University of Groningen

Monodentate secondary phosphine oxides (SPO's), synthesis and application in asymmetriccatalysisJiang, Xiaobin

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Chapter 5

Chapter 5

Iridium (I)- catalyzed hydrogenation of imines

using secondary phosphine oxides (SPO’s) as ligands*

This chapter describes the Ir(I)- catalyzed asymmetric hydrogenation of acetophenone- based imines using enantiomerically pure secondary phosphine oxides (SPO’s) as ligands. Details about optimization of the reaction conditions and various parameters, like solvents, metal precursors, metal/ligand ratios, temperature and pressure, additives, substrates, ligands and preformed catalysts, are discussed. Contents 5.1 Introduction

5.1.1 Asymmetric imine hydrogenation 102

5.1.2 Influence of several parameters in asymmetric hydrogenation of imines 107

5.2 Synthesis of imines 107

5.3 Initial tests of SPO’s as ligands in asymmetric imine hydrogenation 112

5.4 Optimization of reaction conditions

5.4.1 Solvent effects 114

5.4.2 Metal precursors 116

5.4.3 Metal/ligand ratio 117

5.4.4 Effects of additives 117

5.4.5 Pressure and temperature 121

5.4.6 Substrates 122

5.4.7 Ligands 124

5.4.8 Preformed catalysts 127

5.4.9 Conclusions 128

5.5 Experimental section 129

5.6 References and notes 148 * Part of this chapter has been published, see: Jiang, X. -B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5, 1503.

101

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

5.1 Introduction 5.1.1 Asymmetric imine hydrogenation Compared to the numerous highly efficient chiral catalysts known for enantioselective reduction of C=O or C=C bonds, only relatively few effective catalysts have been developed for the reduction of C=N bonds.1 Imines and related C=N bond containing compounds have some special properties which make their enantioselective reduction more difficult than that of C=C and C=O compounds. (a) They are easily prepared from the corresponding amines and carbonyl compounds,

however, full conversion is not always obtained and trimer or oligomers of imines can form. Most homogeneous catalysts can also form complexes with these impurities in the imine substrate. This may lead to a dramatic reduction in the activity of the catalysts.

(b) Most C=N compounds are sensitive to hydrolysis and the resulting amines may be catalyst inhibitors. In addition, imines usually occur as a mixture of syn/anti isomers which may interconvert during the reaction presenting an additional problem to achieve high enantioselectivity.

For these reasons highly enantioselective imine hydrogenation is a problematic reaction and a major challenge up to now. As chiral amines are important intermediates for synthetic and pharmaceutical chemistry,2 asymmetric hydrogenation or asymmetric transfer hydrogenation of imines has received much attention over the last decades. Different catalysts based on chiral ligands and metal precursors like Ir,3 Rh,4 Ru,5 Ti,6 Co7 have been developed for this purpose. On the basis of this extensive work, quite a few successful examples with high enantioselectivity have been reported.1,14b Very high e.e. (up to 94%) in this field were achieved for the first time by de Vries and coworkers,8 who developed a water-soluble mono-sulfonated diphosphine (L5.1) and corresponding rhodium complex [Rh(COD)2BF4-bdppsulf] for asymmetric hydrogenation of several acyclic N-benzyl imines 5.1 to 5.2 in an aqueous bi-phasic (EtOAc-H2O) medium (Scheme 5.1).

PPhArPPh2

Ar = NaSO2C6H4

bdppsulf L5.1

N

R

R'

NH

R

R'

R=R'=H, 94% ee

H2, EtOAc-H2O

Rh-bdppsulf L5.1

5.1 5.2

Scheme 5.1 Monosulfonated diphosphine in hydrogenation of acyclic N-alkyl imines

Buchwald6 and co-workers developed a highly selective chiral ansa-titanocene catalyst

102

Chapter 5

(Ti-ebthi) L5.2. Treatment of L5.2 first with n-BuLi, then with PhSiH3 and H2 generates a catalyst with which α–substituted cyclic imines 5.3 can be hydrogenated to secondary amines 5.4 with excellent enantioselectivity (>98% e.e.) 6 (Scheme 5.2). However, for most acyclic imines, the e.e. values reduced to less than 85%. This catalyst has some disadvantages, such as air sensitivity, difficulty of preparation and handling (2 steps are required for the activation) and slow reaction rate (T.O.F. 0.2-2.4 h-1). Subsequently, this group developed a new catalyst (S,S)-(ebthi)TiF2 L5.3 with a structure similar to that of L5.2. It was applied successfully in imine hydrosilylation with PhSiH3. Using pyrrolidine, piperidine or t-BuONa as base, excellent e.e.’s (up to 99%) were reached not only for cyclic imine 5.3 but also for acyclic acetophenone-based alkyl imines 5.5 to 5.6 (Scheme 5.2). 9 They proposed that monohydride ebthi-TiH is the active species.10

NPh NH

Ph

Ti OR*R*O L5.2, 133 bar H2

THF, 65oC( )n ( )n

n =1, 2; ee >98%

R*=(R, R)-BINOL Ti-ebthi L5.2 5.3 5.4

Ti FFN NH

PhSiH3

e.e. up to 99%

L5.3

Ti-F2 L5.3 5.5 5.6

Scheme 5.2 Titanium catalyzed enantioselective hydrogenation

and hydrosilylation of imines

Several other effective catalysts have been developed. A major breakthrough was achieved by the use of transfer hydrogenation catalysts. Based on their previous work with Ru-BINAP, Noyori and co-workers11 developed catalysts based on Ru-BINAP and a semi-N-sulfonated chiral diamine ligand L5.4. High enantioselectivity (>95% ee) was achieved for cyclic imine (5.7, 5.8) reduction with HCOOH/Et3N as reducing agent, providing a new general route to alkaloids 5.9, 5.10 (Scheme 5.3). Furthermore, this catalyst exhibited a high chemoselectivity towards the reduction of C=N vs. C=O double bond. Thus cyclic imines 5.7 and 5.8 can be hydrogenated in acetone with <5%

103

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

reduction of acetone itself.

Ph2P

PPh2

Ru

Cl

Cl NH2

NH

SO2 (p-Tol)

Ru-BINAP diamine catalyst L5.4

N

R

MeO

MeONH

R

MeO

MeO

HCOOH/Et3N

R=3,4-(MeO)2C6H3(CH2)2 95% ee, TOF 30 h-1

Catalyst L5.4

5.7 5.9

NH

N

RNH

NH

R

HCOOH/Et3N

97% ee, TOF 83h-1R=Me, Ph

Catalyst L5.4

5.8 5.10

Scheme 5.3 Ru-BINAP catalyzed transfer hydrogenation of cyclic imines

Other catalysts, like the Co-Salen complex L5.512 using a modified hydrogen source (hydride 5.11) in the reduction of N-phosphoryl imine 5.12 to secondary amine 5.13 (Scheme 5.4) and Rh-DuPhos13 for the hydrogenation of N-acetyl hydrazones 5.14 to 5.15 (Scheme 5.5), also give high to excellent enantioselectivity for the specific substrates shown (TOF 20.8 h-1).

CoO

N

O

N

OO

ArAr

Co-salen catalyst L5.5

R

NP

OPh

Ph

R

NHP

OPh

Ph

R = H, OMe

ONaBH2(OEt)O+

99% ee

Co-salen L5.5

0 oC

5.12 modified hydride 5.11 5.13

Scheme 5.4 Co-salen catalyst L5.5 catalyzed asymmetric reduction of 5.12

104

Chapter 5

NNH O

Ph

Ph

NHNH O

Ph

Ph

NH2

Ph

SmI2

92% ee

Rh-DuPhos catalyst

4 bar H2, i-PrOH, 0 oC

5.14 5.15

Scheme 5.5 Rh-DuPhos catalyzed asymmetric hydrogenation of 5.14

From a practical point of view, the rate of these reactions is still far too low for any possible industrial application. As rhodium- and titanium- based catalysts gave low TOF’s, new catalysts based on iridium and L5.6 (xyliphos) or L5.7 (josiphos) with I2 and HOAc as additives were developed by Blaser and co-workers, resulting in very fast imine hydrogenation. With this catalyst (Ir-L5.6), imine 5.16 was successfully hydrogenated to chiral amine 5.17, which is a key intermediate for the synthesis of the herbicide (S)-Metolachlor with extremely high TON = 2×106, TOF ≥ 2×105 h-1 (Scheme 5.6). 14 However, the enantioselectivity does not exceed 80%. For an agrochemical this enantioselectivity proved to be sufficient. Nevertheless, this process is used industrially, presently run on a scale of 10,000 ton/year and is the largest asymmetric catalytic process today. It is the first example of asymmetric imine hydrogenation that was successfully applied in industry. The use of the iridium complex of L5.7 as catalyst with N-phosphoryl imine 5.40 as substrate (Scheme 5.12), resulted in product 5.40H with excellent e.e.’s (up to 99%).15

PAr2

H

PPh2Fe

PR2

H

PPh2Fe

xyliphos L5.6, Ar = 3,5-xylyl josiphos L5.7, R = c-hexyl or t-Bu

N

O

ClCH2

OMeNO

NH

O

ClCH2COCl

(S)-Metolachlor80% ee

Ir-xyliphos L5.6

H2 80bar, 50oC

5.16 5.17

Scheme 5.6 Ir-xyliphos- catalyzed hydrogenation of imine 5.16

In conclusion, there is no highly efficient catalyst for the asymmetric hydrogenation of

105

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

general alkyl and aryl imines by now. Only a few detailed studies about the mechanism of imine hydrogenation have been reported so far. 10-16 It appears to be rather difficult to propose a general mechanism of this hydrogenation due to two reasons: (1) Quite different types of catalysts are effective which probably act by different

mechanisms; (2) The effect of certain additives (like iodine, acid, base) is often crucial to achieve

high e.e.’s and reaction rates. These additives often lead to a change of mechanism. The mechanism of imine hydrogenation was thought to be similar to that of the rhodium-phosphine catalyzed alkene hydrogenation. The only difference is that imines are η1-coordinated via the nitrogen lone pair to the metal center and not via the π-system of the C=N bond, as was found by James and coworkers when they studied rhodium- catalyzed asymmetric hydrogenation of imines 5.16, 5.18, 5.20, 5.21, 5.26 as well as other imines (Scheme 5.7). These authors also suggested that the hydrogen activation happens after the imines are coordinated to the rhodium center.16

N

ONH

O

Ir or Rh cat.*

H2

5.18 5.19

Scheme 5.7 Asymmetric hydrogenation of imine 5.18

Osborn and co-workers studied iridium-diphosphine (DIOP, BDPP, Binap, for their structures, see chapter 1) catalyzed hydrogenation of imine 5.18 to 5.19 with iodine as additive.17 Three intermediates were isolated, characterized as [Ir(diphosphine)I4]-, [Ir (diphosphine)HI2]2, [Ir(diphosphine) I3]2 and found to be active in the hydrogenation reaction. This suggests that the active monomeric iridium species in hydrogenation are formed by the dissociation of the Ir-iodine dinuclear complexes under H2 (Figure 5.1). The imine substrate binds to the iridium monohydride, presumably, the imine coordination changes from η1 to π bonding before the migratory insertion can take place. The amido-iridium complex then reacts with hydrogen to reform the iridium monohydride complex under formation of the amine. The iodine is important for maintaining the activity of the catalysts as it can stabilize the active species and prevent the deactivation of the catalysts to iridium metal. Other halides like Cl, Br are less effective than iodine. The proposed mechanism is shown in figure 5.1:

106

Chapter 5

H2

NH

R1 R2

R

HN

R1 R2

R

Ir HP*

P*I

I

Sol.

IrH

P*

P*

N

R

R2

R1

I

I

IrH

P*

P* I

IN

R1 R2

R

IrSol.

P*

P*

N

R

R2

R1 H

I

I

IrIP*

P*

I

IHIr

H

I

P*

P*

H2

+

Figure 5.1 Proposed mechanism of Ir-diphosphine- catalyzed imine hydrogenation 5.1.2 Influence of parameters in asymmetric hydrogenation of imines The results of all asymmetric hydrogenation reactions of C=C and C=O containing prochiral substrates strongly depended on a variety of parameters, including solvents, metal precursors, pressure, temperature, additives, substrates and ligands. How these parameters influence the results is often not clear. So it is very difficult to predict these effects for an unknown reaction. For example, in the field of rhodium phosphine catalyzed hydrogenation, almost every catalyst-substrate system has its own unique properties and the catalytic system needs to be optimized for each case.18 The parameters mentioned above can also strongly influence the e.e. and reaction rates in asymmetric imine hydrogenation. Among them, the effects of various additives, such as iodine, acid, base etc are very complicated and difficult to predict. Additives might be integral parts of the catalysts (Ir-phosphine-I2 complex, see figure 5.1). However, the effective additives in a particular reaction might exert a negative effect in other reactions. A rather detailed study about the effect of additives in Ir- catalyzed asymmetric imine hydrogenation has been reported by Zhang and co-workers.19 5.2 Synthesis of imines 20

Imines are also called azomethines or Schiffs’ bases. In principle, they can be easily prepared by a condensation reaction between ketones or aldehydes and the correspon- ding primary amines (Scheme 5.8).

107

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

O NNH2 R3 + H2O+

R1

R2 R3

R2

R1

Scheme 5.8 Synthesis of imines

The substituent groups have a large effect on imine synthesis. If R1, R2, R3 are aryl groups, the imines are more stable than the corresponding alkyl ones and the equilibrium is shifted to the right. Aldehydes (R1 = H) give more stable imines than ketones, which is attributed to steric effects.*,20

In order to push the reaction to completion, removal of water is often necessary. This can be done in several ways: (a) By distilling the water out of the reaction mixture, which can be achieved by

azeotropic distillation either with benzene or toluene under Dean-Stark conditions. (b) By the addition of 4 Å molecular sieves to absorb the water formed during the

reaction.21 (c) Using some Lewis acids such as TiCl4

22 in toluene at 0 C or Buo2 2 as

catalyst to accelerate the reaction. SnCl at RT23

In this thesis, the synthesis of several ketimines based on acetophenone and other ketones is discussed using the methods mentioned above (Scheme 5.9).

NH2

ON

+ + H2O

R1

R2

R1

R2

Scheme 5.9 Synthesis of acetophenone or substituted acetophenone-based ketimines

Of all acyclic imines, the isolated yields strongly depend on their stabilities and structures. Since the substituted cyclic imines are more stable than acyclic imines, higher yields are usually obtained. Two synthetic procedures were chosen for the preparation of various ketimines:

(a) Solvent-free route

Ketimines 5.20-5.27 are prepared by mixing 1.1 eq. of acetophenone or p-MeO-, p-Cl-, m-NO2-, o-MeO- substituted acetophenone with benzylamine or p-substituted benzyl amine in the presence of 4 Å molecular sieves at RT for 1 week without any solvent.

* It has to be mentioned here that imines prepared from ketones and aldehydes are given different names. When imines are prepared from ketones, they are called “ketimines”; while from aldehydes, they are named “aldimines”.

108

Chapter 5

After all benzylamine was consumed according to 1H NMR, the imines were purified simply by removing the unreacted acetophenone or substituted acetophenone by bulb-to-bulb vacuum distillation and the residues were further purified by crystallizing from n-hexane (5.20) or n-hexane:Et2O= 2:1 (5.21-5.22, 5.27). Ketimine 5.23 is semi-solid. Other oily ketimines 5.24-5.26 are difficult to purify by vacuum distillation (high boiling points and partial decomposition under vacuum distillation); further purification is achieved by filtration through an active neutral Al2O3 column with Et2O as eluent. Isolated yields are around 35-65% (Table 5.1).

Table 5.1 Synthesis of ketimines 5.20-5.27 N

R1

R2

Imines R1 R2 Isolated yields (%)

5.20 H H 49 5.21 p-CH3O H 35 5.22 H CH3O 36 5.23 H Cl 44 5.24 p-Cl H 54 5.25 m-NO2 H 38 5.26 o-MeO H 43 5.27 p-Cl p-MeO 65

(b) Dean-Stark condition Ketimines 5.20-5.27 prepared under Dean-Stark condition were obtained in similar yields. But in general, ketimines prepared under Dean-Stark conditions contain more side-products such as dimers or trimers, than the products prepared via method a. In view of their poor reactivity, sterically hindered ketimine 5.28 and N-aryl ketimines 5.29, 5.3047 were prepared by mixing acetophenone and the corresponding primary amines in toluene under Dean-Stark conditions. After refluxing 5 days, full conversion was reached. To remove traces of primary amines, the products were passed through an active neutral Al2O3 column (eluted with Et2O) as catalysts for imine hydrogenation are very sensitive to primary amines. They were further purified by crystallizing from n-hexane:Et2O, 2:1. Ketimines 5.31-5.34 were synthesized using the same procedure with yields of 35-50%. Other structure variations were obtained by using alkyl ketones (5.35 and 5.36) or sterically hindered primary amines (5.37). Unfortunately, the products are rather unstable and partially decompose on the Al2O3 column, especially ketimine 5.37, which fully decomposed after purification over an Al2O3 column (Figure 5.2).

109

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

N

Ph

Ph

Ph

NR

Ph

N Ph

Ph

CF3

N Ph

Ph

N Ph

5.28 5.29 R = H; 5.30 R = Cl 5.31 48 5.32 49 5.33

N

Ph

N Ph

N Ph

N

Ph N

5.3437 5.35 5.36 53 5.37 5.38

Figure 5.2 Structures of sterically hindered and other ketimines

All of the above mentioned ketimines are mixtures of E/Z isomers, which could not be separated. In most cases, the E/Z ratio is quite high (>7/1) except for 5.26, which is a mixture with a ratio of 2/1. For example, pure ketimine 5.20 is a mixture with E/Z >12/1 according to 1H NMR. In order to exclude the problematic aspect of the E/Z mixtures, cyclic imines 5.38 and 5.39 were considered as substrates, as they do not have this problem at all (E or Z conformation, exclusively). Cyclic hindered imine 5.38 is commercially available (Figure 5.2). Cyclic imine 5.39 was synthesized according to two different reported procedures: (i) PhMgCl addition to 4-chloro-butyronitrile (Scheme 5.10)24

NPhH2O

20%ClN

Ph

MgCl

Cl CN PhMgCl+

5.39

Scheme 5.10 Grignard addition to 4-chloro-butyronitrile

Grignard reagent PhMgCl was added to an Et2O solution of 4-chloro-butyronitrile to form an imino-Mg intermediate, which, after cyclization gave the desired product 5.39 in low yield (around 20%). (ii) Via decarboxylation (Scheme 5.11) This route starts from N-vinyl 2-pyrrolidinone (NVP) and methyl benzoate to give 5.45 as intermediate. Hydrolysis with aqueous 6 N HCl was followed by decarboxylation and cyclization to the desired product imine 5.39. The products were purified by flash column chromatography [SiO2, petroleum ether (40-60 oC):Et2O, 2:1] in good yield over two steps (74%).

110

Chapter 5

N

OO

Ph OMe

NaH

N

OO

Ph

H3O+

-CH3CHO+

5.45

NH

OO

Ph+ H2O

O OH

NH3+OPh

-CO2NH3+

O

Ph

-H2O NPh74%

5.39

Scheme 5.11 Synthesis of cyclic imine 5.39

The N-phosphoryl imine 5.40, which is known to have a very high ratio of E/Z isomers (>20/1), was prepared starting from acetophenone oxime 5.46 and Ph2PCl in the presence of Et3N as base at –60 oC through a rearrangement reaction to give imine 5.40. It was then purified over neutral Al2O3 using EtOAc as eluent to remove the Et3N.HCl salt resulting a light yellow solid (isolated yield 76%) (Scheme 5.12).25

NP

O Ph

PhNOH

Ph2PClEt3N

O

H2NOH

91%+

76%

5.46 5.40

Scheme 5.12 Synthesis of N-phosphoryl imine 5.40

A specific type of ketimine 5.41, 5.42, 5.43, based on acetophenone or p-substituted acetophenone and glycinamide (prepared from its HCl salt and Et3N), was synthesized by mixing neat ketone and glycinamide, heating to 70 oC for 12 h in the presence of 4 Å molecular sieves. They are easily purified by crystallizing from EtOAc, as the products themselves are difficult to dissolve in medium to apolar solvents. Isolated yields are 36-48% (Scheme 5.13). Under Dean-Stark condition with toluene, due to the very poor solubility of glycinamide, only traces of the desired product could be isolated. In 1H NMR, they were found to have a high ratio of E/Z isomers (>10/1).

111

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

O

NH2

NH270oC

NO

NH2

R

O

R

O

NH2

NH2.HCl

Et3N

+neat

36-48% 5.41, R=H; 5.42, R=OMe; 5.43, R=Cl

Scheme 5.13 Synthesis of ketimine 5.41-5.43

Attempts to introduce an additional nitrogen donor group by reaction of 2-acetyl pyridine and benzylamine under RT or Dean-Stark condition to prepare ketimine 5.44, was not successful. It is not clear why the formation of 5.44 failed but possibly it is due to the formation of the dimer or trimer of 2-acetyl pyridine, which is quite reactive26 (Scheme 5.14).

N

O

NH2PhN

N Ph

+

5.44

Scheme 5.14 Attempted synthesis of ketimine 5.44 5.3 Initial tests of SPO’s as ligands in asymmetric hydrogenation of imines Secondary phosphine oxides (SPO’s) have been shown to be very effective ligands for platinum catalyzed nitrile hydrolysis, hydroformylation (Pt) and cross coupling reactions (Pd).27 They exist in two forms as the result of a tautomeric equilibrium between the phosphine oxide (R2HP=O) and the phosphite form (R2P-OH). Several racemic and enantiopure SPO’s have been synthesized (see chapter 3). In order to further explore their application as ligands in catalysis, several catalytic reactions, such as hydrogenation of various substrates (see chapter 6), allylic substitution, epoxide ring opening and hydroformylation were examined. From this screening, we found that SPO’s are quite effective ligands for asymmetric imine hydrogenation. Initial experiments were performed in DCM with imine 5.20 as substrate, enantiopure (R)-(+)-L3.4 as ligand and Rh(COD)2BF4 or [Ir(COD)Cl]2 as metal precursors. It turned out that the complex made from [Ir(COD)Cl]2 and (R)-(+)-L3.4 was quite an effective catalyst for this hydrogenation, whereas with

112

Chapter 5

(R)-(+)-L3.4 and Rh(COD)2BF4, hardly any conversion to the desired product 5.20H was observed (Scheme 5.15).*

N

O

*

Ac2ON

t-BuP

O

HPh

*

NH

[Ir(COD)Cl]2, H2

(R)-(+)-L3.4 5.20 5.20H 5.20HA

Scheme 5.15 Preliminary experiments on the hydrogenation of imine 5.20

In the initial experiments, it was also found that the metal/ligand (M/L) ratio was a crucial parameter both for the reaction rate as well as the enantioselectivity. With an M/L of 1/1 (per Ir to ligand) in hydrogenation, a high reaction rate was observed, unfortunately, accompanied with very low enantioselectivity. Upon increasing the M/L ratio to 1/2, quite a low reaction rate was found, however, with reasonable enantioselectivity (Table 5.2). Similar trends were found when using other imines as substrates (imine 5.21, 5.22).

Table 5.2 Initial results of imine hydrogenation a

Entry Ir/L ratio t (h) Conv. (%) b e.e. (%) c

1 1/1 (per Ir) 0.8 100 8 2 1/2 (per Ir) 24 75 45

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, 2 mol% catalyst loading, imine 5.20 (0.067 M), 25 bar H2, in DCM, at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. With an Ir/L ratio of 1/1 in DCM, the reaction was very fast and the hydrogenation could be followed in time. When using [Ir(COD)Cl]2 as metal precursor, the reaction was faster than using Ir(COD)2BF4 (Figure 5.3). There was hardly any change in enantioselectivity during the reaction (5-8% max.).

* In this thesis, the hydrogenation products are named after the starting material by adding H after the number, and their N-acetyl derivatives for HPLC analysis are named by adding HA. For example, imine 5.20, its hydrogenation product is named 5.20H and its N-acetyl derivative sample for HPLC analysis is 5.20HA (Scheme 5.15).

113

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

Figure 5.3 Time course of the imine 5.20 hydrogenation in DCM (Ir/L, 1/1, 25 bar H2) Also in the hydrogenation of 5.20 with an Ir/L ratio of 1/2 in toluene, we found almost no change in enantioselectivity over time (67-69%). 5.4 Optimization of the reaction conditions It is well known that several parameters can strongly influence reaction rates and selectivities in asymmetric hydrogenation (see section 5.1.2). Based on the preliminary results, we tried to optimize these parameters such as solvents, metal precursors, metal/ligand ratio, H2 pressure, reaction temperature, additives, ligands, substrates, etc. In order to speed up the screening process, some equipment specially designed for high-throughput experimentation (HTE) screening was used, which are the Endeavor (8 reactions at one time) and a custom made (at DSM) high throughput device in which 96 high-pressure reactions (Premex) can be performed simultaneously. As all parameters influence the hydrogenation in different ways, it is hard to change all of them at once to find the optimal combination. Using standard reaction conditions, one parameter was varied every time. The results are discussed below. 5.4.1 Solvent effects It is well known that solvent effects can be quite dramatic in asymmetric hydrogenation.28 From the initial experiments, DCM seems to be a good solvent for asymmetric imine hydrogenation. To evaluate the solvent effect, a standard reaction condition was used: (R+)-L3.4 as ligand, [Ir(COD)Cl]2 as metal precursor, Ir/L ratio of 1/1 or 1:2, 5 mol% of catalyst loading, imine 5.20 as substrate, 25 bar H2, 24 h at RT in different solvents. In addition to DCM, the solvents cyclohexane, Et2O, toluene,

114

Chapter 5

α,α,α-trifluorotoluene, benzene, EtOAc, THF, methanol and 2-propanol were tested. The results are shown in table 5.3. From these experiments, it turned out that toluene was the best solvent for our system with respect to both reaction rate and enantioselectivity (table 5.3, entry 6, 7).

Table 5.3 Imine hydrogenation in different solvents without additives a

Entry Solvents Ir/L ratio Cat. (mol%) Conv. (%) b e.e. (%) c

1 DCM 1/1 1 100 8 2 DCM 1/2 2 75 45 3 THF 1/1 1 100 18 4 Et2O 1/1 1 100 18 5 EtOAc 1/1 1 100 14 6 toluene 1/1 2 100 25 7 toluene 1/2 5 74 69 8 d α,α,α-trifluoro

toluene 1/2 5 89 70

9 cyclohexane 1/2 2 18 70 10 2-propanol 1/2 2 37 9

(a) General condition: [Ir(COD)Cl]2 5 mol%, (R+)-L 3.4, imine 5.20 (0.067 M), 25 bar H2, 24 h at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC(OD column, n-heptane:2-propanol=95:5) based on their N-acetyl derivatives. (d) 114 h. From our HTE screening, pyridine is found to be the best additive for our system. Details will be discussed in paragraph 5.4.4. With 1 or 2 equivalents of pyridine as additive, different solvents were tested again using similar conditions.

Table 5.4 Imine hydrogenation in different solvents with pyridine as additive a

Entry Solvents t (h) Conv. (%) b e.e. (%) c

1 DCM 24 >95 55 2 THF 24 >95 67 3 Et2O 24 >95 65 4 d Toluene 25 70 77 5 Toluene 25 100 78 6 EtOAc 24 >95 62 7 c-hexane 25 30 68 8 Benzene 72 85 74 9 MeOH 24 80 3 10 2-propanol 24 10 29 11 CH3CN 24 0 0

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L/py=1/2/2, 5 mol% catalyst loading, imine 5.20, 25 bar H2, at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) base on their N-acetyl derivatives in HPLC. (d) Ir/L/py=1/2/1. These results show that toluene is the best solvent both in terms of conversion and

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

enantioselectivity (table 5.4, entry 4, 5). In most solvents, the reactions in which pyridine was used as an additive were more selective than without pyridine. In DCM, THF, Et2O, EtOAc, e.e.’s were slightly lower but comparable to those in toluene (table 5.4, entry 1-3, 5). With cyclohexane or benzene as solvent, reactions were much slower but the product showed similar e.e’s as in toluene (table 5.4, entry 7, 8). In α,α,α-trifluorotoluene, the reaction became even slower with the same selectivity as in toluene (table 5.3, entry 8). In MeOH, the reaction was quite fast but gave nearly racemic product (table 5.4, entry 9). In 2-propanol, very low conversion and e.e. were observed (table 5.4, entry 10). The hydrogenation didn’t work in CH3CN, probably due to solvent coordination (table 5.4, entry 11). 5.4.2 Metal precursors As [Ir(COD)Cl]2 is a neutral dimer complex, and it is known that cationic metal precursors have dramatic influences in asymmetric hydrogenation,1,19 several other metal precursors were tested in imine hydrogenation. The rhodium analogs, [Rh(COD)Cl]2, [Rh(NBD)Cl]2 and the cationic species [Rh(COD)2]BF4 and [Ir(COD)2]BF4 were tested as metal precursors in our system.

Table 5.5 Different metal precursors in imine hydrogenation a

Entry Metal precursors Pyr. (eq.) t (h) Conv. (%) b e.e. (%) c

1 [Ir(COD)Cl]2 2 25 100 78 2 [Ir(COD)Cl]2 0 25 74 69 3 d [Ir(COD)2]BF4 2 11 35 3 4 [Ir(COD)2]BF4 0 25 100 4 5 [Rh(COD)Cl]2 2 46 36 43 6 [Rh(COD)Cl]2 0 46 45 56 7 [Rh(NBD)Cl]2 2 46 25 48 8 [Rh(COD)2]BF4 0 24 <5 <5

(a) General conditions: (R+)-L3.4, M/L=1/2, 5 mol% catalyst loading, imine 5.20 (0.067 M), 25 bar H2, in toluene at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) 40 oC. (e) NBD = cyclo[2.2.1]hepta-2,5-diene, COD = 1,5-cyclooctadiene. It has to been mentioned here that when using [Rh(COD)Cl]2 and [Rh(NBD)Cl]2 as metal precursors, a large amount of acetophenone (resulting from imine decomposition) was formed accompanied by other unknown compounds after hydrogenation, which could not be identified by normal methods (table 5.5, entry 5-7). From the results in table 5.5, [Ir(COD)Cl]2 emerges as the most suitable metal precursor for our system both in terms of reaction rate and selectivity (Table 5.5, entry 1, 2). The cationic complex Ir(COD)2BF4 gave full conversion but very low e.e’s. The addition of pyridine to Ir(COD)2BF4 slows down the reaction rate without any change in selectivity

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(Table 5.5, entry 3, 4). 5.4.3 Metal/ligand ratio In initial experiments, [Ir(COD)Cl]2 was proven to be the best metal precursor. An Ir/L ratio of 1/1 leads to high reaction rate but low enantioselectivities. In order to optimize the reaction conditions, other Ir/L ratios were tested. All results are summarized in table 5.6.

Table 5.6 Imine hydrogenation with different Ir/L ratio a

Entry Solvents Ir/L ratio Conv. (%) b e.e. (%) c

1 d DCM 1/1 100 8 2 DCM 1/2 75 45 3 DCM 1/3 35 70 4 DCM 1/4 32 70 5 Toluene 1/1 100 25 6 Toluene 1/2 74 69 7 Toluene 1/3 26 68 8 Toluene 1/4 23 66

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, 2 mol% catalyst loading, imine 5.20 (0.067 M), 25 bar H2, 24 h at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) 50 min. It can be concluded from this table that Ir/L of 1/2 is the best compromise between optimal reaction rate and enantioselectivity both in DCM and toluene (table 5.6, entry 6). When increasing this ratio to 1:3 or 1:4 in toluene, the reaction still proceeds smoothly and gives similar e.e’s accompanied by a drop in conversion (table 5.6, entry 7, 8). In DCM, with Ir/L of 1/1, the reaction was fast (reaction finished in 50 min) but with low e.e. (table 5.6, entry 1). Interestingly, increasing the Ir/L ratio to 1/3 or 1/4 in DCM, the reaction becomes much slower but with higher enantioselectivities than in the case of 1/1 or 1/2 ratio’s (table 5.6, entry 3, 4). It seems that the catalyst is stabilized by the increasing amount of ligand. 5.4.4 Effects of additives 19

In asymmetric imine hydrogenation, additives can have dramatic effects on the reaction rate as well as on the enantioselectivity. Additives that have been reported included I2,29 Et4NI,30 Et4NBr, acids and bases. To test these additives, a large number of screening experiments were performed under standard conditions. Initial results are shown in table 5.7.

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

Table 5.7 Some additives in imine hydrogenation a

Entry Additives Solvent Ir/L Conv. (%) b e.e. (%) c

1 Benzylamine DCM 1/1 9 62 2 Diphenylamine DCM 1/1 100 6 3 I2 MeOH 1/1 100 1 4 Et4NI+CH3COOH DCM 1/1 75 4 5 d Et4NI Et2O 1/2 50 60 6 CH3COOH DCM 1/2 100 22 7 (t-Bu)4NBr DCM 1/2 24 42 8 t-BuOK Toluene 1/2 0 0 9 AgCOOCF3 Toluene 1/2 0 0 10 n-BuLi Toluene 1/2 0 0 11 e t-BuOK Toluene +H2O 1/2 60 5 12 e Na2CO3 Toluene +H2O 1/2 65 6 13 e, f K2CO3 Toluene +H2O 1/2 55 6 14 none DCM 1/1 100 8 15 none DCM 1/2 75 45 16 none Toluene 1/2 74 69

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, 5 mol% catalyst loading, imine 5.20 (0.067 M), 2-3 equivalents of additives, 25 bar H2, 24 h at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) Imine 5.21. (e) In bi-phasic solution, toluene/H2O, 2/1.(f) Ir(COD)2BF4. It can be seen from this table that all these additives have a negative effect on our system. No positive halogen effect was found, although for imine 5.21 as well as other imines such as 5.22 and 5.23, the addition of Et4NI induced a reasonable e.e. (table 5.7, entry 5). The addition of I2, led to the formation of unknown byproducts and decomposition of imines (table 5.7, entry 3). The addition of acid seems to increase the rate of the reaction somewhat but leads to a lower e.e. (table 5.7, entry 6). A primary amine4e such as benzylamine seems to inhibit the catalyst but improves the enantioselectivity (table 5.7, entry 1). Secondary amines have no influence on the reaction rate and selectivity at all (table 5.7, entry 2). Other bases such as t-BuOK, Na2CO3, K2CO3, n-BuLi either didn’t work at all or led to very poor selectivities (table 5.7, entry 8, 11-13). With n-Buli, which might remove one proton from the ligand to form an anionic catalyst, the color of the solution changed immediately to red upon addition. However, no conversion to product 5.20H was observed (table 5.7, entry 10). The use of AgO2CCF3

31 to remove chloride led to the formation of AgCl precipitate, but no hydrogenation occurred (table 5.7, entry 9). Inspired by Crabtree’s catalyst, [Ir(COD)(PCy3)Py]PF6, which shows high activity in alkene hydrogenation,32 we decided to test the effectiveness of pyridine as additive. Using 2 equivalents of pyridine with respect to iridium, the hydrogenation became faster and the e.e. goes up to 78% with full conversion after 25 h. Surprisingly, when 1

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equivalent of ligand was used in combination with 2 equivalents of pyridine, the reaction worked equally well (table 5.8, entry 2). This seems to imply that pyridine exerts its effect as a ligand. Different pyridine/metal ratios, a series of pyridine analogs and other organic bases were tested as additives in our experiments. The results are shown in table 5.8.

Table 5.8 Pyridine and other additives in imine hydrogenation a

Entry Additives Equiv. Ir/L Conv. (%) b e.e. (%) c

1 Pyridine 1 1/1 100 39 2 Pyridine 2 1/1 85 77 3 Pyridine 5 1/1 59 78 4 Pyridine 1 1/2 70 77 5 Pyridine 2 1/2 100 78 6 Pyridine 5 1/2 72 78 7 Pyridine 10 1/2 40 70 8 d Pyridine 10 1/2 25 71 9 2-Me-pyridine 2 1/2 95 68 10 2,6-di-Me-pyridine 2 1/2 100 69 11 4-N, N-di-Me-pyridine 2 1/2 75 71 12 4-Me-2,6-di-t-Bu

pyridine 2 1/2 100 70

13

NN

2

1/2

85

62

14 2,2’-bipyridine 1 1/2 28 60 15 quinine 2 1/2 27 37 16 pyrrole 2 1/2 79 66 17

N

2

1/2

85

65

18

N N

1

1/2

93

63

19

NH

N

1

1/2

26

55

20 imidazole 2 1/2 9 61 2133

NH

O

O

2

1/2

47

66

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, 5 mol% catalyst loading, imine 5.20 (0.067 M), 25 bar H2, in toluene, 24 h at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) In bi-phasic solution, toluene/H2O, 2/1. From these results, 2 equiv. of pyridine as additive seems to be the best choice (table 5.8,

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

entry 2, 5). The use of more pyridine will slow down the reaction rate a little bit (table 5.8, entry 3, 6-8). The amount of pyridine is quite important to get fast reaction and high selectivity for different Ir/L ratios. If the Ir/L ratio is 1/1, the addition of 2 or 5 equivalents of pyridine are required to get good enantioselectivities (table 5.8, entry 1-3). The use of 1 equivalent of pyridine resulted in poor selectivity (39%, table 5.8, entry 1). For Ir/L ratio of 1/2, the amount of pyridine seems less crucial. It only changes the reaction rate; enantioselectivities are more or less the same (table 5.8, entry 4-7). Under these conditions, using only 1 equivalent of pyridine, the e.e. still remains 77%, which was nearly the same as with 2 or 5 equivalents (table 5.8, entry 4-6). With 10 equivalents of pyridine in the bi-phasic solvent system toluene/H2O, 2/1, the reaction became a little slower with similar e.e., which indicates this system is not sensitive to water (table 5.8, entry 8). Other pyridine analogs or derivatives gave comparable or worse e.e’s than pyridine itself (table 5.8, entry 9-21). The stronger base 4-N, N-dimethyl pyridine (DMAP) gave somewhat lower e.e. (table 5.8, entry 11). Based on these findings, pyridine was considered to be a ligand for the catalyst and not merely acting as a base. Interestingly, the addition of pyridine did not always give a positive effect in our system. For example, with other ligands such as L3.9-L3.11 (for structures, see figure 5.4), the pyridine effect was not apparent (table 5.9, entry 1-8). For imine 5.21, the addition of pyridine using L3.9 gave a lower e.e (table 5.9, entry 3, 4). Sometimes, the addition of pyridine can even slow down the reaction dramatically (table 5.9, entry 7, 8).

Table 5.9 Imine hydrogenation with ligands L3.9-L3.11 a

Entry Imine Ligand b Pyridine t (h) Conv. (%) c e.e. (%) d

1 5.20 L3.9 0 24 100 7 2 5.20 L3.9 2 24 94 8 3 5.21 L3.9 0 26 100 4 4 5.21 L3.9 2 26 100 1 5 5.20 L3.10 0 24 100 2 6 5.20 L3.10 2 24 100 4 7 5.20 L3.11 0 48 95 9 8 5.20 L3.11 2 48 25 2

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L=1/2, 5 mol% catalyst loading, imine 5.20, 5.21 (0.067 M), 25 bar H2, in toluene. (b) For structure of ligands L3.9-L3.11, see figure 5.4. (c) Conversions were determined by 1H NMR (CDCl3). (d) e.e.’s were determined by HPLC (AD or OD column, see experimental part) based on their N-acetyl derivatives. A blank reaction was observed when using only [Ir(COD)Cl]2 with or without pyridine in the hydrogenation of imine 5.20 (24h in toluene, 85% conversion). This was accompanied by the appearance of Ir black precipitate. When using SPO’s as ligands, no metal precipitated from the solution.

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5.4.5 Pressure and temperature In most cases, hydrogen pressure and temperature are important parameters in asymmetric hydrogenation (this chapter, section 5.1.2). Increasing hydrogen pressure means that the rate of hydrogen up-take goes up, resulting in a higher reaction rate. Unfortunately, this is often accompanied by low enantioselectivities. In our experiments, different H2 pressures were used in the presence or absence of 2 equiv. of pyridine as additive. All results are shown in table 5.10.

Table 5.10 Effect of hydrogen pressure on imine hydrogenation a

Entry H2 (bar) t (h) Conv. (%) b e.e. (%) c

1 70 24 100 62 2 d 70 24 100 73 3 25 25 74 69 4 d 25 25 100 78 5 d 5 116 85 74 6 e 1 168 >99 76

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L=1/2, 5 mol% catalyst loading, imine 5.20 (0.067 M), in toluene at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were measured by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) With 2 equivalents of pyridine. (e) H2 balloon. From the results in table 5.10, it can be concluded that 25 bar is the most suitable H2 pressure for this system considering the balance of reaction rate and enantioselectivity (table 5.10, entry 3, 4). Surprisingly, this hydrogenation even works smoothly with good selectivity at H2 pressure as low as 1 bar, although a long reaction time is needed (table 5.10, entry 6). As far as we know, there is only one other example known of imine hydrogenation at 1 bar pressure.16

Generally, lowering the temperature results in a decrease in reaction rate accompanied by an increase in enantioselectivity.34 Different temperatures ranging from 0 oC to 40 oC, were evaluated in our system (Table 5.11).

Table 5.11 Temperature effect in imine hydrogenation a

Entry Imine T(oC) t (h) Conv. (%) b e.e. (%) c

1 5.20 40 11 93 70 2 5.20 25 24 100 78 3 5.20 0 120 75 82 4 5.21 40 11 100 73 5 5.21 25 24 100 80 6 5.21 0 120 80 83

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L/py.=1/2/2, 5 mol% catalyst loading, imine 5.20, 5.21 (0.067 M), 25 bar H2, in toluene. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (AD or OD column, see experimental part) based on their N-acetyl derivatives.

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

From the results in this table, it can be concluded that room temperature (25 oC) gives the best balance of reaction rate and selectivity (table 5.11, entry 2, 5). By lowering the temperature to 0 oC, the enantioselectivity goes up to 83%, but the reaction rate drops dramatically (reaction time up to 120 h, table 5.11, entry 3, 6). Increasing the temperature to 40 oC, the reaction became much faster (11 h, full conversion), however, the e.e. drops to 70- 73% for imines 5.20 and 5.21, respectively (table 5.11, entry 1, 4). 5.4.6 Substrates We next studied the substrate scope of this new hydrogenation reaction. In addition to imine 5.20, imines 5.21-5.27 (see table 5.1) with different substituents at the phenyl ring, hindered imines 5.28-5.31 (see figure 5.2) and other imines were tested in our system under standard conditions. The results are shown in table 5.12.

Table 5.12 Imine hydrogenation without pyridine a

Entry Imine Solvent Ir/L t (h) Conv. (%) b e.e. (%) c

1 5.20 Toluene 1/2 24 74 69 2 5.21 Toluene 1/2 24 75 72 3 5.22 DCM 1/2 24 65 64 4 5.23 Toluene 1/2 24 95 71 5 5.24 DCM 1/2 24 45 15 6 5.26 DCM 1/2 24 20 17 7 d 5.27 Toluene 1/2 24 100 7 8 e 5.28 Toluene 1/2 51 10 3 9 e 5.29 Toluene 1/2 24 100 0 10 e 5.30 Toluene 1/2 24 100 0 11 5.31 Toluene 1/1 24 100 0 12 5.33 Toluene 1/2 24 15 48 13 5.34 Toluene 1/2 24 18 26 14 5.35 Toluene 1/1 24 75 13 15 5.38 DCM 1/1 9 100 5 16 f 5.38 DCM 1/2 24 0 0 17 g 5.40 Toluene 1/2 24 100 75 18 h 5.40 Toluene 1/2 24 100 -18 19 i 5.40 Toluene 1/2 24 100 -20 20 j 5.41 DCM 1/1 24 100 2 21 j 5.42 DCM 1/1 24 100 5 22 j 5.43 DCM 1/1 24 100 2

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, 5 mol% catalyst loading, 25 bar H2, at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (AD or OD column, see experimental part) based on their N-acetyl derivatives. (d) R-(+)-L3.6. (e) e.e. was determined on free amine. (f) 70 bar H2. (g) 40 oC. (h) Ir(COD)2BF4, 40 oC. (i) [Rh(COD)Cl]2, 40 oC. (j) e.e. was determined by NMR method. In these experiments, it was found that some imines such as 5.31, 5.35, 5.38 (Figure 5.2), 5.41-5.43 (Scheme 5.13) could only be hydrogenated using Ir/L of 1/1 resulting in

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very low e.e.’s (<10%) (table 5.12, entry 11, 14-16, 20-21). Increasing this ratio to 1/2, 1/3 or even 1/4 stopped the reaction completely. When pyridine was added, even at an Ir/L of 1/1, no reaction was observed. For imine 5.31, 5.35, 5.38, this might be due to the steric effects in the substrates. For imine 5.41-5.43, it might be due to the strong coordination of the amide group present in these substrates, which allows only one ligand to be coordinated to the metal center. We also studied the effect of pyridine as additive on the asymmetric hydrogenation of these substrates in toluene as the solvent. The results are shown in table 5.13.

Table 5.13 Imine hydrogenation with 2 equiv. of pyridine a

Entry Imine H2 (bar) T (oC) t (h) Conv. (%) b e.e. (%) c

1 5.20 25 25 24 100 78 2 5.21 25 25 24 100 80 3 5.22 25 25 24 85 76 4 5.23 25 25 24 75 77 5 5.24 25 25 17 76 62 6 5.25 25 25 24 52 68 7 5.26 25 25 24 20 54 8 5.27 25 25 26 60 68 9 d 5.28 70 25 48 50 57 10 d 5.29 25 25 24 100 0 11 5.33 25 25 24 12 32 12 5.34 25 25 24 10 49 13 5.39 25 25 69 <5 n.d. 14 5.40 25 25 140 85 12 15 e 5.40 25 40 24 100 -32 16 f 5.40 25 25 140 65 75 17 g 5.40 25 40 24 85 -43

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L/py.=1/2/2, 5 mol% catalyst loading, 25 bar H2, in toluene. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (AD or OD column) based on their N-acetyl derivatives. (d) e.e. was determined on free amine. (e) Ir(COD)2BF4. (f) 2 equiv. of 4-methyl-2,6-dimethyl pyridine as additive. (g) [Rh(COD)Cl]2. In general, addition of 2 equivalents of pyridine gave better results than the hydrogenation without any additives in most cases (80% vs 72% in e.e. for imine 5.21). From the results shown in tables 5.12 and 5.13, it appears that changing the substituents in the phenyl ring of imines does not change the reaction rate and selectivity dramatically. It is well known that some impurities present in the imines can cause problems in the hydrogenation.1,4 Crystalline imines based on acetophenone are easily obtained in highly pure form by crystallization; this might be the reason that quite good rates and selectivities were reached with these substrates (table 5.12, 5.13, entry 1-4). However, oily imines are difficult to obtain in pure form. Rather poor reaction rates and selectivities were found (table 5.12, entry 5-6). These oily imines are not very stable

123

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

over time; even when kept at low temperature; they partly decompose to ketones and amines. Interestingly, in the presence of pyridine as additive, N-phosphoryl imine 5.40 can be hydrogenated but with very low reaction rate and e.e. (table 5.13, entry 14). The use of Ir(COD)2BF4 and [Rh(COD)Cl]2 instead of [Ir(COD)Cl]2 for the hydrogenation of 5.40 led to the major isomer with the opposite configuration, although e.e.’s were lower (table 5.12, entry 18, 19; table 5.13, entry 15, 17). However, using 4-methyl-2,6- dimethyl pyridine as additive, 5.40 could be hydrogenated with reasonable enantioselectivity (75% e.e.) although the reaction was quite slow (table 5.13, entry 16). When increasing the temperature to 40 oC, the reaction became faster and the e.e. remained the same, even without additive (table 5.12, entry 17). Surprisingly, N-aryl imines 5.29 and 5.30 were hydrogenated with 100% conversion but racemic product was obtained with or without pyridine as additive (table 5.12, entry 9, 10; table 5.13, entry 10) and many side products were formed as a result of decomposition of substrates. These imines decompose easily to acetophenone and aniline or 4-Cl-aniline under the hydrogenation conditions (approx. 40% according to 1HNMR). The two enantiomers of 5.32H or its N-acetyl derivative could not be separated by chiral HPLC or GC, thus we were unable to determine the e.e. Cyclic imine 5.39 only gave a very low conversion (5%) with Ir/L of 1/2; the e.e. was not determined (table 5.13, entry 13). 5.4.7 Ligands Besides all these above-mentioned parameters, the ligands are a key factor influencing the reaction rate and enantioselectivity. Several enantiopure SPO’s were synthesized and separated successfully by preparative HPLC (see chapter 3) (Figure 5.4). We investigated their efficiencies in asymmetric imine hydrogenation under standard conditions. The results are shown in tables 5.14 and 5.15.

124

Chapter 5

PO

H

R1

R2PPh Ph

O H

L3.4 R1= t-Bu, R2=PhL3.5 R1= i-Pr, R2=PhL3.6 R1= t-Bu, R2=2-naphthylL3.7 R1= t-Bu, R2=2-MeOPhenylL3.8 R1= t-Bu, R2=3,5-di-MePhenylL3.9 R1= t-Bu, R2=2,4,6-tri-MePhenylL3.10 R1=Ph, R2=2-naphthyl

L3.3

OP

O

O

O

O

H

PhPh

PhPh

PPh2

PO

H

L3.12

L3.11

OPPh2

OPPh2

L3.13

PO

H

O

L3.14 (rac.)

PN

N

L 3.15

Figure 5.4 Structures of enantiopure SPO’s and other ligands

Initially, these ligands were tested in imine hydrogenation without any additives (Table 5.14).

Table 5.14 Different ligands in imine hydrogenation without pyridine a

Entry Imine Ligands Conv. (%) b e.e. (%) c

1 5.20 L3.4 74 69 2 5.26 L3.5 >95 20 3 5.21 L3.6 >95 17 4 5.26 L3.6 80 39 5 5.21 L3.7 80 9 6 5.21 L3.8 >95 11 7 5.20 L3.9 100 7 8 5.21 L3.9 100 4 9 5.21 L3.10 100 2 10 5.20 L3.12 100 5 11 5.20 L3.3 >95 36 12 5.21 L3.3 >95 51 13 d 5.20 L3.11 95 9 14 5.20 L3.13 100 2

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L=1/2, 5 mol% catalyst loading, imine 5.20, 5.21, 5.26 (0.067 M), 25 bar H2, in toluene at RT for 24 h. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (AD or OD column, see experimental part) based on their N-acetyl derivatives. (d) 48 h.

125

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

From table 5.14, it can be seen that all the catalysts based on the respective ligands lead to high or full conversion to the desired products. L3.4 is the most effective ligand for this hydrogenation. Ligand L3.6 and cyclic ligand L3.3 led to somewhat lower but comparable e.e’s (table 5.14, entry 4, 11, 12). The results with the other ligands were quite poor (table 5.14, entry 2, 3, 5-10, 13-14). Bidentate SPO-phosphine ligand L3.11 gave disappointing results (table 5.14, entry 13). There seems no large difference in the reaction rate upon variation of the ligands. To compare the efficiency of the additives, 2 equiv. of pyridine were added, as pyridine was already found to be the best additive with ligand L3.4. Results are collected in table 5.15. Table 5.15 Different ligands in imine hydrogenation with 2 equivalents of pyridine a

Entry Imine Ligands t (h) Conv. (%) b e.e. (%) c

1 5.20 L3.4 24 100 78 2 5.21 L3.5 17 >95 33 3 5.21 L3.6 17 >95 68 4 5.21 L3.7 17 60 70 5 5.20 L3.8 17 >95 66 6 5.20 L3.9 24 94 8 7 5.20 L3.10 24 100 4 8 5.20 L3.3 24 >95 23 9 5.20 L3.12 48 25 2 10 5.21 L3.9 24 100 1 11 5.21 L3.10 24 100 3 12 5.21 L3.3 24 >95 3

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4, Ir/L/py.=1/2/2, 5 mol% catalyst loading, imine 5.20, 5.21 (0.067 M), 25 bar H2, in toluene at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (AD or OD column, see experimental part) based on their N-acetyl derivatives. It can be seen from this table that ligand L3.4 was again the best ligand with pyridine as additive. Ligands L3.6-L3.8 gave lower but still comparable e.e’s (table 5.15, entry 3-5). Ligand L3.5 gave quite poor e.e. (table 5.15, entry 2). All other ligands gave very low e.e.’s (<10%, table 5.15, entry 2, 6-7, 10-11). The effect of pyridine on the enantioselectivity appears to be quite general, although there are a few exceptions: with the addition of pyridine, Taddol-based phosphite L3.12 and cyclic ligand L3.3 gave either worse conversion or e.e. compared to the hydrogenation without pyridine (table 5.15, entry 8, 9, 12). Intrigued by my colleagues’ work35 who studied mixtures of different monodentate phosphoramidites as ligands in the hydrogenation of β–dehydroamino acids35a and conjugate addition of boronic acids,35b several mixtures of ligands were also tested in the present hydrogenation. The results are collected in table 5.16.

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Table 5.16 Imine hydrogenation with mixed ligand systems a

Entry Ligands t (h) Conv. (%) b e.e. (%) c

1 d R-(+)-L3.4/Ph3P = 2/1 40 35 49 2 d R-(+)-L3.4/Ph3P = 1/1 40 30 51 3 R-(+)-L3.4/Ph3P = 1/1 40 20 66 4 R-(+)-L3.4/R-(+)-L3.6 = 1/1 69 65 60 5 R-(+)-L3.4/S-(-)-L3.6 = 1/1 69 100 16 6 R-(+)-L3.4/R-(+)-L3.5 = 1/1 69 80 7 7 R-(+)-L3.4/L3.14 = 1/1 69 17 38 8 R-(+)-L3.4/L3.15 = 1:1 69 <5 n.d. 9 R-(+)-L3.4 24 100 78 10 R-(+)-L3.5 24 100 19 11 R-(+)-L3.6 24 100 63

(a) General conditions: [Ir(COD)Cl]2, (R+)-L 3.4 and other ligands, Ir/L/py.=1/2/2, 5 mol% catalyst loading, imine 5.20 (0.067 M), 25 bar H2, in toluene at RT. (b) Conversions were determined by 1H NMR (CDCl3). (c) e.e.’s were determined by HPLC (OD column, n-heptane:2-propanol = 95:5) based on their N-acetyl derivatives. (d) Without pyridine. However, none of these “mixed ligand-based” catalysts gave better results than the catalysts based on single ligands. The addition of achiral ligands Ph3P, L3.14, L3.15 led to decrease of e.e’s as well as reaction rate (Table 5.16, entry 1-3, 7-8). Combinations of enantiopure SPO’s L3.5, L3.6, also led to a drop in e.e.’s, especially with L3.5 (table 5.16, entry 4, 6). Using the opposite enantiomer of L3.6 resulted in an even lower e.e. (table 5.16, entry 5). 5.4.8 Preformed catalysts With the optimized conditions, we also tried to use preformed catalysts or pre-hydrogenated catalysts in the imine hydrogenation. The preformed catalysts were prepared by one of the following methods: (1) Mixing [Ir(COD)Cl]2 /(R)-(+)-L3.4 = 1/2 in 3 ml toluene and the mixture was stirred for 1 h under N2 followed by the addition of 2 or 10 equiv. of pyridine. The mixture was then stirred for another 30 min, imine 5.20 was added and hydrogenation was performed at 25 bar H2 for 24 h at RT. With 2 equiv. of pyridine, 62% e.e. was obtained with 50% conversion; while with 10 equiv. of pyridine, the e.e. went up to 70% with 49% conversion. (2) Mixing [Ir(COD)Cl]2 /(R)-(+)-L3.4 = 1/2 in 3 ml DCM or toluene and the mixture was stirred for 1 h under N2. The solvent was removed under vacuum, 2 or 10 equiv. of pyridine in 3 ml toluene was added and the mixture was stirred for another 30 min. After the addition of imine 5.20, hydrogenation was performed at 25 bar H2 for 24 h at RT. The conversion and enantioselectivity are nearly the same as above. The pre-hydrogenated catalysts (the catalysts were hydrogenated before the addition of substrate) were performed as follows:

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

Mixing [Ir(COD)Cl]2/(R)-(+)-L3.4 = 1/2 in 3 ml toluene and the mixture was stirred for 5 h under 25 bar H2. The H2 was released and purged with N2. Subsequently, under N2, imine 5.20 was added and the mixture was hydrogenated at 25 bar for 24 h. The result was comparable to those with the catalyst prepared in situ: e.e. 72% vs 69% with similar conversion. 5.4.9 Conclusions Several conclusions can be drawn from these investigations: (a) The combination of [Ir(COD)Cl]2 and an SPO forms an effective catalyst for asymmetric imine hydrogenation. With an Ir/L ratio of 1/1, the reaction is very fast but low enantioselectivities are found; with an Ir/L ratio of 1/2, the reaction is much slower, however, with higher enantioselectivity. (b) After testing several solvents, toluene was found to be the solvent of choice for this reaction. For acetophenone-based imines in toluene, with an Ir/L ratio of 1/2, 69% e.e. was reached under optimized conditions; however a long reaction time (24 h) was needed, which means a very low TOF. Other solvents such as DCM, THF, Et2O, EtOAc gave lower but comparable e.e’s. Reactions in benzene, cyclohexane or α,α,α-trifluorotoluene were much slower than in other solvents. Alcohols, like methanol or 2-propanol, were not suitable solvents for this reaction. No reaction was observed in acetonitrile. (c) After optimization of the reaction conditions, pyridine was found to be the best additive for this system. It seems not merely to act as a base but rather as a ligand for the catalyst. With 2 equivalents of pyridine as additive, 78% e.e. was reached at RT in the hydrogenation of imine 5.20 but the reaction is quite slow even at 25 bar H2. Pyridine analogues or derivatives gave lower but comparable e.e’s. Other additives gave poor results. (d) Lowering the temperature to 0 oC leads to an increase of the e.e. to 83%, however, this is accompanied by a dramatic drop in reaction rate. Increasing the temperature to 40 oC leads to an increase in reaction rate (11h) accompanied by a slight decrease in enantioselectivities. It was found that 25 bar H2 pressure was suitable for the hydrogenation of most imines. With 70 bar H2, the reaction was a little bit faster accompanied by a few percent drop in e.e.. With 5 bar H2, the reaction was very slow with similar enantioselectivity. Surprisingly, this hydrogenation even works smoothly with good enantioselectivity at a H2 pressure as low as 1 bar, although a very long reaction time was needed. As far as we know, there is only one reported example of imine hydrogenation at 1 bar.16

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(e) Ligand L3.4 (t-BuPhPHO) turned out to be the best one in our experiments. Changing the t-Bu to i-Pr in L3.5 lead to lower e.e.’s. Changing the phenyl ring to 2-naphthyl group in L3.6 gave slightly lower but still comparable e.e.’s. The introduction of substituents in the phenyl ring, like 2-MeO, 2, 4, 6-trimethyl (mesityl) or 3, 5-di-methyl did not improve the enantioselectivity. Replacing the t-Bu with a 2-naphthyl group also gave poor results. Cyclic ligand L3.3 also did not work that well, as only moderate e.e.’s were observed. With Taddol-based phosphite L3.12 even worse e.e.’s were obtained and bidentate ligand L3.11 gave disappointing results. The combination of (R)-(+)-L3.4 with other enantiopure or racemic SPO’s and achiral phosphine ligands did not have any positive effects. The preformed or pre- hydrogenated catalysts did not lead to any improvements either in reaction rate or enantioselectivities. (f) Of the acetophenone-based imines, the unsubstituted-(5.20) and p-MeO-substituted- (5.21) gave the best results with respect to enantioselectivities. Substitutions in other positions with either electron-donating (MeO) or electron-withdrawn groups (Cl) resulted in somewhat lower e.e.’s. The purity of imines was crucial for the hydrogenation, as the catalysts seem to be quite sensitive to traces of primary amines and trimers or oligmers of the imines. The ratio of E/Z isomers in imines seems not to be a major parameter for the hydrogenation reaction. (g) Imines based on glycinamide 5.41-5.43, cyclic imines 5.38, 5.39 and steric hindered imines 5.31, 5.35 could only be hydrogenated with an Ir/L ratio of 1/1; a ratio of 1/2 or the use of pyridine as additive resulted in no reaction. Surprisingly, N-aryl imines 5.29 or 5.30 can be hydrogenated to the right product with full conversion; however, the products were racemic, either with or without using pyridine as additive. The exact reason for this is not clear. The imines themselves quite easily decompose to acetophenone and aniline or 4-Cl-aniline. In conclusion, [Ir(COD)Cl]2, L3.4 and pyridine together gave an efficient catalyst for asymmetric imine hydrogenation. However, there is still considerable space for improvement, particularly with regard to the reaction rate. In addition, the enantioselectivity needs to be improved further, which might due to monodentate way of coordination of this type of ligands to the metal center. A bidentate analogue L3.11 show poor enantioselectivity. 5.5 Experimental section General conditions: For general conditions, see chapter 3. Enantiomeric excess (e.e.) was measured by

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

HPLC (Daicel, chiralpak AD or OD column, n-heptane/2-propanol, 95/5 or 90/10) based on their N-acetyl derivatives. To ensure accurate determination of e.e.’s, racemic samples of the hydrogenation products were prepared by reducing imines with NaBH4 in a mixture of CHCl3/MeOH, 4/1 followed by the addition of Ac2O. For details of enantiopure SPO’s ligands, see chapter 3. Typical procedure for the synthesis of imines 5.20-5.27 at RT. In a 50 ml round flask was placed neat acetophenone or substituted acetophenone (100 mmol) and benzylamine or substituted benzylamine (100 mmol). To this mixture was added 10 g of dried 4 Å molecular sieves and the mixture was stirred at RT for at least 1 week. The progress of the reaction was monitored by 1H NMR (CDCl3). In most cases, the reaction was finished in 1 week. After that, the mixture was diluted with 20 ml dry DCM, filtered and washed with 80 ml dry DCM. The combined solvent was removed under vacuum to obtain a thick yellow oil, which was then crystallized from n-hexane or n-hexane:Et2O, 2:1 to give nicely crystalline compounds for imine 5.20-5.22, 5.27. Oily imines 5.23-5.26 were purified through an active neutral Al2O3 column eluted with petroleum ether (40-60 oC):Et2O, 2:1. After purification, imine 5.23 solidified in the refrigerator. N-Benzyl-N-[1-phenylethylidene]amine (5.20)6 Prepared from acetophenone (200 mmol, 23.4 ml) and benzylamine (200 mmol, 21.9

ml), crystallized from n-hexane to give 5.20 as off-white cubic crystals. Isolated yield 49% (20.5 g, 98 mmol). mp 46-47 oC (lit.36 44-46 oC), 1H NMR (CDCl3) major isomer: δ 2.29 (s, 3H, CH3), 4.70 (s, 2H, CH2), 7.18-7.39 (m, 9H), 7.80-7.83 (m, 1H);

minor isomer: δ 2.33, 4.40. 13C NMR (CDCl3) major isomer: δ 164.4, 139.63, 139.19, 128.20, 127.00, 126.81, 126.30, 125.33, 125.15, 54.27, 14.40; minor isomer: δ 127.22, 124.63, 55.83. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C15H15N 209.1212, calcd. 209.1205. N-Benzyl-N-(1-phenylethyl)amine (5.20H) Racemate, prepared from 5.20 (50 mg, 0.24 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to provide 5.20H as a colorless oil. Isolated yield 92% (47 mg, 0.22 mmol). 1H NMR (CDCl3) 1.32 (d, J = 6.59 Hz, 3H, CH3), 1.51 (br, 1H,

NH), 3.58 (q, J = 8.79 Hz, 2H, CH2), 3.77 (q, J = 6.59 Hz, 1H, CH), 7.17-7.31 (m, 10H). 13C NMR (CDCl3) 144.08, 139.15, 126.98, 126.88, 126.65, 125.44, 125.36, 125.22, 56.00, 50.18, 23.03. MS (EI+) 212 (M+1), 211 (M), 210 (M-1), 197, 196, 134, 120, 106,

N

NH

130

Chapter 5

105, 103, 92, 91 (100%), 79, 77, 65, 51. HRMS (EI+) M+ for C15H17N, found 211.1364, calcd. 211.1361. 5.20H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to obtain N-acetyl derivative 5.20HA for analytical HPLC (Daicel, chiralpak OD, n-heptane: 2-propanol = 95:5, 1 ml/min, 220 nm), tR = 11.57 min, tS = 14.10 min. This result was further confirmed using commercial available R- and S-5.20H which were reacted with Ac2O and subjected to HPLC analysis. N-[1-(4-Methoxyphenyl)ethylidene](phenyl)methanamine (5.21)37

N

O

Prepared from p-MeO-acetophenone (100 mmol, 15 g) and benzylamine (100 mmol, 10.9 ml), crystallized from n-hexane:Et2O, 2:1 to give 5.21 as an off-white solid. Isolated yield 35% (8.4 g, 35 mmol). mp 55-57 oC (lit.37 55-56.8 oC), 1H NMR (CDCl3) major isomer: δ 2.25 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.67 (s, 2H, CH2), 6.85 (d, J = 8.79 Hz, 2H), 7.19-7.38 (m, 5H), 7.80 (d, J = 8.79 Hz,

2H); minor isomer: δ 2.35, 3.82, 4.42. 13C NMR (CDCl3) major isomer: δ 163.61, 159.43, 139.39, 132.28, 126.91, 126.80, 126.23, 125.03, 111.99, 54.04, 53.83, 14.04; minor isomer: δ 129.14, 112.42, 112.23. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C16H17NO, 239.1296, calcd. 239.1310. N-Benzyl-N-[1-(4-methoxyphenyl)ethyl]amine (5.21H)

NH

O

Racemate, prepared from 5.21 (50 mg, 0.21 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4 ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.21H as a colorless oil. Isolated yield 91% (46 mg, 0.19 mmol). 1H NMR (CDCl3) δ 1.30 (d, J = 6.59 Hz, 3H, CH3), 3.56 (q, J = 8.05 Hz, 2H, CH2), 3.72 (q, J = 6.59 Hz, 1H, CH),

3.76 (s, 3H, OCH3), 6.84 (d, J =7.69 Hz, 2H), 7.21-7.29 (m, 7H). 13C NMR (CDCl3) δ 157.14, 139.01, 135.94, 126.94, 126.77, 126.33, 125.45, 125.27, 112.40, 55.32, 53.80, 50.06, 22.97. MS (EI+) 242 (M+1), 241 (M), 240 (M-1), 227, 226, 222, 221, 137, 136, 134, 122, 121(100%), 120, 113, 109, 106, 105, 104, 91, 79, 77, 51. HRMS (EI+) M+ for C16H19NO, found 241.1455, calcd. 241.14667. 5.21H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.21HA for analytical HPLC (Daicel, chiralpak AD, n-heptane: 2-propanol = 95:5, 1 ml/min, 220 nm), t1 = 16.82 min, t2 = 18.96 min.

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

(4-Methoxyphenyl)-N-[1-phenylethylidene]methanamine (5.22)38

Prepared from acetophenone (100 mmol, 11.6 ml) and p-MeO-benzylamine (100 mmol,

13.1 ml), crystallized from n-hexane:Et2O, 2:1 to give 5.22 as white cubic crystals. Isolated yield 36% (8.6 g, 36 mmol). mp 43-45 oC (lit. 38 44-46 oC), 1H NMR (CDCl3) major isomer: δ 2.30 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.67 (s, 2H, CH2),

6.87-6.91 (m, 2H), 7.33-7.38 (m, 5H), 7.84-7.87 (m, 2H); minor isomer: δ 4.41, 2.36. 13C NMR (CDCl3) major isomer: δ 164.18, 156.90, 139.65, 131.28, 128.10, 127.31, 126.74, 125.27, 112.35, 53.804, 53.66, 14.31; minor isomer: δ 127.15, 124.61. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C16H17NO 239.1306, calcd. 239.1310. N-(4-Methoxybenzyl)-N-(1-phenylethyl)amine (5.22H) Racemate, prepared from 5.22 (50 mg, 0.21 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.22H as a colorless oil. Isolated yield 88% (44 mg, 0.18 mmol). 1H NMR (CDCl3) δ 1.43 (d, J = 6.59Hz, 3H, CH3),

1.69-1.76 (br, 1H, NH), 3.62-3.64 (m, 2H, CH2), 3.83 (s, 3H, OCH3), 3.87 (q, J = 6.83 Hz, 1H, CH), 6.92 (d, J = 8.55 Hz, 2H), 7.29-7.49 (m, 7H). 13C NMR (CDCl3) δ 157.13, 144.19, 131.31, 127.88, 127.52, 127.05, 126.42, 125.49, 125.30, 112.74, 112.61, 112.33, 55.96, 53.80, 49.59, 23.09. MS (EI+) 242 (M+1), 241 (M), 240 (M-1), 227, 226, 136, 122, 121 (100%), 105, 103, 91, 79, 77, 65, 51. HRMS (EI+) M+ for C16H19NO, found 241.1472, calcd. 241.1467.

N

O

NH

O

5.22H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.22HA for analytical HPLC (Daicel, chiralpak AD, n-heptane:2-propanol = 95:5, 1 ml/min, 220 nm), t1 = 14.83 min, t2 = 17.17 min. (4-Chlorophenyl)-N-[1-phenylethylidene]methanamine (5.23) Prepared from acetophenone (100 mmol, 11.6 ml) and p-Cl-benzylamine (100 mmol,

12.2 ml). It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.23 as a yellow thick oil which solidified in the refrigerator. Isolated yield 44% (10.6 g, 44 mmol). 1H NMR (CDCl3)

major isomer: δ 2.28 (s, CH3), 4.63 (s, 2H, CH2), 7.20-7.39 (m, 6H), 7.79-7.82 (m, 2H), 7.91 (d, J = 7.32 Hz, 1H); minor isomer: δ 4.88, 2.33. 13C NMR (CDCl3) major isomer: δ 165.53, 137.98, 130.78, 127.76, 127.29, 127.09, 126.91, 125.40, 53.48, 16.83; minor

N

Cl

132

Chapter 5

isomer: δ 164.69, 139.41, 127.83, 126.43, 124.45, 54.74, 14.44. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C15H14NCl 243.0803, calcd. 243.0815. N-(4-Chlorobenzyl)-N-(1-phenylethyl)amine (5.23H)

Racemate, prepared from 5.23 (50 mg, 0.21 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4 ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.23H as light

yellow oil. Isolated yield 90% (44 mg, 0.18 mmol). 1H NMR (CDCl3) 1.32 (d, J = 6.59 Hz, 3H, CH3), 1.72 (br, 1H, NH), 3.54 (dd, 2H, J = 7.69, 13.18 Hz, CH2), 3.73 (q, 1H, J = 6.59 Hz, CH), 7.16 (d, J = 8.42 Hz, 2H, 2CH), 7.22 (d, J =8.42 Hz, 2H, 2CH), 7.255-7.3 (m, 5H).

NH

Cl

It was then added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.23HA for analytical HPLC (Daicel, chiralpak AD, n-heptane:2-propanol = 95:5, 1 ml/min, 220 nm), t1 = 11.40 min, t2 = 13.69 min. N-[1-(4-Chlorophenyl)ethylidene](phenyl)methanamine (5.24)39

Prepared from p-Cl-acetophenone (100 mmol, 13 ml) and benzylamine (100 mmol,

10.9 ml). It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.24 as a yellow oil. Isolated yield 54% (13.1 g, 54 mmol). 1H NMR (CDCl3) major isomer: δ 2.26 (s, 3H, CH3), 4.67 (s,

2H, CH2), 7.20-7.40 (m, 7H), 7.77 (q, J = 6.59 Hz, 2H); minor isomer: δ 2.31, 4.38. 13C NMR (CDCl3) major isomer: δ 163.10, 139.04, 137.91, 134.24, 127.05, 126.94, 126.75, 126.31, 125.27, 54.33, 14.18; minor isomer: δ 128.04, 127.868, 127.656, 127.474, 127.345, 126.396, 125.145, 55.585, 16.722. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C15H14NCl 243.0817, calcd. 243.0815. N-Benzyl-N-[1-(4-chlorophenyl)ethyl]amine (5.24H) Racemate, prepared from 5.24 (100 mg, 0.41 mmol) and NaBH4 (19 mg, 0.5 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.24H as light yellow oil. Isolated yield 86% (87 mg, 0.35 mmol). 1H NMR (CDCl3) δ 1.28 (d, J = 6.59 Hz, 3H,

CH3), 1.51 (br, 1H, NH), 3.55 (q, J = 9.52 Hz, 2H, CH2), 3.74 (q, J = 6.6 Hz, 1H, CH), 7.03-7.45 (m, 9H).

N

Cl

NH

Cl

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

5.24H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.24HA for analytical HPLC (Daicel, chiralpak AD, n-heptane:2-propanol = 95:5, 1 ml/min, 220 nm), t1 = 12.54 min, t2 = 13.80 min. N-[1-(3-Nitrophenyl)ethylidene](phenyl)methanamine (5.25)40

Prepared from m-NO2-acetophenone (100 mmol, 16.5 g) and benzylamine (100 mmol,

10.9 ml). It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.25 as a light yellow-brown oil. Isolated yield 38% ( 9.6 g, 38 mmol). 1H NMR (CDCl3) major isomer: δ 2.35 (s, 3H, CH3), 4.72 (s, 2H, CH2), 7.20-7.39 (m, 5H), 7.51 (t, J = 8.06 Hz, 1H),

8.21 (d, J = 1.83 Hz, 2H), 8.63 (d, J = 1.84 Hz, 1H); minor isomer: δ 2.64, 4.38. 13C NMR (CDCl3) major isomer: δ 161.97, 144.93, 140.82, 138.66, 131.21, 127.75, 127.03, 126.29, 125.31, 122.63, 120.10, 54.43, 14.17; minor isomer: δ 132.40, 128.47, 127.63, 127.31, 126.79, 125.89, 125.78, 121.49. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 255 (M+1), 254 (M), 253 (M-1), 252, 237, 207, 176, 165, 103, 92, 91(100%), 77, 65, 51. HRMS (EI+) M+ for C15H14N2O2, found 254.1042, calcd. 254.1055.

N

NO2

N-Benzyl-N-[1-(3-nitrophenyl)ethyl]amine (5.25H) Racemate, prepared from 5.25 (50 mg, 0.2 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.25H as a light yellow oil. Isolated yield 85% (43 mg, 0.17 mmol). 1H NMR (CDCl3) δ 1.33 (d, J = 6.59 Hz, 3H, CH3), 1.53 (br, 1H, NH), 3.57 (q, J = 5.49 Hz, 2H, CH2), 3.89 (q, J = 6.59 Hz,

1H, CH), 7.17-7.29 (m, 5H), 7.43-7.48 (m, 1H), 7.67 (d, J = 7.69 Hz, 1H), 8.04-8.08 (m, 1H), 8.17-8.21 (m, 1H). 13C NMR (CDCl3) δ 146.99, 146.28, 138.32, 131.71, 128.01, 127.37, 127.03, 126.84, 126.69, 125.68, 120.64, 120.32, 55.52, 50.14, 22.88. MS (EI+) 257 (M+1), 256 (M), 255 (M-1), 242, 241, 197, 196, 165, 153, 152, 150, 135, 134, 125, 121, 120, 107, 106, 105, 103, 92, 91 (100%), 78, 77, 65, 51. HRMS C15H16N2O2, found 256.1217, calcd. 256.1212.

NH

NO2

5.25H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.25HA for analytical HPLC (Daicel, chiralpak AD, n-heptane:2-propanol = 90:10, 1 ml/min, 220 nm), t1 = 11.67 min, t2 = 13.00 min. N-[1-(2-Methoxyphenyl)ethylidene](phenyl)methanamine (5.26)41

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Chapter 5

Prepared from o-MeO-acetophenone (100 mmol, 13.7 ml) and benzylamine (100 mmol, 10.9 ml). It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.26 as a light yellow oil. Isolated yield 43% (10.1 g,

43 mmol). 1H NMR (CDCl3) major isomer: δ 2.22 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.23 (s, 2H, CH2), 6.82-6.95 (m, 5H), 7.27-7.34 (m, 4H); minor isomer: δ 2.27 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.82 (s, 2H, CH2), major/minor isomer ratio = 2/1. 13C

NMR (CDCl3) major isomer: δ 166.34, 155.56, 153.58, 138.91, 128.40, 128.07, 126.87, 126.78, 126.47, 126.34, 125.65, 124.95, 119.25, 109.36, 55.09, 52.88, 26.27; minor isomer: δ 164.92, 132.19, 130.74, 128.88, 127.83, 127.14, 125.81, 125.01, 119.05, 110.06, 53.07, 52.78, 17.21. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 240 (M+1), 239 (M), 238 (M-1), 224, 208, 195, 148, 133, 131, 119, 105, 92, 91 (100%), 77, 65, 51. HRMS (EI+) M+ for C16H17NO, found 239.1313, calcd. 239.1310.

N

O

N-Benzyl-N-[1-(2-methoxyphenyl)ethyl]amine (5.26H) Racemate, prepared from 5.26 (50 mg, 0.21 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.26H as a colorless oil. Isolated yield 87% (44 mg, 0.18 mmol). 1H NMR (CDCl3) δ 1.35 (d, J = 6.59 Hz, 3H, CH3), 1.69-1.78 (br,

1H, NH), 3.53-3.64 (m, 2H, CH2), 3.79 (s, 3H, OCH3), 4.13 (q, J = 6.59 Hz, 1H, CH), 6.85 (d, J = 8.05 Hz, 1H), 6.91-6.96 (m, 1H), 7.15-7.36 (m, 7H). 13C NMR (CDCl3) δ 155.88, 139.51, 131.72, 127.69, 127.09, 126.94, 126.85, 126.31, 125.88, 125.40, 119.40, 109.23, 53.82, 51.02, 50.36, 21.02. MS (CI+) 243, 242 (M+1, 100%), 241 (M), 227, 226, 152, 135, 108, 91.

NH

O

5.26H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.26HA for analytical HPLC (Daicel, chiralpak OD, n-heptane:2-propanol = 90:10, 1 ml/min, 220 nm), t1 = 7.95 min, t2 = 9.28 min. N-[1-(4-Chlorophenyl)ethylidene](4-methoxyphenyl)methanamine (5.27)42

Prepared from p-Cl-acetophenone (66.7 mmol, 8.7 ml) and p-MeO-benzylamine (66.7

mmol, 8.7 ml); crystallized from n-hexane:Et2O, 2:1 to give 5.27 as a white powder. Isolated yield 45% ( 8.2 g, 30 mmol). mp 54-56 oC. 1H NMR (CDCl3) major isomer: δ 2.25 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 4.61 (s, 2H, CH2),

6.84 (d, J = 8.78 Hz, 2H), 7.19-7.30 (m, 4H), 7.75 (d, J = 8.79 Hz, 2H); minor isomer: δ

N

Cl

O

135

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

2.30, 3.73, 4.32. 13C NMR (CDCl3) major isomer: δ 161.76, 155.98, 136.93, 133.11, 130.10, 126.33, 125.86, 125.69, 111.41, 52.78, 52.72, 13.05; minor isomer: δ 127.27, 126.43, 125.15. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 275, 274 (M+1), 273 (M), 272 (M-1), 138, 122, 121 (100%), 119, 103, 91, 78, 77, 65, 51. HRMS (EI+) M+ for C16H16NOCl, found 273.0909, calcd. 273.0920. N-[1-(4-Chlorophenyl)ethyl]-N-(4-methoxybenzyl)amine (5.27H) Racemate, prepared from 5.27 (50 mg, 0.18 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.27H as a colorless oil. Isolated yield 91% (46 mg, 0.17 mmol). 1H NMR (CDCl3) 1.27 (d, J = 6.6 Hz, 3H,

CH3), 1.57 (m, 1H, NH), 3.48 (q, J = 8.43 Hz, 1H, CH), 3.69-3.77 (m, 5H), 6.78-6.86 (m, 2H), 7.06-7.35 (m, 6H). 13C NMR (CDCl3) 156.10, 141.66, 135.66, 130.02, 128.52, 128.32, 128.20, 127.60, 126.92, 126.79, 126.48, 126.08, 125.95, 125.62, 125.30, 124.39, 124.20, 111.90, 111.74, 111.28, 54.27, 52.78, 48.49, 22.03.

NH

Cl

O

5.27H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.27HA for analytical HPLC (Daicel, chiralpak Wh01, n-heptane: ethanol = 90:10, 1 ml/min, 220 nm), t1 = 14.75 min, t2 = 21.30 min. Typical procedure for the synthesis of imine 5.28-5.34 under Dean-Stark conditions.43

In a 250 ml round flask was placed acetophenone (100 mmol), primary amine (100 mmol) and 60 ml of dry toluene. This mixture was heated to reflux under Dean-Stark condition for 5 days, water formed in the reaction was collected and removed. It was then filtered and washed with dry EtOAc. The combined solvent was removed under vacuum to obtain a slightly yellow oil, which was then crystallized from n-hexane or n-hexane:Et2O, 2:1 which gave crystalline compounds for imines 5.28-5.31. Oily imines 5.32-5.34 were purified through an active neutral Al2O3 column chromatography, eluted with petroleum ether (40-60 oC):Et2O, 2:1. Diphenyl-N-[1-phenylethylidene]methanamine (5.28)44

Prepared from acetophenone (100 mmol, 11.6 ml) and aminodiphenylmethane (100 mmol, 17 ml) and crystallized from n-hexane:Et2O, 2:1 5.28 was obtained as white cubic crystals. Isolated yield 39% (11.2 g, 39 mmol). mp 54-56 oC, 1H NMR (CDCl3) major isomer: δ 2.28 (s, 3H, CH3), 5.88 (s, 1H, CH), 7.15-7.46 (m,

N

PhPh

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Chapter 5

13H), 7.91-7.94 (m, 2H); minor isomer: δ 2.25, 5.42. 13C NMR (CDCl3) δ 161.95, 142.36, 138.71, 127.14, 125.93, 125.67, 125.09, 124.49, 124.21, 123.40, 65.91, 13.49. In 1H and 13C NMR, some resonances of the minor isomer were obscured. HRMS (EI+) M+ for C21H19N 285.1513, calcd. 285.1518. N-Benzhydryl-N-(1-phenylethyl)amine (5.28H) Racemate, prepared from 5.28 (50 mg, 0.18 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH overnight at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.28H as a colorless oil. Isolated yield 89% (45 mg, 0.16 mmol). 1H NMR (CDCl3) δ 1.31 (d, J = 6.59 Hz, 3H, CH3), 1.58 (br, 1H, NH), 3.62 (q, J = 6.59 Hz, 1H, CH), 4.57 (s, 1H, CH), 7.09-7.31 (m, 15H). It was

found that the free amine did not react with Ac2O even with DMAP as catalyst, presumably due to steric effects. Fortunately, the free amine could be separated directly by analytical HPLC (Daicel, chiralpak OJ, n-heptane: Ethanol = 90:10, 1 ml/min, 220 nm), t1 = 9.93 min, t2 = 13.17 min.

NH

PhPh

N-[1-Phenylethylidene]aniline (5.29)45

Prepared from acetophenone (100 mmol, 11.6 ml) and aniline (100 mmol, 9.1 ml),

crystallized from n-hexane:Et2O, 2:1 to give 5.29 as a yellow solid, isolated yield 36% (7.1 g, 36 mmol). mp 36-38 oC (lit.46 39-40 oC), 1H NMR (CDCl3) major isomer: δ 2.18 (s, 3H, CH3), 6.74 (d, J = 7.33 Hz, 2H), 7.01-7.13 (m, 2H), 7.20-7.32 (m, 2H), 7.37-7.41 (m, 2H), 7.90-7.94 (m, 2H); minor isomer: δ 2.16, 6.62, 6.65. 13C

NMR (CDCl3) major isomer: δ 163.99, 150.27, 138.01, 129.04, 127.53, 126.93, 125.74, 121.78, 117.95, 15.92; minor isomer: δ 131.66, 127.81, 127.13, 113.60. In 1H and 13C NMR, some resonances of the minor isomer are obscured. HRMS (EI+) M+ for C14H13N 195.1055, calcd. 195.1048. N-phenyl-N-(1-phenylethyl)amine (5.29H) Racemate, prepared from 5.29 (50 mg, 0.26 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.29H as light yellow oil. Isolated yield 90% (45 mg, 0.23 mmol). 1H NMR (CDCl3) 1.47 (d, J = 6.96 Hz, 3H, CH3), 3.75 (br, 1H, NH), 4.44 (q, J=6.59 Hz, 1H, CH), 6.47 (d, J = 7.69 Hz, 2H), 6.60 (t, J = 7.32 Hz,

1H), 7.05 (t, J = 7.69 Hz, 2H), 7.27-7.34 (m, 5H).

N

NH

The free amine 5.29H was separated as such by analytical HPLC (Daicel, chiralpak OD, n-heptane:2-propanol = 90:10, 1 ml/min, 220 nm), t1 = 6.84 min, t2 = 8.12 min.

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Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

4-Chloro-N-[1-phenylethylidene]aniline (5.30)47

Prepared from acetophenone (100 mmol, 11.6 ml) and p-Cl-aniline (100 mmol, 12.8 g)

and crystallized from n-hexane:Et2O, 2:1 to give 5.30 as a light yellow powder. Isolated yield 53% (12.2 g, 53 mmol). mp 75-77 oC (Lit.47 75-76 oC). 1H NMR (CDCl3) major isomer: δ 2.18 (s, CH3, 3H), 6.68 (dd, J = 1.83, 8.42 Hz, 2H), 7.26 (dd, J = 2.2, 8.42 Hz, 2H), 7.36-7.43 (m, 3H), 7.89-7.92 (m, 2H); minor

isomer: δ 2.20, 6.65. 13C NMR (CDCl3) major isomer: δ 163.57, 147.86, 136.74, 128.31, 126.64, 126.01, 124.88, 118.50, 14.86; minor isomer: δ 125.83, 125.31, 123.83, 117.45. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 231, 230 (M+1), 229 (M), 228 (M-1), 216, 215, 214 (100%), 152, 151, 113, 111, 104, 91, 85, 83, 77, 75, 65, 51, 48. HRMS (EI+) M+ for C14H12NCl, found 229.0653, calcd. 229.0658.

N

Cl

N-(4-Chlorophenyl)-N-(1-phenylethyl)amine (5.30H) Racemate, prepared from 5.30 (50 mg, 0.22 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.30H as a colorless oil. Isolated yield 92% (47 mg, 0.2 mmol). 1H NMR (CDCl3) δ 1.51 (d, J = 6.84 Hz, 3H, CH3), 4.43 (q, J = 6.84 Hz, 1H), 6.40-6.45 (m, 2H), 7.00-7.08 (m, 2H), 7.22-7.38

(m, 5H). 13C NMR (CDCl3) δ 144.58, 143.46, 127.71, 127.51, 127.36, 127.07, 125.93, 125.65, 124.44, 120.15, 119.57, 113.06, 52.10, 23.53.

NH

Cl

The free amine 5.30H was separated as such by analytical HPLC (Daicel, chiralpak OD, n-heptane:2-propanol = 90:10, 1 ml/min, 220 nm), t1 = 6.98 min, t2 = 8.43 min. N-[2,2-Dimethyl-1-phenylpropylidene](phenyl)methanamine (5.31)48

Prepared from 2,2-dimethylpropiophenone (6.2 mmol, 1 g) and benzylamine (6.2 mmol,

0.7 ml), crystallized from n-hexane:Et2O, 2:1 to give 5.31 as colorless cubic crystals. Isolated yield 50% (0.76 g, 3 mmol). mp 62-63 oC (Lit.48 62-63 oC). 1H NMR (CDCl3) δ 1.15 (s, 9H, 3CH3), 4.16 (s, CH2, 2H), 6.91-6.94 (m, 2H), 7.13-7.31 (m, 8H).

13C NMR (CDCl3) δ 178.16, 139.56, 136.18, 126.71, 126.62, 126.00, 125.83, 125.51, 124.77, 55.04, 38.81, 27.09. MS (EI+) 252 (M+1), 251 (M), 250 (M-1), 195, 194, 104, 92, 91 (100%), 89, 77, 65, 57. HRMS (EI+) M+ for C18H21N, found 251.1679, calcd. 251.1674.

N

N-Benzyl-2,2-dimethyl-1-phenyl-1-propanamine (5.31H)

138

Chapter 5

Racemate, prepared from 5.31 (50 mg, 0.2 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4 ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.31H as a colorless oil. Isolated yield 90% (46

mg, 0.18 mmol). 1H NMR (CDCl3) major isomer: 0.85 (s, 9H, 3CH3), 1.68 (br, 1H, NH), 3.30 (s, 1H, CH), 3.35 (d, J = 13.18 Hz, 1H) 3.60 (d, J = 13.18 Hz, 1H), 7.21-7.28 (m, 5H); minor isomer: δ 0.89, 3.82, 4.36. 13C NMR (CDCl3) 139.99, 139.65, 127.73,

126.78, 126.72, 126.11, 125.30, 70.27, 50.56, 33.36, 25.71. MS (CI+) 255, 254 (M+1, 100%), 253 (M), 252 (M-1), 196, 108, 91. 5.31H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.31HA for analytical HPLC (Daicel, chiralpak Wh01, n-heptane:2- propanol = 99:1 to 90:10, 1 ml/min, 220 nm), t1 = 21.45 min, t2 = 23.67 min. Phenyl-N-[2,2,2-trifluoro-1-phenylethylidene]methanamine (5.32)49

Prepared from 2,2,2-trifluoroacetophenone (25 mmol, 3.5 ml) and benzylamine (25

mmol, 2.76 ml). It was purified by flash column chromato- graphy [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.32 as a light yellow oil. Isolated yield 38% (2.5 g, 10 mmol). 19F NMR (CDCl3) δ –75.17 (d). 1H NMR (CDCl3) major

isomer: δ 4.76 (q, J = 7.69 Hz, 2H, CH2), 7.19-7.52 (m, 5H), 7.78-7.71 (m, 3H), 8.34 (s, 2H); minor isomer: δ 4.78, 7.80, 8.36. 13C NMR (CDCl3) major isomer: δ 163.67, 133.07, 129.36, 127.97, 126.64, 126.51, 126.35, 125.35, 125.31, 125.28, 124.96, 124.93, 124.54, 72.98, 55.50; minor isomer: δ 163.62, 133.03, 126.03, 125.86, 125.48, 120.80, 72.61. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 264 (M+1), 263 (M), 262 (M-1), 195, 194 (100%), 186, 165, 159, 140, 116, 109, 104, 91, 89, 77, 65, 63, 51. HRMS (EI+) M+ for C15H12NF3, found 263.0938, calcd. 263.0922. N-Benzyl-2,2,2-trifluoro-1-phenyl-1-ethanamine (5.32H) Racemate, prepared from 5.32 (50 mg, 0.19 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.32H as a colorless oil. Isolated yield 87% (45 mg, 0.17 mmol). 19F NMR (CDCl3) δ –75.23 (q). 1H NMR (CDCl3) 1.82 (br, 1H,

NH), 3.69 (s, 1H, CH), 4.14 (d, J = 7.57 Hz, 1H), 4.81 (d, J = 7.57 Hz, 1H), 7.28-7.47 (m, 7H), 7.83-7.88 (m, 2H), 8.40 (s, 1H).

N

FF

F

NH

NH

FF

F

The e.e. determination was attempted by different methods such as chiral GC, HPLC,

139

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

NMR. However, neither free amine 5.32H nor its N-acetyl derivative could be separated, thus the e.e. was not determined. N-[3,4-Dihydro-1(2H)-naphthalenylidene](phenyl)methanamine (5.33)50

Prepared from α-tetralone (100 mmol, 13.3 ml) and benzylamine (100 mmol, 10.9 ml).

It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60oC):Et2O, 2:1] to give 5.33 as a brown- yellow oil. Isolated yield 35% (8.2 g, 35 mmol). 1H NMR (CDCl3) major isomer: δ 1.96-2.05 (m, 2H, CH2), 2.65-2.69 (m, 2H, CH2),

2.85-2.96 (m, 2H, CH2), 4.77 (s, 2H, CH2), 7.20-7.22 (m, 1H), 7.31-7.47 (m, 5H), 7.56 (d, J = 7.32 Hz, 2H), 8.455 (d, J = 6.59 Hz, 1H); minor isomer: δ 4.79, 7.58. 13C NMR (CDCl3) major isomer: δ 162.81, 138.62, 138.12, 132.44, 127.35, 125.98, 125.33, 124.11, 123.99, 123.57, 52.11, 27.44, 25.84, 20.24; minor isomer: δ 126.20, 126.12, 125.61, 124.99, 124.77. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 236 (M+1), 235 (M), 234 (M-1), 233, 220, 206, 129, 128, 116, 115, 91 (100%), 89, 77, 65, 51. HRMS (EI+) M+ for C17H17N, found 235.1349, calcd. 235.1361. N-Benzyl-1,2,3,4-tetrahydro-1-naphthalenamine (5.33H) Racemate, prepared from 5.33 (50 mg, 0.21 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.33H as a light yellow oil. Isolated yield 91% (46 mg, 0.19 mmol). 1H NMR (CDCl3) δ 1.79-1.98 (m, 2H, CH2), 2.01-2.20

(m, 2H, CH2), 2.75-3.01 (m, 2H, CH2), 3.90-3.97 (m, 2H, NHCH2), 4.02-4.09 (m, 1H, CH), 7.13-7.39 (m, 4H), 7.41-7.54 (m, 5H). 13C NMR (CDCl3) δ 139.51, 137.87, 136.08, 127.66, 127.40, 127.00, 126.81, 125.47, 125.27, 124.33, 53.20, 49.73, 28.03, 26.76, 17.69. MS (EI+) 238 (M+1), 237 (M), 236 (M-1), 209, 208, 194, 146, 132, 131, 130 (100%), 129, 128, 118, 116, 115, 109, 108, 106, 104, 92, 91, 79, 77, 65, 51. HRMS (EI+) M+ for C17H19N, found 237.1512, calcd. 237.1518.

N

NH

5.33H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.33HA for analytical HPLC (Daicel, chiralpak OD, gradient eluent, n- heptane:2-propanol = 99:1 to 90:10, 1 ml/min, 220 nm), t1 = 20.77 min, t2 = 22.12 min. N-[1-(1-Naphthyl)ethylidene](phenyl)methanamine (5.34) Prepared from 1’-acetonaphthone (100 mmol, 15.2 ml) and benzylamine (100 mmol, 10.9 ml). It was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to give 5.34 as a light red oil. Isolated yield 45% (11.6 g, 45

140

Chapter 5

mmol). 1H NMR (CDCl3) major isomer: δ 2.43 (s, CH3, 3H), 4.80 (s, CH2, 2H), 7.13-7.26 (m, 5H), 7.42-7.52 (m, 3H), 7.63-7.78 (m, 1H), 7.80-7.89 (m, 3H); minor isomer: δ 2.40, 4.77. 13C NMR (CDCl3) major isomer: δ 167.08, 137.76, 135.48, 131.12, 130.64, 126.53, 126.38, 126.04, 126.01, 125.96, 125.64, 124.55, 124.26, 124.05, 123.08, 122.34, 120.72, 55.32 (CH2), 27.18 (CH3); minor isomer: δ 166.73, 138.88, 137.82, 131.56, 127.94,

126.16, 126.11, 125.69, 124.36, 123.47, 123.99, 122.53, 121.95, 53.83, 27.49. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 259 (100%, M), 258 (M-1), 244, 215, 168, 153, 127, 91, 65. N-Benzyl-1-(1-naphthyl)-1-ethanamine (5.34H) Racemate, prepared from 5.34 (50 mg, 0.19 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to give 5.34H as a light yellow oil. Isolated yield 88% (44 mg, 0.17 mmol). 1H NMR (CDCl3) 1.49 (d, J = 6.59 Hz, 3H), 1.67 (br, 1H), 3.71 (q, J = 12.08 Hz, 2H), 4.66 (q, J = 6.59 Hz, 1H), 7.21-7.29 (m, 5H), 7.44-7.50 (m, 3H), 7.74 (d, 2H), 7.84-7.87

(m, 1H), 8.11-8.14 (m, 1H). 13C NMR (CDCl3) 139.89, 139.56, 132.90, 139.28, 127.82, 127.21, 127.02, 126.11, 125.71, 125.22, 124.63, 124.56, 124.16, 123.54, 121.91, 121.76, 51.92, 50.69, 22.56.

N

NH

5.34H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.34HA for analytical HPLC (Daicel, chiralpak Wh01, n-heptane: ethanol = 90:10, 1 ml/min, 220 nm), t1 = 6.60 min, t2 = 8.65 min. Typical procedure for the synthesis of imines 5.35-5.37 at RT.51

These imines were prepared using a similar procedure as for 5.20-5.27 with neat acetophenone or alkylketone and benzylamine or t-butylamine. After the reaction was finished, imine 5.35 was purified through an active neutral Al2O3 column, eluted with petroleum ether (40-60 oC):Et2O, 2:1 to give a slightly yellow oil. However, imines 5.36 and 5.37 were not sufficiently stable on the Al2O3 column, especially imine 5.37, which decomposed completely. Imine 5.36 was then purified by bulb-to-bulb distillation at 100 oC / 0.5 mmHg to provide a light yellow oil. N-Benzyl-N-[1,2,2-trimethylpropylidene]amine (5.35)52

Prepared from 3,3-dimethyl-2-butanone (105 mmol, 13 ml) and benzylamine (100 mmol, 10.9 ml). It was purified by flash column chromatography [neutral Al2O3,

141

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

petroleum ether (40-60 oC):Et2O, 2:1] to provide 5.35 as a light yellow oil. Isolated yield 51% (9.6 g, 51 mmol). 1H NMR (CDCl3) δ 1.22 (s, 9H, 3CH3), 1.88 (s, 3H, CH3), 4.53 (s, 2H, CH2), 7.22-7.42 (m, 5H). 13C NMR (CDCl3) δ 173.75, 138.67, 125.78,

124.86, 123.79, 51.94, 38.31, 25.41, 11.04.

N

N-Benzyl-3,3-dimethyl-2-butanamine (5.35H) Racemate, prepared from 5.35 (50 mg, 0.26 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to provide 5.35H as a colorless oil. Isolated yield 89% (44 mg, 0.23 mmol). 1H NMR (CDCl3) δ 0.83 (s, 9H, 3CH3), 0.96 (d, J = 6.22 Hz, 3H, CH3), 2.24 (q,

J = 6.23 Hz, 1H, CH), 3.74 (q, J =13.18 Hz, 2H, CH2), 7.16-7.30 (m, 5H).

NH

5.35H was added directly to neat Ac2O. After stirring for 15 min, the solution was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-acetyl derivative 5.35HA for analytical HPLC (Daicel, chiralpak Wh01, n- heptane: ethanol = 90:10, 1 ml/min, 220 nm), t1 = 6.97 min, t2 = 9.34 min. N-Benzyl-N-[1-methylpropylidene]amine (5.36)53

Prepared from 2-butanone (105 mmol, 9.5 ml) and benzylamine (100 mmol, 10.9 ml). It

was purified by flash column chromatography [neutral Al2O3, petroleum ether (40-60 oC):Et2O, 2:1] to obtain 5.36 as a light yellow oil. Isolated yield 45% (7.2 g, 45 mmol). 1H NMR (CDCl3) δ

1.10 (t, 3H, CH3), 1.85 (s, 3H, CH3), 2.35 (q, J =7.33 Hz, 2H, CH2), 4.44 (s, 2H, CH2), 7.16-7.32 (m, 5H). 13C NMR (CDCl3) major isomer: δ 169.56, 140.87, 126.01, 125.85, 125.15, 124.55, 124.25, 52.51, 44.03, 15.86, 8.41; minor isomer: δ 138.10, 128.23, 125.27, 123.92, 52.00, 33.25, 9.27. In 1H and 13C NMR, some resonances of the minor isomer are obscured. MS (EI+) 162 (M+1), 161 (M), 160 (M-1), 146, 132, 117, 106, 92, 91 (100 %), 89, 77, 65, 51.

N

2,3,3-Trimethylindoline (5.38H)54

Racemate, prepared from 5.38 (100 mg, 0.63 mmol) and NaBH4 (30 mg, 0.79 mmol) in

4 ml CHCl3 and 1 ml MeOH overnight at RT. After addition of water and extraction with CHCl3, the solvent was removed to obtain 5.38H as a colorless oil. Isolated yield 91% (92 mg, 0.57 mmol). 1H NMR (CDCl3) 0.99 (s, 3H, CH3), 1.13 (d, J = 6.59 Hz, 3H, CH3),

1.23 (s, 3H, CH3), 3.47 (q, J = 6.59 Hz, 1H), 6.57 (d, J = 8.06 Hz, 2H), 6.69 (t, J = 7.32 Hz, 1H), 6.97 (t, J = 7.33 Hz, 1H). The e.e. determination was done by NMR at DSM using (R)-(+)-mandelic acid as chiral shifting reagent; see the end of this paragraph).

NH

142

Chapter 5

General procedure for the synthesis of 5-phenyl-3,4-dihydro-2H-pyrrole (5.39) Method 1 PhMgCl addition to 4-chloro-butyronitrile (Scheme 5.10): In a 50 ml 2-necked round flask, was placed 4-chloro-butyronitrile (20 mmol, 1.8 ml) and 10 ml dry Et2O. A solution of PhMgCl (2.0 M in THF, 23 mmol, 11.5 ml) was slowly added at RT. The solution became white turbid immediately. After addition, the mixture was heated under reflux for 6 h, allowed to come to RT, hydrolyzed by the addition of 10 ml H2O, extracted with 3x30 ml Et2O, backwashed with brine, dried over MgSO4 and purified by flash column chromatography [SiO2, petroleum ether (40-60 oC):Et2O, 2:1] to provide 5.39 as a light brown oil. The isolated yield was 20% (0.61 g, 4.2 mmol). Method 2 From decarboxylation (Scheme 5.11):55

3-Benzoyl-1-vinyl-2-pyrrolidinone (5.45) In a 500 ml 3-necked round flask, was placed NaH (600 mmol, 13 g) and 60 ml of dry

THF and the mixture was heated to reflux. To this solution was added N-vinyl 2-pyrrolidinone (250 mmol, 26.7 ml), methyl benzoate (250 mmol, 31.1 ml) and 80 ml dry THF. After addition, reflux was maintained for 4 h. It was then cooled and

followed by work-up with 50 ml saturated NH4Cl solution, extraction with 3x100 ml Et2O, back washing with brine and drying over MgSO4. After removing the solvent, 5.45 was obtained as a light brown oil, which was directly used in the next step without any purification. 1H NMR (CDCl3) δ 2.20-2.38 (m, 1H, CH2), 2.60-2.68 (m, 1H, CH2), 3.40-3.53 (m, 1H, CH2), 3.59-3.68 (m, 1H, CH2), 4.28-4.44 (m, 2H, =CH2), 4.49-4.53 (m, 1H, CH), 6.91-6.99 (m, 1H, =CH), 7.35-7.64 (m, 3H), 8.04 (d, 2H). 13C NMR (CDCl3) δ 192.75, 166.03, 133.41, 131.17, 127.05, 126.08, 124.75, 93.11, 48.65, 41.06, 18.91.

N

OO

The above light brown oil 5.45 was dissolved in 50 ml THF again and added slowly to a refluxing 50 ml 6 N HCl solution. After heating at reflux overnight, it was cooled to 0 oC, the pH was adjusted to >12 using saturated NaOH solution. Extraction with Et2O 3x100ml after normal work-up yielded a brown oil. It was then purified by flash column

chromatography [SiO2, petroleum ether (40-60 oC):Et2O, 2:1] to yield 5.39 as a light yellow oil which solidified in the refrigerator but melted at RT (isolated yield 74% over two steps, 26.4 g, 0.19 mol). 1H NMR (CDCl3) δ 1.79-1.94 (m, 2H, CH2), 2.71-2.81 (m, 2H, CH2), 3.89-3.99 (m, 2H, CH2), 7.25-7.31 (m, 3H), 7.71-7.76 (m, 2H). 13C NMR (CDCl3) δ 171.48, 133.04, 128.63, 126.78, 125.99, 59.97, 33.26, 21.07. MS (EI+) 146 (M+1), 145 (M), 144 (M-1), 119, 118, 117 (100%), 115, 105, 104, 103, 91, 85, 83, 77,

N

143

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

65, 51. HRMS (EI+) M+ for C10H11N, found 145.0892, calcd. 145.0892. 2-Phenylpyrrolidine (5.39H) Racemate, prepared from 5.39 (100 mg, 0.69 mmol) and NaBH4 (30 mg, 0.79 mmol) in

4 ml CHCl3 and 1 ml MeOH overnight at RT. After addition of water and extraction with CHCl3, the solvent was removed to provide 5.39H as a brown-yellow oil. Isolated yield 90% (91 mg, 0.62 mmol). 1H NMR (CDCl3) 1.56-1.98 (m, 4H), 2.84-2.99 (m,1H), 3.02-3.14

(m, 1H), 4.02 (t, J = 8.55 Hz, 1H), 5.51 (s, 1H, NH), 7.19-7.31 (m, 5H). 13C NMR (CDCl3) 140.66, 127.31, 126.87, 125.97, 125.68, 125.38, 60.75, 44.54, 31.99, 23.46.

NH

It was then added directly to neat 1-naphthyl acid chloride. After stirring for 1 h, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to yield N-naphthyl derivative 5.39HA for analytical HPLC (Daicel, chiralpak OD, n- heptane:2-propanol = 85:15, 1 ml/min, 220 nm), t1 = 8.08 min, t2 = 9.97 min. Diphenyl-N-[1-phenylethylidene] phosphinic amide (5.40) 1-Phenyl-1-ethanone oxime (5.46)56

In a 100 ml round flask, was placed NH2OH.HCl (0.4 mol, 27.8 g), Et3N (0.4 mol, 55

ml) and 50 ml of absolute EtOH. The mixture was stirred at RT for 1 h. After that, acetophenone (0.1 mol, 11.7 ml) was added and the reaction mixture was heated to reflux for 4 h, cooled to RT, the solvent removed, 100 ml H2O added. The mixture was extracted with EtOAc

3x50 ml, back washed with brine followed by drying over MgSO4. Removing the solvent under vacuum to give 5.46 as a white solid. Isolated yield 91% (12.3 g, 91 mmol). The product was used directly in the next step without any purification. mp 57-58 oC. (lit.56 58-59 oC). 1H NMR (CDCl3) δ 2.26 (s, 3H, CH3), 7.31-7.36 (m, 3H), 7.55-7.59 (m, 2H), 9.27 (s, 1H, OH). 13C NMR (CDCl3) δ 153.51, 134.01, 126.75, 126.03, 123.53, 9.81. MS (EI+) 136 (M+1), 135 (M, 100%), 134 (M-1), 118, 107, 106, 103, 94, 92, 91, 78, 77, 76, 66, 65, 51. HRMS (EI+) M+ for C8H9NO, found 135.0696, calcd. 135.0684.

NOH

In a 100 ml 3-necked round flask, was placed the above oxime 5.46 (33.5 mmol, 4.52 g), Et3N (36 mmol, 5 ml) and 20 ml of dry DCM. The solution was cooled to –60 oC, a solution of Ph2PCl (33.5 mmol, 6 ml) and 20 ml of DCM was added via a dropping funnel in 30 min, while keeping this temperature for 1 h. Next, the mixture was allowed to warm to RT overnight. The reaction mixture was filtered over an active neutral

Al2O3 column and eluted with EtOAc. After evaporation of the solvent, the product 5.40 was obtained as a light yellow power. Isolated yield 76% (8.1 g, 25 mmol). mp

NP

O Ph

Ph

144

Chapter 5

116-118 oC (lit.25b 128-130 oC). 31P NMR (CDCl3) δ 18.51 (s). 1H NMR (CDCl3) δ 2.91 (d, J = 2.19 Hz, 3H, CH3), 7.35-7.52 (m, 10H), 7.89-7.96 (m, 3H), 8.04 (d, J = 7.33 Hz, 2H). 13C NMR (CDCl3) δ 180.03 (d, J = 7.63 Hz), 137.80 (d, J = 23.65 Hz), 134.54, 131.94, 130.97, 130.40, 130.14, 129.96, 129.90, 127.06, 126.81, 126.43, 21.54 (d, J = 12.59 Hz). HRMS (EI+) M+ for C20H18NOP 319.1139, calcd. 319.1126. Diphenyl-N-(1-phenylethyl)phosphinic amide (5.40H) Racemate, prepared from 5.40 (50 mg, 0.16 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to obtain 5.40H as a light yellow oil. Isolated yield 88% (44 mg, 0.14 mmol). 31P NMR (CDCl3) δ 22.21 (s). 1H NMR (CDCl3) δ 1.57 (d, J = 6.84 Hz, 3H, CH3), 3.21-3.22 (m, 1H, NH), 4.39 (q, J = 6.84 Hz, 1H, CH),

7.20-7.53 (m, 11H), 7.76-7.96 (m, 4H).

NHP

O Ph

Ph

5.40H was added directly to neat Ac2O. After stirring for 15 min, it was diluted with 2-propanol and filtered through a short pipette plugged with silica gel to provide N-acetyl derivative 5.40HA for analytical HPLC (Daicel, chiralpak OD, n-heptane: 2-propanol = 95:5, 1 ml/min, 220 nm), t1 = 10.73 min, t2 = 15.31 min. General procedure for the synthesis of imine 5.41-5.43 In a 50 ml round flask, was placed neat acetophenone or p-substituted acetophenone (64 mmol), glycinamide (60 mmol, 3.6 g) and 10 g dried 4 Å molecular sieves. This mixture was heated to 70 oC for 12 h, cooled, filtered and washed with 50 ml of dry EtOAc. The combined liquids were concentrated to about 20 ml of EtOAc and left in a refrigerator overnight. A light yellow solid precipitate from the solution, which was collected by filtration, washed with cold dry EtOAc and dried under vacuum. 2-{[1-Phenylethylidene]amino}acetamide (5.41) Prepared from acetophenone (64 mmol, 7.5 ml) and glycinamide (60 mmol, 3.6 g),

crystallized from EtOAc to provide 5.41 as a light yellow powder. Isolated yield 39% (4.1 g, 23 mmol). 1H NMR (CDCl3) major isomer: δ 2.26 (s, CH3, 3H), 4.06 (d, J = 5.49 Hz, 2H, CH2), 6.60 (br, 2H, NH2), 7.36-7.44 (m, 3H), 7.77-7.82 (m, 2H); minor

isomer: δ 2.26, 4.05, 7.52-7.56. 13C NMR (CDCl3) major isomer: δ 172.79, 165.85, 138.76, 128.70, 126.84, 125.07, 53.40, 15.34; minor isomer: δ 166.23, 126.46. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 177 (M+1), 176 (M, 2.9%), 175 (M-1), 161, 133, 132 (100%), 117, 104, 103, 92, 91, 77, 65, 58, 51. HRMS (EI+) M+ for C10H12N2O, found 176.0954, calcd. 176.0950.

NO

NH2

145

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

2-{[(E)-1-(4-Methoxyphenyl)ethylidene]amino}acetamide (5.42) Prepared from p-MeO-acetophenone (64 mmol, 9.6 g) and glycinamide (60 mmol, 3.6

g), crystallized from EtOAc to give 5.42 as a light yellow solid. Isolated yield 48% (5.9 g, 29 mmol). 1H NMR (CDCl3) major isomer: δ 2.21 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.99 (s, 2H, CH2), 5.57 (br, 2H, NH2), 6.86 (d, J = 8.78 Hz, 2H),

7.73 (d, J = 8.78 Hz, 2H); minor isomer: δ 2.24, 4.13. 13C NMR (CDCl3) major isomer: δ 172.85, 164.55, 159.78, 130.99, 126.63, 112.06, 53.86, 53.28, 15.03; minor isomer: δ 167.56, 125.98. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 207 (M+1), 206 (M), 191, 163, 162, 147, 135, 134, 132, 122, 121 (100%), 118, 91, 78, 77, 65, 58, 51. HRMS (EI+) M+ for C11H14N2O2, found 206.1059, calcd. 206.1055. 2-{[1-(4-Methoxyphenyl)ethyl]amino}acetamide (5.42H) Racemate, prepared from 5.42 (50 mg, 0.24 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to obtain 5.42H as a light yellow semi-solid. Isolated yield 90% (45 mg, 0.22 mmol). 1H NMR (CDCl3) δ 1.34 (d, J = 6.59 Hz, 3H, CH3), 2.02 (br, 1H, NH), 3.12 (s, 2H, CH2),

3.71 (q, J = 6.59 Hz, 1H, CH), 3.79 (s, 3H, OCH3), 6.13 (br, 1H, NH2), 6.96 (br, 1H, NH2), 6.83-6.89 (m, 2H), 7.17-7.31 (m, 2H). 13C NMR (CDCl3) δ 173.72, 157.27, 134.95, 126.08, 112.45, 56.08, 53.77, 48.68, 22.43. MS (EI+) 209 (M+1), 208 (M), 193, 153, 152, 151, 150, 149, 139, 138, 137, 135, 121, 119, 109, 105, 103, 94, 91, 89, 79, 77, 65, 51. HRMS (EI+) M+ for C11H16N2O2, found 208.1215, calcd. 208.1212. The e.e. determination was performed using an NMR method at DSM, see the end of this paragraph. 2-{[1-(4-Chlorophenyl)ethylidene]amino}acetamide (5.43) Prepared from p-Cl-acetophenone (64 mmol, 8.3 ml) and glycinamide (60 mmol, 3.6 g)

and after crystallization from EtOAc 5.43 was obtained as a light yellow powder. Isolated yield 36% (4.6 g, 22 mmol). 1H NMR (CDCl3) major isomer: δ 2.21 (s, CH3, 3H), 4.01 (s, CH2, 2H), 6.63 (br, 2H, NH2), 7.31-7.34 (m, 2H), 7.68-7.70

(m, 2H); minor isomer: δ 4.06, 7.37-7.40. 13C NMR (CDCl3) major isomer: δ 172.51, 164.31, 136.68, 134.82, 127.01, 126.45, 53.45, 15.23; minor isomer: δ 166.32, 126.50. In 1H and 13C NMR, some resonances of the minor isomer were obscured. MS (EI+) 212 (M+1), 211 (M), 210 (M-1), 195, 169, 168, 167, 166, 154, 151, 139, 138, 137, 131, 127,

NO

NH2

Cl

NO

NH2

O

NHO

NH2

O

146

Chapter 5

126, 125 (100%), 111, 103, 101, 91, 89, 77, 75, 65, 51. 2-{[1-(4-Chlorophenyl)ethyl]amino}acetamide (5.43H) Racemate, prepared from 5.43 (50 mg, 0.24 mmol) and NaBH4 (15 mg, 0.39 mmol) in 4

ml CHCl3 and 1 ml MeOH for 4 h at RT. After addition of water and extraction with CHCl3, the solvent was removed to provide 5.43H as a light yellow semi-solid. Isolated yield 92% (47 mg, 0.22 mmol). 1H NMR (CDCl3) δ 1.33 (d, J =

6.59 Hz, 3H, CH3), 2.13 (br, 1H, NH), 3.09 (s, 2H, CH2), 3.73 (q, J = 6.59 Hz, 1H, CH), 6.35 (br, 1H, NH2), 6.89 (br, 1H, NH2), 7.18-7.32 (m, 4H). 13C NMR (CDCl3) δ 173.54, 141.46, 131.97, 127.25, 126.43, 56.13, 48.66, 22.48. MS (CI+) 214, 213 (100%, M), 170, 168, 154, 141, 139, 75. The e.e. determination was performed using an NMR method at DSM, see the end of this paragraph.

NHO

NH2

Cl

General procedure for asymmetric imine hydrogenation: (a) In a 5 ml autoclave and Endeavor In a 5 ml reaction vial closed with a septum were placed [Ir(COD)Cl]2 (0.005 mmol, 3.4 mg) or other metal precursors (0.01 mmol), enantiopure SPO’s (Ir/L = 1/1, 0.01 mmol; Ir/L = 1/2, 0.02 mmol), imines (0.2 mmol), 2 µl of pyridine and 3 ml of dry toluene or other solvent with a magnetic stirrer bar and a needle through the septum (except Endeavor). 7 or 8 of these small vials were put into the autoclave (or Endeavor) and closed. The autoclave was purged 3 times with N2, 3 times with H2, then set to the desired H2 pressure and stirred for the set time. After reaction, all solvents were removed. Conversions of the reactions were determined by 1H NMR in CDCl3 with a part of the crude products. About 10 mg of the crude products was added to 0.1 ml Ac2O. After stirring for 15 min, the residues were filtered through a pipette with short SiO2 gel plug and washed with 2-propanol to yield N-acetyl derivatives for analytical HPLC. (b) Transformation performed in 96-HTE (at DSM)* Stock solutions of reagents were prepared separately in the reaction solvent, and then transferred to a Lissy (Zinnser) robot for automatic dispensing under inert atmosphere. The vials were then capped and transferred to the 96-HTE,§ purged with N2 (3x), H2 (3x), pressurized with H2 and stirred for the duration of the reaction. After the reaction was complete the results were analyzed as above. Methods of e.e. determination of the hydrogenation products * For a description of the apparatus, see: www.premex-reactorag.ch/e/spezialloesungen/produkteneuheiten.

147

Ir(I) catalyzed hydrogenation of imines using secondary phosphine oxides (SPO’s) as ligands

The e.e.’s of the hydrogenation products were determined by NMR on the free amines or by the HPLC method (Daicel, chiralpak AD or OD column) on their N-acetyl derivatives, respectively. By the NMR method, 2 equivalents of (R)-(+)-mandelic acid were added to the NMR tube as chiral shift reagent and e.e.’s were calculated based on the integral of CH3 group (dd) or CH2 (d) of the products. The disadvantages of this method are: (a) This method requires the use of substantial amounts of CDCl3 when screening a lot of reactions; also it is difficult to run a large amount of samples automatically; (b) They have to be measured with 500MHz NMR; otherwise it is difficult to identify the right peaks; (c) The amount of (R)-(+)-mandelic acid is crucial to obtain well-separated peaks, thus it must be weighed carefully each time, which is time consuming. (d) Sometimes, the e.e. determination by this method is not very accurate. The e.e’s of some hydrogenation products such as 5.41H-5.43H were determined by the NMR method, as it was not possible to measure these by chiral HPLC or other methods. With the HPLC method, it is possible to run many samples automatically and the results are more accurate and more reliable than with the NMR method. The major disadvantage of this method is that in most cases the e.e.’s are determined on their N-acetyl derivatives and not the products directly (no good separation of free amines on HPLC column), which means acetic anhydride has to be added after hydrogenation each time. It is laborious to measure all these samples. Nevertheless, it is much more reliable than the NMR method. 5.6 References and notes 1 Blaser, H.-U.; Spindler, F. in Jacobsen E. N.; Pfaltz, A.; Yamamoto H. eds., Comprehensive Asymmetric Catalysis, 1999, Springer-Verlag, Berlin, Vol. I, chapter 6.2, p248. 2 (a). Collins, A. N. ; Sheldrake, G. N.; Crosby, J. eds., Chirality in Industry: The Commercial Manufacture and Applications of Optical Active Compounds, Wiley, Chichester, Vol I (1992); Vol II (1997). (b). Sheldon, R. A. ed., Chirotechnology: Industrial Synthesis of Optically Active Compounds, Marcel Dekker, New York, 1993. 3 (a). Togni, A.; Breurel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4061. (b). Schnider, P.; Koch, G.; Pretôt, A.; Wang, G.; Bohnen, F. M.; Kruger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887. (c). Zhu, G.; Zhang, X. Tetrahedron: Asym. 1998, 9, 2415. (d). Patent, Bayer, EP0749973, DE10027154, 1998. (e). Xiao, D.; Zhang, X. Angew. Chem. Int. Ed. 2001, 40, 3425. 4 (a). Buriak, J. M.; Osborn, J. A. Organometallics 1996, 15, 3161. (b). see ref. 8, 13. (c). Vastag, S.; Bakos, J.; Toros, S.; Takach, N. E.; King, R. B.; Heil, B.; Marko, L. J. Mol.

148

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Catal. 1984, 22, 283. (d). Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Börner, A. Tetrahedron: Asymm. 1999, 10, 4009. (e). Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26, 763. 5 (a). Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1990, 31, 4117. (b). see ref.11. (c). Fogg, D. E.; James, B. R. Inorg. Chim. Acta 1994, 222, 85. (d). Abdur-Rashid, K.; Lough, A. J.; Morris, R. H. Organometallics 2001, 20, 1047. 6 Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952; ibid, 1992, 114, 7563. 7 (a). Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669. (b). see ref. 12. 8 Lensink, C.; Rijnberg, E.; de Vries, J. G. J. Mol. Catal. A: Chem. 1997, 116, 199. 9 Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 6784. 10 (a). see ref. 6. (b). Campora, J.; Buchwald, S. L.; Gutierrez-Puebla, E.; Monge, A. Organometallics 1995, 14, 2039. 11 Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. 12 Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1997, 493. 13 Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266. 14 (a). Bader, R. R.; Baumeister, P.; Blaser, H.-U. Chimia 1996, 50, 99. (b). Spindler, F.; Pugin, B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.; Blaser, H.-U. in Catalysis of Organic Reactions, Malz, R.E. Jr. ed., Chemical Industries 68, 1996, p 153. 15 Spindler, F.; Blaser, H. -U. Adv. Synth. Catal. 2001, 343, 68. 16 (a). James, B. R. Catalysis Today 1997, 37, 209. (b). Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kang, G. -J.; Rettig, S. J. Inorg. Chem. 1991, 30, 5002. 17 Cheong, C. Y. N.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400. 18 Nogradi, M. ed., Stereoselective Synthesis--A Practical Approach, 2nd edition, VCH, 1995. 19 For a general study of additives effects in Ir-catalyzed asymmetric imine hydrogenation, see ref 3c. 20 Brown, B. R. ed., The Organic Chemistry of Aliphatic Nitrogen Compounds, Oxford University Press, Oxford, 1994; p 205. 21 Kyba, E. P. Org. Prep. Proc. 1970, 2, 149. 22 (a). Weingarten, H.; Chipp, J. P.; White, W. A. J. Org. Chem. 1967, 32, 3246. (b). Moretti, I.; Torre, G. Synthesis 1970, 141. 23 Stetin, C.; de Jeso, B.; Pommier, J. C. Synth. Commun. 1982, 12, 495. 24 (a). Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836. (b). Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin, P. L. E. J. Org. Chem. 1984, 49, 4397. (c). Fukuda, Y.; Matsubara, S.; Utimoto, K. J. Org. Chem. 1991, 56, 5812. 25 (a). Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 4, 270. (b). Kobayashi, T.; Kawate, H.; Kakiuchi, H.; Kato, H. Bull. Chem. Soc. Jpn. 1990, 63, 1937. 26 2-Acetyl pyridine has been reported to react with primary amines to form polymers,

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see: (a). Dong, G.; Pang, K. –L.; Duan, C. –Y.; Cheng, H.; Meng, Q. –J. Inorg. Chem. 2002, 41, 5978. (b). Cordaro, J. G.; McCusker, J. K.; Bergman, R. G. Chem. Comm. 2002, 1496. 27 (a). Van Leeuwen, P. W. N. M.; Roobeek, C. F. Advances in Chemistry Series, 230 (Homogeneous Transition Met. Catal. React.), 1992, 367. (b). Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657. (c). Cobley, C. J.; van den Heuvel, M.; Abbadi, A.; de Vries, J. G. Tetrahedron Lett. 2000, 41, 2467. (d). Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677. (e). Li, G. Y.; Fagan, P. J.; Watson, P. L. Angew. Chem., Int. Ed. 2001, 40, 1513. (f). Li, G. Y. Patent, Du Pont, US6124462, 2000. (g). Li, G. Y. Patent, Du Pont, US6291722 B1, 2001. (h). Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077. 28 It has been suggested that protic solvents are a prerequisite for rhodium- catalyzed imine hydrogenation since the proton of the solvent bound to rhodium aids in shifting the imine from its n bonded form to the π bonded form that is required for its migratory insertion into the Rh-H bond, See: Longley, C.; Goodwin, T. J.; Wilkinson, G. Polyhedron 1986, 5, 1625. 29 (a). See ref. 4c, 16b. (b). Spindler, F.; Pugin, B.; Blaser, H.-U. Angew. Chem. Int. Ed. 1990, 29, 558. 30 Morimoto, T.; Nakajima, N.; Achiwa, K. Synlett 1995, 748. 31 Sablong, R.; Osborn, J. A. Tetrahedron: Asymmetry 1996, 7, 3059. 32 Crabtree R. H. Acc. Chem. Res. 1979, 12, 331. 33 Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles 1996, 43, 2557. 34 (a). Cullen, W. R.; Sugi, Y. Tetrahedeon Lett. 1978, 1635. (b). Uehara, A.; Kubota, T.; Tsuchiya, R. Chem. Lett. 1983, 441. (c). Halpern, J. Pure Appl. Chem. 1983, 55, 99. 35 (a). 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. (b). Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 3111. (c). Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem. Int. Ed. 2003, 42, 790. 36 Guthrie, R. D.; Burdon, L.; Lovell, F. J. Org. Chem. 1973, 38, 3114. 37 Lenz, G. R.; Costanza, C.; Lessor, R. A.; Ezell, E. F. J. Org. Chem. 1990, 55, 1753. 38 Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. 39 Lensink, C.; de Vries, J. G. Tetrahedron: Asymm. 1992, 3, 235. 40 Manrao, M. R.; Sharma, R. C.; Dhir, B. S.; Kalsi, P. S. J. Indian Chem. Soc. 1982, 59, 901. 41 (a). Kang, G. J.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kutbey, J. P. J. Chem. Soc., Chem. Commun. 1988, 22, 1466. (b). Bakos, J.; Orosz, A.; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou, D. J. Chem. Soc., Chem. Commun. 1991, 23, 1684. (c). See ref 16b. 42 Verdguer, X.; Lange, U. E. W.; Buchwald, S. L. Angew. Chem. Int. Ed. 1998, 37, 1103. 43 Patai, S. ed., The Chemistry of Carbon-Nitrogen Double Bond, Interscience, London, 1970.

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44 Hsue, I. J. Chem. Soc. 1935, 1778. 45 Vetter, A. H.; Berkessel, A. Synthesis 1995, 4, 419. 46 Satterthwait, A. C.; Westheimer, F. H. J. Am. Chem. Soc. 1980, 102, 4464. 47 (a). Stadlbauer, W.; Fiala, W.; Fischer, M.; Hojas, G. J. Prakt. Chem. 2000, 342, 33. (b). Barluenga, A. Synthesis 1977, 195. (c). Kim, S. Y.; An, G.; Rhee, H. Synlett 2003, 112. 48 (a). Richey, H. G.; Erickson, W. F. J. Org. Chem. 1983, 48, 4349. (b). Verevkin, S. P.; Morgenthaler, J.; Ruechardt, C. J. Chem. Thermodynamics 1997, 29, 1175. 49 (a). Soloshonok, V. A.; Kirilenko, A. G.; Kukhar, V. P.; Resnati, G. Tetrahedron Lett. 1994, 35, 3119. (b). Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J. Org. Chem. 1996, 61, 6563. 50 (a). Johnson, G. P.; Marples, B. A. Tetrahedron Lett. 1984, 25, 3359. (b). Johnson, G. P.; Marples, B. A. J. Chem. Soc., Perkin Trans. I 1988, 3399. (c). See ref 11. (d). Lopez, R. M.; Fu, G. C. Tetrahedron 1997, 53, 16349. (e). Banik, B. K.; Zegrocka, O.; Banik, I.; Hackfeld, L.; Becker, F. F. Tetrahedron Lett. 1999, 40, 6731. (f). Jun, C. H.; Moon, C. W.; Hong, J. B.; Lim, S. G.; Chung, K. Y.; Kim, Y. H. Chem. Eur. J. 2002, 8, 485. 51 A similar procedure as literature reported: Norton, D. G.; Haury, V. E.; Davis, F. C.; Mitchell, L. J.; Ballard, S. A. J. Org. Chem. 1954, 19, 1054. 52 (a). see ref 38. (b). Artmesto, D.; Esteban, S.; Horspool, W. M.; Martin, J. A. F.; Martinez, A. P.; Perez, O. R. J. Chem. Soc., Perkin Trans I 1989, 751. (c). Knettle, B. W.; Flowers, R. A. Org. Lett. 2001, 3, 2321. 53 (a). Hickmott, P. W.; Sheppard, G. J Chem. Soc. C 1971, 1358. (b). Fraser, R. R.; Banville, J.; Akiyama, F.; Noemi, C. O. Can. J. Chem. 1981, 59, 705. 54 (a). Bard, R. R.; Bunnett, J. F. J. Org. Chem. 1980, 45, 1546. (b). Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195. (c). Blaser, H. -U.; Buser, H. -P.; Häusel, R.; Jalett, H. -P.; Spindler, F. J. Organomet. Chem. 2001, 621, 34. (d). Morimoto, T.; Nakajima, N.; Achiwa, K. Chem. Pharm. Bull. 1994, 42, 1951. 55 Haslego, M. L.; Maryanoff, C. A.; Scott, L.; Sorgi, K. L. Heterocycles 1993, 35, 643. 56 (a). Moehrle, H.; Wehefritz, B.; Steigel, A. Tetrahedron 1987, 43, 2255. (b). Ohwada, T.; Ohta, T.; Shudo, K. Tetrahedron 1987, 43, 297.

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