DD268689A1 - METHOD FOR PRODUCING TERTIA TERRACEOLYLVINYLAMINE - Google Patents

Abstract

The invention relates to the field of organic synthesis chemistry and has a method to target, can be recovered with the tertiary tetrazolylvinylamines of formula III. The invention has for its object to produce the title compounds from non-heterocyclic starting materials with preformed aminovinyl skeleton. According to the invention, the object is achieved by dissolving at least two molar equivalents of an alkali metal azide, eg. As sodium azide, in lower aliphatic alcohols such as methanol, ethanol, n-propanol or isopropanol at 50 to 100C, preferably at the boiling temperature of the reaction mixture, with one molar equivalent of 3-halo-prop-2-en-1-ylidene-dimethyliminiumsalz of formula I. in which R1 is an aryl radical, Hal is a halogen atom, preferably chlorine, and X is any anion, to aryl-substituted dimethylaminovinyl-1H-tetrazoles II and these after isolation with secondary amines of the formula R2R3NH, in which R2 is an alkyl group carrying substituents R3 may denote an identical or non-identical alkyl group or an aryl radical, R2 and R3 also being able to form a common ring system, in boiling alcoholic (eg methanolic or ethanolic) solution in the presence of acid. The title compounds are useful as intermediates for the preparation of novel substituted tetrazole derivatives.

Description

In addition to Ii arise in the implementation of I with Alkalirneidllaziden in subordinate Mengo stelli.ngsisorr.ere 5-aryl-1- (2-dimethylamino-vinyl) -1H-tetrazoles, which remain in the isolation of Γ -Rößtenteils in the mother liquor and lead in the subsequent subsequent reaction only to traces of corresponding isomeric by-products; By purification (eg recrystallization) of the crude II crystals, by-product formation can be eliminated. The erfindungsgernäße method is characterized in that it

- the z. B. from dimethylformamide, phosphorus oxychloride and aryl methyl ketones particularly easy to _; , In general, 3-haloprop-2-en-1-ylidene dimethyliminium salts I (compare J. LIEBSCHER and H.HARTMANN, Synthesis 197S, 241) are used as starting compounds and the desired R ² R ³ N group is only used in the second Reaction step introduces, thereby eliminating the (otherwise required) position of corresponding corresponding formamides R ² R ³ NCHO or iminium R ² R ³ ^ N = CH-CH = CR'-Hal X "unnecessary;

- moreover, especially the introduction of R ² R ³ N allows groups in those cases where appropriate starting materials R ² R ^{3 +} N = CH-CH = CR'-Ha! X "are not easily accessible (eg R ² = R ³ = HOCH ₂ CH ₂ ) or do not react as desired with alkali metal azide (eg R ² = alkyl, R ³ = A.7 ¹ );

When using bifunctional secondary amines in the second reaction step leads to systems with two bridged tertiary tetrazolylvinyiaminogruppen;

Consistently provides (E) -configured tetrazolylvinylamines.

The invention will be explained below with reference to 7 embodiments; the yields of III given herein are based on the 3-halo-prop-2-en-1-ylidene-dimethimidinium salts I.

embodiments

example 1

(E) -5- (2-diethylamino-vinyl) -1- (4-methyl-phenyl) -1H-tetrazole (III, R '= 4-Me-C ₆ H _4, R ² = R ³ = Et) in a suspension of 1.50 g f23mmol) Natrii ^ir nazi1 in 25ml of methanol under refluxing and transmits intense magnetic stirring 3,08g dOmmol) 3-chloro-3 · 'T-methyl-phenyD-prop ^ -en-i-ylidene Dimethylirrinium perchlorate (I, R ¹ = 4-Me-C ₆ M ₄ , Hai = Cl, X = CIO ₁ ) by a long Liebig condenser partially in such a way that the associated with the implementation of N ₂ -development is limited and does not cause foaming. The mixture is subsequently rinsed with 5 ml of methanol and the main amount of methanol (about 25 ml) is distilled off with continued stirring. The crystal mass forming it when grinding the cooled concentrated reaction solution is sucked off, washed first with ice-cold 70% aqueous methanol to remove adhering dark mother liquor, then with water several times to remove inorganic salt (sodium perchlorate) and dried. The solution of the intermediate II thus obtained (R ¹ = 4-Me-C ₆ H ₄ ) in 15 ml of ethanol is heated after addition of 5.49 g (75 mmol) of diethylamine and 4.50 g (75 mmol) of acetic acid for 1 hour under magnetic stirring at reflux , Then distilled 12 ml of ethanol and brings ü ^b -p cooled residue by adding portions of water and trituration to crystallize; further addition of water completes the deposition. After filtration with suction, washing with water and drying, 1.70 g (66%) of crude product result; Recrystallization from diethyl ether gives colorless crystals of melting point 102-103 ⁰ C.

Analogously, from sodium azide, correspondingly substituted S-chloro-prop-1-ylidene-dimethyliminium perchlorates (I, Hai = Cl, X = CIO ₄ ) and secondary amines R ² R ³ NH are obtained:

(fci-5- (2-diethylamino-vinyl) -1- (4-methc. <y-phenyl) -1H-tetrazole (III, R ¹ = 4-MeO-C ₆ H _4, R ² = R ³ = Et) / 67% pure colorless crystals (from diethyl ether), mp 125-126 ° C.

(E) -5- (2-diethylamino-vinyl) -1- (4-iodo-phenyl) -1H-tetrazole (III, R ¹ = 4-1-C ₆ H _4, R ² = R ³ = Et) Yield 59%. Colorless needles (from methanol). Melting point 127-128 ⁰ C.

(E) -1- (4-biphenylyl) -5- (2-diethylamino-vinyl) -1H-tetrazole (III, R ¹ = 4-Ph-C ₆ H ₄ , R ² = R ³ = Et) Yield 71 %. Pale yellow crystals (from methanol), mp 157-158 ° C.

(E) -1- (4-chloro-phenyl) -5- [2-bis (2-hydroxy-ethyl) amino-vinyl] -1H-tetrazole (III, R ¹ = 4-CI-C ₆ H _4, R ² = R ³ = HIGH ₂ CH ₂ ) Yield 43% Colorless crystals (from tetrahydrofuran / diethyl ether), mp 105-106.5X.

(E) -1- (4-Bromophenyl) -5- [2-bis (2-hydroxy-ethyl) amino-vinyl] -1H-tetrazole (III, R '= 4-Br-C ₆ H ₄ , R ² = R ³ = HIGH ₂ CH ₂ ) Yield 56%. Colorless crystals (from tetrahydrofuran / diethyl ether), m.p. 122-123 ° C.

(E) -5- [2-bis (2-r ydroxy-ethyl) amino-vinyl] -1- (4-iodo-phenyl) -1H-tetrazole (III, R ¹ = 4-1-C ₆ H ₄ , R ² = R ² = HIGH ₂ CH ₂ ) Yield 55%. Colorless crystals (from tetrahydrofuran / diethyl ether), mp 134-135 ° C.

(E) 1-Phenyl-5- (2-piperidino-vinyl) -1H-tetrazole [IM, R '= Ph, R ² / R ³ = (CH ₂ I ₅ I

Yield 58%. Colorless crystals (from diethyl ether). Melting point 86.5-87.5 ° C.

(E) -1- (4-methoxy-phenyl) -5- (2-piperidino-vinyl) -1H-tetrazole [III, R ¹ = 4-MeO-C ₆ H _4, R ² / R ³ = (CH ₂ I ₅ ] Yield 67% Colorless crystals (from diethyl ether), mp 125-126 ° C.

(E) -1- (4-fluoro-phenyl-5- (2-piperidino-vinyl) -1H-tetrazole [III, R ¹ = 4-FC ₆ H _4, R ² / R ³ = (CH _{2) 5} ) Yield 55%. Colorless crystals (from methanol), m.p. 140-141 ⁰ C.

(E) -1- (4-bromo-phenyl) -5- (2-piperidino-vinyl) -1H-tetrazole [III, R ¹ = 4-Br-C ₆ H _4, R ² / R ³ = (CH ₂ I ₆ I Yield 59% Colorless crystals (from methanol) Melting point 154-155 ° C.

(E) -5- (2-morpholino-vinyl) -1-phenyl-1 H -totrazole [III, R ¹ = Ph, R ² / R ³ = (CH ₂ ) ₂ O (CH ₂ ) ₂ ] Yield 61%. Colorless crystals (from methanol), m.p. 138-139 ⁰ C.

(E) -1- (4-methoxy-phenyl) -5- (k morpholino-vinyl) -1H-tetrazole [III, R ¹ = 4-MeO-C ₆ H _4, R ² / R ³ = (CH ₂ ) ₂ O (CH ₂ ) ₂ ] Yield 73%. Colorless needles (from methanol), m.p. 170-171 ⁰ C.

(E) -1- (4-Bromo-phenyl) -5 (2-morpholino-v nyl) -1H-tetrazole [III, R ¹ = 4-Br-C ₆ H _4, R ² / R ³ = (CHj ) O (CH ₂ J _2] 59% yield. Colorless flake (from n-propanol ", melting point 213-214 ⁰ C.

-3- 2C8 689

(E) -5- (2-Hexamethyleneimino-vinyl) -1- (4-methoxyphenyl) -1K .otrazo! [Ill, R '= 4-MeO-C ₆ H ₄ , B ² ZR ³ = (CH ₂ IeI Yield 68%, colorless needles (from methanol / diethyl ether), mp 107-108 ⁰ C. (E) -1- (4-chloro-phenyl) -5- (2-hexamethyleneimino-vinyl) -1H-tetrazole [IM, R ¹ = 4-CI-C ₆ H ₄ , R ² / R ³ = (Ch ₂ I ₆ ] Yield 57 %. Colorless crystals (from methanol), mp 159-16O ⁰ C.

Example 2

(E) -1- (4-BiDhenylyl) -5- [2-bis (2-hydroxy-ethyl) amino-vinyl] -iH-tetrazole INI, R '= 4-Ph-C ₆ H ₄ , R ² = R ³ = HIGH ₂ CHj) 1.50 g (23 mmol) of sodium azide and 3.70 g (10 mmol) of S - ^ -biphenylyl-S-chloro-prop-1-ylidene-dimethyliminium perchlorate (I, R '= 4 -Ph-C ₆ H ₄ , Hai = Cl, X = CIO ₄ ) are reacted using n-propanol as reaction medium analogously to Example 1 and worked up to give intermediate II (R ¹ = 4-Ph-C ₆ H ₄ ). Its subsequent lation with 7.89 g (75 mmol) of diethanolamine and 4.50 g (75 mmol) of acetic acid in 15 ml of ethanol according to Example 1 gives 2.39 g (68%) of reaction product. After recrystallization from tetrahydrofuran / methanol / diethylet colorless crystals of melting point 165-166 ⁰ C.

Example 3

(E) -5- [2-bis (2-chloro-ethyl) -amino-viryl] -1-phenyl-1H-tetrazole (III, R '= Ph, R ² = R ³ = CICH ₂ CHj ) Analogously to Example 1 from 1.50 g (23 mmol) of sodium azide and 2.94 g (10 mmol) of S-chloro-S-phenyl-prop-1-ylidenedimethyliminiutn perchlorate (I, R '= Ph, Hai = Cl, X = CIO ₄₎ obtained intermediate Il R ¹ = Ph) w '.' d -amine hydrochloride heated together with 8,92g (50mmo!) bis (2-chloro-ethyl) in 15 ml of ethanol for 1 hour under magnetic stirring jerk fluent ,

After distilling off 10 ml of ethanol and trituration of the residue with water crystallize 1.17 g (75%) of the reaction product.

Recrystallization from tetrahydrofuran / diethyl ether affords colorless crystals of Si I. Iielzpunkt 77.5-78.5 "J.

Analogously, from appropriately substituted 3-chloro-prop-2-en-i-ylidene dimethyliminium perchlorates (I, Hai = Cl, X = CIO ₄ ) are obtained:

(E) -5-I2-bis (2-chloro-ethyl) amino-vinyll-1- (4-methyl-phenyl) -1H-tetrazole (III, R '= 4-Me-C ₆ H _4, R ² = R ³ = CICH ₂ CH ₂ ) Yield 61%. Colorless crystals (from methanol), m.p. 110-111 ⁰ C.

(E) -5- [2-bis (2-chloro-ethyl) amino-vinyl] -1- (4-chloro-phenyl) -1H-tetrazole (III, R '= 4-CI-C ₆ H _4, R ² = R ³ = CICH ₂ CH ₂ ) Yield 45%. Colorless needles (from methanol), mp 139-14O ⁰ C.

Example 4

(E) -N-Methyl-N- [2- (1-phenyl-1H-tetrazol-5-yl) -vinyl) -aniline (III, R ¹ = R ³ = Ph, R ² = Me) A solution of analogously to example 1 from 1.50g (23mmol) of sodium azide and 2,94g (lOmmol) S-chloro-S-phenyl-prop ^ -en-i-ylidendimethyliminium-perchloratd, R '= Ph, Hal = Cl, X = CIO ₄ ) obtained intermediate II (R ¹ = Ph) and 1.61 g (15 mmol) of N-methyl-aniline in 7.5 ml of methanol is treated with 4.5 ml of 50% acetic acid and refluxed with magnetic stirring for 15 minutes. Upon digestion of the cooled mixture with water, 1.16 g (60%) of the reaction product precipitate.

Recrystallization from methanol gives colorless needles of melting point 101-102 ⁰ C.

Analogously, from sodium azide, correspondingly substituted S-chloro-prop-1-ylidene-dimethyliminium perchlorates (I, Hai = Cl, X = CIO ₄ ) and secondary amines R ² R ³ NH are obtained:

(E) -N-Methyl-N- {2- [1- (4-methylphenyl) -1H-tetrazol-5-yl] -vinyl} -aniline (III, R ¹ = 4-Me-C ₆ H ₄ , R ² = Me, R ³ = Ph) Yield 69%. Colorless leaflets (from methanol), mp 147-148 ⁰ C.

(E) -N- {2-1- (4-Lthylphenyl) -1H-tetrazol-5-yl] -vinyl} -N-methyl-aniline (III, R ¹ = 4-Et-C ₆ H ₄ , R ² = Me, R ³ = Ph) Yield 38%. Colorless crystals (from methanol), m.p. 107-108 ⁰ C.

iE) -N- {2- [1- (4-methoxy-fienyl) -1H-tetrazol-5-yl] -vinyl} -N-methyl-aniline (III, R ¹ = 4-MeO-C ₆ H ₄ , R ² = Me, R ³ = Ph) built up 69%. Colorless flake (from tetrahydrofuran), melting point 160-161 ⁰ C.

(5) -N- {2- [1- (4-fluoro-phenyl) -1H-tetrazol-5-yl] -vinyl} -N-methyl-aniline (III, R '= 4-FC ₆ H ₄ , R ² = Me, R ³ = Ph) Yield 55%. Colorless crystals (from methanol), m.p. 140-141 "C.

(E) -N- {2- [1- (4-chloro-phenyl) -1H-tetrazol-5-yl] -vinyl} -N-N-ethyl-aniline) (III, R '= 4-CI-C ₆ H ₄ , R ² = Me, R ³ = Ph) Yield 53%. Colorless needles (made of ethanol), original point 197-198 ⁰ C.

(E) -N- {2- [1- (4-iodo-ph6nyl) -1Htetrazol-5-yl) -vinyl} -N-methyl-aniline (III, R '= 4-1-C ₆ H _4, R ² = Me, R ³ = Ph) Yield 59%. Colorless crystals (from dioxane), mp 190-191 ⁰ C.

(E) -N-Benzyl-N- [2- (1-phenyl-1H-tetrazol-5-yl) -vinyl] -aniline (III, R ¹ = R ³ = Ph, R ² = PhCH ₂ ). Yield 50 %. Colorless crystals (from methanol), mp 112-113 ° C.

(E) -N-Benzyl-N- {2- | 1- (4-rom L-phenyl) -1H-tetrazol-5-yl] -vinyl} '= aniline (III, R 4-Br-C ₆ H ₄ , R ² = PhCH ₂ , R ³ = Ph) Yield 38%. Colorless crystals (from methanol), mp 146-147 ° C.

Examples

(E) -N-ethyl-N- {2- [1- (4-chloro-phenyl) -1H-tetrazol-5-yl] -vinyl) aniline (III, R '= 4-CI-C ₆ H _4, R ² = Et, R ³ = Ph) 1.50 g (23 mmol) of sodium azide and 3.28 g (10 mmol) of 3-chloro-3- (4-chloro-phenyl-prop-2-en-1-ylidene-dimethyl-perinium perchlorate (I, R '= 4-CI-C ₆ H ₄ , Hai = Cl, X = CIO ₄ ) are reacted using ethanol as the reaction medium analogously to Example 1 and.! Intermediate II (R' - 4-CI-C . ₆ H ₄₎ worked its subsequent reaction with 1.82 g (15 mmol) of N-ethylaniline in example 4 yields 1.60 g (49%) of light gray reaction product, after recrystallization from methanol resulting colorless needles of melting point '.22-123 ⁰ C.

Example 8

(E) -N- {2- [1- (4-bromo-phenyl) -1H-tetrazol-5-yl] -vinyl -) - N-methyl-aniline (III, R ¹ = 4-Br-C ₆ H ₄ , R ² = Me, R ³ = Ph) 1.50 g (623 mmol) of sodium azide and 3.73 g (10 mmol) of 3- (4-bromo-phenyl) -3-chloro-prop-2-en-1-ylidene Dimethyliminium perchlorate (I, R ¹ = 4-Br-C ₆ H ₄ , Hai = Cl, X = CIO ₄ ) are reacted using isopropanol as reaction medium analogously to Example 1 and the intermediate product Il (R ¹ = 4-Br -C ₆ H ₄ ) worked up. Its subsequent reaction with 1.61 g (10 mmol) of N-methylaniline according to Example 4 gives 1.71 g (48%) of reaction product; after recrystallization from dioxane result in colorless crystals of melting point 204-205 ⁰ C.

Example 7

(E), (E) -N, N'-bis {2-I1- (4-chloro-phenyl) -1H-tetrazol-5-yl] -vinyl} -N, N'-dimethyl-ethylenediamine (III, R ¹ = 4-CI-C ₆ H ₄ , R ² = Me, R ³ 4-CkC ₆ H ₄ -N ₄ C-CH = CH-NMe-CH ₂ CH ₂ )

A hot solution of the analogous example 1 from 1.5Og (23 mmol) of sodium azide and 3.28 g (10 mmol) of 3-chloro-3- (4-chloro-uhenyl) -prop-2-en-1-ylidene-dimethyliminium- perchlorate (I, R ¹ = 4-CI-CeH ₄ , Hai = Cl, X = CIO ₄ ) obtained intermediate Il (R ¹ = 4-CI-C ₆ H ₄ ) and 0.26 g (2.9 mmol) Ν, Ν'-Dimethyl-ethylenediamine is combined with 3.5 ml of 50% acetic acid and refluxed for 15 minutes with magnetic stirring. This gives 1.14 g (46%) of crystalline reaction product; Recrystallization from dimethyl sulfoxide gives colorless crystals of melting point 242-244 ° C.

-s

formula page

CH ₃

CH ₃

Hal

MN ₃ / Δ

CH ₃

-MHaI

MX (M = alkali metal, e.g., Na)

- N ₂

R ² R ³ NH / H '

- HN (CH ₃ J ₂

Claims (2)

1. A process for the preparation of tertiary tetrazolylvinylamines of the general formula III in which R ^{1 is} an aryl radical, R ^{2 is} an alkyl group which can carry substituents, and R ^{3 is} an identical or non-identical R ² alkyl group or an aryl radical, where R ² and R ^{3 can} also form a common ring system, characterized in that a suspension of at least two molar equivalents einas Alkalirnetallazides, z. As sodium azide, in lower aliphatic alcohols such as methanol, ethanol, n-propanol or isopropanol at 50 to 100 ⁰ C, preferably boi boiling temperature of the reaction mixture, with stirring, partly with one molar equivalent of 3-halo-prop-2-en-1-ylidene dimethyliminium salt of the formula I in which R ^{1 is} an aryl radical, Hal is a halogen atom, preferably chlorine, and X is an arbitrary anion, and the aryl-substituted dimethylaminovinyl-1H-tetrazoles II formed after isolation with secondary amines of the formula R ² R ³ NH, in which R ² and R ^{3 have} the abovementioned meaning, in boiling alcoholic (eg methanolic or ethanolic) solution in the presence of acid brings to reaction. 2. The method according Pkt.!, Characterized in that when using bifunctional secondary amines R ² R ³ NH, in which R ² or R ^{3 contains} a second secondary amino function, can produce systems with two bridged tertiary tetrazolylvinylamino groups. For this 1 page formulas Field of application of the invention The invention relates to a process for preparing tertiary Tetrazolylvinylamine of the general formula III, in which R ¹ is an aryl group, R ^2, may bear the substituents an alkyl group and R ³ is a with R ^2, identical or non-identical alkyl group or an aryl group, wherein R ² and R ^{3 can} also form a common ring system. Compounds of this type represent enaminophenyl substituted tetrazolyl acetaldehydes, which are suitable as intermediates for synthesizing novel substituted tetrazole derivatives because of their potential for modification. Substituted tetrazoles are of particular interest as biologically active compounds (eg, pharmaceuticals, pesticides, growth regulators). Characteristic of the known state of the art Tertiary tetrazolylvinylamines of general formula III are hitherto unknown. The underlying tetrazolylacetaldehydes, which could possibly serve as starting materials for the preparation of III, have not been described in the literature so far! (See FR BENSON, Chem. Rev. 41 (1947) 1; FR BENSON in "Heterocyclic Compounds" (Ed. RC Elderfield), Vol.8, p.1, Wiley, New York, 1967; RNBUTLER, Adv. Heterocycl Chem 21 (1977) 324; RN BUTLER in "Comprehensive Heterocyclic Chemistry" ed. AR Katritzky and CW.Rees), Vol.5, Part 4a, Chapter 13, Pergamon Press, Oxford, 1984). Structurally related are tetrazole derivatives having a functionalized C ₂ -side chain such as substituted tetrazolylethylamines (EKHARVILL, RMHER3ST and EGSCHREINER, J. Org. Chem. 17 (1952) 1597) or tetrazolylacetic acid derivatives [CR JACOBSON and ED AMSTU TZ, J. Org. Chem. 1953] 1183), but it is not known whether compounds of this type can be converted into tertiary tetrazolylvinylamines. Object of the invention The invention has for its object a method by which tertiary Tetrazolylvinylamine of formula III can be prepared in a simple manner from readily available starting materials. Explanation of the essence of the invention The invention is based on the object, tertiary tetrazolylvinylamines of the formula III, in which R 'is an aryl radical, R ^{2 is} an alkyl group which can carry substituents, and R ^{3 is} an identical or non-identical R ² alkyl group or an aryl radical, where R ² and R ^{3 can} also form a common ring system to produce non-heterocyclic starting materials with preformed Aminovinyl-Skeiett. According to the invention, the object is achieved by reacting a suspension of at least two molar equivalents of an alkali metal azide, z. For example, sodium azide, in lower aliphatic alcohols such as methanol, ethanol, n-propanol or isopropanol at 50 to 100 ⁰ C, preferably at the boiling point of the reaction mixture, with stirring, partially with one molar equivalent of 3-halo-prop-2-en-1-ylidene dimethyliminium salt of the formula I in which R 'is an aryl radical, Hal is a halogen atom, preferably chlorine, and X is an arbitrary anion, and the aryl-substituted dimethylaminovinylmH-tetrazoles II formed here are isolated after their isolation with secondary amines of the formula R ² N ³ NH in which R ² and R ^{3 have} the abovementioned meaning, is reacted in boiling alcoholic (for example methanolic or ethanolic) solution in the presence of acid.