KAWADA ET AL.
3
purified by flash column chromatography on silica gel
with a 50:1‐20:1 mixture of CHCl3 and MeOH to afford
the pure 1b (342 mg, 87%). White powder; mp 124‐
1H), 3.70 (brs, 2H), 4.30 (brs, 1H), 7.15‐7.19 (m, 1H),
7.24‐7.30 (m, 3H), 7.60 (d, J = 7.8 Hz, 1H), 7.92 (brs,
1H); 13C NMR (100 MHz, CDCl3): δ = 23.0, 27.3, 37.3,
44.5, 45.0, 46.7, 57.2, 59.1, 108.4‐118.9 (Complex signals
of ‐CF2‐ and ‐CF3), 125.8, 128.0, 129.2, 139.3, 182.2;
HRMS (ESI‐TOF): calcd for C19H24N4O2F9S2 (M + H)+:
125°C; [α]25 = − 82.2° (c 0.50, CHCl3); 1H NMR
D
(400 MHz, CDCl3): δ = 0.92 (d, J = 6.8 Hz, 3H), 0.94 (d,
J = 6.8 Hz, 3H), 1.62‐1.72 (m, 1H), 1.7‐1.83 (m, 1H),
2.02‐2.10 (m, 2H), 2.20 (brs, 1H), 3.22‐3.28 (m, 2H), 3.40
(d, J = 12.2 Hz, 2H), 3.70‐3.84 (m, 3H), 4.23 (brs, 1H),
6.83 (brs, 1H), 7.05 (brs, 1H), 8.13 (brs, 1H); 13C NMR
(100 MHz, CDCl3): δ = 18.3, 18.9, 23.8, 28.6, 32.3, 44.6,
47.0, 47.7, 59.4, 61.8, 109.2‐119.0 (Complex signals of
―CF2― and ―CF3), 183.4; HRMS (ESI‐TOF): calcd for
C15H24N4O2F9S2 (M + H)+: 527.1191, found: 527.1201;
Anal. Calcd for C15H23N4O2F9S2: C, 34.22; H, 4.40; N,
10.64. Found: C, 33.98; H, 4.36; N, 10.45
575.1191,
found:
527.1196;
Anal.
Calcd
for
C19H23N4O2F9S2: C, 39.72; H, 4.04; N, 9.75. Found: C,
39.73; H, 4.11; N, 9.75
2.2 | Typical procedure for a conjugate
addition using organocatalyst 1a (Table 3)
To a solution of dimethyl 2‐(4‐nitrobenzylidene)malonate
(5a, 53.1 mg, 0.200 mmol) and organocatalyst 1a
(21.1 mg, 0.040 mmol) in cyclohexanone (311 μL,
3.00 mmol) was added water (0.2 mL) at room tempera-
ture. After stirring at room temperature for 48 hours,
the reaction mixture was directly purified by flash col-
umn chromatography on silica gel with a 5:1 mixture of
hexane and AcOEt to afford the pure 6a (57.5 mg, 72%)
as a white powder
2.1.3 | Preparation of the organocatalyst
1c
To a stirred solution of tert‐butyl (S)‐2‐(isothiocyanatomethyl)
pyrrolidine‐1‐carboxylate50 (769 mg, 3.17 mmol) in THF
(32 mL) was added (S)‐N‐(2‐amino‐3‐phenylpropyl)‐
perfluorobutanesulfonamide (2c)45 (1.37 g, 3.17 mmol). The
reaction mixture was stirred at room temperature for
20 hours. The solvent was removed under reduced pressure.
The residue was purified by flash column chromatography
on silica gel with a 5:1‐1:1 mixture of hexane and ethyl ace-
tate to afford the pure 3c (1.36 g, 64%). White powder; mp
2.2.1 | Dimethyl 2‐{(S)‐(4‐nitrophenyl)
[(1S)‐2‐oxocyclohexyl]methyl}
propanedioate (6a)39
69‐71°C; [α]26 = − 12.8° (c 1.00, CHCl3), 1H NMR
D
(400 MHz, CDCl3): δ = 1.49 (s, 9H), 1.77‐2.00 (m, 4H), 2.78
(brs, 1H), 2.94‐2.99 (m, 1H), 3.06‐3.11 (m, 1H), 3.21 (brs,
1H), 3.29‐3.38 (m, 2H), 3.47 (brs, 1H), 3.63 (d, J = 12.2 Hz,
1H), 3.77 (brs, 1H), 5.05 (brs, 1H), 7.19‐7.23 (m, 1H), 7.26‐
7.28 (m, 4H), 7.57 (brs, 1H), 8.21 (brs, 1H); 13C NMR
(100 MHz, CDCl3): δ = 23.5, 28.5, 30.2, 37.8, 46.7, 48.7,
55.6, 56.6, 81.4, 108.4‐118.7 (Complex signals of ―CF2―
and ―CF3), 126.9, 128.7, 129.3, 137.0, 156.4, 180.9; HRMS
(ESI‐TOF): calcd for C24H31N4O4F9S2Na (M + Na)+:
697.1535, found: 649.1543
87% ee: Enantiomeric excess was determined by HPLC
with ChiralPak AS‐H column (hexane/2‐propanol = 94:6),
flow rate = 1.0 mL/min; λ = 254 nm; tmajor = 35.2 min,
tminor = 42.6 min.
2.2.2 | Dimethyl 2‐{(S)‐(3‐nitrophenyl)
[(1S)‐2‐oxocyclohexyl]methyl}
propanedioate (6b)39
To a stirred solution of compound 3c (1.36 mg,
2.00 mmol) in CH2Cl2 (20 mL) was added TFA
(1.6 mL) at 0°C. After stirring at room temperature for
20 hours, the reaction mixture was added saturated
aqueous NaHCO3 and extracted three times with CHCl3.
The CHCl3 layers were combined, washed with brine,
dried over anhydrous Na2SO4, and evaporated. The resi-
due was purified by flash column chromatography on
silica gel with a 50:1‐10:1 mixture of CHCl3 and MeOH
to afford the pure 1c (1.09 g, 95%). White powder; mp
85% ee: Enantiomeric excess was determined by HPLC
with
ChiralPak
AS‐H
column
(hexane/2‐
propanol
=
80:20), flow rate
=
0.4 mL/min;
λ = 254 nm; tmajor = 35.1 min, tminor = 37.3 min.
2.2.3 | Dimethyl 2‐{(S)‐(2‐nitrophenyl)
[(1S)‐2‐oxocyclohexyl]methyl}
propanedioate (6c)39
204°C (decompose); [α]26 = − 19.1° (c 0.50, DMSO‐
84% ee: Enantiomeric excess was determined by HPLC
with ChiralCel OJ‐H column (hexane/2‐propanol = 90:10),
flow rate = 0.8 mL/min; λ = 254 nm; tmajor = 37.9 min,
tminor = 39.5 min.
D
d6); 1H NMR (400 MHz,DMSO‐d6): δ = 1.59‐1.64
(m, 1H), 1.77‐1.93 (m, 2H), 1.95‐2.03 (m, 1H), 2.78‐2.83
(m, 2H), 3.05 (brs, 2H), 3.08‐3.20 (m, 2H), 3.61 (brs,