University of Groningen Rhodium-Catalyzed Asymmetric ...Monodentate Phosphoramidites as Ligands in the Rhodium-catalyzed Asymmetric Hydrogenation of Aromatic Enamides 115 4.2.1.2 Synthesis

University of Groningen

Rhodium-Catalyzed Asymmetric Hydrogenation using Phosphoramidite LigandsBerg, Michel van den

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109

Chapter 4

Monodentate Phosphoramidites as Ligands in the Rhodium-catalyzed Asymmetric Hydrogenation

of Aromatic Enamides1

Abstract The synthesis of several prochiral aromatic enamides and the asymmetric hydrogenation reaction using a cationic rhodium(I) complex [RhL2(COD)]BF4 with chiral phosphoramidites acting as ligands is described. The products were obtained with various degrees of enantioselectivity ranging from 21% up to 99 % e.e.

Chapter 4

110

4.1 Introduction

ue to the importance of chiral amines as resolving agents,2 chiral auxiliaries3 and as key building blocks for pharmaceutical agents3 asymmetric hydrogenation of enamides has been studied over thirty years by now.4,5,6,7,8,9,10,11 Asymmetric

hydrogenation of enamides gives access to enantioenriched acylated amines (Figure 4.1) that can be hydrolyzed to the free chiral amines.12 Development of the rhodium-catalyzed asymmetric hydrogenation of N-acetyl enamides emerged a number of years after the first homogeneous asymmetric hydrogenation of dehydroamino acids with a homogeneous rhodium catalyst was reported.13 Using rhodium with DIOP (Figure 4.2) as chiral ligand in the hydrogenation of N-(1-phenylprop-1-enyl)isobutyramide resulted in full conversion and an enantioselectivity of 85%.4

Figure 4.1 Hydrogenation of an enamide using DIOP as chiral ligand.

Although a promising result, the level of stereo control was lower than that obtained in the hydrogenation of dehydroamino acids where selectivities of over 95% e.e. had been reached.14 Judging from the reports in literature,4-11 aromatic enamides are often the next class of compounds tested once a certain catalytic system has shown good results in the asymmetric hydrogenation of dehydroamino acids. We thus screened a range of enamides in the asymmetric hydrogenation with rhodium complexes and phosphoramidite ligands. The enamides are usually more difficult to hydrogenate (i.e. lower rates) compared to dehydroamino acids,15 consequently higher pressures are required. Burk et al. suggested that the enamides are sterically more demanding substrates compared to the corresponding dehydroamino acids.15 This was concluded after a series of experiments with various DuPHOS and BPE ligands with decreasing steric demand (phospholane 2,5 substituents = Me, Et, Pr, iPr, Cy) which resulted in increasing enantioselectivities. The degree of stereoselectivity obtained is often lower compared to the selectivity in the hydrogenation of dehydroamino acids, and the ligands used therefore need to be optimised for this class of substrates. This is clearly demonstrated by the hydrogenation of N-(3,4-dihydronaphthalen-1-yl)acetamide (7) (see Figure 4.5 for structure) using Me-DuPHOS and Me-BPE as chiral ligands. Enantioselectivities of 1% and 69% were obtained, respectively.16,17 Generally the ligands which provide good to excellent results are bidentate phosphines as can be seen in Figure 4.2.18 For the hydrogenation of endocyclic enamides (e.g. 7) the bidentate phosphine Me-PennPhos is the ligand of choice to induce high enantioselectivities.17

D

O

O

PPh2PPh2

H2

*

HN O HN O

[Rh(C2H4)2Cl]2

Monodentate Phosphoramidites as Ligands in the Rhodium-catalyzed Asymmetric Hydrogenation of Aromatic Enamides

111

Figure 4.2 Typical examples of bidentate chiral ligands that show excellent selectivities in

the hydrogenation of enamides.16,17,18,19 The enamides can be synthesized in various ways: a) Grignard addition to an aromatic nitrile followed by acylation of the magnesium

intermediate.20 b) Reaction of a primary amide with a functionalized carbonyl moiety,21 an acetal or ketal22

in the presence of a catalytic amount of acid. Condensation of a carbonyl moiety with ammonia in the presence of titanium tetrachloride followed by the acylation of the obtained mixture of tautomers (imine/enamine).23

c) Beckmann rearrangement of an unsaturated oxime.24 d) Reduction of oximes in the presence of acetic anhydride.25,26

e) Pyrolysis of 2-acylaminonitriles.27 Up to this day there are only a few methods available which allow the synthesis of enamides in poor to good yields. Two of these closely related methods are reported by Burk16 and Zhang.17 Both methods are developed from the methods described by Barton25 and Zard.26 The enamides were prepared via Burk’s method by the reduction of the corresponding oximes28 with iron powder in the presence of acetic anhydride (4.2.1.1). The heteroaromatic enamides were prepared using the Grignard addition to the corresponding nitrile (4.2.1.2).

P

P

Me-DuPHOS

P

P

Me-BPE

NN

O

Ph2P PPh2

bdpmi

Me-PennPhos Binaphane

DIOP*

O

O

PPh2PPh2

P PMe

MeP P

Me

Me

H2*

HN O HN O

O OPh2P PPh2

spirOP

Chapter 4

112

Figure 4.3 Typical examples of some excellent monodentate ligands for the hydrogenation of

enamides.29 Monodentate ligands have been used in the rhodium-catalyzed asymmetric hydrogenation of enamides with excellent results. These ligands are primarily phosphites and phosphoramidites and are depicted in Figure 4.3. The results obtained using these ligands in the rhodium-catalyzed hydrogenation of N-(1-phenylvinyl)acetamide are shown in Table 4.1.

Table 4.1 Rhodium-catalyzed hydrogenation of N-(1-phenylvinyl)acetamide using monodentate ligands.29

entry L* cat. (%) sol. pH2 (bar) t (h) T e.e. (%)

1 X1 0.2 CH2Cl2 60 20 30°C 94.9 2 X2 1 THF 20 4 r.t. 95 3 X3 1 CH2Cl2 10 12 r.t. 95 4 X4 2 CH2Cl2 3 24 r.t. 81 5 H8-MonoPhos 1 THF 20 8 -10°C 96 6 SIPHOS 1 toluene 50 12 5°C 98.7

a Rh(COD)2BF4 was used as the catalyst precursor. Full conversion in all cases. b Rh(COD)2OTf was used as the catalyst precursor.

H2*

HN O HN O[Rh(COD)2]BF4 / L*

solvent

OOO

O

O O

OO

POO

P N

OO

P N

OO

P O

O PO

N

OO OO

PO

Ph

SIPHOSH8-MonoPhos

X2X1 X3

X4


113

4.2 Results and Discussion

4.2.1 Substrate synthesis

4.2.1.1 Synthesis of the enamides via oxime intermediates Oxime 2 was synthesized by heating acetophenone (1) and hydroxylamine hydrochloride in dry ethanol under reflux with pyridine as base (Scheme 4.1).28 For the conversion of the oxime into the enamide the Burk’s variant16 of the Barton and Zard25,26 method was used. The reaction requires a carefully controlled temperature below 70 °C in order to suppress product decomposition. This decomposition is also prevented by the introduction of acetic acid into the reaction mixture. The initial product mixture generally also contains the N,N-diacetyl enamide that, by a simple aq. NaOH (2M) wash, is converted into the desired N-monoacetyl enamide. Substrates 3 – 7 and 10 (Scheme 4.1 and Figure 4.1) were prepared with this method with yields ranging from 30% to 70% depending on the ketone used. The low yields are partly due to the decomposition of the products during the reaction and partly due to the purification.

Scheme 4.1 Synthesis of enamides from the corresponding ketone via the oxime.

The conversion of the oxime to the enamide starts by the acylation of the hydroxyl moiety (Scheme 4.2). Subsequently the nitrogen is acylated forming a species with electron deficient nitrogen atom, activating the adjacent methyl. By deprotonation of the α-methyl the carbon-carbon double bond is formed. The final cleavage of the nitrogen oxygen bond is accomplished via a tentative radical mechanism involving the iron.25 Trimethylsilyl chloride is added in a small amount to activate the iron powder. Enamides 5 and 6 were obtained as an E/Z mixture based on 1H NMR and separated by column chromatography. The E-configuration was assigned to substrate 6 based on X-ray crystal structure determination, vide infra. Consequently substrate 5 has the Z-configuration.

pyridine Fe, TMSClToluene

Ac2O, AcOHH2NOH·HCl HN OO N

OH

EtOH1 2 370°C∆

Chapter 4

114

Scheme 4.2 Proposed mechanism for the conversion of the oxime into the enamide.25

Figure 4.4 Crystal structure of 6.

NO

NOH

2

O

Ac2O Ac2ON

O

OO

NO

OO

Fe

N

O

NH

O

3

N

O

Ac2O

NaOH

O

NH

O

6


115

4.2.1.2 Synthesis of the enamides via Grignard addition The synthesis of enamide 8 via the route described in 4.2.1.1 from the corresponding ketone was not successful (Scheme 4.3). The formation of the oxime did not give any problems. However, the conversion of the oxime into the enamide resulted in only a minimal amount of product, determined by 1H NMR, when the reaction was performed at 70°C. Performing the reaction at 40°C and otherwise the same conditions the oxime was partly converted into the enamide, but there was excessive formation of by-products as well. Multiple attempts to isolate the product by column chromatography failed.

Scheme 4.3 Formation of heteroaromatic enamide 8.

Lowering the temperature of this reaction to room temperature resulted in hardly any conversion of the oxime into 8. Facing the problem that temperatures higher than r.t. were necessary for conversion of the oxime into the enamide and temperatures lower than 40°C were necessary to prevent decomposition and formation of side products we decided to use another approach. For the synthesis of the heteroaromatic enamides 8 and 9 the method that had previously been employed by Burk et al. for the preparation of various enamides with moderate to good results was therefore chosen.15 A typical example, the synthesis of furyl-based enamide 8 is shown in Scheme 4.4.

Scheme 4.4 Synthesis of enamides from the corresponding nitrile via a Grignard addition.

This route starts with the conversion of nitrile 11 to imide magnesium bromide 12 via a Grignard addition using MeMgBr in ether. The magnesium salt was then converted into the enamide via a reaction with acetic anhydride at 50 °C. Before the addition of the acetic anhydride the magnesium salt formed in the first step must be finely dispersed in ether. In case there is a large solid mass, only a small part of the salts react and the majority is left unchanged while the part that did react is transformed into an unknown side product.

MeMgBrO ON

OHN O

MgBr

11 12 8

NEt2O

Ac2O

Et2O

pyridine Fe, TMSClToluene

Ac2O, AcOHH2NOH·HCl HN OO N

OH

EtOH8rt - 70°C∆

O O Ox

Chapter 4

116

Table 4.2 Synthesis of the enamides from the corresponding oximes.

enamide yield (%) enamide yield (%)

3 65 7 26 4 30 8b 9 5 30 9b 16 6 28 10 33

a yields are not optimized b synthesis of the enamide from the corresponding nitrile.

In an attempt to enhance the solubility, anhydrous THF was added to the reaction mixture. Unfortunately, the effect on the yield was negligible. Following this synthetic procedure two substrates were synthesized, N-(1-furan-2-yl-vinyl)-acetamide (8) in 9% and N-(1-thiophen-2-yl-vinyl)-acetamide (9) in 16% yield.30

Figure 4.5 Enamide substrates for asymmetric hydrogenation.

4.2.2 Hydrogenation of enamides using phosphoramidites Enamides 3 - 10 were subjected to rhodium-catalyzed asymmetric hydrogenation using phosphoramidite ligands (Scheme 4.5). Various monodentate phosphoramidites derived from BINOL as well as bidentate ligands derived from BINOL were used (Figure 4.6). The catalyst was made in situ using the catalyst precursor ([Rh(COD)2]BF4) also used for the hydrogenation of dehydroamino acids (Chapter 3). The solvents ethyl acetate and dichloromethane were the ones that gave the best results in the hydrogenation of

HN O HN O

Cl

HN O HN O

HN O

OHN O S

HN OHN O

3 4 5 6

7 8 9 10


117

dehydroamino acids. Hydrogen pressures were varied from 5 to 27 bar in order to reach full conversion in an overnight reaction. 1H NMR was used to determine the conversion whereas GC analysis was used to determine the conversion as well as the enantioselectivity.

Scheme 4.5 Rhodium-catalyzed asymmetric hydrogenation of enamides.

Figure 4.6 Ligands tested for use in enamide hydrogenation.

Scheme 4.6 Rhodium-catalyzed hydrogenation of enamide 3.

OO

P N

OO

P N

OO

P N

OO

P NPh

Ph

OO

P NPh

H

N PNP

Ph Ph

NP N POO

OOO

OOO

Ph Ph

(S,R,R) L1 (S,R) L2 (S) L3

(S) L4 (S) L5

(S,R,R,S) L6 (S,S,S,S) L7

H2 15 bar *

HN O HN O[Rh(COD)2]BF4 / L4

3 12CH2Cl2

86% e.e.

H2*R

HN O

R

HN O

R' R'

[Rh(COD)2]BF4 / L*

solvent

Chapter 4

118

Hydrogenation of 3 with a rhodium complex containing L4 at r.t. in dichloromethane under a hydrogen atmosphere of 15 bar resulted in full conversion towards 12 which was isolated with 86% e.e. (Scheme 4.6, Table 4.3 entry 1). Lowering the temperature to -5ºC resulted in an increase in e.e. from 86% to 90 % (entry 2). Using ethyl acetate instead of dichloromethane at -5ºC resulted in a lower enantioselectivity and 12 was obtained with 87% e.e. (entry 3). This difference between the use of ethyl acetate and dichloromethane is not observed when the reaction is performed at r.t. with 27 bar of hydrogen pressure (entries 4-5). Changing the ligand to L3 which has a pyrrolidine instead of a dimethylamino moiety (L4) resulted in full conversion of 3 albeit with a lower enantioselectivity. Product 12 was obtained with 76% e.e. compared to 86% when L4 was used (entries 1 and 6). Using L5, which contains a piperidine moiety, instead of L4 resulted in full conversion with a higher enantioselectivity isolating 12 with 99% e.e. (entry 7). Bidentate phosphoramidites L6 and L7 were used in the hydrogenation of N-(1-(4-chlorophenyl)vinyl)acetamide (4). Ligand L6 which has an ethyl spacer between the two nitrogen atoms gave full conversion of 4; however the enantioselectivity was only modest (56% e.e. entry 8). Use of ligand L7 which has a propyl spacer resulted in only 75% conversion and modest enantioselectivity (45% e.e.) after 20h at 15 bar of hydrogen in dichloromethane (entry 9). Monodentate ligands L1 and L2 with two or one 1-phenylethyl moiety on the nitrogen respectively were also used in the hydrogenation of 4. Rhodium-catalyzed asymmetric hydrogenation using ligand L1 did not give full conversion (23%) after 20h at r.t. with 15 bar of hydrogen with a disappointing enantioselectivity (21% e.e., entry 10). Use of L2 did give full conversion under similar conditions used for L1 and gave a fair e.e. of 54% (entry 11). Ligand L3 with the pyrrolidine moiety used in the hydrogenation of 4 resulted in full conversion after 20h with 5 bar of hydrogen pressure and the product was isolated with 79% e.e. (entry (12). When MonoPhos (L4) was used to hydrogenate 4 in dichloromethane at r.t. with 15 bar of hydrogen full conversion was reached after 1h to give the product with 89% e.e. (entry 13). Increasing the amount of L4 from 2.1 equivalents compared to rhodium to 2.9 equivalents did not change the outcome of the catalysis (entry 14). A small drop in enantioselectivity (89% e.e. to 86% e.e.) was observed when the amount of catalyst with ligand L4 was lowered from 2% to 1% (entries 13-16). An increase in enantioselectivity (87% e.e. to 92% e.e.) was observed when the reaction temperature was lowered to -5ºC (entries 15, 17). The hydrogenation of 4 with L4 works equally well in ethyl acetate as in dichloromethane concluding from the full conversion and 93% e.e. at -5ºC (entry 18). Using 2% of rhodium catalyst with L5 in dichloromethane at r.t. with 5 bar of hydrogen to hydrogenate 4 resulted in full conversion with excellent e.e. (99%, entry 19). Using phosphoramidite ligands with sterically more demanding substituents on the nitrogen (L1, L2, L6 and L7) results in equal to lower conversion and lower enantioselectivities when compared to the ligands with sterically less demanding substituents (L3, L4 and L5) in the hydrogenation of enamide 4.


119

Table 4.3 Results of the hydrogenation of aromatic enamides.

entry sub. S/C ligand L/Rh pH2

(bar) T solv.

time (h)

conv. (%)

e.e. (%)

1 3 50 L4 2.1 15 r.t. CH2Cl2 20 100 86 2 3 50 L4 2.1 15 -5 °C CH2Cl2 20 100 90 3 3 50 L4 2.1 15 -5 °C EtOAc 40 100 87 4 3 100 L4 2.2 27 r.t. CH2Cl2 5 100 83 5 3 100 L4 2.2 27 r.t. EtOAc 5 100 84 6 3 50 L3 2.1 5 r.t. CH2Cl2 20 100 76 7 3 50 L5 2.1 5 r.t. CH2Cl2 20 100 99 8 4 50 L6 2.1 15 r.t. CH2Cl2 20 100 56 9 4 50 L7 2.1 15 r.t. CH2Cl2 20 75 45 10 4 50 L1 2.1 15 r.t. CH2Cl2 20 23 21 11 4 50 L2 2.1 15 r.t. CH2Cl2 20 100 54 12 4 50 L3 2.1 5 r.t. CH2Cl2 20 100 79 13 4 50 L4 2.1 15 r.t. CH2Cl2 1 100 89 14 4 50 L4 2.9 15 r.t. CH2Cl2 3.5 100 89 15 4 100 L4 2.1 15 r.t. CH2Cl2 20 100 87 16 4 100 L4 2.8 15 r.t. CH2Cl2 20 100 86 17 4 100 L4 2.1 15 -5 °C CH2Cl2 20 100 92 18 4 50 L4 2.1 15 -5 °C EtOAc 40 100 93 19 4 50 L5 2.1 5 r.t. CH2Cl2 20 100 99 20 5 20 L4 2.2 5 r.t. CH2Cl2 20 100 82 21 5 30 L4 2.2 10 r.t. CH2Cl2 6 100 85 22 5 50 L4 2.1 15 r.t. CH2Cl2 20 100 84 23 5 50 L4 2.1 15 -5 °C CH2Cl2 20 47 89 24 5 30 L4 2.2 10 r.t. EtOAc 6 100 82 25 5 50 L4 2.1 15 -5 °C EtOAc 40 52 87 26 6 50 L2 2.1 15 r.t. CH2Cl2 20 62 89 27 6 50 L4 2.1 15 r.t. CH2Cl2 20 17 24 28 7 20 L4 2.2 5 r.t. CH2Cl2 24 52 35

a Reactions were performed using the catalyst precursor [Rh(COD)2]BF4 (11). b All products have the (R)-configuration.31

H2*R

HN O

R

HN O

R' R'

[Rh(COD)2]BF4 / L*

Chapter 4

120

Substitution at the β-position of the alkene does not have a major influence as long as the enamine has the Z-configuration. With changing hydrogen pressures from 5 to 15 bar the enantioselectivity hardly changes (82% - 85%) using L4 (entries 20-22). Lowering of the reaction temperature has a beneficial effect on the e.e. (from 85% to 89%), however only 47% conversion was obtained compared to the full reached at r.t. (entries 22, 23). Performing the reaction in ethyl acetate instead of dichloromethane resulted in a similar outcome with respect to conversion as well as enantioselectivity (entries 21, 24 and 23, 25). If, on the other hand, the enamine has an E-configuration the hydrogenation becomes more difficult, longer reaction times or higher pressures are needed and the enantioselectivities are low except when ligand L2 is used (entries 26, 27). In the hydrogenation of E-enamide 6 an isomerization to Z-enamide 5 was observed. After an overnight hydrogenation 8% of 6 was still present along with 30% of 5 together with 62% of product 14 (Table 4.3, entry 26). Whether 6 is first isomerized followed by hydrogenation needs to be examined in more detail. Our findings are in contrast with the published results obtained using a rhodium catalyst with diphosphines like DuPHOS, which can be used to hydrogenate a mixture of 5 and 6 with excellent result (96.6% e.e.).15 The rhodium catalyst containing DuPHOS does not show any sign of interconversion of the E and Z-enamides in deuteration studies.32 The more rigid substrate 7 with an endocyclic double bond does not present the solution to the problem of hydrogenating an enamide with an E-configuration. Generally these cyclic enamides are more difficult to hydrogenate with high enantioselectivity, results range from 1% e.e. using Me-DuPHOS17 to 66% e.e. when using ligand X4.29g Ligands which yield excellent results in the hydrogenation of various cyclic enamides, are Me-BPE16 and Me-PennPhos.17 The stereoselective hydrogenation of the aromatic enamides was further studied by the use of heteroaromatic enamides 8 and 9 (results compiled in Table 4.4). The hydrogenations show comparable or slightly better results when compared to the other aromatic substrates, e.g. 3. For reactions with substrate 9, the positive effect of decreasing temperature on enantioselectivity is much more outspoken in ethyl acetate than it is in dichloromethane (Table 4.4, entries 5 - 8). Surprising is the fact that for hydrogenations of 8 in ethyl acetate the enantioselectivity remains moderate (entries 3 and 4), while for substrate 9 an excellent e.e. of 93% was reached in this solvent (entry 8). Another general trend is that the reactivity in ethyl acetate sharply drops for both substrates when the temperature is lowered (entries 4 and 8). This effect was not observed when dichloromethane was used instead of ethyl acetate. The change of the phenyl group of the enamide into a bulky tert-butyl group leads to the more challenging substrate 10. Although full conversions were reached, the enantioselectivity was only modest (48% e.e., entry 9). When increasing the pressure a slight drop in enantioselectivity was observed from 48% to 43% e.e. (entries 9 - 11). The use of ethyl acetate as solvent provides even worse results, whereas, also a drop in e.e. is observed when the pressure in raised (entries 12 and 13).


121

Table 4.4 Results of the hydrogenation of heteroaromatic and aliphatic enamides.

entry sub. S/C L/Rh pH2 (bar)

T solv. time (h)

conv. (%)

e.e. (%)

1 8 50 2.1 15 r.t. CH2Cl2 20 100 85 2 8 50 2.1 15 -5 °C CH2Cl2 20 100 92 3 8 50 2.1 15 r.t. EtOAc 20 100 69 4 8 50 2.1 15 -5 °C EtOAc 40 23 72 5 9 50 2.1 15 r.t. CH2Cl2 20 100 90 6 9 50 2.1 15 -5 °C CH2Cl2 20 100 94 7 9 50 2.1 15 r.t. EtOAc 20 100 81 8 9 50 2.1 15 -5 °C EtOAc 40 22 93 9 10 20 2.2 5 r.t. CH2Cl2 2 100 48c 10 10 100 2.2 10 r.t. CH2Cl2 6 100 46c 11 10 50 2.1 15 -5 °C CH2Cl2 20 100 43c 12 10 100 2.2 10 r.t. EtOAc 6 100 39c 13 10 50 2.1 15 -5 °C EtOAc 40 62 36c

a Reactions were performed using the catalyst precursor [Rh(COD)2]BF4 (11). b All products had the (R)-configuration unless mentioned otherwise.31 c Product obtained had the (S)-configuration.31

It should be noted that the absolute configuration of the product (18) has the opposite sign compared to the hydrogenation product of the aromatic enamides 3-9.31 Hydrogenation of tBu and aromatic enamides with the aid of (S)-MonoPhos gives the (S)- and (R)-configuration, respectively.31 This is in agreement with earlier observations of a switch of configuration with these substrates upon the use of Rh with Me-DuPHOS16 or tBu-Bis-P*33,34 as catalysts. The coordination of 3 with the rhodium hydride complex of BisP*, Figure 4.7, can occur in a favourable or an unfavourable fashion. The favourable coordination leads to the final product.33

Figure 4.7 Rhodium hydride complexes of BisP* and enamide 3.33

H2*R

HN O

R

HN O[Rh(COD)2]BF4 / L4

PRh

H

P

S

HBut Me

Me tBu

tBu

MeOCHN

PRh

H

P

S

HBut Me

Me tBu

NHCOMe

But

favorable unfavorable

Chapter 4

122

In Scheme 4.7 the rationalization of the difference in absolute configuration of the hydrogenation products of 3 and 10. From 31P and 13C NMR it was concluded that the coordination of enamide 10 the does not involve the coordination of the carbonyl oxygen to the rhodium.33 This in contrast to the coordination of 3 which does involve the chelation of the carbonyl oxygen. This different coordination results in the formation of products with opposite absolute configuration.

Scheme 4.7 Rationalization of the different absolute configurations of the hydrogenation

products of enamides 3 and 10.33 The reversal in absolute configuration has been rationalised by Imamoto et al. by a change in binding of substrate 10 to the rhodium catalyst. The considerable more bulky tert-butyl group prevents it to adopt the same mode of complexation as substrate 3, leading to the opposite configuration after the migratory insertion step of the mechanism.33

4.3 Conclusions The use of monodentate phosphoramidite ligands in the asymmetric hydrogenation of (hetero)aromatic enamides shows that full conversions to the chiral protected amine can be obtained with high enantioselectivities. These substrates are more difficult to hydrogenate compared to the dehydroamino acids, however, by applying a higher hydrogen pressure the products can be formed quantitatively. As was the case with the dehydroamino acid substrates (Chapter 3) the bidentate phosphoramidites are not able to outperform their monodentate analogs. Corresponding to the substrates in Chapter 3 ligand L6 is the best ligand for the use in the hydrogenation of enamides, with e.e.’s up to 99%. This ligand, 1-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)-piperidine, can match itself with the best ligands known in literature, see Table 4.5. For instance, Burk et al. deployed substrate 9 in asymmetric hydrogenation using their ligand (S,S)-Me-DuPHOS and obtained an e.e. of 97.5%. Moreover, several groups reported the use of monodentate phosphoramidites and

PRh

H

P

D

tBu

NHCOMe

Ph

NHO

PRh

S

H

PS

D

PRh

H

PS

D

PRh

P

D

tBu

NHCOMe

Ph

NHO

PRh

S

PS

D H

S

Ph

MeOCHN D

CH2DtBu

H NHCOMe

10

3


123

phosphites with excellent results.11,29c,29e,29f Most of these ligands have a BINOL backbone, which in our case also provides the best chiral induction. The TADDOL moiety is less effective for these substrates.

Table 4.5 Hydrogenation of 3 and 4 compared with reported values.11,19,15,17,18c,18d,29c,29e,29f

Entry Ligand (3), e.e. (%) (4), e.e. (%) 1 Me-PennPhos 75 - 2 spirOP 89 86.1 3 X1 94.9d 95.8d 4 X2 95 - 5 Me-DuPHOS 95.2 - 6 H8-MonoPhos 96.2b - 7 bdpmi 98.5 97.8 8 SIPHOS 98.7c 99.3c 9 DIOP* 98.8 - 10 L6 99 99

a at r.t. unless mentioned otherwise. b -10ºC. c 5ºC. d 30ºC.

4.4 Experimental General remarks: For general information, see Chapter 3. GC measurements were performed either on a HP 5890 A, HP 5890 series II or a HP 6890 gas chromatograph using a flame ionization detector. Ligands L1, L2, L3, L4, L5, L6 and L7 are described in Chapter 3.

Acetophenone oxime (2)28 A mixture of acetophenone (11.7 mL, 100 mmol), hydroxylamine hydrochloride (14.8 g, 213 mmol), and pyridine (15 mL) in ethanol (abs. 150 mL) was refluxed for 3 h and subsequently the ethanol was removed under

vacuum. While stirring vigorously in an ice-bath, ice water (150 mL) was added upon which the oxime crystallized from the solution. These crystals were filtrated, washed with ice water (50 mL) and dried. The product was quantitatively isolated as a white solid, and was used in the next step without further purification. 1H NMR and 13C NMR data were in good agreement with the data in literature.35 All other oximes used to synthesize the various enamides were prepared using this procedure.

NOH

Chapter 4

124

N-(1-Phenylvinyl)acetamide (3)16 To toluene (45 mL) was added acetophenone oxime (2, 4.06 g, 30 mmol), acetic anhydride (8.5 mL, 90 mmol), acetic acid (5.1 mL, 90 mmol) and iron powder -325 mesh (3.36 g, 60 mmol). This mixture was stirred at 70 °C for 4 hours, then allowed to cool down to room temperature and filtered over

Celite® 545 and subsequently washed with toluene (2 × 30 mL). The filtrate was washed with 2N NaOH (2 × 45 mL), dried over MgSO4 and evaporated in vacuo. The product was purified by column chromatography using SiO2 and EtOAc:hexane 2:1 as the eluent. The product was obtained as an off-white solid (3.14 g, 65 %). 1H NMR and 13C NMR data were in good agreement with the data in literature.36

N-(1-(4-Chlorophenyl)vinyl)acetamide (4)16 Compound 4 was synthesized as described for compound 3. The crude product was purified by recrystallization affording a white solid (4.01 g, 30 %).1H NMR (CDCl3) δ 2.03 (s, 3H), 5.06 (s, 1H), 5.67 (s, 1H), 7.31 (s, 4H), 7.44 (s, 1H). 13C NMR (CDCl3, APT) δ 22.7 (s), 102.4 (s), 125.9

(s), 127.2 (s), 132.9 (s), 135.1 (s), 138.2 (s), 168.0 (s). EI-MS m/z = 51 (4), 75 (9), 138 (82), 153 (100), 195 (65) [M]+·; HRMS (EI+) calculated for C10H10NOCl: 195.0451, found: 195.0451.

(Z)-N-(1-Phenylbut-1-enyl)acetamide (5)16 & (E)-N-(1-phenylbut-1-enyl)acetamide (6)16 Compound 5 and 6 were synthesized as described for compound 3. The crude mixture of 5 and 6 was purified by column chromatography using SiO2 and EtOAc:hexane 2:1 as the eluent affording two white solids (5,

5.72 g 30 %; 6, 5.07 g, 28 %). 1H NMR and 13C NMR data of the E/Z-mixture were in good agreement with the data in literature.15

N-(3,4-Dihydronaphthalen-1-yl)acetamide (7)16 Compound 7 was synthesized as described for compound 3. The crude product was purified by precipitation with ether affording a white solid (0.22 g, 26 %). 1H NMR and 13C NMR data were in good agreement with the data in literature.37

N-(1-(Furan-2-yl)vinyl)acetamide (8)15 To a solution of methylmagnesium bromide (3M, 16.7 mL, 50 mmol) in anhydrous ether (60 mL) was added dropwise a solution of 2-furonitrile (3.9 mL, 45 mmol) in anhydrous ether (20 mL). After addition, 5 mL of THF

was added to the mixture to dissolve the formed magnesium salts. The mixture was left stirring for about 2 hours until a finely dispersed suspension had formed. To this suspension a solution of acetic anhydride (4.7 mL, 50 mmol) in anhydrous ether (25 mL) was added dropwise and stirring was continued for another 2.5 hours. Methanol (~ 70 mL) was added to

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obtain a clear solution followed by the addition of water (200 mL). The product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo. The crude product was purified by column chromatography over silica gel with hexane:EtOAc 4:1 as the eluent. The product was obtained as a yellowish solid (0.62 g, 9 %).1H NMR and 13C NMR data were in good agreement with the data in literature.15

N-(1-(Thiophen-2-yl)vinyl)acetamide (9)15 Compound 9 was synthesized as described for compound 8. The crude product was purified by column chromatography affording a greenish solid (0.45 g, 16 %). 1H NMR and 13C NMR data were in good agreement with

the data in literature.15

N-(3,3-Dimethylbut-1-en-2-yl)acetamide (10)16 Compound 10 was synthesized as described for compound 3. The crude product was purified by precipitation with hexane from toluene affording colourless crystals (1.40 g, 33 %). 1H NMR and 13C NMR data were in good

agreement with the data in literature.16

(R)-N-(1-Phenylethyl)acetamide (12) This product was obtained after hydrogenation of substrate 3 using method D, see Chapter 3. E.e. determination by GC analysis: CP Chirasil-Dex CB (25 m × 250 µm × 0.25 µm), N2-flow: 1.3 mL/min., 140 °C isothermal, Tr = 15.8 min. (S), Tr = 16.7 min. (R). 1H NMR and 13C NMR data were in good

agreement with the data in literature.38

(R)-N-(1-(4-Chlorophenyl)ethyl)acetamide (13) This product was obtained after hydrogenation of substrate 4 using method D, see Chapter 3. E.e. determination by GC analysis: Supelco β-Dex (30 m × 250 µm × 0.25 µm), N2-flow: 1 mL/min., 150 °C 20 min. heating 2 °C/min. to 170 °C 30 min., cooling 10 °C/min. to 150 °C, Tr =

47.7 min. (S), Tr = 48.5 min. (R). 1H NMR data was in good agreement with the data in literature.39

(R)-N-(1-Phenylbutyl)acetamide (14) This product was obtained after hydrogenation of substrate 5 or 6 using method D, see Chapter 3. E.e. determination by GC analysis: CP Chirasil-Dex CB (25 m × 250 µm × 0.25 µm), N2-flow: 1.3 mL/min., 130 °C isothermal, Tr = 39.4 min. (S), Tr = 41.0 min. (R). 1H NMR and 13C NMR

data were in good agreement with the data in literature.15

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(R)-N-(1,2,3,4-Tetrahydronaphthalen-1-yl)acetamide (15) This product was obtained after hydrogenation of substrate 7 using method D, see Chapter 3. E.e. determination by GC analysis: CP Chirasil-Dex CB (25 m × 250 µm × 0.25 µm), N2-flow: 1.3 mL/min., 170 °C isothermal, Tr = 14.0 min. (S), Tr = 15.4 min. (R). 1H NMR data was in good agreement with

the data in literature.40

(R)-N-(1-(Furan-2-yl)ethyl)acetamide (16) This product was obtained after hydrogenation of substrate 8 using method D, see Chapter 3. E.e. determination by GC analysis: Supelco β-Dex (30 m × 250 µm × 0.25 µm), N2-flow: 1 mL/min., 140 °C isothermal, Tr = 14.1

min. (S), Tr = 14.5 min. (R). 1H NMR and 13C NMR data were in good agreement with the data in literature.15

(R)-N-(1-(Thiophen-2-yl)ethyl)acetamide (17) This product was obtained after hydrogenation of substrate 9 using method D, see Chapter 3. E.e. determination by GC analysis: Supelco β-Dex (30 m × 250 µm × 0.25 µm), N2-flow: 1 mL/min., 140 °C 20 min. heating 10

°C/min. to 180 °C, cooling 10 °C/min. to 140 °C, Tr = 24.8 min. (S), Tr = 25.3 min. (R). 1H NMR and 13C NMR data were in good agreement with the data in literature.15

(S)-N-(3,3-Dimethylbutan-2-yl)acetamide (18) This product was obtained after hydrogenation of substrate 10 using method D, see Chapter 3. E.e. determination by GC analysis: CP Chirasil-Dex CB (25 m × 250 µm × 0.25 µm), N2-flow: 1.3 mL/min., 100 °C isothermal, Tr = 12.8 min.

(S), Tr = 13.9 min. (R). 1H NMR data was in good agreement with the data in literature.41

4.5 Crystal structure determination A crystal with the dimensions of 0.45 × 0.11 × 0.10 mm was mounted on top of a glass fiber, by using inert-atmosphere handling techniques, and aligned on a Bruker42 SMART APEX CCD diffractometer (platform with full three-circle goniometer). The diffractometer was equipped with a 4K CCD detector set 60.0 mm from the crystal. The crystal was cooled to 100(1) K using the Bruker KRYOFLEX low-temperature device. Intensity measurements were performed using graphite monochromated Mo-Kα radiation from a sealed ceramic diffraction tube (SIEMENS). Generator settings were 50 KV/ 40 mA. SMART was used for preliminary determination of the unit cell constants and data collection control. The intensities of reflections of a hemisphere were collected by a combination of 3 sets of exposures (frames). Each set had a different φ angle for the crystal and each exposure

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covered a range of 0.3° in ω. A total of 1800 frames were collected with an exposure time of 10.0 s per frame. The overall data collection time was 8.0 h. Data integration and global cell refinement was performed with the program SAINT. The final unit cell was obtained from the xyz centroids of 4653 reflections after integration. Intensity data were corrected for Lorentz and polarization effects, scale variation, for decay and absorption: a multi-scan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS),43 and reduced to Fo2. The program suite SHELXTL was used for space group determination (XPREP).42 The unit cell44 was identified as orthorhombic; reduced cell calculations did not indicate any higher metric lattice symmetry45 The |E| distribution statistics were indicative of a non-centrosymmetric space group46 The space group P212121, was derived from the systematic extinctions. Examination of the final atomic coordinates of the structure did not yield extra metric symmetry elements.47,48 The structure was solved by direct methods SIR-97.49 The positional and anisotropic displacement parameters for the non-hydrogen atoms were refined. A subsequent difference Fourier synthesis resulted in the location of all the hydrogen atoms, which coordinates and isotropic displacement parameters were refined. Final refinement on F2 carried out by full-matrix least-squares techniques converged at wR(F2) = 0.0855 for 2462 reflections and R(F) = 0.0383 for 2191 reflections with Fo ≥ 4.0 σ(Fo) and 187 parameters. A final difference Fourier map did not show residual peaks outside the range ±0.21(4) e/Å3. The absolute configuration of the structure of the crystal could not be determined reliably (there are only elements in the structure with very small anomalous effects by the used X-ray wavelength): the Flack's50,51,52,53 refinement gave an ambiguous result (x = 0.4(14)). The positional and anisotropic displacement parameters for the non-hydrogen atoms and isotropic displacement parameters for hydrogen atoms were refined on F2 with full-matrix least-squares procedures minimizing the function Q = ∑h[w(│(Fo2) - k(Fc2)│)2], where w = 1/[σ2(Fo2) + (aP)2 + bP], P = [max(Fo2,0) + 2Fc2] / 3, F0 and Fc are the observed and calculated structure factor amplitudes, respectively; ultimately the suggested a (=0.0423) and b (= 0.1173) were used in the final refinement. Crystal data and numerical details on data collection and refinement are given in Table 4.6. Neutral atom scattering factors and anomalous dispersion corrections were taken from International Tables for Crystallography.54 All refinement calculations and graphics were performed on a Pentium III / Debian-Linux computer at the University of Groningen with the program packages SHELXL55 (least-square refinements) and PLATON56 package (checking the final results for missed symmetry with the MISSYM option, solvent accessible voids with the SOLV option, calculation of geometric data and the ORTEP56 illustrations).

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Table 4.6 Crystal data and details of the structure determination.

(E)-N-(1-phenylbut-1-enyl)acetamide (6) formula C12H15NO formula weight 189.26 F(000) 408 crystal system orthorhombic temperature (K) 100(1) crystal color, habit colorless, needle θ range (deg) 2.65-27.50 size (mm) 0.45 × 0.11 × 0.10 data collected (h,k,l) -11:11, -13:13, -14:14 space group P212121, (No19)57 min. and max. transm. 0.9673–0.9926 a (Å) 9.0712(7) refl. collected / unique 9351/2191 b (Å) 10.7364(9) observed refl. 2191 (Fo ≥ 4.0 σ (Fo) c (Å) 10.9977(9) R(F) (%) 3.83 V (Å3) 1071.09(15) wR(F2) (%) 8.55 Z 4 GoF 1.030 ρcalc (g.cm-3) 1.174 weighting a, b 0.0423, 0.1173 µ(Mo-Kα) (cm-1) 0.74 parameters refined 187

4.6 References and Notes 1 a) Robert M. Haak (MSc) is gratefully acknowledged for carrying out part of the research described in this chapter. b) A. Meetsma (MSc) is gratefully acknowledged for carrying out the X-ray determination. 2 J. Jacques, A. Collet, S.H. Wilen in Enantiomers, Racemates and Resolutions, Wiley, New York, 1981. 3 M. Nógrádi in Stereoselective Synthesis, 2nd ed., Weinheim, Germany, 1995. 4 H.B. Kagan, N. Langlois, T.P. Dang, J. Orgmet. Chem. 1975, 90, 353. 5 D. Sinou, H.B. Kagan, J. Orgmet. Chem. 1976, 114, 325. 6 T. Morimoto, M. Chiba, K. Achiwa, Chem. Pharm. Bull. 1992, 40, 2894. 7 N.E. Lee, S.L. Buchwald, J. Am. Chem. Soc. 1994, 116, 5985. 8 F.-Y. Zhang, C.-C. Pai, A.S.C. Chan, J. Am. Chem Soc. 1998, 120, 5808. 9 W. Hu, M. Yan, C.-P. Lau, S.M. Yang, A.S.C. Chan, Tetrahedron Lett. 1999, 40, 973-976. 10 Y.-Y. Yan, T.V. RajanBabu, Org. Lett. 2000, 2, 4137. 11 A.-G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.X. Wang, Q.-L. Zhou, Ang. Chem. Int. Ed. 2002, 41, 2348. 12 P.J. Palmer, R.B. Trigg, J.V. Warrington, J. Med. Chem. 1971, 14, 1228. 13 a) W.S. Knowles, M.J. Sabacky, J. Chem. Soc. Chem. Commun. 1968, 1445. b) W.S. Knowles, Acc. Chem. Res. 1983, 16, 106. c) L. Horner, H. Siegel, H. Büthe, Angew. Chem. Int. Ed. Engl. 1968, 7, 942. 14 a) B.D. Vineyard, W.S. Knowles, M.J. Sabackey, G.L. Bachman, D.J. Weinkauff, J. Am. Chem. Soc. 1977, 99, 5946. b) G.W. Parshall, R.E. Putscher, J. Chem. Educ. 1986, 63, 189.


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15 M.J. Burk, Y.M. Wang, J.R. Lee, J. Am. Chem. Soc. 1996, 118, 5142. 16 M.J. Burk, G. Casy, N.B. Johnson, J. Org. Chem. 1998, 63, 6084. 17 Z. Zhang, G. Zhu, Q. Jiang, D. Xiao, X. Zhang, J. Org. Chem. 1999, 64, 1774. 18 a) Z. Zhang, G. Zhu, Q. Jiang, D. Xiao, X. Zhang, J. Org. Chem 1999, 64, 1774. b) D. Xiao, Z. Zhang, X. Zhang, Org. Lett. 1999, 1, 1679. c) W. Li, X. Zhang, J. Org. Chem. 2000, 65, 5871. d) S.-G. Lee, Y.J. Zhang, C.E. Song, J.K. Lee, J.H. Choi, Ang. Chem. Int. Ed. 2002, 41, 847. 19 W. Hu, M. Yan, C.-P. Lau, S.M. Yang, A.S.C. Chan, Tetrahedron Lett. 1999, 40, 973. 20 Y. Heng Suen, A. Horeau, H.B. Kagan, Bull. Soc. Chim. Fr. 1965, 1454. 21 U. Zehavi, D. Ben-Ishai, J. Org. Chem. 1961, 26, 1097. 22 D. M. Colvin, B.C. Uff, J.W. Lewis, Tetrahedron Lett. 1966, 7, 6079. 23 H. Ahlbrecht, G. Rauchschwalbe, Tetrahedron Lett. 1971, 12, 4897. 24 G. Rosenkranz, O. Mancera, F. Sondheimer, C. Djerassi, J. Org. Chem. 1956, 21, 520. 25 R.B. Boar, J.F. McGhie, M. Robinson, D.H.R. Barton, D.C. Horwell, R.V. Stick, J. Chem. Soc., Perkin Trans. I 1975, 1237. 26 D.H.R. Barton, S.Z. Zard, J. Chem. Soc., Perkin Trans. I 1985, 2191. 27 P. Kurtz, H. Disselnkötter, Liebigs Ann. 1972, 764, 69. 28 A.I. Vogel in Vogel‘s Textbook of Practical Organic Chemistry 5th ed. (Eds: B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell), Longman, London, 1989, pp 1259. 29 a) X. Jia, R. Guo, X. Li, X. Yao, A.S.C. Chan, Tetrahedron Lett. 2002, 43, 5541. b) M. van den Berg, R.M. Haak, A.J. Minnaard, A.H.M. de Vries, J.G. de Vries, B.L. Feringa, Adv. Synth. Catal. 2002, 344, 1003. c) M.T. Reetz, G. Mehler, A. Meiswinkel, T. Sell, Tetrahedron Lett. 2002, 43, 7941. d) A.-G. Hu, Y. Fu, J.-H. Xie, H. Zhou, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2002, 41, 2348. e) X. Jia, X. Li, L. Xu, Q. Shi, X. Yao, A.S.C. Chan, J. Org. Chem. 2003, 68, 4539. f) X. Li, X. Jia, G. Lu, T.T.-L. AU-Yeung, K.-H. Lam, T.W.H. Lo, A.S.C. Chan, Tetrahedron: Asymmetry 2003, 14, 2687. g) P. Hannen, H.-C. Militzer, E.M. Vogl, F.A. Rampf, Chem. Commun. 2003, 2210. h) M. van den Berg, A.J. Minnaard, R.M. Haak, M. Leeman, E.P. Schudde, A. Meetsma, B.L. Feringa, A.H.M. de Vries, C.E.P. Maljaars, C.E. Willans, D. Hyett, J.A.F. Boogers, H.J.W. Henderickx, J.G. de Vries, Adv. Synth. Catal. 2003, 345, 308. i) H. Huang, Z. Zheng, H. Luo, C. Bai, X. Hu, H. Chen, Org. Lett. 2003, 5, 4137. 30 Burk had a yield of 15% for the synthesis of enamide 9 indicating that the low yields obtained for this reaction are inherent to the reaction used. 31 Enantiopure samples of (S)-1-phenylethylamine, (S)-3,3-dimethyl-2-butylamine and (S)-1,2,3,4-tetrahydro-1-naphthylamine were purchased from Lancaster and checked by optical rotation. After acylation these products were used to determine the chiral GC elution order. The absolute configurations of the other products were determined through analogy of elution order on chiral GC. 32 a) M.J. Burk, J.E. Feaster, W.A. Nugent, R.L. Harlow, J. Am. Chem. Soc. 1993, 115, 10125. b) M.J. Burk, M.F. Gross, J.P. Martinez, J. Am. Chem. Soc. 1995, 117, 9375. 33 I.D. Gridnev, N. Higashi, T. Imamoto, J. Am. Chem. Soc. 2000, 122, 10486.

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34 I.D. Gridnev, M. Yasutake, N. Higashi, T. Imamoto, J. Am. Chem. Soc. 2001, 123, 5268. 35 a) J.R. Hwu, W.N. Tseng, H.V. Patel, F.F. Wong, D.-N. Horng, B.R. Liaw, L.C. Lin, J. Org. Chem. 1999, 64, 2211 b) J.R. Hwu, S.-C. Tsay, Tetrahedron 1990, 46, 7413. 36 a) H.B. Kagan, N. Langlois, T.P. Dang, J. Organomet. Chem. 1975, 90, 353. b) M.R. Johnson, L.R. Sousa, J. Org. Chem. 1977, 42, 2439. 37 G. Zhu, X. Zhang, J. Org. Chem. 1998, 63, 9590. 38 P. López-Serrano, J.A. Jongejan, F. van Rantwijk, R.A. Sheldon, Tetrahedron: Asymmetry 2001, 12, 219. 39 X.-P. Hu, Z. Zheng, Org. Lett. 2004, 6, 3585. 40 G. Zhu, X. Zhang, J. Org. Chem. 1998, 63, 9590. 41 J.P. Idoux, J.M. Scandrett, J.A. Sikorski, J. Am. Chem. Soc. 1977, 99, 4577. 42 Bruker. SMART, SAINT, SADABS, XPREP and SHELXTL/NT. Area Detector Control and Integration Software. Smart Apex Software Reference Manuals. Bruker Analytical X-ray Instruments. Inc., Madison, Wisconsin, 2000, USA. 43 G.M. Sheldrick SADABS. Version 2. Multi-Scan Absorption Correction Program, University of Göttingen, 2001, Germany. 44 A.J.M. Duisenberg, J. Appl. Cryst. 1992, 25, 92. 45 A.L. Spek, J. Appl. Cryst. 1988, 21, 578. 46 M.R. Snow, E.R.T. Tiekink, Acta Cryst. 1988, B44, 676. 47 Y. Le Page, J. Appl. Cryst. 1987, 20, 264. 48 Y. Le Page, J. Appl. Cryst. 1988, 21, 983. 49 A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo, A. Guagliardi, A.G.G. Moliterni, G. Polidori, R. Spagna, J. Appl. Cryst. 1999, 32, 115. SIR-97. A Package for crystal structure solution by direct methods and refinement. University of Bari, University of Perugia and University of Roma, Italy. 50 H.D. Flack, Acta. Cryst. 1983, A39, 876. 51 H.D. Flack, G. Bernardinelli, Acta Cryst. 1999, A55, 908. 52 H.D. Flack, G. Bernardinelli, J. Appl. Cryst. 2000, 33, 1143. 53 R. Herbst-Irmer, G.M. Sheldrick, Acta Cryst. 1998, B54, 443. 54 International Tables for Crystallography Vol. C. (Ed.: A.J.C. Wilson), Kluwer Academic Publishers, Dordrecht, 1992, The Netherlands. 55 G.M. Sheldrick SHELXL-97. Program for the Refinement of Crystal Structures, University of Göttingen, 1997, Germany. 56 A.L. Spek, PLATON. Program for the Automated Analysis of Molecular Geometry (A Multipurpose Crystallographic Tool). Version of Febr. 2002 University of Utrecht, 2002, The Netherlands. 57 International Tables for Crystallography 1983, Vol. A. Space-group symmetry, Ed. T. Hahn. Dordrecht: Reidel. (Present distributor Kluwer Academic Publishers, Dordrecht).

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