Asymmetric ring opening reaction of oxabenzonorbornadienes with amines promoted by iridium/NMDPP complex

Article abstract of DOI:10.1016/j.tetlet.2014.09.089

As an efficient catalyst, the [Ir(COD)Cl]₂/NMDPP complex has been successfully applied to promote the asymmetric ring opening reaction of oxabenzonorbornadienes with various amines, which afforded the corresponding products in good yields (72-9

Full text of DOI:10.1016/j.tetlet.2014.09.089

Tetrahedron Letters 55 (2014) 6315–6318
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric ring opening reaction of oxabenzonorbornadienes
with amines promoted by iridium/NMDPP complex
a,b
Lu Yu a, Yongyun Zhou a, Xin Xu a, Sifeng Li a, Jianbin Xu a, Baomin Fan a,b, , Chengyuan Lin
,
⇑
Zhaoxiang Bian b, Albert S. C. Chan c
a YMU-HKBU Joint Laboratory of Traditional Natural Medicine, Yunnan Minzu University, Kunming 650500, China
b School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
c Institute of Creativity, Hong Kong Baptist University, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2014
Revised 13 September 2014
Accepted 19 September 2014
Available online 28 September 2014
As an efficient catalyst, the [Ir(COD)Cl]2/NMDPP complex has been successfully applied to promote the
asymmetric ring opening reaction of oxabenzonorbornadienes with various amines, which afforded the
corresponding products in good yields (72–98%) with good enantioselectivities (80–90% ee).
Ó 2014 Published by Elsevier Ltd.
Keywords:
Oxabenzonorbornadienes
ARO reaction
(S)-NMDPP
Amines
As a type of important building blocks with great potential in
organic synthesis, chiral hydronaphthalenes exist widely in natural
products and bioactive molecules.1 The transition metal catalyzed
asymmetric ring opening (ARO) reactions of oxa/azabenzonorbor-
nadienes with heteroatom nucleophiles undoubtedly provide an
efficient method to construct such structures with multiple func-
tional groups. Pioneered by Lautens, a series of rhodium catalysts
bearing ferrocenyl diphosphine ligands had been developed suc-
cessfully for this kind of reaction. Based on the rhodium catalysts,
phenols,2 alcohols,3 amines,4 thiols,5 and other heteroatom com-
pounds6 had been applied as efficient hetero-nucleophiles in ARO
reactions of oxa/azabenzonorbornadienes. As a new improvement
of such reactions, some iridium complexes with Binap family
and other ligands were recently found effective to promote the
corresponding transformations.7 However, both asymmetric
induction and catalytic activity remain important issues in these
iridium-catalyzed reactions.
[Ir(COD)Cl]2 and monophosphine ligand (S)-NMDPP ((S)-(+)-Neo-
menthyldiphenylphosphine) was found to be an efficient catalyst
for the asymmetric ring opening reaction of oxabenzonorbornadi-
enes with phenols or naphthols.11 As an extension, here we report
the application of this Ir/NMDPP catalyst in the asymmetric ring
opening reaction of oxabenzonorbornadienes with amines.
Under the optimized reaction conditions for the asymmetric
ring opening reaction of oxabenzonorbornadienes with phenols,
oxabenzonorbornadiene 1a and N-methylaniline 2a were chosen
as benchmark substrates to evaluate the applicability of the
[Ir(COD)Cl]2/NMDPP complex. After heating and stirring at 80 °C
for 4 h in DMF (N,N-dimethylformamide), oxabenzonorbornadiene
1a was completely consumed and translated into the ring opening
product 3aa in 93% yield. HPLC analysis showed that good optical
purity, about 88% ee, was obtained for 3aa (Table 1, entry 1). The
absolute stereochemistry of 3aa was determined as S,S configura-
tion by comparing the HPLC chromatogram with those of the
corresponding compound reported in literature.3a This encourag-
ing result indicated that this iridium/NMDPP catalyst was also
effective to this ARO reaction of oxabenzonorbornadienes with
N-methylaniline. The further solvent screening showed that THP
(tetrahydropyran), toluene, DME (1,2-dimethoxyethane), dioxane,
DMAc (N,N-dimethylacetamide), and THF (tetrahydrofuran) gave
similar results (Table 1, entries 2–7). MTBE (methyl tert-butyl
ether) resulted in a low yield, even after a longer reaction time
(Table 1, entry 8). Inferior results were obtained when the reaction
Our group has been interested in the asymmetric reactions of
norbornadiene derivatives in the past years. We had developed
several efficient chiral catalysts or catalytic systems for asymmet-
ric [2+2] cycloaddition reaction,8 hydroalkynylation reaction9 and
alkynylative ring opening reaction10 between norbornadiene
derivatives and terminal alkynes. Moreover, the combination of
⇑
Corresponding author. Fax: +86 871 65913103.
E-mail address: adams.bmf@hotmail.com (B. Fan).
http://dx.doi.org/10.1016/j.tetlet.2014.09.089
0040-4039/Ó 2014 Published by Elsevier Ltd.

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L. Yu et al. / Tetrahedron Letters 55 (2014) 6315–6318
Table 1
Table 2
Optimization of reaction conditionsa
Ir-catalyzed ARO reaction of 1a with various aminesa
1.5 mol% [Ir(COD)Cl]2
9.0 mol% (S)-NMDPP
[Ir(COD)Cl]2
(S)-NMDPP
R1
R2
Ph
HN
Me
O
HN
R1
O
Ph
solvent, 80 o
C
N
DMF, 80 oC
N
OH R2
PPh2
Me
OH
3aa
1a
Entry
2a-2r
3aa-3ar
1a
2a
(S)-NMDPP
Amines
t (h)
Yieldb (%)
93 (98)d
eec (%)
Entry
Solvent
L/Ir
t (h)
Yieldb (%)
eec (%)
NHMe
1
2
3
4
5
6
7
8
DMF
THP
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
0:1
1:1
2:1
4:1
3:1
3:1
4
21
21
21
7
93
92
90
82
93
93
87
36
18
27
N.R.d
93
97
94
44
98
88
87
86
87
88
87
88
88
54
72
/
85
86
88
90
86
1
2
4
88
2a
NHMe
Toluene
DME
Dioxane
DMAc
THF
MTBE
DCE
DMSO
DMF
DMF
DMF
DMF
DMF
2
86
87
MeO
Br
3
2b
23
72
74
48
5
36
13
2
NHMe
3
4
6
2
92
93
87
87
9
2c
10
11
12
13
14
15e
16f
NHEt
2d
48
0.67
DMF
5
6
1.5
90
72
88
80
N
a
H
2e
Reaction conditions: 1a (0.3 mmol), 1a/2a = 1:5, solvent (2 mL), heated at 80 °C
in oil bath under Ar for indicated period of time.
H
N
b
Isolated yields after silica gel column chromatography.
Determined by HPLC on a Chiralcel OD-H column.
N.R. = No Reaction.
The reaction was carried out at 60 °C.
46
c
d
2f
e
NHMe
f
The reaction was carried out at 100 °C.
7
8
9
2
91
95
82
88
2g
NHMe
was carried out in DCE (1,2-dichloroethane) and DMSO (dimethyl
sulfoxide), respectively (Table 1, entries 9 and 10). Without
NMDPP, [Ir(COD)Cl]2 itself could not make the reaction take place
(Table 1, entry 11). With DMF as solvent, the effect of the ratio of
ligand to metal was then investigated. Increasing the (S)-NMDPP/
Ir ratio from 1:1 to 4:1 led to the acceleration of the reaction rate
with similar yields and enantioselectivities (Table 1, entries 1 and
12–14). The effect of reaction temperature was also evaluated. It
was found that the reaction temperature had an obvious effect
on the reaction rate but little effect on the enantioselectivity of
the reaction. When the reaction was carried out at 60 °C, the ee
value of 3aa increased slightly to 90%, and 44% yield was obtained
even after 48 h heating and stirring (Table 1, entry 15). When the
reaction temperature was raised to 100 °C, the reaction could be
completed in 40 min and 98% yield with 86% ee was obtained
(Table 1, entry 16).
Under the new optimized reaction conditions, a series of amines
were then investigated and the results are summarized in Table 2.
Both of the N-methyl arylamines with electron-donating groups or
electron-withdrawing groups could react with 1a smoothly. How-
ever, little lower yield was obtained for the former (Table 2, entry
2), and only a slightly decreased ee was observed for the latter
(Table 2, entry 3). It seemed that the steric property of the alkyl
groups in the alkyl substituted phenylamines had little effect on
the reaction, since the amines 2d (Table 2, entry 4) and 2e (Table 2,
entry 5) gave close yields, enantioselectivities, and reaction rates to
2a. When N-vinylaniline 2f, which held an alkenyl group, was used
as nucleophile in the reaction, an obvious reduction of reaction rate
had been observed. Almost two days were needed to complete the
reaction, and a lower yield and ee were obtained (Table 2, entry 6).
2h
NH
9
10
11
28
22
48
89
87
92
87
89
82
2i
NH
O
2j
NH
Ph
N
2k
N
H
12
13
72
5
76
78
85
87
2l
N
H
2m
NH2
14
15
16
17
18
12
11
11
12
5
83 (90)d
91
90
85
84
87
88
2n
NH2
MeO
Me
2o
2p
2q
2r
NH2
NH2
NH2
91
89 (93)d
94 (98)d
Br
Cl
a
Reaction conditions: 1a (0.3 mmol), 1a/2/[Ir]/(S)-NMDPP = 1:5:0.03:0.09, DMF
(2 mL), heated in oil bath under Ar for indicated period of time.
b
Isolated yields after silica gel column chromatography.
c
Both N-methyl
a-naphthylamine 2g and N-methyl b-naphthyl-
Determined by HPLC on a Chiralcel OD-H and AD-H column.
Yields in parentheses were determined by 1H NMR using weighted 5,6-dib-
d
amine 2h could be served as suitable nucleophilic reagents here,
but the latter was a little superior than the former (Table 2, entry
romobenzo[1,3]dioxole as internal standard.

L. Yu et al. / Tetrahedron Letters 55 (2014) 6315–6318
6317
Table 3
Ir-catalyzed ARO reaction of substituted oxabenzonorbornadienes with N-methylaniline 2aa
R3
R3
R4
R4
1.5 mol % Ir(COD)Cl]2
9.0 mol % (S)-NMDPP
Me
R4
R4
O
Ph
Ph
N
H
DMF, 80 o
C
N
R3
R3 OH Me
2a
3aa-3ga
1a-1g
Entry
1
Oxabenzonorbornadienes
t (h)
Yieldb (%)
93 (98)d
eec (%)
O
4
88
1a
OMe
O
2
3
7
78 (86)d
84
OMe
Me
1b
O
60
81
86
1c
Me
Me
O
4
5
9
85
80
87
86
Me
Br
1d
1e
O
60
Br
O
O
O
6
7
7
85
82
80
O
O
1f
27
82 (83)d
O
1g
a
b
c
Reaction conditions: 1 (0.3 mmol), 1/2a/[Ir]/(S)-NMDPP = 1:5:0.03:0.09, DMF (2 mL), heated in oil bath under Ar for indicated period of time.
Isolated yield after silica gel column chromatography.
Determined by HPLC on a Chiralcel OD-H column.
d
Yields in parentheses were determined by 1H NMR using weighted 5,6-dibromobenzo[1,3]dioxole as internal standard.
7 to entry 8). In addition to N-alkyl arylamines, dialkylamines
were also examined in this iridium-catalyzed ARO reaction of
oxabenzonorbornadiene 1a (Table 2, entries 9–13). In all of these
reactions, good enantioselectivities with moderate to high yields
were obtained, though relatively long reaction times were gener-
ally needed. It should be noted that diisopropylamine, which had
bulky substituents, was found outstanding from other dialkylam-
ines, since a fast reaction rate had been observed for it and only
5 h were needed to complete the reaction (Table 2, entry 13). Along
with secondary amines, primary aryl amines were also found
applicable nucleophiles in this iridium/NMDPP catalyzed ring
opening reaction. A series of aryl amines with/without various sub-
stituents on the phenyl ring could afford the aimed products in
high yields with good enantioselectivities (Table 2, entries 14–18).
To further explore the scope of the reaction, a series of substi-
tuted oxabenzonorbornadienes (1b–1g) were then tested in this
Ir/NMDPP catalyzed asymmetric ring opening reaction with
N-methylaniline 2a as nucleophile (Table 3). It could be seen from
the results that promoted by the complex of [Ir(COD)Cl]2 and
(S)-NMDPP, all of these substituted oxabenzonorbornadienes could
react smoothly with N-methylaniline 2a and generate the corre-
sponding ring opening products with good yields. It seemed
that the positions and electronic properties of the substituents
had little effect on the enantioselectivities of the reaction, since
the products’ ee values just varied from 80% to 88%.
In summary, we have successfully applied the [Ir(COD)Cl]2/
NMDPP complex as an efficient catalyst to promote the asymmet-
ric ring opening reaction of oxabenzonorbornadienes with various
amines as nucleophiles. Both secondary amines and primary
amines were found suitable nucleophiles in this catalytic reaction,
and good enantioselectivities with moderate to good yields could
be obtained. Furthermore, various substituents on the phenyl rings
of different oxabenzonorbornadienes were well tolerated by this
iridium catalytic system, and good results could be obtained for
all of the corresponding reactions with N-methylaniline. Further
modification of this iridium catalyst for a wider scope of substrates
and higher enantioselectivities is still in progress.
Acknowledgments
We thank the National Natural Science Foundation of China –
China (21362043, 21162040, 21302162), the Government of
Yunnan Province (2012FB170), and the State Key Laboratory of
Elemento-organic Chemistry, Nankai University, (201302) for
financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.089.

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L. Yu et al. / Tetrahedron Letters 55 (2014) 6315–6318
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