Asymmetric synthesis of 1,2-diaryl-2-amino ethanols

Article abstract of DOI:10.1016/S0957-4166(02)00181-7

A straightforward procedure for the asymmetric synthesis of 1,2-diaryl-2-amino ethanols is described. The key step relies on the diastereoselective electrophilic amination of the enolates derived from the corresponding (S,S)-(+)-pseudoephedrine arylacetam

Full text of DOI:10.1016/S0957-4166(02)00181-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 745–751
Asymmetric synthesis of 1,2-diaryl-2-amino ethanols
Jose L. Vicario, Dolores Bad´ıa,* Luisa Carrillo and Eneritz Anakabe
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco-Euskal Herriko Unibertsitatea,
PO Box 644, 48080 Bilbao, Spain
Received 25 March 2002; accepted 16 April 2002
Abstract—A straightforward procedure for the asymmetric synthesis of 1,2-diaryl-2-amino ethanols is described. The key step
relies on the diastereoselective electrophilic amination of the enolates derived from the corresponding (S,S)-(+)-pseudoephedrine
arylacetamides with di-tert-butylazodicarboxylate, followed by a hydrolysis/hydrogenolysis procedure to yield a-amino amide
derivatives with a very high degree of diastereoselection. These substrates were subsequently subjected to a non-racemizing
1,2-addition step with several aryllithium reagents to yield the corresponding a-amino ketones which, upon diastereoselective
reduction with NaBH4 afforded the desired b-amino alcohols as single enantiomers with 1,2-anti relative configuration. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
the possibility of preparing 1,2-diarylamino ethanols in
a stereocontrolled way by addition of aryllithium
reagents to the already mentioned (S,S)-(+)-pseudo-
ephedrine-based a-amino substituted arylacetamides,
followed by diastereoselective reduction of the so-
obtained a-amino ketone derivatives (Scheme 1).
The stereocontrolled synthesis of 1,2-diarylamino
ethanols remains a challenging and worthwhile task in
the field of organic synthesis,1 since these compounds
have shown very interesting applications as biologically
active compounds,2 chiral auxiliaries or ligands in
asymmetric catalysis,3 chiral stationary phases for
HPLC applications4 and also as building blocks for the
preparation of natural products.5 In this context, these
interesting compounds have been obtained in non-
racemic form using several different approaches like
resolution,6 modification of the corresponding chiral
1,2-diols,7 stereocontrolled cyanohydrin formation/aryl-
ation,8 asymmetric aminohydroxylation,9 asymmetric
reduction of 1,2-diaryl-2-alkoxyiminoethanones10 or
diastereoselective reductive amination of chiral non-
racemic benzoins.11
2. Results and discussion
We proceeded to perform the diastereoselective amina-
tion of (S,S)-(+)-pseudoephedrine arylacetamide eno-
lates using the procedure already published by us,12,15
which consisted of an initial deprotonation step of the
starting arylacetamides 1a–c with 2 equiv. of LDA in
THF at –78°C, followed by treatment of the formed
intermediate dianion with di-tert-butylazodicarboxylate
In our group we have recently developed a procedure
for the asymmetric synthesis of arylglycines in which
the key step relied on the diastereoselective amination
of (S,S)-pseudoephedrine-based arylacetamide enol-
ates.12 Myers et al.13 and our group14 have also shown
that these pseudoephedrine amide adducts are suitable
substrates to undergo reactions with organolithium
reagents, affording the corresponding chiral nonracemic
a-substituted ketones. In this context, and in connec-
tion with these previous studies, we decided to explore
* Corresponding author. Tel.: +34-94-6012633; fax: +34-94-4648500;
e-mail: qopbaurm@lg.ehu.es
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00181-7

746
J. L. Vicario et al. / Tetrahedron: Asymmetry 13 (2002) 745–751
(BocNꢀNBoc) at –105°C (Scheme 2). The amination
adducts 2a–c were obtained cleanly in good yields and
excellent diastereoselectivities, as could be checked by
NMR and HPLC analysis of the crude reaction mixture
(Table 1). These hydrazine derivatives 2a–c were then
subjected to hydrolysis with TFA in CH2Cl2 at rt
followed by hydrogenation using Pd/C at catalyst
affording the corresponding a-amino amides 3a–c in
excellent yields after column chromatography
purification.
These a-amino ketone adducts 4a–d were found to be
rather unstable, as several reported data suggested.16g,k
Therefore, they were directly reduced with NaBH4 in
THF, affording the desired 1,2-diarylamino ethanols in
excellent yield. The reduction proceeded in a fully
diastereoselective way, leading to the amino alcohols
5a–d as single diastereoisomers with 1,2-anti relative
configuration.
The 1,2-anti relative configuration was assigned accord-
ing to the J1,2 coupling constants found between both
benzylic protons (J=6.3 Hz for 5d) by comparison with
data found in the literature.4–11 However, for a more
rigorous determination, we proceeded to prepare the
corresponding cyclic oxazolidine derivative 6 starting
from amino alcohol 5c, by means of an N-methylation–
cyclization sequence (Scheme 4).
Next, we proceeded to perform the 1,2-addition reac-
tion of an in situ formed aryllithium reagent across the
CꢀO amide double bond, which would afford the corre-
sponding 2-amino-1,2-diarylethanone derivatives.16
When we tested the reaction using amides 2a–c as
starting materials and different reaction conditions, we
observed only the formation of complicated mixtures of
products and none of the desired a-amino ketone
derivatives. However, when changing to the unpro-
tected a-amino amides 3a–c the addition proceeded
cleanly under analogous conditions to those published
by Myers et al. for the addition of organolithium
reagents to pseudoephedrine amides (Scheme 3, Table
2).13 Therefore, an alternative method was used: the
reaction of amides 3a–c with 3.5 equiv. of an aryl-
lithium reagent prepared in situ at –78°C followed by
warming to rt and subsequent acidic work-up afforded
the desired a-amino ketone derivatives 4a–d in good
yields.
The predominant 1,2-anti configuration of the products
can be explained using Cram’s cyclic model17 in which
an intermediate metal monoamidoborohydride species
is formed by reaction of NaBH4 with one of the acidic
amine protons followed by coordination to the car-
bonyl oxygen. The reduction then would take place by
intramolecular hydride delivery from the hydride
reagent to the carbonyl moiety (Fig. 1). According to
this arrangement, the hydride would attack from the Si
face of the CꢀO bond thus leading to the formation of
the 1,2-anti isomer as observed experimentally.
Scheme 3. Reagents and conditions: (i) 1. ArLi, THF, −78“
0°C; 2. i-Pr2NH, 0°C; 3. AcOH/Et2O; (ii) NaBH4, THF,
−20°C.
Scheme 2. Reagents and conditions: (i) 1. LDA, THF, −78°C,
2. BocNꢀNBoc, THF, −105°C; (ii) 1. TFA, CH2Cl2, rt; 2. H2,
Pd/C, CH2Cl2/EtOH.
Table 1. Diastereoselective amination of (S,S)-(+)-pseudoephedrine arylacetamides 1a–c
R1
R2
R3
Prod.
Yield (%)a
D.r.b
Prod.
Yield (%)a
OMe
OMe
OMe
OMe
OMe
H
H
2a
2b
2c
90
91
89
\95/5
\95/5
\95/5
3a
3b
3c
78
79
78
OCH2O
a Yield of pure product isolated after column chromatography.
b Determined by NMR analysis of the crude reaction mixture.

J. L. Vicario et al. / Tetrahedron: Asymmetry 13 (2002) 745–751
747
Table 2. 1,2-Addition/diastereoselective reduction sequence performed on a-amino amides 3a–c
R1
R2
R3
R4
Prod.
Yield (%)a
Prod.
Yield (%)b
D.r.c
OMe
OMe
OMe
H
H
OMe
OMe
H
4a
4b
4c
4d
82
72
79
77
5a
5b
5c
5d
83
79
89
93
\95/5
\95/5
\95/5
\95/5
OCH2O
OMe
OMe
OMe
OMe
H
OMe
a Yield of crude product.
b Yield of pure product isolated after column chromatography.
c Ratio of 1,2-anti/1,2-syn products determined by NMR analysis of the crude reaction mixture.
final compounds proceeded without racemization in the
stereogenic centre that was obtained after the asymmet-
ric amination step.
It should be pointed out that, to our surprise, even
under such basic conditions during the 1,2-addition
step of the aryllithium reagent to the amide moiety, the
benzylic proton at the stereogenic centre remained
untouched and no epimerization was observed. This is
especially surprising considering the large excess of
organometallic reagent necessary for the reaction to
proceed. We believe that this is due to the possible
deprotonation of the amino group which would gener-
ate an amide anion, substantially modifying the acidity
of the benzylic proton and thus minimizing the possible
epimerization of the stereogenic center. In the related
work by Myers et al.,13b a similar 1,2-addition proce-
dure was employed but in this case the amino function-
ality was protected as the N-Boc derivative and also in
this case the addition proceeded without epimerization,
which leads us to think that despite the high acidity of
the benzylic proton of the a-amino amides 3a–c, it is
somehow well protected against attack by basic species.
Scheme 4. Reagents and conditions: (i) 1. HCONH2, 150°C, 2.
,
LAH, THF, reflux; (ii) HCHO, 4 A molecular sieves, ben-
zene, rt.
Figure 1.
For the determination of the enantiomeric excess of the
1,2-diarylamino ethanols 5a–d, we could not find any
conditions for the separation of the enantiomers by
HPLC in a chiral stationary phase, mainly due to the
fact that they are very highly polar compounds. There-
fore, we resolved to convert them into the correspond-
ing O-TBDMS protected analogues 7a–d (Scheme 5)
and in this case, separation of the enantiomers was
possible by HPLC using a Chiracel OD® chiral column.
The conditions for the separation were optimized work-
ing with racemic standards prepared by an alternative
procedure also developed by us.18 In all cases, the
O-TBDMS protected 1,2-diarylamino ethanols 7a–d
showed to be in >99% ee. This also showed that all the
transformations performed from hydrazines 2a–c to the
3. Conclusions
A very efficient, high yielding procedure has been
devised and carried out to prepare chiral non-racemic
1,2-diaryl-2-amino ethanols in a stereoselective way
using (S,S)-(+)-pseudoephedrine as a chiral auxiliary.
The procedure involves the reaction of stereodefined
a-amino amides prepared by a procedure previously
reported by us with aryllithium reagents, followed by
diastereoselective reduction of the obtained a-amino
ketones. The sequence proceeded cleanly and without
racemization of the starting stereogenic center, afford-
ing the target compounds with 1,2-anti relative
configuration.
Advantageous features of this procedure are that the
chiral auxiliary, (S,S)-pseudoephedrine is inexpensive
and commercially available in both enantiomeric forms.
Additionally, using this methodology different substitu-
tion patterns can be introduced at both aryl rings of the
1,2-diarylaminoethanol moiety, thus allowing the
preparation of a wide range of modified compounds,
which could find applicability as chiral ligands in asym-
metric synthesis or may show improved biological
activities compared to other known derivatives.
Scheme 5. Reagents and conditions: (i) TBDMSCl, imidazole,
DMF, rt.

748
J. L. Vicario et al. / Tetrahedron: Asymmetry 13 (2002) 745–751
4. Experimental
110.0; 110.3; 111.5; 122.6; 128.2; 131.1; 148.3; 148.8;
149.2; 153.4; 198.5. MS (EI) m/z (rel. int.): 361 (M+, 1),
346 (11), 207 (15), 165 (18), 142 (65), 127 (22), 115 (17),
111 (52), 97 (38), 91 (100), 85 (24), 77 (17), 69 (32), 65
(33), 57 (48).
4.1. General procedures
Melting points were determined in unsealed capillary
tubes and are uncorrected. IR spectra were obtained on
KBr pellets (solids) or CHCl3 solution (oils). NMR
spectra were recorded at 20–25°C, running at 250 MHz
4.2.2.
(2S)-2-Amino-1-(3,4-dimethoxyphenyl)-2-(3,4-
methylenedioxyphenyl)ethanone, 4b. The reaction of the
amide 3b (118 mg, 0.34 mmol) with (3,4-MeO)2C6H3Li
(prepared in situ by reaction of (3,4-MeO)2C6H3Br (0.17
mL, 1.21 mmol) with n-BuLi (0.81 mL of a 1.5 M solution
in hexanes, 1.21 mmol) in THF (15 mL) at −78°C for 2
h) following the general procedure afforded ketone 4b (77
mg, 0.24 mmol) as a yellowish oil. Yield: 72%. IR
for H and 62.8 MHz for 13C in CDCl3 solution and
1
resonances are reported in ppm relative to tetra-
methylsilane unless otherwise stated. Assignment of
individual 13C resonances are supported by DEPT exper-
iments. H–{1H} NOE experiments were carried out in
1
the difference mode by irradiation of all the lines of a
multiplet.19 Mass spectra were recorded under electron
impact at 70 eV. TLC was carried out with 0.2 mm thick
silica gel plates (Merck Kiesegel GF254). Visualization was
accomplished by UV light or by spraying with Dragen-
dorff’s reagent.20 Flash column chromatography21 on
silica gel was performed with Merck Kiesegel 60 (230–400
mesh). Determination of enantiomeric excess was per-
formed by chiral HPLC analysis of non crystallized
samples using a Chiracel OD® column with a UV detector
and the eluents and flow rates as indicated in each case.
All solvents used in reactions were dried and purified
according to standard procedures.22 n-BuLi was titrated
with diphenylacetic acid periodically prior to use. All air-
or moisture-sensitive reactions were performed under
argon. The glassware was oven dried (140°C) overnight
and purged with argon. Amides 1a–c, 2a–c, and 3a–c were
prepared by already reported procedures.15
1
(CHCl3): 3345 (NH2); 1665 (CꢀO). H NMR (l, ppm):
2.31 (bs, 2H); 3.45 (s, 3H); 3.71 (s, 3H); 5.28 (s, 1H); 5.98
(s, 2H); 6.60–6.69 (m, 4H); 7.41–7.46 (m, 2H). 13C NMR
(l, ppm): 55.8; 56.3; 60.5; 98.6; 110.2; 110.6; 111.2; 111.9;
120.3; 122.5; 128.3; 133.5; 148.9; 150.1; 150.3; 153.2;
196.5. MS (EI) m/z (rel. int.): 315 (M+, 1), 300 (8), 237
(2), 207 (15), 184 (12), 165 (23), 142 (55), 115 (19), 111
(53), 97 (22), 91 (100), 85 (17), 69 (49), 65 (63), 57 (43),
51 (29).
4.2.3. (2S)-2-Amino-2-(3,4-dimethoxyphenyl)-1-phenyl-
ethanone, 4c. The reaction of the amide 3c (123 mg, 0.34
mmol) with PhLi (prepared in situ by reaction of PhBr
(0.13 mL, 1.20 mmol) with n-BuLi (0.80 mL of a 1.5 M
solution in hexanes, 1.20 mmol) in THF (15 mL) at −78°C
for 2 h) following the general procedure afforded ketone
4c (81 mg, 0.30 mmol) as a yellowish oil. Yield: 79%. IR
1
(CHCl3): 3360 (NH2); 1680 (CꢀO). H NMR (l, ppm):
4.2. General procedure for the 1,2-addition of aryl-
lithium reagents over the amides 3a–c. Synthesis of 1,2-
diaryl-2-aminoethanones 4a–d
3.77 (s, 3H); 3.79 (s, 3H); 4.0–4.4 (bs, 2H); 5.55 (s, 1H);
6.70–6.84 (m, 2H); 7.21–7.48 (m, 5H); 7.87 (d, 1H, J=7.0
Hz). 13C NMR (l, ppm): 55.7; 55.8; 60.5; 110.3; 111.3;
120.3; 126.7; 126.8; 127.6; 133.2; 134.7; 148.8; 149.4; 198.
MS (EI) m/z (rel. int.): 271 (M+, 1), 256 (5), 211 (30), 151
(21), 134 (74), 127 (26), 111 (12), 105 (32), 97 (25), 91 (100),
85 (24), 77 (32), 65 (24), 57 (78), 51 (28).
A solution of the organolithium reagent (3.50 mmol) was
added dropwise over a cooled (−78°C) solution of the
a-amino amide 3a–c in dry THF (10 mL). After the
addition was complete, the mixture was allowed to reach
rt and after 25 min diisopropylamine (1.00 mmol) was
added at once to avoid the excess of organolithium
reagent. The reaction was quenched after additional 15
min by adding a 10% solution of AcOH in Et2O. The
mixture was basified with 10% NaOH, extracted with
CH2Cl2 and the organic extracts were collected, dried over
Na2SO4, filtered and the solvent removed under reduced
pressure to afford crude a-amino ketones 4a–d which
were characterized and used in the next step without
further purification.
4.2.4.
(2S)-2-Amino-1,2-bis(3,4-dimethoxyphenyl)-
ethanone, 4d. The reaction of the amide 3c (110 mg, 0.31
mmol) with (3,4-MeO)2C6H3Li (prepared in situ by
reaction of the aryl bromide (0.16 mL, 1.08 mmol) with
n-BuLi (0.72 mL of a 1.5 M solution in hexanes, 1.08
mmol) in THF (15 mL) at −78°C for 2 h) following the
general procedure afforded ketone 4d (79 mg, 0.24 mmol)
as a yellowish oil. Yield: 77%. IR (CHCl3): 3340 (NH2);
1
1660 (CꢀO). H NMR (l, ppm): 2.28 (bs, 2H); 3.58 (s,
3H); 3.72 (s, 3H); 3.75 (s, 3H); 3.78 (s, 3H); 5.33 (s, 1H);
6.64–6.79 (m, 4H); 7.43–7.48 (m, 2H). 13C NMR (l, ppm):
55.9; 56.0; 60.4; 110.0; 110.4; 110.9; 111.5; 119.9; 122.6;
128.1; 133.6; 148.8; 148.9; 149.5; 153.3; 197.6. MS (EI)
m/z (rel. int.): 331 (M+, 1), 316 (8), 207 (20), 165 (22),
151 (12), 142 (68), 111 (41), 105 (9), 97 (31), 91 (100), 85
(12), 77 (25), 65 (61), 57 (58).
4.2.1.
(2S)-2-Amino-1-(3,4-dimethoxyphenyl)-2-(3,4,5-
trimethoxyphenyl)ethanone, 4a. The reaction of the amide
3a (123 mg, 0.34 mmol) with (3,4-MeO)2C6H3Li (pre-
pared in situ by reaction of (3,4-MeO)2C6H3Br (0.17 mL,
1.21 mmol) with n-BuLi (0.81 mL of a 1.5 M solution
in hexanes, 1.21 mmol) in THF (15 mL) at −78°C for 2
h) following the general procedure afforded ketone 4a
(102 mg, 0.28 mmol) as a yellowish oil. Yield: 82%. IR
4.3. General procedure for the diastereoselective reduc-
tion of the a-amino ketones 4a–d: synthesis of 1,2-
diaryl-2-amino ethanols 5a–d
1
(CHCl3): 3350 (NH2); 1655 (CꢀO). H NMR (l, ppm):
2.32 (bs, 2H); 3.59 (s, 3H); 3.72 (s, 6H); 3.74 (s, 3H); 3.79
(s, 3H); 5.36 (s, 1H); 6.50 (s, 2H); 6.61 (s, 1H); 7.31–7.39
(m, 2H). 13C NMR (l, ppm): 55.9; 56.0; 56.3; 56.5; 60.1;
A solution of NaBH4 (1.00 mmol) in dry THF (5 mL)
was added dropwise within 10 min over a cooled

J. L. Vicario et al. / Tetrahedron: Asymmetry 13 (2002) 745–751
749
(−20°C) solution of the a-amino ketone 4a–d (1.00
mmol). The reaction was stirred for 2 h at this temper-
ature then quenched with a saturated Na2CO3 solution
(10 mL). The mixture was extracted with CH2Cl2 and
the organic fractions were collected, dried over Na2SO4,
filtered and the solvent removed under reduced pressure
to afford pure b-amino alcohols 5a–d after atmospheric
pressure column chromatography purification (CH2Cl2/
MeOH 9:1 as eluent).
4.3.4.
(1R,2S)-(−)-2-Amino-1,2-bis(3,4-dimethoxy-
phenyl)-ethanol, 5d. The reaction of the amino ketone
4d (65 mg, 0.19 mmol) with NaBH4 (8 mg, 0.19 mmol)
according to the general procedure afforded b-amino
alcohol 5d (48 mg, 0.18 mmol) as a white solid. Yield:
93%. Mp: 155–160°C (MeOH). [h]2D0: −122.6 (c=0.70,
EtOH). IR (KBr): 3320 (OH+NH2). 1H NMR (l, ppm):
1.7–2.3 (bs, 3H); 3.80 (s, 3H); 3.83 (s, 3H); 3.87 (s, 6H);
4.07 (d, 1H, J=6.3 Hz); 4.63 (d, 1H, J=6.3 Hz);
6.66–6.92 (m, 6H). 13C NMR (l, ppm): 55.7; 55.8; 61.7;
78.4; 109.8; 110.4; 110.7; 110.8; 119.4; 119.9; 133.2;
134.0; 148.5; 148.6; 148.7; 148.9. MS (EI) m/z (rel. int.):
333 (M+, 1), 315 (1), 254 (3), 166 (9), 139 (12), 115 (17),
106 (100), 91 (35), 79 (9), 77 (24), 51 (9). Anal. calcd for
C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C,
64.75; H, 6.78; N, 4.12%.
4.3.1. (1R,2S)-(−)-2-Amino-1-(3,4-dimethoxyphenyl)-2-
(3,4,5-trimethoxyphenyl)ethanol, 5a. The reaction of the
amino ketone 4a (69 mg, 0.19 mmol) with NaBH4 (8
mg, 0.19 mmol) according to the general procedure
afforded b-amino alcohol 5a (57 mg, 0.16 mmol) as a
white solid. Yield: 83%. Mp: (as HCl salt) 176–177°C
(MeOH). [h]2D0: −119.3 (c=0.75, EtOH). IR (KBr): 3340
1
(OH+NH2). H NMR (l, ppm): 1.8–2.2 (bs, 3H); 3.78
4.4. General procedure for O-silylation of the b-amino
alcohols, 5a–d
(s, 3H); 3.79 (s, 3H); 3.80 (s, 6H); 3.81 (s, 3H); 4.01 (d,
1H, J=6.4 Hz); 4.59 (d, 1H, J=6.4 Hz); 6.50 (s, 2H);
6.73 (s, 1H); 6.79 (d, 1H, J=8.2 Hz); 6.84 (dd, 1H,
J=1.1, 8.2 Hz). 13C NMR (l, ppm): 55.7; 55.8; 56.0;
60.7; 62.1; 78.2; 104.4; 109.7; 110.6; 119.3; 133.2; 137.2;
148.5; 148.8; 149.0; 153.0. MS (EI) m/z (rel. int.): 363
(M+, 1), 345 (1), 196 (100), 180 (4), 169 (4), 154 (8), 115
(10), 106 (84), 95 (3), 79 (2), 77 (5), 51 (3). Anal. calcd
for C19H26ClNO6: C, 57.07; H, 6.55; N, 3.50. Found: C,
57.26; H, 6.34; N, 3.55%.
A solution of the b-amino alcohol 5a–d (1.00 mmol),
imidazole (2.20 mmol) and TBDMSCl (1.00 mmol) in
dry DMF (10 mL) was stirred at rt for 90 min, after
which AcOEt (15 mL) was added at once. The organic
layer was washed twice with water and the organic
fraction was dried over Na2SO4, filtered and the solvent
removed under reduced pressure to afford the silylated
alcohols 7a–d after flash column chromatography
purification (AcOEt as eluent).
4.3.2. (1R,2S)-(−)-2-Amino-1-(3,4-dimethoxyphenyl)-2-
(3,4-methylenedioxyphenyl)ethanol, 5b. The reaction of
the amino ketone 4b (63 mg, 0.20 mmol) with NaBH4
(9 mg, 0.20 mmol) according to the general procedure
afforded b-amino alcohol 5b (50 mg, 0.16 mmol) as a
white solid. Yield: 79%. Mp: 174–177°C (MeOH). [h]2D0:
−118.3 (c=0.72, EtOH). IR (KBr): 3310 (OH+NH2).
1H NMR (l, ppm): 1.6–2.0 (bs, 3H); 3.86 (s, 3H); 3.87
(s, 3H); 4.02 (d, 1H, J=6.4 Hz); 4.61 (d, 1H, J=6.4
Hz); 5.91 (s, 2H); 6.62–6.98 (m, 6H). 13C NMR (l,
ppm): 55.7; 55.9; 61.4; 78.6; 100.5; 109.6; 110.5; 110.8;
111.2; 119.3; 119.9; 133.5; 134.8; 148.5; 148.6; 151.7;
152.3. MS (EI) m/z (rel. int.): 317 (M+, 1), 299 (1), 252
(3), 167 (5), 139 (15), 115 (22), 106 (100), 91 (36), 79
(17), 77 (32), 51 (8). Anal. calcd for C17H19NO5: C,
64.34; H, 6.03; N, 4.41. Found: C, 64.54; H, 6.18; N,
4.43%.
4.4.1. (1R,2S)-(−)-2-[Dimethyl(2,2-dimethylethyl)-silyl-
oxy] - 2 - (3,4 - dimethoxyphenyl) - 1 - (3,4,5 - trimethoxy-
phenyl)ethylamine 7a. Reaction of the amino alcohol 5a
(37 mg, 0.11 mmol) with imidazole (16 mg, 0.24 mmol)
and TBDMSCl (16 mg, 0.11 mmol) according to the
general procedure afforded O-silylated b-amino alcohol
7a (40 mg, 0.08 mmol) as a yellowish oil. Yield: 77%.
[h]2D0: −117.3 (c=0.40, CH2Cl2). IR (CHCl3): 3410
1
(NH2). H NMR (l, ppm): −0.36 (s, 3H); −0.21 (s, 3H);
0.83 (s, 9H); 2.11 (bs, 2H); 3.78 (s, 3H); 3.79 (s, 3H);
3.81 (s, 3H); 3.87 (s, 6H); 4.06 (d, 1H, J=6.5 Hz); 4.68
(d, 1H, J=6.5 Hz); 6.38 (s, 2H); 6.58–6.74 (m, 3H). 13C
NMR (l, ppm): −5.7; −4.1; 18.2; 25.8; 55.6; 56.1; 56.9;
62.3; 77.8; 110.2; 110.7; 111.4; 112.9; 133.4; 139.1;
148.5; 148.9; 149.3; 151.1. MS (EI) m/z (rel. int.): 477
(M+, 1), 386 (6), 372 (9), 282 (31), 281 (100), 195 (12),
167 (7), 106 (26), 91 (11), 79 (38), 77 (9), 73 (32), 51
(44). Anal. calcd for C25H39NO6Si: C, 62.86; H, 8.23;
N, 2.93. Found: C, 62.81; H, 8.18; N, 2.91%.
4.3.3. (1R,2S)-(−)-2-Amino-2-(3,4-dimethoxyphenyl)-1-
phenylethanol, 5c. Reaction of the amino ketone 4c (73
mg, 0.27 mmol) with NaBH4 (11 mg, 0.27 mmol)
according to the general procedure afforded b-amino
alcohol 5c (66 mg, 0.24 mmol) as a white solid. Yield:
89%. Mp: 154–156°C (EtOH). [h]2D0: −110.9 (c=0.70,
EtOH). IR (KBr): 3450 (OH+NH2). 1H NMR (l, ppm):
2.1–2.6 (bs, 3H); 3.77 (s, 3H); 3.86 (s, 3H); 4.10 (d, 1H,
J=6.2 Hz); 4.71 (d, 1H, J=6.2 Hz); 6.69 (s, 1H); 6.81
(m, 2H); 7.21–7.33 (m, 5H). 13C NMR (l, ppm): 55.7;
55.8; 61.5; 78.1; 110.3; 110.5; 119.7; 126.9; 127.7; 128.1;
133.4; 140.6; 148.3; 148.6. MS (EI) m/z (rel. int.): 273
(M+, 1), 240 (1), 195 (1), 166 (18), 137 (15), 115 (18),
106 (100), 91 (22), 79 (13), 77 (11), 51 (5). Anal. calcd
for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.28; H, 6.95; N, 5.19%.
4.4.2. (1R,2S)-(−)-2-[Dimethyl(2,2-dimethylethyl)-silyl-
oxy]-2-(3,4-dimethoxyphenyl)-1-(3,4-methylenedioxy-
phenyl)ethylamine, 7b. The reaction of the amino
alcohol 5b (60 mg, 0.19 mmol) with imidazole (29
mg, 0.43 mmol) and TBDMSCl (29 mg, 0.19 mmol)
according to the general procedure afforded O-
silylated b-amino alcohol 7b (69 mg, 0.16 mmol)
as a white solid. Yield: 84%. Mp: 159–162°C (Et2O).
[h]2D0: −133.8 (c=0.50, CH2Cl2). IR (KBr): 3410
1
(NH2). H NMR (l, ppm): −0.30 (s, 3H); −0.21 (s, 3H);
0.71 (s, 9H); 2.12 (sa, 2H); 3.75 (s, 3H); 3.81 (s, 3H);

750
J. L. Vicario et al. / Tetrahedron: Asymmetry 13 (2002) 745–751
3.98 (d, 1H, J=6.6 Hz); 4.59 (d, 1H, J=6.6 Hz); 5.97
(s, 2H); 6.51 (d, 1H, J=1.3 Hz); 6.56 (dd, 1H, J=
1.3, 8.6 Hz); 6.61–6.79 (m, 4H). 13C NMR (l, ppm):
−5.6; −4.0; 18.2; 24.5; 55.7; 57.3; 62.4; 76.8; 101.6;
110.4; 110.5; 111.6; 112.4; 118.1; 118.6; 133.4; 136.9;
148.4; 148.7; 149.3; 150.8. MS (EI) m/z (rel. int.): 431
(M+, 1), 386 (1), 384 (1), 372 (9), 282 (21), 281 (100),
195 (3), 167 (9), 106 (6), 91 (13), 79 (22), 77 (26), 73
(15), 51 (3). Anal. calcd for C23H33NO5Si: C, 64.01;
H, 7.71; N, 3.25. Found: C, 63.98; H, 7.67; N, 3.20%.
References
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4.4.3.
(1R,2S)-(−)-2-[Dimethyl(2,2-dimethylethyl)silyl-
7c.
oxy]-1-(3,4-dimethoxyphenyl)-2-phenylethylamine,
Reaction of the amino alcohol 5c (53 mg, 0.19 mmol)
with imidazole (29 mg, 0.43 mmol) and TBDMSCl
(29 mg, 0.19 mmol) according to the general proce-
dure afforded O-silylated b-amino alcohol 7c (63 mg,
0.16 mmol) as a yellowish oil. Yield: 86%. [h]2D0:
−137.2 (c=0.50, CH2Cl2). IR (CHCl3): 3400 (NH2).
1H NMR (l, ppm): −0.30 (s, 3H); −0.25 (s, 3H); 0.74
(s, 9H); 2.03 (bs, 2H); 3.75 (s, 3H); 3.85 (s, 3H); 3.99
(d, 1H, J=6.6 Hz); 4.63 (d, 1H, J=6.6 Hz); 6.56–
6.75 (m, 3H); 7.22–7.36 (m, 5H). 13C NMR (l, ppm):
−5.7; −5.0; 18.2; 25.1; 55.6; 55.9; 62.3; 78.9; 110.1;
110.3; 119.2; 126.8; 127.7; 128.3; 133.4; 142.6; 148.5;
148.7. MS (EI) m/z (rel. int.): 387 (M+, 1), 315 (34),
282 (23), 272 (100), 167 (5), 106 (21), 91 (17), 79 (22),
77 (5), 73 (41), 51 (3). Anal. calcd for C22H33NO3Si:
C, 68.17; H, 8.58; N, 3.61. Found: C, 68.15; H, 8.53;
N, 3.59%.
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oxy]-1,2-bis(3,4-dimethoxyphenyl)ethylamine, 7d. The
reaction of the amino alcohol 5d (48 mg, 0.14 mmol)
with imidazole (21 mg, 0.31 mmol) and TBDMSCl
(22 mg, 0.14 mmol) according to the general proce-
dure afforded O-silylated b-amino alcohol 7d (51 mg,
0.11 mmol) as a yellowish oil. Yield: 82%. [h]2D0:
−126.9 (c=0.50, CH2Cl2). IR (CHCl3): 3400 (NH2).
1H NMR (l, ppm): −0.32 (s, 3H); −0.27 (s, 3H); 0.79
(s, 9H); 2.00 (bs, 2H); 3.77 (s, 3H); 3.79 (s, 3H); 3.85
(s, 6H); 4.03 (d, 1H, J=6.5 Hz); 4.66 (d, 1H, J=6.5
Hz); 6.48 (d, 1H, J=1.5 Hz); 6.54 (dd, 1H, J=1.5,
8.6 Hz); 6.67–6.83 (m, 4H). 13C NMR (l, ppm): −5.9;
−4.6; 18.7; 24.6; 55.7; 56.2; 57.1; 62.5; 77.2; 110.2;
110.5; 111.2; 112.6; 117.4; 118.5; 133.6; 139.5; 148.3;
148.7; 148.9; 151.2. MS (EI) m/z (rel. int.): 447 (M+,
1), 386 (1), 372 (12), 282 (18), 281 (100), 195 (5), 167
(3), 106 (12), 91 (23), 79 (33), 77 (6), 73 (52), 51 (12).
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3.13. Found: C, 64.31; H, 8.39; N, 3.09%.
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Financial support from the Basque Government (a
fellowship to J.L.V. and E.A. and Project
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Basque Country (Subvencio´n general a Grupos de
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