CS265498B1 - Alkylidene malonaldehydes and the process for their pH adjustment - Google Patents

Abstract

The solution relates to alkylidenemalonaldehydes of the general formula R-CH=C(CHO)2 where R is alkyl with 1 to 8 carbon atoms, cycloalkyl with one to seven carbon atoms in the ring, phenyl, naphthyl, pyridyl, or R1 C=C where R1 is alkyl with 1 to 6 carbon atoms or phenyl and a method of their preparation. The method of preparation consists in the reaction of an organometallic compound with a triformylmethane derivative and hydrolysis of the resulting intermediate in an acidic medium

Description

The present invention relates to alkali metal malonal aldehydes and to a process for their preparation.

The compounds of the invention are novel and have not been described. Several cases are described in the literature where this type of substance is believed to be an intermediate of synthesis but has not been isolated or characterized (French Patent 1 495 047); J. Am. Chem. Soc. 88, 852 (1966). Furthermore, the tetraacetals obtained several alkylidene malonalonaldehydes but failed to hydrolyze them to free dialdehydes (Reichardt. Ch. Angew. Chem. 88, 88 (1976)). Some of the compounds of the group of iridoids and secoiridoids have also been successfully synthesized using in situ generated alkeneidenalonalonaldehydes, but no detailed information regarding these compounds has been reported (Tietze L. - F. Angew. Chem., 94, 793 (1982); 95, 840 (1983).

Alkylidenemalonaldehydes appear to be very useful in two respects. Thanks to the reactivity of the activated double bond and the formyl groups, they can be used to prepare a variety of hitherto inaccessible heterocyclic compounds.

The second aspect of their possible use results from their biological activity, both of the substances themselves and of the prepared heterocyclic compounds.

The following are the closest substituted methylene malonal aldehydes: aralkylidene malonal aldehydes (AO 221 362); and alkenylidenemalonaldehydes (AO 240 371).

The present invention relates to alkylidene malonaldehydes of the formula I

CHO

R-CH = C (I) ^S CHO wherein R is alkyl of one to eight carbon atoms, cycloalkyl of 3 to 7 carbons in the cycle, phenyl, naphthyl, pyridyl or R ¹ C ^and C wherein R ¹ is alkyl of 1 up to 6 carbon atoms or phenyl. A process for the preparation of these compounds is characterized in that the organometallic compound of formula II

R _n X (II) wherein R is as defined above and where η = 1 X is MgBr, MgCl, MgJ or Li and when n = 2 is X CuLi, is reacted with a triformylmethane derivative of formula III CHO

Y-CH = C

CHO where Y is OH, OR ² or NR ² , where R ² is C 1 -C 4 alkyl, in an anhydrous ether type solvent at -80 to 0 ° C under an inert atmosphere, then at room temperature the intermediate is formed of formula IV

R. CH-OX

Y r 'CH = O (IV) wherein R, X, Y are as defined above, converted to the final product by acid hydrolysis.

As compound III, dimethylaminomethylenemalonaldehyde can be used which gives the highest yields of the above derivatives III. Absolute tetrahydrofuran appears to be the most preferred solvent.

The reaction is usually carried out by dropwise adding a solution of an organometallic reagent, preferably a Chrignard compound, to a solution of the triformylmethane derivatives in tetrahydrofuran under an inert atmosphere of nitrogen or preferably argon under cooling (temperature ranging from -80 to -40 ° C depending on the type of organometallic reagent). at this temperature the reaction is maintained for 30 min and then at room temperature for 1-2 h. The reaction yields an intermediate of formula IV, the structure of which is determined by NMR spectroscopy.

After evaporation of the solvent, the solid intermediate is hydrolyzed in a slightly acidic medium, wherein the volatile product is continuously extracted into an organic solvent (benzene, ether, methylene chloride) or captured by a suitable cycloaddition reaction.

The process of the present invention is useful for the preparation of a variety of substituted alkylidene malonal aldehydes (starting materials being the respective organometallic compounds and the triformylmethane derivative). This process can also be used to prepare the previously described aralkylidene malonal aldehydes (AO 217 376).

A great advantage of the process of the present invention is that in a simple experimental setup with readily available raw materials, the hitherto unwritten alkylidene malonal aldehydes are obtained in very good yields. These compounds are important in their biological activity and as starting materials for the preparation of a variety of novel heterocyclic compounds. The present invention is illustrated by the following non-limiting examples.

Example 1

Ethylidenmalonaldehyde

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (argon atmosphere) at -40 ° C was slowly added dropwise 3 ml of a 1M methylmagnesium bromide solution. It was stirred at this temperature for 20 min and then allowed to gradually warm to room temperature and stirred at this temperature (25 ° C) for 1 h. The reaction mixture was evaporated to dryness on a rotary evaporator (bath temperature 20 ° C). of ether and added 20 mL of dilute perchloric acid (pH 3-4). The progress of the hydrolysis was followed by thin layer chromatography on silica gel, usually with stirring for 3 to 4 hours.

The reaction mixture was further worked up as follows:

a) The ether extract was dried over MgSO 4, the ether carefully evaporated on a evaporator, the product characterized by NMR and MS spectrometry. Yield 0.147 g (50%). Mass spectrum (m / e): M ⁺ = 98 ^x H NMR (CDSlgX): d 2.0 (3H, CH, J = 7 Hz), 6.6 q (1H, = CH, J = 7Hz) 9.2 s (1H, CHO), 9.33 d (1H, CHO, J = 1.5 Hz).

b) The ether extract was dried over MgSO 4 and then excess (0.5 mL) of ethyl vinyl ether was added.

Stirring for 12 h, after evaporation of the solvent by column chromatography, eluent chloroform, in 25% yield. 2-Ethoxy-3,4-dihydro-4-methyl-2H-pyran-5-carbaldehyde was obtained. 1H NMR <CHC1 ₃ <J): 1.1 to 1.4 m (6H, 2CH _3>, 1.82 m (2H, _CH2), from 2.55 to 2.9 m (1H, CH) , 3.5 to

4.0 m (2H, OCH ₂ ), 5:28 t (1H, O-CHO), J = 3.5, 7.15 s (1H, CH =), 9.21 s (1H, CHO).

c) When the product was extracted into ether during acid hydrolysis, excess ethyl vinyl ether was added to the ether and stirred with a magnetic stirrer. Thin-layer chromatography (TLC) was used to monitor the course of the cycloaddition reaction, which is probably faster than the hydrolysis of the intermediate because only dihydropyran is visible on the plasticine. TLC (silica, chloroform). The obtained ethereal dihydropyran solution was shaken with NaHCO 3 solution, dried, the solvent was evaporated; chromatography on silica gel afforded 0.21 g (40%) of dihydro pyran.

d) the crystalline intermediate of type IV, R = _{CH3> 2,} Y = N / CH _3/2, X = MgBr, was characterized by

NMR spectroscopy in DjO with 5% NaOD as solvent.

Example 2

Butylidenmalonaldehyde

To a solution of 0.381 g (3 mmol) of dimethylaminomethylene malonaldehyde in absolute tetrahydrofuran was added dropwise 4 ml of a 0.8 M solution of butylmagnesium bromide at -40 ° C under an argon atmosphere. After stirring at this temperature for 20 min, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1 h. The reaction mixture was evaporated to dryness on a rotary evaporator (bath temperature up to 25 ° C). (solvent D, 0 with 5% NaOD). The reaction mixture can be worked up according to procedures a to d as described in Example 1.

In the NMR spectrum of butylidene malonaldehyde visible signals of CHO groups: 9.74 s (1H, CHO), 10.2s (1H, CHO). Mass spectrum (m / e): M ⁺ = 140

c) Ethyl vinyl ether cyclo-product prepared according to process c) of Example 1 in 63% yield.

NMR spectroscopy indicated a 65:35 mixture of the trans and cis isomers of 4-butyl-2-ethoxy-3,4-dihydro-2H-pyran-5-carbaldehyde. This product is distilled at a water pump at 140 ° C with partial decomposition. For ^{C 12 H} 20 ° 3 ( ²¹² ' ³ * calculated: 67.89% C, 9.50% H; found 67.73% C, 9.53% H. Mass spectrum (m / e): M ⁺ = 212.

d) Intermediate after drying over phosphorus pentoxide, characterized by NMR spectroscopy, ^X H NMR (CDCl) ,: 0.9 to 1.33 m (12H, C ₄ H _g, CH), 1.9 m (2H, CH) 2.3 to 2.7 m (1H, CH), 3.4 to 4.0 m (2H, OCH 3), 5.17 t (1H, OCHO, J = 3.5), 7.13 s ( 1 H, CH =), 9.2 s (1 H, CHO).

Example 3

Butylidene malonaldehyde was prepared by reaction with butyllithium at -70 ° C in a yield of 73%. Carry out the reaction and work-up similar to Example 2.

Example 4

Isopropylidenmalonaldehyde

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran was added at -40 ° C with 3 mL of a 1M solution of isopropylmagnesium bromide. Stirring was continued at this temperature for 30 min, then allowed to warm to room temperature and stirred for an additional 1 h. The reaction mixture was worked up as in Experiment 1c. Yield: 0.31 g (52%) of 2-ethoxy-3,4-dihydro-4-isopropyl-2H-pyran-5-carb-aldehyde. For C 18 H 18 O 3 (198.3) calculated: 66.64% C, 9.15% H; Found: 66.42% C, 9.18% H ^X H NMR (CDCl,?: 0.9 (6H, 2 CH _3, J = 6). 1.27 t (3H, CH, J = 7), 1.7 to 1.9 m (2H, CH3), 2.4-2.8 m (1H, CH), 3.4-4.0 m (2H, OCH3), 5.17 t (1H, O-CH-O) J = 3.5), 7.13 s (1H, CH =), 9.2 (1H, CHO).

Example 5

Cyclopropylmethylenemalonaldehyde

Cyclopropylmagnesium bromide was prepared as a 0.8M solution in absolute tetrahydrofuran by reacting cyclopropyl bromide with magnesium under an argon atmosphere to dissolve the metal under the solvent reflex. Dimethylaminomethylenemalonaldehyde (0.381 g; 3 mmol) was dissolved in absolute tetrahydrofuran and to this solution was added dropwise 4 mL of 0.8M cyclopropylmagnesium bromide solution under argon atmosphere while cooling to -40 ° C. The reaction was carried out in the usual manner and worked up as in Example 1c. Obtained 0.28 g (47%) of 4-cyclopropyl-2-ethoxy-3,4-dihydro-2H-pyran-5-carbaldehyde (trans: cis ratio 70:30). For <X96> 2) calculated: 67.32% C,

8.22 H; Found: 67.13% C, 8.30% H. ¹ H NMR Spectrum (CDCl 3): 0.34-0.60 m 1.1-1.6 m (8H, 5H cyclopropane, CH 3), 7 to 2.23 m (3H, _CH2, CH), 3.3 to 4.1 m (2H, OCHp, 5.2 to 5.4 m (1 H, O-CH-O), 7.2 d (H , CH =, J = 1.5., 9.3 d (1H, CHO, J = 1.5).

Example 6

Preparation and spontaneous cyclization of 1,1-diformyl-4,4-dimethylbutyl-1,3-diene

The corresponding Grignard compound was prepared by reacting 2-methyl-1-propenyl bromide with magnesium under argon in absolute tetrahydrofuran.

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (argon atmosphere) at -40 ° C was added dropwise 3 ml of a 1M solution of 2-methyl-1-propenylmagnesium bromide. The reaction was carried out in the usual manner, the progress of the acid hydrolysis was followed by thin-layer chromatography, and it was found that the primarily formed 1,1-diformyl-4,4-dimethylbutyl-1,3-diene undergoes an intramolecular hetero-Diels-Alder reaction under these conditions. formation of 2,2-dimethyl-2H-pyran-5-carbaldehyde. Yield of product 0.33 g (79%). For ^C 8 ^H 14 ° 2 (438.2) calculated: 69.52% C, 7.29% H, found: 69.39% C, 7.32% H. ¹ H NMR (CDCl 3)? 1.45 m (6H, 2CH3 ₎ , 5.33 dt (lH, C / 4 / H =, J = 1.2, 1.2, 10.2), 6.31 dd (lH, C) 5 / H =,

J = 1.5, 10.2 Hz), 7.20 t (1H, C./2/H=, J = 1.4 Hz), 9.18 m (1H, CHO). ¹³ C-NMR (CDC1 _3): 28.45 q) (C-8), 81.59 s (C-6) d 114.40 (C-4), 116.97 s (C-3 ), 124.75 d (C-5)

163.58 d (C-2), 186.76 d (C-7). ·

Example 7

Phenylethinylenmalonaldehyde

The appropriate Grignard reagent was prepared by reacting butylmagnesium bromide with phenylacetylene in absolute tetrahydrofuran.

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (argon atmosphere) at -60 ° C was added dropwise 4 ml of a 0.8 M solution of phenylethynyl magnesium bromide. It was stirred at this temperature for 30 min, then allowed to warm to room temperature and stirred at this temperature for 10 h. After evaporation of tetrahydrofuran, the intermediate was washed with dry ether (3x) and then slurried in benzene and water and perchloric acid added. 3.5. The product passes into a benzene layer which has been cast 3 times. The hydrolysis proceeds completely within 3-5 hours, which can preferably be monitored by thin layer chromatography. The combined benzene extracts were dried over MgSO 4, the solvent was evaporated and the product was chromatographed on silica gel. Obtained 0.47 g (84%), mp 65 ° C (carbon tetrachloride). For ^{C 12 H} 8 ° 2 (184.2) calculated: 78.23% C, 4.38% H, found: 77.97% C, 4.40% H, ¹ H NMR spectrum (CDCl ₃ , J) 7.35 s (1H, CH =), 7.5 m (5H, phenyl), 10.03 s (1H, CHO), 10.43 s (1H, CHO).

Example

1-Pentinylmethylenemalonaldehyde

1-Pentinylmagnesium bromide was prepared by reacting butylmagnesium bromide with 1-pentin in tetrahydrofuran.

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (argon atmosphere) at -60 ° C was added dropwise 4 ml of a 0.8 M solution of 1-pentinylmagnesium bromide. Allow to warm to room temperature while stirring with a magnetic stirrer, standing overnight. Thereafter, the tetrahydrofuran was evaporated, the intermediate washed 3 times with dry ether, poured over 30 ml of dilute hydrochloric acid (1: 9). Extracted 5x into 20 ml benzene, hydrolysis progress monitored by thin layer chromatography. The combined benzene extracts were dried over MgSO 4, the solvent was evaporated, yielding 0.16 g (36%) of 1-pentinylmethylenemalonaldehyde. For C ₈ H ₁₀ O ₂ (150.2) calculated:

71.98 ° C, 6.71% H; Found: 71.86 »C, 6.66. H. ¹ H NMR Spectrum (CDCl 3): 0.83-1.33 m (3H, CH 3), 1.47-1.8 m <2H (CH3), 2.2-2.65 m (2H, CHp), 7.2 m (1H, CH =), 9.97 s (1H, CHO),

10.27 s (lH, CHO).

Working up the reaction according to Procedure 1 c) gave 0.20 g (30%) of 2-ethoxy-3,4-dihydro-4- (1-pentynyl) -2H-pyran-5-carbaldehyde. For Cj ^H H gOO (222.3) calculated: 70.24% C, 8.16% H; Found: 70.05% C, 8.23% H. ¹ H NMR Spectrum (CDCl 3): 0.9-1.4 m (10H, CH 3),

1.9 to 2.3 m <3, CH ₂ <CH), 3.4 to 4.0 (2H, _OCH2), 5.1 to 5.4 m (1H, OCH-O) 7.2 d (lH, CH =,

J = 1.5 Hz), 9.25 s (1H, CHO, J = 1.5 Hz).

Example 9

Benzylidenemalonaldehyde

This substance has already been described by us (AO 217 376/1982). Here we present a synthetic approach which is the subject of the invention, which can also be used for the preparation of the above substance.

To a solution of 0.381 g (3 mmol) of dimethylaminomethylene malonaldehyde in absolute tetrahydrofuran was added dropwise at -40 ° C 3 ml of a 1M solution of phenylmagnesium bromide. Stir at this temperature for 30 min, then allow to warm to room temperature and stir for an additional 8 h. Evaporate the reaction mixture to dryness, wash the intermediate 3 times with ether, carry out the hydrolysis in the usual manner.

After chromatography on silica gel, 0.375 g (78%) of benzylidene malonaldehyde was obtained. The characteristics of the substance are described in the aforementioned patent.

Example 10

Preparation of ethylidene malonaldehyde using an organohydrate

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (inert atmosphere) at -78 ° C was added dropwise 3 ml of a 1M solution of lithium dimethyl acetate. Stir at this temperature for 30 min, then allow to warm to room temperature and stir for 3 h. The reaction mixture was evaporated to dryness on a evaporator, the product obtained by hydrolysis and extraction into ether. Yield 0.165 g (56%) of ethylidene malonaldehyde, the characteristics of which are the same as in Example 1.

Example 11

Reaction of dimethylaminomethylene malonaldehyde with two equivalents of organometallic reagent

To a solution of 0.381 g (3 mmol) of dimethylaminomethylenemalonaldehyde in absolute tetrahydrofuran (inert atmosphere) was added 2 equivalents of methylmagnesium bromide (6 mL of a 1M solution) while cooling to -40 ° C: stirring at this temperature for 30 min. The reaction mixture was allowed to warm to room temperature and further stirred with a magnetic stirrer for 3 h. The solvent was removed on a rotary evaporator, the intermediate stirred with dilute perchloric acid (pH 3), followed by rapid extraction into ether (3x). The ether extracts were dried over MgSO 4, the pure product obtained by silica gel chromatography. Yield of 2- (hydroxyethyl) -2-buten-1-alU 0.21 g (61%). For ^C 6 ^H 10 ° 2 calculated: 63.13% C, 8.83% H; found: 63.07% C, 8.90% Η. ¹ H NMR spectrum (CDCl 3,?): 1.4 d (3H, CH 3, J = 7 Hz), 2.0 d (3H, CH 3, J = 7 Hz), 3.7 m (1H, CH-OH ), 4.7 m (lH, OH), 6.54 q (lH, CH =, J = 7 Hz), 9.33 d (lH, CHO, J = 1.5 Hz).

Claims (2)

1. Alkylidenemalonaldehydes of the general formula I R = CH = C CHO CHO wherein R is alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms in the ring, phenyl, naphthyl, pyridyl and or R ⁺ C = C, wherein R ^x is alkyl of 1 to 6 carbon atoms or phenyl. A process for the preparation of alkyldenmalonaldehydes of the formula I, characterized in that the organometallic compound of the formula II R _n X (II) wherein R is as defined above and where η = 1 X is MgBr, MgCl, MgJ or Li and if n = 2 X is CuLi, is reacted with a triformylmethane derivative of the formula III / CHO Y-CH = C CHO 2 2 2 wherein Y is OH, OR, or NR, where R is alkyl of 1 to 4 carbon atoms in an anhydrous ether type solvent at a temperature of ^- 80 to 0 ° C in an inert atmosphere and then at room temperature, the resulting intermediate of formula IV R CH-OX 4CH-C (IV) CH Ζ ^X CH = O where R, X, Y are as defined above, converted to the final product by acid hydrolysis.