DE1203793B - Process for the preparation of five-membered heterocycles containing at least two adjacent nitrogen atoms - Google Patents

Description

Process for the production of five-membered, at least two adjacent Heterocycles containing nitrogen atoms It is already known that nitrile imines and compounds with strained olefinic double bonds with each other with formation of a 22-pyrazoline system react (Journal of Organic Chemistry, Vol. 24 [1959], Pp. 892, 893).

It has now been found that other five-membered heterocycles containing at least two adjacent nitrogen atoms are obtained if azomethine imines of the general formulas which are optionally generated in situ are obtained in which R1 is a hydrogen atom, an alkyl radical, an unsubstituted or substituted aryl radical, the cyano or carboxamide group, R2 and Ra are each an unsubstituted or substituted aryl radical or, together with the nitrogen and carbon atom of the azomethine imine, a mono- or polyunsaturated ring system, Rq a Hydrogen atom or an unsubstituted or substituted aryl radical or R3 and R4 together with the carbon atom of the azomethine imine mean a ring system, with compounds with reactive CC multiple bonds, CN double bonds or CS double bonds.

On the one hand, the so-called azomethine imines are used as starting products or the N-imines of aromatic nitrogen bases of the pyridine or quinoline type in question, on the other hand, compounds with 1st reactive CC double bonds, z. B.

Norbornene, dicyclopentadiene, norbornadiene, 3,6 - endomethylene - 1,2,3,6 - dimethyl tetrahydrophthalate, 3,6-endomethylene-1, 2,3,6-tetrahydrophthalic anhydride, 3, 6-endomethyl-3,6-dihydrophthalic acid dimethyl ester, styrene, α-methylstyrene, Indene, 1,2-dihydronaphthalene, 1-diphenylethylene, acrylic acid ethyl ester, crotonic acid ethyl ester, Maleic acid dimethyl ester, fumaric acid dimethyl ester, p - nitrocinnamic acid ethyl ester, Quinones, acrylic acid nitrile, cyclopentadiene. Cyclopentene, allylbenzene, allyl alcohol, Diphenylketene and dihydropyran, 2. reactive CC triple bonds, e.g. B.

Acetylenedicarboxylic acid dimethyl ester, propinaldimethylacetal, phenylacetylene, Tolane and l-hexyne, 3. reactive CN double bonds, e.g. B.

Phenyl isocyanate, phenyl mustard oil and diisopropyl carbodiimide. and 4. reactive CS double bonds, e.g. B.

Carbon disulfide.

The zwitterionic reactants can be obtained in the following ways: a) Pure, crystallized azomethine imines are not yet described in the literature. Connections of this type can be, for. B. can be prepared at room temperature from aryl diazo cyanides and aliphatic diazo compounds with elimination of nitrogen in good yield. b) The azomethine imines can also be prepared by treating hydrazonium salts or semicarbazonium salts with tertiary bases in the absence of water or alcohols according to the following scheme, where X is an acid radical.

Some types of such hydrazonium and semicarbazonium salts are accessible by the method of E. Schmitz (Chemischeberichte, Vol. 91, [1958], pp. 1495 to 1503). The 2- [N-arylamino] -3,4dihydroiso quinolinium salts and the [2-N-ureido] -3,4 dihydroisoquinolinium bromide are mentioned as representatives. c) These azomethine imines can also be obtained by thermal elimination of alcohol from compounds that form the group in which Rg denotes a lower alkyl radical. Sometimes there is a small equilibrium concentration of azomethine imines in addition to the above alkoxy compounds even at room temperature. For example, 1-alkoxy-2- [N-arylamino] -1, 1,2,3,4-tetrahydroisoquinolines are suitable. d) The acid treatment of diazacyclopropane derivatives also leads to azomethine imines. e) Finally, N-aminopyridinium salts and analogous derivatives of condensed systems (quinoline, isoquinoline) with bases (preferably tertiary amines) also provide zwitterionic compounds which can occur in the same limiting formulas as azomethineimines. In the following scheme, X- means an acid anion.

As a starting material for the preparation of the zwitterion z. B. N-amino-pyridinium iodide cited.

The processes for making the raw material used Azomethine imines are not part of the invention.

The implementation according to the invention proceeds according to the following general equation: in which a = b represent compounds with reactive multiple bonds. However, it is not necessary to introduce the azomethine imines in the pure, isolated state into the process according to the invention; it is enough to generate them in situ.

To carry out the addition, the information given below is omitted a) prepared, crystallized azomethine imines with compounds of type a = b advantageous either in excess of the component or in hydroxyl-free solvents Temperatures between 2 (1, and 90 "C react.

According to the information under b), crystallized azomethine imines can also be found win that react with compounds of type a = b at room temperature. More convenient is to forego isolation; one solves connections of type a = b in one Solvents, e.g. B. dimethylformamide, there add a hydrazonium salt and shake after adding a tertiary base, e.g. B. pyridine or triethylamine, at room temperature. When using semicarbazonium salts, it is advisable to use without solvents and to work at elevated temperature.

In many cases, the course of the reaction can be traced back to the changes in color follow the reaction solutions easily. So is z. B. the solution of 2- [p-nitroanilino] -3,4-dihydroisoquinolinium bromide produced azomethine imines red, while those of the addition products, z. B. at Norbornene, which are light yellow. The drop in color to yellow thus shows the end of the reaction at.

If you want to use e.g. a l-alkoxy-2-arylamino-1 * 2 as the starting material for the azomethine imine, Use 3, 4-tetrahydroisoquinoline, the appropriate procedure is to use the called alkoxyisoquinoline with a connection of type a = b in one Indifferent solvent heated to temperatures around 100 "C. Highly active compounds of type a = b, such as phenyl isocyanate, already react at room temperature.

Acid treatment also changes diazacyclopropane derivatives into the open form ready for addition, as shown in the example of 1,2-methylimino-1,2,3,4-tetrahydroisoquinoline.

The zwitterionic compounds of the des type mentioned under e) Pyridinimines sometimes occur even at room temperature with compounds of type a = b in response. When reacting pyridinimine with acetylenedicarboxylic acid dimethyl ester z. B. the hydroaromatic primary adduct of a second molecule of acetylenedicarboxylic acid ester dehydrated to the 3-aza-indolizine dicarboxylic acid (l 2) dimethyl ester. The latter reaction is accelerated by palladium carbon as a hydrogen carrier.

As can be seen from the examples, an abundance of compounds of the ab type can be combined with azomethine imines to form five-membered rings HB NO2 H2 NO2 (C6H5 = C - O ¼¼ <Canv 1 quantitative N H NO2 H t | 11 C6H5 C6H5 O Phenyl isocyanate and phenyl isothiocyanate (phenyl mustard oil) add azomethine imines on the CN double bond to form 1, 2, 4-triazolidoneni3) or 1, 2,4-triazolidine-Ehionen- (3) in very good yields: some. "Tense" CC double bonds of the bicyclo [1,2,2] -heptene or trans-cyclooctene type are particularly ready to react. The bicyclo-heptene derivatives can contain further double bonds, carbon ester or acid anhydride groups as well as additional attached rings.

Conjugated double bonds of 1,3-dienes are also accepted as acceptors of azomethine imine suitable.

1,3-dienes, e.g. B. Cyclopentadiene, can have one or two equivalents Combine azomethine imine.

Aryl-conjugated olefins, for example, are successfully used: styrene, α-methylstyrene, I, l-diphenylethylene, indene and 1,2-dihydronaphthalene. a, -unsaturated Carbonyl, nitro or cyano compounds, e.g. B. ethyl acrylate, ethyl crotonate, Maleic acid dimethyl ester, fumaric acid dimethyl ester, p-nitro-cinnamic acid ethyl ester and Acrylonitrile, give good adduct yields with azomethine imines.

Normal unconjugated olefins, e.g. B. cyclopentene, allyl alcohol and Allylbenzene, react slowly and require higher reaction temperatures or longer Response times. The proximity of an oxygen function increases the willingness to react, z. B. in the vinyl acetate.

While CC double bonds produce pyrazolidines, the addition leads of azomethine imines on CC triple bonds, e.g. on l-hexyne, phenylacetylene, diphenylacetylene, Acetylenedicarboxylic acid dimethyl ester and propargylaldehyde dimethyl acetal to give pyrazolines (3,4).

Cumulative double bond systems are particularly active when azomethine imines are absorbed. Diphenylketene gives pyrazolidone- (3) as a representative of the system CC = 0: The CN bond of the carbodiimide and the CS bond of carbon disulfide have also been found to be reactive. The reaction products are 3-imino-1, 2, triazolidines or 1, 1, 3,4-thiiodiazolidine-4hione2): Most additions of the azomethine imines take place smoothly at room temperature. Less active compounds of type a = b can be converted at higher temperatures without disadvantage.

With regard to the choice of solvent, there is a wide range of freedom Limits, however compounds with accumulated double bonds, e.g.

Ketenes, isocyanates, carbodiimides, with azomethine imines in water and alcohol-free media are implemented. In the excess of the additive, unsaturated compound work; but one can also use open or cyclic ethers, z. B.

Diethyl ether, dioxane, ketones, e.g. acetone, and hydrocarbons or halogenated hydrocarbons, e.g. B. toluene, chlorobenzene or bromobenzene, use. For the release of azomethine imines from hydrazonium salts by means of tertiary bases (Pyridine, triethylamine), dimethylformamide is particularly suitable. Although azomethine imines If you add alcohol yourself, you can also use very active compounds of type a = b in Implement alcohol as a solvent, since the ring closure is extremely rapid he follows.

The process products are pharmaceuticals and can be considered valuable Intermediate products for the manufacture of other medicinal products or other fine chemicals be used.

Those described in the following examples according to the invention compounds produced are listed in the equation.

In order to avoid the cumbersome, rational designations, in the following examples the reaction products each with a Roman numeral referring to the structural formula shown in the formula scheme.

Example 1 Compound I 1.75 g of 2- [p-nitro-anilino] -3, 4-dihydro-isoquinolinium bromide (5 mmol) are mixed with the solution of 2.36 g of norbornene (25 mmol) and 1 cc of pyridine (13 mmol) shaken in 40 cc of ethanol for 20 hours at room temperature. Afterward is refluxed for 2 hours. After cooling in the refrigerator, 1.8 g a yellow-brown crystal cake (990/0 of theory) sucked off. Dissolve from benzene-ethanol leads to golden yellow crystals with a melting point of 185 to 188 ° C (decomposition).

Example 2 Compound II In the same molar ratios Dicyclopentadiene, pyridine and ethanol with the in the case game 1 called hydrazonium bromide brought to reaction. After three days of shaking, a red solution is obtained, which is concentrated in vacuo after 2 hours of heating on the steam bath. You get 2.01 g of yellow crystals (100% of theory) with a melting point of 219 to 222 ° C. (decomposition).

After recrystallization from benzene-ethanol, the pure substance melts at 226 to 228 "C with decomposition.

Example 3 Compound III Under the conditions given in Example 1 becomes norbornadiene {bicyclo [1,2,2] heptadiene- (2,5)} with the same hydrazonium bromide implemented.

The yellow adduct obtained in 97% yield has a melting point from 169 to 170 ° C (decomposition).

Example 4 Compound IV 1.75 g of said hydrazonium bromide (5 mmol) dissolve on shaking for 18 hours in the mixture of 20 ccm of dimethylformamide, 2.1 g of 3,6 - endomethylene - 1,2,3,6 - tetrahydrophthalic acid dimethyl ester (lOmMol) and 1 cc of pyridine at room temperature. The immediately appearing deep red color goes back to the azomethine imine. After concentration in vacuo, the residue is dissolved in methylene chloride taken up and crystallized from methanol. 1.64 g of lemon-yellow, matted ones are obtained Needles (690 / o of theory) with a melting point of 226 to 228 "C (decomposition).

Example 5 Compound V According to Example 4, 1.64 g of 3,6-endomethylene are obtained - 1,2,3,6 - tetrahydrophthalic anhydride (10 mmol) brought to reaction. the Golden yellow crystals isolated in almost quantitative yield can be removed Dissolve acetonitrile and melt around 300 ° C with decomposition.

Example 6 Compound VI 1. 75 g (5 mmol) of the hydrazonium bromide mentioned are mixed with 3.6 cc indene (30 mmol) and 3.0 cc pyridine in 30 cc dimethylformamide brought into solution by shaking. After 42 hours of warming to 55 "C, suction takes place the crystallized precipitate and washed with methanol.

After the filtrate has been worked up, the yield is 630/0 the theory. Dissolution from dioxane leads to yellow crystals with a melting point of 257 up to 258 "C (decomposition).

Example 7 Compound VII As in Example 6, 2.60cm (20 mmol) 1,2-dihydro-naphthalene reacted. It is concentrated in vacuo and digested the residue with hot methanol and sucks the crystalline precipitate after Cool off. After dissolving from benzene-ethanol, bright yellow, matted ones are obtained Needles that melt at 232 "C with decomposition.

Example 8 Compound VIII According to Example 6, the Reaction carried out with 7.0 ccm (60 mmol) of α-methylstyrene.

The orange-red clear solution is concentrated in vacuo and the residue is taken in methylene chloride and brings by evaporation with the addition of methanol to Crystallization. The excess olefin can easily be recovered. This in 82% yield obtained reaction product melts after redissolving from methylene chloride-methanol at 206 to 207 "C with decomposition.

Example 9 Compound IX The course described in Example 6 also takes the implementation with 5.4 ccm (30 mmol) 1,1-diphenylethylene. The deep red The reaction mixture is concentrated, finally in a high vacuum, and the initially oily one brings The residue gradually crystallizes by rubbing with ether-ethanol. By Digestion with hot benzene and suction to separate from unreacted starting material and causes the adduct to crystallize by concentrating the filtrate with the addition of ethanol. Dissolving from benzene-ethanol leads to golden-yellow, shiny crystals, which at Melts 218 to 220 "C with decomposition.

Example 10 Compound X 1.75 g (5 mmol) of that mentioned in Example I. Hydrazonium bromides are mixed with 3.08 ccm of ethyl crotonate (25 mmol) and 1.0 ccm Pyridine in 20 cc of dimethylformamide with shaking at room temperature for reaction brought. The orange-red solution is concentrated in vacuo, and the residue is taken up a little hot ethanol and allowed to slowly crystallize. That obtained in 85% yield Reaction product melts after redissolving from methylene chloride-ethanol at 162 to 1630 C with decomposition.

Example 11 Compound XI Analogously to Example 10, 2.5 ccm of dimethyl maleate are obtained (18 mmol) reacted. The reaction solution is concentrated in vacuo, the crystalline residue with methanol in the heat digested and after cooling and Store vacuumed in the refrigerator. The reaction product obtained to 640/0 of theory forms lemon-yellow, matted crystal needles after dissolving from chloroform-methanol, which melt at 219 to 220 "C with decomposition.

Example 12 Compound XII Reaction with 2.89 g of dimethyl fumarate (20 mmol) is carried out analogously to the method described in Example 10. After 26 hours If a high-melting by-product is sucked off, the filtrate is concentrated in vacuo and digests the residue with warm methylene chloride. One sucks off again and constricts the filtrate with the addition of methanol. The only slowly crystallizing Reaction product becomes thicker when redissolved from methylene chloride-methanol, golden yellow needles that melt at 148 "C.

In game 13 compound XIII 1, 75 g (5 mmol) of said hydrazonium bromide are mixed with 3.4 g (SOmmol) of cyclopentene and 3.0 ccm of pyridine in 30 ccm of dimethylformamide dissolved by shaking and finally heated to 55 ° C. for a further 46 hours Evaporation in vacuo is taken up in methylene chloride and concentrated with the addition of Methanol. Yield 58% of theory. From benzene-ethanol crystallize golden yellow, glittering crystals with a melting point of 170 to 171 ° C. with decomposition.

Example 14 Compound XIV Analogously to Example 13, 1.75 g (5 mmol) of hydrazonium bromide with 5.0 cc allylbenzene and 2.0 cc pyridine in 30 cc dimethylformamide reacted, but heated to 80 "C for 23 hours.

The crude product isolated as in Example 13 melts after dissolving from methylene chloride-methanol at 162 to 164 ° C. The mother liquor becomes less Amount of a second, more difficult to dissolve compound. The overall yield is 740/0 of theory. The main amount is first dissolved in methylene chloride-methanol cleaned, then you dissolve several times for safe isomer separation. partially in ether, sucks off and concentrated with the addition of methanol. You get orange-yellow, rather coarse crystals that melt indistinctly at 160 to 1630 C with decomposition.

The second component is redissolved from methylene chloride-methanol Preserved in the form of lemon-yellow, fine, matted needles, numbered at 229 to 231 0C melt with decomposition.

Example 15 Compound XV Analogously to that described in Example 13 In the process, the reaction takes place with 1.7 cc of allyl alcohol (25 mmol). That in 3S01o The reaction product obtained in the yield initially crystallizes from ethanol-cyclohexane in the form of yellow crystals from Melting point 181 to 183 "C (under Red color), but then as a bright red crystal powder. The red crystal modification After being redissolved from acetone-cyclohexane, it melts at 199 to 200 "C with decomposition. If the melt of the yellow crystals is inoculated with the red modification, it solidifies the substance again and then also melts at 200 ° C, Example 16 compound XVI Analogously to Example 4, 1.75 g (5 mmol) of hydrazonium bromide and 1.1 ccm (10 mmol) Phenyl isocyanate reacted and worked up. The residue is taken up in benzene, freed from insoluble impurities and concentrated with the addition of ethanol. 1.9 g of yellow needles (99010 of theory) are obtained. After dissolving from benzene, ethanol shiny, light lemon yellow needles with a melting point of 157 to 159 ° C are obtained.

Example 17 Compound XVII Analogously to the previous example with 1.20 ccm (10 mmol) phenyl mustard oil with the addition of the azomethine imine 1.83 g (910/0 theory) yellow crystals are obtained, which melt at 178 "C with decomposition.

Example 18 Compound XVIII Corresponding to that described in Example 4 In the process, 1.703 g of hydrazonium bromide are reacted with 2.0 cc of diphenylketene. It is filtered off with suction, the residue is recrystallized from acetonitrile and a light yellow color is obtained Crystal powder with a melting point of 199 ° C. that changes color in the light.

After working up the mother liquor, the yield is 74 ° lo of the Theone.

Example 19 Compound XIX 1.3 1 g 2- [2. 4-dinitro-anilino] -3, 4-dihydro-isoquinolinium bromide (3.3 mmol) are mixed with 1 g of norbornene (11 mmol), 0.3 cc of pyridine and 8p cc of dioxane Heated for 12 hours to 55 ° C. After concentration in vacuo, the crystalline residue becomes (0.9 g, 67% of theory) suctioned off and dissolved from benzene to ethanol. Yellow crystals from melting point 192.5 to 193.5 "C (decomposition).

In boiling benzene, the same reaction gives a yield of 91 ° lo the theory of the same adduct XIX.

Example 20 Compound XX A mixture of 1.97 g of that in the example 19 mentioned hydrazonium bromide (5 mmol), 2.1 g of 3,6-endomethylene - 1,2,3,6 - tetrahydrophthalic acid - Dimethyl ester (10 mmol), 20 cc of dimethylformamide and 1.0 cc of pyridine is 17 hours shaken. After concentration in vacuo, the residue is boiled with methanol and vacuumed after cooling in the refrigerator. After processing the Mother liquor the yield is 690/0 of theory.

Dissolution from chloroform-methanol gives orange crystals which completely decompose after previous browning at temperatures between 252 and 258 ° C.

Example 21 Compound XXI The reaction takes place analogously to Example 20 with 3.12 g (15 mmol) of 3,6-endomethylene-3,6-dihydrophthalic acid dimethyl ester in 75% yield of an adduct, which when redissolved from chloroform-methanol in the form of orange Needles with a melting point of 241 to 242 "C (decomposition) are obtained.

Example 22 Compound XXII Analogously to Example 20, 7.0 ccm of α-methyl-styrene are obtained implemented. Finally, after adding a little hydroquinone, the mixture is heated for a further 8 hours to 70 ° C. After concentrating in vacuo, it is taken up in methylene chloride and taken under Concentrated addition of methanol. The crystalline substance (yield 560/0 of theory) When dissolving from methylene chloride, ethanol produces bright yellow crystals which after turning brown, melt at 231 ° C. with decomposition.

Example 23 Compound XXIII According to Example 20, the hydrazonium bromide implemented with ten times the molar amount of indene. Digested in vacuo after concentration one in the heat with methylene chloride, sucking off unreacted starting material and the filtrate is concentrated with the addition of methanol. The dark, greasy material it is digested with acetone, filtered off with suction, and the residue is redissolved from benzene-ethanol and receives golden yellow crystals which melt at 228 to 229 ° C with decomposition.

Example 24 Compound XXIV Reaction with 0.46 g (7 mmol) fresh distilled cyclopentadiene is carried out analogously to Example 20.

The oily residue is taken up in acetone; the one when constricting The greasy crystals obtained are digested intensively with in acetone solution Animal charcoal and concentrated with the addition of methanol.

The pure product obtained in a yield of 46 ° lo crystallizes from chloroform-methanol in orange-yellow crystals from melting point 204 to 205 "C with decomposition.

Example 25 Compound XXV The reaction with 2.31 ccm (25 mmol) Ethyl acrylate follows the procedure described in Example 20. The oily one The residue is taken up in ethanol, from which only gradual crystallization takes place. The dark colored substance is digested in acetone with activated charcoal and finally concentrated with the addition of ethanol. The reaction product crystallizes from benzene-ethanol in yellow. glittering chopsticks that are below at 149 to 1500C Melt discoloration.

Example 26 Compound XXVI 1.97 g of the hydrazonium bromide mentioned in Example 20 are mixed with 5.0 ccm dihydropyran and 1.0 ccm pyridine in 20 ccm dimethylformamide 15 Heated to 128 ° C. for hours. After the solvent has been stripped off, it remains in vacuo a dark Dl that slowly crystallizes. After pressing on clay and releasing Acetonitrile gives yellow needles with a melting point of 216 ° C.

Example 27 Compound XXVII a) The reaction is carried out analogously to the example 20 with 1.1 cc (10 mmol) phenyl isocyanate. Orange-red crystallize from benzene-ethanol Needles (950/0 of theory) from melting point 171 to 172.5 C with decomposition. b) 156 g of the crude azomethine imine described below are in 2 cc pure phenyl isocyanate dissolved. After 4 hours, the mixture is concentrated in a high vacuum and taken the crystalline residue in benzene and filtered from 65 mg of triethylammonium bromide away. After concentrating the benzene solution and adding ethanol, 111 mg crystallize of the adduct that has a mixed melting point with the reaction product described under a) matches. Yield 89 ° lo of theory. c) 156 mg of 1-ethoxy-2- [2,4-dinitro-anilino] - 1.2.3.

Stetrahydroisoquinoline is mixed with 2 cc of phenyl isocyanate, as below b) described, implemented and processed. 163 mg of the at 171 to 172 "C are obtained with decomposition of the melting adduct of the formula XXVII (870/0 of theory).

The azomethine imine mentioned under b), the 3,4-dihydroisoquinolinium-2- [2, 4-dinitro-anilino], is prepared in such a way that 10.2 g of finely powdered Hydrazonium bromide (26 mmol) suspended in 80 cc of dimethylformamide and stirring and exclusion of moisture with 3. 50 ccm of anhydrous triethylamine (25 mmol). The free azomethine imine separates from the red solution as an orange-red, finely crystalline one Precipitate from, which washed after suction with benzene and with absolute ether will. After drying, 6.37 g of a melt at 151 to 152 ° C. with decomposition are obtained the substance still contaminated with triethylammonium bromide.

Example 28 Compound XXVIII According to Example 27, a) 3.0 ccm (25 mmol) of phenyl mustard oil have also been converted, but you are already working after 4 Hours on. Red needles with a melting point crystallize from methylene chloride-methanol 151 to 153 "C (discoloration).

Example 29 Compound XXIX Reaction with 2.0 cc of diphenylketene as well follow the procedure given in Example 20.

After the solvent has been stripped off in vacuo, the crystalline ones are digested Residue with warm petroleum ether. Pressing on clay and dissolving from acetonitrile or ethyl acetate gives shiny, yellow flakes in almost quantitative yield of melting point 243 "C (decomposition).

Example 30 Compound XXX I 17 g of 1-ethoxy-2- [2,4-dinitroanilinoj- -1,2,3,4-tetrahydroisoquinoline (3.3 mmol) are mixed with 2.3 ccm of dicyclopentadiene and 20 cc of toluene heated to 100 to 105 ° C for 31/2 hours on a riser. One sucks from a few black flakes off, concentrated in vacuo, dissolving the crystalline residue (590/0 of theory) from benzene-ethanol and receives red crystals from the melting point 200 to 202 ° C (decomposition).

Example 31 Compound XXXI The procedure is analogous to Example 30 Implementation with norbornene. The one already described in Example 19 is obtained Compound in good yield.

Example 32 Compound XXXII 0.985 g of 2- [p-chloro-anilino] -3,4-dihydro-isoquinolinium bromide (orange-colored prisms with a melting point of 156 to 157 "C) (3 mmol) are added with 3.0 g Dicyclopentadiene and 1.0 cc pyridine in 20 cc dimethylformamide for several hours shaken.

After concentration in vacuo, it is redissolved from acetonitrile and obtained 830/0 yield colorless needles with a melting point of 200 to 201 "C.

Example 33 Compound XXXIII 1.0 cc phenyl isocyanate, 20 cc dimethylformamide and 1.0 cc of triethylamine are mixed with 1.97 g of 2- [p-chloro-anilino] -3,4-dihydroisoquinolinium bromide implemented analogously to Example 32. The triethylammonium bromide is filtered off with suction and concentrated Filtrate in a vacuum and separated by taking up in benzene from the remaining ammonium salt. Concentration with the addition of ethanol gives quantitatively the expected adduct. the end Benzene-ethanol crystallizes colorless, matted needles with a melting point of 176 up to 177 ° C.

Example 34 Compound XXXIV 2.05 g of the hydrazonium bromide from Example 32 are in 20ccm dimethylformamide with 10.0 ccm diisopropyl-carbodiimide and 1.0 ccm of triethylamine heated to 90 ° C for 4 hours. The triethylammonium bromide is sucked off from, the filtrate is mixed with dilute caustic soda and ether out. After drying over sodium sulfate and concentration (finally in a high vacuum), the crystalline residue from acetonitrile to form colorless prisms (88% of theory) of melting point 147 ° C.

Example 35 Compound XXXV 2.04 g of the hydrazonium bromide from Example 32 are mixed with 10.0 cc carbon disulfide, 10 cc dimethylformamide and 1.0 cc Triethylamine heated under reflux for 5 hours. One makes with very dilute caustic soda alkaline, sucks off the separating yellow crystals and dissolves them from acetonitrile around. Light yellow crystals with a melting point of 1760 ° C. are obtained in 91% yield.

Example 36 Compound XXXVI 1.8 g of 2-anilino-3,4-dihydro-isoquinolinium bromide (yellow needles with melting point 147 to 148 ° C) are with 2.76 ccm styrene, 20 ccm Dimethylformamide and 1.0 cc pyridine heated to 60 ° C for 18 hours. It is concentrated in a vacuum a, separates from insoluble components and concentrates with the addition of ethanol. That gives reaction product obtained in 570/0 yield, redissolved from benzene-ethanol, colorless crystals. which melt at 187 to 188 ° C.

Example 37 Compound XXXVII A solution of 25 cc of styrene in 50 ccm of ethanol is added dropwise at 60 "C with 1.0 g of 1,2-methylimino-1,2,3,4-tetrahydroisoquinoline offset. Then it is acidified with alcoholic hydrochloric acid and held for another 2 hours with stirring at 60 ° C. One makes alkaline with alcoholic potassium hydroxide solution, heated another 2 hours, concentrated in a vacuum and worked up with water-ether. When distilling off the ether remains a yellow DI, which gradually solidifies in a crystalline manner. After releasing colorless, matted needles with a melting point of 830 ° C. are obtained from aqueous methanol.

Example 38 Compound XXXVIII 0.425 g fluorenone - p - chloranil - Cyanamide (1.29 mmol) are dissolved in 15 cc of dicyclopentadiene (115 mmol) for 12 hours 90 to 100 ° C heated.

It is concentrated in vacuo and a little ethanol is added to make the colorless Precipitate adduct. After redissolving from a lot of ligroin, 0.29 g of pure product is obtained (470/0 of theory) from melting point 221 ° C (decomposition).

The solutions are used to produce the fluorenone-p-chloranil-cyanamide of 8 g of p-chlorobenzene diazocyanide (48 mmol) and of 9.5 g of diazofluorene (49 mmol) combined in 45 ccm of ethylene chloride at room temperature. With slight self-warming begins nitrogen evolution; after about 10 minutes the deposition of Crystals. To complete the reaction, the mixture is heated in a water bath for some time to about 50 ° C. After cooling, the bright red crystals are suctioned off and from a second fraction obtained from the mother liquor. The yield is 14.8 g (92 ° Wo the theory). After dissolving from dioxane, the compound melts at about 192 ° C (decomposition).

Example 39 Compound XXXIX 0.5 g of the azomethine imine mentioned in Example 38 (1.52 mmol) are mixed with 10 g of norbornene {bicyclo [1,2,2] hepten (2)} for 10 hours Refluxed. Excess norbornene is sublimed off and the crystalline ones are washed Residue twice with a little cold petroleum ether (40 to 80 ° C).

The adduct remaining undissolved (0.61 g, 96% of theory) results after redissolving from ligroin, colorless crystals with a melting point of 188 to 189 ° C (decomposition).

Example 40 Compound XL The reaction takes place analogously to Example 39 with 12.5 cc of norbornadiene fBicydo [1,2,2jheptadien- (2,5 ». It is concentrated in vacuo and dissolves the crystalline residue from ligroin. The yield of colorless pure product from a melting point of 187 ° C. (decomposition) is 680/0 of theory.

Example 41 Compound XLI 0.486 g of the azomethine imine mentioned in Example 38 are heated to 70 ° C for 10 hours with excess styrene and a little hydroquinone. After the styrene has been stripped off in vacuo, the crystalline residue is briefly boiled with it 3 cc of ethanol, sucks off after cooling and dissolves the obtained in 950/0 yield Reaction product from ligroin. Melting point 183 to 184 ° C (decomposition).

Example 42 Compound XLII 0.543 g of that mentioned in Example 38 Azomethine imines are mixed with 5.0 cc of acrylonitrile and a little hydroquinone in 15 cc of chlorobenzene Heated to 80 ° C for 41/2 hours. After evaporation in a vacuum, the mixture is briefly cooked 20 ccm of methanol, sucks in the refrigerator after cooling and dissolves that in 83% Yield of isolated reaction product from ligroin. Colorless crystals are obtained melting point 176 ° C (decomposition).

In game 43 compound XLIII 0.508 g of that mentioned in Example 38 Azomethinimines are heated with 5.0ccm of ethyl acrylate and a trace of hydroquinone in 15 cc of chlorobenzene at 80 ° C. for 5 hours. The mixture is concentrated in vacuo and crystallized from ligroin-dioxane (10: 1). The reaction product isolated in 850/0 yield forms colorless crystals which melt at 125 ° C with decomposition.

Example 44 Compound XLIV Analogously to Example 43, 0.55 g of des Azomethine imines with 3.5 cc of maleic acid dimethyl ester in bromobenzene for 13 hours 800 C heated. After the solvent has been stripped off in vacuo, something is added Ether, sucks off after standing in the refrigerator and dissolves from ethanol. That in 66% yield isolated reaction product melts at 177 "C (decomposition).

Example 45 Compound XLV The reaction with excess ethyl p-nitrocinnamate is carried out analogously to Example 43. After 10 hours you let it cool down and suck it up Part of the nitro-cinnamic acid ester is removed and the remainder is removed after the filtrate has been concentrated in a vacuum by careful high vacuum sublimation. The residue is removed with LigroinDioxan the pyrazolidine (750/0 of theory), which at 156 to 158 "C with decomposition melts.

Example 46 Compound XLVI 1.04 g of the azomethine imine mentioned in Example 38 are dissolved in excess phenyl isocyanate by shaking. After 40 hours one sucks off and dissolves from ethanol. Colorless prisms are obtained, those at 172 to 173 "C melt with decomposition. After working up the mother liquor, the Yield 77% of theory.

Example 47 Compound XLVII The reaction proceeds analogously to Example 46 with phenyl mustard oil. Petroleum ether is added and, after standing for a while, suction in the refrigerator removes, dissolves from carbon disulfide and acquires colorless flakes with a melting point 183 to 185 "C (decomposition).

The yield is 930/0 of theory.

Example 48 Compound XLVIII Analogously to Example 46, Q555 g is used of azomethine imine with 1.0 cc of acetylene dicarboxylic acid dimethyl ester in 20 cc of dioxane around and concentrated in vacuo after 12 hours. From the oily residue is obtained with Ligroin the pyrazoline derivative, which melts at 98-105 ° C, in 93% yield.

Example 49 Compound XLIX Analogously to Example 44, 3 cc of propinal dimethylacetal are used implemented. The adduct isolated in 670% yield melts after being dissolved in ethanol at 1680 C with decomposition.

Example 50 Compound L According to Example 44 one also sets 4.0 ccm of phenylacetylene with the azomethine mentioned there imin around and takes after the Concentrate in vacuo in ligroin. The reaction product obtained in 70% yield after recrystallization from ligroin, melts at 172 ° C.

Example 51 Compound LI The reaction with 5.0 cc of 1-hexyne is also carried out analogously to Example 44. After concentrating in a vacuum, you cook with a little methanol, lets cool in the refrigerator and dissolves from ligroin. The so obtained compound shows a melting point of 196 to 197 ° C (decomposition).

Example 52 Compound LII 0.247 g of that listed in Example 38 Azomethine imines are heated to 82 ° C. with 1.05 g of tolane in 15 cc of dioxane for 22 hours. The solvent is removed in vacuo, excess tolane by cautious High vacuum sublimation removed and the residue briefly boiled with 5 ccm of ethanol. After cooling in the refrigerator, suction and dissolve from ligroin-dioxane (10: 1) around. The reaction product isolated in 280/0 yield is colorless needles, which melt at 202.5 to 203 "C with decomposition.

Example 53 Compound LIII 0.988 g of benzophenone-p-chloroanil-cyanamide (3 mmol) are mixed with 2.0 ccm acetylenedicarboxylic acid dimethyl ester (about 13 mmol) in 40 ccm of dioxane dissolved by shaking briefly at room temperature. To Standing for 15 hours, the solvent is removed in vacuo, and 5 cc is added Ether and sucks off after standing in the refrigerator for some time (raw yield 690 / o). Redeem from ethanol leads to colorless needles, which decompose at 173 to 173.50 C melt.

The benzophenone - p - chloranil - cyanamide is analogous to the azomethine imine of Example 38 from diphenyldiazomethane and p-chlorobenzene diazocyanide in 89 ° ln yield prepares and forms light yellow needles with a melting point of 130 to 132 "C with decomposition.

Example 54 Compound LIV 0.497 g of fluorenone - p - nitroanil - cyanamide are in 15 cc of chlorobenzene with 4.0 cc of styrene with the addition of a little hydroquinone Heated to 800 C for 20 hours. After the solvent has been stripped off, it remains in vacuo a crystalline residue, first from ligroin-dioxane (10: 1), then from ethanol is redeemed. The reaction product isolated in 710/0 yield melts at 166 up to 167 "C with decomposition.

The fluorenone-p-nitroanil-cyanamide is made from diazofuene and p-nitrobenzene-diazocyanide Obtained analogously to Example 38 in 880/0 yield when working below 10 ° C. the Orange-red prisms melt at 123 to 124 "C with decomposition.

Example 55 Compound LV A mixture of 1.25 g of 2-ureido-3,4-dihydroisoquinolinium bromide (4.6 mmol), 2.60 g of dicyclopentadiene (20 mmol) and 7.0 cc of pyridine (90 mmol) Heated to 110 ° C for 17 hours. It is concentrated in vacuo and crystallized from ethanol-cyclohexane um: Colorless needles which after browning above 245 ° C at 250 to 251 CC under Melt decomposition. The yield is 480/0 of theory.

Example 56 Compound LVI 2.63 g 2- [N - (p - Nitranilino)] - 3,4- 4-dihydroiso quinolinium bromide (7.5 mmol) are mixed with 0.66 g of cyclopentadiene (10 mmol) and 1.0 cc of pyridine in 25 cc of dimethylformamide reacted with shaking. After 14 hours, it is concentrated in vacuo, the residue is digested with methanol and finally recrystallizes from chlorobenzene.

Yellow-brown crystals of the diadduct are obtained, those at 268 to Melting 270 ° C with decomposition.

Example 57 Compound LVII The blue-violet solution of the zwitterion, by shaking a solution of 2.22 g of N-amino-pyridinium iodide for 90 minutes (10 mmol) in 50ccm dimethylformamide with freshly calcined potassium carbonate under nitrogen and subsequent suction has been obtained, 2.85 g of dimethyl acetylenedicarboxylate are added (20 mmol), the color of the solution turning brown. After 2 hours at room temperature is concentrated in vacuo, the residue taken up in ether and some insoluble ones Shares separately. After the solvent has been stripped off, it is distilled in vacuo. Colorless needles of dimethyl fumarate sublime at 80 to 100 ° C./0.4 Torr (Melting point 101 ° C). At 140 to 150 ° C / 10-3 Torr a colorless Dl is obtained, which soon solidifies and, after dissolving from a little cyclohexane, has a melting point of 69 bis 70 °. The compound LVII is obtained in a yield of 0.332 g (150/0 of Theory).

By adding 300 mg of 5% palladium carbon to the reaction mixture the yield of LVII can be increased to 22%. The work-up is in this Fall made after shaking for 24 hours.

Example 58 Compound LVIII A suspension of 1.75 g of 2- [2-nitro-phenylamino] -3,4-dihydro-isoquinolinium bromide (5 mmol) is mixed with 1.1 cc of phenyl isocyanate (10 mmol) and 1.0 cc of triethylamine in 20 cc of dimethylformamide implemented. It is concentrated in a high vacuum, separated by sensors in hot benzene from the triethylammonium bromide and bring the filtrate by concentration with the addition of ethanol for crystallization.

The yield is quantitative. Come from methylene chloride-methanol golden yellow matted needles with a melting point of 143 to 144 ° C.

Example 59 Compound LIX As described in Example 58, obtained 1.75 g of the hydrazonium salt (5 mmol) with 0.6 cc of carbon disulfide are 1.33 g (780 / o of theory) of yellow crystals with a melting point of 153 ° C. (decomposition).

Example 60 Compound LX A solution of 0.76 g carbon disulfide and 0.24 cc of pyridine in 20 cc of dimethylformamide is mixed with 0.604 g of 2-methylamino-3,4-dihydro-isoquinolinium bromide Shaken for 20 hours and finally heated to 80 ° C. for a further 2 hours. The mixture is concentrated in a vacuum, pulls out the crystalline residue with water and then dissolves Methanol by: 0.41 g of yellowish crystals (70% of theory) with a melting point of 145 bis 146 "C. The colorless analysis sample melts at 148.5 to 149 ° C.

Example 61 Compound LXI 1.51 g of 2-anilinoisoquinolinium bromide (5 mmol) are dissolved in 75 cc of water with the addition of a drop of glacial acetic acid. Man filtered, mixed with 25 ccm of saturated aqueous soda solution and takes the red one Precipitation in 125 cc of ether. The solution is briefly dried over sodium sulfate and then filtered. Then 0.655 g of phenyl isocyanate (5.5 mmol) are added and leaves the mixture to itself for 2 days. Rapid color change.

The solvent is evaporated off and the crystalline residue is digested with 5 cc of ether: 1.47 g of almost colorless crystals (870/0 of theory) with a melting point 125 to 127 ° C (decomposition). The analysis sample melts after dissolving from ethanol at 133 "C.

Example 62 Compound LXII A as in Example 61 from 1.51 g des Hydrazonium salt (5.0 mmol) prepared ethereal solution of the imine is 0.81 g phenyl mustard oil (6.0 mmol) were added. After storing overnight, it is concentrated and obtained by digestion with 5 cc of ether 1.36 g of almost colorless crystals (770 / or Theory) with a melting point of 125 ° C. From acetonitrile colorless coarse, at 130 to 131 ° C needles that melt with decomposition.

Example 63 Compound LXIII Analogously to Example 61, one prepares an aqueous solution of 25 mmol of 2- [4-chlorophenylamino3-isoquinolinium bromide with Soda solution, the free imine, which is taken up in 225 cc of methylene chloride. One is added with 4.32 g of dimethyl maleate (30 mmol) and the mixture is left overnight itself. Glue constriction separates 5.96 g of colorless leaflets (600 / o der Theory), which melt at 166.5 to 167 ° C after redissolving from methylene chloride-methanol.

Claims (1)

Claim: A process for the preparation of five-membered heterocycles containing at least two adjacent nitrogen atoms, characterized in that azomethine imines of the general formulas generated in situ are optionally produced in which R1 is a hydrogen atom, an alkyl radical, an unsubstituted or substituted aryl radical. the cyano or carboxamide group R2 and R3 each represent an unsubstituted or substituted aryl radical or together with the nitrogen and carbon atom of the azomethine imine a mono- or polyunsaturated ring system, R4 a hydrogen atom or an unsubstituted or substituted aryl radical or R3 and Rq together with the carbon atom of Azomethine imines mean a ring system, reacts with compounds with reactive CC multiple bonds, CN double bonds or CS double bonds. Publications considered: Journal of Organic Chemistry, Vol. 24 (1959), pp. 892/893.