AU7012798A - Reduction of aromatic halogenides - Google Patents

Description

The invention concerns a method for the reduction of aromatic halide. Several methods for the reduction of aromatic halides are known. For the reduction of aromatic halides, reducing agents such as Cr(C104)2/ethylene diamine [88OSCo 116/821], tin/HBr [550SCol 13/132], catalytic reduction with Raney nickel [91 CEX109] or Pd/hydrazine hydrate [59JOC421], reducing agents such as K-selectride/CuI [NaBH4/Me3Si)3SiH [89TL2733], LiAlH4 [83JA631, 82TL1643, 59JOC917, 59JOC917, 89TH3329] or similar complex hydrides such as LiAlH4(OMe)3/CuI [73JA6452] are known. The reducing agent LiAlH 4 has often been used together with anorganic halides in catalytic or stoechiometric amounts, such as CeCl3 [85CL1491], TiCl4 [73CL291], FeC12, CoCl2, TiC13, NiCl2 [78JOC1263], or else other reducing agents were generated by these additions. In reducing aromatic halides, known variants of the use of LiAIH4 are simultaneous photoirradiation [83CC907] or ultrasound [82TL1643]. The codes in square brackets refer to the list of literature references. In spite of the multitude 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. use of 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 object of the invention is to provide a method for the reduction of aromatic and heteroaromatic halides that can accomplish this reduction faster and with high yields, even if larger reaction volumes are used. According to the invention this is achieved using the method of claim 1. Preferred and advantageous embodiments of the method of the invention are subjects of the subclaims.

-2 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-selectride@ (lithium-tri-sec. butyl borohydride (Aldrich)), KS-selectride@ (potassium-tri-siamyl borohydride (Aldrich)), LS selectride@ (lithium-tri-siamyl borohydride (Aldrich)), Li-tri-t-butoxy-AIH, Li-tdi-t-ethoxy-AlH, 9BBN (9-boroabicyclo[3.3.1 ]nonan), Super-Hydride@ (lithium triethylborohydride (Aldrich)), NaBH4, Zn(BH4)2, AIH3.AlCl2H 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 uged 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: LiAlH 4 /0 2 (Het) Ar X ------- > (Het) Ar - H LiAlH 4 /0 2 (Het) Ar ---------- > (Het) Ar - H, -3 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, LiAlH4 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. 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: CH 0 4LAH4 CH 3 r Y r cl 3 Further examples of reductions performed according to the invention are represented in the following scheme 3.

-4 Scheme 3: Example: 1-X-naphtaline Example: n-X-thiophene x s

UAIH

4 10 2 - x LiAIH 4

IO

2 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, 5 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 naphtaline 8 hours > 16 hours 1 -chloronaphtaline naphtaline 4 hours > 16 hours 1-bromonaphtaline naphtaline 2 hours > 16 hours 1-iodonaphtaline naphtaline 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 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) bromoforrnylnarwedine narwedine 3-4 hours Not done propyleneglycol ketal (14 kg) 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 I equivalent of LiAIH4 ( = 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.

-6 EXAMPLE 1 A solution of 9.7 ml of LiAIH4 (10% in THF; 24 mMol) was added dropwise to a solution of 5 g 1-bromonaphtaline (24 mMol) in 40 ml THF and at 50'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 5 ml of water and 5 ml of saturated aquaeous NaHCO3, 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 miMol) was added dropwise to a solution of 5 g 1-bromonaphtaline (24 mMol) in 40 ml THF, and the mixture was stirred at 50'C under a gentle argon stream. After 4 hours a thin-layer chromatogram demonstrated 25% yield of the reaction. After 24 hours, 50% 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. EXAMPLE 2 To a solution of 100 ml THF and 5 g 1-halogenonaphtaline 1.5 equivalents of LiAIH4 in THF (10%) were added and the mixture stirred at 50*C. Synthetic air (80% N2, 20% 02) was passed through the mixture at a rate of 50 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 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 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 5 g 1-halogenonaphtaline 1.5 equivalents of LiAIH4 in THF -7 (10%) were added and the mixture stirred at 50'C under N 2 . For analysis, approximately I 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 I hour 2 hours 4 hours 8 hours 16 hours Educt Product Educt Product Educt Product Educt Product Educt Product F N2 89 11 83 17 80 20 73 27 66 34 02 52 48 29 71 13 87 1 99 -- - Cl N2 87 13 81 19 77 23 64 36 50 50 02 26 64 2 98 00 100 -- - Br N2 83 17 76 24 70 30 52 48 48 62 02 30 70 1.5 98.5 00 100 - J N2 52 48 39 61 30 70 18 82 12 88 02 1.5 98.2 00 100 -- __ 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 OVI DF 0.25 Temperature Program: Starting temperature 50* C 1 min.; heating rate 100 C/min. Retention times: naphtaline 5.2 min. l-fluoronaphtaline 6.65 min 1 -chloronaphtaline 7.85 min. 1-bromonaphtaline 9.1 min. 1-iodonaphtaline 10.5 min.

-8 EXAMPLE 3 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 LiAIH4 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 N 2 . After the specified tire, 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. TABLE 3 Reduction of n-X-thiophene (n = 2,3; X = Cl, Br) X Gas Temp. Time I Time 2 Time 3 Time 4 Time 5 Remarks

(

0 C) (figures represent reaction yields in %) 2-Br N2 50 1 hr.: 2 hrs.: 17.5 hrs.: 22.5 hrs.: 90 hrs.: 23% 46% 83% 96% 100% 02 50 0.5 hrs.: I hr.: 2 hrs.: 3.25 hrs.: 8.25 hrs.: lack of THF 46% 65% 74% -- N2 30 1 hr.: 2 hrs.: 4 hrs.: 19.25 hr.: 45.5 hr.: 17% 26% 33% 65% 100% 02 30 0.5 hrs.: I hr.: 2.25 hrs.: 4 hrs.: 8.25 hrs.: 1 eq. LiAlH4 52% 58% 58% --- - consumed *) 3-Br N2 30 0.5 hrs.: 2 hrs.: 7.75 hrs.: 29 hrs.: - 21% 31% 36% 100% 02 30 0.5 hrs.: I 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% 25% 48% 96% added 02 30 0.1 hrs.: I hr.: 2 hrs.: 3.5 hrs.: --- 2 eq. LiAlH4 35% 59% 94% 100% added 3-Cl N2 30 1 hr.: 3 hrs.: 8.5 hrs: 32 hrs.: 95 hrs.: 2 eq. LiAIH4 8% 9% 8% 17% 44% added 02 30 0.5 hrs.: I hr.: 2 hrs.: 4 hrs.: 5.5 hrs.: 2 eq. LiAlH4 12% 21% 36% 42% 50% added *) Initially, the air stream at 50'C evaporated too much THF. This reduced the temperature to 30'C. In addition, the oxygen comsumes LiAlH4, so one equivalent LiAIH4 is not enough when air is used. In subsequent experiments, two equivalents were employed. Analytical methods: HPLC Wavelength 235 nm Injection volume 20 ul Mobile phase: MeOH:H20 (75:25) Column: Lichrosorb RP 18, 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 30 1 double-mantle reaction vessel and 10 1 of LiA1H4 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 50'C for 4 hours using a gas introduction tube providing a flow of 10 1/min. Subsequently, 1200 ml water and 1200 ml NaOH (15%) are added dropwise (massive development of gases, reflux), 5 liters of toluol are added and stirring continues for 30 min. at 60'C. The reaction mixture is filtered -10 through a pressure filter while hot, the precipitate is washed twice with 4 1 Toluol/THF 1:1 at 60'C, the solvent is removed from the combined organic phases using a 50 1 rotavapor, the oily residue is taken up with 121 4n HCl and then warmed to 60'C for 15 min. Two extractions with 4 1 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 0 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% EXAMPLE 5 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. TABLE 4 Batch Size Reaction Time Yield Reaction Time Yield (g educt) without 02 (narwedine) (with 02) (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% - 11 The reaction scheme for the process of Examples 4 and 5 ("with 02") is represented below:

CH

3 0 "LijlH 4

CH

3 0 LiAlH 4 A CH 3 O >1- H3 Br cHO r CHA 3 3 -0 II CH 3 CH 3 rac. narwedine

Claims (13)

1. 2. Method according to claim 1, characterized by the fact that a hydrid reagent, such as DiBAL H, DiBAL-H/ZnCI2, Al-isopropylat, Red-Al®, K-Selectride@, L-Selectride@, KS-Selectride@, LS-Selectride@, Li-tri-t-butoxy-AlH, Li-tri-ethoxy-AlH, 9BBN, Super-Hydride@, NaBH4, Zn(BH4)2, AlH3 x A1C12H or a combination of at least two of the reducing agents listed above is used.
2. 3. Method according to claim 2, characterized in that LiAlH4 is used as the reducing agent.
3. 4. Method according to one of the claims 1 to 3, characterized in that oxygen is added to the reaction mixture as pure oxygen.
4. 5. Method according to one of the claims 1 to 3, characterized in that oxygen is added to the reaction mixture as a mixture of oxygen and an inert gas.
5. 6. Method according to claim 5, characterized in that the inert gas is nitrogen or a noble gas, in particular argon or helium. - 13 7. Method according to claim 5, characterized in that the oxygen-containing mixture is a mixture of 20% oxygen and 80% of inert gas.
6. 8. Method according to claim 5, characterized in that the oxygen-containing mixture is air.
7. 9. Method according to one of the claims 1 to 8, characterized in that dried oxygen or a dried oxygen-containing mixture is used.
8. 10. Method according to one of the claims 1 to 9, characterized in that the reduction is carried out in a solvent and in that oxygen or the oxygen-containing mixture contains the solvent, in particular is saturated with the solvent.
9. 11. Method according to one of the claims 1 to 10, characterized in that a compound of the general formula (I) is reduced, in which X is for bromine.
10. 12. Method according to one of the claims 1 to 11, characterized in that a compound of the general formula (1) is reduced, in which Ar is a moiety of the narwedine type.
11. 13. Method according to claims 11 and 12, characterized in that bromonarwedine is reduced.
12. 14. Method according to claim 13, characterized in that bromonarwedineketal is reduced.
13. 15. Method according to claim 14, characterized in that bromonarwedine-propyleneglycolketal of the formula 0 CH3 BrC is reduced. - 14 16. 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 2 and 3 in the absence of oxygen to bromonarwedine, in particular, bromonarwedineketal, and the latter is reduced with a reducing agent, in particular one of the reducing agents of claims 2 and 3 in the presence of oxygen to narwedine, in particular narwedineketal and the protecting ketal group, if present, is removed.