Asymmetric ring-opening of oxabenzonorbornadiene with amines promoted by a chiral iridium-monophosphine catalyst

Article abstract of DOI:10.1039/c3cc46009f

A new iridium-monophosphine catalyst is 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%).

Full text of DOI:10.1039/c3cc46009f

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Asymmetric ring-opening of oxabenzonorbornadiene
with amines promoted by a chiral iridium-
monophosphine catalyst†
Cite this: Chem. Commun., 2013,
49, 9959
Received 9th August 2013,
Renshi Luo,*ab Jianhua Liao,b Ling Xie,b Wenjun Tang*a and Albert S. C. Chanc
Accepted 2nd September 2013
DOI: 10.1039/c3cc46009f
www.rsc.org/chemcomm
A new iridium-monophosphine catalyst is 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%).
Syntheses of chiral substituted dihydronaphthalene have
gained great interest, because it is an important core structure
found in many bioactive compounds.1 Among the chemical
synthesis methods of these useful bioactive compounds, the
Scheme 1 Ligand synthesis.
transition metal-catalyzed asymmetric ring-opening (ARO) of high tunability of these monophosphorus ligands may be able
oxabicyclic alkenes is the most attractive synthetic strategy. to promote the iridium-catalyzed asymmetric ring-opening of
Since initial studies in this field reported by Caple2 and oxabenzonorbornadiene with amines. We report herein the
Lautens,3 significant progress has been achieved in rhodium- asymmetric ring-opening of oxabenzonorbornadiene with amines
catalyzed asymmetric ring-opening of oxabenzonorbornadiene catalyzed by iridium-monophosphorus ligand L1 (Scheme 1).
using a wide range of nucleophiles such as thiols,4 phenols,5
With the phosphorus ligands L1–L4 in hand, we firstly
organoboronic acids,6 dialkylzincs,7 carboxylates,8 sulfur screened the effects of ligands (Table 1). Initial screening
nucleophiles,9 amines10 and alcohols.11 Besides, other metals of the reaction conditions demonstrated that the additives
including copper,12 palladium,7,13 iron,14 nickel15 and iri- and ligands had a significant role to play in both reactivity
dium16,17 catalyzing asymmetric ring-opening reactions of oxa- and selectivity (entries 1–9). Using 2.0 mol% [Ir(coe)2Cl]2 and
bicyclic alkenes were also reported.
4.8 mol% L1 as the catalyst no ring-opening product was
The asymmetric ring-opening of oxabicyclic alkenes with obtained in the absence of an additive or by addition of NaCl
amines is useful for the construction of chiral amino alcohols (entries 1 and 2), whereas the desired product was achieved in
which can be employed to synthesize bioactive compounds.10c low yield (91%) but a good ee (88% ee) in the presence of 0.2 eq.
In 2009, Yang reported the first iridium-catalyzed asymmetric NaBr (entry 3). Excellent yield and ee (>99% ee) were observed
ring-opening of oxabenzonorbornadiene with amines.17 How- by the use of NaI (entry 4). The fact that NaI gave excellent
ever, only moderate to good ees were achieved. Recently we results may be due to its binding ability to iridium and relative
have developed a series of chiral monophosphorus ligands for trans-effect as well as its size being at the opposite extreme
asymmetric Suzuki–Miyaura coupling reactions18 and addition within the group.20 The enantioselectivities were decreased by
of arylboronic acids to aryl aldehydes.19 We envisioned that the the introduction of bulky group at the position of R or R0
(entries 5–7). For example, only 89% ee was obtained with
ligand L2 (entry 5) and sharply reduced ees were observed with
the use of ligands L3 and L4 with a bulky group at the R0
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road,
position (entries 6 and 7). Additives also affected the perfor-
Shanghai, 200032, China
b School of Pharmaceutical Sciences, Gannan Medical University, 1 Yixueyuan Road, mance of the catalyst sharply. Only 81% ee and 58% ee were
Ganzhou, Jiangxi, 341000, China. E-mail: luorenshi2010@163.com;
observed for the additives Bu4NI or KI respectively (entries 8
and 9). The iridium precursors also significantly affected the
enantioselectivities of the products. Only moderate enantio-
Tel: +86-0797-8169775
c Institute of Creativity, Hong Kong Baptist University, Hong Kong, China
† Electronic supplementary information (ESI) available. CCDC 943665. For ESI
selectivities were observed with the iridium precursors
[Ir(cod)Cl]2 or Ir(cod)BF6 (entries 10–12). This could be largely
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc46009f
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 9959--9961 9959

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Table 1 Optimization of iridium-catalyzed ring-opening reaction of 1a with 2
Table 2 Substrates scope of iridium-catalyzed ring-opening reaction of oxaben-
zonorbornadiene with piperazines
Entrya
Solvent
Additive
L*
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DME
Toluene
THF
No
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
o5
o5
35
91
95
95
93
93
95
91
93
93
96
88
51
ND
ND
88
>99
89
NaCl
NaBr
NaI
NaI
NaI
NaI
Bu4NI
KI
NaI
NaI
NaI
NaI
NaI
NaI
Entry a
1
R1
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1d
1e
1e
1e
2-OMeC6H4
2-FC6H4
14
14
14
14
14
14
14
14
12
14
12
12
12
12
12
10
12
93(5aa)
93(5ab)
95(5ac)
97(5ad)
82(5ae)
93(5af)
92(5ag)
95(5ah)
90(5ai)
93(5ba)
95(5ca)
97(5da)
96(5db)
98(5dc)
93(5ea)
95(5eb)
87(5ec)
>99
>99
95
>99
>99
89
>99
>99
98
93
88
86
86
13
3-ClC6H4
4-CH3C6H4
4-CF3C6H4
2,4-Di-CH3C6H3
3,4-Di-ClC6H3
3-Cl-Bn
Boc
C6H5
C6H5
C6H5
2-FC6H4
4-OCH3C6H4
C6H5
2-OmeC6H4
4-CF3C6H4
ꢀ61
81
9
58
79
78
69
93
80
>99
10d
11e
12 f
13
14
15g
9
10
11
12
13
14
15
16
17
a
The reactions were carried out at 80 1C in THF (2.0 mL) for 14 h with
1a (0.35 mmol), 2 (0.105 mmol), and NaI (0.07 mmol) in the presence of
[Ir(coe)2Cl]2 and (2.0 mol%) and ligand (4.8 mol%) under nitrogen. The
absolute configurations were assigned on the basis of the absolute
configuration of 5ae21 (Table 2, entry 5) through a similar stereo-
chemical model. b Yield of isolated product. c The ee value was determined
by HPLC analysis on a chiral phase (Chiralcel Lux Amylose-2 column).
88
83
85
86
a
The reactions were carried out at 80 1C in THF (2.0 mL) for 14 h with 1
(0.35 mmol), 4 (0.105 mmol), and NaI (0.07 mmol) in the presence of
[Ir(coe)2Cl]2 and (2.0 mol%) and ligand (4.8 mol%) under nitrogen. The
absolute configurations were assigned on the basis of the absolute
d
f
e
[Ir(cod)Cl]2 as the Ir precursor. The ratio of [Ir(cod)Cl]2/L1 was 1 : 4.
g
Ir(cod)BF6 as the Ir precursor. Performed at RT.
configuration of 5ae21 through a similar stereochemical model. Yield
of isolated product. The ee value was determined using HPLC analysis
b
c
on a chiral phase (Chiralcel OD-H, AD-H or Lux Amylose-2 column).
attributed to the slow complex formation between iridium
precursors and ligands. A slightly lower enantioselectivity was
observed in the solvent DME (entry 13). Only 80% ee was
obtained in the solvent toluene (entry 14). The reaction temper-
ature affected the reactivity but not the selectivity (entry 15).
Under the optimized reaction conditions, the Ir–L1 catalyst
proved to be efficient for the synthesis of substituted dihydro-
naphthalenes in high yields with excellent enantioselectivities
(Table 2). For example, various N-phenylpiperazines with either
electron-donating or electron-withdrawing substituents at the
phenyl position afforded excellent yields and enantioselectiv-
ities (entries 1–7). N-Boc piperazine and N-Bn piperazine were
also applied to provide high yields and ees with 1,4-dihydro-6,
7-dimethoxy-1,4-epoxynaphthalene (1a) as the substrate
(entries 8 and 9). Other substituted oxabenzonorbornadiene
substrates were also applied (entries 10–17). Electron-donating
or electron-withdrawing substrate such as 1b or 1c could also
be employed to provide excellent yields and ees with N-phenyl-
piperazine (entries 10 and 11). High yields and good ees were
also obtained with smaller steric substrates such as 1d and 1e
with various substituted N-phenylpiperazines (entries 12–17).
After the success of asymmetric ring-opening reaction of
oxabenzonorbornadiene with piperazines, the reaction of other
amines was also investigated (Table 3). As can be seen in
Table 3, various amines including primary or secondary aro-
matic amines (entries 1 and 2) and aliphatic amines (entries 4
and 5) can be used in the reaction to get the desired ring-
opening products in high yields and enantioselectivities. Dis-
appointingly, no desired products were observed when 2-chloro-
N-methylaniline and pyrrole were employed in the reaction
Table 3 Substrate scope of iridium-catalyzed ring-opening reaction of oxaben-
zonorbornadiene with amines
Entry a
1
NHR1R2
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
1a Aniline
1a N-Methylaniline
1a 2-Chloro-N-methylaniline
1a N-Methyl-1-phenylmethanamine
1a 1,2,3,4-Tetrahydroisoquinoline
1a 1H-Pyrrole
81(7aa)
65(7ab)
93
93
ND
89
89
ND
70
77
87
80
o5
95(7ac)
93(7ad)
o5
1c N-Methylaniline
95(7ca)
91(7cb)
93(7cc)
91(7cd)
1c 4-Chloro-N-methylaniline
1c N,4-Dimethylaniline
1c N-Ethylaniline
a
The reactions were carried out at 80 1C in THF (2.0 mL) for 14 h with 1
(0.35 mmol), 6 (0.105 mmol), and NaI (0.07 mmol) in the presence of
[Ir(coe)2Cl]2 and (2.0 mol%) and ligand (4.8 mol%) under nitrogen. The
absolute configurations were assigned on the basis of the absolute
configuration of 5ae21 (Table 2, entry 5) through a similar stereo-
b
c
chemical model. Isolated product. Determined using HPLC (Chiralcel
OD-H or AD-H).
(entries 3 and 6). The negative results may be attributed to the
hindered ortho-substituted group and weak nucleophilic of
pyrrole. In the case of the less sterically hindered substrate 1c,
high yield but decreased enantioselectivities were achieved
(entries 7–10).
c
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form the corresponding monomer by solvent. And then the
possible catalytic asymmetric ring-opening cycle with amines
may go through four main steps:10a,b,17a,b (a) the monomer
iridium catalyst complexed with oxabenzonorbornadiene; (b)
oxidative insertion to produce the iridium alkoxide; (c) proto-
nation of the iridium alkoxide; (d) nucleophilic attack and
regeneration of the monomer iridium(I) species B. This stereo-
chemical model is in accordance with the absolute configu-
ration observed in the ring-opening product 5ae.21
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 9959--9961 9961