Sulfenofunctionalization of Chiral α‐Trifluoromethyl Allylboronic Acids: Asymmetric Synthesis of SCF₃, SCF₂R, SCN and SAr Compounds

Abstract

We report herein a new method for the synthesis of densely functionalized chiral allyl SCF₃, SCF₂R, SCN and SAr species with a separate CF₃ functionality. The synthetic approach is based on selenium‐catalyzed sulfenofunctionalization of chiral α‐CF₃ allylboronic acids. The reactions proceeded with remarkably high stereo‐, diastereo‐ and site‐selectivity, based on the formation of a stable thiiranium ion followed by rapid deborylative ring opening.

Densely functionalized chiral allyl species, with an alkenyl CF₃ group, were prepared with excellent selectivity by selenium‐catalyzed sulfenofunctionalization of allylboronic acids. The method can be used to access chiral allyl SCF₃, SCF₂R, SCN and SAr compounds.

Introduction

Sulfur and fluorine are major constituents in drug substances together with the principal elements of C, H, N, O. ^[1] Sulfur containing drugs are used for treatment of bacterial infections (Scheme 1), diabetes, cancer, AIDS and many other clinical conditions.[ ¹ , ² ] About 30 % of the recently approved pharmaceuticals contain at least one carbon‐fluorine bond. ^[3] The beneficial pharmacokinetical properties of fluorinated bioactive compounds include high metabolic stability, usually low polarity and possibilities to alter the acid‐base properties of the drug substances. ^[4] Thus, an increasing number of drug substances expected to appear, which contain both sulfur and fluorine.

Scheme 1.

Examples of organosulfur drugs and natural products.

Today there is a large interest in application of di‐ and trifluoromethylthiol containing drugs, such as Cefazaflur, Cangrelor and Flomoxef (Scheme 1).[ ¹ , ^3d ] However, considering that a trifluoromethyl group has excellent properties for modification of the polarity, solubility and metabolic stability of the drug substances, the simultaneous presence of CF₃ and sulfur containing groups (SCF₃, SCF₂R, SCN, SR etc.) is an attractive approach for design of modern pharmaceuticals with complex bioactivity and fine‐tuned pharmacokinetic properties. Carbon‐sulfur ^[5] and carbon‐fluorine ^[6] bond formation reactions have been the subject of many excellent synthetic studies because of the high importance of these principal motifs in drug design. Among these methods the most challenging ones are directed to synthesis of chiral C−S/C−F motifs, which are important for the bioactivity of the drug substances.[ ⁵ , ^6c , ⁷ ] In this paper we report our results on asymmetric synthesis of chiral sulfur compounds (SCF₃, SCF₂R, SCN, SR etc.) comprising a separate CF₃ group (Scheme 2a). This synthesis can be achieved by thiofunctionalization of allylic α‐CF₃ boronic acids, which are available via a recently reported simple and efficient organocatalytic method. ^[8] This procedure leads to trifluoromethylated chiral allyl sulfides comprising an alkene unit, which is a useful handle for further asymmetric functionalizations.

Scheme 2.

Asymmetric electrophilic thiolation reactions of alkenes.

Results and Discussion

Several excellent transition metal catalyzed allylic thiofunctionalization methods have been reported for synthesis of chiral allyl sulfides. ^[9] Although, palladium catalysis can be employed for stereoselective transformation of allylboron compounds, ^[10] the presence of an α‐CF₃ group requires application of other synthetic approaches. The reason is that transmetallation of the boronate functionality with transition metals, such as Pd, leads to formation of an M−L bond in α‐position to the CF₃ group, triggering a β‐fluorine elimination due to the M−C(σ) → C−F(σ*) anomeric effect. ^[11]

To avoid this anomeric β‐defluorination, the buildup of the negative charge at the stereogenic carbon has to be avoided. Thus, we selected an electrophilic thiofunctionalization method proceeding via Lewis base stabilized thiiranium ion intermediates.[ ^5c , ¹² ] This methodology has been pioneered by Denmark and co‐workers[ ^5c , ¹² , ¹³ ] (Scheme 1b) and further developed by the Zhao group ^[14] and others ^[15] (Scheme 2c). This approach has been demonstrated to be highly efficient for synthesizing various aryl, alkyl and trifluoromethyl thioethers with high selectivity.

Initially we targeted the asymmetric synthesis of allylic SCF₃ compounds with CF₃ substituent (3 a) using α‐CF₃ allylboronic acid derivatives ^[8] 1 a (Table 1). As a source of the sulfenyl group we used electrophilic SCF₃ transfer reagent 2 a reported independently by Zhao ^[14b] and Shen. ^[16] Zhao and co‐workers[ ^14a , ^14b , ^14c , ^14d ] reported several trfluoromethylthiolation reactions by 2 a (Scheme 2c) using selenium based Lewis base catalysts in the presence of strong acids (such as Tf₂NH, TMSOTf etc.). We used commercially available diphenyl selenide as catalyst in the presence of various acids to activate 2 a. Using pinacol boronate 1 a‐Bpin and 2 a as substrates in the presence of Ph₂Se and Tf₂NH at 25 °C resulted in allyl‐SCF₃ product 3 a in 8 % NMR yield (entry 1). In this reaction 1 a‐Bpin was completely consumed. The low yield indicated that the thiiranium intermediate of the process was probably unstable at this temperature. Decrease of the temperature to 0 °C and −20 °C led to improvement of the yields to 23 and 31 %, respectively (entries 2, 3). However, further decrease of the temperature to −50 °C lowered the yield to 21 % (entry 4). Variation of the acidic additives by using TfOH or TMSOTf led to 30 and 23 % yields, respectively (entries 5 and 6).

Table 1.

Optimization of the reaction conditions.^[a]

Entry	Substrate	Acid	T [°C]	Yield [%][b]	ee/es [%][c]
1	1 a‐Bpin	Tf2NH	25	8	–
2	1 a‐Bpin	Tf2NH	0	23	–
3	1 a‐Bpin	Tf2NH	−20	31	–
4	1 a‐Bpin	Tf2NH	−50	21	–
5	1 a‐Bpin	TfOH	−20	30	–
6	1 a‐Bpin	TMSOTf	−20	23	–
7	1 a	Tf2NH	−20	55	–
8[d]	1 a	Tf2NH	−20	60	–
9[d,e]	1 a	Tf2NH	−20	80	–
10[d,e]	1 a	No acid	−20	24	–
11[d,e,f]	1 a	Tf2NH	−20	0	–
12[d,e,g]	1 a	Tf2NH	−20	81(63)[h]	98/100

[a] Unless otherwise stated: 1 a (0.05 mmol), 2 a (0.06 mmol), Ph₂Se (20 mol %) and acid (0.05 mmol) dissolved in CH₂Cl₂ (0.5 mL) and stirred at indicated temperature for 16 h. [b] Determined by ¹⁹F NMR. [c] Determined by chiral GC. [d] 1.5 equivalent of 2 a. [e] 3 Å Molecular sieves was used. [f] Reaction without selenide catalyst. [g] 0.3 mmol scale. [h] Isolated yield, regioselectivity: γ/α>50/1.

The above results indicated that Bpin is not a sufficiently reactive leaving group in the desired sulfenofunctionalization process. A possible way of activation of Bpin would be the application of ArLi reagents, which was employed by Aggarwal ^[17] and Denmark ^[13d] in sulfenofunctionalization of Bpin derivatives. However, we had to avoid this activation method, as it involves conversion of the Bpin group to a hypervalent ate complex. Formation of the negatively charged ate complex would lead to β‐fluoride elimination (see above) and possibly other undesired side reactions. Instead we opted to use of allylboronic acid ^[8] 1 a instead of the Bpin derivative (1 a‐Bpin). Our previous allylboration studies indicated that allylboronic acids or the corresponding boroxines are much more reactive species than the corresponding allyl‐Bpin reagents.[ ⁸ , ¹⁸ ] Indeed, replacement of 1 a‐Bpin with 1 a, under otherwise identical reaction conditions, led to a major increase of the yield from 31 to 55 % (c.f. entries 3 and 7). When the amount of 2 a was increased to 1.5 equiv. the yield was slightly increased to 60 % (entry 8). A substantial increase of the yield (to 80 %) was observed by adding molecular sieves (entry 9). Previous studies indicate that addition of the molecular sieves to allylboronic acids leads to formation of the corresponding allylboroxines.[ ^18c , ^18d ] Allylboroxines are stronger Lewis acids than the corresponding allylboronic acids, and thus the reactivity of allylboronic acids is increased by boroxine formation under anhydrous conditions.[ ^18c , ^18d ] Apparently, this is also the case for selenium‐catalyzed sulfenylation reactions, as the yield of 3 a was improved from 60 % to 80 % by addition of molecular sieves (c.f. entries 8 and 9). Activation of 2 a by Tf₂NH is apparently important ^[14b] as in the absence of acids, the yield is poor (24 %, entry 10). In the absence of Ph₂Se catalyst formation of SCF₃ product 3 a was not observed at all (entry 11). When the reaction was scaled up to 0.3 mmol, the NMR yield was 81 % and the 3 a could be isolated in 63 % yield. The isolation loss was due to the high volatility of 3 a, which can be explained by the simultaneous presence of the CF₃ and SCF₃ groups. The reaction proceeded with excellent stereoselectivity with 98 % ee, which corresponds to a full chirality transfer (100 % es). In addition, the reaction occurred with high site selectivity, as we observed exclusively the formation of the γ‐SCF₃ product, which occurred by allylic rearrangement. In the selenium catalyzed asymmetric trifluoromethylthiolation of tri‐substituted alkenes (c.f. Scheme 2c), the diastereoselectivity is difficult to control. ^[14a] Yet, in the present reaction exclusively the E isomer of alkenyl trifluoromethyl compound was formed.

With the optimal conditions (Table 1, entry 12) in hand, the synthetic scope of the trifluoromethylthiolation reaction was studied using allylboronic acids 1 a–h as substrates (Table 2, entries 1–8). Notably, a very high, stereo‐, diastereo‐ and site selectivity was observed as for trifluoromethylthiolation of 1 a (Table 1, entry 12). The reactions usually proceeded with a high degree of functional group tolerance. Replacement of the alkyl moiety (1 a) with a benzyl one (1 b) did not alter the outcome of the reaction (c.f. entries 1 and 2). The chloro substituent in 1 c was tolerated maintaining the high diastereo‐ and site‐selectivity but the ee dropped to 88 % (entry 3). The tosylester group of 1 d remained unchanged in the reaction, resulting in 3 d with very high selectivity offering two handles for further derivatizations. Phthalimide derivative 1 e was converted to 3 e (entry 5), which contains all six principal elements of drug design, with great opportunities for further asymmetric transformations. In this process, formation of traces of the α‐SCF₃ product (γ/α=16/1) could also be detected. The absolute configuration of crystalline 3 e was determined to be (S) by X‐ray diffraction (Scheme 3a). ^[19] Considering the structural similarities and reaction conditions, we tentatively assigned the configuration of the other thiofunctionalized products based on the absolute configuration of 3 e. In the presence of an alkenyl cyclohexyl group (1 f), the high selectivity could be still maintained (entry 6). Selective sulfenofunctionalization of cinnamylboronic acid 1 g is expected to be challenging. Considering the highly selective formation of 3 f (entry 6), we predicted a high diastereo‐ and stereoselectivity in case of replacement of the cyclohexyl (1 f) with phenyl (1 g) group. However, the reactivity and the site selectivity were anticipated to decrease, because of the allylic rearrangement, which disrupts the π‐conjugation between the phenyl group and the double bond in 1 g. Initial attempts using the standard optimized conditions gave 3 g with low yield. However, changing the catalyst to (p‐OMePh)₂Se and using MsOH instead of Tf₂NH as activator 3 g was formed in acceptable yield (53 %) and excellent siteselectivity. We also attempted to obtain substituted analogs of 3 g. However, when 1 g with p‐chloro phenyl group was used, we obtained an intractable mixture of products, probably because of the instability of the allylboronic acid under the applied reaction conditions. On the other hand, the p‐methoxy phenyl analog of 1 g had a very low reactivity towards trifluoromethylthiolation, as we got only traces of the product. Compound 1 h with bulky tert‐butyl group was converted to product 3 h under the standard conditions (entry 8). The reactions proceeded with excellent stereo‐, diastereo‐ and site selectivity in 64 % yield indicating that bulky alkenyl substituents did not affect the selectivity of the reaction.

Table 2.

Substrate scope for trifluoromethylthiolation and difluoromethylthiolation.^[a]

[a] Unless otherwise stated: 1 (0.3 mmol), 2 (0.45 mmol), Ph₂Se (20 mol %) and Tf₂NH (0.3 mmol) dissolved in CH₂Cl₂ (3 mL) and stirred at −20 °C for 16 h. [b] Unless otherwise stated: γ/α>50/1. [c] Reaction was performed with (p‐OMePh)₂Se as catalyst, MsOH as additive at −50 °C for 48 h. [d] Reaction was performed on 0.1 mmol scale with (p‐OMePh)₂Se (20 mol %) as catalyst and MsOH as additive.

Scheme 3.

a. X‐ray structure of compound 3 e. b. Suggested structure of the thiiranium ion intermediate for formation of 3 e.

Difluoromethylthio motif is a rising star in modern drug design. For example Flomoxef has slightly different antibacterial activity compared to the SCF₃ analogue Cefazaflur (Scheme 1).[ ¹ , ^3d ] In addition, difluoromethyl groups are bioisosteres for hydroxy and thiol functionalities. ^[20] Asymmetric electrophilic difluoromethylthiolation reactions based on Lewis‐base catalysis have never been reported. Synthesis of chiral SCF₂R species was not described either. As far as we know, only two studies have been published on asymmetric synthesis of SCF₂H species by the groups ^[21] of Cahard and Shibata and the Shen group. ^[22] The success of the above asymmetric trifluoromethylthiolation reactions inspired us to extend the same concept to the highly challenging difluoromethylthiolation reactions. In these studies, we used electrophilic, aniline based difluoromethyltiolation reagents 2 b–c (entries 9–13) reported by Billard and co‐workers. ^[23] Because of using these SCF₂ sources, we slightly modified the reaction conditions used for the SCF₃ transfer reactions. Thus, we used electron‐rich (p‐OMePh)₂Se catalyst, which is more efficient (stronger Lewis base) than Ph₂Se. In addition, an excess of acid additive was required to inhibit the competitive nucleophilic amination by aniline. Aliphatic allylboronic acid derivative 1 a gave the chiral SCF₂COOEt product 4 a with full allylic rearrangement, in good yield (60 %) and with remarkably high stereo‐, diastereo‐ and site‐selectivities (entry 9). Slightly lower yields but still very high selectivity were observed for benzyl and cyclohexyl allylboronic acid substrates 1 b and 1 f (entries 10–11). Cinnamylboronic acid 1 g was reacted with 2 b to give benzylic difluoromethylthiolated product 4 d with excellent γ‐siteselectivity in 40 % yield (entry 12). The sulfone‐containing reagent 2 c reacted with 1 a in somewhat lower yield and with slightly lower selectivity than the carbethoxy analogue 2 b (c.f. entries 9 and 13).

Considering that the selenium catalyzed transformation of allylboronic acids proceeded with usually good yield and remarkably high selectivity for synthesis of densely functionalized chiral di‐ and trifluoromethyl thiols 3 a–h and 4 a–e, we sought to extent the concept to other sulfenofunctionalization reactions. Chiral thiocyanates (Scheme 1) such as Fasicularin ^[24] attracted a considerable attention in medicinal applications. An obvious reason is that organic thiocyanates can be easily converted into various sulfur‐containing drug intermediates especially to sulfur‐heterocycles. ^[25] One of the problems in wide application of this functionality in modern drug design is that very few methods are available for asymmetric synthesis of organic thiocyanates. Zhao and co‐workers reported a selenium catalyzed asymmetric thiocyanation method but this reaction occurred with poor enantioselectivity. ^[14d] We used saccharin based electrophilic SCN transfer reagent 2 d in the presence of (p‐OMePh)₂Se catalyst in the thiocyanation of allylboronic acids (Table 3, entries 1–3). Using aliphatic allylboronic acid substrate 1 a with reagent 2 d, the corresponding densely functionalized thiocyanate 5 a was formed in high yield (81 %) and excellent stereo‐, diastereo‐ and site‐selectivity (entry 1). Phthalimide derivative 1 e gave a homoallyl amine 5 b with SCN and CF₃ functionalities (entry 2) with still high ee (90 %) and high γ‐selectivity (γ/α=32/1). As expected from the above thiofunctionalization reactions cyclohexyl substrate 1 f gave the corresponding SCN product with allylic rearrangement and with high level of chirality transfer (entry 3).

Table 3.

Substrate scope for thiocyanation, arylthiolation and halogenation.^[a]

[a] Unless otherwise stated: 1 (0.1 mmol), 2 (0.15 mmol), (p‐OMePh)₂Se (20 mol %) and Tf₂NH (0.1 mmol) dissolved in CH₂Cl₂ (1 mL) and stirred at −20 °C for 16 h. [b] Unless otherwise stated: γ/α>50/1. [c] With Ph₂Se as catalyst. [d] With Ph₂S as catalyst.

We have also studied the arylthiolation of α‐CF₃ allylboronic acids (entries 4–7). In these reactions we employed succinimide based reagents 2 e and 2 f. The stereo‐, diastereo‐ and siteselectivity was high for reaction of aliphatic allylboronic acid derivative 1 a and 2 e (entry 4). However, a major drop of the site‐selectivity occurred for the reaction of benzyl derivative 1 b and 2 e as allylic aryl sulfide 6 b was formed with an γ/α ratio of 6/1 (entry 5). The site selectivity for sulfenofunctionalization of 1 c was high (γ/α=12/1) but the ee dropped to 88 % (entry 6). The lowest site selectivity (γ/α=3.5/1) was obtained for thiofunctionalization of phthalimide substrate 1 e (entry 7). Apparently, the site selectivity is significantly lower in arylthiolation, than in transfer of other groups with electron deficient sulfur (SCF₃, SCF₂R or SCN).

Considering the successful thiofunctionalization reactions with succinimide derivatives 2 e–f and the similar chemical behavior of halogenides and SCN groups (also called pseudohalogenides), we also extended the electrophilic substitution of allylboron species to chlorination and bromination reactions (entries 8–10). In these processes, we used standard electrophilic halogenation reagents 2 g–h. The reactions with aliphatic (1 a) and phthalimide (1 e) derivatives proceeded with high selectivities. The chiral allylic bromides (7 a–b) and chloride (7 c) with CF₃ group are very useful building blocks in asymmetric synthesis. We have also attempted to extend this reaction to fluorination and iodination. The reaction of 1 a under standard conditions with NFSI and NIS gave complex reaction mixtures from which we were not able to isolate halogenated products.

Based on the above results and the literature reports,[ ^5c , ^14a ] we suggest a mechanism for the selenium catalyzed sulfenofunctionalization of chiral α‐CF₃ allylboronic acids exemplified with trifluoromethylthiolation by 2 a (Scheme 4). The catalytic cycle is initiated by acid catalyzed ^[14b] formation of 8 from the diphenyl selenide catalyst and 2 a. Reagent 8 is apparently more reactive than 2 a as trifluoromethylthiolation of 1 a did not occur with 2 a in the absence of Ph₂Se (Table 1, entry 11). The next step is formation of chiral thiiranium ion 9 by the reaction of 8 and allylboronic acid (or its boroxine) 1. This is the stereoselectivity determining step. As the absolute configuration of the stereogenic center in 1 e is (S), ^[8] the (S) configuration in 3 e (Scheme 3a) suggests that addition of the sulfenium ion to the double bond occurs anti to the CF₃ group (Scheme 3b). This geometry also leads to formation of the CF₃‐alkene moiety (3) with a high E‐selectivity. The observed high selectivities can be explained by an interaction involving the sulfur of the thiiranium ring and an oxygen atom of the boronate group in 9.

Scheme 4.

Plausible mechanism for the allylic trifluoromethylthiolation of allyl boronic acid.

A thiiranium ion is usually thermally unstable and it may undergo isomerization reactions.[ ^5c , ^14a , ²⁶ ] Strong carbon‐sulfur bonds in thiiranium ions lead to high configurational stability. An explanation of the high level of chirality transfer in the presented sulfenylation reactions may be that the thiiranium ions formed are relatively stable intermediates. A possible stabilizing factor is the presence of the CF₃ group, which would destabilize a carbocationic intermediate formed by opening of the thiiranium ion. Yet, slight drops of the chirality transfer (Table 2, entry 3, Table 3 entries 2, 6) may be explained by minor stability issues of the thiiranium ion. The decrease of the site‐selectivity is a bit more difficult to explain. We had site selectivity issues mainly in case of arylthiolation reactions (Table 3 entries 5 and 7). The steric hindrance by the arylthiol group may contribute to the slow formation/low stability of the thiiranium ion. ^[13e] This instability may be coupled with rearrangement of the thiiranium ion ^[27] leading to a partial formation of the α‐substituted allyl product. The next step in the catalytic cycle is probably activation of the boronate group of 9 for elimination. This may occur by coordination of a nucleophile present in the reaction mixture (such as (PhSO₂)₂NH) to form intermediate 10. Due to the acidic conditions (presence of Tf₂NH) the nucleophilicity of (PhSO₂)₂NH is relatively poor. Therefore, it is important that the boron atom is highly Lewis acidic, such as in B(OH)₂ or boroxine groups. Otherwise, the elimination of boronate is very slow and the thiiranium ion may undergo rearrangements or decomposition. This could be the explanation of the low reactivity/poor yield of 1 a‐Bpin substrate in the above trifluoromethylthiolation reactions (Table 1, entries 1–6). The deborylative opening of the thiiranium ion in 10 leads to formation of 3, which is preceded by folding the Cα‐Cβ bond to ensure the formation of the alkene unit with E‐selectivity. In addition, the Cα‐Cβ bond rotation renders Cα‐B and Cβ‐S bonds to antiperiplanar position. This geometry allows occurring a deborylative ring‐opening by interaction of the Cα‐B(σ) and Cβ‐S(σ*) MOs. The highly selective formation of the chiral allyl‐SCF₃ product with CF₃ group (3) leads to regeneration of the Ph₂Se catalyst.

Conclusion

We have developed a highly stereo‐, diastereo‐ and site‐selective method for sulfenofunctionalization of α‐CF₃ allylboronic acids. This method is suitable for synthesis of densely functionalized SCF₃, SCF₂R, SCN and SAr compounds containing a CF₃ group and one or more handles for further stereoselective derivatization. The stereo‐ and diastereoselectivity of the reaction is remarkably high for all substrates and the allylic γ‐site selectivity is also very high for most of the substrates and thiofunctional groups. Very few methods are available in the literature for introduction of chiral SCF₂R and SCN groups and synthesis of allylthio derivatives in the presence of alkenyl CF₃ group is also very limited. The presented synthetic concept can also be extended to preparation of allylic chlorides and bromides. A possible explanation of the high selectivity and broad synthetic scope is the intermediacy of a relatively stable thiiranium ion, which undergoes rapid deborylative ring opening in case of application of allylboronic acid/boroxine substrates. We hope that the above method can be readily used in designing multifunctional drugs comprising all the 6 fundamental elements (C, H, O, N, S, F) and synthesis of sulfur containing natural products.[ ¹ , ² , ³ , ^5a , ^5b , ^5c , ⁷ ]

Conflict of interest

The authors declare no conflict of interest.

Supporting information

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Supporting Information

Supporting Information

Q. Wang, T. Nilsson, L. Eriksson, K. J. Szabó, Angew. Chem. Int. Ed. 2022, 61, e202210509; Angew. Chem. 2022, 134, e202210509.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.