Abstract
The direct, catalytic arylation of simple arenes in small excess with aryl bromides is disclosed. The developed method does not require the assistance of directing groups and relies on a synergistic catalytic cycle in which phosphine-ligated silver complexes cleave the aryl C–H bond, while palladium catalysts enable the formation of the biaryl products. Mechanistic experiments, including kinetic isotope effects, competition experiments, and hydrogen-deuterium exchange, support a catalytic cycle in which cleavage of the C–H bond by silver is the rate-determining step.
Keywords: direct arylation, C–H activation, palladium and silver catalysts, synergistic catalysis, aryl bromides
Graphical Abstract
The functionalization of carbon–hydrogen bonds enables the construction of carbon–carbon and carbon–heteroatom bonds from readily available starting materials.1 The direct arylation of arenes with aryl electrophiles is a process by which an sp2 C–H bond is transformed into a C–aryl linkage in biaryl structures, which are common motifs in pharmaceuticals, agrochemicals, and organic materials (Scheme 1a).2 Despite the many reported catalytic methods for direct arylation, the intermolecular arylation of simple arenes, which do not contain strongly coordinating functional groups that accelerate and control the site of C–H activation, remains a longstanding synthetic challenge. Existing methods for direct arylation in the absence of directing groups with transition-metal catalysts either require a large excess of arene3 or require activated substrates containing several electron-donating or electron-withdrawing groups that facilitate C–H activation (Scheme 1b, left).4
Scheme 1.
Biaryls in Bioactive Compounds and Strategies for their Synthesis via Direct Arylation
A strategy for the direct arylation of simple arenes was published recently by Larrosa and co-workers. In this work, the coordination of Cr(CO)3 to the arene π-system facilitated the activation of aryl C–H bonds (Scheme 1b, right).5 However, these methods require the separate installation of the Cr(CO)3 unit prior to the direct arylation and removal of this unit after the arylation process. A few reports describe conditions for direct arylation without such activation of the arene, but these reactions lacking an excess of the arene include a specific functional group that directs the C–H activation step,6 even if the reaction occurs beyond the position ortho to this group.7 The most efficient undirected reactions occur with a diimine ligand on palladium, but even these reactions have been demonstrated to occur only with three arenes and only at the positions ortho to a fluoro, a nitro, or a cyano group.8
We report a method for the direct arylation of a series of arenes containing one or more substituents with commercially available aryl bromides and transition-metal catalysts with a small excess of the arene (1.5 to 5 equiv). This process stems from our previous report of the direct allylation of simple arenes with palladium and silver;9 a series of mechanistic data, including kinetic isotope effects, competition experiments and H/D exchange reactions, imply that this direct arylation reaction occurs by a synergistic combination of a silver complex that cleaves the C–H bond of the arene and a palladium system that forms the biaryl product by trans-metalation with an arylsilver intermediate and subsequent reductive elimination (Scheme 1c).10
Our initial efforts to increase the efficiency of direct arylation reactions focused on conditions comprising a combination of silver and palladium for the reaction of 1-fluoronaphthalene (1a) with 3-bromotoluene (2a) under conditions with just 1.5 equiv of the arene. We examined a series of reaction parameters, including a range of silver- and palladium-catalysts, ligands, bases, and solvents (see SI for details). These experiments demonstrated that the biaryl product 3aa formed selectively in 81% yield in the presence of 0.5 mol % of Pd(OAc)2 and 5 mol % of commercially available Cy2PtBu as ligand with Ag2O and Cs2CO3 as the silver component and base (Table 1, entry 1).
Table 1.
Evaluation of Reaction Conditions for the Direct Arylation of 1-Fluoronaphthalene (1a)
| ||
|---|---|---|
| entry | deviation on reaction conditions | yield (%)a |
| 1 | none | 81 |
| 2 | Cy3P, instead of tBuPCy2 | 50 |
| 3 | Cy2PPh, instead of tBuPCy2 | 41 |
| 4 | tBu3P, instead of tBuPCy2 | 35 |
| 5 | Ph3P, instead of tBuPCy2 | 10 |
| 6 | (o-Tolyl)3P, instead of tBuPCy2 | <5 |
| 7 | AgOAc (1 equiv), instead of Ag2O | 38 |
| 8 | Ag2CO3, instead of Ag2O | 43 |
| 9 | AgNO3, instead of Ag2O | 56 |
| 10 | K2CO3, instead of Cs2CO3 | 24 |
| 11 | Na2CO3, instead of Cs2CO3 | 20 |
| 12 | without Pd(OAc)2 | <5 |
| 13 | without tBuPCy2 | <5 |
| 14 | without Ag2O | <5 |
Determined by 19F NMR in CDCl3 with C6H5F as internal standard.
The effect of reaction parameters on the direct arylation of 2a with 1a is shown in Table 1. The yields for the formation of 3aa decreased when the arylation reaction was catalyzed by complexes bearing ligands other than Cy2PtBu, including aromatic and trialkylphosphines (Table 1, entries 2–6). Reactions conducted with stoichiometric silver additives and bases other than Ag2O and Cs2CO3 gave 3aa in yields that were lower than those obtained under the standard conditions (Table 1, entries 7–11). Reactions conducted without the palladium catalyst, the silver additive, or Cy2PtBu formed 3aa in only trace amounts (Table 1, entries 12–14).
Having established conditions for the direct arylation of aryl bromides in which the arene is used in small excess, the scope of reactions with a variety of substituted arenes was investigated. As shown in Scheme 2, 4-substituted anisoles containing chloro and trifluoromethoxy groups underwent arylation with 3-bromotoluene. These reactions formed biaryls 3ba–3ca in a nearly equimolar mixture of constitutional isomers in good yield. A reaction with 1,4-nitroanisole led to the formation of 3da in high selectivity, albeit in moderate yield. Notably, 4-chlorobenzotrifluride and 2,2-difluorobenzodioxole reacted smoothly under the developed reaction conditions to form biaryls 3eb and 3fa in good yield and excellent selectivity.
Scheme 2. Scope of Arenes that Underwent Direct Arylationa.
aSee SI for experimental details.
bPerformed with 4-bromoanisole.
cPerformed with 4-bromoanisole for 48 h.
Biaryls containing a single fluorine atom are common motifs in pharmaceuticals and agrochemicals,11 but methods to prepare these structures by direct arylation with low equivalents of arene have been limited to monofluorobenzenes containing additional electron-withdrawing groups or fluoroarenes containing directing groups.6d–g,12 In contrast, our developed method enables the direct arylation of several substituted anisoles and of both electron-rich and electron-poor fluorobenzenes selectively at the position ortho to the fluorine atom (Scheme 2). Fluorobenzene (1g) itself has been a challenging substrate with which to achieve C–H arylation previously, often requiring this arene to be solvent.13 However, our method enabled the synthesis of 3ga with just 5 equiv of arene in 52% yield at 140 °C. Electron-donating functional groups at the 2-, 3-, and 4-positions (1h–1j) were tolerated, although reactions of such arenes required 5 equiv of arene. A range of fluorobenzenes bearing electron-withdrawing groups at the 2-, 3-, and 4-positions, including trifluoromethyl, fluorine, and benzoyl moieties also reacted. In this case, the reactions occurred in high yields (3ka–3mb) with low equivalents of arene (1.5–2 equiv).
The scope of aryl bromides that underwent direct arylation with 1-fluoronaphthalene (1a) is shown in Scheme 3. Aryl bromides containing electron-donating groups (2b–e) at the para and meta positions, such as methoxy, morpholinyl, phenoxy, and thiomethoxy, were tolerated, providing biaryl products in good yields. The reactions of aryl halides containing electron-withdrawing groups at the 4- and 3-positions gave only moderate yields of their corresponding biaryls (3af–3ah). A 3,4-dibustituted aryl bromide and 1-bromonaphthalene reacted smoothly, leading to the synthesis of 3ai and 3aj in good yields. The developed direct arylation also allowed the synthesis of biaryls in high yield from sterically demanding 2-substituted bromobenzenes, as shown for 3ak and 3al.
Scheme 3. Scope of Aryl Bromides that Underwent Direct Arylation with 1aa.
aSee SI for experimental details.
bWith 1.0 mol % of Pd(OAc)2, 10 mol % of tBuPCy2, and 4 equiv of 1a for 48 h.
cReaction performed at 140 °C for 48 h.
Having stablished that the efficiency of this direct arylation process is higher than that of the direct arylations published previously, we performed a series of experiments to gain insights into its reaction mechanism. To investigate if C–H bond cleavage at the arene is rate determining, we compared the initial rates of the direct arylation of 2-bromotoluene (2a) with fluorobenzene (1g) and its deuterated analogue [2H]1g in separate vessels (Scheme 4a). These experiments gave a primary kinetic isotope effect with a value of 4.0 ± 0.3, a value that is consistent with a mechanism in which C–H bond cleavage is rate determining. To gain further insight into the mechanism of the C–H bond cleavage, we conducted a competition experiment between 1k and 1h. As shown in Scheme 4b, the electron-poor arene 1k was the more reactive substrate, which is consistent with a mechanism in which C–H bond cleavage proceeds by a concerted metalation deprotonation step.14
Scheme 4. Determination of KIE and Competition Experimenta.
aSee SI for experimental details.
A series of experiments summarized in Table 2 probed our initial mechanistic hypothesis that silver-complexes cleave the aryl C–H bond during the arylation process (Scheme 1c). To do so, we conducted H/D exchange reactions with 1,3-difluorobenzene (1l) and 10 equiv of D2O in tert-amyl alcohol-d1. In the presence of 0.5 equiv of Ag2O, 40% mol of tBuPCy2, and stoichiometric Cs2CO3, [2H]1l formed with 84% incorporation of deuterium into the 2-position (entry 1). A lower degree of deuterium incorporation in 1l was observed in the presence of Pd(OAc)2 (entry 2). Reactions conducted in the absence of Ag2O or ligand led to only trace levels of H/D exchange (entries 3–4). Moreover, Pd(OAc)2 in the presence of ligand without silver additive did not catalyze H/D exchange with 1l. These results imply that a phosphine-ligated silver complex, instead of a palladium-species, cleaves the C–H bond during the rate-determining step of the arylation reaction.
Table 2.
Evaluation of Reaction Conditions for the Deuteration of 1l
| ||
|---|---|---|
| entry | deviation from above conditions | yield (%)a |
| 1 | none | 83 |
| 2 | with Pd(OAc)2 (5 mol %) and Ag2O | 71 |
| 3 | without Ag2O | <5 |
| 4 | without Iigand | <5 |
| 5 | with Pd(OAc)2 (5 mol %) without Ag2O | <5 |
Determined by 19F and 1H NMR in CDCl3.
In summary, we have developed a catalytic method for the direct arylation of simple arenes with commercially available aryl bromides and a catalyst system comprising a combination of silver and palladium that react synergistically. This method does not require directing groups and allows the arylation reaction to proceed with one of the smallest excesses of arene for any direct arylation with arenes lacking a directing group. Mechanistic experiments imply that C–H bond cleavage occurs by a phosphine-ligated silver complex, presumably by a concerted metalation-deprotonation step, and that this step of the catalytic cycle is rate determining. Current work in our laboratory is being conducted to fully understand the mechanism of the proposed catalytic cycle involving reactions of both Ag and Pd and to use this knowledge for the development of further improved, undirected, C–H bond functionalization reactions.
Supplementary Material
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the NIH (R35 GM130387 to J.F.H. and F32-GM113404 to S.Y.L.). We thank the College of Chemistry’s NMR facility for resources provided and the staff for their assistance. Instruments in CoC-NMR are supported in part by the NIH (S10OD024998). A.T.A Thanks UC MEXUS-CONACYT for a Postdoctoral Research Fellowship.
Footnotes
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.0c05254.
Experimental procedures and spectroscopic data on the reaction products (PDF)
Complete contact information is available at: https://pubs.acs.org/10.1021/acscatal.0c05254
The authors declare no competing financial interest.
NOTE ADDED AFTER ASAP PUBLICATION
Originally published ASAP on January 14, 2021; Scheme 1 updated January 21, 2021.
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