Synthesis of pyridine trans-tetrafluoro-λ6-sulfane derivatives via radical addition

Prajwalita Das a, Masahiro Takada a, Etsuko Tokunaga a, Norimichi Saito b and Norio Shibata *a
aDepartment of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan. E-mail:
bPharmaceutical Division, Ube Industries, Ltd., Seavans North Bldg., 1-2-1 Shibaura, Minato-ku, Tokyo 105-8449, Japan

Received 1st November 2017 , Accepted 16th November 2017

First published on 16th November 2017

Pyridine tetrafluoro-λ6-sulfanes (SF4) with alkenyl or alkyl substituents have been synthesized for the first time via the radical addition reactions of pyridine-SF4 chlorides to alkynes or alkenes in good to high yields. X-Ray crystallographic analysis and DFT calculations disclosed an octahedral symmetrical trans-configuration of the hypervalent tetrafluorosulfanyl center. In contrast to phenyl-SF4 analogues, pyridine-SF4 compounds were found to be stable, which expands the utility of pyridine-SF4 compounds.

Hypervalent sulfur chemistry has been a topic of interest for the past several decades due to its synthetic and theoretical importance.1 A member of the hypervalent sulfur family, the tetrafluoro-λ6-sulfane unit (tetrafluorosulfanyl, “-SF4-”) is truly unique. Tetrafluoro-λ6-sulfane can connect two independent functional groups via the central hypervalent sulfur atom to create attractive structural motifs with a trans- or cis-configuration (Fig. 1a).2 While the related pentafluorosulfanyl (SF5) compounds have gained attention in recent decades,3 there is much less research on SF4 compounds.4–9 An early report by Gupta and Shreeve in 1985 described the addition reaction of trans-trifluoromethyl tetrafluorosulfanyl chloride to alkenes to provide alkyl trifluoromethyl tetrafluorosulfanes under photolytic conditions.4 Although the reaction is interesting, not many reports in this area have emerged since then. More than a decade later, Kirsch and co-workers focused on the arene tetrafluoro-λ6-sulfanes and reported several liquid crystal materials with a trans-SF4 connection.5 The symmetrical octahedral geometry of the trans-SF4 group serves as a non-conjugated linear conformation in the mesogenic core structure of liquid crystals, which is difficult to be constructed by carbon-based chemistry (Fig. 1b and c). The synthesis of these trans-SF4-linked arenes was achieved by direct fluorination of the corresponding aryl thioethers, followed by BF3·OEt2-mediated SF4 isomerization from a cis- to a trans-conformation.6 Welch and co-workers reported a new approach for the preparation of trans-SF4-linked arenes by the addition of aryl tetrafluoro-λ6-sulfanyl chlorides to alkenes and alkynes; however, the scope of the reaction was limited due to the lack of stability of the products.7 Consequently, further application of arene-SF4 products has not been actively investigated.8 Also, to date, there have been literally only a handful of methods that are available for the synthesis of arene-SF4 compounds (Fig. 1d)4–9 and it is quite notable that there are no reports on the synthesis of SF4-connected heteroarenes such as pyridine-SF4 compounds (Fig. 1e).
image file: c7qo00994a-f1.tif
Fig. 1 Structures containing a SF4 unit. (a) SF4 compounds with trans- and cis-geometry. (b) Aryl-SF4 compound (liquid crystal). (c) Diaryl-SF4 compound (liquid crystal). (d) Arene-SF4 compounds. (e) Pyridine-SF4 compounds (unknown, this work).

Considering the importance of pyridines as liquid crystal materials10 and biologically active compounds,11 as well as the market contribution of fluorine in liquid crystals12 and pharmaceuticals,13 we are interested in SF4-connected pyridine compounds as potential candidates for future materials in the aforementioned fields (Fig. 1e). Besides, from the perspective of the octahedral symmetry of the “-SF4-” moiety, we envisaged that a pyridine-SF4 unit would behave as an isostere to a pyridine-yne system.14 In the compounds having the pyridine-yne scaffold, the linearity of the alkynyl moiety is known to play a crucial role in rendering bioactivity.15 With the octahedral trans-geometry of the pyridine-SF4 at the hypervalent sulfur, where the fluorine atoms occupy the equatorial plane, the bond angle for R–S–R′ is almost linear, which can possibly mimic the linearity of the alkynyl group. The potential energy surfaces (PES) of the four systems exemplified by pyridine–C[triple bond, length as m-dash]C–Me, pyridine–SF4–Me, pyridine–C[triple bond, length as m-dash]C–CH[double bond, length as m-dash]CH2, and pyridine–SF4–CH[double bond, length as m-dash]CH2 were thus examined by DFT calculations (Fig. 2). As can be seen, the electron density in the alkyne region and SF4 region is high in all the corresponding systems. The bond angle of SF4 compounds is almost linear, i.e., the angle of Cpyridine–S–Cmethyl (Fig. 2b) is 179.49°, and that of Cpyridine–S–Cvinyl (Fig. 2d) is 176.43°. The corresponding bond length of each system is estimated to be 4.256 Å (Fig. 2a), 3.641 Å (Fig. 2b), 4.054 Å (Fig. 2c), and 3.721 Å (Fig. 2d). Despite the lack of one atom in SF4 systems, in comparison with alkyne models, their lengths are just 9% to 11% shorter than that of alkynes.

image file: c7qo00994a-f2.tif
Fig. 2 Structures of (a) pyridine-yne-Me, (b) pyridine-SF4-Me, (c) pyridine-yne-vinyl and (d) pyridine-SF4-vinyl. DFT calculations were performed by the B3LYP/6-311+G** level of theory.

With this proposal in hand, we were interested in attempting a radical addition of pyridine tetrafluoro-λ6-sulfanyl chloride derivatives with alkynes and alkenes. Radical reactions on alkynes and alkenes have proven to be of great synthetic application, such as tandem radical cyclization from alkynes16a–d and radical group migration triggered by alkene functionalization.16e–g These unsaturated systems are significant scaffolds in organic synthesis.16 Thus, we began with the reaction of 5-bromo-pyridine ortho-tetrafluoro-λ6-sulfanyl chloride (1a)3c,e,h with ethynylbenzene (2a) under radical conditions in the presence of Et3B in ether.7 The reaction proceeded smoothly in 30 minutes to furnish the pyridine-SF4-alkene 3aa in a 54% yield (entry 1, Table S1). The trans-geometry of tetrafluoro-λ6-sulfanyl chloride 1a was retained in product 3aa. The trans- or cis-geometry was easily ascertained by 19F NMR analysis (see the ESI for details).2,3e After screening the reaction conditions, we found that CH2Cl2 was a suitable solvent for this transformation (see Table S1 in the ESI for details) and 3aa was obtained in an 88% yield (entry 12 in Table S1 and Scheme 1). X-Ray crystallographic analysis of 3aa clearly revealed the 3D structure containing a SF4 unit with a trans-configuration (CCDC 1576319). As we had expected, the bond length of Cpy–S–Cvinyl and the angle of Cpy–S–Cvinyl are 3.641 Å and 176.29°, respectively, and are in good agreement with the DFT calculations (Fig. 2). The optimized conditions were found to be general for a variety of pyridine ortho-tetrafluoro-λ6-sulfanyl chlorides 1 (Scheme 1). Changing the substituent on the pyridine ring from bromo to chloro 1b and nitro 1c also provided products 3ba and 3ca in 81% and 34% yields, respectively. Even in the presence of an electron-donating Me group (1d) or no substitution (1e) on the pyridine ring, we isolated products 3da and 3ea in a 67–88% yield (Scheme 1). The isolation of 3da is of interest since its non-pyridine phenyl variant is too unstable to be isolated.7a

image file: c7qo00994a-s1.tif
Scheme 1 Addition of pyridine tetrafluorosulfanyl chloride 1 to aryl alkyne. The reaction of 1 (0.2 mmol) with 2a (0.3 mmol) was performed in the presence of Et3B (0.03 mmol) in CH2Cl2 (0.5 mL) for 30 min at 0 °C—rt. X-Ray crystallographic structure of 3a drawn at 50% probability ellipsoids (CCDC 1576319). Bond length (Cpy–S–Cvinyl: 3.641 Å), angle (Cpy–S–Cvinyl: 176.29°).

We next investigated the reaction of 1a with aliphatic alkyne 2b and alkene 4a. We were delighted to observe that 1a gave pyridyne-SF4-alkene 3ab with the reaction of alkyne 2b in a 91% yield and gave pyridyne-SF4-alkane 5aa after the addition to alkene 4a in a 68% yield (Scheme 2). Both adducts 3ab and 5aa were stable and we did not observe any decomposition, either during isolation via column chromatography or in their shelf life. Again, the stability of pyridine-SF4 compounds merits great attention since their reported non-pyridine analogues are too unstable to be isolated.7b

image file: c7qo00994a-s2.tif
Scheme 2 Addition of pyridine tetrafluorosulfanyl chloride 1a to aliphatic alkyne 2b and alkene 4a. The reaction of 1 (0.2 mmol) with 2 and 4 (0.3 mmol) was performed in the presence of Et3B (0.03 mmol) in CH2Cl2 (0.5 mL) for 30 min at 0 °C—rt.

Further substrate scope for the radical addition reaction of pyridine tetrafluoro-λ6-sulfanyl chlorides 1 was explored (Scheme 3). We began by using 1a with various aryl alkynes 2. The presence of electron-withdrawing group(s) (NO2, F) on the aryl ring of alkyne 2 resulted in the desired products 3ac–ae in good to excellent yields up to 91%. Alkynes with electron-donating groups (OMe, Me) also underwent the reaction to give the pyridine-SF4-alkenes 3af and 3ag in 71% and 69% yields, respectively. The use of a diethynyl aryl substrate 2h gave the mono-addition product 3ah in a 60% yield and a bis-addition product was not observed. Encouraged by the success in isolating adduct 3ab (Scheme 2), we next examined the effect of the chain length of alkyne 3. We noticed that decreasing the chain length by one carbon gave adduct 3ai in a 58% yield while increasing it by one carbon gave 3aj in an excellent yield of 90%. Thus, a longer alkyl chain in alkynes 2 is favorable in giving product 3 in higher yields because the free radical intermediate is stabilized by the positive I (inductive) effect of the increased number of alkyl groups. We then moved on to use ethynylcyclopropane (2k) and propynylbenzene (2l). The pyridine-SF4 adducts 3ak and 3al were formed, although the yields were 24% and 20%, respectively. The use of the heteroaromatic ethynylthiophene 2m gave adduct 3am in a 71% yield. The reaction with ethynyltrimethylsilane (2n) gave 3an in a 33% yield. We also attempted a radical reaction using pyridine tetrafluoro-λ6-sulfanyl chlorides having meta-SF4Cl substitution 1f,g with aryl alkyne 2a. Gratifyingly, the desired products 3fa and 3ga were obtained in moderate to excellent yields. Pyridine para-chlorotetrafluoro-λ6-sulfane 1h also provided product 3ha in a 60% yield. Thus, this radical reaction is in general independent of the substitutions and their positions, including ortho-, meta- or para-SF4Cl substituted pyridine 1 as well as alkynes 2. In all the cases, the trans-geometry of starting materials 1 was retained in product 3. We observed trace amounts of the Z-isomer of 3 from the crude NMR of a few compounds 3, but the E-isomer was formed almost exclusively. The reason for this E-isomer formation should be the thermodynamic stability of the E-isomer, which avoids the steric repulsions. The Z/E stereochemistry of 3 was assigned from the 1H NMR spectra. In the E-isomer, the alkene proton was downfield for all compounds, approximately around δ 7.0, due to the de-shielding of the Cl, which was close to the alkene proton.

image file: c7qo00994a-s3.tif
Scheme 3 Addition of pyridine tetrafluorosulfanyl chlorides 1 to alkynes 2. The reaction of 1 (0.2 mmol) with 2 (0.3 mmol) was performed in the presence of Et3B (0.03 mmol) in CH2Cl2 (0.5 mL) for 30 min at 0 °C—rt.

We further investigated the reaction of 1a with alkenes 4 to obtain pyridine-SF4-alkanes 5. Using aliphatic alkenes 4b,c, where the carbon chain length was increased to 6 and 10, gave the pyridine-SF4-addition products 5ab and 5ac in 69% and 71% yields, respectively. The reaction of styrene (4d) and butenylbenzene (4e) also provided pyridine-SF4-alkanes 5ad and 5ae in 78% and 59% yields, respectively. When a substrate 4f having two terminal alkenes was used, we obtained product 5af with an addition in only one of the alkene sites. Neither bis-addition nor any cyclization product was observed in the reaction mixture (Scheme 4).

image file: c7qo00994a-s4.tif
Scheme 4 Addition of pyridine tetrafluorosulfanyl chloride 1a to alkenes 4. The reaction of 1a (0.2 mmol) with 4 (0.3 mmol) was performed in the presence of Et3B (0.03 mmol) in CH2Cl2 (0.5 mL) for 30 min at 0 °C—rt.

In contrast to benzene analogues,7b all the adducts 3 and 5 are rather stable and isolable. In particular, the higher stability of 3ab and 5aa over their non-pyridine counterparts is obvious. To understand the enhanced stability of 3ab and 5aa over its benzene analogues, we evaluated the “chemical hardness”17 of these compounds by DFT calculations using the B3LYP/6-311+G** level of theory (see the ESI for details). The initial results were in accordance with the experimental findings, where 3ab and 5aa were found to be kinetically more stable than their benzene analogues (entries 1–4 in Table S2). However, on further evaluation, we obtained contradictory results for the p-NO2-benzene analogues, which were previously reported to be stable7b (entries 5 and 6 in Table S2), and realized that this scale cannot be used solely to explain the stability of the pyridine-SF4 compounds. Thus, we performed further calculations on pyridine–SF4–Me 6a, benzene–SF4–Me 6b and p-NO2-benzene–SF4–Me 6c, by taking into account the effect of the electron-withdrawing group in stabilizing the hypervalent sulfur atom having a three-center–four-electron (3c–4e) bond.3h,18 The pyridine is comparatively more electron deficient than benzene and this effect might be similar to that of p-NO2-benzene. We calculated the bond lengths and partial atomic charge on the sulfur atom and mapped the potential energy surfaces (Fig. 3). The Cpyridine/benzene–S bond lengths of 6a, 6b and 6c were found to be 1.819 Å, 1.853 Å and 1.855 Å, respectively, where 6a was the shortest. Also for the Cmethyl–S bond length, 6a (1.823 Å) was shorter than 6b (1.847 Å) and 6c (1.845 Å). These shorter bond lengths lead to the strengthening of the 3c–4e bond. The evaluation of the Mulliken charges reveal that the sulfur atom in 6c (0.647) has the highest charge followed by 6a (0.552), but the charge for sulfur in 6b is much lower (0.178). These values propose that the hypervalent sulfur with the 3c–4e bond is more stabilized in pyridine–SF4–Me 6a and p-NO2-benzene–SF4–Me 6c than that in benzene–SF4–Me 6b. Thus, we can conclude from these calculations that the electron-withdrawing effects of pyridine and p-NO2-benzene are comparable and that makes the pyridine-SF4-aliphatic adducts (3 and 5) and the previously reported p-NO2-benzene analogues thermodynamically stable, while the benzene-SF4-aliphatic adducts are not thermodynamically stable and are easily decomposed.

image file: c7qo00994a-f3.tif
Fig. 3 (a) Bond lengths and Mulliken charge. (b) Electrostatic potential maps of 6a, 6b and 6c.

In conclusion, we have examined the radical addition reactions of pyridine tetrafluoro-λ6-sulfanyl chlorides 1 to alkynes 2 or alkenes 4 to provide previously unknown pyridine-SF4-alkenes 3 or pyridine-SF4-alkanes 5 in good to high yields. The hypervalent sulfur center of the pyridine-SF4 derivatives 3 and 5 was revealed to be a symmetrical octahedral trans-configuration which is structurally almost linear. Besides, all the pyridine-SF4 derivatives 3 and 5 were found to be rather stable than those of non-pyridine phenyl variants of this type. DFT calculations provided insight into the stability of compounds 3 and 5 in terms of the thermodynamic stability of the hypervalent sulfur's 3c–2e bonds. These facts suggest that the pyridine-SF4 derivatives 3 and 5 can serve as potential building blocks for the synthesis of new candidates in liquid crystals and pharmaceuticals. We believe that this publication will inspire chemists to explore the possibilities with heteroaryl-SF4 compounds, which had previously been unexplored due to the limited access and stability of aryl-SF4 compounds. Further investigations for the application of 3 and 5 are underway.

Experimental section

For general information and details of DFT calculations, see the ESI.

General procedure for the radical addition of pyridine chlorotetrafluoro-λ6-sulfane 1 to alkynes 2 or alkenes 4

An oven-dried 10 mL narrow-mouth FEP test tube (Nalgene®) equipped with a magnetic stirring bar was charged with pyridine chlorotetrafluoro-λ6-sulfane 1 (0.20 mmol, 1.0 equiv.) inside the glove box. The test tube was sealed with a closure and taken out of the glove box. The closure was replaced with a septum. Then, an appropriate alkyne 2 or alkene 4 (0.30 mmol, 1.5 equiv.) and anhydrous dichloromethane (0.50 mL) were added under an argon atmosphere. The reaction mixture was cooled to 0 °C in an ice bath. Et3B (30 μL of 1.0 M solution in n-hexane, 0.030 mmol, 0.15 equiv.) was then added dropwise, and the mixture was stirred at room temperature in the presence of argon. (Although an inert atmosphere is needed for the stability of 1, oxygen is also required for the activation of Et3B.19 The required oxygen was in the reaction tube, which must have entered in a catalytic amount during the addition of reagents.) The reaction was monitored by 19F NMR, and 30 minutes after the addition of Et3B, there was complete conversion of the starting material. Then, saturated aq. NaHCO3 solution was added, and the aqueous layer was extracted with Et2O three times. The organic layer was washed with brine and dried over MgSO4. From the filtrate, the solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel by eluting with an n-hexane/AcOEt mixture, to give product 3 or 5.

The regiochemistry of 3 was identified from 19F NMR. The trans-isomer should produce only one fluorine peak as all the fluorines occupy the equatorial position and the cis-isomer should produce at least three separate fluorine peaks belonging to the three equatorial and one axial fluorines. We observed only one fluorine doublet peak for all 3 products and thus, assigned them with trans-configuration.

Conflicts of interest

There are no conflicts to declare.


This research is partially supported by the Tokyo Chemical Industry Foundation, the Pesticide Science Society of Japan, and JSPS KAKENHI Grant Number JP16H01017 in Precisely Designed Catalysts with Customized Scaffolding.

Notes and references

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Electronic supplementary information (ESI) available. CCDC 1576319. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7qo00994a

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