DE10113710A1 - Oxo-ammonium salts with a sterically-hindered oxo-ammonium group attached to an insoluble support material, used as oxidizing agents, especially for the oxidation of alcohol to ketone or aldehyde - Google Patents

Abstract

Oxo-ammonium salts with a sterically-hindered oxo-ammonium group attached to an insoluble support material by a linking group, are new. Oxo-ammonium salts of formula (I) in isolated form, are new. T-L-Z<+> X<-> (I) T = insoluble support material; L = linking group; Z<+> = group of formula (II), (III) or (IV); R<1>-R<5> = alkyl, allyl, aryl or benzyl; and X<-> = a counter-ion. An Independent claim is included for a method for the oxidation of organic compounds by reaction with compounds of formula (I).

Description

The invention relates to new oxoammonium salts, the Use as well as new oxidation processes.

From the prior art, oxoammonium salts are reactive Intermediates in Oxidations Using the 2,2,6,6- Tetramethylpiperidinoxyl radical (TEMPO), which also polymer-bound, is known (Review: Arjan E. J. de Nooy, Arie C. Besemer, Hermann von Bekkum, Synthesis 1996, 1153). The TEMPO is initially carried out by a Co oxidant (e.g. NaOCl) in the corresponding oxoammonium salt transferred to oxidie in the same reaction batch oxidizing substrate. A disadvantage, which is characterized by the Use of this radical especially for desired oxidations from alcohols to aldehydes is the overoxidation of Aldehydes to carboxylic acids. Another disadvantage that the Use of TEMPO in oxidation reactions, is the low reactivity towards non-benzylic Alcohols.  

The use of the is also known from the literature TEMPO precursors 1-hydroxy-4-oxo-2,2,6,6-tetramethyl-piperi din, which is bound to silica gel. This is at Oxidation reactions first by a cooxidant in the TEMPO transferred, which then - probably via an inter medically generated, non-isolated oxoammonium intermediate - the substrate to be oxidized is oxidized (Carsten Bolm, Thomas Fey, Chem. Commun., 1999, 1795-1796). Although with the mentioned TEMPO precursor also oxidizes aliphatic alcohols , but the yields, especially in the Oxidation of secondary alcohols, to be desired.

To the actually usual oxidizing agents for the order Settlement of alcohols to carbonyl compounds include Di methyl sulfoxide (DMSO), periodinans and various heavy metal reagents, the latter mostly based on either Chromium or ruthenium oxides. There are some examples of polymer-assisted oxidation reagents (A. Akelah, D. C. Sherrington, Chem. Rev. 1981, 81, 557-587) and for Schwer metal oxides bound to ion exchange resins (G. Gardillo, M. Orena, S. Sandri, Tetrahedron Lett. 1976, 17, 3985-3988; B. Hinzen, S.V. Ley, J. Chem. Soc. Perkin Trans. 1 1997, 1907-1910). However, the possible whereabouts limits of highly toxic heavy metals as well as those already at the Low TEMPO compounds described above Reactivity to non-benzylic alcohols and the Overoxidation of aldehydes using these reagents on.

The object of the invention is therefore new, as an oxidation medium usable compounds and oxidation processes for To make available that overcome the disadvantages mentioned.  

This problem is solved by the connection as described in Claim 1 is defined and according to the method Claim 11. Preferred embodiments can be found in the dependent claims 2-9 or 12-16 and in use claim 10. The wording of all claims is hereby made by reference to the content of this description.

The oxoammonium salt according to the invention has a positively charged reactive section Z ⁺ , which has one of the following structures:

The counter ion, which is denoted by X ^- , is an anion, in particular a halide ion, preferably a chloride ion.

Z ⁺ is connected via a linker group L with an insoluble carrier material T as a solid phase.

Z ⁺ has 4 or 5 radicals R which are selected independently of one another from the group of alkyl, allyl, aryl and benzyl, C ₁ -C ₅ -alkyl being preferred. Particularly high yields of oxidized product are achieved when R ¹ -R ⁴ or R ^{5 are} methyl groups.

The one commonly used in organic synthesis Solvent-insoluble carrier material T can be a polymer, especially 1% divinylbenzene polystyrene resin. Next Polymers are other materials for T, such as as a polycondensate of spherical polysilicic acids, too Called silica gel, possible.

The linker group L preferably has an ether group. However, it is also possible for L to have one or more amide, Has amine or ester groups or the like. Also alkyl Groups without heteroatoms are conceivable as linker groups.

In a particularly preferred embodiment, the oxoammonium salt consists of the above-mentioned positively charged 6-ring (a), a chloride ion, a CH ₂ -O linker group, the methylene group being connected to the insoluble carrier material T, and 1% divinylbenzene Polystyrene resin as an insoluble carrier material T.

As already mentioned above, polymer-bound oxoammonium So far, salts have only been used as reactive intermediates in oxides tion using TEMPO. With the inventors Compounds according to the invention, on the other hand, are polymeric bound oxoammonium salts in isolated form. Such iso gated salts are not known from the prior art.

With the oxoammonium salts according to claims 1-9 Oxidation of various substrates possible. As special The salts described have been efficient for the oxide tion of both aliphatic and benzylic alcohols proved. For example, when implementing  Heptanol to heptanal achieved a yield of over 95%. In addition to alcohols to ketones or aldehydes Ketones to diketones, diols to lactones and phenols to chinos oxidize.

The inventive method for the oxidation of organic Compounds according to claim 11 is characterized in that the compound to be oxidized with an inventive Oxoammoniumsalz is implemented. In this process, in which the oxoammonium salt used in pure, isolated form the formation of by-products, especially of Overoxidation products, largely avoided. This will Product yields achieved that are significantly higher than those with the previously known polymer-assisted oxidizing agents, such as for example the 1-hydroxy-4-oxo- 2,2,6,6-tetramethylpiperidine from Carsten Bolm and Thomas Fey, achievable yields.

Last but not least, the connection according to the invention offers their use in the polymer-assisted Solution synthesis the possibility of taking advantage of solid phases synthesis, which combinatorial chemistry in its first Decade dominated (Combinatorial Chemistry-Synthesis, Analysis, Screening, (Ed .: G. Jung), Wiley-VCH, Weinheim, 1999; Combinatorial Paptide and Non-Peptide Libraris, (ed gb .: G. Jung), VCH, Weinheim, 1996), with the advantages of Connect synthesis in solution. Polymeric reagents can be used in large excess and by filtration are removed, whereas the products are easily analyzed and can be further implemented in solution. polymers Reagents are excellent for parallel combinators suitable synthesis. They enable the production of complex compound libraries through multi-stage syntheses in solution, they can be used in automated as well as in flow systems  be used. Finally, they can be set to single connections as well as complex ones To transform mixtures. As advantages of synthesis in The solution is the versatility of reactions that ver are reversible, and the extensive, in synthesis instructions experiences.

Further details and features of the invention emerge from the following description of the representation of the compound of the invention and of preferred embodiment form the method according to the invention in connection with the Dependent claims. The respective characteristics for alone or in combination with each other be realized.

The drawings show:

Fig. 1 reaction scheme to illustrate a fiction, contemporary connection. The oxoammonium resin 2 was prepared in a three-step synthesis from chloromethylated polystyrene resin and was used in the oxidation of the alcohols 3 a to 22 a. The oxidation of resin 1 was carried out with Br ₂ , Cl ₂ or NCS / HCl.

Fig. 2 Collection of 20 chemically diverse alcohols 3 a to 22 a, which represent benzylic, allylic, primary aliphatic, secondary aliphatic alcohols and diols.

Fig. 3 GC analysis of the reaction of alcohol 9 a in DCM (1 mg / ml) for 1 h with 1, 2 and 3 equivalents of the polymeric oxoammonium salt 2 using a flame ionization detector (FID).

Fig. 4 Secondary oxidation products of alcohols 3 a to 22 a.

Fig. 5 GC-FID of a mixture of 15 alcohols (top) and product mixture obtained after oxidation with resin 2 (bottom).

Experimental examples I. For the synthesis of the compounds according to the invention

The 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl radical was coupled with sodium hydride as a base to 1% divinylbenzene polystyrene resin ( Fig. 1). Elemental analysis of resin 1 showed a loading of 0.93 mmolg ^{-1 of} the radical. ESR spectroscopy confirmed the presence of the free radical electron and showed the characteristic triplet signal that is generated by the coupling with the ¹⁴ N nucleus. Accordingly, a clear line broadening was observed in the HR-MAS NMR spectrum, which can be explained by the increased relaxation of the nuclear magnetization due to the interaction with the persistent electron spins. The radical was oxidized with elemental bromine, chlorine and N-chlorosuccinimide / HCl (methods AC). Following the oxidation, resin 2 in FT-ATR-IR showed a strong absorption band at 1700 cm ^-1 , which is probably characteristic of the N = O double bond of the reactive intermediate. The oxidation is accompanied by a clear color change from colorless to a bright orange-red in the case of chloride.

Detailed description of the synthesis of a fiction moderate connection

• A) Representation of the TEMPO resin 1 . Sodium hydride (1.28 g, stabilized with paraffin oil, 60%, 32.1 mmol) was suspended in dry DMF (dimethylformamide, 40 ml) in a 100 ml round-necked flask. 2,2,6,6-Tetramethyl-piperidine-1-oxyl (3.57 g, 20.7 mmol) was slowly added, the flask was sealed with a drying tube and stirred for 3 h. Chloromethylated 1% divinylbenzene / polystyrene resin (loading 1.07 mmolg ^-1 , 100-200 mesh, 2 g, 2.14 mmol) was added and the reaction mixture was shaken at RT for 3 days. The resin was filtered off and washed thoroughly with water, water / DMF (1: 1), DMF, THF, DCM (dichloromethane) and MeOH and dried in vacuo. Load: 0.93 mmolg ^-1 chlorine content: 0.07%.
• B) Oxidation to oxoammonium resin 2 (method C). N-chloro succinimide (6 equiv) was dissolved in DCM, 4 M HCl in dioxane was added (5 equiv). After 5 min. the solution was added to Resin 1 (1 equiv), which was pre-swollen in dry DCM. After 15 min. Shaking the resin was filtered off and washed with dry DCM.

II. Bu the reactions of the compound of the invention

The reactivity of reagent 2 towards a selection of 20 different alcohols 3 a - 22 a was investigated, which represent benzylic, allylic, primary and secondary aliphatic ( Fig. 2). In the comparison of the different counterions, chloride was more reactive than bromide and led to fewer by-products, presumably due to the Br ₃ ^- anions present in the bromide resin. Different temperatures were tested, all comparative reactions were carried out at room temperature (RT) (Table 1). Analysis and quantification of all reactions was carried out using GC, either with a flame ionization detector (FID) or a mass-sensitive detector (EI-MS, 70 eV). The compounds were identified by comparison with pure substance samples, by comparing the mass spectra with those obtained from the NIST spectral library or by NMR analysis.

First alcohol 9 a was reacted with different equivalents of resin 2 . Complete conversion within 1 h was achieved with 3 equiv of resin 2 ( Fig. 3).

The results of the oxidations (Table 1) can be summarized as follows: Clean and rapid quantitative conversion of the alcohols was generally observed; only in the case of alcohol 17 a were residues of the starting material detected after the reaction. All benzylic or allylic alcohols gave aldehyde or ketone products in very good purity. The same was found for open-chain primary and secondary alcohols. Representative yields for the less volatile products such as the aldehydes 9 b, 10 b, or 20b were determined by weighing and were 90%.

Table 1

Very easily enolizable ketones, such as those obtained from cyclohexanol ( 19 a), 1-phenylpropan-2-ol ( 21 a) and cholesterol ( 22 a), were further converted to the dions 19 c, 21 c and 22 c become. In this reaction the primary oxidation product, e.g. B. cyclohexanone via an enol form as an intermediate to ketone. In contrast, the diols ( 15 a, 17 a) were converted to lactones in the secondary oxidation step ( 15 c, 17 c) ( Fig. 4). Interestingly, two cascade-like reactions were observed with terpene alcohols such as ge raniol ( 11 a) and citronellol ( 14 a) with an excess of reagent. They cyclized in an ene reaction to form the secondary alcohols ( 11 c, 14 c). These secondary products could be further oxidized to the terpene ketones ( 11 d, 14 d). In the geraniol system, this reaction was particularly good.

Finally, a compound collection consisting of 15 alcohols ( 3 a - 10 a, 12 a, 13 a, 15 a, 16 a, 18 a - 20 a) was used to investigate the implementation of complex mixtures of chemically diverse alcohols ( Fig. 5). The mixture (1 mgml ^-1 per alcohol) was analyzed with both GC-FID and GC-MS. In the starting mixture, all alcohols could be separated and identified by their mass spectrum. Following treatment with Resin 2 for 2 h, GC analysis revealed the complete disappearance of all alcohols. All but one of the expected aldehyde, ketone, lactone or dione products could be separated and identified. 8b and 12b co-eluted, whereas 16b was not detected at all. The concentration of the products with a low boiling point, which elute first in the GC, was reduced, whereas the concentration of the higher-boiling aldehydes and ketones in the complex mixture remained unchanged.

In summary it could be shown that the polymer The oxoammonium reagent is highly efficient in the polymer sub supported oxidation of various alcohols. The reagent is usable in high excess and delivered very pure Products based on individual connections. Beyond that it is possible to cleanly move complex connection collections put. No over-oxidation to carboxylic acids was observed. It is obvious that this reagent is of great value in polymer-assisted transformations in solution in which automated parallel synthesis and in flow applications in production processes with larger approaches.

Detailed description of the oxidation of alcohols with a compound of the invention

• A) Oxidation of the alcohols. The alcohols 3 a - 22 a (1 equiv) were dissolved in dry DCM. Freshly prepared oxoammonium resin 2 (5 equiv, calculated after loading resin 1 ) was added and shaken at RT, for 1 hour in the case of the primary alcohols and for 2 hours in the case of the secondary alcohols. The resin was filtered off and washed with DCM. The solution obtained was examined by GC analysis, for which a fused silica capillary was used (25 m × 0.32 mm Permabond SE 54, d _f = 1.0 μ). Temperature program: 50 ° C, 2 min. isothermal, 5 ° Cmin ^-1 to 200 ° C. H ₂ was used as the carrier gas for FI detection (p _i = 50 kPa) and He for GC-MS in EI mode (70 eV). Purity levels are given in Table 1. Exemplary yields for 10 mg alcohol, with a reaction time of 1 h, washing 4 times with 3 ml DCM each and after evaporation of the solvent at RT: 9b (8.9 mg, 90%), 10b (8.7 mg, 88%) and 20b (9.2 mg, 91%).

Claims (16)

1. Oxoammonium salt in isolated form with the general formula
TLZ ⁺ X ^- (I)
in which
T is an insoluble carrier material,
L is a linker group,
Z ⁺ either a)
or b)
or c)
is
R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} independently selected from the group of alkyl, allyl, aryl and benzyl, X ^{- is} a counter ion to the oxoammonium ion. 2. oxoammonium salt according to claim 1, characterized in that L has an ether group. 3. oxoammonium salt according to claim 1, characterized in that L is an alkyl group. 4. oxoammonium salt according to claim 1, characterized in that L has an ester group. 5. oxoammonium salt according to claim 1, characterized in that L has an amide group. 6. Oxoammonium salt according to one of the preceding claims, characterized in that R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} C ₁ -C ₅ alkyl groups, preferably methyl groups. 7. Oxoammonium salt according to one of the preceding claims, characterized in that X ^{- is} an inorganic ion, preferably a halide ion. 8. oxoammonium salt according to one of the preceding claims, characterized in that T is a polystyrene resin, preferably 1% divinylbenzene polystyrene resin. 9. oxoammonium salt according to claim 1, characterized in that Z ⁺ = a), X ^- = Cl ^- , L = -CH ₂ -O-, the CH ₂ group being connected to T, and T = 1% divinylbenzene -Poly styrene resin. 10. Use of an oxoammonium salt according to one of the Claims 1-9 as an oxidizing agent, especially for Oxidation of alcohols to ketones or aldehydes. 11. Process for the oxidation of organic compounds, characterized in that the compound to be oxidized dung with an oxoammonium salt according to one of the claims 1-9 is implemented. 12. The method according to claim 11, characterized in that the dissolved in a first solvent, to oxidie rende connection with at least 2, preferably 5 Equivalents of the oxoammonium salt according to one of the Claims 1-9 is implemented. 13. The method according to claim 12, characterized in that the reaction product is removed from the first solvent, is preferably filtered off, then with a second solvent is washed and the second Solvent is removed. 14. The method according to claim 13, characterized in that the first and second solvents are identical. 15. The method according to any one of claims 11-14, characterized characterized in that the compound to be oxidized Alcohol, especially an aliphatic alcohol. 16. The method according to any one of claims 10-15, characterized characterized in that a mixture of to be oxidized Connections is implemented.