One-pot syntheses of N-(α-fluorovinyl)azole derivatives from N-(diphenylmethylene)-2,2,2-trifluoroethanamine

Abstract

N-(Diphenylmethylene)-2,2,2-trifluoroethanamine acts as a versatile fluorine-containing building block, and from which N-(α-fluorovinyl)azole derivatives were readily prepared in good yields with relatively high stereoselectivity by using various N–H containing heterocycles as nucleophiles via vinylic substitution reactions (S_NV) in the presence of LDA and K₃PO₄ in a one-pot process.

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Introduction

The incorporation of a fluorine-containing group into an organic molecule alters its physical, chemical, and biological properties in such a way that it often enhances the molecule's desirable properties, including higher levels of metabolic stability, solubility, lipophilicity, bioavailability and biopotency.¹ Hence, the development of efficient and mild methods for the preparation of organofluorine compounds have attracted considerable attention in a broad area of organic chemistry.² Among them, special interest has focused on fluoroalkenes which as versatile building blocks can be transformed to many valuable functionalities.³ Nowadays, numerous approaches⁴ such as carbonyl olefination methods for synthesizing vinyl fluoride have been developed, and many applications of vinyl fluoride in pharmaceuticals and fluoropolymers have been found.⁵ The major transformation of vinyl fluoride in synthesis includes nucleophilic vinylic substitution reaction (S_NV)⁶ and metal mediated C–F bond activated cross coupling reaction.⁷

N-(diphenylmethylene)-2,2,2-trifluoroethanamine 1 was firstly reported by Langlois in 2002 (Scheme 1).⁸ Comparing to ethyl N-(diphenylmethylene)glycinate which served as a versatile synthon,⁹ the application of 1 in synthetic chemistry is rare though the protons near trifluoromethyl group are acidic. Only one example involving the transformation of 1 was realized by anodic α-acetoxylation.¹⁰ The reason is that the anion intermediate from deprotonation of 1 with strong base is not stable, which easily undergoes β-fluorine elimination to form fluoroenamine. The fluoroenamine usually is not stable which readily reacted with water to give the corresponding amide and hydrogen fluoride in an addition-elimination process.¹¹ Our investigations for designing new fluorine-containing building blocks, recently led us to find that the gem-difluoroenamine 4 is stable and can be isolated. Considering that 4 is a typical vinyl fluoride, the transformation with 4 is worth to try because it may provide an efficient strategy for preparation of fluoroenamines.

Scheme 1 The synthesis of N-(diphenylmethylene)-2,2,2-trifluoroethanamine (1).

In 2014, Cao and co-workers reported the S_NV reaction of 2,2-difluorovinylarene with various N–H-containing heterocycles in the presence of K₃PO₄ affording the (E)-N-α-fluorovinyl derivatives of azoles in excellent yields with relatively high stereoselectivity.⁶ⁱ Considering the typical vinyl fluoride structure of 4, N–H-containing heterocycles would also be suitable nucleophiles. In this paper, we report an efficient method for synthesizing N-(α-fluorovinyl)azole derivatives from 1 in a one-pot process, in which the isolation of gem-difluoroenamine 4 is not necessary. Especially, the resulting fluoroenamine are stable solid and did not undergo hydrolysis on contacting with water.

Results and discussion

The literature method for preparation of 1 used methyl hemiketal of fluoral as a starting material in a three-step process (Scheme 1).^8,12 However, we found that trifluoroethylamine hydrochloride 2 as a cheap and commercial available fluorinated compound can react with diphenylmethanimine 3 smoothly with simple stirring at room temperature in dichloromethane to afford 1 in 85% yield (Scheme 2). And the reaction can scale up to more than 20 gram. The gem-difluoroenamine 4 was then prepared in 81% yield through dehydrofluorination of 1 with LDA as a base. It was found that 4 is stable during the aqueous workup process.

Scheme 2 The synthesis of fluorinated building blocks 1 and 4.

With N-(diphenylmethylene)-2,2,2-trifluoroethanamine 1 in hand, we focused on the one-pot synthesis of N-(α-fluorovinyl)azoles. Keeping LDA as the dehydrofluorination base, the reaction of 1 with 1H-imidazole 5a was carried out in the presence of K₃PO₄ using THF as a solvent (Table 1). It was observed that the nucleophilic substitution of vinylfluoride took place smoothly to give the corresponding product 6a in 80% yield with good stereoselectivity (E/Z = 88 : 12) (entry 1). The effect of the second base for deproton of 5a was studied. Na₂CO₃, K₂CO₃, Cs₂CO₃ or EtONa gave nearly the same yields and E/Z selectivities as that of K₃PO₄ (entries 1–5), but only gem-difluoroenamine 4 was obtained in the absence of the second base (entry 6). Furthermore, 2 equiv. of K₃PO₄ is necessary to promise a reasonable yield, the decrease in the amount of K₃PO₄ (e.g., 1 equiv.; entry 8) led to an obvious decrease in the yield, while the increase in the amount of K₃PO₄ from 2 equiv. to 3 equiv. resulted in no significant improvement of yield (entry 7). The reaction proceeded efficiently at room temperature and the increase of reaction temperature is not necessary (entries 9–10). An investigation of the solvent effect showed that the ethereal solvents were better than other solvents, and tetrahydrofuran (THF) gave the highest yield (Table 1, entries 5, 11–14). Thus, the optimized reaction conditions are as follows: 1H-imidazole 5a (1.0 equiv.), imine 1 (1.1 equiv.), LDA (2.5 equiv.), K₃PO₄ (2.0 equiv.), and THF as solvent, stirring for 1 h at −78 °C then 16 h at room temperature. It is need to be pointed out that only (E)-6a was obtained after purification by flash chromatography, and the configuration of (E)-6a was confirmed by X-ray single crystal analysis (Fig. 1).¹³ Usually, the trans ³J_H–F coupling constant in Z isomer is higher than the cis ³J_H–F coupling constant in E isomer in the ¹H NMR spectrum of vinylfluoride,¹⁴ so the configuration of other major products were tentatively assigned according to the ³J_H–F coupling constant.

Table 1 Survey of reaction conditions between imine 1 and imidazole 5a^a

Entry	Temp (°C)	Base (equiv.)	Solvent	Yield^b (%)	E/Z^c
a Reaction conditions: 1 (0.44 mmol), imidazole 5a (0.4 mmol), solvent (5 mL), LDA (2.5 eq.) at −78 °C for 1 h, then at rt for 16 h.b Yields determined by ^19F NMR which using benzotrifluoride as the internal standard.c The ratios of E/Z isomers were determined by ^19F NMR.d No product was detected.
1	25	Na2CO3 (2)	THF	74	88 : 12
2	25	K2CO3 (2)	THF	74	86 : 14
3	25	Cs2CO3 (2)	THF	72	86 : 14
4	25	EtONa (2)	THF	76	87 : 13
5	25	K3PO4 (2)	THF	80	88 : 12
6	25	None	THF	NR
7	25	K3PO4 (3)	THF	76	88 : 12
8	25	K3PO4 (1)	THF	60	84 : 16
9	40	K3PO4 (2)	THF	75	88 : 12
10	60	K3PO4 (2)	THF	76	89 : 11
11	25	K3PO4 (2)	Et3N	22	89 : 11
12	25	K3PO4 (2)	n-Hexane	12	85 : 15
13	25	K3PO4 (2)	Et2O	58	88 : 12
14	25	K3PO4 (2)	CH2Cl2	N.D.^d

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Fig. 1 X-Ray single crystal structure of (E)-6a.

With the optimized condition in hand, the scope of nitrogen-containing heterocyclic compounds as nucleophiles was investigated, and the results were shown in Table 2. Similarly to 5a, substituted imidazoles reacted smoothly to give the N-(α-fluorovinyl)azoles in moderate to good yields, and only pure E-isomers (6a, 6c–f) as major product were obtained after column chromatography. However, both isomers (E)-6b and (Z)-6b could be isolated for 4-methylimidazole (5b) due to their relatively lower stereoselectivity. The reactions of imine 1 with pyrazole (5g), 1H-1,2,3-triazole (5h), 1H-1,2,4-triazole (5i), 1H-benzo[d]imidazole (5j–l), 5-nitro-1H-indazole (5m) and 1H-benzo[d][1,2,3]triazole (5n) were also proceeded well to afford the expected N-(α-fluorovinyl)azoles in moderate to good yields. The best yield (81%, 6k) was achieved by using 2-methyl-1H-benzo[d]imidazole (5k) as the nucleophile. It is noteworthy that the azole bearing a strong electron-withdrawing group such as NO₂ (5-nitro-1H-indazole, 5m) also reacted smoothly but with Z-isomer as the major product. The stereoselective outcome of the reaction is consistent with the reported methods in which terminal vinylic fluorine was substituted by heterocycle⁶ⁱ or cyanide anion¹⁵ via vinylic nucleophilic substitution reaction (S_NV).

Table 2 Preparation of N-(α-fluorovinyl)azoles^a

Entry	Azole 5	Product 6	Yield^b (%)	Isomer ratio^c (E/Z)
a Reaction conditions: azoles 5a–n (0.4 mmol), 1 (0.44 mmol), K3PO4 (0.8 mmol), THF (5 mL), LDA (2.5 eq.) at −78 °C for 1 h, then at rt for 16 h.b Isolated yields.c Determined by^19F NMR of the crude product.d Not obtained after column chromatography.e Total yield of (E/Z)-6g which can't be isolated from each other.
1		(E)-6a	70	89 : 11
		(Z)-6a	—^d
2		(E)-6b	45	74 : 26
		(Z)-6b	20
3		(E)-6c	51	85 : 15
		(Z)-6c	—^d
4		(E)-6d	60	91 : 9
		(Z)-6d	—^d
5		(E)-6e	61	95 : 5
		(Z)-6e	—^d
6		(E)-6f	75	93 : 7
		(Z)-6f	—^d
7		(E)-6g	73^e	37 : 63
		(Z)-6g
8		(E)-6h	46	62 : 38
		(Z)-6h	9
9		(E)-6i	43	63 : 37
		(Z)-6i	12
10		(E)-6j	68	85 : 15
		(Z)-6j	5
11		(E)-6k	81	90 : 10
		(Z)-6k	—^d
12		(E)-6l	45	82 : 18
		(Z)-6l	—^d
13		(E)-6m	9	13 : 87
		(Z)-6m	46
14		(E)-6n	46	79 : 21
		(Z)-6n	7

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In order to expand the application of 1 as a building block, we further examined the reactivity of the C–F bond in the N-(α-fluorovinyl)azoles 6 towards azoles. As shown in Table 3, the one-pot reaction of 1 equiv. of 1 with 2 equiv. of 1H-imidazole 5a under the aforementioned optimized reaction condition gave diazole substituted enamine 7a in 40% yield accompanied with trace 6a (Table 3, entry 1). The yield of 7a increased slightly (from 40% to 55%) with the increase of reaction temperature from 25 °C to 70 °C (Table 3, entries 2–4). The best result (yield 81%) was achieved when the amount of K₃PO₄ was increased from 2 equiv. to 4 equiv. (Table 3, entry 6). Under the optimized reaction condition (Table 3, entry 6), 4-methylimidazole (5b), pyrazole (5g), 1H-benzo[d]imidazole (5j) were readily reacted with 1 to afford the trisubstituted alkene 7b, 7g and 7j in 65%, 63% and 70% yield, respectively (Table 4). However, attempts to get the trisubstituted alkenes containing two different type of azoles were failed to achieve acceptable yields no matter the two different azoles were added in one portion or stepwise.

Table 3 Reaction of imine 1 with 5a under different reaction conditions^a

Entry	Amt of 5a (equiv.)	Temp (°C)	Base (equiv.)	Yield^b (%)
a Reaction conditions: 1 (0.4 mmol), THF (5 mL), LDA (2.5 eq.) at −78 °C for 1 h, then at different temperatures for 16 h.b Isolated yield.
1	2.0	25	K3PO4 (2)	40
2	2.1	25	K3PO4 (2)	43
3	2.0	50	K3PO4 (2)	52
4	2.0	70	K3PO4 (2)	55
5	2.0	70	K3PO4 (3)	62
6	2.0	70	K3PO4 (4)	81
7	2.0	70	K3PO4 (5)	62

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Table 4 Reactions of 1 with azoles^a,b

a Reaction conditions: azoles 5 (0.8 mmol), 1 (0.4 mmol), K₃PO₄ (1.6 mmol), THF (5 mL), LDA (2.5 eq.) at −78 °C for 1 h, then at 70 °C for 16 h.b Isolated yield.

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Conclusion

In summary, we have described a versatile fluorine-containing building block N-(diphenylmethylene)-2,2,2-trifluoroethanamine 1 from which a facile and straightforward method for the synthesis of N-(α-fluorovinyl)azoles was developed. The gem-difluoroenamine can be prepared by utilizing the good leaving tendency of fluoride ion. N-(α-fluorovinyl)azoles were then prepared in moderate to good yield by the reaction of 1 with various N–H-containing heterocycles in the absence of metal catalyst under mild reaction conditions via vinylic nucleophilic substitution reaction (S_NV). Notably, the C–F bond cleavage of –CF₃ in 1 could occur one by one in a one-pot process to afford the corresponding fluorinated or non-fluorinated products. This method can be considered as a valuable strategy for direct access to various N-functionalized fluoroenamines and polysubstituted enamines.

Experimental section

General information

All reagents were of analytical grade, obtained from commercial suppliers, and used without further purification. All solvents were dried by standard methods prior to use. ¹H NMR and ¹³C NMR spectra were recorded on a 400 spectrometer (400 MHz for ¹H and 100 MHz for ¹³C) using TMS as internal standard. The ¹⁹F NMR spectra were obtained using a 400 spectrometer (376 MHz). DMSO-d₆ or CDCl₃ was used as the NMR solvent in cases and benzotrifluoride as the internal standard. High-resolution mass spectra (HRMS) were acquired in the electron impact mode (EI) using a TOF mass analyzer.

Synthesis of N-(diphenylmethylene)-2,2,2-trifluoroethanamine (1)

Under nitrogen atmosphere, trifluoroethylamine hydrochloride 2 (4.88 g, 36.0 mmol), diphenylmethanimine 3 (5.44 g, 30.0 mmol) and CH₂Cl₂ (50 mL) were added to a 100 mL round bottom flask. The reaction mixture was stirred at room temperature for 12 h, and then concentrated in vacuum. The crude product was purified by flash chromatography on silica gel using petroleum ether as eluent to afford pure 1 as white crystal (6.71 g, yield 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.30 (m, 8H), 7.15 (d, J = 7.3 Hz, 2H). 3.85 (q, J = 9.2 Hz, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ −75.8 (t, J = 9.2 Hz).

Synthesis of N-(2,2-difluorovinyl)-1,1-diphenylmethanimine (4)

To a solution of 1 (0.263 g, 1.0 mmol) in THF (5 mL) was added dropwise LDA (1.7 mL, 2.5 mmol, 1.5 M in THF) at −78 °C. The mixture was stirred at −78 °C for further 2 h. After warming to room temperature, the reaction mixture was quenched by brine (8 mL), extracted with ethyl acetate (3 × 10 mL). After drying over anhydrous MgSO₄ and concentration of the combined organic phases, the crude product was purified by flash chromatography on silica gel using petroleum ether as eluent to afford pure 4 as yellow liquid (0.197 g, yield 81%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.62–7.56 (m, 3H), 7.50 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.30–7.24 (m, 2H), 6.01 (dd, J = 18.2, 0.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 168.0 (dd, J = 12.2, 3.4 Hz), 162.2, 159.3, 159.2, 156.3 (d, J = 15.5 Hz), 140.0 (t, J = 21.4 Hz), 136.4, 132.6, 131.1, 130.8, 130.2, 130.1 (d, J = 5.0 Hz), 130.0 (d, J = 16.5 Hz), 98.4 (dd, J = 43.6, 9.7 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −86.4 (dd, J = 22.4, 18.1 Hz), −96.0 (d, J = 22.2 Hz). IR (neat) ν_max 3067, 1710, 1237, 693 cm⁻¹; HRMS (EI) calcd for C₁₅H₁₂F₂N. [M + H]⁺ 244.0932, found 244.0932.

General procedure for preparation of N-(α-fluorovinyl)azoles

Under nitrogen atmosphere, a solution of 1 (0.116 g, 0.44 mmol), imidazole 5a (0.027 g, 0.4 mmol) and K₃PO₄ (0.17 g, 0.8 mmol) in THF (5 mL) was stirred for 30 min at −78 °C. Then LDA (0.67 mL, 1.0 mmol, 1.5 M in THF) was added dropwise, the reaction mixture was stirred at −78 °C for 1 h and at room temperature for further 16 h. The reaction mixture was quenched by brine (10 mL), extracted with ethyl acetate (3 × 10 mL). After drying over anhydrous MgSO₄ and concentration of the combined organic phases, the crude product was purified by flash chromatography (silica gel, petroleum ether/ethyl acetate 5/1) to afford (E)-6a as yellow solid (83 mg, yield 70%), mp 102–105 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 7.66 (d, J = 7.0 Hz, 3H), 7.52 (d, J = 6.4 Hz, 3H), 7.45–7.40 (m, 1H), 7.37 (t, J = 7.3 Hz, 2H), 7.25–7.17 (m, 3H), 6.62 (d, J = 7.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2 (d, ²J_CF = 11.6 Hz), 149, 146.5, 138.7, 137, 135.1, 130.7, 129.5, 129.2, 128.9 (d, ¹J_CF = 17.5 Hz), 128.4 (d, ³J_CF = 10.1 Hz), 117.4, 109.5, 109.1, ¹⁹F NMR (376 MHz, CDCl₃) δ −114.2 (d, J = 6.4 Hz); IR (neat) ν_max 3042, 1673, 1219 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₄FN₃, [M]⁺ 291.1169, found 291.1172.

(E)-6b yield 45% (55 mg), yellow solid; mp 108–109 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.64 (d, J = 6.9 Hz, 3H), 7.51 (t, J = 5.9 Hz, 3H), 7.46–7.41 (m, 2H), 7.38–7.33 (m, 2H), 6.90 (s, 1H), 6.81 (d, J = 3.4 Hz, 1H), 2.28 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.9 (d, J = 11.5 Hz), 149.7, 147.1, 140.4, 139.8, 136.2, 132.7, 131.1, 130.6, 130.1, 130.0, 129.5, 128.4, 117.5, 117.0, 10.8 (d, J = 2.7 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −101.6 (d, J = 2.9 Hz). IR (neat) ν_max 3059, 2927, 1670, 1424, 1202, 690 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₆FN₃. [M + H]⁺ 306.1399, found 306.1401.

(Z)-6b yield 20% (25 mg), yellow solid. mp 103–105 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.62 (dd, J = 11.9, 6.9 Hz, 5H), 7.55–7.46 (m, 4H), 7.38–7.31 (m, 2H), 6.54 (d, J = 6.5 Hz, 1H), 2.24 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.1 (d, J = 11.2 Hz), 139.5, 139.2, 137.9, 135.7, 132.0, 130.5, 130.1, 129.6 (d, J = 12.1 Hz), 129.4, 115.1, 110.7, 110.3, 14.5. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.8 (d, J = 7.0 Hz). IR (neat) ν_max 3061, 2923, 1671, 1411, 1224, 693 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₆FN₃. [M + H]⁺ 306.1399, found 306.1401.

(E)-6c yield 51% (75 mg), white solid; mp 108–111 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (s, 1H), 7.73–7.69 (m, 2H), 7.62–7.57 (m, 3H), 7.50–7.43 (m, 4H), 7.42–7.36 (m, 4H), 7.30 (s, 1H), 7.11 (dd, J = 6.3, 2.7 Hz, 2H), 6.70 (d, J = 2.0 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.2 (d, J = 11.2 Hz), 150.2, 149.0, 147.6, 139.5, 136.1, 132.7, 131.5, 131.1, 130.9, 130.6 (d, J = 16.5 Hz), 130.2, 130.1, 129.9, 129.7, 128.9, 125.1 (d, J = 3.6 Hz), 118.4, 118.0. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −98.8 (d, J = 1.1 Hz). IR (neat) ν_max 3061, 1674, 1292, 1120, 694 cm⁻¹; HRMS (EI) calcd for C₂₄H₁₈FN₃. [M]⁺ 367.1487, found 367.1485.

(E)-6d yield 60% (81 mg), yellow solid; mp 124–128 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (s, 1H), 7.65 (d, J = 5.0 Hz, 3H), 7.61 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 7.0 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.43–7.34 (m, 2H), 6.82 (d, J = 5.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.3 (d, J = 11.3 Hz), 149.2, 148.3, 145.8, 139.7, 139.0, 136.0, 133.1, 131.4, 130.7, 130.2, 130.0, 121.7, 115.0 (d, J = 43.0 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.12 (d, J = 5.6 Hz). IR (neat) ν_max 3061, 1675, 1547, 1268, 693 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₃FN₄O₂. [M + H]⁺ 337.1093, found 337.1095.

(E)-6e yield 61% (85 mg), yellow solid; mp 150–152 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 7.65 (dd, J = 5.0, 1.6 Hz, 3H), 7.56–7.49 (m, 3H), 7.48–7.42 (m, 2H), 7.38 (dd, J = 6.5, 2.9 Hz, 2H), 6.93 (d, J = 2.7 Hz, 1H), 2.50 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.4 (d, J = 11.6 Hz), 147.7, 147.4, 147.3, 144.7, 139.0, 135.5, 132.7, 130.9, 130.1, 129.8 (d, J = 6.0 Hz), 129.4, 123.8 (d, J = 2.5 Hz), 119.1, 118.6, 14.5. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −104.0 (d, J = 3.0 Hz); IR (neat) ν_max 3061, 2923, 1678, 1550, 1375, 1269, 695 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₅FN₄O₂. [M + H]⁺ 351.1249, found 351.1252.

(E)-6f yield 75% (95 mg), white solid; mp 100–101 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.63 (s, 1H), 7.65 (d, J = 5.3 Hz, 3H), 7.60 (d, J = 7.5 Hz, 2H), 7.58–7.53 (m, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.41–7.33 (m, 2H), 6.76 (d, J = 5.5 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.3, 170.2, 147.7, 144.9, 140.6, 139.0, 135.3, 132.3, 130.6, 129.8 (d, J = 17.2 Hz), 129.3 (t, J = 16.5 Hz), 115.5, 114.3, 113.6 (d, J = 44.0 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −111.5 (d, J = 5.3 Hz). IR (neat) ν_max 3053, 2238, 1673, 1550, 1545, 1205, 694 cm⁻¹; HRMS (EI) calcd for C₁₉H₁₃FN₄ [M]⁺ 316.1127, found 316.1124.

(E/Z)-6g yield 73% (84 mg), yellow solid; mp 97–105 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 0.37H), 8.22 (s, 0.64H), 7.93 (s, 0.36H), 7.78 (s, 0.66H), 7.71–7.31 (m, 10H), 6.76 (d, J = 21.8 Hz, 0.63H), 6.68 (s, 0.37H), 6.64 (d, J = 4.7 Hz, 0.37H), 6.57 (s, 0.62H). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.1 (d, J = 11.5 Hz), 150.7, 148.2, 143.0, 139.0, 135.3, 134.6, 131.6, 130.1, 129.7, 129.2, 129.0, 111.7, 111.3, 108.4 (d, J = 1.8 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.9 (d, J = 3.6 Hz), δ −111.8 (d, J = 22.9 Hz); IR (neat) ν_max 3052, 1653, 1438, 1384, 762, 687 cm⁻¹; HRMS (EI) calcd for C₁₈H₁₄FN₃. [M + H]⁺ 292.1241, found: 292.1245.

(E)-6h yield 46% (54 mg), yellow solid; mp 94–96 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 5.7 Hz, 3H), 7.54 (dd, J = 11.7, 7.4 Hz, 3H), 7.46 (t, J = 7.5 Hz, 2H), 7.41–7.34 (m, 2H), 6.87 (d, J = 4.4 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.2 (d, J = 11.5 Hz), 147.8, 145.2, 138.5, 134.9, 133.8, 131.9, 130.2, 129.4 (d, J = 17.5 Hz), 129.0, 128.8, 128.4, 114.8 (d, J = 43.8 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.7 (d, J = 4.9 Hz). IR (neat) ν_max 3055, 1673, 1238, 1188 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₃FN₄. [M]⁺ 292.1119, found 292.1124.

(Z)-6h yield 9% (10 mg), yellow solid; mp 148–152 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.57 (dd, J = 20.3, 6.0 Hz, 4H), 7.48 (t, J = 7.4 Hz, 2H), 7.38–7.30 (m, 2H), 6.85 (d, J = 21.1 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.1 (d, J = 3.6 Hz), 146.44, 143.7, 138.7, 135.0, 134.5, 131.9, 130.2, 129.4 (d, J = 9.3 Hz), 128.9 (d, J = 19.2 Hz), 124.9, 112.2 (d, J = 7.7 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −107.9 (d, J = 21.4 Hz). IR (neat) ν_max 3097, 1683, 1238 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₃FN₄. [M]⁺ 292.1127, found 292.1136.

(E)-6i yield 43% (50 mg), yellow solid; mp 83–85 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.43 (s, 1H), 7.65 (d, J = 6.1 Hz, 3H), 7.54 (t, J = 9.3 Hz, 3H), 7.46 (t, J = 7.4 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 6.85 (d, J = 3.8 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.5 (d, J = 11.5 Hz), 153.9, 149.0 (d, J = 2.0 Hz), 148.6, 146.0, 139.2, 135.6, 132.4, 130.8, 130.1, 129.8, 129.6, 129.4, 115.8, 115.4. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.2 (d, J = 3.6 Hz). IR (neat) ν_max 3061, 1673, 1436, 1216 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₃FN₄. [M]⁺ 292.1130, found 292.1124.

(Z)-6i yield 12% (14 mg), yellow solid; mp 116–119 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.27 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 5.4 Hz, 3H), 7.59–7.53 (m, 1H), 7.50 (t, J = 7.3 Hz, 2H), 7.35 (d, J = 7.3 Hz, 2H), 6.79 (d, J = 21.2 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.6 (d, J = 3.5 Hz), 154.2, 147.3, 144.9, 144.6, 139.2, 135.5, 132.1, 130.5, 129.9, 129.6, 129.3 (d, J = 19.1 Hz), 110.8 (d, J = 7.0 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −111.2 (d, J = 21.2 Hz). IR (neat) ν_max 3061, 1682, 1280 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₃FN₄. [M]⁺ 292.1121, found 292.1124.

(E)-6j yield 68% (97 mg), yellow solid; mp 108–111 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.86 (d, J = 4.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 3H), 7.53 (d, J = 6.9 Hz, 3H), 7.43–7.29 (m, 5H), 7.25 (d, J = 5.9 Hz, 2H), 6.84 (d, J = 4.9 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 167.6 (d, ³J_CF = 12.0 Hz), 149.7, 147.2, 144.4, 143.3, 138.5, 135.2, 132.5, 130.9, 130.1, 129.3, 128.9 (d, ³J_CF = 6.7 Hz), 128.4, 124.4, 123.7, 120.6, 112.6 (d, ²J_CF = 14.8 Hz), 112.3 (d, ¹J_CF = 26.7 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −111.1 (d, J = 4.0 Hz); IR (neat) ν_max 3059, 1669, 1223 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₆FN₃. [M]⁺ 341.1324, found 341.1328.

(Z)-6j yield 5% (7 mg), yellow solid; mp 118–120 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.78 (dd, J = 7.0, 1.6 Hz, 1H), 7.75–7.71 (m, 2H), 7.63–7.54 (m, 5H), 7.53–7.48 (m, 2H), 7.42–7.33 (m, 4H), 6.62 (d, J = 20.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 168.5 (d, J = 3.5 Hz), 143.5, 143.2, 138.9, 135.1, 131.6, 130.0, 129.29 (d, J = 15.4 Hz), 129.0 (d, J = 8.4 Hz), 124.9, 124.1, 120.7, 113.5 (d, J = 12.6 Hz), 111.6 (d, J = 2.2 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −99.0 (d, J = 21.4 Hz); IR (neat) ν_max 3052, 1671, 1222 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₆FN₃. [M]⁺ 341.1402, found 341.1401.

(E)-6k yield 81% (118 mg), white solid. mp 144–146 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.74–7.63 (m, 4H), 7.51 (dd, J = 5.9, 3.2 Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 7.42–7.33 (m, 8H), 7.00 (d, J = 1.5 Hz, 1H), 2.63 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6 (d, J = 11.7 Hz), 153.5 (d, J = 3.4 Hz), 148.9, 146.3, 143.9, 139.6, 136.3, 136.0, 132.9, 131.3, 130.6, 130.2, 129.7, 125.0, 124.8, 120.5, 119.6, 119.1, 112.4, 15.6. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −102.0 (d, J = 0.4 Hz). IR (neat) ν_max 3058, 2963, 1674, 1269, 693 cm⁻¹; HRMS (EI) calcd for C₂₃H₁₈FN₃. [M + H]⁺ 356.1558, found 356.1558.

(E)-6l yield 45% (64 mg), yellow solid; mp 158–160 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (d, J = 7.1 Hz, 3H), 7.46 (t, J = 7.1 Hz, 3H), 7.42 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.90 (s, 1H), ¹³C NMR (100 MHz, DMSO-d₆) δ 169.5 (d, J = 12.1 Hz), 155.2 (d, J = 3.4 Hz), 148.7, 146.1, 144.9, 139.8, 136.1, 135.0 (d, J = 4.5 Hz), 132.6, 131.0, 130.4, 129.9 (d, J = 10.2 Hz), 124.0, 120.9, 119.7, 119.2, 116.9, 110.5. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −103.3. IR (neat) ν_max 3433, 3064, 1671, 1550, 1414, 1261, 691 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₇FN₄. [M + H]⁺ 357.1506, found 357.1510.

(E)-6m yield 9% (14 mg), yellow solid; mp 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.80 (s, 1H), 8.20 (d, J = 9.3 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 5.4 Hz, 3H), 7.61 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.50–7.41 (m, 4H), 6.98 (d, J = 5.4 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.9 (d, J = 11.1 Hz), 149.7, 148.0, 147.4, 147.2, 138.5, 135.0, 131.9 (s), 131.9, 130.4 (d, J = 11.5 Hz), 129.5 (s), 129.0 (d, J = 17.2 Hz), 124.3, 123.7 (d, J = 2.6 Hz), 116.7, 115.0, 114.9 (d, J = 43.5 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.3 (d, J = 5.5 Hz). IR (neat) ν_max 3061, 1660, 1337, 1216 cm⁻¹, 685 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₅FN₄O₂ [M]⁺ 386.1172, found 386.1179.

(Z)-6m yield 43% (66 mg), yellow solid; mp 156–158 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.55 (s, 1H), 8.17 (s, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.58 (ddd, J = 21.5, 12.9, 7.5 Hz, 6H), 7.42 (d, J = 6.6 Hz, 2H), 6.78 (d, J = 21.2 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.15 (d, J = 3.5 Hz, 1H), 149.4, 148.8, 146.7, 140.5, 139.9, 139.2, 136.4, 132.6, 131.1, 130.5, 130.1 (d, J = 12.4 Hz), 129.9, 129.4, 124.9, 119.0, 112.8 (d, J = 10.2 Hz), 109.1 (d, J = 6.1 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −106.6 (d, J = 22.0 Hz). IR (neat) ν_max 3061, 1664, 1525, 1191, 691 cm⁻¹; HRMS (EI) calcd for C₂₂H₁₅FN₄O₂ [M]⁺ 386.1174, found 386.1179.

(E)-6n yield 46% (59 mg), yellow solid; mp 108–110 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.63 (dd, J = 14.0, 7.3 Hz, 4H), 7.45–7.38 (m, 3H), 7.28 (d, J = 4.0 Hz, 4H), 7.07 (d, J = 1.9 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.7 (d, J = 11.9 Hz), 147.4, 145.2, 144.8, 138.8, 135.3, 134.1, 132.3, 130.5 (d, J = 19.8 Hz), 129.9, 129.3 (d, J = 9.1 Hz), 126.3, 120.7, 118.3, 117.8, 112.6; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −105.87 (d, J = 1.6 Hz); IR (neat) ν_max 3023, 1674, 1292, 1200 cm⁻¹, 1024, 698 cm⁻¹; HRMS (EI) calcd for C₂₁H₁₅FN₄. [M + H]⁺ 343.1351, found 343.1353.

(Z)-6n yield 7% (10 mg), yellow solid; mp 114–117 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.76 (t, J = 9.8 Hz, 3H), 7.65–7.51 (m, 7H), 7.43 (d, J = 7.2 Hz, 2H), 6.88 (d, J = 20.9 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.9 (d, J = 3.7 Hz), 145.9, 139.3, 135.7, 132.9, 132.6, 130.9 (d, J = 20.0 Hz), 130.1 (d, J = 3.0 Hz), 129.7, 129.5, 126.8, 121.2, 115.3 (d, J = 10.0 Hz), 112.0 (d, J = 3.0 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −105.7 (d, J = 21.6 Hz). IR (neat) ν_max 3055, 1677, 1291, 1200 cm⁻¹; HRMS (EI) calcd for C₁₇H₁₃FN₄. [M + H]⁺ 343.1352, found 343.1354.

Typical procedure for preparation of 7

Under nitrogen atmosphere, a solution of 1 (0.4 mmol), 5 (0.8 mmol) and K₃PO₄ (1.6 mmol) in THF (5 mL) was stirred at −78 °C for 30 min, then LDA (1.0 mmol, 0.67 mL, 1.5 mol L⁻¹ in THF) was added dropwise. After stirring at −78 °C for 1 h, the reaction mixture was heated to 70 °C and stirred for further 16 h. After cooling to room temperature, the reaction mixture was quenched with H₂O (10 mL), extracted with ethyl acetate, filtered and washed by ethyl acetate (15 mL × 3). After drying over anhydrous MgSO₄ and concentration of the combined organic phases, the crude product was purified by flash chromatography (silica gel, CH₂Cl₂/MeOH 20/1).

7a yield 81% (110 mg), yellow solid; mp 108–110 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.92 (s, 1H), 7.65–7.58 (m, 5H), 7.57–7.53 (m, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.45–7.41 (m, 2H), 7.34 (d, J = 13.1 Hz, 2H), 7.16 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.3, 140.1, 139.2, 138.3, 135.6, 132.2, 130.9, 130.5, 130.1, 129.7, 129.5, 127.7, 124.0, 120.4 (d, J = 17.7 Hz). IR (neat) ν_max 3061, 1644, 1478, 1301, 696 cm⁻¹; HRMS (EI) calcd for C₂₁H₁₇N₅ [M]⁺ 339.1480, found 339.1484.

7b yield 65% (74 mg), yellow solid; mp 132–134 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.70–7.60 (m, 5H), 7.51 (d, J = 7.0 Hz, 3H), 7.43 (dd, J = 16.4, 7.2 Hz, 4H), 7.06 (s, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 2.10 (s, 3H), 1.92 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.0, 140.3, 139.8, 139.2, 136.6, 135.6, 132.1, 130.5, 129.5 (dd, J = 26.8, 14.8 Hz), 129.1, 127.7, 127.2, 125.8, 115.2, 14.3, 9.6. IR (neat) ν_max 3096, 2920, 1643, 1483, 1431, 1286, 697 cm⁻¹; HRMS (EI) calcd for C₂₃H₂₁N₅ [M]⁺ 367.1792, found 367.1797.

7g yield 63% (83 mg), yellow sold; mp 130–132 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J = 1.8 Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.62 (t, J = 7.6 Hz, 3H), 7.58–7.49 (m, 4H), 7.43 (dd, J = 20.4, 7.3 Hz, 4H), 7.23 (s, 1H), 6.65 (s, 1H), 6.46 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ 169.2, 142.6 (d, J = 4.4 Hz), 139.3, 136.4, 136.0, 134.1, 131.9, 131.2, 130.3, 129.8, 129.7, 129.1, 122.5, 108.3, 107.4. IR (neat) ν_max 3051, 1642, 1448, 1395, 751, 694 cm⁻¹; HRMS (EI) calcd for C₂₁H₁₇N₅ [M]⁺ 339.1488, found 339.1484.

7j yield 70% (122 mg), yellow solid; mp 186–188 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.64 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67–7.51 (m, 8H), 7.45 (t, J = 7.5 Hz, 2H), 7.29 (td, J = 7.4, 4.0 Hz, 2H), 7.24 (s, 1H), 7.17 (dt, J = 18.5, 7.6 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 170.6, 146.5, 144.4, 144.0, 139.1, 135.7, 133.6 (d, J = 3.0 Hz), 132.2, 130.5, 129.6 (dd, J = 26.9, 8.3 Hz), 127.1, 126.0, 125.0, 124.9 (d, J = 26.4 Hz), 124.2, 123.9, 121.1 (d, J = 17.3 Hz), 111.5 (d, J = 18.3 Hz). IR (neat) ν_max 3064, 1641, 1491, 1450, 740, 696 cm⁻¹; HRMS (EI) calcd for C₂₉H₂₁N₅ [M]⁺ 439.1801, found 439.1797.

Acknowledgements

We thank the Innovation Program of Shanghai Municipal Education Commission (No. 13ZZ047) and the Fundamental Research Funds for the Central Universities (2232015D3-13) for financial support.

References

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13. ESI.†.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 1455899. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra12187j

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