Catalytic asymmetric bromoamination of chalcones: Highly efficient synthesis of chiral α-bromo-β-amino ketone derivatives

Article abstract of DOI:10.1002/anie.201002355

Stand and deliver: The first highly regio- and enantioselective bromoamination of chalcones has been developed which proceeds via an unusual bromonium-based mechanism to deliver the title compounds. Excellent results were obtained using 0.05 mol % of the

Full text of DOI:10.1002/anie.201002355

Communications
DOI: 10.1002/anie.201002355
Asymmetric Catalysis
Catalytic Asymmetric Bromoamination of Chalcones: Highly Efficient
Synthesis of Chiral a-Bromo-b-Amino Ketone Derivatives**
Yunfei Cai, Xiaohua Liu, Yonghai Hui, Jun Jiang, Wentao Wang, Weiliang Chen, Lili Lin, and
Xiaoming Feng*
Catalytic asymmetric difunc-
tionalization of carbon–carbon
double bonds, such as dihy-
droxylation,[1] aminohydroxy-
lation,[2] and diamination[3] has
been broadly studied and has
also matured to the extent that
the transformations are rou-
tinely applied in organic syn-
thesis. However, asymmetric
electrophilic halofunctionaliza-
tion reactions attract less atten-
tion, and still pose a great
challenge.[4] Among them, bro-
moaminations[5] of chalcones
are of great interest, because
the resulting vicinal bromo-
amines are extremely versatile
building blocks in organic and
medicinal chemistry.[6] More-
over, optically active bromine-
containing products can serve
as key intermediates[7] for fur-
ther manipulations.[8] Nonethe-
Scheme 1. Regioselectivity and enantioselectivity of the bromoamination reaction.
less, an efficient catalytic asym-
metric bromoamination reac-
tion to afford chiral a-bromo-b-amino ketone derivatives B
(Scheme 1, path b) has been elusive. The main difficults are as
follows:
1) The regioselectivity of the difunctionalization reaction:
chalcones prefer an aminobromination process (Scheme 1,
path a) probably through an aziridinium-based mecha-
nism.[9a] Therefore, the catalytic aminobromination of
chalcones to synthesize racemic amino-brominated pro-
ducts A (Scheme 1, path a) was widely reported in the
literature.[9] While few examples involve a bromoamina-
tion procedure which generates a-bromo-b-amino ketone
products B via a bromonium ion intermediate (Scheme 1,
path b).
2) The enantioselectivity of the bromoamination reaction:
the bromonium ion intermediate possibly suffers racemi-
zation through olefin-to-olefin transfer (Scheme 1,
path c), which is competitive with intermolecular capture
by anionic nucleophiles.[10]
Herein, we developed the first catalytic regio- and
enantioselective bromoamination of chalcones by chiral
N,N’-dioxide/scandium(III) complexes to afford a-bromo-b-
amino ketone derivatives with excellent outcomes (up to 99%
yield, 99% ee, and 99:1 d.r.) under mild reaction conditions.
In our initial study, the catalytic activity of a series of
Lewis acids such as Cu(OTf)2, Fe(OAc)2, Zn(OTf)2, InBr3,
Zr(OiPr)4, SnCl2·2H2O, Mn(OAc)2·4H2O, and Cd-
(OAc)2·2H2O was examined in the bromoamination of
chalcones with p-toluenesulfonamide (TsNH2) and N-bromo-
succinimide (NBS; for details, see the Supporting Informa-
tion). However, no a-bromo-b-amino ketone derivatives B
were obtained and only a-amino-b-bromo ketone deriva-
[*] Y. F. Cai, Dr. X. H. Liu, Y. H. Hui, J. Jiang, W. T. Wang, W. L. Chen,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[**] We appreciate the financial support from the National Natural
Science Foundation of China (Nos. 20732003 and 20872097), the
PCSIRT (No. IRT0846), and the National Basic Research Program of
China (973 Program; No. 2010CB833300). We also thank Sichuan
University Analytical & Testing Center for NMR analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002355.
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Table 1: Optimization of the reaction conditions in the asymmetric
bromoamination of chalcone.
tives A were detected as the major product—this outcome is
similar to previously reported results.[9] Further investigation
of other Lewis acids showed that trace amounts of bromo-
aminated products B could be obtained by employing Yb-
(OTf)3 or La(OTf)3 as the catalyst. Pleaseingly, Sc(OTf)3 gave
the desired compound B as a major product in 31% yield. The
addition of molecular sieves (M.S.; 4 ꢀ) notably improved the
yield to 70%.
Next, we carried out chiral Lewis acid catalyzed regio-,
diastereo-, and enantioselective bromoamination of chal-
cones. In our previous studies, it was demonstrated that N,N’-
dioxide/metal complexes exhibited an excellent ability to
catalyze various asymmetric reactions.[11] Therefore, the
catalytic activity of a series of N,N’-dioxide/Sc(OTf)3 com-
plexes was examined for the synthesis of chiral a-bromo-b-
amino ketone derivatives. Initially, by coordination with
Sc(OTf)3 the chiral N,N’-dioxide ligand L1 derived from
(S)-pipecolic acid could catalyze the asymmetric bromoami-
nation of chalcone 1aa, and produced 2aa in 34% yield with
85% enantiomeric excess (ee) and up to 99:1 diastereomeric
ratio (d.r., Table 1, entry 1). Encouraged by this result, other
amines and chiral backbone moieties of N,N’-dioxide ligands
were investigated (Table 1, entries 2–6). It was found that
phenylethanamine and (S)-pipecolic acid derived N,N’-diox-
ide L3/Sc(OTf)3 was the most promising catalyst (70% yield,
91% ee, > 99:1 d.r.; Table 1, entry 3). Then, the effect of
temperature was examined, and the enantioselectivity was
increased to 96% ee at 08C (Table 1, entry 7). Remarkably,
when M.S. (4 ꢀ) were used as an additive, the yield was
greatly improved to 95% with maintained stereoselectivity
(Table 1, entry 8). Investigation of solvent effect showed that
CH2Cl2 was the best solvent and higher concentration gave
better yield (Table 1, entry 9). Pleaseingly, the catalytic
activity of N,N’-dioxide L3/Sc(OTf)3 catalyst was prominent,
and the catalyst loading could be decreased from 10 mol% to
0.05 mol% without any loss in the yield and enantioselectivity
(Table 1, entry 10). Exclusion of air and moisture was also
unnecessary, and made the protocol more simple, convenient,
and practical (Table 1, entry 11). Notably, further decreasing
the catalyst loading to 0.001 mol% maintained the enantio-
selectivity with moderate yield (Table 1, entry 12). The
stability test of the catalyst showed that the activity and
selectivity could be maintained when using a solution of
catalyst kept at room temperature for three months (Table 1,
entry 13).
Entry[a]
Ligand
Catalyst loading Yield [%][b]
[x mol%]
ee [%][c]
d.r.[d]
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
L3
10
10
10
10
10
10
10
10
10
34
24
72
71
36
47
59
95
99
99
99
58
99
85
91
91
91
84
91
96
96
96
96
96
96
96
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
7[e]
8[e,f]
9[e,f,g]
10[h]
11[h,i]
12[h,j]
13[h,i,k]
0.05
0.05
0.001
0.05
[a] Unless otherwise noted, all reactions were performed with ligand
(10 mol%), Sc(OTf)3 (10 mol%), 1aa (0.1 mmol), TsNH2 (0.11 mmol),
and NBS (0.12 mmol) in CH2Cl2 (0.5 mL) under nitrogen at 358C for
24 h. [b] Yield of isolated product. [c] Determined by HPLC on a chiral
stationary phase using a Chiralcel AD-H column. [d] Determined by
1H NMR spectroscopy and HPLC on a chiral stationary phase. [e] Reac-
tion was performed at 08C. [f] M.S. (4 ꢀ, 20 mg) was added. [g] Only
0.2 mL of CH2Cl2 was used. [h] Catalyst (0.05 mol%, 25 mL, 0.002m L3/
Sc(OTf)3 in THF), 1aa (0.1 mmol), TsNH2 (0.11 mmol), NBS
(0.12 mmol), M.S. (4 ꢀ, 20 mg) in CH2Cl2 (0.2 mL) under nitrogen at
08C for 24 h. [i] Not under N2. [j] The reaction was carried out on a
1 mmol scale with 0.001 mol% catalyst for 72 h. [k] Using the catalyst
solution that was kept at room temperature for three months. THF=
tetrahydrofuran.
Under the optimized reaction conditions (Table 1,
entry 11), the substrate scope was extended. As summarized
in Table 2, all substrates gave the desired a-bromo-b-amino
ketone derivatives in excellent diastereoselectivity
(>99:1 d.r.). The reaction performed well with b-phenyl-
substituted chalcone derivatives, and gave the corresponding
products in nearly quantitative yields with 90–97% ee—
regardless of the electronic nature or the position of the
benzoyl moiety (Table 2, entries 1–12). Moreover, the elec-
tronic nature and the position of the substituents on b-phenyl
group also had little influence on yields and enantioselectiv-
ities (90–99% yield, 94–98% ee; Table 2, entries 16–27).
Furthermore, fused-ring, multi-substituted, and heteroaro-
matic-substituted chalcones were also suitable substrates for
the reaction, and delivered the corresponding products with
up to 99% ee and over 99:1 d.r. (Table 2, entries 13–15, and
28). The substrate with a cinnamyl group still gave good yield
with 99% ee (Table 2, entry 29). Finally, when rigid enones
were subjected to the reaction, the desired vicinal bromo-
amines 2bd and 2be, which have a quarternary carbon center,
were obtained in good yield with 97% ee and over 99:1 d.r.,
respectively (Scheme 2).
Next, the scope of the nucleophile was explored, and the
results were shown in Table 3. In all cases, excellent enantio-
selectivity and diastereoselectivity were obtained regardless
of the nature of substituents on the sulfonyl group. 4-
Methylbenzenesulfonamide, 2-methylbenzenesulfonamide,
and benzenesulfonamide equally gave the corresponding
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Table 2: Substrate scope of chalcones when using TsNH2 and NBS in the
asymmetric bromoamination.
Table 3: Sulfonamide scope in the catalytic asymmetric bromoamination
of chalcone.
Entry[a] R5
Product t [h] Yield [%][b] ee [%][c] d.r.[d]
Entry[a] R3
R4
Product Yield [%][b] ee [%][c]
1
2
3
4-CH3C6H4
2-CH3C6H4
Ph
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-MeOC6H4 4ag
Me 4ah
2aa
4ab
4ac
4ad
4ae
4af
24
24
24
48
48
48
48
48
99
98
97
38
70
46
66
95
96
97
97
94
93
95
97
92
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2aa
2ab
2ac
2ad
2ae
2af
99
98
99
99
99
99
90
92
98
90
91
99
99
98
99
91
97
96
99
93
97
94
93
97
96
91
90
96
96
96
97
96
97
97
90
96
97
95
95
99
95
98
94
96
95
96
96
96
96
95
96
96
97
99
(1R,2R)[e]
97
99
4-CH3C6H4
3-CH3C6H4
4-ClC6H4
3-ClC6H4
4-FC6H4
4-BrC6H4
2-CH3OC6H4 2ah
3-CH3OC6H4 2ai
4-CH3OC6H4 2aj
4-NO2C6H4
3-NO2C6H4
2-naphthyl
3,4-Cl2C6H3
2-fural
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4[e]
5[e]
6[e]
7[e]
8[e]
2ag
9
[a] Unless specified, the reactions were performed with 1aa (0.2 mmol),
L3/ScIII complex (0.05 mol%, 1:1), and M.S. (4 ꢀ, 40 mg) in CH2Cl2
(0.4 mL) at 08C for 5 min, then a mixture of sulfonamide 3 (0.22 mmol)
and NBS (0.24 mmol) was added. [b] Yield of isolated product.
[c] Determined by HPLC on a chiral stationary phase (see the Supporting
Information). [d] Determined by 1H NMR spectroscopy and HPLC using
a chiral stationary phase. [e] 0.5 mol% catalyst loading was used.
10
11
12
13
14
15[d]
16
17
18
19
20
21
22
23
24
25
26
27
2ak
2al
2am
2an
2ao
2ap
2aq
2ar
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
3-MeOC6H4 Ph
3-PhOC6H4 Ph
4-PhC6H4
was still a suitable reagent for the reaction, and produced 4ah
in 95% yield with 92% ee (Table 3, entry 8).
In addition, a,b regioselectivity of the bromoaminated
products has been completely controlled for all these cases.
The regiochemistry was assigned on the basis of the high-
resolution mass spectrometry (HRMS) analysis, which
2as
2at
2au
2av
2aw
2ax
2ay
2az
2ba
Ph
showed
a
prominent signal corresponding to the
4-NO2C6H4 Ph
3-NO2C6H4 Ph
[ArCHNHTs]+ ion fragment. The anti stereoselectivity was
confirmed by converting the vicinal bromoamine 2aa into the
corresponding known trans-aziridine 5aa (Jtrans = 4.0 Hz;
Scheme 3b). The absolute configuration (1R,2R) was unam-
biguously determined by the X-ray crystallographic analysis
of 2ba, which further confirmed the anti stereoselectivity and
regiochemistry assignment.[12]
28
3,4-Cl2C6H3 Ph
PhCH CH
2bb
2bc
96
80
29[f]
Ph
=
[a] Unless specified, the reactions were performed with 1 (0.2 mmol), L3/
ScIII complex (0.05 mol%, 1:1), and M.S. (4 ꢀ, 40 mg) in CH2Cl2 (0.4 mL)
at 08C for 5 min, then a mixture of TsNH2 (0.22 mmol) and NBS
(0.24 mmol) was added, and the reaction mixture was stirred at 08C for
24 h. [b] Yield of isolated product. [c] Determined by HPLC using a chiral
stationary phase (see the Supporting Information). [d] d.r.=98:2.
[e] Absolute configuration was determined by X-ray crystallography of
2ba (see the Supporting Information). [f] d.r. =96:4.
To show the synthetic utility of the catalyst system,
bromoamination of chalcone 1aa was expanded to gram-scale
preparation. As shown in Scheme 3a, the desired synthesis of
bromoamine 2aa was accomplished in 96% yield with
96% ee using only 0.05 mol% of L3/Sc(OTf)3 complex
Scheme 2. Asymmetric bromoamination of rigid enones 1bd and 1be
with NBS and TsNH2.
vicinal bromoamines in nearly quantitative yields with 96–
97% ee (Table 3, entries 1–3). Other benzenesulfonamides
substituted with electron-donating or electron-withdrawing
groups also gave excellent enantioselectivity and moderate
yield (Table 3, entries 4–7). Meanwhile, methanesulfonamide
Scheme 3. The synthetic utility of this catalyst system.
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catalyst. In addition, the a-bromo-b-amino ketone derivative
2aa was easily transformed into the corresponding aziridine
5aa, which is a versatile building block in organic synthesis,[13]
by adding Et3N directly to the reaction system. This protocol
offers an efficient process for the synthesis of the chiral
aziridine (97% yield, 96% ee, > 99:1 d.r.; Scheme 3b).
Preliminary studies of the mechanism were carried out
(see the Supporting Information). Firstly, Michael-type addi-
tion of TsNH2 to the chalcone did not occur in this catalyst
system, thus suggesting that a mechanism involving Michael-
type addition should be excluded. Furthermore, the trans-a-
bromo-b-amino products obtained indicated that the aziridi-
nium-based mechanism[9a] was also unlikely. The observations
of the high anti stereoselectivity and formation of trace
amounts of dibromide product indicate that a possible
bromonium intermediate[4,9e] is likely. Secondly, HRMS
analysis on the catalyst structure showed that [L3/Sc(OTf)]+
was the main fragment ion, and nonlinear effects[14] were not
observed, which indicates that the monomeric catalyst should
be the main catalytically active species. In light of the X-ray
structures of 2ba[12] and the N,N’-dioxide/scandium(III) com-
plex,[15] the oxophilic property of ScIII,[16] and the above
experimental results, a proposed chiral-bromonium-based
mechanism and the transition-state T3 are proposed to
explain the observed sense of asymmetric induction
(Scheme 4).
group. Therefore, attack at the Re face relative to the bromine
atom of NBS through T3 yields the corresponding chiral
bromonium ion T4 and the negatively charged succinimide
ion. Then, the negatively charged p-toluenesulfonamide
would be generated from the negatively charged succinimide
ion by reaction with TsNH2. And immediately, intermolecular
capture of a chiral bromonium ion by the nucleophilic
p-toluenesulfonamide through an SN2 mechanism led to the
desired product 2aa with excellent anti stereoselectivity. The
regioselective outcome can be rationally explained by this
bromonium-based mechanism, because the b position of the
bromonium ion intermediate has more positive charge than
its a position as a result of the stablization effect from phenyl
ring. Furthermore, the observation that 3-(4-methoxyphenyl)-
1-phenylprop-2-en-1-one and 3-(2-methoxyphenyl)-1-phenyl-
prop-2-en-1-one gave poor ee values (see the Supporting
Information), can also be explained on the basis that electron-
rich bromonuim ions may be more easily racemized through
the bimolecular olefin-to-olefin pathway.[10b]
In conclusion, the first highly regio- and enantioselective
bromoamination of chalcones has been developed which
proceeds via an unusual bromonium-based mechanism and
delivers important chiral a-bromo-b-amino ketone deriva-
tives. Excellent results (up to 99% ee, > 99:1 d.r., and nearly
quantitative yields) were obtained using 0.05 mol% of the C2-
symmetric N,N’-dioxide L3/scandium(III) complex under
mild reaction conditions. The remarkable features of the
method, such as low catalyst loading, convenient operation,
and simple procedure allow the practical asymmetric con-
struction of difunctional molecules that are useful for further
synthesis. The insight into the mechanism of the regioselective
changes will provide interesting
In the initial step, two carbonyl oxygen atoms and the N-
oxide oxygen atom of L3, the chalcone, and OTf coordinate
with ScIII to give the transition-state T1. Next, exchange of
OTf with NBS forms the key intermediate T2. In T2 the
Si face of the chalcone was blocked by the bulky phenethyl
and useful information for realiza-
tion of other asymmetric difunc-
tionalization such as bromoamin-
ation of olefins.
Experimental Section
A dry reaction tube was charged with
50 mL (0.05 mol% loading) of catalyst
solution (0.002m L3/Sc(OTf)3 in THF).
After the solvent was removed under
vacuum, chalcone 1aa (0.2 mmol) and
M.S. (4 ꢀ, 40 mg) were weighed into
the tube before CH2Cl2 (0.4 mL) was
added. The mixture was stirred at 358C
for 5 min, and then cooled to 08C.
Finally, a mixture of p-toluenesulfon-
amide (37.5 mg, 0.22 mmol) and N-
bromosuccinimide (NBS, 42.7 mg,
0.24 mmol) was added while stirring.
The reaction mixture was stirred at 08C
for 24 h. The residue was purified by
flash chromatography on silica gel to
afford the desired product.
Received: April 21, 2010
Revised: June 11, 2010
Published online: July 20, 2010
Scheme 4. Proposed catalytic process for bromoamination of chalcone.
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Communications
Chen, J.-F. Wei, M.-Z. Wang, L.-Y. Zhou, C.-J. Zhang, X.-Y. Shi,
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Chen, W. Lei, L.-H. Zhang, M.-Z. Wang, X.-Y. Shi, R.-T. Li, Org.
Lett. 2009, 11, 4216 – 4219.
Keywords: asymmetric catalysis · bromoamination · chalcones ·
scandium · sulfonamides
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