Insertion of [1.1.1]propellane into aromatic disulfides

Abstract

Herein we present the synthesis of symmetrically and unsymmetrically substituted 1,3-bissulfanylbicyclo[1.1.1]pentanes from disulfides and [1.1.1]propellane. Bicyclo[1.1.1]pentanes (BCPs) recently gained interest as rigid linkers and as bioisosters of para-substituted benzene and alkyne moieties. The most promising precursor for BCPs is [1.1.1]propellane (1). The available methods to synthesize BCPs are quite limited and many groups contribute to the development of novel methods. The insertion of 1 into disulfide bonds is known, but has never been thoroughly investigated. In this study, we show that an UV initiated radical reaction can be used to synthesize symmetrically and unsymmetrically substituted BCP sulfides by reaction of [1.1.1]propellane (1) with disulfides. Depending on the ratio of 1 to the disulfide, only the BCP product (with up to 98% yield) or a mixture of BCP and [2]staffane can be obtained. The reaction tolerates functional groups such as halogens, alkyl and methoxy groups. The separation of the corresponding BCP and [2]staffane products is challenging but possible by column chromatography and preparative TLC in most cases. Single crystal X-ray diffraction analysis confirms the rod-like structure of the [2]staffanes that is often required in material applications.

Keywords: [1.1.1]propellane; bicyclo[1.1.1]pentane; bioisosteres; disulfides; linkers.

Scheme 1

Summary of the most recent methods to obtain different BCPs from 1.

Scheme 2

Screening reaction performed with different types of irradiation (see Figure 1).

Figure 1

Optimization of the reaction conditions. The relative conversion was determined by GC–MS. The use of a radical initiator (di-tert-butyl peroxide, DTBP) led to increased amounts of insoluble polymer.

Figure 2

Molecular structure of 6a (displacement parameters are drawn at 50% probability level), distance C1–C3 1.844(3) Å.

Scheme 3

Proposed mechanism of the propellane insertion into disulfide bonds.

Scheme 4

The insertion of 1 into dibenzyl disulfide (12) led to the formation of BCP 13 and traces of [2]staffane 14. The structure of 14 could be proven by single-crystal X-ray diffraction (displacement parameters are drawn at 50% probability level).

Scheme 5

Reaction of propellane (1) with the two disulfides 10a and 10d. When two different disulfides were used, all three possible products were obtained. The yields were determined by NMR spectroscopy (Figure 3).

Figure 3

NMR spectra of pure 6a (green) and 6d (red) and the obtained mixture with the new compound 15 (blue).

Scheme 6

The reaction of 1 with the two disulfides 10a and 10e led to the known products 6a, 6e and to the unsymmetrically substituted BCP 16 as the main product. The compounds could be separated by column chromatography and preparative TLC. The structure of 16 could be confirmed by single-crystal X-ray diffraction (displacement parameters are drawn at 50% probability level).