Palladium-Catalyzed Carbonylation of β-Arylethylamide Directed by Oxalyl Amide in the Presence of Carbon Monoxide

Article abstract of DOI:10.1021/acs.joc.6b00932

Pd-catalyzed regioselective coupling of β-C(sp²)-H bonds in aromatic amines protected by oxalyl amide with carbon monoxide is reported. The reaction could tolerate various functional groups and could afford good to excellent yields of the corresponding 3,4-dihydroisoquinolinone derivatives. Remarkably, it could also tolerate β-arylethylamino acid and thiopheneethylamine derivatives, thus showing their potential for producing several important units for bioactive compound synthesis.

Full text of DOI:10.1021/acs.joc.6b00932

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Note
Palladium-catalyzed carbonylation of beta-arylethylamide
directed by oxalyl amide in the presence of carbon monoxide
Li Zhang, Chao Wang, Jian Han, Zhi-Bin Huang, and Yingsheng Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00932 • Publication Date (Web): 23 May 2016
Downloaded from http://pubs.acs.org on May 30, 2016
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The Journal of Organic Chemistry
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Palladiumꢀcatalyzed carbonylation of βꢀarylethylamide
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directed by oxalyl amide in the presence of carbon monoxide
Li Zhang, Chao Wang, Jian Han, ZhiꢀBin Huang* and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, China
*Eꢀmail: zbhuang@suda.edu.cn; yszhao@suda.edu.cn
.
ABSTRACT: Pdꢀcatalyzed regioselective coupling of βꢀC(sp2)–H bonds in aromatic amines protected by oxalyl amide with carbon
monoxide is reported. The reaction could tolerate various functional groups and could afford good to excellent yields of the
corresponding 3,4ꢀdihydroisoquinolinones derivatives. Remarkably, it could also tolerate βꢀarylethylamino acid and
thiopheneethylamine derivatives, thus showing their potential for producing several important units for bioactive compound
synthesis.
Over the past decades, transitionꢀmetalꢀcatalyzed direct CꢀH functionalization has become a powerful approach for
forming carbon–carbon and carbon–heteroatom bonds. It provides an alternative route for the synthesis of bioactive
compounds, natural products, and pharmaceutical agents.1–3 Meanwhile, development in the carbonylation of C–H bonds
using CO as the carbon source has also been seen significant progress.4–11 The first carbonylation of arene C–H bond was
reported by Fujiwara group in 1980. Carbonylation of some arenes is carried out in an autoclave utilizing CO (15 atm) and
palladium catalyst, which afforded poor to moderate yields of the corresponding carboxylic acids.12 The method lacked of
regioselectivity with substituted arenes hindered its application, then Some research groups have addressed this problem by
using a directingꢀgroup strategy or special substrates.13 For example, a Pd(OAc)2ꢀcatalyzed selective ethoxycarbonylation
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reactions of arene CꢀH bonds employing diethyl azodicarboxylated together with Oxone or K2S2O8 has been disclosed by
Yu and coꢀworkers in 2008.13a Palladiumꢀcatalyzed oxidative carbonylation of Nꢀsulfonylꢀ2ꢀaminobiaryls via C–H bond
activation has been reported by Chung and Coꢀworkers.13b Yu and coꢀworkers reported a protocol for the carboxylation of
anilides that yielded Nꢀacetylanlin acids.14 Daugulis group developed carbonylation of aminoquinoline benzamides using
cobalt as the catalyst.15 Orito group reported a procedure for benzolactam synthesis via direct carbonylation of
Nꢀalkylꢀωꢀarylalkylamines using a Pd(OAc)2/Cu(OAc)2/air system.16 Similarly, Granell group described free NH2ꢀassisted
carbonylation for preparing benzolactams.17 However, their substrates were limited to quaternary αꢀamino αꢀalkyl esters. A
concurrent study by Gaunt and coꢀworkers reported carbonylation directed by a secondary amine for benzolactam synthesis
using a palladium catalyst.18 Recently years, the oxidative carbonylation of Csp3ꢀH bonds has also achieved. For example, the
Yu group reported the γꢀC–H carbonylation of aliphatic acids by using a combination of a quinolineꢀbased ligand and a
weakly coordinating amide directing group.13c The groups of Wang13d and Zhao13e respectively developed the oxidative
γꢀC(sp3)–H carbonylation reaction to afford the pyrrolidones via the directing group strategy.
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3,4ꢀDihydroisoquinolinones are key synthetic units in many natural products and in biologically active moieties of
pharmaceuticals (Figure 1).19ꢀ20 Examples of such pharmaceuticals include palonosetron A, which is a potent, highly selective
antagonist of the serotonin 5ꢀHT(3) receptor and it has been studied for its use in the prevention of chemotherapyꢀinduced
nausea and vomiting; compound C, an inhibitor of glycogen synthase kinaseꢀ3 compound; and D, which is a potent inhibitor
used in treating thromboembolic disorders. Herein, we report a palladiumꢀcatalyzed CꢀH carbonylation assisted by oxalyl
amide for 3,4ꢀdihydroisoquinolinone synthesis.
Figure 1. Representative drugs from 3, 4ꢀDihydroisoquinolinones
At the outset of our study, we treated βꢀphenylethylamine protected by oxalyl amide 1a with CO (1 atm) in toluene at 100
°C for 5 h, using Pd(OAc)2 as catalyst and AgOAc as oxidant. The desired 3,4ꢀdihydroisoquinolinone 2a was obtained in 72%
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yield. We then used various oxidants, including Cu(OAc)2, 1,4ꢀBenzoquinone, Ag2O, AgOAc, O2, and PhI(OAc)2 (Table 1,
entries 1ꢀ6). The results reveal that AgOAc is indispensable for the carbonylation. It might be the appropriate oxidant to
oxidize the Palladium(0) to Palladium(II) in the catalytic cycle. We subsequently tested different additives to optimize the
yield of 2a. Wellꢀknown additives such as PivOH, AcOH, AcꢀGlyꢀOH, (BnO)2PO2H, MesCO2H, and Na2CO3, afforded 2a in
low yields.21 We found that among the tested additives, benzoic acid gave the best result. Although the role of benzoic acid
remains unclear, it probably takes part in proton transferring and in stabilization of palladium (0) during the catalytic cycle.
During optimization studies, the reaction proceeded cleanly, only 2a and starting material 1a were observed by GC. The
control reaction revealed that no reaction proceeded without the palladium catalyst, indicating the indispensable role of
Pd(OAc)2 in the carbonylation.
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Table 1. Optimization of the Reaction Conditionsa
1 atm CO
10 mol % Pd(OAc)2
2.5 equiv Oxidant
HN
N
OA
OA
0.5 equiv additive
solvent, 100 oC, 5 h
O
2a
1a
entry oxidant
additive
solvent
yield
(%)b
none
none
none
none
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1
Cu(OAc)2
<5
<5
39
72
<5
6
BQ
2
Ag2O
AgOAc
O2
3
4
5
PhI(OAc)2 none
PivOH
6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
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54
62
31
43
58
72
55
76
70
87 (84)c
68
53
32
70
0
Na2CO3
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HOAc
AcꢀGlyꢀOH
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21d
(BnO)2PO2H toluene
MesCO2H
C2H5CO2H
toluene
toluene
mꢀCF3CO2H toluene
toluene
toluene
DCE
9ꢀAnthroic
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
1,4ꢀdioxane
HFIP
PhCF3
toluene
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aConditions: Reaction conditions: 1a (0.2 mmol), CO (1 atm), Pd(OAc)2 (10 mol %), oxidant (2.5 equiv), additive (0.5
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o
b
c
d
equiv)
catalyst.
With the optimized conditions, various βꢀarylethylamines protected by oxalyl amide were examined (Table 2). In general,
,
solvent (1 mL), 100 C, 5 h. GC yield of 2a determined using tridecane as internal standard. Isolated yield. No
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carbonylation proceeded smoothly with substrates bearing electronꢀrich (methyl, methoxy, and methylenedioxy) or
electronꢀwithdrawing (fluoride, chlorides, bromides, and trifluoromethyl) functional groups, affording the corresponding
products in moderate to high yield. The multiple substituted βꢀarylethylamines also have good yields of carbonylation
products. It is worthy to note that the functional group bromide, which could be easily transformed to other functional groups,
was well tolerated (2q, 2x, 2v). Stronger electronꢀwithdrawing substituent afforded lower yield under standard reaction
conditions (2s). Notably, the carbonylation was selective, occurring only at less sterically hindered positions, leading to
single products.
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Table 2. Substrate scope of βꢀarylethylamidea
aReaction conditions: 1a (0.2 mmol), CO (1 atm), Pd(OAc)2 (10 mol %), AgOAc (2.5 equiv), PhCO2H (0.5 equiv), toluene(1
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mL), 100 oC, 5 h.
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To further expand the substrate scope, amino esters protected by oxalyl amide were also subjected to standard conditions.
To our satisfaction, the carbonylation products were obtained in good yields (Table 3). For example, βꢀarylethylamino ester
could be carbonylated well in this transformation (2y, 2z). It is worth to mention that several thiopheneethylamine
derivatives could produce good yields of the corresponding carbonylated products (2aa, 2ab, 2ac).
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Table 3. Substrate Scope of βꢀarylethylamino estera
aReaction conditions: 1a (0.2 mmol), CO (1 atm), Pd(OAc)2 (10 mol %), AgOAc (2.5 equiv), PhCO2H (0.5 equiv), toluene(1
mL), 100 oC, 5 h.
The gramꢀscale reaction was achieved in 82% yield using 5 mol % Pd(OAc)2, CO (1 atm), and toluene at 120 °C for 16 h.
Subsequent removal of oxalylamide under basic conditions afforded 3 in quantitative yield (Scheme 1).
Scheme 1. LargeꢀScale Synthesis and Removal of Directing Group
A plausible mechanism for carbonylation assisted by oxalyl amide is proposed on the basis of our previous studies and
pioneering reports (Scheme 2). In the path A, the palladium complex II could be generated through a concerted
metalation–deprotonation pathway. The combination of one molecule of CO with the Pd(II) center is followed by 1,1
migratory insertion of CO into the PdꢀC bond, which then forms the key palladium intermediate IV. The catalytic cycle
might be undergo a pathway, the palladium complex I combined with one molecular of CO and then with the insertion of CO
generating the palladium complex III (Path B), followed by CꢀH activation, affording the key intermediate IV.This
sevenꢀmembered palladacycle IV then undergoes reductive elimination to the desired product.
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Scheme 2. Proposed Catalytic Cycle
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CONCLUSION
In summary, we have developed a practical approach for the synthesis of 3,4ꢀdihydroisoquinolinone derivatives from
βꢀarylethylamines protected by oxalyl amide, using palladium as catalyst under 1 atm CO. The reaction could tolerate
various functional groups and could afford good to excellent yields of the corresponding 3,4ꢀdihydroisoquinolinones
derivatives. Remarkably, it could also tolerate βꢀarylethylamino acid and thiopheneethylamine derivatives, thus showing
their potential for producing several important units for bioactive compound synthesis
.
EXPERIMENTAL SECTION
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. HRMS
analysis were carried out using TOFꢀMS instrument with ESI source. Multiplicities are recorded as: s = singlet, d = doublet, t
= triplet, dd = doublet of doublets, m = multiplet. General procedures for the synthesis of products are represented as
follows:
General Procedure for Palladiumꢀcatalyzed carbonylation of γꢀC(sp2)–H bonds (Table 2ꢀ3) (2aꢀ2z, 2aaꢀ2ac). A mixture
of oxalamide (0.2 mmol, 1.0 eq), Pd(OAc)2 (4.5 mg, 0.1 eq), AgOAc (83.4 mg, 2.5 eq), PhCO2H (12.2 mg, 0.5 eq) and
toluene (0.5 mL) in a 20 mL glass vial was purged with CO (3ꢀtimes), and sealed with a teflon septa. The vial was heated at
100 oC in an oil bath for 5 hours, then the reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue
was purified by column chromatography on silica gel to give the product 2.
N,N-diisopropyl-2-oxo-2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (2a). Purified by column chromatography on
silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 84% (50.8 mg); pale yellow soild; mp = 118–121°C; 1H
NMR (400 MHz, CDCl3) δ 8.12 (t, J = 6.7 Hz, 1H), 7.57–7.47 (m, 1H), 7.36 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.35 (s, 1H),
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3.82 (s, 1H), 3.69ꢀ3.58 (m, 1H), 3.57–3.44 (m, 1H), 3.16 (s, 1H), 3.00 (s, 1H), 1.52 (s, 6H), 1.25 (s, 6H); 13C NMR (101
MHz,CDCl3) δ 167.1, 164.6, 163.8, 140.1, 134.0, 129.7, 127.8, 127.6, 127.5, 51.1, 45.7, 41.1, 27.8, 20.2, 19.9; HRMS Calcd
for C17H22N2O3Na [M+Na+]: 325.1528; Found: 325.1535.
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N,N-diisopropyl-2-(5-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide
(2b).
Purified
by
column
8
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chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 90% (56.9 mg); pale yellow solid;
mp = 159–161 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H),
4.36 (s, 1H), 3.79 (s, 1H), 3.68–3.61 (m, 1H), 3.56–3.49 (m, 1H), 3.00 (d, J = 5.2 Hz, 2H), 2.33 (s, 3H), 1.53 (s, 6H), 1.26 (s,
6H); 13C NMR (101 MHz, CDCl3) δ 167.0, 164.8, 163.8, 138.6, 135.4, 135.3, 127.9, 127.6, 126.9, 51.1, 45.7, 40.4, 24.7,
20.2, 19.9, 19.1; HRMS Calcd for C18H24N2O3Na [M+Na+]: 339.1685; Found: 339.1684.
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N,N-diisopropyl-2-(5-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamideo) (2c). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an eluent; Yield 74% (49.2 mg); pale yellow solid;
mp = 142–145 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H),
4.33 (s, 1H), 3.87 (s, 3H), 3.78 (s, 1H), 3.66–3.60 (m, 1H), 3.55–3.48 (m, 1H), 3.08 (s, 1H), 3.01 (s, 1H), 1.53 (s, 6H), 1.25
(d, J = 3.5 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 167.1, 164.6, 163.8, 155.8, 129.0, 127.8, 121.3, 115.10, 55.9, 51.1, 45.7,
40.7, 21.2; HRMS Calcd for C18H24N2O4Na [M+Na+]: 355.1634; Found: 355.1641.
2-(6,7-dimethoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide (2d). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (4/1) as an eluent; Yield 70% (50.68 mg); pale yellow solid;
mp = 179–182 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 6.66 (s, 1H), 4.35 (s, 1H), 3.91 (d, J = 9.8 Hz, 6H), 3.75 (d, J
= 9.1 Hz, 1H), 3.61–3,61 (m, 1H), 3.55–3.48 (m, 1H), 3.11 (s, 1H), 2.89 (s, 1H), 1.54 (s, 3H), 1.51 (s, 3H),1.24 (m, 6H); 13
C
NMR (101 MHz, CDCl3) δ 167.0, 164.2, 163.9, 153.8, 148.4, 134.8, 120.0, 111.2, 109.5, 56.3, 51.1, 45.7, 41.3, 27.5, 20.5,
20.3, 19.9, 19.7; HRMS Calcd for C19H26N2O5Na [M+Na+]: 385.1739; Found: 385.1730.
N,N-diisopropyl-2-oxo-2-(5-oxo-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)acetamide (2e). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (5/1) as an eluent; Yield 78% (53.9 mg); pale yellow solid;
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mp = 168–169 °C; H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 6.67 (s, 1H), 6.03 (s, 2H), 4.34 (s, 1H), 3.75 (s, 1H),
3.66ꢀ3.59 (m, 1H), 3.54–3.57 (m, 1H), 3.08 (s, 1H), 2.99–2.80 (m, 1H), 1.52 (s, 6H), 1.24 (d, J = 14.9 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 167.1, 163.9, 152.6, 147.5, 136.9, 121.7, 108.9, 107.3, 102.1, 51.1, 45.7, 41.1, 28.0, 20.3, 20.1, 19.8,
19.6, 20.1; HRMS Calcd for C18H22N2O5Na [M+Na+]: 369.1429; Found: 369.1453.
2-(6,7-dimethyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide (2f). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 80% (52.8 mg); pale yellow solid;
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mp = 174–175 °C; H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.01 (s, 1H), 4.32 (s, 1H), 3.77 (s, 1H), 3.66–3.59 (m, 1H),
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3.54–3.47 (m, 1H), 3.08 (s, 1H), 2.90 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 1.53 (s, 6H), 1.24 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 167.2, 164.8, 163.9, 143.9, 137.8, 136.2, 130.4, 128.8, 125.3, 51.1, 45.7, 41.3, 27.4, 20.2, 19.4; HRMS Calcd for
C19H26N2O3Na [M+Na+]: 353.1841; Found: 353.1852.
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N,N-diisopropyl-2-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide (2g). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (5/1) as an eluent; Yield 89% (59.1 mg); pale yellow solid;
mp = 163–164 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.8, 2.0 Hz, 1H), 6.71 (d, J = 2.0 Hz,
1H), 4.37 (s, 1H), 3.86 (s, 3H), 3.76 (s, 1H), 3.66–3.60 (m, 1H), 3.54–3.47 (m, 1H), 3.15 (s, 1H), 2.94 (s, 1H), 1.52 (d, J =
15.0 Hz, 6H), 1.25 (s, 6H); 13C NMR (101 MHz,CDCl3) δ 167.1, 164.3, 163.9, 142.6, 132.2, 120.5, 113.6, 112.2, 55.7, 51.1,
45.7, 41.1, 28.3; HRMS Calcd for C18H24N2O4Na [M+Na+] 355.1634; Found: 355.1622.
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N,N-diisopropyl-2-(6-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide (2h).
Purified
by column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 78% (49.3 mg); pale yellow solid;
1
mp = 162–164 °C; H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 4.34 (s,
1H), 3.79 (s, 1H), 3.66–3.60 (m, 1H), 3.55–3.48 (m, 1H), 3.12 (s, 1H), 2.94 (s, 1H), 2.39 (s, 3H), 1.53 (s, 6H), 1.25 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 167.2, 164.6, 163.9, 145.1, 140.2, 129.9, 128.5, 128.2, 125.3, 51.1, 45.8, 41.2, 27.9, 21.9;
HRMS Calcd for C18H24N2O3Na [M+Na+]: 339.1689; Found: 339.1694.
N,N-diisopropyl-2-(7-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide (2i). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 78% (51.1 mg); pale yellow solid;
mp = 145–148 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.4, 2.7 Hz,
1H), 4.31 (s, 1H), 3.84 (s, 4H), 3.67–3.60 (m, 1H), 3.55–3.49 (m, 1H), 3.03 (s, 1H), 2.99ꢀ2.84 (m, 1H), 1.53 (s, 6H), 1.26 (s,
6H); 13C NMR (101 MHz, CDCl3) δ 167.1, 164.6, 163.8, 159.0, 132.6, 128.8, 121.9, 112.4, 55.8, 51.1, 45.8, 41.4, 27.0;
HRMS Calcd for C18H24N2O4Na [M+Na+]: 355.1634; Found: 355.1646.
N,N-diisopropyl-2-(7-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide
(2j).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent; Yield 75% (47.4 mg); pale yellow solid;
mp = 127–129 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.4, 2.7
Hz, 1H), 4.31 (s, 1H), 3.84 (s, 4H), 3.67–3.60 (m, 1H), 3.55–3.48 (m, 1H), 3.11 (s, 1H), 2.95 (s, 1H), 2.37 (s, 3H), 1.53 (s,
6H), 1.26 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 167.1, 164.6, 163.8, 159.0, 132.6, 128.8, 121.9, 112.6, 55.8, 51.1, 45.7,
41.4, 27.0; HRMS Calcd for C18H24N2O3Na [M+Na+]: 339.1685; Found: 339.1692.
N,N-diisopropyl-2-(7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide
(2k).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (3/1) as an eluent; Yield 72% (49.9 mg); pale yellow solid;
mp = 209ꢀ210 °C; 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.4, 2.4 Hz, 1H), 7.49 (d, J = 8.4 Hz,
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1H), 4.43 (s, 1H), 3.82 (s, 1H), 3.69–3.61 (m, 1H), 3.58–3.49 (m, 1H), 3.21 (s, 2H), 1.52 (d, J = 5.9 Hz, 6H), 1.28 (d, J = 5.7
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.6, 163.2, 162.8, 147.7, 146.6, 129.3, 128.1, 125.0, 51.3, 45.9, 40.5, 28.0;
HRMS Calcd for C17H21N3O5Na [M+Na+]: 370.1379; Found: 370.1392.
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2-(2-(diisopropylamino)-2-oxoacetyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-ylacetate (2l). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 72% (51.8 mg); pale yellow solid;
mp = 148–150 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.2 Hz, 1H), 7.30 – 7.23 (m, 2H), 4.37 (s, 1H), 3.78 (s, 1H),
3.63–3.57 (m, 1H), 3.54–3.47 (m, 1H), 3.13 (s, 1H), 3.00 (s, 1H), 2.29 (s, 3H), 1.51 (s, 6H), 1.24 (d, J = 5.3 Hz, 6H); 13C
NMR (101 MHz, CDCl3) δ 169.4, 167.0, 163.8, 163.6, 150.0, 137.6, 129.0, 127.5, 122.7, 51.1, 45.8, 41.1, 27.3, 21.0; HRMS
Calcd for C19H24N2O5Na [M+Na+]: 383.1583; Found: 383.1589.
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N,N-diisopropyl-2-(4-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoacetamide (2m). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an eluent; Yield 92% (58.1 mg); pale yellow oil; 1H
NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 0.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 4.22
(s, 1H), 3.83 (s, 1H), 3.66 (s, 1H), 3.55–3.49 (m, 1H), 3.20 (s, 1H), 1.53 (s, 6H), 1.38 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.5 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 164.3, 163.6, 133.9, 129.6, 127.1, 50.9, 45.5, 19.5; HRMS Calcd for C18H24N2O3Na
[M+Na+]: 339.1685; Found: 339.1689.
2-(5-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamidea (2n). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 70% (44.8 mg); pale yellow solid;
mp = 162–165 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.37 (dd, J = 13.3, 7.9 Hz, 1H), 7.33 – 7.28 (m,
1H), 4.41 (s, 1H), 3.82 (s, 1H), 3.68–3.62 (m, 1H), 3.57–3.50 (m, 1H), 3.12 (s, 2H), 1.54 (d, J = 4.7 Hz, 6H), 1.28 (d, J = 6.0
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.9, 163.8, 163.5, 159.0 (d, JCꢀF = 240.0 Hz), 129.8 (d, JCꢀF = 4.0 Hz), 128.4 (d,
JCꢀF = 8.0 Hz), 127.3 (d, JCꢀF = 190.0 Hz), 125.4 (d, JCꢀF = 3.0 Hz), 120.7 (d, JCꢀF = 8.0 Hz), 120.5, 51.2, 45.8, 40.5, 20.7;
HRMS Calcd for C17H21FN2O3Na [M+Na+]: 343.1434; Found: 343.1444.
2-(5-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2o).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (9/1) as an eluent; Yield 68% (45.7 mg); pale yellow solid;
mp = 172–173 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 7.8, 0.9 Hz, 1H), 7.60 (dd, J = 8.0, 1.2 Hz, 1H), 7.33 (t, J =
7.9 Hz, 1H), 4.36 (s, 1H), 3.83 (s, 1H), 3.66–3.60 (m, 1H), 3.55–3.49 (m, 1H), 3.18 (s, 2H), 1.52 (d, J = 5.8 Hz, 6H), 1.26 (d,
J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.2, 163.2, 162.9, 137.4, 133.9, 132.5, 129.2, 127.7, 50.6, 45.2, 39.6, 24.6;
HRMS Calcd for C17H21ClN2O3Na [M+Na+] 359.1138; Found: 359.1147.
2-(5,7-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide (2p). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (10/1) as an eluent; Yield 48% (35.5 mg); pale yellow solid;
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mp = 208–210 °C; H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 4.39 (s, 1H), 3.78 (s,
1H), 3.65–3.58 (m, 1H), 3.56–3.49 (m, 1H), 3.15 (s, 2H), 1.51 (d, J = 5.9 Hz, 6H), 1.26 (d, J = 6.2 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 166.7, 163.3, 162.9, 136.5, 134.1, 130.7, 128.3, 127.1, 51.2, 45.9, 40.2, 24.9; HRMS Calcd for
C17H20Cl2N2O3Na [M+Na+]: 393.0749; Found: 393.0762.
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2-(5-bromo-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2q).
Purified
by
column
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chromatography on silica gel with petroleum ester/ethyl acetate (10/1) as an eluent; Yield 60% (45.6 mg); pale yellow solid;
mp = 175–177 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (m, 1H), 7.77 (m, 1H), 7.26 (d, J = 15.8 Hz, 1H), 4.36 (s, 1H), 3.82 (s,
1H), 3.68–3.58 (m, 1H), 3.57–3.47 (m, 1H), 3.18 (s, 2H), 1.52 (s, 6H), 1.26 (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 166.8, 163.8, 163.5, 139.8, 137.8, 129.9, 129.1, 128.6, 123.4, 51.2, 45.9, 40.3, 28.1, 20.1, 20.0; HRMS Calcd for
C17H21BrN2O3Na [M+Na+]: 403.0633; Found: 403.0642.
2-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2r).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 69% (44.2 mg); pale yellow solid;
mp = 168–171 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.37 (dd, J = 13.3, 7.9 Hz, 1H), 7.33 – 7.28 (m,
1H), 4.41 (s, 1H), 3.82 (s, 1H), 3.68–3.62 (m, 1H), 3.57–3.50 (m, 1H), 3.12 (s, 2H), 1.54 (d, J = 4.7 Hz, 6H), 1.28 (d, J = 6.0
Hz, 6H);13C NMR (101 MHz, CDCl3) δ 166.9, 166.6, 164.4, 163.3 (d, JCꢀF = 2 Hz), 142.9 (d, JCꢀF = 10 Hz), 132.5 (d, JCꢀF
=
10 Hz), 123.9 (d, JCꢀF = 3 Hz), 114.8 (d, JCꢀF = 22 Hz), 114.1 (d, JCꢀF = 22 Hz), 50.8, 45.4, 40.6, 27.6; HRMS Calcd for
C17H21FN2O3Na [M+Na+]: 343.1434; Found: 343.1441.
N,N-diisopropyl-2-oxo-2-(1-oxo-6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide (2s). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 57% (42.2 mg); pale yellow solid;
mp = 116–119 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 4.36 (s, 1H),
3.88 (s, 1H), 3.64 (m, 1H), 3.53 (m, 1H), 3.17 (s, 2H), 1.53 (d, J = 6.1 Hz, 6H), 1.27 (d, J = 6.3 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 166.2, 162.9, 162.8, 140.2, 134.7 (d, JCꢀF = 33 Hz), 130.4, 129.8, 124.2 (d, JCꢀF = 4 Hz), 123.8 (d, JCꢀF = 4
Hz), 122.9 (d, JCꢀF = 271 Hz), 50.6, 45.3, 40.3, 27.2; HRMS Calcd for C18H21F3N2O3Na [M+Na+]: 393.1402; Found:
393.1397.
2-(6,7-dichloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide (2t). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (7/1) as an eluent; Yield 79% (58.5 mg); pale yellow solid;
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mp = 196–197 °C; H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.39 (s, 1H), 4.37 (s, 1H), 3.78 (s, 1H), 3.65–3.58 (m, 1H),
3.55–3.48 (m, 1H), 3.05 (d, J = 40.3 Hz, 2H), 1.51 (d, J = 5.5 Hz, 6H), 1.26 (d, J = 6.0 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 166.8, 163.4, 163.0, 139.5, 138.5, 132.4, 131.5, 129.7, 127.6, 51.2, 45.9, 40.9, 27.2 ;HRMS Calcd for C17H20Cl2N2O3Na
[M+Na+]: 393.0749; Found: 393.0759.
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2-(6-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2u).
Purified
by
column
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3
4
5
6
7
8
9
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 71% (47.7 mg); pale yellow solid;
mp = 135–138 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H), 7.32 (m, 1H), 7.25 (s, 1H), 4.35 (s, 1H), 3.78 (s,
1H), 3.60 (m, 1H), 3.51 (m, 1H), 3.13 (s, 1H), 2.99 (s, 1H), 1.51 (s, 6H), 1.24 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 166.8,
163.8, 163.6, 141.8, 140.4, 131.3, 128.0, 127.7, 126.3, 51.2, 45.8, 40.9, 27.7, 20.0; HRMS Calcd for C17H21ClN2O3Na
[M+Na+]: 359.1138; Found: 359.1146.
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2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2v).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (8/1) as an eluent; Yield 27% (20.5 mg); pale yellow solid;
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mp = 183–184 °C; H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 1H), 7.51 (m 1H), 7.44 (s, 1H), 4.36 (s, 1H), 3.80 (s,
1H), 3.62 (m, 1H), 3.51 (m, 1H), 3.16 (s, 1H), 2.98 (s, 1H), 1.52 (s, 6H), 1.25 (d, J = 3.4 Hz, 6H); 13C NMR (101
MHz,CDCl3) δ 166.9, 164.0, 163.6, 141.9, 131.4, 131.1, 130.8, 129.2, 126.8, 51.2, 45.8, 40.9, 27.6, 20.3, 20.0; HRMS Calcd
for C17H21BrN2O3Na [M+Na+]: 403,0633; Found: 403,0645.
2-(7-chloro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide (2w).
Purified
by column
chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 78% (52.4 mg); pale yellow solid;
mp = 168–170 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.1, 2.2 Hz, 1H), 7.22 (d, J = 8.1 Hz,
1H), 4.36 (s, 1H), 3.78 (s, 1H), 3.65ꢀ3.58 (m, 1H), 3.55ꢀ3.48 (m, 1H), 3.10 (s, 1H), 3.00 (s, 1H), 1.52 (s, 6H), 1.25 (d, J = 5.5
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.9, 163.6, 138.4 (s), 133.9, 133.7, 129.6, 129.0, 51.2, 45.8, 41.02, 27.3; HRMS
Calcd for C17H21ClN2O3Na [M+Na+]: 359.1138; Found: 359.1148.
2-(7-bromo-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-diisopropyl-2-oxoacetamide
(2x).
Purified
by
column
chromatography on silica gel with petroleum ester/ethyl acetate (5/1) as an eluent; Yield 65% (49.4 mg); pale yellow solid;
mp = 169–171 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.1, 2.1 Hz, 1H), 7.16 (d, J = 8.1 Hz,
1H), 4.37 (s, 1H), 3.79 (s, 1H), 3.67–3.59 (m, 1H), 3.56–3.49 (m, 1H), 3.09 (s, 1H), 2.98 (s, 1H), 1.53 (s, 6H), 1.26 (d, J =
5.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 166.3, 162.9, 138.3, 136.2, 131.9, 129.0, 128.8, 120.8, 50.6, 45.2, 40.4, 30.5,
26.8; HRMS Calcd for C17H21BrN2O3Na [M+Na+]: 403.0633; Found: 403.0645.
methyl2-(2-(diisopropylamino)-2-oxoacetyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2y). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 80% (57.6 mg); pale yellow solid;
mp = 137–138 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.8 Hz, 1H), 7.52 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24 (d, J
= 7.6 Hz, 1H), 5.46 (d, J = 4.7 Hz, 1H), 3.81 (d, J = 3.9 Hz, 1H), 3.64 (s, 3H), 3.58–3.39 (m, 3H), 1.59 (d, J = 6.8 Hz, 3H),
1.51 (d, J = 6.7 Hz, 3H), 1.32 (d, J = 6.5 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.3, 166.9,
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163.5, 163.4, 136.6, 134.4, 129.8, 128.1, 127.9, 127.3, 53.2, 50.9, 45.8, 30.1, 20.6, 20.4, 19.8, 19.6; HRMS Calcd for
C19H24N2O5Na [M+Na+]: 383.1583; Found: 383.1589.
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5
methyl-7-acetoxy-2-(2-(diisopropylamino)-2-oxoacetyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2z). Purified
6
7
by column chromatography on silica gel with petroleum ester/ethyl acetate (3/1) as an eluent; Yield 82% (68.6 mg); pale
1
8
9
yellow solid; mp = 152–153 °C; H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.28 (d, J = 2.3 Hz, 2H), 5.46 (s, 1H), 3.80 (s,
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1H), 3.66 (s, 3H), 3.57–3.50 (m, 1H), 3.48 (d, J = 3.5 Hz, 2H), 2.29 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H),
1.31 (d, J = 6.5 Hz, 3H), 1.22 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 149.7, 133.4, 128.5, 127.29, 122.0, 52.7,
52.5, 50.3, 45.2, 28.9, 20.5, 19.9, 19.6, 19.5, 19.1; HRMS Calcd for C21H26N2O7Na [M+Na+]: 441.1638; Found: 441.1643.
N,N-diisopropyl-2-oxo-2-(4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetamide (2aa). Purified by column
chromatography on silica gel with petroleum ester/ethyl acetate (4/1) as an eluent; Yield 71% (43.7 mg); pale yellow solid;
mp = 114–117 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 4.56 (s, 1H), 3.85 (s, 1H),
3.70–3.58 (m, 1H), 3.56–3.44 (m, 1H), 3.20 (s, 1H), 3.14 (s, 1H), 1.51 (s, 6H), 1.25 (s, 6H); 13C NMR (101 MHz, CDCl3) δ
167.1, 163.7, 160.7, 150.5, 131.2, 126.7, 124, 51.1, 45.7, 42.2, 24.3, 20.5, 19.8; HRMS Calcd for C15H20N2O3SNa [M+Na+]:
331.1092; Found: 331.1101
methyl 5-(2-(diisopropylamino)-2-oxoacetyl)-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylate (2ab). Purified
by column chromatography on silica gel with petroleum ester/ethyl acetate (6/1) as an eluent; Yield 75% (54.9 mg); pale
yellow solid; mp = 157–158 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 5.59 (d, J
= 5.4 Hz, 1H), 3.89–3.78 (m, 1H), 3.74–3.65 (m, 4H), 3.55ꢀ3.47 (m, 2H), 1.57 (d, J = 6.7 Hz, 3H), 1.49 (d, J = 6.3 Hz, 3H),
1.32 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.4, 162.8, 158.8, 146.5, 130.4, 126.2,
124.5, 53.6, 52.8, 50.3, 45.2, 25.9, 20.0, 19.9, 19.2, 19.0; HRMS Calcd for C17H22N2O5SNa [M+Na+]: 389.1147; Found:
389.1149.
methyl2-bromo-5-(2-(diisopropylamino)-2-oxoacetyl)-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-6-carboxylate (2ac).
Purified by column chromatography on silica gel with petroleum ester/ethyl acetate (5/1) as an eluent; Yield 72% (63.9 mg);
pale yellow solid; mp = 172–174 °C; 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 5.55 (d, J = 5.5 Hz, 1H), 3.83–3.75 (m, 1H),
3.72 (s, 3H), 3.60 (d, J = 17.2 Hz, 1H), 3.51 (dd, J = 13.7, 6.8 Hz, 1H), 3.42 (dd, J = 17.3, 6.3 Hz, 1H), 1.54 (d, J = 6.8 Hz,
3H), 1.48 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 166.0,
162.6, 157.5, 147.5, 131.0, 128.4, 111.7, 53.3, 52.9, 50.3, 45.2, 26.0, 20.0, 19.7, 19.0; HRMS Calcd for C17H21BrN2O5SNa
[M+Na+]: 467.0252; Found: 467.0266.
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Gram-Scale Preparation of 2a (Scheme 1) A mixture of oxalamide (1.0 g, 3.6 mmol, 1.0 equiv), Pd(OAc)2 (40.8 mg, 0.05
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equiv), AgOAc (1.5 g, 2.5 equiv), PhCO2H (221 mg, 0.5 equiv) and toluene (20 mL) in a 100 mL glass vial was purged with
o
CO (3ꢀtimes) and CO ballon, sealed with a teflon septa. The vial was heated at 120 C in an oil bath for 16 hours, then the
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reaction mixture was cooled to rt, and concentrated in vacuo. The resulting residue was purified by column chromatography
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on silica gel to give the product 2a as a pale yellow solid (1.09 g) in 82% yield.
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Gram-Scale Preparation of 3 (Scheme 1) Compound 2a (0.15 g, 0.5 mmol, 1.0 equiv) was dissolved in a mixture of
THF/MeOH (0.4/0.1 mL). NaOH (80 mg, 2.0 mmol, 4.0 equiv) was added later. The mixture was heated at 80 °C for 24 h
and then diluted with water (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with
brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to give the desired product 3 (68.4 mg) as a pale yellow oil in 93% yield.
3,4-dihydroisoquinolin-1(2H)-one (3). Purified by column chromatography on silica gel with petroleum ester/ethyl acetate
(2/1) as an eluent; Yield 93% (68.4 mg); pale white solid; mp = 61ꢀ63 °C; 1H NMR (400 MHz, CDCl3) δ 8.07–8.05 (m, 1H),
7.46–7.42 m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.74 (s, 1H), 3.69ꢀ3.55 (m, 2H), 2.99 (t, J = 6.6 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 166.6, 139.0, 132.3, 129.1, 128.1, 127.3, 40.3, 28.0; HRMS Calcd for C9H9NONa [M+Na+]:
170.0582; Found: 170.0585.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported financially by the Natural Science Foundation of China (NO. 21572149) and the Young
National Natural Science Foundation of China (NO. 21403148). The support of PAPD is also greatly acknowledged.
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