Suzuki-Miyaura Coupling Enabled by Aryl to Vinyl 1,4-Palladium Migration.

The Suzuki-Miyaura coupling is a fundamentally important transformation in modern organic synthesis. The development of new reaction modes for new chemical accessibility and higher synthetic efficiency is still the consistent pursuance in this field. An efficient Suzuki-Miyaura coupling enabled by a controllable 1,4-palladium migration was realized to afford stereodefined multisubstituted olefins and 1,3-dienes. The reaction exhibits remarkable broad substrate scope, excellent functional-group tolerance, versatile conversion with obtained products, and easy scalability. The practicality of this method is highlighted by the aggregation-induced emission feature of the produced olefins and 1,3-dienes, as well as the capability of affording geometric isomer pairs with a marked difference on photoluminescent quantum yield values.

Introduction

Since the introduction of the Suzuki-Miyaura coupling in 1979 (Miyaura et al., 1979), this Nobel Prize winning chemistry has developed into one of the most synthetically valuable processes for the construction of carbon-carbon bonds and been widely applied in both academia and industry (Beletskaya et al., 2019, Maluenda and Navarro, 2015, Miyaura and Suzuki, 1995). For example, according to statistics, over 60% of the carbon-carbon bond-forming processes in medicinal chemistry now are accomplished through this reaction (Schneider et al., 2016). Despite brilliant achievements, the continuing efforts for broader reaction scope and higher efficiency have never ceased.

Mechanistically, this reaction is initiated by the generation of a key organopalladium(II) intermediate, normally a result of direct oxidative addition of palladium(0) to a carbon-heteroatom bond. Later, direct C-H bond activation by palladium(II) becomes a second important route (Chen et al., 2006, Giri et al., 2007, Shi et al., 2007, Wang et al., 2008, Yang et al., 2008). Compared with these direct generation modes, the organopalladium(II) intermediate can also be produced via an indirect manner, which has been far less developed and mainly focused on the generation via a migratory insertion of organopalladium to olefins (Grigg et al., 1997, Schempp et al., 2017, Zhang et al., 2019) or alkynes (Couty et al., 2004, Monks and Cook, 2012) (Figure 1A).

Figure 1

Suzuki-Miyaura Coupling Enabled by Aryl to Vinyl 1,4-Palladium Migration

(A) Two Suzuki-Miyaura coupling modes.

(B) Aryl to vinyl 1,4-palladium migration/Suzuki-Miyaura coupling sequence.

(C) Possible applications in material science.

Palladium migration, which can relay the palladium from the original place to a remote position, is a novel strategy for the indirect generation of the desired palladium(II) intermediate and has been applied in several efficient organic transformations (Ma and Gu, 2005, Shi and Larock, 2010, Rahim et al., 2019). Early attempts to execute Suzuki-Miyaura coupling via palladium migration were made, but only limited success has been achieved.

Buchwald and co-workers realized a Suzuki-Miyaura coupling through a complete aryl to alky 1,4-palladium migration (Barder et al., 2005). However, only a single arylbromide with two neighboring positions blocked by tert-butyl groups was tested. Later, Larock and co-workers tried Suzuki-Miyaura coupling via aryl to aryl 1,4-palladium migration and found it was hard to control this migration process efficiently (Campo et al., 2007). Usually, a significant amount of non-migrated product was generated. Therefore, Suzuki-Miyaura coupling enabled by controllable palladium migration, further expanding this important transformation and affording new chemical accessibility, is highly desirable. As a continuing effort on developing reactions via palladium migration (Hu et al., 2016, Hu et al., 2018), herein we present the first Suzuki-Miyaura coupling enabled by aryl to vinyl 1,4-palladium migration (Figure 1B), which offered an efficient way to synthesize stereodefined, multisubstituted olefins (Gao et al., 2010, Wang, 2012, Wencel-Delord et al., 2012, Zhang et al., 2016a, Li et al., 2017, Li and Duan, 2018, Lin et al., 2019) and 1,3-dienes (Besset et al., 2011, Boultadakis-Arapinis et al., 2014, De Paolis et al., 2012, Hu et al., 2015, Liang et al., 2017, Liu et al., 2019, Šiaučiulis et al., 2019). Notably, multi-aryl substituted olefins and 1,3-dienes may display interesting electronic and photonic properties owing to their π-extended systems and have been widely applied in many diverse fields, such as chemical or biological sensors, stimuli response material, and fluorescent materials (Figure 1C) (Kong et al., 2018, Yang et al., 2014, He et al., 2019). Despite the fact that the geometry of double bonds in these molecules has great influence on the material performance, effective synthetic approaches toward these structures remain to be limited, in which the application of symmetric starting material or a homo-coupling reaction is often necessary to overcome the geometric problem (Xie and Li, 2019, Zhang et al., 2016b).

Results and Discussion

Reaction Conditions Development

We began our investigation by studying the coupling of ortho-vinyl bromobenzene 1a and various phenylboron reagents 2a, and some representative results are listed in Scheme 1. With phenylboronic acid 2a as the coupling partner, the expected triphenyl substituted olefin 3aa was obtained in 56% reaction yield, but a significant amount of the direct coupling product 4aa was formed, along with some side products from the dimerization of 1a (entry 1). Screening of ligands, solvents, or bases failed to improve the migration efficiency. We speculated that the arylboron reagent should have its reactivity in a reasonable zone (Lennox and Lloyd-Jones, 2014, Tobisu and Chatani, 2009), allowing for the completion of the palladium migration process prior to the subsequent coupling step, meantime keeping a faster Suzuki-Miyaura coupling with the generated alkenylpalladium species over the self-Heck reaction. Therefore, a variety of other organoboron types were evaluated (entries 2–9), including triphenylboroxine (2a), potassium trifluoroborate salt (2a), and different boronate esters (2a-2a). Triphenylboroxine 2a gave a comparable result, but the coupling reaction was almost shut down with potassium trifluoroborate 2a where the dimerization of 1a became the major reaction pathway. Pinacol boronate ester 2a gave excellent regioselectivity (3aa/4aa = 97:3) albeit in a low reaction yield, possibly due to its low reactivity. Slightly more reactive boronate esters with less sterically hindered protection could improve reaction yields with maintained high regioselectivities. However, catechol boronate ester 2a was too reactive, thus affording the direct coupling product 4aa as the major product. Six-membered boronate esters (2a and 2a) could also give product 3aa in moderate yields and with high regioselectivities but failed to offer better results compared with the best five-membered one 2a.

Scheme 1

Reaction Conditions Optimization

aAll reactions were conducted with 1a (1.0 equiv, 0.2 mmol), phenylboron 2 (3.0 equiv, 0.6 mmol), Pd(OAc)2 (5 mol %), L1-L6 (10 mol %), or L7-L8 (5 mol %) and base (2.0 equiv, 0.4 mmol) in THF (2.0 mL) at 110°C for 3 h. bDetermined by GC analysis using dodecane as an internal standard.

With boronate ester 2a as the coupling partner, further screening of different ligands (entries 10–16, and Table S1 for details) was carried out. Slight modifications by removing o-MeO substituents (L2), replacing them with Me substituents (L3), or moving them to the other positions (L4 and L5) led to a sever loss of catalyst activity, as well as the capability to control regioselectivity, further demonstrating the important beneficial effect enabled by the hemilabile o-MeO coordination (Wakioka et al., 2014). Other types of ligands could not improve this transformation, either. Bulky electron-rich dialkylbiaryl phosphine L6 gave a higher regioselectivity but a reduced yield of 3aa. The open-chain bisphosphine ligands (L7 and L8) afforded low yield of 3aa and poor regioselectivity. Base also played an important role in this reaction. Both yield of 3aa and regioselectivity were further enhanced by switching CsOAc to CsOPiv (entry 18, and Table S2 for details). A more thorough list of variable screening is given in the Supplemental Information (Tables S1–S3).

Substrate Scope

Synthesis of Trisubstituted Olefins

With the optimal reaction conditions identified, the generality of this reaction was then investigated. First, the coupling of various ortho-vinyl aromatic bromides 1 with aryl boronate esters 2a was carried out (Scheme 2). In general, very good reaction yields were observed for the substrates bearing substituents with different electronic and steric properties at the phenyl ring A. Replacement of the phenyl ring with a naphthyl (3ia) or pyridyl (3ja) group was also well accommodated. It is worth mentioning that the possible coordination of pyridine moiety with palladium catalyst did not affect this catalytic process, and an excellent reaction yield of 3ja (91%) was achieved.

Scheme 2

Coupling of ortho-Vinyl Aromatic Bromides with Aryl Boronate Esters

All reactions were conducted with substrate 1 (1.0 equiv, 0.3 mmol), phenylboronate ester 2a (3.0 equiv, 0.9 mmol), Pd(OAc)2 (5 mol %), L1 (10 mol %), and CsOPiv (2.0 equiv, 0.6 mmol) in THF (3 mL) at 110°C for 3 h.

Variation of the phenyl ring B was also examined. Methyl substitution at different positions of the phenyl ring was tested to explore the spatial effect on this reaction. Ortho-methyl substitution gave the best reaction yield, suggesting the steric hindrance from this methyl group prohibited the potential dimerization of 1. Electronic effect at this phenyl ring B was also evaluated with different substitutions installed to its para-position, and the electron-withdrawing groups showed a beneficial effect on the reaction. When the phenyl ring B was replaced by naphthyl group, sterically more hindered 1-naphthyl (3ta) substitution showed a higher reaction yield than 2-naphthyl (3sa) one, which was consistent with the above observations. Switching the phenyl group to heteroaromatic rings, like substituted pyridyl (3ua) and 2-thienyl (3va) groups, was also compatible for this reaction, giving 92% and 67% reaction yields, respectively. The aryl ring can also be replaced by alkyl (3wa and 3xa), cyano (3ya), and ester (3za) groups, affording the products in high reaction yields.

Next, the scope of arylboronates was examined. When ortho-methyl phenylboronate ester was applied, the reaction yield decreased a little to 60% due to steric effect (3ab). However, more sterically congested 2,6-dimethyl one could still offer a decent yield of 3ac (44%). Good to excellent reaction yields were obtained with boronate esters bearing an electron-withdrawing or electron-donating substitution at its para-position of the phenyl ring. Chemically reactive functional groups, such as aldehyde (3al), ketone (3am), and ester (3an), were well tolerated. Free amino group (3ao) and thioether (3ap), which can frequently deactivate palladium catalyst owing to their strong coordination with palladium, were also compatible. In search for wide application of our palladium-catalyzed transformation in material science, the examples with Cl (3aq) and TMS (3ar) substitutions offered useful handles for their future incorporation to functional material molecules (Siamaki et al., 2011, Carsten et al., 2011).

The introduction of polycyclic aromatic moiety to a molecule can quickly expand the existing π-extended system, which is often of great importance for enhanced electronic and photonic performance (Itami et al., 2005). Therefore, a variety of aryl boronate esters bearing commonly used polycyclic aromatic rings (Scheme 3), including naphthyl (6aa, 6ab), phenanthryl (6ac), anthryl (6ad), triphenylenyl (6ae), and pyrenyl (6af) groups, were examined in the coupling with ortho-vinyl bromobenzene 1a. All reactions proceeded quite well with good to excellent isolated yields. The structure of 6af was further confirmed by X-ray crystallography.

Scheme 3

Coupling of ortho-Vinyl Bromobenzene 1a with Polycyclic Aromatic and Heteroaryl Boronate Esters

All reactions were conducted with substrate 1a (1.0 equiv, 0.3 mmol), (hetero)arylboronate 5 (3.0 equiv, 0.9 mmol), Pd(OAc)2 (5 mol %), P(2-MeO-Ph)3 (10 mol %), and CsOPiv (2.0 equiv, 0.6 mmol) in THF (3 mL) at 110°C for 3 h (unless otherwise noted). aPinacol esters were used instead of glycol ester.

Heteroaromatic rings are another family of substructures with wide existence in material molecules (Li et al., 2010). Although the coupling with heteroarylboron reagents is a straightforward way to install these important subunits, the strong coordinating capability of hetero atoms to palladium center may raise potential concerns (Billingsley et al., 2006, Billingsley and Buchwald, 2007). To our delight, a wide range of heteroaromatic rings (Scheme 3), including furyl (6ag), benzofuryl (6ah), thienyl (6ai, 6aj), benzothiophenyl (6ak), thieno[3,2-b]thienyl (6al), pyridyl (6am), pyrazolyl (6an), quinolyl (6ao), indolyl (6ap), pyrimidyl (6aq), and carbazolyl (6ar), were successfully assembled in good to excellent yields, further demonstrating the potential of this method for material science.

Synthesis of Multisubstituted 1,3-Dienes

Encouraged by the above success in preparing trisubstituted olefins, we envision that the coupling reaction with arylethenyl boron reagents would lead to the generation of stereodefined multisubstituted 1,3-dienes. A number of arylethenyl boron reagents are commercially available, and several stereoselective synthetic methods were developed, which laid a firm base for this strategy (Yoshii et al., 2019). The optimized conditions used in the above coupling with arylboronate esters were also suitable for the arylethenyl boron esters. Further screening of the reaction conditions led to the use of boronate pinacol ester as the best choice. In addition, the reaction could go to completion with a decreased catalyst loading (2.5 mol %), a lower reaction temperature (70°C), and a shorter reaction time (1 h).

By employing the above newly optimized reactions, the reaction scope was examined (Scheme 4). Unlike the reactions with arylboronate esters, variation on ortho-vinyl arylbromides 1 showed marginal effect on the couplings with phenylethenyl boronate pinacol ester. Excellent yields were achieved in all cases when substitutions with different steric and electronic profiles were introduced to either phenyl ring A or B. Replacement of phenyl ring B with 1-naphthenyl (8ta), 2-naphthenyl (8sa), or 2-thienyl (8va) group still maintained high reaction yield.

Scheme 4

Coupling of ortho-Vinyl Aromatic Bromides with Alkenylboronate Esters

All reactions were conducted with substrate 1 (1.0 equiv, 0.3 mmol), arylethenyl boronate ester 7 (2.0 equiv, 0.6 mmol), Pd(OAc)2 (2.5 mol %), L1 (5 mol %), and CsOPiv (2.0 equiv, 0.6 mmol) in THF (3 mL) at 70°C.

A variety of E-arylethenyl boronates with different substitutions at the para-position of the phenyl ring were evaluated. Both electron-withdrawing and -donating groups gave the desired (E)-1,3-dienes in excellent yields (8ab–8af). (Z)-phenylethenyl boronate pinacol ester led to (Z)-1,3-diene as the predominant product (8ag), along with some (E)-1,3-diene due to the partial isomerization of its double bond during the reaction process. Aryl substitutions can also be replaced by various alkyl groups (8ah and 8ai), and slightly lower yields were observed with sterically more hindered cyclic alkenyl boronates (8aj-8al). The use of β,β-diaryl-substituted vinyl boronates can potentially generate stereodefined tetra-aryl substituted 1,3-dienes. Therefore, several stereodefined vinyl boronates, which were prepared according to our previous results (Hu et al., 2016), were applied in this transformation. Despite slightly decreased yields, likely due to the increased steric hindrance, the desired tetra-aryl substituted 1,3-dienes were produced in geometrically pure form (8qm, 8em, 8qn, and 8en), overcoming the synthetic challenges in the preparation of such single stereoisomers by traditional methods. The stereochemistry of the obtained products was further confirmed by the X-ray crystallography of diene 8ka.

Transformation of the Products and Gram Scale Synthesis

To demonstrate the practicality of this method, we illustrated some chemical transformations of the produced trisubstituted olefins, providing potentials to embody these subunits to the designed material molecules (Scheme 5A). The chloride in olefin 3aq offered a handle for versatile derivatization using palladium-catalyzed coupling reactions, like Miyaura borylation with (Bpin)2 and Suzuki-Miyaura coupling with aryl- or alkenylboronates, which are widely used transformations in material science (Yu et al., 2017, Li et al., 2018, Wang et al., 2020). The CHO group also offers potential use in versatile functionalization. The aldehyde 3al could be converted to diaminomaleonitrile-modified olefin 9d (Huang et al., 2017). Such a special imine derivative displayed photo- and mechano-responsive properties, further expanding the application of this method in the field of multi-responsive material. In addition, the compounds 9e and 9f with triphenylethylene skeleton, a kind of donor-π-acceptor fluorophores with color-tunable aggregation-induced emission (AIE) behaviors (Wen et al., 2016), were prepared from aldehyde 3al through Knoevenagel condensation and HWE olefination reaction, respectively. All these high-yielding transformations provide infinite potentials in commercial application for full-color displays.

Scheme 5

Practicality Demonstrations

(A) Transformations of the obtained products.

(B) Gram-scale reactions.

The scalability of the reaction was also investigated with two representative examples (Scheme 5B). The coupling of ortho-vinyl bromobenzene 1a with arylboronate 2j produced the desired olefin 3ak in excellent yield (92%), similar to the small trial. It is also the case for the coupling of ortho-vinyl bromobenzene 1A with phenylethenylboronate 7a.

Proposed Reaction Mechanism

Although the mechanism of this reaction is not clear at this stage, a tentative catalytic cycle is proposed in Scheme 6. Initial oxidative addition of arylbromide to palladium(0) generates the intermediate II (step A), which may exchange its bromide anion with PivO− (step B) to facilitate the following C-H activation step (step C). Instead of a second oxidative addition to form a palladium(IV) species, theoretical studies have revealed that a concerted metalation-deprotonation (CMD) mechanism would be energetically favored, in which carboxylates were often needed to act as an inner base (Cheng et al., 2014, Gorelsky et al., 2008). The generated five-membered palladacycle IV undergoes a formal proton transfer to render a net 1,4-palladium shift from the aryl to alkenyl position (step D) and then proceeds through the following Suzuki coupling sequences to afford the desired product VII (step E and F).

Scheme 6

Plausible Catalytic Cycle

Application in Aggregation-Induced Emission Materials

AIE Characteristics

To shed light on the potential application of our methodology in material science, some obtained products with rotatable aryl rings were subjected to the AIE properties test according to the restriction of intramolecular motion (Mei et al., 2014, Mei et al., 2015). Since the first report by Tang and co-workers in 2001, AIE concept and phenomenon have attracted considerable research attention and created a variety of potential applications in various fields (Luo et al., 2001, An et al., 2002). Several AIE systems have been elaborately designed and well studied, where multi-aryl-substituted olefins and 1,3-dienes represent two of the most effective structures (Kong et al., 2018, Yang et al., 2014, He et al., 2019).

Some of the obtained products exhibited a distinct AIE effect. Non-emission was observed in dilute solutions, whereas the solid states gave strong emission. To further confirm the AIE feature of these compounds, the photoluminescence (PL) was studied in THF and THF/water mixtures with varying water fractions (fw). As shown in Figure 2, olefin 6af was negligibly emissive in dilute THF solution. However, the PL intensity was greatly enhanced in THF/water mixtures with fw >70%, probably due to the formation of nanoaggregate, exhibiting typical AIE characteristics. Notably, the luminescence intensity achieved a maximum at 469 nm when water fraction reached 90%. 1,3-Dienes also showed similar AIE behavior. The fluorescence intensity of 8na was about 5.0-fold higher in THF/water mixtures with fw >90% than in pure THF.

Figure 2

AIE Activity of Products

(A) PL spectra of 6af in THF/water mixtures with different water fractions.

(B) Plots of relative PL intensity versus the composition of THF/water mixtures of 6af.

(C) PL spectra of 8na in THF/water mixtures with different water fractions.

(D) Plots of relative PL intensity versus the composition of THF/water mixtures of 8na.

PL Quantum Yields of Geometric Isomers

It is well known that structurally similar geometric isomers may exhibit different AIE properties. However, the accessibility of all corresponding isomers in pure form restricted such systematic studies.

Our new method allowed for the convenient generation of various pure geometric isomers, and several pairs of multi-aryl substituted olefins and 1,3-dienes were prepared. Figure 3 listed the PL quantum yields (PLQY, ΦF) of these geometric isomers in solid states (for further details, see Table S4). E-TriPE-F (3na) and E-TriPE-Me (3ma) showed higher ΦF (12.0% and 20.8%, respectively) than those of Z-TriPE-F (3ga, ΦF = 0.1%) and Z-TriPE-Me (3ca, ΦF = 0.1%). These results suggest that rigidification of the E-isomers is higher than that of Z-ones (Mei et al., 2014). Similar phenomena were also observed for 1,3-dienes. Compared with 3Z-TPBDE (8ag, ΦF = 3.1%) and 1Z-TPBDE-F (8ga, ΦF = 12.0%), 3E-TPBDE (8aa, ΦF = 23.0%) and 1E-TPBDE-F (8na, ΦF = 41.5%) exhibited significantly enhanced ΦF. These results indicated that the geometry of double bond significantly affects the photophysical properties in solid state. Therefore, our synthetic methodology provided a powerful tool for the discovery of advanced material through precise control of the double bond geometry.

Figure 3

Comparison of PL Quantum Yields of Geometric Isomers

Conclusion

We have developed an efficient Suzuki-Miyaura coupling through a controllable 1,4-palladium migration process for the stereospecific synthesis of multisubstituted olefins and 1,3-dienes. A precise reactivity balance of the used organoboronates played a vital role in this process. The practicality of this method was demonstrated by the excellent capability and flexibility in stereochemical control, broad substrate scope, excellent functional group tolerance, as well as versatile conversion with obtained products and easy scalability. The power of this method is also highlighted by the AIE feature studies of some obtained products. Several pairs of pure geometrical isomers were prepared and showed significant differences in photoluminescent quantum yield values.

Limitations of the Study

All ortho-vinyl aromatic bromides used in the current 1,4-palladium migration/Suzuki-Miyaura coupling sequence were terminal alkenes. Effort to use trisubstituted olefins as starting material is unsuccessful, and only a trace amount of desired product can be observed.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.