Convenient synthesis of 1,3-dithiolane-2-thiones: cyclic trithiocarbonates as conformational locks 1

A series of novel 1,3-dithiolane-2-thiones, or cyclic trithiocarbonates, has been prepared by a new simple procedure: a treatment of the corresponding epoxides with the commercially available potassium ethyl xanthogenate, KSC(S)OEt. The stereochemistry of the products was determined by 1 H NMR and in some cases by single-crystal X-ray data. Cyclohexane-based 1,3-dithiolane-2-thiones revealed a trans -fusion of the carbo-and hetero-cycles. The products obtained from the mono-substituted cyclohexene oxides demonstrated an axial position of the substituents. Thus the epoxide transformation into trithiocarbonate can be used as a method for locking cyclic compounds in unstable conformations.


Introduction
1,3-Dithiolane-2-thiones, or cyclic trithiocarbonates, attract much attention due to their variety of useful properties. 2,38][10][11][12][13][14] However, these procedures often suffer from low yields and poor selectivity.Depending on the catalyst and reaction conditions, a variety of products can be formed.In addition, use of the volatile, inflammable and toxic carbon disulfide is definitely a serious disadvantage.
Herein we report a new procedure for the synthesis of 1,3-dithiolane-2-thiones: a treatment of epoxides with commercially available potassium ethyl xanthogenate, KSC(S)OEt (for a preliminary communication see ref. 1) The procedure is simple, safe, inexpensive, and relatively fast.It does not require high pressure and catalyst, and often gives 1,3-dithiolane-2-thione as the only product in good to moderate yields.The mechanism and stereochemistry of the reaction are discussed.
When cyclohexene oxide was used as a starting material in catalytic reaction with CS 2 , the newly formed five-membered cyclic trithiocarbonate was trans-fused to the cyclohexane ring. 2 Our modified procedure has the same stereochemical outcome.When it is applied to epoxides of substituted cyclic alkenes, the substituent(s) on the ring could be forced to adopt a sterically unfavourable axial position.Thus, the five-membered trithiocarbonate ring can serve as a lock for unfavourable conformations.We suggest this approach in addition to a set of other conformational locks (acetals, ortho-esters, urethanes, etc.) that have previously been used in various stereoselective syntheses. 15,16

Synthesis of trithiocarbonates
In the course of our studies on the cleavage of epoxides with sulfur nucleophiles, 17,18 we found that treatment with potassium xanthogenate transformed epoxides into 1,3-dithiolane-2-thiones (cyclic trithiocarbonates) in good to moderate yields. 1 The procedures described previously for such a transformation used carbon disulfide in presence of a base and/or catalyst, and included an in situ formation of a xanthogenate or a similar intermediate, and then its reaction with an epoxide 2,5-8,10-14 (for a detailed critical consideration of the literature data see ref. 2).Thus, our modified procedure eliminates the most inconvenient step, which used the toxic, volatile and inflammable CS 2 , by employing a safe commercially available reagent.We carried out the reaction of cyclohexene oxide with KSC(S)OEt (Scheme 1) under various conditions as summarized in Table 1.The isolated yield of the product was dependent on the molar ratio KSC(S)OEt to epoxide.The best result was achieved when the ratio was 2:1 (entry 3).Upon increase of the ratio to 3:1 and 5:1 the yield decreased, but no starting epoxide was recovered (entries 6, 7).Most likely the yield declined due to side reactions of epoxide such as an intermediate/product polymerization.Upon increase of the reaction time the yield decreased (experiment 4).Therefore it was important to monitor the reaction by TLC and to stop it immediately after the complete conversion of epoxide.A reaction temperature of 35-40 o C was found to be optimal, because a lowering of temperature reduced the yield of the product significantly (experiment 5).

Scheme 1. Synthesis of trans-hexahydro-1,3-benzodithiole-2-thione (2a)
Because the conditions of experiment 3 in Table 1 gave the best yield, they were used as standard conditions for the synthesis of a series of trithiocarbonates (Table 2).The starting epoxides were prepared by reaction of corresponding commercially available alkenes with mCPBA.
In some experiments, the reaction yielded intermediate products -thiiranes (see discussion of the mechanism below) or the products of polymerization.

Stereochemistry of products
The structures of all compounds were determined by 1 H NMR, 13 C NMR and HRMS analysis.The vicinal coupling constants 3 J HH between protons attached to the cyclohexane moiety are strongly conformation-dependent, which allows an assignment of the predominant conformation and an estimation of the position of conformational equilibrium. 30For the products with nonsymmetrical molecules, most coupling constants in 1 H NMR could be measured directly from the corresponding multiplets assuming the first order of spectra (for methodology see ref. 31).The large vicinal coupling constants between the cyclohexane protons H3a and H7a geminal to the sulphur atoms (12.1-12.4Hz) proved unambiguously the trans-diaxial position of these protons and, correspondingly, the trans-diequatorial position of the sulphur atoms in the cyclohexane derivatives 2c -2i (Figure 1).This means a trans-fusion of two rings, which has also been shown recently by X-ray analysis for the compound 2a. 2 The configuration of remote substituents was also established from the couplings of their geminal protons.Thus, the couplings of H5 in the product 2f(e) (triplet of triplets with 3 J HH of 12.3 Hz and 3.8 Hz) indicated an equatorial position of the methoxycarbonyl group, while all the couplings of H5 in the stereoisomer 2f(a) were small ( 3 J HH ≈ 2.5 -5.0 Hz) indicating an axial position of the substituent (Figure 1).The axial position of methyl group in the compound 2c resulted in small couplings of H5, and was also confirmed by NOE with H3a (Figure 1).
The coupling constants in the half-chairs of epoxides and thiiranes are not characteristic, therefore we used ROESY and STEP-NOESY techniques 32,33 to establish or confirm the configuration of these compounds (Figure 2; for the details see Supplementary data).The STEP-NOESY technique makes use of optimized 1D-pfg-TOCSY magnetization transfer from a wellseparated signal in the spectrum to a neighbouring proton in a crowded spectral region for a subsequent 1D-pfg-NOESY irradiation.When literature data were available, our results confirmed the assignments made previously (for instance, for epoxide 1l).However, in case of a novel compound 1i (the major syn-product of epoxidation) this approach was inefficient because of conformational peculiarities, and we had to transform 1i into methoxycyclohexanol 4 in order to assign its configuration unambiguously (Scheme 3; see Supplementary data).The single-crystal X-ray analysis has been performed for the products 2f(a), 2f(e), 2h(ee), 2i, and 3h (Figures 3-7).Similar to the published research on compound 2a, 2 the analysis was complicated by the extremely small size and fiber-like shape of the crystals, necessitating the use of synchrotron radiation.The X-ray data clearly demonstrate a chair conformation of the cyclohexane rings, a trans ring fusion, a nearly planar heterocycle, and in case of 2f(a) an axial position of the substituent.Noteworthy, the molecules of racemic compound 2f(a) are paired in asymmetric unit, and the components of the pair have the same configuration (Figure 3).The same kind of stereoselection occurs in case of compound 2f(e) (Figure 4).

Mechanism and stereochemistry of the reaction
As described above, the 1 H NMR and X-ray data showed that all the obtained cyclohexanotrithiocarbonates were trans-isomers with equatorial position of both sulphur atoms.This requires an inversion of configuration at one of the epoxide carbons during the reaction.The configuration at the second epoxide carbon seems to remain the same as in the substrate, although the original oxygen is replaced by sulphur.This implies a double inversion at the second carbon.A plausible mechanism addressing these major peculiarities is presented in Scheme 4 for the case of mono-substituted cyclohexene epoxides.Similar, although less complete mechanistic considerations were published earlier for the formation of trithiocarbonates from the epoxides of non-cyclic alkenes using carbon disulfide in presence of a base. 2,13,14he key steps include the cleavage of epoxide 1 by xanthogenate anion, then cyclization of the intermediate 5 into the trans-fused bicyclic structure 6, which requires a transfer of the substituent R into a sterically strained axial position (Scheme 4).Then 6 may eliminate ethoxide ion and give 1,3-oxathiolane-2-thione 7 (route a).We did not isolate these compounds, but the formation of some 1,3-oxathiolane-2-thiones in certain conditions was observed previously. 2,5,6,14t is also known that these compounds react with excess carbon disulfide to give trithiocarbonates. 2,6Apparently, in our case the subsequent addition of a nucleophile (Nuc = EtOCS 2 -, EtO -, or MeO -from the solvent) to probable intermediates 7 occurred quickly and caused cleavage of the heterocycle.An alternative detour (b) seems to be also possible. 13Both ways include an intramolecular substitution leading to thiirane 8, where the group R occupies again a more relaxed and stable equatorial position.We isolated thiirane 2l as a major product in reaction of epoxide 1l (entry 12 in Table 2).The epoxides 1i and 1r (entries 9 and 18 in Table 2) produced mostly the corresponding thiiranes after 15-16 h, but finally gave trithiocarbonates when the time was extended to 72 h.Other researchers also reported isolation of thiiranes in certain conditions, 2,6,34 and the reaction of some thiiranes with carbon disulfide and base towards trithiocarbonates was described previously. 21,34,35Noticeably, the configuration of the threemembered cycle in 8 is opposite to the configuration of the starting epoxide 1.The thiiranes 8 (Scheme 4) are in turn subjected to nucleophilic cleavage by xanthogenate anion, followed by yet another cyclization, which forces the group R again into the sterically strained axial position.Despite this strain, the resulting 1,3-dithiolane-2-thiones 2 must be much less susceptible to addition of nucleophiles than their analogues 7, and they have been isolated in most cases as the major products of reaction.Thus, the monosubstituted cyclohexene oxides 1c, 1d and 1f (entries 3, 4 and 6 in Table 2) yielded trithiocarbonates 2c, 2d and 2f(a) respectively, with an axial substituent R (Figures 1, 3).According to the suggested mechanism, the configuration of 2 does not depend on the configuration of the starting epoxide 1 (syn-or antiposition of R and O).Indeed, when a mixture of diastereomeric epoxides was used (entries 3, 4 in Table 2), only one product was isolated.

S
The transfer of substituent R into a sterically strained axial position is a barrier that occurs twice on the way of reaction in the case of epoxycyclohexanes and similar epoxides.It has to be overcome in conformational interconversions 5A 5B and 9A 9B.The second transition is more difficult, because the form 9B must be additionally destabilized by a substantial gaucherepulsion between two equatorial atoms of sulfur as it was found in trans-1-RS-2-R′Scyclohexanes. 36,37This can explain why the reaction proceeds only up to thiirane in the case of sterically loaded epoxide 1l (entry 12 in Table 2), or can be stopped at the thiirane step in the case of epoxides 1i and 1r (entries 9 and 18).Similarly, steric strain in reaction intermediates prevented transformation of steroid thiiranes into trithiocarbonates (with one questionable exception). 35No trithiocarbonate or even thiirane was isolated in the reactions of 4-tbutylcylohexene oxide 1e (mixture of stereoisomers; entry 5) and cis-2,6-disubstituted epoxytetrahydropyran 1m (entry 13), which produced only polymeric side products.Obviously, it is very difficult to force the bulky t-butyl group or the cis-oriented substituents into axial/syndiaxial positions already at the step of intermediate 5B.
The studied reaction is sensitive to steric hindrance in general.Thus, no trithiocarbonate was obtained from the epoxycyclododecane 1j (entry 10 in Table 2).The simple dimethyl oxiranes 1n and 1o (entries 14 and 15) produced the corresponding trithiocarbonates in moderate yields, while the yield from the bulkier diphenyl oxirane 1r (entry 18) was much lower, and the tetramethyl oxirane 1p (entry 16) gave no product at all.As described earlier, the gemdimethyloxirane 1o and trimethyloxirane gave no product in catalytic reaction with carbon disulfide. 2However, the absence of steric hindrance may be also harmful because of fast side reactions: thus, styrene oxide 1q (entry 17) produced only a polymer.Evidently, this polymerization is related to the benzylic moiety, because the structurally similar epoxide 1s gave the expected product 2s (entry 19).
Monosubstituted cyclohexene oxide 1f with R = COOMe (entry 6, Table 2) did not produce a single product 2f(a), but yielded a mixture of diastereomers 2f(a) and 2f(e) with axial and equatorial positions of the ester group, respectively (Figures 1, 3, 4).The ratio of diastereomers was highly dependent on the time of reaction.After 0.5 h the ratio of products 2f(a):2f(e) in their mixture purified by column chromatography was (2.2-3.3):1 by 1 H NMR, while after 2-3 h the ratio almost inverted to 1:1.3.The longer time of reaction also decreased the overall yield from 57% (0.5 h) to 43-48% (2 h).This reaction was performed with pure syn-or anti-isomer of epoxide 1f, or with their 1:1 mixture, and always produced approximately the same proportion of products regardless of the starting stereochemistry.Evidently, due to relative acidity of α-proton H5, a base-catalyzed epimerization of the expected ester 2f(a) have occurred in the course of reaction, and the more stable diastereomer 2f(e) was formed.This hypothesis was confirmed by conversion of pure 2f(a) into a mixture of diastereomers 2f(a) and 2f(e) (1:1.3) after 72 h at 40 o C with one equivalent of KSC(S)OEt (Scheme 5).Assuming this is a ratio at equilibrium, the equatorial form 2f(e) is 0.7 kJ/mol more stable than the axial 2f(a) in the conditions of reaction.Scheme 5. Base-induced epimerization of the product 2f(a) with axial ester group.
We noticed that the epimerization of the final product 2f(a) with KSC(S)OEt (Scheme 5) required a longer time than that observed in the reaction of starting epoxides under the same conditions (that is in presence of EtOCS 2 -, EtO -, or MeO -from the solvent).This may indicate that a faster α-deprotonation occurs intramolecularly within one or several intermediates of the reaction, when α-proton happens to be in a vicinity of an alcoholate or thiolate anion (Scheme 4).
The results obtained with the cyclohexene oxides 1g and 1h bearing two ester-groups also confirmed the proposed epimerization.Thus the cis-disubstituted epoxide 1h (entry 8) yielded two diastereomers, 2h(ee) and 2h(ea), in the ratio 10 : 1 (by 1 H NMR). The formation of the allequatorial 2h(ee) (Figure 5) can be explained by epimerization of the initially formed diastereomer 2h(ea) containing one axial ester group.In the case of trans-disubstituted epoxide 1g (entry 7, Table 2), a polymer was mostly obtained, and only small amount of the product 2g(ee) was isolated.The configuration of both groups COOEt in the latter compound was opposite to what should have been expected.This can be explained by the relative instability of the expected product with both ester groups in axial positions, and by the base-catalyzed epimerization of these substituents.

Trithiocarbonate ring as a conformational lock
Control of molecular conformation is a powerful way to modulate the physical, chemical and biological properties of compounds.It can be achieved by a shift of conformational equilibrium towards unusual (relatively unstable) forms via modification of substituents or construction of bridged structures. 15,16The synthesis of cyclic trithiocarbonates from epoxides is, in fact, a construction of a bridge that affixes one of possible conformations.Moreover, the stereochemical course of the reaction (the inversion of configuration at one of the former epoxide carbons and the double inversion at the second carbon) forces the structure to perform a flip into a conformation alternative to an original one.It was shown previously that the similar procedure with CS 2 as a reagent transformed the epoxides of cis-alkenes into trithiocarbonates with transarrangement of substituents. 13We observed the same result in reactions of epoxides 1n and 1r (entries 14 and 18 in Table 2).When our procedure was applied to epoxides of substituted cyclic alkenes, these substituent(s) were forced to adopt a sterically unfavourable axial position (see above).Thus, the five-membered ring of trithiocarbonate can serve as a lock for unfavourable conformations.This lock is powerful enough to make a methyl group axial, which requires 7.3 kJ/mol, 38 but fails to do the same with t-butyl (~20 kJ/mol 38 ).The lock can be subsequently removed or cleaved by reduction 4,13,26,27 or hydrolysis 27 of trithiocarbonates to dithiols.We suggest this approach as a potentially useful addition to a set of other conformational locks (acetals, ortho-esters, urethanes, etc.) that have been used in various syntheses previously. 15,16In particular, the results of our study clearly point to a possible application of the trithiocarbonate lock for a stereoselective epimerization of ester substituents in basic conditions.

Conclusions
A simple and convenient procedure for the selective synthesis of 1,3-dithiolane-2-thiones (cyclic trithiocarbonates) from epoxides has been developed.The mechanism and stereochemistry of the reaction have been studied.The formation of cyclic trithiocarbonates can be used to lock unstable conformations.

Experimental Section
General.The chemicals used in this study were purchased from commercial sources (Sigma-Aldrich, TCI) and used without additional purification.All solvents were purified by conventional techniques prior to use.Column chromatography was performed on silica gel (40-75 μm, Sorbent Technologies) and aluminum oxide (activated basic, 58Å, Aldrich).The reactions were monitored by TLC on silica gel 2.5 × 7.5 cm plates, J. T. Baker (visualization by staining with KMnO 4 -sulfuric acid), or alumina 8 × 2 cm plates, Analtech Inc. (visualization by staining with I 2 ). 1 H NMR and 13 C NMR spectra were acquired on JEOL ECA-600 NMR-spectrometer (600 MHz for 1 H and 150 MHz for 13 C) with spinning at rt. 1 H-1 H-COSY and 1 H- 13 C-HMQC techniques were used to assign the signals.1D-pfg-ROESY and 1D-pfg-STEP-NOESY experiments 32,33 were carried out non-spinning at rt with selective Gauss-shaped 180º-pulses and with 10 s recovery times between pulses.After initial gradient shimming, the spinner was turned off and the shims were manually touched up for best field homogeneity.The optimal mixing time for TOCSY magnetization transfer to a specific neighboring proton was established with an arrayed experiment of 5-10 mixing times between 20-200 ms in 20 ms increments.The ROESY and STEP-NOESY experiments were run for 1024 scans and the raw data were zero-filled four times prior to Fourier transformation.High resolution mass spectra (HRMS) were obtained on a JEOL AccuTOF time-of-flight mass spectrometer (Peabody, MA) coupled with an Ionsense DART open-air ionization source (Saugus, MA).The instrument was tuned to a resolving power of 7,000 with reserpine directly infused into the electrospray ionization source; this provides a stable ion current to tune the timeof-flight parameters.Samples were introduced into the DART sample gap with a glass melting point capillary by first dipping the closed end of the capillary into the sample then immediately placing it into the helium metastable beam.The helium gas temperature was set to 250 o C to aid in the desorption of the analyte from the capillary.The samples were held in the sample gap for 10-15 seconds to acquire several mass spectra to average for an accurate m/z assignment.Crystallographic Data for compounds 2f(a), 2f(e), 2h(ee), 3h and 2i were collected on Beamline 11.3.1 at the Advanced Light Source, Lawrence Berkeley National Lab using monochromatic radiation (λ = 0.7749 Å) at 150(2) K. Data reduction and cell refinement for all compounds were performed with SAINT. 39We used SADABS to obtain the absorption-corrected data. 40rystallographic data are given in Table S1 (Supplementary data).Selected bond distances, bond angles and torsion angles are given in Tables S2-S6.CCDC 972800 (2f(a)), 972796 (2f(e)), 972799 (2h(ee) ), 972797 (3h) and 972798 (2i) contain the supplementary crystallographic data for this paper.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Figure 3 .
Figure 3. X-ray crystal structure of compound 2f(a) with thermal ellipsoids set at the 50% probability level for non-H atoms (crystals were grown from MeOH).There are two molecules per asymmetric unit.

Figure 4 .
Figure 4. X-ray crystal structure of compound 2f(e) with thermal ellipsoids set at the 50% probability level for non-H atoms (crystals were grown from MeOH).There are two molecules per asymmetric unit.

Figure 5 .
Figure 5. X-ray crystal structure of compound 2h(ee) with thermal ellipsoids set at the 50% probability level for non-H atoms (crystals were grown from MeOH).

Figure 6 .
Figure 6.X-ray crystal structure of compound 3h.Thermal ellipsoids set at the 50% probability level for non-H atoms (crystals were grown from MeOH).

Figure 7 .
Figure 7. X-ray crystal structure of compound 2i.Thermal ellipsoids set at the 50% probability level for non-H atoms (crystals were grown from MeOH).

Scheme 4 .
Scheme 4. Plausible mechanism for the formation of cyclic trithiocarbonates.

Table 2 .
Reaction of various epoxides with potassium ethyl xanthogenate.a