Umpolung reactivity of strained C-C σ-bonds without transition-metal catalysis

Abstract

Umpolung is an old and important concept in organic chemistry, which significantly expands the chemical space and provides unique structures. While, previous research focused on carbonyls or imine derivatives, the umpolung reactivity of polarized C-C σ-bonds still needs to explore. Herein, we report an umpolung reaction of bicyclo[1.1.0]butanes (BCBs) with electron-deficient alkenes to construct the C(sp³)-C(sp³) bond at the electrophilic position of C-C σ-bonds in BCBs without any transition-metal catalysis. Specifically, this transformation relies on the strain-release driven bridging σ-bonds in bicyclo[1.1.0]butanes (BCBs), which are emerged as ene components, providing an efficient and straightforward synthesis route of various functionalized cyclobutenes and conjugated dienes, respectively. The synthetic utilities of this protocol are performed by several transformations. Preliminary mechanistic studies including density functional theory (DFT) calculation support the concerted Alder-ene type process of C-C σ-bond cleavage with hydrogen transfer. This work extends the umpolung reaction to C-C σ-bonds and provides high-value structural motifs.

Fig. 1. Transformation of strained C–C σ-bonds in BCBs.

A Previous strategies for the transformation of bicyclo[1.1.0]butane (BCBs). B The regular Alder-ene reaction of bicyclo[1.1.0]butanes (BCBs) with activated alkenes. C Umpolung Alder-ene reaction of BCBs with electron-deficient alkenes.

Fig. 2. Optimization of reaction conditions.^a

a Reaction conditions A: BCB 1a (0.2 mmol), alkene 2a (0.1 mmol), Na₂SO₄ (0.17 mmol), 80 °C in DMSO (0.1 mL) under argon, 24 h, isolated yield. b Reaction conditions B: BCB 1a (0.1 mmol), alkene 2a (0.4 mmol).

Fig. 3. Substrate scope of monosubstituted alkenes.^a

a Reaction conditions A: BCB 1 (0.2 mmol), alkene 2 (0.1 mmol), Na₂SO₄ (0.17 mmol), 80 °C in DMSO (0.1 mL) under argon, 24 h, isolated yield. b 100 °C. c neat without any solvent, BCB 1 (0.1 mmol), alkene 2 (0.5 mmol), Na₂SO₄ (0.17 mmol). d Reaction conditions B:BCB 1 (0.1 mmol), alkene 2 (0.4 mmol), Na₂SO₄ (0.17 mmol), 80 °C in DMSO (0.1 mL). e MgSO₄ instead of Na₂SO₄. f 40 °C.

Fig. 4. Substrate Scope of 1, 2-disubstituted alkenes.^a

a Reaction conditions: BCB 1 (0.3 mmol), alkene 2 (0.1 mmol), Na₂SO₄ (0.17 mmol), 80 °C in DMSO (0.1 mL) under argon, 48 h, isolated yield. b Reaction conditions: BCB 1 (0.2 mmol), alkene 2 (0.1 mmol), Na₂SO₄ (0.17 mmol), 130 °C in DMSO (1.0 mL) under argon, 48 h, isolated yield.

Fig. 5. The influence of the substituent at the β-position of bicyclo[1.1.0]butanes.^a

a Reaction conditions: BCB 1a’ (0.2 mmol), alkene 2 (0.1 mmol), Na₂SO₄ (0.17 mmol), 80 °C in DMSO (0.1 mL) under argon, 24 h, isolated yield.

Fig. 6. Synthetic applications.

Scale-up synthesis and derivatization of 3r.

Fig. 7. Mechanistic studies.

A Deuterium experiments. B Radical-probe experiments. C Radical clock experiments. D EPR experiments. E Kinetic studies. F The experimentally measured Gibbs free energy.

Fig. 8. Computational studies.

The corresponding energy profiles of the chemoselective pathways for the selected model reaction between BCB 1a and β-trifluoromethyl enone 2aa.