Highly efficient rhodium-catalyzed asymmetric ring-opening reactions of oxabenzonorbornadiene with amine nucleophiles

Article abstract of DOI:10.1007/s10562-010-0383-3

Rhodium-catalyzed asymmetric ring-opening reactions of oxabenzonorbornadienes with aliphatic primary amines and substituted N-phenylpiperazines were investigated. These reactions are featured with the formation of a new carbon-nitrogen bond via an intermolecular allylic displacement of the bridgehead oxygen with amine nucleophiles, which offered the corresponding products in good to excellent yields (up to 97%) with excellent enantioselectivities (up to 99%ee). Graphical Abstract: Rhodium-catalyzed asymmetric ring-opening reactions of oxabenzonorbornadienes with aliphatic primary amines and substituted N-phenylpiperazines were investigated. These reactions are featured with the formation of a new carbon-nitrogen bond via an intermolecular allylic displacement of the bridgehead oxygen with amine nucleophiles, which offered the corresponding products in good to excellent yields (up to 97%) with excellent enantioselectivities (up to 99 %ee).

Full text of DOI:10.1007/s10562-010-0383-3

Catal Lett (2010) 138:124–133
DOI 10.1007/s10562-010-0383-3
Highly Efficient Rhodium-Catalyzed Asymmetric Ring-Opening
Reactions of Oxabenzonorbornadiene with Amine Nucleophiles
•
•
•
Yuhua Long Shuangqi Zhao Heping Zeng
Dingqiao Yang
Received: 23 April 2010 / Accepted: 25 May 2010 / Published online: 10 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Rhodium-catalyzed asymmetric ring-opening
reactions of oxabenzonorbornadienes with aliphatic pri-
mary amines and substituted N-phenylpiperazines were
investigated. These reactions are featured with the forma-
tion of a new carbon-nitrogen bond via an intermolecular
allylic displacement of the bridgehead oxygen with amine
nucleophiles, which offered the corresponding products
in good to excellent yields (up to 97%) with excellent
enantioselectivities (up to 99%ee).
catalyzed asymmetric ring-opening reactions of oxa-
benzonorbornadiene with many nucleophiles including
alcohols [8, 9], phenols [10], amines [11], carboxylates
[12], 1,3-dicarbonyl nucleophiles [13], and sulfur nucleo-
philes [14] which demonstrated the great promising on
providing novel and simple routes to optically active
compounds [15–18]. We herein report a novel extension to
Lautens’s method, in which the ring of oxabenzonorbor-
nadiene 1a was opened by aliphatic primary amines or
substituted N-phenylpiperiazines secondary amines as
nucleophiles in the presence of rhodium complex catalyst
to afford the corresponding trans-1,2-dihydronaphth-1-ols
derivatives with excellent enantioselectivities. In this
paper, we used six different ligands to form complexes
with rhodium for ring-opening reaction to explore the
rhodium-catalyzed asymmetric ring-opening reaction of
oxabenzonorbornadiene with amine nucleophiles.
Keywords Rhodium catalysis Á
Asymmetric ring-opening Á Oxabenzonorbornadienes Á
Chiral bisphosphine ligand
1 Introduction
To explore efficient methods for creating carbon-carbon
bond and carbon-heteroatom bonds via asymmetric catal-
ysis is among the hot topics in field of organic synthesis,
and has been attracted increasing interests in recent years
due to their great potential to offer practical methods for
the synthesis of complicated molecules with biological
interests. Asymmetric ring-opening of oxabenzonorborna-
diene mediated by rhodium-catalyst are particularly
remarkable, which offers products with more than one
chiral center in a single step. In general, this type of
reaction is highly efficient and characterized with low
catalyst loading, high yield and enantioselectivities [1–7].
Lautens’s group has extensively investigated the rhodium-
2 Results and Discussion
By using appropriate rhodium catalysts, aliphatic primary
amines, despite their low activities in this type of reactions,
can efficiently attach the ring to give the corresponding
trans-1,2-dihydronaphth-1-ols 2a–2e in good yields with
reasonable enantioselectivities (Table 1).
Aliphatic primary amines were known as good ligands
for rhodium, which appeared to decrease the efficiency of
the rhodium catalysts via their irreversible binding to the
metal center. We found that, by using equal molar amount
of NH4I as competitive ligand, the reactivity of rhodium
catalysts was fully recovered, and both yields and enanti-
oselectivities ([60%ee) were good (Table 1, entries 2, 5, 7,
9 and 12). In the case (R,R)-BBPPX and C2-Ferriphos as
ligands, the reactions afforded excellent yields and
Y. Long Á S. Zhao Á H. Zeng Á D. Yang (&)
School of Chemistry and Environment, South China Normal
University, Guangzhou 510006, People’s Republic of China
e-mail: yangdq@scnu.edu.cn
123

Oxabenzonorbornadiene with Amine Nucleophiles
125
Table 1 Rhodium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes 1a–1c with aliphatic primary amine nucleophiles using
different bisphosphine ligands
R1
R1
R2
R2
[Rh(COD)Cl]2 (2.5 mol%), Ligand (5 mol%)
O
R3NH2
THF, 80 oC
R2
NHR3
R2
R1 OH
R1
2a-2e
1a-1c
1a: R1=R2=H
1b: R1=OCH3, R2=H
1c: R1=H, R2=OCH3
Entry
R
R3
Ligand
DPPF
(S,R)-PPF-PtBu2
(R,R)-BBPPX
DPPF
Prod
Yield (%)a
ee (%)b
1
R1 = R2 = H
R1 = R2 = H
R1 = R2 = H
R1 = OCH3, R2 = H
R1 = OCH3, R2 = H
R1 = R2 = H
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
2a
2a
2a
2b
2b
2c
2c
2d
2d
2d
2e
2e
2e
97
57
86
87
57
50
66
53
54
97
71
68
62
–
2
60
93
–
3
4
5
(S,R)-PPF-PtBu2
63
–
6
3,4-(OCH3)2C6H3
DPPF
(S,R)-PPF-PtBu2
DPPF
(S,R)-PPF-PtBu2
C2-Ferriphos
DPPF
7
R1 = R2 = H
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
60
–
8
R1 = OCH3, R2 = H
R1 = OCH3, R2 = H
R1 = OCH3, R2 = H
R1 = H, R2 = OCH3
R1 = H, R2 = OCH3
R1 = H, R2 = OCH3
9
52
88
–
10
11
12
13
(S,R)-PPF-PtBu2
71
89
C2-Ferriphos
Conditions: [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), 1a dissolved in THF followed by the addition of primary amine (1 equiv. to 1a).
Reacted at 80 °C until complete as determined by TLC analysis
a
Isolated yield
b
ee determined by HPLC with a Chiralcel OD-H column
H
H
PtBu2
Bu2Pt
Ph2P
enantioselectivities (up to 93%ee) (Table 1, entries 3, 10
and 13). Therefore, (R,R)-BBPPX and C2-Ferriphos were
better than (R,S)-PPF-PtBu2 ligand for this type reaction in
rhodium catalyst system. These ligands enhanced the yields
and enantioselectivities.
PPh2
PPh2
PPh2
Fe
Fe
Fe
(R,S)-PPF-PtBu2
S,R
t
(
)-PPF-P Bu2
DPPF
NMe2
PPh2
To expand our investigations, we tried to use the sec-
ondary amines, such as substituted N-phenlypiperazines,
for ring opening in the presence of different rhodium cat-
alysts generated from [Rh(COD)Cl]2 and different ligands
(Scheme 1; Table 2). Interestingly, the reactions were
found to offer good yields (up to 97%) with excellent
enantioselectivities (up to 99%ee).
PPh2
PPh2
P
ph
Fe
P
PPh2
NMe2
ph
(S)-BINAP
C2-Ferriphos
(R,R)-BBPPX
Scheme 1 Ligands
To optimize the ratio of the nucleophile to rhodium, we
examined different amount of the amines, which showed
that 1a reacted with N-phenylpiperazine to form product 2f
in high yield and enantioselectivity in the presence of
2.5 mol% of Rh(COD)Cl]2/5 mol% of (R,S)-PPF-PtBu2
(Table 2). We further found that the amount of N-phenyl-
piperazine could be lowered to 3 equivalents (Table 2,
entry 2), even at 1 equivalent, the reactions were completed
within 4 hours with good yield (Table 2, entry 3).
However, when the secondary amine was used with
quantity below 1 molar equivalent, the reaction gave lower
yield even at longer reaction time (Table 2, entry 4).
Overall, the oxabenzonorbornadiene 1a reacted with
different substituted N-phenylpipeazines to give the cor-
responding ring-opening products 2h–2j with high yields
(82–95%) and excellent enantioselectivities (90–95%ee) in
the presence of 2.5 mol% [Rh(COD)Cl]2 and 5 mol% of
123

126
Y. Long et al.
Table 2 Effects of the number of equivalents of nucleophile used
[Rh(COD)Cl]2 (2.5 mol%)
O
(R,S)-PPF-PtBu2 (5 mol% )
THF, 80 oC
N
[Rh(COD)Cl]2 (2.5 mol%)
O
N
COOC2H5
OH
R S
( ,
)-PPF-PtBu2 (5 mol%)
N
N
(1R, 2R)-2g
(ee; 99.89 %)
1a
OH
(1
(1 equiv.)
N COOC2H5
H
N
HN
N
(1 equiv)
1a
R
, 2
R
) - 2f
o
THF, 80 C
Scheme 2 The high enantioselectivity of ring-opening of 1a with
piperazine-1-carboxylic acid ethyl ester nucleophile
Entry N-Phenyl piperazine
equivalent
Time
(h)
Yield
(%)a
ee (%)b
1
2
3
4
5
4
4
4
8
92
93
95
78
97
95
93
87
3
1
0.5
Conditions: [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), 1a dis-
solved in THF followed by the addition of N-phenylpipeazine (1
equiv. to 1a). Reacted at 80 °C until complete as determined by TLC
analysis
Fig. 1 Crystal structure of 2g
To investigate the effects of the substituted groups on the
phenyl ring of N-phenylpiperazines, we chose 6 different
compounds as shown in Table 4. The results showed
that p-substituted N-phenylpiperazines or disubstituted
N-phenylpiperazines gave higher yields and better enanti-
oselectivities(Table 4, entries 2, 5 and 6), while the N-phenyl-
piperazines with substituted groups of o-CH3 or o-F at the
phenylringsofferedpoorerresults(Table 4, entries1and3). It
was further observed that the electron-donating groups at the
nucleophies facilitated the reaction with increasing yields and
enantioselectivities (Table 4, entries 5 and 6).
a
Isolated yield
b
ee determined by HPLC with a Chiralcel OD-H column
(R,S)-PPF-PtBu2 (Table 3). Therefore, (R,S)-PPF-PtBu2
was found to be a very good ligand for this ring-opening
reaction.
The oxabenzonorbornadiene 1a reacted with 1 equiva-
lent of piperazine-1-carboxylic acid ethyl ester in the
presence of 2.5 mol% of [Rh(COD)Cl]2 and 5 mol% of
(R,S)-PPF-PtBu2 to give the corresponding ring-opening
product 2g in nearly quantitative yield (97%) with excel-
lent enantioselectivity (99.89%ee) (Scheme 2). The con-
figuration of 2g was determined by single crystal X-ray
diffraction to be (1R, 2R) (Fig. 1).
To investigate the influences of two chiral ligands on the
ring-opening reactions, we chose to use (R,S)-PPF-PtBu2 or
Table 4 The effects of the locations of substituted N-phenylpiper-
azine derivatives
[Rh(COD)Cl]2 (2.5 mo l%)
O
Table 3 The effects of substituent group on N-phenylpiperazine
derivatives
(R, S
)-PPF-PtBu2 (5 mol%)
N
N
X
OH
(1R, 2R) - 2h-2o
[Rh(COD)Cl]2 (2.5 mol%)
O
HN
N
(1 equiv.)
X
1a
(R, S
)-PPF-PtBu2 (5 mol%)
THF, 80 oC
N
N
OH
(1 equiv.)
HN
N
X
1a
(1R
, 2 ) - 2h-2j
R
Entry
X
Product
Yield (%)a
ee (%)b
X
THF, 80 oC
1
2
3
4
5
6
o-CH3
2h
2k
2l
55
82
51
81
90
96
86
90
81
95
92
90
p-CH3
Entry
X
Product
Yield (%)a
ee (%)b
o-F
1
2
3
CH3
OCH3
CN
2h
2i
82
93
95
90
95
93
p-F
2m
2n
2o
3,4-Dimethyl
2,5-Dimethyl
2j
Conditions: [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), 1a dis-
solved in THF followed by the addition of substituted N-phenylpip-
erazine (1 equiv. to 1a). Reacted at 80 °C until complete as
determined by TLC analysis
Conditions: [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), 1a dis-
solved in THF followed by the addition of substituted N-phenylpip-
erazine (1 equiv. to 1a). Reacted at 80 °C until complete as
determined by TLC analysis
a
a
Isolated yield
Isolated yield
b
b
ee determined by HPLC with a Chiralcel OD-H column
ee determined by HPLC with a Chiralcel OD-H column
123

Oxabenzonorbornadiene with Amine Nucleophiles
127
O
(S)-BINAP. The resulted were summarized in Table 5.
When (R,S)-PPF-PtBu2 was used, the ring opening reaction
gave 93% yield of 2p with 94%ee (Table 5, entry 1). While
in the case of (S)-BINAP, the reaction offered the ring-
opening product 2p in 68% yield with 78%ee (Table 5,
entry 2). Therefore, (R,S)-PPF-PtBu2 was a better ligand
than (S)-BINAP in terms of yield and enantioselectivity.
The results further revealed that the nature of the chiral
ligand had the significant impact on the reactivity of the
catalyst as shown in Table 5.
(a)
H2NR2
P
P
O
P
X
X
Rh
Rh
P
(b)
RhIII
X
(g)
Rh
(a)
(h)
(f)
O
P
X
P
P
Productive
Catalytic
Cycle
Rh
H+ and X-
P
X
R2NH
RhIII
H
(d)
(e)
H2NR2
P
P
X
O
(c)
Rh
NHR2
"poisoned"
HNR2
(i)
The proposed mechanism for the ARO of oxabenzo-
norbornadiene was outlined in Scheme 3.
R2N
P
P
X
OH
Rh
H
NR
When [Rh(COD)Cl]2 was used as the rhodium source,
the dimeric complex was dissociated to form the corre-
sponding monomer by solvation. Based on the favorable
steric arrangement, the rhodium catalyst would approach
the oxabenzonorbornadienes through the exo direction in
two possible cycles. One involved the following 4 steps
(Scheme 3): (a) oxabenzonorbornadiene binding on the
exo-face (displacement of a halide ligand or dimer bridge
cleavage); (b) oxidative insertion between carbon and
R'
Scheme 3 The possible mechanism for the asymmetric ring-opening
of oxabenzonorbornadiene 1a
oxygen bond to produce a p-allyl rhodium intermediate; (c)
protonation of the rhodium alkoxide; (d) amine nucleo-
philic endo-attack and trans-product liberation. While the
other cycle included the following steps (Scheme 3): (e)
amine binding with rhodium; (f) amine ligand protection
and nucleophilic displacement by a halide nucleophile; (g)
dimer formation with loss of a halide ligand; (h) dimer
cleavage by nucleophilic displacement with a halide; (i)
a-oxidation of the amine ligand.
Table 5 The effects of different chiral ligands for the ring-opening
reaction
[Rh(COD)Cl]2 (2.5 mol%)
Ligand (5 mol%)
O
THF, 80 oC
N
R1
R1
R2
OH
N
(1S,2S)-2p-2r
1a
R2
3 Experimental
HN
N
R3
R3
3.1 General
All flasks were flame-dried under a stream of nitrogen and
cooled before use. Solvents and solutions were transferred
with syringes and cannulae using standard inert atmosphere
Entry R
Ligand
Product Time (h) Yield ee
(%)a (%)b
R1 = R2 = H, (S,R)-
R3 = COCH3 PPF-PtBu2
R1 = R2 = H, (S)-BINAP 2p
R3 = COCH3
R1 = R3 = F, (S,R)-
R2 = H PPF-PtBu2
R1 = R3 = F, (S)-BINAP 2q
R2 = H
R1 = R3 = Cl, (S,R)-
R2 = H PPF-PtBu2
R1 = R3 = Cl, (S)-BINAP 2r
R2 = H
2p
4
8
5
8
5
8
93
68
83
72
78
66
94
78
96
68
94
52
1
1
2
3
4
5
6
techniques. H NMR spectra were recorded at 300 MHz
using a Varian Gemini NMR spectrometer or at 400 MHz
using a Varian XL 400 spectrometer with CDCl3 as ref-
erence standard (7.24 ppm) or some other suitable solvent.
Spectral features are reported in the following order:
Chemical shift (d, ppm); number of protons; multiplicity
(s-singlet, d-doublet, t-triplet, q-quartet, m-complex mul-
tiplet); coupling constants (J. Hz), 13C NMR spectra were
recorded at 100 MHz with CDCl3 as reference standard
(d = 77.23 ppm) or some other suitable solvent. IR spectra
were obtained using a Nicolet DX FT-IR spectrometer as a
KBr pellet or neat film between KBr plates. High resolution
mass was obtained from a VG 70-250S (double focusing)
mass spectrometer at 70 ev. Melting points were recorded
using a Fisher-Johns melting point apparatus and are
uncorrected. Optical rotations were measured with a
JASCO P-1010 polarimeter. HPLC analysis was performed
on a Waters 600E with Chiralcel OD or OJ columns.
2q
2r
Conditions: [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), 1a dis-
solved in THF followed by the addition of substituted N-phenylpip-
erazine (1 equiv. to 1a). Reacted at 80 °C until complete as
determined by TLC analysis
a
Isolated yield
b
ee determined by HPLC with a Chiralcel OD-H column
123

128
Y. Long et al.
3.2.2 (1S,2S)-(?)-2-Isopropylamino-5,8-dimethoxy-1,
2-dihydronaphthalen-1-ol (2b)
Analytical TLC was performed using EM separations
percolated silica gel 0.2 mm layer UV 254 fluorescent
sheets. Column chromatography was performed as ‘Flash
chromatography’ as reported by still using (200–400 mesh)
Merck grade silica gel. The THF was distilled from sodium
benzophenone ketyl immediately prior to use. CH2Cl2 was
distilled from calcium hydride. All other reagents were
obtained from Aldrich and used as received unless other-
wise stated.
Following the general procedure starting from the 1,4-
dihydro-5,8-dimethoxy-1,4-epoxynaphthalene 1b (80 mg,
0.392 mmol) and using (S,R)-PPF-PtBu2 rhodium chloride
complex (2 mol% to 1b) as a catalyst and the nucleophile 2-
isopropylamine (23 mg, 0.392 mmol), 2b was obtained as a
yellow oil (60 mg, 57%) by flash chromatography (ethyl
acetate:hexanes:methanol = 1:1:0.2, v/v). Rf = 0.43 on
silica gel (50% ethyl acetate in hexanes). The ee was deter-
mined to be 63% using HPLC analysis on a CHIRALCEL
OD-H column, k = 254 nm. Retention times in 10% iso-
propanol in hexanes were 14.73 min (major) and 20.16 min
(minor). [a]2D5 = ? 71.9 (c = 2.6 mg/mL, CHCl3); IR
(KBr, cm-1) 3290 (br), 2963(w), 2935(w), 2866(w),
1596(w), 1484(s), 1463(m), 1436(m), 1259(s), 1103(m),
1087(m), 1019(m), 953(m), 803(m), 714(m). 1H NMR
(400 MHz, CDCl3) d 6.94(1H, d, J = 9.89 Hz), 6.81(2H, d,
J = 1.09 Hz), 6.17(1H, q, J = 4.95 Hz), 5.21(1H, d,
J = 2.93 Hz), 3.86(3H, s), 3.83(3H, s), 3.65(1H, t, J =
3.66 Hz), 3.15–3.19(1H, m), 2.44(1H, s(br)), 1.14(3H, d,
J = 1.65 Hz), 1.13(3H, d, J = 1.65 Hz). 13C NMR
(100 MHz, CDCl3) d 152.1, 149.9, 127.8, 123.7, 121.9,
121.3, 111.7, 111.1, 65.8, 56.4, 56.2, 54.9, 46.5, 23.2, 23.1;
FABMS m/z, 263(M?, 20). HRMS Calcd for C15H21NO3,
263.1521. Found: 263.1517.
3.2 General Procedure
To a flame-dried round bottomed flask under inert atmo-
sphere were added [Rh(COD)Cl]2 (4.3 mg, 0.009 mmol)
and DPPF (9.6 mg, 0.017 mmol), which were dissolved in
3 mL THF and stirred at room temperature for 10 min to
produce a dark red rhodium chloride complex, and then
oxabenzonorbornadiene 1a (50 mg, 0.347 mmol) and the
nucleophile isopropylamine (21 mg, 0.347 mmol) were
added to the flask, the reaction was allowed to stir at reflux
until 1a was consumed as determined by TLC analysis. The
solvent was then removed in vacuo and the resulting
mixture was purified by flash chromatography (ethyl ace-
tate:hexanes:methanol = 1:1:0.2, v/v) to give 2a as a yel-
low oil (60 mg, 86%).
3.2.1 (1S,2S)-(-)-2-Isopropylamino-1,
2-dihydronaphthalen-1-ol (2a)
3.2.3 (1S,2S)-(-)-2-[2-(3,4-Dimethoxy-phenyl)-
ethylamino]-1,2-dihydronaphthalen-1-ol (2c)
Following the general procedure starting from the 1,4-
dihydro-1,4-epoxynaphthalene 1a (50 mg, 0.347 mmol) and
using the (R,R)-BBPPX rhodium chloride complex (2 mol%
to 1a) and the nucleophile isopropylamine (21 mg, 0.347
mmol), 2a was obtained as a yellow oil (60 mg, 86%) by
flash chromatography (ethyl acetate:hexanes:methanol =
1:1:0.2, v/v). Rf = 0.12 on silica gel (ethyl acetate:hex-
anes:methanol = 1:1:0.2, v/v). The ee was determined to be
93% using HPLC analysis on a CHIRALCEL OD-H column,
k = 254 nm. Retention times in 5% isopropanol in hexanes
Following the general procedure starting from 1,4-dihydro-
1,4-epoxynaphthalene 1a (100 mg, 0.694 mmol) and
using (S,R)-PPF-PtBu2 rhodium chloride complex (2 mol%
to 1a) as a catalyst and the nucleophile 3,4-dimethox-
yphenethylamine (126 mg, 0.694 mmol), 2c was obtained as
a brown oil (150 mg, 66%) by flash chromatography (ethyl
acetate:hexanes:methanol = 1:1:0.2, v/v). Rf = 0.12 on
silica gel (ethyl acetate:hexanes:methanol = 1:1:0.2). The
ee was determined to be 70% using HPLC analysis on a
CHIRALCEL AD column, k = 254 nm. Retention times in
8% isopropanol in hexanes were 27.301 min (major)
and 22.757 min (minor). [a]2D5 = -7.3 (c = 7.5 mg/mL,
CHCl3); IR (KBr,cm-1), 3289(br), 3033(w), 2999(w),
2934(w), 2834(s), 1605(m), 1590(m), 1515(s), 1463(s),
1452(s), 1261(s), 1236(s), 1156(s), 1140(s), 1028(s), 911(s),
were 7.45 min (major) and 10.82 min (minor). [a]D25
=
-3.3° (c = 3 mg/mL, CHCl3); IR (KBr, cm-1) 3288(br),
3035(w), 2965(w), 2859(w), 1600(s), 1451(s), 1381(s),
1168(s), 1085(m), 1042(m), 779(s), 747(s). 1H NMR
(400 MHz, CDCl3) d 7.55 (1H, d, J = 6.78 Hz), 7.21–7.28
(2H, m), 7.05(1H, d, J = 6.59 Hz), 6.42(1H, dd, J = 9.71,
1.83 Hz), 5.99(1H, dd, J = 9.71, 2.19 Hz), 4.59(1H, d,
J = 10.99 Hz), 3.45(1H, ddd, J = 10.99, 2.19, 2.19 Hz),
3.07–3.13(1H, m), 2.72(2H, s(br)), 1.14(3H, d, J =
6.23 Hz), 1.06(3H, d, J = 6.04 Hz). 13C NMR (100 MHz,
CDCl3) d 136.6, 132.2, 128.8, 128.3, 127.9, 127.7, 126.4,
125.1, 71.9, 59.2, 58.6. 47.4, 24.3, 23.3, 21.9, 19.9, 13.8.
FABMS m/z, 204[M ? H]?. (117, 100). HRMS Calcd for
C13H17NO, 203.1310. Found: 204.1396.
1
781(s), 731(s). H NMR (400 MHz, CDCl3) d 7.52(1H, t,
J = 6.59 Hz), 7.21(2H, m), 7.04(1H, t, J = 6.59 Hz), 6.72–
6.76(3H, m), 6.43(1H, dd, J = 9.16, 7.51 Hz), 5.96(1H, dd,
J = 9.17, 6.96 Hz), 4.66(1H, t, J = 10.07 Hz), 3.85(3H, s),
3.83(3H, s), 3.45–3.49(1H, m), 3.08–3.13(1H, m), 2.84–
2.91(1H, m), 2.72–2.82(4H, m). 13C NMR (100 MHz,
CDCl3) d 148.8, 147.4, 136.7, 132.1, 128.8, 127.8, 127.6,
123

Oxabenzonorbornadiene with Amine Nucleophiles
129
126.1, 124.8, 120.4, 111.9, 111.3, 71.8, 60.5, 55.7, 47.9. 36.0.
FAB-MS m/z, 325(M?, 4). HRMS Calcd for C20H23NO3
(M?), 325.1678. Found: 325.1669.
5.88(1H, dd, J = 9.71, 2.38 Hz), 4.65(1H, d,
J = 11.17 Hz), 3.91(3H, s), 3.87(3H, s), 3.86(6H, s), 3.47–
3.49(1H, m), 3.12–3.17(1H, m), 2.91–2.95(2H, m), 2.82–
2.86(3H, m). 13C NMR (100 MHz, CDCl3) d 149.2, 148.9,
148.4, 147.8, 132.1, 129.5, 128.2, 126.3, 124.9, 120.8,
112.1, 111.6, 110.2, 109.1, 72.0, 61.2, 56.3, 56.2, 56.1,
48.2, 36.0. FABMS m/z, 385(M?, 10). HRMS Cacld for
C22H27NO5, 385.1889. Found: 385.1883.
3.2.4 (1S,2S)-(?)-2-[2-(3,4-Dimethoxy-phenyl)-ethyl-
amino]-5,8-dimethoxy-1,2-dihydronaphthalen-1-ol
(2d)
Following the general procedure starting from 1,4-dihydro-5,8-
dimethoxy-1,4-epoxynaphthalene 1b (60 mg, 0.294 mmol)
and using the C2-Ferriphos rhodium chloride complex (2 mol%
to 1b) as a catalyst and the nucleophile 3,4-dimethoxy-phe-
nethylamine (53 mg, 0.294 mmol), 2d was obtained as a brown
oil (110 mg, 97%) by flash chromatography (ethyl ace-
tate:hexanes:methanol = 1:1:0.2). Rf = 0.10 on silica gel
(ethyl acetate:hexanes:methanol = 1:1:0.2, v/v). The ee was
determined to be 88% using HPLC analysis on a CHIRALCEL
AD column, k = 254 nm. Retention times in 15% isopropanol
in hexanes were 29.11 min (major) and 37.85 min (minor).
[a]2D5 = ? 163.2 (c = 7.8 mg/mL, CHCl3); IR (KBr, cm-1),
3502(br), 3310(br), 3030(w), 2937(s), 2835(s), 1592(m),
1515(s), 1482(s), 1259(s), 1143(s), 1087(s), 1027(s), 913(m),
3.2.6 (1R, 2R)-(?)-2-(4-Phenyl-piperazin-1-yl)-1,
2-dihydro-naphthalen-1-ol (2f)
To a flame dried round bottomed flask containing oxa-
benzonorbornadiene 1a (50 mg, 0.347 mmol) was added to
a THF (2 mL) solution of the rhodium chloride (R,S)-PPF-
PtBu2 complex (2.5 mol% to 1a). This red-brown solution
was then heated to reflux followed by addition of N-phe-
nyl-piperazine (56.3 mg, 0.347 mmol) and ammonium
iodide (50 mg, 0.347 mmol). The reaction was allowed to
stir at reflux for 4 hours, the solvent was then removed in
vacuo and the resulting mixture was purified by flash
chromatograph (20% petroleum ether in ethyl acetate) to
give 2f as a white crystalline solid (102 mg, 95%). The ee
was determined to be 93% using HPLC analysis on a
CHIRALCEL OD column, k = 254 nm. Retention times
in 2% isopropanol in hexanes were 28.78 min (major) and
32.26 min (minor). Rf = 0.25 on silica gel (ethyl ace-
tate:petroleum ether = 4:1, v/v). [a]2D0 = ? 70° (c = 22.9
1
804(s), 730(s). H NMR (400 MHz, CDCl3) d 6.91(1H, d,
J = 9.89 Hz), 6.76–6.78(3H, m), 6.70(2H, d, J = 6.59 Hz),
6.06(1H, q, J = 4.67 Hz), 5.13(1H, d, J = 2.47 Hz), 3.84(6H,
s), 3.81(3H, s), 3.78(3H, s), 3.58(1H, s), 2.93–2.97(2H, m),
2.71–2.76(2H, m), 2.43(2H, s(br)). 13C NMR (100 MHz,
CDCl3)d151.9, 149.9, 149.0, 147.6, 132.5, 127.0, 123.9, 121.9,
121.8, 120.7, 112.1, 111.5, 111.4, 111.1, 65.8, 57.6, 56.3, 56.2,
56.1, 55.9, 48.4, 36.1. FABMS m/z, 385(M?, 15). HRMSCacld
for C22H27NO5, 385.1889. Found: 385.1875.
mg/mL, CHCl3); mp.162–163 °C; IR (KBr, cm-1
)
3458(br), 3063(m), 2943(s), 1608(s), 1498(s), 1248(s),
1045(m), 781(m), 724(s), 690(m); 1H NMR (400 MHz,
CDCl3) d 7.60 (1H, d, J = 7.2 Hz), 7.30–7.23 (4H, m),
7.11 (1H, d, J = 7.2 Hz), 6.96–6.88 (3H, m), 6.58 (1H, dd,
J = 2.8, 2.4 Hz), 6.16 (1H, dd, J = 2.4, 2.4 Hz), 4.95(1H,
d, J = 11.6 Hz), 3.55–3.51(1H, m), 3.35–3.19(5H, m),
3.02–3.19(2H, m), 2.76–2.70(2H, m). 13C NMR (100
MHz, CDCl3) d 151.5, 137.2, 131.9, 129.6, 128.1, 127.7,
3.2.5 (1S,2S)-(?)-2-[2-(3,4-Dimethoxy-phenyl)-ethyl-
amino]-6,7-dimethoxy-1,2-dihydronaphthalen-1-ol
(2e)
Following the general procedure starting from the 1,4-
dihydro-6,7-dimethoxy-1,4-epoxynaphthalene 1c (60 mg,
0.294 mmol) and using the C2-ferriphos rhodium chloride
complex (2 mol% to 1c) as a catalyst and 3,4-dimethox-
yphenethylamine (53 mg, 0.294 mmol) nucleophile, 2e
was obtained as a brown oil (70 mg, 62%) by flash chro-
matography (ethyl acetate:hexanes:methanol = 1:1:0.2,
v/v). Rf = 0.11 on silica gel (ethyl acetate:hexanes:meth-
anol = 1:1:0.2, v/v). The ee was determined to be 89%
using HPLC analysis on a CHIRALCEL AD column,
k = 254 nm. Retention times in 20% isopropanol in hex-
anes were 17.00 min (major) and 18.86 min (minor).
[a]2D5 = ? 408, (c = 6 mg/mL, CHCl3); IR (KBr, cm-1),
3502(br), 3304(br), 3003(w), 2935(s), 2832(m), 1604(m),
1514(s), 1464(s), 1262(s), 1232(s), 1154(m), 1126(m),
1027(s). 1H NMR (400 MHz, CDCl3) d 7.12(1H, s), 6.75–
6.81(3H, m), 6.61(1H, s), 6.36(1H, dd, J = 9.71, 2.02 Hz),
126.4, 124.9, 124.6, 120.1, 116.5, 67.9, 67.7, 50.0, 49.2.
?
ESI-MS m/z:307.06 [M ? H]
C20H22N2O:C 78.40, H 7.24, N 9.14; found:C 78.28, H
7.44, N 9.40.
.
Anal. calcd for
3.2.7 (1R,2R)-(?)-4-(1-Hydroxy-1,2-dihydro-naphthalen-
2-yl)-piperazine-1-carboxylic acid ethyl ester (2g)
To a flame dried round bottomed flask [Rh(COD)Cl]2
(4.3 mg, 0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347
mmol) and 1a (50 mg, 0.347 mmol) were added in THF
(2.5 mL). Ammonium iodide (50 mg, 0.347 mmol) and
4-piperazin-1-yl-benzoic acid ethyl ester (81.2 mg, 0.347
mmol) were then added and followed by heating to 80 °C for
2 h. The solvent was then removed in vacuo and the resulting
mixture was purified by flash chromatograph (20% petroleum
123

130
Y. Long et al.
etherinethylacetate)togive2g asaolourlesscrystal(102 mg,
97%). Rf = 0.25 on silica gel (ethyl acetate:petroleum
ether = 1:4, v/v). The ee was determined to be 99.88% using
1H NMR (400 MHz, CDCl3) d 7.53 (1H, d, J = 7.6 Hz),
7.22–7.08 (4H, m), 7.02–6.90 (3H, m), 6.50(1H, dd, J = 2,
2.4 Hz), 6.14(1H, dd, J = 2.4, 2.4 Hz), 4.87(1H, d,
J = 12 Hz), 3.46–3.42(1H, m), 3.28(1H, S), 2.95–2.85(6H,
m), 2.66–2.60(2H, m), 2.25(3H, s). 13C NMR (100 MHz,
CDCl3) d 151.5, 137.3, 132.7, 132.0, 131.3, 129.5, 128.1,
127.6, 126.8, 126.4, 125.0, 124.9, 123.4, 119.2, 67.9, 67.7,
52.4, 18.1. ESI-MS m/z: 321.17 [M ? H] ?; Anal. calcd for
C21H24N2O: C 78.31, H 7.55, N 8.74; found: C 78.18, H 7.26,
N 8.93.
HPLC analysis on
a CHIRALCEL OD-H column,
k = 254 nm. Retention times in 2% isopropanol in hexanes
were 26.64 min (major) and 22.65 min (minor). [a]2D0 = ?
120° (c = 31.5 mg/mL, CHCl3); m.p. 176–177 °C; IR (KBr,
cm-1); 3445(br), 2986(w), 1679(s), 764(s); 1H NMR
(400 MHz, CDCl3) d 7.49 (1H, d, J = 7.6 Hz), 7.21–7.14
(2H, m), 7.01(1H, dd, J = 1.6, 1.6 Hz), 6.48(1H, dd, J = 2.4,
2.4 Hz), 5.96(1H, dd, J = 2.4, 2.4 Hz), 4.82(1H, d,
J = 11.2 Hz), 4.09–4.04 (2H, m), 3.45–3.38 (5H, m),
3.18(1H, s),2.69–2.66(2H, m), 2.46–2.43(2H, m), 1.21–
1.17(3H, m). 13C NMR (100 MHz, CDCl3) d 155.6, 136.9,
131.8, 129.7, 128.1, 127.7, 126.4, 125.1, 124.4, 67.9, 67.8,
61.2, 49.0, 44.3, 14.8. ESI-MS m/z: 302.37 [M]?; Anal. calcd
for C17H22N2O3: C 67.53, H 7.33, N 9.26; found: C 67.71, H
7.46, N 9.28.
3.2.10 (1R,2R)-(?)-2-[4-(2-Methoxy-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2i)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(2-methoxyphenyl)-
piperazine (66.67 mg, 0.347 mmol) were then added and
followed by heating to 80 °C for 5 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2i as a white crystalline solid (108.5 mg, 93%). The ee was
determined to be 95% using HPLC analysis on a CHIRALCEL
OD-H column, k = 254 nm. Retention times in 2% isopro-
panol in hexanes were 23.05 min (major) and 24.77 min
(minor). Rf = 0.30 on silica gel (ethyl acetate:petroleum
ether = 4:1, v/v). [a]D20 = ? 120° (c = 22.7 mg/mL, CHCl3);
m.p. 149–150 °C; IR (KBr, cm-1) 3298(br), 3024(m),
2993(m), 2845(s), 1583(v), 1500(s), 1250(s), 1013(s), 783(m),
3.2.8 Crystal data for 2g
C17H22N2O3, MW = 302.37, monoclinic, space group P21/c,
˚
˚
˚
a = 45.9403(13) A, b = 8.4577(3) A, c = 16.4653(4) A,
b = 90.0710(10)o, V = 6397.6(3) A , Z = 16, Dc =
3
˚
1.256 mg/m3, l = 0.087 mm-1, F(000) = 2592 reflec-
tions were collected, of which 11100 were considered to be
observed with I [ 2r (I). The structure was determined by
direct methods using the SHELXL-97 suite of programs.
Hydrogen atoms were placed in calculated positions. Full-
matrix least squares refinement based on F2 with aniso-
tropic thermal parameters for the non-hydrogen atom led to
agreement factors R1 = 0.0600 and wR2 = 0.1929.
1
750(s), 698(m); H NMR (400 MHz, CDCl3) d 7.60 (1H, d,
J = 6.8 Hz), 7.30–7.22 (2H, m), 7.10 (1H, d, J = 7.2 Hz),
7.05–6.92 (3H, m), 6.89(1H, d, J = 8 Hz), 6.58(1H, d,
J = 10 Hz), 6.22 (1H, d, J = 10 Hz), 4.95 (1H, d, J =
11.6 Hz), 3.88 (3H, S), 3.53 (1H, d, J = 11.6 Hz), 3.14 (4H, s),
3.05 (3H, s), 2.80 (2H, s).13C NMR (100 MHz, CDCl3)d152.4,
141.3, 137.3, 132.0, 129.5, 128.0, 127.6, 126.3, 125.0, 124.9,
123.2, 121.2, 118.4, 111.3, 67.8, 55.5, 51.4, 49.3. ESI-MS m/z:
337.28 [M ? H] ?; Anal. calcd for C21H24N2O2: C 74.97, H
7.19, N 8.33; found; C 74.76, H 7.40, N 8.63.
3.2.9 (1R,2R)-(?)-2-(4-o-Tolyl-piperazin-1-yl)-1,
2-dihydro-naphthalen-1-ol (2h)
To a flame dried round bottomed flask [Rh(COD)Cl]2
(R,S)-PPF-PtBu2
(4.3 mg,
0.347 mmol),
(9.5 mg,
0.347 mmol) and 1a (50 mg, 0.347 mmol) were added in
THF (2.5 mL). Ammonium iodide (50 mg, 0.347 mmol)
and 1-(o-tolyl)piperazine (61.2 mg, 0.347 mmol) were
then added and followed by heating to 80 °C for 5 hours.
The solvent was then removed in vacuo and the resulting
mixture was purified by flash chromatograph (20% petro-
leum ether in ethyl acetate) to give 2h as a white crystalline
solid (61.2 mg, 55%). The ee was determined to be 90%
using HPLC analysis on a CHIRALCEL OD-H column,
k = 254 nm. Retention times in 2% isopropanol in hex-
anes were 14.09 min (major) and 15.24 min (minor). Rf =
0.32 on silica gel (ethyl acetate:petroleum ether = 4:1, v/v).
[a]2D0 = ? 48° (c = 24.2 mg/mL, CHCl3); m.p.145–146 °C;
IR (KBr, cm-1) 3456(br), 3022(m), 2947(s), 2816(s),
1595(v), 1498(s), 1225(s), 1049(m), 781(m), 767(s), 727(m);
3.2.11 (1R,2R)-(?)-2-[4-(1-Hydroxy-1,2-dihydro-
naphthalen-2-yl)-piperazin-1-yl]-benzonitril (2j)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(2-cyanephe-
nyl)piperazine (65 mg, 0.347 mmol) were then added and
followed by heating to 80 °C for 4 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2j as a white crystalline solid (109.2 mg, 95%). The ee was
123

Oxabenzonorbornadiene with Amine Nucleophiles
131
determined to be 93% using HPLC analysis on a CHIRALCEL
OD column, k = 254 nm. Retention times in 2% isopropanol
in hexanes were 21.491 min (major) and 27.900 min (minor).
Rf = 0.18 on silica gel (ethyl acetate:petroleum ether = 5:1,
v/v). [a]2D0 = ? 65° (c = 24.1 mg/mL, CHCl3); m.p. 132–
133 °C; IR (KBr, cm-1) 3422(br), 2937(m), 2822(s), 1593(v),
1480(s), 1228(s), 1043(m), 785(s), 769(m), 696(w); 1H NMR
(400 MHz, CDCl3) d 7.52–7.40 (3H, m), 7.22–7.15 (2H, m),
7.03–6.93 (3H, m), 6.51 (1H, dd, J = 2.8, 2.8 Hz), 6.11 (1H,
dd, J = 2.4, 2.4 Hz), 4.87 (1H, d, J = 11.6 Hz), 3.47–3.43
(1H, m), 3.25–3.14 (5H, m), 2.98–2.93 (2H, m), 2.73–2.68 (2H,
m). 13C NMR (100 MHz, CDCl3) d 155.7, 137.1, 134.5, 132.0,
129.6, 128.0, 127.7, 126.4, 124.9, 124.6, 122.1, 118.9, 118.6,
106.3, 67.9, 67.6, 52.3, 49.2. ESI-MS m/z: 332.14 [M ? H] ?;
Anal. calcd for C21H21N3O: C 76.11, H 6.39, N 12.68; found: C
75.78, H 6.56, N 12.64.
Ammonium iodide (50 mg, 0.347 mmol) and 1-(2-fluoro-
phenyl)piperazine (62.5 mg, 0.347 mmol) were then added
and followed by heating to 80 °C for 5 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2l as a white crystalline solid (57.4 mg, 51%). The ee was
determined to be 87% using HPLC analysis on a CHIRALCEL
OD-H column, k = 254 nm. Retention times in 2% isopro-
panol in hexanes were 15.945 min (minor) and 19.339 min
(major). Rf = 0.26 on silica gel (ethyl acetate:petroleum
ether = 4:1, v/v). [a]D20 = ? 63° (c = 26.0 mg/mL, CHCl3);
m.p.122–123 °C; IR (KBr, cm-1) 3439(br), 2951(m), 2826(s),
2760(w), 1608(m), 1500(s), 1246(s), 1048(m), 781(s), 760(s),
748(m); 1H NMR (400 MHz, CDCl3) d 7.52 (1H, d,
J = 7.2 Hz), 7.22–7.14 (2H, m), 7.02–6.83 (5H, m), 6.50 (1H,
dd, J = 2.4, 2.4 Hz), 6.10 (1H, dd, J = 2.4, 2.4 Hz), 4.86 (1H,
d, J = 11.6 Hz), 3.45–3.41 (1H, m), 3.25 (1H, s), 3.16–3.01
(4H, m), 2.94–2.90 (2H, m), 2.70–2.64 (2H, m). 13C NMR
(100 MHz, CDCl3) d 157.2, 154.8, 140.3, 137.3, 132.0, 129.6,
128.1, 127.7, 126.5, 125.0, 124.8, 124.7, 123.0, 122.9, 119.2,
116.5, 67.9, 67.8, 51.3, 49.3. ESI-MS m/z: 325.13 [M ? H]?;
Anal. calcd for C20H21FN2O:C 74.05, H 6.53, N 8.64; found: C
74.08, H 6.63, N 8.54.
3.2.12 (1R,2R)-(?)-2-(4-p-Tolyl-piperazin-1-yl)-1,
2-dihydro-naphthalen-1-ol (2k)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R, S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(4-methyl-
phenyl)piperazine (62 mg, 0.347 mmol) were then added and
followed by heating to 80 °C for 6 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2k as a white crystalline solid (91.2 mg, 82%). The ee was
determined to be 90% using HPLC analysis on a CHIRALCEL
OD-H column, k = 254 nm. Retention times in 2% isopro-
panol in hexanes were 18.36 min (minor) and 20.10 min
(major). Rf = 0.26 on silica gel (ethyl acetate:petroleum
ether = 4:1, v/v). [a]D20 = ? 63° (c = 27.8 mg/mL, CHCl3);
m.p.196–197 °C; IR (KBr, cm-1) 3460(br), 2943(w), 2835(m),
1524(s), 1448(m), 1242(s), 1045(m), 810(m), 781(s), 750(m);
1H NMR (400 MHz, CDCl3) d 7.52 (1H, d, J = 7.2 Hz), 7.21–
7.17 (2H, m), 7.02 (3H, d, J = 8.5 Hz), 6.80 (2H, d,
J = 8.5 Hz), 6.50 (1H, dd, J = 9.8, 2.1 Hz), 6.08 (1H, dd,
J = 9.8, 2.3 Hz), 4.87 (1H, d, J = 11.7 Hz), 3.46 (1H, d,
J = 12.1 Hz), 3.28 (1H, s), 3.14–3.09 (4H, m), 2.91–2.89 (2H,
m), 2.68–2.65 (2H, m), 2.2 (3H, s). 13C NMR (100 MHz,
CDCl3)d149.4, 137.3, 132.0, 130.0, 129.8, 129.6, 128.1, 127.7,
126.5, 125.0, 124.7, 116.9, 68.0, 67.7, 50.6, 49.2, 20.7. ESI-MS
m/z: 318.59 [M ? 2] ?; Anal. calcd for C21H24N2O: C 78.71, H
7.55, N 8.74; found: C. 78.52, H 7.75, N 8.65.
3.2.14 (1R,2R)-(?)-2-[4-(4-Fluoro-phenyl)-piperazin-1-
yl]-1,2-dihydro-naphthalen-1-ol (2m)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 ml). Ammo-
nium iodide (50 mg, 0.347 mmol) and N-(4-fluoro-
phenyl)piperazine (62.5 mg, 0.347 mmol) were then added
and followed by heating to 80°C for 5 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2m as a white crystalline solid (91.2 mg, 81%). The ee was
determined to be 95% using HPLC analysis on a CHIRALCEL
OD-H column, k = 254 nm. Retention times in 2% isopro-
panol in hexanes were 22.97 min (minor) and 25.55 min
(major). Rf = 0.26 on silica gel (ethyl acetate:petroleum
ether = 4:1, v/v). [a]D20 = ? 91° (c = 26.6 mg/mL, CHCl3);
m.p.171–172 °C; IR (KBr, cm-1) 3448(br), 3061(w), 2947(m),
2837(s), 2763(w), 1510(s), 1238(s), 1045(m), 825(m), 780(s);
1H NMR (400 MHz, CDCl3) d 7.61 (1H, d, J = 6.8 Hz), 7.31–
7.23 (2H, m), 7.11 (1H, d, J = 8 Hz), 7.00–6.87 (4H, m), 6.59
(1H, dd, J = 2.4, 2.4 Hz), 6.15 (1H, dd, J = 2.8, 2.4 Hz), 4.95
(1H, d, J = 11.6 Hz), 3.55–3.51 (1H, m), 3.35 (1H, s), 3.20–
3.10 (4H, m), 3.00–2.95 (2H, m), 2.75–2.72 (2H, m). 13C NMR
(100 MHz, CDCl3) d 158.6, 156.2, 148.0, 137.1, 131.9, 129.6,
128.1, 127.7, 126.4, 125.0, 124.8, 124.5, 118.2, 115.8, 67.8,
50.9, 49.1, 48.9. ESI-MS m/z: 325.56 [M ? 1] ?; Anal. calcd
for C20H21FN2O: C 74.05, H 6.53, N 8.64; found: C 74.03, H
6.73, N 8.64.
3.2.13 (1R,2R)-(?)-2-[4-(2-Fluoro-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2l)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL).
123

132
Y. Long et al.
3.2.15 (1R,2R)-(?)-2-[4-(3,4-Dimethyl-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2n)
6.14 (1H, dd, J = 2.4, 2.4 Hz), 4.86 (1H, d, J = 11.6 Hz),
3.45–3.40 (2H, m), 2.91–2.83 (6H, m), 2.65–2.59 (2H, m), 2.23
(6H, d, J = 15.6 Hz). 13C NMR (100 MHz, CDCl3) d 151.5,
137.4, 136.4, 132.1, 131.2, 129.5, 128.1, 127.6, 126.4, 125.1,
124.9, 124.1, 110.0, 67.9, 67.8, 52.5, 21.5, 17.8. ESI-MS m/z:
335.09 [M ? H] ?; Anal. calcd for C22H26N2O: C 79.00, H
7.84, N 8.38; found: C 78.79, H 8.05, N 8.57.
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(3,4-dimethyl-
phenyl)piperazine (66.035 mg, 0.347 mmol) were then added
and followed by heating to 80 °C for 5 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2n as a white crystalline solid (104.4 mg, 90%). The ee
was determined to be 92% using HPLC analysis on a CHI-
RALCEL OD-H column, k = 254 nm. Retention times in 2%
isopropanol in hexanes were 18.71 min (minor) and 19.95 min
(major). Rf = 0.26 on silica gel (ethyl acetate:petroleum
ether = 1:1, v/v). [a]D20 = ? 19.3° (c = 27.1 mg/mL, CH
Cl3); m.p. 128–129 °C; IR (KBr, cm-1) 3381(b), 2956(m),
2828(s), 2762(m), 1608(s), 1508(s), 1246(s), 1045(s), 817 (m),
3.2.17 (1R,2R)-(?)-1-{4-[4-(1-Hydroxy-1,2-dihydro-
naphthalen-2-yl)-piperazin-1-yl]-phenyl}-ethanone
(2p)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 4-piperazinoacetophe-
none (70.83 mg, 0.347 mmol) were then added and followed
by heating to 80 °C for 6 hours. The solvent was then removed
in vacuo and the resulting mixture was purified by flash chro-
matograph (20% petroleum ether in ethyl acetate) to give 2p as
a white crystalline solid (112.4 mg, 93%). The ee was deter-
mined to be 94% using HPLC analysis on a CHIRALCEL OD-
H column, k = 254 nm. Retention times in 2% isopropanol in
hexanes were 32.02 min (minor) and 34.63 min (major).
Rf = 0.23 on silica gel (ethyl acetate:petroleum ether = 1:1,
v/v). [a]2D0 = ? 121° (c = 22.3 mg/mL, CHCl3); m.p. 198–
200 °C; IR (KBr, cm-1) 3396(b), 3012 (m), 2966(m), 2833(s),
2767(w), 1641(s), 1598(s), 1250(s), 1049(m), 802 (m), 780(s),
748(m); 1H NMR (400 MHz, CDCl3) d 7.87 (2H, d,
J = 9.2 Hz), 7.56 (1H, d, J = 8 Hz), 7.26–7.22 (2H, m), 7.08
(1H, d, J = 9.2 Hz), 6.86 (2H, d, J = 9.2 Hz), 6.56 (1H, dd,
J = 2.4, 2.4 Hz), 6.08 (1H, dd, J = 2.4, 2.4 Hz), 4.92 (1H, d,
J = 12.4 Hz), 3.53 (1H, d, J = 11.2 Hz), 3.43–3.32 (4H, m),
3.20 (1H, s), 2.95–2.90 (2H, m), 2.72–2.67 (2H, m), 2.50 (3H,
s). 13C NMR (100 MHz, CDCl3) d 196.7, 154.3, 137.0, 131.9,
130.6, 129.9, 128.2, 127.8, 126.5, 125.1, 124.2, 113.8, 68.0,
67.7, 48.9, 48.2, 26.3. ESI-MS m/z: 349.11 [M ? 1] ?; Anal.
calcd for C22H24N2O2: C 75.83, H 6.94, N 8.04; found: C 75.56,
H 6.88, N 7.90.
1
762(s), 746(m); H NMR (400 MHz, CDCl3) d 7.61 (1H, d,
J = 7.2 Hz), 7.31–7.23 (2H, m), 7.11–7.04 (2H, m), 6.78 (1H,
s), 6.73 (1H, dd, J = 2.8, 2.4 Hz), 6.58 (1H, dd, J = 2.8,
2.8 Hz), 6.17 (1H, dd, J = 2.4, 2.4 Hz), 4.95 (1H, d,
J = 12 Hz), 3.55–3.50 (1H, m), 3.40(1H, s), 3.24–3.13 (4H,
m), 3.01–2.96 (2H, m), 2.75–2.70 (2H, m), 2.25(2H, s), 2.20
(4H, d, J = 10 Hz). 13C NMR (100 MHz, CDCl3) d 149.8,
137.3, 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, 31.1, 20.4, 18.9. ESI-
MS m/z: 335.11 [M ? H] ?; Anal. calcd for C22H26N2O:C
79.00, H 7.84, N 8.38; found: C 79.23, H 7.80, N 8.58.
3.2.16 (1R,2R)-(?)-2-[4-(2,5-Dimethyl-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2o)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(2,5-dimethyl-
phenyl)piperazine (66.03 mg, 0.347 mmol) were then added
followed by heating to 80 °C for 6 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2o as a white crystalline solid (111.4 mg, 96%). The ee
was determined to be 90% using HPLC analysis on a CHI-
RALCEL OD column, k = 254 nm. Retention times in 2%
isopropanol in hexanes were 11.37 min (minor) and 12.18 min
(major). Rf = 0.32 on silica gel (ethyl acetate:petroleum
ether = 1:1, v/v). [a]D20 = ? 16° (c = 35.5 mg/mL, CHCl3);
m.p.134–135 °C; IR (KBr, cm-1) 3481(b), 3034(m), 2941(m),
2822(s), 2754(m), 1502(s), 1244(m), 1043(s), 802 (m), 780(s),
748(m); 1H NMR (400 MHz, CDCl3) d 7.53 (1H, d,
J = 7.6 Hz), 7.22–7.13 (2H, m), 7.02–6.98 (2H, m), 6.79 (1H,
s), 6.74 (1H, d, J = 7.6 Hz), 6.50 (1H, dd, J = 2.8, 2.8 Hz),
3.2.18 (1R,2R)-(?)-2-[4-(2,4-Difluoro-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2q)
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 mL). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(2,4-difluoro-
phenyl)piperazine (68.78 mg, 0.347 mmol) were then added
and followed by heating to 80 °C for 5 h.The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2q as a white crystalline solid (101 mg, 85%). The ee was
determined to be 96% using HPLC analysis on a CHIRALCEL
123

Oxabenzonorbornadiene with Amine Nucleophiles
133
OD-H column, k = 254 nm. Retention times in 2% isopro-
panol in hexanes were 17.40 min (minor) and 19.82 min
(major). Rf = 0.25 on silica gel (ethyl acetate:petroleum
ether = 2:1, v/v). [a]D20 = ? 44° (c = 9.6 mg/mL, CHCl3);
m.p. 135–136 °C; IR (KBr, cm-1) 3462(b), 3070 (w), 2949(m),
2835(s), 2758(w), 1509(s), 1454(m), 1047(m), 813 (m), 783(s),
750(m); 1H NMR (400 MHz, CDCl3) d 7.52 (1H, d,
J = 7.2 Hz), 7.22–7.14 (2H, m), 7.02 (1H, dd, J = 1.6,
1.6 Hz), 6.87–6.70 (3H, m), 6.50 (1H, dd, J = 2.4, 2.4 Hz),
6.10 (1H, dd, J = 2.4, 2.4 Hz), 4.86 (1H, d, J = 11.6 Hz),
3.46–3.41 (1H, m), 3.24 (1H, s), 3.06–2.89 (6H, m), 2.69–2.64
(2H, m). 13C NMR (100 MHz, CDCl3) d 159.4, 157.0, 154.6,
137.1, 136.8, 132.0, 129.6, 128.1, 127.7, 126.4, 124.9, 119.8,
111.0, 110.8, 105.2, 105.0, 104.7, 67.9, 67.7, 51.7, 49.2. ESI-
MS m/z: 343.06 [M ? H] ?; Anal. calcd for C20H20F2N2O: C
70.16, H 5.89, N 8.18; found: C 70.05, H 6.03, N 8.34.
oxabenzonorbornadienes by aliphatic primary amines and
substituted N-phenylpiperazine secondary amine nucleo-
philes under neutral conditions to give the corresponding
trans-1,2-addition products. By employing NH4I additives in
the presence of a protic additive, the poisoning effect of ali-
phatic primary amines was reversed. Among tested ligands,
(R,R)-BBPPX and C2-Ferriphos were found to offer better
enantioselective ligand for primary amine nucleophiles.
Moreover, (R,S)-PPF-PtBu2 was found to offer excellent
enantioselective ligand for secondary amine nucleophiles in
this type of ring-opening reactions. The results further
revealed that the nature of the chiral ligand had the significant
impactonthering-openingreactivityofthecatalyst. Ourwork
also demonstrated that the nature of the chiral ligand had the
significant impact on the reactivity of the catalyst. Applica-
tions of these ligands in catalytic asymmetric synthesis are
currently being investigated in our laboratory.
3.2.19 (1R,2R)-(?)-2-[4-(3,4-Dichloro-phenyl)-piperazin-
1-yl]-1,2-dihydro-naphthalen-1-ol (2r)
Acknowledgments We are grateful to the National Natural Science
Foundation of China (No. 20772036 and No. 20802021) and the
Natural Science Foundation of Guangdong Province (No.
8251063101000002 and No. 7005804) for financial support.
To a flame dried round bottomed flask [Rh(COD)Cl]2 (4.3 mg,
0.347 mmol), (R,S)-PPF-PtBu2 (9.5 mg, 0.347 mmol) and 1a
(50 mg, 0.347 mmol) were added in THF (2.5 ml). Ammo-
nium iodide (50 mg, 0.347 mmol) and 1-(3,4-dichloro-
phenyl)piperazine (80.2 mg, 0.347 mmol) were then added
and followed by heating to 80 °C for 5 h. The solvent was then
removed in vacuo and the resulting mixture was purified by
flash chromatograph (20% petroleum ether in ethyl acetate) to
give 2r as a white crystalline solid (101.6 mg, 78%). The ee
was determined to be 94% using HPLC analysis on a CHI-
RALCEL OD-H column, k = 254 nm. Retention times in 2%
isopropanol in hexanes were 32.99 min (minor) and 34.97 min
(major). Rf = 0.25 on silica gel (ethyl acetate:petroleum
ether = 2:1, v/v). [a]D20 = ?56° (c = 33.6 mg/mL, CHCl3);
m.p. 143–144 °C; IR (KBr, cm-1) 3483(b), 2949(s), 2825(s),
2769(m), 1593(s), 1480(s), 1248(s), 1045(s), 815 (m), 783(s),
754(m); 1H NMR (400 MHz, CDCl3) d 7.59 (1H, d,
J = 7.2 Hz), 7.31–7.23 (3H, m), 7.11 (1H, dd, J = 1.2, 1.2
Hz), 6.97 (1H, d, J = 2.8 Hz), 6.76–6.73 (1H, m), 6.59 (1H, dd,
J = 2.4, 2.4 Hz), 6.12 (1H, dd, J = 2.4, 2.4 Hz), 4.94 (1H, d,
J = 11.2 Hz), 3.55–3.51 (1H, m), 3.26–3.15 (5H, m), 2.98–
2.93 (2H, m), 2.73–2.68 (2H, m) . 13C NMR (100 MHz,
CDCl3)d150.8, 137.0, 133.0, 131.9, 130.7, 129.9, 128.2, 127.8,
126.5, 125.1, 124.2, 122.6, 117.6, 115.7, 67.9, 67.6, 49.5, 48.9.
ESI-MS m/z: 375.10 [M ? H] ?; Anal. calcd for C20H20Cl2
N2O: C 64.01, H 5.37, N 7.46; found: C 63.95, H 5.52, N 7.62.
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4 Conclusions
In conclusion, our work had demonstrated that [Rh(COD)Cl]2
was an efficient catalyst to facilitate the ring-opening of
123