TABLE 1. Evaluation of Effects of Catalyst Amount, Solvent, and
Temperature
2,6-Bis((4S,5S)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyri-
dine (1). Amidoalcohol 3 (1.44 g, 2.6 mmol, 100 mol %) was
suspended in THF (80 mL) and CH2Cl2 (25 mL). Burgess reagent
(1.8 g, 7.6 mmol, 290 mol %) was added. The solid dissolved in
20 min. The reaction mixture was stirred for 17 h at room
temperature, after which time the solvents were evaporated. The
crude product was crystallized from ethyl acetate. The product was
1
collected to yield 1 (1.02 g, 76%) as colorless crystals. H NMR
entry
cat. mol %
solvent
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MTBE/CH2Cl2
MeCN
CH2Cl2
CH2Cl2
temp
yield %
% ee
(400 MHz, CDCl3) δ 8.39 (d, 2H, J ) 7.9 Hz), 7.98 (t, 1H, J )
7.9 Hz), 7.33-7.26 (m, 20H), 5.53 (d, 2H, J ) 8.4 Hz), 5.33 (d,
2H, J ) 8.4 Hz).10
1
2
3
4
5
6
7
8
9
10
5
rt
rt
rt
rt
0
75
77
97
83
95
93
88
95
82
2b
66
81
85
70a
92
92
89
89
70
0
10
10
10
10
10
10
10
0
General Procedure for the Asymmetric Conjugate Addi-
tion: (S)-3-(3-(Phenylthio)butanoyl)oxazolidin-2-one (5a). 2,6-
Bis((4S,5S)-4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine (16 mg,
0.03 mmol, 10 mol %), Sc(OTf)3 (15 mg, 0.03 mmol, 10 mol %),
and crotonoyl-oxazolidinone (47 mg, 0.3 mmol, 100 mol %) were
dissolved in CH2Cl2 (1.2 mL). The solution was stirred for 1 h at
room temperature. The mixture was then cooled to 0 °C, and
thiophenol (48 µL, 0.45 mmol, 150 mol %) was added. After stirring
for 20 h at 0 °C, the products were isolated by adding the cold
reaction mixture directly to a silica gel column and eluting with a
CH2Cl2/MeOH solvent mixture. The product was collected to yield
5a (75 mg, 95%) as a colorless oil; Rf ) 0.72 in 1:30 MeOH/CH2-
Cl2; HPLC13 Rtmajor ) 40.6 min, Rtminor ) 34.2 min, ee ) 92%;
[R]D20 ) -28 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.45
(d, 2H, J ) 7.0 Hz), 7.32-7.22 (m, 3H), 4.36 (t, 2H, J ) 8.0 Hz),
3.94 (t, 2H, J ) 8.0 Hz), 3.77 (ddq, 1H, J ) 6.8 Hz, 6.8 Hz, 6.8
Hz), 3.26 (dd, 1H, J ) 7.0 Hz, 17.0 Hz), 3.13 (dd, 1H, J ) 7.0 Hz,
17.0 Hz), 1.36 (d, 3H, J ) 6.8 Hz).9
-12
0
0
0
0
10
11
0
rt
17b
0
a Proton sponge (10 mol %) was used. b Conversion calculated by
1
integrating the H NMR spectrum.
TABLE 2. (4S,5S)-Diphenyl PYBOX (1)-Catalyzed Conjugate
Addition
entry
thiol
thiophenol
thiophene thiol
p-toluenethiol
p-chlorothiophenol
1-butanethiol
mercaptoethanol
yield %
% eea
(S)-3-(3-(Thiophen-2-ylthio)butanoyl)-oxazolidin-2-one (5b).
Yield 91% (slightly yellow oil); Rf ) 0.78 in 1:30 MeOH/CH2Cl2;
1
2
3
4
5
6
95
91
96
92
85
86
86
68
91
20
HPLC14 Rtmajor ) 59.4 min, Rtminor ) 42.2 min, ee ) 85%; [R]D
1
) -7 (c 0.3, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.40 (dd,
92
23b
81b
1H, J ) 1.2 Hz, 5.4 Hz), 7.18 (dd, 1H, J ) 1.2 Hz, 3.5 Hz), 7.01
(dd, 1H, J ) 3.5 Hz, 5.4 Hz), 4.41 (t, 2H, J ) 7.9 Hz), 4.01 (t, 2H,
J ) 7.9 Hz), 3.53 (ddq, 1H, J ) 6.8 Hz, 6.8 Hz, 6.8 Hz), 3.33 (dd,
1H, J ) 6.8 Hz, 17.3 Hz), 3.07 (dd, 1H, J ) 6.8 Hz, 17.3 Hz),
1.34.(d, 3H, J ) 6.8 Hz).9
a Absolute stereochemistries were established for entries 1 and 3 (ref 8)
and 2 (ref 9), others by analogy. b No complete conversion.
(S)-3-(3-(p-Tolylthio)butanoyl)-oxazolidin-2-one (5c). Yield
96% (colorless oil); Rf ) 0.76 in 1:30 MeOH/CH2Cl2; HPLC13
Rtmajor ) 35.2 min, Rtminor ) 29.1 min, ee ) 86%; [R]D20 ) -22 (c
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.34 (d, 2H, J ) 8.0
Hz), 7.12 (d, 2H, J ) 8.0 Hz), 4.37 (t, 2H, J ) 8.0 Hz), 3.96 (t,
2H, J ) 8.0 Hz), 3.69 (ddq, 1H, J ) 6.8 Hz, 6.8 Hz, 6.8 Hz), 3.25
(dd, 1H, J ) 6.8 Hz, 17.0 Hz), 3.10 (dd, 1H, J ) 6.8 Hz, 17.0 Hz),
2.33 (s, 3H), 1.33.(d, 3H, J ) 6.8 Hz).10
then obtained by workup with column chromatography. The
Sc(III) triflate complex of (4S,5S)-diphenyl pybox gives products
5a and 5b with an absolute configuration (S). With aryl thiols,
yields and enantiomeric excesses were high. 1-Butanethiol
reacted more slowly than its aromatic counterparts. Erosion in
enantioselectivity was also witnessed. The results are sum-
marized in Table 2.
In conclusion, we have demonstrated the effectiveness of the
Sc complex of (4S,5S)-diphenyl PYBOX for the enantioselective
conjugate addition of thiols to 3-crotonoyl-2-oxazolidinone.
Further studies on the scope of PYBOX-derived catalysts in
asymmetric Michael addition of thiols are currently underway.
(S)-3-(3-(4-Chlorophenylthio)butanoyl)oxazolidin-2-one (5d).
Yield 92% (colorless oil); Rf ) 0.74 in 1:30 MeOH/CH2Cl2;
20
HPLC13 Rtmajor ) 38.9 min, Rtminor ) 35.4 min, ee ) 86%; [R]D
) -21 (c 1.0, CH2Cl2); IR (CH2Cl2, cm-1): 3064, 2970, 2927,
2871, 1783, 1702, 1477, 1387. 1H NMR (400 MHz, CDCl3) δ 7.39
(d, 2H, J ) 8.5 Hz), 7.28 (d, 2H, J ) 8.5 Hz), 4.39 (t, 2H, J ) 8.1
Hz), 3.97 (t, 2H, J ) 8.1 Hz), 3.73 (ddq, 1H, J ) 6.8 Hz, 6.8 Hz,
6.8 Hz), 3.26 (dd, 1H, J ) 6.8 Hz, 17.1 Hz), 3.11 (dd, 1H, J ) 6.8
Hz, 17.1 Hz), 1.35.(d, 3H, J ) 6.8 Hz). 13C NMR (100 MHz,
CDCl3) δ 170.9, 153.3, 134.2, 133.6, 132.5, 129.0, 62.1, 42.4, 42.2,
39.2, 21.2. HRMS (ESI) calcd for C13H14NO3NaSCl [M + Na]+
322.0269, found 322.0281.
Experimental Section
N2,N6-Bis((1S,2S)-2-hydroxy-1,2-diphenylethyl)pyridine-2,6-
dicarboxamide (3). (1R,2S)-2-Amino-1,2-diphenylethanol (2.1 g,
10.0 mmol, 200 mol %) and triethylamine (3.4 mL, 24.5 mmol,
490 mol %) were dissolved in CH2Cl2 (35 mL), and the mixture
was cooled to 0 °C. 2,6-Pyridinedicarbonylchloride (1.0 g, 5.0
mmol, 100 mol %) was dissolved in CH2Cl2 (15 mL) and added to
the reaction mixture via cannula. The cooling bath was removed,
and the solution was stirred for 20 h at room temperature. The
reaction mixture was filtered, and the solid was washed with water
4 times. The product was collected to yield 3 (2.6 g, 92%) as a
(S)-3-(3-(Butylthio)butanoyl)-oxazolidin-2-one (5e). Yield 66%
(colorless foam); Rf ) 0.63 in 1:30 MeOH/CH2Cl2; HPLC13 Rtmajor
20
) 24.9 min, Rtminor ) 22.6 min, ee ) 68%; [R]D ) -1 (c 1.0,
CH2Cl2); IR (CH2Cl2, cm-1): 3062, 2962, 2929, 2874, 1782, 1702,
1
1386. H NMR (400 MHz, CDCl3) δ 7.44 (t, 2H, J ) 8.1 Hz),
4.34 (t, 2H, J ) 8.1 Hz), 3.97 (t, 2H, J ) 8.1 Hz), 3.25 (m, 1H),
2.97 (m, 1H), 2.51 (t, 2H, J ) 7.3 Hz), 1.5 (tt, 2H, J ) 7.3 Hz, 7.3
1
white solid. H NMR (400 MHz, CDCl3) δ 8.99 (d, 2H, J ) 8.8
Hz), 8.12-8.04 (m, 3H), 7.42-7.14 (m, 20H), 5.84 (d, 2H, J )
(13) HPLC analysis was performed on a Daicel OD column eluting with
10% 2-propanol/hexanes.
4.8 Hz), 5.25-5.14 (m, 4H).10
5412 J. Org. Chem., Vol. 72, No. 14, 2007