Synthesis of enantiopure 2-aminoalkylphenols by stereoselective addition of Grignard reagents to chiral 2-imidoylphenols

Article abstract of DOI:10.1016/S0957-4166(02)00544-X

The stereoselective addition of Grignard reagents to chiral 2-imidoylphenols affords enantiopure 2-aminoalkylphenols, a class of ligands useful in stereoselective synthesis. Unusually benzyl- and allyl-magnesium chlorides add to ketimines derived from enolizable o-acylphenols with high yields and stereoselectivities. In this way a stereogenic quaternary C-1 carbon atom is introduced, which could not be obtained by other methods available till now. The mechanism and the asymmetric induction have been explained in agreement with previously obtained results.

Full text of DOI:10.1016/S0957-4166(02)00544-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2011–2018
Synthesis of enantiopure 2-aminoalkylphenols by stereoselective
addition of Grignard reagents to chiral 2-imidoylphenols
Cristina Cimarelli, Gianni Palmieri* and Emanuela Volpini
Dipartimento di Scienze Chimiche via S. Agostino 1, 62032 Camerino, Italy
Received 17 July 2002; accepted 5 September 2002
Abstract—The stereoselective addition of Grignard reagents to chiral 2-imidoylphenols affords enantiopure 2-aminoalkylphenols,
a class of ligands useful in stereoselective synthesis. Unusually benzyl- and allyl-magnesium chlorides add to ketimines derived
from enolizable o-acylphenols with high yields and stereoselectivities. In this way a stereogenic quaternary C-1 carbon atom is
introduced, which could not be obtained by other methods available till now. The mechanism and the asymmetric induction have
been explained in agreement with previously obtained results. © 2002 Published by Elsevier Science Ltd.
1. Introduction
lective addition of diethylzinc to benzaldehyde (see
Scheme 1).14,18
The synthesis of enantiopure amines is an important
subject of research because this class of compounds is
widespread in biological systems, shows pharmacologi-
cal activity and has recently found application in asym-
metric synthesis as chiral bases, auxiliaries and ligands.
The addition of organometallic reagents to chiral
imines constitutes an interesting approach to the
stereoselective formation of the CꢀC bond.1–9 However,
this methodology has some drawbacks, owing to the
poor electrophilicity of the azomethine carbon and the
competition with the enolization in imines containing
a-hydrogen. These problems have been partially solved
either by activating the CꢁN bond with a Lewis acid, by
converting the imine function to the more reactive
iminium salt, nitrone,10 oximes,11 or acylimines or alter-
natively, by using more nucleophilic and less basic
reagents, such as organocerium12 and organocopper13
compounds. In the literature the additions of
organometallic reagents to aldimines are widely
reported, while additions to ketimines remain an impor-
tant challenge. In addition, ketimines can exist in both
the E and Z conformations, so the achievement of high
levels of diastereoselectivities is more difficult.
Recently, we have found that organolithium reagents
add in very good yields and with high diastereoselectiv-
ities to chiral 2-imidoylphenols derived not only from
o-salicylaldehyde, but more interestingly also from o-
acylphenols, affording a quaternary stereogenic carbon
atom (C-1).19 Herein, we wish to report our studies on
the diastereoselective addition of Grignard reagents to
imidoylphenols, prepared from (R)-1-phenylethylamine.
The use of Grignard reagents is particularly justified in
the case of allyl and benzyl organometallics because the
corresponding organolithium reagents are not commer-
cially available. In the synthesis of the allylmetal
reagents a coupling reaction between the allylmetal
For some time we have been interested in the synthesis
of aminoalkylphenols14–16 and aminoalkylnaphthols,17
a
specific group of amines, since this class of compounds
has found application as chiral ligands in the enantiose-
* Corresponding author. Tel.: +39 737 402241; fax: +39 737 637345;
e-mail: gianni.palmieri@unicam.it
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00544-X

2012
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
compounds and the allylic halide is a serious complicat-
ing factor and no satisfactory preparation of allyl-
lithium appears to be available at present.20 Generally
Grignard reagents have found less application than
organolithium compounds because of their poor reac-
tivity towards inactivated imines and their propensity
to act as bases with enolizable imines.21 The more
reactive allylmagnesium bromide and benzylmagnesium
bromide add to the non-enolizable N-(diphenyl-
methylene)aniline.22,23 More recently Spero and co-
workers reported the stereoselective addition of various
Grignard reagents to ketimines prepared from 2-
acetylpyridine24 or methoxyacetone25 and phenylgly-
cinol as chiral auxiliary, in the presence of MgBr2.
Ketimines react only with the more reactive Grignard
reagents derived from stabilized carbanions (allyl- and
benzylmagnesium chloride), while with more basic
reagents, such as methylmagnesium chloride, the start-
ing material was recovered unchanged, also in the
presence of several Lewis acid (BF3·Et2O, ZnCl2,
MgBr2·Et2O, TiCl4), since most probably the enoliza-
tion predominates on the addition. Organolithium
reagents appear to be more reactive than Grignard
reagents, because MeLi or BuLi also add in high yields
to imidoylphenols derived from o-acylphenols.19 When
the ketimine (R)-5h was allowed to react with phenyl-
magnesium chloride or methylmagnesium chloride in
the presence of the boron trifluoride etherate, only the
formation of the borate (R)-7h in high yields was
observed, this does not react with the Grignard reagent
present (see Scheme 2).
2. Results and discussion
The addition of Grignard reagents was carried out at
low temperature (−70°C) in toluene, a non-coordinating
hydrocarbon solvent. The results are listed in Table 1.
High yields in the addition reaction were obtained both
with aldimines (entries 6–12) and enolizable ketimines
having a coordinating atom in the aryl group at the
o-position to the imine function, such as the nitrogen in
the pyridine ring (entries 4, 5) and the phenolic oxygen
(entries 13–18).
Scheme 2.
Table 1. Synthesis of enantiopure 2-aminoalkylphenols 6 by stereoselective addition of Grignard reagents to chiral 2-imi-
doylphenols (R)-5
Entry
5
Z
R
R1
R2
X
6a
Time (h)
Yields (%)b
Si/Re
D.e.
1
2
3
4
5
6
7
8
(R)-5a
(R)-5a
(R)-5b
(R)-5c
(R)-5c
(R)-5d
(R)-5d
(R)-5d
(R)-5d
(R)-5d
(9)-5e
(9)-5e
(R)-5f
(R)-5f
(R)-5f
(9)-5g
(R)-5h
(R)-5h
(R)-5i
(R)-5i
(R)-5j
CH
CH
N
N
H
H
H
Me
Me
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
Et
Ph
Ph
Me
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(9)-NpEt
(9)-NpEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(9)-NpEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
(R)-PhEt
Allyl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
(R,R)-6aa31
(S,R)-6ab
(S,R)-6bb
(S,R)-6ca
(S,R)-6cb
(S,R)-6da
(S,R)-6da
(S,R)-6db
(S,R)-6dc14
(S,R)-6dd
(S*,R*)-6ea
(S*,R*)-6eb
(S,R)-6fa
(S,R)-6fa
(S,R)-6fb
(S*,R*)-6ga
(S,R)-6ha
(S,R)-6hb
(R,R)-6ia
(R,R)-6ib
6jac
3
23
5
4
3
1
1
5
23
23
1
3
3
3
4
2
3
95
18
91
90
76
94
95
73
75
52
95
71
89
86
66
95
94
95
78
40
65
42/58
62/38
57/43
68/32
91/9
67/33
75/25
62/38
63/34
52/48
61/39
76/24
88/12
87/13
95/5
16
24
14
36
82
34
50
24
32
4
22
52
76
74
90
82
56
98
64
80
16
Benzyl
Benzyl
Allyl
Benzyl
Allyl
N
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OH
C-OMe
Allyl
Benzyl
Propyl
Vinyl
Allyl
Benzyl
Allyl
Allyl
Benzyl
Allyl
Allyl
Benzyl
Allyl
Benzyl
Allyl
9
10
11
12
13
14
15
16
17
18
19
20
21
91/9
78/22
99/1
82/18
90/10
58/42c
5
4
8
23
a Major diastereomer.
b Combined yields of the two diastereomers isolated.
c Spectroscopic data are insufficient to assign the configuration.

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
2013
Changing the phenol for naphtholic groups does not
afford the same good results. In fact the imidoylnaph-
thol prepared from (R)-1-phenylethylamine and 1%-
the most stable conformation obtained with semiempir-
ical minimization (PM3),27 or X-ray diffraction on
analogous structure.17,28 To assign the configuration of
hydroxy-2%-acetonaphthone
adds
allylmagnesium
compounds with a quaternary stereogenic centre,
chloride only in 40% yield and 77:23 d.r. Moreover, in
contrast to aminoalkylphenols, the aminoalkylnaphthol
bearing a quaternary stereogenic center is not stable on
SiO2 and eliminates the amine, affording the conjugate
alkene. On the other hand the imidoylnaphthol derived
from 2%-hydroxy-1%-acetonaphthone does not add allyl-
magnesium chloride, nor benzylmagnesium chloride.
molecular modeling conformational analysis and NOE
experiments were carried out. The more stable confor-
mation was obtained by a systematic search procedure
(PM3 semiempirical level minimization). As illustrated
in the Fig. 1 for the aminophenol (1S,1%R)-6fa, NOE
1H NMR experiments were carried out.
Irradiation of the H-1% quartet line enhances the gemi-
nal Me-1% and both the alkyl group signals at the C-1
carbon atom, validating the results obtained by confor-
mational analysis. In this conformation the Ph-1% group
causes a shielding effect on the C-1 group under it,
Low to moderate diastereoselectivities are obtained in
the addition of Grignard reagents to aldimines, while a
higher increase asymmetric induction is observed with
ketimines, because of the major steric hindrance of
alkyl groups (d.r. up 99:1, entry 18). This trend is
similar to that previously seen in the addition of
organolithium reagents. Generally benzylmagnesium
chloride affords aminoalkylphenols with better
diastereoselectivities than the more reactive allylmagne-
sium chloride. When the phenol is replaced with a
pyridine ring lower stereoselectivity is observed (entries
3–5 compared with entries 8, 13, 15, respectively). How-
ever, using imines derived from (R)-1-phenylethylamine
with a coordinating atom in the other aryl group the
addition of organometallic reagents takes place prefer-
entially to the Si face of the double bond of the iminic
function in all cases.
1
explaining the H NMR chemical shift of these prod-
ucts and justifying the configurational assignment.
When imidoylphenols are used as starting materials, an
initial acid–base reaction between the phenolic OH and
the Grignard reagent takes place, forming a reactive
imine–Mg six-membered chelate complex. The bridged
magnesium atom coordinates to both the O and N
atoms and activates the CꢀN double bond towards the
nucleophilic addition, retaining the E configuration (see
Scheme 3).
Subsequently, the complex (R)-5-Mg should coordinate
a second molecule of organomagnesium reagent and
Entry 21 shows the importance of the free OH group:
in fact when it is converted into a methoxy group, the
diastereoselectivity of the addition decreases markedly
from 76% d.e. to 16% d.e. (entries 13 and 21, respec-
tively). This lowering can be explained observing that
the imine (R)-5j exists as a mixture of E/Z isomers in a
2:1 ratio,26 and this invalidates the possibility of a
highly stereoselective addition. On the other hand the
CꢁN bond of imidoylphenols is forced in the E configu-
ration by the presence of the intramolecular hydrogen
bond and the same configuration is retained in the
magnesium six-membered chelate complex intermediate
(R)-5-Mg. Changing the chiral auxiliary (R)-1-
phenylethylamine to the bulkier 1-naphthylethylamine
affords a moderate increase in the diastereoselectivity,
as does the substitution of Cl with Br in the Grignard
reagent.
3. Stereochemistry
The absolute configuration was assigned on the basis of
the chemical shifts general trend observed in the 1H
NMR spectra and the more stable conformations calcu-
lated by molecular modeling. For amines derived from
aldimines it can be seen that the methine proton H-1
bound at the new stereogenic center on the C-1 carbon
atom in the (R,R)-diastereomers is always shifted
upfield compared to the corresponding proton on the
(S,R) diastereomers. This shift was attributed to the
phenyl ring of the auxiliary amine, that exerts a shield-
ing magnetic anisotropy effect on the benzylic H-1
proton in the (R,R) diastereomers, in agreement with
Figure 1. The more stable conformation for the aminophenol
(1S,1%R)-6fa (PM3 semiempirical level minimization).

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C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
4. Conclusion
In summary, a diastereoselective synthesis of enantio-
pure aminoalkylphenols by addition of Grignard
reagents to chiral 2-imidoylphenols and 2-pyridylimines
is reported. These classes of imines are very reactive
towards allylmagnesium chloride and benzylmagnesium
chloride and the reaction takes place rapidly at low
temperature even when enolizable ketimines are used,
allowing the construction of a quaternary stereogenic
centre with high diastereoselectivity (up 99:1 d.r.) and
allowing the preparation of aminophenols that cannot
be prepared with organolithium reagents. The sense of
asymmetric induction was explained and the absolute
configuration of all of the new compounds prepared was
assigned.
Scheme 3.
5. Experimental
5.1. General methods
convert to the amine 6 through a polycyclic transition
state Si-6-TS, which is more stable than Re-6-TS (see
Fig. 2). In this mechanistic hypothesis we have consid-
ered that a molecule of THF, derived from the commer-
cial solution of the Grignard reagents, enters the
coordination sphere of the magnesium atoms. These
transition state models explain both the asymmetric
induction and the high reactivity of the imidoyl phenols
toward the nucleophiles, as a result of the important
role of the oxygen atom in the reaction mechanism. The
asymmetric induction is dictated by the orientation of
the auxiliary group: the nucleophile preferentially
attacks the less hindered Si-p face of the imine (see Fig.
2).
1H and 13C NMR spectra were recorded at 200 or 300
MHz and 50 or 75 MHz, respectively. Chemical shifts
are given in ppm downfield from Me4Si in CDCl3
solution. Coupling constants are given in Hz. IR spectra
were recorded using a FTIR apparatus. Optical rota-
tions were measured in a 1 dm cell at 20°C. All melting
points were uncorrected. All reagents were commercially
available, were purchased at the highest quality and
were purified by distillation when necessary. THF and
toluene were distilled and stored on sodium wire before
use. The following organometallic reagents were used:
AllMgCl (2.0 M, solution in THF), AllMgBr (1.0 M,
solution in Et2O), BnMgCl (2.0 M, solution in THF)
VinylMgCl (1.6 M in THF) and PrMgCl (2.0 M,
solution in THF). Where only the major diastereomer
1
The reaction pathway of imines (R)-5b,c, containing a
pyridine ring, is similar to that of imidoylphenols and
the formation of a five-membered Mg–imine complex is
invoked. Also in this case the attack of the Grignard
reagents takes place preferentially on the Si face of the
double bond.
were obtained pure, the H NMR signals for the minor
diastereomer were deduced from the spectra of the
crude reaction mixture or from enriched chromato-
graphic fractions. When it was impossible to obtain the
aminoalkylphenol with high d.r., the determination of
the optical rotation was omitted.
Figure 2. The (1S,1%R)-6fa-TS and (R,R)-6fa-TS transition structures for the allylation of the imidoylphenol (R)-5f (PM3
semiempirical level minimization).

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
2015
Imines 5a–c, and 5j were prepared by mixing the appro-
priate aldehyde and (R)-1-phenylethylamine on acidic
Al2O3.29 All imidoylphenols 5d–i were prepared by a
solventless procedure.30
5.2.5. (2S)-1-Phenyl-N-[(1R)-1-phenylethyl]-2-pyridin-2-
ylpropan-2-amine, (S,R)-6cb. Oil; [h]2D0 +62.7 (c 1.1,
CHCl3); IR (liquid film): wmax 3337, 1587, 1151, 791,
1
748, 700 cm−1; H NMR (300 MHz, CDCl3): l 1.38 (d,
3H, J=6.6 Hz), 1.43 (s, 3H), 2.32 (br s, 1H), 3.19 (d,
1H, J=12.8 Hz), 3.26 (d, 1H, J=12.8 Hz), 3.91 (q, 1H,
J=6.6 Hz), 6.62–6.72 (m, 2H), 7.00–7.45 (m, 11H),
8.55–8.60 (m, 1H); 13C NMR (75 MHz, CDCl3): l 23.7,
26.8, 48.7, 53.2, 62.2, 121.2, 121.3, 126.0, 126.1, 126.5,
127.6, 128.0, 130.4, 135.5, 138.0, 148.0, 148.4, 165.4.
Anal. calcd for C22H24N2 (316.4): C, 83.50; H, 7.64; N,
8.85. Found: C, 83.45; H, 7.74; N, 8.81%.
5.2. General procedure for the addition of Grignard
reagents to imines, 5a–j
The imines 5a–j (1.0 mmol) were dissolved in dry
toluene (5 mL) under a nitrogen atmosphere and the
solution was cooled to −70°C. The Grignard reagent
(4.0 mmol) was added dropwise and the reaction mix-
ture was stirred for the time required with the tempera-
ture allowed to rise slowly. The reaction mixture was
quenched with NH4Cl saturated solution (5 mL) and
extracted with CH2Cl2 (2×30 mL). The organic layer
was dried with anhydrous Na2SO4, then filtered and the
solvent was removed under reduced pressure. Chro-
matographic separation of the crude oil on silica gel
with AcOEt/cyclohexane (1/30–1/5, v/v) afforded the
pure diastereomers. Amines 6aa31 and 6dc14 were
known compounds. The characterization of the newly
prepared 6ab–6db and 6dd–6ja follows.
5.2.6. (2R)-1-Phenyl-N-[(1R)-1-phenylethyl]-2-pyridin-2-
ylpropan-2-amine, (R,R)-6cb. 1H NMR (300 MHz,
CDCl3): l 1.13 (s, 3H), 1.22 (d, 3H, J=6.6 Hz), 2.40
(br s, 1H), 2.99 (d, 1H, J=12.8 Hz), 3.13 (d, 1H,
J=12.8 Hz), 3.45 (q, 1H, J=6.6 Hz), 6.70–6.75 (m,
2H), 6.98–7.60 (m, 11H), 8.70–8.76 (m, 1H).
5.2.7. 2-((1S)-1-{[(1R)-1-Phenylethyl]amino}but-3-enyl)-
phenol, (S,R)-6da. Oil; [h]2D0 +43.2 (c 0.8, CHCl3); IR
(liquid film): wmax 3303, 1638, 1587, 1256, 1096, 922,
1
755, 699 cm−1; H NMR (300 MHz, CDCl3): l 1.46 (d,
5.2.1. (1S)-2-Phenyl-N-[(1R)-1-phenylethyl]-1-pyridin-2-
ylethan-1-amine, (S,R)-6bb. Oil; [h]2D0 +34.6 (c 1.2,
CHCl3); IR (liquid film): wmax 3324, 1590, 1370, 1126,
3H, J=6.6 Hz), 2.30 (br s, 1H), 2.49–2.57 (m, 2H), 3.86
(q, 1H, J=6.6 Hz), 3.98 (t, 1H, J=7.0 Hz), 5.10–5.24
(m, 2H), 5.66–5.86 (m, 1H), 6.70–7.40 (m, 9H), 11.50
(br s, 1H); 13C NMR (75 MHz, CDCl3): l 20.2, 40.3,
54.3, 59.8, 117.0, 119.1, 125.3, 126.6, 127.3, 128.4,
128.5, 128.6, 128.7, 134.6, 143.7, 157.5. Anal. calcd for
C18H21NO (267.4): C, 80.86; H, 7.92; N, 5.24. Found:
C, 80.80; H, 7.96; N, 5.21%.
1
748, 700 cm−1; H NMR (300 MHz, CDCl3): l 1.31 (d,
3H, J=6.6 Hz), 1.89 (br s, 1H), 3.04 (dd, 1H, J=13.2,
7.3 Hz), 3.13 (dd, 1H, J=13.2, 6.6 Hz), 3.75 (q, 1H,
J=6.6 Hz), 4.02 (t, 1H, J=7.0 Hz), 6.85–7.50 (m,
13H), 8.65–8.70 (m, 1H); 13C NMR (75 MHz, CDCl3):
l 22.8, 42.5, 55.3, 62.9, 121.5, 122.3, 125.9, 126.4, 126.5,
127.9, 128.0, 129.1, 135.6, 138.6, 145.5, 149.0, 162.5.
Anal. calcd for C21H22N2 (302.4): C, 83.40; H, 7.33; N,
9.26. Found: C, 83.45; H, 7.30; N, 9.28%.
5.2.8. 2-((1R)-1-{[(1R)-1-Phenylethyl]amino}but-3-enyl)-
phenol [(R,R)-6da]. 1H NMR (300 MHz, CDCl3): l 1.43
(d, 3H, J=7.0 Hz), 2.30 (br s, 1H), 2.38–2.47 (m, 2H),
3.50 (dd, 1H, J=9.3, 5.3 Hz), 3.74 (q, 1H, J=7.0 Hz),
5.10–5.26 (m, 2H), 5.48–5.65 (m, 1H), 6.70–5–7.50 (m,
9H), 11.50 (br s, 1H).
5.2.2. (1R)-2-Phenyl-N-[(1R)-1-phenylethyl]-1-pyridin-2-
ylethan-1-amine, (R,R)-6bb. 1H NMR (300 MHz,
CDCl3): l 1.25 (d, 3H, J=6.7 Hz), 2.14 (br s, 1H), 2.91
(dd, 1H, J=13.4, 8.2 Hz), 3.01 (dd, 1H, J=13.4, 6.4
Hz), 3.45 (q, 1H, J=6.7 Hz), 3.70 (dd, 1H, J=8.2, 6.4
Hz), 6.90–7.65 (m, 13H), 8.60–8.65 (m, 1H).
5.2.9. 2-((1S)-2-Phenyl-1-{[(1R)-1-phenylethyl]amino}-
ethyl)phenol, (S,R)-6db. Oil; [h]2D0 +29.4 (c 1.2, CHCl3);
IR (liquid film): wmax 3305, 1587, 1492, 1255, 1099, 756,
1
699 cm−1; H NMR (300 MHz, CDCl3): l 1.20 (d, 3H,
5.2.3. (2S)-N-[(1R)-1-Phenylethyl]-2-pyridin-2-ylpent-4-
en-2-amine, (S,R)-6ca. Oil; [h]2D0 +30.7 (c 1.2, CHCl3);
IR (liquid film): wmax 3334, 1638, 1587, 1154, 913, 749,
J=6.6 Hz), 2.10 (br s, 1H), 2.91 (dd, 1H, J=13.9, 9.0
Hz), 3.00 (dd, 1H, J=13.9, 5.9 Hz), 3.72 (q, 1H, J=6.6
Hz), 4.08 (dd, 1H, J=9.0, 5.9 Hz), 6.55–7.30 (m, 14H),
11.80 (br s, 1H); 13C NMR (75 MHz, CDCl3): l 19.9,
42.3, 54.4, 62.4, 117.2, 119.2, 125.3, 126.3, 126.6, 127.1,
127.5, 128.7, 128.8, 128.9, 129.3, 137.9, 143.8, 157.7.
Anal. calcd for C22H23NO (317.4): C, 83.24; H, 7.30; N,
4.41. Found: C, 83.20; H, 7.36; N, 4.35%.
1
701 cm−1; H NMR (300 MHz, CDCl3): l 1.31 (d, 3H,
J=6.6 Hz), 1.39 (s, 3H), 2.16 (br s, 1H), 2.55–2.75 (m,
2H), 3.78 (q, 1H, J=6.6 Hz), 4.93–5.03 (m, 2H), 5.39–
5.56 (m, 1H), 7.03–7.57 (m, 8H), 8.50–8.56 (m, 1H); 13
C
NMR (75 MHz, CDCl3): l 25.5, 26.8, 45.6, 53.2, 61.1,
117.9, 121.0, 121.3, 126.4, 126.7, 128.2, 135.0, 135.9,
148.3, 148.7, 166.2. Anal. calcd for C18H22N2O (266.4):
C, 81.16; H, 8.32; N, 10.52. Found: C, 81.10; H, 8.35;
N, 10.47%.
5.2.10. 2-((1R)-2-Phenyl-1-{[(1R)-1-phenylethyl]amino}-
1
ethyl)phenol, (R,R)-6db. H NMR (300 MHz, CDCl3):
l 1.30 (d, 3H, J=6.6 Hz), 2.07 (br s, 1H), 2.92–3.01 (m,
2H), 3.57–3.75 (m, 2H), 6.60–7.40 (m, 14H), 11.70 (br s,
1H).
5.2.4. (2R)-N-[(1R)-1-Phenylethyl]-2-pyridin-2-ylpent-4-
1
en-2-amine, (R,R)-6ca. H NMR (300 MHz, CDCl3): l
1.20 (d, 3H, J=6.6 Hz), 1.21 (s, 3H), 2.35 (br s, 1H),
2.51 (br d, 2H, J=7.3 Hz), 3.48 (q, 1H, J=6.6 Hz),
4.89–5.02 (m, 2H), 5.48–5.69 (m, 1H), 7.10–7.40 (m,
7H), 7.60–7.70 (m, 1H), 8.60–8.65 (m, 1H).
5.2.11.
2-((1R)-1-{[(1R)-1-Phenylethyl]amino}prop-2-
enyl)phenol, (R,R)-6dd. Oil; [h]2D0 +2.6 (c=0.7, CHCl3,
d.r.= 70:30); IR (liquid film): wmax 3298, 1639, 1587,

2016
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
1254, 1100, 755, 700 cm−1; 1H NMR (300 MHz,
CDCl3): l 1.48 (d, 3H, J=6.6 Hz), 2.05 (br s, 1H), 3.80
(q, 1H, J=6.6 Hz), 4.13 (d, 1H, J=7.3 Hz), 5.05–5.14
(m, 2H), 5.89–6.10 (m, 1H), 6.70–7.50 (m, 9H), 11.50
(br s, 1H); 13C NMR (75 MHz, CDCl3): l 23.3, 54.9,
63.4, 116.1, 116.9, 119.3, 126.3, 126.9, 127.6, 127.0,
128.8, 128.8, 137.9, 143.3, 157.7. Anal. calcd for
C17H19NO (253.3): C, 80.60; H, 7.56; N, 5.53. Found:
C, 81.72; H, 7.51; N, 5.48%.
5.2.17. 2-((1S)-1-Methyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol, (S,R)-6fa. Oil; [h]2D0 +1.5 (c 3.1,
CHCl3); IR (liquid film): wmax 3298, 1638, 1608, 1583,
1253, 1092, 752, 700 cm−1; 1H NMR (300 MHz,
CDCl3): l 1.36 (d, 3H, J=7.0 Hz), 1.42 (s, 3H), 2.10
(br s, 1H), 2.66–2.88 (m, 2H), 4.01 (q, 1H, J=7.0 Hz),
5.21 (d, 1H, J=10.6 Hz), 5.22 (d, 1H, J=16.5 Hz),
5.60–5.82 (m, 1H), 6.70–7.40 (m, 9H), 12.28 (br s, 1H);
13C NMR (75 MHz, CDCl3): l 24.7, 26.1, 42.1, 52.9,
60.4, 117.3, 118.7, 119.9, 125.8, 126.5, 127.3, 128.6,
128.8, 129.3, 133.3, 145.5, 157.7. Anal. calcd for
C19H23NO (281.4): C, 81.10; H, 8.24; N, 4.98. Found:
C, 81.00; H, 8.36; N, 4.87%.
5.2.12.
2-((1S)-1-{[(1R)-1-Phenylethyl]amino}prop-2-
1
enyl)phenol, (S,R)-6dd. H NMR (300 MHz, CDCl3): l
1.50 (d, 3H, J=6.6 Hz), 2.05 (br s, 1H), 4.01 (q, 1H,
J=6.6 Hz), 4.26 (d, 1H, J=8.4 Hz), 5.15 (dd, 1H,
J=17.4, 1.6 Hz), 5.34 (dd, 1H, J=10.1, 1.6 Hz), 5.89–
6.10 (m, 1H), 6.75–7.40 (m, 9H), 11.50 (br s, 1H).
5.2.18. 2-((1R)-1-Methyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol, (R,R)-6fa. 1H NMR (300 MHz,
CDCl3): l 1.27 (d, 3H, J=7.0 Hz), 1.43 (s, 3H), 2.05
(br s, 1H), 2.40–2.60 (m, 2H), 3.94 (q, 1H, J=7.0 Hz),
5.09 (d, 1H, J=16.8 Hz), 5.11 (d, 1H, J=10.3 Hz),
5.45–5.70 (m, 1H), 6.40–6.70 (m, 9H), 12.70 (br s, 1H).
5.2.13.
2-(1-{[1-(1-Naphthyl)ethyl]amino}but-3-enyl)-
phenol, (S*,R*)-6ea. Oil; IR (liquid film): wmax 3303,
1638, 1588, 1257, 922, 798, 755 cm−1; H NMR (300
1
MHz, CDCl3): l 1.59 (d, 3H, J=6.6 Hz), 2.56 (t, 2H,
J=7.1 Hz), 2.60 (br s, 1H), 4.09 (t, 1H, J=7.1 Hz),
4.75 (q, 1H, J=6.6 Hz), 5.14–5.24 (m, 2H), 5.62–5.83
(m, 1H), 6.70–8.00 (m, 11H), 11.30 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l 21.4, 40.6, 49.6, 59.8, 117.2,
119.2, 119.3, 122.4, 123.0, 125.5, 125.7, 125.8, 126.2,
127.9, 128.6, 128.7, 129.1, 130.8, 134.1, 134.9, 140.1,
157.8. Anal. calcd for C22H23NO (317.4): C, 83.24; H,
7.30; N, 4.41. Found: C, 83.29; H, 7.23; N, 4.52%.
5.2.19.
2-((1S)-1-Methyl-2-phenyl-1-{[(1R)-1-phenyl-
ethyl]amino}ethyl)phenol, (S,R)-6fb. Oil; [h]2D0 +95.0 (c
1.6, CHCl3); IR (liquid film): wmax 3298, 1604, 1582,
1252, 1089, 753, 700 cm−1; 1H NMR (300 MHz,
CDCl3): l 1.36 (d, 3H, J=6.7 Hz), 1.51 (s, 3H), 1.98
(br s, 1H), 3.06 (d, 1H, J=13.1 Hz), 3.19 (d, 1H,
J=13.1 Hz), 3.91 (q, 1H, J=6.7 Hz), 6.57–7.20 (m,
14H), 11.95 (br s, 1H,); 13C NMR (75 MHz, CDCl3): l
24.2, 25.9, 46.2, 52.7, 61.5, 117.0, 118.5, 126.4, 126.6,
126.8, 127.1, 128.0, 128.3, 128.6, 128.7, 130.7, 136.6,
144.9, 157.4. Anal. calcd for C23H25NO (331.5): C,
83.34; H, 7.60; N, 4.23. Found: C, 83.45; H, 7.51; N,
4.26%.
5.2.14.
2-(1-{[1-(1-Naphthyl)ethyl]amino}but-3-enyl)-
1
phenol, (R*,R*)-6ea. Oil; H NMR (300 MHz, CDCl3):
l 1.55 (d, 3H, J=7.0 Hz), 2.35–2.75 (m, 3H), 3.56 (dd,
1H, J=9.5, 4.8 Hz), 4.71 (br q, 1H, J=7.0 Hz), 5.20 (d,
1H, J=16.5 Hz), 5.21 (d, 1H, J=10.6 Hz), 5.50–5.72
(m, 1H), 6.60–8.00 (m, 11H), 12.00 (br s, 1H). Anal.
calcd for C22H23NO (317.4): C, 83.24; H, 7.30; N, 4.41.
Found: C, 83.15; H, 7.41; N, 4.37%.
5.2.20.
2-((1R)-1-Methyl-2-phenyl-1-{[(1R)-1-phenyl-
ethyl]amino}ethyl)phenol [(R,R)-6fb]. 1H NMR (300
MHz, CDCl3): l 1.25 (d, 3H, J=6.7 Hz), 1.30 (s, 3H),
2.19 (br s, 1H), 2.89 (d, 1H, J=12.8 Hz), 3.01 (d, 1H,
J=12.8 Hz), 3.91 (q, 1H, J=6.7 Hz), 6.60–7.35 (m,
14H), 12.80 (br s, 1H).
5.2.15. 2-(1-{[1-(1-Naphthyl)ethyl]amino}-2-phenylethyl)-
phenol, (S*,R*)-6eb. Oil; IR (liquid film): wmax 3306,
1
1588, 1494, 1455, 1257, 910, 755, 700 cm−1; H NMR
5.2.21. 2-(1-Methyl-1-{[1-(1-naphthyl)ethyl]amino}but-3-
(300 MHz, CDCl3): l 1.40 (d, 3H, J=6.6 Hz), 2.15 (br
s, 1H), 3.02 (dd, 1H, J=13.2, 9.2 Hz), 3.12 (dd, 1H,
J=13.2, 5.8 Hz), 4.25 (dd, 1H, J=9.2, 5.8 Hz), 4.67 (br
q, 1H, J=6.6 Hz), 6.70–7.90 (m, 16H), 11.40 (br s, 1H);
13C NMR (75 MHz, CDCl3): l 20.8, 42.5, 49.8, 62.1,
117.3, 119.2, 122.4, 122.8, 125.5, 125.7, 126.2, 127.1,
127.9, 128.7, 128.8, 128.9, 129.1, 129.2, 129.3, 130.7,
134.1, 137.7, 139.9, 157.8. Anal. calcd for C26H25NO
(367.5): C, 84.98; H, 6.86; N, 3.81. Found: C, 84.85; H,
6.97; N, 3.75%.
enyl)phenol, (S*,R*)-6ga. Oil; IR (liquid film): wmax
3303, 1608, 1583, 1463, 1253, 912, 778, 753 cm−1; H
1
NMR (300 MHz, CDCl3): l 1.42 (s, 3H), 1.50 (d, 3H,
J=6.6 Hz), 2.28 (br s, 1H), 2.83 (d, 2H, J=7.0 Hz),
4.80–4.96 (m, 1H), 5.18 (dd, 1H, J=9.9, 2.2 Hz), 5.21
(dd, 1H, J=17.2, 1.8 Hz), 5.58–5.82 (m, 1H), 6.70–8.10
(m, 11H), 12.40 (br s, 1H); 13C NMR (75 MHz,
CDCl3): l 25.4, 26.5, 42.1, 47.5, 61.0, 117.6, 119.0,
120.0, 122.5, 123.7, 125.7, 125.9, 126.2, 126.3, 127.7,
128.9, 129.4, 129.6, 130.1, 133.4, 134.1, 142.4, 158.0.
Anal. calcd for C23H25NO (331.4): C, 83.34; H, 7.60; N,
4.32. Found: C, 83.21; H, 7.71; N, 4.26%.
5.2.16. 2-(1-{[1-(1-Naphthyl)ethyl]amino}-2-phenylethyl)-
phenol, (R*,R*)-6eb. White crystals; mp 163–166°C (n-
1
hexane–AcOEt); H NMR (300 MHz, CDCl3): l 1.43
5.2.22. 2-((1S)-1-Ethyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol [(S,R)-6ha]. Oil; [h]2D0 −28.0 (c 3.0,
CHCl3); IR (liquid film): wmax 3306, 1638, 1606, 1583,
1252, 1094, 753, 700 cm−1; 1H NMR (300 MHz,
CDCl3): l 0.57 (t, 3H, J=7.5 Hz), 1.28 (d, 3H, J=6.6
Hz), 1.56 (sext, 1H, J=7.0 Hz), 1.92 (br sext, 1H,
(d, 3H, J=7.0 Hz), 2.47 (br d, 1H, J=11.4 Hz),
2.91–3.07 (m, 2H), 3.70 (dd, 1H, J=8.8, 6.2 Hz), 4.61
(br s, 1H), 6.45–7.95 (m, 16H), 12.10 (br s, 1H). Anal.
calcd for C26H25NO (367.5): C, 84.98; H, 6.86; N, 3.81.
Found: C, 85.05; H, 6.97; N, 3.88%.

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
2017
J=7.0 Hz), 2.19 (br s, 1H), 2.75–2.95 (m, 2H), 4.09
(q, 1H, J=6.6 Hz), 5.21 (dt, 1H, J=9.9, 1.1 Hz), 5.25
(dt, 1H, J=17.0, 1.1 Hz), 5.55–5.80 (m, 1H), 6.70–7.40
(m, 9H), 12.75 (br s, 1H); 13C NMR (75 MHz,
CDCl3): l 8.4, 23.5, 29.8, 36.2, 53.0, 63.5, 117.3, 118.4,
119.7, 126.6, 126.9, 127.0, 127.4, 128.6, 128.8, 132.8,
145.8, 158.2. Anal. calcd for C20H25NO (295.4): C,
81.31; H, 8.53; N, 4.74. Found: C, 81.45; H, 8.62; N,
4.62%.
129.1, 130.2, 130.7, 135.3, 144.5, 146.1, 157.7. Anal.
calcd for C28H27NO (393.5): C, 85.46; H, 6.92; N,
3.56. Found: C, 85.58; H, 6.87; N, 3.69%.
5.2.28.
2-((1S)-1,2-Diphenyl-1-{[(1R)-1-phenylethyl]-
amino}ethyl)phenol, (S,R)-6ib. 1H NMR (300 MHz,
CDCl3): l 1.23 (d, 3H, J=6.6 Hz), 2.68 (br s, 1H),
3.39 (d, 1H, J=13.9 Hz), 3.70 (d, 1H, J=13.9 Hz),
3.86 (q, 1H, J=6.6 Hz), 6.30–7.50 (m, 19H), 11.25 (br
s, 1H).
5.2.23. 2-((1R)-1-Ethyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol, (R,R)-6ha. 1H NMR (300 MHz,
CDCl3): l 0.82 (t, 3H, J=7.3 Hz), 1.28 (d, 3H, J=6.6
Hz), 2.05–2.35 (m, 3H), 2.65–2.75 (m, 2H), 3.96 (q,
1H, J=6.6 Hz), 4.84–4.98 (m, 2H), 5.25–5.45 (m, 1H),
6.70–7.40 (m, 9H), 12.70 (br s, 1H).
5.2.29. N-[1-(2-Methoxyphenyl)-1-methylbut-3-enyl]-N-
[(1R)-1-phenylethyl]amine, major diastereomer. Oil;
[h]2D0 +66.9 (c 0.97, CHCl3); IR (liquid film): wmax 3360,
1
1638, 1598, 1237, 1028, 910, 752, 700 cm−1; H NMR
(300 MHz, CDCl3): l 1.33 (d, 3H, J=6.6 Hz), 1.52 (s,
3H), 2.40 (dd, 1H, J=13.4, 7.9 Hz), 2.81 (dd, 1H,
J=13.4, 6.8 Hz), 3.00 (br s, 1H), 3.39 (s, 3H), 3.44 (q,
1H, J=6.6 Hz), 4.83–4.96 (m, 2H), 5.34–5.54 (m, 1H),
6.60–7.30 (m, 9H); 13C NMR (75 MHz, CDCl3): l
25.3, 26.6, 45.1, 53.5, 54.1, 59.9, 110.6, 116.5, 119.9,
126.2, 126.3, 127.8, 128.0, 128.6, 133.1, 135.6, 147.9,
157.5. Anal. calcd for C20H25NO (295.4): C, 81.31; H,
8.53; N, 4.74. Found: C, 81.25; H, 8.63; N, 4.62%.
5.2.24. 2-((1S)-1-Ethyl-2-phenyl-1-{[(1R)-1-phenylethyl]-
amino}ethyl)phenol, (S,R)-6hb. Oil; [h]2D0 +83.51 (c 1.2,
CHCl3); IR (liquid film): wmax 3306, 1605, 1583, 1251,
1
1078, 753, 701 cm−1; H NMR (300 MHz, CDCl3): l
0.68 (t, 3H, J=7.3 Hz), 1.37 (d, 3H, J=6.7 Hz), 1.80
(q, 2H, J=7.3 Hz), 2.33 (br s, 1H), 3.15 (d, 1H,
J=13.4 Hz), 3.40 (d, 1H, J=13.4 Hz), 4.11 (q, 1H,
J=6.7 Hz), 6.56–7.30 (m, 14H), 12.65 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l 7.8, 25.4, 26.6, 41.1, 52.4,
65.4, 117.2, 118.1, 118.5, 126.4, 126.5, 127.4, 127.8,
128.6, 128.7, 128.9, 130.5, 136.7, 145.1, 158.3. Anal.
calcd for C24H27NO (345.5): C, 83.44; H, 7.88; N,
4.05. Found: C, 83.32; H, 7.96; N, 4.12%.
5.2.30. N-[1-(2-Methoxyphenyl)-1-methylbut-3-enyl]-N-
1
[(1R)-1-phenylethyl]amine, minus diastereomer. Oil; H
NMR (300 MHz, CDCl3): l 1.09 (s, 3H), 1.16 (d, 3H,
J=6.9 Hz), 2.54 (dd, 1H, J=13.3, 7.9 Hz), 2.75 (br s,
1H), 2.88 (dd, 1H, J=13.3, 6.6 Hz), 3.44 (q, 1H,
J=6.9 Hz), 3.88 (s, 3H), 4.85–5.00 (m, 2H), 5.44–5.65
(m, 1H), 6.90–7.40 (m, 9H). Anal. calcd for C20H25NO
(295.4): C, 81.31; H, 8.53; N, 4.74. Found: C, 81.39;
H, 8.65; N, 4.78%.
5.2.25. 2-((1R)-1-Phenyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol, (R,R)-6ia. Oil; [h]2D0 +52.9 (c 1.6,
CHCl3); IR (liquid film): wmax 3296, 1604, 1583, 1251,
912, 756, 699 cm−1; 1H NMR (300 MHz, CDCl3):
l=1.32 (d, 3H, J=6.7 Hz), 2.75 (br s, 1H), 3.09 (d,
2H, J=7.0 Hz), 3.87 (q, 1H, J=6.7 Hz), 4.83 (dd, 1H,
J=17.1, 1.5 Hz), 4.93 (dd, 1H, J=10.2, 1.4 Hz), 5.20–
5.45 (m, 1H), 6.75–7.70 (m, 14H), 11.85 (br s, 1H);
13C NMR (75 MHz, CDCl3): l 24.6, 41.0, 53.4, 66.6,
117.7, 119.0, 119.8, 126.6, 126.8, 127.0, 127.4, 127.7,
128.2, 128.9, 129.2, 129.6, 133.0, 144.2, 146.0, 158.0.
Anal. calcd for C24H25NO (343.5): C, 83.93; H, 7.34;
N, 4.08. Found: C, 84.03; H, 7.25; N, 4.03%.
5.3. Addition of MeMgCl and PhMgCl to imidoyophe-
nol (R)-5h in the presence of BF3·Et2O: formation of
the borate, (R)-7h
(R)-5h (0.253g, 1.0 mmol) was dissolved in dry toluene
(5 mL), under a nitrogen atmosphere and BF3·Et2O
(0.2 mL, 1.6 mmol) was added. The solution was
stirred for 10 min at room temperature, then cooled to
−70°C and the Grignard reagent (4.0 mmol) was
added dropwise. The reaction mixture was stirred for
4 h and the temperature slowly allowed to rise. The
reaction mixture was quenched with NH4Cl saturated
solution (5 mL) and extracted with CH2Cl2 (2×30
mL). The organic layer was dried with anhydrous
Na2SO4, then filtered and the solvent was removed
under reduced pressure. Chromatographic purification
of the crude oil on silica gel with AcOEt/cyclohexane
(1/9–1/1, v/v) afforded the borate (R)-7h in 88% yield:
Oil; IR (liquid film): wmax 1644, 1610, 1561, 1318 cm−1;
1H NMR (300 MHz, CDCl3): l 0.92 (t, 3H, J=7.7
Hz), 1.98 (d, 3H, J=6.7 Hz), 2.66–3.00 (m, 2H), 5.72
(q, 1H, J=6.7 Hz), 6.90–7.60 (m, 9H). Anal. calcd for
C17H18BF2NO (301.1): C, 67.80; H, 6.02; N, 4.65.
Found: C, 67.65; H, 6.17; N, 4.62%.
5.2.26. 2-((1S)-1-Phenyl-1-{[(1R)-1-phenylethyl]amino}-
but-3-enyl)phenol [(S,R)-6ia]. 1H NMR (300 MHz,
CDCl3): l=1.18 (d, 3H, J=6.6 Hz), 2.77 (dd, 1H,
J=14.5, 6.8 Hz), 2.80 (br s, 1H), 2.99 (dd, 1H, J=
14.5, 7.0 Hz), 3.65 (q, 1H, J=6.6 Hz), 4.75 (dd, 1H,
J=16.8, 1.5 Hz), 4.85 (br d, 1H, J=8.1 Hz), 5.22–5.45
(m, 1H), 6.60–7.60 (m, 14H), 12.40 (br s, 1H).
5.2.27.
2-((1R)-1,2-Diphenyl-1-{[(1R)-1-phenylethyl]-
amino}ethyl)phenol [(R,R)-6ib]. Oil; [h]2D0 +61.8 (c 2,
CHCl3); IR (liquid film): wmax 3310, 1583, 1494, 1252,
754, 699 cm−1; H NMR (300 MHz, CDCl3): l 1.28
1
(d, 3H, J=6.6 Hz), 2.65 (br s, 1H), 3.70–3.85 (m, 2H),
4.18 (q, 1H, J=6.6 Hz), 6.39–6.44 (m, 2H), 6.80–7.45
(m, 17H), 11.20 (br s, 1H); 13C NMR (75 MHz,
CDCl3): l 24.1, 42.2, 53.6, 66.6, 117.5, 118.9, 126.4,
126.5, 126.6, 126.7, 127.0, 127.3, 127.7, 127.8, 128.8,

2018
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2011–2018
14. Palmieri, G. Eur. J. Org. Chem. 1999, 805–811.
Acknowledgements
15. Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron 2001,
57, 6089–6096.
16. Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron 2001,
57, 6809–6814.
Financial support from Ministero dell’Universita` e
della Ricerca Scientifica e Tecnologica, Rome, and the
University
of
Camerino
(National
Project
‘Stereoselezione in Sintesi Organica. Metodologie ed
applicazioni’) is gratefully acknowledged.
17. Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J.
Org. Chem. 2001, 66, 4759–4765.
18. Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 3361–
3373.
19. Cimarelli, C.; Palmieri, G.; Volpini, E. J. Org. Chem.
2002, 67, in press.
20. Seyferth, D.; Weiner, M. A. J. Org. Chem. 1961, 26,
4797–4800.
21. Dowd, S. R.; Stork, G. J. Am. Chem. Soc. 1963, 85,
2178–2180.
22. Fuson, R. C.; Lokken, R. J.; Pedrotti, R. L. J. Am.
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