Synthesis and Reactivity of Novel Benzoisothiazolone Organocatalysts for Redox Condensation Reactions Open Access

Morimoto, Mariko (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/n583xv045?locale=en
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Abstract

In oxidation-reduction condensation reactions, loss of water can be driven stoichiometrically through the use of an organic reductant--most typically triphenylphosphine--and an organic oxidant. These traditional dehydration methods, however, are largely wasteful processes that are additionally accompanied by the use of hazardous oxidants and inseparable products. The objective of this project is to streamline redox dehydration reactions by optimizing a catalytic approach that involves the coupling of an organocatalytic benzoisothiazolone (BIT) as the oxidant and O2 in the air as the terminal oxidant with triethylphosphite as the reductant (instead of triphenylphosphine), thus eliminating chemical waste and enhancing energy efficiency. Several novel BIT analogs retaining N-2 or N-4 pyridyl functionalization both with and without nitro-substitution on the primary aromatic ring were successfully synthesized. BIT catalyzed peptide reactions were performed open to air at room temperature and at 50ºC in acetonitrile and THF, and the carboxylic acid to amide % conversions were compared over a period of 24 h.

Table of Contents

Introduction 1

Mechanistic Complexities 5

Results and Discussions 7

I. Synthesis of Benzoisothiazolone Organocatalysts 7

II. Catalytic Studies of Benzoisothiazolone Organocatalysts 11

Conclusions and Future Directions 18

Experimental 19

References 28

Figures, Tables, and Schemes:

Figure 1: Prototype of benzoisothiazolone organocatalysts 3

Figure 2: BIT organocatalyst screening in acetonitrile at room temperature over 24h 12

Figure 3: BIT organocatalyst screening in acetonitrile at 50ºC over 24h 13

Figure 4: Crystal structure of 5-nitro-2-(pyridin-2-yl)benzo[d]isothiazol-3(2H)-one 14

Figure 5: Proposed mechanism of phosphate attack 15

Figure 6: BIT organocatalyst screening in THF at 50ºC over 24h 16

Scheme 1: Dehydrative bond forming reactions can be acylative, alkylative, or arylative 1

Scheme 2: Presumed aerobic catalytic cycle of BIT in acylative bond formation 4

Scheme 3: Proton-facilitated thioester pathway for N-alkyl BITs in non-polar solvents 5

Scheme 4: The direct deoxygenation pathway for N-aryl BITs in polar solvents 6

Scheme 5: Initial synthesis attempt for 2-(tert-butylthio)-5-nitro-N-(pyridin-2-yl)benzamide 7

Scheme 6: Synthesis pathway of 5-nitro-2-(pyridin-2-yl)benzo[d]isothiazol-3(2H)-one 9

Scheme 7: Initial synthesis attempt of 5-nitro-2-(pyridin-4-yl)benzo[d]isothiazol-3(2H)-one 10

Scheme 8: Synthesis pathway for 5-nitro-2-(pyridin-4-yl)benzo[d]isothiazol-3(2H)-one 10

Scheme 9: Synthesis pathway for 2-(pyridin-4-yl)benzo[d]isothiazol-3(2H)-one 11

Scheme 10: Model amide bond synthesis reaction in BIT organocatalyst screening 12

Scheme 11: Regenerative and inactivating processes for BIT organocatalysts 17

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