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. 2022 Oct 7;87(19):12854-12866.
doi: 10.1021/acs.joc.2c01444. Epub 2022 Sep 14.

Switchable Cycloadditions of Mesoionic Dipoles: Refreshing up a Regioselective Approach to Two Distinctive Heterocycles

M Pilar Romero-Fernández  1 , Pedro Cintas  1 , Sergio Rojas-Buzo  1
Affiliations

Switchable Cycloadditions of Mesoionic Dipoles: Refreshing up a Regioselective Approach to Two Distinctive Heterocycles

M Pilar Romero-Fernández et al. J Org Chem. .

Abstract

Mesoionic rings are among the most versatile 1,3-dipoles, as witnessed recently by their incorporation into bio-orthogonal strategies, and capable of affording unconventional heterocycles beyond the expected scope of Huisgen cycloadditions. Herein, we revisit in detail the reactivity of thiazol-3-ium-4-olates with alkynes, leading to thiophene and/or pyrid-2-one derivatives. A structural variation at the parent mesoionic dipole alters sufficiently the steric outcome, thereby favoring the regioselective formation of a single transient cycloadduct, which undergoes chemoselective fragmentation to either five- or six-membered heterocycles. The synthetic protocol benefits largely from microwave (MW) activation, which enhances reaction rates. The mechanism has been interrogated with the aid of density functional theory (DFT) calculations, which sheds light into the origin of the regioselectivity and points to a predictive formulation of reactivity involving competing pathways of mesoionic cycloadditions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Some FDA-approved small molecule drugs containing 2-pyridone or thiophene units.
Figure 2
Figure 2
Representative structural variations in monocyclic thioisomünchnones employed in cycloaddition reactions with alkynes.
Scheme 1
Scheme 1. Sequential Cyclization and Mesoionization Leading to 2-Methylthiothiazol-3-ium-4-olate Derivatives
Scheme 2
Scheme 2. Divergent Fragmentation of Thioisomünchnone-alkyne Cycloadducts Producing Pyrid-2-ones or Thiophenes
Scheme 3
Scheme 3. Alternative Regiochemistry for the Tandem Cycloaddition-Fragmentation of Thioisomünchnones 5 and 6 and Activated Acetylenes
Figure 3
Figure 3
Plots obtained for correlations between GIAO-computed 13C-shifts of either (A) 9d (black squares) or (B) 9′d (black circles) structures and experimental carbon chemical shifts of the reaction product (from 6 and 7d).
Figure 4
Figure 4
Heteronuclear HMBC spectrum for regioisomeric pyridone 10b highlighting the diagnostic correlations with the H-4 proton.
Figure 5
Figure 5
Linear correlations between GIAO-computed 13C chemical shifts of (A) 10b (black squares) or (B) 10′b (black circles) structures and experimental resonances for the reaction product derived from 5 and 7b.
Figure 6
Figure 6
Optimized geometries of TS8b (higher energy) and TS8’b at the M06-2X/6-311++G(d,p) level in toluene.
Scheme 4
Scheme 4. Potentially Competitive Routes for the Dipolar Cycloaddition of Mesoionics 5 and 6 with Methyl Propiolates 7b and 7d
Figure 7
Figure 7
Energy profiles computed for the cycloadditions of heterocycle 5 with methyl propiolate (7b) and methyl phenyl propiolate (7d), producing either pyrid-2-ones (routes a/b) or thiophenes (routes c/d) with identification of all stationary points relative to the two reacting partners.
Figure 8
Figure 8
Optimized geometries of TS18b, Int8b, TS28b, and TS8’b at the M06-2X/6-311++G(d,p) level in toluene.
Figure 9
Figure 9
Energy profiles computed for the cycloadditions of heterocycle 6 with methyl propiolate (7b) and methyl phenyl propiolate (7d) with identification of all stationary points relative to the two reacting partners. Pyrid-2-one derivatives (not observed in experiments) arise from routes a/b, whereas thiophenes emerge from routes c/d; only 9b and 9d through path c were isolated.
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