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was obtained in a lower yield due to the formation of mix-
tures of benzyl ethers or difficulties in the demethylation
using BBr3 in later stages. However, selective protection
of the phenolic OH group as its tosylate 4 (p-toluenesulfo-
nyl chloride in CH2Cl2 and aq NaOH), followed by protec-
tion of the free alcohol gave mesylate 5. Displacement of
the mesylate group of 5 with diisopropylamine (Na2CO3,
NaI, in DMF) gave tosyl protected (R)-tolterodine 6,
which was then deprotected under basic conditions to
afford (R)-tolterodine (7) in increased yield of 82%; 95%
10. (a) Da Costa, J. C. S.; Pais, K. C.; Fernandes, E. L.; De Oliveira, P. S.
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25
ee {½aꢁD +21.8 (c 1.5, CH3OH)}.16 The enantiomeric excess
of 4 was determined using Mosher’s ester analysis and
found to be 95%.
Mechanistically, it may be reasoned that the participa-
tion of the oxygen lone pair in resonance with aromatic
rings results in a higher carbonyl bond order in phenyl
esters than in the corresponding ethyl esters so that the
addition of ‘hydride’ from the reagent is faster to the more
reactive phenyl esters, which is rate determining; thus pro-
bably accounting for higher selectivity.
12. (a) Li, L.-C.; Jiang, J.-X.; Ren, J.; Ren, Yi.; Pittman, C. U., Jr.; Zhu,
H.-J. Eur. J. Org. Chem. 2006, 1981; (b) Patra, A.; Batra, S.; Bhaduri,
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In conclusion, we have shown that CoCl2ꢀ6H2O in com-
bination with NaBH4 reduces specifically both C@C bond
and ester carbonyls in the case of phenyl esters or couma-
rins in the presence of various other reducible groups such
as CN and NO2 under mild conditions to give the corres-
ponding saturated alcohols. The methodology has been
applied successfully to the synthesis of (R)-tolterodine (7)
(61% overall yield and 95% ee). Ambient reaction condi-
tions, easy handling and good chemoselectivity are advan-
tages of this methodology; an alternative to expensive
lithium aluminium hydride. The method has also proven
useful in easy reductive removal of phenolic acetates as
well.
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Acknowledgements
A.R.J. thanks CSIR, New Delhi for the award of
research fellowships. The authors are also thankful to
Dr. B. D. Kulkarni, Head, CEPD, for his constant support
and encouragement.
17. (a) Botteghi, C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O.
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References and notes
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21. Typical experimental procedure for the synthesis of (R)-2-(3-hydroxy-
1-phenylpropyl)-4-methylphenol (2b): To a mixture of coumarin 3
(944 mg, 4 mmol) in distilled ethanol (8 mL) and dry DMF (2 mL)
were added CoCl2ꢀ6H2O (9.4 mg, 1 mol %) and ligand 8 (15.9 mg, 1.2
mol %). The reaction mixture was stirred for 30 min and then cooled
to 0 °C, NaBH4 (624 mg, 16 mmol) was added and the reaction
mixture was allowed to stir at 0 °C for 36 h. After the completion of
the reaction (monitored by TLC), it was diluted with 50 mL of water
and 50 mL of ethyl acetate. The organic layer was separated, washed
with brine solution (2 ꢂ 20 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Flash column chromatographic
purification using silica gel (230–400 mesh) and petroleum ether/ethyl
acetate (70:30) as eluent afforded 948 mg of the saturated alcohol 2b
in pure form.