Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide

Article abstract of DOI:10.1021/jo300566p

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH₄ reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.

Full text of DOI:10.1021/jo300566p

Note
pubs.acs.org/joc
Concise Enantioselective Synthesis of Duloxetine via Direct Catalytic
Asymmetric Aldol Reaction of Thioamide
Yuta Suzuki,†,‡ Mitsutaka Iwata,† Ryo Yazaki,‡ Naoya Kumagai,*,† and Masakatsu Shibasaki*,†
†Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Direct catalytic asymmetric aldol reaction of
thioamide offers a new entry to the concise enantioselective
synthesis of duloxetine. The direct aldol protocol was scalable
(>20 g) to afford the aldol product in 92% ee after LiAlH4
reduction, and 84% of the chiral ligand was recovered after
recrystallization. The following four steps of transformation
delivered duloxetine.
uloxetine [(S)-N-methyl-3-(1-naphthalenyloxy)-2-thio-
phenepropanamine (1)], marketed as Cymbalta, func-
bench stable aldol donor and acceptor are assembled by the
actions of an asymmetric catalyst.8,9 The need of preactivation/
preformation of active enolate is obviated, and the overall
process proceeds through proton transfer, generating the aldol
product in an enantiomerically enriched form without the
formation of any waste. Our studies in this field based on
cooperative catalysis10 revealed that thioamides 2 are
particularly suitable aldol donors amenable to chemoselective
activation to catalytically generate active enolate.11−13 Given
the feasibility of diverse functional group transformation of a
thioamide functionality,12 the aldol product 4 derived from
thiophene-2-carboxaldehyde (3) was anticipated to give γ-
amino alcohol 5, allowing for an rapid and efficient access to
the carbon framework of 1 with the requisite S secondary
alcohol (Scheme 1).
D
tions as a dual serotonin and norepinephrine reuptake inhibitor
in presynaptic cells (Figure 1).1 It was approved by the U.S.
Figure 1. Structure of duloxetine (1) and fluoxetine.
We previously developed a soft Lewis acid/hard Brønsted
base cooperative catalyst comprising [Cu(CH3CN)4]PF6,
(S,S)-Ph-BPE, and Li(OC6H4-p-OMe), in which chemo-
selective activation of thioamide by a soft−soft interaction of
Cu+ and sulfur atom allowed for the exclusive generation of
thioamide enolate in the presence of aldehyde.11b−e First, we
set out to identify the best thioamide 2 (aldol donor) for the
direct catalytic asymmetric aldol reaction with aldehyde 3 (aldol
acceptor). Use of a thioamide bearing an N-methyl substituent
streamlines the synthesis of 1, and reactions with thioamides
2a−c and 3 were initially examined under the standard direct
aldol conditions (Table 1).11c The use of N-methylthioaceta-
mide (2a) allowed for direct access to the N-Me secondary
amine moiety of 1, but the aldol reaction with 2a failed,
presumably because the acidic thioamide N−H prevented the
Food and Drug Administration in August 2004 and is
prescribed for the treatment of major depressive disorders as
well as stress urinary incontinence. In contrast to the preceding
drug fluoxetine (Prozac), which is an approved racemate, 1 is
marketed in enantiomerically pure form,2 and the development
of its scalable and enantioselective synthesis is of broad interest.
Commonly explored synthetic approaches are optical reso-
lution,3 dynamic kinetic resolution,4 catalytic asymmetric
reduction,5 and catalytic asymmetric hydrogenation.6 Although
the catalytic asymmetric C−C bond-forming reaction is rarely
implemented,7 it allows for construction of the requisite carbon
framework concomitant with the introduction of chirality.
Herein we envisioned that our direct aldol technology would
provide a viable approach for concise enantioselective synthesis
of duloxetine (1) based on catalytic asymmetric C−C bond
formation.
The direct catalytic asymmetric aldol reaction is the most
advanced form of the conventional aldol reaction, in which
Received: March 20, 2012
Published: April 11, 2012
© 2012 American Chemical Society
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Note
a
Scheme 1. Efficient Access to Duloxetine (1) via Direct
Table 2. Further Optimization Using 2d
Catalytic Asymmetric Aldol Reaction
stoichiometry
b
entry
1
3/2d
X
temp (°C)
yield (%)
ee (%)
1.5/1
1/1.5
1.5/1
1.5/1
1.2/1
1.2/1
5
−70
−70
−60
−70
−70
−70
71 (trace)
63 (trace)
50 (20)
93
91
92
92
92
92
c
2
5
3
5
d
4
5
68 (trace)
68 (trace)
74 (trace)
5
6
5
7.5
Table 1. Direct Catalytic Asymmetric Aldol Reaction of
a
Thioamides 2a−d
a
b
1
3: 0.3 mmol. 2d: 0.2 mmol. Determined by H NMR analysis with
toluene as an internal standard. Yield of dehydrated product 4d′ is
c
d
shown in parentheses. 3: 0.2 mmol. 2d: 0.3 mmol. Mesitylcopper/
HOC6H4-p-OMe was used instead of [Cu(CH3CN)4]PF6/Li(OC6H4-
p-OMe).
2
b
entry
R1
R2
product yield (%) ee (%)
duloxetine (1), it is imperative to recycle the expensive (S,S)-
Ph-BPE. Trials for the recovery of (S,S)-Ph-BPE after the aldol
reaction failed, likely because of the tight complexation of (S,S)-
Ph-BPE and Cu+. Attempts to liberate free (S,S)-Ph-BPE by
adding chelating agent, acids, and bases were unsuccessful.14
We then turned our attention to proceeding without
purification at this stage, on the basis of the following
hypotheses: (1) subsequent LiAlH4 reduction of the crude
sample of the aldol reaction would lead to easier isolation of the
reduced aldol product, and (2) Cu+ would be reduced to
Cu(0), and free (S,S)-Ph-BPE would be liberated.15 Upon
confirmation of the validity of this two-step protocol with 89%
recovery of (S,S)-Ph-BPE in small scale trials, we performed a
23.9 g scale reaction of the direct aldol/LiAlH4 reduction. The
aldol reaction was quenched by AcOH/THF after 48 h of
stirring at −70 °C, and the concentrated ether extracts were
taken up with dry THF for the subsequent LiAlH4 reduction. A
small aliquot of the extract was purified and analyzed by chiral
stationary phase HPLC to determine the enantioselectivity of
the aldol reaction (92% ee). LiAlH4 reduction was conducted at
−78 °C, and short pad column chromatography on silica gel
delivered the recovered (S,S)-Ph-BPE in 84% (after recrystal-
lization) and γ-amino alcohol 5d in 56% yield (2 steps).
Removal of allyl groups on nitrogen under Pd catalysis and
treatment with methyl chloroformate gave carbamate 6.
Reduction with LiAlH4 under reflux conditions in THF
afforded N-methylated γ-amino alcohol 7 and ether formation
by ipso substitution with 1-fluoronaphthalene furnished
duloxetine (1) (Scheme 2).
1
2
3
4
Me
Me
Me
allyl
H
2a
2b
2c
2d
4a
4b
4c
4d
−
17
43
71
−
72
73
93
Bn
C6H4-p-OMe
allyl
a
b
1
3: 0.3 mmol. 2: 0.2 mmol. Determined by H NMR analysis with
toluene as an internal standard.
formation of the thioamide enolate (Table 1, entry 1). The next
candidates were substituted thioamides 2b and 2c, whose N-
substituent can undergo facile deprotection to provide the
−NHMe terminus, but these showed insufficient reactivity
(Table 1, entries 2, 3). Although product 4d required a
deprotection/methylation sequence for the synthesis of 1, the
preferable reactivity and enantioselectivity led us to focus on
the further optimization using 2d (Table 2). The use of
thioamide 2d in excess to aldehyde 3 resulted in a lower yield
(Table 2, entry 2). The aldol reaction is highly sensitive to the
reaction temperature, and a higher reaction temperature
significantly increased the formation of the unfavorable
dehydrated product 4d′ (Table 2, entry 3). The more advanced
form of the cooperative catalyst mesitylcopper/HOC6H4-p-
OMe,11e which does not require preparation of Li(OC6H4-p-
OMe), did not improve the reaction efficiency (Table 2, entry
4). The amount of thioamide 2d can be reduced to 1.2 equiv to
close to the ideal 1:1 stoichiometry of thioamide 2d and
aldehyde 3 (Table 2, entry 5). Slightly increasing the catalyst
loading improved the yield to a level suitable for the large-scale
production of 4d (Table 2, entry 6).
In conclusion, we developed a concise enantioselective
synthetic route to duloxetine (1) based on the direct catalytic
asymmetric aldol reaction. The major drawback of the use of
costly chiral bisphosphine ligands was eliminated by its efficient
recovery after LiAlH4 reduction. The subsequent four-step
sequence efficiently afforded duloxetine (1), a dual serotonin
and norepinephrine reuptake inhibitor.
The remaining issue to be resolved before the large-scale
demonstration of the direct aldol reaction was the recovery of
(S,S)-Ph-BPE. To develop a cost-effective synthetic scheme for
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Note
Scheme 2. Enantioselective Synthesis of Duloxetine (1)
were added to the reaction mixture, and the aqueous layer was
extracted with diethyl ether. The combined organic layers were washed
with 1 N HCl 3 times and with brine and then dried over Na2SO4. The
residue obtained after filtration/concentration was purified by silica gel
column chromatography (acetone/n-hexane = 1/9) yielding aldol
product 4b (9.9 mg, 0.034 mmol, yield 17%) as a colorless oil.
Enantiomeric excess was determined by HPLC analysis. Colorless oil:
EXPERIMENTAL SECTION
■
The direct catalytic asymmetric aldol reaction was performed in a glass
test tube with a Teflon-coated magnetic stirring bar unless otherwise
noted. The flasks or test tubes were fitted with a 3-way glass stopcock,
and reactions were run under Ar atmosphere. Air- and moisture-
sensitive liquids were transferred via a gastight syringe and a stainless-
steel needle. All workup and purification procedures were carried out
with reagent-grade solvents under ambient atmosphere. Flash
chromatography was performed using silica gel 60 (230−400 mesh).
Chemical shifts for proton are reported as δ in units of parts per
million downfield from tetramethylsilane and are referenced to
residual protium in the NMR solvent (CDCl3: δ 7.26 ppm). For
13C NMR, chemical shifts were reported in the scale relative to NMR
solvent (CDCl3: 77.0 ppm) as an internal reference. For 31P NMR,
chemical shifts were reported in the scale relative to H3PO4 (0.0 ppm
in D2O) as an external reference. NMR data are reported as follows:
chemical shifts, multiplicity (s: singlet, d: doublet, dd: doublet of
doublets, t: triplet, q: quartet, sep: septet, m: multiplet, br: broad
signal), coupling constant (Hz), and integration. Optical rotation was
measured using a 2 mL cell with a 1.0 dm path length. HPLC analysis
was conducted with chiral-stationary-phase columns (0.46 cm ϕ × 25
cm).
1
IR (KBr) ν 3377, 2930, 2245, 1502, 700 cm−1; H NMR (399.78
MHz, CDCl3) δ 7.40−6.89 (m, 8H, rotamer A + B), 5.67−5.61 (m,
1H, rotamer A), 5.62−5.56 (m, 1H, rotamer B), 5.35 (d, J = 14.4 Hz,
1H, rotamer A), 5.30 (d, J = 14.4 Hz, 1H, rotamer A), 5.04 (d, J = 3.2
Hz, 1H, rotamer A), 5.02 (d, J = 3.2 Hz, 1H, rotamer B), 4.87 (d, J =
16.5 Hz, 1H, rotamer B), 4.72 (d, J = 16.5 Hz, 1H, rotamer B), 3.45 (s,
3H, rotamer B), 3.15−3.07 (m, 2H, rotamer A + B), 3.10 (s, 3H,
rotamer A); 13C NMR (100.53 MHz, CDCl3) δ 200.5, 200.3, 146.3,
146.3, 134.6, 134.0, 128.9, 128.5, 127.8, 127.6, 127.5, 126.4, 125.9,
124.2, 124.1, 123.1, 123.0, 68.3, 68.2, 57.7, 56.9, 53.3, 50.2, 49.8, 42.7,
38.8; HRMS (ESI TOF (+)) calcd. for C15H17ONNaS2 m/z 314.0644
24
[M + Na]+, found 314.0642; [α]D −74.0 (c 0.26, CHCl3, 72% ee);
HPLC [Daicel CHIRALCEL OD-H, detection at 254 nm, 9:1 n-
hexane/iPrOH, flow rate = 1.0 mL/min, tR = 18.7 min (major), tR =
25.7 min (minor)].
Preparation of Li(OC6H4-p-OMe)/THF. A flame-dried 10 mL
pear-shaped flask equipped with a magnetic stirring bar and 3-way
stopcock was charged with p-methoxyphenol (12.4 mg, 0.10 mmol)
and dried under vacuum for 30 min. Ar was backfilled to the flask, and
dry THF (440 μL) was added via a syringe and a stainless steel needle.
nBuLi (60 μL, 0.1 mmol, 1.65 M in n-hexane) was then added at 0 °C,
and the resulting solution was stirred at the same temperature for 60
min to give colorless 0.2 M Li(OC6H4-p-OMe) solution in THF,
which was stored at room temperature in the dark and used within a
day.
N-Benzyl-N-methylethanethioamide (2b). Pale yellow solid:
mp 80−81 °C; IR (KBr) ν 2964, 2360, 1503, 1235, 953 cm−1; H
1
NMR (399.78 MHz, CDCl3) δ 7.33−7.03 (m, 5H, rotamer A + B),
5.25 (s, 2H, rotamer A), 4.75 (s, 2H, rotamer B), 3.37 (s, 3H, rotamer
B), 3.08 (s, 3H, rotamer A), 2.65 (s, 3H, rotamer B), 2.63 (s, 3H,
rotamer A); 13C NMR (100.53 MHz, CDCl3) δ 200.8, 200.4, 135.4,
134.6, 129.0, 128.6, 127.9, 127.8, 127.7, 126.1, 58.2, 57.9, 42.7, 39.1,
32.9, 32.4; HRMS (ESI TOF (+)) calcd. for C10H14NS m/z 180.0841
[M + H]+, found 180.0841.
N-(4-Methoxyphenyl)-N-methylethanethioamide (2c). Pale
yellow solid: mp 44 °C; IR (KBr) ν 2958, 2360, 1511, 1248, 1030
cm−1; 1H NMR (399.78 MHz, CDCl3) δ 7.05 (d, J = 9.0 Hz, 2H), 6.90
(d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H), 2.34 (s, 3H); 13C NMR
(100.53 MHz, CDCl3) δ 201.4, 159.0, 138.5, 126.1, 114.8, 55.4, 45.7,
33.6; HRMS (ESI TOF (+)) calcd. for C10H14ONS m/z 196.0791 [M
+ H]+, found 196.0791.
(S)-3-Hydroxy-N-(4-methoxyphenyl)-N-methyl-3-(thiophen-
2-yl)propanethioamide (4c). The above-mentioned procedure for
direct aldol reaction was applied. Colorless liquid: IR (KBr) ν 3380,
1
2926, 1509, 1249, 704 cm−1; H NMR (399.78 MHz, CDCl3) δ 7.17
(dd, J = 5.0, 1.1 Hz, 1H), 7.01−6.88 (m, 5H), 6.79 (d, J = 3.4 Hz, 1H),
5.48−5.43 (m, 1H), 4.89 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s,
3H), 2.86−2.82 (m, 2H); 13C NMR (100.53 MHz, CDCl3) δ 201.8,
159.4, 146.7, 137.7, 126.5, 124.3, 123.1, 115.1, 68.7, 55.5, 51.2, 45.7;
HRMS (ESI TOF (+)) calcd. for C15H17NO2S2 m/z 330.0593 [M +
Na]+, found 330.0591; [α]D24 −53.9 (c 0.84, CHCl3, 73% ee); HPLC
[Daicel CHIRALCEL OZ-H, detection at 254 nm, 9:1 n-
hexane/iPrOH, flow rate = 1.0 mL/min, tR = 28.1 min (major), tR =
33.3 min (minor)].
(S)-3-(Diallylamino)-1-(thiophen-2-yl)propan-1-ol (5d)
(Large-Scale Reaction). To a flame-dried 3 L flask equipped with
a magnetic stirring bar and a three-way glass stopcock were added
(S,S)-Ph-BPE (5.70 g, 11.25 mmol), [Cu(CH3CN)4]PF6 (4.19 g,
11.25 mmol), dry THF (188 mL), and dry DMF (1313 mL). After
stirring for 20 min at room temperature, N,N-diallylthioacetamide 2d
(23.9 mL,150 mmol) and 2-thiophencarboxaldehyde (3) (18 mL, 180
2d is reported in ref 11b, and spectroscopic data of 2d used in this
study was fully consistent with the reported data.
(S)-N-Benzyl-3-hydroxy-N-methyl-3-(thiophen-2-yl)-
propanethioamide (4b). To a flame-dried 3 L flask equipped with a
magnetic stirring bar and a three-way glass stopcock were added (S,S)-
Ph-BPE (5.1 mg, 0.01 mmol), [Cu(CH3CN)4]PF6 (3.7 mg, 0.01
mmol), dry THF (350 μL), and dry DMF (1.75 mL). After stirring for
20 min at room temperature, N-benzyl-N-methylethanethioamide
(2b) (35.9 mg, 0.2 mmol) and 2-thiophenecarboxaldehyde (3) (27.4
μL, 0.3 mmol) were added. The flask was immersed into the cooling
bath at −70 °C. To the solution was added Li(OC6H4-p-OMe) (0.2
M/THF, 50 mL, 0.01 mmol), and the mixture was stirred at −70 °C.
After 48 h of stirring, AcOH in THF (0.1 M, 150 μL), and NH4Cl aq
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Note
mmol) were added. The flask was immersed into the cooling bath at
−70 °C with 2-propanol as medium. To the solution was added
Li(OC6H4-p-OMe) (0.2 M/THF, 56.3 mL, 11.25 mmol), and the
mixture was stirred at −70 °C. After 48 h of stirring, AcOH in THF
(0.1 M, 169 mL), and NH4Cl aq were added to the reaction mixture,
and the aqueous layer was extracted with diethyl ether. The combined
organic layers were washed with 1 N HCl 3 times and with brine and
then dried over Na2SO4 . The filtrate was concentrated under reduced
pressure, and the resulting residue was submitted to 1H NMR analysis
to estimate the yield of the product 4d (59% yield) and dehydrated
byproduct 2d′ (20% yield). Enantiomeric excess was determined by
HPLC analysis (92% ee). The resulting crude mixture was directly
used for the following reaction. To a flame-dried 1 L flask equipped
with dropping funnel was charged LiAlH4 (17.1 g, 450 mmol) and dry
THF (300 mL), and the mixture was cooled to −78 °C. A THF (300
mL) solution of the crude mixture was slowly added through a
dropping funnel, and the reaction mixture was additionally stirred for
10 min at room temperature. After the flask was cooled to −78 °C,
saturated aqueous solution of Rochelle salt was slowly added through
dropping funnel, and then the reaction mixture was stirred for
additional 30 min at room temperature. Resulting mixture was
extracted with CHCl3 three times, and the combined organic phase
was dried over Na2SO4. Volatiles were removed under reduced
pressure, and the resulting residue was immediately passed through a
short-pad of silica gel (n-hexane/CH2Cl2 = 3/1 for (S,S)-Ph-BPE; n-
hexane/AcOEt = 3/1 for product 5d) to isolate (S,S)-Ph-BPE (partial
decomposition of (S,S)-Ph-BPE should be involved when the crude
sample was applied to usual silica gel column chromatography). The
obtained (S,S)-Ph-BPE was then recrystallized with AcOEt and MeOH
to give pure (S,S)-Ph-BPE as a white solid (4.77 g, 84% recovery).
Roughly separated crude product mixture was purified again by silica
gel column chromatography (n-hexane/AcOEt = 3/1) to give desired
amine 5d as a red oil (19.9 g, 83.8 mmol, 56%, 2 steps): IR (KBr) ν
2979, 1708, 1633, 1178, 754 cm−1; 1H NMR (399.78 MHz, CDCl3) δ
7.20 (dd, J = 5.0, 1.1 Hz, 1H), 6.96 (dd, J = 5.0, 3.6 Hz, 1H), 6.93−
6.90 (m, 1H), 5.92−5.80 (m, 2H), 5.23−5.19 (m, 2H), 5.19−5.16 (m,
2H), 5.17−5.12 (m, 1H), 3.29 (dd, J = 14.0, 6.1 Hz, 2H), 2.99 (dd, J =
14.0, 7.6 Hz, 2H), 2.85 (ddd, J = 13.0, 9.6, 3.7 Hz, 1H), 2.67 (ddd, J =
13.0, 5.3, 3.4 Hz, 1H), 2.04−1.87 (m, 2H); 13C NMR (100.53 MHz,
CDCl3) δ 149.4, 134.2, 126.4, 123.7, 122.2, 118.7, 72.0, 56.5, 51.8,
34.4; HRMS (ESI TOF (+)) calcd. for C18H20NOS m/z 298.1260 [M
Ethylenediamine (600 μL), 600 μL of 1 N NaOH aq, and 1 mL of
H2O were subsequently added with 10 min intervals. The gray mixture
was filtered through a pad of Celite, and the filtrate was washed with
THF. The organic solvent was removed under reduced pressure. The
crude mixture was diluted with H2O and extracted with CH2Cl2 three
times. The combined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (CH2Cl2 100%, then (8 M NH3 in MeOH)/
CH2Cl2 = 1/15) yielding amino alcohol 7 (449 mg, 2.870 mmol, 74%
(3 steps), from 5d) as a colorless oil that crystallized upon standing.
Pale yellow solid: mp 59 °C; IR (KBr) ν 3297, 2852, 2361, 1073, 700
1
cm−1; H NMR (399.78 MHz, CDCl3) δ 7.14 (dd, J = 5.0, 1.1 Hz,
1H), 6.90 (dd, J = 5.0, 3.4 Hz, 1H), 6.87−6.84 (m, 1H), 5.08−5.02
(m, 1H), 4.15 (br, 2H), 2.84−2.68 (m, 2H), 2.32 (s, 3H), 1.94−1.78
(m, 2H); 13C NMR (100.53 MHz, CDCl3) δ 149.6, 126.2, 123.4,
122.1, 70.7, 49.5, 37.0, 35.6; HRMS (ESI TOF (+)) calcd. for
C8H14NOS m/z 172.0791 [M + H]+, found 172.0791; [α]D24 −9.1 (c
0.55, CHCl3, 92% ee).
Duloxetine (1). To a solution of 7 (54.1 mg, 0.32 mmol, 92% ee
sample) dissolved in 2.1 mL of dry DMSO was added NaH (60% in
mineral oil, 19.0 mg, 0.47 mmol). The mixture was stirred at room
temperature for 1 h followed by the addition of 1-fluoronaphthalene
(56.7 μL, 0.44 mmol). After stirring at 50 °C for 1 h, the mixture was
cooled to room temperature, and 5 mL of 1 N NaOH aq was added.
The product was extracted with AcOEt three times, and the combined
organic phase was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography ((8 M NH3 in MeOH)/CH2Cl2 = 1/20) to
afford duloxetine (61.1 mg, 0.21 mmol, 65%) as a pale yellow oil: IR
(KBr) ν 3052, 2924, 2851, 1397, 1094 cm−1; 1H NMR (399.78 MHz,
CDCl3) δ 8.40−8.34 (m, 1H), 7.81−7.76 (m, 1H), 7.52−7.47 (m,
1H), 7.40 (d, J = 8.5 Hz, 1H), 7.31−7.25 (m, 1H), 7.21 (dd, J = 5.0,
1.1 Hz, 1H), 7.08−7.05 (m, 1H), 6.94 (dd, J = 5.0, 3.4 Hz, 1H), 6.87
(d, J = 7.6 Hz, 1H), 5.81 (dd, J = 7.8, 5.2 Hz, 1H), 2.86−2.80 (m, 2H),
2.52−2.40 (m, 4H), 2.29−2.18 (m, 1H); 13C NMR (100.53 MHz,
CDCl3) δ 153.1, 144.9, 134.3, 127.2, 126.3, 126.1, 125.8, 125.5, 125.0,
124.5, 124.4, 121.9, 120.3, 106.7, 74.5, 48.0, 38.7, 36.3; HRMS (ESI
TOF (+)) calcd. for C18H20NOS m/z 298.1260 [M + H]+, found
25
298.1261; [α]D 107.0 (c 0.08, MeOH).
ASSOCIATED CONTENT
■
23
+ H]+, found 298.1261; [α]D −99.8 (c 0.41, CHCl3).
S
* Supporting Information
1
Recovered (S,S)-Ph-BPE. Spectral data: H NMR (399.78 MHz,
1H and 13C NMR charts and HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
CDCl3) δ 7.26−6.96 (m, 20H), 3.53−3.44 (m, 2H), 2.88−2.81 (m,
2H), 2.41−2.30 (m, 2H), 2.23−2.15 (m, 2H), 2.06−1.94 (m, 2H),
1.79−1.69 (m, 2H), 0.93−0.82 (m, 2H), 0.55−0.43 (m, 2H); 13C
NMR (100.53 MHz, CDCl3) δ 144.7−144.6 (m), 138.3 (m), 128.5
(s), 128.3 (s), 127.9−127.8 (m), 127.2 (m), 125.8 (s), 125.7 (s),
50.7−50.5 (m), 46.2−46.1 (m), 37.4 (s), 31.9 (s), 21.5−21.4 (m); 31P
NMR (161.83 MHz, CDCl3) δ 14.2.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp.
(S)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol (7). To a
stirred solution of 5d (870 mg, 3.67 mmol, 92% ee) in CH2Cl2 (20
mL) were added Pd(PPh3)4 (219 mg, 0.18 mmol) and N,N-
dimethylbarbituric acid (2.96 g, 18.33 mmol), and the resulting
solution was stirred at 50 °C (bath temp.) 6 h. After cooling to rt, the
mixture was diluted with CHCl3. The solution was washed with
saturated Na2CO3 three times to remove barbituric acid and then dried
over Na2SO4. Volatiles were removed under reduced pressure to give
crude primary amine as a red oil. To a CH2Cl2 (7 mL) solution of the
crude mixture were added methyl chloroformate (426 μL, 5.50 mmol,
1.5 equiv) and 2.5 M K2CO3 aq (7 mL, 18.33 mmol, 5 equiv), and the
mixture was stirred for 2.5 h at room temperature. Resulting mixture
was diluted with H2O, and the biphasic mixture was extracted with
CH2Cl2 three times. The combined organic phase was washed with
brine and dried over Na2SO4. Volatiles were removed under reduced
pressure to give crude carbamate as a red oil. A flame-dried 100 mL
flask was charged with the crude carbamate (3.58 mmol; a small
portion was used for the following experiments). To the flask was
added LiAlH4 (402 mg, 10.60 mmol) suspended in 35 mL of dry THF.
The suspension was heated to reflux and stirred for 48 h.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by KAKENHI (No.
20229001 and 23590038) from JSPS. Y.S. thanks JSPS for a
predoctoral fellowship.
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