Triazene oxide and preparation method thereof

Abstract

The invention provides a novel amination coupling strategy, and discloses a triazene oxide and a preparation method thereof. The method for preparing the triazene oxide comprises the following steps: taking an amine substance, an iso-head amide reagent and a nitroso aromatic hydrocarbon substance as raw materials, and reacting in an optional solvent under the action of an optional alkali additive to generate the triazene oxide. According to the synthesis strategy of the invention, isoamide is used as a linking reagent, and the nitrogen terminals of secondary aliphatic amine and nitroso aromatic hydrocarbon are efficiently crosslinked in the form of N-N = N + (O-) fragments, so that the triazene oxides with novel and diversified structures are efficiently prepared through one-pot reaction, and the use of toxic high-valence metal oxidants in traditional methods is avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and more particularly to triazene oxide and a preparation method thereof. Background Art

[0002] Transition metal-catalyzed (TMC) coupling reactions, including Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig reactions, have become indispensable tools for constructing carbon-carbon (CC) and carbon-nitrogen (CN) bonds, typically between nucleophiles and electrophiles (Nu-E). These methods are widely used in the synthesis of natural products, drugs, and pesticides. Correspondingly, TMC oxidative coupling reactions enable direct connection of two nucleophiles (Nu1-Nu2), providing an effective strategy to expand chemical space and molecular diversity. In contrast, amination coupling reactions that simultaneously connect nitrogen atoms to two reactants remain extremely challenging and largely unexplored. Recently, Richard Y. Liu and his colleagues reported a palladium-catalyzed amination Suzuki-Miyaura coupling reaction, which achieved a formal nitrene insertion process (Nu-N*-E) between nucleophiles and electrophiles (references: Onnuch, P.; Ramagonolla, K.; Liu, RY, Science 2024, 383, 101-1024.). However, the amination coupling between two nucleophiles (Nu1-N*-Nu2) remains extremely challenging. The main difficulty lies in the inherent high electronegativity of the nitrogen element. After the nitrogen atom is installed on the first nucleophile (Nu1), the nitrogen end still retains its nucleophilic properties. If there is no effective polarity reversal strategy to convert the nucleophilic nitrogen into an electrophilic nitrogen species (such as nitrene or nitrogen radical intermediate), the bonding with the second component nucleophile (Nu2) will be hindered. Based on this, developing new strategies based on amination coupling reactions will provide more efficient strategies for the synthesis of nitrogen-containing molecules. Summary of the invention

[0003] In order to solve the problems in the prior art, the present invention proposes triazene oxide and a preparation method thereof. The synthesis strategy of the present invention is to use an isomeric amide (Formula II) as a linking reagent, react with a fatty amine (Formula I) and a nitroso aromatic compound (Formula III) in one pot, and thus triazene oxides with diversified structures can be efficiently prepared. The preparation method of the triazene oxide of the present invention has mild conditions, simple operation, and readily available raw materials.

[0004] In order to solve the above problems, the present invention proposes the following technical solutions:

[0005] The first aspect of the present invention provides a method for preparing triazene oxide, which comprises the following steps: using amine substances, isomeric amide reagents and nitroso aromatic substances as raw materials, reacting in an optional solvent under the action of an optional base additive to generate triazene oxide.

[0006] As a preferred implementation:

[0007] The amine substance is selected from at least one of the compounds of the general structural formula shown in Formula I: Among them, when the R 1 and R 2 When not connected to form a ring, the R 1 and R 2 are the same or different and are independently selected from substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; when the R 1 and R 2 When connected into a ring, the R 3 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ester, hydroxyl, substituted or unsubstituted ether; a is any integer from 0 to 3;

[0008] The isomeric amide reagent is selected from at least one of the compounds of the general structural formula shown in Formula II: The R 4 is selected from alkyl, substituted or unsubstituted aryl; R 5 is selected from substituted or unsubstituted acyloxy; R 6 is selected from substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy;

[0009] The nitroso aromatic hydrocarbon substance is selected from at least one of the compounds of the general structural formula shown in Formula III: Ar in the structure of formula III is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0010] The triazene oxide is selected from at least one of the compounds of the general structural formula shown in Formula IV: R in Formula IV 1 , R 2 , R 3 and a and R in Formula I 1 , R 2 , R 3 and a correspond to the same; Ar in formula IV corresponds to Ar in formula III.

[0011] As a preferred embodiment: in the formula I, when the R 1 and R 2 When not connected to form a ring, the R1 and R 2 The same or different, each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C5-C8 cycloalkyl;

[0012] When the R 1 and R 2 When not connected into a ring, Selected from the following groups:

[0013] Among them, the R 3 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ester, hydroxyl, substituted or unsubstituted ether; a is any integer between 0 and 2.

[0014] As a preferred embodiment: the formula I is selected from at least one of the following compounds:

[0015]

[0016] As a preferred embodiment: R described in formula II 4 is selected from C1-C3 alkyl, substituted or unsubstituted phenyl; preferably, the R 4 Any one of the following groups: and / or,

[0017] R described in Formula II 5 is selected from C1-C6 acyloxy; preferably, the R 5 Any one of the following groups:

[0018] R described in Formula II 6 is selected from C1-C3 alkoxy or phenoxy; preferably, the R 6 Any one of the following groups:

[0019] Further preferably, the formula II is selected from at least one of the following compounds:

[0020]

[0021] As a preferred embodiment: Ar described in formula III is selected from The R 7 It is selected from halogen, substituted or unsubstituted ester, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl, substituted or unsubstituted alkyl and alkoxy.

[0022] As a preferred embodiment: the formula III is selected from at least one of the following compounds:

[0023]

[0024] As a preferred embodiment: the molar ratio of the amine substance, the isomeric amide reagent, and the nitroso aromatic hydrocarbon substance is 1: (1.2-1.5): (1.5-2.0); and / or,

[0025] The molar ratio of the amine substance to the alkaline additive is 1:(0-2.0); and / or,

[0026] The concentration of the amine substance in the solvent is 0.05-1.0 mol / L; and / or,

[0027] The reaction temperature is room temperature; and / or,

[0028] The reaction time is 5 to 8 hours; and / or,

[0029] The solvent is selected from at least one of an organic solvent, water and a mixed solvent of an organic solvent; preferably, the organic solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane or diethyl ether; and / or,

[0030] The base additive is selected from organic amine additives; preferably, the base additive is selected from any one of the following compounds:

[0031]

[0032] The second aspect of the present invention is to provide triazene oxide prepared by the preparation method described in the first aspect of the present invention:

[0033] The triazene oxide is selected from at least one of the compounds of the general structural formula shown in Formula IV: R in Formula IV 1 , R 2 , R 3 and a and R in Formula I 1 , R 2 , R 3 and a correspond to the same; Ar in formula IV corresponds to Ar in formula III.

[0034] As a preferred embodiment, the triazene oxide is selected from the following compounds:

[0035]

[0036] The third aspect of the present invention is to provide an application of the preparation method described in the first aspect of the present invention in the preparation of triazene oxygen bond-containing compounds.

[0037] In the preparation method of the triazene oxide of the present invention, formula I, formula II and formula III are used as raw materials, and react in a solvent at room temperature to generate the triazene oxide corresponding to formula IV. The specific reaction process is shown in the following example:

[0038]

[0039] The present invention proposes a new amination coupling strategy. The synthesis strategy of the present invention is to use an anomeric amide as a linking reagent to connect the nitrogen end of the secondary fatty amine and the nitroso aromatic hydrocarbon with NN=N + (O - ) fragments are efficiently cross-linked, thereby efficiently preparing novel and diverse triazene oxides through a one-pot reaction, avoiding the use of toxic high-valent metal oxidants in traditional methods.

[0040] The endpoints and any values ​​of the scope disclosed in the present invention are not limited to the precise scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, the endpoint values ​​of each scope, the endpoint values ​​of each scope and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this article. Hereinafter, in principle, each technical solution can be combined with each other to obtain a new technical solution, which should also be regarded as specifically disclosed in this article.

[0041] Compared with the prior art, the present invention has at least the following advantages:

[0042] The reaction of the present invention uses a cheap and readily available isomeric amide reagent (compound shown in formula II), with a widely available secondary amine (compound shown in formula I) and a nitroso aromatic hydrocarbon (compound shown in formula III) as reaction substrates, and prepares a novel and diverse triazene oxide in one pot under mild conditions. The reaction has a wide range of applications and is compatible with a series of secondary fatty amine compounds, especially complex drug molecular structures. The reaction is compatible with a variety of active groups, and can achieve diversified modification of the nitrogen end of a variety of drug molecules such as vortioxetine, amoxapine, paroxetine, ciprofloxacin, ceritinib, and palbociclib.

[0043] The isomeric amide reagent of the present invention is an easily accessible amine source. Compared with the traditional synthesis method of triazene oxide, the invention can achieve the construction of nitrogen-nitrogen-nitrogen fragments in one pot through a one-step reaction, avoiding the use of equivalent amounts of harmful oxidizing reagents such as lead tetraacetate and mercuric oxide in conventional methods. In addition, the reaction provides a model for the amination coupling between two types of nucleophilic reagents.

[0044] In summary, the present invention discloses for the first time the preparation of triazene oxides by a three-component coupling reaction of amines, isomeric amides and nitrosoarene. The reaction conditions of the present invention are mild and simple, the raw materials are convenient and easy to obtain, and triazene oxide molecules with diverse structures can be synthesized in one pot in one step. Compared with existing synthesis technologies, this method has the characteristics of low cost, stronger step economy, and green environmental protection. DETAILED DESCRIPTION

[0045] The present invention is described in detail below in conjunction with specific embodiments. It is necessary to point out that the following embodiments are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made to the present invention by those skilled in the art based on the contents of the present invention still fall within the scope of protection of the present invention.

[0046] The raw materials used in the examples and comparative examples, unless otherwise specified, are disclosed in the prior art, for example, they can be directly purchased or prepared according to the preparation methods disclosed in the prior art.

[0047] A method for synthesizing a triazene oxide, i.e., a compound of formula IV, has the following general reaction formula:

[0048]

[0049] The method comprises the following steps: amine (Formula I), nitrosoaromatic hydrocarbon (Formula III), and base additive are sequentially added to tetrahydrofuran (THF) solvent under air atmosphere, an isomeric amide reagent (Formula II) is added at one time under stirring, and stirring is performed at room temperature for 5 hours. It should be noted that the molar ratio of Formula I, Formula II, Formula III and base additive is 1:1.2:1.5:2.0, and the concentration of amine (Formula I) in the mixed system is 0.05 mol / L. After the reaction is completed, the THF solvent is dried and silica gel column chromatography is performed to obtain a product of Formula IV.

[0050] The amine I structural formula is: Further preferably, the formula I is selected from any one of the following compounds:

[0051]

[0052] The structural formula of the isomeric amide (Formula II) is: Further preferably, the formula II is selected from any one of the following compounds:

[0053]

[0054] The nitrosoarene (Formula III) has the structural formula: Ar described in formula III is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0055] Preferably, the formula III is any one of the following substances:

[0056]

[0058] Examples 1-16

[0059]

[0060] Example 1 adopts the reaction conditions in the above reaction equation, that is, compound A 1 Compound N 1 , compound NO 1 and DABCO in tetrahydrofuran solvent, and reacted at room temperature for 5 hours to obtain the target compound 1 and possible by-product BP. 1 Compound N 1 , compound NO 1 The molar ratio of compound A to DABCO is 1:1.2:1.5:2.0. 1 The molar concentration is 0.05M.

[0061] The reaction conditions used in Examples 2-16 are basically the same as those in Example 1, and the differences and the corresponding reaction results of each example are shown in the following table.

[0062]

[0063]

[0064] Wherein %(a) refers to the crude NMR yield measured by the internal standard method, the internal standard used is 1,1,2,2-tetrachloroethane, and %(b) refers to the column chromatography separation yield.

[0065] Examples 1-16 mainly investigate the effect of changing conditions on the reaction yield. As can be seen from the above table, tetrahydrofuran (THF) is the best reaction solvent, and other polar protic solvents are not conducive to the production of target compound 1 and may cause A 1 decomposition. In addition, the reaction has good compatibility with water. The reaction is more conducive to the formation of by-product BP under high concentration or even solvent-free conditions. Alkaline additives can promote the reaction to a certain extent, but alkali is not a necessary factor for the reaction to occur.

[0066] Examples 17-21

[0067] In Example 1, N 1 Replace with other types of isomeric amide reagents (N 2 ~N 6 ), and the following reaction results were obtained.

[0068]

[0069] Investigation of the acyl substituents at the nitrogen terminal of the isomeric amide revealed that the reactivity decreased after replacing the acetyl group with a substituted or unsubstituted phenyl group (N 2 With N 3 、N 4 For the ester group at the nitrogen end, OPiv is a better leaving group (N 3 With N 5 Comparison), the sulfinate substituent corresponds to N 6 No reactivity; modification of the nitrogen-terminal alkoxy group showed that the simpler ethoxy group (N 2 ) is not as effective as the benzyloxy (N 1 ). Taking all factors into consideration, isomeric amide N 1 Give the best response effect.

[0070] Embodiment 22

[0071] The preparation methods of other triazene oxides, the specific contents and the characterization data of the corresponding compounds are as follows:

[0072]

[0073] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (71.9 mg) could be synthesized with a yield of 85%. 1 HNMR (400MHz, CDCl 3 )δ8.04(d,J=6.2Hz,2H),7.51–7.40(m,3H),7.30(t,J=7.9Hz,2H),6.98(d, J=8.1Hz,2H),6.91(t,J=7.3Hz,1H),3.85–3.75(m,4H),3.45–3.34(m,4H). 13 CNMR (101MHz, CDCl 3 )δ151.0,145.7,130.6,129.3,128.9,121.3,120.4,116.5,50.9,48.7.HRMS(ESI)m / zCalcd for C 16 H 19 N 4 O + [M+H] + :283.1553,found:283.1552.

[0074]

[0075] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (74.3 mg) could be synthesized with a yield of 81%. 1 HNMR (400MHz, CDCl 3 )δ8.03–7.96(m,2H),7.49–7.38(m,3H),3.65–3.58(m,4H),3.57–3.51(m,4H),1.46(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ154.7,145.5,130.7,128.8,121.2,80.2,50.7,28.5,27.2.HRMS(ESI)m / z Calcd for C 15 H 22 N 4 NaO 3 + [M+Na] + :329.1584,found:329.1582.

[0076]

[0077] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (53.8 mg) could be synthesized with a yield of 69%. 1 HNMR (400MHz, CDCl 3 )δ8.03–7.95(m,2H),7.51–7.39(m,3H),4.59–4.50(m,1H),4.21–4.06(m,2H),3.90–3.79(m,1H),3.14(td,J=12.9,3.7 Hz,1H),2.88(td,J=12.3,3.6Hz,1H),2.57(t,J=11.4Hz,1H),2.45–2.37(m,2H),2.28–2.16(m,1H),1.69–1.56(m,1H). 13 C NMR (101 MHz, CDCl 3 )δ173.4,145.4,130.8,128.9,121.1,56.6,54.6,50.4,38.7,30.1,22.2.HRMS(ESI)m / zCalcd for C 13 H 16 N 4 NaO 2 + [M+H] + :283.1166,found:283.1165.

[0078]

[0079] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (41.6 mg) could be synthesized with a yield of 59%. 1 HNMR (400MHz, CDCl 3 )δ8.05–7.93(m,2H),7.50–7.35(m,3H),4.17(d,J=12.3Hz,2H),3.96–3.83(m,2H),2.64(t,J=11.3Hz,2H),1.22(s,3H),1.21(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ145.6,130.5,128.8,121.1,71.0,56.5,19.0.HRMS(ESI)m / z Calcd for C 12 H 18 N 3 O 2 + [M+H] + :236.1394,found:236.1395.

[0080] The target product (53.5 mg) was synthesized with a yield of 80%. 1 H NMR (400 MHz, CDCl 3 )δ8.05–7.96(m,2H),7.51–7.39(m,3H),3.97–3.84(m,4H),2.86–2.73(m,4H). 13 C NMR (101 MHz, CDCl 3 )δ145.6,130.6,128.9,121.1,53.3,26.8.HRMS(ESI)m / z Calcd for C 10 H 14 N 3 OS + [M+H] + :224.0852,found:224.0854.

[0081]

[0082] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (60.0 mg) could be synthesized with a yield of 76%. 1 HNMR (400MHz, CDCl 3)δ8.03–7.95(m,2H),7.48–7.37(m,3H),3.97(s,4H),3.73(t,J=5.8Hz,4H),1.87(t,J=5.8Hz,4H). 13 C NMR (101 MHz, CDCl 3 )δ145.7,130.4,128.8,121.1,106.8,64.5,49.0,34.3.HRMS(ESI)m / z Calcd for C 13 H 18 N 3 O 3 + [M+H] + :264.1343,found:264.1348.

[0083]

[0084] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (52.6 mg) could be synthesized with a yield of 59%. 1 HNMR (400MHz, CDCl 3 )δ8.08–7.99(m,2H),7.54–7.49(m,2H),7.47–7.41(m,3H),7.40–7.34(m,2H),7.31–7.27(m,1H), 4.29–4.20(m,2H),3.45(td,J=12.5,2.5Hz,2H),2.36(td,J=13.5,4.4Hz,2H),1.91–1.82(m,3H). 13 C NMR (101 MHz, CDCl 3 )δ147.8,145.7,130.4,128.8,128.6,127.4,124.6,121.2,71.3,47.2,37.7.HRMS(ESI)m / z Calcd for C 17 H 19 N 3 NaO 2 + [M+Na] + :320.1370,found:320.1370.

[0085] The raw materials and conditions were the same as in Example 1, and the target product (29.8 mg) was synthesized in a yield of 52%. 1 H NMR (400 MHz, CDCl 3)δ8.07–7.96(m,2H),7.46–7.37(m,3H),3.78–3.67(m,4H),2.00–1.87(m,4H). 13 CNMR (101MHz, CDCl 3 )δ145.1,129.7,128.7,120.7,53.3,24.1.HRMS(ESI)m / z Calcd forC 10 H 14 N 3 O + [M+H] + :192.1131,found:192.1133.

[0086]

[0087] The reaction materials and conditions were the same as those in Example 1, and the target product (38.1 mg) was synthesized with a yield of 62%. 1 H NMR (400 MHz, CDCl 3 )δ8.07–7.95(m,2H),7.50–7.34(m,3H),3.68–3.52(m,4H),1.76(p,J=5.8Hz,4H),1.69–1.57(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ144.8,129.0,127.6,120.0,51.1,24.2,23.5.HRMS(ESI)m / z Calcd for C 11 H 16 N 3 O + [M+H] + :206.1288,found:206.1289.

[0088]

[0089] Same as Example 1, with A 14 and NO 1 As a substrate, the target product (35.4 mg) can be synthesized with a yield of 54%. 1 H NMR (400 MHz, CDCl 3 )δ8.03–7.95(m,2H),7.47–7.38(m,3H),3.92–3.83(m,4H),1.81–1.70(m,4H),1.65–1.57(m,4H). 13 C NMR (101 MHz, CDCl 3)δ145.5,129.3,128.6,120.6,55.4,28.6,26.6.HRMS(ESI)m / z Calcd for C 12 H 18 N 3 O + [M+H] + :220.1444,found:220.1446.

[0090] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (25.2 mg) was synthesized with a yield of 36%. 1 H NMR (400 MHz, CDCl 3 )δ8.06–7.93(m,2H),7.52–7.34(m,3H),3.94–3.80(m,4H),1.88–1.74(m,4H),1.71–1.56(m,6H). 13 C NMR (101 MHz, CDCl 3 )δ145.5,129.0,128.6,120.3,56.0,27.9,26.6,25.5.HRMS(ESI)m / z Calcd for C 13 H 20 N 3 O + [M+H] + :234.1600,found:234.1601.

[0091] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (68.6 mg) could be synthesized with a yield of 72%. 1 H NMR (400 MHz, CDCl 3 )δ8.19(dd,J=4.8,1.7Hz,1H),8.02(dd,J=8.1,1.9Hz,2H),7.60(dd,J=7.8,1.7Hz,1H) ,7.49–7.38(m,3H),6.86(dd,J=7.8,4.7Hz,1H),3.85–3.74(m,4H),3.59–3.52(m,4H). 13 C NMR (101 MHz, CDCl 3 )δ158.0,145.9,138.9,130.4,128.8,122.7,121.1,118.3,50.9,48.2.HRMS(ESI)m / z Calcd for C 15 H 17C1N 5 O + [M+H] + :318.1116,found:318.1118.

[0092] The substrate, other raw materials and reaction conditions were the same as those in Example 1, and the target product (92.5 mg) could be synthesized with a yield of 91%. 1 H NMR (400 MHz, CDCl 3 )δ8.04(dd,J=7.8,2.0Hz,2H),7.92(d,J=8.2Hz,1H),7.82(d,J=8.1Hz,1H),7 .53–7.41(m,4H),7.38(t,J=7.6Hz,1H),3.92–3.83(m,4H),3.79–3.70(m,4H). 13 CNMR (101MHz, CDCl 3 )δ152.9,145.6,130.6,128.9,128.0,127.8,124.2,123.8,121.2,120.7,50.7,49.3.HRMS(ESI)m / z Calcd for C 17 H 18 N 5 OS + [M+H] + :340.1227,found:340.1227.

[0093] and NO 1 As substrate, the other reaction materials and conditions were the same as those in Example 1, and the target product (62.4 mg) could be synthesized with a yield of 57%. 1 H NMR (400 MHz, CDCl 3 )δ8.07–7.98(m,2H),7.51–7.39(m,3H),7.15(d,J=8.5Hz,2H),6.92(d,J=9.0Hz,2H),4.56 –4.46(m,1H),3.88–3.76(m,2H),3.69–3.56(m,2H),2.21–2.08(m,2H),2.06–1.93(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ155.7,145.6,142.9,130.4,128.7,122.6,121.1,116.8,72.0,47.5,29.7. 19 F NMR (376 MHz, CDCl3 )δ-58.4.HRMS(ESI)m / z Calcd forC 18 H 18 F 3 N 3 NaO 2 + [M+Na] + :388.1243,found:388.1246.

[0094] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (37.4 mg) was synthesized with a yield of 54%. 1 H NMR (400 MHz, CDCl 3 )δ8.04–7.96(m,2H),7.47–7.37(m,3H),3.80(dd,J=10.6,7.8Hz,2H),3.45(dd ,J=10.6,3.9Hz,2H),2.76–2.65(m,2H),1.89–1.70(m,3H),1.64–1.50(m,3H). 13 C NMR (101 MHz, CDCl 3 )δ145.4,129.9,128.8,120.9,58.9,40.7,32.9,25.9.HRMS(ESI)m / z Calcd forC 13 H 18 N 3 O + [M+H] + :232.1444,found:232.1446.

[0095]

[0096] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (40.5 mg) could be synthesized with a yield of 58%. 1 HNMR (400MHz, CDCl 3 )δ8.07–7.92(m,2H),7.51–7.35(m,3H),3.30(s,3H),3.22–3.09(m,1H),2.11–1.97 (m,2H),1.92–1.80(m,2H),1.74–1.65(m,1H),1.64–1.51(m,2H),1.42–1.16(m,3H). 13 C NMR (101 MHz, CDCl 3)δ145.8,129.6,128.6,120.7,66.1,36.9,30.6,29.7,25.9,25.8.HRMS(ESI)m / z Calcd for C 13 H 20 N 3 NO + [M+H] + :234.1601,found:234.1602.

[0097]

[0098] The remaining reaction materials and conditions were the same as those in Example 1, and the target product (45.1 mg) was synthesized with a yield of 68%. 1 H NMR (400 MHz, CDCl 3 )δ8.02–7.94(m,2H),7.44–7.34(m,3H),3.57(t,J=7.6Hz,4H),1.63(h,J=7.4Hz,4H),0.93(t,J=7.4Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ145.7,129.6,128.7,120.7,56.9,22.0,11.5.HRMS(ESI)m / z Calcd for C 12 H 20 N 3 O + [M+H] + :222.1601,found:222.1609.

[0099] The target product (112.9 mg) was synthesized with a yield of 1.1447 W / v. 1 H NMR (400 MHz, CDCl 3 )δ8.12–8.02(m,2H),7.54–7.43(m,3H),7.40(d,J=7.8Hz,1H),7.16(s,1H),7.10(d,J=4.2Hz,2H),7.05(dd,J=7.8,2.0H z,1H),6.94–6.86(m,1H),6.56(d,J=7.9Hz,1H),3.85(t,J=4.7Hz,4H),3.29(t,J=4.9Hz,4H),2.37(s,3H),2.34(s,3H). 13 C NMR (101 MHz, CDCl 3)δ148.8,145.8,142.4,139.3,136.3,136.2,134.7,131.9,131.7,130.4,128.9,128.8,127.9,127.9,126.5,125.8,125.7,124.7,121.2,120.0,51.5,50.9,21.4,21.2,20.8,20.6.HRMS(ESI)m / z Calcd forC 24 H 27 N 4 OS + [M+H] + :419.1900,found:419.1898.

[0100]

[0101] 1 H NMR(400MHz,CDCl 3 )δ7.81–7.74(m,2H),7.38–7.27(m,3H),7.23–7.15(m,1H),6.33(dd,J=9.1,1.4Hz,1H),6.04(dd,J=6.9,1.4Hz,1H),4.59(dt,J=12.0,2.5Hz,1H),4.36–4.23(m,2H),3.99–3.89(m,1H),3.18–3.05(m,3H),2.61–2.53(m,1H),1.96(t,J=3.2Hz,2H). 13 CNMR(101MHz,CDCl 3 )δ163.7,149.4,145.4,138.9,130.4,128.7,120.9,117.4,105.5,57.5,56.6,49.3,35.3,28.1,26.4.HRMS(ESI)m / z Calcd for C 17 H 18 N 4 NaO 2 + [M+Na] + :333.1322,found:333.1325.

[0102] (m,3H),7.42–7.38(m,1H),7.35(d,J=2.6Hz,1H),7.23–7.16(m,2H),7.14–7.08(m,2H),7.01(td,J=7.6,1.7Hz,1H),3.74(s,8H). 13 C NMR(101MHz,CDCl 3 )δ159.5,158.8,151.9,145.6,140.0,132.8,130.7,130.5,129.0,128.9,127.2,125.9,124.9,124.9,122.9,121.2,120.2,50.6.HRMS(ESI)m / z Calcd for C 23 H 21 ClN 5 O 2 + [M+H] + :434.1378,found:434.1384.

[0103] 2H),7.52–7.41(m,3H),7.21–7.13(m,2H),6.99(t,J=8.7Hz,2H),6.63(d,J=8.5Hz,1H),6.38(d,J=2.5Hz,1H),6.16(dd,J=8.5,2.5Hz,1H),5.88(s,2H),4.60–4.49(m,2H),3.65(dd,J=9.5,2.8Hz,1H),3.52(dd,J=9.5,6.0Hz,1H),3.11–2.93(m,2H),2.82(td,J=11.9,4.1Hz,1H),2.46–2.32(m,1H),2.14–2.01(m,1H),1.98–1.89(m,1H). 13 C NMR(101MHz,CDCl 3 )δ162.9,160.4,154.3,148.2,145.6,141.7,138.9,138.9,130.4,128.9,128.8,128.8,121.1,121.1,115.7,115.5,108.1,107.9,106.7,105.7,101.1,101.1,98.4,98.1,68.9,54.7,51.2,43.9,41.5,33.0. 19 F NMR(376MHz,CDCl 3) δ-116.0. HRMS(ESI) m / z Calcd for C 25 H 25 FN 3 O 4 + [M + H] + : 450.1824, found: 450.1824.

[0104] Substance (62.7 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 8.06–7.95 (m, 2H), 7.41 (d, J = 8.9 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 3.87–3.74 (m, 4H), 3.44–3.31 (m, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ 151.0, 144.0, 136.6, 129.4, 129.0, 122.5, 120.5, 116.5, 51.0, 48.7. HRMS(ESI) m / z Calcd for C 16 H 18 ClN 4 O + [M + H] + : 317.1164, found: 317.1165.

[0105] Product (48.0 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 7.54–7.23 (m, 4H), 4.23–4.07 (m, 2H), 3.86–3.70 (m, 3H), 3.15–3.00 (m, 2H), 2.84–2.71 (m, 2H), 2.67–2.54 (m, 1H), 2.17–1.96 (m, 4H), 1.40–1.22 (m, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 174.8, 145.9, 137.6, 129.9, 126.5, 124.2, 124.2, 51.8, 49.9, 49.9, 40.8, 27.1, 27.1, 24.5, 15.0. HRMS(ESI) m / z Calcd for C 15 H 21 N3 NaO 3 + [M+Na] + :314.1475,found:314.1466.

[0106] A 23 and NO 4 As substrate, the other reaction materials and conditions were the same as those in Example 1, and the target product (72.3 mg) could be synthesized with a yield of 56%. 1 H NMR (400 MHz, CDCl 3 )δ7.50–7.42(m,1H),7.36–7.21(m,4H),7.21–7.04(m,4H),6.84(s,1H),6.76–6 .68(m,2H),5.92(s,2H),4.11(s,2H),3.56–3.28(m,6H),2.53(t,J=5.0Hz,4H). 13 C NMR (101 MHz, CDCl 3 )δ147.8,146.8,146.1,139.5,134.6,131.7,131.5,129.9,129.1,128.5,127.2,12 6.4,124.4,122.3,109.5,108.0,101.0,62.5,51.9,50.6,37.0.HRMS(ESI)m / zCalcd for C 25 H 21 N 4 O 3 + [M+H] + :431.2078,found:431.2080.

[0107] The target product (72.9 mg) was synthesized with a yield of 61%. 1 H NMR (400 MHz, CDCl 3 )δ8.62(t,J=1.9Hz,1H),8.23–8.17(m,1H),8.10(dt,J=7.8,1.4Hz,1H),7.50(t,J=8.0Hz,1H),6.86(s,1H) ,6.74(d,J=1.0Hz,2H),5.93(s,2H),3.94(s,3H),3.68(t,J=5.0Hz,4H),3.44(s,2H),2.61(t,J=5.1Hz,4H). 13 C NMR (101 MHz, CDCl 3)δ166.0,147.8,146.8,145.8,131.8,131.2,131.1,129.0,125.2,122.3,122.2,109.5,108.0,101.0,62.5,52.5,52.2,51.1.HRMS(ESI)m / zCalcd for C 20 H 23 N 4 O 5 + [M+H] + :399.1663,found:399.1671.

[0108] The target product (102.9 mg) was synthesized in 71% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.06(d,J=8.5Hz,2H),7.60(dd,J=14.9,8.0Hz,4H),7.45(t,J=7.5Hz,2H),7.32–7.23 (m,4H),7.20(t,J=7.3Hz,1H),4.26(s,1H),3.65(t,J=4.9Hz,4H),2.58(t,J=5.0Hz,4H). 13 C NMR (101 MHz, CDCl 3 )δ144.7,143.4,141.9,141.1,139.8,132.9,129.2,129.0,128.9,128.8,128.1,127.9,127.5,127.4,127.3,121.6,75.4,51.1.HRMS (ESI) m / z Calcd for C 29 H 28 C1N 4 O + [M+H] + :483.1946,found:483.1943.

[0109] The target product (80.3 mg) was synthesized with a yield of 58%. 1 H NMR (400 MHz, CDCl 3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 4.67–4.39 (m, 3H), 4.03–3.84 (m, 1H), 3.77–3.58 (m, 1H), 3.55–3.28 (m, 4H), 2.86 (t, J = 7.0 Hz, 2H), 2.06–1.98 (m, 1H), 1.96–1.85 (m, 1H), 1.44 (s, 9H), 1.43 (s, 9H). 13 C NMR(101 MHz, CDCl 3 ) δ 155.8, 154.0, 141.6, 129.1, 120.9, 80.0, 79.4, 62.5, 61.8, 57.1, 56.0, 51.4, 50.9, 41.6, 35.9, 35.3, 28.4. HRMS(ESI) m / z Calcd for C 23 H 35 N 5 NaO 5 + [M + Na] + : 484.2530, found: 484.2537.

[0110] Product (50.4 mg). 1 H NMR(400 MHz, CDCl 3 ) δ 7.56 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 8.8, 2.6 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.75 (s, 2H), 4.27 (s, 4H), 3.59 (t, J = 5.8 Hz, 4H), 2.38 (t, J = 5.8 Hz, 4H). 13 C NMR(101 MHz, CDCl 3 ) δ 145.5, 145.1, 143.2, 139.6, 117.0, 114.5, 110.8, 109.0, 64.6, 64.4, 52.5, 33.8. HRMS(ESI) m / z Calcd for C 14 H 17 N 3 NaO 3 + [M + Na] + : 298.1162, found: 298.1169.

[0111] 2H),7.20(t,J=6.8Hz,4H),7.16–7.05(m,5H),4.12–3.98(m,3H),3.55(s,4H),2.93–2.78(m,2H),2.51(t,J=5.1Hz,4H),2.37(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ145.7,139.7,138.9,138.6,132.0,130.9,130.8,127.9,125.6,118.9,78.9,51.1,51.0,31.8,21.3.HRMS(ESI)m / z Calcd for C 27 H 30 N 4 NaO + [M+Na] + :449.2312,found:449.2307.

[0112] The target product (109.2 mg) could be synthesized in 83% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.24(d,J=2.7Hz,1H),8.17(dd,J=9.1,2.7Hz,1H),7.01(d,J=9.1Hz,1H),6.86(s,1H),6.77–6 .72(m,2H),5.93(s,2H),3.94(s,3H),3.63(t,J=4.8Hz,4H),3.45(s,2H),2.62(t,J=5.0Hz,4H). 13 C NMR (101 MHz, CDCl 3 )δ158.8,147.8,138.2,131.7,125.9,124.3,122.3,121.6,120.6,120.6,120 .5,120.5,119.0,118.7,111.8,109.5,108.0,101.0,62.6,56.5,52.1,51.0. 19 F NMR (376 MHz, CDCl 3 )δ-62.8.HRMS(ESI)m / z Calcd for C 20 H 22 F 3 N 4 O 4 + [M+H] +:439.1588,found:439.1586.

[0113] Petroleum ether: ethyl acetate = 3:1, v / v), according to the synthesis steps of the method described in Example 11, 0.3 mmol scale was added, with A 29 and NO 13 As substrate, the other reaction materials and conditions were the same as those in Example 1, and the target product (148.3 mg) could be synthesized with a yield of 56%. 1 H NMR (400 MHz, CDCl 3 )δ9.51(s,1H),8.58(d,J=8.4Hz,1H),8.16(s,1H),8.08–7.99(m,3H),7.93(dd,J=7.9,1.6Hz,1H),7.67–7.58(m,1H ),7.57(s,1H),7.33–7.24(m,3H),7.16(d,J=7.9Hz,2H),7.08(d,J=9.0Hz,2H),6.79(s,1H),4.54(p,J=6.1Hz,1H),4 .43(d,J=12.0Hz,2H),3.96(q,J=7.1Hz,1H),3.27(p,J=6.9Hz,1H),3.01–2.87(m,3H),2.48(d,J=7.2Hz,2H),2.19( s,3H),2.05–1.82(m,5H),1.62(d,J=7.1Hz,3H),1.36(d,J=6.1Hz,6H),1.32(d,J=6.9Hz,6H),0.91(d,J=6.6Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ172.9,157.6,155.4,152.4,144.8,143.0,141.1,138.6,137.0,136.9,134.7,131.4,129.7,127.8,127.3,126.9,125.0,123.8,1 23.2,122.3,121.8,120.8,110.8,105.9,71.6,55.6,51.9,45.4,45.1,38.3,32.1,30.3,22.5,22.3,19.1,18.6,15.5.HRMS(ESI)m / z Calcd forC 47 H 57 C1N 7 O 6 S + [M+H] +:882.3774,found:882.3772.

[0114] To obtain the target product (162.0 mg). 1 H NMR (400 MHz, CDCl 3 )δ8.16–8.03(m,4H),7.38(d,J=8.5Hz,1H),7.32(s,1H),7.24(s,2H),7.20 –7.11(m,2H),7.03–6.95(m,1H),5.55(d,J=4.4Hz,1H),4.63(d,J=7.9Hz,1 H),4.58–4.49(m,1H),4.48–4.40(m,1H),4.37–4.26(m,2H),4.21–4.13(m, 1H),3.94–3.58(m,8H),1.49(s,3H),1.46(s,3H),1.33(s,3H),1.31(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ165.3,159.4,158.6,151.8,148.4,139.9,132.8,131.8,130.4,130.4,128.9,127.2,125.9,124.9,124.8,12 2.9,121.1,120.2,109.8,108.8,96.3,71.1,70.8,70.5,66.1,64.4,50.8,26.0,26.0,25.0,24.5.HRMS(ESI)m / z Calcd for C 36 H 39 C1N 5 O 9 + [M+H] + :720.2431,found:720.2434.

[0115] The target product (117.4 mg) could be synthesized in 40% yield. 1 H NMR (400 MHz, CDCl 3)δ8.80(d,J=6.8Hz,2H),8.26–8.13(m,4H),8.11–7.97(m,4H),7.85(d,J=8.5Hz,1H),7.62(s,1H),7.57(d,J=8.5Hz,1H),7.39(d,J=8.7Hz,3H),7.02(d,J=8.6Hz,1H),5.95–5.82(m,1H),5.37–5.28(m,1H),3.92(s,3H),3.88–3.78(m,4H),3.46–3.34(m,4H),2.55(s,3H),2.38(s,4H),2.19(s,6H),2.15–2.00(m,6H),1.95–1.85(m,2H),1.81(s,6H),1.75–1.67(m,2H). 13 C NMR(101MHz,CDCl 3 )δ165.2,152.7,142.2,139.1,136.2,132.1,129.9,128.7,126.9,126.0,125.8,125.7,124.8,122.5,122.3,77.5,77.2,76.8,55.2,50.7,50.1,49.9,49.7,49.4,49.2,49.0,48.8,40.7,37.2,31.6,29.7,29.2,28.2,25.8.HRMS(ESI)m / z Calcd forC 58 H 60 N 9 O 6 + [M+H] + :978.4661,found:978.4659.

[0116] MHz,CDCl 3 )δ8.74(s,1H),8.04–7.90(m,3H),7.46(d,J=8.7Hz,2H),7.40(d,J=7.0Hz,1H),3.86–3.73(m,4H),3.61–3.48(m,5H),1.45–1.38(m,2H),1.34(s,9H),1.24–1.18(m,2H). 13 C NMR(101MHz,CDCl 3)δ177.2,167.0,155.0,154.5,152.5,147.6,145.7,145.5,143.2,139.2,125.9,120.9,1 20.3,120.2,112.7,112.5,108.3,105.2,105.2,50.5,49.1,49.0,35.5,35.0,31.3,8.4. 19 F NMR (376 MHz, CDCl 3 )δ-120.8.HRMS(ESI)m / z Calcd forC 27 H 31 FN 5 O 4 + [M+H] + :508.2355,found:508.2370.

[0117] The triazene oxide synthesized by the present invention has important uses in the fields of bioactive molecules, metal ion detection, and liquid crystal materials. For example, the triazene oxide synthesized by the present invention and the corresponding method have the following application values:

[0118] (1) It greatly expands the chemical space of this type of molecules and makes up for the reliance of traditional synthetic strategies on toxic chemical oxidizing agents;

[0119] (2) Rapid assembly and modification of complex drug molecules. Newly synthesized molecules may serve as potential pharmacophores or skeletons;

[0120] (3) The novel amination coupling strategy was demonstrated to be highly effective in constructing molecules containing nitrogen-nitrogen bonds, and is expected to be applied to amination coupling between a broad spectrum of nucleophiles, thereby providing a more efficient and mild method for the synthesis of complex nitrogen-containing skeletons.

[0121] The present invention is described in detail above with reference to specific examples, but these descriptions cannot be understood as limiting the present invention. Those skilled in the art understand that, without departing from the spirit and scope of the present invention, various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its implementation methods, all of which fall within the scope of the present invention. The protection scope of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing triazene oxide, characterized in that: The method comprises the following steps: using amine substances, isomeric amide reagents and nitroso aromatic substances as raw materials, reacting in an optional solvent under the action of an optional base additive to generate triazene oxide.

2. The method for preparing triazene oxide according to claim 1, characterized in that: The amine substance is selected from at least one of the compounds of the general structural formula shown in Formula I: Among them, when the R 1 and R 2 When not connected to form a ring, the R 1 and R 2 are the same or different and are independently selected from substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; when the R 1 and R 2 When connected into a ring, the R 3 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ester, hydroxyl, substituted or unsubstituted ether; a is any integer from 0 to 3; The isomeric amide reagent is selected from at least one of the compounds of the general structural formula shown in Formula II: The R 4 is selected from alkyl, substituted or unsubstituted aryl; R 5 is selected from substituted or unsubstituted acyloxy; R 6 is selected from substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy; The nitroso aromatic hydrocarbon substance is selected from at least one of the compounds of the general structural formula shown in Formula III: Ar in the structure of formula III is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; The triazene oxide is selected from at least one of the compounds of the general structural formula shown in Formula IV: R in Formula IV 1 , R 2 , R 3 and a and R in Formula I 1 , R 2 , R 3 and a correspond to the same; Ar in formula IV corresponds to Ar in formula III.

3. The method for preparing triazene oxide according to claim 2, characterized in that: In the formula I, when the R 1 and R 2 When not connected to form a ring, the R 1 and R 2 The same or different, each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C5-C8 cycloalkyl; When the R 1 and R 2 When not connected into a ring, Selected from the following groups: Among them, the R 3 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted ester, hydroxyl, substituted or unsubstituted ether; a is any integer between 0 and 2.

4. The method for preparing triazene oxide according to claim 3, characterized in that: The formula I is selected from at least one of the following compounds:

5. The method for preparing triazene oxide according to claim 2, characterized in that: R described in Formula II 4 is selected from C1-C3 alkyl, substituted or unsubstituted phenyl; preferably, the R 4 Any one of the following groups: and / or, R described in Formula II 5 is selected from C1-C6 acyloxy; preferably, the R 5 Any one of the following groups: R described in Formula II 6 is selected from C1-C3 alkoxy or phenoxy; preferably, the R 6 Any one of the following groups: Further preferably, the formula II is selected from at least one of the following compounds:

6. The method for preparing triazene oxide according to claim 2, characterized in that: Ar described in formula III is selected from The R 7 It is selected from halogen, substituted or unsubstituted ester, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl, substituted or unsubstituted alkyl and alkoxy.

7. The method for preparing triazene oxide according to claim 6, characterized in that: The formula III is selected from at least one of the following compounds:

8. The method for preparing triazene oxide according to claim 1, characterized in that: The molar ratio of the amine substance, the isomeric amide reagent and the nitroso aromatic hydrocarbon substance is 1:(1.2-1.5):(1.5-2.0); and / or, The molar ratio of the amine substance to the alkaline additive is 1:(0-2.0); and / or, The concentration of the amine substance in the solvent is 0.05-1.0 mol / L; and / or, The reaction temperature is room temperature; and / or, The reaction time is 5 to 8 hours; and / or, The solvent is selected from at least one of an organic solvent, water and a mixed solvent of an organic solvent; preferably, the organic solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane or diethyl ether; and / or, The base additive is selected from organic amine additives; preferably, the base additive is selected from any one of the following compounds:

9. The triazene oxide prepared by the preparation method according to any one of claims 1 to 8, characterized in that: The triazene oxide is selected from at least one of the compounds of the general structural formula shown in Formula IV: R in Formula IV 1 , R 2 , R 3 and a and R in Formula I 1 , R 2 , R 3 and a correspond to the same; Ar in formula IV corresponds to Ar in formula III.

10. The triazene oxide according to claim 9, characterized in that: The triazene oxide is selected from the following compounds:

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