WO1996003379A1

WO1996003379A1 - The alkoxylation of heterocyclic compounds in the presence of fluorine

Info

Publication number: WO1996003379A1
Application number: PCT/GB1995/001742
Authority: WO
Inventors: Richard Dickinson Chambers; Christopher John Skinner; Graham Sandford
Original assignee: BNFL Fluorochemicals Ltd
Current assignee: F2 Chemicals Ltd
Priority date: 1994-07-26
Filing date: 1995-07-24
Publication date: 1996-02-08
Anticipated expiration: 1997-01-26
Also published as: ZA956176B; GB9414973D0

Abstract

A method for introducing a functionalising group as a ring substituent into a nitrogen-containing heterocyclic aromatic compound which method comprises reacting a compound containing the functionalising group with the heterocyclic aromatic compound in the presence of elemental fluorine. The functionalising group may be a group -ROH or a group -Sra or a group -NRbRc wherein R, Ra, Rb and Rc are each independently selected from the following groups which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.

Description

The alkoxylatlon of heterocyclic compounds 1n the presence of fluorine

The present invention relates to the preparation of organic compounds in particular heterocyclic aromatic compounds.

There is currently great interest in substituted heterocyclic compounds such as 2-substituted pyridines as ligands for metals, as building blocks in organic synthesis and for the preparation of biologically active agents. However, few methods exist for the direct introduction of a substituent at the 2-and/or 6- positions of pyridine. The most widely used synthetic approach involves nucleophilic attack by strong nucleophiles such as alkoxides, hydrazines, thiolates and stabilised carbanions on a 2-halopyridine.

One of the few examples of nucleophilic displacement of hydride at the 2-and/or 6- position is the well known Chichibabin reaction. Amination is carried out by heating pyridine with powdered sodamide in an inert solvent such as N, N- dimethylaniline at temperatures up to 140°C. An oxygen equivalent of this reaction is known in which 2- pyridone is prepared but only in poor yield by passing pyridine vapour over molten potassium hydroxide at 300°C. This process can only be used for the hydroxylation of pyridines and functionalisation of pyridines using alcohols in a similar way has not been reported. Furthermore, the severe reaction conditions required limits these methods to only insensitive substrates. However, analogous reactions concerning quinoline and isoquinoline are preparatively useful. Recently, it was demonstrated that acetyl hypofluorite reacts with pyridine in dichloromethane at low temperature to produce a mixture of 2-acetoxypyridine and 2-chloropyridine. The highly reactive and unstable acetyl hypofluorite must be prepared at low temperature prior to the addition of the pyridine. Storage of such an unstable, highly oxidising species for long periods at low temperature on a large scale is not always convenient and/or safe. More importantly, the acetyl hypofluorite method only provides a route for the acetylation of pyridines whereas the present invention offers a general route for a large number of functionalities to be introduced into a heterocyclic ring system. N-fluoropyridinium salts react with nucleophiles to give 2-substituted derivatives. However, these salts must first be prepared from pyridine and fluorine at low temperatures, isolated and purified prior to functionalisation.

According to the present invention there is provided a method for introducing a functionalising group as a ring substituent into a nitrogen-containing heterocyclic aromatic compound which method comprises reacting a compound containing the functionalising group with the aromatic compound in the presence of elemental fluorine.

The method according to the present invention provides a novel, convenient and general method for introducing one or more functionalising groups directly into an aromatic heterocyclic ring compound with good overall yield at room temperature in a single step reaction. It permits the use of common organic solvents. The present invention allows the simple synthesis of compounds which generally require multistep processes for their production.

The functionalising group may comprise a group -OR where R is selected from -one of the following which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl. In this case the compound containing the group OR is an alcohol of the form ROH.

The functionalising group may alternatively comprise a group SR_a where R_a is selected from the same groups as for R, or the functionalising group may comprise a nitrogen containing group such as NRj-₎R_c, where R_j-, and R_c are each independently selected from hydrogen or the same group as for R. The heterocyclic compound is preferably a one- or two- ring heterocyclic compound such as pyridine or a related heterocycle such as pyrimidine or pyridazine or triazine or quinoline or isoquinoline or bipyridine which may optionally be substituted by from one to five substituents (which may themselves include optional substituents) independently selected from alkyl, alkoxy, halogen, -CN, -OH, -N0₂, -NH₂, -NHalkyl, -N(alkyl) ₂ -NHCOalkyl, -COOalkyl, -COOH, -COalkyl, -CONH₂, -CONH(alkyl) , -CON(alkyl) ₂, -COY, CY¹ ₃ and S0₂Y² wherein

Y is -H, -F, Cl, -Br, alkyl, -OH or -Oalkyl

Y¹ is -F or -Cl

Y² is -F, -Cl, -Br, -NH₂, -NHalkyl, or -N(alkyl)₂.

In each of these substituents alkyl is preferably C^.4 alkyl, alkoxy is preferably C- -₄ alkoxy and halogen is preferably -F or -Cl. When the heterocyclic aromatic compound is pyridine it is preferably unsubstituted or monosubstituted or disubstituted. When pyridine is monosubstituted it is preferably substituted in the 4- position. When pyridine is disubstituted it is preferably substituted in the 2- and 4- positions. Preferred substituents for the heterocyclic compound are selected from -OH, -CN, -N0₂, -NHCOCH3, -OCH₃, -COOCH3, -COOH, -COCH3 , -CH₃ , -F,-C1, -Br, and -CONH₂ and combinations thereof.

Where the functionalising group is introduced by use of an alcohol, the alcohol may be a primary alcohol or a secondary alcohol or a substituted secondary alcohol or a tertiary alcohol or a substituted tertiary alcohol or a cyclic alcohol or a substituted cyclic alcohol or a benzyl alcohol or a substituted benzyl alcohol or a polyol such as a diol or a substituted polyol or a phenol are a substituted phenol or an allyl alcohol or substituted allyl alcohol.

The ratio of the reagent containing the functionalising group, eg the alcohol, to the heterocyclic compound may be varied within wide limits although it is preferred that the molar ratio is in the range 0.5 to 8.0:1, especially 2.0 to 5.0:1, especially 2.0 to 5.0:1 (alcohol: heterocyclic compound).

The method according to the present invention may be carried out by passing fluorine gas into a liquid which contains the heterocyclic compound. The reaction may be carried out in a vessel in which the liquid is present or alternatively a flow stream of the liquid may be contacted with a gaseous flow of fluorine in a countercurrent fashion. The said liquid may comprise a solvent for the heterocyclic compound and/or a solvent for the fluorine. If two or more solvents are employed these may or may not be miscible with one another.

The reaction medium may for example contain inert solvents such as acetonitrile, fluorinated alkanes and especially perfluorinated solvents such as perfluorocyclohexane and perfluorodecane.

The method according to the invention may be carried out at a temperature in the range from -78°C to 80°C, preferably at a temperature from -30°C to 30°C and especially at a temperature from -10°C to 10°C.

The fluorine gas employed in the method according to the invention is preferably diluted before use by mixing with an inert gas such as nitrogen or helium. The concentration of fluorine is preferably from 1% to 50% by volume, more preferably from 2% to 25% and especially from 5% to 15%.

The ratio of fluorine to heterocyclic aromatic compound in the method according to the invention may be varied within wide limits although it is preferred that the molar ratio of fluorine to heterocyclic aromatic compound is from 0.5:1 to 6:1, and especially from 1:1 to 4:1. Use of higher ratios of fluorine to heterocyclic compounds ensures that multiple functionalising groups are introduced into the heterocyclic compound. When functionalising is substantially complete the functionalised products may be isolated by purging the reaction mixture with nitrogen to remove any residual fluorine gas followed by dilution with excess water and neutralisation followed by extraction into a suitable solvent, followed by distillation. The substituted heterocyclic products may be separated by fractional distillation, chromatography or by crystallisation from a suitable solvent.

The method according -to the present invention offers a convenient route to substituted heterocyclic compounds which are difficult to prepare or may only be prepared in poor yield by the process which have been used in the prior art.

Examples of reactions embodying the invention are as follows:

where R^ to R5 are single or multiple ring substituents existing prior to fluorination and are independently selected from the ring substituents specified hereinbefore.

Examples of methods embodying the present invention to prepare various substituted heterocyclic compounds will now be described. 1. Methoxylation of Pyridine

A solution containing pyridine (I0.9g, I38.0mmol) and methanol (15.8g, 494 mmol) in Arklone (CF C1CC1₂F) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residual fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloro ethane over a period of 8hrs and then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 67% and the oil contained 2-methoxypyridine, 2-fluoropyridine and starting material. Distillation under vacuum afforded pure 2-methoxypyridine (4.1g, 57%) b.p. 140-142°C; δ_H (200 MHz; CDC1₃; TMS) 3.91 (s, OCH₃) , 6.7 (dd, ³J_H-_H 9.2, ³J_H-_H ^s- 5H) , 6.8 (m, 3H) , 7.5 (td, ³J_H-_H 6.7, ⁴J_H-_H 2.0, 4H) , 8.2 (d, ³J_H-_H 4.0, 6H) ; δ_c(50.3MHz; CDC1₃; TMS) 53.5 (s, OCH₃) , 111.3 (s, 5C) , 116.9 (s, 3C) , 138.7 (s, 4C) , 147.2 (s, 6C) and 164.5 (s, 2C) .

2. Ethoxylation of Pyridine

A solution containing pyridine (10.9g, 138.0 mmol) and ethanol (20.Og, 434 mmol) in Arklone (CF₂C1CC1₂F) (100 mmol) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.ε. showed a conversion of 61% and the oil contained 2-ethoxypyridine, 2-fluoropyridine and starting material. Distillation under vacuum afforded pure 2-ethoxypyridine (4.0g, 50%); δ_H(200MHz; CDC1₃; TMS) 1.1 (m, CH₃) , 4.2 (m, 0CH₂) , 6.5 (m, 5H) , 6.6 ( , 3H) , 7.3 (m, 4H) , 7.9 (m, 6H) ; δ_c(50.3MHz; CDC1₃; TMS) 14.6 (s, CH₃) , 61.4 (s, CH₂0) , 111.1 (s, 5C) , 116.4 (s, 3C) , 138.4 (s, 4C) , 146.9 (s, 6C) and 164.0 (s, 2C) .

3. Butoxylation of Pyridine

A solution containing pyridine (10.9g, 138.0 mmol) and methanol (15.8g, 494 mmol) in Arklone (CF₂C1CC1₂F) (100ml) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a ^'10% mixture in nitrogen was then passed through the stirred solution at about 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residual fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 86% and the oil contained 2-butoxypyridine, 2-fluoropyridine and starting material. Distillation under vacuum afforded pure 2-butoxypyridine (6.4g, 58%)bp 47°C/lmm; δ_H (200MHz; CDC1₃; TMS) 0.96 (t, ³J_H-H 7.24, CH₃ ⁴), 1.5 (q, ³J_H-_H 8.1, CH₂ ³) , 1.7 (q, ³J_H__H 7.0, CH₂ ²), 4.3 (t, ³J_H__H 6.5, OCH₂) , 6.7 (dd, ³J_H-_H 9-2, ³J_H-_h 8.4, 5H) , 6.8 (m, 3H) , 7.5 (m,^" 4H) , 8.1 (d, ³J_H-H 4.0, 6H) ; δ_c (50.3 MHz; CDC1₃; TMS) 13.9 (s, CH₃ ⁴) , 19.4 (s, CH₂ ³) , 31.3 (s, CH₂ ²) , 65.7 (s, OCH2¹) , 111.1 (s, 5C) , 116.6 (s, 3C) , 138.5 (S, 4C) , 146.9 (s, 6C) and 164.1 (s, 2C) .

4. Trifluoroethoxylation of Pyridine

A solution containing pyridine (10.9g, 138.0 mmol) and 2, 2 , 2-trifluoroethanol (49.5g, 495.0 mmol) , in Arklone (CF₂CICCI₂F) (100 ml) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 10°C. Elemental fluorine (165 inmol) as a 10% mixture in nitrogen was then passed through the stirred solution at ca 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgSO-_j) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 63% and the oil contained 2-(2,2,2-trifluoroethoxy) - pyridine, 2-fluoropyridine and starting material. Distillation under vacuum afforded some pure 2-(2,2,2-trifluoroethoxy) -pyridine; δ_H(200MHz, CDC1₃; TMS) 4.8 (q, ³J_H-H 7.24, CH₃ ⁴) , 1.5 (q, ³J_H-_H 8.1, CH₂ ³) , 1.7 (q, ³J_H-_H 7.0, CH₂ ²), 4.3 (t, ³J_H-F 8.6, OCH₂) 6.8 (d, ³J_H-_H 8.4, 5H) , 6.9 (m, 3H) , 7.6 (td, ³J_H-H 8.7, ⁴J_H-H 1-9, 4H) , 8.1 (dd, ³J_H-H - , ⁴JH-H 1-1, ⁶H) ; δ_c(50.3MHz; CDC1₃; TMS) 62.2 (q, ²J_C__F 35.0, OCH₃)., 111.3 (s, 5C) , 118.4 (s, 3C) , 124.1 (q, ^_C-F 275.0, CF₃) , 139.4 (s, 4C) , 146.8 (s, 6C) and 162.0 (s, 2C) . 5. Heptoxylation of Pyridine

A solution containing pyridine (10.9g, 138.0 mmol) and heptanol (77.9g, 495 mmol) in Arklone (CF₂C1CC1₂F) (100 ml) was placed in a fluorination apparatus with an attached soda line filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 70% and the oil contained 2-heptoxypyridine, 2-fluoropyridine and starting material. Distillation under vacuum afforded pure 2-heptoxypyridine (9.0g, 43%); δ_H(200MHz; CDC1₃; TMS) 0.9 (t, ³J_H-H 5.2, CH₃ ⁷), 1.3 (b, CH₂ ^3"6), 1.8 (m, CH₂ ²), 4.2 (t, ³J_H__H 6.7, 0CH₂) 6.7 (in, ³J_H-_H 8.4, 5H) , 6.8 (m, 3H) , 7.5 (td, ³J_H-_H 8.4, ⁴J_H-H .3, 4H), 8.1 (dd, ³J_H-_H 4.7, J_H__H 1-2 6H) ; δ_c(50.3MHz; CDC1₃; TMS) 14.1 (s, CH₃ ⁷) , 22.7 (s, CH₂ ⁶) , 26.1 (s, CH₂ ⁵) , 29.2 (s, CH₂ ⁴) , 31.9 (s, CH₂ ³) , 32.9 (s, CH₂ ²), 66.1 (s, OCH₂ ¹) , 111.2 (s, 5C) , 116.5 (s, 3C) , 138.5 (s, 4C) , 146.8 (s, 6C) and 164.1 (s, 2C) . 6. Methoxylation of 4-Ethylpyridine

A solution containing 4-ethylpyridine (14.8g, 138.0 mmol) and methanol (15.8g, 495 mmol) in Arklone (CF₂C1CC1 F) (100 ml) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40 ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 58%. The oil contained 4-ethyl-2-methoxypyridine, 2- fluoro-4-ethylpyridine and starting material. Distillation under vacuum afforded pure 4-ethyl-2- methoxypyridine (6.0g, 61%); δ_H (200MHz; CDC1₃; TMS) 1.2 (t, ³J_H-_H 7.6, CH₃), 2.6 (q, ³J_H-H 7.8, CH₂) , 3.9 (s, 0CH₃) , 6.6 (dd, ⁴J_H-H 1- , J_H-_H 0.7, 3H) 6.7 (dd, ³J_H-_H 5.3, J_H__H 1.4, 5H) , 8.0 (d, ³J_H-H ⁵ _'3, 6H) ; δ_c(50.3 Mhz; CDC1₃; TMS) 14.3 (s, CH₃) , 28.1 (s, CH₂) , 53.3 (s, OCH₃) , 109.7 (s, 5C) , 117 . 1 ( Ξ , 3C) , 146 . 6 ( s , 6C) , 155 . 9 ( s , 4C) , 164 . 6 ( s , 2C) .

7. Methoxylation of Ouinoline

A solution containing quinoline (17.3g, 137.5 mmol) and ethanol (21. lg, 660 mmol) in Arklone (CF₂C1CC1₂F) (100 ml) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at ca 40ml/min. After the fluorinate had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then extracted with dichloromethane (3 x 25 ml) then dried (MgS0 ) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed the oil contained 2-methoxyquinoline, 2-fluoroquinoline and some starting material.

8. Phenoxylation of Pyri-dine

A solution containing pyridine (10.9g, 138.0 mmol) and phenol (31.Og, 247 mmol) in Arklone (CF₂C1CC1₂F) (100 ml) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40 ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then extracted with dichloromethane (3 x 25 ml) then dried (MgS0₄) . The dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed the oil contained 2- phenoxypyridine, 2-fluoropyridine, fluorophenol and some starting material.

Claims

1. A method for introducing a functionalising group as a ring substituent into a nitrogen-containing heterocyclic aromatic compound which method comprises reacting a compound containing the functionalising group with the heterocyclic aromatic compound in the presence of elemental fluorine.

2. A method as in Claim 1 and wherein the functionalising group comprises a group -OR where R is selected from the following groups which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl, the compound containing the functionalising group being an alcohol of the form R-OH.

3. A method as in Claim 1 and wherein the functionalising group comprises a group -SR_a wherein R_a is selected from the following groups which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.

4. A method as in Claim 1 and wherein the functionalising group comprises a group as in -NRj-,R_c wherein R^ and R_c are each independently selected from hydrogen and the following groups which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.

5. A method as in any one of the preceding claims and wherein two or more functionalising groups, which may be the same or different groups, are introduced into the heterocyclic aromatic compound.

6. A method as in any one of the preceding claims and wherein the heterocyclic aromatic compound is a one- or two-ring compound.

7. A method as in Claim 6 and wherein the heterocyclic aromatic compound is an optionally substituted pyridine, pyrimidine, pyridazine, triazine, quinoline, isoquinoline or bipyridine.

8. A method is in any one of the preceding claims and wherein the method is carried out by passing fluorine gas into a liquid which contains the heterocyclic aromatic compound.

9. A method as in Claim 8 and wherein the said liquid comprises a solvent for the heterocyclic aromatic compound and/or a solvent for the fluorine.

10. A method as in Claim 8 or Claim 9 and wherein the fluorine gas is diluted before use with an inert gas.