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Metal-Catalyzed and Metal-Free Syntheses of

Von der Fakultät für Mathematik, Informatik und Naturwissenschaften
der RWTH Aachen University
zur Erlangung des akademischen Grades
eines Doktors der Naturwissenschaften
genehmigte Dissertation
vorgelegt von

Ankur Pandey
(Master in Organic Chemistry)

aus Pune, India

Berichter: Universitätsprofessor Dr. C. Bolm
Universitätsprofessor Dr. D. Enders

Tag der mündlichen Prüfung: 26.08.2011
Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.

The work presented in this thesis was carried out from October 2006 until December 2010,
at the Institute of Organic Chemistry, RWTH Aachen University, under the supervision of
Professor Dr. Carsten Bolm.

I would like to thank Prof. Dr. Carsten Bolm for the interesting research topic, excellent
support and working conditions in the laboratory. I would also like to thank my second
examiner Prof. Dr. Dieter Enders.

Part of this work has already been published:
Pandey, A.; Bolm, C. Synthesis 2010, 2922.
Pandey, A.; McGrath, M. J.; Mancheño-Garcia, O.; Bolm, C. Synthesis 2011 (Accepted for

Table of Contents

1. Introduction 9
1.1. Introduction to sulfoximines 9
1.2. Synthesis of sulfoximines: Introduction 11
1.3. Imination of sulfides/sulfoxides 14
1.3.1. Synthesis of sulfoximines under metal-free
conditions 14 Iminations of sulfoxides using hydrazoic acid 15 O-Mesitylenesulfonylhydroxylamine (MSH) 15 N-Aminophthalimide 17 Electrochemical Method 18 HMDS and 3-acetoxyaminoquinazoline 19 Iodobenzene diacetate 20 Cyanogen amide 20
3 Sulfonylimino-λ -bromane 21
1.4. Metal-catalyzed imination reactions of sulfides/sulfoxides 22
1.4.1. Metal-catalyzed synthesis of sulfoximines: General Introduction 22 Bach’s procedure 23 Müller’s procedure 24 Malacria’s procedure 25 Tye’s procedure 26 Katsuki’s Mn-salen catalyzed procedure 28 Katsuki’s Ru-salen catalyzed procedure 29 Bolm’s rhodium catalyzed procedure 31 Bolm’s silver catalyzed procedure 32 Bolm’s iron (III) catalyzed procedure 33 Bolm’s iron (II) catalyzed procedure 34 Comparative study of metal-catalyzed iminations of
sulfides and sulfoxides 36
1.5. Alternative methods for the synthesis of sulfoximines 38
1.5.1. From other sulfoximines 38 Synthesis of allylic and vinylic sulfoximines 38 Synthesis of N-substituted sulfoximines 44 Heterocyclic sulfoximines 52
1.6. Uses of sulfoximines in medicinal chemistry 62

2. Results and Discussion 66
2.1. Metal-free synthesis of N-cyano sulfilimines and sulfoximines 66
2.1.1. Research objective 68
2.1.2. Synthesis of N-cyano sulfilimines 68
2.1.3. Synthesis of N-cyano sulfoximines 71
2.1.4. Deprotection of N-cyano sulfoximines 72
2.2. In search for an alternative nitrogen source for imination at sulfur
atom of a sulfide/sulfoxide 73
2.2.1. Research objective 75
2.2.2. Attempts at using different nitrogen sources as iminating agents 75
2.3. Attempted C-C coupling reactions of sulfoximines 80
2.3.1. Research objective 81
2.3.2. Attempts at aryl cross coupling reactions with N-substituted
methyl phenyl sulfoximines 81
2.4. Synthesis of a heterocyclic and a bioactive sulfoximine 86
2.4.1. Research objective 88
2.4.2. Synthesis of heterocyclic sulfoximines 89
2.4.3. Synthesis of an enantiopure sulfoximine analogue of myristic acid 92

3. Summary and Outlook 99
3.1. Metal-free synthesis of N-cyano sulfilimines and sulfoximines 99
3.2. In search for an alternative nitrogen source for imination at sulfur
centre of a sulfide/sulfoxide 100
3.3. Attempted C-C coupling reactions of sulfoximines 100
3.4. Synthesis of a heterocyclic and a bioactive sulfoximine 101

4. Experimental Section 103
4.1. General information 103
4.2. Solvents 103
4.3. Chromatography 104
4.4. Determination of physical data 104
4.4.1. Optical rotations 104
4.4.2. Melting points 105
4.4.3. HPLC analysis 105
4.4.4. IR spectroscopy 105
4.4.5. Mass spectroscopy 105
1 4.4.6. H NMR spectroscopy 105
13 4.4.7. C NMR spectroscopy 106
4.4.8. HRMS analysis 106
4.5. Synthesis of substrates 106
4.6. General procedure for the synthesis of N-cyano sulfilimines 107
4.6.1. N-cyano methyl phenyl sulfilimine 107
4.6.2. N-cyano benzyl methyl sulfilimine 108
4.6.3. N-cyano di-phenyl sulfilimine 109
4.6.4. N-cyano tert-butyl methyl sulfilimine 110
4.6.5. N-cyano methyl 4-nitrophenyl sulfilimine 111
4.6.6. N-cyano methyl 4-methoxyphenyl sulfilimine 111
4.7. General procedure for the synthesis of N-cyano sulfoximines 112
4.7.1. N-cyano methyl phenyl sulfoximine 112
4.7.2. N-cyano benzyl methyl sulfoximine 113
4.7.3. N-cyano di-phenyl sulfoximine 114
4.7.4. N-Cyano tert-butyl methyl sulfoximine 115
4.7.5. N-cyano methyl 4-nitrophenyl sulfoximine 116
4.7.6. N-cyano methyl 4-methoxyphenyl sulfoximine 116
4.8. Synthesis of NH-sulfoximine 117
4.8.1. NH-methyl phenyl sulfoximine 117
4.9. Synthesis of heterocyclic sulfoximine 118
4.9.1. Synthesis of N-(tert-butyldi-phenylsilyl)(2-bromophenyl)ethyl
di-methyl sulfoximine 118
4.9.2. Synthesis of (2-bromophenyl)ethyl di-methyl sulfoximine 120
4.9.3. Synthesis of 2λ4-2,2-benzothiazine-3,4-dihydro-2-methyl-2-oxide 121
4.10. Synthesis of sulfoximine myristic acid analogue 122
4.10.1. Synthesis of (−)-bromophenyl methyl sulfoxide 122
4.10.2. Synthesis of (−)-methyl n-tridecyl sulfoxide 123
4.10.3. Synthesis of (−)-N-tosyl methyl n-tridecyl sulfoximine 124
4.10.4. Synthesis of (−)-N-nosyl methyl n-tridecyl sulfoximine 125
4.10.5. Synthesis of (−)-NH-methyl n-tridecyl sulfoximine 126
4.10.6. Synthesis of (−)-N-nosyl methyl n-tridecyl sulfoximine from
(−)-NH-methyl n-tridecyl sulfoximine 127

5. Refernces 129
6. Appendix 140
6.1. List of Abbreviations 140
6.2. Acknowledgements 145
6.3. Curriculum Vitae 146 1. Introduction

1. Introduction
1.1. Introduction to sulfoximines
1Sulfoximines as a class of compounds were first discovered in the late 1940’s, during the
2search for a toxic substance, formed as a result of bleaching wheat with NCl . In 1949, 3
Bentley and Whitehead isolated and identified a molecule with the empirical formula
C H N O S and formally regarded it as being derived from methionine sulfoxide by addition 5 12 2 3
of NH or from methionine sulfone by the replacement of O by NH and proposed the
possibility of the sulfur atom to be asymmetric which they later confirmed. This new class of
compounds was called sulfoximines and the sulfoximine derivative of methionine, identified
as the toxic factor for the disease canine hysteria, was termed methionine sulfoximine
3(Figure 1).

(2S,5S)-methionine sulfoximine
Figure 1

Sulfoximines, the monoaza analogues of sulfones have several interesting features. They
have a distorted tetrahedral structure with S-N bond lengths (d = 153.7 pm) lying between a
typical S-N single bond and a S-N triple bond (d = 144.1 pm). This data coupled with IR data
provides evidence for the presence of double bond character of the S-N and S-O bonds in
1 2sulfoximines. The sulfur atom is stereogenic in nature (R ≠ R ). The nitrogen attached to the
sulfur atom has a nucleophilic character. Hydrogen atoms α to the S-atom are acidic and
3 3their acidity depends greatly on the R group present on the N-atom (pKa = 32 if R = Me,
3 1g, 4pKa = 23 if R = Ts) (Figure 2).
1. Introduction

Nucleophilic N-atomStereogenic S-atom
1 2(only if R = R )
S1 2R R
Acidic H-atom
3(Acidity depends on R )

Figure 2

Sulfoximines are constitutionally and configurationally very stable compounds and serve an
1g-k, 5important role in asymmetric synthesis as ligands or chiral auxiliaries. They have also
6been used as building blocks of pseudopeptides and are known to exhibit biological
8Since the first reported synthesis of an enantiopure sulfoximine in 1965, several strategies
for their preparation have been developed, however they have largely been limited to the
preparation of diaryl or alkyl aryl sulfoximines. Several bioactive dialkyl sulfoximines are
known but the effect of absolute configuration of the sulfur centre on the potency of some
of these compounds has not been determined. For example, (S,S)-methionine sulfoximine
(1) has been identified as the most active diastereoisomer for the inhibition of glutathione
3csynthetase while the sulfoximine myristic acid analogue (2) that exhibits monoley leukemia
9virus (MoLV) replication antagonism has only been used as a racemate.

H C C H3 13 27
Figure 3


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