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Chalcogen-Chalcogen Bonding Catalysis Enables Assembly of Discrete Molecules Wei Wang, Haofu Zhu, Shuya Liu, Zhiguo Zhao, Liang Zhang, Jingcheng Hao, and Yao Wang J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03806 • Publication Date (Web): 24 May 2019 Downloaded from http://pubs.acs.org on May 24, 2019
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O
O
H
2 O
O
Me
O
Me
N 1 H
O
Me
H
(Scheme 1). Recent investigation suggests that the binding ability of
R1 Ch R2
Me
H
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Table 1. Substrate Scopea
Me
O Ch = Se, S catalyst (15 mol %) DCE , rt, 15 h
O R2
N
Me
Me
R2 O
O
Me X-ray crystal structure 3 Chalcogen-Chalcogen Bonding Catalysis O
assembly of discrete small molecules
1
R
N H
Ch9 (15 mol %)
O
+ R3
H
NaBF4 or NaBArF4 (0.6-0.8 equiv) Na2SO4, DCE, rt
R1
OTf
Me N S N
Me N S N
O o
O F
Ch0 21 %
Me
O
F
O
Ch1 (0 mol %), no reaction Ch1 (15 mol %), 22% Ch1 (15 mol %), NaBF4 (30 mol %), 48% Ch1 (15 mol %), NaBF4 (30 mol %), Na2SO4 (0.5 g), 71% Ch1 (15 mol %), NaBArF4 (30 mol %), Na2SO4 (0.5 g), 52% Ch1 (0 mol %), NaBF4 (30 mol %), Na2SO4 (0.5 g), no reaction NaBF4 and Na2SO4 were used for catalysts Ch0-Ch10.
Ph Ph Ph P Se Ph Ch1
GaCl4
GaCl4
OMe
Ph Cy Cy P Se Cy
GaCl4
Ph
Ph
P Se
P Se
F3C
3
3
OMe
4, R1 = F, 54%b, c, d 5, R1 = OMe, 50% 6, R1 = OBn, 46% R1
Me Me
O
OTf
GaCl4
N
O
Ch5 59%
Ph
Se
Se
P Ph
Ph
Ph
Ph
Ph P
O Ph P Ph Ph P Ph
Ph Ph
Ch8 73%
Ch7 76%
2GaCl4 Ph P P Ph
P Ph
Se Se
Ph
Me
Me O
Me
Me O
Me
8, 72%
10, R1 = Me, 77% Me 11, R1 = OBn, 63% 1 12, R1 = OMe, 60% R Me N O 13, R1 = F, 59%b, c, d 1 b, c, d O Me14, R = Cl, 68% 15, R1 = Br, 60%b, c, d O Me 16, R1 = Ph, 73%
Me
Me
17, R1 = Me, 81% 18, R1 = OMe, 75% 19, R1 = F, 68%b, c, d O 20, R1 = Cl, 69%b, c, d 1 b, c, d Me 21, R = Br, 73% 22, R1 = 3-furyl, 49% 23, R1 = 2-thienyl, 72% Me
O
N
Me O
Me
Me
9, 45%
R2
O
O
N
O
27, R2 = Et, 62% 28, R2 = i-Pr, 58%b, c, d 29, R2 = cyclopentyl, 61%b, c, d 30, R2 = Ph, 40%b, c, d
O
N
O R3
R3 O
R3
31, R3 = n-Pr, 72%b, c, e 32, R3 = i-Pr, 41%b, c, e 33, R3 = i-Bu, 67%b, c, e
3.50 Å
Ph Ph
aUnless otherwise indicated, reactions were carried out with indole derivative (0.20 mmol), -ketoaldehyde (3.0 mmol), Ch9 (15 mol %, 0.03 mmol), NaBF4 (0.12 mmol, 0.6 equiv), and Na2SO4 (0.50 g) in DCE (2.0 mL) at room temperature. The data are reported as isolated yields. b20 mol % Ch9 was used. cRun in DCM. dRun at 0 oC using NaBArF4 (0.16 mmol, 0.8 equiv). eNaBF (0.16 mmol, 0.8 equiv). DCE: 1,2-dichloroethane, DCM: 4 dichloromethane.
Ch9 78%
3.56 Å
Ph Ph Se Se
O
Me O
N
O
7, 60%, dr: 1:1
24, R1 = Me, 79% 25, R1 = OMe, 47%b, c, d 26, R1 = F, 43%b, c, d
3.50 Å
Ph P
Ph
Se Se
O
Me
2GaCl4
2OTf
Me Me
O
N
Ch6 Br– >> I–.18 In agreement with the trend of Se···halide anion-binding property, the addition of tetrabutylammonium chloride (2 equiv, 0.2 M) to the standard reaction system led to a substantial suppression of the cyclization reaction (< 5% 3, Scheme 1A), as Se···Cl– interaction is more favorable than Se···O bonding. The addition of tetrabutylammonium bromide (2 equiv, 0.2 M) resulted in a considerable decrease in reaction rate while there was relatively lesser effect on the reaction outcome in the presence of tetrabutylammonium iodide (2 equiv, 0.2 M). Furthermore, it was observed that the addition of a catalytic amount (0.4 equiv, 0.04 M) of stronger chalcogen-based bonding competitor, 2,6-dimethyl-pyridine-N-oxide (Se···O– versus Se···O), led to a complete suppression of the desirable transformation. As the noncovalent Se···P interaction has been observed,19 the addition of PPh3 (50 mol %, 0.05 M) to the standard reaction system resulted in a complete suppression of the assemble process, probably owing to the dominance of the noncovalent Se···P interaction over Se···O interaction. As chalcogen-bond is highly directional, we modified chalcogen catalyst Ch1 for comparison (Scheme 1B). The new catalyst Ch11 significantly increases the steric hindrance of the incoming Se···O interaction part while the rest part maintains the same as Ch1. In contrast to Ch1, the steric hindrance in the direction of Se···O interaction led to a substantial decrease in the
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Scheme 2. Achieving Elusive Transformations through Chalcogen-Chalcogen Bonding Catalysis
R1 Ch R2
R2
R1 Se O
R2 O
O
O
a) unprecedented transformation: merely noncovalent force (NF) activates linear unactivated ketones to achieve a chemical transformation under neutral conditions. NF NF
Page 4 of 6 R1 Se
O
NF
R
OH
R
R
inter- or intramolecular reaction
R1 Ch
no precedent
N
R
O
N
Ch7 (15 mol %)
R
N Ac
Me
OH H
R1 Ch
Me
N
O
O
Me M2
O
Me
R1 Ch R2
O
O 35, R = H, 53%, dr > 25:1 36, R = F, 57%, dr > 25:1 37, R = OMe, 65%, dr > 25:1
Me
merely Se···O activation
c) exceptional activation ability of a noncovalent force Me O Ch7 (15 mol %) +
Me
Me
NaBF4 (0.6 equiv) Na2SO4, DCM, rt, Ar
merely Se···O activation
N
N
O Me
38, 57% yield
Based on these significant observations, it can be concluded that these chalcogen-bonding catalysts developed herein have exceptional ability to activate carbonyl groups, thus potentially capable of promoting previously elusive transformations. Indeed, using these chalcogen-bonding catalysts, we achieved two unusual reactions involving linear ketone addition of unsaturated ketones and N-alkylation of indoles under neutral conditions, which significantly expand the capacity of catalysis with noncovalent forces (Scheme 2). It is well-known that merely weak noncovalent forces are extremely difficult to generate enol from linear unactivated ketones (Scheme 2a).3 Enabled by catalyst Ch7, we discovered that Se···O activation of methyl ketone could generate enol which adds to the double bond to give bridged Nheterocycles 35-37 in moderate yields (Scheme 2b). In contrast, the use of routine bases, such as Cs2CO3, KHMDS, generated complex mixtures. Meanwhile, we found that Se···O activation enables achieving a difficult intermolecular aza-Michael reaction involving a weak nucleophile 3-methyl indole addition of unsaturated ketones under neutral conditions. In contrast, analogous intermolecular aza-Michael reaction required using more acidic indoles bearing electron-withdrawing substituent group to generate more nucleophilic nitrogen anion through deprotonation of NH by strong bases (Scheme 2c).20
Scheme 3. Proposed Reaction Pathway
OH dehydration
Me
Me
X-ray crystal structure of 35
Me
Me
O 3rd activation Aldol condensation Me
Me
Me
N H
R1 Se
H
2nd activation Michael addition
Me O isolated intermediate M1
O
OH
O
O
Ac
NaBArF4 (0.6 equiv) Na2SO4, DCE/MeOH, 50 oC, Ar
O O
R2
Me
Me
Me
R1 Se
H
R2
b) uncover a new ability of noncovalent forces
R2
OH O
Me
1st activation functionalization at position 1
R1 Se
H
Me
N H
R2
H
O
O
R1 Se OH O
O
H
R2
R2
O
N
Me
Me
OH
O O
Me
O
O M4
O
intramolecular cyclization
O
N
Me
Me O
Me
OH Me O M3
Based on the experimental results and the observation of intermolecular noncovalent S···O interactions between proteins and drug molecules,4-5 a plausible reaction pathway for the assemble process was proposed (Scheme 3). Initially, upon activation of -ketoaldehyde via Se···O interaction in the presence of a chalcogen catalyst, the condensation of indole with ketoaldehyde occurs to give an isolable intermediate M1, which further undergoes a Michael-addition process with chalcogen catalyst-activated ketoaldehyde to generate intermediate M2. Subsequently, an aldol condensation reaction takes place enabled by a chalcogen catalyst to afford intermediate M3 bearing suitably positioned functional groups. Finally, an intramolecular cyclization and followed by a dehydration process occur to deliver the cyclization product. In summary, a class of powerful chalcogen-bonding catalysts were developed to catalyze assembly of -ketoaldehydes and indoles, generating seven-membered N-heterocycles in a highly efficient manner. Furthermore, chalcogen-chalcogen bonding catalysis can be applied to solve elusive synthetic problems, thus well showing the power and potential of this activation mode. We envisage that this research will stimulate chalcogen-chalcogen bonding catalysis to emerge as a new tool in addressing synthetic problems.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Crystallographic data (CIF) Full experimental procedures and compound characterization (PDF)
AUTHOR INFORMATION Corresponding Author *
[email protected].
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We gratefully acknowledge the National Natural Science Foundation of China (21772113, 21302075), the Natural Science Foundation of Shandong Province (ZR2018ZA0547), the Key Research and Development Plan of Shandong Province (2017GGX70109), the Fundamental Research Funds of Shandong
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Journal of the American Chemical Society University (2017JC004). We thank Prof. Di Sun for assistance with the X-ray crystal structure analysis.
(20) Yang, J.; Lia, T.; Zhou, H.; Li, N.; Xie, D.; Li, Z. Potassium hydroxide catalysed intermolecular aza-Michael addition of 3-cyanoindole to aromatic enones. Synlett 2017, 28, 1227–1231.
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