Introduction

F-containing organic compounds are frequently prepared by pharmaceutical and agrochemical researchers because incorporating F atoms can finely adjust the chemical and metabolic stabilities, lipophilicities, and acidities/basicities of these species1,2,3. In medicinal aspects, methodologies and reagents used to synthesize organofluorine compounds efficiently have been intensely developed over recent decades4,5,6,7, and more than 350 fluoro-pharmaceuticals8 and 430 fluoro-agrochemicals9 are registered. Organofluorine compounds are abundant and readily accessible, rendering them attractive as functional moieties and as building blocks for use in further organic synthesis. However, the chemical conversions of fluorinated moieties to other functional groups are very challenging10,11,12,13,14,15. Compared with C–I/Br/Cl bonds, the C–F bond is relatively inert and has the highest bond dissociation energy. In addition to the high reaction temperatures required in C–F bond cleavage, a strong base is necessary to facilitate the transformation.

Aromatic tertiary amine moieties are critical structural features of molecules used in pharmaceuticals, agroscience, bioactive natural products, and materials science (Fig. 1a)16,17,18,19,20,21,22. To date, the most reliable preparation methods of aromatic tertiary amines are the transition-metal-catalyzed C(sp2)–N couplings of aryl (pseudo)halides with amine nucleophiles, such as the Ullmann coupling23,24, the Buchwald–Hartwig reaction25,26,27, and metallaphotoredox amination28,29,30 (Fig. 1b). Although efficient syntheses of aromatic tertiary amines are among the top five reactions performed globally to synthesize high-value products31, green chemistry requires the development of transition-metal-free systems. Generally, transition-metal-free aminations of aryl (pseudo)halides have limitations such as low regioselectivities and the requirement of a strong base and high temperature32,33,34,35,36,37,38,39. Moreover, inert C–F-containing organic fluorides are seldom used in such C–N couplings, particularly under mild conditions, owing to the high bond dissociation energies of the C–F bonds. Although the defluorinative aminations of aryl fluorides have gained attention, the reported methods require strong bases, transition metal catalysis, harsh conditions, or activation of aromatic rings with strong electron-withdrawing groups10,11,12,13,14,15. Besides, strong base-meditated amination reactions of aromatic C–F bonds provide the amination products as mixtures of regio-isomers, as these reactions proceed via benzyne intermediates32,33,34. In 2015, Cao, Shi et al. reported a direct SNAr reaction of aromatic fluorides by aromatic amines using tBuOK in DMSO35. Diness et al. disclosed the SNAr reaction of aromatic fluorides with alkyl amines using LiHMDS36. However, both methods require a high reaction temperature of 90–100 °C, except for the selected perfluorinated benzenes35,36. Furthermore, the SNAr reaction of perfluorinated benzenes with pyrroles by NaH37 and N-heterocycle-assisted SNAr reaction of ortho-heterocyclic aryl fluorides with aryl amines using LiH were reported38, 110–153 °C temperature conditions are required. Recently, the amination of electron-rich aryl fluorides was achieved under the 20–50 °C using photocatalysts and blue LEDs; however, such methods require electron-rich moieties, such as the OMe group, on the aromatic moieties, to activation of the substrates40,41 Thus, these methods are not useful for electron-poor aryl fluorides, in contrast to the traditional SNAr reaction of aryl fluorides, which favors electron-poor substrates. Aminations involving the cleavage of C(sp3)–F bonds of alkyl fluorides are also a challenging issue, and the protocols are hitherto mostly limited to active benzyl or allylic fluorides, with strong Lewis acids, such as La[N(SiMe3)2]3 and YbI3, generally required42,43,44,45.

Fig. 1: Cross-couplings and related reactions of aryl or alkyl halides with secondary amines.
figure 1

a Representative pharmaceutical molecules containing aryl and alkyl amines. b Previous studies. c This study.

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As a continuation of our studies regarding C–F bond functionalization46,47,48, we herein report the transition-metal-free defluorinative aminations of aryl fluorides using secondary amines, which proceed in the presence of triethylsilylboronate (Et3SiBpin) and potassium tert-butoxide (KOtBu, Fig. 1c). A wide variety of aryl fluorides react with secondary acyclic and/or cyclic N-alkylanilines and/or dialkylamines at room temperature. This reaction affords aromatic tertiary amines in good-to-excellent yields via the cleavage of a C(sp2)–F bond in the presence of Et3SiBpin, without employing transition-metal catalysis or a photoredox system. The (hetero)aryl fluorides easily react with unsubstituted N-alkylanilines and substituted N-methylanilines, enabling the syntheses of numerous structurally varied aromatic tertiary amines that regioselectively incorporate aryl, heteroaryl, and/or alkyl groups at the N centers. Defluoroamination progresses with high regio- and chemoselectivity. The potentially cleavable C–O bonds of ethers, C–Cl and C–CN bonds, and C(sp2)–H bonds of heteroaromatic compounds are unaffected. Additionally, the C(sp3)–F bonds of the CF3 and OCF3 groups are unaffected. Notably, despite the unaffected CF3 groups, this cross-coupling protocol is extended to the reactions of alkyl fluorides containing C(sp3)–F bonds with secondary amines to yield defluoroamination products with newly formed C(sp3)–N bonds.

Results and discussion

Silylboronate-mediated cross-coupling reactions of organic fluorides and N-alkylanilines

Initially, 4-fluorobiphenyl (1a) and N-methylaniline (3a) were used as model substrates to investigate defluoroamination. The desired product, N-methyl-N-phenyl-4-biphenylamine (4aa), was obtained in a yield of 41% under specific conditions [Et3SiBpin (1.5 equiv.) and KOtBu (2.5 equiv.) in diglyme at room temperature, entry 1, Table 1]. Although higher amounts of Et3SiBpin (2.0 equiv.) and KOtBu (4.0 equiv.) insignificantly improved the yield (44%, entry 2), the use of 3.0 equiv. of 3a increased the yield to 58% (entry 3). Remarkably, the solvent affected the outcome of the defluoroamination. A yield of 81% of 4aa was obtained under the same conditions as that of entry 3 but in triglyme (entry 4). When the reaction was carried out in THF, the yield significantly decreased to 5% (entry 5); however, it increased to 75% in the presence of 18-crown-6 (entry 6). The defluoroamination proceeded effortlessly when the reaction time was extended to 24 h in triglyme, generating a yield of 91% (88% isolated, entry 7). Control experiments revealed the necessity of using Et3SiBpin and KOtBu (entries 8 and 9). Slight modifications to the reactant ratio and those of KOtBu and Et3SiBpin did not improve the yields (entries 10−14). We confirmed the reproducibility of the optimal result (entry 7) by completing the reaction at double the scale to produce 4aa in a 93% yield (89% isolated, entry 15). A gram-scale reaction was also performed using 5.0 mmol of 1a to demonstrate the reproducibility of the reaction (1.13 g, 87%). We further examined the reaction using different silylboronates (tBuMe2SiBpin, PhMe2SiBpin, (Me3Si)3SiBpin). Interestingly, the yield decreased as the steric hindrance of the silylboronates increased (entries 16–18), and some amount of the starting material (1a) remained unreacted. Further details on the optimization of the reaction conditions are shown in the Supplementary Information (Supplementary Tables 1–5).

Table. 1 Optimization of the defluoroamination conditionsaView full size image
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Scope and limitations

The substrate scope of this silylboronate-mediated direct amination was further evaluated using the optimal reaction conditions (entry 7, Table 1). As shown in Fig. 2, aryl fluorides 1 with various electronic properties were reacted with 3a. First, four types of π-extended aryl fluorides (1a–1d), including the sterically hindered ortho-substituted substrate 1c, reacted efficiently with 3a under the optimal conditions to generate the corresponding cross-coupling amination products (4aa–4da) in high yields (80–89%). The use of non-substituted (1e) and para-substituted fluorobenzenes with electron-donating (Me, 1f; MeO, 1g) or electron-withdrawing groups (CF3, 1h) also successfully yielded the corresponding products (4ea, 79%; 4fa, 74%; 4ga, 66%; 4ha, 82%) via defluoroamination with 3a. The chemoselectivity of this defluoroamination process was achieved successfully when other halide-substituted aryl fluorides (Cl, 1i; Br, 1j) were employed (4ia, 51%; 4ja, 39%). Furthermore, the fluoroarenes 1k–1t, which contained π-extended moieties with various electronic properties, were efficiently converted to the corresponding cross-coupling amination products 4ka–4ta in good-to-high yields (51–86%) and were almost independent of the attached functional group. Remarkably, the excellent chemoselectivity of this process was revealed by the tolerance toward the reaction conditions of functional groups such as ethers (OMe, 1m; OBn, 1n) and Cl (1o), Br (1p), CN (1q), and CF3 groups (1r, 1s, and 1t), which may be cleaved via C–F bond activation; for example, 4-(naphthalen-1-yl)phenyl- (4ka: 77%), 4-methylphenyl- (4la: 86%), and ether-containing biphenyl products (4ma: 83%; 4na: 61%) and biphenyl products containing electron-withdrawing groups (4oa: 77%; 4pa: 59%; 4qa: 51%; 4ra: 84%; 4sa: 82%; 4ta: 54%). The aryl fluoride-containing benzo[1,3]dioxole, 1u, was also converted to the defluoroamination product 4ua and obtained a yield of 81% without cleaving the C–O bonds. Additionally, N-containing heteroaromatic fluorides (1v, 1w, 1x, 1y, 1z, and 1aa) were successfully defluoroaminated using 3a under the same conditions in higher yields (≤97%). Pyridine derivatives (4va: 93%; 4wa: 91%; 4xa: 94%; 4ya: 94%) and a 1H-pyrrole derivative (4za: 97%) were obtained via the cross-coupling reactions. Indole- (1aa and 1ab) and benzofuran-containing (1ac) aryl fluorides were also functionalized well even though they contained several reactive aryl C(sp2)–H bonds, selectively yielding defluorinative amination products (4aaa: 85%; 4aba: 96%; 4aca: 90%) via C–F bond cleavage without forming the corresponding C–H bond-activated byproducts. All results clearly demonstrate the remarkable functional group tolerance of these silylboronate-mediated cross-coupling amination reactions of aryl fluorides and amines.

Fig. 2: Substrate scope of 1, 2, and 3.
figure 2

Unless otherwise noted, all reactions were conducted using 1 or 2 (0.2 mmol), 3 (3.0 equiv.), Et3SiBpin (96.8 mg, 2.0 equiv.), KOtBu (89.6 mg, 4.0 equiv.), and triglyme (1.0 mL) at room temperature for 24 h, with isolated yields shown. aReaction performed using 0.4 mmol of 1. bReaction performed without Et3SiBpin, and yield was determined by 1H NMR.

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Next, substituted N-methylanilines 3 were examined via coupling with 1a under standard conditions. Methyl substituents at the para- (3b), meta- (3c), or ortho- (3d and 3e) positions of N-methylaniline were evaluated via reaction with 1a. High yields of coupling products (4ab: 87%; 4ac: 82%) were obtained using 3b or 3c and 1a, while the yields of the sterically hindered products (4ad: 31%; 4ae: 32%) were low. N-Methylanilines bearing electron-donating (4-OMe: 3f, 1,3-dioxole: 3g) or electron-withdrawing (4-OCF3: 3h; 4-Cl: 3i; 3-Cl: 3j; 4-Br: 3k) groups underwent defluoroamination to afford the desired products in good yields (4af: 61%; 4ag: 67%; 4ah: 49%; 4ai: 60%; 4aj: 54%; 4ak: 33%).

Because broad ranges of 1 and 3 are applicable in this coupling reaction, we demonstrated the further scope of the defluoroamination using various combinations of 1 and 3. Phenyl (1b, 1c), naphthyl (1d), electron-donating 4-OMe (1g), and electron-withdrawing 4-CF3 (1r)-substituted fluorobenzenes were coupled with various N-methylanilines (3c, 3d, 3h) to generate the desired amines 4 in good yields (4bc: 76%; 4dh: 54%; 4gc: 68%; 4hh: 45%), including the sterically unfavorable product (4cd: 22%). In addition, the use of biphenyl fluorides 1 with electron-donating (1l, 1m), electron-withdrawing (1q, 1r, 1s, 1t), or chloride (1o) functional groups efficiently generated the corresponding products 4 via reaction with anilines 3 in good yields (4li: 69%; 4lh: 54%; 4mf: 66%; 4mh: 47%; 4oi: 92%; 4qi: 87%; 4rf: 89%; 4rh: 91%; 4si: 86%; 4tj: 85%). The reactions of N-heterocycle-containing aryl fluorides (1v, 1w, 1z, 1ab) with chloro- (3i, 3j) or benzo[1,3]dioxole anilines (3g) resulted in good-to-high yields (4vi: 97%; 4wj: 96%; 4zg: 65%; 4abg: 98%).

To understand the limitations of this defluorinative coupling with aryl fluorides 1 in terms of secondary amines, several representative secondary amines, such as N-alkylanilines (3l, 3m), cyclic anilines (3n–3q), and cyclic and acyclic alkylamines (3r–3u) were reacted with 1a under standard conditions. Remarkably, in all cases, the defluoroamination with 1a generated the desired products, while the yields varied depending on the type of amine (Fig. 2, IV). The use of N-ethyl- (3l) or N-butylaniline (3m) afforded the corresponding products in low yields (4al: 27%; 4am: 27%) via coupling with 1a. Conversely, cyclic N-alkylanilines reacted more favorably with 1a to produce the corresponding products in moderate yields (4an: 47%; 4ao: 46%; 4ap: 59%; 4aq: 35%). Therefore, the steric hindrance around the N center is strongly related to the reactivity, and the bulkier anilines generally afford lower yields. Notably, this coupling reaction can be extended to non-aryl cyclic and acyclic dialkyl secondary amines, such as morpholine (3r), pyrrolidine (3s), 1,2,3,4-tetrahydroisoquinoline (3t), and diethylamine (3u), in generating the corresponding products (4ar: 21%; 4as: 11%; 4at: 26%; 4au: 18%). However, in these cases, 1a was partially consumed. Additionally, byproducts, mainly the defluorosilylation product, PhC6H4-SiEt3 (6), were detected42. The low yields and the formation of byproducts are possibly attributed to the low reactivities of the reactants and the steric hindrance of the aniline moieties.

Finally, we attempted the defluorinative aminations of alkyl fluorides 2 containing C(sp3)–F bonds using 3a under optimal reaction conditions (Fig. 2, V). Primary benzyl fluorides (2a–2c) efficiently underwent defluoroamination with 3a to generate the desired coupling products in the yields of ≤87% (5aa: 81%; 5ba: 76%; 5ca: 87%). Notably, the C(sp3)–F bond in 2b was cleaved without affecting the OCF3 substituent. Further, using the secondary benzyl fluoride 2-(1-fluoroethyl)naphthalene (2d) yielded the corresponding defluoroamination product 5da in a yield of 43%. In contrast, 5ea was obtained in a yield of 20% using 1-fluorodecane (1e) and 3a under identical standard reaction conditions. Thus, the reactions of non-activated alkyl fluorides are limited using this method, although the yields may be improved via the extensive optimization of the reaction conditions. Interestingly, while benzyl fluoride 2a gave the amination product 5aa in 86% yield even in the absence of Et3SiBpin, 1-fluorodecane (1e) remained unreacted.

Application of silylboronate-mediated defluorinative coupling reaction

To highlight the synthetic applications of this silylboronate-mediated defluorinative coupling reaction, we examined the functionalization of several drug derivatives with fluoroarene moieties (Fig. 3). The (±)-α-tocopherol-derived fluoroarene 1ad underwent the coupling reaction with 3a to generate the (±)-α-tocopherol derivative 4ada in a yield of 83%. Moreover, the bioactive motif (-)-menthol-derived N-methylaniline 3v was successfully functionalized using this reaction with 1a or the fluoro-containing estrone derivative 1ae to generate 4av and 4aev in yields of 75% and 62%, respectively. Furthermore, we extended the protocol to the late-stage syntheses of deuterated N-alkyl pharmaceuticals. Because >50% of the best-selling drugs contain N-alkyl groups49, the development of deuterated N-alkyl pharmaceuticals is gaining considerable attention. Isotope labeling is generally critical in medicinal chemistry as the C–D bonds are more stable than C–H bonds50. Therefore, incorporating deuterated N-methyl (N-CD3) moieties into pharmaceuticals should improve the pharmacodynamic properties51,52,53,54,55,56. Considering this aspect, several representative fluoro-containing derivatives of bioactive molecules, 1ad–1ag, were reacted with deuterated N-methylaniline d3−3a under standard conditions. 1ae and d3−3a were initially used in the presence of Et3SiBpin and KOtBu in triglyme, generating the estrone derivative d3−4aea in a 77% yield. The reaction with (-)-menthol-derived fluorobenzene 1af also proceeded well under identical conditions to afford the deuterated product d3−4afa in a yield of 88%. The deuterated (R)-naproxen derivative d3−4aga was also synthesized in a 70% yield using the fluoro-propanoate 1ag. Moreover, 1ad was again investigated via reaction with d3−3a under standard conditions to yield the corresponding deuterated (±)-α-tocopherol derivative d3−4ada (79% yield).

Fig. 3: Synthetic applications.
figure 3

a–c Late-stage cross-coupling aminations of pharmaceutically attractive molecules. d–g Late-stage syntheses of pharmaceutically attractive molecules containing deuterated N-methyl groups.

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Reaction mechanism

Several control experiments were conducted to gain insight into the reaction mechanism (Fig. 4, left). First, the silylated compound 6 was used in the coupling reaction with 3a under optimal reaction conditions. However, the amination product 4aa was not detected (Fig. 4a); thus, 6 did not participate in the reaction. We then examined the defluoroamination of 1a with 3a in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO, Fig. 4b). Although 4aa was obtained in a yield of 89% under standard conditions, the yields considerably decreased when the amount of TEMPO increased: 40% (1.0 equiv. of TEMPO), 26% (2.0 equiv. of TEMPO), and 9% (4.0 equiv. of TEMPO). The reaction of benzyl fluoride 2a was also inhibited by the addition of TEMPO (2.0 equiv. Figure 4c). The reaction of 1 with the freshly prepared potassium salt of 3a in the presence of tBuOBpin57 was attempted; however, no reaction occurred (Fig. 4d). Thus, the process should not involve the formation of potassium anilide. Furthermore, d3−3a was employed under optimal reaction conditions, and the corresponding defluoroamination product d3−4aa was isolated in an 84% yield (Fig. 4e), whereas d2−4aa was not obtained. Therefore, the N-methyl moiety is not involved in the process. In addition, a radical clock experiment with 1a and N-cyclopropylaniline (3w) was conducted. 1a was almost recovered (about 90%), whereas 3w disappeared to give a complex mixture (Fig. 4f). Furthermore, the treatment of only 3w under standard conditions resulted in the same complex mixture, whereas 3w was recovered under the same treatment in the absence of Et3SiBPin (Fig. 4g). These facts are consistent with the ring-opening of the aminyl radical 3w’ into the primary carbon radical 3w” under Et3SiBpin/tBuOK conditions58,59,60. The ring-opening primary carbon radical 3w” is unstable towards decomposition (Fig. 4f-g). When the reaction of 3a was conducted without 1a, hydrazine 7 was formed in an isolated yield of 27% (Fig. 4h) due to the dimerization of the N-methylanilino radical PhN•Me. These control experiments indicate that the defluorinative C–N cross-coupling proceeds via a radical pathway. The uniqueness of this reaction using aryl fluorides 1 rather than the conventional aryl halides Ar–X 8a–c (X = Cl, Br, or I) in the silylboronate-mediated cross-coupling was revealed via comparison studies (Fig. 4i). Under identical conditions, 4-chlorobiphenyl (8a) was converted to the desired coupling product 4aa; however, the yield of 8% was inadequate. In contrast, the use of bromo- or iodo-substituted biphenyl (Br: 8b; I: 8c) generated a mixture of amination product 4aa and silylation product 6: 4aa (Br: 6% and I: trace) and 4-biphenylyl(trimethyl)silane 6 (Br: 9% and I: 26%), respectively. Thus, the chemoselectivity of this cross-coupling reaction toward the C–F bond over C–Cl/Br/I bonds is excellent.

Fig. 4: Mechanistic studies.
figure 4

a Stepwise attempted reaction. b, c Effect of TEMPO on the silylboronate-mediated coupling reaction. d Reaction of 1a with the potassium salt of 3a (PhNKMe) in the presence of tBuOBpin. e Reaction between 1a and the deuterated 3a (d3-3a). f, g Radical clock experiments. h Evidence suggesting the generation of an N-methylanilino radical. i Chemoselectivites of organic halides Ar–X. j–l Different reactivities of alkyl halides under the standard conditions in the presence and absence of Et3SiBipn. m Proposed reaction mechanism.

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Next, we compared the reactivities of alkyl halides under the standard conditions in the presence and absence of Et3SiBpin. Alkyl bromide reacted with N-Me-aniline 3a under standard conditions, affording the desired amination product in 91% yield (Fig. 4j). However, even in the absence of Et3SiBpin, the amination product formed quantitatively (Fig. 4j). Alkyl chloride also gave the desired amination product in high yield without Et3SiBpin (Fig. 4k). Alkyl fluoride 2e gave 5ea under standard conditions, but no reaction occurred in the absence of Et3SiBpin (Fig. 4l). Notably, the alkyl bromides and chlorides, and not alkyl fluorides, react easily with the nucleophilic species by a common SN2 reaction61. These results indicate the apparent difference between the C‒F and C‒X (Br, Cl) bonds and demonstrate that C‒F bond cleavage is indeed challenging.

Based on our results and those reported in previous studies, we propose a single-electron-transfer/radical-mediated defluorinative amination mechanism using frustrated radical pair chemistry62,63,64,65,66,67 (Fig. 4m). Initially, Et3SiBpin reacts with KOtBu to form an intermediate, A. The formation of this intermediate was previously proposed by Avasare et al. based on density functional theory calculations68. A was also identified via 11B and 29Si nuclear magnetic resonance (NMR) studies42,43. The increase in the steric hindrance of the alkyl moieties of R3SiBpin decreased the conversion and the yields of the reactions (Table 1, entries 16–18). This observation indicates that the initial step of the nucleophilic addition of t-butoxy anion (−OtBu) to R3SiBpin highly depends on the steric factor and is independent of the radical stability of the R3Si species generated in the next step. These results also agree with the solvent effect (Table 1, entries 4–6). It is known that the potassium cation is capsuled by glymes and by 18-crown-6, which results in the generation of naked, reactive −OtBu69,70,71,72,73. The naked −OtBu anion should accelerate the generation of intermediate A. Next, owing to a single electron reductant property of −OtBu74,75, intermediate A splits into a sterically demanding frustrated radical pair of B, which comprises the triethylsilyl radical (•SiEt3) and a boron-radical species (B•), via the homolytic cleavage of the Si–B bond. Hydrogen abstraction from N-methylaniline 3 by •SiEt3 in B yields a frustrated radical pair C consisting of a N-methylanilino radical (Ar-N•-Me) and the boron-radical species, accompanied by the formation of HSiEt3 (detected using gas chromatography-mass spectrometry). The generation of the N-methylanilino radical is supported by the low yields of 4aa obtained under optimal reaction conditions in the presence of increased equivalents of TEMPO. Subsequently, the frustrated radical pair C attracts organic fluoride 1 (or 2) by preferable interaction between the F atom and B center to afford TS-I. Since the C–F bond of 1 (or 2) is activated by the interaction of the B atom in TS-I, N-methylanilino radical selectively attacks at the carbon center of the C–F bond, as shown in TS-I. Finally, the desired cross-coupling product 4 or 5 is obtained with C–N bond formation, accompanied by the release of D ([Bpin(OtBu)F]K, which promptly reacts with KOtBu to provide a stable ([Bpin(OtBu)2] species (detected using 11B NMR spectroscopy) and KF (detected using 19F NMR spectroscopy) (see the Supplementary Information). The fluorine-selective reaction over the other halogens could be explained based on bond dissociation energy (BDE)76. The C‒F bond in Ph–F (BDE: 125.6 kcal/mol) is more stable than the C‒Br (BDE: 80.4 kcal/mol) and C‒Cl (95.5 kcal/mol) bonds in Ph–X. However, the B‒F (boron-fluorine) bond is the strongest among the other B‒X bonds (X = F, Cl, Br) in terms of the reported (B(O)-X; X–F: 163.0 kcal/mol), X–Cl: 104.6 kcal/mol; X–Br: 86.7 kcal/mol)61 and predicted values of the corresponding intermediate structures (PinB-(X)OtBu; X = F: 105.2 kcal/mol; X = Cl: 91.9 kcal/mol; X = Br: 83.9 kcal/mol)77. Therefore, the B atom of the intermediate selectively approaches the F atom over the Cl or Br atoms on the substrates, resulting in the preferential attack of the amino radical at the carbon attached to the F atom over other halogen-attached carbons. The preferable interactions between the F and B centers are essential for the cleavage of the C–F bond instead of those between the B centers and other halogens. Another mechanistic pathway based on the nucleophilic SNAr reaction of organic fluoride 1 or 2 with the anilino anion in the frustrated ion pair C’ was ruled out by the control experiments shown in Fig. 4d.

In conclusion, we developed the first silylboronate-mediated radical coupling of organic fluorides with secondary amines via inert C–F bond activation at room temperature. A wide variety of secondary acyclic and cyclic N-alkylanilines and dialkylamines reacted with different organic fluorides to generate structurally diverse aromatic tertiary amines in moderate-to-excellent yields under very mild conditions. The most significant feature of this protocol is the production of electrically opposing scaffolds, particularly tolerating reactants containing OR-, Cl-, CN-, or CF3 functional groups. Additionally, this method avoids the use of transition metals and specialized ligands. While the Buchwald–Hartwig amination is undoubtedly a powerful strategy to access several secondary/tertiary amines by using aryl halides (I, Br, and Cl) and the Pd catalyst system, the use of aryl fluorides is not practical in this reaction. However, as the utilization of fluorine-containing drugs in pharmaceutical and agrochemical industries has recently increased8,9, the present C–F bond transformation strategy is desirable for preparing new drug candidates. In fact, the late-stage syntheses of N-alkyl pharmaceuticals, including deuterated analogs, were effectively achieved. Due to the very mild reaction conditions, ease of execution, and wide substrate scope of this protocol, in addition to the structurally derivatizable complex pharmaceuticals produced, this silylboronate-mediated C–F and N–H bond coupling should be used in organic syntheses, pharmaceuticals, and agrochemicals. Further studies regarding this defluorinative functionalization are currently underway.

Methods

General procedure of the silylboronate-mediated cross-coupling reactions of organic fluorides and secondary amines

In an N2-filled glovebox, organic fluorides 1 or 2 (0.2 mmol, 1.0 equiv.), KOtBu (89.6 mg, 0.8 mmol, 4.0 equiv.), dry triglyme (1.0 mL), secondary amines 3 (0.6 mmol, 3.0 equiv.), and Et3SiBpin (0.4 mmol, 2.0 equiv.) were sequentially added to a flame-dried screw-capped test tube. The tube was then sealed and removed from the glovebox, and the solution was stirred at room temperature for 24 h. The mixture was diluted (5 mL) and then extracted using diethyl ether and water, washed with brine, dried over Na2SO4, and concentrated under a vacuum. Subsequently, 3-fluoropyridine (8.6 μL, 0.1 mmol) was added as an internal standard before NMR spectroscopy. The mixture was then concentrated again to yield the crude product, which was purified via column chromatography on silica gel to yield the corresponding products 4 or 5.