5,5 ′ -Thiobis(3-bromoisothiazole-4-carbonitrile)

: The reaction of sodium 2,2-dicyanoethene-1,1-bis(thiolate) with bromine (2 equiv.) in CCl 4 gave 3,5-dibromoisothiazole-3-carbonitrile and 5,5 ′ -thiobis(3-bromoisothiazole-4-carbonitrile) in 7% and 18% yields, respectively. The latter novel compound was fully characterized.

Our interest in isothiazoles focuses on their preparation from 1,2,3-dithiazoles 6 by treatment with gaseous HCl or HBr [24,25] (Scheme 1), halide or alkylamines [26].Moreover, we were interested in the investigation of the chemistry of halo and cyano-substituted isothiazoles.Halogen atoms in the C-5 position were substituted by carbon nucleophiles in Suzuki [27], Stille and Sonogashira couplings [28] (Scheme 1), while the coupling chemistry of the C-3 [28] and later the C-4 positions [29] was also investigated.Interestingly, the isothiazole C-4 cyano group has been converted to a bromo group via a Hunsdiecker strategy or to an iodo group via a Hoffmann and Sandmeyer strategy [29].
Our interest in isothiazoles focuses on their preparation from 1,2,3-dithiazoles 6 by treatment with gaseous HCl or HBr [24,25] (Scheme 1), halide or alkylamines [26].Moreover, we were interested in the investigation of the chemistry of halo and cyano-substituted isothiazoles.Halogen atoms in the C-5 position were substituted by carbon nucleophiles in Suzuki [27], Stille and Sonogashira couplings [28] (Scheme 1), while the coupling chemistry of the C-3 [28] and later the C-4 positions [29] was also investigated.Interestingly, the isothiazole C-4 cyano group has been converted to a bromo group via a Hunsdiecker strategy or to an iodo group via a Hoffmann and Sandmeyer strategy [29].
An important isothiazole scaffold that we required in the course of our investigations is 3,5-dibromoisothiazole-3-carbonitrile (8b) (Scheme 1).The synthesis of this highly functionalized isothiazole that offers many options for functional group modifications is reported in the literature [30,31].
functionalized isothiazole that offers many options for functional group modifications is reported in the literature [30,31].Herein, we report our findings in performing this reaction that led to the isolation of 5,5′-thiobis(3-bromoisothiazole-4-carbonitrile) (10).The formation of this compound through the treatment of 3,5-dibromoisothiazole-4-carbonitrile with sodium thiocyanate is mentioned in the patent literature [31], but no yield or characterization data are described.
The preparation of sulfide 10 differs from most reported methods of preparation of isothiazole sulfides that commonly involve the nucleophilic aromatic substitution of haloisothiazoles with thiols [32] or palladium-catalyzed C-S coupling [33].
Mechanistically, we attribute the formation of sulfide 10 to a reaction of product 8b with a source of nucleophilic sulfur.The initial displacement of the 5-bromide should lead Herein, we report our findings in performing this reaction that led to the isolation of 5,5 ′ -thiobis(3-bromoisothiazole-4-carbonitrile) (10).The formation of this compound through the treatment of 3,5-dibromoisothiazole-4-carbonitrile with sodium thiocyanate is mentioned in the patent literature [31], but no yield or characterization data are described.
The preparation of sulfide 10 differs from most reported methods of preparation of isothiazole sulfides that commonly involve the nucleophilic aromatic substitution of halo-isothiazoles with thiols [32] or palladium-catalyzed C-S coupling [33].
functionalized isothiazole that offers many options for functional group modifications is reported in the literature [30,31].Herein, we report our findings in performing this reaction that led to the isolation of 5,5′-thiobis(3-bromoisothiazole-4-carbonitrile) (10).The formation of this compound through the treatment of 3,5-dibromoisothiazole-4-carbonitrile with sodium thiocyanate is mentioned in the patent literature [31], but no yield or characterization data are described.
The preparation of sulfide 10 differs from most reported methods of preparation of isothiazole sulfides that commonly involve the nucleophilic aromatic substitution of haloisothiazoles with thiols [32] or palladium-catalyzed C-S coupling [33].
Product 10 was isolated as yellow plates, mp 141-142 • C (from PhH).UV-vis spectroscopy in dichloromethane supported an intact isothiazole ring [λ max (DCM) 279 nm, log ε 4.18], while FTIR spectroscopy showed the presence of a ν(C≡N) stretch at 2334 cm −1 .Mass spectrometry revealed a molecular ion (MH + ) peak of m/z 407 (38%) along with a MH + + 2 isotope peak at 408 (85%) and a MH + + 4 at 411 (54%) that supported the presence of two bromine atoms. 13C NMR spectroscopy showed the presence of four quaternary carbon resonances (see Supplementary Information), while a correct elemental analysis (CHN) was obtained for the molecular formula C 8 Br 2 N 4 S 3 .The multifunctional nature of isothiazole 10 makes it a potentially useful synthetic scaffold.
Mechanistically, we attribute the formation of sulfide 10 to a reaction of product 8b with a source of nucleophilic sulfur.The initial displacement of the 5-bromide should lead to 3-bromo-5-mercaptoisothiazole-4-carbonitrile 12, which could condense with another molecule of isothiazole 8b to yield product 10 (Scheme 3).Interestingly, sulfide 13, which is the chloro analogue of sulfide 10, can be prepared by the reaction of 3,5-dichloroisothiazole-4-carbonitrile 8a with either CuCN (1 equiv.),NaSCN (1 equiv.)or Na 2 S (0.5 equiv.)[34] (Scheme 3).In the latter two methods, it is clear that nucleophilic sulfur is involved similarly to our proposal for the formation of sulfide 10.

Materials and Methods
The reaction mixture was monitored by TLC using commercial glass-backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F254).The plates were observed under UV light at 254 and 365 nm.The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany).The solvent used for recrystallization is indicated after the melting point.The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV-vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf".The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA), and strong, medium and weak peaks are represented by s, m and w, respectively. 1H and 13 C NMR spectra were recorded on a Bruker Avance 500 machine [at 500 and 125 MHz, respectively, (Bruker, Billerica, MA, USA)].Deuterated solvents were used for homonuclear lock and the signals were referred to with the deuterated solvent peaks.Attached proton test (APT) NMR studies were used for the assignment of the 13 C peaks as CH3, CH2, CH and Cq (quaternary).MALDI-TOF mass spectra were recorded on a Bruker Autoflex III Smartbeam instrument.Sodium 2,2-dicyanoethene-1,1-bis(thiolate) (11) [30] was prepared according to the literature procedure.

Materials and Methods
The reaction mixture was monitored by TLC using commercial glass-backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F 254 ).The plates were observed under UV light at 254 and 365 nm.The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany).The solvent used for recrystallization is indicated after the melting point.The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV-vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf".The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA), and strong, medium and weak peaks are represented by s, m and w, respectively. 1H and 13 C NMR spectra were recorded on a Bruker Avance 500 machine [at 500 and 125 MHz, respectively, (Bruker, Billerica, MA, USA)].Deuterated solvents were used for homonuclear lock and the signals were referred to with the deuterated solvent peaks.Attached proton test (APT) NMR studies were used for the assignment of the 13 C peaks as CH 3 , CH 2 , CH and Cq (quaternary).MALDI-TOF mass spectra were recorded on a Bruker Autoflex III Smartbeam instrument.Sodium 2,2-dicyanoethene-1,1-bis(thiolate) (11) [30] was prepared according to the literature procedure.

Supplementary Materials:
The following supporting information can be downloaded online: mol file, 13 C NMR and IR spectra.