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DOI: 10.1055/a-1770-1078
Palladium-Catalyzed Coupling of Biphenyl-2-yl Trifluoromethanesulfonates with Dibromomethane to Access Fluorenes
The work was supported by the National Natural Science Foundation of China (No. 21971196) and the Science and Technology Commission of Shanghai Municipality (19DZ2271500).
Abstract
A facile and efficient method has been developed for the synthesis of fluorenes by Pd-catalyzed C–H alkylation of biphenyl-2-yl trifluoromethanesulfonates. The trifluoromethanesulfonates are more readily available and more environmentally benign than biphenyl iodides, and are advantageous substrates for traceless directing-group-assisted C–H activation. The reaction generates C,C-palladacycles as the key intermediates that form two C(sp2)–C(sp3) bonds through reaction with CH2Br2. The reaction tolerates various functional groups, permitting easy access to a range of fluorene derivatives.
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Key words
palladium catalysis - fluorenes - C–H bond activation - biphenyl triflates - dibromomethaneDue to its economically attractive and environmentally benign features, C–H functionalization has emerged as an ideal tool for the construction of various chemical bonds in organic synthesis, and it has developed rapidly over recent decades.[1] In most current transition-metal-catalyzed C–H conversions, directing groups are used to enable C–H bond cleavage and to provide high regioselectivity.[2] However, this strategy results negatively in a limitation of the reaction scope due to the lengthy synthetic operations required for the installation and removal of the directing groups. Halogens as traceless directing groups can address these drawbacks to some extent.[1f] [3] Reactions of this type are initiated by the oxidative addition of aryl halides to Pd(0). The resulting aryl–Pd(II) species then cleave C–H bonds to form C,C-palladacycles. The halo groups disappear after the reaction and therefore serve as traceless directing groups.
In recent decades, a range of reactions of this type have been developed that permit ready access to valuable compounds from halogenated precursors.[4] However, syntheses of these halo-substituted substrates are sometimes troublesome. For example, the synthesis of 2-iodobiphenyls, which are among the most extensively studied substrates for halogen-directed C–H functionalization reactions, requires the transformation of 2-phenylanilines into diazonium salts and subsequent iodination (Scheme [1]).[5] Furthermore, the reactions also form undesired halogen-containing chemical wastes.




As alternative or complementary electrophiles, pseudohalides are appealing.[6] Pseudohalides are usually phenol-derived electrophiles, most of which are aryl sulfonates. Due to their natural abundance, ready availability, and facile transformation into pseudohalides, phenols are ideal as precursors of these compounds. Furthermore, phenol-derived electrophiles are more environmentally friendly than halides. In particular, aryl sulfonates exhibit better performance than aryl bromides/iodides in many cross-coupling processes.[7] Like halo groups, sulfonates should also be able to act as traceless directing groups in transition-metal-catalyzed C–H functionalization reactions, and they have several great advantages. Although some reactions of this type have been reported,[4b] [d] [8] they are comparatively underexplored.
Our group has been working on Pd-catalyzed intermolecular C–H functionalizations of aryl halides. Because of the drawbacks of aryl halides, we set out to develop C–H functionalization reactions of aryl sulfonates. As mentioned previously, 2-halobiphenyls are among the most extensively studied substrates for halogen-directed C–H functionalization reactions, because their reactions permit easy access to intriguing cyclic aromatic compounds.[9] We therefore began our studies by investigating the reactions of biphenyl-2-yl sulfonates.
Fluorene is a fundamental skeleton in polycyclic aromatic chemistry. Moreover, fluorene derivatives have been widely explored in the fields of organic synthesis, materials science, and pharmaceutical research.[10] The conventional routes for the preparation of fluorenes often require harsh conditions or involve complicated processes.[11] Notably, direct C–H activation has been applied to the construction of fluorenes, and a range of examples of this kind are well documented.[12] We recently developed a protocol for the synthesis of fluorene through a Pd-catalyzed annulation of 2-iodobiphenyl with CH2Br2.[9a] Here, we report a Pd-catalyzed C–H activation of biphenyl-2-yl trifluoromethanesulfonate (triflate) and a subsequent coupling reaction with CH2Br2. Triflates are more readily available and more environmentally benign than iodides, and the reaction represents a desirable method to access fluorenes.
We first studied the reaction of biphenyl-2-yl triflate (1a) with CH2Br2 (2) as model substrates (Table [1]). To our delight, we obtained a 45% yield of 9H-fluorene (3a) when the reaction was carried out under the conditions shown in entry 1. The yield increased to 76% when a combination of K2CO3 and KOAc was used (entry 2). Other inorganic bases gave lower yields or even suppressed the formation of 3a (entries 3–7). Solvents were also surveyed, and the reaction failed to give the fluorene in MeCN, toluene, or DMSO (entries 8–10). A slightly higher yield was obtained on substituting KHCO3 for K2CO3 (entry 11). The yield was further enhanced to 85% when a mixture of KHCO3 (2.0 equiv) and KOAc (3.0 equiv) was used (entry 12). Reducing the quantity of the base led to a lower yield (entry 13). i-PrOH plays a crucial role, because the yield dramatically decreased when it was removed (entry 14). i-PrOH might act as a reductant to reduce Pd(II) to Pd(0). Yields of 65 and 42% were obtained when four equivalents of CH2Br2 or 5 mol% of Pd(OAc)2, respectively, were used (entries 15 and 16). Furthermore, the reaction gave a slightly lower yield after eight hours (entry 17).
a Determined by 1H NMR analysis of the crude reaction mixture with 1,1,2,2-tetrachloroethane as the internal standard.
b Isolated yield based on 1a.
c No i-PrOH.
d CH2Br2 (4 equiv).
e Pd(OAc)2 (5 mol%).
f 8 h.
With the optimal conditions in hand, we next examined the scope of the reaction (Scheme [2]). We first explored the compatibility of various substituents on the benzene ring lacking the OTf group. A variety of substituents on the benzene ring, including alkyl, alkoxy, phenyl, and halo groups, were compatible with this conversion, affording the corresponding fluorenes 3a–o in moderate to excellent yields. For electron-donating alkyl or alkoxy groups, moderate to good yields of 3b–f were generally obtained, with the exception of the ortho-methyl group (3d). The low yield of 3d might result from steric hindrance by the methyl group hampering the formation of the key palladacycle intermediate. Notably, halo groups were well tolerated (3i–k). In comparison, electron-withdrawing groups such as CN and CF3 reduced the yield (3l–n). However, a good yield was still obtained for an ester group (3o). Next, we examined the performance of aryl triflates with substituents on the benzene ring bearing the OTf group (3p–y). A range of biphenyl-2-yl triflates bearing electron-donating or electron-withdrawing groups underwent cross-coupling to give the corresponding fluorenes 3p–s, 3x, and 3y in moderate to good yields. Substrates bearing halogens were also suitable (3t–w). Moreover, the compatibility of polysubstituted biaryl triflates was also investigated (3z–ai). A series of symmetrically or asymmetrically substituted biphenyls were found to be compatible with the coupling process. Intriguingly, a substrate bearing two OTf groups (1aj) afforded the OTf-bearing fluorene product 3aj.
A mechanism was proposed according to previous studies.[13] As shown in Scheme [3], the reaction starts with the oxidative addition of 1a to Pd(0). The resulting Pd(II) species A cleaves the C–H bond to form the C,C-palladacycle B. A second oxidative addition of CH2Br2 to palladacycle B forms the Pd(IV) species C. A subsequent reductive elimination yields the arylpalladium(II) species D, which inserts C–Br bonds to form the Pd(IV) species E. This might also be formed directly from B via a carbene intermediate F. Intramolecular reductive elimination of E gives fluorene (3a) with release of a Pd(II) species that is reduced to Pd(0) to continue the next catalytic cycle.


In conclusion, we have developed a simple and efficient protocol for the construction of fluorenes by using biphenyl-2-yl triflates and CH2Br2 as coupling partners.[14] Aryl triflates were shown to exhibit such merits as easy availability and environmental friendliness as substrates for traceless directing-group-assisted C–H functionalization reactions.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1770-1078.
- Supporting Information
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- 14 Fluorenes 3; General Procedure A 25 mL Schlenk tube equipped with a stirrer bar was charged with the appropriate biphenyl-2-yl triflate 1 (0.2 mmol, 1.0 equiv), CH2Br2 (1.4 mmol, 7.0 equiv), Pd(OAc)2 (0.02 mmol, 0.1 equiv), KHCO3 (0.4 mmol, 2.0 equiv), KOAc (0.6 mmol, 3.0 equiv), i-PrOH (0.2 mL), and DMF (2.0 mL). The tube was then frozen with liquid N2 and exchanged with N2 to remove air. The mixture was then stirred at 60 °C for 12 h until the reaction was complete. The resulting mixture was diluted with EtOAc and washed with sat. aq NaCl (3×). The organic phase was collected and dried (MgSO4), and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc). 9H-Fluorene (3a) White solid (80%). 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 2 H), 7.56 (d, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 2 H), 7.32 (td, J = 7.3, 0.9 Hz, 2 H), 3.92 (s, 2 H). 13C NMR (101 MHz, CDCl3): δ = 143.2, 141.7, 126.7, 126.7, 125.0, 119.8, 36.9. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11: 167.0855; found: 167.0865. 2-Methyl-9H-fluorene (3b) White solid (56%). 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 1 H), 7.68 (d, J = 7.7 Hz, 1 H), 7.53 (d, J = 7.4 Hz, 1 H), 7.39–7.35 (m, 2 H), 7.31–7.25 (m, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 3.87 (s, 2 H), 2.44 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.5, 143.0, 141.8, 139.0, 136.5, 127.5, 126.6, 126.2, 125.7, 124.9, 119.6, 119.5, 36.8, 21.6. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0866. 3-Methyl-9H-fluorene (3c) White solid (70%). 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 1 H), 7.62 (s, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.34–7.27 (m, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 3.87 (s, 2 H), 2.47 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.6, 141.8, 141.7, 140.3, 136.3, 127.6, 126.6, 126.5, 125.0, 124.7, 120.4, 119.70, 36.5, 21.5. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0873. 4-Methyl-9H-fluorene (3d) White solid (44%). 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.7 Hz, 1 H), 7.58 (d, J = 7.4 Hz, 1 H), 7.40 (t, J = 7.9 Hz, 2 H), 7.32 (td, J = 7.4, 0.7 Hz, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.16 (d, J = 7.4 Hz, 1 H), 3.92 (s, 2 H), 2.74 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.6, 143.6, 142.7, 139.8, 133.0, 129.0, 126.6, 126.4, 126.0, 124.9, 123.1, 122.4, 37.1, 21.1. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0880.
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Corresponding Author
Publication History
Received: 16 January 2022
Accepted after revision: 11 February 2022
Accepted Manuscript online:
11 February 2022
Article published online:
10 March 2022
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References and Notes
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- 14 Fluorenes 3; General Procedure A 25 mL Schlenk tube equipped with a stirrer bar was charged with the appropriate biphenyl-2-yl triflate 1 (0.2 mmol, 1.0 equiv), CH2Br2 (1.4 mmol, 7.0 equiv), Pd(OAc)2 (0.02 mmol, 0.1 equiv), KHCO3 (0.4 mmol, 2.0 equiv), KOAc (0.6 mmol, 3.0 equiv), i-PrOH (0.2 mL), and DMF (2.0 mL). The tube was then frozen with liquid N2 and exchanged with N2 to remove air. The mixture was then stirred at 60 °C for 12 h until the reaction was complete. The resulting mixture was diluted with EtOAc and washed with sat. aq NaCl (3×). The organic phase was collected and dried (MgSO4), and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc). 9H-Fluorene (3a) White solid (80%). 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 2 H), 7.56 (d, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.3 Hz, 2 H), 7.32 (td, J = 7.3, 0.9 Hz, 2 H), 3.92 (s, 2 H). 13C NMR (101 MHz, CDCl3): δ = 143.2, 141.7, 126.7, 126.7, 125.0, 119.8, 36.9. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11: 167.0855; found: 167.0865. 2-Methyl-9H-fluorene (3b) White solid (56%). 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 1 H), 7.68 (d, J = 7.7 Hz, 1 H), 7.53 (d, J = 7.4 Hz, 1 H), 7.39–7.35 (m, 2 H), 7.31–7.25 (m, 1 H), 7.20 (d, J = 7.7 Hz, 1 H), 3.87 (s, 2 H), 2.44 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.5, 143.0, 141.8, 139.0, 136.5, 127.5, 126.6, 126.2, 125.7, 124.9, 119.6, 119.5, 36.8, 21.6. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0866. 3-Methyl-9H-fluorene (3c) White solid (70%). 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 1 H), 7.62 (s, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.34–7.27 (m, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 3.87 (s, 2 H), 2.47 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.6, 141.8, 141.7, 140.3, 136.3, 127.6, 126.6, 126.5, 125.0, 124.7, 120.4, 119.70, 36.5, 21.5. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0873. 4-Methyl-9H-fluorene (3d) White solid (44%). 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.7 Hz, 1 H), 7.58 (d, J = 7.4 Hz, 1 H), 7.40 (t, J = 7.9 Hz, 2 H), 7.32 (td, J = 7.4, 0.7 Hz, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.16 (d, J = 7.4 Hz, 1 H), 3.92 (s, 2 H), 2.74 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 143.6, 143.6, 142.7, 139.8, 133.0, 129.0, 126.6, 126.4, 126.0, 124.9, 123.1, 122.4, 37.1, 21.1. HRMS (ESI-TOF): m/z [M – H]+ calcd for C14H11: 179.0855; found: 179.0880.
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