Expanding the Scope of Donor/Acceptor Carbenes and the Synthesis of Novel Therapeutic Agents for Cocaine Abuse Open Access

Alford, Joshua Shane (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/9s161632h?locale=en


Donor/acceptor metallocarbenes are capable of undergoing many synthetically useful transformations primarily catalyzed by dirhodium(II) complexes. It is well established that the donor group plays a crucial role in modulating the reactivity of these donor/acceptor metallocarbenes. Therefore, it is great interest to expand the range of the donor groups to heteroatoms; however, strongly donating groups tend to decrease the thermal stability of the carbene precursor.

The second chapter is devoted to exploring whether it is feasible to expand the "donor" group to amino or alkoxy functionality. A major breakthrough in this area was discovered using a different type of carbene precursor, the N-sulfonyl triazole. This was a very important advance because these types of diazo compounds were previously too unstable to be isolated. The first part describes the development of 4-amino N-sulfonyl triazoles, which participate in the stereoselective cyclopropanation of olefins. A variety of alkenes and dienes undergo a highly diastereoselective cyclopropanation leading to a-amino cyclopropylcarboxaldehydes in good to excellent yields. Furthermore, the reaction can be conducted in a one-pot procedure starting from the N-ethynylphthalimide. The second part of this chapter describes the extension of this breakthrough to 4-oxy N-sulfonyl triazoles, which also participate in an enantioselective cyclopropanation of styrene derivatives. During these studies, a novel amino acylation reaction that is specific to this class was discovered. This transformation includes a multicomponent one-pot cascade reaction creating four different bonds regioselectively.

The third chapter focuses on extending the N-sulfonyl triazole methodology for the synthesis of alkenyl carbene precursors. During these studies, it was discovered that in the absence of a suitable trapping agent, 4-alkenyl N-sulfonyl triazoles participate in a rhodium(II)-catalyzed 4p-electrocyclization with the adjacent alkenyl moiety to furnish 2,3-fused pyrroles. The reaction was further extended to the synthesis of substituted indoles.

The fourth chapter focuses selective C-H functionalization of tertiary C-H bonds with N-sulfonyl triazoles, which are typically inaccessible to diazoacetates. The change in chemoselectivity towards tertiary C-H bonds is attributed to the lower steric demand of the imino carbene compared to the keto carbene.

Table of Contents

Table of Contents
Chapter I: Introduction to Donor/Acceptor Carbene Chemistries

1.1 Diazo Compounds...1
1.2 Metallocarbenes...4

1.2.1 Cyclopropanation of olefins...6
1.2.2 C-H functionalization...8

1.3 Diazo Synthesis...9

1.3.1 Nitrosation of an amine...10
1.3.2 Bamford-Stevens Reaction...11
1.3.3 The Forster reaction...12
1.3.4 Terminal diazo ketone synthesis...12
1.3.5 Regitz diazo transfer...13

Chapter II: Introduction of a Heteroatom Donor Group into the Donor/Acceptor Metallocarbene Scaffold

2.1 Introduction...14
2.2 Synthesis of N-Sulfonyl Triazoles...19

2.2.1 The Copper-Catalyzed Azide Alkyne Cycloaddition...20
2.2.2 The Anionic Azide Alkyne Cycloaddition...26

2.3 Ring Opening/Rearrangement of Triazoles...27
2.4 Early Reaction Development of N-Sulfonyl Triazoles...29

2.4.1 Imidazole synthesis from nitriles...30
2.4.2 Pyrrole synthesis from alkynes...31
2.4.3 Cyclopropanation of olefins...33

2.5 Development of a 4-Amino-N-Sulfonyl Triazole...36
2.6 Reactions of a 4-Amino-N-Sulfonyl Triazole...45
2.7 Development of 4-Oxy-N-Sulfonyl Triazoles...58
2.8 Conclusion...73

Chapter III: Utilizing N-Sulfonyl Triazoles for Heterocycle Synthesis

3.1 Introduction...75

3.1.1 Early reports with N-sulfonyl triazoles...75
3.1.2 New heterocycle syntheses with N-sulfonyl triazoles...77

3.2 Investigations into Alkenyl N-Sulfonyl Triazoles...86
3.3 Cyclization Reactions of Alkenyl N-Sulfonyl Triazoles...89

3.3.1 Fused pyrrole synthesis...89
3.3.2 Substituted indole synthesis...94
3.3.3 Acyclic pyrrole synthesis...98

3.4 Summary...100

Chapter IV: C-H Functionalization of Tertiary C-H Bonds with N-Sulfonyl Triazoles

4.1 Introduction...101
4.2 Preliminary Results...108
4.3 Conclusion...113

Chapter V: The Study of Rh2(S-ptad)4 with Various Substituted Methyl Phenyldiazoacetates

5.1 Introduction...115
5.2 Results and Discussion...116
5.3 Conclusion...118

Chapter VI: Efforts Towards The Design and Synthesis of Therapeutic Agents for Cocaine Addiction

6.1 Introduction...120
6.2 Results and Discussion...124

6.2.3 Cross-coupling derivation...135

6.3 Biological Data...139
6.4 Conclusion...143

Experimental Part
General Methods...144
7.1 Experimental Part to Chapter 2...145

Starting Materials...145
General Procedure 2.1 for Cyclopropanation of Triazole (GP 2.1):...150
General Procedure 2.2 for One-Pot Cyclopropanation Starting from the Ynimide (GP 2.2):...151
General Procedure 2.3 for Pinnick Oxidation of Aldehyde to Acid (G.P. 2.3):...163
General Procedure 2.4 for Phthalimide Deprotection (G.P. 2.4):...169
General Procedure 2.5 for Phthalimide Deprotection (G.P. 2.5):...169
General Prodecure 2.6 for CuTC-catalyzed Azide-Alkyne Cycloaddition (G.P. 2.6):...174
General Procedure 2.7 for Indole Acylation from an Enol N-Sulfonyl Triazole (G.P. 2.7):...181
General Procedure 2.8 for Indole Acylation from Ynol Ether (G.P. 2.8):...182
General Procedure 2.9 for Indole Acylation from an Ynol Ether (Conventional heating and Scale-Up; G.P. 2.9):...183
General Procedure 2.10 for Dearomatizing [3+2] Annulation of C(3)-Substituted Indoles with 4-Oxy N-Sulfonyl Triazoles (G.P. 2.10):...197
General Procedure 2.11 for Pyrrole Acylation from Enol N-Sulfonyl Triazoles (G.P. 2.11):...201

7.2 Experimental Part to Chapter 3...207

Starting Materials...207
General Procedure for Enyne Synthesis (G.P. 3.1):...207
General Procedure 3.2 for CuTC-catalyzed Azide-Alkyne Cycloaddition (G.P. 3.2):...216
General Procedure 3.3 for Electrocyclization of Triazole (G.P. 3.3):...227
General Procedure 3.4 for One-Pot Pyrrole Sythesis Starting from the Enyne (G.P. 3.4):...228
General Procedure 3.5 for One-Pot Indole Sythesis Starting from the Enyne (G.P. 3.5):...243

7.3 Experimental Part to Chapter 4...251
7.4 Experimental Part to Chapter 5...267

General Procedure for the Synthesis of Methyl Phenyldiazoacetates...267
General Procedure 5.1 for the Synthesis of Methyl Phenylcyclopropanecarboxylates with Rh2(S-PTAD)4 (G.P. 5.1):...267
General Procedure 5.2 for the Synthesis of Methyl Phenylcyclopropanecarboxylates with Rh2(R-DOSP)4 (G.P. 5.2):...268

7.5 Experimental Part to Chapter 6...282

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