An efficient [3+2] cycloaddition for the synthesis of substituted pyrazolo[1,5-c]quinazolines

Accepted Manuscript An Efficient [3+2] Cycloaddition for the Synthesis of Substituted Pyrazolo[1,5-c] Quinazolines Tao Wang, Ailong Shao, Haiyan Feng, Shuwu Yang, Meng Gao, Jun Tian, Aiwen Lei PII:

S0040-4020(15)00317-8

DOI:

10.1016/j.tet.2015.03.019

Reference:

TET 26501

To appear in:

Tetrahedron

Received Date: 14 January 2015 Revised Date:

4 March 2015

Accepted Date: 5 March 2015

Please cite this article as: Wang T, Shao A, Feng H, Yang S, Gao M, Tian J, Lei A, An Efficient [3+2] Cycloaddition for the Synthesis of Substituted Pyrazolo[1,5-c] Quinazolines, Tetrahedron (2015), doi: 10.1016/j.tet.2015.03.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Graphical Abstract

An Efficient [3+2] Cycloaddition for the Synthesis of Substituted Pyrazolo[1, 5-c] Quinazolines Tao Wanga,b , Ailong Shaoa,b , Haiyan Fenga,b, Shuwu Yanga,b, Meng Gao a,b,*, Jun Tianb and Aiwen Leia,c,* R2

N N

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N2, DMSO

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N R1 20 examples, up to 92% yield

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Tetrahedron journal homepage: www.elsevier.com

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An Efficient [3+2] Cycloaddition for the Synthesis of Substituted Pyrazolo[1,5-c] Quinazolines Tao Wanga, Ailong Shaoa, Haiyan Fenga, Shuwu Yanga, Meng Gaoa*, Tian Junb and Aiwen Leia,b∗ a

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National Research Center for Carbohydrate Synthesis and Key Laboratory of Chemical Biology, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China b College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A simple and efficient [3+2] cycloaddition reaction between N-iminoquinazolinium ylide and nitrooefins was developed. From a synthetic point of view, this protocol represents an efficient way to pyrazolo[1, 5-c]quinazolines derivatives.

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Keywords: Pyrazolo[1, 5-c]quinazolines Reagent-Free Nitrooefins [3+2] cycloaddition

∗ Corresponding author. Tel.: +86 79188120385; fax: +86 79188120385; e-mail: [email protected] ∗ Corresponding author. Tel.: +86 02768754672; fax: (86)27-68754672; e-mail: [email protected]

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Table 1. Optimization of the reaction conditions.a

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In recent years, the application of nitrooefins in cycloaddition reactions has been particularly valued.5 Various heterocyclic compounds could be synthesized via 1, 3-dipolar cycloaddition by utilizing the easily available nitrooefins as the dipolarophile. Since 1,3-dipolar cycloaddition of N-imido ylides is a powerful method for the construction of complex N-heterocycles,6 and we have been placing our continued interest in the development of nitrooefins to construct heterocycles,5a we envisioned that the pyrazolo[1, 5-c]quinazolines might be generally achieved by [3+2] cycloaddition between nitrooefins and N-imide ylides. Here in, we communicate our efforts in the reagent-free synthesis of pyrazolo[1, 5-c]quinazolines through [3+2] cycloaddition between N-iminoquinazolinium ylides and nitrooefins (Scheme 1). This protocol would address the previous limitations and furnish a diverse collection of valuable pyrazolo[1, 5c]quinazolines derivatives under simple reaction conditions.

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Pyrazolo[1, 5-c]quinazoline and their partially saturated derivatives are widely found in numerous natural products and pharmaceuticals that exhibit significant biological or medical activities.1 For example, the pyrazolo[1, 5-c]quinazoline derivatives have been used as Gly/NMDA receptor and excitatory amino acid antagonists, potent phosphodiesterase 10A inhibitors and potential vaccinia virus inhibitors (Figure 1). The traditional chemical synthesis of pyrazolo[1, 5-c]quinazolines always employs prior functionalized pyrazoles and acyl chlorides or aldehydes/ketones as the reactants, in which strong base or acid are usually required.2 Recently, the groups of Fu3 and Guo and Fan,4 respectively, reported a copper-catalyzed tandem reaction to realize the synthesis pyrazolo[1, 5-c]quinazolines derivatives. However, the transition-metal catalysts are inevitable in these methods. Concerning environmental, step-ecomomical issues and the pharmacological importance of pyrazolo[1, 5c]quinazoline, the search for simple, efficient and transitionmetal-free methods are always highly attractive.

feasibility of this [3+2] cycloaddition reaction. In the further experiments we then found the reaction conditions to be best under a nitrogen atmosphere in DMSO at 110 °C (Table 1, entry 8). Various Lewis acid such as Cu(OAc)2, CuI, CuO, FeCl3, and AgOTf turned out to be totally ineffective (Table 1, entry 3-7). Decreases in the reaction time reduced the yield distinctly; however, further extension of the reaction time did not observably improve the yield (Table 1, entry 9-10). The reaction could proceed in other solvents, such as DMF and DCE, albeit in lower yields (Table 1, entry 11–12). When the reaction temperature was decreased to 60 °C, only trace amount of the desired product could be obtained (Table 1, entry 13). However, increasing the temperature did not improve the yield (Table 1, entries 14). It is noteworthy that the intermediate 4 could be obtained when the reaction temperature was decreased to 60 °C, and the intermediate 4 could be transformed into the product 3a smoothly by further increasing the reaction time and temperature. (Scheme 2).

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1. Introduction

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Figure 1. Examples of important pyrazolo[1, 5-c]quinazolines derivatives.

Scheme 1. Reagent-free [3+2] cycloaddition reaction.

2. Results and discussions For the initial model reaction, we selected Niminoquinazolinium ylide (1a) and 1-(2-nitroprop-1-enyl) benzene (2a) as the substrates. To our delight, we found that the corresponding cyclization pyrazolo[1, 5-c]quinazoline product 3a was indeed obtained when either DABCO (1, 4diazabicyclo[2.2.2]octane) or K2CO3 were employed in the reaction, albeit in moderate yields (Table 1, entries 1 and 2). This interesting transformation encouraged us to further examine the

Scheme 2. Isolation of the intermediates 4.

With the optimized conditions in hand, various Niminoquinazolinium ylides 1 were found to be the suitable reaction partners with different nitroolefins 2 to provide the corresponding pyrazolo[1, 5-c]quinazoline products 3 (Scheme 3). Both electronwithdrawing and electron-donating substituted groups or halogen groups at the aromatic ring of nitroolefins

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product in good yield (Scheme 3, 3m). It was noteworthy that were well tolerated in the reactions, such as Br, F, Cl, N(Me)2, MANUSCRIPT ACCEPTED the nitroolefins which R3 group was substituted by the hydrogen OMe, CF3, Me, CN , SMe and naphthyl (Scheme 3, 3a−3l). or ethyl could also react smoothly to afford the desired products Scheme 3. Substrate Scope. in moderate to good yields (Scheme 3, 3n−3o). In addition, the beta-aliphatic nitroolefin, such as cyclohexyl and isopropylsubstituted nitroolefins were also well tolerated in the reactions, albeit with moderate yields (Scheme 3, 3p−3q). Various Niminoquinazolinium ylides 1 were also tested to access the pyrazolo[1, 5-c]quinazoline rings. Derivatives with different substitutions on the arene of N-iminoquinazolinium ylides 1 could react with 1-bromo-4-(2-nitroprop-1-enyl)benzene smoothly to afford the respective products in moderate yields (Scheme 3, 3r−3t). In addition, the structures of the product were further confirmed by X-ray crystallographic analysis of 3g (Figure 2).

Figure 2. X-ray crystal structure of 3g.

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On the basis of above results and the previous reports,5a, 6d a proposed mechanism for the reaction is illustrated in Scheme 4. Firstly, the quinazolin-3-ium-3-yl(tosyl)amide 1a and 1-(2nitroprop-1-enyl)benzene 2a undergo a [3+2] cycloaddition to produce the intermediate 4. After release of tosyl group, the intermediate 5 was then afforded, and finally elimination of HNO2 occurs to generate the product 3a.

Scheme 4. Proposed mechanism

3. Conclusion

In summary, we have developed a simple and efficient [3+2] cycloaddition reaction between N-iminoquinazolinium ylide and nitrooefins. From a synthetic point of view, this protocol addresses the previous limitations and furnishes a diverse collection of valuable pyrazolo[1, 5-c]quinazolines derivatives from basic chemical materials.

4. Experimental Meanwhile, the nitrooefins possessing a naphthyl group could also transformed into the target pyrazolo[1, 5-c]quinazoline

4.1. General Information

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4.3.6 1-(4-Methoxyphenyl)-2-methylpyrazolo[1,5-c] quinazoline (3f): White solid. Isolated yield = 60%. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.24 – 8.17 (m, 1H), 7,98 – 7.90 (m, 1H), 7.71 – 7.56 (m, 4H), 7.08 – 7.01 (m, 2H), 3.88 (s, 3H), 2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.02, 155.72, 140.07, 139.57, 135.58, 130.29, 128.96, 128.72, 127.78, 124.87, 122.84, 121.52, 114.16, 108.11, 55.39, 11.00. HRMS (ESI) calcd for C18H15N3O [M+H]+: 290.1283; found: 290.1288.

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4.2.1 Quinazolin-3-ium-3-yl(tosyl)amide 1a (71.8 mg, 0.24 mmol) and 1-(2-nitroprop-1-enyl)benzene 2a (32.6 mg, 0.20 mmol) were added in a clean sealed Schlenk tube equipped with a stir bar. After flushing the Schlenk tube three times with N2 atmosphere, DMSO (2 mL) was injected in the tube through a syringe. The reaction was then stirred at 110 oC for 24 h. After completion of the reaction, as indicated by TLC, the mixture was quenched by saturated brine and extracted with ethyl ether (3 x 10 mL). The organic layers were combined and dried over anhydrous Na2SO4. The pure product 3a (yield 90%, 46.6 mg) was obtained by flash column chromatography on silica gel (petroleumether : ethyl acetate 15 : 1).

4.3.5 N,N-dimethyl-4-(2-methylpyrazolo[1,5-c] quinazolin -1yl)aniline (3e): Orange solid. Isolated yield = 45%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.25 – 8.19 (m, 1H), 7.97 – 7.89 (m, 1H), 7.67 – 7.56 (m, 4H), 6.87 – 6.82 (m, 2H), 3.04 (s, 6H), 2.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.34, 150.64, 140.15, 139.66, 135.50, 129.84, 128.82, 128.66, 127.64, 122.87, 121.60, 120.08, 112.24, 108.01, 40.44, 11.16. HRMS (ESI) calcd for C19H18N4 [M+H]+: 303.1600; found: 303.1604.

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4.2. General procedure

White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.21 (dd, J = 7.6, 1.6 Hz, 1H), 8.02 – 7.95 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.49 – 7.41 (m, 2H), 7.38 – 7.32 (m, 1H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.11, 139.99, 139.59, 135.08, 133.71, 132.91, 132.22, 130.52, 129.16, 128.77, 128.03, 127.36, 124.06, 122.97, 121.58, 110.01, 10.85. HRMS (ESI) calcd for C17H12BrN3 [M+H]+: 338.0283; found: 338.0287.

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Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates. Flash chromatography columns were packed with 200 – 300 mesh silica gel in petroleum (boiling point is between 60 – 90 oC). Gradient flash chromatography was conducted eluting with a continuous gradient from petroleum to the indicated solvent, and they are listed as volume/volume ratios. NMR spectra were recorded on a Bruker spectrometer at 400 MHz (1H NMR), 101 MHz (13C NMR). Tetramethylsilane was used as an internal standard. All 1H NMR spectra were reported in delta (δ) units, parts per million (ppm) downfield from the internal standard. Coupling constants are reported in Hertz (Hz). High resolution mass spectra (HRMS) were measured with a Waters Micromass GCT instrument, accurate masses are reported for the molecular ion ([M+H]+)

4.3. Detailed descriptions for products:

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4.3.1 2-Methl-1-phenylpyrazolo[1,5-c]quinazoline (3a): White solid. Isolated yield = 90%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.23 – 8.20 (m, 1H), 7.98 – 7.68 (m, 1H), 7.77 – 7.70 (m, 2H), 7.66 – 7.43 (m, 5H), 2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.83, 139.98, 139.53, 135.58, 132.43, 129.03, 128.97, 128.71, 128.67, 127.81, 122.79, 121.48, 108.32, 10.91. HRMS (ESI) calcd for C17H13N3 [M+H]+: 260.1179; found: 260.1182.

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4.3.2 1-(4-Bromophenyl)-2-methylpyrazolo[1,5-c] quinazoline (3b): White solid. Isolated yield = 92%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.22 – 8.17 (m, 1H), 7.97 – 7.92 (m, 1H), 7.69 – 7.56 (m, 6H), 2.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.65, 139.99, 139.43, 135.78, 131.89, 131.42, 130.56, 129.15, 128.83, 127.97, 123.11, 122.81, 121.39, 108.25, 10.92. HRMS (ESI) calcd for C17H12BrN3 [M+H]+: 338.0283; found: 338.0287. 4.3.3 1-(4-Fluorophenyl)-2-methylpyrazolo[1,5-c] quinazoline (3c): White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.27 – 8.19 (m, 1H), 8.00 – 7.93 (m, 1H), 7.76 – 7.58 (m, 4H), 7.28 – 7.18 (m, 2H), 2.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.14 (d, JC-F = 249.5 Hz), 155.00, 140.09, 139.53, 135.77, 130.87 (d, JC-F = 9.1 Hz), 129.16, 128.86, 128.59 (d, JC-F = 3.0 Hz), 127.98, 122.88, 121.50, 115.80 (d, J = 21.2 Hz), 108.22, 10.93. HRMS (ESI) calcd for C17H12FN3 [M+H]+: 278.1084; found: 278.1088. 4.3.4 1-(2-Bromophenyl)-2-methylpyrazolo[1,5-c] quinazoline (3d):

4.3.7 1-(2-Chlorophenyl)-2-methylpyrazolo[1,5-c] quinazoline (3g): White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.24 – 8.19 (m, 1H), 8.00 – 7.94 (m, 1H), 7.70 – 7.59 (m, 2H), 7.57 – 7.53 (m, 1H), 7.52 – 7.48 (m, 1H), 7.47 – 7.37 (m, 2H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.63, 140.00, 139.56, 135.10, 134.22, 132.21, 131.63, 130.37, 129.80, 129.14, 128.78, 128.01, 126.84, 122.95, 121.55, 110.23, 10.79. HRMS (ESI) calcd for C17H12ClN3 [M+H]+: 294.0788; found: 294.0793. 4.3.8 4-(2-Methylpyrazolo[1,5-c]quinazolin-1-yl) benzonitrile (3h): White solid. Isolated yield = 90%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.25 – 8.17 (m, 1H), 7.99 – 7.93 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.70 – 7.59 (m, 2H), 2.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.53, 139.89, 139.26, 137.16, 136.00, 132.42, 129.52, 129.33, 128.91, 128.16, 122.78, 121.25, 118.66, 112.24, 108.54, 10.92. HRMS (ESI) calcd for C18H12N4 [M+H]+: 285.1130; found: 285.1135.

4.3.9 2-Methyl-1-(4-(trifluoromethyl)phenyl)pyrazolo [1,5c]quinazoline (3i): White solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.26 – 8.20 (m, 1H), 8.00 – 7.95 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 – 7.60 (m, 2H), 2.70 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.32, 140.03, 139.45, 136.18, 135.95, 130.65 (q, JC-F = 32.3 Hz), 129.37, 129.28, 128.95, 128.12, 125.65 (q, JC-F = 4.0 Hz), 124.14 (q, JC-F = 272.7 Hz), 122.87, 121.44, 108.54, 10.92. HRMS (ESI) calcd for C18H12F3N3 [M+H]+: 328.1054; found: 328.1056. 4.3.10 2-Methyl-1-(4-(methylthio)phenyl)pyrazolo[1,5-c] quinazoline (3j): White solid. Isolated yield = 62%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.26 – 8.16 (m, 1H), 7.97 – 7.92 (m, 1H), 7.69 –

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7.57 (m, 4H), 7.39 (d, J = 8.4 Hz, 2H), 2.67 (s,ACCEPTED 3H), 2.55 (s, 3H). MANUSCRIPT 4.3.17 1-Isopropyl-2-methylpyrazolo[5,1-a]isoquinoline (3q): 13 Yellow solid. Isolated yield = 50%. 1H NMR (400 MHz, CDCl3) C NMR (101 MHz, CDCl3) δ 155.34, 140.03, 139.56, 139.52, 135.68, 129.33, 129.04, 128.77, 127.87, 126.33, 122.83, 121.48, δ 8.97 (s, 1H), 8.16 – 8.10 (m, 1H), 7.93 – 7.86 (m, 1H), 7.62 – 108.27, 15.57, 10.99. HRMS (ESI) calcd for C18H15N3S [M+H]+: 7.52 (m, 2H), 3.31 – 3.18 (m, 1H), 2.52 (s, 3H), 1.41 (d, J = 6.8 306.1055; found: 306.1059. Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.36, 140.05, 139.70, 134.90, 128.72, 128.51, 127.55, 122.82, 121.47, 107.58, 26.41, 21.89, 9.76. HRMS (ESI) calcd for C14H15N3 [M+H]+: 226.1336; 4.3.11 2-Methyl-1-(m-tolyl)pyrazolo[5,1-c]isoquinoline (3k): White solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ found: 226.1339. 9.06 (s, 1H), 8.27 – 8.20 (m, 1H), 7.99 – 7.93 (m, 1H), 7.68 – 7.59 (m, 2H), 7.57 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 4.3.18 2-(4-bromophenyl)-8,9-dimethoxy-1-methyl- pyrazolo 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 2.68 (s, 3H), 2.46 (s, 3H). [1,5-c]quinazoline (3r): 13 C NMR (101 MHz, CDCl3) δ 156.09, 140.07, 139.61, 138.49, White solid. Isolated yield = 45%. 1H NMR (400 MHz, CDCl3) δ 135.63, 132.35, 129.67, 129.51, 129.02, 128.78, 128.55, 127.87, 8.98 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 126.19, 122.88, 121.58, 108.39, 21.56, 10.97. HRMS (ESI) calcd 7.55 (s, 2H), 7.38 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 2.64 (s, 3H). 13 for C18H15N3 [M+H]+: 274.1334; found: 274.1339. C NMR (101 MHz, CDCl3) δ 154.49, 150.49, 149.58, 138.07, 135.92, 135.46, 131.87, 131.60, 130.55, 122.99, 115.15, 109.68, 105.92, 102.90, 56.18, 56.15, 10.79. HRMS (ESI) calcd for 4.3.12 2-Methyl-1-(naphthalen-1-yl)pyrazolo[1,5-c] C19H16BrN3O2 [M+H]+: 398.0491; found: 398.0499. quinazoline (3l): Yellow solid. Isolated yield = 55%. 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.25 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 – 7.92 (m, 3H), 4.3.19 1-(4-Bromophenyl)-9-chloro-2-methylpyrazolo [1,57.84 (d, J = 8.4 Hz, 1H), 7.72 – 7.59 (m, 4H), 7.57 – 7.45 (m, 2H), c]quinazoline (3s): 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.71, 140.15, White solid. Isolated yield = 60%. 1H NMR (400 MHz, CDCl3) δ 139.68, 135.29, 133.70, 132.20, 129.78, 129.37, 129.16, 128.83, 8.99 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 128.62, 128.42, 128.00, 126.67, 126.10, 125.78, 125.24, 122.99, 7.65 (d, J = 8.8 Hz, 2H), 7. 59 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 121.56, 110.34, 10.81. HRMS (ESI) calcd for C21H15N3 [M+H]+: 8.8, 2.4 Hz, 1H), 2.62 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 310.1334; found: 310.1339. 154.85, 139.52, 138.41, 134.67, 133.66, 131.96, 131.10, 130.54, 130.22, 129.47, 123.31, 122.35, 122.21, 108.87, 10.84. HRMS (ESI) calcd for C17H11BrClN3 [M+H]+: 371.9892; found: 4.3.13 2-Methyl-1-(naphthalen-2-yl)pyrazolo[1,5-c] 371.9898. quinazoline (3m): Yellow solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.26 – 8.21 (m, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.0 4.3.20 9-bromo-2-(4-bromophenyl)-1-methylpyrazolo [1,5-c] Hz, 2H), 7.96 – 7.84 (m, 3H), 7.69 – 7.59 (m, 2H), 7.57 – 7.50 quinazoline (3t): (m, 2H), 2.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.04, White solid. Isolated yield = 40%. 1H NMR (400 MHz, CDCl3) δ 139.74, 139.60, 135.75, 133.27, 133.25, 129.82, 129.14, 128.61, 9.04 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 128.50, 128.44, 128.39, 128.01, 127.80, 126.67, 126.53, 126.48, 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J 122.91, 121.49, 108.80, 11.11. HRMS (ESI) calcd for C21H15N3 = 8.4 Hz, 2H), 2.65 (s, 3H). 13C NMR (101 MHz, CDCl3) δ [M+H]+: 310.1335; found: 310.1339. 154.98, 139.72, 138.83, 134.58, 132.36, 132.00, 131.13, 130.58, 130.46, 125.37, 123.34, 122.84, 121.77, 108.96, 10.89. HRMS (ESI) calcd for C17H11Br2N3 [M+H]+: 415.9384; found: 415.9392. 4.3.14 Phenylpyrazolo[1,5-c]quinazoline (3n): White solid. Isolated yield = 83%. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.04 – 7.88 (m, 4H), 7.67 – 7.53 (m, 2H), 7.51 – 4.3.21 1-methyl-1-nitro-2-phenyl-3-tosyl-1,2,3,10b-tetra7.37 (m, 3H), 7.20 (s, 1H). 13C NMR (101 MHz, CDCl3) δ hydropyrazolo[1,5-c]quinazoline (4): 155.87, 140.02, 139.75, 139.26, 132.16, 129.78, 129.27, 128.90, Quinazolin-3-ium-3-yl(tosyl)amide 1a (71.8 mg, 0.24 mmol), 1128.75, 128.10, 126.71, 123.25, 119.97, 95.34. HRMS (ESI) (2-nitroprop-1-enyl)benzene 2a (32.6 mg, 0.20 mmol) were calcd for C16H11N3 [M+H]+: 246.1022; found: 246.1026. added in a clean sealed Schlenk tube equipped with a stir bar. After flushing the Schlenk tube three times with N2 atmosphere, DMSO (2 mL) was injected in the tube through a syringe. The 4.3.15 2-Ethyl-1-phenylpyrazolo[1,5-c]quinazoline (3o): White solid. Isolated yield = 40%. 1H NMR (400 MHz, CDCl3) δ reaction was then stirred at 60 oC for 24 h. After completion of 9.08 (s, 1H), 8.21 – 8.15 (m, 1H), 8.00 – 7.93 (m, 1H), 7.74 – the reaction, as indicated by TLC, the mixture was quenched by 7.69 (m, 2H), 7.69 – 7.60 (m, 2H), 7.56 – 7.44 (m, 3H), 3.10 (q, J saturated brine and extracted with ethyl ether (3 × 10 mL). The = 7.6 Hz, 2H), 1.42 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, organic layers were combined and dried over anhydrous Na2SO4. CDCl3) δ 155.59, 140.12, 139.71, 135.26, 132.66, 129.08, 128.94, The pure product 4 (yield 67%, 41.0 mg) was obtained by flash 128.77, 128.74, 128.09, 122.88, 121.22, 115.46, 17.70, 14.78. column chromatography on silica gel (petroleumether : ethyl HRMS (ESI) calcd for C18H15N3 [M+H]+: 274.1336; found: acetate = 4 : 1). White solid. 1H NMR (400 MHz, CDCl3) δ 7.98 274.1339. (d, J = 8.4 Hz, 2H), 7.54 – 7.30 (m, 10H), 7.18 – 7.11 (m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H), 4.76 (s, 1H), 2.54 (s, 3H), 0.92 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.87, 146.39, 4.3.16 1-Cyclohexyl-2-methylpyrazolo[5,1-a]isoquinoline (3p): 1 White solid. Isolated yield = 40%. H NMR (400 MHz, CDCl3) δ 139.04, 134.14, 130.72, 130.51, 130.41, 129.57, 129.27, 129.08, 8.96 (s, 1H), 8.15 – 8.07 (m, 1H), 7.91 – 7.84 (m, 1H), 7.62 – 127.43, 127.13, 126.73, 126.24, 118.40, 97.98, 68.96, 65.22, 7.48 (m, 2H), 2.91 – 2.81 (m, 1H), 2.50 (s, 3H), 1.99 (d, J = 12.4 21.92, 14.81. HRMS (ESI) calcd for C24H22N4O4S [M+H]+: Hz, 2H), 1.91 (d, J = 12.8 Hz, 2H), 1.79 (d, J = 11.6 Hz, 1H), 463.1443; found: 463.1439. 1.75 – 1.61 (m, 2H), 1.53 – 1.28 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 161.58, 139.98, 139.64, 134.71, 128.64, 128.44, 127.47, This work was financially supported by the National Natural 122.78, 121.44, 107.62, 36.20, 32.27, 26.67, 26.08, 9.75. HRMS Science Foundation of China (Nos. 21262018 and 20862007) (ESI) calcd for C17H19N3 [M+H]+: 266.1648; found: 266.1652.

and the Natural Science Foundation of Jiangxi Province

2

Tetrahedron

ACCEPTED MANUSCRIPT

(2010GZH0070).

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1. (a) Asproni, B.; Murineddu, G.; Pau, A.; Pinna, G. A.; Langgard, M.; Christoffersen, C. T.; Nielsen, J.; Kehler, J. Bioorg. Med. Chem. 2011, 19, 642; (b) Asproni, B.; Murineddu, G.; Pau, A.; Pinna, G. A.; Langgård, M.; Christoffersen, C. T.; Nielsen, J.; Kehler, J. Bioorgan. Med. Chem. 2011, 19, 642-649; (c) Beaulieu, F.; Ouellet, C.; Ruediger, E. H.; Belema, M.; Qiu, Y.; Yang, X.; Banville, J.; Burke, J. R.; Gregor, K. R.; MacMaster, J. F.; Martel, A.; McIntyre, K. W.; Pattoli, M. A.; Zusi, F. C.; Vyas, D. Bioorg. Med. Chem. Lett 2007, 17, 1233-1237; (d) Jew, S. S.; Kim, H. J.; Kim, M. G.; Roh, E. Y.; Cho, Y. S.; Kim, J. K.; Cha, K. H.; Lee, K. K.; Han, H. J.; Choi, J. Y.; Lee, H. Bioorg. Med. Chem. Lett. 1996, 6, 845; (e) Nagarajan, S.; Skoufias, D. A.; Kozielski, F.; Pae, A. N. J. Med. Chem. 2012, 55, 2561; (f) Nuth, M.; Huang, L.; Saw, Y. L.; Schormann, N.; Chattopadhyay, D.; Ricciardi, R. P. J. Med. Chem. 2011, 54, 3260. 2. (a) Varano, F.; Catarzi, D.; Colotta, V.; Calabri, F. R.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C.; Deflorian, F.; Moro, S. Bioorgan. Med. Chem. 2005, 13, 5536-5549; (b) Varano, F.; Catarzi, D.; Colotta, V.; Calabri, F. R.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C.; Deflorian, F.; Moro, S. Bioorg. Med. Chem. 2005, 13, 5536; (c) Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli, A.; Costagli, C.; Carlà, V. J. Med. Chem. 2002, 45, 1035; (d) Varano, F.; Catarzi, D.; Colotta, V.; Lenzi, O.; Filacchioni, G.; Galli, A.; Costagli, C. Bioorgan. Med. Chem. 2008, 16, 2617-2626; (e) Janjić, M.; Prebil, R.; Grošelj, U.; Kralj, D.; Malavašič, Č.; Golobič, A.; Stare, K.; Dahmann, G.; Stanovnik, B.; Svete, J. Helv. Chim. Acta 2011, 94, 1703; (f) deStevens, G.; Halamandaris, A.; Bernier, M.; Blatter, H. M. J. Org. Chem. 1963, 28, 1336. 3. Yang, X.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. RSC Adv. 2012, 2, 11061. 4. Guo, S.; Wang, J.; Fan, X.; Zhang, X.; Guo, D. J. Org. Chem. 2013, 78, 3262-3270. 5. (a) Gao, M.; Tian, J.; Lei, A. Chemistry – An Asian Journal 2014, 9, 20682071; (b) Tang, D.; Wu, P.; Liu, X.; Chen, Y.-X.; Guo, S.-B.; Chen, W.-L.; Li, J.-G.; Chen, B.-H. J. Org. Chem. 2013, 78, 2746-2750; (c) Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Org. Lett. 2011, 13, 4668-4671; (d) Yan, R.-L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. J. Org. Chem. 2012, 77, 2024-2028; (e) Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green Chem. 2011, 13, 1664-1668; (f) Zhu, H.; Shao, N.; Chen, T.; Zou, H. Chem. Commun. 2013, 49, 7738-7740; (g) Liu, X.; Wang, D.; Chen, B. Tetrahedron 2013, 69, 9417-9421; (h) Yang, D.; Fan M.; Zhu, H.; Guo, Y.; Guo, J. Sythesis 2013, 45, 1325-1332; (i) Fuito, H.;Tominga, Y.; Matsuda, Y.; Kobayashi, G.Heterocycles 1977, 6, 379. 6. (a) Huang, P.; Yang, Q.; Chen, Z.; Ding, Q.; Xu, J.; Peng, Y. J. Org. Chem. 2012, 77, 8092-8098; (b) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778-10779; (c) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469-3471; (d) Qiu, G.; Kuang, Y.; Wu, J. Adv. Synth. Catal. 2014, 356, 3483-3504; (e) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. Adv. Synth. Catal. 2009, 351, 1692-1698; (f) Xu, X.; Doyle, M. P. Acc. Chem. Res. 2014, 47, 13961405.

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References and notes

Supplementary Material

Supplementary material that may be helpful in the review process should be prepared and provided as a separate electronic file. That file can then be transformed into PDF format and submitted along with the manuscript and graphic files to the appropriate editorial office.

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Supporting Information An Efficient [3+2] Cycloaddition for the Synthesis of Substituted

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Pyrazolo[1,5-c] Quinazolines

a

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Tao Wanga, Ailong Shaoa, Haiyan Fenga, Shuwu Yanga, Jun Tianc, Meng Gaoa * and Aiwen Leia, b, * National Research Center for Carbohydrate Synthesis and Key Laboratory of Chemical Biology, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China

College of Chemistry and Molecular Sciences Wuhan University, Wuhan 430072,

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b

P. R. China

E-mail:

[email protected]

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[email protected]

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Table of Contents

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General information……………………………………………………………….S2 General procedure………………………………………………………………....S3 X-Ray data of complex 3g………………………………………………..………..S5 Detailed descriptions for products………………………………………………..S18 References……………………………….…………………………………....…....S28

1

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General Information Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates. Flash chromatography columns were packed with 200 – 300 mesh silica gel in petroleum

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(boiling point is between 60 – 90 oC). Gradient flash chromatography was conducted eluting with a continuous gradient from petroleum to the indicated solvent, and they are listed as volume/volume ratios. NMR spectra were recorded on a Bruker

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spectrometer at 400 MHz (1H NMR), 101 MHz (13C NMR). Tetramethylsilane was

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used as an internal standard. All 1H NMR spectra were reported in delta (δ) units, parts per million (ppm) downfield from the internal standard. Coupling constants are reported in Hertz (Hz). High resolution mass spectra (HRMS) were measured with a Waters Micromass GCT instrument, accurate masses are reported for the molecular

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ion ([M+H]+).

2

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1. General Procedures 1.1 General procedure for preparation of pyrazolo[1,

1a

(71.8

mg,

0.24

mmol),

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Quinazolin-3-ium-3-yl(tosyl)amide

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2-methyl-1-phenylpyrazolo[1,5-c]quinazoline (3a)

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5-c]quinazolines derivatives

1-(2-nitroprop-1-enyl)benzene 2a (32.6 mg, 0.20 mmol) were added in a clean sealed Schlenk tube equipped with a stir bar. After flushing the Schlenk tube three times with N2 atmosphere, DMSO (2 mL) was injected in the tube through a syringe. The

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reaction was then stirred at 110 oC for 24 h. After completion of the reaction, as indicated by TLC, the mixture was quenched by saturated brine and extracted with ethyl ether (3 × 10 mL). The organic layers were combined and dried over anhydrous

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Na2SO4. The pure product 3a (yield 90%, 46.6 mg) was obtained by flash column

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chromatography on silica gel (petroleumether : ethyl acetate = 15 : 1).

1.2

General

procedure

N-iminoquinazolinium ylides1 2-Nitro-benzylidene hydrazide:

3

for

preparation

of

ACCEPTED MANUSCRIPT Tosylhydrazide (1.55 g, 8.3 mmol) was added to a solution of 2-nitrobenzaldehyde (1.25 g, 8.3 mmol) in 30 mL of ethanol. The solution was stirred at reflux for 1 h. During the reaction, a large amount of solid generated. After the filtration, washed by

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ether, dried, the crude product was crystallized from ethanol to give yield 80% of the N,-(2-nitro-benzylidene) hydrazide. N,-(2-Amino-benzylidene) hydrazide:

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A mixture of 2-nitro-benzylidene hydrazide (0.99 g, 3 mmol), iron powder (1.12 g, 20

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mmol), concd HCl (2 drops), and a mixture of EtOH, HOAc and H2O (10 mL: 10 mL : 5 mL) was refluxed for 15 min and then stirred at 25 °C for 25 min. The solution was filtered and diluted with 20 mL of water. The mixture was then extracted with CH2Cl2 (3 × 30 mL). The organic layer was washed with saturated NaHCO3 (2 × 30 mL), H2O

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(2 × 10 mL) and dried using anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel to provide the corresponding yield 87% of N,-(2-amino-benzylidene) hydrazide.

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Quinazolin-3-ium-3-yl(tosyl)amide: hydrazide

(2.89

g,

10.00

mmol)

and

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N,-(2-Amino-benzylidene)

Diethoxy-methoxy-ethane (5.00 g, 37.79 mmol) were dissolved in 100 mL flask, and the reaction was stirred 80 oC for 1 h. During the reaction, a large amount of solid generated. After the filtration, washed by ether, dried, the crude product was crystallized

from

acetonitrile

to

quinazolin-3-ium-3-yl(tosyl)amide.

4

give

yield

85%

of

the

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2. X-Ray data of complex 3g

Figure S1. X-Ray crystal structure of complex 3g (Thermal ellipsoids are drawn at 30% probability level)

Table 1. Crystal data and structure refinement for 12.

Empirical formula Formula weight

12

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Identification code

C17 H12 Cl N3 293.75 296(2) K

Wavelength

0.71073 A

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Temperature

Crystal system, space group Unit cell dimensions

Monoclinic, P2(1)/c a = 7.4330(15) A

Volume Z, Calculated density

b = 24.311(5) A

beta = 101.805(3) deg.

c = 8.0510(15) A

gamma = 90 deg.

1424.1(5) A^3 4, 1.370 Mg/m^3 5

alpha = 90 deg.

ACCEPTED MANUSCRIPT Absorption coefficient F(000)

0.264 mm^-1 608 0.29 x 0.28 x 0.27 mm

Theta range for data collection

-9<=h<=6, -32<=k<=26, -10<=l<=10

Completeness to theta = 28.39 Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters

99.7 %

Semi-empirical from equivalents 0.9321 and 0.9274

Full-matrix least-squares on F^2

3558 / 0 / 192 2.419

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Goodness-of-fit on F^2

10464 / 3558 [R(int) = 0.0238]

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Reflections collected / unique

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Limiting indices

1.68 to 28.39 deg.

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Crystal size

Final R indices [I>2sigma(I)]

R1 = 0.0534, wR2 = 0.0790 R1 = 0.0781, wR2 = 0.0809

Extinction coefficient

0.0035(7)

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R indices (all data)

0.427 and -0.391 e.A^-3

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Largest diff. peak and hole

Table 2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for 12.

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

6

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y

z

U(eq)

________________________________________________________________ 2551(1)

6856(2)

C(2)

9430(2)

2720(1)

6191(2)

C(3)

10611(3)

2337(1)

5759(2)

C(4)

10332(3)

1785(1)

5987(2)

C(5)

8891(3)

1610(1)

C(6)

7645(3)

N(1)

6200(2)

N(2)

5249(2)

C(10)

4717(2)

57(1)

73(1)

86(1)

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6657(2)

75(1)

1987(1)

7093(2)

52(1)

1782(1)

7771(2)

57(1)

2687(1)

8007(1)

41(1)

3538(1)

8014(2)

41(1)

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C(9)

44(1)

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7928(2)

SC

C(1)

6291(2)

3483(1)

7322(2)

42(1)

7390(3)

3939(1)

6752(2)

64(1)

C(12)

3767(2)

4049(1)

8348(2)

44(1)

C(13)

3807(2)

4210(1)

10007(2)

50(1)

C(14)

2921(3)

4679(1)

10363(2)

63(1)

C(15)

1999(3)

4998(1)

9080(3)

71(1)

C(16)

1925(3)

4854(1)

7422(3)

77(1)

C(17)

2801(3)

4380(1)

7074(2)

63(1)

Cl(1)

2614(1)

4187(1)

4967(1)

121(1)

C(7)

5085(3)

2129(1)

8199(2)

51(1)

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C(11)

7

ACCEPTED MANUSCRIPT C(8)

6617(2)

2925(1)

7328(2)

39(1)

N(3)

4062(2)

3059(1)

8452(2)

45(1)

________________________________________________________________

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Table 3. Selected bond lengths [A] and angles [deg] for 12. _____________________________________________________________ _____________________________________________________________

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Symmetry transformations used to generate equivalent atoms:

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Table 4. Bond lengths [A] and angles [deg] for 12.

_____________________________________________________________ C(1)-C(2)

1.395(2)

C(1)-C(6)

1.406(2)

C(2)-C(3) C(2)-H(2)

1.4389(19)

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C(1)-C(8)

1.371(2) 0.9300 1.377(2)

C(3)-H(3)

0.9300

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C(3)-C(4)

C(4)-C(5)

1.362(3)

C(4)-H(4)

0.9300

C(5)-C(6)

1.398(2)

C(5)-H(5)

0.9300

C(6)-N(1)

1.393(2)

N(1)-C(7)

1.2788(19) 8

1.3620(15)

N(2)-C(7)

1.3719(16)

N(2)-C(8)

1.3768(17)

C(10)-N(3)

1.3365(16)

C(10)-C(9)

1.401(2)

C(10)-C(12)

1.4823(18)

C(9)-C(8)

1.3788(18)

C(9)-C(11)

1.5036(19)

C(11)-H(11B) C(11)-H(11C)

0.9600

0.9600

0.9600

1.3859(18)

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C(12)-C(13)

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C(11)-H(11A)

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N(2)-N(3)

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1.383(2)

C(13)-C(14)

1.3756(19)

C(13)-H(13)

0.9300

C(14)-C(15)

1.361(2)

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C(12)-C(17)

C(14)-H(14)

0.9300

C(15)-C(16)

1.371(2)

C(15)-H(15)

0.9300

C(16)-C(17)

1.380(2)

C(16)-H(16)

0.9300

C(17)-Cl(1)

1.7375(17) 9

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119.45(14)

C(2)-C(1)-C(8)

123.70(14)

C(6)-C(1)-C(8)

116.85(15)

C(3)-C(2)-C(1)

120.18(17)

C(3)-C(2)-H(2)

119.9

C(1)-C(2)-H(2)

119.9

C(2)-C(3)-C(4)

120.38(19)

C(2)-C(3)-H(3) C(4)-C(3)-H(3) C(5)-C(4)-C(3)

119.8 119.8

120.59(17) 119.7

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C(5)-C(4)-H(4)

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C(2)-C(1)-C(6)

119.7

C(4)-C(5)-C(6)

120.66(18)

C(4)-C(5)-H(5)

119.7

C(6)-C(5)-H(5)

119.7

EP

C(3)-C(4)-H(4)

AC C

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0.9300

SC

C(7)-H(7)

C(5)-C(6)-N(1)

117.85(16)

C(5)-C(6)-C(1)

118.73(18)

N(1)-C(6)-C(1)

123.41(14)

C(7)-N(1)-C(6)

117.63(13)

N(3)-N(2)-C(7)

123.33(13)

N(3)-N(2)-C(8)

113.32(11) 10

N(3)-C(10)-C(9)

113.68(12)

N(3)-C(10)-C(12)

118.03(13)

C(9)-C(10)-C(12)

128.26(12)

C(8)-C(9)-C(10)

104.60(12)

C(8)-C(9)-C(11)

128.39(14)

C(10)-C(9)-C(11)

126.99(13)

C(9)-C(11)-H(11A)

109.5

C(9)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(9)-C(11)-H(11C)

109.5

109.5

109.5

109.5

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H(11A)-C(11)-H(11C) H(11B)-C(11)-H(11C)

109.5

117.19(13)

C(13)-C(12)-C(10)

119.59(13)

C(17)-C(12)-C(10)

123.21(13)

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C(13)-C(12)-C(17)

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SC

123.35(12)

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C(7)-N(2)-C(8)

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C(14)-C(13)-C(12)

121.13(15)

C(14)-C(13)-H(13)

119.4

C(12)-C(13)-H(13)

119.4

C(15)-C(14)-C(13)

120.22(16)

C(15)-C(14)-H(14)

119.9

C(13)-C(14)-H(14)

119.9 11

C(14)-C(15)-H(15)

119.8

C(16)-C(15)-H(15)

119.8

C(15)-C(16)-C(17)

119.02(16)

C(15)-C(16)-H(16)

120.5

C(17)-C(16)-H(16)

120.5

C(16)-C(17)-C(12)

121.98(15)

C(16)-C(17)-Cl(1)

118.46(14)

C(12)-C(17)-Cl(1) N(1)-C(7)-N(2) N(1)-C(7)-H(7)

119.53(12)

122.97(16) 118.5 118.5

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N(2)-C(7)-H(7)

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120.45(15)

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C(14)-C(15)-C(16)

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105.77(12)

N(2)-C(8)-C(1)

115.77(12)

C(9)-C(8)-C(1)

138.46(14)

C(10)-N(3)-N(2)

102.62(12)

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N(2)-C(8)-C(9)

_____________________________________________________________ Symmetry transformations used to generate equivalent atoms:

Table 5. Anisotropic displacement parameters (A^2 x 10^3) for 12.

The anisotropic displacement factor exponent takes the form: 12

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U22

U33

U23

U13

U12

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_______________________________________________________________________ 42(1)

53(1)

32(1)

-9(1)

-3(1)

11(1)

C(2)

48(1)

77(1)

44(1)

-10(1)

5(1)

12(1)

C(3)

50(1)

113(2)

52(1)

-18(1)

1(1)

23(1)

C(4)

73(2)

109(2)

67(1)

-31(1)

-3(1)

48(1)

C(5)

82(2)

65(1)

C(6)

58(1)

53(1)

N(1)

70(1)

41(1)

N(2)

44(1)

36(1)

C(10)

42(1)

C(9)

45(1)

C(11) C(12)

M AN U

SC

C(1)

-19(1)

-6(1)

33(1)

39(1)

-11(1)

-7(1)

16(1)

52(1)

-7(1)

-2(1)

7(1)

41(1)

-3(1)

5(1)

1(1)

TE D

67(1)

40(1)

-3(1)

6(1)

1(1)

40(1)

40(1)

-3(1)

9(1)

-2(1)

73(2)

51(1)

73(1)

-6(1)

28(1)

-9(1)

41(1)

38(1)

53(1)

-2(1)

12(1)

1(1)

AC C

EP

39(1)

C(13)

59(1)

37(1)

59(1)

1(1)

24(1)

-2(1)

C(14)

79(2)

43(1)

78(1)

-5(1)

42(1)

1(1)

C(15)

73(2)

44(1)

105(2)

0(1)

41(1)

13(1)

C(16)

78(2)

61(1)

89(2)

14(1)

10(1)

25(1)

C(17)

66(1)

62(1)

57(1)

0(1)

7(1)

16(1)

Cl(1)

163(1)

128(1)

58(1)

-2(1) 13

-11(1)

63(1)

ACCEPTED MANUSCRIPT C(7)

62(1)

40(1)

45(1)

-1(1)

0(1)

-6(1)

C(8)

40(1)

44(1)

31(1)

-5(1)

4(1)

0(1)

N(3)

43(1)

42(1)

50(1)

-4(1)

10(1)

2(1)

Table 6. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for 12.

RI PT

_______________________________________________________________________

y

z

M AN U

x

SC

________________________________________________________________ U(eq)

________________________________________________________________ 9631

H(3)

11606

H(4)

11135

H(5)

3092

6040

68

2452

5309

88

1528

5681

103

TE D

H(2)

8734

1236

6827

89

8616

3935

7422

96

H(11B)

6822

4286

6891

96

H(11C)

7432

3888

5578

96

H(13)

4445

3997

10895

60

H(14)

2951

4777

11485

76

H(15)

1417

5317

9330

85

H(16)

1292

5072

6544

92

H(7)

4119

1998

8662

61

AC C

EP

H(11A)

________________________________________________________________ 14

ACCEPTED MANUSCRIPT Table 7. Selected torsion angles [deg] for 12. ________________________________________________________________ ________________________________________________________________

Table 8. Torsion angles [deg] for 12.

RI PT

Symmetry transformations used to generate equivalent atoms:

________________________________________________________________ 0.5(2)

SC

C(6)-C(1)-C(2)-C(3)

C(1)-C(2)-C(3)-C(4) C(2)-C(3)-C(4)-C(5) C(3)-C(4)-C(5)-C(6)

TE D

C(4)-C(5)-C(6)-N(1)

-179.51(14)

M AN U

C(8)-C(1)-C(2)-C(3)

-0.4(2) -0.5(3) 1.4(3) 179.97(17) -1.2(3)

C(2)-C(1)-C(6)-C(5)

0.2(2)

C(8)-C(1)-C(6)-C(5)

-179.71(14)

C(2)-C(1)-C(6)-N(1)

179.01(14)

AC C

EP

C(4)-C(5)-C(6)-C(1)

C(8)-C(1)-C(6)-N(1)

-0.9(2)

C(5)-C(6)-N(1)-C(7)

178.63(14)

C(1)-C(6)-N(1)-C(7)

-0.2(2)

N(3)-C(10)-C(9)-C(8)

0.36(16)

C(12)-C(10)-C(9)-C(8)

178.48(14)

N(3)-C(10)-C(9)-C(11)

-178.11(14) 15

ACCEPTED MANUSCRIPT C(12)-C(10)-C(9)-C(11)

0.0(2) 66.66(19)

C(9)-C(10)-C(12)-C(13)

-111.38(18)

N(3)-C(10)-C(12)-C(17)

-112.49(17)

RI PT

N(3)-C(10)-C(12)-C(13)

C(9)-C(10)-C(12)-C(17)

69.5(2)

C(17)-C(12)-C(13)-C(14)

0.0(2)

-179.17(15)

SC

C(10)-C(12)-C(13)-C(14)

C(13)-C(14)-C(15)-C(16) C(14)-C(15)-C(16)-C(17) C(15)-C(16)-C(17)-C(12)

TE D

C(15)-C(16)-C(17)-Cl(1)

-0.8(3)

M AN U

C(12)-C(13)-C(14)-C(15)

0.9(3) -0.2(3) -0.6(3) 177.39(16)

C(13)-C(12)-C(17)-C(16)

0.6(3)

C(10)-C(12)-C(17)-C(16)

179.82(17) -177.30(12)

C(10)-C(12)-C(17)-Cl(1)

1.9(2)

AC C

EP

C(13)-C(12)-C(17)-Cl(1)

C(6)-N(1)-C(7)-N(2)

0.5(2)

N(3)-N(2)-C(7)-N(1)

179.66(14)

C(8)-N(2)-C(7)-N(1)

0.4(2)

N(3)-N(2)-C(8)-C(9)

-0.43(16)

C(7)-N(2)-C(8)-C(9)

178.89(12)

N(3)-N(2)-C(8)-C(1)

179.20(11) 16

ACCEPTED MANUSCRIPT C(7)-N(2)-C(8)-C(1)

-1.48(19) 0.04(15)

C(11)-C(9)-C(8)-N(2)

178.48(14)

C(10)-C(9)-C(8)-C(1)

-179.46(16)

RI PT

C(10)-C(9)-C(8)-N(2)

C(11)-C(9)-C(8)-C(1)

-1.0(3)

C(2)-C(1)-C(8)-N(2)

-178.29(13)

1.66(18)

SC

C(6)-C(1)-C(8)-N(2)

C(6)-C(1)-C(8)-C(9) C(9)-C(10)-N(3)-N(2) C(12)-C(10)-N(3)-N(2)

TE D

C(7)-N(2)-N(3)-C(10)

1.2(3)

M AN U

C(2)-C(1)-C(8)-C(9)

C(8)-N(2)-N(3)-C(10)

-178.88(16) -0.60(15) -178.92(12) -178.69(12) 0.62(15)

________________________________________________________________

EP

Symmetry transformations used to generate equivalent atoms:

AC C

Table 9. Hydrogen bonds for 12 [A and deg.]. ____________________________________________________________________________ D-H...A

d(D-H)

d(H...A)

17

d(D...A)

<(DHA)

ACCEPTED MANUSCRIPT

2-Methyl-1-phenylpyrazolo[1,5-c]quinazoline (3a):

RI PT

Detailed descriptions for products:

White solid. Isolated yield = 90%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.23 –

SC

8.20 (m, 1H), 7.98 – 7.68 (m, 1H), 7.77 – 7.70 (m, 2H), 7.66 – 7.43 (m, 5H), 2.66 (s,

M AN U

3H). 13C NMR (101 MHz, CDCl3) δ 155.83, 139.98, 139.53, 135.58, 132.43, 129.03, 128.97, 128.71, 128.67, 127.81, 122.79, 121.48, 108.32, 10.91. HRMS (ESI) calcd for

TE D

C17H13N3 [M+H]+: 260.1179; found: 260.1182.

EP

1-(4-Bromophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3b):

AC C

White solid. Isolated yield = 92%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.22 – 8.17 (m, 1H), 7.97 – 7.92 (m, 1H), 7.69 – 7.56 (m, 6H), 2.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.65, 139.99, 139.43, 135.78, 131.89, 131.42, 130.56, 129.15, 128.83, 127.97, 123.11, 122.81, 121.39, 108.25, 10.92. HRMS (ESI) calcd for C17H12BrN3 [M+H]+: 338.0283; found: 338.0287.

18

RI PT

ACCEPTED MANUSCRIPT

1-(4-Fluorophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3c):

White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.27 –

SC

8.19 (m, 1H), 8.00 – 7.93 (m, 1H), 7.76 – 7.58 (m, 4H), 7.28 – 7.18 (m, 2H), 2.67 (s,

M AN U

3H). 13C NMR (101 MHz, CDCl3) δ 163.14 (d, J = 249.5 Hz), 155.00, 140.09, 139.53, 135.77, 130.87 (d, JC-F = 9.1 Hz), 129.16, 128.86, 128.59 (d, JC-F = 3.0 Hz), 127.98, 122.88, 121.50, 115.80 (d, JC-F = 21.2 Hz), 108.22, 10.93. HRMS (ESI) calcd for

EP

TE D

C17H12FN3 [M+H]+: 278.1084; found: 278.1088.

1-(2-Bromophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3d):

AC C

White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.21 (dd, J = 7.6, 1.6 Hz, 1H), 8.02 – 7.95 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.49 – 7.41 (m, 2H), 7.38 – 7.32 (m, 1H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.11, 139.99, 139.59, 135.08, 133.71, 132.91, 132.22, 130.52, 129.16, 128.77, 128.03, 127.36, 124.06, 122.97, 121.58, 110.01, 10.85. HRMS (ESI) calcd for C17H12BrN3 [M+H]+: 338.0283; found: 338.0287.

19

RI PT

ACCEPTED MANUSCRIPT

N,N-dimethyl-4-(2-methylpyrazolo[1,5-c]quinazolin-1-yl)aniline (3e):

SC

Orange solid. Isolated yield = 45%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.25 – 8.19 (m, 1H), 7.97 – 7.89 (m, 1H), 7.67 – 7.56 (m, 4H), 6.87 – 6.82 (m, 2H), 3.04 (s,

M AN U

6H), 2.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.34, 150.64, 140.15, 139.66, 135.50, 129.84, 128.82, 128.66, 127.64, 122.87, 121.60, 120.08, 112.24, 108.01, 99.98, 40.44, 11.16. HRMS (ESI) calcd for C19H18N4 [M+H]+: 303.1600; found:

EP

TE D

303.1604.

AC C

1-(4-Methoxyphenyl)-2-methylpyrazolo[1,5-c]quinazoline (3f): White solid. Isolated yield = 60%. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.24 – 8.17 (m, 1H), 7.98 – 7.90 (m, 1H), 7.71 – 7.56 (m, 4H), 7.08 – 7.01 (m, 2H), 3.88 (s, 3H), 2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.02, 155.72, 140.07, 139.57, 135.58, 130.29, 128.96, 128.72, 127.78, 124.87, 122.84, 121.52, 114.16, 108.11, 55.39, 11.00. HRMS (ESI) calcd for C18H15N3O [M+H]+: 290.1283; found: 290.1288.

20

RI PT

ACCEPTED MANUSCRIPT

1-(2-Chlorophenyl)-2-methylpyrazolo[1,5-c]quinazoline (3g):

White solid. Isolated yield = 70%. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.24 –

SC

8.19 (m, 1H), 8.00 – 7.94 (m, 1H), 7.70 – 7.59 (m, 2H), 7.57 – 7.53 (m, 1H), 7.52 – 7.48 (m, 1H), 7.47 – 7.37 (m, 2H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ

M AN U

154.63, 140.00, 139.56, 135.10, 134.22, 132.21, 131.63, 130.37, 129.80, 129.14, 128.78, 128.01, 126.84, 122.95, 121.55, 110.23, 10.79. HRMS (ESI) calcd for

EP

TE D

C17H12ClN3 [M+H]+: 294.0788; found: 294.0793.

4-(2-Methylpyrazolo[1,5-c]quinazolin-1-yl)benzonitrile (3h):

AC C

White solid. Isolated yield = 90%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.25 – 8.17 (m, 1H), 7.99 – 7.93 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.70 – 7.59 (m, 2H), 2.68 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 153.53, 139.89,

139.26, 137.16, 136.00, 132.42, 129.52, 129.33, 128.91, 128.16, 122.78, 121.25, 118.66, 112.24, 108.54, 10.92. HRMS (ESI) calcd for C18H12N4 [M+H]+: 285.1130; found: 285.1135.

21

RI PT

ACCEPTED MANUSCRIPT

2-Methyl-1-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-c]quinazoline (3i):

White solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.26 –

13

C NMR (101 MHz, CDCl3) δ 154.32, 140.03,

M AN U

7.70 – 7.60 (m, 2H), 2.70 (s, 3H).

SC

8.20 (m, 1H), 8.00 – 7.95 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H),

139.45, 136.18, 135.95, 130.65 (q, JC-F = 32.3 Hz), 129.37, 129.28, 128.95, 128.12, 125.65 (q, JC-F = 4.0 Hz), 124.14 (q, JC-F = 272.7 Hz), 122.87, 121.44, 108.54, 10.92.

EP

TE D

HRMS (ESI) calcd for C18H12F3N3 [M+H]+: 328.1054; found: 328.1056.

AC C

2-Methyl-1-(4-(methylthio)phenyl)pyrazolo[1,5-c]quinazoline (3j): White solid. Isolated yield = 62%. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.26 – 8.16 (m, 1H), 7.97 – 7.92 (m, 1H), 7.69 – 7.57 (m, 4H), 7.39 (d, J = 8.4 Hz, 2H), 2.67 (s, 3H), 2.55 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.34, 140.03, 139.56, 139.52, 135.68, 129.33, 129.04, 128.77, 127.87, 126.33, 122.83, 121.48, 108.27, 15.57, 10.99. HRMS (ESI) calcd for C18H15N3S [M+H]+: 306.1055; found: 306.1059.

22

2-Methyl-1-(m-tolyl)pyrazolo[5,1-a]isoquinoline (3k):

RI PT

ACCEPTED MANUSCRIPT

White solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.27 –

SC

8.20 (m, 1H), 7.99 – 7.93 (m, 1H), 7.68 – 7.59 (m, 2H), 7.57 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 2.68 (s, 3H), 2.46 (s, 3H). 13

M AN U

C NMR (101 MHz, CDCl3) δ 156.09, 140.07, 139.61, 138.49, 135.63, 132.35,

129.67, 129.51, 129.02, 128.78, 128.55, 127.87, 126.19, 122.88, 121.58, 108.39,

EP

TE D

21.56, 10.97. HRMS (ESI) calcd for C18H15N3 [M+H]+: 274.1334; found: 274.1339.

2-Methyl-1-(naphthalen-1-yl)pyrazolo[1,5-c]quinazoline (3l):

AC C

Yellow solid. Isolated yield = 55%. 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.25 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 – 7.92 (m, 3H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 – 7.59 (m, 4H), 7.57 – 7.45 (m, 2H), 2.46 (s, 3H).

13

C NMR (101 MHz, CDCl3) δ 155.71,

140.15, 139.68, 135.29, 133.70, 132.20, 129.78, 129.37, 129.16, 128.83, 128.62, 128.42, 128.00, 126.67, 126.10, 125.78, 125.24, 122.99, 121.56, 110.34, 10.81. HRMS (ESI) calcd for C21H15N3 [M+H]+: 310.1334; found: 310.1339.

23

RI PT

ACCEPTED MANUSCRIPT

2-Methyl-1-(naphthalen-2-yl)pyrazolo[1,5-c]quinazoline (3m):

SC

Yellow solid. Isolated yield = 80%. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.26 – 8.21 (m, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.96 – 7.84 (m, 3H), 7.69 – 7.59

M AN U

(m, 2H), 7.57 – 7.50 (m, 2H), 2.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.04, 139.74, 139.60, 135.75, 133.27, 133.25, 129.82, 129.14, 128.61, 128.50, 128.44, 128.39, 128.01, 127.80, 126.67, 126.53, 126.48, 122.91, 121.49, 108.80, 11.11.

EP

TE D

HRMS (ESI) calcd for C21H15N3 [M+H]+: 310.1335; found: 310.1339.

AC C

Phenylpyrazolo[1,5-c]quinazoline (3n): White solid. Isolated yield = 83%. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.04 – 7.88 (m, 4H), 7.67 – 7.53 (m, 2H), 7.51 – 7.37 (m, 3H), 7.20 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 155.87, 140.02, 139.75, 139.26, 132.16, 129.78, 129.27, 128.90, 128.75, 128.10, 126.71, 123.25, 119.97, 95.34. HRMS (ESI) calcd for C16H11N3 [M+H]+: 246.1022; found: 246.1026.

24

RI PT

ACCEPTED MANUSCRIPT

2-Ethyl-1-phenylpyrazolo[1,5-c]quinazoline (3o):

White solid. Isolated yield = 40%. 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.21 –

SC

8.15 (m, 1H), 8.00 – 7.93 (m, 1H), 7.74 – 7.69 (m, 2H), 7.69 – 7.60 (m, 2H), 7.56 – 7.44 (m, 3H), 3.10 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz,

M AN U

CDCl3) δ 155.59, 140.12, 139.71, 135.26, 132.66, 129.08, 128.94, 128.77, 128.74, 128.09, 122.88, 121.22, 115.46, 17.70, 14.78. HRMS (ESI) calcd for C18H15N3

TE D

[M+H]+: 274.1336; found: 274.1339.

EP

1-Cyclohexyl-2-methylpyrazolo[5,1-a]isoquinoline (3p):

AC C

White solid. Isolated yield = 40%. 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.15 – 8.07 (m, 1H), 7.91 – 7.84 (m, 1H), 7.62 – 7.48 (m, 2H), 2.91 – 2.81 (m, 1H), 2.50 (s, 3H), 1.99 (d, J = 12.4 Hz, 2H), 1.91 (d, J = 12.8 Hz, 2H), 1.79 (d, J = 11.6 Hz, 1H), 1.75 – 1.61 (m, 2H), 1.53 – 1.28 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 161.58, 139.98, 139.64, 134.71, 128.64, 128.44, 127.47, 122.78, 121.44, 107.62, 36.20, 32.27, 26.67, 26.08, 9.75. HRMS (ESI) calcd for C17H19N3 [M+H]+: 266.1648; found: 266.1652. 25

ACCEPTED MANUSCRIPT

RI PT

1-Isopropyl-2-methylpyrazolo[5,1-a]isoquinoline (3q): Yellow solid. Isolated yield = 50%. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.16 – 8.10 (m, 1H), 7.93 – 7.86 (m, 1H), 7.62 – 7.52 (m, 2H), 3.31 – 3.18 (m, 1H), 2.52 (s,

SC

3H), 1.41 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.36, 140.05, 139.70,

M AN U

134.90, 128.72, 128.51, 127.55, 122.82, 121.47, 107.58, 26.41, 21.89, 9.76. HRMS

TE D

(ESI) calcd for C14H15N3 [M+H]+: 226.1336; found: 226.1339.

EP

2-(4-bromophenyl)-8,9-dimethoxy-1-methylpyrazolo[1,5-c]quinazoline (3r): White solid. Isolated yield = 45%. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.65 (d,

AC C

J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 2.64 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.49, 150.49, 149.58, 138.07, 135.92, 135.46, 131.87, 131.60, 130.55, 122.99, 115.15, 109.68, 105.92, 102.90, 56.18, 56.15, 10.79. HRMS (ESI) calcd for C19H16BrN3O2 [M+H]+: 398.049; found: 398.0499.

26

RI PT

ACCEPTED MANUSCRIPT

1-(4-Bromophenyl)-9-chloro-2-methylpyrazolo[1,5-c]quinazoline (3s):

White solid. Isolated yield = 60%. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.08 (d,

SC

J = 2.0 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7. 59 (d, J = 8.8

M AN U

Hz, 2H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 2.62 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.85, 139.52, 138.41, 134.67, 133.66, 131.96, 131.10, 130.54, 130.22, 129.47, 123.31, 122.35, 122.21, 108.87, 10.84. HRMS (ESI) calcd for C17H11BrClN3 [M+H]+ :

EP

TE D

371.9892; found: 371.9898.

AC C

9-bromo-2-(4-bromophenyl)-1-methylpyrazolo[1,5-c]quinazoline (3t): White solid. Isolated yield = 40%. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 2.65 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.98, 139.72, 138.83, 134.58, 132.36, 132.00, 131.13, 130.58, 130.46, 125.37, 123.34, 122.84, 121.77, 108.96, 10.89. HRMS (ESI) calcd for C17H11Br2N3 [M+H]+: 415.9384; found: 415.9392. 27

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1-methyl-1-nitro-2-phenyl-3-tosyl-1,2,3,10b-tetrahydropyrazolo[1,5-c]quinazolin e (4) :

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White solid. Isolated yield = 50%. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.54 – 7.30 (m, 10H), 7.18 – 7.11 (m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H),

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4.76 (s, 1H), 2.54 (s, 3H), 0.92 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.87, 146.39, 139.04, 134.14, 130.72, 130.51, 130.41, 129.57, 129.27, 129.08, 127.43, 127.13, 126.73, 126.24, 118.40, 97.98, 68.96, 65.22, 21.92, 14.81. HRMS (ESI) calcd for

References:

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C24H22N4O4S [M+H]+: 463.1443; found: 463.1439.

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1. Wang, T.; Luo, J.; Gu, C.; Li, R.; Tang, X.; Yu, D.; Li, J. CN 103172575A.

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