N.A. Paras et al. / Tetrahedron 65 (2009) 3232–3238
3237
vacuo to give a red-orange oil. Purification of the crude residue by
silica gel chromatography (gradient elution: 5–20% EtOAc in hex-
anes) afforded the product (R)-3-(2-methoxy-5-methyl-4-(1-pyr-
rolidino)-phenyl)-dihydrocinnamaldehyde as a colorless oil in 88%
yield (571 mg, 1.77 mmol); 83% ee. IR (film) 2959, 2860, 2817, 1723,
(0.6 mL) was added in one portion. After 10 min, the reaction
mixture was quenched with saturated aq sodium bicarbonate. The
mixture was diluted with diethyl ether and stirred at ambient
temperature until most of the ammonia had evaporated. The
resulting ether suspension was diluted with water and the phases
were separated. The aqueous layer was extracted with ether
(2ꢂ5 mL) and the combined organics were washed with brine
(2ꢂ5 mL) and dried over sodium sulfate. Concentration and sub-
sequent purification via silica gel chromatography (25% EtOAc/1%
triethylamine/74% hexanes) afforded 10 in 82% yield (478 mg,
1.41 mmol). IR (film) 2963, 2867, 2834, 1494, 1456, 1381, 1360, 1241,
1611, 1569, 1505, 1445, 1403, 1320, 1222, 1114, 1022, 700 cmꢁ1
;
1H
NMR (300 MHz, CDCl3)
d
9.71 (t, J¼2.2 Hz, 1H, CHO), 7.28–7.32 (m,
4H, ArH), 7.16–7.24 (m, 1H, ArH), 6.80 (s, 1H, ArH), 6.44 (s, 1H, ArH),
4.94 (t, J¼8.0 Hz, 1H, Ar2CH), 3.80 (s, 3H, OCH3), 3.19–3.23 (m, 4H,
N(CH2)2), 3.09 (dd, J¼2.2, 8.2 Hz, 2H, CH2CHO), 2.23 (s, 3H, ArCH3),
1.90–2.00 (m, 2H, CH2(CH2)2CH2); 13C NMR (75 MHz, CDCl3)
d
202.6, 155.3, 149.0, 143.8, 1314, 128.6, 128.2, 126.4, 122.7, 120.2,
99.8, 55.8, 51.3, 49.0, 38.3, 25.4, 20.5; HRMS [EIþ] requires m/z
323.1885 for [M]þ, found m/z 323.1896; [
1162, 1115, 1036, 804, 735, 698 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.20–7.32 (m, 4H, ArH), 7.14 (tt, J¼1.8, 6.9 Hz, 1H, ArH), 7.08 (d,
a]
D þ20.9 (c 0.95, CHCl3).
J¼2.3 Hz, 1H, ArH), 6.95 (dd, J¼1.5, 8.5 Hz, 1H, ArH), 6.72 (d,
J¼8.1 Hz, 1H, ArH), 4.36 (t, J¼7.7 Hz, 1H, Ar2CH), 3.75 (s, 3H, OCH3),
2.98 (dt, J¼6.6, 6.6 Hz, 2H, CH2N(i-Pr)2), 2.23–2.38 (m, 2H, N(CH)2),
2.27 (s, 3H, ArCH3), 2.12–2.17 (m, 2H, CH2(CH2)2CH), 0.94 (d,
The enantiomeric ratio of the product was determined by HPLC
analysis of the corresponding alcohol (obtained by NaBH4 re-
duction) using a Chiralpak AD column (0.46ꢂ25 cm) and AD guard
(0.46ꢂ5 cm) (5.0% isopropanol/hexanes, 1 mL/min);
tR¼13.6 min, R isomer tR¼16.1 min.
S
isomer
J¼6.5 Hz, 12H, N(CH(CH3)2)2); 13C NMR (75 MHz, CDCl3)
d 155.1,
145.4, 133.7, 129.8, 128.6, 128.4, 128.3, 127.4, 125.9, 110.9, 55.8, 49.0,
In a dry 10 mL round-bottom flask equipped with a magnetic
44.4, 41.5, 37.3, 21.0, 20.8; HRMS [EIþ] requires m/z 339.2562 for
stir bar, a solution of (R)-3-(2-methoxy-5-methyl-4-(1-pyrroli-
[M]þ, found m/z 339.2564; [
a
]
D
ꢁ6.14 (c 0.95, CHCl3).
dino)-phenyl)-dihydrocinnamaldehyde
(571 mg,
1.77 mmol,
1.00 equiv) in THF (4.0 mL) was treated with diisopropylamine
(0.722 mL, 3.54 mmol, 2.00 equiv) and sodium triacetoxyborohy-
dride (0.746 g, 3.54 mmol, 2.00 equiv). The reaction mixture was
stirred for 6 h at ambient temperature and then diluted with 50 mL
of Et2O. The suspension was then treated with 25 mL aq 2 N NaOH.
The layers were separated and the aqueous phase was extracted
with 2ꢂ20 mL Et2O. The combined organics were washed with
brine, dried over Na2SO4, and concentrated in vacuo to afford the
product as a colorless oil in 97% yield (702 mg, 1.71 mmol) without
further purification. IR (film) 2964, 2871, 2806, 1611, 1502, 1458,
3.3.14. (R)-Tolterodine: (R)-diisopropyl-[3-(2-hydroxy-5-methyl-
phenyl)-3-phenyl]-amine
In a dry 10 mL round-bottom flask equipped with a magnetic
stir bar, a solution of 7 (478 mg, 1.41 mmol, 1.00 equiv) in CH2Cl2
(1.0 mL) was cooled to ꢁ78 ꢀC. A solution of boron tribromide
(1.00 M in CH2Cl2, 2.71 mL, 2.71 mmol, 1.91 equiv) was added
dropwise over the course of 30 min. The resulting solution was
stirred for an additional 30 min before the reaction vessel was
transferred to an ice-water bath. The reaction mixture was main-
tained at 0 ꢀC for 1 h then cooled to ꢁ78 ꢀC, and quenched with
methanol. The mixture was then allowed to warm to ambient
temperature and neutralized with saturated aq NaHCO3. The mix-
ture was then diluted with 50 mL of CH2Cl2 and treated with 75 mL
of saturated aq NH4Cl. The layers were separated and the aqueous
layer was extracted with 3ꢂ50 mL CH2Cl2. The organics were
combined, dried over Na2SO4, and concentrated. The residue was
purified by column chromatography (25–50% i-PrOH/CH2Cl2) to
afford (R)-tolterodine in 91% yield (418 mg) as a colorless oil, which
solidified on standing; 81% ee. This material was spectroscopically
identical to the literature compound in all respects. The enantio-
meric ratio of the product was determined by HPLC ChromTech
Chiral-AGP (0.2ꢂ10 cm) (isopropanol/0.01 M potassium phosphate
buffer 0.22 mL/min); S isomer tR¼13.6 min, R isomer tR¼16.1 min.
The tartrate salt was prepared and recrystallized to optical purity as
previously described.9
1440, 1354, 1317, 1220, 1114, 699 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
7.20–7.32 (m, 4H, ArH), 7.12 (tt, J¼2.2, 7.1 Hz, 1H, ArH), 6.99 (s, 1H,
ArH), 6.41 (s, 1H, ArH), 4.24 (t, J¼7.7 Hz, 1H, Ar2CH), 3.74 (s, 3H,
OCH3), 3.10–3.22 (m, 4H, N(CH2)2), 2.98 (dt, J¼6.6, 6.6 Hz, 2H,
CH2N(i-Pr)2), 2.26–2.38 (m, 2H, N(CH)2), 2.24 (s, 3H, ArCH3), 1.90–
2.00 (m, 2H, CH2(CH2)2CH2), 0.94 (d, J¼6.5 Hz, 12H, N(CH(CH3)2)2);
13C NMR (75 MHz, CDCl3)
d 155.5, 148.1, 145.9, 130.8, 128.3, 128.2,
125.6, 125.3, 120.3, 100.1, 56.0, 51.3, 49.3, 44.8, 41.3, 37.6, 25.3, 21.0,
20.9, 20.3; HRMS [EIþ] requires m/z 408.3141 for [M]þ, found m/z
408.3148; [
a
]
D
þ1.20 (c 0.48, CHCl3).
3.3.13. (R)-Diisopropyl-[3-(2-methoxy-5-methyl-phenyl)-3-
phenyl]-amine (10)
In a dry 10 mL round-bottom flask equipped with a magnetic
stir
bar,
methyl
trifluoromethanesulfonate
(0.600 mL,
5.30 mmol, 3.00 equiv) was added to a stirring solution of 9
(702 mg, 1.71 mmol, 1.00 equiv) in CH2Cl2 (8.8 mL). The result-
ing mixture was stirred at ambient temperature for 20 h. The
volatiles were then evaporated to afford the corresponding
ammonium salt quantitatively (1.25 g, 1.25 mmol), which was
used without further purification. 1H NMR (300 MHz, CD3OD)
Acknowledgements
Financial support was provided by the NIHGMS (R01
GM078201-01-01) and kind gifts from Amgen and Merck. This ar-
ticle is dedicated to Justin ‘sweet hands’ DuBois on the occasion of
him winning the Tetrahedron Young Investigator Award.
d
7.43 (s, 1H, ArH), 7.19–7.39 (m, 5H, ArH), 7.17 (s, 1H, ArH),
4.46–4.55 (m, 2H, ArN(CHH)2), 4.32 (dd, J¼6.0, 9.3 Hz, 1H,
Ar2CH), 3.87–4.06 (m, 4H, ArN(CHH)2, CHCH2CH2), 3.91 (s, 3H,
ArNCH3), 3.41 (s, 3H, OCH3), 3.23–3.35 (m, 1H, CHCH2), 3.02–
3.14 (m, 1H, CHCH2), 2.86 (s, 3H, NCH3(i-Pr)2), 2.63 (s, 3H,
ArCH3), 2.49–2.65 (m, 2H, N(CH)2), 2.31–2.38 (m, 4H,
NCH2(CH2)2), 1.21–1.39 (m, 12H, N(CH(CH3)2)2).
A solution of sodium (393 mg, 17.1 mmol, 10.0 equiv) in freshly
condensed liquid ammonia (100 mL) was prepared in a three-neck
round-bottomed flask equipped with a cold finger and a mechani-
cal stirrer. The flask was maintained at ꢁ78 ꢀC using a dry ice/ac-
etone bath. To this stirring blue mixture, a homogeneous solution of
previous salt (1.71 mmol, 1.00 equiv) in THF (12 mL) and DMF
References and notes
1. Asymmetric Friedel–Crafts alkylation reviews: (a) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550; (b) Wan, Y.; Ding, K.; Dai,
L.; Ishii, A.; Soloshonok, V. A.; Mikami, K.; Gathergood, N.; Zhuang, W.; Jor-
gensen, K. A. J. Chemtracts 2001, 14, 610; Our work: (c) Paras, N. A.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 7894; (d) Austin, J. F.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 1172; (e) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482; (f) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370; (g) Lee, S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2007, 129, 15438.