DE3141640A1 - Processes for the preparation of cyanoheterocycles - Google Patents

Abstract

Processes for the preparation of cyanoheterocycles of the general formula I <IMAGE> in which W, X, Y and Z denote a nitrogen atom or the radicals CH or CR1 where R1 denotes a hydrogen atom, a straight-chain or branched alkyl radical having 1-10 C atoms, which may be substituted, an aralkyl having 7-10 C atoms, aryl, heteroaryl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, carboxyl, a hydroxyl radical, an amino radical, a mono- or dialkylamino radical, a mono- or diarylamino radical, alkylsulphonyl, arylsulphonyl, trifluoromethyl, a halogen substituent or a cycloalkyl, or W-X, X-Y and Y-Z form part of an aliphatic, aromatic or heterocyclic ring, which may contain one or more nitrogen, oxygen or sulphur atoms and be substituted by R1 where R1 has the meaning given, are characterised in that an N-oxide of the general formula II <IMAGE> in which W, X, Y, Z and R1 have the meanings given, is reacted with trimethylsilyl cyanide.

Description

Process for the preparation of cyanoheterocycles

Description Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline Pyrimidine N-oxide can be after O-alkylation or acylation and then Treatment with aqueous cyanide solution into the corresponding 2- or 4-substituted Convert cyano compounds. The less reactive pyridine-N-oxides arise often only in poor yields mixtures of 2- and 4-cyano compounds (E. Ochiai, Aromatic Amine Oxides, Elsevier Publishing Co., Amsterdam 1968, A.R. Katritzky, J. M. Lagowski, Chemistry of the Heterocyclic N-Oxides, Academic Press London-New Pork 1971).

It has now been found that heterocyclic N-oxides in only one Reaction stage and selectively in high yields into the corresponding 2-cyanoheterocycles let convert if you either the heterocyclic N-oxides with trimethylsilyl cyanide heated or heated to an inert solvent without solvent *

more economical the heterocyclic N-oxide with an alkali cyanide and Trimethylsilyl chloride heated in a polar solvent, i.e. the trimethylsilyl cyanide generated in situ.

The invention thus relates to processes for the preparation of cyanoheterocycles of the general formula I. wherein W, X, Y and Z are a nitrogen atom or the radicals OH or CR1 with R1 meaning a hydrogen atom, a straight-chain or branched alkyl radical with 1-10 C atoms, which can optionally be substituted, of an aralkyl with 7-10 C -Atoms, aryls, heteroaryls, methoxycarbonyls, ethoxycarbonyls, phenoxyearbonyls, carboxyls, hydroxy radicals, amino radicals, mono- or dialkylamino radicals, mono- or diarylamino radicals, alkylsulfonyls, arylxulfonyls, trifluoromethylsubstituents, a haloalkylsubstituent. represent or WX, XY and YZ are part of an aliphatic, aromatic or heterocyclic ring which is optionally substituted by R1 in the meaning given and which may contain one or more nitrogen, oxygen or sulfur atoms, characterized in that an N-oxide is used general formula II with the meanings given for W, X, Y, Z and R1 with trimethylsilyl cyanide.

The N-oxides of the general formula II are either solvent-free or in an inert solvent such as acetonitrile, pyridine, dimethylformamide, N-methylpyrrolidone etc., preferably in dimethylformamide, with about 2-3 equivalents Trimethylsilyl cyanide or with an alkali metal cyanide, such as sodium or galium cyanide, with trimethylchlorosilane in an inert polar solvent such as dimethylformamide or methylpyrrolidone, e.g. also in the presence of a phase R 0 transfer catalyst such as Adogen k64 at 50-250 ° C, preferably at 70-180 ° C, where according to literature (S. Rünig, Synthesis 1979, 522) trimethylsilyl cyanide in situ forms, so that the representation of the expensive and relatively unstable reagent unnecessary.

The reactions are faster and in higher yields if you in the presence of a tertiary amine, such as triethylamine, tripropyl, tributyl as well as diisopropylethylamine or DBN or DBU carries out.

As the alkyl group R1 are straight or branched alkyl groups with 1-10 C-atoms meant, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, heptyl, hexyl, decyl.

The alkyl groups R1 can optionally be substituted one to more than once be by halogen atoms, alkoxy groups, optionally substituted aryl groups, Dialkylamino and trialkylammonium.

Those alkyl groups which are monosubstituted are preferred.

Examples of substituents that may be mentioned are fluorine, chlorine or Bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.

Preferred alkyl groups R1 are those having 1-4 carbon atoms, such as e.g. Methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl may be mentioned. As aryl groups R1 are both substituted and unsubstituted aryl groups, such as phenyl, 1-naphthyl and 2-naphthyl, each of which is substituted can be replaced by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 Carbon atoms, a chloromethyl, fluoromethyl, frifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 carbon atoms.

The substituents in the 3- and 4-positions on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position Hydroxy. The aralkyl group R1 can contain 7-10, preferably 7 and 8 carbon atoms. Unsubstituted phenyl and substituted phenyl are suitable as Ar radicals. * ßtstituenten correspond to those for R1 as aryl group. Straight-chain ones are used as alkyl radicals and branched alkylene radicals with 1-4 carbon atoms. As heterocyclic groups R1 are 5- and 6-membered heterocycles in question, the at least 1-heteroatom, preferably contain nitrogen, oxygen or sulfur.

Examples include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.

As alkyl groups of the radicals monoalkylamino, dialkylamino or alkylsulfonyl straight and branched chain alkyl radicals with 1-6, preferably with 1-4 carbon atoms, in question. For example methyl, ethyl, propyl, Butyl, isobutyl, tert.

Butyl, pentyl, hexyl.

The cycloalkyl group P1 can have 4-10, preferably 5 and 6 carbon atoms in the ring contain. The rings can be substituted by alkyl groups with 1-4 carbon atoms be. Examples include cyclopentyl, cyclohexyl and methyl-cyclohexyl and adamantyl.

As aryl groups of the radicals monoarylamino, diarylamino or arylsulfonyl for example: phenyl, 1-naphthyl and 2-naphthyl come into consideration.

As halogens are meant fluorine, chlorine and bromine.

The method also has the advantage that reactive groups such as Hydroxyl, carboxyl and amino groups silylated during the reaction and thereby protected will. This silylation also facilitates work-up, since most persilylated end products after addition of ice water by extraction with hexane or toluene can be easily separated from polar solvents such as N-methylpyrrolidone.

The following N-, O- or S-containing compounds are used as starting compounds II heterocyclic N-oxides, consisting of 1 ring or a fused ring system, in consideration: pyridine-N-oxides, pyridazine-N-oxides, pyrimidine-N-oxides, pyrazine-N-oxides, Quinoline-N-oxides, isoquinoline-N-oxides, acridine-N-oxides, ß- or g-carboline-N-oxides, Purine-N-oxides, etc.

Let heterocyclic N-oxides containing the reactive groups mentioned According to the conventionally mentioned methyl denotes only poorly in the corresponding Convert cyan derivatives, since according to the known methods first the N-oxide group acylated or alkylated, the reactive group acylated at the same time or is alkylated, while the reactive Groups are protected by the very easily cleavable silyl group.

According to the process according to the invention, for example, from 3-hydroxypyridine-N-oxide produce the not yet described 5-hydroxy-2-cyanopyridine in about 80% yield, which is a valuable starting material e.g. for the synthesis of analogues of fusaric acid (DOS 29 11 492 and DAS 27 43 944).

Example 1 Conversion of Pyridine-N-Oxide to 2-Ovanopyridine To a Solution of 2.4 g (25'mmol) of freshly distilled pyridine-N-oxide and 5.0 ml (37.5 mmol) triethylamine in 20 ml of boiling abs. Acetonitrile was stirred while 7.8 ml (62.5 mmol) of trimethylsilyl cyanide were added dropwise for 1 h. After another 8 hours of cooking and standing the reaction mixture at 240 for 1 week, 10 ml of methanol was added and concentrated after 30 min. The residue was dissolved in 50 ml of methylene chloride and extracted with approx. 50ml ice-cold sat. NaH0O3 solution. After drying (Na2S04) and Filtration of the methylene chloride phase was concentrated. The dark residue was taken up in a little ether and passed through a column of 100 g of neutral aluminum oxide (AII) filtered. The eluates were concentrated and the residue was distilled on a bulb tube, 2.08 g (so%) slightly yellowish distillate was obtained, which after the gas chromatic Analysis consists of approx. 9526 2-cyano-pyridine and approx. 0.5 * 4-cyanopyridine.

Example 2 Conversion of 2-methylpsridine-N-oxide to 2-oyano-6-methylpyridine 2.75 g (25 mmol) of 2-ethylpyridine-N-oxide, 6.9 ml (55 mmol) of trimethylsilyl cyanide and 3.5 ml (25 mmol) of triethylamine were excluded for 30 hours at a bath temperature of 1000 boiled of moisture, 100 ml of H20 added and 3 times with 100 ml of methylene chloride extracted. The organic phase was dried (Na2S04) and evaporated and the dark residue in hexane-ethyl acetate (9: 1) over a column of 150 g of neutral aluminum oxide (AII) filtered, the first 600 ml of eluate after evaporation and recrystallization from hexane 1.3 g (39 *) 2-cyano-6-methyl-pyridine, m.p.

71.5-72 resulted.

Example 3 Conversion of 4-methylpyridine-N-oxide to 2-cvano-4-methylpyridine 2.75 g (25 mmol) of 4-methylpyridine-N-oxide and 6.7 ml (50 mmol) of triethylamine were with 12.52 ml (100 mmol) trimethylsilyl cyanide in 10 ml abs. Acetonitrile with exclusion of moisture Boiled under reflux for 20 h. After addition of 30 ml of methanol was evaporated and the The residue is extracted in 100 ml of H20 with 3 × 100 ml of methylene chloride. After drying (Na2S04) the extracts and evaporation were obtained 4.01 g of crude product, which in hexane-ethyl acetate (9: 1) was filtered through a column of 150 g of neutral aluminum oxide (AII). the first 750 ml eluate gave 2.66 g (89.3 *) slightly yellowish crystals of 2-cyano-4-methylpyridine, Schmpt. 89-91 °.

Example 4 Conversion of 3-hydroxypyridine-N-oxide to 2-coano-5-hsdroxy-pvri din a) 2.78 g (25 mmol) 3-hydroxypyridine-N-oxide, 11 ml (87.5 mmol) trimethylsilyl cyanide and 8.3 ml (62.5 mmol) of triethylamine in 20 ml of abs. Acetonitrile was boiled under for 8 h Exclusion of moisture at the reflux. After adding 5 ml of hexamethyldisilazane (HMDS) was boiled again for 30 min and concentrated on a rotary evaporator. The residue it was distilled at 120-130 / 2 mbar in a bulb tube and the yellowish-brown one was added Distillate with methanol, whereby spontaneously crude 2-cyano-5-hydroxypyridine with heating crystallized. After recrystallization from ethyl acetate with the addition of animal charcoal were in several portions 2.19 g (73 *) of pure 2-cyano-5-hydroxypyridine, mp.

2100 (dec.) Obtained.

b) To a suspension of 3.33 g (30 mmoi) 3-hydroxypyridine-N-oxide, 2.94 g (60 mmol) of sodium cyanide and 20.8 ml (150 mmol) of triethylainin in 40 ml of abs. N, N-dimethylformamide (DMF) was stirred and water-cooled within 1 h 15.1 ml (120 mmol) trimethylchlorosilane were added dropwise and the reaction mixture finally heated to 110-100 oil bath temperature. After cooling to 240, filter the salts and washing with 50 ml of DMF, the filtrate was concentrated. After adding methanol the residue warmed up, which after renewed concentration from 100 ml of ethyl acetate under Addition of charcoal was recrystallized. In 2 portions you received 3.21 g (90.1 *) pure 2-gyano-5-hydroxypyridine.

Example 5 Conversion of nicotinic acid N-oxide to 2-cyano-5-carboxypyridine 4.17 g (30 mmol) of nicotinic acid-N-oxide, 4.41 g (90 mmol) of sodium vanide and 20.8 ml (Triethylamine) were abs in 100 ml. N, N-dimethylformamide (DEDF) suspended and with cooling and stirring, 15.1 ml (120 mmol) trimethylchlorosilane for one hour added dropwise, the suspension turning orange-red. After 10 h heating to 100-110 ° Bath temperature and cooling to 230-, the insoluble salts were filtered off and washed with 50 ml abs. DMF and concentrated the filtrate at 60-650 / 12 mm. The brown crystalline The residue was dissolved in 120 ml of 2N HCl and extracted with 6 × 100 ml of methylene chloride. After drying (Na2S04) and evaporating the methylene chloride phase the residue dissolved in 100 ml of hot H20, treated with charcoal, filtered and concentrated, 3.3 g (76 *) of pale yellow 2-cyano-5-carboxy-pyridine were obtained, which from 25 ml H20 analytically pure product from Schmpt. 198-2010.

Example 6 Conversion of quinoline-N-oxide to 2-cyanoquinoline 4.9 g (30 mmol) quinoline N -oxide monohydrate, 2.94 g (60 mmol) sodium cyanide and 24.93 ml (180 mmol) of triethyl amine were abs in 60 ml. N, N-dimethylformamide (DMF) stirred and 19 ml (150 mmol) of trimethylchlorosilane were added dropwise over 45 minutes, the Solution initially warmed to 40. The temperature was then increased to 240 by cooling held. After heating to 100-1100 oil bath temperature for 3 hours, the temperature was cooled to 250 Salts filtered off and washed with 60 ml of DMF. After adding 20 ml of methanol the organic phase was evaporated and the yellow-brown crystalline was filtered off Residue (7 g) over 140 g of neutral aluminum oxide (AII). Elution with 250 ml of hexane-methylene chloride (1: 1) yielded 4.2 g (90.1 *) of colorless crystalline 2-cyanoquinoline, which was obtained from approx. 150 ml of hexane was recrystallized and analytically pure in several portions 2-cyanoquinoline, m.p. 94.70 delivered.

Example 7 Conversion of isoquinoline N-oxide to 2-cyanoisoquinoline 2.9 g (20 mmol) of isoquinoline N-oxide was dissolved in 10 ml of abs.

Dissolved N-methylpyrrolidone and 7.5 ml (60 mmol) of trimethylsilyl cyanide added, the reaction mixture heated to 500. After 17 h at 240 was on 300 ml H20 enjoyed the fancy slightly gray Sucked off crystals and dried in vacuo, with 2.58 g (82.7%) of crude 2-cyanoisoquinoline were obtained. Recrystallization from approx. 200 μl of hexane resulted in several portions 2.46 g (78.9%) pure substance, m.p. 900

Claims (1)

A process for the preparation of cyanoheterocycles of the general formula I wherein W, 1, Y and Z are a nitrogen atom or the radicals CH or CR1 with R1 meaning a hydrogen atom, a straight-chain or branched alkyl radical with 1-10 C atoms, which may optionally be substituted, of an aralkyl with 7-10 C Atoms, aryls, heteroaryls, methoxycarbonyls, ethoxycarbonyls, phenoxycarbonyls, carboxyls, hydroxy radicals, amino radicals, mono- or dialkylamino radicals, mono- or diarylamino radicals, alkylsulphonyls, arylsulphonyls, trifluoromethylsubstituent of a cycloalkyl or a substituent of a cycloalkyl or of a cycloalkyl or of a cycloalkyl Aliphatic, aromatic or heterocyclic ring optionally substituted with R1 in the meaning given, which ring may contain one or more nitrogen, oxygen or sulfur atoms, are characterized in that an N-oxide of the general formula II with the meanings given for W, X, Y, Z and R1 with trimethylsilyl cyanide.