WO1996004229A1

WO1996004229A1 - The preparation of organic compounds

Info

Publication number: WO1996004229A1
Application number: PCT/GB1995/001764
Authority: WO
Inventors: Richard Dickinson Chambers; Graham Sandford
Original assignee: BNFL Fluorochemicals Ltd
Current assignee: F2 Chemicals Ltd
Priority date: 1994-07-29
Filing date: 1995-07-26
Publication date: 1996-02-15
Anticipated expiration: 1997-01-29
Also published as: GB9415312D0; ZA956322B

Abstract

A method for the oxidation of one or more hydroxyl groups in an organic compound to one or more carbonyl groups which comprises reacting the organic compound with elemental fluorine. The said organic compound may be an aliphatic or aromatic alcohol, diol or polyol and is contained in a liquid through which fluorine is passed as a gas.

Description

The preparation of organic compounds

The present invention relates to the preparation of organic compounds. In particular, it relates to the synthesis of compounds containing one or more carbonyl groups by oxidation of alcohols, diols and polyols.

The oxidation of an alcohol to a carbonyl compound is one of central importance in organic synthesis and, accordingly, many reagents have been devised to perform such transformations. The development of oxidising systems that are capable of achieving high alcohol to carbonyl conversions with good selectivity in a variety of substrates continues to interest both industry and academia.

The majority of oxidation methods for preparing carbonyl compounds from alcohols utilise metal compounds as oxidising agents. Oxidants derived from chromium, manganese, ruthenium, silver, aluminium and cerium have all been the subject of intense study. However, the toxicity and, therefore, disposal problems associated with using such materials makes these methods environmentally less acceptable. Non-metallic oxidants in general use include DMSO (dimethyl sulfoxide) with various oxidants, but the formation of significant quantities of by-products in such oxidations again causes disposal problems.

Halogens and related halogen containing compounds have also been studied as potentially useful oxidation systems. Yields of oxidations using these reagents are generally low and both chlorine and bromine may be used only if the structural features of the product do not allow chlorination or bromination at the α-position to the carbonyl.

An alternative to these oxidants is the use of the HOF.MeCN system which has previously been studied by others. In this process .the HOF.MeCN reagent is pre¬ formed at low temperature (-10°C) by passing dilute fluorine through a solution of water and acetonitrile followed by the addition of the substrate alcohol at. low temperature. However, this process suffers from a number of drawbacks. As the HOF.MeCN complex is unstable at room temperature and has a half life of around 4 hours, the storage of such a reagent is very difficult, and, due to the highly oxidising nature of the reagent, potentially hazardous. This factor alone precludes the use of such an oxidising system on a large scale. Furthermore, the degree of oxidation cannot be controlled since the alcohol is added to a large excess of the oxidising reagent, resulting in concomitant Baeyer-Villager oxidation of the product ketone.

The oxidation of 1,2-diols to 1,2-hydroxycarbonyl compounds is a special case and is not easily achieved by reaction of the free diols as, generally, oxidation of 1,2-diols results in carbon-carbon bond cleavage. The formation of 1,2-hydroxycarbonyl compounds from 1,2-diols requires the use of oxidants such as silver carbonate, dimethyl sulfoxide-phosphorous pentoxide, dimethyl sulfoxide-chlorine, dimethyl sulfide-N-chlorosuccinimide or dimethyl sulfide-chlorine to effect such transformations. Oxidation of 1,2-diols to 1,2-diones may be achieved with DMSO-oxalyl chloride.

According to the present invention there is provided a method for the oxidation of one or more hydroxyl groups in an organic compound to one or more carbonyl groups which comprises reacting the organic compound with elemental fluorine. The said organic compound may be an aliphatic or aromatic alcohol, diol or polyol.

Desirably, the organic compound is contained in a liquid through which fluorine is passed as a gas. The rate of delivery of fluorine gas may vary between wide limits depending upon the scale of the reaction and may be adjusted to control the rate of the oxidation reaction.

The said liquid may comprise the appropriate organic compound to be oxidised together with a substantially inert solvent, eg a neutral substance such as water optionally together with an inert neutral organic solvent such as acetonitrile. The liquid may optionally include also a solvent for fluorine, eg a fluorinated or perfluorinated organic compound such as a fluoro- or perfluoro-alkane.

The amount of water in the solvent or solvent system to which the organic compound is added to form the said liquid may vary between 0% and 100% although a water volume content of from 5% and 25% of the solvent system is preferred.

The method according to the present invention may be carried out in a vessel in which the solution is present or alternatively a flowing stream of the solution may be contacted with a gaseous flow of fluorine in countercurrent fashion.

The method according to the present invention may be carried out at a temperature in the range -60°C to +90°C although a temperature of from -20°C to +50°C is preferred. Ambient temperatures eg 15°C to 25°C may conveniently be employed.

The ratio of fluorine to the organic compound to be oxidised may be varied within wide limits although it is preferred that the molar ratio is in the range 0.5 to 2.0:1, especially 1.1 to 1.25:1 (fluorine: organic compound) .

Thus we now provide an improved method for the oxidation of hydroxyl groups to carbonyl groups using elemental fluorine as the oxidant. Fluorine is preferably passes slowly through a solution of the alcohol, diol or polyol in a solvent containing water at room temperature, thus oxidising the alcohol, diol or polyol in a reaction that can be easily controlled simply by adjusting the flow rate of the introduction of fluorine gas into the reaction vessel. In other words, the desired product can be selected by adjustment of the amount of fluorine taking part in the reaction. Also, by controlling the rate of reaction potentially dangerous reactions are prevented from going out of control. the rate may for example be less than lOml/min eg less than 5ml/min, for small scale apparatus and at higher rates for larger scale apparatus.

The ability to control the level of oxidation in the method according to the present invention allows for example 1,2-diols to be converted to either 1,2-hydroxycarbonyl compounds when one equivalent of fluorine is used in the oxidation, or to 1,2-diones when two equivalents of fluorine are passed through the reaction medium. Such control of the level of oxidation is not possible if the oxidant is the preformed HOF.MeCN reagent as employed in the prior art. The present invention also allows, for example, the selective oxidation of any number of hydroxyl groups in either a cyclic or acyclic polyalcohol to the corresponding polycarbonyl derivative. .

As further examples of the method according to the present invention there is provided a method for the production of carbonyl containing molecules of formula (1), (2), (3) , (4), (5) and (6) as follows:

(1) (2) (3) (4)

(5) (6) which comprises converting the corresponding compound of formula (7), (8) , (9) or (10) as follows:

(7) (8) (9) (10)

into compounds of formula (1) , (2) , (3) , (4) , (5) or (6) by reaction with elemental fluorine, wherein R, R_lf R₂ , R3 , R4, R5 and R₆ are each independently selected from hydrogen or the following groups which may be optionally substituted or contain optional hetero atoms: alkyl, alkoxy, cycloalky] , aryl, acyl, acyloxy nitro, cyano halogen. Where any of the groups is or contains an alkyl group the group is preferably C- -n alkyl.

In the above formulae, n is an integer in the range 1 to 8 inclusive.

When oxidation is complete the fluorinated product in the process according to "the present invention may be isolated by purging the reaction mixture with inert gas to remove any residual fluorine gas followed by neutralisation with sodium bicarbonate solution and extraction into a suitable solvent followed by purification by distillation or column chromatography.

Thus the present process according to the present invention provides an inexpensive and convenient synthetic route for the oxidation of alcohols to the corresponding carbonyl derivatives.

Embodiments of the present invention will now be described by way of example only with reference to the following Examples: Example 1: Oxidation of cvclohexanol

Cyclohexanol (2.0g, 20mmol) dissolved in acetonitrile (30ml) was placed in a PTFE fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (20mmol) as a 10% mixture in nitrogen was passed through the stirred mixture at room temperature at ca. lOml/min for 6 hours. The mixture was poured into water (30 ml) , neutralised with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 30 ml) . The crude carbonyl product was dried (MgS0 ) and concentrated by removal of solvent under reduced pressure to give a yellow oil containing cyclohexanone; GC/MS (60% conversion; 100% yield) which was identified as the 2,4- dinitrophenylhydrazone derivative, as follows:

A solution of acidified 2,4-dinitrophenylhydrazine (2.4g, 12 mmol) in hot methanol (50ml) was added to methanolic solution of crude cyclohexanone (12 mmol, as estimated from GC/MS) . The mixture was cooled (ice) until an orange precipitate formed. The precipitate was filtered off and recrystalised (MeOH) to give the 2,4- dinitrophenylhydrazone of cyclohexanone (3.0g, 90% yield based on 60% conversion of cyclohexanol); .p. 160°C (lit. 162°C); (Found: C, 51.8; H, 5.4; N, 20.2. C₁₂H₁₄N₄θ₄ requires C, 51.8; H, 5.0; N, 20.1%); δ_H (200MHz, CDC1₃, Me₄Si) 11.21ppm (br s, 1 H, NH) , 9.12 (d, J 2.40, 1 H, aryl) , 8.29 (d d, J 2.40, J 9.87, 1 H, aryl) , 7.97 (d,m J 9.87, 1 H, aryl) and 2.49-1.58 (m, 10 H) ; δ_c (100MHz, CDCI₃, Me Si) 161.42ppm (C=N) , 155.20, 145.33, 137.45, 129.95, 123.63, 116.24, 35.61, 27.22, 27.05, 26.01 and 25.50; m/z (Cl⁺, NH₃) 279 (M⁺+l, 76%), 239 (100%) and 58 (37%) . Example 2: Oxidation of trans-cvclohexane-1.2-diol

By a similar process to that described in Example 1, trans-cyclohexane-l,2-diol (2.0g, 17mmol) and fluorine (17mmol) gave a crude yellow oil of 2-hydroxy- cyclohexanone; GC/MS (87% conversion; 100% yield) . Reaction with 2, 4-dinitrophenylhydrazine gave the 2,4- dinitrophenylhydrazone of 2-hydroxy-cyclohexanone as an orange solid (3.7g, 85% yield based on 87% conversion); .p. 153°C (lit. 150°C) ; (Found: C, 49.4; H, 4.6; N, 18.9. C₁₂H₁₃N₄0₅ requires C, 49.1; H, 4.4; N, 19.1%); δ_H (200MHz, CDC1₃, Me₄Si) 11.45ppm (br s, 1 H, NH) , 9.21 (d, J=2.58 Hz, 1 H, aryl), 8.32 (dd, J=2.58 Hz, 9.65 Hz, l H, aryl), 7.97 (d, J=9.65 Hz, 1 H, -aryl), 3.40-3.30 (m, 1 H, CHOH) , 2.62-1.51 (m, 8H) and 1.1 (br s, OH); δ_c (100MHz, CDC1₃, Me₄Si) 160.31ppm (C=N) , 147.94, 140.55, 139.67, 128.99, 123.59, 117.21, 43.42 (C-OH) , 32.67, 27.43, 23.87 and 23.26; m / z (Cl⁺, NH₃) 295 (M⁺+l, 32%), 277 (100%) , 230 (34%) and 112 (46%) . Example 3: Oxidation of cyclopentanol

By a similar process to that described in Example 1, cyclopentanol (1.7g, 20mmol) and fluorine (20mmol) gave a crude yellow oil containing cyclopentanone; GC/MS (78% conversion; 71% yield). Reaction with 2,4- dinitrophenylhydrazine (2.2g, llmmol) gave the 2,4- dinitrophenyl-hydrazone of cyclopentanone as an orange solid (2.5g, 61% yield based on 78% conversion) ; m.p. 142°C (lit. 146°C) ; (Found: C, 47.5; H, 4.4; N, 19.9. C₁₁H₁₂N 0 requires C, 47.-1; H, 4.3; N, 20.0%); δ_H (200MHz, CDCI₃, Me₄Si) 10.90ppm (br s, 1 H, NH) , 9.12 (d, J=2.58 Hz, 1 H, aryl), 8.28 (dd, J=2.58 Hz, 9.66 Hz, 1 H, aryl), 7.92 (d, J=9.66 Hz, 1H, aryl) and 2.30-1.90 (m, 8 H) ; δ_c (100MHz, CDCI₃, Me₄Si) 171.05ppm (C=N) , 151.01, 144.01, 140.99, 129.95, 123.58, 116.20, 33.61, 28.15, 24.89 and 24.81; / z (Cl⁺, NH₃) 265 (M⁺+l, 68%) and 84 (30%). Example 4: Oxidation of 2-methyl-pentan-3-ol

By a similar process to that described in Example 1, 2-methyl-pentan-3-ol (l.Og, lOmmol) and fluorine (lOmmol) gave a crude yellow oil containing 2-methyl-pentan-3-one; GC/MS (46% conversion; 97% yield). Reaction with 2,4- dinitrophenylhydrazine (0.9g, 4.5mmol) gave the 2,4- dinitrophenylhydrazone of 2-methyl-pentan-3-one as an orange solid (1.2g, 93% yield based on 46% conversion) ; m.p. 110°C (lit. 112°C) ; (Found: C, 51.1; H, 5.8; N, 20.4. C₁₂H₁₆N₄0 requires C, 51.4; H, 5.7; N, 20.0%); δ_H (200MHz, CDC1₃, Me₄Si) 11.21ppm (br s, 1 H, NH) , 9.15 (d, J=2.57 Hz, 1 H, aryl), 8.29 (dd, J=2.57 Hz, 9.60 Hz, 1 H, aryl) 7.98 (d, J=9.60 Hz, 1 H, aryl), 2.45 (m, 1H, CHMe₂) , 1.31-1.25 (m, 5H, CH₂CH₃) , 1.23 (d, J=3.0 Hz, 3H, CH₃) and 1.21 (d, J=3.0 Hz, 3H, CH₃,); δ_c (100MHz, CDC1₃, Me₄Si) 160.41ppm, 143.31, 139.51, 138.01, 130.42, 124.06, 116.96, 36.45, 22.03, 20.56, 19.05 and 18.01; m / z (Cl⁺, NH₃) 281 (M⁺+l, 77%), 124 (17%) and 100 (31%). Example 5: Oxidation of hexan-2-ol

By a similar process to that described in Example 1, hexan-2-ol (l.Og, lOmmol) and fluorine (lOmmol) gave a crude yellow oil of hexan-2-one; GC/MS showed (100% conversion; 100% yield) . Reaction with 2,4- dinitrophenylhydrazine (2.0g, lOmmol) gave the 2,4- dinitrophenylhydrazone of hexan-2-one as an orange solid (2.7g, 97% yield based on 100% conversion); m.p. 107°C (lit. 106°C) ; (Found: C, 51.5; H, 5.6; N, 23.1. C₁₂H₁₆N₄0₄ requires C, 51.4; H, 5.7; N, 20.0%); δ_H (200MHz, CDC1₃, Me₄Si) 11.21ppm (br s, 1 H, NH) , 9.13 (d, J=2.56 Hz, 1 H, aryl), 8.29 (dd, J=2.56 Hz, 9.59 Hz, 1 H, aryl), 7.89 (d, J=9.59 Hz, 1H, aryl), 2.42-1.51 (m, 6H, CH₂CH₂CH₂) , 1.07 (s, 3H, CH₃) and 0.92 (t, J=6.02 Hz, 3H, CH₃) ; δ_c (100MHz, CDC1₃, Me₄Si) 160.39ppm (C=N) , 146.03, 136.93, 135.01, 128.95, 122.61, 116.14, 31.03, 24.01, 23.91, 20.19 and 18.32; m / z (Cl⁺, NH₃) 281 (M⁺+l, 34%) and 100 (9%) . Example 6: Oxidation of hexane-1.2-diol

By a similar process .to that described in Example l, hexane-l,2-diol (0.6g, 5mmol) and fluorine (5mmol) gave a crude yellow oil l-hydroxy-hexan-2-one; GC/MS (91% conversion; 95% yield). Reaction with 2,4- dinitrophenylhydrazine (0.9g, 4.3mmol) gave the 2,4- dinitrophenylhydrazone of l-hydroxy-hexan-2-one as an orange solid (1.2g, 89% yield based on 91% conversion) ; m.p. 179°C; (Found: C, 48.8; H, 5.6; N, 18.9. C₁₂H₁₆N₄0₅ requires C, 48.6; H, 5.4; N, 18.5%); δ_H (200MHz, CDC1₃, Me Si) 11.02ppm (br s, 1 H, NH) , 9.14 (d, J=2.59 Hz, 1 H, aryl), 8.33 (dd, J=2.59 Hz, 9.60 Hz, 1 H, aryl) 7.25 (br s, OH), 7.92 (d, J=9.60 Hz, 1H, aryl), 4.19 (s, 2H, CH₂) , 2.95-0.90 (m, 9H, CH₂ and CH₃) ; δ_c (100MHz, CDC1₃, Me₄Si) 159.28ppm (C=N) , 146.49, 144.89, 138.15, 130.19 (CH) , 123.52 (CH) , 115.91 (CH) , 64.50 (CH₂OH) , 28.02 (CH₂) , 26.98 (CH₂) , 23.01 (CH₂) and 13.62 (CH₃) ; m / z (Cl⁺, NH₃) 297 (M⁺+l, 100%), 279 (25%) and 261 (10%). Example 7: Oxidation of butane-l .3-diol

By a similar process .to that described in Example 1, butane-l, 3-diol (0.9g, lOmmol) and fluorine (lOmmol) gave a crude yellow oil containing l-hydroxy-butan-3-one; GC/MS (98% conversion; 53% yield) . Reaction with 2,4- dinitrophenylhydrazine (l.Og, 5.2mmol) gave the 2,4- dinitrophenylhydrazone of l-hydroxy-butan-3-one as an orange solid (1.2g, 46% yield based on 98% conversion); m.p. 158°C; (Found: C, 45.0; H, 4.8; N, 21.0. C₁₀H₁₂N₄O₅ requires C, 44.8; H, 4.5; N, 20.9%); δ_H (200MHz, CDC1₃, Me₄Si) 11.12ppm (br s, 1 H, NH) , 9.14 (d, J=2.60 Hz, 1 H, aryl), 8.20 (dd, J=2.60 Hz, 9.62Hz, 1H, aryl), 7.88 (d, J=9.60 Hz, 1H, aryl), 4.02 (m, 2H, CH₂OH) and 2.20-2.01 (m, 5 H) ; δ_c (100MHz, CDC1₃, Me₄Si) 156.44ppm (C=N) , 144.91, 130.30, 130.17, 123.56, 123.07, 116.03, 59.22 (CH₂OH) , 45.21 and 16.76; m / z (Cl⁺, NH₃) 269 (M⁺+l, 100%), 251 (84%) and 249 -(84%) . Example 8: Oxidation of tetrahvdro-4H-pyran-4-ol

By a similar process to that described in Example 1, tetrahydro-4H-pyran-4-ol (l.Og, lOmmol) and fluorine (lOmmol) gave a crude yellow oil containing tetrahydro-4H- pyran-4-one. Reaction with 2,4-dinitrophenylhydrazine (2.0g, lOmmol) gave the 2 ,4-dinitrophenylhydrazone of tetrahydro-4H-pyran-4-one as an orange solid (l.25g, 45% yield); m.p. 188°C (lit. 186°C) ; (Found: C, 45.0; H, 4.8; N, 21.0. C₁₀H₁₂N₄θ₅ requires C, 44.8; H, 4.5; N, 20.9%); δ_H (200MHz, CDC1₃, Me Si) 11.12ppm (br s, 1 H, NH) , 9.14 (br s, IH, aryl) , 8.29 (br d, J=9.60 Hz, IH, aryl) , 7.96 (d, J=9.60 Hz, IH, aryl), 3.93-3.90 (m, 4H, CH₂OCH₂) and 2.20-2.00 ( , 4H) ; δ_c (100MHz, CDC1₃, Me Si) 156.23ppm (C=N) , 145.13, 137.62, 129.99, 128.92, 116.36, 68.30 (C- O) , 66.25 (C-O) , 28.43 and 25.53; m / z (Cl⁺, NH₃) 269 (M⁺+l, 100%), 251 (84%) and 249 (84%).

Claims

1. A method for the oxidation of one or more hydroxyl groups in an organic compound to one or more carbonyl groups which comprises reacting the organic compound with elemental fluorine.

2. A method as in Claim 1 and wherein the said organic compound is an aliphatic or aromatic alcohol, diol or polyol.

3. A method as in Claim 2 and wherein the said organic compound which is treated by the method is a compound of any one of formulae (7) , (8) , (9) or (10) specified herein.

4. A method as in Claim 1, 2 or 3 and wherein the organic compound is contained in a liquid into which the fluorine is passed as a gas.

5. A method as in Claim 4 and wherein the liquid comprises an inert, neutral solvent.

6. A method as in Claim 5 and wherein the inert, neutral solvent comprises water.

7. A method as in Claim 6 and wherein the water forms from 5% to 25% by volume of the solvent system to which the organic compound is added.

8. A method as in claim 5, 6, or 7 and wherein the solvent also comprises a fluorinated or perfluorinated organic solvent.

9. A method as in any one Claims 4, 5, 6, 7 or 8 and wherein the fluorine gas is diluted before application to the said organic compound with an inert gas.