Iridium/copper-cocatalyzed asymmetric ring opening reaction of azabenzonorbornadienes with amines

Article abstract of DOI:10.1039/c5ob01243k

A combination of iridium/copper associated with (R)-Difluorphos catalyst for the asymmetric ring opening reaction of azabenzonorbornadienes with amines was developed, which afforded chiral trans-vicinal diamines in 80-97% yields with 93-95% enantioselecti

Full text of DOI:10.1039/c5ob01243k

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DOI: 10.1039/C5OB01243K
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Iridium/Copper-Cocatalyzed Asymmetric Ring Opening Reaction
of Azabenzonorbornadienes with Amines
Chaoyuan Zeng,a Fan Yang,a Jingchao Chen,a Jun Wang,*b and Baomin Fan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An Iridium/copper associated with (R)-Difluorphos catalyst for with amines9, herein, we report Ir/Cu cocatalyzed asymmetric ring
asymmetric ring opening reaction of azabenzonorbornadienes opening reaction of azabenzonorbornadienes with amine
with amines was developed, which afforded chiral trans-vicinal nucleophiles, where 80-97% yields were generally observed with
diamines in 80-97% yields with 93-95% enantioselectivities.
93-95% enantioselectivities.
We embarked this investigation using azabenzonorbornadiene 1a
and aniline 2a as benchmark substrates with [Ir(cod)Cl]2 catalyst
and Lewis acid CuI as co-catalyst (Table 1). Gratifyingly,
commercially available ligand (R)-Binap gave trans-1,2-diamines 3aa
in 90% yield with 72% ee in dioxane at 70 oC for 12 h (Table 1, entry
1). Encouraged by this good result, a range of chiral diphosphine
ligands were investigated.10 Almost same ees (86-88%) were
obtained when using (R)-SDP, (R)-Tol-SDP, or (R)-Xyl-SDP as ligand,
while (R)-Xyl-SDP could give a better yield (96%) (Table 1, entries 2-
4). (R)-Pphos, (R)-Synphos and (R)-Segphos are also effective ligands
in this reaction, but only afford moderate ees (Table 1, entries 5-7).
Under this reaction condition, the best product enantioselectivity
(90%) was obtained by employing (R)-Difluorphos as the ligand
(Table 1, entry 8). Thus, we chose (R)-Difluorphos as the ligand of
choice for further optimization.
Chiral vicinal diamines are versatile building blocks in organic
synthesis and important structural motifs in natural products and
biologically active compounds1, and their derivatives have been
wildly employed as chiral auxiliaries and ligands in asymmetric
catalysis2. Conventional synthetic method for chiral vicinal diamines
is from 2-amino alcohols3 or α-amino acids4, new method for the
preparation of functionalized chiral diamines is still demanding.
Asymmetric ring opening reactions of azabenzonorbornadienes
with amines offer potentially useful synthetic routes to chiral vicinal
diamines. After Lautens and co-workers’ pioneer work in the Rh-
catalyzed
asymmetric
ring
opening
reactions
of
azabenzonorbornadienes with amines5, Yang and co-workers
developed the Ir-catalyzed asymmetric ring opening reactions of
azabenzonorbornadiene with amines.6 Moderate to good yields and
ees were achieved in their Ir/Binap-catalyst system with primary
and secondary amine nucleophiles. Recently, Luo and Tang applied
their chiral monophosphine ligand in Ir-catalyzed asymmetric ring
opening of N-phenylpiperazine to azabenzonorbornadiene, but the
result was not as good as the reaction with oxabenzonorbornadiene
for azabenzonorbornadienes were found to be less reactive than
the corresponding oxabenzonorbornadienes.7 Thus, the continuous
development of new and efficient catalyst systems for ARO reaction
of azabenzonorbornadienes with amine nucleophiles is still
desirable and interesting. Based on our previous finding on Pd/Cu-
cocatalyzed ARO reaction of azabenzonorbornadienes with terminal
alkynes8 and Ir-catalyzed ARO reaction of oxabenzonorbornadienes
Table 1. Ligand screening for Ir-catalyzed ARO reaction of
azabenzonorbornadiene 1a with aniline 2a.a
OCH3
N
PPh2
PPh2
PAr2
PAr2
H3CO
H3CO
PPh2
PPh2
N
(R)-SDP (Ar = C6H5
)
(R)-Binap
(R)-Tol-SDP (Ar = 4-MeC6H4
)
OCH3
(R)-Pphos
(R)-Xyl-SDP (Ar = 3,5-Me2C6H3
)
O
O
O
F
F
O
PPh2
O
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
O
F
F
O
O
O
(R)-Difluorphos
(R)-Segphos
(R)-Synphos
Entry
Ligand
Time
Yield
ee
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Journal Name
(h) b
12
16
12
16
20
24
20
10
(%) c
90
91
92
96
96
89
92
94
(%) d
72
88
86
87
75
78
86
90
11
12
13
14
15
70
70
70
50
90
70
CuBr
CuBr
CuBr
CuBr
CuBr
-
DME
MTBE
Toluene
Toluene
Toluene
Toluene
10
9V8iew Articl9e4Online
94
95
D10OI: 10.109389/C5OB01243K
1
2
3
4
5
6
7
(R)-Binap
(R)-SDP
10
48
4
97
88
98
87
95
92
79
(R)-Tol-SDP
(R)-Xyl-SDP
(R)-Pphos
(R)-Synphos
(R)-Segphos
(R)-Difluorphos
16
10
a
Reaction conditions: [Ir(cod)Cl]2 (5 mol % Ir), Lewis acid (20
mol %), and (R)-Difluorphos (6 mol %) in solvent (2 mL) was
stirred at room temperature for 30 min under Ar atm. 1a (0.2
mmol) and 2a (0.6 mmol) were added, and the reaction mixture
was stirred at indicated temperature for indicated period of
8
a
Reaction conditions: [Ir(cod)Cl]2 (5 mol % Ir), CuI (20 mol %),
and ligand (6 mol %) in dioxane (2 mL) was stirred at room
temperature for 30 min under Ar atm. 1a (0.2 mmol) and 2a
(0.6 mmol) were added, and the reaction mixture was stirred
time. Based on the full conversion of the substrate. c Yield of
b
d
isolated product.
tetrahydrofuran,
dimethoxyethane, MTBE = methyl tert-butyl ether.
Determined by HPLC analysis. THF
DCE dichloroethane, DME
=
=
at 60 oC for indicated period of time. Based on the full
b
=
c
d
conversion of the substrate. Yield of isolated product.
Determined by HPLC analysis.
The substrate scope of amines were summarized in Table 3. No
significant electronic effect on primary aniline nucleophile as the
corresponding ring-opening products 3aa-3af could be obtained in
high yields (95-97%) with good enantioselectivities (91-95%). The
sterically hindered 1-naphthylamine 2g resulted in a lower yield
(80%) with good ee (93%). Secondly aniline nucleophile, N-
methylanilines and N-ethylaniline reacted with 1a smoothly,
afforded the desired product in good yields with high ees (Table 2,
entries 8-11). It was observed that dibenzylamine 2l was also
suitable substrate in this catalyst system (Table 3, entry 12).
The addition of Lewis acid is crucial for higher yield and
enantioselectivity. When the reaction was carried out in the
absence of CuI, only 51% yield and 86% ee were obtained (Table 2,
entry 1). Many Lewis acids, such as ZnI2, CuOTf and CuBr were
efficient additive in this reaction, giving higher yields and better ees.
Among them, CuBr, which was used as an effective catalyst in the
asymmetric ring opening of oxabicyclic alkenes,11 gave the best
result (98% yield and 94% ee, Table 2, entry 8). The reaction
conditions for this [Ir(cod)Cl]2/CuBr co-catalyzed asymmetric ring
opening reaction were further surveyed. Solvents such as THF,
toluene, DME, and MTBE all resulted in good yields with high ees
(Table 2, entries 9, 11-13). The highest ee of 3aa (95%) along with a
good yield (97%) was afforded in toluene (entry 13). The effects of
the temperature were investigated. Decreasing the reaction
Table 3. Ir-catalyzed ARO reaction of azabenzonorbornadiene 1a
with various aromatic amines 2a-2l.a
Boc
NH R1
Boc
R1
HN
N
[Ir(cod)Cl]2 / (R)-Difluorphos
N
R2
o
+
R2
temperature to 50 C, decreased the yield of 3aa to 88% without
CuBr, Toluene, 70°C
affecting the ee, but 48 h was required for full conversion (Table 2,
entry 14). Increasing the reaction temperature to 90 C resulted in
2a-2l
1a
3aa-3al
o
Entry Amines
1
Time
Yield
Ee
a similar yield but a lower enantioselectivity (Table 2, entry 15).
Without using CuBr, the reaction yield and enantioselectivity
decreased dramatically (Table 2, entry 16).
2
(h) b
(%) c
97
(%) d
95
10
NH2
2a
Br
2
16
95
91
Table 2. Optimization of reaction conditions for Ir-catalyzed ARO
reaction of azabenzonorbornadiene 1a with aniline 2a.a
2b
NH2
3
4
5
6
7
6
96
96
97
97
80
95
94
93
94
93
Br
NH2
NH2
NH2
NH2
2c
6
Cl
2d
8
H3C
H3CO
2e
8
2f
Entry Temp Lewis acid solvent
(oC)
Time
(h) b
24
Yield
Ee
NH2
(%) c (%) d
16
2g
1
2
3
4
5
6
7
8
9
10
70
70
70
70
70
70
70
70
70
70
-
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
51
94
98
93
48
58
64
98
84
18
86
90
90
92
89
89
90
94
86
90
CH3
NH
CuI
10
8
10
94
83
96
96
90
95
94
95
94
93
2h
ZnI2
10
CH3
NH
9
40
CuOTf
Cu(OTf)2
Zn(OTf)2
CuCl
10
16
16
16
Br
2i
CH3
NH
10
11
12
10
H3CO
2j
Et
10
2k
NH
CuBr
CuBr
CuBr
10
16
48
N
H
30
2l
DCE
2 | J. Name., 2012, 00, 1-3
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On the basis of literature12 and our own observations, the
proposed mechanism for this asymmetric ring opening reaction is
a Reaction conditions: [Ir(cod)Cl]2 (5 mol % Ir), CuBr(20 mol %),
and (R)-Difluorphos (6 mol %) in solvent (2 mL) was stirred at
room temperature for 30 min under Ar atm. 1a (0.2 mmol)
and 2a-l (0.6 mmol) were added, and the reaction mixture was
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DOI: 10.1039/C5OB01243K
shown in Scheme 1. The catalytic cycle is initiated by the
coordination of [Ir(cod)Cl]2 with (R)-Difluorphos to generate the
chiral iridium complex A, the following coordination with 1a,
cuprous ion, and aniline to afford the intermediate B. Subsequently,
the intramolecular addition reaction generates intermediate C,
which then undergoes β-elimination to give the ring-opened species
D. Finally, the product 3aa was formed by cation exchange.
b
stirred at indicated temperature for indicated period of time.
Based on the full conversion of the substrate. c Yield of isolated
d
product.
Determined by HPLC analysis. ND = not
determined.
The nature of the substituent group on the nitrogen in the
azabenzonorbornadiene plays a significant role in the yields and
enantioselectivities of the products. When electron-withdrawing
group Ts, Ns or -COOMe was used to instead of Boc group, the yield
of the products decreased though the ee value still very high (Table
4, entries 1-4). To further extend the substrate scope of this
transformation, substituted azabenzonorbornadienes 1e-1i with
various substituents were examined. All the ring openings products
were obtained in 93-95% yield with 93-94% ee (Table 4, entries 5-9).
The bromide remained intact under the present reaction conditions
(3ga), that allows further potential functionalization.
Table
4.
Ir-catalyzed
ARO
reaction
of
various
azabenzonorbornadiene 1a-1i with aniline 2a.a
Scheme 1. Proposed mechanism for asymmetric ring opening
reaction of azabenzonorbornadiene with aniline.
Azabenzonor
-bornadiene
Time
(h) b
Yield
Ee
Entry
1
(%) c
(%) d
Boc
N
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
10
48
48
24
24
24
24
5
97
95
88
84
84
93
93
94
94
94
Conclusions
Ts
N
In conclusion, we have successfully developed an asymmetric ring
opening reaction of azabenzonorbornadienes with a number of
primary and secondary aromatic amine nucleophiles in the
presence of Ir/Cu associated with (R)-Difluorphos catalyst. It
provides an efficient and practical access to trans-vicinal diamine
derivatives in good yields (80-97%) with high enantioselectivities
(93-95%). Further investigations are underway to clarify the
mechanism of this transformation and to explore the scope of the
cocatalyst system in asymmetric ring opening (ARO) reactions.
90
86
88
93
94
93
95
95
Ns
N
H3C
H3C
H3CO
H3CO
Boc
Boc
N
N
Br
Boc
Boc
Boc
Acknowledgements
We gratefully thank National Natural Science Foundation of China
(NSFC 21402081, 21362043, 21302162) for financial support.
N
N
N
1g
1h
1i
Br
O
O
O
O
4
Notes and references
a
Reaction conditions: [Ir(cod)Cl]2 (5 mol % Ir), CuBr (20 mol %),
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2a (0.6 mmol) were added, and the reaction mixture was stirred
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at indicated temperature for indicated period of time. Based
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on the full conversion of the substrate. Yield of isolated
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