Enantioselective Copper-Catalyzed Intramolecular N?H Bond Insertion: Synthesis of Chiral 2-Carboxytetrahydroquinolines

Article abstract of DOI:10.1002/adsc.201600390

The first highly enantioselective intramolecular N?H bond insertion was realized by using copper catalysts modified with chiral spirobisoxazoline ligands, which provides a novel strategy for the synthesis of chiral 2-carboxytetrahydroquinolines. This reaction features fast reaction rate, high yield, high enantioselectivity, and mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201600390

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DOI: 10.1002/adsc.201600390
Very Important Publication
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Enantioselective Copper-Catalyzed Intramolecular N H Bond
Insertion: Synthesis of Chiral 2-Carboxytetrahydroquinolines
Xiao-Guang Song,a Yuan-Yuan Ren,a Shou-Fei Zhu,a,* and Qi-Lin Zhoua,b,*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-6177; e-mail: sfzhu@nankai.edu.cn or qlzhou@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, Peopleꢀs Republic of
b
China
Received: April 12, 2016; Revised: July 2, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600390.
Abstract: The first highly enantioselective intramo-
lecular N H bond insertion was realized by using
action provides a novel strategy for the synthesis
of chiral 2-carboxytetrahydroquinolines (Figure 1),
which are the ubiquitous building blocks in pharma-
ceuticals,[9] natural products,[10] and other useful
motifs.[11]
À
copper catalysts modified with chiral spirobisoxazo-
line ligands, which provides a novel strategy for the
synthesis of chiral 2-carboxytetrahydroquinolines.
This reaction features fast reaction rate, high yield,
high enantioselectivity, and mild reaction condi-
tions.
Our investigation started from the intramolecular
À
N H bond insertion of methyl 4-(2-aminophenyl)-2-
diazobutanoate (2a) using a chiral copper catalyst
prepared in situ from copper chloride, ligand (Sa,S,S)-
1a, and sodium tetrakis[3,5-bis(trifluoromethyl)phe-
nyl]borate (NaBArF) in dichloromethane (DCM) at
258C. The reaction was complete in 15 min, affording
the product, methyl 1,2,3,4-tetrahydroquinoline-2-car-
boxylate, in 74% yield with 85% ee (Table 1, entry 1).
Under otherwise identical reaction conditions, ligand
(Ra,S,S)-1a gave only racemic product (entry 2). This
result clearly indicated that the ligand (Sa,S,S)-1a had
Keywords: asymmetric catalysis; carbene insertion;
2-carboxytetrahydroquinolines; chiral spiro ligands;
copper
À
Transition metal-catalyzed carbene insertion into X
H (X=O, N, S, Si, B, etc.) bonds is one of the funda- matched chiralities in this reaction.[12] A variety of
À
mental reactions for constructing C X bonds in or- chiral spirobisoxazoline ligands with different alkyl
ganic synthesis.[1] In the past decade, catalytic asym- substituents on the oxazoline ring were compared,
À
metric X H insertion reactions have been developed and the enantioselectivities gradually decreased with
with high enantioselectivities.[2] The highly enantiose- bulkier substituents (entries 3–6). Moreover, the
À
lective intermolecular N H bond insertions were ac-
complished by using chiral copper,[3] rhodium[4] and
palladium[5] catalysts or achiral rhodium-chiral phos-
phoric acid cooperative catalysts.[6] However, the
À
asymmetric intramolecular N H bond insertion,
which provides a potential for the efficient construc-
tion of chiral cyclic amines,[7] remains a challenge to
date. To the best of our knowledge, only one example
À
for catalytic asymmetric intramolecular N H inser-
tion reaction was reported by McKervey and co-
workers[8] in 1996. By using chiral rhodium(II) car-
boxylate catalysts, they gained pipecolic acid deriva-
tives in up to 45% ee. As a part of our ongoing study
on the catalytic asymmetric X H bond insertion, we
here report a highly enantioselective intramolecular
À
À
N H bond insertion catalyzed by copper catalysts
modified with chiral spirobisoxazoline ligands. The re- a core structure of chiral tetrahydroquinoline.
Figure 1. Selected bioactive compounds and ligand with
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[a]
À
Table 1. Copper-catalyzed asymmetric intramolecular N H bond insertion of 2a: optimization of the reaction conditions.
Entry
[M]
Ligand
Solvent
Time [min]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuOTf·0.5(toluene)
Cu(MeCN)4PF6
CuCl2
(Sa,S,S)-1a
(Ra,S,S)-1a
(Sa,S,S)-1b
(Sa,S,S)-1c
(Sa,S,S)-1d
(Sa,S,S)-1e
(Sa)-1f
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-1a
(Sa,S,S)-4
(Ra,S,S)-4
(S,S)-5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
15
10
20
5
5
5
120
5
74
73
89
84
89
71
82
79
66
85
74
71
26
18
89
78
71
37
73
75
55
98
52
85
rac
77
73
61
28
43
74
76
91
73
83
rac
rac
87
91
84
7
9
5
5
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuBr2
CuSO4
FeCl2·4H2O
PdCl2(PhCN)2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
over night
over night
over night
45
5
60
5
toluene
THF
MeCN
DCM
DCM
DCM
DCM
over night
rac
rac
rac
rac
8
5
5
5
5
CuCl2
CuCl2
(S,S)-6
[a]
Reaction conditions: [Cu]/ligand/NaBArF/2a=0.02:0.024:0.024:0.4 mmol, in 4 mL solvent at 258C.
Isolated yield.
Determined by HPLC using a Chiralcel AD-H column.
[b]
[c]
ligand (Sa)-1f having no substituent at the 4-position ble for the reaction (entries 18 and 19). The spirobiin-
of the oxazoline ring, can also give some chiral induc- dane scaffold of the chiral ligands is crucial for ob-
tion (entry 7). To improve the yield and enantioselec- taining enantioselectivity.[14] Other chiral bisoxazoline
tivity of the reaction, we studied various copper cata- ligands with different backbones gave only racemic
lyst precursors (entries 8–12). All tested copper salts product or very low enantioselectivity under other-
À
can promote the intramolecular N H insertion with wise identical reaction conditions (entries 20–23).
good to high enantioselectivities, with CuCl2 giving
The scope of diazo substrates was examined under
the best result (85% yield, 91% ee, entry 10). We also the optimized reaction conditions (Table 2). The yield
tested iron and palladium salts,[13] but neither exhibit- and enantioselectivity decreased when a more steri-
ed enantioselectivity (entries 13 and 14). In addition cally demanding ester group was employed (entries 1–
to DCM, chloroform and 1,2-dichloroethane (DCE), 3). On the other hand, the substituents on the ben-
toluene was also a suitable solvent for the reaction zene ring of diazoesters 2 also affected the yield and
(entries 15–17), while the polar and coordinative sol- enantioselectivity. The substrates with an electron-
vents tetrahydrofuran and acetonitrile were unsuita- withdrawing group (Cl, Br, CO2Me) at the 3-position
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[a]
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Table 2. Copper-catalyzed asymmetric intramolecular N H bond insertion: substrate scope.
[a]
The reaction conditions and analyses were the same as those in Table 1, entry 10.
[b]
The absolute configuration was determined by comparing the specific optical rotation
with the reported data.[15]
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References
of the benzene ring generally afforded high enantiose-
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when an electron-donating group was introduced at
the 3-position of the benzene ring, the enantioselec-
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stituent gave excellent enantioselectivity (96% ee,
entry 9), while the fluoro and ester substituents af-
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In summary, we have developed a highly enantiose-
À
lective copper-catalyzed intramolecular N H bonds
insertion reaction, which provided a new method for
the synthesis of chiral 2-carboxytetrahydroquinolines.
The fast reaction rate, high yield, high enantioselectiv-
ity of the reaction further demonstrate the power of
À
these catalytic asymmetric X H bond insertion reac-
tions in organic synthesis.
Experimental Section
Typical Procedure for Copper-Catalyzed Asymmetric
À
Intramolecular N H Bond Insertion
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Acknowledgements
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China
(2012CB821600), the “111” project (B06005) of the Ministry
of Education of China, and the National Program for Sup-
port of Top-notch Young Professionals for financial support.
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6 Enantioselective Copper-Catalyzed Intramolecular N H
Bond Insertion: Synthesis of Chiral 2-
Carboxytetrahydroquinolines
Adv. Synth. Catal. 2016, 358, 1 – 6
Xiao-Guang Song, Yuan-Yuan Ren, Shou-Fei Zhu,*
Qi-Lin Zhou*
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