RU2240303C1 - Method for preparing alpha-adamantyl-containing aldehydes - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, namely, to a new method for preparing α-adamantyl-containing aldehydes of the general formula:

wherein R₁ means hydrogen atom (H); R₂ means CH₃, C₃H₇, C₄H₉; R₁ = R₂ mean CH₃ that are intermediate substances used in synthesis of biologically active compounds and method involves using derivative of adamantine. Method involves addition of corresponding aldehyde to derivative of adamantine wherein 1,3-dehydroadamantane is used as derivative of adamantine and the following compounds as aldehyde: propanal, pentanal, hexanal, isobutanal and process is carried out in the mole ratio 1,3-dehydroadamantane to aldehyde = 1:(4-6) in the parent aldehyde medium, at temperature 35-40^oC for 3-5 h. method provides simplifying the preparing process and to synthesize compounds with the branched structure.

EFFECT: improved preparing method.

4 ex

Description

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method for producing α-adamantyl-containing aldehydes of the general formula:

which are intermediates for the synthesis of biologically active substances.

There is a method of obtaining the simplest representative of this class of adamantylcarbaldehyde, which consists in the decomposition of N-tert-butyladamantyl-1-aziridine with mineral acids [Boot K. Synthese von 1-Adamanan-carbaldehyden // Angew Chem. - 1968, 80, No. 22, - p. 970].

The disadvantage of this method is, first of all, the difficulty of obtaining the original N-tert-butyladamantyl-1-aziridine, as well as the lack of the ability to synthesize other adamantyl-containing aldehydes.

Another way to obtain adamantylcarbaldehyde is to purge with carbon monoxide a mixture of adamantane, methylene chloride and aluminum chloride cooled to 0 ° C. The yield of adamantylcarbaldehyde is 49% [a.s. 1793313 USSR, MKI 3 C 07 C 47/44. The method of obtaining adamantyl-1-aldehyde / Ya. Yu. Policy, B.P. Raugel, E.E. Liepins. - Publ. in B.I., 1977, No. 5].

The disadvantages of this method are: the complexity and multi-stage selection of the target product, the technological complexity of the process and the low yield of the target product.

The most common methods for producing adamantyl-containing aldehydes are the oxidation of the corresponding alcohols with lead tetraacetate or the hydrolysis of the corresponding diacetals obtained by the interaction of orthoform ether and the corresponding Grignard reagents. The yield by both methods is approximately the same and amounts to 37-57% [Stepanov F.N., Dovgan N.L. Aldehydes of the Adamantane Series // Zhork. - 1968. - T.4. - Issue 2. - S. 277-280].

The disadvantages of this method are: the multi-stage process, the low yield of the target compounds (in terms of the initial adamantane, including the stages of synthesis of the starting compounds, the yield of the target products does not exceed 12%), the complexity and low adaptability of the individual stages, in particular the stages of organomagnesium synthesis, which are dangerous in fire-fighting and high requirements for the purity of the starting reagents.

Closest to the proposed invention is a method in which 1-adamantylaldehyde is obtained from a functional derivative of adamantane, characterized in that the functional derivative is used nitrile 1-adamantanecarboxylic acid, which is reduced by the product of the interaction of tin (II) chloride with hydrogen chloride in the presence of diethyl ether to obtain hexachlorotin salt of 1-adamantylaldimine, which is treated with excess water to obtain 1-adamantylaldehyde in a molar ratio of nitr silt of adamantanecarboxylic acid to tin chloride and diethyl ether equal to 1: 1.5-2: 6.2: 7 [Pat. 2163591 RF, MKI 7 C 07 47/34, 45/44/2001].

The disadvantages of this method is that the implementation of this reaction requires the use of a tin (II) chloride catalyst, diethyl ether is used - it is a fire hazard, the synthesis of the target 1-adamantylaldehyde is a multi-stage process, in addition, the synthesis of the starting nitrile of 1-adamantanecarboxylic acid is complex and multi-stage.

A common drawback of all of the above methods is that with the help of them it is possible to synthesize adamantyl-containing aldehydes having only a linear structure.

The objective of the invention is to develop a technologically advanced low-stage method for the synthesis of α-adamantyl-containing aldehydes, including a branched structure, proceeding in high yield.

The technical result is a simplification of the production method, as well as the possibility of obtaining target compounds of a branched structure.

The technical result is achieved in a new method for producing α-adamantyl-containing aldehydes of the general formula:

consisting in attaching the corresponding aldehyde to the adamantane derivative, wherein 1,3-dehydroadamantane is used as the adamantane derivative, and propanal, pentanal, hexanal, isobutanal is used as the aldehyde, and the process is carried out at a molar ratio of 1,3-dehydroadamantane and aldehyde equal to 1 : 4-6, in the environment of the starting aldehyde, at a temperature of 35-40 ° C, for 3-5 hours.

The essence of the method is the reaction of addition of aldehydes to 1,3-dehydroadamantane at the α-carbon atom:

The high nucleophilicity of 1,3-dehydroadamantane allows one to obtain the products of the addition of these aldehydes in high yields under fairly mild conditions.

It should be noted that aldehydes are characterized by reactions involving a carbonyl group and are not typical of reactions in which the aldehyde reacts via the C — H bond of an α-carbon atom.

The advantage of this method is a high yield (60-78%), as well as the possibility of obtaining almost any homologues of this series, which are also intermediates for the synthesis of biologically active substances.

As shown by studies, the selectivity of the reaction is very sensitive to temperature. It was found that at a reaction temperature from 35-40 ° C the yield of the target products is 60-78%. A further increase in temperature (to 65 ° C) leads to a decrease in the yield of the target products to 42%, which is apparently due to the occurrence of a side reaction of aldol condensation. The presence of aldol condensation by-products of the starting and α-adamantyl-containing aldehydes was confirmed by mass spectroscopy. Lowering the temperature below 35 ° C leads to a decrease in the yield of the target products.

The optimal molar ratio of reagents 1,3-DHA: aldehyde is 1: 4-6. In the case of the ratio of 1,3-DGA: aldehyde equal to 1: 2, along with the target product of the reaction, unreacted 1,3-dehydroadamantane was isolated. The increase in the ratio of 1,3-DHA: aldehyde more than 1: 6 does not affect the yield of the target product.

The optimal reaction time is 3-5 hours, ceteris paribus. A further increase in the duration of the reaction does not lead to a significant change in the yield of the target product. When reducing the reaction time to 1-2 hours, the yield of the target product decreases by 20-30%.

The reaction is carried out in the environment of the starting aldehyde, which greatly simplifies the process. Carrying out the reaction in an environment of non-polar or low-polar solvents, such as hexane and diethyl ether, reduces the yield of the target product to 0-5%. The use of more polar solvents is unacceptable in view of the high reactivity of 1,3-DHA, which reacts with the solvent.

The method is as follows.

A solution of 1,3-dehydroadamantane in the same aldehyde is added to a 4-6-fold molar excess of aldehyde. A mixture of 1,3-dehydroadamantane and aldehyde is heated for 3-5 hours at a temperature of 35-40 ° C, after which the aldehyde is distilled off. The regenerated aldehyde does not contain any impurities and is suitable for reuse in a similar synthesis. Thus, in industry, it is possible to organize aldehyde recycling with the addition of a calculated amount of fresh reagent. The synthesized α-adamantyl-containing aldehydes after distillation of the starting reagents are sent to the purification stage. The yield of target products is 60-78%.

The structure of the target products is confirmed by IR spectroscopy, elemental analysis and a qualitative reaction for the presence of a carbonyl group - the interaction of α-adamantyl-containing aldehydes with dinitrophenylhydrazine. This interaction was carried out immediately after the isolation of α-adamantyl-containing aldehydes from the adamantylation reaction with 1,3-dehydroadamantane. The interaction was carried out in ethanol, in the presence of an acid catalyst, with an aldehyde: dinitrophenylhydrazine molar ratio of 1: 1.2, at room temperature, and for 15-20 minutes led to the target compounds in 84-98% yield. The high speed of this interaction allows us to conclude that the adamantyl radical practically does not reduce the reactivity of aldehydes in condensation reactions on the carbonyl group. At the end of the reaction, the target products were filtered and recrystallized from aqueous alcohol.

The invention is illustrated by the following examples:

Example 1. Synthesis of 2- (1-adamantyl) propanal.

In a reactor with a stirrer of 9 g (0.15 mol) of propanal in a dry nitrogen atmosphere at room temperature, a solution of 4 g (0.03 mol) of freshly distilled 1,3-DGA (molar ratio of 1.3 DGA: aldehyde = 1: 5) in 20 ml of absolute diethyl ether. The solvent is distilled off, after which the temperature of the reaction mixture is brought to 35-40 ° C, kept under stirring for 3 hours until the disappearance of 1,3-DGA insoluble in the aldehyde.

At the end of the reaction, the excess aldehyde is removed by distillation, the residue is evacuated to remove unreacted 1,3-DHA, after which the product is distilled (bp = 137-138 / 4 mm Hg) and 4.6 g (0.023 mol, 60%) are obtained. ) 2- (1-adamantyl) propanal, which is a white clear liquid with an aldehyde odor, n _D = 1.5104.

Found,%: C 81.32; H 10.55; About 8.13

C ₁₃ N ₂₀ O

Calculated,%: C 81.20; H 10.48; About 8.32

IR spectrum ν, cm ^-1 : 2890, 2848, 1720, 1450, 1417, 1352, 1064, 1028

Synthesis of 2- (1-adamantyl) propanal-N- (2,4-dinitrophenyl) hydrazone.

To 2.4 g (0.012 mol) of dinitrophenylhydrazine was added 10 ml of concentrated sulfuric acid, followed by stirring with 15 ml of water. 30 ml of alcohol are poured into a warm solution, and a solution of 2 g (0.01 mol) of 2- (1-adamantyl) propanal in 5 ml of alcohol is added with stirring. Maintain the reaction mass for 15 minutes at room temperature, the precipitated crystals are filtered off and recrystallized from isopropanol. 3.4 g (0.0087 mol, 84.2%) of 2- (1-adamantyl) -propanal-N- (2,4-dinitrophenyl) -hydrazone, which is a yellow crystalline substance, are obtained, mp = 80-81 ° C.

1 H-NMR spectrum (ppm: 0.95-0.97 m (3H, CH ₃ ); 1.68 s, 2.0 s (Ad, 15H); 2.0-2.1 m (1H, CH); 7.92, 8.2, 8.85 s (3H, Ph), 8.59 s (1H, CH = N); 11.35 s (1H, NH);

Mass spectrum, m / e: 372 (1%)% M ⁺ , 135 (14.3%) Ad ⁺ , 41 (100%) [C ₃ H ₅ ] ⁺

Found,%: C 61.31; H 6.56; N, 15.12; O 17.01

C ₁₉ H ₂₄ N ₄ O ₄

Calculated,%: C 61.28; H 6.50; N, 15.04; O 17.18

Example 2. Synthesis of 2-methyl-2- (1-adamantyl) propanal.

Similarly, from 13 g (0.18 mol) of isobutanal and 4 g (0.03 mol) of freshly-digested 1,3-DHA, 4.6 g (0.022 mol, 76%) of 2-methyl-2- (1-adamantyl) are obtained -propanal, which is a colorless transparent liquid, n _D = 1.5185, bp = 121-123 / 4 mm Hg

Found,%: C 81.65; H 10.92; About 7.43

C ₁₄ H ₂₂ O

Calculated,%: C 81.50; H 10.75; About 7.75

IR spectrum ν, cm ^-1 : 2892, 2846, 1718, 1452, 1420, 1351, 1062, 1026

Synthesis of 2-methyl-2- (1-adamantyl) -propanal-N- (2,4-dinitrophenyl) -hydrazone.

Similarly, from 2.3 g (0.011 mol) of dinitrophenylhydrazine and 2 g (0.0097 mol) of 2-methyl-2- (1-adamantyl) propanal, 3.8 g (0.0094 mol, 96.2%) of 2 are obtained -methyl-2- (1-adamantyl) -propanal-N- (2,4-dinitrophenyl) -hydrazone, which is a yellow crystalline substance, mp = 250-251 ° C.

1 H-NMR spectrum (ppm: 1.1 s (6H, 2CH ₃ ); 1.7 s, 1.99 s (Ad, 15H); 7.9, 8.1, 8.8 s (3H, Ph); 8.4 s (1H, CH = N) ; 11.3 s (1H, NH)

Mass spectrum, m / e: 386 (2.3%) M ⁺ , 135 (100%) Ad ⁺ , 41 (9.4%) [C ₃ H ₅ ] ⁺

Found,%: C 62.22; H 6.86; N, 14.57; O 16.35

C ₂₀ H ₂₆ N ₄ O ₄

Calculated,%: C 62.16; H 6.78; N, 14.50; O 16.56

Example 3

Synthesis of 2- (1-adamantyl) pentanal.

Similarly, 10 g (0.12 mol) of pentanal and 4 g (0.03 mol) of freshly-digested 1,3-DGA were kept at a temperature of 35-40 ° C for 5 hours and 5 g (0.22 mol, 75, 6%) 2- (1-adamantyl) pentanal, which is a colorless transparent liquid, n _D 1.5150, bp = 141-143 / 3 mm Hg

Found,%: C 81.90; H 11.04; About 7.06

C ₁₅ H ₂₄ O

Calculated,%: C 81.76; H 10.98; About 7.26

IR spectrum ν, cm ^-1 : 2886, 2840, 1715, 1450, 1417, 1350, 1061, 1021

Synthesis of 2- (1-adamantyl) -pentanal-N- (2,4-dinitrophenyl) hydrazone.

Similarly, from 2.2 g (0.011 mol) of dinitrophenylhydrazine and 2 g (0.009 mol) of 2- (1-adamantyl) hexanal, 3.5 g (0.0084 mol, 92.7%) of 2- (1-adamantyl) are obtained ) -pentanal-N- (2,4-dinitrophenyl) -hydrazone, which is a yellow crystalline substance, mp = 97-98 ° C.

PMR spectrum δ ppm: 0.91-0.94 m (3H, CH ₃ ); 1.45-1.49 m (4H, CH ₂ ); 1.59 s, 1.97 s (Ad, 15H); 1.98-2.0 m (1H, CH); 7.9, 8.25, 9.0 s (3H, Ph); 7.94 s (1H, CH = N); 11.12 s (1H, NH);

Mass spectrum, m / e: 400 (2.2%) M ⁺ , 135 (22%) Ad ⁺ , 41 (100%) [C ₃ H ₅ ] ⁺ , 233 (11%) [M-C ₆ H ₃ (NO ₂ ) ₂ ] ⁺

Found,%: C 63.01; H, 7.12; N, 13.60; 0 16.27

C _2l H ₂₈ N ₄ O ₄

Calculated,%: C 62.98; H 7.05; N 13.52; O 16.45

Example 4

Synthesis of 2- (1-adamantyl) hexanal.

Similarly, from 12 g (0.12 mol) of hexanal and 4 g (0.03 mol) of freshly-digested 1,3-DHA, 5.5 g (0.023 mol, 78.1%) of 2- (1-adamantyl) hexanal are obtained , which is a colorless transparent liquid, n _D = 1.5216, bp = 151-154 / 3 mm Hg

Found,%: C 82.06; H 11.26; About 6.68

C ₁₆ H ₂₆ O

Calculated,%: C 81.99; H 11.18; About 6.83

IR spectrum ν, cm ^-1 : 2884, 2842, 1715, 1451, 1412, 1348, 1058, 1020

Synthesis of 2- (1-adamantyl) -hexanal-N- (2,4-dinitrophenyl) -hydrazone.

Similarly, from 2 g (0.01 mol) of dinitrophenylhydrazine and 2 g (0.0085 mol) of 2- (1-adamantyl) hexanal, 3.6 g (0.0083 mol, 98.1%) of 2- (1 -adamantyl) -hexanal-N- (2,4-dinitrophenyl) -hydrazone, which is a yellow crystalline substance, mp = 167-168 ° C.

PMR spectrum δ ppm: 0.85-0.9 m (3H, CH ₃ ); 1.39-1.42 (6H, CH ₂ ); 1.55 s, 1.95 s (Ad, 15H); 1.97-1.99 m (1H, CH); 7.6 s (1H, CH = N); 7.8, 8.24, 9.0 s (3H, Ph); 11.0 s (1H, NH);

Mass spectrum, m / e: 414 (8%) M ⁺ , 135 (100%) Ad ⁺ , 41 (18%) [C ₃ H ₅ ] ⁺

Found,%: C 63.82; H 7.33; N, 14.06; About 14.79

C ₂₂ H ₃₀ N ₄ O ₄

Calculated,%: C 63.75; H, 7.30; N, 13.99; About 14.96

Conclusions.

A technologically low-stage method for the synthesis of α-adamantyl-containing aldehydes has been developed, proceeding in high yield. The structure of the described compounds was confirmed by elemental analysis, qualitative reaction, ¹ H NMR and mass spectra.

Claims (1)

The method of obtaining α-adamantyl aldehydes of the General formula

where R ₁ = H; R ₂ = CH ₃ , C ₃ H ₇ , C ₄ H ₉ ; R ₁ = R ₂ = CH ₃ , using an adamantane derivative, characterized in that the method comprises attaching the corresponding aldehyde to the adamantane derivative, wherein 1,3-dehydroadamantane is used as an adamantane derivative, and propanal, pentanal, hexanal, isobutanal as an aldehyde, and the process is carried out in a molar ratio 1,3-dehydroadamantane and aldehyde, equal to 1: 4-6, in the medium of the starting aldehyde, at a temperature of 35-40 ° C, for 3-5 hours