CN113980044B - Preparation method of Ir-O-P type catalyst diboronic acid/ester compound - Google Patents

Abstract

The invention discloses a preparation method of an Ir-O-P type catalyst diboronic acid/ester compound, which belongs to the technical field of organic synthesis and comprises the following steps: under air conditions, an Ir metal complex and a phosphine ligand form an active Ir-O ‑P type catalyst; under anhydrous and oxygen-free conditions, organic boron source [B], β‑N‑aryl (alkane) base substrate, Ir‑O‑P type catalyst is added in an organic solvent, and reacted at 60‑120 °C, After the reaction is finished, the aryl (alkyl) base diboronic acid/boric acid ester compound is obtained through post-treatment. This reaction can be used to obtain aryl (alkyl) diboronic acid/boronate compounds through a one-pot method, which makes up for the limitations of multi-step synthesis of such compounds and limited substrate scope. In addition, in the preparation of aryltriazene-type diborides, even if no ligand is added, the target compound can be obtained in a higher yield. Based on the above advantages, this method also shows a very high yield when it is expanded to a gram-level reaction. Yield, laying a good foundation for the application in the field of drug synthesis or material development.

Description

A kind of preparation method of Ir-O-P type catalyst diboronic acid/ester compound

technical field

The invention belongs to the technical field of organic synthesis, and specifically relates to the research and development of a new Ir-O-P catalyst and its application in the preparation of aryl (alkyl) diboronic acid/boric acid ester compounds.

Background technique

Metal-catalyzed C–H bond activation is a rapidly developing new method in organic synthesis. The formation of C-B bond is one of the important forms of C-H bond activation. Due to the unique chemical properties of organoboron (borane, boric acid, borate ester), various forms of functional group transformation can be realized, which has important application value for the modification of drug structure and the development of new materials.

In the prior art, limited by raw materials and methods, only arylhydrazone diborides and diborides of 2-phenylpyridine derivatives can be synthesized.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides a method for preparing Ir-O-P catalyst diboronic acid/ester compound. The method is simple to operate, and the raw materials are cheap and easy to obtain, while avoiding the use of expensive organic ligands and facilitating large-scale Preparation and application, in addition, aryl oximes, aryl hydrazones, aryl triazenes and 2-phenylpyridine derivatives all have very mature and simple synthetic methods. However, limited by raw materials and methods, traditional methods can only synthesize arylhydrazone diborides and diborides of 2-phenylpyridine derivatives. However, with this method, a wide variety of aryl(alkyl)diboronic acid/boronate compounds can be obtained in one pot only by using cheap and readily available triphenylphosphine as a ligand. What is more noteworthy is that in the preparation of aryl triazene diborides, even without adding ligands, the target compound can be obtained in a higher yield. Based on the above advantages, this method also shows a very high yield when extended to the gram-level reaction, which lays a good foundation for the application in the field of drug synthesis or material development, and solves the problems raised in the above background technology.

In order to achieve the above object, the present invention provides the following technical scheme: a kind of preparation method of Ir-O-P type catalyst diboronic acid/ester compound, comprises the following steps:

S1. Under air conditions, form an Ir-O-P type active catalyst by reacting metal iridium species and ligands in an organic solvent, and then add a β-N aromatic (alkane) base substrate and an organic boron source [B] under anaerobic conditions. , Aryl (alk) base diboronic acid/boric acid ester compound can be obtained; Under anhydrous and oxygen-free conditions, pass metal iridium catalyst and β-N aromatic (alk) base substrate in organic solvent, and organic boron source [B ] Oxidative addition obtains aryl (alkyl) base diboronic acid/boric acid ester compound;

S2, Ir-O-P type active catalyst and β-N-aryl (alkane) type substrate oxidative addition to activate carbon-hydrogen bond, form aryl (alkyl) base diboronic acid/boric acid ester compound through boron transfer and reduction elimination process; The metal iridium catalyst undergoes oxidative addition with organic boron sources, and then forms ortho-substituted aryltriazene diboronic acid/boronate compounds with aryltriazene-type substrates through oxidative addition, boron transfer and reduction elimination processes ;

S3. Post-treating the formed aryl(alkyl)diboronic acid/boronate compound.

To further optimize this technical solution, the reaction temperature of the steps S1-S2 is 60-120°C, and the reaction time is 12-120 hours;

The organic boron source [B] includes pinacol diborate, neopentyl glycol diborate, biscatechol borate, tetramethylbiboron, tetrakis(dimethylamino)biboron, 1 - pinacol-2-(1,8)naphthalenediamine bisboronate;

The β-N aryl (alk) bases include β-N-aryl (alk) base compounds including aryl oximes, aryl hydrazones, aryl triazenes and 2-phenylpyridine derivatives;

The metal iridium catalyst comprises methoxycyclooctadiene iridium, cyclooctadiene iridium chloride, iridium acetate, iridium dioxide, iridium chloride, dodecacarbonyl tetrairidium, tri(acetylacetonate) iridium, 1 ,5-cyclooctadiene(η5-indene)iridium, tris[2-phenylpyridine-C2,N]iridium, bis(triphenylphosphine)iridium carbonyl chloride, bis(1,5-cyclooctadiene ) iridium tetrafluoroborate, bis(4,6-difluorophenylpyridine-N,C2) iridium picolinate;

The phosphine-containing ligands include triphenylphosphine, tri(p-methylphenyl)phosphine, tributylphosphine, 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl, benzyldiphenyl Arylphosphine, tris(2-tolyl)phosphine, bis[(2-diphenylphosphino)phenyl]ether, arylphosphine and alkyl including 2,2'-bis(diphenylphosphino)biphenyl Phosphine ligands;

Described organic solvent comprises tetrahydrofuran, toluene, p-xylene, cyclohexane dichloromethane, chloroform, ethyl acetate, acetonitrile, benzene or above-mentioned mixed solvent, and described organic solvent will fully dissolve the raw material that participates in reaction, can be proton solvents, aprotic solvents or a mixture of the two;

Further, the structure of the organic boron source [B] is shown in formulas (I) to (VI):

Further, the structure of the β-N-aryl (alkane) base substrate is shown in formulas (VII) to (XV):

Further, the structure of the aryl (alkyl) diboronic acid/boronate compound is shown in formulas (XVI) to (XXIV):

Further, in formulas (VII)～(XXIV), R ₁ includes: halogen substituted in any position, such as F, Cl, Br, I, alkyl and substituted alkyl, such as methyl, trifluoromethyl, methyl Oxygen, aryl, such as phenyl, heteroaryl, such as pyridine, some substituents are shown below;

H,

_R2 includes: halogen substituted in any position, such as F, Cl, Br, I, hydrogen atom, alkyl and substituted alkyl, such as methyl, isopropyl, isobutyl, benzyl, saturated chain or ring Alkyl, partial substituents as shown below:

H,

R ₃ includes alkyl and substituted alkyl, such as methyl, R ₂ and R ₃ form a ring, such as piperidine ring, morpholine ring, piperazine ring.

Further optimize this technical scheme, the preparation method of described active catalyst also includes following other methods:

1) Use iridium element to react with acid to form a salt first, and then react with triaryl/alkylphosphine in an organic solvent under air conditions, wherein the iridium element is iridium powder, and the acid is sulfuric acid, hydrochloric acid, hydrofluoric acid or acetic acid.

2) Using iridium-containing salt or complex and triaryl/alkylphosphine to react in an organic solvent under air conditions.

Further, the molecular formula of the active catalyst formed by reacting with a representative triphenylphosphine is C ₅₄ H ₄₃ IrOP ₃ , and its structure is characterized by containing an Ir-OP bond, and the structure is as follows:

To further optimize this technical scheme, the molar ratio of the β-N-aryl (alkane) base substrate and organic boron source [B] is 1.0: 1.0-4.0, and the addition of catalyst and ligand is 1% of the substrate. 0.005%-10%, fully reacted under optimized conditions, used to reduce the amount of reactants and improve atom economy.

Further optimize this technical scheme, described aryl (alkyl) base diboronic acid/boric acid ester compound is a kind of of compound shown in formula (I-1)-(I-37), described formula (I-1)- (I-37) as follows:

Further optimize this technical scheme, the reaction formula of described β-N-aryl (alkane) base substrate and organoboron source [B] is as follows:

To further optimize this technical solution, in the S3, the post-treatment process includes: concentration, sample mixing with silica gel, and finally purification by column chromatography, and some products can be purified by recrystallization or beating.

Compared with the prior art, the present invention provides a method for preparing an Ir-O-P catalyst diboronic acid/ester compound, which has the following beneficial effects:

1. The preparation method of the Ir-O-P type catalyst diboronic acid/ester compound obtains the aryl (alkyl) base diboronic acid/boric acid ester compound through a one-pot method, which makes up for the need for multi-step synthesis of this type of compound and the limited range of substrates However, in the preparation of aryl triazene diborides, the target compound can be obtained in a higher yield even without adding a ligand. The high yield lays a good foundation for the application in the field of drug synthesis or material development.

2. The preparation method of the Ir-O-P type catalyst diboronic acid/ester compound is easy to operate, simple in post-treatment, cheap and easy to obtain reaction raw materials, strong designability of reaction substrates, good compatibility of substrate functional groups, and can be designed according to actual needs The required aryl (alkyl) base diboronic acid/boric acid ester compound is synthesized, which has strong practicability.

Description of drawings

Fig. 1 is the structural representation of various aryl (alkyl) base diboronic acid/boric acid ester compounds (I-1)-(I-22) prepared by the preparation method proposed by the present invention;

Fig. 2 is a schematic structural diagram of various ar(alk)yl diboronic acid/boronate compounds (I-23)-(I-37) prepared by the preparation method proposed by the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Embodiment one:

A kind of preparation method of Ir-O-P type catalyst diboronic acid/ester compound comprises the steps: under anhydrous and oxygen-free condition, organic boron source [B], β-N-aryl (alkane) substrate, metal iridium catalyst and The organic phosphine ligand is added into the organic solvent and reacted at 60-120° C. After the reaction is completed, the aryl (alkyl) diboronic acid/boric acid ester compound is obtained through post-treatment.

The structure of the organic boron source [B] is shown in formulas (I) to (IV):

The structure of the β-N-aryl (alkane) base substrate is shown in formulas (IV) to (VII):

The structure of described aryl (alkyl) base diboronic acid/boric acid ester compound is as shown in the formula:

The molar ratio of the β-N-aryl(alkane)-based substrate to the organic boron source [B] is 1.0:1.0-4.0.

The reaction formula is as follows:

After our study of the reaction mechanism, the oxidative addition and reductive elimination processes were demonstrated through controlled experiments. Coordination of metal iridium with β-N-aryl (alkane) substrate or phosphine-containing ligand, and then oxidative addition of organic boron source to generate active catalyst; active catalyst and β-N-aryl (alkane) substrate oxidative addition to Activate the carbon-hydrogen bond to form aryl (alkyl) diboronic acid/boronate compounds through boron transfer and reduction elimination process.

In the present invention, the optional post-treatment process includes: concentration, sample mixing with silica gel, and finally purification by column chromatography, and some products can be purified by recrystallization or beating.

As preferably, _R Can be any position of fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, phenyl, at this time, the described β-N aromatic (alkane) base substrate is easy to obtain , and the reaction yield is higher.

As preferably, _R2 can be a hydrogen atom or a methyl group, and can also form a pyridine ring or a pyrazole ring with _R3 . At this time, the described β-N aromatic (alkane) base material is easy to obtain, and the yield of the reaction is relatively high. high.

As preferably, _R3 can be diisopropylamino, methoxy group, also can form pyridine ring or pyrazole ring with _R2 , at this moment, described β-N aromatic (alkyl) base substrate obtains easily, and the reaction The yield is higher.

Preferably, the reaction time is 12-120 hours. If the reaction time is too short, it is difficult to ensure the completeness of the reaction, and if the reaction time is too long, the reaction cost will be increased.

In the present invention, any organic solvent that can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency is quite different, preferably an aprotic solvent, which can avoid interaction with the imine structural unit of the reaction substrate , the reaction can proceed normally.

Preferably, the organic solvent is tetrahydrofuran, n-hexane, N,N-dimethylformamide, N,N-dimethylsulfoxide; as a further preference, when the organic solvent is tetrahydrofuran, various The conversion rate of the raw material is high and the post-treatment is simple. The amount of the organic solvent can completely dissolve the raw materials, and the amount of the organic solvent used for 1 mmol β-N-aryl (alkane) base substrate is 1-2 mL.

The triphenylphosphine described therein is the most preferred ligand because the yield of triphenylphosphine is higher and the cheapest and easy to obtain. Other triaryl (alkyl) phosphines can also be used as ligands to make the reaction happen, such as triphenylphosphine, tri(p-methylphenyl)phosphine and tricyclohexylphosphine.

Preferably, the metal iridium catalyst is methoxycyclooctadiene iridium, and the reaction yield is the highest at this time. Other iridium catalysts also allow the reaction to proceed, such as cyclooctadiene iridium chloride.

As a further preference, as shown in Figure 1 and Figure 2, the ar(alk)yl diboronic acid/boronate compound is one of the compounds shown in formulas (I-1) to (I-37).

In the above-mentioned preparation method, described organoboron source [B], metal iridium catalyst, triaryl (alkyl) phosphine all adopt commercially available products, can be purchased directly from the market, and described β-N-aryl (alk) base The substances can be directly purchased or prepared by simple and convenient methods.

Embodiment two:

Add methoxycyclooctadiene iridium, triphenylphosphine, β-N-aryl (alkane) base substrate, bispinacol borate, organic solvent 2mL in the Schlenk tube of 10mL according to the raw material ratio of Table 1, React with heating and stirring at 60-120°C. After the reaction is completed according to the reaction conditions in Table 2, concentrate, mix the sample with silica gel, and purify by column chromatography to obtain the corresponding aryl (alkyl) diboronic acid/boric acid ester compound. The reaction process is as follows: Shown:

Table 1

The reaction conditions of the foregoing examples of table 2 and the resulting product

In Table 2, T is the reaction temperature, and t is the reaction time.

Structural confirmation data of some compounds

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data of the aryl (alkyl) diboronic acid/boronate compound (I-1) prepared in Example I1 are:

¹ H NMR (400MHz, Chloroform-d) δ7.83(d, J=7.3Hz, 2H), 7.13(t, J=7.4Hz, 1H), 5.16–5.08(m, 1H), 3.97-3.93(m ,1H),1.32(d,J=6.8Hz,12H),1.25(s,24H); ¹³ C NMR(101MHz,Chloroform-d)δ165.2,138.7,123.6,83.1,48.1,45.3,25.0,23.9,19.8 .IR(ν,cm ^-1 ):2976,1580,1460,1392,1369,1331,1310,1300,1256,1221,1148,1132,966,881,847,775,652.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data of the aryl (alkyl) base diboronic acid/boronate compound (I-2) prepared by Example I2 is

¹ H NMR (400MHz, Chloroform-d) δ7.89(s,2H), 1.36(s,6H), 1.31(s,12H), 1.26(s,6H), 1.24(s,12H); ¹³ C NMR (101MHz,Chloroform-d)δ163.9,133.7(d,J＝3.6Hz),117.6,83.6,24.9,24.5.IR(ν,cm ^-1 ):2978,2926,1468,1368,1271,1140,1103, 1067,850,720.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data of the aryl (alkyl) base diboronic acid/boronate compound (I-3) prepared by Example I3 are

¹ H NMR (400MHz, Chloroform-d) δ7.90 (s, 2H), 5.14–5.03 (m, 1H), 4.01–3.90 (m, 1H), 1.31 (d, J=6.7Hz, 18H), 1.24 (s,18H); ¹³ C NMR(101MHz,Chloroform-d)δ163.9,140.7,117.6,83.3,48.3,45.6,24.9,23.7,19.6.IR(ν,cm ^-1 ):2978,1468,1371,1337 ,1313,1271,1140,1103,1067,964,849,603.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the aryl (alkyl) base diboronic acid/boronate compound (I-23) prepared by Example I23 is

¹ H NMR (400MHz, Chloroform-d) δ8.79(d, J=8.2Hz, 1H), 8.66(d, J=5.6Hz, 1H), 7.92(t, J=7.8Hz, 1H), 7.78( d,J=7.3Hz,2H),7.35(q,J=7.5Hz,2H),1.40(s,24H); ¹³ CNMR(101MHz,Chloroform-d)δ157.8,142.7,141.8,141.7,135.0,130.0, 122.5, 121.7, 82.1, 26.2.

The nuclear magnetic resonance ( ¹ HNMR and ¹³ C NMR) detection data of the aryl (alkyl) base diboronic acid/boronate compound (I-35) prepared by Example I35 is

¹ H NMR (400MHz, Chloroform-d) δ8.93(d, J=2.5Hz, 1H), 7.80(d, J=2.2Hz, 1H), 7.77(d, J=7.3Hz, 2H), 7.26( d, J＝14.6Hz, 1H), 6.46(t, J＝2.5Hz, 1H), 1.34(s, 24H); ¹³ CNMR (101MHz, Chloroform-d) δ145.8, 136.4, 135.1, 129.6, 126.8, 108.4, 82.7, 25.3.

Embodiment three:

The invention also discloses a water-resistant and oxygen-resistant Ir-O-P bond-containing novel metal iridium catalyst when preparing aryl (alkyl)-based diboronic acid/boric acid ester compounds, which can be widely used in various C-H bond boronations, substrates Good tolerance, catalytic activity is better than all kinds of commercially available metal iridium catalysts.

The beneficial effects of the present invention are:

1. The preparation method of the Ir-O-P type catalyst diboronic acid/ester compound obtains the aryl (alkyl) base diboronic acid/boric acid ester compound through a one-pot method, which makes up for the need for multi-step synthesis of this type of compound and the limited range of substrates However, in the preparation of aryl triazene diborides, the target compound can be obtained in a higher yield even without adding a ligand. The high yield lays a good foundation for the application in the field of drug synthesis or material development.

2. The preparation method of the Ir-O-P type catalyst diboronic acid/ester compound is easy to operate, simple in post-treatment, cheap and easy to obtain reaction raw materials, strong designability of reaction substrates, good compatibility of substrate functional groups, and can be designed according to actual needs The required aryl (alkyl) base diboronic acid/boric acid ester compound is synthesized, which has strong practicability.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (5)

1. a preparation method of diboronic acid/ester compound, is characterized in that, comprises the following steps: S1, under air conditions, form an active catalyst through the reaction of metal iridium species and ligands in an organic solvent; S2, under anaerobic conditions, add β-N aryl/alkyl substrate and organoboron source [B] to obtain aryl/alkyl diboronic acid/boronate compound; S3, post-processing the formed aryl diboronic acid/boric acid ester compound; The organic boron source [B] is selected from the group consisting of pinacol diborate, neopentyl glycol diborate, biscatechol borate, tetramethylbiboron, tetrakis(dimethylamino)biboron, 1-pinacol-2-(1,8) naphthalene diamine biborate, the structure is shown in formula (Ⅰ)～(VI):

The ligand is a phosphine-containing ligand selected from triphenylphosphine, tri(p-methylphenyl)phosphine, tri(2-tolyl)phosphine, bis[(2-diphenylphosphino)phenyl]ether , 2,2'-bis(diphenylphosphine)biphenyl; the structure of the β-N-aryl/alkyl substrate is selected from formulas (VII)～(XV-2):

The structure of the aryl/alkyl diboronic acid/boronate compound is selected from the following formulas (XVI)～(XXIV-2):

In formulas (VII)～(XXIV), R ₁ includes: H, any position substituted halogen, alkyl, trifluoromethyl, methoxy, phenyl, pyridine, R ₂ is selected from: a halogen hydrogen atom substituted in any position, an alkyl group, a benzyl group; R ₃ is selected from alkyl; The reaction temperature of the steps S1-S2 is 60-120°C, and the reaction time is 12-120 hours; The metal iridium species is selected from the group consisting of methoxycyclooctadiene iridium, cyclooctadiene iridium chloride, iridium acetate, iridium dioxide, iridium chloride, dodecacarbonyl tetrairidium, tri(acetylacetonate) iridium, 1,5-cyclooctadiene (η5-indene) iridium, tris[2-phenylpyridine-C2,N]iridium, bis(triphenylphosphine)iridium carbonyl chloride, bis(1,5-cyclooctadiene En) iridium tetrafluoroborate, bis(4,6-difluorophenylpyridine-N,C2) iridium picolinate; The organic solvent is selected from tetrahydrofuran, toluene, p-xylene, cyclohexane dichloromethane, chloroform, ethyl acetate, acetonitrile, benzene or the above-mentioned mixed solvents, and the organic solvent fully dissolves the raw materials participating in the reaction. 2. the preparation method of a kind of diboronic acid/ester compound according to claim 1 is characterized in that, the feed ratio of described β-N-aryl/alkyl substrate and organic boron source [B] in molar quantity is 1.0: 1.0-4.0, the amount of catalyst and ligand added is 0.005%-10% of the substrate. 3. The preparation method of a diboronic acid/ester compound according to claim 1, characterized in that, the aryl diboronic acid/boric acid ester compound is represented by formula (I-1)-(I-37) One of the compounds shown, the formulas (I-1)-(I-37) are as follows:

. 4. the preparation method of a kind of diboronic acid/ester compound according to claim 1, is characterized in that, the reaction formula of described β-N-aryl substrate and organoboron source [B] is as follows:

. 5. the preparation method of a kind of diboronic acid/ester compound according to claim 1 is characterized in that, in described S3, aftertreatment process comprises: concentrating, silica gel sample mixing, finally through column chromatography purification, part product can be Purified by recrystallization or beating.

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