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Journal ArticleDOI: 10.1016/J.TETLET.2020.152809

Acid-promoted selective synthesis of trifluoromethylselenolated benzofurans with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate

02 Mar 2021-Tetrahedron Letters (Pergamon)-Vol. 66, pp 152809
Abstract: A Bronsted acid-promoted trifluoromethylselenolation of benzofurans was disclosed by using Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate as a stable and easily prepared electrophilic trifluoromethylselenolating reagent. A wide range of SeCF3-substituted benzofuran derivatives were obtained in moderate to good yields with excellent regioselectivity. The tandem cyclization/trifluoromethylselenolation procedure of 1-methoxy-2-(arylethynyl)benzenes were also realized by engaging FeCl3 as the catalyst.

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Topics: Trifluoromethyl (58%), Benzofuran (54%), Regioselectivity (53%)

7 results found

Open access
01 Jun 2011-
Abstract: 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.

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Topics: XPhos (62%), Aryl (60%), Transmetalation (55%) ... read more

272 Citations

Open accessJournal ArticleDOI: 10.1002/CHEM.202100053
Abstract: The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch-Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.

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Topics: Photoredox catalysis (56%), Flow chemistry (51%), Lipophilicity (50%)

5 Citations

Journal ArticleDOI: 10.1016/J.TET.2021.132476
22 Oct 2021-Tetrahedron
Abstract: The trifluoromethylseleno group (SeCF3) possesses unique electrosteric effect and high lipophilicity and has been verified as a pharmaceutically relevant functionality in modulating the physicochemical and biological properties of drug-like molecules. The formation of C–SeCF3 bonds by reactions with [Me4N][SeCF3] under transition-metal-catalyzed or -free conditions has emerged in the last decade. [Me4N][SeCF3] proves to be a versatile and promising SeCF3 reagent among all trifluoromethylselenolation reagents in the synthesis of CF3Se-containing compounds, which is thermally stable, readily accessible, non-volatile and easy to control. This review describes the advances of trifluoromethylselenolation reactions with [Me4N][SeCF3] and is divided into three parts (synthesis of metal-SeCF3 complexes with [Me4N][SeCF3], transition-metal-catalyzed trifluoromethylselenolations with [Me4N][SeCF3], and transition-metal-free trifluoromethylselenolations with [Me4N][SeCF3]). Although the use of [Me4N][SeCF3] has achieved a variety of trifluoromethylselenolation reactions, the approaches for C–SeCF3 bond formation are still lacking in comparison with the homologous C-OCF3 and C-SCF3 bonds formation. We anticipate that continuous efforts will focus on the development of more widely applicable trifluoromethylselenolation reactions with [Me4N][SeCF3] by transition-metal catalysis, transition-metal-free conditions, oxidation, or photoredox strategies. Since there have been no CF3Se-containing pharmaceuticals used in clinical trials so far, efforts will also be devoted to exploring the biological activities of trifluoromethylselenolated compounds in the future for discovery of CF3Se-drugs with big challenges as well as great opportunities.

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54 results found

Journal ArticleDOI: 10.1021/CR00002A004
01 Mar 1991-Chemical Reviews
Abstract: The Hammett equation (and its extended forms) has been one of the most widely used means for the study and interpretation of organic reactions and their mechanisms. Although the Hammett methodology has been criticized by theoreticians because of its empirical foundation, it is astonishing that u constants, obtained simply from the ionization of organic acids in solution, can frequently predict successfully equilibrium and rate constants for a variety of families of reactions in solution. Almost every kind of organic reaction has been treated via the Hammett equation, or its extended form. The literature is so voluminous and extensive that there is no complete review of all that has been accomplished. Hammett's success in treating the electronic effect of substituents on the rates and equilibria of organic reactions1P2 led Taft to apply the same principles to steric and inductive and resonance effects? Then, more recently, octanol/ water partition coefficients (P) have been used for rationalizing the hydrophobic effects of organic compounds interacting with biological systems? The use of log P (for whole molecules) or n (for substituents), when combined with electronic and steric parameters, has opened up whole new regions of biochemical and pharmacological reactions to study by the techniques of physical organic chemistry.sf3 The combination of electronic, steric, hydrophobic, hydrophilic, and hydrogen-bonding7 parameters has been used to derive quantitative structure-activity relationships (QSAR) for a host of interactions of organic compounds with living systems or parts thereof. The binding of organic compounds to proteins,8 their interaction with enzymess and with cellsloJ1 and tiasues,12 their inhibition of organelles,l' and as antimalarial^'^

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Topics: Yukawa–Tsuno equation (69%), Taft equation (67%), Hammett equation (65%) ... read more

6,186 Citations

Journal ArticleDOI: 10.1021/CR020033S
22 Feb 2003-Chemical Reviews
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

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2,434 Citations

Journal ArticleDOI: 10.1021/CR020085H
Gilson Zeni1, Richard C. Larock1Institutions (1)
20 Feb 2004-Chemical Reviews
Topics: Alkyne (57%), Palladium (52%), Olefin fiber (51%)

966 Citations

Journal ArticleDOI: 10.1021/JA0639719
Abstract: The direct and selective synthesis of phenols from aryl/heteroaryl halides and KOH has been achieved through the use of highly active monophosphine-based catalysts derived from Pd(2)dba(3) and ligands L1 or L2 and the biphasic solvent system 1,4-dioxane/H(2)O We have also demonstrated a one-pot method of phenol formation/alkylation for the preparation of alkyl aryl ethers from aryl halides In many instances, this protocol overcomes limitations in existing Pd-catalyzed coupling reactions of aliphatic alcohols with aryl halides Finally, we demonstrate that substituted benzofurans can be prepared efficiently via a Pd-catalyzed phenol formation/cyclization protocol starting from 2-chloroaryl alkynes

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Topics: Aryl (60%), Ether (57%), Alkylation (56%) ... read more

374 Citations