Enantioselective Iridium-Catalyzed Ring Opening of Low-Activity Azabenzonorbornadienes with Amines

Article abstract of DOI:10.1021/acs.organomet.8b00239

An iridium catalyst (2.5 mol %) generated in situ from [Ir(coe)₂Cl]₂ and a nitrogen phosphorus ligand was efficient in the asymmetric ring-opening reactions of low-activity azabenzonorbornadiene with various aliphatic and aromatic amines, providing the corresponding chiral vicinal 1,2-diamine scaffolds in high yields (up to 98%) and excellent enantioselectivities (up to 97% ee). The synthetic utility of the transformation was demonstrated by performing a gram-scale reaction.

Full text of DOI:10.1021/acs.organomet.8b00239

Communication
Cite This: Organometallics XXXX, XXX, XXX−XXX
Enantioselective Iridium-Catalyzed Ring Opening of Low-Activity
Azabenzonorbornadienes with Amines
Ren shi Luo,† Gengjinsheng Cheng,† Yifei Wei, Rinuan Deng, Miao Huang, and Jianhua Liao*
School of Pharmaceutical Sciences, Gannan Medical University, 1 Yi Xue Yuan Road, Ganzhou, Jiangxi 341000, People’s Republic of
China
S
* Supporting Information
ABSTRACT: An iridium catalyst (2.5 mol %) generated in
situ from [Ir(coe)2Cl]2 and a nitrogen phosphorus ligand was
efficient in the asymmetric ring-opening reactions of low-
activity azabenzonorbornadiene with various aliphatic and
aromatic amines, providing the corresponding chiral vicinal
1,2-diamine scaffolds in high yields (up to 98%) and excellent
enantioselectivities (up to 97% ee). The synthetic utility of the
transformation was demonstrated by performing a gram-scale reaction.
hiral vicinal 1,2-diamines have attracted much attention,
owing to their importance in a large number of bioactive
Scheme 2. Chirality Transfer Effect on Enantioselectivity in
Ring Opening of Azabenzonorbornadienes
C
natural compounds and medicinal products.1−7 Due to their
importance, various synthesis methods have been developed to
construct the chiral 1,2-diamine frameworks.8,9 Notably, the
transition-metal-catalyzed asymmetric ring-opening reaction of
azabenzonorbornadienes with amines is an attractive and useful
synthetic strategy (Scheme 1). Initially, Lautens and co-workers
Scheme 1. Transition-Metal-Catalyzed Asymmetric Ring-
Opening Reactions of Azabenzonorbornadienes with
Amines
Additionally, it was quite possible that the lower enantiose-
lectivity and yield were due to the strong steric hindrance effect
caused by the tert-butyl substituent backbone and the lower
coordination of the phosphorus chiral center. Thus, we
envisioned that the high tunability of these nitrogen
phosphorus ligands ((R,S)-PPFA) with a carbon chiral center
may be able to increase the activity and enantioselectivity of
iridium-catalyzed asymmetric ring opening of azabenzonorbor-
nadienes via the increased coordination of the substrate to the
catalyst (Scheme 2). On the basis of our previous work with
oxabenzonorbornadienes and our continuous interest in
iridium-catalyzed asymmetric ring opening of azabenzonorbor-
nadienes, we herein report the asymmetric ring-opening
reaction of azabenzonorbornadienes with amines catalyzed by
the iridium nitrogen phosphorus ligand L1 (Scheme 3).
reported the first example of rhodium-catalyzed asymmetric
ring opening of azabenzonorbornadienes with amines (Scheme
1a).10,11 Subsequently, iridium/Binap-catalyzed asymmetric
ring opening of azabenzonorbornadienes with primary and
secondary amines proceeding with moderate to good yields and
enantioselectivities was developed by Yang and co-workers
(Scheme 1b).12−14 In addition, Fan and co-workers have
employed palladium-catalyzed and iridium/copper-catalyzed
asymmetric ring opening of azabenzonorbornadienes with
aromatic amines, respectively (Scheme 1c,d).15,16
Recently, we also have studied a chiral monophosphine
ligand in the iridium-catalyzed asymmetric ring opening of both
oxabenzonorbornadienes and azabenzonorbornadienes with
amines (Scheme 2).17 Unfortunately, the result was not as
good as that for the reaction with oxabenzonorbornadienes,
owing to the low activities of azabenzonorbornadienes.
At the outset of this project, a series of ligands L1−L5 were
used, considering that the carbon chiral center would increase
the activity of the asymmetric ring-opening reaction (Scheme
Received: April 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00239
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
To further employ these reaction conditions, a range of
solvents, reaction temperatures, and reaction times were
systematically explored (Table 2). As a result, the asymmetric
Scheme 3. Tunable Chiral Nitrogen Phosphorus Ligands
Table 2. Effects of Solvents in Ring-Opening Reactions of
Azabenzonorbornadiene with N-Phenylpiperazine
3). The ligands L1−L5 can be easily prepared by the method in
a previous report.18
We have subsequently studied the asymmetric ring opening
of low-activity 1a with N-phenylpiperazine 2a in the presence
of 2.5 mol % of [Ir(coe)2Cl]2. Not surprisingly, the desired
ring-opening product 3a was not obtained; instead, there was
complete recovery of the starting material (Table 1, entry 1).
a
b
entry
solvent
T/°C
t/h
yield/%
ee/%
1
2
THF
80
40
60
60
80
80
90
80
80
90
15
15
15
24
15
15
24
15
24
24
95
93
90
87
93
93
60
87
90
90
93
90
50
25
92
91
81
88
92
91
Et2O
c
3
MTBE
4
DMF
Table 1. Optimization of Asymmetric Iridium-Catalyzed
Ring Opening of Azabenzonorbornadiene with N-
Phenylpiperazine
5
CH3CN
DCE
6
7
dioxane
DME
8
9
hexane
10
toluene
a
b
Isolated product. Determined by HPLC (Chiralcel OD-H column).
a
b
c
entry
catalyst
additive
NaI
L*
yield/%
ee/%
MTBE = methyl tert-butyl ether.
1
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(coe)2Cl]2
[Ir(cod)Cl]2
Ir(NBD)BF4
[IrCp*Cl]2
<5
<5
<5
<5
95
92
93
90
91
98
96
95
70
95
93
<5
2
products proceeded with excellent yields and enantioselectivi-
tives in the solvents THF, Et2O, CH3CN, DCE, hexane, and
toluene while modest enantioselectivitives were obtained in the
solvents methyl tert-butyl ether (MTBE, 50% ee) and DMF
(only 25% ee) (Table 2, entries 1−10). Thus, THF was
employed as the terminal solvent. In addition, the reaction time
affected the reactivity but not the enantioselectivity.
3
L1
4
NaI
NaI
NaI
NaI
NaI
NaI
Bu4NI
KI
BINAP
L1
ND
93
77
68
21
20
60
39
92
85
79
55
ND
5
6
L2
7
L3
8
L4
9
L5
With the optimal conditions in hand, the scope of N-Boc-
protected azabenzonorbornadienes and various N-phenyl-
piperazine was evaluated (Table 3). In all cases, a wide variety
of electron-rich and -poor substituted dihydronaphthalenes
were synthesized in excellent yields and high enantioselectiv-
ities. Of particular interest was the low-activity dimethoxy-
substituted 2a, which furnished the desired dihydronaphthalene
products in high yields and good enantioselectivities (Table 3,
enties 1−13). For example, a series of ortho-substituted phenyl
rings with electron-donating and electron-withdrawing groups
afforded high yields and ee values with low-activity 6,7-
dimethoxy-substituted 1a (3ab−ad). Notably, the reactions of
phenyl-substituted piperazines with both electron-rich and
-poor groups in the para and meta positions proceeded
efficiently in good to excellent yields and ee values (3ae−ak).
N-Bn piperazine and N-Boc piperazine provided the corre-
sponding products 3al,am in excellent yields of 90% and 92%
with 76% and 96% ee values, respectively (Table 3, entries 12
and 13).
10
11
12
L1
L1
LiI
L1
c
13
NaI
NaI
NaI
L1
14
15
16
L1
L1
NaI
b
L1
a
Yield of isolated product. The ee value was determined by HPLC
analysis on a chiral phase (Chiralcel OD-H). 1.0 mol % of
c
[Ir(coe)2Cl]2 and 2.4 mol % of L1 were used.
Initial control experiments of the reaction conditions showed
that the ligands and additives played key roles in both reactivity
and enantioselectivity, which was in accordance with the results
obtained by Fagnou and Lautens19 (Table 1, entries 2 and 3). A
variety of ligands and additives were then screened.
Surprisingly, excellent yields were obtained when the nitrogen
phosphorus ligands L1−L5 were employed in contrast to the
previous BINAP ligand which was routinely used in ring-
opening reactions of azabenzonorbornadienes12−14 (Table 1,
entries 4−9). Notably, the introduction of a bulky group at the
R position resulted in significantly reduced enantioselectivities.
Meanwhile, NaI, which was found to be an important additive
in many asymmetric reactions,19 was proved to be optimal with
an isolated yield of 95% and 93% ee (Table 1, entries 10−12).
Additionally, further investigations were examined which
revealed 2.5 mol % of the iridium precursor [Ir(coe)2Cl]2
furnished product 3a with an optimal yield and ee (Table 1,
entries 13−16).
Similarly, phenyl-substituted piperazines with both electron-
rich and -poor groups in ortho and para positions also worked
well to complete the ring-opening transformation with the
simple N-Boc protected azabenzonorbornadiene 1b (3ba−bg).
Interestingly, 2-methoxyphenyl-substituted piperazine was
subjected to this reaction with 1b to give a high yield of 91%
and up to 97% ee (3bc). To our delight, various N-
phenylpiperazine substrates were also compatible with the
electron-withdrawing group of 1c under the optimal reaction
conditions (3ca−cd).
To further demonstrate the generality of this transformation,
we explored the scope of other amines for dihydronaphthalene
B
DOI: 10.1021/acs.organomet.8b00239
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Disappointingly, no desired products were observed when
aromatic amines and 1H-pyrrole were employed in the reaction,
which may be attributed to the weak nucleophilicities (Table 4,
entries 1, 2, and 5). In addition, 2-chloro-N-methylaniline failed
to give the desired products also probably owing to the
hindered ortho-substituted group in the reaction (Table 4,
entry 2).
Table 3. Substrate Scope of Iridium-Catalyzed Ring-Opening
Reactions of Azabenzonorbornadiene with Piperazines
As a demonstration of the scalability of this protocol, the
iridium-catalyzed ring opening of azabenzonorbornadiene 1b
with N-phenylpiperazine 2a was performed on a gram scale
(Scheme 4). The corresponding dihydronaphthalene product
3ba was isolated with 98% yield (1.9840 g) and 96% ee through
a pad of silica gel after 36 h.
a
b
entry
R
R1
t/h
yield/%
.ee/%
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
C6H5
24
16
16
24
24
16
16
24
14
36
24
18
14
16
16
16
14
14
16
14
12
12
12
12
95 (3aa)
98 (3ab)
98 (3ac)
93 (3ad)
93 (3ae)
96 (3af)
98 (3ag)
92 (3ah)
96 (3ai)
78 (3aj)
93 (3ak)
90 (3al)
92 (3am)
95 (3ba)
90 (3bb)
91 (3bc)
93 (3bd)
93 (3be)
88 (3bf)
93 (3bg)
93 (3ca)
91 (3cb)
90 (3cc)
95 (3 cd)
93
92
91
86
90
95
94
92
84
85
92
75
96
93
94
97
93
90
96
90
96
89
96
96
2
2-OMeC6H4
2-CH3C6H3
2-FC6H4
3
4
5
3-ClC6H4
6
4-CH3C6H4
4-OCH3C6H3
4-ClC6H4
Scheme 4. Gram-Scale Iridium-Catalyzed Ring-Opening of
Azabenzonorbornadiene 1b with N-Phenylpiperazine 2a
7
8
9
2,4-di-CH3C6H3
3,4-di-ClC6H3
4-FC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3-Cl-Bn
Boc
C6H5
On the basis of the above results and previous reports,17,20
the proposed mechanistic details of the current reaction are
depicted in Scheme 5. The dimeric complex A was initially
2-FC6H4
2-OCH3C6H4
4-CH3C6H4
4-OCH3C6H4
3,4-di-ClC6H3
2,4-di-CH3C6H3
C6H5
Scheme 5. Proposed Mechanism of Iridium-Catalyzed Ring
Opening of Azabenzonorbornadienes with Amines
2-OMeC6H4
4-ClC6H4
4-OCH3C6H4
a
b
Yield of isolated product. The ee value was determined by HPLC
analysis on a chiral phase (Chiralcel OD-H, AD-H, Chiralcel AS-H, or
Chiralcel IC-H column).
synthesis (Table 4). As can be seen from Table 4, a series of
aliphatic amines were also found to give excellent yields but
moderate enantioselectivities (Table 4, entries 3 and 4).
Table 4. Substrate Scope of Iridium-Catalyzed Ring-Opening
Reactions of Azabenzonorbornadiene with Amines
generated from the iridium precursor [Ir(coe)2Cl]2 and NaI.
Subsequently, the intermediate A was dissociated by solvent to
afford the corresponding monomer. Then the monomer
iridium catalyst B complexed with azabenzonorbornadienes 1
to give the intermediate C, followed by oxidative insertion to
form the iridium alkoxide species D. Protonation of D and then
nucleophilic attack by amine 2 or 3 afforded the desired
product 3 or 5. Finally, the monomeric iridium(I) species B
were regenerated, thereby initiating the new catalytic cycle.
This trans stereochemical model is in accordance with the
absolute configuration obtained for the ring-opening product
3ae.12
In summary, an efficient and convenient protocol for the
synthesis of a variety of substituted dihydronaphthalenes with
excellent yields and high enantioselectivities by Ir-L1-catalyzed
ring opening of azabenzonorbornadienes with amines has been
developed. The new nitrogen phosphorus ligand L1 with a
carbon chiral center with strong coordination contributed to
the success of this reaction.
a
b
Yield of isolated product. The ee value was determined by HPLC
analysis on a chiral phase (Chiralcel OD-H or AD-H).
C
DOI: 10.1021/acs.organomet.8b00239
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
(18) Nie, H.; Yao, L.; Li, B.; Zhang, S.; Chen, W. Organometallics
2014, 33, 2109−2114.
ASSOCIATED CONTENT
■
S
* Supporting Information
(19) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26−47.
(20) (a) Lautens, M.; Fagnou, K.; Yang, D. Q. J. Am. Chem. Soc.
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Acad. Sci. U. S. A. 2004, 101, 5455−5460. (c) Long, Y. H.; Zhao, S. Q.;
Zeng, H. P.; Yang, D. Q. Catal. Lett. 2010, 138, 124−133. (d) Yang, D.
Q.; Hu, P.; Long, Y. H.; Wu, Y. J.; Zeng, H. P.; Wang, H.; Zuo, X. J.
Beilstein J. Org. Chem. 2009, 5, 53−62. (e) Yang, D. Q.; Long, Y. H.;
Zhang, J. F.; Zeng, H. P.; Wang, S. Y.; Li, C. R. Organometallics 2010,
29, 3477−3480. (f) Yang, W.; Luo, R.; Yang, D. Molecules 2015, 20,
21103−21124.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00239.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for J.L.: liaojianhua715@163.com.
ORCID
Jianhua Liao: 0000-0001-8564-5841
Author Contributions
†R.s.L. and G.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21562004), the Jiangxi Education Hall Science and
Technology Foundation (GJJ150944 and GJJ170867), Jiangxi
Health Hall Science and Technology Foundation (2013A043)
and the Fundamental Research Funds for Gannan Medical
University (QD201303 and YB201415) for financial support.
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DOI: 10.1021/acs.organomet.8b00239
Organometallics XXXX, XXX, XXX−XXX