Catalytic asymmetric chloroamination reaction of α,β-Unsaturated γ-keto esters and chalcones

Article abstract of DOI:10.1021/ja110668c

Highly efficient catalytic chloroamination reaction of α,β- unsaturated γ-keto esters and chalcones has been developed via a chloronium-based mechanism to deliver anti-regioselective vicinal chloroamines instead of the aziridinium intermediates delivered

Full text of DOI:10.1021/ja110668c

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Catalytic Asymmetric Chloroamination Reaction of r,β-Unsaturated
γ-Keto Esters and Chalcones
Yunfei Cai, Xiaohua Liu, Jun Jiang, Weiliang Chen, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
S Supporting Information
b
Scheme 1. Contrast between Chloroamination Reaction and
Bromoamination Reaction of Chalcone
ABSTRACT: Highly efficient catalytic chloroamination
reaction of R,β-unsaturated γ-keto esters and chalcones
has been developed via a chloronium-based mechanism to
deliver anti-regioselective vicinal chloroamines instead of
the aziridinium intermediates delivered aminochlorides.
The combination of TsNCl2 and TsNH2 as reagents made
the transformation highly efficient, delivering the γ-carbo-
nyl-β-chloro-R-amino acid derivatives and R-chloro-β-ami-
no-ketone derivatives in nearly quantitative yields with up to
99% ee and 99:1 dr under 0.05ꢀ0.5 mol % catalyst loading.
TsNHCl was demonstrated to act as the key reactive species
to form a bridged chloronium ion intermediate in the
presence of a chiral scandium complex. The method might
provide useful information for further realization of other
haloamination reactions.
Herein, we address this issue and report the first highly enantio-
selective chloroamination reaction to afford enantiomerically
enriched γ-carbonyl-β-chloro-R-amino acid derivatives and
R-chloro-β-amino-ketone derivatives in excellent outcomes.
Initially, activated R,β-unsaturated γ-keto ester 1a was chosen
as a model substrate to optimize the reaction conditions which
could afford useful β-chloro-R-amino acid derivative 2a. With N-
chlorosuccinimide (NCS) and p-toluenesulfonamide (TsNH2)
as chlorine and nitrogen sources, an investigation on a series of
ligands and central metals (see Supporting Information for
details) showed that (S)-pipecolic acid derived N,N0-dioxide
L-Sc(OTf)3 could produce 2a exclusively with 96% ee and 97:3
dr but in 45% yield (Table 1, entry 1). The low yield prompted
us to examine other active chlorine and nitrogen sources.
N,N-Dichloro-4-methylbenzene-sulfonamide (TsNCl2) was
widely used as both a chlorine and nitrogen source in amino-
chloronation reactions.4e When it was employed in the reaction,
pleasingly, the yield of 2a increased from 45% to 72% without the
formation of an aminochlorinated product (Table 1, entry 2).
However, the source of where the hydrogen on the nitrogen of
the product 2a came from intrigued us. We speculated that it
most probably came from a trace amount of water in the system.
Thus, the combination of additives which contain an active
proton might further accelerate the reaction. Meanwhile, TsNH2
can serve as not only an additive to meet the above prerequisite
but also a reagent to participate in the reaction. When TsNH2
was combined with TsNCl2, the transformation became highly
efficient, and complete conversion was accomplished in less than
2 h without any loss of stereoselectivity even under 0.05 mol %
catalyst loading (>95% yield, 94% ee, 96:4 dr; Table 1, entries
3ꢀ4). Furthermore, use of 0.6 equiv of TsNH2/TsNCl2 (1:1)
still gave complete conversion with higher ee (98% yield, 97% ee,
Table 1, entry 5). It was noteworthy that the absence of 4 Å MS
led to a sharply decreased yield (61% yield, Table 1, entry 6 vs
entry 4).
he functionalization of olefins with halogen and amine
T
groups remains an intriguing challenge in modern organic
synthesis.1 Moreover, the resulting vicinal haloamine deriva-
tives represent very useful structure moieties in medicinal
chemistry2 and can also serve as key intermediates for further
manipulations.3 In the past decades, considerable progress has
been made in developing efficient synthetic approaches to this
functionality.4 However, asymmetric synthesis of these haloa-
mines through direct aminohalogenation or haloamination reac-
tion remains quite limited and only two examples reported by Li
group gave vicinal chloroamines with moderate diastereoselec-
tivities via a chiral substrate-directed process.5 Recently, our
group reported the efficient catalytic asymmetric bromoamina-
tion of chalcones to synthesize vicinal bromoamines using NBS/
TsNH2 as bromine and nitrogen sources.6 Unfortunately, the
attempt to employ NCS/TsNH2 as chlorine and nitrogen
sources in the chloroamination of chalcones, even under
20 mol % catalyst loading at 35 °C, seemed unsuccessful
(Scheme 1).
We postulated that the main issues were as follows: (1) the low
reactivity of NCS or chalcones in the chloroamination reaction
led to the sluggish formation of the bridged chloronium ion
intermediate; (2) the bridged chloronium ion was more unstable
than the bromonium ion due to its smaller atomic radius and
higher electronegativity. Thus, searching for more reactive sub-
strates or reagents, which could form and capture the chloronium
ion intermediate, is essential to solve this challenging objective.
Received: November 28, 2010
Published: March 28, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Reaction Conditionsa
Table 2. Substrate Scope for the Catalytic Asymmetric
Chloroamination Reaction of r,β-Unsaturated γ-Keto Estersa
n
time
(h)
ee (%),
drb
yield
(%)c
entry
NꢀCl source
(mol %)
1
NCS/TsNH2
TsNCl2
5
48
48
0.5
2
96, 97:3
94, 96:4
94, 96:4
94, 96:4
97, 96:4
97, 96:4
45
2
5
72
>95d
3
TsNCl2/TsNH2
TsNCl2/TsNH2
TsNCl2/TsNH2
TsNCl2/TsNH2
5
4e
5e,f
6f,g
0.05
0.05
5
98
6
98
24
61
a Unless otherwise noted, all reactions were performed with L-Sc(OTf)3
(1:1), new activated 4 Å MS (20 mg), 1a (0.1 mmol), NꢀCl source (1:1,
0.12 mmol) in CH2Cl2 (0.5 mL) under N2 at 35 °C for the
c
indicated time. b Determined by chiral HPLC. Isolated yield. d Total
conversion, less than 5% yield of byproducts. e Using 0.05 mol % catalyst
f
(8 μL, 0.006 M L-Sc(OTf)3 in THF). Using 0.6 equiv of TsNCl2/
TsNH2 (1:1). g Without 4 Å MS.
a Unless otherwise noted, all reactions were carried out with 0.05 mol %
L/Sc(OTf)3 (1/1), 1 (0.1 mmol), TsNCl2 (0.06 mmol), TsNH2 (0.06
mmol), new activated 4 Å MS (20.0 mg) in 0.5 mL of CH2Cl2 at 35 °C
(for details, see Supporting Information). b Isolated yield. c Determined
Under the optimized conditions (Table 1, entry 5), the
substrate scope was investigated. As shown in Table 2, in all
cases, the ee values of the products 2 were excellent (93ꢀ99% ee,
Table 2) and the yields were as well (Table 2, entries 1ꢀ2, 5ꢀ17)
except for substrates with a bulky group on the ester moiety
(Table 2, entries 3 and 4). The diastereoselectivity was influ-
enced a little by the electronic property of the substituents at the
aromatic ring. Generally, the substrates with an electron-donat-
ing group gave the desired products with a high dr (Table 2,
entries 7ꢀ8), while the electron-withdrawing substituents on the
phenyl group reduced the stability of the chloronium intermedi-
ate which resulted in a relatively lower diastereoselectivity
(Table 2, entries 9ꢀ13). Notably, fused-ring esters as well as
multisubstituted and heteroaromatic-substituted ones were tol-
erated under the current system (Table 2, entries 14ꢀ17).7
Encouraged by the extremely high reactivity of TsNCl2/
TsNH2, we then returned to realize the chloroamination reaction
of chalcones 3. As shown in Table 3, the desired R-chloro-
β-amino-ketone derivatives 4 were obtained in good to excellent
yield with excellent diastereoselectivities (>99:1 dr) and excel-
lent enantioselectivities (96ꢀ99% ee) under a 0.05ꢀ0.5 mol %
catalyst loading. Remarkably, fused-ring chalcones as well as
cinnamyl-, heteroaromatic-, and multisubstituted ones were also
suitable substrates for the reaction (Table 3, entries 10ꢀ12,
23ꢀ26). Distinctively, for a chalcone derivative with a para-
methoxy substituent on the β-phenyl group, a poor ee value
(Table 3, entry 27) was obtained which was in accord with that in
the bromoamination reaction. It implied that a similar bridged
chloronium ion intermediate was possible and an electron-rich
chloronium ion might be easier to racemize through the bimo-
lecular olefin-to-olefin transfer pathway.6,8
1
by chiral HPLC. d Determined by chiral HPLC or H NMR analysis.
e Using 0.2 mol % catalyst. f Reaction was performed at 20 °C for 40 h.
absolute configuration (1R,2R) was determined by X-ray crystal-
lography of product 4u,9 which also confirmed the anti-config-
uration and stereostructure assignment.
Based on the control experiments (see Supporting Informa-
tion for details) as well as the full transformation using 0.6 equiv
of TsNH2/TsNCl2 (1:1) as reagents and the observation of two
N-protected products employing 0.6 equiv of MeSO2NH2/
TsNCl2 (1:1) as reagents,7 TsNHCl was demonstrated to be
an extremely active species in the chloroamination reaction. It
was also notable that 4 Å MS played a crucial role in accelerating
the formation of TsNHCl from the mixture of TsNCl2 and
1
TsNH2, which was unambiguously monitored by H NMR
analysis (see Supporting Information for details). Although
TsNCl2 could also work as a chlorine/nitrogen reagent, the
directly functionalized product B (Scheme 2) could not be
transformed into the product A under the current catalytic
conditions which indicated that TsNCl2 was not the reagent to
form the chlorinum ion intermediate and further confirmed that
TsNHCl from the reaction of TsNCl2 with a trace amount of
H2O should be the real reactant.
In light of the anti-configuration, a bridged chloronium ion
intermediate should be conceivable (Scheme 2). The same
absolute configuration of the chloroamination products10 as that
of bromoaminated ones6 brought around an onium intermediate.
Therefore, a possible mechanism was that the highly reactive
species TsNHCl was generated upon the promotion of the 4 Å
MS initially. Then, a N,N0-dioxide-Sc(III) complex mediated the
formation of the chiral chloronium ion intermediate following
instantly nucleophilic attack of negative nitrogen to deliver the
Additionally, the stereostructures of the chloroaminated
products 2 and 4 were assigned on the basis of HRMS analysis,
which showed the prominent peaks corresponding to the
[TsNHCHCOOR]þ or [ArCHNHTs]þ ion fragment. The
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Table 3. Substrate Scope for the Catalytic Asymmetric
Chloroamination Reaction of Chalconesa
Scheme 2. Possible Mechanism of the Chloroamination
Reaction
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and ana-
b
lytic data (NMR, HPLC, and ESI-HRMS). This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
xmfeng@scu.edu.cn
’ ACKNOWLEDGMENT
We appreciate the National Natural Science Foundation of
China (Nos. 20732003 and 21021001) and National
Basic Research Program of China (973 program: No.
2010CB833300) for financial support. We also thank Sichuan
University Analytical & Testing Center for NMR analysis and
X-ray analysis.
’ REFERENCES
a Unless otherwise noted, all reactions were carried out with 0.05 mol %
L/Sc(OTf)3 (1/1), 3 (0.1 mmol), TsNCl2 (0.06 mmol), TsNH2 (0.06
mmol), new activated 4 Å MS (20.0 mg) in 0.5 mL of CH2Cl2 at 35 °C
(See Supporting Information for details). b Isolated yield. c Determined
(1) Kemp, J. E. G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 469ꢀ513 and
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(2) Thomas, G. Medicinal Chemistry: An Introduction; John Wiley &
Sons: New York, 2000.
1
by chiral HPLC. d Determined by chiral HPLC or H NMR analysis.
e Using 0.5 mol % catalyst. f Reaction was performed at 0 °C with
(3) De Kimpe, N.; Verhꢀe, R. The Chemistry of R-Haloketones,
R-Haloaldehydes, and R-Haloimines; John Wiley & Sons: New York, 1988.
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(7) In this catalytic system the sulfonyl group seemed very important
to the activity. We tested other RNH2 donors combined with TsNCl2,
preactivated reagents. g Determined by X-ray crystallography.
final product A, and a trace amount of byproduct B10 could be
formed by the reaction of product A with TsNHCl.11
In summary, we have developed a highly efficient catalytic
enantioselective chloroamination reaction. Remarkably, with
0.05ꢀ0.5 mol % chiral N,N0-dioxide-Sc(III) complex, the reac-
tion was performed well over a series of (E)-R,β-unsaturated
γ-keto esters and chalcones,12 giving the desired products
regioselectively in excellent yields (up to 99%) with excellent
diastereoselectivities (>99:1) and enantioselectivities (up to
99% ee) under mild conditions. The demonstration that
TsNHCl performed as the key reactive species to form the
chloronium ion intermediate might provide a new entry for
further realization of other haloamination reactions. Further
efforts will be dedicated to explore the application to simple
olefins and other R,β-unsaturated compounds as well as the
protection group of the N-source to make the reaction more
useful.
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such as PhNH2, PhCONH2, and CH3CONH2, but no corresponding
products were observed. The combination of MsNH2 and TsNCl2
provided the TsNH and MsNH products together with compatible
stereoselectivity (97% ee, 96:4 dr for TsNH product and 96% ee, 98:2 dr
for MsNH product 2r). The yield of the latter increased from 51% to
76% when the amount of MsNH2 increased from 0.6 to 5 equiv which
implied that MsNHCl or TsNHCl might be the active chloride/nitrogen
species. The products of 1a with PhSO2NH2 and TsNCl2 could not be
separated, but the amount of sulfonamide had a similar influence on the
yield (from 43% to 51% determined by 1H NMR).
(8) (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137. (b) Denmark,
S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232–1233.
(9) CCDC 798271 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambrige Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
(10) Trace amounts of byproduct B were observed for the substrates
surveyed. Substrate 1m gave the corresponding byproduct 5m in 6%
yield (see Supporting Information).
(11) (a) Banerji, K. K.; Jayaram, B; Mahadevappa, D. S. J. Sci. Ind.
Res. 1987, 46, 65. (b) Puttaswamy; Jagadeesh, R. V. Appl. Catal. A: Gen.
2005, 292, 259–271. (c) Puttaswamy; Suresha, N. Indian J. Chem., Sect.
A: Inorg., Bio-inorg., Phys., Theor. Anal. Chem. 2008, 1649–1655.
(12) Under the current catalyst system, the investigation of other
olefins such as styrene, cinnamone, and nitroalkene indicated that the
benzoyl group on the enones had direct influences on the reactivity as
well as regio- and stereoselectivity. When styrene was used, racemic
products with poor regioselectivity (1:3) and moderate yield (50%)
were obtained. For cinnamone as the substrate, moderate yield and
stereoselectivity (70% ee, 87:13 dr) were obtained with the problem that
byproducts from the R-chloriantion reaction were generated. Compli-
cated products were obtained with nitroalkene as the substrate (see
Supporting Information for details).
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