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Highly Enantioselective Asymmetric Transfer Hydrogenation (ATH)of α-Phthalimide Ketones†

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Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x

Zhou Xu,*ab Yong Li,b Jing Liu,b Nan Wu,c Ke Li,b Songlei Zhuab, Rongli Zhanga ,

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Yi Liu*b

A mild catalyst system for the synthesis of chiral amino alcohols via asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones has been developed by using a chiral Ru-TsDPEN complex as the catalyst in DMF/MeOH at 40oC.The reaction exhibits high reaction activity and excellent enantioselectivity where up to 96% yield and 99% ee of the product was obtained.

hydrogen. These advantages have even allowed the development of interesting industrial processes.9 Previous resluts: a.

Introduction Varieties of optical amino alcohols has been reported as important compounds due to their special biologically activites.1 They can also been used as chiral building blocks and ligands in a variety of asymmetric reactions.2 Lots of stuides have been focused on the development of efficient methods for the synthesis of chiral amino alcohols.3 One of the preferred method is the selective reduction of protected amino ketone derivatives due to their good stability. αPhthalimide ketones are such kinds of presubstrates which can be conveniently transferred to α-primary amino alcohols. For examples, Zhang et.al first reported the asymmetric hydrogenation of α-phthalimide ketones using Ru TunePhos-derived complex with high enantioselectivity under high pressure of hydrogen at 80 oC (Scheme 1, L1).4 Lin et.al used the modified bisphosphine (Scheme 1, L2) combing with Ru(II) to catalyze the reaction.5 Zhou and co-workers reported a homogeneous palladium (R, R)-MeDuPhos (Scheme 1, L3) to catalyze the reaction where up to 92.2% ee was achieved under 100 atm H2.6 While with the modification of the (S)-TunePhos, Zhang et.al found that the modified TuenPhos L4 combined with Pd(II) could catalyze the reaction giving the corresponding product with good to excellent ee at 80oC under high pressure of hydrogen (Scheme 1, L4).7 Although good results have been achieved, all of these reactions are catalytic enantioselective hydrogenations. The high pressure of the reactions made them difficult to operate. In addition, all of the above methods focused on the usage of disphosphrious ligands. In other words, challenges still exisit, such as high reaction temperature, high reaction pressure and so on. Developing safety, easy to handle and highly enantioselective methods to prepare amino alcohols with efficiency still in great demand. In recent years, transition-metal catalyzed asymmetric transfer hydrogenation (ATH) has gained much attention due to its versatility, operational simplicity and safety.8 Without using explosive hydrogen gas or moisture-sensitive hydride reagents, ATH reactions use a hydrogen donor, such as HCOOH which is much safer than molecular

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b.

This work:

Scheme 1 Ligands used for the asymmetric reduction of αphthalimide ketone. Hererin, we reported an asymmetric transfer hydrogenation (ATH) reaction via asymmetric transfer hydrogenation (ATH) of αphthalimide ketones using HCOOH as hydrogen resource under very mild reaction conditions which may sulpply an alternative method to synthesze chiral amino alcohols.

Results and discussion Initially, the reaction was carried out in DMF at 25oC using (1S, 2S)TsDPEN (Noyori ligand) as the ligand. However, no desired product

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was observed (Table 1, entry 1). To our delight, when the reaction temperature was enhanced to 40 oC, 67% isolated yield of the product with 95% ee was obtained (Table 1, entry 2). Futher increased the temperature to 60 oC has no significant effects on the reaction (Table 1, entry 3).

DMF/MeOH (v/v, 4/1, 4 ml); f DMF/MeOH (v/v, 3/1, 4 ml); g DMF/MeOH (v/v, 5/1, 4 ml); h DMF/MeOH (v/v, 4/1), [Ru(cymene)Cl2]2 (15.2 mg, 0.025 mmol) and (1S, 2S)-Ts-DPEN (18.4 mg, 0.05 mmol) were used; i DMF/MeOH (v/v, 4/1), [Ru(cymene)Cl2]2 (3.8 mg, 0.0063 mmol) and (1S, 2S)-Ts-DPEN (4.6 mg, 0.0125 mmol) were used.

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Table 1 Optimization of the reaction condition. a

Entry

Solvent

L

Time (h) 24

Yield (%)b

L5

T (oC) 25

NR

Ee (%)c -

1

DMF

2

DMF

L5

40

30

67

95

3

DMF

L5

60

30

69

95

4

DMF

L6

40

30

NR

-

5

DMF

L7

40

30

NR

-

6

DMSO

L5

40

72

35

96

7

THF

L5

40

72

51

96

8

CH3CN

L5

40

24

NR

-

9

EtOAc

L5

40

24

NR

-

10

DCM

L5

40

24

NR

-

11

MeOH

L5

40

72

46

>99

12d

MeOH

L5

40

72

82

95

13

i

PrOH

L5

40

48

trace

-

14

CF3CH2OH

L5

40

48

trace

-

15e

DMF/MeOH

L5

40

72

92

97

16f

DMF/MeOH

L5

40

72

90

97

17g

DMF/MeOH

L5

40

72

92

95

18h

DMF/MeOH

L5

40

54

91

97

19i

DMF/MeOH

L5

40

120

87

97

a

Reactions were performed with 1a (0.25 mmol), [Ru(cymene)Cl2]2 (7.6 mg, 0.0125 mmol) and (1S, 2S)-Ts-DPEN (9.2 mg, 0.0250 mmol) in solvent (4 ml) under Ar; b Yield after chromatography; c Enantiomeric excess was determined by HPLC using Chiracel IC column. The absolute configuration was determinded to be R with comparing to the literature;4-7 d MeOH (10 ml) was used; e

2 | J. Name., 2012, 00, 1-3

Ligands L6 and L7 which showed good activities on other asymmetric transfer hydrogenation reactions were also studied.10 However, neither ligand L6 nor L7 can catalyze the reaction (Table 1, entries 4-5). Thus, (1S, 2S)-TsDPEN (L5) was chosen as the best ligand for further studies. Firstly, solvent effects were considered. As can be seen from Table 1, this reaction was strongly solvent-dependent. When the reaction was carried out in DMSO or THF, it needs longer reaction time than in DMF (Table 1, entries 2, 6-7). Although the ee values were slightly higher in DMSO, the yields were decreased dramatically. When CH3CN and other moderate polarity solvents such as AcOEt, DCM were chosen as the solvents, the reaction can hardly proceed (Table 1, entries 8-10). Interestingly, MeOH gave the highest ee, but it led to low activity with only 46% yield (Table 1, entry 11). This may be due to the solubility of the substrate in MeOH. The substrate can not compeletely dissolve in 4 ml MeOH. Lowered the concentration of the substrate to increase the solubiltiy of the substrate can improve the yield to 82% (Table 1, entry 12). Unfortunately, the ee value was decreased to 95%. Other alcohols, such as iPrOH, CF3CH2OH were also studied. None of them can improve the result (Table 1, entries 13-14). In this situation, mixture of MeOH and DMF was considered. When the ratio of DMF/MeOH was 4/1 (v/v), it gave the best result. The product can be obtained with 92% yield and 97% ee (Table 1, entry 15-17). Finally, catalyst loading was investigated. Increasing the catalyst amount can shorten the reaction time with ee and yield kept, while decreasing the catalyst amount required a significantly extended reaction time for the complete consumption of 1a and thus resulted in a lower yield (Table 1, entry 18-19). Having established reaction conditions for highly enantioselective transfer hydrogenation of substrate 1a, we next studied the substrate scope. As can be seen from Table 2, both electron-deficient and electron-rich aryl ketones could be converted to the corresponding products with high yields and excellent enantioselectivities. To make the reaction more practical, lower catalyst loading for the reaction was also studied. When the loading of the catalyst decreased to only 1.25%, the ATH reaction could still work well with yield and ee value kept though it took longer reaction time (Table 2, entries 3-4). Substrates bearing with different substituted group of R have significant effects on the enantioselectivies of the products. Those substrates with substituted group at the meta- position gave the product with higher enantioselectivities than at the orth- or paraposition. For example, substrate 1b, which the R group bearing with fluoro at the meta- position gave 94% ee of the corresponding product, exhibiting higer ee than either orth- substituted substrate 1c or parasubstituted substrate 1d (Table 2, entries 3-6). The same phenomenon was also observed between substrates 1e and 1f. When R was 3ClC6H5, 1e could convert into the product with 95% ee which was much higher than 1f where R was 4-ClC6H5 showing 90% ee of product (Table 2, entries 7-8). The same results were also happened between substrates 1g and 1h (Table 2, entries 9-10). Steric effects also have important effects on the reaction. With less hinder group on the substrate, the corrosponding product can be obained with much higher enantioselectivies. For example, substrate 1d with sustituted group fluoro atom on the orth position on the benzen ring gave lower ee of the product which showed only 80% ee,

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while 1b or 1c which has less hinder group could give the product with 94%, 93% respectively (Table 2, entries 4-6). Another example, for substrate 1l where the R gruoup was 2-naphthyl which is obviously less hinder comparing to substrate 1k, gave the product with much higer ee (Table 2, entries 13-14). For the aliphatic substituted α-phthalimide ketone 1m, the reaction can proceed smoothly though the ee was not good (Table 2, entry 15).

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Table 2 Scope of the reaction. a

Scheme 2 Synthesis of chiral amino alcohol 3a on gram scale.

Conclusions Time

Yield

Ee

(h)

(%)b

(%)c

1a

72

92

97

C6H5

1a

96

52

>99

3

m-FC6H5

1b

12

95

94

4e

m-FC6H5

1b

19

94

94

5

p-FC6H5

1c

72

87

93

6

o-FC6H5

1d

20

96

80

7

m-ClC6H5

1e

72

70

95

Entry

R

Substrate

1

C6H5

2d

In conclusion, we have developed highly efficient catalytic enantioselective transfer hydrogenation reaction of α-phthalimide ketones by a chiral Ru(II)/(1S, 2S)-Ts-DPEN complex, which provide a facile access to the optically active amino alcohols in 65-96% yields with 80-99% ee. The remarkable features of the method, such as mild reaction conditions, simple procedure and broad substrate scopes allow the practical asymmetric synthesis of chiral amino molecules that are useful for further synthesis. We are grateful for the financial support from the Natural Science Foundation of Higher Education Institutions of Jiangsu Province, China (No. 10KJB150018) and the Project of Science and Technology of Xuzhou Government (No. XM12B012). The project was also sponsored by Zhen Xing Project of Xuzhou Medical Collge.

Notes and references a

8

p-ClC6H5

1f

15

78

90

9

m-BrC6H5

1g

20

90

97

10

p-BrC6H5

1h

14

82

91

11

p-IC6H5

1i

28

78

92

12

m-MeOC6H5

1j

72

82

98

13

1-Naphthyl

1k

72

65

91

14

2-Naphthyl

1l

72

72

95

15

Methyl

1m

12

89

25

a

Reactions were performed with 1a (0.25 mmol), [Ru(cymene)Cl2]2 (7.6 mg, 0.0125 mmol) and (1S, 2S)-Ts-DPEN (9.2 mg, 0.0250 mmol) in solvent (4 ml) under Ar. The absolute configurations of the product was determined by comparing with the literature5-8; b Yield after chromatography; c Enantiomeric excess was determined by HPLC using Chiracel IC column or OJ-H column; d The reaction was carried out in MeOH; e. The catalyst loading was 1.25%. Scheme 2 shows an example for a potential synthetic application of the method to synthesis chiral amino alcohol in gram scale. The starting materials 1a can be obtained easily and the reaction can run on a gram scale with good yield. The hydrolysis of 2a in water at 60 oC gave the chiral amino alcohol 3a in 89% yield with 96% ee. According to the known method, amino alchol 3a could be easily converted to 4a which can use as ligand in asymmetric reactions.11

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Department of Chemistry, Xuzhou Medical College, Jiangsu, Xuzhou, 221004, P.R. China. b School of Pharmacy, Xuzhou Medical College, Jiangsu, Xuzhou, 221004, P.R. China. c Department of Chemistry, Xuzhou Airforce College, Jiangsu, Xuzhou, 221004, P.R. China. E-mail: [email protected] and [email protected] † Electronic supplementary information (ESI) available: Experimental procedures, HPLC spectra, 1H NMR and 13C NMR spectroscopic data of all of the products and analytic data of the compound 3a are included. This material is available free of charge via the Internet. see DOI: 10.1039/c4cc07978g 1. For the representative examples, see: (a) D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev., 1996, 96, 835; (b) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561; (c) G. Cardillo, C. Tomasini, Chem. Soc. Rev., 1996, 25, 117; (d) E. Juaristi, D. Quintana, J. Escalante, Aldrichimica Acta, 1994, 27, 3. 2. For selected examples, see: (a) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561; (b) C. Palomo, M. Oiarbide, A. Laso, Angew. Chem., Int. Ed., 2005, 44, 3881; (c) G. Cardillo, C. Tomasini, Chem. Soc. Rev., 1996, 25, 117; (d) E. Juaristi, D. Quintana, J. Escalante, Aldrichimica Acta, 1994, 27, 3; (e) A. Bogevig, I. M. Pastor, H. Adolfsson, Chem. Eur. J. 2004, 10, 394; (f) D. G. I. Petra, J. N. H. Reek, J. W. Handgraaf, E. J. Meijer, P. Dierkes, P. C. J. Kamer, J. Brussee, H. E. Schoemaker, P. W. N. M. Van Leeuwen, Chem. Eur. J. 2000, 6, 2818; (g) S. D. Rychnovsky, Chem. Rev., 1995, 95, 2021; (h) N. V. Dubrovina, V. I. Tararov, A. Monsees, R. Kadyrov, C. Fischer, A. Borner, Tetrahedron: Asymmetry, 2003, 14, 2739.

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3. (a) C. Bolm, J. P. Hildebrand, K. Muniz, In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed., Wiley-VCH: New York, 2000, p 399; (b) M. J. McKennon, A. I. Meyer, K. Drautz, M. Schwarm, J. Org. Chem., 1993, 58, 3568; (c) X. P. Yin, X. X. Zeng, Y. L. Liu, F. M. Liao, J. S. Yu, F. Zhou, J. Zhou, Angew. Chem. Int. Ed., 2014, 53, 13740; (d) L. Chen, X. P. Yin, C. H. Wang, J. Zhou, Org. Biomol. Chem., 2014, 12, 6033. 4. A. Lei, S. Wu, M. He, X. Zhang, J. Am. Chem. Soc., 2004, 126, 1626. 5. A. Hu, W. Lin, Org. Lett., 2005, 7, 455. 6. C. Wang, G. Yang, J. Zhuang, W. Zhang, Tetrahedron Lett., 2010, 51, 2044. 7. Y. Q. Wang, S. M. Lu, Y. G. Zhou, Org. Lett., 2005, 7, 3235. 8. Some slective examples: (a) R. Noyori, S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97; (b) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry, 1999, 10, 2045; (c) R. Noyori, Angew Chem., Int. Ed., 2002, 41, 2008; (d) A. Zanotti-Gerosa, W. Hems, M. Groarke, F. Hancock, Platinum Met. Rev. 2005, 49, 158; (e) S. Gladiali, E. Alberico, Chem. Soc. Rev., 2006, 35, 226; (f) J. S. M. Samec, J.-E. Bäckvall, P. G. Andersson, P.Brandt, Chem. Soc. Rev., 2006, 35, 237; (g) T. Ikariya, A. J. Blacker, Acc. Chem. Res., 2007, 40, 1300; (h) C. Wang, X. Wu, J. Xiao, Chem. Asian J., 2008, 3, 1750; (i) R. H. Morris, Chem. Soc. Rev., 2009, 38, 2282; (j) T. Ohkuma, Proc. Jpn. Acad., Ser. B, 2010, 86, 202; (k) R. Malacea, R. Poli, E. Manoury, Coord. Chem. Rev., 2010, 254, 729; (l) M. Darwish, M. Wills, Catal. Sci. Technol. 2012, 2, 243; (m) B. Seashore-Ludlow, F. Saint-Dizier, P. Somfai, Org. Lett., 2012, 14, 6334; (n) Y. Su, Y. Q. Tu, P. Gu, Org. Lett., 2014, 16, 4204; (o) J.-i. Ito, H. Nishiyama, Tetrahedron Lett., 2014, 55, 3133; (p) D. Zhang, T. Cheng, Q. Zhao, J. Xu, G. Liu, Org. Lett., 2014, 16, 5764. 9. (a) K. B. Hansen, J. R. Chilenski, R. Desmond, P. N. Devine, E. J. J. Grabowski, R. Heid, M. Kubryk, D. J. Mathre, R. Varsolona, Tetrahedron: Asymmetry, 2003, 14, 3581; (b) J. Blacker, J. Martin, in: Asymmetric Catalysison Industrial Scale: Challenges, Approaches and Solutions (Eds.: H. U. Blaser, E. Schmidt), Wiley-VCH, Weinheim, Germany, 2004, p.201–216; (c) J. Whittall, in: Catalysts for Fine Chemical Synthesis Regio- and Stereo- Controlled Oxidations and Reductions, vol. 5 (Eds.: S. M. Roberts, J. Whittall), Wiley Chichester, UK, 2007, p. 1–33. 10. (a) R. S. Atkinson, B. J. Kelly, J. Chem. Soc., Chem. Commun. 1987, 1362; (b) A. Bogevig, I. M. Pastor, H. Adolfsson, Chem. Eur. J., 2004, 10, 394; (c) D. G. I. Petra, J. N. H. Reek, J. W. Handgraaf, E. J. Meijer, P. Dierkes, P. C. J. Kamer, J. Brussee, H. E. Schoemaker, P. W. N. M.Van Leeuwen, Chem. Eur. J., 2000, 6, 2818; (d) Oleksandr O. Kovalenko, Helena Lundberg, Dennis Hübner, Hans Adolfsson, Eur. J. Org. Chem., 2014, 2014, 6639; (e) Óscar P, D. Guijarro, M. Yus, Eur. J. Org. Chem., 2014, 2014, 7034; (f) X. Daia, D. Caharda, Adv. Synth. Catal., 2014, 356, 1317. 11. G. K. Patra, I. Goldberg, S. K. Chowdhury, B. C. Maiti, A. Sarkar, P. R. Bangal, S. Chakravorti, N. Chattopadhyay, D. A. Tocher, M. G. B. Drew, G. Mostafa, S. Chowdhury, D. Datta, New Journal of Chemistry, 2001, 25, 1371.

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Highly enantioselective asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones.

A mild catalyst system for the synthesis of chiral amino alcohols via asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones has been develo...
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