EP0983215A1

EP0983215A1 - Reduction of aromatic halogenides

Info

Publication number: EP0983215A1
Application number: EP98916623A
Authority: EP
Inventors: Laszlo Czollner; Johannes Fröhlich; Ulrich Jordis; Bernhard Küenburg
Original assignee: Sanochemia Pharmazeutika AG
Current assignee: Sanochemia Pharmazeutika AG
Priority date: 1997-05-21
Filing date: 1998-04-30
Publication date: 2000-03-08
Also published as: PL336906A1; KR20010012795A; ATA86597A; HUP0004681A2; NO995494D0; CA2289992A1; BG103880A; AU7012798A; JP2001525828A; AT405051B; NO995494L; CN1257467A; SK158399A3; WO1998052885A1; NZ500733A; BR9809661A

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

Reduction of aromatic halides

The invention relates to a process for the reduction of aromatic halides.

Numerous processes are known for the reduction of aromatic halides.

For the reduction of aromatic halides, reducing agents, such as Cr (C10 ₄ ) ₂ / ethylenediamine [880SColl6 / 821], tin / HBr [550SColl3 / l32], the catalytic reduction with Raney nickel 91CEX109] or Pd / hydrazine hydrate [ 59JOC421], further reducing agents such as K-Selectride / Cul [NaBH ₄ / (Me ₃ Si) ₃ SiH [89TL2733], iAlH ₄ [83JA631, 82TL1643, 59JOC917, 59JOC917, 89TH3329], or similar complex hydrides such as LiAlH (OMe) ₃ / CuI [73JA6452] known. The reducing agent LiAlH ₄ was often used together with catalytic or stoichiometric amounts of inorganic halides such as CeCl ₃ [85CL1491], TiCl ₄ [73CL291], FeCl _{2 /} CoCl ₂ , TiCl ₃ , NiCl ₂ [78JOC1263] or at most through these additions other reducing agents produced. The simultaneous exposure [83CC907] or the use of ultrasound [82TL1643] in the reduction of aromatic halides are known as further variants of the use of iAlH ₄ . For the information in square brackets: see the list of references.

Despite the large number of known processes, there are always cases in practice in which the reduction with LiAlH ₄ proceeds slowly and / or with unsatisfactory yields. Despite prolonging the reduction times, using a larger molar excess of LiAlH ₄ , changing the solvents (for example using tetrahydrofuran instead of diethyl ether), increasing the reaction temperature, in particular with larger batches, difficulties, reduced yields and side reactions occur. Other substituents present in the compound to be reduced are often incompatible with catalytic reduction methods or with nascent hydrogen. Other complex hydrides or hydride reagents are often not sufficiently reactive compared to LiAlH ₄ to reduce aromatic halides in satisfactory yields. The invention has for its object to provide a process for the reduction of aromatic and heteroaromatic halides with which the reduction can be carried out more quickly and in high yields even when working in larger batches.

This object is achieved according to the invention with the method of claim 1.

Preferred and advantageous embodiments of the method according to the invention are the subject of the dependent claims.

Many reducing agents can be used within the scope of the invention. Examples of reducing agents that can be used are: hydride reagents such as DiBAL-H (diisobutylaluminum hydride), DiBAL-H / ZnCl ₂ , Al-isopropylate, Red-Al ^R (sodium bis (2-methoxyethoxy) aluminum hydride (Aldrich)), K- Selectride ^R (potassium tri-sec.-butyl borohydride (Aldrich)), L-Selectride ^R (lithium tri-sec.-butyl borohydride (Aldrich)), KS-Selectride ^R (potassium trisiamyl borohydride (Aldrich)), LS -Selectride ^R (lithium-trisiamylborohydride (Aldrich)), Li-tri-t-butoxy-AlH, Li-tri-ethoxy-AlH, 9BBN

(9-borabicyclo (3.3.1) onan), super hydride ^R (lithium triethyl borohydride (Aldrich)), NaBH ₄ , Zn (BH ₄ ) ₂ , A1H ₃ ^• A1C1 ₂ H or one

Combination of these reducing agents, with LiAlH _{4 being} preferred.

In the process of the invention, (hetero-) aromatic halides are reduced with a reducing agent, in particular LiAlH _4f in the presence of oxygen, for example air, or an oxygen / inert gas mixture. In contrast to the commonly used reaction instructions for reducing agents, such as LiAlH ₄ , which are used under inert gas (for example nitrogen, argon, helium), oxygen, which may be diluted with an inert gas, is blown into the reaction solution or sucked through. The reduction times can thereby be shortened and the yields reproducibly increased.

The invention provides an efficient and industrially applicable process for the reduction of (hetero) aromatic halides with a reducing agent, such as LiAlH ₄ , in the presence of oxygen.

The reduction according to the invention proceeds, for example, according to the following scheme:

Scheme 1:

LiAlH _4/0 ₂

(Het) Ar X (Het) Ar - - H

LiAlH _4/0 ₂

(Het) Ar - X _n> (Het) Ar - - H.

The reduction of aromatic halogen compounds is significantly accelerated by introducing oxygen, in particular (synthetic) air, into a solution of the halogenated aromatic and the reducing agent in a solvent. In many cases the reduction of (hetero) aromatic halogen compounds is made possible, which cannot be reduced with LiAlH ₄ alone. Further advantages of the presence of oxygen or air in the reduction are the higher achievable yields and less undesirable by-products which arise from long reaction times (without oxygen).

In addition to the general usability of the reduction method according to the invention on a laboratory scale, the method of the invention is particularly suitable for the reduction of compounds of the bromine-narwedin type (see scheme 2) on a kilogram scale and for the economical reduction of large quantities.

All of this is surprising since it was not expected that one

Reduction under oxidative conditions, i.e. in the presence of an oxidizing agent such as oxygen, would proceed smoothly.

Scheme 2:

The following scheme 3 shows further examples of the reduction according to the invention.

Scheme 3:

Example 1 -X-naphthalene Example: n-X-thiophene

The method according to the invention has i.a. the advantage that the reaction time is reduced when reducing (hetero) aromatic halides. To show this, several halogen-substituted aromatics and heteroaromatics with and without oxygen were reduced in a direct comparison and different batch sizes of a reaction (bromine-narwedinketal) with and without oxygen were examined (Table 1).

Table 1:

Educt product reaction time reaction time (5 g batch) with 0 ₂ (up to without 0 ₂ (up to a conversion a conversion greater than greater than 99%, determined 99%, determined by HPLC) by 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

Bromformylnarwedin-Narwedin 2-3 hours 24 hours propylene glycol ketal

(50 g)

- "- (200 g) Narwedin 3-4 hours> 48 hours

- "- (800 g) Narwedin 3-4 hours> 14 days

- "- (14 kg) Narwedin 3-4 hours no attempt

Instead of (technically pure) oxygen, mixtures of oxygen with one or more inert gases (such as nitrogen, argon, helium) can be used in the invention.

In the context of the invention, preference is given to blowing in synthetic air (mixture nitrogen / oxygen 80:20) or sucking in dried ambient air. When sucking in room air, it is advantageous if the air is dried, as otherwise the inlet pipe may stick. Reducing agents such as LiAlH ₄ would be consumed by moist air. Above all, the risk of ignition and explosion in (very) humid air cannot be excluded.

In the reduction of bromnarwedinketal with LiAlH ₄ to narwedin on a 50 g scale, a gas mixture of 95% N ₂ and 5% O was used, with complete conversion being achieved after 3 hours. The use of a gas mixture of 99% N ₂ and 1% 0 ₂ only gave complete conversion after 7 hours in a batch of the same size.

It has also proven convenient to pass the air through a gas wash bottle so that it can be used To saturate solvents (eg THF) in order not to cause loss of solvent by blowing out and to continuously add solvents. Operating the reflux cooler with cooling brine at -40 ° C also significantly reduces solvent loss.

Experiments have shown that an excess of reducing agent, such as LiAlH ₄ , is advantageous since, for example, LiAlH ₄ is decomposed by air and forms unreactive oxides. A sufficiently large excess of reducing agent, such as LiAlH ₄ , should therefore be used to ensure that sufficient active reducing agent, such as LiAlH _4, is available in the reaction mixture. Experiments with 1 equivalent of LiAlH ₄ (= 4 equivalents of hydrides) on monohalogenated thiophenes did not give a complete conversion, whereas 100% conversion was easily achieved with 2 equivalents. In contrast, naphthalene derivatives, especially 1-bromo and 1-iodonaphthalene, already give complete conversion with 1 equivalent of LiAlH ₄ and air. Technical approaches to the reduction to Narwedin were successfully completed with 1.5 equivalents after 3 hours. With 1.3 equivalents, complete conversion was still not achieved after 6 hours, since this reduction also requires LiAlH ₄ to reduce the formyl group (Scheme 2).

Examples of the method of the invention and comparative experiments are described below.

Example 1:

9.7 ml of LiAlH ₄ (10% in THF, 24 mmol) were added dropwise to a solution of 5 g of 1-bromonaphthalene (24 mmol) in 40 ml of THF and air at 50 ° C. for 4 hours through a drying tube filled with CaCl ₂ and sucked a gas wash bottle filled with THF. After 4 hours a thin layer chromatogram showed complete conversion. Now it was decomposed with 5 ml of water and 5 ml of saturated NaHC0 ₃ solution, the precipitate was filtered off with suction and washed twice with hot THF. The filtrate was evaporated and the crude product was recrystallized from ether: 2.42 g of naphthalene, as colorless crystals (78% of theory). Thin layer chromato- grams: petroleum ether (run twice).

Comparative experiment 1:

9.7 ml of LiAlH ₄ (10% in THF, 24 mmol) were added dropwise to a solution of 5 g of 1-bromonaphthalene (24 mmol) in 40 ml of THF and the mixture was stirred at 50 ° C. under a gentle stream of argon. After 4 hours, a thin layer chromatogram showed approximately 25% conversion. After 24 hours 50% sales. Working up (analogous to Example 1 above) and column chromatography (100 g of silica gel 60, hexane) gave: 0.95 g of bromonaphthalene and 1.2 g of naphthalene.

Example 2:

1.5 equivalents of LiAlH ₄ in THF (10%) were added to a solution of 100 ml of THF and 5 g of 1-halonaphthalene and the mixture was stirred at 50.degree. Synthetic air (80% N ₂ , 20% O ₂ ) was bubbled into the solution at a rate of 50 ml per minute with vigorous magnetic stirring. THF was continuously added dropwise in order to keep the volume constant. About 1 ml of sample was taken for analysis, decomposed with 5 ml of water and extracted with 2 ml of hexane. The hexane phase was used for gas chromatography analysis. About 0.5 ml of the organic phase is pipetted into a gas chromatography sample tube using a syringe with the interposition of a filter between the syringe and syringe needle, and the remaining volume of the sample tube is filled up with petroleum ether.

Comparative experiment 2:

1.5 equivalents of LiAlH ₄ in THF (10%) were added to a solution of 100 ml of THF and 5 g of 1-halonaphthalene and the mixture was stirred at 50 ^* ^ 0 under N ₂ . About 1 ml of sample was taken for analysis, decomposed with 5 ml of water and extracted with 2 ml of hexane. The hexane phase was used for gas chromatography analysis. About 0.5 ml of the organic phase is pipetted into a gas chromatography sample tube using a syringe with the interposition of a filter between the syringe and syringe needle, and the remaining volume of the sample tube is filled up with petroleum ether. 1-Fluoro, 1-chloro, 1-bromo and 1-iodo-naphthalene were reduced by the methods given in Example 2 and in Comparative Experiment 2. The results are summarized in Table 2.

Table 2:

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

Gas 1 hour 2 hours 4 hours 8 hours 16 hours

Educt prod. Educt prod. Educt prod. Educt prod. Educt prod.

N ₂ 89 11 83 17 80 20 73 27 66 34

0 ₂ 52 48 29 71 13 87 1 99 Cl N ₂ 87 13 81 19 77 23 64 36 50 50

0 ₂ 26 64 2 98 00 100

Br N ₂ 83 17 76 24 70 30 52 48 48 62

0 ₂ 30 70 1.5 98.5 00 100

N, 52 48 39 61 30 70 18 82 12 88

O, 1.5 98.2 00 100

Note on table 2:

N ₂ = continuous nitrogen flow through the solution

0 ₂ = continuous flow of "synthetic air" (80% N ₂ , 20% 0 ₂ ) through the solution

Analysis: gas chromatography: HP 5890 column: silica gel, Permabond OV1 DF 0.25

Temperature program: Initial temperature: 50 ° C for 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:

1.0 g of halothiophene was placed in 10 ml of anhydrous THF and 1 (later 2) equivalent of LiAlH ₄ solution (1 mmol in THF) was added. Now 10-20 ml synthetic air (N _2/0 ₂ 80:20) was heated to the specified reaction temperature and vigorous, magnetic stirring passed through. After the specified time, 0.5 ml of solution was hydrolyzed with 10 ml of HCl 2N, extracted twice with 5 ml of diethyl ether and diluted with 30 ml of methanol. This solution was used directly for the content determination by means of HPLC (high pressure liquid chromatography).

Comparative experiment 3:

1.0 g of halothiophene were placed in 10 ml of anhydrous THF and 1 (later 2) equivalent of LiAlH ₄ solution (1 mol in THF) was added. The mixture was then heated to the reaction temperature given and stirred under N ₂ . After the specified time, 0.5 ml of solution was hydrolyzed with 10 ml of HCl 2N, extracted twice with 5 ml of diethyl ether and diluted with 30 ml of methanol.

This solution was used directly for the content determination by means of HPLC (high pressure liquid chromatography).

According to the procedures given in Example 3 and Comparative Example 3, n-X-thiophenes were reduced. The results are summarized in Table 3.

Table 3:

Reduction of n-X-thiophene (n = 2, 3 X = C1, Br)

X Gas Temp. Time 1 Time 2 Time 3 Time 4 Time 5 Notes in ° C each indication of the educt in%

2-Br 1 h 2 h 17.5 h 22.5 h 90 h

N, 50 23% 46% 83% 96% 100%

0.5 h 1 h 2 h 3.25 h 8.25 h O ₂ 50 46% 65% 74% THF deficiency ^*

1 h 2 h 4 h 19.25 h 45.5 h

N ₂ 30 17% 26% 33% 65% 100%

0.5 h 1 h 2.25 h 4 8.25 equiv. ^*

LiAIH ₄ consumed

O ₂ 30 52% 58% 58% - -

3-Br 0.5 h 2 h 7.75 h 29 h

N ₂ 30 21% 31% 36% 100% 2 equiv. LiAIH ₄ 0.5 h 1 h 2 h

0 ₂ 30 74% 100% 100% 2 equiv.

LiAIH ₄

2-CI 1 h 2 h 7.8 h 29 h 120 h

N ₂ 30 0% 6% 25% 48% 96% 2 equiv. LiAIH ₄ 0.1 h 1 h 2 h 3.5 h

0 ₂ 30 35% 59 94% 100% 2 equiv. LiAIH ₄

3-CI 1 h 3 h 8.5 h 32 h 95 h

N ₂ 30 8% 9% 8% 17% 44% 2 equiv. LiAIH ₄

0.5 h 1 h 2 h 4 h 5.5 h

0 ₂ 30 12% 21% 36% 42% 50% 2 equiv. LiAIH ₄

* Initially, too much THF was evaporated by the air flow at 50 ° C. The temperature was reduced to 30 ° C. Furthermore, the LiAlH _{4 is} consumed by oxygen, so that 1 equivalent of LiAlH _{4 is} too little when using air. Subsequently, two equivalents were used.

Analytics: HPLC

Wavelength: 235 nm

Feed volume 20 μl

Eluent: MeOH: H ₂ 0 (75:25)

Column: Lichrosorb RP 18, 10 μ flow: 0.9 ml / min. Example 4:

10 l of THF (H ₂ 0 <0.1%) and 4 kg of bromoformylnarwedin-propylene glycol ketal are placed in a 30 l double-jacketed vessel and slowly 10 liters with mechanical stirring. LiAlH ₄ solution (10%) in THF is added, initially violent gas evolution occurs and the reflux temperature is reached. Now synthetic air (80% nitrogen, 20% oxygen) is introduced for 4 hours at 50 ° C through a gas inlet tube with a volume flow of 10 1 / min. Then 1200 ml of water and 1200 ml of NaOH (15%) are added dropwise (violent gas evolution, reflux), 5 lit. Toluene added and stirred at 60 ° C for 30 min. The reaction mixture is filtered hot through a pressure filter, the precipitate twice with 4 lit. Washed toluene / THF 1: 1 at 60 ° C, the combined organic phases on 50 lit. Rotovap evaporated, the oily residue with 12 lit. 4N HCl was added and heated to 60 ° C for 15 min. Now with 2 lit. EtOAc extracted and the aqueous phase to 2.4 lit. conc. NH ₄ OH dropped. The suspension is cooled to 0-5 ° C, filtered, washed 2 × 2000 ml of water and dried in vacuo (40 mBar, 70 ° C): 2104.8 g (80.5% of theory). TLC: CHCl ₃ / MeOH (9: 1) HPLC: content> 95%

Example 5:

According to the procedure given in Example 4, bromformylnarwedin-propylene glycol ketal was reduced in various sizes in the presence of oxygen ("with 0 ₂ ") and in the absence of oxygen ("without 0 ₂ "). The batches, the reaction times and the yields are shown in Table 4.

Table 4:

Approach Reaction time Yield Reduction time Yield (g educt) (without 0 ₂ ) (Narwedin) (with 0 ₂ ) (Narwedin)

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%

4000 g - - 3-4 hours 80%

14 kg - - 3-4 hours 76%

The reaction scheme of the procedure of Examples 4 and 5 ("with 0 ₂ ") is given below.

rac. Nar edi n

Literature:

[550SCO113 / 132] Koelsch, CF Org. Synth. Coll. Vol. III, 132 (1954), Sn / HBr [59JOC421] Mosby, WLJOrg. Chem. 24, 421 (1959), Pd / N ₂ H ₄ .H ₂ 0 [59JOC917] Benington, F ^ _ Morin, RD; Clarck Jr., LCJ Org., Chem. 24, 917 (1959), LiAlH ₄ [59JOC917] Szewcyk, J., Lewin, AH; Carrol, FIJ Heterocycl., Chem. 25, 1809 (1988), LiAlH ₄ on bromformylnarwedin 53% I

[73CL291] Mukaiyama, T.; Hayashi, M.; Narasaka, K.Chem.Lett, 291, (1973) LiAlH ₄ / TiCl ₄ [73JA6452] Masumane, S. ; Rossey, PA; Bates, GSJ Am. Chem.Soc. 95, 6452, 1973, LiAlH (OMe) ₃ / CuI [74CC762] Yoshida, T., Negishi, EJ Chem. Soc. Chem. Commun., 762 (1994), K-Selectrid / Cul

[78JOC1263] Ashby, EC, Lin. JJJOrg. Chem. 43, 1263 (1978), LiAlH ₄ / FeCl ₂ , CoCl ₂ , TiCl ₃ , NiCl ₂

[82TL1643] Han, BH, Boudjouk, P .; Terahedron Lett. 23, 1643 (1982), LiAlH ₄

[82TL1643] Han, BH; Boudjouk, P Tetrahedron Lett. 23, 1643 (1982), LiAlH ₄ / ultrasound

[83CC907] Beckwith, LJ Goh. SH J, Chem. Soc. Chem. Commun. 907 (1983), LiAlH ₄ / liv [83JA631] Falck, JR Manna, Sj Am. Chem. Soc. 105, 631 (1983), LiAlH ₄

[880SCO116 / 82I] Wade, RS Castro, CE Org. Synth. Coll .Vol. VI, 821 (1988), Cr (Cl0 ₄ ) ₂ / H ₂ N (CH ₂ ) ₂ NH ₂

[89TL2733] Lesage, M. Chatgilialoglu, C. Griller, D. Tetrahedron Lett. 30, 2733 (1989), (Me ₃ Si) ₃ SiH

[89TH3329] Vlahov, R. Krikorian, D. Spassov, G. Chino va, M; , LiAlH ₄ on bromine,

Vlahov, I. Parushev, S. Snatzke, G. Ernst L. Kieslich, K.,

Abraham, W.-R. Sheldrick, W.S. Tetrahedron 45, 3329 (1989), galantaminone 96%

[85CL1491] Imamoto, T. Takeyama, T. Kusumoto, T. Chem. Lett. 1491, (1985) LiAlH ₄ / CeCl ₃ [91CEX109] Nishiyama, T. Kameopka, H. Chem. Express 6

(2) 109, 112 (1991) Raney-Ni / H ₃

Claims

Claims:

1. Process for the reduction of aromatic halides of the general formula (I)

Ar X n (I)

wherein Ar is an aromatic group, optionally mono- or polysubstituted, optionally fused and optionally containing one or more heteroatoms (0, S, N), X is fluorine, chlorine, bromine and / or J and n is 1 to 10, with a Reducing agent to a compound of general formula (II)

Ar - H _n , (II)

wherein Ar and n have the meanings given above for formula (I), characterized in that the reduction is carried out in the presence of oxygen.

2. The method according to claim 1, characterized in that a hydride reagent, such as DiBAL-H, DiBAL-H / ZnCl ₂ , Al-isopropylate, Red-A1 ^R , K-Selectride ^R , L-Selectride ^R , KS-Selectride as reducing agent ^R , LS-Selectride ^R , Li-tri-t-butoxy-AIH, Li-tri-ethoxy-AlH, 9BBN, Super-Hydride ^R , NaBH ₄ , Zn (BH ₄ ) ₂ , AlH ₃ ^• A1C1 ₂ H or one Combination of at least two of the aforementioned reducing agents is used.

3. The method according to claim 2, characterized in that LiAlH _{4 is} used as the reducing agent.

4. The method according to any one of claims 1 to 3, characterized in that oxygen is added to the reaction mixture as pure oxygen.

5. The method according to any one of claims 1 to 3, characterized in that oxygen is added to the reaction mixture as a mixture of oxygen and an inert gas becomes .

6. The method according to claim 5, characterized in that the inert gas is nitrogen or a noble gas, in particular argon or helium.

7. The method according to claim 5, characterized in that the oxygen mixture is a mixture of 20% oxygen and 80% inert gas.

8. The method according to claim 5, characterized in that the oxygen mixture is air.

9. The method according to any one of claims 1 to 8, characterized in that dried oxygen or a dried oxygen mixture is used.

10. The method according to any one of claims 1 to 9, characterized in that the reduction is carried out in a solvent and that the oxygen or the oxygen mixture contains the solvent, in particular is saturated with the solvent.

11. The method according to any one of claims 1 to 10, characterized in that a compound of general

Formula (I) is reduced, in which X is bromine.

12. The method according to any one of claims 1 to 11, characterized in that a compound of general formula (I) is reduced, in which Ar is a group of

Narwedin type means.

13. The method according to claim 11 and 12, characterized in that bromnarwedin is reduced.

14. The method according to claim 13, characterized in that Bromnarwedinketal is reduced.

15. The method according to claim 14, characterized in that bromnarwedin propylene glycol ketal of the formula

is reduced.

16. A process for the preparation of narwedin, characterized in that bromformylnarwedin, in particular bromoformylnarwedinketal, with a reducing agent, in particular with one of the reducing agents of claims 2 and 3 in the absence of oxygen to bromnarwedin, in particular bromnarwedinketal, and the latter with a reducing agent, in particular is reduced with one of the reducing agents of claims 2 and 3 in the presence of oxygen to narwedin, in particular narwedinketal, and that any ketal protective group that may be present is split off.