RU2476421C1 - Method of producing 1,3-dicarbonyl derivatives of adamantanes - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,3-dicarbonyl derivatives of adamantane of general formula I

where R=H, X=OH, OMe, OEt, OPrⁱ, OBu^s, OCH₂CH(Et)Bu, OCH₂CF₃, OCH(CH₃)CF₃, OCH₂CF₂CF₂H, OCH₂CH₂CH₂Br, OCH₂C=CH, NEt₂, NC₅H10 (piperdyl), NC₄H₈O (morpholyl), C₆H₅NH, C₆H₄OMe, C₄H₃O (furyl); R=Me, X-OH, Me, OMe, O-Prⁱ, X=NC₄H₈O (morpholyl), C₄H₃O (furtyl), NEt₂, C₆H₅NH, C₆H₄OMe; involving carbonylation of an adamantane compound in the presence of electrophilic catalysts, where the adamantane compound used is adamantane or 1,3-dimethyladamantane and carbonylation is carried out under the action of CO at atmospheric pressure in a solution of CH₂Br₂ at temperature of 0-25°C for 0.5-3 hours, and the catalyst used is a super-electrophilic CBr₄·2AlBr₃ complex, in molar ratio [CBr₄-2AlBr₃]: [adamantane compound] = (1.5-2):1, and a nucleophilic substrate - water or alcohol - is added to the carbonyl derivative formed in situ, without extraction thereof, in an atmosphere of CO, said substrate containing an alkyl or acetylene or bromoalkyl or polyfluoroalkyl group; or an amine of an aliphatic or heterocyclic or aromatic series; or an aromatic hydrocarbon or an aromatic heterocycle; and reaction with a nucleophile is carried out at temperature of 0-25°C.

EFFECT: single-step method of producing 1,3-dicarbonyl derivatives of adamantanes with two identical carbonyl-containing groups in nodal positions of the adamantane nucleus enables to use readily available adamantane compounds as starting compounds.

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Description

The invention relates to the field of organic chemistry, namely to a 1,3-dicarbonyl derivative of adamantanes with two identical functional groups in the nodal positions of the adamantane nucleus, and more particularly, to a method for producing adamantanes of the general formula

where R = H, X = OH, OMe, OEt, OPr ⁱ ; OBu ^s , OCH ₂ CH (Et) Bu, OCH ₂ CF ₃ , OCH (CH ₃ ) CF ₃ , OCH ₂ CF ₂ CF ₂ H, OCH ₂ CH ₂ CH ₂ Br, OCH ₂ C≡CH, NEt ₂ , NC ₅ H ₁₀ (piperidyl), NC ₄ H ₈ O (morpholyl), C ₆ H ₅ NH, C ₆ H ₄ OMe, C ₄ H ₃ O- (furyl);

R = Me, X = OH, Me, OMe, O-Pr ⁱ , X = NC ₄ H ₈ O (morpholyl), C ₄ H ₃ O (furyl), NEt ₂ , C ₆ H ₅ NH, C ₆ H ₄ OMe.

Carbonyl derivatives of adamantanes (AdCO), in particular 1,3-dicarbonyl derivatives of adamantanes, are of great interest for use in various fields, including pharmacology, polymer chemistry and materials science.

The introduction of the AdCO group into the molecules of drug and biologically active compounds facilitates their transfer through cell membranes. Therefore, AdCO-modified biologically active compounds with improved drug parameters are promising as new-generation drugs (V.Yu. Kovtun, Khim.-Pharm. Journal, 1987, 28, 931). It is known that the introduction of an AdCO group into polymer molecules increases their thermal and chemical stability. (A.R. Khardin et al., Advances in Chemistry, 1982, 51, 480). The use of compounds containing the AdCO group as crown ethers (A.G. Yurchenko et al. ZhORKh, 1990, 26.1808), peptide ionophores (D. Ranganathan et al. J. Am. Chem. Soc., 1997) is described. 119, 11578; Angew. Chem. Int. Ed., 1996, 35, 1105), plasticizers (A.G. Yurchenko et al. ZhORKh, 1990, 26, 1808), insecticides, pesticides (S. Nakagawa et al. Agric. Biol. Chem, 1987, 51, 1355), optical materials (Y. Okada, WO 2007125829 A1), thermal coatings (T. Dang. J. Polymer Science, Part A. Polymer Chemistry, 2004, 42, 6134) and other valuable products (O. Josto, et al. JP 2007332068 A20071227; H. Yamamoto et al. WO 2003081295), as well as starting compounds for the production of biologically active substances promising for pharmaceuticals (Y. He Synthesis, 1994, 9, 989; V.Yu. Kovtun, Chem.-Pharm. Journal, 1987, 28, 931; M.-G.A. Schweigheimer, Usp. Chemistry, 1996, 65, 603). Compounds with an anisyl group, Ad '(COC ₆ H ₄ OMe) ₂ , (where Ad' is a mono- or disubstituted adamantyl group) can easily be converted into diols, Ad '(COC ₆ H ₄ OMe) ₂ , which are promising monomers for synthesis of valuable polymers. (D.Thuy et al. US Patent Application US 2005043449 A1).

Of particular interest among 1,3-dicarbonyl derivatives of adamantanes are dicarboxylic acids, 1,3-Ad (COOH) ₂ and 1,3-Me ₂ -5,7-Ad (COOH), which are the main synthons for the synthesis of other 1,3 -dicarbonyladamantanes (esters, amides, ketones), as well as polymers, crown ethers, dendrimers, ionophores. Currently known methods for producing 1,3-dicarbonyl derivatives of adamantanes are based on the use of 1,3-Ad (COOH) ₂ dicarboxylic acids as key intermediates.

Various methods are known for preparing l, 3-Ad (COOH) ₂ from AdH using formic acid in a medium of strong protic acids (a mixture of 60-65% nitric and 94% sulfuric acid) and 60% oleum. Yields are 65% (at 20 ° C for 1 h) (J.Dohm et al. Chem. Ber. Ger. 1991, 124, 915) and 83% (at 28 ° C for 4 h) (L.N. Butenko et al. ZhORKh, 1973, 9 (4), 728). A known method of producing 1,3-Ad (COOH) ₂ from AdH in a 20-fold excess of 90-103% sulfuric acid at a pressure of CO (6-150 atm) and a temperature of 90-160 ° C (A. Lamola. Pat. France No. 1353906, S.A. 1964, 61, 593). The disadvantages of this method is the use of aggressive media, high pressure and high temperature.

Other methods for producing Ad (COOH) _{2 are} known, based on the carbonylation of 1,3-disubstituted adamantanes with labile groups, for example 3-Br-1-AdCOOH (H. Stetter and C. Wullf, Chem. Ber. Ger. 1962, 95 , 667) or 3- (ONO) ₂ 1-AdCOOH (I.K. Moiseev et al., Zhork, 1983, 19, 5) in concentrated H ₂ SO ₄ . The disadvantages of the above methods are the need to carry out the reaction in harsh conditions: in an aggressive environment (sulfuric acid, nitric acid, oleum), which requires special equipment, and the use of expensive formic acid.

A known method for producing 1,3-dicarbonyl derivatives of adamantanes from 1,3-dibromo-adamantane (AdBr ₂ ), including the stage of formation of 1,3-Ad (COOH) ₂ as a result of carbonylation of AdBr ₂ under the influence of HCOOH in a less aggressive environment (in concentrated H ₂ SO ₄ ), but in the presence of Ag ₂ SO ₄ . The specified method includes the following stages:

(1) obtaining 1,3-Ad (COOH) ₂ ;

(2) isolation of 1,3-Ad (COOH) ₂ ;

(3) preparation and isolation of 1,3-Ad (COCl) ₂ ;

(4) the interaction of 1,3-Ad (COCl) ₂ with a nucleophilic substrate.

The disadvantages of this method are, firstly, that it is multi-stage; secondly, it uses 1,3-AdBr ₂ as the starting compound, which is synthesized using dry Br ₂ in the presence of extremely inconvenient for work and expensive BBr ₃ . In addition, the reaction is carried out in an aggressive environment (concentrated H ₂ SO ₄ ) and expensive HCOOH is used.

The known method for producing 1,3-Ad (COOH) ₂ from 1,3-Ad (OH) ₂ includes an additional step for producing a diol from 1,3-AdBr ₂ under the influence of AgNO ₃ . (H. Stetter and C. Wullf, Chem. Ber. Ger. 1960, 93, 1366).

A known method of producing 1,3-Ad (COOH) ₂ from 1-AdCOOH (LNButenko et al. Synthetic Commun., 1984, 14,2, 113), one of the disadvantages of which is to carry out both stages of obtaining 1-AdCOOH and 13-Ad (COOH) ₂ in a very aggressive environment, consisting of a mixture of concentrated HNO ₃ and H ₂ SO ₄ and oleum. The method includes the following steps:

(1) carbonylation of 1-AdCOOH with formic acid in a mixture of concentrated nitric, sulfuric acids and oleum;

(2) isolation of 1,3-Ad (COOH) ₂ ;

(3) preparation of 1,3-Ad (COCl) ₂ adamantanedicarboxylic acid dichloride by reaction of 1,3-Ad (COOH) ₂ with phosphorus pentachloride and its isolation;

(4) the interaction of 1,3-Ad (COCl) ₂ with a nucleophilic substrate (alcohol, amine, etc.).

The disadvantages of this method also include multi-stage, the need to use aggressive environments, special equipment and low-tech procedures for the isolation of the key intermediate product 1,3-Ad (COOH) ₂ from the aggressive environment.

Note that in some cases, the last stage of obtaining 1,3-dicarbonyl compounds from 1,3-Ad (COCl) ₂ dichloride with a nucleophile proceeds with poor selectivity and low yield. For example, the reaction of 1,3-Ad (COCl) ₂ with anisole and aluminum chloride as a catalyst leads to a mixture of 1,3-alkylated 1,3-Ac '(C ₆ H ₄ OMe) ₂ and acylated 1,3-Ad '(COC ₆ H ₄ OMe) ₂ products with a yield of the last 30% (I.N. Yagushkina et al., MLC, 1994, 30, 6, 842).

A known method for producing 1,3-dicarbonyl derivatives of adamantanes from adamantane, which was selected as a prototype (L.N. Butenko et al. ZhORKh, 1973, 9 (4), 728), which includes:

(1) obtaining 1,3-Ad (COOH) _{2 by} carbonylation of adamantane under the influence of HCOOH in a medium consisting of a mixture of 60% nitric and 94% sulfuric acid and 60% oleum;

(2) isolation of 1,3-Ad (COOH) ₂ from the above mixture of concentrated HNO ₃ and H ₂ SO ₄ and oleum;

(3) obtaining 1,3-Ad (COCl) ₂ from 1,3-Ad (COOH) ₂ by reaction with phosphorus pentachloride at 100 ° C and its isolation;

(4) the interaction of 1,3-Ad (COCl) ₂ with a nucleophilic substrate (alcohol, amine, etc.).

The disadvantages of the prototype are multi-stage, the need to use aggressive media (concentrated acids, oleum), which requires special equipment to obtain 1,3-Ad (COOH) ₂ , the need for a complex procedure for the isolation of 1,3-Ad (COOH) ₂ from an aggressive environment.

Thus, all the aforementioned known methods for producing 1,3-dicarbonyl derivatives of adamantanes are multi-stage (the necessary steps are the preparation and isolation of 1,3-Ad (COOH) ₂ dicarboxylic acids used as key intermediates), obtaining 1,3- Ad (COOH) _{2 is} carried out in hostile environments, hard-to-reach adamantane derivatives are used as starting compounds, with the exception of the prototype method, in which adamantane is used as starting compound.

The objective of the present invention is to develop a new one-step method for producing 1,3-dicarbonyl derivatives of adamantanes with two identical carbonyl-containing groups in the nodal positions of the adamantane core, in which the most available compounds of the adamantane series are used as starting materials.

The problem is solved by creating a new method for producing 1,3-dicarbonyl derivatives of adamantanes with two identical carbonyl-containing groups in the nodal positions of the adamantane core of the general formula

where R = H, X = OH, OMe, OEt, OPr ⁱ ; OBu ^s , OCH ₂ CH (Et) Bu, OCH ₂ CF ₃ , OCH (CH ₃ ) CF ₃ , OCH ₂ CF ₂ CF ₂ H, OCH ₂ CH ₂ CH ₂ Br, OCH ₂ CH≡, NEt ₂ , NC ₅ H ₁₀ (piperidyl), NC ₄ H ₈ O (morpholyl), C ₆ H ₅ NH, C ₆ H ₄ OMe, C ₄ H ₃ O- (furyl);

R = Me, X = OH, Me, OMe, O-Pr ⁱ , X = NC ₄ H ₈ O (morpholyl), C ₄ H ₃ O (furyl), NEt ₂ , C ₆ H ₅ NH, C ₆ H ₄ OMe

which consists in the carbonylation of the adamantane compound in the presence of electrophilic catalysts, characterized in that adamantane or 1,3-dimethyladamantane is used as the adamantane compound and carbonylation is carried out by the action of CO at atmospheric pressure in a solution of CH ₂ Br ₂ at 0-25 ° C for 0 , 5-3 hours, and the superelectrophilic complex CBr ₄ · 2AlBr ₃ , with a molar ratio [CBr ₄ · 2AlBr ₃ ]: [adamantane compound] = (1.5-2): 1, and to the in situ formed is used as a catalyst carbonyl derivative without releasing it into the atmosphere Here, a nucleophilic substrate is added to CO, and water, an alcohol containing an alkyl, or polyfluoroalkyl, or bromoalkyl, or acetylene group (selected from the group: MeOH, EtOH, i-PrOH, sec-BuOH, 2-ethylhexanol-1 are used as nucleophiles) , 1-trifluoromethylmethanol, 1-methyl-1-trifluoromethylmethanol-1, 2,2-difluoro-3,3-difluoropropanol, 3-bromopropanol-1, propargyl alcohol), an aliphatic, cyclic or aromatic amine (selected from the group: diethylamine, morpholine, piperidine, aniline), an aromatic or heteroaromatic hydrocarbon (selected from the group: anisole, furan); in the case of 1,3-dimethyladamantane, water, an aliphatic alcohol (selected from the group: MeOH, ⁱ PrOH), an aliphatic or heterocyclic or aromatic amine (selected from the group: diethylamine, morpholine, aniline), aromatic hydrocarbon or aromatic are used as the nucleophile heterocycle (selected from the group: anisole, furan).

The main advantages of the proposed method are:

- obtaining the target products without isolation of intermediate compounds, according to the type of "one-pot" process, ie in one technological stage;

- the method does not require the use of aggressive environments;

- high yields of target products and high selectivity of the process;

- mild conditions for the implementation of the method: temperature 0-25 ° C and atmospheric pressure CO instead of high temperatures and high pressure CO, necessary for other methods;

- ease of implementation, the method does not require special equipment;

- the claimed one-step method is quite general and can be used to obtain a wide range of 1,3-dicarbonyl derivatives of adamantane using nucleophiles that are stable under the conditions of the method and characterized by sufficient donor ability. In the case of nucleophiles that do not satisfy these conditions, the corresponding 1,3-dicarbonyl-containing adamantanes can be obtained by known methods from 1,3-adamantanedicarboxylic acids, which can be easily and in high yield synthesized by the claimed method using water as a nucleophile.

Another very important advantage of the proposed method (and the prototype method) in comparison with other known methods for producing 1,3-dicarbonyl derivatives of adamantanes is the use of adamantane or 1,3-dimethyladamantane, which are the most accessible compounds of the adamantane series, as initial compounds.

The inventive method for producing 1,3-dicarbonyl derivatives of adamantanes was not previously known. The catalysts used in the inventive method were previously used for the one-step functionalization of alkanes and cycloalkanes (ISAkhrem et al. Chem. Rev. 2007, 707, 2037). The peculiarity of this process is that in this case, under the action of the CBr ₃ ⁺ cation, two inert CH bonds are split and two CBr ₄ molecules are reduced:

The conversion scheme of adamantane (or 1,3-dimethyladamantane) to the products of formula (I) involves the separation of two hydride ions from adamantanes with the formation in the atmosphere of CO first of acylium cation AdCO ⁺ , and then an intermediate such as diacylium of dication Ad '(CO ⁺ ) ₂ which, upon addition of a nucleophilic substrate, forms the corresponding 1,3-dicarbonyl derivatives of adamantanes.

The method according to the invention is as follows. In a round-bottom flask equipped with a crane for carrying out the reaction in a CO atmosphere at a temperature of 15-25 ° C and stirring with a magnetic stirrer, a catalyst is prepared by mixing CBr ₄ with a twofold molar excess of aluminum bromide in a dibromomethane solution. At 0 ° C, adamantane or 1,3-dimethyladamantane was added to the resulting catalyst solution in a CO atmosphere, and the reaction mixture was stirred at the same temperature for 2.5-3 hours. The corresponding nucleophile (alcohol or amine, or arene) is added to the resulting mixture at 0 ° C without stopping the supply of CO, the reaction temperature is allowed to rise to room temperature and the reaction is continued for 0.3-0.75 hours. Then the reaction mixture is carefully, with cooling, treated with water and extracted with chloroform. The organic layer was separated, washed with water until neutral and dried with Na ₂ SO ₄ . In the case of carbonylation at room temperature (15-25 ° C), the reaction time is reduced to 30-45 minutes.

Reactions with water are carried out at 20-25 ° C in a CO atmosphere using a 100-150 molar excess of water with respect to the superelectrophilic complex until the formation of a dicarboxylic acid precipitate ceases. In this case, dicarboxylic acids precipitate from the reaction mixtures in the form of white precipitates, which are separated, washed thoroughly with water, dried and recrystallized. In other cases, analyze the resulting mixture using GLC. After distillation of the solvent on a rotary evaporator, products are recovered and purified by recrystallization or reprecipitation. The yields of the products are determined by ¹ H NMR according to the internal standard - mesitylene or by weighing the product after cleaning and drying. The conversion of the starting adamantanes is determined by GLC. The structure of the obtained products was proved by ¹ H, ¹⁹ F and ¹³ C NMR and mass spectra, as well as elemental analysis data. ¹⁹ F NMR spectra, as well as ¹ H NMR (for determining the product yield by internal standard) are recorded on a Bruker AV-300 spectrometer), ¹ H and ¹³ C NMR spectra are recorded on a Bruker AV-400 spectrometer). All spectra are recorded in CDCl ₃ unless otherwise indicated in the examples. Chemical shifts δ are given in ppm. from Me ₄ Si, the spin-spin interaction constants (J) are given in hertz (Hz).

EXAMPLES

In parentheses are links to publications that describe these compounds.

Example 1. Obtaining 1,3-Ad (COOH) ₂

In a dry round-bottom flask at room temperature in a CO atmosphere, with stirring using a magnetic stirrer, a super-electrophilic complex CBr ₄ · 2AlBr ₃ from CBr ₄ and AlBr ₃ is prepared at a molar ratio of 1: 2 in anhydrous CH ₂ Br ₂ . After the formation of a homogeneous solution, the temperature in the flask was adjusted to 0 ° C, and dry AdH (0.20 g, 1.47 mmol) was added to 3 ml of anhydrous CH ₂ Br ₂ to the freshly prepared super electrophilic complex CBr ₄ · 2AlBr ₃ (2.50 g, 2.87 mmol). The reaction mixture was stirred for 3 hours. Then, in a CO atmosphere, with cooling, 15 ml of water were slowly added to the flask. At room temperature and atmospheric pressure, the reaction mixture is left until the precipitation stops (from several hours to several days). The precipitated 1,3-Ad (COOH) _{2 was} separated by filtration, washed with water and dried, after which it was recrystallized from CH ₃ COOH. The yield of analytically pure compound is 80%. Mp 285-286 ° C. Calculated

Claims (1)

The method of obtaining 1,3-dicarbonyl derivatives of adamantantane of the General formula

where R = H, X = OH, OMe, OEt, OPr ⁱ , OBu ^s , OCH ₂ CH (Et) Bu, OCH ₂ CF ₃ , OCH (CH ₃ ) CF ₃ , OCH ₂ CF ₂ CF ₂ H, OCH ₂ CH ₂ CH ₂ Br, OCH ₂ C≡CH, NEt ₂ , NC ₅ H ₁₀ (piperidyl), NC ₄ H ₈ O (morpholyl), C ₆ H ₅ NH, C ₆ H ₄ OMe, C ₄ H ₃ O ( furyl);
R = Me, X = OH, Me, OMe, O-Pr ⁱ , X = NC ₄ H ₈ O (morpholyl), C ₄ H ₃ O (furyl), NEt ₂ , C ₆ H ₅ NH, C ₆ H ₄ OMe
comprising carbonylation of the adamantane compound in the presence of electrophilic catalysts, characterized in that adamantane or 1,3-dimethyladamantane is used as the adamantane compound and carbonylation is carried out by the action of CO at atmospheric pressure in a solution of CH ₂ Br ₂ at a temperature of 0-25 ° C for 0, 5-3 hours, and the super-electrophilic complex CBr ₄ · 2AlBr _{3 was} used as a catalyst with a molar ratio of [CBr ₄ · 2AlBr ₃ ]: [adamantane compound] = (1.5-2): 1, and to the in situ carbonyl derivative formed without highlighting it, in the atmosphere On the nucleophilic substrate is added: water or an alcohol containing an alkyl, or acetylene, or bromoalkyl, or polyfluoroalkyl group; or an amine of an aliphatic or heterocyclic or aromatic series; or an aromatic hydrocarbon, or an aromatic heterocycle; and carry out a reaction with a nucleophile at a temperature of 0-25 ° C.