Enantioselective synthesis of (S)-dapoxetine

Article abstract of DOI:10.1016/j.tetasy.2007.07.028

An efficient enantioselective synthesis leading directly to (+)-(S)-dapoxetine has been described for the first time using a Sharpless asymmetric dihydroxylation, Barton-McCombie deoxygention, and Mitsunobu reaction as the key steps.

Full text of DOI:10.1016/j.tetasy.2007.07.028

Tetrahedron: Asymmetry 18 (2007) 2099–2103
Enantioselective synthesis of (S)-dapoxetine
Shafi A. Siddiqui and Kumar V. Srinivasan*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 17 July 2007; accepted 30 July 2007
Abstract—An efficient enantioselective synthesis leading directly to (+)-(S)-dapoxetine has been described for the first time using a
Sharpless asymmetric dihydroxylation, Barton–McCombie deoxygention, and Mitsunobu reaction as the key steps.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
Dapoxetine is structurally related to fluoxetine (Prozac)
with antidepressant activity. Dapoxetine is the D-enantio-
mer of LY 243917 and is 3.5 times more potent as a sero-
tonin reuptake inhibitor than the L-enantiomer.4
Depression is a common psychiatric disorder and one of
the most frequent illnesses in the world-affecting people
of all gender, ages, and backgrounds. Stimulant abuse is
a serious problem, with 37% of state and local law enforce-
ment agencies identifying cocaine as their greatest drug
threat.1,2 The asymmetric synthesis of an individual
enantiomer is extremely important because the (S)- and
(R)-isomers usually display very different pharmacological
or physiological properties.3 For example, the enantiomer
(S)-(+)-N,N-dimethyl-a-[2-(1-naphthalenyloxy)ethyl]benz-
ene methanamine [(S)-dapoxetine] originally known as
LY 210448 credited to Wong of Eli Lilly and Company
is a potent selective serotonin re-uptake inhibitor (SSRIs),
but is slightly different from the SSRIs (such as Zoloft,
Paxil, and Prozac) (Fig. 1) widely prescribed for depres-
sion and other psychiatric disorders such as bulimia or
anxiety.
Moreover, (S)-dapoxetine (Fig. 2) is currently being tested
as a treatment for premature ejaculation in men, 23–30% of
men are suffering worldwide due to this problem.5 Recent
phase 3 clinical trials in patients with premature ejaculation
have shown dapoxetine to be effective in improving the
time of ejaculation, without any major adverse events,
except nausea. Dapoxetine would make it join the ranks
of sildenafil (Viagraꢁ), tadalafil (Cialisꢁ), and vardenafil
(Levittraꢁ), the erectile dysfunction drugs and cabergoline
(Dostinexꢁ) as a drug invented to improve male sexual
health.6
Very few methods are currently available for the synthesis
of this important and potent pharmacologically active
H
N
H
HN
O
N
O
O
O
Cl
Cl
CF3
Prozac
Zoloft
Paxil
F
Figure 1. Structures of Zoloft, Paxil, and Prozac.
*
Corresponding author. Tel.: +91 20 25902098; fax: +91 20 25902629; e-mail: kv.srinivasan@ncl.res.in
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.07.028

2100
S. A. Siddiqui, K. V. Srinivasan / Tetrahedron: Asymmetry 18 (2007) 2099–2103
using Sharpless asymmetric dihydroxylation as a source
of chiral induction.
NMe2
O
2. Results and discussion
1
Our retro synthetic strategy for the synthesis of (+)-(S)-
dapoxetine is outlined in Scheme 1. We envisioned that
(+)-(S)-dapoxetine 1 could be prepared from amino alco-
hol 2, which in turn would be obtained from intermediate
3, which can be obtained from easily available trans-cinn-
amyl ester 4 by Sharpless asymmetric dihydroxylation as
the source of chirality induction.
(S)-Dapoxetine
Figure 2. (S)-Dapoxetine.
(S)-dapoxetine. Gotor et al. recently reported the asymmet-
ric synthesis of (S)-dapoxetine in good overall yield and
high enantiomeric excess by enzymatic resolution of 3-ami-
no-3-phenylpropan-1-ol derivatives using Candida antarc-
tica lipase A (CAL-A).7 Toru Koizumi et al.8 reported
the synthesis of intermediate 2 (see Scheme 2) by employing
asymmetric induction in the 1,3-dipolar cycloaddition of
(R)-(+)-p-tolyl vinyl sulfoxide with acyclic nitrones in
excellent isolated yield with high enantiomeric excess.
Employing a chiral starting material, they did not elaborate
the synthesis further to (S)-dapoxetine. Another method
described in the literature to synthesize (S)-dapoxetine
is a radiochemical synthesis from (S)-(+)-N-methyl-a-
[2-(1-naphthalenyloxy)ethyl]benzene methanamine hydro-
The synthesis of (+)-(S)-dapoxetine was carried out via the
synthetic route as shown in Scheme 2. The enantioselective
synthesis of (+)-(S)-dapoxetine started with the trans-cinn-
amyl ester 4 on subjecting it to asymmetric dihydroxylation
under Sharpless conditions using osmium tetroxide and
NMO as cooxidant in the presence of the chiral ligand
(DHQ)2PHAL to afford (2R,3S)-methyl-2,3-dihydroxy-3-
phenylpropanoate 5 in 80% yield with 99% ee and
25
½aꢀD ¼ þ3:2 (c 1.19, EtOH).10b
The vicinal diol on treatment with thionyl chloride in the
presence of Et3N in CH2Cl2 at 0 ꢂC gave the corresponding
cyclic sulfite 6 as a diastereomeric mixture in a 1:1 ratio.11
Several attempts to oxidize cyclic sulfite 6 to cyclic sulfate
were unsuccessful, possibly due to the formation of several
by-products, which were difficult to isolate.12
11
chloride using CH3I.9
To the best of our knowledge, there have been no chemical
methods reported so far, which directly lead to the asym-
metric synthesis of (+)-(S)-dapoxetine. In the chemical
methodology presented for the first time herein, the Sharp-
less asymmetric dihydroxylation10 and subsequent trans-
formation of the diols formed via a cyclic sulfite11 were
envisioned as powerful tools offering considerable opportu-
nities for synthetic manipulation.
The synthetic strategy shown in Scheme 1 was based on the
presumption that the nucleophilic opening of cyclic sulfite 6
would occur in a regiospecific manner at the a-carbon
atom. Indeed, the cyclic sulfite reacted with NaN3 with
apparent complete selectivity for attack at C-2 to furnish
azido alcohol 7 in 85% yield. The aromatic ring must be
responsible for the increased reactivity of the a-position.
Thus, we turned our attention to reduce the azide and pro-
tect it as its Boc derivative. Accordingly, the azide on reac-
tion with Pd/C in EtOAc in the presence of (Boc)2O and
As part of our ongoing project for the synthesis of biolog-
ically active compounds from easily available starting
materials, we herein report the enantioselective synthesis
of (S)-dapoxetine from the easily available cinnamyl ester
N
N
O
OH
1
2
O
O
O
NH
O
OMe
OMe
4
3
Scheme 1. Retrosynthetic analysis for (S)-dapoxetine.

S. A. Siddiqui, K. V. Srinivasan / Tetrahedron: Asymmetry 18 (2007) 2099–2103
2101
The ester group was reduced by LAH in THF to give inter-
mediate 10 in 75% yield. In the IR spectrum, the disappear-
ance of the strong absorption at 1735 cmꢁ1 indicative of
the reduction of the ester was observed. The Boc group
was subsequently deprotected by TFA in chloroform at
room temperature to give 11 in good yield. Spectral data
of 11 were in good agreement with the known literature
values. Then, amine 11 was alkylated using the Clarke–
Eschweiler15 method using formaldehyde and formic acid
as the hydrogen source, which gave 2 in 83% isolated yield.
The final reaction in the sequence is the coupling between
the alcohol hydroxyl of 2 and 1-naphthol for which we
attempted the Ullmann protocol, which did not work
despite the use of a variety of bases for the study. We
ultimately opted for Mitsunobu reaction16 conditions,
which gave (+)-(S)-dapoxetine 1 in 72% yield.
OH
O
O
O
i
OMe
OMe
OH
4
5
O
S
N3
O
O
OMe
iv
iii
ii
OH
O
MeO
7
6
O
O
O
NH
O
O
NH
O
OMe
SMe
v
OMe
O
3. Conclusion
OH
8
S
9
In conclusion, we have developed an enantioselective total
chemical synthesis of (+)-(S)-dapoxetine for the first time,
comprising of 10 steps in an overall yield of 17% and
stereoselectivity of 96% ee.
O
NHBoc
O
NH
O
OH
vi
vii
OMe
10
4. Experimental
3
4.1. General experimental
N
NH2
The solvents were purified and dried by the standard
procedures prior to use; petroleum ether of boiling range
60–80 ꢂC was used. Optical rotations were measured using
sodium D line on a JASCO-P-1020-polarimeter. Enantio-
meric excess was measured using either the chiral HPLC
or by comparison with specific rotation. Elemental analy-
ses were carried out with a Carlo Erba CHNS-O analyzer.
OH
ix
viii
OH
N
11
2
x
O
4.2. Synthesis of (2R,3S)-methyl 2,3-dihydroxy-3-phenyl-
propanoate 5
1
A
100 mL round-bottomed flask was charged with
(DHQ)2PHAL (0.120 g, 0.5 mol %), trans-cinnamyl methyl
ester (5 g, 3 mmol), NMO (7.71 mL, 60% w/v in water),
and t-BuOH (15.42 mL). Under stirring, OsO4 (0.156 mL,
0.2 mol %) was added. The reaction mixture was stirred
at room temperature until completion of the reaction (pro-
gress of reaction was monitored by TLC, 24 h) and then
poured into a solution of sodium sulfite (6.66 g) in water
(22.2 mL). The mixture was stirred at room temperature
for 2 h. The organic phase was separated and solvent was
evaporated under reduced pressure. The residue was
dissolved in ethyl acetate (50 mL). The aqueous phase
was extracted with ethyl acetate (2 · 25 mL). The organic
phases were combined and washed with 5% aqueous HC1
(2 · 5 mL) and dried over MgSO4. After the solvent was
removed under reduced pressure, the crude diol was pure
enough for processing in further steps (single spot on
TLC) and was recrystallized from toluene to give 5
(5 g, 83%,) as colorless needles. Mp = 86–87 ꢂC;
Scheme 2. Reagents and conditions: (i) (DHQ)2PHAL (5 mol %), OsO4,
NMO, t-BuOH, rt, 16 h; (ii) CH2Cl2, Et3N, SOCl2, 0 ꢂC to rt, 1 h; (iii) NaN3
(5 equiv), DMF, rt, 48 h; (iv) H2/Pd–C, EtOAc, rt, 24 h, (Boc)2O, Et3N; (v)
MeI, CS2, MsCl, Et3N, CH2Cl2, 0 ꢂC to rt, 12 h; (vi) n-Bu3SnH, AIBN,
toluene, reflux, 75% after two steps; (vii) LiAlH4, THF, rt, 12 h; (viii) TFA,
DCM, rt; (ix) HCHO, HCOOH; (x) Ph3P, DEAD, 1-naphthol, THF, rt.
Et3N delivered the Boc protected 8.13 In the IR spectrum
disappearance of strong absorption at 2106 cmꢁ1 was ob-
1
served. The H NMR and 13C NMR data were in good
agreement with the structure.
Another task was the deoxygenation of the secondary alco-
hol 8, which we achieved by converting the corresponding
alcohol to its xanthate derivative followed by deoxygen-
ation under the Barton–McCombie14 protocol using n-
Bu3SnH and a catalytic amount of AIBN in toluene under
reflux conditions to give product 3 in 75% isolated yield
25
1
1
after two steps. The H NMR and 13C NMR-DEPT data
½aꢀD ¼ þ3:5 (c 1.19, EtOH); H NMR (200 MHz, CDCl3):
were in good agreement with the structure.
d = 2.69 (br s, 2H), 3.74 (s, 3H), 4.3–4.31 (d, J = 2.94 Hz,

2102
S. A. Siddiqui, K. V. Srinivasan / Tetrahedron: Asymmetry 18 (2007) 2099–2103
1H), 4.94–4.96 (d, J = 3 Hz, 1H), 7.19–7.32 (m, 5H); 13C
NMR (50 MHz, CDCl3): d = 52.5, 74.3, 74.8, 126.1,
127.8, 128.2, 139.7, 173. Anal. Calcd for C10H12O4: C,
61.22; H, 6.16. Found: C, 61.18; H, 6.02.
pressure) for 12 h. After the completion of reaction (moni-
tored by TLC), the reaction mixture was filtered off and
concentrated under reduced pressure and the residue was
further purified by flash column chromatography using
light petroleum ether/EtOAc (3:1) as an eluent to afford
4.3. Synthesis of sulfite 6
pure 8 as a white solid (1.761 g, 88%). Mp = 123–124 ꢂC;
25
½aꢀD ¼ ꢁ78:4 (c 1.91, acetone); 1H NMR (200 MHz,
To a stirred solution of diol 5 (1 g, 0.5 mmol) in dry
CH2Cl2 (10 mL) cooled at 0 ꢂC was added Et3N (2.34 g,
1.2 mmol) and a solution of SOCl2 (2.34 g, 1.45 mL,
2.3 mmol) in CH2Cl2 (5 mL) was added over a period of
20 min. After the addition was over, the reaction mixture
was continued for a further 45 min at 0 ꢂC. After the reac-
tion was over (monitored by TLC), the reaction mixture
was quenched by chilled water (10 mL) followed by the
addition of CH2Cl2 (10 mL). The organic layer was washed
with water (3 · 5 mL), brine (5 mL), dried over MgSO4,
and the mixture was filtered through a pad of silica gel.
The filtrate was concentrated under reduced pressure to
give a yellow oily liquid 6 (1.1g, 90%) (its mixture of diaste-
CDCl3): d = 1.31 (s, 9H), 3.33 (s, 3H), 5.25–5.29 (d,
J = 9.21 Hz, 1H), 5.49–5.53 (d, J = 8.91 Hz, 1H), 7.27–
7.41 (m, 5H); 13C NMR (50 MHz, CDCl3): d = 27.5, 52.1,
60.6, 74.6, 84.3, 126.5, 128.5, 129.1, 134.9, 148.1, 151.1,
165.8. Anal. Calcd for C15H21NO5: C, 61.00; H, 7.17; N,
4.74. Found: C, 60.69; H, 7.02; N, 4.56.
4.6. Synthesis of tert-butyl (1R,2R)-2-(methoxy carbonyl)-2-
O-(S-methyl dithiocarbonate)-1-phenyl ethyl carbamate 9
The reaction vessel was flushed with nitrogen and the nitro-
gen atmosphere was maintained during the ensuing steps.
To a solution of 8 (0.315 g, 1.06 mmol) in THF (10 mL)
at 0 ꢂC was added sodium hydride (50% oil dispersion,
0.053 g, 2.2 mmol). Vigorous gas evolution was observed.
After the reaction mixture was stirred for 20 min carbon
disulfide (0.255 g, 0.202 mL, 3.3 mmol) was added at once.
Stirring was continued for the next 30 min after which
iodomethane (0.272 g, 0.123 mL, 1.9 mmol) was added in
a single portion. The reaction mixture was stirred for
another 2 h (progress of reaction mixture was monitored
by TLC). On completion, glacial acetic acid (5 mL) was
added drop wise to destroy any excess sodium hydride.
The solution was filtered and the filtrate was concentrated
under reduced pressure. The semisolid residue was
extracted with diethyl ether (3 · 5 mL) and the combined
ether extracts were washed with saturated sodium
bicarbonate (5 mL) solution and water (5 mL). The ether
solution was dried over anhydrous MgSO4, after which
the drying agent was removed by filtration, and the solvent
evaporated under reduced pressure. The crude product was
purified by flash column chromatography, which gave 9 as
reomers 1:1), which was separated by flash column chro-
25
matography. ½aꢀD ¼ ꢁ92:3 (c 1.1, CH2Cl2); 1H NMR
(200 MHz, CDCl3): d = 3.85 (s, 3H), 4.82–4.86 (d,
J = 7.51 Hz, 0.5H), 5.19–5.23 (d, J = 8.38 Hz, 0.5H),
5.58–5.62 (d, J = 8.45 Hz, 0.5H), 6.15–6.18 (d,
J = 7.44 Hz, 0.5H), 7.26–7.51 (m, 5H); 13C NMR
(50 MHz, CDCl3): d = 53.2, 81.2, 87.8, 127.8, 129.0,
129.5, 133.9, 166.5.
4.4. Synthesis of (2R,3R)-methyl-3-azido-2-hydroxy-3-
phenylpropanoate 7
To a solution of 6 (1 g, 0.4 mmol) in DMF (10 mL),
sodium azide (1.3 g, 2 mmol) was added and the reaction
mixture stirred at 80 ꢂC for 48 h (progress of reaction
was monitored by TLC) under an argon atmosphere. After
the completion of the reaction, the solvent was evaporated
under a reduced pressure. The resulting solid mass was dis-
solved in methanol (20 mL) and filtered through a pad of
silica gel–Celite mixture. Methanol was evaporated and
the thick solid mass diluted by water (10 mL). The resulting
suspension was stirred for 30 min. The suspension was
extracted with ethyl acetate (3 · 5 mL) and the organic
layer was separated and washed with water (2 · 5 mL),
dried over MgSO4, and the solvent was evaporated under
reduced pressure. The residue was purified further by flash
a pale yellow solid (0.337 g, 82%). Mp = 118–119 ꢂC;
25
½aꢀD ¼ ꢁ47:3 (c 1.13, acetone); 1H NMR (200 MHz,
CDCl3): d = 1.43 (s, 9H), 2.56 (s, 3H), 3.62 (s, 3H), 5.37
(d, 1H), 6.12–6.14 (d, J = 4.94 Hz, 1H), 7.30–7.40 (m, 5H).
4.7. Synthesis of tert-butyl (S)-2-(methoxy carbonyl)-1-
phenylethyl carbamate 3
column chromatography to afford 7 as a yellow liquid
25
(0.73 g, 80%). ½aꢀD ¼ ꢁ60:0 (c 4.44, EtOH); 1H NMR
To a solution of 9 (0.2 g, 0.519 mmol) in toluene (10 mL),
tri-n-butyltin hydride (0.453 g, 1.558 mmol), and catalytic
amount of AIBN (0.1 mol % w/w based on 9) were added
at room temperature under an inert atmosphere. The reac-
tion mixture was heated at reflux till the completion of
reaction (progress of reaction was monitored by TLC).
During the course of the reaction, the solution of the reac-
tion mixture changed from deep yellow to nearly colorless.
After the reaction was over, toluene was removed under a
reduced pressure to give a thick oily residue, which was
partitioned between petroleum ether and acetonitrile. The
acetonitrile layer was separated and washed with petro-
leum ether (3 · 5 mL). The acetonitrile was evaporated un-
der reduced pressure. The crude product separating out
was purified by flash column chromatography, which affor-
(200 MHz, CDCl3): d = 2.91 (br s, 1H), 3.74 (s, 3H),
4.55–4.57 (d, J = 4.3 Hz, 1H), 4.90–4.92 (d, J = 4.3 Hz,
1H), 7.30–7.41 (m, 5H). 13C NMR (50 MHz, CDCl3):
d = 52.5, 67.1, 73.6, 126.5, 127.6, 128.5, 128.8, 134.2.
171.7. Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N,
19.00. Found: C, 54.10; H, 4.81; N, 18.78.
4.5. Synthesis of tert-butyl (1R,2R)-2-(methoxy carbonyl)-2-
hydroxy-1-phenylethylcarbamate 8
To a solution of 7 (1.5 g, 5.74 mmol) in EtOAc were added
Et3N (0.88 mL, 6.32 mmol), (Boc)2O (1.45 mL, 6.32 mmol),
and 10 % Pd/C (0.05 g). The mixture was stirred at room
temperature under a hydrogen atmosphere (1 atm balloon

S. A. Siddiqui, K. V. Srinivasan / Tetrahedron: Asymmetry 18 (2007) 2099–2103
2103
ded
3
as
a
solid (0.116 g, 80%). Mp = 95–96 ꢂC;
room temperature and then stirred further for 15 h. After
the reaction was completed (progress of reaction moni-
tored by TLC), the solution was evaporated and the crude
product was purified by flash column chromatography
25
½aꢀD ¼ ꢁ31:5 (c 1.31, acetone); 1H NMR (200 MHz,
CDCl3): d = 1.42 (s, 9H), 2.85–2.87 (q, 2H), 3.61 (s, 3H),
5.08–5.48 (t, 1H), 7.25–7.37 (m, 5H); 13C NMR (50 MHz,
CDCl3): d = 28.2, 40.7, 51.6, 79.6, 126.1, 127.4, 128.5,
155.0, 171.3. Anal. Calcd for C15H21NO4: C, 64.50; H,
7.58; N, 5.01. Found: C, 64.33;H, 7.19; N, 4.88.
using EtOAc/MeOH mixture, which afforded (S)-dapoxe-
25
tine as a colorless oil (0.02 g, 74%). ½aꢀD ¼ þ64:2 (c 0.3,
1
CHCl3); H NMR (200 MHz, CDCl3): d = 2.22 (s, 6H),
2.34–2.45 (m, 1H), 2.59–2.71 (m, 1H), 3.55–3.63 (m, 1H),
3.93–4.12 (m, 2H), 7.19–7.52 (m, 9H), 7.7–7.74 (m, 1H),
7.95–8.21 (m, 2H); 13C NMR (50 MHz, CDCl3):
d = 32.0, 36.4, 63.1, 67.5, 104.5, 120.1, 127.1, 127.4,
127.8, 128.3, 128.9, 136.0, 138.1, 155.2. Anal. Calcd for
C21H23NO: C, 82.58; H, 7.59, N, 4.59. Found: C, 82.19;
H, 7.38; N, 4.31.
4.8. Synthesis of tert-butyl (S)-3-hydroxy-1-phenylpropyl-
carbamate 10
A solution of tert-butyl (S)-2-(methoxycarbonyl)-1-phenyl-
ethylcarbamate 9 (0.1 g, 3.98 mmol) in dry THF (10 mL)
was cooled to 0 ꢂC and LiAlH4 (0.06 g, 15.9 mmol) added
in small portions. The reaction mixture was refluxed for
2 h following the complete disappearance of the starting
material by TLC analysis. The reaction mixture was cooled
to 0 ꢂC, and the excess hydride was destroyed by chilled
water (5 mL). The gray mixture was extracted by ethyl ace-
tate (3 · 5 mL) and the organic phases were combined,
dried over MgSO4, and the solvent evaporated under re-
duced pressure. The crude mixture separating out was puri-
fied by flash column chromatography using petroleum
Acknowledgment
S.A.S. thanks CSIR, New Delhi, for the award of Research
Fellowship.
References
ether and ethyl acetate as eluents, which gave 10 as a white
25
solid (0.073 g, 81%). Mp = 104–105 ꢂC; ½aꢀD ¼ ꢁ53:0 (c
1. Melloni, P.; Della Torre, A.; Lazzari, E.; Mazzini, G.;
Alberto, B.; Matilde, B.; Ottorino, X.; Sante, R.; Alessandro,
R. C. Eur. J. Med. Chem. 1984, 19, 235.
2. Federsel, H. J. CHEMTECH 1993, 23, 24.
3. Feret, B. Formulary 2005, 40, 227.
1
1.27, acetone); H NMR (200 MHz, CDCl3): d = 1.44 (s,
9H); 1.77–2.17 (m, 2H), 3.66–3.72 (m, 2H), 4.89–5.09 (t,
1H) 7.27–7.39 (m, 5H); 13C NMR (50 MHz, CDCl3):
d = 28.2, 39.3, 51.5, 58.9, 79.9, 126.3, 127.4, 128.7, 141.9,
156.3. Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N,
5.57. Found: C, 66.75; H, 8.29; N, 5.28.
4. Anon, N. Z. Drugs R&D 2005, 6, 307.
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Gupta, S. J. Clin. Pharmacol. 2006, 46, 301.
6. http://www.jnj.com.
7. Torre, O.; Gotor-Fernandez, V.; Gotor, V. Tetrahedron:
Asymmetry 2006, 17, 860.
4.9. Synthesis of (S)-3-(dimethyl amino)-3-phenylpropan-
1-ol 2
8. Koizumi, T.; Hirai, H.; Yoshii, E. J. Org. Chem. 1982, 47,
4005.
To a solution of (S)-3-amino-3-phenylpropan-1-ol (0.05 g,
0.19 mmol) in formic acid (39 lL), was added a 30% aque-
ous solution of formaldehyde (78 lL, 1.05 mmol) and the
mixture refluxed over 8 h when the reaction is complete
as monitored by TLC. The solution was then acidified with
concd HCl to pH 1 and basified with 4 M NaOH. The
organic phases were combined, dried over MgSO4, and
the solvent evaporated under reduced pressure. The crude
9. (a) Robertson, D. W.; Thompson, D. C.; Wong, D. T. Eur.
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Satterlee, R. W.; Robey, R. L.; Alt, C. A.; Van Meter, E. E.;
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B. J. Org. Chem. 1994, 59, 5104; (d) Kumar, P.; Naidu, S. V.;
Gupta, P. J. Org. Chem. 2005, 70, 2843; (e) Kumar, P.;
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2006, 1771.
was purified by flash column chromatography to give 2
25
(0.05 g, 85%). ½aꢀD ¼ þ39:2 (c 0.6, CHCl3); 1H NMR
(200 MHz, CDCl3): d = 1.66–1.75 (m, 1H); 2.15 (s, 6H);
2.51–2.68 (m, 1H); 3.39–3.66; (m, 1H); 3.88–3.94 (m, 1H);
7.30–7.41 (m, 5H); 13C NMR (50 MHz, CDCl3):
d = 32.1, 36.4, 63.1, 67.5, 127.1, 127.8, 128.3, 128.8,
128.9, 136.1. Anal. Calcd for C11H17NO: C, 73.70; H,
9.56; N, 7.81. Found: C, 73.44; H, 9.27; N, 7.65.
11. Byun, H. S.; He, L.; Bittman, R. Tetrahedron 2000, 56,
7051.
12. Sayyed, I. A.; Sudalai, A. Tetrahedron: Asymmetry 2004, 15,
3111.
13. Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005,
16, 3238.
14. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
15. (a) Eschweiler, W. Chem. Ber. 1905, 38, 880; (b) Clarke, H. T.
J. Am. Chem. Soc. 1933, 55, 4571; (c) Moore, M. L. Org.
React. 1949, 5, 301.
16. (a) Mistunobu, O. Synthesis 1981, 1; (b) Hughes, D. L. Org.
React. 1992, 42, 335.
4.10. (S)-N,N-Dimethyl-3-(naphthalen-1-yloxy)-1-phenyl-
propan-1-amine 1
To a solution of 2 (20 mg, 0.11 mmol) in dry THF (2.4 mL)
under a nitrogen atmosphere was added 1-naphthol
(32 mg, 0.22 mmol). The mixture was cooled to 0 ꢂC
and PPh3 (0.22 mmol) and DEAD (0.22 mmol) were suc-
cessively added. The solution was allowed to warm till