A method for the regioselective c3-h alkenylation of triazolopyridazines

Abstract

The application discloses a method for regionally selective C3-H alkyne of triazolopyridazine compounds, and belongs to the field of organic synthesis. The method uses triazolopyridazine and high-valence iodine (III) alkyne reagent as raw materials, and a double catalytic system composed of Ph3PAuNTf2 (5 mol%), AgOTf (5 mol%) and 1,10-phenanthroline (20 mol%) in dichloromethane, and after reaction at 50 DEG C, the C3 alkyne product is obtained through purification. The method solves the problems of catalyst deactivation and poor selectivity caused by nitrogen-rich heterocyclic rings through gold / silver synergistic catalysis, and realizes precise functionalization of the C3 position. The reaction condition is mild, the substrate is widely applicable (R¹ contains various aryl groups and heteroaryl groups, and R² is compatible with different substituted aryl groups), the yield is 60% to 95%, the step is economical, and the method is suitable for large-scale preparation.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry technology, specifically relating to a method for regioselective C3-H alkynylation of triazolopyridazine compounds. Background Technology

[0002] Triazolopyridazine compounds modified with an alkynyl group at the C3 position have broad application prospects in medicinal chemistry, pesticide chemistry, and materials science due to their abundant aza-aromatic skeletons and alkynyl functional groups. These compounds can serve as lead structures for various potentially bioactive drugs, used in the development of antitumor, anti-anxiety, antiviral, and central nervous system active drugs. Simultaneously, the introduction of the alkynyl functional group provides convenient reaction sites for further structural modifications (such as click chemistry and coupling reactions), expanding their application in the construction of diverse molecular libraries. Furthermore, some alkynylated triazolopyridazine derivatives can also serve as organic light-emitting materials or metal chemical ligands, showing application potential in the development of functional materials and catalysts. Therefore, the C3-alkynylated triazolopyridazine products obtained by the method of this invention are not only of great significance in pharmaceutical research and development but can also serve as important intermediates for the synthesis of novel pesticides and functional materials.

[0003] Triazolopyridazines, as a class of nitrogen-containing heteroaromatic skeletons, have attracted widespread attention in medicinal chemistry and pesticide chemistry due to their excellent bioactivity. However, structural modification of these compounds still faces significant challenges, especially in the direct functionalization of their C3 site. Because triazolopyridazine molecules are rich in nitrogen atoms with strong coordinating abilities, they readily form coordination complexes with metal catalysts during reactions, resulting in poor reaction selectivity and severely limiting their application in C–H bond functionalization reactions. Currently, C3-substituted triazolopyridazine products are mainly obtained through two strategies: one is intermolecular cyclization reaction using 6-chloro-3-hydrazidopyridazine as a substrate, and the other is cross-coupling reaction using triazolopyridazine bromide as a starting material. However, these methods are typically complex, require harsh reaction conditions, have low yields, and are difficult to scale up, hindering their widespread application. Furthermore, traditional C–C bond construction methods often rely on pre-functionalized substrates, further increasing synthetic complexity.

[0004] Currently, the reported synthetic methods for C3-substituted products of triazolopyridazine have significant limitations:

[0005] Traditional strategies often rely on pre-functionalized substrates, such as using triazolopyridazine bromide as a starting material and introducing functional groups like alkynyl groups through cross-coupling reactions (e.g., the Sonogashira reaction). However, such methods require prior halogenation modification of the substrate, increasing the number of synthetic steps and the cost of raw materials. Furthermore, the halogenation reaction itself may be accompanied by regioselectivity issues.

[0006] Another approach involves constructing a C3-substituted triazolopyridazine skeleton through a multi-step cyclization reaction, for example, using 6-chloro-3-hydrazinopyridazine as a starting material and generating the target structure via intermolecular cyclization. However, this method requires harsh reaction conditions (such as high temperature and strong acid / base environments), involves cumbersome steps, and generally yields low yields, making it difficult to meet the needs of large-scale preparation.

[0007] Existing C-C bond construction methods also suffer from narrow substrate adaptability. They are often inefficiently compatible with triazolopyridazine derivatives containing sensitive groups (such as ester or cyano groups) or complex substituents, which limits their application in the diversified derivatization of drug molecules. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of existing methods for the functionalization of C3-position triazolopyridazines, such as cumbersome steps, poor selectivity, and harsh conditions, and to provide a regioselective C3-H alkyneation method based on a gold / silver dual-catalytic system. This method uses a bimetallic (gold / silver) synergistic catalytic system and a high-valent iodine(III) alkyne reagent to achieve selective activation of the C(sp²)–H bond and introduction of alkyne groups in the triazolopyridazine skeleton, which has advantages such as high selectivity, mild conditions, broad substrate adaptability, and scalability.

[0009] The technical solution of the present invention is as follows:

[0010] A regioselective C3-H alkynylation method based on a gold / silver dual-catalytic system includes the following steps:

[0011] The reactants, triazolopyridazine compounds and high-valent iodine(III) ynyl reagent, were dissolved in 2.0 mL of dichloromethane to form a reaction mixture. The catalyst, triphenylphosphine trifluoromethanesulfonylimide gold (Ph3PAuNTf2, 5 mol%), the co-catalyst, silver trifluoromethanesulfonate (AgOTf, 5 mol%), and the ligand, 1,10-phenanthroline (Phen, 20 mol%), were added sequentially to the reaction mixture. The reaction system was heated at 50 °C, and the reaction progress was monitored using thin-layer chromatography (TLC) until the substrate, the triazolopyridazine compounds, was completely reacted. After the reaction was completed, the reaction solvent was removed to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the target product, C3 ynylated triazolopyridazine compounds.

[0012]

[0013] The R 1Selected from p-tolyl, o-tolyl, m-tolyl, phenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, naphthyl, 3-furanyl, 3-thienyl, 3-pyridyl (referred to as: 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m);

[0014] The R 2 Selected from triisopropylsilyl, phenyl, p-tolyl, o-tolyl, m-tolyl, and p-methyl ester phenyl (referred to as: 2a, 2b, 2c, 2d, 2e, 2f, respectively);

[0015] The molar ratio of the triazolidine compound to the high-valent iodine(III) alkynyl reagent is 1:1.5;

[0016] The amounts of the catalyst triphenylphosphine trifluoromethanesulfonyl imide gold and the co-catalyst silver trifluoromethanesulfonate were both 5 mol% of 1 mole of the compound.

[0017] The amount of the ligand 1,10-phenanthroline is 20 mol% of 1 mole of the compound.

[0018] The organic solvent is dichloromethane; the reaction temperature is 50 °C;

[0019] The method for removing the reaction solvent is vacuum distillation using a rotary evaporator; the purification method is silica gel column chromatography.

[0020] The reaction mechanism is as follows: Under the action of Ph3PAuNTf2 and 1,10-o-phenanthroline, an active Au(I) catalytic species A is first generated in situ. Subsequently, the Au(I) species undergoes oxidative addition with a high-valent iodine(III) alkynyl reagent to generate the key alkynyl Au(III) intermediate B. Afterward, the alkoxy anion generated in the reaction is transferred from the Au(III) intermediate to the Ag(I) species, thereby promoting the activation of the C–H bond and forming a silver-containing intermediate F. This silver intermediate then undergoes a transmetallic transfer reaction with another Au(III) species to generate a new Au(III) intermediate G. Subsequently, the target product 3 is obtained through reductive elimination, while the Au(I) catalyst is regenerated, thus completing the entire catalytic cycle. Silver salts (such as AgOTf) in this reaction not only act as a co-catalyst to promote C–H activation but also enhance their electrophilicity by co-combining with Au(I) to generate cationic gold species, thereby accelerating the oxidative addition step. This bimetallic synergistic catalytic mechanism provides a new solution for the regioselective C–H alkynylation of nitrogen-containing heterocyclic substrates and significantly improves the efficiency and selectivity of the reaction.

[0021] The strong coordination of nitrogen atoms with metal catalysts easily leads to catalyst deactivation, making it difficult to achieve highly selective C3-position functionalization. This invention utilizes a gold / silver dual-catalytic system, leveraging the coordination of 1,10-phenanthroline to first form a monovalent gold species. Under the oxidation of high-valent iodine, a key intermediate trivalent gold species is obtained. Since the chemical orbitals of gold are already filled and the added ligand provides even stronger coordination, nitrogen atoms on the substrate cannot participate in coordination, thus solving the problem in nitrogen-dense triazolidine substrates.

[0022] The beneficial effects of this invention are:

[0023] (1) High regioselectivity: For the first time, precise alkynylation of triazolopyridazine compounds at the C3 position is achieved, overcoming the problem of poor functionalization selectivity in nitrogen-dense heterocycles, solving the problem of complex products caused by multi-site reactions in existing methods, and the reaction can specifically introduce alkynyl groups at the C3 position of triazolopyridazine, avoiding side reactions.

[0024] (2) Gold / silver dual catalytic synergistic mechanism: Taking advantage of the strong coordination characteristics of nitrogen atoms in triazolopyridazine to metals, a Ph3PAuNTf2 / AgOTf dual catalytic system was designed. The gold species is responsible for generating the alkyne Au(III) active intermediate, while the silver species enhances its electrophilicity through synergistic effect with gold and participates in CH bond activation, effectively avoiding catalyst deactivation and significantly improving reaction efficiency.

[0025] (3) Mild conditions and wide applicability: The reaction is carried out at 50 °C in dichloromethane, without the need for high temperature or strong corrosive reagents; the substrate has a wide range of applicability, R¹ covers a variety of substituents such as aryl and heteroaryl, and R² is compatible with aryl with different substitution modes, all of which can obtain the target product in 60%-95% yield, meeting the needs of large-scale preparation.

[0026] (4) Step economy: Breaking through the traditional synthetic strategy that relies on pre-functionalized substrates (such as bromides) or multi-step cyclization, the C-C bond is constructed by direct CH bond alkynylation, reducing reaction steps, conforming to the principle of atom economy, and reducing raw material costs. Attached Figure Description

[0027] Figure 1 This is a diagram of the reaction mechanism;

[0028] Figure 2 The 1H NMR spectrum of the product in Example 1;

[0029] Figure 3 The carbon spectrum of the product in Example 1;

[0030] Figure 4 The hydrogen NMR spectrum of the product in Example 2;

[0031] Figure 5 The carbon spectrum of the product in Example 2;

[0032] Figure 6 The 1H NMR spectrum of the product in Example 3;

[0033] Figure 7 The carbon spectrum of the product in Example 3;

[0034] Figure 8 The 1H NMR spectrum of the product in Example 4;

[0035] Figure 9 The carbon spectrum of the product in Example 4;

[0036] Figure 10 The hydrogen NMR spectrum of the product in Example 5;

[0037] Figure 11 The carbon spectrum of the product in Example 5;

[0038] Figure 12 The 1H NMR spectrum of the product in Example 6;

[0039] Figure 13 The carbon spectrum of the product in Example 6;

[0040] Figure 14 The hydrogen NMR spectrum of the product in Example 7;

[0041] Figure 15 The carbon spectrum of the product in Example 7;

[0042] Figure 16 The hydrogen NMR spectrum of the product in Example 8;

[0043] Figure 17 The carbon spectrum of the product in Example 8;

[0044] Figure 18 The 1H NMR spectrum of the product in Example 9;

[0045] Figure 19 The carbon spectrum of the product in Example 9;

[0046] Figure 20 The 1H NMR spectrum of the product in Example 10;

[0047] Figure 21 The carbon spectrum of the product in Example 10;

[0048] Figure 22 The hydrogen NMR spectrum of the product in Example 11;

[0049] Figure 23 The carbon spectrum of the product in Example 11;

[0050] Figure 24 The 1H NMR spectrum of the product in Example 12;

[0051] Figure 25 The carbon spectrum of the product in Example 12;

[0052] Figure 26 The 1H NMR spectrum of the product in Example 13;

[0053] Figure 27 The carbon spectrum of the product in Example 13;

[0054] Figure 28 The 1H NMR spectrum of the product in Example 14;

[0055] Figure 29 The carbon spectrum of the product in Example 14;

[0056] Figure 30 The 1H NMR spectrum of the product in Example 15;

[0057] Figure 31 The carbon spectrum of the product in Example 15;

[0058] Figure 32 The 1H NMR spectrum of the product in Example 16;

[0059] Figure 33 The carbon spectrum of the product in Example 16;

[0060] Figure 34 The 1H NMR spectrum of the product in Example 17;

[0061] Figure 35 The carbon spectrum of the product in Example 17;

[0062] Figure 36 The 1H NMR spectrum of the product in Example 18;

[0063] Figure 37 The image shows the carbon spectrum of the product from Example 18. Detailed Implementation

[0064] To make the above-mentioned objectives, features, and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to examples. The following content is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, as long as they do not deviate from the concept of the invention, they should all fall within the protection scope of the present invention.

[0065] The preparation method of the present invention will be described below through specific embodiments. Example 1

[0066] This embodiment provides a regioselective C3-H alkynylation method based on a gold / silver dual-catalytic system.

[0067] The specific steps are as follows: Triazolopyridazine derivative 1a (0.2 mmol) and high-valent iodoynyl reagent 2a (0.3 mmol) were added to a dry 4 mL reaction flask and dissolved in anhydrous dichloromethane (2 mL). Then, Ph3PAuNTf2 (gold catalyst, 5 mol%), AgOTf (silver catalyst, 5 mol%), and 1,10-phenanthroline (ligand, 20 mol%) were added sequentially. The reaction mixture was heated to 50 °C, and the reaction was monitored by TLC for 24 hours until complete. After the reaction, the mixture was cooled to room temperature, quenched with saturated NaHCO3 solution, extracted, dried the organic layer (Na2SO4), concentrated, and purified by column chromatography to obtain the target product 3aa, a yellow solid with a melting point of 72-73 °C and a yield of 95%.

[0068] according to Figure 2 The product's 1H NMR spectrum and Figure 3 The carbon spectrum of the product yields the following structural formula of the target product:

[0069]

[0070] 1 H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 9.7 Hz, 1H), 7.91 (d, J = 8.0Hz, 2H), 7.62 (d, J = 9.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H), 1.21 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 154.0, 143.1, 141.7, 136.4, 131.0,129.9, 127.1, 124.7, 119.8, 104.3, 90.1, 21.4, 18.6, 11.1. HRMS (ESI, m / z)calc'd for C 23 H 31 N4Si [M+H] + : 391.2312, found: 391.2310. Example 2

[0071] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1b.

[0072] The target product 3ba was obtained as a yellow solid with a melting point of 66-67 °C and a yield of 81%.

[0073] according to Figure 4 The product's 1H NMR spectrum and Figure 5 The carbon spectrum of the product yields the following structural formula of the target product:

[0074]

[0075] 1 H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 9.5 Hz, 1H), 7.49 (d, J = 7.3Hz, 1H), 7.38 (m, 4H), 2.50 (s, 3H), 1.14 (m, 21H). 13 C NMR (75 MHz, CDCl3) δ HRMS (ESI, m / z) calc'd for C 23 H 31 N4Si [M+H] + :391.2312, found: 391.2312. Example 3

[0076] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1c.

[0077] The target product 3ca was obtained as a yellow solid with a melting point of 110-111 °C and a yield of 61%.

[0078] according to Figure 6 The product's 1H NMR spectrum and Figure 7 The carbon spectrum of the product yields the following structural formula of the target product:

[0079]

[0080] 1 H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 9.7 Hz, 1H), 7.91 (s, 1H), 7.78(d, J = 7.3 Hz, 1H), 7.65 (d, J = 9.7 Hz, 1H), 7.47 – 7.31 (m, 2H), 2.45 (s, 3H), 1.21 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ HRMS (ESI, m / z) calc'd for C 23 H 31 N4Si [M+H] + : 391.2312, found: 391.2311. Example 4

[0081] The difference between this embodiment and Example 1 is that the triazolidine derivative is selected as 1d.

[0082] The target product 3da was obtained, a white solid with a melting point of 142-143 °C and a yield of 62%.

[0083] according to Figure 8 The product's 1H NMR spectrum and Figure 9 The carbon spectrum of the product yields the following structural formula of the target product:

[0084]

[0085] 1 H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 9.7 Hz, 1H), 8.03 (m, 2H), 7.65(d, J = 9.7 Hz, 1H), 7.54 (m, 3H), 1.21 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ154.1, 143.1, 136.5, 133.9, 131.1, 129.1, 127.3, 124.9, 119.8, 104.5, 90.1,18.6, 11.1. HRMS (ESI, m / z) calc'd for C 22 H 29 N4Si [M+H] + : 377.2156, found:377.2156. Example 5

[0086] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1e.

[0087] The target product 3ea was obtained as a yellow solid with a melting point of 120-121 °C and a yield of 95%.

[0088] according to Figure 10 The product's 1H NMR spectrum and Figure 11 The carbon spectrum of the product yields the following structural formula of the target product:

[0089]

[0090] 1 H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 9.7 Hz, 1H), 7.98 (d, J = 8.7Hz, 2H), 7.60 (d, J = 9.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H), 1.21 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 162.1, 153.6, 143.1, 136.3, 128.8,126.2, 124.6, 119.7, 114.5, 104.3, 90.2, 55.5, 18.6, 11.1. HRMS (ESI, m / z)calc'd for C 23 H 31 N4OSi [M+H] + : 407.2262, found: 407.2260. Example 6

[0091] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1f.

[0092] The target product 3fa was obtained as a white solid with a melting point of 142-143 °C and a yield of 90%.

[0093] according to Figure 12 The product's 1H NMR spectrum and Figure 13 The carbon spectrum of the product yields the following structural formula of the target product:

[0094]

[0095] 1 H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 9.7 Hz, 1H), 8.10 (dd, J = 8.3, 5.3 Hz, 2H), 7.67 (d, J = 9.7 Hz, 1H), 7.30 (d, J = 9.1 Hz, 2H), 1.27 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 164.7 (d, 1 J C-F = 252.6 Hz), 153.1, 143.0,136.5, 130.1 (d, 4 J C-F = 3.3 Hz), 129.4 (d, 3 J C-F = 8.8 Hz), 125.1, 119.5, 116.4(d, 2 J C-F = 22.0 Hz), 104.7, 90.0, 18.6, 11.1. HRMS (ESI, m / z) calc'd forC 22 H 28 FN4Si [M+H] + : 395.2062, found: 395.2062. Example 7

[0096] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected at 1g.

[0097] The target product 3ga was obtained as a yellow solid with a melting point of 137-138 °C and a yield of 85%.

[0098] according to Figure 14 The product's 1H NMR spectrum and Figure 15 The carbon spectrum of the product yields the following structural formula of the target product:

[0099]

[0100] 1 H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 9.7 Hz, 1H), 7.97 (d, J = 8.4Hz, 2H), 7.63 (d, J = 9.7 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 1.19 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 153.0, 143.0, 137.5, 136.4, 132.3, 129.4, 128.5,125.1, 119.4, 104.7, 89.9, 18.5, 11.0. HRMS (ESI, m / z) calc'd forC 22 H 28 35 ClN4Si [M+H] + : 411.1766, found: 411.1766. Example 8

[0101] The difference between this embodiment and Example 1 is that the triazolidine derivative is selected for 1h.

[0102] The target product was obtained in 3 ha, a yellow solid with a melting point of 148-149 °C, and the yield was 94%.

[0103] according to Figure 16 The product's 1H NMR spectrum and Figure 17 The carbon spectrum of the product yields the following structural formula of the target product:

[0104]

[0105] 1 H NMR (300 MHz, CDCl3) δ8.20 (d, J = 9.7 Hz, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 9.7 Hz, 1H), 1.20 (d, J = 3.5Hz, 21H). 13 C NMR (75 MHz, CDCl3) δ 153.1, 143.0, 136.5, 132.8, 132.4, 128.7,126.0, 125.2, 119.3, 104.8, 89.9, 18.6, 11.1. HRMS (ESI, m / z) calc'd forC 22 H 28 79 BrN4Si [M+H] + : 455.1261, found: 455.1259. Example 9

[0106] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1i.

[0107] The target product 3ia was obtained as a yellow solid with a melting point of 137-138 °C and a yield of 75%.

[0108] according to Figure 18 The product's 1H NMR spectrum and Figure 19 The carbon spectrum of the product yields the following structural formula of the target product:

[0109]

[0110] 1 H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 9.7 Hz, 1H), 8.16 (d, J = 8.1Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 9.7 Hz, 1H), 1.20 (d, J = 3.7Hz, 21H). 13 C NMR (75 MHz, CDCl3) δ152.8, 143.0, 137.3, 136.6, 132.9 (q, 2 J C-F = 33.0 Hz), 127.7, 126.1 (q, 3 J C-F = 3.6 Hz), 125.5, 123.7 (q, 1 J C-F = 271.7Hz), 119.5, 105.1, 89.8, 18.6, 11.1. HRMS (ESI, m / z) calc'd for C 23 H 28 F3N4S [M+H] + : 445.2030, found: 445.2029. Example 10

[0111] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative 1j is selected.

[0112] The target product 3ja was obtained as a yellow solid with a melting point of 75-76 °C and a yield of 93%.

[0113] according to Figure 20 The product's 1H NMR spectrum and Figure 21 The carbon spectrum of the product yields the following structural formula of the target product:

[0114]

[0115] 1 H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 8.03 (d, J = 8.1 Hz, 1H), 7.96(d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.64 – 7.46 (m, 4H), 1.11 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ156.0, 142.9, 136.5, 133.9, 132.4, 131.0,130.4, 128.74, 128.65, 127.4, 126.5, 125.1, 124.7, 124.3, 124.0, 104.7, 90.0,18.5, 11.0. HRMS (ESI, m / z) calc'd for C 26 H 31 N4Si [M+H] + : 427.2312, found:427.2312. Example 11

[0116] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1k.

[0117] The target product 3ka was obtained as a yellow solid with a melting point of 131-132 °C and a yield of 88%.

[0118] according to Figure 22 The product's 1H NMR spectrum and Figure 23 The carbon spectrum of the product yields the following structural formula of the target product:

[0119]

[0120] 1 H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.36(d, J = 9.6 Hz, 1H), 6.97 (s, 1H), 1.20 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 148.7, 144.9, 143.3, 143.1, 136.3, 124.7, 122.7, 119.8, 108.1, 104.4, 90.0,18.6, 11.1. HRMS (ESI, m / z) calc'd for C 20 H 27 N4OSi [M+H] + : 367.1949, found:367.1949. Example 12

[0121] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative is selected as 1l.

[0122] The target product 3la was obtained as a yellow solid with a melting point of 140-141 °C and a yield of 95%.

[0123] according to Figure 24 The product's 1H NMR spectrum and Figure 25 The carbon spectrum of the product yields the following structural formula of the target product:

[0124]

[0125] 1 H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 9.6 Hz, 1H), 7.98 (s, 1H), 7.74(d, J = 4.8 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 7.47 (m, 1H), 1.20 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 150.1, 143.0, 136.5, 136.3, 127.5, 126.9, 125.8,124.7, 120.0, 104.3, 90.1, 18.6, 11.1. HRMS (ESI, m / z) calc'd for C 20 H 27 N4SSi[M+H] + : 383.1720, found: 383.1720. Example 13

[0126] The difference between this embodiment and Example 1 is that the triazolidine derivative is selected as 1m.

[0127] The target product 3ma was obtained as a yellow solid with a melting point of 137-138 °C and a yield of 62%.

[0128] according to Figure 26 The product's 1H NMR spectrum and Figure 27 The carbon spectrum of the product yields the following structural formula of the target product:

[0129]

[0130] 1 H NMR (300 MHz, CDCl3) δ9.25 (s, 1H), 8.78 (d, J = 4.2 Hz, 1H), 8.34(d, J = 7.9 Hz, 1H), 8.26 (d, J = 9.6 Hz, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.53– 7.43 (m, 1H), 1.19 (s, 21H). 13 C NMR (75 MHz, CDCl3) δ 152.0, 151.9, 148.4,142.9, 136.5, 134.6, 129.9, 125.6, 123.9, 119.1, 105.1, 89.7, 18.5, 11.1.HRMS (ESI, m / z) calc'd for C 21 H 28 N5Si [M+H] + : 378.2108, found: 378.2108. Example 14

[0131] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative 1l was selected and the high-valent iodoalkynyl reagent 2b was selected. 3lb of the target product was obtained as a brown solid with a melting point of 141-142 °C, and a yield of 61%.

[0132] according to Figure 28 The product's 1H NMR spectrum and Figure 29 The carbon spectrum of the product yields the following structural formula of the target product:

[0133]

[0134] 1 H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 9.6 Hz, 1H), 8.03 (d, J = 1.4Hz, 1H), 7.81 (d, J = 4.9 Hz, 1H), 7.75 – 7.67 (m, 2H), 7.57 (d, J = 9.6 Hz, 1H), 7.50 (dd, J = 4.9, 2.8 Hz, 1H), 7.44 (m, 3H). 13C NMR (75 MHz, CDCl3) δ HRMS (ESI, m / z) calc'd for C 17 H 11 N4S [M+H] + :303.0699, found: 303.0698. Example 15

[0135] The difference between this embodiment and Example 1 is that the triazolidine derivative is selected as 1l and the high-valent iodoalkynyl reagent is selected as 2c. The target product 3lc was obtained as a yellow solid with a melting point of 169-170 °C and a yield of 60%.

[0136] according to Figure 30 The product's 1H NMR spectrum and Figure 31 The carbon spectrum of the product yields the following structural formula of the target product:

[0137]

[0138] 1 H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 8.03 (s, 1H), 7.80 (d, J = 4.8Hz, 1H), 7.59 (d, J = 7.9 Hz, 3H), 7.49 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 7.8Hz, 2H), 2.41 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 150.2, 140.4, 136.5, 132.1,129.4, 127.6, 127.1, 126.1, 124.9, 120.2, 118.1, 99.7, 73.5, 21.7. HRMS (ESI,m / z) calc'd for C 18 H 13 N4S [M+H] + : 317.0855, found: 317.0855. Example 16

[0139] The difference between this embodiment and Example 1 is that the triazolidine derivative is selected as 1l and the high-valent iodoalkynyl reagent is selected as 2d. The target product 3ld was obtained as a yellow solid with a melting point of 170-171 °C and a yield of 61%.

[0140] according to Figure 32 The product's 1H NMR spectrum and Figure 33 The carbon spectrum of the product yields the following structural formula of the target product:

[0141]

[0142] 1 H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 9.3 Hz, 1H), 8.05 (s, 1H), 7.81(d, J = 4.6 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H), 7.52 (m, 3H), 7.38 – 7.26 (m, 2H), 2.41 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 150.2, 143.2, 138.3, 136.5,136.3, 132.5, 130.7, 129.2, 128.4, 127.5, 127.1, 126.0, 124.8, 120.9, 120.1,99.5, 73.6, 21.2. HRMS (ESI, m / z) calc'd for C 18 H 13 N4S [M+H] + : 317.0855, found:317.0855. Example 17

[0143] The difference between this embodiment and Example 1 is that the triazolopyridazine derivative 1l was selected and the high-valent iodoalkynyl reagent 2e was selected. The target product 3e was obtained as a yellow solid with a melting point of 170-171 °C and a yield of 66%.

[0144] according to Figure 34 The product's 1H NMR spectrum and Figure 35 The carbon spectrum of the product yields the following structural formula of the target product:

[0145]

[0146] 1 H NMR (300 MHz, CDCl3) δ 8.20 (d, J = 9.4 Hz, 1H), 8.05 (s, 1H), 7.82(d, J = 4.9 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.53(m, 1H), 7.44 – 7.33 (m, 2H), 7.29 (s, 1H), 2.71 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 150.2, 143.4, 141.0, 136.7, 136.5, 132.3, 129.8, 129.7, 127.6,127.0, 125.9, 125.8, 124.9, 121.0, 120.1, 98.4, 77.7, 20.7. HRMS (ESI, m / z)calc'd for C 18 H 13 N4S [M+H] + : 317.0855, found: 317.0854. Example 18

[0147] The difference between this embodiment and Example 1 is that the triazolidine derivative 1l was selected and the high-valent iodoalkynyl reagent 2f was selected. The target product 3lf was obtained as a yellow solid with a melting point of 191-192 °C and a yield of 62%.

[0148] according to Figure 36 The product's 1H NMR spectrum and Figure 37 The carbon spectrum of the product yields the following structural formula of the target product:

[0149]

[0150] 1 H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 9.0 Hz, 1H), 8.12 – 8.00 (m,3H), 7.77 (m, 3H), 7.60 (d, J= 9.2 Hz, 1H), 7.50 (m, 1H), 3.94 (s, 3H). 13 CNMR (75 MHz, CDCl3) δ 166.2, 150.5, 136.2, 132.0, 130.9, 129.6, 127.7, 127.3,126.0, 125.6, 124.9, 120.5, 98.3, 76.4, 52.4. HRMS (ESI, m / z) calc'd forC 19 H 13 N4O2S [M+H] + : 361.0754, found: 361.0753.

[0151] Example 19: Scale-up Experiment

[0152] The scale-up experiment was conducted according to the method in Example 1, with substrate 1a scaled up to 5 mmol and other reagents scaled up proportionally. After the reaction was completed, a purified product was obtained with a yield of 81%, indicating that the method has good potential for large-scale production.

[0153] Examples 1-19 illustrate that this invention achieves precise alkynylation at the C3 position of triazolopyridazine compounds, overcoming the problem of poor functionalization selectivity in nitrogen-dense heterocycles and solving the product complexity issue caused by multi-site reactions in existing methods. Furthermore, the reaction specifically introduces an alkynyl group at the C3 position of triazolopyridazine, avoiding side reactions. Mild conditions and wide applicability: The reaction is carried out at 50 °C in dichloromethane, requiring no high-temperature or highly corrosive reagents; the substrate scope is broad, with R¹ covering various substituents such as aryl and heteroaryl, and R² compatible with aryl groups of different substitution modes, all yielding the target product in 60%-90% yield, meeting the requirements for large-scale preparation.

[0154] Step economy: Breaking away from the traditional synthetic strategy that relies on pre-functionalized substrates (such as bromides) or multi-step cyclization, this method constructs C-C bonds through direct CH-bond alkynylation, reducing reaction steps, conforming to the principle of atom economy, and lowering raw material costs.

[0155] Figure 1 The reaction mechanism is as follows: targeting the strong coordination characteristics of nitrogen atoms in triazolopyridazine with metals, a Ph3PAuNTf2 / AgOTf dual catalytic system is designed - the gold species is responsible for generating the alkyne Au(III) active intermediate, and the silver species enhances its electrophilicity through synergistic effect with gold, while participating in CH bond activation, effectively avoiding catalyst deactivation and significantly improving reaction efficiency.

Claims

1. A method for regioselective C3-H alkynylation of triazolopyridazine compounds, characterized in that, The method involves the direct alkynylation of triazolopyridazine compounds under the co-catalysis of gold and silver catalysts to synthesize 3-substituted alkyne triazolopyridazine compounds, and includes the following steps: Compound 1 and Compound 2 were dissolved in 2.0 mL of organic solvent to form a reaction mixture. The catalyst triphenylphosphine trifluoromethanesulfonylimide gold, the co-catalyst silver trifluoromethanesulfonate, and the ligand 1,10-phenanthroline were added sequentially to the reaction mixture. The reaction system was heated in a water bath, and the reaction progress was monitored using thin-layer chromatography until Compound 1 was completely reacted. After the reaction was completed, the reaction solvent was removed to obtain a crude product. The crude product was purified to obtain Compound 3. The molecular structural formulas of compounds 1, 2, and 3 are as follows: ； Among them, R 1 Selected from C6~C 10 aryl groups, substituted aryl groups, heterocyclic aryl groups; R 2 Selected from triisopropylsilyl, C6~C 10 aryl and substituted aryl groups; The heteroatom of the heterocyclic aryl group is O, S or N, and the number of heteroatoms is 1; The substituents of the substituted aromatic ring group are selected from methyl, alkoxy, and halogen, and the number of substituents is an integer from 1 to 3.

2. The method according to claim 1, characterized in that, The R 1 Selected from p-tolyl, o-tolyl, m-tolyl, phenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, naphthyl, 3-furanyl, 3-thienyl, 3-pyridyl; The R 2 Selected from triisopropylsilyl, phenyl, p-tolyl, o-tolyl, and m-tolyl.

3. The method according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1.

5.

4. The method according to claim 1, characterized in that, The catalyst triphenylphosphine trifluoromethanesulfonyl imide gold and the co-catalyst silver trifluoromethanesulfonate were both used in amounts of 5 mol of 1 mole of the compound.

5. The method according to claim 1, characterized in that, The amount of the ligand 1,10-phenanthroline is 20 mol of 1 mole of the compound.

6. The method according to claim 1, characterized in that, The organic solvent is dichloromethane.

7. The method according to claim 1, characterized in that, The reaction water bath temperature is 50 ℃.

8. The method according to claim 1, characterized in that, The method for removing the reaction solvent is vacuum distillation using a rotary evaporator.

9. The method according to claim 1, characterized in that, The purification method is silica gel column chromatography.

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