DE1770170A1 - 1,2,3,4-tetrahydroquinolines - Google Patents

Description

CHEMISCHE WERKE HÜLS AG 4370 Marl, August 5th, 1970

- Patent Department - 2063 / D

Our mark »O.Z. 2277

1,2,3, ^ tetrahydroquinolines

The invention relates to substituted 1,2,3,4-tetrahydroquinolines and a process for their preparation

It is known that 1,2,3,4-tetrahydroquinolines by reduction of quinolines, by cyclization of o- (jT-chloropropyl) - -aniline or by synthesis from o-TolAdin and l-bromo-3-chloropropane. Also by pyrolysis of o -, - ^ T-Atninopropyl) aniline or by reductive cyclization of 1,2,3,4-tetrahydroquinoline was obtained from o- (β-acetylethyl) nitrobenzene. However, these synthetic routes are general quite expensive and in some cases exclude the production of polysubstituted 1,2,3,4-tetrahydroquinolines.

It has now been found that substituted 1,2,3,4-tetrahydroquinolines can be obtained in a simple manner if a primary, aromatic amine of the general formula I.

NH ₂

R *

in which R, R, R ^- and R "* denote hydrogen, alkyl radicals with 1 to 4 carbon atoms, alkoxy radicals with 1 to 4 carbon atoms, amino groups optionally substituted by alkyl radicals with 1 to 4 carbon atoms, or halogen,

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12 2 3 3 4

or R and R or R and R or · R and R can be closed to form a fused aliphatic or aromatic six-membered ring, with an »aldehyde of the general formula XZ

R ⁵ - C ^ Xl

in the R a saturated straight-chain or branched chain Denotes an alkyl radical having 1 to 8 carbon atoms or an aryl radical optionally substituted by alkyl or alkoxyl groups having 1 to 4 carbon atoms,.

and an olefin of the general formula XXX

R ⁸ - CH - tC III 0

6 8 *

in which R and R represent hydrogen or an alkyl radical with 1

7 to 10 carbon atoms and R is the phenyl radical, the Vi nyl radical or an alkyl radical with 1 to 2 carbon atoms

• j g

indicates, but R must not be an alkyl radical when R is hydrogen, reacted in the presence of a strong acid at temperatures between 0 and 70 ° C, optionally in the presence of solvents, and the 1,2,3,4-tetrahydroquinoliniuroeals formed in «I am known to be in the free base is convicted, _> i?

Primary aromatic amines suitable for the process of the invention are, for example, aniline, mono-, di-, tri- and tetra-methyl, -Xthyl- or -Methoxyl-substituted anilines with the exception of 2,6-substituted anilines and bromo- or chloro-aniline. Aniline, toluidines and anisidines are particularly suitable and the Xy lid ine with the exception of the 2,6-3CyUdInS. .In addition to such- Amines of higher aromatics can also be used with benzene derivatives use successfully for the method according to the invention, so-

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far with them - as also applies to the benzene derivatives - an electrophilic substitution in at least one of the two o-positions to the amino group is possible and provided that the amines used have sufficient solubility in the solvent that may be used. Suitable amines higher aromatics are e.g. β-naphthylamine 4-amino-diphenyl or 2-aminophenanthrene.

Suitable aldehydes are, for example, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, pentanal, hexanal, heptanal, ^ 2-ethyl-hexanal, caprylaldehyde, pelargonaldehyde, benzaldehyde, o-, m- or p-tolylaldehyde and o-, m- or p-methoxybenzaldehyde.

Instead of the free aldehydes, compounds from which the aldehyde is only formed in the course of the reaction, such as paraldehyde, are also suitable. It is still possible, the free amines and aldehydes in place the appropriate Schiff ¹ look to use bases, but the use of amines and aldehydes is preferred.

Suitable olefins are, for example, isobutene, butadiene, isoprene or diisobutene. Styrene and df-methylstyrene are particularly suitable. I.

Suitable strong acids are e.g. hydrogen chloride, trifluoroacetic acid and sulfuric acid, the use of sulfuric acid being preferred.

Although the reaction can in principle also be carried out in bulk, it is preferred to work in solvents. Suitable solvents are generally all against Reactant inert and sufficiently polar solvents, in particular ethylene carbonate and lower aliphatic monocarboxylic acids, such as formic acid, acetic acid, propionic acid and butyric acid; Acetic acid is the preferred solvent.

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The reactants amine, aldehyde and olefin are in the Usually used in equimolar amounts, but an excess of individual components is harmless.

The acid is used in an amount of 1 to 5, preferably 1 to 3 equivalents, based on the amount of amine. A low water content (up to 25 %) of the acid is possible, but concentrated acids are preferably used.

The process according to the invention is generally carried out in such a way that a mixture of amine, aldehyde and olefin in a suitable solvent at temperatures between 0 and 70 ^° C., preferably between 20 and 40 ° C., is mixed with the strong acid - expediently also diluted with solvents will. Of course, a different sequence for adding the reactants can also be selected; it is, for example, also possible and often expedient to add a mixture of olefin and aldehyde to a suspension of a salt of amine and strong acid in the desired solvent without the progress of the reaction being adversely affected. To avoid disruptive secondary reactions, the reaction is expediently carried out in a protective gas atmosphere, for which a suitable protective gas is nitrogen, for example; however, this precaution is not required. After about 2 to 3 hours - usually after 2 hours - the reaction is over.

In some cases, the tetrahydroquinoline salts crystallize out of the reaction solution and can be filtered off. The salts, which are soluble in any solvent used, are obtained by concentrating the solution or adding solvents such as benzene. By neutralization they are converted into the free bases with alkaline agents such as caustic soda.

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The neutralization can, however, also be carried out directly in the reaction mixture without isolating the salts, which then follows the usual work-up methods for organic bases.

The process according to the invention can be carried out either batchwise or continuously.

The 1,2,3,4-tetrahydroquinolines prepared according to the invention Can be used, for example, as anti-aging agents and stabilizers for plastics and as intermediate products for manufacture used by pharmaceuticals

In the following examples, the parts by weight are related to parts by volume like the kilogram to the liter.

example 1

2 _f 4-dimethyl-4-phenyl-l , 2, 3,4-tetrahydroquinoline

46.6 parts by weight of aniline in 300 parts by volume of acetic acid are slowly concentrated at 20 C with 50 parts by weight of sulfuric acid g was added. 59 parts by weight of Y-methylstyrene and 22 parts by weight of paraldehyde are added dropwise at 30.degree. C. in the course of one hour with stirring and under a nitrogen atmosphere into the suspension formed. ^{The clear solution is stirred at 30 °} C. for a further 1 to 2 hours. The main amount of acetic acid is then distilled off in vacuo and the residue is added to a mixture of 1,500 parts by volume of 10 percent sodium hydroxide solution and 400 parts by volume of benzene. After the benzene phase has been separated off, dried and concentrated, the remaining oily residue is distilled in vacuo.

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Kpt 155 to 160 ° C at 0.05 Torr

n £ ° ι 1.606

Yields 71 parts by weight (61% of theory)

I ₁₉ N (237.33) Ber.t C 86.03% H 8.07% N 5.90% Gef.t C 85.99% B 8.09% N 5.96%

Example 2

To 300 parts by weight of molten Xthylencarbonat is added 46.6 parts by weight of aniline, dropwise with stirring under nitrogen <- atmosphere at 30 ⁰ C 50 parts by weight of sulfuric acid and anschlieftend to within an hour a mixture of 59 parts by weight of methyl styrene and 22 weight parts of paraldehyde. After a post-reaction of 2 hours at 35 ° C, it is worked up as in Example 1 «

• Yields 52 parts by weight (44% of theory)

Example 3

Zn 300 parts by volume of acetic acid is suspended 64.8 parts by weight of aniline hydrochloride, dropwise under nitrogen atmosphere at 30 ⁰ C in one hour 59 weights parts a'-methylstyrene and 22 weight parts of paraldehyde to invites about 1 hour at 40 ° C to react further and worked up as in Example 1 .

Yields 32 parts by weight (27% of theory)

Example 4

To a solution of 85.3 parts by weight of trifluoroacetic acid in ' 200 parts by volume of acetic acid are 46, G Parts by weight of aniline and then under nitrogen

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SpSre at 30 ° C within one hour a mixture of 59 parts by weight oC-methylstyrene and 22 parts by weight paraldehyde dripped. After an after-reaction of 2 hours at 35 ° C., work-up is carried out as in Example 1.

Yields 26 parts by weight (22 % of theory)

Example 5

2,4,6-Tr imethy 1-4-phenyl-l, 2, 3,4-Tetrah In ydrpchinol

53.6 parts by weight of p-methylaniline, 22.1 parts by weight of paraldehyde and 59.1 parts by weight of methylene styrene are dissolved in 100 parts by volume of glacial acetic acid. Then 50 parts by weight of Icon he centers sulfuric acid in 25 parts by volume of glacial acetic acid are added dropwise at 25 ° C. within 45 minutes, stirring is continued for 2 hours at 30 ° C. and the viscous solution is added dropwise under nitrogen to a mixture of 1000 parts by volume of 20 percent sodium hydroxide solution and 400 parts by volume of benzene "Di * ^ the cipliase is separated, washed with water and - übar NaOH after aeia drying - distilled.

Bp: 150 to 160 ° C at 0.0.1 Torr

n £ ° »1,596

Yields 84 parts by weight (76 % of theory)

of a slowly crystallizing oil of pp. 84OC

C ₁₈ H ₂₁ N (251.36) Calc .: C 86.01 % H 8.42 % N 5.57 %

Found i C 85.80 % H 8.49 % N 5.82 %

Example .6

2,4,8-Trimethy 1-4-phenyl -1,2,3,4 -tetrahydroc hinoliri

53.6 parts by weight of o-methylaniline, 22.1 parts by weight of paraldehyde and 59.1 parts by weight of C 1-4 methylstyrene are used in ICO Parts by volume of glacial acetic acid dissolved and fcei within 45 minutes

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25 to 30 ⁰ C with concentrated sulfuric acid 50 weight bodies in 25 parts by volume EsβigeKure with good stirring. After a reaction time of 2 hours at 30 ° C. to 35 ° C., the resulting precipitate is filtered off with suction and added in portions to a mixture of 750 parts by volume of 20 percent sodium hydroxide solution and 250 parts by volume of benzene. The benzene phase is separated off and, after drying, distilled.

Bp: 148 to 155 ° C at 0.01 torr A slowly crystallizing oil is obtained,

Recrystallize the calibration from ethanol IKBt.

Pp: 86 ^° C

C ₁₈ H ₂₁ N (251.3ε) Der .: C 86.01 % H 6.42 % N 5.57 £

Oef.i C 85.55 % H 8.46 % N 5.99 %

Example 7 2 _< 4-dimethyl-4-phenyl-1-aza-1.2.3 »4-tetrahydro-phenanthrene

4 ^ parts by weight of beta-naphthylamine, 15.2 parts by weight of paraldehyde and 55.4 parts by weight of cr-methyl styrene are dissolved in 500 parts by volume of glacial acetic acid and concentrated at 5O ⁰ C within 50 minutes with stirring under nitrogen at 5 ° # 5 weight bodies sulfuric acid in 25 parts by volume of Glacial acetic acid added. The resulting suspension is stirred for a further 2 to 5 hours at 40 ° C., after cooling the precipitate is suctioned off and it is introduced in portions under nitrogen into a mixture of 500 parts by volume of 20 percent sodium hydroxide solution and 500 parts by volume of benzene. The benzene phase is separated off, dried and concentrated, whereupon the residue is crystallized from 15Ο parts by volume of ethanol.

Yield: 39 parts by weight (45 % of theory), Pp: 144 ^° C

C ₃₁ H ₂₁ N (287.59) Calc .: C 87.76 % H 7.57 % N 4.87 %

Found: C 87.12 % II 7.58 % N 5.22 %

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. 177017?

Example 8

2,4-Dimethyl-4-phenyl-e-methoxy-l «2,3,4-tetrahydroquinoline

123 parts by weight of p-anisidine, 44 parts by weight of paraldehyde and 118 parts by weight of O ^ -methylstyrene are dissolved in 200 parts by volume of ice acetic acid. At 30 ⁰ C are added dropwise under stirring and nitrogen within 45 minutes, 100 parts by weight of sulfuric acid in 25 parts by volume centered Leon of glacial acetic acid and allowed to react for about two hours at 4O ⁰ C. The solution is added dropwise to a mixture of 1,500 parts by volume of 20 percent strength sodium hydroxide solution and 500 parts by volume of benzene, the benzene phase is separated off and dried. .

Kp; 170 to 175 ° C at 0.01 torr

n ² , ⁰ : 1.602

Yield: 135 parts by weight (50 % of theory) C ₁₈ H ₂₁ NO. (267.56) Ber.JC 80.86 # H 7.925 * N 5,? 4 # Gef.i C 8Oi92Si H 8.00 * N 5.60 * Example 9

2.4.5.8-Tetramethyl-4-phenyl-1.2,3 «4-» tetrahydroquinoline

■. i

To a solution of 60.6 parts by weight of 2,5-dimethylaniline in 300 parts by volume of acetic acid at 20 ⁰ C 50 parts by weight of concentrated sulfuric acid and then beil 3O ⁰ C within one hour with stirring and under nitrogen atmosphere a mixture of 59 Oewichtsteilen Of-methylstyrene and 22 weight bodies Paraldehyde dripped. The solution, from which part of the salt formed gradually crystallizes out, is allowed to react for a further 2 hours at 40 ° C., most of the acetic acid is distilled off in vacuo and the residue is added to a mixture of 200 parts by weight of NaOH in 1,500 parts by volume of water and 400 parts by volume of benzene. The benzene phase is dried and distilled.

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Kpt U3 ° C at 0.05 Torr

η * ⁰ «1.6005 1770170

Yields 65 parts by weight (49 % of theory) C ₁₉ H ₂₃ N (265.3β) ΒβΓ.ί C 85.98 % H 8.7 * % N 5 * 28 *

Oef.t C 85.77 * H 8.70 % N 5.68 *

Belepiel 10 2 ~ isopropyl- "4-methyl" 4 "" phenyl-1.2.3.4-tetrahydrocholine

He converts sulfuric acid in 300 parts by volume into a suspension of 46.6 parts by weight of aniline and 50 parts by weight of consent Acetic acid is added dropwise to an amount of 59 parts by weight of 06-methylstyrene and 36 parts by weight of Iaobutyraldehyde and the resulting solution worked up as in Example 9.

Kpt 134 to 135 C at 0.005 Torr

n £ ° «. 1.59> 5

Yields 79 parts (60 % of theory) C ₁₉ H ₂₃ N (265.38) calcd. T O 85.98 Jl H 8.74 ί H 5.28

Oef.i O 85.90 Jf H 8.81 % M 5.32

Example 11

2-n-Propyl-4-methyl-4-phenyl-1.2.3.4-tetrahydroquinoline

To a suspension of 46.6 parts by weight of aniline and 50 parts by weight of concentrated sulfuric acid in 300 parts by volume of acetic acid becomes a mixture of -59 parts by weight of or-methylstyrene and 37 Parts by weight of n-butyraldehyde were added dropwise and the resulting solution as worked up in example 9,

Kpt 150 to 153 ° C at 0.01 Torr

ng ⁰ ! 1,587

Yield: 40.5 parts by weight (30 % of theory)

C ₁₉ H ₂₃ N (265.38) Calc .: C 85.98 % H- 8.74 % N 5.20 %

Oef.t C 85.99 % H 8.86 % N 5.14 %

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Example 12 2-n-pentyl-4-methyl-4-phenyl-1 _J

46.6 parts by weight aniline and 50 parts by weight more concentrated Sulfuric acid in 500 parts by volume of glacial acetic acid is added according to the procedure of Example 9 with 59 parts by weight of cx-methyl styrene and 50 parts by weight of caproaldehyde reacted and worked up.

Bp: 16? up to 171 ⁰ C at 0.01 gate

ng ⁰ : 1.575

Yields 42.5 parts by weight (29 Ji of theory) C ₂₁ H ₂₇ H (295.45) Ber.t C 85.95 * H 9.27 % N 4.77 %

Oef. " C 85 # * 5 % H 9 / ^ 5 % N 4.91 %

Example I3 2.4-Diphenyl-4-methyl-1 ^ 2.3.4-tetrahydroquinoln

46.6 parts by weight of aniline are dissolved in 500 parts by volume of glacial acetic acid. First, is added dropwise at 20 ⁰ C 50 weight point of concentrated sulfuric acid, then at 25 ⁰ C within one hour with stirring and under nitrogen atmosphere a mixture of 59 parts by weight of Or-MethyIstyrol and 55 parts by weight of benzaldehyde to and stirred for 2 hours at 40 ° C to react for · Den after The residue remaining by concentration in vacuo is added to a mixture of 150 parts by weight of NaOH in 1,500 parts by volume of water and 400 parts by volume of benzene. After the benzene phase has been separated off and dried, benzene and low-boiling by-products are distilled off in vacuo. The residue is recrystallized from ethanol.

Exploits 99 parts by weight (6 ^ of theory) Mp: 104-105 ⁰ C (analytically pure product:

. Pp. 112 ° C)

C ₂₂ H ₂₁ N (399.40) Calc .: C 88.25 % H 7.07 % N 4.68 %

Found: C 87.99 % H 7.15 % N 4.76 %

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Example 14 1770170

2 » 4-D1methyl-4-vinyl-1. 2, 3.4-tetrahydrocholine

According to the procedure of Example 9, 46.6 parts by weight of aniline and 50 parts by weight of concentrated sulfuric acid in parts by volume of glacial acetic acid are reacted with 34 parts by weight of isoprene and 22 parts by weight of paraldehyde and worked up.

Kp: 101-102 ⁰ C at 0.05 Torr ng ^0: 1.566

Yields 27 parts by weight (29 % of theory)

C ₁₅ H ₁₇ N (187.27) Calc .: C 83.37 % H 9.15 % N 7.48 %

Found: C 82.93 # H 9.06 % N 7.83 %

Example I5

2-methyl-4-phenyl-1,2,3,4-tetrahydrocholine

93.2 parts by weight of aniline are dissolved in 600 parts by volume of acetic acid. Under stirring and nitrogen atmosphere is first dropwise 150 parts by weight of concentrated sulfuric acid and then at 3O ⁰ C a mixture of 104 parts by weight of styrene and 44 parts by weight of paraldehyde Within one hour, and allowed to react for about 2 to STUN at 40 ° C. The salt obtained on cooling is filtered off and added to a mixture of 120 parts by weight of NaOH in 1,500 parts by volume of water and 500 parts by volume of benzene. The benzene phase is separated off, dried and distilled, the product being obtained in a very pure form. Another, not quite as pure part can be obtained by working up the filtrate .

Bp: 140 ° C at 0.005 torr

Yield: 163 parts by weight (73 % of theory) of a slowly crystallizing oil with a melting point of 66 to 67 ^° C.

(223.30) Elder: C 86.05 % H 7.67 % H 6.27 %. Found: C 85.99 % H 7.67 % N 6.07 %

0 0 9 "P Γ? 7/2 7 1 Β

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Example 16

2 , 4- Dipheny1-1 , 2 , 3,4-tetrahydrochynoline

46.6 parts by weight of aniline are dissolved in 300 parts of acetic acid. First 75 parts by weight of concentrated sulfuric acid are added dropwise with stirring and then a mixture of 53.1 parts by weight of benzaldehyde and 52.1 parts by weight of styrene ^{at 30 ° C. over the course of one hour.} The mixture is left for 2 hours at about 30 ⁰ C after-react and worked up as described in Example 9.

Bp: 190 to 195 ° C at 0.01 torr

Mp: 97 to 98 ° C (unicrystallized from ethanol)

Yield: 76 parts by weight (53% of theory)

C ₃₁ H ₁₉ N (285.37) Der .: C 88.38 % H 6.71 % U 4.91 %

Found: C 88.48 % H 6.67 % N 4.76%

Example 17

2-isopropyl-4-phenyl-l, 2, 3,4-tetrahydroquinoline

46.6 parts by weight of aniline are dissolved in 300 liters of acetic acid. First 75 g / ichtstella le-concentrated is added dropwise with stirring Sulfuric acid and then a mixture of 52 parts by weight of styrene and 37.1 parts by weight at 30 ° C. within one hour Isobutyraidehyde too. After a Nachreakti0na2e.it of 1 Hour is worked up as described in Example 9.

Kpt 16l ° c: at 0.005 Torr

Developed: - i: 70 0 i.vi -.-; htstäi'li-j [S ^% -d \ iv Thi-vc ia)

for r> γ.- · ' τ'; · ■:: ■

ORIGINAL

Claims (1)

- 14 - OZ 2277 5.8.1970 1770Ί70 Patents b a η s pr Uch e 1. Ancestors for the preparation of substituted 1,2,3,4-tetrahydro chinoLine, characterized in that a primary aromatic amine of the general formula I. in which R, R , R and R are hydrogen, alkyl radicals with 1 to 4 carbon atoms, alkoxy radicals with 1 to 4 carbon atoms, optionally substituted by alley radicals with 1 to 4 carbon atoms 1 2 tuated amino groups, or halogen, or R and R or R and R or R and R can be closed to form a fused aliphatic or aromatic six-membered ring, with a Aldehyde of the general formula II II 5
in which R denotes a saturated straight-chain or branched alkyl radical with 1 to ß carbon atoms or an Aryircst optionally substituted by alkyl or alkoxy groups with 1 to 4 carbon atoms, and an olefin of the general formula III BATH - 15 - OZ 2277 5.β.1970 r ⁸ - cn = C III • R ⁷ in which R and R stand for hydrogen or an alkyl radical with 1 to 10 carbon atoms and R denotes the phenyl radical, the vinyl radical, or an alkyl radical with 1 to 2 carbon atoms, but then R must not be an alkyl radical when R is hydrogen, in the presence of a strong acid at temperatures between 0 and 70 ⁰ C, optionally in the presence of solvents, and the 1,2,3,4-tetrahydroquinolinium salt formed is converted into the free base in a manner known per se. 2. The method according to claim 1, characterized in that the reaction is carried out at temperatures between 20 and 40 ° C 3. The method according to claim 1 and 2, characterized in that the reactants are used in equimolar amounts. i 4i method according to claim 1 to 3, characterized in that the olefin used is styrene or <"f-methylstyrene. 5. The method according to claim 1 to 4, characterized in that sulfuric acid is used as / strong acid. 0 Π 9 8 F 2/2? 1 8 - 16 - OZ 2277 5.8.1970 • · 6. 1,2,3, '! - Tetrahydroquinolines of the general formula ZV •1 IV in which R, R ² , R ³ and R ^{4 are} hydrogen, alkyl radicals with 1 to 4 carbon atoms, alkoxy radicals with 1 to 4 carbon atoms, optionally by alkyl radicals with 1 to 4 carbon atoms. 1 mean 2 substituted amino groups, or halogen, or R and R 2 3 3 4 or «R and R or R and R can be closed to form a fused aliphatic or aromatic six-membered ring, R is a saturated straight-chain or branched alkyl radical with 1 to 8 carbon atoms or one, optionally through Alkyl or alkoxyl groups with 1 to 4 carbon atoms substituted 6 8 tuierten, means aryl radical, R and R for hydrogen or a Are alkyl radicals with 1 to 10 carbon atoms and R denotes the phenyl radical, the vinyl radical or an alkyl radical with 1 to 2 carbon ^{atoms, but R may not be an alkyl radical when R 6 is} hydrogen. 7. 1,2,3,4-tetrahydroquinolines according to claim 6, in where R of the general formula IV for the methyl, isopropyl, or Pheny! group. 8. 1,2,3,4-tetrahydroquinolines according to claim 6 and 7, 6 8 in which R and R of the general formula IV are hydrogen or mean the methyl group and R of the general formula IV for stands for the phenyl radical. 009852/2218 -17 - OZ 2277 5.8.1970 9. 1,2,3, ^ tetrahydroquinolines according to claim 6, 7 and 8, 12 3 4 in which R, R, R and R of the general formula ZV are hydrogen 009852/2218