Enantioselective synthesis of (R)-tolterodine using lithiation/borylation- protodeboronation methodology

Article abstract of DOI:10.1139/v2012-069

The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.

Full text of DOI:10.1139/v2012-069

965
Enantioselective synthesis of (R)-tolterodine using
lithiation/borylation–protodeboronation
methodology
Stefan Roesner and Varinder K. Aggarwal
Abstract: The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation–protodeboronation of a
homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate
reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic
ester. It was found that the latter arrangement was considerably better than the former. Further improvements were
achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the
lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a
30% overall yield and 90% ee.
Key words: asymmetric synthesis, boronic esters, gem-diarylalkyl, lithiation/borylation reaction, tolterodine.
Résumé : La synthèse du médicament : la (R)-toltérodine a été réalisé suivant une étape clé de lithiation/bo-
rylation-protodéboronation d’un carbamate homoallilyque. Deux permutations ont été évalué. Premièrement un carbamate
d’aryle et de lithuim éléctronqiuement neutre réagissant sur un estre boronique riche en électron et deuxièmement un carba-
mate d’aryle et de lithium riche en électron réagissant sur un ester boronique électroniquement neutre. Cette dernière s’est
révélée être la meilleure. D’autres améliorations ont été obtenues : notament en utilisant le bromure de magnésium en
solution dans le méthanol. Cette méthodologie donne un rendement et une énantiosélectivité élevé pour la réaction de
lithiation/borylation. L’étape clé permet de réaliser une synthèse éfficace de la (R)-toltérodine en huit étapes avec un
rendement global de 30% et un ee de 90%.
Mots-clés : synthèse asymétrique, esters boroniques, gem-diarylalkyle, réaction de lithiation/borylation, toltérodine.
processes including hydrogenation,7 hydroformylation,8 or
Introduction
arylboration.9
The enantioselective synthesis of pharmaceuticals and bio-
logically active natural products is a major theme for synthetic
chemists. In particular, the formation of chiral gem-diarylalkyl
compounds, a motif that is present in many therapeutically
important molecules, is especially challenging owing to the
lack of nearby functional groups that might be enlisted to
enable the formation of C–C bonds.1 Examples of these com-
pounds include (R)-tolterodine (1, Detrol), (ϩ)-sertraline (2,
Zoloft), and (ϩ)-indatraline (3) (Fig. 1).
(R)-Tolterodine (1) is a potent competitive muscarine
receptor antagonist for the treatment of urinary inconti-
nence and other symptoms related to an overactive blad-
der,2 a compound that has achieved blockbuster status ($1.21
billion in sales in 20083). Because of its importance and
challenging gem-diarylalkyl stereocenter, it has become a pop-
ular target for asymmetric synthesis. Whereas the original
route relied on optical resolution to separate (R)-tolterodine
from the racemate,4 initial asymmetric routes used chiral aux-
iliaries5 or asymmetric Me-CBS (Corey–Bakshi–Shibata) re-
duction6 to introduce the stereogenic center. More recently,
asymmetric strategies have utilized transition-metal-catalyzed
Recently, we reported the highly enantioselective syntheses
of (ϩ)-sertraline (2) and (ϩ)-indatraline (3) using a lithiation/
borylation10–protodeboronation11 strategy (Scheme 1). (ϩ)-
Sertraline (2), a potent competitive selective serotonin reuptake
inhibitor (SSRI), is a commonly prescribed therapeutic for the
treatment of depression and other anxiety-related disorders
and has also achieved blockbuster status12 ($3.36 billion in
sales in 200413). The related molecule, (ϩ)-indatraline (3), is
a potent psychoactive compound that acts as a monoamine
reuptake inhibitor14 and has the potential to be used in
maintenance therapy to treat cocaine abuse.15 A lithiation/
borylation reaction and subsequent protodeboronation gave
access to both 2 and 3 in high yield and excellent enantiose-
lectivity. In contrast with other substrates devoid of the alkene
function, for homoallylic carbamate 4 it was found necessary
to add a crown ether or to carry out a solvent exchange to
CHCl3 to achieve 1,2-metalate rearrangement of the interme-
diate ate complex.11b The requirement for such unusual con-
ditions has made us probe this type of rearrangement further
with a view to applying it in the asymmetric synthesis of
(R)-tolterodine. Once again, we found that modifications of
Received 25 June 2012. Accepted 30 July 2012. Published at www.nrcresearchpress.com/cjc on 29 November 2012.
S. Roesner and V.K. Aggarwal. School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK.
Corresponding author: Varinder K. Aggarwal (e-mail: V.Aggarwal@bristol.ac.uk).
This paper is part of a Special Issue dedicated to Professor Derrick Clive and is for his many creative contributions to synthetic chemistry.
Can. J. Chem. 90: 965–974 (2012)
doi:10.1139/v2012-069
Published by NRC Research Press

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Can. J. Chem. Vol. 90, 2012
Fig. 1. Pharmaceutically important molecules containing the
gem-diaryl substructure.
steric hindrance of the aryl boronic ester (bearing an ortho
substituent) was perhaps responsible for the low reactivity. We
therefore investigated the use of the less-hindered neopentyl
boronic ester 12, instead of the pinacol boronic ester 7, under
the same reaction conditions. Utilizing carbamate 10 and neo-
pentyl boronic ester 12 in the lithiation/borylation reaction
gave tertiary boronic ester 13 in 62% isolated yield after
column chromatography. To our delight, lithiation/borylation
of homoallylic carbamate 4 (99% enantiomeric excess (ee))
and neopentyl boronic ester 12 gave tertiary boronic ester 14
in good yield and high enantioselectivity (Table 1, entry 1).
This showed that the presence of the double bond was not
interfering in the reaction. However, attempts to improve both
yield and enantioselectivity by the addition of additives after
ate complex formation were not successful (Table 1, entries
2–8).
We therefore considered an alternative protocol. Instead of
using carbamate 4 with 2-methoxy-5-methylphenyl boronic ester
we decided to switch the two aryl groups. In other words, we
considered the possibility of the reaction of homoallylic carba-
mate 18 with phenyl boronic ester in a lithiation/borylation reac-
tion. Although the two ate complexes have similar steric
properties, we believed that the presence of the ortho-methoxy
group might assist in the expulsion of the carbamate, thereby
promoting the 1,2-metallate rearrangement.
Homoallylic carbamate 18 was synthesized in a three-step
sequence starting from the commercially available aldehyde
15 (Scheme 5). The phenolic hydroxyl group was protected
as the methyl ether to give aldehyde 16. Subsequent,
Brown-mediated asymmetric allylation using (ϩ)-B-allyl
(diisopinocampheyl)borane ((ϩ)-Ipc2Ball) gave alcohol 17 in
92% ee,16 which was followed by carbamoylation furnishing
the desired carbamate in 97% yield and 92% ee.
The lithiation/borylation reaction between racemic homoal-
lylic carbamate 18 and phenyl pinacol boronic ester 19 now
proceeded well to give tertiary boronic ester 8 in 40% yield
(Table 2, entry 1). In contrast with our earlier work, the
reaction gave only a poor yield when neopentyl boronic ester
20 was used (Table 2, entry 2). Therefore, an optimization of
the lithiation/borylation reaction of carbamate 18 with phenyl
pinacol boronic ester 19 was carried out. Better results were
obtained with the Lewis acidic additives TMSCl or MgBr2 in
anhydrous MeOH (Table 2, entries 6 and 8). The optimum
conditions/additives of the lithiation/borylation reaction
(MgBr2/MeOH; Table 2, entry 8) were applied to the enantio-
enriched carbamate 18 and we were pleased to find that the
reaction proceeded with 98% es (Scheme 6). Hence, we used
these optimized conditions to complete the synthesis of (R)-
tolterodine.
Interestingly, when we reinvestigated the lithiation/borylation
reaction as applied in the synthesis of sertraline, the reaction with
an electron-rich aryl group associated with carbamate 4 and an
electron-deficient aryl group (3,4-Cl2C6H4) on boronic ester 21
worked much better than having an electron-deficient aryl group
associated with carbamate 22 and an electron-rich aryl group on
boronic ester 19 (Scheme 7). This suggests that this arrange-
ment of electronic substitution of the aryl rings is likely to be
general.
the improved conditions for this class of substrates were
required to promote 1,2-metallate rearrangement, but this
did ultimately enable us to complete a successful synthesis of
(R)-tolterodine using our lithiation/borylation–protodeboronation
strategy.
Results and discussion
Encouraged by the results for the synthesis of (ϩ)-sertraline
and (ϩ)-indatraline, we applied a similar strategy for the
synthesis of (R)-tolterodine (1). The retrosynthetic analysis for
1 (Scheme 2) involves, as a key step, the lithiation/borylation
of benzylic carbamate 4 with boronic ester 7 to form 8.
Subsequent protodeboronation of tertiary boronic ester 8
would lead to olefin 9. Both the lithiation/borylation10 and
protodeboronation11 have been found to be highly stereoselec-
tive, occurring with retention of the stereochemistry. Func-
tional group manipulation of the key intermediate 9 would
then provide (R)-tolterodine (1).
However, attempts to realize this in practice were not
straightforward: when we carried out the lithiation/borylation
of carbamate 4 with boronic ester 7, using 12-crown-4, trimeth-
ylsilyl chloride (TMSCl), and H2O as additives, no product
was formed (Scheme 3). A solvent switch after ate complex
formation from diethyl ether to CHCl3 gave only trace
amounts of tertiary boronic ester 8. Both sets of conditions had
been successfully employed in the synthesis of sertraline;
the only difference here was the use of 2-methoxy-
5-methylphenyl boronic ester in place of 3,4-dichlorophenyl
boronic ester. Monitoring the reaction by 11B NMR revealed
that an intermediate boron–ate complex (A) formed (~5 ppm),
but instead of a 1,2-migration to the product, ate complex A
decomposed over time returning some starting material.
Previous experiments in the syntheses of 2 and 3 revealed
that the double bond can interfere in the lithiation/borylation
process, presumably by formation of a Li–␲ complex, as the
saturated compound underwent smooth lithiation/borylation
under standard conditions (either (i) no additives were re-
quired, simply warming to room temperature (RT) or (ii) the
addition of MgBr2/MeOH prior to warming to RT).11b To
determine whether the problem was related to the double bond,
propylcarbamate 10 was tested in the lithiation/borylation
reaction with pinacol boronic ester 7 (Scheme 4). The forma-
tion of a boron–ate complex was confirmed by 11B NMR, but
again no product could be isolated. We believed that the extra
With the lithiation/borylation problem solved, we focused
on the next step: protodeboronation of tertiary boronic ester 8.
Published by NRC Research Press

Roesner and Aggarwal
967
Scheme 1. Enantioselective syntheses of (ϩ)-sertraline (2) and (ϩ)-indatraline (3) using a lithiation/borylation–protodeboronation strategy.
Scheme 2. Retrosynthetic scheme for the synthesis of
(R)-tolterodine (1).
the formation of (R)-tolterodine (1) in an excellent yield. The
R configuration was confirmed by comparison of the optical
rotations, [α]2D0 ϩ28.0 (c 0.50, MeOH) for 1 with that reported
in the literature ([α]D20 ϩ32.5 (c 0.89, MeOH)).7e Thus, using
our lithiation/borylation–protodeboronation methodology as a
key step, (R)-tolterodine was synthesized through an eight-
step sequence in an overall yield of 30%.
Conclusion
In conclusion, lithiation/borylation and subsequent protode-
boronation has been used in the generation of gem-diarylalkyl
stereocenters in both high yield and high enantioselectivity.
More importantly, we have found that the optimum arrange-
ment of groups is to have an electron-rich aryl group
associated with the carbamate to promote the 1,2-metallate
rearrangement, otherwise, reversion to starting materials tends
to dominate. This methodology has been applied to a highly
enantioselective synthesis of (R)-tolterodine.
Experimental
Reaction mixtures were stirred magnetically. Air- and
moisture-sensitive reactions were carried out in flame-dried
glassware under argon atmosphere using standard Schlenk
manifold technique. All required fine chemicals were pur-
chased from Acros Organics, Alfa Aesar, Inochem-Frontier
Scientific, or Sigma-Aldrich and used as received unless oth-
erwise mentioned. Anhydrous solvents were prepared using
anhydrous solvent drying columns.18 Microwave reactions
were carried out in a Biotage Initiator EXP EU microwave
synthesizer. Analytical thinlayer chromatography (TLC) was
performed on aluminum-backed silica plates (Merck, silica gel
60 F254, 0.25 mm). Compounds were visualized by exposure
to UV light or by staining the plates with a 5% solution of
phosphomolybdic acid (H3PMo12O40) in EtOH followed by
heating. Flash column chromatography was performed on
silica gel (Sigma-Aldrich, silica gel 60, 40–63 ␮m). 1H NMR
spectra were recorded in CDCl3 at 400 or 500 MHz on a Joel
ECP 400, a Varian 400, or a Varian 500 Fourier transform
(FT) spectrometer. Chemical shifts (␦H) are quoted in parts per
Unfortunately, our standard procedure for the protodeborona-
tion of diarylalkyl boronic esters (1.5 equiv CsF, 2.5 equiv
H2O, 1,4-dioxane)11 proceeded very sluggishly and it took
48 h at 80 °C until full conversion of 8 was achieved. This is
probably due to the electron-rich aryl ring, which makes
deboronation more difficult. In the case of protodeboronation
of aryldialkyl boronic esters, we also found that CsF/H2O
was very slow, but that tetrabutylammonium fluoride trihy-
drate (TBAF·3H2O) was considerably superior.11a Using these
previously reported conditions (1.5 equiv TBAF·3H2O, tolu-
ene), tertiary boronic ester 8 was smoothly protodeboronated
at ambient temperature within 90 min in excellent yield and
enantioselectivity to give key intermediate 9 (Scheme 6).
The remaining synthesis was completed in a three-step
sequence (Scheme 6). The double bond in olefin 9 was
successfully cleaved by a Lemieux–Johnson oxidation,17 with
in situ generated osmium tetroxide, to the corresponding
aldehyde 23. Subsequent reductive amination with diiso-
propylamine and sodium triacetoxyborohydride gave the
protected tolterodine precursor 24 in a good yield. Finally,
removal of the methyl group by acidic hydrolysis resulted in
1
million (ppm) and referred to CHCl3 (7.27 ppm). H NMR
coupling constants are reported in hertz and refer to apparent
multiplicities. Data are reported as follows: chemical shift,
multiplicity (s ϭ singlet, br s ϭ broad singlet, d ϭ doublet,
Published by NRC Research Press

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Can. J. Chem. Vol. 90, 2012
Scheme 3. Lithiation/borylation of carbamate 4 and boronic ester 7.
Scheme 4. Lithiation/borylation of carbamate 10, pinacol boronic
ester 7, and neopentyl boronic ester 12.
Table 1. Optimization of the lithiation/borylation reaction
conditions for carbamate 4.
Entry
Conditions
Yield (%)
es (%)a
1
2
3
4
5
6
7
8
No additives
52
10
19
32
8
1
1
50
94
90
45
53
93
93
96
13
Solvent exchange to CHCl3
Reaction in toluene
12-Crown-4
TMSCl
12-Crown-4, TMSCl
MgBr2/MeOH
MgBr2·Et2O
Note: es, enantiospecifity. Reaction conditions: 4 (0.3 mol/L in diethyl
ether), s-BuLi (1.3 mol/L in cyclohexane/hexane, 98:2), 12 (0.9 mol/L in
diethyl ether). Where applicable, 1.2 equiv of additive were used. The
enantiomeric excess (ee) was determined after oxidation of an aliquot of
the tertiary boronic ester by chiral HPLC.
aes ϭ (product ee/starting material ee) ϫ 100.
t ϭ triplet, m ϭ multiplet, dd ϭ doublet of doublet, etc.),
coupling constant, integration, and assignment. 13C NMR
spectra were recorded at 101 or 126 MHz on a Jeol ECP 400,
a Varian 400, or a Varian 500 instrument. Chemical shifts
(␦C) are quoted in ppm and referenced to CHCl3 (77.0 ppm).
11B NMR spectra were measured using quartz NMR tubes at 96 or
128 MHz on a Jeol Lambda 300, a Joel ECP (Eclipse) 300, or
a Varian 400 with complete proton decoupling using BF3·Et2O
(0.0 ppm) as an external standard. Mass spectra were recorded
by the University of Bristol, School of Chemistry departmen-
tal mass spectrometry service using chemical ionization (CI)
or electrospray ionization (ESI) techniques for low- and high-
resolution mass spectra (LR-MS and HR-MS, respectively).
All IR spectra were recorded on the neat compounds using
a PerkinElmer Spectrum One FT-IR spectrometer. Optical
rotations were obtained using a Bellingham ϩ Stanley Ltd.
ADP220 polarimeter. Melting points were measured with a
Reichert hot stage apparatus and are uncorrected. Chiral
HPLC separations were performed on an Agilent 1100
Series HPLC unit equipped with a UV–vis diode array
detector using a Daicel Chiralpak IB column (4.6 ϫ
250 mm2, 5 ␮m) fitted with a guard (4 ϫ 10 mm2). (Chiral
Scheme 5. Synthesis of carbamate 18.
2-(2-Methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (7)
This compound was synthesized following a literature pro-
cedure performed on a different substrate.19 Boronic ester 7
(2.02 g, 8.14 mmol, Ͼ99%) was obtained as a white solid,
which was used without further purification; mp 75–76 °C
1
HPLC traces and H and 13C NMR spectra can be found in
the Supplementary data).
Published by NRC Research Press

Roesner and Aggarwal
Table 2. Optimization of the lithiation/borylation reaction conditions for carbamate 18.
969
Entry
Boronic ester
Conditions
Yield (%)
1
2
3
4
5
6
7
8
9
19
20
19
19
19
19
19
19
19
No additives
No additives
Solvent exchange to CHCl3
Reaction in toluene
12-Crown-4
40
13
44
16
33
51
17
74
15
TMSCl
12-Crown-4, TMSCl
MgBr2/MeOH
MgBr2·Et2O
Note: Reaction conditions: 18 (0.3 mol/L in diethyl ether), s-BuLi (1.3 mol/L in cyclohexane/hexane,
98:2), 19 or 20 (0.9 mol/L in diethyl ether). Where applicable, 1.2 equiv of additive were used.
(diethyl ether). IR (neat, cm–1) ␯max: 2981, 1605, 1585, 1243.
1H NMR (400 MHz, CDCl3, ppm) ␦⌯: 7.49 (d, J ϭ 2.3 Hz,
1H, HAr), 7.20 (dd, J ϭ 8.4, 2.3 Hz, 1H, HAr), 6.77 (d, J ϭ
8.4 Hz, 1H, HAr), 3.81 (s, 3H, OCH3), 2.29 (s, 3H, CArCH3),
1.36 (s, 12H, CH3). 13C NMR (101 MHz, CDCl3, ppm) ␦C:
162.2 (COCH3), 137.1 (CH), 132.9 (CH), 129.2 (C), 110.5
(CH), 83.4 (OC(CH3)2), 56.0 (OCH3), 24.8 (CH3), 20.2
(CArCH3). 11B NMR (96 MHz, CDCl3, ppm) ␦B: 30.0 (br s).
MS m/z (%) (CIϩ): 249 ([M ϩ H]ϩ, 100), 248 ([M]ϩ, 60), 247
(18), 145 (15), 123 ([Ar ϩ H]ϩ, 15), 101 (24). HR-MS (CIϩ)
calcd for C14H22O311B [M ϩ H]ϩ: 249.1662; found:
249.1664.
was stirred for 75 min at RT. A solution of N,N-diisopropylcar-
bamoyl chloride (982 mg, 6.00 mmol, 1.2 equiv) in anhydrous
THF (5.0 mL) was added and the reaction mixture was heated
under reflux for 44 h. The solvent was removed in vacuo and
the residue was portioned between water and diethyl ether.
The phases were separated and the aqueous layer was re-
extracted with diethyl ether. The combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was subjected to flash
chromatography (SiO2, pentane/EtOAc, 6:1) to obtain carba-
mate 10 (1.13 g, 4.07 mmol, 81%) as a colourless oil. TLC
(pentane/EtOAc, 6:1): 0.46. IR (neat, cm–1) ␯max: 2962, 1687.
1H NMR (400 MHz, CDCl3, ppm) ␦H: 7.37–7.29 (m, 4H,
HAr), 7.29–7.23 (m, 1H, HAr), 5.71 (t, J ϭ 6.9 Hz, 1H,
CHOCb), 4.04 (br m, 1H, CH(CH3)2), 3.84 (br m, 1H,
CH(CH3)2), 1.94 (m, 1H, CHHCHO), 1.76 (m, 1H, CHH-
CHO), 1.44–1.27 (m, 2H, CH2CH3), 1.22 (br m, 12H,
CH(CH3)2), 0.92 (t, J ϭ 7.4 Hz, 3H, CH2CH3). 13C NMR
(101 MHz, CDCl3, ppm) ␦C: 155.1 (NCO), 141.8 (C), 128.2
(CH), 127.3 (CH), 126.5 (CH), 76.4 (CHOCb), 46.1 (br,
CH(CH3)2), 39.0 (CH2CHO), 21.4 (br, CH(CH3)2), 18.9
(CH2CH3), 13.9 (CH2CH3). MS m/z (%) (CIϩ): 278 ([M ϩ
H]ϩ, 77), 236 (11), 218 (10), 146 ([CbOH ϩ H]ϩ, 100), 133
([Ph(CH2)4]ϩ, 57), 128 (16), 102 (12), 91 ([PhCH2]ϩ, 30).
HR-MS (CIϩ) calcd for C17H28NO2 [M ϩ H]ϩ: 278.2120;
found: 278.2116.
2-(2-Methoxy-5-methylphenyl)-5,5-dimethyl-1,3,2-
dioxaborinane (12)
This compound was synthesized following a literature pro-
cedure performed on a different substrate.19 Boronic ester 12
(3.51 g, 14.4 mmol, 96%) was obtained as a white solid, which
required no further purification; mp 59–61 °C (diethyl ether).
IR (neat, cm–1) ␯max: 2936, 1603, 1584, 1241. 1H NMR
(400 MHz, CDCl3, ppm) ␦⌯: 7.47 (d, J ϭ 2.2 Hz, 1H, HAr),
7.17 (dd, J ϭ 8.4, 2.2 Hz, 1H, HAr), 6.78 (d, J ϭ 8.4 Hz, 1H,
HAr), 3.82 (s, 3H, OCH3), 3.80 (s, 4H, OCH2), 2.29 (s, 3H,
CArCH3), 1.05 (s, 6H, CH3). 13C NMR (101 MHz, CDCl3,
ppm) ␦C: 161.7 (COCH3), 136.2 (CH), 132.0 (CH), 129.1 (C),
110.4 (CH), 72.4 (OCH2), 55.9 (OCH3), 31.7 (C(CH3)2), 21.9
(CH3), 20.3 (CArCH3). 11B NMR (96 MHz, CDCl3, ppm) ␦B:
26.3 (br s). MS m/z (%) (CIϩ): 235 ([M ϩ H]ϩ, 100), 234
([M]ϩ, 53), 233 (19), 123 ([Ar ϩ H]ϩ, 31), 75 (53). HR-MS
(CIϩ) calcd. for C13H20O311B [M ϩ H]ϩ: 235.1506; found:
235.1500.
2-(1-(2-Methoxy-5-methylphenyl)-1-phenylbutyl)-5,5-
dimethyl-1,3,2-dioxaborinane (13)
1-Phenylbutyl diisopropylcarbamate (10; 139 mg, 0.50 mmol,
1.0 equiv) was dissolved in anhydrous diethyl ether (1.5 mL)
and chilled to Ϫ78 °C. s-BuLi (500 ␮L, 1.3 mol/L solution
in cyclohexane/hexane, 98:2, 0.65 mmol, 1.3 equiv) was
added dropwise and the mixture was stirred at this temper-
ature for 1 h. A solution of neopentyl ester 12 (176 mg,
0.75 mmol, 1.5 equiv) in anhydrous diethyl ether (0.5 mL)
1-Phenylbutyl diisopropylcarbamate (10)
To a suspension of sodium hydride (60% dispersion in
mineral oil, 300 mg, 7.50 mmol, 1.5 equiv) in anhydrous
tetrahydrofuran (THF; 20 mL), 1-phenylbutan-1-ol (751 mg,
5.00 mmol, 1.0 equiv) was added dropwise and the mixture
Published by NRC Research Press

970
Can. J. Chem. Vol. 90, 2012
Scheme 6. Synthesis of (R)-tolterodine (1).
13C NMR (101 MHz, CDCl3, ppm) ␦C: 154.9 (C), 144.0 (C),
136.3 (C), 130.9 (CH), 129.4 (CH), 129.3 (C), 127.2 (CH),
126.7 (CH), 124.5 (CH), 110.4 (CH), 72.3 (OCH2), 56.1
(OCH3), 34.8 (CH2CH2), 31.6 (C(CH3)2), 21.5 (CH3), 20.8
(CArCH3), 17.9 (CH2CH3), 14.8 (CH2CH3). 11B NMR
(96 MHz, CDCl3, ppm) ␦B: 27.9 (br s). MS m/z (%) (CIϩ): 367
([M ϩ H]ϩ, 16), 366 ([M]ϩ, 30), 351 ([M – Me]ϩ, 14), 323
([M – n-Pr]ϩ, 5), 289 ([M – Ph]ϩ, 30), 253 ([M – Bneop]ϩ, 7),
245 ([M – Ar]ϩ, 100), 203 (28), 177 (16), 149 (12), 131 (34),
123 (46), 105 (15), 93 (99). HR-MS (CIϩ) calcd for
C23H32O311B [M ϩ H]ϩ: 367.2445; found: 367.2457.
Scheme 7. Lithiation/borylation of carbamates 4 and 22.
2-(1-(2-Methoxy-5-methylphenyl)-1-phenylbut-3-enyl)-5,5-
dimethyl-1,3,2-dioxaborinane (14)
Following the experimental procedure for tertiary boronic ester
13, 1-phenylbut-3-enyl diisopropylcarbamate (4) (139 mg,
0.50 mmol, 1.0 equiv) in anhydrous diethyl ether (1.5 mL),
s-BuLi (570 ␮L, 1.14 mol/L solution in cyclohexane/hexane,
98:2, 0.65 mmol, 1.3 equiv), and neopentyl ester 12 (176 mg,
0.75 mmol, 1.0 equiv) in anhydrous diethyl ether (0.75 mL)
gave, after purification by column chromatography (SiO2,
pentane/EtOAc, 30:1), tertiary boronic ester 14 (94 mg,
0.26 mmol, 52% or 97% BRSM) as a colourless oil. TLC
(pentane/EtOAc, 30:1): 0.12. IR (neat, cm–1) ␯max: 2928,
1495, 1245. 1H NMR (400 MHz, CDCl3, ppm) ␦⌯: 7.49–7.42
(m, 2H, HAr), 7.30–7.23 (m, 2H, HAr), 7.18–7.13 (m, 1H,
HAr), 6.98 (ddd, J ϭ 8.1, 2.2, 0.6 Hz, 1H, HAr), 6.85–6.78 (m,
2H, HAr), 5.68 (dddd, J ϭ 17.3, 10.2, 7.4, 6.2 Hz, 1H,
CHCH2), 4.97–4.84 (m, 2H, CHCH2), 3.86 (s, 3H, OCH3),
3.56 (s, 4H, OCH2), 3.13 (ddt, J ϭ 15.4, 7.4, 1.2 Hz, 1H,
CHH), 2.84 (ddt, J ϭ 15.4, 6.2, 1.6 Hz, 1H, CHH), 2.20 (s, 3H,
CArCH3), 0.71 (s, 6H, CH3). 13C NMR (101 MHz, CDCl3,
ppm) ␦C: 154.8 (C), 143.7 (C), 137.1 (CHCH2), 135.8 (C),
130.7 (CH), 129.6 (CH), 129.4 (C), 127.3 (CH), 126.9 (CH),
124.8 (CH), 115.6 (CHCH2), 110.4 (CH), 72.3 (OCH2), 56.1
(OCH3), 37.5 (CH2), 31.6 (C(CH3)2), 21.6 (CH3), 20.8
(CArCH3). 11B NMR (96 MHz, CDCl3, ppm) ␦B: 28.1 (br s).
MS m/z (%) (CIϩ): 365 ([M ϩ H]ϩ, 89), 364 ([M]ϩ, 75), 349
([M – Me]ϩ, 49), 323 ([M – allyl]ϩ, 49), 287 ([M – Ph]ϩ, 32),
243 ([M – Ar]ϩ, 100), 203 (12), 149 (36), 131 (33), 123 (19), 105
was added dropwise and the mixture was stirred for 2 h
at Ϫ78 °C. The cooling bath was removed and stirring was
continued at RT overnight (15 h). The reaction mixture was
cooled to 0 °C and 1 mol/L KH2PO4(aq) (2.0 mL) was added
slowly. After stirring for 10 min at RT, the phases were
separated and the aqueous phase was extracted with diethyl
ether. The combined organic phases were dried over anhy-
drous MgSO4, filtered, and the solvent was removed in vacuo.
The crude product was purified by column chromatography
(SiO2, pentane/EtOAc, 30:1) to give tertiary boronic ester 13
(114 mg, 0.31 mmol, 62% or 92% based on recovered starting
material (BRSM)) as a colourless oil, which crystallized upon
standing to white cubes; mp 86–87 °C (pentane/EtOAc). TLC
(pentane/EtOAc, 30:1): 0.22. IR (neat, cm–1) ␯max: 2955,
1
2873, 1494, 1244. H NMR (400 MHz, CDCl3, ppm) ␦⌯:
7.42–7.38 (m, 2H, HAr), 7.28–7.23 (m, 2H, HAr), 7.16–7.11
(m, 1H, HAr), 6.97 (ddd, J ϭ 8.2, 2.2, 0.6 Hz, 1H, HAr),
6.82–6.79 (m, 2H, HAr), 3.85 (s, 3H, OCH3), 3.53 (s, 4H,
OCH2), 2.25–2.17 (m, 1H, CHHCH2), 2.19 (s, 3H, CArCH3),
2.02–1.93 (m, 1H, CHHCH2), 1.31–1.21 (m, 1H, CHHCH3),
0.87–0.78 (m, 4H, CH2CH3, CHHCH3), 0.65 (s, 6H, CH3).
Published by NRC Research Press

Roesner and Aggarwal
971
(24), 93 (77). HR-MS (CIϩ) calcd for C23H30O311B [M ϩ H]ϩ:
365.2288; found: 365.2278.
(s, 3H, CArCH3), 1.24 (br m, 12H, CH3). 13C NMR (101 MHz,
CDCl3, ppm) ␦C: 154.9 (NCO), 154.0 (C), 134.7 (CHCH2),
129.6 (C), 129.3 (C), 128.5 (CH), 127.3 (CH), 116.9
(CHCH2), 110.5 (CH), 70.8 (CHOCb), 55.5 (OCH3), 45.7 (br,
CH(CH3)2), 40.1 (CH2), 21.1 (br, CH3), 20.7 (CArCH3). MS
m/z (%) (ESIϩ): 342 ([M ϩ Na]ϩ, 100), 220 ([M – Ar ϩ Na]ϩ,
4), 175 ([M – OCb]ϩ, 7), 114 (4). HR-MS (ESIϩ) calcd for
C19H29O3NaN [M ϩ Na]ϩ: 342.2040; found: 342.2033.
HPLC: Chiralpak IB, 0 °C, 0.2% i-PrOH in hexane, 0.5 mL/min,
UV detection at 210.8 nm, retention times: (S)-1-(2-methoxy-
5-methylphenyl)but-3-enyl diisopropylcarbamate, 36.3 min;
(R)-1-(2-methoxy-5-methylphenyl)but-3-enyl diisopropylcarbamate,
40.9 min; 92% ee.
2-Methoxy-5-methylbenzaldehyde (16)
This compound was synthesized following a literature pro-
cedure20 and yielded a pale yellow oil (4.44 g, 29.6 mmol,
99%), which was used without further purification. IR (neat, cm–1)
1
␯
max: 2863, 1676, 1494, 1250. H NMR (400 MHz, CDCl3,
ppm) ␦⌯: 10.45 (s, 1H, CHO), 7.64 (d, J ϭ 2.5 Hz, 1H, HAr),
7.36 (dd, J ϭ 8.6, 2.5 Hz, 1H, HAr), 6.90 (d, J ϭ 8.6 Hz, 1H,
HAr), 3.91 (s, 3H, OCH3), 2.32 (s, 3H, CH3). 13C NMR
(101 MHz, CDCl3, ppm) ␦C: 190.0 (CHO), 160.0 (C), 136.6
(CH), 130.0 (C), 128.6 (CH), 124.5 (C), 111.6 (CH), 55.7
(OCH3), 20.2 (CH3). MS m/z (%) (CIϩ): 151 ([M ϩ H]ϩ,
100), 123 ([Ar ϩ H]ϩ, 26), 89 (68). HR-MS (CIϩ) calcd for
C9H11O2 [M ϩ H]ϩ: 151.0759; found: 151.0756.
(R)-2-(1-(2-Methoxy-5-methylphenyl)-1-phenylbut-3-enyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8)
(R)-Carbamate 18 (515 mg, 1.61 mmol, 1.0 equiv) was
dissolved in anhydrous diethyl ether (5.0 mL) and chilled
to Ϫ78 °C. s-BuLi (1.41 mL, 1.49 mol/L solution in cyclo-
hexane/hexane, 98:2, 2.10 mmol, 1.3 equiv) was added drop-
wise and the reaction mixture was stirred at this temperature
for 1 h. A solution of PhBpin (4,4,5,5-tetramethyl-2-phenyl-
1,3,2-dioxaborolane, 490 mg, 2.42 mmol, 1.5 equiv) in anhy-
drous diethyl ether (2.5 mL) was added dropwise and the
mixture was stirred for 2 h at Ϫ78 °C. Afterwards, a 1.0 mol/L
solution of MgBr2 in anhydrous MeOH10b (1.93 mL, 1.93 mmol,
1.2 equiv) was added slowly. After 5 min, the cooling bath
was removed and stirring was continued at RT overnight
(16 h). Then, the reaction mixture was cooled to 0 °C and
1 mol/L KH2PO4(aq) (2.0 mL) was added slowly. After
stirring for 10 min at RT, the phases were separated and the
aqueous phase was extracted with diethyl ether. The com-
bined organic phases were dried over anhydrous MgSO4,
filtered, and the solvent was removed in vacuo. The crude
product was purified by column chromatography (SiO2, pen-
tane/EtOAc, 30:1) to give tertiary boronic ester 8 (449 mg,
1.19 mmol, 74%) as a white solid; mp 134–136 °C (pentane/
(R)-1-(2-Methoxy-5-methylphenyl)but-3-en-1-ol (17)
This compound was synthesized following a literature pro-
cedure performed on a different substrate.16 Flash chromatog-
raphy (SiO2, pentane/diethyl ether, 9:1) gave alcohol 17
(74 mg, 0.38 mmol, 77%) as white needles; mp 44–45 °C
(pentane/diethyl ether). [α]2D0 ϩ56.3 (c 1.79, CHCl3, for
98% ee). TLC (pentane/diethyl ether, 9:1): 0.08. IR (neat, cm–1)
1
␯
max: 3361, 2922, 1498, 1243. H NMR (400 MHz, CDCl3,
ppm) ␦⌯: 7.16 (d, J ϭ 2.0 Hz, 1H, HAr), 7.05 (dd, J ϭ 8.2,
2.0 Hz, 1H, HAr), 6.79 (d, J ϭ 8.2 Hz, 1H, HAr), 5.93–5.81
(ddt, J ϭ 16.9, 10.3, 6.9 Hz, 1H, CHCH2), 5.19–5.10 (m, 2H,
CHCH2), 4.93 (dt, J ϭ 8.1, 5.3 Hz, 1H, CHOH), 3.84 (s, 3H,
OCH3), 2.62–2.47 (m, 3H, CH2, OH), 2.31 (s, 3H, CH3). 13C
NMR (101 MHz, CDCl3, ppm) ␦C: 154.3 (C), 135.3 (CHCH2),
131.4 (C), 129.9 (C), 128.5 (CH), 127.5 (CH), 117.5
(CHCH2), 110.4 (CH), 69.8 (CHOH), 55.4 (OCH3), 42.0
(CH2), 20.6 (CH3). MS m/z (%) (ESIϩ): 215 ([M ϩ Na]ϩ,
100), 175 ([M – allyl ϩ Na]ϩ, 10), 107 ([Ar – Me]ϩ, 5).
HR-MS (ESIϩ) calcd. for C12H16O2Na [M ϩ Na]ϩ: 215.1043;
found: 215.1038. HPLC: Chiralpak IB, 20 °C, 0.5% i-PrOH in
hexane, 0.7 mL/min, UV detection at 210.8 nm, retention times:
(S)-1-(2-methoxy-5-methylphenyl)but-3-en-1-ol, 27.6 min;
(R)-1-(2-methoxy-5-methylphenyl)but-3-en-1-ol, 30.1 min; 92% ee.
EtOAc). [α]2D1 –88.0 (c 1.00, CHCl3, for 90% ee). TLC
(pentane/EtOAc, 30:1): 0.10. IR (neat, cm–1) ␯max: 2974,
1
1497, 1240. H NMR (400 MHz, CDCl3, ppm) ␦⌯: 7.46 (d,
(R)-1-(2-Methoxy-5-methylphenyl)but-3-enyl
J ϭ 7.8 Hz, 2H, HAr), 7.26 (t, J ϭ 7.8 Hz, 2H, HAr), 7.15 (t,
J ϭ 7.8 Hz, 1H, HAr), 6.96 (dd, J ϭ 8.2, 1.7 Hz, 1H, HAr), 6.81
(d, J ϭ 1.7 Hz, 1H, HAr), 6.76 (d, J ϭ 8.2 Hz, 1H, HAr), 5.65
(ddt, J ϭ 17.1, 10.2, 6.8 Hz, 1H, CHCH2), 4.95 (dd, J ϭ 17.1,
1.4 Hz, 1H, CHCHtransH), 4.87 (dd, J ϭ 10.2, 1.4 Hz, 1H,
CHCHcisH), 3.77 (s, 3H, OCH3), 3.10 (dd, J ϭ 15.2, 6.8 Hz,
1H, CHH), 2.94 (dd, J ϭ 15.2, 6.8 Hz, 1H, CHH), 2.19 (s, 3H,
CArCH3), 1.11 (s, 6H, CH3), 1.10 (s, 6H, CH3). 13C NMR
(101 MHz, CDCl3, ppm) ␦C: 154.8 (C), 143.0 (C), 136.7
(CHCH2), 134.4 (C), 130.4 (CH), 129.9 (CH), 129.2 (C),
127.3 (CH), 127.1 (CH), 125.1 (CH), 115.7 (CHCH2), 110.1
(CH), 83.0 (C), 55.1 (OCH3), 38.8 (br, CB), 37.8 (CH2),
24.6 (CH3), 24.4 (CH3), 20.8 (CArCH3). 11B NMR
(96 MHz, CDCl3, ppm) ␦B: 30.2 (br s). MS m/z (%) (ESIϩ):
401 ([M ϩ Na]ϩ, 100), 279 (9), 223 (4), 134 (5). HR-MS
(ESIϩ) calcd for C24H31O3Na11B [M ϩ Na]ϩ: 401.2258;
found: 401.2245. The enantiomeric excess of the chiral
boronic ester was determined by HPLC analysis of an
aliquot oxidized to 25.
diisopropylcarbamate (18)
Alcohol 17 (1.32 g, 6.84 mmol, 1.0 equiv), N,N-diisopro-
pylcarbamoyl chloride (1.34 g, 8.21 mmol, 1.2 equiv), and
Et3N (1.23 mL, 8.89 mmol, 1.3 equiv) were dissolved in
anhydrous toluene (7.0 mL) in a microwave vial. The vial was
sealed and heated for 2 h at 150 °C. After cooling to ambient
temperature, the salts were removed by filtration through a
plug of silica and the solids were thoroughly washed with
diethyl ether. The solvent was removed in vacuo and the
residue was subjected to flash chromatography (SiO2, pentane/
EtOAc, 9:1) to obtain 2.11 g (R)-carbamate 18 (6.6 mmol,
97%) as a pale yellow oil. [α]2D1 Ϫ1.0 (c 1.00, CHCl3). TLC
(pentane/EtOAc, 9:1): 0.27. IR (neat, cm–1) ␯max: 2969, 1686,
1
1249. H NMR (400 MHz, CDCl3, ppm) ␦⌯: 7.09 (d, J ϭ
2.2 Hz, 1H, HAr), 7.02 (dd, J ϭ 8.2, 2.2 Hz, 1H, HAr), 6.76 (d,
J ϭ 8.2 Hz, 1H, HAr), 6.15 (dd, J ϭ 7.1, 5.3 Hz, 1H, CHOCb),
5.80 (ddt, J ϭ 17.1, 10.1, 7.0 Hz, 1H, CHCH2), 5.08–4.99 (m,
2H, CHCH2), 4.01 (br m, 1H, CH(CH3)2), 3.90 (br m, 1H,
CH(CH3)2), 3.81 (s, 3H, OCH3), 2.65–2.53 (m, 2H, CH2), 2.28
Published by NRC Research Press

972
Can. J. Chem. Vol. 90, 2012
275.1406; found: 275.1413. The enantiomeric excess of the
chiral olefin was determined by HPLC analysis of an aliquot,
which has been hydroborated and oxidized to 26.
(S)-1-(2-Methoxy-5-methylphenyl)-1-phenylbut-3-
en-1-ol (25)
A solution of tertiary boronic ester 8 (38 mg, 0.10 mmol,
1.0 equiv) in THF (5.0 mL) was cooled to 0 °C and a mixture
of 2 mol/L NaOH(aq) (2.0 mL) and 30% H2O2 (1.0 mL) was
added slowly under vigorous stirring. The reaction mixture
was stirred at RT for 2 h. The solvent was removed under
reduced pressure and the residue was portioned between water
and diethyl ether. The phases were separated and the aqueous
layer was extracted with diethyl ether. The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and the solvent was removed in vacuo. The residue
was purified by flash chromatography (SiO2, pentane/EtOAc,
9:1) to give tertiary alcohol 25 (21 mg, 79 ␮mol, 79%) as a
colourless oil, which crystallized on standing to form a white
(R)-4-(2-Methoxy-5-methylphenyl)-4-phenylbutan-1-ol (26)
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN; 390 ␮L,
0.5 mol/L in THF, 0.20 mmol, 1.75 equiv) was added to a
solution of olefin 9 (29 mg, 0.11 mmol, 1.0 equiv) in anhy-
drous THF (1.0 mL) and stirred for 2 h at ambient temperature.
The reaction mixture was cooled to 0 °C and a mixture of
2 mol/L NaOH(aq) (1.0 mL) and 30% H2O2 (0.5 mL) was
added slowly. The reaction mixture was stirred vigorously for
2 h at RT. The solution was diluted with water and extracted
with diethyl ether. The combined organic layers were dried
over anhydrous MgSO4, filtered, concentrated under reduced
pressure, and the residue was purified by column chromatog-
raphy (SiO2, pentane/EtOAc, 4:1) to give alcohol 26 (23 mg,
solid; mp 52–53 °C (pentane/EtOAc). [α]2D4 ϩ100.2 (c 1.57,
CHCl3, for 94% ee). TLC (pentane/EtOAc, 9:1): 0.32. IR
(neat, cm–1) ␯max: 3517, 2923, 1497, 1237. 1H NMR
(400 MHz, CDCl3, ppm) ␦⌯: 7.35–7.31 (m, 2H, HAr), 7.30–
7.24 (m, 3H, HAr), 7.22–7.17 (m, 1H, HAr), 7.08 (ddd, J ϭ 8.2,
2.2, 0.6 Hz, 1H, HAr), 6.78 (d, J ϭ 8.2 Hz, 1H, HAr), 5.86 (ddt,
J ϭ 17.2, 10.3, 6.8 Hz, 1H, CHCH2), 5.15–5.05 (m, 2H,
CHCH2), 4.64 (br s, 1H, OH), 3.56 (s, 3H, OCH3), 3.14 (ddd,
J ϭ 14.5, 6.8, 1.1 Hz, 1H, CHH), 2.89 (ddd, J ϭ 14.5, 6.8,
1.1 Hz, 1H, CHH), 2.35 (s, 3H, CH3). 13C NMR (101 MHz,
CDCl3, ppm) ␦C: 155.0 (C), 147.7 (C), 134.5 (CHCH2), 134.0
(C), 129.9 (C), 128.8 (CH), 128.1 (CH), 127.5 (CH), 126.3
(CH), 125.6 (CH), 117.6 (CHCH2), 112.5 (CH), 77.5 (COH),
55.8 (OCH3), 45.8 (CH2), 20.9 (CH3). MS m/z (%) (CIϩ): 269
([M ϩ H]ϩ, 4), 251 ([M – OH]ϩ, 100), 227 ([M – allyl]ϩ, 85),
149 [(M – Ar ϩ H]ϩ, 30), 135 (20), 105 (34). HR-MS (CIϩ)
calcd for C18H21O2 [M ϩ H]ϩ: 269.1542; found: 269.1545.
HPLC: Chiralpak IB, 20 °C, 3.0% i-PrOH in hexane, 0.7 mL/min,
UV detection at 210.8 nm, retention times: (R)-1-(2-methoxy-
5-methylphenyl)-1-phenylbut-3-en-1-ol, 8.6 min; (S)-1-(2-methoxy-
5-methylphenyl)-1-phenylbut-3-en-1-ol, 9.7 min; 90% ee.
85 ␮mol, 75%) as a colourless oil. [α]2D1 ϩ6.5 (c 0.62, CHCl3,
for 90% ee). TLC (pentane/EtOAc, 4:1): 0.10. IR (neat, cm–1)
1
␯
max: 3334, 2937, 1498, 1243. H NMR (400 MHz, CDCl3,
ppm) ␦⌯: 7.31–7.24 (m, 4H, HAr), 7.19–7.12 (m, 1H, HAr),
7.03–7.00 (m, 1H, HAr), 6.96 (dd, J ϭ 8.2, 2.2 Hz, 1H, HAr),
6.74 (d, J ϭ 8.2 Hz, 1H, HAr), 4.39 (t, J ϭ 7.8 Hz, 1H, CH),
3.76 (s, 3H, OCH3), 3.67 (t, J ϭ 6.6 Hz, 2H, CH2OH), 2.27 (s,
3H, CH3), 2.14–2.00 (m, 2H, CH2CH), 1.60–1.51 (dq, J ϭ
8.1, 6.6 Hz, 2H, CH2CH2OH), 1.35 (br s, 1H, OH). 13C NMR
(101 MHz, CDCl3, ppm) ␦C: 154.8 (C), 144.8 (C), 133.2 (C),
129.6 (C), 128.3 (CH), 128.1 (CH), 128.1 (CH), 127.3 (CH),
125.8 (CH), 110.7 (CH), 62.9 (CH2OH), 55.7 (OCH3), 42.7
(CH), 31.1 (CH2), 31.0 (CH2), 20.7 (CH3). MS m/z (%)
(ESIϩ): 293 ([M ϩ Na]ϩ, 100), 290 (13), 282 (2), 211 ([M –
(CH2)3OH)]ϩ, 2). HR-MS (ESIϩ) calcd for C18H22ONa [M ϩ
Na]ϩ: 293.1512; found: 293.1517. HPLC: Chiralpak IB,
20 °C, 1.5% i-PrOH in hexane, 0.7 mL/min, UV detection at
210.8 nm, retention times: (S)-1-(2-methoxy-5-methylphenyl)-
1-phenylbut-3-en-1-ol, 48.8 min; (R)-4-(2-methoxy-5-
methylphenyl)-4-phenylbutan-1-ol, 50.2 min; 90% ee.
(R)-1-Methoxy-4-methyl-2-(1-phenylbut-3-enyl)benzene (9)
A solution of tertiary boronic ester 8 (328 mg, 0.87 mmol,
1.0 equiv) and TBAF·3H2O (411 mg, 1.30 mmol, 1.5 equiv) in
anhydrous toluene (9.0 mL) was stirred for 1.5 h at RT.
Afterwards, the reaction mixture was washed with 0.5 mol/L
NaOH(aq), water, and brine. The organic phase was dried over
anhydrous MgSO4, filtered, and the solvent was removed
under reduced pressure to give olefin 9 (207 mg, 0.82 mmol,
(R)-3-(2-Methoxy-5-methylphenyl)-3-phenylpropanal (23)
This compound was synthesized following a literature pro-
cedure performed on a different substrate.17 The crude mate-
rial was filtered through a plug of silica (pentane/EtOAc, 1:1),
and the solvent was removed in vacuo to afford aldehyde 23
(163 mg, 0.64 mmol, 97%) as a pale yellow oil, which re-
quired no further purification. [α]2D2 ϩ14.0 (c 1.00, CHCl3)
95%) as a colourless oil, which required no purification. [α]D20
–10.0 (c 1.00, CHCl3, for 90% ee). IR (neat, cm–1) ␯max: 2922,
1498, 1240. 1H NMR (400 MHz, CDCl3, ppm) ␦⌯: 7.30–7.25
(m, 4H, HAr), 7.19–7.12 (m, 1H, HAr), 7.02 (d, J ϭ 2.2 Hz,
1H, HAr), 6.96 (dd, J ϭ 8.3, 2.2 Hz, 1H, HAr), 6.74 (d, J ϭ
8.3 Hz, 1H, HAr), 5.75 (ddt, J ϭ 17.1, 10.2, 6.8 Hz, 1H,
CHCH2), 5.03 (ddt, J ϭ 17.1, 2.8, 1.3 Hz, 1H, CHCHtransH),
4.93 (ddt, J ϭ 10.2, 2.8, 1.3 Hz, 1H, CHCHcisH), 4.47 (t, J ϭ
7.9 Hz, 1H, CH), 3.75 (s, 3H, OCH3), 2.78 (ddt, J ϭ 7.9, 6.8,
1.3 Hz, 2H, CH2), 2.27 (s, 3H, CH3). 13C NMR (101 MHz,
CDCl3, ppm) ␦C: 154.9 (C), 144.5 (C), 137.3 (CHCH2), 132.8
(C), 129.5 (C), 128.5 (CH), 128.2 (CH), 128.1 (CH), 127.4
(CH), 125.8 (CH), 115.8 (CHCH2), 110.8 (CH), 55.6 (OCH3),
43.3 (CH), 39.1 (CH2), 20.7 (CH3). MS m/z (%) (ESIϩ): 275
([M ϩ Na]ϩ, 100), 270 ([M ϩ NH4]ϩ, 18), 211 ([M – allyl]ϩ,
22). HR-MS (ESIϩ) calcd for C18H20ONa [M ϩ Na]ϩ:
(lit.21 value [α]D20 Ϫ16.2 (c 1.4, CHCl3, for 99% ee of
the (S)-isomer)). IR (neat, cm–1) ␯max: 2919, 1721, 1498, 1241.
1H NMR (400 MHz, CDCl3, ppm) ␦⌯: 9.70 (t, J ϭ 2.2 Hz, 1H,
CHO), 7.32–7.23 (m, 4H, HAr), 7.22–7.16 (m, 1H, HAr), 6.98
(dd, J ϭ 8.3, 2.0 Hz, 1H, HAr), 6.87 (d, J ϭ 2.0 Hz, 1H, HAr),
6.75 (d, J ϭ 8.3 Hz, 1H, HAr), 5.00 (t, J ϭ 7.8 Hz, 1H, CH),
3.77 (s, 3H, OCH3), 3.09 (dd, J ϭ 7.8, 2.2 Hz, 2H, CH2), 2.23
(s, 3H, CH3). 13C NMR (126 MHz, CDCl3, ppm) ␦C: 201.9
(CHO), 154.5 (C), 142.9 (C), 131.3 (C), 129.8 (C), 128.8
(CH), 128.4 (CH), 128.0 (CH), 128.0 (CH), 126.3 (CH), 110.8
(CH), 55.5 (OCH3), 48.5 (CH2), 38.3 (CH), 20.6 (CH3). MS
m/z (%) (ESIϩ): 277 ([M ϩ Na]ϩ, 38), 237 (11), 211 ([M –
CH2CHO], 100). HR-MS (ESIϩ) calcd for C17H18O2Na [M ϩ
Na]ϩ: 277.1199; found: 277.1204. HPLC: Chiralpak IB, 0 °C,
2.0% i-PrOH in hexane, 0.5 mL/min, UV detection at 210.8 nm,
retention times: (S)-3-(2-methoxy-5-methylphenyl)-3-
Published by NRC Research Press

Roesner and Aggarwal
973
phenylpropanal, 24.7 min; (R)-3-(2-methoxy-5-methylphenyl)-
3-phenylpropanal, 27.6 min; 90% ee.
Supplementary data
Supplementary data are available with the article through
the journal Web site http://nrcresearchpress.com/doi/supp/
10.1139/v2012-069.
(R)-N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-
3-phenylpropan-1-amine (24)
A mixture of aldehyde 23 (25 mg, 98 ␮mol, 1.0 equiv),
diisopropylamine (28 ␮L, 0.20 mmol, 2.0 equiv), and NaB-
H(OAc)3 (42 mg, 0.20 mmol, 2.0 equiv) in anhydrous THF
(1.0 mL) was stirred for 18 h at ambient temperature. Then,
saturated NaHCO3(aq) solution (0.5 mL) was added, the
phases were separated, and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with
3.0 mol/L HCl(aq) and brine, dried over anhydrous Na2SO4,
filtered, and the solvent was removed under reduced pressure.
Purification of the residue by column chromatography (SiO2,
pentane/EtOAc/Et3N, 75:24:1) afforded tertiary amine 24
Acknowledgements
We wish to thank the Engineering and Physical Sciences
Research Council (EPSRC) and the European Research Coun-
cil (ERC: FP7/2007–2013, ERC grant No. 246785) for finan-
cial support. V.K.A. thanks the Royal Society for a Wolfson
Research Merit Award and EPSRC for a Senior Research
Fellowship. We thank Inochem-Frontier Scientific for the gen-
erous donation of boronic acids and boronic esters.
References
(23 mg, 68 ␮mol, 69%) as a pale yellow oil. [α]2D0 Ϫ11.0 (c
1.00, CHCl3) (lit.22 value [␣]D Ϫ6.14 (c 0.95, CHCl3, for
81% ee). TLC (pentane/EtOAc/Et3N, 75:24:1): 0.16. IR
(neat, cm–1) ␯max: 2962, 1497, 1239. 1H NMR (400 MHz, CDCl3,
ppm) ␦⌯: 7.31–7.22 (m, 4H, HAr), 7.16–7.12 (m, 1H, HAr),
7.07 (d, J ϭ 2.2 Hz, 1H, HAr), 6.94 (dd, J ϭ 8.2, 2.2 Hz, 1H,
HAr), 6.72 (d, J ϭ 8.2 Hz, 1H, HAr), 4.35 (t, J ϭ 7.7 Hz, 1H,
CH), 3.75 (s, 3 H, OCH3), 2.98 (sept, J ϭ 6.5 Hz, 2H,
CH(CH3)2), 2.37–2.30 (m, 2H, CHHN ϩ CHHCH), 2.26 (s,
3H, CArCH3), 2.16–2.09 (m, 2H, CHHN ϩ CHHCH), 0.94
(d, J ϭ 6.5 Hz, 6H, CH3), 0.93 (d, J ϭ 6.5 Hz, 6H, CH3).
13C NMR (126 MHz, CDCl3, ppm) ␦C: 154.9 (C), 145.1 (C), 133.5
(C), 129.5 (C), 128.3 (CH), 128.2 (CH), 128.0 (CH), 127.1
(CH), 125.6 (CH), 110.6 (CH), 55.6 (OCH3), 48.7
(CH(CH3)2), 44.1 (CH2N), 41.3 (CArCH), 37.0 (CH2CH), 20.7
(CH3), 20.5 (CArCH3). MS m/z (%) (ESIϩ): 340 ([M ϩ H]ϩ,
100), 298 ([M – i-Pr]ϩ, 15), 211 ([M – (CH)2N(i-Pr)2]ϩ, 7),
113 (4). HR-MS (ESIϩ) calcd for C23H34ON [M ϩ H]ϩ:
340.2635; found: 340.2625.
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(R)-Tolterodine (1)
This compound was synthesized following a literature pro-
cedure performed on a different substrate.7e Flash chromatog-
raphy (SiO2, pentane/EtOAc, 70:30, 2% Et3N) yielded a pale
yellow oil, which crystallized upon standing. (R)-tolterodine
(1; 91 mg, 0.28 mmol, 87%) was obtained as an off-white
solid; mp 78–79 °C (pentane/EtOAc/Et3N). [α]20 ϩ28.0 (c
0.50, MeOH) (lit.7e value [␣]D ϩ32.5 (c 0.89,DMeOH, for
99% ee). TLC (pentane/EtOAc, 70:30, 2% Et3N): 0.18. IR (neat,
cm–1) ␯max: 3249, 2971, 2927, 1493. H NMR (500 MHz,
1
CDCl3, ppm) ␦⌯: 10.27 (br s, 1H, CArOH), 7.36–7.32 (m, 4H,
HAr), 7.26–7.22 (m, 1H, HAr), 6.87 (dd, J ϭ 8.2, 2.0 Hz, 1H,
HAr), 6.82 (dd, J ϭ 8.2, 1.5 Hz, 1H, HAr), 6.57 (s, 1H, HAr),
4.50 (dd, J ϭ 10.8, 3.2 Hz, 1H, CH), 3.25 (sept, J ϭ 6.7 Hz,
2H, CH(CH3)), 2.79–2.70 (m, 1H, CHHN), 2.46–2.33 (m, 2H,
CHHN ϩ CHHCH), 2.14 (s, 3H, CArCH3), 2.13–2.04 (m, 1H,
CHHCH), 1.15 (d, J ϭ 6.7 Hz, 6H, CH3), 1.10 (d, J ϭ 6.7 Hz,
6H, CH3). 13C NMR (126 MHz, CDCl3, ppm) ␦C: 153.2 (C),
144.7 (C), 132.3 (C), 129.3 (C), 128.6 (CH), 128.5 (CH),
128.3 (CH), 127.7 (CH), 126.1 (CH), 118.1 (CH), 48.0
(CH(CH3)2), 42.1 (CH2N), 39.4 (CArCH), 33.2 (CH2CH), 20.7
(CArCH3), 19.9 (CH3), 19.5 (CH3). MS m/z (%) (ESIϩ): 348
([M ϩ Na]ϩ, 1), 326 ([M ϩ H]ϩ, 100), 284 ([M – i-Pr ϩ H]ϩ, 2),
197 ([M – (CH2)2N(i-Pr)2]ϩ, 1), 109 ([Ar]ϩ, 5). HR-MS (ESIϩ)
calcd for C22H32ON [M ϩ H]ϩ: 326.2478; found: 326.2466.
Published by NRC Research Press

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