Enantioenriched synthesis of Escitalopram using lithiation-borylation methodology

Article abstract of DOI:10.1016/j.tet.2011.09.142

The asymmetric synthesis of Escitalopram has been completed using a lithiation-borylation reaction as the key step. Suitably functionalized enantioenriched carbamate (er 98:2) and boronic ester coupling partners were prepared and following deprotonation with s-BuLi and borylation, the tertiary alcohol was obtained in 42% yield and 93:7 er. The lithiation-borylation reaction was found to tolerate nitrile, benzylic alcohol and N-Boc functionalities. The tertiary alcohol was converted to Escitalopram in three further steps.

Full text of DOI:10.1016/j.tet.2011.09.142

Tetrahedron 67 (2011) 10082e10088
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioenriched synthesis of Escitalopram using lithiationeborylation
methodology
*
Benjamin M. Partridge, Stephen P. Thomas, Varinder K. Aggarwal
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Received in revised form 28 September 2011
Accepted 29 September 2011
Available online 6 October 2011
The asymmetric synthesis of Escitalopram has been completed using a lithiationeborylation reaction as
the key step. Suitably functionalized enantioenriched carbamate (er 98:2) and boronic ester coupling
partners were prepared and following deprotonation with s-BuLi and borylation, the tertiary alcohol was
obtained in 42% yield and 93:7 er. The lithiationeborylation reaction was found to tolerate nitrile,
benzylic alcohol and N-Boc functionalities. The tertiary alcohol was converted to Escitalopram in three
further steps.
This paper is dedicated with deep admira-
tion to Professor Gilbert Stork, a true gen-
tleman and outstanding scientist, on the
occasion of his 90th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lithiationeborylation
Escitalopram
Total synthesis
Carbamate
Boronic ester
1. Introduction
give both the enantioenriched diol (S)-2a and ether (S)-1.1,6deg En-
zymatic resolution by either acylation of the benzyl alcohol (ꢀ)-2a
Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI)
antidepressant. Developed by Lundbeck, it rapidly achieved
blockbuster status generating over $1.5B sales in 2010.1,2 Originally
marketed as a racemate, Citalopram, it was later found that the (S)-
enantiomer (Escitalopram) was significantly more potent than both
the (R)-enantiomer and the racemic mixture.3
Having recently developed lithiationeborylation methodology
for the synthesis of enantioenriched tertiary alcohols we were keen
to explore the applications of this transformation in the asym-
metric synthesis of a complex, and challenging target.4 This would
help establish the scope and limitations of the methodology.
A number of syntheses of Escitalopram have been reported that
rely on a resolution to obtain enantiopure material (Scheme 1). In
these syntheses a double Grignard addition is used to elaborate
lactone 35 and then either resolution of the diol (ꢀ)-2a and cycli-
zation, or cyclization and resolution of cyclic ether (ꢀ)-1 is used to
give the enantioenriched product.1,6 Resolution byco-crystallization
(R¼H) or deacylation of the benzyl acetate (ꢀ)-2b (R¼Ac) have also
been used to give the enantioenriched diol (S)-2a.6b,c
An impressive enantioselective synthesis of Escitalopram has
been reported by Albert (Scheme 2).7 Here the diaryl ketone 7 was
initially complexed with methyl boronic acid and N-methyl-
pseudoephedrine 8. Subsequent addition of the amino Grignard
reagent 10 to the complexed ketone 9 occurred with high selectivity
leading to the tertiary alcohol (S)-11 in 77% yield and 92% ee. The ee
was further enhanced to 99.3% by resolution with (þ)-DPTTA 6.
As with previous syntheses we envisaged that Escitalopram
could be made via the diol (S)-12. In turn, the diol (S)-12, being
a
tertiary alcohol, could be obtained through
a
lith-
iationeborylation reaction of the enantioenriched benzyl carba-
mate (S)-13 and an aryl boronic ester (Fig. 1). Not only would this
represent a convergent synthesis, but it would also enable us to test
the functional group compatibility of the lithiationeborylation re-
action. We envisaged that two boronic esters 14 and 15 could be
used. Boronic ester 14 would require late-stage functionalization of
the benzylic position to allow ring-closing ether formation and
boronic ester 15, which incorporated a protected benzylic alcohol,
ready-primed for ring-closure. Careful choice of protecting group
on the benzylic alcohol would allow this otherwise incompatible
with (þ)-di-p-toluoyl- -tartaric acid [(þ)-DPTTA 6] has been used to
D
* Corresponding author. Tel.: þ44 0 117 954 6315; fax: þ44 0 117 925 1295;
e-mail addresses: stephen.thomas@bristol.ac.uk (S.P. Thomas), V.Aggarwal@bris-
tol.ac.uk (V.K. Aggarwal).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.142

B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
10083
Scheme 1. Previous synthesis of Escitalopram using resolution.
functionality to be used in the lithiationeborylation reaction, and
also act as a leaving group for the ring-closing etherification. For
these reasons we chose the THP protecting group.
2. Results and discussion
The synthesis of Escitalopram began with the preparation of the
coupling partners needed for the lithiationeborylation reaction,
boronic esters 14 and 15, and the enantioenriched carbamate (S)-
12. Boronic ester 14 was readily synthesized in two steps, in a single
pot, from aryl bromide 16 (Scheme 3). Using the method of Hall,8
lithiumehalogen exchange at ꢁ98 ꢂC, to prevent addition of the
organolithium to the nitrile, and quenching with trimethoxyborane
gave an intermediate boronic ester. Transesterification with pina-
col, via the boronic acid, gave the target pinacol boronic ester in 89%
yield over the two steps. Boronic ester 15 was prepared by a similar
lithiumehalogen exchange, following benzylic oxidation and THP
Scheme 2. Enantioselective synthesis of Escitalopram.
Scheme 3. Synthesis of boronic esters 14 and 15.
Fig. 1. Retrosynthetic analysis of Escitalopram.

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B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
protection of the benzyl alcohol, in a slightly reduced yield com-
pared to the non-oxygenated boronic ester 14. This was due to
partial hydrolysis of the THP group followed by intramolecular
trapping of the alcohol to give a cyclic boronic ester.
competing inversion in the attack of the lithiated carbamate on the
boronic ester 14 (it occurs predominantly with retention).4c In
addition to the tertiary alcohol, we also observed a significant
amount of phenol 23. This came from lithiation ortho to fluorine,
followed by trapping of the boronic ester and oxidation to the
phenol. In an attempt to counter the ortho-lithiation we added
TMEDA during the deprotonation as it was hoped this would inhibit
the precomplexation of s-BuLi to the fluorine and so prevent the
ortho-lithiation.10 Pleasingly, this completely stopped ortho-lith-
iation, but now gave another side product; the lactam 24.
Lithiationeborylation using the more functionalized boronic
ester 15 was also successful (Scheme 5). Once again, the addition of
TMEDA in the deprotonation step stopped any ortho-lithiation but
competing formation of the corresponding lactam was observed.
We found it beneficial to add the boronic ester at ꢁ98 ꢂC to prevent
addition of the lithiated carbamate to the aromatic nitrile.
With the tertiary alcohol (S)-22a in hand we turned our atten-
tion to benzylic oxidation and cyclization to form the cyclic ether
(S)-25. Initial attempts focused on the radical bromination of the
benzylic methyl group. However, no conditions were found to effect
the benzylic bromination using either AIBN or light as the radical
initiator. Fortunately, basic Pb(OAc)4 and I2 successfully mediated
the intramolecular etherification but in low yield, although im-
portantly, without racemization of the tertiary alcohol. Our syn-
thesis was completed by Boc-deprotection and reductive amination
to give Escitalopram (Scheme 6).
The enantioenriched carbamate (S)-13 was prepared in four
steps from propargylamine 18 (Scheme 4). Boc-protection of the
commercially available propargylamine 18 and zinc-mediated ad-
dition of the alkyne to 4-fluorobenzaldehyde using (þ)-N-methyl-
ephedrine ((þ)-NME) as
a chiral ligand on zinc gave the
enantioenriched alcohol (R)-20 with an er of 98:2. The asymmetric
alkyne addition was developed by Carreira and had previous been
employed for the addition of N,N-dibenzylpropargylamine to al-
dehydes.9 Here the methodology was extended to include the ad-
dition of N-Boc protected amines. Hydrogenation using PtO2 and
carbamoylation gave the enantioenriched carbamate (S)-13 in 74%
yield over the four steps and with 98:2 er.
In order to address the low yield in the cyclization reaction of
tertiary alcohol (S)-22a we decided to complete an additional
synthesis of Escitalopram using the more functionalized tertiary
alcohol (S)-22b from the lithiationeborylation reaction using bo-
ronic ester 15 (Scheme 7). In this case, acid-catalyzed THP-
deprotection with concomitant Boc-deprotection and intra-
molecular ether cyclization gave a mixture of ether (S)-26 and diol
(S)-12, arising from THP-deprotection alone. It is worth high-
lighting that the careful choice of the THP and Boc protecting
groups allowed both deprotection reactions to be carried out in
a single step and the acidic conditions mediate simultaneous ring-
closing etherification. Presumably any adventitious water present
prevents complete ether formation. However, this mixture was
subjected to N-methylation and the free diol was cyclized using
mesyl chloride and base to give Escitalopram in 62% overall yield
from (S)-22b.
Scheme 4. Synthesis of enantioenriched carbamate (S)-13.
With both of the coupling partners prepared, we turned our
attention to the key lithiationeborylation reaction. This would be
a significant test of the methodology as both the required boronic
esters 14 and 15 bear significant functionality. Boronic ester 14
incorporates a nitrile group, which could be susceptible to attack by
the lithiated carbamate and an ortho-methyl group, which could
sterically hinder attack at the boronic ester. Boronic ester 15 is even
more sterically hindered. The carbamate (S)-13 also bears func-
tionality, which could hinder the reaction. The electrophilic Boc-
group could trap the lithiated carbamate in an intramolecular
manner or decrease the nucleophilicity of the organolithium by
coordination of the amine or carbonyl groups.
In practice, lithiation of carbamate (S)-13 with s-BuLi, followed
by addition of the boronic ester 14 and further addition of MgBr2/
MeOH gave the enantioenriched tertiary alcohol (S)-22 in 42%
isolated yield and excellent 93:7 er after oxidation (Scheme 5). The
starting carbamate was reisolated in 27% yield. These conditions
were developed to maximize the er of the reaction since the in-
termediate boronate complex is prone to reversibility, and the
lithiated carbamate generated undergoes competing racemization
and readdition to the boronic ester.4c The addition of MgBr2/MeOH
not only reprotonates any lithiated carbamate generated by the
reverse process thereby preventing racemization and re-
combination but it also promotes the 1,2-metallate rearrangement.
In the absence of MgBr2 the tertiary alcohol was obtained in lower
yield (21%). The slight decrease in er of the product alcohol (S)-22
3. Conclusion
In this paper we set out to test the applicability of the lith-
iationeborylation reaction for the synthesis of a highly function-
alized target molecule, Escitalopram. Using
a novel set of
disconnections, the lithiationeborylation reaction was successfully
applied to two syntheses of Escitalopram. Pleasingly, we found that
boronic esters bearing functionality susceptible to nucleophilic
attack (aromatic nitrile and benzylic alcohol) and a carbamate with
both chelating substituents and a N-Boc protecting group were
tolerated in the lithiationeborylation reaction. However, caution
needs to be taken when using aromatic substituents that can direct
ortho-lithiation as competing aromatic lithiation can occur during
deprotonation of the carbamate. In our case, ortho-lithiation to
fluorine was observed. The addition of TMEDA in the deprotonation
step of the reaction was found to inhibit such ortho-lithiation.
4. Experimental
4.1. General methods
All air and moisture sensitive manipulations were performed
either under argon using standard Schlenk techniques. Anhydrous
compared to the carbamate arises from
a small degree of

B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
10085
Scheme 5. Key lithiationeborylation to construct the tertiary alcohol (S)-22.
Scheme 7. Alternative synthesis of Escitalopram using the more functionalized ter-
tiary alcohol (S)-22b.
Scheme 6. Cyclization and methylation to give Escitalopram.
Spectrum 100 FT-IR spectrometer with an ATR diamond cell, irra-
diating between 4000 cmꢁ1 and 600 cmꢁ1. Chiral HPLC separations
were done using an Agilent 1100 series high performance liquid
chromatography units using HP Chemstation for LC or LC-MS.
solvents were purified by means of a Grubbs-type solvent system.11
In addition, Et2O was stored over oven dried 4 A molecular sieves
ꢀ
under argon for at least 16 h prior to use. All reagents and solvents
were used as purchased if not otherwise stated. Melting points
were determined with a Kofler hot stage apparatus and were not
corrected. Mass spectrometry was carried out by the University of
Bristol Mass Spectrometry service. Elemental analysis was carried
out by the University of Bristol Microanalysis service. Optical ro-
tations were obtained using a PerkineElmer 241MC polarimeter at
the sodium D line (589 nm) and are reported as follows: ½aꢃTD,
concentration (g/100 mL), and solvent. NMR spectra were acquired
on either a Jeol Lambda 300 (1H: 300 MHz, 11B: 96 MHz), a Varian
400 (1H: 400 MHz, 13C: 101 MHz) or a Varian 500 (13C: 126 MHz)
NMR spectrometer. 1H and 13C NMR spectra were referenced to
external tetramethylsilane via the residual protio solvent (1H) or the
solvent itself (13C). All chemical shifts are reported in parts per
million. Infrared spectra were recorded using a PerkineElmer
4.2. Preparation of compound 14
Using a modification of the procedure by Hall and co-workers,8
n-BuLi (1.6 M, 7.5 mL, 12.0 mmol) was added drop-wise to a solu-
tion of 4-bromo-3-methylbenzonitrile (2.34 g, 12.0 mmol) in an-
hydrous THF (24 mL) at ꢁ98 ꢂC. The mixture was stirred at ꢁ98 ꢂC
for 10 min and trimethylborate (2.0 mL, 18 mmol) was added drop-
wise. The reaction mixture was kept at ꢁ98 ꢂC for 30 min before
being warmed to room temperature and stirred for a further
15 min. Aqueous HCl (1 M, 5 mL, 5 mmol) was added and the
mixture was stirred for 15 min before being diluted with H2O
(20 mL) and extracted with EtOAc (3ꢄ20 mL). The combined or-
ganic phases were dried (MgSO4) and concentrated in vacuo.
Pinacol (1.42 g, 12.0 mmol) and MgSO4 (1.44 g, 12.0 mmol) were

10086
B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
added to a solution of the residue dissolved in CH2Cl2 (25 mL). The
mixture was stirred for 15 h at room temperature, MgSO4 removed
by filtration and the filtrate concentrated in vacuo. The product was
purified by column chromatography (5% EtOAc/petroleum ether) to
give the boronic ester 14 (2.59 g, 89%) as needles (petroleum ether);
[Found: C, 69.44; H, 7.68, N, 5.61. C14H18NO2B requires C, 69.17; H,
7.46; N, 5.76%]; mp¼139.5e140.5 ꢂC (petroleum ether); nmax (neat):
4.5. Preparation of compound 15
n-BuLi (1.6 M, 3.3 mL, 5.24 mmol) was added drop-wise to
a solution of 17 (1.55 g, 5.24 mmol) in anhydrous THF (15 mL) at
ꢁ98 ꢂC. The mixture was stirred at ꢁ98 ꢂC for 15 min and trime-
thylborate (1.23 mL, 10.5 mmol) was added drop-wise. The reaction
mixture was kept at ꢁ98 ꢂC for 40 min before being warmed to
room temperature and stirred for a further 1 h H2O (5.0 mL) was
added and the mixture was stirred for 1 h. The mixture was diluted
with H2O (15 mL) and extracted with EtOAc (3ꢄ20 mL). The com-
bined organic phases were dried (Na2SO4) and concentrated in
vacuo. Pinacol (0.619 g, 5.24 mmol) and MgSO4 (0.628 g,
5.24 mmol) were added to a solution of the residue dissolved in
CH2Cl2 (20 mL). The mixture was stirred for 15 h at room temper-
ature, MgSO4 removed by filtration and the filtrate concentrated in
vacuo. The product was purified by column chromatography (10%
EtOAc/petroleum ether) to give the boronic ester 15 (0.915 g, 51%) as
an amorphous solid (hexanes); [Found: C, 66.65; H, 7.88, N, 4.19.
C19H26BNO4 requires C, 66.49; H, 7.64; N, 4.08%]; mp¼64e65 ꢂC
2969, 2235, 1347, 1146, 1062 cmꢁ1
; dH (400 MHz, CDCl3) 7.83 (1H, d,
J 8.0 Hz, ArH), 7.41e7.47 (2H, m, ArH), 2.56 (3H, s, AreMe), 1.36
(12H, s, 2ꢄ CMe2); dC (101 MHz, CDCl3) 145.6, 136.1, 132.6, 128.0,
119.0, 113.9, 84.1, 24.8, 21.9; dB (96 MHz, CDCl3): 30.7; m/z (EI): 243
(Mþ, 10), 228 (80), 84 (100); HRMS (EI): Mþ, found 243.1440.
C14H18NO2B requires 243.1431.
4.3. Preparation of compound 27
Using a modification of the procedure byBakerand co-workers,12
1,10-azobis(cyclohexanecarbonitrile) (0.343 g, 1.41 mmol) was
added to a solution of 4-bromo-3-methylbenzonitrile (2.75 g,
14.1 mmol) and N-bromosuccinimide (2.75 g, 15.5 mmol) in
a,a,
a-
(hexanes); nmax (neat): 2946, 2225, 1340, 1264, 1113, 1029 cmꢁ1
; dH
trifluorotoluene (70 mL). The mixture was heated to reflux for 18 h.
Upon cooling to room temperature, H2O (75 mL) was added and the
mixture extracted with CH2Cl2 (3ꢄ50 mL). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. NaOAc
(5.76 g, 70.0 mmol) was added to a solution of the residue in di-
methyl formamide (45 mL) and the mixture was heated to 90 ꢂC for
18 h. Upon cooling to room temperature, H2O (100 mL) was added
andthe mixturewasextracted withEtOAc(3ꢄ75 mL). Thecombined
organic phases were washed with brine (75 mL), dried (MgSO4) and
concentrated in vacuo. Aqueous NaOH (2 M, 7.1 mL,14.2 mmol) was
added to a solution of the residue in MeOH (60 mL) and the mixture
was stirred for 4 h. The solution was concentrated to ¼ of its volume
in vacuo and the mixture was extracted with EtOAc (3ꢄ50 mL). The
combined organic phases were washed with brine (50 mL), dried
(MgSO4) and concentrated in vacuo. The product was purified by
column chromatography (20% EtOAc/petroleum ether) to give the
alcohol 27 (1.51 g, 51%) as needles (hexane); mp¼152e154 ꢂC
(hexane); dH (400 MHz, DMSO-d6): 7.83e7.86 (1H, m, ArH); 7.81 (1H,
d, J 8.2 Hz, ArH), 7.68 (1H, dd, J 8.2, 2.1 Hz, ArH), 5.69 (1H, t, J 5.6 Hz,
OH), 4.53 (2H, d, J 5.6 Hz, CH2); dC (101 MHz, DMSO-d6): 143.1,133.4,
131.9, 131.0, 126.6, 118.3, 110.6, 62.1. The data were consistent with
those reported by Baker and co-workers.12
(400 MHz, CDCl3) 7.87 (1H, d, J 7.7 Hz, ArH), 7.82e7.84 (1H, m, ArH),
7.54 (1H, dd, J 7.7, 1.6 Hz, ArH), 4.97 (1H, d, J 13.6 Hz, ArCHaHb), 4.82
(1H,d, J 13.6 Hz, ArHaHb), 4.77 (1H, t, J 3.4 Hz, CH), 3.89 (1H, ddd, J
11.5, 8.5, 3.3 Hz, OCHaHb), 3.53e3.59 (1H, m, OCHaHb), 1.51e1.96
(6H, m, OCH2CH2CH2CH2), 1.35 (12H, s, 2ꢄ CMe2); dC (101 MHz,
CDCl3) 146.2, 136.0, 130.3, 129.6, 119.0, 114.2, 98.2, 84.3, 67.4, 62.0,
30.5, 25.4, 24.8, 24.8, 19.3; dB (96 MHz, CDCl3): 30.4; m/z (CI): 344
(MHþ, 50), 260 (80), 85 (100); HRMS (CI): found 344.2026.
C19H17NO4B requires 344.2033.
4.6. Preparation of compound 19
Di-tert-butyl dicarbonate (14.0 mL, 65.3 mmol) was added to
a solution of 18 (4.10 g, 59.4 mmol) and Et3N (9.1 mL, 65.3 mmol) in
CH2Cl2 (120 mL). The mixture was stirred at room temperature for
15 h before being diluted with H2O (50 mL). Saturated aqueous
NaHCO3 (50 mL) was added and the mixture was extracted with
CH2Cl2 (3ꢄ100 mL). The combined organic phases were washed
with water (100 mL), dried (MgSO4) and concentrated in vacuo to
give the alkyne 19 (10.0 g, 100%) as a pale yellow oil; The product
was used without further purification. dH (400 MHz, CDCl3), 4.05
(2H, br s, CH2), 2.92 (3H, s, NMe), 2.22 (1H, t, J 2.4 Hz, CH),1.41 (9H, s,
CMe3); dC (101 MHz, CDCl3) 155.2, 80.1, 79.2, 71.2, 37.9, 33.4, 28.3.
The data were consistent with those reported by Paul and co-
workers.13
4.4. Preparation of compound 17
para-Tolylsulfonic acid monohydrate (52.0 mg, 0.270 mmol)
was added to a solution of 27 (0.575 g, 2.73 mmol) and dihydro-
2H-pyran (0.29 mL, 3.27 mmol) in anhydrous CH2Cl2 (5.5 mL) and
the mixture was stirred at room temperature for 15 h. Saturated
aqueous NaHCO3 (10 mL) was added and the mixture was diluted
with water (10 mL) and extracted with CH2Cl2 (3ꢄ15 mL). The
combined organic phases were dried (MgSO4) and concentrated
in vacuo. The product was purified by column chromatography
(10% EtOAc/petroleum ether) to give the bromide 17 (0.666 g, 83%)
as needles (petroleum ether); [Found: C, 53.01; H, 4.80, N, 4.74.
C13H14NO2Br requires C, 52.72; H, 4.76; N, 4.73%]; mp¼61e63 ꢂC
4.7. Preparation of compound (R)-20
Zn(OTf)2 (0.517 g, 1.42 mmol) was dried in vacuo (0.5 mbar) at
120 ꢂC for 3 h (þ)-N-methylephedrine (0.214 g, 1.19 mmol), Et3N
(0.17 mL, 1.23 mmol) and anhydrous toluene (1.5 mL) were added
and the mixture was stirred at room temperature for 3 h. Alkyne 19
(0.190 g, 1.23 mmol) was added and the mixture stirred for 15 min.
The mixture was cooled to 5 ꢂC and 4-fluorobenzaldehyde (0.10 mL,
0.95 mmol) was added. After stirring at 5 ꢂC for 16 h, H2O (10 mL)
was added and the mixture was extracted with EtOAc (3ꢄ10 mL).
The combined organic phases were washed with brine (15 mL),
dried (MgSO4) and concentrated in vacuo. The product was purified
by column chromatography (20% EtOAc/petroleum ether) to give
(petroleum ether); nmax (neat): 2941, 2232, 1465, 1121, 1022 cmꢁ1
;
dH (400 MHz, CDCl3) 7.80e7.86 (1H, m, ArH), 7.64 (1H, d, J 8.2 Hz,
ArH), 7.42 (1H, dd, J 8.2, 2.1 Hz, ArH), 4.82 (1H, d, J 14.4 Hz,
ArCHaHb), 4.79 (1H, t, J 3.4 Hz, CH), 4.54 (1H, d, J 14.4 Hz, ArCH-
aHb), 3.87 (1H, ddd, J 11.5, 8.7, 3.2 Hz, OCHaHbCH2), 3.54e3.62 (1H,
m, OCHaHbCH2), 1.51e1.98 (6H, m, OCH2CH2CH2CH2); dC
(126 MHz, CDCl3) 140.0, 133.2, 131.6, 131.5, 127.2, 118.4, 111.5, 98.6,
67.6, 62.2, 30.3, 25.3, 19.2; m/z (CI): 296 (MHþ, 30), 212 (45), 85
(100); HRMS (CI): MHþ, found 296.0294. C13H15NO2Br requires
296.0286.
the alcohol (R)-20 (0.120 g, 85%, er¼98:2) as a colourless oil; ½a D21
ꢃ
ꢁ16.0 (c 1.1, CHCl3); nmax (neat): 3385, 2978, 1673, 1391, 1222,
1148 cmꢁ1
; dH (400 MHz, CDCl3) 7.40e7.56 (2H, m, ArH), 6.96e7.10
(2H, m, ArH), 5.45 (1H, d, J 3.5 Hz, CH), 4.10 (2H, br s, NCH2), 2.89
(3H, s, NMe), 1.44 (9H, s, CMe3); dC (101 MHz, CDCl3) 162.5 (d, JF
246.0 Hz), 155.3, 136.5, 128.4 (d, JF 7.8 Hz), 115.2 (d, JF 21.8 Hz), 83.3,
82.0, 80.3, 63.7, 38.3, 33.6, 28.3; m/z (ESI) 316 (MNaþ), 260; HRMS

B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
10087
(ESI): MNaþ, found 316.1319428. C16H20NO3FNa requires
316.1306110.
1.0, CHCl3); mp¼151e153 ꢂC (hexane/EtOAc); nmax (neat): 3422,
2934, 2229, 1669, 1222, 1156 cmꢁ1
; dH (300 MHz, CDCl3): 7.81 (1H,
d, J 7.9 Hz, ArH); 7.53 (1H, d, J 8.0 Hz, ArH), 7.36 (1H, s, ArH),
7.12e7.26 (m, 2H, ArH), 6.96 (2H, t, J 8.4 Hz, ArH), 4.05 (1H, br s, OH),
3.34 (1H, br s, NCHaHb), 3.23 (1H, br s, NCHaHb), 2.77 (3H, s, NMe),
2.29 (1H, dt, J 14.1, 7.2, 7.2 Hz, OCCHaHb), 2.06e2.22 (1H, m,
OCCHaHb), 2.01 (3H, s, ArMe), 1.34e1.58 (2H, m, NCH2CH2), 1.42 (9H,
s, CMe3); dC (126 MHz, CDCl3): 161.6 (d, JF 249 Hz), 156.7, 149.5,
141.7, 138.9, 135.6, 129.0, 127.6 (d, JF 7.8 Hz), 126.9, 118.8, 114.9 (d, JF
15.4 Hz), 111.1, 79.7, 77.8, 48.9 (NCH2 rotamer), 48.1 (NCH2), 38.1
(OCCH2 rotamer), 36.7 (OCCH2), 34.0, 28.3, 21.9, 21.3; m/z (CI): 339
(MHþꢁt-BuO, 98), 295 (100); HRMS (ESI): MNaþ, found
435.2061220. C24H29N2O3FNa requires 435.2054421.
4.8. Preparation of compound (S)-21
PtO2 (16 mg, 0.070 mmol) was added to a solution of alcohol (R)-
20 (0.418 g, 1.43 mmol) in EtOAc (8 mL). The mixture was purged
with nitrogen (ꢄ3) then hydrogen (ꢄ3) before being stirred under
hydrogen (1 atm) for 15 h. The mixture was filtered through Celite,
which was washed with EtOAc (30 mL), and the filtrate was con-
centrated in vacuo. The product was purified by column chroma-
tography (20% EtOAc/petroleum ether) to give the alcohol (S)-21
(0.385 g, 91%, er¼98:2) as pale yellow needles (hexanes); ½a D22
ꢃ
ꢁ16.0 (c 1.5, CHCl3); mp¼81e83 ꢂC (hexanes); nmax (neat): 3416,
2934, 1664, 1395, 1215, 1155, 1078 cmꢁ1
; dH (400 MHz, CDCl3)
4.11. Preparation of compound 23
7.28e7.35 (2H, m, ArH), 7.02 (2H, t, J 8.6 Hz, ArH), 4.70 (1H, s, CH),
3.31 (1H, br s, NCHaHb), 3.21 (1H, br s, NCHaHb), 2.80 (3H, s, NMe),
1.50e1.74 (4H, m, CHCH2CH2), 1.43 (9H, br s, CMe3); dC (126 MHz,
CDCl3) 162.1 (d, J 246 Hz), 155.9, 140.6, 127.4 (d, JF 7.8 Hz), 115.1 (d,
JF¼21.5 Hz), 79.3, 73.5, 48.2, 35.9, 34.0, 28.4, 23.9; m/z (ESI): 320
(MNaþ), 264; HRMS (ESI): MNaþ, found 320.1632429.
C16H24NO3FNa requires 320.1631870.
s-BuLi (1.3 M, 0.24 mL, 0.312 mmol) was added drop-wise to
a solution of (ꢀ)-13 (0.116 g, 0.282 mmol) in anhydrous Et2O (1 mL)
cooled to ꢁ78 ꢂC. The mixture was stirred at ꢁ78 ꢂC for 15 min
before 14 (0.98 M in anhydrous Et2O, 0.43 mL, 0.423 mmol) was
added drop-wise. The solution was stirred at ꢁ78 ꢂC for 1 h before
warming and stirring at room temperature for 2 h. A pre-cooled
solution of aqueous NaOH (2 M, 1.33 mL) and aqueous H2O2 (30%,
0.51 mL) was added to the mixture at 0 ꢂC. The mixture was stirred
for 16 h at room temperature before being diluted with water
(5 mL). The mixture was extracted with Et2O (3ꢄ5 mL) and the
combined organic phases were washed with brine (10 mL), dried
(MgSO4) and concentrated in vacuo. The product was purified by
column chromatography (30% EtOAc/petroleum ether) to give the
phenol 23 (54.6 mg, 44%) as a colourless oil; nmax (neat): 3264, 2973,
4.9. Preparation of compound (S)-13
Et3N (0.46 mL, 3.00 mmol) was added to a solution of (S)-21
(0.447 g, 1.50 mmol) and N,N-diisopropylcarbamoyl chloride
(0.492 g, 3.00 mmol) in CH2Cl2 (15 mL) and the mixture was heated
to reflux for 6 days. Upon cooling to room temperature, H2O
(30 mL) and saturated aqueous NaHCO3 (20 mL) were added and
the mixture was extracted with CH2Cl2 (3ꢄ30 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo. The
product was purified by column chromatography (30% EtOAc/pe-
troleum ether) to give the carbamate (S)-13 (0.609 g, 99%, er¼98:2)
1665, 1301, 1159 cmꢁ1
; dH (400 MHz, CDCl3) 7.00 (1H, dd, JH 8.4 Hz,
JF 10.3 Hz, ArH); 6.95 (1H, dd, JH 2.1 Hz, JF 8.4 Hz, ArH), 6.79 (1H,
ddd, JH 8.4, 2.1 Hz, JF 4.5 Hz, ArH), 6.19 (1H, d, JF 22.2 Hz, OH), 5.60
(1H, t, J 6.8 Hz, OCH), 4.07 (1H, br s, NCH), 3.80 (1H, br s, NCH), 3.20
(2H, br s, NCH2), 2.78 (3H, s, NMe), 1.82e1.93 (1H, m, OCHCHaHb),
1.66e1.77 (1H, m, OCHCHaHb), 1.52 (2H, s, NCH2CH2), 1.43 (9H, s,
CMe3), 1.22 (12H, br s, 2ꢄ CHMe2); dC (101 MHz, CDCl3) 155.8, 155.1,
150.6 (d, JF 241 Hz) 143.9 (d, JF 14.0 Hz), 137.9, 118.1 (d, J 3.9 Hz),
115.7 (d, JF 5.5 Hz), 115.6 (d, JF 25.7 Hz), 79.4, 75.9, 48.3, 45.9, 34.0,
33.9, 28.4, 23.9, 21.1; m/z (CI): 340 (MHþꢁBoc, 45), 196 (80) 57
(100); HRMS (ESI): found 463.2597190. C23H37N2O5FNa requires
463.257816.
as a colourless oil; ½a D24
ꢃ
ꢁ3.2 (c 0.6, CHCl3); nmax (neat): 2971, 1685,
dH (300 MHz, CDCl3) 7.23e7.35 (2H, m,
1366, 1286,1134,1047 cmꢁ1
;
ArH), 6.94e7.08 (2H, m, ArH), 5.67 (1H, t, J 6.8 Hz, OCH), 4.03 (1H, br
s, NCH), 3.79 (1H, br s, NCH), 3.20 (2H, br s, NCH2), 2.78 (3H, s,
NCMe), 1.82e1.99 (1H, m, CHCHaHb), 1.65e1.82 (1H, m, CHCHaHb),
1.42 (9H, br s, CMe3), 1.32e1.64 (2H, m, NCH2CH2), 1.06e1.32 (12H,
m, N(CHMe2)2); dC (126 MHz, CDCl3) 162.1 (d, JF 246 Hz), 155.7,
154.8, 137.1, 128.1 (d, JF 7.8 Hz), 115.2 (d, JF 21.5 Hz), 79.2, 75.5, 48.2,
45.8, 34.0, 33.9, 28.4, 24.0, 21.1; m/z (CI): 425 (MHþ, 8), 224 (95),180
(100); HRMS (CI): MHþ found 425.2805, C23H38N2O4F requires
425.2816.
4.12. Preparation of compound 24
4.10. Preparation of compound (S)-22a
s-BuLi (1.3 M, 0.10 mL, 0.130 mmol) was added drop-wise to
a solution of (ꢀ)-13 (0.2 M in anhydrous Et2O, 0.61 mL, 0.122 mmol)
and TMEDA (0.02 mL, 0.134 mmol) cooled to ꢁ78 ꢂC. The mixture
was stirred at ꢁ78 ꢂC for 3 h before CD3OD (0.05 mL) was added.
The mixture was warmed to room temperature and diluted with
water (2 mL). The mixture was extracted with Et2O (3ꢄ2 mL) and
the combined organic phases were concentrated in vacuo. The
product was purified by column chromatography (95% CH2Cl2, 4%
MeOH, 1% Et3N) to give the lactam 24 (13.9 mg, 33%) as a colourless
s-BuLi (1.3 M, 0.16 mL, 0.210 mmol) was added drop-wise to
a solution of (S)-13 (67.4 mg, 0.164 mmol) in anhydrous Et2O
(0.8 mL) cooled to ꢁ78 ꢂC. The mixture was stirred at ꢁ78 ꢂC for
30 min before 14 (87.8 mg, 0.328 mmol in anhydrous Et2O (1.2 mL))
was added drop-wise. The solution maintained at ꢁ78 ꢂC for 1 h.
Magnesium bromide (0.83 M in MeOH, 0.40 mL, 0.328 mmol) was
added drop-wise before warming to room temperature and stirring
the reaction mixture for 15 h. A solution of BHT in anhydrous THF
(w1 mg/mL, 0.4 mL) was added to the reaction mixture, which was
subsequently cooled to 0 ꢂC. A pre-cooled solution of aqueous
NaOH (2 M, 0.67 mL) and aqueous H2O2 (30%, 0.45 mL) was added
to the mixture at 0 ꢂC. The mixture was stirred for 16 h at room
temperature before being diluted with water (10 mL). The mixture
was extracted with Et2O (3ꢄ10 mL) and the combined organic
phases were washed with brine (20 mL), dried (MgSO4) and con-
centrated in vacuo. The product was purified by column chroma-
tography (30% EtOAc/petroleum ether) to give the alcohol (S)-22a
oil; nmax (neat): 2934, 1658, 1303, 1046 cmꢁ1
: dH (400 MHz, CDCl3):
7.38e7.50 (2H, m, ArH), 6.99e7.10 (2H, m, ArH), 4.12 (1H, br s, NCH),
3.70 (1H, br s, NCH), 3.63 (1H, td, J 12.0, 4.5 Hz, NCHaHb), 3.28 (0.5H,
dt, J 5.2, 1.9 Hz, CbOCCHaHb), 3.25 (0.5H, dt, J 5.1, 1.9 Hz, CbOC-
CHaHb), 3.09 (3H, s, NMe), 3.03e3.13 (1H, m, NCHaHb), 2.18 (0.5H, td,
J 3.5, 1.9 Hz, CbOCCHaHb), 2.15 (0.5H, td, J 3.5, 1.9 Hz, CbOCCHaHb),
1.64e1.82 (2H, m, NCH2CH2), 1.15e1.32 (12H m, 2ꢄ CHMe2); dC
(101 MHz, CDCl3): 168.8, 162.2 (d, JF 247 Hz), 154.4, 137.6 (d, JF
3.1 Hz), 128.8 (d, JF 7.8 Hz), 114.9 (d, JF 21.0 Hz), 81.1, 50.0, 46.6, 45.3,
35.3, 35.2, 21.2, 20.0; m/z (CI): 351 (MHþ, 50), 206 (100); HRMS (CI):
found 351.2078. C19H28N2O3F requires 351.2084.
(29.7 mg, 44%, er¼93:8) as needles (hexane/EtOAc); ½a D25
ꢁ17.2 (c
ꢃ

10088
B.M. Partridge et al. / Tetrahedron 67 (2011) 10082e10088
4.13. Preparation of compound (S)-25
Acknowledgements
Iodine (70.3 mg, 0.277 mmol) was added to a suspension of (S)-
22a (45.7 mg, 0.111 mmol), lead tetraacetate (0.123 g, 0.277 mmol)
and Na2CO3 (29.4 mg, 0.277 mmol) in a,a,a-trifluorotoluene (3 mL).
V.K.A. thanks the EPSRC for a Senior research Fellowship and the
Royal society for a Woolfson Research Merit Award. B.M.P. thanks
EPSRC for a Ph.D. studentship.
The mixture was stirred at 70 ꢂC for 20 h before being cooled to
room temperature. Aqueous sodium thiosulfate (1.0 M, 10 mL) was
added and the mixture was extracted with CH2Cl2 (3ꢄ10 mL). The
combined organic phases were dried (MgSO4) and concentrated in
vacuo. The product was purified by column chromatography (30%
EtOAc/petroleum ether) to give the carbamate (S)-22a (13.5 mg,
30%, er¼93:8) as a pale yellow oil; nmax (neat): 2926, 2230, 1690,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.142.
References and notes
1508, 1168 cmꢁ1
; dH (400 MHz, CDCl3) 7.61 (1H, d, J 7.8 Hz, ArH);
7.52 (1H, s, ArH), 7.34e7.44 (2H, m, ArH), 7.38 (1H, d, J 7.9 Hz, ArH),
6.95e7.08 (2H, m, ArH), 5.20 (1H, d, J 13.0 Hz, OCHaHb), 5.15 (1H, d, J
13.0 Hz, OCHaHb), 3.20 (2H, br s, NCH2), 2.76 (3H, s, NMe), 2.17 (1H,
ddd, J 14.2, 11.4, 4.8 Hz, OCCHaHb), 2.00e2.12 (1H, m, OCCHaHb),
1.32e1.54 (2H, m, NCH2CH2), 1.41 (9H, br s, CMe3); dC (126 MHz,
CDCl3) 162.1 (d, JF¼247 Hz),155.8, 149.3,140.3, 139.4,131.9,126.7 (d,
JF¼7.8 Hz), 125.2, 122.6, 118.6, 115.4 (d, JF¼21.5 Hz), 111.8, 90.9, 79.3,
71.3, 48.3, 38.3, 34.0, 28.4, 22.4; m/z (ESI): 433 (MNaþ), 411 (MHþ);
HRMS (ESI): MNaþ, found 433.1906700. C24H27N2O3FNa requires
433.1897920.
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citalopram enantiomers and their pharmaceutical compositions. EP347066A1,
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4.14. Preparation of Escitalopram
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the mixture was stirred at room temperature for 4 h. Saturated
aqueous NaHCO3 (5 mL) was added and the mixture was extracted
with CH2Cl2 (3ꢄ10 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The residue was dissolved in
CH2Cl2 (1 mL) and aqueous formaldehyde (37%, 0.02 mL,
0.753 mmol), NaBH(OAc)3 (13.9 mg, 0.066 mmol) and acetic acid
(0.02 mL, 0.329 mmol) were added and the mixture was stirred at
room temperature for 16 h. Saturated aqueous NaHCO3 (5 mL) was
added and the mixture was diluted with H2O (5 mL) and extracted
with CH2Cl2 (3ꢄ10 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The product was purified by
column chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to give
7. Albert, M.; Sturm, H.; Berger, A.; Kremminger, P. Process for asymmetric al-
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the amine Escitalopram (7.6 mg, 71%) as a yellow oil; ½a D25
ꢁ15.4 (c
ꢃ
0.1, MeOH), lit.¼ꢁ11.8 (c 1.0, MeOH);1 dH (400 MHz, CDCl3): 7.61
(1H, d, J 7.9 Hz, ArH); 7.51 (1H, s, ArH), 7.40e7.48 (3H, m, ArH),
6.95e7.07 (m, 2H, ArH), 5.21 (1H, d, J 13.0 Hz, OCHaHb), 5.15 (1H, d, J
13.0 Hz, OCHaHb), 2.40 (2H, t, J 7.1 Hz, NCH2), 2.26 (6H, s, NMe2),
2.13e2.33 (2H, m, CCH2), 1.35e1.61 (2H, m, NCH2CH2); dC (101 MHz,
CDCl3): 162.0 (d, JF 246 Hz); 149.3, 140.2, 139.3, 131.9, 126.7 (d, JF
7.8 Hz), 125.2, 122.8, 118.6, 115.4 (d, JF 21.8 Hz), 111.8, 91.0, 71.3, 59.1,
44.8, 38.7, 21.6. The data were consistent with those reported by
Boegesoe and co-workers.1
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Alley, M. R. K.; Sanders, V.; Plattner, J. J. J. Med. Chem. 2006, 49, 4447e4450.
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