Construction of 2,3,4,5-tetrahydro-1,2,4-triazines via [4 + 2] cycloaddition of α-halogeno hydrazones to imines

Abstract

In the presence of sodium carbonate, the [4 + 2] cycloaddition of α-halogeno hydrazones to imines proceeded readily, and furnished 2,3,4,5-tetrahydro-1,2,4-triazines in moderate to high chemical yields.

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1. Introduction

α-Halogeno hydrazones represent a class of versatile and robust building blocks, which have been widely applied in the construction of structurally diverse and complex N-containing heterocycles possessing varying ring sizes. Normally, α-halogeno hydrazones can undergo [4 + 1],¹ [4 + 2]² or [4 + 3]³ cycloadditions with structurally different dienophiles via the in situ formed 1,2-diaza-1,3-diene intermediates under basic reaction conditions. For example, in 2012, Bolm and co-workers realized the enantioselective synthesis of dihydropyrazoles by means of the [4 + 1] cycloaddition of α-halogeno hydrazones to sulphur ylides (Scheme 1, eqn. (1)).⁴ In 2015, the Luo research group reported the [4 + 2] cycloaddition of α-halogeno hydrazones to simple olefins for the preparation of tetrahydropyridazines (Scheme 1, eqn (2)).⁵ Recently, our research group successfully designed the [4 + 3] cycloaddition of α-halogeno hydrazones to nitrones for the preparation of 1,2,4,5-oxatriazepines (Scheme 1, eqn (3)).⁶ In particular, most of the previously reported [4 + 2] cycloadditions of α-halogeno hydrazones mainly focused on the use of the differently functionalized olefins as dienophiles.⁷ In addition, only three other pioneering works respectively dealt with the use of arylacetic acids,⁸ methoxyallene⁹ or azodicarboxylates¹⁰ as dienophiles in the [4 + 2] cycloadditions of α-halogeno hydrazones. It is well known that the employment of imines as dienophiles in [4 + 2] cycloaddition of α-halogeno hydrazones has been fully unexplored to date. So, the development of novel [4 + 2] cycloadditions of α-halogeno hydrazones with imines is highly demanded for the synthesis of potentially bioactive heterocycles.

Scheme 1 Representative cycloadditions of α-halogeno hydrazones.

On the basis of the previously published elegant examples, in this work, we first attempted the novel [4 + 2] cycloaddition of α-halogeno hydrazones with synthetically useful and important imines¹¹ for the construction of 2,3,4,5-tetrahydro-1,2,4-triazines bearing potential biological activities¹² (Scheme 1, eqn (4)). To our delight, under the mild reaction conditions, the [4 + 2] cycloaddition of α-halogeno hydrazones with imines underwent readily, and furnished the target molecules in moderate to high chemical yields. To the best of our knowledge, such a work has not been reported in the literature so far.

2. Results and discussion

At the outset, we explored the base effects on the chemical yield of the [4 + 2] cycloaddition of α-halogeno hydrazone 1a with imine 2a in DCM solvent at room temperature as summarized in Table 1. Indeed, the used base affected the chemical yield of the [4 + 2] cycloaddition significantly. Using DBU as a base gave product 3aa in a trace amount after 48 h (entry 8). The choice of NaHCO₃ and Et₃N as bases did not enhance the chemical yield of 3aa dramatically (entries 4 & 7). By comparison with the former cases, the chemical yield of [4 + 2] cycloaddition increased differently by using KOH and MeONa as bases (entries 5–6). Moreover, when Na₂CO₃, K₂CO₃ and Cs₂CO₃ were examined as bases, the chemical yield of the [4 + 2] cycloaddition ranged from 33% to 44% (entries 1–3). Obviously, among all the bases screened, Na₂CO₃ performed best and delivered product 3aa in highest chemical yield (entry 1).

Table 1 Screening of bases^a

Entry	Base	Time (h)	Yield^b (%)
a Unless otherwise noted, reactions were carried out with 1a (0.2 mmol), 2a (0.3 mmol), base (0.4 mmol) in DCM (1.0 mL) at room temperature.b Isolated yield.
1	Na2CO3	25	44
2	K2CO3	25	34
3	Cs2CO3	25	33
4	NaHCO3	36	8
5	KOH	36	13
6	MeONa	36	19
7	Et3N	48	2
8	DBU	48	Trace

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Simultaneously, by using Na₂CO₃ (2.0 equiv.) as base, we investigated the solvent effects on the chemical yield of the [4 + 2] cycloaddition of α-halogeno hydrazone 1a with imine 2a as shown in Table 2. Remarkably, the chemical yield of the [4 + 2] cycloaddition was largely influenced by the attempted solvents. In MeOH solvent, the [4 + 2] cycloaddition furnished product 3aa in 20% chemical yield in 36 h (entry 7). In contrast with the former case, the chemical yield of the [4 + 2] cycloaddition increased to 35% by choosing MeCN as solvent (entries 6 vs. 7). As for solvents DCE, THF, Et₂O and DME, they afforded product 3aa in similar chemical yields (entries 1–4). Finally, with the use of toluene, PhCl and benzene as solvents, the chemical yield of the [4 + 2] cycloaddition changed from 68% to 75% (entries 5 and 8–9). Therefore, Na₂CO₃ behaved most efficiently in toluene solvent, thus providing 3aa in the highest chemical yield (entry 5). In addition, we examined other equivalent amounts of Na₂CO₃ in the [4 + 2] cycloaddition by using toluene as solvent, and found that use of 2.0 equiv. of Na₂CO₃ furnished product 3aa in the highest chemical yield (Table 2, entries 5 vs. 10–11).

Table 2 Screening of solvents^a

Entry	Solvent	Time (h)	Yield^b (%)
a Unless otherwise noted, reactions were carried out with 1a (0.2 mmol), 2a (0.3 mmol), Na2CO3 (0.4 mmol) in the solvent (1.0 mL) at room temperature.b Isolated yield.c 0.5 equiv. of Na2CO3.d 1.0 equiv. of Na2CO3.
1	DCE	24	54
2	THF	24	52
3	Et2O	24	52
4	DME	24	51
5	Toluene	24	75
6	MeCN	24	35
7	MeOH	36	20
8	PhCl	24	68
9	Benzene	24	71
10^c	Toluene	24	16
11^d	Toluene	24	46

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Subsequently, under the optimal reaction conditions, we broadened the reaction scope of the [4 + 2] cycloaddition by diversifying α-halogeno hydrazones 1 and imines 2 as outlined in Table 3. Noticeably, the chemical yield of the [4 + 2] cycloaddition highly depended on the structural nature of the used α-halogeno hydrazones 1 and imines 2. Regarding the [4 + 2] cycloaddition with α-halogeno hydrazone 1a, most imine substrates 2 well tolerated the structural variation of R³ and R⁴ groups, thus delivering products 3 in 62–88% chemical yields (entries 1–8 & 10–12). In contrast with the former cases, the imines 2i and 2m individually bearing a para-methoxy-substituted benzyl group or a phenyl group at R³ position furnished products 3ai and 3am in the dramatically decreased chemical yields in the [4 + 2] cycloaddition with 1a (entries 1 vs. 9, 1 vs. 13). Meanwhile, it was noted that in the [4 + 2] cycloaddition with 1a, the regioisomers 2c–2e, which derived from the different substitution pattern of nitro group at R⁴ moiety, provided products 3ac–3ae in the quite different chemical yields (entries 3–5).

Table 3 Extension of reaction scope^a

Entry	1 (X, R^1, R^2)	2 (R^3, R^4)	3	Time (h)	Yield^b (%)
a Unless otherwise noted, reactions were carried out with 1 (0.2 mmol), 2 (0.3 mmol), Na2CO3 (0.4 mmol) in toluene (1.0 mL) at room temperature.b Isolated yield.
1	1a (Br, Me, Ph)	2a (Bn, Ph)	3aa	24	75
2	1a (Br, Me, Ph)	2b (Bn, 4-MeOC6H4)	3ab	30	85
3	1a (Br, Me, Ph)	2c (Bn, 4-NO2C6H4)	3ac	30	67
4	1a (Br, Me, Ph)	2d (Bn, 3-NO2C6H4)	3ad	30	62
5	1a (Br, Me, Ph)	2e (Bn, 2-NO2C6H4)	3ae	30	75
6	1a (Br, Me, Ph)	2f (Bn, 4-BrC6H4)	3af	24	88
7	1a (Br, Me, Ph)	2g (Bn, 2-naphthyl)	3ag	30	66
8	1a (Br, Me, Ph)	2h (Bn, 2-furyl)	3ah	30	80
9	1a (Br, Me, Ph)	2i (4-MeO C6H4CH2, Ph)	3ai	24	29
10	1a (Br, Me, Ph)	2j (4-FC6H4CH2, Ph)	3aj	24	77
11	1a (Br, Me, Ph)	2k (4-ClC6H4CH2, Ph)	3ak	24	77
12	1a (Br, Me, Ph)	2l (Me, Ph)	3al	24	75
13	1a (Br, Me, Ph)	2m (Ph, Ph)	3am	36	33
14	1b (Cl, Me, Ph)	2a (Bn, Ph)	3aa	24	61
15	1c (Br, Me, 4-MeOC6H4)	2a (Bn, Ph)	3ca	24	57
16	1d (Br, Me, 4-MeC6H4)	2a (Bn, Ph)	3da	24	71
17	1e (Br, Me, 4-BrC6H4)	2a (Bn, Ph)	3ea	24	80
18	1f (Br, Me, 4-ClC6H4)	2a (Bn, Ph)	3fa	24	86
19	1g (Br, Me, 4-FC6H4)	2a (Bn, Ph)	3ga	24	74
20	1h (Br, Me, 3-ClC6H4)	2a (Bn, Ph)	3ha	24	80
21	1i (Br, Me, 4-NO2C6H4)	2a (Bn, Ph)	3ia	30	71
22	1j (Br, Me, t-Bu)	2a (Bn, Ph)	3ja	36	21
23	1k (Cl, Ph, Ph)	2a (Bn, Ph)	3ka	36	34
24	1l (Cl, MeO, Ph)	2a (Bn, Ph)	3la	30	59
25	1m (Br,MeO, CO2Et)	2a (Bn, Ph)	3ma	30	70
26		2a (Bn, Ph)	3na	30	64
27	1f (Br, Me, 4-Cl C6H4)	2b (Bn, 4-MeOC6H4)	3fb	30	81
28	1f (Br, Me, 4-ClC6H4)	2f (Bn, 4-BrC6H4)	3ff	24	71
29	1h (Br, Me, 3-ClC6H4)	2f (Bn, 4-BrC6H4)	3hf	24	81
30	1d (Br, Me, 4-MeC6H4)	2f (Bn, 4-BrC6H4)	3df	24	73

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In case of the [4 + 2] cycloaddition with 2a, most α-halogeno hydrazones 1 could better endure the wide variation in R¹ and R² groups, and led to the formation of products 3 in 57–86% chemical yields (entries 14–21 & 24–26). With respect to the imines 1j with a bulky tert-butyl as R² group and 1k with a phenyl as R¹ group, they preferred to afford products 3 in the relatively lowered chemical yields in the [4 + 2] cycloaddition with 2a (entries 1 vs. 22, 14 vs. 23). Generally, in the [4 + 2] cycloaddition with 2a, the imines 1 including an electron-poor phenyl group at R² position usually behaved better than the imines 1 containing an electron-rich phenyl group at R² position, and produced products 3 in higher chemical yields (entries 15–16 vs. 17–20). Simultaneously, it should be addressed that α-halogeno hydrazones 1a and 1b, which differ from each other in X group, gave rise to the same product 3aa in the tremendously different chemical yield in the [4 + 2] cycloaddition with 2a (entries 1 vs. 14). Moreover, the [4 + 2] cycloaddition of 1f with 2b gave product 3fb in 81% chemical yield (entry 27). At last, we further performed the extension of the reaction scope of the [4 + 2] cycloaddition by treating α-halogeno hydrazone 2f with imines 1d, 1f and 1h, and the chemical yield of the [4 + 2] cycloaddition changed from 71–83%. Of course, the α-halogeno hydrazones 1f and 1d, where R² group individually has an electron-withdrawing or -donating group attached to the phenyl moiety, did not behaved quite differently in the [4 + 2] cycloaddition with 2f, and furnished products 3ff and 3df in the similar chemical yields (entries 28 vs. 30).

Moreover, the chemical structure of 3aa was firmly confirmed by single crystal X-ray analysis as depicted in Fig. 1.¹³ The conformational analysis showed that the 2,3,4,5-tetrahydro-1,2,4-triazine ring of 3aa adopts a highly twisted conformation. By virtue of the non-planar structure of the 2,3,4,5-tetrahydro-1,2,4-triazine ring of 3aa, as a result, the two protons at C-5 become chemically non-equivalent: one proton occupies the pseudo-oxial position; the other one resides in the pseudo-equatorial position. This fact was clearly identified by the ¹H NMR performance of the two protons at C-5: one proton resonates at 3.48 ppm; the other one signals at 3.55 ppm (see details in ESI†). These observations proved that the inversion barrier of 2,3,4,5-tetrahydro-1,2,4-triazine ring is big enough at room temperature, and as a consequence, the two protons exchange pretty slowly at ¹H NMR timescale. Meanwhile, we proposed the reaction mechanism for the formation of 3aa (Scheme 2). In the presence of Na₂CO₃, the elimination reaction of 1a takes place to give 1,2-diaza-1,3-diene 4. Then, two possible transition states TS1 and TS2 will be produced for the [4 + 2] cycloaddition between 4 and 2a. With the aid of the molecular model, it was found that in TS2 phenyl group at C-6 sterically repulse benzyl group at N-4 severely; whereas, this strong destabilizing interaction does not exist in TS1 at all. Therefore, the transition state TS1 is more stable than the transition state TS2, and mainly accounts for the formation of the desired cycloadduct 3aa.

Fig. 1 X-ray single crystal structure of 3aa (with thermal ellipsoid shown at the 50% probability level).

Scheme 2 Proposed mechanism for the formation of 3aa.

3. Conclusions

In conclusion, the [4 + 2] cycloaddition of α-halogeno hydrazones with imines underwent efficiently, and provided the easy access to the novel potentially bioactive 2,3,4,5-tetrahydro-1,2,4-triazines in the reasonable chemical yields. Furthermore, the exploration of other novel cycloadditions of α-halogeno hydrazones with various 1,3-, 1,4- and 1,5-dipoles is ongoing in our laboratory, and will be reported in due course.

4. Experimental section

4.1 General information

Proton (¹H) and carbon (¹³C) NMR spectra were recorded on 400 MHz instrument (400 MHz for ¹H NMR, 100 MHz for ¹³C NMR) and calibrated using tetramethylsilane (TMS) as internal reference. High resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI) conditions. Flash column chromatography was performed on silica gel (0.035–0.070 mm) using compressed air. Thin layer chromatography (TLC) was carried out on 0.25 mm SDS silica gel coated glass plates (60F254). Eluted plates were visualized using a 254 nm UV lamp. Unless otherwise indicated, all reagents were commercially available and used without further purification. All solvents were distilled from the appropriate drying agents immediately before using. α-Chloro- or α-bromo hydrazones (1a–1n) were prepared according to literature procedures.^3c,4,7b Imines (2a–2m) were synthesized according to known procedures.¹⁴

4.2 Procedure for the synthesis of products 3

Na₂CO₃ (2.0 equiv., 0.4 mmol) was added to a solution of α-chloro- or α-bromo hydrazone 1 (1.0 equiv., 0.2 mmol) and imine 2 (1.5 equiv., 0.3 mmol) in toluene (1.0 mL). The mixture was monitored by TLC plate and stirred for 24–36 h at room temperature. The crude products were purified by flash column chromatography on silica gel using EtOAc–petroleum as eluent to give products 3 (21–88% yield).

1-(4-Benzyl-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethanone (3aa). White solid, yield: 55.6 mg, 75%; mp = 164.0–165.2 °C ¹H NMR (400 MHz, CDCl₃): δ 7.66–7.64 (m, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.42–7.38 (m, 5H), 7.36–7.29 (m, 6H), 6.45 (s, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 3.58–3.46 (m, 2H), 2.66 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 145.4, 137.6, 137.5, 135.8, 129.7, 129.1, 128.8, 128.7, 128.6, 128.1, 127.8, 126.4, 125.0, 69.6, 58.7, 43.0, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₄N₃O [M + H]⁺: 370.19139, found 370.19046.

1-(4-Benzyl-3-(4-methoxyphenyl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ab). Oil, yield: 68.1 mg, 85%; ¹H NMR (400 MHz, CDCl₃): δ 7.65–7.63 (m, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.40–7.37 (m, 5H), 7.34–7.31 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J = 13.2 Hz, 1H), 3.55–3.46 (m, 2H), 2.63 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 159.5, 145.4, 137.7, 135.8, 129.7, 129.6, 129.0, 128.7, 128.6, 127.8, 127.6, 125.0, 114.1, 69.3, 58.5, 55.3, 42.9, 20.9 ppm; HRMS (ESI) calculated for C₂₅H₂₆N₃O₂ [M + H]⁺: 400.20195, found 400.20111.

1-(4-Benzyl-3-(4-nitrophenyl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ac). Light yellow solid, yield: 55.5 mg, 67%; mp = 143.4–144.9 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, J = 8.8 Hz, 2H), 7.64–7.62 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.42–7.36 (m, 8H), 6.45 (s, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.80 (d, J = 12.8 Hz, 1H), 3.64–3.39 (m, 2H), 2.66 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.7, 147.9, 145.7, 144.9, 136.9, 135.2, 130.1, 129.1, 128.8, 128.7, 128.1, 127.7, 124.9, 124.0, 68.6, 58.9, 43.2, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃N₄O₃ [M + H]⁺: 415.17647, found 415.17526.

1-(4-Benzyl-3-(3-nitrophenyl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ad). Light yellow solid, yield: 51.4 mg, 62%; mp = 129.4–131.1 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.20–8.16 (m, 2H), 7.65–7.61 (m, 3H), 7.53 (t, J = 8.0 Hz, 1H), 7.45–7.43 (m, 3H), 7.41–7.36 (m, 5H), 6.46 (s, 1H), 3.95–3.79 (m, 2H), 3.65–3.41 (m, 2H), 2.68 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.8, 148.9, 145.7, 140.1, 136.9, 135.3, 132.7, 130.0, 129.9, 129.2, 128.8, 128.7, 128.1, 125.0, 123.3, 121.9, 68.4, 58.8, 43.0, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃N₄O₃ [M + H]⁺: 415.17647, found 415.17505.

1-(4-Benzyl-3-(2-nitrophenyl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ae). White solid, yield: 62.5 mg, 75%; mp = 153.3–154.5 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.88–7.86 (m, 1H), 7.56–7.54 (m, 2H), 7.51–7.45 (m, 2H), 7.40–7.31 (m, 6H), 7.27–7.24 (m, 3H), 7.05–7.03 (m, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.52 (d, J = 12.8 Hz, 1H), 3.43–2.91 (m, 2H), 2.66 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 149.2, 145.3, 137.0, 135.3, 132.3, 131.7, 130.0, 129.4, 129.2, 128.7, 128.6, 127.9, 127.2, 125.5, 125.0, 68.1, 59.0, 40.4, 20.9 ppm; HRMS (ESI) calculated for C₂₄H₂₃N₄O₃ [M + H]⁺: 415.17647, found 415.17542.

1-(4-Benzyl-3-(4-bromophenyl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3af). Oil, yield: 78.6 mg, 88%; ¹H NMR (400 MHz, CDCl₃): δ 7.65–7.63 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.44–7.38 (m, 7H), 7.36–7.33 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.38 (s, 1H), 3.92–3.74 (m, 2H), 3.59–3.44 (m, 2H), 2.65 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 145.5, 137.4, 136.7, 135.6, 131.9, 129.9, 129.1, 128.7, 128.7, 128.3, 127.9, 125.0, 122.2, 68.9, 58.7, 43.0, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃BrN₃O [M + H]⁺: 448.10190, found 448.10135.

1-(4-Benzyl-3-(naphthalen-2-yl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ag). White solid, yield: 55.2 mg, 66%; mp = 52.3–53.6 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, J = 8.4 Hz, 1H), 7.85–7.80 (m, 2H), 7.65–7.63 (m, 2H), 7.59–7.56 (m, 2H), 7.50–7.46 (m, 4H), 7.45–7.41 (m, 2H), 7.39–7.34 (m, 4H), 6.60 (s, 1H), 4.00–3.80 (m, 2H), 3.59–3.47 (m, 2H), 2.73 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 145.6, 137.6, 135.8, 134.9, 133.3, 133.2, 129.7, 129.2, 128.9, 128.7, 128.6, 128.3, 127.9, 127.6, 126.2, 126.2, 125.2, 125.0, 124.6, 69.7, 58.8, 43.2, 21.0 ppm; HRMS (ESI) calculated for C₂₈H₂₆N₃O [M + H]⁺: 420.20704, found 420.20602.

1-(4-Benzyl-3-(furan-2-yl)-6-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ah). White solid, yield: 57.3 mg, 80%; mp = 91.3–92.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.71–7.68 (m, 2H), 7.43–7.41 (m, 6H), 7.39–7.34 (m, 3H), 6.46 (s, 1H), 6.34–6.33 (m, 1H), 6.26 (d, J = 3.2 Hz, 1H), 3.87–3.79 (m, 2H), 3.68 (s, 2H), 2.56 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 171.9, 150.2, 145.0, 142.9, 137.0, 135.6, 129.8, 129.0, 128.7, 128.6, 127.8, 125.0, 110.3, 108.6, 64.0, 58.2, 44.0, 20.9 ppm; HRMS (ESI) calculated for C₂₂H₂₂N₃O₂ [M + H]⁺: 360.17065, found 360.16971.

1-(4-(4-Methoxybenzyl)-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ai). White solid, yield: 23.2 mg, 29%; mp = 126.2–127.9 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.66–7.64 (m, 2H), 7.40–7.38 (m, 3H), 7.36–7.32 (m, 4H), 7.29–7.28 (m, 3H), 6.93 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 3.85–3.82 (m, 4H), 3.70 (d, J = 12.8 Hz, 1H), 3.57–3.44 (m, 2H), 2.65 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 159.3, 145.4, 137.6, 135.8, 130.3, 129.7, 129.6, 128.7, 128.6, 128.1, 126.4, 125.0, 114.1, 69.2, 58.0, 55.3, 42.9, 20.8 ppm; HRMS (ESI) calculated for C₂₅H₂₆N₃O₂ [M + H]⁺: 400.20195, found 400.20111.

1-(4-(4-Fluorobenzyl)-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3aj). White solid, yield: 59.3 mg, 77%; mp = 132.1–133.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.66–7.64 (m, 2H), 7.43–7.38 (m, 5H), 7.35 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 8.4 Hz, 3H), 7.11–7.07 (m, 2H), 6.42 (s, 1H), 3.89–3.72 (m, 2H), 3.56–3.46 (m, 2H), 2.66 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 163.7, 161.2, 145.3, 137.4, 135.7, 133.3, 133.3, 130.7, 130.6, 129.8, 128.8, 128.6, 128.2, 126.4, 124.9, 115.6, 115.4, 69.3, 57.9, 43.1, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃FN₃O [M + H]⁺: 388.18197, found 388.18085.

1-(4-(4-Chlorobenzyl)-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ak). White solid, yield: 62.2 mg, 77%; mp = 175.7–176.4 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.65–7.63 (m, 2H), 7.40–7.37 (m, 7H), 7.34 (d, J = 7.2 Hz, 2H), 7.31–7.27 (m, 3H), 6.41 (s, 1H), 3.89–3.71 (m, 2H), 3.50 (s, 2H), 2.64 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 145.3, 137.3, 136.1, 135.7, 133.6, 130.4, 129.8, 128.9, 128.8, 128.6, 128.2, 126.4, 124.9, 69.4, 57.9, 43.1, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃ClN₃O [M + H]⁺: 404.15242, found 404.15152.

1-(4-Methyl-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3al). White solid, yield: 44.0 mg, 75%; mp = 92.7–93.2 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.69–7.67 (m, 2H), 7.40 (t, J = 3.2 Hz, 3H), 7.37–7.33 (m, 2H), 7.31–7.27 (m, 3H), 6.35 (s, 1H), 3.55–3.40 (m, 2H), 2.61 (s, 3H), 2.60 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.7, 145.0, 137.3, 135.9, 129.7, 128.7, 128.6, 128.2, 126.4, 124.9, 71.3, 45.1, 42.7, 20.7 ppm; HRMS (ESI) calculated for C₁₈H₂₀N₃O [M + H]⁺: 294.16009, found 294.15924.

1-(3,4,6-Triphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3am). White solid, yield: 23.4 mg, 33%; mp = 131.1–132.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.74–7.71 (m, 2H), 7.42 (t, J = 3.2 Hz, 3H), 7.37–7.34 (m, 5H), 7.32–7.30 (m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 7.02–6.99 (m, 1H), 4.42–3.96 (m, 2H), 2.58 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 171.8, 148.8, 146.1, 136.6, 135.1, 129.9, 129.7, 129.0, 128.7, 128.6, 128.4, 128.2, 126.2, 125.0, 121.7, 117.9, 67.6, 43.5, 32.6, 20.8 ppm; HRMS (ESI) calculated for C₂₃H₂₂N₃O [M + H]⁺: 356.17574, found 356.17426.

1-(4-Benzyl-6-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ca). Oil, yield: 45.2 mg, 57%; ¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 6.8 Hz, 2H), 7.41–7.38 (m, 2H), 7.35–7.30 (m, 6H), 6.90 (d, J = 8.8 Hz, 2H), 6.44 (s, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.84 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 3.54–3.42 (m, 2H), 2.64 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.4, 160.9, 145.2, 137.7, 137.6, 129.1, 128.7, 128.6, 128.5, 128.1, 127.8, 126.4, 126.4, 113.9, 69.5, 58.6, 55.4, 42.9, 20.8 ppm; HRMS (ESI) calculated for C₂₅H₂₆N₃O₂ [M + H]⁺: 400.20195, found 400.20105.

1-(4-Benzyl-3-phenyl-6-(p-tolyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3da). White solid, yield: 54.5 mg, 71%; mp = 93.3–94.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.42–7.38 (m, 2H), 7.36–7.29 (m, 6H), 7.19 (d, J = 8.0 Hz, 2H), 6.45 (s, 1H), 3.94–3.75 (m, 2H), 3.56–3.44 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 145.5, 139.9, 137.7, 137.6, 133.1, 129.3, 129.1, 128.7, 128.7, 128.1, 127.8, 126.4, 124.9, 69.5, 58.7, 43.0, 21.4, 20.9 ppm; HRMS (ESI) calculated for C₂₅H₂₆N₃O [M + H]⁺: 384.20704, found 384.20621.

1-(4-Benzyl-6-(4-bromophenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ea). White solid, yield: 71.1 mg, 80%; mp = 159.4–160.8 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.50 (s, 4H), 7.45–7.40 (m, 3H), 7.38–7.35 (m, 4H), 7.31–7.29 (m, 3H), 6.46 (s, 1H), 3.94–3.73 (m, 2H), 3.52–3.42 (m, 2H), 2.65 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 144.3, 137.4, 137.4, 134.6, 131.7, 129.1, 128.8, 128.7, 128.2, 127.9, 126.4, 126.4, 124.0, 69.6, 58.7, 42.8, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃BrN₃O [M + H]⁺: 448.10190, found 448.10092.

1-(4-Benzyl-6-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3fa). White solid, yield: 69.2 mg, 86%; mp = 138.5–139.9 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J = 8.4 Hz, 2H), 7.45–7.39 (m, 5H), 7.36–7.34 (m, 4H), 7.32–7.30 (m, 3H), 6.46 (s, 1H), 3.93 (d, J = 12.8 Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.53–3.43 (m, 2H), 2.65 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 144.3, 137.4, 137.4, 135.7, 134.2, 129.1, 128.8, 128.7, 128.2, 127.9, 126.4, 126.2, 69.6, 58.7, 42.8, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃ClN₃O [M + H]⁺: 404.15242, found 404.15161.

1-(4-Benzyl-6-(4-fluorophenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ga). White solid, yield: 57.1 mg, 74%; mp = 121.9–123.6 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.64–7.60 (m, 2H), 7.45–7.43 (m, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.36–7.29 (m, 6H), 7.09–7.04 (m, 2H), 6.44 (s, 1H), 3.94–3.73 (m, 2H), 3.53–3.42 (m, 2H), 2.64 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 164.9, 162.4, 144.4, 137.5, 137.4, 132.0, 132.0, 129.1, 128.8, 128.7, 128.2, 127.8, 126.9, 126.8, 126.4, 115.7, 115.5, 69.5, 58.7, 42.9, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃FN₃O [M + H]⁺: 388.18197, found 388.18100.

1-(4-Benzyl-6-(3-chlorophenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ha). White solid, yield: 64.9 mg, 80%; mp = 126.2–127.3 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.66 (s, 1H), 7.46–7.42 (m, 4H), 7.40–7.38 (m, 2H), 7.37–7.35 (m, 3H), 7.32–7.28 (m, 4H), 6.45 (s, 1H), 3.93–3.73 (m, 2H), 3.48 (s, 2H), 2.65 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 144.1, 137.5, 137.4, 137.3, 134.8, 129.9, 129.6, 129.1, 128.8, 128.7, 128.2, 127.9, 126.4, 125.0, 123.1, 69.6, 58.7, 43.0, 20.9 ppm; HRMS (ESI) calculated for C₂₄H₂₃ClN₃O [M + H]⁺: 404.15242, found 404.15158.

1-(4-Benzyl-6-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ia). Light yellow solid, yield: 58.7 mg, 71%; mp = 116.2–117.5 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.22 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.43–7.39 (m, 4H), 7.37–7.33 (m, 3H), 7.31–7.27 (m, 3H), 6.46 (s, 1H), 3.94–3.73 (m, 2H), 3.52 (s, 2H), 2.66 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 148.1, 143.0, 141.4, 137.2, 137.1, 129.0, 128.9, 128.8, 128.4, 128.0, 126.3, 125.6, 123.9, 69.9, 58.7, 42.9, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₃N₄O₃ [M + H]⁺: 415.17647, found 415.17514.

1-(4-Benzyl-6-(tert-butyl)-3-phenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ja). White solid, yield: 14.7 mg, 21%; mp = 63.1–63.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.44 (d, J = 7.2 Hz, 2H), 7.41–7.37 (m, 2H), 7.35–7.29 (m, 4H), 7.24 (d, J = 7.2 Hz, 2H), 6.30 (s, 1H), 3.85–3.56 (m, 2H), 3.04 (s, 2H), 2.51 (s, 3H), 1.08 (s, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 156.2, 137.9, 137.8, 129.0, 128.6, 127.9, 127.7, 126.3, 69.4, 58.2, 41.0, 37.5, 27.5, 20.7 ppm; HRMS (ESI) calculated for C₂₂H₂₈N₃O [M + H]⁺: 350.22269, found 350.22183.

(4-Benzyl-3,6-diphenyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl) (phenyl)methanone (3ka). Light yellow solid, yield: 29.6 mg, 34%; mp = 134.0–135.3 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J = 6.8 Hz, 2H), 7.61–7.55 (m, 3H), 7.51–7.49 (m, 4H), 7.45–7.37 (m, 6H), 7.35–7.30 (m, 5H), 6.61 (s, 1H), 4.12–3.90 (m, 2H), 3.65–3.55 (m, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 170.3, 145.6, 137.5, 137.3, 135.6, 134.5, 130.8, 130.4, 129.7, 129.1, 128.9, 128.8, 128.6, 128.2, 127.9, 127.6, 126.5, 125.0, 70.4, 58.9, 43.3, 27.0 ppm; HRMS (ESI) calculated for C₂₉H₂₆N₃O [M + H]⁺: 432.20704, found 432.20627.

Methyl 4-benzyl-3,6-diphenyl-4,5-dihydro-1,2,4-triazine-2(3H)-carboxylate (3la). White solid, yield: 45.8 mg, 59%; mp = 55.7–56.4 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.66 (s, 2H), 7.48 (d, J = 6.8 Hz, 2H), 7.44–7.40 (m, 2H), 7.38–7.31 (m, 9H), 6.20 (s, 1H), 4.02–3.84 (m, 5H), 3.56–3.43 (m, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 155.0, 146.8, 137.9, 137.6, 135.9, 129.6, 129.1, 128.8, 128.7, 128.5, 128.2, 127.8, 126.3, 125.2, 72.0, 58.6, 53.7, 43.1 ppm; HRMS (ESI) calculated for C₂₄H₂₄N₃O₂ [M + H]⁺: 386.18630, found 386.18539.

6-Ethyl 2-methyl 4-benzyl-3-phenyl-4,5-dihydro-1,2,4-triazine-2,6(3H)-dicarboxylate (3ma). Oil, yield: 53.5 mg, 70%; ¹H NMR (400 MHz, CDCl₃): δ 7.41–7.39 (m, 4H), 7.37–7.32 (m, 4H), 7.25 (d, J = 7.2 Hz, 2H), 6.07 (s, 1H), 4.34–4.29 (m, 2H), 3.96 (s, 3H), 3.82–3.73 (m, 2H), 3.56–3.51 (m, 1H), 3.26 (d, J = 19.2 Hz, 1H), 1.39–1.35 (m, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 163.0, 154.2, 140.2, 137.2, 137.0, 129.0, 128.9, 128.7, 128.5, 127.9, 126.1, 72.3, 62.0, 58.3, 54.3, 42.6, 14.1 ppm; HRMS (ESI) calculated for C₂₁H₂₄N₃O₄ [M + H]⁺: 382.17613, found 382.17499.

4-Benzyl-3,6-diphenyl-2-tosyl-2,3,4,5-tetrahydro-1,2,4-triazine (3na). White solid, yield: 61.3 mg, 64%; mp = 110.5–111.3 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J = 8.4 Hz, 2H), 7.61–7.58 (m, 2H), 7.42–7.39 (m, 1H), 7.38–7.36 (m, 9H), 7.34–7.31 (m, 5H), 6.12 (s, 1H), 3.72 (d, J = 13.6 Hz, 1H), 3.50–3.43 (m, 2H), 3.35 (d, J = 18.4 Hz, 1H), 2.49 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 145.2, 144.0, 138.5, 137.3, 135.7, 129.5, 129.4, 129.0, 128.6, 128.5, 128.4, 128.3, 127.8, 126.9, 124.9, 74.4, 58.4, 42.1, 27.0, 21.7 ppm; HRMS (ESI) calculated for C₂₉H₂₈N₃O₂S [M + H]⁺: 482.18967, found 482.18881.

1-(4-Benzyl-6-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3fb). Oil, yield: 70.0 mg, 81%; ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, J = 8.8 Hz, 2H), 7.43–7.37 (m, 4H), 7.35–7.33 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 3.71 (d, J = 12.8 Hz, 1H), 3.46 (s, 2H), 2.63 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.4, 159.5, 144.2, 137.5, 135.6, 134.2, 129.4, 129.0, 128.8, 128.7, 127.8, 127.6, 126.2, 114.2, 69.4, 58.5, 55.3, 42.7, 20.8 ppm; HRMS (ESI) calculated for C₂₅H₂₅ClN₃O₂ [M + H]⁺: 434.16298, found 434.16229.

1-(4-Benzyl-3-(4-bromophenyl)-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3ff). White solid, yield: 68.3 mg, 71%; mp = 153.2–154.0 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.40–7.39 (m, 4H), 7.36–7.34 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 6.37 (s, 1H), 3.91–3.71 (m, 2H), 3.52–3.39 (m, 2H), 2.62 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 144.4, 137.2, 136.6, 135.8, 134.0, 132.0, 129.0, 128.8, 128.7, 128.2, 128.0, 126.2, 122.2, 69.0, 58.7, 42.8, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₂BrClN₃O [M + H]⁺: 482.06293, found 482.06226.

1-(4-Benzyl-3-(4-bromophenyl)-6-(3-chlorophenyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3hf). Oil, yield: 77.8 mg, 81%; ¹H NMR (400 MHz, CDCl₃): δ 7.65 (s, 1H), 7.49 (s, 1H), 7.47–7.43 (m, 2H), 7.41–7.40 (m, 4H), 7.38–7.36 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.37 (s, 1H), 3.90–3.72 (m, 2H), 3.53–3.41 (m, 2H), 2.64 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 144.1, 137.3, 137.1, 136.5, 134.9, 132.0, 129.9, 129.7, 129.0, 128.8, 128.2, 128.0, 125.0, 123.0, 122.3, 69.0, 58.7, 43.0, 20.8 ppm; HRMS (ESI) calculated for C₂₄H₂₂BrClN₃O [M + H]⁺: 482.06293, found 482.06238.

1-(4-Benzyl-3-(4-bromophenyl)-6-(p-tolyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)ethan-1-one (3df). White solid, yield: 67.5 mg, 73%; mp = 133.9–134.7 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.44–7.33 (m, 5H), 7.21–7.19 (m, 4H), 6.38 (s, 1H), 3.92–3.74 (m, 2H), 3.57–3.42 (m, 2H), 2.65 (s, 3H), 2.40 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 172.5, 145.6, 140.1, 137.4, 136.8, 132.8, 131.9, 129.3, 129.1, 128.7, 128.3, 127.9, 124.9, 122.1, 68.9, 58.6, 42.9, 21.4, 20.8 ppm; HRMS (ESI) calculated for C₂₅H₂₅BrN₃O [M + H]⁺: 462.11755, found 462.11670.

Acknowledgements

We thank Beijing Municipal Commission of Education (No. JC015001200902), Beijing Municipal Natural Science Foundation (No. 7102010, No. 2122008), Basic Research Foundation of Beijing University of Technology (X4015001201101), Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR201008025), Doctoral Scientific Research Start-up Foundation of Beijing University of Technology (No. 52015001200701) for financial supports.

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Footnote

† Electronic supplementary information (ESI) available: Copies of NMR spectra for all products related to this article; X-ray single crystal structure analysis data for 3aa. CCDC 1508810. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra27767e

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