Regioselective routes to tetrasubstituted aromatic compounds

Close, Adam James (2016) Regioselective routes to tetrasubstituted aromatic compounds. Doctoral thesis (PhD), University of Sussex.

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Polysubstituted aromatics are highly desirable in medicinal chemistry for library generation and the tetrasubstituted aryl motif appears in many pharmaceuticals. Current methods to access 1,2,4,5- and 1,2,3,4- tetrasubstituted aromatics are problematic. Therefore new routes giving defined regiochemical outcomes with four different orthogonal functionalities were sought.
This work took two directions; 1) the bromination and nitration of trisubstituted aryl MIDA boronates, and 2) the nitration of trisubstituted aryl bromides, both leading to the desired tetrasubstituted aromatics.
MIDA boronates are boronic acids masked with N-methyliminodiacetic acid (MIDA). This allows for iterative palladium cross-coupling reactions. The first step in the work was developing a new rapid microwave-mediated method (5-15 min) towards MIDA boronates using ether poly-ethylene glycol 300, acetonitrile or dimethylformamide as a solvent. This methodology gave a library of over 20, mainly aryl or heteroaryl MIDAboronates.1,2
Trisubstituted aryl-MIDAboronates were then brominated or nitrated giving 6 novel tetrasubstituted aromatic compounds. The 3 new tetrasubstituted aryl-MIDAboronates bromides were then used in a selection of iterative Suzuki–Miyaura cross coupling reactions (SM) to show the potential uses of the compound in library generation.
Three different bromo-fluorobenzaldehyde regioisomers were nitrated giving 3 different tetrasubstituted aromatics. These 3 compounds were then subjected to several different conditions to modify them i.e. nitro reduction, Sonogashira couplings, reductive aminations, Clauson-Kaas pyrrole synthesis. A number of tetrasubstituted anilines were reacted with 4-chloro-6,7-dimethoxyquinazoline to afford novel, potential kinase inhibitors.


(1) Close, A. J.; Kemmitt, P.; Emmerson, M. K.; Spencer, J. Tetrahedron 2014, 70, 9125–9131.
(2) Close, A. J.; Corden, V.; Spencer, J. Use of a camera to monitor reaction stirring and reagent dissolution during a reaction; a MIDA boronate library generation case study. (accessed Nov 15, 2015).

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Depositing User: Library Cataloguing
Date Deposited: 03 Nov 2016 16:22
Last Modified: 03 Nov 2016 16:22

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