1.
The Teflon paddle of the mechanical stirrer is 6.5 cm in length and 1.8 cm in height.
2.
L-Alanine tert-butyl ester hydrochloride (99%) was purchased from Acros Organics and used as received.This reagent is also available from Watanabe Chemical Industries, Ltd.and Sigma-Aldrich Co.
3.
D-Alanine and DL-alanine tert-butyl ester hydrochloride can be also used as starting materials instead of L-alanine tert-butyl ester hydrochloride.
4.
4-Chlorobenzaldehyde (>98.5%) was purchased from Acros Organics and used as received.This reagent is also available from Wako Pure Chemical Industries, Ltd.
5.
Triethylamine (>99%) was purchased from Sigma-Aldrich Co.and used as received.This reagent is also available from Kanto Chemical Co., Inc.
6.
The internal temperature was kept below 30 °C during the addition of triethylamine.
7.
1H NMR analysis of the reaction mixture indicated nearly complete consumption of the starting materials.An aliquot of the reaction mixture (30 µL) was diluted with DMSO-d6 (0.7 mL), and analyzed by 1H NMR [4-chlorobenzaldehyde: d 10.00 (ArCHO, s, 1H), aldimine product: d 8.39 (ArCH=N, s, 1H)].A residual amount of 4-chlorobenzaldehyde (1%) was observed after 4 h.
8.
The crude aldimine product includes 1mol % of 4-chlorobenzaldehyde (determined by 1H NMR analysis).
9.
The product gradually decomposes in air at room temperature.The compound should be kept in a refrigerator under an inert atmosphere where it is stable for at least 2 weeks.The product solidifies to a low-melting, white solid upon storage at -20 °C. 1H NMR pdf (500 MHz, DMSO-d6) δ: 1.34 (d, J = 6.8 Hz, 3 H), 1.39 (s, 9 H), 4.09 (q, J = 6.6 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.78 (d, J = 8.6 Hz, 2 H), 8.39 (s, 1 H); 13C NMR pdf (125 MHz, DMSO-d6) δ: 19.0, 27.6, 67.1, 80.3, 128.8, 129.7, 134.6, 135.5, 161.4, 170.9; 1H NMR pdf (500 MHz, CDCl3) δ: 1.47 (s, 9 H), 1.48 (d, J = 7.1 Hz, 3 H), 4.04 (q, J = 6.9 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 2 H), 7.71 (d, J = 8.6 Hz, 2 H), 8.25 (s, 1 H); 13C NMR pdf (125 MHz, CDCl3) δ: 19.5, 28.2, 68.5, 81.4, 128.7, 129.8, 134.6, 137.0, 161.3, 171.8; IR (neat) 2975, 2926, 2871, 1732, 1642, 1365, 1153, 1125, 1087, 844, 824 cm-1.HRMS (ESI-TOF) m/z calcd for C14H19 ClNO2+: 268.1104 ([M + H]+).Found: 268.1108.
10.
The full amount of crude aldimine product in procedure A was used for the next step (procedure B).Reagent equivalents in procedure B were based upon amount of 4-chlorobenzaldehyde (26.2 mmol).
11.
(S)-4,4-Dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepinium bromide (Nagase purity) was purchased from Sigma-Aldrich Co.and used as received.This catalyst is also available from Kanto Chemical Co., Inc.and Strem Chemicals, Inc.
12.
Benzyl bromide (98%) was purchased from Sigma-Aldrich Co.and used as received.
13.
Cesium hydroxide solution (80 wt %) was prepared from cesium hydroxide monohydrate (96%) purchased from Alfa-Aesar Co.as follows: Cesium hydroxide monohydrate (44.81 g) was weighed into a neoprene bottle.The neoprene bottle was then cooled in an ice bath, followed by addition of distilled water (5.2 mL).The solution was shaken to incorporate solid into solution and allowed to stand for 2 h to ensure dissolution.The homogenous, colorless solution was stored in a neoprene bottle.[Caution: Cooling with an ice bath is necessary for preparation of 80 wt % cesium hydroxide solution.The dissolution of cesium hydroxide in water is very exothermic.] Cesium hydroxide monohydrate (>95%) is also available from Sigma-Aldrich Co.
14.
During the addition of the cesium hydroxide solution, the internal temperature was kept under 5 °C.
15.
1H NMR analysis of the reaction mixture indicates complete consumption of the starting materials.An aliquot of the reaction mixture (30 µL) was diluted with d6-DMSO (0.7 mL), and analyzed by 1H NMR [starting aldimine substrate: d 8.39 (ArCH=N, s, 1H), alkylation product: d 8.25 (ArCH=N, s, 1H)].The checkers observed highly variable reaction times ranging from 18 h to 48 h to reach full conversion.
16.
Citric acid monohydrate (>99.0%) was purchased from Sigma-Aldrich Co.and used as received.This reagent is also available from Kanto Chemical Co., Inc.
17.
Sodium hydroxide solution (50 wt %) was purchased from Acros Organics and used as received.This reagent is also available from Kanto Chemical Co., Inc.During the addition of 50 wt % sodium hydroxide solution, the internal temperature was kept under 37 °C.A room temperature water bath was necessary to control the internal temperature.
18.
Silica gel was purchased from SiliCycle., Inc.(SiliaFlash F-60-40/63).TLC: Rf 0.11 (hexane/EtOAc, 1:1, visualized using ninhydrin stain).
19.
Column chromatography was performed without collecting a forecut and 20 mL fractions were collected using 16 mm × 150 mm test tubes.The desired product tailed significantly and was isolated from fractions 13 through 64 using rotary evaporation (15 mmHg, 35 °C).
20.
The final product was obtained as a pale yellow oil but did not show the presence of an impurity by 1H NMR.The colored impurity was removed from a portion of the final product (1.0 mL) by Kugelrohr distillation at 70 °C under reduced pressure (4.3 × 10-5 mmHg) to afford a colorless oil (956 mg) prior to elemental analysis and further characterization.Characterization data for the product: [α]24D = 15.3 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d: 1.34 (s, 3 H), 1.46 (s, 9 H), 1.51 (br s, 2 H), 2.77 (d, J = 13.2 Hz, 1 H), 3.11 (d, J = 13.2 Hz, 1 H), 7.21-7.29 (m, 5 H); 13C NMR (125 MHz, CDCl3) d: 27.1, 28.1, 46.6, 58.9, 81.2, 126.9, 128.3, 130.3, 137.0, 176.4; IR 3372, 3310, 2975, 2926, 1722, 1365, 1153, 1105, 848, 737, 699 cm-1.HRMS (ESI-TOF) m/z calcd for C14H22NO2+: 236.1651 ([M + H]+); Found: 236.1657.Calcd.for C14H21NO2: C; 71.46, H; 8.99, N; 5.95.Found: C; 71.50, H; 9.14, N; 6.17.The enantioselectivity was determined by chiral stationary phase HPLC analysis [Daicel Chiralcel AD-H column, 3.3% 2-propanol/hexane, 0.50 mL/min, λ = 220 nm, 5.0 mg/mL, retention times: (R)-enantiomer (major): 13.1 min, (S)-enantiomer (minor): 22.4 min].The racemate was prepared for comparison following the above procedure by substituting tetrabutylammonium bromide as the catalyst.