The unique chemical properties of aryl trifluoromethyl sulfides (ArSCF3) have been known for over 60 years.[1] The capacity of SCF3 to act as a lipophilic electron-withdrawing group has resulted in the incorporation of ArSCF3 components into a number of pharmaceutical and agrochemical agents.[2] Unfortunately, direct access to this important class of compounds is complicated by a lack of efficient, safe and general methods.[1a, 3]

Significant advances in Pd-catalyzed cross-coupling processes have allowed for efficient access to a diverse array of functionalized aromatic products, including aryl sulfides.[4] While the coupling of many aromatic or aliphatic thiols with aryl halides has been achieved with very high efficiency,[5] the analogous transformation to form aryl trifluoromethyl sulfides has not been reported. As gaseous CF3SH (b.p. = -36 °C)[6] can be difficult to handle in a laboratory setting, several SCF3 salts have been developed, however, most of these decompose under standard cross-coupling conditions.[3c]

It has been postulated that reductive elimination of Ar–SR from a palladium center is initiated via a nucleophilic attack on the electrophilic hydrocarbyl group by the metal-bound thiolate.[7] Thus, metal-catalyzed Ar–SCF3 coupling might be complicated by the reduced nucleophilicity of the SCF3 anion[2b] as compared to a standard thiolate.

Recent reports from our group regarding novel ligands including BrettPhos (1), t-BuBrettPhos (2), XPhos (3) and 3,4,5,6-tetramethyl(t-Bu)XPhos (4) (Scheme 1), have allowed for the successful coupling of weak nucleophiles traditionally thought to be reluctant participants in the transmetalation or reductive elimination steps of a typical Pd(0)/Pd(II) catalytic cycle. Specifically, using these catalyst systems has allowed for the direct formation of diaryl ether,[8] aryl fluoride,[9] aryl trifluoromethyl,[10] and aryl nitro compounds[11] from their corresponding aryl halides or pseudo halides. In light of these results, we hypothesized that a similar Pd-based system might allow for the formation of an aromatic C–SCF3 bond.



Scheme 1

Various ligands used in Pd-catalyzed cross-coupling reactions.



As we suspected that reductive elimination from putative intermediate 11 would be rate limiting in any catalytic process, we began our investigation by attempting its preparation from oxidative addition complex 10 via treatment with AgSCF3 (Scheme 2). We were surprised when this procedure did not provide the expected transmetalation complex but instead led directly to the Ar–SCF3 product 12 (presumably via 11).



Scheme 2

Formation of ArSCF3 via transmetalation and reductive elimination from an isolated LPdAr(Br) complex.



Given this finding, we attempted to convert 4-(4-bromophenyl)morpholine to the corresponding trifluoromethyl sulfide using AgSCF3 and a catalytic quantity of 1 and (COD)Pd(CH2TMS)2 (Table 1). However, under these conditions, none of 13 was observed. We surmised that failure to observe the coupled product might be due to the inefficient transfer of ⊖SCF3 to 10 under catalytic conditions. Thus, we elected to examine the use of a number of alternative previously reported ⊖SCF3 sources (Table 1).[3c, e]



Table 1

Examination of different SCF3 sources.[a]



Clark’s[3d] work on the use of (Bu)4NI and AgSCF3 for SNAr reactions with aryl halides indicated to us that the addition of a quaternary ammonium salt might be beneficial. Consistent with this hypothesis, the addition of 1 equivalent of (Bu)4NI to the reaction mixture increased the yield of 13 from 0 % to 55 % (Table 1). Further examination of different ammonium salts revealed that Ph(Me)3NI was more effective than (Bu)4NI and that switching to a more soluble ammonium salt, Ph(Et)3NI, provided a nearly quantitative yield of the desired product (Table 1). Based on work done by Clark, it is presumed that the iodide anion binds to AgSCF3 in order generate an anionic “ate” complex. We hypothesize that a large diffuse cation further aids in the solubility of this complex. It is worth noting that while the use of quaternary ammonium iodides and bromides allowed for catalytic turnover, the corresponding chloride analogs were ineffective.

With the optimal combination of Ph(Et)3NI and AgSCF3 realized, we re-examined various other previously reported ligands, which have enjoyed a measure of success in Pd-catalyzed cross-coupling reactions.[12] Our survey revealed that only dialkylbiarylphosphine based ligands were successful carrying out this transformation, while other ligands such as 5 or 6 did not perform well even with higher catalyst loadings.

Accordingly, we were successful in converting electron-rich, -neutral and -deficient aryl bromides to their respective aryl trifluoromethyl sulfides in 2 hours at 80 °C using 1.5 - 3.5 mol % of Pd and 1.65 – 3.85 mol % of 1. Electron-neutral and electron-rich substrates were coupled more efficiently than their electron-poor analogs. This effect has previously been noted in the coupling of aryl halides with NaNO2.[11] Substrates containing acid-sensitive functional groups, such as BOC-protected anilines and nitriles, were tolerated and coupled in high yield along with substrates containing ketones, esters, and free NH groups of anilines (Table 3). Aryl bromides containing bulky ortho-groups, e.g., o-cyclohexyl and o-phenyl groups, could also be coupled successfully, although they required the use of the smaller ligand XPhos (3) (Table 3).



Table 3

Pd-catalyzed coupling of aryl bromides.[a]



Heteroaryl bromides such as those containing indoles, pyridines, quinolines, thiophenes and furans, were also viable substrates (Table 4). Unfortunately, attempts to extend this methodology to the coupling of aryl chlorides or aryl triflates were unsuccessful. We are currently working to understand and overcome these limitations.



Table 4

Pd-catalyzed formation of heteroaryl–SCF3 compounds.[a]



Finally, to demonstrate the utility of this method, we prepared an intermediate in the reported synthesis of Toltrazuril,[13] an antiprotozoal agent. Intermediate 14 can be assembled from readily available starting materials in an overall yield of 88%. The key C–SCF3 bond-forming process proceeded in 95% yield (Scheme 3).



Scheme 3

Synthesis of Toltrazuril intermediate.



In summary, we have developed a general method for the Pd-catalyzed Ar–SCF3 bond-forming reaction. Using this method, a wide range of aryl bromides were converted into their corresponding aryl trifluoromethyl sulfides. Additionally, we have been successful in generating a variety of heterocyclic aryl trifluoromethyl sulfides from heteroaryl bromide precursors. Due to the utility of Ar–SCF3 compounds as biologically active agents, and the mild reaction conditions employed, we expect this method to be immediately implemented in the discovery of novel compounds with pharmaceutical and agrochemical applications.

Pd-Catalyzed Synthesis of Ar-SCF3 Compounds under Mild Conditions

Evodiamine: A review of its pharmacology, toxicity, pharmacokinetics and preparation researches

H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.

Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs.

Accumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC). Cell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment. We showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8+ T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft, which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8+ T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice. Evodiamine can suppress NSCLC by elevating of CD8+ T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.

/pdf/evodiamine-suppresses-non-small-cell-lung-cancer-by-i3kqemqynp.pdf

Evodiamine suppresses non-small cell lung cancer by elevating CD8+ T cells and downregulating the MUC1-C/PD-L1 axis.

Catalyst-free direct C(sp3)–H sulfenylation of xanthene derivatives using air as the oxidant

https://pubs.rsc.org/en/content/articlepdf/2019/CC/C9CC00434C

A concise synthesis and biological study of evodiamine and its analogues

Sulfur-containing scaffold, as a ubiquitous structural motif, has been frequently used in natural products, bioactive chemicals and pharmaceuticals, particularly C-S/N-S bonds are indispensable in many biological important compounds and pharmaceuticals. Development of mild and general methods for C-S/N-S bonds formation has great significance in modern research. Iodine and its derivatives have been recognized as inexpensive, environmentally benign and easy-handled catalysts or reagents to promote the construction of C-S/N-S bonds under mild reaction conditions, with good regioselectivities and broad substrate scope. Especially based on this, several new strategies, such as oxidation relay strategy, have been greatly developed and accelerated the advancement of this field. This review focuses on recent advances in iodine and its derivatives promoted hybridized C-S/N-S bonds formation. The features and mechanisms of corresponding reactions are summarized and the results of some cases are compared with those of previous reports. In addition, the future of this domain is discussed.

Recent Advances in Iodine-Promoted C-S/N-S Bonds Formation.

Hydrogen sulfide donors: Therapeutic potential in anti-atherosclerosis

Direct access to α-sulfenylated amides/esters via sequential oxidative sulfenylation and C–C bond cleavage of 3-oxobutyric amides/esters

Alzheimer's disease (AD), as the fourth leading cause of death among the elderly worldwide, has brought enormous challenge to the society. Due to its extremely complex pathogeneses, the development of multi-target directed ligands (MTDLs) becomes the major strategy for combating AD. Carbamate moiety, as an essential building block in the development of MTDLs, exhibits structural similarity to neurotransmitter acetylcholine (ACh) and has piqued extensive attention in discovering multifunctional cholinesterase inhibitors. To date, numerous preclinical studies demonstrate that carbamate-based cholinesterase inhibitors can prominently increase the level of ACh and improve cognition impairments and behavioral deficits, providing a privileged strategy for the treatment of AD. Based on the recent research focus on the novel cholinesterase inhibitors with multiple biofunctions, this review aims at summarizing and discussing the most recent studies excavating the potential carbamate-based MTDLs with cholinesterase inhibition efficacy, to accelerate the pace of pleiotropic cholinesterase inhibitors for coping AD. 

Honghua Zhang

Papers

A concise synthesis and biological study of evodiamine and its analogues

Recent Advances in Iodine-Promoted C-S/N-S Bonds Formation.

Hydrogen sulfide donors: Therapeutic potential in anti-atherosclerosis

Direct access to α-sulfenylated amides/esters via sequential oxidative sulfenylation and C–C bond cleavage of 3-oxobutyric amides/esters

Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer's disease.