Carbohydrate Research 404 (2015) 83–86

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New sugar-derived bifunctional chiral ureas as highly effective organocatalysts in asymmetric aza-Henry reaction Jolanta Robak, Bogusław Kryczka, Barbara S´wierczyn´ska, Anna Zawisza, Stanisław Porwan´ski ⇑ Department of Organic and Applied Chemistry, University of Łódz´, Tamka 12, 91-403 Łódz´, Poland

a r t i c l e

i n f o

Article history: Received 24 June 2014 Received in revised form 19 November 2014 Accepted 23 November 2014 Available online 31 December 2014

a b s t r a c t A simple synthesis of series of new catalysts derived from chiral bifunctional ureas is described. The azaHenry reaction of imines with nitromethane was promoted by sugar derived bifunctional organocatalysts to give optically active b-nitroamines. The aza-Henry reaction products were obtained in good yields (35–98%) and ee up to 99%. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Aza-Henry Saccharides Urea Organocatalyst

1. Introduction Among the organic compounds provided by nature, carbohydrates contain the highest density of stereochemical information. As inexpensive and readily available natural materials they have recently been used as chiral backbones of organocatalysts or ligands.1 The use of chiral bifunctional catalysts for the synthesis of optically active compounds has become a new and exciting area of contemporary synthetic organic chemistry.1a Chiral bifunctional urea and thiourea derivatives have recently been applied as enantioselective catalysts for different organic transformations.1b,c Pioneering examples include the work of Jacobsen, who showed that chiral urea or thiourea containing Schiff base catalyst can successfully be used in asymmetric cyanation reaction of aldimines and ketimines.2 Additionally, urea and thiourea derivatives are capable of catalyzing Acyl-Pictet–Spengler,3 Nitro-Mannich,4 Michael,5 Morrita–Baylis–Hillman,6 Strecker,7 or aza-Henry8 reactions. The aza-Henry reaction is a carbon-carbon bond-forming process which allows a simple entry to a variety of nitrogencontaining chiral building blocks.9 For example, 1,2-diamines a structural motif present in biologically active natural products and as a stem unit in chiral ligands for asymmetric synthesis can be obtained by reduction of the nitro group in the b-nitroamines derivatives.10

⇑ Corresponding author. Tel.: +48 42 6355764; fax: +48 42 6655162. E-mail address: [email protected] (S. Porwan´ski). http://dx.doi.org/10.1016/j.carres.2014.11.019 0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

In our previous report, bifunctionalized ureas with chiral phosphine built of carbohydrate skeletons have proven to be very efficient catalysts for asymmetric Morita–Baylis–Hillman reaction and less efficient for the asymmetric aza-Henry reaction.11 Due to our current interest in the synthesis and applications of urea derivatives in asymmetric synthesis, we herein report a convenient and efficient protocol for the preparation of a new class of organocatalyst.

2. Results and discussion 2.1. Synthesis organocatalysts We present novel urea derivatives with tertiary amino groups which act as bifunctional organocatalysts in asymmetric aza-Henry reaction of nitromethane with imine. The simple procedure synthesis of a series of new chiral catalysts is presented in Scheme 1. The synthesis of the organocatalysts L1–L6 was carried out in a straightforward way by stirring the carbohydrate azide 1,12 2,13 3,12 or 412 and triphenylphosphine in anhydrous toluene for 1 h at room temperature. Then, the appropriate chiral amines 5–7 were added and the mixture was stirred for 24 h under CO2 bubbling conditions. The final products were obtained from 42% to 73% yields (Scheme 1). The spectroscopic data of L1–6 by IR, 1 H, 13C NMR, and elemental analyses are in full accordance with the proposed structures. Selected, characteristic chemical shifts (ppm) of the carbons in the 13C NMR are shown in Table 1.

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J. Robak et al. / Carbohydrate Research 404 (2015) 83–86

AcO AcO

OAc O HN

O N

OAc

N

73%

L1 N OAc O AcO AcO

OAc 1

PPh3 /CO2

O

N3 O

O

OO

AcO AcO

AcO N 6

H2 N

2

OAc O

AcO

N3

O

5

N H

O

OO

N3

AcO

5

N H

H2N N

OAc

42% O

AcO

OAc L3

N

60%

OAc O

O HN

O

N

OAc

N

L 4 56%

OAc O

O

AcO AcO O

7

NH

HN

O

AcO AcO

N3

N

AcO AcO O

PPh3 /CO 2

OAc O

N

L2

OAc O

AcO AcO O

N

OAc

OAc O O AcO AcO OAc AcO 4

O

AcO AcO

O

AcO AcO 3

O

NH O

O

AcO AcO

HN

HN

OAc

N

L5 49% O OAc O O AcO AcO OAc AcO

OAc O HN OAc L6

HN N

52%

Scheme 1.

2.2. Application of the organocatalysts L1–6 in asymmetric aza-Henry reaction The catalytic activity of novel organocatalysts L1–L6 was tested in the asymmetric aza-Henry reaction of N-Tosyl imine with nitromethane as the model transformation. The reactions were carried out under standard conditions—in THF or dichloromethane in room temperature. The results are shown in Table 2. The obtained results (Table 2) clearly show that the new organocatalysts L1–6 efficiently catalyze the selected model aza-Henry reaction and give the desired products with good chemical yields and high enantiomeric excesses in favor of (S)-enantiomer. The absolute configurations of obtained stereoisomers were determined on the basis of literature data.14 The cellobiose derivative L6 proved to be less effective under these reaction conditions (Table 2, entries 9, 10). We observed also the effect of solvent on the course of reaction (Table 2, entries 1–4). When a less polar solvent such as dichloromethane was used as reaction media, the aza-Henry reaction was sluggish and resulted in poor chemical yield. The exception was urea melibiose derivative L5 (Table 2,

Table 1 Selected chemical shifts (ppm) of the carbons in the

entries 7, 8) which has proven the best catalyst in terms of yield and enantioselectivity (98% yield, 99% ee in THF and 98% yield, 97% ee in CH2Cl2). Our results led us to conclude that the fragment tertiary amino group influences the course of aza-Henry reaction. Proposed transition state for catalyst L5 of this asymmetric azaHenry reaction is illustrated in Figure 1. The urea moiety forms a hydrogen-bond with the nitromethane and a tertiary nitrogen detaches proton from the methyl group.

Table 2 Screening of the catalysts in the aza-Henry reaction of N-Tosyl imine and nitromethane NTs + CH3NO2

C NMR (CDCl3) of L1–6

Organocatalysts

C-1

C-10

[email protected] (urea)

1 2 3 4 5 6

L1 L2 L3 L4 L5 L6

80.32 96.38 79.94 80.00 80.50 80.28

— — 96.00 96.36 96.37 100.65

158.33 151.80 156.70 157.19 158.20 156.77

THF, 7d

H3CO

OCH3

13

Entry

NTs NO2 *

10 mol% L1-6

a

Entry

Catalyst

Solvent

% Yielda

% eeb

1 2 3 4 5 6 7 8 9 10

L1 L1 L2 L2 L3 L4 L5 L5 L6 L6

THF CH2Cl2 THF CH2Cl2 THF THF THF CH2Cl2 THF CH2Cl2

59 35 82 35 65 53 98 98 95 88

72 70 75 67 89 64 99 97 37 15

(S) (S) (S) (S) (S) (S) (S) (S) (S) (S)

Yield refers to isolated products after column chromatography. Enantioselectivity was measured by HPLC on a Chiralpak OD-H column (25 cm  4.6 mm); flow rate = 1.0 ml min1; hexane/i-propanol (85/15), detection 215 nm, tR (S) = 34.0 min, and tR (R) = 38.3 min.14 b

J. Robak et al. / Carbohydrate Research 404 (2015) 83–86

AcO

OAc O

O

AcO AcOO AcO AcO

AcO

O OAc

N H

N H O H

N

OAc O

O

AcO AcO O AcO AcO

O

O OAc

O

N H

H

N H

N H

H

O

N H

N H

Figure 1.

These effects of the catalyst facilitate the controlled attack of nitromethane for imine carbonyl atom. 3. Conclusions We have developed a simple and efficient methodology for the synthesis of new sugar-derived bifunctional chiral urea organocatalysts. The effectiveness of this class of organocatalysts was demonstrated in the aza-Henry reaction (ee up to 99%). The further refinement of the catalyst structure and extension of their utility to other asymmetric reaction is under active study. 4. Experimental 4.1. General comments All solvents and reagents (amines 4–6, nitromethane, and imine) were purchased from Sigma–Aldrich and used as supplied, without additional purification. NMR spectra were recorded in CDCl3, on Brucer Avance III (600 MHz for 1H NMR, 150 MHz for 13 C NMR), coupling constants are reported in Hz. Optical rotation was measured on a Perkin-Elmer 241 MC polarimeter with a sodium lamp at room temperature. Melting points were determined on a DigiMelt apparatus and are uncorrected. Chromatographic purification of compounds was achieved with 230–400 mesh size silica gel. The progress of the reactions was monitored by silica gel thin-layer chromatography plates (Merck TLC Silica gel 60 F254). IR spectra were recorded on a FT-IR Nexus spectrometer. The enantiomeric excess (ee) of the product was determined by HPLC (ProStar Varian) employing a Chiralpak OD-H column (25 cm  4.6 mm) with 2-propanol—hexane as eluent.

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H-10 , H-40 a); 3.24 (m, 1H, H-40 b); 2.71–2.37 (m, 6H, H-200 a, H-200 b, H-100 a, H-1b00 , H-60 a, H-60 b); 1.95 (m, 13H, 4CH3, H-20 b); 1.81 (m, 4H, H-30 a, H-300 b, H-400 a, H-400 b); 1.60 (m, 2H, H-300 a, H-30 b); 1.44 (m, 1H, H-20 a). NMR 13C (150 MHz, CDCl3): 170.51–169.60 ([email protected]); 158.33 [email protected]; 80.32 C1; 63.29 C10 ; 47.15 C4; 54.31 C200 ; 61.88 C600 ; 32.03 C20 ; 23.77 C300 ; 23.48 C400 ; 73.61 C3; 72.92 C5; 70.91 C2; 68.50 C6; 20.82–20.58 Ac. 4.2.2. N-[(S)-(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine]-N0 -(6deoxy-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose)]urea (L2) Yield%: 42 (184 mg) as a white solid (acetone/MeOH 1:1, Rf = 0.24); mp: 58–61 °C, [a]25 64.0 (c 0.5, CH2Cl2); Anal. for D C22O6H37N3 (439.27), Calcd: C, 60.12; H, 8.48; N, 9.56. Found: C, 60.28; H, 8.72; N, 9.31. IR (KBr, cm1): 3424, 1751, 1648, 1373, 1069. NMR 1H (600 MHz, CDCl3): 5.41 (d, 1H, J1–2 = 4.9, H-1); 4.51 (dd, 1H, J2–3 = 2.34, J3–4 = 7.9, H-3); 4.21 (dd, 1H, J2–3 = 2.3; J = 1–2 = 4.9, H-2), 4.15 (dd, 1H, J4–5 = 1.7; J3–4 = 7.9, H-4); 3.84 (ddd, 1H, J4–5 = 1.7; J5–6a = 4.0 J5–6b = 7.0, H-5); 3.53 (ddd, 1H, J5–60 = 7.00; JN-6 = 14.0, J6–60 = 11.5, H-6a); 3,20–3,18 (m, 1H, H-6b); 3.13–2.98 (m, 1H, H-20 ); 2.88–1.21 (m, 17H, H-30 a, H-30 b, H-40 a, H-40 b, H-50 a, H-50 b, H-60 a, H-60 b, H-80 a, H-80 b, H-90 a, H-90 b, H-100 a, H-100 b, H-110 a, H-110 b, H-120 a, H-120 b, NH); 1.44; 1.37, 1.26, 1.24 (4s, 12H, CH3). NMR 13C (150 MHz, CDCl3): 151.80 [email protected]; 109.27; 108.63 Cq; 96.38 C1; 71.88 C4; 70.93 C2; 70.78 C3; 67.4 C5; 46.66 C20 ; 40.81 C6; 26.12, 26.02, 25.11, 24.46 CH3; 23.88, 23.60, 23.52, 21.00, (C30 , C40 C50 , C60 , C80 , C90 C100 , C110 , C120 ).

Triphenylphosphine (865 mg, 3.3 mmol) was added to a solution of azidosaccharide (1.1 mmol) in toluene (8 mL). The resulting solution was stirred at room temperature for 1 h and then flushed with CO2. Next, the appropriate amine (1 mmol) was added. The mixture was stirred for 24 h under CO2 bubbling conditions. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel eluting with ethyl EtOAc/hexane or EtOAc/MeOH.

4.2.3. N-[2S,4S,5R)-Aminomethyl-5-ethylquinuclidine]-N0 -(2,3,4, 20 ,30 ,40 ,60 -hepta-O-acetyl-b-D-melibiosyl)-urea (L3) Yield%: 60 (614 mg) as a white solid (AcOEt/MeOH 1:1, Rf = 0.22); mp: 112–114 °C, [a]25 D +40.8 (c 0.5, CH2Cl2); Anal. for C37O18H55N3 (829.35), Calcd: C, 53,55; H, 6.68; N, 5.06. Found: C, 53.98; H, 7.01; N, 5.02. IR (KBr, cm1): 3409, 1751, 1671; 1374, 1228, 1034. NMR 1H (600 MHz, CDCl3): 5.57–5.50 (m, NHsac, 1H); 5.45 (d, 1H, J30 -40 = J40 -50 = 3.4, H-40 ); 5.35 (dd, 1H, J30 -40 = 3.4, J20 -30 = 10.9, H-30 ); 5.30 (t, 1H, J2–3 = J3–4 = 9.5, H-3); 5.29 (d, 1H, J10 -20 = 3.5, H-10 ); 5.15 (t, 1H, J4–5 = 6.06, J3–4 = 9.5, H-4); 5.10 (t, 1H, JNH-1 = 8.0, J1–2 = 9.5, H-1); 5.07 (dd, 1H, J10 -20 = 3.5, J20 -30 = 10.9, H-20 ); 4.83 (t, 1H, J2–3 = J1–2 = 9.5, H-2); 4.26 (t, 1H, J40 -50 = 3.4, J50 -60 = 6.8, H-50 ); 4.13–4,07 (m, 2H, H-60 a, H-60 b); 3.79–3.77 (m, 1H, H-5), 3.72 (dd, 1H, J5–6a = 2.6, J6a-6b = 11.9, H-6a); 3.68 (dd, 1H, J5–6b = 4.14, J = 11.82, H-6b); 3.48–3.42 (bs, 1H, NH), 2.97– 2.87 (m, 1H, H-100 ), 3.23–1.0 (m, 17H, NH, H-200 , H-400 a, H-400 b, H-500 a, H-500 b, H-600 , H-700 a, H-7b, H-800 , H-900 a, H-900 b, H-1000 a, H-1000 b, H-11000 a, H-11000 b, H-11000 c); 2.12, 2.04, 1.98, 1.96, 1.95, 1.92, 1.90 (7s, 21H, 7 CH3, Ac). 13C NMR (150 MHz, CDCl3): 170.70–169.40 [email protected]; 156.70 [email protected]; 96.00 C10 ; 79.94 C1; 73.95 C5; 73.42 C3; 70.48 C2; 69.06 C4; 68.27 C40 ; 68.23 C20 ; 67.63 C30 ; 66.31 C50 ; 65.43C6; 61.98 C60 ; 56.73 C200 ; 56.15 C600 ; 42.10 C900 ; 40.19 C700 ; 36.61 C500 ; 27.07 C300 ; 25.22 C1000 ; 24.85 C400 ; 20.86 - 20.57 Ac; 11.85 C1100 .

4.2.1. N-[(S)-(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine]-N0 -(2,3,4, 6-tetra-O-acetyl-b-D-glucopyranosyl)-urea (L1) Yield%: 73 (387 mg) as a white solid (AcOEt/MeOH 1:1, Rf = 0.40); mp: 153–156 °C, [a]25 D +2.35 (c 0.35, CH2Cl2); Anal. for C24O10H37N3 (527.25), Calcd: C, 54.64; H, 7.07; N, 7.96. Found: C, 54.35; H, 6.79; N, 7.67. IR (KBr, cm1): 3442, 1751, 1654, 1370, 1227, 1037. NMR 1H (600 MHz, CDCl3): 5.18 (t, 1H, J2–3 = J3–4 = 9.2, H-3); 5.10 (t, 1H, J1–2 = 9.2, H-1); 4.95 (t, 1H, J4–5 = J = 3–4 = 9.7, H-4); 4.76 (t, 1H, J1–2 = J2–3 = 9.2, H-2); 4.18 (d, 1H, J6a-6b = 12.0, H-6a); 4.03 (dd, 1H, J5–6b = 2.3; J6a-6b = 12.0, H-6b); 3.72 (ddd, 1H, J5–6b = 2.3, J5–6a = 3.4, J4–5 = 9.7, H-5); 3.62 (m, 2H,

4.2.4. N-[(S)-(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine]-N0 -(2,3,6, 20 ,30 ,40 ,60 -hepta-O-acetyl-b-D-melibiosyl)-urea (L4) Yield%: 56 (456 mg) as a white solid (AcOEt/MeOH 4:3, Rf = 0.40); mp: 106–108 °C, [a]25 D +51,2 (c 0.5, CH2Cl2); Anal. for C36O18H53N3 (815.33), Calcd: C, 53.00; H, 6.55; N, 5.15. Found: C, 52.84; H, 6.43; N, 5.26. IR (KBr, cm1): 3439, 1751, 1662, 1373, 1226, 1036. NMR 1H (600 MHz, CDCl3): 5.44 (d, 1H, J30 -40 = J40 -50 = 3.1, H-40 ); 5.35 (dd, J30 40 = 3.1, J20 -30 = 10.8, H-30 ); 5.24 (t, 1H, J2–3 = J3–4 = 9.3, H-3); 5.17–5.14 (m, 1H, H-1); 5,12 (d, 1H, J10 -20 = 3.2, H-10 ); 5.10–5.08 (m, 1H, H-20 ); 5.00 (t, 1H, J4–5, J3–4 = 9.5, H-4); 4.81 (t, 1H, J2–3 = J1–2 = 9.5, H-2); 4.20–4.18

4.2. General procedure for the synthesis of catalysts L1–6

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(m, 1H, H-50 ); 4.10–4.02 (m, 2H, H-60 a, H-60 b), 3.78- 3.62 (m, 5H, H-5, H-6a, H-6b, NH, H-300 ); 3.30–1.52 (m, 14H, H-20 b, H-20 a, H-30 a, H-30 b, H-60 a, H-60 b, H-100 a, H-100 b, H-200 a, H-200 b, H-300 a, H-300 b, H-400 a, H-400 b); 2.16, 2.12, 2.05, 2.03, 2.01, 1.99, 1.97 (7s, 21H, 7CH3, Ac). NMR 13C (150 MHz, CDCl3): 170.50–169.47 [email protected]; 158.20 [email protected]; 96.37 C10 ; 80.43 C1; 73.01 C5; 73.72 C3; 70.92 C2; 69.91 C4; 68.08 C40 ; 67.97 C20 ; 67.45 C30 ; 66.42 C50 ; 66.42 C6; 61.60 C60 ; 57.07 C1000 ; 54.43–20.83 (C3000 , C6000 , C500 , C200 , C4000 , C5000 , C400 ), 20.83–20.59 Ac. 4.2.5. N-[(1R, 2R)-trans-2-(1-Piperidinyl)cyclohexylamine]-N0 (2,3,6,20 ,30 ,40 ,60 -hepta-O-acetyl-b-D-melibiosyl)-urea (L5) Yield%: 49 (408 mg) as a white solid (AcOEt/MeOH 9:1, Rf = 0.62); mp: 124–127 °C, [a]25 D +24.8 (c 0.32, CH2Cl2); Anal. for C38H57N3O18 (843.36), Calcd: C, 54.09; H, 6.81; N, 4.98. Found: C, 54.06; H, 6.79; N, 4.83. IR (KBr, cm1): 3432, 2936, 1754, 1686, 1229, 1038. NMR 1H (600 MHz, CDCl3): 5.80 (bs, 1H, NHsac), 5.37 (d, 1H, J30 -40 = 3,4, J40 -50 = 7.0, H-40 ); 5.24 (dd, 1H, J30 -40 = 3,4, J20 -30 = 10,9, H-30 ); 5.19 (t, 1H, J2–3 = J3–4 = 9.6, H-3); 5.17 (d, 1H, J10 -20 = 3.6, H-10 ), 5.07 (t, 1H, J3–4 = J4–5 = 9.6, H-4); 5.03 (t, 1H, JN-1 = 8.8, J1–2 = 9.5, H-1), 4.95 (dd, 1H, J10 -20 = 3.6, J20 -30 = 10.9, H-20 ); 4.81 (t, 1H, J2–3 = J1–2 = 9.5, H-2); 4.09 (t, 1H, J30 -40 = 3.4, J50 -60 = 7.0, H-50 ); 3.99–3.97 (m, 2H, H-60 a, H-60 b); 3.86–3.63 (m, 1H, H-5); 3.63–3.57 (m, 2H, H-6a, H-6b); 3.57–3.48 (m, 1H, H-100 ); 2.86–1.08 (m, 20H, NH, H-200 , H-300 a, H-300 b, H-400 a, H-400 b, H-500 a, H-500 b, H-600 a, H-600 b, H-2000 a, H-2000 b, H-3000 a, H-3000 b, H-4000 a, H-4000 b, H-5000 a, H-5000 b, H-6000 a, H-6000 b); 2.12, 2.04, 1.98, 1.96; 1.95; 1.92; 1.90 (7s, 21H, 7 CH3, Ac). NMR 13C (150 MHz, CDCl3): 170.39–169.19 7 [email protected]; 157.19 [email protected]; 96.38 C10 ; 80.00 C1; 74.12 C5; 73.52 C3; 70.50 C2; 69.00 C4; 68.19 C40 ; 68.11 C20 ; 67.54 C30 ; 66.31 C50 ; 65.58 C6; 61.75 C60 ; 50.45 C200 ; 50.12 C100 ; 38.78–10.93 (C300 , C400 , C500 , C600 , C2000 , C3000 , C4000 , C5000 , C6000 ), 20.96– 20.52 (Ac); 10.94 C200 . 4.2.6. N-[(1R, 2R)-trans-2-(1-Piperidinyl)cyclohexylamine]-N0 (2,3,6,20 ,30 ,40 ,60 -hepta-O-acetyl-b-D-cellobiosyl)-urea (L6) Yield%: 52 (438 mg) as a white solid (AcOEt/MeOH/CH2Cl2 3:1:1, Rf = 0.54); mp: 108–110)°C, [a]25 D 26.0 (c 0.5, CH2Cl2); Anal. for C38H57N3O18 (843.36), Calcd: C, 54.09; H, 6.81; N, 4.98. Found: C, 54.17; H, 7.05; N, 4.76. IR (KBr, cm1): 3401, 1755, 1654, 1233, 1038. NMR 1H (600 MHz, CDCl3): 5.50 (s, 1H, NHsac.); 5.37 (t, 1H, J2–3 = 9.4, J3–4 = 9.4, H-3), 5.14 -5.04 (m, 3H, H-10 , H-30 ; H-40 ), 4.90 (t, 1H, J1–2 = 8.0, J2–3 = 8.0, H-2), 4.84 (t, 1H, J10 -20 = 9.5, J20 -30 = 9.5, H-20 ), 4.49 (d, 1H, J1–2 = 8.0, H-1), 4.35 (dd, 2H, J = 4.6, J = 12.5, H-60 a, H-60 b), 4.50–4.49 (m, 1H, H-6b), 4.14–4.11 (m, 1H, H-6a), 4.0 (dd, 1H, J = 2.1, J = 12.6, H-50 ); 3.76 (t, 1H, J3–4 = 9.4, J4–5 = 9.4, H-4), 3.69–3.63 (m, 1H, H-5), 2.58 (bs, 1H, H-100 ), 2,44–1.18 (m, 21H, CH2, 2H-200 , 2H-300 , 2H-400 , 2H-500 , H-600 , 2H-1000 , 2H-2000 , 2H-3000 , 2H-4000 , 2H-5000 ) 2,11–1.97 (7s, 7 CH3, 21H, Ac). NMR 13C (150 MHz, CDCl3): 170.45–168.96 Ac; 156,77 [email protected]; 100. 65 C1; 80.28 C10 ; 74,50 C5; 73.00 C4; 72.5 C3; 71.65 C20 ; 72.00 C50 ;71.08 C2; 67,98 C30 ; 67.98 C40 ; 62.02C60 ; 61.70 C6; 51,17 C100 ; 36,54–11,70 (C200 , C300 , C400 , C500 , C600 , C2000 , C3000 , C4000 , C5000 , C6000 ); 20,96–20.50 (CH3, Ac). 4.3. Typical procedure for enantioselective aza-Henry reaction To a solution of the appropriate organocatalyst (0.01 mmol, 20 mol %) and (4-metoxybenzylidene)-4-methylbenzenesulfonamide (14 mg, 0.05 mmol) in THF or CH2Cl2 (1.0 ml) nitromethane (15 mg, 0.25 mmol) was added. The mixture was stirred for 7 days at room temperature and directly purified by column chromatography on silica gel (petroleum ether/EtOAc 2/1 as eluent) to afford

the desired product (2-nitro-1-(40 -methoxyphenyl)-N-tosylethanamine). (2-Nitro-1-(40 -methoxyphenyl)-N-tosylethanamine is known and our spectroscopic data are in agreement with published data.10d NMR 1H (600 MHz, CDCl3); 7.69–7.68 (m, 1H, H-8), 7.29–7.27 (m, 2H, H-9), 7.03–7.02 (m, 2H, H-4), 6.81–6.79 (m, 2H, H5), 5.13 (d, J = 5.5, 1H, NH), 4.91 (dd, 1H, J = 12.7; J = 6.2, H-2), 4.86 (dd, 1H, J = 12.8; J = 6.4, H-1), 4.68 (dd, 1H, J = 13.0; J = 6.7; H-1), 3.79 (s, 3H, OMe), 2.44 (s, 3H, Ar-Me). HPLC: (Chiralcel OD-H column, Hexane/2-propanol = 85/15, flow 1.0 mL/min, detection at 215 nm) tr = 34.0 [(S)-major and tr = 38.3 (R)-minor].14 Acknowledgement This work was partly financed by the European Union within the European Regional Development Fund (POIG.01.01.02-14102/09). References 1. (a) Pellissier, H. Tetrahedron 2007, 63, 9267–9331; (b) Tsakos, M.; Kokotos, Ch. G. Tetrahedron 2013, 69, 10199–10222; (c) Pu, X.-W.; Peng, F.-Z.; Zhang, H.-B.; Shao, Z.-H. 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New sugar-derived bifunctional chiral ureas as highly effective organocatalysts in asymmetric aza-Henry reaction.

A simple synthesis of series of new catalysts derived from chiral bifunctional ureas is described. The aza-Henry reaction of imines with nitromethane ...
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