Computational and Experimental Studies of Allylic C-H Functionalization of Internal Olefins via Group IX Metal-Pi-Allyl Intermediates and Invention of a Chiral Indenylrhodium(III) Catalyst Open Access

Kowal-Safron, Thomas (Spring 2020)

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Transition metal-catalyzed allylic C-H functionalization has found its place on the cutting edge of C-H functionalization due to its vast potential to access allylic C-H bonds for direct modification. Recent advances of this methodology have significant applications in pharmaceutically relevant syntheses for more facile methodologies that will curtail cost and waste generation. Based on the elucidation of reaction conditions that facilitated the regioselective allylic C-H amination of internal olefins by Blakey, it was hypothesized that similar reaction conditions for allylic C-H alkylation with malonate-derivative carbon nucleophiles could be developed. An optimization study was carried out using dimethyl malonate as the nucleophile for the alkylation of 1,3-trans-diphenylpropene. The optimal reaction conditions were found to tolerate five malonate-derivative carbon nucleophiles, and it was noted that all compatible nucleophiles had some combination of nitro, ketone, or ester functionalities. Additionally, eight of the potential nucleophiles were found to be incompatible with the optimal reaction conditions. Mechanistic studies were carried out that supported the hypothesis that this reaction goes through a similar mechanism to that elucidated for the allylic C-H amination reaction. Following this investigation, a computational study was carried out to discover the origins of the complementary regioselectivity profiles reported by Blakey for the allylic C-H amidation of the asymmetric internal olefinic substrate 1-phenylbut-2-ene with tertbutyl dioxazolone via Rh(III)Cp* or Ir(III)Cp* catalysis. Using density functional theory calculations with distortion/interaction-activation fragment analysis, it was found that rhodium imbues significantly more distortional strain in the transition state at the rate determining step than iridium does, and this difference leads to complementary regioselectivity profiles. Finally, a study into the invention of a novel chiral indenylrhodium(III) sulfoxide catalyst was undertaken. Previous reports indicated that indenyl ligand scaffolds could catalyze organometallic syntheses with much higher rates, regio-, and enantioselectivity than other popular ligand scaffolds such as cyclopentadienyl ligands. Although the development of a novel chiral indenylrhodium(III) sulfoxide complex is ongoing, its successful synthesis and application in enantioselective allylic C-H functionalization will represent a significant advance in this field by offering unprecedented regio- and stereocontrol of allylic C-H functionalization reactions.

Table of Contents

1. Introduction 1-6

2. Results and Discussion 6-34

2.1. Allylic C-H Alkylation 6-14

2.2. Probing the Regioselectivity of Rhodium versus Iridium Catalysts 14-28

2.3. Development of a Novel Chiral Indenylrhodium Catalyst 28-34

3. Conclusions and Future Directions 34-36

4. Supplemental Information 36-53

4.1. General Information 36-37

4.2. Materials Preparation 37-51

4.3. Procedures for the Density Functional Theory Calculations 51-53

5. References 53-57


1. Palladium-catalyzed accession of a π-allyl complex 2

2. Rhodium (III)-catalyzed allylic C-H functionalization of a terminal alkene 2

3. Isolation of a Rh(III) π-allyl complex 3

4. Complementary regioselectivity profiles in allylic C-H amidation 4

5. Illustration of the indenyl “ring slip” phenomenon 5

6. Overview of the reaction conditions subject to optimization for allylic C-H alkylation 7

7. Reaction conditions for the silver mechanistic study 13

8. Reaction conditions for the rhodium mechanistic study 14

9. Complementary regioselectivity profiles in allylic C-H amidation 15

10. General mechanistic hypothesis used to construct energy profiles 19

11. Energy profile of Rh(III)-catalyzed allylic C-H amidation 20

12. Energy profile of Ir(III)-catalyzed allylic C-H amidation 21

13. Molecular orbital diagrams of rhodium intermediates 24

14. Rhodium (III) distortion/interaction-activation fragment analysis 25

15. Iridium (III) distortion/interaction-activation fragment analysis 26

16. Illustrations of the distorted dioxazolone fragments 27

17. Synthetic scheme for the indenyl-sulfoxide ligand scaffold 28

18. Reflux complexation attempts 31

19. Microwave complexation attempt 32

20. Current attempts at complexation 33


1. Optimization of the dimethyl malonate reaction 8

2. Scope of malonate-type carbon nucleophiles for allylic C-H alkylation 10

3. Transition states for reductive elimination from nitrenoid intermediates 17

4. Transition states for reductive elimination from bidentate intermediates 18

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