University of Groningen

Manganese complexes as catalysts in epoxidation reactionsla Crois, Rene

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15

CHAPTER 2

Ligand Synthesis

2.1 Introduction

The activity and selectivity of oxidation catalysts depend to a large extent on thenature of the ligands. Fine tuning of steric and electronic requirements often is essential toaccomplish efficient oxygen transfer. In chapter 4, it will be shown that various ligands canbe used in epoxidation reactions catalyzed by manganese complexes. Steric and electronicaspects of the ligands and complexes will not be discussed here but in the context of theoxidation activity. The synthesis and characterization of the ligands is the subject of thischapter. As will become clear in the following chapters, we mainly focussed on usingtetradentate pyridine/phenol type ligands with imine or amine functionalities, which have notbeen used as such in the past. A few ligands have been made that required new buildingblocks and some were synthesized just for the beauty of their structure .

The intention is to design and prepare new ligands which are able to stabilizecomplexes that allow selective epoxidation of olefins, primarily with cheap oxidants likeH2O2. The second goal is enantioselective oxidation of alkenes, which will be the subject ofchapter 5.

N

N

N

N

NH

N

O

NH

HN

O

ON

N

N

N

N

NN

N

NN

N N

N

N

N N

NN

1

Figure 2.1 Ligands containing one coordination moiety per ‘arm’ and N4Py 1,containing the di-(2-pyridyl)methyl amine moiety

Chapter 2

16

The di-(2-pyridyl)methylamine moiety, found in several ligands published earlier byour group, is quite a unique tridentate structural element.1 The attachment of one coordinatingmoiety e.g. a picolyl moiety, to the central nitrogen atom gives rise to a tetradentate ligand.Most other ligands contain only one coordination moiety per arm attached to the nitrogenatom (Figure 2.1).2

The primary amine function in di-(2-pyridyl)methylamine is available for a variety ofmodifications such as alkylation and reductive amination. Reductive amination is the methodof choice, since non reductive alkylation leads not only to mono-alkylated product but alsodialkylated products and even quaternary ammonium compounds (Scheme 2.1, reaction a).3

Moreover, pyridine nitrogen is not inert under most alkylation conditions and highly coloredspecies produced on alkylation of pyridine nitrogen are formed using reactive alkyl halides asthe alkylating reagents.4

The introduction of alkyl groups on the primary amine can be performed by reductiveamination by first formation of the imine followed by reduction (Scheme 2.1, reaction b) in aone-pot synthesis or in a two step fashion.5 The imines themselves are often easy to isolate asthey crystallize from the reaction mixture. Reduction of the imines proceeds cleanly withNaBH4 in ethanol or methanol, and purification is not necessary in most cases. If themultidentate ligands are not sufficiently pure after reduction, purification is often a problemsince the polarity of the compounds and the molecular weight are too high to allowdistillation. Column chromatography on silica or alumina is also often difficult due toextensive ‘tailing’, probably caused by hydrogen bonding to the stationary phase. Solventresidues are particularly hard to remove from these compounds that are usually viscous oils.

R NH2 R' CHO+ R NR'

RHN

R'

RHN

R'

R NR'

R'' CHO

R NR'

R''

RHN

R'R'' CH2OH+

R NR'

R'' R''HO

+

b

c

d

R NH2 RHN

R'R N

R'

R'aR'+ R N

R'

R'R'

+ +X

NaBH4

Scheme 2.1 Alkylation of amines

The introduction of a second alkyl group (R”CH2) on the secondary amine can alsoproceed via a reductive amination procedure (Scheme 2.1, reaction c) but only one potprocedures are available. Methods include reducing reagents such as NaBH3CN19 andrecently a method was published using NaBH(OAc)3.

6 There is, however, a delicate balancebetween reduction of the intermediate iminium ion and reduction of the aldehyde or ketone

Ligand Synthesis

17

(Scheme 2.1, reaction d) and conditions have to be chosen carefully. The secondary aminemoiety suffers often from severe steric hindrance and the iminium ions, especially the onesformed with ketones or bulky aldehydes, are obviously not formed quantitatively, if they areformed at all. In the latter cases the preferred method of introducing an alkyl group isalkylation with an alkyl halide.

2.2 Pentadentate nitrogen-donor ligands

In our group the design of functional mimics for iron-bleomycine is a subject of studyand for this reason model compounds have been developed.1,16,28 The most prominentexample of these mimics is the N4PyFe system 2 in which the metal is surrounded by apentadentate 5N donor set (Figure 2.2, 1 and 2). The ligand 5Py 3 has been developedrecently and the Fe complex showed similar behavior in catalytic oxidations.16

Fe

N NN

NN N

NN

NN N

N

N N

N N

H3CO OCH3

1 2 3

2+

Figure 2.2 N4Py, the [FeN4PyCH3CN]2+ cation and 5Py

The synthesis of N-[di(2-pyridyl)methyl]-N,N-bis(2-pyridylmethyl)amine, the N4Pyligand 1 , was developed a few years ago by Lubben et al. and is illustrated below (Scheme2.2).1,24

NN

NN N

NN

O

NN

NH2

NN

NOH

NH2OH.HCl

Pyridine

Zn

NH3

2-Picolylchloride

4 5 6

1

5 M aq. NaOH

Scheme 2.2 Synthesis of N4Py 1

Chapter 2

18

Commercially available di-2-pyridyl ketone 4 is converted into the oxime 5, which isreduced with zinc in ammonia.7 The resulting amine 6 is bis-alkylated with 2-picolylchlorideunder basic conditions to give the desired ligand N4Py 1.

2.2.1 Synthesis of N4Py derivatives

The design of chiral analogues of N4Py 1 required a new route towards these ligands.Several chiral amines are readily available in both enantiomeric forms by resolution8 andfurthermore, the use of a chiral variant of 2-picolylamine (vide infra) makes the developmentof a new route desirable. Instead of di-2-pyridylmethylamine 6, di-2-pyridylmethylchloride 8or the corresponding mesylate, derived from alcohol 7, would be suitable synthons (Scheme2.3). Di-(2-pyridyl)methylbromide has already been used in alkylations of aliphatic aminesbut was reported to be rather unstable.9 Di-(2-pyridyl)methylchloride has also been preparedand used in other synthesis but was not obtained pure.10 In this synthesis, starting from di-(2-pyridyl)methanol 7, chloride 8 was obtained by reaction with thionyl chloride and withoutpurification reduced tot di-(2-pyridyl)methane.10 We expected the chloride 8 to be morestable and less reactive than the corresponding bromide since pyridine nitrogen atoms canalso be alkylated when reactive alkylating agents are used.

Di-2-pyridylketone 4 was reduced with NaBH4 in methanol to the correspondingalcohol 7 (92%). Alternatively, alcohol 7 could be prepared by reaction of 2-pyridyl-lithiumwith 2-pyridinecarboxaldehyde although in lower yield (52%). Di-(2-pyridyl)methanol 7 wasconverted into the chloride 8 under Mitsunobu conditions with CCl4 and PPh3 inacetonitrile.11 The latter reaction could be performed on a reasonable large scale (15 g) butyields dropped dramatically (56%) compared to reactions performed on 1 g scale (nearlyquantitative yield). The chloride was stable and could be stored for over 6 months with onlyminor decomposition at room temperature.

NN

O

NaBH4NN

OH

NN

Cl

CCl4, PPh3

CH3CN4 7 892 % 56 %

MeOH

Scheme 2.3 Synthesis of di-2-pyridylmethylchloride

Chloride 8 reacted smoothly and in 50 – 90% yield under mild conditions with avariety of amines: ethanolamine 9, piperazine 12, triamine 14 and bis-picolylamine 11 (50-90%). The latter reaction provided N4Py 1 in 63% yield. The results of the amine alkylationswith chloride 8 and the new ligands prepared by this procedure using this procedure aresummarized in Scheme 2.4. Based on various amine alkylations the chloride 8 has proven tobe a versatile synthon. Also, Schudde has shown that the route given in Scheme 2.4 to N4Py1 and derivatives is highly effective.12 Following this approach, it therefore seemed feasibleto prepare chiral N4Py analogues from chloride 8.

Ligand Synthesis

19

NN

Cl

HN NH

HO

H2N

N

NN

NH

NN

NN

NN N

8

9

12

11

1

13

10OH

N

14

NN

N

15

N

NN

90 % 63%

67 %50 %

NNH

NN

HN

NN

Scheme 2.4 Ligands prepared by alkylation of amines with 2-dipyridylmethylchloride 8

The optically active picolylamine, R-(+)-1-aminoethylpyridine 17a, was synthesizedaccording to Van der Haest et al.13 The odiferous 2-acetylpyridine 16 was converted by aLeuckart reaction into the amine 17, which was subsequently resolved with tartaric acid byrepeated crystallization (4 times) of the diastereomeric salts from ethanol.13,14 The amine 17awas separated from tartaric acid by extraction with diethylether of an aqueous ammoniasolution of the salt. The enantiomeric purity was determined by chiral HPLC (e.e. > 99%).

N

O

N

NH2

N

NH2

*

S,S-(-)-Tartaric acid

N

HN N

NaBH4

16 17 17a

18

2-pyridinecarboxaldehyde

1) CHONH2 HCO2H

2) HCl

Resolution

22 %55 %

86 %

R-(+)-enantiomere.e. > 99%

Scheme 2.5 Synthesis of chiral bis-picolylamine 18

The optically active primary amine 17 could be condensed with 2-pyridinecarboxaldehyde, which was followed by reduction with NaBH4 to give the chiral bis-picolylamine 18. Subsequent reactions were initially performed with racemic bis-picolylamine 18 to find the proper conditions prior to the reaction with optically active 18.

Chapter 2

20

The construction of chiral N4Py based on amine 17a, however, proved difficult andattempts to synthesize a chiral N4Py analogue were also first made with racemic amine 17.Two routes have been investigated (Scheme 2.6). Reaction of 18 with di-(2-pyridine-methyl)chloride 8 under various conditions yielded starting material or complex mixtures.Steric hindrance probably prevents coupling of these compounds. Reaction of 1-aminoethyl-2-pyridine 17 with chloride 8 yielded the desired chiral secondary amine 19. The influence ofthe asymmetric carbon atom in this structure is nicely observed in the 13C-NMR spectra inwhich the carbon atoms of the three pyridyl-moieties all give separate absorptions.Subsequent reaction of secondary amine 19 with 2-picolylchloride gave starting materials orcomplex mixtures. We suspect that also in the latter reaction steric hindrance presents aninsurmountable problem. A chiral tris-2-picolyl amine, a trispyridine analogue of N4Py 1was, however, obtained enantiomerically pure by this route,14 providing a strong indicationthat this assumption is correct.

NN

Cl

N

NH2

NN

HN N

NN

N NNNN

Cl

N

HN N

178

19

18

8

20

2-picolylchloride54 %

Scheme 2.6 Attempted synthesis of chiral N4Py analogue 20

2.2.2 Synthesis of 5Py

Another approach to pentadentate N-donor atom ligands is based on 2,6-bis{methoxy[di(2-pyridyl)]methyl}pyridine 3 (5Py). A similar coordination environment(Figure 2.2) as with N4Py 1 can be created with a ligand, which instead of 4 pyridinemoieties and an aliphatic nitrogen function as in 1, contains 5 pyridine moieties. Moreover,instead of the methoxy functionalities of 5Py 3, other functiononalities at this position mighteasily be used to incorporate the 5Py ligand into various macromolecular structures inapproaches towards synthetic enzymes.15

The 5Py ligand was prepared in a three step procedure starting from pyridine-2,6-dicarboxylic acid 21.16 Conversion of the diacid with SOCl2 to the di-acid chloride 22 was

Ligand Synthesis

21

followed by reaction with excess (6 eq) 2-pyridyllithium 23 and the diol 24 was obtained in20 % isolated yield. The low yield of the reaction arises because the 5Py-diol is a verydifficult to handle compound. The only method of purification is by precipitation. Also, thenucleophilic attack of pyridyllithium proceeds very slowly and the rate of degradation ofpyridyllithium is competitive. Pyridyllithium is only stable at low temperatures. Furthermore,the formation of 5Py diol 24 consists of 4 consecutive reactions. The diol was protected as itsdimethyl ether with methyliodide under basic conditions in THF to give 5 Py 3a.17 The ligand5Py 3a could be purified by crystallization from ethylacetate. Typical resonances in the 1H-NMR spectrum of 5Py 3a are the signals at 8.63 ppm and 3.27 ppm, which are assigned tothe pyridine ortho protons and the methoxy protons respectively.

N

N N

N N

HO OH

NOH

O

HO

ON

Cl

O

Cl

O N Li

N

N N

N N

H3CO OCH3

SOCl2

NaH

MeI

21 22

23

24 3a

80 % 20 %

60 %

Scheme 2.7 Synthesis of 5Py 3a

2.2.3 Modification of the 5Py ligand

Both hydroxy groups in 24 are available for modification without altering thechelation properties of the ligand. Attachment of a suitable spacer would enable the couplingof substrate recognition units to the ligand in our pursuit of artificial enzymes andsupramolecular catalysts.15

The attachment of the substrate recognition units without using a spacer was alsoconsidered but abandoned since both alcohol groups suffer from severe steric hindrance andcoupling at these functional groups with large entities seemed difficult. Moreover, reactionconditions had to be mild since tertiary alcohols at benzylic positions can easily dehydrate togive a relatively stable cation and subsequent reactions.3

Reaction of the bis-sodium salt of 24, obtained after treatment with NaH in DMF,with 1-bromo-2-chloroethane resulted in isolation of starting material, and no reaction wasobserved. We were able to couple 1-bromo-3-chloropropane under similar conditions but 1H-NMR analysis of the reaction mixture revealed incomplete reaction and even in the case ofusing excess (8 eq.) alkyl halide no full conversion was reached. The use of THF as a solventhad no influence on the yield of the reaction. The alkylation using ethylbromoacetate did notoccur either and starting material was recovered.

Chapter 2

22

N

N N

N N

HO OH24

N

N N

N N

O O

Cl Cl3b

N

N N

N N

O O

80oC, 20h

3cClCl

1) NaH

N

N N

N N

O O

OO3dO O

BrO

O

incomplete reaction

2) BrCl

1) NaH

Cl Br2)

1) NaH

2)

Scheme 2.8 Attachment of spacers to the 5Py ligand

Introduction of an alkyl spacer by the use of more reactive alkylating agents was moresuccessful (Scheme 2.9). Alkylation of the disodium salt of 24 with allylbromide or benzylbromide under similar conditions employed in the methylation of 24, resulted in quantitativeformation of the desired products 3e and 3f. The compounds were obtained pure enough forfurther synthesis. The synthetic route of ligand 3e offers possibilities to introducefunctionalized benzyl spacers to which recognition units might be attached.15

An attempt was made to functionalize ligand 3f by hydroboration and subsequentoxidation of the resulting alkylborane to give an alcohol functionality at the terminal positionof the alkyl spacer, as depicted in Scheme 2.9. The alcohol moieties can easily be convertedinto a reactive alkylating moiety or used in a direct coupling reaction. Upon addition ofBH3.THF the reaction mixture turned orange. The color did not change upon addition of basicH2O2 and 1H-NMR spectra of the reaction mixtures displayed broad resonances. It is verylikely that upon addition of borane to 3f stable pyridine-borane complexes are formed and thedesired reaction doesn’t occur. Oxidation of the boron complex at higher temperatures gavealso the orange product indicating that no conversion had taken place.

Ligand Synthesis

23

N

N N

N N

HO OH24

N

N N

N N

O O

3e

3f

N

N N

N N

O O

Br

NaH

NaHBr

N

N N

N N

O O

BH3.THF

NaOH, H2O2

HO OH3g

100 %

95 %

Scheme 2.9 Attachment of alkyl spacers to the 5Py ligand

2.3 Tetradentate pyridine/phenol ligands

In our research towards pentadentate ligands containing pyridine and phenol moieties,tetradendate analogues seem obvious precursors. Moreover, these compounds form a newclass of ligands, which have not been used in catalysis before.

2.3.1 Imine ligands

As shown before, imines are an easy accessible class of compounds are imines,formed from aldehydes and primary amines. Salicylaldehydes form imines with a variety ofprimary amines, usually in a very clean and rapid reaction. The compounds often crystallizedirectly from the reaction mixture and further purification is usually not necessary. Wesynthesized a variety of substituted and unsubstituted imines 25 following this approach.18

The yields obtained in this reaction varied considerably due to solubility differences of theimines in the reaction mixtures. In the 1H-NMR (CDCl3) spectra typical resonances appeararound 6.0 and 8.6 ppm, which correspond to the benzylic proton and the imine protonrespectively.

Chapter 2

24

N N

NN N

NH2 OH

R1 R2

Salicylaldehyde

MeOH

a

b

c

d

e

Compound R1

H

Cl

NO2

MeO

t-Bu

H

H

H

t-Bu

H

R2

6

25

Yield (%)

83

30

85

47

78

Scheme 2.10 Synthesis of the imine ligands

2.3.2 Reduction of imine ligands

The imines described in the former paragraph can easily be reduced to thecorresponding secondary amines 26 (Scheme 2.11). In all cases the amines 26 are very stickyoils that turned into glasses over a long period (months). In a few cases they could besolidified by sonication of an emulsion of the amine in hexane. 1H-NMR spectra of the crudereaction mixtures show no impurities and further purification was therefore not performed.The most typical resonances in the 1H-NMR (CDCl3) spectra appear around 5.0 ppm andstem from the single benzylic proton, and around 3.9 ppm, which are attributed to themethylene protons.

N N

HN

OH

R1 R2

NaBH4

MeOHN N

N

OH

R1 R2

25 26

a

b

c

d

e

Compound R1

H

Cl

NO2

MeO

t-Bu

H

H

H

t-Bu

H

R2 Yield (%)

86

96

99

99

93

Scheme 2.11 Reduction of imine ligands

2.4 Substitution at the secondary amine by reductive alkylation

Alkylation of the central amine has been attempted by a variety of methods. Directalkylation with alkyliodides resulted in no reaction or dark colored mixtures indicatingalkylation on pyridine nitrogen. No evidence (NMR) of alkylation on the aliphatic nitrogenwas found in these cases. Reductive alkylation using aqueous formaldehyde and NaBH3CNresulted only in trace amounts of methylated product 27.19 Nearly quantitative formation ofthe desired methylated product was obtained by a one pot reductive alkylation usingNaBH(OAc)3 in dichloroethane (Scheme 2.12).6 The products 27 could be isolated as oils

Ligand Synthesis

25

which solidified on standing or after sonification in ether or hexanes. The 1H-NMRabsorption (CDCl3) of the methyl group appears around 2.1 ppm, the methylene protons at3.9 ppm and the benzylic proton at 5.0 ppm and integrate for 3, 2 and 1 protons, respectively.

This method was only successful for methylation. Attempts to introduce benzyl orhigher alkyl chains by this method only resulted in isolation of starting materials and alcoholsstemming from the corresponding aldehydes. Also other reductive alkylation methods werenot successful.

N N

N

OH

R1 R2

CH2O, NaBH(OAc)3N N

HN

OH

R1 R2

H3CClCH2CH2Cl

26

a

b

c

d

e

Compound R1

H

Cl

NO2

MeO

t-Bu

H

H

H

t-Bu

H

R2 Yield (%)

81

61

65

51

61

27

Scheme 2.12 Reductive methylation of secondary amines

2.5 Synthesis of pentadentate, pyridyl phenol ligands

A possibly successful ligand in manganese catalyzed epoxidations, as will beexplained in the next chapter, can be a pentadentate ligand in which a similar environment forcoordinated metals is created as in a salen ligand. We therefore designed a ligand with 2pyridine moieties (imines), 2 phenol moieties, and an aliphatic amine acting as the apicalligand necessary in Mn-salen catalyzed epoxidations with H2O2.

20 In addition we wished toinvestigate the effect of replacement of one phenol moiety in the ligand by a pyridine moiety.

A possible route (Scheme 2.13) to both desired compounds 29 and 37 (Scheme 2.18,vide supra) could involve coupling of chloride 8 with a secondary amine as previously usedin the synthesis of N4Py 3 (Scheme 2.4). The synthesis starts with 2-{[(2-pyridylmethyl)amino]methyl}phenol 28, prepared according to literature procedures,21 whichwas coupled to the dipyridine moiety at 85 oC in the presence of diisopropylethylamine.Besides the desired product we found the unexpected byproduct 30, which lacks thecharacteristic signal at 5.0 ppm in the 1H-NMR spectrum for the benzylic hydrogen althoughotherwise the 1H-NMR spectra are as would be expected. The structure of 30 was establishedby independent synthesis according to literature procedures.21

Chapter 2

26

N N

Cl

NH

NOH

N N

N N

N

NOH

+

8

28

29

30

47 %

28 %

NaBH4/salicylaldehyde

CH3CN, K2CO3

OH

OH

Scheme 2.13 Synthesis of pentadentate mono-phenol ligand 29

In an attempt to rationalize the formation of 30, two pathways were considered. In thefirst one 28 or 29 undergoes a retro-Michael reaction in which intermediate 31 is formed.This reaction is followed by a Michael reaction of 28 with 31 to form product 30. Theintermediate o-quinone-methide 31 is known to be formed from salicylic alcohols andderivatives by pyrolysis,22 and has been postulated to be formed from Mannich-bases in aphotochemical reaction.23

O

H2N

NO N

HN

H +

O

OH N

N

H

28

31 32

28 31 30

+

N

NOH

OH

Scheme 2.14 Possible mechanism of the formation of bisphenol 30 via a retro-Michael,Michael addition reaction sequence

Ligand Synthesis

27

The second hypothesis involves a retro-Mannich reaction of a tautomer of 28 (or 29).In this manner an imine is formed of picolylamine 32 and formaldehyde and one equivalentof phenol 33. The imine is hydrolyzed to give picolylamine 32 and formaldehyde, which cansubsequently participate in a Mannich reaction with secondary amine 28 to give 30. Lubbenpostulated this sequence in his thesis after finding similar reactions in his studies onsequential aromatic Mannich reactions but evidence for this mechanism was notestablished.24

O N

N

H

H

OHN

H2N

+

OH N

N

H

CH2O +

OH

Mannich+

2833

CH2O+

32

28

33 30

N

NOH

OH

Scheme 2.15 Possible mechanism of the formation of bisphenol 30 via a retro-Mannich,Mannich reaction sequence.

Since we had no evidence for the actual operating mechanism in the formation of 30we decided to investigate this reaction more thoroughly. If a mechanism like the onepostulated in Scheme 2.15 is operating, evidence would be supplied by an experiment inwhich the phenol moiety is substituted for a substituted phenol moiety in a scramblingexperiment. The retro-Mannich hypothesis would be supported by finding both compounds30 and 35 (Scheme 2.16) after applying reaction conditions similar to the conditions appliedin the synthesis of 29 but now in the presence of p-cresol 34. It might even be possible to findthe Mannich product of picolylamine 32, p-cresol 34 and formaldehyde.

Applying the above mentioned conditions to a mixture of 2-{[(2-pyridylmethyl)amino]methyl}phenol 28 and 0.25 eq of p-cresol 34 yielded a mixture ofcompounds. 1H-NMR signals in the 3.5 – 4.0 ppm region indicated formation ofbis(hydroxybenzyl)picolylamine 30 and very few byproducts.

Chapter 2

28

OH N

N

H N

NOHOH

+

OHN

NOHOH

+

2830

34

35

Mannich-mechanism

Scheme 2.16 Scrambling experiment with p-cresol

CI-MS confirmed formation of the bisphenol 30, (m/z = 321) but bisphenol 35(m/z=335) was not found, so scrambling with p-cresol did not occur. This implies that theretro-Mannich reaction (Scheme 2.15) is not occurring and a retro-Michael reaction (Scheme2.14) is most likely.

NN

NNOH

OH

HO

Figure 2.3. CI-MS of the reaction mixture containing p-cresol.

Reports on substitutions of amine moieties in salicylamines by other amine moietiesare rare in the literature.25 Few authors postulate such a retro-Michael addition mechanism orintermediates like o-quinone-methide 31 in thermal reactions.26 Our findings support such amechanism and a retro-Mannich reaction, as postulated by Lubben,24 is not likely to occur.

N N

N NOH

29

NN

NH2

N N

HN NOAc Br

2) NaBH4 2) K2CO3, MeOH/H2O6

35

1) 2-pyridine carboxaldehyde 36

quant.51 %

Scheme 2.17 Synthesis of tris-pyridine-mono-phenol ligand 29

Ligand Synthesis

29

Since the yield of the synthesis of ligand 29, via the amination of chloride 8 (Scheme2.13) was only moderate due to this side-reaction, we tried another route. Reaction of neatbispyridylmethylamine 8 with pyridine-2-carboxaldehyde followed by reduction with NaBH4

yielded the trispyridine 35.28 The phenol moiety could be attached by reaction with acylprotected o-hydroxy-benzylbromide 36,2a followed by basic hydrolysis of the acetate to yieldthe desired pentadentate ligand 29 (Scheme 2.17).

In a similar fashion, the bisphenol-bispyridylmethylamine 37 was synthesized. Bothligands, 29 and 37 were obtained pure via column chromatography of the acetate protectedligands, obtained after coupling of the protected phenol moiety to the amine, followed byclean hydrolysis of the acetate protective group. No purification was possible afterhydrolysis. Typical resonances in the 1H-NMR spectra of compounds 29 and 37 appeararound 5.3 ppm and 3.9 ppm, which are attributed to the benzylic and methylene protons,respectively.

N N

NOH

37

OAc Br

2) K2CO3, MeOH/H2O

36N N

HN

OH

26a

OH

49 %

Scheme 2.18 Synthesis of bisphenol-bispyridylmethylamine ligand 37

2.6 Conclusions

The chemistry of the di(2-pyridyl)methylamine moiety has been expanded asdescribed in this chapter. Reductive alkylation of the aliphatic nitrogen with formaldehyde ispossible with several pyridine moieties present in the molecule and alkylation proceedsspecific at nitrogen in the presence of phenolic oxygen moieties.

2-[Chloro(2-pyridyl)methyl]pyridine 8 has proven to be a versatile synthon and avariety of ligands were synthesized using this compound. Compounds otherwise difficultlyaccessible were successfully prepared. A route to chiral analogues of these ligands usingchloride 8 and an easily resolvable amine has been found. It was, however, not possible tosynthesize a chiral N4Py analogue by means of this route, possibly due to steric hindranceduring coupling of the amines with chloride 8.

Pentadentate as well as tetradentate ligands with pyridine and phenol moieties havebeen synthesized on a preparative (gram) scale. Mild reaction conditions during synthesisand purification by column chromatography provided the ligands in good yields.

In the coupling reaction of amine 28 with chloride 8 an unexpected transaminationproduct was found. The retrograde Mannich reaction is at least in this case not the operativemechanism of the transamination reaction of the aromatic Mannich base. More likely is theinvolvement of a retrograde Michael addition reaction in which an o-quinone methide 31 isan intermediate.

Chapter 2

30

2.7 Experimental Section

2.7.1 General information.1H-NMR spectra were recorded on a Varian Gemini-200 (at 200 MHz) or on a Varian VXR-300 (at300 MHz). The splitting patterns are designated as follows: s (singlet); d (doublet); dd (doubledoublet); t (triplet); q (quartet); m (multiplet) and br (broad). 13C NMR spectra were recorded on aVarian Gemini 200 (at 50.3 MHz) or on a Varian VXR-300 (at 75.4 MHz) following APT protocol.The splitting patterns are deduced from the sign and chemical shift in the APT spectra and designatedas mentioned. Chemical shifts are denoted in δ-units (ppm) relative to CDCl3 (TMS = 0). Couplingconstants J, are denoted in Hz. Elemental analyses were performed in our laboratory by H. Draayer, J.Ebels and J. Hommes. Merck silica gel 60 (230-400 mesh) was used for filtration and for flashchromatography. The solvents were distilled and dried, if necessary, using standard methods.Reagents and starting materials were used as obtained from Acros Chimica, Aldrich, Fluka or Merck.Reactions were performed under dry nitrogen atmosphere, unless protic solvents were used. Alldrying of solutions and reaction mixtures was performed with Na2SO4. 3,5-di(tert-butyl)-2-hydroxybenzaldehyde,27 2-(bromomethyl)phenylacetate,2a N-(di(2-pyr-idyl)methyl)-N-(2-pyridyl-methyl)amine,28 di(2-pyridyl)methylamine,7 N4Py,1 1-amino-ethyl-2-pyridine,13 N,N-bis(1-pyrrolidinylethyl)amine,29 di-2-pyridyl-ketoxime7, 2-(((2-pyridylmethyl)-amino)methyl)phenol21 weresynthesized according to literature procedures. The e.e. determination of 1-aminoethyl-2-pyridinewas performed by E. van Echten on a Crownpack CR column using aqueous HClO4 as eluens (pH=1).

2.7.2 Synthesis

N-[Di(2-pyridyl)methyl]-N,N-bis(2-pyridylmethyl)amine (1)A mixture of bispicolyl amine 11 (307 mg, 1.54 mmol), chloride 8 (316 mg, 1.54 mmol) and K2CO3

(212 mg, 1.54 mmol) in 3 mL of acetonitrile was refluxed overnight and the solvent was removedunder vacuum. The residue was taken up into 15 mL of water and 15 mL of CH2Cl2 and the mixturewas made alkaline with ammonia (pH = 8). After separation of the layers, the aqueous layer wasextracted thrice with 20 mL CH2Cl2. The combined organic layers were dried and concentrated undervacuum. After column chromatography (neutral alumina ethylacetate:NEt3:hexane = 50:5:33) N4Py 1was obtained as a yellow oil. Yield: 360 mg (0.98 mmol), 63 %. 1H-NMR as well as 13C-NMR spectrawere identical compared to spectra obtained from the compound prepared according to procedures ofLubben et al.1

2,6-Pyridinedicarboxylic acid chloride (22)To a solution of 2,6-pyridinedicarboxylic acid (25.15 g, 0.15 mol) in 100 mL of thionylchloride wereadded a few drops of DMF. The solution was refluxed for 4 h and the excess thionylchloride removedunder vacuum. The resulting solid was recrystallized from hexanes to yield white crystalline material.Yield: 24.7 g (0.12 mol), 80 %. 1H-NMR (200 MHz, CDCl3) δ 8.19 (m, 1H), 8.69 (m, 2H). 13C-NMR

(75.4 MHz, CDCl3) δ 126.53 (d), 136.95 (d), 146.71 (s), 166.89 (s).

(6-(Hydroxy(di(2-pyridyl))methyl)-2-pyridyl)(di(2-pyridyl))methanol (24)To a cooled (–80oC) solution of 2-bromopyridine (14.1 g, 88.89 mmol) in 125 mL THF was slowlyadded n-BuLi in hexanes (35.6 mL, 2.5 M, 88.8 mmol). The temperature was kept below –65oC andstirring continued for another 30 min. To the red reaction mixture was added a solution of 2,6-pyridinedicarboxylic acid chloride 22 (3.0 g, 14.7 mmol) in 25 mL THF over 30 min and the reactionmixture was quenched with 30 mL of methanol and subsequently the mixture was allowed to warm to

Ligand Synthesis

31

room temperature. Next, 30 mL of water and 30 mL of 10 % aq. HCl were added and the layers wereseparated. The aqueous layer was neutralized with NaHCO3 and extracted twice with CH2Cl2. Allorganic layers were combined and dried, the solvents were removed under vacuum and a brown oilwas obtained. Upon addition of acetone an off-white solid separated, which was crystallized fromacetone y and there was obtained an off-white powder. Yield: 1.36 g (3.0 mmol), 20%. 1H-NMR (300MHz, CDCl3) δ 7.57 (m, 15 H), 8.61 (m, 4H). 13C-NMR (75.4 MHz, CDCl3) δ 78.00 (s), 117.34 (d),120.30 (d), 132.98 (d), 134.26 (d), 144.31 (d), 158.42 (d), 159.36 (s). CI-MS: 448 (M + H+).

2,6-Bis{methoxy[di(2-pyridyl)]methyl}pyridine (3a)To a mixture of NaH (310 mg, 60% dispersion in oil, 7.57 mmol) in THF was added diol 24 (800 mg,1.79 mmol), and the solution was stirred for 1 h. Neat MeI (1.08 g, 7.57 mmol) was added and thereaction mixture was refluxed overnight. Ether was added and the reaction mixture was washed withwater. The aqueous layer was extracted twice with 50 mL CH2Cl2. The combined organic layers weredried and solvents were removed under vacuum. Pure product was obtained by recrystallization fromethylacetate. Yield: 0.50 g (1.12 mmol), 60%. 1H-NMR (300 MHz, CDCl3) δ 3.27 (s, 6H), 7.52 (m,

15H), 8.63 (m, 4H). 13C-NMR (75.4 MHz, CDCl3) δ 53.10 (q), 88.36 (s), 121.39 (d), 121.75 (d),124.89 (d), 135.14 (d), 136.82 (d), 148.09 (d), 160.52 (d), 161.23 (s). CI-MS: 476 (M + H+).

2,6-Bis{(benzyloxy)[di(2-pyridyl)]methyl}pyridine (3e)NaH (300 mg, 60% suspension in mineral oil, 7.5 mmol) was washed with pentane and dissolved in25 mL of DMF. Diol 24 (100 mg, 0.22 mmol) was added and the mixture was stirred for 1 h while thesolution turned clear brown. Benzylbromide (151 mg, 0.88 mmol) was added and the reaction mixturewas stirred at 80o C overnight. After the DMF was removed under vacuum, the residue was dissolvedin 100 mL of CH2Cl2 and washed 6 times with 50 mL of water. The organic layer was dried enconcentrated under vacuum. The excess benzylbromide was removed by bulb to bulb distillation toleave the crude product, as a light brown oil, pure enough for further synthesis. Yield: 137 mg (0.22

mmol), 100 %. 1H-NMR (200 MHz, CDCl3) δ 4.30 (s, 4H), 6.95 – 7.60 (m, 25H), 8.40 (d, J = 4.8,

4H). 13C-NMR (75.4 MHz, CDCl3) δ 64.3 (t), 85.8 (s), 119.3 (d), 119.7 (d), 122.1 (d), 124.2 (d), 124.9(d), 125.5 (d), 133.1 (d), 134.1 (d), 136.9 (s), 145.5 (d), 157.8 (s), 159.2 (s).

2,6-Bis{(allyloxy)[di(2-pyridyl)]methyl}pyridine (3f)NaH (300 mg, 60% suspension in mineral oil, 7.5 mmol) was washed with pentane and dissolved in100 mL of DMF. Diol 24 (1.0 g, 2.2 mmol) was added and the mixture was stirred for 1 h while thesolution turned clear brown. Allylbromide (0.76 mL, 8.8 mmol) was added and the reaction wasstirred at 80oC overnight. After the DMF was removed under vacuum, the residue was dissolved in100 mL of CH2Cl2 and washed 6 times with 50 mL of water. The organic layer was dried enconcentrated under vacuum to leave the crude product, as an off white solid, pure enough for furthersynthesis. Yield: 1.1 g (2.0 mmol), 95 %. 1H-NMR (300 MHz, CDCl3) δ 3.73 (d, J = 5.1, 2H), 4.90 (d,J = 10.2, 1H), 5.04 (d, J = 17.2, 1H), 5.64 – 5.73 (m, 1H), 6.96 – 7.00 (m, 4H), 7.16 – 7.53 (m, 11H),8.40 (d, J = 4.0, 4H). 13C-NMR (75.4 MHz, CDCl3) δ 63.8 (t), 85.6 (s), 112.9 (t), 119.2 (d), 119.4 (d),121.9 (d), 133.0 (d), 134.1 (d), 145.6 (d), 157.8 (s), 159.2 (s).

Di(2-pyridyl)methanol (7) (from 2-pyridyllithium 23 and 2-pyridinecarboxaldehyde)To a solution of 80 mL of n-BuLi in hexanes (2.5 M, 0.2 mol) was added 2-bromopyridine (31.6 g,0.2 mol) in 100 mL of ether at –80°C - –60°C. The suspension was stirred for 1 h and the temperature

was allowed to raise to -45°C. Subsequently 2-pyridinecarboxaldehyde (21.42 g, 0.2 mol) in 100 mLof ether was added over 30 min. To the thick slurry was added 200 mL of THF and the mixture was

Chapter 2

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stirred for another 1.5 h at -40 °C - -30 °C and subsequently the mixture was allowed to warm to -10° C. The mixture was poured into 200 mL of water and acidified with 2 M HCl to pH = 1-2 whereupon the layers were separated. The aqueous layer was extracted twice with ether and neutralized withsaturated Na2CO3, pH = 8. The aqueous layer was extracted thrice with CH2Cl2. Drying andevaporation of the solvent yielded a brown oil. Vacuum distillation afforded a yellow oil. Yield: 19.42g (104.4 mmol), 52 %. (bp 118 ° C, 0.2 mm Hg). 1H-NMR (200 MHz, CDCl3) δ 5.88 (s, 2H, CHand OH), 7.11 - 7.19 (m, 2H), 7.47 - 7.67 (m, 4H), 8.50 - 8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3)δ 75.0 (d), 121.0 (d), 122.5 (d), 136.8 (d), 1448.1 (d), 160.7 (s). CI-MS: 187 (M + H+).

Di(2-pyridyl)methanol (7) (via reduction of di-2-pyridylketone 4)To a solution of di-2-pyridylketone (5 g, 27.1 mmol) in 50 mL of methanol was added slowly NaBH4

(27.1 mmol) at 0oC. After all the NaBH4 was added, the icebath was removed and stirring continuedovernight. Removal of the solvent under vacuum was followed by addition of 20 mL of water and themixture was acidified with 2M aq. HCl and stirred for 10 min. The clear solution was treated with dil.aqueous ammonia till basic and extracted thrice with 50 mL of CH2Cl2. Drying and evaporation of thesolvent yielded a yellow oil which was used in the next step without purification. Yield: 4.6 g (0.25mol), 92 %. Spectral data as above.

2-[Chloro(2-pyridyl)methyl]pyridine (8)To alcohol 7 (8.73 g, 46.94 mmol) in 100 mL CH3CN at 0oC was added in 1.5 h PPh3 (14.77 g, 56.32mmol) in 80 mL of CCl4. The solution was left overnight. After adding 10 mL of MeOH and stirringfor 15 min the mixture was concentrated in vacuum to ca 50 mL. To the residue was added 100 mL ofwater and the mixture was acidified with 2M aq. HCl (pH = 1) and washed twice with 100 mL ofCHCl3. The aqueous layer was neutralized with K2CO3 and extracted 4 times with 75 mL of ether.Drying and evaporation of the solvent yielded a pale brown solid. Analytically pure material wasobtained by column chromatography on silica using ether as the eluent Yield: 5.41 g (26.3 mmol), 56

%. 1H-NMR (200 MHz, CDCl3) δ 6.20 (s, 1H), 7.14 - 7.20 (m, 2H), 7.60 - 7.73 (m, 4H), 8.51 - 8.54

(m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 62.84 (d), 121.3 (d), 121.5 (d), 135.7 (d), 147.7 (d), 156.9(s). Anal. Calcd. for C11H9ClN2: C, 64.56 %; H, 4.43 %; Cl, 17.32 %, N, 13.69 %; Found: C, 64.48 %;H, 4.45 %; Cl 17.29 %, N, 13.49 %. CI-MS: 205 (M + H+).

2-((Di(2-pyridyl)methyl)amino)-1-ethanol (10)A solution of chloride 8 (514 mg, 2.5 mmol) in 3 mL of ethanolamine 9 was stirred at 85oC overnightand the excess ethanolamine was removed by bulb to bulb distillation under vacuum. The residue waspurified by chromatography on silica (CH2Cl2:MeOH:NEt3 = 9:1:0.5) and a slightly orange oil wasobtained. Yield: 0.52 g (2.26 mmol), 90 %. 1H-NMR (200 MHz, CDCl3) δ 2.68 (t, J = 5.2, 2H), 3.60(t, J = 5.2, 4H, CH2 and NH/OH), 5.04 (s, 1H), 7.05 (ddd, J = 1.2, 4.9, 7.3, 2H), 7.36 (d, J = 8, 2H),7.62 (dt, J = 7.7, 1.8), 8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 48.1 (t), 59.6 (t), 67.3 (d), 120.8(d), 120.9 (d), 135.3 (d), 147.5 (d), 159.6 (s). CI-MS: 230 (M + H+).

1,4-Bis[di(2-pyridyl)methyl]piperazine (13)A mixture of piperazine (100 mg, 1.16 mmol), chloride 8 (488 mg, 2.37 mmol) anddiisopropylethylamine (307 mg, 2.37 mmol) in 5 mL acetonitrile was refluxed overnight andevaporated to dryness. The residue was taken up in CH2Cl2 and washed with 3 mL 2 N aq. NaOH.Drying and evaporation of the solvent yielded a brown solid which was dissolved in CH2Cl2. An off-white solid precipitated upon addition of ether. Yield: 329 mg, (0.77 mmol), 67%. 1H-NMR (200MHz, CDCl3) δ 2.51 (s, 8H), 4.65 (s, 2H), 7.03 - 7.10 (m, 4H), 7.58 - 7.60 (m, 8H), 8.49 (d, 4H). 13C-

Ligand Synthesis

33

NMR (50.3 MHz, CDCl3) δ 50.2 (t), 77.6 (d), 120.7 (d), 121.8 (d), 135.0 (d), 147.7 (d), 158.8 (s). CI-MS: 423 (M + H+).

N-[Di(2-pyridyl)methyl]-N,N-bis(1-pyrrolidinylethyl)amine (15)A mixture of chloride 8 (578 mg, 2.81 mmol), amine 14 (516 mg, 2.81 mmol) and K2CO3 (389 mg,2.81 mmol) in 3 mL of acetonitrile was refluxed for 5 h and the solvent was removed under vacuum.The residue was taken up into 10 mL of water and a few drops of diluted aq. ammonia were added.The emulsion was extracted thrice with 15 mL of CH2Cl2 and the combined organic layers were driedand concentrated. The residue was purified by chromatography on silica (CH2Cl2:MeOH:NEt3 =9:1:0.5). The last traces of NEt3 were removed in a kugelrohr apparatus under high vacuum and a lightbrown solid was obtained. Yield: 491 mg (1.40 mmol), 50 %. 1H-NMR (200 MHz, CDCl3) δ 1.67 –1.73 (m, 8H), 2.36 – 2.42 (m, 8H), 2.58 – 2.67 (m, 4H), 2.73 – 2.82 (m, 4H), 5.19 (s, 1H), 7.07 – 7.15

(m, 2H), 7.56 – 7.68 (m, 4H), 8.51 – 8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 23.0 (t), 49.7 (t),53.4 (t), 54.1 (t), 74.8 (d), 122.0 (d), 123.5 (d), 136.3 (d), 149.0 (d), 160.7 (s). CI-MS: 380 (M + H+).

1-(2-Pyridyl)-N-(2-pyridylmethyl)-1-ethanamine (18)To a solution of 1-(2-pyridyl)ethylamine (450 mg, 3.69 mmol) in 15 mL methanol was added 2-pyridinecarboxaldehyde (395 mg, 3.69 mmol) and the solution was stirred for 1 h and cooled to 0oC.NaBH4 (140 mg, 3.70 mmol) was added in portions and after all the NaBH4 was added the ice-bathwas removed and stirring was continued overnight. Removal of the solvent was followed by additionof 10 mL of water and the mixture was acidified (pH=1) with 2M aq. HCl. After stirring for 10 minthe mixture was made basic with dil. aqueous ammonia and extracted thrice with 40 mL of CH2Cl2.Drying of the combined organic layers and evaporation of the solvent yielded a colorless oil. Yield:676 mg (3.17 mmol), 86 %. 1H-NMR (200 MHz, CDCl3) δ 1.41 (d, J = 6.6, 3H), 3.76 (s, 2H), 3.93(q, J = 6.6, 1H), 7.09 – 7.16 (m, 2H), 7.22 – 7.27 (m, 1H), 7.33 – 7.39 (m, 1H), 7.54 – 7.63 (m, 2H),8.50 – 8.56 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 21.4 (q), 51.6 (t), 57.7 (d), 119.5 (d), 120.3 (d),120.4 (d), 120.7 (d), 134.9 (d), 135.1 (d), 147.7 (d), 147.8 (d), 158.3 (s), 162.9 (s).

N-[Di(2-pyridyl)methyl]-1-(2-pyridyl)-1-ethanamine (19)A mixture of 2-[chloro(2-pyridyl)methyl]pyridine 8 (1.058 g, 5.16 mmol), 1-(2-pyridyl)ethylamine 17(630 mg, 5.16 mmol) and K2CO3 (712 mg, 5.16 mmol) in 3 mL of acetonitrile was refluxed 40 h.After cooling the solvent was removed under vacuum and the residue was suspended in 20 mL ofether and the mixture was filtered. The solvent was removed under vacuum and the dark brownresidue (1.4 g) was submitted to chromatography on neutral alumina with ether as eluens andsubsequently with ether:methanol (98:2). A light brown oil was obtained after evaporation. Yield: 810mg (2.80 mmol), 54 %. (According to 1H-NMR the compound is pure before chromatography and thelatter was only performed to remove the trace amounts of highly colored impurities.) 1H-NMR (200MHz, CDCl3) δ 1.40 (d, J = 6.6, 3H), 3.79 (q, J =6.6, 1H), 4.90 (s, 1H), 6.97 – 7.10 (m, 3H), 7.26 –

7.32 (m, 2H), 7.39 – 7.61 (m, 4H), 8.44 – 8.51 (m, 3H). 13C-NMR (50.3 MHz, CDCl3) δ 21.6 (q),55.6 (d), 65.4 (d), 119.5 (d), 120.3 (d), 120.4 (d), 120.5 (d), 120.6 (d), 121.1 (d), 134.8 (d), 134.9 (d),135.0 (d), 147.5 (d), 147.7 (d), 147.8 (d), 159.9 (s), 160.2 (s), 162.9 (s).

2-({[Di(2-pyridyl)methyl]imino}methyl)phenol (25a)procedure 1: To a stirred solution of di-2-pyridyl-methylamine 6 (1.85 g, 10 mmol) in 15 mL ofmethanol was added neat salicylaldehyde (1.22 g, 10 mmol). The solution immediately turned yellow.After stirring for about 10 min a yellow crystalline material separated. The reaction mixture wascooled to 0oC and stirred for another 30 min. The solids were isolated by vacuum filtration, washed

Chapter 2

34

with ice-cold methanol, dried and a yellow micro crystalline powder was obtained. Yield 2.39 g (8.3mmol), 83 %. 1H-NMR (200 MHz, CDCl3) δ 5.94 (s, 1H), 6.83-7.00 (m, 2H), 7.14-7.21 (m, 2H),7.26-7.36 (m, 2H), 7.44 (dd, J = 7.8, J=0.5, 2H), 8.56-8.60 (m, 2H), 8.64 (s, 1H). 13C-NMR (50.3MHz, CDCl3) δ 80.1 (d), 116.9 (d), 118.5 (s), 118.8 (d), 122.0 (d), 122.5 (d), 131.9 (d), 132.7 (d),136.9 (d), 149.5 (d), 160.2 (s), 160.9 (s), 166.5 (d). Anal. Calcd. for C18H15N3O: C, 74.72 %; H, 5.23%; N, 14.52 %; Found: C, 74.74 %; H, 5.21 %; N, 14.46 %.

2-({[Di(2-pyridyl)methyl]amino}methyl)phenol (26a)procedure 2: To a stirred solution of imine 25a (6.0 g, 20.7 mmol) in 150 mL methanol at 0oC wasadded NaBH4 (0.78 g, 20.7 mmol) in 3 portions during 15 min. The reaction mixture was stirred for 4h. The mixture was acidified with 2 M aq. HCl to pH 1 and stirred for 15 min. Subsequently thereaction was neutralized with 2 M aq. NH3 and 30 mL water was added. Methanol was removed undervacuum and the mixture extracted twice with ethylacetate. The combined organic layers were driedand solvents were removed under vacuum to yield a reddish oil which turned into a glass after severalweeks. Yield: 5.2 g (17.8 mmol), 86 %. 1H-NMR (200 MHz, CDCl3) δ 3.91 (s, 3H), 5.10 (s, 1H),6.70-6.92 (m, 3H), 7.11-7.19 (m, 3H ), 7.26-7.32 (m, 2H), 7.57 (dt, 2H, J = 7.7, J = 2.0), 8.57-8.60(m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 50.1 (t), 67.0 (d), 116.3 (d), 118.9 (d), 122.4 (d), 122.5 (d),122.6 (s), 128.6 (d), 128.7 (d), 136.7 (d), 149.3 (d), 158.0 (s), 159.7 (s). Anal. Calcd. for C18H17N3O:C, 74.20 %; H, 5.88 %; N, 14.42 %; Found: C, 73.41 %; H, 5.80 %; N, 14.29 %.

2-{[[Di(2-pyridyl)methyl](methyl)amino]methyl}phenol (27a)procedure 3: To a solution of amine 26a (3.04 g, 10.45 mmol) in 50 mL of 1,2-dichloroethane wasadded aqueous 30 % formaldehyde (1.70 g, 20.9 mmol) and after 15 min of stirring NaBH(OAc)3

(4.42 g, 20.9 mmol) was added in small portions during 20 min. Subsequently the reaction wasvigorously stirred overnight. CH2Cl2 (50 mL) was added and the organic layer was washedconsecutively with 2 M aq. NH3, and twice with water. After drying and evaporation of the solventsunder vacuum the product was obtained as a sticky oil which was purified by chromatography onsilica using ether as the eluens to obtain white solid material. Yield: 2.6 g, (8.5 mmol), 81%. 1H-NMR(200 MHz, CDCl3) δ 2.17 (s, 3H), 3.62 (s, 2H), 4.88 (s, 1H), 7.73 (dt, J = 7.3, 1.2, 1H), 6.87 - 6.97(m, 2H), 7.12 - 7.20 (m, 3H), 7.50 - 7.68 (m, 4H), 8.58 - 8.62 (m, 2H). 13C-NMR (50.3 MHz, CDCl3)δ 39.6 (q), 57.6 (d), 77.4 (s), 116.2 (d), 118.6 (d), 122.5 (d), 122.7 (s), 123.6 (d), 128.6 (d), 129.5 (d),136.8 (d), 149.1 (d), 157.4 (s), 159.5 (s). Anal. Calcd. for C19H19N3O: C, 74.73 %; H, 6.27 %; N,13.76 %; Found: C, 74.56 %; H, 6.18 %; N, 13.77 %.

4-Chloro-2-({[di(2-pyridyl)methyl]imino}methyl)phenol (25b)Procedure 1. Starting from chloro-salicylaldehyde (1.56 g, 10 mmol). The reaction mixture wascooled in a methanol/liquid nitrogen bath until a precipitate was observed and subsequently rapidlyfiltered. Yield: 0.98 g (3.0 mmol), 30%. 1H-NMR (200 MHz, CDCl3) δ 5.93 (s, 1H), 6.89 (d, J = 9.2,1H), 7.14 - 7.26 (m, 3H), 7.40 (dd, J = 7.8, J = 1, 2H), 7.66 (dt, J = 7.8, J = 2, 2H), 8.54 - 8.59 (m,3H), 13.41 (s, 1H). 13C-NMR (50.3 MHz, CDCl3) δ 78.4 (d), 117.1 (d), 118.1 (s), 120.7 (d), 121.2 (d),121.9 (s), 129.5 (d), 131.1 (d), 135.5 (d), 148.1 (d), 158.1 (s), 158.4 (s), 163.9 (d).

4-Chloro-2-({[di(2-pyridyl)methyl]amino}methyl)phenol (26b)Procedure 2: Starting with imine 25b (1.25 g, 3.86 mmol) there was obtained a brown oil whichturned into a glass after several weeks. Yield: 1.21 g (3.6 mmol), 96 %. 1H-NMR (200 MHz, CDCl3)δ 3.96 (s, 2H), 5.11, (s, 1H), 6.83, (d, J = 8.8, 1H), 7.16 - 7.28 (m, 4H), 7.59 - 7.60 (m, 2H), 7.83 (d, J

= 1.7, 1H), 8.03 (dd, J = 9, J = 2.7, 1H), 8.57 (d, J = 3.9, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 48.1

Ligand Synthesis

35

(t), 65.5 (d), 115.3 (d), 121.3 (d), 121.4 (d), 121.7 (s), 123.4 (d), 123.4 (d), 123.8 (d), 135.6 (d), 138.3(s), 147.9 (d), 157.4 (s), 163.4 (s).

4-Chloro-2-{[[di(2-pyridyl)methyl](methyl)amino]methyl}phenol (27b)procedure 3: Starting with amine 26b (446 mg, 1.3 mmol) there was obtained an orange-brown oilwhich turned into a glass after several weeks. Yield: 270 mg (0.8 mmol), 61 %. 1H-NMR (200 MHz,CDCl3) δ 2.19 (s, 3H), 3.65 (s, 2H), 5.02 (s, 1H), 6.92 (d, J = 9, 1H), 7.19 - 7.25 (m, 2H), 7.38 (d, J =7.8, 2H), 7.66 (dt, J = 7.8, J = 1.7, 2H), 7.89 (d, J = 2.9, 1H), 8.07 (dd, J = 9, J = 2.7, 1H), 8.63 - 8.59(m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 38.5 (q), 55.2 (t), 74.7 (d), 115.5 (d), 121.4 (d), 122.2 (s),122.5 (d), 123.9 (d), 124.6 (d), 135.8 (d), 138.1 (s), 147.5 (d), 157.3 (s), 162.8 (s).

2-({[Di(2-pyridyl)methyl]imino}methyl)-4-nitrophenol (25c)Procedure 1. Starting with p-nitrosalicylaldehyde(1.67 g, 10 mmol). Yield: 2.85 g (8.5 mmol), 85%.1H-NMR (200 MHz, CDCl3) δ 6.03 (s, 1H), 6.98 (d, J = 9, 1H), 7.19 - 7.26 (m, 2H), 7.39 (d, J = 8,2H), 7.69 (dt, J = 7.8, J = 1.8, 2H), 8.15 - 8.26 (m, 2H), 8.59 - 8.63 (m, 3H), 14.74 (br ,1H). 13C-NMR(50.3 MHz, CDCl3) δ 76.4 (d), 115.7 (s), 117.4 (d), 120.9 (d), 121.5 (d), 126.9 (d), 127.2 (d), 135.7(d), 137.6 (s), 148.3 (d), 157.3 (s), 163.6 (d), 167.1 (s).

2-({[Di(2-pyridyl)methyl]amino}methyl)-4-nitrophenol (26c)Procedure 2: Starting with imine 25c (1.25 g, 3.73 mmol) there was obtained a brown oil whichturned into a glass after several weeks. Yield: 1.25 g (3.73 mmol), 99%. 1H-NMR (200 MHz, CDCl3)δ 3.86 (s, 2H), 5.08 (s, 1H), 6.75 (d, J = 8.6, 1H), 6.86 (d, J = 4.4, 1H), 7.06 - 7.22 (m, 3H), 7.26 -

7.30 (m, 2H), 7.62 (dt, J = 7.8, J = 1.7, 2H), 8.56 - 8.60 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 48.4(t), 65.6 (d), 116.3 (d), 116.7 (d), 121.2 (d), 121.9 (s), 122.9 (s), 126.8 (d), 127.0 (d), 135.4 (d), 147.9(d), 155.3 (s), 157.9 (s).

2-{[[Di(2-pyridyl)methyl](methyl)amino]methyl}-4-nitrophenol (27c)Procedure 3: Starting with amine 26c (413 mg, 1.23 mmol) there was obtained an orange-brown oilwhich turned into a glass after several weeks. Yield: 280 mg (0.8 mmol), 65%. 1H-NMR (200 MHz,CDCl3) δ 2.16 (s, 3H), 3.55 (s, 2H), 4.90 (s, 1H), 6.81 (d, J = 8.6, 1H), 6.91 (d, J = 2.7, 1H), 7.07 -7.20 (m, 3H), 7.45 (d, J = 7.8, 2H), 7.60 (dt, J= 7.8, J = 1.8, 2H), 8.58 - 8.61 (m, 2H). 13C-NMR (50.3MHz, CDCl3) δ 38.6 (q), 55.7 (t), 75.5 (d), 116.2 (d), 121.3 (d), 121.5 (s), 122.3 (d), 123.1 (s), 127.0(d), 127.8 (d), 135.5 (d), 147.7 (d), 154.8 (s), 157.8 (s).

2-({[Di(2-pyridyl)methyl]imino}methyl)-4-methoxyphenol (25d)Procedure 1: Starting from p-methoxy-salicylaldehyde (1.52 g, 10 mmol). The reaction mixture wascooled in a methanol/liquid nitrogen bath until a precipitate was observed and subsequently rapidlyfiltered. Yield: 1.50 g (4.7 mmol), 47%. 1H-NMR (200 MHz, CDCl3) δ 3.74 (s, 3H), 5.92 (s, 1H),6.79 (dd, J = 1.2, 2.5, 1H), 6.92 (d, J = 2.4, 2H), 7.14-7.20 (m, 2H), 7.43 (dd, J = 7.8, 1.0, 2H), 7.66(dt, J = 7.5, 1.8, 2H), 8.55-8.59 (m, 3H), 12.88, (br, 1H). 13C-NMR (50.3 MHz, CDCl3) δ 54.4 (q),78.8 (d), 113.6 (d), 116.3 (d), 116.9 (s), 118.6 (d), 120.6 (d), 121.1 (d), 135.5 (d), 148.0 (d), 150.6 (s),153.6 (s), 158.8 (s), 164.8 (d). Anal. Calcd. for C19H17N3O2: C, 71.46 %; H, 5.37 %; N, 13.16 %;Found: C,71.28 %; H, 5.30 %; N, 12.84%.

2-({[Di(2-pyridyl)methyl]amino}methyl)-4-methoxyphenol (26d)Procedure 2: Starting with imine 25d (1.0 g. 3.13 mmol) there was obtained a yellow-brown oil,which turned into a glass during several weeks. Yield: 1.02 g (3.13 mmol), 99%. 1H-NMR (200 MHz,

Chapter 2

36

CDCl3) δ 3.69 (s, 3H), 3.87 (s, 2H), 5.09 (s, 1H), 6.47-6.48 (m, 1H), 6.72 - 6.75 (m, 2H), 7.12 - 7.19(m, 2H), 7.30 (dt, J = 7.8, J = 1, 2H), 7.60 (dt, J = 7.6, J = 1.9, 2H), 8.54 - 8.58 (m, 2H). 13C-NMR

(50.3 MHz, CDCl3) δ 48.9 (t), 54.2 (q), 65.7 (d), 112.2 (d), 113.0 (d), 115.3 (d), 121.0 (d), 121.2 (d),122.0 (s), 135.4 (d), 147.9 (d), 150.3 (s), 150.9 (s), 158.2 (s). Anal. Calcd. for C19H19N3O2: C, 71.01%; H, 5.96 %; N, 13.07 %; Found: C, 70.45 %; H, 5.95 %; N, 12.87 %.

2-{[[Di(2-pyridyl)methyl](methyl)amino]methyl}-4-methoxyphenol (27d)Procedure 3: Starting with amine 26d (480 mg, 1.5 mmol) There was obtained an orange brown oilwhich turned into a glass in several weeks. Yield: 257 mg (0.77 mmol), 51%. 1H-NMR (200 MHz,CDCl3) δ 2.17 (s, 3H), 3.58 (s, 2H), 3.70 (s, 3H), 4.87 (s, 1H), 6.52 (d, J = 2.9, 1H), 6.69 -6.85 (m,

2H), 7.12 - 7.19 (m, 2H), 7.47 - 7.66 (m, 4H), 8.57 - 8.61 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ38.5 (q), 54.2 (q), 56.5 (t), 76.2 (d), 112.1 (d), 113.9 (d), 115.1 (d), 121.2 (d), 122.0 (s), 122.2 (d),135.4 (d), 147.7 (d), 149.8 (s), 150.6 (s), 158.3 (s).

2,4-Di(tert-butyl)-6-({[di(2-pyridyl)methyl]imino}methyl)phenol (25e)Procedure 1: Starting from di-t-butylsalicylaldehyde (2.34 g, 10 mmol). A few drops of water wereadded to induce precipitation. Yield: 3.12 g (7.8 mmol), 78%. 1H-NMR (200 MHz, CDCl3) δ 1.29 (s,9H), 1.46 (s, 9H), 5.92 (s, 1H), 7.13 - 7.22 (m, 3H), 7.40 (d, J = 2.5, 1H), 7.45 - 7.50 (m, 2H), 7.38(dt, J = 7.8, J = 2, 2H), 8.57 - 8.60 (m, 2H), 8.67 (s, 1H), 13.61 (s, 1H). 13C-NMR (50.3 MHz, CDCl3)δ 27.9 (3q), 29.9 (3q), 32.6 (s), 33.5 (s), 79.0 (d), 116.5 (s), 120.7 (d), 121.0 (d), 125.1 (d), 126.0 (d),126.3 (d), 130.4 (d), 135.2 (s), 135.4 (d), 138.9 (s), 148.0 (d), 156.5 (s), 159.1 (s), 166.4 (d). Anal.Calcd. for C26H31N3O:C, 77.77 %; H, 7.78 %; N, 10.46 %; Found C, 77.56 %; H, 7.74 %; N, 10.34 %.

2,4-Di(tert-butyl)-6-({[di(2-pyridyl)methyl]amino}methyl)phenol (26e)Procedure 2: Starting from imine 25e, (1.51 g, 3.76 mmol) there was obtained a light-brown oilwhich solidified on standing. Yield:1.45 g (3.5 mmol), 93 %. 1H-NMR (200 MHz, CDCl3) δ 1.26 (s,9H), 1.42 (s, 9H), 3.92 (s, 2H), 5.11 (s, 1H), 6.76 (d, J = 2.4, 1H), 7.14 - 7.26 (m, 3H), 7.32 - 7.37 (m,

2H), 7.60 - 7.69 (m, 2H), 8.56 - 8.60 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 28.1 (3q), 30.2 (3q),32.6 (s), 33.4 (s), 49.9 (t), 65.9 (d), 120.6 (s), 121 (d), 121.1 (d), 121.5 (d), 122.1 (d), 134.3 (s), 135.2(d), 138.9 (s), 147.9 (d), 153.0 (s), 158.5 (s).

2,4-Di(tert-butyl)-6-{[[di(2-pyridyl)methyl](methyl)amino]methyl}phenol (27e)Procedure 3: Starting with amine 26e (515 mg, 1.3 mmol), there was obtained a white powder.Yield: 330 mg (0.8 mmol), 61 %. 1H-NMR (200 MHz, CDCl3) δ 1.25 (s, 9H), 1.48 (s, 9H), 2.23 (s,3H), 3.65 (s, 2H), 4.87 (s, 1H), 6.77 (d, J = 2.4, 1H), 7.12 - 7.21 (m, 3H), 7.57 - 7.69 (m, 4H), 8.57 -8.61 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 28.1 (3q), 30.2 (3q), 32.5 (s), 33.5 (s), 38.5 (q), 57.8 (t),76.5 (d), 120.0 (s), 121.1 (d), 121.3 (d), 122.1 (d), 122.4 (d), 133.8 (s), 135.2 (d), 138.6 (s), 147.8 (d),152.6 (s), 158.0 (s). Anal. Calcd. for C27H35N3O:C, 77.66 %; H,8.45 %; N,10.06 %; Found: C, 77.57%; H, 8.43 %; N, 10.01%.

2-(((Di(2-pyridyl)methyl)(2-pyridylmethyl)amino)methyl)phenol (29)A solution of amine 35 (910 mg, 3.4 mmol), bromoacetate 36 (1.00 g, 4.38 mmol) anddiisopropylethylamine (652 mg, 5.05 mmol) in 20 mL of ethylacetate was refluxed overnight. Thereaction mixture was taken up in into CH2Cl2 and washed with water, dried and the solvents wereremoved under vacuum. The residue was purified by chromatography on silica(ethylacetate:triethylamine:hexane = 50:5:11) and there was obtained a yellow syrup consisting of amixture of de desired compound and the deacylated derivative. Yield: 780 mg, 60%. To 1.47 g of a

Ligand Synthesis

37

mixture of acylated and deacylated 29 in 50 mL of methanol were added 10 mL of water and 10 mLof sat. aq. NaHCO3 and the mixture was stirred overnight. 50 mL Of water, was added and themixture was extracted thrice with 50 mL of CH2Cl2. Drying of the combined organic layers andevaporation of the solvents under vacuum provided a brown sticky solid. Yield: 1.27 g, (3.3 mmol),85 %. 1H-NMR (200 MHz, CDCl3) δ 3.77 (s, 2H), 3.92 (s, 2H), 5.27 (s, 1H), 6.66 - 6.74 (m, 1H), 6.91- 6.98 (m, 2H), 7.06 - 7.26 (m, 7H), 7.42 - 7.68 (m. 4H), 8.51 (d, J = 5.1, 1H), 8.66 (dd, J = 3.9, J =0.7, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 53.5 (t), 55.5 (t), 69.0 (d), 116.5 (d), 118.4 (d), 121.8 (d),122.3 (d), 123.0 (s), 123.2 (d), 124.6 (d), 128.9 (d), 131.0 (d), 136.4 (d), 136.6 (d), 148.4 (d), 148.8(d), 157.8 (s), 158.5 (s), 159.5 (s). CI-MS: 383 (M + H+).

2-(((Di(2-pyridyl)methyl)(2-hydroxybenzyl)amino)methyl)phenol (37)A solution of aminophenol 26a (1.13 g, 3.9 mmol), bromoacetate 36 (1.79 g, 7.76 mmol) anddiisopropylamine in 25 mL of ethylacetate was refluxed for 2 d and left for 1 d at RT. The mixturewas washed with 25 mL sat. aq. NaHCO3, and the aqueous layer was extracted thrice with 25 mLCH2Cl2. The combined organic layers were dried and solvents were evaporated under vacuum. Theresidue was purified by chromatography on silicagel and eluted with a mixture of ethylacetate, hexaneand triethylamine to yield a dark yellow syrup. Yield 927 mg, ca 60%. To a mixture of acetylated anddeacetylated compound 37, (917 mg, 2.3 mmol) in 50 mL of methanol was added 15 mL of water and15 mL of sat. aq. NaHCO3. The mixture was stirred overnight, 75 mL of water was added and themixture was extracted thrice with CH2Cl2. The combined organic layers were dried and solvents wereremoved under vacuum to yield an off-white solid. Yield: 759 mg (1.9 mmol), 83 %. 1H-NMR (200

MHz, CDCl3) δ 3.78 (s, 4H), 5.45 (s, 1H), 6.77 (dt, J = 7.3, J=1.2, 2H), 6.90 - 7.04 (m, 6H), 7.13 -7.32 (m, 2H), 7.63 - 7.71 (dt, J = 7.8, J = 1.7, 2H), 8.70 - 8.73 (m, 2H). 13C-NMR (50.3 MHz, CDCl3)δ 52.9 (t), 66.8 (d), 116.8 (d), 119.0 (d), 121.8 (s), 122.9 (d), 124.9 (d), 129.2 (d), 130.8 (d), 136.9 (d),148.5 (d), 156.9 (s), 157.9 (s). CI-MS: 398 (M + H+).

2-(((Di(2-pyridyl)methyl)(2-hydroxybenzyl)-amino) methyl)phenol (29)A mixture of chloride 8 (750 mg, 3.66 mmol), 2-(((2-pyridylmethyl)amino)methyl)phenol 28 (782mg, 3.66 mmol), and diisopropylethylamine (566 mg, 4.39 mmol), was stirred at 85 oC overnight andafter cooling to RT, divided between 10 mL dilute aq. ammonia and 25 mL CH2Cl2. After separationof the layers, the aqueous layer was extracted twice with 25 mL of CH2Cl2, and the combined organiclayers were dried and concentrated under vacuum. The residue was purified by chromatography(twice) on silica (CH2Cl2/MeOH, 9:1) to give the bishydroxy-benzylamine 30 as a greenish solid andthe desired product 29 as a light brown solid. 29, Yield: 670 mg (1.75 mmol), 47 %. 30, Yield: 320mg (1.00 mmol), 28 %.

Cresol scrambling experimentA mixture of 2-(((2-pyridylmethyl)amino)methyl)phenol 28 (214 mg, 1 mmol), p-cresol (25 mg, 0.23mmol) and diisopropylethylamine (129 mg,1 mmol) was heated at 85 oC overnight. The volatiles wereremoved under vacuum and the residues analyzed by CI-MS and 1H-NMR.

2.8 References

1 M. Lubben, A. Meetsma, E.C. Wilkinson, B. Feringa, L. Que, Jr., Angew. Chem. Int. Ed. 1995, 34,1512 - 1513; G. Roelfes, M. Lubben, S.W. Leppard, E.P. Schudde, R.M. Hermant, R. Hage, E.C.Wilkinson, L. Que Jr., B.L. Feringa, J. Mol.Cat. 1997, 117, 223 - 228; R.Y.N. Ho, G. Roelfes, B. L.Feringa, L. Que, Jr., J. Am. Chem. Soc. 1999, 121, 264 - 265; G. Roelfes, M. Lubben, K. Chen, R.Y.N.

Chapter 2

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Ho, A. Meetsma, S. Genseberger, R.M. Hermant, R. Hage, S.K. Mandal, Inorg. Chem. 1999, 38, 1929 -1936; R.Y.N. Ho, G. Roelfes, R. Hermant, R. Hage, B.L. Feringa, L. Que, Jr., Chem. Commun. 1999,2161 - 2162.

2 K.D. Karlin, B.I. Cohen, J.C. Hayes, A. Farooq, J. Zubieta, Inorg. Chem. 1987, 26, 147 - 153; Z.Shirin, V.G. Young, A.S. Borovik, Chem. Commun. 1997, 1967 - 1968; M.S. Lah, H. Chen, Inorg.Chem. 1997, 36, 1782 - 1785; J. Brinksma, R. Hage, J. Kershner, B.L. Feringa, Chem. Commun. 2000,537 - 538.

3 J. March, Advanced Organic Chemistry, 4th ed. 1992, 411 - 413.4 During the research described in this thesis various attempts to alkylate amines in the presence of

pyridine moieties have been performed. Highly colored species were often found and 1H-NMR showeddegradation of the pyridine structure.

5 J. March, Advanced Organic Chemistry, 4th ed. 1992, 898 - 900; R.O. Hutchins, M.K. Hutchins inComprehensive Organic Synthesis, 1991, vol 8, B.M. Trost, ed. 25 - 78.

6 A.F. Abdel-Magid, K.G. Carson, B.D. Harris, C.A. Maryanoff, R.D. Shah. J.Org. Chem. 1996, 61,3849 - 3862.

7 E. Niemers, R. Hiltmann, Synthesis, 1976, 593 - 595.8 Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet, S.H. Wilen, 1981, Wiley & Sons, New

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10 P.J. Chivers, T.A. Crabb, Tetrahedron, 1970, 26, 3369 - 3387.11 R. Appel, Angew. Chem. Int. Ed. 1975 14, 801 - 811.12 E.P. Schudde, personal communication.13 A.D. van der Haest, thesis: Classical resolutions; Design of resolving agents and studies of

diasteromeric salts, University of Groningen, 199214 J.W. Canary, C.S. Allen, J.M. Castagnetto, Y. Wang, J. Am. Chem. Soc. 1995, 117, 8484 - 8485.15 C.T. Choma, E.P. Schudde, R.M. Kellogg, G.T. Robillard, B.L. Feringa, J. Chem. Soc. Perkin Trans.1,

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Commun. 1997, 1549 - 1550.17 Shortly after publication of our work (ref. 16) an article appeared about the same 5Py system: R.T.

Jonas, T.D.P. Stack, J. Am. Chem. Soc, 1997, 119, 8566 - 8567.18 A.G.J. Ligtenbarg, A.L. Spek, R. Hage, B.L. Feringa, J. Chem. Soc. Dalton Trans 1999, 659 - 661.19 R.O. Hutchins, N.R. Natale, Org. Prep. Proced. Int. 1979, 11, 201 - 246.20 P. Pietikainen, Tetrahedron Lett. 1994, 35, 941 - 944; R. Irie, N. Hosoya, T. Katsuki, Synlett, 1994, 255

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21 Y. Wong, Y. Yan, E.S.H. Chan, Q.Yang, T.C.W. Mak, D.K.P. Ng, J.Chem. Soc. Dalton Trans. 1998,3057 - 3064.

22 See for example: R.F. Heldeweg, H. Hogeveen, J. Am. Chem. Soc. 1976, 98, 6040 - 6042; E.Dorrestein, O.J. Epema, W.B. van Scheppingen, P. Mulder, J. Chem. Soc. Perkin Trans. 2, 1998, 1173- 1178.

23 K. Nakatani, N. Higashida, I. Saito, Tetrahedron Lett. 1997, 38, 5005 - 5008.24 M. Lubben, thesis: Model studies towards iron and copper containing oxygenases, University of

Groningen, 1994.25 D.D. Reynolds, J. Heterocyclic Chem. 1970, 7, 1397 - 1400; E.L. Eliel, J. Am. Chem. Soc. 1951, 73, 43

- 45.26 G.P. Ng, C.R. Dawson, J. Org. Chem. 1978, 43, 3205 - 3208; H. Möhrle, D. Schake, Z. Naturforsch.

1995, 50b, 1859 - 1868.27 G. Casiraghi, G. Casnati, G. Puglia, G. Sarori, G. Terenghi, J. Chem. Soc. Perkin Trans. 1, 1980, 1862-

1865.28 J.G. Roelfes, M.E. Branum, L. Que, Jr., B.L. Feringa, Patent filed 22 April 1999.’Pentadentate

Complexes for DNA Cleavage.’29 M. Lubben, B.L. Feringa, J. Org. Chem. 1994, 59, 2227 - 2233.