SUPPORTING INFORMATION Chiral 2-Aminobenzimidazoles as ...
SUPPORTING INFORMATION
Chiral 2-Aminobenzimidazoles as Recoverable Organocatalysts for the Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes Diana Almaşi,a Diego A. Alonso,a,* Enrique Gómez-Bengoa,b and Carmen Nájeraa,* a
b
Departamento de Química Orgánica and Instituto de Síntesis Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080, Alicante (Spain)
Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080, San Sebastián (Spain) [email protected], [email protected]
Table of Contents 1. General……………………………………………………………………………………..
S2
2. Synthesis of catalysts 7……………………………………………………………………
S2
3. Acid cocatalyst screening for the conjugate addition of diethyl malonate to β-nitrostyrene catalyzed by organocatalyst 7b………………………………………………….
S7
4. General procedure for the conjugate addition of 1,3-dicarbonyl copounds to nitroalkenes and recovery of catalyst 7b……………………………………………………...
S8
5. HPLC conditions and retention times for compounds 8…………………………………..
S20
6. Computational data………………………………………………………………………….
S21
7. Crystallographic data………………………………………………………………………..
S66
8. NMR spectra for compounds 7, 8 and 9…………………………………………………....
S67
9. HPLC spectra for compounds 8…………………………………………………………...
S94
10. References………………………………………………………………………………...
S103
S1
1. General Melting points were determined with a hot plate apparatus and are uncorrected. 1H NMR (300 MHz, 400 MHz),
13
C NMR (75 MHz, 100 MHz), and 2DNMR (COSY, NOESY, HSQC) spectra were
obtained at 25 ºC using CDCl3 as solvent, otherwise stated; chemical shifts are reported as δ (ppm) values relative to TMS as internal standard and coupling constants (J) in Hz. Hydrogen multiplicity (C, CH, CH2, CH3) information was obtained from Carbon DEPT spectra. IR data were collected on a FTIR or ATR apparatus, and peaks are reported in cm–1. Specific rotations were determined at 20 ºC with a digital polarimeter. HPLC analyses were performed on equipped with a chiral column and automatic inyector, using mixtures of n-hexane/isopropyl alcohol (IPA) as mobile phase, at 25 ºC. Low-resolution electron impact (EI) mass spectra were obtained at 70 eV and mass spectra fragment ions m/z with relative intensities (%) is reported in parenthesis. Analytical TLC was visualized with UV light at 254 nm. Thin layer chromatography was carried out on TLC aluminum sheets with silica gel 60 F254 . Flash chromatography (silica gel 60: 0.040-0.063 mm) was performed employing a Pump system. Reactions under argon atmosphere were performed in oven-dried glassware sealed with a rubber septum using anhydrous solvents. Data collection for X ray analysis was performed on a diffractometer based on three ω-scan runs (starting = -34º) at values φ =0º, 120º, 240º with the detector at 2θ =-32º. For each of these runs, 606 frames were collected at 0.3º intervals and 30 s per frame for compound 5b and 40 s per frame for compound 6m. An additional run at φ =0º of 100 frames was collected to improve redundancy. 2. Synthesis of catalysts 7 N
NH2 + NH2
TEA
Cl N H
R
N
195-200 ºC NH2
N H
N H
R
7a, R = H 7e, R = CF3
A mixture of 2-chloro-1H-benzo[d]imidazole (233 mg, 1.53 mmol, 1 eq.) or 2-chloro-6(trifluoromethyl)-1H-benzo[d]imidazole1 (338 mg, 1.53 mmol, 1 eq.), (1R,2R)-cyclohexane-1,2-diamine (698 mg, 6.12 mmol, 4 eq.), and TEA (213 µL, 1.53 mmol, 1 eq.) was heated under argon atmosphere at S2
195-200 ºC during 16 h. The reaction mixture was then allowed to reach 50 ºC, water (20 mL) was added and the reaction mixture was extracted with CH2Cl2 (3×20 mL) before the temperature rise rt (to avoid solubility problems). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give the corresponding crude products which were purified by flash chromatography (EtOAc/MeOH) to give pure 7a (229 mg, 65%) or 7e (296 mg, 56%). N NH2
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (7a). Yield 65%; pale yellow solid; mp 235-240 ºC (Et2O); [α]D20 – 55.0 (c 1.0, MeOH); IR (KBr) 2929, 2855, 1700, 1644, 1606, 1580, 1468, 1270, 1116, 1030; δH (CD3OD) 1.19-1.49 (m, 4H, 2×CH2), 1.741.77 (m, 2H, CH2), 1.98-2.11 (m, 2H, CH2), 2.50-2.58 (m, 1H, CHNH2), 3.34-3.40 (m, 1H, CHNH), 6.93-6.97 (m, 2H, ArH), 7.15-7.18 (m, 2H, ArH); δC 26.0, 26.2, 33.8, 34.9 (4×CH2), 55.6 (CHNH), 60.4 (CHNH2), 112.7, 121.3 (4×ArCH), 139.1 (2×ArC), 156.9 (C=N); m/z 230 [M+, 10%], 172 (14), 160 (24), 146 (14), 134 (100), 133 (59), 132 (12), 118 (12), 97 (28); HRMS calcd. for C13H18N4 [M]+ 230.1531; found 230.1532. N NH2
N H
N H
CF3
(1R,2R)-N1-{6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl}cyclohexane-1,2-diamine (7e). Yield 56%; pale yellow solid; mp 108-110 ºC (Et2O); [α]D20 – 19.6 (c 1.35, MeOH); IR (KBr) 2925, 2844, 16642, 1579, 1447, 1325, 1165, 1119, 1050; δH (CD3OD, 400 MHz) 1.24-1.48 (m, 4H, 2×CH2), 1.75-1.77 (m, 2H, CH2), 1.99-2.13 (m, 2H, CH2), 2.61-2.65 (m, 1H, CHNH2), 3.39-3.46 (m, 1H, CHNH), 7.22-7.24 (m, 1H, ArH), 7.24-7.28 (m, 1H, ArH), 7.42 (s, 1H, ArH); δC (100 MHz) 25.9, 26.1, 33.6), 34.7 (4×CH2), 55.8 (CHNH), 60.0 (CHNH2), 109.6, 112.5 (2×ArCH), 118.3 (q, J = 4.5 Hz, CHCCF3), 123.3 (q, J = 32 Hz, CCF3), 126.7 (q, J = 268 Hz, CF3), 139.2, 142.0 (2×ArC), 158.5 (C=N); S3
m/z 298 [M+, 7%], 234 (17), 228 (24), 226 (13), 214 (16), 202 (42), 201 (61), 200 (12), 97 (100), 96 (16), 69 (14); HRMS calcd. for C14H17F3N4 [M]+ 298.1405; found 298.1389. In both cases small amounts (5-15%) of diarylated diamine derivative were observed by 1HNMR on the crude reaction mixture In the case of catalyst 7a, compound 7f could be isolated by flash chromatography (EtOAc/MeOH) and characterized as follows. N N H
N H
N H
N HN
(1R,2R)-N1,N2-Di[1H-benzo[d]imidazol-2-yl]cyclohexane-1,2-diamine (7f). White solid; mp 193-196 ºC (Et2O); [α]D20 + 241 (c 0.35, MeOH); IR (KBr) 2944, 2916, 2847, 1630, 1603, 1580, 1461, 1410, 1259, 1112, 1047; δH (CD3OD) 1.35-1.47 (m, 4H, CH2), 1.76 (br s, 2H, CH2), 2.18-2.23 (m, 2H, CH2), 3.71-3.74 (m, 2H, CHNH), 6.90-6.95 (m, 4H, ArH), 7.11-7.15 (m, 4H, ArH); δC 25.6 (CH2), 33.9 (CH2), 57.6 (CHNH), 112.6, 121.2 (8×ArCH), 138.9 (4×ArC), 156.7 (2×C=N); m/z 346 [M+, 33%], 214 (64), 213 (100), 212 (36), 184 (16), 173 (19), 172 (15), 170 (10), 160 (14), 159 (21), 158 (11), 146 (11), 145 (16), 134 (32), 133 (37), 132 (16); HRMS calcd. for C20H22N6 [M]+ 346.1906; found 346.1904.
N NH2
N H
N H 7a 7e
N
HCO2H, HCHO R
120 ºC
N
N H
N H
R
7b, R = H 7d, R = CF3
A mixture of 7a (168 mg, 0.73 mmol, 1 eq.) or 7e (218 mg, 0.73 mmol, 1 eq.), 80% HCO2H (3.5 mL) and 36% aqueous solution of HCHO (127 µL, 1.61 mmol, 2.2 eq.) was stirred at 120 ºC for 16 h. Then, the solvent was removed under reduced pressure. Saturated NaHCO3 solution (15 mL) and 10% NaOH solution (until pH 8) were added and the product was extracted with CH2Cl2 (3×15 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give the corresponding crude S4
products which were purified by flash chromatography (EtOAc/MeOH) and then recrystallized in CH2Cl2 to give pure 7b (87 mg, 46%) or 7d (178 mg, 75%). N N
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (7b). Yield 46%; white solid; mp 248-250 ºC (CH2Cl2); [α]D20 – 55.3 (c 1.0, CH2Cl2); IR (KBr) 2923, 2856, 2818, 2775, 1700, 1633, 1576, 1499, 1461, 1375, 1265, 1064; δH (CDCl3) 1.09-1.42 (m, 4H, 2×CH2), 1.65-1.70 (m, 1H, 1×CH2), 1.82-1.87 (m, 2H, CH2), 2.22 (s, 6H, CH3), 2.33 (td, J = 10.9, 3.2 Hz, 1H, CHNMe2), 2.65-2.69 (m, 1H, 1×CH2), 3.44 (td J = 10.4, 4.0 Hz, 1H, CHNH), 5.46 (br s, 1H, NH), 6.916.96 (m, 2H, ArH), 7.14-7.20 (m, 2H, ArH); δC (CD3OD) 23.7, 25.8, 26.4, 34.8 (4×CH2), 40.5 (2×CH3), 54.7 (CHNH), 67.7 (CHNMe2), 112.6, 121.2 (4×ArCH), 139.1 (2×ArC), 156.6 (C=N); m/z 258 [M+, 1.5%], 134 (11), 133 (30), 126 (10), 125 (100), 124 (19), 84 (20), 58 (12); HRMS calcd. for C15H22N4 [M]+ 258.1844; found 258.1844. N N
N H
N H
CF3
(1R,2R)-N1,N1-Dimethyl-N2-{6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl}cyclohexane-1,2diamine (7d). Yield 75%; white solid; mp 223-225 ºC (CH2Cl2); [α]D20 – 21 (c 0.55, CH2Cl2); IR (KBr) 2935, 2860, 1638, 1580, 1451, 1325, 1156, 1112, 1049; δH 1.12-1.41 (m, 4H, 2×CH2), 1.68-1.72 (m, 1H, 1×CH2), 1.84-1.90 (m, 2H, CH2), 2.26 (s, 6H, 2×CH3), 2.36 (td, J = 10.4, 3.4 Hz, 1H, CHNMe2), 2.58-2.62 (m, 1H, 1×CH2), 3.44 (td, J = 10.4, 3.6 Hz,1H, CHNH), 5.56 (br s, 1H, NH), 7.26 (s, 1H, ArH), 7.29 (s, 1H, ArH), 7.49 (s, 1H, ArH); δC 21.2, 24.3, 25.0, 33.2 (4×CH2), 39.8 (2×CH3), 53.9 (CHNH), 67.3 (CHNMe2), 109.2, 111.9 (2×ArCH), 117.5 (q, J = 3.1 Hz, CHCCF3), 122.3 (q, J = 32 Hz, CCF3), 125.2 (q, J = 270 Hz, CF3), 137.6, 141.0 (2×ArC), 157.4 (C=N); m/z 326 [M+, 1%], 201 (19), 126 (11), 125 S5
(100), 124 (23), 84 (38), 71 (16), 58 (21); HRMS calcd. for C16H21F3N4 [M]+ 326.1718; found 326.1714.
N NH2
N H
N H 7a
N
CH3CHO, NaHB(OAc)3 ClCH2CH2Cl, tª amb.
N
N H
N H
7c
To a mixture of 7a (460 mg, 2 mmol, 1 eq.) and CH3CHO (455 µL, 8 mmol, 4 eq.) in 1,2dichloroethane (20 mL) and under argon atmosphere was added NaHB(OAc)3 (2.4 g, 11.2 mmol, 5.6 eq.). The resulting mixture was stirred at rt during 16 h and then quenched with a NaHCO3 saturated aqueous solution. The product was then extracted with EtOAc (3×20 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give crude product which was purified by flash chromatography (EtOAc/MeOH) and then recrystallized in CH2Cl2 to give pure 7c (166 mg, 29%). N NEt2
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2,N2-diethylcyclohexane-1,2-diamine (7c). Yield 29%; white solid; mp 245-246 ºC (CH2Cl2); [α]D20 – 102 (c 0.91, CH2Cl2); IR (KBr) 2971, 2931, 2851, 2811, 1629, 1576, 1475, 1275, 1208, 1111; δH (CD3OD) 0.96-1.01 (t, J = 7.02 Hz, 6H, 2×CH3), 1.14-1.51 (m, 4H, 2×CH2), 1.51-1.69 (m, 1H, 1×CH2), 1.73-1.92 (m, 2H, CH2), 2.33-2.44 (m, 2H, CH2CH3), 2.50-2.72 (m, 4H, 2×CH2CH3, 1×CHN, 1×CH2), 3.44 (td, J = 10.6, 3.9 Hz, 1H, CHNH), 6.92-6.97 (m, 2H, ArH), 7.15-7.19 (m, 2H, ArH); δC 15.0 (2×CH3), 24.8, 25.6, 26.8, 34.7, 44.4 (6×CH2), 54.8 (CHNH), 64.6 (CHNEt2), 112.7, 121.2 (4×ArCH), 139.1 (2×ArC), 157.1 (C=N); m/z 286 [M+, 1%], 214 (11), 186 (17), 154 (13), 153 (100), 138 (10), 134 (14), 133 (46), 124 (14), 112 (25), 86 (26); HRMS calcd. for C17H26N4 [M]+ 286,2157, [M+-C4H10N] 214.1339; found 214.1330.
S6
3. Acid cocatalyst screening for the conjugate addition of diethyl malonate to β-nitrostyrene catalyzed by 7b. To a stirred solution of catalyst 7b (6.7 mg, 0.026 mmol, 10 mol%), acid (0.026 mmol, 10 mol%) and β-nitrostyrene (38.7 mg, 0.26 mmol) in toluene (520 µL), diethyl malonate (80 µL, 0.52 mmol) was added. The reaction mixture was stirred at rt for 36 hours, then the solvent was remove under reduce pressure to give crude product 8a. The conversion and the ee of the pruduct 8a was determined by 1
HNMR and chiral HPLC, respectively, on the crude reaction mixture. 7b (10 mol%) cocatalyst (10 mol%) EtO2C
CO2Et
+
Ph
NO2
EtO2C
toluene, rt, 36 h
CO2Et NO2
Ph 8a
Table S1. Acid cocatalyst screening for the conjugate addition of diethyl malonate to βnitrostyrene catalyzed by 7b ent.
cocatalyst
pKa
conv.%a
eeb
1
-
-
99
76
2
H2O
14
94
74
3
O 2N
7.10
99
74
4
CH3CO2H
4.76
99
72
4.40
99
76
4.20
99
78
3.44
37
87
CO2H
2
99
74
CO2H
2
99
74
5
Me
6 7 8
9
OH
N N N N H
CO2H
O 2N
CO2H
N H
N H
S7
O
10
O P OH
O
O
11 O
12
O P OH
F3CCO2H
13
SO3H
1.5-2
66
72
1.5-2
66
72
0.52
74
92
- 2.8
99
80
Determined by 1HNMR on the crude reaction mixture. b Determined by HPLC on the crude reaction mixture using a Chiralpak AD column, 90/10 Hx/i-Pr, 1 mL/min, 210 nm, tR (major enantiomer) = 14.4 min and tR (minor enantiomer) = 33.5 min. a
4. General procedure for the conjugate addition of diethyl malonate to β -nitrostyrene and recovery of catalyst 7b. To a stirred solution of catalyst 7b (30 mg, 0.116 mmol, 10 mol%) and β-nitrostyrene (173 mg, 1.16 mmol) in toluene (2.3 mL) were added trifluororacetic acid (8.7 µL, 0.116 mmol, 10 mol%) and then diethyl malonate (357 µL, 2.32 mmol). Once the reaction was completed (TLC), the mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give crude compounds 8a which was purified by flash chromatography (EtOAc/hexane) to give pure compounds 8a (348 mg, 97%). The aqueous layer was treated with a 10% NaOH aqueous solution (10 mL) until pH = 8 and then was extracted with CH2Cl2 (3×10 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give pure (by 1HNMR) catalyst 7b {28.2 mg, 94%, [α]D20 – 55.3 (c 1.0, CH2Cl2)}. The recovered catalyst was used in a second catalytic cycle obtaining similar results for the obtention of 8a: 2d, 88% conversion, 90% ee.
S8
O
O
MeO
OMe NO2
Dimethyl (R)-2-(2-nitro-1-phenylethyl)malonate (8b).2 Yield 95%; white solid; mp 59-61 ºC; Rf 0.18 (hexane/EtOAc: 4/1); [α]D20 – 2.5 (c 1.04, CH2Cl2) for 89% ee; IR (neat) 2955, 1731, 1559, 1544, 1427, 1297, 1232, 1155, 1092, 1023, 702; δH 3.57, 3.77 (2s, 6H, 2×CH3), 3.87 [d, J = 9.2 Hz, 1H, CH(CO2Me)2], 4.25 (td, J = 8.7, 5.6 Hz, 1H, CHCH2), 4.88 (dd, J = 13.2, 8.5 Hz, 1H, CHHNO2), 4.93 (dd, J = 13.2, 5.6 Hz, 1H, CHHNO2), 7.21-7.36 (m, 5H, ArH); δC 42.9 (CHCH2), 52.8, 53.0 (2×CH3), 54.7 [CH(CO2Me)2], 77.3 (CH2), 127.8, 128.4, 129.0 (5×ArCH), 136.1 (ArC), 167.2, 167.8 (2×C=O); m/z 281 [M+,
Chiral 2-Aminobenzimidazoles as Recoverable Organocatalysts for the Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes Diana Almaşi,a Diego A. Alonso,a,* Enrique Gómez-Bengoa,b and Carmen Nájeraa,* a
b
Departamento de Química Orgánica and Instituto de Síntesis Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080, Alicante (Spain)
Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080, San Sebastián (Spain) [email protected], [email protected]
Table of Contents 1. General……………………………………………………………………………………..
S2
2. Synthesis of catalysts 7……………………………………………………………………
S2
3. Acid cocatalyst screening for the conjugate addition of diethyl malonate to β-nitrostyrene catalyzed by organocatalyst 7b………………………………………………….
S7
4. General procedure for the conjugate addition of 1,3-dicarbonyl copounds to nitroalkenes and recovery of catalyst 7b……………………………………………………...
S8
5. HPLC conditions and retention times for compounds 8…………………………………..
S20
6. Computational data………………………………………………………………………….
S21
7. Crystallographic data………………………………………………………………………..
S66
8. NMR spectra for compounds 7, 8 and 9…………………………………………………....
S67
9. HPLC spectra for compounds 8…………………………………………………………...
S94
10. References………………………………………………………………………………...
S103
S1
1. General Melting points were determined with a hot plate apparatus and are uncorrected. 1H NMR (300 MHz, 400 MHz),
13
C NMR (75 MHz, 100 MHz), and 2DNMR (COSY, NOESY, HSQC) spectra were
obtained at 25 ºC using CDCl3 as solvent, otherwise stated; chemical shifts are reported as δ (ppm) values relative to TMS as internal standard and coupling constants (J) in Hz. Hydrogen multiplicity (C, CH, CH2, CH3) information was obtained from Carbon DEPT spectra. IR data were collected on a FTIR or ATR apparatus, and peaks are reported in cm–1. Specific rotations were determined at 20 ºC with a digital polarimeter. HPLC analyses were performed on equipped with a chiral column and automatic inyector, using mixtures of n-hexane/isopropyl alcohol (IPA) as mobile phase, at 25 ºC. Low-resolution electron impact (EI) mass spectra were obtained at 70 eV and mass spectra fragment ions m/z with relative intensities (%) is reported in parenthesis. Analytical TLC was visualized with UV light at 254 nm. Thin layer chromatography was carried out on TLC aluminum sheets with silica gel 60 F254 . Flash chromatography (silica gel 60: 0.040-0.063 mm) was performed employing a Pump system. Reactions under argon atmosphere were performed in oven-dried glassware sealed with a rubber septum using anhydrous solvents. Data collection for X ray analysis was performed on a diffractometer based on three ω-scan runs (starting = -34º) at values φ =0º, 120º, 240º with the detector at 2θ =-32º. For each of these runs, 606 frames were collected at 0.3º intervals and 30 s per frame for compound 5b and 40 s per frame for compound 6m. An additional run at φ =0º of 100 frames was collected to improve redundancy. 2. Synthesis of catalysts 7 N
NH2 + NH2
TEA
Cl N H
R
N
195-200 ºC NH2
N H
N H
R
7a, R = H 7e, R = CF3
A mixture of 2-chloro-1H-benzo[d]imidazole (233 mg, 1.53 mmol, 1 eq.) or 2-chloro-6(trifluoromethyl)-1H-benzo[d]imidazole1 (338 mg, 1.53 mmol, 1 eq.), (1R,2R)-cyclohexane-1,2-diamine (698 mg, 6.12 mmol, 4 eq.), and TEA (213 µL, 1.53 mmol, 1 eq.) was heated under argon atmosphere at S2
195-200 ºC during 16 h. The reaction mixture was then allowed to reach 50 ºC, water (20 mL) was added and the reaction mixture was extracted with CH2Cl2 (3×20 mL) before the temperature rise rt (to avoid solubility problems). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give the corresponding crude products which were purified by flash chromatography (EtOAc/MeOH) to give pure 7a (229 mg, 65%) or 7e (296 mg, 56%). N NH2
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)cyclohexane-1,2-diamine (7a). Yield 65%; pale yellow solid; mp 235-240 ºC (Et2O); [α]D20 – 55.0 (c 1.0, MeOH); IR (KBr) 2929, 2855, 1700, 1644, 1606, 1580, 1468, 1270, 1116, 1030; δH (CD3OD) 1.19-1.49 (m, 4H, 2×CH2), 1.741.77 (m, 2H, CH2), 1.98-2.11 (m, 2H, CH2), 2.50-2.58 (m, 1H, CHNH2), 3.34-3.40 (m, 1H, CHNH), 6.93-6.97 (m, 2H, ArH), 7.15-7.18 (m, 2H, ArH); δC 26.0, 26.2, 33.8, 34.9 (4×CH2), 55.6 (CHNH), 60.4 (CHNH2), 112.7, 121.3 (4×ArCH), 139.1 (2×ArC), 156.9 (C=N); m/z 230 [M+, 10%], 172 (14), 160 (24), 146 (14), 134 (100), 133 (59), 132 (12), 118 (12), 97 (28); HRMS calcd. for C13H18N4 [M]+ 230.1531; found 230.1532. N NH2
N H
N H
CF3
(1R,2R)-N1-{6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl}cyclohexane-1,2-diamine (7e). Yield 56%; pale yellow solid; mp 108-110 ºC (Et2O); [α]D20 – 19.6 (c 1.35, MeOH); IR (KBr) 2925, 2844, 16642, 1579, 1447, 1325, 1165, 1119, 1050; δH (CD3OD, 400 MHz) 1.24-1.48 (m, 4H, 2×CH2), 1.75-1.77 (m, 2H, CH2), 1.99-2.13 (m, 2H, CH2), 2.61-2.65 (m, 1H, CHNH2), 3.39-3.46 (m, 1H, CHNH), 7.22-7.24 (m, 1H, ArH), 7.24-7.28 (m, 1H, ArH), 7.42 (s, 1H, ArH); δC (100 MHz) 25.9, 26.1, 33.6), 34.7 (4×CH2), 55.8 (CHNH), 60.0 (CHNH2), 109.6, 112.5 (2×ArCH), 118.3 (q, J = 4.5 Hz, CHCCF3), 123.3 (q, J = 32 Hz, CCF3), 126.7 (q, J = 268 Hz, CF3), 139.2, 142.0 (2×ArC), 158.5 (C=N); S3
m/z 298 [M+, 7%], 234 (17), 228 (24), 226 (13), 214 (16), 202 (42), 201 (61), 200 (12), 97 (100), 96 (16), 69 (14); HRMS calcd. for C14H17F3N4 [M]+ 298.1405; found 298.1389. In both cases small amounts (5-15%) of diarylated diamine derivative were observed by 1HNMR on the crude reaction mixture In the case of catalyst 7a, compound 7f could be isolated by flash chromatography (EtOAc/MeOH) and characterized as follows. N N H
N H
N H
N HN
(1R,2R)-N1,N2-Di[1H-benzo[d]imidazol-2-yl]cyclohexane-1,2-diamine (7f). White solid; mp 193-196 ºC (Et2O); [α]D20 + 241 (c 0.35, MeOH); IR (KBr) 2944, 2916, 2847, 1630, 1603, 1580, 1461, 1410, 1259, 1112, 1047; δH (CD3OD) 1.35-1.47 (m, 4H, CH2), 1.76 (br s, 2H, CH2), 2.18-2.23 (m, 2H, CH2), 3.71-3.74 (m, 2H, CHNH), 6.90-6.95 (m, 4H, ArH), 7.11-7.15 (m, 4H, ArH); δC 25.6 (CH2), 33.9 (CH2), 57.6 (CHNH), 112.6, 121.2 (8×ArCH), 138.9 (4×ArC), 156.7 (2×C=N); m/z 346 [M+, 33%], 214 (64), 213 (100), 212 (36), 184 (16), 173 (19), 172 (15), 170 (10), 160 (14), 159 (21), 158 (11), 146 (11), 145 (16), 134 (32), 133 (37), 132 (16); HRMS calcd. for C20H22N6 [M]+ 346.1906; found 346.1904.
N NH2
N H
N H 7a 7e
N
HCO2H, HCHO R
120 ºC
N
N H
N H
R
7b, R = H 7d, R = CF3
A mixture of 7a (168 mg, 0.73 mmol, 1 eq.) or 7e (218 mg, 0.73 mmol, 1 eq.), 80% HCO2H (3.5 mL) and 36% aqueous solution of HCHO (127 µL, 1.61 mmol, 2.2 eq.) was stirred at 120 ºC for 16 h. Then, the solvent was removed under reduced pressure. Saturated NaHCO3 solution (15 mL) and 10% NaOH solution (until pH 8) were added and the product was extracted with CH2Cl2 (3×15 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give the corresponding crude S4
products which were purified by flash chromatography (EtOAc/MeOH) and then recrystallized in CH2Cl2 to give pure 7b (87 mg, 46%) or 7d (178 mg, 75%). N N
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (7b). Yield 46%; white solid; mp 248-250 ºC (CH2Cl2); [α]D20 – 55.3 (c 1.0, CH2Cl2); IR (KBr) 2923, 2856, 2818, 2775, 1700, 1633, 1576, 1499, 1461, 1375, 1265, 1064; δH (CDCl3) 1.09-1.42 (m, 4H, 2×CH2), 1.65-1.70 (m, 1H, 1×CH2), 1.82-1.87 (m, 2H, CH2), 2.22 (s, 6H, CH3), 2.33 (td, J = 10.9, 3.2 Hz, 1H, CHNMe2), 2.65-2.69 (m, 1H, 1×CH2), 3.44 (td J = 10.4, 4.0 Hz, 1H, CHNH), 5.46 (br s, 1H, NH), 6.916.96 (m, 2H, ArH), 7.14-7.20 (m, 2H, ArH); δC (CD3OD) 23.7, 25.8, 26.4, 34.8 (4×CH2), 40.5 (2×CH3), 54.7 (CHNH), 67.7 (CHNMe2), 112.6, 121.2 (4×ArCH), 139.1 (2×ArC), 156.6 (C=N); m/z 258 [M+, 1.5%], 134 (11), 133 (30), 126 (10), 125 (100), 124 (19), 84 (20), 58 (12); HRMS calcd. for C15H22N4 [M]+ 258.1844; found 258.1844. N N
N H
N H
CF3
(1R,2R)-N1,N1-Dimethyl-N2-{6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl}cyclohexane-1,2diamine (7d). Yield 75%; white solid; mp 223-225 ºC (CH2Cl2); [α]D20 – 21 (c 0.55, CH2Cl2); IR (KBr) 2935, 2860, 1638, 1580, 1451, 1325, 1156, 1112, 1049; δH 1.12-1.41 (m, 4H, 2×CH2), 1.68-1.72 (m, 1H, 1×CH2), 1.84-1.90 (m, 2H, CH2), 2.26 (s, 6H, 2×CH3), 2.36 (td, J = 10.4, 3.4 Hz, 1H, CHNMe2), 2.58-2.62 (m, 1H, 1×CH2), 3.44 (td, J = 10.4, 3.6 Hz,1H, CHNH), 5.56 (br s, 1H, NH), 7.26 (s, 1H, ArH), 7.29 (s, 1H, ArH), 7.49 (s, 1H, ArH); δC 21.2, 24.3, 25.0, 33.2 (4×CH2), 39.8 (2×CH3), 53.9 (CHNH), 67.3 (CHNMe2), 109.2, 111.9 (2×ArCH), 117.5 (q, J = 3.1 Hz, CHCCF3), 122.3 (q, J = 32 Hz, CCF3), 125.2 (q, J = 270 Hz, CF3), 137.6, 141.0 (2×ArC), 157.4 (C=N); m/z 326 [M+, 1%], 201 (19), 126 (11), 125 S5
(100), 124 (23), 84 (38), 71 (16), 58 (21); HRMS calcd. for C16H21F3N4 [M]+ 326.1718; found 326.1714.
N NH2
N H
N H 7a
N
CH3CHO, NaHB(OAc)3 ClCH2CH2Cl, tª amb.
N
N H
N H
7c
To a mixture of 7a (460 mg, 2 mmol, 1 eq.) and CH3CHO (455 µL, 8 mmol, 4 eq.) in 1,2dichloroethane (20 mL) and under argon atmosphere was added NaHB(OAc)3 (2.4 g, 11.2 mmol, 5.6 eq.). The resulting mixture was stirred at rt during 16 h and then quenched with a NaHCO3 saturated aqueous solution. The product was then extracted with EtOAc (3×20 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give crude product which was purified by flash chromatography (EtOAc/MeOH) and then recrystallized in CH2Cl2 to give pure 7c (166 mg, 29%). N NEt2
N H
N H
(1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2,N2-diethylcyclohexane-1,2-diamine (7c). Yield 29%; white solid; mp 245-246 ºC (CH2Cl2); [α]D20 – 102 (c 0.91, CH2Cl2); IR (KBr) 2971, 2931, 2851, 2811, 1629, 1576, 1475, 1275, 1208, 1111; δH (CD3OD) 0.96-1.01 (t, J = 7.02 Hz, 6H, 2×CH3), 1.14-1.51 (m, 4H, 2×CH2), 1.51-1.69 (m, 1H, 1×CH2), 1.73-1.92 (m, 2H, CH2), 2.33-2.44 (m, 2H, CH2CH3), 2.50-2.72 (m, 4H, 2×CH2CH3, 1×CHN, 1×CH2), 3.44 (td, J = 10.6, 3.9 Hz, 1H, CHNH), 6.92-6.97 (m, 2H, ArH), 7.15-7.19 (m, 2H, ArH); δC 15.0 (2×CH3), 24.8, 25.6, 26.8, 34.7, 44.4 (6×CH2), 54.8 (CHNH), 64.6 (CHNEt2), 112.7, 121.2 (4×ArCH), 139.1 (2×ArC), 157.1 (C=N); m/z 286 [M+, 1%], 214 (11), 186 (17), 154 (13), 153 (100), 138 (10), 134 (14), 133 (46), 124 (14), 112 (25), 86 (26); HRMS calcd. for C17H26N4 [M]+ 286,2157, [M+-C4H10N] 214.1339; found 214.1330.
S6
3. Acid cocatalyst screening for the conjugate addition of diethyl malonate to β-nitrostyrene catalyzed by 7b. To a stirred solution of catalyst 7b (6.7 mg, 0.026 mmol, 10 mol%), acid (0.026 mmol, 10 mol%) and β-nitrostyrene (38.7 mg, 0.26 mmol) in toluene (520 µL), diethyl malonate (80 µL, 0.52 mmol) was added. The reaction mixture was stirred at rt for 36 hours, then the solvent was remove under reduce pressure to give crude product 8a. The conversion and the ee of the pruduct 8a was determined by 1
HNMR and chiral HPLC, respectively, on the crude reaction mixture. 7b (10 mol%) cocatalyst (10 mol%) EtO2C
CO2Et
+
Ph
NO2
EtO2C
toluene, rt, 36 h
CO2Et NO2
Ph 8a
Table S1. Acid cocatalyst screening for the conjugate addition of diethyl malonate to βnitrostyrene catalyzed by 7b ent.
cocatalyst
pKa
conv.%a
eeb
1
-
-
99
76
2
H2O
14
94
74
3
O 2N
7.10
99
74
4
CH3CO2H
4.76
99
72
4.40
99
76
4.20
99
78
3.44
37
87
CO2H
2
99
74
CO2H
2
99
74
5
Me
6 7 8
9
OH
N N N N H
CO2H
O 2N
CO2H
N H
N H
S7
O
10
O P OH
O
O
11 O
12
O P OH
F3CCO2H
13
SO3H
1.5-2
66
72
1.5-2
66
72
0.52
74
92
- 2.8
99
80
Determined by 1HNMR on the crude reaction mixture. b Determined by HPLC on the crude reaction mixture using a Chiralpak AD column, 90/10 Hx/i-Pr, 1 mL/min, 210 nm, tR (major enantiomer) = 14.4 min and tR (minor enantiomer) = 33.5 min. a
4. General procedure for the conjugate addition of diethyl malonate to β -nitrostyrene and recovery of catalyst 7b. To a stirred solution of catalyst 7b (30 mg, 0.116 mmol, 10 mol%) and β-nitrostyrene (173 mg, 1.16 mmol) in toluene (2.3 mL) were added trifluororacetic acid (8.7 µL, 0.116 mmol, 10 mol%) and then diethyl malonate (357 µL, 2.32 mmol). Once the reaction was completed (TLC), the mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give crude compounds 8a which was purified by flash chromatography (EtOAc/hexane) to give pure compounds 8a (348 mg, 97%). The aqueous layer was treated with a 10% NaOH aqueous solution (10 mL) until pH = 8 and then was extracted with CH2Cl2 (3×10 mL). The organic phases were dried over MgSO4 and evaporated under reduced pressure to give pure (by 1HNMR) catalyst 7b {28.2 mg, 94%, [α]D20 – 55.3 (c 1.0, CH2Cl2)}. The recovered catalyst was used in a second catalytic cycle obtaining similar results for the obtention of 8a: 2d, 88% conversion, 90% ee.
S8
O
O
MeO
OMe NO2
Dimethyl (R)-2-(2-nitro-1-phenylethyl)malonate (8b).2 Yield 95%; white solid; mp 59-61 ºC; Rf 0.18 (hexane/EtOAc: 4/1); [α]D20 – 2.5 (c 1.04, CH2Cl2) for 89% ee; IR (neat) 2955, 1731, 1559, 1544, 1427, 1297, 1232, 1155, 1092, 1023, 702; δH 3.57, 3.77 (2s, 6H, 2×CH3), 3.87 [d, J = 9.2 Hz, 1H, CH(CO2Me)2], 4.25 (td, J = 8.7, 5.6 Hz, 1H, CHCH2), 4.88 (dd, J = 13.2, 8.5 Hz, 1H, CHHNO2), 4.93 (dd, J = 13.2, 5.6 Hz, 1H, CHHNO2), 7.21-7.36 (m, 5H, ArH); δC 42.9 (CHCH2), 52.8, 53.0 (2×CH3), 54.7 [CH(CO2Me)2], 77.3 (CH2), 127.8, 128.4, 129.0 (5×ArCH), 136.1 (ArC), 167.2, 167.8 (2×C=O); m/z 281 [M+,
