CC BY ND NC 4.0 · Synlett 2019; 30(04): 401-404
DOI: 10.1055/s-0037-1610408
letter
Copyright with the author

Design of New Amino Tf-Amide Organocatalysts: Environmentally Benign Approach to Asymmetric Aldol Synthesis

Hyo-Jun Lee
a  Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan   Email: maruoka@kuchem.kyoto-u.ac.jp
,
Natarajan Arumugam
b  Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
,
Abdulrahman I. Almansour
b  Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
,
Raju Suresh Kumar
b  Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
,
a  Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan   Email: maruoka@kuchem.kyoto-u.ac.jp
c  School of Chemical Engineering and Light Industry, Guangdong University of Technology, No.100, West Waihuan Road, HEMC, Panyu District, Guangzhou, 510006, P. R. of China
› Author Affiliations
This work was partially supported by a Grant-in-Aid for Scientific Research from MEXT, Japan (Grant Number JP26220803, JP17H06450). The authors also extend their gratitude to the International Scientific Partnership Program (ISPP) at the King Saud University for financial support via ISPP#0072.
Further Information

Publication History

Received: 08 October 2018

Accepted after revision: 13 November 2018

Publication Date:
19 December 2018 (eFirst)

 

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A new type of optically pure primary amino aromatic Tf-amide organocatalyst can be easily prepared from 8-amino-1-tetralone, and its chemical behavior was investigated in the context of asymmetric aldol and Mannich reactions. Most notably, the asymmetric aldol reaction proceeded smoothly in brine.


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Among various types of amine-based, chiral, and bifunctional organocatalysts, amino Tf-amide organocatalysts are very reliable in various asymmetric transformations that include asymmetric aldol, Mannich, and conjugate addition reactions.[1] [2] In 2005, we reported the design of chiral binaphthyl-modified secondary amino Tf-amide organocatalysts of the type 1, which effectively promote anti-selective direct asymmetric Mannich reactions and syn-selective direct asymmetric cross-aldol reactions (Figure [1]).[3] Later, we prepared structurally similar chiral biphenyl-modified secondary amino Tf-amide organocatalysts of type 2.[4] Moreover, we also designed primary amino Tf-amide organocatalysts of the type 3 and 4 for asymmetric aldol reactions and asymmetric conjugate additions.[5] [6] Compared to primary amino aliphatic Tf-amide organocatalysts of the type 3 and 4, which are not applicable to asymmetric ­Mannich-type reactions, the catalysts 1 and 2 exhibit a high nucleophilicity of the secondary amino moiety in addition to the acidic, aromatic Tf-amide hydrogen atom. However, due to the laborious synthesis of 1 and 2,[3] [4] the design and synthesis of easily accessible reactive amine Tf-amide organocatalysts represent a desirable research target.[7] [8] Our strategy is based on the enhancement of the reactivity of the acidic Tf-amide moiety by introducing an aromatic Tf-amide moiety as illustrated in primary amino Tf-amide organocatalysts of type 5, which could accelerate asymmetric aldol and Mannich reactions.

Zoom Image
Figure 1 Previously and newly designed amino Tf-amide organocatalysts 15

Initially, we prepared various types of primary amino aromatic Tf-amide organocatalysts (610) and evaluated their reactivity and selectivity in asymmetric direct aldol reactions (Table [1]). For this purpose, a series of aldol reactions between 4-nitrobenzaldehyde and cyclohexanone was carried out in the presence of catalysts 610 in aqueous THF at room temperature (Table [1], entries 1–5).[9] Among these catalysts, 9 afford the highest stereoselectivity, giving the anti-aldol product (anti-11a) with 97% anti-selectivity and 99% ee, albeit that 120 h are required for 60% yield (Table [1], entry 4). Subsequently, we carried out a solvent screening in order to improve the reactivity (Table [1], entries 6–11). Among the solvents tested, aqueous solvents, in particular brine, dramatically accelerated the rate of the asymmetric aldol reactions (Table [1], entries 9 and 10), furnishing anti-11a in high yield with excellent stereoselectivity.[10] However, the low reactivity and selectivity were observed in the reaction in anhydrous DMSO (Table [1], entry 11).[5b] Lowering the catalyst loading to 5 mol% did not affect the anti- or enantioselectivity (Table [1], entry 12). However, carrying out the reaction with 2 mol% of 9 slightly diminished the reactivity and afforded anti-11 with lower stereoselectivities (Table [1], entry 13).

Table 1 Optimization of the Catalysts and Reaction Conditions in the Asymmetric Direct Aldol Reactions between 4-Nitrobenzaldehyde and Cyclohexanonea

Entry

Catalyst (x mol%)

Solvent

Time (h)

Yield (%)b

anti/syn c

ee (%)d

 1

6 (10)

THF/H2O

168

32

75:25

89

 2

7 (10)

THF/H2O

168

 8

45:55

11

 3

8 (10)

THF/H2O

 48

96

90:10

97

 4

9 (10)

THF/H2O

120

60

97:3

99

 5

10 (10)

THF/H2O

120

96

93:7

86

 6

9 (10)

DMSO/H2O

 40

92

97:3

99

 7

9 (10)

EtOH/H2O

120

72

87:13

83

 8

9 (10)

neat

 24

69

94:6

99

 9

9 (10)

H2O

 20

91

97:3

99

10

9 (10)

brine

 12

91

97:3

99

11

9 (10)

DMSO

 72

62

95:5

98

12

9 (5)

brine

 24

92

97:3

99

13

9 (2)

brine

 48

92

97:3

99

a Unless otherwise specified, the asymmetric direct aldol reaction between cyclohexanone and 4-nitrobenzaldehyde was carried out in the presence of 2–10 mol% of 610 at room temperature.

b Isolated yield.

c The anti/syn ratio was determined by 1H NMR analysis.

d % ee of major anti-isomer.

Subsequently, the scope of the asymmetric direct aldol reaction between cycloalkanones and various benzaldehydes in brine solvent was investigated under the optimized conditions using 5 mol% of 9 (Table [2]).[11] The reactions involving benzaldehydes bearing strong electron-withdrawing substituent(s) at any position of the phenyl group furnished the corresponding aldol products 11 in high yields, with excellent anti- and enantioselectivity (Table [2], entries 1–7). Especially the heteroaromatic nicotinic and isonicotinic aldehydes afforded 11 in excellent yield and selectivity (Table [2], entries 8 and 9). Even though the reactivity for 4-halobenzaldehydes was slightly lower, these reactions still showed excellent stereoselectivity (Table [2], entries 10 and 11). When benzaldehyde was employed, the corresponding aldol product 11l (Ar = Ph; R1 and R2 = -(CH2)4-) was obtained in moderate yield with high anti- and enantioselectivity (Table [2], entry 12). The use of cyclopentanone as the aldol donor also showed high reactivity and stereoselectivity for the corresponding aldol product 11m (Ar = 4-NO2-C6H4; R1 and R2 = -(CH2)3-; Table [2], entry 13). Cycloheptanone and acetone provided the corresponding aldol products in good yield with high stereoselectivity, though 10 mol% of 9 were required (Table [2], entries 14 and 15).

Table 2 Asymmetric Direct Aldol Reaction of Cycloalkanone and Substituted Benzaldehydes Catalyzed by Organocatalyst 9 a

Entry

Ar, R1, R2

11

Time (h)

Yield (%)b

anti/syn c

ee (%)d

 1

4-NO2-C6H4, –(CH2)4

11a

24

92

97:3

99

 2

4-CF3-C6H4, –(CH2)4

11b

30

96

95:5

99

 3

4-CN-C6H4, –(CH2)4

11c

30

96

97:3

98

 4

4-CO2Me-C6H4, –(CH2)4

11d

48

88

97:3

99

 5

2-NO2-C6H4, –(CH2)4

11e

24

88

97:3

99

 6

3-NO2-C6H4, –(CH2)4

11f

48

84

98:2

99

 7

C6F5, –(CH2)4

11g

30

88

99:1

97

 8

3-pyridyl, –(CH2)4

11h

36

92

96:4

99

 9

4-pyridyl, –(CH2)4

11i

20

98

94:6

99

10

4-Cl-C6H4, –(CH2)4

11j

48

55

97:3

99

11

4-Br-C6H4, –(CH2)4

11k

48

72

97:3

99

12

C6H5, –(CH2)4

11l

48

47

94:6

98

13

4-NO2-C6H4, –(CH2)3

11m

18

89

91:9

99

14e

4-NO2-C6H4, –(CH2)5

11n

48

92

88:12

89

15e

4-NO2-C6H4, CH3, H

11o

48

80

87

a Unless otherwise specified, the asymmetric direct aldol reaction between cycloalkanone and the substituted benzaldehydes was carried out in brine in the presence of 5 mol% of 9 at room temperature.

b Isolated yield.

c The anti/syn ratio was determined by 1H NMR analysis.

d % ee of major anti-isomer.

e 10 mol% of 9 was used.

In order to demonstrate the applicability of the catalyst 9 in asymmetric transformations, we carried out asymmetric direct Mannich reaction between cyclic ketones and α-imino ester 12 in the presence of catalytic amounts of 9 in THF at room temperature (Scheme [1]), which afforded the anti-Mannich products 13a (anti/syn = 93:7; 95% ee (anti)), 13b (anti/syn = 96:4; 97% ee (anti)), and 13c (anti/syn = 97:3; 92% ee (anti)) in high yield.[12]

Zoom Image
Scheme 1 Asymmetric Mannich reaction between cyclic ketone and α-imino ester 13 catalyzed by organocatalyst 9.
Zoom Image
Scheme 2 Reagents and conditions: (a) Ti(OEt)4, THF, 70 °C or 90 °C; (b) DIBAL-H, THF, –78 °C; (c) (i) HCl, dioxane, MeOH, rt; (ii) Boc2O, CH2Cl2, rt; (d) (i) Tf2O, Et3N, CH2Cl2, –78 °C; (ii) TFA, CH2Cl2, rt.

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Supporting Information

  • References and Notes


    • Recent reviews on amine-based organocatalysts:
    • 1a Kano T, Maruoka K. Chem. Commun. 2008; 5465
    • 1b Lui X, Lin L, Feng X. Chem. Commun. 2009; 6145
    • 1c Yang H, Carter RG. Synlett 2010; 2827
    • 1d Giacalone F, Gruttadauria M, Agrigento P, Noto R. Chem. Soc. Rev. 2012; 41: 2406
    • 1e Melchiorre P. Angew. Chem. Int. Ed. 2012; 52: 9748
    • 1f Kano T, Maruoka K. Chem. Sci. 2013; 4: 907
    • 1g Duan J, Li P. Catal. Sci. Technol. 2014; 4: 311
    • 1h Kumar P, Sharma BM. Synlett 2018; 29: 1994
    • 1i Zhu L, Wang D, Jia Z, Lin Q, Huang M, Luo S. ACS Catal. 2018; 8: 5466

      Recent reviews on amino-catalyzed asymmetric aldol and Mannich reactions:
    • 2a Trost BM, Brindle CS. Chem. Soc. Rev. 2010; 39: 1600
    • 2b Hernández JG, Juaristi E. Chem. Commun. 2012; 48: 5396
    • 2c Heravi MM, Zadsirjan V, Dehghani M, Hosseintash N. Tetrahedron: Asymmetry 2017; 28: 587
    • 2d Saranya S, Harry NA, Krishnan KK, Anilkumar G. Asian J. Org. Chem. 2018; 7: 613
    • 2e Yamashita Y, Yasukawa T, Yoo W.-J, Kitanosono T, Kobayashi S. Chem. Soc. Rev. 2018; 47: 4388
    • 3a Kano T, Yamaguchi Y, Tokuda O, Maruoka K. J. Am. Chem. Soc. 2005; 127: 16408
    • 3b Kano T, Yamaguchi Y, Tanaka Y, Maruoka K. Angew. Chem. Int. Ed. 2007; 46: 1738
    • 3c Kano T, Yamamoto A, Maruoka K. Tetrahedron Lett. 2008; 49: 5369
    • 3d Kano T, Yamaguchi Y, Maruoka K. Angew. Chem. Int. Ed. 2009; 48: 1838
    • 3e Kano T, Yamaguchi Y, Maruoka K. Chem. Eur. J. 2009; 15: 6678

    • See also:
    • 3f Kano T, Ueda M, Takai J, Maruoka K. J. Am. Chem. Soc. 2006; 128: 6046
    • 4a Kano T, Sugimoto H, Maruoka K. J. Am. Chem. Soc. 2011; 133: 18130
    • 4b Kano T, Song S, Maruoka K. Angew. Chem. Int. Ed. 2012; 51: 1191
    • 4c Kano T, Song S, Maruoka K. Chem. Commun. 2012; 48: 7037
    • 5a Nakayama K, Maruoka K. J. Am. Chem. Soc. 2008; 130: 17666
    • 5b Moteki SA, Maruyama H, Nakayama K, Li H.-B, Petrova G, Maeda S, Morokuma K, Maruoka K. Chem. Asian. J. 2015; 10: 2112
    • 5c Lee H.-J, Moteki SA, Arumugam N, Almansour AI, Kumar RS, Liu Y, Maruoka K. Asian J. Org. Chem. 2017; 6: 1226
    • 5d Lee H.-J, Arumugam N, Almansour AI, Kumar RS, Maruoka K. Tetrahedron 2018; 74: 5263
  • 6 Moteki SA, Xu S, Arimitsu S, Maruoka K. J. Am. Chem. Soc. 2010; 132: 17074
  • 7 The synthesis of the primary amino aromatic Tf-amide organocatalysts 610 was carried out according to Scheme 2 (see Supporting Information for details).
  • 8 The absolute configurations of the catalysts were assigned based on the X-ray diffraction analysis of the sulfonamide intermediate of catalyst 9b. The corresponding data have been deposited at the Cambridge Crystallographic Data Center and can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures. CCDC 1870339 contains the supplementary crystallographic data for this paper.

    • Reviews of amino-catalyzed asymmetric aldol reaction in aqueous media:
    • 9a Bhowmick S, Bhowmick KC. Tetrahedron: Asymmetry 2011; 22: 1945
    • 9b Kitanosono T, Kobayashi S. Adv. Synth. Catal. 2013; 355: 3095
    • 9c Mlynarski J, Bas S. Chem. Soc. Rev. 2014; 43: 557
    • 9d Bhowmick S, Mondal A, Ghosh A, Bhowmick KC. Tetrahedron: Asymmetry 2015; 26: 1215

      Selected examples for asymmetric aldol reaction in water or brine:
    • 10a Mase N, Nakai Y, Ohara N, Yoda H, Takabe K, Tanaka J, Barbas III CF. J. Am. Chem. Soc. 2006; 128: 734
    • 10b Ma X, Da C.-S, Yi L, Jia Y.-N, Guo Q.-P, Che L.-P, Wu F.-C, Wang J.-R, Li W.-P. Tetrahedron: Asymmetry 2009; 20: 1419
    • 10c Miura T, Kasuga H, Imai K, Ina M, Tada N, Imai N, Itoh A. Org. Biomol. Chem. 2012; 10: 2209
    • 10d Qiao Y, Chen Q, Lin S, Ni B, Headley AD. J. Org. Chem. 2013; 78: 2693
    • 10e Hu X.-M, Zhang D.-X, Zhang S.-Y, Wang P.-A. RSC Adv. 2015; 5: 39557
  • 11 General Procedure for the Asymmetric Aldol Reaction Using the Catalyst 9 for the Preparation of 11 To a mixture of catalyst 9 (3 mg, 5 mol%) and benzaldehyde (0.2 mmol) in brine (1.2 mL) was added ketone (6.0 mmol). The homogenous mixture was stirred at room temperature for the appropriate time until the reaction was completed (TLC). Then, a saturated NH4Cl solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:3) to afford the product 11. (R)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one (anti-11a) White solid. 1H NMR (CDCl3, 500 MHz): δ = 8.22–8.11 (m, 2 H), 7.52–7.49 (m, 2 H), 4.90 (d, J = 8.0 Hz, 1 H), 4.07, (br s, 1 H), 2.61–2.56 (m, 1 H), 2.52–2.47 (m, 1 H), 2.40–2.33, (m, 1 H), 2.14–2.08 (m, 1 H), 1.85–1.80 (m, 1 H), 1.72–1.62 (m, 1 H), 1.60–1.51 (m, 2 H), 1.42–1.33 (m, 1 H). 13C NMR (CDCl3, 125 MHz): δ = 214.7, 148.3, 147.5, 127.8, 123.5, 74.0, 57.1, 42.6, 30.7, 27.6, 24.6. HRMS (ESI): m/z calcd for C13H15O4NNa: 272.0893 [M + Na]+; found: 272.0895. [α]D 24 –11.2 (CHCl3, c 0.9, 99% ee).
  • 12 General Procedure for the Asymmetric Mannich Reaction Using Catalyst 9 for the Preparation of 13 To a mixture of catalyst 9 (3 mg, 5 mol%) and α-imino ester 12 (42 mg, 0.2 mmol) in THF (1.2 mL) was added ketone (6.0 mmol). The mixture was stirred at room temperature for 12 h. Then, a saturated NH4Cl solution was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:4) to afford the product 13. Ethyl (R)-2-[(4-Methoxyphenyl)amino]-2-[(S)-2-oxocyclohexyl]-acetate (anti-13a) Colorless oil. 1H NMR (CDCl3, 500 MHz): δ = 6.77–6.73 (m, 2 H), 6.64–6.61 (m, 2 H), 4.24 (br s, 1 H), 4.18–4.10 (m, 2 H), 3.98 (d, J = 4.5 Hz, 1 H), 3.73 (s, 3 H), 3.12–3.08 (m, 1 H), 2.45–2.40 (m, 1 H), 2.35–2.29 (m, 1 H), 2.13–2.09 (m, 1 H), 2.07–2.02 (m, 1 H), 1.96–1.87 (m, 2 H), 1.78–1.62 (m, 2 H), 1.21 (t, J = 7.5 Hz, 3 H). 13C NMR (CDCl3, 125 MHz): δ = 210.9, 173.0, 152.7, 142.1, 115.6, 114.7, 61.1, 59.0, 55.7, 53.5, 41.8, 30.5, 26.8, 24.5, 14.1. HRMS (ESI): m/z calcd for C17H23O4NNa: 328.1519 [M + Na]+; found: 328.1526. [α]D 24 –22.4 (CHCl3, c 0.7, 95% ee).

  • References and Notes


    • Recent reviews on amine-based organocatalysts:
    • 1a Kano T, Maruoka K. Chem. Commun. 2008; 5465
    • 1b Lui X, Lin L, Feng X. Chem. Commun. 2009; 6145
    • 1c Yang H, Carter RG. Synlett 2010; 2827
    • 1d Giacalone F, Gruttadauria M, Agrigento P, Noto R. Chem. Soc. Rev. 2012; 41: 2406
    • 1e Melchiorre P. Angew. Chem. Int. Ed. 2012; 52: 9748
    • 1f Kano T, Maruoka K. Chem. Sci. 2013; 4: 907
    • 1g Duan J, Li P. Catal. Sci. Technol. 2014; 4: 311
    • 1h Kumar P, Sharma BM. Synlett 2018; 29: 1994
    • 1i Zhu L, Wang D, Jia Z, Lin Q, Huang M, Luo S. ACS Catal. 2018; 8: 5466

      Recent reviews on amino-catalyzed asymmetric aldol and Mannich reactions:
    • 2a Trost BM, Brindle CS. Chem. Soc. Rev. 2010; 39: 1600
    • 2b Hernández JG, Juaristi E. Chem. Commun. 2012; 48: 5396
    • 2c Heravi MM, Zadsirjan V, Dehghani M, Hosseintash N. Tetrahedron: Asymmetry 2017; 28: 587
    • 2d Saranya S, Harry NA, Krishnan KK, Anilkumar G. Asian J. Org. Chem. 2018; 7: 613
    • 2e Yamashita Y, Yasukawa T, Yoo W.-J, Kitanosono T, Kobayashi S. Chem. Soc. Rev. 2018; 47: 4388
    • 3a Kano T, Yamaguchi Y, Tokuda O, Maruoka K. J. Am. Chem. Soc. 2005; 127: 16408
    • 3b Kano T, Yamaguchi Y, Tanaka Y, Maruoka K. Angew. Chem. Int. Ed. 2007; 46: 1738
    • 3c Kano T, Yamamoto A, Maruoka K. Tetrahedron Lett. 2008; 49: 5369
    • 3d Kano T, Yamaguchi Y, Maruoka K. Angew. Chem. Int. Ed. 2009; 48: 1838
    • 3e Kano T, Yamaguchi Y, Maruoka K. Chem. Eur. J. 2009; 15: 6678

    • See also:
    • 3f Kano T, Ueda M, Takai J, Maruoka K. J. Am. Chem. Soc. 2006; 128: 6046
    • 4a Kano T, Sugimoto H, Maruoka K. J. Am. Chem. Soc. 2011; 133: 18130
    • 4b Kano T, Song S, Maruoka K. Angew. Chem. Int. Ed. 2012; 51: 1191
    • 4c Kano T, Song S, Maruoka K. Chem. Commun. 2012; 48: 7037
    • 5a Nakayama K, Maruoka K. J. Am. Chem. Soc. 2008; 130: 17666
    • 5b Moteki SA, Maruyama H, Nakayama K, Li H.-B, Petrova G, Maeda S, Morokuma K, Maruoka K. Chem. Asian. J. 2015; 10: 2112
    • 5c Lee H.-J, Moteki SA, Arumugam N, Almansour AI, Kumar RS, Liu Y, Maruoka K. Asian J. Org. Chem. 2017; 6: 1226
    • 5d Lee H.-J, Arumugam N, Almansour AI, Kumar RS, Maruoka K. Tetrahedron 2018; 74: 5263
  • 6 Moteki SA, Xu S, Arimitsu S, Maruoka K. J. Am. Chem. Soc. 2010; 132: 17074
  • 7 The synthesis of the primary amino aromatic Tf-amide organocatalysts 610 was carried out according to Scheme 2 (see Supporting Information for details).
  • 8 The absolute configurations of the catalysts were assigned based on the X-ray diffraction analysis of the sulfonamide intermediate of catalyst 9b. The corresponding data have been deposited at the Cambridge Crystallographic Data Center and can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures. CCDC 1870339 contains the supplementary crystallographic data for this paper.

    • Reviews of amino-catalyzed asymmetric aldol reaction in aqueous media:
    • 9a Bhowmick S, Bhowmick KC. Tetrahedron: Asymmetry 2011; 22: 1945
    • 9b Kitanosono T, Kobayashi S. Adv. Synth. Catal. 2013; 355: 3095
    • 9c Mlynarski J, Bas S. Chem. Soc. Rev. 2014; 43: 557
    • 9d Bhowmick S, Mondal A, Ghosh A, Bhowmick KC. Tetrahedron: Asymmetry 2015; 26: 1215

      Selected examples for asymmetric aldol reaction in water or brine:
    • 10a Mase N, Nakai Y, Ohara N, Yoda H, Takabe K, Tanaka J, Barbas III CF. J. Am. Chem. Soc. 2006; 128: 734
    • 10b Ma X, Da C.-S, Yi L, Jia Y.-N, Guo Q.-P, Che L.-P, Wu F.-C, Wang J.-R, Li W.-P. Tetrahedron: Asymmetry 2009; 20: 1419
    • 10c Miura T, Kasuga H, Imai K, Ina M, Tada N, Imai N, Itoh A. Org. Biomol. Chem. 2012; 10: 2209
    • 10d Qiao Y, Chen Q, Lin S, Ni B, Headley AD. J. Org. Chem. 2013; 78: 2693
    • 10e Hu X.-M, Zhang D.-X, Zhang S.-Y, Wang P.-A. RSC Adv. 2015; 5: 39557
  • 11 General Procedure for the Asymmetric Aldol Reaction Using the Catalyst 9 for the Preparation of 11 To a mixture of catalyst 9 (3 mg, 5 mol%) and benzaldehyde (0.2 mmol) in brine (1.2 mL) was added ketone (6.0 mmol). The homogenous mixture was stirred at room temperature for the appropriate time until the reaction was completed (TLC). Then, a saturated NH4Cl solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:3) to afford the product 11. (R)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one (anti-11a) White solid. 1H NMR (CDCl3, 500 MHz): δ = 8.22–8.11 (m, 2 H), 7.52–7.49 (m, 2 H), 4.90 (d, J = 8.0 Hz, 1 H), 4.07, (br s, 1 H), 2.61–2.56 (m, 1 H), 2.52–2.47 (m, 1 H), 2.40–2.33, (m, 1 H), 2.14–2.08 (m, 1 H), 1.85–1.80 (m, 1 H), 1.72–1.62 (m, 1 H), 1.60–1.51 (m, 2 H), 1.42–1.33 (m, 1 H). 13C NMR (CDCl3, 125 MHz): δ = 214.7, 148.3, 147.5, 127.8, 123.5, 74.0, 57.1, 42.6, 30.7, 27.6, 24.6. HRMS (ESI): m/z calcd for C13H15O4NNa: 272.0893 [M + Na]+; found: 272.0895. [α]D 24 –11.2 (CHCl3, c 0.9, 99% ee).
  • 12 General Procedure for the Asymmetric Mannich Reaction Using Catalyst 9 for the Preparation of 13 To a mixture of catalyst 9 (3 mg, 5 mol%) and α-imino ester 12 (42 mg, 0.2 mmol) in THF (1.2 mL) was added ketone (6.0 mmol). The mixture was stirred at room temperature for 12 h. Then, a saturated NH4Cl solution was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:4) to afford the product 13. Ethyl (R)-2-[(4-Methoxyphenyl)amino]-2-[(S)-2-oxocyclohexyl]-acetate (anti-13a) Colorless oil. 1H NMR (CDCl3, 500 MHz): δ = 6.77–6.73 (m, 2 H), 6.64–6.61 (m, 2 H), 4.24 (br s, 1 H), 4.18–4.10 (m, 2 H), 3.98 (d, J = 4.5 Hz, 1 H), 3.73 (s, 3 H), 3.12–3.08 (m, 1 H), 2.45–2.40 (m, 1 H), 2.35–2.29 (m, 1 H), 2.13–2.09 (m, 1 H), 2.07–2.02 (m, 1 H), 1.96–1.87 (m, 2 H), 1.78–1.62 (m, 2 H), 1.21 (t, J = 7.5 Hz, 3 H). 13C NMR (CDCl3, 125 MHz): δ = 210.9, 173.0, 152.7, 142.1, 115.6, 114.7, 61.1, 59.0, 55.7, 53.5, 41.8, 30.5, 26.8, 24.5, 14.1. HRMS (ESI): m/z calcd for C17H23O4NNa: 328.1519 [M + Na]+; found: 328.1526. [α]D 24 –22.4 (CHCl3, c 0.7, 95% ee).

 
Zoom Image
Figure 1 Previously and newly designed amino Tf-amide organocatalysts 15
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Scheme 1 Asymmetric Mannich reaction between cyclic ketone and α-imino ester 13 catalyzed by organocatalyst 9.
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Scheme 2 Reagents and conditions: (a) Ti(OEt)4, THF, 70 °C or 90 °C; (b) DIBAL-H, THF, –78 °C; (c) (i) HCl, dioxane, MeOH, rt; (ii) Boc2O, CH2Cl2, rt; (d) (i) Tf2O, Et3N, CH2Cl2, –78 °C; (ii) TFA, CH2Cl2, rt.