Copper-Catalyzed Synthesis of Axially Chiral Biaryls with Diaryliodonium Salts as Arylation Reagents

NOBIN and BINAM derivatives harboring biaryl frameworks are recognized as a class of important atropisomers with versatile applications. Here, we present an efficient synthetic route to access such compounds through copper-catalyzed domino arylation of N-arylhydroxylamines or N-arylhydrazines with diaryliodonium salts and [3,3]-sigmatropic rearrangement. This reaction features mild conditions, good substrate compatibility, and excellent efficiency. The practicality of this protocol was further extended by the synthesis of biaryl amino alcohols.

For NOBIN and its derivatives, they could be accessed from other binaphthyl compounds such as BINOL or BINAM [14][15][16]. However, in these synthetic processes, excess noble metal reagents, harsh conditions, or expensive reagents were commonly required to achieve satisfactory efficiency [17]. The oxidative cross-coupling of 2-naphthol and 2-naphthylamine catalyzed by transition metal represents the most effective and direct method to establish the aryl-aryl axis. Kočovský and coworkers pioneered the strategy of oxidative cross-coupling using copper amine complexes as oxidants [18][19][20][21]. Subsequently, Ding [22] and Carreira [23] provided a series of improved approaches to enhance the synthetic efficiency and applicability in large-scale preparations and inhibit inseparable homo-coupling by-products. Recently, Tu and coworkers successfully constructed enantioenriched 3,3 -disubstituted NOBINs by aerobic oxidative cross-coupling utilizing a novel Cu/SPDO catalytic system [24]. The redox potential difference between two coupling partners ensured good chemoselectivity and chemical yield during the coupling process. Our group developed an efficient coupling approach for the synthesis of NOBINs via a palladium-catalyzed highly site-selective C-H arylation reaction of N-Boc-2naphthylamines with diazoquinones under mild conditions [25]. droxy-1,1′-binaphthyl (NOBIN) and 1,1′-binaphthyl-2,2′-diamine (BINAM) are among the most frequently utilized structures [1][2][3][4]. Now, NOBIN and BINAM derivatives have been involved in metal catalysis [5][6][7], organocatalysis [8,9], photocatalysis [10], and even heterogeneous catalysis [11] for effective chirality induction. Meanwhile, the significance of such backbones is further illustrated by their prevalence in functional materials [12,13] ( Figure 1). Accordingly, the construction of NOBIN and BINAM scaffolds has attracted extensive attentions from the synthetic research community. For NOBIN and its derivatives, they could be accessed from other binaphthyl compounds such as BINOL or BINAM [14][15][16]. However, in these synthetic processes, excess  As an effective Ar-Ar bond formation method, [3,3]-sigmatropic rearrangement reaction was emerged as an attractive alternative [26][27][28][29][30][31][32]. In this context, Gao [33] and our group [34] independently developed a transition metal-free approach to generate NOBIN derivatives following a domino arylation of naphthylhydroxylamines with diaryliodonium salts and [3,3]-sigmatropic rearrangement. It should be mentioned that moderate yields were normally obtained for Gao's conditions, while the mixed solvent of dichloromethane and trifluoroethanol was required to improve reaction results.
The progress in synthesis of biaryls employing diaryliodonium salts as aryl cation equivalents has made this class of bench-stable, nontoxic, and readily available reagents attract attention [35][36][37][38][39]. Moreover, copper catalyst can be oxidized in the presence of diaryliodonium salts to form a highly electrophilic aryl-Cu(III) intermediate and a range of latent nucleophiles undergo arylation reactions to form synthetically versatile products [39,40]. In view of the advantages and reliability with diaryliodonium salts, Cucatalyzed arylation of N-arylhydroxylamine or N-arylhydrazine can effectively generate transient diaryl groups linked by heteroatoms, which can easily undergo rearrangement reactions. Motivated by our continuous research interests in constructing biaryl frameworks [41][42][43][44], we turned our attention to construct the NOBIN and BINAM derivatives via copper-catalyzed N-/O-arylation with diaryliodonium salts and subsequent [3,3]sigmatropic rearrangement under mild conditions ( Figure 2). The properties of biaryls are affected by the steric hindrance and electronic effect of substituents, which will bring new opportunities in application and expansion. The arylation-rearrangement sequence that allows new library synthesis is still desired. noble metal reagents, harsh conditions, or expensive reagents were commonly r to achieve satisfactory efficiency [17]. The oxidative cross-coupling of 2-naphtho naphthylamine catalyzed by transition metal represents the most effective an method to establish the aryl-aryl axis. Kočovský and coworkers pioneered the str oxidative cross-coupling using copper amine complexes as oxidants [18][19][20][21] quently, Ding [22] and Carreira [23] provided a series of improved approaches to the synthetic efficiency and applicability in large-scale preparations and inhibit in ble homo-coupling by-products. Recently, Tu and coworkers successfully constru antioenriched 3,3′-disubstituted NOBINs by aerobic oxidative cross-coupling ut novel Cu/SPDO catalytic system [24]. The redox potential difference between t pling partners ensured good chemoselectivity and chemical yield during the c process. Our group developed an efficient coupling approach for the synthesis of N via a palladium-catalyzed highly site-selective C-H arylation reaction of N-Boc thylamines with diazoquinones under mild conditions [25].
As an effective Ar-Ar bond formation method, [3,3]-sigmatropic rearrangem action was emerged as an attractive alternative [26][27][28][29][30][31][32]. In this context, Gao [33] group [34] independently developed a transition metal-free approach to generate derivatives following a domino arylation of naphthylhydroxylamines with d donium salts and [3,3]-sigmatropic rearrangement. It should be mentioned that m yields were normally obtained for Gao's conditions, while the mixed solvent of d methane and trifluoroethanol was required to improve reaction results.
The progress in synthesis of biaryls employing diaryliodonium salts as ary equivalents has made this class of bench-stable, nontoxic, and readily available attract attention [35][36][37][38][39]. Moreover, copper catalyst can be oxidized in the presen aryliodonium salts to form a highly electrophilic aryl-Cu(III) intermediate and a latent nucleophiles undergo arylation reactions to form synthetically versatile p [39,40]. In view of the advantages and reliability with diaryliodonium salts, Cu-c arylation of N-arylhydroxylamine or N-arylhydrazine can effectively generate t diaryl groups linked by heteroatoms, which can easily undergo rearrangement re Motivated by our continuous research interests in constructing biaryl framewo 44], we turned our attention to construct the NOBIN and BINAM derivatives via catalyzed N-/O-arylation with diaryliodonium salts and subsequent [3,3]-sigmat arrangement under mild conditions ( Figure 2). The properties of biaryls are aff the steric hindrance and electronic effect of substituents, which will bring new o nities in application and expansion. The arylation-rearrangement sequence tha new library synthesis is still desired.

Optimization of Reaction Conditions
Upon exploring some reaction conditions through variation of the copper catalysts, solvents and bases (see Supplementary Materials for details), the following protocol was identified to be optimal: reaction of 1a and 2a with the molar ratio of 1.0:1.2 by using Cu(TFA) 2 (10 mol%) as catalyst in dichloromethane (DCM) at room temperature, 3a was obtained almost quantitatively ( Table 1, entry 1). When evaluating different solvents, DCM outcompeted others to form a desired product (Table 1, entries 2-5). As far as the catalyst is concerned, other screened Cu(II) or Cu(I) bearing different anions also gave 3a in high yield under mild conditions ( Table 1, entries 6-9). Finally, other carbonate salts, NaOH, tBuOK, and amine are inferior to Na 2 CO 3 in facilitating the arylation process (Table 1, entries 10-14). Upon exploring some reaction conditions through variation of the copper catalysts, solvents and bases (see Supplementary Materials for details), the following protocol was identified to be optimal: reaction of 1a and 2a with the molar ratio of 1.0:1.2 by using Cu(TFA)2 (10 mol%) as catalyst in dichloromethane (DCM) at room temperature, 3a was obtained almost quantitatively ( Table 1, entry 1). When evaluating different solvents, DCM outcompeted others to form a desired product (Table 1, entries 2-5). As far as the catalyst is concerned, other screened Cu(II) or Cu(I) bearing different anions also gave 3a in high yield under mild conditions ( Table 1, entries 6-9). Finally, other carbonate salts, NaOH, tBuOK, and amine are inferior to Na2CO3 in facilitating the arylation process ( Table 1, entries 10-14). a All reactions were performed with Cu(TFA)2 (10 mol%), 1a (0.10 mmol), 2a (0.12 mmol), and base (0.13 mmol) in DCM (2.0 mL) at room temperature; b Yield was determined by 1 H-NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard.

Substrate Scope
With the optimized conditions in hand, the generality of this transformation was then explored with respect to N-naphthylhydroxylamines 1 and diaryliodonium salts 2. As shown in Figure 3, all the investigated substrates were completely transformed and furnished the respective product in generally high efficiency with a yield of up to 98%. In detail, the replacement of the Cbz-protecting group with a methyl formate gave the desired product in 91% yield. Different substituents on the aromatic ring including halides, methyl ester, phenyl, and methoxy were all compatible for this set of reaction conditions, and meanwhile, the substitution patterns and electronic properties of substituents exerted a limited influence on the reaction outcome. Further evaluations revealed that all the tested N-naphthylhydroxylamines 1 and diaryliodonium salts 2 with varied substitutions could undergo effective combination to give multi-substituted NOBINs 3m-x in 81-92% yield. In addition, diaryliodonium salt with an extended fused ring system proved to be NaOH instead of Na 2 CO 3 75 13 NaO t Bu instead of Na 2 CO 3 66 14 Et 3 N instead of Na 2 CO 3 73 a All reactions were performed with Cu(TFA) 2 (10 mol%), 1a (0.10 mmol), 2a (0.12 mmol), and base (0.13 mmol) in DCM (2.0 mL) at room temperature; b Yield was determined by 1 H-NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard.

Substrate Scope
With the optimized conditions in hand, the generality of this transformation was then explored with respect to N-naphthylhydroxylamines 1 and diaryliodonium salts 2. As shown in Figure 3, all the investigated substrates were completely transformed and furnished the respective product in generally high efficiency with a yield of up to 98%. In detail, the replacement of the Cbz-protecting group with a methyl formate gave the desired product in 91% yield. Different substituents on the aromatic ring including halides, methyl ester, phenyl, and methoxy were all compatible for this set of reaction conditions, and meanwhile, the substitution patterns and electronic properties of substituents exerted a limited influence on the reaction outcome. Further evaluations revealed that all the tested N-naphthylhydroxylamines 1 and diaryliodonium salts 2 with varied substitutions could undergo effective combination to give multi-substituted NOBINs 3m-x in 81-92% yield. In addition, diaryliodonium salt with an extended fused ring system proved to be an applicable arylation reagent and produced the corresponding NOBINs in about 90% yield (products 3v-x). It should be mentioned that the Br atom, which could act as an effective handle for further transformation, survived during this process. an applicable arylation reagent and produced the corresponding NOBINs in about 90% yield (products 3v-x). It should be mentioned that the Br atom, which could act as an effective handle for further transformation, survived during this process. Subsequently, N-phenylhydroxyamines or diphenyliodonium salts were evaluated for this reaction to synthesize the biaryl amino alcohols. A series of structurally diverse compounds (Figure 4a, 3y-ac) were obtained in good yields under the standard conditions. Cyclic diaryliodonium salt was verified to be a suitable arylation reagent, and the expected diaxial product was obtained in 72% yield as a pair of diastereomers with a ratio of 1.2:1 (Figure 4a, 3ad). The successful establishment of a highly efficient domino approach to construct NOBINs inspired us to explore the feasibility in constructing BINAMs, which is another type of privileged biaryl atropisomers, to further extend the applicability and flexibility of the developed method. Pleasingly, when N-naphthylhydrazines 4 were utilized, the reactions with diaryliodonium salts 2 underwent smoothly to give BINAMs in moderate yield (Figure 4b, 5a-d). Subsequently, N-phenylhydroxyamines or diphenyliodonium salts were evaluated for this reaction to synthesize the biaryl amino alcohols. A series of structurally diverse compounds (Figure 4a, 3y-ac) were obtained in good yields under the standard conditions. Cyclic diaryliodonium salt was verified to be a suitable arylation reagent, and the expected diaxial product was obtained in 72% yield as a pair of diastereomers with a ratio of 1.2:1 (Figure 4a, 3ad). The successful establishment of a highly efficient domino approach to construct NOBINs inspired us to explore the feasibility in constructing BINAMs, which is another type of privileged biaryl atropisomers, to further extend the applicability and flexibility of the developed method. Pleasingly, when N-naphthylhydrazines 4 were utilized, the reactions with diaryliodonium salts 2 underwent smoothly to give BINAMs in moderate yield (Figure 4b, 5a-d).

Control Experiments and Plausible Mechanism
Under transition metal-free conditions, the substrates could be completely converted, and the desired product 3a was obtained in 70% yield (Figure 5a), along with several by-products. The use of Cu(TFA) 2 not only improved the yield significantly but also shortened the reaction time, indicating that copper salt had an obvious catalytic effect on this type of reactions. Moreover, other examined Lewis acids such as the triflate of aluminum, magnesium, zinc, or nickel brought about a negligible effect on the reaction outcome (Figure 5b). In addition, a stoichiometric base was necessary for this reaction. When sodium carbonate was removed from the standard conditions, the target product 3a could only be obtained in 33% yield (Figure 5c).

Control Experiments and Plausible Mechanism
Under transition metal-free conditions, the substrates could be completely converted, and the desired product 3a was obtained in 70% yield (Figure 5a), along with several byproducts. The use of Cu(TFA)2 not only improved the yield significantly but also shortened the reaction time, indicating that copper salt had an obvious catalytic effect on this type of reactions. Moreover, other examined Lewis acids such as the triflate of aluminum, magnesium, zinc, or nickel brought about a negligible effect on the reaction outcome (Figure 5b). In addition, a stoichiometric base was necessary for this reaction. When sodium carbonate was removed from the standard conditions, the target product 3a could only be obtained in 33% yield (Figure 5c).  According to the results of the control experiments and previous reports on coppercatalyzed arylation reactions with diaryliodonium salts [36,39,[45][46][47][48], a plausible reaction pathway involving 2-naphthyl-Cu(III) species was proposed, as shown in Figure 6. At first, the Cu(I) salt initially formed by Cu(II) disproportionation [49][50][51] undergoes oxidative addition into the Ar-I(III) bond to form the highly electrophilic aryl-Cu(III) intermediate A. Then, the complexation or nucleophilic substitution of aryl-Cu(III) species A with Narylhydroxylamine 1 produces intermediate B under basic conditions. Upon reductive elimination, N,O-dinaphthylhydroxylamine C is generated, and active Cu(I) catalyst is released to continue the catalytic cycle. Next, the [3,3]-sigmatropic rearrangement step and subsequent rearomatization proceed rapidly to afford the product NOBIN 3. As a transient precursor, C is quite difficult to be isolated from the reaction system, indicating a strong driving force for the following rearrangement. According to the results of the control experiments and previous reports on copper catalyzed arylation reactions with diaryliodonium salts [36,39,[45][46][47][48], a plausible reaction pathway involving 2-naphthyl-Cu(III) species was proposed, as shown in Figure 6. A first, the Cu(I) salt initially formed by Cu(II) disproportionation [49][50][51] undergoes oxida tive addition into the Ar-I(III) bond to form the highly electrophilic aryl-Cu(III) interme diate A. Then, the complexation or nucleophilic substitution of aryl-Cu(III) species A with N-arylhydroxylamine 1 produces intermediate B under basic conditions. Upon reductive elimination, N,O-dinaphthylhydroxylamine C is generated, and active Cu(I) catalyst i released to continue the catalytic cycle. Next, the [3,3]-sigmatropic rearrangement step and subsequent rearomatization proceed rapidly to afford the product NOBIN 3. As a transient precursor, C is quite difficult to be isolated from the reaction system, indicating a strong driving force for the following rearrangement.

Materials and Methods
Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Cu(TFA) 2 was purchased from Energy Chemical (Shanghai, China); Na 2 CO 3 was purchased from Aladdin (Shanghai, China); Dichloromethane was purchased from TiTan (Shanghai, China). Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 F254 plates (Qingdao, China). Flash column chromatography was performed using Tsingdao silica gel (60, particle size 0.040-0.063 mm; Qingdao, China). Visualization on TLC was achieved by use of UV light (254 nm). NMR spectra were recorded on a Bruker DPX 400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) at 400 MHz for 1 H-NMR, 100 MHz for 13 C-NMR and 376 MHz for 19 F-NMR in CDCl 3 or Acetone-d 6 with tetramethylsilane (TMS) as internal standard. Chemical shifts are reported in ppm and coupling constants are given in Hz. Data for 1 H-NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet), coupling constant (Hz), integration. Data for 13 C-NMR are reported in terms of chemical shift (δ, ppm). High resolution mass spectra (HRMS) were recorded on a LC-TOF spectrometer (Thermo Fisher Scientific, Waltham, MA, USA).
General procedures for synthesis of NOBIN and BINAM derivatives: 1 or 4 (0.20 mmol), 2 (0.24 mmol), Na 2 CO 3 (27.6 mg, 0.26 mmol), and Cu(TFA) 2 (5.8 mg, 10 mol%) were added to a bottle with a magnetic stirring bar. DCM (4.0 mL) was added, and the reaction mixture was stirred at room temperature until 1 or 4 was completely consumed (monitored by TLC). After the solvent evaporated, the residue was purified by flash chromatography eluted with DCM to afford the corresponding product 3 or 5.