Asymmetric Organocatalytic Strecker-Type Reactions of Aliphatic N,N- Dialkylhydrazones Aurora Martínez-Muñoz, David Monge,* Eloísa Martín-Zamora, Eugenia Marqués-López, Eleuterio Álvarez, Rosario Fernández,* and José M. Lassaletta* Instituto de Investigaciones Químicas (CSIC-US), C/ Américo Vespucio 49, E-41092 Sevilla (Spain), and Departamento de Química Orgánica, Universidad de Sevilla, C/ Prof. García González, 1, 41012 Sevilla (Spain) ffernan@us.es; jmlassa@iiq.csic.es Contents Page General information 2 (E)-N-(3-Phenylpropylidene)pyrrolidin-1-amine (1C): 2 4-Phenyl-2-(pyrrolidin-1-ylamino)butanenitrile: 2 General procedure for the synthesis of N,N-dibenzylhydrazones 1 3 Preliminary experiments 5 Addition of TMSCN to N,N-dibenzyl hydrazones 1 (racemic version) 9 Screening of solvents and temperature for the enantioselective reaction 9 Screening of additives for the enantioselective reaction 10 NMR spectra and HPLC traces for compounds 2, 4-8 11 1
General Information. 1 H NMR spectra were recorded at 300 MHz or 500 MHz; 13 C NMR spectra were recorded at 75 MHz or 125 MHz with the solvent peak used as the internal reference (7.26 and 77.16 ppm for 1 H and 13 C respectively). Column chromatography was performed on silica gel (Merck Kieselgel 60). Analytical TLC was performed on aluminum backed plates (1.5 5 cm) pre-coated (0.25 mm) with silica gel (Merck, Silica Gel 60 F 254 ). Compounds were visualized by exposure to UV light or by dipping the plates in solutions of Mostain, anisaldehyde or phosphomolibdic acid stains followed by heating. Melting points were recorded in a metal block and are uncorrected. Optical rotations were measured on a Perkin-Elmer 341 MC polarimeter. The enantiomeric excesses (ee) of the products were determined by chiral stationary-phase HPLC (Daicel Chiralpak AD-H, OD, OJ-H columns). Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. N,N-dialkyl hydrazones type 1A (piperidine-containing), and 1D (based on N,N-dimethylamino group) and their corresponding strecker adducts 2 were synthesized as described previously. 1 (E)-N-(3-Phenylpropylidene)pyrrolidin-1-amine (1C): A mixture of 1-amino-pirrolidine (2.2 g, 25 mmol), hydrocinamaldehyde (3.3 ml, 25 mmol) and anhydrous Na 2 SO 4 (1 g) was stirred overnight at room temperature. The mixture was filtered, dried (Na 2 SO 4 ), concentrated, and the residue was purified by flash chromatography (hexane-et 2 O, 6:1) affording 1C (3.9 g, 78%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.30-7.13 (m, 5H), 6.60 (t, J = 5.5 Hz, 1H), 3.12-3.09 (m, 4H), 2.82-2.79 (m, 2H), 2.57-2.53 (m, 2H), 1.91-1.84 (m, 4H); 13 C NMR (125 MHz, CDCl 3 ) δ 141.8, 137.8, 128.7, 128.6, 126.1, 51.7, 35.1, 34.6, 23.2. HRMS: calculated for [C 13 H 19 N 2 ] + 203.1551, found: 203.1548. 4-Phenyl-2-(pyrrolidin-1-ylamino)butanenitrile: TMSCN (0.2 ml, 1.5 mmol) was added to a solution of hydrazone 1C (0.5 mmol) in MeOH (3 ml) at room temperature. The mixture was stirred for 22 h. FC (Hexane/AcOEt, 15:1) afforded the corresponding rac-strecker adduct (72 mg, 63%) as an oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.32-7.20 (m, 5H), 3.68 (t, J = 7.5 Hz, 1H), 2.90-2.76 (m, 6H), 2.12-2.06 (m, 1 E. Marqués-López, R. P. Herrera, R. Fernández and J. M. Lassaletta, Eur. J. Org. Chem. 2008, 3457; 2
2H), 1.80-1.73 (m, 4H); 13 C NMR (125 MHz, CDCl 3 ) δ 140.3, 128.8, 128.6, 126.5, 121.6, 57.2, 51.3, 33.6, 31.9, 22.1. HRMS: calculated for [C 14 H 19 N 3 ] + 229.1579, found: 229.1567. General procedure for the synthesis of N,N-dibenzylhydrazones 1: A mixture of N,N-1,1-dibenzylhydrazine (2.5 g, 12 mmol), the corresponding aldehyde (1.2 eq., 14.4 mmol) and anhydrous Na 2 SO 4 (1 g) in CH 2 Cl 2 (7 ml) was stirred overnight at room temperature. The mixture was filtered, concentrated, and the residue was purified by flash chromatography (Cyclohexane/Et 2 O). (E)-1,1-Dibenzyl-2-(3-methylbutylidene)hydrazine (1a): Colourless oil (98%); 1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.20 (m, 10H), 6.52 (t, J = 5.7 Hz, 1H), 4.29 (s, 4H), 1.98 (t, J = 6.6 Hz, 2H), 1.63 (hept, J = 6.6 Hz, 1H), 0.79 (d, J = 6.6 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 139.5, 138.3, 128.5, 128.0, 127.1, 59.0, 42.0, 27.6, 22.4; HRMS: calculated for [C 19 H 25 N 2 ] + 281.2017, found: 281.2019. (E)-1,1-Dibenzyl-2-(2-methylpropylidene)hydrazine (1b): White solid (91%); MP: 36-38 C; 1 H NMR (300 MHz, CDCl 3 ) δ 7.24-7.18 (m, 10H), 6.47 (d, J = 6.8 Hz, 1H), 4.21 (s, 4H), 2.46-2.35 (m, 1H), 0.97 (d, J = 6.8 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 145.4, 138.3, 128.2, 128.1, 126.9, 58.2, 31.8, 20.7; HRMS: calculated for [C 18 H 23 N 2 ] + 267.1861, found: 267.1858. (E)-1,1-Dibenzyl-2-propylidenehydrazine (1c): N NBn 2 Yellow oil (93%); 1 H NMR (300 MHz, CDCl 3 ) δ 7.29-7.20 (m, 10H), 6.61 (t, J = 5.2 Hz, 1H), 4.28 (s, 4H), 2.24-2.15 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 140.7, 138.2, 127.9, 127.7, 127.2, 58.4, 26.3, 11.86; HRMS: calculated for [C 17 H 21 N 2 ] + 253.1705; found: 253.1704. (E)-1,1-Dibenzyl-2-(3,3-dimethylbutylidene)hydrazine (1d): Colourless oil (60%); 1 H NMR (300 MHz, CDCl 3 ) δ 7.25-7.15 (m, 10H), 6.56 (t, J = 6.1 Hz, 1H), 4.27 (s, 4H), 2.06 (d, J = 6.1 Hz, 2H), 0.74 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ) δ 138.3, 128.4, 127.8, 126.9, 58.5, 46.8, 31.0, 29.3; HRMS: calculated for [C 20 H 26 N 2 ] + 294.2096 found: 294.2088. 3
(E)-1,1-Dibenzyl-2-(2-phenylethylidene)hydrazine (1e): Orange oil (80%); 1 H NMR (300 MHz, CDCl 3 ) δ 7.25-7.06 (m, 15H), 6.62 (t, J = 5.7 Hz, 1H), 4.30 (s, 4H), 3.52 (d, J = 5.7 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 136.7, 138.7, 137.8, 128.7, 128.4, 127.9, 127.2, 127.0, 126.2, 58.37, 39.4; HRMS: calculated for [C 22 H 23 N 2 ] + 315.1861; found: 315.1852. (E)-1,1-Dibenzyl-2-(3-phenylpropylidene)hydrazine (1f): White solid (73%); MP: 76-78 C; 1 H NMR (300 MHz, CD 3 COCD 3 ) δ 7.33-7.10 (m, 15H), 6.55 (t, J = 5.1 Hz, 1H), 4.28 (s, 4H), 2.69 (t, J = 7.5 Hz, 2H), 2.45-2.38 (m, 2H); 13 C NMR (75 MHz, CD 3 COCD 3 ): δ 142.6, 139.5, 136.5, 129.3, 129.2, 129.1, 128.6, 127.7, 126.5, 58.9, 35.5, 34.5; HRMS: calculated for [C 23 H 25 N 2 ] + 329.2017; found: 329.2003. (E)-1,1-Dibenzyl-2-(2,2-dimethylpropylidene)hydrazine (1g): White solid (82%); MP: 41-43 C; 1 H NMR (300 MHz, CDCl 3 ) δ 7.24-7.11 (m, 10H), 6.43 (s, 1H) 4.11 (s, 4H), 0.91 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ) δ 148.0, 138.4, 128.4, 128.3, 127.0, 58.2, 34.6, 28.3, 22.4; HRMS: calculated for [C 19 H 25 N 2 ] + 281.2018, found: 281.2031. (E)-1,1-Dibenzyl-2-(cyclohexylmethylene)hydrazine (1h): Colourless oil (80%); 1 H NMR (300 MHz, CDCl 3 ) δ 7.35-7.21 (m, 10H), 6.49 (d, J = 5.8 Hz, 1H), 4.25 (s, 4H), 2.25-2.10 (m, 1H), 1.73-1.61 (m, 4H),1.37-1.04 (m, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 144.7, 138.3, 128.3, 128.0, 126.9, 58.2, 41.2, 31.2, 26.1, 25.7; HRMS: calculated for [C 21 H 26 N 2 ] + 306.2096; found: 306.2084. (E)-1,1-Dibenzyl-2-benzylidenehydrazine (1i): White solid (86%); MP: 82-84 C; 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.22 (m, 15H), 7.13 (s, 1H), 4.47 (s, 4H); 13 C NMR (125 MHz, CDCl 3 ) δ 137.8, 137.2, 132.0, 128.7, 128.6, 127.8, 127.3, 125.7, 58.1; HRMS: calculated for [C 21 H 21 N 2 ] + 301.1705, found: 301.1703. (E)-tert-Butyl 1-benzyl-2-benzylidenehydrazinecarboxylate (1j): (E)-tert-butyl 2-(3-methylbutylidene) hydrazinecarboxylate (1.1 g, 5.5 mmol) and bencyl bromide (0.8 ml, 6.3 mmol) were sequentially added to a solution of NaH (158 mg, 6.6 4
mmol) in anhydrous THF (30 ml). The reaction was stirred for 2 days, diluted with water (15 ml) and extracted with diethyl ether (3 x 15 ml). The organic extracts were dried over Na 2 SO 4 and the solvent was removed in-vacuo. FC (Cyclohexane/Et 2 O) affrorded 1j (798 mg, 50%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.34-7.15 (m, 5H), 7.0 (t, J = 5.8 Hz, 1H), 4.97 (s, 2H), 2.14 (dd, J = 6.9, 5.8 Hz, 2H), 1.69-1.60 (m, 1H), 1.54 (s, 9H), 0.82 (d, J = 6.4 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 153.6, 146.6, 136.2, 128.7, 127.2, 126.3, 81.6, 53.4, 41.7, 28.3, 27.0, 22.2. HRMS: calculated for [C 17 H 26 N 2 O 2 ] + 290.1994; found: 290.2000. Preliminary experiments A preliminary study of reaction conditions was performed as follows: cyanide reagent (0.3 mmol) was added to a solution of hydrazone (0.1 mmol), catalyst (20 mol%) and additive (in some cases, 0.3-0.4 mmol) in the chosen solvent (0.5 ml) at room temperature. Conversions (NMR) are shown in Tables 1-3. 5
Table 1. Preliminary experiments (PTCs) Entry Hydrazone CN - Cat. Solvent Additive t [h] Conv. (%) 1 A KCN H 2 O 96 nr 2 B KCN H 2 O 96 nr 3 A KCN I H 2 O 96 nr 4 B KCN I H 2 O 96 nr 5 B KCN II H 2 O 96 nr 6 B KCN III H 2 O 96 nr 7 A KCN Toluene H 2 O 96 nr 8 B KCN Toluene H 2 O 96 nr 9 B KCN CHCl 3 MeOH 96 nr 10 A KCN I Toluene H 2 O 96 10 11 B KCN I Toluene H 2 O 96 10 12 B KCN II Toluene H 2 O 96 10 13 B KCN III Toluene H 2 O 96 10 14 A TMSCN I Toluene 72 20/ rac 15 B TMSCN I Toluene 72 30/ rac 16 A TMSCN I CHCl 3 72 30/ rac 17 B TMSCN I CHCl 3 72 40/ rac 18 A TMSCN IV CHCl 3 72 40/ rac 19 B TMSCN IV CHCl 3 72 50/ rac 20 B TMSCN IV Toluene 72 45/ rac 21 B TMSCN IV Et 2 O 72 40/ rac 6
Table 2. Preliminary experiments (Binol, Binol-Phosphate) Entry Hydrazone Cat. Solvent t [h] Conv. (%) 1 A Toluene 72 nr 2 B Toluene 72 5 3 A CHCl 3 72 10 4 B CHCl 3 72 15 5 A MeOH 4 >95 6 B MeOH 4 >95 7 A V CHCl 3 72 22/ rac 8 B V CHCl 3 72 30/ rac 9 A V Toluene 72 nr 10 B V Toluene 72 10 11 A VI Et 2 O 72 nr 12 B VI Et 2 O 72 nr 13 B VI t BuMeO 72 nr 14 B VI THF 72 nr 15 B VI Toluene 72 nr 16 A VI CHCl 3 96 12/ rac 17 B VI CHCl 3 96 20/ rac 18 B VI CH 3 CN 72 30/ rac 7
Table 3. Preliminary experiments (Thiourea) Entry Hydrazone CN - Cat. Solvent Additive t [h] Conv. (%) 1 B TMSCN CHCl 3 72 15 2 B KCN VII CHCl 3 MeOH 96 10 3 A TMSCN VII CHCl 3 96 46 4 B TMSCN VII CHCl 3 72 67 5 B TMSCN VII CHCl 3 MeOH 48 >95 6 B TMSCN VII CH 2 Cl 2 72 58 7 B TMSCN CH 3 CN 72 30 8 B TMSCN VII CH 3 CN 72 72 9 B TMSCN Toluene 72 5 10 A TMSCN VII Toluene 72 35 11 B TMSCN VII Toluene 72 47 12 B CH 3 COCN VII Toluene 72 15 13 B TMSCN VII Toluene PhOH 48 >95 14 C TMSCN VII Toluene 72 10 15 D TMSCN VII Toluene 72 24 16 E TMSCN VII CHCl 3 72 nr 17 E TMSCN VII Toluene 72 nr 18 E TMSCN VII Toluene PhOH 72 nr 19 E TMSCN VII CHCl 3 72 nr 20 F TMSCN VII Toluene 72 nr 21 F TMSCN VII Toluene PhOH 72 nr 8
Addition of TMSCN to N,N-dibenzyl hydrazones 1 (racemic version): TMSCN (0.2 ml, 1.5 mmol) was added to a solution of hydrazone 1 (0.5 mmol) in MeOH (3 ml) at room temperature. The mixture was stirred for 4 h. FC (Cyclohexane/Et 2 O) afforded rac-2. Isolated yields are shown in Table 4: Table 4. Synthesis of racemic products 2 Entry R 2 Yield (%) 1 i-bu, 1a 2a 98 2 i-pr, 1b 2b 94 3 Et, 1c 2c 90 4 (CH 3 ) 3 CH 2, 1d 2d 94 5 CH 2 Ph, 1e 2e 90 6 CH 2 CH 2 Ph, 1f 2f 95 7 t-bu, 1g 2g 82 8 C 6 H 11, 1h 2h 85 Screening of solvents and reaction temperature for the enantioselective Strecker-type reaction of 1a. Table 5 Optimization for the enantioselective Strecker-type reaction of 1a. a Entry Solvent T [ºC] t [days] Conv. [%] b ee (%) c 1 Toluene 0 3 >95 72 2 CH 2 Cl 2 0 2 >95 54 3 CHCl 3 0 2 >95 44 4 Hexane 0 2 >95 56 5 Heptane 0 2 >95 52 6 Methyl-cyclohexane 0 2 >95 46 7 Acetone 0 3 22 36 8 Propionitrile 0 3 58 30 9 Trifluorotoluene 0 1 >95 52 10 Toluene 10 5 89 48 11 CH 2 Cl 2 10 3 >95 54 12 Hexane 10 3 >95 48 13 Trifluorotoluene 30 3 85 60 a Unless otherwise stated, reactions were performed with 1a (0.1 mmol), TMSCN (0.3 mmol), 3h (10 mol%) and PhOH (0.2 mmol) in the chosen solvent (1 ml) and temperature. b Determined by 1 H NMR. c Determined by HPLC on chiral stationary phases. 9
Screening of additives for the enantioselective Strecker-type reaction of 1a. A screening of additives was performed as follows: TMSCN (0.3 mmol) was added to a solution of 1a (0.1 mmol), catalyst 3h (10 mol%) and additive (x mmol) in Toluene (1 ml) at 0 C. Conversions (NMR)/ enantiomeric excesses (HPLC) are shown in the Table 6: Table 6. Screening of additives Entry Additive (x equiv.) t (days) Conv. [%] ee (%) 1-7 79 44 2 PhOH (3) 2 >95 54 3 PhOH (2) 3 >95 72 4 PhOH (1.5) 3 >95 64 5 PhOH (0.2) 3 68 52 6 i-proh (2) 3 >95 66 7 t-buoh (2) 4 22 46 8 HFIP (2) 3 >95 64 9 BnOH (2) 3 64 66 10 11 (2) (2) 3 >95 54 4 57 44 10
6. NMR spectra and HPLC traces for compounds 2, 4 8: 1 H NMR (300 MHz, CDCl 3 ) of 2a: 13 C NMR (125 MHz, CDCl 3 ) of 2a: 11
HPLC conditions for 2a: Chiralpak AD- H column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic 12
1 H NMR (500 MHz, CDCl 3 ) of 2b: 13 C NMR (125 MHz, CDCl 3 ) of 2b: 13
HPLC conditions for 2b: Chiralpak AD- H column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic 14
1 H NMR (CDCl 3, 300 MHz) of 2c: 13 C NMR (CDCl 3, 125 MHz) of 2c: 15
HPLC conditions for 2c: Chiralpak AD- H column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic 16
1 H NMR (300 MHz, CDCl 3 ) of 2d: 13 C NMR (125 MHz, CDCl 3 ) of 2d: 17
HPLC conditions for 2d: Chiralpak AD- H column [hexane/ i- PrOH (99:1) 1 ml/min] Racemic Non Racemic 18
1 H NMR (300 MHz, CDCl 3 ) of 2e: 13 C NMR (125 MHz, CDCl 3 ) of 2e: 19
HPLC conditions for 2e: Chiralpak OD column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic Crystallized: 20
1 H NMR (500 MHz, CDCl 3 ) of 2f: 13 C NMR (125 MHz, CDCl 3 ) of 2f: 21
HPLC conditions for 2f: Chiralpak AD- H column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic Crystallized: 22
1 H NMR (300 MHz, CDCl 3 ) of 2g: 13 C NMR (75 MHz, CDCl 3 ) of 2g: 23
HPLC conditions for 2g: Chiralpak AD- H column [hexane/ i- PrOH (99:1) 1 ml/min] Racemic Non Racemic 24
1 H NMR (300 MHz, CDCl 3 ) of 2h: 13 C NMR (75 MHz, CDCl 3 ) of 2h: 25
HPLC conditions for 2h: Chiralpak AD- H column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic 26
1 H NMR (300 MHz, CDCl 3 ) of 4a: 13 C NMR (125 MHz, CDCl 3 ) of 4a: 27
HPLC conditions for 4a: Chiralpak OD column [hexane/ i- PrOH (98:2) 1 ml/min] Racemic Non Racemic 28
1 H NMR (300 MHz, DMSO, 363K) of 4b: 13 C NMR (75 MHz, DMSO, 363K) of 4b: 29
HPLC conditions for 4b: Chiralpak OJ- H column [hexane/ i- PrOH (96:4) 1 ml/min] Racemic Non Racemic 30
1 H NMR (300 MHz, CDCl 3 ) of 5a: 13 C NMR (75 MHz, CDCl 3 ) of 5a: 31
HPLC conditions for 5a: Chiralpak OJ- H column [hexane/ i- PrOH (90:10) 1 ml/min] Racemic Non Racemic 32
1 H NMR (300 MHz, CDCl 3 ) of 5b: 13 C NMR (125 MHz, CDCl 3 ) of 5b: 33
HPLC conditions for 5b: Chiralpak AD- H column [hexane/ i- PrOH (95:5) 1 ml/min] Racemic Non Racemic 34
1 H NMR (300 MHz, DMSO- d 6 ) of 6a: HN NBn 2 COOH 13 C NMR (75 MHz, DMSO- d 6 ) of 6a: 35
HPLC conditions for 6a: Chiralpak AD- H column [hexane/ i- PrOH (95:5) 1 ml/min] Racemic Non Racemic 36
1 H NMR (500 MHz, CDCl 3 ) of 7a: 13 C NMR (125 MHz, CDCl 3 ) of 7a: 37
HPLC conditions for 7a: Chiralpak AD- H column [hexane/ i- PrOH (90:10) 1 ml/min] Racemic Non Racemic 38
1 H NMR (300 MHz, CDCl 3 ) of 7b: 13 C NMR (75 MHz, CDCl 3 ) of 7b: 39
HPLC conditions for 7b: Chiralpak AD- H column [hexane/ i- PrOH (90:10) 1 ml/min] Racemic Non Racemic 40
1 H NMR (300 MHz, DMSO, 333K) of 8: 13 C NMR (75 MHz, DMSO, 333K) of 8: 41
HPLC conditions for 8: Chiralpak OJ- H column [hexane/ i- PrOH (80:20) 1 ml/min] Racemic: (S)- 8: (R)- 8: 42