Eur. J. Org. Chem. 2008 · © WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2008 · ISSN 1434–193X

SUPPORTING INFORMATION

Title: Sugar-Derived Bifunctional Thiourea Organocatalyzed Asymmetric Michael Addition of Acetylacetone to Nitroolefins Author(s): Peng Gao, Chungui Wang, Yang Wu, Zhenghong Zhou,* Chuchi Tang Ref. No.: O200800555

Table of Contents

1. Experimental section 2. Characterization of the catalysts 6 3. Copies of NMR Spectra of the Michael addition products 4. Copies of HPLC data of the Michael addition products

1. Experimental Section

General information All reagents and solvents were commercial grade and purified prior to use when necessary.

NMR spectra were acquired on either a Bruker AMX-300 or Varian 400 MHz instrumental. Specific rotations were measured on a Perkin-Elmer 341MC polarimeter. Enantiomeric excesses were determined on a HP-1100 instrument (chiral column; mobile phase: Hexane/i-PrOH). Melting points were determined on a T-4 melting point apparatus. All temperatures were uncorrected.

Preparation of the chiral thiourea organocatalysts 6

RNCSH2N

NMe2CH2Cl2

rt, 8–12 h

OAcO OAc

OAcO

AcOOAc

O

AcO OAc6

6a, R =

6b, R =

6c, R =

OAcO

OAc

AcO OAc

RHN

S

HN

NMe2+

To a solution of (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (1.10 g, 7.7 mmol) in methylene chloride (10 mL) was added dropwise a solution of the corresponding sugar-derived isothiocyanate (7.0 mmol) in methylene chloride (25 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature until total consumption of the isothiocyanate (monitored by TLC). After removal of solvent, the residue was purified through column chromatography on silica gel (200–300 meshes, eluted with ethyl acetate / petroleum ether: 1/2) to give the thiourea catalyst as a white solid.

OAcOAcO

OAc

AcO

HN

S

HN

NMe2

(+)-6a: 79% yield, m.p 105–106 °C, [α]20,D +18.0 (c 1.0,

CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.95–1.24 (m, 5 H, 2 CH2 and one prton of CH2), 1.61–1.83 (m, 3 H, CH2 and one prton of CH2), 1.95 (s, 3 H, COCH3), 1.97 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3), 2.11–2.50 (m, 3 H, 3 NCH), 2.16 (s, 6 H, 2 NCH3), 3.77–3.81 (m, 1 H, OCH), 4.02–4.07 (m, 1 H, OCH), 4.28 (dd, 1 H, J = 9.3 and 4.2 Hz, OCH), 4.91 (t, 1 H, J = 9.6 Hz, OCH), 5.01 (t, 1 H, J = 9.6 Hz, OCH), 5.25–5.31 (m, 1 H, OCH), 5.70 (br. s, 1 H, NH), 6.65 (br. s, 1 H, NH). 13C NMR (75.0 MHz, CDCl3): δ = 20.58, 20.73, 21.61, 24.49, 24.90, 32.65, 33.95, 39.95, 55.80, 61.76, 66.81, 68.31, 71.04, 73.06, 73.29, 76.72, 77.15, 77.57, 82.90, 100.00, 169.60, 169.83, 170.60, 170.96, 183.48. IR (KBr): ν 3358, 2938, 1754, 1541, 1370, 1228, 1038, 908, 758, 600 cm–1. HMS (ESI) m/z calc'd for C23H37N3O9S [M+H]+: 532.2323, found 532.2320.

OAcO

OAc

HN

S

HN

NMe2AcO OAc

(+)-6b: 67% yield, m.p 94–95 °C, [α]20,D +22.9 (c 1.02,

CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.96–1.28 (m, 5 H, 2 CH2 and one prton of CH2), 1.62–1.83 (m, 3 H, CH2 and one prton of CH2), 1.92 (s, 3 H, COCH3), 1.97 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.17 (s, 6 H, 2 NCH3), 2.34–2.41 (m, 2 H, 2 NCH), 3.58–3.59 (m, 1 H, NCH), 3.98–4.07 (m, 3 H, OCH), 5.05–5.14 (m, 2 H, 2 OCH), 5.38 (d, 1 H, 1.6 Hz, OCH), 5.63 (br. s, 1 H, NH), 6.69 (br. s, 1 H, NH). 13C NMR (100.6 MHz, CDCl3): δ = 20.74, 20.77, 20.91, 21.04, 24.72, 39.99, 40.09, 55.92, 61.24, 66.87, 67.40, 68.93, 71.22, 72.21, 77.06, 77.38, 77.70, 83.45, 169.97, 170.19, 170.60, 171.46, 183.47. IR (KBr): ν 3360, 2936, 1751, 1541, 1370, 1228, 1050, 954, 915, 761, 600 cm–1. HRMS (ESI) m/z calc'd for C23H37N3O9S [M+H]+: 532.2323, found 532.2333.

O

AcOOAc

OAc

HN

S

HN

NMe2OAcO

OAcO

AcO OAc

(–)-6c: 64% yield, m.p 118–120 °C,

[α]20,D –1.12 (c 0.98, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.10–1.20 (m, 4 H, 2 CH2),

1.60–1.81 (m, 4 H, 2 CH2), 1.89 (s, 3 H, COCH3), 1.97 (s, 9 H, 3 COCH3), 1.99 (s, 3 H, COCH3), 2.04 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.15 (s, 6 H, 2 NCH3), 2.28–2.40 (m, 2 H, 2 NCH), 3.69–3.84 (m, 4 H), 3.99–4.12 (m, 4 H, OCH), 4.38 (d, 1 H, J = 11.6 Hz), 4.42 (d, 1 H, J = 11.6 Hz), 4.81 (t, 1 H, J = 9.6 Hz), 5.03 (dd, 1 H, J = 8.0 and 10.4 Hz), 5.22–5.28 (m, 2 H, OCH and NH), 5.59 (br. s, 1 H, NH). 13C NMR (100.6 MHz, CDCl3): δ = 20.79, 20.86, 220.97, 55.94, 61.03, 62.24, 66.82, 69.16, 70.79, 71.18, 71.48, 72.96, 74.37, 76.29, 77.06, 77.38, 77.69, 82.85, 100.95, 169.12, 169.59, 170.25, 170.35, 170.55, 171.37, 183.73. IR (KBr): ν 3362, 2938, 1754, 1541, 1370, 1229, 1047, 952, 904, 759, 602 cm–1. HRMS m/z (ESI) calc'd for C35H53N3O17S [M+H]+: 820.3169, found 820.3168.

General Procedure for the 6a catalyzed asymmetric Michael addition of acetylacetone to nitroolefins

To A solution of nitrooelfins (0.2 mmol), thiourea catalyst 6a (10.7 mg, 0.02 mmol) in toluene (0.5 mL) was added acetylacetone (40 mg, 0.4 mmol) in one portion at the temperature as depicted in the text. The resulting mixture was stirred at the same temperature and monitored by TLC. The solution was concentrated and purified by column chromatography on silica gel (200–300 meshes, eluted with ethyl acetate / petroleum ether: 1/10–1/5) to furnish the desired products. Enantiomeric excess was determined by chiral HPLC analysis.

(R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (7a)

NO2

O O

White solid, 96% yield, m.p. 112–114 °C, [α]20,D –184.9 (c , CHCl3), 96% ee. 1H NMR (CDCl3, 400 MHz): δ = 1.94 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 4.21–4.27 (m, 1 H, CH), 4.37 (d, 1 H, J = 10.4 Hz, CH), 4.59–4.66 (m, 2 H, CH2), 7.17–7.19 (m, 2 Harom), 7.27–7.35 (m, 3 Harom). 13C NMR (CDCl3, 75.0 MHz): 29.58, 30.41, 42.80, 70.69, 78.16, 127.95, 128.53, 129.32, 136.05, 200.99, 201.73. HPLC analysis (Chiralpak AD-H column, Hexane:ethanol = 85:15, flow rate = 1.5 mL/min, wavelength = 210 nm): Rt = 12.11 (minor) and 20.90 min (major).

(R)-3-[1-(4-Methylphenyl)-2-nitroethyl]pentane-2,4-dione (7b)

NO2

O O

Me White solid, 80% yield, m.p. 101–103 °C, [α]20,D –167.7 (c 1.50,

CHCl3), 89% ee. 1H NMR (CDCl3, 400 MHz): δ = 1.94 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 4.17–4.23 (m, 1 H, CH), 4.35 (d, J = 11.2 Hz, 1 H, CH), 4.56–4.64 (m, 2 H, CH2), 7.06 (d, 1 Harom, J = 8.0 Hz), 7.12 (d, 1 Harom, J = 8.0 Hz). HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 85:15, flow rate = 1.5 mL/min, wavelength = 210 nm): Rt = 12.28 (minor) and 22.01 min (major).

(R)-3-[1-(4-Benzyloxyphenyl)-2-nitroethyl]pentane-2,4-dione (7c)

NO2

O O

BnO Pale yellow solid, >99% yield, m.p. 152–154 °C, [α]20,D –96.4 (c

1.10, CHCl3), 85% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.94 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 4.16–4.23 (m, 1 H, CH), 4.33 (d, 1 H, J = 10.8 Hz, CH), 4.59 (d, 2 H, J = 5.7 Hz, CH2), 5.01 (s, 2

H, OCH2), 6.92 (d, 2 Harom, J = 8.7 Hz), 7.10 (d, 2 Harom, J = 8.7 Hz), 7.33–7.40 (m, 5 Harom). 13C NMR (CDCl3, 75.0 MHz): 29.45, 30.15, 42.15, 70.60, 70.95, 78.40, 115.61, 127.52, 128.03, 128.10, 128.62, 129.12, 136.60, 158.81, 201.10, 201.83. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 10.19 (minor) and 13.53 min (major).

(R)-3-[1-(4-Methoxyphenyl)-2-nitroethyl]pentane-2,4-dione (7d)

NO2

O O

MeO White solid, >99% yield, m.p. 116–118 °C, [α]20,D –137.1 (c 1.10,

CHCl3), 88% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.94 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 3.77 (s, 3 H, OCH3), 4.16–4.22 (m, 1 H, CH), 4.33 (d, 1 H, J = 10.8 Hz, CH), 4.58 (d, 2 H, J = 6.0 Hz, CH2), 6.84 (d, 2 Harom, J = 8.4 Hz), 7.10 (d, 2 Harom, J = 8.4 Hz). 13C NMR (CDCl3, 75.0 MHz): 29.96, 30.50, 40.91, 69.11, 77.42, 123.23, 126.61, 128.43, 128.66, 135.61, 201.53, 201.81. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 80:20, flow rate = 0.8 mL/min, wavelength = 210 nm): Rt = 12.02 (minor) and 17.67 min (major).

(R)-3-[1-(3-Methoxyphenyl)-2-nitroethyl]pentane-2,4-dione (7e)

NO2

O O

OMe White solid, >99% yield, m.p. 96–98 °C, [α]20,D –197.6 (c 0.82, CHCl3),

92% ee. 1H NMR (CDCl3, 400 MHz): δ = 1.96 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.77 (s, 3 H, CH3), 4.17–4.23 (m, 1 H, CH), 4.36 (d, 1 H, J = 10.8 Hz), 4.57–4.65 (m, 2 H, CH2), 6.70 (s, 1 Harom), 6.75 (d, Harom, J = 8.0 Hz), 6.80 (dd, 1 Harom, J = 8.0, 2.4 Hz), 7.23 (t, 1 Harom, J = 8.0 Hz). 13C NMR (CDCl3, 75.0 MHz): 29.65, 30.40, 42.80, 55.24, 70.65, 78.13, 113.63, 114.16, 119.92, 130.37, 137.63, 160.11, 200.91, 201.72. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 99:1, flow rate = 0.8 mL/min, wavelength = 210 nm): Rt = 40.16 (minor) and 43.73 min (major).

(R)-3-[1-(2-Methoxyphenyl)-2-nitroethyl]pentane-2,4-dione (7f)

NO2

O O

OMe Pale yellow viscous oil, 89% yield, [α]20,D –200.0 (c 0.94, CHCl3), 92%

ee. 1H NMR (CDCl3, 400 MHz): δ = 1.91 (s, 3 H, CH3), 2.24 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3),

4.42–4.48 (m, 1 H, CH), 4.54–4.60 (m, 2 H, CH2), 4.76 (dd, 1 H, J = 12.0, 8.0 Hz, CH), 6.87 (d, 21 Harom, J = 8.0 Hz), 7.05 (dd, 1 Harom, J = 8.0, 1.2 Hz), 7.24 (dt, 1 Harom, J = 8.0, 1.2 Hz). HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 51.82 (minor) and 56.85 min (major).

(R)-3-[1-(2,4-dimethoxyphenyl)-2-nitroethyl]pentane-2,4-dione (7g)

NO2

O O

MeO OMe Pale yellow viscous oil, >99% yield, [α]20,D –165.0 (c 0.50,

CHCl3), 84% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.92�(s, 3 H, CH3), 2.26 (s, 3 H, CH3), 3.76 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.35–4.43 (m, 1 H, CH), 4.50–4.57 (m, 2 H, CH2), 4.73 (dd, J = 8.1, 12.0 Hz, 1 H, CH), 6.39 (dd, 1 Harom, J = 8.4, 2.4 Hz), 6.43 (d, 1 Harom, J = 2.4 Hz), 6.95 (d, 1 Harom, J = 8.4 Hz). HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 14.47 (minor) and 17.29 min (major).

(R)-3-[1-(4-Trifluoromethylphenyl)-2-nitroethyl]pentane-2,4-dione (7h)

NO2

O O

F3C White solid, 76% yield, m.p. 144–146 °C, [α]20,D –78.1 (c 1.13,

CHCl3), 91% ee. 1H NMR (CDCl3, 300 MHz): δ = 2.00 (s, 3 H, CH3), 2.32 (s, 3 H, CH3), 4.28–4.41 (m, 2 H, 2 CH), 4.60–4.72 (m, 2 H, CH2), 7.33 (d, 2 Harom, J = 8.1 Hz), 7.60 (d, 2 Harom, J = 8.1 Hz). 13C NMR (CDCl3, 75 M Hz): 29.74, 30.46, 42.43, 70.31, 77.63, 126.27, 126.32, 128.49, 140.30, 200.27, 201.15. HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 12.21 (minor) and 15.57 min (major).

(R)-3-[1-(3-Trifluoromethylphenyl)-2-nitroethyl]pentane-2,4-dione (7i)

NO2

O O

CF3 White solid, 82% yield, m.p. 85–87 °C, [α]20,D –119.2 (c 0.94, CHCl3),

89% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.98 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 4.29–4.35 (m, 1 H, CH), 4.39 (d, 1 H, J = 10.4 Hz, CH), 4.62–4.71 (m, 2 H, CH2), 5.93 (s, 2 H, CH2), 7.39 (d, 1 Harom, J = 7.6 Hz), 7.43–7.47 (m, 2 Harom), 7.55 (d, 1 Harom, J = 7.6 Hz). 13C NMR (CDCl3, 75.0 MHz): 29.97, 30.52, 40.92, 69.12, 77.43, 123.21, 126.62, 128.44, 128.67, 135.62, 201.55,

201.83. HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol = 85:15, flow rate = 0.8 mL/min, wavelength = 210 nm): Rt = 10.94 (minor) and 15.71 min (major).

(R)-3-[1-(2-Trifluoromethylphenyl)-2-nitroethyl]pentane-2,4-dione (7j)

NO2

O O

CF3 White solid, 81% yield, m.p. 96–98 °C, [α]20,D –190.1 (c 0.25, CHCl3),

95% ee. 1H NMR (CDCl3, 400 MHz): δ = 2.00 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 4.59–4.68 (m, 3 H, CH and CH2), 4.84 (dd, J = 8.4, 5.2 Hz, 1 H, CH), 7.25 (d, 1 Harom, J = 7.6 Hz), 7.43 (t, 1 Harom, J = 7.6 Hz), 7.52 (t, 1 Harom, J = 7.6 Hz), 7.74 (d, 1 Harom, J = 7.6 Hz). HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 96:4, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 20.97 (minor) and 23.96 min (major).

(R)- 3-[1-(4-Chlorophenyl)-2-nitroethyl]pentane-2,4-dione (7k)

NO2

O O

Cl White solid, 91% yield, m.p. 119–121 °C, [α]20,D –132.5 (c 1.04,

CHCl3), 88% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.97 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 4.18–4.26 (m, 1 H, CH), 4.32 (d, 1 H, J = 10.8 Hz, CH), 4.60 (d, 2 H, J = 5.7 Hz, CH2), 7.13 (d, 2 Harom, J = 8.4 Hz), 7.30 (d, 2 Harom, J = 8.4 Hz). 13C NMR (CDCl3, 75.0 MHz): 29.68, 30.42, 42.15, 70.50, 77.91, 129.34, 129.55, 134.54, 134.60, 200.56, 201.37. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 80:20, flow rate = 0.8 mL/min, wavelength = 210 nm): Rt = 11.33 (minor) and 28.60 min (major).

(R)-3-[1-(naphthalen-1-yl)-2-nitroethyl]pentane-2,4-dione (7l)

NO2

O O

Orange viscous oil, 97% yield, [α]20,D –182.0 (c 1.10, CHCl3), 95% ee. 1H NMR (CDCl3, 300 MHz): δ = 1.86 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 4.68–4.75 (m, 2 H, CH2), 4.81 (dd, 1 H, J = 12.0, 6.6 Hz, CH), 5.20 (m, 1 H, CH), 7.27 (d, 1 Harom, J = 8.1 Hz), 7.40 (t, 1 Harom, J = 8.1 Hz), 7.53 (t, 1 Harom, J = 7.8 Hz), 7.61 (dt, 1 Harom, J = 8.4, 1.2 Hz), 7.80 (d, 1 Harom, J = 8.1 Hz), 7.89 (d, 1 Harom, J = 8.1 Hz), 8.18 (d, 1 Harom, J = 8.4 Hz). 13C NMR (CDCl3, 75.0 MHz): 28.70, 30.96, 36.48, 70.43, 77.75, 121.94, 124.82, 125.23, 126.31, 127.33, 129.18, 129.45, 130.84, 132.03, 134.29, 200.78, 202.29. HPLC analysis (Chiralpak AD-H column,

Hexane:2-propanol = 97:3, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 31.69 (minor) and 32.86 min (major).

(S)-3-[1-(Furan-2-yl)-2-nitroethyl]pentane-2,4-dione (7m)

NO2

O O

O Yellow solid, >99% yield, m.p. 101–103 °C, [α]20,D –123.0 (c 0.90,

CHCl3), 94% ee. 1H NMR (CDCl3, 400 MHz): δ = 2.07 (s, 3 H, CH3), 2.27 (s, 3 H, CH3), 4.30–4.36 (m, 1 H, CH), 4.39 (d, 1 H, J = 10.0 Hz, CH), 4.65 (d, 2 H, J = 5.6 Hz, CH2), 6.16 (d, 1 Harom, J = 3.2 Hz), 6.29 (t, 1 Harom, J = 2.4 Hz), 7.35 (t, 1 Harom, J = 1.2 Hz). HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 9.90 (minor) and 11.59 min (major).

(S)-3-[1-(5-Methylfuran-2-yl)-2-nitroethyl]pentane-2,4-dione (7n)

NO2

O O

OMe Yellow solid, >99% yield, 43–45 °C, [α]20,D –140.3 (c 0.76, CHCl3),

85% ee. 1H NMR (CDCl3, 300 MHz): δ = 2.07 (s, 3 H, CH3), 2.21 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 4.22–4.28 (m, 1 H, CH), 4.35 (d, 1 H, J = 9.6 Hz, CH), 4.62 (d, 2 H, J = 5.6 Hz, CH2), 5.83 (d, 1 Harom, J = 3.2 Hz), 6.01 (d, 1 Harom, J = 3.2 Hz). 13C NMR (CDCl3, 75.0 MHz): 13.40, 29.19, 30.62, 36.66, 60.08, 75.96, 106.63, 109.58, 147.41, 152.63, 200.88, 201.64. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 6.94 (minor) and 7.51 min (major).

(S)-3-[(E)-1-nitro-4-phenylbut-3-en-2-yl)pentane-2,4-dione (7o)

NO2

OO

White solid, 85% yield, m.p. 135–138 °C, [α]20,D –128.1 (c 0.80, CHCl3), 81% ee. 1H NMR (CDCl3, 400 MHz): δ = 2.21 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.69–3.77 (m, 1 H, CH), 4.06 (d, 1 H, J = 9.2 Hz, CH), 4.52–4.58 (m, 2 H, CH2), 6.01 (dd, 1 H, J = 16.0, 9.6 Hz, =CH), 6.55 (d, 1 H, J = 16.0 Hz, =CH), 7.27–34 (m, 5 Harom). 13C NMR (CDCl3, 75.0 MHz): 29.96, 30.50, 40.91, 69.11, 77.42, 123.23, 126.61, 128.66, 135.61, 201.53, 201.81. HPLC analysis (Chiralpak AS-H column, Hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wavelength = 210 nm): Rt = 15.47 (minor) and 19.41 min (major).

2. Characterization of the catalysts 6

3. Copies of the NMR spectra of the Michael addition products

4. Copies of the HPLC data of the Michael addition products