Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

Herein we report a reliable method to synthesize mono-functionalized S-diazocines in reproducible yields via intramolecular Baeyer–Mills reactions. Diazocines exhibit excellent photoswitchable properties. As opposed to azobenzenes they are more stable in their cis configuration. Particularly in photopharmacology mono-functionalized diazocines should be potentially useful and superior to the frequently used azobenzenes because the sterically more demanding cis configuration should be inactive, and the slender trans configuration should fit in a tight binding pocket of a receptor. Hence, it should be possible to administer the stabile inactive compound and switch it on at the site of illness with visible light. To date only a limited number of diazocine derivatives have been published of which most are symmetrically functionalized. Using the Baeyer–Mills reaction for the synthesis of diazocines opens a novel and convenient access to unsymmetrically substituted diazocines.


Melting point
Melting points were measured with a Melting Point B-560 (Büchi) in melting point tubes.

Mass spectrometry
The high resolution (HR-EI) mass spectra were measured with an AccuTOF GCv 4G (Joel) with ionization energy of 70 eV and the high resolution (HR-ESI) mass spectra were measured with a Thermo Fischer Q Exactive Plus MS, Hybrid Quadrupol-Orbitrap.

IR spectroscopy
Infrared spectra were measured on a Perkin-Elmer 1600 Series FT-IR spectrometer with an A531-G Golden-Gate-Diamond-ATR-unit. Signals were abbreviated with w, m, s, vs for weak, medium, strong and very strong signal intensity.

II.3. General method for the synthesis of the substituted thioether derivatives 13-16:
2,2'-Disulfanediyldianiline (12) (0.55 equiv) was dissolved in dry THF under nitrogen atmosphere. Sodium borohydride (1.5 equiv) was added and the solution was heated at 60 °C for 1 h. In the process the initially yellow solution turns to a milky white. The solution was cooled to 45 °C and the substituted benzylchoride/bromide 8, 9, 10 or 11 (1 equiv) was added. After stirring for 1 h at 45 °C the solution was cooled to room temperature and diluted with water. The mixture was extracted with DCM, the combined organic layers were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified on silica using flash column chromatography.

II.3.5. (4-(((2-Aminophenyl)thio)methyl)-3-nitrophenyl)methanol (17)
4-(((2-Aminophenyl)thio)methyl)-3-nitrobenzoic acid (16) (2.03 g, 6.68 mmol) was dissolved in 90 mL dry THF under nitrogen atmosphere. Borane tetrahydrofuran complex (19.3 mL, 1 M in THF) was added dropwise and the reaction was allowed to stir at room temperature for 22 h. 2 M hydrogen chloride solution was added and the organic layer was washed with saturated sodium bicarbonate solution (2 × 40 mL) and saturated sodium chloride solution (2 × 40 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. Due to the instability of the compound it was used without further purification in the next synthesis. It is not recommended to store the product 17. The NMR shows small impurities. An orange solid was obtained (1.22 g, 4.16 mmol, 62%).

II.4. General method for the synthesis of the substituted S-diazocine derivatives 1-5:
The substituted thioether derivate 13, 14, 15, 16 or 17 (1 equiv) was dissolved in ethanol (20 mL/mmol). Water (5 mL/mmol) and 2 M ammonia chloride solution (1.5 mL/mmol) were added and the reaction mixture was heated to 65 °C. Zinc powder (3.8 equiv) was added and the mixture was stirred at 65 °C for 10 min. The reaction mixture was filtered hot, the filtrate was diluted with ethanol (8 mL/mmol) and cooled with ice. The cooled solution was added dropwise to a 0 °C cooled iron(III) chloride hexahydrate (1.7 equiv) mixture in water (1.7 mL/mmol) and ice (1 g/mmol). The reaction mixture was stirred for 30 min at 0 °C, diluted with acetic acid (13 mL/mmol) and stirred at room temperature for 18 h. The reaction mixture was extracted with DCM, the combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The crude product was filtered over silica (ethyl acetate) and then purified by flash column chromatography. (13)

III. 6-chlorobenzo[c]isothiazole (19)
In the reductive azo coupling of the halogenated S-diazocines the respective isothiazoles were formed as a byproduct. For the chloro-functionalized S-diazocine 1 the byproduct 19 could be isolated and fully characterized, which is in agreement with literature [2] [3].
A colorless solid was obtained via sublimation.

VI. UV-vis switching experiments
A solution of the respective S-diazocine in acetone 1, 2, 3, 4 or 5 was prepared in the dark and the UV-vis cis spectra (black) were recorded. Then the solution was irradiated with 405 nm for 30 seconds and the UV-vis PSS spectra (red) were recorded. Figure S27: UV-vis spectra measured at 24 °C of the functionalized S-diazocines 1, 2, 3, 4 and 5; the cis spectra is plotted in black and the spectra of the PSS between cis/trans in red.

S31
V. Crystallographic data for compound 3 Comments A numerical absorption correction was performed (Tmin(max: 0.5901/0.7425). All non-hydrogen atoms were refined anisotropic. The C-H H atoms were located in difference map but were positioned with idealized geometry and refined isotropic with U iso (H) = 1.2 U eq (C) using a riding model.