Broadening the applications of rhodium donor/acceptor carbene mediated C–H functionalization Restricted; Files Only

Zhang, Bowen (Summer 2020)

Permanent URL: https://etd.library.emory.edu/concern/etds/7s75dd61h?locale=en
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Abstract

ABSTRACT

The first chapter is a general review of rhodium stabilized carbenes and their reactions, including introduction of basic concepts, development of carbene reactions and metal catalysts as well as recent progress with rhodium donor/acceptor carbene in C–H functionalization.

The second chapter is focused on exploring new reactions with rhodium vinyl carbenes, a special type of donor/acceptor carbene. A novel reaction of siloxydienes with E-vinyldiazoacetates in the presence of the bulky chiral dirhodium tetracarboxylate catalyst, Rh2(R-p-PhTPCP)4 results in an enantioselective [4+2] cycloaddition, in which three new stereogenic centers are formed.  The [4+2] cycloadducts are generated as single diastereomers with high enantiocontrol (95-98% ee). When the diene contains an additional stereogenic center, effective kinetic resolution can be achieved.

The third chapter is focused on solving the limitation of the fixed aryl-ester moiety in products from our rhodium donor/acceptor carbene chemistry. The first attempt was exploring the reactivity profile of acceptor only carbene under our latest dirhodium catalysts. Secondary and tertiary selective C–H insertion with 2-methylpentane were achieved in moderate to good site-selectivity. However, these results did not surpass previous studies with other metal catalysts. Further test reactions with pentane showed serious issues of site-selectivity compared to donor/acceptor carbenes. The second attempt was to check the behavior of asymmetric cyclopropanation with rarely used donor only carbenes generated from retro-Büchner reaction under rhodium catalysis. The best ee achieved is 30%, suggesting poor catalyst-controlled chiral induction for donor only carbenes. The third try of developing general derivatizations of products from our rhodium donor/acceptor carbene turned out to be successful. Firstly, derivatization by removing the aryl part through Ru(VIII) oxidation/decarboxylation was studied. A few examples were achieved but the strong Ru(VIII) oxidation has narrow functional group tolerance. Therefore, we moved our focus to removing the ester part and a general derivatization was developed using hydrolysis followed by a photoredox decarboxylation. Under these mild conditions, various unique C–H functionalization compounds reported by our group were transformed to formal benzylation type of products in good yield and with maintained high stereoselectivity.

The fourth chapter describes a C–H functionalization approach for the synthesis of chiral C2 symmetric 1,5-cyclooctadienes ligands. This is an example of applying our rhodium donor/acceptor carbene chemistry on relatively simple molecules to generate valuable chiral products. Chiral cyclooctadiene (COD) derivatives are readily prepared by rhodium-catalyzed allylic C–H functionalization of COD. Either mono- or di-functionalization of COD is possible generating the products in high yield, diastereoselectivity and enantioselectivity. The double C–H functionalization generates C2 symmetric COD derivatives with four new stereogenic centers in >99% ee, which can be readily converted to a series of chiral COD ligands. Preliminary evaluations revealed that these COD ligands can be used in rhodium-catalyzed asymmetric arylation of cyclohex-2-enone, leading to the conjugate addition products in up to 76% ee.

The last chapter covers my experimental studies with an unusual observation initially discovered by Dr. Wenbin Liu. A direct cyclopropanation with N-sulfonyl piperidines and rhodium donor/acceptor carbenes was observed as minor byproducts during her piperidine C2 insertion studies. This unexpected observation intrigued us to explore the possibility of a catalyst controlled direct cyclopropanation of protected piperidines, which would save the trouble of preparing enamines as substrates as described in our reported methodology.  Therefore, a systematic optimization was performed with this reaction regarding factors such as dirhodium catalysts, aryldiazoacetates, and reaction solvents. The best ratio of desired cyclopropanation versus the standard C2 insertion obtained to date was 1.87 : 1, suggesting achieving clean cyclopropanation will be challenging. Miscellaneous studies with other protected cyclic amines under the same conditions observed no cyclopropanation, suggesting the unique structural properties of N-sulfonylpiperidines for this type of reaction.

Table of Contents

TABLE OF CONTENTS

ABSTRACT................................................................................................................................5

ACKNOWLEDGEMENTS........................................................................................................7

TABLE OF CONTENTS............................................................................................................8

LIST OF DIRHODIUM CATALYSTS....................................................................................13

CHARPTER ONE  Overview of Rhodium Carbene Chemistry ............................................14  

1.1  Introduction........................................................................................................................14

1.2  Conclusion.........................................................................................................................21

References................................................................................................................................22

CHARPTER TWO  Enantioselective [4+2] Cycloaddition of Rh-vinylcarbenes with Dienes

 ..................................................................................................................................................27  

2.1  Introduction........................................................................................................................27

2.2  Early optimization study....................................................................................................33

2.3  Reaction scope for the Rh2(S-p-PhTPCP)4 catalyzed 4+2 cycloaddition..........................34

2.4  Detailed study for the kinetic resolution in the 4+2 cycloaddition....................................35

2.5  Diene steric influence on the 4+2 cycloaddition................................................................36

2.6  Proposed reaction mechanism............................................................................................37

2.7  Conclusion .........................................................................................................................37

References................................................................................................................................38

CHARPTER THREE  Broadening the Application of Rhodium Carbene chemistry............40

3.1  Introduction........................................................................................................................40

3.2  Exploring site-selective intermolecular C–H insertion with Rh acceptor only carbene....45

3.2.1  Early study of alkyl diazoester as carbene precursor .........................................46

3.2.2  Rh acceptor-only carbene mediated site-selective C–H insertion reactions  ......46

3.2.2.1  Test reactions with 2-methylpentane as substrate .......................................47

3.2.2.1.1  Study of site-selective tertiary (3°) C–H insertion .......................47

3.2.2.1.2  Study of site-selective secondary (2°) C–H insertion ...................49

3.2.2.2  Preliminary test reactions with pentane as substrate ...................................53

3.2.2.3  Preliminary test reactions for benzylic C–H insertion.................................54

3.2.3  Conclusion for site-selective C–H insertion with Rh acceptor-only carbene….54

3.3  Asymmetric cyclopropanation with Rh donor-only carbene generated from retro-Büchner reaction.....................................................................................................................................55

3.3.1  Introduction ........................................................................................................55

3.3.2  Chiral dirhodium catalysts screening .................................................................56

3.3.3  Conclusion for asymmetric cyclopropanation with Rh donor-only carbene ......57

3.4 Derivatization of C–H insertion products from Rh donor/acceptor carbene ......................58

3.4.1  Remove aryl of C–H insertion products from Rh donor/acceptor carbene ........58

3.4.1.1  Ru(VIII) oxidation/decarboxylation with benzylic C–H insertion products....59

3.4.1.2  Ru(VIII) oxidation/decarboxylation with other C–H insertion products........61

3.4.1.3 Conclusion for the Ru(VIII) oxidation/decarboxylation derivatization...........62

3.4.2  Remove ester of C–H insertion products from Rh donor/acceptor carbene .......62

3.4.2.1  Hydrolysis/decarboxylation with 3° C–H insertion products.......................63

3.4.2.2  Hydrolysis/decarboxylation with 2° C–H insertion products.......................64

3.4.2.2.1 Derivatization of products from Rh2(S-2-Cl,5-BrTPCP)4 catalysts..65

3.4.2.2.2 Derivatization of products from Rh2(S-TPPTTL)4 catalysts...........67

3.4.2.3  Demonstrating the aryl scope with Ac-protected Cholesterol 3° C–H    

             formal benzylation.......................................................................68

3.4.2.4 Conclusion for hydrolysis/decarboxylation derivatization ...............69

References................................................................................................................................69

CHARPETER FOUR  C–H Functionalization Approach for the Synthesis of Chiral C2 Symmetric 1,5-cyclootadienes Ligands ...............................................................................72

4.1  Introduction...................................................................................................................................72

4.2  Mono-allylic C–H functionalization experiments...................................................................75

4.2.1  Catalyst optimization study.............................................................................................75

4.2.2  Diazo compound scope for the mono allylic C–H functionalization..............................76

4.3  Double-allylic C–H functionalization experiments.................................................................77

4.4  Evaluation of related cycloalkanes.............................................................................................78

4.5  Evaluation of C2 symmetric chiral COD ligands for enantioselective conjugate addition..79

4.5.1  Evaluation of chiral COD ligands directly from bis-allylic C–H insertion.....................79

4.5.2  Evaluation of the further derivatized chiral COD ligands................................................80

4.6  Conclusion.........................................................................................................................80

References................................................................................................................................81

CHARPTER FIVE  Exploring the Direct Cyclopropanation with N-sulfonyl Protected 

Piperidines ................................................................................................................................83

5.1 Introduction.........................................................................................................................83

5.2 Optimization study..............................................................................................................86

5.2.1  Stoichiometry influence..........................................................................................86

5.2.2  Solvent influence....................................................................................................87

5.2.3  N-sulfonyl protecting group (PG) influence (part I) ..................................................88

5.2.4  Temperature influence5.2.1 Stoichiometry influence.................................................88

5.2.5  Dirhodium catalyst influence (part I)........................................................................89

5.2.6  N-sulfonyl protecting group (PG) influence (part II) .................................................90

5.2.7  Aryl diazoester influence.........................................................................................91

5.2.8  Dirhodium catalyst influence (part II).......................................................................92

5.3  Extension study with different cyclic amine substrates or protecting group.....................93

5.4  Conclusion .........................................................................................................................94

References ................................................................................................................................95

CHARPTER SIX   Experimental Procedure............................................................................96

6.1  Chapter 2 (Experimental procedure)...................................................................................96

6.1.1  General procedure for diene synthesis ................................................................96

6.1.2  General procedure for vinyl diazo compounds..................................................100

6.1.3  General Procedure for 4+2 cycloaddition and miscellaneous............................103

References ..............................................................................................................................110

6.2  Chapter 3 (Experimental procedure).................................................................................111

6.2.1 Exploring site-selective C–H insertion with Rh acceptor only carbene.................111

*General method for the preparation of acceptor-only diazo compounds............................111

6.2.2  Asymmetric cyclopropanation with Rh donor-only carbene generated from retro-

         Büchner reaction ................................................................................................116

*General procedure for the retro-Buchner reaction............................................................116

References  for 6.2.1 and 6.2.2.......................................................................................116

6.2.3  Derivatization of C–H insertion products from Rh donor/acceptor carbene ....117

6.2.3.1  Remove the aryl of  insertion products from Rh donor/acceptor carbene....117

6.2.3.1.1  Experimental procedure for C–H insertion reactions..................117

6.2.3.1.2  General procedure for the Ru(VIII) mediated oxidation...............120

6.2.3.1.3  General procedure for the microwave-assisted decarboxylation...121

6.2.3.2  Remove the ester of insertion products from Rh donor/acceptor carbene....123

6.2.3.2.1  Experimental procedure for C–H insertion reactions..................123

6.2.3.2.2  General procedure for the Zn/AcOH hydrolysis..........................133

6.2.3.2.3  Procedure for recrystallization of carboxylic acid intermediates...143

6.2.3.2.4  General procedure for the photoredox decarboxylation...............146

References  for 6.2.3.....................................................................................................155

6.3  Chapter 4 (Experimental procedure).................................................................................156

6.3.1  General procedure for the diazo compound synthesis...........................................157

6.3.2  General Procedure for mono-allylic-insertion...................................................157

6.3.3  General Procedure for bis-allylic-insertion........................................................166

6.3.4  Derivatization for Bis-insertion C2 symmetric chiral COD ligands...................172

6.3.5  General Procedure for conjugate addition test..................................................179

References ..............................................................................................................................180

6.4  Chapter 5 (Experimental procedure).................................................................................181

6.4.1  General procedure for sulfonyl cyclic amine substrates.....................................181

6.4.2  Procedure for TBS protected cyclic amine substrates.......................................183

6.4.3  General procedure for N-sulfonyl piperidine direct cyclopropanation..............184

References ..............................................................................................................................184

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