Acyl Phosphates from Low Oxidation State Phosphorus for the Synthesis of Amides, Ketones and Heterocycles

Green, Michael T. (2022) Acyl Phosphates from Low Oxidation State Phosphorus for the Synthesis of Amides, Ketones and Heterocycles. PhD thesis, University of Nottingham.

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Abstract

Chapter I described the use of diethyl phosphite to activate carboxylic acids via acyl phosphate formation, using an aerobic copper-catalysed system. The acyl phosphates were used to synthesise a variety of amides in good yields (35-78 %), using 10 mol % catalyst. Simple methods of purification such as precipitating the amide from the reaction mixture produced amides in high purity. Initial insight into a potential mechanism suggests the reaction proceeds via the copper (II) oxidation state and that the halide counter anion can participate in the reaction.

Chapter II further explored other nucleophilic additions to acyl phosphates by reacting with Grignard reagents to generate ketones. Acyl phosphates were generated in good to excellent yields (48 to 88 %) from carboxylic acids and triethyl phosphite in the presence of iodine (Arbuzov-type reaction). Reacting Grignard reagents with acyl phosphates produced almost exclusively ketone at low temperature, with good to excellent isolated yields (68-90 %). ReactIR showed that acyl phosphates are 60-70 times more reactive towards Grignard reagents than acid chlorides, therefore, selectivity towards ketone formation was achieved by short reaction times and performing the reaction at low temperature.

In chapter III acyl phosphates were reacted with esters to give β-ketoesters (23- 73 %). The Arbuzov-type reaction used to generate the acyl phosphates was telescoped allowing the β-ketoesters to be prepared from the carboxylic acid without isolation of the acyl phosphate. In some cases, the telescoped reaction was higher yielding than when the pure acyl phosphate was used. Some of the prepared β-ketoesters were subsequently converted to the corresponding 5-membered heterocycles by condensing with hydroxyl amine or hydrazine.

Accessing heterocycles from 1,3-dicarbonyls is not the only method for available, the final part of this thesis applied the 1,3-dipolar cycloaddition reaction to diazophosphonates and alkynes to give N-P pyrazoles via a [1,5]-sigmatropic shift of the phosphonate group. The N-P pyrazoles were subsequently hydrolysed to N-H pyrazoles (16-83 %).

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Hayes, Christopher J.
Keywords: carboxylic acids, organometallic synthesis, Acyl phosphates
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 69193
Depositing User: Green, Michael
Date Deposited: 02 Aug 2022 04:40
Last Modified: 02 Aug 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/69193

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