SK158399A3 - Reduction of aromatic halogenides - Google Patents

Abstract

The invention relates to the reduction of (hetero)aromatic halogenides of general formula (I) Ar-Xn to compounds of general formula (II) Ar-Hn. To achieve this, a reduction agent is used, in particular a hydride reactant such as lithium aluminium hydride (LiAlH4) in the presence of oxygen, in particular in the form of an oxygen-inert gas mixture. Reduction in the presence of oxygen gives a good yield in short reaction times, even when working on a semi-industrial or industrial basis. Reduction using LiAlH4 in the presence of oxygen can also be used to reduce complicated heteroaromatic halogenides, for instance for reducing bromonarwedine ketone acetal to narwedine ketone acetal on an industrial scale.

Description

The invention relates to a process for reducing aromatic halides.

BACKGROUND OF THE INVENTION

Various methods are known for reducing aromatic halides.

The following reducing agents are known for reducing aromatic halides:

Cr (CIO ₄ ) 2 / ethylene diamine (Wade, R. S. Castro, CE Org Synth Coli Vol. V1, 821 (1988), Cr (CIO ₄ ) 2 / H ₂ N (CH ₂ ) NH 2, tin / HBr ( Koelsch, CF, Org Synth. Coli, Vol. IIE, 132 (1954), Sn / HBr), catalytic reduction with Raney nickel (Nishyama, T. Kameopka, H. Chem. Express 6 (2) 109, 112 (1991), Raney-Ni / H 3) or Pd / hydrazine hydrate (Mosby, WLJ Org Chem. 24, 421 (1959), Pd / N ₂ H ₄ .H ₂ O), reducing agents such as K-selectride / CuI [NaBHVMeaSi ^ SiH (Lesage, N. Chatgilialoglu, C. Griller, D. Tetrahedron Lett. 30, 2733 (1989), (NeaSibSiH), LIAIH4 [(Falck, JR Nanna, S.J. Am Chem. Soc 105, 631 (1983), LiAIH ₄ )) , Han,

BH; Boudjouk, P; Tetrahedron Lett 23, 1643 (1982), LiAlH ₄ ), (Benington, F; Norin, RD; Clarck Zr LCJ Org., Chem 24, 917 (19S9), LiAlH ₄ ), (Szewcyk, J. Lewin, AH; Carrol , FIJ Heterocycl, Chem 25, 1809 (1988), LiAlH4 - am Bromformylnarwedin 53%. I), (Vlahov, R. Krikorian, D Spassov, G Chinova, M; LiAlH4 and brom, Vlahov, I Parushev, S Snatzke, G. Ernst L. Kieslich, K. Abraham, N. Sheldrick, WS Tetrahedron 45, 3329 (1989), Galanthaminone 96%] or similar complex hydrides such as LiAlH 4 (OMe) 3 / Cul (Masumane, S; Rossey, PA; Bates, GS J. Am Chem., Soc., 95, 6452, 1973, LiAlH ₄ (OMe) 3 / CuI) LiAlH 4 is often used as a reducing agent together with inorganic halides such as CeCl 3 (Imamoto, T Takeyama, T. Kusumoto, T Chem I. ett. 1491, (1985), LiAlHVCeCl 3), TiCl ₄ (Mukaiyama, T; Hayashi, M; Narasaka, K. Chem Lett, 291, (1973 LiAlH 4 / TiCl ₄ ), FeCl ₂ , CoCl ₂ , TiCl ₃ NiCI ₂ (Ashby, EC, Lin JJJ Org Chem 43, 1263 (1978), LiAlH 4 / FeCl ₂ ,

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CoCl ₂ , T 1 Cl 3. NiCl ₂ ) in a catalytic or stoichiometric amount. Additional reducing agents were prepared by these additions. Methods for reducing aromatic halides are known in which LiAlH ₄ is used in conjunction with photo irradiation (Beckwith, LJ Goh. SHJ, Chem Soc Chem. Commun 907 (1983), LiAlhU / liv) or ultrasound (Han, BH; Boudjouk, P Tetrahedron Lett). 23, 1643 (1982), LiAlhU / Ultraschall).

In B. Menuir, "Reduction of aromatic halides with sodium borohydride catalysed by titanium complexes. Unexpected role of air in Journal of Organometalic Chemistry, vol. 204, no. 3, January 20, 1981, Lausanne, Ch, p. 345 to 346, a method for reducing aromatic halides using NaBH ₄ , which is catalyzed by Cp ₂ TiCl ₂ or CpTiCl ₂ in the presence of air, is described. In this known manner, however, exclusively aromatic iodides are reduced, for example chlorine and bromine cannot be reduced.

EP 0 370 325 A discloses a process for the reductive dehalogenation of aromatics by treating halogen aromatics with Raney nickel and an alkali metal formate in an aqueous alkaline medium at a temperature of 80 to 250 ° C and a pressure of 0.1 to 10 Pa. the presence of air in the reaction vessel is not excluded in this process.

J. Szewcyk, improvedη improved synthesis of galanthamine, Journal of Heterocyclic Chemistry, Vol. 6, 199, p. 1809-1811, describes a process for debromination of bromoformylnarwedine in a batch of 3.0 by refluxing in tetrahydrofuran for 12 hours. Thus a mixture of galantamine and epigalantamine is obtained in a yield of 53%. The presence of air is not expressly excluded in this publication.

Despite the large number of known methods, in practice there are still cases in which reduction by LiAlH 4 is slow and often associated with insufficient yield. Varying the reaction parameters such as prolonging the reaction time, using a larger molar excess of LiAlH ₄ , changing the solvent (e.g., using tetrahydrofuran instead of diethyl ether), increasing the reaction temperature often leads to problems associated with the occurrence of undesirable side reactions and lower yields. Often, other non-substituents are present in the reduced compounds

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2a Compatible with the catalytic reduction method or with the hydrogen at birth. Other complex hydrides or hydride reagents are not sufficiently reactive compared to LiAlH 4 and do not provide sufficient yields to reduce aromatic halides.

In spite of the large number of known methods, in practice there are still recurring cases in which reduction by LiAlH 4 is slow and often associated with insufficient yield. Varying the reaction parameters as extended reaction time, using a larger molar excess of LiAlH ₄ , changing the solvent (e.g., using tetrahydrofuran instead of diethyl ether), increasing the reaction temperature often leads to problems associated with the occurrence of unwanted side reactions and lower yield at larger batches. Often, additional substituents are present in the reduced compounds which are incompatible with the catalytic reduction method or with the hydrogen at birth. Other complex hydrides or hydride reagents are not sufficiently reactive compared to LiAlH ₄ and do not provide sufficient yields to reduce aromatic halides.

It is an object of the present invention to provide a process for the reduction of aromatic and heteroaromatic halides which allow a faster reaction with higher yields, even if larger volumes are used.

SUMMARY OF THE INVENTION

The present invention provides a process for reducing aromatic halides of formula (I)

Ar-Xn

I.

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Ar is an aromatic group optionally substituted one or more times, optionally fused and optionally containing one or more heteroatoms selected from the group consisting of O, S, N,

X is fluoro, chloro, bromo and / or iodo and n is from 1 to 10, with a reducing agent to the compound of formula (II)

Ar-Hn (II) wherein Ar and n have the same meaning as in Formula (I), the essence of which is that the reduction is carried out in the presence of oxygen.

The invention permits the use of a variety of reducing agents. Examples of reducing agents that may be used are:

hydride reagents such as DiBAL-H (diisobutylaluminium hydride), DiBAL-H / ZnCb, Alisopropylate, Red-AI® (sodium- (bis- (2-methoxyethoxy) -aluminium hydride (Aldrich)), K-Selectride® (potassium-tri-sec) -butylborohydride (Aldrich)), L-Selectride® (lithium-trisec.-butylborohydride (Aldrich)), KS-Selectride® (potassium-trisiamylborohydride (Aldrich)), LS-Selectride® (lithium tri-thiamylborohydride (Aldrich)) Li -tri-t-butoxyAlH, Li-tri-t-ethoxy-AlH, 9BBN (9-borabicyclo [3.3.1] -nonane), Super-Hydride (lithium triethylborohydride) (Aldrich)), NaBH ₄ , Zn ( BH _{4) 2,} AIH _third AlCl ₂ H or a combination of these reducing agents, with LiAlH ₄ being preferred.

The process according to the invention consists in reducing (hetero) aromatic halides with a reducing agent, in particular LiAlH ₄ , in the presence of oxygen, for example air or mixtures of oxygen and inert gas. Unlike commonly used reaction regulations for reducing agents such as LiAlH ₄ , which operate in an inert gas environment (such as nitrogen, argon or helium), the use of oxygen is a factor that accelerates the reaction and increases the yield. The oxygen can be diluted with an inert gas and is blown or soaked with the reaction mixture by pressure or suction. This allows the reaction times to be shortened and the yields reproducibly increased.

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The present invention provides an efficient and industrially useful method of reducing (hetero) aromatic halides using a reducing agent such as LiH ₄ in the presence of oxygen.

According to the invention, the reduction process is carried out according to the following reaction scheme:

Scheme 1:

LÍAIH4 / O2 (Het) Ar - X ......... »(Het) Ar - H

LÍAIH4 / O2 (Het) Ar - X _n '......... * (Het) Ar - H _n

By introducing oxygen, in particular (synthetic) air, into a solution containing halogen aromatics and a reducing agent in a solvent, the reduction of the aromatic halogen compounds is greatly accelerated. In many cases, it is also possible to reduce (hetero) aromatic halogen compounds which, for example, cannot be reduced by LiAlH ₄ alone. Another advantage of the presence of oxygen or air in the reduction is in the possibility of achieving higher yields and in suppressing the formation of undesired by-products, which arise during long reaction times (without the use of oxygen).

In addition to the general applicability of the invention to laboratory scale reduction methods, this method of the present invention is particularly advantageous for reducing the bromo-narwedine-type compounds (see Scheme 2) on a kilogram scale and for economically reducing industrial quantities.

These facts are surprising because it could not be expected that the reduction could proceed without problems under oxidizing conditions, i.e. in the presence of oxidizing agents such as oxygen.

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Scheme 2:

LiAlHyc 1 CH ₃ o

Further examples of the reductions made according to the invention are outlined in Scheme 3.

Scheme 3:

Example:

1-X-Naphthalene Example:

n-X-thiophene

One advantage of the process of the present invention is to reduce the reaction time of the reduction of (hetero) aromatic halides. To confirm this, several halogen-substituted aromatic and (hetero) aromatic compounds were reduced in direct comparison in the presence and absence of oxygen. Further, reactions (bromo-narwedinketal) in different sized reaction batches were observed in the presence and absence of oxygen (Table 1).

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Table 1

Edukt Produkt (5 g charge) Reaction time at presence of oxygen (time needed for reach> 99% - transformation, determined by HPLC) Reaction time at absence of oxygen (time needed for reach> 99% - transformation, determined by the HPLC) 1-fluoronaphthalene naphthalene 8 hours > 16 hours 1-Chloronaphthalene Naphthalene 4 hours > 16 hours 1-bromonaphthalene naphthalene 2 hours > 16 hours 1-iodonaphthalene naphthalene 1 hour > 16 hours 2-bromothiophene thiophene 2-3 hours 90 hours 3-bromothiophene thiophene 2 hours 29 hours 2-chlorothiophene thiophene 3.5 hours 120 hours 3-chlorothiophene thiophene > 5 hours > 95 hours bromoformylnarwedin-narwedin propylene glycol ketal (50 g) 2-3 hours 24 hours bromoformylnarwedin-narwedin propylene glycol ketal (200 g) 3-4 hours > 48 hours bromoformylnarwedin-narwedin propylene glycol ketal (800 g) 3-4 hours > 14 days bromoformylnarwedin-narwedin propylene glycol ketal (14 kg) 3-4 hours not determined

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Instead of oxygen (technical purity) according to the invention, it is possible to use a mixture of oxygen with one or more inert gases (such as nitrogen, argon or helium).

According to the present invention, it is preferable either to inject synthetic air (80:20 nitrogen / oxygen mixture) into the reaction mixture or to suck in ambient air. If ambient air is sucked in, it is preferable to dry it to prevent deposits in the inlet pipe. Wet air would consume a reducing agent, such as e.g. LiAlH4. In particular, the risk of spontaneous ignition and explosion cannot be excluded when using (very) humid air.

To reduce the bromoarwedine ketal by LiAlH 4 to narwedine on a 50-gram scale, a gas mixture of 95% N ₂ and 5% O _{2 is used} , with complete conversion within 3 hours. If a gas mixture of 99% N ₂ and 1% O _{2 was used} for the same batch size, complete conversion is not achieved until 7 hours.

It has also been found to be advantageous to pass air through the scrubber in order to saturate the solvent used (e.g. tetrahydrofuran) and thus avoid the loss of solvent by blowing, which would otherwise have to be constantly replenished. Also, operating the reflux condenser with brine at -40 ° C greatly reduces solvent losses.

The experiments carried out have shown that it is also advantageous to use an excess of a reducing agent such as LiAlH ₄ , since for example LiAlH 4 decomposes in air and forms non-reactive oxides. A sufficient excess of a reducing agent such as LiAlH 4 should be used to provide a sufficient amount of a reducing agent such as LiAlH ₄ in the reaction mixture. Experiments with one equivalent of LiAlH 4 (= 4 equivalents of hydride) and monohalogen thiophene compounds showed insufficient conversion, whereas using two equivalents achieved 100% conversion without problems. In contrast, for naphthalene derivatives, especially for 1-bromonaphthalene and 1-iodonaphthalene, complete conversion was achieved with one equivalent of LiAlH 4 and air. On an operational technical scale, it can successfully convert to narwedine with 1.5 equivalents after 3 hours. Using 1.3 equivalents

31340 / H does not undergo 100% conversion even after 6 hours, since this reduction also requires LiAlH 4 to reduce the formyl residues (Scheme 2).

The methods of the present invention and comparative experiments are described below.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 9.7 mL of LiAlH 4 (10% in THF; 24 mMol) was added dropwise to a solution of 5 g of 1-bromonaphthalene (24 mMol) in 40 mL of THF and air was aspirated at 50 ° C for 4 h through a drying column packed CaCl 2 and a gas scrubber filled with THF. After 4 h, the reaction was complete by thin layer chromatography. The mixture is quenched by the addition of 5 mL of water and 5 mL of saturated aqueous NaHCO 3 solution, the precipitate is filtered off with suction and washed twice with hot THF. The filtrate was evaporated and the resulting crude product was recrystallized from diethyl ether: 2.42 g of naphthalene as colorless crystals (78% of theory). Thin layer chromatography: light petroleum (repeated twice)

Comparative Example 1

A solution of 9.7 mL of LiAlH 4 (10% in THF; 24 mMol) was added dropwise to a solution of 5 g of 1-bromonaphthalene (24 mMol) in 40 mL of THF and stirred at 50 ° C under a gentle stream of argon. After 4 hours, 25% conversion was shown by thin layer chromatography. After 24 hours the conversion is 25%. Working up according to Example 1 and column chromatography (100 g silica gel 60, hexane) gave 0.95 g of bromonaphthalene and 1.2 g of naphthalene.

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Example 2

To a solution of 100 mL of THF and 5 g of 1-halo-naphthalene was added 1.5 equivalents of UAIH4 in THF (10%) and the mixture was stirred at 50 ° C. The mixture was bubbled with synthetic air (80% N ₂ , 20% O ₂ ). 50 ml / min with vigorous magnetic stirring. THF is added dropwise constantly to maintain a constant volume. About 1 ml of the sample taken for analysis is quenched with 5 ml of water and extracted with 2 ml of hexane. The hexane phase is used for analysis by gas chromatography. Approximately 0.5 ml of the organic phase is injected into a gas chromatography vial with a syringe equipped with a filter between the needle and the syringe. Add the remaining volume of the sample vessel to light petroleum.

Comparative Example 2:

To a solution of 100 mL of THF and 5 g of 1-halo-naphthalene was added 1.5 equivalents of LiAlH 4 in THF (10%) and the mixture was stirred at 50 ° C under N ₂ . About 1 ml of the sample taken for analysis is quenched with 5 ml of water and extracted with 2 ml of hexane. The hexane phase is used for analysis by gas chromatography. Approximately 0.5 ml of the organic phase is pipetted into the gas chromatography vial with a syringe equipped with a filter between the needle and the syringe. Add the remaining volume of the sample vial to light petroleum.

According to Example 2 and Comparative Example 2, 1-fluoro-, 1-chloro-, 1-bromo and 1-iodo naphthene is reduced. The results are summarized in Table 2:

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Table 2

Reduction of 1-X-naphthalene (X = F, Cl, Br, I)

X gas 1 hour 2 hours 4 hours 8 hours 16 hours starting material Product starting material Product starting material Product starting material Product starting material Product F n ₂ 89 11 83 17 80 20 73 27 66 34 o ₂ 52 48 29 71 13 87 1 99 - - Cl n ₂ 87 13 81 19 77 23 64 36 50 50 o ₂ 26 64 2 98 0 100 - - - - br n ₂ 83 17 76 24 70 30 52 48 48 62 o ₂ 30 70 1.5 98.5 0 100 - - - - I n ₂ 52 48 39 61 30 70 18 82 12 88 0 ₂ 1.5 98.2 0 100 - - - - - -

Notes on Table 2:

N ₂ = continuous stream of nitrogen through the solution

O ₂ = continuous flow of synthetic air (80% N ₂ , 20% O ₂ ) through the solution

Analytical methods:

Gas Chromatography: HP5890

Column: Permabond OV1 DF 0.25 silica gel Temperature program: Initial temperature 50 ° C 1 min .;

heating rate 10 ° C / min.

Retention times: naphthalene 5,2 min. 1-fluoronaphthalene 6.65 min. 1-chloronaphthalene 7.85 min. 1-bromonaphthalene 9.1 min. 1-iodonaphthalene 10.5 min.

Example 3

One (later 2) equivalent of a solution of LiAlH 4 (1 mMol in THF) was added to 1.0 g of halothiophene in 10 mL of anhydrous THF. The mixture is brought to said reaction temperature and vigorously stirred with a magnetic stirrer while bubbling synthetic air (N2 / O2 80:20). After some time, 0.5 ml of the solution was hydrolyzed in 10 ml of 2N HCl, extracted twice with 5 ml of diethyl ether and diluted with 30 ml of methanol. The composition of this solution is then directly determined by HPLC (high pressure liquid chromatography).

Comparative Example 3:

One (later 2) equivalent of a solution of LiAlH 4 (1 mol in THF) was added to 1.0 g of halothiophene in 10 ml of anhydrous THF. The mixture is brought to said reaction temperature and vigorously stirred with a magnetic stirrer while N 2 is bubbled through. After this time, 0.5 ml of the solution was hydrolyzed in 10 ml of 2N HCl, extracted twice with 5 ml of diethyl ether and diluted with 30 ml of methanol. The composition of this solution is then directly determined by HPLC (high pressure liquid chromatography).

The N-X-thiophene derivatives are reduced according to the methods described in Example 3 and Comparative Example 3. The results are summarized in Table 3.

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Table 3

Reduction of n-X-thiophene (n = 2.3; X = Cl, Br)

x gas temperature Time 1 Time 2 Time 3 Time 4 Time 5 notes 0 ° C data of educt in% 2-Br n ₂ 50 1 h 23% 2 h 46% 17.5 h 83% 22.5 h 96% 90 h 100% ° 2 50 0.5 h 46% 1 h 65% 2 h 74% 3.25 h 8.25 h insufficient THF flow *) n ₂ 30 1 h 17% 2 h 26% 4 h 33% 19.25 h 65% 45.5 h 100% o ₂ 30 0.5 h 52% 1 h 58% 2.25 h 58% 4 h 8.25 h Consumed *) 1 eq. LiAlH, 3-Br N _a 30 0.5 h 21% 2 h 31% 7.75 h 36% 29 h 100% - o ₂ 30 0.5 h 74% 1 h 100% 2 h 100% - - T 2-Cl n ₂ 30 1 h 0% 2 h 6% 7/8 h 25% 29 h 48% 120 h 96% 2 eq. LiAlH, o ₂ 30 0.1 h 35% 1 h 59% 2 h 94% 3,5 h 100% - 2 eq. LiAlH ₄ 3-Cl N ₂ 30 1 h 8% 3 h 9% 8.5 h 8% 32 h 17% 95 h 44% 2 eq. LiAlH ₄ ° ₂ 30 0.5 h 12% 1 h 21% 2 h 36% 4 h 42% 5,5 h 50% 2 eq. LiAlH ₄

*) The original air stream at 50 ° C vaporized very much THF. The temperature was lowered to 30 ° C. In addition, oxygen was consumed with LiAlH 4, so that one equivalent of LiAlH 4 is very little when using air. Therefore, two equivalents were used in the following experiments.

Analytical methods: HPLC

Wavelength: 235 nm

Injection volume: 20 μΙ

Mobile phase: MeOH: H ₂ O (75: 25)

Column: Lichrosorb RP 18.10 μ

Flow rate: 0.9 ml / min.

EXAMPLE A 4 liter two-jacket reaction vessel was charged with 10 liters of THF (H ₂ O <0.1%) and 4 kg of bromoformylnarwedine-propylene glycol ketal and 10 liters of a 10% LiAlH 4 solution in THF was slowly added under mechanical stirring resulting in massive gas evolution. and the mixture reaches the reflux temperature. Synthetic air (80% nitrogen, 20% oxygen) is introduced at 50 ° C for 4 hours, using a gas inlet tube providing a flow rate of 10 L / min. Subsequently, 1200 ml of water and 1200 NaOH (15%) (with massive gas evolution, reflux) are added dropwise, further 5 liters of toluene are added and stirring is continued for 30 minutes at 60 ° C. , the precipitate is washed twice with 4 L of toluene / THF 1: 1 at 60 ° C, the solvent is removed from the combined organic phases using a 50 L rotary evaporator, the oily residue is removed with 12 L of 4N HCl and then heated at 60 ° C for 15 min. This is followed by two extractions with 4 L of ethyl acetate and the aqueous phase is added dropwise to 2.4 L of concentrated NH ₄ OH under vigorous mechanical stirring. The suspension is cooled to 0-5 ° C, filtered, washed with 2 x 2000 mL water and dry in vacuo (4 kPa, 70 ° C).

Yield: 2104.8 g (80.5% of theory).

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DC: CHCl 3 / MeOH (9: 1)

HPLC: content> 95%

Example 5

According to the procedure given in Example 4, bromoformylnarwedine-propylene glycol ketal is reduced in various batch sizes either in the presence of oxygen ("with O ₂ ") or in the absence ("without O ₂ ") of oxygen. The batch size, reaction times and yields are shown in Table 4.

Table 4

size charge Reaction time yield Reduction time yield (g educt) without O ₂ (Narwedine) with O ₂ narwedine 5 g 24 hours 80% 2 hours 80% 50 g 48 hours 72% 2-3 hours 82% 200 g 6 days 56% 3-4 hours 92% 800 g > 14 days 30% 3-4 hours 78% 4 kg - - 3-4 hours 80% 14 kg - - 3-4 hours 76%

The reaction scheme for the process of Examples 4 and 5 ("with O ₂ ") is as follows:

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Br CHO lie ₄ ä ^ ch ₃ o

YH.

/ HCl ch ₃ o

'CH.

rac. Narwedi n

31340 / H w M i Ίΐ spare side

PATENT CLAIMS

Claims (12)

A process for the reduction of aromatic halides of the general formula (I) Ar-Xn (I) wherein Ar is an aromatic group optionally substituted one or more times, optionally fused and optionally containing one or more heteroatoms selected from the group consisting of O, S, N, X is fluorine, chlorine, bromine and / or iodine and n is from 1 to 10, a hydride reagent as a reducing agent in the presence of oxygen to a compound of formula (II) Ar-Hn (II) wherein Ar and n have the same meaning as in formula (I), characterized in that diisobutylaluminium hydride, diisobutylaluminium hydride / ZnCl ₂ , Al-isopropylate, sodium bis (2-methoxy-ethoxy) are used as reducing agent -aluminium hydride, potassium-tri-sec-butylborohydride, lithium-tri-sec-butylborohydride, potassium m-trisiamylborohydride, lithium trisiamylborohydride, Li-tri-t-butoxy-AIH, Li-tri-ethoxy-AIH, 9- borabicyclo (3.3.1) nonane, lithium triethylborohydride, AIH ₃ . AlCl ₂ H or a combination of at least two of said reducing agents, that the reaction is carried out while avoiding moisture in the solvent and that oxygen is bubbled through or bubbled into the reaction mixture as a dried mixture of oxygen and inert gas. The method according to claim 1, characterized in that a LiAlH 4 surrogate is used as the reducing agent Method according to claim 1 or 2, characterized in that the inert gas is nitrogen or a noble gas, in particular argon or helium. Method according to any one of claims 1 to 3, characterized in that the oxygen-containing mixture is a mixture of 20% oxygen and 80% inert gas. Method according to either of Claims 1 or 2, characterized in that the oxygen-containing mixture is air. Method according to one of claims 1 to 5, characterized in that the oxygen-containing mixture contains a solvent in which the reduction is carried out, in particular it is saturated with the solvent. Process according to any one of claims 1 to 6, characterized in that a compound of formula (I) wherein X is bromine is reduced. A process according to any one of claims 1 to 7, characterized in that the compound of formula (I) wherein Ar is a narwedine type group is reduced. The method according to claims 7 and 8, characterized in that bromarwedine is reduced. Method according to claim 9, characterized in that bromobededetetal is reduced. Process according to claim 10, characterized in that the bromoarwedine-propylene glycol ketal of the formula Br is reduced. CH. A process for the preparation of narwedine, characterized in that bromoformylnarwedine, in particular bromoformylnarwedine ketal, is reduced by a reducing agent, in particular by one of the reducing agents according to claims 1 and 2, in the absence of oxygen to 2 in the presence of oxygen to narwedine, in particular narwedinketal, and that any ketal protecting group present is cleaved off.