Beilstein J. Org. Chem.2015,11, 1194–1219, doi:10.3762/bjoc.11.134
which although commercially available was expensive and could be generated from 1,3-cyclohexadione (104). The sequence consisted of O-acetylation, a Steglichrearrangement, oxidation and a final methylation reaction. As the use of flow chemistry had already improved the O-acetylation during scale-up
tests (130 mmol) by avoiding exotherms, it was anticipated that the subsequent Steglichrearrangement could be accomplished in flow using catalytic DMAP instead of stoichiometric AlCl3 as precedented (Scheme 19). This was eventually realised by preparing a monolithic flow reactor functionalised with
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Graphical Abstract
Figure 1:
Pharmaceutical structures targeted in early flow syntheses.
Beilstein J. Org. Chem.2013,9, 2812–2820, doi:10.3762/bjoc.9.316
derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglichrearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0
:13.0).
Keywords: catalysis; enantioselectivity; fluorine; gauche effect; organo-fluorine; Steglichrearrangement; Introduction
Molecular editing using fluorine is a powerful strategy to modulate the conformation and reactivity of small molecule organocatalysts [1][2][3]. The negligible steric penalty
substitution is evaluated in the NHC-catalysed, enantioselective Steglichrearrangement of oxazolyl carbonates 3 to C-carboxyazlactones 4 [29], recently reported by Smith and co-workers [30][31][32][33][34][35][36].
Fluorination sites were selected based on their proximity to the ring junction nitrogen of the
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Graphical Abstract
Figure 1:
Exploring the effect of fluorine incorporation in triazolium pre-catalysts (2) for the enantioselec...