Synthesis of dihydrobenzodithiepines by the reactions of 1,2-dichloro-and 1-chloro-2-nitrobenzenes with 1,3-dithiols

The reactions of nucleophilic substitution of the chlorine atoms and the nitro group in 1,2- dichloro-and 1-chloro-2-nitrobenzenes 2 by the thiolate anions generated from 2,2-disubstituted 1,3-propanedithiols 1 under the action of bases afford dihydrobenzodithiepines 3.


Introduction
There are several examples of nucleophilic substitution of halogen in aryl halogenides by thiolate groups. 1 The reactivity of non-activated phenyl halogenides decreases in the order PhI>PhF>PhBr>PhCl. 2 A different order has been observed for 1-halogen-2,4-dinitrobenzenes. 3 Compared to substitutions with mono-thiolates, reactions between aliphatic or aromatic dithiolates and mono-or dihalogenoarenes have been poorly substituted.Examples of known reactions are the formation of benzodithianes from 1,2-di-iodobenzene and 1,2-ethanethiol, 4 and of 1,1'-dinaphthyl-2,2'-ethanedithiol and 4,5-dichloro-1,2-dicyanobenzene, 5 while condensation of 1,2-dimercaptobenzene with 1,2,3,4-tetra-and hexa-fluorobenzenes afforded benzodithianes with two or three dithiane rings. 6n the present work, which is aimed at synthesizing macrocyclic sulfides and thia-crown ethers, we report the first results of our study of nucleophilic substitution of the halogen atoms and the nitro group in the aromatic cycle by thiolate anions.

ISSN 1551-7012
We first optimized the conditions for synthesis of the benzodithiepine 3с using the reaction of 1b with 2a.The results presented in Table 1 were obtained under the optimal conditions.The thiylation of the dichlorobenzene 2a with the dithiols 1a-c occurred under the action of sodium hydride in dimethylacetamide (DMA) solution at reactant concentrations of ~0.1 M. The complete conversion of dithiols 1a-c (GLC monitoring) at 105°С took 6-9 h (Table 1).The trifluoromethyl group in the benzene ring activates the chlorine atoms, and the reaction of dichlorobenzene, 2b, with dithiols 1b,c occurred much more rapidly, and its selectivity was higher.The yield of dithiepines 1a-f varies from 48 to 99%, depending on the substituents in reactants 1 and 2. The bulkier substituents in the dithiols 1a-c provide a higher yield of the target products.For example, the reaction of 1c with dichlorobenzene 2b affords the benzodithiepine 3f in ~100% yield.Like the substituted dithiols 1a-c, unsubstituted 1,3-propanedithiol reacted readily with 2a.However, in this case, only resin-like substances, probably polycondensation products, were formed.In order to extend the range of starting reactants in the synthesis of 3a and 3c, we used 2a along with 1-chloro-2-nitrobenzene, 2с.However, this variant was inappropriate under the conditions presented in Table 1 because of the low yield of the target products and side reactions.The selectivity of the reaction was enhanced using the one-pot synthesis in two steps.In the first step, the thiolate anion substituted only the chlorine atom in 2с under the action of the weak base NaHCO 3 .This resulted in the formation of intermediate thiol 4 (Scheme 1), which was isolated and identified (4b, R=Et) in one of the experiments.In the second step, KOH was introduced into the reaction mixture without isolating the thiol 4, and the process formed the dithiepines 3a,c by intramolecular substitution of the nitro group by the thiolate anion.

Scheme 1
The reaction of the dithiols 1a,b with 1,2-dichloro-4-nitrobenzene 2d (Scheme 2) was performed similarly.In the two-step variant, we succeeded in decreasing the probability of substitution of the nitro group in 2d by the thiolate anion.The benzodithiepines 3g,h containing the nitro group in the aromatic ring were prepared in satisfactory yields.

Scheme 2
The structures of compounds 3a-h were proved by 1 Н-and 13 С-NMR spectra, elemental analysis, and mass spectra.

Summary
The simple and convenient one-pot synthesis of new benzodithiepines 3a-h was developed on the basis of aromatic nucleophilic reactions of 2-substituted 1,3-propanedithiols 1 with easily accessible 1,2-dichloro-and 1-chloro-2-nitrobenzenes.The reaction occurred under the action of bases at a ratio of reactants close to stoichiometric.The yields of dihydrobenzodithiepines 3 ranged from 48% to ~100%, depending on the character of substituents in the starting reactants.In the synthesis of 3 we also used 1,2-dichloro-4-trifluoromethyl and 1,2-dichloro-4nitrobenzene.

Experimental Section
General Procedures.GLC analysis was carried out on a Chrom 5 chromatograph with a flameionization detector and a column 3m×3mm using Сhromaton N-super (0.160-0.200 mm) as the sorbent with the SE-Superphase (5%) liquid phase.NMR spectra of solutions in CDCl 3 were recorded on Bruker AC-200, Bruker WM-250, and Bruker AM300 spectrometers.Coupling constants (J) were reported in Hz.NMR chemical shifts, δ were expressed in ppm, and were related to the internal solvent peak.Mass spectra were obtained on a Kratos-MS30 instrument.Silica gel 60 (0.063-0.200 mm) Merck was used in column chromatography.TLC analysis was carried out on Sorbfil plates.Melting points were determined on a Kofler hot-stage apparatus.
This work was supported by the Federal Program on Support of Leading Scientific Schools (Grant 2121.2003.3).