Donghua Zhang,
Haihua Liu,
Pengcheng Zhu,
Weidong Meng and
Yangen Huang*
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China. E-mail: hyg@dhu.edu.cn
First published on 27th July 2016
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 (SNV) in the presence of LDA and K3PO4 in a one-pot process.
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.
In 2014, Cao and co-workers reported the SNV 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.
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 3JH–F coupling constant in Z isomer is higher than the cis 3JH–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 3JH–F coupling constant.
Entry | Temp (°C) | Base (equiv.) | Solvent | Yieldb (%) | E/Zc |
---|---|---|---|---|---|
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![]() ![]() |
2 | 25 | K2CO3 (2) | THF | 74 | 86![]() ![]() |
3 | 25 | Cs2CO3 (2) | THF | 72 | 86![]() ![]() |
4 | 25 | EtONa (2) | THF | 76 | 87![]() ![]() |
5 | 25 | K3PO4 (2) | THF | 80 | 88![]() ![]() |
6 | 25 | None | THF | NR | |
7 | 25 | K3PO4 (3) | THF | 76 | 88![]() ![]() |
8 | 25 | K3PO4 (1) | THF | 60 | 84![]() ![]() |
9 | 40 | K3PO4 (2) | THF | 75 | 88![]() ![]() |
10 | 60 | K3PO4 (2) | THF | 76 | 89![]() ![]() |
11 | 25 | K3PO4 (2) | Et3N | 22 | 89![]() ![]() |
12 | 25 | K3PO4 (2) | n-Hexane | 12 | 85![]() ![]() |
13 | 25 | K3PO4 (2) | Et2O | 58 | 88![]() ![]() |
14 | 25 | K3PO4 (2) | CH2Cl2 | N.D.d |
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 (SNV).
Entry | Azole 5 | Product 6 | Yieldb (%) | Isomer ratioc (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 by19F 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![]() ![]() |
(Z)-6a | —d | |||
2 | ![]() |
(E)-6b | 45 | 74![]() ![]() |
(Z)-6b | 20 | |||
3 | ![]() |
(E)-6c | 51 | 85![]() ![]() |
(Z)-6c | —d | |||
4 | ![]() |
(E)-6d | 60 | 91![]() ![]() |
(Z)-6d | —d | |||
5 | ![]() |
(E)-6e | 61 | 95![]() ![]() |
(Z)-6e | —d | |||
6 | ![]() |
(E)-6f | 75 | 93![]() ![]() |
(Z)-6f | —d | |||
7 | ![]() |
(E)-6g | 73e | 37![]() ![]() |
(Z)-6g | ||||
8 | ![]() |
(E)-6h | 46 | 62![]() ![]() |
(Z)-6h | 9 | |||
9 | ![]() |
(E)-6i | 43 | 63![]() ![]() |
(Z)-6i | 12 | |||
10 | ![]() |
(E)-6j | 68 | 85![]() ![]() |
(Z)-6j | 5 | |||
11 | ![]() |
(E)-6k | 81 | 90![]() ![]() |
(Z)-6k | —d | |||
12 | ![]() |
(E)-6l | 45 | 82![]() ![]() |
(Z)-6l | —d | |||
13 | ![]() |
(E)-6m | 9 | 13![]() ![]() |
(Z)-6m | 46 | |||
14 | ![]() |
(E)-6n | 46 | 79![]() ![]() |
(Z)-6n | 7 |
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.
Entry | Amt of 5a (equiv.) | Temp (°C) | Base (equiv.) | Yieldb (%) |
---|---|---|---|---|
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 |
(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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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, 3JCF = 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, 3JCF = 6.7 Hz), 128.4, 124.4, 123.7, 120.6, 112.6 (d, 2JCF = 14.8 Hz), 112.3 (d, 1JCF = 26.7 Hz); 19F NMR (376 MHz, CDCl3) δ −111.1 (d, J = 4.0 Hz); IR (neat) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 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) νmax 3055, 1677, 1291, 1200 cm−1; HRMS (EI) calcd for C17H13FN4. [M + H]+ 343.1352, found 343.1354.
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) νmax 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) νmax 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) νmax 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) νmax 3064, 1641, 1491, 1450, 740, 696 cm−1; HRMS (EI) calcd for C29H21N5 [M]+ 439.1801, found 439.1797.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1455899. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra12187j |
This journal is © The Royal Society of Chemistry 2016 |