Highly enantioselective direct michael addition of 1H-benzotriazole to chalcones catalyzed by Sc(OTf)3/N,N′-dioxide complex

Article abstract of DOI:10.1002/ejoc.201100021

The N,N′-dioxide-Sc(OTf)₃ complex was applied in the asymmetric Michael reaction of 1H-benzotriazole with chalcones to give the corresponding N-1 products in excellent yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). Fur

Full text of DOI:10.1002/ejoc.201100021

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100021
Highly Enantioselective Direct Michael Addition of 1H-Benzotriazole to
Chalcones Catalyzed by Sc(OTf)3/N,NЈ-Dioxide Complex
Jing Wang,[a] Wentao Wang,[a] Xiaohua Liu,*[a] Zongrui Hou,[a] Lili Lin,[a] and
Xiaoming Feng*[a]
Keywords: Asymmetric synthesis / Michael addition / Nitrogen heterocycles / Chalcones
The N,NЈ-dioxide–Sc(OTf)3 complex was applied in the
asymmetric Michael reaction of 1H-benzotriazole with chalco-
nes to give the corresponding N-1 products in excellent
yields (up to 99%) with excellent enantioselectivities (up to
99%ee). Further transformation into other optically active
derivatives such as β-benzotriazolyl ester, alcohol, and amide
were also realized with excellent results.
describe a direct asymmetric Michael addition of 1H-
benzotriazole to chalcones by using the Sc(OTf)3/N,NЈ-di-
oxide complex.[10] Excellent results (up to 99% yield and
99%ee) were obtained for a broad range of substrates. The
reaction also featured N-1 adducts as the final products
compared with chiral Al-salen system and chiral primary
amines, which usually afforded a mixture of N-1 and N-2
addition products.[4]
Introduction
Nitrogen-containing heterocycles and their derivatives
have been widely applied in organic and medicinal chemis-
try as well as material science.[1] Catalytic asymmetric ad-
dition of azoles to electron-deficient olefins (e.g., aza-
Michael reaction) provided a protocol for the introduction
of optically active azole moieties that can be found in many
drugs.[2,3] However, to date only a few examples can be
identified. For example, Jacobsen described the chiral Al-
salen catalyzed asymmetric addition reaction of a range of
different aromatic N-heterocycles to α,β-unsaturated
ketones and imides bearing aliphatic β-substituents with
high enantioselectivities.[4] More recently, organocatalytic
nitro-Michael reactions have received considerable atten-
tion. Jørgensen and co-workers reported the conjugate ad-
dition of azoles to aliphatic α,β-unsaturated aldehydes using
a chiral secondary amine.[5] Vicario and co-workers suc-
ceeded in the asymmetric addition of 5-phenyltetrazole to
α,β-unsaturated aldehydes with high enantioselectivity by
using a chiral imidazolidinone as the catalyst.[6] Wang and
co-workers accomplished the addition of azoles to nitro-
alkenes and α,β-unsaturated ketones with moderate to good
enantioselectivities.[7,8] Despite these important contri-
butions, searching for a highly effective catalyst system with
high chemoselectivity and enantioselectivity is still challeng-
ing and interesting. As an excellent chiral scaffold, N,NЈ-
dioxides could coordinate with many metals and exhibited
great potential in many asymmetric reactions.[9] Herein, we
Results and Discussion
Initial attempts were made by treating chalcone 2a with
1H-benzotriazole (1a) under Sc(OTf)3/N,NЈ-dioxide (1:1,
2.5 mol-%) catalysis in CHCl3 at –20 °C (Table 1). It was
revealed that the Sc(OTf)3/N,NЈ-dioxide complex indeed
catalyzed this transformation to give desired N-1 addition
product 3a after 24 h. With regard to the chiral backbone
moiety, N,NЈ-dioxide L3 (derived from l-pipecolic acid) ex-
hibited superior results to L1 (derived from l-proline, Fig-
ure 1) and L2 (derived from l-ramipril acid) in terms of
both yield and enantioselectivity (Table 1, Entry 3 vs. En-
tries 1 and 2). As indicated in Table 1, we found that the
amide moiety in the N,NЈ-dioxide ligand had a significant
effect on the yield of the reaction. Ligand L6 with an elec-
tron-withdrawing group in the para position of aniline pro-
vided a higher yield, whereas L4 with an electron-donating
group and L5 with bulky isopropyl groups led to a signifi-
cant decrease in the yield (Table 1, Entry 6 vs. Entries 4 and
5). Further screening of the reaction conditions identified
that the solvent obviously influenced the formation of ad-
duct 3a (Table 1, Entries 6–8), and the best result (Ͼ99%
yield, 83%ee) was obtained with CHCl3. To improve the
efficiency of the reaction, other reaction conditions such as
the molar ratio of metal to ligand and reaction temperature
were investigated (Table 1, Entries 10–13). Excitingly, a re-
markable improvement was achieved when the molar ratio
[a] Key Laboratory of Green Chemistry & Technology, Ministry
of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China
Fax: +86-28-8541-8249
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100021.
Eur. J. Org. Chem. 2011, 2039–2042
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Wang, W. Wang, X. Liu, Z. Hou, L. Lin, X. Feng
SHORT COMMUNICATION
Sc(OTf)3/L6 was 1.3:1. Lowering the reaction temperature tively). Notably, when the β-substituent R1 was an unsatu-
to –20 °C resulted in an improved enantioselectivity (up to rated cinnamyl group or aliphatic cyclohexyl group,
96%ee; Table 1, Entry 13). Moreover, reducing the catalyst Michael adducts 3o and 3p could also be obtained in mod-
loading to 1 mol-% produced no decrease in ee the value erate yields with 82 and 88%ee, respectively (Table 2, En-
(Table 1, Entry 14).
tries 15 and 16). Significantly, substrates bearing heteroaro-
matic substituents, either in R1 or R2, were also suitable
acceptors for the conjugate addition reaction and afforded
corresponding products 3u–w with good enantioselectivities
(Table 2, Entries 21–23).
Table 1. Optimization of the reaction conditions.[a]
Table 2. Catalytic asymmetric Michael Addition of 1H-benzotri-
azole to chalcones promoted by the Sc(OTf)3/N,NЈ-dioxide com-
plex.[a]
Entry
Ligand
Solvent Metal/Ligand Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhCH3
Et2O
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1.3:1
1.5:1
2:1
1.3:1
1.3:1
71
79
86
31
52
83
89
ND
83
69
62
84
88
88
89
96
96
12
Ͻ5
Ͼ99
9
50
85
Ͼ99
98
95
Ͼ99
80
9
10
11
12
13[d]
14[d,e]
[a] Unless noted otherwise, reactions were carried out with 1H-
benzotriazole (1a, 0.12 mmol), 2a (0.1 mmol), ligand/Sc(OTf)3
(2.5 mol-%), and 5 Å MS (10 mg) in CHCl3 (1.0 mL) under a nitro-
gen atmosphere at 0 °C for 24 h. [b] Yield of isolated product.
[c] Determined by HPLC analysis. [d] The reaction was performed
at –20 °C for 48 h. [e] 1 mol-% of the catalyst was used.
Figure 1. Chiral ligands used in the study.
[a] Unless noted otherwise, reactions were carried out with 1H-
benzotriazole (1a, 0.12 mmol), 2 (0.1 mmol), L6/Sc(OTf)3 (1:1.3,
2.5 mol-%), and 5 Å MS (10 mg) in CHCl3 (1.0 mL) under a nitro-
gen atmosphere at –20 °C. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis. [d] The absolute configuration was deter-
mined to be R by comparison to literature data.[7b] [e] The absolute
configuration was determined to be R by CD spectra.
Under the optimized conditions, a series of chalcone de-
rivatives was examined in the asymmetric Michael reaction
with 1H-benzotriazole,[11] and the corresponding N-1 ad-
ducts were isolated in moderate to excellent yields with ex-
cellent ee values in the range 80–99% (Table 2). It was note-
worthy that this catalyst system exhibited a broad substrate
scope. As shown in Table 2, the electronic nature and the
To show the synthetic utility of the catalyst system, a
position of the substituents at the aromatic ring of R1 or gram-scale synthesis of 3a by using the chiral Sc(OTf)3/
R2 had little influence on the enantioselectivity (Table 2, N,NЈ-dioxide complex was performed. As shown in
Entries 1–14, 17–20). The electronic and stereochemical ef- Scheme 1, by treatment of the starting materials (5 mmol)
fects of the β-aromatic substituents are greater than those under the optimized conditions, excellent results (95% yield
of the aromatic substituents of the carbonyl moiety and 95%ee) were still obtained. Further transformation
(Table 2, Entries 8, 12, and 14 vs. 18, 19, and 20, respec- into other derivatives was also realized (Scheme 2). Baeyer–
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Highly Enantioselective Direct Michael Addition of 1H-Benzotriazole
Villiger oxidation of 3s proceeded with m-CPBA to afford ner to form two six-membered chelate rings. Meanwhile, the
β-benzotriazolyl ester 4 in 80% yield without any racemiza- chalcone is attached to Sc3+ from the favorable side. The
tion. Benzotriazolyl alcohol 5 was then obtained by treat- incoming 1H-benzotriazole prefers to attack the Re face
ment of 4 with NaBH4 in THF in 78% yield. Additionally, rather than the Si face, as the latter is strongly shielded by
exposure of 3s (95%ee) to hydroxylamine hydrochloride in the nearby 4-chorlophenyl group, giving the R configured
pyridine and ethanol for 12 h and subsequent one-pot treat- product.
ment with TsCl afforded β-benzotriazolyl amide 6 in 77%
yield with complete preservation of the enantiopurity
(95%ee).
Conclusions
In conclusion, we have developed an efficient Sc(OTf)3/
N,NЈ-dioxide complex for the asymmetric Michael reaction
of chalcone derivatives and 1H-benzotriazole. Significant
progress has been obtained with a broad substrate scope,
giving chiral N-1 addition compounds in moderate to excel-
lent yields (up to 99%) with excellent enantioselectivities
(up to 99%ee). The reaction could be amplified to gram
scales at 2.5 mol-% catalyst loading without loss of enantio-
selectivity. Further transformation into other derivatives
was also realized with excellent results. Future work will be
Scheme 1. Catalytic asymmetric Michael addition of 1a to 2a on a
gram scale.
To gain insight into the reaction mechanism, C2-symmet-
ric amide L7[13] was synthesized, which was the precursor
of chiral N,NЈ-dioxide L6. As expected, only a trace amount
of adduct was obtained, and with almost all the starting
materials was left unconverted when L7/Sc(OTf)3 was used.
This fact illuminated that the N-oxide and the central metal
played a key role for this reaction. In light of the X-ray
structure of the N,NЈ-dioxide/ScIII complex[10b] and the ex-
perimental results, a proposed transition state rationalizing
the observed sense of asymmetric induction was proposed.
As shown in Figure 2, the N-oxides and the amide oxygen
atoms of L6 are coordinated to Sc3+ in a tetradentate man-
directed to the extension of mechanistic studies and syn-
thetic application.
Experimental Section
Typical Experimental Procedure for the Enantioselective aza-
Michael Reaction: The complex L6/Sc(OTf)3 (1:1.3, 2.5 mol-%),
1H-benzotriazole (1a, 0.12 mmol), and 5 Å molecular sieves
(10 mg) in CHCl3 (1 mL) was stirred in a test tube under a N2
atmosphere at room temperature for 1 h. After the mixture was
cooled to –20 °C, 2a (0.1 mmol) was then added sequentially, and
the reaction mixture was stirred at this temperature. The process
was monitored by TLC. The reaction mixture was purified by col-
umn chromatography on silica gel (ethyl acetate/petroleum ether,
1:4 to 1:6) to give product 3a: 99% yield, 96%ee. HPLC (Chiralpak
AS-H, iPrOH/n-hexane = 30:70, flow rate = 0.8 mL/min, λ =
254 nm): tR = 15.6 (minor), 19.3 (major) min. [α]2D8 = –15.7 (c =
0.21, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J =
8.5 Hz, 1 H), 7.93 (d, J = 8.5 Hz, 2 H), 7.55–7.27 (m, 10 H), 6.54
(dd, J = 9.0, 5.0 Hz, 1 H), 4.84 (dd, J = 18.0, 9.0 Hz, 1 H), 3.81
(dd, J = 18.0, 5.0 Hz, 1 H) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data, copies of the NMR spectra, HPLC
traces, and ellipticity vs. wavelength graphs.
Figure 2. Proposed transition state.
Scheme 2. Synthesis of chiral β-benzotriazolyl ester, β-benzotriazolyl alcohol, and β-benzotriazolyl amide.[12]
Eur. J. Org. Chem. 2011, 2039–2042
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J. Wang, W. Wang, X. Liu, Z. Hou, L. Lin, X. Feng
SHORT COMMUNICATION
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Acknowledgments
We acknowledge the National Natural Science Foundation of
China (Nos. 20732003 and 21021001) and the National Basic Re-
search Program of China (973 Program: No. 2011CB808600) for
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Received: January 7, 2011
Published Online: February 18, 2011
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