SOCl2 rt, CH2Cl2

COOH COOH Pd/C Cl Cl H H NH2 NO2

Raney nickel ROH, KOH H2NNH2

COOH N H

Scheme 5.1 Synthesis of (S)-indoline-2-carboxylic acid via reduction using (D)-Proline as a chiral auxiliary

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Preparation of enantiopure (S)-indoline-2-carboxylic acid and its methyl ester is generally achieved via classical resolution,6 chemical synthesis through an asymmetric reduction with a chiral auxiliary7 or via enzymatic methods such as resolution via hydrolysis of indole-2-carboxylic esters,8 or using phenylammonia lyase for the preparation of ortho- chlorophenylalanine followed by a copper-catalyzed ring-closure.9 The disadvantage of the classical resolution method is the fact that the resolving agent is expensive and difficult to recover. In addition, the yield never exceeds 50%. The synthesis method through asymmetric reduction,

using a chiral auxiliary, involves NaBH4 reduction of prochiral 3-(ortho- nitro-phenyl)pyruvic acid applying the chiral auxiliary D-proline. The resulting alcohol derivative is then converted into enantioenriched (S)- indoline-2-carboxylic acid with an overall yield of 32%, using expensive D- (+)-proline (Scheme 5.1).7

Ito et al., 2000

1 mol% [Rh(nbd)2]SbF6 1.05 mol% (S,S)-(R,R)-PhTRAP R3 R3 10 mol% base, 50 bar H 1 N 2 1 N R o R R2 i-PrOH, 60 C R2 1 R = Me, MeO, CF3 up to 95% ee R2 = Ac, Boc H Ph P R3 = Bu, Ph, COOMe 2

Fe Fe

PPh2 H (S,S)-(R,R)-PhTRAP

Scheme 5.2 Ito’s asymmetric hydrogenation of N-protected-2-substituted indoles

In 2000, Ito and co-workers reported the asymmetric hydrogenation of N-acetyl and N-Boc protected indoles with excellent conversions and enantioselectivities (up to 95% and 78% ee, respectively) using a rhodium catalyst based on the trans-chelating bis-phosphine ligand PhTRAP and

178

Asymmetric hydrogenation of 2-substituted N-protected-indoles

10 using cesium carbonate as a base (Scheme 5.2). The addition of the base was shown to play an important role in obtaining both good catalytic activity and high enantioselectivity. Authors presume that a Rh(I)H complex is an active species for the asymmetric hydrogenation. The base additive possibly deprotonates from a cationic Rh(III)H2 complex, generating a neutral Rh(I)H complex. Later on, Kuwano and co-workers reported the Rh-catalyzed asymmetric hydrogenation of N-tosyl-3- substitued indoles11 and the Rh- and Ru-catalyzed hydrogenation of N- protected-2- and 3-substituted indoles with excellent enantioselectivities and conversions using the same PhTRAP ligand.12

1 mol% Rh(acac)(cod) Bu 1.05 mol% Ligand Bu N i-PrOH, 50 bar H2 N O 60 oC, 2h O

NMe2 PPh2 O PPh PPh2 Fe 2 PPh2 PPh2 O PPh2 PPh2 PPh2

(R)-BINAP (2S,3S)-Chiraphos (R)-(S)-BPPFA (2R,3R)-DIOP 100% yield 100% yield 100 yield 100% yield 1% ee 1% ee 0% ee 0% ee H Ph2P Ph2P

Fe Fe P P N Boc PPh2 PPh2 H (R,R)-Me-DUPHOS (2S,4S)-BPPM (S,S)-(R,R)-PhTRAP 100% yield 100% yield 75% yield 0% ee 0% ee 85% ee

Scheme 5.3 Evaluation of chiral ligands for the hydrogenation of N-acetyl- 2-butylindole

In Ito’s study, a broad range of chiral bidentate phosphine ligands was evaluated for the asymmetric hydrogenation of N-acetyl-2-butylindole

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using Rh(acac)(COD) (Scheme 5.3). The product was isolated in quantitative yield upon the use of various commercially available chiral phosphines. However, all ligands led to the formation of racemic product, except the trans-chelating PhTRAP ligand. The steric and electronic properties of the ligands have an enormous effect on the structure and the reactivity of metal complexes.13 The bite angle (P−M−P angle) of the bidentate ligands can have an impact on the hybridization at the metal centre and the resulting energies of valence orbitals. Thorn and Hoffmann calculated that during migration a phosphine ligand would have a tendency to widen the bite angle in the process to “pursue” the migrating group.14 It was expected that ligands enforcing an enlarged P−M−P angle (resembling the transition state), would accelerate migration reactions. Dekker et al. provided the experimental confirmation of the calculation, and discovered increasing migration rates with larger bite angles of palladium diphosphine complexes.15 Only a limited number of P ligands are known that enforce trans coordination toward a transition-metal center. Among these are the TRANSphos ligand introduced by Venanzi16 and the PhTRAP ligand developed by Ito.10 However, these ligands are rather flexible and cis complexes are accessible as well. It is noteworthy that the orientation of the lone pair at the phosphorus atoms is as important as the P−P distance. If within a certain backbone conformation the orientation of the lone pairs does not comply with the trans configuration of the metal, a slight distortion leads just as easily to a cis complex.

5.2 Goal of the research

As mentioned in earlier chapters, in our group phosphoramidite ligands have been successfully applied in rhodium, ruthenium and iridium catalyzed asymmetric hydrogenation.17 We have shown in chapters 2 and 3 that asymmetric hydrogenation of 2- and 2,6-disubstituted quinolines and quinoxalines using an iridium catalyst based on the monodentate phosphoramidite ligand (S)-PipPhos L1 proceeds with excellent conversions and ee’s. We were interested in examining the possibility to use monodentate phosphoramidites in the asymmetric hydrogenation of another class of heteroaromatic compounds; the indoles. In this chapter

180

Asymmetric hydrogenation of 2-substituted N-protected-indoles

we report the asymmetric hydrogenation of 2-substituted N-protected indoles using a rhodium catalysts with monodentate phosphoramidite ligands.

5.3 Initial screening and ligand optimization

Initial screening of reaction conditions was performed in dichloromethane at various hydrogen pressures and temperatures using methyl N-acetylindole-2-carboxylate 1 as a substrate, 5 mol% of

[Rh(COD)2]BF4 precursor and 10 mol% of monodentate (S)-PipPhos ligand (Table 5.1). In reactions without additives no conversion was detected at room temperature and only low conversion and enantioselectivity were observed at 40 °C (Entries 1 and 2). As reported by Ito, the addition of a base seems to be crucial in the rhodium-catalyzed asymmetric hydrogenation of N- acetyl-2-substituted indoles.10 Indeed, when 10 mol% of cesium carbonate was added to the reaction mixture in the hydrogenation of 1, full conversion and ee’s up to 74% were obtained (Entries 3-7). Full conversion and the highest enantioselectivities were obtained at room temperature and 40 °C (73-74% ee, Entries 3 and 5). Upon increasing the temperature to 60 °C, both conversion and the ee decreased (71% conv. and 61% ee, Entry 7). At a pressure of 100 bar and room temperature the ee remained at a similar level as in the reactions at 25 bar of hydrogen pressure (61% ee, Entry 4). Doubling the amount of cesium carbonate resulted in a significant decrease of the enantioselectivity (38% ee, Entry 6). At 25 bar of hydrogen pressure and 40 °C, cesium carbonate and cesium fluoride gave similar results (74% and 72% ee respectively, Entries 5, 8). Addition of other bases like potassium acetate, sodium carbonate or lithium carbonate, led to lower conversions and enantioselectivities (Entries 9-11). Potassium hydrogenphosphate as additive also gave low conversion and ee (Entry 12). In the case of Ito’s PhTRAP-derived catalyst, addition of triethylamine resulted in the same ee as observed with the addition of cesium carbonate.10

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Table 5.1 Asymmetric hydrogenation of 1 using Rh(COD)2]BF4/(S)- PipPhosa

5 mol% [Rh(COD)]2BF4 10 mol% (S)-PipPhos COOMe COOMe N Additive, CH2Cl2 N 25 bar H , 20h O 2 O

1 1a O P N O

(S)-PipPhos L1

Achiral Entry Additive Temp (°C) Conv.b ( %) Eec (%) phosphine 1 - - 25 0 - 2 - - 40 13 12

3 10% Cs2CO3 - 25 100 73 e 4 10% Cs2CO3 - 25 100 68

5 10% Cs2CO3 - 40 100 74

6 20% Cs2CO3 - 40 95 38

7 10% Cs2CO3 - 60 71 61 8 10% CsF - 40 100 72 9 10% KOAc - 40 66 60

10 10% Na2CO3 - 40 2 24

11 10% Li2CO3 - 40 16 20

12 10% KH2PO4 - 40 15 10

13 10% Et3N - 40 100 55 14 10% Cs2CO3 5% P(o-tolyl)3 25 65 49 aReaction conditions: 0.2 mmol 1, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of CH2Cl2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was assigned by measuring the optical rotation and comparing it with literature data. eReaction performed at 100 bar.

Using phosphoramidites, the addition of triethylamine still resulted in full conversion, however the ee decreased (55% ee, Entry 13). The addition of tri-o-tolylphosphine as achiral ligand (mixed ligand approach,18 Rh/L*/L = 1/2/1) led to slightly lower conversion and ee than without the addition of the phosphine (65% conversion, 49% ee, Entry 14).

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Asymmetric hydrogenation of 2-substituted N-protected-indoles

Table 5.2 Solvent screening in the asymmetric hydrogenation of 1 under the optimal reaction conditionsa

5 mol% [Rh(COD)]2BF4 10 mol% (S)-PipPhos COOMe COOMe N 10 mol% Cs2CO3 N Solvent, 40 oC, 25 bar H O 2 O

11a

Entry Solvent Conv.b (%) Eec (%)

1 CH2Cl2 100 74 2 EtOAc 59 27 3 i-PrOH 95 8 4 MeOH 0 - 5 THF 16 4 6 Toluene 62 5 aReaction conditions: 0.2 mmol 1, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of solvent, 40 °C, 25 bar H2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was determined by measuring the optical rotation and comparing it with literature data.

We examined the influence of the solvent on the reaction outcome using cesium carbonate as an additive (Table 5.2). The best result was obtained in dichloromethane (Entry 1), while ethyl acetate, i-propanol and toluene gave moderate to high conversion, however with low ee (up to 27% ee, Entries 2, 3 and 6). The reaction in THF proceeded with low conversion and ee (Entry 5), while in methanol no conversion was observed (Entry 4). We assume that the reason for lower enantioselectivity in toluene and dichloromethane lies in lower solubility of cesium carbonate in those solvents. Although solubility of base is higher in i-propanol, methanol and THF, the ee is low possibly due to the stronger coordination of these solvents to the metal.

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Chapter 5

O P R R = N N N N O

L1a L1b L1c L1d

N Ph

Ph L1e L1f L1g (R, S, S)(S, S, S)

O O P N P N O O

L2 L3

Figure 5.3 Ligands screened in the asymmetric hydrogenation of 1

Various phosphoramidite ligands were examined under the optimal conditions in the asymmetric hydrogenation of 1 (Figure 5.3). The results are presented in Table 5.3. The best result was still obtained with (S)- PipPhos L1 as a ligand (Entry 1). Excellent conversion and an ee of 59% was achieved with the ligand derived from azepane (L1d, Entry 5), while pyrrolidine-derived ligand L1c gave moderate conversion, however the product had low ee (Entry 4). With Monophos L1a 77% conversion and 33% ee was obtained, whereas use of ligand L1b surprisingly led to no conversion (Entries 2 and 3).

184

Asymmetric hydrogenation of 2-substituted N-protected-indoles

Table 5.3 Ligand screening in the asymmetric hydrogenation of 1a

5 mol% [Rh(COD)]2BF4 10 mol% L* COOMe COOMe N 10 mol% Cs2CO3 N CH Cl 40 oC, 25 bar H O 2 2, 2 O

11a

Entry Ligand Conv.b (%) Eec (%) 1 (S)-L1 100 74 2 (S)-L1a 77 33 3 (S)-L1b 0 - 4 (S)-L1c 64 2 5 (S)-L1d 93 59 6 (S)-L1e 87 10 7 (R,S,S)-L1f 9 26e 8 (S,S,S)-L1g 0 - 9 (R)-L2 60 24e 10 (R)-L3 64 31e aReaction conditions: 0.2 mmol 1, 0.01 mmol of Rh(COD)2BF4, 0.02 mmol of (S)-PipPhos, 0.02 mmol of Cs2CO3, 4 mL of CH2Cl2, rt, 25 bar H2. bConversion was determined by 1H NMR. cEnantioselectivity was determined by GC. dAbsolute configuration was determined by measuring the optical rotation and comparing it with literature data). eOpposite configuration of the product obtained.

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5.4 Scope

Various indole substrates were also screened using (S)-PipPhos L1 at 25 bar of hydrogen pressure (Table 5.4).

Table 5.4 Screening of indole substrates in the Rh/PipPhos catalyzed asymmetric hydrogenationa

5 mol% [Rh(COD)2]BF4 10 mol% (S)-PipPhos R2 * R2 N 10 mol% Cs2CO3, 25 bar H2 N R1 R1

2-4 2a, R1 = H, R2 = COOMe 3a, R1 = Boc, R2 = COOMe 4a, R1 = Acetyl, R2 = COOH 10 mol% Entry Indoline Solvent Temp (°C) Conv.b (%) Eec (%) Cs2CO3 1 2a CH2Cl2 - 25 0 -

2 2a CH2Cl2 + 25 0 -

3 2a CH2Cl2 - 60 0 -

4 2a CH2Cl2 + 60 0 - 5 2a Toluene + 60 0 -

6 3a CH2Cl2 + 40 48 4

7 4a CH2Cl2 - 40 5 22

8 4a CH2Cl2 + 40 54 37 9 4a Toluene + 40 50 23 10 4a HOAc - 40 4 13 aReaction conditions: 0.2 mmol indole, 0.01 mmol of [Rh(COD)2]BF4, 0.02 mmol of (S)- PipPhos, 0.02 mmol of Cs2CO3, 4 mL of solvent, rt, 25 bar H2. cConversion was determined by 1H NMR. dEnantioselectivity was determined by HPLC.

It was observed that in the hydrogenation of unprotected ester 2 to indoline 2a did not proceed in dichloromethane or toluene, at room temperature or 40 °C, with or without the addition of base (Entries 1-5). This possibly implies that the protective group on the nitrogen is required in order to achieve coordination of the substrate to the metal. Boc- protected substrate 3 was hydrogenated with 48% conversion, surprisingly only 4% ee was found (Entry 6). Hydrogenation of acid 4 was accomplished with low ee. In this case 10 mol% of Cs2CO3 was also sufficient, which suggests that it is not so much the pH that is important, but rather the

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Asymmetric hydrogenation of 2-substituted N-protected-indoles

presence of the cation (Entries 7 and 8). The best result was obtained in dichloromethane, with the addition of cesium carbonate (54% conversion, 37% ee, Entry 8). When acetic acid was used as solvent almost no conversion was achieved (Entry 10).

5.5 Mechanistic considerations

No mechanistic proposals have been published for the base dependent rhodium-catalyzed asymmetric hydrogenation of indoles. In view of the fact that a catalytic amount of base suffices, the assumption seems justified that the base is part of the catalytic cycle. This is a well-known phenomenon in ruthenium-catalyzed hydrogenations, where the base serves to create a ruthenium monohydride species, which is the actual catalyst.19 Thus we propose the mechanism as pictured in Scheme 5.4.

L L H [Rh(COD)2]BF4 + 2L Rh Rh L L H A B Cs2CO3

R L N Rh H O * R L N C O L L Rh H R D N L L O H2 Rh R N O

Scheme 5.4 Proposed hydrogenation mechanism

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Chapter 5

After formation of the cationic bisligated rhodium COD-complex A, reaction with hydrogen furnishes dihydrogen complex B, which upon reaction with base will form the neutral rhodium monohydride complex C. Reaction with the substrate gives complex D. Insertion of the indole olefin into the rhodium hydride bond leads to formation of rhodium alkyl complex E, which reacts with dihydrogen to yield the product and reform hydride C. Unfortunately, so far we have not been able to observe any intermediates using ESI-MS.

5.6 Conclusion

Full conversion and up to 74% ee was obtained in the asymmetric hydrogenation of methyl N-Acetyl indole-2-carboxylate 1 using 5 mol% of rhodium catalyst with 10 mol% of monodentate phosphoramidite ligand PipPhos L1 and 10 mol% of cesium carbonate. A protective group on the nitrogen was shown to be crucial in order to obtain conversion. The presence of cesium salts has shown to be neccesary in order to obtain high ee. Boc-protected indole ester 3 was hydrogenated with 48% conversion and only 4% ee, while 1-acetyl-2,3-indoline-2-carboxylic acid 4 was hydrogenated with up to 54% conversion and 37% ee. In view of the fact that only Rh/PhTRAP catalytic system has been reported to give results in the hydrogenation of indoles, it is apparent that the field is underdeveloped. The demand for efficient catalysts and ligands which would be easily accessible is evident. Since phosphoramidites, phosphites and phosphoramidites are readily available, these classes of ligands represent good candidates. A larger library of ligands should be screened in the hydrogenation of N-acetyl-indoles. Ligands having different backbones, such as catechol or TADDOL should be considered, as well as various rhodium precursors.

5.7 Experimental section

General remarks (see Chapter 2)

The metal precursor [Rh(COD)2]BF4 was purchased from Strem. Substrates 1, 2 and 3 were prepared according to the literature

188

Asymmetric hydrogenation of 2-substituted N-protected-indoles

procedure.10 1-Acetyl-indole-2-carboxylic acid 4 was obtained as a gift from DSM Pharmaceutical Chemicals and used as such. The catalyst was prepared in situ. Reactions were performed in a stainless steal autoclave containing 7 glass vessels (8 mL volume). The vessels were closed with caps containing septa. Magnetic stir bars were placed inside of each vessel and needles were placed through the septa in order to enable entrance of hydrogen. Vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. The enantiomeric excess was determined by HPLC with chiral columns (Chiralcel OD and OD-H) or by GC with Chiralsil DEX CB, in comparison with racemic products. Ligands L1,20 L1a,20 L1b,20 L1c,21 L1d,21 L1e,21 L1f,20 L1g,20 L2,22 L322 were prepared according to the literature procedure.

General experimental procedure for Hydrogenation

A mixture of Rh(COD)2BF4 (4.06 mg, 0.01 mmol), (S)-PipPhos (7.99 mg, 0.02 mmol), substrate (0.2 mmol) and a base (0.02 mmol) were dissolved in 4 mL of solvent, in a glass vial equipped with the stirring bar. The vial was placed in a stainless steel autoclave. After the reaction, hydrogen pressure was carefully released. Solvent was removed in vacuo and conversion was determined by NMR.

Methyl N-Acetylindole-2-carboxylate (1)10

COOMe N O This compound was synthesized according to a literature procedure;10 1H

NMR (400 MHz, CDCl3) 2.62 (s, 3H), 3.95 (s, 3H), 7.26 − 7.33 (m, 2H), 7.46 (t, J = 8.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H) ppm.

Methyl Indole-2-carboxylate (2)23

COOMe N H This compound was synthesized by esterification of the indole-2-carboxylic acid with thionyl chloride in methanol.

189

Chapter 5

1 Yellow solid, 89% yield, Mp = 150.6 – 151.0 °C; H NMR (400 MHz, CDCl3) 3.90 (s, 3H), 7.08 − 7.13 (m, 1H), 7.18 − 7.21 (m, 1H), 7.25 − 7.30 (m, 1H), 13 7.36 − 7.39 (m, 1H), 7.63 − 7.66 (m, 1H) ppm; C NMR (100 MHz, CDCl3) 53.0, 109.8, 112.9, 121.8, 123.6, 126.4, 128.0, 128.4, 138.0, 163.7 ppm.

Methyl N-tert-Butoxycarbonylindole-2-carboxylate (3)10

Boc O, DMAP COOMe 2 COOMe N THF, rt, 1h N H Boc

Methyl indole-2-carboxylate 3a (2.2 g, 12.5 mmol), Boc2O (3.2 g, 14.8 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol) were stirred in 50 mL of THF for 1h. Water was added (50 mL) and the reaction mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried, solvent evaporated and the crude product was purified by column chromatography (heptane:EtOAc = 24:1). The product was isolated as a white solid in 77% yield (2.7 g).

COOMe N Boc

1 White solid, 77% yield, Mp = 66.6 − 66.9 °C; H NMR (400 MHz, CDCl3) 1.63 (s, 9H), 3.92 (s, 3H), 7.11 (s, 1H), 7.26 (t, J = 7.10, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.42 Hz, 1H) ppm; 13C

NMR (100 MHz, CDCl3) 28.6, 53.2, 85.4, 115.7, 115.8, 123.1, 124.2, 127.7, 128.4, 131.3, 138.7, 150.1, 163.2 ppm.

1-Acetyl-indole-2-carboxylic acid (4)

COOH N Ac Compound was obtained from DSM- Pharmaceutical Chemicals.

190

Asymmetric hydrogenation of 2-substituted N-protected-indoles

Methyl (S)-N-Acetylindoline-2-carboxylate (1a)10

COOMe N O Compound exists as mixture of two configurations due to a hindered rotation of the acetyl moiety. Both configurations are observed at rt by 1H NMR. 1 White solid, Mp = 124.7 − 124.8 °C, 74% ee, [α]D = -43.8 (c 1.03, CHCl3); H

NMR (400 MHz, CDCl3) 2.16 and 2.48 (pair of s, 3H), 3.09 and 3.26 (pair of br d, J = 16.3 Hz and J = 16.8 Hz, 1H), 3.43 − 3.65 (pair of m, 1H), 3.73 and 3.76 (pair of s, 3H), 4.91 and 5.16 (pair of d, J = 10.5 Hz and J = 10.7 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 7.13 − 7.26 (m, 2H), 8.21 (d, J = 8.0 Hz, 1H) ppm; GC Chiralsil DEX CB, (initial temp. 95 °C for 5 min, then 2

°C/min to 180 °C, then 10 °C/min to 95 °C), t1 = 81.0 min, t2 = 81.7 min.

Methyl (S)-N-tert-Butoxycarbonylindoline-2-carboxylate (3a)10

∗ COOMe N Boc This compound exists as mixture of two configurations due to a hindered rotation of the Boc group. Both configurations are observed at rt by 1H NMR. 1 Colorless oil; H NMR (400 MHz, CDCl3) 1.47 and 1.58 (pair of br, s, 9H),

3.05 (dd, J1 = 4.06 Hz, J2 = 16.57 Hz, 1H), 3.44 (dd, J1 = 11.88 Hz, J2 = 16.05 Hz, 1H), 3.70 (s, 3H), 4.82 (br, 1H), 6.90 (t, J = 7.43 Hz, 1H), 7.05 (d, J = 7.26 Hz, 1H), 7.15 (t, J = 7.57 Hz, 1H), 7.87 (d, J = 5.70 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3) 28.9, 33.3, 53.0, 61.0, 81.9, 115.3, 123.2, 125.0, 125.4, 128.5, 143.2, 152.3, 173.1 ppm; HPLC (OD-H, eluent:heptane/i-PrOH = 98/2, detector: 254 nm, flow rate: 0.5 mL/min),

t1 = 15.7 min, t2 = 19.3 min.

191

Chapter 5

1-Acetyl-2,3-indoline-2-carboxylic acid (4a)

∗ COOH N Ac This compound exists as mixture of two configurations due to a hindered rotation of the acetyl moiety. Both configurations are observed at rt by 1H and 13C NMR. At 60 oC only one configuration is observed (broad signals). 1 White solid; H NMR (500 MHz, (CD3)2NCOD, 60 °C) 2.38 (s, 3H), 3.46 - 3.48 (br, 1H), 3.82 − 3.84 (br, 1H), 5.37 (d, J = 8.63 Hz, 1H), 7.20 (t, J = 7.35 Hz, 1H), 7.38 − 7.44 (m, 2H), 8.36 (br, 1H), 13.3 (br, 1H) ppm; 13C

NMR (125 MHz, (CD3)2NCOD, 60 °C) 23.3, 33.5, 61.5, 116.6, 123.5, 124.8,

127.5, 129.9, 143.6, 169.2, 173.4 ppm; HRMS Calcd. for C11H11NO3 (M+1) 206.07389, found 206.08064; HPLC (OD, eluent:heptane/i-PrOH/HCOOH

= 80/20/1, detector: 254 nm, flow rate: 1 mL/min), t1 = 9.7 min, t2 = 11.2 min.

5.8 References

(1) Comprehensive Natural Products Chemistry, Eds. Barton, D. H. R.; Nakanishi, K.; Meth-Cohn, O. Elsevier: Oxford, 1999; Vol. 1-9. (2) a) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357; b) Bianchini, C.; Meli, A.; Vizza, F. The Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. Wiley-VCH: Weinheim, 2007; Vol. 1, Chapter 16, 455; c) Glorius, F. Org. Biomol. Chem. 2005, 3, 4171. (3) a) Cushman, D. W.; Cheung, H. S.; Sabo, E. F.; Ondetti, M. A. Biochemistry 1977, 16, 5484; b) Ondetti, M. A.; Cushman, D. W. US4046889 to Squibb & Sons Inc., 1977. (4) Remond, G.; Laubie, M.; Vincent, M. EP0049658 to Science Union et Cie Societé Française de Recherche Medical., 1982. (5) Ksander, G. M.; Zimmerman, M. B. EP0336950 to Ciba Geigy AG, 1992. (6) a) Chava, S.; Bandari, M.; Madhuresh, K. S. WO2006013581 to Matrix Lab Ltd., 2006; b) Wang, Z.-X.; Raheem, M. A.; Weeratunga, G. WO2006053440 to Apotex Pharmachem Inc. 2006; c) Fujino, T.; Ogawa, R.; Sato, H. JP2004182670 to Toray Industries, 2004; d) Souvie, J.-C.;

192

Asymmetric hydrogenation of 2-substituted N-protected-indoles

Lecouve, J.-P. EP1348684 to Servier Lab., 2003; e) Hendrickx , A. J. J.; Kuilman, T. EP0937714 to DSM NV, 1999; f) Vlattas, I. US4665087 to Ciba Geigy Corp., 1987; g) Miyata, S.; Fukuda, H.; Imamura, S. EP0171616, 1986; h) Buzby, G. C. US4520205 to American Home Prod. 1985; i) Vincent, M.; Rémond, G.; Portevin, B.; Serkiz, B.; Laubie, M. Tetrahedron Lett. 1982, 23, 1677. (7) Buzby, G. C.; Winkley, M. W.; Mccaully, R. J. US4614806 to American Home Prod., 1986. (8) a) Le Goffic, F. FR2883874 to Substipharm Lab., 2006; b) Cho, N. R.; Lim, J. H.; Kim, J. K. WO2005051910 to SK Corp., 2005; c) Asada, M.; Hamaguchi, S.; Kutsuki, H.; Nakamura, Y.; Takashi, H.; Takahara, K.; Shimada, Y.; Ohashi, T.; Watanabe, K. US4898822 to Kanegafuchi Chemical Ind., 1990; d) Ghisalba, O.; Ramos, G.; Schaer, H.-P. DE3727411 to Ciba Geigy AG, 1988. (9) de Vries, A. H. M.; de Vries, J. G.; van Assema, F. B. J.; de Lange, B.; Mink, D.; Hyett, D. J.; Maas, P. J. D. WO2006069799 to DSM IP Assets bv, 2006. (10) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614. (11) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213. (12) a) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653; b) Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521. (13) a) Müller, C.; Freixa, Z.; Lutz, M.; Spek, A. L.; Vogt, D.; van Leeuwen, P. W. N. M. Organometallics 2008, 27, 834; b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895. (14) Thorn, D. L.; Hoffmann, R. J. Am. Chem. Soc. 1978, 100, 2079. (15) Dekker, G. P. C. M.; Elsevier, C. J.; Vrieze, K.; van Leeuwen, P. W. N. M. J. Organomet. Chem. 1992, 430, 357. (16) a) Bracher, G.; Grove, D. M.; Venanzi, L. M.; Bachechi, F.; Mura, P.; Zambonelli, L. Helv. Chim. Acta 1980, 63, 2519; b) DeStefano, N. J.; Johnson, D. K.; Venanzi, L. M. Angew. Chem. 1974, 86, 133. (17) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267.

193

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(18) Reetz, M. T. Angew. Chem. Int. Ed. 2008, 47, 2556. (19) Morris, R. H. Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G. E., C. J. Wiley-VCH: Weinheim, 2007; Vol. 3, Chapter 3, 45. (20) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (21) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (22) Maciá, B.; Fernández-Ibáñez, M. Á.; Mršić, N.; Minnaard, A. J.; Feringa, B. L. Tetrahedron Lett. 2008, 49, 1877. (23) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500.

194

Chapter 6 Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

In this chapter the asymmetric hydrogenation of N-aryl β-enamino acid esters is described. Full conversions and enantioselectivities of up to 70% were obtained using an iridium catalyst with a mixture of the phosphoramidite ligand PipPhos and an achiral phosphine.

Chapter 6

6.1 Introduction

6.1.1 Asymmetric hydrogenation of enamines

The synthesis of optically active amines is of considerable interest due to the presence of these motifs in natural products and in other molecules which show interesting biological activities.1 One of the approaches in the synthesis of chiral amines is the asymmetric hydrogenation of imines or enamines (Figure 6.1).2,3 Chiral cyclic tertiary amines are essential structural units in natural products and drugs.1,4

R1 R2 N NH O Ar 2 2 NH O N R R1 R2 1 2 R1 R OR R3 R4

R1 N N Ar1 N R H 2 Ar2 R

Figure 6.1 Model substrates for the hydrogenation of enamines

Pioneering work on the enantioselective catalytic hydrogenation of simple enamines was done by Buchwald et al. using a chiral titanocene catalyst (Scheme 6.1).5

Buchwald et al., 1994

R2 R3 N 2 3 1 R R Ti X X O 2 eq n-BuLi R N X = ∗ X O 2.5 eq PhSiH 3 R1 up to 5 bar H2 up to 98% ee

Scheme 6.1 The first asymmetric hydrogenation of enamines

196

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

With 5 mol% of catalyst and up to 5 bar of hydrogen pressure, excellent enantioselectivities and high yields were obtained. However, the use of expensive phenylsilane is a disadvantage of this method. In 2000, Börner et al. reported the first rhodium-catalyzed hydrogenation of enamines with up to 72% ee, using a bisphosphine ligand.6 Most of the current examples in the hydrogenation approaches require an acyl protecting and chelating group on the nitrogen of the unsaturated β-amino acids or enamines in order to achieve high reactivity and enantioselectivity.3,7,8 A major drawback of these approaches are additional steps of introducing and removing the acyl protecting group, which limits their application.9 In addition, to obtain high enantioselectivity, this method typically requires prior separation of the (Z)- and (E)-N-acyl enamine isomers, as most synthetic approaches to these precursors are poorly selective.

O O O P OR P R P R P N X O O O

X = C, O up to 97% ee up to 99% ee Minnaard, de Vries, Reetz et al., 2004 Feringa et al., 2004

R1 2 N O R O MeO PPh2 O P N P R O MeO PPh2 N O R2 R1

1 2 R = PhCH2, R = Me 1 2 R = Me, i-Pr, t-Bu, NR (S)-MeO-BIPHEP R = 3,5-(t-Bu)2C6H3CH2, R = Me 2 up to >99% ee up to >99% ee up to 96% ee Ding et al., 2005 Zhou, Q.-L. et al., 2006, 2009 Zhou, Y.-G. et al., 2009

Figure 6.2 Representative monodentate ligands reported for the asymmetric hydrogenation of simple enamines and N-acyl enamines

197

Chapter 6

Developing new catalysts that allow the asymmetric hydrogenation of simple enamines and N-acyl enamines is still in great demand, due to the fact that suitable catalytic systems are scarce and substrate scope is rather limited. In recent years, however, a rapid development has taken place.5,10-15 Figure 6.2 shows the most efficient monodentate ligands reported for the asymmetric hydrogenation of simple enamines and N-acyl enamines. In 2004 Reetz et al. reported the use of a mixed ligand approach in the asymmetric hydrogenation of N-acyl enamines. With the use of a rhodium catalyst and a mixture of BINOL-derived phosphites, phosphonites and phosphines up to 97% ee was obtained.15 In our group, a library of ligands was tested in the rhodium catalyzed asymmetric hydrogenation of N-acyldehydroamino acid esters, acyclic and cyclic N-acyl enamines.13 It was found that use of the simple monodentate ligands PipPhos and MorphPhos led to excellent ee’s and conversions. Ding also reported the use of a Rh/monodentate phosphoramidite catalytic system in the hydrogenation of both N-acetyl enamines and α- dehydroamino acids with excellent ee’s.14 The asymmetric hydrogenation of cyclic N,N-dialkyl enamines provides a direct approach to the synthesis of optically active cyclic tertiary amines. Since the acyl protecting group on the nitrogen of the unsaturated β-amino acids is often needed as a chelating group, the chiral catalysts that proved to be successful in the asymmetric hydrogenation of enamides can not be simply applied in the asymmetric hydrogenation of N,N-dialkyl enamines. The group of Zhou reported the highly efficient Rh(I)-catalyzed asymmetric hydrogenation of cyclic enamines11 and N,N-dialkylenamines12 using monodentate spiro phosphonite ligands, in which the addition of iodine and acetic acid was shown to be crucial for excellent activity and selectivity. Recently, Zhou et al. reported the use of iridium catalyzed hydrogenation of exocyclic enamines, with bisphosphine MeO-BIPHEP and iodine as additive. They also described applications to the synthesis of optically active alkaloid (S)-Cusparein and the key intermediate for the synthesis of NMDA-glycine antagonists.10

198

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

6.1.2 Asymmetric hydrogenation of β-dehydroamino acids

O O HO O O Br HN O O NH O HN O H O O O N O OH OH O O NH

Taxol Jasplakinolide N

O H COOH N H N

O NH Elarobifan

Figure 6.3 Biologically active compounds with β-amino acid units

Enantiomerically pure β-amino acids and their derivatives not only exhibit broad biological activity but are also the building blocks for the synthesis of β-peptides, β-lactam antibiotics and other chiral pharmaceuticals (Figure 6.3).16 Peptides containing β-amino acids show high stability towards enzymatic hydrolysis and are being valuated as promising pharmaceutical products. In addition, β-peptides show interesting three-dimensional structures,17 and they have played an important role in advancing the understanding of enzyme mechanisms, protein conformations, and properties related to molecular recognition.

199

Chapter 6

Therefore the asymmetric synthesis of β-amino acids attracts significant attention.18,19 Figure 6.3 shows some examples of pharmaceutically interesting structures containing a β-aryl-substituted β-amino acid as a common structural component.20,21 Taxol is a cancer chemotherapeutic agent, Jasplakinolide exhibits anthelminthic (drugs that expel parasitic worms), insecticidal, and antifungal properties and Elarobifan is an integrin antagonist. The cyclization of β-amino acids leads to the important family of the β- lactams. The beta-lactam ring is part of the structure of several antibiotic families, principally the penicillins, cephalosporins, carbapenems and monobactams (Figure 6.4).

H R H NH2 COOH N H H H O H S N N S O N O O N CH2OH O HO O H COOH COOH Clavulanic acid Penicilin Amoxicilin

O NH Cl N 2 H H N S NH S O N F O O N OH O O O HO Ampicilin Flucloxacilin

Figure 6.4 β-lactam antibiotics

Methods for the preparation of optically enriched β-amino acids are predominantly based on stoichiometric reactions with chiral auxiliary agents and to a clearly smaller extent on stereoselective catalytic reactions.19,21,22 The most important approach to β-amino acids is from the chiral pool, in particular through the Arndt-Eistert homologation of α- amino acids. One of the most promising methodologies, also regarding industrial application, is the asymmetric hydrogenation of the appropriate β-dehydroamino acid precursors catalyzed by homogeneous Rh or Ru

200

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

complexes containing chiral phosphane ligands.23 Whereas the asymmetric hydrogenation of α-dehydroamino acids is a standard method with many industrial applications,24 the hydrogenation of β-dehydroamino acids is still an underdeveloped area, mainly because the catalytic behaviour is highly dependent on the structure of the substrate (E or Z isomers, aliphatic or aromatic side chains). Although some results on the asymmetric hydrogenation of β-dehydroamino acid derivatives were published before,7,25 the breakthrough was made by Zhang et al. (Scheme 6.2).26 Using bisphosphine BICP and Duphos ligands, β-amino acid esters were prepared with excellent enantioselectivities and yields. While BICP leads to excellent results in the hydrogenation of (E)-isomer, Duphos is the ligand of choice for both (E) and (Z) β-enamino acid derivatives.

R1OOC COOR1 COOR1 Rh precursor, L* or R2 NHAc R2 NHAc rt, H2 R2 NHAc (E)(Z)

Ph2P H

H P P PPh2

(R,R)-BICP (R,R)-Me-Duphos up to 97% ee up to 99% ee

Scheme 6.2 Zhang’s asymmetric hydrogenation of β-dehydroamino acids

While the hydrogenation of acylated enamines is well known, it was quite unexpected that unprotected substrates are amenable to the asymmetric hydrogenation with high ee’s as well. Merck27 and Takasago28 reported independently asymmetric Rh-Josiphos and Ru-BINAP (and analogues) catalyzed hydrogenation of unprotected enamines leading to β- amino acid derivatives. With both catalysts high enantioselectivities were achieved, although the rate is somewhat lower than the hydrogenation of the acylated precursors. Merck has developed a process for the asymmetric hydrogenation of 1, which is an intermediate in the synthesis of Sitagliptin, an oral

201

Chapter 6

antihyperglycemic drug of the dipeptidyl peptidase-4 (DPP-4) inhibitor class (Scheme 6.3).29 Employing a rhodium catalyst with Josiphos as ligand, 1 was hydrogenated with 98% ee on a >50 kg scale, although with low to medium TONs and TOFs.

CF3 CF3 F N F N N N N N Rh-Josiphos N N o NH O 50 C, 90 psi H2 NH O F 2 F 2 F F 1 98% ee TON 350 P(t-Bu)2 -1 Fe P(p-CF3-Ph)2 TOF ~ 50 h pilot process

(RC,SFe)-Josiphos

Scheme 6.3 Hydrogenation of the β-dehydroamino acid amide intermediate for Sitagliptin

Figure 6.5 shows the most efficient ligands/catalysts employed in the asymmetric hydrogenation of β-dehydroamino acid derivatives.27,30-34 Zhang reported the first highly enantioselective hydrogenation of β-aryl- substituted β-N-acetyl enamino esters, using a ruthenium catalyst with the phosphinite BINAPO ligand.33 Excellent enantioselectivities were obtained even though the substrates were used as mixture of (E) and (Z) isomers. Subsequently, the same group reported the use of rhodium/Tangphos catalysts in the asymmetric hydrogenation of N-aryl β- enamino esters with excellent ee’s.30 In our group, β-dehydroamino acid derivatives were hydrogenated with the use of a Rh/phosphoramidite catalysts with excellent ee’s.34 Imamoto reported in 2002 the use of unsymmetrical bis(phosphane) ligands in the rhodium catalyzed hydrogenation of α- and β-dehydroamino acid derivatives and enamides, with up to 72% ee in the hydrogenation of β-dehydroamino acid derivatives.32

202

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

R - BF4 OPAr2 1 O R OPAr2 P N 2 Rh O R 1 3 R P P R R Me R2 BINAPO R = Ph, Ar = Ph R = 3,5-Me2C6H3, Ar = Ph R = Ph, Ar = 3,5-Me2C6H3 up to >99% ee up to 72% ee up to 99% ee Minnaard, Feringa, Imamoto et al., 2002 de Vries et al., 2002 Zhang et al., 2002

O H PPh2 N N P R PPh 2 P H P t-Bu t-Bu

Ph2P PPh2 BINAP (S,S,R,R)-Tangphos Me-BDPMI

up to 96% ee up to >97% ee up to 96% ee up to 94% ee

Lee et al., 2004 TAKASAGO, 2005 Zhang et al., 2006 Gladiali, Beller et al., 2007 Figure 6.5 Ligands/catalyst reported for the asymmetric hydrogenation of β-dehydroamino acid precursors

Lee described the asymmetric synthesis of cyclic β-amino acid derivatives (homoproline derivatives) via asymmetric hydrogenation, using a rhodium catalysts with chiral bisphosphine ligands.31 The groups of Gladiali and Beller have shown that monodentate chiral BINOL-derived phosphepine ligands can be used for various rhodium- and ruthenium-catalyzed hydrogenations. Their application towards the synthesis of β-amino acid derivatives is shown, and enantioselectivities up to 94% ee were achieved.35 N-Aryl β-amino acid derivatives are key structural elements of many natural products and drug intermediates.36 One of the ways to prepare such compounds is to perform asymmetric hydrogenation of N-aryl β- enamino esters. For example, the most efficient way to introduce a phenyl group on the drugs CGP-68730A or LG-121104 is the enantioselective hydrogenation of a N-aryl β-enamine. Other approaches include the

203

Chapter 6

coupling of an amine and a phenyl moiety, however, the route via asymmetric hydrogenation is more direct (Scheme 6.4).

O O Na

OEt S S N O NH O

Br N O Br H

CGP-68730A O CF3

N NH2 N N O H N H H H

LG-121104

NH COOEt

Scheme 6.4 Drug candidates with N-aryl amino acid units and potential enamine substrates for the hydrogenation

6.2 Goal of the research

As mentioned earlier, asymmetric hydrogenation of β-enamino acid derivatives represents a direct approach to β-amino acids. In our group phosphoramidite ligands were successfully used in the asymmetric hydrogenation of α- and β-dehydroamino acids with excellent enantioselectivity.13,34 We have also shown that iridium with phosphoramidite ligands gives excellent results in the hydrogenation of N- aryl imines (Chapter 4).37 The goal of this research was to develop an efficient catalyst for the hydrogenation of N-aryl β-enamino esters, as precursors for the synthesis of pharmaceuticals. Therefore, we studied different classes of ligands and different metals in the hydrogenation of N- aryl β-enamino esters.

204

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

6.3 Substrate synthesis

A family of enamino esters was prepared from β-keto esters and aniline derivatives.30,38 Only one isomer of the enamines was obtained. Two methods for their synthesis were employed. The β-alkyl N-aryl enamino esters were prepared by stirring of the β-keto ester with aniline in the presence of acetic acid, in an ultrasonic bath (Scheme 6.7, method A). β- Aryl N-aryl enamino esters were prepared by refluxing of the β-keto esters with aniline (or an aniline derivative) in the presence of p-toluenesulfonic acid in ethanol (Scheme 6.5, method B).

Method A

O O H2N R NH O O HOAc R ultrasonic bath, 3h O

1, R = Me, 60% yield 2, R = Et, 76% yield Method B

R R O O H2N NH O O p-TsOH, EtOH reflux overnight O

3, R = H, 44% yield 4, R = o-OMe, 31% yield 5, R = p-OMe, 31% yield

Scheme 6.5 Synthesis of enamines

6.4 Results

Inspired by the results of the Merck group27 in the asymmetric hydrogenation of unprotected enamines leading to β-amino acid derivatives, we decided to test two ferrocenyl ligands in the rhodium catalyzed hydrogenation of five different N-aryl β-enamino esters.

205

Chapter 6

The reactions were performed using 5 mol% of rhodium precursor and 5 mol% of the ligand, at 5 bar of hydrogen pressure and room temperature, in trifluoroethanol (TFE). High throughput methodology was used for the first set of experiments (see chapter 2 about HTE). Since in the HTE experiment 96 reactions are performed in a single run of the autoclave, reaction mixtures were analyzed after the hydrogenation without purification. Catalysts and ligands used, as well as substrates and additives were dispensed as stock solutions, using a robot. Hydrogenation was performed in a Premex 96-Multi Reactor. The results of the high throughput experiments are presented in Tables 6.1 - 6.5. Although the role of TFE in hydrogenation reactions has not been completely clarified yet, there have been several reports in which fluorinated alcohols were shown to have a positive effect on the selectivity and rate of the transition metal-promoted reactions, including hydrogenation.39 It has been reported that the dramatic improvement of enantioselectivity and conversion was obtained in the asymmetric hydrogenation of imines40 and ketones41 when trifluoroethanol was used as a solvent . The role of fluorinated alcohols is rationalized as a stabilizer of the active catalyst (as a weekly coordinating ligand), or as a hydrogen bond donor. Therefore, we decided to perform the initial hydrogenation experiments of enamino esters 1-5 in trifluoroethanol. Results obtained with ferrocenyl ligands are presented in Table 6.1. At 5 bar of hydrogen pressure, high conversions were obtained for all tested substrates with Taniaphos as a ligand (Entries 2, 4, 6, 8, 10). In the case of anisidine substituted enamino esters 4 and 5 conversions were high with both Josiphos and Taniaphos (Entries 7-10). However, determination of the enantiomeric excess of 4a and 5a was unsuccessful both on HPLC or GC. The highest enantioselectivity was obtained in the hydrogenation of β- phenyl N-phenyl enamino ester 3, using Taniaphos (73% ee, Entry 6). The same ligand induced only 3% ee in the hydrogenation of β-methyl N-phenyl enamino ester 2. On the contrary, good enantioselectivity was obtained for enamines 1 and 2 using Josiphos (51% and 63% ee, respectively, Entries 1, 3).

206

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Table 6.1 Asymmetric hydrogenation of N-aryl β-enamino estersa

3 R R3 NH O NH O 5 mol% [Rh(COD) ]BF 5 mol% L* R2 2 4, ∗ 2 1 1 R R O 5 bar H2, rt, TFE, 16h R O 1-51a-5a

1a, R1 = Me, R2 = Me, R3 = Ph 2a, R1 = Me, R2 = Et, R3 = Ph 3a, R1 = Ph, R2 =Et, R3 = Ph 4a, R1 = Ph, R2 = Et, R3 = o-anisyl 5a, R1 = Ph, R2 = Et, R3 = p-anisyl

NMe2 PCy2 Ph2P Fe PPh2 Fe Ph2P

(RC,SFe)-Josiphos (RC,RFe)-Taniaphos

Entry Product Ligand Conv.b (%) eec (%) 1 1a Josiphos 53 51 2 Taniaphos 100 ndd 3 2a Josiphos 68 63 4 Taniaphos 100 3 5 3a Josiphos 50 30 6 Taniaphos 91 73 7 4a Josiphos 86 nd 8 Taniaphos 99 nd 9 5a Josiphos 85 nd 10 Taniaphos 76 nd aReaction conditions: 100 µmol enamino ester, 5 µmol [Rh(COD)2]BF4, 5 µmol L*, 2.55 mL of TFE, rt, 5 bar H2, 16h. bConversion was determined by GC. cEnantiomeric excess was determined by HPLC. dEnantiomeric excess was not determined due to the overlapping of the peak of an impurity with the peak of the product.

In addition, we examined iridium and ruthenium catalysts in the asymmetric hydrogenation of β-enamino esters (Figure 6.6, Table 6.2). Two cationic iridium catalysts with bidentate P,N-bidentate ligands and a ruthenium catalyst with a phosphoramidite ligand and a chiral diamine were used. Since this ruthenium catalyst gives excellent results in the

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hydrogenation of ketones and β-keto esters,42 we decided to study its performance also in the hydrogenation of enamino esters. Using QUINAP as ligand good to excellent conversions were obtained, while the highest ee obtained was in the hydrogenation of 3 (21% ee, Entry 7).

Table 6.2 Ligands/catalysts employed in the asymmetric hydrogenation of N-aryl β-enamino estersa

3 R R3 NH O NH O 5 mol% catalyst R2 ∗ 2 1 1 R R O 5 bar H2, rt, TFE, 16h R O 1-51a-5a

1a, R1 = Me, R2 = Me, R3 = Ph 2a, R1 = Me, R2 = Et, R3 = Ph 3a, R1 = Ph, R2 =Et, R3 = Ph 4a, R1 = Ph, R2 = Et, R3 = o-anisyl 5a, R1 = Ph, R2 = Et, R3 = p-anisyl

Entry Product Catalyst Conv.b (%) eec (%) 1 Ir/QUINAP 37 ndd 2 1a Ir/Pfaltz 3 nd 3 Ru Cat A 0e - 4 Ir/QUINAP 26 0 5 2a Ir/Pfaltz 2 nd 6 Ru Cat A 0e - 7 Ir/QUINAP 69 21 8 3a Ir/Pfaltz 53 46 9 Ru Cat A 0e - 10 Ir/QUINAP 46 nd 11 4a Ir/Pfaltz 30 nd 12 Ru Cat A 0e - 13 Ir/QUINAP 94 nd 14 5a Ir/Pfaltz 89 nd 15 Ru Cat A 0e - aReaction conditions: 100 µmol enamino ester, 5 µmol catalyst, 2.55 mL of TFE, rt, 5 bar H2, 16h. bConversion was determined by GC. cEnantiomeric excess was determined by HPLC. dEnantiomeric excess was not determined due to the overlapping of the peak of an impurity with the peak of the product. eReaction performed in i-PrOH.

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Use of the Pfaltz’ oxazolidine ligand resulted in poor conversion in the Ir-catalyzed hydrogenation of β-alkyl N-phenyl β-enamino esters (1, 2, Entries 2 and 5), whereas in the case of β-aryl N-phenyl β-enamino esters up to 89% conversion was observed (Entries 8, 11, 14). The highest ee was obtained in the hydrogenation of substrate β-phenyl N-phenyl β-enamino ester 3 (53% conversion, 46% ee, Entry 8). Ruthenium catalyst A gave no conversion in the hydrogenation of any of the substrates (Entries 3, 6, 9, 12, 15).

- - PF6 PF6

O N Ir P N PPh2 Ir

Ir/QUINAP cat. Ir/Pfaltz cat.

H2 H2 N L* Cl L* N O Ru Ru L* = P N N Cl Cl Cl N O H2 H2

Cat A

Figure 6.6 Catalysts employed in the asymmetric hydrogenation of N-aryl β-enamino esters

As shown by the Merck group,27 results of the deuterium labelling studies showed that the hydrogenation of unprotected β-dehydroamino acid derivatives proceeds through the imine tautomer, making the reaction mechanistically analogue to β-ketoester and -amide hydrogenations.43 As mentioned earlier, since the [Ir(COD)2]BArF/PipPhos L1 catalyst gave excellent results in the hydrogenation of N-aryl imines, quinolines and quinoxalines, we examined the possibility to use the same catalytic system in the hydrogenation of β-enamino esters. This hydrogenation was

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performed using 5 mol% of iridium precursor and 10 mol% of (S)-PipPhos L1 ligand, at 5 bar of hydrogen pressure and room temperature, in dichloromethane. The results are presented in Table 6.3.

Table 6.3 Asymmetric hydrogenation of N-aryl β-enamino esters using a [Ir(COD)2]BArF/(S)-PipPhos L1

3 R R3 NH O NH O 5 mol% [Ir(COD)2]BArF, 10 mol% (S)-PipPhos R2 ∗ 2 1 1 R R O 5 bar H2, rt, CH2Cl2, 16h R O

1-51a-5a

1a, R1 = Me, R2 = Me, R3 = Ph O P N 2a, R1 = Me, R2 = Et, R3 = Ph O 3a, R1 = Ph, R2 =Et, R3 = Ph 4a, R1 = Ph, R2 = Et, R3 = o-anisyl 1 2 3 (S)-PipPhos L1 5a, R = Ph, R = Et, R = p-anisyl

Entry Product Conv.b (%) eec (%) 1 1a 21 20 2 2a 13 36 3 3a 46 8 4 4a 37 nd 5 5a 89 nd aReaction conditions: 100 µmol enamino ester, 5 µmol [Ir(COD)2]BArF, 10 µmol (S)-PipPhos, 2.55 mL of solvent, CH2Cl2, 5 bar H2, 16h. bConversion was determined by GC. cEnantiomeric excess was determined by HPLC.

All substrates tested except enamino ester 5, were hardly converted at 5 bar of hydrogen pressure and room temperature. Substrate 5 was hydrogenated with 89% conversion. In general low enantioselectivities were obtained. The highest ee was obtained in the hydrogenation of β-methyl N- phenyl enamino ester 2, however, with low conversion (13% conversion, 36% ee, Entry 2). Since reactions with Ir/PipPhos L1 at 5 bar of hydrogen pressure gave low conversions and ee’s, the following experiments were performed at 25 bar of pressure. Various solvents as well as additives were screened in the asymmetric hydrogenation of β-methyl N-phenyl enamino ester 2, β-phenyl

210

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

N-phenyl enamino ester 3 and cyclic enamine 6. The results are presented in Table 6.4. When reactions were performed in dichloromethane and 25 bar of pressure, results for the hydrogenation of β-enamino esters 2 and 3 were comparable to the experiments performed at 5 bar (Entries 1, 8). A wide variety of Lewis acid catalysts have been developed on the basis of the Lewis acid-base complexes in organic polar solvents.44 Lewis acids are among the most useful reagents in reactions with ketones as substrates. We wanted to examine if the addition of the Lewis acid would promote the oxidative addition of the enamine substrate to the iridium.45 When 5 mol% of Lewis acid (indium bromide) was added to the hydrogenation of 2, the conversion increased from 45% to 68% however, the enantioselectivity dropped from 25 to 12% (Entry 2). In the case of the substrate 3, the conversion dropped significantly by the addition of indium bromide (Entry 9). Using toluene as a solvent, conversions in the hydrogenation of 2 and 3 were somewhat higher, however, the ee stayed low (16 and 17% ee, respectively). In i-propanol, both substrates were hydrogenated with low ee (Entries 4, 11 and 18). As described in Chapter 4, it is well known that the addition of the Brönsted acid often increases the enantioselectivity46 or rate47 of the asymmetric hydrogenation. When 5 mol% of salicylic acid was added to the reaction mixture in the hydrogenation of 2 and 3 in i-propanol the enantioselectivity of 2a increased from 5% to 33%, while for the product 3a an insignificant drop of ee occurred (Entries 5, 12). The explanation of the positive effect of the addition of organic acid on the enantioselectivity may be that the acid protonates the product of the hydrogenation and in this way prevents its coordination to the metal center, and in this way preventing the “catalyst poisoning”.

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Table 6.4 Solvents and additives screening using Ir/PipPhos L1 a

3 R R3 NH O NH O 2 ∗ 2 1 R R R O R1 O

2, 32a5 mol% [Ir(COD)2]BArF , 3a 10 mol% (S)-PipPhos 2a, R1 = Me, R2 = Et, R3 = Ph 25 bar H2, rt, Solvent, 16h 3a, R1 = Ph, R2 = Et, R3 = Ph

N ∗ N

6 6a

Entry Product Solvent Additive Conv.b (%) eec (%) 1 DCM - 45 25 2 DCM 5 mol% InBr3 68 12 3 Toluene - 73 16 4 IPA - 98 5 2a 5 mol% salicylic 5 IPA 93 33 acid 6 THF - 99 2 7 THF 10 mol% I2 100 3 8 DCM - 34 20 9 DCM 5 mol% InBr3 6 nd 10 Toluene - 47 17 11 IPA - 48 9 3a 5 mol% salicylic 12 IPA 50 2 acid 13 THF - 73 20 14 THF 10 mol% I2 43 0 15 DCM - 100 6 16 DCM 5 mol% InBr3 100 6 17 Toluene - 100 6 18 IPA - 100 0 6ad 5 mol% salicylic 19 IPA 100 4 acid 20 THF - 100 4 21 THF 10 mol% I2 100 20 aReaction conditions: 100 µmol substrate, 5 µmol [Ir(COD)2]BArF, 10 µmol PipPhos L1, 2.55 mL of solvent, rt, 25 bar H2, 16h. bConversion was determined by GC. cEnantiomeric excess was determined by HPLC. dEnantiomeric excess was determined by GC analysis.

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

When the reaction was performed in tetrahydrofuran, no ee was observed for product 2a while product 3a was hydrogenated with 73% conversion and 20% ee (Entries 6 and 13). Adding 10 mol% of iodine as additive in THF, gave racemic products 2a and 3a (Entries 7 and 14). In the case of the hydrogenation of cyclic enamine 6, full conversion was obtained in all solvents and with all additives, however, the highest ee was obtained in the reaction in which iodine was added (20% ee, Entry 21). We decided to examine the possibility to use a mixtures of phosphoramidites with achiral P-ligands or amines (see Chapter 2).

Reactions were performed using 5 mol% of [Ir(COD)2]BArF and (S)-PipPhos L1 as a ligand, at 25 bar of hydrogen pressure and room temperature. When achiral phosphine was used as a second ligand, the ratio between PipPhos L1 and achiral ligand was 2/1. In the reactions where an amine was used as the second ligand, the ratio of ligands was PipPhos L1/amine = 1/1, as in the case of Crabtree’s catalyst.48 The results of the hydrogenation of substrates 2, 3 and 6 are presented in Table 6.5. In the case of the addition of the amine ligand, an excellent conversion, but no enantioselectivity was observed with any of the substrates, both when (S,S)-2-Phenyl-1-(1-phenyl-ethyl)-propylamine or triethylamine were added (Entries 2, 3, 7, 8, 12 and 13). When achiral phosphines were added in combination with (chiral) PipPhos, the highest ee was achieved using triphenylphosphine in the hydrogenation of both 2 and 3 (up to 65% ee, Entries 4 and 9). In the case of substrate 3, the conversion was somewhat lower (54%, Entry 9). Substrate 6 was again hydrogenated with excellent conversion however almost racemic product was isolated in all cases (Entries 11-15).

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Table 6.5 Asymmetric hydrogenation of enamines using Ir catalysts with mixed ligandsa

3 R 5 mol% [Ir(COD) ]BArF 3 NH O 2 R (S)-PipPhos NH O 2 ∗ 2 1 R R R O achiral ligand R1 O 25 bar H2, rt, CH2Cl2, 16h 2, 32a, 3a

2a, R1 = Me, R2 = Et, R3 = Ph 3a, R1 = Ph, R2 = Et, R3 = Ph

5 mol% [Ir(COD)2]BArF N (S)-PipPhos ∗ achiral ligand N 25 bar H2, rt, CH2Cl2, 16h 6 6a

Entry Product Achiral ligand Ir/L*/L Conv.b (%) eec (%) 1 - 1/2/0 45 25

2 Et3N 1/1/1 100 0

3 2a Ph N Ph 1/1/1 94 0 H 4 PPh3 1/2/1 100 65 Tri-o- 5 1/2/1 48 16 tolylphosphine 6 - 1/2/0 34 20

7 Et3N 1/1/1 100 2

8 3a Ph N Ph 1/1/1 100 0 H 9 PPh3 1/2/1 54 45 Tri-o- 10 1/2/1 15 5 tolylphosphine 11 - 1/2/0 100 6

12 Et3N 1/1/1 100 2

13 6ad Ph N Ph 1/1/1 100 0 H 14 PPh3 1/2/1 100 8 Tri-o- 15 1/2/1 100 6 tolylphosphine aReaction conditions: 100 µmol substrate, 5 µmol [Ir(COD)2]BArF, 10 µmol (S)-PipPhos L1, 2.55 mL of CH2Cl2 rt, 25 bar H2, 16h. bConversion was determined by GC. cEnantiomeric excess was determined by HPLC. dEnantiomeric excess was determined by GC analysis.

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Since the PipPhos/triphenylphosphine mixture induced the highest enantioselectivity in the hydrogenation of N-aryl β-enamino esters, we decided to perform this reaction at higher concentration (1 mmol scale, 4 mL of solvent) and lower catalyst loading, on model substrate 1. Various achiral P-ligands were tested in combination with PipPhos L1 (Figure 6.7). Results are depicted in Table 6.6. Reactions were performed at 25 bar of

hydrogen pressure and room temperature, using 1 mol% of [Ir(COD)2]BArF, 2 mol% of PipPhos L1 and 1 mol% of achiral ligand, in dichloromethane. The best result was again obtained using triphenylphosphine in combination with PipPhos L1, providing full conversion and 70% ee (Entry 1). With the use of tri-o-tolylphosphine L3 no conversion was obtained, while use of other phosphines having a substituent in the ortho-position also led to low conversions (L5 and L7, Entries 4 and 6).

Table 6.6 Achiral ligands screened in the asymmetric hydrogenation of 1a

1 mol% [Ir(COD)2]BArF, 2 mol% PipPhos NH O NH O 1 mol% achiral ligand ∗ O CH2Cl2, rt, 25 bar H2, 16h O 1 1a

Entry Achiral ligand Conv.b (%) eec (%) 1 L2 100 70 2 L3 0 - 3 L4 100 52 4 L5 5 - 5 L6 100 63 6 L7 29 42 7 L8 6 nd 8 L9 100 47 9 L10 42 40 10 L11 26 38 aReaction conditions: 1 mmol 1, 0.01 mmol [Ir(COD)2]BArF, 0.02 mmol (S)-PipPhos L1, 0.01 mmol achiral ligand, 4 mL of toluene, 60 °C, 70 bar H2, 20h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by HPLC.

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The sterically bulky phosphine L8 cased low conversion (6%, Entry 7). Full conversions and ee’s up to 63% were achieved using phosphines with substituents in the meta or para positions (Entries 3 and 5). This result suggests that o-substituted achiral phosphines as well as the sterically bulky phosphine L8 are perhaps sterically too demanding for coordination to the iridium together with the PipPhos L1 ligand.

P P P P

L2 L3 L4 L5

O O

P P P

L6 L7 L8

O P O O O P N P N O N

L9 L10 L11

Figure 6.7 Achiral P-ligands screened in the asymmetric hydrogenation of 1

When trimethylphosphite L9 was used with PipPhos L1, full conversion was accomplished, whereas with addition of triphenylphosphine oxide L10 and HMPA L11 only up to 42% conversion and 40% ee was achieved (Entries 8-10).

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Table 6.7 Ligand screening in the asymmetric hydrogenation of 1a

1 mol% [Ir(COD)2]BArF, 2 mol% L* NH O NH O ∗ 1 mol% PPh3 O CH2Cl2, rt, 25 bar H2, 16h O 1 1a

O P N O O P N O

L12 L13

Ph Ph O O P N P N O O Ph Ph

L14-(S,R,R) L15-(S,S,S)

Entry Ligand PPh3 Conv.b (%) eec (%) 1 L12 - 19 6 2 L12 + 7 nd 3 L13 - 4 nd 4 L13 + 8 46 5 L14 - 11 10 6 L14 + 11 0 7 L15 - 20 3 8 L15 + 20 6 aReaction conditions: 1 mmol 1, 0.01 mmol [Ir(COD)2]BArF, 0.02 mmol L*, 4 mL of DCM, rt, 25 bar H2, 16h. bConversion was determined by 1H NMR. cEnantiomeric excess was determined by HPLC.

Apart from the screening of various achiral ligands, we screened four different phosphoramidite ligands in combination with triphenylphosphine L2 in the hydrogenation of 1. The reactions were performed using 1 mol%

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of iridium precursor, 2 mol% of phosphoramidite ligand and 1 mol% of triphenylphosphine, at 25 bar of hydrogen pressure and room temperature, in dichloromethane. Results are presented in Table 6.7. Phosphoramidite ligands L12 and L13 are derived from different

backbones; one has a H8-BINOL and another the 3,3’-substituted BINOL backbone. Ligands L14 and L15 are derived from chiral 2-phenyl-1-(1- phenyl-ethyl)-propylamine with different configurations. Unfortunately all the ligands employed induced disappointingly low conversions. The highest enantioselectivity, however, accompanied by very low conversion was obtained using phosphoramidite L13 in combination with triphenylphosphine (Entry 4, 8% conversion, 46% ee). We decided to perform the reaction at higher concentration (1 mmol scale, 4 mL of solvent) and lower catalyst loading (1 mol%), on model substrate 1, for the rhodium/ferrocene-based bisphosphine, as well as the rhodium/PipPhos L1 catalytic system. Various solvents were used, and the results are presented in Table 6.8. The experiment with Josiphos in dichloromethane, led to a similar result as in the HTE experiment with the use of 5 mol% of the catalyst and higher dilution (49% conversion, 48% ee, Entry 1). Also a similar result was obtained in trifluoroethanol (64% conversion, 52% ee, Entry 2). In ethyl acetate a somewhat lower conversion and ee was obtained (30% conversion, 28% ee, Entry 4). In the case of PipPhos L1 no conversion was achieved in dichloromethane and trifluoroethanol, while in ethyl acetate 27% conversion and 20% ee was observed (Entry 8). Very low conversions were obtained in toluene, in the case of both Josiphos and PipPhos L1 (3% and 6%, respectively, Entries 3 and 7).

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Table 6.8 Asymmetric hydrogenation of 1 using Josiphos and PipPhos L1 ligandsa,b

1 mol% [Rh(COD)2]BF4, L* NH O NH O ∗ Solvent, rt, 25 bar H2, 16h O O

1 1a

Entry Solvent Ligand Conv.c (%) Eed (%) 1 DCM Josiphos 49 48

2 CF3CH2OH Josiphos 64 52 3 Toluene Josiphos 6 nd 4 EtOAc Josiphos 30 28 5 DCM PipPhos 0 -

6 CF3CH2OH PipPhos 0 - 7 Toluene PipPhos 3 nd 8 EtOAc PipPhos 27 20 aReaction conditions: 1 mmol 1, 0.01 mmol [Rh(COD)2]BF4, 0.01 mmol Josiphos, 4 mL of solvent, rt, 25 bar H2, 16h. b1 mmol 1, 0.01 mmol [Rh(COD)2]BF4, 0.02 mmol (S)-PipPhos, 4 mL of solvent, rt, 25 bar H2, 16h. cConversion was determined by 1H NMR. dEnantiomeric excess was determined by HPLC.

6.5 Conclusion

In conclusion, we examined various catalytic systems in the hydrogenation of β-dehydroamino acid derivatives. The highest enantioselectivity was obtained using an iridium catalyst with a mixture of the phosphoramidite ligand PipPhos L1 and triphenylphosphine L2 (full conversion, 70% ee). As shown previously in the literature, rhodium catalysts with ferrocene-based bisphosphine ligands led to excellent results in the hydrogenation of unprotected β-dehydroamino acid derivatives.27 In our case, Josiphos and Taniaphos ligands induced good conversions and ee’s in the hydrogenation of N-aryl β-amino acid derivatives. Phosphoramidites are interesting from the point of view of industrial application, due to their low cost, easy preparation and excellent performance in the asymmetric hydrogenation.49 Therefore, in the view of future results, a broad screening of both chiral phosphoramidites and

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achiral ligands should be performed. It would be also interesting to see whether the same catalytic system could be used in the hydrogenation of unprotected β-dehydroamino acid derivatives, which would make the hydrogenation approach to β-amino acids more attractive and useful.

6.6 Experimental section

General remarks (see Chapter 2)

Metal precursor [Rh(COD)2]BF4 was purchased from Strem.

[Ir(COD)2]BArF was obtained from Umicore and used as such. Reactions were performed in a stainless steal autoclave containing 7 glass vessels (8 mL volume). These vessels were closed with septum caps. Magnetic stir bars were placed inside of each vessel and needles were placed through the septa in order to enable entrance of hydrogen. Vessels were filled under air and then flushed with nitrogen before hydrogen pressure was applied. The enantiomeric excess was determined by HPLC with chiral columns (Chiralcel OD and OD-H) and GC (Chirasil Dex CB), in comparison with racemic products. High throughput experiment was performed in a Premex 96 autoclave. Solutions of substrate were dispensed into the vials, followed by the solutions of the metal precursor, ligand and additive. Ligands L1,50 L12,13 L13,51 L1450 and L1550 were prepared according to the literature procedure. Ruthenium catalyst (Cat A) was prepared according to the procedure from our group.52 Cyclic enamine 6 was obtained from DSM Pharmaceuticals and used as such.

220

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

Preparation of enamino-esters

Method A

O O H2N R NH O O HOAc R ultrasonic bath, 3h O

1, R = Me 2, R = Et Alkyl acetoacetate (10 mmol), aniline (905 µL, 10 mmol) and acetic acid (57 µL, 1 mmol) were placed in a 25 mL round bottom flask. The reaction mixture was placed in an ultrasonic bath for 3h. The crude product was purified by Kugelrohr distillation.

3-Phenylamino-but-2-enoic acid methyl ester (1)30

NH O

1 White solid, 60% yield, Mp = 47.8 – 48.0 °C; H NMR (400 MHz, CDCl3) 1.99 (s, 3H), 3.68 (s, 3H), 4.70 (s, 1H), 7.08 (d, J = 7.39 Hz, 2H), 7.15 (t, J = 7.47 Hz, 1H), 7.32 (t, J = 7.87 Hz, 2H), 10.37 (br, 1H) ppm; 13C NMR

(100 MHz, CDCl3) 20.2, 50.2, 85.5, 124.4, 124.9, 129.0, 139.2, 159.0,

+ 170.6 ppm; HRMS Calcd. for C11H13NO2 (M ) 191.0946, found 191.0950.

3-Phenylamino-but-2-enoic acid ethyl ester (2)30

NH O

1 Yellow liquid, 76% yield; H NMR (400 MHz, CDCl3) 1.28 (t, J = 7.12 Hz, 3H), 1.99 (s, 3H), 4.15 (q, J = 7.12 Hz, 2H), 4.70 (s, 1H), 7.08 (d, J = 8.05 Hz, 2H), 7.14 (t, J = 7.40 Hz, 1H), 7.31 (t, J = 7.55 Hz, 2H), 10.40 (br, 1H) 13 ppm; C NMR (100 MHz, CDCl3) 14.5, 20.2, 58.6, 85.9, 124.3, 124.8, + 128.9, 139.2, 158.8, 170.3 ppm; HRMS Calcd. for C12H15NO2 (M ) 205.1103, found 205.1110.

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Preparation of enamino-esters

Method B

R R O O H2N NH O O p-TsOH, EtOH reflux overnight O

3, R = H, 44% yield 4, R = o-OMe, 31% yield 5, R = p-OMe, 31% yield

Ethyl-benzoylacetate (5.16 mL, 30 mmol), aniline (30 mmol) and p- toluenesulfonic acid (571 mg, 3.3 mmol) were dissolved in 30 mL of ethanol and heated at 80 °C overnight. The crude product was purified by column chromatography on silica (heptane/EtOAc = 30/1), previously inactivated by triethylamine. After chromatography the product was recrystallized.

3-Phenyl-3-phenylamino-acrylic acid methyl ester (3)30

NH O

White solid, 44% yield. After column chromatography the product was 1 washed with heptane. Mp = 71.2 – 71.6 °C; H NMR (400 MHz, CDCl3) 1.34 (t, J = 7.11 Hz, 3H), 4.24 (q, J = 7.13 Hz, 2H), 5.04 (s, 1H), 6.69 (d, J = 7.49 Hz, 2H), 6.92 (t, J = 7.39 Hz, 1H), 7.09 (t, J = 8.40 Hz, 2H), 7.27 – 7.39 (m, 13 5H), 10.37 (br, 1H) ppm; C NMR (100 MHz, CDCl3) 14.4, 59.2, 91.1, 122.1, 122.8, 128.1, 128.3, 128.5, 129.3, 135.9, 140.3, 158.9, 170.0 ppm; + HRMS Calcd. for C17H17NO2 (M ) 267.1259, found 267.1273.

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

3-(2-Methoxy-phenylamino)-3-phenyl-acrylic acid methyl ester (4)

NH O

Yellow solid, 31% yield. After column chromatography the product was recrystallized from heptane/EtOAc. Mp = 104.4 – 106.8 °C; 1H NMR (400

MHz, CDCl3) 1.32 (t, J = 7.12 Hz, 3H), 3.90 (s, 3H), 4.23 (q, J = 6.54 Hz, 2H), 5.01 (s, 1H), 6.21 (d, J = 8.00 Hz, 1H), 6.52 (t, J = 6.57 Hz, 1H), 6.82 – 6.89 (m, 2H), 7.28 – 7.38 (m, 5H), 10.28 (br, 1H) ppm; 13C NMR (100 MHz,

CDCl3) 14.5, 55.6, 59.1, 91.5, 110.4, 119.7, 121.6, 122.8, 127.8, 128.2,

129.2, 129.5, 136.2, 150.3, 158.2, 169.7 ppm; HRMS Calcd. for C18H19NO3 (M+) 297.1365, found 297.1381.

3-(4-Methoxy-phenylamino)-3-phenyl-acrylic acid methyl ester (5)

NH O

Yellow solid, 31% yield. After column chromatography the product was recrystallized from heptane/EtOAc. Mp = 113.1 – 113.3 °C; 1H NMR (400

MHz, CDCl3) 1.32 (t, J = 7.13 Hz, 3H), 3.65 (s, 3H), 4.21 (q, J = 7.10 Hz, 2H), 4.97 (s, 1H), 6.61 – 6.66 (m, 4H), 7.22 – 7.33 (m, 5H), 10.28 (s, 1H) 13 ppm; C NMR (100 MHz, CDCl3) 14.4, 55.0, 58.9, 89.4, 113.7, 124.1, 128.1, 128.2, 129.0, 133.3, 135.9, 155.6, 159.7, 170.1 ppm; HRMS Calcd. + for C18H19NO3 (M ) 297.1365, found 297.1379.

1-Methyl-2-phenyl-piperidine (6)

This compound was obtained from DSM Pharmaceuticals.

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1 H NMR (400 MHz, CDCl3) 1.78 – 1.85 (m, 2H), 2.17 – 2.23 (m, 2H), 2.49 (s, 3H), 3.12 – 3.15 (m, 2H), 5.03 (t, J = 3.40 Hz, 1H), 7.28 – 7.47 (m, 5H) ppm.

3-Phenylamino-butyric acid methyl ester (1a)30

NH O * O

1 H NMR (400 MHz, CDCl3) 1.28 (d, J = 6.42 Hz, 3H), 2.43 (dd, J1 = 6.94 Hz,

J2 = 15.05 Hz, 1H), 2.65 (dd, J1 = 5.19 Hz, J2 = 15.05 Hz, 1H), 3.68 (s, 3H), 3.75 (br, 1H), 3.95 (sextet, J = 6.03 Hz, 1H), 6.63 (d, J = 7.60 Hz, 2H), 6.71 13 (t, J = 7.33, 1H), 7.17 (t, J = 7.48 Hz, 2H) ppm; C NMR (100 MHz, CDCl3) 20.3, 40.5, 45.7, 51.3, 113.3, 117.4, 129.1, 146.6, 172.0 ppm; HRMS + Calcd. for C11H15NO2 (M ) 193.1103, found 193.1105; HPLC (OD, eluent:heptane/i-PrOH = 99/1, detector: 210 nm, flow rate: 0.5 mL/min), t1 = 15.1 min, t2 = 17.9 min.

In HTE experiment conversion was determined by GC:

Column: Agilent HP-5, temperature: 120 ºC for 2min, 10°C/min to 280 ºC (hold 2min). Retention times: starting enamine t = 8.1 min, product t = 7.2 min.

3-Phenylamino-butyric acid ethyl ester (2a)30

NH O ∗ O

1 H NMR (400 MHz, CDCl3) 1.24 – 1.29 (m, 6H), 2.42 (dd, J1 = 6.89 Hz, J2

= 14.97 Hz, 1H), 2.63 (dd, J1 = 5.23 Hz, J2 = 14.97 Hz, 1H), 3.76 (br, 1H), 3.95 (sextet, J = 6.34 Hz, 1H), 4.14 (q, J = 7.14 Hz, 2H), 6.63 (d, J = 8.60 Hz, 2H), 6.71 (t, J = 6.35 Hz, 1H), 7.18 (t, J = 7.30 Hz, 2H) ppm; 13C NMR

(100 MHz, CDCl3) 14.0, 20.3, 40.8, 45.8, 60.2, 113.4, 117.4, 129.1, 146.7, + 171.6 ppm; HRMS Calcd. for C12H17NO2 (M ) 207.1259, found 207.1284; HPLC (OD, eluent:heptane/i-PrOH = 98/2, detector: 210 nm, flow rate: 0.5 mL/min), t1 = 12.0 min, t2 = 13.6 min.

224

Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

In HTE experiment conversion was determined by GC:

Column: Agilent HP-5, temperature: 120 ºC for 2min, 10°C/min to 280 ºC (hold 2min). Retention times: starting enamine t = 8.8, product t = 7.9 min.

3-Phenyl-3-phenylamino-propionic acid ethyl ester (3a)30

NH O * O

1 H NMR (400 MHz, CDCl3) 1.24 (t, J = 7.13 Hz, 3H), 2.88 (d, J = 6.59 Hz, 2H), 4.17 (q, J = 7.14 Hz, 2H), 4.64 (br, 1H), 4.94 (t, J = 6.64 Hz, 1H), 6.66 (d, J = 8.56 Hz, 2H), 6.75 (t, J = 7.33, 1H), 7.17 (t, J = 7.48 Hz, 2H), 7.30 (t, J = 6.59 Hz, 1H), 7.38 (t, J = 7.08 Hz, 2H), 7.45 (d, J = 7.96 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3) 13.9, 42.7, 55.0, 60.4, 113.6, 117.6, 126.1,

127.2, 128.5, 128.9, 142.2, 146.8, 170.8 ppm; HRMS Calcd. for C17H19NO2 (M+) 269.1416, found 269.1430; HPLC (AS-H, eluent:heptane/i-PrOH =

99/1, detector: 210 nm, flow rate: 0.5 mL/min), t1 = 15.7 min, t2 = 20.2 min.

In HTE experiment conversion was determined by GC:

Column: Agilent HP-5, temperature: 120 ºC for 2min, 10°C/min to 280 º C (hold 2min). Retention times: starting enamine t = 13.5 min, product t = 13.0 min.

3-(2-Methoxy-phenylamino)-3-phenyl-propionic acid ethyl ester (4a)

NH O ∗ O

1 H NMR (400 MHz, CDCl3) 1.27 (t, J = 7.15 Hz, 3H), 2.90 - 2.94 (m, 2H), 3.45 (s, 3H), 4.17 (q, J = 7.60 Hz, 2H), 4.92 (br, 1H), 5.12 (br, 1H), 6.44 (d, J = 8.00 Hz, 1H), 6.67-6.85 (m, 3H), 7.24 - 7.40 (m, 5H) ppm; HRMS Calcd. + for C18H21NO3 (M ) 299.15214, found 299.15160.

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Chapter 6

In HTE experiment conversion was determined by GC:

Column: Agilent HP-5, temperature: 180°C for 2min), 5 ºC/min to 250 ºC (hold 6min), 10 ºC/min to 300 ºC (hold 3min). Retention times: starting enamine t = 12.3 min, product t = 11.0 min.

3-(4-Methoxy-phenylamino)-3-phenyl-propionic acid ethyl ester (5a)

NH O ∗ O

1 H NMR (400 MHz, CDCl3) 1.26 (t, J = 7.13 Hz, 3H), 2.89 - 2.92 (m, 2H), 3.47 (s, 3H), 4.20 (q, J = 7.60 Hz, 2H), 4.96 (br, 1H), 5.10 (br, 1H), 6.44 - + 6.80 (m, 4H), 7.24 - 7.40 (m, 5H) ppm; HRMS Calcd. for C18H21NO3 (M ) 299.15214, found 299.15160.

In HTE experiment conversion was determined by GC:

Column: Agilent HP-5, temperature: 180°C for 2min, 5 ºC/min to 250 ºC (hold 6min), 10 ºC/min to 300 ºC (hold 3min). Retention times: starting enamine t = 12.4 min, product t = 13.2 min.

1-Methyl-2-phenyl-piperidine (6a)

* N

1 H NMR (400 MHz, CDCl3) 1.17 – 1.36 (m, 1H), 1.46 – 1.76 (m, 5H), 1.92

(s, 3H), 2.00 – 2.08 (m, 1H), 2.68 (dd, J1 = 3.02 Hz, J2 = 10.79 Hz, 1H), 13 2.94 – 2.99 (m, 1H), 7.15 – 7.26 (m, 5H) ppm; C NMR (100 MHz, CDCl3) 25.0, 26.1, 35.8, 44.5, 57.5, 71.1, 126.9, 127.4, 128.4, 144.8 ppm; Conversion and ee determined by GC: Chirasil Dex CB, 50°C for 1min, then 10°C/min to 250°C (hold 5min). Retention times: starting enamine t =

11.9 min, product (enantiomers) t1 = 11.0 min, t2 = 11.1 min.

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Synthesis of N-aryl β-amino acid derivatives via asymmetric hydrogenation

6.7 References

(1) Comprehensive Natural Products Chemistry, Eds. Barton, D. H. R.; Nakanishi, K.; Meth-Cohn, O. Elsevier: Oxford, 1999; Vol. 1-9. (2) Spindler, F.; Blaser, H.-U. The Handbook of Homogeneous Hydrogenation, Eds. de Vries, J. G.; Elsevier, C. J. Wiley-VCH: Weinheim, 2007; Vol. 3, Chapter 34, 1193. (3) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (4) Keay, J. G. Comprehensive Organic Synthesis, Eds. Trost, B. M.; Fleming, I. Pergamon: Oxford, 1991; Vol. 8, 579. (5) Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985. (6) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Börner, A. Tet. Lett. 2000, 41, 2351. (7) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543. (8) Halpern, J. Science 1982, 217, 401. (9) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084. (10) Wang, X.-B.; Wang, D.-W.; Lu, S.-M.; Yu, C.-B.; Zhou, Y.-G. Tetrahedron: Asymmetry 2009, 20, 1040. (11) Hou, G.-H.; Xie, j.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366. (12) Hou, G.-H.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 11774. (13) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (14) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488. (15) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron: Asymmetry 2004, 15, 2165. (16) a) Hoekstra, W. J. Curr. Med. Chem. 1999, 6, 905; b) Drey, C. N. Chemistry and Biochemistry of the Amino Acids, Ed. Barrett, G. C. Chapman and Hall: New York, 1985, 25; c) Spzatola, A. F. Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Ed. Weinstein, B. Marcel Dekker: New York, 1983; Vol. 7, 331.

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(17) a) Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905; b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; c) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V. Helv. Chim. Acta 1998, 81, 932; d) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015; e) Iverson, B. L. Nature 1997, 385, 113; f) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.; Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381. (18) Ma, J.-A. Angew. Chem. Int. Ed. 2003, 42, 4290. (19) a) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983; b) Enantioselective Synthesis of β-Amino Acids, Ed. Juaristi, E. Wiley-VCH: New York, 1997. (20) a) Bull, S. D.; Davies, S. G.; Fox, D. J.; Gianotti, M.; Kelly, P. M.; Pierres, C.; Savory, E. D.; Smith, A. D. J. Chem. Soc., Perkin Trans 1 2002, 1858; b) Wehner, V.; Blum, H.; Kurz, M.; Stilz, H. U. Synthesis 2002, 14, 2032; c) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927; d) Guénard, D.; Guéritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160. (21) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117. (22) a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991; b) Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002, 41, 2197; c) Cole, D. C. Tetrahedron 1994, 50, 9517. (23) Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.; Heller, D. Org. Process Res. Dev. 2003, 7, 355. (24) a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103; b) Blaser, H.-U.; Spindler, F.; Studer, M. Appl. Catal. A 2001, 221, 119. (25) a) Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm. Bull. 1979, 27, 2223; b) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 19, 1119; c) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachmann, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946. (26) Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907. (27) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.

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(28) a) Sodeoka, M.; Hamashima, Y. WO2005016866 to Takasago Perfumery Co. Ltd., 2005; b) Matsumura, K.; Zhang, X.; Saito, T. EP1386901 to Takasago Perfumery Co. Ltd., 2004. (29) Hansen, K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E. J. J.; Armstrong, J. D. J. Am. Chem. Soc. 2009, 131, 8798. (30) Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343. (31) Zhang, Y. J.; Park, J. H.; Lee, S.-G. Tetrahedron: Asymmetry 2004, 15, 2209. (32) Ohashi, A.; Kikuchi, S.-I.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem. 2002, 2535. (33) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952. (34) Peña, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552. (35) Enthaler, S.; Erre, G.; Junge, K.; Holz, J.; Börner, A.; Alberico, E.; Nieddu, I.; Gladiali, S.; Beller, M. Org. Process Res. Dev. 2007, 11, 568. (36) a) Pozza, M. F.; Zimmermann, K.; Bischoff, S.; Lingenhöhl, K. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2000, 24, 647; b) Zhi, L.; Tegley, C. M.; Marschke, K. B.; Jones, T. K. Bioorg. Med. Chem. Lett. 1999, 9, 1009. (37) Mršić, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am. Chem. Soc. 2009, 131, 8358. (38) Brandt, C. A.; Silva, A. C.; Pancote, C. G.; Brito, C. L.; Solveira, M. Synthesis 2004, 10, 1557. (39) a) Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Synthesis 2007, 19, 2925; b) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 1, 18. (40) a) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org. Lett. 2008, 10, 2071; b) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729; c) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Chem. 2004, 69, 5132; d) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (41) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. Org. Lett. 2005, 7, 3235. (42) Stegink, B. PhD Thesis, Groningen 2010.

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(43) a) Catalytic Asymmetric Synthesis, Ed. Ojima, I. Wiley-VCH: New York, 2000; b) Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New York, 1994. (44) Lewis Acids in Organic Synthesis, Yamamoto, H. VCH: Weinheim, 2000; Vol. 1. (45) Sun, Y.-H.; Wan, X.-B.; Wang, J.-P.; Meng, Q.-H.; Zhang, H.-W.; Jiang, L.-J.; Zhang, Z.-G. Org. Lett. 2005, 7, 5425. (46) Mashima, K.; Kusano, K.-H.; Sato, N.; Matsumura, Y.-I.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064. (47) a) Starodubtseva, E. V.; Turova, O. V.; Vinogradov, M. G.; Gorshkova, L. S.; Ferapontov, V. A.; Struchkova, M. I. Tetrahedron 2008, 64, 11713; b) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40; c) Kitamura, M.; Yoshimura, M.; Kanda, N.; Noyori, R. Tetrahedron 1999, 55, 8769; d) King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57, 6689; e) Noyori, R.; Ohkuma, T.; Kitamura, M. J. Am. Chem. Soc. 1987, 109, 5856. (48) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977, 141, 205. (49) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (50) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (51) Hoen, R., PhD Thesis, Groningen 2006, Chapter 5, 138. (52) Stegink, B. PhD Thesis, Groningen 2010, Chapter 2.

230

Samenvatting

De asymmetrische hydrogenerings (AH) reactie vertegenwoordigt een veelzijdige, schone en atoom efficiënte methode voor de synthese van enantiozuivere verbindingen. De focus van dit onderzoek lag op de AH van imines en enamines, met name in heteroaromatische verbindingen. De reden hiervoor is dat deze structuren veelvuldig voorkomen in geneesmiddelen en fysiologisch actieve verbindingen. Dit proefschrift beschrijft het gebruik van Iridium complexen van op binol gebaseerde fosforamidiet liganden als katalysator voor de AH van 2- en 2,6-gesubstitueerde quinolines1 en quinoxalines.2 De enantioselectiviteit die behaald werd was 89, respectievelijk 96%. Pimaire chirale amines konden worden verkregen via de AH van N-aryl imines gevolgd door ontscherming van het ontstane secundaire amine. Een enantiomere overmaat tot meer dan 99% werd bij deze AH behaald.3 Tevens waren wij in staat om de hydrogenering van indolen te bewerkstelligen met behulp van rhodium-fosforamidiet complexen. Hierbij werden volledige conversies en selectiviteit tot 74% behaald in de hydrogenering van N-beschermde indolen.4 Ten slotte is er een methode ontwikkeld voor de synthese van β-amino zuren. gebaseerd op de AH van N-aryl β-enamino zure esters. Volledige conversies en een enantioselectiviteit tot 70% konden worden behaald met het iridium-fosforamidiet system. De nieuw ontwikkelde technologie is voornamelijk van belang voor de productie van geneesmiddelen, maar kan ook toegepast worden voor de productie van landbouwchemicaliën en geur- en smaakstoffen.

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1) Adv. Synth. Catal. 2008, 350, 1081. 2) Adv. Synth. Catal. 2009, 351, 2549. 3) J. Am. Chem. Soc., 2009, 131, 8358. 4) Tetrahedron:Asymmetry 2009, in press.

232

Summary

Asymmetric hydrogenation (AH) represents a versatile, clean and atom economic method for the preparation of enantiopure compounds. We were in particularly interested in the AH of heteroaromatic compounds such as quinolines, quinoxalines and indoles, due to the fact that chiral heterocyclic compounds are often found as part of the structures of pharmaceuticals and physiologically active compounds. In this thesis AH of 2- and 2,6-substituted quinolines1 and quinoxalines2 catalyzed by iridium complexes of BINOL-derived phosphoramidites is described. Enantioselectivities of up to 89% and 96%, respectively, were obtained. Primary chiral amines were obtained via the asymmetric hydrogenation of N-aryl imines, followed by the subsequent deprotection of the secondary amines. Enantioselectivities up to >99% were obtained.3 We were also able to perform hydrogenation of indoles catalyzed by rhodium complexes with phosphoramidite ligands. Full conversions and enantioselectivities up to 74% were obtained in the hydrogenation of N- protected indoles.4 Finally, we developed a route to β-amino acid derivatives via the AH of N-aryl β-enamino acid esters. Full conversions and enantioselectivities of up to 70% were obtained using an Ir/phosphoramidite catalytic system. The products that are made by this technology are mostly used as building blocks for medicines and to a lesser extent also for agrochemicals and flavours and fragrances.

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1) Adv. Synth. Catal. 2008, 350, 1081. 2) Adv. Synth. Catal. 2009, 351, 2549. 3) J. Am. Chem. Soc., 2009, 131, 8358. 4) Tetrahedron:Asymmetry 2009, in press.

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Acknowledgements

It is very difficult to write the acknowledgements, because it makes me a bit sad to think that this wonderful part of my life in Groningen is coming to an end. I am very happy that numerous friendships came out of that period, and I am sure they will last.

All this work described in this thesis would not be possible without support and understanding of people around me. Therefore, I would like to thank them in this moment.

First of all, I would like to thank my promotors Prof. de Vries, Prof. Feringa and Prof. Minnaard for giving me an opportunity to come to work in their group. It was a great pleasure to work in the group where we are challenged with amazing research. You have built a great atmosphere among people in the group, where knowledge is shared and all this talented people work as a great team. Thank you for always being there for me, and for making sure that we publish excellent papers together. At the same time you were taking care that we are all happy in your group, while being far from home. Thank you for all the motivation that you were continuously giving me over the last 4 years. Adri, you were patiently correcting articles in my English. I guess in these acknowledgments you would also have lots of work!

I would also like to thank Laurent Lefort, André de Vries and Jeroen Boogers from DSM for the daily guidance during my stay in DSM. Together we obtained a nice publication. To Imre Tóth from DSM I would like to thank for performing the high pressure NMR experiments. My special thanks goes to Lavinia, who was helping me a lot in the beginning of my PhD and during my stays in DSM. I would like to thank Theodora Tiemersma-Wegman from RUG, for all the help with the HPLC, GC and mass analysis.

I would like to thank to my „office-mates“ Bas and Bjorn, for proving to me that writing of the thesis doesn’t have to be stressful, that it can also be fun! My special thanks goes to all my labmates over 4 years. It was great to work with you, to discuss chemistry, listen to the music, laugh, dance and all the other things we used to do together. I will miss all of you.

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My witches (Bea, Syuzi, Tati), thank you for being there for me always, without exception. We had lots of fun and you were a substitute for my family while living in Groningen. Thank you most of all for listening to me when a girl just „needs attention“. I am sure we will always visit each other. It can not be any other way. Tati I loved to live with you. I enjoyed all the „kitchen talks“ and our lunches and movies with Jérôme. Jérôme you are the fifth witch. Your friendship meant a lot to me bro. You are a joke machine! Bjorni, many thanks for all the fun and friendship over the last 4 years. You are a great listener! Thanks for always being in a good mood.

I made lots of friendships in Groningen. So let’s start! Thomas thanks for all the chemistry discussions that always ended with jokes. Pieter, Johannes, Nop and Giuseppe, it was great to spend time with you. We had so many fun moments together! Toon and Gabry, I enjoyed the time with you in Groningen so much. Your friendship and all the nice dinners you made! Ashoka and Adi, you always made me smile and think positive. Thanks for all the yummy Indian food! Lachlan and Lorina, I loved to talk to you and to go out with you. I wish we have done it more! Eva and Steve, I am really hoping to see you on my promotion day. I miss you a lot. Nico and Stéphanie, I enjoyed our stay with you in Belgium, and Nico, thanks for all the fun times in Pintelier. Gareth, you are so funny! Thanks for your friendship too. We need to talk about football some more. Gisela, I hope to see you soon. You left long time ago, but I had amazing time with you in Groningen. Arnaud, I hope you are happy in Switzerland, and I hope to see you again. There are many more people that made my life in Groningen great. I can not mention everyone. Thank you all.

Mare, Six, Tomas, Ivana, Hrvoje, Anke, hvala vam što me niste zaboravili tokom zadnje četiri godine i što ste mi uvijek davali potporu i razumijevanje. Ana, hvala za sate podrške na Skype-u dok si bila u Münsteru.

Tata, mama, Zoki i Marija, puno hvala na svoj podršci tokom godina mojeg studija. Hvala vam na toploti i ljubavi, svakoj riječi i poruci. Uvijek su stigle kad mi je trebalo. Ovaj doktorat posvećujem vama. Volim vas najviše na svijetu.

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