Synthesis of Azidodifluoromethyl Phenyl Sulfone and Its Use as a Synthetic Equivalent of the Azidodifluoromethyl Anion

Azidodifluoromethyl phenyl sulfone, a new stable fluorinated azide, was synthesized on a multi-gram scale from difluoromethyl phenyl sulfone. The synthetic utility of the title azide in the preparation of N-difluoro(phenylsulfonyl)methyl-1,2,3-triazoles was demonstrated on examples of azide–alkyne cycloaddition reactions. Subsequent reductive desulfonylation/silylation afforded N-difluoro(trimethylsilyl)methyl-1,2,3-triazoles, and rhodium(II)-catalyzed transannulation with nitriles provided N-difluoro(phenylsulfonyl)methyl-substituted imidazoles. The title azide thus represents a synthetic equivalent of the azidodifluoromethyl anion.


■ INTRODUCTION
Organic azides are highly valuable compounds in synthesis. 1,2 Their utility, however, extends outside this realm, especially since the development of copper-catalyzed 3,4 and strainpromoted azide−alkyne cycloaddition reactions. 5−7 Nowadays, organic azides are widely used in bioconjugation, drug discovery, pharmacology, and also in materials science. 8−14 Fluorinated analogues of organic azides, especially αfluorinated azidoalkanes, were very rare until 2017, when we reported the synthesis of azidoperfluoroalkanes by the reaction of fluorinated carbanion precursors and an electrophilic azide source. 15 Since then, many new fluorinated azides have been prepared and their stability and reactivity investigated. 16,17 They serve as versatile intermediates in the synthesis of new nitrogen heterocycles and N-alkenyl compounds. 18−20 The following one-carbon fluorinated azidoalkanes, azidotrifluoromethane (CF 3 N 3 ), azidodifluoromethane (HCF 2 N 3 ), and azidofluoromethane (FCH 2 N 3 ), were reported. However, simple halogenated or silylated difluoromethyl azides XCF 2 N 3 (X = Cl, Br, I, TMS), which might potentially serve as azidodifluoromethyl carbanion or radical precursors, are unknown. Our experience with azidofluoroalkanes suggests that this is caused by a lack of suitable methods for their synthesis rather than low product stability. We therefore set out to attempt the synthesis of new difluoromethylated azides which could serve as azidodifluoromethyl carbanion precursors for the synthesis of previously unknown N-CF 2 X-substituted nitrogen heterocycles by [3 + 2] cycloaddition with alkynes and follow-up chemistry.

■ RESULTS AND DISCUSSION
For the synthesis of azidobromodifluoromethane (BrCF 2 N 3 ), we attempted to substitute the bromine atom of CF 2 Br 2 with sodium azide, however, without success (Scheme 1A). TMSCF 2 N 3 might be accessible by the deprotonation of azidodifluoromethane with a suitable base, followed by silylation with trimethylsilyl chloride. This approach, however, led only to the elimination of the azide-leaving group and the formation of tetrafluoroethylene by dimerization of difluor-ocarbene (Scheme 1B). The other approach to the synthesis of TMSCF 2 N 3 was based on the use of a masked phenylsulfonyl group, from which the silyl group would be formed by a reductive desulfonylation/silylation process. 21,22 Deprotonation of difluoromethyl phenyl sulfone with t-BuOLi and a reaction with nonaflyl azide (NfN 3 ) smoothly produced the new azide 1 in good isolated yield (Scheme 1C). Subsequent silylation in the presence of magnesium metal was again unsuccessful and gave tetrafluoroethylene decomposition side products. These initial investigations point to a low stability of the azidodifluoromethyl anion; its decomposition proceeds by azide anion elimination. However, sulfone 1 can act as a synthetic equivalent of the azidodifluoromethyl anion, as demonstrated herein below.
Optimization of the synthesis of azide 1 was performed. The reaction proceeded well at low temperatures with an excess of t-BuOLi or t-BuOK, with nonaflyl azide (NfN 3 ), or with the more readily available tosyl azide (TsN 3 ) ( Table 1). The highest isolated yield of 1 was achieved using excess t-BuOK and an equimolar amount of TsN 3 at low temperature (entry 7). Scaling up to 6 grams of 1 was straightforward.
Thermal stability is an important characteristic of each new organic azide. The stability of azide 1 was determined by heating CDCl 3 or DMSO-d 6 solutions in a thick wall, sealable NMR tube and analysis by 1 H and 19 F NMR and by differential scan calorimetry (DSC) and thermogravimetric (TG) analyses. No signs of decomposition were observed when the sample was heated to 100°C for 1 h. Trace amounts of decomposition products were observed by heating the DMSO-d 6 solution to 140°C for 1 h, and complete decomposition was observed upon heating the sample to 180°C for 1 h. DSC and TG analysis confirmed these observations (onset of decomposition at 130−140°C and exotherm maximum at 176°C). Fallhammer test established the insensitivity of the compound to the impact of energy below 50 J. We therefore concluded that azide 1 is safe to use on a laboratory scale at ambient temperature.
With azide 1 in hand, copper(I)-catalyzed azide−alkyne cycloaddition was performed under conditions previously employed for the click reaction with other known fluorinated azides 15 (Table 2). With the use of a slight excess of various aryl, heteroaryl, alkyl, cycloalkyl, cycloalkenyl, and substituted aryl and alkyl acetylenes, a catalytic amount of copper(I) methylsalicylate in THF under mild conditions, a variety of Ndifluoro(phenylsulfonyl)methyl-1,2,3-triazoles (2) were prepared in good to excellent yields (Table 2). Ether, hydroxyl, ester, and halogen groups, as well as unsaturation, are all compatible with the reaction. A double click reaction was performed, and bis(triazole) 2p was isolated in high yield. In addition, triazole 2a was prepared on a scale of 6.3 g.
Triazole 3a was investigated as a substrate for Ndifluoromethyl group manipulation (Scheme 3). In the presence of potassium fluoride in methanol-d 4 , 3a is converted to N-CF 2 D triazole 4 in almost quantitative yield. An analogous reaction, only using the stronger base potassium carbonate, capable of deprotonating the triazole at position five, promoted the formation of the doubly deuterated triazole 5. Silica gel converted triazole 3a into N-difluoromethyl triazole 6 in quantitative yield. Other electrophiles were also tested with good success. Ditolyl disulfide afforded product 7 in good yield. Carbon dioxide or sulfur dioxide were also competent electrophiles in this anion transfer reaction and cesium carboxylate 8 and sulfinate 9, respectively, were isolated in high yields. Nonaflyl azide as the electrophile yielded the unique N-azidodifluoromethyl triazole 10 ready for the next click reaction to form the asymmetrical bis(triazole) 11. The use of various aryl and alkyl aldehydes as electrophiles produced secondary alcohols 12−14.
In 2018, we published rhodium-catalyzed transannulation reactions of N-perfluoroalkyl-1,2,3-triazoles to access various N-perfluoroalkylated five-membered nitrogen heterocycles. 23 The application of this methodology to triazole 2a and aryl or alkyl nitriles under short microwave heating provided new imidazoles with N-difluoro(phenylsulfonyl)methyl functionality 15 and 16 in good yields (Scheme 4).

■ CONCLUSIONS
In conclusion, azidodifluoromethyl phenyl sulfone (1), a new stable azide, was prepared on a multi-gram scale in 90% yield from the commercially available reagents difluoromethyl phenyl sulfone and tosyl azide. Copper(I)-catalyzed azide− alkyne cycloaddition of structurally diverse terminal alkynes and azide 1 proceeded with high efficiency, yielding 1,2,3triazoles with a difluoro(phenylsulfonyl)methyl substitution on the nitrogen atom. Reductive desulfonylation/silylation of those triazoles with Mg/TMSCl afforded triazoles with the N-CF 2 TMS moiety. In addition, nucleophilic triazolyldifluoromethyl transfer to various electrophiles was demonstrated on numerous examples. Finally, rhodium(II)-catalyzed transannulation of N-difluoro(phenylsulfonyl)methyl-1,2,3-triazole with nitriles provided N-difluoro(phenylsulfonyl)methyl-imidazoles. Although the synthesis of neither BrCF 2 N 3 nor TMSCF 2 N 3 , intended to serve for the transfer of the azidodifluoromethyl anion or radical, was achieved, the title azide turned out to be an effective synthetic equivalent of the azidodifluoromethyl anion, making it possible to obtain new substituted N-difluoromethyl triazoles and imidazoles with potential applications in the life sciences. ■ EXPERIMENTAL SECTION Materials and Methods. All synthetic reactions were carried out in oven-dried vessels under a dry N 2 atmosphere. All chemicals were obtained from commercial sources and used as received. THF was Table 1. Optimization of Sulfone 1 Preparation F NMR yield; in parentheses, isolated yield. b Reaction temperature: −50°C to rt. c Reaction performed on a 6 g scale. Nf = n-C 4 F 9 SO 2 , Ts = p-TolSO 2 .
freshly distilled over Na/benzophenone prior to use. CDCl 3 and DMF were dried using molecular sieves (3 and 4 Å, respectively). Microwave heating was performed using sealed flasks on a CEM Discover System 908010. Automated flash column chromatography was performed on a Teledyne ISCO CombiFlash Rf + Lumen automated flash chromatography System with UV/vis detection. 1 H, 13 C, and 19 F NMR spectra were measured at ambient temperature using 5 mm diameter NMR tubes. The chemical shift values (δ) are reported in ppm relative to internal Me 4 Si (0 ppm for 1 H and 13 C NMR) or residual solvents and internal CFCl 3 (0 ppm for 19 F NMR). High-resolution MS spectra (HRMS) were recorded on an LTQ Orbitrap XL using electrospray (ESI) or APCI ionization on a Waters Micromass AutoSpec Ultima or Agilent 7890A GC coupled with Waters GCT Premier orthogonal acceleration TOF detector using electron impact (EI) or chemical ionization (CI). Simultaneous thermogravimetric and differential scan calorimetry (TG-DSC) was carried out using a Setaram Sensys Evo thermal analyzer equipped with a symmetrical balance and a Calvet 3D sensor.
Once the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography on silica gel.  General Procedure for the Synthesis of Triazoles 3 via Reductive Desulfonylation/Silylation. To an oven-dried high-pressure tube containing Mg turnings (43.8 mg, 1.8 mmol) in dry DMF (2.5 mL), TMSCl (570 μL, 4.5 mmol) was added under N 2 and stirred for 2 min at 0°C. A solution of the corresponding 2 (0.9 mmol) in DMF (3 mL) was added to the mixture and stirred for 1 h at 0°C and 2 h at room temperature ( 19 F NMR monitoring). The reaction mixture was poured over water/ice and extracted with Et 2 O. The organic layer was washed with water (2−3 times), dried (MgSO 4 ), and filtered, and the solvent was removed under reduced pressure to yield pure 3.  19 F NMR and HRMS data corresponded to previously published ones. 24 Synthesis of 1-(Difluoro(p-tolylthio)methyl)-4-phenyl-1H-1,2,3triazole (7). Ditolyl disulfide (246 mg, 1 mmol) and anhydrous CsF (m, 3H), 2.75 (t, 3  General Procedure for the Synthesis of Alcohols 12−14. The corresponding aldehyde (0.75 mmol, 1.5 equiv) and anhydrous CsF (0.075 mmol, 10 mol %) were dissolved in DMF (2 mL) under an inert atmosphere. To the resulting solution, a solution of 3a (134 mg, 0.5 mmol, 1.0 equiv) in DMF (2 mL) was added, and the mixture was stirred for 3 h at room temperature. Ice-cold HCl (2 M, 3 mL) was added, and the product was extracted with Et 2 O. The organic phase was washed with brine, dried (MgSO 4 ), and filtered, and the solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (hexane/EtOAc, 9:1) to afford pure 12−14. General Procedure for the Synthesis of Imidazoles 15 and 16. Triazole 2a (0.5 mmol, 1.0 equiv) was dissolved in anhydrous CHCl 3 (4 mL) in a microwave tube. Rh 2 (Oct) 4 (5 μmol, 1 mol %) and the corresponding nitrile (1.0 mmol, 2.0 equiv) were added, the tube was closed, and briefly sonicated. The reaction mixture was heated at 140°C for 15 min in a microwave reactor. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography on silica gel (cyclohexane/EtOAc, 0:100 to 10:90).

* sı Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00256. DSC and TG analyses; X-ray crystallography, and copies of NMR spectra (PDF)