CA1297098C - Substituted aromatic compounds and preparation process thereof - Google Patents

Abstract

The present invention relates to new aromatic compounds useful for the preparation of heterocyclic derivatives. These compounds correspond to the general formula: <IMG> (I) in which R'1 represents a halogen atom chosen from the group consisting of chlorine, bromine and iodine, a COOH or COCl radical, R'2 represents a 1,1dimethyldecyl, 1-methyl cyclohexyl or 1-adamantyl radical, R'3 represents a hydrogen atom, a linear or branched alkyl radical comprising from 1 to 10 carbon atoms, or a radical: <IMG> with R '4 representing a lower alkyl radical comprising from 1 to 4 carbon atoms and R'5 representing a lower alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical. The invention also relates to a process for the manufacture of these compounds of formula (I).

Description

9 ~ 3 The subject of the present invention is again arornatic compounds and process for obtaining them.
These new compounds are particularly useful for the preparation of heterocyclic derivatives that have made the subject of Canadian patent application no. 491.024 filed September 18, 1985.
The aromatic compounds according to the invention can be represented by the general formula (I):

R 2 ~ R'l (I) 15R'3O

in which:
- R'l represents a halogen atom chosen from the group consisting of chlorine, bromine and iodine, a COOH or COC1 radical, ~ R ~ 2 represents a rad.ical 1,1-dimethyldecyl,.
1-methyl cyclohexyl or 1-adamantyl, - R'3 represents a hydrogen atom, a radical linear or branched alkyl comprising from 1 to 10 atoms of carbon, or a radical:

/ R ~ 4 If - R'5 30R'4 with R'4 representing a lower alkyl radical comprising from 1 to 4 carbon atoms and R'5 representing a radical lower alkyl containing 1 to 4 carbon atoms or one ";.
~ ' ~ 37 ~ 98 phenyl radical.
Among the compounds which are the subject of the present invention tion, we can cite any particular ~: 2 ~ (1-adamantyl) -4-bromophenol, 2- (1-adamantyl) -4-bromo-1-decyloxybenzene, 3- (1-adamantyl) -4-decyloxybenzoic acid, 2- (1-adamantyl) -4-bromo-1-tert-butyldimethyl silyloxybenzoic acid 3-adaEntyl ~ -4-tert-butyldimethyl silyloxybanzene, 3- acid (1-adamantyl) -4 methoxybenzoic, 2- (1-adamantyl) -4-bromo anisole, 4-bromo-2- (l, l ~ dimethyldecyl) phenol, 4-bromo-2-(1,1-dimethyldecyl) -anisole, 3- (1,1-dimethyldecyl) -4- acid methoxybenzoic acid 3- (1-adamantyl) -4-methoxybenzoic acid 3- (1-adamantyl) -4-decyloxybenzo ~ that, 3- (1,1-dimethyl- acid chloride) decyl) -4 methoxybenzoic acid chloride 3- (1-adamantyl) -4-tert-butyldimethylsilyloxybenzoique.
The present invention also relates to the process for the preparation of the compounds of formula (I) in which:
- R'l represents a halogen atom chosen from the group consisting of chlorine, bromine and iodine, a COOH or COCl radical, ~ R'2 represents a 1,1-dimethyldecyl radical, 1-methylcyclohexyl or l-adamantyl, - -.

~ 2 ~

- R'3 represents ~ a hydrogen atom, an alkyl radical linear or branched comprising from I to 10 carbon atoms, or a radical ~ R ~ 4 If ~ R 5 - R ' with R'4 representing a lower alkyl radical comprising from 1 to 4 carbon atoms and R'5 representing an alkyl radical in ~ er containing from I to 4 carbon atoms or a phenyl radical.
This process is characterized by the fact that it consists of react a p-halophenol of general formula (II):

~, ~ (II) OH

in which X is a chlorine, bromine or iodine atom, - either with an alkyl halide or an alkene, - either with a cyclanol in the presence of either al ~ mi trichloride nium, or sulfuric acid in a solvent, to obtain a p-halophenol substituted with ormule (III):

X

OH (III

:,: -a ~ _ in which ~ is a chlorine, bromine or iodine atom, which llon subjected to an O-alkylation reaction using a halide of linear or branched alkyl, containing from 1 to 10 carbon atoms or a trialkyl or dialkyl-phenyl ~ ilyl halide whose por-elons alkyl ~ contain 1 to 4 carbon atoms, depending on the methods conventional, to obtain the compound of general formula (IV ~:
R2 ~ ~

R '~ (IV) in which X, R'2 and R'3 have the same meanings as above above, which is isolated and, if desired, reacted with magnesium ~
to obtain the corresponding llor ~ anomagnesian, which we then do react with carbon dioxide to obtain the co ~ posP of ormule (I) where R'l represents a radical -COOH, which we i ~ ole and trans ~ elm, ~ i desired, in corresponding acid chloride.

The organic solvent CAN be used for the preparation work of the manufacturing process is notam ~ ent chosen from the dichloromethane and nitrobenzene.

The p-halophenol obtained little ~ -be O-alkylated preerence by ~ or ~ a ~ prior ion of an alkaline phenate.

;, , ~, ~ 2 ~ 7 ~ 9 ~

As mentioned above, the compounds of ~ ormule I
according to the invention can be used as an intermediary ~ for the production of compounds of formula (A ~:

~ X ~
1 ~ A) in which:
Rl represents (i) - CH
(ii) - CH20H
(iii) - ~ -R3 in which R3 represents a hydrogen atom, the radical -OR4, R4 representing a hydrogen atom, an alkylc radical having from 1 to 20 carbon atoms, a mono or polyhydro radical ~ yalkyl or R3 represented feel the radical -NOT
~ "

where r '~ tr "represents ~ entent a hydrogen atom or a rad ~ cal alkyl lower, or taken together form a heterocycle;
R2 represents a hydrogen atom or the radical -CH3 Ar represents a radical of formula:

R 3o where R'3 represents a hydrogen atom or a linear alkyl radical or branched comprising ae 1 to 10 carbon atoms, and R'2 represents a radical l, l-dim ~ thyldecyle, l-methyl ~ yclohexyle or l- ~ damant ~ le, ,., ~ 2 ~
.

Y represents CH or a drazote atom, and X represents an oxygen atom, a sulfur atom or the rad ~ cal -NR5, R5 representing a hydrogen atom, an alkyl radical lower or an inner alkoxycarbonyl radical.

These compounds of formula (A) are obtained by a process characterized by the fact that it consists in reacting a derivative aromatic carboxylic acid of formula:

Where Ar Q

in which :
Ar is as defined above and Q represents OH or Cl, (a) either on a carboxylic acid derivative of ~ ormule:

HX ~ Y

in which:
R2 and R4 are as defined above ~ e ~ X represents `, NH, -O- or -S-, and to carry out a cycli ~ ation reaction desiccant in the presence of an aci.de catalyst, ;

:. . ,::

g ~

(b ~ or a carboxylic acid derivative of formula:
CH ~

4 (4) in which :
R2 and R4 are as de ~ inis above and X represents -NH, -O- or -S-, and to carry out a bromination of the methyl substituent in position 4 and then cycling the carrier intermediate derivative a group ~ phosphonium or phosphinyl according to the conditions of the Wittig reaction, and possibly to trans ~ ormer, according to known methods, the said compounds obtained with a view to obtaining any of the others signi ~ lcat ~ ons of the radical Rl.
We give below, by way of illustration and without any limiting character, several examples of preparation of the compounds of ~ ormule (I) according to the invention.

E ~ EMPLE 1 Z- (1-adaman ~ yl) -4-bromophenol -34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1-amandsntanol are dissolved in 100 ml of dichlorome ~ hane. ~ We have ~ or ~ e drop by drop 10ml of concentrated sulfuric acid and stir hult uh-res at room temperature ~. We pour in water, neutralized by sodium bicarbonate, methylene chloride extract, dry and Evaporates it. After recrystallization from isooctane, 52.8 are obtained.
g (yield: 86 ~) of the expected compound.
Usion point: 140-141C.

2 ~ adamantyl? -4-bromo-1-decylo ~ ybenzene In a balloon, ~ 3.2 g (104 ~ moles) of hydride are introduced.
sodium (80 ~ in ~ oil) and 100ml of N, N-dimethylormamide. We : 3L2 ~ 9 ~

Add a drop by drop a 601ution of 2 ~ adamantyl) 4-bromophenol obtained in Example 1 (29g, 95 mmole ~) in 100 ~ 1 of dimethylformamide 9 and agitates ~ until the release of gas has stopped. 23 ml (104 mmol) of l-iododecane are then added and stirred 8 hours at 20C. We throw in water, dry over sulphate magnesium, and evaporates the solvents. The product ~ es ~ puriflé by chromatography on a silica column (eluent: heptane).
40.7 g (96%) of 2 ~ adamantyl) -4-bro ~ o-1-decyloxybenzene.
F: 69-70C.

4-bromo-2- (1,1-dimethyldecyl) phenol A mixture of 2-methyl-1-undecene (35.6 g, 211 ~ moles) of parabromophenol (36.6 g, 311 mmol) and Dowex resin (brand of trade) 50x12 (100-200 mesh ~ previously ~ washed with water, rinsed at acetone and dried in an oven for 3 hours at 80C, is heated to 100-110C for 48 hours ~ Cool to room temperature ~ ee ~
chromatography on a silica column (eluent: mixture dichloromethane 40 ~ / hexane 60 ~). We thus obtain the 4-bromo-2- (1,1-dimethyldecyl) phenol 50US la ~ elm of an oil ~ ~ alder pale (30.85 g: 43 ~).

E ~ EMP ~ E 4 2- (1-adamantyl) -4-bromoa ~ isolates .
To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50m1 of THF, added dropwise, maintaining the temperature at 20C, 36.8 g (120 ~ mol) of 2 ~ adamantyl) -4-bromophenol obtained in Example 1 and stirred for 1 hour ambient temperature, we then have 9 ml (144 mmol) of iodide methyl and agl ~ e stick 2h at 20C, Pour into water, extract at ether, dry and evaporate. The product is purified by passage, on a silica column (10 X 30cm), eluting with a mixture of hexane (90%) and dichloromethans (10 ~. By evaporation, we obtain 26.2 g of a white solid (Yield: 68 ~).
Usion point: 138-139 ~ C.

~,.

~ 2 ~

g E ~ FMPT`E _ `
Acid 3 ~ adamantyl) ~ 4-methoxybenzoic Dan6 a balloon, we introduce 5.4g (Z25 mAtome ~) of magnesium sium in turnings, and 30ml of I ~] F. One adds drop by drop 48.5 g (150 mmol) solutlon of 2- (1-adamantyl) -4-bromoanisole, o ~ given in Example 4, and 6 ml (70 mmol) of 1,2-dibromoethane in 300 ml of T ~ F.

We heat at reflux for 2 hours, reroidlt at -70 ~ C and make pass a current of C02 for one hour. We let the temperature at 20C, throw into water, acidify to pH 1 with acid concentrated hydrochloric acid, and extracted with ethyl ether. We decant the organic p ~ ase, dry over magnesium sulfate and evaporate.
The solid obtained is recrystallized from ethyl acetate ~ 3.7 g, 86%).
F: 238-239C.

3- (1 adamantyl) -4-decyloxybenzoic acid Analogously to Example S, from ~ ir of 17.9 g (40 mmoles) of the derivative obtained in Example 2, we ob ~ ient, after crystallization tion in a mixture of ethyl acetate and isopropyl ether, 3- (1-adamantyl) -4-decyloxybenzolque acid (13.5 g: 82%).
F: 151-152C.

PL ~ 7 30.7 g (100 mmol) of 2- (1-adamantyl) -4-bromophenol, obtained in Example 1, 15.4 ml (110 mmol) of triethylamine, 50G ~ g (4 mmol) of 4- (N, N-dimethylamino) pyridine and 20 ~ m1 of dimethylormamide (DMF) ~
SOu6 nitrogen, we have ~ drip a solution of 1i, 7 g (104 mmol) tert-butyldimethylsilyl chloride in 100 ml of DoM ~ F ~ We act ~ e 4 hours, ~ ette in water, extract with eeher and decant the organic phase. After washing with water, drying on sul-~ magnesium ate, evaporation of solvents, the residue obtained are ~

~ 2 ~

puri ~ lé by passing over a silica column, eluting with hexane.
36.2 g of the expected product are thus obtained.
F ~ 112C.

3-tert-butyl-4-methoxybenzolque acid Analogously to Example 5, from 12.16 g (50 mmoles) ~ e 4 ~ 2-bromo tert-butyl-methoxybenzene, 1.34 g (55 mAtomes g) of magnesium, of an excess of carbon dioxide, one obt ~ ient 8.31g (80%) 3-tert-butyl-4-methoxybenzoic acid with melting point 190C.

E ~ EMPLE 9 3-tert-butyl-4-methoxybenæoic acid chloride 19.0 g (92 mmol) of acid obtained are introduced into a flask in Example 8 in 100 ml of anhydrous dichloromethane. We add 18.3 ml (92 mmol) of dicyclohexylam ~ ne and stirred for 2 hours at 20 ~ C.
The solvan ~ s are evaporated and taken up in anhydrous ether. On ~ iltre le salt obtained and he was ~ looml of dichloromethane and 6.7 ml (92 mmoles) of thionyl chloride. Stir for 4 hours at 20 ~ C, evaporates and 19.8 g (95%) of the acid chloride are obtained (oil ~ alder p ~ ale).

E ~ E
Acid chloride 3- (1-adamantyl) -4-methoxybenzo ~ q ~
200 ml of thionyl chloride are introduced into a flask, e ~ aJoute by small quantities 35g (122 mmol) of the acid obtained at Example 5. The mixture is heated under reflux until the evolution of gas.
stops. Evaporated to dryness, taken up in 100 ml of anhydrous benzene and evaporates to dryness. The acid chloride is thus obtained

3- (1-adamantyl) -4-mé ~ hoxybenzo ~ que (37g) F: 153-154C.

EXAMPLE _

4-bromo-2- (1 ~ 1-dimethyldecyl) anisole ~ e 4-bromo 2 ~ 1 dimethyldecyl) phenol described in the example-ple 3 (30.85 g, 90 mmol) is dissolved in 100 ml of dry T ~ F, then treated with 2.7 g (90 ~ moles) of sodium hydride (80% in hulle), ,, ~.

7 ~

that we have ~ out by small reactions. The addition finished, we stir 30mn at room temperature, then a ~ 12.8g (90 mmol) driodure methyl. Stir 2 hours at 20C, evaporate the solvent, and purify the residue by chromatography on a silica column (eluent: mixture dichloromethane 40% / hexane 60%).
After evaporation of the solvents6, the desired product is obtained in the form of an oil ~ alder (29.3 g, 91 ~).

Acid 3 ~ dimethyldecyl) -4 ~ methoxybenzo ~ that The brominated derivative obtained in Example 11 (28.46 g, 80 mmol) dissolved in 80 ~ 1 of dry THF, is added slowly to magnesium in turnings (2.34 g, 96mAtg) and an iodine crystal ~ Au start of the addition, heating until the reaction is initiated third party (establishment of a re1ux). This reflux is then maintained by the rate of addition of the brominated derivative.
The addition finished, the stirring is continued 30mm at 50 ~ C, cooled to 0C and passed a stream of carbon dioxide during 3 hours.
The THF is then evaporated, we have ~ 300 ml of water and acid ~ at pH 1 (using 6N hydrochloric acid) Extracted by 3x300ml of ethyl herbal tea. The organic phase is washed with a saturated NaCl solution, dried over magnesium sulate, and evaporated solvents.
The solid obtained is washed with 50 ml of cold hexane, and dried in the oven at 80C.
15.25 g of acid are obtained 3- (1,1-dimethyldecyl) -4-methoxybenzo ~ that (592) F: 112 ~ C.

Acid chloride 3 ~ (1,1-dlmethyldecyl) -4 Analogously to Example 9, from 14.4 g (44.8 7 ~ ~

mmol) of acid obtained above, 9 ml (44.8 mmol) of dicyclohexylamine, the salt obtained being treated with 3.26 ml (44.8 mmol) of thionyl chloride for 16 hours at 20C, we obtain the acid chloride reached.

E ~ PL'3 1 4 3- (lradamantyl) -4 decyloxybenzo ~ acid chloride In a manner analogous to example 10, one obtains from 7.45g (18mmoles) 3- (1-adamantyl) -4-decyloxybenzo ~ acid, 7.7g corresponding acid chloride (100%) EXEMP ~ E _ Aclde 3 ~ adamantvl) -4-ter ~ -butvldiméthYl-.
silyloxybenzolque 1.18 g (48.8 mAtg ~ magnesium and 50 ml of T. ~ .F.) Are introduced into a flask, we have ~ lg drop (32.5 mmol) of the product obtained in Example 7 in 100 ml of THF, and heating ~ ea reflux during for 2 hours. Cool to -78C and ~ pass through a medium reaction a stream of carbon dioxide. Leave to return to tempera-ambient ture, ~ was in water and acidified ~ until pH 1 with 5N hydrochloric acid. After extraction with ether and treatment classic, the solid ob ~ enu is heated in 200m1 of ether isopropyllic ~ reflux.
After cooling, the solid is ~ iltr ~ and we obtain thus 8.2g (65 ~) of acid 3 ~ adamantyl) -4-tert-butyldimé ~ hyl-silyloxybenzoic.
F: 245-246C.

__ Acid chloride 3- (1-adaman ~ yl) -4-tert-butyl-dimethylsilyloxybenzo ~ that 6.45 g (16.7 mmol) of the acid are introduced into a flask obtained in Example 15, 3.3 ml (16.7 mmol) of dicyclohexylamine and 100 ml of methylene chloride. We stir at tsmp ~ rature ambianee 2 hours, then has 1.35 ml (18.4 mmol ~) of thionyl chloride and shakes for 2 hours. Evaporate to dryness, take up in 200m1 of ether, ~ re :
;.,,:.
, '. :

~ 2 ~

~ icyclohexylammoniu chloride ~ and evaporates the solvents. We ob- -alnsi holds 6.9g of acid chloride 3 ~ ada ~ antyl) -4- ~ ert-butyl-di ~ eth ~ lsilyloxybenzoique SOU9 ~ elm of a solid.

Claims (5)

1. Aromatic compounds characterized by the fact that they correspond to the general formula (I):

(I) in which:
- R'1 represents a halogen atom chosen from the group consisting of chlorine, bromine and iodine, a COOH or COCl radical, - R'2 represents a 1,1-dimethyldecyl radical, 1-methylcyclohexyl or 1-adamantyl, - R'3 represents a hydrogen atom, a radical linear or branched alkyl comprising from 1 to 10 atoms of carbon, or a radical:

with R'4 representing a lower alkyl radical comprising from 1 to 4 carbon atoms and R'5 representing a radical lower alkyl containing 1 to 4 carbon atoms or one phenyl radical. 2. Aromatic compounds according to claim 1, characterized by the fact that they are chosen from the group consisting of 2- (1-adamantyl) -4-bromophenol, 2- (1-adaman-tyl) -4-bromo-1-decyloxybenzene, 3- (1-adamantyl) -4- acid decyloxybenzoic, 2- (1-adamantyl) -4-bromo-1-tert-butyldi-methyl silyloxybenzoic acid 3- (1-adamantyl) -4-tert-butyl-dimethyl silyloxybenzene, 3- (1-adamantyl) -4 methoxy- acid benzoic, 2- (1-adamantyl) -4-bromo anisole, 4-bromo-2- (1,1-dimethyldecyl) -phenol, 4-bromo-2- (1,1-dimethyldecyl) -ani-sole, 3- (1,1-dimethyldecyl) -4-methoxybenzoic acid, 3- (1-adamantyl) -4-methoxybenzoic acid chloride, 3- (1-adamantyl) -4-decyloxybenzoic acid chloride, 3- (1,1-dimethyldecyl) -4 methoxybenzoic acid chloride and 3- (1-adamantyl) -4-tert-butyldimethyl- acid chloride silyloxybenzoic acid. 3. Process for the manufacture of the compounds aromatics of general formula (I):

(I) in which:
- R'1 represents a halogen atom chosen from the group consisting of chlorine, bromine and iodine, a COOH or COCl radical, - R'2 represents a 1,1-dimethyldecyl radical, 1-methylcyclohexyl or 1-adamantyl, - R'3 represents a hydrogen atom, an alkyl radical linear or branched comprising from 1 to 10 carbon atoms, or a radical with R'4 representing a lower alkyl radical comprising from 1 to 4 carbon atoms and R'5 representing a lower alkyl radical containing 1 to 4 carbon atoms or a phenyl radical, characteristic laughed at by the fact that it consists in reacting a p-halophenol from general formula (II):

(II) in which X is a chlorine, bromine or iodine atom, - either with an alkyl halide or an alkene, either with a cyclanol in the presence of aluminum trichloride, either sulfuric acid in a solvent, to obtain a substituted p-halophenol of formula (III):

(III) in which X is a chlorine, bromine or iodine atom, which we subjected to an O-alkylation reaction using a halide alkyl, linear or branched, containing from 1 to 10 carbon atoms or a trialkyl- or dialkyl-phenylsilyl halide, the carriers of which alkyl ions contain 1 to 4 carbon atoms, depending on conventional methods, to obtain the compound of general formula (IV):

(IV) in which X, R'2 and R'3 have the same meanings as above, which is isolated and, if desired, reacted with the magnesium to get the corresponding organomagnesium that we then react with carbon dioxide to obtain the compound of formula (I) where R'1 represents a radical -COOH, which is isolated and transformed, if desired, into chloride corresponding acid. 4. Method according to claim 3, characterized in that the organic solvent is selected from the group consisting of dichloromethane and nitrobenzene. 5. Method according to claim 3 or 4, characterized in that the O-alkylation is carried out by prior formation of the corresponding alkaline phenate.