CA2289992A1 - 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

REDUCTION OF AROMATIC HALOGENIDES
The invention concerns a method for the reduction of aromatic halides.
Several methods for the reduction of aromatic halides are known.
For the reduction of aromatic halides, reducing agents such as Cr(CI04)2/ethylene diamine [880SCol 16/821], Sn/HBr [SSOSColl3/132], catalytic reduction with Raney nickel [9I CE~C 109] or Pd/hydrazine hydrate [59JOC421 ], reducing agents such as K-selectride/CuJ
[77CC762], NaBH4/(Me3Si)3SiH [89TL2733], LiAlH4 [83JA631, 82TL1643, 59JOC917, 59JOC917, 89TH3329] or similar complex hydrides such as LiAlH4(OMe)3/CuJ
[73JA6452]
are known. The reducing agent lithium aluminum hydride has often been used together with anorganic halides in catalytic or stoechiometric amounts, such as CeCI3 [85CL1491], TiCl4 [73CL291], FeCl2, CoCl2, TiCl3, NiCl2 [78JOC1263], or else other reducing agents were generated by these additions. In reducing aromatic halides, known variants of the use of LiAlH4 are simultaneous photoirradiation [83CC907] or ultrasound [82TL1643].
The codes in square brackets refer to the list of literature references.
In B. Meunier, "Reduction of aromatic halides with sodium borohydrate catalysed by titanium complexes. Unexpected role of air" in Journal of Organometallic Chemistry, vol. 204(3), 345-346 [January 20, 1981, Lausanne, Switzerland]) a method for reducing aromatic halogenides is described in which NaBH4 which is catalyzed by Cp2TiC12 or CpTiCl3 in the presence of air. However only iodinated aromates are reduced by this known process, since for instance bromine and chlorine are not reduced.
In EP 0 370 325 A a method for the reductive dehalogenation of aromates by treatment of the halogenated aromates with Raney nickel and alkali formate in an aqueous alkaline medium, at 80 - 250°C and 1 to 100 bar is described. The presence of air in the reaction vessel is not excluded by this state of the art.

- la -J. Szewcyk "An improved synthesis of galanthamine", Journal of Heterocyclic Chemistry Vol.
25 Nr. 6, 199, p. 1809-1811 describes a process for debromination of bromoformylnarwedine in an amount of 3.0 grams by by boiling in THF for 12 hours under reflux. In this way a mixture of galanthamine and epigalanthamine is obtained with a 53% yield. The presence of air is not explicitly excluded in this literature document.
In spite of the number of known methods, in practice cases keep occurring where reduction with LiAlH4 proceeds slowly and/or with unsatisfactory yield. In spite of extending the reaction times, using a larger molar excess of LiAlH4, change of solvents (e.g., tetrahydrofuran instead of diethylether), or increasing the reaction temperature especially larger starting volumes often create problems, reduced yields and side reactions. Frequently, other additional substituents that are present in the compound that is subjected to reduction are not compatible with catalytic reduction methods or hydrogen in statu nascendi. Other complex hydrides or hydride reagents are often not reactive enough in comparison with LiAlH4 to reduce aromatic halogenides in satisfactory yields.

The invention allows to employ many reducing agents. Examples for reducing agents that can be used are: hydride reagents such as DiBAL-H (diisobutylaluminum hydride), DiBAL-H/ZnCl2, Al-isopropylate, Red-Al ~ (sodium bis-(2-methoxyethoxy)aluminum hydride (Aldrich)), K-selectride~ (potassium-tri-sec. butyl borohydride (Aldrich), L-selectrideC~
(lithium-tri-sec. butyl borohydride (Aldrich)), KS-selectride~ (potassium-tri-siamyl borohydride (Aldrich)), LS-selectride~ (lithium-tri-siamyl borohydride (Aldrich)), Li-tri-t-butoxy-AlH, Li-tri-t-ethoxy-A1H, 9BBN (9-boroabicyclo[3.3.1 Jnonan), Super-Hydride~ (lithium triethylborohydride (Aldrich)), NaBH4, Zn(BH4)2, A1H3.A1C12H or a combination of these reducing agents, LiAlH4 being preferred.
The method according to the invention consists in the reduction of (hetero)aromatic halides with a reducing agent, in particular LiAlH4, in the presence of oxygen, for instance of air or a mixture of oxygen and an inert gas. In contrast to commonly used reaction protocols for reducing agents such as LiAlH4, according to which one works under inert gases (for instance, nitrogen, argon or helium), oxygen which might be diluted with an inert gas is blown or sucked through the reaction mixture by pressure or suction. This allows to shorten the reaction times, and to increase the yields reproducibly.
The invention provides an efficient and industrially exploitable method for the reduction of (hetero)aromatic halides with a reducing agent, such as LiAlH4, in the presence of oxygen.
According to the invention, the reduction proceeds for example according to the following scheme:
Scheme 1:
LiAlHg/02 -(Het) Ar - X ---------> (Het) Ar - H
Li.AlH4 /02 .
(Het) Ar - Xn ___-_-___> (Het) Ar - Hn The introduction of air, in particular (synthetic) air, into a solution containing the aromatic halide and the reducing agent in a solvent the reduction of the aromatic halide compounds is significantly accelerated. In many cases it becomes possible to reduce (hetero)aromatic halides that are not amenable to reduction by, for example, LiAIH4 alone. Additional advantages of the presence of oxygen or air during reduction consist in the higher yields that are achieved and in diminished undesired side products, which are created during extended reaction time (without oxygen).
Besides the general applicability of the reduction method according to the invention on the scale of laboratory synthesis, the process of the invention is particularly suitable for the reduction of compounds of the bromonarwedine type (see scheme 2) on the kilogram scale, and for economic large-scale reductions.
x All this is surprising because it was not to be expected that a reduction would proceed without problems under oxidant conditions, i.e., in the presence of an oxidant such as oxygen.
Scheme 2:
CN30 11H4 fyl l~~ f H3~
,..... _ ~ - ~ ~E3 Further examples of reductions performed according to the invention are represented in the following scheme 3.

Scheme 3:
Example: 1-X-naphtaline Example: n-X-thiophene x H / \-s x LiAlH4/OZ / / LiAIH l0 ~ ~
S
One of the advantages of the method according to the invention is that the reaction time for reducing (hetero)aromatic halides is shortened. To demonstrate this, several aromatic and heteroaromatic compounds that were substituted by halogen were reduced with and without oxygen in direct comparison, and also varying reaction batch sizes of a reaction (bromo-narwedineketal) was investigated with and without oxygen (Table 1).
Table 1:
Compound (batch size, S Product Reaction time in the Reaction time in the grams) presence of oxygen absence of oxygen (time required to (time required to reach >99% turnover reach >99% turnover as determined by as determined by HPLC) HPLC) 1-fluoronaphtaline naphtaline8 hours > 16 hours 1-chloronaphtaline naphtaline4 hours > 16 hours 1-bromonaphtaline naphtaline2 hours > 16 hours 1-iodonaphtaline naphtaline1 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 bromoformylnarwedine narwedine 2-3 hours 24 hours propyleneglycol ketal (50 g) bromoformylnarwedine narwedine 3-4 hours >48 hours propyleneglycol ketal (200 g) bromoformylnarwedine narwedine 3-4 hours >14 days propyleneglycol ketal (800 g) bromoformylnarwedine narwedine 3-4 hours Not done propyleneglycol ketal ( 14 kg) _j_ Instead of technical grade oxygen, according to the invention mixtures of oxygen with one or more inert gases (such as nitrogen, argon or helium) can be used.
In the context of the invention, the introduction of synthetic air (nitrogen/oxygen mixture 80:20) into the reaction mixture by external pressure, or the introduction of ambient air by suction is preferred. If ambient air sucked through it is preferable to dry the air to avoid occlusion by deposits in the introduction pipe. Moist air would consume reducing agents, such as LiAlH4. In particular, the danger of spontaneous combustion and explosion cannot be ruled out with (very) moist air.
For the reduction of bromonarwedine ketal with LiAlH4 to narwedine on the 50 gram scale, a gas mixture of 95% N2 and 5% 02 was used, which resulted in completion of the reaction within 3 hours. Using a mixture of 99% N2 and 1 % 02 with the same batch size gave a complete reaction only after 7 hours.
Also, it was found advantageous to pass the air through a gas washing bottle to saturate the air with the solvent used (for instance, THF) to avoid loss of solvent by outblowing that would otherwise require to replenish solvent constantly. Cooling the condenser unit to -40°C using cooling brine also significantly reduces solvent loss.
Experiments have shown that an excess of reducing agent, such as LiAlH4, is advantageous because for instance, LiAlH4 is decomposed by air and forms non-reactive oxides. A sufficient excess of the reducing agent, such as LiAlH4, should therefor be used to guarantee the presence of sufficient amounts of active reducing agent, such as LiAlH4, in the reaction mixture. Trials with 1 equivalent of LiAlH4 ( = 4 equivalents of hydride) and monohalogenated thiophene compounds have shown incomplete yields, while 2 equivalents gave 100% turnover without problems. In contrast, for naphtaline derivatives, in particular 1-bromo- and 1-iodonaphtaline, the reaction went to completion with 1 equivalent LiAlH4 and air. On the technikum scale, the reaction to narwedine could be completed with 1.5 equivalents after 3 hours.
With 1.3 equivalents, complete turnover was still not reached after 6 hours because this reduction also requires LiAlH4 to reduce the formyl moiety (Scheme 2).
In the following examples for the method of the invention and comparative experiments are described.

A solution of 9.7 ml of LiAIH4 (10% in THF; 24 mMol) was added dropwise to a solution of S
g 1-bromonaphtaline (24 mMol) in 40 ml THF and at SO°C for 4 hours, air was sucked through a drying column filled with CaCl2 and a gas washing bottle filled with THF.
After 4 hours, thin-layer chromatography demonstrated completeness of the reaction. The mixture was decomposed by addition of S ml of water and S ml of saturated aquaeous NaHC03, the precipitate was filtered off, washed twice with hot THF. The filtrate was evaporated and the resultant crude product was recrystallized from ether: 2.42 g of naphtaline as colorless cyrstals (78% of the theoretical yield).
TLC:
petrol ether (two passages) Comparative Example 1 A solution of 9.7 ml of LiAlH4 (10% in THF; 24 mMol) was added dropwise to a solution of S
g 1-bromonaphtaline (24 mMol) in 40 ml THF, and the mixture was stirred at SO°C under a gentle argon stream. After 4 hours a thin-layer chromatogram demonstrated 2S% yield of the reaction.
After 24 hours, SO% yield. Work-up (according to Example 1 above) and column chromatography (100 g silicagel 60, hexan) gave 0.95 g bromonaphtaline and 1.2 g naphtaline.

To a solution of 100 ml THF and S g 1-halogenonaphtaline 1.S equivalents of LiAIH4 in THF
(10%) were added and the mixture stirred at SO°C. Synthetic air (80%
N2, 20% 02) was passed through the mixture at a rate of SO ml/min. under vigorous magnetic stirring. THF was constantly added dropwise to keep the volume constant. For analysis, approximately 1 ml sample was removed, decomposed with S ml of water, and extracted with 2 ml hexane. The hexane phase was used for analysis by gas chromatography. About O.S ml of the organic phase were into a gas chromatography sample vial using a syringe with a filter inserted between the needle and the syringe body, and the remaining volume of the sample vial was filled with petrol ether.
Comparative Example 2:
To a solution of 100 ml THF and S g 1-halogenonaphtaline 1.S equivalents of LiAIH4 in THF

( 10%) were added and the mixture stirred at 50°C under N2. For analysis, approximately 1 ml sample was removed, decomposed with 5 ml of water, and extracted with 2 ml hexane. The hexane phase was used for analysis by gas chromatography. About 0.5 ml of the organic phase were pipetted into a gas chromatography sample vial using a syringe with a filter inserted between the needle and the syringe body, and the remaining volume of the sample vial was filled with petrol ether.
1-fluoro-, 1-chloro-, 1-bromo- and 1-iodonaphtaline were reduced according to Example 2 and Comparative Example 2. The results are summarized in Table 2:
TABLE 2:
Reduction of 1-X-naphtaline (X = F, Cl, Br, J) X Gas 1 hour 2 4 8 l6 hours hours hours hours Educt oductEductProductEductProductEductProductEductProduct Pr Br N2 83 17 76 24 70 30 52 48 48 62 02 30 70 1.5 98.5 00 100 -- -- -- --_ 02 1.5 98.200 100 -- -- -- -- -- _-Remarks to Table 2:
N2 = continuous nitrogen stream through the solution 02 = continuous stream of "synthetic air" (80% N2, 20% 02) through the solution Analytical Methods: -Gas chromatography: HP 5890 Column: Silicagel Permabond OV 1 DF 0.25 Temperature Program: Starting temperature 50° C 1 min.; heating rate 10° C/min.
Retention times:
naphtaline 5.2 min.
1-fluoronaphtaline 6.65 min 1-chloronaphtaline 7.85 min.
1-bromonaphtaline 9.1 min.
1-iodonaphtaline 10.5 min.

_8_ One (later, 2) equivalents of LiAlH4 solution (1 mMol in THF) was added to 1.0 g of halogenthiophene in 10 ml anhydrous THF. The mixture was brought to the specified reaction temperature and vigorously magnetic stirred with a stirrer while 10-20 ml synthetic air (N2/02 80:20) were passed through it. After the specified time, 0.5 ml of the solution were hydrolyzed with 10 ml 2N HCI, extracted with 2 x 5 ml diethylether, and diluted with 30 ml methanol. This solution was then directly used for determination of content by HPLC (high-pressure liquid chromatography).
Comparative Example 3 One (later 2, ) equivalent of LiAlH4 solution (I Mol in THF) was added to 1.0 g of halogenothiophene in 10 ml anhydrous THF. The mixture was brought to the specified reaction temperature and stirred under N2. After the specified time, 0.5 ml of the solution were hydrolyzed with 10 ml 2N HCI, extracted with 2 x 5 ml diethylether, and diluted with 30 ml methanol. This solution was then directly used for determination of content by HPLC (high-pressure liquid chromatography).
N-X-thiophene derivatives were reduced according to the methods described in Example 3 and Comparative Example 3. The results are summarized in Table 3.

Reduction of n-X-thiophene (n = 2,3; X = Cl, Br) X Gas Temp. Time Time Time Time Time S Remarks (C) (figures in ~) represent reaction yields 2-Br N2 SO 1 hr.: 2 hrs.:17.5 22.5 90 hrs.:
hrs.: hrs.:

23% 46% 83% 96% 100%

02 50 0.5 hrs.:1 hr.: 2 hrs.: 3.25 8.25 hrs.: lack hrs.: of THF

46% 65% 74% ___ ___ *) N2 30 1 hr.: 2 hrs.:4 hrs.: 19.25 45.5 hr.:
hr.:

17% 26% 33% 65% 100%

g _ 02 30 O.S hrs.: 1 hr.:2.25 hrs.:4 hrs::8.25 1 eq. LiAlH4 hrs.:

S2% S8% S8% --- --- consumed *) 3-Br N2 30 O.S hrs.: 2 hrs.:7.75 hrs.:29 hrs.:----21 % 31 36% I 00%
%

02 30 O.S hrs.: 1 hr.:2 hrs.: --- ---74% 100% 100%

2-Cl N2 30 1 hr: 2 hrs.:7.8 hrs.:29 hrs.:120 hrs.:2 eq. LiAlH4 0% 6% 2S% 48% 96% added 02 30 0.1 hrs.: I hr.:2 hrs.: 3.S --- 2 eq. LiAIH4 hrs.:

3S% S9% 94% 100% added 3-Cl N2 30 1 hr.: 3 hrs.:8.S hrs: 32 hrs.:9S hrs.:2 eq. LiAlH4 8% 9% 8% 17% 44% added 02 30 O.S hrs.: 1 hr.:2 hrs.: 4 hrs.:S.S hrs.:2 eq. LiAlH4 12% 21% 36% 42% SO% added *) Initially, the air stream at SO°C evaporated too much THF. This reduced the temperature to 30°C. In addition, the oxygen comsumes LiAIH4, so one equivalent LiAlH4 is not enough when air is used. In subsequent experiments, two equivalents were employed.
Analytical methods: HPLC
Wavelength 23S nm Injection 20 ul volume Mobile phase:MeOH:H20 (7S:2S) Column: Lichrosorb RP18, 10 micrometer Flow rate: 0.9 ml/min.

EXAMPLE 4:
Ten liters of THF (H20 < 0.1 %) and 4 kg bromoformylnarwedine-propyleneglycoketal are filled into a 301 double-mantle reaction vessel and 101 of LiAlH4 solution (10%) in THF are slowly added with mechanical stirring, whereupon massive development of gases occurs and the mixture reaches reflux temperature. Synthetic air (80% nitrogen, 20%oxygen) is introduced at SO°C for 4 hours using a gas introduction tube providing a flow of 101/min.
Subsequently, 1200 ml water and 1200 ml NaOH (1 S%) are added dropwise (massive development of gases, reflux), S liters of toluol are added and stirring continues for 30 min. at 60°C. The reaction mixture is filtered through a pressure filter while hot, the precipitate is washed twice with 4 1 ToluoUTHF 1: I at 60°C, the solvent is removed from the combined organic phases using a SO I rotavapor, the oily residue is taken up with 1214n HCl and then warmed to 60°C for IS min.
Two extractions with 41 EtOAc follow, and the aqueous phase is added dropwise to 2.4 1 concentrated NH40H under vigorous mechanical stirring. The suspension is cooled to 0 - 5°C, filtered, washed with 2 x 2000 ml water, and dried in vacuum (40 mbar, 70°C): 2104.8 g (80.5% of theory).
DC: CHCl3/MeOH (9:1 ) HPLC: content >95%

According to the protocol given in Example 4, bromoformylnarwedine-propyleneglycolketal was reduced in batches of varying sizes either in the presence ("with 02" in the table) or the absence ("without 02") of oxygen. The batch sizes, reaction times and yields are documented in Table 4.

Batch SizeReaction Time Yield Reaction Time Yield (g educt) without 02 (narwedine)(with 02) (narwedine) g 24 hours 800 2 hours 800 50 g 48 hours 720 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 800 14 kg --- --- 3-4 hours 760 The reaction scheme for the process of Examples 4 and 5 ("with 02") is represented below:
CH C AlH4 CH30 ~ LiAlH4/tl~ CH3( 3 i f w r. ~ . HC1 ~

S
rac. narwedine References:

[550SCo113/132] Koelsch, C.F. Org. Synth. Coll. Vol_ III, 132 (1954), Sn/HBr (59JOC421] Mosby, W.L.J.Org. Chem. 24, 421 (1959), Pd/NzH4.H20 [59JOC917] Benington, F; Morin, R.D.; Clarck Jr., L.C.J.Org., Chem. 24, 917 (1959), LiAlH4 [59JOC917] Szewcyk, J_, Lewin, A.H_; Carrol, F.I.J.

Heterocycl., Chem. 25, 1809 (1988), LiAlH4 am Bromformylnarwedin 53sI

[73CL291] Mukaiyama, T.; Hayashi, M.; Narasaka, K.Chem_Lett, 291, (1973) LiAlH4/TiCl4 [73JA6452] Masumane, S.; Rossey, P.A.; Bates, G.S. J.

Am. Chem.Soc. 95, 6452,1973, LiAlH(OMe)3/CuI

[74CC762] Yoshida, T., Negishi, E.J. Chem. Soc_ Chem.

Commun.,762 (1994), K-Selectrid/CuI

[78JOC1263] Ashby, E.C., Lin. J_J.J.Org.Chem_43, 1263 ( 1978 ) , LiAlH4/FeCl2 , CoCl2 , TiCl3 , NiCl2 [82TL1643] Han, B.H., Boudjouk, P.; Terahedron Lett.

23, 1643 (1982), LiAlH4 (82TL1643] Han, B.H.; Boudjouk, P Tetrahedron Lett.
23, 1643 (1982), LiAlH4/Ultraschall [83CC907] Beckw~th, L.J. Goh. S.H_ J, Chem.Soc_Chem.

Commun. 907 (1983), LiAlH4/liv [83JA631] Falck, J.R_ Manna, S.j. Am.Chem.Soc_ 105, 631 (1983), LiAlH4 [880SCo116/82I] Wade, R.S. Castro, C_E. Org.Synth_Coll.Vol.

VI, 821 (1988) , Cr(C104)2/HzN(CHZ)2NH2 (89TL2733] Lesage, M. Chatgilialoglu,. C_ Griller, D.

Tetrahedron Lett: 30, 2733 (1989), (Me3Si)3SiH

[89TH3329] Vlahov, R. Krikorian, D. Spassov, G_ Chino va, M;, LiAlH4 an Brom, Vlahov, I. Parushev, S. Snatzke, G. Ernst L.

Kieslich, K., Abraham, W.-R. Sheldrick, W.S. Tetrahedron 45, 3329 (1989), Galanthaminon 960 [85CL1491] Imamoto, T_- Takeyama, T. Kusumoto, T.

Chem.Lett. 1491, (1985), LiAlH4/CeCl3 f, [91CEX109] Nishiyama, T. Kameopka, H_ Chem_Express 6 (2) 109, 112 (1991), Raney-Ni/H3 r

Claims (12)

Claims:

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

Ar - Xn (I) where Ar represents an aromatic moiety that can be substituted at one or several positions, might be condensed, or might contain one or several heteroatoms (O, S, N); X
represents F, Cl, Br and/or J; and n = 1-10, with a hydride reagent as a reducing agent in the presence of oxygen, to a compound of the genral formula (II) Ar - Hn (II) where Ar and n have the meanings as given for formula (I), characterized by the use of diisobutylaluminum hydride, diisobutylaluminum hydride/ZnCl2, Al-isopropylat, sodium-bis-(2-methoxy-ethoxy)aluminumhydride, potassium-tri-sec-butylborohydride, lithium-tri-sec-butylborohydride, potassium trisiamylborohydride, lithium trisiamylborohydride, Li-tri-t-butoxy-A1H, Li-tri-ethoxy-A1H, 9-boroabicyclo(3.3.1)nonan, lithium triethylborohydride, A1H3 x A1C12H or a combination of at least two of the reducing agents mentioned before; that the reduction is carried out under the exclusion of moisture in a solvent; and that oxygen, in the form of a dried mixture of oxygen and an inert gas is blown or sucked through the reaction mixture.

2. Method according to claim 2, characterized in that LiAlH4 is employed as the reducing agent.

3. Method according to claim 1 or 2; characterized in that the inert gas is nitrogen or a noble gas, in particular argon or helium.

4. Method according to one of the claims 1-3, characterized in that the oxygen-containing mixture is a mixture of 20% oxygen and 80% of inert gas.

5. Method according to claim 1 or 2, characterized in that the oxygen mixture is air.

6. Method according to one of the claims 1-5, characterized in that the oxygen mixture contains the solvent in which the reaction is carried out, in particular is saturated with the solvent.

7. Method according to one of the claims 1-6, characterized in that a compound according to general formula (I) is being reduced, X being bromine.

8. Method according to one of the claims 1-7, characterized in that a compound according to general formula (I) is being reduced, Ar being a moiety of the narwedin type.

9. Method according to claim 7 and 8, characterized in that the compound being reduced is bromonarwedine.

10. Method according to claim 9, characterized in that the compound being reduced is bromonarwedineketal.

11. Method according to claim 10, characterized in that the compound being reduced is bromonarwedine-polypropyleneglycolketal with the formula

12. Method for producing narwedine, characterized in that bromoformylnarwedine, in particular bromoformylnarwedineketal is reduced by a reducing agent, in particular one of the reducing agents of claims 1 and 2 in the absence of oxygen to bromonarwedine (in particular, bromonarwedinketal), and the latter is reduced to narwedine (in particular, narwedineketal by one of the reducing agents listed in claims 1 and 2 in the presence of oxygen, and in the protecting ketal group, if present, is removed.