1,4-Silicon-Nitrogen Heterocyclic Compounds, Their Synthetic Methods, and Applications

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to 1,4-silicon-nitrogen heterocyclic compounds, their synthesis methods, and applications. The synthesis method includes the following steps: using diethyleneamine and disiloxane as substrates and B(C6F5)3 as catalyst, the 1,4-silicon-nitrogen heterocyclic compound is synthesized in solvent one. The reaction formula is as follows: The synthesis method of this invention has advantages over existing technologies, such as safety and environmental friendliness, wide substrate adaptability, low reaction temperature, short reaction time, high yield, fewer by-products, and fewer reaction reagents.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to 1,4-silicon nitride heterocyclic compounds, their synthesis methods, and applications. Background Technology

[0002] Aza-hexa-membered rings are among the most important structural units in drug, natural product, and material molecules. As a silane-isosteric biomolecule of piperidine, 4-silanepiperidine has received increasing attention in recent years and is currently the most widely used silicon-nitrogen heterocycle, demonstrating significant application value in drug development and novel fluorescent probes. Examples include the dopamine receptor antagonist sila-haloperidol, sila-anti-tubercular and sila-linezolid (which have stronger blood-brain barrier permeability than their parent molecules), the hepatitis C virus inhibitor sila-HCV inhibtor, and the silicon-containing organic optoelectronic material sila-OLED (structural formulas shown below).

[0003]

[0004] Currently, the most commonly used synthetic method for 4-silazidepiperidine is the divinylsilane hydrobromination / nitrogen cyclization method. However, divinylsilane first undergoes addition with hydrobromic acid to generate a dibromoethyl-substituted silane intermediate 2, which then undergoes successive intermolecular / intramolecular nitrogen nucleophilic substitutions, subsequently transforming into 4-silazidepiperidine 3 (as shown below). The main drawbacks of this method include: 1) the need to use environmentally harmful HBr gas, and the inconvenience of operation; 2) many acid-sensitive functional groups are difficult to tolerate under these conditions, thus limiting the types of silicon substituents.

[0005]

[0006]

[0007] In 2021, Oestreich's research group developed a C–H bond activation strategy based on B(C6F5)3 catalysis, and used it to synthesize 4-silazidepiperidine 3 (as shown in the formula below). This method uses tertiary amine compound 4 and dihydrosilane 5 as substrates. Under the action of B(C6F5)3 catalyst, the corresponding 4-silazidepiperidine is synthesized through successive dehydrogenation to generate imine / imine isomerization to enamine / hydrosilylation. However, this method has drawbacks such as high reaction temperature (150℃), large catalyst amount (20 mol%), the need for additional additives, and relatively low yield (around 50-60%).

[0008] Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a 1,4-silicon nitride heterocyclic compound, its synthesis method, and its application.

[0010] The objective of this invention is achieved through the following technical solution: a method for synthesizing 1,4-silicon-nitrogen heterocyclic compounds, comprising the following steps: using diethyleneamine and disiloxane as substrates and B(C6F5)3 as catalyst in solvent one to synthesize 1,4-silicon-nitrogen heterocyclic compounds;

[0011] The reaction temperature range is 0-100℃, the reaction time is 0.2-6 hours, the molar ratio of diethyleneamine to disiloxane is 1:1-5, the amount of B(C6F5)3 is 5-15 mol%, and the solvent is one of xylene, toluene, chlorobenzene, dichloromethane, and dichloroethane. The reaction formula is as follows:

[0012]

[0013] In the formula, R is one of p-tolyl, n-butyl, tert-butyl, and 2-thiophene. 1 and R 2 Each of the following is a hydrogen atom, a C1-C6 alkyl group, a C5-C7 cycloalkyl group, and an aryl group (preferably phenyl), wherein the C1-C6 alkyl group, the C5-C7 cycloalkyl group, and the aryl group (preferably phenyl) are respectively substituted by one or more independent hydrogen atoms, C1-C6 alkyl groups, halogens, and aryl groups, and R 1 and R 2 They are not both hydrogen atoms.

[0014] Preferably, the reaction temperature range is 10-40℃, and the time is 0.5-1 hour;

[0015] Preferably, the molar ratio of diethyleneamine to disilidine is in the range of 1:1-2;

[0016] Preferably, the amount of B(C6F5)3 used ranges from 8 to 12 mol%.

[0017] Furthermore, the addition method of the diethyleneamine, disiloxane and B(C6F5)3 is as follows: first react the disiloxane and B(C6F5)3 for 0.5-10 minutes, preferably 0.5-2 minutes, and then add the diethyleneamine.

[0018] Furthermore, when R 1 and R 2 When one of the atoms is a hydrogen atom and the other is a phenyl, p-tolyl, or alkyl atom, the 1,4-silazane heterocyclic compound is a silazane piperidine compound, and the compound further includes the following steps:

[0019] First add N,N-dimethylaniline and solvent two, and remove solvent one; or first add N,N-dimethylaniline, remove solvent one, and then add solvent two.

[0020] Then, an aryl compound, a base, and a palladium catalyst are added to carry out a coupling reaction.

[0021] Wherein, the base is potassium phosphate or diisopropylamine; the palladium catalyst is di(tri-tert-butylphosphine)palladium, tetra(triphenylphosphine)palladium or tri(dibenzylacetone)dipalladium; and the solvent is N-methylpyrrolidone or toluene.

[0022] The reaction formula is as follows:

[0023]

[0024] In the formula, X is either iodine or bromine; aryl is either a benzene ring or an aromatic heterocycle, wherein one or more hydrogen atoms on the aromatic ring or aromatic heterocycle are replaced by C1-C4 alkyl, aryl, halogen, ester, ketone carbonyl, or heterocycles containing sulfur, nitrogen, or oxygen atoms.

[0025] Furthermore, the amount of N,N-dimethylaniline added is 1-5 equivalents; preferably 1.5-2.5 equivalents.

[0026] Furthermore, the molar ratio of the silypiperidine compound to the aryl compound is in the range of 1:0.5-2, preferably 1:0.5-1;

[0027] Furthermore, the amount of alkali used ranges from 1 to 3, preferably from 1.5 to 2;

[0028] Furthermore, the amount of palladium catalyst used is 2.5-15 mol%, preferably 5-7.5 mol%.

[0029] Furthermore, the coupling reaction is carried out at a temperature of 15-30°C for 10-24 hours.

[0030] Furthermore, the method for removing solvent one is vacuum distillation.

[0031] Furthermore, after adding solvent two, it is necessary to mix thoroughly for 10-60 minutes, preferably 10-40 minutes.

[0032] The present invention also provides a 1,4-silicon nitride heterocyclic compound obtained by the above method.

[0033] The present invention also provides the above-mentioned 1,4-silicon nitride heterocyclic compound for the synthesis of amide compounds, benzylamine compounds, aromatic amine derivatives, and for the structural modification of various active molecules.

[0034] Furthermore, when used to synthesize amide compounds, the synthesis method is as follows: the 1,4-silicon nitride heterocyclic compound is first subjected to a deprotection reaction to remove the R-SO2 protecting group, and then undergoes an acylation reaction with adamantyl chloride to obtain the amide compound;

[0035] And / or, when used to synthesize benzylamine compounds, the synthesis method is as follows: the 1,4-silicon nitride heterocyclic compound is first subjected to a deprotecting agent reaction to remove the R-SO2 protecting group, and then subjected to an N-alkylation reaction with 3,5-dimethoxybenzyl bromide under the action of K2CO3 to obtain the benzylamine compound;

[0036] And / or, when used to synthesize aromatic amine derivatives, the synthesis method is as follows: the 1,4-silicon-acid heterocyclic compound is first subjected to a deprotecting agent reaction to remove the R-SO2 protecting group, and then the aromatic amine derivative is obtained by a Buchwald-Hartwig reaction in 4-iodophenyl ether under Pd catalysis.

[0037] The beneficial effects of this invention are as follows: Existing methods all have certain drawbacks; for example, the use of toxic and difficult-to-operate hydrobromic acid gas, or the strong reducing conditions required for substrate preparation when using silanediol as a substrate, limit the preparation of silanediol substrates. In this invention, when using silanetrihydrogen and aryliodine as substrates, both silanetrihydrogen and aryliodine are commercially available and inexpensive reagents, thus the method developed in this invention has certain advantages in terms of substrates. Furthermore, this method allows for the large-scale, high-yield preparation of the corresponding silanepiperidine products, and the reagents used in the reaction process are all non-toxic, odorless, and flammable / explosive. Therefore, the synthetic method for 1,4-silane-nitrogen heterocyclic compounds provided by this invention has advantages such as safety and environmental friendliness, wide substrate adaptability, low reaction temperature, short reaction time, high yield, few byproducts, and few reaction reagents. Detailed Implementation

[0038] The technical solution of the present invention will be described in further detail below, but the scope of protection of the present invention is not limited to the following description.

[0039] Screening of Addition Reaction Conditions between Dieneamine and Silane in Example 1B

[0040] Choosing R as p-tolyl, thus forming the Ts protecting group, R 1 and R 2 All were phenyl compounds, with B(C6F5)3 added at 10 mol% and solvent at 0.2 M. The optimal experimental conditions were determined by screening the substrate-to-solvent ratio, solvent, temperature, and reaction time, and the final result was group 14. The reaction equation and experimental results are as follows:

[0041]

[0042] Comparison of feeding sequence in Example 2

[0043] Based on the optimal experimental conditions in Example 1, this invention compared two different feeding sequences. Method A: A dichloromethane solution of B(C6F5)3 was added to a dichloromethane solution of N,N-diethylene-p-toluenesulfonamide and silanediol. Method B: A dichloromethane solution of B(C6F5)3 was added to a dichloromethane solution of silanediol and reacted for one minute, then a dichloromethane solution of N,N-diethylene-p-toluenesulfonamide was added to the reaction system. The reaction equations and experimental results are as follows:

[0044]

[0045] As can be seen, Method B demonstrates a significant advantage for both diphenylsilanedihydrogen and phenylisopropylsilanedihydrogen. In particular, the yield of the reaction using phenylisopropylsilanedihydrogen as the substrate can be increased from 28% in Method A to 60% in Method B. Furthermore, this yield maintains good stability in repeated experiments.

[0046] Example 3: Expansion of the reaction substrate

[0047] Based on the optimal experimental conditions in Example 1, the reaction time was adjusted to 3 hours to further screen the applicable range of the substrate. The reaction formula and experimental results are as follows:

[0048]

[0049] Using dienamine compounds as substrates, the reaction was carried out under optimal conditions with multi-substituted dihydrosilanes. Experimental data show that this reaction is applicable to a variety of alkyl and aryl-substituted dihydrosilanes. Regardless of whether the sterically hindered aryl substituent is sterically hindered or the alkyl substituent is sterically weak, the corresponding silypiperidine products are obtained in high yields. When the substrate is aryl dihydrosilane, the method exhibits excellent reactivity, with relatively high yields regardless of whether the substituent is an electron-withdrawing or electron-retaining substituent.

[0050] Example 4B: Synthesis of aryl-substituted 4-silazoperidine via (C6F5)3 / Pd relay catalytic reaction

[0051] This invention utilizes a transition metal-catalyzed Ar-Si bond coupling reaction between silane and aryl bromide or aryl iodine, employing a B(C6F5)3 and transition metal relay catalysis, to synthesize 4-silazoneidin, a three-component formulation with greater diversity of aryl substituents on silicon. The reaction formula is as follows:

[0052]

[0053] Since the reaction conditions before and after the above formula differ significantly, this invention further investigated the effects of solvent, reaction temperature, reaction method, and substrate feed ratio on the reaction. Specific reaction results are shown below:

[0054]

[0055] Method A: 10 and 22a were used as substrates, DCM as the reaction solvent, and B(C6F5)3 as the catalyst. After the reaction was complete at room temperature, PhNMe2 was added and stirred for half an hour. DCM was then removed from the system under reduced pressure. The resulting mixture was then placed in a glove box with NMP, 28a, K3PO4, and Pd(t-Bu3P)2. After being removed from the glove box, the mixture was stirred at room temperature for 10 hours for separation and purification.

[0056] Method B: 10 and 22a were used as substrates, DCM as the reaction solvent, and B(C6F5)3 as the catalyst. After the reaction was complete at room temperature, PhNMe2 was added and stirred for half an hour, followed by NMP and stirring for another half hour. DCM was removed from the system under reduced pressure. Subsequently, 28a, K3PO4, and Pd(t-Bu3P)2 were added in a glove box. After removing the glove box, the mixture was stirred at room temperature for 10 hours for separation and purification.

[0057] Method A yielded 37% for 4-silazinopiperidine (entry 1), using trifluorotoluene as the solvent. However, this solvent was unfavorable for subsequent coupling reactions and difficult to remove. Therefore, DCE and DCM, which have lower boiling points and are easier to remove, were used as reaction solvents (entries 2 and 3), but the yield was not significantly improved. To more effectively remove the solvent from the first step and enhance the compatibility of the two reaction conditions, we adjusted the experimental method as follows: NMP was added...

[0058] After solvent removal, the mixture was stirred thoroughly for 0.5 hours, followed by rotary evaporation to remove residual DCM (Method B). Results showed that the yield could be increased from 29% in Method A to 47% in Method B (entries 5,6). Further optimization of the substrate-to-reactant ratio was then performed, with the highest yield achieved at a substrate-to-reactant equivalence ratio of 1.5:2.25:1. The optimal experimental conditions were finally determined and are shown in entry 8.

[0059] Example 5: Scope of application of aryl iodine substrates

[0060] Based on the optimal experimental conditions identified in Example 4, this invention further screens the substrate applicability of aryl iodine. The reaction formula and experimental results are as follows:

[0061]

[0062] This reaction is applicable to most aryl iodine compounds, greatly expanding the diversity of 1,4-silypiperidine compounds. Various heteroatom-substituted aryl groups yield the corresponding compounds in good yields. In particular, when the substrate contains a phenolic hydroxyl or arylamine group with an active proton, the reaction exhibits excellent functional group tolerance, with yields of 95% and 97%, respectively. Coupling with aryl compounds substituted with electron-withdrawing functional groups (-F, -Cl; -CF3) also yields the corresponding compounds in high yields. Furthermore, the reaction is also applicable when the functional groups are ester or ketone groups. In drug development, O-, S-, N-, N=N-, or N=S- heterocycles are important structural units in many bioactive molecules. Aryl compounds containing such heterocycles can still be coupled using this method, yielding the corresponding heterocyclic-substituted aryl compounds in high yields. This method can also be applied to the structural modification and alteration of some drug molecules, such as salicylate esters and estrone derivatives.

[0063] Example 6: Derivatization Experiment of 4-Silazoperidine

[0064] In the development of silicon-nitrogen heterocyclic bioactive molecules and fluorescent probe molecules, 4-silazoperidine is a widely used ring structural unit. The properties and functions of the molecule can be effectively improved by regulating the substituents at the N site. To further explore the application scope of the synthesized 4-silazoperidine, this invention has performed diverse derivatizations at its N site.

[0065] As shown in the reaction equations below, piperidine compound 37 can be deprotected by the Ts protecting group under sodium / naphthalene conditions, or by acid hydrolysis to remove the t-Bus protecting group, both with relatively good yields. Compound 37 undergoes acylation with adamantyl chloride to convert to amide compound 38 in 96% yield. Under K2CO3, compound 37 undergoes N-alkylation with 3,5-dimethoxybenzyl bromide to generate benzylamine 39 in 60% yield. Alternatively, 37 can also undergo a Buchwald-Hartwig reaction with 4-iodophenyl ether under Pd catalysis to generate aromatic amine derivative 40 (42%). In the above transformations, the 4-silazine-piperidine ring system, especially the silicon center, exhibits good tolerance.

[0066]

[0067] Specific operating methods and data

[0068] I. Synthesis of silypiperidine 11

[0069]

[0070] Method A: Under argon protection, B(C6F5)3 solution (10.2 mg dissolved in 0.2 mL DCM, 10 mol%) was slowly added to silane solution 5 (0.3 mmol dissolved in 0.4 mL DCM, 1.5 equiv.). After reacting at room temperature for 1 minute, N,N-divinyl p-toluenesulfonamide 10 (45 mg dissolved in 0.4 mL DCM, 1.0 equiv.) was added to the system. After the reaction was completed at room temperature, it was quenched with triethylamine (0.2 mL). The organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the corresponding silanidine compound 11.

[0071]

[0072] 2.42(s,3H),1.48(t,J=6.4Hz,4H); 13 C NMR (150MHz, CDCl3) δ143.2,136.4,134.7,134.1,129.9,129.8,128.2,127.1,45.9,21.5,12.0; IR(neat)cm -1 3005,1493,1334,1260,1075,750; HRMS(ESI-TOF,m / z)calcd for C 23 H 26 NO2SSi(M+H) + 408.1448, found 408.1450.

[0073]

[0074] 3.44–3.37(m,2H),2.40(s,3H),1.24(ddd,J=14.4,9.0,5.4Hz,2H),1.04(ddd,J=14.4,9.0,5.4Hz,2H),0.28(s,3H); 13 C NMR (150MHz, CDCl3) δ143.1,136.2,136.1,133.7,129.7,129.6,128.1,127.1,45.9,21.5,13.0,4.2; IR(neat)cm -1 3006,1597,1275,1260.748; HRMS(ESI-TOF,m / z)calcd for C 18 H 24 NO2SSi(M+H) + 346.1292, found 346.1293.

[0075]

[0076] 1H),0.83(d,J=6.4Hz,6H); 13 C NMR(100MHz,CDCl3)δ143.1,136.3,134.4,133.9,129.7,129.5,128.1,127.2,45.9,21.6,17.37,12.65,9.47;IR(neat)cm -1 3005,2989,1260,1275,764;HRMS(ESI-TOF,m / z)calcd for C 20 H 27 NO2SSi(M+H) + 374.1605,found 374.1609.

[0077]

[0078] 2.84(ddd,J=12.8,10.8,3.6 Hz,2H),2.38(s,3H)1.70–1.59(m,4H),1.30–1.09(m,8H),1.06–0.96(m,2H),0.81(tt,J=12.4,3.2 Hz,1H); 13 C NMR(100 MHz,CDCl3)δ143.1,136.5,134.4,134.2,129.7,129.5,128.1,127.2,45.9,27.9,27.3,26.8,24.5,21.6,9.4;IR(neat)cm -1 2920,2864,1335,1260,1275,852,755;HRMS(ESI-TOF,m / z)calcdfor C 23 H 32 NO2SSi(M+H) + 414.1918,found.414.1920.

[0079]

[0080] 4H); 13 C NMR(150 MHz,CDCl3)δ143.0,136.1,129.7,127.2,46.1,21.5,10.3,7.2,3.4;IR(neat)cm -1 3005,1463,1275,1260,748,681;HRMS(ESI-TOF,m / z)calcd forC15 H 26 NO2SSi(M+H) + 312.1448,found.312.1450.

[0081]

[0082] 1.16(tt,J=18.0,12.0,10.0 Hz,16H),0.83(t,J=6.4 Hz,4H),0.72(tt,J=12.2,3.2 Hz,2H); 13 C NMR(150 MHz,CDCl3)δ143.0,136.8,129.7,127.2,46.3,28.2,28.1,27.0,21.6,7.9;IR(neat)cm -1 2918,2864,1275,1260,1158,1092,750;HRMS(ESI-TOF,m / z)calcd for C 23 H 37 NO2SSi(M+H) + 420.2387,found.420.2384.

[0083]

[0084] (d,J=7.6 Hz,4H),3.49(t,J=6.4 Hz,4H),2.42(s,3H),2.36(s,6H),1.43(t,J=6.4 Hz,4H); 13 C NMR(100 MHz,CDCl3)δ143.1,139.8,136.4,134.7,130.6,129.7,129.0,127.1,46.0,21.6,21.5,12.1;IR(neat)cm -1 3007,2989,1599,1334,1275,1260.750;HRMS(ESI-TOF,m / z)calcd for C 25 H 30 NO2SSi(M+H) + 436.1761,found.436.1765.

[0085]

[0086] 135.23,132.8,129.8,129.0,127.8,127.2,127.0,46.0,21.6,12.1;IR(neat)cm - 1 3005,1462,1275,1260.764;HRMS(ESI-TOF,m / z)calcd for C 35 H 34 NO2SSi(M+H) + 560.2074,found 560.2073.

[0087]

[0088] 129.4(d,J=4.0 Hz),127.2,115.6(d,J=20.0 Hz),45.8,21.5,12.2;IR(neat)cm -1 3005,1587,1499,1275,1261,895,760.

[0089]

[0090] CDCl3)δ143.2,137.7,136.5,135.22,134.1,131.8,130.7,129.8,128.1,127.2,46.0,21.6,21.6,12.0;IR(neat)cm -1 3006,1334,1275,1261.895,750;HRMS(ESI-TOF,m / z)calcd for C 25 H 30 NO2SSi(M+H) + 436.1761,found.436.1762.

[0091]

[0092] J=8.0,1H),7.84(d,J=8.8 Hz,2H),7.69–7.62(m,3H),7.49–7.40(m,4H),7.39–7.32(m,2H),7.29(d,J=7.2 Hz,2H),7.25(d,J=8.0 Hz,2H),3.63(ddd,J=12.8,7.6,4.8Hz,2H),3.41(ddd,J=12.8,7.6,4.8 Hz,2H),2.38(s,3H),1.72–1.53(m,4H); 13C NMR (100MHz, CDCl3) δ143.2,137.1,136.2,135.2,135.2,134.7,133.6,131.6,131.0,129 .8,129.8,129.3,128.3,128.2,127.2,126.2,125.8,125.2,46.1,21.6,13.0;IR(neat)cm -1 3005,2987,1462,1275,1260.764; HRMS(ESI-TOF,m / z)calcd for C 27 H 28 NO2SSi(M+H) + 458.1605, found 458.1609.

[0093]

[0094] 4H). 13 C NMR(100MHz, CDCl3)δ143.1,135.9,134.4,133.0,130.0,129.7,128.1,127.1,46.1,21.5,10.4.HRMS(ESI-TOF,m / z)calcd for C 17 H 22 NO2SSi(M+H) + 332.1135, found 332.1136.

[0095] II. Synthesis of aryl-substituted 4-silazinonidine via B(C6F5)3 / Pd relay catalysis

[0096]

[0097] Method B: Under argon protection, B(C6F5)3 solution (15.3 mg dissolved in 0.5 mL DCM, 15 mol%) was slowly added to a phenylsilane 22a solution (49 mg dissolved in 0.5 mL DCM, 0.45 mmol, 2.25 equiv.). After reacting for 1 minute, 10 μL of N,N-divinyl-p-toluenesulfonamide solution (67 mg dissolved in 0.5 mL DCM, 1.5 equiv.) was added to the system, and the reaction was carried out at room temperature for 3 hours. Subsequently, N,N-dimethylaniline (64 μL, 2.5 equiv.) was added to the system, and the mixture was stirred for 30 minutes before adding NMP (1.0 mL). Dichloromethane was removed from the system under reduced pressure. The mixture was then transferred to a glove box, and aryl iodine compound 28 (0.2 mmol, 1.0 equiv.), potassium phosphate (88 mg, 0.4 mmol, 2.0 equiv.), and Pd(tBu3P)2 (5 mg, 5 mol%) were added sequentially. The mixture was removed from the glove box and stirred at room temperature for 10 hours. After the reaction was complete, the mixture was diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified under reduced pressure to remove the organic solvent. The crude product was purified by column chromatography using silica gel to obtain the corresponding silypiperidine 29.

[0098]

[0099] 1.41 (t, J = 6.0 Hz, 4 H); 13 C NMR (100MHz, CDCl3) δ161.1,143.1,136.3,136.2,134.6,134.5,129.8,129.7,128.2,127.1,124.6,114.0,55.1,45.0,21.5,12.1.IR(neat)cm -1 3006,2989,2845,1593,1260,1157,851; HRMS(ESI-TOF,m / z)calcd for C 24 H 27 NO3SSiNa(M+Na) + 460.1373, found 460.1375.

[0100]

[0101] 143.2,136.4,134.7,134.1,129.9,129.8,128.2,127.1,45.9,21.5,12.0;IR(neat)cm -13005,1493,1334,1260,1075,750.;HRMS(ESI-TOF,m / z)calcd for C 23 H 26 NO2SSi(M+H) + 408.1448,found408.1450.

[0102]

[0103] 4H); 13 C NMR(100 MHz,CDCl3)δ143.2,140.0,134.8,134.7,134.4,130.3,129.9,129.8,129.1,128.2,127.2,46.0,21.6,12.1;IR(neat)cm -1 3007,2928,1598,1334,1275,852;HRMS(ESI-TOF,m / z)calcd for C 24 H 27 NO2SSiNa(M+Na) + 444.1424,found444.1426.

[0104]

[0105] (100 MHz,CDCl3)δ157.8,143.4,136.3,135.9,134.6,134.4,129.9,129.8,128.2,127.1,124.1,115.6,46.1,21.6,12.1;HRMS(ESI-TOF,m / z)calcd forC 23 H 25 NO3SSiNa(M+Na) + 446.1217,found 446.1220.

[0106]

[0107] 1.37(t,J=6.4 Hz,4H). 13 C NMR(100 MHz,CDCl3)δ148.1,143.1,136.3,136.1,135.0,134.7,129.8,129.7,128.1,127.2,121.2,114.9,46.1,21.6,12.2;IR(neat)cm - 13473,3379,3017,2929,1579,1329,1154,850;HRMS(ESI-TOF,m / z)calcd forC 23 H 26 N2O2SSiNa(M+Na) + 445.1376,found445.1380.

[0108]

[0109] 164.2(d,J=249.7 Hz),143.3,136.7(d,J=7.6 Hz),136.3,134.6,133.8,130.1,129.8,129.7,128.4,127.2,115.6(d,J=19.8 Hz),45.9,21.6,12.1;IR(neat)cm - 1 3006,2931,2849,1588,1260,1113,1040,852;HRMS(ESI-TOF,m / z)calcd forC 23 H 24 FNO2SSiNa(M+Na) + 448.1173,found448.1176.

[0110]

[0111] 136.0,134.6,133.6,132.6,130.2,129.8,128.6,128.4,127.2,45.9,21.6,12.0;IR(neat)cm -1 3006,2930,1576,1261,1082,852;HRMS(ESI-TOF,m / z)calcd forC 23 H 24 ClNO2SSiNa(M+Na) + 464.0878,found 464.0880.

[0112]

[0113] 1.47(dd,J=7.2,5.2 Hz,4H); 13C NMR(100 MHz,CDCl3)δ167.1,143.3,140.5,136.3,134.7,134.7,133.3,131.4,130.2,129.9,129.0,128.4,127.2,52.3,45.9,21.6,11.8;IR(neat)cm -1 3006,1721,1429,1334,1277,1158,852;HRMS(ESI-TOF,m / z)calcd forC 25 H 27 NO4SSiNa(M+Na) + 488.1322,found 488.1325.

[0114]

[0115] 3H),1.47(t,J=6.4 Hz,4H); 13 C NMR(100 MHz,CDCl3)δ198.3,143.3,140.9,138.1,136.3,135.0,134.7,133.3,130.3,129.9,128.5,127.7,127.2,45.9,26.8,21.6,11.8;IR(neat)cm -1 2929,2850,1683,1596,1333,1265,1156,852;HRMS(ESI-TOF,m / z)calcdfor C 25 H 27 NO3SSiNa(M+Na) + 472.1373,found472.1375.

[0116]

[0117] CDCl3)δ143.4,139.5,136.4,135.0,134.6,133.1,131.9(q,J=32.4 Hz),130.3,

[0118] 129.9,128.5,127.2,124.8(q,J=3.7 Hz),124.1(q,J=270.9 Hz),45.8,21.6,11.8.;IR(neat)cm -1 3006,1428,1392,1325,1275,1059,853;HRMS(ESI-TOF,m / z)calcd forC 24 H24 F3NO2SSiNa(M+Na) + 498.1141,found 498.1146.

[0119]

[0120] (m,1H),3.62–3.52(m,2H),3.48–3.36(m,2H),2.38(s,3H),1.53–1.40(m,4H).; 13 CNMR(100 MHz,CDCl3)δ143.2,136.9,136.3,135.3,134.8,129.8,129.7,128.1,128.1,127.6,127.2,124.6,123.0,111.4,102.6,46.2,21.6,12.4;IR(neat)cm -1 3380,1329,1260,1155,1075,850;HRMS(ESI-TOF,m / z)calcd for C 25 H 26 N2O2SSiNa(M+Na) + 469.1376,found469.1380.

[0121]

[0122] 2.38(s,3H),1.48(t,J=6.4 Hz,4H); 13 C NMR(100 MHz,CDCl3)δ156.2,145.3,143.2,136.4,134.7,134.5,130.3,129.9,129.8,128.3,128.2,127.7,127.5,127.2,111.7,106.5,46.0,21.6,12.4;IR(neat)cm -1 2929,1597,1457,1332,1157,851;HRMS(ESI-TOF,m / z)calcd for C 25 H 25 NO3SSiNa(M+Na) + 470.1217,found470.1220.

[0123]

[0124] 3H),1.51(t,J=6.4 Hz,4H); 13C NMR(100 MHz,CDCl3)δ155.1,154.3,143.3,136.3,134.7,134.1,133.6,131.8,131.7,130.2,129.8,128.5,128.4,127.2,123.5,45.9,21.6,12.1;IR(neat)cm -1 3053,2930,1597,1333,1264,1155,851;HRMS(ESI-TOF,m / z)calcdfor C 24 H 24 N2O2S2SiNa(M+Na) + 487.0941,found 487.0942.

[0125]

[0126] (s,3H),1.48–1.34(m,4H); 13 C NMR(100 MHz,CDCl3)δ149.2,147.8,143.2,136.4,134.6,134.2,123.0,129.8,129.0,128.3,127.2,126.8,113.7,109.0,100.9,45.9,21.6,12.2;IR(neat)cm -1 3006,1484,1419,1275,1235,1157,851;HRMS(ESI-TOF,m / z)calcd forC 24 H 25 NO4SSiNa(M+Na) + 474.1166,found 474.1168.

[0127]

[0128] 1.25(m,2H); 13 C NMR(100 MHz,CDCl3)δ148.3,147.4,143.3,136.8,135.9,134.2,133.4,130.3,129.8,128.3,127.1,112.7,86.0,45.8,27.9,21.5,12.5;IR(neat)cm -1 2987,1747,1355,1260,1154,961;HRMS(ESI-TOF,m / z)calcd for C 25 H 31N3O4SSiNa(M+Na) + 520.1697,found 520.1700.

[0129]

[0130] (m,2H),1.45–1.37(m,2H); 13 C NMR(100 MHz,CDCl3)δ143.3,136.6,136.3,134.4,134.0,133.1,132.2,130.2,129.8,128.7,128.3,127.2,45.9,21.6,13.2;IR(neat)cm - 1 3006,1428,1333,1260,1157,994,854;HRMS(ESI-TOF,m / z)calcd for C 21 H 23 NO2S2SiNa(M+Na) + 436.0832,found436.0835.

[0131]

[0132] 143.6,143.2,136.2,134.6,134.1,130.0,129.8,128.3,127.2,115.8,106.8;HRMS(ESI-TOF,m / z)calcd for C 27 H 33 N2O3SSi(M+H) + 493.1976,found 393.1973.

[0133]

[0134] 3.58–3.38(m,4H),2.39(s,3H),1.46(t,J=6.4 Hz,4H).; 13 C NMR(100 MHz,CDCl3)δ143.2,141.4,141.3,136.1,135.9,134.6,133.8,131.9,130.0,129.8,128.3,127.1,126.7,118.7,108.0,45.8,21.5,12.0;IR(neat)cm -12924,2849,1596,1521,1260,1157,1091,852;HRMS(ESI-TOF,m / z)calcd for C 26 H 27 N3O2SSiNa(M+Na) + 496.1485,found496.1486.

[0135]

[0136] (s,3H),1.44(t,J=6.4 Hz,4H); 13 C NMR(150 MHz,CDCl3)δ170.5,163.1,143.2,141.6,136.7,136.3,134.6,134.0,130.1,129.8,128.3,127.2,123.8,117.9,112.8,52.5,45.9,21.6,12.1;IR(neat)cm -1 3006,1674,1580,1440,1331,1260,1175,851;HRMS(ESI-TOF,m / z)calcd for C 25 H 27 NO5SSiNa(M+Na) + 504.1271,found 504.1275.

[0137]

[0138] 1H),6.79(dd,J=8.4,2.8 Hz,1H),6.73(d,J=2.8 Hz,1H),5.03(s,2H),3.60–3.40(m,4H),2.96–2.87(m,2H),2.55–2.35(m,5H),2.31–2.21(m,1H),2.21–1.94(m,4H),1.71–1.49(m,6H),1.46(t,J=6.4 Hz,4H),0.92(s,3H); 13C NMR(150 MHz,CDCl3)δ220.9,156.9,143.2,139.1,138.0,136.4,135.0,134.7,134.1,133.7,132.6,123.0,129.8,128.3,127.2,127.2,126.5,114.9,112.4,69.8,50.5,48.1,45.9,44.1,38.5,36.0,31.7,29.8,26.6,26.1,21.7,21.6,13.96,12.0;IR(neat)cm -1 2927,2855,1735,1606,1574,1333,1091,851;HRMS(ESI-TOF,m / z)calcd for C 42 H 47 NO4SSiNa(M+Na) + 712.2887,found712.2880.

[0139]

[0140] 2981,2929,1749,1454,1313,1260,897,850;HRMS(ESI-TOF,m / z)calcd forC 20 H 27 NO2SSiNa(M+Na) + 396.1424,found 396.1425.

[0141]

[0142] (m,2H),1.49(t,J=6.4 Hz,4H),1.45–1.37(m,2H),0.92(t,J=7.2 Hz,3H). 13 CNMR(100 MHz,CDCl3)δ134.74,134.23,130.02,128.35,51.15,45.73,25.48,21.79,13.72,12.73.;IR(neat)cm -1 3005,2987,1460,1275.;HRMS(ESI-TOF,m / z)calcd forC 20 H 27 NO2SSiNa(M+Na) + 396.1424,found 396.1422.

[0143]

[0144] 127.55,46.18,11.91.;IR(neat)cm -1 2931,2849,1427,1336,1150,850.;HRMS(ESI-TOF,m / z)calcd for C 20 H 21 NO2S2SiNa(M+Na) + 422.0675, found 422.0670.

[0145] III. Derivatization Experiments and Data Characterization

[0146]

[0147] Under argon protection, naphthalene (770 mg, 6 mmol, 6.0 equiv), anhydrous tetrahydrofuran (5.0 mL), and sodium granules (209 mg, 6.0 mmol, 6.0 equiv.) were added sequentially to a dry 15 mL reaction tube. The mixture was stirred at room temperature until the solution turned dark green. At -20 °C, 29b (407 mg in 2.0 mL of THF, 1.0 mmol, 1.0 equiv.) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 30 minutes. Once the starting material had completely disappeared, MeOH (5.0 mL) was added to quench the reaction. The pH was adjusted to alkaline, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified under reduced pressure to remove the organic solvent. The crude product was separated by silica gel column chromatography to give 130 mg of a colorless viscous liquid 37 in 51% yield.

[0148]

[0149] Under argon protection, compound 29u (40 mg, 0.11 mmol, 1.0 equiv.), anisole (118 mg, 11.0 mmol, 10.0 equiv.), and dichloromethane (2.0 mL) were added sequentially to a dry 15 mL reaction tube. At 0 °C, trifluoromethanesulfonic acid solution (0.44 mmol, 0.2 M in DCM, 4.0 equiv.) was slowly added to the reaction system and stirred for 2 hours. The mixture was then transferred to room temperature until the reactants had completely reacted. The reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane (3 × 30 mL), and the combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified under reduced pressure to remove the organic solvent. The crude product was separated by silica gel column chromatography to give 15.6 mg of a colorless viscous liquid 37 in 62% yield. f =0.2 (dichloromethane:methanol = 5:1);1 H NMR (400MHz, CDCl3) δ7.56–7.52(m,4H),7.50–7.38(m,6H),3.46(t,J=6.4Hz,4H),1.66(t,J=6.4Hz,4H); 13 C NMR(100MHz, CDCl3)δ134.7,131.7,130.7,128.7,45.2,9.1; HRMS(ESI-TOF,m / z)calcd for C 16 H 19 NSiNa(M+Na) + 276.1179, found 276.1176.

[0150]

[0151] Under argon protection, adamantyl chloride (30.0 mg, 0.1 mmol, 0.2 M in DCM, 1.0 equiv.) and DIPEA (38.7 mg, 0.3 mmol, 3.0 equiv.) were added sequentially to a solution of compound 37 (25.3 mg, 0.1 mmol, 1.5 equiv.). After reacting at room temperature for 2 hours, the reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane (3 × 5.0 mL), and the combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified under reduced pressure to remove the organic solvent, and the crude product was separated by column chromatography with silica gel to give 40 mg of pale yellow solid 38 in 96% yield. Melting point: 141.6–147.9 °C; R f =0.3 (petroleum ether: ethyl acetate = 15:1); 1 H NMR (400MHz, CDCl3) δ7.53(d,J=6.4Hz,4H),7.45–7.34(m,6H),3.88(t,J=6.0Hz,4H),2.05(s,9H),1.74(s,6H),1.38(t,J=6.0Hz,4H); 13 C NMR (100MHz, CDCl3) δ176.3,134.9,134.7,129.8,128.3,45.3,42.3,39.5,36.8,28.8,12.4; IR(neat)cm -1 2904,2850,1619,1427,1260,1114,854; HRMS(ESI-TOF,m / z)calcd forC 27 H 34 NOSSi(M+H) + 416.2404, found 416.2403.

[0152]

[0153] Under argon protection, compound 37 (25.3 mg, 0.1 mmol, 1.0 equiv.), 3,5-dimethoxybenzyl bromide (26.0 mg, 0.11 mmol, 1.1 equiv.), potassium carbonate (28.0 mg, 0.2 mmol, 2.0 equiv.), and acetonitrile (1.0 mL) were added sequentially to a dry reaction tube. After reacting for 3 hours at room temperature, water (5.0 mL) was added to dilute the system. The mixture was extracted with dichloromethane (3 × 5.0 mL), and the combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified under reduced pressure to remove the organic solvent. The crude product was separated by silica gel column chromatography to give 24 mg of a yellow oily liquid 39 in 60% yield. f =0.4 (dichloromethane:methanol = 20:1); 1 H NMR (400MHz, CDCl3) δ7.58–7.52(m,4H),7.42–7.34(m,6H),6.55(s,2H),6.36(t,J= 2.4Hz,1H),3.79(s,6H),3.55(s,2H),2.83(t,J=6.4Hz,4H),1.38(t,J=6.0Hz,4H); 13 C NMR (100MHz, CDCl3) δ160.9,134.8,129.5,128.1,106.7,99.1,62.8,55.5,52.4,11.4; IR(neat)cm -1 2925,2797,1596,1463,1428,1152,973,700; HRMS(ESI-TOF,m / z)calcd for C 25 H 30 NO2Si(M+H) + 404.2040, found 404.2035.

[0154]

[0155] In a glove box, compound 37 (37.8 mg, 0.15 mmol, 1.0 equiv.), p-bromoanisole (28.0 mg, 0.15 mmol, 1.0 equiv.), Pd(t-Bu3P)2 (5 mmol%), sodium tert-butoxide (10 mol%), and xylene (1.0 mL) were added sequentially to a dry reaction tube. The reaction was then removed from the glove box and the mixture was reacted at 100 °C for 12 hours. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography using silica gel to give 23 mg of a white solid 40 in 42% yield. Melting point: 99.4–108.9 °C; R f =0.4 (petroleum ether:ethyl acetate = 10:1); 1 H NMR (400MHz, CDCl3) δ7.57–7.50(m,4H),7.43–7.33(m,6H),6.91(d,J=8.8Hz,2H) ,6.86(d,J=9.2Hz,2H),3.79(s,3H),3.70(t,J=6.0Hz,4H),1.41(t,J=6.0Hz,4H); 13 C NMR (100MHz, CDCl3) δ152.0,143.2,135.7,134.7,129.7,128.2,116.0,115.1,55.8,47.8,9.2; IR(neat)cm -1 3005,2930,1509,1260,1143,750; HRMS(ESI-TOF,m / z)calcd for C 23 H 26 NOSi(M+H) + 360.1778, found 360.1774.

[0156] The above description is merely a preferred embodiment of the present invention. It should be understood that the present invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or related technologies or knowledge. Modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the present invention should be within the protection scope of the appended claims.

Claims

1. A process for the synthesis of 1,4-silazacyclic compounds, characterized in that, The method comprises the following steps: synthesizing 1,4-silazacyclic compounds by using divinylamine and disilane as substrates, B(C6F5)3 as a catalyst, mixing disilane and B(C6F5)3 in a solvent I first, and then adding divinylamine in the solvent I; The temperature of the reaction is 0-100 ℃, the time is 0.2-6 hours, the molar ratio of the divinylamine to the disilane is 1:1-5, the amount of the B(C6F5)3 is 5-15 mol%, the solvent I is one of dimethylbenzene, toluene, chlorobenzene, dichloromethane and dichloroethane, and the reaction formula is as follows: wherein R is one of p-tolyl, n-butyl, t-butyl, 2-thienyl, R 1 and R 2 are each one of hydrogen, C1-C6 alkyl, C5-C7 cycloalkyl, aryl, said C1-C6 alkyl, C5-C7 cycloalkyl, aryl being each independently substituted by one or more of each independently hydrogen, C1-C6 alkyl, halogen, aryl, and R 1 and R 2 are not simultaneously hydrogen.

2. The method of synthesis of claim 1, wherein, The temperature of the reaction is 10-40 ℃, and the time is 0.5-1 hour; The molar ratio of the divinylamine to the disilane is 1:1-2; The amount of the B(C6F5)3 is 8-12 mol%.

3. The method of synthesis of claim 1, wherein, The feeding mode of the divinylamine, the disilane and the B(C6F5)3 is that the disilane and the B(C6F5)3 are reacted for 0.5-10 minutes first, and then the divinylamine is added.

4. A method for producing a sila-piperidine compound, characterized by, The method comprises the following steps: The 1,4-silazacyclic compounds are synthesized by the method in any one of claims 1-3; The method further comprises the following steps: The N,N-dimethyl aniline is added first, the solvent I is removed, and then the solvent II is added; or the N,N-dimethyl aniline is added first, the solvent I is removed, and then the solvent II is added; Then, the aryl compound, the base and the palladium catalyst are added to perform a coupling reaction; The base is potassium phosphate or diisopropylamine; the palladium catalyst is bis(tri-tert-butylphosphine)palladium, tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium; and the solvent II is N-methylpyrrolidone or toluene; The reaction formula is as follows: wherein said R is one of p-tolyl, n-butyl, t-butyl, 2-thienyl; said R 1 and one of said R 2 is a hydrogen atom, the other is a phenyl or p-tolyl group; said X is one of iodine or bromine; aryl is one of a benzene ring or an aromatic heterocycle, one or more hydrogen atoms of said benzene ring or aromatic heterocycle is replaced by a C1-C4 alkyl group, an aryl group, a halogen, an ester group, or a heterocycle containing sulfur, nitrogen, or oxygen atoms.

5. The method of synthesis of claim 4, wherein, The amount of the N,N-dimethyl aniline added is 1-5 equivalents; The molar ratio of the silapiperidine compound to the aryl compound is 1:0.5-2; The amount of the base is 1-3 equivalents; The amount of the palladium catalyst is 2.5-15 mol%.

6. The method of synthesis of claim 5, wherein, The amount of the N,N-dimethyl aniline added is 1.5-2.5 equivalents; The molar ratio of the silapiperidine compound to the aryl compound is 1:0.5-1; The amount of the base is 1.5-2 equivalents; The amount of the palladium catalyst is 5-7.5 mol%.

7. The method of synthesis of claim 4, wherein, The temperature of the coupling reaction is 25 ℃, and the time is 10-24 hours; The method for removing the solvent I is a reduced-pressure distillation method; After the solvent II is added, the mixture needs to be fully mixed for 10-60 minutes.

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