Highly efficient dynamic kinetic resolution of benzylic amines with palladium catalysts on oxidized multiwalled carbon nanotubes for racemization

Tetrahedron Letters 56 (2015) 2714–2719

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Highly efficient dynamic kinetic resolution of benzylic amines with palladium catalysts on oxidized multiwalled carbon nanotubes for racemization Gang Xu, Shuqin Lan, Simin Fu, Jianping Wu ⇑, Lirong Yang Institute of Bioengineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China

a r t i c l e

i n f o

Article history: Received 7 February 2015 Revised 3 April 2015 Accepted 6 April 2015 Available online 11 April 2015 Keywords: Benzylic amines Dynamic kinetic resolution Racemization catalyst Pd/oxidized MWCNTs

a b s t r a c t A new and efficient dynamic kinetic resolution (DKR) process of benzylic amines was developed using palladium supported on surface-oxidized multiwalled carbon nanotubes (Pd/oxidized MWCNTs) as racemization catalyst. The catalyst Pd/oxidized MWCNTs was first used in the DKR of amines. Enantiomerically pure benzylic amide was obtained with high conversion and enantiomeric excess (ee) at 55 °C. Possible side reactions were strongly suppressed and the catalyst system was used in ten successive reactions without loss of conversion or ee. The likely utility of the method was also reflected by the broad range of possible reaction substrates. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Enantiomerically pure amines are important intermediates in the synthesis of fragrances, surfactants, agrochemicals, and pharmaceuticals. Dynamic kinetic resolution (DKR) is a widely researched method for preparing these compounds. DKR is a kinetic resolution (KR) coupled with an in situ racemization of slow-reacting substrate,1 which is able to overcome the shortcomings of KR and increase the theoretical maximum conversion to 100%. For an efficient chemo-enzymatic DKR, resolution and racemization catalysts and their good compatibility are required. To date, some enzymes including Novozym 435 have shown good performance in KR of amines, but further research is still needed on the preparation of efficient racemization catalysts for DKR of amines. In recent years, many racemization catalysts have been investigated for DKR of benzylic amines, including Ru complexes,2 Pd nanoparticles,3 Raney nickel,4 Ir complexes,5 and Pt microcapsules.6 Accordingly, DKR of amines should be performed at elevated temperature for considerable time (usually 24 h or longer) to obtain good conversion and a satisfactory enantiomeric excess (ee), although ethylbenzene (ETB) can be easily generated as reaction by-product. Among these catalysts, Pd nanoparticles are preferred. Some, such as Pd/C,7 Pd/BaSO4,8,9 and Pd/CaCO3,8,9

⇑ Corresponding author. Tel./fax: +86 571 87952363. E-mail address: [email protected] (J. Wu). http://dx.doi.org/10.1016/j.tetlet.2015.04.021 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

have been well used for DKR of certain amines, but these racemization catalysts still have some drawbacks: (1) the catalysts are only suitable for preparing a limited range of amines; (2) good selectivity and high conversion are not easy to obtain together; and (3) the compatibilities between the racemization catalysts and enzymes are not ideal. Studies have shown that the support for Pd catalysts strongly affects their performance in racemization and DKR of chiral amines.10 It is considered that the number of active sites influences the reaction rate, while the alkalinity or acidity of the support can influence the selectivity. Multiwalled carbon nanotubes (MWCNTs) appear to be an alternative support worth considering because they provide a large surface-to-volume ratio and can be modified by oxidation to add carboxylic, carbonyl, and hydroxyl groups. In using oxidized MWCNTs, the active metal particles, such as Pd, are able to deposit on the internal and external walls.11 Of note, Pd supported on MWCNTs has been proven as an excellent catalyst in selective hydrogenation reactions,12 but its application to DKR of benzylic amines has received little attention despite the similarities in the mechanisms of selective hydrogenation and DKR of amines. Parvulesu3 suggested that racemization likely occurs by a hydrogenation/dehydrogenation mechanism (Scheme 1), so we considered that Pd/oxidized MWCNTs could be used as an efficient racemization catalyst and note that the unique morphology and size of the nanotubes may help to suppress any side reactions. This Letter describes our preparation of Pd/oxidized MWCNTs13,14 as a racemization catalyst for DKR of benzylic amines. The reaction proceeded smoothly at 55 °C for 15 h to

G. Xu et al. / Tetrahedron Letters 56 (2015) 2714–2719

NH

NH 2 -H 2

NH 2 +H 2

(S)-1-phenylethylamines

(R)-1-phylethylamines

-NH 3

N

+H2

entries 2, 3, 4) showed better results, suggesting that weakly alkaline carrier favors racemization more than the weakly acidic carrier. The carrier of the Pd/oxidized MWCNTs catalyst was also weakly acidic, but the excellent racemization and lack of by-product flag this catalyst as being near to ideal for racemization. This is likely related to the special structure and properties of the nanotube support. Surface-oxidized MWCNTs possess extensive

ethylbenzene(ETB)

+H2

ethylbenzene(ETB)

2715

+H2 HN

Scheme 1. Reaction mechanism of Pd/oxidized MWCNT catalyzed racemization of (S)-1-phenyl amine.

achieve high conversion (>99%) and eep (>99%) with no by-product. Furthermore, the scope of available benzylic amine substrates reflects the likely utility of this method. Figure 1. FT-IR spectra of (a) purified MWCNTs and (b) oxidized MWCNTs.

Results and discussion From previous research, surface acidity or alkalinity and the specific surface area of the racemization catalyst are known to affect the racemization of amines. In the current study, we compared the performance of six Pd catalysts through the racemization of (S)-1-phenylethyl amine. The results in Table 1 show that compared with other Pd catalysts, Pd/oxidized MWNTs (Table 1, entry 6) was more active and selective in racemization of (S)-1phenylethylamine. After reaction for 15 h, ETB by-product was not detected and the eeamine was 0%, demonstrating that (S)-1-phenylethyl amine undergoes complete racemization under the condition used. In contrast, the Pd/purified MWCNTs catalyst (Table 1, entry 5) showed the worst result with a likely factor of the inactivity of purified MWCNTs. The result with Pd/C was poor, with an eeamine of 60% and significant generation of ETB by-product 15%. In that case, it is possible that the carrier carbon is weakly acidic, thereby promoting the hydrogenolysis of C–N bounds on Pd,15 decreasing the ammonia concentration, and promoting production of ETB. Compared with Pd/C, Pd metal on alkaline earths (Table 1,

Table 1 Racemization of (S)-1-phenylethyl amine over Pd catalysts Entry

Catalyst

Specific surface area (m2/g)

eeaminea (%)

Sel.ETB (%)

0 1 2 3 4 5 6

Ideal catalyst Pd/C Pd/BaSO4 Pd/CaCO3 Pd/BaCO3 Pd/purified MWCNTsb Pd/oxidized MWCNTsc

— 793.8 2.53 68.87 31.02 250.6 243.3

0 60 8 10 31 90 0

0 15 11 12 2 0 0

Reaction and conditions: 0.33 mmol (S)-1-phenylethyl amine, 4 mL toluene, 40 mg Pd catalysts, 55 °C, 15 h, 0.03 MPa H2, 200 rpm, catalyst loading 5 wt% Pd on support. a eeamine is the enantiomeric excess value of 1-phenylethyl amine. b The law MWCNTs dispersed in 4.0 mol/L HCl under ultrasound for 4 h for purification were named purified MWCNTs. c The purified MWCNTs oxidized by concentrated H2SO4/HNO3 (3:1 by volume) under ultrasound for 4 h were named oxidized MWCNTs.

Figure 2. SEM pictures of catalyst Pd/oxidized MWCNTs. (a) has a 2.00 lm scale bar, (b) has a 1.00 lm scale bar.

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G. Xu et al. / Tetrahedron Letters 56 (2015) 2714–2719

Figure 3. XRD patterns of (a) purified MWCNTs and (b) Pd/oxidized MWCNTs.

specific surface area, thereby providing a massive number of active sites for catalyst substrate association. The unique morphology and size of the nanotubes may also appear to strongly suppress side reactions. So changes of the surface chemical properties of MWCNTs were investigated by recording Fourier transform infrared (FT-IR) spectra before and after modification of the material surface (Fig. 1). The results indicate the oxidation of MWCNTs with HNO3–H2SO4 can introduce some functional groups onto the nanotube surface (Fig. 1b). In comparison with purified MWCNTs (Fig. 1a), the spectrum of oxidized MWCNTs clearly shows new peaks at 950– 1300 cm 1 (C–O stretching), 1600–1700 cm 1 (carbonyl and/or carboxyl groups), and 3300–3600 cm 1 (hydroxyl and phenolic groups). Such surface functionalization can enhance reactivity, improve specificity, provide hydrophilicity, and promote ion adsorption and metal deposition.16 After Pd was added to the oxidized MWCNTs, the material was characterized by scanning electron microscopy (SEM) (Fig. 2). Figure 2(b) is a zoomed picture of Figure 2(a). Carbon nanotubes were observed to be inextricably intertwined in forms that provided increased specific surface area. The Pd metal was evenly and abundantly deposited on the surface layer to provide a high density of catalytic active sites available for reaction. X-Ray diffraction (XRD) patterns of Pd/oxidized MWCNTs are shown in Figure 3. All the patterns show typical peaks of (0 0 2), (1 0 0), and (1 0 1) phases of MWCNTs or graphite (Fig. 3a). The diffraction peaks at 39°, 46°, and 68° are due to the Pd (1 1 1), (2 0 0) and (2 2 0) planes (Fig. 3b), respectively, which are typical of the crystalline Pd face-centered cubic (fcc) pattern.17 Apart from the diffraction peaks of Pd and the carbon support, no other diffraction peaks were observed indicating that Pd was successfully loaded on the surface of oxidized MWCNTs. Although aware that Pd/oxidized MWCNTs shows good racemization activity, we sought to ensure the accuracy and reliability of the experiment, and the speed of racemization by monitoring of the racemization of (S)-1-phenylethyl amine with Pd/oxidized MWCNTs catalyst at 55 °C. The results are presented in Figure 4. It is shown that in 15 h, eeamine was almost 0 indicating the good racemization of the catalyst. DKR of benzylic amine was also performed using Pd/oxidized MWCNTs and Novozym 435. Based on our previous work, we knew

Figure 4. Pd/oxidized MWCNTs catalyzed racemization of (S)-1-phenylethyl amine.

that longer and more complex acyl donors led to the suppression of non-selective amidation reactions catalyzed by amines. This is one reason for the high ee value in the DKR of 1-phenylethylamine. According to our previous work, 4-chlorophenyl valerate performed very well as an acyl donor in the DKR of 1-phenylethylamine, so it was preferentially used in the Pd/MWCNTs– Novozym 435 reaction system. The result given in Table 2 (entry 1) shows that the model reaction using 1-phenylethylamine as substrate was effectively catalyzed by lipase Novozym435 and Pd/oxidized MWCNTs with excellent eep (>99%) and conversion (>99%) (heating in toluene, 55 °C, 15 h). Similarly, the DKR of other benzylic amines was observed to proceed with high conversion and high eep value when using Pd/ oxidized MWCNTs as racemization catalyst under the same reaction conditions. The results, shown in Table 2, reveal that substrates with electron-donating groups on the benzene ring could generally achieve 100% optical purity at 100% conversion (Table 2, entries 1, 6, 9, 11–15). In contrast, substrates with electron-withdrawing groups on the benzene ring usually achieved low eep values (Table 2, entries 2, 3, 8, 10). From our previous

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G. Xu et al. / Tetrahedron Letters 56 (2015) 2714–2719 Table 2 DKR of benzylic amines catalyzed by Pd/oxidized MWCNTs with 4-chlorophenyl valerate as acyl donor Entry

Substrate

Product

eepa (%)

Conv.b (Yieldc) (%)

>99

>99(95)

94.9

98.1(89)

96.2

99(90)

98.0

>99(89)

98.3

>99(92)

>99

>99(95)

98.0

>99(88)

97.4

>99(90)

>99

>99(94)

93

>99(88)

O

NH 2

HN

1

(CH 2) 3CH3

R

1a

2a O

NH 2

HN

2

F

(CH2) 3CH3

R

1b F

2b O

NH 2

HN

3

Cl

(CH2) 3CH3

R

1c

Cl

2c O

NH 2

HN

4

(CH2) 3CH3

R

Br

1d Br

2d O

NH 2

HN

5

(CH2 )3CH3

R

O

1e O

2e O

NH 2

HN

6

(CH2 )3CH3

R

1f 2f O

NH 2

Cl

HN

Cl

7

(CH2 )3CH3

R

1g

2g O

NH 2 Cl

HN

(CH2 )3CH3

Cl

8

R

1h

2h O

NH 2 F3 C

HN

(CH2 )3CH3

F3C

9

R

1i 2i Cl

O

NH 2

Cl

10

HN

R

Cl

(CH2 )3CH3

1j Cl

2j (continued on next page)

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G. Xu et al. / Tetrahedron Letters 56 (2015) 2714–2719

Table 2 (continued) Entry

Substrate

Product

eepa (%)

Conv.b (Yieldc) (%)

>99

>99(93)

>99

>99(95)

>99

>99(95)

>99

>99(90)

>99

>99(92)

O

NH 2

HN

11

(CH2 )3CH3

R

1k

2k O

NH 2

HN

12

(CH2 )3CH3

R

1l 2l H N

NH 2

(CH2) 3CH3

R O

13

1m

2m O

NH2

HN

R

14

(CH2 )3CH3

1n 2n O

NH 2

HN

(CH2) 3CH3

R

15

1o 2o Reaction and condition: 4 ml toluene, 0.33 mmol racemic benzylic amine, 0.35 mmol 4-chlorophenyl valerate, 40 mg Pd/oxidized MWCNTs, 100 mg Novozym 435, 0.03 MPa H2, 55 °C, rotation speed 200 r/min. a eep is the enantiomeric excess value of product. b Conversion ratio (%) = [converted substrate (mol)]/[total initial substrate (mol)]  100%. c Isolated yield (%) = [isolated product (mol)]/[total initial substrate (mol)]  100%. The enantiomerically pure DKR products were isolated from the reactant by column chromatography using n-hexane/ethyl acetate = 10:1 (v/v) as a developing agent.

ten successive reactions, the system still achieved eep >99% and conversion >99%, indicating that the Novozym 435–Pd/oxidized MWCNTs catalysts possessed good operational stability. Conclusions A new and efficient DKR of benzylic amines catalyzed by Pd/oxidized MWCNTs as racemization catalysts and Novozym 435 as resolution catalysts was investigated. The racemization catalyst Pd/oxidized MWCNTs were first used in the DKR of amines. When employing complex acyl donors in the system, enantiomerically pure benzylic amide was obtained in excellent yields under relatively mild reaction conditions (55 °C, 15 h) that could be tolerated by a lipase. Other perceived advantages of the method include a lack of ETB by-product, the potential application to a wide range of reaction substrates, and good stability of the catalyst system. Notably, the Novozym 435–Pd/oxidized MWCNTs system was used in ten successive reactions without a loss of conversion or ee value. Figure 5. Catalyst reuse with 4-chloropheny valerate as acyl donor.

work,18 we believe that the reduced eep is probably a result of low selectivity of the enzyme. An important aspect of establishing the merit of any catalyst is determining its ability to be reused. Accordingly, we assessed the reusability of the Novozym 435–Pd/oxidized MWCNTs catalyst system. As shown in Figure 5, after using the same catalyst in

Acknowledgments This work was supported by the National Basic Research Program of China (973 Program, No. 2011CB710800), Hi-Tech Research and Development Program of China (863 Program, 2011AA02A209), National Natural Science Foundation of China (No. 20936002), and Research on Public Welfare Technology Application Projects of Zhejiang Province, China (No. 2010C31127).

G. Xu et al. / Tetrahedron Letters 56 (2015) 2714–2719

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