Copper Cocatalyzed Highly trans-Selective 1,2

Article Cite This: J. Am. Chem. Soc. 2017, 139, 15724-15737

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Rhodium/Copper Cocatalyzed Highly trans-Selective 1,2Diheteroarylation of Alkynes with Azoles via C−H Addition/Oxidative Cross-Coupling: A Combined Experimental and Theoretical Study Guangying Tan,† Lei Zhu,‡ Xingrong Liao,† Yu Lan,*,‡ and Jingsong You*,† †

Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China ‡ School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China S Supporting Information *

ABSTRACT: Transition metal-catalyzed addition of diaryl alkynes with arylating reagents for the synthesis of tetraarylethylenes generally encounters rigorous reaction conditions and relies on the use of prefunctionalized substrates such as organic halides or surrogates and organometallic reagents. In this work, we establish a highly trans-selective 1,2-diheteroarylation of alkynes with azoles via a rhodium/copper cocatalyzed C−H addition/oxidative coupling process. Moreover, the diheteroarylation developed herein could open a door for the synthesis of heteroarene-doped tetraarylethylenes, and the photoluminescence (PL) spectra in THF−water mixtures and solid powder verify that these tetra(hetero)arylethylenes are aggregation-induced emission (AIE) active, building a new AIE molecule library. With a combination of experimental and theoretical methods, the reaction mechanism for addition/oxidative cross-coupling of internal alkynes with azoles has been investigated. Theoretical calculations reveal that the metalation/deprotonation of azole could occur with either rhodium or copper species. When azolylrhodium is formed, an alkyne could insert into the Rh−C bond. Another azolyl group could then transfer to rhodium from azolylcopper compound. The subsequent intramolecular trans-nucleophilic addition generates the second C−C bond. Meanwhile, the putative pathway for the formation of the hydroheteroarylated byproduct has also been explained by theoretical calculations.

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INTRODUCTION Stereodefined tetrasubstituted alkenes are found frequently in pharmaceuticals, natural products, biologically active molecules, and functional materials.1 In particular, tetraarylethylene (TAE) derivatives, as a prototypical AIEgen, have been extensively applied to diverse scientific fields like organic light emitting devices (OLED) and biolabels.2,3 Aggregation-induced emission (AIE) refers to nonplanar organic molecules that are actually nonluminescent or weakly emissive in solution but become strongly emissive when aggregated.4 Due to inherent advantages in solid-state luminescence, AIE molecules have attracted extensive attention especially in the field of materials science.2−4 Currently, the synthesis of TAE derivatives depends largely on the classical double bond forming methods like the McMurry reaction5a−c or the Wittig reaction.5d However, these procedures typically suffer from problems associated with synthetic efficiency and stereoselectivity. Considering that diaryl alkynes are easily accessible synthetic precursors, transition metal-catalyzed addition of diaryl alkynes with arylating reagents would be a rapid and concise route to tetraarylethylenes. The synthesis of tetraarylethylenes via the addition of alkyne roughly involves three categories: (1) intermolecular carbometalation (metal = B, Li, or Sn) of alkyne, © 2017 American Chemical Society

followed by a cross-coupling with aryl halide via palladium catalysis (Scheme 1a);6 (2) palladium-catalyzed diarylation of Scheme 1. Transition Metal-Catalyzed Addition of Alkyne for the Synthesis of Tetraarylethylene

Received: July 11, 2017 Published: October 17, 2017 15724

DOI: 10.1021/jacs.7b07242 J. Am. Chem. Soc. 2017, 139, 15724−15737

Article

Journal of the American Chemical Society alkyne with organometallic reagent (Scheme 1b);7 and (3) palladium-8 or nickel9-catalyzed domino reaction of alkyne, aryl iodide, and arylboronic acid/aryl Grignard reagent (Scheme 1c). Despite significant progress, these approaches generally require stringent reaction conditions and preactivated substrates such as organic halides or surrogates and organometallic reagents. Undoubtedly, expanding this chemistry to direct addition/oxidative coupling of alkyne with aromatic C−H bond is considerably appealing yet conceptually challenging. Over the past decade, the chemistry involving the addition of (hetero)arene with internal alkyne via transition metal catalyzed C−H bond activation has been developed well. These reactions are categorized into two main types as follows. The first type is chelation-assisted C−H oxidative annulation or addition-type alkenylation of (hetero)arene with alkyne (Scheme 2a).10 The

Scheme 3. Synthesis of Acyclic All-Carbon Tetrasubstituted Ethylenes via a C−H Addition/Oxidative Cross-Coupling Process

Scheme 2. Transition Metal-Catalyzed Addition of (Hetero)arene with Internal Alkyne

unknown. Therefore, the structural robustness and reactivity of the alkenyl metal species B would be a key, yet challenging issue for the combination of addition and oxidative crosscoupling processes. Two recent reports on the rhodium(III)catalyzed heteroaryl acyloxylation of alkynes15 and palladiumcatalyzed trimerization of terminal alkyne16 have forcefully exemplified the viability of this addition/oxidative-couplingtype reaction. Established herein is a rhodium/copper cocatalyzed trans-selective 1,2-diheteroarylation of alkynes with azoles via a C−H addition/oxidative cross-coupling process, which provides a rapid gateway to a variety of tetra(hetero)arylethylenes (Scheme 3b).

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pathway involves the formation of a cyclometallic intermediate via an ortho-aromatic C−H bond activation and a subsequent internal alkyne insertion. These high-efficiency methods have been applied extensively to synthesize a large number of biologically active molecules,11 pharmaceuticals,12 and functional materials.13 Another type refers to the direct hydro(hetero)arylation of alkynes through transition metal (Pd, Pt, Au, Ni, Co, etc.) catalysis.14 In this type, the metalation of a (hetero)arene C−H bond with a metal catalyst affords an σaryl−metal complex, which further adds to an alkyne to deliver a hydro(hetero)arylated product (Scheme 2b). However, there are surprisingly unavailable catalytic systems to perform 1,2di(hetero)arylation of alkynes for the synthesis of acyclic allcarbon tetrasubstituted ethylenes, rendering the process more difficult (Scheme 2c). We envisage that the transition metal-catalyzed 1,2-di(hetero)arylation of alkyne with (hetero)arene C−H bond could possibly undergo the pathway illustrated in Scheme 3a. First, a metalation of an arene with a transition metal catalyst affords an σ-aryl−metal complex A. Then, an addition migratory insertion of A to internal alkyne gives an alkenyl metal species B. The resulting B then reacts with the second arene to produce the intermediate C, which further undergoes a reductive elimination to generate tetrasubstituted ethylene. In this proposed addition/oxidative coupling pathway, the feasibility of the steps I and II has been demonstrated widely as illustrated in Scheme 2a,b, but the steps III and IV remain

RESULTS AND DISCUSSION Optimization of the Reaction Conditions. Our investigation commenced with the reaction between 1,2-diphenylethyne 1a (0.3 mmol) and benzoxazole 2a (0.20 mmol) (Table 1). Initially, by employing [Cp*RhCl2]2 (5 mol %) as the catalyst, Cu(OAc)2 (2.0 equiv) as the oxidant, and AgSbF6 (20 mol %) as the additive in DCE (1.0 mL) at 120 °C for 12 h, (E)-1,2-bis(benzo[d]oxazol-2-yl)-1,2-diphenylethene (3a) was obtained in 75% yield along with 16% of the hydroheteroarylated byproduct (3aa, (E)-2-(1,2-diphenylvinyl)benzo[d]oxazole) (Table 1, entry 2). The structures of 3a and 3aa were confirmed by X-ray crystallography (Figure 1). ICP-AES analysis showed that the contents of residual copper and rhodium in the isolated product 3a were 42.8 and 20.4 ppb, respectively. [Cp*IrCl2]2 and Cp*Co(CO)I2, the congeners of [Cp*RhCl2]2, showed negligible catalytic activity (Table 1, entries 1 and 3). Removal of the oxidant Cu(OAc)2 led to only the hydroheteroarylated 3aa in 42% yield (Table 1, entry 5). Other oxidants such as Ag2O, Ag2CO3, AgOAc, and O2 were proven to be less effective than Cu(OAc)2 (Table 1, entries 2 and 6−9). The addition of 0.50 equiv of PivOH could improve the yield to 89% (Table 1, entry 10). It is notable that nothing could be detected except for the recovery of 1a and 2a in the absence of AgSbF6 (Table 1, entry 4), indicating that AgSbF6 played a crucial role in this transformation. Considering the fact that AgSbF6 is the most effective additive for activating 15725


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Journal of the American Chemical Society Table 1. Reaction Discovery and Catalytic System Evaluationa

entry 1 2 3 4 5 6 7 8 9 10 11 12c 13c 14c 15c 16c 17c 18c 19c 20c 21c,d 22c,e

metal salt [Cp*IrCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) Cp*Co(CO)I2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*RhCl2]2 (5 mol %) [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2 [Cp*Rh(MeCN)3][SbF6]2

oxidant Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

(10 mol %) (10 mol %) (10 mol %) (5 mol %) (2.5 mol %) (10 mol %) (10 mol %) (10 mol %) (10 mol %) (10 mol %) (10 mol %) (10 mol %)

(0.40 (0.40 (0.40 (0.40

additive

mmol) mmol) mmol) mmol)

AgSbF6 AgSbF6 AgSbF6

Ag2O (0.40 mmol) Ag2CO3 (0.40 mmol) AgOAc (0.40 mmol) O2 (1 atm) Cu(OAc)2 (0.40 mmol) Cu(OAc)2 (0.40 mmol) Cu(OAc)2 (0.40 mmol) CuOAc (0.40 mmol) Cu(OAc)2 (0.40 mmol) Cu(OAc)2 (0.40 mmol) Cu(OAc)2 (10 mol %, 0.02 mmol) Cu(OAc)2 (0.20 mmol) Cu(OAc)2 (0.30 mmol) Cu(OAc)2 (10 mol %)/O2 (1 atm) Cu(OAc)2 (20 mol %)/O2 (1 atm) Cu(OAc)2 (0.40 mmol) Cu(OAc)2 (0.40 mmol)

AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6/PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH

yield of 3a (%)b

yield of 3aa (%)b

trace 75 5 f trace 25 13 20 trace 89 89 91 51 53 15 18 68 82 69 85 65 88

trace 16 trace f 42 12 7 10 45 8 7 trace trace trace trace 16 11 6 11 8 19 7

a

Reaction conditions: 1a (0.30 mmol), 2a (0.20 mmol), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %, if required), oxidant, PivOH (0.10 mmol), and DCE (1.0 mL) at 120 °C for 12 h under air. bIsolated yield. c10 h. dAt 80 °C. eAt 150 °C. fNo reaction.

Cu(OAc)2 as the additive under an O2 atmosphere (Table 1, entry 20). Decreasing reaction temperature disfavored the 1,2diheteroarylation of alkyne (Table 1, entry 21). Finally, we established the optimal catalytic system composed of [Cp*Rh(MeCN)3][SbF6]2 (10 mol %), Cu(OAc)2 (2.0 equiv), and PivOH (0.5 equiv) in DCE at 120 °C under air for 10 h (Table 1, entry 12). Substrate Scope. With the optimized conditions in hand, we next explored the scope of internal alkynes. First, as shown in Scheme 4, various symmetric alkynes smoothly underwent the 1,2-diheteroarylation with benzoxazole (2a), giving the desired products. This protocol was compatible with electrondonating groups such as methyl, methoxyl, and tert-butyl on the phenyl ring of internal alkynes, delivering the corresponding tetra(hetero)arylethylenes in good yields (Scheme 4, 3b−3e). No matter whether the electron-withdrawing substituent (F, Cl, Br, CF3, CH3CO, CO2Et, and CN) is located at the para-, metaor ortho-position of the phenyl ring of internal alkynes, the 1,2diheteroarylated products could be obtained in moderate to excellent yields (Scheme 4, 3f−3n). 1,2-Di(naphthalen-2yl)ethyne (1o) and 1,2-di(9H-fluoren-2-yl)ethyne (1p) could also provide the desired products (Scheme 4, 3o and 3p) in moderate yields (64% and 58%, respectively). To our delight, the protocol could be extended to diheteroarylethynes (Scheme 4, 3q−3u). A range of symmetric diheteroarylethynes smoothly reacted with benzoxazole (2a), delivering the corresponding fully heteroaryl-substituted ethylenes in satisfactory yields. Due to the excellent electron-donating property, the triphenylamine (TPA) unit is frequently installed in organic optoelectronic

Figure 1. ORTEP diagrams of 3a and 3aa with the thermal ellipsoids set at 50% probability.

[Cp*RhCl2]2 by striping chloride to release a cationic Rh(III) species, we envisioned that the real catalyst is probably a cationic Rh(III) species. Indeed, using [Cp*Rh(MeCN)3][SbF6]2 (10 mol %) as the catalyst, an equal yield of 3a could be obtained (Table 1, entry 11). Reducing the reaction time to 10 h, 3a could be produced in 91% yield concomitant with only a trace amount of 3aa (Table 1, entry 12). When Cu(OAc)2 was replaced with CuOAc, 3a was given in 51% yield (Table 1, entry 13). When the [Cp*Rh(MeCN)3][SbF6]2 loading was reduced to 5.0 and 2.5 mol %, 3a was obtained in 53% and 15% yields, respectively (Table 1, entries 14 and 15). Reducing the dosage of Cu(OAc)2 led to a diminished yield of 3a (Table 1, entries 16−18). 10 mol % of Cu(OAc)2 only delivered 3a in 18% yield under air (Table 1, entry 16), but the use of O2 led to 69% yield (Table 1, entry 19). The yield of 3a could be further improved to 85% along with the generation of the hydroheteroarylated byproduct 3aa in 8% yield by using 20 mol % of 15726


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Journal of the American Chemical Society Scheme 4. Scope of Internal Alkynesa

a

Reaction conditions: 1 (0.30 mmol), 2a (0.20 mmol), [Cp*Rh(MeCN)3][SbF6]2 (10 mol %), Cu(OAc)2 (0.4 mmol), PivOH (0.1 mmol), and DCE (1.0 mL) at 120 °C for 10 h under air. Isolated yields are provided.

materials.17 Gratifyingly, the TPA-containing alkynes could smoothly undergo the 1,2-diheteroarylation with 2a to form the tetra(hetero)arylethylene derivatives (Scheme 4, 3v and 3w) in good yields. Unsymmetrical di(hetero)arylacetylenes were also suitable for this transformation (Scheme 4, 3x−3ad). In addition, it is needed to emphasize that the reaction conditions were tolerant of synthetically useful reactive functional groups such as Cl, Br, acyl, ester, nitrile, formyl, and nitro. In contrast, the halogeno groups (Cl and Br) are usually incompatible with the previous procedures illustrated in Scheme 1. In addition to diaryl alkynes, dialkyl alkynes and aryl alkyl alkynes could also undergo this type of addition/oxidative cross-coupling process under the optimal reaction conditions, affording the 1,2-diheteroarylated products in moderate to good yields (Scheme 5, 3ae−3aj). Subsequently, the scope of azoles was investigated, and Scheme 6 summarizes the reactions of diphenylacetylene (1a) with a variety of azoles (2). Benzoxazoles with the electrondonating (methyl and tert-butyl), electron-withdrawing (Cl, Br, and NO2), or aryl group all could engage in this reaction in moderate to excellent yields (Scheme 6, 4a−4j). 5-Aryl oxazoles such as phenyl, p-methoxylphenyl, p-chlorophenyl,

xenyl, naphthyl, thienyl, and pyrenyl oxazoles could smoothly react with 2a to give the desired products in good yields (Scheme 6, 4k−4q and 4s). Furthermore, (E)-5-styryloxazole successfully underwent this addition/oxidative coupling reaction, providing 4r in 68% yield. More importantly, this protocol was tolerant of the electron-rich triphenylamine (TPA) and 9phenyl-9H-carbazole units, known as the important electrondonor segments in materials science (Scheme 6, 4t−4v). Other heterocycles such as (benz)imidazoles or thiazoles did not undergo this transformation. To further demonstrate the efficiency and practicality of this protocol, we tried to perform the reaction of diarylacetylene with two different azoles, affording the products bearing three different (hetero)aryl units (Scheme 7). To our delight, when diphenylacetylene (1a) reacted with benzoxazole (2a) and 5phenyloxazole (2l) under the optimized conditions, the tetra(hetero)arylethylene 5a with three different (hetero)arenes could be obtained as a major product in 63% yield, and two byproducts, 3a and 4k, were obtained in 25% and 14% yields, respectively. Similarly, the 1,2-diheteroarylated products 5b and 5c were also smoothly attained in moderate yields. 15727


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Journal of the American Chemical Society Scheme 5. Scope of Dialkyl Alkynes and Aryl Alkyl Alkynesa

In addition to the deuterium exchange experiments, we performed the Operando IR experiments to duly monitor the consumption of diphenylacetylene (1a) and benzoxazole (2a) and the generation of 3a, which were tracked by the change of the peaks at 1623 cm−1, 1521 cm−1, and 1003 cm−1, respectively (Figure 2a−c). As shown in Figure 2d−f, both the consumption of 1a and the generation of 3a showed an induction period, and during the first 1.5 h, the absorption intensities of 1a and 3a varied very slightly. After 1.5 h, increasing reaction time led to a rapid diminution and growth in the absorption intensities of 1a and 3a. Upon increasing the time to 3.5 h, the absorption intensities remained unchanged. Compared with 1a and 3a, the absorption intensity of 2a decreased quickly during the early 3 h. To further clarify whether Cu(I) was invoked as the key catalytic species in this transformation, we tried to take advantage of in situ IR measurements to monitor CuOAc. To our delight, the absorption intensity of CuOAc could be monitored by the in situ IR measurements, which were tracked by the change of the peak at 1532 cm−1 (Figure 2g−h). As shown in Figure 2h, a rapid growth in the absorption intensity of CuOAc was observed within the first hour. Then, the absorption intensity showed a continuous decrease until 3.5 h. These phenomena implied that one part of Cu(OAc)2 could be disproportionated quickly to CuOAc to activate azole in this transformation. In addition, the addition of extra CuOAc (0.5 equiv) to the standard reaction system could shorten an induction period in the generation of 3a (Figure 2i). These results imply that the induction period in the formation of product might be related to the generation of CuOAc (the disproportionation of Cu(OAc)2). The above Operando IR experiments revealed the possible pathway of 1,2-diheteroarylation of alkynes. During the initial 1.5 h, the reaction mainly underwent the disproportionation of Cu(OAc)2 (the formation of the catalytically active CuOAc) and the C−H metallization of benzoxazole 2a (the formation of azolylmetal species). After 1.5 h, the formed azolylmetal species reacted quickly with diphenylacetylene 1a along with the release of 3a. In combination with the H/D exchange experiments and the small KIE of 2.2, we proposed that the C−H cleavage of azole might occur before the rate-determining step. Next, we performed the MALDI-TOF experiment by using a reaction mixture of 1a and 2a running for 2 h under the standard conditions (Figure 3). To our delight, four rhodiumcontaining complexes (IM1, calcd 356.052, found 356.088; IM2, calcd 534.130, found 534.145; IM3, calcd 652.159, found 652.170; IM4, calcd (M + H) 596.167, found 596.164) and two copper-containing complexes (IM5, calcd 755.108, found 755.105; IM6, calcd (M + H) 537.087, found 537.082) were detected, which could offer additional support for the proposed reaction pathway. On the basis of preliminary mechanistic studies and previous reports,15,16,19−23 a plausible mechanism is proposed to account for this rhodium-catalyzed trans-selective C−H addition/ oxidative coupling for 1,2-diheteroarylation of alkynes with azoles. As shown in Scheme 12, all these pathways begin with the cationic rhodium complex I. Initially, the metalation− deprotonation with benzoxazole 2a could afford an oxazolylrhodium intermediate II, followed by an alkyne insertion with the generation of vinylrhodium complex III. In Path-A, a transmetalation20 between complex III and oxazolylcopper IV 21−23 would lead to the formation of the neutral

a

Reaction conditions: 1 (0.30 mmol), 2a (0.20 mmol), [Cp*Rh(MeCN)3][SbF6]2 (10 mol %), Cu(OAc)2 (0.4 mmol), PivOH (0.1 mmol), and DCE (1.0 mL) at 120 °C for 10 h under air. Isolated yields are provided.

In addition, 1,3-bis(phenylethynyl)benzene (6a) and 1,4bis(phenylethynyl)benzene (6b) could react with benzoxazole (2a), delivering the highly substituted alkenes 8a and 8b, respectively (Scheme 8a,b). Considering the synthetic usefulness, we further illustrated the scalability of the reaction. When the reaction was scaled up to 8 mmol with a gram scale, the desired 3a was isolated in 83% yield (Scheme 9, condition A). To our delight, 3a could be also obtained in 70% yield by employing Cu(OAc)2 (20 mol %) together with O2 (1 atm) as the oxidant (Scheme 9, condition B). Mechanism Investigation. To obtain a clearer perception of the reaction, a series of control experiments were performed. In the absence of Cu(OAc)2, both catalytic and stoichiometric amounts of [Cp*Rh(MeCN)3][SbF6]2 furnished the hydroheteroarylated 3aa in moderate yields along with a trace amount of the diheteroarylated 3a (Scheme 10a,b), suggesting that Cu(OAc)2 not only played the role of the oxidant but also served as a promoter together with [Cp*Rh(MeCN)3][SbF6]2. Moreover, the separated 3aa did not further react with benzoxazole (2a) under the standard reaction conditions (Scheme 10c). In order to gain some insight into the reaction mechanism, hydrogen/deuterium exchange experiments were performed.18 Under the standard conditions, the reaction of benzoxazole (2a) with 20 equiv of D2O led to 12% or 10% of the H/D exchange ratio of 2a in either the presence or absence of diphenylacetylene (1a) for 1 h (Scheme 11a,e). Treatment of 2a with D2O in the presence of either [Cp*Rh(MeCN)3][SbF6]2 or Cu(OAc)2 gave rise to 12% or 14% of the H/D exchange ratio of 2a (Scheme 11b,c). Furthermore, we performed a control experiment omitting both [Cp*Rh(MeCN)3][SbF6]2 and Cu(OAc)2 (Scheme 11d). This experiment did not lead to any deuterated benzoxazole, which could exclude the possibility that the exchange is neither rhodiumnor copper-mediated. Despite relatively low D/H ratios, these results could imply that the C−H metalation of azole is reversible via the CMD mechanism. In addition, a primary KIE of 2.2 was observed for 2a and [D]-2a with 1a (Scheme 11f). 15728


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Journal of the American Chemical Society Scheme 6. Scope of Azolesa

a Reaction conditions: 1a (0.30 mmol), 2 (0.20 mmol), [Cp*Rh(MeCN)3][SbF6]2 (10 mol %), Cu(OAc)2 (0.4 mmol), PivOH (0.1 mmol), and DCE (1.0 mL) at 120 °C for 10 h under air. Isolated yields are provided.

catalyst 9 proceeds via transition state 10-ts, generating oxazolylrhodium intermediate 11 reversibly, with an activation free energy of 29.9 kcal/mol. Subsequently, an alkyne insertion into the Rh−C bond occurs via transition state 12-ts with a free energy barrier of 20.3 kcal/mol and concomitant generation of vinylrhodium intermediate 13, which is 22.0 kcal/mol exothermic compared with rhodium catalyst 9. The relative free energy of transition state 12-ts is 2.6 kcal/mol higher than that of 10-ts, and therefore, the rate-limiting step of this reaction is considered to be alkyne insertion step. In the catalytic cycle, the C−H bond cleavage step is reversible and earlier than alkyne insertion, and therefore a small KIE could be observed experimentally. Meanwhile, the deprotonation of oxazole 2a with Cu(I) catalyst 14 was also conducted (Figure 4b).21−23,26 Oxazolylcopper intermediate 16 could be generated through this procedure with 9.3 kcal/mol endothermic, and the

oxazolylvinylrhodium species V. The following nucleophilic addition of the oxazolyl toward the double bond of the vinyl moiety would generate metallahydropyrrole complex VI. The final product 3a could be released from complex VI with the assistance of Cu(II) species and concomitant regeneration of active rhodium catalyst I. Alternatively, a competing pathway, following the formation of complex III, is the protonation to afford the side product 3aa and rhodium catalyst I in the presence of acetic acid (Path-B). Computational Method. To further identify the proposed mechanism, density functional theory (DFT) method M11-L24 was employed to investigate this reaction.25 As shown in Figure 4a, the active catalyst 9 is chosen as relative zero for the free energy profiles, which could be generated by the ligand exchange of the additive [Cp*Rh(MeCN)3][SbF6]2. Initially, the metalation−deprotonation of oxazole 2a by rhodium 15729


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Journal of the American Chemical Society Scheme 7. 1,2-Diheteroarylation of Alkynes with Two Different Azolesa

Scheme 10. Control Experiments for the Reaction

a

Scheme 11. Deuterium-Labeling Experiments

Reaction conditions: 1a (0.30 mmol), 2 (0.10 mmol), 2′ (0.10 mmol), [Cp*Rh(MeCN)3][SbF6]2 (10 mol %), Cu(OAc)2 (0.4 mmol), PivOH (0.1 mmol), and DCE (1.0 mL) at 120 °C for 10 h under air. Isolated yields are provided. The yields of 5a−5c were calculated based on 0.1 mmol. The yields of 3a, 3t, 4c, 4h, and 4k were calculated based on 0.05 mmol.

Scheme 8. Synthesis of Highly Substituted Alkenes

Scheme 9. Gram-Scale Reaction of 1a with 2a

which is 9.5 kcal/mol lower than that of 17. In transition state 18-ts, the bond length of C4−Cu is 1.90 Å, which indicates that the Cu−C4 bond has not been broken when the C4−Rh bond is forming. The release of the copper moiety, which could react with diacetoxycuprate to generate acetoxycopper catalyst 14, yields oxazolylrhodium intermediate 21 with 5.4 kcal/mol free energy exothermic.27 Subsequently, the intramolecular nucleophilic addition of the oxazolyl moiety toward the double bond takes place via transition state 22-ts with an activation free energy of 17.7 kcal/mol and concomitant generation of metallahydropyrrole complex 23. In the optimized structure of 23 (Figure 6), the bond lengths of C1−C2 and C2−C3 are 1.37 and 1.50 Å, respectively, which indicates that the CC double transfers to the C1−C2 after nucleophilic addition. The Wiberg bond order of Rh−N and Rh−C3 bonds is 0.52 and 0.46, respectively, which indicates that covalent bonds are present in Rh−N and Rh−C3, and thus the oxidation state of rhodium is +3 in metallahydropyrrole complex 23. Meanwhile, the dihedral angle of C1−C2−C3−C4 is −131.5°, which

corresponding activation free energy is calculated to be 31.2 kcal/mol (via transition state 15-ts). The computational results showed that the C−H bond cleavage of oxazole could be assisted by either rhodium or copper catalyst. As depicted in Figure 5, when the vinylrhodium intermediate 13 and the oxazolylcopper intermediate 16 are formed, the coordination of the nitrogen atom in 16 toward the rhodium in 13 forms dimetallic intermediate 17 with release of a molecular acetonitrile. In this step, the higher relative free energy of intermediate 17 could be attributed to the generation of intermediate 16 being endothermic. Then an oxazolyl-transfer occurs through transition state 18-ts with an activation free energy of 13.7 kcal/mol to generate a copper-involving oxazolylrhodium intermediate 19, the relative free energy of 15730


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Journal of the American Chemical Society

Figure 2. Operando IR experiments (a) of characteristic infrared absorption peak of 1a, (b) of characteristic infrared absorption peak of 2a, (c) of characteristic infrared absorption peak of 3a, (d) of normalized absorbance intensity change of 1a, 2a, and 3a with reaction time, (e) of threedimensional image of absorbance intensity of 2a, (f) of three-dimensional image of absorbance intensity of 3a, (g) of characteristic infrared absorption peak of Cu(OAc)2 and CuOAc, (h) of absorbance intensity change of CuOAc with reaction time, and (i) of absorbance intensity change of 3a with different copper salt components.

Figure 3. Matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF-MS) (a) of IM1 (calcd mass 356.052), (b) of IM2 (calcd mass 534.130), (c) of IM3 (calcd mass 652.159), (d) of IM4 (calcd mass (M + H) 596.167), (e) of IM5 (calcd mass 755.108), and (f) of IM6 (calcd mass (M + H) 537.087) obtained from the reaction of 1a and 2a under standard conditions for 2 h.

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exothermic, in which the final product dissociates from the rhodium with concomitant regeneration of the active catalyst 9. An alternative transmetalation between vinylrhodium and Cu(II) complex to afford vinylcopper species, which was postulated in Cramer’s work,15 was also calculated. As depicted in Figure 8, this transmetalation proceeds via transition state 32-ts with a free energy barrier of 32.6 kcal/mol, leading to the formation of vinylcopper species 33. The relative free energy of the transition state 32-ts is 10.6 kcal/mol higher than that of 18-ts, which indicates that the transmetalation to afford vinylcopper species 33 is kinetically disfavored in this system. Elucidating the origin of trans-selectivity could also enable better understanding of the reaction and determine the wider synthetic applications of this methodology. We also considered the alternative pathway to afford the cis product, and the computational results are summarized in Figure 9. After the formation of intermediate 23, the C2−C3 bond rotation in intermediate 23 occurs via transition state ts-rotation, generating the corresponding cis-isomer 23-cis, with a free energy barrier of only 3.5 kcal/mol. This low free energy barrier suggests that the mutual transformation between intermediate 23 with 23-cis could proceed rapidly. The relative free energy of intermediate 23-cis is 1.8 kcal/mol higher than that of 23, indicating that the trans-isomer exhibits enhanced stability. Subsequent single electron transfer from 23-cis to Cu(OAc)2 leads to a cationic radical intermediate 25-cis with 5.9 kcal/mol endothermic. The relative free energy of intermediate 25-cis is 2.5 kcal/mol higher than that of trans-isomer 25. This energetic discrepancy further indicates that the trans-product would be primarily generated in this system. Finally, the competing pathway leading to the formation of hydroheteroarylated side product has also been considered in this work. As shown in Figure 5, this pathway also starts from vinylrhodium intermediate 13. After ligand exchange, acetic acid coordinated intermediate 27 is formed with endothermic 12.5 kcal/mol in Path-B. The subsequent proton transfer via a six-membered ring type transition state 28-ts affords a sideproduct coordinated intermediate 29 with a free energy barrier

Scheme 12. Proposed Mechanism for Rhodium-Catalyzed trans-Selective C−H Addition/Oxidative Coupling

suggests that a trans product would be formed when the organic moiety is released from the transition metal. The subsequent single electron transfer from 23 to Cu(OAc)2 leads to the generation of a cationic radical intermediate 25 with only 5.2 kcal/mol endothermic. As shown in Figure 7, distribution of spin density in intermediate 25 reveals that the radical mostly locates at the C2 atom and it is stabilized by the conjugative aryls. Moreover, the natural population analysis of 25 shows that the positive charge primarily locates at the C1 atom. With cationic radical intermediate 25 in hand, the second single electron transfer occurs from Cu(OAc)2 with 13.3 kcal/mol

Figure 4. (a) Free energy profiles of the metalation/deprotonation and alkyne insertion steps with rhodium catalyst. (b) Free energy profiles of the deprotonation step with copper catalyst. The values have been given in units of kcal/mol and represent the relative free energies calculated using the M11-L method in DCE solvent. 15732


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Figure 5. Free energy profiles of oxazolyl transfer and nucleophilic addition steps for rhodium-catalyzed trans-selective C−H addition/oxidative coupling. The values have been given in units of kcal/mol and represent the relative free energies calculated using the M11-L method in dichloroethane (DCE).

Figure 6. Geometry information of some selected intermediates and transition states around the free energy profiles. The bond lengths are given in angstroms.

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Figure 7. (a) Spin density distribution and (b) electrostatic potential maps of cationic free radical intermediate 25.

Figure 9. Free energy profiles for the generation of cis-selective C−H addition/oxidative coupling product. The values have been given in units of kcal/mol and represent the relative free energies calculated using the M11-L method in dichloroethane (DCE).

Figure 8. Free energy profile for the transmetalation between vinylrhodium and Cu(II) complex to afford vinylcopper species.

of 10.9 kcal/mol. Because the ligand exchange is 12.5 kcal/mol endothermic, the overall activation free energy of the protonation step is 23.4 kcal/mol, which is 1.6 kcal/mol higher than that of the oxazolyl-transfer step via transition state 18-ts in Path-A. The computational results showed that the generation of diheteroarylated product 3a would be favored in the presence of Cu(OAc)2, which is consistent with the experimental phenomena. Photophysical Properties. With tetra(hetero)arylethylenes in hand, their photophysical properties were studied. These tetra(hetero)arylethylenes exhibit weaker emission properties in solution. Subsequently, we measured the emission spectra of solid powder of representative luminogens. The majority of luminogens emit strong kelly or aurantius light upon photoexcitation. As shown in Figure 10, compared to tetraphenylethylene (TPE) (λem = 444 nm), these luminogens show bathochromic emission maxima at approximately 480−600 nm. Notably, both electron-withdrawing and electron-donating groups on the phenyl or oxazole ring of tetra(hetero)arylethylenes lead to red-shifts in the PL spectra (3m, 3w, 3x, 3ac, 3ad, 4n, and 4v), but the latter can induce more significant bathochromic shifts (See the comparison of 3m, 3ad, and 3x). Heteroarenes have proven well-suited to build material molecules with excellent performance because of their unique π-electron density.28 However, the large majority of examples of tetraarylethylene derivatives with AIE nature are restricted to

Figure 10. Photoluminescence (PL) spectra of representative tetra(hetero)arylethylene products in solid powder.

arene substituents. Thus, the development of novel heteroarene-doped tetraarylethylenes is an appealing issue. To confirm the AIE nature of luminogens developed herein, taking 3e as a representative example, the photoluminescence (PL) spectra of 3e in THF/H2O mixtures with different water fractions (f w) were investigated, as shown in Figure 11. When f w is no more than 60%, the PL emission remains very weak and varies only slightly. Upon increasing the f w value to 62%, an emission peak at 475 nm appears. A further increase of f w leads to a rapid growth of the PL intensity, which indicates that the 15734


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Figure 11. (a) PL spectra of 3e in THF−water mixtures with different water fractions ( f w). (b) Plots of fluorescence intensity vs water fraction in THF/water mixtures. Inset: Fluorescent photographs of 3e in THF/water mixtures ( f w = 0 and 75%), taken under the illumination of a UV lamp. (c) Fluorescence photographs of 3e (1 × 10−5 M) in THF/water mixtures with different fractions of water.

luminogen molecules begin to aggregate. As f w reaches 75%, the PL intensity rises to an approximately maximum value. Since 3e is nearly insoluble in water, the f w value exceeding 75% causes 3e to separate out from the mixture, and the fluorescent intensity becomes gradually weaker. These observations clearly demonstrate the AIE nature of 3e.

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CONCLUSIONS In summary, we have developed a novel rhodium/copper cocatalyzed direct C−H addition/oxidative coupling of internal alkynes with azoles, producing a series of tetra(hetero)arylethylenes in excellent trans-selectivity. This work presents the first use of transition metal-catalyzed C−H activation strategy for the synthesis of acyclic all-carbon tetrasubstituted ethylene via addition of alkyne and exhibits a potential of rhodium catalysis in the construction of stereodefined tetrasubstituted alkenes. With the help of a combination of experimental and theoretical methods, the reaction mechanism for addition/oxidative coupling of internal alkynes with heteroarenes has been explored. DFT calculations show that the metalation/deprotonation of oxazoles could occur with either rhodium or copper compounds. When oxazolylrhodium is formed, alkynes could insert into Rh−C bond. Then another oxazolyl group could transfer to rhodium from oxazolylcopper species. The intramolecular trans-nucleophilic addition forms the second C−C bond. The final product is released by two steps of single electron transfer in the presence of Cu(II). Through the 1,2-diheteroarylation developed herein, a new AIE molecule library has been established. The PL spectra in THF/ water mixtures and in solid powder verify that this type of tetra(hetero)arylethylenes are AIE active. On the basis of the insights afforded in this work, efforts are currently under way for the deep exploration of photophysical properties and application of the new-type AIE molecules.

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Detailed information on experimental procedures, characterization data, photophysical data, computational calculations, and crystallographic and spectroscopic data (PDF) X-ray crystal structures of 3a (CCDC-1528765) (CIF) X-ray crystal structures of 3aa (CCDC-1528766) (CIF) checkCIF/PLATON report for 3a (PDF) checkCIF/PLATON report for 3aa (PDF)

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Yu Lan: 0000-0002-2328-0020 Jingsong You: 0000-0002-0493-2388 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the National NSF of China (No 21432005 and 21372266) for financial support. REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b07242. 15735


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Ong, T.-G. Org. Lett. 2014, 16, 4826. Co catalyst, see: (k) Ding, Z.; Yoshikai, N. Org. Lett. 2010, 12, 4180. (15) Pham, M. V.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 14575. (16) Lee, J. T. D.; Zhao, Y. Angew. Chem., Int. Ed. 2016, 55, 13872. (17) Zhu, M.; Yang, C. Chem. Soc. Rev. 2013, 42, 4963. (18) While a small amount of 2,2′-bibenzo[d]oxazole was formed under the H/D exchange reactions in the absence of alkyne, the homocoupled product was not observed under the standard reaction conditions. (19) Li, Y.; Liu, S.; Qi, Z.; Qi, X.; Li, X.; Lan, Y. Chem. - Eur. J. 2015, 21, 10131. (20) The Cu-to-Rh transmetalation pathway is proposed in precedent reports. See: (a) Too, P. C.; Chua, S. H.; Wong, S. H.; Chiba, S. J. Org. Chem. 2011, 76, 6159. (b) Chiba, S. Chem. Lett. 2012, 41, 1554. (c) Song, C.; Wang, J.; Xu, Z. Org. Biomol. Chem. 2014, 12, 5802. For azolylcopper(I) species to azolylpalladium(II) species, see refs 22c and 23a. (21) For the disproportionation of Cu(II), see: (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044. (b) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068. (22) Although both Cu(I) and Cu(II) have been employed as catalyst for the C−H functionalization of azole, given the Operando IR experiments and DFT calculations, the oxazolylcopper(I) intermediate 16 is more reasonable in this transformation. Considering that the oxazolylcopper(II) species are also proposed in precedent reports, the oxazolylcopper(II) species cannot be excluded thoroughly at the present stage. For selected examples of copper(I) salts as the catalyst in direct arylation of azoles, see: (a) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (b) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (c) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674. (d) Zhu, M.; Fujita, K.; Yamaguchi, R. Chem. Commun. 2011, 47, 12876. For selected examples of copper(II) salts as the catalyst in direct arylation of azoles, see: (e) Li, Y.; Jin, J.; Qian, W.; Bao, W. Org. Biomol. Chem. 2010, 8, 326. (f) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2011, 133, 2160. (g) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 6993. (h) Qin, X.; Feng, B.; Dong, J.; Li, X.; Xue, Y.; Lan, J.; You, J. J. Org. Chem. 2012, 77, 7677. (i) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, 4457. (j) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2014, 53, 10784. (23) In our previous works on Pd/Cu cocatalyzed C−H heteroarylation of azoles, while both Cu(I) and Cu(II) species were added, the Cu(I) species was proposed as the cocatalyst together with Pd. See: (a) Liu, B.; Qin, X.; Li, K.; Li, X.; Guo, Q.; Lan, J.; You, J. Chem. - Eur. J. 2010, 16, 11836. (b) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365. (24) (a) Peverati, R.; Truhlar, D. G. Phys. Chem. Chem. Phys. 2012, 14, 16187. (b) Peverati, R.; Truhlar, D. G. J. Phys. Chem. Lett. 2012, 3, 117. (c) Zhu, L.; Qi, X.; Lan, Y. Organometallics 2016, 35, 771. (25) For more computational details, please see Supporting Information. (26) (a) Bai, R.; Zhang, G.; Yi, H.; Huang, Z.; Qi, X.; Liu, C.; Miller, J. T.; Kropf, A. J.; Bunel, E. E.; Lan, Y.; Lei, A. J. Am. Chem. Soc. 2014, 136, 16760. (b) Qi, X.; Bai, R.; Zhu, L.; Jin, R.; Lei, A.; Lan, Y. J. Org. Chem. 2016, 81, 1654. (27) We also considered the oxazolyl transfer via a cyclic transition state. However, we could not locate a cyclic transition state such as 34ts after many attempts. However, the related intermediate 35 linking that cyclic transition state was optimized, which is 6.9 kcal/mol more endergonic than intermediate 17. This result indicates that the dissociation of N atom to destroy the five-membered chelated skeleton is thermodynamically unfavorable. 15736


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