Synthesis of functionalized tetrahydropyridazines via catalyst-free self [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes

Abstract

An efficient method for the synthesis of structurally diverse functionalized tetrahydropyridazines via self [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes was developed, which may play an important role in drug discovery.

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Introduction

The synthesis of diverse nitrogen-containing heterocyclic compounds has received wide interest due to their important applications and special activities in medicinal chemistry and related sciences.¹ Among them, tetrahydropyridazines represent one of the important building blocks found in a variety of bioactive and natural compounds (Fig. 1).² Antrimycin, which was isolated from a soil sample, has been shown to have antibacterial activity against Mycobacterium smegmatis ATCC 607.³ Quinoxapeptin A and B isolated from a nocardioform actinomycete with indeterminate morphology are potent inhibitors of HIV-1 and HIV-2 reverse transcriptase.⁴ Tetrahydropyridazines can also be found in lots of synthetic pharmaceutical compounds, for instance 3-aryl-1-benzoxyl-1,4,5,6-tetrahydropyridazines have been identified as nonsteroidal progesterone receptor ligands (e.g. I),⁵ 3-aryl-1-(arylsulfonyl)-1,4,5,6-tetrahydropyridazines are a class of nonsteroidal allosteric modulators at the GABA_A receptor (e.g. II).⁶ As a result, the distinctive structures and medicinal potential of molecules containing tetrahydropyridazines have become popular targets in target-oriented synthesis.^7,8 Among these well known methods, the hetero Diels–Alder reaction of 1,2-diaza-1,3-dienes generated in situ from hydrazones with alkenes has proved to be an attractive strategy for the construction of structurally diverse tetrahydropyridazines.⁷ However, such reactions are limited to electron-rich or electron-neutral alkenes and electron-deficient or in situ generated alkenes remain challenging substrates.⁷ⁿ So we want to explore these substrates considering the importance of structurally diverse functionalized tetrahydropyridazines. To our surprise, the 6-diazenyl substituted tetrahydropyridazine formed via self [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes is the only product even in the presence of methyl acrylate or methyl buta-2,3-dienoate under various conditions (Scheme 1). It should be noted that the substituted tetrahydropyridazine derivative with a diazenyl substituent is not easily accessed by known methods, and could be potentially be useful in medicinal science. Herein, we report our systematic study on the self [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes under catalyst free conditions to construct diverse 6-diazenyl substituted tetrahydropyridazine derivatives.⁹

Fig. 1 Examples of tetrahydropyridazine derivatives in natural products and bioactive compounds.

Scheme 1 Synthesis of tetrahydropyridazines.

Results and discussion

Our study commenced with the self [4 + 2] cycloaddition reaction of α-chloro-N-acylhydrazones (1) in the presence of different bases, solvents and reaction time to optimize the reaction conditions. To our delight, the reaction proceeded successfully via dimerization of the in situ generated 1,2-diaza-1,3-butadiene to provide product 2a in 18% yield when it was conducted in CH₂Cl₂ with DMAP (1.0 equiv.) at room temperature without any catalyst (Table 1, entry 1). A series of bases were then screened. Organic bases, such as DIPEA and Et₃N, were ineffective (Table 1, entry 2–4). While the use of inorganic bases resulted in an improvement of the yield (Table 1, entries 5–11) and K₂CO₃ was shown to be the most effective in this reaction. Based on this encouraging result, we evaluated several other solvents, but none of these performed any better than CH₂Cl₂ (Table 1, entries 12–19). Next, we examined the influence of the reaction time on the model reaction and we found that 1.0 h was still the most suitable time for the reaction (Table 1, entries 20–22). However, no desired products were obtained when the benzoyl group of 1 was replaced by phenyl or benzenesulfonyl group (Table 1, entries 23 and 24). Further investigation toward the influence of leaving group revealed that bromine as the leaving group gave the best yield, whereas tosyl was ineffective (Table 1, entries 25 and 27).

Table 1 Optimization of the reaction conditions^a

Entry	PG	X	Base	Solvent	Product	Yield^b
a The reaction was carried out with 1 (0.5 mmol) and base (1.0 equiv.) at room temperature under an atmosphere of air for 1.0 h.b Isolated yields.c 15 min.d 30 min.e 1.5 h.
1	PhCO	Cl	DMAP	CH2Cl2	2a	18
2	PhCO	Cl	Pyridine	CH2Cl2	2a	12
3	PhCO	Cl	Et3N	CH2Cl2	2a	Trace
4	PhCO	Cl	DIPEA	CH2Cl2	2a	Trace
5	PhCO	Cl	Na2CO3	CH2Cl2	2a	57
6	PhCO	Cl	NaHCO3	CH2Cl2	2a	44
7	PhCO	Cl	NaOH	CH2Cl2	2a	11
8	PhCO	Cl	K2CO3	CH2Cl2	2a	89
9	PhCO	Cl	Cs2CO3	CH2Cl2	2a	50
10	PhCO	Cl	AcOK	CH2Cl2	2a	32
11	PhCO	Cl	K3PO4	CH2Cl2	2a	81
12	PhCO	Cl	K2CO3	AcOEt	2a	38
13	PhCO	Cl	K2CO3	CH3OH	2a	Trace
14	PhCO	Cl	K2CO3	THF	2a	19
15	PhCO	Cl	K2CO3	DMF	2a	Trace
16	PhCO	Cl	K2CO3	CH3CN	2a	21
17	PhCO	Cl	K2CO3	(CH2)2Cl2	2a	45
18	PhCO	Cl	K2CO3	Toluene	2a	62
19	PhCO	Cl	K2CO3	1,4-Dioxane	2a	Trace
20^c	PhCO	Cl	K2CO3	CH2Cl2	2a	33
21^d	PhCO	Cl	K2CO3	CH2Cl2	2a	57
22^e	PhCO	Cl	K2CO3	CH2Cl2	2a	85
23	Ph	Cl	K2CO3	CH2Cl2	—	—
24	PhSO2	Cl	K2CO3	CH2Cl2	—	—
25	PhCO	Br	K2CO3	CH2Cl2	2a	85
26	PhCO	I	K2CO3	CH2Cl2	2a	63
27	PhCO	Tosyl	K2CO3	CH2Cl2	—	—

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With the optimized conditions in hand, the generality and scope of the catalyst-free self [4 + 2] cycloaddition reaction were explored. A variety of α-chloro-N-acylhydrazones bearing electron-donating or -withdrawing groups were subjected to the standard conditions (Table 2, entries 1–16), most of them resulting in the expected functionalized tetrahydropyridazines in good to excellent yields. It is noteworthy that the reaction demonstrated wide tolerance for diverse substituents. Benzoyl hydrazones bearing electron-neutral (4-H), electron-rich (e.g. 4-Me, 4-OMe), and electron-deficient (e.g. 4-Cl) phenyl rings were successfully converted to the corresponding products 2a–d in good yields (83–92%; Table 2, entries 1–4). Furthermore, the hydrazone substrate with a thiophene skeleton afforded the target heterocycles in 95% yield. Gratifyingly, the naphthalene attached tetrahydropyridazines could be obtained in 98% yield. Regrettably, the reaction of nonaromatic acylhydrazones under standard conditions led to complicated mixtures, and a trace amount of the products were obtained (Table 2, entries 7–9). The compatibility and generality of the present method were further explored by variations of the R¹ group. Halogen substituents on the R¹ benzene group were tested. Thus, 4-chlorobenzene and 4-fluorobenzene reacted and gave products 2j–n in 89–92% yields. In addition, styrene or alkyl substituted hydrazones did not work well, leading to no desired product (Table 2, entry 15 and 16).

Table 2 Synthesis of structurally diverse functionalized tetrahydropyridazines^a

Entry	R^1	R^2	2	Yield^b [%]
a The reaction was carried out with 1 (0.5 mmol) and K2CO3 (1.0 equiv.) at room temperature under an atmosphere of air for 1.0 h.b Isolated yields.
1	Ph	Ph	2a	89
2	Ph	4-MeOPh	2b	92
3	Ph	4-MePh	2c	90
4	Ph	4-ClPh	2d	83
5	Ph	2-Thienyl	2e	95
6	Ph	2-Naphthyl	2f	98
7	Ph	Me	2g	Trace
8	Ph	OEt	2h	Trace
9	Ph	O^tBu	2i	Trace
10	4-ClPh	4-MeOPh	2j	90
11	4-ClPh	4-MePh	2k	90
12	4-FPh	Ph	2l	89
13	4-FPh	4-MeOPh	2m	91
14	4-FPh	2-Thienyl	2n	92
15		Ph	—	NR
16	^tBu	Ph	—	NR

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To further expand the substrate scope, we next tested other α-chloro-N-acylhydrazones. As shown in Scheme 2, when 3 was treated under standard conditions, instead of the desired self [4 + 2] cycloaddition, an eliminated product 4 was obtained in 92% yield. Notably, a novel diazenyl substituted tetrahydropyridazine derivative 6 was obtained in 87% yield when α-chloro-N-acylhydrazone 5 derived from 2-chloro-3,4-dihydronaphthalen-1(2H)-one was used under standard conditions even though a longer reaction time was needed to completely consume 5.

Scheme 2 Substrate scope for hydrazones.

Next, the functionalized tetrahydropyridazine derivative 2a could also be successfully converted to a pharmaceutically important tetrahydropyridazine compound 7 in 86% yield. Treatment of 2a with Pd/C under H₂ atmosphere in methanol led to the reduced and ring-opened product N′-(1,4-diphenylbutyl)benzohydrazide in 82% yield (Scheme 3). The developed cycloaddition could be performed on a gram scale. The reaction of α-chloro-N-benzoyl hydrazone 1 afforded 2a (1.03 g) in 87% yield (Scheme 4).

Scheme 3 Transformation of 2a.

Scheme 4 Synthesis of 2a on a gram scale.

Experimental

Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. All reactions were performed in anhydrous solvents. Reactions were monitored by thin layer chromatography (TLC), and column chromatography purifications were performed using 200–300 mesh silica gel. Melting points were obtained on a melting point apparatus and are uncorrected. ¹H and ¹³C NMR spectra were recorded in DMSO-d₆ or CDCl₃ using a 300 MHz spectrometer. Chemical shifts are reported in delta (δ) units in parts per million (ppm) relative to the singlet (0 ppm) for tetramethylsilane (TMS). High-resolution mass spectra were recorded in ESI mode on a QTOF MS spectrometer. The α-chloro-N-acylhydrazones were prepared according to literature procedures.¹⁰

General procedure for the synthesis of structurally diverse functionalized tetrahydropyridazines

To the solution of α-chloro-N-acylhydrazones (0.5 mmol) in dry CH₂Cl₂ (5 mL) was added K₂CO₃ (69.1 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for the required period of time. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with 15 mL CH₂Cl₂, which was washed with water and brine successively, dried over MgSO₄, filtered, and concentrated in vacuo. Purification by flash chromatography (ethyl acetate/PE, 1 : 20–1 : 5) yielded the desired products.

((2-Benzoyl-3,6-diphenyl-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(phenyl)methanone (2a). Yellow solid (105.2 mg, 89% yield); mp = 122–124 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J = 7.3 Hz, 2H), 7.89–7.81 (m, 2H), 7.76 (d, J = 7.4 Hz, 2H), 7.69–7.53 (m, 2H), 7.45–7.41 (m, J = 14.6, 13.1, 7.7 Hz, 8H), 7.36–7.27 (m, 4H), 2.92–2.70 (m, 2H), 2.37 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.66, 169.48, 145.24, 141.96, 136.01, 134.79, 134.31, 130.41, 130.23, 129.59, 128.87, 128.60, 128.49, 128.43, 127.97, 127.16, 126.95, 125.03, 124.25, 86.14, 31.72, 17.68, ppm; HRMS (ESI) calcd for C₃₀H₂₄O₂N₄Na⁺ (M + Na)⁺ 495.6174, found 495.6177.

((2-(4-Methoxybenzoyl)-3,6-diphenyl-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(4-methoxyphenyl)methanone (2b). Yellow solid (122.5 mg, 92% yield); mp = 135–137 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.97 (t, J = 5.8 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H), 7.78–7.70 (m, 2H), 7.67–7.57 (m, 2H), 7.43–7.27 (m, 6H), 6.95 (m, 4H), 3.87 (t, J = 5.7 Hz, 6H), 2.93–2.65 (m, 2H), 2.50–2.21 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.38, 169.18, 164.84, 161.78, 145.28, 142.78, 136.72, 133.34, 132.59, 132.26, 129.22, 128.83, 128.45, 127.50, 125.53, 124.77, 121.74, 114.33, 112.75, 86.42, 55.53, 55.38, 32.19, 18.26, ppm; HRMS (ESI) calcd for C₃₂H₂₈O₄N₄Na⁺ (M + Na)⁺ 555.6257, found 555.6251.

((2-(4-Methylbenzoyl)-3,6-diphenyl-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(p-tolyl)methanone (2c). Yellow solid (112.6 mg, 90% yield); mp = 116–118 °C; ¹H NMR (300 MHz, DMSO) δ 7.90–7.80 (m, 4H), 7.72 (d, J = 7.7 Hz, 4H), 7.59 (d, J = 6.3 Hz, 4H), 7.36 (s, 5H), 7.29 (s, 1H), 2.73 (dd, J = 48.2, 28.5 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.25–1.89 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 183.00, 169.69, 145.86, 145.38, 142.65, 141.04, 135.68, 132.27, 130.97, 130.37, 130.20, 129.65, 129.19, 128.80, 128.40, 128.07, 127.48, 125.52, 124.73, 86.48, 32.20, 21.89, 21.55, 18.21, ppm; HRMS (ESI) calcd for C₃₂H₂₈O₂N₄Na⁺ (M + Na)⁺ 0.523.4922, found 523.4919.

((2-(4-Chlorobenzoyl)-3,6-diphenyl-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(4-chlorophenyl)methanone (2d). Yellow solid (112.1 mg, 83% yield); mp = 130–132 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.97–7.91 (m, 2H), 7.81–7.75 (m, 2H), 7.74–7.68 (m, 2H), 7.57 (dd, J = 6.7, 3.0 Hz, 2H), 7.47–7.33 (m, 10H), 2.80 (m, 2H), 2.37 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.00, 168.89, 146.44, 142.03, 141.61, 136.93, 136.23, 133.53, 132.16, 131.56, 129.58, 129.41, 128.96, 128.54, 127.80, 127.75, 127.43, 125.49, 124.65, 86.82, 32.19, 18.23, ppm; HRMS (ESI) calcd for C₃₀H₂₂Cl₂N₄O₂Na⁺ (M + Na)⁺ 563.0999, found 563.0992.

((3,6-Diphenyl-2-(thiophene-2-carbonyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(thiophen-2-yl)methanone (2e). Yellow solid (115.0 mg, 95% yield); mp = 160–162 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.35–8.33 (m, 1H), 7.94–7.95 (m, 4H), 7.61 (m, 1H), 7.53–7.51 (m, 4H), 7.44–7.35 (m, 5H), 6.89 (m, 1H), 2.86–2.60 (m, 2H), 2.56–2.26 (m, 2H), ppm; ¹³C NMR (75 MHz, DMSO) δ 176.04, 160.30, 149.65, 142.27, 139.53, 137.94, 136.22, 136.07, 135.94, 132.88, 132.75, 129.75, 129.62, 128.75, 128.59, 127.32, 126.65, 126.61, 124.60, 86.64, 32.08, 18.79, ppm; HRMS (ESI) calcd for C₂₆H₂₀N₄O₂S₂Na⁺ (M + Na)⁺ 507.0898, found 507.0908.

((2-(2-Naphthoyl)-3,6-diphenyl-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(naphthalen-2-yl)methanone (2f). Yellow solid (140.4 mg, 98% yield); mp = 198–200 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.40 (s, 1H), 8.10 (dd, J = 8.6, 1.6 Hz, 1H), 8.00 (dd, J = 8.6, 1.5 Hz, 1H), 7.95 (s, 1H), 7.93–7.82 (m, 6H), 7.54–7.51 (m, 8H), 7.38–7.22 (m, 5H), 2.99–2.74 (m, 2H), 2.63–2.31 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.99, 170.98, 145.76, 142.49, 136.46, 134.54, 132.03, 130.82, 130.26, 129.49, 129.36, 129.31, 128.90, 128.83, 128.56, 128.44, 128.26, 128.11, 127.78, 127.73, 127.65, 127.36, 126.96, 126.85, 126.72, 126.65, 126.24, 125.50, 125.40, 124.83, 124.23, 86.70, 29.67, 18.26, ppm; HRMS (ESI) calcd for C₃₈H₂₉O₂N₄⁺ (M + H)⁺ 573.1468, found 573.1456.

((3,6-Bis(4-chlorophenyl)-2-(4-methoxybenzoyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(4-methoxyphenyl)methanone (2j). Yellow solid (135.0 mg, 90% yield); mp = 107–109 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.8, 5.9 Hz, 4H), 3.87 (d, J = 3.0 Hz, 6H), 2.88–2.65 (m, 2H), 2.41–2.22 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.09, 169.18, 164.93, 161.96, 144.27, 141.23, 135.28, 135.0, 133.33, 13.27, 132.49, 129.06, 128.65, 126.77, 126.14, 121.50, 114.36, 113.72, 112.82, 85.81, 55.54, 55.38, 31.84, 18.03, ppm; HRMS (ESI) calcd for C₃₂H₂₆Cl₂N₄O₄Na⁺ (M + Na)⁺ 623.1213, found 623.1214.

((3,6-Bis(4-chlorophenyl)-2-(4-methylbenzoyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(p-tolyl)methanone (2k). Yellow solid (127.8 mg, 90% yield); mp = 97–99 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.62–7.56 (m, 2H), 7.45–7.38 (m, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.21–7.13 (m, 6H), 2.81–2.51 (m, 2H), 2.33 (d, J = 2.1 Hz, 6H), 2.27–2.15 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.72, 169.72, 146.08, 144.39, 141.41, 141.12, 135.30, 134.96, 133.36, 131.85, 130.90, 130.26, 129.97, 129.71, 129.24, 128.63, 128.16, 126.78, 126.12, 85.88, 31.87, 21.90, 21.55, 17.99, ppm; HRMS (ESI) calcd for C₃₂H₂₆Cl₂N₄O₂Na⁺ (M + Na)⁺ 591.1312, found 593.1310.

((2-Benzoyl-3,6-bis(4-fluorophenyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(phenyl)methanone (2l). Yellow solid (113.1 mg, 89% yield); mp = 84–86 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.02–7.95 (m, 2H), 7.84–7.77 (m, 2H), 7.73 (dd, J = 8.9, 5.2 Hz, 2H), 7.57–7.40 (m, 8H), 7.10 (t, J = 8.7 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 2.78 (m, 2H), 2.43–2.25 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.88, 169.99, 165.13, 163.65, 160.38, 144.80, 138.10, 135.12, 134.83, 132.55, 131.26, 130.80, 129.88, 129.57, 128.97, 127.97, 127.66, 127.46, 127.44, 127.33, 126.54, 126.43, 126.27, 116.25, 115.96, 115.67, 115.56, 115.27, 86.05, 32.14, 18.15, ppm; HRMS (ESI) calcd for C₃₀H₂₂F₂N₄O₂Na⁺ (M + Na)⁺ 531.1585, found 531.1590.

((3,6-Bis(4-fluorophenyl)-2-(4-methoxybenzoyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(4-methoxyphenyl)methanone (2m). Yellow solid (129.3 mg, 91% yield); mp = 135–137 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.8, 5.9 Hz, 4H), 3.87 (d, J = 3.0 Hz, 6H), 2.88–2.65 (m, 2H), 2.41–2.22 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 182.18, 169.20, 165.06, 164.90, 163.57, 161.87, 161.75, 160.31, 144.34, 138.43, 133.27, 132.76, 132.45, 127.43, 127.32, 127.03, 126.53, 126.42, 121.57, 115.87, 115.59, 115.55, 115.26, 114.33, 112.78, 85.82, 55.52, 55.36, 32.08, 18.23, ppm; HRMS (ESI) calcd for C₃₂H₂₆F₂O₄N₄Na⁺ (M + Na)⁺ 591.1904, found 591.1805.

((3,6-Bis(4-fluorophenyl)-2-(thiophene-2-carbonyl)-2,3,4,5-tetrahydropyridazin-3-yl)diazenyl)(thiophen-2-yl)methanone (2n). Yellow solid (119.6 mg, 92% yield); mp = 170–172 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (dd, J = 3.9, 1.3 Hz, 1H), 7.93–7.85 (m, 2H), 7.82 (dd, J = 4.9, 1.0 Hz, 1H), 7.78 (dd, J = 3.8, 1.0 Hz, 1H), 7.74–7.63 (m, 3H), 7.21–7.05 (m, 6H), 2.79–2.68 (m, 2H), 2.43–2.40 (m, 2H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 176.76, 167.21, 165.34, 163.60, 148.33, 138.29, 137.10, 136.52, 134.88, 133.72, 133.14, 132.57, 130.79, 130.67, 129.14, 128.79, 128.68, 127.76, 126.46, 126.34, 115.99, 115.83, 115.72, 115.70, 115.54, 115.45, 86.31, 32.51, 19.14, ppm; HRMS (ESI) calcd for C₂₆H₁₈F₂N₄O₂S₂Na⁺ (M + Na)⁺ 543.0705, found 543.0715.

N′-(1-Phenylallylidene)benzohydrazide (4). White solid (115.1 mg, 92% yield); mp = 125–127 °C; ¹H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 7.88 (d, J = 6.1 Hz, 2H), 7.52 (dd, J = 18.7, 11.4 Hz, 8H), 7.15 (dd, J = 17.5, 11.3 Hz, 1H), 5.87 (d, J = 12.2 Hz, 1H), 5.53 (d, J = 17.5 Hz, 1H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 163.18, 156.33, 136.99, 131.95, 130.03, 129.76, 128.56, 128.43, 128.33, 128.11, 126.99, 123.79, ppm; HRMS (ESI) calcd for C₁₆H₁₅ON₂⁺ (M + H)⁺ 251.1179, found 251.1157.

((14-Benzoyl-5,6b,7,8,14,14a-hexahydrobenzo[h]naphtha[1,2-c]cinnolin-6a(6H)-yl)diazenyl)(phenyl)methanone (6). Yellow solid (114.0 mg, 87% yield); mp = 198–200 °C; ¹H NMR (300 MHz, DMSO) δ 7.70 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.7 Hz, 4H), 7.50–7.42 (m, 2H), 7.35 (dd, J = 14.7, 8.1 Hz, 4H), 7.27 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 6.9 Hz, 1H), 7.17 (d, J = 7.3 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 5.35 (dd, J = 11.4, 4.7 Hz, 1H), 3.53 (dd, J = 11.2, 5.7 Hz, 1H), 3.14 (t, J = 16.2 Hz, 2H), 2.88 (s, 2H), 2.38 (s, 2H), 2.24 (s, 2H), ppm; ¹³C NMR (75 MHz, DMSO) δ 182.09, 169.60, 144.63, 139.83, 136.20, 135.88, 135.58, 135.04, 131.79, 130.70, 130.30, 130.18, 129.79, 129.70, 129.60, 129.29, 128.85, 128.55, 127.81, 126.73, 125.70, 124.15, 72.99, 52.19, 28.92, 27.51, 25.00, 22.57, ppm; HRMS (ESI) calcd for C₃₄H₂₉O₂N₄⁺ (M + H)⁺ 525.2272, found 525.2272.

(3,6-Diphenyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl)methanone (7). Yellow solid (146.3 mg, 86% yield); mp = 147–149 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.90–7.77 (m, 2H), 7.59 (dd, J = 6.7, 2.9 Hz, 2H), 7.47–7.45 (m, 3H), 7.35–7.24 (m, 6H), 7.18 (d, J = 7.1 Hz, 2H), 6.09 (s, 1H), 2.69 (dd, J = 16.9, 2.4 Hz, 1H), 2.45–2.14 (m, 3H), ppm; ¹³C NMR (75 MHz, CDCl₃) δ 170.21, 146.89, 139.93, 137.17, 135.34, 130.20, 130.01, 129.17, 128.80, 128.40, 127.38, 127.32, 125.46, 125.38, 51.69, 23.98, 18.72, ppm; HRMS (ESI) calcd for C₂₃H₂₁ON₂⁺ (M + H)⁺ 341.1648, found 341.1623.

N′-(1,4-Diphenylbutyl)benzohydrazide (8). White solid (140.3 mg, 82% yield); mp = 99–101 °C; ¹H NMR (300 MHz, DMSO) δ 9.88 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.54–7.46 (m, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.31–7.34 (m, 4H), 7.28–7.18 (m, 3H), 7.14 (t, J = 7.2 Hz, 3H), 5.27 (s, 1H), 4.06 (s, 1H), 1.86 (dd, J = 13.3, 8.9 Hz, 1H), 1.67–1.38 (m, 3H), ppm; ¹³C NMR (75 MHz, DMSO) δ 166.72, 143.35, 142.90, 134.11, 132.05, 129.10, 129.07, 129.05, 128.96, 128.49, 127.99, 127.92, 126.47, 64.67, 35.90, 35.32, 28.42, ppm; HRMS (ESI) calcd for C₂₃H₂₅ON₂⁺ (M + H)⁺ 345.1961, found 345.1964.

Conclusions

In summary, we have developed an efficient protocol for the preparation of various functionalized tetrahydropyridazines via catalyst-free self [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes. The methodology features accessible starting reagents, convenient operating conditions, a broad substrate scope, and high efficiency. Further studies to explore the application of 1,2-diaza-1,3-dienes to other reaction systems and the evaluation of biological activity of the products are ongoing in our laboratory.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21102179, 21572271 and 81473078), Qing Lan Project, the project-sponsored by SRF for ROCS, SEM and National Found for Fostering Talents of Basic Science (Grant No. J1030830).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra13985j

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