Synthesis of 1,3-aminonaphthols by diastereoselective Betti-type aminoalkylation of dihydroxy naphthalenes; Diastereoselectivity, absolute configuration, and application

Article abstract of DOI:10.1016/j.tetasy.2013.09.023

Dihydroxy naphthalenes have been applied in Betti-type solventless condensation between aldehydes and (S)-phenylethylamine as a chiral auxiliary. A series of chiral 1,3-aminonaphthols has been synthesized and isolated in diastereoisomerically pure form. The absolute configurations of the aminonaphthols synthesized have been determined by means of advanced NMR experiments and confirmed by X-ray crystallography. The new chiral aminonaphthols have been tested as pre-catalysts for the addition of diethyl zinc and alkynyl-Zn-reagents to aldehydes with enantioselectivities of up to 98% ee.

Full text of DOI:10.1016/j.tetasy.2013.09.023

Tetrahedron: Asymmetry 24 (2013) 1453–1466
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of 1,3-aminonaphthols by diastereoselective Betti-type
aminoalkylation of dihydroxy naphthalenes; diastereoselectivity,
absolute configuration, and application
a
a
a
a
a
Maya Marinova , Kalina Kostova , Pavleta Tzvetkova , Maya Tavlinova-Kirilova , Angel Chimov ,
b
b
a,
⇑
Rosica Nikolova , Boris Shivachev , Vladimir Dimitrov
a
Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, Sofia 1113, Bulgaria
Institute of Mineralogy and Crystallography ‘Acad. Ivan Kostov’, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 107, Sofia 1113, Bulgaria
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2013
Accepted 24 September 2013
Dihydroxy naphthalenes have been applied in Betti-type solventless condensation between aldehydes
and (S)-phenylethylamine as a chiral auxiliary. A series of chiral 1,3-aminonaphthols has been synthe-
sized and isolated in diastereoisomerically pure form. The absolute configurations of the aminonaphthols
synthesized have been determined by means of advanced NMR experiments and confirmed by X-ray
crystallography. The new chiral aminonaphthols have been tested as pre-catalysts for the addition of
diethyl zinc and alkynyl-Zn-reagents to aldehydes with enantioselectivities of up to 98% ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1
1
. Introduction
2 and ammonia and was able to resolve 3 into enantiomers. How-
ever, ‘Betti bases’ did not attract much attention for a long period
In recent years, interest in so-called ‘Betti bases’ obtained by
means of ‘Betti condensation reaction’ has grown. Betti was the
first to prepare 1-( -aminobenzyl)-2-naphthol (‘Betti base’ 3,
Fig. 1) by simple condensation of 2-naphthol 1 with benzaldehyde
of time and only in the recent decade have they gained interest
for applications in asymmetric synthesis. The renewed interest in
the synthesis of ‘Betti bases’ has been awakened by Naso et al.2
who extended the original procedure to new reactants, realizing
efficient resolution into enantiomers followed by configuration
determination and demonstrating catalytic application in asym-
metric synthesis. The scope of the current knowledge about the
synthesis and application of ‘Betti base’ aminobenzylnaphthols
a
1
. NH3
. HCl
. NaOH
NH2
3
2
*
has recently been demonstrated in review articles.
OH
3
One of the most important recent achievements for ‘Betti bases’
is the condensation of enantiopure amines with 2-naphthol and
aldehydes leading to aminobenzylnaphthols of type 4 that formed
3
4
OH
with high to excellent diastereoselectivities. The relatively easy
O
+
access to these chiral aminoalcohols makes them interesting as
precatalysts for enantioselective additions of dialkylzinc reagents
to aldehydes. The versatile utility of the aminobenzylnaphthols
has recently been demonstrated by applying them as chiral auxil-
1
2
*
R
5
a
*
NH
iaries for the determination of enantiomeric excess, as reagents
for the resolution of enantiomers, or as the starting compounds
for the synthesis of amino-phosphine ligands for asymmetric
R-NH2
*
OH
6
transformations.
Until recently the three component condensation reaction of a
4
5
‘
Betti-type’ was performed mainly with variation of the amine
7
and aldehyde components using 2-naphthol as the third compo-
nent in most of the cases. Reports that describe the application
Figure 1.
8
9
of substituted 2-naphthols or 1-naphthol within the Betti-
condensation are rare. To date there are only two reports that
⇑
Corresponding author. Tel.: +359 2 9606 157; fax: +359 2 8700 225.
E-mail address: vdim@orgchm.bas.bg (V. Dimitrov).
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.023

1
454
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
describe the utilization of dihydroxy naphthalenes as the naphthol
component in the Betti condensation protocol.10
Herein we report our results on the applicability of 2,6-, 2,3-,
and 1,5-dihydroxy naphthalenes used in the condensation reaction
with aldehydes and with (S)-phenylethylamine as the chiral
auxiliary.
disubstituted aminonaphthol 10. The separation of the major dia-
stereoisomer 9a of the monosubstituted aminonaphthol was per-
formed by crystallization from Et O/hexane. The diastereomers
2
9b and 10a, 10b, and 10c could not be isolated in pure form.
The condensation of 5, 6, and 1-naphthaldehyde 8 was carried
out without a solvent at 80 °C for 24 h. The monosubstituted ami-
nonaphthol 11 and disubstituted analogue 12 were isolated after
work up and column chromatography (Scheme 1). The yields of
isolated compounds 11 and 12 were 61% and 1%, respectively, with
the corresponding diastereoselectivities of 11a/11b = 96:4 and
2
. Results and discussion
Our interest in performing a ‘Betti-type’ of condensation by
1
2a/12b/12c = 9:82:9. The isolation of an individual pure diaste-
using dihydroxy naphthalenes was substantiated mainly by the
opportunity to realize ‘double’ condensation within one
reoisomer was only possible in the case of 11a by crystallization
from acetonitrile. All attempts to purify 11b or to isolate at least
one of the diastereoisomers of 12 (chromatography and crystalliza-
tion) were unsuccessful. Variation of the reaction time for the con-
densation of 5, 6, and 8 led to an increase in the formation of the
disubstituted product 12 (up to 17% within 7 days) and a decrease
in the yield of 11 (44% for 7 days). There was no change in the dia-
stereoselectivity observed. The conversion based on the 2,6-dihy-
droxynaphthalene was almost the same (62%) when varying the
reaction time between 24 h and 7 days.
In further experiments, we investigated the ability of 2,3-
dihydroxynaphthalene to participate in a three component Betti
condensation, particularly with respect to the ‘double’ condensa-
tion at the 1- and 4-position of the naphthalene moiety. The
reaction between 13, 6, and 7 (Scheme 2) was performed without
a solvent by heating the mixture at 80 °C for 24 h. After work-up
and column chromatography, only the mono-condensation prod-
uct 14 could be isolated in 33% yield as a mixture of diastereoiso-
mers 14a/14b (94:6). The major diastereoisomer 14a was isolated
a
dihydroxy naphthyl unit. The condensation reaction of 2,6-dihy-
droxynaphthalene 5, (S)-phenylethylamine 6, and m-methylbenz-
aldehyde 7 was performed at 80 °C for 48 h without use of
solvent (Scheme 1).
The conversion based on 2,6-dihydroxynaphthalene was 69% by
taking into account the isolated condensation products. Products 9
and 10 were isolated by column chromatography as mixtures of
diastereoisomers 9a/9b = 90:10 and 10a/10b/10c = 18:64:18,
respectively. For the optimization of the reaction conditions with
the purpose of obtaining the best yields and diastereoselectivities,
a series of experiments were performed by varying the reaction
temperature and time. A convenient temperature of 80 °C was
established for the condensation reaction. Varying the reaction
time led to irreproducible results with respect to the yield and dia-
stereoselectivity. The general trend was that a prolonged reaction
time (up to 4 days) caused a decrease in the yields of 9 and 10
and a slight lowering of the diastereoselectivity in the case of
compound 9 (in case of 10 the change of diastereoselectivity as a
function of reaction time was not significant). No convenient
conditions could be established to improve the yield of the
2
in pure form after crystallization from hexane/Et O. The minor iso-
mer could not be isolated in pure form. During the condensation
NH
OH
NH
+
O
OH
HO
HN
HO
7
9
(45%)
10 (24%)
10a/10b/10c = 18:64:18
OH
H2N
9
a/9b = 90:10
+
HO
5
6
O
NH
8
OH
NH
+
HO
OH
HN
HO
1
1 (61%)
12 (1%)
12a/12b/12c = 9:82:9
1
1a/11b = 96:4
Scheme 1.

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1455
O
OH
NH
H2N
+
+
OH
OH
OH
13
6
7
14 (33%)
14a/14b = 94:6)
(
O
OH
H2N
+
+
no condensation product
OH
1
5
6
7
Scheme 2.
reaction, the formation of several by-products was observed,
although among them only the imine formed by reaction between
thol 16 in 67% yield as a mixture of diastereoisomers 16a/
16b = 83:17. The major diastereoisomer 16a was isolated in pure
form by crystallization. Diastereoisomer 16b could not be isolated
in pure form either by crystallization or by column chromatogra-
phy. Compound 16b was not stable and decomposed upon stand-
ing to a mixture of unknown products that were not identified.
6
and 7 could be identified. The formation of a double-condensa-
tion product (1,4-disubstitution within the naphthalene moiety)
could not be detected. It was of further interest to attempt the con-
densation between 1,5-dihydroxynaphthalene 15, amine 6 and
aldehyde 7 (Scheme 2). By using similar reaction conditions as
described above for the Betti-condensation of 2,6- and 2,3-dihydr-
oxynaphthalenes, no condensation product, even in trace amounts
could be detected in this case. The formation of several decompo-
sition species was observed, although it was not possible to isolate
defined compounds.
1
1
The formation of 16 has been previously described and diastereo-
isomer 16a has been isolated in 80% yield. However, no data were
provided with regard to the diastereoselectivity and 16a was
1
11
characterized by H NMR spectroscopy only.
The reaction of aldehyde 8 proceeded smoothly producing the
desired aminonaphthol 17 in high yield (82%) as a mixture of
diastereoisomers 17a/17b = 98:2 (determined by NMR). The
For the sake of comparison, aldehydes 7 and 8 were used also in
the condensation with 2-naphthol 1 and amine 6 (Scheme 3). In
both cases, the reaction was carried out without a solvent at
2
crystalline mixture was washed with Et O to give the major
diastereoisomer 17a in pure form (78% yield). The synthesis of
aminonaphthol 17a has been previously described (in 54% yield),
8
0 °C. The Betti-condensation of aldehyde 7 produced aminonaph-
4
b
however by using the (R)-enantiomer of 6.
It has been mentioned above that in all cases, with the excep-
tion of the reaction of 1, 6, and 8, the formation of imines was
observed, due to the condensation between amine (S)-6 and the
corresponding aldehyde. Moreover, the imines formed could be
isolated in most cases after work-up of the crude reaction mixtures
and separation of the products by column chromatography. In sev-
NH
O
OH
4
b,12
eral papers
it has been discussed that the first step of the so
called Betti condensation is the formation of an imine from the
respective amine and aldehyde, which then participates in the con-
densation reaction. The C–C bond formation proceeds in a second
step from the imine formed and 2-naphthol and is most probably
accelerated by hydrogen-bond formation between the hydroxy
proton of the naphthol and the amine nitrogen.
7
1
6 (67%)
1
6a/16b = 83:17
OH
H2N
+
We were interested in obtaining a better understanding of the
condensation reaction outcome. Therefore imine 18 was synthe-
sized by mixing (S)-1-phenylethylamine 6 and aldehyde 7 in
1
6
O
2 2 2 4
CH Cl (using Na SO as a drying agent). After filtration and
removal of the solvent, pure imine 18 was obtained as an oil (this
was shown to be pure and have a trans-configuration by NMR).
Imine 18 was mixed with 2,6-dihydroxy naphthalene and heated
at 80 °C for 72 h. After work-up and column chromatography
aminonaphthols 9 and 10 were isolated and showed yields and
diastereoselectivities comparable with those obtained by the usual
reaction procedure (compare Schemes 1 and 4 and Section 4).
The major diastereoisomers 9a, 11a, 14a, 16a, and 17a were
easily transformed into the corresponding 1,3-oxazines (Scheme 5)
by reacting them with formaldehyde (in the form of paraformalde-
hyde or formalin). The general reason to carry out these
8
NH
OH
1
7 (82%)
1
7a/17b = 98:2
Scheme 3.

1
456
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
NH
OH
OH
N
NH
+
+
HO
HO
OH
HN
18
5
HO
9
(39%)
10 (25%)
9a/9b = 84:16
10a/10b/10c = 16:68:16
Scheme 4.
1
7
27
1
6
26
25
28
27
18
19
1
4
15
23
29
30
22
13
24
24
23
(
S)
20
(S)
25
11 N12
(S)N
28
21
31
21
26
22
(
S)
9
1
10
O
O
8
7
2
3
5
HO
6
HO
4
1
9a
20a
(
S)
R
NH
(HCHO)n
or
(
S)
(S)
OH
37% aq HCHO
N
(
S)
X
O
X = H, OH
a, 11a, 14a,
6a, 17a
OH
9
21a
1
(
S)
(S)
N
S)N
(
(
S)
O
O
22a
23a
(
S)
(S)
(S)
NH
N
N
(R)
(
S)
37% aq HCHO
OH
O
+
O
1
6
22a
Scheme 5.
22b
transformations was to obtain NMR data about structures possess-
ing a rigid conformation with respect to the C1–C11-rotation (for
numbering see Scheme 5; the numbering is tentative). All oxazine
formation reactions proceeded smoothly. In the case of compound
The determination of the configurations of the newly formed
stereogenic centers was of particular interest. The application of
advanced NMR experiments (HSQC, HMBC, and NOESY) provided
an excellent opportunity to obtain data about the positions of the
substituents relative to each other within the structures synthe-
sized. The NOESY experiments provided extensive information
about the proton neighborhood next to the new stereogenic center
C11. For the major diastereoisomers 9a, 11a, 14a, 16a, and 17a, the
1
6, the corresponding oxazines were synthesized either from the
pure diastereoisomer 16a or from a mixture of 16a/16b. The indi-
vidual diastereoisomeric oxazines 22a and 22b formed from 16a/
1
6b could be isolated in pure form by column chromatography.

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1457
observed NOEs indicated short distances of the C11 protons with
the protons attached to C9, C13, and the ortho-proton C16 of the
phenyl group, which is part of the amine moiety (Fig. 2). In most
cases, the C11 proton was in close proximity to the ortho-proton
of the methyl-substituted phenyl group compounds 9a, 14a, and
16a and the naphthyl group compound 17a. In all cases, the close
proximity of the hydroxy protons of the 2-hydroxynaphthyl moi-
ety and the N-atoms suggested the existence of strong hydrogen
bonding. This was also supported by the observed chemical shifts
of HO-C2-protons, which were downfield positioned; 13.48 ppm
1
6
16
16
2
2
13
29
13
26
13
a
1
3
26
a
11
31
11
11
b
9
22
11
2
8
b
9
9
9
1
1a
20a
9
a
19a
1
1S, 13S
11S, 13S
1
1S, 13S
11S, 13S
1
6
22
22
13
13
11
1
9
1
9
a
28
b
1
4a
21a
1
6
1S, 13S
11S, 13S
1
22
22
1
3
13
a
22
1
3
22
11
13
11
11
2
8
11
9
16
9
b
16
9
28
1
6a
22a
11S, 13S
1
1S, 13S
16b
1R, 13S
22b
11R, 13S
1
16
22
13
29
2
13
1
11
a
22
31
11
9
b
9
1
7a
23a
1
1S, 13S
11S, 13S
Figure 2. Observed proton proximities (obtained through NOESY spectra), allowing the determination of the absolute configuration of compounds 9a, 11a, 14a, 16a, 16b, and
7a.
1

1
458
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1
6
for 9a, 14.08 ppm for 11a, 14.82 ppm for 14a, 13.76 for 16a, and
3.69 for 17a. The data obtained for the corresponding 1,3-oxa-
two molecules in the asymmetric unit. The ORTEP drawing of the
molecular structures of 11a and 16a is shown in Figure 3. A sum-
mary of the fundamental crystal and refinement parameters for
11a and 16a is provided in Table 3 (Section 4).
1
zines confirmed these observations. The formation of the 1,3-oxa-
zine caused conformational restriction, which allowed us to
acknowledge the proton proximities determined within the
aminonaphthols. This also indicated that the aminonaphthols
themselves possessed rigid conformations very similar to that of
the corresponding oxazines. Most probably, hydrogen bonding
within the aminonaphthols is the reason for this conformational
The conformation of 11a with respect to the naphthyl-group
position attached to the C11 stereogenic center in the crystal and
in solution is the same. The solution conformation of 17a differed
from that of 11a considering the relative position of the naph-
thyl-group with respect to simple rotation about Cnaphth-C11. The
conformation of compound 16a with respect to the rotation of
the meta-methyl phenyl-group differs in solution and in the crys-
tal. Only the conformation of oxazine 19a, when considering the
position of the meta-methyl phenyl-group, fits with those of the
16a crystal structure.
4
b
rigidity. Similar conclusions have been published by Palmieri.
The protons of the oxazine CH -group provided substantial infor-
mation with respect to the relative position of the C11 proton.
The corresponding H -protons lie on the side of the methyl group
while the H -protons are in close proximity to the C11 and C13
2
a
b
protons. Consequently, the results of this approach allowed the
determination of the absolute configuration of C11 (as shown in
Fig. 2), by taking into account the known configuration of the cor-
responding C-atom of the amine moiety (C13).
The bond lengths and angles of the molecules in 11a and 16a
are comparable. The aromatic ring systems present in the mole-
cules are essentially planar. The methyl group in 16a (see molecule
1, C271 and C273, Fig. 3b) of the methyl-phenyl moiety exhibits a
disorder over two positions, the major one being 65%. The disorder
probably arises due to the observed close contact of 1.89 Å
between the hydrogen atoms of the neighboring molecules. The
values of the atomic displacement parameters (ADP) of the methyl
group in the second molecule (molecule 2, C272) suggest a similar
disorder over two positions. However, our attempts to introduce
disorder for the second molecule did not improve the refinement
indicators. The superposition of the independent molecules of
16a shows a slight rotation (14.93°) of the phenyl moiety with
respect to the C13–C15 bond (Fig. 4a). Since 11a and 16a are
enantiomerically pure and the chirality sense of the molecules is
the same, the superposition of the molecules reveals that the
overall geometry is conserved (Fig. 4b).
Considering the structural similarity, we expected similar
hydrogen bonding interactions. Indeed in both compounds an
intramolecular O–Hꢀ ꢀ ꢀN hydrogen bond stabilizes the molecular
geometry (Fig. 5). However, compounds 11a and 16a feature a dif-
ferent number of donors and acceptors (two donor/acceptor atoms
in 11a and three donor/acceptor atoms in 16a; see Table 4). In the
case of 16a, an intermolecular N–Hꢀ ꢀ ꢀO hydrogen bond stabilizes
the three-dimensional crystal packing. Such an intermolecular
hydrogen bond interaction (N–Hꢀ ꢀ ꢀO) could not be located in
11a. The second hydroxy-group within 11a led to intermolecular
stabilization through O–Hꢀ ꢀ ꢀO hydrogen bonding with the forma-
tion of molecular chains (see Fig. 5a). This is actually reasonable
It is essential to point out that in all of the cases studied, the
application of (S)-1-phenylethylamine 6 as the amine component
in the condensation reaction caused the formation of a new
stereogenic center C11 with an (S)-configuration. Considering the
4
a–d,g,7c,13
data available in the literature
and the discussion pre-
4
b
sented by Palmieri with respect to the relative stability of the
diastereoisomers formed during the Betti-condensation, as well
1
4
as unpublished results (5 additional examples of aminoalcohols
of Betti-type with configurations proved by X-ray crystallography),
it is necessary to emphasize that the configuration of the chiral
amine used in the condensation clearly defines the configuration
of the new stereogenic center within the major diastereoisomer
formed. Consequently for the three component Betti-type conden-
sation, it is possible to produce aminonaphthols with a predictable
configuration depending on the configuration of the starting amine
used. In a recently published paper15 the configurations and cer-
tain intra- and intermolecular interactions of nine 1-(a-aminoben-
zyl)-2-naphthols were discussed and the dependence of the
stereogenic center formation on the configuration of the starting
amine has been shown unequivocally.
The crystal structures obtained for compounds 11a and 16a
confirmed the conclusions made from the NMR experiments and
the determined configurations. The single crystal X-ray studies
showed that compounds 11a and 16a crystallized in a non-centro-
1 1 1 3
symmetric manner (SG P2 2 2 and P4 , respectively) with one and
Figure 3. ORTEP View of the asymmetric units of compounds (a) 11a and (b) 16a showing the absolute configuration of the stereogenic centers of (11S,13S)-11a and (11S,13S)-
6a. H-atoms are presented with spheres of arbitrary radii; ellipsoids are with 50% probability.
1

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1459
Table 1
2
Enantioselective addition of Et Zn to aldehydes catalyzed by ligands 9a, 11a, 14a, 16a, and 17a
OH
*
O
3
mol% chiral ligand
+
Et2Zn
R
R
H
Entry
Aldehyde
Ligand
Reaction time (h)
Yielda (%)
ee (%), config.b
1
2
3
4
5
6
7
8
9
Benzaldehyde
9a
9a
9a
9a
9a
9a
9a
9a
144
48
24
72
62
46
62
59
144
24
24
72
22
144
96
96
114
48
96
27
28
96
24
144
24
17
72
24
66
59
80
87
62
46
62
59
88
81
88
78
67
88
70
74
51
41
61
77
88
76
96
88
80
85
83
98
32 (R)b
b
2-Methoxybezaldehyde
Ferrocencarbaldehyde
1-Naphthaldehyde
82 (R)
c
96 (R)
84 (R)b
b
2-Naphthaldehyde
84 (R)
4-Chlorobenzaldehyde
Cyclohexanecarbaldehyde
Cinnamaldehyde
56 (R)c
b
85 (R)
44 (R)c
Benzaldehyde
11a
11a
11a
11a
11a
14a
14a
14a
14a
14a
16a
16a
16a
16a
16a
17a
17a
17a
17a
17a
73 (R)b
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2-Methoxybezaldehyde
Ferrocencarbaldehyde
1-Naphthaldehyde
Cyclohexanecarbaldehyde
Benzaldehyde
2-Methoxybezaldehyde
Ferrocencarbaldehyde
1-Naphtaldehyde
Cyclohexanecarbaldehyde
Benzaldehyde
2-Methoxybezaldehyde
Ferrocencarbaldehyde
1-Naphthaldehyde
Cyclohexanecarbaldehyde
Benzaldehyde
2-Methoxybezaldehyde
Ferrocencarbaldehyde
1-Naphthaldehyde
95 (R)
98 (R)c
b
94 (R)
89 (R)b
2 (ꢁ)
b
13 (R)
80 (R)c
2 (ꢁ)
b
14 (R)
60 (R)b
b
93 (R)
96 (R)c
b
90 (R)
86 (R)b
18 (R)b
b
96 (R)
98 (R)c
b
92 (R)
Cyclohexanecarbaldehyde
91 (R)b
a
b
c
Isolated pure products after column chromatography.
Enantiomeric excess determined by GC analysis.
Enantiomeric excess determined by HPLC analysis. The absolute configuration was determined by comparison of the specific rotation to the literature value.
19,20
Table 2
Enantioselective addition of alkynyl-zinc reagents to aldehydes catalyzed by ligands 16a and 17a
OH
*
O
OH
R1
ligand 16a, 17a
R2
R1
H
+
+
Et2Zn
+
R1
R2
*
A
B
C
D
Entry
Aldehyde A R1
=
Alkyne B R2
=
Ligand
Yielda C (%)
ee Cb (%)
Yield D (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
4-Cl-C
1-Naphthyl
Cyclohexyl
4-NO
Ph
4-Cl-C
Ph
4-Cl-C
Ph
4-Cl-C
3-Me-C
Ph
Ph
Ph
Ph
Ph
Ph
16a
99
88
58
98
99
23
98
56
60
45
66
56
52
81
57
45
75
38
10
39
16
26
50
10
31
10
25
12
9
11
8
15
25
5
—
11
27
—
—
—
16a (without Et
16a
16a
16a
16a
16a
16a
16a
16a
17a
17a
17a
17a
17a
17a
17a
3
N)
6
H
4
2
-C
6
H
4
Cyclopropyl
Cyclopropyl
3-Cl-propyl
3-Cl-propyl
Ph
Ph
Ph
Ph
2
6
6
6
H
4
25
40
29
—
19
21
15
41
17
25
10
11
12
13
14
15
16
17
H
4
H
4
6
H
4
1-Naphthyl
2-Naphthyl
Cyclohexyl
Ph
Ph
4-Cl-C
6
H
4
Cyclopropyl
a
Isolated pure products after column chromatography.
Enantiomeric excess determined by HPLC analysis.
b

1
460
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
Table 3
Crystal data and structure refinement indicators for compounds 11a and 16a
Compound
11a
16a
Empirical formula
Molecular weight
Crystal size (mm)
Crystal system
Space group
T (K)
C
29
H
25 N O
26
C H25 N O
367.47
419.50
0.23 ꢂ 0.22 ꢂ 0.18
0.26 ꢂ 0.24 ꢂ 0.22
Orthorhombic
Tetragonal
P2
290
1
2
1
2
1
P4
3
290
Radiation wavelength (Å)
a (Å)
b (Å)
1.5418 (Cu K
10.2964(5)
14.7434(7)
14.8179(8)
2249(2)
4
a)
1.5418 (Cu K
9.89.71(2)
9.89.71(2)
43.5016(11)
4261.1(2)
8
a)
c (Å)
3
V (Å )
Z
a
(°)
b (°)
(°)
d (mg mꢁ3)
(mm-1
Reflections collected/unique
(I > 2 (I))
wR (all data)
GOF
Absolute structure/Flack25 parameter
90
90
90
1.239
0.61
4965/3097
0.086
0.128
1.02
90
90
90
1.146
0.53
19,399/6510
0.046
0.128
1.05
c
l
)
R
1
r
2
Classical Flack method preferred over Parsons because s.u. lower (ꢁ0.4 (2))
Refined as an inversion twin.0.1(2)
Table 4
Hydrogen bonds in 11a and 16a (distances in Å and angle in
good yields. Excellent enantioselectivities were generally achieved
with all of the aminonaphthols, considering selected aldehydes. It
s
)
seems, however, that aminoalcohol 14a, which has
dihydroxy-naphthyl moiety and showed acceptable results only
for the Et Zn addition to ferrocene carbaldehyde (entry 16), is by
a 2,3-
D—Hꢀ ꢀ ꢀA (11a)
O2-H2ꢀ ꢀ ꢀN12
D—H
Hꢀ ꢀ ꢀA
1.892
2.231
Dꢀ ꢀ ꢀA
2.616(3)
3.191(4)
Angle D-Hꢀ ꢀ ꢀA
146.6
180.0
0.82
0.86
i
O7-H7ꢀ ꢀ ꢀO2
2
Symmetry codes: (i) ꢁx ꢁ 1/2, ꢁ1 ꢁ y, ½ + z;
D—Hꢀ ꢀ ꢀA (16a)
far less efficient as a ligand with respect to the enantioselectivity,
in comparison with 9a, 11a, 16a, and 17a. Comparable results
regarding the enantioselectivities achieved were realized with
the couples 9a and 11a, and 16a and 17a (entries 1–13 and
19–28). It seems that the second hydroxy-group within the 2,6-
dihydroxy substituted aminonaphthols 9a and 11a does not have
any significant contribution to the enantioselectivity. This is also
valid when comparing the ligands with meta-methyl phenyl- and
D—H
Hꢀ ꢀ ꢀA
1.858
1.878
2.269
2.181
Dꢀ ꢀ ꢀA
2.578(3)
2.592(3)
3.252(5)
Angle D—Hꢀ ꢀ ꢀA
O1—H11ꢀ ꢀ ꢀN121
0.82
0.82
1.00
145.9
144.8
159.6
157.6
O11—H2ꢀ ꢀ ꢀN122
i
N121—H121ꢀ ꢀ ꢀꢀ ꢀ ꢀO11
i
N122—H122ꢀ ꢀ ꢀꢀ ꢀ ꢀO1
1.07
3.201(5)
1
1
Symmetry codes: (i) y, 1 ꢁ x,
4
+ z; (ii) 1 ꢁ y, 1 + x, ꢁ
4
+ z
1
-naphthyl-moieties within the structures synthesized; no signifi-
considering that the strength of O–Hꢀ ꢀ ꢀO hydrogen bond is supe-
cant differences in the achieved enantioselectivities could be
obtained. Thus aminonaphthols 9a, 11a, 16a, and 17a have shown
high efficiency as pre-catalysts with enantioselectivities realized of
up to 98% ee. It is also remarkable to point out that these ligands
ꢁ1
ꢁ1 17
rior to that of N–Hꢀ ꢀ ꢀO (21 kJ mol vs. 8 kJ mol ). The remain-
ing H-donor (N–H) is involved in the
neighboring chains.
p interaction between the
The chiral aminonaphthols 9a, 11a, 14a, 16a, and 17a synthe-
2
were very efficient within the addition of Et Zn to cyclohexane-
sized were tested as pre-catalysts (3 mol %) for the enantioselec-
carbaldehyde (entries 7, 13, 23 and 28). This is an encouraging
result for the generally poor selectivity in the additions to aliphatic
aldehydes.
Ligands 16a and 17a, which showed the best results for the
2
Et Zn additions to aldehydes, were further applied as pre-catalysts
2
tive addition of Et Zn to aldehydes (Table 1) by using a standard
1
8
procedure. The yields of the secondary alcohols obtained were
generally very good, although in some cases only moderate conver-
sions could be achieved (entries 6, 17, 18). The reaction times were
usually in the range of 1 to 3 days. In several cases (entries 1, 9, 14–
for enantioselective zinc-mediated alkynyl-additions to aldehydes
(Table 2). The reaction protocol used was similar to that published
1
7, 19, 22, 24) prolonged reaction times were necessary to obtain
Figure 4. Overlay of (a) the independent molecules present in the asymmetric sub unit of 16a and (b) the molecules of 11a (gray) and 16a (green).

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1461
Figure 5. Hydrogen bonding interactions in (a) 11a and (b) 16a.
in the literature.21 For the alkyne equivalents, we used phenyl-,
cyclopropyl-, and 5-chloro-propyl-acetylenes. Since Et Zn is the
mediator to obtain the corresponding alkynyl-Zn-reagents in situ,
it is understandable that the Et Zn-addition to the corresponding
aldehydes might be a competing reaction leading to products D
simultaneously with the desired alkynyl carbinols C. Compound
tained as pure diastereoisomers have been applied as pre-
catalysts in the enantioselective addition of diethyl zinc to
aldehydes. In most cases, high enantioselectivity was achieved
(up to 98% ee). In contrast the addition of alkynyl-zinc
compounds generated in situ, catalyzed by two of the most
effective aminonaphthols, proceeded with low to
moderate enantioselectivities.
2
2
1
6a provided better results in terms of the yields of the alkyne
addition and the amount of the competing Et Zn-addition (entries
, 3–10). When the reaction was carried out in the absence of Et
2
1
3
N
additive, a lower enantioselectivity was observed (entry 2). In the
addition reactions catalyzed by 17a the formation of ethyl-addition
product D was substantial (compare in particularly entries 1–10
and 11–17). It seems that the formation of by-product D strongly
depends on the ligand structure and the ability of the ligand/zinc
complex to catalyze efficiently the alkynyl- or ethyl-group transfer.
In all cases, the enantioselectivities observed were low to moder-
ate, although the results with 16a were better compared with 17a.
4. Experimental
4.1. General
Commercial reagents were used for the synthesis of the amino-
naphthols, the corresponding oxazines and for the enantioselective
additions, as well. The reactions with diethylzinc were carried out
in Schlenk flasks under an argon atmosphere. The toluene for the
enantioselective organozinc additions was dried by refluxing over
LiAlH4 and distilled under an argon atmosphere. Thin layer chro-
matography (TLC) was performed on aluminum sheets pre-coated
with Merck Kieselgel 60 F254 (0.063–0.200 mm Merck). Flash col-
umn chromatography was carried out using Silica Gel 60 230–
400 mesh, (Merck). The melting points of the compounds were
determined by using BOETIUS, type PHMK 05, and SPS MPA100
3
. Conclusion
A series of chiral aminonaphthols has been synthesized dia-
stereoselectively by applying a solvent free ‘Betti-type’ condensa-
tion using dihydroxy naphthalenes as the naphthol component,
(S)-phenylethylamine, and m-methylbenzaldehyde or 1-naph-
2
D
0
thaldehyde. The major diastereoisomers formed could be isolated
in pure form. All new aminonaphthols easily form oxazines
through simple reaction with formaldehyde. By means of ad-
vanced NMR experiments, the configurations of the newly
formed stereogenic centers were determined. The correctness
of the NMR approach was confirmed by X-ray crystallography
of two of the compounds synthesized. The aminonaphthols ob-
OptiMelt apparatus (uncorrected). Optical rotations (½
a ) were
ꢃ
measured on a Perkin Elmer 241 polarimeter. The NMR spectra
1
were recorded on a Bruker DRX 250 (250.13 MHz for H NMR,
1
3
62.9 MHz for C NMR) and Bruker Avance II+ 600 (600.13 MHz
1
13
for H NMR, 150.92 MHz for C NMR) spectrometers with TMS
1
13
as the internal standard for chemical shifts (d, ppm). H and
NMR data are reported as follows: chemical shift, multiplicity
C

1
462
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
(
s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = mul-
(90:10). The main diastereoisomer 9a was isolated in a pure form
by crystallization from Et O/hexane (0.157 g, 22%).
tiplet), coupling constants (Hz), integration, and identification. The
2
1
13
assignment of the H and C NMR spectra was made on the basis
of DEPT, HSQC, HMBC, and NOESY experiments. The NMR spectra
of the compounds even at a moderately strong magnetic field, as
the Avance II+ 600 MHz spectrometer used for the assignment of
the investigated compounds, show some signal overlapping. The
primes are used as an indication for those protons whose signals
are potentially of a second order being pseudo doublets or pseudo
triplets, respectively. The multiplicity of the completely overlap-
ping signals could only be addressed in the heteronuclear 2D
P.E.HSQC experiment, which is less sensitive towards the second
order effects. Since this experiment has been applied for all com-
pounds with a focus on the aromatic region, the scalar couplings
can be in principle measured from the slices of the P.E.HSQC exper-
iment and some still within the 1D proton experiment, however it
was considered as not necessary. In fact, the accuracy will be ham-
pered by the influence of the second order effects as well as the
lower accuracy of the 2D experiment compared to 1D. In addition
the values of these couplings will not contribute to the assignment
and/or to the stereochemistry determination, therefore will not
provide new/unknown information. Mass spectra (MS) were re-
corded on a Thermo Scientific DFS (Double Focusing Magnetic Sec-
tor) mass spectrometer using chemical ionization or with electro
spray ionization techniques, and reported as fragmentation in m/
z with relative intensities (%) in parentheses. High performance li-
quid chromatography (HPLC) separations were performed with an
Agilent 1100 System fitted with a diode array detector and a man-
4.2.1.1. 1-((S)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
2
0
thalene-2,6-diol 9a. Mp 74–75 °C, ½
a
ꢃ
¼ þ142:6 (c 1.00, CHCl
3
).
D
1
H NMR (600 MHz, CDCl
3
) d 1.48 (d, JH,H = 6.9 Hz, 3H, H-14), 2.23
(s, 3H, H-27), 2.27 (br s, 1H, NH), 3.87 (br q, JH,H = 6.8 Hz, 1H, H-
0
13), 5.03 (br s, 1H, HO-C(7)), 5.34 (s, 1H, H-11), 6.86 (dd ,
0
J
H,H = 9.2, 2.7 Hz, 1H, H-8), 6.96 (d , 1H, H-26), 6.97 (s, 1H, H-22),
0
0
0
7.00 (d , 1H, H-24), 7.07 (d , JH,H = 2.6 Hz, 1H, H-6), 7.11 (t , 1H,
H-25), 7.17 (d , 2H, H-16, H-20), 7.19 (d , JH,H = 9.0 Hz, 1H, H-3),
7.26 (d , JH,H = 9.1 Hz, 1H, H-9), 7.36 (t , 1H, H-18), 7.39 (t , 2H, H-
17, H-19), 7.56 (d , JH,H = 8.9 Hz, 1H, H-4), 13.48 (br s, 1H, HO-
0
0
2
6
0
0
0
0
1
3
3
C(2)) ppm. C NMR (CDCl ) d 21.44 (q, C-27), 22.90 (q, C-14),
56.64 (d, C-13), 60.38 (d, C-11), 110.74 (d, C-6), 113.39 (s, C-1),
117.83 (d, C-8), 120.70 (d, C-3), 122.94 (d, C-9), 124.74 (d, C-26),
126.75 (2d, C-16, C-20), 127.71 (s, C-10), 127.90 (d, C-18), 128.05
(d, C-4), 128.23 (d, C-22), 128.81 (d, C-24), 128.92 (d, C-25),
128.92 (2d, C-17, C-19)
(s, C-21), 142.81 (s, C-15), 150.88 (s, C-7), 155.23 (s, C-2) ppm.
Anal. Calcd for C26 (383.48): C, 81.43; H, 6.57; N, 3.65.
,
129.76 (s, C-5), 138.77 (s, C-23), 141.10
H25NO
2
Found: C, 81.14; H, 6.95; N, 3.73. MS (CI) m/z (rel int.) = 384 (18,
+
[M+H] ).
4.2.1.2. 1-((R)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
1
thalene-2,6-diol 9b. H NMR (250 MHz, CDCl
3
)
d
1.55 (d,
JH,H = 6.41 Hz, 3H, H-14), 2.24 (s, 3H, H-27), 3.95 (q, JH,H = 6.6 Hz,
1H, H-13), 5.76 (s, 1H, H-11) ppm.
ual injector with a 20 lL injection loop. Gas chromatography (GC)
was performed with a Shimadzu GC-17A. Elemental analyses were
performed by Microanalytical Service Laboratory of the Institute of
Organic Chemistry, Bulgarian Academy of Sciences.
4.2.1.3. 1,5-Bis(((S)-1-phenylethylamino)(m-tolyl)methyl)naph-
thalene-2,6-diol 10. (Mixture of three diastereoisomers): H NMR
(250 MHz, CDCl ) d 1.43, 1.49, 1.53 (3d, JH,H = 6.8, 6.8, 6.7 Hz, 9H, H-
3
1
X-Ray crystallography: crystals of 11a and 16a were mounted
on a glass capillary and all data were collected at room tempera-
ture on an Oxford diffraction Supernova diffractometer using
14), 2.21, 2.26, 2.32 (3s, 9H, H-27), 5.37, 5.39, 5.78 (3s, 3H, H-11)
ppm. MS (ESI) m/z (rel int.) = 607 (63, [M+H] ).
+
Cu-K
a
radiation (k = 1.5418 Å) from micro-focus source. The deter-
4.2.2. 1-(Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
naphthalene-2,6-diol 11 and 1,5-bis(naphthalen-1-yl((S)-1-
phenylethylamino)methyl)naphthalene-2,6-diol 12
mination of the cell parameters, data integration, scaling, and
absorption correction were carried out using the CrysalisPro.
The structures were solved with ShelxS-2013 and refined using
full-matrix least-squares on F with the ShelxL-2013 package.
In both 11a and 16a, the nitrogen and hydrogen atoms were posi-
tioned from difference Fourier map. In 16a H7 coordinates were
obtained using DHA. The non-hydrogen atoms were refined
anisotropically and the hydrogen atoms were placed at idealized
positions and refined using the riding model. Crystallographic data
2
2
23
A mixture of naphthalene-2.6-diol 5 (0.300 g, 1.87 mmol),
1-naphtaldehyde 8 (0.614 g, 3.93 mmol), and (S)-(ꢁ)-1-phenyleth-
ylamine 6 (0.545 g, 4.50 mmol) was stirred and heated at 80 °C for
24 h. Methanol was then added and the insoluble material was fil-
tered to give 0.477 g (61%) of 11 as a mixture of two diastereoiso-
mers 11a/11b (96:4). The methanol filtrate was chromatographed
(hexane/MTBE = 5:1) to give 0.589 g of a mixture containing
aldehyde 8 and the corresponding imine (resulting from the reac-
tion of aldehyde 8 and amine 6) in a ratio of 43:57 (NMR data) and
0.010 g (1%) of 12 as mixture of three diastereoisomers in a ratio of
12a/12b/12c = 9:82:9. The major diastereoisomer 11a was isolated
in pure form by crystallization from acetonitrile (0.202 g, 26%).
2
23
2
4
(
excluding structure factors) for the structural analysis were
deposited with the Cambridge Crystallographic Data Centre, CCDC
No 948405 and 948406. A copy of this information may be ob-
tained free of charge from: The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK. Fax: +44 1223 336 033, e-mail: depos-
it@ccdc.cam.ac.uk, or www.ccdc.cam.ac.uk
4
.2.2.1. 1-((S)-Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
2
0
4
.2. Synthesis of chiral aminonaphthols
naphthalene-2,6-diol 11a. Mp 179–180 °C, ½
aꢃ
¼ þ522:9 (c 1.00,
D
1
DMSO). H NMR (600 MHz, DMSO-d
6
) d 1.45 (d, JH,H = 6.9 Hz, 3H,
4
2
.2.1. 1-(((S)-1-Phenylethylamino)(m-tolyl)methyl) naphthalene-
,6-diol 9 and 1,5-bis(((S)-1-phenyl-ethylamino) (m-tolyl)methyl)
H-14), 3.76 (dq, JH,H = 11.8, 6.9 Hz, 1H, H-13), 3.94 (d, JH,H = 11.8 Hz,
1H, HN), 6.02 (s, 1H, H-11), 6.69 (dd , JH,H = 9.2, 2.5 Hz, 1H, H-8),
0
0
0
naphthalene-2,6-diol 10
6.92 (d , JH,H = 9.3 Hz, 1H, H-9), 6.99 (d , JH,H = 8.6 Hz, 1H, H-29),
0
0
A mixture of naphthalene-2,6-diol 5 (0.300 g, 1.87 mmol),
7.03 (d , JH,H = 2.5 Hz, 1H, H-6), 7.10 (d , JH,H = 8.9 Hz, 1H, H-3),
0
0
0
3
-methylbenzaldehyde (7) (0.473 g, 3.93 mmol), and (S)-(ꢁ)-1-
phenylethylamine 6 (0.545 g, 4.95 mmol) was heated at 80 °C for
8 h. The crude reaction mixture was chromatographed (hexane/
7.27 (t , 1H, H-28), 7.28 (d , 1H, H-22), 7.33 (t , 1H, H-23), 7.34
(d , 2H, H-16, H-20), 7.47 (t , 2H, H-17, H-19), 7.48 (t , 1H, H-18),
0
0
0
0
0
4
7.50 (t , JH,H = 7.8 Hz, 1H, H-27), 7.59 (d , JH,H = 8.9 Hz, 1H, H-4),
0
0
MTBE = 5:1) to give 0.267 g of a mixture containing aldehyde 7
and the corresponding imine (resulting from the reaction of alde-
hyde 7 and amine 6) in a ratio of 62:38 (by NMR), 0.277 g (24%)
of 10 as a mixture of three diastereoisomers (18:64:18) and
7.80 (d , 1H, H-24), 7.93 (d , 1H, H-26), 9.3 (s, 1H, HO-C(7)), 14.08
1
3
(s, 1H, HO-C(2)) ppm. C NMR (DMSO) d 21.90 (q, C-14), 54.64
(d, C-11), 56.23 (d, C-13), 110.26 (d, C-6), 113.97 (s, C-1), 118.70
(d, C-8), 120.12 (d, C-3), 121.55 (d, C-9), 121.99 (d, C-29), 125.68
(d, C-23), 125.78 (d, C-27), 126.35 (d, C-22), 126.53 (d, C-28),
0
.320 g (45%) of 9 as mixture of two diastereoisomers 9a/9b

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1463
1
26.63 (s, C-10), 127.59 (d, C-4), 127.86 (2d, C-16, C-20)
,
127.94 (d,
two diastereoisomers in ratio of 16a/16b = 95:5. The methanol fil-
trate was chromatographed (hexane/MTBE = 5:1) to give 0.201 g of
a mixture containing the aldehyde 7 and the corresponding imine
(resulting from the reaction of aldehyde 7 and amine 6) in a ratio of
47:53 (NMR data), and 16 (0.209 g, 27%) as a mixture of two diaste-
reoisomeres in a ratio of 16a/16b = 64:36. The major diastereoiso-
C-18), 128.34 (d, C-24), 128.53 (2d, C-17, C-19), 128.94 (d, C-26),
1
2
29.58 (s, C-5), 130.24 (s, C-30), 133.60 (s, C-25), 136.31 (s, C-
1), 142.84 (s, C-15), 152.46 (s, C-7), 155.48 (s, C-2) ppm. Anal.
Calcd for C29
2
H25NO (419.51): C, 83.03; H, 6.01; N, 3.34. Found:
+
C, 82.73; H, 6.30; N, 3.57. MS (CI) m/z (rel int.) = 420 (2, [M+H] ).
2
mer 16a was isolated by crystallization from hexane/Et O (0.184 g,
4
.2.2.2. 1-((R)-Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
24%). The calculated total yield of 16 was 67% in a diastereoiso-
meric ratio of 16a/16b = 83:17.
1
naphthalene-2,6-diol 11b. H NMR (250 MHz, DMSO-d
6
) d 1.57
(
d, JH,H = 6.6 Hz, 3H, H-14), 4.68 (q, JH,H = 6.5 Hz, 1H, H-13).
4
.2.4.1. 1-((S)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
2
0
4
.2.2.3. 1,5-Bis(Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
thalen-2-ol 16a. Mp 170–171 °C, ½
a
ꢃ
¼ þ197:0 (c 1.00, CHCl
3
),
D
1
1
naphthalene-2,6-diol 12. (Mixture of three diastereoisomers):
NMR (250 MHz, CDCl ) d 1.46, 1.55, 1.68 (3d, JH,H = 6.9, 6.9,
.6 Hz, 9H, H-14), 3.92, 4.03, 4.15 (3q, JH,H = 6.6, 7.5, 6.6 Hz, 3H,
H-13), 6.29, 6.33, 6.76 (3s, 3H, H-11) ppm. MS (ESI) m/z (rel. int.)
H
3
H NMR (600 MHz, CDCl ) d 1.49 (d, JH,H = 6.9 Hz, 3H, H-14),
3
2.22 (s, 3H, H-27), 2.27 (br s, 1H, HN), 3.88 (q, JH,H = 6.4 Hz,
0
6
1H, H-13), 5.41 (s, 1H, H-11), 6.97 (d , JH,H = 8.2 Hz, 1H, H-26),
0
0
6.98 (s, 1H, H-22), 7.00 (d , 1H, H-24), 7.12 (t , JH,H = 7.5 Hz, 1H,
+
0
0
=
679 (5, [M+H] ).
H-25), 7.18 (d , JH,H = 7.3 Hz, 2H, H-16, H-20), 7.20 (t , 1H, H-7),
.21 (d , 1H, H-3), 7.22 (t , 1H, H-8), 7.36 (t , 1H, H-9), 7.37 (t ,
1H, H-18), 7.37 (d , 1H, H-6), 7.39 (t , 2H, H-17, H-19), 7.72 (d ,
1H, H-6), 7.73 (d , JH,H = 8.7 Hz, 1H, H-4), 13.76 (br. s, 1H, HO-
0
0
0
0
7
0
0
0
4
2
.2.3. 1-(((S)-1-Phenylethylamino)(m-tolyl)methyl) naphthalene-
,3-diol 14
0
1
3
A mixture of naphthalene-2,3-diol 13 (0.300 g, 1.87 mmol),
-methylbenzaldehyde (7) (0.472 g, 3.93 mmol), and (S)-(ꢁ)-1-
3
C(2)) ppm. C NMR (CDCl ) d 21.45 (q, C-27), 22.97 (q, C-14),
3
56.63 (d, C-13), 60.31 (d, C-11), 113.11 (s, C-1), 120.04 (d, C-
3), 121.14 (d, C-9), 122.33 (d, C-7), 124.73 (d, C-26), 126.34 (d,
C-8), 126.71 (2d, C-16, C-20), 128.64 (s, C-5), 128.21 (d, C-22),
128.70 (d, C-6), 128.75 (d, C-24), 127.86 (d, C-18), 128.91 (d,
C-25), 128.91 (2d, C-17, C19), 129.63 (d, C-4), 132.57 (s, C-10),
138.75 (s, C-23), 141.46 (s, C-21), 143.08 (s, C-15), 157.22 (s,
phenylethylamine 6 (0.450 g, 4.50 mmol) was stirred and heated
at 80 °C for 24 h. The crude mixture was then chromatographed
hexane/MTBE = 5:1) to give 0.373 g of a mixture containing the
aldehyde 7 and the corresponding imine (resulting from the reac-
tion of aldehyde 7 and amine 6) in a ratio of 45:55 (NMR data), and
(
1
1
4 (0.239 g, 33%) as a mixture of two diastereoisomers in a ratio of
4a/14b = 94:6. The major diastereoisomer 14a was isolated by
C-2) ppm. Anal. Calcd for C26H25NO (367.19): C, 84.98; H, 6.86;
N, 3.81. Found: C, 85.11; H, 6.98; N, 3.77. MS (CI) m/z (rel.
+
crystallization from hexane/Et
2
O (0.097 g, 13%).
int.) = 368 (12, [M+H] ).
4
.2.3.1. 1-((S)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
4.2.4.2. 1-((R)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
20
20
D
1
thalene-2,3-diol 14a. Mp 130–131 °C.
CHCl
½
a
ꢃ
¼ þ194:2 (c 1.00,
thalen-2-ol 16b. Mp 98 °C, ½
(600 MHz, CDCl
H-27), 3.97 (q, JH,H = 6.6 Hz, 1H, H-13), 5.84 (s, 1H, H-11), 7.04
a
ꢃ
¼ ꢁ70:7 (c 1.00, CHCl
3
). H NMR
D
1
3
). H NMR (600 MHz, CDCl
3
) d 1.50 (d, JH,H = 6.9 Hz, 3H, H-
3
) d 1.58 (d, JH,H = 6.7 Hz, 3H, H-14) 2.28 (s, 3H,
1
4), 1.57 (br s, 1H, HN), 2.23 (s, 3H, H-27), 3.88 (q, JH,H = 6.5 Hz,
0
0
0
0
1
H, H-13), 5.38 (s, 1H, H-11), 6.28 (br s, 1H, HO-C(3)), 6.92 (d ,
(d , JH,H = 7.3 Hz, 1H, H-24), 7.13 (d , 1H, H-3), 7.16 (t , 1H, H-25),
0
0
0
J
H,H = 8.3 Hz, 1H, H-26), 6.93 (s, 1H, H-22), 7.01 (d , JH,H = 7.5 Hz,
7.19 (s, 1H, H-22), 7.19 (d , JH,H = 7.2 Hz, 1H, H-26), 7.21 (t , 1H,
H-7), 7.24 (t , 1H, H-18), 7.26 (d , JH,H = 8.2 Hz, 2H, H-16, H-20),
7.31 (t , JH,H = 7.4 Hz, 2H, H-17, H-19), 7.34 (dd , JH,H = 8.4, 6.9 Hz,
1H, H-8), 7.68 (d , JH,H = 8.9 Hz, 1H, H-4), 7.71 (d , JH,H = 8.1 Hz,
0
0
0
0
1
H, H-24), 7.09 (ddd , JH,H = 8.3, 6.8, 1.5 Hz, 1H, H-8), 7.12 (t ,
0
0
0
0
J
H,H = 8.0 Hz, 1H, H-25), 7.19 (t , 1H, H-7), 7.19 (d , 2H, H-16,
0
0
0
0
0
H-20), 7.27 (s , 1H, H-4), 7.28 (d , JH,H = 8.2 Hz, 1H, H-9), 7.38 (t ,
0
0
0
13
1
1
H, H-18), 7.41 (t , 2H, H-17, H-19), 7.63 (dd , JH,H = 8.1, 1.2 Hz,
1H, H-6), 7.73 (d , 1H, H-9), 13.21 (br s, 1H, HO-C(2)) ppm.
C
H, H-6), 14.82 (br s, 1H, HO-C(2)) ppm. 13C NMR (CDCl
) d 21.45
NMR (CDCl ) d 21.49 (q, C-27), 20.97(q, C-14), 55.35 (d, C-13),
3
3
(
(
(
q, C-27), 22.83 (q, C-14), 56.75 (d, C-13), 60.68 (d, C-11), 108.83
d, C-4), 113.17 (s, C-1), 120.94 (d, C-9), 123.05 (d, C-7), 123.70
d, C-8), 124.64 (d, C-26), 126.69 (2d, C-16, C-20), 127.18 (s, C-
60.17 (d, C-11), 114.21 (s, C-1), 120.28 (d, C-3), 121.04 (d, C-9),
122.35 (d, C-7), 124.98 (d, C-26), 126.46 (d, C-8), 126.71 (2d,
C-16, C-20), 127.49 (d, C-18), 128.48 (d, C-22), 128.58 (s, C-5),
128.64 (2d, C-17, C-19), 128.77 (d, C-24) 128.81 (d, C-6), 128.89
(d, C-25), 129.57 (d, C-4), 132.33 (s, C-10), 138.73 (s, C-23),
143.07 (s, C-15), 143.28 (s, C-21), 156.69 (s, C-2) ppm.
1
0), 127.30 (d, C-6), 128.04 (d, C-18), 128.12 (d, C-22), 128.94 (d,
C-24), 128.95 (s, C-5), 128.99 (d, C-25), 129.00 (2d, C-17, C-19),
38.87 (s, C-23), 140.91 (s, C-21), 142.61 (s, C-15), 145.55 (s,
C-3), 147.28 (s, C-2) ppm. Anal. Calcd for C26 (383.48):
C, 81.43; H, 6.57; N, 3.65. Found: C, 81.48; H, 6.65; N, 3.85. MS
1
H25NO
2
4.2.5. 1-(Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
naphthalene-2-ol 17
+
(
ESI) m/z (rel int.) = 384 (50, [M+H] ).
A
mixture of naphthalene-2-ol (1) (0.500 g, 3.47 mmol),
4
.2.3.2. 1-((R)-((S)-1-Phenylethylamino)(m-tolyl)methyl)naph-
1-naphthaldehyde 8 (0.677 g, 4.33 mmol), and (S)-(ꢁ)-1-phenyl-
ethylamine 6 (0.546 g, 4.51 mmol) was stirred and heated at
80 °C for 72 h. Methanol was then added and the insoluble material
was filtered to give 17 (1.150 g, 82%) as a mixture of two diastere-
1
thalene-2,3-diol 14b. H NMR (250 MHz, CDCl
3
) d 1.60 (d,
J
H,H = 6.7 Hz, 3H, H-14), 2.28 (s, 3H, H-27), 3.96 (q, JH,H = 6.6 Hz,
1
H, H-13), 5.81 (s, 1H, H-11) ppm.
oisomers 17a/17b (98:2). After trituration with 2 ml of Et
tration, 17a (1.094 g, 78%) was isolated in pure form.
2
O and fil-
4
2
.2.4. 1-(((S)-1-Phenylethylamino)(m-tolyl)methyl)naphthalen-
-ol 16
A mixture of naphthalene-2-ol 1 (0.300 g, 2.08 mmol), 3-meth-
4.2.5.1. 1-((S)-Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
2
0
ylbenzaldehyde 7 (0.275 g, 2.29 mmol), and (S)-(ꢁ)-1-phenylethyl-
naphthalen-2-ol 17a. Mp 169–170 °C,
½
a
ꢃ
¼ þ449:4 (c 1.00,
D
4
b
amine 6 (0.322 g, 2.50 mmol) was stirred and heated at 80 °C for
CHCl
figuration: mp 195–197 °C, ½
(600 MHz, CDCl ) d 1.55 (d, JH,H = 6.9 Hz, 3H, H-14), 2.21 (d,
3
). (data from lit. for the diastereoisomer with an (R,R)-con-
2
D
0
1
4
8 h. Methanol was then added to the crude mixture and the insol-
uble material was filtered to give 16 (0.306 g, 40%) as a mixture of
a
ꢃ
¼ ꢁ484:7 (c 2.1, CHCl
3
)). H NMR
3

1
464
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
J
(
7
7
H,H = 11.6 Hz, 1H, HN), 3.99 (dq, JH,H = 11.6, 6.9 Hz, 1H, H-13), 6.30
JH,H = 9.0, 2.5 Hz, 1H, H-8), 6.94 (d, JH,H = 9.1 Hz, 1H, H-9), 6.96
(d , JH,H = 7.2 Hz, 1H, H-22), 7.12 (d , JH,H = 2.4 Hz, 1H, H-6), 7.17
0
0
0
0
0
s, 1H, H-11), 6.98 (d , 1H, H-29), 7.15 (t , 1H, H-8), 7.21 (t , 1H, H-
0
0
0
0
0
0
0
), 7.24 (t , 1H, H-23), 7.26 (d , 2H, H-16, H-20), 7.27 (t , 1H, H-28),
(d , 1H, H-3), 7.17 (t , 1H, H-23), 7.19 (d , 1H, H-29), 7.21 (t , 1H,
0
0
0
0
0
0
0
.29 (d , 1H, H-3), 7.29 (d , 1H, H-9), 7.32 (d , 1H, H-22), 7.46 (t , 1H,
H-28), 7.38 (d , 2H, H-16, H-20), 7.43 (t , 2H, H-17, H-19), 7.44 (t ,
1H, H-27), 7.44 (t , 1H, H-18), 7.63 (d , JH,H = 9.0 Hz, 1H, H-4),
7.68 (d , H,H = 8.2 Hz, 1H,
H-26) ppm. C NMR (CDCl ) d 20.21 (q, C-14), 54.31 (d, C-11),
0
0
0
0
0
H-27), 7.48 (t , 2H, H-17, H-19), 7.48 (t , 1H, H-18), 7.70 (d , 1H, H-
2
(
0
0
0
0
0
4), 7.77 (d , 1H, H-6), 7.81 (d , 1H, H-4), 7.85 (d , 1H, H-26), 13.69
J
H,H = 8.1 Hz, 1H, H-24), 7.82 (d ,
J
1
3
13
s, 1H, HO-C(2)) ppm. C NMR (CDCl
3
) d 21.63 (q, C-14), 55.53 (d,
3
C-11), 56.48 (d, C-13), 113.17 (s, C-1), 119.99 (d, C-3), 121.06 (d, C-
59.49 (d, C-13), 74.08 (t, C-31), 110.70 (d, C-6), 112.90 (s, C-1),
118.00 (d, C-8), 118.98 (d, C-3), 123.92 (d, C-9), 124.17 (d, C-29),
124.80 (d, C-23), 125.53 (d, C-27), 125.95 (d, C-28), 127.37 (d, C-
4), 127.64 (s, C-10), 127.90 (d, C-18), 128.36 (d, C-24), 128.53 (2d,
9
2
), 121.66 (d, C-29), 122.49 (s, C-7), 125.56 (d, C-27), 125.98 (d, C-
3), 126.60 (d, C-8), 126.71 (d, C-28), 127.00 (d, C-22), 127.60 (2d,
C-16, C-20)
,
128.31 (d, C-18), 128.72 (d, C-24), 128.77
(
d, C-6), 128.78 (s, C-5), 128.92 (2d, C-17, C-19), 129.29 (d, C-26),
,
C-17, C-19), 128.62 (d, C-26), 129.00 (2d, C-16, C-20) 129.45 (d, C-
1
29.85 (d, C-4), 130.22 (s, C-30), 132.76 (s, C-10), 134.07
22), 130.20 (s, C-5), 131.16 (s, C-30), 134.08 (s, C-25), 138.09 (s, C-
21), 143.76 (s, C-15), 151.31 (s, C-2), 151.38 (s, C-7) ppm. MS (ESI)
m/z (rel int.) = 432 (2, [M+H] ).
(
s, C-25), 135.27 (s, C-21), 142.07 (s, C-15), 158.11 (s, C-2) ppm.
Anal. Calcd for C29 25NO (403.51): C, 86.32; H, 6.24; N, 3.47.
Found: C, 86.06; H, 6.20; N, 3.39. MS (ESI) m/z (rel int.) = 404 (13,
+
H
+
[
M+H] ).
4.3.3. (S)-2-((S)-1-Phenylethyl)-1-m-tolyl-2,3-dihydro-1H-naphtho
[1,2-e][1,3]oxazin-5-ol 21a
4
.2.5.2. 1-((R)-Naphthalen-1-yl((S)-1-phenylethylamino)methyl)
According to the general procedure a mixture of 14a (0.156 g,
0.41 mmol) and formalin (10 equiv) in EtOH (2.5 ml) was stirred
at 20 °C for 2 h. This gave 0.078 g (48%) of 21a as colorless crystals
1
naphthalen-2-ol 17b. H NMR (250 MHz, CDCl
3
) d 1.57 (d,
JH,H = 6.6 Hz, 3H, H-14), 4.69 (q, JH,H = 6.5 Hz, 1H, H-13), 6.11 (s,
2
0
1
1
H, H-11) ppm.
.3. General procedure for the preparation of oxazines
To a solution of the corresponding compounds 11a, 14a, 16 (as a
(mp 79 °C). ½
CDCl ) d 1.54 (d, JH,H = 6.6 Hz, 3H, H-14). 2.23 (s, 3H, H-27), 3.97
(q, JH,H = 6.6 Hz, 1H, H-13), 5.04 (d, JH,H = 10.5 Hz, 1H, H-28), 5.19
s, 1H, H-11), 5.29 (dd, J = 10.5, 1.6 Hz, 1H, H-28), 5.90 (s, 1H,
aꢃ
3
¼ þ131:4 (c 1.00, CHCl ). H NMR (600 MHz,
D
3
4
(
0
0
OH), 6.77 (br s , 1H, H-26), 6.83 (s, 1H, H-22), 6.99 (d , JH,H = 8.3 Hz,
1H, H-9), 7.00 (d , JH,H = 7.3 Hz, 1H, H-24), 7.04 (ddd, JH,H = 8.2, 6.8,
1.3, 1H, H-8), 7.08 (t , 1H, H-25), 7.24 (ddd, JH,H = 8.1, 6.7, 1.2, 1H,
H-7), 7.28 (s , 1H, H-4), 7.33 (t , 1H, H-18), 7.37 (t , 2H, H-17, H-
19), 7.38 (d , 2H, H-16, H-20), 7.66 (br d , 1H, H-6) ppm. C NMR
(CDCl ) d 21.47 (q, C-27). 21.54 (q, C-14), 56.93 (d, C-11), 59.17
0
mixture of 16a/16b = 68:32), and 17a in ethanol was added 37% aq
solution of formaldehyde (calculated to provide 10 equiv of
formaldehyde) and the mixture was stirred at 20 °C or 55 °C for
the given time (see below). For compounds 9a and 16a, parafor-
maldehyde (1.5 equiv) in EtOH was used. After evaporation of
the solvent, the crude products were chromatographed (hexane/
MTBE = 5:1).
0
0
0
0
0
0
13
3
(d, C-13), 75.51 (t, C-28), 108.67 (d, C-4), 113.04 (s, C-1), 122.48
(d, C-9), 123.82 (d, C-7), 123.89 (d, C-8), 126.17 (d, C-26), 127.10
(
d, C-6), 127.54 (s, C-10), 127.60 (d, C-18), 127.80 (2d, C-16,
4
.3.1. (S)-2-((S)-1-Phenylethyl)-1-m-tolyl-2,3-dihydro-1H-naphtho
C-20), 127.99 (d, C-25), 128.09 (d, C-24), 128.61 (2d, C-17, C-19),
128.84 (s, C-5), 129.63 (d, C-22), 137.71 (s, C-23), 142.49 (s,
C-21), 142.77 (s, C-2), 144.19 (s, C-3), 144.96 (s, C-15) ppm. MS
[1,2-e][1,3]oxazin-8-ol 19a
According to the general procedure, a mixture of 9a (0.117 g,
.31 mmol) and paraformaldehyde in EtOH (1 ml) was stirred at
0 °C for 2 h. This gave 0.094 g (78%) of 19a as colorless crystals
+
0
5
(ESI) m/z (rel int.) = 396 (33, [M+H] ).
2
D
0
1
(
mp 84–85 °C). ½
a
ꢃ
¼ þ129:4 (c 1.00, CHCl
3
). H NMR (600 MHz,
4.3.4. (S)-2-((S)-1-Phenylethyl)-1-m-tolyl-2,3-dihydro-1H-naphtho
[1,2-e][1,3]oxazine 22a
CDCl
3
) d 1.54 (d, JH,H = 6.6 Hz, 3H, C-14), 2.23 (s, 3H, C-27), 3.96
(
q, 1H, JH,H = 6.6 Hz, C-13), 4.76 (br s, 1H, HO-C(7)), 4.94 (dd,
According to the general procedure a mixture of 16a (0.120 g,
0.33 mmol) and paraformaldehyde in EtOH (1 ml) was stirred at
50 °C for 2 h. This gave 0.113 g (91%) of 22a as colorless crystals
JH,H = 11.3, 1.6 Hz, 1H, H-28), 5.11 (dd, JH,H = 11.0, 1.9 Hz, 1H, H-
0
0
2
8), 5.10 (s, 1H, C-11), 6.78 (d , JH,H = 9.1 Hz, 1H, H-8), 6.79 (d ,
0
20
D
1
JH,H = 9.0 Hz, 1H, H-26), 6.83 (br s, 1H, H-22), 6.95 (d , JH,H = 9.1 Hz,
(mp 98-100 °C).
(600 MHz, CDCl
½
a
ꢃ
¼ þ164:7 (c 1.00, CHCl
3
).
H
NMR
0
0
1
1
H, H-9), 6.99 (d , JH,H = 7.5 Hz, 1H, H-24), 7.06 (s, 1H, H-6), 7.07 (t ,
3
) d 1.54 (d, JH,H = 6.6 Hz, 3H, H-14), 2.22 (s, 3H,
0
0
0
H, H-25), 7.11 (d , 1H, H-3), 7.32 (t , 1H, H-18), 7.37 (t , 2H, H-17,
H-27), 3.96 (q, JH,H = 6.6 Hz, 1H, H-13), 4.97 (d, JH,H = 10.5 Hz, 1H,
H-28), 5.14 (dd, JH,H = 10.7, 1.8 Hz, 1H, H-28), 5.16 (s, 1H, H-11),
0
0
H-19), 7.38 (d , 2H, H-16, H-20), 7.59 (d , JH,H = 8.9 Hz, 1H, H-4)
ppm. C NMR (CDCl
C-11), 59.06 (d, C-13), 74.19 (t, C-28), 110.56 (d, C-6), 112.48 (s,
C-1), 117.78 (d, C-8), 119.13 (d, C-3), 124.45 (d, C-9), 126.22 (d,
C-26), 127.24 (d, C-4), 127.46 (d, C-18), 127.86 (2d, C-16, C-20)
1
1
1
1
3
0
0
3
) d 21.48 (q, C-27), 21.58 (q, C-14), 57.18 (d,
6.80 (br s , 1H, H-26), 6.98 (s, 1H, H-22), 6.99 (d , JH,H = 7.5 Hz,
0
0
0
1H, H-24), 7.05 (d , 1H, H-9), 7.07 (t , 1H, H-25), 7.14 (d , JH,H =
8.8 Hz, 1H, H-3), 7.17 (t , 1H, H-8), 7.24 (t , 1H, H-7), 7.32 (t , 1H,
H-18), 7.37 (t , 2H, H-17, H-19), 7.38 (d , 2H, H-16, H-20), 7.74
(d , JH,H = 8.8 Hz, 1H, H-4), 7.76 (d , JH,H = 8.6 Hz, 1H, H-6) ppm.
0
0
0
0
0
,
0
0
27.92 (d, C-25), 127.94 (d, C-24), 128.01 (s, C-5), 128.55 (2d, C-
7, C-19), 129.71 (d, C-22), 130.02 (s, C-10), 137.64 (s, C-23),
1
3
3
C NMR (CDCl ) d 21.48 (q, H-27). 21.60 (q, H-14), 57.13 (d, C-
43.13 (s, C-21), 145.39 (s, C-15), 151.15 (s, C-2), 151.25 (s, C-7)
11), 59.08 (d, C-13), 74.31 (t, C-31), 112.19 (s, C-1), 118.42 (d,
C-3), 122.63 (d, C-9), 123.05 (d, C-7), 126.24 (d, C-26), 126.41 (d,
C-8), 127.45 (d, C-18), 127.84 (2d, C-16, C-20), 127.92 (d, C-25),
127.92 (d, C-24), 128.42 (d, C-6), 128.54 (2d, C-17, C-19), 128.81
(d, C-4), 128.93 (s, C-5), 129.70 (d, C-22), 132.86 (s, C-10), 137.62
(s, C-23), 143.10 (s, C-21), 145.38 (s, C-15), 152.75 (s, C-2) ppm.
+
ppm. MS (CI) m/z (rel int.) = 396 (16, [M+H] ).
4
1
.3.2. (S)-1-(Naphthalen-1-yl)-2-((S)-1-phenylethyl)-2,3-dihydro-
H-naphtho[1,2-e][1,3]oxazin-8-ol 20a
According to the general procedure, a mixture of 11a (0.120 g,
.29 mmol) and formalin (10 equiv) in EtOH (1 ml) was stirred at
5 °C for 2 h. This gave 0.123 g (99%) of 20a as colorless crystals
+
0
5
MS (ESI) m/z (rel int.) = 380 (3, [M+H] ).
2
D
0
1
(
mp 109 °C). ½
aꢃ
¼ þ257:4 (c 1.00, CHCl
3
). H NMR (600 MHz,
4.3.5. (R)-2-((S)-1-Phenylethyl)-1-m-tolyl-2,3-dihydro-1H-naphtho
[1,2-e][1,3]oxazine 22b
CDCl
3
) d 1.64 (d, JH,H = 6.7 Hz, 3H, H-14). 4.14 (q, JH,H = 6.7 Hz, 1H,
H-13), 4.75 (s, 1H, OH), 5.03 (dd, JH,H = 10.7, 1.2 Hz, 1H, H-31),
According to the general procedure, a diastrereoisomeric mix-
ture of 16a/16b = 68:32 (0.120 g, 0.316 mmol) and formalin
0
5
.15 (d, JH,H = 10.8 Hz, 1H, H-31), 6.00 (s, 1H, H-11), 6.73 (dd ,

M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
1465
(
10 equiv) in EtOH (2.5 ml) was stirred at 20 °C for 30 min. After
column chromatography (hexane/MTBE = 300:1) 0.007 g (5.7%) of
2a, 0.100 g (81%) of a mixture of 22a and 22b and 0.009 g
7.3%) of 22b were isolated. Data of 22a: in agreement with
the data obtained by the reaction of 16a with formaldehyde
of the products was determinated by HPLC or GC with chiral
columns.
2
(
4
.5. General procedure for enantioselective addition of alkynylzinc
20
compounds to aldehydes
(
see above). Data of 22b: mp 169–171 °C. ½
a
ꢃ
¼ ꢁ64:8 (c 0.45,
D
1
CHCl
H-14), 2.29 (s, 3H, H-27), 4.10 (q, JH,H = 6.5 Hz, 1H, H-13), 4.45
dd, JH,H = 10.5, 2.2 Hz, 1H, H-28), 4.69 (d, JH,H = 10.4 Hz, 1H,
3 3
). H NMR (600 MHz, CDCl ) d 1.57 (d, JH,H = 6.0 Hz, 3H,
To a solution of the corresponding ligand 16a or 17a (0.3 equiv)
in toluene, Et Zn (2 equiv of 1 M solution in hexane) and Lewis
2
(
0
base (Et N, 2 equiv) were added under an Ar atmosphere at room
H-28), 5.71 (s, 1H, H-11), 7.00 (br s, 1H, H-26), 7.05 (d ,
3
0
temperature. After 1 h of stirring, the corresponding alkyne
J
H,H = 7.5 Hz, 1H, H-24), 7.08 (br s, 1H, H-22), 7.12 (d , JH,H = 8.9 -
0
0
0
(1.5 equiv) was added. The mixture was cooled to 0 °C and the
aldehyde (1 equiv) was added. The reaction was stirred at rt and
monitored by TLC (hexane/MTBE = 5:1) until the aldehyde was
Hz, 1H, H-3), 7.15 (t , 1H, H-25), 7.28 (t , 1H, H-18), 7.30 (t , 1H,
H-7), 7.31 (t , 1H, H-8), 7.35 (t , 2H, H-17, H-19), 7.40 (d , 1H, H-
9
1
C-27), 21.97 (q, C-14), 54.59 (d, C-11), 58.08 (d, C-13), 76.03 (t,
C-28), 112.10 (s, C-1), 118.70 (d, C-3), 122.46 (d, C-9), 123.09 (d,
C-7), 126.45 (d, C-26), 126.61 (d, C-8), 127.37 (d, C-18), 127.83
0
0
0
0
0
), 7.44 (d , JH,H = 7.2 Hz, 2H, H-16, H-20), 7.75 (d , JH,H = 8.9 Hz,
0
13
consumed. The mixture was quenched (aq. NH Cl), extracted with
H, H-4), 7.79 (d , 1H, H-6) ppm. C NMR (CDCl
3
) d 21.48 (q,
4
Et
2
O (3 ꢂ 20 ml), and dried. After evaporation of the solvent the
crude product was purified by column chromatography (hexane/
MTBE = 5:1). The enantiomeric excess was determinated by HPLC
(
chiral columns).
(
2d, C-16, C-20), 127.90 (d, C-24), 127.97 (d, C-25), 128.45 (2d,
C-17, C-19), 128.56 (d, C-6), 128.89 (s, C-5), 129.00 (d, C-4),
29.84 (d, C-22), 132.61 (s, C-10), 137.75 (s, C-23), 143.33 (s,
C-21), 143.95 (s, C-15), 152.58 (s, C-2) ppm.
4
.6. Conditions for the determination of enantiomeric excess
1
(
GC or HPLC)
1
-Phenylpropan-1-ol determined by GC analysis (MN-
Hydrodex-b-TBAc column, 1 ml/min, He, split 21, Tdet = 230 °C,
inj = 220 °C) retention time minor = 9.8 min, major = 10.1 min.
-(2-Methoxyphenyl)propan-1-ol determined by GC analysis
FS-Cyclolex beta—I/P, 150 °C isothermal, 1 ml/min He, split 21:1,
det = 230 °C, inj = 220 °C) retention time minor = 9.6 min,
major = 10.1 min. 1-Ferrocenylpropan-1-ol determined by HPLC
analysis (Chiralpak IC, 5% i-PrOH in hexane, 25 °C, 1 mg/4 ml)
retention time tminor = 7.5 min, tmajor = 8.0 min. 1-(Naphthalen-1-
yl)propan-1-ol determined by GC analysis (FS-Cyclolex beta—I/P,
4
1
.3.6. (S)-1-(Naphthalen-1-yl)-2-((S)-1-phenylethyl)-2,3-dihydro-
H-naphtho[1,2-e][1,3]oxazine 23a
T
1
(
T
t
t
According to the general procedure, a mixture of 17a (0.120 g,
.290 mmol) and formalin (10 eq) in EtOH (2.5 ml) was stirred at
0 °C for 24 h. After column chromatography, 0.028 g (23%) of
3a as colorless crystals and 0.029 g (24%) of unreacted 17a
0
2
2
T
t
t
2
D
0
were isolated. Data of 23a: mp 85 °C. ½
a
ꢃ
¼ þ283:7 (c 1.00,
1
CHCl
3
). H NMR (600 MHz, CDCl
3
) d 1.64 (d, JH,H = 6.7 Hz, 3H,
H-14), 4.14 (q, JH,H = 6.7 Hz, 1H, H-13), 5.06 (dd, JH,H = 10.8,
1
60 °C isothermal, 1 ml/min He, split 21:1,
Tdet = 230 °C,
1
.8 Hz, 1H, H-31), 5.18 (d, JH,H = 10.8 Hz, 1H, H-31), 6.06 (s, 1H,
0
T
inj = 220 °C) retention time minor = 29.2 min, major = 30.0 min.
t
t
H-11), 6.97 (d , JH,H = 7.1 Hz, 1H, H-22), 7.05 (d, JH,H = 8.5 Hz,
0
0
1-Cyclohexylpropan-1-ol determined by GC analysis ((Cyclosilb
(JB), 115 °C isothermal, 1 ml/min He, split 21:1, Tdet = 200 °C,
Tinj = 190 °C) retention time tminor = 18.4 min, tmajor = 18.8 min.
1-(4-Chlorophenyl)propan-1-ol determined by HPLC analysis
(Chiralpak IC, 2% i-PrOH in hexane, 25 °C, 1 mg/4 ml) retention
time tminor = 8.1 min, tmajor = 7.5 min. 1-(Naphthalen-2-yl)propan-
1-ol determined by GC analysis (MN-Hydrodex-b-TBAc, 160 °C iso-
thermal, 1 ml/min, He, split 21:1, Tdet = 240 °C, Tinj = 240 °C)) reten-
tion time tminor = 31.9 min, tmajor = 30.9 min. 1-Phenylpent-1-en-3-
ol determined by HPLC analysis (Chiralpak IC, 10% THF in hexane,
1
H, H-9), 7.12 (ddd , JH,H = 8.2, 6.8, 1.2 Hz, 1H, H-8), 7.16 (t ,
0
0
0
1
H, H-23), 7.20 (d , 1H, H-3), 7.21 (d , 1H, H-29), 7.21 (t , 1H,
0
0
H-28), 7.24 (ddd , JH,H = 8.0, 6.9, 1.1 Hz, 1H, H-7), 7.38 (d , 2H,
H-16, H-20), 7.43 (t , 2H, H-17, H-19), 7.44 (t , 1H, H-27), 7.44
0
0
0
0
0
(
t , 1H, H-18), 7.63 (d , JH,H = 8.6 Hz, 1H, H-4), 7.68 (d , JH,H = 8.0 -
0
0
Hz, 1H, H-24), 7.78 (d , JH,H = 7.0 Hz, 1H, H-6), 7.82 (d , JH,H = 8.2 -
Hz, 1H, H-26) ppm. C NMR (CDCl ) d 20.23 (q, C-14), 54.29 (d,
3
C-11), 59.55 (d, C-13), 74.24 (t, C-31), 110.70 (d, C-6), 112.90 (s,
C-1), 118.00 (d, C-8), 118.98 (d, C-3), 123.16 (d, C-7), 123.92 (d,
C-9), 124.21 (d, C-29), 124.81 (d, C-23), 125.53 (d, C-27), 125.96
1
3
2
5 °C, 1 mg/4 ml) retention time tminor = 6.1 min, tmajor = 5.3 min.
(
d, C-28), 127.90 (d, C-18), 128.36 (d, C-24), 128.54 (2d, C-17, C-
1
,3-Diphenylprop-2-yn-1-ol determined by HPLC analisys (Chir-
1
1
9), 128.62 (d, C-26), 128.96 (d, C-4), 129.00 (2d, C-16, C-20),
29.13 (s, C-5), 129.43 (d, C-22), 131.19 (s, C-30), 132.52 (s,
alpak IC, 30% MTBE in hexane, 25 °C, 1.1 mg/ 2 ml) retention time
minor = 8.6 min, major = 9.6 min. 1-(4-Chlorophenyl)-3-phenyl-
t
t
C-10), 134.08 (s, C-25), 138.06 (s, C-21), 143.77 (s, C-15),
+
prop-2-yn-1-ol determined by HPLC analysis (Chiralpak IC, 1%
i-PrOH in hexane, 25 °C, 1.4 mg/ 2 ml) retention time tminor = 18.8
min, tmajor = 19.9 min. 1-(Naphthalen-1-yl)-3-phenylprop-2-yn-1-
ol determined by HPLC analysis (Chiralpak IC, 4% i-PrOH in hexane,
25 °C, 1.3 mg/2 ml) retention time tminor = 15.4 min, tmajor = 18.6 -
min. 1-(Naphthalen-2-yl)-3-phenylprop-2-yn-1-ol determined by
HPLC analysis (Chiralpak IA, 8% i-PrOH in hexane, 25 °C, 1.3 mg/
2 ml) retention time tminor = 15.1 min, tmajor = 17.3 min. 1-(4-Nitro-
phenyl)-3-phenylprop-2-yn-1-ol determined by HPLC analysis
(Chiralpak IA, 10% i-PrOH in hexane, 25 °C, 1 mg/1.5 ml) retention
time tminor = 11.5 min, tmajor = 14.7 min. 3-Phenyl-1-m-tolylprop-2-
yn-1-ol determined by HPLC analysis (Chiralpak IC, 17% MTBE in
hexane, 25 °C, 1.7 mg/2.5 ml) retention time tminor = 18.0 min,
1
52.99 (s, C-2) ppm. MS (ESI) m/z (rel int.) = 416 (22, [M+H] ).
4
.4. General procedure for enantioselective addition of diethylzinc
to aldehydes
To a solution of the corresponding ligand 9a, 11a, 14a, 16a,
2
and 17a (3 mol %) in 4 ml of toluene, Et Zn (2.22 mmol of 1 M
solution in hexane) was added dropwise at 0 °C. The mixture
was stirred for 30 min at 0 °C and then the corresponding
aldehyde (1.30 mmol) was added at ꢁ25 °C. The reaction was
stirred at rt and monitored by TLC (hexane/MTBE = 2:1) until
the aldehyde was consumed. The mixture was quenched (aq.
NH
4
Cl), extracted with Et
2
O (3 ꢂ 20 ml), and dried. After evapo-
tmajor = 21.6 min. 1-Cyclohexyl-3-phenylprop-2-yn-1-ol deter-
mined by HPLC analysis (Chiralpak IC, 3% i-PrOH in hexane,
25 °C, 1.4 mg/2 ml) retention time tminor = 10.5 min, tmajor = 11.4 -
ration of the solvent, the crude product was purified by column
chromatography (hexane/MTBE = 5:1). The enantiomeric excess

1
466
M. Marinova et al. / Tetrahedron: Asymmetry 24 (2013) 1453–1466
min. 3-Cyclopropyl-1-phenylprop-2-yn-1-ol determined by HPLC
analysis (Chiralpak IA, 5% i-PrOH in hexane, 25 °C, 1.3 mg/2 ml)
6. Wang, Y.; Li, X.; Ding, K. Tetrahedron: Asymmetry 2002, 13, 1291–1297.
7.
(a) Ma, F.; Ai, L.; Shen, X.; Zhang, C. Org. Lett. 2007, 9, 125–127; (b) Szatmari, I.;
Lazar, L.; Fülöp, F. Tetrahedron 2003, 59, 2844–2877; (c) Li, Z.; Sun, Y.; Shen, X.;
Al, L.; Zhang, C. Chin. J. Org. Chem. 2006, 26, 465–469; (d) Sun, Y.; Li, Z.; Shen, X.;
Ma, F.; Zhang, C. Chin. Chem. Lett. 2005, 16, 879–882.
retention time
tminor = 9.7 min, tmajor = 11.5 min. 1-(4-Chloro-
phenyl)-3-cyclopropylprop-2-yn-1-ol determined by HPLC analy-
sis (Chiralpak IA, 10% i-PrOH in hexane, 25 °C, 1.3 mg/2 ml)
retention time tminor = 6.7 min, tmajor = 8.0 min. 6-Chloro-1-phenyl-
hex-2-yn-1-ol determined by HPLC analysis (Chiralpak IA, 5%
i-PrOH in hexane, 25 °C, 1.1 mg/2 ml) retention time tminor = 11.7
min, tmajor = 13.4 min. 6-Chloro-1-(4-chlorophenyl)hex-2-yn-1-ol
determined by HPLC analysis (Chiralpak IA, 5% i-PrOH in hexane,
8
9
.
.
(a) Szatmari, I.; Fülöp, F. Synthesis 2009, 775–778; (b) Saidi, M.; Azizi, N.;
Naomi-Jamal, R. Tetrahedron Lett. 2001, 42, 8111–8113.
Liu, G.; Zhang, S.; Li, H.; Zhang, T.; Wang, W. Org. Lett. 2011, 13, 828–831.
10. (a) Xiong, R. Lett. Org. Chem. 2008, 5, 265–268; (b) Shafiee, M.; Khosropour, A.
R.; Mohammadpoor-Baltork, I.; Moghadam, M.; Tangestaninejad, S.; Mirkhani,
V. Tetrahedron Lett. 2012, 53, 3086–3090.
1
1. Wei, H.; Yin, L.; Luo, X.; Chan, A. S. C. Chirality 2011, 23, 222–227.
12. (a) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Bioorg. Med. Chem. Lett. 2008,
8, 788–792; (b) Cimarelli, C.; Fratoni, D.; Mazzanti, A.; Palmieri, G. Eur. J. Org.
1
2
=
5 °C, 1.2 mg/2 ml) retention time tminor = 12.5 min, tmajor
15.7 min.
Chem. 2011, 2094–2100; (c) Jiang, C.; Geng, X.; Zhang, Z.; Xu, H.; Wang, C. J.
Chem. Res. 2010, 19–21.
1
3. (a) Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi, M. C.
K.; Chan, A. S. C. Org. Lett. 2001, 3, 2733–2735; (b) Heydenreich, M.; Koch, A.;
Klod, S.; Szatmari, I.; Fülöp, F.; Kleinpeter, E. Tetrahedron 2006, 11081–11089.
4. Zagranyarska, I.; Kostova, K.; Chimov, A.; Zagranyarski, Y.; Nikolova, R.;
Shivachev, B.; Dimitrov, V. in preparation.
Acknowledgements
1
1
Generous financial support by program SCOPES—Swiss National
Science Foundation, project No. IZ73ZO_128013 is gratefully
acknowledged. Support by the National Science Fund of Bulgaria
5. Cardellicchio, C.; Capozzi, M. A. M.; Alvarez-Larena, A.; Piniella, J. F.; Capitelli, F.
Cryst. Eng. Commun. 2012, 14, 3972–3981.
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