DBU-Promoted [4 + 4] Domino Cycloaddition of Ynones with

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DBU-Promoted [4+4]-Domino Cycloadditon of Ynones with Benzylidenepyrazolones to Access Eight-Membered Cyclic Ethers Cheng Cheng, Jiayong Zhang, Xue Wang, and Zhiwei Miao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00352 • Publication Date (Web): 27 Apr 2018 Downloaded from http://pubs.acs.org on April 27, 2018

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The Journal of Organic Chemistry

DBU-Promoted [4+4]-Domino Cycloadditon of Ynones with Benzylidenepyrazolones to Access Eight-Membered Cyclic Ethers Cheng Cheng†, Jiayong Zhang†, Xue Wang†, and Zhiwei Miao*,†,‡,ζ †

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Weijin Road 94, Tianjin 300071, China

‡

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China ζ

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology

(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China R3

O

O R2 R1

DBU(150 mol%)

R3 R4

N N

DCM, r.t., Time

R2

R4 N

O

O N R1 Ph Yield: 34-99%

R1 = aryl, 2-thienyl, biphenyl R2 = H, Me R3 = phenyl, aryl, 2-thienyl, 2-furyl,2-naphthyl R4 = Me, phenyl

ABSTRACT An efficient DBU-promoted [4+4] domino annulation reactions of ynones and benzylidenepyrazolones has been developed. This process resulted finally in the formation of an eight-membered cyclic ethers in moderate to good yields. The easy availability of starting materials and the simple cyclization procedure make this approach suitable for the preparation of a wide range of useful oxocino [2,3-c] pyrazoles. INTRODUCTION Eight-membered cyclic ethers are privileged structural motifs which are often

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found in natural products and biologically active molecules (Figure 1).1 For example, (+)-(3E)-Pinnatifidenyne2 and (+)-Laurencin 13 are red algae metabolite which is a structural milestone of numerous marine natural products. (+)-Heliannuol A is a naturally occurring sesquiterpenoid exhibiting strong allelopathic activity.4 Because such compounds have shown great potential in drug discovery, the synthesis of such medium-ring heterocycles has attracted much attention from the organic and biological community.5 To gain access to such molecular architectures, a key synthetic challenge is how to effectively construct the eight-membered rings. In comparison with five to seven-membered rings, the construction of eight-membered rings has been much less explored so far and still remains a great challenge.6 Cl

OAc O

Br

O H H

HO O

OH

Br (+)-(3E)-Pinnatifidenyne

(+)-Laurencin 1

(+)-Heliannuol A

Figure 1. Representative examples of eight-membered ethers possessing biological activities

In spite of the obstacles, several strategies have been reported to construct the medium-ring structures, such as ring-closing metathesis,7 ring expansion,8 intramolecular alkylation,9 retro-Claisen rearrangement,10 and others.11 However, the diversity of the existing methods still lags behind considering the high importance of such medium-ring cyclic ether natural products. Especially, these synthetic methods are mainly concentrated on the intramolecular cyclization. Therefore, developing highly efficient synthetic methods to build such compounds with medium-sized rings is still of great significance and is highly desirable.


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In 2015, Huang reported an efficient method for the construction of functionalized eight-membered cyclic ethers through DABCO-mediated [4+4] domino annulation reactions of ynones and α-cyano-α,β-unsaturated ketones.12 Recently, Lu, Ullah and co-workers reported the enantioselective phosphine-catalyzed [4+4] annulation of α,β-unsaturated imines and allene ketones for the construction of benzofuran- or indole-fused azocines.13 Lewis base catalyzed domino reactions has been demonstrated to be a versatile tool in organic synthesis.14 DABCO is widely used as a Brφnsted base or Lewis base in domino reactions.15 More recently literatures report DABCO promoted process, where ynones could be used as a C3 or C4 synthon to furnish various annulation reactions.16 Along this line of reasoning, we envisioned that electrophilic partners α,β-unsaturated pyrazolones and suitable ynones may be employed as annulation partners. Herein, we document an unprecedented DBU-promoted

formed

[4+4]

annulation

reaction

between

α,β-unsaturated

pyrazolones and ynones, thus leading to facile construction of eight-membered cyclic ethers. RESULTS AND DISCUSSION Initially,

the

reaction

of

4-phenylbut-3-yn-2-one

1a[17]

and

4-benzylidene-5-methyl-2-phenylpyrazolone 2a[18] was employed as the model reaction to investigate the optimal reaction conditions. To our great delight, in the presence of 100 mol% DABCO in DCM at room temperature, after 1h, the desired product was isolated in 21% yield (Table 1, entry 1). Attempts to improve the yield by employing other nitrogen-containing Lewis bases turned out to be unavailing. The use



of DMAP, Et3N, DIPEA, and TMEDA failed to give any product (Table 1, entries 2-5). Further investigations showed that DBU gave better yield for the desired product 3a compared to DABCO (Table 1, entry 6). Subsequently, other solvents, such as CHCl3, toluene, AcOEt, THF, Et2O, and CH3CN were screened, of which DCM was found to be suitable as the medium (Table 1, entries 7-12). Changing the ratio of the substrates in DCM improved the yield to 82% (Table 1, entry 13). Although catalytic transformation was realized in some cases, more DBU was needed to obtain a satisfactory conversion and yield. In order to improve the yield, 150 mol% of DBU was employed in this reaction and the best yield was obtained at 99% within 10 minutes (Table 1, entry 14). Meanwhile, when 50 mol% DBU was used, the desired product was isolated in 62% yield (Table 1, entry 15). It should be noted that the use of K2CO3 failed to give any product (Table 1, entry 16). Finally, the optimal reaction conditions for this transformation were determined to be 4-phenylbut-3-yn-2-one 1a (0.12 mmol), 4-benzylidene-5-methyl-2-phenylpyrazolone 2a (0.1 mmol), and DBU (150 mol%) in DCM (2 mL) as a solvent at room temperature. In addition, the structure and stereochemistry of 3a were characterized by a combination of NMR, HRMS spectra, and single-crystal X-ray analysis (see supporting information).19


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Table 1. Optimization of the [4+4] Cycloaddition Reaction Conditionsa

O O

O promoter (x mol%)

N N

1a

a

solvent, r.t.

N

N

2a

O

3a

Entry

Base

x

Solvent

Time (min)

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14 15 16

DABCO DMAP Et3N DIPEA TMEDA DBU DBU DBU DBU DBU DBU DBU DBU DBU DBU K2CO3

100 100 100 100 100 100 100 100 100 100 100 100 100 150 50 100

DCM DCM DCM DCM DCM DCM CHCl3 toluene AcOEt THF Et2O CH3CN DCM DCM DCM DCM

60 60 60 60 60 60 50 60 60 60 60 60 60 10 60 60

21     74 74 37 62 70 42 54 82 99 62 

Unless otherwise specified, all reactions were carried out using 4-phenylbut-3-yn-2-one 1a (0.12

mmol, 1.2 equiv) and 4-benzylidene-5-methyl-2-phenylpyrazolone 2a (0.10 mmol) in 2 mL solvent with 100 mol% of bases as promoter at room temperature. b Yield of isolated product of 3a after column chromatography. c Reactions were performed using 1a (0.3 mmol), 2a (0.10 mmol), 100 mol% base in solvent (2 mL). DABCO = 1,4-diazobicyclo [2.2.2] octane, DMAP = N,N-4-dimethylaminopyridine,

DIPEA

=

Diisopropylethylamine,

TMEDA

=

Tetramethylethylenediamine, DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene.

Using these optimized reaction conditions, we then examined the scope and limitations of the DBU-catalyzed [4+4] cycloaddition reaction between alkynoate



derivatives 1 and unsaturated pyrazolones 2, and the results are shown in Table 2. In the cases of benzylidenepyrazolone 2, either bearing a neutral, electron-withdrawing, or electron-donating group at the ortho, meta or para position of the benzene ring, the reactions proceeded smoothly to give the anticipated products 3a-m in moderate to good yields (Table 2, entries 1-13). Notably, the electronic properties of the substituent on 2 have a certain influence on this reaction, and substrate 2 bearing electron-withdrawing groups on the benzene ring provided somewhat lower yields of the cyclization products than did those bearing electron-donating groups (Table 2, entries 9-13). The reactions employing aryl substituted unsaturated pyrazolones containing para-substituted benzene rings required longer times and furnished the eight-membered cyclic ethers in modest yields. We were delighted to find that pyrazolone derivatives 2n, 2o and 2p, bearing thienyl, furyl, and naphthyl groups, respectively, underwent smooth sequential annulations with 1a, to give the corresponding products (i.e., 3n, 3o and 3p) in good yields (Table 2, entries 14-16).


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Table 2. Scope of the reactiona

O

O R2

DBU(150 mol%)

R3

R1

N N

R4 1

a

R3

DCM, r.t., Time

R2 O

R4 N

2

N Ph

O

R1

3

Entry

Product

R1

R2

R3

R4

Time (min)

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s 3t 3u 3v 3w 3x 3y 3z

C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 3-MeC6H5 4-MeC6H5 4-EtC6H5 3-ClC6H5 4-ClC6H5 2-FC6H5

H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1a) H (1b) H (1c) H (1d) H (1e) H (1f) H (1g) H (1h) H (1i) Me (1j) H (1a)

C6H5

Me (2a) Me (2b) Me (2c) Me (2d) Me (2e) Me (2f) Me (2g) Me (2h) Me (2i) Me (2j) Me (2k) Me (2l) Me (2m) Me (2n) Me (2o) Me (2p) Me (2a) Me (2a) Me (2a) Me (2a) Me (2a) Me (2a) Me (2a) Me (2a) Me (2a) C6H5 (2q)

10 15 15 120 20 10 10 120 60 10 10 10 10 60 60 60 10 10 30 10 10 30 30 10 10

99 98 83 97 95 95 99 99 81 57 81 99 34 98 90 87 88 92 94 71 74 85 81 73 97 71

2-thienyl

biphenyl C6H5 C6H5

2-MeC6H4 3-Me-C6H4 4-MeC6H4 3,4-(Me)2C6H3

4-iPrC6H4 3-MeOC6H4 4-MeOC6H4 3-NO2C6H4 3-FC6H4 4-ClC6H4 4-BrC6H4 3-CF3C6H4 2-thienyl

2-furyl 2-naphthyl

C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5

20

Reaction conditions: ethyl 5-arylpent-2-ynoate 1 (0.12 mmol), unsaturated pyrazolones 2 (0.10

mmol), in 2 mL of DCM at room temperature in the presence of 150 mol% of DBU. b Isolated yield after silica gel chromatography of 3.

Next, we investigated the reactions of a range of distinctly substituted ynones with



4-benzylidene-5-methyl-2-phenylpyrazolone 2a in the presence of 150 mol% of DBU. The substituents in the ynone 1 were well tolerated, leading to formation of desired [4+4] cycloaddition products 3 in moderate to good yields (Table 2, entries 17-22). Pleasingly, a substrate with 2-thienyl or -biphenyl groups could participate in the reaction efficiently ((Table 2, entries 23-24). The substituents R2 were not limited to hydrogen, when 1-phenylpent-1-yn-3-one was used, the product 3y was obtained in 97% yield (Table 2, entry 25). It was worth noting that R4 was also suitable to the aryl group; when R4 was a phenyl group, the desired product was produced in 71% yield (Table 2, entry 26). Following the exploration of the substrate scope, we performed this [4+4]-annulation reaction on gram-scale. When 1a and 2a were employed under the optimal reaction conditions, the reaction proceed smoothly to afford desired product 3a in 81% yield. Further treatment of the product 3a with NaBH4 in methanol at room temperature for 12h led to the derivative 4a in 92% yield with good diastereoselectivity (dr > 20:1) (Scheme 1). The absolute configuration and stereochemistry of 4a were determined unambiguously by single crystal X-ray crystallographic analysis (see supporting information).20


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O O

O N

O

N

DCM, r.t.

N

1a (4.8 mmol)

N

DBU (150%)

2a (4 mmol)

3a (81% yield)

S

O

OH R

N

NaBH4 (3 equiv) N

O

MeOH , r.t.

N

N

3a (0.3mmol)

O

4a (92% yield)

Scheme 1. Gram-Scale DABCO-Mediated [4+4]-Annulation and Further Transformation of 3a.

In order to gain insight into the mechanism, we performed an isotopic labeling experiment by adding 20 equiv. of D2O to the reaction system; the reaction was carried out under the standard conditions. The deuterated product D-3a was obtained in 81% yield. 1H NMR analysis showed 94% deuterium incorporation at the A position, 86% deuterium incorporation at B position, and 92% deuterium incorporation at C position, indicating the possibility of the involvement of a carbanion intermediate (Scheme 2). B H O

O N N

1a

DBU(150 mol%) D2O (20 equiv) DCM, r.t.

2a

C

D (86%) O A

D (92%) N O N

D (94%)

D-3a (81% yield)

Scheme 2. Deuterium labeling experiment for mechanism study.

On the basis of the above experimental results and the previous investigation on



Page 10 of 28

the mechanism,21 a plausible mechanism was proposed (Scheme 3). The reaction was rationalized to proceed in a tandem manner. First, 4-phenylbut-3-yn-2-one 1a was deprotonated by DBU to generate enolate intermediate A, which subsequently underwent conjugate nucleophilic addition to the carbon-carbon double bond of benzylidenepyrazolone 2a to furnish intermediate B. Subsequently, intermediate B abstracted a proton from the protonated DBU to afford the corresponding key intermediate C, which underwent the second Michael addition of DBU to the alkynyl group generating zwitterionic intermediate D. Intermediate D was followed by a proton transfer to afford the intermediate D’. Another enol tautomerism process gives rise to the intermediate E. Intramolecular nucleophilic addition of the negative oxygen ions to the double bond, then delivered cyclic intermediate F. Finally release of DBU afforded the product 3a.

H

O

H H A

1a

O N

O

O

O

N N

N N

H-B

O

F

N N

O

C

HO

O

B N

B

E

OH

B

2a

B: 3a

:B

O

:B

O

O

O

N N

N N

B

D'

OH

B

N N D

Scheme 3. Proposed reaction mechanism. CONCLUSION In conclusion, we have developed an efficient method for the synthesis of highly substituted eight-membered cyclic ethers through a formal [4+4] cycloaddition


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promoted by DBU. This cyclization reaction is operationally simple and proceed smoothly under mild reaction conditions, providing a broad range of fused eight-membered oxocino[2,3-c] pyrazoles in moderate to good yields. The positive characteristics of this protocol including readily available starting materials, mild reaction conditions, and an inexpensive base as promoter. Studies to address the further applications in the synthesis of eight-membered cyclic ethers in natural products and the development of asymmetric variants of this annulation are ongoing in our laboratory. EXPERIMENTAL SECTION General. All reactions were performed under N2 atmosphere in oven-dried glassware with magnetic stirring. Solvents were dried and distilled prior to use according to the standard methods. Unless otherwise indicated, all materials were obtained from commercial sources, and used as purchased without dehydration. Column chromatography was performed on silica gel 200-300 mesh. Nitrogen gas (99.999%) was purchased from Boc Gas Inc. 1H NMR (400 MHz) and

13

C

NMR (100 MHz) were recorded on a Bruker AV 400 (400 MHz) spectrometer with CDCl3 as solvent. Chemical shifts were recorded in parts per million (ppm) relative to tetramethylsilane as an internal reference. The crystal structure was determined on a Bruker SMART 1000 CCD diffractometer. Mass spectra were obtained using an electrospray ionization (ESI-TOF) mass spectrometer. Melting points were determined on a T-4 melting point apparatus (uncorrected). General Procedure for Formal [4+4] Cycloaddition Reaction for Products 3. Under a nitrogen atmosphere, to a mixture of unsaturated pyrazolone 2 (0.1 mmol, 1.0 equiv), and DBU (22.5 mg, 0.15 mmol, 150 mol%) was added CH2Cl2 (2 mL) via a syringe and allowed to stir for 5 min at



Page 12 of 28

room temperature. Ynoate 1 (0.12 mmol, 1.5 equiv.) was added and the reaction was allowed to stir at room temperature. The reaction was monitored by TLC spectroscopy. After the reaction was completed, the reaction mixture was directly purified by flash column chromatograph (eluted with 10:1 petroleum ether/EtOAc) to afford the product 3. (Z)-3-Methyl-1,4,8-triphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3a): white

solid

(40.1 mg, 99% yield); mp 122-124 °C; 1H NMR (400 MHz, CDCl3) δ 7.36-7.11 (m, 13H), 7.04 (t, J = 7.7 Hz, 2H), 6.14 (s, 1H), 4.25-4.08 (dd, J = 12.1 Hz, 4.7 Hz, 1H), 3.78 (t, J = 12.0 Hz, 1H), 2.81 (dd, J = 12.2, 4.7 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.3, 166.3, 150.2, 147.9, 142.9, 137.7, 132.7, 130.7, 128.9, 128.8, 128.6, 128.3, 127.5, 127.0, 126.9, 126.4, 113.8, 108.2, 48.2, 38.9, 12.9; HRMS (ESI) m/z calcd for C27H23N2O2 [M+H]+ 407.1754, found 407.1758. (Z)-3-Methyl-1,8-diphenyl-4-(o-tolyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3b): white solid (40.1 mg, 98% yield); mp166-168 oC; 1H NMR (400 MHz, CDCl3) δ 7.44-7.21 (m, 9H), 7.21-7.03 (m, 5H), 6.27 (s, 1H), 4.47 (dd, J = 12.5, 4.4 Hz, 1H), 3.76 (t, J = 12.3 Hz, 1H), 2.81 (dd, J = 12.3, 4.4 Hz, 1H), 2.62 (s, 3H), 1.90 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 200.3, 166.3,

140.9, 135.1, 130.6, 128.9, 128.6, 128.3, 127.5, 127.1, 126.8, 126.6, 126.4, 113.8, 108.6, 46.5, 35.3, 19.2, 12.8; HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1915. (Z)-3-Methyl-1,8-diphenyl-4-(m-tolyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3c): brown solid (34.8 mg, 83% yield); mp135-137oC; 1H NMR (400 MHz, CDCl3) δ 7.28-7.12 (m, 9H), 7.07-7.01 (m, 4H), 6.99-6.96 (m, 1H), 6.14 (d, J = 1.3 Hz, 1H), 4.14 (dd, J = 12.7, 4.8 Hz, 1H), 3.77 (dd, J = 12.7, 11.3 Hz, 1H), 2.79 (ddd, J = 11.3, 4.8, 1.4 Hz, 1H), 2.29 (s, 3H), 1.88 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 199.4, 165.3, 149.2, 146.9, 141.8, 137.4, 136.6, 131.6, 129.6,


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127.8, 127.6, 127.5, 127.2, 127.1, 126.7, 125.9, 125.4, 123.5, 112.7, 107.2, 47.2, 37.9, 20.5, 11.9; HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1916. (Z)-3-Methyl-1,8-diphenyl-4-(p-tolyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3d): yellow solid (41.0 mg, 97% yield); mp131-133oC; 1H NMR (400 MHz, CDCl3) δ 7.18-7.15 (m, 10H), 7.11-6.94 (m, 4H), 6.14 (s, 1H), 4.14 (dd, J = 12.6, 4.6 Hz, 1H), 3.76 (t, J = 12.3 Hz, 1H), 2.80 (dd, J = 11.1, 4.6 Hz, 1H), 2.27 (s, 3H), 1.87 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 199.4, 165.3,

149.1, 146.9, 138.9, 136.7, 135.5, 131.7, 129.6, 128.4 , 127.8, 127.6, 127.2, 126.3, 125.9, 125.4, 112.8 8, 107.3, 47.3, 37.6, 20.0, 11.9; HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1913.

(Z)-4-(3,4-Dimethylphenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3e): brown solid (41.2 mg, 95% yield); mp185-187 oC; 1H NMR (400 MHz, CDCl3) δ 7.27-7.12 (m, 8H), 7.09-6.99 (m, 4H), 6.96-6.93 (m, 1H), 6.14 (d, J = 1.2 Hz, 1H), 4.11 (dd, J = 12.7, 4.8 Hz, 1H), 3.76 (dd, J = 12.7, 11.4 Hz, 1H), 2.98-2.64 (m, 1H), 2.19 (d, J = 8.1 Hz, 6H), 1.89 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 199.5, 165.3, 149.2, 146.9, 139.4, 136.7, 135.9, 134.1, 131.7,

129.6, 128.9, 127.8, 127.7, 127.5, 127.2, 125.9, 125.4, 123.8, 112.8, 107.4, 47.4, 37.6, 18.9, 18.4, 12.0; HRMS (ESI) m/z calcd for C29H27N2O2 [M+H]+ 435.2067, found 435.2072.

(Z)-4-(4-Isopropylphenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3f): brown solid (42.4 mg, 95% yield); mp116-118 oC; 1H NMR (400 MHz, CDCl3) δ 7.25-7.10 (m, 12H), 7.04-7.00 (m, 2H), 6.14 (s, 1H), 4.22-4.03 (m, 1H), 3.84-3.69 (m, 1H), 2.96-2.67 (m, 2H), 1.89 (s, 3H), 1.19 (t, J = 8.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 199.5, 165.3, 149.1, 146.9, 146.4, 139.2, 136.7, 131.6, 129.6, 127.8, 127.6, 127.2, 126.3, 125.9, 125.7, 125.4, 112.7,



107.4, 47.2, 37.5, 32.7, 22.9, 11.9; HRMS (ESI) m/z calcd for C30H28N2O2Na [M+Na]+ 471.2043, found 471.2048.

(Z)-4-(3-Methoxyphenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3g): white solid (43.0 mg, 99% yield); mp 162-164 oC; 1H NMR (400 MHz, CDCl3) δ 7.38-7.11 (m, 10H), 7.06-7.02 (m, 2H), 6.81-6.76 (m, 2H), 6.14 (s, 1H), 4.14 (dd, J = 12.6, 4.5 Hz, 1H), 3.78 (s, 1H), 3.73 (d, J = 8.4 Hz, 3H), 2.80 (dd, J = 11.1, 4.5 Hz, 1H), 1.88 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.4, 166.3, 158.5, 150.1, 147.9, 128.9, 128.5, 128.2, 126.9, 126.4, 114.1, 113.8, 108.5, 55.3, 48.5, 38.2, 12.9; HRMS (ESI) m/z calcd for C28H25N2O3 [M+H]+ 437.1860, found 437.1862. (Z)-4-(4-Methoxyphenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3h): red solid (43.0 mg, 99% yield); mp164-166 oC; 1H NMR (400 MHz, CDCl3) δ 7.25-7.12 (m, 10H), 7.03-6.99 (m, 2H), 6.81-6.78 (m, 2H), 6.13 (d, J = 1.1 Hz, 1H), 4.14 (dd, J = 12.6, 4.8 Hz, 1H), 3.81-3.73 (m, 1H), 3.72 (d, J = 6.0 Hz, 3H), 2.79 (ddd, J = 11.3, 4.8, 1.2 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.4, 165.2, 157.4, 149.1, 146.9, 136.7, 134.0, 131.6, 129.6, 127.8, 127.5, 127.2, 125.9, 125.4, 113.1, 112.8, 107.4, 54.3, 47.4, 37.2, 11.9; HRMS (ESI) m/z calcd for C28H25N2O3 [M+H]+ 437.1860, found 437.1863. (Z)-3-Methyl-4-(3-nitrophenyl)-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3i): yellow solid (46.5 mg, 81% yield); mp154-156 oC; 1H NMR (400 MHz, CDCl3) δ 8.31-7.99 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.50 (m, 1H), 7.37-7.21 (m, 8H), 7.15-7.12 (m, 2H), 6.23 (d, J = 1.1 Hz, 1H), 4.36 (dd, J = 12.7, 4.7 Hz, 1H), 3.84 (dd, J = 12.6, 11.4 Hz, 1H), 2.89 (ddd, J = 11.4, 4.7, 1.2 Hz, 1H), 1.92 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.2, 166.6, 150.3, 148.8, 147.5, 145.1, 137.4, 133.7, 132.4, 130.9, 129.9, 128.9, 128.3, 127.0, 126.4, 122.4, 122.3, 113.7, 106.9, 47.7,


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38.7, 13.0; HRMS (ESI) m/z calcd for C27H22N3O4 [M+H]+ 452.1605, found 452.1606. (Z)-4-(3-fluorophenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3j): red solid (24.4 mg, 57% yield); mp 137-139 oC; 1H NMR (400 MHz, CDCl3) δ 7.30-7.12 (m, 9H), 7.05-7.02 (m, 3H), 6.97-6.81 (m, 2H), 6.16 (s, 1H), 4.18 (dd, J = 12.6, 4.4 Hz, 1H), 3.81-3.71 (m, 1H), 2.80 (dd, J = 11.2, 4.4 Hz, 1H), 1.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.9, 166.4, 147.8, 137.6, 132.5, 130.8, 130.3, 128.9, 128.8, 128.3, 127.0, 126.4, 123.3, 114.5, 114.3, 114.1, 113.8, 113.7, 107.6, 47.9, 38.7, 12.9; HRMS (ESI) m/z calcd for C27H22FN2O2 [M+H]+ 425.1660, found 425.1663. (Z)-4-(4-Chlorophenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3k): yellow solid (36.8 mg, 81% yield); mp 126-128 oC; 1H NMR (400 MHz, CDCl3) δ 7.30-7.11 (m, 12H), 7.06-7.02 (m, 2H), 6.15 (s, 1H), 4.16 (dd, J = 12.7, 4.7 Hz, 1H), 3.89-3.55 (m, 1H), 2.79 (dd, J = 11.3, 4.7 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.8, 165.3, 149.1, 146.7, 140.4, 136.5, 131.7, 131.5, 129.7, 127.9, 127.8, 127.7, 127.2, 125.9, 125.4, 112.7, 106.7, 47.0, 37.4, 11.9; HRMS (ESI) m/z calcd for C27H22ClN2O2 [M+H]+ 441.1364, found 441.1368. (Z)-4-(4-bromophenyl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3l): red solid (47.1 mg, 99% yield); mp141-143 oC; 1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.34-7.10 (m, 10H), 7.05-7.02 (m, 2H), 6.15 (s, 1H), 4.15 (dd, J = 12.2, 4.7 Hz, 1H), 3.73 (t, J = 12.0 Hz, 1H), 2.79 (dd, J = 12.2, 4.7 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.8, 166.4, 150.2, 147.8, 142.0, 137.6, 132.6, 130.8, 129.3, 128.9, 128.3, 127.0, 126.4, 120.8, 113.8, 107.6, 48.0, 38.5, 12.9; HRMS (ESI) m/z calcd for C27H22BrN2O2 [M+H]+ 485.0859, found 485.0863. (Z)-3-methyl-1,8-diphenyl-4-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1



Page 16 of 28

H)-one (3m): yellow solid (16.8 mg, 34% yield); mp 145-147 oC; 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.48-7.35 (m, 3H), 7.29-7.13 (m, 8H), 7.05-7.02 (m, 2H), 6.16 (s, 1H), 4.25 (dd, J = 12.7, 4.7 Hz, 1H), 3.97-3.51 (m, 1H), 2.81 (dd, J = 10.9, 4.7 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.6, 165.5, 149.25 (s), 146.6, 142.9, 136.5, 131.4, 129.9, 129.8, 128.3, 127.9, 127.8, 127.3, 126.0, 125.4, 123.2, 123.0, 122.9, 112.7, 106.3, 46.9, 37.8, 11.9; HRMS (ESI) m/z calcd for C28H22F3N2O2 [M+H]+ 475.1628, found 475.1648. (Z)-3-Methyl-1,8-diphenyl-4-(thiophen-2-yl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3n): white solid (40.2 mg, 98% yield); mp132-134 oC; 1H NMR (400 MHz, CDCl3) δ 7.31-7.10 (m, 9H), 7.03-7.01 (m, 2H), 6.93-6.87 (m, 1H), 6.85 (s, 1H), 6.13 (s, 1H), 4.49 (dd, J = 12.4, 4.5 Hz, 1H), 3.86 (t, J = 11.9 Hz, 1H), 2.96 (dd, J = 11.9, 4.5 Hz, 1H), 2.00 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.5, 165.2, 148.5, 146.9, 146.2, 136.5, 131.5, 129.7, 127.8, 127.6, 127.2, 125.9, 125.8, 125.4, 123.4, 123.2, 112.7, 107.3, 47.4, 32.8, 11.9; HRMS (ESI) m/z calcd for C25H21N2O2S [M+H]+ 413.1318, found 413.1321. (Z)-4-(Furan-2-yl)-3-methyl-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3o): red solid (35.8 mg, 90% yield); mp 149-151 oC; 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.28-7.17 (m, 8H), 7.08-7.05 (m, 2H), 6.30 (s, 1H), 6.17 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 4.34 (dd, J = 12.3, 4.7 Hz, 1H), 3.88 (t, J = 11.9 Hz, 1H), 3.04 (dd, J = 12.1, 4.7 Hz, 1H), 2.10 (s, 3H);

13

C NMR

(101 MHz, CDCl3) δ 199.9, 166.1, 155.2, 149.8, 147.9, 142.0, 137.6, 132.6, 130.7, 128.8, 128.6, 128.2, 126.8, 126.4, 113.9, 110.2, 106.0, 105.8, 44.3, 32.2, 12.9; HRMS (ESI) m/z calcd for C25H21N2O3 [M+H]+ 397.1547, found 397.1549. (Z)-3-Methyl-4-(naphthalen-2-yl)-1,8-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3p): white solid (39.4 mg, 87% yield); mp 157-160 oC; 1H NMR (400 MHz, CDCl3) δ 7.77-7.75


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(m, 3H), 7.66 (s, 1H), 7.46-7.35 (m, 3H), 7.27-7.24 (m, 2H), 7.21-7.16 (m, 6H), 7.06-7.04 (m, 2H), 6.17 (s, 1H), 4.36 (dd, J = 12.7, 4.6 Hz, 1H), 3.87 (t, J = 12.5 Hz, 1H), 2.89 (dd, J = 12.2, 4.6 Hz, 1H), 1.88 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.4, 166.4, 150.3, 148.0, 140.3, 137.7, 133.5, 132.6, 132.5, 130.8, 128.9, 128.7, 128.3, 127.7, 127.0, 126.5, 126.3, 126.0, 125.9, 125.7, 113.8, 108.0, 48.2, 39.2, 13.1. HRMS (ESI) m/z calcd for C31H25N2O2 [M+H]+ 457.1911, found 457.1915. (Z)-3-Methyl-1,4-diphenyl-8-(m-tolyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3q): white solid (36.8 mg, 88% yield); mp 145-147 oC; 1H NMR (400 MHz, CDCl3) δ 7.42-7.33 (m, 6H), 7.29-7.24 (m, 4H), 7.12-7.10 (m, 2H), 7.09-7.00 (m, 2H), 6.24 (s, 1H), 4.28 (dd, J = 12.7, 4.4 Hz, 1H), 3.85 (t, J = 12.5 Hz), 2.91 (dd, J = 12.6, 4.4 Hz, 1H), 2.17 (s, 3H), 1.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.3, 166.5, 150.2, 147.9, 142.9, 137.9, 137.8, 132.5, 131.7, 128.7, 128.2, 127.5, 127.3, 127.0, 123.8, 113.6, 108.3, 48.3, 38.9, 21.3, 12.9; HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1913. (Z)-3-Methyl-1,4-diphenyl-8-(p-tolyl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3r): white solid (38.6 mg, 92% yield); mp 170-172 oC; 1H NMR (400 MHz, CDCl3) δ 7.39-7.35 (m, 7H), 7.33-7.24 (m, 3H), 7.13-7.09 (m, 2H), 6.94-6.92 (m, 2H), 6.22 (s, 1H), 4.27 (dd, J = 12.8, 4.8 Hz, 1H), 3.98-3.75 (m, 1H), 3.02 (dd, J = 12.8, 4.8 Hz, 1H), 2.32 (s, 3H), 1.97 (s, 3H);

13

C NMR

(101 MHz, CDCl3) δ 200.4, 166.7, 150.2, 147.9, 143.0, 141.4, 137.8, 129.7, 129.0, 128.9, 128.8, 128.7, 127.5, 127.1, 126.9, 126.6, 112.7, 108.3, 48.3, 38.9, 21.4, 12.9; HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1914. (Z)-8-(4-Ethylphenyl)-3-methyl-1,4-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3s):

white solid (40.8 mg, 94% yield); mp 158-161 oC; 1H NMR (400 MHz, CDCl3) δ 7.31-7.21 (m,



7H), 7.21-7.16 (m, 3H), 7.07-7.04 (m, 2H), 6.86-6.84 (m, 2H), 6.12 (d, J = 1.2 Hz, 1H), 4.25-4.11 (m, 1H), 3.77 (dd, J = 12.7, 11.4 Hz, 1H), 2.80 (ddd, J = 11.3, 4.8, 1.3 Hz, 1H), 2.50 (t, J = 7.6 Hz, 2H), 1.87 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 200.4, 166.7, 150.3, 147.9, 147.6, 143.0, 137.8, 129.9, 128.9, 128.8, 128.7, 127.8, 127.5, 127.1, 126.9, 126.7, 112.9, 108.2, 48.6, 39.0, 28.7, 15.4, 13.0; HRMS (ESI) m/z calcd for C29H27N2O2 [M+H]+ 435.2067, found 435.2070. (Z)-8-(3-Chlorophenyl)-3-methyl-1,4-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3t): white solid (31.2 mg, 71% yield); mp 125-127 oC; 1H NMR (400 MHz, CDCl3) δ 7.30-7.22 (m, 8H), 7.20-7.16 (m, 3H), 7.13-7.06 (m, 2H), 7.01-6.98 (m, 1H), 6.12 (d, J = 1.1 Hz, 1H), 4.17 (dd, J = 12.7, 4.8 Hz, 1H), 3.82 (t, J = 4.8 Hz, 1H), 2.86 (dd, J = 12.7, 4.8 Hz, 1H), 1.88 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.1, 163.6, 149.1, 146.9, 141.7, 136.3, 133.5, 133.4, 129.6, 128.4, 128.0, 127.9, 127.8, 127.6, 127.5, 126.7, 126.4, 125.9, 125.8, 125.5, 123.3, 118.9, 113.7, 107.0, 47.2, 37.9, 11.9; HRMS (ESI) m/z calcd for C27H22ClN2O2 [M+H]+ 441.1364, found 441.1368. (Z)-8-(4-Chlorophenyl)-3-methyl-1,4-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3u): white solid (32.4 mg, 74% yield); mp 146-148 oC; 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 11H), 7.14-7.06 (m, 2H), 7.01-6.99 (m, 1H), 6.12 (s, 1H), 4.17 (dd, J = 12.2, 4.8 Hz, 1H), 3.77 (t, J = 12.1 Hz, 1H), 2.81 (dd, J = 12.1, 4.8 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.1, 164.7, 150.1, 147.9, 142.8, 137.4, 134.6, 134.5, 130.6, 129.5, 129.1, 128.9, 128.8, 127.5, 127.0, 126.9, 126.6, 124.3, 114.7, 108.1, 48.2, 39.0, 12.9; HRMS (ESI) m/z calcd for C27H22ClN2O2 [M+H]+ 441.1364, found 441.1368. (Z)-8-(2-Fluorophenyl)-3-methyl-1,4-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3v): brown solid (36.0 mg, 85% yield); mp 179-181 oC; 1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (m,


Page 18 of 28

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2H), 7.38-7.35 (m, 2H), 7.27-7.24 (m, 6H), 7.19-7.16 (m, 4H), 6.20 (d, J = 1.1 Hz, 1H), 4.19 (dd, J = 12.7, 4.8 Hz, 1H), 3.80 (dd, J = 12.6, 11.5 Hz, 1H), 2.82 (ddd, J = 12.6, 4.8, 1.2 Hz, 1H), 1.88 (s, 3H);

13

C NMR (101 MHz, CDCl3) δ 199.2, 165.1, 149.2, 146.8, 142.3, 141.9, 138.7, 136.7,

130.3, 128.1, 127.9, 127.8, 127.7, 127.0, 126.5, 126.2, 126.0, 125.9, 125.8, 125.7, 112.5, 107.2, 47.2, 37.9, 11.9. HRMS (ESI) m/z calcd for C27H22FN2O2 [M+H]+ 425.1660, found 425.1663. (Z)-3-Methyl-1,4-diphenyl-8-(thiophen-2-yl)-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3w): yellow solid (33.4 mg, 81% yield); mp 179-181 oC; 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 5H), 7.30-7.21 (m, 5H), 7.18-7.15 (m, 1H), 6.69-6.67 (m, 2H), 6.04 (s, 1H), 4.16 (dd, J = 12.5, 4.5 Hz, 1H), 3.71 (t, J = 12.5 Hz, 1H), 2.78 (dd, J = 12.3, 4.4 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.4, 161.4, 149.8, 147.9, 142.9, 137.9, 136.5, 130.4, 129.8, 129.2, 129.1, 128.8, 128.0, 127.6, 127.5, 126.9, 111.6, 108.3, 48.3, 39.1, 13.0; HRMS (ESI) m/z calcd for C25H21N2O2S [M+H]+ 413.1318, found 413.1320. (Z)-8-([1,1'-Biphenyl]-4-yl)-3-methyl-1,4-diphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3x): brown solid (35.2 mg, 73% yield); mp 142-144 oC; 1H NMR (400 MHz, CDCl3) δ 7.34-7.21 (m, 6H), 7.21-7.11 (m, 3H), 7.08-7.04 (m, 3H), 6.99-6.95 (m, 1H), 6.87-6.85 (m, 1H), 6.78-6.69 (m, 1H), 6.16 (d, J = 1.0 Hz, 1H), 4.28-4.10 (m, 1H), 3.87 (dd, J = 12.5, 11.4 Hz, 1H), 2.84 (ddd, J = 11.3, 4.7, 1.3 Hz, 1H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199.3, 160.3, 159.6, 157.0, 149.2, 146.9, 141.7, 136.4, 130.7, 130.6, 127.8, 127.7, 127.6, 127.0, 126.5, 125.9, 124.8, 122.8, 122.7, 120.7, 120.6, 118.7, 118.6, 115.1, 114.9, 107.0, 47.2, 37.9, 11.9. HRMS (ESI) m/z calcd for C33H27N2O2 [M+H]+ 483.2067, found 483.2070. (Z)-3,5-Dimethyl-1,4,8-triphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3y): white solid (40.8 mg, 97% yield); mp 167-169 oC; 1H NMR (400 MHz, CDCl3) δ 7.26-7.24 (m, 3H),



7.23-7.10 (m, 10H), 7.10-7.04 (m, 2H), 6.15 (s, 1H), 3.92 (dd, J = 11.8, 6.5 Hz, 1H), 3.62 (d, J = 11.8 Hz, 1H), 1.89 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 205.7, 149.6, 147.5, 142.0, 137.6, 132.5, 130.7, 128.9, 128.6, 128.5, 128.3, 127.0, 126.9, 126.4, 112.3, 110.3, 48.4, 45.5, 15.9, 12.9. HRMS (ESI) m/z calcd for C28H25N2O2 [M+H]+ 421.1911, found 421.1913. (Z)-1,3,4,8-Tetraphenyl-4,5-dihydrooxocino[2,3-c]pyrazol-6(1H)-one (3z): white solid (33.3 mg, 71% yield); mp 159-161 oC; 1H NMR (400 MHz, CDCl3) δ 7.48-7.25 (m, 8H), 7.25-7.11 (m, 10H), 7.06-7.03 (m, 2H), 6.13 (s, 1H), 4.47 (dd, J = 12.5, 5.5 Hz, 1H), 3.83 (t, J = 12.1 Hz, 1H), 2.87 (dd, J = 12.5, 5.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 200.4, 166.4, 151.2, 150.2, 143.9, 137.6, 132.9, 132.5, 130.7, 128.9, 128.3, 128.2, 128.1, 127.9, 127.5, 127.1, 126.9, 126.3, 114.2, 108.1, 49.1, 38.9; HRMS (ESI) m/z calcd for C32H24N2O2Na [M+Na]+ 491.1730, found 491.1735. (Z)-3-methyl-1,4,8-triphenyl-1,4,5,6-tetrahydrooxocino[2,3-c]pyrazol-6-ol (4a): red solid (37.4 mg, 92% yield); mp 109-111 oC; 1H NMR (400 MHz, CDCl3) δ 7.59-7.53 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.29 (m, 3H), 7.27-7.14 (m, 8H), 5.33 (d, J = 7.2 Hz, 1H), 4.78 (ddd, J = 9.9, 7.2, 5.7 Hz, 1H), 4.52 (dd, J = 11.7, 4.6 Hz, 1H), 2.33 (td, J = 11.7, 5.7 Hz, 2H), 1.95 (ddd, J = 11.7, 10.1, 4.6 Hz, 1H), 1.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 149.23, 147.93, 147.40, 141.16, 138.26, 134.77, 128.95, 128.46, 127.78, 126.61, 125.55, 122.80, 111.65, 104.16, 67.65, 36.04, 34.90, 14.19; HRMS (ESI) m/z calcd for C27H24N2O2Na [M+Na]+ 431.1730, found 431.1734.

ASSOCIATED CONTENT *Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01016. 1

H and 13C NMR spectra for all products (PDF)


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X-ray data for compound 3a (CIF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We thank the National Key Research and Development Program of China (2016YFD0201200), the Committee of Science and Technology of Tianjin (15JCYBJC20700) and State Key Laboratory of Elemento-Organic Chemistry in Nankai University for financial support.

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