CHIRALITY (2014)

Synthesis of Novel Camphor-Derived Bifunctional Thiourea Organocatalysts SEBASTIJAN RIČKO,1 AMALIJA GOLOBIČ,1 JURIJ SVETE,1,2 BRANKO STANOVNIK,1,2 AND UROŠ GROŠELJ1* 1 University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia 2 EN-FIST Centre of Excellence, Ljubljana, Slovenia

ABSTRACT Synthesis and catalyst performance of 2,3- (types B and C) and 2,8-disubstituted (type D) thiourea bifunctional organocatalysts was attempted. The synthesis of catalyst of type B has, so far, not been realized, while catalysts of type C, i.e., the 2,3-exo- and the 2-endo-3-exo-thiourea catalysts, were prepared in six steps starting from (+)-camphor. The catalysts of type D were prepared from (+)-camphor in eight steps. All the potential catalysts as well as most of the intermediate products were carefully structurally characterized. The thiourea bifunctional organocatalysts were tested in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc. KEY WORDS: oxime reduction; camphor derived amines; organocatalysis; bifunctional amine– thioureas INTRODUCTION

Chiral bifunctional amine–(thio)ureas comprise the bulk of noncovalent organocatalysts, which can achieve electrophile and nucleophile binding and activation through hydrogenbonding interactions and in the case of primary and secondary amine functionalities also via covalent interactions. For selected reviews see references,1–4 for selected stereoselective transformations/organocatalysts see references.5–16 Frequently, the electron-poor 3,5-bis(trifluoromethyl)phenylgroup is the preferred substituent attached through thiourea functionality to a suitable chiral scaffold.8–14,17–22 Recently, a class of chiral bifunctional thiourea organocatalysts based on terpenes has been reviewed.23 Among them, no camphorderived bifunctional thiourea organocatalysts can be found. Despite the fact that camphor is one of nature’s privileged scaffolds readily available in both enantiomeric forms and that camphor undergoes a wide variety of chemical transformations which functionalize, at first glance, inactivated positions,24,25 demonstrated in the preparation of a wide variety of compounds ranging from natural products24,25 to chiral auxiliaries,26,27 ligands in asymmetric synthesis,28–32 nuclear magnetic resonance (NMR) shift reagents,33 etc., only a few ketopic acid-derived thiourea-prolinamide bifunctional organocatalysts have been prepared.34,35 Previously, we reported the preparation and performance of camphor 1,3-diamine-derived bifunctional organocatalysts of type A.36 In continuation of our research of 3,5-bis(trifluoromethyl) phenyl thiourea-derived bifunctional organocatalysts with camphor as the exclusive chiral framework, we herein report our attempts to prepare camphor-derived thiourea bifunctional organocatalysts of type B-D (Fig. 1), and their performance in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene. EXPERIMENTAL Materials and Methods All reactions were performed under argon in dried glassware using anhydrous solvents except when using aqueous reagents. Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical-grade Na2SO4. Melting points were determined on a Kofler micro hot stage and on an © 2014 Wiley Periodicals, Inc..

SRS OptiMelt MPA100 - Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA). The NMR spectra were obtained on a 1 Bruker UltraShield 500 plus (Bruker, Billerica, MA) at 500 MHz for H 13 and 126 MHz for C nucleus, using DMSO-d6 and CDCl3 with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA), IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA). Microanalyses were performed on a Perkin-Elmer CHN Analyzer 2400 II (PerkinElmer). Catalytic hydroTM genation was performed on H-Cube Continuous-flow Hydrogenation Reactor (H-Cube, ThalesNano Nanotechnology, Budapest, Hungary). Synthesis of compounds 23 and 30 was performed in a High-Pressure Autoclave HR-100, 150 mL (Berghof Products + Instruments, Eningen, Germany). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm; Sigma-Aldrich, St. Louis, MO). Medium-pressure liquid chromatography (MPLC) was performed with Büchi Flash Chromatography System (Buchi Labortechnik, Flawil, Switzerland) (Büchi Fraction Collector C-660, Büchi Pump Module C-605, Büchi Control Unit C-620) on silica gel (LiChrosphere Si 60 (12 μm) and/or LiChroprep Si 60 (15-25 μm) (Merck, Darmstadt, Germany)); column dimensions (wet filled): 22 × 460 mm, 36 × 460 mm, and 40 × 460 mm; backpressure: 10–20 Bar; detection: UV 254 nm. Low temperatures were maintained using Julabo FT902 immersion cooler (Julabo, Seelbach, Germany). High-performance liquid chromatography (HPLC) analyses were performed on an Agilent 1260 Infinity LC (Agilent Technologies) using CHIRALPAK AD-H (Chiral Technologies, West Chester, PA) (0.46 cm ø × 25 cm) as chiral column. (+)-Camphor (1), potassium tert-butoxide, tert-butyl nitrite, LiAlH4 (2 M in THF), Celite, benzyl chloroformate, N,N-diisopropylethylamine, phthalic anhydride, methanesulfonyl chloride, pyrrolidine, 3,5-bis(trifluoromethyl)phenyl isothiocyanate (17), dimethyl malonate (32), and trans-β-nitrostyrene (33) are commercially available (Sigma-Aldrich ). (1R,4S,3E)-3-(Hydroxyimino)1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2),37(1R,2S,3R,4S)-3-amino1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (3),38 (1R,2S,3R,4S)-1,7,7-trimethyl-3(pyrrolidin-1-yl)bicyclo[2.2.1]heptan-2-ol (7),39 (1R,4R,2E)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one oxime (12), 40 N-((1R,4R)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-ylidene)nitramide (13),40 N-((1R,4S)-3-bromo-

*Correspondence to: Uroš Grošelj, University of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerčeva cesta 5, P.O. Box 537, 1000 Ljubljana, Slovenia. E-mail: [email protected] Received for publication 10 July 2014; Accepted 13 August 2014 DOI: 10.1002/chir.22386 Published online in Wiley Online Library (wileyonlinelibrary.com).

RIČKO ET AL.

2-((1S,2R,3S,4R)-3-Hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan2-yl)isoindoline-1,3-dione (5). To a solution of amino alcohol

Fig. 1. 3,5-Bis(trifluoromethyl)phenyl thiourea-derived bifunctional organocatalysts of type A-D.

1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)nitramide (14),41 41 amino oximes 9a-d , (1R,4S)-3,3-dibromo-1,7,7-trimethylbicyclo [2.2.1]heptan-2-one (20),42 (1R,4S,7S)-3,3-dibromo-7-(bromomethyl)1,7-dimethylbicyclo[2.2.1]heptan-2-one (21),42 and (1R,4R,7S)-7(bromomethyl)-1,7-dimethylbicyclo[2.2.1]heptan-2-one (22)42 were prepared following the literature procedures. The source of chirality: (+)-Camphor (1), product number 21300, 20 purum, natural, ≥97.0% (GC, sum of enantiomers), [α]D = +42.5 ± 2.5 (c = 10, EtOH), mp 176–180 °C, enantiomeric excess (e.e.) not specified.

Syntheses Benzyl ((1S,2R,3S,4R)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1] heptan-2-yl)carbamate (4). To a solution of amino alcohol 3

(202 mg, 1.19 mmol) and N,N-diisopropylethylamine (270 mL, 1.55 mmol) in anhydrous CH2Cl2 (5 mL) under argon at –5 °C CbzCl (215 μL, 1.43 mmol) was added and the resulting reaction mixture was stirred for 30 min at –5 °C and for 3 h at room temperature. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (EtOAc/petroleum ether = 1:5). Fractions containing the product 4 were combined and volatile components evaporated in vacuo. Yield: 199 mg (55%) of white solid; mp 74.6–84.3 °C. [α]r.t. D = +28.8 (c = 0.32, CHCl3). (C18H25NO3 requires: C, 71.26; H, 8.31; N, 4.62. found C, 71.33; H, 8.59; N, 4.61); EI-HRMS: m/z = 304.1909 (MH+); C18H26NO3 requires: m/z = 304.1907 (MH+); νmax 3397, 3035, 2952, 2917, 2887, 1682, 1489, 1456, 1367, 1341, 1308, 1269, 1241, 1210, 1077, 1037, 1023, 693 cm-1. 1HNMR (500 MHz, CDCl3): δ 0.80 (3H, s, Me); 0.92 (3H, s, Me); 0.99–1.08 (1H, m, 1H of CH2); 1.06 (3H, s, Me); 1.10–1.19 (1H, m, 1H of CH2); 1.49 (1H, dt, J = 3.9; 12.5 Hz, 1H of CH2); 1.66–1.74 (1H, m, 1H of CH2); 1.80 (1H, d, J = 4.5 Hz, H-C(4)); 2.20 (1H, d, OH); 3.68 (1H, t, J = 6.9 Hz, H-C(3)); 3.74–3.79 (1H, m, H-C(2)); 5.06–5.13 (2H, m, CH2); 5.45 (1H, d, J = 5.0 Hz, NH); 7.29–7.38 (5H, m, Ph). 13C-NMR (126 MHz, CDCl3): δ 11.4, 21.1, 21.7, 26.3, 33.3, 46.9, 49.3, 50.6, 59.0, 66.8, 79.8, 128.2, 128.3, 128.7, 136.7, 156.5. Chirality DOI 10.1002/chir

338 (1.145 g, 6.76 mmol) in anhydrous toluene (80 mL) phthalic anhydride (1.002 g, 6.76 mmol) was added and the resulting reaction mixture was heated under reflux under Dean-Stark conditions for 5 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (CH2Cl2/MeOH = 30:1). Fractions containing the product 5 were combined and volatile components evaporated in vacuo. Yield: 1.40 g (69%) of white solid; mp 228-242 °C. [α]r.t. D = +27.5 (c = 0.31, CHCl3). EI-HRMS: m/z = 300.1592 (MH+); C18H22NO3 requires: m/z = 300.1594 (MH+); νmax 2953, 2879, 1707, 1652, 1482, 1447, 1365, 1336, 1312, 1269, 1248, 1221, 1107, 1082, 997, 966, 908, 798, 771, 729, 720, 706, 686, 649 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.83 (3H, s, Me); 0.89 (3H, s, Me); 0.99 (3H, s, Me); 1.05–1.15 (2H, m, J = 2.9; 8.1 Hz, 2H of CH2); 1.39–1.56 (1H, m, 1H of CH2); 1.62–1.77 (1H, m, 1H of CH2); 2.01 (1H, d, J = 4.4 Hz, CH); 4.13 (1H, d, J = 8.5 Hz, CH); 4.39 (1H, d, J = 8.5 Hz, CH); 7.55–7.61 (2H, m, 2H of Arl); 7.63 (1H, m, 1H of Arl); 7.66–7.71 (1H, m, 1H of Arl), 13.30 (1H, s, OH). 13C-NMR (126 MHz, DMSO-d6): δ 11.3, 18.8, 23.2, 25.5, 31.3, 46.7, 48.1, 48.3, 75.9, 91.1, 126.7, 128.5, 128.9, 130.5, 130.9, 134.1, 163.6, 168.8. N-((1S,2R,3S,4R)-3-Hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan2-yl)-2-(pyrrolidine-1-carbonyl)benzamide (6). To a solution of

alcohol 5 (481 mg, 1.61 mmol) in anhydrous CH2Cl2 (10 mL) under argon cooled to –10 °C MsCl (161 μL, 2.08 mmol) was added and the resulting reaction mixture was stirred for 15 min at –10 °C and for 3 h at room temperature. Then pyrrolidine (1.335 mL, 16 mmol) was added at room temperature and the reaction mixture was stirred for a further 48 h at room temperature. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (EtOAc). Fractions containing the product 6 were combined and volatile components evaporated in vacuo. Yield: 475 mg (79%) of white solid; mp 72–82 °C. [α]r.t. D = +23.9 (c = 0.16, CHCl3). EI-HRMS: m/z = 371.2328 (MH+); C22H31N2O3 requires: m/z = 371.2329 (MH+); νmax 3385, 2950, 2873, 1614, 1594, 1508, 1475, 1448, 1427, 1340, 1281, 1097, 1053, 774 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.80 (3H, s, Me); 0.91 (3H, s, Me); 1.03–1.08 (1H, m, 1H of CH2); 1.10 (3H, s, Me); 1.15–1.12 (1H, m, 1H of CH2); 1.48 (1H, td, J = 4.0; 12.3 Hz, 1H of CH2); 1.68–1.76 (1H, m, 1H of CH2); 1.82–1.99 (5H, m, CH, 4H of CH2); 3.17–3.27 (2H, m, 2H of CH2); 3.53–3.68 (3H, m, 2H of CH2, OH); 3.77 (1H, d, J = 7.6 Hz, CH); 3.85–3.88 (1H, m, CH); 7.10 (1H, d, J = 6.0 Hz, NH), 7.28 (1H, dd, J = 1.3; 7.6 Hz, 1H of Arl); 7.36 (1H, td, J = 1.4; 7.6 Hz, 1H of Arl); 7.44 (1H, td, J = 1.3; 7.5 Hz, 1H of Arl); 7.62 (1H, dd, J = 1.3; 7.7 Hz, 1H of Arl). 13C-NMR (126 MHz, CDCl3): δ 11.4, 21.2, 21.6, 24.6, 25.9, 26.4, 33.3, 45.7, 46.9, 49.0, 49.1, 50.2, 58.6, 79.5, 126.5, 128.0, 129.0, 130.4, 133.9, 136.7, 167.7, 169.8. (1R,3R,4S)-1,7,7-Trimethyl-3-(pyrrolidin-1-yl)bicyclo[2.2.1]heptan2-one (8). To a solution of oxalyl chloride (511 μL,

6.04 mmol) in anhydrous CH2Cl2 (12 mL) under argon cooled to –78 °C a solution of DMSO (1.17 mL, 16.5 mmol) in anhydrous CH2Cl2 (5 mL) was slowly (10 min) added. The resulting mixture was stirred for 20 min at –78 °C followed by slow (10 min) addition of a solution of alcohol 7 (1.225 g, 5.48 mmol) in anhydrous CH2Cl2 (10 mL). The resulting mixture was stirred for further 20 min at –78 °C. Then, anhydrous Et3N (3.83 mL, 27.5 mmol) was added and the resulting reaction mixture was stirred for 2 h at –78 °C.

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

The reaction mixture was warmed to room temperature and after stirring for 30 min at room temperature the reaction mixture was quenched with the addition of H2O (20 mL). The resulting mixture was extracted with CHCl3 (3 x 70 mL), the combined organic phase dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (EtOAc). Fractions containing the product 8 were combined and volatile components evaporated in vacuo. Yield: 923 mg (76%) of yellowish oil. EI-HRMS: m/z = 222.1850 (MH+); C14H24NO requires: m/z = 222.1852 (MH+). 1H-NMR (500 MHz, CDCl3): δ 0.90 (3H, s, Me); 0.91 (3H, s, Me); 1.09 (3H, s, Me); 1.28–1.42 (2H, m, 2H of CH2); 1.58–1.65 (1H, m, 1H of CH2); 1.66–1.71 (4H, m, 4H of CH2); 1.91–1.99 (1H, m, 1H of CH2); 2.17 (1H, d, J = 4.5 Hz, H-C(4)); 2.28 (1H, s, H-C(3)); 2.52–2.60 (2H, m, 2H of CH2); 2.68–2.77 (2H, m, 2H of CH2). 13C-NMR (126 MHz, CDCl3): δ 9.6, 20.6, 20.9, 23.4, 26.9, 30.0, 46.8, 48.0, 53.9, 57.7, 75.9, 218.6. (1S,3R,4R,Z)-3-Hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-one oxime (10) and (1S,3R,4R,E)-3-hydroxy-4,7,7-trimethylbicyclo 43 [2.2.1]heptan-2-one oxime (11). To a solution of amino ke-

tone 8 (330 mg, 1.49 mmol) in a mixture of EtOH (7 mL) and H2O (2 mL) NH2OHxHCl (715 mg, 10.3 mmol) and NaOAc (972 mg, 11.8 mmol) were added and the resulting mixture was heated under reflux for 24 h. Volatile components were evaporated in vacuo, to the residue NaHCO3 (aq. sat., 30 mL) was added, and the resulting suspension was extracted with EtOAc (3 x 70 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified/separated by column chromatography (1. EtOAc/petroleum ether = 1:2 for the elution of product 10; 2. EtOAc/petroleum ether = 1:1 for the elution of product 11). Fractions containing the separated products were combined and volatile components evaporated in vacuo to give 10 and 11, respectively. Compound 10: Eluted first. Yield: 100 mg (36%) of white solid; mp 88.0–100.5 °C. [α]r.t. D = +0.61 (c = 0.33, CHCl3). (C10H17NO2 requires: C, 65.54; H, 9.35; N, 7.64. found C, 65.51; H, 9.64; N, 7.82); EI-HRMS: m/z = 184.1332 (MH+); C10H18NO2 requires: m/z = 184.1332 (MH+); νmax 3508, 3213, 2957, 2927, 2883, 1745, 1671, 1643, 1453, 1416, 1389, 1371, 1323, 1294, 1233, 1210, 1187, 1113, 1062, 1015, 980, 942, 926, 892, 863, 799, 747, 679, 646, 616 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.84 (3H, s, Me); 0.93 (3H, s, Me); 0.98 (3H, s, Me); 1.28–1.36 (1H, m, 1H of CH2); 1.44–1.52 (1H, m, 1H of CH2); 1.88–1.97 (1H, m, 1H of CH2); 2.02–2.13 (1H, m, 1H of CH2); 2.33 (1H, d, J = 4.5 Hz, H-C(4)); 3.61 (1H, br s, OH); 4.48 (1H, s, H-C(2)); 9.59 (1H, br s, N-OH). 13 C-NMR (126 MHz, CDCl3): δ 12.9, 18.5, 19.1, 25.6, 26.1, 45.9, 50.2, 51.26, 74.21, 168.36. Compound 1143: Eluted second. Yield: 40 mg (14%) of white solid; mp 120–133.6 °C (lit43: mp 174-176 °C). [α]r.t. D = +154 (c = 0.36, CHCl3) [lit43: [α]25 D = +181.5 (c = 0.96, EtOH)]. (C10H17NO2 requires: C, 65.54; H, 9.35; N, 7.64. found C, 65.45; H, 9.66; N, 7.93); EI-HRMS: m/z = 184.1330 (MH+); C10H18NO2 requires: m/z = 184.1332 (MH+); νmax 3240, 3144, 2953, 2914, 2877, 1696, 1454, 1390, 1373, 1331, 1297, 1247, 1173, 1116, 1070, 1012, 975, 933, 895, 855, 837, 801, 778, 702, 638 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.83 (3H, s, Me); 0.92 (3H, s, Me); 0.96 (3H, s, Me); 1.28–1.36 (1H, m, 1H of CH2); 1.40–1.50 (1H, m, 1H of CH2); 1.80–1.90 (1H, m, 1H of CH2); 1.97–2.06 (1H, m, 1H of CH2); 2.97 (1H, d, J = 4.6 Hz, H-C(4));

4.25 (1H, s, H-C(2)); 4.94 (1H, br s, OH); 9.70 (1H, br s, N-OH). 13C-NMR (126 MHz, CDCl3): δ 13.0, 18.4, 19.4, 24.4, 25.8, 45.1, 48.6, 50.1, 75.4, 169.0. Reduction of Amino Oximes With Raney-Ni–General Procedure 1 (GP1) A solution of amino oxime (1 equivalent) in EtOH (20 mL) was reduced TM flow hydrogenator using a Raney-Nickel cartridge on an H-Cube (T = 100 °C; P(H2) = 100 bar; flow rate: 0.2 mL/min). Volatile components were evaporated in vacuo to give the crude diamine used in the following transformation without further purification. (1R,2S,3R,4S)-1,7,7-Trimethyl-3-(pyrrolidin-1-yl)bicyclo[2.2.1] heptan-2-amine (15a). GP1: Prepared from 9a (60 mg,

0.254 mmol), EtOH (20 mL). Yield: 45 mg (79%) of yellowish oil. EI-HRMS: m/z = 223.2172 (MH+); C14H27N2 requires: m/z = 223.2169 (MH+); 1H-NMR (500 MHz, CDCl3): δ 0.75 (3H, s, Me); 0.91 (3H, s, Me); 1.02–1.08 (2H, m, 2H of CH2); 1.13 (3H, s, Me); 1.42–1.51 (1H, m, 1H of CH2); 1.64–1.74 (5H, m, 5H of CH2); 1.92 (1H, d, J = 4.7 Hz, HC(4)); 2.33 (1H, d, J = 7.9 Hz, H-C(3)); 2.35–2.50 (2H, m, 2H of CH2); 2.65–2.84 (2H, m, 2H of CH2); 2.79 (1H, d, J = 7.9 Hz, H-C(2)). 13C-NMR (126 MHz, CDCl3): δ 12.6, 20.4, 22.1, 23.4, 27.9, 35.7, 46.6, 49.1, 49.5, 54.9, 64.1, 73.8. (1R,2S,3R,4S)-1,7,7-Trimethyl-3-(piperidin-1-yl)bicyclo[2.2.1] heptan-2-amine (15b). GP1: Prepared from 9b (93 mg,

0.371 mmol), EtOH (20 mL). Yield: 74 mg (84%) of yellow oil. EI-HRMS: m/z = 237.2327 (MH+); C15H29N2 requires: m/z = 237.2325 (MH+). 1H-NMR (500 MHz, CDCl3) δ: 0.80 (3H, s, Me); 0.92 (3H, s, Me); 1.06 (3H, s, Me); 2.04 (1H, d, J = 4.9 Hz, H-C(4)); 2.28 (1H, d, J = 8 Hz, H-C(3)); 2.78 (1H, d, J = 7.8 Hz, H-C(2)). (1R,2S,3R,4S)-1,7,7-Trimethyl-3-morpholinobicyclo[2.2.1]heptan2-amine (15c). GP1: Prepared from 9c (239 mg, 0.947 mmol),

EtOH (20 mL). Yield: 190 mg (84%) of yellow oil. EI-HRMS: m/z = 239.2119 (MH+); C14H27N2O requires: m/z = 239.2118 (MH+). 3

3

(1R,2S,3R,4S)-N ,N ,1,7,7-Pentamethylbicyclo[2.2.1]heptane2,3-diamine (15d). GP1: Prepared from 9d (118 mg,

0.561 mmol), EtOH (20 mL). Yield: 76 mg (69%) of yellow oil. [α]r.t. D = +13.3 (c = 0.28, CH2Cl2). EI-HRMS: m/z = 197.2014 (MH+); C12H25N2 requires: m/z = 197.2012 (MH+); νmax 3399, 3325, 2948, 2879, 2815, 2767, 2717, 1662, 1594, 1469, 1457, 1387, 1367, 1310, 1295, 1257, 1216, 1201, 1179, 1148, 1121, 1096, 1081, 1041, 1019, 928, 901, 877, 826, 786, 729, 696, 641 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.76 (3H, s, Me); 0.93 (3H, s, Me); 1.02–1.10 (2H, m, 2H of CH2); 1.09 (3H, s, Me); 1.48 (1H, td, J = 3.6; 12.1 Hz, 1H of CH2); 1.70 (1H, tt, J = 4.6; 12.5 Hz, 1H of CH2); 1.98 (1H, d, J = 4.9 Hz, H-C(4)); 2.17 (1H, d, J = 7.8 Hz, H-C(3)); 2.25 (6H, s, NMe2); 2.83 (1H, d, J = 7.8 Hz, H-C(2)); 3.14 (br s, 2H, NH2). 13CNMR (126 MHz, CDCl3): δ 12.5, 20.4, 21.9, 28.0, 35.5, 46.2 (br s, NMe2), 47.8, 49.1, 63.0, 74.9. (1R,2R,4R,7S)-1,7-Dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo [2.2.1]heptan-2-amine (25). GP1: Prepared from 24 (61 mg,

0.258 mmol), EtOH (20 mL). Yield: 50 mg (87%) of yellow oil. EI-HRMS: m/z = 223.2166 (MH+); C14H27N2 requires: m/z = 223.2169 (MH+). 1H-NMR (500 MHz, CDCl3) δ: 0.82 (3H, s, Me); 0.87 (3H, s, Me); 1.90 (1H, t, J = 4.2 Hz, H-C(4)); 2.73 (1H, dd, J = 5.1; 8.4 Hz, H-C(2)); 2.25 (1H, d, J = 13.4 Hz, Ha-C(8)); 2.78 (1H, d, J = 13.5 Hz, Hb-C(8)). Chirality DOI 10.1002/chir

RIČKO ET AL.

Reduction of Amino Oximes With Sodium–General Procedure 2 (GP2) To a solution of amino oxime (1 equivalent) in anhydrous nPrOH under argon at 95 °C sodium (ca. 100–200 mg) was added. Before all the added sodium reacted, another piece of sodium (ca. 100–200 mg) was added, followed by addition of further sodium (ca. 100–200 mg) to ensure a continuous evolution of hydrogen for 1 h. After all the sodium reacted, volatile components were evaporated in vacuo and to the residue H2O (100 mL) was added followed by extraction with Et2O (3x70 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo to give the crude diamine used in the following transformation without further purification. (1R,2R,3R,4S)-1,7,7-Trimethyl-3-(pyrrolidin-1-yl)bicyclo[2.2.1] heptan-2-amine (16a). GP2: Prepared from 9a (390 mg,

1.65 mmol), nPrOH (25 mL). Yield: 333 mg (90%) of yellowish oil. [α]r.t. = +32.9 (c = 0.45, CHCl3). EI-HRMS: D m/z = 223.2171 (MH+); C14H27N2 requires: m/z = 223.2169 (MH+); νmax 2948, 2878, 2779, 1662, 1611, 1478, 1458, 1389, 1370, 1344, 1287, 1227, 1199, 1153, 1116, 1081, 1026, 948, 904, 876, 819, 769, 737, 657 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.80 (3H, s, Me); 0.83 (3H, s, Me); 1.03–1.09 (1H, m, 1H of CH2); 1.12 (3H, s, Me); 1.20 (1H, m, 1H of CH2); 1.26 (2H, br s, NH2); 1.54 (1H, d, J = 4.1 Hz, H-C(3)); 1.56–1.62 (1H, m, 1H of CH2); 1.68–1.72 (5H, m, 5H of CH2); 1.75 (1H, d, J = 4.7 Hz, H-C(4)); 2.42–2.49 (4H, m, 4H of CH2); 2.99 (1H, dd, J = 2.0; 4.1 Hz, H-C(2)). 13C-NMR (126 MHz, CDCl3): δ 13.4, 18.9, 21.7, 23.5, 26.2, 27.7, 47.7, 48.8, 49.8, 53.0, 63.2, 81.9. (1R,2R,3R,4S)-1,7,7-Trimethyl-3-(piperidin-1-yl)bicyclo[2.2.1] heptan-2-amine (16b). GP2: Prepared from 9b (528 mg,

2.11 mmol), nPrOH (25 mL). Yield: 483 mg (97%) of yellow oil. [α]r.t. D = +39.7 (c = 0.25, CH2Cl2). EI-HRMS: m/z = 237.2325 (MH+); C15H29N2 requires: m/z =237.2325 (MH+). νmax 2929, 2753, 1609, 1538, 1453, 1384, 1274, 1231, 1177, 1133, 1107, 1040, 999, 962, 884, 818, 764, 727, 701, 608, 654 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.80 (3H, s, Me); 0.82 (3H, s, Me); 0.99–1.04 (1H, m, 1H of CH2); 1.09 (3H, s, Me); 1.16–1.26 (3H, m, 1H of CH2, NH2); 1.35–1.43 (3H, m, H-C(3), 2H of CH2); 1.46–1.61 (5H, m, 5H of CH2); 1.68–1.75 (1H, m, 1H of CH2); 1.85 (1H, d, J = 4.8 Hz, H-(4)); 2.23–2.52 (4H, br s, 4H of CH2); 2.95 (1H, dd, J = 2.0; 4.3 Hz, H-C(2)). 13C-NMR (126 MHz, CDCl3): δ 13.4, 18.8, 21.8, 25.0, 26.4, 27.5, 46.6, 47.6, 50.0, 53.0, 62.5, 81.6. (1R,2R,3R,4S)-1,7,7-Trimethyl-3-morpholinobicyclo[2.2.1]heptan2-amine (16c). GP2: Prepared from 9c (400 mg, 1.59 mmol),

nPrOH (20 mL). Yield: 375 mg (98%) of yellow oil. [α]r.t. D = +29.6 (c = 0.34, CH2Cl2). EI-HRMS: m/z = 239.2122 (MH+); C14H27N2O requires: m/z = 239.2118 (MH+). νmax 2949, 2866, 2807, 2763, 1609, 1450, 1400, 1364, 1275, 1256, 1113, 1069, 869, 821, 733, 660, 640 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.80 (3H, s, Me); 0.83 (3H, s, Me); 1.00–1.05 (1H, m, 1H of CH2); 1.10 (3H, s, Me); 1.19–1.26 (3H, m, 1H of CH2, NH2); 1.51 (1H, d, J = 4.2 Hz, H-C(3)); 1.52–1.60 (1H, m, 1H of CH2); 1.71–1.77 (1H, m, 1H of CH2); 1.83 (1H, d, J = 4.8 Hz, H-C(4)); 2.37–2.56 (4H, m, 4H of CH2); 2.96 (1H, dd, J = 2.0; 4.4 Hz, H-C(2)); 3.64–3.72 (4H, m, 4H of CH2). 13C-NMR (126 MHz, CDCl3): δ 13.2, 18.7, 21.7, 26.1, 27.3, 45.8, 47.6, 50.0, 52.3, 62.1, 67.2, 80.8. 3

3

(1R,2R,3R,4S)-N ,N ,1,7,7-Pentamethylbicyclo[2.2.1]heptane2,3-diamine (16d). GP2: Prepared from 9d (250 mg,

1.19 mmol), nPrOH (15 mL). Yield: 211 mg (90%) of yellow oil. [α]r.t. = +32.2 (c = 0.26, CH2Cl2). EI-HRMS: D Chirality DOI 10.1002/chir

m/z = 197.2013 (MH+); C12H25N2 requires: m/z = 197.2012 (MH+). νmax 2949, 2881, 2814, 2764, 1665, 1586, 1463, 1388, 1367, 1291, 1252, 1226, 1208, 1158, 1124, 1083, 1042, 1022, 1002, 952, 923, 897, 861, 819, 771, 724, 655, 620 cm-1. 1 H-NMR (500 MHz, CDCl3): δ 0.81 (3H, s, Me); 0.83 (3H, s, Me); 1.02–1.07 (1H, m, 1H of CH2); 1.08 (3H, s, Me); 1.21 (1H, dddd, J = 2.0; 4.2; 11.7; 13.5 Hz, 1H of CH2); 1.33 (1H, d, J = 4.3 Hz, H-C(3)); 1.57–1.62 (1H, m, 1H of CH2); 1.37–1.55 (2H, br s, NH2); 1.70–1.77 (1H, m, 1H of CH2); 1.81 (1H, d, J = 4.8 Hz, H-C(4)); 2.20 (6H, s, NMe2); 2.97 (1H, dd, J = 2.0; 4.4 Hz, H-C(2)). 13C-NMR (126 MHz, CDCl3): δ 13.4, 18.9, 21.7, 26.2, 27.7, 44.6, 47.5, 47.7, 50.2, 62.7, 83.4. (1R,2S,4R,7S)-1,7-Dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo[2.2.1] heptan-2-amine (26). GP2: Prepared from 24 (111 mg,

0.470 mmol), nPrOH (15 mL). Yield: 95 mg (90%) of yellow oil. EI-HRMS: m/z = 222.2167 (MH+); C14H24N2 requires: m/z = 222.2169 (MH+). 1H-NMR (500 MHz, CDCl3) δ: 0.79 (3H, s, Me); 0.99 (3H, s, Me); 1.93 (1H, t, J = 4.5 Hz, H-C(4)); 2.33 (1H, d, J = 12.9, Hz, Ha-C(8)); 2.43 (1H, d, J = 13.0 Hz, Hb-C(8)); 3.08 (1H, ddd, J = 1.9; 4.5; 10.7 Hz, H-C(2)). Synthesis of Thiourea Derivatives–General Procedure 3 (GP3) To a solution of crude amine (1 equivalent) in anhydrous Et2O under argon at 0 °C 3,5-bis(trifluoromethyl)phenyl isothiocyanate (17) (1 equivalent) was added and the resulting reaction mixture was stirred for 30 min at 0 °C and for a further 24 h at room temperature. Volatile components were evaporated in vacuo. The residue was purified by column chromatography. Fractions containing the product were combined and volatile components evaporated in vacuo. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,3R,4S)-1,7,7-trimethyl3-(pyrrolidin-1-yl)bicyclo[2.2.1]heptan-2-yl)thiourea (18a). GP3: Pre-

pared from 15a (45 mg, 0.202 mmol), Et2O (5 mL), 17 (38 μL, 0.202 mmol), column chromatography [1. EtOAc/petroleum ether = 1:5 to elute the nonpolar impurities; 2. EtOAc/MeOH = 10:1 to elute the product 18a]. Yield: 54 mg (54%) of yellowish oil. [α]r.t. D = –25.6 (c = 0.09, CHCl3). EIHRMS: m/z = 494.2061 (MH+); C23H30F6N3S requires: m/z = 494.2059 (MH+); νmax 3194, 2962, 2929, 2869, 2825, 1724, 1667, 1620, 1525, 1500, 1467, 1375, 1274, 1170, 1134, 1118, 1107, 947, 901, 886, 846, 832, 702, 681, 666, 612 cm-1. 1 H-NMR (500 MHz, DMSO-d6): δ 0.77 (3H, s, Me); 0.87 (3H, s, Me); 1.08–1.15 (1H, m, 1H of CH2); 1.16 (3H, s, Me); 1.20–1.26 (1H, m, 1H of CH2); 1.47–1.55 (1H, m, 1H of CH2); 1.55–1.66 (4H, m, 4H of CH2); 1.67–1.76 (1H, m, 1H of CH2); 1.98 (1H, d, J = 4.6 Hz, H-C(4)); 2.20–2.45 (4H, m, 4H of CH2); 2.47 (1H, d, J = 8.2 Hz, H-C(3)); 4.63 (1H, t, J = 8.5 Hz, H-C(2)); 7.60 (1H, d, J = 8.9 Hz, NH); 7.76 (1H, s, 1H of Arl); 8.38 (2H, s, 2H of Arl); 10.73 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 11.6, 20.0, 21.3, 22.8, 26.9, 34.4, 46.6, 48.2, 50.1, 53.6, 63.4, 72.0, 116.1, 121.3, 123.2 (q, J = 273 Hz), 130.3 (q, J = 32 Hz), 141.8, 180.3. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,3R,4S)-1,7,7-trimethyl3-(piperidin-1-yl)bicyclo[2.2.1]heptan-2-yl)thiourea (18b). GP3:

Prepared from 15b (74 mg, 0.313 mmol), Et2O (5 mL), 17 (58 μL, 0.313 mmol), column chromatography [1. Et3N/ EtOAc/petroleum ether = 1:1:20 to elute the non-polar impurities; 2. EtOAc to elute the product 18b]. Yield: 55 mg (34%) of yellow solid; mp 157.9-159.2 °C. [α]r.t. = –66.3 (c = 0.12, D CH2Cl2). EI-HRMS: m/z = 508.2208 (MH+); C24H32F6N3S requires: m/z = 508.2216 (MH+). νmax 3119, 3010, 2987, 2954, 1530, 1493, 1466, 1376, 1302, 1274, 1242, 1171 1134,

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

1106, 1070, 1040, 1012, 950, 924, 892, 877, 846, 809, 705, 681, 649, 625 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.75 (3H, s, Me); 0.89 (3H, s, Me); 1.00–2.47 (8H, m, 8H of CH2); 1.06–1.10 (1H, m, 1H of CH2); 1.07 (3H, s, Me); 1.20–1.25 (1H, m, 1H of CH2); 1.27–1.38 (2H, m, 2H of CH2); 1.49 (1H, td, J = 4.2; 12.2 Hz, 1H of CH2); 1.68–1.75 (1H, m, 1H of CH2); 2.11 (1H, d, J = 4.7 Hz, H-C(4)); 2.39 (1H, d, J = 8.3 Hz, HC(3)); 4.60 (1H, d, J = 8.2 Hz, H-C(2)); 7.61 (1H, d, J = 8.4 Hz, NH); 7.79 (1H, s, 1H of Arl); 8.31 (2H, s, 2H of Arl); 10.70 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 11.6, 20.1, 21.3, 25.3, 27.1, 34.1, 44.6, 46.7, 50.0, 63.0, 71.4, 116.4, 121.7, 123.18 (q, J = 273 Hz), 130.5 (q, J = 33 Hz), 141.5, 180.5. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,3R,4S)-1,7,7-trimethyl3-morpholinobicyclo[2.2.1]heptan-2-yl)thiourea (18c). GP3:

Prepared from 15c (132 mg, 0.554 mmol), Et2O (5 mL), 17 (103 μL, 0.554 mmol), column chromatography [1. EtOAc/petroleum ether = 1:10 to elute the nonpolar impurities; 2. EtOAc/ petroleum ether = 1:5 to elute the product 18c]. Yield: 103 mg (36%) of yellow solid; mp 188.9-196.2 °C. [α]r.t. D = -73.5 (c = 0.39, CH2Cl2). EI-HRMS: m/z = 510.2011 (MH+); C23H30F6N3O requires: m/z = 510.2008 (MH+). νmax 3285, 2960, 2890, 2850, 2827, 1621, 1497, 1482, 1466, 1382, 1280, 1266, 1171, 1137, 1112, 1020, 911, 898, 874, 844, 706, 682, 653 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.76 (3H, s, Me); 0.87 (3H, s, Me); 1.06–1.14 (1H, m, 1H of CH2); 1.11 (3H, s, Me); 1.19–1.27 (1H, m, 1H of CH2); 1.50 (1H, td, J = 4.2; 12.3 Hz, 1H of CH2); 1.68–1.76 (1H, m, 1H of CH2); 2.10 (1H, d, J = 4.7 Hz, H-C(4)); 2.45 (1H, d, J = 8.1 Hz, HC(3)); 2.01–2.48 (4H, m, 4H of CH2); 3.38–3.82 (4H, m, 4H of CH2); 4.68 (1H, t, J = 8.5 Hz, H-C(2)); 7.60 (1H, d, J = 8.9 Hz, NH); 7.77 (1H, s, 1H of Arl); 8.36 (2H, s, 2H of Arl); 10.74 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 11.5, 20.1, 21.2, 26.8, 34.1, 44.3, 46.7, 50.0, 62.8, 65.8, 71.3, 116.2, 121.5, 123.2 (q, J = 273 Hz), 130.3 (q, J = 33 Hz), 141.6, 180.4. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,3R,4S)-3-(dimethyl amino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)thiourea (18d). GP3:

Prepared from 15d (53 mg, 0.270 mmol), Et2O (5 mL), 17 (50 μL, 0.270 mmol), column chromatography (1. CHCl3/ MeOH = 100:1 to elute the non-polar impurities; 2. CHCl3/ MeOH = 30:1 to elute the product 18d). Yield: 92 mg (72%) of yellow solid; mp 141.5–142.9 °C. [α]r.t. D = –26.2 (c = 0.22, CH2Cl2). EI-HRMS: m/z = 468.1898 (MH+); C21H28F6N3S requires: m/z = 468.1903 (MH+). νmax 3230, 3056, 2955, 2871, 2827, 2782, 1624, 1587, 1505, 1469, 1382, 1345, 1274, 1168, 1130, 1117, 1051, 977, 957, 929, 883, 700, 680 cm-1. 1 H-NMR (500 MHz, DMSO-d6): δ 0.75 (3H, s, Me); 0.85 (3H, s, Me); 1.12 (3H, s, Me); 1.08–1.13 (1H, m, 1H of CH2); 1.21–1.26 (1H, m, 1H of CH2); 1.50 (1H, td, J = 4.2; 12.1 Hz, 1H of CH2); 1.69–1.76 (1H, m, 1H of CH2); 2.04 (1H, d, J = 4.8 Hz, H-(4)); 2.06–2.15 (6H, m, NMe2); 2.30 (1H, d, J = 8.0 Hz, H-C(3)); 4.65 (1H, t, J = 8.5 Hz, H-C(2)); 7.66 (1H, d, J = 9.0 Hz, NH); 7.73 (1H, s, 1H of Arl); 8.44 (2H, s, 2H of Arl); 10.8 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 11.5, 19.9, 21.2, 27.0, 30.7, 34.2, 46.5, 46.6, 50.1, 62.9, 73.2, 115.8, 120.8, 123.4 (q, J = 273 Hz), 130.2 (q, J = 33 Hz), 142.0, 180.4. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-1,7,7-trimethyl3-(pyrrolidin-1-yl)bicyclo[2.2.1]heptan-2-yl)thiourea (19a). GP3:

Prepared from 16a (147 mg, 0.661 mmol), Et2O (15 mL), 17 (123 μL, 0.661 mmol), column chromatography [1.

EtOAc/petroleum ether = 1:5 to elute the non-polar impurities; 2. EtOAc/MeOH = 10:1 to elute the product 19a). Yield: 175 mg (53%) of yellowish oil. [α]r.t. D = +21.5 (c = 0.065, CHCl3). EI-HRMS: m/z = 494.2056 (MH+); C23H30F6N3S requires: m/z = 494.2059 (MH+); νmax 3278, 2957, 2884, 2790, 1535, 1472, 1382, 1346, 1304, 1274, 1221, 1172 1128, 961, 883, 847, 725, 701, 680 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.80 (3H, s, Me); 0.82 (3H, s, Me); 1.08–1.20 (1H, m, 1H of CH2); 1.19 (3H, s, Me); 1.22–1.32 (1H, m, 1H of CH2); 1.50–1.60 (1H, m, 1H of CH2); 1.60–1.70 (4H, m, 4H of CH2); 1.71–1.79 (1H, m, 1H of CH2); 1.81 (1H, d, J = 3.9 Hz, H-C(3)); 1.85 (1H, d, J = 3.7 Hz, H-C(4)); 2.26–2.38 (2H, m, 2H of CH2); 2.43–2.54 (2H, m, 2H of CH2); 4.87 (1H, br d, J = 4.8 Hz, H-C(2)); 7.72 (1H, s, 1H of Arl); 8.32 (3H, m, 3H, 2H of Arl, NH); 9.96 (s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 13.7, 18.8, 21.1, 23.0, 27.3, 27.6, 47.2, 48.0, 51.0, 52.5, 64.3, 77.2, 115.7, 121.2, 123.3 (q, J = 273 Hz), 130.2 (q, J = 33 Hz), 142.0, 180.5. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-1,7,7-trimethyl3-(piperidin-1-yl)bicyclo[2.2.1]heptan-2-yl)thiourea (19b). GP3:

Prepared from 16b (599 mg, 2.53 mmol), Et2O (20 mL), 17 (471 μL, 2.53 mmol), column chromatography (1. EtOAc/petroleum ether = 1:20 to elute the non-polar impurities; 2. EtOAc to elute the product 19b). Yield: 1.25 g (97%) of yellow solid; mp 61.3–62.7 °C. [α]r.t. D = +11.1 (c = 0.24, CH2Cl2). EI-HRMS: m/z = 508.2212 (MH+); C24H32F6N3S requires: m/z = 508.2216 (MH+). νmax 3274, 2933, 2801, 2760, 1622, 1533, 1471, 1457, 1380, 1347, 1274, 1173, 1129, 1107, 963, 885, 701, 681 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.81 (3H, s, Me); 0.82 (3H, s, Me); 1.07–1.12 (1H, m, 1H of CH2); 1.17 (3H, s, Me); 1.25–1.27 (1H, m, 1H of CH2), 1.32–1.38 (2H, m, 2H of CH2); 1.42–1.49 (4H, m, 4H of CH2); 1.53–1.42 (1H, m, 1H of CH2); 1.73–1.79 (1H, m, 1H of CH2); 1.76 (1H, d, J = 4.7 Hz, H-C(3)); 1.97 (1H, d, J = 4.7 Hz, H-C(4)); 2.14–2.42 (4H, m, 4H of CH2); 4.81–4.86 (1H, m, H-C(2)); 7.72 (1H, s, 1H of Arl); 8.31–8.33 (3H, m, NH, 2H of Arl); 9.89 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 13.9, 18.8, 21.0, 24.3, 25.8, 27.1, 27.7, 45.8, 47.1, 51.4, 52.3, 63.7, 77.7, 115.7, 121.1, 123.3 (q, J = 273 Hz), 130.2 (q, J = 33 Hz), 142.0, 180.1. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-1,7,7trimethyl-3-morpholinobicyclo[2.2.1]heptan-2-yl)thiourea (19c).

GP3: Prepared from 16c (325 mg, 1.36 mmol), Et2O (10 mL), 17 (253 μL, 1.36 mmol), column chromatography (1. EtOAc/petroleum ether = 1:5 to elute the nonpolar impurities; 2. EtOAc to elute the product 19c). Yield: 600 mg (86%) of yellow solid; mp 88.1-89.7 °C. [α]r.t. D = +27.9 (c = 0.39, CH2Cl2). EIHRMS: m/z = 510.2004 (MH+); C23H30F6N3O requires: m/z = 510.2008 (MH+). νmax 3295, 2956, 2811, 1702, 1622, 1532, 1471, 1381, 1304, 1273, 1216, 1171, 1125, 1067, 1001, 956, 924, 872, 825, 764, 726, 700, 680, 654, 626 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.81 (6H, s, 2 × Me); 1.07–1.13 (1H, m, 1H of CH2); 0.81 (3H, s, Me); 1.23–1.32 (1H, m, 1H of CH2); 1.53–1.58 (1H, m, 1H of CH2); 1.74–1.80 (1H, m, 1H of CH2); 1.82 (1H, d, J = 4.6 Hz, H-C(3)); 1.98 (1H, d, J = 4.7 Hz, H-C(4)); 2.21–2.47 (4H, m, 4H of CH2); 3.51–3.58 (4H, m, 4H of CH2); 4.84–4.87 (1H, m, H-C(2)); 7.73 (1H, s, 1H of Arl); 8.28 (2H, s, 2H of Arl); 8.36 (1H, d, J = 9.5 Hz, NH); 9.89 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 13.7, 18.8, 21.0, 27.0, 27.6, 45.1, 47.2, 51.4, 52.0, 63.3, 66.3, 77.3, 115.9, 121.3, 123.3 (q, J = 273 Hz), 130.0 (q, J = 33), 141.9, 180.1. Chirality DOI 10.1002/chir

RIČKO ET AL.

1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-3-(dimethyl amino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)thiourea (19d).

GP3: Prepared from 16d (98 mg, 0.499 mmol), Et2O (5 mL), 17 (93 μL, 0.499 mmol), column chromatography (1. CHCl3/MeOH = 100:1 to elute the non-polar impurities; 2. CHCl3/MeOH = 20:1 to elute the product 19d). Yield: 147 mg (63%) of yellow solid; mp 62.3-64.2 °C. [α]r.t. D = +32.3 (c = 0.22, CH2Cl2). EI-HRMS: m/z = 468.1902 (MH+); C21H28F6N3S requires: m/z = 468.1903 (MH+). νmax 3286, 2952, 2827, 2782, 1622, 1536, 1468, 1378, 1342, 1305, 1273, 1220, 1167, 1130, 1106, 1051, 1040, 1003, 964, 925, 905, 891, 864, 846, 811, 761, 720, 705, 682, 657, 645, 617 cm-1. 1HNMR (500 MHz, DMSO-d6): δ 0.80 (6H, s, 2 × Me); 1.14 (3H, s, Me); 1.07–1.16 (1H, m, 1H of CH2); 1.25–1.29 (1H, m, 1H of CH2); 1.51–1.58 (1H, m, 1H of CH2); 1.62 (1H, br s, HH(3)); 1.72–1.80 (1H, m, 1H of CH2); 1.86–1.93 (1H, m, HC(4)); 2.06–2.14 (6H, br s, NMe2); 4.83 (1H, br s, H-C(2)); 7.71 (1H, s, 1H of Arl); 8.29 (2H, s, 2H of Arl); 8.25–8.38 (1H, br s, NH); 9.90 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 13.7, 18.8, 21.0, 27.2, 27.5, 44.2, 46.7, 47.1, 51.5, 64.0, 115.8, 121.4, 123.3 (q, J = 273 Hz), 130.2 (q, J = 33 Hz), 142.0, 167.0, 180.4. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,4R,7S)-1,7-dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo[2.2.1]heptan-2-yl)thiourea (27). GP3: Prepared from 25 (61 mg, 0.274 mmol), Et2O

(5 mL), 17 (51 μL, 0.274 mmol), column chromatography (1. EtOAc/petroleum ether = 1:4 to elute the nonpolar impurities; 2. CHCl3/MeOH = 7:1 to elute the product 27). Yield: 57 mg (42%) of yellow oil. [α]r.t. D = –40.8 (c = 0.12, CH2Cl2). EI-HRMS: m/z = 494.2058 (MH+); C23H30F6N3S requires: m/z = 494.2059 (MH+). νmax 3154, 2959, 2882, 2809, 1620, 1526, 1468, 1375, 1273, 1170, 1126, 1000, 949, 881, 847, 757, 701, 681 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.93 (3H, s, Me); 0.94 (3H, s, Me); 1.14–1.27 (2H, m, 2H of CH2); 1.51–1.70 (6H, m, 6H of CH2); 1.72–1.90 (2H, m, 2H of CH2); 1.96 (1H, m, H-C(4)); 2.25–2.48 (4H, m, 2H of CH2); 2.48–2.67 (2H, m, 2H of CH2); 4.22–4.28 (1H, m, HC(2)); 7.72 (1H, s, 1H of Arl); 8.10 (1H, d, J = 7.4 Hz, NH); 8.24 (2H, s, 2H of Arl); 10.1 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 12.5, 16.4, 23.3, 26.7, 36.2, 38.6, 42.6, 49.5, 51.2, 55.4, 58.8, 61.0, 115.9, 121.2, 123.3 (q, J = 273 Hz), 130.3 (q, J = 33 Hz), 142.0, 179.9. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,4R,7S)-1,7-dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo[2.2.1]heptan-2-yl)thiourea (28). GP3: Prepared from 26 (105 mg, 0.472 mmol), Et2O

(5 mL), 17 (88 μL, 0.472 mmol), column chromatography (CHCl3/MeOH = 5:1). Yield: 110 mg (47%) of yellow solid; mp 168.2–173.0 °C. [α]r.t. D = 0 (c = 0.1, CH2Cl2). EI-HRMS: m/z = 494.2056 (MH+); C23H30F6N3S requires: m/z = 494.2059 (MH+). νmax 2958, 2874, 2777,1738, 1686, 1458, 1413, 1377, 1333, 1283, 1233, 1297, 1138, 1064, 1047, 905, 856, 767 cm-1. 1H-NMR (500 MHz, DMSO-d6): δ 0.84 (3H, s, Me); 0.95 (3H, s, Me); 1.24–1.40 (3H, m, 3H of CH2); 1.62–1.76 (7H, m, 7H of CH2); 1.97 (1H, br s, H-C(4)); 2.33–2.71 (6H, m, 6H of CH2); 4.74 (1H, br s, H-C(2)); 7.72 (1H, s, 1H of Arl); 8.26 (1H, d, J = 9.7 Hz, NH); 8.30 (2H, s, 2H of Arl); 10.08 (1H, s, NH). 13C-NMR (126 MHz, DMSO-d6): δ 14.2, 15.4, 23.5, 27.9, 28.0, 36.2, 42.1, 50.8, 52.1, 55.6, 57.5, 57.7, 115.8, 121.4, 123.3 (q, J = 272 Hz), 130.1 (q, J = 33 Hz), 142.0, 180.8. Chirality DOI 10.1002/chir

(1R,4R,7S)-1,7-Dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo[2.2.1] heptan-2-one (23) and (1R,4R,7S)-7-methyl-1,7-bis(pyrrolidin-1ylmethyl)bicyclo[2.2.1]heptan-2-one (30). To a solution of

crude bromo ketone 22 (1.00 g, 4.33 mmol) in anhydrous EtOH (5 mL) under argon pyrrolidine (5 mL, 59.9 mmol) was added. The closed reaction vessel (autoclave) was heated at 170 °C for 24 h. Volatile components were evaporated in vacuo and the residue was purified by column chromatography (1. EtOAc/petroleum ether = 1:5 to elute the non-polar impurities; 2. EtOAc/Et3N = 30:1 to elute the products 23 and 30). Fractions containing the separated products were combined and volatile components evaporated in vacuo to give 23 and 30, respectively. Compound 23: Eluted first. Yield: 605 mg (63%) of pale yellow oil. [α]r.t. = –10.2 (c = 0.21, CH2Cl2). EI-HRMS: D m/z = 222.1855 (MH+); C14H24NO requires: m/z = 222.1852 (MH+). νmax 2959, 2929, 2873, 2780, 1740, 1445, 1414, 1376, 1319, 1283, 1148, 1043, 908, 882, 857, 766, 674 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.89 (3H, s, Me); 1.06 (3H, s, Me); 1.33–1.41 (2H, m, 2H of CH2); 1.67–1.76 (5H, m, 5H of CH2); 1.86 (1H, d, J = 18.1 Hz, 1H of CH2); 1.88–1.95 (1H, m, 1H of CH2); 2.12 (1H, d, J = 13.6 Hz, 1H of CH2); 2.26 (1H, d, J = 13.6 Hz, 1H of CH2); 2.40 (1H, t, J = 4.5 Hz, CH); 2.44–2.59 (5H, m, 5H of CH2). 13C-NMR (126 MHz, CDCl3): δ 9.4, 16.2, 23.8, 27.1, 30.0, 40.5, 43.1, 51.0, 56.0, 58.3, 59.5, 219.7. Compound 30: Eluted second. Yield: 200 mg (16%) of pale yellow oil. [α]r.t. = –38.8. (c = 0.25, CH2Cl2). EI-HRMS: D m/z = 291.2431 (MH+); C18H31N2O requires: m/z = 291.2431 (MH+). νmax 2958, 2874, 2777, 1738, 1686, 1458, 1413, 1377, 1333, 1284, 1233, 1197, 1138, 1064, 1047, 905, 856, 767, 690 cm-1. 1H-NMR (500 MHz, CDCl3): δ 1.14 (3H, s, Me); 1.33–1.38 (1H, m, 1H of CH2); 1.42–1.47 (1H, m, 1H of CH2); 1.66–1.75 (8H, m, 8H of CH2); 1.85 (1H, d, J = 18 Hz, 1H of CH2); 1.91–1.98 (1H, m, 1H of CH2); 2.00–2.05 (1H, m, 1H of CH2); 2.21 (1H, d, J = 14 Hz, 1H of CH2); 2.37 (1H, t, J = 4.5 Hz, CH); 2.37–2.66 (12H, m, 12H of CH2). 13C-NMR (126 MHz, CDCl3): δ 17.0, 24.0, 24.1, 26.6, 27.1, 40.7, 43.5, 51.8, 52.5, 56.3, 56.5, 59.9, 62.2, 219.0. Synthesis of Oximes–General Procedure 4 (GP4) To a solution of amino ketone (1 equivalent) in anhydrous EtOH (5 mL), NH2OH · HCl and pyridine were added and the resulting mixture was heated under reflux for 3–6 h. Volatile components were evaporated in vacuo and to the residue H2O (15 mL) and NaOH were added till pH = 12–14 followed by extraction with Et2O (3 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and volatile components evaporated in vacuo. The residue was purified by column chromatography (EtOAc/Et3N/petroleum ether = 1:1:20). Fractions containing the product were combined and volatile components evaporated in vacuo to give the desired oxime. (1R,4R,7S,E)-1,7-Dimethyl-7-(pyrrolidin-1-ylmethyl)bicyclo[2.2.1] heptan-2-one oxime (24). GP4: Prepared from 23 (240 mg,

1.08 mmol), NH2OH · HCl (151 mg, 2.17 mmol), pyridine (125 μL, 1.55 mmol), t = 3 h. Yield: 240 mg of white solid (94%); mp 82.2-93.4°. [α]r.t. D = +43.2 (c = 2.0), CH2Cl2). EIHRMS: m/z = 237.1964 (MH+); C14H25N2O requires: m/z = 237.1961 (MH+). νmax 3286, 2957, 2874, 2791, 1678, 1445, 1377, 1151, 1105, 1093, 924, 883, 858 cm-1. 1H-NMR (500 MHz, CDCl3): δ 0.99 (3H, s, Me); 1.03 (3H, s, Me); 1.23–1.28 (1H, m, 1H of CH2); 1.40–1.45 (1H, m, 1H of CH2); 1.69–1.76 (5H, m, 5H of CH2); 1.78–1.86 (1H, m, 1H of CH2); 2.08 (1H, d, J = 17.9 Hz, 1H of CH2); 2.15 (1H, d,

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

J = 13.5 Hz, 1H of CH2); 2.26–2.29 (2H, m, 1H of CH2, CH); 2.48–2.52 (2H, m, 2H of CH2); 2.56–2.60 (2H, m, 2H of CH2); 2.64 (1H, dt, J = 3.5; 18.0 Hz, 1H of CH2); 8.99 (1H, s, OH). 13C-NMR (126 MHz, CDCl3): δ 11.4, 15.4, 23.9, 27.5, 32.8, 33.0, 41.2, 52.4, 52.5, 56.2, 59.2, 169.8. (1R,4R,7S,E)-7-Methyl-1,7-bis(pyrrolidin-1-ylmethyl)bicyclo[2.2.1] heptan-2-one oxime (31). GP4: Prepared from 30 (200 mg,

0.69 mmol), NH2OH · HCl (139 mg, 2.00 mmol), pyridine (121 μL, 1.50 mmol), t = 6 h. Yield: 147 mg (69 %) of white solid. mp 64.4–69.5 °C. [α]r.t. D = +37.1 (c = 0.25, CH2Cl2). EIHRMS: m/z = 306.2545 (MH+); C18H32N3O requires: m/z = 306.2540 (MH+). νmax 3255, 3109, 2959, 2874, 2779, 1672, 1457, 1444, 1379, 1347, 1334, 1289, 1242, 1198, 1089, 1035, 1008, 960, 927, 878, 781, 761, 696, 628 cm-1. 1H-NMR (500 MHz, CDCl3): δ 1.10 (3H, s, Me); 1.23–1.29 (1H, m, 1H of CH2); 1.55–1.60 (1H, m, 1H of CH2); 1.67–1.78 (8H, m, 8H of CH2); 1.80–1.86 (1H, m, 1H of CH2); 1.99–2.06 (2H, m, 2H of CH2); 2.19 (1H, t, J = 4.4 Hz, 1H of CH); 2.26 (1H, d, J = 13.5 Hz, 1H of CH2); 2.34 (1H, d, J = 13.5 Hz, 1H of CH2); 2.46 (1H, d, J = 13.4 Hz, 1H of CH2); 2.49–2.67 (9H, m, 9H of CH2); 2.82 (1H, d, J = 13.4 Hz, 1H of CH2).13C-NMR (126 MHz, CDCl3): δ 16.4, 23.8, 23.9, 27.5, 29.6, 32.9, 40.9, 53.8, 54.2, 55.9, 56.2, 56.6, 59.4, 168.6. General Procedure for Organocatalyzed Michael Addition Reaction To a solution of catalyst (0.05 mmol, 10 mol %) and trans-β-nitrostyrene (33) (74.5 mg, 0.5 mmol) in a solvent (toluene, CH2Cl2, or THF) (1 mL) at room temperature or at –24 °C dimethyl malonate (32) (114.5 μL, 1.0 mmol) was added and the resulting mixture was stirred for 1 or 3 days. The reaction mixture was passed through a plug of Silica gel 60 (l = 7 cm; ø =1–2 cm; EtOAc/petroleum ether = 1:1) to remove the catalyst. Volatile components were evaporated in vacuo and the residue was used for the 1 determination of conversion ( H-NMR (CDCl3)) and HPLC analysis. Characterization of the Michael addition product 34: HPLC analysis: CHIRALPAK AD-H, nhexane/iPrOH = 80:20, flow rate: 1.0 mL/min, 25 °C, UV: λ = 210 nm, t (first) = 11 min, t (second) = 16 min. Absolute configuration was determined by comparing the relative retention time of the HPLC analysis with the reported data.10,44

Single Crystal X-Ray Structure Analysis for Compounds 5, 11, and exo-14 Single crystal diffraction data for compounds 5 and 11 have been collected on a Nonius Kappa CCD diffractometer at room temperature with MoKα radiation (0.71072 Å) and graphite monochromator using the Nonius Collect Software.45 The reflection data were processed using DENZO software.46 Single crystal diffraction data for compound exo-14 were collected on an Agilent SuperNova dual source diffractometer with an Atlas detector at room temperature with MoKα radiation. These data were processed using CrysAlis PRO software.47 All structures were solved by direct methods, using SIR97.48 A full-matrix least-squares re2 finement on F was employed with anisotropic displacement parameters for all nonhydrogen atoms. H atoms were placed at calculated positions and treated as riding. SHELXL97 software49 was used for structure refinement and interpretation. Drawings of the structures were produced using ORTEP-3.50 Structural and other crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1012091-1012093 for compounds 5, 11, and exo-14, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: [email protected]).

RESULTS AND DISCUSSION Syntheses

An attempt was made to prepare bifunctional catalysts of type B beginning from (+)-camphor (1). Following the literature procedures,37,38 1 was first transformed into keto oxime 237 in 87% yield, followed by reduction with LiAlH4 to give the amino alcohol 338 in 88% yield. Next, amino alcohol 3 was Nprotected. Thus, treatment of 3 with benzyl chloroformate in the presence of N,N-diisopropylethylamine yielded N-Cbz protected alcohol 4 in 55% yield, whereas reaction of 3 with phthalic anhydride under azeotropic removal of water furnished N-Phth protected alcohol 5 in 69% yield. Next, alcohols 4 and 5 were treated with methanesulfonyl chloride in anhydrous CH2Cl2 in order to obtain the corresponding mesylates for the upcoming substitution with secondary amines. Unfortunately, upon isolation, all experiments furnished the starting alcohols, 4, i.e., 5, respectively. In the last attempt, the mesylate formed in situ from N-Phth protected alcohol 5 was treated with excess pyrrolidine. The following isolation furnished bisamide 6 in 79% yield, thus confirming the unsuccessful in situ mesylation (Scheme 1). The structure of compound 5 was confirmed by a single crystal X-ray analysis (Fig. 2). Next, we focused on the preparation of bifunctional catalysts of type C. Starting from amino alcohol 3 following the literature procedure, pyrrolidine 739 was prepared in 62% yield. Swern oxidation furnished amino ketone 8 in 76% yield. A simple three-step synthesis from 8 should give the desired final products of type C, starting with the formation of oxime 9a followed by reduction and addition to isothiocyanate. Surprisingly, reaction of 8 with NH2OH · HCl in the presence of NaOAc in refluxing ethanol yielded a separable mixture of hydroxy oximes 10 and 1143 in 36% and 14% yield, respectively (Scheme 2). The structure of compound 1143 was confirmed by a single crystal X-ray analysis (Fig. 3). The formation of hydroxy oximes 10 and 11 could be explained by the initial protonation of pyrrolidine nitrogen followed by nucleophilic substitution with NH2OH. Finally, double tautomerization yields the two oxime products 10 and 11 (Scheme 3). To the best of our knowledge, no such transformations of α-amino ketones have been found in the literature (SciFinder search). A literature survey offered an alternative, already established synthetic route to 3-pyrrolidino-camphor-2-oxime 9a and other tert-amino oximes 9b-c.40,41 Following the literature procedures, (+)-camphor (1) was first transformed into the corresponding oxime 12 in 88% yield followed by nitrosation with NaNO2 in acetic acid to give the nitroimine 13 in 64% yield as a mixture of the major (E)- and the minor (Z)-isomer in the ratio of 20:1.40 In accordance with the literature,41 nitroimine 13 was brominated in acetic acid to give 3bromo derivative 14 as a mixture of exo- and endo-epimers in a ratio of 1:1 in 40% yield. Eventually, 3-exo-14 crystallized from the oily mixture of epimers, giving single crystals suitable for X-ray analysis (Fig. 4). Treatment of the epimer mixture of 14 with secondary amines in the presence of NH2OH · HCl followed by chromatographic isolation gave the desired exo-amino oximes 9a-d.41 The ensuing reduction of oximes 9 could be performed diastereoselectively to give either 2,3-exo-diamines 15 or 2-endo-3-exo-diamines 16. Thus, reduction of 9a-d in an H-CubeTM flow hydrogenator using Raney-Nickel cartridge at 100 °C and Chirality DOI 10.1002/chir

RIČKO ET AL.

Scheme 1. An attempt of the preparation of organocatalysts of type B.

Fig. 2. Single crystal X-ray analysis of compound 5.

100 bar of H2 furnished 2,3-exo-diamines 15a-d, while reduction with sodium in nPrOH at 95 °C yielded 2-endo-3exo-diamines 16a-d. In general, reduction with sodium gave crude diamines 16a-d sufficiently clean for characterization, whereas hydrogenation products 15a-d, due to byproducts, were not fully characterized (see the Supporting Information and the Experimental part). In both cases, crude reduction products were used in the following step without further purification. Finally, treatment of the crude amines 15a-d and 16a-d with 3,5-bis(trifluoromethyl) phenylisothiocyanate (17) gave, after chromatographic purification, the desired thiourea organocatalysts 18a-d and 19a-d, respectively (Scheme 4, Table 1). Synthesis of potential organocatalysts of type D began from (+)-camphor (1). Following the literature procedures, 8Chirality DOI 10.1002/chir

bromocamphor 22 was prepared in three steps from 1 starting with two consecutive bromination steps (1 → 20 (92% yield); 20 → 21 (95% yield)) and concluded with Zn debromination of vicinal Br-atoms (21 → 22 (49% yield)).42 Treatment of 22 with excess pyrrolidine in EtOH at 170 °C in an autoclave for 24 h furnished the desired 8-pyrrolidinocamphor 23 in 63% yield. The preparation of regioisomeric 9-pyrrolidino camphor was reported in the literature using similar reaction conditions.51 Reaction of amino ketone 23 with hydroxylamine gave the corresponding oxime 24 in 94% yield. Once more, reduction of oxime 24 in an H-CubeTM flow hydrogenator using Raney-Nickel cartridge at 100 °C and 100 bar of H2 gave, selectively, the exo-diamine 25 in 87% yield, while reduction of 24 with sodium in nPrOH delivered, selectively, the endo-epimer 26 in 90% yield. The synthesis concluded with the treatment of 25, i.e., 26 with 3,5-bis(trifluoromethyl)phenyl isothiocyanate (17), giving, after chromatographic purification, the corresponding thiourea derivatives 27 and 28 in 42% and 47% yield, respectively (Scheme 5). Reaction of a crude batch of 22 with excess pyrrolidine furnished, after chromatographic separation, besides the desired product 23, also the bis-pyrrolidinyl-camphor side product 30 in 16% yield. Further treatment of 30 with hydroxylamine gave the corresponding oxime 31 in 69% yield. 2D-NMR spectroscopic determination of the structure of 31, i.e., 30 confirmed the 8,10-regioisomeric structure of the bis-pyrrolidinyl-camphor derivatives 30 and 31. The formation of 30 must therefore originate from the double nucleophilic substitution of 8,10-dibromo camphor 2952 (Scheme 6).

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

Scheme 2. An attempt of the preparation of organocatalysts of type C.

Structure Determination

Fig. 3. Single crystal X-ray analysis of compound 11.

The structures of novel compounds 4, 5, 6, 8, 10, 11, 15a-d, 16a-d, 18a-d, 19a-d, 23-28, 30, and 31 were determined by spectroscopic methods (IR, NMR spectroscopy (1H- and 13C-NMR, DEPT 90 and 135, COSY, HSQC, HMBC and NOESY experiments), and MS-HRMS) and by elemental analyses for C, H, and N. Compounds 4, 10, and 11 were prepared in analytically pure form. The identities of compounds 15b, 15c, 25, and 26 were confirmed only by MSHRMS. Identities of compounds 5, 6, 8, 15a, 15d, 16a-d, 18a-d, 19a-d, 23, 24, 27, 28, 30, and 31 were confirmed by MS-HRMS and 13C-NMR. Crude amines 15a-d, 16a-d, 25, and 26 were used in the following transformation without further purification.

Scheme 3. Proposed formation of hydroxyl oximes 10 and 11. Chirality DOI 10.1002/chir

RIČKO ET AL.

TABLE 1. Yields of isolated products 9, 15-19. Yield (%) Compound 9a, 15a, 16a, 18a, 19a 9b, 15b, 16b, 18b, 19b 9c, 15c, 16c, 18c, 19c 9d, 15d, 16d, 18d, 19d Fig. 4. Single crystal X-ray analysis of compound exo-14.

The configuration(s) at the 2- and/or 3-position of compounds 4, 5, 6, 8, 10, 11, 15a, 16a-d, 18a-d, 19a-d, 27, and 28 was/were determined/confirmed on the basis of NOEs observed in the NOESY spectra between the corresponding key proton signals. Attachment of the pyrrolidine ring at position 8 in compound 30 (i.e., 31) was determined on the basis of the observed NOE between H(3)-C(9) and Hexo-C(5)/Hexo-C(6) in the NOESY spectra. The position of the second pyrrolidine group of compound 31 (i.e., 30) was established on the basis of crosspeaks between oxime C(1) atom (168.6 ppm) and Ha-C(10) (2.46 ppm) and HbC(10) (2.82 ppm) protons and the absence of a crosspeak between C(1) and the Me-group observed in the HMBC spectra

R

9

15

16

18

19

-(CH2)4-

82

79

90

54

53

-(CH2)5-

48

84

97

34

97

-(CH2)2-O-(CH2)2-

64

84

98

36

86

Me

23

69

90

72

63

(Fig. 5). For details of 1H-, 13C-NMR and selected parts of NOESY and HMBC spectra, see the Supporting Information. Also, correlation of the selected 1H-NMR data in a series of compounds with the same configuration and comparison with the corresponding epimers is in very good agreement (Table 2). Thus, H-C(2) signals of diamines 15a-d are slightly upfield-shifted compared to their C(2) epimers 16a-d, while the signals for H-C(3) and H-C(4) are slightly downfieldshifted, respectively. The same observation holds for their respective thiourea derivatives 18a-d versus 19a-d. The HC(2) signals of exo-amine 25 and exo-thiourea 27 are again upfield-shifted with regard to their epimers 26 and 28, respectively (Table 2). There is also a distinct change of the sign of optical rotation of polarized light on going from (–)-sign for the 2-exo-epimers 18a-d, and 27, to (+)-sign for the 2-endo-epimers 18a-d and 28, respectively (see the Experimental part).

Scheme 4. Synthesis of organocatalysts 18 and 19. Chirality DOI 10.1002/chir

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

Scheme 5. Synthesis of organocatalysts 27 and 28.

Organocatalysts Performance

Compounds 18a-d, 19a-d, 27, and 28 have been evaluated as organocatalysts in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene (Table 3). One equivalent of trans-β-nitrostyrene (33), 2 equivalents of dimethyl malonate (32), and 10% of catalyst in a selected solvent were used.10 The following conclusions can be drawn: (1) all the catalyst evaluated gave Michael addition product 34 in, at best, low enantioselectivities, with catalyst 19d giving the highest enantiomeric excess (23%; Entry 8) at room temperature—practically in all cases, the major addition product 34 has (S)-configuration10,44; (2) only with catalysts 19a, b,d and 28 was a full conversion achieved at room temperature (Entries 5,6,8,13); (3) lowering of the reaction temperature (–24 °C) resulted in a drastic decrease of conversion, i.e., for catalyst 19d (from 99% to 5%) with minimal increase of selectivity (23% e.e. versus 35% e.e.; see Entries 8 and 9)— the use of THF or CH2Cl2 instead of toluene slightly decreased the selectivity (Entries 9–11); (4) the 2,3-exo-

catalysts 18a-d gave marginal conversions even at room temperature compared to their 2-endo-3-exo-counterparts 19a,b,c with exception of 19c (see and compare Entries 1–4 and 5–11), presumably because of the steric hindrance with the 2,3-exo-catalysts, which disables the efficient activation and interaction of both the electrophile and the nucleophile. On the other hand, catalysts 27 and 28 most probably possess too much conformational freedom and mismatched geometry for an efficient catalyst. CONCLUSION

Syntheses and catalytic evaluation of novel camphorderived thiourea bifunctional organocatalysts of type B-D (Fig. 1) was attempted. The synthesis of organocatalysts of type B via N-protection of amino alcohol 3 followed by mesylation and substitution failed (Scheme 1). Also, the attempted formation of oxime 9a from amino ketone 8 followed by reduction, in order to prepare compounds of type C, failed, giving instead unexpectedly the 2-hydroxy oximes

Scheme 6. Synthesis of 8,10-bis-pyrrolidinil-camphor derivatives 30 and 31. Chirality DOI 10.1002/chir

RIČKO ET AL.

Fig. 5. Determination of structure and configuration of compounds 4, 5, 6, 10, 11, 15a, 16a-d, 18a-d, 19a-d, 27, 28, 30, and 31 based on the NOESY and HMBC spectra.

10 and 11 (Schemes 2 and 3). Finally, reduction of 3-amino oximes 941 with sodium or Raney-Ni furnished, after treatment with isothiocyanate 17, the 2-endo-3-exo- and 2,3-exothiourea organocatalysts 18 and 19, respectively (Scheme 4). The catalysts of type D were prepared from 8bromocamphor.42 Thus, substitution of 22 with pyrrolidine followed by the formation of oxime 24 and reduction with sodium or Raney-Ni yielded catalysts 27 and 28, respectively. Compounds 18a-d, 19a-d, 27, and 28 have been evaluated as organocatalysts in a model reaction of Michael addition of dimethyl malonate 32 to trans-β-nitrostyrene 33, giving the addition product 34 in low enantioselectivity and in the case of catalysts 19a,b,d and 28 with full conversion at room temperature. The cis-2,3-exo-catalysts 18a-d gave marginal

conversions even at room temperature, presumably because of steric factors and mismatched relative stereochemistry (cis) of the activating substituents. Nevertheless, catalysts 18 and 19 represent only two out of eight possible 2,3disubstituted regio- and stereoisomeric catalyst frameworks. ACKNOWLEDGMENTS

Contract grant sponsor: Slovenian Research Agency (financial support); Contract grant numbers: P1-0179 and J1-0972; Contract grant sponsor: Ministry of Science and Technology, Republic of Slovenia (financial contribution for the purchase of Kappa CCD Nonius diffractometer); Contract grant numbers: Packet X-2000 and PS-511-102.

TABLE 2. Selected 1H-NMR data of compounds 15, 16, 18, 19, and 25-28. δ (ppm)

15a

15b c

15c c

2.79 c 2.33 c 1.92

2.78 c 2.28 c 2.04

δ (ppm) H-C(2) H-C(3) H-C(4)

18a d 4.63 d 2.47 d 1.98

18b d 4.60 d 2.39 d 2.11

δ (ppm) H-C(2) H-C(4)

25 c 2.73 c 1.90

26 c 3.08 c 1.93

H-C(2) H-C(3) H-C(4)

a

Extracted from 2D-HSQC spectra; overlapped with other signals; c recorded in CDCl3; d recorded in DMSO-d6. b

Chirality DOI 10.1002/chir

b,c

— —b,c —b,c

15d

16a c

c

16b c

16c c

16d c

2.83 c 2.17 c 1.98

2.99 c 1.54 c 1.75

2.95 a 1.42 c 1.85

2.96 c 1.51 c 1.83

2.97 c 1.33 c 1.81

18c d 4.68 d 2.45 d 2.10

18d d 4.65 d 2.30 d 2.04

19a d 4.87 d 1.81 d 1.85

19b d 4.83 d 1.76 d 1.97

19c d 4.86 d 1.82 d 1.98

19d d 4.83 d 1.62 d 1.90

27 d 4.25 d 1.96

28 d 4.74 d 1.97

SYNTHESIS OF CAMPHOR THIOUREA ORGANOCATALYSTS

TABLE 3. Organocatalytic enantioselective addition of dimethyl malonate to trans-β-nitrostyrene.

Entry

Catalyst

Solvent

T (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13

18a 18b 18c 18d 19a 19b 19c 19d 19d 19d 19d 27 28

toluene toluene toluene toluene toluene toluene toluene toluene toluene CH2Cl2 THF toluene toluene

-24 r.t. r.t. r.t. r.t. r.t. r.t. r.t. -24 -24 -24 r.t. r.t.

a

t (days) 3 3 3 3 1 3 3 3 3 3 3 3 3

Conversion (%) — 2 99 >99 99 5 7 2 86 >99

a

E.e. (%)

b

— 1; (R) 23; (S) 1.8; (S) 17; (S) 14; (S) — 23; (S) 35; (S) 27; (S) 24; (S) 14; (S) 6; (S)

1

Conversion was determined using H-NMR (CDCl3); e.e. was determined using CHIRALPAK AD-H using n hexane/i PrOH = 80:20 as a mobile phase.

b

SUPPORTING INFORMATION

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