CN114478576A - Synthetic method of spiroheterocyclic compound - Google Patents

Abstract

The invention provides a synthesis method of a spiro-heterocyclic compound, which is used for solving the technical problems of complex substrate synthesis, limited functional group, inadequately mild reaction conditions, difficult industrialization in the later period and other practical defects in the synthesis of the existing spiro-heterocyclic compound, and comprises the following specific steps: adding a 3-aryl benzoxazine compound, a diazo compound, a catalyst and an additive into a solvent, reacting under the protection of inert atmosphere, and purifying after the reaction is finished to obtain the spiroheterocyclic compound. The invention provides a simple and effective synthesis method for the construction of a complex spiro ring, and the method has the characteristics of mild reaction conditions, simple operation, atom economy, economic steps, strong functional group tolerance, good yield and the like; the obtained product has wide industrial application prospect, and provides a new idea and a new method for the fields of medicine, natural product synthesis, luminescent materials and the like.

Description

A kind of synthetic method of spiro heterocyclic compound

technical field

The invention belongs to the technical field of organic synthetic chemistry, in particular to a method for synthesizing a spiro heterocyclic compound.

Background technique

The C-H bond is the basic structural unit of organic compounds, which is widely found in petrochemicals, biomass, natural products, drugs and organic functional materials, etc. The development of simple, efficient and highly selective C-H bond functionalization has always been an effort of chemists. The fundamental reason for the important direction of research is: by reducing the synthesis steps of compounds, saving costs, improving the atom economy of synthetic transformation, and reducing the harm to the environment. Therefore, the use of C-H bond activation strategy to construct complex cyclic compounds becomes an ideal strategy. Efficient functionalization of C-H bonds is an important research content in organic synthetic chemistry, and it is also one of the most challenging frontier research areas. The significance of it was once hailed by scholars as the "Holy Grail of Chemistry" (Acta Chim. Sinica 2015, 73, 1223).

A spiro ring is a special ring system in which two rings share one carbon atom, and its skeleton often has strong rigidity and good stability. At the same time, it is not difficult to find that spiro skeletons are often seen in biologically active natural products and biologically active molecules, and such skeletons are usually the core skeletons of many drug molecules (Bioorg.Med.Chem.Lett. 1999, 9, 2921; Chem. Rev. 2007, 107, 1011; Nat. Chem. 2018, 9, 1). In addition, the spiro-ring skeleton has also been shown in the field of asymmetric catalysis (Acc.Chem.Res.2018, 41, 581) and optoelectronic materials (Chem. Rev., 2016, 116, 14675; Org. Electron., 2018, 61, 376) Excellent catalytic and optical properties. In view of this, the efficient synthesis of this type of framework has always been the focus of synthetic chemists. Scientists at home and abroad have realized the construction of a wide variety of spiro molecules by means of various synthetic methods, especially under the promotion of transition metal catalysts. , the synthesis of the spiro skeleton has stepped to a new level. Existing synthetic methods often require pre-functionalization of substrates (introduction of halogens and guiding groups, etc.), which increases the difficulty of substrate synthesis, and the later removal of guiding groups also limits the further development of this type of reaction. develop. At the same time, the substrates used by the existing synthetic methods generally require multi-step synthesis, which limits the diversity of the obtained scaffolds. In addition, for complex spiro rings containing multiple ring systems, it is generally necessary to construct ring-by-ring, and the steps are less economical. Therefore, exploring simple and efficient synthetic methods has always been the goal of synthetic chemists.

SUMMARY OF THE INVENTION

The existing method of synthesizing spiro compounds using spiro[4.5] skeleton has technical problems such as complex synthesis of substrates, limited functionalization, mild enough reaction conditions, and difficulty in industrialization in the later stage. The present invention proposes a spiro heterocyclic compound. The method for synthesizing cyclic compounds is to select simple and easily available 3-arylbenzoxazine compounds and diazo compounds as reactants. The tandem strategy of +3] completes the cleavage and reorganization of multiple chemical bonds in one-step chemical transformation, and prepares a spiro[5.5]heterocyclic skeleton containing a quaternary carbon center. Purpose.

In order to achieve the above object, the technical scheme of the present invention is achieved in this way:

A method for synthesizing a spiroheterocyclic compound, using 3-arylbenzoxazine compounds and diazo compounds as raw materials, under the promotion of a catalyst, a novel spiroheterocyclic compound is synthesized, and the reaction formula is as follows:

其中，R为H、Me、F、Cl、Br中的任意一种；R¹为Me、Pr、Ph中的任意一种；R²为Me、Et、ⁱPr中的任意一种；Ar为Me、OMe、F、Cl、Br、Ph、CF₃中任意一个取代的苯环。

Wherein, R is any one of H, Me, F, Cl, and Br; R ¹ is any one of Me, Pr, Ph; R ² is any one of Me, Et, ⁱ Pr; Ar is A benzene ring substituted by any one of Me, OMe, F, Cl, Br, Ph, CF ₃ .

The method for synthesizing a spiroheterocyclic compound comprises the following steps: adding a 3-arylbenzoxazine compound, a diazo compound, a catalyst and an additive to a solvent, performing the reaction under the protection of an inert atmosphere, and purifying after the reaction. A spiro heterocyclic compound is obtained.

The catalyst comprises a rhodium catalyst and a silver salt; the molar ratio of the rhodium catalyst and the silver salt is 1: (2-4); the rhodium catalyst is a dichloro(pentamethylcyclopentadienyl) rhodium dimer ( [Cp*RhCl ₂ ] ₂ ), rhodium pentamethylcyclopentadienyl acetate (Cp*Rh(OAc) ₂ ), or bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium ( Any one of Cp*Rh(CH ₃ CN) ₃ (SbF6) ₂ ); the silver salt is silver hexafluoroantimonate (AgSbF ₆ ), silver bistrifluoromethanesulfonimide (AgNTf ₂ ), tetrafluoroboric acid Any of silver (AgBF ₄ ), silver trifluoromethanesulfonate (AgOTf), silver sulfate (Ag ₂ SO ₄ ), silver acetate (AgOAc), and silver trifluoroacetate (AgTFA).

The catalyst is composed of dichloro(pentamethylcyclopentadienyl) rhodium dimer and silver hexafluoroantimonate, dichloro(pentamethylcyclopentadienyl) rhodium dimer and hexafluoroantimony The molar ratio of silver acid is 1:4.

The additive is any one of mestrimethylbenzoic acid, pivalic acid, acetic acid, benzoic acid, proline, adamantanecarboxylic acid, zinc acetate, sodium carbonate, potassium acetate and potassium carbonate.

The solvent is any one of dichloroethane, dichloromethane, methanol, acetonitrile, 1,4-dioxane and toluene.

The molar ratio of the 3-arylbenzoxazine compound:diazo compound:catalyst:additive is 1:2.2:0.02-0.04:0.08-0.16.

The concentration of the reaction system in the solvent is 0.05M-0.2M.

The inert atmosphere is a nitrogen atmosphere.

The reaction temperature is 30-90°C, and the reaction time is 0.5h-6h.

For the reaction mode of this reaction, the reaction principle is shown in FIG. 35 . First, the substrate 1a is co-catalyzed by rhodium and silver to obtain a five-membered rhodium heterointermediate A, and then the diazo reagent and the intermediate A are coordinated to obtain the rhodium carbene intermediate B, followed by the migration and insertion of the carbene to obtain the intermediate C, then the elimination of the metal occurs to obtain the intermediate compound D, and the compound D undergoes enol isomerization, wherein the enol-type hydroxyl group attacks the imine bond to obtain the intermediate E, and the intermediate E and the metal rhodium catalyst react again to obtain the intermediate Intermediate F, intermediate F also rapidly interconvert to enol intermediate G, intermediate G undergoes further nucleophilic attack to obtain intermediate H, and finally intermediate H undergoes a one-step addition-elimination reaction to give the final target compound 4aa .

Beneficial effects of the present invention: The present invention innovatively selects simple and easy-to-obtain oxazine compounds and diazonium compounds as reactants, and under the catalysis of rhodium cyclopentyl complexes, through the synthesis of [4+2] and [3+3] The tandem strategy realizes the construction of a novel spiro[5.5]heterocyclic skeleton containing a quaternary carbon center in one step, providing a simple and effective synthetic method for the construction of complex spiro rings, and this method has the advantages of mild reaction conditions, simple operation, atom economy, The steps are economical, functional group tolerance is strong, and yields are good. The obtained product has broad industrial application prospects, and provides a new idea and a new method for the fields of medicine, natural product synthesis and luminescent materials.

Description of drawings

Fig. 1 is the nuclear magnetic ¹ H spectrum of compound 4aa; Fig. 2 is the nuclear magnetic ¹³ C spectrum of compound 4aa.

Figure 3 is the NMR ¹ H spectrum of the compound 4ba; Figure 4 is the NMR ¹³ C spectrum of the compound 4ba.

Fig. 5 is the NMR ¹ H spectrum of the compound 4ca; Fig. 6 is the NMR ¹³ C spectrum of the compound 4ca.

FIG. 7 is the ^1H NMR spectrum of compound 4da; FIG. 8 is the ^13C NMR spectrum of compound 4da.

FIG. 9 is the ^1H NMR spectrum of compound 4ea; FIG. 10 is the ^13C NMR spectrum of compound 4ea.

FIG. 11 is the ^1H NMR spectrum of compound 4fa; FIG. 12 is the ^13C NMR spectrum of compound 4fa.

Fig. 13 is the NMR ¹ H spectrum of the compound 4ga; Fig. 14 is the NMR ¹³ C spectrum of the compound 4ga.

Figure 15 is the nuclear magnetic ¹ H spectrum of compound 4ha; Figure 16 is the nuclear magnetic ¹³ C spectrum of compound 4ha.

Figure 17 is the nuclear magnetic ¹ H spectrum of compound 4ia; Figure 18 is the nuclear magnetic ¹³ C spectrum of compound 4ia.

Fig. 19 is the nuclear magnetic ¹ H spectrum of compound 4ja; Fig. 20 is the nuclear magnetic ¹³ C spectrum of compound 4ja.

Figure 21 is the nuclear magnetic ¹ H spectrum of compound 4ka; Figure 22 is the nuclear magnetic ¹³ C spectrum of compound 4ka.

Figure 23 is the nuclear magnetic ¹ H spectrum of compound 4la; Figure 24 is the nuclear magnetic ¹³ C spectrum of compound 4la.

Figure 25 is the nuclear magnetic ¹ H spectrum of the compound 4ma; Figure 26 is the nuclear magnetic ¹³ C spectrum of the compound 4ma.

Figure 27 is the nuclear magnetic ¹ H spectrum of compound 4na; Figure 28 is the nuclear magnetic ¹³ C spectrum of compound 4na.

Figure 29 is the nuclear magnetic ¹ H spectrum of compound 4ab; Figure 30 is the nuclear magnetic ¹³ C spectrum of compound 4ab.

Fig. 31 is the NMR ¹ H spectrum of compound 4ac; Fig. 32 is the NMR ¹³ C spectrum of compound 4ac.

Figure 33 is the nuclear magnetic ¹ H spectrum of compound 4ad; Figure 34 is the nuclear magnetic ¹³ C spectrum of compound 4ad.

Figure 35 is a reaction schematic diagram of the synthetic route.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

Under nitrogen, 3-arylbenzoxazine compound 1a (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 30 degrees for 30 min. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 8,14-dimethyl was obtained by separation with a silica gel column. -6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate diethyl ester ( 4aa), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: Brown liquid, 88% yield. As shown in Figures 1 and 2, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (dd, J=8.0, 1.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.18-7.06 (m , 3H), 6.97–6.88 (m, 2H), 4.55 (d, J=11.4Hz, 1H), 4.37–4.31 (ddt, J=9.4, 7.1, 3.7Hz, 4H), 4.16 (d, J=11.4 Hz, 1H), 2.14 (s, 3H), 2.09 (s, 3H), 1.37 (t, J=7.1 Hz, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 168.5, 166.6, 160.2, 149.3, 143.7, _{130.2,128.2,128.1,126.9,125.5,121.6,121.5,119.9,116.7,115.0,109.0,105.7,86.2,64.1,60.9,60.8,19.5,19.3,14.4.HRMS} [M+H] ⁺ calculated _forC NO ₆ ⁺ = 448.1755, found: 448.1758.

Example 2

Under nitrogen, 3-arylbenzoxazine compound 1b (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (2 mol %), AgSbF ₆ (8 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 40 degrees for 1 h. After the reaction, the solvent was removed under reduced pressure, and the target product 4-bromo-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ba), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 88% yield. Melting range: 127–128℃. As shown in Figures 3 and 4, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J=7.9 Hz, 1H), 7.43 (dd, J=8.0, 1.2 Hz, 1H), 7.32 (t, J ＝8.0Hz,1H),7.14(d,J＝7.9Hz,1H),7.06(dd,J＝8.0,1.2Hz,1H),6.83(t,J＝8.0Hz,1H),4.71(d,J = 11.4Hz, 1H), 4.39–4.30 (m, 4H), 4.24 (d, J=11.4Hz, 1H), 2.12 (s, 3H), 2.09 (s, 3H), 1.38–1.35 (m, 6H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ168.2, 166.4, 159.7, 146.1, 142.9, 130.4, 130.3, 128.1, 127.9, 127.3, 126.7, 121.8, 121.6, 120.4, 114.9, 110.3, 109, 4.9, 106 60.9, 60.8, 19.3, 19.2, 14.4, 14.4. HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ BrNO ₆ ⁺ =526.0860, found: 526.0861.

Example 3

Under nitrogen, 3-arylbenzoxazine compound 1c (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (3 mol %), AgSbF ₆ (12 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 40 degrees for 30 min. After the reaction, the solvent was removed under reduced pressure, and the target product 3-fluoro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ca), all eluents were petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 73% yield. Melting range: 180-181℃. As shown in Figures 5 and 6, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=7.9 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.03 (dd, J=8.5, 6.1Hz, 1H), 6.67 (dd, J=13.2, 5.7Hz, 2H), 4.52 (d, J=11.4Hz, 1H), 4.43–4.27 (m , 4H), 4.15(d, J=11.5Hz, 1H), 2.10(s, 3H), 2.10(s, 3H), 1.38–1.35(m, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168. 3,166.5,161.1(d,J＝244.8Hz),159.8,150.2,150.0,143.5,130.3,128.7(d,J＝10.0Hz),128.1,121.8(d,J＝3.0Hz),121.7,121.5,114.7, 109.0,107.1(d,J＝23.0Hz),105.9,103.9(d,J＝26.0Hz),86.1,64.0,60.9,60.8,19.3,19.3,14.4,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ FNO ₆ ⁺ = 466.1660, found: 466.1661

Example 4

Under nitrogen, 3-arylbenzoxazine compound 1d (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module at 40 degrees for 2h. After the reaction, the solvent was removed under reduced pressure, and the target product 3-chloro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4da), all eluents were prepared from petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 84% yield. Melting range: 201-202℃. As shown in Figures 7 and 8, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J=7.8 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 6.95–6.91 (m, 2H), 4.54 (d, J=11.4Hz, 1H), 4.40–4.28 (m, 4H), 4.14 (d , J=11.4Hz, 1H), 2.11(s, 3H), 2.11(s, 3H), 1.39–1.35(m, 6H). ¹³ C NMR(101MHz, CDCl ₃ )δ168.3,166.5,159.9,149.8,143.0 ,131.9,130.3,128.7,128.2,128.0,124.3,121.8,121.6,120.2,116.9,114.7,109.1,106.2,86.0,64.1,61.0,60.9,19.3,19.3,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ ClNO ₆ ⁺ =482,1365, found: 482.1364.

Example 5

Under nitrogen, 3-arylbenzoxazine compound 1e (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (2 mol %), AgSbF ₆ (8 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module of 30 degrees for 0.5h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3-bromo-8 was obtained by separation with a silica gel column. 14-Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate Diethyl acid (4ea), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 81% yield. Melting range: 195-196℃. As shown in Figures 9 and 10, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=7.4 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.16-7.03 (m, 3H) ),6.95(d,J＝8.5Hz,1H),4.54(d,J＝11.4Hz,1H),4.45–4.25(m,4H),4.13(d,J＝11.4Hz,1H),2.11(s , 3H), 2.11(s, 3H), 1.39–1.35(m, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.3,166.5,159.9,149.9,142.9,130.3,129.0,128.2,128.0,124.8,123.1 ,121.8,121.6,119.8,119.5,114.7,109.1,106.2,86.0,64.1,61.0,60.9,19.3,19.3,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ BrNO ₆ ⁺ =526.0860, found: 526.0858 .

Example 6

Under nitrogen, 3-arylbenzoxazine compound 1f (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 30 degrees for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3,8,14- Trimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate Ethyl ester (4fa), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 87% yield. Melting range: 178-182℃. As shown in Figures 11 and 12, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (d, J=7.9 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.9 Hz,1H),6.96(d,J＝7.9Hz,1H),6.73(d,J＝7.7Hz,2H),4.52(d,J＝11.4Hz,1H),4.41–4.28(m,4H), 4.13(d, J=11.4Hz, 1H), 2.33(s, 3H), 2.14(s, 3H), 2.10(s, 3H), 1.38–1.35(m, 6H). ¹³ C NMR (101 MHz, CDCl ₃ )δ168.5,166.6,160.2,148.8,144.0,136.9,130.1,128.3,128.2,127.6,122.9,121.5,121.4,120.8,117.0,114.9,108.9,105.3,86.3,64.0,194.8,6.9 , 14.4.HRMS[M+H] ⁺ calculated for C ₂₇ H ₂₈ NO ₆ ⁺ =462.1911, found: 462.1913.

Example 7

Under nitrogen, 3-arylbenzoxazine compound 1 g (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module of 50 degrees for 2h. After the reaction, the solvent was removed under reduced pressure, and the target product 2-chloro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ga), all eluents were prepared from petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 80% yield. Melting range: 151-152℃. As shown in Figures 13 and 14, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.12-7.08 (m, 3H ),6.85(d,J＝8.6Hz,1H),4.53(d,J＝11.4Hz,1H),4.41–4.26(m,4H),4.12(d,J＝11.4Hz,1H),2.14(s , 3H), 2.10(s, 3H), 1.36(t, J=7.1Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.2, 166.5, 159.9, 148.0, 142.6, 130.3, 128.1, 127.9, 127.6, 126.8,126.3,124.5,121.8,121.6,117.6,114.7,109.0,106.3,85.9,64.0,61.0,60.8,19.4,19.2,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ ClNO ₆ ⁺ =482.1365 ,found:482.1366.

Example 8

Under nitrogen, 3-arylbenzoxazine compound 1h (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module of 50 degrees for 2h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 1-fluoro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ha), all eluents were prepared from petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 47% yield. Melting range: 142-143℃. As shown in Figures 15 and 16, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=7.5 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.16-7.10 (m, 2H ), 6.77–6.73 (m, 2H), 4.54 (d, J=11.5Hz, 1H), 4.41–4.28 (m, 4H), 4.20 (d, J=11.5Hz, 1H), 2.15 (d, J= 2.7Hz, 3H), 2.09(s, 3H), 1.37(t, J=7.1Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 168.2, 166.6, 159.7, 157.7 (d, J=248.0Hz), 150.9(d,J＝3.6Hz),144.8,130.3,128.1(d,J＝18.8Hz),126.9,126.8,121.8(d,J＝7.5Hz),115.6(d,J＝15.6Hz),115.1, 112.2(d, J＝2.9Hz), 109.0, 107.9, 107.7, 106.5, 85.9, 64.2, 60.9, 60.9, 19.3, 17.3, 17.2, 14.4. HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ FNO ₆ ⁺ =466.1660,found:466.1664.

Example 9

Under nitrogen, 3-arylbenzoxazine compound 1i (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (3 mol %), AgSbF ₆ (12 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module at 30 degrees for 1h. After the reaction, the solvent was removed under reduced pressure, and the target product 11-fluoro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ia), all eluents were prepared with petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 80% yield. Melting range: 132-133℃. As shown in Figures 17 and 18, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (dd, J=10.6, 2.4 Hz, 1H), 7.19-7.13 (m, 1H), 7.09 (dd, J=7.9, 1.4Hz, 1H), 6.97–6.87 (m, 3H), 4.51 (d, J=11.5Hz, 1H), 4.43–4.27 (m, 4H), 4.11 (d, J=11.5Hz, 1H), 2.17 ( s, 3H), 2.10 (s, 3H), 1.39–1.35 (m, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 167.9, 166.2, 164.2 (d, J=243.7 Hz), 161.8, 149.2, 145.4, 130.5(d, J=2.8Hz), 130.4(d, J=3.3Hz), 128.0, 127.1, 125.1, 120.0, 116.7, 110.3(d, J=2.1Hz), 108.8(d, J=26.3Hz), 108.4(d,J＝23.2Hz),108.2,104.8(d,J＝2.3Hz),86.2,64.2,61.0,60.9,19.6,19.6,14.4,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ FNO ₆ ⁺ = 466.1660, found: 466.1661.

Example 10

Under nitrogen, 3-arylbenzoxazine compound 1j (0.20 mmol), diazo compound 2a (0.44 mmol, [Cp*RhCl ₂ ] ₂ (2 mol %), AgSbF ₆ (8 mol %), MesCOOH ( 0.4mmol) and solvent DCE (2.0mL) were added to a 10mL sealed tube, and reacted in a reaction module at 40 degrees for 0.5h. After the reaction, the solvent was removed under reduced pressure, and the target product 11-chloro-8,14 was obtained by separation with a silica gel column. -Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylic acid Diethyl ester (4ja), all eluents were petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 82% yield. Melting range: 155-156℃. As shown in Figures 19 and 20, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (d, J=1.7 Hz, 1H), 7.20-7.14 (m, 2H), 7.09 (d, J=7.8 Hz, 1H) ), 6.98–6.89 (m, 2H), 4.51 (d, J=11.5Hz, 1H), 4.43–4.28 (m, 4H), 4.12 (d, J=11.5Hz, 1H), 2.16 (s, 3H) , 2.10(s, 3H), 1.38(t, J=7.0Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.9, 166.1, 161.6, 149.1, 145.3, 136.6, 129.9, 129.8, 128.0, 127.1, 125.1 ,121.5,121.3,120.0,116.8,112.8,108.1,104.6,86.1,64.1,61.1,61.0,19.7,19.6,14.4,14.4.HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ ClNO ₆ ⁺ =482, 1365,found:482.1362.

Example 11

Under nitrogen, 3-arylbenzoxazine compound 1k (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added to a 10mL sealed tube, and reacted in a reaction module of 30 degrees for 0.5h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 11-bromo-8 was obtained by separation with a silica gel column, 14-Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate Diethyl acid (4ka), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: Yellow solid, 85% yield. Melting range: 150-151℃. As shown in Figures 21 and 22, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (d, J=1.4 Hz, 1H), 7.34 (d, J=1.4 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.09(d, J＝7.8Hz, 1H), 6.93(dd, J＝12.0, 8.1Hz, 2H), 4.51(d, J＝11.5Hz, 1H), 4.44–4.27(m, 4H ), 4.12(d, J=11.5Hz, 1H), 2.16(s, 3H), 2.10(s, 3H), 1.38(t, J=7.1Hz, 6H). ¹³ C NMR(101MHz, CDCl ₃ )δ167 .8,166.0,161.6,149.1,145.3,130.0,129.9,128.0,127.1,125.1,124.9,124.3,124.2,120.0,116.7,113.2,108.0,104.4,86.1,64.0,61.0,4.6.9 .HRMS[M+H] ⁺ calculated for C ₂₆ H ₂₅ BrNO ₆ ⁺ =526.0860, found: 526.0856.

Example 12

Under nitrogen, 3-arylbenzoxazine compound 11 (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 30 degrees for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 11-phenyl-8 was obtained by separation with a silica gel column. ,14-Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-di Diethyl carboxylate (4la), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 59% yield. Melting range: 156-157℃. As shown in Figures 23 and 24, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J=7.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.5 Hz, 2H), 7.39–7.33 (m, 2H), 7.16 (t, J=7.7Hz, 1H), 7.11 (d, J=7.8Hz, 1H), 6.94 (t, J=7.8Hz, 2H), 4.59(d, J=11.4Hz, 1H), 4.45–4.28(m, 4H), 4.19(d, J=11.4Hz, 1H), 2.18(s, 3H), 2.12(s, 3H), 1.38(t , J=7.1Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.4, 166.6, 160.6, 149.3, 144.2, 143.3, 141.4, 128.9, 128.6, 128.1, 127.7, 127.4, 126.9, 125.4, 120.7, 120.5 119.9,116.7,113.9,108.9,105.6,86.3,64.2,60.9,60.8,19.6,19.4,14.5,14.5.HRMS[M+H] ⁺ calculated for C ₃₂ H ₃₀ NO ₆ ⁺ =524.2068, found:524.2066.

Example 13

Under nitrogen, 3-arylbenzoxazine compound 1m (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (2 mol %), AgSbF ₆ (8 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 60 degrees for 0.5 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 11-trifluoromethyl was obtained by separation with a silica gel column. -8,14-Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13 - Diethyl dicarboxylate (4ma), all eluents were prepared with petroleum ether and ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 72% yield. Melting range: 79-80℃. As shown in Figures 25 and 26, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (s, 1H), 7.46 (s, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.10 (d, J ＝7.6Hz,1H),6.95(dd,J＝11.9,8.0Hz,2H),4.54(d,J＝11.5Hz,1H),4.46-4.26(m,4H),4.15(d,J＝11.5Hz , 1H), 2.20(s, 3H), 2.13(s, 3H), 1.38(t, J=7.1Hz, 6H). ¹³ C NMR(101MHz, CDCl ₃ )δ167.8,166.0,162.0,149.1,145.9,132.5 (d, J=31.9Hz), 129.2, 129.1, 128.0, 127.3, 125.03, 124.1 (q, J=266.3Hz), 120.1, 118.3, 118.3 (d, J=3.8Hz), 116.8, 108.3, 104.6, 86.1 ,63.9,61.1,61.1,19.6,19.5,14.3,14.3.HRMS[M+H] ⁺ calculated for C ₂₇ H ₂₅ F ₃ NO ₆ ⁺ =516.1628, found: 516.1626.

Example 14

Under nitrogen, 3-arylbenzoxazine compound 1n (0.20 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added to a 10mL sealed tube, and reacted in a reaction module at 90 degrees for 6h. After the reaction, the solvent was removed under reduced pressure, and the target product 11-methoxy-8 was obtained by separation with a silica gel column. ,14-Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-di Diethyl carboxylate (4na), all eluents were prepared from petroleum ether ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 69% yield. Melting range: 183-184℃. As shown in Figures 27 and 28, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16-7.08 (m, 3H), 6.94-6.90 (m, 2H), 6.70 (d, J=2.2 Hz, 1H), 4.50 (d, J=11.4Hz, 1H), 4.09(d, J=11.4Hz, 1H), 3.86(s, 3H), 3.85(s, 3H), 3.80(s, 3H), 2.14(s, 3H) _The ^_ ,105.1,86.2,64.3,55.4,51.7,51.6,19.6,19.5.HRMS[M+H] ⁺ calculated for C ₂₅ H ₂₄ NO ₇ ⁺ =450.1547, found: 450.1546.

Example 15

Under nitrogen, 3-arylbenzoxazine compound 1a (0.20 mmol), diazo compound 2b (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 30 degrees for 0.5 h. After the reaction, the solvent was removed under reduced pressure, and the target product 8,14-dimethyl was obtained by separation with a silica gel column. Diisopropyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate Ester (4ab), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 74% yield. Melting range: 138-139℃. As shown in Figures 29 and 30, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17–7.12 (m, 1H), 7.11–7.08 (m, 2H), 6.94–6.90 (m, 2H), 6.71 (d, J=2.3Hz, 1H), 5.28–5.20(m, 2H), 4.52(d, J=11.4Hz, 1H), 4.12(d, J=11.4Hz, 1H), 3.79(s, 3H), 2.13( s, 3H), 2.08 (s, 3H), 1.41–1.31 (m, 12H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 167.9, 166.2, 161.1, 160.4, 149.3, 143.7, 129.6, 129.5, 128.1, 126.8, 125.5,119.8,116.6,109.0,107.7,107.1,107.1,105.9,86.2,68.5,68.4,64.4,55.4,22.2,22.2,22.1,22.0,19.5,19.4.HRMS[M+H] ⁺ calculated for C ₂₉ H ₃₂ NO ₇ ⁺ = 506.2173, found: 506.2173.

Example 16

Under nitrogen, 3-arylbenzoxazine compound 1a (0.20 mmol), diazo compound 2c (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4mmol) and solvent DCE (2.0mL) were added into a 10mL sealed tube, and reacted in a reaction module of 30 degrees for 0.5h. After the reaction, the solvent was removed under reduced pressure, and the target product 8,14-dipropane was obtained by separation with a silica gel column. Dimethyl-6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate (4ac), all eluents were prepared from petroleum ether ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: Yellow solid, 50% yield. As shown in Figures 31 and 32, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17 (dd, J=12.1, 4.6 Hz, 2H), 7.04 (d, J=2.3 Hz, 1H), 6.96-6.87 (m ,2H),6.70(d,J＝2.3Hz,1H),4.45(d,J＝11.4Hz,1H),4.14(d,J＝11.4Hz,1H),3.85(s,3H),3.84(s ,3H),3.79(s,3H),2.71-2.47(m,4H),1.42-1.25(m,4H),0.80(t,J＝7.4Hz,3H),0.73(t,J＝7.3Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.7,167.2,163.3,161.2,149.8,149.2,129.6,129.3,127.3,127.1,125.7,120.0,116.5,108.4,107.5,107.3,107.1,1 64.5, 55.5, 51.8, 51.7, 34.4, 31.8, 22.4, 20.6, 14.0, 13.9. HRMS[M+H] ⁺ calculated for C ₂₉ H ₃₂ NO ₇ ⁺ =506.2173, found: 506.2164.

Example 17

Under nitrogen, 3-arylbenzoxazine compound 1a (0.20 mmol), diazo compound 2d (0.44 mmol), [Cp*RhCl ₂ ] ₂ (4 mol %), AgSbF ₆ (16 mol %), MesCOOH (0.4 mmol) and solvent DCE (2.0 mL) were added to a 10 mL sealed tube, and reacted in a reaction module at 30 degrees for 5 h. After the reaction, the solvent was removed under reduced pressure, and the target product 8,14-diphenyl was obtained by separation with a silica gel column. -6H-benzo[5,6][1,4]oxazine[3,4-a]pyrano[4,3,2-ij]isoquinoline-9,13-dicarboxylate diethyl ester ( 4ad), all eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 30:1:1.

Product Data Characterization: White solid, 49% yield. Melting range: 186-187℃. As shown in Figures 33 and 34, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52-7.45 (m, 2H), 7.39-7.17 (m, 7H), 7.12 (d, J=1.7 Hz, 1H), 7.07 (t, J=7.6Hz, 1H), 6.98 (dt, J=15.2, 7.8Hz, 2H), 6.73 (d, J=7.8Hz, 1H), 6.39 (t, J=7.6Hz, 1H), 6.16 (d, J=8.0Hz, 1H), 4.87 (d, J=11.4Hz, 1H), 4.47 (d, J=11.4Hz, 1H), 4.14–3.95 (m, 2H), 3.87 (s, 3H) , 3.86-3.73(m, 2H), 0.92(t, J=7.1Hz, 3H), 0.76(t, J=7.1Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.6, 167.5, 161.7, 157.9 , 148.9,146.7,134.7, 1133.9 ,130.6,130.4,130.2,129.8,129.3,128.6,128.1, 128.1,127.7, 126.7.7.7.7.7.8, 107.8, 107.8,17.8,107.8,107.8,107.8,107.8,107.8,107.8,107.8,107.8. ,64.5,61.0,60.6,55.6,13.6,13.6.HRMS[M+H] ⁺ calculated for C ₃₇ H ₃₂ NO ₇ ⁺ =602.2173, found: 602.2173.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of the present invention. within the scope of protection.

Claims (10)

1. A method for synthesizing a spiroheterocyclic compound, characterized in that: a3-aryl benzoxazine compound and a diazo compound are used as raw materials, and a novel spiro-heterocyclic compound is synthesized under the promotion of a catalyst, wherein the reaction formula is as follows:

wherein R is any one of H, Me, F, Cl and Br; r is¹Any one of Me, Pr and Ph; r²Is Me, Et,ⁱAny one of Pr; ar is Me, OMe, F, Cl, Br, Ph, CF₃Any one of the substituted benzene rings.

2. A synthesis method of spiro-heterocyclic compounds according to claim 1, characterized by comprising the specific steps of: adding a 3-aryl benzoxazine compound, a diazo compound, a catalyst and an additive into a solvent, reacting under the protection of inert atmosphere, and purifying after the reaction is finished to obtain the spiroheterocyclic compound.

3. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the catalyst comprises a rhodium catalyst and a silver salt; the molar ratio of rhodium catalyst to silver salt is 1: (2-4); the rhodium catalyst is dichloro (pentamethylcyclopentadienyl) rhodium dimer, pentamethylcyclopentadienyl rhodium acetate or bis (hexafluoroantimonic acid) triethylenenitrile (pentamethylcyclopentadienyl) rhodium; the silver salt is silver hexafluoroantimonate, silver bistrifluoromethanesulfonylimide, silver tetrafluoroborate, silver trifluoromethanesulfonate, silver sulfate, silver acetate and silver trifluoroacetate.

4. A method of synthesizing a spiroheterocyclic compound according to claim 3, characterized in that: the catalyst consists of dichloro (pentamethyl cyclopentadienyl) rhodium dimer and silver hexafluoroantimonate; the molar ratio of dichloro (pentamethylcyclopentadienyl) rhodium dimer to silver hexafluoroantimonate was 1: 4.

5. a method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the additive is any one of trimesobenzoic acid (MesCOOH), pivalic acid, acetic acid, benzoic acid, proline, adamantanecarboxylic acid, zinc acetate, sodium carbonate, potassium acetate and potassium carbonate.

6. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the solvent is any one of dichloroethane, dichloromethane, methanol, acetonitrile, 1, 4-dioxane and toluene.

7. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the 3-aryl benzoxazine compound: diazo compound: catalyst: the molar ratio of the additive is 1: 2.2: 0.02-0.04: 0.08-0.16.

8. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the concentration of the reaction system in the solvent is 0.05M-0.2M.

9. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the inert atmosphere is nitrogen atmosphere.

10. A method of synthesizing a spiroheterocyclic compound according to claim 2, characterized in that: the reaction temperature is 30-90 ℃, and the reaction time is 0.5-6 h.

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