CZ411699A3 - Reduction process of aromatic halides - Google Patents

Abstract

For the reduction of aromatic halides of formula Ar-X ", wherein Ar represents an aromatic group, optionally once or multiple-substituted, optionally fused and optionally containing one or more heteroatoms from the group including O, S, N; X denotes fluorine, chlorine, bromine and / or iodine and n is from 1 to 10, to compounds of formula Ar-EJ ' it uses a reducing agent such as diisobutylaluminum hydride or lithium aluminum hydride in the presence of oxygen, especially in the form of an oxygen mixture with inert gas and to prevent moisture access in a solvent. Reduction with LiAlH4 in presence oxygen suitable for heteroaromatic reductions halides, for example to reduce bromnarwedinketal to narwedinketal on a production scale.

Description

Technical field

The invention relates to a method for reducing aromatic halides.

BACKGROUND OF THE INVENTION

Various methods are known for reducing aromatic halides.

The following reducing agents are known for the reduction of aromatic halides:

Cr (010 ^ 2 / ethylene diamine (Vada, R. S. Castro, CE Org Synth Coli Vol. VI, 821 (1988), Cr (C10 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 / Hg) or Pd / hydrazine hydrate (Mosby, VLJ Org Chem. 24, 421 (1959), Pd / N ₂ H ₄ .H ₂ O), reducing agents such as K-selectride / CuJ (Yoshida T, Negishi, EJ Chem. Soc. Chem. Commun, 762 (1994), K-Selectrid / CuI), [NaBH 4 / MegSi] 3 S 1 H (Lesage, N Chatgilialoglu, C Griller Tetrahedron Lett.

30, 2733 (1989), (Ne ^ Si) g SiH), L1AIH4 [(Falck, JR Nanna, SJ Am Chem.Soc 105, 631 (1983), L1AIH4)], (Han, BH; Boudjouk, P; Tetrahedron Lett 23 1643 (1982), L1AIH4), (Benington, F .; Norin, RD; Clarck Zr LCJ Org., Chem 24,

917 (19S9), L1AIH4), (Szewcyk, J, Lewin, A. H; Carrol.,

F. I. J. Heterocycl, Chem. 25, 1809 (1988), LiAlH4-am

Bromformylnarwedine 53%. (I), (Vlahov, R. Krikorian,

D Spassov, G Chinova, M; L1AIH4 an Brom, Vlahov,

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

N -R. Sheldrick, VS Tetrahedron 45, 3329 (1989), Galanthaminone 96%] or similar complex hydrides such as LiAlH 4 (OMe) 3 / CuJ (Masumane, S; Rossey, PA; Bates, GS J. Am Chem. Soc 95, 6452, 1973, LiAlH (OMe) ₃ / CuI). L1AIH4 is often used as a reducing agent together with inorganic halides such as CeCl3 (Imamoto, T Takeyama, T Kusumoto, T. Chem I.ett. 1491, (1985), LiAlH4 / CeClg), T1Cl4 (Mukaiyama,

T; Hayashi, M .; Narasaka, K. Chem Lett, 291, (1973) LiAlH 4 / TiCl 4), FeCl ₂ , CoCl ₂ , TiCl ₃ , NiCl ₂ (Ashby, EC, Lin JJJ Org Chem 43, 1263 (1978), LiAlH ₄ / FeCl ₂ , CoCl ₂ , TiCl ₃ , NiCl ₂ ) in catalytic or stoichiometric amounts. Additional reducing agents were prepared by these additions. Methods for the reduction of 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), LiAlH 4 / IV) or ultrasound (Han, BH; Boudjouk, P Tetrahedron). Lett 23, 1643 (1982), LiAlH 4 / Ultraschall).

In B. Menuir Reduction of aromatic halides with sodium borohydride catalysed by titanium complexes. Unexpected role of air in Journal of Organometalic Chemistry, Volume 204, No. 3, Jan. 20, 1981, Lausanne, CH, pp. 345-346, describes a method for reducing aromatic halides using NaB 4, which is catalyzed by Cp. ₂ TiCl ₂ or CpTiCl _3, přítomnoati air. However, only aromatic iodides are reduced in this known manner, for example chlorine and bromine cannot be reduced.

EP 0 370 325 A discloses a process for the reductive dehalogenation of aromatics by treating halogenated aromatics with Raney2 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, An Improved Synthesis of Galanthamine, Journal of Heterocyclic Chemistry, Vol. 25, No. 6, 199, pp. 1809-1811, describes a process for debromination of bromoformylnarwedine at a batch of 3.0 g by refluxing in tetrahydrofuran for 12 hours. A mixture of galanthamine and epigalanthamine is thus obtained in a yield of 53%.

The presence of air is not explicitly 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 L 1 AlH 4, changing the solvent (eg using tetrahydrofuran instead of diethyl ether), increasing the reaction temperature often leads to problems associated with undesirable side reactions and lower yields 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 as compared to LiAlH4 and do not provide sufficient yields in the reduction of aromatic halogens.

9 ·

9 99 d.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for reducing aromatic and heteroaromatic halides which allows 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 (I) in which

Ar represents an aromatic group which is optionally mono- or polysubstituted, optionally fused and optionally contains one or more heteroatoms from the group consisting of O, S, N,

X is fluorine, chlorine, bromine and / or iodine and n is 1 to 10, with a reducing agent to the compound of formula (II)

Ar - H _n (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 agents such as DiBAL-H (diisobutylaluminium hydride), DiBAL-H / ZnCl 2, Al-isopropylate, Red-Al 2 (sodium- (bis- (2-methoxyethoxy) aluminum hydride) (Aldrich )), K-Selectride (potassium tri-sec-butyl borohydride (Aldrich)), L-Selectride (lithium tri-sec-butyl borohydride (Aldrich)), KS-Selectride (potassium trisiamyl borohydride (Aldrich)) ), LS-Selectride (lithium tri-thiamylborohydride (Aldrich)), Li-tri-t-butoxy-αΙΗ, Li-tri-t-ethoxy-AlH, 9BBN (9-borabicyclo [3.3.1] nonane), Super- Hydride 4 (lithium triethyl borohydride (Aldrich)), NaBH 4, Zn (BH 4, AlH 4, AlCl 2 H or a combination of these reducing agents, with L 1 AlH 4 being preferred.

The process according to the invention consists in reducing (hetero) aromatic halides with a reducing agent, in particular L 1 AlH 4, in the presence of oxygen, for example air or mixtures of oxygen and inert gas. In contrast to 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 makes it possible to shorten the reaction times and reproducibly increase the yields.

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

According to the invention, the reduction process proceeds according to the following

φ φ · φ φ φ φ φ φ φ φ φ φ φ φ

The following reaction scheme: Scheme 1: (Het) Ar-X LIA1H ₄ / O ₂ ---------> (Het) Ar-H (Het) Ar - X _n LIA1H ₄ / O ₂ -------__> (Het) Ar - H _n

By introducing oxygen, in particular (synthetic) air, into a solution containing halogenated aromatics and a reducing agent in a solvent, the reduction of aromatic halogen compounds is greatly accelerated. In many cases, it is possible to reduce (hetero) aromatic halogen compounds which, for example, cannot be reduced by LiAlH ₄ alone. A further advantage of the presence of oxygen or air in the reduction is that it is possible to achieve higher yields and to suppress 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 the reduction of bromo-narwedine-type compounds (see Scheme 2) on a kilogram scale and for economical reduction of industrial quantities.

These facts are surprising since 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.

000 000 0 0 0

Scheme 2:

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

Scheme 3:

Example 1-X-Naphthalene

Example n-X-thiophene

1 / v

LiAIHyO ₂

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 have been reduced in direct comparison in the presence and absence of oxygen. Further, reactions (bromo-narwedinketal) in different sized reaction batches were monitored in the presence and absence of oxygen (Table 1).

• · »* * * * * * * * * * * *

Table 1

Edukt (5 g charge) Product Reaction time at presence of oxygen Time required to reach > 99% conversion by HPLC) Reaction time at absence of oxygen Time to achieve > 99% conversion, determined by HPLC) 1-Fluoraphthalene naphthalene 8 hours > 16 hours 1-Chlomaphthalene naphthalene 4 o'clock > 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 (50g) bromformylnarwedin- narwedin 3-4 hours > 48 hours propylene glycol ketal (200g) bromformylnarwedin- narwedin 3-4 hours > 14 days propylene glycol ketal (800g) bromformylnarwedin- narwedin 3-4 hours not specified propylene glycol ketal (14kg)

»» T t t t t t t t t t t t t t t t t t t t t

Mixtures of oxygen with one or more inert gases (such as nitrogen, argon or helium) may be used in place of oxygen (technical grade) according to the invention.

According to the present invention, it is preferable either to inject synthetic air (80:20 nitrogen / oxygen mixture) into the reaction mixture or by suctioning ambient air. If ambient air is sucked in, it is preferable to dry it to prevent deposits in the lance. Moist air would consume a reducing agent such as L1AlH4. In particular, the risk of spontaneous ignition and explosion cannot be avoided when using (very) humid air.

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

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

Experiments have shown that it is also advantageous to use an excess of a reducing agent such as LiAlH 4, for example, just LiAlH 4 decomposes in air to form non-reactive oxides. A sufficient excess of a reducing agent such as LiAlH 4 should be used to ensure sufficient

0 · ·· · · · · · · ·

An amount of a reducing agent, such as LiAlH 4, in the reaction mixture is present. Experiments with one equivalent of LiAlH 4 (= 4 equivalents of hydride) and monohalogenated thiophene compounds showed insufficient conversion, whereas with two equivalents 100% conversion was achieved without problems. In contrast, for naphthalene derivatives, mainly for 1-bromonaphthalene and 1-iodonaphthalene, complete conversion was achieved with one equivalent of LiAlH 4 and air. On an industrial scale, conversion to narwedine with 1.5 equivalents after 3 hours can be successfully accomplished. Using 1.3 equivalents, 100% conversion does not occur even after 6 hours, since this reduction also requires LiAlH 2 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 mL) is added dropwise to a solution of 5 g of 1-bromonaphthalene (24 mMol) in 40 mL of THF and air is sucked through a drying oven at 50 ° C for 4 h. a column packed with CaCl ₂ and a gas scrubber packed with THF. After 4 h, the reaction was complete by thin layer chromatography. The mixture was quenched by the addition of 5 mL of water and 5 mL of saturated aqueous NaHCO 3 solution, the precipitate was 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: petroleum ether • 4 »(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 the mixture was stirred at 50 ° C under a gentle stream of argon. After 4 hours, 25% conversion was demonstrated by thin layer chromatography. After 24 hours the conversion is 50%. 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.

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. The mixture is bubbled with synthetic air (80% N2, 20%

O2) at 50 ml / min with vigorous magnetic stirring. THF is constantly added dropwise 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 gas chromatography analysis. Approximately 0.5 ml of the organic phase is injected into a gas chromatography vial with a syringe fitted with a needle-syringe filter. Make up the remaining volume of the sample vial with light petroleum.

Comparative Example 2:

To a solution of 100 mL of THF and 5 g of 1-halonaphthalene was added 1.5 equivalents of LiAlH 4 in THF (10%) and the mixture was stirred at 50 ° C under N 2. · · •.... · Ί · I · I I I i · ·. Quench with 5 ml of water and extract with 2 ml of hexane. The hexane phase is used for gas chromatography analysis. Approximately 0.5 ml of the organic phase is pipetted into the gas chromatography vial with a syringe fitted with a needle-syringe filter. Make up the remaining volume of the sample vial with light petroleum.

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

Table 2

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

X Gas 1 hour 2 hours 4 o'clock 8 hours 16 hours Edukt Product Edukt Product Edukt Product Edukt Product Edukt Product F N ₂ 89 11 83 17 80 20 May 73 27 Mar: 6 6 34 0 ₂ 52 48 29 71 13 87 1 99 - - Cl n ₂ 87 13 81 19 Dec 77 23 64 36 50 50 0 ₂ 26 64 2 98 0 100 ALIGN! - - - . - Br n ₂ 83 17 76 24 70 30 52 48 48 62 0 ₂ 30 70 1.5 98.5 0 100 ALIGN! - - - - AND n ₂ 52 48 39 61 30 70 18 82 12 88 0 ₂ 1.5 98.2 0 100 ALIGN! - - - - - -

* «·

111 »

Notes to Table 2:

N2 = continuous stream of nitrogen through the solution

O2 = continuous flow of synthetic air (80% N2,% O2) through the solution

Analytical methods:

Gas chromatography: HP5890

Column: silica gel Permabond 0V1 DF 0.25

Temperature program: Initial temperature 50 ° C 1 min;

heating rate 10 ° C / min.

Retention times: Naphthalene 1-fluoro-naphthalene 1-chloro-naphthalene

1-Bromo-naphthalene 1-Iodo-naphthalene

5,2 min. 6.65 min 7.85 min 9.1 min.

10.5 min.

Example 3

One (later 2) equivalent of L1AlH4 solution (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 stirred vigorously 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).

φ * φ φ φ φ

ΦΦ · · · • ♦ • • • • • • • • • • • • • • • • • • • • • • • • •

Comparative Example 3:

One (later 2) equivalent of a solution of LiAlH 4 (1 Mole in THF) was added to 1.0 g of halothiophene in 10 mL of anhydrous THF. The mixture is brought to the reaction temperature and stirred vigorously with a magnetic stirrer while bubbling. After this time, 0.5 ml of the solution is 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.

4 44

4444 4444 9944

4,444 4,444

4444 · 4494 «

444 «« φ 4444

4444 44 4444 44

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 Comment Low: 14 ° C educt data in r% 2-Br n ₂ 50 1 h 2 h 17.5 22.5 90 h 23% 46% h h 100% 83% 96% o ₂ 50 0.5 h 1 h 2 h 3.25 8.25 not- 46% 65% 74% h h THF - - *) n ₂ 30 1 h 2 h 4 h 19.25 45.5 17% 26% 33% h h 65% 100% o ₂ 30 0.5 h 1 h 2.25 4 h 8.25 Spotre- 52% 58% h - h bován *) 58% - 1 eq. LiAlH ₄ 3-Br n ₂ 30 0.5 h 2 h 7.75 29 h 21% 31% h 100% - 36% o ₂ 30 0.5 h 1 h 2 h 74% 100% 100% - - 2-C1 n ₂ 30 1 h 2 h 7.8 29 120 h 2 eq. 0% 6% h h 96% LiAlH ₄ 25% 48% 0 ₂ 30 0.1 h i h 2 h 3,5 h 2 eq. 35% 59 94% 100% - LíA1H ₄ 3-C1 N ₂ 30 1 h 3 h 8.5 h 32 h 95 h 2 eq. 8% 9% 8% 17% 44% LíA1H ₄ 0 ₂ 30 0.5 h i h 2 h 4 h 5,5 h 2 eq. 12% 21% 36% 42% 50% LíA1H ₄

• ·

9 99

9 9 9

9 9 ♦

• ·

9 9

999

9 9

9999

*) Originally a 50 ° C air stream vaporized too much THF. The temperature was lowered to 30 ° C. In addition, LiAlH4 was consumed with oxygen, so that one equivalent of LiAlH4 is too little when using air. Therefore, two equivalents were used in subsequent experiments.

Analytical methods: HPLC

Wavelength: 235 nm

Injection volume: 20 μΐ

Mobile phase: MeOH: H ₂ 0 (75: 25)

Column: Lichrosorb RP 18, 10 μ

Flow rate: 0.9 ml / min.

Example 4 A two-tube liter reaction vessel was charged with 10 liters of THF (H ₂ 0 <0.1%) and 4 kg of bromoformylnarwedine-propylenglykoketalu and mechanical stirring is slowly added 10 l of 10% solution of LiAlH ^ in THF, whereupon a massive evolution of gas and the mixture reaches the reflux temperature. Synthetic air (80% nitrogen, 20% oxygen) was 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 ml of NaOH (15%) are added dropwise (with massive evolution of gas, reflux), further 5 liters of toluene are added and stirring is continued for 30 minutes at 60 ° C. The still hot reaction mixture was filtered through a pressure filter, the precipitate was washed twice with 4 L of toluene / THF 1: 1 at 60 ° C, the solvent was removed from the combined organic phases using a 50 L rotary evaporator, the oily residue was removed with 12 L of 4N. HCl and then heated to 60 ° C for 15 minutes. This is followed by two extractions with 4 L of ethyl acetate and the aqueous phase is added after 99

9 98 9 9

9 9 9 9 • 9 9 9 9 9 9 999 9 999 99 9

999 999 9999

9999 99 9999 99 99 drops to 2.4 liters of concentrated NH 4 OH with vigorous mechanical stirring. The suspension is cooled to 0-5 ° C, filtered, washed with 2 x 2000 mL water and dried under vacuum (4 kPa, 70 ° C).

Yield: 2104.8 g (80.5% of theory).

DC: CHCl ₃ / MeOH 9: 1

HPLC: content> 95%

Example 5

According to the protocol of Example 4, bromoformylnarwedine-propyleneeglycoketal is reduced in various batch sizes either from the presence of oxygen (with O2) or in the absence (without O2) of oxygen. The batch size, reaction times and yields are shown in Table 4.

TABLE 4

Size batch Reaction time Yield Reducing time Yield (g educt) Without O ₂ (narwedin) SO ₂ narwedin 5g 24 hours 80% 2 hours 80% 50g 48 hours 72% 2-3 hours 82% 200g 6 days 56% 3-4 hours 92% 800g > 14 days 30% 3-4 hours 78% 4kg - - 3-4 hours 80% 14kg - - 3-4 hours 76%

4 4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9999 99

The reaction scheme for the process of Examples 4 and 5 (with O2) is as follows:

Claims (13)

A process for the reduction of aromatic halides of the general formula (I) Ar - X _n (I) in which Ar represents an aromatic group which is optionally mono- or polysubstituted, optionally fused and optionally contains one or more heteroatoms from the group consisting of O, S, N, X denotes fluorine, chlorine, bromine and / or iodine and n denotes the number 1 to 10 with a hydride reagent as a reducing agent in the presence of oxygen to the compound of formula (II) Ar - H _n (II) wherein Ar and _n have the same meaning as in formula (I), characterized in that diisobutylaluminum hydride, diisobutylaluminum hydride / ZnCl 2 is used as reducing agent. Al-isopropylate, sodium bis (2-methoxy-ethoxy) aluminum hydride, potassium tri-sec-butylborohydride, lithium tri-sec-butylborohydride, potassium trisiamylborohydride, lithium trisiamylborohydride, Li-tri-t-butoxy -AlH, Li-tri-ethoxy-AlH, 9-borabicyclo (3.3.1) nonane, lithium-tri · lithium-tri 19 - »» »· bor bor bor ethyl bor bor ethyl bor bor bor bor bor bor bor bor ethyl borohydride, AIH3. AlCl3H 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. Process according to claim 1, characterized in that LiAlH 4 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. The method of claim 1 or 2, wherein the oxygen-containing composition is air. Method according to any one of claims 1 to 5, characterized in that the oxygen-containing mixture comprises a solvent in which the reduction is carried out, in particular saturated with a solvent. A method according to any one of claims 1 to 6, characterized in that a compound of formula (I) wherein X is bromine is reduced. 8. Method according to one of claims 1 to 7, φφ · · ΦΦ φφ ΦΦΦΦ ΦΦΦΦ φ φ φ φ φ Φ Φ ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ vyznačující vyznačující vyznačující vyznačující vyznačující vyznačující vyznačující vyznačující vyznačující φ vyznačující vyznačující vyznačující φ φ vyznačující vyznačující vyznačující φ φ φ φ φ φ φ Method according to claims 7 and 8, characterized in that: The process is characterized in that bromnarwedine is reduced. 10. A process according to claim 9, wherein the bromnarededetetal is reduced. Process according to claim 10, characterized in that the bromnarwedine-propylene glycol ketal of the formula 12. A process for the preparation of narwedine, characterized in that bromoformylnarwedine, in particular bromformylnarwedinketal, is reduced by a reducing agent, in particular one of the reducing agents according to claims 1 and 2, in the absence of oxygen to bromnarwedine, especially bromnarwedinketal. 2 in the presence of oxygen to narwedine, in particular narwedinketal, and that any ketal protecting group present is cleaved off. φφ φφ φφ φφ φφ φφ ΦΦΦΦ · φ · φ φ φ φ »» »» φ φ φ φ φ • φ φ φ φ 16. A process for the preparation of narwedine, characterized in that bromoformylnarwedine, in particular bromformylnarwedinketal, is reduced by a reducing agent, in particular one of the reducing agents according to claims 2 and 3, in the absence of oxygen to bromnarwedine, especially bromnarwedinketal. reducing agents according to claims 2 and 3, in the presence of oxygen to narwedine, in particular narwedinketal, and that the optionally present ketal protecting group is cleaved off.