Zinc-mediated enantioselective addition of terminal 3-en-1-ynes to cyclic trifluoromethyl ketimines

Journal of Fluorine Chemistry 208 (2018) 1–9

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Zinc-mediated enantioselective addition of terminal 3-en-1-ynes to cyclic trifluoromethyl ketimines ⁎

Yue Zhang, Jing Nie, Fa-Guang Zhang , Jun-An Ma

T

⁎

Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin 300072, China

A R T I C L E I N F O

A B S T R A C T

keywords: Trifluoromethyl Ketimine Enantioselectivity BINOL Dimethylzinc Alkyne

A facile enantioselective addition of terminal 3-en-1-ynes to cyclic N-acyl trifluoromethyl ketimines is reported. In the presence of Zinc/BINOL complexes, a series of enynylated tertiary carbinamines were readily obtained in 90–97% yield with 70–97% enantiomeric excess in a single chemical operation under mild reaction conditions.

1. Introduction The incorporation of CF3 group into organic molecules can substantially alter their physical properties, such as metabolic stability, lipophilicity and conformational behavior [1]. In particular, the presence of the strong electron-withdrawing CF3 group adjacent to the CeN bond makes α-(trifluoromethyl)-amines function as an effective peptide bond replacement by generating a metabolically stable, poorly basic amine [2]. Owing to these promising properties, α-(trifluoromethyl)-amines have been found wide applications in pharmaceuticals and chemical biology [3]. For the enantioselective preparation of α-(trifluoromethyl)-amines, a variety of efficient methods has been established which include catalytic hydrogenation [4], nucleophilic addition to trifluoromethylated imines [5], and trifluoromethylation of imines [6]. Among these, the nucleophilic addition of terminal alkynes to fluorinated imines represents a convergent and efficient approach to the synthesis of optically active propargylic amines [7]. In this context, a great effort has been devoted the development of highly selective metal-promoted systems for these enantioselective alkynylation reactions [8]. However, despite significant progress in this area, previous studies are mainly focused on simple terminal alkynes as nucleophilic species [9]. In particular, the terminal 3-en-1-ynes as nucleophiles could rapidly provide enyne carbinamines which are present in some biologically important natural products and medicinally relevant synthetic compounds [10]. Recently, our group has disclosed that terminal 3-en-1-ynes could act as a suitable nucleophilic species for the enynylation of N-sufonyl aldimines and ketones catalyzed by chiral metal

⁎

complexes, which provide enynylated amine and alcohol adducts in a single chemical operation with excellent chiral induction [11]. Thus, encouraged by these results and as a part of our continuous interests in the synthesis of new class of chiral trifluoromethylated amines [12], herein, we report the results of our investigations on asymmetric enynylation of cyclic N-acyl trifluoromethyl ketimines. With this method, a range of chiral tertiary trifluoromethylated carbinamines were obtained with up to 97% yield and 97% ee in the presence of chiral ZincBIONL complexes. Notably, this study represents the first catalytic enantioselective enynylation of ketimines to access chiral trifluoromethylated tertiary carbinamines in a single chemical operation. Moreover, the obtained dihydroquinazolinones bearing the trifluoromethyl moiety at the quaternary stereogenic carbon center are the core units present in many anti-HIV agents, such as DPC 961, DPC 963, and DPC 083 (Fig. 1) [13]. 2. Results and discussion On the basis of our precedent enantioselective diynylation of cyclic trifluoromethyl ketimines [9d], we first examined the model reaction of ketimine 1a with enyne 2a under otherwise identical reaction conditions. However, the use of chloramphenicol-amine derivatives as ligands together with dimethylzinc could only give up to 50% enantiomeric excess. Inspired by the success of enynylation of N-sufonyl aldimines catalyzed by chiral Zn-BINOL complexes [11b], we subsequently investigated the use of (1,1-binaphthalene)-2,2-diol (BINOL) derivatives as chiral inductor. As illustrated in Table 1, the 4-phenyl-

Corresponding authors. E-mail addresses: [email protected] (F.-G. Zhang), [email protected] (J.-A. Ma).

https://doi.org/10.1016/j.jfluchem.2018.01.008 Received 29 November 2017; Received in revised form 15 January 2018; Accepted 15 January 2018 0022-1139/ © 2018 Elsevier B.V. All rights reserved.

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Fig. 1. Dihydroquinazolinone-based anti-HIV agents and analogues.

substituted ligand L1 could deliver the desired product 3a in 97% yield at room temperature in toluene, albeit with low enantioselectivity (28% ee, Table 1, entry 1). Subsequently, a series of BINOL-type ligands containing various groups at the 3,3′-positions of the binaphthol backbone were evaluated for the model reaction (Table 1, entries 2–12). To our delight, when the subsitituted group at the 3,3′-position of BINOL was a strong electron-withdrawing group such as trifluoromethyl group, nitrogroup, trifluoromethylsulfonyl group and multiple-fluorine atoms on the phenyl group, high enantiomeric excess up to 86% together with excellent yield was obtained (Table 1, entries 2–3, 9–10). On the contrary, low enantioselectivity was observed when electron-donating or electron-neutral subsititued groups was placed on the BINOL backbone (Table 1, entries 1, 4–5, 8). Moderate outcome was obtained for halogen-substituted BINOL at it’s 3,3′-positions (entries 6–7). Finally, to further increase steric hindrance of strong electronwithdrawing groups on the substituted phenyl group of BINOL derivative, ligand L11 and L12 were prepared and employed in the reaction. Gradually, the ee of afforded product could be improved to 92%. Optimized reaction conditions regarding chemical yield and enantioselectivity was established with ligand L12 by screening different solvents, lowering the reaction temperature, and the amount of ligand (entries 13–17). Overall, the addition reaction of terminal 3-en-1-yne 2a to cyclic trifluoromethyl ketimines 1a could be efficiently performed in toluene at 10 °C to afford the trifluoromethylated product 3a in 97% yield and 94% ee with 10 mol% ligand L12. With the optimized reaction conditions in hand, we then set out to

investigate the substrate scope of this transformation. Representative results are summarized in Table 2. A series of phenylbuta-3-en-1-ynes substituted by different groups including electron-rich and electronwithdrawing groups or at different positions on the phenyl ring are all tolerated in the reaction and provided constantly excellent yields (90% to 97%) with ee values ranging from 69% to 97% (Table 2, entries 1–11). Generally, electron-donating substituted enynes deliver desired product with higher enantioselectivity than that of electron-withdrawing ones (for example, entry 2 vs 8, entry 3 vs 4, entry 4 vs 10). 2-Thiophenyl- and 2-naphthyl-substituted enynes were also feasible substrates, providing the corresponding products 3f and 3g both with 86% ee. Then, other cyclic N-acyl trifluoromethyl ketimines bearing electron-withdrawing, electron-donating, or electron-neutral groups on the phenyl ring were also probed under identical reaction conditions with enyne 2a. Pleasingly, these substrates could undergo the enantioselective addition smoothly with excellent yield and high ee (entries 12–18). It is worth noting that di-substituted dihydroquinazolinones were also viable substrates, thus delivering 3n with 95% ee (entry 14). Furthermore, chiral trifluoromethylated tertiary carbinamines 3s–3u, which are the analogues of anti-HIV agents, were also obtained by employing but-1-en-3-yn1-ylcyclopropane as nucleophile, albeit with decreasing enantioselectivity. However, notably, an improvement of the enantiopurity of adducts could be achieved by simple recrystallization (entries 3, 5, 8–11 and 17–21). Additionally, another alkyl-substituted enyne was also examined in this reaction, affording adduct 3v with high yield and moderate enantioselectivity which is one limitation of current method (entry 2

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Table 1 Optimization of conditions for the enantioselective addition of terminal 3-en-1-yne 2a to CF3-ketimine 1a.a

Entry

Ligand

Solvent

T (°C)

Yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d 17e 18f 19g

L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L12 L12 L12 L12 L12 L12 L12

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene CH2Cl2 toluene toluene toluene toluene

rt rt rt rt rt rt rt rt rt rt rt rt 10 0 10 10 10 10 10

97 97 97 91 91 97 97 97 97 97 97 97 97 95 95 97 97 85 75

−28 80 85 −30 −30 66 52 72 82 86 92 92 94 82 77 94 90 90 88

a

Reaction conditions: 1a (0.1 mmol), 2a (0.4 mmol), 1.2 M ZnMe2 in toluene (0.3 mmol), Ligand (20 mol%) at rt for 24 h. Isolated yield. c Enantiomeric excess was determined by chiral HPLC analysis. d Ligand (10 mol%). e Ligand (5 mol%). f 0.2 mmol of enyne 2a was employed. g 0.2 mmol of ZnMe2 was employed. b

22). It should also be pointed out that a mixture of E/Z isomers (E/ Z = 92:8 to 95:5) were obtained for alkyl-substituted enynes owing to double bond’s geometry configuration (entries 19–22). Finally, simple protection of the adduct 3i furnished the crystalline derivative 4 whose absolute stereochemistry was determined from single-crystal X-ray structural analysis (Scheme 1). Moreover, when the trifluoromethyl group on the quinazolin-2(1H)-one ring was replaced with a difluoromethyl group, the enynylation product 3w could still be obtained in 97% yield with 84% ee (Scheme 2). In conclusion, we have successfully developed a catalytic enantioselective addition of terminal 3-en-1-ynes to cyclic trifluoromethyl ketimines. In the presence of Zinc-BIONL complexes, a series of trifluoromethylated tertiary carbinamines were readily obtained in 90–97% yields with 63–97% ee under mild reaction conditions. Notably, higher enantiopurity of the adducts could be achieved by simple recrystallizaiton. Further extension of this enynylation reaction to other substrates and investigation on the potential biological activity of the derivatives are ongoing in our laboratory.

well as 376 MHz (19F NMR). Chemical shifts were reported in ppm from the solvent resonance as the internal standard (CDCl3: 7.26 ppm). Melting points were measured on a WRS-1A digital melting point apparatus and are uncorrected. Optical rotations were determined using an Autopol IV-T. HPLC analyses were carried out on a Hewlett Packard Model HP 1200 instrument. Tetrahydrofuran (THF), diethyl ether and toluene were distilled from sodium/benzophenone prior to use; CH2Cl2 was distilled from CaH2. Analytical thin layer chromatography was performed on 0.20 mm Qingdao Haiyang silica gel plates. Silica gel (200–300 mesh) (from Qingdao Haiyang Chem. Company, Ltd.) was used for flash chromatography. Dimethylzinc, 1.2 M solution in toluene were purchased from ACROS. 3,3-Disubstituted (S)-BINOL-derived ligands L1–L11 were synthesized in accordance with the known method [11a]. The synthetic route to Ligand L12 was described in Section 3.4. Substituted terminal 3-en-1-ynes 2 were synthesized in accordance with the literature [11b]. Trifluoromethyl ketimines 1 were prepared as described in the literature [12d]. Standard reagents and solvents were purified according to known procedures.

3. Experimental section

3.2. General procedures for the enynylation of cyclic trifluoromethyl ketimines 1

3.1. General information A 1.2 M solution of Me2Zn in toluene (0.3 mmol) was added dropwise to a solution of terminal 3-en-1-yne 2 (0.4 mmol) in toluene (0.5 mL) at 10 °C under nitrogen in about 5 min. After stirring for 1 h,

1

H, 13C and 19F NMR spectra were recorded on a Bruker AV 400 MHz spectrometer at 400 MHz (1H NMR), 100 MHz (13C NMR), as 3

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the BINOL ligand L12 (0.01 mmol) was added as a solid in one portion. The reaction mixture was stirred for 30 min at the same temperature, after which the cyclic ketimine (0.1 mmol) in toluene (0.5 mL) was added dropwise at 10 °C. The solution was stirred at 10 °C until the reaction was complete (detected by TLC, around 24 h). The reaction mixture was quenched with 1N HCl (10 mL), extracted with EtOAc (10 mL × 3), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Petroleum ether/Ethyl acetate = 10/1) afforded the product 3. For compound 3c, 3e, 3h–3k, 3q–3u, a simple recrystallization of this product from CH2Cl2/hexane gave the white solid (ee < 20%), and the mother liquid was concentrated under reduced pressure to afford the desired product with high enantioselectivity.

Table 2 The scope of the addition of terminal 3-en-1-ynes 2 to CF3-ketimines 1 to afford the adducts 3.a

Entry

Product 3 (R; R′)

Yield (%)b

ee (%)c

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

3a (6-Cl; Ph) 3b (6-Cl; 4-MeOC6H4) 3c (6-Cl; 3-MeOC6H4) 3d (6-Cl; 2-MeOC6H4) 3e (6-Cl; 4-MeC6H4) 3f (6-Cl; 2-Thienyl) 3g (6-Cl; 2-naphthyl) 3h (6-Cl; 4-FC6H4) 3i (6-Cl; 4-BrC6H4) 3j (6-Cl; 2-ClC6H4) 3k (6-Cl; 2-BrC6H4) 3l (6-H; Ph) 3m (6-F; Ph) 3n (5-F,6-Cl; Ph) 3o (6-MeO; Ph) 3p (6-Me; Ph) 3q (6-CF3; Ph) 3r (6-Br; Ph) 3s (6-Cl; cyclopropyl) 3t (6-F; cyclopropyl) 3u (5,6-F2; cyclopropyl) 3v (6-Cl; PhCH2CH2)

97 97 97 97 95 94 92 96 95 96 90 97 96 92 97 96 96 97 94 90 92 90

94 95 83 97 84 86 86 88 69 88 85 95 97 95 93 91 74 73 74 80 83 63

(96)

3.2.1. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3a) 48 mg, mp 203–204 °C, 97% yield, 94% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 8.4 min, tR (minor) = 17.6 min, [α]D 20 +50.0 (c 1.0, CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.40–7.32 (m, 5H), 7.23 (dd, J = 8.8, 2.2 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 16.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.9 Hz, 1H), 6.54 (s, 1H), 6.20 (d, J = 16.4 Hz, 1H), 5.17 (d, J = 16.3 Hz, 1H), 5.05 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.0, 151.9, 145.1, 136.5, 135.4, 131.0, 129.6, 129.0, 128.7, 128.2, 128.0, 127.8, 126.7, 122.3 (q, 1JF-C = 287 Hz), 117.3, 116.2, 114.4, 105.5, 87.1, 83.3, 59.3 (q, 2JF-C = 33 Hz), 55.4, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.55 (s, 3F); HRMS (ESI): found: m/z 519.1063 [M+Na]+; calcd. for C27H20ClF3N2O2 + Na 519.1058.

(97)

(99) (99) (98) (98)

(94) (98) (98) (99) (99)

a Reaction conditions (unless otherwise specified): 1 (0.1 mmol), 2 (0.4 mmol), 1.2 M ZnMe2 in toluene (0.3 mmol), L12 (10 mol%) at 10 °C for 24 h. b Isolated yield. c Enantiomeric excess was determined by chiral HPLC analysis and values in parentheses are for recrystallized products.

3.2.2. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(4-methoxyphenyl)but-3en-1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3b) 52 mg, mp 198–200 °C, 97% yield, 95% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 12.8 min, tR (minor) = 43.8 min, [α]D 20 +63.4 (c 1.0, Scheme 1. Further transformation of product 3i to 4 (top) and X-ray structure of 4 (bottom) for determination of the absolute configuration.

4

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Scheme 2. Change of CF3 group to CF2H on the cyclic ketimine.

CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.22 (dd, J = 8.9, 2.3 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.3 Hz, 1H), 6.86 (dd, J = 11.9, 8.7 Hz, 4H), 6.80 (d, J = 8.9 Hz, 1H), 6.49 (s, 1H), 6.04 (d, J = 16.3 Hz, 1H), 5.17 (d, J = 16.4 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 160.8, 159.0, 151.9, 144.6, 136.5, 130.9, 128.7, 128.3, 128.2, 128.2, 128.0, 127.8, 123.8 (q, 1JF-C = 287 Hz), 117.5, 116.2, 114.4, 102.9, 87.6, 82.5, 59.3 (q, 2JF-C = 33 Hz), 55.5, 55.4, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.59 (s, 3F); HRMS (ESI): found: m/z 549.1167 [M+Na]+; calcd. for C28H22ClF3N2O3 + Na 549.1163.

3.78 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.0, 152.0, 145.0, 139.8, 136.5, 132.7, 130.9, 129.7, 128.7, 128.2, 128.0, 127.8, 126.7, 123.8 (q, 1JF-C = 287 Hz), 117.4, 116.2, 114.4, 104.3, 87.3, 82.9, 59.3 (q, 2JF-C = 33 Hz), 55.3, 45.8, 21.5; 19F NMR (376 MHz, CDCl3) δ −81.55 (s, 3F); HRMS (ESI): found: m/z 533.1213 [M+Na]+; calcd. for C28H22ClF3N2O2 + Na 533.1214. 3.2.6. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(thiophen-2-yl)but-3-en1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3f) 47 mg, mp 211–213 °C, 94% yield, 86% ee, (after recrystallization, mother liquid, 99% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 0.9 mL/min, 254 nm): tR (major) = 10.4 min, tR (minor) = 31.8 min, [α]D20 +51.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.26 (d, J = 5.2 Hz, 1H), 7.24–7.19 (m, 2H), 7.18–7.16 (m, 2H), 7.04 (s, 1H), 7.02–6.99 (m, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.9 Hz, 1H), 6.58 (s, 1H), 5.99 (d, J = 16.0 Hz, 1H), 5.16 (d, J = 16.3 Hz, 1H), 5.03 (d, J = 16.3 Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.0, 152.0, 140.5, 137.7, 136.5, 131.0, 128.7, 128.6, 128.1, 128.0, 128.0, 127.8, 126.8, 123.7 (q, 1 JF-C = 287 Hz), 117.3, 116.2, 114.4, 104.3, 86.8, 83.5, 59.3 (q, 2JF19 F NMR (376 MHz, CDCl3) δ −81.55 (s, 3F); C = 33 Hz), 55.4, 45.8; HRMS (ESI): found: m/z 525.0622 [M+Na]+; calcd. for C25H18ClF3N2O2S + Na 525.0622.

3.2.3. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(3-methoxyphenyl)but-3en-1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3c) 51 mg, mp 138–140 °C, 97% yield, 83% ee, (after recrystallization, mother liquid, 96% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 11.3 min, tR 1 (minor) = 52.3 min, [α]D 20 +54.0 (c 1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.27 (dd, J = 19.2, 9.5 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 16.3 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.84 (dt, J = 26.1, 13.8 Hz, 5H), 6.21 (d, J = 16.3 Hz, 1H), 5.20 (d, J = 16.2 Hz, 1H), 5.07 (d, J = 16.2 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 160.0, 159.0, 152.0, 144.9, 136.8, 136.5, 134.0, 131.0, 129.9, 128.7, 128.0, 127.8, 123.7 (q, 1JFC = 287 Hz), 119.4, 117.3, 116.2, 115.3, 114.4, 111.9, 105.8, 86.9, 83.4, 59.3 (q, 2JF-C = 33 Hz), 55.4, 55.3, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.54 (s, 3F); HRMS (ESI): found: m/z 549.1164 [M+Na]+; calcd. for C28H22ClF3N2O3 + Na 549.1163.

3.2.7. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(naphthalen-2-yl)but-3en-1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3g) 50 mg, mp 180–182 °C, 92% yield, 86% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 11.3 min, tR (minor) = 70.1 min, [α]D20 +40.0 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.79 (t, J = 8.0 Hz, 3H), 7.71 (s, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.51–7.41 (m, 2H), 7.25–7.19 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.9 Hz, 1H), 6.71 (s, 1H), 6.28 (d, J = 16.3 Hz, 1H), 5.16 (d, J = 15.6 Hz, 1H), 5.04 (d, J = 15.7 Hz, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.1, 152.1, 145.1, 136.6, 134.0, 133.5, 132.9, 131.0, 128.7, 128.5, 128.2, 128.1, 127.9, 127.9, 127.8, 127.0, 126.8, 123.8 (q, 1JF-C = 287 Hz), 122.7, 117.4, 116.3, 114.5, 105.7, 87.3, 83.6, 59.4 (q, 2JF-C = 33 Hz), 55.3, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.50 (s, 3F); HRMS (ESI): found: m/z 569.1210 [M+Na]+; calcd. for C31H22ClF3N2O2 + Na 569.1214.

3.2.4. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(2-methoxyphenyl)but-3en-1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3d) 52 mg, mp 214–216 °C, 97% yield, 97% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 10.3 min, tR (minor) = 41.1 min, [α]D20 +62.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.40 (t, J = 10.9 Hz, 2H), 7.31 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 6.98–6.88 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 16.5 Hz, 1H), 6.26 (s, 1H), 5.16 (d, J = 16.3 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.87 (s, 3H), 3.76 (s, 3H); 13 C NMR (100 MHz, CDCl3), δ 159.0, 157.5, 151.8, 140.6, 136.5, 130.9, 130.7, 128.8, 128.2, 128.0, 127.8, 127.6, 124.4, 123.8 (q, 1JFC = 287 Hz), 120.9, 117.4, 116.2, 114.4, 111.2, 106.1, 88.0, 82.7, 59.3 (q, 2JF-C = 33 Hz), 55.6, 55.4, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.56 (s, 3F); HRMS (ESI): found: m/z 549.1160 [M+Na]+; calcd. for C28H22ClF3N2O3 + Na 549.1163.

3.2.8. (R,E)-6-chloro-4-(4-(4-fluorophenyl)but-3-en-1-yn-1-yl)-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3h) 49 mg, mp 214–216 °C, 96% yield, 88% ee, (after recrystallization, mother liquid, 99% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 90:10, 1.0 mL/min, 254 nm): tR (major) = 16.1 min, tR (minor) = 22.6 min, [α]D20 +41.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.39–7.30 (m, 2H), 7.23 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.05 (dd, J = 16.9, 9.2 Hz, 3H), 6.85 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.9 Hz, 1H), 6.69 (s, 1H), 6.10 (d, J = 16.3 Hz, 1H), 5.17 (d, J = 16.4 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 163.5 (d, 1JF-C = 248 Hz), 159.0, 152.0, 143.7, 136.5, 131.7, 131.0, 128.7, 128.5 (d, 3JF1 C = 8 Hz), 128.2, 128.0 127.8, 123.7 (q, JF-C = 287 Hz), 117.3, 116.2,

3.2.5. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(4-(p-tolyl)but-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3e) 49 mg, mp 208–210 °C, 95% yield, 84% ee, (after recrystallization, mother liquid, 97% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 8.6 min, tR (minor) = 14.5 min, [α]D20 +50.8 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 8.9, 2.3 Hz, 1H), 7.20 (dd, J = 11.3, 8.4 Hz, 4H), 7.11 (d, J = 16.4 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.9 Hz, 1H), 6.68 (s, 1H), 6.17 (d, J = 16.3 Hz, 1H), 5.20 (d, J = 16.3 Hz, 1H), 5.07 (d, J = 16.4 Hz, 1H), 5

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116.1 (d, 2JF-C = 22 Hz), 114.4, 105.2, 86.9, 83.3, 59.3 (q, 2JF19 F NMR (376 MHz, CDCl3) δ −81.56 (s, 3F), C = 32 Hz), 55.4, 45.8; −110.91 to −110.97 (m, 1F); HRMS (ESI): found: m/z 537.0969 [M +Na]+; calcd. for C27H19ClF4N2O2 + Na 537.0963.

129.5, 129.0, 128.9, 128.7, 127.8, 126.7, 124.0 (q, 1JF-C = 287 Hz), 122.7, 115.7, 114.9, 114.3, 105.7, 86.5, 84.1, 59.6 (q, 2JF-C = 33 Hz), 55.3, 45.7; 19F NMR (376 MHz, CDCl3) δ −81.65 (s, 3F); HRMS (ESI): found: m/z 485.1444 [M+Na]+; calcd. for C27H21F3N2O2 + Na 485.1447.

3.2.9. (R,E)-4-(4-(4-bromophenyl)but-3-en-1-yn-1-yl)-6-chloro-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3i) 55 mg, mp 208–210 °C, 95% yield, 69% ee, (after recrystallization, mother liquid, 99% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 90:10, 1.0 mL/min, 254 nm): tR (major) = 16.6 min, tR (minor) = 20.4 min, [α]D20 +54.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.25–7.16 (m, 5H), 7.02 (d, J = 16.4 Hz, 1H), 6.90 (s, 1H), 6.82 (dd, J = 17.0, 8.7 Hz, 3H), 6.17 (d, J = 16.3 Hz, 1H), 5.17 (d, J = 16.3 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 158.9, 152.0, 143.6, 136.4, 134.2, 132.0, 130.9, 128.5, 128.0, 127.9, 127.7, 123.6, 123.6 (q, 1 JF-C = 288 Hz), 117.1, 116.2, 114.3, 106.2, 86.6, 83.7, 59.2 (q, 2JF19 F NMR (376 MHz, CDCl3) δ −81.53 (s, 3F); C = 33 Hz), 55.3, 45.7; HRMS (ESI): found: m/z 597.0166 [M+Na]+; calcd. for C27H19BrClF3N2O2 + Na 597.0163.

3.2.13. (R,E)-6-fluoro-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3m) 46 mg, mp 209–211 °C, 96% yield, 97% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 9.0 min, tR (minor) = 19.7 min, [α]D20–4.0 (c 1.0, CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 15.5, 10.7 Hz, 6H), 7.20 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 16.4 Hz, 1H), 6.99 (t, J = 7.0 Hz, 1H), 6.84 (dd, J = 16.8, 6.5 Hz, 3H), 6.58 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.17 (d, J = 16.3 Hz, 1H), 5.06 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.0, 158.1 (d, 1JF-C = 242 Hz), 152.1, 145.0, 135.4, 134.2, 129.6, 129.0, 128.3, 127.8, 126.7, 123.8 (q, 1JF2 3 C = 287 Hz), 117.8 (d, JF-C = 22 Hz), 117.3 (d, JF-C = 7 Hz), 116.3 (d, 3 2 JF-C = 8 Hz), 115.8 (d, JF-C = 25 Hz), 114.4, 105.5, 86.9, 83.3, 59.4 (q, 2JF-C = 33 Hz), 55.3, 45.9; 19F NMR (376 MHz, CDCl3) δ −81.48 (s, 3F), −120.20 (dd, J = 12.1, 7.8 Hz, 1F); HRMS (ESI): found: m/z 503.1365 [M+Na]+; calcd. for C27H20F4N2O2 + Na 503.1353.

3.2.10. (R,E)-6-chloro-4-(4-(2-chlorophenyl)but-3-en-1-yn-1-yl)-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3j) 51 mg, mp 193–195 °C, 96% yield, 88% ee, (after recrystallization, mother liquid, 98% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 0.9 mL/min, 254 nm): tR (major) = 9.8 min, tR (minor) = 20.7 min, [α]D20 +32.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.50 (dd, J = 10.8, 5.3 Hz, 2H), 7.40–7.36 (m, 1H), 7.27–7.20 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 13.1, 8.8 Hz, 3H), 6.75 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.17 (d, J = 16.3 Hz, 1H), 5.04 (d, J = 16.3 Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.0, 152.0, 140.8, 136.5, 133.7, 133.5, 131.0, 130.4, 130.2, 128.7, 128.1, 128.0, 127.8, 127.2, 126.5, 123.7 (q, 1JF2 JFC = 287 Hz), 117.2, 116.3, 114.4, 108.2, 86.6, 84.1, 59.3 (q, 19 F NMR (376 MHz, CDCl3) δ −81.47 (s, 3F); C = 33 Hz), 55.3, 45.8; HRMS (ESI): found: m/z 553.0665 [M+Na]+; calcd. for C27H19Cl2F3N2O2 + Na 553.0668.

3.2.14. (R,E)-6-chloro-5-fluoro-1-(4-methoxybenzyl)-4-(4-phenylbut-3en-1-yn-1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3n) 50 mg, mp 175–177 °C, 92% yield, 95% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 7.6 min, tR (minor) = 19.0 min, [α]D20 +31.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 5H), 7.32–7.27 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 16.4 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 6.84 (s, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.20 (d, J = 16.4 Hz, 1H), 5.19 (d, J = 16.3 Hz, 1H), 5.08 (d, J = 16.2 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.1, 155.8 (d, 1JF-C = 255 Hz), 151.4, 144.7, 138.3, 135.6, 132.4, 129.5, 128.9, 127.9, 127.8, 126.7, 123.7 (q, 1 JF-C = 287 Hz), 115.9 (d, 2JF-C = 19 Hz), 114.5, 114.4, 111.2 (d, 3JF2 19 F C = 4 Hz), 105.8, 86.9, 82.0, 56.6 (q, JF-C = 35 Hz), 55.4, 46.1; NMR (376 MHz, CDCl3) δ −81.71 (d, J = 13.8 Hz, 3F), −108.05 to −108.39 (m, 1F).; HRMS (ESI): found: m/z 537.0962 [M+Na]+; calcd. for C27H19ClF4N2O2 + Na 537.0963.

3.2.11. (R,E)-4-(4-(2-bromophenyl)but-3-en-1-yn-1-yl)-6-chloro-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3k) 52 mg, mp 204–206 °C, 90% yield, 85% ee, (after recrystallization, mother liquid, 98% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 8.9 min, tR (minor) = 19.8 min, [α]D20 +28.4 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 22.2, 11.9 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 7.9 Hz, 3H), 6.84 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.9 Hz, 1H), 6.19 (dd, J = 25.0, 15.2 Hz, 2H), 5.16 (d, J = 16.1 Hz, 1H), 5.04 (d, J = 16.2 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.1, 151.9, 143.4, 136.6, 135.4, 133.5, 131.0, 130.7, 128.7, 128.1, 128.1, 127.8, 126.7, 124.2, 123.7 (q, 1JF-C = 287 Hz), 117.2, 116.3, 114.4, 108.3, 86.5, 84.1, 59.4 (q, 2JF-C = 33 Hz), 55.4, 45.9; 19F NMR (376 MHz, CDCl3) δ −81.47 (s, 3F); HRMS (ESI): found: m/z 597.0170 [M+Na]+; calcd. for C27H19BrClF3N2O2 + Na 597.0168.

3.2.15. (R,E)-6-methoxy-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn1-yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3o) 48 mg, mp 203–205 °C, 97% yield, 93% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 15.9 min, tR (minor) = 36.3 min, [α]D20 +24.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.36 (dt, J = 11.4, 5.9 Hz, 5H), 7.19 (d, J = 8.8 Hz, 3H), 7.10 (d, J = 16.4 Hz, 1H), 6.87–6.78 (m, 4H), 6.20 (d, J = 16.4 Hz, 1H), 6.12 (s, 1H), 5.15 (d, J = 16.3 Hz, 1H), 5.04 (d, J = 16.4 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 158.9, 155.1, 152.1, 144.7, 135.5, 131.4, 129.5, 129.0, 128.8, 127.8, 126.7, 123.9 (q, 1JF-C = 287 Hz), 116.8, 116.0, 116.0, 114.7, 114.3, 105.7, 86.5, 84.0, 59.6 (q, 2JF-C = 33 Hz), 55.8, 55.4, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.33 (s, 3F); HRMS (ESI): found: m/z 515.1555 [M+Na]+; calcd. for C28H23F3N2O3 + Na 515.1553. 3.2.16. (R,E)-1-(4-methoxybenzyl)-6-methyl-4-(4-phenylbut-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3p) 46 mg, mp 220–222 °C, 96% yield, 91% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 11.7 min, tR (minor) = 23.6 min, [α]D20 +26.4 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41-7.33 (m, 5H), 7.20 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 13.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.30 (s, 1H), 6.21 (d, J = 16.3 Hz, 1H), 5.18 (d, J = 16.3 Hz, 1H), 5.05 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 158.9, 152.2, 144.6, 135.6, 135.5, 132.3, 131.6, 129.5, 129.1, 129.0, 128.9, 127.8, 126.7, 124.0 (q,

3.2.12. (R,E)-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn-1-yl)-4(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one 8(3l) 45 mg, mp 215–217 °C, 97% yield, 95% ee, HPLC (DAICEL Chiralpak IC, hexane/IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 11.3 min, tR (minor) = 28.4 min, [α]D20–9.0 (c 1.0, CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 1H), 7.43–7.34 (m, 5H), 7.29 (d, J = 9.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.16–7.09 (m, 2H), 6.89 (t, J = 9.6 Hz, 3H), 6.39 (s, 1H), 6.22 (d, J = 16.4 Hz, 1H), 5.21 (d, J = 16.3 Hz, 1H), 5.11 (d, J = 16.3 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 158.9, 152.2, 144.7, 137.8, 135.5, 131.0, 6

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CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.99–6.93 (m, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.79 (dd, J = 9.1, 4.4 Hz, 1H), 6.19 (s, 1H), 5.81 (dd, J = 15.8, 9.5 Hz, 1H), 5.58 (d, J = 15.8 Hz, 1H), 5.13 (d, J = 16.4 Hz, 1H), 5.03 (d, J = 16.4 Hz, 1H), 3.77 (s, 3H), 1.51 (ddd, J = 12.7, 8.1, 4.2 Hz, 1H), 0.90–0.84 (m, 2H), 0.55–0.50 (m, 2H); 13C NMR (100 MHz, CDCl3), δ 159,0, 158.1 (d, 1JF-C = 242 Hz), 153.1, 152.0, 134.2, 128.4, 127.8, 123.8 (q, 1JF-C = 287 Hz), 117.8, 117.6, 116.2 (d, 3JF-C = 8 Hz), 115.9 (d, 2JF-C = 25 Hz), 114.4, 104.3, 86.8, 80.2, 59.3 (q, 2JF-C = 33 Hz), 55.4, 45.9, 15.1, 8.2; 19F NMR (376 MHz, CDCl3) δ −81.66 (s, 3F), −120.39 to −120.44 (m, 1F); HRMS (ESI): found: m/z 467.1366 [M +Na]+; calcd. for C24H20F4N2O2 + Na 467.1353.

1

JF-C = 287 Hz), 115.5, 114.9, 114.3, 105.9, 86.4, 84.3, 59.6 (q, 2JF19 F NMR (376 MHz, CDCl3) δ −81.54 (s, C = 33 Hz), 55.3, 45.6, 20.7; 3F); HRMS (ESI): found: m/z 499.1607 [M+Na]+; calcd. for C28H23F3N2O2 + Na 499.1604. 3.2.17. (R,E)-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn-1-yl)-4,6-bis (trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3q) 51 mg, mp 175–177 °C, 96% yield, 74% ee, (after recrystallization, mother liquid, 94% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 90:10, 1.0 mL/min, 254 nm): tR (major) = 8.7 min, tR (minor) = 16.3 min, [α]D20 +3.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.40–7.32 (m, 5H), 7.20 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 16.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.3 Hz, 3H), 6.20 (d, J = 16.4 Hz, 1H), 5.23 (d, J = 16.3 Hz, 1H), 5.10 (d, J = 16.3 Hz, 1H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.2, 151.9, 145.3, 140.8, 135.4, 129.7, 129.0, 128.2 (q, 3JF-C = 3 Hz), 127.9, 127.9, 126.8, 126.2 (q, 3JF-C = 4 Hz), 124.9 (q, 2JF-C = 33 Hz), 123.9 (q, 1JF-C = 270 Hz), 123.7 (q, 1JF2 JFC = 287 Hz), 116.4, 115.2, 114.6, 105.4, 87.5, 83.1, 59.5 (q, 19 = 33 Hz), 55.4, 46.0; F NMR (376 MHz, CDCl ) δ −62.04 (s, 3F), 3 C −81.72 (s, 3F); HRMS (ESI): found: m/z 553.1318 [M+Na]+; calcd. for C28H20F6N2O2 + Na 553.1321.

3.2.21. (R,E)-4-(4-cyclopropylbut-3-en-1-yn-1-yl)-5,6-difluoro-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3u) 43 mg, a mixture of E/Z isomers due to double bond’s geometry configuration, E/Z = 92:8, mp 158–160 °C, 92% yield, 83% ee (E isomer, after recrystallization, mother liquor, 99% ee) HPLC (DAICEL Chiralpak IC, hexane/IPA = 90:10, 1.0 mL/min, 254 nm, E isomer): tR (major) = 11.3 min, tR (minor) = 17.2 min, [α]D20 +5.6 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.15 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 17.3, 9.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.57 (dd, J = 9.2, 2.0 Hz, 1H), 6.00 (s, 1H), 5.80 (dd, J = 15.8, 9.5 Hz, 1H), 5.58 (d, J = 15.8 Hz, 1H), 5.07 (dd, J = 41.7, 16.2 Hz, 2H), 3.77 (s, 3H), 1.59–1.39 (m, 1H), 0.92–0.80 (m, 2H), 0.60–0.42 (m, 2H); 13C NMR (100 MHz, CDCl3), δ 159.1, 152.8, 151.2, 148.7 (dd, 1JF-C = 256 Hz, 2 JF-C = 15 Hz), 146.7 (dd, 1JF-C = 244 Hz, 2JF-C = 13 Hz), 135.0, 128.1, 127.8, 123.8 (q, 1JF-C = 287 Hz), 119.0 (d, 2JF-C = 18 Hz), 114.5, 110.1 (d, 3JF-C = 10 Hz), 106.5 (d, 3JF-C = 10 Hz), 104.6, 86.8, 78.7, 56.4 (q, 2 JF-C = 36 Hz), 55.4, 46.2, 15.1, 8.1; 19F NMR (376 MHz, CDCl3) δ −81.92 (d, J = 13.2 Hz, 3F), −131.31 to −132.02 (m, 1F), −143.79 (ddd, J = 21.2, 9.3, 3.7 Hz, 1F); HRMS (ESI): found: m/z 485.1254 [M +Na]+; calcd. for C24H19F5N2O2 + Na 485.1259.

3.2.18. (R,E)-6-bromo-1-(4-methoxybenzyl)-4-(4-phenylbut-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3r) 52 mg, mp 183–185 °C, 97% yield, 73% ee, (after recrystallization, mother liquid, 98% ee,) HPLC (DAICEL Chiralpak IC, hexane/ IPA = 90:10, 1.0 mL/min, 254 nm): tR (major) = 13.3 min, tR (minor) = 30.5 min, [α]D20 +80.2 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.75 (s, 1H), 7.35 (dd, J = 13.4, 6.9 Hz, 6H), 7.17 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 16.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.65–6.45 (m, 1H), 6.18 (d, J = 16.4 Hz, 1H), 5.15 (d, J = 15.9 Hz, 1H), 5.03 (d, J = 16.1 Hz, 1H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3), δ 159.1, 151.9, 145.1, 137.1, 135.5, 133.9, 131.5, 129.6, 129.0, 128.2, 127.8, 126.8, 123.8 (q, 1JF-C = 287 Hz), 117.7, 116.6, 115.3, 114.5, 105.5, 87.2, 83.3, 59.3 (q, 2JF-C = 33 Hz), 55.4, 45.8; 19F NMR (376 MHz, CDCl3) δ −81.54 (s, 3F); HRMS (ESI): found: m/z 563.0558 [M+Na]+; calcd. for C27H20BrF3N2O2 + Na 563.0552.

3.2.22. (R,E)-6-chloro-1-(4-methoxybenzyl)-4-(6-phenylhex-3-en-1-yn-1yl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3v) 47 mg, a mixture of E/Z isomers due to double bond’s geometry configuration, E/Z = 92:8, mp 108–110 °C, 90% yield, 63% ee (E isomer), HPLC (DAICEL Chiralpak IC, hexane/IPA = 90:10, 1.0 mL/ min, 254 nm, E isomer): tR (major) = 12.9 min, tR (minor) = 16.6 min, 1 [α]D 20 +31.2 (c 1.0, CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 1.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.23–7.20 (m, 2H), 7.19 (d, J = 7.2 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.9 Hz, 1H), 6.40 (dd, J = 18.4, 11.4 Hz, 1H), 5.73 (s, 1H), 5.59 (d, J = 16.0 Hz, 1H), 5.13 (d, J = 16.3 Hz, 1H), 5.02 (d, J = 16.4 Hz, 1H), 3.77 (s, 3H), 2.75 (t, J = 7.8 Hz, 2H), 2.50 (q, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3), δ 158.9, 151.5, 147.9, 140.7, 136.3, 130.8, 128.6, 128.5, 128.3, 127.9, 127.8, 127.6, 126.2, 123.5 (q, 1JF2 JFC = 287 Hz), 117.2, 116.1, 114.3, 108.0, 86.4, 80.2, 59.0 (q, 19 F NMR (376 MHz, CDCl3) δ C = 33 Hz), 55.2, 45.7, 34.9, 34.7; −81.72 (s, 3F); HRMS (ESI): found: m/z 547.1375 [M+Na]+; calcd. for C29H24ClF3N2O2 + Na 547.1371.

3.2.19. (R,E)-6-chloro-4-(4-cyclopropylbut-3-en-1-yn-1-yl)-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3s) 43 mg, a mixture of E/Z isomers owing to double bond’s geometry configuration, E/Z = 95:5, mp 180–182 °C, 94% yield, 74% ee (E isomer, after recrystallization, mother liquor, 99% ee), HPLC (DAICEL Chiralpak IC, hexane/IPA = 90:10, 1.0 mL/min, 254 nm, E isomer): tR (major) = 12.6 min, tR (minor) = 20.4 min, [α]D 20 +48.5 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.20 (dd, J = 8.8, 2.3 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.9 Hz, 1H), 6.18 (s, 1H), 5.82 (dd, J = 15.8, 9.5 Hz, 1H), 5.59 (d, J = 15.8 Hz, 1H), 5.14 (d, J = 16.3 Hz, 1H), 5.01 (d, J = 16.4 Hz, 1H), 3.77 (s, 3H), 1.52 (ddd, J = 12.6, 8.2, 4.1 Hz, 1H), 0.90–0.84 (m, 2H), 0.55–0.52 (m, 2H); 13C NMR (100 MHz, CDCl3), δ 159.1, 153.2, 151.8, 136.6, 130.9, 128.7, 128.2, 127.9, 127.8, 123.4 (q, 1JF-C = 287 Hz), 117.6, 116.2, 114.4, 104.3, 87.0, 80.1, 59.2 (q, 2JF-C = 33 Hz), 55.4, 45.8, 15.1, 8.2; 19F NMR (376 MHz, CDCl3) δ −81.73 (s, 3F); HRMS (ESI): found: m/z 483.1054 [M+Na]+; calcd. for C24H20ClF3N2O2 + Na 483.1058.

3.2.23. (R,E)-6-chloro-4-(difluoromethyl)-1-(4-methoxybenzyl)-4-(4phenylbut-3-en-1-yn-1-yl)-3,4-dihydroquinazolin-2(1H)-one (3w) 46 mg, mp 205–207 °C, 97% yield, 84% ee, (after recrystallization, mother liquid, 99% ee), HPLC (DAICEL Chiralpak IC, hexane/ IPA = 80:20, 1.0 mL/min, 254 nm): tR (major) = 14.0 min, tR 1 (minor) = 20.1 min, [α]D 20 +38.2 (c 1.0, CH2Cl2); HNMR (400 MHz, d6-DMSO) δ 8.56 (s, 1H), 7.59 (d, J = 7.1 Hz, 2H), 7.50 (s, 1H), 7.37 (d, J = 7.9 Hz, 4H), 7.17 (d, J = 8.9 Hz, 3H), 6.90 (dd, J = 15.8, 8.7 Hz, 3H), 6.57 (d, J = 16.4 Hz, 1H), 6.29 (t, J = 55.4 Hz, 1H), 5.10 (d, J = 16.2 Hz, 1H), 4.98 (d, J = 16.2 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, d6-DMSO), δ 158.2, 151.5, 143.8, 136.7, 135.3, 130.0, 129.3, 128.7, 128.6, 127.6, 127.3, 126.7, 125.7, 118.2, 116.2, 114.5 (t,

3.2.20. (R,E)-4-(4-cyclopropylbut-3-en-1-yn-1-yl)-6-fluoro-1-(4methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (3t) 40 mg, a mixture of E/Z isomers owing to double bond’s geometry configuration, E/Z = 92:8, mp 161–163 °C, 90% yield, 80% ee (E isomer, after recrystallization, mother liquor, 99% ee) HPLC (DAICEL Chiralpak IC, hexane/IPA = 90:10, 1.0 mL/min, 254 nm, E isomer): tR (major) = 13.1 min, tR (minor) = 21.2 min, [α]D20 +7.0 (c 1.0, 7

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+63.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 2H), 7.98–7.95 (m, 2H), 7.93 (t, J = 2.5 Hz, 4H), 7.62 (t, J = 1.6 Hz, 2H), 7.51–7.46 (m, 2H), 7.36 (d, J = 5.5 Hz, 4H), 7.33–7.30 (m, 6H), 4.54 (d, J = 5.7 Hz, 2H), 4.46 (d, J = 5.7 Hz, 2H), 2.49 (s, 6H); 13C NMR (100 MHz, CDCl3), δ 151.7 (ddd, J = 248.7, 10.0, 4.1 Hz), 151.2, 141.0, 139.8 (dt, J = 251.3, 15.2 Hz), 139.5, 136.7 (td, J = 7.7, 4.6 Hz), 136.6, 134.3, 134.0, 131.1, 128.3, 128.2, 127.1, 126.7, 126.5, 125.8, 124.5, 111.6, 111.5, 111.5, 111.4, 98.9, 56.3; 19F NMR (376 MHz, CDCl3) δ −133.44 (dd, J = 20.5, 8.4 Hz, 8F), −161.44 (tt, J = 20.5, 6.3 Hz, 4F); HRMS (ESI): found: m/z 1069.2019 [M+Na]+; calcd. for C60H34F12O4 + Na 1069.2158. Compound 7 was transferred to a round-bottom flask. A mixture of THF and methanol (50 mL, 1:1.5) was added, followed by 6 drops of conc.HCl. The reaction mixture was heated to 65 °C and stirred for 4 h. After completion, the reaction was filtered through a celite plug and concentrated to yield the crude product, which was purified by column chromatography (gradient 0–4% EtOAc/hexanes). The product was obtained as a white solid. 1.0 g, 89% yield, mp 170–172 °C, [α]D 20–12.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 1.5 Hz, 4H), 7.62 (s, 2H), 7.49–7.44 (m, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.33–7.26 (m, 10H), 5.45 (s, 2H); 13C NMR (100 MHz, CDCl3), δ 151.7 (ddd, J = 248.8, 10.0, 4.1 Hz), 150.2, 139.9 (dt, J = 251.4, 15.2 Hz), 139.5, 139.4, 136.8 (td, J = 7.7, 4.7 Hz), 133.2, 132.1, 129.7, 129.5, 128.9, 128.4, 128.3, 125.1, 124.8, 124.3, 112.1, 111.6, 111.6, 111.5, 111.4; 19F NMR (376 MHz, CDCl3) δ −133.42 (dd, J = 20.5, 8.3 Hz, 8F), −161.44 (tt, J = 20.5, 6.4 Hz, 4F); HRMS (ESI): found: m/z 981.1666 [M+Na]+; calcd. for C56H26F12O2 + Na 547.1371.

1JF-C = 252 Hz), 114.0, 106.4, 86.2, 86.0, 57.6 (t, 2JF-C = 24 Hz), 55.0, 44.0; 19F NMR (376 MHz, d6-DMSO) δ −127.92 (dd, J = 266, 55 Hz, 1F), −128.88 (dd, J = 266, 55 Hz, 1F); HRMS (ESI): found: m/z 501.1156 [M+Na]+; calcd. For C27H21ClF2N2O2 + Na 501.1152. 3.3. Further transformation of the adduct 3 3.3.1. (R,E)-4-(4-(4-bromophenyl)but-3-en-1-yn-1-yl)-6-chloro-1-(4methoxybenzyl)-3-(4-nitrobenzoyl)-4-(trifluoromethyl)-3,4dihydroquinazolin-2(1H)-one (4) To a 25 mL Schlenk tube, 3i (60 mg, 0.1 mmol), triethylamine (30 mg, 0.3 mmol), anhydrous dichloromethane (5 mL) were sequentially added, then 4-nitrobenzoyl chloride (61 mg, 0.3 mmol) was added. The mixture was stirred at room temperature. After TLC shows the reaction is complete, the mixture was washed by 5 mL water, and organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography (PE/EA = 20:1) on silica gel to give the product. After simple recrystallization in dichloromethane and hexane to obtain colorless needle solid 4 with 99.99% ee, mp 183–184 °C, HPLC (DAICEL Chiralpak IC, hexane/ IPA = 90:10, 1.0 mL/min, 254 nm): tR (minor) = 24.9 min, tR (major) = 84.1 min, [α]D20 +186.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, d6-DMSO) δ 8.30 (t, J = 9.2 Hz, 3H), 8.17 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.54 (s, 3H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 16.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 16.4 Hz, 1H), 5.17–4.99 (m, 2H), 3.72 (s, 3H); 13C NMR (100 MHz, d6-DMSO), δ 168.1, 165.7, 158.6, 150.2, 149.7, 143.7, 140.3, 135.5, 134.2, 131.6, 130.6, 129.3, 128.8, 128.4, 128.1, 127.2, 124.0, 123.6, 123.0 (q, 1JF-C = 289 Hz), 122.8, 118.8, 118.1, 114.0, 106.3, 91.5, 79.9, 61.5 (q, 2JF-C = 33 Hz), 55.0, 46.0; 19F NMR (376 MHz, d6-DMSO) δ −75.43 (s, 3F); HRMS (ESI): found: m/z 746.0274 [M+Na]+; calcd. for C34H22BrClF3N3O5 + Na 746.0276; CCDC 892771.

Acknowledgments This research was supported financially by the National Natural Science Foundation of China (No. 21225208, 21472137 and 21532008) and the National Basic Research Program of China (973 Program: 2014CB745100).

3.4. Synthesis of ligand L12 References Both of BINOL derivative 5 and boronic acid 6 were reported in the literature [14]. As shown in the following scheme, Ligand L12 was obtained by Suzuki cross-coupling of 5 with 6, followed by deprotection of 7.

[1] (a) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Blackwell Publishing, 2009; (b) V. Gouverneur, K. Müller, Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications, Imperial College Press, London, 2012. [2] (a) M. Sani, A. Volonterio, M. Zanda, ChemMedChem 2 (2007) 1693–1700. [3] (a) For selected reviews, see: J.-A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119–6146; (b) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 111 (2011) 455–529; (c) Y.-Y. Huang, X. Yang, Z. Chen, F. Verpoort, N. Shibata, Chem. Eur. J. 21 (2015) 8664–8684; (d) For selected examples, see: N. Zhang, S. Ayral-Kaloustian, T. Nguyen, J. Afragola, R. Hernandez, J. Lucas, J. Gibbons, C. Beyer, J. Med. Chem. 50 (2007) 319–327; (e) G.L. Grunewald, J. Lu, K.R. Criscione, C.O. Okoro, Bioorg. Med. Chem. Lett. 15 (2005) 5319–5323; (f) P.D. O’Shea, C.-Y. Chen, D. Gauvreau, F. Gosselin, G. Hughes, C. Nadeau, R.P. Volante, J. Org. Chem. 74 (2009) 1605–1610. [4] (a) For examples: H. Abe, H. Amii, K. Uneyama, Org. Lett. 3 (2001) 313–315; (b) M.W. Chen, Y. Duan, Q.-A. Chen, D.-S. Wang, C.-B. Yu, Y.G. Zhou, Org. Lett. 12 (2010) 5075–5077; (c) A. Henseler, M. Kato, K. Mori, T. Akiyama, Angew. Chem. Int. Ed. 50 (2011) 8180–8183. [5] (a) For examples: D. Enders, K. Funabiki, Org. Lett. 3 (2001) 1575–1577; (b) C. Lauzon, A.B. Charette, Org. Lett. 8 (2006) 2743–2745; (c) P. Fu, M.L. Snapper, A.H. Hoveyda, J. Am. Chem. Soc. 130 (2008) 5530–5541; (d) E. Husmann, S. Sugiono, G. Mersmann, M. Raabe, Org. Lett. 13 (2011) 1044–1047; (e) Y.-L. Liu, T.-D. Shi, F. Zhou, X.L. Zhao, X. Wang, J. Zhou, Org. Lett. 13 (2011) 3826–3829; (f) G. Huang, J. Yang, X. Zhang, Chem. Commun. 47 (2011) 5587–5589. [6] (a) For examples: H. Kawai, A. Kusuda, S. Nakamura, M. Shiro, N. Shibata, Angew. Chem. Int. Ed. 48 (2009) 6324–6327; (b) G.K.S. Prakash, M. Mandal, G.A. Olah, Angew. Chem. Int. Ed. 40 (2001) 589–590. [7] (a) For reviews, see: P.G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.

A 100-mL Schlenk flask was charged with BINOL derivative 5 (1.00 g, 1.5 mmol, 1 equiv), boronic acid 6 (1.15 g, 3 mmol, 3 equiv), potassium carbonate (414 mg, 21 mmol, 3 equiv), palladium acetate (34 mg, 0.15 mmol, 0.1 equiv) and triphenylphosphine (157 mg, 0.6 mmol, 0.4 equiv). The flask was degassed and backfilled with argon (3 times). Degassed tetrahydrofuran and H2O (55 mL, 10:1) was finally added and the reaction mixture was heated to 75 °C with stirring for 20 h. After completion, EtOAc was added and the reaction mixture was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield a crude mixture. Purification by column chromatography (gradient 0–4% EtOAc/hexanes) afforded the MOM protected intermediate. 1.29 g, yellow solid, mp 150–152 °C, [α]D 20 8

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(2004) 4095–4105; (b) L. Zani, C. Bolm, Chem. Commun. (2006) 4263–4275; (c) B.M. Trost, A.H. Weiss, Adv. Synth. Catal. 351 (2009) 963–983. [8] (a) For reviews, see, M. Shibasaki, M. Kanai, Chem. Rev. 108 (2008) 2853–2873; (b) V. Bisai, V.K. Singh, Tetrahedron Lett. 57 (2016) 4771–4784; (c) N. Kumagai, M. Shibasaki, Bull. Chem. Soc. Jpn. 88 (2015) 503–517; (d) For selected previous contributions in catalytic asymmetric addition of terminal alkynes to ketimines, see, T. Hashimoto, M. Omote, K. Maruoka, Angew. Chem. Int. Ed. 50 (2011) 8952–8955; (e) L. Yin, Y. Otsuka, H. Takada, S. Mouri, R. Yazaki, N. Kumagai, M. Shibasaki, Org. Lett. 15 (2013) 698–701; (f) K. Morisaki, M. Sawa, J. Nomaguchi, H. Morimoto, Y. Takeuchi, K. Mashima, T. Ohshima, Chem. Eur. J. 19 (2013) 8417–8420; (g) K. Morisaki, M. Sawa, R. Yonesaki, H. Morimoto, K. Mashima, T. Ohshima, J. Am. Chem. Soc. 138 (2016) 6194–6203; (h) B. Jiang, Y.-G. Si, Angew. Chem. Int. Ed. 43 (2003) 216–218. [9] (a) For the use of 1,3-diynes as nucleophilic species, see: T.-L. Liu, H. Ma, F.G. Zhang, Y. Zheng, J. Nie, J.-A. Ma, Chem. Commun. 47 (2011) 12873–12875; (b) F.-G. Zhang, H. Ma, Y. Zheng, J.-A. Ma, Tetrahedron 68 (2012) 7663–7669; (c) T.-L. Liu, H.-X. Zhang, Y. Zheng, Q.-W. Yao, J.-A. Ma, Chem. Commun. 48 (2012) 12234–12236; (d) F.-G. Zhang, H. Ma, J. Nie, Y. Zheng, Q.-Z. Gao, J.-A. Ma, Adv. Synth. Catal. 354 (2012) 1422–1428; (e) B.M. Trost, V.S. Chan, D. Yamamoto, J. Am. Chem. Soc. 132 (2010) 5186–5192;

[10] [11] [12]

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