Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with N-substituted piperazine nucleophiles

Article abstract of DOI:10.3390/molecules201219748

Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with N-substituted piperazines was described. The reaction afforded the corresponding ring-opening products in high yields and moderate enantioselectivities in the presence of 2.5 mol % [Ir(COD)Cl]₂ and 5.0 mol % (S)-p-Tol-BINAP. The effects of various chiral bidentate ligands, catalyst loading, solvent, and temperature on the yield and enantioselectivity were also investigated. A plausible mechanism was proposed to account for the formation of the corresponding trans-ring opened products based on the X-ray structure of product 2i.

Full text of DOI:10.3390/molecules201219748

Article
Iridium-Catalyzed Asymmetric Ring-Opening of
Oxabenzonorbornadienes with N-Substituted
Piperazine Nucleophiles
Wen Yang 1, Renshi Luo 2 and Dingqiao Yang 1,
*
Received: 5 October 2015 ; Accepted: 19 November 2015 ; Published: 27 November 2015
Academic Editor: Derek J. McPhee
1
Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education,
School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China;
18971194938@yeah.net
School of Pharmaceutical Sciences, Gannan Medical University, Yi Xue Yuan Road, Ganzhou 341000, China;
2
luorenshi2010@163.com
*
Correspondence: yangdq@scnu.edu.cn; Tel.: +86-20-3931-0068; Fax: +86-20-3104-0403
Abstract: Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with N-substituted
piperazines was described. The reaction afforded the corresponding ring-opening products in high
yields and moderate enantioselectivities in the presence of 2.5 mol % [Ir(COD)Cl]2 and 5.0 mol
% (S)-p-Tol-BINAP. The effects of various chiral bidentate ligands, catalyst loading, solvent, and
temperature on the yield and enantioselectivity were also investigated. A plausible mechanism was
proposed to account for the formation of the corresponding trans-ring opened products based on the
X-ray structure of product 2i.
Keywords: iridium catalyst; asymmetric ring-opening; oxabenzonorbornadiene; chiral bisphosphine
ligand; N-substituted piperazines
1. Introduction
The use of oxabicyclic templates to introduce trans-1,2-bifunctional groups to the carbocyclic
molecule skeleton is an effective strategy for the synthesis of complex molecules. Pioneering work
in this field was first described by Lautens and co-workers [1–17] who reported rhodium-catalyzed
asymmetric ring-opening (ARO) of oxabicyclic alkenes to produce the corresponding products in
high yields and excellent enantioselectivities (up to 99% ee). The asymmetric ring-opening has been
extensively studied with a broad range of nucleophiles, including organomagnesium, organolithium,
organozinc reagents, organoboronic acids, alcohols, phenols, carboxylic acids, terminal alkynes, and
aromatic amines. In addition, many other transition metal catalysts have been tested, including
Cu [18–23], Pd [24
–35], Ni [36–42], Zr [43], Fe [44], Ru [45–52], and Pt [53–55] catalysts. For example,
Cheng et al. [56
–
59] recently described asymmetric ring-opening of oxabenzonorbornadiene with
alkyl- or alkenyl- or allylzirconium reagents and zinc powder under mild conditions catalyzed by
Ni(dppe)Br2 or Pd((R)-binap)Cl2, which yielded the corresponding 1,2-dihydronaphth-1-ols in good
to excellent yields with high enantioselcetivities (up to 90% ee). Carretero et al. [60
,61] reported a
general copper-catalyzed ring-opening of oxabicylic alkenes with Grignard reagents. Hou et al. [30
]
investigated the asymmetric ring-opening of oxabicyclic alkenes with arylboronic acids catalyzed by the
chiral phosphine-containing palladacycle, providing corresponding products in high yields and high ee.
On the other hand, the different kinds of ligands previously used were bisphosphine ligands, including
(S)-BINAP, (R)-(S)-PPF-PtBu2 and DPPF. Halide and triflate salts such as NH4F, Et3N
NH4I, Bu4NI, and AgOTf were also used as additives to enhance the enantioselectivities of the ARO
¨
HCl, NH4Br,
Molecules 2015, 20, 21103–21124; doi:10.3390/molecules201219748
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Molecules 2015, 20, 21103–21124
reaction. Recently, our group demonstrated that iridium-catalyzed asymmetric ring-opening of oxa-
and azabicyclic alkenes with nitrogen- or oxygen-based nucleophiles, such as amines, alcohols, phenols
and Grignard reagents [62–74]. Furthermore, a new iridium-monophosphine catalyst was found to
be efficient for asymmetric ring-opening of benzonorbornadiene with amines, providing a series of
chiral substituted dihydronaphthalenes in high yields (up to 98%) and excellent enantioselectivities
(>99% ee) [71]. To expand the scope of this novel Ir-catalyzed reaction, we are interested in
studying the asymmetric ring-opening of oxabicyclic olefins with nitrogen-based nucleophiles in
the presence of an iridium catalyst. Meanwhile, we also tried to optimize the catalytic system by using
additive of NH4I in the reaction. Herein, we reported iridium-catalyzed asymmetric ring-opening of
1,4-dihydro-1,4-epoxynaphthalene (1a) or 1,4-dihydro-6,7-dimethoxy-1,4-epoxynaphthalene (1b) with
N-substituted piperazine nucleophiles, which afforded the corresponding ring-opening products in
good yields (up to 99%) with moderate enantioselectivities. This new method also offered potentially
useful synthetic routes to optically active 2-N-substituted piperazine 1,2-dihydronaphthalen-1-ols.
2. Results and Discussion
The substrates 1a–1b were readily prepared by Diels-Alder reactions of benzynes with furan
according to literature procedures [75]. To understand the nature of the catalytic ring-opening and
optimize the reaction conditions, we first chose different chiral bisphosphine ligands, including
(S)-BINAP, (R)-(S)-PPF-Pt´Bu2, (S)-p-Tol-BINAP, and (S)-(R)-NMe2-PPh2-Mandyphos, to validate the
catalytic activity of the iridium complexes. Consequently, a more efficient iridium catalyst system for
the ring-opening reaction was explored. The different types of chiral ligands reacted with [Ir(COD)Cl]2
to form iridium complexes to determine the viability of the enantioselectivity (Scheme 1). To probe the
iridium-catalyzed asymmetric ring-opening of oxabicyclic alkene 1a with 1-(2-fluorophenyl)piperazine,
chiral bisphosphine ligand (S)-p-Tol-BINAP was used and 1 equivalent of NH4I was added as the
additive. We found that the ring-opening product 2a was obtained in high yield (up to 99%) with
moderate enantioselectivity (54% ee) (Table 1, entry 4). However, the enantiomeric excess value was
low (2%–58% ee) when (S)-BINAP and ferrocene bisphosphine ligands were used as the chiral ligands
(Table 1, entries 1–3). The enantiomeric excess value was 55% ee when (S)-p-Tol-BINAP was used as
the ligand in the presence of 1.25% mol [Ir(COD)Cl]2 (Table 1, entry 5). Therefore, (S)-p-Tol-BINAP
was chosen as the optimized ligand.
P
[Ir(COD)Cl]2
+
=
P(Tol)2
P(Tol)2
P
NH4I
I
(S)-p-Tol-BINAP
P
Ir
P
P
Ir
P
I
A
THF
O
P
P
N
O
I
Ir
OH
N
B
R
1a
2
exo-coordination
I
Ring-opening catalytic cycle
P
P
Ir
P
Ir
O
P
O
Nucleophilic
displacement
I
E
C
I
P
Ir
oxidative insertion
P
O
HN
N R
D
Scheme 1. The proposed mechanism for asymmetric ring-opening of 1a with N-substituted piperazines.
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Molecules 2015, 20, 21103–21124
Table 1. Effects of chiral bisphosphine ligands and catalyst loading a.
[Ir(COD)Cl]2
ligand
NH4I
+
HN
N
O
N
F
F
THF, reflux
OH
N
2a
1a
Me2N
H
Ph
PtBu2
PPh2
PPh2
Fe
P(Tol)2
P(Tol)2
PPh2
PPh2
Ph
Fe
H
NMe2
PPh2
(R)-(S)- PPF-PtBu2
(S)-p-Tol-BINAP
(S)-BINAP
(S)-(R)-NMe2-PPh2-
Mandyphos
Yield b (%)
Entry
Ligand (mol %)
[Ir(COD)Cl]2 (mol %)
Time (h)
ee c (%)
1
2
3
4
5
(S)-BINAP(5.0)
(R)-(S)-PPF-Pt´Bu2(5.0)
(S)-(R)-NMe2-PPh2-Mandyphos(5.0)
(S)-p-Tol-BINAP(5.0)
2.5
2.5
2.5
2.5
1.25
12
12
12
12
12
76
76
30
99
83
37
2
58
54
55
(S)-p-Tol-BINAP(2.5)
a Conditions: [Ir(COD)Cl]2 (2.5 mol %) and chiral ligand (5 mol %) were dissolved in 2.0 mL THF. NH4I (1 equiv.)
was then added and stirred for another 10–20 min. Substrate 1a (0.3 mmol, 1 equiv.) was added and the mixture
was heated to reflux. 1-(2-Fluorophenyl)piperazine (2 equiv.) was added at the first sign of reflux; b Isolated
yield; c ee was determined by HPLC with a Chiralcel OD or AD column.
With the catalyst system consisting of [Ir(COD)Cl]2 and (S)-p-Tol-BINAP in hand, other reaction
parameters were further optimized. We screened several commonly used solvents (Table 2, entries 1–9),
the solvent effect on enantioselectivities of ring-opening reaction was remarkable, as seen from Table 2.
Table 2. Effects of solvent on the ring-opening a.
[Ir(COD)Cl]2
(S)-p-Tol-BINAP
HN
N
O
+
N
N
NH4I, solvent, reflux
F
OH
F
1a
2a
Yield b (%)
Entry
Solvent
Time (h)
ee c (%)
1
2
3
4
5
6
7
8
9
ClCH2CH2Cl
DMF
12
12
12
12
12
12
12
12
12
nr
nr
nr
99
81
79
88
15
95
–
–
–
54
53
52
52
56
50
DME
THF
THP
toluene
CH3CN
CH2Cl2
1,4-dioxane
a Conditions: [Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %) were dissolved in 2.0 mL solvent. NH4I
(1 equiv.) was then added and stirred for another 10–20 min. Substrate 1a (0.3 mmol, 1 equiv.) was added and
the mixture was heated to reflux. 1-(2-Fluorophenyl)piperazine (2 equiv.) was added at the first sign of reflux;
b
Isolated yield; c ee was determined by HPLC with a Chiralcel OD or AD column.
It was found that in 1,4-dioxane, CH3CN, toluene, tetrahydropyran (THP) and tetrahydrofuran
(THF), the reactions were much faster than in any other solvents, and the reactions were completed
in 12 h (Table 2, entries 4–7, and 9). However, the enantioselectivity was found to be 54% ee (Table 2,
entry 4). There were no ring-opening products formed when the reactions were performed in
dimethylformamide (DMF), 1,2-dimethoxyethane (DME) or 1,2-dichloroethane (Table 2, entries 1–3).
Reactions in CH2Cl2 afforded the ring-opening products in a low yield (15%) with moderate
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Molecules 2015, 20, 21103–21124
enantioselectivity (56% ee) (Table 2, entry 8). Among several solvents examined, THF turned out
to be the best, yielding the corresponding ring-opening product 2a in 99% yield with 54% ee.
The influence of temperature was also investigated in the iridium-catalyzed asymmetric
ring-opening reaction of oxabicyclic alkene 1a with 1-(2-fluorophenyl)piperazine. No product was
obtained when the reaction mixture was stirred at 25 ˝C for 12 h (Table 3, entry 1). It was further
found that the temperature had little effect on the enantioselectivity (Table 3, entries 2–4). The product
2a was obtained in 50% yield with 40% ee when the reaction mixture was stirred at 50 ˝C for 12 h
(Table 3, entry 2). Furthermore, the product 2a was obtained in 99% yield with 54% ee when the
reaction mixture was stirred at reflux (80 ˝C) (Table 3, entry 3). Consequently, the optimum reaction
conditions were determined to be as follows: 2.5 mol % [Ir(COD)Cl]2, 5.0 mol % (S)-p-Tol-BINAP,
2 equiv. of˝1-(2-fluorophenyl)piperazine, and 1 equiv. of NH4I to oxabicyclic alkene 1a as additive in
THF at 80 C.
Table 3. Effects of the temperature on the ring-opening a.
[Ir(COD)Cl]2
(S)-p-Tol-BINAP
HN
N
+
N
N
O
NH4I, THF, reflux
OH
F
F
1a
2a
Yield b (%)
Entry
Temperature (˝C)
Product
Time (h)
ee c (%)
1
2
3
4
25
50
80
2a
2a
2a
2a
12
12
12
12
nr
50
99
82
–
40
54
48
100
a
Conditions: [Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %) were dissolved in 2.0 mL THF. NH4I
(1 equiv.) was then added and stirred for another 10–20 min. Substrate 1a (0.3 mmol, 1 equiv.) was added and
the mixture was heated. 1-(2-Fluorophenyl)piperazine (2 equiv.) was added at the first sign of reflux; b Isolated
yield; c ee was determined by HPLC with a Chiralcel OD or AD column.
Under the optimized reaction conditions, the iridium-catalyzed ring-opening reaction of 1a with
different N-substituted piperazines was demonstrated to be an efficient method for the synthesis
of trans-1,2-N-substituted piperazines 1,2-dihydronaphthalen-1-ols in high yields with moderate
enantioselectives (Table 4). For example, various N-phenylpiperazines with either electron-donating or
electron-withdrawing substituents at the phenyl position afforded the corresponding products in high
yields (up to 99%) and good enantioselectivity in the presence of 2.5 mol % [Ir(COD)Cl]2 and 5.0 mol
% (S)-p-Tol-BINAP (Table 4, entries 1–16, 18–19, and 22–24). 1,4-Dihydro-1,4-epoxynaphthalene (1a
)
with 1-(2-methoxyphenyl)piperazine however afforded the corresponding ring-opening product 2f in
high yield with poor enantioselectivity (Table 4, entry 6).
To further extend the scope of this transformation, the reaction of dimethoxy substituted
oxabenzonorbornadiene 1b with various N-substituted piperazines were also examined. It was
found that the reactions of 1,4-dihydro-6,7-dimethoxy-1,4-epoxynaphthalene (1b), a less reactive
substrate, with N-substituted piperazines offered the desired products in good yields with moderate
enantioselectivity (Table 5, entries 1–9).
Unfortunately, the reaction of 1,4-dihydro-6,7-dimethoxy-1,4-epoxynaphthalene (1b) with
1-(3,4-dichlorophenyl)piperazine afforded the corresponding ring-opening product 3e in a lower
yield (47%) with poor enantioselectivity (16% ee) (Table 5, entry 5).
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Molecules 2015, 20, 21103–21124
Table 4. Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadiene 1a with N-substituted
piperazines a.
[Ir(COD)Cl]2
(S) -p-Tol-BINAP
O
+ NuH
NH4I, THF, reflux
Nu
OH
2a~2x
1a
Entry
NuH
Product
2a
Time (h)
ee c (%)
Yield b (%)
HN
N
F
1
12
99
87
86
54
HN
N
2
3
2b
2c
12
12
36
67
HN
N
Cl
Cl
HN
N
COCH3
4
5
2d
2e
8
8
87
98
38
49
HN
N
CHPh2
HN
N
6
7
8
2f
2g
2h
8
8
8
81
89
87
33
50
54
H3CO
HN
N
Cl
N
HN
H3C
F
HN
N
9
2i
2j
10
10
91
85
45
54
HN
N
OCH3
10
CH3
HN
N
11
2k
10
98
36
H3C
F
12
13
14
2l
2m
2n
10
12
10
97
88
95
43
47
54
HN
N
F
H3C
CH3
HN
N
HN
N
NC
HN
N
CH3
CH3
15
2o
10
96
58
HN
N
CH3
O
16
17
2p
2q
10
12
85
86
27
57
N
HN
O
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Molecules 2015, 20, 21103–21124
Table 4. Cont.
Yield b (%)
Entry
NuH
Product
Time (h)
ee c (%)
H3C
18
19
2r
2s
12
89
59
HN
N
CH3
HN
N
10
90
59
CH3
HN
N
20
21
2t
8
6
78
85
50
51
OC2H5
O
HN
N
2u
HN
N
22
2v
7
83
54
CF3
CF3
HN
N
23
24
2w
2x
8
8
76
82
56
39
HN
N
Cl
a
Conditions: [Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %) were dissolved in 2.0 mL THF and
stirred for 10–20 min. NH4I (1 equiv.) was then added and stirred for another 10–20 min. Substrate 1a (0.3 mmol,
1 equiv.) was added and the mixture was heated to reflux. N-Substituted piperazine nucleophiles (2 equiv.)
were added at the first sign of reflux; b Isolated yield; c ee was determined by HPLC with a Chiralcel OD or
AD column.
Table 5. Substrate scope of the iridium-catalyzed asymmetric ring-opening reaction a.
[Ir(COD)Cl]2
H3CO
H3CO
H3CO
(S)-Tol-BINAP
O
+ NuH
NH4I, THF, reflux
Nu
H3CO
OH
3a~3i
1b
NuH
Entry
Product
3a
Time (h)
ee c (%)
Yield b (%)
HN
N
1
24
77
37
NC
F
HN
N
2
3
4
5
3b
3c
24
24
24
24
73
79
62
47
49
38
59
16
HN
N
F
HN
N
OCH3
3d
3e
HN
N
Cl
Cl
HN
N
6
7
3f
24
24
51
76
43
38
Cl
HN
N
3g
H3C
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Molecules 2015, 20, 21103–21124
Table 5. Cont.
Yield b (%)
Entry
NuH
Product
Time (h)
ee c (%)
CH3
HN
N
8
3h
3i
24
86
35
H3C
HN
N
CH3
CH3
Conditions: [Ir(COD)Cl]2 (2.5 mol %) and (S)-p-Tol-BINAP (5.0 mol %) were dissolved in 2.0 mL THF. NH4I
9
24
81
45
a
(1 equiv.) was then added and stirred for another 10–20 min. Substrate 1b (0.3 mmol, 1 equiv.) was added and
the mixture was heated to reflux. N-Substituted piperazine nucleophiles (2 equiv.) were added at the first sign
of reflux; b Isolated yield; c ee was determined by HPLC with a Chiralcel OD or AD column.
The stereochemistry of 1,2-trans ring-opened product 2i was unambiguously confirmed by X-ray
crystallography. The single crystal of 2i was achieved by solvent evaporation from a mixture of
dichloromethane, petroleum ether and ethyl acetate. Its configuration was assigned as (1S, 2S) and
confirmed as 1,2-trans configuration, as shown in Figure 1 (See Supplementary Materials for details).
It is obvious that the ring-opening reaction favors the formation of trans-2-N-substituted piperazine
1,2-dihydro-naphthalen-1-ol products.
a
a
Figure 1. ORTEP plot for 2i
.
Crystal data. C20H21FN2O, M = 342.39. Monoclinic a = 9.572 (3),
b = 10.034 (3), c = 17.732 (5), alpha = 90, beta = 90 (8), gamma = 90, T =296 K, space group. Orthorhombic,
P 21 21 21, Z = 4. wR2 (reflections) = 0.1882 (3432). The Cambridge Crystallographic Data Centre
(CCDC) 1415336 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html.
Based on our findings above, we propose a mechanism, outlined in Scheme 1. When [Ir(COD)Cl]2
was used as the iridium source, and reacted with (S)-p-Tol-BINAP to form the complex of
[Ir(S)-p-Tol-BINAP)I]2
monomeric iridium complex
iridium complex , followed by oxidative insertion with retention to form a bridgehead C–O bond
and produce the -allyl iridium alkoxide complex . We further propose that the oxidative cleavage of
the C–O bond is the enantioselectivity discriminating step in the catalytic cycle. Once iridium complex
is formed, the iridium alkoxide complex could be protonated by the N-substituted piperazine
nucleophiles to generate cationic iridium complex . This proton transfer has two effects. First, the
A
in the presence of NH4I, which is then cleaved by solvent to give the
B. Reversible exo coordination of oxabenzonorbornadiene 1a leads to
C
π
D
C
E
iridium species are made more electrophilic as a result of the positive charge, and the nucleophile
is rendered more nucleophilic by deprotonation. Second, the positioning of the iridium metal on
the
inversion is proposed to occur adjacent to the alkoxy group in an SN2 fashion relative to the iridium
metal. Finally, product is subsequently liberated and the iridium monomer is regenerated, which
π-allyl moiety will influence the regioselectivity of nucleophilic attack. Nucleophilic attack with
2
will either reform the dimer or continue the catalytic cycle.
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Molecules 2015, 20, 21103–21124
3. Experimental Section
3.1. Chemistry
3.1.1. General
1
Solvents and solutions were transferred with syringes. H-NMR spectra were recorded at
400 MHz using a Varian XL (Palo Alto, CA, USA) 400 spectrometer with CDCl3 as reference standard
(7.27 ppm). Spectral features are tabulated in the following order: Chemical shift (ppm); number of
protons; multiplicity (s—singlet, d—doublet, t—triplet, q—quartet, m—multiplet, br—broad); coupling
constants (J, Hz), 13C-NMR spectra were recorded at 400 MHz with CDCl3 as reference standard
(77.23 ppm). IR spectra were obtained using a Nicolet DX (Madison, WI, USA) FT-IR spectrometer.
High resolution mass was obtained from a VG 70-250S (double focusing) mass spectrometer at
70 ev (Waters, Milford, MA, USA). The enantiomeric excess value was measured by HPLC with
CHIRALCEL OD or AD columns (Chiral Technologies, Minato-ku, Japan). Melting points were taken
with a Tai-Ke melting point apparatus (Beijing, China). Analytical TLC was performed using EM
separations percolated silica gel 0.2 mm layer UV 254 nm fluorescent sheets (Beijing, China). Column
chromatography was performed as “Flash chromatography” as reported by using (200–300 mesh)
Merck grade silica gel (Merck, Beijing, China). The THF, toluene, DME, and THP was distilled from
sodium benzophenone ketyl immediately prior to use. DMF, CH2Cl2, CH3CN, ClCH2CH2Cl, and
1,4-dioxane were distilled from calcium hydride. Furan was distilled prior to use. All other reagents
were obtained from Alfa Aesar (Shanghai, China) and J & K (Guangzhou, China) and used as received
unless otherwise stated.
3.1.2. Preparation of 1,4-Dihydro-1,4-epoxynaphthalene (1a)
To a 100 mL round-bottomed flask with a reflux condenser tube, 10 mL furan and 10 mL DME
were added. Taking two 25 mL dropping bottles, one with 4 mL iso-amyl nitrite and 10 mL DME (A),
another with 2-aminobenzoic acid (2.75 g, 0.02 mol) dissolved by 10 mL DME (B). Then 1 mL A and
1 mL B were added to the refluxing furan solution per 4 minute. Firstly, the A was added, then the
B. The solution became red brown, giving off gas when the reagents were added. Let the mixture
refluxing until the solution did not release gas after all the reactants were added (about 15 min). After
completion 2% sodium hydroxide (25 mL) was added to the mixture and transferred to separating
funnel to rinse, which we can get the organic phase and the aqueous solution extracted three times by
˝
15 mL petroleum ether (bp. 30–60 C). Then the extractive solution and the organic phase were mixed
together. The mixture was washed by water (15 mL 4) and dried by anhydrous magnesium sulfate.
ˆ
After completion the reaction mixture was concentrated in vacuo and the solvents were removed, the
crude mixture was purified by flash chromatography gave 1a a yellow solid (1.72 g, 60%). Rf = 0.45 on
˝
silica gel (25% ethyl acetate in petroleum ether). m.p.: 55–56 C. IR (thin film, cm´1) 3125 (s), 3040 (s),
3020 (s), 1958 (s), 1916 (s), 1814 (s), 1620 (s), 1562 (s), 1449 (s), 1345 (s), 1278 (s), 1195 (s), 1164 (s), 1128 (s),
1
1073 (s), 986 (s), 938 (s), 844 (s), 765 (s), 689 (s), 635 (s). H-NMR (400 MHz, CDCl3)
7.05 (t, J = 1.0 Hz, 1H), 7.02–6.94 (m, 1H), 5.74 (s, 1H). 13C-NMR (100 MHz, CDCl3)
120.3, 82.3.
δ
7.36–7.20 (m, 1H),
149.0, 143.0, 125.0,
δ
3.1.3. Preparation of 1,4-Dihydro-6,7-dimethoxy-1,4-epoxynaphthalene (1b)
A stirred solution of 1,2-dibromo-4,5-dimethoxybenzene (2.0 g, 6.8 mmol) and furan (20 mL)
˝
in anhydrous THF (20 mL) was maintained at
´
78 C under N2 and was treated dropwise with
˝
n-butyl lithium (1.29 mol/L) in hexane (5.3 mL). The solution was stirred at
´78 C for 0.5 h and
then allowed to room temperature during 2 h. The work-up yielded a crude product was purified by
flash chromatography (30% ethyl acetate in hexanes) to give 1b a white solid (0.9 g, 65%). Rf = 0.21
on silica gel (30% ethyl acetate in hexanes); m.p.: 128–130 ˝C; IR (thin film, cm´1) 2926 (s), 2924 (s),
2839 (s), 1599 (s), 1485 (s), 1467 (s), 1325 (s), 1285 (s), 1063 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.04 (2H, t,
21110

Molecules 2015, 20, 21103–21124
J = 0.91 Hz, Ar-H), 6.97 (2H, s, =CH), 5.68 (2H, s, CH), 3.85 (6H, s, CH3O); 13C-NMR (100 MHz, CDCl3)
δ 146.1, 143.6 141.9, 107.0, 82.8, 56.7.
3.1.4. General Procedure for the Asymmetric Ring-Opening of 1a with N-Substituted Piperazines
A 5.0 mL round-bottomed flask was equipped with a reflux condenser, 2.5 mol %
chloro(1,5-cyclooctadiene)iridium (I) dimer [Ir(COD)Cl]2 and 5.0 mol % (S)-p-Tol-BINAP were added
and followed by addition of anhydrous tetrahydrofuran (2.0 mL). After they were stirred for 10 min to
produce a yellow solution. 1,4-Dihydro-1,4-epoxynaphthalene 1a (50 mg, 0.3468 mmol) was added;
then 10 min later, additive of ammonium iodide (1.0 equiv. to 1a) was added and heated to reflux. At the
first sign of reflux, N-substituted piperazine nucleophiles (2.0 equiv. to 1a) were added. The reaction
mixture was stirred at reflux and monitored by TLC until completion (typically 6–12 h). The solvent
was removed in vacuo and the crude mixture was purified by column chromatography on silica gel to
afford the desired products.
(1S,2S)-2-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2a). Prepared according to
general procedure. 2a was obtained as a white solid (111.9 mg, 99%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.21 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v).
The ee was determined to be 54% using HPLC analysis on a CHIRALCEL AD column, λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 19.0 min (major) and
25
˝
˝
20.9 min (minor). m.p.: 125–126 C; rαsD = +83.2 (c = 68.9 mg, CHCl3); IR (thin film, cm´1) 3510 (br),
1
3054 (w), 2977 (s), 2934 (s), 2862 (s), 1490 (s), 1445 (s), 1383 (s), 1351 (s), 1077 (s), 846 (s); H-NMR
(400 MHz, CDCl3)
δ 7.60 (1H, d, J = 7.2 Hz), 7.31–7.23 (2H, m), 7.11–6.93 (5H, m), 6.58 (1H, dd,
J = 2.4 Hz, J = 2.4 Hz), 6.17 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.93 (1H, 11.6), 3.53 (1H, dt, J = 11.6 Hz,
J = 2.4 Hz), 3.22 (1H, br), 3.21–3.05 (4H, m), 3.02–2.98 (2H, m), 2.78–2.73 (2H, m); 13C-NMR (100 MHz,
CDCl3)
δ 157.1, 154.7, 140.2, 137.2, 131.9, 129.6, 128.1, 127.6, 126.4, 124.8, 124.7, 122.8, 119.2, 116.4, 67.9,
67.7, 51.3, 49.2. MS (ESI): calcd m/z for C20H21FN2O (M+) 324.16, found: 325.12 [M + H]+. Anal. Calcd
for C20H21FN2O: C, 74.05; H, 6.53; N, 8.64. Found: C, 74.29; H, 6.74; N, 8.56.
(1S,2S)-2-(4-Phenyl-piperazin-1-yl)-1,2-dihydro-naphthalen-1-ol (2b). Prepared according to general
procedure. 2b was obtained as a white solid (93 mg, 87%) by flash chromatography (ethyl acetate:
petroleum ether = 1:1, v/v). Rf = 0.42 on silica gel (ethyl acetate: petroleum ether = 1:1, v/v). The
ee was determined to be 36% using HPLC analysis on a CHIRALCEL OD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 2% 2-propanol in hexanes were 31.3 min (minor) and
25
˝
˝
35.9 min (major). m.p.: 162–163 C; rαsD = + 62.8 (c = 39.5 mg, CHCl3); IR (thin film, cm´1) 3345 (br),
3016 (w), 2928 (s), 2824 (s), 1597 (m), 1492 (s), 1452 (s), 1369 (m), 1226 (s), 1169 (s), 1133 (m), 1045 (m),
7.56 (1H, d, J = 7.2 Hz), 7.26–7.19 (4H, m), 7.05 (1H, dd, J = 4.2 Hz
J = 2.8 Hz), 6.91–6.82 (3H, m), 6.52 (1H, dd, J = 2.8 Hz, J = 2.8 Hz), 6.08 (1H, dd, J = 2.4 Hz, J = 2.4 Hz)
763 (s); 1H-NMR (400 MHz, CDCl3)
δ
,
,
4.89 (1H, J = 7.6 Hz), 3.50 (1H, J = 2.8 Hz), 3.37 (1H, br), 3.23–3.13 (4H, m), 2.95–2.89 (2H, m), 2.70–2.65
(2H, m); 13C-NMR (100 MHz, CDCl3)
δ 151.4, 137.2, 131.9, 129.6, 129.3, 128.1, 127.6, 126.4, 125.0, 124.5,
120.1, 116.4, 67.9, 67.6, 49.9, 49.1. MS (ESI): calcd m/z for C20H22N2O (M+) 306.17, found: 307.16
[M + H]+. Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C, 78.21; H, 7.31; N, 9.28.
(1S,2S)-2-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2c). Prepared according to
general procedure. 2c was obtained as a white solid (112 mg, 86%) by flash chromatography (ethyl
acetate: petroleum ether = 1:1, v/v). Rf = 0.37 on silica gel (ethyl acetate: petroleum ether = 1:1, v/v).
The ee was determined to be 67% using HPLC analysis on a CHIRALCEL. AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 33.9 min (major) and
25
˝
˝
36.9 min (minor). m.p.: 142–143 C; rαsD = +100.4 (c = 45.6 mg, CHCl3); IR (thin film, cm´1) 3456 (br),
3027 (w), 2936 (m), 2836 (s), 1594 (s), 1552 (m), 1483 (s), 1452 (m), 1237 (s), 1139 (m), 1044 (s), 782 (s);
1H-NMR (400 MHz, CDCl3)
δ 7.51 (1H, d, J = 7.2 Hz), 7.30–7.20 (3H, m), 7.05 (1H, d, J = 6.8 Hz), 6.91
(1H, d, J = 2.8 Hz), 6.72 (1H, dd, J = 2.4 Hz, J = 2.8 Hz), 6.46 (1H, dd, J = 2.0 Hz, J = 1.6 Hz), 6.02 (1H, dd,
J = 2.4 Hz, J = 2.4 Hz), 4.83 (1H, d, J = 11.6 Hz), 3.42 (1H, d, J = 10.8 Hz), 3.22–3.05 (5H, m), 2.98–2.85
21111

Molecules 2015, 20, 21103–21124
(2H, m), 2.70–2.61 (2H, m); 13C-NMR (100 MHz, CDCl3)
δ 150.7, 137.0, 132.9, 131.8, 130.6, 129.7, 128.1,
127.7, 126.4, 125.1, 124.3, 122.4, 117.5, 115.6, 67.9, 67.5, 49.4, 48.8. MS (ESI): calcd m/z for C20H20Cl2N2O
(M+) 374.10, found: 375.05 [M + H]+. Anal. Calcd for C20H20Cl2N2O: C, 64.01; H, 5.37; N, 7.46. Found:
C, 63.82; H, 5.69; N, 7.47.
(1S,2S)-1-{4-(1-Hydroxy-1,2-dihydro-naphthalen-2-yl)-piperazin-1-yl]-phen-yl}-ethanone (2d). Prepared
according to general procedure. 2d was obtained as a white solid (105 mg, 87%) by flash
chromatography (ethyl acetate: petroleum ether = 2:1, v/v). Rf = 0.40 on silica gel (ethyl acetate:
petroleum ether = 2:1, v/v). The ee was determined to be 38% using HPLC analysis on a CHIRALCEL
OD column,
λ
= 254 nm. Flow rate = 0.5 mL/min; Retention times in 2% 2-propanol in hexanes were
25
30.3 min (minor) and 34.9 min (major). m.p.: 202–203 ˝C; rαsD
=
´
3.0˝ (c = 26.3 mg, CHCl3); IR (thin
film, cm´1) 3396 (br), 3018 (w), 2923 (s), 2841 (s), 1739 (m), 1643 (s), 1597 (s), 1388 (s), 1245 (s), 1086 (s),
817 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.88 (2H, d, J = 8.8 Hz), 7.58 (1H, d, J = 6.8 Hz), 7.27 (2H, td,
J = 7.6 Hz, J = 7.2 Hz), 7.10 (1H, d, J = 6.8 Hz), 6.88 (2H, d, J = 7.6 Hz), 6.57 (1H, d, J = 6.0 Hz), 6.08 (1H,
d, J = 9.6 Hz), 4.93 (1H, d, J = 11.2 Hz), 3.54 (1H, d, J = 2.0 Hz), 3.41–3.35 (4H, m), 3.19 (1H, br), 2.97–2.94
(2H, m), 2.73–2.71 (2H, m), 2.52 (3H, s); 13C-NMR (100 MHz, CDCl3)
δ 196.7, 154.3, 137.0, 131.9, 130.6,
129.8, 128.2, 128.0, 127.8, 126.5, 125.2, 124.3, 113.7, 68.0, 67.6, 48.9, 48.1, 26.3. MS (ESI): calcd m/z for
C22H24N2O2 (M+) 348.18, found: 349.15 [M + H]+. Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N,
8.04. Found: C, 75.65; H, 7.34; N, 8.01.
(1S,2S)-2-(4-Benzhydryl-piperazin-1-yl)-1,2-dihydro-naphthalen-1-ol (2e). Prepared according to general
procedure. 2e was obtained as a white solid (135 mg, 98%) by flash chromatography (ethyl acetate:
petroleum ether = 1:4, v/v). Rf = 0.22 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v). The
ee was determined to be 49% using HPLC analysis on a CHIRALCEL OD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 2% 2-propanol in hexanes were 18.2 min (major) and
25
19.8 min (minor). m.p.: 160–161 ˝C; rαsD = +150.2˝ (c = 33.3 mg, CHCl3); IR (thin film, cm´1) 3429
(br), 3027 (w), 2923 (s), 2807 (m), 1594 (s), 1487 (m), 1451 (s), 1383 (m), 1133 (s), 1040 (s), 741 (s), 697 (s);
1H-NMR (400 MHz, CDCl3)
δ 7.66 (1H, d, J = 7.2 Hz), 7.52 (4H, d, J = 7.6 Hz), 7.39–7.25 (8H, m), 7.15
(1H, d, J = 7.2 Hz), 6.62 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.26 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.94 (1H,
J = 11.6 Hz), 4.34 (1H, s), 3.53 (1H, dt, J = 11.6 Hz, J = 2.4 Hz), 3.45 (1H, br), 2.98–2.84 (2H, m), 2.69–2.61
(2H, m), 2.49–2.42 (4H, m); 13C-NMR (100 MHz, CDCl3)
δ 142.8, 137.3, 132.0, 129.3, 128.7, 128.5, 128.1,
127.9, 127.5, 127.1, 126.3, 125.0, 124.9, 67.8, 67.3, 52.5, 49.2. MS (ESI): calcd m/z for C27H28N2O (M+)
396.22, found: 397.19 [M + H]+. Anal. Calcd for C27H28N2O: C, 81.87; H, 7.12; N, 7.06. Found: C, 81.52;
H, 7.43; N, 7.02.
(1S,2S)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2f). Prepared according to
general procedure. 2f was obtained as a white solid (95 mg, 81%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.17 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v);
The ee was determined to be 33% using HPLC analysis on a CHIRALCEL OD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 2% 2-propanol in hexanes were 27.6 min (minor) and
25
˝
˝
29.3 min (major); m.p.: 148–149 C; rαsD = +53.8 (c = 69.9 mg, CHCl3); IR (thin film, cm´1) 3519 (br),
3089 (w), 2978 (s), 2934 (s), 2863 (s), 2805 (s), 1490 (s), 1445 (s), 1415 (s), 1383 (s), 1351 (s), 1297 (m),
1076 (s), 1044 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.61 (1H, d, J = 7.2 Hz), 7.29–7.25 (2H,
m), 7.10 (1H, d, J = 7.2 Hz), 7.02 (1H, dt, J = 8.0 Hz, J = 2.4 Hz), 6.98–6.95 (2H, m), 6.88 (1H, d, J = 8.0 Hz),
6.57 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.20 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.95 (1H, d, J = 11.6 Hz), 3.88
(3H, s), 3.54 (1H, J = 6.4 Hz), 3.41 (1H, br), 3.18–3.01 (4H, m), 3.01–2.98 (2H, m), 2.79–2.70 (2H, m);
13C-NMR (100 MHz, CDCl3)
δ 152.4, 141.3, 137.3, 132.0, 129.4, 128.0, 127.6, 126.3, 125.0, 124.9, 123.2,
121.1, 118.4, 111.2, 67.8, 67.7, 55.5, 51.4, 49.3. MS (ESI): calcd m/z for C21H24N2O3 (M+) 336.18, found:
337.10 [M + H]+. Anal. Calcd for C21H24N2O3: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.89; H, 7.44; N, 8.56.
21112

Molecules 2015, 20, 21103–21124
(1S,2S)-2-[4-(2-Chloro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2g). Prepared according to
general procedure. 2g was obtained as a white solid (105 mg, 89%) by flash chromatography (ethyl
acetate: petroleum ether = 1:3, v/v). Rf = 0.25 on silica gel (ethyl acetate: petroleum ether = 1:3, v/v).
The ee was determined to be 50% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 19.4 min (major) and
25
˝
˝
20.3 min (minor). m.p.: 122–123 C; rαsD = +91.6 (c = 29.7 mg, CHCl3); IR (thin film, cm´1) 3468 (br),
3060 (w), 2927 (s), 2828 (s), 1588 (s), 1480 (s), 1453 (s), 1377 (m), 1230 (s), 1123 (s), 1040 (s), 781 (s),
1
749 (s); H-NMR (400 MHz, CDCl3)
δ 7.61 (1H, d, J = 7.2 Hz), 7.37 (1H, d, J = 7.2 Hz), 7.31–7.22
(3H, m), 7.11–6.99 (2H, m), 6.97 (1H, d, J = 8.4 Hz), 6.58 (1H, dd, J = 2.8 Hz, J = 2.8 Hz), 6.21 (1H, dd,
J = 2.8 Hz J = 2.4 Hz), 4.95 (1H, 11.6), 3.53 (1H, dt, J = 11.6 Hz, J = 2.4 Hz), 3.34 (1H, br), 3.15–3.09
,
(4H, m), 3.05–2.95 (2H, m), 2.79–2.74 (2H, m); 13C-NMR (100 MHz, CDCl3) δ 149.3, 137.3, 132.0, 130.9,
129.6, 129.0, 128.1, 127.8, 127.6, 126.4, 124.9, 124.0, 120.6, 67.9, 67.8, 51.9, 49.4. MS (ESI): calcd m/z for
C20H21ClN2O (M+) 340.13, found: 341.11 [M + H]+. Anal.Calcd for C20H21ClN2O: C, 70.48; H, 6.21;
N, 8.22. Found: C, 70.20; H, 6.49; N, 8.49.
(1S,2S)-2-[4-o-Toyl-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2h). Prepared according to general
procedure. 2h was obtained as a white solid (97 mg, 87%) by flash chromatography (ethyl acetate:
petroleum ether = 1:3, v/v). Rf = 0.2 on silica gel (ethyl acetate: petroleum ether = 1:3, v/v). The
ee was determined to be 54% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 14.7 min (major) and
25
˝
˝
16.4 min (minor). m.p.: 115–116 C; rαsD = +95.9 (c = 49.1 mg, CHCl3); IR (thin film, cm´1) 3461 (br),
3019 (m), 2949 (s), 2878 (s), 2816 (w), 1596 (w), 1490 (s), 1453 (s), 1256 (m), 1224 (s), 1195 (m), 1132 (m),
1049 (s), 781 (s), 768 (s); H-NMR (400 MHz, CDCl3)
1
δ 7.69 (1H, d, J = 7.2 Hz), 7.38–7.25 (4H, m),
7.19–7.07 (3H, m), 6.66 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.29 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 5.03 (1H,
J = 12.0 Hz), 3.60 (1H, dt, J = 12.0 Hz, J = 2.8 Hz), 3.39 (1H, br), 3.11–3.02 (6H, m), 2.83–2.79 (2H, m),
2.42 (3H, s); 13C-NMR (100 MHz, CDCl3)
δ 151.6, 137.4, 132.8, 132.0, 131.3, 129.5, 128.1, 127.6, 126.3,
125.0, 124.9, 123.5, 119.2, 67.9, 67.8, 52.5, 49.6, 18.1. MS (ESI): calcd m/z for C21H24N2O (M+) 320.19,
found: 321.16 [M + H]+. Anal. Calcd for C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C, 78.49; H, 7.82;
N, 8.69.
(1S,2S)-2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2i). Prepared according to
general procedure. 2i was obtained as a white solid (101 mg, 91%) by flash chromatography (ethyl
acetate: petroleum ether = 1:2, v/v). Rf = 0.34 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v).
The ee was determined to be 45% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 26.9 min (major) and
25
˝
˝
29.4 min (minor). m.p.: 167–168 C; rαsD = +133.2 (c = 48.2 mg, CHCl3); IR (thin film, cm´1) 3592 (br),
3214 (w), 2978 (s), 2934 (s), 2872 (s), 2806 (s), 1627 (w), 1489 (s), 1445 (s), 1415 (s), 1298 (s), 1067 (s),
1044 (s), 935 (m), 846 (s); H-NMR (400 MHz, CDCl3)
1
δ 7.59 (1H, d, J = 7.2 Hz), 7.29–7.25 (2H, m),
7.09 (1H, d, J = 7.2 Hz), 7.00–6.96 (2H, m), 6.91–6.87 (2H, m), 6.57 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 6.13
(1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.93 (1H, d, J = 11.6 Hz), 3.53 (1H, dt, J = 11.6 Hz, J = 2.8 Hz), 3.27
(1H, br), 3.18–3.13 (4H, m), 3.00–2.95 (2H, m), 2.75–2.71 (2H, m); 13C-NMR (100 MHz, CDCl3)
δ 158.7,
156.3, 148.1, 137.2, 131.9, 129.7, 128.1, 127.7, 126.4, 125.0, 125.0, 118.2, 115.9, 67.9, 67.6, 51.0, 49.1. MS
(ESI): calcd m/z for C20H21FN2O (M+) 324.16, found: 325.15 [M + H]+. Anal. Calcd for C20H21FN2O:
C, 74.05; H, 6.53; N, 8.64. Found: C, 74.19; H, 6.74; N, 8.66.
(1S,2S)-2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2j). Prepared according to
general procedure. 2j was obtained as a white solid (99 mg, 85%) by flash chromatography (ethyl
acetate: petroleum ether = 1:2, v/v). Rf = 0.23 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v).
The ee was determined to be 54% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL / min; Retention times in 10% 2-propanol in hexanes were 32.5 min (major) and
25
˝
˝
36.4 min (minor). m.p.: 178–179 C; rαsD = +102.5 (c = 59.9 mg, CHCl3); IR (thin film, cm´1) 3566 (br),
3219 (w), 2978 (s), 2934 (s), 2862 (s), 2805 (s), 1491 (s), 1445 (s), 1416 (m), 1383 (s), 1351 (s), 1297 (m),
21113

Molecules 2015, 20, 21103–21124
1
1077 (s), 1044 (s), 935 (s), 846 (s); H-NMR (400 MHz, CDCl3)
δ 7.60 (1H, d, J = 7.2 Hz), 7.31–7.23
(2H, m), 7.10 (1H, d, J = 8.4 Hz), 6.95–6.84 (4H, m), 6.57 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.15 (1H, dd,
J = 2.0 Hz, J = 2.4 Hz), 4.93 (1H, J = 11.6 Hz), 3.73 (3H, s), 3.51 (1H, dt, J = 11.6 Hz, J = 2.4 Hz), 3.32
(1H, br), 3.19–3.08 (4H, m), 3.01–2.97 (2H, m), 2.76–2.71 (2H, m); 13C-NMR (100 MHz, CDCl3)
δ 154.2,
145.8, 137.3, 132.0, 129.6, 128.1, 127.7, 126.5, 125.0, 124.7, 118.6, 114.7, 68.0, 67.7, 55.8, 51.5, 49.3. MS
(ESI): calcd m/z for C21H24N2O2 (M+) 336.18, found: 337.10 [M + H]+. Anal. Calcd for C21H24N2O2:
C, 74.97; H, 7.19; N, 8.33. Found: C, 74.77; H, 7.40; N, 8.25.
(1S,2S)-2-[4-(2,5-Dimethyl-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2k). Prepared according to
general procedure. 2k was obtained as a white solid (119 mg, 98%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.32 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v).
The ee was determined to be 36% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 13.8 min (major) and
25
˝
˝
14.3 min (minor). m.p.: 128–130 C; rαsD = +100.0 (c = 44.7 mg, CHCl3); IR (thin film, cm´1) 3509 (br),
3216 (w), 2977 (s), 2934 (s), 2862 (s), 2806 (s), 1490 (s), 1445 (s), 1415 (s), 1383 (s), 1351 (s), 1298 (m),
1127 (s), 1077 (s), 1044 (m), 935 (s), 846 (s); H-NMR (400 MHz, CDCl3)
1
δ 7.52 (1H, d, J = 7.2 Hz),
7.21–7.13 (2H, m), 6.98 (2H, t, J = 6.8 Hz), 6.73 (2H, t, J = 11.6 Hz, J = 7.6 Hz), 6.47 (1H, dd, J = 2.4 Hz,
J = 2.8 Hz), 6.10 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.84 (1H, 12.0), 3.42 (1H, dt, J = 12.0 Hz, J = 2.4 Hz), 3.37
(1H, br), 2.90–2.82 (6H, m), 2.64–2.58 (2H, m), 2.23 (3H, s), 2.19 (3H, s); 13C-NMR (100 MHz, CDCl3)
δ
151.4, 137.3, 136.3, 132.0, 131.1, 129.4, 129.4, 128.0, 127.5, 126.3, 125.0, 124.8, 124.0, 119.9, 67.9, 67.7, 52.4,
49.3, 21.4, 17.7. MS (ESI): calcd m/z for C22H26N2O (M+) 334.20, found: 335.23 [M + H]+. Anal. Calcd
for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.83; H, 8.12; N, 8.32.
(1S,2S)-2-[4-(2,5-Difluoro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2l). Prepared according
to general procedure. 2l was obtained as a white solid (115 mg, 97%) by flash chromatography
(ethyl acetate: petroleum ether = 1:4, v/v). The absolute stereochemistry was determined by X-ray
crystallography. Rf = 0.14 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v). The ee was determined
to be 43% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm. Flow rate = 0.5 mL/min;
Retention times in 10% 2-propanol in hexanes were 20.2 min (major) and 23.2 min (minor). m.p.:
25
122–124 ˝C; rαsD = +150.7˝ (c = 26.8 mg, CHCl3); IR (thin film, cm´1) 3507 (br), 3203 (w), 2988 (s),
1
2943 (s), 2872 (s), 1509 (s), 1445 (s), 1383 (s), 1297 (m), 1131 (s), 935 (s), 846 (s), 793 (s); H-NMR
(400 MHz, CDCl3) δ 7.59 (1H, d, J = 7.2 Hz), 7.31–7.23 (2H, m), 7.09 (1H, d, J = 6.0 Hz), 6.95–6.78 (3H,
m), 6.57 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.16 (1H, dd, J = 2.8 Hz, J = 2.8 Hz), 4.93 (1H, 11.6), 3.53 (1H, dt,
J = 11.6 Hz, J = 2.8 Hz), 3.31 (1H, br), 3.13–2.96 (4H, m), 2.96–2.92 (2H, m), 2.75–2.70 (2H, m); 13C-NMR
(100 MHz, CDCl3)
δ 159.4, 157.0, 154.6, 137.2, 136.9, 131.9, 129.6, 128.1, 127.7, 126.4, 125.0, 119.7, 111.0,
110.8, 105.2, 104.7, 67.9, 67.7, 51.7, 49.2. MS (ESI): calcd m/z for C20H20F2N2O (M+) 342.15, found:
343.20 [M + H]+. Anal. Calcd for C20H20F2N2O: C, 70.16; H, 5.89; N, 8.18. Found: C, 70.19; H, 5.94; N, 8.26.
(1S,2S)-2-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2m). Prepared according to
general procedure. 2m was obtained as a white solid (102 mg, 88%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.29 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v).
The ee was determined to be 47% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 13.5 min (major) and
25
˝
˝
14.4 min (minor). m.p.: 163–164 C; rαsD = +82.7 (c = 99.7 mg, CHCl3); IR (thin film, cm´1); 3590 (br),
3228 (w), 2974 (s), 2934 (s), 2873 (s), 2806 (s), 1490 (s), 1445 (s), 1415 (m), 1383 (s), 1351 (s), 1297 (m),
1133 (s), 1077 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.60 (1H, d, J = 7.2 Hz), 7.27–7.23 (2H,
m), 7.08 (2H, t, J = 7.2 Hz), 6.91 (2H, dd, J = 4.8 Hz, J = 4.4 Hz), 6.55 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 6.19
(1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.92 (1H, J = 14.6 Hz), 3.50 (1H, dt, J = 11.6 Hz, J = 2.8 Hz), 3.41 (1H, br),
2.97–2.88 (6H, m), 2.69 (2H, t, J = 2.4 Hz), 2.27 (3H, s), 2.24 (3H, s); 13C-NMR (100 MHz, CDCl3)
δ 151.7,
138.3, 137.5, 132.1, 131.5, 129.6, 128.2, 127.7, 126.5, 126.2, 125.4, 125.2, 125.0, 116.9, 68.0, 67.8, 53.0, 49.7,
21.0, 14.3. MS (ESI): calcd m/z for C22H26N2O (M+) 334.20, found: 335.28 [M + H]+. Anal. Calcd for
C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.84; H, 8.17; N, 8.27.
21114

Molecules 2015, 20, 21103–21124
(1S,2S)-2-[4-(1-Hydroxy1,2-dihydro-naphthalen-2-yl-piperazin-1-yl]–benzo-nitrile (2n). Prepared according
to general procedure. 2n was obtained as a white solid (109 mg, 95%) by flash chromatography (ethyl
acetate: petroleum ether = 1:2, v/v). Rf = 0.20 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v).
The ee was determined to be 54% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 43.6 min (major) and
25
˝
˝
53.4 min (minor). m.p.: 126–127 C; rαsD = +111.4 (c = 64.9 mg, CHCl3); IR (thin film, cm´1); 3692 (br),
3210 (w), 2934 (s), 2874 (s), 2805 (s), 2272 (w), 1627 (w), 1597 (w), 1491 (s), 1445 (s), 1383 (s), 1298 (s),
1118 (s), 1077 (s), 935 (s), 846 (s), 795 (m); 1H-NMR (400 MHz, CDCl3)
δ 7.61–7.57 (2H, m), 7.51 (1H,
td, J = 7.6 Hz, J = 1.6 Hz), 7.31–7.23 (2H, m), 7.10 (1H, d, J = 5.6 Hz), 7.05–7.02 (2H, m), 6.58 (1H, dd,
J = 2.4 Hz, J = 2.4 Hz), 6.18 (1H, dd, J = 2.4 Hz, J = 2.8 Hz), 6.15 (1H, dd, J = 2.0 Hz, J = 2.4 Hz), 4.94
(1H, J = 11.2 Hz), 3.53 (1H, dt, J = 11.6 Hz, J = 2.4 Hz), 3.33–3.23 (4H, m), 3.07–3.01 (2H, m), 2.82–2.76
(2H, m); 13C-NMR (100 MHz, CDCl3)
δ 155.8, 137.1, 134.5, 134.0, 132.5, 131.9, 128.1, 127.7, 126.4, 124.9,
122.1, 118.6, 106.3, 67.9, 67.7, 52.3, 49.2. MS (ESI): calcd m/z for C21H21N3O (M+) 331.17, found: 332.22
[M + H]+. Anal. Calcd for C21H21N3O: C, 76.11; H, 6.39; N, 12.68. Found: C, 76.01; H, 6.69; N, 12.51.
(1S,2S)-2-[4-(3,4-Dimethyl-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2o). Prepared according to
general procedure. 2o was obtained as a white solid (111 mg, 96%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.20 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v).
The ee was determined to be 58% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 22.6 min (minor) and
25
˝
˝
23.8 min (major). m.p.: 125–126 C; rαsD = +109.7 (c = 59.5 mg, CHCl3); IR (thin film, cm´1); 3512 (br),
3211 (w), 2974 (s), 2806 (s), 1615 (s), 1490 (s), 1445 (s), 1416 (s), 1383 (m), 1298 (s), 1142 (s), 1044 (s),
935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.59 (1H, d, J = 7.2 Hz), 7.31–7.23 (2H, m), 7.07 (1H, d,
J = 7.2 Hz), 7.04 (1H, d, J = 7.2 Hz), 6.78 (1H, d, J = 2.4 Hz), 6.71 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.56 (1H,
dd, J = 2.4 Hz, J = 2.8 Hz), 6.15 (1H, dd, J = 2.0 Hz, J = 2.4 Hz), 4.93 (1H, 12.0), 3.53 (1H, dt, J = 11.6 Hz
J = 2.8 Hz), 3.37 (1H, br), 3.24–3.14 (4H, m), 3.01–2.96 (2H, m), 2.75–2.70 (2H, m), 2.25 (3H, s), 2.20 (3H,
,
s); 13C-NMR (100 MHz, CDCl3)
δ 149.8, 137.3, 137.2, 131.9, 130.4, 129.6, 128.5, 128.1, 127.6, 126.4, 124.9,
124.7, 118.5, 114.2, 67.9, 67.7, 50.6, 49.2, 20.4, 19.0. MS (ESI): calcd m/z for C22H26N2O (M+) 334.20,
found: 335.28 [M + H]+. Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.72; H, 8.31;
N, 8.48.
(1S,2S)-2-[4-p-Tolyl-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2p). Prepared according to general
procedure. 2p was obtained as a white solid (94 mg, 85%) by flash chromatography (ethyl acetate:
petroleum ether = 1:3 , v/v). Rf = 0.28 on silica gel (ethyl acetate: petroleum ether = 1:3, v/v). The
ee was determined to be 27% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 23.0 min (major) and
25
˝
˝
23.6 min (minor). m.p.: 193–194 C; rαsD = +108.9 (c = 57.1 mg, CHCl3); IR (thin film, cm´1) 3422 (br),
3022 (w), 2918 (w), 2833 (m), 1649 (s), 1515 (s), 1499 (s), 1382 (s), 1241 (s), 1140 (s), 1046 (s), 781 (s),
746 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.60 (1H, d, J = 6.8 Hz), 7.31–7.23 (2H, m), 7.09 (3H, d, J = 7.2 Hz),
6.86 (2H, d, J = 7.2 Hz), 6.57 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.15 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.94
(1H, d, J = 11.6 Hz), 3.52 (1H, dt, J = 11.2 Hz, J = 2.8 Hz), 3.36 (1H, br), 3.24–3.14 (4H, m), 3.01–2.96 (2H,
m), 2.75–2.70 (2H, m), 2.29 (3H, s); 13C-NMR (100 MHz, CDCl3)
δ 149.4, 137.2, 131.9, 129.9, 129.7, 129.6,
128.1, 127.6, 126.4, 124.9, 124.6, 116.8, 67.9, 67.7, 50.6, 49.2, 20.6. MS (ESI): calcd m/z for C21H24N2O
(M+) 320.19, found: 321.25 [M + H]+. Anal. Calcd for C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found:
C, 78.52; H, 7.81; N, 8.66.
(1S,2S)-2-(4-Benzo[1,3] dioxol-5-yl-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2q). Prepared according to
general procedure. 2q was obtained as a white solid (108 mg, 86%) by flash chromatography (ethyl
acetate: petroleum ether = 1:1, v/v). Rf = 0.27 on silica gel (ethyl acetate: petroleum ether = 1:1, v/v).
The ee was determined to be 57% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were 20.5 min (minor) and
25
˝
˝
25.5 min (major). m.p.: 112–113 C; rαsD = +81.8 (c = 99.3 mg, CHCl3); IR (thin film, cm´1) 3514 (br),
21115

Molecules 2015, 20, 21103–21124
3211 (w), 2925 (s), 2868 (s), 1627 (w), 1488 (s), 1446 (s), 1415 (s), 1298 (s), 1044 (s), 935 (s), 846 (s), 795 (s);
1H-NMR (400 MHz, CDCl3)
δ 7.59 (1H, d, J = 6.8 Hz), 7.29–7.25 (2H, m), 7.09 (1H, d, J = 8.4 Hz), 6.89
(1H, s), 6.78 (2H, s), 6.55 (1H, dd, J = 2.4 Hz, J = 2.8 Hz), 6.45 (1H, dd, J = 2.0, J = 2.4 Hz), 5.97 (2H, s),
4.90 (1H, d, J = 11.2 Hz), 3.49–3.46 (4H, m), 2.89–2.84 (2H, m), 2.63–2.53 (6H, m); 13C-NMR (100 MHz,
CDCl3)
δ 147.8, 146.8, 137.3, 132.0, 132.0, 129.3, 128.0, 127.6, 126.3, 125.0, 124.8, 122.5, 109.7, 108.1, 67.9,
67.5, 62.9, 53.6, 49.0. MS (ESI): calcd m/z for C22H24N2O3 (M+) 364.18. Found 365.26 [M + H]+. Anal.
Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69. Found: C, 72.29; H, 6.44; N, 7.76.
(1S,2S)-2-[4-(2,4-Dimethyl-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2r). Prepared according to
general procedure. 2r was obtained as a white solid (103 mg, 89%) by flash chromatography (ethyl
acetate: petroleum ether = 1:4, v/v). Rf = 0.26 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v).
The ee was determined to be 59% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were 13.1 min (major) and
25
˝
˝
14.7 min (minor). m.p.: 113–114 C; rαsD = +67.6 (c = 65.1 mg, CHCl3); IR (thin film, cm´1) 3589 (br),
3209 (w), 2990 (s), 2806 (s), 2778 (s), 1627 (w), 1491 (s), 1445 (s), 1415 (s), 1383 (s), 1298 (m), 1141 (s), 1076
(s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.62 (1H, d, J = 7.6 Hz), 7.31–7.23 (2H, m), 7.09 (1H, d,
J = 7.2 Hz, J = 2.4 Hz), 7.02–6.95 (3H, m), 6.57 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.21 (1H, dd, J = 2.4 Hz
J = 2.4 Hz), 4.94 (1H, d, J = 11.6 Hz), 3.51 (1H, dt, J = 12 Hz, J = 2.4 Hz), 3.38 (1H, s), 2.99–2.90 (6H, m),
3.72–2.69 (2H, m), 2.31 (6H, s); 13C-NMR (100 MHz, CDCl3)
149.2, 137.4, 132.8, 132.6, 132.0, 132.0,
,
δ
129.4, 128.0, 127.6, 127.2, 126.3, 125.1, 124.9, 119.1, 67.9, 67.7, 52.6, 49.6, 20.9, 17.9. MS (ESI): calcd m/z
for C22H26N2O (M+) 334.20, found: 335.25 [M + H]+. Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84;
N, 8.38. Found: C, 79.03; H, 8.13; N, 8.27.
(1S,2S)-2-[4-m-Tolyl-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2s). Prepared according to general
procedure. 2s was obtained as a white solid (100 mg, 90%) by flash chromatography (ethyl acetate:
petroleum ether = 1:4, v/v). Rf = 0.26 on silica gel (ethyl acetate: petroleum ether = 1:4, v/v). The
ee was determined to be 59% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were 22.2 min (minor) and 22.7
25
˝
˝
min (major). m.p.: 94–96 C; rαsD = +107.4 (c = 46.2 mg, CHCl3); IR (thin film, cm´1) 3507 (br), 3158
(w), 2978 (s), 2934 (s), 2861 (s), 2806 (m), 1491 (s), 1445 (s), 1416 (s), 1383 (s), 1351 (s), 1298 (m), 1154 (s),
1077 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.69 (1H, d, J = 7.2 Hz), 7.36 (2H, td, J = 2.4 Hz
,
J = 7.2 Hz), 7.27 (1H, t, J = 7.6 Hz), 7.19 (1H, d, J = 7.2 Hz), 6.84 (3H, dd, J = 4.8 Hz J = 7.6 Hz), 6.66 (1H,
,
dd, J = 2.4 Hz, J = 2.4 Hz), 6.23 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 5.03 (1H, d, J = 11.6 Hz), 3.62 (1H, dt,
J = 11.6 Hz, J = 2.0 Hz), 3.43 (1H, br), 3.36–3.27 (4H, m), 3.09–3.04 (2H, m), 2.83–2.78 (2H, m); 13C-NMR
(100 MHz, CDCl3)
δ 151.5, 139.0, 137.2, 131.9, 129.7, 129.1, 128.1, 127.6, 126.4, 124.6, 121.0, 117.3, 113.6,
67.9, 67.7, 50.1, 49.2, 21.9. MS (ESI): calcd m/z for C21H24N2O (M+) 320.19, found: 321.25 [M + H]+.
Anal. Calcd for C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C, 78.69; H, 7.94; N, 8.56.
(1S,2S)-2-(4-Phenethyl-cyclohexyl)-1,2-dihydro-naphthalen-1-ol (2t). Prepared according to general
procedure. 2t was obtained as a white solid (90 mg, 78%) by flash chromatography (ethyl acetate:
petroleum ether = 1:2, v/v). Rf = 0.20 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v). The
ee was determined to be 50% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were 10.1 min (major) and
25
˝
˝
11.4 min (minor). m.p.: 112–113 C; rαsD = +87.9 (c = 36.5 mg, CHCl3); IR (thin film, cm´1) 3519 (br),
3089 (w), 2978 (s), 2934 (s), 2863 (s), 2805 (s), 1490 (s), 1445 (s), 1415 (s), 1383 (s), 1351 (s), 1297 (m),
1076 (s), 1044 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.60 (1H, d, J = 7.2 Hz), 7.34–7.21 (7H,
m), 7.09 (1H, d, J = 1.2 Hz), 6.56 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.15 (1H, dd, J = 2.4 Hz, J = 2.4 Hz),
4.91 (1H, d, J = 11.6 Hz), 3.48 (2H, ddd, J = 2.4 Hz, J = 2.4 Hz, J = 6.8 Hz), 2.85–2.96 (4H, m), 2.65 (8H,
dd, J = 4.8 Hz, J = 6.4 Hz); 13C-NMR (100 MHz, CDCl3)
δ 140.5, 137.4, 132.1, 129.5, 128.9, 128.8, 128.7,
128.6, 128.1, 127.6, 126.3, 125.1, 67.7, 67.6, 60.7, 53.9, 49.1, 33.9. MS (ESI): calcd m/z for C22H26N2O (M+)
334.20, found: 335.18 [M + H]+. Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 79.89;
H, 8.05; N, 8.26.
21116

Molecules 2015, 20, 21103–21124
(1S,2S)-4-(1-Hydroxy-1,2-dihydro-naphthalen-2-yl)-piperazine-1-carboxy-lic acid ethyl ester (2u). Prepared
according to general procedure. 2u was obtained as a white solid (89 mg, 85%) by flash
chromatography (ethyl acetate: petroleum ether = 1:2, v/v). Rf = 0.17 on silica gel (ethyl acetate:
petroleum ether = 1:2, v/v). The ee was determined to be 51% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were
25
˝
˝
16.0 min (minor) and 21.7 min (major). m.p.: 147–148 C; rαsD = +93.2 (c = 65.3 mg, CHCl3); IR (thin
film, cm´1) 3517 (br), 3087 (w), 2977 (s), 2934 (s), 2867 (s), 2806 (s), 1710 (m), 1490 (s), 1445 (s), 1415 (m),
1383 (s), 1351 (s), 1298 (m), 1077 (s), 1044 (m), 935 (m), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.57 (1H, d,
J = 7.6 Hz), 7.31–7.23 (2H, m), 7.09 (1H, d, J = 6.8 Hz), 6.56 (1H, dd, J = 2.0 Hz, J = 2.0 Hz), 6.03 (1H, dd,
J = 2.4 Hz, J = 2.8 Hz), 4.90 (1H, d, J = 10.8 Hz), 4.16 (2H, dd, J = 14.4 Hz, J = 6.8 Hz), 3.56–3.47 (5H, m),
3.38 (1H, br), 2.74 (2H, t, J = 6.8 Hz), 2.54 (2H, t, J = 6.0 Hz), 1.29 (3H, t, J = 7.2 Hz); 13C-NMR (100 MHz,
CDCl3) δ 155.5, 137.0, 131.8, 129.5, 128.0, 127.6, 126.3, 125.2, 124.5, 67.8, 67.6, 61.4, 48.9, 44.2, 14.7. MS
(ESI): calcd m/z for C17H22N2O3 (M+) 302.16, found: 303.08 [M + H]+. Anal. Calcd for C17H22N2O3:
C, 67.53; H, 7.33; N, 9.26. Found: C, 67.39; H, 7.68; N, 9.15.
(1S,2S)-2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-1,2-dihydro–naphthalen-1-ol
(
2v).
Prepared
according to general procedure. 2v was obtained as a white solid (107 mg, 83%) by flash
chromatography (ethyl acetate: petroleum ether = 1:3, v/v). Rf = 0.26 on silica gel (ethyl acetate:
petroleum ether = 1:3, v/v). The ee was determined to be 54% using HPLC analysis on a CHIRALCEL
AD column,
λ
= 254 nm. Flow rate = 1.0 mL/min; Retention times in 2% 2-propanol in hexanes were
25
35.2 min (minor) and 36.3 min (major). m.p.: 120–121 C; rαsD = +87.6˝ (c = 46.8 mg, CHCl3); IR
˝
(thin film, cm´1) 3517 (br), 3092 (w), 2978 (s), 2869 (s) 1628 (w), 1491 (m), 1444 (s), 1383 (s), 1351 (s),
1297 (m), 1133 (s), 1077 (s), 934 (s), 846 (s); H-NMR (400 MHz, CDCl3)
1
δ 7.59 (1H, d, J = 7.2 Hz),
7.34 (1H, t, J = 8.0 Hz), 7.29–7.23 (2H, m), 7.13–7.06 (4H, m), 6.57 (1H, d, J = 10.0 Hz), 6.11 (1H, dd,
J = 2.0 Hz J = 2.0 Hz), 4.94 (1H, d, J = 12.0 Hz), 3.53 (1H, dd, J = 2.4 Hz, J = 2.0 Hz), 3.30–3.22 (5H, m),
2.97 (2H, dd, J = 3.2 Hz, J = 5.2 Hz), 2.72 (2H, t, J = 11.2 Hz); 13C-NMR(100 MHz, CDCl3)
151.5,
,
δ
137.1, 131.9, 129.8, 129.7, 128.2, 127.8, 126.5, 125.1, 124.7, 119.1, 116.2, 116.2, 112.5, 112.5, 68.0, 67.6, 49.5,
49.0. MS (ESI): calcd m/z for C21H21F3N2O (M+) 374.16, found: 375.12 [M + H]+. Anal. Calcd for
C21H21F3N2O: C, 67.37; H, 5.65; N, 7.48. Found: C, 67.16; H, 5.89; N, 7.36.
(1S,2S)-2-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-1,2-dihydro-naphth-alen-1-ol
(2w). Prepared
according to general procedure. 2w was obtained as a white solid (98 mg, 76%) by flash
chromatography (ethyl acetate: petroleum ether = 1:3, v/v). Rf = 0.20 on silica gel (ethyl acetate:
petroleum ether = 1:3, v/v). The ee was determined to be 56% using HPLC analysis on a CHIRALCEL
AD column,
λ
= 254 nm. Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were
25
˝
˝
13.7 min (major) and 15.5 min (minor). m.p.: 215–216 C; rαsD = +102.8 (c = 52.7 mg, CHCl3); IR (thin
film, cm´1) 3591 (br), 3210 (w), 2978 (s), 2873 (s), 2805 (s) 1617 (w), 1490 (s), 1445 (s), 1416 (s), 1389 (s),
1297 (s), 1131 (s), 1077 (s), 935 (s), 845 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.51 (1H, d, J = 7.2 Hz), 7.42
(2H, d, J = 8.8 Hz), 7.18 (2H, m), 7.02 (1H, d, J = 7.2 Hz), 6.86 (2H, d, J = 8.8 Hz), 6.50 (1H, dd, J = 2.8 Hz
J = 2.4 Hz), 6.03 (1H, dd, J = 2.4 Hz, J = 2.8 Hz), 4.86 (1H, d, J = 11.2 Hz), 3.47 (1H, d, J = 11.2 Hz),
3.30–3.20 (5H, m), 2.93–2.88 (2H, m), 2.68–2.63 (2H, m); 13C-NMR (100 MHz, CDCl3)
153.5, 137.1,
,
δ
131.9, 129.9, 128.3, 127.8, 126.7, 126.7, 126.7, 126.6, 126.5, 125.1, 124.2, 114.9, 68.1, 67.8, 49.0, 48.9. MS
(ESI): calcd m/z for C21H21F3N2O (M+) 374.16, found: 375.25 [M + H]+. Anal. Calcd for C21H21F3N2O:
C, 67.37; H, 5.65; N, 7.48. Found: C, 67.13; H, 5.86; N, 7.36.
(1S,2S)-2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (2x). Prepared according to
general procedure. 2x was obtained as a white solid (97 mg, 82%) by flash chromatography (ethyl
acetate: petroleum ether = 1:2, v/v). Rf = 0.3 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v).
The ee was determined to be 39% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were 15.2 min (major) and 16.9
25
min (minor). m.p.: 203–204 ˝C; rαsD = +100.1˝ (c = 65.1 mg, CHCl3); IR (thin film, cm´1) 3585 (br),
3212 (w), 2978 (s), 2935 (s), 2806 (s) 1634 (w), 1490 (s), 1445 (s), 1415 (s), 1351 (s), 1298 (s), 1134 (s),
21117

Molecules 2015, 20, 21103–21124
1076 (s), 935 (s), 845 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.60 (d, 1H, J = 7.2 Hz), 7.30–7.22 (m, 4H), 7.1 (d,
1H, J = 7.2 Hz), 6.86 (d, 2H, J = 8.8 Hz), 6.58 (dd, 1H, J = 2.0 Hz, J = 2.4 Hz), 6.13 (dd, 1H, J = 2.4 Hz
,
J = 2.4 Hz), 4.94 (d, 1H, J = 11.6 Hz), 3.54 (d, 1H, J = 11.6 Hz), 3.24–3.19 (m, 5H), 3.00–2.96 (m, 2H),
2.76–2.71 (m, 2H); 13C-NMR (100 MHz, CDCl3)
δ 150.1, 137.2, 131.9, 129.8, 129.2, 128.2, 127.8, 126.5,
125.1, 125.0, 124.4, 117.6, 68.0, 67.7, 50.0, 49.1. MS (ESI): calcd m/z for C20H21ClN2O (M+) 340.13, found:
341.20 [M + H]+. Anal. Calcd for C20H21ClN2O: C, 70.48; H, 6.21; N, 8.22. Found: C, 70.29; H, 6.44; N, 8.16.
(1S,2S)-2-[4-(1-Hydroxy-6,7-dimethoxy-1,2-dihydro-naphthalen-2-yl)-piper-azin-1-yl]-benzonitrile
(3a).
Prepared according to general procedure. 3a was obtained as a white solid (74 mg, 77%) by flash
chromatography (ethyl acetate: petroleum ether = 1:1, v/v). Rf = 0.16 on silica gel (ethyl acetate:
petroleum ether = 1:1, v/v). The ee was determined to be 37% using HPLC analysis on a CHIRALCEL
AD column,
λ
= 254 nm. Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were
25
˝
˝
73.4 min (major) and 86.0 min (minor). m.p.: 192–193 C; rαsD = +65.5 (c = 37.8 mg, CHCl3); IR (thin
film, cm´1) 3512 (br), 3018 (w), 2927 (s), 2809 (s), 2271 (w), 1635 (w), 1490 (s), 1445 (s), 1351 (s), 1297 (s),
1135 (s), 1078 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.57 (1H, dd, J = 1.2 Hz, J = 1.2 Hz),
7.48 (1H, t, J = 7.2 Hz), 7.13 (1H, s), 7.03–6.99 (2H, m), 6.45 (1H, s), 6.47 (1H, dd, J = 2.4 Hz, J = 2.4 Hz),
6.07 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.86 (1H, d, J = 11.2 Hz), 3.93 (3H, s), 3.87 (3H, s), 3.45 (1H, d,
J = 7.2 Hz), 3.28–3.22 (4H, m), 3.15 (1H, br), 2.99–2.98 (2H, m), 2.78–2.77 (2H, m); 13C-NMR (100 MHz,
CDCl3) δ 155.7, 148.8, 148.2, 134.5, 134.0, 130.0, 129.1, 124.8, 122.1, 118.8, 110.2, 108.8, 106.2, 68.0, 67.8,
56.2, 56.2, 52.2, 49.2. MS (ESI): calcd m/z for C23H25N3O3 (M+) 391.19, found: 392.10 [M + H]+. Anal.
Calcd for C23H25N3O3: C, 70.57; H, 6.44; N, 10.73. Found: C, 70.46; H, 6.67; N, 10.55.
(1S,2S)-2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-dihydro-Naphthalen-1-ol (3b). Prepared
according to general procedure. 3b was obtained as a white solid (69 mg, 73%) by flash
chromatography (ethyl acetate: petroleum ether = 1:1, v/v). Rf = 0.20 on silica gel (ethyl acetate:
petroleum ether = 1:1, v/v). The ee was determined to be 49% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were
25
˝
˝
40.5 min (major) and 42.9 min (minor). m.p.: 200–201 C; rαsD = +79.1 (c = 41.2 mg, CHCl3); IR (thin
film, cm´1) 3516 (br), 3022 (w), 2972 (s), 2935 (s), 2806 (s), 1635 (w), 1490 (s), 1445 (s), 1351 (s), 1298 (s),
1135 (s), 1078 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.15 (1H, s), 6.97 (2H, d, J = 8.4 Hz),
6.91–6.87 (2H, m), 6.66 (1H, s), 6.49 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.03 (1H, dd, J = 2.8 Hz, J = 2.4 Hz),
4.87 (1H, d, J = 11.2 Hz), 3.94 (3H, s), 3.88 (3H, s), 3.49 (1H, dt, J = 11.2 Hz, J = 2.4 Hz), 3.25 (1H, br),
3.18–3.13 (4H, m), 2.96–2.94 (2H, m), 2.74–2.73 (2H, m); 13C-NMR (100 MHz, CDCl3)
δ 158.7, 156.3,
148.9, 148.3, 148.1, 130.0, 129.2, 124.8, 122.5, 118.2, 115.8, 115.6, 110.3, 108.9, 67.9, 67.8, 56.3, 56.3, 51.0,
49.2. MS (ESI): calcd m/z for C22H25FN2O3 (M+) 384.18, found: 385.07 [M + H]+. Anal. Calcd for
C22H25FN2O3: C, 68.73; H, 6.55; N, 7.29. Found: C, 68.56; H, 6.78; N, 7.19.
(1S,2S)-2-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-dihydro-naphthalen-1-ol (3c). Prepared
according to general procedure. 3c was obtained as a white solid (74 mg, 79%) by flash
chromatography (ethyl acetate: petroleum ether = 1:1, v/v). Rf = 0.29 on silica gel (ethyl acetate:
petroleum ether = 1:1, v/v). The ee was determined to be 38% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 0.5 mL/min; Retention times in 10% 2-propanol in hexanes were
25
55.6 min (minor) and 60.3 min (major). m.p.: 160–161 ˝C; rαsD = 70.9˝ (c = 35.9 mg, CHCl3); IR (thin
film, cm´1) 3507 (br), 3188 (w), 2968 (s), 2890 (s), 2811 (s), 1610 (w), 1458 (s), 1379 (s), 1281 (s), 1183 (s),
1099 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.14 (1H, s), 7.06–6.93 (4H, m), 6.65 (1H, s), 6.47
(1H, dd, J = 2.4 Hz, J = 2.0 Hz), 6.05 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.86 (1H, d, J = 11.6 Hz), 3.93 (3H, s),
3.87 (3H, s), 3.46 (1H, d, J = 11.2 Hz), 3.22 (1H, br), 3.15–3.11 (4H, m), 2.98–2.95 (2H, m), 2.76–2.72 (2H,
m); 13C-NMR (100 MHz, CDCl3)
δ 148.8, 148.2, 130.0, 129.1, 124.8, 124.6, 122.7, 119.1, 119.1, 116.4, 116.2,
110.1, 108.8, 67.9, 67.8, 56.2, 56.2, 51.2, 51.2, 49.2. MS (ESI): calcd m/z for C22H25FN2O3 (M+) 384.18,
found: 385.10 [M + H]+. Anal. Calcd for C22H25FN2O3: C, 68.73; H, 6.55; N, 7.29. Found: C, 68.62;
H, 6.73; N, 7.18.
21118

Molecules 2015, 20, 21103–21124
(1S,2S)-6,7-Dimethoxy-2-(4-(4-methoxy-phenyl)-piperazin-1-yl]-1,2-dihydro–naphthalene-1-ol (3d). Prepared
according to general procedure. 3d was obtained as a white solid (60 mg, 62%) by flash
chromatography (ethyl acetate: petroleum ether = 1:1, v/v). Rf = 0.20 on silica gel (ethyl acetate:
petroleum ether = 1:1, v/v). The ee was determined to be 59% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 0.5 mL / min; Retention times in 5% 2-propanol in hexanes were
25
˝
˝
92.2 min (major) and 110.1 min (minor). m.p.: 174–175 C; rαsD = +77.4 (c = 26.5 mg, CHCl3); IR (thin
film, cm´1) 3696 (br), 3036 (w), 2924 (s), 2877 (s), 1682 (s), 1512 (s), 1452 (s), 1383 (w), 1244 (s), 1111 (s),
1013 (s), 935 (w), 815 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.15 (1H, s), 6.92 (2H, d, J = 2.0 Hz), 6.85 (2H, d,
J = 2.0 Hz), 6.66 (1H, s), 6.48 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 6.05 (1H, dd, J = 2.4 Hz, J = 2.8 Hz), 4.86
(1H, d, J = 11.2 Hz), 3.94 (3H, s), 3.88 (3H, s), 3.77 (3H, s), 3.48 (1H, dt, J = 11.2 Hz, J = 2.4 Hz), 3.25
(1H, br), 3.15–3.10 (4H, m), 2.98–2.93 (2H, m), 2.75–2.70 (2H, m); 13C-NMR (100 MHz, CDCl3)
δ 154.2,
148.9, 148.3, 145.9, 130.1, 129.1, 124.8, 122.8, 118.6, 114.7, 110.3, 108.9, 68.0, 67.9, 56.3, 56.3, 51.5, 49.3. MS
(ESI): calcd m/z for C23H28N2O4 (M+) 396.20, found: 397.14 [M + H] +. Anal. Calcd for C23H28N2O4:
C, 69.67; H, 7.12; N, 7.07. Found: C, 74.89; H, 7.44; N, 8.56.
(1S,2S)-2-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-dihydronaphthalen-1-ol (3e). Prepared
according to general procedure. 3e was obtained as a white solid (50 mg, 47%) by flash
chromatography (ethyl acetate: petroleum ether = 2:3, v/v). Rf = 0.20 on silica gel (ethyl acetate:
petroleum ether = 2:3, v/v). The ee was determined to be 16% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 10% 2-propanol in hexanes were
25
˝
44.9 min (major) and 49.4 min (minor). m.p.: 187–188 C; rαsD = +25.2˝ (c = 11.9 mg, CHCl3); IR
(thin film, cm´1) 3591 (br), 3210 (w), 2973 (s), 2933 (s), 2874 (s), 2806 (s), 1676 (s), 1490 (s), 1445 (s),
1415 (s), 1383 (s), 1297 (m), 1077 (s), 1044 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.28 (1H,
dd, J = 2.8 Hz
, J = 2.8 Hz), 7.15 (1H, s), 6.97 (1H, t, J = 2.8 Hz), 6.75 (1H, dt, J = 8.8 Hz, J = 2.7 Hz), 6.66
(1H, d, J = 2.4 Hz), 6.50 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 6.01 (1H, dd, J = 2.8 Hz, J = 2.4 Hz), 4.86 (1H, d,
J = 11.6 Hz), 3.95 (3H, d, J = 2.4 Hz), 3.89 (3H, J = 2.4 Hz), 3.49 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 3.24–3.16
(5H, m), 2.95–2.91 (2H, m), 2.73–2.69 (2H, m); 13C-NMR (100 MHz, CDCl3) δ 150.8, 148.9, 148.3, 133.0,
130.6, 129.9, 129.3, 124.7, 122.5, 122.2, 117.5, 115.6, 110.3, 109.0, 68.0, 67.8, 56.2, 56.2, 49.4, 48.9. MS (ESI):
calcd m/z for C22H24Cl2N2O3 (M+) 434.12, found: 435.04 [M + H]+. Anal. Calcd for C22H24Cl2N2O3:
C, 60.70; H, 5.56; N, 6.43. Found: C, 60.57; H, 5.84; N, 6.36.
(1S,2S)-2-[4-(2-Chloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-dihydro-naphthalen-1-ol (3f). Prepared
according to general procedure. 3f was obtained as a white solid (50 mg, 51%) by flash
chromatography (ethyl acetate: petroleum ether = 1:1, v/v). Rf = 0.22 on silica gel (ethyl acetate:
petroleum ether = 1:1, v/v). The ee was determined to be 43% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 2% 2-propanol in hexanes were
25
˝
˝
114.4 min (minor) and 125.3 min (major). m.p.: 140–141 C; rαsD = +75.3 (c = 38.3 mg, CHCl3); IR (thin
film, cm´1) 3591 (br), 3211 (w), 2975 (s), 2934 (s), 2875 (s), 2806 (s), 1678 (w), 1490 (s), 1445 (s), 1378 (s),
1297 (m), 1108 (s), 1077 (s), 918 (s), 846 (s); H-NMR (400 MHz, CDCl3)
1
δ 7.49 (1H, dd, J = 2.4 Hz,
J = 2.4 Hz), 7.39–7.33 (1H, m), 7.27 (1H, s), 7.18 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.95 (1H, t, J = 7.2 Hz),
6.77 (1H, s), 6.60 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.21 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.98 (1H, d,
J = 11.6 Hz), 4.07 (3H, s), 3.99 (3H, s), 3.61 (1H, d, J = 11.6 Hz), 3.24 (4H, br), 3.15–2.95 (2H, m), 2.83–2.64
(2H, m); 13C-NMR (100 MHz, CDCl3)
δ 149.4, 148.9, 148.3, 130.9, 130.1, 139.1, 129.0, 127.8, 124.9, 124.0,
122.9, 120.6, 110.3, 108.9, 68.0, 56.3, 56.3, 52.0, 49.4, 29.9. MS (ESI): calcd m/z for C22H25ClN2O3 (M+)
400.16, found: 401.12 [M + H]+. Anal. Calcd for C22H25ClN2O3: C, 65.91; H, 6.29; N, 6.99. Found:
C, 65.79; H, 6.48; N, 6.76.
(1S,2S)-6,7-Dimethoxy-2-(4-o-tolyl-piperazin-1-yl]-1,2-dihydro-naphthalen-1-ol (3g). Prepared according
to general procedure. 3g was obtained as a white solid (71 mg, 76%) by flash chromatography (ethyl
acetate: petroleum ether = 1:2, v/v). Rf = 0.18 on silica gel (ethyl acetate: petroleum ether = 1:2, v/v).
The ee was determined to be 38% using HPLC analysis on a CHIRALCEL AD column,
λ = 254 nm.
Flow rate = 1.0 mL/min; Retention times in 2% 2-propanol in hexanes were 79.8 min (minor) and
21119

Molecules 2015, 20, 21103–21124
25
˝
˝
85.1 min (major). m.p.: 120–121 C; rαsD = +40.1 (c = 38.9 mg, CHCl3); IR (thin film, cm´1) 3693 (br),
3218 (w), 2980 (s), 2869 (s), 1681 (w), 1498 (s), 1445 (s), 1381 (s), 1351 (s), 1297 (m), 1142 (s), 935 (s),
1
846 (s);. H-NMR (400 MHz, CDCl3)
δ
7.21–7.18 (3H, m), 7.06–6.99 (2H, m), 6.67 (1H, s), 6.50 (1H, dd,
J = 2.4 Hz, J = 2.4 Hz), 6.12 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 4.88 (1H, d, J = 11.6 Hz), 3.96 (3H, s), 3.89
(3H, s), 3.49 (1H, dt, J = 6.8 Hz, J = 2.4 Hz), 3.27 (1H, br), 3.02–2.96 (6H, m), 2.75–2.71 (2H, m), 2.34
(3H, s); 13C-NMR (100 MHz, CDCl3)
δ 151.6, 148.8, 148.2, 132.7, 131.3, 130.2, 128.9, 126.8, 124.8, 123.4,
123.0, 119.2, 110.2, 108.8, 68.0, 68.0, 56.3, 56.2, 52.4, 49.7, 18.1. MS (ESI): calcd m/z for C23H28N2O3
(M+) 380.21, found: 381.15 [M + H]+. Anal. Calcd for C23H28N2O3: C, 72.60; H, 7.42; N, 7.36. Found:
C, 72.30; H, 7.64; N, 7.18.
(1S,2S)-2-[4-(2,5-Dimethyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-di-hydro-naphthalen-1-ol (3h). Prepared
according to general procedure. 3h was obtained as a white solid (83 mg, 86%) by flash
chromatography (ethyl acetate: petroleum ether = 1:2, v/v). Rf = 0.29 on silica gel (ethyl acetate:
petroleum ether = 1:2, v/v). The ee was determined to be 35% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 2% 2-propanol in hexanes were
25
˝
˝
63.6 min (minor) and 65.1 min (major). m.p.: 138–139 C; rαsD = +73.2 (c = 68.5 mg, CHCl3); IR (thin
film, cm´1) 3592 (br), 3211 (w), 2975 (s), 2934 (s), 2863 (s), 2805 (s), 1677 (w), 1490 (s), 1444 (s), 1381 (s),
1297 (m), 1119 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ 7.19 (1H, s), 7.08 (1H, d, J = 7.6 Hz),
6.87 (1H, s), 6.83 (1H, d, J = 7.6 Hz), 6.67 (1H, s), 6.50 (1H, dd, J = 2.0 Hz, J = 2.0 Hz), 6.12 (1H, dd,
J = 2.0 Hz, J = 2.0 Hz), 4.89 (1H, d, J = 11.6 Hz), 3.96 (3H, s), 3.90 (3H, s), 3.49 (1H, d, J = 12.0 Hz),
3.37 (1H, br), 3.04–2.95 (6H, m), 2.72 (2H, t, J = 6.8 Hz), 2.33 (3H, s), 2.29 (3H, s); 13C-NMR (100 MHz,
CDCl3)
δ 151.4, 148.8, 148.2, 136.3, 131.1, 130.2, 129.4, 129.0, 124.8, 124.0, 123.0, 119.9, 110.2, 108.8, 68.0,
67.9, 56.2, 56.2, 52.4, 49.7, 21.3, 17.6. MS (ESI): calcd m/z for C24H30N2O3 (M+) 394.23, found: 395.15
[M + H]+. Anal. Calcd for C24H30N2O3: C, 73.07; H, 7.66; N, 7.10. Found: C, 73.16; H, 7.91; N, 6.95.
(1S,2S)-2-[4-(3,4-Dimethyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-1,2-di-hydro-naphthalen-1-ol (3i). Prepared
according to general procedure. 3i was obtained as a white solid (78 mg, 81%) by flash
chromatography (ethyl acetate: petroleum ether = 1:2, v/v). Rf = 0.16 on silica gel (ethyl acetate:
petroleum ether = 1:2, v/v). The ee was determined to be 45% using HPLC analysis on a CHIRALCEL
AD column, λ = 254 nm. Flow rate = 1.0 mL/min; Retention times in 2% 2-propanol in hexanes were
25
˝
21.6 min (major) and 22.6 min (minor). m.p.: 145–146 C; rαsD = +95.6˝ (c = 29.3 mg, CHCl3); IR
(thin film, cm´1) 3695 (br), 3219 (w), 2978 (s), 2936 (s), 2867 (s), 1699 (w), 1490 (w), 1445 (s), 1383 (s),
1351 (s), 1297 (m), 1124 (s), 1077 (s), 935 (s), 846 (s); 1H-NMR (400 MHz, CDCl3)
δ
7.16 (1H, s), 7.04
(1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 6.77 (1H, dd, J = 2.4 Hz, J = 2.4 Hz), 6.66 (1H, s), 6.48 (1H,
dd, J = 2.4 Hz J = 2.4 Hz), 4.88 (1H, d, J = 6.8 Hz), 3.95 (3H, s), 3.89 (3H, s), 3.48 (1H, dt, J = 6.8 Hz
J = 2.4 Hz), 3.20 (1H, br), 3.19–3.16 (4H, m), 2.95–2.87 (2H, m), 2.75–2.69 (2H, m), 2.25 (3H, s), 2.21 (3H,
s); 13C-NMR (100 MHz, CDCl3)
149.7, 148.7, 148.1, 137.2, 130.3, 130.0, 129.0, 128.4, 124.7, 122.6, 118.4,
,
,
δ
114.1, 110.1, 108.8, 67.8, 67.8, 56.2, 56.2, 50.6, 49.2, 20.3, 18.9. MS (ESI): calcd m/z for C24H30N2O3
(M+) 394.23, found: 395.15 [M + H]+. Anal. Calcd for C24H30N2O3: C, 73.07; H, 7.66; N, 7.10. Found:
C, 73.30; H, 8.16; N, 6.74.
4. Conclusions
In conclusion, we have developed the iridium-catalyzed asymmetric ring-opening of oxabicyclic
alkenes with N-substituted piperazine nucleophiles. It may provide an efficient and practical
access to optically pure trans-2-N-substituted piperazine 1,2-dihydronaphthalen-1-ols in high yields
and moderate enantioselectivities. Catalyst systems consisting of four different kinds of chiral
bisphosphine ligands with [Ir(COD)Cl]2 to form complexes as iridium catalysts were investigated,
and (S)-p-Tol-BINAP ligand was found to give high yields and moderate enantioselectivities. Further
investigation to expand the scope of the reactions as well as the study of the iridium-catalyzed
asymmetric ring-opening reactions of oxabicyclic alkenes with other nucleophiles are in progress in
our laboratory.
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Molecules 2015, 20, 21103–21124
Supplementary Materials: The full characterization data for all compounds 1a–1b, 2a–2x and 3a–3i,
including optical rotations, 1H-NMR and 13C-NMR, MS, elemental analysis and X-ray structure data for
compound 2i in CIF format
,
and HPLC conditions and spectra of compounds 2a
, 2c, 2g–2h, 2i–2k, 2m–2o,
2q–2r, 2u–2x and 3b are provided in the Supplementary materials at: http://www.mdpi.com/1420-3049/
20/12/19748/s1.
Acknowledgments: We gratefully thank the National Natural Science Foundation of China (21172081, 21372090),
the Natural Science Foundation of Guangdong Province (S2013020013091), the City of Guangzhou Science and
Technology Plan Projects (156300018), and Graduate Student Research and Innovation Foundation of South China
Normal University (2015lkxm32) for Financial Support.
Author Contributions: D.Y. and R.L. conceived and designed the experiments; W.Y. performed the experiments;
D.Y. and W.Y. analyzed the data; W.Y., R.L., and D.Y. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1a–1b, 2a–2x and 3a–3i are available from the authors.
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2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
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