Asymmetric hydroazidation of α-substituted vinyl ketones catalyzed by chiral primary amine

Article abstract of DOI:10.1016/j.cclet.2017.01.014

We report herein the first example of asymmetric hydroazidation of α-substituted vinyl ketones by using chiral primary amines as the catalysts. A simple chiral primary-tertiary diamine catalyst derived from L-phenylalanine was found to readily promote this aza-Michael addition reaction with enamine protonation as the key stereogenic step, thus enabling the effective synthesis of α-chiral β-azido ketones with good yields and moderate enantioselectivities.

Full text of DOI:10.1016/j.cclet.2017.01.014

Accepted Manuscript
Title: Asymmetric hydroazidation of α-substituted vinyl
ketones catalyzed by chiral primary amine
Authors: Zai-Kun Xue, Nian-Kai Fu, San-Zhong Luo
PII:
S1001-8417(17)30038-4
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.01.014
CCLET 3963
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Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
12-11-2016
30-12-2016
16-1-2017
Please cite this article as: Zai-Kun Xue, Nian-Kai Fu, San-Zhong Luo, Asymmetric
hydroazidation of ␣-substituted vinyl ketones catalyzed by chiral primary amine,
Chinese Chemical Letters http://dx.doi.org/10.1016/j.cclet.2017.01.014
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Original article
Asymmetric hydroazidation of α-substituted vinyl ketones catalyzed by chiral
primary amine
Zai-Kun Xue, Nian-Kai Fu, San-Zhong Luo 
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China
ARTICLE INFO
Article history:
Received 14 November 2016
Received in revised form 16 December 2016
Accepted 29 December 2016
Available online
—
——

Corresponding author.
E-mail address: luosz@iccas.ac.cn

Graphical Abstract
Asymmetric hydroazidation of α-substituted vinyl ketones catalyzed by chiral primary amine
Zai-Kun Xue, Nian-Kai Fu, San-Zhong Luo *
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
We report herein the first example of asymmetric hydroazidation of α-substituted vinyl ketones by using chiral primary amines as the catalysts.
A simple chiral primary-tertiary diamine catalyst derived from L-phenylalanine was found to promote this aza-Michael addition reaction with
enamine protonation as the key stereogenic step, thus enabling the effective synthesis of α-chiral β-azido ketones with good yields and
moderate enantioselectivities.
ABSTRACT
We report herein the first example of asymmetric hydroazidation of α-substituted vinyl ketones by using chiral primary amines as the catalysts. A
simple chiral primary-tertiary diamine catalyst derived from L-phenylalanine was found to readily promote this aza-Michael addition reaction with
enamine protonation as the key stereogenic step, thus enabling the effective synthesis of α-chiral -azido ketones with good yields and moderate
enantioselectivities.
Keywords:
Chiral primary amine catalysis
Hydroazidation
Enamine protonation
α-Substituted vinyl ketones
Aza-Michael addition
Chiral -azido ketones

1. Introduction
Organic azides are important precursors for the synthesis of N-containing structural motifs in organic synthesis [1] and their
applications in click chemistry have also attracted intensive attentions in fields of pharmaceutical chemistry, supramolecular chemistry
and material science [2]. As such, mild and efficient methods for their synthesis are of increasing importance and aza-Micahel addition
of azide ion to unsaturated carbonyl compounds represents one of the most straightforward approaches for the synthesis of organic
azides [3]. The resulted -azido carbonyls could be readily converted into -amino acids [4], an intriguing structural motif widely
distributed in biologically and pharmacologically active compounds [5]. In this context, the asymmetric hydroazidation of unsaturated
carbonyl compounds is highly desirable [6]. In 1999, Jacobsen and co-workers reported that chiral (salen)Al(III) complexes could
effectively promote the enantioselective addition of hydrazoic acid to unsaturated imides [6b]. Subsequently, the first organocatalytic
enantioselective hydroazidation of Michael acceptors was reported by Miller and co-workers by using a small peptide as the catalyst
[6c-d]. Nitroalkenes have also been attempted as Michael acceptors in reaction with azide for the synthesis of optically enriched -nitro
azides, but unfortunately with limited success [6g-h]. Recently, Jang and co-workers reported a tandem reaction of enals with azide in
the presence of chiral aminocatalyst and iron complex for the asymmetric synthesis of -amino -hydroxy aldehydes [7]. Most of these
studies utilized -substituted Michael acceptors, however, the reactions with -unsubstituted vinyl carbonyls have not been achieved so
far (Scheme 1). The most difficulty associated with this type of substrates comes from the challenging -stereogenic protonation step.
Recently, we have developed chiral primary aminocatalysis for asymmetric conjugate addition to α-substituted acroleins and vinyl
ketones with a wide range of nucleophiles [8]. These reactions feature enamine protonation as the key stereogenic step [9] and our
detail mechanistic studies have disclosed a Curtin-Hammett stereocontrol for the reactions of α-substituted vinyl ketones [8f]. To
further explore the potentials of this reaction, we have examined other types of nucleophiles such as azide in the reaction with α-
substituted vinyl ketones. Following the established mechanistic scenario, the targeted reaction would provide a straightforward access
of chiral -azido ketones with promising enantioselectivity [8f]. In this communication, we wish to present the unprecedented
stereoselective addition of azide to α-substituted vinyl ketones catalyzed by a simple chiral primary-tertiary diamine catalyst derived
from L-phenylalanine.
2. Results and discussion
Our studies on this asymmetric Michael addition-protonation reaction with azide were carried out using TMSN as the azide source.
3
Using EtOH as the proton source, a preliminary result indicated that the vicinal primary-tertiary diamine catalyst 1 could promote the
targeted reaction, with not unexpectedly low activity, but fortunately with a promising enantioselectivity (Table 1, entry 1). Further
investigation led to the identification of 3a/TfOH as the optimum catalyst system (Table 1, entries 2-9). In the presence of 10 mol%
3a/TfOH, the reaction gave the desired product 5a in 52% isolated yield and with 42% ee (Table 1, entry 3). The screening of reaction
mediums demonstrated that the solvents had an obvious effect on both of the yield and stereocontrol. As can be seen from Table 1, the
use of chlorinated solvent, especially 1,2-dichloroethane (DCE), could greatly improve the reaction outcome, affording the desired
product in 63% isolated yield and 57% ee (Table 1, entry 10). Interestingly, when tetrahydrofuran was employed as solvent nearly no
product could be detected (Table 1, entry 13).
Bearing in mind the dramatic effect of proton donors in enantioselective enamine protonation reactions [8], we next examined a
range of proton donors, such as alcohols, water and phenols, in order to further improve the activity and stereoselectivity (Table 2). In
general, the use of alcohol additives led to better results but have no significant effect on the stereocontrol and, the use of methyl
alcohol afforded the product with the best yield outcome (Table 2, entry 1). Moreover, we disclosed that the drop-wise addition of
TNSN in one hour could greatly increase the enantioselectivity to 69% ee (Table 2, entry 10). Extensive efforts to improve the
3
enantioselectivity were all in vain, reflecting the difficulties in controlling a stereogenic enamine protonation in this context.
Nevertheless, the current results represent the best for this hydroazidation reaction with vinyl ketones. Finally, 10 mol% of 3a as
catalyst, 4.0 equipment of methyl alcohol as proton source and 1,2-dichloroethane as the solvent were chosen as the optimal conditions
for our subsequent scope examination.
Under the optimal conditions, the substrate scope of the reaction was next explored. As shown in Table 3, α-substituted vinyl
ketones are well tolerated in this reaction. Aromatic α-substituted vinyl ketones were identified as one class of preferred substrates, and
para-substitution on the phenyl group bearing either electron-rich or electron-deficient substituents are equally applicable, giving the
desired adducts with moderate to good enantioselectivity (Table 3, entries 2-7). Unfortunately, meta-substitution on the phenyl group,
especially the incorporation of the elemental fluorine seems somehow detrimental to the reaction (Table 3, entries 8-11). We also found
that a more bulky α-substituted group could lead to a sharp drop of the enantioselectivity (Table 3, entries 13-15).
To evaluate the practicality of this methodology, the Staudinger reduction procedure was performed to furnishe the -chiral -amino
ketone 5a in good isolated yield, and erosion of the enantioselectivity was observed, likely a result of the subsequent non-optimized
basic reaction conditions (Scheme 2). Meanwhile, the click reaction between 5a and 7 can also be readily achieved, affording the

benzotriazole addition product 8 in excellent yield.
3. Conclusion
In summary, we have developed the first example of asymmetric conjugate addition-protonation reactions of trimethylsilylazide to
α-substituted vinyl ketones by chiral primary amine catalysis. The reaction proceeds under very mild reaction conditions and further
synthetic modification of the products could provide chiral β-amino ketones or related compounds easily in one step.
4. Experimental
General procedure for chiral primary amine catalyzed asymmetric hydroazidation of α-substituted vinyl ketones: Catalyst 3a/ TfOH
o
(
10 mol%), α-substituted vinyl ketone 4 (0.2 mmol) and methanol (0.4 mmol) in 0.5 mL 1,2-dichloroethane at 35 C. To the mixture,
trimethylsilylazide (0.1 mmol) was added in 0.5 mL DCE to this tube in 1 h and the progress of the reaction was monitored by TLC.
After completion, the reaction mixture was directly separated by flash column chromatography on silica gel eluting with a mixture of
petrol ether and EtOAc (PE/EA: 20/1). Collected fractions were concentrated under vacuum to afford the desired product. The
characterization data of the products are summarized in the Supporting information.
Acknowledgment
We thank National Natural Science Foundation of China (NSFC Nos. 21390400, 21521002 and 21502198) and the Ministry of
Science and Technology, Chinese Academy of Sciences (No. QYZDJ-SSW-SLH023) for generous financial support. S. L. is supported
by National Program for Support of Top-notch Young Professionals, CAS Youth Innovation Promotion Association and CAS one-
hundred talented program (D).

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Scheme 1. Asymmetric Michael addition of trimethylsilylazide to enones.

Scheme 2. Transformations of the azido adducts.

Table 1
Screening of catalysts and solvents. a
Entry
Amine
1
2
Solvent
Yield (%)b
8
ee (%)c
44
5
42
41
23
19
18
46
4
1
2
3
4
5
6
7
8
9
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
DCE
3
3
3
3
3
3
3
3
3
12
52
51
50
45
45
8
81
63
42
5
3a
3b
3c
3d
3e
3f
3g
3a
3a
3a
3a
1
1
1
1
a
0
1
2
3
57
25
33
-
PhH
CH
3
CN
THF
Trace
o
General conditions: 4a (0.20 mmol), trimethylsilylazide (0.10 mmol), EtOH (0.4 mmol), amine/TfOH (10 mol%) in solvent (0.10 mol/L) at 35 C, 16 h.
Isolated yields.
Determined by chiral HPLC.
b
c

Table 2
Screening of proton sources.
a
Entry Proton
Yield (%)b
ee (%)c
58
57
57
57
56
45
46
30
1
2
3
4
5
6
7
8
9
MeOH
EtOH
BnOH
77
63
57
49
28
34
60
40
34
72
H
2
O
PhOH
t-BuOH
CF
3
CH
2
OH
PhCOOH
Ethylene glycol
19
69
1
a
0
MeOHd
o
General conditions: 4a (0.20 mmol), trimethylsilylazide (0.10 mmol), proton source (0.4 mmol), 3a/TfOH (10 mol%) in DCE (0.10 mol/L), 5 C, 16 h.
b
Isolated yields.
Determined by chiral HPLC.
Trimethylsilylazide was add in 1 h.
c
d

Table 3
Substrate scope.
a
Entry
R
1
R
2
Product b
Time
h)
Yield
(%)
72
76
78
91
78
67
90
72
74
76
79
69
68
68
56
ee
c
(
(%)
69
70
70
75
69
59
45
44
55
54
38
56
43
11
16
1
2
3
4
5
6
7
8
9
H
4-F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
16
16
16
16
20
24
16
20
20
20
24
24
20
24
32
4-Cl
4-Br
4-OMe
4-CF
4-Et
3-F
3-Cl
3-Br
3-OMe
3
1
1
1
1
1
0
1
2
3
4
5
3-Br,4-F
H
H
H
n-Pr
Bn
1
a
General conditions: 4 (0.20 mmol), trimethylsilylazide (0.10 mmol), MeOH (0.4 mmol), 3a/TfOH (10 mol%) in DCE (0.10 mol/L) at 35 oC, at 1 h,
trimethylsilylazide was add.
b
Isolated yields.
Determined by chiral HPLC.
c