First diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines

Journal of Fluorine Chemistry 216 (2018) 33–42

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First diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1a]isoquinoline-1,5’-pyrimidines

T

Minhui Yua, Yueci Wua, Xin Pengb, Jing Hana, Jie Chena, Yuhe Kanc, Hongmei Dengd, Min Shaod, ⁎ ⁎ Hui Zhanga,d, , Weiguo Caoa,e,f, a

Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai, 200444, PR China Qianweichang College, Shanghai University, Shanghai, 200444, PR China c Jiangsu Province Key Laboratory for Chemistry of Low Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian, 223300, PR China d Laboratory for Microstructures, Instrumental Analysis and Research Center of Shanghai University, Shanghai, 200444, PR China e State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, PR China f Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, PR China b

ARTICLE INFO

ABSTRACT

Keywords: Multicomponent reaction (MCR) Fused-isoquinoline Barbiturate Perfluoroalkyl-substituted Diastereoselective synthesis

The 1,4-dipoles derived from isoquinolines and methyl perfluoroalk-2-ynoates reacted readily with arylidenesubstituted N,N-dimethylbarbituric acids resulting in the first diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidine derivatives in good to excellent yields under mild conditions. The reaction mechanism was proposed to illustrate the formation of the diastereoisomers and proton-promoted transformation of trans-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines to the more thermodynamically stable cis-isomers. The DFT calculation demonstrated the diastereoselectivity of the reaction.

1. Introduction Barbiturates 2,4,6(1H,3H,5H)-pyrimidinetriones are well known in medicinal chemistry due to their wide range of biological and therapeutic values, acting as sedatives, anesthetic, anxiolytic, and anticonvulsant agents [1]. They have also displayed additional pharmacological potential as analeptics, immune-modulating, anti-AIDS, and anticancer agents [2]. As a type of barbiturate, spirobarbiturates showed various pronounced pharmacological and physiological activities as well [3]. Furthermore, owing to their steric strain associated with the quaternary carbon, spirobarbiturates can be precursors of a variety of cyclic products by rearrangement reactions, thus being used immensely as a template for drug discovery. Many synthetic methods for spirobarbiturates have been developed [4], and one powerful approach among them is using barbiturate olefins [4k-q]. Fused-isoquinolines are core structures found in many pharmacological motifs because of their outstanding biological activities [5]. On the other hand, the insertion of CF3 or other perfluoroalkyl groups has a strong impact on the physical, chemical, and biological properties of bioactive compounds [6].

⁎

Efficient introduction of both spirobarbiturate moiety and perfluoroalkyl group into bioactive fused-isoquinoline molecules such as pyrido[a]isoquinolines is very appealing in the search for medicinally active compounds. However, the literature survey showed that only one report has been directed to efficient synthetic methodology for these spirobarbiturate-based pyrido[a]isoquinolines [4n]. Moreover, only a limited number of examples have been reported on the diastereoselective or enantioselective synthesis of spirobarbiturates [4g,4m-q]. Therefore, the development of novel methods for the diastereoselective or enantioselective synthesis of perfluoroalkylated spirobarbituratebased pyrido[a]isoquinolines is highly desirable. As the MCR strategy is a powerful tool in organic, medicinal and combinatorial chemistry to create diverse heterocyclic scaffolds of miscellaneous biological activities [7], and in continuation of our enduring research efforts towards the synthesis of novel perfluoroalkylated heterocyclic compounds [8], herein, we wish to report a MCR of isoquinolines, methyl perfluoroalk-2-ynoates and 1,3-dimethylbarbituric acid-based olefins for the first diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5’pyrimidines.

Corresponding authors at: Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai, 200444, PR China. E-mail addresses: [email protected] (H. Zhang), [email protected] (W. Cao).

https://doi.org/10.1016/j.jfluchem.2018.09.007 Received 27 August 2018; Received in revised form 22 September 2018; Accepted 25 September 2018 Available online 30 September 2018 0022-1139/ © 2018 Elsevier B.V. All rights reserved.

Journal of Fluorine Chemistry 216 (2018) 33–42

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Table 1 Optimization of the reaction conditions.a

Entry

Solvent

Temp. (oC)

Time (h)

Yield (%)b

Molar ratio 4a/4a′ (dr)c

1 2 3 4 5 6 7 8 9 10 11

MeCN MeCN MeCN MeCN DCM Toluene THF DMF EtOH DMSO MeCN

r.t. 0 50 75 50 50 50 50 50 50 50

2h 2h 2h 2h 2h 2h 2h 2h 2h 2h 6h

75 69 86 79 42 27 44 65 0 37 83

1:0.7 1:0.8 1:0.5 1:0.1 1:0.4d 1:0.4 1:0.5d 1:0.5 – 1:0.5 1:0.5

a Reaction conditions: 5-benzylidene-1,3-dimethyl-barbituric acid 1a (0.2 mmol), isoquinoline 2a (0.2 mmol) and methyl 4,4,4-trifluorobut-2-ynoate 3a (0.24 mmol) were stirred in MeCN (2.0 mL) at the confined temperature for the referred time, then the solvent was removed under reduced pressure, DCM (1.0 mL) and silica gel (200 mesh, 0.5 g) were added. The mixture was stirred at room temperature for another 1h. b Total isolated yields for the two steps. c Determined by 19F NMR spectroscopy for the first step. d The reaction was carried out in a sealed tube.

2. Results and discussion

Lowering the temperature to 0 °C did not improve the diastereoselectivity and the total yield of 4a for two steps (Table 1, entry 2). When the reaction was carried out at 50 °C, the total yield of 4a was up to 86% with 1:0.5 dr. At 75 °C, the chemical yield dropped a little but the diastereoselectivity was much better (Table 1, entry 4, dr 1:0.1). These results displayed that cis-isomer 4a is more thermodynamically stable than trans-isomer 4a′. After considering the chemical yield and diastereoselectivity, 50 °C was determined as the optimal reaction temperature. The solvent effect on the chemical yield and diastereoselectivity for the first step was also examined. With DCM, toluene, THF, DMF, MeOH and DMSO as solvents, they furnished 4a in 0−65% yields with similar diastereoselectivitiy as MeCN (Table 1, entries 5–10 vs entry 3). Prolonging the reaction time to 6h, the yield of the reaction for the two steps decreased a little (Table 1, entry 11 vs entry 3). As illustrated in Table 2, the reaction scope by using structurally diverse barbiturate-based olefins and various substituted isoquinolines was explored. All the reactions proceeded smoothly under optimal conditions (Table 1, entry 3), furnishing trifluoromethylated cis-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines 4 in 30–92% yields. A variety of functional groups on 1,3-dimethylbarbituric acids 1 and isoquinolines 2 were well-tolerated. Substantial steric hindrance was also tolerated and afforded good results (Table 2, entries 2–5). However, when a sterically bulkier substituent such as C2F5 or n-C3F7 group was applied instead of CF3 group in 3, the corresponding products were obtained with lower yields, and a mixture of cis/transisomers were obtained after stirring with silica gel in DCM (Table 2, entries 20–22). This experimental results showed that the acidity of silica gel may be too weak to accomplish such transformation, therefore, 37% HCl was applied. To our delight, the transformation of C2F5substituted trans-isomer to cis-isomer was fully furnished though nC3F7 group gave only 68% conversion, which may be due to the latter’s bulkier size (Scheme 1). It is noteworthy that the reaction was not amenable to alkylidene 1,3-dimethylbarbituric acids such as 1o and no expected product obtained (Table 2, entry 15). The relative configuration of 4v′ was also characterized by its single-crystal X-ray analysis to be trans (Fig. 2) [10]. The structure and stereochemistry of other 4 and 4′ were established by comparision with the data of 1H NMR, 13C NMR, 19F NMR, IR,

Under the previously established reaction conditions for the reaction of isoquinoline, DMAD and arylidene-substituted N,N-dimethylbarbituric acids [4n], the three-component reaction of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 1a, isoquinoline 2a with methyl 4,4,4-trifluorobut-2-ynoate 3a in MeCN at room temperature proceeded very smoothly to give the two main products 4a and 4a′ with dr 1:0.7 (Table 1, entry 1). However, after stirring the mixture of 4a and 4a′ in DCM with silica gel for 1h, 4a′ disappeared totally and 4a was obtained as final sole product. The outcome of this reaction is thus different from the previous report by Yan et al [4n]. Yan and his coworkers reported only one diastereoisomer formed in their reaction. The structure and stereochemistry of 4a was unambiguously established by single-crystal X-ray analysis (Fig. 1) and was assigned as cis-isomer [9]. 4a′ was then supposed to be transisomer. The cis/trans-isomerism comes from the cis/trans configuration of the two protons (2,11b-dihydrogen) at 1,3-positions of the newly formed tetrahydropyridyl ring in the product.

Fig. 1. X-ray structure of compound 4a. 34

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Table 2 Synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5′-pyrimidines 4.a

Entry

R1

1

R2

2

RF

3

Products

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

C6H5 2-MeC6H4 2-NO2C6H4 2-MeOC6H4 2-BrC6H4 3-MeC6H4 3-MeOC6H4 3-ClC6H4 3-BrC6H4 4-MeC6H4 4-MeOC6H4 4-BrC6H4 4-CNC6H4 4-FC6H4 cyclohexyl C6H5 C6H5 C6H5 C6H5 C6H5

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1a 1a 1a 1a 1a

H H H H H H H H H H H H H H H 5-OMe 5-NO2 6-Me 6-Br H

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c 2d 2e 2a

CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 C2F5

3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3b

21

C6H5

1a

H

2a

n-C3F7

3c

22

C6H5

1a

5-OMe

2b

C2F5

3b

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4t' 4u 4u' 4v 4v'

86 73 58 67 66 76 87 70 44 72 64 63 50 76 NRc 92 30 91 81 36,(65d,e) 29 26 (38d,e) 18 37 (68d,e) 28

a Reaction conditions: 5-arylidene-1,3-dimethyl-barbituric acids 1 (0.2 mmol), isoquinolines 2 (0.2 mmol) and methyl perfluoroalk-2-ynoates 3 (0.24 mmol) were stirred in MeCN (2.0 mL) at 50 °C for 2h, then the solvent was removed under reduced pressure, DCM (1.0 mL) and silica gel (200 mesh, 0.5 g) were added. The mixture was stirred at room temperature for another 1h. b Total isolated yields for two steps. c No reaction. d Reaction conditions for the second step: the mixture of 4 and 4′ (0.2 mmol) with 37% HCl (0.06 mol) was stirred in DCM (1.0 mL) at r.t. for 36h. e Total isolated yields for two steps with the second step using HCl.

MS and HRMS of 4a or 4v′ In order to explain the stereochemistry of the reaction, a plausible mechanism is proposed (Scheme 2) on the basis of the known 1,4-dipolar addition of Huisgen’s 1.4-dipoles [11] and our previous reported three-component reaction containing isatins [12]. At first, isoquinoline attacks methyl 4,4,4-trifluorobut-2-ynoate to give the Huisgen 1,3-dipole I′ and its resonance hybrid 1,4-dipole I. Then, this 1,4-dipole I could react with 5-benzylidene-1,3-dimethylbarbituric acid directly from two different directions of the olefinic bond plane, affording zwitterionic intermediates II and II′. Subsequently, the coupling of the negative carbon atom with the positive carbon adjacent to nitrogen atom of isoquinoline in II and II′ resulted in four isomeric spirobarbiturates.

The major formation of cis-isomer 4a in the first step has prompted us to examine the factors on the control of the diastereoselectivity observed in this reaction. The DFT computation results are listed in Table 3. Calculated structures of three pairs of diasteroisomers 4a/4a′, 4t/4t′ and 4u/4u′ are shown in Fig. 3. The calculated results and X-ray data of 4a were compared and found to have satisfying consistency between them (Table 4). According to the calculated data, atomic distance (Å) between C1 on benzene ring and C4 on ester group for trans-isomer is shorter than that for cis-isomer. And dihedral angle of C1-C2-C3-C4 for cis-isomer is negative angle, but positive angle for trans-isomer. Moreover, Cg1-Cg2 distance is longer in cis-isomer than in trans isomer. For example, Cg1Cg2 distance in 4a is 3.394 Å, longer than 3.341 Å in 4a′, indicating less

Scheme 1. Transformation of trans-isomer to cis-isomer. 35

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Table 3 The relative energies (kcal/mol) at the M06-2X level, in conjunction with the Def 2-TZVP basis sets, dihedral angle (°) of C1-C2-C3-C4, Cg1-Cg2 distances (Å) between Nr1 (dihydroisoquinoline ring) and Nr2 (barbiturate ring) (Cg indicates a ring centroid) at the level of B3LYP/ 6-31G (d) for compound 4a/4a', 4t/4t', 4u/ 4u'. Dihedral Angle

4a/4a'

4t/4t'

4u/4u'

Relative Energies Dihedral Angle (C1-C2-C3-C4) Cg Distance

−30.1/0.0 −47.4/51.9 3.394/3.341

−8.6/0.0 −48.8/51.0 3.350/3.337

−17.4/0.0 −45.42/51.6 3.342/3.328

To interpret the diastereoselective transformation of trans to cisisomer, the reaction mechanism for the second step was predicted as presented in Scheme 3 [13]. Protonation of 4a′ led to the formation of the intermediate ammonium salt III. Then, the cleavage of the isoquinolizine C–N bond towards the azecine ring produced the intermediate carbon cation IV with a newly formed olefinic bond. The nitrogen atom originally from isoquinolizine attacks the alkenyl carbon from the less steric side of olefinic bond plane to realize recyclization to give ammonium V. Finally, the deprotonation of V delivered the cisisomer.

Fig. 2. X-ray structure of compound 4v′.

steric and π electron repulsion between dihydroisoquinoline ring and barbiturate ring in cis-isomer 4a. Such computation results suggest that steric and electronic interactions between benzene ring moiety and ester group or dihydroisoquinoline ring and barbiturate ring are responsible for the diastereoselectivity observed in this three-component reaction. Furthermore, the calculated relative energy values coincide with the experimental results, demonstrating that cis-isomer is more stable.

3. Conclusions We have developed an efficient protocol for the synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines by

Scheme 2. Proposed mechanism for the first step of the reaction. 36

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Fig. 3. The optimized geometries of compound 4a/4a', 4t/4t', and 4u/4u' at the level of B3LYP/ 6-31G (d), with atom-numbering scheme.

pathway for the transformation of trans/cis-isomers under acidic conditions was proposed as well. Using the DFT calculation, the structural factors influencing the diastereoselectivity have been studied. Good consistency between the DFT computation results and experimental data demonstrates the validity of the approach and allows its use for the interpretation of diastereoselectivity in the studied process. The simple procedure, readily available substrates, and ease of handling all render this protocol applicable for the synthesis of structurally diverse perfluoroalkylated spirobarbiturates.

Table 4 Comparison of the calculated structure results with X-ray data of 4a.

C1-C2 C2-C3 C3-C4 C1-C2-C3 C2-C3-C4

4aa

4ab

1.532 1.521 1.504 113.7 112.8

1.503 1.504 1.485 113.9 113.1

a Selected bond lengths (Å) and angles (°) for optimized 3D model 4a at B3LYP/6-31G(d) level. b Selected bond lengths (Å) and angles (°) for 4a from X-ray analysis data.

4. Experimental 4.1. General information

the three-component reactions of isoquinolines, methyl perfluoroalk-2ynoates, and arylidene-substituted N,N-dimethylbarbituric acids. The formation mechanism for the two diastereoisomers is discussed. The

Reagents and solvents were purchased from commercially sources and used without further purification. Methyl perfluoroalk-2-ynoates

Scheme 3. Proposed mechanism for the second step of the reaction (transformation of trans to cis isomer). 37

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were prepared according to the known literature [14]. Melting points were recorded on a WRS-1 instrument and are uncorrected. 1H, 19F and 13 C NMR spectra were recorded on Bruker DRX-500 MHz and JNMECZ400S/L-400 MHz spectrometers. All chemical shifts are reported in parts per million downfield (positive) of the standard: C6F6 for 19F, TMS for 1H and 13C NMR spectra. IR spectra were obtained on an AVATAR370 FTIR spectrometer. LR-MS (lower resolution mass spectra) and HR-MS (high resolution mass spectra) were obtained on Agilent 6230, Thermo Fisher Scientific LTO FT Ultra and HP-5989 instruments, respectively. X-ray analysis was performed on a Bruker Smart Apex2 CCD spectrometer. Yields reported in this publication refer to isolated ones of compounds and their purity was determined by 1H NMR. All calculations were performed using the Gaussian 09 program [15]. Geometry optimizations of models are performed at the density functional theory (DFT) level of theory using the hybrid functional B3LYP [16] at the 6-31G (d) level. The relative free energy (ΔG) at 298 K is computed at the M06-2X [17] level, in conjunction with the Def 2-TZVP [18] basis sets.

4.3.2. Methyl trans-1′,3′-dimethyl-2′,4′,6′-trioxo-2-phenyl-4-(trifluoromethyl) -1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a]isoquinoline-1,5′pyrimidine]-3-carboxylate (4a′) White solid; m.p.: 78.3–78.8 °C; 1H NMR (400 MHz, CDCl3) δ: 2.98 (s, 3H), 3.16 (s, 3H), 3.56 (s, 3H), 4.52–4.53 (m, 1H), 5.22 (s, 1H), 5.79 (d, J = 7.6 Hz, 1H), 6.52–6.55 (m, 2H), 7.00–7.04 (m, 2H), 7.10–7.13 (m, 2H), 7.20–7.23 (m, 1H), 7.32–7.34 (m, 3H); 19F NMR (376 MHz, CDCl3) δ: −60.3 (s, CF3) ppm. IR (KBr): υ 2920, 1732, 1680, 1631, 1452, 1429, 1381, 1278, 1182, 1139, 1097, 773 cm−1. MS (ESI) m/z (%): 526 [(M+H)]+. HRMS (ESI) calcd. for C27H22F3N3O5 [(M+H)]+: 526.1602; found: 526.1591. 4.3.3. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-2-(o-tolyl)-4-(trifluoromethyl) -1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a]isoquinoline-1,5′pyrimidine]-3-carboxylate (4b) White solid; yield: 73%; m.p.: 216.5–216.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.41 (s, 3H), 2.97 (s, 3H), 3.00 (s, 3H), 3.39 (s, 3H), 5.41 (s, 1H), 5.47 (d, J = 8.0 Hz, 1H), 5.55–5.57 (m, 1H), 6.33–6.34 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.93–6.94 (m, 1H), 6.99–7.09 (m, 4H), 7.20–7.22 (m, 1H), 7.51–7.53 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 20.3, 28.3, 29.1, 45.1, 52.2, 58.1, 69.2, 101.7, 120.6 (q, 1JCF = 275.1 Hz), 122.5, 124.6, 125.6, 125.8, 126.6, 126.8, 128.4, 130.2, 130.4 (q, 2JC-F = 34.0 Hz), 130.8, 131.1, 131.3, 131.9, 132.1, 138.8, 149.8, 165.8, 166.1, 166.7 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1724, 1676, 1633, 1456, 1423, 1381, 1205, 1176, 1143, 1112, 777 cm−1. MS (ESI) m/z (%): 540 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O5 [(M+H)]+: 540.1746; found: 540.1740.

4.2. General procedure for the preparation of perfluoroalkylated spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines 4 and 4′ 1,3-Dimethylbarbituric acid-based alkenes [4p] 1 (0.2 mmol), isoquinolines 2 (0.2 mmol) and methyl perfluoroalk-2-ynoates 3 (0.24 mmol) were stirred in MeCN (2.0 mL) at 50 °C for 2h. When methyl 4,4,4-trifluorobut-2-ynoate 3a was used as substrate, the solvent was removed under reduced pressure, DCM (1.0 mL) and silica gel (200 mesh, 0.5 g) were added. The mixture was stirred at room temperature for another 1h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel by eluting with petroleum ether / ethyl acetate (10:1) to afford the desired products 4; If methyl 4,4,5,5,5-pentafluoropent-2-ynoate 3b or methyl 4,4,5,5,6,6,6-heptafluorohex-2-ynoate 3c was served as starting material, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel by eluting with petroleum ether/ethyl acetate (10:1) to afford the desired products 4 and 4′.

4.3.4. Methyl cis-1′,3′-dimethyl-2-(2-nitrophenyl)-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4c) Yellow solid; yield: 58%; m.p.: 186.6–187.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.92 (s, 3H), 2.97 (s, 3H), 3.56 (s, 3H), 5.33 (s, 1H), 5.51 (d, J = 8.0 Hz, 1H), 6.08–6.10 (m, 1H), 6.30 (d, J = 8.0 Hz, 1H), 6.76–6.78 (m, 1H), 6.93–6.95 (m, 1H), 7.04–7.08 (m, 1H), 7.22–7.25 (m, 1H), 7.35–7.43 (m, 2H), 7.53–7.55 (m, 1H), 7.84–7.86 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.2, 42.6, 52.6, 59.1, 69.4, 102.4, 120.4 (q, 1JC-F = 275.5 Hz), 121.8, 124.3, 124.4, 124.6, 126.1, 126.5, 126.7, 129.6, 130.4, 130.5, 131.2, 131.7, 132.5 (q, 2JC-F = 34.3 Hz), 133.4, 149.4, 151.6, 165.3, 165.4, 165.5 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1732, 1681, 1633, 1454, 1427, 1381, 1217, 1180, 1143, 1097, 779 cm−1. MS (ESI) m/z (%): 571 [(M+H)]+. HRMS (ESI) calcd. for C27H21F3N4O7 [(M+H)]+: 571.1442; found: 571.1436.

4.3. General procedure for the transformation of perfluoroalkylated spiropyrido[2,1-a]isoquinoline-1,5’-pyrimidines 4′ to 4 in 37% HCl The mixture of compounds 4′ (0.2 mmol, RF = C2F5, n-C3F7) and 37% HCl (0.06 mol) in DCM (1.0 mL) was stirred at room temperature for 36h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel by eluting with petroleum ether/ethyl acetate (10:1) to afford the desired products 4.

4.3.5. Methyl cis-2-(2-methoxyphenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4d) Yellow solid; yield: 67%; m.p.: 170.0–171.0 °C; 1H NMR (500 MHz, CDCl3) δ: 2.75 (s, 3H), 3.16 (s, 3H), 3.56 (s, 3H), 3.68 (s, 3H), 5.42–5.43 (m, 2H), 5.57–5.59 (m, 1H), 6.33 (d, J = 7.5 Hz, 1H), 6.69–6.71 (m, 1H), 6.80–6.84 (m, 1H), 6.88–6.92 (m, 2H), 7.00–7.04 (m, 1H), 7.14–7.20 (m, 2H), 7.41–7.43 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 27.9, 28.9, 43.4, 52.4, 55.1, 59.6, 67.5, 101.8, 110.2, 120.0, 120.6 (q, 1JC-F = 275.5 Hz), 122.6, 122.9, 124.6, 125.7, 126.7, 129.4, 129.9, 130.9, 131.6, 132.1, 133.0 (q, 2JC-F = 34.3 Hz), 150.2, 157.1, 166.2, 167.2 ppm;19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2951, 1737, 1680, 1637, 1456, 1425, 1381, 1213, 1176, 1138, 1116, 775 cm−1. MS (ESI) m/z (%): 556 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O6 [(M+H)]+: 556.1697; found: 556.1692.

4.3.1. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-2-phenyl-4-(trifluoromethyl)1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a]isoquinoline-1,5′pyrimidine]-3-carboxylate (4a) White solid; yield: 86%; m.p.: 205.5–205.9 °C; 1H NMR (500 MHz, CDCl3) δ: 2.89 (s, 3H), 3.00 (s, 3H), 3.51 (s, 3H), 5.26 (s, 1H), 5.41 (s, 1H), 5.49 (d, J = 8.0 Hz, 1H), 6.27–6.29 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.92–6.93 (m, 1H), 7.05–7.08 (m, 1H), 7.15–7.16 (m, 3H), 7.20–7.23 (m, 1H), 7.32–7.33 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.3, 29.1, 48.9, 52.4, 60.2, 68.6, 101.9, 120.6 (q, 1JC-F = 275.3 Hz), 122.3, 124.5, 125.8, 126.1, 126.5, 128.1, 128.2, 130.3, 130.6, 131.7 (q, 2 JC-F = 34.1 Hz), 132.2, 134.1, 149.7, 165.4, 166.1, 166.2 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.5 (s, CF3) ppm. IR (KBr): υ 2953, 1728, 1681, 1633, 1454, 1425, 1383, 1217, 1180, 1139, 1097, 777 cm−1. MS (ESI) m/z (%): 526 [(M+H)]+. HRMS (ESI) calcd. for C27H22F3N3O5 [(M+H)]+: 526.1602; found: 526.1597.

4.3.6. Methyl cis-2-(2-bromophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4e) Yellow solid; yield: 66%; m.p.: 187.9–188.5 °C; 1H NMR (500 MHz, 38

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CDCl3) δ: 2.89 (s, 3H), 3.09 (s, 3H), 3.46 (s, 3H), 5.48 (d, J = 8.0 Hz, 1H), 5.51 (s, 1H), 5.80–5.82 (m, 1H), 6.35 (d, J = 8.0 Hz, 1H), 6.89–6.90 (m, 1H), 6.92–6.94 (m, 1H), 7.02–7.08 (m, 2H), 7.14–7.22 (m, 2H), 7.47–7.49 (m, 1H), 7.60–7.62 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.2, 29.2, 48.1, 52.4, 58.1, 68.3, 102.1, 120.5 (q, 1 JC-F = 275.5 Hz), 122.6, 124.7, 125.3, 126.0, 126.9, 130.0, 130.1, 130.8, 131.5, 132.2 (q, 2JC-F = 34.0 Hz), 133.1, 133.4, 133.7, 149.7, 165.5, 165.9, 166.2 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1737, 1681, 1633, 1456, 1425, 1382, 1213, 1180, 1141, 1093, 773 cm−1. MS (ESI) m/z (%): 604 [(M+H)]+. HRMS (ESI) calcd. for C27H21BrF3N3O5 [(M+H)]+: 604.0692; found: 604.0690.

(m, 1H), 5.51 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 6.78–6.80 (m, 1H), 6.95–6.96 (m, 1H), 7.05–7.11 (m, 2H), 7.24–7.27 (m, 1H), 7.29–7.30 (m, 1H), 7.32–7.35 (m, 1H), 7.49–7.50 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.2, 48.2, 52.5, 60.2, 68.7, 102.1, 120.4 (q, 1JC-F = 275.4 Hz), 122.1, 124.5, 125.3, 125.9, 126.5, 129.3, 129.6, 130.5, 132.0 (q, 2JC-F = 34.3 Hz), 132.1, 133.5, 136.5, 149.6, 165.3, 165.9 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1737, 1680, 1631, 1454, 1427, 1384, 1261, 1180, 1141, 1095, 775 cm−1. MS (ESI) m/z (%): 604 [(M+H)]+. HRMS (ESI) calcd. for C27H21BrF3N3O5 [(M+H)]+: 604.0692; found: 604.0687. 4.3.11. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-2-(p-tolyl)-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4j) White solid; yield: 72%; m.p.: 155.9–157.7 °C; 1H NMR (500 MHz, CDCl3) δ: 2.24 (s, 3H), 2.91 (s, 3H), 3.01 (s, 3H), 3.54 (s, 3H), 5.26 (s, 1H), 5.36–5.37 (m, 1H), 5.48 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.80–6.81 (m, 1H), 6.93–6.98 (m, 3H), 7.06–7.09 (m, 1H), 7.19–7.24 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.1, 29.1, 48.6, 52.4, 60.2, 68.5, 101.8, 120.6 (q, 1JC-F = 275.1 Hz), 122.4, 124.5, 125.8, 126.3, 126.5, 128.8, 130.3, 130.4, 130.6, 130.9, 131.4 (q, 2JC19 F NMR F = 34.4 Hz), 132.3, 137.9, 149.8, 165.5, 166.2, 166.3 ppm; (470 MHz, CDCl3) δ: −59.5 (s, CF3) ppm. IR (KBr): υ 2953, 1730, 1687, 1631, 1494, 1425, 1382, 1213, 1176, 1141, 1095, 775 cm−1. MS (ESI) m/z (%): 540 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O5 [(M +H)]+: 540.1746; found: 540.1743.

4.3.7. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-2-(m-tolyl)-4-(trifluoromethyl) -1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a]isoquinoline-1,5′pyrimidine]-3-carboxylate (4f) White solid; yield: 76%; m.p.: 218.8–219.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.24 (s, 3H), 2.91 (s, 3H), 3.02 (s, 3H), 3.54 (s, 3H), 5.26 (s, 1H), 5.35–5.37 (m, 1H), 5.48 (d, J = 7.5 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 6.80–6.81 (m, 1H), 6.93–6.95 (m, 1H), 6.98–7.00 (m, 1H), 7.04–7.09 (m, 2H), 7.11–7.13 (m, 2H), 7.22–7.25 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.3, 28.3, 29.1, 48.8, 52.4, 60.2, 68.5, 101.8, 120.6 (q, 1JC-F = 275.2 Hz), 122.4, 124.5, 125.8, 126.2, 126.6, 127.6, 127.9, 129.0, 130.3, 130.6, 131.2, 131.5 (q, 2JC-F = 34.1 Hz), 132.3, 134.0, 137.7, 149.8, 165.5, 166.2, 166.4 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.5 (s, CF3) ppm.IR (KBr): υ 2953, 1737, 1672, 1633, 1452, 1429, 1382, 1205, 1178, 1141, 1101, 779 cm−1. MS (ESI) m/z (%): 540 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O5 [(M +H)]+: 540.1746; found: 540.1745.

4.3.12. Methyl cis-2-(4-methoxyphenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4k) White solid; yield: 64%; m.p.: 136.1–137.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.92 (s, 3H), 3.01 (s, 3H), 3.55 (s, 3H), 3.73 (s, 3H), 5.25 (s, 1H), 5.33–5.35 (m, 1H), 5.48 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 6.69–6.71 (m, 1H), 6.79–6.80 (m, 1H), 6.93–6.95 (m, 1H), 7.05–7.07 (m, 1H), 7.08–7.09 (m, 1H), 7.21–7.24 (m, 2H) ppm, 7.25–7.26 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.3, 29.1, 48.3, 52.4, 55.0, 60.3, 68.6, 101.8, 113.4, 120.6 (q, 1JC-F = 275.1 Hz), 122.4, 124.5, 125.7, 125.8, 126.4, 126.5, 130.3, 130.6, 131.2 (q, 2JC19 F F = 34.4 Hz), 131.9, 132.3, 149.8, 159.3, 165.6, 166.2, 166.3 ppm; NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1734, 1689, 1663, 1510, 1454, 1425, 1215, 1180, 1138, 1033, 775 cm−1. MS (ESI) m/z (%): 556 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O6 [(M+H)]+: 556.1697; found: 556.1694.

4.3.8. Methyl cis-2-(3-methoxyphenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,-pyrimidine]-3-carboxylate (4g) White solid; yield: 87%; m.p.: 1H NMR (500 MHz, CDCl3) : 2.92 (s, 3H), 3.02 (s, 3H), 3.56 (s, 3H), 3.73 (s, 3H), 5.26 (s, 1H), (m, 1H), 5.48 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) : 28.3, 29.1, 48.8, 52.4, 55.1, 60.1, 68.5, 101.8, 114.3, 115.7, 120.6 (q, 1JCF = 275.2 Hz), 122.3, 122.8, 124.5, 125.8, 126.0, 126.5, 129.0, 130.3, 130.6, 131.7 (q, 2JC-F = 34.3Hz), 132.2, 135.6, 149.7, 159.1, 165.5, 166.1, 166.3 ppm; 19F NMR (470 MHz, CDCl3) : −59.5 (s, CF3) ppm. IR (KBr): υ 2953, 1734, 1678, 1631, 1456, 1427, 1384, 1211, 1178, 1141, 1097, 777 cm1. MS (ESI) (%): 556 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O6 [(M+H)]+: 556.1697; found: 556.1691.

4.3.13. Methyl cis-2-(4-bromophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4l) White solid; yield: 63%; m.p.: 208.4–209.2 °C; 1H NMR (500 MHz, CDCl3) δ: 2.92 (s, 3H), 3.00 (s, 3H), 3.57 (s, 3H), 5.23 (s, 1H), 5.37–5.39 (m, 1H), 5.51 (d, J = 8.0 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.78–6.79 (m, 1H), 6.94–6.96 (m, 1H), 7.07–7.10 (m, 1H), 7.22–7.25 (m, 3H), 7.30–7.32 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.2, 48.1, 52.6, 60.1, 68.7, 102.1, 120.5 (q, 1JC-F = 275.2 Hz), 122.1, 122.5, 124.5, 125.4, 125.9, 126.5, 130.4, 130.5, 131.3, 131.9 (q, 2JC19 F F = 34.1 Hz), 132.1, 132.4, 133.2, 149.6, 165.4, 165.9, 166.0 ppm; NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1737, 1689, 1631, 1485, 1452, 1382, 1211, 1180, 1139, 1070, 777 cm−1. MS (ESI) m/z (%): 604 [(M+H)]+. HRMS (ESI) calcd. for C27H21BrF3N3O5 [(M+H)]+: 604.0692; found: 604.0689.

4.3.9. Methyl cis-2-(3-chlorophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4h) White solid; yield: 70%; m.p.: 200.0–200.3 °C; 1H NMR (500 MHz, CDCl3) δ: 2.93 (s, 3H), 3.02 (s, 3H), 3.57 (s, 3H), 5.24 (s, 1H), 5.38–5.40 (m, 1H), 5.51 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 6.78–6.80 (m, 1H), 6.95–6.96 (m, 1H), 7.06–7.14 (m, 2H), 7.17–7.19 (m, 1H), 7.24–7.27 (m, 2H), 7.34–7.35 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.2, 48.2, 52.5, 60.1, 68.7, 102.1, 120.5 (q, 1JC-F = 275.1 Hz), 122.1, 124.5, 125.3, 125.9, 126.5, 128.5, 128.9, 129.3, 130.4, 130.5, 130.6, 132.0 (q, 2JC-F = 34.1 Hz), 132.1, 133.9, 136.2, 150.0, 165.3, 165.9 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1734, 1680, 1631, 1456, 1429, 1384, 1217, 1178, 1141, 1097, 775 cm−1. MS (ESI) m/z (%): 560.0 [(M+H)]+. HRMS (ESI) calcd. for C27H21ClF3N3O5 [(M+H)]+: 560.1202; found: 560.1197.

4.3.14. Methyl cis-2-(4-cyanophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4m) Yellow solid; yield: 50%; m.p.: 238.1–239.4 °C; 1H NMR (500 MHz, CDCl3) δ: 2.91 (s, 3H), 3.01 (s, 3H), 3.56 (s, 3H), 5.23 (s, 1H), 5.48–5.49 (m, 1H), 5.54 (d, J = 7.5 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 6.77–6.79

4.3.10. Methyl cis-2-(3-bromophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4i) Yellow solid; yield: 44%; m.p.: 197.3–197.9 °C; 1H NMR (500 MHz, CDCl3) δ: 2.93 (s, 3H), 3.02 (s, 3H), 3.58 (s, 3H), 5.23 (s, 1H), 5.37–5.38 39

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3H), 7.31–7.33 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.2, 28.3, 29.1, 48.9, 52.4, 60.2, 68.5, 102.0, 119.6, 120.6 (q, 1JC-F = 275.3 Hz), 125.1, 125.8, 126.4, 126.5, 128.1, 128.2, 130.4, 130.5, 131.8 (q, 2JC19 F F = 34.2 Hz), 132.1, 134.2, 140.3, 149.8, 165.5, 166.1, 166.4 ppm; NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1735, 1678, 1629, 1450, 1425, 1382, 1213, 1178, 1141, 1097, 756 cm−1. MS (ESI) m/z (%): 540 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O5 [(M+H)]+: 540.1746; found: 540.1744.

(m, 1H), 6.96–6.98 (m, 1H), 7.09–7.12 (m, 1H), 7.25–7.28 (m, 1H), 7.48–7.49 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.3, 48.3, 52.6, 60.3, 68.9, 102.4, 112.3, 118.3, 120.4 (q, 1JC-F = 275.4 Hz), 121.8, 124.6, 126.0, 126.5, 130.5, 130.6, 131.4, 131.8, 131.9, 132.6 (q, 2 JC-F = 34.4 Hz), 140.0, 149.4, 165.2, 165.7, 165.8 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2951, 2230, 1735, 1680, 1631, 1454, 1429, 1384, 1215, 1182, 1139, 1093, 777 cm−1. MS (ESI) m/z (%): 551 [(M+H)]+. HRMS (ESI) calcd. for C28H21F3N4O5 [(M+H)]+: 551.1543; found: 551.1537.

4.3.19. Methyl cis-9-bromo-1′,3′-dimethyl-2′,4′,6′-trioxo-2-phenyl-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4s) Yellow solid; yield: 81%; m.p.: 234.3–234.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.92 (s, 3H), 3.06 (s, 3H), 3.52 (s, 3H), 5.24 (s, 1H), 5.35–5.37 (m, 1H), 5.41 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 6.67–6.69 (m, 1H), 7.08 (s, 1H), 7.17–7.19 (m, 4H), 7.27–7.29 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.2, 49.3, 52.5, 59.9, 67.8, 100.7, 120.5 (q, 1JC-F = 275.3 Hz), 121.3, 124.4, 126.5, 127.2, 128.1, 128.3, 128.4, 128.6, 130.5, 131.5 (q, 2JC-F = 34.1 Hz), 132.8, 133.6, 133.8, 149.7, 165.4, 165.9, 166.5 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2953, 1734, 1680, 1629, 1398, 1176, 1143, 1097, 754 cm−1. MS (ESI) m/z (%): 604 [(M+H)]+. HRMS (ESI) calcd. for C27H21BrF3N3O5 [(M+H)]+: 604.0692; found: 604.0692.

4.3.15. Methyl cis-2-(4-fluorophenyl)-1′,3′-dimethyl-2′,4′,6′-trioxo-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4n) Yellow solid; yield: 76%; m.p.: 197.8–198.5 °C; 1H NMR (500 MHz, CDCl3) δ: 2.92 (s, 3H), 3.01 (s, 3H), 3.55 (s, 3H), 5.24 (s, 1H), 5.38–5.40 (m, 1H), 5.50 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 6.78–6.79 (m, 1H), 6.85–6.88 (m, 2H), 6.94–6.95 (m, 1H), 7.07–7.10 (m, 1H), 7.22–7.26 (m, 1H), 7.32–7.35 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.3, 29.1, 48.0, 52.4, 60.2, 68.7, 102.0, 115.0 (d, 2JC-F = 21.3 Hz, Ar-F), 120.5 (q, 1JC-F = 275.1 Hz, CF3), 122.2, 124.5, 125.8, 126.5, 129.8, 130.4, 130.5, 131.6 (q, 2JC-F = 34.5 Hz, CF3), 132.1, 132.4, 132.5, 150.0, 162.5 (d, 1JC-F = 246.0 Hz, Ar-F), 165.4, 166.0 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.7 (s, CF3), −113.3 (s, ArF) ppm. IR (KBr): υ 2949, 1722, 1680, 1625, 1508, 1454, 1425, 1226, 1182, 1136, 1101, 775 cm−1. MS (ESI) m/z (%): 544 [(M+H)]+. HRMS (ESI) calcd. for C27H21F4N3O5 [(M+H)]+: 544.1497; found: 544.1490.

4.3.20. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-4-(pentafluoroethyl)-2phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4t) Yellow solid; yield: 36%; m.p.: 186.6–186.9 °C; 1H NMR (500 MHz, CDCl3) δ: 2.93 (s, 3H), 2.99 (s, 3H), 3.48 (s, 3H), 5.17 (s, 1H), 5.37–5.38 (m, 1H), 5.48 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 6.68–6.79 (m, 1H), 6.93–6.94 (m, 1H), 7.06–7.10 (m, 1H), 7.17–7.20 (m, 3H), 7.22–7.26 (m, 1H), 7.35–7.37 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.4, 29.1, 50.0, 52.3, 60.4, 69.4, 102.0, 111.3 (tq, 1JC-F = 258.4 Hz, 2 JC-F = 37.1 Hz, CF2), 118.8 (qt, 1JC-F = 286.9 Hz, 2JC-F = 37.2 Hz, CF3), 122.4, 124.2, 125.7, 126.5, 127.9, 128.3 (t, 2JC-F = 25.0 Hz, CF2), 128.3, 130.3, 130.6, 131.3, 131.8, 133.4, 133.6, 149.7, 165.6, 166.0, 166.1 ppm; 19F NMR (470 MHz, CDCl3) δ: −81.0 (s, CF3), −108.7 (m, CF2) ppm. IR (KBr): υ 2953, 1740, 1688, 1680, 1452, 1427, 1385, 1329, 1269, 1217, 1177, 1136, 1096, 1038, 775 cm−1. MS (ESI) m/z (%): 576 [(M+H)]+. HRMS (ESI) calcd. for C28H22F5N3O5 [(M+H)]+: 576.1564; found: 576.1562.

4.3.16. Methyl cis-8-methoxy-1′,3′-dimethyl-2′,4′,6′-trioxo-2-phenyl-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4p) Yellow solid; yield: 92%; m.p.: 234.3–234.6 °C; 1H NMR (500 MHz, CDCl3) δ: 2.94 (s, 3H), 3.03 (s, 3H), 3.54 (s, 3H), 3.81 (s, 3H), 5.26 (s, 1H), 5.43 (s, 1H), 5.89 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 6.43–6.44 (m, 1H), 6.78–6.80 (m, 1H), 7.05–7.08 (m, 1H), 7.20 (s, 3H), 7.34–7.36 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.5, 29.3, 48.9, 52.6, 55.9, 60.1, 68.6, 96.4, 111.7, 118.8, 120.1, 120.6 (q, 1JCF = 275.1 Hz), 123.3, 126.0, 126.6, 128.1, 128.2, 130.6, 131.5, 131.7 (q, 2JC-F = 34.3 Hz), 134.2, 149.9, 153.4, 165.5, 166.2 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.6 (s, CF3) ppm. IR (KBr): υ 2951, 1734, 1678, 1629, 1452, 1427, 1384, 1211, 1180, 1141, 1083, 761 cm−1. MS (ESI) m/z (%): 556 [(M+H)]+. HRMS (ESI) calcd. for C28H24F3N3O6 [(M +H)]+: 556.1697; found:556.1697.

4.3.21. Methyl trans-1′,3′-dimethyl-2′,4′,6′-trioxo-4-(pentafluoroethyl)-2phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4t') Yellow solid; yield: 29%; m.p.: 71.4–71.6 °C; 1H NMR (500 MHz, CDCl3) δ: 2.85 (s, 3H), 2.97 (s, 3H), 3.52 (s, 3H), 4.78–4.79 (m, 1H), 5.31 (s, 1H), 5.63 (d, J = 8.0 Hz, 1H), 6.46–6.48 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.97–6.99 (m, 1H), 7.00–7.03 (m, 1H), 7.11–7.12 (m, 2H), 7.19–7.20 (m, 1H), 7.26–7.29 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.6, 28.7, 51.5, 52.4, 67.1, 73.4, 102.9, 111.7 (tq, 1JC2 1 2 F = 258.9 Hz, JC-F = 36.9 Hz, CF2), 118.6 (qt, JC-F = 286.8 Hz, JC-F = 37.3 Hz, CF3), 124.6, 125.1, 125.6, 126.0, 128.5, 129.5, 129.8, 130.7, 130.8, 130.8 (t, 2JC-F = 25.6 Hz, CF2), 131.3, 134.6, 136.1, 149.6, 165.5, 166.9, 169.1 ppm; 19F NMR (470 MHz, CDCl3) δ: −82.1 (s, CF3), −112.4 (m, CF2) ppm. IR (KBr): υ 2955, 1740, 1684, 1454, 1425, 1377, 1327, 1267, 1248, 1215, 1179, 1153, 1103, 1051, 773 cm−1. MS (ESI) m/z (%): 576 [(M+H)]+. HRMS (ESI) calcd. for C28H22F5N3O5 [(M+H)]+: 576.1564; found: 576.1556

4.3.17. Methyl cis-1′,3′-dimethyl-8-nitro-2′,4′,6′-trioxo-2-phenyl-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4q) Yellow solid; yield: 30%; m.p.: 217.9–218.3 °C; 1H NMR (500 MHz, CDCl3) δ:2.98 (s, 3H), 3.01 (s, 3H), 3.54 (s, 3H), 5.34 (s, 1H), 5.39–5.40 (m, 1H), 6.23 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 7.04–7.05 (m, 1H), 7.15–7.16 (m, 1H), 7.18–7.21 (m, 3H), 7.28–7.30 (m, 2H), 7.89–7.91 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.6, 29.2, 49.1, 52.6, 60.3, 67.8, 95.9, 120.2 (q, 1JC-F = 275.0 Hz), 124.5, 125.2, 126.3, 126.8, 127.7, 128.3, 128.5, 130.5, 130.7 (q, 2JC-F = 34.8 Hz), 131.3, 133.3, 137.1, 143.8, 149.5, 165.1, 165.5, 165.8 ppm; 19F NMR (470 MHz, CDCl3) δ: −59.7 (s, CF3) ppm. IR (KBr): υ 2949, 1732, 1685, 1627, 1450, 1429, 1384, 1217, 1176, 1139, 1103, 758 cm−1. MS (ESI) m/z (%): 571 [(M+H)]+. HRMS (ESI) calcd. for C27H21F3N4O7 [(M +H)]+: 571.1443; found: 571.1438. 4.3.18. Methyl cis-1′,3′,9-trimethyl-2′,4′,6′-trioxo-2-phenyl-4(trifluoromethyl)-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4r) Yellow solid; yield: 91%; m.p.: 205.2–205.8 °C; 1H NMR (500 MHz, CDCl3) δ: 2.27 (s, 3H), 2.90 (s, 3H), 3.03 (s, 3H), 3.52 (s, 3H), 5.24 (s, 1H), 5.38–5.40 (m, 1H), 5.44 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 6.68–6.70 (m, 1H), 6.75 (s, 1H), 6.87–6.89 (m, 1H), 7.17–7.18 (m,

4.3.22. Methyl cis-1′,3′-dimethyl-2′,4′,6′-trioxo-4-(tetrafluoroethyl)-2phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4u) Yellow solid; yield: 26%; m.p.: 193.3–193.5 °C; 1H NMR (500 MHz, CDCl3) δ: 2.93 (s, 3H), 2.99 (s, 3H), 3.47 (s, 3H), 5.15 (s, 1H), 5.38–5.39 (m, 1H), 5.48 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.78–6.80 40

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(m, 1H), 6.93–6.95 (m, 1H), 7.06–7.10 (m, 1H), 7.16–7.20 (m, 3H), 7.23–7.26 (m, 1H), 7.36–7.37 (m, 2H) ppm; 13C NMR (125 MHz,CDCl3) δ: 28.3, 29.1, 50.2, 52.2, 60.4, 69.6, 102.1, 109.2 (m, CF2), 113.2 (tt, 1 JC-F = 259.3 Hz, 2JC-F = 31.3 Hz, CF2), 117.7 (qt, 1JC-F = 286.6 Hz, 2 JC-F = 34.1 Hz, CF3), 122.4,124.2,125.7,126.4,127.9, 128.2 (t, 2JCF = 25.3 Hz, CF2), 128.3, 130.3, 130.6, 131.4, 132.3, 133.3, 133.7 149.6, 165.6, 166.0 ppm; 19F NMR (470 MHz, CDCl3) δ: −80.6 (m, CF3), −106.5 (m, CF2), −123.3 (m, CF2) ppm. IR (KBr): υ 2953, 1739, 1683, 1631, 1384, 1325, 1269, 1213, 1176, 1138, 1112, 1089, 775 cm−1. MS (ESI) m/z (%): 626 [(M+H)]+. HRMS (ESI) calcd. for C29H22F7N3O5 [(M+H)]+: 626.1530; found: 626.1524.

Acknowledgment The authors are grateful to the National Natural Science Foundation of China (Grant Nos. 21672138, 21542005, 21272152) for their financial support. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jfluchem.2018.09.007. References

4.3.23. Methyl trans-1′,3′-dimethyl-2′,4′,6′-trioxo-4-(tetrafluoroethyl)-2phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro[pyrido[2,1-a] isoquinoline-1,5′-pyrimidine]-3-carboxylate (4u') Yellow solid; yield: 18%; m.p.: 142.3–142.9 °C; 1H NMR (500 MHz, CDCl3) δ: 2.85 (s, 3H), 2.96 (s, 3H), 3.51 (s, 3H), 4.78–4.80 (m, 1H), 5.32 (s, 1H), 5.63 (d, J = 8.0 Hz, 1H), 6.48–6.50 (m, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.97–7.03 (m, 2H), 7.12–7.13 (m, 2H), 7.19–7.22 (m, 1H), (m, 3H) ppm; 13C NMR (125 MHz,CDCl3) δ: 28.8, 51.6, 52.3, 67.0, 73.1, 103.0, 108.9 (m, CF2), 112.8 (m, CF2), 117.8 (qt, 1JC2 F = 286.0 Hz, JC-F = 34.1 Hz, CF3), 124.6, 125.1, 125.7, 126.0, 128.5, 129.6, 129.9, 130.8 (t, 2JC-F = 25.8 Hz, CF2), 130.9, 131.3, 134.7, 136.3, 149.6, 165.6, 166.8, 169.1 ppm; 19F NMR (470 MHz, CDCl3) δ: −80.6 (m, CF3), −109.2 (m, CF2), −123.8 (m, CF2) ppm. IR (KBr): υ 2955, 1732, 1681, 1627, 1379, 1310, 1261, 1211, 1143, 1114, 1091, 771 cm−1. MS (ESI) m/z (%): 626 [(M+H)]+. HRMS (ESI) calcd. for C29H22F7N3O5 [(M+H)]+: 626.1530; found: 626.1523

[1] (a) J.T. Bojarski, J.L. Mokrosz, H.J. Bartoń, M.H. Paluchowska, Recent progress in barbituric acid chemistry, Adv. Heterocycl. Chem. 38 (1985) 229–297, https://doi. org/10.1016/S0065-2725(08)60921-6; (b) J.N. Delgado, W.A. Remers, J.B. Lippincott, Organic Medicinal and Pharmaceutical Chemistry, Wolters Kluwer Health, Philadephia, 1991; (c) M.C. Smith, B.J. Riskin, The clinical use of barbiturates in neurological disorders, Drugs 42 (1991) 365–378, https://doi.org/10.2165/00003495199142030-00003; (d) S. Sudha, M.K. Lakshmana, N. Pradhan, Phenobarbital in the anticonvulsant dose range does not impair learning and memory or alter brain AChE activity or monoamine levels, Pharmacol. Biochem. Behav. 54 (1996) 633–638, https://doi. org/10.1016/0091-3057(95)02283-X; (e) H. Brunner, K.P. Ittner, D. Lunz, S. Schmatloch, T. Schmidt, M. Zabel, Highly enriched mixtures of methohexital stereoisomers by palladium-catalyzed allylation and their anaesthetic activity, Eur. J. Org. Chem. 5 (2003) 855–862, https://doi. org/10.1002/ejoc.200390129; (f) L.L. Brunton, J.S. Lazo, L.P. Keith, The Pharmacological Basis of Therapeutics, McGraw-Hill, Inc., New York, 2006; (g) K.E. Lyons, R. Pahwa, Pharmacotherapy of essential tremor, CNS Drugs 22 (2008) 1037–1045, https://doi.org/10.2165/0023210-200822120-00006; (h) D.J. Abraham, D.P. Rotella, Medicinal Chemistry, Drug Discovery and Development, Wiley, Hoboken, NJ, USA, 2010. [2] (a) F. Grams, H. Brandstetter, S. D’Alo, D. Gepperd, H.W. Krel, H. Leinert, V. Livi, E. Menta, A. Oliva, G. Zimmermann, Pyrimidine-2,4,6-triones: a new effective and selective class of matrix metalloproteinase inhibitors, Biol. Chem. 382 (2001) 1277–1285, https://doi.org/10.1515/bc.2001.159; (b) E. Maquoi, N.E. Sounni, L. Devy, F. Oliver, F. Frankenne, H.W. Krell, F. Grams, J.M. Foidart, A. Noel, Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor, Clin. Cancer Res. 10 (2004) 4038–4047, https://doi. org/10.1158/1078-0432.ccr-04-0125; (c) C. Uhlmann, W. Froscher, Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study, CNS Neurosci. Ther. 15 (2009) 24–31, https://doi.org/10. 1111/j.1755-5949.2008.00073.x; (d) J. Wang, C. Medina, M.W. Radomski, J.F. Gilmer, N-substituted homopiperazine barbiturates as gelatinase inhibitors, Bioorg. Med. Chem. 19 (2011) 4985–4999, https://doi.org/10.1016/j.bmc.2011.06.055. [3] (a) R.J. Prankerd, R.H. McKeown, Physico-chemical properties of barbituric acid derivatives. III: partition coefficients of cycloalkane-l’, 5-spirobarbituric acids at 25 °C, Int. J. Pharm. 83 (1992) 39–45, https://doi.org/10.1016/0378-5173(82) 90005-9; (b) E.M. Galati, M.T. Monforte, N. Miceli, E. Raneri, Anticonvulsant and sedative effects of some 5-substituted bromopyrazolinic spirobarbiturates, Farmaco 56 (2001) 459–461, https://doi.org/10.1016/S0014-827X(01)01062-X; (c) P. Singh, K.J. Paul, A practical approach for spiro- and 5-monoalkylated barbituric acids, Prog. Heterocycl. Chem. 43 (2006) 607–612, https://doi.org/10. 1002/chin.200641165; (d) J.W. Dundee, P.D.A. McIlroy, The history of the barbiturates, Anaesthesia 37 (1982) 726–734, https://doi.org/10.1111/j.1365-2044.1982.tb01310.x; (e) L. Lomlin, J. Einsiedel, F.W. Heinemann, K. Meyer, P.J. Gmeiner, Proline derived spirobarbiturates as highly effective β-turn mimetics incorporating polar and functionalizable constraint elements, J. Org. Chem. 73 (2008) 3608–3611, https://doi.org/10.1021/jo702573z; (f) A. Renard, J. Lhomme, M.J. Kotera, Synthesis and properties of spiro nucleosides containing the barbituric acid moiety, J. Org. Chem. 67 (2002) 1302–1307, https://doi.org/10.1021/jo016194y; (g) S.H. Kim, A.T. Pudzianowski, K.J. Leavitt, J. Barbosa, P.A. McDonnell, W.J. Metzler, B.M. Rankin, R. Liu, W. Vaccaro, W. Pitts, Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13), Bioorg. Med. Chem. Lett. 15 (2005) 1101–1106, https://doi.org/10.1016/j.bmcl.2004.12.016; (h) D.B. Ramachary, M. Kishor, Y.V. Reddy, Development of pharmaceutical drugs, drug intermediates and ingredients by using direct organo-click reactions, Eur. J. Org. Chem. 2008 (2008) 975–993, https://doi.org/10.1002/ejoc.200701014. [4] (a) For recent examples, see: M. Jalilzadeh, N. Noroozi Pesyan, F. Rezaee, S. Rastgar, Y. Hosseini, E. Şahin, New one-pot synthesis of spiro[furo[2,3-d]pyrimidine-6,5’-pyrimidine]pentaones and their sulfur analogues, Mol. Diversity 15 (2011) 721–731, https://doi.org/10.1007/s11030-011-9302-9; (b) K. Mori, S. Sueoka, T. Akiyama, Expeditious construction of a carbobicyclic

4.3.24. Methyl cis-8-methoxy-1′,3′-dimethyl-2′,4′,6′-trioxo-4(pentafluoroethyl)-2-phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro [pyrido[2,1-a]isoquinoline-1,5′-pyrimidine]-3-carboxylate (4v) Yellow solid; yield: 37%; m.p.: 229.1–229.4 °C; 1H NMR (500 MHz, CDCl3) δ: 2.94 (s, 3H), 2.98 (s, 3H), 3.48 (s, 3H), 3.79 (s, 3H), 5.14 (s, 1H), 5.37–5.38 (m, 1H), 5.84 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 6.39–6.41 (m, 1H), 6.76–6.78 (m, 1H), 7.03–7.06 (m, 1H), 7.16–7.19 (m, 3H), 7.35–7.37 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.5, 29.1, 50.0, 52.3, 55.6, 60.2, 69.4, 96.6, 111.3 (tq, 1JC-F = 257.6 Hz, 2JC-F = 38.1 Hz, CF2), 111.7, 118.6, 118.8 (qt, 1JC-F = 287.0 Hz, 2JC-F = 36.8 Hz, CF3), 120.1, 123.4, 126.4, 127.9, 128.3, 128.3 (t, 2JC-F = 25.0 Hz, CF2), 131.3, 131.6, 132.7, 133.5, 149.8, 153.2, 165.7, 165.9, 166.2 ppm; 19F NMR (470 MHz, CDCl3) δ: −81.0 (s, CF3), −108.7 (m, CF2) ppm. IR (KBr): υ 2955, 1740, 1682, 1630, 1466, 1452, 1384, 1327, 1263, 1217, 1174, 1136, 1094, 1042, 795 cm−1. MS (ESI) m/z (%): 606.0 [(M+H)]+. HRMS (ESI) calcd. for C29H24F5N3O6 [(M+H)]+: 606.1671; found: 606.1666. 4.3.25. Methyl trans-8-methoxy-1′,3′-dimethyl-2′,4′,6′-trioxo-4(pentafluoroethyl)-2-phenyl-1′,3′,4′,6′-tetrahydro-2H,2′H,11bH-spiro [pyrido[2,1-a]isoquinoline-1,5′-pyrimidine]-3-carboxylate (4v′) Yellow solid; yield: 28%; m.p.: 171.5–172.1 °C; 1H NMR (500 MHz, CDCl3) δ: 2.87 (s, 3H), 2.96 (s, 3H), 3.51 (s, 3H), 3.81 (s, 3H), 4.76–4.77 (m, 1H), 5.29 (s, 1H), 6.00 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 6.45–6.47 (m, 1H), 6.72–6.73 (m, 1H), 6.93–6.96 (m, 1H), 7.10–7.11 (m, 2H), 7.24–7.27 (m, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ: 28.8, 51.6, 52.4, 55.5, 66.9, 73.2, 97.4, 110.7 (m, CF2), 110.9, 118.6 (m, CF3), 117.8, 120.9, 125.7, 126.7, 128.4, 129.8, 129.9, 130.0, 130.9 (t, 2 JC-F = 25.5 Hz, CF2), 134.7, 135.8, 149.7, 153.8, 165.6, 166.9, 169.0 ppm; 19F NMR (470 MHz, CDCl3) δ: −82.0 (s, CF3), −112.3 (m, CF2) ppm. IR (KBr): υ 2951, 1736, 1684, 1632, 1460, 1450, 1375, 1317, 1263, 1217, 1184, 1165, 1150, 1113, 1082, 1043, 762 cm−1. MS (ESI) m/z (%): 606 [(M+H)]+. HRMS (ESI) calcd. for C29H24F5N3O6 [(M +H)]+: 606.1671; found: 606.1661. 41

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