Stereoselective synthesis of new vicinal diaminoalkyl naphthols by three component Mannich type reaction of α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetasy.2011.08.025

The application of the aromatic Mannich reaction to α,β- unsaturated aldehydes, affords a series of new diaminoalkyl naphthols, by a convenient solventless reaction, starting from inexpensive and easily available starting materials. The absolute configura

Full text of DOI:10.1016/j.tetasy.2011.08.025

Tetrahedron: Asymmetry 22 (2011) 1560–1567
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of new vicinal diaminoalkyl naphthols by three
component Mannich type reaction of a,b-unsaturated aldehydes
⇑
Cristina Cimarelli , Davide Fratoni, Gianni Palmieri
School of Science and Technology, Chemistry Division, Via S. Agostino 1, 62032 Camerino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of the aromatic Mannich reaction to a,b-unsaturated aldehydes, affords a series of new
Received 25 July 2011
Accepted 31 August 2011
Available online 1 October 2011
diaminoalkyl naphthols, by a convenient solventless reaction, starting from inexpensive and easily avail-
able starting materials. The absolute configurations of the products obtained are attributed on the basis of
the coupling constant values of 1H NMR spectra, joined with the conformational analysis of the molecules
by molecular modelling.
intermediate.
A
mechanistic hypothesis is proposed, which involves an imino–amino
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aminols are important building blocks in organic synthesis and
are privileged structural elements in the search for chiral ligands.1,2
They find application in asymmetric catalysis, a field of great inter-
est in modern organic chemisty.3–7 Enantiopure vicinal diamines
and aminols are also subunits often present in a large number of
pharmaceutical compounds and bioactive natural products.
Chiral diamines and aminols are frequently prepared by stereo-
selective nucleophilic addition to readily available starting materi-
als, such as aldimines or related compounds. In these syntheses the
Mannich reaction is often used, in which C–N and C–C single bonds
replace the C@O double bond.8,9 This makes the three-component
aminoalkylation of aldehydes one of the most important multi-
component reactions in organic synthesis.
For some time we have been interested in the stereoselective
synthesis of aminoalcohols by reduction or alkylation of com-
pounds containing the enaminonic unit (enamino ketones,10 ena-
mino esters11–13 and imidoylphenols14–16). We have found for the
first time that a straightforward and stereoselective synthesis of
aminoalkyl naphthols can be performed by Mannich reaction using
enantiopure amines and inexpensive reagents.14 Aminoalkyl naph-
thols are obtained by this methodology in good yields and high
enantiomeric purity and are result effective catalysts in the enan-
tioselective alkylation of aldehydes.15,17,18
The reaction of b-naphthol with a,b-unsaturated aldehydes 1
and aliphatic amines 2 affords diaminoalkyl naphthols 3 in good
yields and in several cases high diastereomeric excesses
(Scheme 1). The reaction is convenient because it is performed
without solvent and using inexpensive and easily available starting
materials. Furthermore the reaction mixture does not require any
workup before the separation on chromatographic column of the
products obtained. The products isolated and the yields obtained
are reported in Table 1.
Normally aldehydes do not react with b-naphthol in the ab-
sence of acids or bases, because of their poor electrophilicity.19
On the other hand, unsaturated aldehydes have been studied in
the reactions with b-naphthol, to prepare 2,3-dihydro-1H-naph-
tho[2,1-b]pyran-3-ol20 or benzochromenes;21,22 in solventless con-
ditions also benzoxanthenes are obtained.23,24 None of the
aforementioned compounds was detected in the reaction mixtures
of our reactions which indicate that the formation of an imine
intermediate takes place first, and this precludes the direct reac-
tion of aldehyde with naphthol.
Furthermore, in our case the presence of twofold excess of
amine, suggests that an intermediate imino–amine, resulting from
the double attack of two molecules of amine on the unsaturated
aldehyde might be involved. The reaction of the aldehyde with
only 1 mol of amine affords only cyclic products such as 525 and
on the basis of the structure of the final product 3 it is possible
to hypothesise that the attack of the second equivalent of amine
on the aldehyde takes place before the attack of imine on b-naph-
thol (Scheme 2).
With the aim of extending the synthetic potential of this reac-
tion, we describe the reaction of b-naphthol with a,b-unsaturated
aldehydes and aliphatic amines, aimed at the preparation of a ser-
ies of new chiral diaminoalkyl naphthols, potential N,N,O-ligands
for metal catalysed enantioselective reactions.
On mixing aldehydes 1 and amines 2 an immediate reaction
takes place that affords to the corresponding imino–amine, as evi-
denced by the formation of same droplets of water on the reaction
⇑
Corresponding author. Tel.: +39 0737 402268; fax: +39 0737 637345.
E-mail address: cristina.cimarelli@unicam.it (C. Cimarelli).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.025

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
1561
H
N
H
N
R
R
OH
OH
O
R1
3
R
1
solventless
r.t.
2
R2
+
2
H
R1
H2N
+
R2
1
2
3
Scheme 1.
Table 1
Starting aldehydes 1 and amines 2 and products 3 obtained in the reaction between b-napthol,
a
,b-unsaturated aldehydes and amines
Entry
1
2
3a
drb
Yield (%)c
Bn
HN
Bn
OH HN
(RS)
(SR)
Threo
69
60
(1RS,3SR)-3a
O
1
1a
BnNH2
2a
Bn
HN
Bn
OH HN
H
(SR)
(RS)
Erythro
31
26
(RS,RS)-3a
Ph
(R)
Ph
(R)
OH HN
HN
Ph
(R)
(S)
2
1a
(R)-2b
Threo
72
54
NH2
(1R,3S)-3b
OH
N
N
(RS)
(SR)
3
1a
2c
Threo
97
64
N
H
(1RS,3SR)-3c
Bn
HN
Bn
OH HN
(SR)
(RS)
Threo
67
60
O
(1RS,3SR)-3d
H
4
1b
2a
Bn
Bn
OH HN
HN
(RS)
(RS)
Erythro
33
29
(RS,RS)-3d
(continued on next page)

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C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
Table 1 (continued)
Entry
1
2
3a
drb
Yield (%)c
Ph
(R)
Ph
(R)
OH HN
HN
(S)
(R)
Threo
66
62
(1R,3S)-3e
5
1b
(R)-2b
Ph
Ph
(R)
(R)
OH HN
HN
(S)
(R)
Threo
Threo
Threo
Threo
34
87
80
82
31
60
56
(1S,3R)-3e
Bn
Bn
OH HN
HN
O
Ph
(RS)
(RS)
6
1c
2a
H
Ph
(RS,RS)-3f
Ph
(R)
Ph
(R)
OH HN
HN
Ph
(R)
(R)
7
1c
(R)-2b
(1R,3R)-3g
Bn
Bn
OH HN
HN
(SR)
(RS)
O
(RS) Ph
8
1d
2a
52
H
H
Ph
(1RS,2SR,3RS)-3h
Bn
HN
Bn
OH HN
O
(RS)
9
1e
2a
63
(RS)-3i
Ph
(R)
Ph
(R)
OH HN
HN
(R)
58
10
1e
(R)-2b
(1R)-3j
22

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
1563
Table 1 (continued)
Entry
1
2
3a
drb
Yield (%)c
Ph
(R)
Ph
(R)
OH HN
HN
(S)
(1S)-3j
OH HN
(RS)
Bn
HN
Bn
(SR)
O
11
1f
2a
38
H
(1RS,2SR)-3k
a
b
c
The absolute configuration was attributed on the basis of the J values observed for the relative aminoalkyl naphthol 3.
The dr values were determined by 1H NMR of the crude reaction mixture.
Yield of the pure isolated diastereomers.
flask. At this point it is assumed that an aldiminium type complex
A is formed by protonation of the imine nitrogen by b-naphthol, in
which the reactivity of both the electrophilic iminium carbon atom
This hypothetical mechanism is reported in Scheme 3.
3. Absolute configuration attribution
and the nucleophilic
the Friedel–Crafts reaction takes place, and in the first step, that
is the rate-limiting one of the whole reaction, the arenium -com-
a-position of b-naphthol are activated. Then
The relative configuration of the new stereogenic centres,
formed in the side chain during the condensation reaction, was
attributed on the basis of the 3J values of 1H NMR spectra, joined
with the conformational analysis of the molecules done by molec-
ular modelling.26 The products 3a–k obtained can have either an er-
ythro or a threo structure. These diastereomers can be distinguished
by observing the 1H NMR signals of the protons in the side chain.
The conformational analysis shows that, in the most populated
conformation, all the products present two intramolecular hydro-
gen bonds: one between the hydroxyl proton and the nitrogen of
the amino group in C-1, and the second between the proton of
the same amino group and the nitrogen atom of the amino group
in C-3, as depicted in Figures 1 and 2. The presence of these hydro-
gen bonds requires the molecules to assume a very rigid and stable
conformation, in which the steric relationships between the pro-
tons of the side chain result that is evident and clearly explainable
on the basis of the 1H NMR signals.
r
plex C is formed through a six-membered transition state B, lead-
ing to the final 1,3-diaminoalkyl-2-naphthols 3.
In particular in Figures 1 and 2 are shown some significant sig-
nals of 1H NMR spectra of both diastereomers of product 3a. In the
spectrum in Figure 1 the C-2 geminal protons (H-2) show, respec-
tively, a doublet of double doublets at 1.68 ppm and a double dou-
blet of doublets at 2.40 ppm. The structure of the signal at
1.68 ppm (H-2e) is explained by a big geminal coupling constant
(J = 15.2 Hz) and by two smaller constants (J = 2.9 and 5.1 Hz)
due to the gauche coupling with H-1 and H-3, respectively. The sig-
Figure 1. Most stable conformation of product threo-(1RS,3SR)-3a and 1H NMR
signals of protons H-2a (left) and H-2e (right).
H
O
R2
H
N
H
N
R2
R
R2
R1
N
OH
R
R2
H
R2
R1
O
H
R
N
N
1) H2NR2, 1 mol
H2NR2
2 mol
β-naphthol
H
R1
R1
1 mol
2) β-naphthol
R
1
3
4
5
Scheme 2.

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C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
R
H
N
R
O
H
R
O
H
N
H
H
N
R
N
H
O
O
H
H
H1
H1
NHR
H
NHR
NHR
NHR
R1
R1
R1
R1
A
B
C
3
Scheme 3.
Figure 2. Most stable conformation of product erythtro-(RS,RS)-3a and 1H NMR
signals of protons H-2a and H-2e.
Figure 3. Most stable conformation of product (1R,3S)-3b.
product (1R,3S)-3b obtained by molecular modelling conforma-
tional analysis26 and are reported in Figure 3, it is possible to see
that this effect is present also in such molecules.
nal at 2.40 ppm (H-2a) presents the geminal coupling constant
(J = 15.2 Hz), a big one (J = 11.4 Hz) due to the trans coupling with
H-1 and a smaller one (J = 3.3 Hz) due to the gauche coupling with
H-3 hydrogen atom. The conformational analysis of this couple of
diastereomers shows that the protons in the side chain are ar-
ranged in this way in the threo isomer (Fig. 1).
4. Conclusions
On the other hand, in the most stable conformation of the ery-
thro isomer the same C2 methylene protons present a different
arrangement with respect to proton H-3. The 1H NMR signals of
the second diastereomer shows that the signals of the geminal C-
2 protons appear partially superimposed, resulting in a double
triplet at 1.84 ppm followed by another double triplet at
1.97 ppm (Fig. 2). Proton H-2e shows a big geminal coupling con-
stant (J = 14.6 Hz) and a second smaller (t, J = 2.9 Hz)one, like pro-
ton H-2a at 1.97 ppm, that shows the geminal coupling constant
(J = 14.6 Hz) and a second large coupling constant (t, J = 9.9 Hz)
due to the anti coupling with H-1 and H-3 hydrogen atoms.
The absolute configuration of aminoalkyl naphthols 3b,e,g,j,
prepared starting from enantiopure (R)-1-phenylethylamine, was
assigned on the basis of the common trend observed in this kind
of reaction27: (R)-1-phenylethylamine drives the reaction towards
the formation of a stereogenic centre in C-1 in which H-1 is on the
same side of the methyl group of the (R)-1-phenylethylamino
group (generally C-1 has an (R) absolute configuration). In the
more stable conformation of the major product, H-1 falls into the
shielding cone of the phenyl group of the chiral group and usually
its 1H NMR signal is shifted upfield with respect to molecules that
have other substituents bonded to nitrogen.
The application of the aromatic Mannich reaction to a,b-unsat-
urated aldehydes, affords a series of new diaminoalkyl naphthols,
by a convenient solventless reaction, starting from inexpensive
and easily available starting materials. A mechanism is proposed
and further studies are underway to better understand the reactiv-
ity of these systems towards amines. The relative and absolute
configurations of the products obtained were attributed on the ba-
sis of the 3J values of 1H NMR spectra, joined with the conforma-
tional analysis of the molecules done by molecular modelling.
5. Experimental
5.1. General methods
1H and 13C NMR spectra were recorded at 200 or 300 MHz and
50 or 75 MHz, respectively. Coupling constants given in Hz. IR
spectra were recorded using a FTIR apparatus. Optical rotations
were measured in a 1 dm cell at 20 °C. All the melting points were
uncorrected. Where only the major diastereomer wasobtained
pure, the 1H NMR signals for the minor diastereomer were deduced
from the spectra of the crude reaction mixture or from enriched
chromatographic fractions.
In particular the signals of H-1a in products 3b,e,g,j are shifted
upfield (D ranging from 0.25 to 0.49 ppm) in comparison to the H-
1a signals of products 3a,d,f,i in which a benzyl group is bonded to
nitrogen (3a 5.05 ppm vs 3b 4.67 ppm; 3d 5.01 ppm vs 3e
4.52 ppm; 3f 4.75 ppm vs 3g 4.50 ppm; 3i 4.84 ppm vs 3j
4.50 ppm). Actually, observing the preferred conformation of the
5.2. Materials and solvents
All reagents were commercially available, and purchased at the
highest quality and were purified by distillation when necessary.

C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
1565
5.3. General procedure for the preparation of aminoalkyl
naphthols 3a–g
128.7, 129.7 135.0, 154.8; Anal. Calcd for C22H30N2O (338.49): C,
78.06; H, 8.93; N, 8.28. Found: C, 77.89; H, 8.71; N, 8.07.
5.3.5. 1-((1RS,3SR)-1,3-Bis(benzylamino)hexyl)naphthalen-2-ol
(1RS,3SR)-3d
A
mixture of 2-naphthol (0.72 g, 5.0 mmol), aldehydes 1
(5.0 mmol) and amine 2 (10.0 mmol) was stirred at 0 °C and left
to reach room temperature in solventless conditions for the time
required (4–72 h). When the aldehyde was added to the reaction
mixture some droplets of water condensed inside the reaction ves-
sel. The reaction was monitored by TLC with ethyl acetate/n-hex-
ane (30:70) mixture as the eluent. Diaminoalkyl naphthols 3a–k
were purified by flash chromatography directly from the reaction
mixture, without any work-up.
Oil; IR (neat) mmax 3199, 1621, 1600, 1468, 1333, 1270, 1238,
817 cmꢀ1 1H NMR (200 MHz, CDC13) d 0.72 (t, 3H, J = 7.1 Hz),
;
1.00–1.50 (m, 4H), 1.66 (ddd, 1H, J 15.4, 4.8, 2.6 Hz, H-2e), 2.38
(ddd, 1H, J = 15.4, 11.4, 2.9 Hz, H-2a), 2.88 (br m, 1H, J1/
2 = 13.3 Hz, H-3a), 3.62 (d, 1H, J = 12.9 Hz), 3.70 (d, 1H,
J = 12.4 Hz), 3.90 (d, 1H, J = 12.9 Hz), 3.99 (d, 1H, J = 12.4 Hz), 5.01
(dd, 1H, J = 11.4, 2.6 Hz, H-1a), 5.70 (br s, 3H), 7.02–7.82 (m,
16H); 13C NMR (100 MHz, CDC13) d 14.4, 19.9, 34.8, 35.9, 51.8,
51.9, 55.0, 56.2, 115.6, 120.3, 120.6, 122.3, 126.5, 127.3, 127.5,
128.4, 128.7, 128.72, 128.74, 129.0; 129.2, 129.3, 132.4, 138.8,
140.1, 157.3; Anal. Calcd for. C30H34N2O (438.60): C, 82.15; H,
7.81; N, 6.39. Found: C, 82.26; H, 7.59; N, 6.18.
5.3.1. 1-[(1RS⁄,3SR)-1,3-Bis(benzylamino)butyl] naphth-2-ol
(1RS,3SR)-3a
Oil; IR (neat) mmax 3200, 1621, 1600, 1468, 1454, 1270,
1237 cmꢀ1 1H NMR (200 MHz, CDC13) d 1.24 (d, 3H, J = 6.2 Hz),
;
5.3.6. 1-((1RS,3RS)-1,3-Bis(benzylamino)hexyl)naphthalen-2-ol
(RS,RS)-3d
1.68 (ddd, 1H, J = 15.2, 5.1, 2.9 Hz, H-2e), 2.32 (ddd, 1H, J = 15.2,
11.4, 3.3 Hz, H-2a), 3.10 (qdd, 1H, J = 6.2, 5.1, 3.3 Hz, H-3a), 3.63
(d, 1H, J = 12.8 Hz), 3.75 (d, 1H, J = 12.8 Hz), 3.89 (d, 2H,
J = 12.8 Hz), 5.05 (dd, 1H, J = 11.4, 2.9 Hz, H-1a), 6.12 (br s, 3H),
7.90–7.05 (m, 16H); 13C NMR (100 MHz, CDC13) d 19.7, 37.5,
51.5, 51.8, 51.9, 54.8, 115.4, 120.3, 120.6, 122.3, 126.4, 126.5,
126.5, 127.3, 127.6, 127.9, 128.4, 129.0, 129.2, 129.3, 132.4,
138.8, 140.1, 157.3; Anal. Calcd for C28H30N2O (410.55): C, 81.91;
H, 7.37; N, 6.82. Found: C, 82.07; H, 7.48; N, 6.66.
Oil; IR (neat) m
max 3202, 1600, 1520, 1467, 1269, 1237 cmꢀ1; 1H
NMR (200 MHz, CDC13) d 0.92 (t, 3H, J = 7.0 Hz), 1.00–1.75 (m, 4H),
1.84 (dt, 1H, J = 14.8, 3.2 Hz, H-2e), 1.98 (dt, 1H, J = 14.8, 9.9 Hz, H-
2a), 2.88 (br m, 1H, J1/2 = 18,5 Hz, H-3a), 3.65 (d, 1H, J = 13.2 Hz),
3.67 (d, 1H, J = 12.5 Hz), 3.94 (d, 1H, J = 13.2 Hz), 3.90 (d, 1H,
J = 12.5 Hz), 4.82 (dd, 1H, J = 9.9, 3.2 Hz, H-1a), 5.88 (br s, 3H),
7.12–7.82 (m, 16H); 13C NMR (100 MHz, CDC13) d 14.4, 18.5,
36.4, 38.3, 50.3, 52.1, 58.3, 60.2 115.7, 120.3, 120.7, 122.3, 126.5,
127.3, 127.5, 128.4, 128.6, 128.69, 128.74, 128.8, 129.2, 129.2,
132.5, 138.9, 140.2, 156.9; Anal. Calcd for C30H34N2O (438.60): C,
82.15; H, 7.81; N, 6.39. Found: C, 82.23; H, 7.62; N, 6.28.
5.3.2. 1-[(1RS,3RS)-1,3-Bis(benzylamino)butyl]-2-naphthol
(1RS,3RS)-3a
Oil; IR (neat) m
max 3202, 1621, 1600, 1467, 1270, 1240 cmꢀ1; 1H
NMR (200 MHz, CDC13) d 1.16 (d, 3H, J = 6.2 Hz), 1.84 (dt, 1H
J = 14.6, 2.9 Hz, H-2e), 1.97 (dt, 1H, J = 14.6, 9.9 Hz, H-2a), 2.96
(dqd, 1H, J = 9.9, 6.2, 2.9 Hz, H-3a), 3.63 (d, 1H, J = 13.2 Hz), 3.68
(d, 1H, J = 13.5 Hz), 3.88 (d, 1H, J = 13.5 Hz), 3.94 (d, 1H,
J = 13.2 Hz), 4.83 (dd, 1H, J = 9.9, 2.9 Hz, H-1a), 6.18 (br s, 3H),
7.85–7.05 (m, 16H); 13C NMR (100 MHz, CDC13) d 5 21.5, 41.4,
51.1, 51.9, 54.2, 59.5, 115.7, 120.3, 120.8, 122.3, 126.5, 127.3,
127.5, 128.3, 128.7, 128.7, 128.8, 128.8, 129.2, 129.2, 132.5,
139.0, 140.2, 156.8; Anal. Calcd for C28H30N2O (410.55): C, 81.91;
H, 7.37; N, 6.82. Found: C, 82.18; H, 7.52; N, 6.61.
5.3.7. 1-((1R,3S)-1,3-Bis((R)-1-phenylethylamino)hexyl)naphtha
len-2-ol (1R,3S)-3e
Oil; ½a 2D0
ꢁ
¼ þ29:7 (c 1.07, CHC13); IR (neat) mmax 3202, 1621,
1600, 1520, 1470, 1453, 1270, 1236 cmꢀ1
;
1H NMR (200 MHz,
CDC13) d 0.80 (t, 3H, J = 6.96 Hz), 1.00–1.90 (m, 5H), 1.49 (d, 3H,
J = 6.6 Hz), 1.64 (d, 3H, J = 6.6 Hz), 2.43 (ddd, 1H, J 15.0, 10.6,
3.7 Hz, H-2a), 2.68 (br m, 1H, J1/2 = 13.0 Hz, H-2e), 3.79 (q, 1H,
J = 7.0 Hz), 4.02 (quint, 1H, J = 6.6 Hz, H-3a), 4.52 (dd, 1H, J = 10.6,
2.6 Hz, H-1a), 5.90 (br s, 3H), 7.13–7.95 (m, 16H); 13C NMR
(100 MHz, CDC13) d 14.2, 18.1, 22.9, 23.3, 36.4, 38.7, 53.7, 54.3,
56.0, 56.2, 116.1, 120.1, 120.6, 122.2, 125.8, 126.3, 126.8, 127.0,
127.6, 127.7, 128.7, 128.8, 129.0, 129.1, 130.6, 135.0, 143.4,
157.8; Anal. Calcd for C32H38N2O (466.66): C, 82.36; H, 8.21; N,
6.00. Found: C, 82.57; H, 8.33; N, 6.22.
5.3.3. 1-{(1R,3S)-[1,3-Bis((1R)-1-phenylethylamine)butyl]}naph
thalen-2-ol (R,S,R,R)-3b
Oil; ½a 2D0
ꢁ
¼ þ35:4 (c 0.67, CHC13); IR (neat) mmax 1623, 1598,
1469, 1451, 1273, 1234 cmꢀ1
;
1H NMR (200 MHz, CDC13) d 0.88
5.3.8. 1-((1S,3R)-1,3-Bis((R)-1-phenylethylamino)hexyl)naphtha
len-2-ol (1S,3R)-3e
(d, 3H, J = 6.6 Hz), 1.38 (d, 3H, J = 7.0 Hz), 1.46 (d, 3H, J = 6.2 Hz),
1.70 (m, 1H), 2.09 (ddd, 1H, J = 14.6, 11.4, 2.7 Hz, H-2e), 2.88
(br s, 1H, J1/2 = 16.3 Hz, H-2a), 3.60 (q, 1H, J = 6.6 Hz), 3.93 (sext,
1H, J = 6.6 Hz, H-3a), 4.67 (dd, 1H, J = 11.4, 2.7 Hz, H-1a), 5.90
(br s, 3H), 7.18–8.02 (m, 16H); 13C NMR (100 MHz, CDC13) d
18.7, 22.6, 24.2, 39.2, 48.8, 52.2, 55.1, 55.7,/116.0, 120.2, 120.3,
122.3, 126.4, 126.7, 126.8, 127.5, 127.9, 128.7, 128.8, 128.9,
129.06, 129.11, 132.1, 143.5, 144.9, 157.7; Anal. Calcd for
Oil; ½a 2D0
ꢁ
¼ þ37:4 (c 1.04, CHC13); IR (neat) mmax 3203, 1621,
1600, 1454, 1376, 1270, 1236, 1105 cmꢀ1
;
1H NMR (200 MHz,
CDC13) d 0.89 (t, 3H, J = 7.3 Hz), 1.10–1.60 (m, 5H), 1.35 (d, 3H,
J = 6.96 Hz), 1.47 (d, 3H, J = 6.59 Hz), 2.24 (ddd, 1H, J = 15.0, 11.4,
3.3 Hz), 2.84 (br m, 1H, J1/2 = 14.0 Hz), 3.60 (q, 1H, J = 7.0 Hz),
4.02 (q, 1H, J = 6.6 Hz), 4.67 (dd, 1H, J = 10.9, 2.2 Hz), 6.02 (br s,
3H), 7.05–7.85 (m, 16H); 13C NMR (100 MHz, CDC13) d 14.2, 19.6,
22.8, 23.2, 35.2, 35.5, 52.3, 53.8, 53.9, 55,1, 116.0, 120.37, 120.43,
122.1, 126.2, 126.3, 126.8, 127.5, 127.8, 128.7, 128.76, 128.78,
129.0, 129.1, 129.5, 132.1, 143.3, 157.9; Anal. Calcd for
C30H34N2O (438.60): C, 82.15; H, 7.81; N, 6.39. Found: C, 82.36;
H, 7.59; N, 6.52.
5.3.4. 1-((1RS,3SR)-1,3-Di(pyrrolidin-1-yl)butyl)naphthalen-2-ol
(1RS,3SR)-3c
C32H38N2O (466.66): C, 82.36; H, 8.21; N, 6.00. Found: C, 82.51;
H, 8.37; N, 5.87.
Oil; IR (neat) mmax 3200, 1622, 1599, 1513, 1466, 1268, 1217,
1120 cmꢀ1 1H NMR (200 MHz, CDC13) d 0.70 (d, 3H, J = 6.2 Hz),
;
5.3.9. 1-((1RS,3RS)-1,3-Bis(benzylamino)-3-phenylpropyl)naph
thalen-2-ol (1RS,3RS)-3f
1.60–2.10 (m, 10H), 2.21 (td, 1H, J = 11.9, 2.9 Hz, H-2a), 2.30–2.80
(m, 9H), 4.51 (br d, 1H, J = 9.2 Hz, H-1), 7.01–8.40 (m, 6H); 13C
NMR (100 MHz, CDC13) d 22.6, 23.7, 23.9, 24.6, 24.7, 45.3, 47.0,
50.6, 54.1, 54.3, 56.1, 60.4, 118.6, 119.4, 121.2, 122.5, 127.9, 128.3,
Oil; IR (neat) mmax 3237, 1621, 1600, 1494, 1469, 1417, 1269,
1238, 1102 cmꢀ1 1H NMR (200 MHz, CDC13) d 2.11 (ddd, 1H,
;

1566
C. Cimarelli et al. / Tetrahedron: Asymmetry 22 (2011) 1560–1567
J = 15.0, 5.5, 2.2 Hz, H-2e), 2.59 (ddd, 1H, J = 15.0, 10.6, 3.5 Hz, H-
2a), 3.65 (d, 1H, J = 12.4 Hz), 3.86 (s, 2H), 3.92 (d, 1H, J = 12.4 Hz),
4.22 (dd, 1H, J = 5.1, 3.5 Hz, H-3a), 4.75 (dd, 1H, J = 10.6, 2.2 Hz,
H-1a), 5.75 (br s, 3H), 7.1–7.9 (m, 21H); 13C NMR (100 MHz,
CDC13) d 40.1, 51.8, 51.9, 55.2, 61.0, 115.1, 119.9, 120.5, 126.4,
126.8, 127.2, 127.5, 127,6, 128.2, 128.6, 128.65, 128.71, 128.8,
128.85. 128.87, 129.0, 129.1, 132.1, 138.6, 139.8, 141.9, 156.8;
Anal. Calcd for C33H32N2O (472.62): C, 83.86; H, 6.82; N, 5.93.
Found: C, 83.97; H, 6.64; N, 5.71.
157.2; Anal. Calcd for C29H32N2O (424.58): C, 82.04; H, 7.60; N,
6.60. Found: C, 82.22; H, 7.49; N, 6.41.
5.3.14. 1-((S)-1,3-Bis((R)-1-phenylethylamino)propyl)naphtha
len-2-ol (S)-3j
Oil; ½a 2D0
ꢁ
¼ þ23:5 (c 1.15 CHC13); IR (neat) mmax 3212. 1620,
1522, 1491, 1414, 1264, 1111 cmꢀ1
;
1H NMR (200 MHz, CDC13) d
1.40 (d, 3H, J = 7.0 Hz), 1.48 (d, 3H, J = 6.5 Hz), 1.80–2.18 (m, 2H,
H-2a/H-2e), 2.64 (ddd, 1H, J = 12.0, 9.4, 3.6 Hz, H-3a), 2.86 (ddd,
1H, J = 12.0, 5.3, 3.5 Hz, H-3e), 3.60–3.87 (m, 2H), 4.94 (dd, 1H,
J = 9.2, 4.0 Hz, H-1a), 6.04 (br s, 3H), 7.00–7.85 (m, 16H); 13C
NMR (100 MHz, CDC13) d 20.4, 24.4, 47.3, 54.5, 56.5, 58.9, 115.9,
120.2. 120.6, 122.3, 126.6, 126.7, 126.9, 127.7, 127.8, 127.9,
128.5, 128.6, 128.8, 129.1, 129.7, 131.9, 144.3, 149.6, 156.8; Anal.
Calcd for C29H32N2O (424.58): C, 82.04; H, 7.60; N, 6.60. Found:
C, 81.88; H, 7.72; N, 6.51.
5.3.10. 1-((1R,3R)-1,3-Bis((R)-1-phenylethylamino)-3-phenylpro
pyl)naphthalen-2-ol (1R,3R)-3g
Oil; ½a 2D0
ꢁ
¼ þ44:2 (c 2.19, CHCl3); IR (neat) mmax 3236, 1623,
1H NMR
1.40 (d, 3H, J = 6.6 Hz), 1.41 (d, 3H,
1600, 1514, 1493, 1454, 1378, 1267, 1237, 846 cmꢀ1
;
(200 MHz, CDC13)
d
J = 7.0 Hz), 1.77 (ddd, 1H, J = 15.0, 5.1, 1.9 Hz, H-2e), 2.37 (ddd,
1H, J = 15.0, 10.4, 4.4 Hz, H-2a), 3.55–3.90 (m, 3H), 4.50 (dd,
1H, J = 10.4, 1.9 Hz, H-1a), 5.80 (br s, 3H), 6.70–7.90 (m, 21H);
13C NMR (100 MHz, CDC13) d 22.1, 24.1, 25.0, 51.6, 52.6, 55.3,
58.7, 125.9, 126.4, 126.5, 126.87, 126.93, 127.1, 127.4, 127.5,
127.6, 127.9, 128.78, 128.83, 128.9, 129.0, 129.8, 131.8, 135.0,
142.9, 143.4, 154.6, 157.1, 162.6; Anal. Calcd for C35H36N2O
(500.67): C, 83.96; H, 7.25; N, 5.60. Found: C, 84.19; H, 7.37;
N, 5.81.
5.3.15. 1-((1RS,2SR)-1,3-Bis(benzylamino)-2-methylpropyl)naph
thalen-2-ol (1RS,2SR)-3k
Oil; IR (neat) mmax 3211, 1622, 1522, 1491, 1414, 1263,
1107 cmꢀ1 1H NMR (200 MHz, CDC13) d 1.07 (d, 3H, J = 7.3 Hz),
;
2.27 (m, 1H, H-2e), 2.78 (dd, 1H, J = 12.1, 3.5 Hz, H-3e), 2.88 (dd,
1H, J = 12.1, 5.9 Hz, H-3a), 3.63 (d, 1H, J = 12.8 Hz), 3.73 (d, 1H,
J = 12.8 Hz), 3.82 (d, 1H, J = 12.8 Hz), 3.94 (d, 1H, J = 12.8 Hz), 4.93
(d, 1H, J = 3.5 Hz, H-1a), 6.02 (br s, 3H), 7.15–7.90 (m, 16H); 13C
NMR (100 MHz, CDC13) d 12.2, 38.0, 52.6, 54.4, 54.7, 62.8, 113.5,
120.2, 121.2, 122.3, 126.5, 127.4, 127.7, 128.3, 128.7, 128.8,
128.9, 129.0, 129.3, 129.4, 132.9, 138.7, 140.0, 157.6; Anal. Calcd
for C28H30N2O (410.55): C, 81.91; H, 7.37; N, 6.82. Found: C,
81.70; H, 7.46; N, 6.62.
5.3.11. 1-((1RS,2SR,3RS)-1,3-Bis(benzylamino)-2-methyl-3-phen
ylpropyl)naphthalen-2-ol (1RS,2SR,3RS)-3h
Oil; IR (neat) mmax 3308, 1628, 1601, 1585, 1454, 1237,
1216 cmꢀ1 1H NMR (200 MHz, CDC13) d 1.22 (d, 3H, J = 7.3 Hz,
;
Me), 2.38 (qdd, 1H, J = 7.3, 5.1, 2.0 Hz, H-2), 3.52 (d, 1H,
J = 13.2 Hz), 3.62 (d, 1H, J = 12.8 Hz), 3.88 (d, 1H, J = 12.4 Hz), 3.91
(d, 1H, J = 13.2 Hz), 3.98 (d, 1H, J = 5.1 Hz, H-3), 4.82 (d, 1H,
J = 2.0 Hz, H-1), 6.3 (br s, 3H), 6.8–7.9 (m, 21H); 13C NMR
(100 MHz, CDC13) d 12.6, 45.0, 52.4, 52.6, 58.6, 64.6, 118.4, 119.9,
120.9, 126.5, 127.4, 127.7, 127.9, 128.3, 128.5, 128.6, 128.7,
128.8, 128.9, 129.1, 129.2, 129.7, 129.9, 132.5, 138.8, 140.0,
141.8, 157.5; Anal. Calcd for C34H34N2O (486.65): C, 83.91; H,
7.04; N, 5.76. Found: C, 83.70; H, 6.83; N, 5.52.
Acknowledgments
The financial support of this research by a grant from the Univer-
sity of Camerino and from MIUR-PRIN is gratefully acknowledged.
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5.3.13. 1-((R)-1,3-Bis((R)-1-phenylethylamino)propyl)naphtha
len-2-ol (R)-3j
Oil; ½a 2D0
ꢁ
¼ þ28:85 (c 1.41 CHC13); IR (neat) mmax 3210, 1621,
1520, 1493, 1416, 1267 cmꢀ1
;
1H NMR (200 MHz, CDC13) d 1.44
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2a/H-2e), 2.44 (ddd, 1H, J = 12,1, 9.5, 3.7 Hz, H-3a), 2.69 (ddd.
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