Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide

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

The fields of C-H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C-H functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C-H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction class-either sp2 or sp3 C-H functionalization-lends perspective and tactical strategies for use of these methods in synthetic applications.

Photoredox-Catalyzed C-H Functionalization Reactions.

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

Late-stage C-H functionalization offers new opportunities in drug discovery

Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.

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Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides.

In this Review, we highlight recent advances in the understanding and design of N-functionalized pyridinium scaffolds as redox-active, single-electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N-bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N-centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single-electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.

Pyridinium Salts as Redox-Active Functional Group Transfer Reagents.

A simple trifluoromethoxylation method enables non-directed functionalization of C-H bonds on a range of substrates, providing access to aryl trifluoromethyl ethers. This light-driven process is distinctly different from conventional procedures and occurs through an OCF3 radical mechanism mediated by a photoredox catalyst, which triggers an N-O bond fragmentation. The pyridinium-based trifluoromethoxylation reagent is bench-stable and provides access to synthetic diversity in lead compounds in an operationally simple manner.

Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N-O Bond Redox Fragmentation.

Fluorine chemistry has taken a pivotal role in chemical reaction discovery, drug development, and chemical biology. NMR spectroscopy, arguably the most important technique for the characterization of fluorinated compounds, is rife with highly inconsistent referencing of fluorine NMR chemical shifts, producing deviations larger than 1 ppm. Herein, we provide unprecedented evidence that both spectrometer design and the current unified scale system underpinning the calibration of heteronuclear NMR spectra have unintentionally led to widespread variation in the standardization of 19 F NMR spectral data. We demonstrate that internal referencing provides the most robust, practical, and reproducible method whereby chemical shifts can be consistently measured and confirmed between institutions to less than 30 ppb deviation. Finally, we provide a comprehensive table of appropriately calibrated chemical shifts of reference compounds that will serve to calibrate 19 F spectra correctly.

Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2 )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.

Pyridyl Radical Cation for C−H Amination of Arenes

We leverage the slow liberation of nitrogen dioxide from a newly discovered, inexpensive succinimide-derived reagent to allow for the C-H diversification of alkenes and alkynes. Beyond furnishing a library of aryl β-nitroalkenes, this reagent provides unparalleled access to β-nitrohydrins and β-nitroethers. Detailed mechanistic studies strongly suggest that a mesolytic N-N bond fragmentation liberates a nitryl radical. Using in situ photo-sensitized, electron paramagnetic resonance spectroscopy, we observed direct evidence of a nitryl radical in solution by nitrone spin-trapping. To further exhibit versatility of N-nitrosuccinimide under photoredox conditions, the late-stage diversification of an extensive number of C-H partners to prepare isoxazolines and isoxazoles is presented. This approach allows for the formation of an in situ nitrile oxide from a ketone partner, the presence of which is detected by the formation of the corresponding furoxan when conducted in the absence of a dipolarophile. This 1,3-dipolar cycloaddition with nitrile oxides and alkenes or alkynes proceeds in a single-operational step using a mild, regioselective, and general protocol with broad chemoselectivity.

Benson J. Jelier

Papers

Pyridinium Salts as Redox-Active Functional Group Transfer Reagents.

Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N-O Bond Redox Fragmentation.

Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy

Pyridyl Radical Cation for C−H Amination of Arenes

Synthetic Diversity from a Versatile and Radical Nitrating Reagent