Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins

Accepted Manuscript Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins Amarjit Kaur, Kamal Nain Singh, Esha Sharma Shilpy, Poonam Rani, Sandeep Kumar Sharma PII:

S0040-4020(18)31055-X

DOI:

10.1016/j.tet.2018.09.002

Reference:

TET 29774

To appear in:

Tetrahedron

Received Date: 5 April 2018 Revised Date:

30 August 2018

Accepted Date: 2 September 2018

Please cite this article as: Kaur A, Singh KN, Shilpy ES, Rani P, Sharma SK, Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins, Tetrahedron (2018), doi: 10.1016/j.tet.2018.09.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins.

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Graphical Abstract

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Amarjit Kaura,* Kamal Nain Singha, Esha Sharma,a Shilpya, Poonam Rania, Sandeep Kumar Sharmaa Department of chemistry, Panjab University, Chandigarh. 160014.

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Tetrahedron journal homepage: www.elsevier.com

Michael addition of ketones to nitroolefins Dedicated to Prof. S. V. Kessar.

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Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric

a

Department of chemistry, Panjab University, Chandigarh, 160014.

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Amarjit Kaura, ∗, Kamal Nain Singha, Esha Sharmaa, Shilpya, Poonam Rania, Sandeep Kumar Sharma.a

ABSTRACT

Article history: Received Received in revised form Accepted Available online

The novel ((S)-pyrrolidin-2-yl)methyl phenylcarbamate was synthesized and used as an efficient organocatalyst for the asymmetric Michael addition of cyclic/acyclic ketones to nitroolefins. Interestingly, the resulting Michael adducts were obtained in good to high yields (up to 96%) with excellent stereoselectivity (ee up to >99%, dr up to >99:1) without using any additive.

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ARTICLE INFO

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Keywords: Pyrrolidine Carbamate Asymmetric synthesis Nitroolefins Michael addition

∗ Corresponding author. Tel.: +91-172-253-4425; fax: +91-172-222-2918; e-mail: [email protected]

2009 Elsevier Ltd. All rights reserved.

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1. Introduction

The development of small molecules as efficient chiral organocatalysts have attracted considerable attention from a large number of research groups working in the area of asymmetric synthesis.1,2 The asymmetric Michael addition reaction of carbonyl compounds and nitroolefins to afford γ–nitrocarbonyls is widely recognized due to its versatile utility in organic synthesis.3,4 Pyrrolidine based organocatalysts bearing other functional groups such as chiral sulfonamides,5a diaryl prolinols,5b the corresponding amide,5c,d triazole,6a-c tetrazole,6d-f amine thiourea,7 thio-hydantoins8 etc. also proved that such bifunctional molecules can catalyze a variety of asymmetric transformations. Carbamates and thiocarbamates have been studied in the field of medicinal chemistry on account of their diverse and useful biological activities.9 However, despite of having been well studied for their synthesis and biological properties, there are only a few reports on their application as organocatalysts for asymmetric organic transformations.10 Stimulated by these findings and in continuation with our search for new and efficient organocatalysts,11 we have developed novel bifunctional organocatalyst by combining L-prolinol with phenylisocyanate to give corresponding carbamate 1. We explored the use of chiral carbamate 1 in asymmetric Michael addition. This catalyst was found to be very efficient for stereoselective conjugate addition of ketones (cyclic/acyclic) to various aryl substituted nitro olefins and afforded the corresponding Michael adducts in high yield (up to 96%), with excellent enantio- and diastereoselectivity (ee up to >99%, dr up to >99:1). The results are described in this paper.

COOH N Boc 3

BMS

N CO

N Boc 4 (93%)

THF

BF3.Et2O THF, reflux

DMAP DCM

N Boc

N H

HN 5 (91%)

S

O

HCOOH N H

HN 6 (42%)

S HN

2 (81%)

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Our initial study commenced with the reaction of cyclohexanone (7a) and trans β-nitrostyrene (8a) in the presence of chiral catalyst 1. Use of 20 mol% of catalyst 1 in chloroform at room temperature, without any additive, gave Michael adduct 9a in 84% yield with high syn diastereoselectivity (dr >99:1) and good enantioselectivity (87% ee) (Table 1, entry 1). Lowering of reaction temperature in chloroform as solvent did not further increase the enantioselectivity (Table 1, entry 2). To further optimize the reaction conditions, a variety of solvents were screened. Catalytic system was found to be effective for non polar, polar and polar-protic solvent systems (Table 1). Best results were obtained using toluene as the solvent medium and the corresponding Michael adduct 9a was obtained in excellent yield 96% and stereoselectivity (ee >99% and dr >99:1) (Table 1, entry 6). However trace amount of product was observed when water or brine was used as solvent. To check the importance of carbamate and O-thiocarbamate functionality in the side chain of organocatalyst on the stereochemical outcome of the reaction, organocatalyst 2 was also screened for asymmetric Michael addition of cyclohexanone (7a) to β-nitrostyrene (8a) under optimized reaction conditions, surprisingly trace amount of product was obtained when organocatalyst 2 was employed (Table 1, entry 13). On changing the solvent system from toluene to toluene:methanol (1:1) under same catalytic system, afforded the Michael adduct in 42% yield after stirring for 4 days at rt with enantioselectivity (23% ee) and high diastereoselectivity (Table 1, entry 14). The observed results clearly showed that carbamate moiety in combination with pyrrolodine –NH itself effectively catalyze and control the stereochemical outcome of the reaction. The phenyl ring of the carbamate 1 need not be substituted with strongly electron withdrawing groups such as – CF3 and -NO2 or with bulkier substituent to stabilize the favored transition state, which controls the stereochemistry of the Michael adduct formed as is the case with most of the bifunctional organocatalysts14 reported in the literature for such transformations.

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Table 1 Optimization of reaction conditionsa:

O

O

NO2

NO2

1, 20 mol % solvent, rt 7a

9a

8a

Entry

Solvent

Time (h)

Yieldb (%)

eec (%)

drd (syn:anti)

1

CHCl3

28

84

87

>99:1

e

CHCl3

36

80

88

99:1

3

CH2Cl2

26

86

90

98:2

2

HN

Scheme 1: Synthesis of organocatalysts 1 and 2

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The chiral catalysts 1 and 2 employed in this work were easily synthesized, according to reaction scheme 1. Reduction of Bocprotected L-proline 3 with borane-methyl sulfide complex (BMS) afforded the alcohol 4.12 On treating alcohol 4 with phenylisocyante in the presence of catalytic amount of DMAP gave corresponding carbamate 5. To synthesize the sulfur analogue of 5, alcohol 4 was refluxed in THF with phenylisothiocyanate in the presence of BF3.Et2O to give corresponding O-thiocarbamate 6. N-Boc deprotection of 5 and 6 with formic acid13 furnished the organocatalysts 1 and 2 respectively.

O

1 (84%)

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2. Results and discussion

O

HCOOH

N C S

O N Boc

O

O

OH

4

91

99:1

5

Ether

35

81

92

>99:1

6

Toluene

24

96

>99

>99:1

7

DMSO

27

75

98

>99:1

8

DMF

30

79

97

99:1

9

MeOH

32

88

97

98:2

10

EtOH

34

85

95

97:3

11

Water

72

traces

-

-

12

Brine

72

traces

-

-

Toluene

72

traces

Toluene:MeOH

96

42

14f

(1:1) a

Reaction conditions: nitrostyrene (1.3 mmol), cyclohexanone (2.6 mmol), catalyst 1 (20 mol %), solvent (10.0 mL), rt. Isolated yield. Determined by chiral HPLC using Chiralpak AS-H column. d Determined by 1H NMR analysis of crude sample. e Reaction was performed at 0 °C. f Reaction was carried out in the presence of 2 (20 mol %) as an organocatalyst. b c

Table 2: Effect of catalyst loadinga

-

99:1

concentration of the catalyst i.e. 10 mol% and 15 mol% (Table 2, entry 2, 3). Increase in the catalyst loading up to 25 mol% did not show any remarkable effect on reaction time, yield and stereoselectivity. Hence, the use of 20 mol% of catalyst at room temperature provided the best optimized reaction conditions.

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Next, using toluene as a solvent, the effect of catalyst loading was evaluated and results are summarized in Table 2. The decrease in catalyst loading (5 mol %) resulted in lower yield, without affecting the stereoselectivity of the reaction. Prolonged reaction time was required to complete the reaction with lower

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Entry

Catalyst 1 (mol%)

Time (h)

Yieldb (%)

eec (%)

drd (syn:anti)

1

5

96

70

99

99:1

2

10

90

88

99

99:1

3

15

71

89

>99

99:1

4

20

24

96

>99

>99:1

5

25

24

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>99:1

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3

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Reaction conditions: nitrostyrene (1.3 mmol), cyclohexanone (2.6 mmol), toluene (10.0 mL), rt. b Isolated yield. c Determined by chiral HPLC using Chiralpak AS-H column. d Determined by 1H NMR analysis of crude sample.

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With the optimized reaction conditions in hand, asymmetric Michael addition of ketones 7 (cyclic/acyclic) to various substituted nitroolefins 8 was investigated and results are shown in Table 3. The corresponding Michael adducts 9 were obtained in good to excellent yields with high enatio- and diastereoselectivity. The catalyst 1 effectively catalyze the Michael addition of cyclohexanone to nitrostyrenes bearing different substituents such as methoxy (Table 3 entries 2-4), nitro as well as chloro (Table 3 entries 7,8) irrespective of their position on aromatic ring. The benzyl substituent on the aryl group of nitroolefin 8f causes the significant decrease in the enantioselectivity (ee =52%) (Table 3, entry 6). The reason may

Table 3: Asymmetric Michael addition catalyzed by 1a

be the bulkier benzyl group hinders the effective approach of nitrostyrene to enamine intermediate formed during the course of reaction. Interestingly, the given catalytic system was also found to be effective for acetone and diethyl ketone as Michael donor to afford the corresponding Michael adduct in excellent yield and stereoselectivity (Table 3, entries 10-12). It is pertinent to note here that most of the catalytic systems reported, for such transformations are not simultaneously effective for both cyclic and acyclic Michael donors.15 However, the reaction with cyclopentanone gave the corresponding adduct in good yield with moderate stereoselectivity (Table 3, entry 13).

Time (h)MANUSCRIPT Product 9 Yield ACCEPTED

4 eec (%)

drd (syn:anti)

96

>99

>99:1

9b

93

>99

>99:1

25

9c

90

99

>99:1

2-Cl,3,4-(OCH3)2C6H2

32

9d

89

>99

99:1

8e

3-OCH3,4-OEt,C6H3

28

9e

93

95

>99:1

6

8f

3-OCH3,4-OCH2PhC6H3

30

9f

89

52

>99:1

7

8g

4-NO2C6H4

28

9g

90

98

98:2

8

8h

4-ClC6H4

30

9h

90

95

>99:1

9

8i

benzo[d][1,3]dioxol-5-yl

27

9i

93

98

>99:1

7

8

1

O

8a

C6H5

24

9a

2

8b

3-OCH3C6H4

26

3

8c

4-OCH3C6H4

8d

5

4

7a

Ar

b

(%)

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Entry

O

8a

C6H5

24

9j

93

98

-

11

7b

8j

4-ClC6H4

25

9k

92

95

-

12

O

8a

C6H5

35

9l

90

99:1

8a

C6H5

82

86:14

O

88

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7d a

9m

84

Reaction conditions: nitroalkene (1.0 equiv, 0.2 g scale), ketone (2.0 equiv), catalyst 1 (20 mol %) toluene (10.0 mL), rt. Isolated yield. Determined by chiral HPLC. d Determined by 1H NMR analysis of crude sample. b

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The possible transition state model15a,16 was proposed to explain the stereochemical outcome of the asymmetric Michael addition reaction (Figure 1). Ketones are activated by the secondary amine of the pyrrolidine ring of the catalyst through the formation of an enamine intermediate. The approach of nitroolefin is controlled by the carbamate functionality by stabilizing the interaction through hydrogen bond formation, which directs the nitroolefin in such a manner, so that E-enamine attacks the olefinic double bond from the Re-face. Finally it seems to be the combined effect of steric factors and the intermolecular hydrogen bonding which leads to higher stereoselectivity in the reaction to furnish S, Rproduct. The configuration of chiral centres in the Michael adduct was assigned as on the basis of comparison of retention time using chiral HPLC with those reported in literature. O

O

N

E-enamine Re -face

N

H O N O

Figure 1 Putative transition state. 3. Conclusion We have developed novel ((S)-pyrrolidin-2-yl)methyl phenylcarbamate 1 as new chiral bifunctional organocatalyst

useful in the asymmetric Michael addition of cyclic/acyclic ketones to nitroolefins. The chiral catalyst was easily prepared from commercially available N-Boc-L-proline and is highly efficient in catalyzing the Michael reaction to afford the corresponding adducts with excellent enantio- as well as diastereoselectivities in high yields, without any additive. Further investigations of such chiral catalysts for related asymmetric transformations are currently in progress. 4. Experimental section 4.1 Material and methods Melting points were obtained on a Thomas-Hoover apparatus in open capillaries and are uncorrected. 1H NMR spectra were recorded in CDCl3 solution on a Jeol AL 300 MHz or Bruker 400 MHz spectrometer; the chemical shifts are reported in parts per million (δ) relative to internal standard TMS (0 ppm) and the coupling constants (J) are reported in hertz (Hz). 13C NMR spectra were obtained at 75 MHz or 100 MHz and are referenced to the internal solvent signals. MS and HRMS data were obtained on a Q-Tof micro™ Mass Spectrometer. Chiral HPLC analysis were carried out on a Waters 2996 system using Daicel Chiralpak AS-H and Chiralcel OD columns. Elemental analysis was performed with a Flash 2000 organic elemental analyzer. Nitroolefins were prepared according to literature procedures.17 Products were isolated and purified by column chromatography over silica gel using hexane–EtOAc (9:1–8:2) as eluent.

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To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2carboxylic acid 3 (2.0 g, 9.3 mmol) in dry THF (25 mL) was added borane dimethyl sulphide complex (1.66 g, 18.6 mmol) dropwise under nitrogen atmosphere at 0°C and the reaction mass was stirred at the same temperature for 5h and then at rt overnight. Water (30 mL) was added carefully to quench the reaction and the contents were extracted with ethyl acetate (3×25 mL). The combined organic extract was washed with saturated sodium bicarbonate solution, water, brine and dried over anhydrous Na2SO4 and concentrated in vacuo to afford 4 as an oil which spontaneously solidified at room temperature as a white solid (1.73 g, 93%). mp 57-59 °C, (Lit.12 mp 58-59 °C).

H NMR (400 MHz, CDCl3): δ 9.46 (br s, 1H), 8.78 (br s, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 4.44-4.33 (m, 2H), 3.81-3.79 (m, 1H), 3.38-3.31 (m, 1H), 3.26-3.20 (m, 1H), 2.07-1.99 (m, 2H), 1.96-1.86 (m, 1H), 1.77-1.67 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 153.0, 138.0, 128.9, 123.4, 118.7, 62.4, 59.0, 45.2, 26.3, 23.5. IR (Neat): ν 3242, 2885, 2739, 2495, 1725, 1596, 1532 cm-1. HRMS (ES+): m/z [M + H]+ calcd for C12H17N2O2: 221.1290; found: 221.1234.

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4.2.1 (S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4).12

4.2.4 O-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl phenylcarbamothioate (6)

1

4.2.2 ((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methyl phenylcarbamate (5)

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To a stirred solution of (S)-tert-butyl 2(hydroxymethyl)pyrrolidine-1-carboxylate (4; 1.0 g, 4.98 mmol) and phenylisocyanate (0.54 g, 4.98 mmol) in dry chloroform (20 mL) was added catalytic amount of DMAP and the reaction mass was allowed to stir at rt. Fine white colored solid product started precipitating out soon after the addition and when TLC showed the complete consumption of both starting materials after about 6h stirring, reaction mass was diluted with chloroform (30 mL) and washed with brine (20 mL). Chloroform layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5 as white solid. Compound 5 could be crystallized from boiling DCM:Hexane to give 5 as colorless crystalline compound (1.45 g, 91%); mp 115-118 °C.

(S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4; 3.0 g, 14.93 mmol) was refluxed in THF (60 ml), with phenylisothiocyanate (1.78 g, 14.93 mmol) in the presence of BF3.Et2O (0.96 g, 7.47 mmol) for 12 h. After the completion of reaction as indicated by TLC, reaction mass was concentrated under reduced pressure to give crude mass which was purified by column chromatography using hexane–EtOAc (9:1–8:2) as eluent, afforded 6 as a colorless oil (2.1 g, 42%).

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H NMR (300 MHz, CDCl3): δ 3.87 (br s, 1 H), 3.52-3.49 (m, 2 H), 3.40-3.31 (m, 1 H), 3.28-3.22 (m, 1 H), 1.95-1.90 (m, 1 H), 1.76-1.69 (m, 2 H), 1.51-1.43 (m, 1 H), 1.40 (s, 9 H).

N-

EP

H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.56 Hz, 2H), 7.32 (t, J = 7.52 Hz, 2H), 7.07 (t, J = 7.08 Hz, 1H), 6.76-6.92 (m, 1H), 4.27 (d, J = 7.44 Hz, 1H), 4.12- 4.00 (m, 2H), 3.36 (br s, 2H), 1.90-1.81 (m, 4H), 1.47 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 154.3, 153.3, 137.8, 129.0, 123.4, 118.6, 79.9, 65.3, 55.8, 46.6, 28.4, 23.0.

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IR (Neat): ν 3267, 2973, 2879, 1732, 1652, 1601, 1544, 1410 cm-

HRMS (ES+): m/z [M + Na]+ calcd for C17H24N2O4Na+: 343.1628; found: 343.1642.

1

H NMR (400 MHz, CDCl3): δ 9.50 (br s, 1H), 7.34-7.30 (m, 2H), 7.27-7.23 (m, 2H), 7.09-7.05 (m, 1H), 4.18 (br s, 2H), 3.703.66 (m, 1H), 3.44-3.39 (m, 2H), 2.12-2.04 (m, 1H), 1.95-1.81 (m, 2H), 1.72-1.70 (m, 1H), 1.18 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 172.7, 158.5, 140.3, 128.5, 125.0, 120.9, 99.9, 75.1, 66.9, 61.3, 52.6, 48.1, 29.7, 27.5, 23.3. IR (Neat): ν 3300, 3108, 2975, 2874, 1632, 1600, 1567, 1497, 1349 cm-1.

4.2.5 O-((S)-pyrrolidin-2-yl)methyl N-phenylcarbamothioate (2) O-((S)-pyrrolidin-2-yl)methyl N-phenylcarbamothioate (2) was synthesized from O-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2yl)methyl N-phenylcarbamothioate (6; 1.0 g, 2.97 mmol) following the same procedure as for compound 1. Purification by column chromatography using hexane–EtOAc (8:2) as eluent, afforded 2 as colorless oil (0.57 g, 81%). 1

H NMR (400 MHz, CDCl3): δ 7.27-7.23 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.95-6.92 (m, 2H), 4.24-4.18 (m, 1H), 3.70-3.63 (m, 1H), 3.41-3.35 (m, 1H), 2.95 (t, J = 9.8 Hz, 1H), 2.27-2.21 (m, 1H), 2.18-2.11 (m, 1H), 2.07-2.00 (m, 1H), 1.62-1.52 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 157.0, 152.0, 128.7, 122.9, 122.0, 64.7, 45.5, 33.8, 30.8, 27.7.

4.2.3 ((S)-pyrrolidin-2-yl)methyl phenylcarbamate (1) Formic acid (10.0 mL) was slowly added to ((S)-1-(tertbutoxycarbonyl)pyrrolidin-2-yl)methyl phenylcarbamate (5, 1.0 g, 3.12 mmol) and the resulting solution was allowed to stir at room temperature for 10 h. Excess formic acid was removed under reduced pressure and the residue was carefully neutralized by saturated Na2CO3 solution. The reaction mixture was extracted with chloroform (3x 20 mL) and washed with brine (20 mL) dried over anhydrous Na2SO4 and concentrated in vacuo to afford 1 as pale yellow viscous mass. Purification by column chromatography (CHCl3-MeOH 9:1) afforded 1 as a colorless oil (0.58 g, 84%).

IR (Neat): ν 2970, 2871, 1614, 1578, 1479, 1385 cm-1 HRMS (ES+): m/z [M + H]+ calcd for C12H17N2OS: 237.1061; found: 237.1052. 4.3. Typical procedure for enantioselective Michael addition catalyzed by organocatalyst 1 Cyclic ketone (2 equiv) was added to the stirred solution of organocatalyst 1 (20 mol%) in toluene (10 mL) and the reaction mixture was allowed to stir at room temperature for half an hour.

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13 trans-β-Nitrostyrene (1 equiv, 0.2 g scale) was added and the MANUSCRIPT C NMR (100 MHz, CDCl3): δ 210.5, 149.0, 148.3, 127.0, ACCEPTED reaction mixture was allowed to stir at rt for appropriate time 125.3, 113.1, 76.5, 56.1, 55.8, 51.5, 42.6, 41.1, 33.1, 28.5, 25.4. After complete consumption of nitrostryene, indicated by TLC, IR (Neat): ν 2937, 2852, 1697, 1604, 1546, 1508, 1445, 1381 cm1 the solvent was evaporated under reduced pressure and residue was dissolved in ethyl acetate (20 mL). The organic layer was Anal. Calcd for C16H20ClNO5: C, 56.23; H, 5.90; N, 4.10. Found: washed with 10% HCl (10 mL), water (10 mL), saturated C, 56.24; H, 5.75; N, 4.02. NaHCO3 solution (10 mL), brine (10 mL) and dried over HPLC (Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate 0.5 anhydrous Na2SO4. The solvent was evaporated under reduced mL/min, λ = 254.0 nm), tR(minor) = 20.88 min, tR(major) = 26.81 pressure to afford the crude product which was purified by min, syn/anti = 99:1; ee >99%. column chromatography over silica gel using hexane-ethyl acetate (9:1-8:2) as an eluent. The configuration of chiral centres 4.3.5(S)-2-((R)-1-(4-Ethoxy-3-methoxyphenyl)-2in the Michael adduct was assigned as on the basis of comparison nitroethyl)cyclohexanone (9e)11b of retention times in chiral HPLC with those reported in Yield: 0.27 g (93%); white solid, mp 125-127 °C (Lit.11b mp 123literature. 125 °C). 1 4.3.1 (S)-2-((R)-2-nitro-1-phenylethyl)cyclohexanone (9a)15b H NMR (400 MHz, CDCl3): δ 6.73 (d, J = 7.8 Hz, 1H), 6.62Yield: 0.31 g (96%); white solid, mp 125-127 °C (Lit.18b mp 1246.59 (m, 2H), 4.85 (dd, J = 12.3, 4.6 Hz, 1H), 4.56 (dd, J = 12.3, 126 °C). 9.9 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.78 (s, 1H), 3.65 (dt, J = 1 9.9, 4.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.41-2.37 (m, 1H), 2.34-2.30 H NMR (300 MHz, CDCl3): δ 7.25-7.17 (m, 3H), 7.08 (d, J = (m, 1H), 2.02-1.97 (m, 1H), 1.74-1.48 (m, 4H), 1.39 (t, J = 7.0 6.3 Hz, 2H), 4.84 (dd, J = 12.3, 4.5 Hz, 1H), 4.57-4.49 (m, 1H), Hz, 3H), 1.21-1.15 (m, 1H). 3.68 (dt, J = 9.9, 4.5 Hz, 1H), 2.65-2.56 (m, 1H), 2.42-2.24 (m, 13 2H), 2.03-1.98 (m, 1H), 1.69-1.51 (m, 4H), 1.19-1.14 (m, 1H). C NMR (100 MHz, CDCl3): δ 212.1, 149.3, 147.8, 130.0, 13 120.1, 112.7, 111.7, 79.0, 64.2, 56.0, 52.7, 43.6, 42.7, 33.1, 28.5, C NMR (75 MHz, CDCl3): δ 211.0, 137.9, 129.0, 128.2, 127.8, 25.0, 14.8. 78.7, 52.5, 44.0, 42.6, 33.2, 28.5, 25.1. HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 mL/min, λ = 233.4 nm), tR(minor) = 18.45 min, tR(major) = 23.0 mL/min, λ= 223.3 nm), tR(minor) = 14.74 min, tR(major) = 17.38 min. syn/anti >99:1; ee = 95%. min, syn/anti >99:1; ee> 99%. 4.3.6 (S)-2-((R)-1-(4-(benzyloxy)-3-methoxyphenyl)-24.3.2 (S)-2-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)cyclohexanone 18c nitroethyl)cyclohexanone (9f) (9b). 6c Yield: 0.24 g (89%); white solid, mp 141-143 °C Yield: 0.29 g (93%); white solid, mp 131-133 °C (Lit. mp 1331 134 °C). H NMR (300 MHz, CDCl3): δ 7.43-7.26 (m, 5H), 6.83-6.62 (m, 1 3H), 5.10 (s, 2H), 4.91-4.86 (m, 1H), 4.62-4.57 (m, 1H), 3.87 (s, H NMR (300 MHz, CDCl3): δ 7.24 (t, J = 7.8 Hz, 1H), 6.783H), 3.70–3.67 (m, 1H), 2.63–2.62 (m, 1H), 2.45–2.36 (m, 2H), 6.67 (m, 3H), 4.89 (dd, J= 12.3, 4.2 Hz, 1H), 4.63-4.55 (m, 1H), 2.08–2.04 (m,1H), 1.80–1.57 (m, 4H), 1.27–1.21 (m,1H). 3.78 (s, 3H), 3.69- 3.68 (m, 1H), 2.70-2.61 (m, 1H), 2.45-2.36 13 (m, 2H), 2.11-2.06 (m, 1H), 1.78-1.49 (m, 4H), 1.30-1.19 (m, C NMR (75 MHz, CDCl3): δ 212.0, 149.7, 147.4, 137.0, 130.6, 1H) 128.5, 127.8, 127.2, 120.0, 114.0, 112.1, 78.9, 71.0, 56.1, 52.7, 13 43.6, 42.7, 33.1, 28.5, 25.0. C NMR (75 MHz, CDCl3): δ 211.0, 159.9, 139.4, 129.9, 120.2, 114.4, 112.7, 78.6, 55.0, 52.5, 44.0, 42.6, 33.2 28.5, 25.1. IR (Neat): ν 3035, 2944, 2868, 1697, 1591, 1549, 1516, 1455, 1385, 1258, 1230 cm-1 HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 mL/min, λ = 254.0 nm), tR(minor) = 20.16 min, tR(major) = 27.11 Anal. Calcd for C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, min, syn/anti >99:1; ee >99%. 68.25; H, 6.41; N, 3.64. 4.3.3 (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 (9c).18b mL/min, λ = 226.5 nm), tR(minor) = 29.93 min, tR(major) = 38.63 min, syn/anti >99:1; ee = 52%. Yield:0.28 g (90%); white solid, mp 151-153 °C (Lit.18d mp 153154 °C). 4.3.7 (S)-2-((R)-2-nitro-1-(4-nitrophenyl)ethyl)cyclohexanone 1 (9g)18a H NMR (300 MHz, CDCl3): δ 6.99 (d, J = 8.4 Hz, 2H), 6.75 (d, J= 8.4 Hz, 2H), 4.80 (dd, J = 4.8, 12.3 Hz, 1H), 4.52 (dd, J = 9.6, Yield: 0.27 g (90%); white solid, mp 124-127 °C. 1 12.0 Hz, 1H), 3.70 (s, 3H), 3.63-3.55 (m, 1H), 2.60-2.52 (m, 1H), H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 8.7 Hz, 2H), 7.31 (d, 2.41-2.28 (m, 2H), 2.03-1.97 (m, 1H), 1.70-1.48 (m, 4H), 1.18J = 8.7 Hz, 2H), 4.87 (dd, J = 12.9, 4.5 Hz, 1H), 4.63 (dd, J = 1.10 (m, 1H) 12.9, 9.9 Hz, 1H), 3.83–3.75 (m, 1H), 2.66–2.57 (m, 1H), 2.43– 13 C NMR (75 MHz, CDCl3): δ 211.3, 159.2, 129.7, 129.3, 114.5, 2.23 (m, 2H), 2.03–1.80 (m, 1H), 1.73–1.37 (m, 4H), 1.25–1.16 79.0, 55.2, 52.8, 43.4, 42.7, 33.2, 28.7, 25.3. (m, 1H). 13 HPLC (Chiralpak AS-H, hexane/i-PrOH = 85:15, flow rate 0.5 C NMR (75 MHz, CDCl3): δ 209.6, 147.2, 145.4, 129.2, 124.2, mL/min, λ = 240.1 nm), tR(minor) = 24.46 min, tR(major) = 26.69 77.8, 52.3, 43.8, 42.6, 33.2, 28.3, 25.3. min, syn/anti >99:1; ee = 99%. HPLC (Chiralpak AS-H), hexane/i-PrOH = 85:15, flow rate 1.0 4.3.4 (S)-2-((R)-1-(2-chloro-3,4-dimethoxyphenyl)-2mL/min, λ = 250.0 nm), tR(minor) = 23.23 min, tR(major) = 26.73 nitroethyl)cyclohexanone (9d). min, syn/anti = 98:2; ee = 98%. Yield:0.25 g (89%); white solid, mp 99-101 °C Anal. Calcd for C14H16N2O5: C, 57.53; H, 5.52; N, 9.58. Found: 1 C, 57.20; H, 5.43; N, 9.49. H NMR (400 MHz, CDCl3): δ 6.75 (s, 1H), 6.59 (s, 1H), 4.874.80 (m, 1H), 4.72-4.67 (m, 1H), 4.06-3.98 (m, 1H), 3.79 (s, 6H), 2.89-2.82 (m, 1H), 2.43–2.26 (m, 2H), 2.08–2.04 (m, 1H), 1.82– 1.55 (m, 4H), 1.33–1.21 (m,1H).

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HPLC (Chiralcel OD, hexane/i-PrOH = 90:10, flow rate 0.5 4.3.8 (S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone ACCEPTED MANUSCRIPT mL/min, λ= 219.7 nm), tR(minor) = 19.3 min, tR(major) = 23.9 (9h)15b min, syn/anti = 99:1; ee = 90%. Yield: 0.28 g (90%); white solid, mp 91-93 °C (Lit.18c mp 93-96 °C). 4.3.13 (S)-2-((R)-2-nitro-1-phenylethyl)cyclopentanone (9m)15b 1 H NMR (300 MHz, CDCl3): δ 7.23 (d, J = 8.4 Hz, 2H), 7.04 (d, Yield: 0.26 g (84%); white solid, mp 115-117 °C (Lit.18b mp 116J = 8.4 Hz, 2H), 4.83 (dd, J = 4.8, 12.6 Hz, 1H), 4.57-4.47 (m, 119 °C). 1 1H), 3.71–3.61 (m, 1H), 2.64–2.52 (m, 1H), 2.41–2.23 (m, 2H), H NMR (300 MHz, CDCl3): δ 7.25-7.14 (m, 3H), 7.07-7.05 (m, 2.05–2.01 (m,1H), 1.76–1.44 (m, 4H), 1.22–1.10 (m,1H). 2H), 5.23 (dd, J= 5.7, 12.9 Hz, 1H), 4.62 (dd, J= 9.0, 12.9 Hz, 13 C NMR (75 MHz, CDCl3): δ 210.6, 136.3, 133.8, 129.5, 129.2, 1H), 3.63 (dt, J= 5.4, 9.0 Hz, 1H), 2.33-2.19 (m, 2H), 2.16-1.90 78.4, 52.4, 43.4, 42.6, 33.1, 28.4, 25.2. (m, 1H), 1.88-1.56 (m, 3H), 1.48-1.34 (m, 1H). 13 CNMR (75 MHz, CDCl3): δ 218.4, 137.8, 128.9, 128.8, 127.9, HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 78.2, 51.2, 44.2, 38.5, 28.4, 20.3. mL/min, λ = 254.0 nm), tR(minor) = 17.10 min, tR(major) = 19.76 min, syn/anti >99:1; ee = 95%. HPLC (Chiralpak AS-H, hexane/i-PrOH = 85:15, flow rate 0.5 4.3.9 (S)-2-((R)-1-(Benzo[d][1,3]dioxol-5-yl)-2mL/min, λ = 228.9 nm), tR(minor) = 17.2 min, tR(major) = 23.6 nitroethyl)cyclohexanone(9i)15b min, syn/anti = 86:14; ee = 82%. Yield: 0.28 g (93%); white solid, mp 141-143 °C (Lit.18b mp 144Acknowledgments 145 °C). 1 H NMR (400 MHz, CDCl3): δ 6.66 (d, J = 7.8 Hz, 1H), 6.55We acknowledge financial support from the Science and 6.52 (m, 2H), 5.88 (s, 2H), 4.81 (dd, J = 12.3, 4.4 Hz, 1H), 4.49 engineering research board (SERB), New Delhi, through Scheme (dd, J = 12.3, 9.9 Hz, 1H), 3.60 (dt, J = 9.9, 4.4 Hz, 1H), 2.56number EEQ/2016/000574. The NMR spectroscopy and Mass 2.49 (m, 1H), 2.41-2.37 (m, 1H), 2.33-2.25 (m, 1H), 2.04-1.99 spectrometry facility of SAIF, Panjab University, Chandigarh is (m, 1H), 1.76-1.42 (m, 4H), 1.22-1.13 (m, 1H). gratefully acknowledged. 13 C NMR (100 MHz, CDCl3): δ 211.2, 148.1, 147.1, 131.2, 121.6, 108.5, 108.0, 101.1, 78.8, 52.6, 43.7, 42.6, 33.1, 28.5, 5. References and notes 25.1. HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 1 For books, see: (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis-From Biomimetic Concepts to Powerful Methods for mL/min, λ = 236.5 nm), tR(minor) = 47.1 min, tR(major) =51.9 Asymmetric Synthesis, ed. Berkessel, A.; Wiley-VCH: Weinheim, min, syn/anti >99:1; ee = 98%. 2005. (b) Dalko, P. I. Enantioselective Organocatalysis Reactions and 15b 4.3.10 (R)-5-nitro-4-phenylpentan-2-one (9j) Experimental Procedure, ed. Dalko, P. I.; Wiley-VCH: Weinheim, Yield: 0.26 g (93%); white solid, mp 88-90 °C, (Lit.3g mp 90-92 2007. 2 For selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, °C). 1 L. Angew. Chem. Int. Ed. 2004, 43, 5138. (b) Seayad, J.; List, B. Org. H NMR (300 MHz, CDCl3): δ 7.24-7.18 (m, 3H), 7.13-7.11 (m, Biomol. Chem. 2005, 3, 719. (c) Enders, D.; Grondal, C.; Hüttl, M. R. 2H), 4.62-4.43 (m, 2H), 3.94-3.83 (m, 1H), 2.84 (d, J = 6.0 Hz, M. Angew. Chem. Int. Ed. 2007, 46, 1570. (d) Gaunt, M. J.; 2H), 2.04 (s, 3H). Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 13 CNMR (75 MHz, CDCl3): δ 204.5, 138.9, 129.0, 127.9, 127.4, 2007, 12, 8. (e) Pellissier, H. Tetrahedron 2007, 63, 9267. (f) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47, 4638. (g) 79.3, 46.1, 39.0, 30.2. Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (h) HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058. mL/min, λ = 224.5 nm), tR(major) = 22.20 min, tR(minor) = 27.79 (i) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem., 2010, 2, 167. (j) min; ee = 98%. MacMillan, D. W. Nature, 2008, 455, 304. (k) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541. (l) Kang, Y. K.; Kim, S. 4.3.11 (R)-4-(4-Chlorophenyl)-5-nitropentan-2-one (9k)19a 12 M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847. (m) Liu, W.; Yield: 0.24 g (92%); white solid, mp 75-77 °C, (Lit. mp 75-77 Mei, D.; Wang, W.; Duan, W. Tetrahedron Lett. 2013, 54, 3791. (n) °C). Mondal, A.; Bhowmick, S.; Ghosh, A.; Chanda, T.; Bhowmick K. C. 1 H NMR (300 MHz, CDCl3): δ 7.24 (d, J = 8.1 Hz, 2H), 7.08 (d, Tetrahedron: Asymmetry 2017, 28, 849. 3 For examples of asymmetric Michael additions of carbonyl J = 8.1 Hz, 2H), 4.60 (dd, J = 12.3, 6.9 Hz, 1H), 4.50 (dd, J = compounds to nitroalkenes, see: (a) Xu, Y.; Córdova, A. Chem. 12.3, 7.5 Hz, 1H), 3.92 (qn, J = 6.9 Hz, 1H), 2.88-2.72 (m, 2H), Commun. 2006, 460. (b) Pansare, S. V.; Pandya, K. J. Am. Chem. 2.05 (s, 3H). Soc. 2006, 128, 9624. (c) Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, 13 C NMR (75 MHz, CDCl3): δ 204.9, 137.9, 134.5, 129.9, 129.4, L. Org. Lett. 2006, 8, 6135. (d) Chi, Y.; Guo, L.; Kopf, N. A.; 79.7, 46.5, 39.0, 30.9. Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608. (e) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem. Int. Ed. 2008, 47, 7539. (f) HPLC (Chiralpak AS-H), hexane/i-PrOH = 90:10, flow rate 0.5 Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem. mL/min, λ = 229.2 nm), tR(minor) = 27.9 min, tR(major) = 34.9 Soc. 2008, 130, 5610. (g) Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou, min; ee = 95%. Z.; Tang, C. Org. Biomol. Chem. 2009, 7, 3141. (h) Gauchot, V.; 4.3.12 (4S,5R)-4-methyl-6-nitro-5-phenylhexan-3-one (9l)19d Gravel, J.; Schmitzer, A. R. Eur. J. Org. Chem. 2012, 6280. (i) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009, 11, Yield: 0.28 g (88%); brownish viscous mass. 1927. (j) Laars, M.; Ausmees, K.; Uudsemaa, M.; Tamm, T.; Kanger, 1 H NMR (400 MHz, CDCl3): δ 7.25-7.15 (m, 3H), 7.08-7.05 (m, T.; Lopp, M. J. Org. Chem. 2009, 74, 3772. (k) Wiesner, M.; Upert, 2H), 4.59-4.54 (m, 1H), 4.51-4.47 (m, 1H), 3.61 (dt, J = 9.2, 4.7 G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010, 132, 6. (l) Hz, 1H), 2.94-2.86 (m, 1H), 2.56-2.46 (m, 1H), 2.36-2.26 (m, Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50. 1H), 1.00 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 7.1 Hz, 3H). (m) Zhao, H.-W.; Li, H.-L.; Yue, Y.-Y.; Sheng, Z.-H. Eur. J. Org. 13 Chem. 2013, 1740. CNMR (100 MHz, CDCl3): δ 213.1, 137.7, 129.0, 128.0, 127.9, 78.3, 48.3, 46.1, 35.4, 16.4, 7.7.

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