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Enantioselective desymmetrization of prochiral 1,3-dinitropropanes via organocatalytic allylic alkylation
Soumya Jyoti Singha Roy and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA
General: Unless stated otherwise, all reactions were carried out with distilled and dried solvents under an atmosphere of N2 or argon, oven (120 °C) dried glassware with standard vacuum line techniques were used. Organic solvents used for carrying out reactions were dried using standard methods. All work up and purification were carried out with reagent grade solvents in air. Thin-layer chromatography was performed using Merck silica gel 60 F254 pre-coated plates (0.25 mm). Column chromatography was performed using silica gel (230-400 or 100- 200 mesh). Infrared (FT-IR) spectra were recorded on a Perkin Elmer Spectrum BX spectrophotometer in cm-1 and the bands are characterized as broad (br), strong (s), medium (m), and weak (w). NMR spectra were recorded on Bruker Ultrashield spectrometer at 400MHz (1H) and 100 MHz (13C). Chemical shifts are reported in ppm from tetramethylsilane (δ 0.00) with the solvent resonance as internal standard (CDCl3: δ 7.26, CD3OD: δ 3.31 for 1H-NMR and CDCl3: δ 77.0, CD3OD: δ 49.00 for 13C NMR). For 1H-NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz) and integration. High-resolution mass spectrometry was performed on Micromass Q-TOF Micro instrument. Optical rotations were measured on JASCO P-1020 polarimeter. Melting points were measured using ANALAB µ-Thermocal 10 melting point apparatus. All melting points were measured in open glass capillary and values are uncorrected. Enantiomeric ratios were determined by HPLC analysis using chiral columns in comparison with authentic racemic materials. Aldehydes were not purified before use. Nitromethane and basic alumina was used as obtained by commercial suppliers. Ethyl acrylate was freshly distilled before use.
Procedure A: For the preparation of 1a, 1c-f, 1h-n modified literature1 procedure was followed.
In an oven-dried round bottom flask fitted with a magnetic stir-bar, aldehyde (1.0 equiv.) was dissolved in nitromethane (25.0 equiv.). To this solution basic alumina (0.6 g/mmol of the aldehyde) was added; the resulting slurry was heated (at the temperature specified for the corresponding compounds) for required amount of time in an argon atmosphere. After completion of the reaction, the reaction mixture was allowed to attain room temperature; the alumina was then filtered off and the filtrate was concentrated to obtain, in all the cases, a thick oil. This was purified by silica gel (230-400 mesh) column chromatography. In most of the cases, the oil obtained after column purification, were crystallized/solidified using appropriate solvent system to obtain solid/crystalline dinitropropanes that were used for the catalytic reactions.
1-(1,3-Dinitropropan-2-yl)-4-methylbenzene (1a): Reaction was performed at 105 °C for 12 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 7-10% EtOAc/pet ether) afforded a red oil. This was subjected to solidification using EtOAc-toluene-pet ether (1:3:5) mixture at –20 °C for overnight to get 1a as a brownish solid (1.975 g, 8.802 mmol; 48% yield). Rf
= 0.30 (25% EtOAc in pet ether); Melting point = 49-50 °C; FT-IR (KBr): ν 2921 (m), 1564 (s), 1557 (s), 1378 (s), 818 (m) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.17 (d, J = 8 Hz; 2H), 7.10 (d, J = 8 Hz; 2H), 4.69-4.79 (m; 4H), 4.23-4.30 (m; 1H), 2.33 (s; 3H); 13C-NMR (100 MHz, CDCl3): δ 139.1, 131.0, 130.2, 127.2, 76.8, 41.4, 21.1; HRMS (ESI+): Calculated for C10H12N2O4Na ([M+Na]+): 247.0695, found: 247.0695. 1-Chloro-4-(1,3-dinitropropan-2-yl)benzene (1c): Reaction was performed at 110 °C for 12 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 5-15% EtOAc/ pet ether) afforded a red oil. This was subjected to crystallization (DCM-pentane 1:3) to get pure 1c as an off-white crystalline solid (2.450 g, 10.0 mmol; 47% yield). Rf = 0.10 (10% EtOAc in pet ether);
4H), 4.27-4.34 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 135.2, 132.5, 129.8, 128.7, 76.4, 41.1; HRMS (ESI+): Calculated for C9H9N2O4ClNa ([M + Na]+): 267.0149, found: 267.0151. 1-Bromo-2-(1,3-dinitropropan-2-yl)benzene (1d): Reaction was performed at 110 °C for 6 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-12% EtOAc in pet ether) afforded a red oil. This was subjected to solidification using DCM-pet ether mixture (1:3) to get pure 1d as an off-white solid (650 mg, 2.248 mmol; 28% yield). Rf = 0.30 (20% EtOAc in pet ether);
Melting point = 45 °C; FT-IR (neat): ν 2926 (m), 1560 (s), 1551 (s), 1385(s), 1374 (s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.64 (dd, J = 1.3, 8.0 Hz; 1H), 7.33 (dt, J = 1.3, 7.6 Hz; 1H), 7.20-7.25 (m; 1H), 7.17-7.19 (m; 1H), 4.87-4.89 (m; 4H), 4.78-4.84 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 134.1, 133.2, 130.4, 128.4, 127.8, 124.3, 75.2, 40.5; HRMS (ESI+): Calculated for C9H9N2O4BrNa ([M + Na]+): 310.9643, found: 310.9646. 1-(1,3-Dinitropropan-2-yl)-2-fluorobenzene (1e): Reaction was performed at 110 °C for 8 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-12% EtOAc/pet ether) afforded 1e as a orange-yellow oil (1.186 g, 5.2 mmol; 42% yield). Rf = 0.40 (20% EtOAc in pet ether); FT-IR (neat): ν 2922 (m), 1557 (s), 1494 (m), 1433 (m), 1378 (s) cm−1; 1H-NMR (400 MHz, CDCl3):
h. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-12% EtOAc/pet ether) afforded a orange-yellow oil. This was subjected to solidification using a chloroform-pet ether mixture (1:3) to obtain 1f as an off-white solid (470 mg, 1.68 mmol; 20% yield). Rf = 0.30 (20%
EtOAc in pet ether); Melting point = 95 °C; FT-IR (KBr): ν 2925 (m), 1571 (s), 1382 (s), 1102 (m) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.49 (d, J = 2.1 Hz; 1H), 7.29 (dd, J = 2.1, 8.4 Hz; 1H), 7.15 (d, J = 8.4 Hz; 1H), 4.87-4.90 (m; 4H), 4.69-4.78 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 135.8, 134.5, 130.7, 130.1, 129.1, 128.2, 74.9, 38.1. 1-(1,3-Dinitropropan-2-yl)naphthalene (1h): Reaction was performed at 110 °C for 6 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-12% EtOAc/pet ether) afforded a red oil. This was subjected to solidification with EtOAc-toluene-pentane (3:3:4) mixture to obtain pure 1h as
h. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-25% EtOAc/pet ether) afforded a orange colored solid. It was re-crystallized from a DCM-pet ether mixture to obtain pure 1i as a white flaky solid (603 mg, 2.370 mmol; 35% yield). Rf = 0.20 (20% EtOAc in pet ether);
used was purified by distillation prior to its use. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 2-7% EtOAc/pet ether) afforded 1j as a grey oil (2.082 g, 10.404 mmol; 51% yield). Rf = 0.35 (10% EtOAc in pet ether); FT-IR (neat): ν 2922 (w), 1560 (s), 1506 (s), 1431 (s), 1376 (s), 1348 (s)
cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.38-7.40 (m; 1H), 6.34-6.35 (m; 1H), 6.28-6.29 (m; 1H), 4.76-4.85 (m; 4H), 4.41-4.48 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 147.1, 143.4, 110.8, 108.8, 74.5, 35.8; HRMS (ESI+): Calculated for C7H8N2O5Na ([M + Na]+): 223.0331, found: 223.0324. 2-(1,3-Dinitropropan-2-yl)thiophene (1k): Reaction was performed at 110 °C for 7 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 5-8% EtOAc/pet ether) afforded 1k as a grey semi-solid. (351 mg, 1.620 mmol; 31% yield). Rf = 0.20 (10% EtOAc in pet ether); FT-IR (neat): ν 2921 (w), 1557 (s), 1428 (m), 1377 (s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.30-7.32 (m;
3-(1,3-Dinitropropan-2-yl)-1H-indole (1l): Reaction was performed at 100 °C for 12 h. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-25% EtOAc/pet ether) afforded pure 1l as a light brown solid (375 mg, 1.505 mmol; 36% yield). Rf = 0.20 (30% EtOAc in pet ether); Melting point = 104 °C; FT-IR (KBr): ν 3431 (br), 2916 (w), 1560 (s), 1547 (s), 1379
(m), 763 (s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 8.22 (bs; 1H), 7.58 (d, J = 7.9 Hz; 1H), 7.40 (d, J = 8.1 Hz; 1H), 7.25-7.29 (m; 1H), 7.18-7.22 (m; 1H), 7.11-7.12 (m; 1H), 4.85-4.94 (m; 4H), 4.61-4.68 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 136.2, 125.2, 123.2, 122.3, 120.6, 117.8, 111.8, 108.7, 76.3, 34.2; HRMS (ESI+): Calculated for C11H11N3O4Na ([M + Na]+): 272.0647, found: 272.0650. (1,3-Dinitropropan-2-yl)cyclohexane (1m): Reaction was performed at 110 °C for 6 h.
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 2-5% EtOAc/pet ether) afforded pure 1m as a orange-yellow semi-solid (1.064 g, 4.920 mmol; 37% yield). Rf = 0.25 (5% EtOAc in pet ether); FT-IR (neat): ν 2929 (s), 2856 (s), 1557 (s), 1434 (m), 1379 (s) cm−1; 1H-NMR (400
MHz, CDCl3): δ 4.52-4.61 (m; 4H), 2.83-2.91 (m; 1H), 1.68-1.82 (m; 5H), 1.48-1.57 (m; 1H), 0.99-1.31 (m; 5H); 13C-NMR (100 MHz, CDCl3): δ 74.5, 41.0, 37.6, 29.4, 25.9, 25.7; HRMS (ESI+): Calculated for C9H16N2O4Na ([M + Na]+): 239.1008, found: 239.1002. 1-Nitro-2-(nitromethyl)heptane (1n): Reaction was performed at 95 °C for 10 h. Purification
by silica gel (230-400 mesh) column chromatography (gradient elution: 2-5% EtOAc/pet ether) afforded pure 1n as a yellow oil (1.031 g, 5.053 mmol; 31% yield). Rf = 0.60 (20% EtOAc in pet ether); FT-IR (neat): ν 2958 (s), 2933 (s), 2863 (m), 1558 (s), 1432 (m), 1381 (s) cm−1; 1H-NMR (400 MHz,
Procedure B: For preparation of 1b and 1o following procedure was adapted:
Nitroolefin2 (1.0 equiv.) was dissolved in nitromethane (15.0 equiv.) and to it basic alumina (0.5 g/mmol of the nitroolefin substrate) was added. The resulting slurry was heated for required amount of time. After complete consumption of the starting material the reaction mixture was cooled to the room temperature. Basic alumina was filtered off and the filtrate was concentrated to obtain, in both the cases, a red oil. This was purified by silica gel (230-400 mesh) column chromatography to obtain the dinitro compounds. (1,3-Dinitropropan-2-yl)benzene (1b): Reaction was performed at 110 °C for 12 h. Purification
by silica gel (230-400 mesh) column chromatography (gradient elution: 10-15% EtOAc/pet ether) afforded pure 1b as a grey semisolid (413 mg, 1.964 mmol; 61% yield). Rf = 0.10 (10% EtOAc in pet ether); FT-IR (neat): ν 1557 (s), 1549 (s), 1374(s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.31-7.36 (m; 3H), 7.18-7.21 (m;
2H), 4.67-4.76 (m; 4H), 4.24-4.31 (m; 1H); 13C-NMR (100 MHz, CDCl3): δ 134.2, 129.3, 128.8, 127.3, 76.5, 41.5; HRMS (ESI+): Calculated for C9H10N2O4Na ([M + Na]+): 233.0538, found: 233.0537. (E)-(4-Nitro-3-(nitromethyl)but-1-enyl)benzene (1o): Reaction was performed at 65 °C for 3
h. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: 10-15% EtOAc/pet ether) afforded a thick grey oil which was subjected to crystallization using DCM-pet ether-pentane (1:2:2) mixture to obtained pure 1o as a light brown needle shaped crystalline solid (181 mg,
Synthesis of (2-(1,3-dinitropropan-2-yl)phenyl)methanol 1g:
(S2): In an oven-dried round bottom flask fitted with a magnetic stir bar aldehyde S13 (2.4 g, 9.58 mmol, 1.0 equiv.) was dissolved in 6 mL nitromethane. To this solution basic alumina (4.0 g) and activated 4Å MS (2.0 g) was added. The resulting slurry was heated at reflux at 110 °C for 12 h. in an argon atmosphere. After completion of the reaction, the resulting red slurry was allowed to attain room
temperature. The alumina was then filtered off and the filtrate was concentrated to obtain a thick oil. This was purified by silica gel (230-400 mesh) column chromatography (gradient elution: 2-5% EtOAC/pet ether) as eluent to obtain S2 as a yellow solid (2.256 g, 6.365 mmol; 67% yield). Rf = 0.90 (25% EtOAc in pet ether); 1H-NMR (400 MHz, CDCl3): δ 7.25-7.35 (m; 3H), 7.16-7.18 (m; 1H), 4.77-4.87 (m; 7H), 0.91 (s; 9H), 0.13 (s; 6H); 13C-NMR (100 MHz, CDCl3): δ 139.2, 133.5, 129.9, 128.7, 128.6, 125.9, 76.5, 64.6, 36.6, 25.8, 18.3, –5.4. (1g): S4 (500 mg, 1.41 mmol, 1.0 equiv.) was taken in a round bottom flask and to it a mixture
of glacial AcOH (2.0 mL) and H2O (1.0 mL) was added at r.t. overnight. The resulting clear yellow color solution was diluted with DCM (35 mL) and washed with sat. aq. NaHCO3 solution (10 mL) and brine (10 mL). The organic layer was dried over anh. Na2SO4 and concentrated to obtain a thick semisolid.
This was then purified by silica gel (230-400 mesh) column chromatography (25% EtOAC/pet ether) afforded pure 1g as a off-white solid (315 mg, 1.310 mmol; 93% yield). Rf = 0.15 (25% EtOAc in pet ether); Melting point = 83-84 °C; FT-IR (KBr): ν 3368 (bs), 2920 (w), 1563 (s), 1428 (w), 1380 (m), 1203 (w), 1004 (m), 981 (w), 772 (m) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.29-7.37 (m; 3H), 7.18-7.20 (m; 1H), 4.77-4.89 (m; 7H), 2.09 (bs; 1H); 13C-NMR (100 MHz, CDCl3): δ 138.8, 133.8, 130.5, 129.2, 128.9, 126.0, 76.7, 64.0, 36.8; HRMS (ESI+): Calculated for C10H12N2O5Na ([M + Na]+): 263.0644, found: 263.0641. (3) C. Aïssa and A. Fürstner, J. Am. Chem. Soc., 2007, 129, 14836.
Representative procedure for the preparation of allylic alcohols:
(S3): Aldehyde (1.0 equiv.) and ethyl acrylate (3-4 equiv.) was taken in a round bottom flask fitted with a magnetic stir bar. To this neat mixture, was added required amount of DABCO (1.0 equiv.) and the resulting slurry was stirred under ambient condition. After stirring vigorously for the specified time, the reaction mixture was diluted with DCM. This solution was then washed with 4 N aqueous HCl followed by saturated aqueous NaHCO3 solution and brine. The organic layer, after drying over anh. Na2SO4, was concentrated in rotary evaporator to get a thick oil that was purified by silica gel (230-400) column chromatography. Ethyl 2-(hydroxy(phenyl)methyl)acrylate (S3a): Reaction time = 3 d. Purification by silica gel
Preparation of ethyl 2-(hydroxymethyl)acrylate S3g:
In a round bottom flask, phosphonate ester4 (2.0 g, 8.92 mmol, 1.0 equiv.) was taken along with formalin solution (2.67 mL, 97.4 mmol, 11.0 equiv.). To this mixture saturated K2CO3 solution (4.0 mL) was added dropwise while stirring. After the addition was complete the reaction mixture was stirred at the ambient condition for 4 h. It was then extracted with diethyl ether (50 mL). The organic layer was dried over anh. Na2SO4, concentrated in a rotary evaporator to obtained an oil. The resulting oil was purified by silica gel column chromatography (gradient elution: 10-15% EtOAc/pet ether) to afford pure S3g as a colorless oil (520 mg, 3.995 mmol; 43% yield). Rf = 0.25 (20% EtOAc in pet ether); FT-IR (neat): ν 3432 (brs), 2984 (m), 1712 (s), 1638 (m), 1307 (s), 1217 (s), 1177 (s), 1157 (s), 1057 (s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 6.26 (s; 1H), 5.84 (d, J = 1.4 Hz; 1H), 4.33 (s; 2H), 4.24 (q, J = 7.1 Hz; 2H), 1.32 (t, J = 7.1 Hz; 3H); 13C-NMR (100 MHz, CDCl3): δ 166.3, 139.5, 125.3, 62.1, 60.8, 14.0; HRMS (ESI+): Calculated for C6H10O3Na ([M + Na]+): 153.0528, found: 153.0523. Preparation of Boc carbonate of allylic alcohols:
Allylic alcohol S3 (1.0 equiv.) was dissolved in DCM (0.6 mL/mmol of S3) in a round bottom flask containing a magnetic stir bar. To this solution, was added Boc2O (1.1 equiv.) as a DCM (0.6 mL/mmol of S3) solution. The resulting solution was cooled to 0 °C. To this well stirred solution was added DMAP (10 mol%) in one portion. The reaction mixture was allowed to attain room temperature and further stirred for the specified time. The reaction mixture was diluted with CH2Cl2. The combined organic layer was washed with 4 N aq. HCl solution followed by saturated aq. NaHCO3 and brine. The organic layer, after drying over anhydrous Na2SO4, was concentrated in rotary evaporator to obtain an oil that was purified by silica gel (230-400) column chromatography.
(4) A. R. Choudhury and S. Mukherjee, Adv. Synth. Catal., 2013, 355, 1989.
Ethyl 2-((tert-butoxycarbonyloxy)(phenyl)methyl)acrylate (2a): Reaction time = 6 h. Purification by silica gel (230-400 mesh) column chromatography (1% EtOAc in pet) afforded pure 2a as a colorless liquid which solidifies on standing in freezer to produce a white semisolid (5.013 g, 16.360 mmol; 96% yield). Rf = 0.40 (10% EtOAc in pet ether); FT-IR (neat): ν 2985 (m), 1745 (s), 1713 (s), 1297 (s), 1277 (s), 1250 (s), 1153 (s), 1081 (m), 880 (m) cm−1; 1H-NMR (400 MHz, CDCl3): δ
The 9-amino(9-deoxy)epicinchonidine S5,2 9-amino(9-deoxy)dihydroepicinchonidine S6,5 and 9-amino(9-deoxy)epicinchonine6 S7 were prepared according to the literature procedures. Catalysts I,2 III,6 IV,7 V,5 VIII,8 IX9 were prepared by following literature procedures.2,5,6, The procedure of preparing catalysts II, VI and VII are mentioned below: Catalyst II:
A solution of 4-(trifluoromethyl)phenyl isothiocyanate (316.0 mg, 1.554 mmol, 1.2 equiv.) in THF (2.0 mL) was added slowly to the solution of S5 (380.0 mg, 1.295 mmol, 1.0 equiv.) in THF (2.0 mL) in a 25 mL round bottom flask at room temperature and stirred at room temperature for 18 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (230-400 mesh silica gel; gradient elution: 99:1 DCM-MeOH to 100:0.5:0.5 DCM-MeOH-Et3N to 100:1.0:0.5 DCM-MeOH-Et3N) to afford a white amorphous solid (419 mg, 0.843 mmol; 65% yield). Melting point = 122-123 °C; FT-IR (thin film): 2929 (m), 1611 (m), 1323 (s); 1H-NMR (400 MHz, CD3OD): δ 8.83 (d, J = 4.6 Hz, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H), 7.74-
(5) C. B. Tripathi, S. Mukherjee, Angew. Chem., Int. Ed., 2013, 52, 8450. (6) M. S. Manna, V. Kumar, S. Mukherjee, Chem. Commun., 2012, 48, 5193. (7) R. Miyaji, K. Asano and S. Matsubara, Org. Lett., 2013, 15, 3658. (8) W. Yang and D.-M. Du., Org. Lett., 2010, 12, 5450. (9) A. Berkessel, S. Mukherjee, T. N. Müller, F. Cleemann, K. Roland, M. Brandenburg, J.-M. Neudörfl and J. Lex, Org. Biomol. Chem., 2006, 4, 4319.
9-Amino(9-deoxy)epicinchonine S7 (257 mg, 0.875 mol, 1.0 equiv.) was taken in 10 mL oven dried round bottom flask fitted with an argon inlet. This was dissolved in 2 mL dry THF and a solution of the isothiocyanate in 1.5 mL THF was added dropwise. The resulting solution was stirred at the room temperature for 24 h. Solvent was then evaporated and the resulting residue was purified by silica gel (230-400 mesh) column chromatography (gradient elution: 99:1 DCM-MeOH to 100:0.5:0.5 DCM-MeOH-Et3N to 100:1.0:0.5 DCM-MeOH-Et3N) to obtain VII as a white amorphous solid (170 mg, 0.341 mmol; 39% yield). Melting point = 156-157 °C; FT-IR (neat): ν 3422 (brs), 2933 (m), 2867 (w), 1645 (s), 1523 (m), 1322 (s), 1119 (s) cm−1; 1H-NMR (400 MHz, CD3OD): δ 8.83 (d, J = 4.6 Hz; 1H), 8.65 (d, J = 8.4 Hz; 1H), 8.05 (d, J = 8.4 Hz; 1H), 7.79 (t, J = 7.4 Hz; 1H), 7.66-7.71 (m; 3H), 7.62 (d, J = 4.7 Hz; 1 H), 7.55 (s; 1H), 7.53 (s; 1H), 6.33-6.36 (m; 1H), 5.90-5.99 (m; 1H), 5.18-5.24 (m; 2H), 3.27-3.39 (m; 1H), 3.01-3.10 (m; 3H), 2.36-2.43 (m; 1H), 1.58-1.64 (m; 3H), 1.23-1.29 (m, 3H), 0.87-0.95 (m, 2H); 13C-NMR (100 MHz, CD3OD): δ 182.4, 150.9, 149.6, 148.9, 144.2, 141.2, 130.99, 129.9, 128.9, 128.0, 126.7 (q, J = 3.9 Hz), 125.9, 125.7 (q, J = 270.0 Hz), 123.5, 115.6, 61.9, 50.1, 49.3, 48.4, 40.1, 28.7, 26.9, 25.9; HRMS (ESI+): Calculated for for C27H28F3N4S ([M+H]+): 497.1987, Found: 497.1983; Optical rotation: [α]D
25 +166.9 (c = 2.0, CHCl3). General procedure for the preparation of racemic desymmetrized products (rac-3):
Racemic products were prepared using the achiral bifunctional catalyst S8.10
In a glass vial fitted with a magnetic stir bar, 10 mg activated 4Å MS was taken along with 1,3-dinitropropane 1 (0.02 mmol, 1.0 equiv.) and the catalyst S8 (0.70 mg, 0.002 mmol, 0.1 equiv.).These three components were mixed properly through stirring. A solution of allylic carbonate 2 (0.022 mmol, 1.1 equiv.) in 0.1 mL CH2Cl2 was added to it; the glass vial was
(10) S. M. Opalka, J. L. Steinbacher, B. A. Lambiris and D. T. McQuade, J. Org. Chem., 2011, 76, 6503.
purged with argon and was sealed. The resulting mixture was then stirred at 25 °C until complete conversion (followed by TLC). The reaction mixture was then filtered using CH2Cl2 (2 mL) and the filtrate was concentrated. The crude mixture was purified by preparative TLC (Merck silica gel 60 F254 pre-coated plates of 0.25 mm thickness) to obtain the racemic desymmetrized products (ent-3).
Optimization of catalyst and reaction conditions: Catalyst Screening:a-c
a All reactions are carried out using 1.0 equiv. of 1a and 1.1 equiv. of 2a. b Conversion and diastereomeric ratio (dr) determined by 1H-NMR analysis of the crude reaction mixture. c Enantiomeric ratio (er) was determined by HPLC analysis using a stationary phase chiral column. n.d. = not determined.
Representative procedure for the catalytic allylic alkylative desymmetrization of prochiral 1,3-dinitropropanes (1) with allylic carbonates (2):
(CH2Cl)2 (2.0 M)4Å MS, -10 °C
R1
NO2
NO2 CO2Et
R2
R1
NO2
NO2 CO2Et
R2
OBoc+II (10 mol%)
1(1.0 equiv.)
2(1.1 equiv.)
3
In a reaction tube fitted with a magnetic stir bar, 100 mg activated 4Å MS was taken along with 1,3-dinitropropane 1 (0.2 mmol, 1.0 equiv.) and the catalyst II (10 mg, 0.02 mmol, 0.1 equiv.) under a postive argon pressure. These three components were mixed properly through stirring and then it was cooled to –78 °C. A solution of allylic carbonate 2 (0.22 mmol, 1.1 equiv.) in 0.1 mL (CH2Cl)2 was added to it. The resulting mixture was then stirred at specified temperature until complete conversion (followed by TLC). The reaction mixture was then diluted with CH2Cl2 (7 mL) at the reaction temperature and molecular sieves were filtered off. The filtrate was washed with 2 N HCl (5 mL) and the organic layer was washed with sat. aq. NaHCO3 (3 mL) and brine (3 mL). The organic layer, after drying over anh. Na2SO4, concentrated to a semisolid which was purified by silica gel (230-400 mesh) column chromatography to obtain the desymmetrized allylic alkylated products 3. (4S,5R,E)-Ethyl 2-benzylidene-4,6-dinitro-5-p-tolylhexanoate (3aa): Purification by silica gel
(230-400 mesh) column chromatography (gradient elution: pet ether to 5% EtOAc in pet ether) afforded 3aa as a colorless thick oil (61 mg, 0.148 mmol; 74% yield). Rf = 0.40 (10% EtOAc in pet ether); FT-IR (neat): ν 2926 (w), 1702 (m), 1557 (s), 1431 (w), 1377 (m), 1263 (m),
(4R,5S,E)-Ethyl 2-benzylidene-4,6-dinitro-5-p-tolylhexanoate (ent-3aa): Reaction was performed on a 0.2 mmol scale under the identical condition as 3aa using the pseudoenantiomeric catalyst VII. Purification by silica gel (230-400 mesh) column chromatography afforded ent-3aa as a colorless thick oil (50 mg, 0.122 mmol; 61% yield). Optical rotation: [α]D
23 +132.1 (c 1.0, CHCl3) for an enantiomerically enriched sample with >99:1 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, n-Hexane/EtOH = 90:10, 1.0 mL min−1, τmajor = 11.03 min, τminor = 11.84 min). (4S,5R,E)-Ethyl 2-benzylidene-4,6-dinitro-5-phenylhexanoate (3ba): Purification by silica gel
(230-400 mesh) column chromatography (gradient elution: pet ether/4% EtOAc in pet ether) afforded pure 3ba as white crystalline solid (59.8 mg, 0.150 mmol; 75% yield). Rf = 0.4 (10% EtOAc in pet ether); Melting point = 125 °C; FT-IR (neat): ν 2926 (w), 1704 (s), 1557 (s), 1435 (w),
21 –52.7 (c 2.0, CHCl3) for an enantiomerically enriched sample with 98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, n-Hexane/EtOH = 90:10, 1.0 mL min−1, τminor = 9.86 min, τmajor = 13.93 min). (4S,5R,E)-Ethyl 2-benzylidene-5-(2-fluorophenyl)-4,6-dinitrohexanoate (3ea): Purification
by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/4% EtOAc in pet ether) afforded 3ea as a white solid (69 mg, 0.166 mmol; 83% yield). Rf = 0.4 (10% EtOAc in pet ether); Melting point = 97 °C; FT-IR (neat): ν 2925 (m), 1695 (m), 1560 (s), 1550 (s), 1435 (w),
(4S,5R,E)-Ethyl 2-benzylidene-5-(2,4-dichlorophenyl)-4,6-dinitrohexanoate (3fa): Purification by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/4% EtOAc in pet ether) afforded 3fa as a thick white oil (70.6 mg, 0.151 mmol; 76% yield). Rf = 0.25 (10% EtOAc in pet ether); FT-IR (neat): ν 2924 (m), 1704 (s), 1623 (w), 1558
20 –68.2 (c 2.0, CHCl3) for an enantiomerically enriched sample with 98:2 er. Enantiomeric purity was determined by HPLC analysis (Phenomenex Cellulose-1 column, 254 nm, n-Hexane /EtOH = 90:10, 1.0 mL min−1, τmajor = 10.12 min, τminor = 12.16 min). (4S,5R,E)-Ethyl 2-benzylidene-5-(2-(hydroxymethyl)phenyl)-4,6-dinitrohexanoate (3ga):
Reaction was performed at 5 °C. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/5% EtOAc in pet ether/10% EtOAc in pet ether) afforded pure 3ga as colorless thick oil (62 mg, 0.145 mmol; 73% yield). Rf = 0.25 (20% EtOAc in pet ether); FT-IR
(4S,5R,E)-Ethyl 2-benzylidene-5-(furan-2-yl)-4,6-dinitrohexanoate (3ja): Purification by silica gel (230-400mesh) column chromatography (gradient elution: pet ether/ 2% EtOAc in pet ether/ 4% EtOAc in pet ether) afforded pure 3ja as thick yellowish oil, which was crystallized from CHCl3/Hexane mixture (57.6 mg, 0.147 mmol; 74% yield). Rf = 0.20 (10% EtOAc in pet ether);
23 –54.9 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97:3 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, n-Hexane/EtOH = 90:10, 1.5 mL min−1, τminor = 16.10 min, τmajor = 17.23 min). (4S,5R,E)-Ethyl 2-benzylidene-4,6-dinitro-5-(thiophen-2-yl)hexanoate (3ka): Purification by
silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/ 5% EtOAc in pet ether) afforded pure 3ka as light brown solid (59 mg, 0.146 mmol; 73% yield). Rf = 0.20 (10% EtOAc in pet ether); Melting point = 96 °C (EtOAc-Heptane 1:3); FT-IR (neat): ν 2924 (m), 1703 (s),
(4S,5R,E)-Ethyl 2-benzylidene-5-(1H-indol-3-yl)-4,6-dinitrohexanoate (3la): Reaction was performed at 5 °C. Product was purified by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/ 10% EtOAc in pet ether) afforded pure 3al as a reddish thick oil (68.8 mg, 0.157 mmol; 79% yield). Rf = 0.25 (30% EtOAc in pet ether); FT-IR (neat): ν 3421 (br),
22 –99.7 (c 2.0, CHCl3) for an enantiomerically enriched sample with >99:1 er. Enantiomeric purity was determined by HPLC analysis (Phenomenex Cellulose-1column, 254 nm, n-Hexane/EtOH = 85:15, 1.0 mL min−1, τmajor = 17.09 min, τmajor = 24.78 min). (4S,5R,E)-Ethyl 2-benzylidene-5-cyclohexyl-4,6-dinitrohexanoate (3ma): Reaction was
performed at 5 °C. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/ 1% EtOAc in pet ether) afforded pure 3ma as yellowish viscous oil (54 mg, 0.133 mmol; 67% yield). Rf = 0.20 (2 % EtOAc in pet ether); FT-IR (neat): ν 2928 (s), 2855
(4S,5R,E)-Ethyl 2-benzylidene-4-nitro-5-(nitromethyl)decanoate (3na): Reaction was performed at 5 °C. Purification by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/ 1% EtOAc in pet ether) afforded pure 3na as colorless viscous oil (57 mg, 0.145 mmol; 73% yield). Rf = 0.30 (2% EtOAc in pet ether); FT-IR (neat): ν 2956 (s),
21 –92.5 (c 2.0, CHCl3) for an enantiomerically enriched sample with >98.5:1.5 er. Enantiomeric purity was determined by HPLC analysis (Daicel Chiralpak AD-H column, 254 nm, n-Hexane/EtOH = 90:10, 1.0 mL min−1, τminor = 6.85 min, τmajor = 8.42 min). (4S,5R,E)-Ethyl 5-(benzo[d][1,3]dioxol-5-yl)-4,6-dinitro-2-propylidenehexanoate (3if):
Purification by silica gel (230-400 mesh) column chromatography (gradient elution: pet ether/ 4% EtOAc in pet ether) afforded pure 3if as colorless viscous oil (50 mg, 0.126 mmol; 63% yield). Rf = 0.25 (10%
In a 10 mL round bottom flask, 3ca (100 mg, 0.230 mmol, 1.0 equiv.) was dissolved in 5 mL glacial AcOH. To this solution, Zn dust was added portion wise over 15 minutes while stirring. After addition was over the resulting slurry was heated at 100 °C for 24 h. The reaction mixture was then allowed to attain room temperature. The white heterogenous mass was then cooled to 0 °C and basified by dropwise addition of an aqueous ammonia solution (10%) until pH 10; during basification the white solid was dissolved resulting in a clear colorless solution. This solution was extracted with CH2Cl2. The organic layer was dried over anh. Na2SO4 and concentrated in vacue to obtain a thick yellow oil (Rf = 0.30; 10% MeOH in DCM). This oil was used directly for the next step without further purification. The oil was dissolved in 1:1 THF/water mixture (0.8 mL). To the resulting solution, Boc2O (75 mg, 0.345 mmol, 1.5 equiv.) was added as a solution in THF (0.4 mL) while vigorously stirring at room temperature. After stirring for 1.5 h the reaction mixture was diluted with CH2Cl2 (15 mL) and washed with brine (5 mL). The organic layer was separated and after drying over anh. Na2SO4, concentrated to obtain a grey semisolid. The product was purified by silica gel (230-400 mess) column chromatography (gradient elution: 40-100% EtOAc/pet ether) to obtain 4 as a white solid (79 mg, 0.185 mmol; 81% yield). Rf = 0.20 (50% EtOAc in pet ether); Melting point = 163-165 °C; FT-IR (KBr): ν 3396 (br), 3204 (m), 2926 (m), 1619 (s), 1654 (s), 1522 (m), 1276 (m), 1249 (m), 1092 (s) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.51 (bs; 1H), 7.37 (s; 1H), 7.28-7.35 (m; 7H), 7.12-7.14 (m; 2H), 4.54-4.58 (m; 1H), 4.02-4.06 (m; 1H), 3.77-3.84 (m; 1H), 3.16-3.19 (m; 1H), 3.03-3.10 (m; 1H), 2.66-2.71 (m; 1H), 2.54-2.58 (m; 1H), 1.44 (s; 9H); 13C-NMR (100 MHz, CDCl3): δ 171.7, 156.5, 137.9, 135.4, 133.2, 130.9, 129.7, 129.6, 129.5, 129.2, 128.6, 128.5, 80.0, 77.2, 52.3, 43.0, 31.8, 28.3; HRMS (ESI+): Calculated for C24H29N2O3ClNa ([M + Na]+): 451.1764, found: 451.1764; Optical rotation: [α]D
In a 25 mL round bottom flask equipped with an argon inlet, 3ca (210 mg, 0.485 mmol; 1.0 equiv.) was dissolved in 6 mL CH2Cl2 and cooled to –78 °C. To this solution, 1M DIBAL-H solution in cyclohexane (2.4 mL, 2.4 mmol; 5 equiv.) was added dropwise at –78 °C and the resulting mixture was allowed to warm to –45 °C over 30 min while stirring. The reaction mixture was again cooled down to –78 °C and to it 2N HCl in MeOH was added dropwise and resulting yellow solution was allowed to attain room temperature. Removal of solvents afforded a thick reddish yellow oil. Purification by silica gel (230-400 mess) column chromatography (gradient elution: toluene to 4% EtOAc in toluene) yield 5 as colorless oil (127 mg, 0.324 mmol; 64% yield). Rf = 0.20 (4% EtOAc in toluene); FT-IR (neat): ν 3418 (bs), 2924 (w), 1744 (m), 1644 (m), 1557 (s), 1494 (m), 1433 (w), 1377 (m), 1228 (m), 1095 (w), 1015 (w), 832 (m) cm−1; 1H-NMR (400 MHz, CDCl3): δ 7.25-7.33 (m; 5H), 7.02-7.04 (m; 2H), 6.96-6.98 (m; 2H), 6.70 (s; 1H), 4.94-5.00 (m; 1H), 4.59-4.65 (m; 1H), 4.41 (dd, J = 4.0, 13.2 Hz; 1H), 4.21 (d, J = 13.2 Hz; 1H), 4.12 (d, J = 13.2 Hz; 1H), 3.85-3.91 (m; 1H), 2.88 (dd, J = 10.7, 14.9 Hz; 1H), 2.56 (dd, J = 2.9, 14.9 Hz; 1H), 1.85 (bs; 1H); 13C-NMR (100 MHz, CDCl3): δ 135.9, 135.0, 134.5, 132.3, 131.5, 129.7, 129.2, 128.6, 128.1, 127.5, 87.5, 76.2, 67.0, 46.2, 31.3; HRMS (ESI+): Calculated for C19H19N2O5ClNa ([M + Na]+): 413.0880, found: 413.0881; Optical rotation: [α]D
23 –22.9 (c 1.0, CHCl3). Conversion of 5 to 6:
In a 10 mL round bottom flask 5 (50 mg, 0.127 mmol; 1.0 equiv.) was taken in 3:1 THF/H2O mixture (4 mL). Aluminium foil (100 mg) was cut into small pieces and was soaked in 2% HgCl2 solution (aqueous) for 10-15 seconds, washed by dipping in THF and added to the vigorously stirred reaction mixture. The resulting heterogeneous mixture was stirred for 2 h and filtered through filter paper washing with THF. The filtrate was dried over anh. Na2SO4 and evaporated under reduced pressure to obtain a white foam. This was purified by silica gel (230-400 mess) column chromatography (gradient elution: DCM to 10% EtOAc in DCM to 20% EtOAc in CH2Cl2) to obtain 6 as a white thick oil (25 mg, 0.076 mmol; 60% yield). Rf = 0.20 (20% EtOAc
A single crystal of 3ka was mounted and the diffraction data were collected at 100 K on a Bruker SMART APEX CCD diffractometer using SMART/SAINT software. Intensity data were collected using graphite-monochromatized Mo-Ka radiation (0.71073 Å) at 100 K. The structures were solved by direct methods using Olex2 and refined using Least Squares minimization. Empirical absorption corrections were applied with SADABS. All Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were included in geometric positions. Structure was drawn using ORTEP-3 and Olex2. The crystallographic refinement parameters are given below:
Table 1. Crystal data and structure refinement for 3ka:
Identification code 3ka Empirical formula C19H20N2O6S Formula weight 404.44 Temperature 100 K Crystal system Monoclinic Space group P21 Unit cell demensions a = 9.9605(13) Å α = 90.00°
b = 7.5342(10) Å β = 98.095(7)° c = 12.8020(16) Å γ = 90.00°
Volume 951.1(2) Å3 Z 2 Density (calculated) (ρcalc) 1.465 mg/mm3 Absorption coefficient 0.315 mm-1 F(000) 438.0 Crystal size 0.25 × 0.23 × 0.20 mm3 Theta range for data collection 3.22 to 55.24° Index ranges -11 ≤ h ≤ 12, -9 ≤ k ≤ 9, -16 ≤ l ≤ 16 Reflections collected 11810 Independent reflections 4045 [Rint = 0.0390] Data/restraints/parameters 3224/1/248 Goodness-of-fit on F2 0.781 Final R indexes [I>2σ (I)] R1 = 0.0466, ωR2 = 0.1299 Final R indexes [all data] R1 = 0.0428, ωR2 = 0.1257 Largest diff. peak and hole 0.88 and –0.50 e.Å–3 Flack parameter –0.02(11)
Table 2. Fractional atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for 3ka. U(eq) is defined as 1/3 of the trace of the orthogonalised Uij
A single crystal of 6 was mounted and the diffraction data were collected at 296 K on a Bruker SMART APEX CCD diffractometer using SMART/SAINT software. Intensity data were collected using graphite-monochromatized Mo-Ka radiation (0.71073 Å) at 296 K. The structures were solved by direct methods using Olex2, the structure was solved with the XS structure solution program using Direct Methods and refined with the XL refinement package using Least Squares minimisation. Empirical absorption corrections were applied with SADABS. All Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were included in geometric positions. Structure was drawn using ORTEP-3 and Olex2. The crystallographic refinement parameters are given below:
Table 8. Crystal data and structure refinement for 6:
Identification code 6 Empirical formula C19H19ClN2O Formula weight 326.81 Temperature/K 296 Crystal system monoclinic Space group C2 Unit cell dimensions a = 75.874(8) α = 90.00°
b = 5.7768(7) β = 92.437(12)° c = 7.7098(8) γ = 90.00°
Volume 3376.2(7) Å3 Z 4 Density (calculated) (ρcalc) 1.286 mg/mm3 Absorption coefficient 0.232 mm-1 F(000) 1376.0 Crystal size 0.24 × 0.21 × 0.2 mm3 Theta range for data collection 2.14 to 50° Index ranges -89 ≤ h ≤ 89, -6 ≤ k ≤ 6, -9 ≤ l ≤ 9 Reflections collected 19770 Independent reflections 5705 [Rint = 0.0675] Data / restraints / parameters 5705 / 1 / 417 Goodness-of-fit on F2 0.980 Final R indexes [I>2σ (I)] R1 = 0.0556, ωR2 = 0.1219 Final R indexes [all data] R1 = 0.1244, ωR2 = 0.1492 Largest diff. peak and hole 0.23 and -0.22 e.Å-3 Flack parameter 0.00(10)
Table 9. Fractional atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for 6. U(eq) is defined as 1/3 of of the trace of the orthogonalised Uij