distillation at reduced pressure (81 °C/32 mmHg), so
furnishing olefin 2a as a colorless oil (3.8 g, 90% yield). 1H
NMR δ 7.41-6.85 (m, 8H), 5.88-5.86 (d, J ) 1.21 Hz,
1H), 5.44-5.42 (d, J ) 1.21 Hz, 1H), 5.02 (s, 1H), 2.31 (s,
3H). MS: m/e 210 (M+, 57), 209 (100), 195 (39), 165 (21),
77 (12). Anal. Calcd for C15H14O: C, 85.68; H, 6.71.
Found: C, 85.42; H, 6.68.
(CO)2acac/(S,R)-Binaphos (see Table 2) was oxidized to the
corresponding 3-[(2-acetoxy-5-methy)phenyl]-3-phenylpro-
panoic acid (5b) with NaClO2, H2O2, and NaH2PO4 in CH3-
CN at 10 °C.24 The enantiomeric excess of 5b was
determined by HPLC analysis using a Chiracel OD 250 mm
× 4.6 mm column (n-hexane/2-propanol/formic acid ) 90/
10/1, flux 0.5 mL/min, loop 10 µL, wavenumber 254 nm):
ee ) 8%. Compound 5b: 1H NMR δ 9.71 (s, 1H), 7.45-
6.71 (m, 8H), 4.8-4.68 (m, 1H), 3.3-2.98 (m, 2H), 2.35
(s, 3H), 1.80 (s, 3H). MS: m/e 298 (M+, 1), 280 (1), 238
(100), 220 (30), 195 (57), 165 (11), 91 (4), 77 (5). Anal.
Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.28;
H, 6.06.
1-[(2-Acetoxy-5-methyl)phenyl]-1-phenylethylene (2b).
This olefin was prepared in 90% yield, starting from olefin
2a, according to a described procedure.22 Bp 175 °C/0.1
1
mmHg. H NMR δ 7.45-6.85 (m, 8H), 5.88-5.86 (d, J )
1.21 Hz, 1H), 5.44-5.42 (d, J ) 1.21 Hz, 1H), 2.32 (s, 3H),
1.80 (s, 3H). MS: m/e 252 (M+, 22), 237 (12), 209 (100),
195 (26), 165 (14), 43 (31). Anal. Calcd for C17H16O2: C,
80.93; H, 6.39. Found: C, 80.65; H, 6.37.
(R,S)-Tolterodine (1). In a 150-mL stainless steel reaction
vessel a solution of 3a (1 g, 4.2 mmol) in 5 mL methanol
was slowly added, under a nitrogen purge, to Pd/C (5%) (0.11
g, 1.03 mmol). Anhydrous N,N-diisopropylamine (0.74 mL,
5.3 mmol) was added and the reactor pressurized to 3 atm
with H2. After 16 h at 50 °C the reactor was cooled to room
temperature and the residual gas released. The reaction
mixture was filtered, and solvent and excess HN(iPr)2 were
distilled off in vacuo; the remaining oil was purified by flash
chromatography as described by Andersson at al.5 Concen-
tration in vacuo yielded 1.32 g (96.8% yield) of (R,S)-
Hydroformylation of 2a. A 150-mL stainless steel
reaction vessel was charged under a nitrogen purge with 2
mmol of olefin 2a, 0.008 mmol of rhodium catalyst and 5
mL of anhydrous toluene. The reactor was then pressurized
to 100 atm with syngas (CO/H2 ) 1) and heated at 80-100
°C for 24-72 h (see Table 1). For analytical purposes
aldehyde 3a (hemiacetalic form), a white solid, was recov-
ered from the reaction mixture by flash silica gel chroma-
1
tography (hexane/ether, 80/20). Mp 82.5 °C. H NMR δ
1
tolterodine 1 as a colorless oil. H NMR δ 7.35-6.83 (m,
7.40-6.60 (m, 8H), 5.67 (t, J ) 3.05, 1H), 4.36-4.28 (m,
1H), 2.34-2.20 (m, 2H), 2.16 (s, 3H). MS: m/e 240 (M+,
100), 222 (66), 221 (72), 195 (57), 145 (70), 115 (25). Anal.
Calcd for C16H16O2: C, 80.0; H, 6.71. Found: C, 79.76; H,
6.69.
8H), 6.55 (s, 1H), 4.53-4.46 (m, 1H), 3.24 (q, J ) 6.71,
2H), 2.77-2.69 (m, 2H), 2.43-2.32 (m, 2H), 2.13 (s, 3H),
1.14 (d, J ) 6.71, 6H), 1.09 (d, J ) 6.71, 6H). 13C NMR
(300 MHz) δ 153.11 (CHOH), 144.6 (ArCHCH), 132.3-
125.9 (5C, C6H3), 77.45.76.6 (5C, C6H5), 48.2 [N(CHCH3)2],
42.2 (NCH2), 39.5 [(Ar)(Ph)CH], 33.2 (CHCH2CH2), 20.9
(PhCH3), 19.8 [CH(CH3)2], 19.4 [CH(CH3)2]. MS: m/e 325
(M+, 8), 310 (13), 114 (100), 100 (5). Anal. Calcd for C18H18-
NO3: C, 81.18; H, 9.6; N, 4.3. Found: C, 80.94; H,9.56; N,
4.1
(R,S)-Tolterodine (1) by Hydrogenation of Enamine
6. A solution of hemiacetal 3a (0.5 g, 2.08 mmol) and
anhydrous N,N-diisopropylamine (1.05 mL, 7.5 mmol) in 2
mL of anhydrous toluene were slowly stirred, under a
nitrogen purge, at 50 °C in the presence of freshly activated
4 Å molecular sieves (2 g). After 72 h the conversion of 3a
to N,N-diisopropyl-3-[(2-Hydroxy-5-methyl)phenyl]-3-phe-
nylprop-1-enamine (6) was complete; the molecular sieves
were filtered off, and the solvent was evaporated at reduced
pressure. Compound 6 was characterized by GC/MS; MS:
m/e 323 (M+, 50), 308 (5), 280 (7), 126(100), 84 (94), 71
(91), 43 (59).
Hydroformylation of 2a in Aqueous Biphase Medium.
In a Schlenk tube [Rh(COD)Cl]2 (4.0 mg, 0.008 mmol) and
TPPTS (27.6 mg, 0.048 mmol) were dissolved under nitrogen
in H2O (2.5 mL); then, a solution of 2a (0.5 g, 2.0 mmol) in
toluene (3 mL) was added. The Schlenk tube containing the
two-phase liquid mixture was transferred to a 150-mL
stainless steel autoclave under nitrogen, pressurized to 100
atm with syngas (CO/H2 ) 1) and heated at 100 °C for 48
h (see Table 1). The reactor was then cooled to room
temperature and the residual gases released. The organic
phase was separated and dried on MgSO4, and toluene was
removed in vacuo; the aldehyde 3a (hemiacetalic form) was
recovered and identified as previously described.
Hydroformylation of 2b. A 150-mL stainless steel
reaction vessel was charged under a nitrogen purge with 2
mmol of olefin 2b, 0.008 mmol of rhodium catalyst, 0.0032
mmol of an external ligand, and 5 mL of anhydrous toluene.
The reactor was then pressurized to 100 atm with syngas
(CO/H2 ) 1) and heated at 80-100 °C for 24-72 h (see
Table 2). For analytical purposes aldehyde 3b, a pale yellow
oil, was recovered from the reaction mixture by flash silica
gel chromatography (hexane/ether, 80/20). 1H NMR δ 9.73
(t, J ) 1.83, 1H), 7.45-6.71 (m, 8H), 4.8-4.68 (t, J ) 7.32,
1H), 3.26-3.0 (m, 2H), 2.35 (s, 3H), 1.81 (s, 3H). MS: m/e
282 (M+, 6), 240 (15), 222 (100), 196 (10), 145 (19). Anal.
Calcd for C18H18O3: C, 76.57; H, 6.42. Found: C, 76.37;
H, 6.40.
The enamine 6, recovered from the reaction mixture
without any further purification, was dissolved in anhydrous
toluene (10 mL) and hydrogenated in the presence of PtO2
(5.0 mg, 0.019 mmol) at 120 °C and 80 atm H2 for 24 h.20
Tolterodine was obtained in about 90% yield and character-
ized as described above.
Acknowledgment
We are grateful to Dr. Daniele Pegoraro and Dr. Daniela
Mazza for the very useful experimental assistance.
Received for review January 28, 2002.
OP020014K
Determination of the Enantiomeric Excess. The hy-
droformylation reaction mixture of 2b catalyzed by Rh-
Vol. 6, No. 4, 2002 / Organic Process Research & Development
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