Switchable Catalysts Used to Control Suzuki Cross–Coupling and Aza

As we envisaged, the switchable bifunctional catalysts are able to manipulate catalytic cascade sequences for the Suzuki cross–coupling/asymmetric t...
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Switchable Catalysts Used to Control Suzuki Cross–Coupling and Aza– Michael Addition/Asymmetric Transfer Hydrogenation Cascade Reactions Jingjing Meng, Fengwei Chang, Yanchao Su, Rui Liu, Tanyu Cheng, and Guohua Liu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01593 • Publication Date (Web): 12 Aug 2019 Downloaded from pubs.acs.org on August 12, 2019

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Switchable Catalysts Used to Control Suzuki Cross–Coupling and Aza–Michael Addition/Asymmetric Transfer Hydrogenation Cascade Reactions Jingjing Meng, Fengwei Chang, Yanchao Su, Rui Liu, Tanyu Cheng, and Guohua Liu* Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai, 200234, PR China. E–mail: [email protected]. ABSTRACT: The development of a switchable strategy to control the catalytic action of dual active species is of great significance toward the precise manipulation of a cascade reaction. Herein, by combining water–soluble thermoresponsive polymer and hollow–shell–structured mesoporous silica as an OH integrated support, we develop a kind of switchable–type OH Ar3 supported molecule catalysts by tethering the achiral organic 1 2 N Ar Ar H functionality in the outer polymer–coating layers and 13 samples, 21 samples, anchoring the chiral ruthenium/diamine functionality in the up to 97% ee up to 97% ee inner mesoporous silica’s nanochannels. As presented in this 15 oC 35 oC study, the created on and off modes of water–soluble O O thermoresponsive polymer–coating layers on the external 60 oC 15 oC I + Ar1B(OH)2 Ar3NH2 + surface of silica shell can open and close the entrances of the Ar2 nanochannels, thereby selectively initiating or terminating the catalytic action of the chiral ruthenium/diamine species within the nanochannels. As we envisaged, the switchable bifunctional catalysts are able to manipulate catalytic cascade sequences for the Suzuki cross–coupling/asymmetric transfer hydrogenation of iodoacetophenones and aryl boronic acid, and the aza–Michael addition/asymmetric transfer hydrogenation of enones and arylamines. KEYWORDS. Asymmetric catalysis, heterogeneous catalyst, immobilization, mesoporous material, silica.

INTRODUCTION Over the past few decades, the fabrication of supported molecule catalysts with two active centers for use in cascade reactions has attracted extensive research interest due to the compatible benefit of eliminating any negative interactions between the dual catalytic species. These kinds of bifunctional catalysts not only overcome the incompatible bottleneck of homogeneous co– catalyst systems but also lead to the enhanced reactivity and selectivity in a variety of cascade reactions.[1] Despite the great achievements made toward the constructions of these supported molecule catalysts reported to date, the main strategies used to control the dual species are arbitrarily divided into two types: i) adjacent-type and ii) isolated-type supported molecule catalysts (Figure 1A).[2] Traditionally, the construction of adjacent–type supported molecule catalysts (Figure 1A1) is a commonly used strategy, where two species are located at adjacent positions. The outstanding advantage of this strategy is attributed to their synergistic catalytic actions, where the dual species enable cooperative catalysis to enhance the reactivity of cascade reactions.[3] The construction of isolated–type supported molecule catalysts (Figure 1A2), referred to

catalytically active site–isolated catalysts, is a special strategy, where the two species are completely separated. The impressive benefit of this strategy is that it can efficiently eliminate the negative interactions of dual species to some content, allowing some incompatible cascade reactions under a homogeneous co–catalyst system to be carried out with improved catalytic efficiency.[4] A: Fabrication of supported molecule catalysts with species I and II in previous reports (1)

I

(2)

II

I

II

Isolated-type dual species

Adjacent-type dual species

B: Fabrication of supported molecule catalysts with species I and II in this work (2)

(1)

I

II

Reversible response Reaction temperature

Switching-type dual species

Species I and II = organometals = Thermoresponsive polymer

Supported molecule catalyst

FIGURE 1. (A) Fabrication of supported molecule catalysts

with species I and II in previous works: (1) Adjacent–type dual species and (2) Isolated–type dual species. (B) Fabrication of supported molecule catalysts with species I

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and II in this work: (1) Switching–type dual species and (2) Schematic illustration of a representative example in the fabrication of supported molecule catalysts via a reversible response to the reaction temperature. Although two strategies have been extensively used in the construction of supported molecule catalysts, a key problem of both strategies is that they lack a switchable ability to adjust the catalytic actions of the dual active species. For example, a yolk–shell-mesostructured, isolated–type supported bifunctional catalyst with the basic amine species (-NH2) in the silica yolk and acidic sulfonic acid species (-SO3H) in the silica shell has been shown as an efficient catalytic system in the one-pot deacetalization-Henry cascade reaction.[4c] However, this catalyst is impossible to solely manipulate one of their catalytic actions because both the basic amine and acidic sulfonic acid species simultaneously catalyze the substrates. Therefore, the exploration of a switching– type supported molecule catalyst is of great fundamental and practical interest, which not only selectively initiates/prohibits single catalytic action of the two species to control the reaction process, but also possesses an extended advantage of isolated–type catalysts to eliminate the negative interactions at the most extent. More importantly, the approach used in this study also offers a new strategy to make up for the methodological deficiency observed in the construction of supported molecule catalysts. Through the use of mesoporous silicas[5] and water– soluble polymers[6] as single–type supports, some well– established adjacent–type and isolated–type supported molecule catalysts have been successfully used in a variety of cascade reactions. The notable benefits of mesoporous silica–supported bifunctional catalysts are attributed to the ordered mesoporous channels and high mechanical stability, where the explored synergistic effects of adjacent–type dual species and site-isolated effects of isolated–type dual species have led to some enhanced reactivity and enantioselectivity.[7] The main advantages of water–soluble polymer–supported bifunctional catalysts derive from the general well– solubility in water, where the adjacent–type and isolated–type supported molecule catalysts greatly promote reactivity due to the mimicking a homo–like catalytic environment.[8] However, both have obvious limitations because of the single–type support itself,[9] where rigid silica–supported catalysts often present a decreased reaction rate due to the diffused shortcoming of mass transfer, whereas flexible polymer–supported catalysts generally provide a decreased enantioselectivity owing to the flexible nature imported in the chiral environment of active centers. In particular, during an enantioselective cascade reaction, the obligatory demand for the chiral catalytic environment is subtle because it is quite difficult for the dual species in the single-type support to differentiate between the two possible enantiomers formed in the reaction, which

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forms more intermediates due to complicated interactions observed among the active species and intermediates. Thus, the combination of the hollow– shell–structured mesoporous silica and water–soluble thermoresponsive polymer as an integrated support to form a switching–type supported molecule catalyst is highly desirable. This integrated immobilization method not only balances both benefits by exploiting their respective advantages and eliminating these drawbacks but also enhances the reactivity and enantioselectivity by overcoming the incompatible disadvantage of the dual species. As shown in Figure 1B, we propose a switchable strategy to selectively control the catalytic actions of dual active species in the formation of a switching–type supported molecule catalyst. The unique feature lies in the fact that species II is switchable in the dotted frame of Figure 1B1, where the single catalytic action of species II can be triggered/prohibited based on a designed aim. In this case, a representative switching–type supported molecule catalyst is constructed by integrating active species I (green color) in the outer water–soluble thermoresponsive polymer–coating layer[10] and active species II (pink color) in the inner hollow–shell– structured silica’s nanochannels[11] as shown in Figure 1B2. This switching–type catalyst has a reversible response to the reaction temperature, in which the unfolded and folded behavior of the outer water–soluble thermoresponsive polymer–coating layer can open and close the entrances of the nanochannels to create an expected on and off mode. In this contribution, we employ a chiral organoruthenium–functionality as active species II and an organopalladium or organoamide as active species I to construct two switching–type supported molecule catalysts. As we designed, both catalysts possess the general advantages of rigid mesoporous silica to maintain a chiral environment for high enantioselectivity and of flexible polymer to promote mass transfer for high reactivity. More importantly, this switching function via a reversible on and off mode to reaction temperature can initiate the single catalytic action of active species I in the off mode, and subsequently cooperates with the catalytic action of active species II for continue relaycatalysis in the on mode. This reversible function not only simplifies a complicated two-step catalysis system into a simple single-step catalysis system, it is also beneficial for a determinable catalytic sequence, which is infeasible when using adjacent-type or isolated-type catalysts. As presented in this study, both switching– type catalysts are able to manipulate a cascade reaction process through a determinable catalytic sequence in the Suzuki cross–coupling/asymmetric transfer hydrogenation (ATH) and the Michael addition/ATH cascade reactions, affording various optically pure products in high yields and enantioselectivities.

EXPERIMENTAL SECTION

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Preparation of Vinyl@ArDPEN@HS (1) and Vinyl@Ru@HS (2). In a typical synthetic route, to a solution of 0.10 g (0.27 mmol) of cetyltrimethylammonium bromide (CTAB) in 45.0 mL of aqueous sodium hydroxide (0.35 mL, 2.0 N) was added 0.43 g of (2.07 mmol) of tetraethoxysilane (TEOS) and 0.40 mL of ethyl acetate, and the mixture was stirred at 80 °C for 2 h. After cooling the above mixture down to 38 °C, an aqueous solution (80.0 mL of water, 50.0 mL of ethanol, 0.30 g (0.82 mmol) of CTAB and 1.0 mL (25 wt%) of NH3·H2O) was added, and the mixture was stirred 38 °C for another 0.5 h. Subsequently, 0.5 mL, 0.47 g (2.26 mmol) of TEOS was added and the mixture was stirred at 38 °C for another 2 h. For coating of above SiO2, to this solution was added an solution (0.04 g (0.044 mmol) of FC–4 (FC–4: [C3F7O(CF(CF3)CF2O)2CF(CF3)CONH(CH2)3N+(C2H5)2CH3] I−), 0.08 g (0.22 mmol) of CTAB and 0.20 mL (25 wt%) of NH3·H2O in 3.0 mL of water), and the mixture was stirred at 38 °C for 0.5 h. Then, 0.89 g (2.50 mmol) of 1,2– bis(triethoxysilyl)ethane and 0.125 g (0.25 mmol) of ArDPEN–siloxane in 2 mL of ethanol (2 min later) was added subsequently, and the mixture was stirred under vigorous stirring for another 1.5 h. Finally, after cooling the above mixture down to room temperature, the resulting solid was collected by filtration. For the postgrafting of triethoxy(vinyl)silane, the collected solids (1.0 g) were suspended in 25.0 mL of dry toluene and 0.95 g (4.52 mmol) of triethoxy(vinyl)silane in 2 mL of dry toluene triethoxy(vinyl)silane was added, and mixture was stirred overnight at room temperature. After that, the mixture was transferred to a Teflon–lined autoclave at 100 °C for 20 h to form hollow–shell structured mesoporous nanoparticles. To remove the surfactant, the collected solids were dispersed in 120 mL of solution (80 mg (1.0 mmol) of ammonium nitrate in 120 mL (95%) of ethanol), and the mixture was stirred at 60 °C for 10 h. After cooling the above mixture down to room temperature, the solid was filtered and washed with excess water and ethanol, and dried at ambient temperature under vacuum overnight to afford 1 as a white powder (0.85 g). The collected 0.50 g of 1 was suspended in 20.0 mL of dry CH2Cl2 and 50.0 mg of (MesRuCl2)2 (0.086 mmol) was added at room temperature, and the resulting mixture was stirred at 25 °C for 12 h. The collected solids were Soxhlet extracted in CH2Cl2 for 3 h to afford catalyst 2 (0.49 g) as a yellow powder. ICP analysis showed that the Ru loading was 17.12 mg (0.168 mmol) per gram of catalyst. 13C CP/MAS NMR (161.9 MHz): 158.1−112.2 (C of Ar and Ph), 108.9, 106.0 (−CH of mesitylene), 74.8−70.3 (−NCHCHN−), 56.6 (−NCH3 in CTAB moiety), 37.9−28.0 (−CH2CH2− in CTAB moiety), 26.8 (−CH2Ar), 23.6 (−CH3 in mesitylene), 17.4 (CH3CH2− in CTAB moiety), 15.1−1.8 (−CH2Si) ppm. 29Si MAS/NMR (79.4 MHz): T2 (δ = −59.1 ppm), T3 (δ = −66.8 ppm), Q2 (δ = −94.3 ppm), Q3 (δ = −102.5 ppm), Q4 (δ = −112.2 ppm). Preparation of catalyst 5. In a typical synthesis, 2.0 g of 1, 1.70 g (15.0 mmol) of N–isopropyl acrylamide were weighed into a 100 mL nitrogen flask and dissolved in 20 mL of distilled DMSO. Then, 65.5 mg (2% mol) of 2,2–

azobisisobutyronitrile (AIBN) was added at room temperature. After a degassed period by three freeze– pump–thaw cycles, the flask was placed into oil to polymerize at 60 °C for 6.0 h. The resulting solids were filtered, rinsed with 10.0 mL DMSO solvent three times and with 10.0 mL methanol three times. The collected solids were suspended in 20 mL of deionized H2O at 40 °C and 0.12 g (0.20 mmol) of (MesRuCl2)2 was added. The resulting mixture was stirred at 40 °C for 12h. After that, the solids were collected, rinsed with excess distilled H2O, and washed with excess CH2Cl2. After Soxhlet extraction in CH2Cl2 solvent to remove the remaining (MesRuCl2)2 for 12 h, the solid was dried at 60 °C under reduced pressure overnight to afford a light yellow powder. And then the collected solid was added to a red solution of Pd2(dba)3 (36.6 mg, 0.04 mmol) and trimethylphosphine (12.2 mg, 0.1mmol) in 20 mL of dichloromethane. The resulting mixture was stirred at 25 °C for 24 h. The mixture was filtered through filter paper and then rinsed with excess CH2Cl2. After Soxhlet extraction for 4 h in CH2Cl2 to remove unreacted starting materials, the solid was dried at ambient temperature under vacuum overnight to afford catalyst 5 (0.28 g) as a grey powder. ICP analysis showed that the Ru loading was 15.59 mg (0.153 mmol) and Pd loading was 12.81 mg (0.121 mmol) per gram of catalyst, respectively. 13C CP/MAS NMR (161.9 MHz): 176.6 (C=O in P2), 158.1−119.1 (C of Ar and Ph), 108.5, 105.8 (−CH of mesitylene), 74.3−70.6 (−NCHCHN−), 64.7 (−NCH3 in CTAB moiety), 36.8−14.9 (−CH2− or −CH− or CH3− in P2, −CH2Ar, −CH2− or CH3− in CTAB moiety), 24.3 (−CH3 in mesitylene), 14.9−0.3 (−CH2Si) ppm. 29Si MAS/NMR (79.4 MHz): T3 (δ = −66.8 ppm), Q2 (δ = −93.5 ppm), Q3 (δ = −103.1 ppm), Q4 (δ = −113.2 ppm). Preparation of catalyst 6. In a typical synthesis, 2.0 g of 1, 1.02 g (14.4 mmol) of acrylamide, 0.19 g (3.6 mmol) of acrylonitrile were weighed into a 100 mL nitrogen flask and dissolved in 20 mL of distilled DMSO. Then, 65.5 mg (2% mol) of 2,2–azobisisobutyronitrile (AIBN) was added at room temperature. After a degassed period by three freeze–pump–thaw cycles, the flask was placed into oil to polymerize at 60 °C for 6.0 h. The resulting solids were filtered, rinsed with 10.0 mL DMSO solvent three times and with 10.0 mL methanol three times. The collected solids were suspended in 20 mL of deionized H2O at 40 °C and 0.12 g (0.20 mmol) of (MesRuCl2)2 was added. The resulting mixture was stirred at 40 °C for 12h. After that, the solids were collected, rinsed with excess distilled H2O, and washed with excess CH2Cl2. After Soxhlet extraction in CH2Cl2 solvent to remove the remaining (MesRuCl2)2 for 24 h, the solid was dried at 60 °C under reduced pressure overnight to afford catalyst 6 (2.58 g) as a light yellow powder. ICP analysis showed that the Ru loading was 13.96 mg (0.137 mmol) per gram of catalyst. 13C CP/MAS NMR (161.9 MHz): 179.3 (C=O in P2), 158.1−112.2 (C of Ar and Ph), 109.7, 106.5 (−CH of mesitylene), 75.3−71.8 (−NCHCHN−), 58.2 (−NCH3 in CTAB moiety), 37.9−16.3 (−CH2− or −CH− or CH3− in P2, −CH2Ar, −CH2− or CH3− in CTAB moiety), 24.5 (−CH3 in mesitylene), 15.4−0.3 (−CH2Si) ppm. 29Si

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MAS/NMR (79.4 MHz): T3 (δ = −66.8 ppm), Q2 (δ = −92.6 ppm), Q3 (δ = −102.7 ppm), Q4 (δ = −112.2 ppm). General procedure for the asymmetric reaction. A typical procedure was as follows for the Suzuki cross– coupling/asymmetric transfer hydrogenation of iodoacetophenones and aryl boronic acids. Catalyst 5 (13.07 mg, 2.0 μmol of Ru and 1.58 μmol of Pd, based on ICP analysis), Cs2CO3 (0.12 mmol), HCO2Na (1.0 mmol), iodoacetophenones (0.10 mmol) and aryl boronic acids (0.12 mmol), and 2.0 mL of H2O/iPrOH (v/v = 1:1) were added sequentially to a 10.0 mL round−bottom flask. The mixture was then stirred at 60 °C for the first 3 hours followed by at 15 °C for 7 h. (For the aza–Michael addition/asymmetric transfer hydrogenation of aryl– substituted enones and arylamines. Catalyst 6 (14.60 mg, 2.0 μmol of Ru, based on ICP analysis), enones (0.10 mmol), amines (0.11 mmol), HCOONa (1.0 mmol), and 2.0 mL of H2O/iPrOH (v/v = 1:1) were added sequentially to a 10.0 mL round−bottom flask. The mixture was then stirred at 15 °C for the first 2 hours followed by at 35 °C for 6 h). During that time, the reaction was monitored constantly by thin layer chromatography (TLC). After completion of the reaction, the heterogeneous catalyst was separated via centrifuge (10000 r/min) for the recycle experiment. The aqueous solution was extracted by Et2O (3 × 3.0 mL). The combined Et2O was washed with brine twice and dehydrated with Na2SO4. After the evaporation of Et2O, the residue was purified by silica gel flash column chromatography to afford the desired product. The yields were determined by 1H–NMR and ee values were determined using an HPLC analysis with a Photo–Diode Array detector using a Daicel chiralcel column (Φ 0.46 × 25 cm).

determination of the well–defined single–site ruthenium/diamine centers in the silica-based support. Then, the free radical polymerization of 1 and N– isopropylacrylamide[12] produced P1@ArDPEN@HS (3), whereas that of 1 with acrylamide and acrylonitrile45 led to the P2@ArDPEN@HS (4). Finally, the complexation of 3 with (MesRuCl2)2 at 15 °C, followed by a continuous reaction with Pd2(dba)3 and PMe3 at 35 °C,[14] formed P1@Pd@Ru (5) as a light−grey powder, where catalyst 5 had similar Pd 3d electron binding energies to its homogeneous Pd(Me2PCH2=CHCONiPr)2, as proven by XPS (see SI in Figure S2). Similar complexation of 4 and (MesRuCl2)2 at 35 °C gave catalyst P2@Ru (6) as a light−yellow powder. In addition, the TG analysis showed the chiral ligand content in the materials was 6.5%, and the contents of thermal responsive polymers in materials were that the content of the chiral ligands in materials in materials were 10.4% and 8.3%, respectively (see SI in Figure S3). Notably, catalysts 5–6 had also the features of isolated–type supported molecule catalysts since dual species were immobilized onto two completely separated parts of the support.

O

O

+

AIBN Step 1'

AIBN Step 1

Vinyl@ArDPEN@HS (1) P2@ArDPEN2@HS (4)

P1@ArDPEN@HS (3)

(MesRuCl2)2

1) (MesRuCl2)2 at 15 oC

Step 2' (MesRuCl2)2

2) Pd2(dba)3+PMe3

at 35 oC

Step 2

at 35 oC

Vinyl@Ru@HS (2) = [Pd]

= [Ru]

RESULTS AND DISCUSSION

Ru Cl SO2N

Syntheses and structural characterizations of the heterogeneous catalysts 5-6 A general procedure for the assembly of two switching– type supported molecule catalysts 5–6, abbreviated as P1@Pd@Ru (5) and P2@Ru (6) (P1 = Polymer:[12] poly(ethene–co–N–isopropylacrylamide), P2 = Polymer: [13] poly(ethene–co–acrylamide–co–acrylonitrile), Pd = [Pd(Me2PCH2=CHCONiPr)2],[14] Ru = MesRuArDPEN: [15] Mes = mesitylene and ArDPEN–siloxane = (S,S)–4– ((trimethoxysilyl)ethyl)phenylsulfonyl–1,2– diphenylethylene–diamine), was outlined in Scheme 1 (see SI in Experimental and Figure S1). The co–condensation of 1,2–bis(triethoxysilyl)ethane and ArDPEN–siloxane onto the SiO2–nanoparticles with subsequent postgrafting of triethoxy(vinyl)silane onto the exterior silanol groups, followed by an etching process according to the reported method with slight modification,[11c] led to the vinyl/ArDPEN–functionalized hollow–shell–structured nanoparticles, Vinyl@ArDPEN@HS (1). Next, the direct complexation of 1 with (MesRuCl2)2 provided the parallel catalyst 2, abbreviated as Vinyl@Ru (2), as a light−red powder, which was a comparable catalyst for the

NH

CN

NH2

O

NH2

iPr

Ph

C

C

N

N

Pd

Ph

MesRuArDPEN

m

Me3P

n O iPr

PMe3

=

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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P2@Ru (6)

P1:

m

n

CONHiPr

P2:

o

n

m

CONH2 CN

P1@Pd@Ru (5)

SCHEME 1. Preparation of catalysts 5-6. With the catalysts in hand, determination of the well– defined single–site ruthenium/diamine centers within the nanochannels in catalysts 5–6 is beneficial to elucidate the enantioselective nature in differentiating the two enantiomers formed during a catalytic process. In this case, we utilized parallel catalyst 2 as a reference to verify the well–defined single-site chiral active centers. The solid– state 13C cross–polarization (CP)/magic angle spinning (MAS) NMR spectra of catalyst 2 and its parent material 1 were shown in Figure 2. These clearly showed that catalyst 2 and its parent material 1 exhibited similar signals at  = 8.0 ppm for the carbon atoms of the SiCH2CH2Si moiety in the ethylene-bridged silica shell,  = 70–75 ppm for the alkyl carbon atoms and  = 119–159 ppm for the aromatic carbon atoms of the -NCHPh moiety in the ArDPEN group. The characteristic signals of catalyst 2 at  = 108.9 and 106.0 ppm for the aromatic carbon atoms, and  = 23.6 ppm for

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the methyl carbon atoms attached to the aromatic ring in the mesitylene group were absent in the spectrum recorded for 1, demonstrating the formation of the well– defined single–site MesRuArDPEN centers since their chemical shift values were similar to those of its homogeneous counterpart, MesRuTsDPEN. [15a] Further comparison of the 13C CP/MAS NMR spectra recorded for catalysts 5–6 found that these characteristic carbon signals in catalysts 5–6 could be clearly recognized but quite weak, which were ascribed to the high intensity of the carbon signals in the outer polymers (See SI in Figure S4). In addition, the 29Si CP/MAS NMR spectra of catalysts 5–6 also revealed their main organic silicate networks since the contents of organic silica (T signals) were markedly higher than those of inorganic silica (Q signals) (See SI in Figure S5). [16] b

e Si

O

Si

c

f

Ru

a

(a)

(d)

(c)

1 Catalyst 2

Cl

O2SN d NH2

Si O

f

Si

Catalyst 2

Ph f

250

200

e

150

FIGURE 2. Solid–state catalyst 2.

13C

(b)

Ph b a *c

f

*

300

(Figure 3d). As we designed, catalyst 6 exhibited a similar structural morphology with an opposite dispersive situation, where catalyst 6 displayed a poor dispersive situation at 15 °C and a highly dispersive situation at 35 ° (See SI in Figure S8).

100

*

d

*

50

*

0

-50 ppm

CP/MAS NMR spectra of 1 and

Control over the monodispersed morphology with orderly pore arrangements of the as–made catalysts can truly reflect their catalytic properties in a cascade reaction. Figure 3 presented the structural morphology of catalyst 5 as a representative. Scanning electron microscopy (SEM) images revealed that the silica nanospheres of catalyst 5 were the uniformly dispersed with an average size of ~230 nm (Figure 3a). Transmission electron microscopy (TEM) images showed the hollow-shell-structured nanospheres in catalyst 5 had a thin silica shell with a thickness of 30 nm (Figure 3b). A typical IV-type adsorption-desorption in the nitrogen adsorption-desorption isotherm confirmed the mesoporous structure of catalyst 5 (see Figure S6). Furthermore, the TEM imaging with a chemical mapping suggested that the dual species, palladium and ruthenium centers, were uniformly distributed within its silica network in catalyst 5 (See SI in Figure S7). In addition, catalyst 5 also exhibited a desirable heating stimuli response in water, where the poor dispersive situation observed at 35 °C was attributed to the folded behavior (Figure 3c) while the highly dispersive situation observed at 15 °C was responded to the unfolded behavior of its water–soluble thermoresponsive polymer–coating layer

FIGURE 3. (a) SEM images of 5, (b) TEM images of 5, and the dispersive situations of catalyst 5 in water indicated at 35 °C (c) and at 15 °C (d). 550 Diameter of 3 (nm)

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ACS Catalysis

500 450 400 350 300 1

2 3 4 Number of recycle experiment 15 ℃

5

35 ℃

FIGURE 4. Average hydrodynamic diameters distribution measurement of catalyst 5 indicated at 15 °C and at 35 °C in water (Error bars represent standard deviations).

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Besides these general morphological investigations, the controllable on and off mode of the water–soluble thermoresponsive polymer–coating layer was beneficial for general application in the recycling experiments. Figure 4 showed a hydrodynamic diameters (Dh) distribution investigation of catalyst 5 via a dynamic light scattering (DLS) to determine the on and off mode in catalyst 5. It was found that, in five consecutive runs, the Dh at 15 °C fluctuated between 480.8 and 492.3 nm, while the Dh at 35 °C was between 392.8 and 407.5 nm (see Figure S9), demonstrating the switching ability of the expected on and off mode via adjusting the temperature. Differing from catalyst 5, a completely opposite on and off mode in catalyst 6 was also obtained, where its water–soluble thermoresponsive polymer–coating layer adopted a folded conformation to close the entrances of the nanochannels at 15 °C and an unfolded conformation to open the entrances of the nanochannels at 35 °C (See SI in Figure S10). Catalytic property of the heterogeneous catalyst On the basis of the well–established switching–type supported molecule catalysts 5–6, we initially used the Suzuki cross–coupling/ATH of 4–iodoacetophenone (7a) and phenylboronic acid (8a) as a model reaction[17] to examine the on and off mode of the water–soluble thermoresponsive polymer–coating layer in catalyst 5, focusing on the feasibility of a switchable cascade reaction and a determinable catalytic sequence. TABLE 1. Feasible investigations in the switchable cascade reaction of 4–iodoacetophenone and phenylboronic acid. O I

7a

Entry

8a

H2O/i-PrOH (1:1), Cs2CO3, I HCOONa

Cat.

1 2

5 5

3

5

4

5' + [Pd]

5

2 + [Pd]

6

[Ru]+[Pd]

°C /h 15/7 60/3 60/3 15/7 60/3 15/7 60/3 15/7 60/3 15/7

O

OH

Catalyst

B(OH)2

+

OH

+

A

B

9a

%Yiel

%Yield

%Yield

of A

of B

99 3

ND 97

of 9a ND ND

trace

trace

97/96

5

trace

94/94

9

trace

90/94

15

3

82/90

d/ee

Reaction conditions: Catalyst (2.0 μmol of Ru and 1.58 μmol of Pd), Cs2CO3 (0.12 mmol), HCO2Na (1.0 mmol), iodoacetophenones (0.10 mmol) and arylboronic acids (0.12 mmol), and 2.0 mL of H2O/iPrOH (v/v = 1:1) were added sequentially to a 10.0 mL round−bottom flask. The mixture was then stirred at 60 °C for the first 3 h followed by at 15 °C for 7 h. Yields were determined by 1H–NMR and ee values were determined chiral HPLC analysis. ND = no detect. [Pd] = homogeneous Pd(Me2PCH2=CHCONiPr)2. [Ru] = MesRuTsDPEN.

Page 6 of 11

In the case of the switchable cascade reaction shown in Table 1, we found that the 5–catalyzed cascade reaction of 4–iodoacetophenone and phenylboronic acid at 15 °C only afforded the sole intermediate of (S)–1–phenylethan–1–ol (A) via an ATH process without coupling the intermediates completely (entry 1), whereas at 60 °C the reaction gave the 1-([1,1'-biphenyl]-4-yl)ethan-1-one (B) intermediate via a Suzuki cross–coupling process with concomitant formation of the tiny intermediate A (entry 2). Both findings disclosed the feasibility of a switchable cascade reaction to the reaction temperature, demonstrating the suitable on and off mode of the polymer–coating layer in catalyst 5. Based on this efficient reaction switching, we combined two single–step reactions together, where the cascade reaction was carried out at 60 °C for the first 3 h followed by a continuous reaction at 15 °C for a further 7 h. The result showed that the reaction could steadily produce the targeting product of (S)–1–([1,1'–biphenyl]–4–yl)ethan– 1–ol (9a) in 97% yield and 96% ee (entry 3). Although the turnover numbers for the ruthenium species (48.5 mol/mol) and the palladium species (61.4 mol/mol) in this cascade reaction were low, the result demonstrated an efficient cascade process could be carried out using this reaction switching process. In particular, it was also notable that the obtained enantioselectivity in this cascade reaction was slightly higher than that attained with the physically mixed catalyst 5' (catalyst 5', abbreviated as P1@Ru, which was synthesized using the same procedure without the reaction of Pd2(dba)3 and PMe3) and Pd(Me2PCH2=CHCONiPr)2 as the dual catalysts (entry 3 versus entry 4), and was remarkedly better than those obtained with the physically mixed catalyst 2 and Pd(Me2PCH2=CHCONiPr)2 or the physically mixed homogeneous MesRuTsDPEN and Pd(Me2PCH2=CHCONiPr)2 as the dual catalysts (entry 3 versus entries 5–6). Notably, the decreased ee values in all three parallel reactions elaborated the benefits of the switching function in catalyst 5 because this switchable cascade reaction not only overcame the cross–interactions of the dual species but also guaranteed the maintainable enantioselectivity. In the case of the determinable catalytic sequence, due to the existence of two possible catalytic sequences comprised of a Suzuki cross–coupling followed by ATH process and an ATH followed by Suzuki cross–coupling process,[21e] we monitored the kinetic process of catalyst 5 through a time course investigation for the transformation of 7a and 8a into chiral product 9a, as shown in Figure 5. Initially, it was found that the Suzuki cross–coupling reaction of 7a and 8a proceeds smoothly as the concentration of 7a decreases sharply, and the coupling intermediate B reaches a maximum yield of 97% in the first 3 h at 60 °C. During this period, the maximum yield of 3% the reductive intermediate A is observed. Subsequently, when the reaction temperature is decreased to 15 °C, the ATH reduction of B occurs and the yield of the chiral product 9a increases rapidly between 3 to 6 h. Finally, the ATH reduction of B smoothly proceeds to provide the

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Page 7 of 11

targeting chiral product 9a in 97% yield after a further 4 h, which is concomitant with the gradual disappearance of tiny intermediate A due to the Suzuki cross–coupling reaction between A and 8a. This kinetic process discloses the determinable catalytic sequence comprised of a Suzuki cross–coupling followed by ATH process. O

7a

H2O/i-PrOH (1:1), Cs2CO3, HCOONa

8a

O

OH

Catalyst 5

B(OH)2

+

I

OH

+

I

+

A

B

9a

100

Transformations (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

80

8a A 7a B

60 40

0 1

2

3

4

5

6

7

8

9

10

15 °C

60 °C

Reaction Time (hours) FIGURE 5. Time course investigation in the transformation of 4–iodoacetophenone and phenylboronic acid (Error bars represent standard deviations). (The reaction of 1 equivalent of 4–iodoacetophenone and 1.2 equivalent of phenylboronic acid in the presence of catalyst 5 with 2.0 mol% of Ru and 1.58 mol % of Pd was carried at 60 °C for the first 3 h followed by a continuous proceeding at 15 °C for the second 7h).

TABLE 2. Suzuki cross–coupling/ATH cascade reactions of iodoacetophenones and arylboronic acids.a OH

O Catalyst 5

1

+ Ar B(OH)2

I 7a-7b

8a-8k

HCOONa, Cs2CO3 H2O/i-PrOH (1:1)

Ar1 9a-9u

Yield

Ee.

(%)b

(%)b

9a

97

96

9b

96

96

Entry

I, Ar1 (8)

9

1

4–I, Ph (8a)

2

4–I, 4–FPh (8b)

3

4–I, 4–ClPh (8c)

9c

96

96

4

4–I, 3–ClPh (8d)

9d

96

95

5

4–I, 4–CF3Ph (8e)

9e

95

95

6

4–I, 3–CF3Ph (8f)

9f

96

96

7

4–I, 4–MePh (8g)

9g

96

8

4–I, 3–MePh (8h)

9h

9

4–I, 4–OMePh (8i)

10 11

3–I, Ph (8a)

9l

96

96

13

3–I, 4–FPh (8b)

9m

97

97

14

3–I, 4–ClPh (8c)

9n

96

96

15

3–I, 3–ClPh (8d)

9o

97

97

16

3–I, 3–CF3Ph (8f)

9p

97

97

17

3–I, 4–MePh (8g)

9q

97

96

18

3–I, 3–MePh (8h)

9r

96

96

19

3–I, 4–OMePh (8i)

9s

97

97

20

3-I, 3-thienyl (8j)

9t

97

95

21

3-I, 4-pyridyl (8k)

9u

72

93

Reaction conditions: Catalyst 5 (13.07 mg, 2.0 μmol of Ru and 1.58 μmol of Pd, based on ICP analysis), Cs2CO3 (0.12 mmol), HCO2Na (1.0 mmol), iodoacetophenones (0.10 mmol) and arylboronic acids (0.12 mmol), and 2.0 mL of H2O/iPrOH (v/v = 1:1) were added sequentially to a 10.0 mL round−bottom flask. The mixture was then stirred at 60 °C for the first 3 h followed by at 15 °C for 7 h. b The yields are confirmed by 1H–NMR and the ee values are determined by chiral HPLC analysis after purification by flash–column chromatography (see SI in Figures S12 and S15). a

20

0

12

On the basis of the switchable cascade reaction (Table 1) and determinable catalytic sequence (Figure 5) in the 5– catalyzed reaction of 4–iodoacetophenone and phenylboronic acid, a series of Suzuki cross–coupling/ATH cascade reactions were examined, as shown in Table 2. It was found that all the iodoacetophenones, regardless of the substituents at 4– or 3–position, could steadily react with various nonheteroaromatic boronic acids to produce the corresponding chiral products with high yields and enantioselectivities (entries 1–9 versus entries 12–19), where no significant influence on their enantioselectivities was observed. However, the aromaticity of the heteroaromatic rings had an obvious effect on the reactivity, where the reactions with pyridinyl–substituted boronic acids displayed significantly lower yields than those with thienyl–substituted boronic acids because of the aromatic nature in Suzuki cross–coupling reactions (entries 10, 20 versus entries 11, 21). TABLE 3. Aza–Michal addition/ATH cascade reactions of arylpropenone and arylamines.a O Ar

+ Ar3NH2

2

10a-10h

11a-11f

OH

Catalyst 6 HCOONa H2O/i-PrOH (1:1)

Ar

2

N H 12a-12m

Ar3

Entry

Ar2 (10), Ar3 (11)

12

Yield (%)b

Ee. (%)b

97

1

Ph (10a), Ph (11a)

12a

93

94

96

96

2

4–FPh (10b), Ph (11a)

12b

95

91

9i

94

94

3

4–ClPh (10c), Ph (11a)

12c

91

95

4-I, 3-thienyl (8j)

9j

96

96

4

4-BrPh (10d), Ph (11a)

12d

88

91

4-I, 4-pyridine (8k)

9k

86

93

5

4–IPh (10e), Ph (11a)

12e

86

93

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ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

6

4–CNPh (10f), Ph (11a)

12f

83

81

7

4–MePh (10g), Ph (11a)

12g

88

96

8

4–MeOPh(10h), Ph(11a)

12h

85

97

9

Ph (10a), 4–ClPh (11b)

12i

89

96

10

Ph (10a), 3–ClPh (11c)

12j

88

96

11

Ph (10a), 4–BrPh (11d)

12k

84

96

12

Ph (10a), 4-MePh (11e)

12l

91

95

13

Ph (10a), 4–MeOPh (11f)

12m

92

96

Reaction conditions: Catalyst 6 (14.60 mg, 2.0 μmol of Ru, based on ICP analysis), enones (0.10 mmol), amines (0.11 mmol), HCOONa (1.0 mmol), and 2.0 mL of H2O/iPrOH (v/v = 1:1) were added sequentially to a 10.0 mL round−bottom flask. The mixture was then stirred at 15 °C for the first 2 h followed by at 35 °C for 6 h. b Yields were determined by 1H–NMR and ee values were determined chiral HPLC analysis (see SI in Figures S12 and S15). a

Similarly, in order to further confirm the switching ability when manipulating the cascade reaction process, catalyst 6 with an opposite reversible response to reaction temperature was also explored in a known aza–Michael addition/ATH cascade reaction of 1–phenylprop–2–enone and aniline, where the organoamide group in the polymercoating layer acted as a basic functionality and the ruthenium/diamine–complex worked as a reductive functionality.[18] Based on the obtained results for the switchable cascade reaction with unfolded conformation at 35 °C and folded conformation at 15 °C (See SI in Table S1), and the determinable catalytic sequence comprised of an aza–Michael addition followed by ATH process (See SI in Figure S11), Table 3 presented the general practicability in the 6–catalyzed aza–Michael addition/ATH cascade reactions of a series of arylpropenone and arylamines for the preparation of optically pure γ–secondary amino alcohols.

Page 8 of 11

investigated the single step Suzuki cross–coupling reaction 4–iodoacetophenone and phenylboronic acid through the setting of 1 h of reaction time under the same reaction conditions, finding no significant palladium loss since the initial turnover frequency (TOF) values lay in between 37.3 and 36.1 h-1 after six reaction recycles. Based on this observation, the 5-catalyzed Suzuki cross–coupling/ATH cascade reaction of 4–iodoacetophenone and phenylboronic acid was also performed, as shown in Figure 6. It was found that, in six consecutive runs, the recycled catalyst 5 still afforded the desired chiral products in 93% yield with 95% ee (see SI in Table S2 and Figure S13). Similarly, the 6–catalyzed aza–Michael addition/ATH enantioselective cascade reaction of 1–phenylprop–2– enone and aniline could be recycled for the six runs, still giving the chiral product in 91% yield with 94% ee (see SI in Table S3 and Figure S14). In conclusions, through the utilization of the water– soluble thermoresponsive polymer to immobilize achiral functionality and hollow–shell–structured mesoporous silica to entrap the chiral ruthenium/diamine functionality, we have developed a switchable strategy to control the catalytic actions of the dual species, assembling two switchable–type supported dual molecule catalysts. By creating the unique on and off modes of the water–soluble thermoresponsive polymer–coating layers on the outer silica shell, the two catalysts can selectively trigger or terminate the catalytic behavior of the chiral ruthenium/diamine centers in the nanochannels, realizing the controllable manipulation of the cascade reaction with the determinable catalytic sequence. As we expected, the Suzuki cross–coupling/asymmetric transfer hydrogenation or the Michael addition/asymmetric transfer hydrogenation catalytic process enable a switchable enantioselective cascade process, providing various chiral products with high yields and enantioselectivity in an aqueous medium. The work presented in this study also highlights an alternative strategy to make up for the methodological deficiency in the construction of supported molecule catalysts.

ASSOCIATED CONTENT Supporting Information Experimental procedures and analytical data of chiral products are available free of charge via the Internet at http://pubs.acs.org. FIGURE 6. Reusability of catalyst 5 for the Suzuki cross– coupling/ATH cascade reaction of 4–iodoacetophenone and phenylboronic acid.

As a new kind of heterogeneous bifunctional catalysts, their recycling abilities of catalysts in the cascade reactions were also investigated using catalyst 5 as a representative. Due to the complicated affecting factors for determining the palladium leaching from solid catalysts that involved in the Suzuki cross–coupling reaction in literature,[19] we

AUTHOR INFORMATION Corresponding Author [email protected]

ACKNOWLEDGMENT We are grateful to the China National Natural Science Foundation (21672149, 21872095) for financial support.

REFERENCES

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ACS Catalysis

Graphical Abstract:

OH Ar

OH Ar3 N H 13 samples, up to 97% ee

1

Ar2

21 samples, up to 97% ee 15 oC

Switchable Catalysts Used to Control Suzuki Cross–Coupling

and

Aza–Michael

O I

+ Ar1B(OH)2

Addition/Asymmetric Transfer Hydrogenation Cascade Reactions

Jingjing Meng, Fengwei Chang, Yanchao Su, Rui Liu, Tanyu Cheng and Guohua Liu *

35 oC

60 oC

15 oC

Ar3NH2 +

O Ar

2

Switchable–type supported dual molecule catalysts manipulate catalytic cascade sequences for the Suzuki cross–coupling/asymmetric transfer hydrogenation of iodoacetophenones and aryl boronic acid, and the aza–Michael addition/asymmetric transfer hydrogenation of enones and arylamines.

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