2
40
E. Schmidt et al. / Journal of Catalysis 289 (2012) 238–248
0
0
0
0
0
(C8 ), 129.6 (C7 ), 127.5 (C6 ), 125.5 (C4a ), 122.8 (C5 ), 114.6
(C11), 60.2 (C8), 56.6 (C2), 42.1 (C6), 39.6 (C3), 39.2 (CH ), 27.7
(C5), 27.4 (C4), and 25.4 (C7). Due to coalescence, the signals of
O
O
O
2
Pd/Al O3
3
OH
OH
OH
OH
conditions e
0
0
0
C5 , C8, C6, and C7 are broad and the signals for C3 , C4 and C9
are obscured (in accordance to lit. [44]); [m/z (ESI) found:
73.1591 (MH; A(HCl)
5
5a
+
3
2
) , C20
H
25
N
2
O
3
S requires 373.1580].
O
2
.2.2. 9-Epi-cinchonidine dihydrochloride salt [46] (Fig. 2B)
9
tartaric acid (9.17 g, 61.1 mmol, 3.7 eq.) were dissolved in water
(100 mL), and the resulting solution was heated at reflux for
-Mesyloxycinchonidine (6.15 g, 16.5 mmol, 1.0 eq.) and L-(+)-
Pd/C
conditions f
1
7 h. The solution was cooled to 0 °C and neutralized by the addi-
tion of solid NaHCO
, and the addition was continued until pH ꢂ 10
was reached. The suspension was extracted with CH Cl , and the
combined organic phases dried over Na SO , filtered, and evapo-
rated to dryness. Purification by flash column chromatography
SiO , CH Cl /MeOH, 4:1) afforded the free base of 9-epi-cinchoni-
dine. The yellow oil was dissolved in MeOH and treated with ex-
cess HCl/MeOH (1 M). Evaporation of the solvents and
2
crystallization of the residue with MeOH ? Et O afforded 9-epi-
3
6
6a
2
2
2
4
(
2
2
2
O
O
O
O
2
Pd/Al O3
conditions g
O
O
O
O
O
cinchonidine dihydrochloride salt (2.56 g, 42%) as an off-yellow
solid.
7
7a
7b
25
D
Analysis: m.p. 165–166 °C; ½
aꢀ
þ 24:0 (c 1.1 in MeOH);
m
max
ꢁ1
(
neat)/cm
3071m, 2948m, 2503m, 2063w, 1984w, 1634m,
Scheme 2. Commonly used test reactions for the Pd-catalyzed hydrogenation of
functionalized C@C bonds.
1600s, 1546m, 1525w, 1497w, 1464m, 1382s, 1335m, 1285m,
1
8
229m, 1170w, 1092m, 1058m, 1036m, 1002m, 978m, 917s,
1
33s, 767s, 666s, 631s; H NMR (400 MHz, MeOD) d = 9.29 (1H,
benzyl amine (Sigma Aldrich, >99.5%) were used as received. The
substrates methyl benzoylformate (1, Acros organics, 99%), keto-
pantolactone (2, Hoffman-La Roche, 99%), methylglyoxal dimethyl-
acetal (3, Fluka, >97%), 2,2,2-trifluoroacetophenone (4, Sigma
Aldrich, 99%), E-2-methyl-2-hexenoic acid (5, ABCR, 98%), 2-phe-
nylcinnamic acid (6, Sigma Aldrich, 98%), 4-methoxy-6-methyl-
0
0
0
d, J 5.6, HAC2 ), 8.99 (1H, d, J 9.0, HAC5 ), 8.39 (1H, d, J 5.7, HAC3 ),
8
0
.35 (1H, dd, J 8.6 and 0.6, HAC8 ), 8.26 (1H, ddd, J 8.3, 7.0 and 0.9,
0
0
HAC7 ), 8.10 (1H, ddd, J 8.3, 7.0 and 1.1, HAC6 ), 5.87 (1H, ddd, J
7.3, 10.4 and 7.0, HAC10), 5.85 (1H, d, J 10.1, HAC9), 5.22 (1H,
1
d, J 17.2, HAC11), 5.13 (1H, d, J 10.4, HAC11), 4.05 (1H, td, J 10.1
and 7.0, HAC8), 3.88–3.98 (2H, m, HAC6), 3.72 (1H, dd, J 13.1
and 10.7, HAC2), 3.32–3.46 (2H, m, HAC2 and HAC6), 2.84–2.94
2H-pyran-2-one (7, Sigma Aldrich, 97%), and the modifiers cincho-
nidine (CD, Fluka, >98%) and cinchonine (CN, Fluka, >98%) were
used as received.
(
1H, m, HAC3), 2.18–2.31 (1H, m, HAC5), 2.03–2.16 (2H, m,
HAC4 and HAC5), 1.73–1.84 (1H, m, HAC7) and 1.38–1.48 (1H,
m, HAC7); C NMR (100 MHz, MeOD) d = 158.8 (C4 ), 145.9 (C2 ),
139.8 (C8a ), 138.9 (C10), 136.4 (C7 ), 131.8 (C6 ), 128.9 (C4a ),
1
(C8), 54.6 (C2), 42.7 (C6), 38.3 (C3), 27.7 (C4), 25.1 (C5) and 23.4
2 23 2
(C7); [m/z (ESI) found: 295.1803 (MH; A(HCl) ) , C19H N O re-
1
3
0
0
0
0
0
0
2
2
.2. Synthesis of epi-cinchonidine
0
0
0
27.0 (C5 ), 122.9 (C3 ), 122.8 (C8 ), 117.7 (C11), 70.2 (C9), 63.0
.2.1. 9-Mesyloxycinchonidine [44] (Fig. 2A)
+
Triethylamine (5.4 mL, 39.1 mmol, 2.3 eq.) and methanesulfo-
nyl chloride (2.6 mL, 34.0 mmol, 2.0 eq.) were added to a suspen-
sion of cinchonidine (5.00 g, 17.0 mmol, 1.0 eq.) in THF (100 mL)
at r.t. under an atmosphere of argon. The suspension was stirred
for 1.5 h and quenched by the addition of a saturated aqueous solu-
quires 295.1805].
To obtain the free base of epi-cinchonidine used in this study,
the dihydrochloride salt was dissolved in MeOH and neutralized
with amberlite A-21. The solution was filtered, evaporated to dry-
ness, and used immediately for hydrogenation studies.
tion of NaHCO
and the combined organic phases dried over Na
and evaporated to dryness. Purification by flash column chroma-
tography (SiO , CH Cl /MeOH, 10:1) afforded 9-mesyloxycinchoni-
3
(50 mL). The mixture was extracted with CH
2 2
Cl ,
2
SO , filtered,
4
2.3. Enantioselective hydrogenations
2
2
2
dine (6.15 g, 97%) as a white solid.
Experiments were carried out in a 50-ml, magnetically stirred
(750 rpm) stainless steel reactor, equipped with a glass liner and
PTFE cover. The pressure was controlled with a constant–volume
constant–pressure system (Büchi BPC 9901). The temperature
was regulated with a Julabo F 25 thermostat. For each substrate,
different conditions were used, which had frequently been applied
for reactions with CD as modifier.
Analysis: m.p. 128–129 °C [lit. m.p. 133–134.5 °C [45]]
2
D
5
25
D
½
a
[
ꢀ
ꢁ 71:3 (c 0.22 in MeOH) [lit. ½
aꢀ
ꢁ 70:5, c 1.02 in CH
2 2
Cl
ꢁ1
45]]
m
max (neat)/cm
3072w, 2940m, 2866w, 1636w, 1593w,
1
1
8
569w, 1510m, 1456w, 1415w, 1354s, 1245w, 1223w, 1171s,
140m, 1089w, 1068m, 1048m, 1028m, 1015m, 973m, 924s,
71s, 857s, 813m, 801m, 757s, 720m, 668m, 630m, 610m; H NMR
1
0
(
400 MHz, MeOD) d = 8.96 (1H, d, J 4.4, HAC2 ), 8.15–8.21 (2H, m,
2 3
A 5 wt.% Pt/Al O catalyst (Engelhard 4759) was used for the
0
0
0
HAC5 and HAC8 ), 7.76 (1H, ddd, J 8.4, 6.9 and 1.3, HAC7 ), 7.64
hydrogenation of C@O bonds. The catalyst was pretreated prior
to use in a fixed-bed reactor. It was heated under flowing nitrogen
up to 400 °C over 30 min, followed by a reduction in hydrogen for
60 min at the same temperature, and finally cooled down in hydro-
gen over a period of 30 min.
0
0
(
(
1H, ddd, J 8.3, 6.9 and 1.2, HAC6 ), 7.49 (1H, br, HAC3 ), 6.20
1H, br, HAC9), 5.84 (1H, ddd, J 17.4, 9.9 and 7.3, HAC10), 4.98–
5
.05 (2H, m, HAC11), 3.43 (1H, br, HAC8), 3.04–3.16 (1H, m,
HAC6), 2.96 (1H, dd, J 13.8 and 10.1, HAC2), 2.47–2.65 (5H, m,
HAC2, HAC6 and CH ), 2.25–2.31 (1H, m, HAC3), 2.04–2.15 (1H,
m, HAC7), 1.88–1.94 (1H, m, HAC4), 1.61–1.81 (3H, m, NH,
3
Conditions a: 4 mmol 1, 42 mg 5 wt.% Pt/Al
2
O
3
, 6.8
lmol mod-
ifier dissolved in 10 mL toluene, at 20 °C and 10 bar.
13
HAC5 and HAC7) and 1.50–1.61 (1H, m, HAC5);
C NMR
2 3
Conditions b: 4 mmol 2, 10 mg 5 wt.% Pt/Al O , 13.5 lmol mod-
ifier in 10 mL toluene, at ꢁ5 °C and 70 bar.
0
0
(
100 MHz, MeOD) d = 150.0 (C2 ), 148.8 (C8a ), 141.5 (C10), 130.9