Rearrangement of N-alkyl 1,2-amino alcohols. Synthesis of (S)-toliprolol and (S)-propanolol

Article abstract of DOI:10.1016/j.tet.2009.05.072

N-alkyl 1,2-amino alcohols were rearranged stereospecifically by using TFAA/Et₃N. This rearrangement has been used to synthesize N-isopropyl-3-(aryloxy)-2-hydroxypropylamines, β-adrenergic blocking agents such as (S)-toliprolol and (S)-propanolol.

Full text of DOI:10.1016/j.tet.2009.05.072

Tetrahedron 65 (2009) 6696–6706
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rearrangement of N-alkyl 1,2-amino alcohols. Synthesis of (S)-toliprolol
and (S)-propanolol
*
*
´
´
Beranger Duthion, Thomas-Xavier Metro, Domingo Gomez Pardo , Janine Cossy
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
N-alkyl 1,2-amino alcohols were rearranged stereospecifically by using TFAA/Et3N. This rearrangement
Received 25 March 2009
Received in revised form 22 May 2009
Accepted 26 May 2009
has been used to synthesize N-isopropyl-3-(aryloxy)-2-hydroxypropylamines,
agents such as (S)-toliprolol and (S)-propanolol.
b-adrenergic blocking
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 3 June 2009
Keywords:
Rearrangement
1,2-Amino alcohols
Aziridinium
(S)-Propanolol
(S)-Toliprolol
1. Introduction
example, the (S)-propanolol II is 100-fold more active than the
(R)-stereoisomer4 (Fig. 1).
The 1,2-amino alcohol functionality is present in a wide variety
of natural products and biologically active compounds.1 Of
particular importance, are the optically active N-isopropyl-3-(ary-
loxy)-2-hydroxypropylamines A. This family of more than 30
Several syntheses of homochiral b-adrenergic blocking agents of
type A have been achieved mainly through the formation of either
the C1–N bond (pathway a) or the C3–O bond (pathway b). The
third pathway (pathway c) corresponds to a reductive amination of
A0 (Scheme 1). The key chiral epoxides can be readily obtained via
enzymatic resolution, nitroaldol reaction, asymmetric ring opening
of aryl glycidyl ethers, Sharpless asymmetric epoxidation or
asymmetric dihydroxylation. An asymmetric synthesis has also
been achieved utilizing the chiral pool.5,6
b
-adrenergic antagonists is used in the therapy of hypertension,
glaucoma, angina pectoris, anxiety, and obesity.2,3 These N-iso-
propyl-3-(aryloxy)-2-hydroxypropylamines, such as (S)-toliprolol I
and (S)-propanolol II, are mainly active as the (S)-enantiomers. For
Recently, we have shown that linear N,N-dialkyl 1,2-amino al-
OH
H
cohols C were obtained by rearrangement of N,N-dialkyl
b-amino
ArO
N
alcohols B7 by treatment with a catalytic amount of TFAA8 or with
A
OH
O
OH
OH
H
N
H
N
ArO
NH2
c
O
O
A'
I
II
(S)-propanolol
(S)-toliprolol
O
H
N
O
ArO
Figure 1.
OH
c
a
b
b
H
N
a
1
ArO
2
3
* Corresponding authors. Tel.: þ33 (0)140794429; fax: þ33 (0)140794660 (J.C.);
tel.: þ33 (0)140794663; fax: þ33 (0)140794660 (D.G.P.).
ArOH
i-PrNH2
A
E-mail addresses: domingo.gomez-pardo@espci.fr (D. Gomez Pardo),
janine.cossy@espci.fr (J. Cossy).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.072

B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
6697
a catalytic amount of sulfuric acid.9 The rearranged N,N-dia-
Table 1
Rearrangement of N-cyclohexyl b-amino alcohol 2
lkylamino compounds C can be transformed to N-alkylamino al-
cohols D, but this strategy necessitates a deprotection step, which is
not atom economical. In order to avoid these protection/depro-
tection steps, the direct rearrangement of N-alkyl 1,2-amino alco-
hols of type E has been considered (Scheme 2).10
OH
1) Reagent
THF, MW
H
N
NH
OH
2) NaOH
Ph
Ph
TFAA (cat.) or H2SO4 (cat.)
R1
R
R2
4
2
N
OH R1
N
MW
OH
R
R2
NaOH
Entry
Reagent (equiv)
TFA (0.06 equiv)
TFAA (0.06 equiv)
TFAA (1 equiv),
Et3N (1 equiv),
NaOH (20 equiv)
Conditions (h,ꢀC)
Yield (%)
B
C
1
2
3
24 h, 180 ꢀ
C
57
54
78
30 h, 180 ꢀC
12 h, 120 ꢀC
protection
OH
deprotection
R1
H
OH R1
N
Ester H could also be formed via an aziridinium intermediate G0,
which could be attacked by the trifluoroacetyl anion released in
the reaction media. After a 1,4-migration of the trifluoroacetyl
group from the hydroxy group to the amino group producing I,
treatment with NaOH led to the rearranged amino alcohol D
(Scheme 4). By analogy with our previous work,11 we assume that
compounds F and I are in equilibrium, and that trifluoroamide I is
the thermodynamic product.
N
R
R
H
E
D
Scheme 2. General scheme.
Here, we would like to report our results concerning the rear-
rangement of N-alkyl 1,2-amino alcohols of type E and the appli-
cation of this rearrangement to the synthesis of (S)-toliprolol I and
(S)-propanolol II.
OH
R'HN
R
2. Rearrangement of N-alkyl 1,2-amino alcohols
E
At first, N-alkyl
b-amino alcohols 1 and 2 were examined under
the catalytic acidic conditions that were previously developed for
the rearrangement of N,N-dialkyl b
-amino alcohols.9 Thus, when
(CF3CO)2O (1 equiv)
Et3N (1 equiv)
113 and 2 were treated with H2SO4 (0.05 equiv), respectively, for 2 h
and 24 h, at 180 ꢀC in THF under microwave irradiation, 3 (22%) and
4 (42%) were obtained in poor yields (Scheme 3).
O
R'N
R
CF3
OH
H2SO4 (0.05 equiv)
THF, 2 h, 180 °C, MW
22%
BnHN
OH
HO
NHBn
F
R'HN
R
1
3
O
G
E''
O
O
F3C
HO
OH
CF3
H
N
NH
NR'
H2SO4 (0.05 equiv)
THF, 24 h, 180 °C, MW
42%
OH
O
R' H
R
Ph
I
NHR'
O
R
N
Ph
F3C
R
2
4
G'
NaOH
NHR'
H
Scheme 3. Rearrangement of N-alkyl b-amino alcohols 1 and 2 with H2SO4.
HO
R
CF3COO
Due to these results, rearrangement of compound 2 was
examined under different conditions in order to improve the yields
in the rearranged product 4. Other reagents such as TFA and TFAA
were used in catalytic amount to rearrange N-alkylamino alcohol 2
(THF, microwave irradiation, 24–30 h). However, the yields in the
rearranged amino alcohol 4 were modest (54–57%) (Table 1, entries 1
and 2). The best yield in 4 (78%) was obtained by using a stoichio-
metric amount of TFAA and Et3N at 120 ꢀC for 12 h under microwave
irradiation, followed by the addition of NaOH (Table 1, entry 3).
In order to explain these results, the mechanism of the rear-
D
Scheme 4. Supposed mechanism for the rearrangement of E with a stoichiometric
amount of TFAA and Et3N.
Furthermore, if one considers the mechanism of the rear-
rangement of E into
TFAA, the first steps will be identical to the rearrangement using
stoichiometric amount but an additional step, trans-
b-amino alcohol D using a catalytic amount of
a
a
amidification between compound I and amino alcohol E can occur
to complete the catalytic cycle by generating the rearranged amino
alcohol D and the trifluoroamide F. This latter can be involved in the
catalytic cycle (Scheme 5). By analogy with our previous work,8 we
assume that compounds E, F, I, and D are in equilibrium, and that
compounds D and I are the thermodynamic products.
rangement of b-amino alcohols E into b-amino alcohols D using
a stoichiometric amount of TFAA and Et3N has been considered. In
this rearrangement, the first step is probably the tri-
fluoroacetylation of the amino group in E, which would produce F.
After a 1,4-migration of the trifluoroacetyl group from the amino
group to the hydroxy group, G was produced and an intra-
molecular rearrangement could take place, leading to ester H.
As the conditions of the rearrangement of N-alkyl
cohols are more drastic (higher temperature and longer reaction
b-amino al-

6698
B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
OH
O
R'HN
R
O
F3C
HO
NHR'
O
R
NR'
F3C
E
R
H
I
(CF3CO)2O cat.
NHR'
HO
R
O
R'N
R
O
CF3
OH
D
O
CF3
NR'
O
R
F3C
O
SN2
O
CF3
NR'
F3C
O
R
J
F
O
R'HN
R
OH
R'HN
J'
O
CF3
O
G
E''
O
O
R
Et3NH
E
F3C
HO
CF3
NR'
O
R' H
R
I
NHR'
O
R
N
NaOH
F3C
R
NaOH
G'
OH
H
NHR'
R
NHR'
HO
R
CF3COO
D
racemized
Scheme 7. Supposed mechanism of racemization.
D
Scheme 5. Supposed mechanism of the rearrangement of E with a catalytic amount of
TFAA.
In order to verify this hypothesis, the rearranged b-amino al-
time) in utilizing a catalytic amount of TFAA than in utilizing
a stoichiometric one, the use of 1 equiv of TFAA and 1 equiv of Et3N
in THF for 12 h at 120 ꢀC followed by the addition of NaOH was
chosen as conditions to study the rearrangement. When these
cohol 6 possessing an enantiomeric excess of 99% was transformed
to amidoester 7 [TFAA (2.2 equiv), Et3N (2.2 equiv), THF, rt]. This
latter was then treated with 1 equiv of triethylammonium tri-
fluoroacetate, in THF under microwave irradiation at 120 ꢀC. After
12 h, the reaction media was treated with NaOH and 6 was isolated
in 80% yield with an enantiomeric excess of 24%, demonstrating
that the trifluoroacetate anion present in the reaction media can
attack 7 according to an SN2 mechanism leading to the racemiza-
tion of 6 (Scheme 8).
conditions were applied to b-amino alcohol 2 and commercially
available compound 5, the corresponding rearranged compounds 4
and 6 were, respectively, obtained in good yields (> 78%) but, very
disappointingly, the enantiomeric excesses were low, 30% for
compound 4 and 46% for compound 6 (Scheme 6).
O
1) TFAA (1 equiv)
Et3N (1 equiv)
TFAA (2.2 equiv)
O
CF3
Ph
Et3N (2.2 equiv)
OH
F3C
Ph
O
THF, 120 °C, 12 h, MW
H
N
NH
OH
Ph
H
N
N
Ph
THF, rt
OH
2) NaOH
78%
(R)
Ph
(S)
Ph
6 (ee = 99%)
7 (ee = 99%)
4 (ee = 30%)a
1) CF3COOH (1 equiv)
Et3N (1 equiv)
2
THF, 120 °C, 12 h
OH
H
N
Ph
Ph
2) NaOH
80%
1) TFAA (1 equiv)
Et3N (1 equiv)
Ph
6 (ee = 24%)a
THF, 120 °C, 12 h, MW
NH
OH
H
Scheme 8. Racemization of optically pure
dibenzylated compound 19 (cf. Scheme 10).
b
-amino alcohol 6. aDetermined on the
OH
N
Ph
2) NaOH
89%
Ph
Ph
(R)
(S)
6 (ee = 46%)a
5
Furthermore, in order to prove that in the absence of the tri-
ethylammonium trifluoroacetate in the reaction media the race-
mization does not occur, trifluoroamide 8 was synthesized from 5
[TFAA (1 equiv), Et3N (1 equiv), THF, rt] and then heated in THF
under microwave irradiation at 120 ꢀC for 12 h without triethyl-
ammonium trifluoroacetate. The reaction media was then treated
with NaOH and 6 was isolated in 43% yield with an enantiomeric
excess of 98%. These experiences demonstrated that triethyl-
ammonium trifluoroacetate was involved in the racemization
process of 6. Unfortunately, the lack of this ammonium salt entailed
a moderate conversion in 6 (54%), demonstrating that triethyl-
ammonium trifluoroacetate is probably involved in the mechanism
Scheme 6. Rearrangement of
benzylated compound 19 and the benzylated compound 22 (cf. Scheme 10).
b
-amino alcohols 2 and 5. aDetermined on the di-
Based on the proposed mechanism, we would not expect to see
this sort of epimerization. An hypothesis can be proposed to explain
this racemisation. After the rearrangement, several species can be
present in the reaction media such as H, I, and J, this latter can be
formed from H and I. The epimerization can occur in species J
according to an SN2 mechanism involving a trifluoroacetyl anion
that can be delivered from triethylammonium trifluoroacetate,
which is present in the reaction media (Scheme 7).

B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
6699
and/or the kinetic of the rearrangement (Scheme 9). Rising the
temperature of the reaction to improve the conversion in 6 un-
fortunately came with the racemization of this latter.
BnBr (1.1 equiv)
K2CO3 (1.5 equiv)
n-Bu4NI (0.15 equiv)
Ph
Ph
OH
OH
H
N
Ph
Ph
N
Ph
Ph
(S)
Ph
(S)
MeCN, reflux
88%
6
Ph
19
Ph
O
1) (CF3CO)2O (1 equiv),
Et3N (1 equiv), THF, rt, 1 h
NH
N
CF3
OH
OH
Ph
BnBr (1.1 equiv)
K2CO3 (1.5 equiv)
n-Bu4NI (0.15 equiv)
Ph
(R)
95%
OH
OH
8
H
N
5 (ee = 99%)
N
Ph
R
(R)
R
(R)
MeCN, reflux
3
R= Me
20 R= Me
21 R= Bn
OH
H
82−85%
1) THF, 120 °C, 12 h, MW
14 R= Bn
N
Ph
Ph
(S)
2) NaOH
6 (ee = 98%)
43%
τC=54%
1) H4NCO2H, 10% Pd/C
MeOH, reflux
Ph
OH
OH
H
N
N
Ph
Scheme 9. Synthesis and rearrangement of b-amido alcohol 8.
2) BnBr (2.2 equiv)
K2CO3 (3 equiv)
n-Bu4NI (0.3 equiv)
MeCN, reflux
R
R
(R)
(R)
18 R= Me
15 R= Bn
20 R= Me
21 R= Bn
In order to obtain the best yield and enantiomeric excess in 6,
the temperature and the reaction time were examined. The best
conditions were 1 equiv of TFAA and 1 equiv of Et3N at 100 ꢀC under
microwave irradiation for 15 h. It is worth noting that when heated
at 110 ꢀC under microwave irradiation for 6 h, 5 was transformed
into 6 with a very good enantiomeric excess (94%) and with a good
yield (72%). The results are reported in Table 2.
51−52%
BnBr (1.1 equiv)
K2CO3 (1.5 equiv)
n-Bu4NI (0.15 equiv)
Ph
R
OH
H
OH
N
N
R
(R)
MeCN, reflux
(R)
Ph
Ph
85−94%
Table 2
22 R= cyclohexyl
23 R= 4-heptyl
24 R= 1-octyl
4
R= cyclohexyl
Optimization of the temperature and reaction time for the rearrangement of 5
16 R= 4-heptyl
17 R= 1-octyl
Ph
1) TFAA (1 equiv)
Et3N (1 equiv)
NH
OH
Scheme 10. Synthesis of b-amino alcohols 19–24.
H
N
OH
Ph
THF, MW
2) NaOH
Ph
Ph
(R)
(S)
5
6
OH
H
N
NH
Entry
Time (h)
Temperature (ꢀC)
s
C (%)
Yield (ee)a[%]
ArO
ArO
OH
1
2
3
4
5
12
6
1
6
15
120
120
180
110
100
100
95
100
91
89 (46)
78 (87)
72 (64)
72 (94)
63 (96)
K
(S)-toliprolol: Ar = m-tolyl
84
(S)-propanolol: Ar = α−naphthyl
a
Determined on the dibenzylated compound 19 (cf. Scheme 10).
NH2
CbzN
O
O
OH
HO
It is worth noting that for each substrate, the conditions have to
be tuned up. The best conditions and results in obtaining 3, 4, 14–18
from, respectively, 1, 2, 9–13 are reported in Table 3.
OMe
D-serine methyl ester
25
The enantiomeric excesses of compounds 3, 4,14–18 were found
to be superior to 93% when amino alcohols 1, 2, 9–13 were heated at
110 ꢀC or 120 ꢀC for 6 h to 12 h.
Scheme 11. Retrosynthetic approach to (S)-toliprolol and (S)-propanolol.
The enantiomeric excesses of compounds 3, 4, 6, 14–18 were
determined by measuring the enantiomeric excesses of either the
dibenzyl b-amino alcohols 19–21 or the benzylalkyl b-amino al-
The common intermediate 25 was synthesized in three steps
from
D
-serine methyl ester.12 After carbamoylation [CbzCl
(1.1 equiv), K2CO3 (3 equiv) in THF/H2O 1/1], protection of the hy-
droxy carbamate [APTS, 2,2-dimethoxypropane] and reduction
[NaBH4, THF/MeOH], 25 was isolated in 59% yield. In order to syn-
thesize (S)-toliprolol, 25 was treated with m-cresol under the Mit-
sunobu conditions (PPh3, DEAD, toluene, 80 ꢀC, 18 h) and the
obtained aryl ether 26 (69%) was hydrogenated (H2, Pd/C 10%,
MeOH) producing amino alcohol 27 (77%). This latter was rear-
ranged to (S)-toliprolol by treatment with TFAA (1 equiv), Et3N
(1 equiv) in THF under microwave irradiation at 110 ꢀC for 12 h
followed by the addition of NaOH. Under these conditions,
(S)-toliprolol was isolated in 69% yield and with an enantiomeric
excess of 92% (Scheme 12).
cohols 22–24. Preparations of 19–24 are reported in Scheme 10.
3. Synthesis of (S)-toliprolol and (S)-propanolol
The rearrangement of N-alkyl
applied to the synthesis of (S)-toliprolol and (S)-propanolol, two
-adrenergic blocking agents, which are active as the (S)-enantio-
b-amino alcohols was then
b
mers. The synthesis of these N-isopropyl-3-(aryloxy)-2-hydroxy-
propylamines would be obtained by rearrangement of 1,2-amino
alcohols K that would be synthesized from
D-serine methyl ester via
the protected amino alcohol 2512 (Scheme 11).

6700
B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
Table 3
Rearrangement of N-alkyl b-amino alcohols
1) TFAA (1 equiv)
Et3N (1 equiv)
R'
NH
OH
H
N
OH
THF, MW
2) NaOH
R
R
R'
(S)
(R)
1, 2, 9−13
3, 4,14−18
Entry
1
Starting material
Time (h)
Temperature (ꢀC)
120
Product
Yield (ee) [%]
70 (98)a
NHBn
OH
OH
NHBn
12
12
(R)
Ph
(S)
Ph
9
14
OH
H
N
NH
2
120
80 (96)a
OH
(R)
(S)
Ph
Ph
15
10
OH
H
NH
N
3
6
110
110
85 (94)b
OH
(R)
Ph
(S)
Ph
4
2
OH
H
N
NH
(R)
4
6
91 (96)b
OH
Ph
(S)
Ph
16
11
OH
H
N
NH
5
6
12
120
78 (93)b
(R)
OH
Ph
(S)
Ph
17
12
NHBn
OH
OH
12
18
120
110
NHBn
88 (93)a
60 (96)a
(S)
(R)
3
1
OH
H
N
NH
7
8
120
74 (93)a
OH
(R)
(S)
18
13
a
Determined on the dibenzylated compounds 20, 21 (cf. Scheme 10).
Determined on the benzylalkyl b-amino alcohols 22–24 (cf. Scheme 10).
b
Similarly, (S)-propanolol was synthesized from 25. After
a Mitsunobu reaction with -naphthol leading to the aryl ether 28
4. Conclusion
a
(67%), classical hydrogenation (H2, Pd/C 10%, MeOH) of this latter
produced the amino alcohol 29 in poor yield (33%). When the hy-
drogenation was conducted in a flow manner using H-CubeÔ
(Thales Nanotechnology Inc.), the amino alcohol 29 was isolated in
a better yield of 75%. This latter was rearranged by treatment with
TFAA (1 equiv), Et3N (1 equiv) inTHF under microwave irradiation at
110 ꢀC for 12 h followed by the addition of NaOH leading to (S)-
propanolol in 60% yield, with an enantiomeric excess of 92%
(Scheme 12).
The rearrangement of optically active N-alkyl 1,2-amino alco-
hols can take place by treatment of these latter with TFAA, Et3N
(1 equiv). For each substrate, the temperature and the reaction time
have to be controlled in order to obtain the best yield and enan-
tiomeric excess in the rearranged products. This simple rear-
rangement can be applied to the synthesis of biologically active
compounds in an efficient manner.

B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
6701
NH2
overlap of non-equivalent resonances, integration). 13C NMR spec-
tra were recorded on a Bruker AVANCE 400 at 100 MHz and data
are reported as follows: chemical shift in parts per million from
tetramethylsilane with the solvent as internal standard (CDCl3,
O
OH
OMe
D-serine methyl ester
d
77.0 ppm), multiplicity with respect to proton (deduced from
DEPT experiments, s¼quaternary C, d¼CH, t¼CH2, q¼CH3). Mass
spectra with electronic impact (MS-EI) were recorded from
a Hewlett-Packard tandem 5890A GC (12 m capillary column)–
5971 MS (70 eV). All reactions were carried out under argon at-
mosphere. Commercially available reagents and solvents were used
as received. Anhydrous solvents were distilled: tetrahydrofuran
and diethyl ether were purified by distillation from sodium and
benzophenone, methylene chloride and toluene were dried by
distillation from CaH2. Flash column chromatography was per-
formed on silica gel (Merck-Kieselgel 60, 230–400 mesh). HRMS
1) CbzCl (1.1 equiv)
K2CO3 (3 equiv)
THF/H2O 1:1
59%
2) APTS
2,2-dimethoxypropane
3) NaBH4
OH
OH
CbzN
HO
´
were performed by the Centre Regional de Microanalyses (Uni-
O
´
versite Pierre et Marie Curie, Paris VI). Microwave irradiation ex-
periments were performed using a single-mode Initiator TM EXP
(0–300 W, 2.45 GHz) from Biotage.
PPh3, DEAD
PPh3, DEAD
25
69%
O
67%
toluene, 80 °C, 18 h
toluene, 80 °C, 18 h
5.2. Reductive amination: compounds 2, 9–13
CbzN
O
CbzN
5.2.1. (S)-2-Cyclohexylamino-3-phenylpropan-1-ol (2)
O
O
To a stirred suspension of (S)-2-amino-3-phenylpropan-1-ol
(1.01 g, 6.6 mmol) and cyclohexanone (690 mL, 6.6 mmol, 1 equiv)
28
26
in 1,2-dichloroethane (23 mL) were successively added NaBH(OAc)3
(2.1 g, 9.9 mmol, 1.5 equiv) and AcOH (0.38 mL, 6.6 mmol, 1 equiv).
After stirring at rt for 12 h, the reaction mixture was hydrolyzed by
addition of an aqueous 1 M NaOH solution. The aqueous layer was
extracted with CH2Cl2 and the combined organic phases were
washed with an aqueous 1 M NaOH solution, dried over MgSO4,
and filtered. The solvent was removed in vacuo and the residue was
H2, Pd/C 10%
EtOH
H2, Pd/C 10%
MeOH
75%
77%
H cube®
purified by flash column chromatography on silica gel (EtOAcþ0.5%
25
NH
OH
Et3N) to give 2 (1.33 g, 5.7 mmol, 85%). [
a
]
þ11.57 (c 0.55, CHCl3);
NH
D
O
O
OH
IR (neat) 3272, 3026, 2849, 1600, 1492, 1477, 1350, 1122, 1037, 805,
698 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.32–7.15 (m, 5H), 3.54 (dd,
27
J¼10.4, 4.1 Hz, 1H), 3.23 (dd, J¼10.4, 5.6 Hz, 1H), 3.0 (tdd, J¼6.8, 5.7,
4.2 Hz, 1H), 2.78–2.67 (m, 2H), 2.45 (tt, J¼10.2, 3.8 Hz, 1H), 2.12 (br
s, 2H), 1.85 (m, 1H), 1.75–1.54 (m, 4H), 1.28–0.9 (m, 5H); 13C NMR
29
(CF3CO)2O (1 equiv)
Et3N (1 equiv)
(CF3CO)2O (1 equiv)
(100 MHz, CDCl3):
d 138.7 (s), 129.2 (d, 2C), 128.5 (d, 2C), 126.3 (d),
60%
Et3N (1 equiv)
69%
63.1 (t), 56.8,(d), 53.7 (d), 38.7 (t), 34.3 (t), 33.9 (t), 26.0 (t), 25.0 (t),
THF, MW, 110 °C, 12 h
THF, MW, 110 °C, 12 h
ꢂ
24.9 (t); MS-EI m/z (relative intensity): 202 (Mþ ꢁCH2OHꢂ, 32), 142
(100), 132 (13), 120 (33), 105 (8), 91 (36), 83 (12), 60 (35), 55 (16);
HRMS calcd for C15H24NO (MHþ): 234.18524, found: 234.18539.
OH
H
OH
H
O
N
O
N
5.2.2. (S)-2-Benzylamino-3-phenylpropan-1-ol (9)14
To a suspension of molecular sieves 4 Å (1.3 g) in CH2Cl2 (13 mL)
were successively added (S)-2-amino-3-phenylpropan-1-ol (1 g,
6.6 mmol) and benzaldehyde (670 mL, 6.6 mmol,1 equiv). After 3 h at
ee = 92%
ee = 92%
(S)-toliprolol
(S)-propanolol
rt without stirring, the suspension was filtered and concentrated
under reduced pressure. The residue was dissolved in EtOH (13 mL)
and sodium borohydride was added (294 mg, 7.9 mmol, 1.2 equiv).
After stirring at rt for 12 h, the reaction mixture was hydrolyzed by
addition of a saturated aqueous solution of NH4Cl and concentrated
under reduced pressure. After addition of an aqueous 1 M NaOH
solution followed by the extraction with CH2Cl2, the organic phase
was dried over MgSO4 and filtered. The solvent was removed in
vacuo and the residue was purified by flash column chromatography
on silica gel (EtOAcþ0.5% Et3N) to give 9 (1.274 g, 5.3 mmol, 80%).
Scheme 12. Synthesis of (S)-toliprolol and (S)-propanolol.
5. Experimental
5.1. General
TLC was performed on Merck 60F254 silica gel plates and visu-
alized with a UV lamp (254 nm), or by using a solution of KMnO4/
K2CO3/NaOH in water followed by heating. Column chromatogra-
phy was performed with Merck Geduran Si 60 silica gel (40–
63
m
m). Infrared (IR) spectra were recorded on a Bruker TENSORÔ
5.2.3. (S)-2-(Naphthalen-1-ylmethylamino)-3-phenyl-
propan-1-ol (10)
27 (IRFT), wave numbers are indicated in cmꢁ1
.
1H NMR spectra
were recorded on a Bruker AVANCE 400 at 400 MHz and data are
reported as follows: chemical shift in parts per million from tet-
ramethylsilane as internal standard, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, h¼heptuplet, m¼multiplet or
To a suspension of molecular sieves 4 Å (1 g) in CH2Cl2 (7 mL)
were successively added (S)-2-amino-3-phenylpropan-1-ol
(500 mg, 3.3 mmol) and 1-naphthaldehyde (450
mL, 3.3 mmol,
1 equiv). After 3 h at rt without stirring, the suspension was filtered

6702
B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
and concentrated under reduced pressure. The residue was dis-
solved in EtOH (7 mL) and NaBH4 was added (150 mg, 4 mmol,
1.2 equiv). After stirring at rt for 12 h, the reaction mixture was
hydrolyzed by addition of a saturated aqueous solution of NH4Cl
and concentrated under reduced pressure. Basification of the
aqueous residue with an aqueous 1 M NaOH solution was followed
by the extraction with CH2Cl2 and the combined organic phases
were dried over MgSO4 and filtered. The solvent was removed in
vacuo and the residue was purified by flash column chromatogra-
126.4 (d), 62.5 (t), 60.1 (d), 47.0 (t), 38.2 (t), 31.8 (t), 30.3 (t), 29.4 (t),
29.2 (t), 27.2 (t), 22.6 (t), 14.1 (q); MS-EI m/z (relative intensity): 232
ꢂ
(Mþ ꢁCH2OHꢂ, 39), 172 (100), 154 (15), 146 (9), 120 (10), 91 (25), 60
(8); HRMS calcd for C17H30NO (MHþ): 264.23219; found: 264.23196.
5.2.6. (S)-2-(Naphthalen-1-ylmethylamino)propan-1-ol (13)
To a suspension of molecular sieves 4 Å (1.5 g) in CH2Cl2 (7 mL)
were successively added (S)-2-amino-propan-1-ol (500
mL,
6.4 mmol) and 1-naphthaldehyde (916 L, 6.4 mmol, 1 equiv). After
m
phy on silica gel (CH2Cl2/EtOAc 50/50þ0.5% Et3N) to give 10
3 h at rt without stirring, the suspension was filtered and con-
centrated under reduced pressure. The residue was dissolved in
EtOH (7 mL) and NaBH4 was added (240 mg, 6.5 mmol, 1.01 equiv).
After stirring at rt for 12 h, the reaction mixture was hydrolyzed by
addition of a saturated aqueous solution of NH4Cl and concen-
trated under reduced pressure. Basification of the aqueous residue
with an aqueous 1 M NaOH solution was followed by the extrac-
tion with CH2Cl2 and the combined organic phases were dried over
MgSO4 and filtered. The solvent was removed in vacuo and the
25
(814 mg, 2.8 mmol, 84%). [
a
]
ꢁ25.2 (c 1.0, CHCl3); IR (neat) 3500–
D
2600, 2334, 2114, 1596, 1495, 1460, 1353, 1229, 1116, 1054, 1028,
963, 881, 842, 777, 747, 700 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.88
(m, 1H), 7.83 (m, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.48–7.32 (m, 4H), 7.29–
7.13 (m, 5H), 4.21 (d, J¼12.8 Hz, 1H), 4.16 (d, J¼12.8 Hz, 1H), 3.71
(dd, J¼10.8, 4.0 Hz, 1H), 3.38 (dd, J¼10.8, 5.3 Hz, 1H), 3.06 (m, 1H),
2.83 (dd, J¼13.8, 7.3 Hz, 1H), 2.79 (dd, J¼13.6, 6.8 Hz, 1H), 1.98 (br s,
2H); 13C NMR (100 MHz, CDCl3):
d 138.4 (s), 135.5 (s),133.9 (s), 131.7
(s), 129.2 (d, 2C), 128.8 (d), 128.6 (d, 2C), 128.1 (d), 126.5 (d), 126.3
(d), 126.2 (d), 125.7 (d), 125.4 (d), 123.4 (d), 62.8 (t), 60.1 (d), 49.3 (t),
residue was purified by flash column chromatography on silica gel
25
(EtOAcþ0.5% Et3N) to give 13 (965 mg, 4.5 mmol, 70%). [
a
]
þ31.9
D
ꢂ
38.2 (t); MS-EI m/z (relative intensity): 273 (Mþ ꢁH2O, 6), 260 (6),
(c 1.0, CHCl3); IR (neat) 3500–2600, 2327, 1598, 1510, 1445, 1371,
200 (26), 141 (100), 132 (20), 115 (17), 91 (8); HRMS calcd for
C20H22NO (MHþ): 292.16959; found: 292.16905.
1262, 1149, 1064, 879, 851, 790, 765, 731 cmꢁ1; 1H NMR (400 MHz,
CDCl3):
d
8.11 (d, J¼8.5 Hz, 1H), 7.86 (d, J¼7.8 Hz, 1H), 7.77 (d,
J¼8.0 Hz, 1H), 7.55–7.39 (m, 4H), 4.31 (d, J¼12.8 Hz, 1H), 4.19 (d,
J¼12.8 Hz, 1H), 3.63 (dd, J¼10.5, 4.0 Hz, 1H), 3.29 (dd, J¼10.8,
7.0 Hz, 1H), 2.95 (m, 1H), 1.91 (br s, 2H), 1.15 (d, J¼6.3 Hz, 3H); 13C
5.2.4. (S)-2-(Heptan-4-ylamino)-3-phenylpropan-1-ol (11)
To a stirred suspension of (S)-2-amino-3-phenylpropan-1-ol
(500 mg, 3.3 mmol) and 4-heptanone (460
m
L, 3.3 mmol,1 equiv) in
NMR (100 MHz, CDCl3): d 135.9 (s), 134.0 (s), 131.8 (s), 128.8 (d),
1,2-dichloroethane (12 mL) were successively added NaBH(OAc)3
(1.5 g, 7.1 mmol, 2.2 equiv) and AcOH (0.19 mL, 3.3 mmol, 1 equiv).
After stirring at rt for 12 h, the reaction mixture was hydrolyzed by
addition of an aqueous 1 M NaOH solution. The aqueous layer was
extracted with CH2Cl2 and the combined organic phases were
washed with an aqueous 1 M NaOH solution, dried over MgSO4,
and filtered. The solvent was removed in vacuo and the residue was
128.0 (d), 126.3 (d), 126.2 (d), 125.7 (d), 125.4 (d), 123.6 (d), 65.7 (t),
54.4 (d), 49.0 (t), 17.3 (q); HRMS calcd for C14H18NO (MHþ):
216.13829; found: 216.13817.
5.3. Rearrangement: compounds 3, 4, 6, 14–18
5.3.1. Typical procedure
purified by flash column chromatography on silica gel (EtOAcþ0.5%
To a solution of b-aminoalcohol of type E in THF (0.5 M) was
25
Et3N) to give 11 (416 mg, 1.7 mmol, 51%). [
a
]
ꢁ5.8 (c 1.0, CHCl3); IR
added dropwise trifluoroacetic anhydride (1 equiv) and then Et3N
(1 equiv). The reaction mixture was then heated under microwave
irradiation in a sealed tube. After addition of an aqueous 2.5 M
NaOH solution (2 mL), the mixture was stirred at rt for 2 h,
extracted with EtOAc, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
D
(neat) 3500–2500, 1602, 1495, 1455, 1377, 1150, 1031, 907, 743,
699 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.32–7.15 (m, 5H), 3.54 (dd,
J¼10.5, 4.0 Hz, 1H), 3.25 (dd, J¼10.5, 4.5 Hz, 1H), 2.94 (m, 1H), 2.75
(dd, J¼13.6, 7.0 Hz, 1H), 2.69 (dd, J¼13.6, 7.3 Hz, 1H), 2.50 (tt, J¼5.6,
5.6 Hz, 1H), 1.41–0.95 (m, 8H), 0.89 (t, J¼6.9 Hz, 3H), 0.80 (t,
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
138.8 (s), 129.2 (d, 2C),
matography on silica gel afforded b-amino alcohol of type D.
128.5 (d, 2C), 126.4 (d), 62.9 (t), 60.4 (d), 57.5 (d), 39.1 (t), 37.3 (t),
36.4 (t), 18.9 (t), 18.3 (t), 14.4 (q), 14.3 (q); MS-EI m/z (relative in-
5.3.2. (R)-1-Benzylaminopropan-2-ol (3)15
Following the typical procedure (120 ꢀC, 12 h, MW), the trans-
formation of 1 (100 mg, 0.6 mmol) afforded an oil that was purified
ꢂ
tensity): 231 (Mþ ꢁH2O,16),188 (81),140 (64),117 (60), 91 (100), 57
(24); HRMS calcd for C16H28NO (MHþ): 250.21654; found:
250.21641.
by flash column chromatography on silica gel (EtOAc/MeOH 90/
25
10þ0.5% Et3N) to give 3 (88 mg, 0.53 mmol, 88%). [
a]
ꢁ25.0 (c
D
5.2.5. (S)-2-(Octylamino)-3-phenylpropan-1-ol (12)
0.50, CHCl3); IR (neat) 2825,1673,1495,1453,1374,1201,1136,1028,
To a stirred suspension of (S)-2-amino-3-phenylpropan-1-ol
918, 841, 736, 697 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.32–7.15 (m,
(500 mg, 3.3 mmol) and octanal (516
m
L, 3.3 mmol, 1 equiv) in 1,2-
5H), 3.74 (d, J¼13.3 Hz, 1H), 3.73 (m, 1H), 3.69 (d, J¼13.3 Hz, 1H), 3.0
(br s, 2H), 2.60 (dd, J¼10.7, 4.0 Hz, 1H), 2.35 (dd, J¼10.7, 7.0 Hz, 1H),
dichloroethane (12 mL) were successively added NaBH(OAc)3
(1.05 g, 5 mmol, 1.5 equiv) and AcOH (0.20 mL, 3.3 mmol, 1 equiv).
After stirring at rt for 48 h, the reaction mixture was hydrolyzed by
addition of an aqueous 1 M NaOH solution. The aqueous layer was
extracted with CH2Cl2 and the combined organic phases were
washed with an aqueous 1 M NaOH solution, dried over MgSO4, and
filtered. The solvent was removed in vacuo and the residue was
1.07 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 139.7 (s), 128.5
(d, 2C), 128.3 (d, 2C), 127.2 (d), 65.5 (d), 56.2 (t), 53.5 (t), 20.7 (q).
5.3.3. (R)-1-Cyclohexylamino-3-phenylpropan-2-ol (4)
Rearrangement with a catalytic amount of H2SO4. To a solution of
(S)-2-cyclohexylamino-3-phenylpropan-1-ol
mmol, 1.0 equiv) in THF (1 mL) was added dropwise sulfuric acid
(3 L, 0.04 mmol, 0.05 equiv). The reaction mixture was then
2
(200 mg, 0.86
purified by flash column chromatography on silica gel (EtOAcþ0.5%
25
Et3N) to give 12 (505 mg,1.92 mmol, 58%). [
a]
ꢁ0.6 (c 1.15, CHCl3);
m
D
IR (neat) 3500–2500, 1496, 1453, 1351, 1120, 1037, 930, 834, 744,
heated at 180 ꢀC for 24 h under microwave irradiation in a sealed
tube. After addition of a saturated aqueous NaHCO3 solution, the
mixture was extracted with EtOAc, dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography on silica gel (EtOAcþ0.5% Et3N)
afforded 4 (84 mg, 0.36 mmol, 42%).
698 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.32–7.15 (m, 5H), 3.59 (dd,
J¼10.5, 4.0 Hz, 1H), 3.30 (dd, J¼10.5, 5.5 Hz, 1H), 2.87 (m, 1H), 2.78
(dd, J¼13.6, 6.8 Hz, 1H), 2.71 (dd, J¼13.6, 7.0 Hz, 1H), 2.58 (m, 2H),
1.45–1.35 (m, 2H), 1.33–1.18 (m, 10H), 0.88 (t, J¼6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 138.7 (s), 129.2 (d, 2C), 128.5 (d, 2CAr),

B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
6703
Rearrangement with a catalytic amount of TFA. To a solution of
(S)-2-cyclohexylamino-3-phenylpropan-1-ol 2 (200 mg, 0.86 mmol,
1.0 equiv) in THF (1 mL) was added dropwise trifluoroacetic acid
J¼13.3 Hz, 1H), 4.12 (d, J¼13.2 Hz, 1H), 3.87 (m, 1H), 2.81 (dd,
J¼12.0, 3.3 Hz, 1H), 2.76 (dd, J¼13.6, 7.3 Hz, 1H), 2.69 (dd, J¼13.8,
5.8 Hz, 1H), 2.60 (dd, J¼12.0, 8.8 Hz, 1H), 2.39 (br s, 2H); 13C NMR
(4
mL, 0.05 mmol, 0.06 equiv). The reaction mixture was then
(100 MHz, CDCl3): d 138.4 (s), 135.6 (s), 133.9 (s), 131.8 (s), 129.4 (d,
heated at 180 ꢀC for 24 h under microwave irradiation in a sealed
tube. After addition of an aqueous 2.5 M NaOH solution (1 mL), the
mixture was stirred at rt for 2 h, extracted with EtOAc, dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography on silica gel
(CH2Cl2/EtOAcþ0.5% Et3N) afforded 4 (114 mg, 0.49 mmol, 57%).
Rearrangement with a catalytic amount of TFAA. To a solution of
(S)-2-cyclohexylamino-3-phenylpropan-1-ol 2 (200 mg, 0.86 mmol,
1.0 equiv) in THF (1 mL) was added dropwise trifluoroacetic anhy-
2C), 128.8 (d), 128.5 (d, 2C), 128.0 (d), 126.4 (d), 126.2 (d, 2C), 125.8
(d), 125.4 (d), 123.7 (d), 70.8 (d), 54.7 (t), 51.5 (t), 41.6 (t); MS-EI m/z
ꢂ
(relative intensity): 291 (Mþ ,1), 285 (4), 273 (6),170 (21),141 (100),
132 (12), 115 (15), 91 (13); HRMS calcd for C20H22NO (MHþ):
292.16959; found: 292.16917.
5.3.7. (R)-1-(Heptan-4-ylamino)-3-phenylpropan-2-ol (16)
Following the typical procedure (110 ꢀC, 6 h, MW), the trans-
formation of 11 (81 mg, 0.33 mmol) afforded an oil that was purified
dride (7
m
L, 0.05 mmol, 0.06 equiv). The reaction mixture was then
by flash column chromatography on silica gel (petroleum ether/
25
heated at 180 ꢀC for 30 h under microwave irradiation in a sealed
tube. After addition of an aqueous 2.5 M NaOH solution (1 mL), the
mixture was stirred at room temperature for 2 h, extracted with
EtOAc, dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatog-
raphy on silica gel (CH2Cl2/EtOAcþ0.5% Et3N) afforded 4 (107 mg,
0.46 mmol, 54%).
EtOAc 50/50þ0.5% Et3N) to give 16 (74 mg, 0.30 mmol, 91%). [
a]
D
ꢁ23.7 (c 1.15, CHCl3); IR (neat) 3500–2500, 1602, 1495, 1454, 1377,
1153, 1084, 1030, 904, 745, 698 cmꢁ1 1H NMR (400 MHz, CDCl3):
7.32–7.18 (m, 5H), 3.77 (m, 1H), 2.82–2.66 (m, 3H), 2.48–2.37 (m,
2H), 2.35 (br s, 2H), 1.37–1.23 (m, 8H), 0.97–0.84 (m, 6H); 13C NMR
(100 MHz, CDCl3): 138.6 (s), 129.3 (d, 2C), 128.4 (d, 2C), 126.3 (d),
;
d
d
70.9 (d), 57.0 (d), 51.8 (t), 41.7 (t), 36.8 (t), 36.6 (t), 19.0 (t), 18.9 (t),
ꢂ
Rearrangement with a stoichiometric amount of TFAA and Et3N.
Following the typical procedure (110 ꢀC, 6 h, MW), the trans-
formation of 2 (91 mg, 0.39 mmol) afforded an oil that was purified
by flash column chromatography on silica gel (EtOAcþ0.5% Et3N) to
14.3 (q, 2C); MS-EI m/z (relative intensity): 231 (Mþ ꢁH2O, 3), 206
(88), 188 (81), 140 (14), 128 (41), 117 (37), 91 (100), 84 (35), 57 (28);
HRMS calcd for C16H28NO (MHþ): 250.21654; found: 250.21635.
give 4 (77 mg, 0.33 mmol, 85%).
5.3.8. (R)-1-(Octylamino)-3-phenylpropan-2-ol (17)
Following the typical procedure (120 ꢀC, 12 h, MW), the trans-
formation of 12 (81 mg, 0.31 mmol) afforded an oil that was puri-
25
[
a]
ꢁ20.2 (c 1.17, CHCl3); IR (neat) 3290, 2922, 2850, 2347,
D
1602, 1451, 1338, 1081, 961, 739, 696 cmꢁ1
CDCl3):
;
1H NMR (400 MHz,
7.31–7.15 (m, 5H), 3.80 (dddd, J¼9.0, 7.3, 5.7, 3.2 Hz, 1H),
d
fied by flash column chromatography on silica gel (EtOAcþ0.5%
25
2.82–2.68 (m, 3H), 2.47 (dd, J¼12.0, 9.1 Hz, 1H), 2.36 (tt, J¼10.4,
Et3N) to give 17 (69 mg, 0.26 mmol, 78%). [
a
]
ꢁ8.9 (c 1.5, CHCl3);
D
3.8 Hz, 1H), 2.16 (br s, 2H), 1.88–1.56 (m, 5H), 1.36–0.83 (m, 5H); 13C
IR (neat) 3500–2500, 1494, 1454, 1377, 1082, 1031, 911, 745,
NMR (100 MHz, CDCl3):
d
138.5 (s), 129.4 (d, 2C), 128.4 (d, 2C), 126.3
698 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.32–7.15 (m, 5H), 3.85 (m,
(d), 70.9 (d), 56.6,(d), 51.8 (t), 41.8 (t), 34.0 (t), 33.6 (t), 26.1 (t), 25.0
1H), 2.78 (dd, J¼13.6, 7.3 Hz, 1H), 2.73–2.67 (m, 2H), 2.62–2.46 (m,
ꢂ
(t), 25.0 (t); MS-EI m/z (relative intensity): 233 (Mþ , 4), 190 (4), 117
3H), 2.40 (br s, 2H), 1.50–1.38 (m, 2H), 1.36–1.20 (m, 10H), 0.88 (t,
(4), 112 (100), 91 (17), 55 (8); HRMS calcd for C15H24NO (MHþ):
234.18524; found: 234.18509.
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 138.5 (s), 129.4 (d, 2C),
128.5 (d, 2C), 126.3 (d), 70.5 (d), 54.8 (t), 49.7 (t), 41.8 (t), 31.8 (t),
30.1 (t), 29.7 (t), 29.5 (t), 27.3 (t), 22.7 (t), 14.1 (q); MS-EI m/z (rel-
ꢂ
5.3.4. (S)-2-N-Benzylamino-1-phenylethanol (6)16
ative intensity): 231 (Mþ ꢁH2O, 3), 218 (37), 206 (37), 188 (21), 158
Following the typical procedure (110 ꢀC, 6 h, MW), the trans-
formation of 5 (54 mg, 0.24 mmol) afforded an oil that was purified
by flash column chromatography on silica gel (EtOAcþ0.5% Et3N) to
give 6 (39 mg, 0.17 mmol, 72%).
(100), 140 (19), 120 (44), 105 (12), 91 (70), 72 (16), 60 (50); HRMS
calcd for C17H30NO (MHþ): 264.23219; found: 264.23203.
5.3.9. (R)-1-(Naphthalen-1-ylmethylamino)propan-2-ol (18)
Following the typical procedure (120 ꢀC, 8 h, MW), the trans-
formation of 13 (115 mg, 0.53 mmol) afforded an oil that was pu-
5.3.5. (R)-1-Benzylamino-3-phenylpropan-2-ol (14)17
Following the typical procedure (120 ꢀC, 12 h, MW), the trans-
formation of 9 (104 mg, 0.43 mmol) afforded an oil that was purified
rified by flash column chromatography on silica gel (EtOAcþ0.5%
25
Et3N) to give 18 (85 mg, 0.40 mmol, 74%). [
a
]
D
ꢁ19.0 (c 1.45,
by flash column chromatography on silica gel (EtOAcþ0.5% Et3N) to
CHCl3); IR (neat) 3500–2600, 1655, 1597, 1509, 1450, 1373, 1325,
25
give 14 (72 mg, 0.30 mmol, 70%). [
a
]
ꢁ20.2 (c 1.0, CHCl3); IR (neat)
1074, 968, 791, 774, 734 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
8.08
D
3026, 2845,1723, 1656, 1602, 1494, 1453, 1274, 1029, 740, 697 cmꢁ1
;
(m, 1H), 7.84 (m, 1H), 7.75 (dd, J¼7.3, 2.2 Hz, 1H), 7.53–7.37 (m, 4H),
4.24 (d, J¼13.3 Hz, 1H), 4.17 (d, J¼13.3 Hz, 1H), 3.78 (m, 1H), 2.78
(dd, J¼12.0, 3.3 Hz, 1H), 2.50 (dd, J¼12.0, 9.3 Hz, 1H), 2.38 (br s, 2H),
1H NMR (400 MHz, CDCl3):
d
7.35–7.12 (m, 10H), 3.87 (m, 1H), 3.78
(d, J¼13.2 Hz, 1H), 3.71 (d, J¼13.2 Hz, 1H), 2.82–2.67 (m, 3H), 2.53
(dd, J¼12.1, 9.0 Hz, 1H), 2.38 (br s, 2H); 13C NMR (100 MHz, CDCl3):
1.13 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 135.7 (s), 134.0
d
140.1 (s),138.3 (s),129.3 (d, 2C),128.6 (d, 2C),128.5 (d, 2C),128.2 (d,
(s), 131.8 (s), 128.8 (d), 128.0 (d), 126.2 (d), 126.1 (d), 125.7 (d), 125.4
(d), 123.6 (d), 65.8 (d), 56.9 (t), 51.4 (t), 20.5 (q); HRMS calcd for
C14H18NO (MHþ): 216.13829; found: 216.13817.
2C), 127.1 (d), 126.4 (d), 70.7 (d), 54.2 (t), 53.7 (t), 41.6 (t); MS-EI m/z
ꢂ
(relative intensity): 223 (Mþ ꢁH2O, 6), 120 (82), 91 (100), 65 (8).
5.3.6. (S)-2-(Naphthalen-1-ylmethylamino)-3-phenyl-
propan-1-ol (15)
5.4. Benzylation: compounds 19–24
Following the typical procedure (120 ꢀC, 12 h, MW), the trans-
formation of 10 (100 mg, 0.52 mmol) afforded an oil that was pu-
Method A. A mixture of N-benzyl or N-alkyl b-amino alcohol,
benzyl bromide (1.1 equiv), K2CO3 (1.5 equiv), n-Bu4NI (0.3 equiv)
in acetonitrile (5 mL), was stirred at reflux for 4 h. The reaction
media was concentrated under reduced pressure and the residue
was dissolved in water (10 mL) and ethyl acetate (10 mL). The
aqueous phase was extracted three times with ethyl acetate and the
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the crude residue by flash
rified by flash column chromatography on silica gel (CH2Cl2/EtOAc
25
50/50þ0.5% Et3N) to give 15 (79 mg, 0.27 mmol, 80%). [
a]
ꢁ25.2 (c
D
1.0, CHCl3); IR (neat) 3500–2500, 2336, 2116, 1597, 1510, 1494, 1453,
1340, 1124, 1099, 1046, 890, 849, 792, 774, 745, 692 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
1H), 7.53–7.42 (m, 2H), 7.41–7.35 (m, 2H), 7.30–7.16 (m, 5H), 4.20 (d,
d
8.06 (d, J¼8.3 Hz, 1H), 7.83 (m, 1H), 7.75 (m,

6704
B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
chromatography on silica gel afforded N,N-dibenzyl or N,N-benzyl-
alkyl -amino alcohol.
Method B. A mixture of N-naphthyl
59.3 (d), 55.9 (t), 55.0 (t), 41.3 (t), 31.4 (t), 26.6 (t), 26.3 (t), 26.2 (t),
ꢂ
b
26.0 (t); MS-EI m/z (relative intensity): 323 (Mþ , 1), 278 (5), 202
b-amino alcohol, ammonium
(100), 146 (5), 120 (17), 91 (84), 65 (6), 55 (6); HRMS calcd for
formate (10 equiv), and 10% Pd/C (25 mg) in MeOH (5 mL) was stir-
red at reflux for 4 h. The reaction media is filtered on Celite and
concentrated under reduced pressure. The residue was mixed with
benzyl bromide (2.2 equiv), K2CO3 (3 equiv), n-Bu4NI (0.3 equiv) in
acetonitrile (5 mL) and was stirred at reflux for 4 h. The reaction
media was concentrated under reduced pressure and the residue
was dissolved in water (10 mL) and ethyl acetate (10 mL). Aqueous
phase was extracted three times with ethyl acetate and the com-
bined organic extracts were dried over MgSO4, filtered, and con-
centrated in vacuo. Purification of the crude residue by flash
C22H30NO (MHþ): 324.23219; found: 324.23220.
5.4.5. (R)-1-[Benzyl(heptan-4-yl)amino]-3-phenylpropan-2-ol (23)
Method A was used to prepare 23 from 16. The transformation of
16 (55 mg, 0.22 mmol) led to an oil that was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc 97.5/2.5) to
25
give 23 (67 mg, 0.20 mmol, 90%). [
a
]
ꢁ74.0 (c 1.05, CHCl3); ee¼96%
D
determined by supercritical fluid chromatography on Daicel
chiralpack OD-H column (MeOH 5%, flow rate 5 mL/min, tR
(major)¼2.5 min, tR (minor)¼2.9 min); IR (neat) 3500–2500, 1602,
1495, 1454, 1376, 1258, 1147, 1072, 1028, 951, 908, 737, 697 cmꢁ1; 1H
chromatography on silica gel afforded N,N-dibenzyl b-amino alcohol.
NMR (400 MHz, CDCl3):
d 7.32–7.15 (m, 10H), 3.76 (m, 1H), 3.67 (d,
5.4.1. (S)-2-N,N-Dibenzylamino-1-phenylethanol (19)11
J¼13.3 Hz,1H), 3.47 (br s,1H), 3.44 (d, J¼13.3 Hz,1H), 2.72 (dd, J¼13.8,
7.3 Hz,1H), 2.61 (dd, J¼13.6, 5.3 Hz, 1H), 2.49 (dd, J¼12.8, 3.3 Hz,1H),
2.45 (tt, J¼4.5, 4.5 Hz,1H), 2.38 (dd, J¼13.1,10.0 Hz,1H),1.59–1.48 (m,
1H),1.47–1.07 (m, 7H), 0.87 (t, J¼7.3 Hz, 3H), 0.78 (t, J¼7.2 Hz, 3H); 13C
Method A was used to prepare 19 from 6. The transformation of
6 (29 mg, 0.13 mmol) led to an oil that was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc 95/5) to give
19 (35 mg, 0.11 mmol, 88%); ee¼94% determined by supercritical
fluid chromatography on Daicel chiralpack OD-H column (MeOH
20%, flow rate 8 mL/min, tR (major)¼1.4 min, tR (minor)¼1.9 min).
NMR (100 MHz, CDCl3):
d 139.9 (s), 138.8 (s), 129.2 (d, 2C), 129.1 (d,
2C), 128.4 (d, 2C), 128.3 (d, 2C), 127.1 (d), 126.1 (d), 68.3 (d), 59.2 (d),
55.7 (t), 54.6 (t), 41.3 (t), 33.7 (t), 31.4 (t), 20.7 (t), 20.3 (t),14.3 (q),14.1
ꢂ
(q); MS-EI m/z (relative intensity): 339 (Mþ , 0.1), 321 (1), 296 (25),
5.4.2. (R)-1-N,N-Dibenzylaminopropan-2-ol (20)11
278 (7), 218 (74), 162 (10), 120 (17), 117 (13), 91 (100), 65 (7); HRMS
Method A was used to prepare 20 from 3. The transformation of
3 (29 mg, 0.13 mmol) led to an oil that was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc 95/5) to give
20 (35 mg, 0.11 mmol, 85%).
Method B was used to prepare 20 from 18. The transformation of
18 (49 mg, 0.23 mmol) led to an oil that was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc 90/
10) to give 20 (30 mg, 0.12 mmol, 51%).
ee¼93% determined by supercritical fluid chromatography on
Daicel chiralpack OD-H column (MeOH 5%, flow rate 5 mL/min, tR
(major)¼1.5 min, tR (minor)¼1.7 min).
calcd for C23H34NO (MHþ): 340.26349; found: 340.26333.
5.4.6. (R)-1-(Benzyloctylamino)-3-phenylpropan-2-ol (24)
Method A was used to prepare 24 from 17. The transformation of
17 (38 mg, 0.14 mmol) led to an oil that was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc 95/5) to give
24 (43 mg, 0.12 mmol, 85%). [
25
a]
ꢁ51.1 (c 1.0, CHCl3); ee¼93% de-
D
termined bysupercritical fluid chromatographyon Daicel chiralpack
OD-H column (MeOH 5%, flow rate 3 mL/min, tR (major)¼7.3 min, tR
(minor)¼8.2 min);IR (neat) 3500–2500,1671,1601,1495,1453,1374,
1075, 1028, 968, 910, 738, 697 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
7.33–7.17 (m, 10H), 3.86 (m, 1H), 3.77 (d, J¼13.3 Hz, 1H), 3.39 (d,
5.4.3. (R)-1-N,N-Dibenzylamino-3-phenylpropan-2-ol (21)11
Method A was used to prepare 21 from 14. The transformation of
14 (44 mg, 0.27 mmol) led to an oil that was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc 90/
10) to give 21 (56 mg, 0.22 mmol, 82%).
J¼13.6 Hz, 1H), 2.78 (dd, J¼13.6, 7.3 Hz, 1H), 2.62 (dd, J¼13.8, 5.5 Hz,
1H), 2.52 (m,1H), 2.43 (m, 2H), 2.34 (m,1H),1.63–1.42 (m, 2H),1.39–
1.13 (m, 12H), 0.87 (t, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
138.8 (s),138.6 (s),129.3 (d, 2C),129.0 (d, 2C),128.4 (d, 2C),128.3 (d,
2C),127.2 (d),126.2 (d), 68.1 (d), 59.9 (t), 58.8 (t), 54.1 (t), 41.4 (t), 31.9
Method B was used to prepare 21 from 15. The transformation of
15 (48 mg, 0.22 mmol) led to an oil that was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc 90/
10) to give 21 (29 mg, 0.11 mmol, 52%).
(t), 29.5 (t), 29.3 (t), 27.3 (t), 27.0 (t), 22.7 (t), 14.1 (q); MS-EI m/z
ꢂ
(relative intensity): 353 (Mþ , 1), 252 (9), 232 (100), 134 (7), 120 (8),
117 (11), 91 (92), 65 (5); HRMS calcd for C24H36NO (MHþ):
354.27914; found: 354.27917.
ee¼98% (21 from 14) and 96% (21 from 15) determined by su-
percritical fluid chromatography on Daicel chiralpack OD-H column
(MeOH 10%, flow rate 8 mL/min, tR (major)¼2.1 min, tR
(minor)¼2.6 min).
5.5. Synthesis of (S)-toliprolol and (S)-propanolol
5.5.1. (S)-Benzyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-
3-carboxylate (25)12,18
5.4.4. (R)-1-(Benzylcyclohexylamino)-3-phenylpropan-2-ol (22)
Method A was used to prepare 22 from 4. The transformation of
4 (42 mg, 0.18 mmol) led to an oil that was purified by flash column
To a solution of D-serine methyl ester hydrochloride (2 g,
12.9 mmol) and K2CO3 (5.33 g, 38.6 mmol, 3 equiv) in H2O (10 mL)
was added at 0 ꢀC a solution of benzyl chloroformate (2.02 mL,
14.15 mmol, 1.1 equiv) in THF (10 mL). The two phases were stirred
vigorously and warmed to rt. After 4 h, hexane (20 mL) was added.
The aqueous layer was extracted with Et2O (2ꢃ10 mL). The com-
bined organic layers were washed with 5% citric acid (20 mL) and
an aqueous saturated NaCl solution (20 mL), dried with MgSO4, and
evaporated. The crude oil was dissolved in 2,2-dimethoxypropane
(35 mL, 285 mmol, 22 equiv) and TsOH$H2O (350 mg, 1.8 mmol,
0.14 equiv) was added. The reaction mixture was refluxed for 4 h
and then concentrated under reduced pressure. The residue was
dissolved in EtOAc (100 mL) and washed with aqueous NaHCO3
(2ꢃ50 mL). The organic layer was dried over MgSO4 and evaporated
in vacuo and the residue purified by flash chromatography (silica
gel, petroleum ether/EtOAc 90/10) to afford (S)-3-benzyl-4-methyl-
chromatography on silica gel (cyclohexane/EtOAc 95/5) to give 22
25
(55 mg, 0.17 mmol, 94%). [
a
]
D
ꢁ64.5 (c 1.57, CHCl3); ee¼94% de-
termined by supercritical fluid chromatography on Daicel
chiralpack OD-H column (MeOH 3%, flow rate 5 mL/min, tR
(major)¼7.3 min, tR (minor)¼8.4 min); IR (neat) 3500–2500, 1601,
1493, 1449, 1349, 1093, 1076, 889, 748, 697 cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d 7.24–7.08 (m, 10H), 3.63 (m, 1H), 3.60 (d,
J¼13.8, 1H), 3.49 (d, J¼13.8, 1H), 3.38 (br s, 1H), 2.67 (dd, J¼13.6,
7.3 Hz, 1H), 2.53 (dd, J¼13.8, 5.5 Hz, 1H), 2.46 (dd, J¼12.8, 3.5 Hz,
1H), 2.40 (m, 1H), 2.35 (dd, J¼12.8, 10.0 Hz, 1H), 1.85 (m, 1H), 1.75–
1.45 (m, 4H), 1.28 (dddd, J¼12.0, 12.0, 12.0, 3.5 Hz, 1H), 1.15–0.90 (m,
4H); 13C NMR (100 MHz, CDCl3):
d 140.1 (s), 138.8 (s), 129.2 (d, 2C),
128.6 (d, 2C),128.5 (d, 2C),128.3 (d, 2C),127.0 (d), 126.2 (d), 68.1 (d),

B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
6705
2,2-dimethyloxazolidine-3,4-dicarboxylate18 (3.13 g, 10.7 mmol,
83%). This latter was dissolved in THF (40 mL) and solid NaBH4
(1.6 g, 42.3 mmol, 4 equiv) was added at ꢁ10 ꢀC and the mixture
was stirred at the same temperature for 30 min. MeOH (17 mL) was
then added dropwise and the mixture was stirred at rt for 16 h. H2O
(5 mL) was added and the mixture stirred for 30 min. The organic
solvent was evaporated under reduced pressure and brine (50 mL)
was added. The mixture was extracted with EtOAc (3ꢃ100 mL) and
the combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
3.73 (dd, J¼10.7, 4.6 Hz, 1H), 3.55 (dd, J¼10.7, 5.7 Hz, 1H), 3.14
(dddd, J¼5.2, 5.2, 5.2, 5.2 Hz, 1H), 3.00 (qq, J¼6.2, 6.2 Hz, 1H), 2.35
(s, 3H), 2.20 (br s, 2H), 1.12 (d, J¼6.2 Hz, 3H), 1.11 (d, J¼6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3):
d 158.7 (s), 139.6 (s), 129.3 (d), 121.9 (d),
115.4 (d), 111.4 (d), 67.8 (t), 61.8 (t), 55.3 (d), 46.1 (d), 23.6 (q), 23.5
ꢂ
(q), 21.5 (q); MS-EI m/z (relative intensity): 192 (Mþ ꢁCH2OHꢂ, 40),
133 (22), 102 (100), 70 (12), 60 (31); HRMS calcd for C13H22NO2
(MHþ): 224.16451; found: 224.16431.
5.5.4. (S)-Benzyl-2,2-dimethyl-4-[(naphthalen-1-
yloxy)methyl]oxazolidine-3-carboxylate (28)
tography on silica gel (petroleum ether/EtOAc 60/40) to give 2512
25
(2.01 g, 7.6 mmol, 59%). [
a]
þ20.2 (c 1.0, CHCl3); IR (neat) 3428,
To a solution of 25 (418 mg, 1.6 mmol), a-naphthol (341 mg,
D
2879, 1679, 1406, 1349, 1257, 1208, 1152, 1069, 839, 737, 697 cmꢁ1
;
2.4 mmol, 1.5 equiv) and triphenylphosphine (621 mg, 2.4 mmol,
1.5 equiv) in toluene (4 mL) was added DEAD (40 wt % solution in
toluene; 1.1 mL, 2.4 mmol, 1.5 equiv). The reaction mixture was
stirred for 18 h at 80 ꢀC in a sealed tube. The solvent was evaporated
and the residue was dissolved in EtOAc (20 mL), washed with an
aqueous 2.5 M NaOH solution (10 mL), dried with MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
1H NMR (400 MHz, toluene-d8, 100 ꢀC):
d
7.22–7.00 (m, 5H), 5.06 (d,
J¼12.3 Hz, 1H), 5.01 (d, J¼12.3 Hz, 1H), 3.84 (m, 1H), 3.68 (m, 2H),
3.60 (dd, J¼10.6, 4.8 Hz, 1H), 3.43 (dd, J¼10.8, 6.6 Hz, 1H), 2.25 (br s,
1H), 1.55 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) mixture of
two rotamers: (major rotamer)
128.3 (d), 128.1 (d), 94.4 (s), 67.7 (t), 65.3 (t), 64.2 (t), 59.8 (d), 27.1
(q), 24.7 (q); (minor rotamer)
d 154.4 (s), 135.9 (s), 128.6 (d, 3C),
d
¼152.3 (s), 136.4 (s), 128.6 (d, 3C),
by flash chromatography on silica gel (petroleum ether/EtOAc 92/8)
25
128.1 (d), 128.0 (d), 94.4 (s), 66.8 (t), 65.5 (t), 62.6 (t), 58.2 (d), 26.5
to give 28 (413 mg, 1.06 mmol, 67%). [
a
]
D
þ44.7 (c 0.9, CHCl3); IR
(q), 23.0 (q); MS-EI m/z (relative intensity): 234 (Mþ ꢁCH2OHꢂ, 7),
(neat) 2877, 1700, 1580, 1402, 1348, 1237, 1209, 1157, 1067, 837, 768,
ꢂ
206 (4), 190 (5), 91 (100), 65 (6).
697 cmꢁ1; 1H NMR (400 MHz, CDCl3) mixture of two rotamers (65/
35): (major rotamer)
d
8.20 (d, J¼7.8 Hz, 1H), 7.78 (d, J¼8.3 Hz, 1H),
5.5.2. (S)-Benzyl 2,2-dimethyl-4-(m-tolyloxymethyl)oxazolidine-
3-carboxylate (26)
7.50–7.33 (m, 8H), 7.16 (dd, J¼7.9, 7.9 Hz, 1H), 6.70 (d, J¼7.5 Hz, 1H),
5.19 (m, 2H), 4.41 (m, 1H), 4.28 (m, 2H), 4.11 (m, 2H), 1.71 (s, 3H),
To a solution of 25 (512 mg, 1.9 mmol), m-cresol (205
m
L,
1.59 (s, 3H); (minor rotamer)
d
8.26 (d, J¼8.0 Hz, 1H), 7.78 (d,
2.0 mmol, 1.1 equiv), and triphenylphosphine (560 mg, 2.13 mmol,
1.1 equiv) in toluene (4 mL) was added DEAD (40 wt % solution in
toluene; 1 mL, 2.18 mmol, 1.1 equiv). The reaction mixture was
stirred for 18 h at 80 ꢀC in a sealed tube. The solvent was evaporated
and the residue was dissolved in EtOAc (20 mL), washed with an
aqueous 2.5 M NaOH solution (10 mL), dried with MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
J¼8.3 Hz, 1H), 7.50–7.33 (m, 9H), 6.96 (d, J¼7.5 Hz, 1H), 5.19 (m, 2H),
4.52 (m, 1H), 4.28 (m, 2H), 4.11 (m, 2H), 1.63 (s, 3H), 1.52 (s, 3H); 13C
NMR (100 MHz, CDCl3): (major rotamer) d 153.8 (s), 152.3 (s), 136.2
(s), 134.5 (s), 128.7 (d, 2C), 128.3 (d, 3C), 127.5 (d), 126.5 (d), 125.8
(d),125.5 (s),125.3 (d),121.8 (d),120.7 (d),104.9 (d), 94.6 (s), 67.1 (t),
66.7 (t), 65.8 (t), 55.6 (d), 26.7 (q), 23.1 (q); (minor rotamer) d 154.1
(s), 153.2 (s), 136.1 (s), 134.5 (s), 128.7 (d, 2C), 128.1 (d, 3C), 127.5 (d),
126.4 (d), 126.0 (d), 125.5 (s),125.2 (d), 122.0 (d), 120.6 (d), 105.0 (d),
94.1 (s), 67.5 (t), 66.2 (t), 65.4 (t), 56.6 (d), 27.6 (q), 24.5 (q); MS-EI
by flash chromatography on silica gel (petroleum ether/EtOAc 90/
25
10) to give 26 (475 mg, 1.34 mmol, 69%). [
a
]
D
þ53.6 (c 1.0, CHCl3);
ꢂ
IR (neat) 2877, 1701, 1585, 1490, 1456, 1403, 1348, 1257, 1209, 1156,
1070, 839, 766, 691 cmꢁ1 1H NMR (400 MHz, CDCl3) mixture of
two rotamers (65/35): (major rotamer) 7.37–7.32 (m, 5H), 7.05
m/z (relative intensity): 391 (Mþ , 6), 248 (13), 190 (12), 127 (6), 115
;
(6), 91 (100), 65 (3); HRMS calcd for C24H25NO4Na (MNaþ):
414.16758; found: 414.16829.
d
(dd, J¼7.8, 7.8 Hz, 1H), 6.77–6.61 (m, 3H), 5.22–5.16 (m, 2H), 4.25
(m, 1H), 4.15–3.98 (m, 3H), 3.81 (dd, J¼9.4, 9.4 Hz 1H), 2.28 (s, 3H),
5.5.5. (R)-2-(Isopropylamino)-3-(naphthalen-1-yloxy)-
propan-1-ol (29)
1.66 (s, 3H), 1.56 (s, 3H); (minor rotamer)
d 7.37–7.32 (m, 5H), 7.15
(dd, J¼8.0, 8.0 Hz, 1H), 6.77–6.61 (m, 3H), 5.22–5.16 (m, 2H), 4.35
(m, 1H), 4.25 (m, 1H), 4.15–3.98 (m, 2H), 3.88 (dd, J¼9.3, 9.3 Hz 1H),
2.32 (s, 3H), 1.58 (s, 3H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3):
A solution of 28 (220 mg, 0.56 mmol) in EtOH (55 mL) was hy-
drogenated in a flow manner using the H-Cube (Thales Nanotech-
nology Inc.) operating at 10–15 bars of in situ H2 pressure at rt with
a flow rate of 1 mL/min. The catalyst bed (Cat-CartÔ) Pd/C 10% used
was available from Thales. The solvent was evaporated and the
(major rotamer)
d 158.3 (s), 152.2 (s), 139.6 (s), 136.4 (s), 129.2 (d),
128.6 (d, 2C), 128.2 (d), 128.1 (d, 2C), 121.9 (d), 115.5 (d), 111.2 (d),
94.5 (s), 66.9 (t), 66.4 (t), 65.7 (t), 55.7 (d), 26.7 (q), 23.1 (q), 21.5 (q);
residue was purified by flash chromatography on silica gel (EtOAc/
25
(minor rotamer)
d
158.5 (s), 153.1 (s), 139.6 (s), 136.1 (s), 129.2 (d),
MeOH 90/10þ0.5% Et3N) to give 29 (109 mg, 0.42 mmol, 75%). [
a]
D
128.6 (d, 2C), 128.2 (d), 128.1 (d, 2C), 121.8 (d), 115.5 (d), 111.4 (d),
94.0 (s), 67.4 (t), 65.7 (t), 65.4 (t), 56.6 (d), 27.5 (q), 24.5 (q), 21.5 (q);
þ25.1 (c 1.5, CHCl3); IR (neat) 3200–2500, 2327, 1578, 1506, 1455,
1403, 1272, 1241, 1099, 1046, 995, 870, 765 cmꢁ1 1H NMR
(400 MHz, CDCl3): 8.23 (m, 1H), 7.84 (m, 1H), 7.55–7.46 (m, 3H),
;
ꢂ
MS-EI m/z (relative intensity): 355 (Mþ , 3), 340 (6), 248 (14), 190
d
(10), 91 (100), 65 (5); HRMS calcd for C21H25NO4Na (MNaþ):
378.16758; found: 378.16751.
7.40 (dd, J¼7.9, 7.9 Hz, 1H), 6.85 (dd, J¼7.5, 0.8 Hz, 1H), 4.22 (dd,
J¼9.5, 5.0 Hz, 1H), 4.14 (dd, J¼9.3, 5.5 Hz, 1H), 3.83 (dd, J¼10.8,
4.5 Hz, 1H), 3.68 (dd, J¼10.8, 5.8 Hz, 1H), 3.32 (dd, J¼5.3, 5.3, 5.3,
5.3 Hz, 1H), 3.08 (qq, J¼6.2, 6.2 Hz, 1H), 2.43 (br s, 2H), 1.18 (d,
J¼6.5 Hz, 3H), 1.16 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
5.5.3. (R)-2-(Isopropylamino)-3-(m-tolyloxy)propan-1-ol (27)
To a solution of 26 (200 mg, 0.56 mmol) in MeOH (10 mL) was
added Pd/C 10% (25 mg) and the mixture was vigorously stirred
under an atmosphere of H2 for 14 h. The suspension was filtered
through Celite and the filtrate was concentrated in vacuo. Purifi-
d
154.3 (s), 134.5 (s), 127.6 (d), 126.5 (d), 125.9 (d), 125.5 (s), 125.4
(d), 121.6 (d), 120.7 (d), 104.7 (d), 68.0 (t), 61.8 (t), 55.5 (d), 46.3 (d),
ꢂ
23.7 (q), 23.5 (q); MS-EI m/z (relative intensity): 244 (Mþ ꢁCH3ꢂ ,
cation of the residue by flash chromatography on silica gel (EtOAc/
100), 165 (83), 152 (19), 115 (17), 56 (10); HRMS calcd for C16H22NO2
(MHþ): 260.16451; found: 260.16489.
25
MeOH 90/10þ0.5% Et3N) gave 27 (96 mg, 0.43 mmol, 77%). [
a]
D
þ30.6 (c 1.0, CHCl3); IR (neat) 2962, 2870, 1601, 1585, 1489, 1462,
1381, 1289, 1257, 1157, 1044, 769, 689 cmꢁ1 1H NMR (400 MHz,
CDCl3):
7.19 (dd, J¼7.8, 7.8 Hz, 1H), 6.83–6.77 (m, 1H), 6.76–6.71
(m, 2H), 4.03 (dd, J¼9.5, 5.3 Hz, 1H), 3.95 (dd, J¼9.4, 5.4 Hz, 1H),
;
5.5.6. (S)-Toliprolol5,6
To a solution of 27 (27 mg, 0.12 mmol) in THF (1 mL) was added
dropwise trifluoroacetic anhydride (17 mL, 0.12 mmol, 1 equiv) and
d

6706
B. Duthion et al. / Tetrahedron 65 (2009) 6696–6706
then Et3N (17
m
L, 0.12 mmol, 1 equiv). The reaction mixture was
J¼7.9, 7.9 Hz, 1H), 6.75 (d, J¼7.5 Hz, 1H), 4.13–4.03 (m, 3H), 2.92 (dd,
J¼12.0, 3.3 Hz, 1H), 2.83–2.73 (m, 2H), 2.35 (br s, 2H), 1.03 (d,
then heated at 110 ꢀC for 12 h under microwave irradiation in
a sealed tube. After addition of an aqueous 2.5 M NaOH solution
(2 mL), the mixture was stirred at rt for 2 h, extracted with EtOAc,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
gel (EtOAc/MeOH 90/10þ0.5% Et3N) afforded (S)-toliprolol (19 mg,
J¼6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 154.3 (s), 134.5 (s),
127.6 (d), 126.5 (d), 125.9 (d), 125.6 (s), 125.3 (d), 121.9 (d), 120.7 (d),
104.9 (d), 70.7 (t), 68.5 (d), 49.5 (t), 49.0 (d), 23.2 (q), 23.1 (q); MS-EI
ꢂ
m/z (relative intensity): 259 (Mþ , 5), 215 (5), 144 (17), 127 (9), 115
(28), 72 (100), 56 (10); HRMS calcd for C16H22NO2 (MHþ):
260.16451; found: 260.16479.
25
25
0.08 mmol, 69%). [
a]
ꢁ7.6 (c 0.9, EtOH) (lit6
[a
]
ꢁ9.9 (c 0.83,
D
D
EtOH)); mp 52–54 ꢀC; ee¼92% determined by supercritical fluid
chromatography on Daicel chiralpack OD-H column (MeOH/Et3N
99.5/0.5 15%, flow rate 5 mL/min, tR (major)¼4.8 min, tR (minor)
¼1.4 min); IR (neat) 3500–2500, 1611, 1584, 1487, 1457, 1377, 1293,
Acknowledgements
1256, 1051, 949, 867, 765, 687 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
Sanofi-Aventis is greatly acknowledged for financial support and
for a Grant to one of us (B.D.).
d
7.16 (dd, J¼7.8, 7.8 Hz, 1H), 6.79–6.76 (m, 1H), 6.75–6.70 (m, 2H),
4.05–3.92 (m, 3H), 2.88 (dd, J¼12.0, 3.8 Hz, 1H), 2.82 (h, J¼6.3 Hz,
1H), 2.72 (dd, J¼12.0, 7.0 Hz,1H), 2.52 (br s, 2H), 2.32 (s, 3H), 1.09 (d,
J¼6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 158.7 (s), 139.6 (s),
References and notes
129.2 (d), 121.9 (d),115.4 (d),111.4 (d), 70.4 (t), 68.4 (d), 49.4 (t), 49.0
1. Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2576 and references therein.
2. Cohen, M. L.; Bloomquist, W.; Kriauciunas, A.; Shuker, A.; Calligaro, D. Br. J.
Pharmacol. 1999, 126, 1018–1024.
3. Dow, R. L. Expert Opin. Investig. Drugs 1997, 6, 1811–1826.
4. Leftheris, K.; Goodman, M. J. Med. Chem. 1990, 33, 216–223.
5. Sayyed, I. A.; Thakur, V. V.; Nikalje, M. D.; Dewkar, G. K.; Kotkar, S. P.; Sudalai, A.
Tetrahedron 2005, 61, 2831–2838 and references therein.
6. Hou, X.-L.; Li, B.-F.; Dai, L.-X. Tetrahedron: Asymmetry 1999, 10, 2319–2326 and
references therein.
(d), 23.0 (q), 22.9 (q), 21.5 (q); MS-EI m/z (relative intensity): 223
ꢂ
(Mþ , 1), 208 (3), 179 (8), 91 (13), 72 (100), 56 (11); HRMS calcd for
C13H22NO (MHþ): 224.16451; found: 224.16481.
5.5.7. (S)-Propanolol5,6
To a solution of 29 (54 mg, 0.21 mmol) in THF (1 mL) was added
dropwise trifluoroacetic anhydride (30
mL, 0.21 mmol, 1 equiv) and
´
7. Metro, T.-X.; Gomez Pardo, D.; Cossy, J. Chem.dEur. J. 2009, 15, 1064–1070 and
then Et3N (30 L, 0.21 mmol, 1 equiv). The reaction mixture was
m
references therein.
then heated at 110 ꢀC for 12 h under microwave irradiation in
a sealed tube. After addition of an aqueous 2.5 M NaOH solution
(2 mL), the mixture was stirred at rt for 2 h, extracted with EtOAc,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
gel (EtOAc/MeOH 90/10þ0.5% Et3N) afforded (S)-propanolol
8. Me´tro, T.-X.; Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2007, 72, 6556–6561.
9. Me´tro, T.-X.; Gomez Pardo, D.; Cossy, J. Synlett 2007, 2888–2890.
10. For a related rearrangement of an N-alkyl
-amino bromide see: Nagle, A. S.; Salvatore, R. N.; Chong, B.-D.; Jung, K. W.
Tetrahedron Lett. 2000, 41, 3011–3014.
b-amino alcohol into an N-alkyl
b
´
11. Metro, T.-X.; Gomez Pardo, D.; Cossy, J. Org. Lett. 2006, 8, 3509–3512.
12. Delle Monache, G.; Di Giovanni, M. C.; Maggio, F.; Misiti, D.; Zappia, G. Synthesis
1995, 1155–1158.
25
25
ꢁ7.6 (c 1.25, EtOH) (lit6 [
a]
ꢁ9.0 (c
13. Bra¨uner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.; Evano, G.; Jensen, A. A.;
Kusk, M.; Nielsen, B.; Rabasso, N. Org. Biomol. Chem. 2005, 3, 3926–3936.
14. McKay, C.; Wilson, R. J.; Rayner, C. M. Chem. Commun. 2004, 1080–1081.
15. Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J. Org. Chem. 1995, 60, 4177–4183.
16. Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasekhar, M.; Singh, V. K.
Tetrahedron 2002, 58, 4693–4706.
(32 mg, 0.12 mmol, 60%). [
a
]
D
D
0.5, EtOH)); mp 73–74 ꢀC; ee¼92% determined by supercritical fluid
chromatography on Daicel chiralpack OD-H column (MeOH/Et3N
99.5/0.5 15%, flow rate 3 mL/min, tR (major)¼7.4 min, tR (minor)
¼4.7 min); IR (neat) 3200–2500, 1596, 1582, 1509, 1459, 1401, 1341,
1268, 1241, 1101, 1067, 1020, 941, 787, 762 cmꢁ1; 1H NMR (400 MHz,
17. Desai, H.; D’Souza, B. R.; Foether, D.; Johnson, B. F.; Lindsay, H. A. Synthesis 2007,
6, 902–910.
CDCl3):
d
8.17 (m, 1H), 7.72 (m, 1H), 7.44–7.35 (m, 3H), 7.29 (dd,
18. Chhabra, S. R.; Mahajan, A.; Chan, W. C. J. Org. Chem. 2002, 67, 4017–4029.