Präsident der Humboldt-Universität zu Berlin

Prof. Dr. Jürgen Mlynek

Prof. Dr. Michael W. Linscheid, Institut für Chemie, HU Berlin (vorsitzender)

Prof. Dr. Jürgen Liebscher, Institut für Chemie, HU Berlin

Prof. Dr. Erhard Kemnitz, Institut für Chemie, HU Berlin

PD. Dr. habil. Rainer Mahrwald, Institut für Chemie, HU Berlin

Prof. Dr. Gunter Fischer, (MPG, Halle)

Die vorliegende Arbeit entstand auf Vorschlag und unter Anleitung von Herrn Prof. Dr. Jürgen Liebscher in der Zeit von Okt. 2001 bis Dez. 2004 am Institut für Organische und Bioorganische Chemie der Humboldt-Universität zu Berlin.

Herrn Prof. Dr. J. Liebscher danke ich für die vielen wertvollen Anregungen und Ratschläge, seine ständige Diskussionsbereitschaft sowie für den großen Freiraum, den er mir bei der Gestaltung und Durchführung dieser Arbeit gewährte.

Weiterhin gilt mein Dank allen, die zum Gelingen dieser Arbeit beigetragen haben:

• Meinen Kolleginnen und Kollegen (Dr. Hamann, Dr. Leistner, Dr.Pätzel, Frau Brosche, Frau Brauer, Frau Werner, Daniela, Oxala, Christoph, Magda, Wolfgang, etc.) für viele hilfreiche Diskussionen und die gute Zusammenarbeit.

• Frau A. Thiesis und Herrn W. D. Bloedorn für die stets rasche Anfertigung von NMR-Specktren.

• Frau U. Kätel und Herrn Dr. U. Hartmann für die Anfertigung der Elementaranalyse.

• Frau. A. Woyda und Herrn Dr. M. Löwis für die Anfertigung der Massenspektren.

• Prof. Dr. Fischer (MPG Halle) für viele hilfreiche Diskussion und die Bestimmung der calcineurin-inhibierenden Wirkung unser Substenzen.

• Meinen chinesischen Freundinnen und Freunden (Lijun, Zhijian, Yanqin, Luxia, Lisong, Zhongyang, Xufei, Xiaojun, etw.) für viele hilfreiche Diskussionen und unsere Freundschaft.

• 1  Introduction

  • 1.1 Background of the project

    • 1.1.1 Calcineurin and its physiological roles

    • 1.1.2 Inhibitors of calcineurin

    • 1.1.3 Our research background

  • 1.2 Target molecules and synthetic strategies

    • 1.2.1 Synthetic target molecules

    • 1.2.2 Disconnection of target molecules

    • 1.2.3  Synthetic strategies for target molecules

  • 1.3  Pd-catalyzed cross-coupling of heterocycles

    • 1.3.1 Overview of relevant Pd-catalyzed cross-coupling

      • 1.3.1.1 Cross-coupling reactions with organometallic reagents

      • 1.3.1.2  The Sonogashira reaction

      • 1.3.1.3  The Heck reaction

      • 1.3.1.4  The Buchwald-Hartwig C-N bond formation

    • 1.3.2  Pd-catalyzed cross-coupling reactions of heterocycles

      • 1.3.2.1 The characteristics and importance of Pd-catalyzed cross-coupling reactions of heterocycles

      • 1.3.2.2 Regioselective Pd-catalyzed cross-coupling of heterocycles

    • 1.3.3 Prospected application of Pd-catalyzed cross-coupling to the synthesis of new calcineurin inhibitors

      • 1.3.3.1 Introducing aryl groups to the heterocycles

      • 1.3.3.2  Introducing the functionalized side chains

• 2  Pyrazolo[1,5-a]pyrimidine derivatives

  • 2.1 Introduction

  • 2.2 Synthesis of substituted pyrazolo[1,5-a]pyrimidines

    • 2.2.1 Synthesis of pyrazolo[1,5-a]pyrimidines by ring closure

    • 2.2.2 Halogen substituted pyrazolo[1,5-a]pyrimidines

  • 2.3  Heck cross-coupling of pyrazolo[1,5-a]pyrimidines

    • 2.3.1 Heck cross-coupling of 3-halopyrazolo[1,5-a]pyrimidines

    • 2.3.2 Heck cross-coupling of 7-iodopyrazolo[1,5-a]pyrimidine

  • 2.4 Sonogashira cross-coupling of halopyrazolo[1,5-a]pyrimidines

    • 2.4.1 Sonogashira cross-coupling of 3-iodopyrazolo[1,5-a]pyrimidines

    • 2.4.2 Sonogashira cross-coupling of 7-halopyrazolo[1, 5]pyrimidine

  • 2.5 Suzuki cross-coupling of halopyrazolo[1,5-a]pyrimidines

  • 2.6  Attempts to Buchwald-Hartwig amination and Negishi coupling of halopyrazolo[1,5-a]pyrimidines

  • 2.7 Pd-free synthesis of pyrazolo[1,5-a]pyrimidine derivatives

    • 2.7.1 Nucleophilic substitution of halopyrazolo[1,5-a]pyrimidine

    • 2.7.2 Synthesis of pyrazolo[1,5-a]pyrimidine derivatives by ring-chain-transformation

• 3  Purines and other bicyclic heterocycles

  • 3.1 Synthesis of purine derivatives

    • 3.1.1 Properties of purine

    • 3.1.2 Overview of Pd-catalyzed coupling reactions of halopurines

    • 3.1.3 Synthesis of aryl-halopurines as starting materials

    • 3.1.4 Introduction of functionalized chains into purines

  • 3.2  Synthesis of pyrido[2,3-b]pyrazine derivatives

    • 3.2.1 Synthesis of 7-alkynylpyrido[2,3-b]pyrazine and related compounds (Sonogashira cross-coupling reaction)

    • 3.2.2 Synthesis of 7-alkenylpyrido[2,3-b]pyrazine compounds (Heck cross-coupling reaction)

    • 3.2.3 Suzuki cross-coupling of 7-bromo-2, 3-diphenylpyrido[2,3-b]pyrazine

    • 3.2.4  Buchwald-Hartwig amination of 7-bromo-2, 3-diphenylpyrido[2,3-b]pyrazine

  • 3.3  Synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives

    • 3.3.1 Literature survey

    • 3.3.2  Preparation of starting materials

    • 3.3.3 Pd-catalyzed introduction of functionalized side chains

• 4  Pyrimidines and other monocyclic heterocycles

  • 4.1 Synthesis of pyrimidine derivatives

    • 4.1.1 Overview of Pd-catalyzed coupling reactions of halopyrimidines

      • 4.1.1.1 Pd-catalyzed cross-coupling reactions of monohalopyrimidines

      • 4.1.1.2  Regioselective Pd-catalyzed couplings of polyhalopyrimidines

    • 4.1.2 Synthesis of aryl substituted halopyrimidines

    • 4.1.3 Introduction of side chains into pyrimidines

      • 4.1.3.1 Sonogashira cross-coupling of halopyrimidines

      • 4.1.3.2 Nucleophilic substitution of halopyrimidines

  • 4.2  Synthesis of pyridine derivatives

    • 4.2.1 Overview of Pd-catalyzed coupling reactions of halopyridines

    • 4.2.2 Introduction of dimethylaminopropyl chain into pyridine

  • 4.3  Synthesis of pyrazine derivatives

  • 4.4 Synthesis of oxazole derivatives

  • 4.5  Synthesis of pyrazole derivatives

  • 4.6 Synthesis imidazole derivatives

• 5  Activities of calcineurin inhibitors

  • 5.1 Measurement of calcineurin inhibitory activity

  • 5.2 Calcineurin inhibitory activity of target molecules

• 6  Summary

• 7  Experimental

  • 7.1 General Remarks

  • 7.2 Synthesis of pyrazolo[1,5-a]pyrimidine derivatives

    • 7.2.1 Synthesis of pyrazolo[1,5-a]pyrimidines by ring closure

      • 7.2.1.1 Synthesis of 2, 5, 7-tri-substituted pyrazolo[1,5-a]pyrimidines

      • 7.2.1.2 Synthesis of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines

      • 7.2.1.3 Hydroxy-substituted pyrazolo[1,5-a]pyrimidines

    • 7.2.2 Synthesis of halogen substituted pyrazolo[1,5-a]pyrimidines

      • 7.2.2.1 Synthesis of 6-bromopyrazolo[1,5-a]pyrimidines

      • 7.2.2.2 Synthesis of 7-halo-3,5-diphenylpyrazolo[1,5-a]pyrimidine

      • 7.2.2.3 Synthesis of 5,7-dichloro-pyrazolo[1,5-a]pyrimidines

      • 7.2.2.4 Synthesis of 3-halo-2,5,7-trisubstituted-pyrazolo[1,5-a]pyrimidines

      • 7.2.2.5 Synthesis of 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine (105)

    • 7.2.3 Synthesis of 3-alkenylpyrazolo[1,5-a]pyrimidines (Heck cross-coupling reactions)

    • 7.2.4 Synthesis of 3-alkynylpyrazolo[1,5-a]pyrimidines and related compounds (Sonogashira cross-coupling reaction)

    • 7.2.5  Synthesis of substituted pyrazolo[1,5-a]pyrimidines via Suzuki cross-coupling reaction

    • 7.2.6  Synthesis of substituted pyrazolo[1,5-a]pyrimidines by Nucleophilic substitution

    • 7.2.7 Synthesis of pyrazolo[1,5-a]pyrimidine derivatives by ring-chain-transformation

  • 7.3 Synthesis of purine derivatives

    • 7.3.1 Synthesis of 2,6-dichloropurine

    • 7.3.2 Benzylation of 2,6-dichloropurine and 6-chloropurine

    • 7.3.3 Suzuki cross-coupling of halopurines

    • 7.3.4 Sonogashira cross-coupling of halo-purines

    • 7.3.5 Nucleophilic substitution of halopurines

  • 7.4  Synthesis of pyrido[2,3-b]pyridazine derivatives

    • 7.4.1 Synthesis of 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (193)

    • 7.4.2 Synthesis of 7-alkynyl-2,3-diphenylpyrido[2,3-b]pyrazine

    • 7.4.3 Buchwald-Hartwig amination of 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine

    • 7.4.4 Synthesis of 7-alkenyl-2,3-diphenylpyrido[2,3-b]pyrazine (Heck reaction)

    • 7.4.5 Synthesis of 7-aryl-2,3-diphenylpyrido[2,3-b]pyrazine (Suzuki reaction)

  • 7.5 Synthesis of imidazo[1,2-a]pyridine derivatives

    • 7.5.1 Synthesis of 6-bromo-2,3-diphenyl-imidazo[1,2-a]pyridine (218)

    • 7.5.2 Synthesis of [3-(2,3-diphenyl-imidazo[1,2-a]pyridin-6-yl)-prop-2-ynyl]-dimethylamine and related compounds (Sonogashira reaction)

    • 7.5.3 Buchwald-Hartwig amination of 6-bromo-2,3-diphenylimidazo[1,2-a]pyridine

  • 7.6 Synthesis of imidazo[1,2-b]pyridazine derivatives

    • 7.6.1 Synthesis of 6-chloro-2,3-diphenylimidazo[1,2-b]pyridazine (219)

    • 7.6.2 Synthesis of [3-(2,3-diphenyl-imidazo[1,2-b]pyridazin-6-yl)-prop-2-ynyl]-dimethylamine (223)

    • 7.6.3 Synthesis of [3-(2,3-diphenyl-imidazo[1,2-b]pyridazin-6-yl)-propyl]-dimethylamine (224)

  • 7.7 Synthesis of pyrimidine derivatives

    • 7.7.1 Synthesis of aryl substituted chloro- or iodopyrimidine

      • 7.7.1.1 Using general methods and starting with benzamidine

      • 7.7.1.2 Using Suzuki cross-coupling and starting with 2,4,6-trichloropyrimidine

    • 7.7.2 Sonogashira cross-coupling of halopyrimidines

      • 7.7.2.1 From 4-iodo-2,6-diphenylpyrimidine 251

      • 7.7.2.2 From 2-chloro-4,6-diarylsubstituted pyrimidine

    • 7.7.3 Nucleophilic substitution of 2-chloropyrimidine

      • 7.7.3.1 To introduce 3-dimethylamino-propylamino group

      • 7.7.3.2 To introduce 2-dimethylamino-ethoxy group

      • 7.7.3.3 To introduce 2-dimethylamino-ethylsulfanyl group

      • 7.7.3.4 To introduce 3-hydroxypropylamino group

  • 7.8 Synthesis of pyridine derivatives

    • 7.8.1 Synthesis of 2-amino-3,5-diphenylpyridine (283):

    • 7.8.2 Synthesis of 2-iodo-3,5-diphenylpyridine (284):

    • 7.8.3 Synthesis of 3-(3,5-diphenyl-pyridin-2-yl)-prop-2-ynyl]-dimethylamine(286):

    • 7.8.4  Synthesis of 3,5-diphenyl-2-(3-dimethylaminopropyl)-pyridine (287):

  • 7.9 Synthesis of pyrazine derivatives

    • 7.9.1 Synthesis of 5-chloro-2,3-diphenylpyrazine

    • 7.9.2 Synthesis of [3-(5,6-diphenyl-pyrazin-2-yl)-prop-2-ynyl]-dimethylamine (298):

    • 7.9.3  Synthesis of [3-(5,6-diphenyl-pyrazin-2-yl)-propyl]-dimethylamine (299):

  • 7.10 Synthesis of oxazole derivatives

    • 7.10.1 Synthesis of 4-bromo-2,5-diphenyloxazole (310):

    • 7.10.2 Synthesis of 4-alkyl-2,5-diphenyloxazole by Sonogashira reactions

    • 7.10.3  Buchwald-hartwig amination of 4-bromo-2,5-diphenyloxazole

  • 7.11 Synthesis of Pyrazole derivatives

    • 7.11.1 Synthesis of 4-iodo-3-methyl-1,5-diphenylpyrazole

    • 7.11.2 Dimethyl-[3-(3-methyl-1,5-diphenyl-pyrazol-4-yl)-prop-2-ynyl]-amine (322)

    • 7.11.3 Dimethyl-[3-(3-methyl-1,5-diphenyl-pyrazol-4-yl)-propyl]-amine (323)

  • 7.12 Synthesis imidazole derivatives

    • 7.12.1 Nucleophilic substitution of 4,5-diphenylimidazole

    • 7.12.2 Sonogashira cross-coupling of 1-benzyl-2-bromo-4,5-diphenylimidazole

• References

• Abbreviations

• Zusammenfassung

• Lebenslauf

• Selbständigkeitserklärung

• Publications from the thesis

• Table 2.1 Pyrazolo[1,5-a]pyrimidines 88 and 89

• Table 2.2 NMR data of of compounds 98, 99, 100 and 120 (δ, ppm)

• Table 2.3 3-Iodopyrazolo[1,5-a]pyrimidines 104a-104h

• Table 2.4 Pyrazolo[1,5-a]pyrimidines 106-111

• Table 2.5 Effect of reaction conditions of Sonogashira cross-coupling

• Table 2.6 Pd/C catalyzed Sonogashira reactions of 3-iodo-pyrazolo[1,5-a]pyrimidines

• Table 2.7 Reaction conditions of Sonogashira cross-coupling

• Table 2.8 Reaction conditions of Buchwald-Hartwig amination

• Table 5.1 Derivatives of pyrazolo[1,5-a]pyrimidine

• Table 5.2 Derivatives of other bicyclic heterocycle

• Table 5.3 Derivatives of pyrimidine

• Table 5.4 Derivatives of other monocyclic heterocycle

• Figure 1.1 Natural product inhibitors of calcineurin

• Figure 1.2 Synthetic inhibitors of calcineurin

• Figure 1.3 The generic structural component of guiding structure

• Scheme 1.1 Synthesis of pyrazolo[1,5-a]pyrimidines by ring-chain-transformation

• Figure 1.4 Potent bicyclic heterocyclic inhibitors

• Figure 1.5 Potent monocyclic heterocyclic inhibitors

• Figure 1.6 Synthetic target molecules

• Scheme 1.2 Disconnection of target molecules

• Scheme 1.3 Introducing branch chains by nucleophilic substitution

• Scheme 1.4 Catalytic cycle of coupling reactions of organometallic reagents

• Scheme 1.5 Example of the Negishi coupling reaction

• Scheme 1.6 Examples of the Stille coupling reactions

• Scheme 1.7 Example of the Suzuki coupling reactions

• Scheme 1.8 Example of the Kumada coupling reaction

• Scheme 1.9 Example of the Hiyama coupling reaction

• Scheme 1.10 Catalytic cycle of the Sonogashira coupling

• Scheme 1.11 Examples of the Sonogashira coupling reactions

• Scheme 1.12 Catalytic cycle of the Heck coupling

• Scheme 1.13 Examples of the Heck coupling reaction

• Scheme 1.14 Catalytic cycle of the Buchwald-Hartwig amination

• Scheme 1.15 Examples of the Buchwald-Hartwig amination

• Scheme 1.16 Intermolecular heteroaryl Heck reaction

• Scheme 1.17 Synthesis of 2,4-disubstituted pyrimidine

• Scheme 1.18 Regioselective Pd-catalyzed cross-couplings of polyhalopyridine

• Scheme 1.19 Regioselective Pd-catalyzed cross-coupling of halopyridines

• Scheme 1.20 Introducing aryl groups to heterocycles by Suzuki couplings

• Scheme 1.21 Introducing side chains by the Heck coupling

• Scheme 1.22 Introducing side chains by the Sonogashira coupling

• Scheme 1.23 Introducing side chains by the Suzuki coupling

• Scheme 1.24 Introducing side chains by the Negishi coupling

• Scheme 1.25 Introducing side chains by the Buchwald-Hartwig amination

• Scheme 2.1 Regioselective cross-coupling reactions of organzinc reagent with 5,7-dichloropyrazolo[1,5-a]pyrimidine

• Scheme 2.2 Suzuki corss-coupling of bromopyrazolo[1,5-a]pyrimidines

• Scheme 2.3 Synthesis of substituted pyrazolo[1,5-a]pyrimidines

• Scheme 2.4 Synthesis of hydroxypyrazolo[1,5-a]pyrimidines

• Scheme 2.5 Synthesis of 6-bromo-pyrazolo[1,5-a]pyrimidines

• Scheme 2.6 Synthesis of 7-halo-2,5-diphenylpyrazolo[1,5-a]pyrimidines

• Scheme 2.7 Synthesis of 5,7-dichloro- pyrazolo[1,5-a]pyrimidines

• Scheme 2.8 Synthesis of 3-halopyrazolo[1,5-a]pyrimidines

• Scheme 2.9 Synthesis of 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine

• Scheme 2.10 Heck cross-coupling of 3-halopyrazolo[1,5-a]pyrimidines with mono-substituted alkenes

• Scheme 2.11 Heck reactions of 3-iodopyrazolo[1,5-a]pyrimidines with di-substituted alkenes

• Scheme 2.12 Heck cross-coupling reaction of 100

• Scheme 2.13

• Scheme 2.14 Catalytic hydrogenations of 113a and 113b

• Scheme 2.15

• Scheme 2.16 Suzuki cross-coupling of 101 with phenylboronic acid

• Scheme 2.17

• Scheme 2.18

• Scheme 2.19

• Scheme 2.20

• Scheme 2.21

• Scheme 2.22

• Scheme 3.1

• Scheme 3.2

• Scheme 3.3

• Scheme 3.4

• Scheme 3.5

• Scheme 3.6

• Scheme 3.7

• Scheme 3.8

• Scheme 3.9

• Scheme 3.10 Pd-catalyzed couplings of halopurines with trimethylaluminium

• Scheme 3.11

• Scheme 3.12

• Scheme 3.13

• Scheme 3.14

• Scheme 3.15

• Scheme 3.16

• Scheme 3.17

• Scheme 3.18

• Scheme 3.19

• Scheme 3.20

• Scheme 3.21

• Scheme 3.22

• Scheme 3.23

• Scheme 3.24

• Scheme 3.25

• Scheme 3.26 Suzuki cross-couplings of 7-bromo-2, 3-diphenylpyrido[2,3-b]pyrazine

• Scheme 3.27

• Scheme 3.28

• Scheme 3.29

• Scheme 3.30

• Scheme 3.31

• Scheme 3.32

• Scheme 3.33

• Scheme 3.34

• Scheme 3.35

• Scheme 3.36

• Scheme 4.1

• Scheme 4.2

• Scheme 4.3

• Scheme 4.4

• Scheme 4.5

• Scheme 4.6

• Scheme 4.7

• Scheme 4.8

• Scheme 4.9

• Scheme 4.10

• Scheme 4.11

• Scheme 4.12

• Scheme 4.13

• Scheme 4.14

• Scheme 4.15

• Scheme 4.16

• Scheme 4.17

• Scheme 4.18

• Scheme 4.19

• Scheme 4.20

• Scheme 4.21

• Scheme 4.22

• Scheme 4.23

• Scheme 4.24

• Scheme 4 25

• Scheme 4.26

• Scheme 4.27

• Scheme 4.28

• Scheme 4.29

• Scheme 4.30

• Scheme 4.31

• Scheme 4.32 Synthesis of 3,5-diphenyl-2-(3-dimethylaminopropyl) pyridine

• Scheme 4.33

• Scheme 4.34

• Scheme 4.35

• Scheme 4.36

• Scheme 4.37

• Scheme 4.38

• Scheme 4.39

• Scheme 4.40

• Scheme 4.41

• Scheme 4.42

• Scheme 4.43

• Scheme 4.44

• Scheme 4.45

• Scheme 4.46

• Scheme 4.47

• Scheme 4.48

• Scheme 4.49

• Scheme 4.50

• Scheme 4.51

• Scheme 4.52

• Scheme 4.53

• Scheme 4.54

• Scheme 4.55

• Scheme 4.56

• Scheme 4.57

• Scheme 4.58

• Scheme 4.59

• Scheme 4.60

• Scheme 4.61

• Scheme 4.62

• Scheme 4.63

• Figure 5.1

• Figure 5.2

• Figure 5.3

• Figure 5.4

• Figure 5.5

• Figure 5.6

• Figure 5.7

• Figure 5.8

• Figure 5.9

• Figure 6.1 General Structure 8

• Figure 6.2 General Structures of Karanik’s thesis

• Scheme 6.1

• Scheme 6.2

• Figure 6.3

• Scheme 6.3

• Scheme 6.4

• Scheme 6.5

• Figure 6.5

• Scheme 7.1

• Scheme 7.2

• Scheme 7.3

• Scheme 7.4

• Scheme 7.5

• Scheme 7.6

• Scheme 7.7

• Scheme 7.8

• Scheme 7.9