Synthesis and Functionalization of Thiophosphonium Salts: A Divergent Approach to Access Thioether, Thioester, and Dithioester Derivatives

Herein, we report a straightforward practical method for efficiently obtaining a diverse range of thiophosphonium salts. This method involves the direct coupling of commercially available thiols and aldehydes with Ph3P and TfOH. The setup is simple and carried out in a metal-free manner. The synthetic utility of these salts is demonstrated through various examples of C–P bond functionalizations, enabling the synthesis of thioether, deuterated thioether, thioester, and dithioester derivatives. These products, which serve as valuable building blocks, are obtained in high yields.

O rganophosphonium salts containing C− + P moieties, 1,2 in particular organophosphorus-based Wittig salts, are among the most utilized reagents in organic synthesis for constructing the C−C double bond. 34][5][6][7][8]10,11 Despite these advancements, there are still limitations that must be addressed. Thereore, it is important to investigate additional methods for synthesizing new variants of organophosphonium species and their functionalizations.Such exploration is expected to greatly enhance the existing approaches for derivatizing noble organophosphonium salts and enable the creation of new connections.10 In this regard, recently, our research group has successfully described a versatile method for synthesizing benzhydryl triarylphosphonium salts (VII) through a convenient one-pot, regioselective four-component coupling reaction using readily available starting materials (Scheme 1A).8 The resulting benzhydryl phosphonium salt building blocks exhibited excellent utility, as demonstrated by their selective postfunctionalization of C-selective electrophilic benzylic C-(sp 3 )− + PPh 3 groups.This allowed for a range of transformations including aminations, thiolations, and arylations, leading to the creation of bioactive arylated scaffolds (Scheme 1A).8 In this method, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are respectively readily accessed.8 Furthermore, Chu 12,13 and co-workers have developed an efficient metal-free difluoroalkylation reaction of these organophosphonium salts (VII) with difluoroenol silyl ethers (Scheme 1A).12,13 As part of our overarching strategies to synthesize a diverse range of thio-based bioactive compounds (I−VI), encompassing thioether, thioester, and dithioester derivatives, we recognized the potential of thiophosphonium salts as versatile core scaffolds for these molecules (Scheme 1B).14−17 However, the synthesis and application of thiophosphonium salts have been relatively uncommon, with few reports addressing their exploration (Scheme 1C).Notably, in 1961, Schlosser 18a described the use of α-chloro sulfides (VIII) as transient intermediates in the synthesis of thiophosphonium salts (Scheme 1C).More recently, in 2021, Magolan 18b utilized a similar approach, utilizing α-chloro sulfides (VIII) as a starting point for the synthesis of thiophosphonium salts IX (Scheme 1C).9 It is important to highlight that the synthesis of αchloro sulfides (VIII) necessitates the use of demanding reaction conditions.18 Moreover, it should be noted that the versatility of these reactions is predominantly limited to thioalkyl phosphonium salts (IX).18 Therefore, it is imperative that a complementary, general, milder, and diversifiable method for thiophosphonium salts will be developed.
With this goal in mind, we envisioned an operationally simple strategy to synthesize thiophosphonium salts 3 and convert them into valuable thio-based motifs (4−6, III) through the C(sp 3 )− + P transformation (Scheme 1D).In fact, drawing inspiration from our recent report 8 and Lin's 20 work (Scheme 1A), our method involves a simple four-component reaction utilizing readily accessible and commercially available starting materials, i.e., aldehydes 1 and thiols 2 (Scheme 1D).
To test our hypothesis, we first treated p-anisaldehyde (1a) with thiophenol (2a), triphenylphosphine (PPh 3 ), and triflic acid in CH 3 CN for 24 h at 45 °C to obtain the desired phosphonium salt 3a in 97% isolated yield (Scheme 2A,B).Notably, no conversion was observed in the absence of either PPh 3 or TfOH (for full details, see the Supporting Information (SI), pp S55−56).
We next explored the synthetic applications of these thiophosphonium products (3), and we aimed to demonstrate their synthetic utility in selective transformations of the C− + P bonds and the synthesis of bioactive chemicals.−25 In this regard, a hydrolysis-based reduction protocol was developed for thiophosphonium salts 3 using H 2 O (Scheme 3A,B).In this method, we explored the reduction of a thiophosphonium salt, specifically utilizing 3a as a standard salt for the reaction optimization.Various organic and inorganic bases were employed for the reaction, and the Supporting Information provides further details on these bases (see SI, pp S23−24).Ultimately, DBU was identified as the optimal base for the hydrolytic reduction of the thiophosphonium salt, leading to the formation of thioether 4a in an isolated yield of 87% (Scheme 3A,B).
Subsequently, we successfully synthesized a variety of thioether derivatives by adapting the standard reaction conditions outlined in Scheme 3. The reaction exhibited a broad scope, encompassing aryls with substituents such as −OMe, −F, −Cl, −Ph, −Bpin, and −Me, in good yields.Notably, even alicyclic and cyclic aliphatic substituents on the thiol part yielded the desired thioether derivatives in good yields.Furthermore, replacing water with D 2 O provided a valuable opportunity to produce almost fully α-deuterated thioether (4-D), exhibiting excellent deuterium labeling (up to 93% D-incorporation) and good yields (Scheme 3C).
−29 On the basis of reports in the literature, this mechanistic process involves the formation of ylide/ylene XI, followed by protonation/ deuteration of ylene XI.−29 Finally, we also successfully prepared the pesticide chemical chlorbenside 16 III from the commercially available 4chlorobenzaldehyde 1f and 4-chlorothiophenol 2d in only two steps. 16,17This was achieved through the selective coupling reaction of 1f and 2d to generate thiophosphonium salt 3ad, which was then reacted with DBU and water through a CH− + P group hydrolysis-based reduction reaction in a single operation (Scheme 3E).Reaction conditions: 3 (0.2 mmol), K 3 PO4 (0.24 mmol), and air balloon in 3 mL of dry THF at room temperature (for thioester synthesis) or 3 (0.2 mmol), K 3 PO 4 (0.24 mmol), and S 8 (0.30 mmol) in 3 mL of dry CH 2 Cl 2 at room temperature (for dithioester synthesis) All the yields of the reactions are isolated after column chromatography.
Encouraged by these results of the reduction methodology, we contemplated the possibility of synthesizing important thioester 30 and dithioester 23 motifs using the thiophosphonium salt 3. 24 We imagined that this could be achieved by the generation of phosphorus ylide (XI) from salt 3 following by a direct oxidation of this ylide (XI). 31,32ur initial optimization efforts focused on the formation of thioester 5a from thiophosphonium salt 3 and a base under air (a source of O 2 ), via the corresponding ylide XI. 31,33 After many experiments, the use of K 3 PO 4 in dry THF was found to be the best reaction condition to obtain the thioester product 5a with a yield of 90%.
Next, we explored the reaction's scope; we employed identical reaction conditions.Consequently, thiophosphonium salt 3 effectively participated in the reaction, resulting in the formation of the desired product 5 with good yields, as depicted in Scheme 4A,B.
To further showcase the synthetic utility of salts 3, we developed their transformation into dithioesters 6 (Scheme 4A,C). 15To this end, we employed basic reaction conditions to treat thiophosphonium salt 3 with elemental sulfur (S 8 ). 32,34e conducted a thorough exploration of the optimal reaction conditions and determined that employing dry CH 2 Cl 2 and K 3 PO 4 as the standard reaction conditions resulted in the highest yield of dithioester 6a, with approximately 78% yield (for more details, see the Supporting Information).Additionally, we showed that various thiophosphonium salts 3 could tolerate these reaction conditions, leading to the formation of the desired dithioester 6 with good yields, as depicted in Scheme 4C.Of note, a possible mechanism for the oxidation pathways is proposed in the SI (see SI, p S59). 33,34b,c In conclusion, we have developed a simple and broadly straightforward protocol for the direct synthesis of a diverse range of thiophosphonium salts.This protocol involves the one-pot, four-component coupling reaction of commercially available thiols and aldehydes with Ph 3 P and TfOH.The utility of the resulting thiophosphonium salt building blocks was demonstrated by the chemoselective postfunctionalization of C(sp 3 )− + PPh 3 groups to achieve divergent reduction and oxidations protocols.In this way, thioether, deuteratedthioether, thioester, and dithioester derivatives, structural motifs that are present in many important chemicals, are readily accessed.This includes the synthesis of the pesticide chemical chlorbenside from simple commercially available materials in only two steps.The setup of these C−P group postfunctionalizations is simple, and the products were obtained in good yields.These protocols should greatly simplify access to bioactive relevant chemicals and further advance their use in a variety of new applications.

Scheme 4 .
Scheme 4. Oxidation of Thiophosphonium Salts to Thioesters and Dithioesters a