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. 2024 Jan 12;26(1):360-364.
doi: 10.1021/acs.orglett.3c04030. Epub 2023 Dec 29.

Bridge Cross-Coupling of Bicyclo[1.1.0]butanes

Ryan E McNamee  1 , Ayan Dasgupta  1 , Kirsten E Christensen  1 , Edward A Anderson  1
Affiliations

Bridge Cross-Coupling of Bicyclo[1.1.0]butanes

Ryan E McNamee et al. Org Lett. .

Abstract

Bicyclo[1.1.0]butanes (BCBs) have gained growing popularity in "strain release" chemistry for the synthesis of four-membered-ring systems and para- and meta-disubstituted arene bioisosteres as well as applications in chemoselective bioconjugation. However, functionalization of the bridge position of BCBs can be challenging due to the inherent strain of the ring system and reactivity of the central C-C bond. Here we report the first late-stage bridge cross-coupling of BCBs, mediated by directed metalation/palladium catalysis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Applications of BCBs in cyclobutane and bioisostere synthesis. (b) Previous work toward the construction of aryl-substituted BCBs. (c) Bridge directed metalation and cross-coupling of BCBs. DMG = directing metalation group.
Scheme 1
Scheme 1. Synthesis of Aryl Bridge-Substituted BCBs
Reaction conditions, unless stated otherwise: 2a or 2b (0.20 mmol, 1.0 equiv); 1. Lithiation: at-BuLi (0.22 mmol, 1.1 equiv, 1.1–1.3 M in pentane, THF, −78 °C, 1.5 h; bs-BuLi (0.22 mmol, 1.1 equiv, 1.1–1.5 M in cyclohexane), THF, −45 °C, 3.0 h; 2. Transmetalation/coupling: ZnCl2 (0.22 mmol, 1.1 equiv), THF, −78 °C (or −45 °C) to rt; Pd(dba)2 (15 mol %), CyJPhos (30 mol %), R–I (0.4 mmol, 2.0 equiv) THF, 1 h, 20 °C; 1 d, 65 °C. cStructure of 3l from single-crystal X-ray diffraction studies (displacement ellipsoids drawn at 50% probability). dThe reaction was conducted on a 1 mmol scale.
Scheme 2
Scheme 2. Unexpected Fragmentation in the Metalation of Bridge-Arylated BCB 3c
The reaction was run on a 0.12 mmol scale using optimized conditions with allyl bromide (0.6 mmol, 5.0 equiv) quench.
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