A practical stereoselective synthesis of secondary and tertiary aminonaphthols: Chiral ligands for enantioselective catalysts in the addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(02)00651-1

A practical procedure for the stereoselective synthesis of a wide group of functionalized aminoalkylnaphthols, using inexpensive starting materials, is reported. Selective N-alkylation was carried out by cyclization of secondary aminoalkylnaphthols with formaldehyde, followed by reduction or alkylation with organometallic reagents. The catalytic activity of this class of compounds was tested in the addition of diethylzinc to benzaldehyde, resulting in moderate to good enantioselectivities. It is noteworthy that the aminonaphthols obtained as the major diastereomer in the solvent free synthesis, have the best asymmetric induction properties in the alkylation reaction.

Full text of DOI:10.1016/S0957-4166(02)00651-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2417–2426
A practical stereoselective synthesis of secondary and tertiary
aminonaphthols: chiral ligands for enantioselective catalysts in
the addition of diethylzinc to benzaldehyde
Cristina Cimarelli, Gianni Palmieri* and Emanuela Volpini
Dipartimento di Scienze Chimiche, Universita` di Camerino, Via S. Agostino, 1, I-62032 Camerino, Italy
Received 3 August 2002; accepted 8 October 2002
Abstract—A practical procedure for the stereoselective synthesis of a wide group of functionalized aminoalkylnaphthols, using
inexpensive starting materials, is reported. Selective N-alkylation was carried out by cyclization of secondary aminoalkylnaphthols
with formaldehyde, followed by reduction or alkylation with organometallic reagents. The catalytic activity of this class of
compounds was tested in the addition of diethylzinc to benzaldehyde, resulting in moderate to good enantioselectivities. It is
noteworthy that the aminonaphthols obtained as the major diastereomer in the solvent free synthesis, have the best asymmetric
induction properties in the alkylation reaction. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
the final 1-(a-aminobenzyl)-2-naphthol as a racemate.
We have found that the condensation of 2-naphthol
with benzaldehyde and (R)-(+)-1-phenylethylamine
affords the aminonaphthol 3j directly, practically as a
single (R,R) diastereoisomer, by using a solvent free
synthesis (93% yield; 99:1 d.r.).14,22 The catalytic activ-
ity of (R,R)-3j in the enantioselective addition of
diethylzinc to benzaldehyde is good and the corre-
sponding (S)-1-phenylpropanol is obtained in 89% yield
and 87% e.e.14 Moreover, aminoalkylnaphthols can be
regarded as aromatic Mannich type bases and they
therefore represent useful synthetic intermediates in
organic synthesis because the amino moiety can be
The search for new chiral ligands, which can be
efficiently applied in asymmetric catalysis, is a field of
great interest in modern organic chemistry. In the last
few years, the enantioselective alkylation of carbonyl
compounds has been the subject of considerable devel-
opment, owing to the use of dialkylzinc reagents1–3 in
the presence of a variety of chiral ligands, such as
b-amino alcohols,4–6 amino thiols7–10 and pyridyl alco-
hols.11–13 In a previous work, we have found that the
enantiopure aminoalkylphenol (R,R)-7 is a useful cata-
lyst for the enantioselective addition of dialkylzincs to
aldehydes (see Scheme 1).14 Moreover, this class of
compound can be prepared easily by the reduction15 or
alkylation16 of 2-imidoylphenols17,18 and by reduction
of 4H-chromen-4-ylideneamines.19
Aminoalkylnaphthols, prepared for the first time by
Betti at the beginning of the 20th century,20 have
recently attracted new interest due to their application
in asymmetric catalysis.14,21–25 As a result, the demand
for practical and straightforward asymmetric syntheses
of these compounds, starting from inexpensive reagents
has increased dramatically. The condensation of 2-
naphthol with ammonia and benzaldehyde produces
* 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 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00651-1

2418
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
converted into a variety of other functionalities.26,27
Herein, we report on the preparation of both secondary
and tertiary, aminoalkylnaphthols, and the study of
their catalytic activity towards the addition of diethyl-
zinc to benzaldehyde.
2-phenylethanol or (R)-(+)-1-(1-naphthyl)ethylamine as
chiral auxiliaries, (Table 1, entries 6 and 7). In both
cases the yields and the stereoselectivities observed in
the condensations with 2-naphthol and benzaldehyde
are lower than those previously obtained with the use
of (R)-(+)-1-phenylethylamine.14,22
A mechanism is given in Scheme 2. It is assumed that
an aldiminium type complex (A) is initially formed
through protonation of the CꢀN nitrogen. In this
iminium species there is an enhancement reactivity of
both the electrophilic iminium carbon atom and the
nucleophilic naphthol. In the first step of this Friedel–
Crafts type reaction, the rate-limiting stage of the whole
reaction, the arenium |-complex ul-(Re,Si )-(R,R)-3j-¬
(C) is formed through a six-membered transition state
ul-(Re,Si )-(R,R)-3j-TS (B) as shown in Scheme 2. The
relative stability of the transition state 3j-TS calculated
for all four possible combinations, at the semi-empirical
PM3 level, are in agreement with the stereoselectivity
observed for this Mannich type reaction. As shown in
2. Results and discussion
A series of novel secondary aminoalkylnaphthols 3a–i
were prepared by heating a mixture of 2-naphthol,
amines 1a–c and aldehydes 2a–h, in a molar ratio
1.0:1.05:1.20, respectively, at 60°C, under solvent free
conditions (see Scheme for Table 1).14,22 The results are
listed in Table 1. In the presence of (R)-(+)-1-
phenylethylamine, aromatic aldehydes reacted with
yields from moderate to good and good d.r. (Table 1,
entries 1–5). When heteroaromatic aldehydes were used,
the reactivity and yields decreased in relation to the
heteroatom, in the order: N>O>S. Besides (R)-(+)-1-
phenylethylamine, it is possible to use (R)-(−)-2-amino-
Table 1. Synthesis of secondary aminoalkylnaphthols 3a–i
Entry
1
R1
2
R2
3a
Time (h)
Yieldb (%)
d.r.c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1c
1c
(R)-PhCHMe
(R)-PhCHMe
(R)-PhCHMe
(R)-PhCHMe
2a
2b
2c
2d
2e
2f
2f
2g
2h
2-Pyridyl
2-Furyl
2-Thienyl
2-MeOC6H5
C6F5
C6H5
C6H5
iPr
Cyclohexyl
(1S,1%R)-3a
(1S,1%R)-3b
(1S,1%R)-3c
(1S,1%R)-3d
(1S,1%R)-3e
(1S,1%R)-3f
(R,R)-3g
8
9
18
9
8
8
14
30
30
95
70
45
75
65
66
80
47
48
71/29
81/19
84/16
75/25
67/33
78/22
80/20
79/21
80/20
(R)-PhCHMe
(R)-PhCHCH2OH
(R)-(1-Naphthyl)CHMe
(R)-(1-Naphthyl)CHMe
(R)-(1-Naphthyl)CHMe
(R,R)-3h
(R,R)-3i
a Configuration of the major diastereomer.
b Combined yields of the two diastereomers.
c The d.r. value was determined by 1H NMR of the reaction mixture.
Scheme 2. The mechanism hypothesis for the Mannich type diastereoselective aminoalkylation of 2-naphthol, with the rationaliza-
tion of the asymmetric induction on the basis of molecular modelling calculation at the semi-empirical PM3 level.

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
2419
Figure 1. Unlike (ul) transition structures for the formation of the (R,R)- and (1S,1%R)-3j, optimized at the PM3 semi-empirical
level (see Scheme 2).
to those obtained by molecular modelling (see Fig. 2),
thus validating the computational analysis.
Scheme 2 and Fig. 1 the two diastereoselective unlike
approaches are favoured and, in particular the CꢁC
forming bond lies between the a-Re naphthol face and
the diastereotopic Si face of the immonium type elec-
trophile. The moderate ZEatt calculated for 3j (0.61
kcal/mol) is in agreement with the diastereoselectivity
observed experimentally for this reaction (34–68% d.e.
in the Table 1). The high diastereoselectivity observed
experimentally in the specific case of (R,R)-3j (d.e.
98%)22 and some other aminonaphthols is due to a
transformation of a second kind, induced by the prefer-
ential crystallization of the diastereomer (R,R)-3j.
Generally, it has been reported in the literature that
ligands containing tertiary amino groups are better
catalysts than those containing secondary ones. Thus,
we became interested in the preparation of tertiary
aminoalkylnaphthols. Previously these compounds were
prepared by direct condensation of 2-naphthol with
aldehydes and secondary amines,28–33 aminoalkylation
The configuration of aminoalkylnaphthols 3a–i was
assigned on the basis of the general trend observed in
1
the H NMR chemical shifts: the signals of H-1 atom,
bonded at the stereogenic C-1 carbon atom, and of H-1%
proton on the chiral auxiliary group in the major
diastereomer are always shifted upfield in comparison
to the corresponding signals from the minor
diastereomer (Dl: 0.34–0.61 ppm for H-1 atom and Dl:
0.02–0.11 for H-1% atom). These shifts can be rational-
ized by observing the preferred conformation of the
respective aminoalkylnaphthols obtained by molecular
modelling conformational analysis (see Fig. 2).15,22,40 As
it is possible to see, in the major diastereomer the
naphthyl ring of the auxiliary amine exerts a shielding
magnetic anisotropy effect on the H-1 proton while the
naphthyl group shields the H-1% proton. The validity of
this diagnostic tool was confirmed by X-ray analysis on
analogous aminonaphthols:22–24 in fact, experimental
structures, obtained by X-ray analysis, are very similar
Figure 2. Conformational analysis of the aminonaphthol
(R,R)-3h, minimized at the semi-empirical PM3 level.

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C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
Scheme 3. Reagents and conditions: (i) CH2O, THF/H2O, rt,
15 h; (ii) R4M, toluene, 0°C; (iii) NaBH(OAc)3/AcOH, THF,
0°C.
Figure 3. Epimerization of the aminonaphthols (R,R)-5j and
(R,R)-6e in CHCl3 solution.
(R,R)-4j,k. The reduction takes place in an acidic
medium (AcOH) with NaHB(OAc)3 as reducting agent,
affording N-methylaminolkylnaphthols (R,R)-5j,k (see
Scheme 3 and Table 2).
of aromatic compounds with iminium salts,34,35 by dis-
placement of the benzotriazole moiety from N-[a-
(dialkylamino)alkyl]benzotriazole with naphtholate
anions36 and additionally, by treatment of a protected
The opening of the N-O cyclic acetal with organometal-
lic reagents allows the introduction of a variety of
N-substituents on the aminonaphthols (see Scheme 3
and Table 3). The reaction occurs in toluene at 0°C,
while it fails at lower temperature (−70°C). Under these
conditions the alkylation took place quickly and with
high yields, except when PhLi and MeMgCl were used
(Table 3, entries 4 and 5). Tertiary aminoalkylnaph-
thols crystallize in diastereomerically pure (R,R) form.
However, when the crystals are dissolved in CHCl3 or
CDCl3, a moderate spontaneous epimerization at the
C-1 carbon atom takes place.38,39 This phenomenon
2-hydroxy-1-naphthaldehyde
with
(trimethylsilyl)-
dialkylamines and various nucleophiles in the presence
of lithium perchlorate.37 All of these methods use only
simple secondary amines, such as dimethylamine and
diethylamine, or cyclic amines, such as morpholine and
piperidine. In a previous work we developed a method-
ology for the preparation of tertiary aminoalkylphenols
by cyclization of secondary aminoalkylphenols with
formaldehyde, followed by reduction or alkylation of
the intermediate benzoxazines.38 We now report the
application of this methodology to aminoalkylnaph-
thols. Enantiopure aminonaphthols (R,R)-3j,k can be
readily cyclized with formaldehyde to naphthoxazines
1
was followed by recording H NMR spectra or measur-
Table 2. Reduction of 2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines 4j,k to aminonaphthols 5j,k
Entry
4
R3
5
Time (h)
Yielda (%)
1
2
(R,R)-4j
(R,R)-4k
H
Me
(R,R)-5j
(R,R)-5k
4
3
63
50
a Isolated yields.
Table 3. Alkylation of the 2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine 4j to aminonaphthols 6a–f
Entry
R4M
(R,R)-6
Time (h)
Yielda (%)
d.r.b
1
2
3
4
5
6
7
BnMgCl
n-BuLi
PhMgCl
PhLi
MeMgCl
AllMgCl
CH2=CHMgCl
(R,R)-6a
(R,R)-6b
(R,R)-6c
(R,R)-6c
(R,R)-6d
(R,R)-6e
(R,R)-6f
1
2
1
2
4
1
1
96
92
95
58
76
92
98
96/4
97/3
96/4
80/20
90/10
95/5
97/3
a Isolated yields.
b The d.r. value was determined by 1H NMR of the crude reaction mixture.

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
2421
ing the specific rotation at various times, as reported in
Fig. 3. When the steric hindrance from the N-sub-
stituent increases, the epimerization becomes more
important: in fact after 15 days a solution of N-methyl-
aminonaphthol (R,R)-5j results in a mixture of (R,R)-
and (1S,1%R)-5j with d.r. of 82:18, while after 8 days
only N-3-butenylaminonaphthol (R,R)-6e affords a
diastereomeric mixture of 75:25, with (R,R)-6e as the
major diastereomer.
with 89 and 87% e.e., respectively. Both diastereomers
of compound 3d were tested in the addition reaction
(Table 4, entries 5 and 6), affording alcohols of oppo-
site configuration and with very different enantioselec-
tivities. It is notable that the 1S,1%R diastereomer, the
one obtained as major product in the solvent free
synthesis, gives the best asymmetric induction in the
alkylation reaction. The change of the (R)-(+)-1-
phenylethylamine chiral auxiliary with (R)-(−)-2-amino-
2-phenylethanol produces ligands (1S,1%R)-3f and
(R,R)-3f which gave poor asymmetric induction. On the
other hand the aminolkylnaphthol (R,R)-3g containing
the (1-naphthyl)ethyl group affords the (S)-1-phenyl-
propanol with a good 81% e.e. Aromatic R2 sub-
The catalytic activity of these aminoalkylnaphthols was
tested in the enantioselective addition of diethylzinc to
benzaldehyde. The results obtained are reported in
Table 4. The stereoselectivity of the addition increases
with the use of larger amounts of the aminoalkylnaph-
thol as catalyst (Table 4, entries 13–15). The use of 10
mol% of ligand is the better compromise solution for
(R,R)-5j; a greater quantity (15 mol%) of (R,R)-5j only
leads to a moderate increase in the stereoselectivity
(86% e.e.), significantly lower than that reported by
Wang and co-workers.24
stituents
on
aminoalkylnaphthols
are
better
substituents than aliphatic ones and determinate higher
enantioselectivities (Table 4, entries 10–12). Tertiary
aminoalkylnaphthols produce enantioselectivities from
moderate to good (58–85% e.e.). The best results were
obtained using compounds (R,R)-5j,k and (R,R)-6f,
which have N-Me and N-allyl groups. Lengthening of
the aliphatic chain on the amino moiety, such as in
(R,R)-6b and (R,R)-6e, led to a slight decrease in the
stereoselectivity.
With the secondary aminoalkylnaphthols derived from
heteroaromatic aldehydes, the stereoselectivity is lower
(Table 4, entries 1–4) than that observed for (R,R)-3j.14
Therefore, the introduction of a third coordination site
in the ligand does not afford better catalytic activity.
Aminolkylnaphthols (1S,1%R)-3d and (1S,1%R)-3e, con-
taining R2=o-MeC6H4 and R2=C6F5, gave higher
enantioselectivities, affording the (S)-1-phenylpropanol
3. Conclusion
In summary a practical procedure for the stereoselective
synthesis of a wide group of functionalized aminoalkyl-
Table 4. Diethylzinc addition to benzaldehyde in the presence of aminoalkylnaphthols 3, 5, 6
Entry
Cat.
Mol. (%)
Time (h)
Yielda (%)
% e.e.b
Config.c
1
2
3
4
5
6
7
8
(1S,1%R)-3a
(R,R)-3a
(1S,1%R)-3b
(1S,1%R)-3c
(1S,1%R)-3d
(R,R)-3d
(1S,1%R)-3e
(1S,1%R)-3f
(R,R)-3f
(R,R)-3g
(R,R)-3h
(R,R)-3i
(R,R)-5j
(R,R)-5j
10
10
10
10
10
10
10
10
10
10
10
10
6
10
15
10
10
10
10
10
10
24
4
7
17
4
4
24
4
24
4
7
7
4
4
2
5
5
5
5
5
86
86
53
87
81
79
85
26
68
84
73
77
97
87
90
97
95
84
88
93
86
20
16
60
58
89
16
87
12
15
81
17
40
74
84
86
85
72
77
58
78
85
R
S
S
S
S
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
9
10
11
12
13
14
15
16
17
18
19
20
21
(R,R)-5j
(R,R)-5k
(R,R)-6a
(R,R)-6b
(R,R)-6c
(R,R)-6e
(R,R)-6f
5
a Isolated yields.
b Determined by integration of peaks in GLC using a chiral stationary phase.41
c Absolute configuration of the obtained major enantiomer determined by the sign of the specific rotation and the relative retention times in
capilliary chiral phase GLC analysis.41

2422
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
naphthols from inexpensive starting materials is
reported. Selective N-alkylation was carried out by
cyclization of secondary aminoalkylnaphthols with
formaldehyde, followed by reduction or alkylation with
organometallic reagents. The catalytic activity of this
class of compounds was tested in the addition of
diethylzinc to benzaldehyde, resulting in moderate to
good enantioselectivities. It is worth noting that the
aminonaphthols, obtained as major diastereomers in
the solvent free synthesis gave the best asymmetric
induction in the alkylation.
148.6, 157.6, 159.2. Anal. calcd for C24H22N2O (354.4):
C, 81.33; H, 6.26; N, 7.90. Found: C, 81.42; H, 6.39; N,
7.75%.
4.2.2.
1-[(R)-{[(1%R)-1%-Phenylethyl]amino}(pyridin-2-
yl)methyl]-2-naphthol, (1R,1%R)-3a. Oil; [h]2D0=+4.3 (c
1.9, CHCl3); IR (liquid film): wmax 3298, 1620, 1592,
1270, 1236, 749 cm−1; H NMR (300 MHz, CDCl3): l
1
1.64 (d, 3H, J=6.6 Hz), 4.00 (q, 1H, J=6.6 Hz), 4.25
(br s, 1H), 6.04 (s, 1H), 6.83 (d, 1H, J=8.1 Hz),
7.10–8.70 (m, 14H), 13.45 (br s, 1H); 13C NMR (75
MHz, CDCl3): l 20.6, 55.4, 59.6, 113.6, 120.3, 120.9,
122.1, 122.5, 122.6, 126.7, 126.8, 127.3, 128.4, 128.5,
128.9, 129.9, 133.3, 137.2, 143.5, 148.8, 157.1, 159.5.
Anal. calcd for C24H22N2O (354.4): C, 81.33; H, 6.26;
N, 7.90. Found: C, 81.21, H 6.40, N 7.95%.
4. Experimental
4.1. General methods
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 spec-
tra were recorded using a FTIR apparatus. Optical
rotations were measured in a 1 dm cell at 20°C. All
melting points were uncorrected. All reagents were
commerially available, were purchased at the highest
quality and were purified by distillation when neces-
sary. THF and toluene were distilled and stored on
sodium wire before use. The following organometallic
reagents were used: BuLi (2.5 M, solution in hexane),
PhLi (1.8 M, solution in cyclohexane/diethylether),
MeMgCl (3.0 M, solution in THF), AllMgCl (2.0 M,
solution in THF), VinylMgCl (1.6 M, solution in
THF), PhMgCl (2.0 M, solution in THF), BnMgCl (2.0
M, solution in THF). Commercial (R)-(+)-1-
phenylethylamine (96% e.e.) was used. Where only the
4.2.3.
1-[(S)-2-Furyl{[(1%R)-1%-phenylethyl]amino}-
methyl]-2-naphthol, (1S,1%R)-3b. Yellow crystals; mp
87–89°C (EtOH); [h]2D0=−121.7 (c 2.1, CHCl3); IR
(Nujol): wmax 3312, 1622, 1601, 1265, 1235, 738 cm−1; 1H
NMR (300 MHz, CDCl3): l 1.52 (d, 3H, J=6.9 Hz),
2.76 (br s, 1H), 3.87 (br q, 1H, J=6.9 Hz), 5.59 (s, 1H),
5.77 (d, 1H, J=3.3 Hz), 6.17 (dd, 1H, J=3.3, 1.9 Hz),
7.15–7.40 (m, 10H), 7.70–7.80 (m, 2H), 13.00 (br s, 1H);
13C NMR (75 MHz, CDCl3): l 23.7, 53.6, 56.1, 108.4,
111.1, 111.7, 120.5, 121.4, 123.0, 127.0, 127.1, 128.3,
129.0, 129.2, 129.4, 130.6, 133.2, 142.8, 143.2, 154.0,
157.9. Anal. calcd for C23H21NO2 (343.4): C, 80.44; H,
6.16; N, 4.08. Found: C, 80.57; H, 6.09; N, 4.00%.
4.2.4.
1-[(R)-2-Furyl{[(1%R)-1%-phenylethyl]amino}-
methyl]-2-naphthol, (R,R)-3b. 1H NMR (300 MHz,
CDCl3): l 1.58 (d, 3H, J=6.6 Hz), 2.76 (br s, 1H), 3.95
(q, 1H, J=6.6 Hz), 5.95 (d, 1H, J=3.3 Hz), 5.99 (s,
1H), 6.22 (dd, 1H, J=3.3, 2.0 Hz), 7.15–7.40 (m, 10H),
7.70–7.80 (m, 2H), 13.00 (br s, 1H).
1
major diastereomer was obtained pure, the H NMR
signals for the minor diastereomer were deduced from
the spectra of the crude reaction mixture or from
enriched chromatographic fractions.
4.2.5.
1-[(S)-2-Thienyl{[(1%R)-1%-phenylethyl]amino}-
methyl]-2-naphthol, (1S,1%R)-3c. White crystals; mp
133–136°C (CH2Cl2–hexane); [h]2D0=−154.6 (c 1.3,
CHCl3); IR (Nujol): wmax 3272, 1624, 1602, 1268, 1240,
4.2. General procedure for the preparation of
aminoalkylnaphthols 3a–k
1
1092, 747, 703 cm−1; H NMR (300 MHz, CDCl3): l
A mixture of 2-naphthol (0.72 g, 5.0 mmol), amine 1a–c
(5.25 mmol) and aldehyde 2a–h (6.0 mmol) was stirred
at 60°C under a nitrogen atmosphere for the time
required (see Table 1). Aminoalkylnaphthols 3a–i were
purified by flash cromatography directly from the reac-
tion mixture, without any work-up. Spectral data of
(R,R)-3j and (R,R)-3k were according to those reported
in Ref. 22. The characterization of the newly prepared
aminolkylnaphthols 3a–i follows.
1.52 (d, 3H, J=6.9 Hz), 2.47 (br s, 1H), 3.89 (br s, 1H),
5.73 (s, 1H), 6.80–7.80 (m, 14H), 13.30 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l 23.6, 55.2, 56.7, 114.1,
120.6, 121.3, 123.0, 125.6, 125.9, 127.0, 127.1, 127.4,
128.4, 129.1, 129.3, 129.5, 130.5, 132.8, 143.3, 145.4,
157.2. Anal. calcd for C23H21NOS (359.5): C, 76.84; H,
5.89; N, 3.90; S 8.92. Found: C, 76.70; H, 5.97; N, 3.98,
S 8.71%.
4.2.6.
1-[(R)-2-Thienyl{[(1%R)-1%-phenylethyl]amino}-
1
4.2.1.
1-[(S)-{[(1%R)-1%-Phenylethyl]amino}(pyridin-2-
methyl]-2-naphthol, (1R,1%R)-3c. H NMR (300 MHz,
CDCl3): l 1.59 (d, 3H, J=6.6 Hz), 2.47 (br s, 1H), 4.00
(q, 1H, J=6.6 Hz), 6.13 (s, 1H), 6.80–7.80 (m, 14H),
13.30 (br s, 1H).
yl)methyl]-2-naphthol, (1S,1%R)-3a. White crystals; mp
135–138°C (EtOH); [h]2D0=+10.9 (c 1.9, CHCl3); IR
(Nujol): wmax 3291, 1621, 1590, 1272, 1237, 748 cm−1; 1H
NMR (300 MHz, CDCl3): l 1.55 (d, 3H, J=7.0 Hz),
3.91 (q, 1H, J=7.0 Hz), 4.25 (br s, 1H), 5.54 (s, 1H),
6.63 (d, 1H, J=7.9 Hz), 7.00–8.65 (m, 14H), 13.45 (br
s, 1H); 13C NMR (75 MHz, CDCl3): l 23.7, 55.5, 58.6,
113.4, 120.2, 121.1, 121.8, 122.3, 122.5, 126.7, 126.8,
127.5, 128.5, 128.7, 128.8, 130.0, 133.7, 136.8, 143.2,
4.2.7. 1-[(S)-(2-Methoxyphenyl){[(1%R)-1%-phenylethyl]-
amino}methyl]-2-naphthol, (1S,1%R)-3d. White crystals;
mp 146–149°C (EtOH); [h]2D0=−267.5 (c 1.7, CHCl3);
IR (Nujol): wmax 3294, 1621, 1600, 1241, 1097, 1028, 742

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
2423
cm−1; 1H NMR (300 MHz, CDCl3): l 1.49 (d, 3H,
J=6.8 Hz), 2.52 (br s, 1H), 3.74 (s, 3H), 3.89 (br s, 1H),
5.86 (s, 1H), 6.60–7.80 (m, 15H), 13.80 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l 22.9, 54.8, 55.5, 57.3, 110.8,
113.5, 120.4, 121.5, 121.8, 122.9, 126.8, 127.8, 128.1,
128.6, 128.8, 129.1, 129.5, 129.7, 129.9, 130.1, 133.2,
143.3, 157.0, 158.5. Anal. calcd for C26H25NO2 (383.5):
C, 81.43; H, 6.57; N, 3.65. Found: C, 81.60; H, 6.63; N,
3.60%.
C25H23NO2 (369.5): C, 81.27; H, 6.27; N, 3.79. Found:
C, 81.34; H, 6.15; N, 3.61%.
4.2.12. 1-[(R)-Phenyl{[(1%R)-2-hydroxy-1%-phenylethyl]-
amino}methyl]-2-naphthol, (R,R)-3f. Oil; [h]2D0=−179.3
(c 1.3, CHCl3); IR (liquid film): wmax 3307, 1620, 1603,
1268, 1237, 735, 700 cm−1; 1H NMR (300 MHz,
CDCl3): l 3.78–4.00 (m, 2H), 4.05–4.10 (m, 1H), 4.50–
6.30 (br s, 3H), 5.91 (s, 1H), 7.15–7.75 (m, 16H); 13C
NMR (75 MHz, CDCl3): l 61.0, 62.0, 65.0, 114.9,
120.7, 121.6, 122.9, 127.0, 127.7, 128.4, 128.5, 129.1,
129.2, 129.3, 129.5, 129.7, 130.2, 132.8, 139.4, 141.5,
157.0. Anal. calcd for C25H23NO2 (369.5): C, 81.27, H
6.27, N 3.79. Found: C, 81.33; H, 6.21; N, 3.89%.
4.2.8. 1-[(R)-(2-Methoxyphenyl){[(1%R)-1%-phenylethyl]-
amino}methyl]-2-naphthol, (R,R)-3d. White crystals; mp
151–155°C (EtOH); [h]2D0=+213.2 (c 2.2, CHCl3); IR
(Nujol): wmax 3293, 1620, 1600, 1243, 1095, 1028, 740
cm−1; 1H NMR (300 MHz, CDCl3): l 1.64 (d, 3H,
J=6.6 Hz), 2.30 (br s, 1H), 4.00 (q, 1H, J=6.6 Hz),
4.04 (s, 3H), 6.42 (s, 1H), 6.70–7.80 (m, 15H), 13.50 (br
s, 1H); 13C NMR (75 MHz, CDCl3): l 20.1, 54.1, 55.5,
55.8, 110.4, 113.1, 120.1, 121.2, 121.3, 122.3, 126.4,
126.5, 126.7, 127.2, 128.3, 128.5, 128.6, 128.7, 129.3,
129.5, 132.8, 143.8, 156.4, 157.8. Anal. calcd for
C26H25NO2 (383.5): C, 81.43; H, 6.57; N, 3.65. Found:
C, 81.50; H, 6.49; N, 3.57%.
4.2.13. 1-[(R)-Phenyl{[(1%R)-1%-(1-naphthyl)ethyl]amino}-
methyl]-2-naphthol, (R,R)-3g. White crystals; mp 159–
162°C (CH2Cl2–hexane); [h]2D0=−288.1 (c 1.0, CHCl3);
IR (Nujol): wmax 3320, 1621, 1589, 1270, 1237, 779, 744
cm−1; 1H NMR (300 MHz, CDCl3): l 1.65 (d, 3H,
J=6.6 Hz), 2.61 (br s, 1H), 4.90 (m, 1H), 5.51 (s, 1H),
7.00–7.95 (m, 18H), 13.95 (br s, 1H); 13C NMR (75
MHz, CDCl3): l 23.1, 51.3, 61.2, 113.5, 120.1, 121.2,
122.3, 122.5, 125.3, 125.6, 125.7, 125.8, 126.2, 126.3,
127.7, 128.0, 128.2, 128.3, 128.6, 128.7, 128.9, 129.1,
129.8, 132.1, 132.6, 141.6, 157.2. Anal. calcd for
C29H25NO (403.5): C, 86.32; H, 6.24; N, 3.47. Found:
C, 86.47; H, 6.29; N, 3.33%.
4.2.9.
1-[(S)-(2,3,4,5,6-Pentafluorophenyl){[(1%R)-1%-
phenylethyl]amino}methyl]-2-naphthol,
(1S,1%R)-3e.
White crystals; mp 159–163°C (CH2Cl2–hexane); [h]2D0=
−251.0 (c 1.1, CHCl3); IR (Nujol): wmax 3292, 1653,
1624, 1602, 1274, 1237, 820, 745, 701 cm−1; H NMR
1
(300 MHz, CDCl3): l 1.57 (d, 3H, J=6.6 Hz), 2.15 (br
s, 1H), 3.99 (m, 1H), 5.91 (s, 1H), 7.10–7.80 (m, 11H),
13.05 (br s, 1H); 13C NMR (75 MHz, CDCl3): l 22.8,
50.6, 57.0, 108.6, 115.2 (m), 119.7, 120.2, 122.5, 126.5,
127.0, 128.2, 128.6, 129.0, 129.1, 130.5, 132.2, 137.6
(dm, J=247.6), 141.0 (dm, J=248.8), 141.9, 145.03
(dm, J=252.0), 158.1. Anal. calcd for C25H18F5NO
(443.4): C, 67.72; H, 4.09; N, 3.16. Found: C, 67.90; H,
4.15; N, 3.12%.
4.2.14. 1-[(S)-Phenyl{[(1%R)-1%-(1-naphthyl)ethyl]amino}-
1
methyl]-2-naphthol, (1S,1%R)-3g. H NMR (300 MHz,
CDCl3): l 1.70 (d, 3H, J=6.6 Hz), 2.00 (br s, 1H), 4.89
(m, 1H), 5.99 (s, 1H), 7.00–8.00 (m, 18H), 13.30 (br s,
1H).
4.2.15. 1-[(1R)-2-Methyl-1-{[(1%R)-1%-(1-naphthyl)ethyl]-
amino}propyl]-2-naphthol, (R,R)-3h. White crystals; mp
147–150°C (hexane); [h]2D0=−193.1 (c 0.9, CHCl3); IR
(Nujol): wmax 3326, 2962, 1621, 1599, 1270, 1236, 778,
1
4.2.10.
1-[(R)-(2,3,4,5,6-Pentafluorophenyl){[(1%R)-1%-
745 cm−1; H NMR (300 MHz, CDCl3): l 0.76 (d, 3H,
phenylethyl]amino}methyl]-2-naphthol, (R,R)-3e. White
crystals; mp 142–144°C (CH2Cl2–hexane); [h]2D0=+226.4
(c 1.0, CHCl3); IR (Nujol): wmax 3301, 1652, 1624, 1522,
J=7.0 Hz), 0.99 (d, 3H, J=6.6 Hz), 1.62 (d, 3H, J=6.6
Hz), 2.07–2.32 (m, 1H), 2.52 (br s, 1H), 4.21 (d, 1H,
J=5.9 Hz), 4.68 (br s, 1H), 7.00–7.95 (m, 13H), 13.40
(br s, 1H); 13C NMR (75 MHz, CDCl3): l 18.3, 20.4,
23.4, 32.9, 50.2, 61.7, 115.2, 119.9, 121.8, 122.2, 122.7,
125.7, 125.9, 126.0, 126.3, 128.1, 128.7, 128.8, 128.9,
129.0, 129.3, 131.6, 133.5, 134.0, 140.3, 156.9. Anal.
calcd for C26H27NO (369.5): C, 84.51; H, 7.37; N, 3.79.
Found: C, 84.37; H, 7.45; N, 3.86%.
1
1275, 1236, 820, 747, 701 cm−1; H NMR (300 MHz,
CDCl3): l 1.63 (d, 3H, J=6.6 Hz), 2.15 (br s, 1H), 4.04
(q, 1H, J=6.6), 6.29 (s, 1H), 7.05–7.80 (m, 11H), 12.60
(br s, 1H); 13C NMR (75 MHz, CDCl3): l 21.6, 51.0,
56.3, 109.6, 115.5 (tm, J=16.5), 120.0, 120.7, 122.7,
126.6, 127.2, 128.1, 128.7, 129.1, 129.3, 130.7, 132.2,
140.0 (dm, J=253.1), 141.2 (dm, J=253.7), 142.4,
142.9 (dm, J=249.2), 157.8. Anal. calcd for
C25H18F5NO (443.4): C, 67.72; H, 4.09; N, 3.16. Found:
C, 67.88; H, 4.01; N, 3.09%.
4.2.16. 1-[(1S)-2-Methyl-1-{[(1%R)-1%-(1-naphthyl)ethyl]-
amino}propyl]-2-naphthol, (1S,1%R)-3h. 1H NMR (300
MHz, CDCl3): l 0.89 (d, 3H, J=7.0 Hz), 1.11 (d, 3H,
J=6.6 Hz), 1.64 (d, 3H, J=6.6 Hz), 2.15–2.50 (m, 2H),
4.75 (q, 1H, J=6.6 Hz), 4.81 (d, 1H, J=6.2 Hz),
7.00–8.00 (m, 13H), 12.80 (br s, 1H).
4.2.11. 1-[(S)-Phenyl{[(1%R)-2-hydroxy-1%-phenylethyl]-
amino}methyl]-2-naphthol, (1S,1%R)-3f. Oil; [h]2D0=
+139.4 (c 2.9, CHCl3); IR (liquid film): wmax 3309, 1622,
1
1601, 1269, 1236, 736, 699 cm−1; H NMR (300 MHz,
4.2.17. 1-[(1R)-Cyclohexyl{[(1%R)-1%-(1-naphthyl)ethyl]-
amino}methyl]-2-naphthol, (R,R)-3i. White crystals;
mp 155–158°C (CH2Cl2); [h]2D0=−227.5 (c 1.03,
CHCl3); IR (Nujol): wmax 3337, 2923, 1619, 1597, 1578,
1269, 1235, 780, 749 cm−1; 1H NMR (300 MHz,
CDCl3): l 0.90–1.35 (m, 6H), 1.50–1.97 (m, 5H), 1.60
CDCl3): l 3.78–4.00 (m, 3H), 4.50–6.30 (br s, 3H), 5.55
(s, 1H), 7.15–7.75 (m, 16H); 13C NMR (75 MHz,
CDCl3): l 60.5, 63.0, 66.8, 113.6, 120.5, 121.6, 123.0,
127.0, 128.1, 128.2, 128.6, 128.9, 129.0, 129.1, 129.3,
129.6, 130.4, 133.1, 139.4, 141.6, 157.2. Anal. calcd for

2424
C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
(d, 3H, J=7.0 Hz), 2.59 (br s, 1H), 4.22 (d, 1H, J=5.9
Hz), 4.67 (br s, 1H), 7.00–7.90 (m, 13H), 13.40 (br s,
1H); 13C NMR (75 MHz, CDCl3): l 23.4, 26.1, 26.2,
26.3, 28.9, 30.5, 42.6, 50.0, 60.9, 115.0, 119.7, 121.7,
122.0, 122.6, 125.5, 125.6, 125.7, 126.0, 127.9, 128.5,
128.6, 128.7, 128.8, 129.1, 131.3, 133.4, 133.8, 140.3,
156.8. Anal. calcd for C29H31NO (409.6): C, 85.04; H,
7.63; N, 3.42. Found: C, 84.91; H, 7.84; N, 3.49%.
monitored by TLC, until complete consumption of the
starting naphthoxazine. Then saturated Na2CO3 was
added and when the development of CO2 was ceased
the organic layer was extracted with CH2Cl2, dried with
anhydrous Na2SO4, filtered and the solvent was evapo-
rated under reduced pressure. The chromatographic
purification over SiO2 (cyclohexane–AcOEt=90:10) of
the crude oil afforded the N-methylaminonaphthols
(R,R)-5j,k.
4.2.18. 1-[(1S)-Cyclohexyl{[(1%R)-1%-(1-naphthyl)ethyl]-
amino}methyl]-2-naphthol, (1S,1%R)-3i. Oil; [h]2D0=+33.2
(c 1.0, CHCl3); IR (liquid film): wmax 3331, 2922, 1621,
4.4.1.
1-[(1R)-Phenyl{methyl[(1%R)-1%-phenylethyl]-
amino}methyl]-2-naphthol, (R,R)-5j. White crystals; mp
157–160°C (CH2Cl2–hexane); [h]2D0=−270.5 (c 1.0,
CHCl3); IR (Nujol): wmax 1622, 1601, 1267, 1237, 736,
1
1599, 1519, 1269, 1234, 778, 741 cm−1; H NMR (300
MHz, CDCl3): l 1.00–1.50 (m, 6H), 1.55–2.10 (m, 5H),
1.63 (d, 3H, J=6.6 Hz), 2.25 (br s, 1H), 4.69 (q, 1H,
J=6.6 Hz), 4.83 (d, 1H, J=6.2 Hz), 7.00–8.00 (m,
13H), 12.70 (br s, 1H); 13C NMR (75 MHz, CDCl3): l
20.9, 26.2, 26.3, 26.4, 29.4, 30.7, 42.5, 49.6, 60.0, 115.0,
120.1, 121.5, 122.1, 122.2, 122.9, 125.3, 125.6, 126.1,
126.2, 127.8, 128.6, 128.9, 129.0, 129.1, 130.6, 133.5,
133.9, 140.2, 156.8. Anal. calcd for C29H31NO (409.6):
C, 85.04; H, 7.63; N, 3.42. Found: C, 85.19; H, 7.78; N,
3.30%.
701 cm−1; H NMR (300 MHz, CDCl3): l 1.55 (d, 3H,
1
J=6.6 Hz), 2.14 (s, 3H), 4.25 (br q, 1H, J=6.6 Hz),
5.37 (s, 1H), 7.10–8.00 (m, 16H), 14.00 (br s, 1H); 13C
NMR (75 MHz, CDCl3): l 19.0, 33.2, 57.4, 68.6, 116.4,
120.2, 121.2, 122.6, 126.7, 127.9, 128.2, 128.4, 128.5,
128.8, 129.0, 129.1, 129.2, 129.3, 129.8, 132.3, 140.3,
156.1. Anal. calcd for C26H25NO (367.5): C, 84.98; H,
6.86; N, 3.81. Found: C, 84.79; H, 7.12; N, 3.69%.
4.4.2.
1-[(1R)-(4-Methylphenyl){methyl[(1%R)-1%-
4.3. General procedure for the preparation of the naph-
phenylethyl]amino}methyl]-2-naphthol, (R,R)-5k. White
crystals; mp 155–160°C (hexane); [h]2D0=−238.5 (c 1.08,
CHCl3); IR (Nujol): wmax 1621, 1600, 1581, 1519, 1267,
thoxazines (R,R)-4j,k
Aminonaphthols (R,R)-3j,k (2 mmol) were dissolved in
THF (3 mL) and 35% aqueous formaldehyde (0.17 mL,
2.2 mmol) was added. The solution was stirred for 15
hours at room temperature. Solvent was removed and
the residue was dried under reduced pressure. The
crude oil was purified by filtration through a SiO2 pad
eluting with cyclohexane/AcOEt (97/3). Spectral data of
(R,R)-4j were according to that reported in Ref. 22.
The characterization of the newly prepared naphthox-
azine (R,R)-4k follows.
1237, 819, 742 cm−1; H NMR (300 MHz, CDCl3): l
1
1.54 (d, 3H, J=7.0 Hz), 2.14 (s, 3H), 2.26 (s, 3H), 4.24
(q, 1H, J=7.0 Hz), 5.34 (s, 1H), 7.00–8.00 (m, 15H),
14.10 (br s, 1H); 13C NMR (75 MHz, CDCl3): l 19.0,
21.2, 33.1, 57.2, 68.3, 116.6, 120.1, 121.2, 122.6, 123.0,
126.6, 127.8, 128.5, 128.6, 129.0, 129.2, 129.3, 129.6,
131.4, 132.3, 137.2, 137.8, 156.0. Anal. calcd for
C27H27NO (381.5): C, 85.00; H, 7.13; N, 3.67. Found:
C, 85.12; H, 7.03; N, 3.59%.
4.5. General procedure for the alkylation of the naph-
4.3.1. (1R)-1-(4-Methylphenyl)-2-[(1%R)-1%-phenylethyl]-
thoxazine (R,R)-4j with organometallic reagents
2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine,
(R,R)-4k.
White crystals; mp 125–127°C (EtOH); [h]2D0=−177.7 (c
1.0, CHCl3); IR (Nujol): wmax 3022, 2974, 1509, 1233,
The naphthoxazine (R,R)-4j (2.0 mmol) was dissolved
in anhydrous toluene (3 mL) under a nitrogen atmo-
sphere and then cooled to 0°C with an ice-water bath.
Then the organometallic reagent (1.5 mmol) was added
and the solution was stirred at 0°C for 1 hour. The
reaction mixture was quenched with saturated aqueous
ammonium chloride (10 mL) and extracted with
CH2Cl2 (3 x 20 mL). The organic layer was dried with
anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The tertiary aminonaphthols
(R,R)-6a–c and (R,R)-6e were purified by crystalliza-
tion from the crude oil.
1
950, 907 cm−1; H NMR (300 MHz, CDCl3): l 1.59 (d,
3H, J=6.6 Hz), 2.32 (s, 3H), 4.02 (q, 1H, J=6.6 Hz),
5.01 (d, 1H, J=10.3 Hz), 5.19 (dd, 1H, J=10.3, 1.8
Hz), 5.21 (s, 1H), 6.90–7.50 (m, 13H), 7.80–7.90 (m,
2H); 13C NMR (75 MHz, CDCl3): l 21.1, 21.7, 56.9,
59.1, 74.4, 112.4, 118.5, 122.6, 123.1, 126.5, 127.5,
127.8, 127.9, 128.5, 128.6, 128.7, 128.8, 129.0, 132.9,
136.8, 140.3, 145.5, 152.8. Anal. calcd for C27H25NO
(379.5): C, 85.45; H, 6.64; N, 3.69. Found: C, 85.32; H,
6.79; N, 3.77%.
4.4. General procedure for the reduction of the naph-
thoxazines (R,R)-4j,k
4.5.1.
1-[(1R)-Phenyl{phenethyl[(1%R)-1%-phenylethyl]-
amino}methyl]-2-naphthol, (R,R)-6a. White crystals; mp
122–125°C (hexane); [h]2D0=−295.0 (c 1.0, CHCl3); IR
(Nujol): wmax 1621, 1600, 1583, 1453, 1267, 1236, 745,
To a solution of naphthoxazine (R,R)-4j,k (2.0 mmol)
in THF (3.5 mL), NaBH4 (0.151 g, 4.0 mmol) was
added. Then the reaction mixture, cooled to 0°C, was
vigorously stirred and a solution of AcOH (2 mL) in
THF (3 mL) was slowly added. At the end of the
addition, the temperature of the mixture was raised to
room temperature. The course of the reaction was
1
700 cm−1; H NMR (300 MHz, CDCl3): l 1.62 (d, 3H,
J=7.0 Hz), 2.19–2.30 (m, 1H), 2.35–2.65 (m, 2H),
3.00–3.25 (m, 1H), 4.33 (q, 1H, J=7.0 Hz), 5.52 (s,
1H), 6.70 (d, 2H, J=7.32 Hz), 7.00–7.90 (m, 19H),
13.90 (s, 1H); 13C NMR (75 MHz, CDCl3): l

C. Cimarelli et al. / Tetrahedron: Asymmetry 13 (2002) 2417–2426
2425
19.1, 38.1, 48.1, 58.8, 67.7, 116.4, 119.9, 121.0, 122.5,
126.1, 126.5, 127.9, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 128.7, 128.9, 129.0, 129.7, 130.2, 130.4, 131.8,
139.6, 156.4. Anal. calcd for C33H31NO (457.6): C,
86.61; H, 6.83; N, 3.06. Found: C, 86.73; H, 6.94; N,
2.94%.
(407.5): C, 85.47; H, 7.17; N, 3.44. Found: C, 85.37; H,
7.03; N, 3.51%.
4.5.6. 1-[(1R)-Phenyl{allyl[(1%R)-1%-phenylethyl]amino}-
methyl]-2-naphthol, (R,R)-6f. Oil; [h]2D0=−234.3 (c 1.0,
CHCl3); IR (liquid film): wmax 1621, 1600, 1267, 1236,
1
781, 744 cm−1; H NMR (300 MHz, CDCl3): l 1.64 (d,
4.5.2. 1-[(1R)-Phenyl{pentyl[(1%R)-1%-phenylethyl]amino}-
methyl]-2-naphthol, (R,R)-6b. White crystals; mp 103–
106°C (hexane); [h]2D0=−256.3 (c 0.8, CHCl3); IR
(Nujol): wmax 1621, 1601, 1268, 1237, 742 cm−1; 1H
NMR (300 MHz, CDCl3): l 0.71 (t, 3H, J=6.6 Hz),
0.77–1.25 (m, 6H), 1.61 (d, 3H, J=6.6 Hz), 2.10–2.50
(m, 1H), 2.75–3.00 (m, 1H), 4.30 (q, 1H, J=6.6 Hz),
5.50 (s, 1H), 7.05–8.00 (m, 16H), 14.30 (s, 1H); 13C
NMR (75 MHz, CDCl3): l 13.8, 19.4, 22.1, 29.6, 30.4,
46.2, 57.8, 67.7, 116.5 120.9, 122.4, 126.4, 127.4, 127.7,
128.0, 128.2, 128.3, 128.5, 128.8, 129.0, 129.5, 129.6,
129.9, 131.9, 139.9, 156.2. Anal. calcd for C30H33NO
(423.6): C, 85.06; H, 7.85; N, 3.31. Found: C, 84.98; H,
7.94; N, 3.26%.
1H, J=7.0 Hz), 3.01–3.25 (m, 1H), 3.53 (dd, 1H,
J=15.4, 5.9 Hz), 4.36 (q, 1H, J=7.0 Hz), 4.70 (dd, 1H,
J=17.2, 1.3 Hz), 4.78 (dd, 1H, J=10.3, 1.3 Hz), 5.53–
5.76 (m, 1H), 5.66 (s, 1H), 7.15–8.00 (m, 16H), 13.90 (s,
1H); 13C NMR (75 MHz, CDCl3): l 14.3, 49.8, 58.0,
67.2, 116.7, 120.1, 121.1, 122.6, 126.6, 127.7, 127.9,
128.1, 128.2, 128.5, 128.6, 128.7, 128.9, 129.0, 129.2,
129.8, 132.0, 136.2, 140.0, 156.2. Anal. calcd for
C28H27NO (393.5): C, 85.46; H, 6.92; N, 3.56. Found:
C, 85.37; H, 6.84; N, 3.69%.
4.6. General procedure for the enantioselective addition
of diethylzinc to benzaldehyde promoted by enantiopure
aminoalkylnaphthols 3a–i, 5j,k and 6a–f
4.5.3.
1-[(1R)-Phenyl{benzyl[(1%R)-1%-phenylethyl]-
Under a nitrogen atmosphere, a toluene solution of
Et2Zn (3.0 mmol, 1.1 M) was added to the appropriate
aminonaphthol at 0°C and the solution was stirred at
room temperature for 40 min. After cooling to 0°C,
benzaldehyde (2.5 mmol) was added and the reaction
mixture was stirred at room temperature for the time
required. Aqueous hydrochloric acid (2 N) was added
to quench the reaction at 0°C. The resulting mixture
was extracted with CH2Cl2 and the organic layer was
dried with anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure. The crude oil was
purified by column chromatography on silica gel (cyclo-
hexane/AcOEt). Enantiomeric excesses (% e.e.) were
determined by GC analyses of the resulting alcohol on
amino}methyl]-2-naphthol, (R,R)-6c. White crystals; mp
153–156°C (hexane); [h]2D0=−156.4 (c 1.0, CHCl3); IR
(Nujol): wmax 1621, 1601, 1454, 1268, 1236, 748 cm−1; 1H
NMR (300 MHz, CDCl3): l 1.73 (d, 3H, J=7.0 Hz),
3.24 (d, 1H, J=15.0 Hz), 4.20 (d, 1H, J=15.0 Hz), 4.48
(q, 1H, J=7.0 Hz), 5.55 (s, 1H), 6.80–7.90 (m, 21H),
13.95 (s, 1H); 13C NMR (75 MHz, CDCl3): l 19.5, 50.7,
59.1, 68.3, 116.4, 119.8, 121.0, 122.5, 126.1, 126.6,
127.5, 127.6, 127.7, 128.0, 128.2, 128.5, 128.9, 129.0,
129.2, 129.4, 129.6, 130.0, 130.1, 131.8, 139.4, 155.9.
Anal. calcd for C32H29NO (443.6): C, 86.65; H, 6.59; N,
3.16. Found: C, 86.57; H, 6.66; N, 3.11%.
4.5.4.
1-[(1R)-Phenyl{ethyl[(1%R)-1%-
a
chiral column MEGADEX DMP
b
(30%
phenylethyl]amino}methyl]-2-naphthol, (R,R)-6d. Oil;
[h]2D0=−146.0 (c 1.1, CHCl3, d.r. 76:24); IR (liquid
dimethylpentyl-b-cyclodextrine on OV1701, 25 m, 0.25
mm ID, 0.25 mm film). The configuration of the major
enantiomer was assigned by comparison of the sign of
the specific rotation of the alcohol with literature data.
film): wmax 1621, 1601, 1583, 1268, 1237, 946 cm−1; H
1
NMR (300 MHz, CDCl3): l 0.72 (t, 3H, J=7.3 Hz),
1.59 (d, 3H, J=7.0 Hz), 2.35–2.70 (m, 1H), 2.85–3.10
(m, 1H), 4.28 (q, 1H, J=7.0 Hz), 5.55 (s, 1H), 7.10–
8.00 (m, 16H), 14.25 (s, 1H); 13C NMR (75 MHz,
CDCl3): l 14.1, 21.6, 40.8, 57.4, 67.4, 116.3, 120.0,
120.9, 122.4, 126.5, 127.6, 127.9, 128.2, 128.3, 128.6,
128.8, 128.9, 129.0, 129.5, 129.7, 131.9, 140.2, 156.2.
Anal. calcd for C27H27NO (381.5): C, 85.00; H, 7.13; N,
3.67. Found: C, 85.16; H, 7.01; N, 3.79%.
Acknowledgements
Financial support from Ministero dell’Universita` e
della Ricerca Scientifica e Tecnologica, Rome, and the
University
of
Camerino
(National
Project
4.5.5. 1-[((1R)-Phenyl{but-3-enyl[(1%R)-1%-phenylethyl]-
amino}methyl]-2-naphthol, (R,R)-6e. White crystals; mp
92–96°C (hexane); [h]2D0=−290.6 (c 1.1, CHCl3); IR
(Nujol): wmax 1621, 1600, 1469. 1454, 1268, 1237, 743,
702 cm−1; 1H NMR (300 MHz, CDCl3): l 1.52–1.89 (m,
2H), 1.62 (d, 3H, J=7.0 Hz), 2.25–2.55 (m, 1H), 2.88–
3.15 (m, 1H), 4.31 (q, 1H, J=7.0 Hz), 4.76 (d, 1H,
J=17.2 Hz), 4.91 (d, 1H, J=9.9 Hz), 5.38–5.65 (m,
‘Stereoselezione in Sintesi Organica. Metodologie ed
applicazioni’) is gratefully acknowledged.
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