10.1002/anie.202015083
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Product derivatization.a
enantioselectivities of the current process, and all give chiral azides in
good to excellent enantioselectivity (Table 2C). However, the
acrylamides with N-alkyl groups and acryl esters were proven to be
unsuitable for the current asymmetric azidation reactions (see SI).
Notably, different heteroaromatic rings were also tolerated (Table 2D),
such as thiophene, benzofuran and pyridine, delivering the desired
products with good yield and satisfactory enantioselectivity (30-33). The
protocol also shows modest functional group tolerance. For example,
ether, halide, ester and silyl groups are all compatible with the reaction
conditions. Finally, the enantioselective C-N3 cross-coupling can be
conducted on a gram scale with a similar outcome (61% yield, and 93.5 :
6.5 er). The absolute configuration of the optically active 9 was
unambiguously determined to be R by X-ray crystallography.
Ph NH
2 H
Ph NH
2 H
N
F3C
N
from 2d
from 2d
Ar'
F3C
Ar'
(a)
(b)
O
34
74%, 93 : 7 er
35
92%, 93.5 : 6.5 er
Ar N3
H
CF3
N
Ar'
O
Ph
N
Ph N3
N
F3C
NH2
(c)
(d)
Ph
F3C
N
H
N
from 2d
from 24
O
Ar'
O
36
77%, 93 : 7 er
37
60%, 91 : 9 er
a Reaction conditions: (a) LiAlH4 (1.2 equiv), THF, 0 oC, 12 h. (b) LiAlH4 (5.0 equiv), THF, 60
oC, 12 h. (c) CuI (1.0 equiv), phenylacetylene (3.0 equiv), sodium ascorbate (1.0 equiv),
CH3CN/H2O, 110 oC, 6 h. (d) CAN (3.0 equiv), CH3CN/H2O, 50 oC, 6 h.
Finally, we moved our attention to the product transformation to
further highlight the anticipated synthetic utility of this asymmetric
radical protocol (Scheme 2). We found that the enantio-enriched
alkylazides could be converted into other families of compounds without
any erosion of the enantioselectivity. For example, the straightforward
reduction of azide 2d delivered the optically active 1,2-diamine 35,
In conclusion, we have developed a protocol for the facile synthesis
of enantioenriched alkylazides, specifically, copper-catalyzed
asymmetric radical azidation of acrylamides. The success of this
reaction relies on the use of anionic cyano-bisoxazoline ligands (CN-
Box), which are expected to have less tendency to form dimeric species
and then lead to improved enantioselectivities. The generality of this
process has beenstrongly supported by the low catalyst loading (1 mol%)
and good substrate scope. Future efforts will be focused on further
detailing the mechanistic underpinnings of this process and discovering
other synthetically useful asymmetric transformations based on the
anionic type ligands.
which is
a common structure moiety in natural products and
pharmaceutical agents.[14] On the other hand, the copper-catalyzed
Huisgen cycloaddition was also employed to transform sterically
demanding azide 2d into the corresponding triazole 36 in excellent yield.
Moreover, the amide 24 could be treated by oxidant CAN to give -
azidyl free amide 37 in good yield with the retention of
enantioselectivity.
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Acknowledgements
We are grateful for financial support from the National Nature Science
Foundation of China (Nos. 21532009, 21821002, 21790330 and
91956202), the Science and Technology Commission of Shanghai
Municipality (Nos. 17XD1404500, 17JC1401200 and 19590750400),
the strategic Priority Research Program (No. XDB20000000), the
Chinese Academy of Sciences (QYZDJSSW-SLH055 and
121731KYSB20190016), and the Research Grants Council of Hong
Kong (HKUST 16302418 and 16300620).
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Conflict of interest
•
[8] The redox potential of the N3 /N3− couple is 1.32 ± 0.01 V vs NHE, see: Z. B.
The authors declare no competing financial interest.
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Keywords: Asymmetric azidation • Copper-catalyzed • Anionic
bisoxazoline • Radical • acrylamides
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