LV13735B - Method for manufacturing substituted adamantylarylmagnesium chalogenides - Google Patents

Abstract

There is worked out method for manufacturing substituted adamantylarylmagnesium halides from adamantylaryl halides by treatment thereof with magnesium in aprotic solvent (direct Grignard reaction), characterized in that the reaction is provided in presence of anhydrous lithium salts. There is find out that using anhydrous lithium salts in equimolar to double excess accordingly adamantylaryl halides results stable high-yield of substituted adamantylarylmagnesium halides.

Description

Description of the Invention

Process for the preparation of substituted adamantylarylmagnesium halides

The invention relates to fine organic synthesis, in particular to a process for the preparation of a substituted adamantylarylmagnesium halide.

Organo-magnesium compounds play a particularly important role in modern preparative organic chemistry. Since the discovery of Grignard in 1900, methods for the synthesis of these intermediates and the potential for further transformations have been constantly expanding and expanding.

A standard preparative method for the synthesis of organo-magnesium compounds (Grignard's reagents) is the direct action of organic halides with metallic magnesium in an apron, a polar solvent such as tetrahydrofuran (THF) or diethyl ether [C. Τ. Μοφφθ, Α. H. HecMeaHOB MeTOflbi οπθμθητο opraHHMecKofi χημμμ. Mamuti, 6epnnnnfi, KanspHM, CTpoHpnii, 6apnii. H3fl. AH CCCPM. 1963, 14-27].

The object of the present invention is to provide a process for the preparation of substituted adamantylmagnesium halides which is simple to implement, provides high and stable product yields, and is easily scalable.

Adamantylmagnesium halides are active synthons that allow the production of various biologically active compounds by reaction with various electrophilic reagents [Charpentier, B .; Bernardon, J.-M.; Eustache, J. et al. Synthesis, structure-affinity relationships, and biological activities of ligand binding to retinoic acid receptor subtypes. J. Med. Chem. 1995, 38 (26), 4993-5006. Cincinnelli, R .; Dallavalle, S.; Nannei, R. Synthesis and structure-activity relationships of a nevv series of retinoid-related biphenyl-4-ylacrylic acids endowed with vvith antiproliferative and proapoptotic activity. J. Med. Chem. 2005, 48 (15), 4931-4946. Pfahl, M .; Tachdjian, C. et al. Heterocyclic derivatives for the treatment of cancer and other proliferative diseases. US 2002/0143182 A1]

An important representative of the substituted adamantylarylmagnesium halides is 3- (1adamantyl) -4-methoxyphenylmagnesium bromide

-2 which is used in the synthesis of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-petroleum acid (adapalene):

Adapalene is a pharmaceutical substance widely used in dermatological practice as an effective remedy for acne [Waue gas-liquid chromatography, J.; Noble, S.; Scott, L. From Spot Slide-Liquid Chromatography on adapalene in acne vulgaris. J.

Am. J. Clin. Dermatol. 2004, 5 (5), 369-371],

Not less important is 3- (1-adamantyl) -4- (tert-butyldimethylsilyloxy) phenylmagnesium bromide

and 3- (1-adamantyl) -4-benzyloxyphenylmagnesium bromide,

MgBr used in the synthesis of 6- [3- (1-adamantyl) -4-hydroxyphenyl] -2-petroleum acid (AHPN, CD 437):

HO

-33- (1-Adamantyl) -4 - (tert -butyldimethylsilyloxy) phenylmagnesium bromide and 3- (1adamantyl) -4-benzyloxyphenylmagnesium bromide can also be used 4- (3- (1-adamantyl) 4-hydroxyphenyl) -3 - synthesis of chlorocinnamic acid (3-CI-AHPC),

which, like 6- (3- (1 -adamantyl) -4-hydroxyphenyl) -2-petroleum acid (AHPN, CD 437), is patented as an anticancer agent [Dawson, M .; Fontan, J; Zhang, X. et al. . Induction of apoptosis in cancer cell. WO 03/048101 A1].

The preparation of substituted adamantylarylmagnesium halides containing electron donor substituents in the aromatic ring is a synthetically difficult task. Classical methods, i.e. the reaction of aryl halides with metallic magnesium in an apron, a polar solvent such as THF or diethyl ether, allows the final products to be obtained with a yield of up to 11%. This reaction results mainly in the formal reduction products of the aryl halide. Thus, 2- (1-adamantyl) -4-bromanisole is reacted with magnesium to form 2- (1-adamantyl) anisole (Example 1) in 78% yield.

Analysis of the reaction mixture by gas-liquid chromatography showed complete conversion of 2- (1-adamantyl) -4-bromoanisole under these reaction conditions. This means that the starting compound in the classical Grignard reaction is in fact very reactive with metallic magnesium, but the desired magnesium organic compound with good yields cannot be obtained due to the formation of a reduction product.

Similar results were obtained with the reaction of magnesium with 2- (1-adamantyl) -5-bromoanisole (Example 2).

Br

H ₃ C-O

The main reaction product of H3C-O and 3- (1-adamantyl) -5-bromo-veratrol (Example 3).

Br

H3C-O

Main reaction product of H3C-O

The change in Grignard's reaction temperature and reaction time did not cause any significant change in the composition of the reaction product (Example 4). Likewise, the simultaneous addition of the starting aryl bromide and dibromoethane to magnesium according to the examples reported in the literature (D.E. Pearson et al., J. Org. Chem., 24, 504 (1959)) did not in any way improve the yield of magnesium organic compound (Example 5).

In principle, the formation of an adamantylaryl halide reduction product under Grignard's reaction can be explained either by the instability of the adamantylaryl magnesium halide or by the low reactivity of the Grignard reagent to the electrophilic agents used. However, the use of various organic electrophilic reagents also did not appear to significantly alter the ratio of the reduction product to the substituted adamantyl-arylmagnesium bromide (Example 6).

We also found that addition of an inorganic electrophile reagent such as D ₂ SO ₄ D ₂ O to Grignard's reagent derived from 2- (1-adamantyl) -4-bromoanisole with D ₂ SO ₄ - D ₂ O gives the product mixture. containing NMR-deuterated 2- (1-adamantyl) -anizole

H3C-O

-5, which in this case is the final product, yields 9% (Example 7).

These results indicate that the Grignard reagent formed from 2- (1-adamantyl) -4-bromoanisole is not a stable compound and is formally reduced before exposure to any electrophilic reagent.

Accordingly, the object of the present invention was to provide a convenient method for obtaining adamantylarylmagnesium halides containing electron-donor substituents, which would avoid the formation of formal reduction products.

The closest prototype to the present invention is a process for the synthesis of magnesium-organic exchange [Krasovskiy, A .; Knochel, P. A LiCI-Mediated Br / Mg Exchange Reaction for Preparation of Functionalized Aryl and Heteroaryl Magnesium Compounds from Organic Bromides. Angew. Chem. Int. Ed. 2004, 43 (25), 3333-3336; Knochel, P. Krasovskiy, A. Method of preparing an organomagnesium compound. EP 1582523 (2005). Krasovskiy, A .; Straub, B. F.;

Knochel, P. Hydrogen-Liquid Chromatography a Highly Effective Reagent for Br / Mg Exchange. Angew. Chem. Int. Ed. 2006, 45 (1), 159-162.].

This process is based on a two-step process in which alkylmagnesium compounds (AlkMgCI LiCl or Alk ₂ MgLiCl complexes) are first obtained and subsequently reacted with substituted aryl or heteroaryl halides

However, we found that when exposed to 2- (1-adamantyl) -4-bromoanisole (Example 8 - by prototype) and 3- (1-adamantyl) -5-bromo veratrol (Example 9 by prototype) with in the technique, the conversion was only 6 to 9% within two days.

Thus, the experimental results obtained show, on the one hand, the instability of the substituted adamantylaryl magnesium halides and, on the other hand, the low reactivity of the substituted adamantylaryl halides in the magnesium-organic synthesis reaction using, for example, / zo-PrMgCI LiCI.

In an attempt to obtain arylmagnesium halides with electron donor substituents in the ring, some authors [Krasovskiy, A .; Straub, BF; Knochel, P. Hydrogen-Liquid Chromatography a Highly Effective Reagent for Br / Mg Exchange. Angew. Chem. Int. Ed. 2006, 45 (1), 159-162] used reagents with higher reactivity, equilibrium in the Schlenka equation for exchange magnesium organic synthesis iso-PrMgCI LiCI <- »iso-Pr ₂ MgCl ₂ LiCl + MgCl ₂ + LiCl

-6 shifting to the / zo-Pr ₂ side of the MgCILiCI dialkylmagnesium derivative by binding MgCl ₂ to various reagents such as dioxane

However, this method of producing the magnesium organo-derivative of 2- (1-adamantyl) -4-bromoanisole (Example 10 - by prototype) also gave only 13% conversion within two days.

The results obtained show that of all the reagents used for the production of magnesium compounds of adamantylaryl halides, metallic magnesium is the most active reagent and it was therefore necessary to invent a method to stabilize the resulting adamantylarylmagnesium halide to prevent further reduction and other adverse reactions.

We have unexpectedly discovered that the goal of developing an efficient and technological process for the preparation of substituted adamantylmagnesium halides can be achieved by the direct synthesis of Grignard's reagent by the reaction of metallic magnesium with substituted adamantylaryl halides in argon atmosphere with anhydrous THF. (Examples 10-41).

We were able to discover that under normal conditions of direct magnesium organic synthesis, i. addition of lithium chloride, on the one hand, increases the stability of the substituted adamantylaryl magnesium halides (forming a complex) and thus prevents undesired further reactions of the resulting product, but on the other hand, it does not lead to the expected reaction capacity of adamantylaryl halides in fatal falls. Thus, for the first time within the scope of the present invention, we have discovered a convenient method for the direct synthesis of organo-magnesium for the production of adamantylarylmagnesium halides in cases where the aromatic ring in the parent compound contains electron donor substituents.

The invention is illustrated, but not limited, by the following examples:

Example 1. Into a 1 L flask with a mechanical stirrer, a reflux condenser and a dropping funnel, place 8 g (0.33 M) of magnesium turnings and 200 ml of dry THF. Air is expelled from the flask with argon and all subsequent operations are performed under a weak inert gas stream. With vigorous stirring, 11 g (5 mL, 0.06 M) of 1,2-dibromoethane are added in a single step. When the rapid reaction is over, the reaction does not cool down

LV Ϊ3735

To the mixture is added 50 g (0.16 M) of a solution of 2- (1-adamantyl) -4-bromoanisole in 400 ml of dry THF at such a rate that the reaction mixture is slowly boiling. After the entire solution of 2- (1-adamantyl) -4-bromoanisole is added, the mixture is heated at this temperature for a further 30 min. Stop stirring and decant the resulting Grignard reagent solution from the excess magnesium in a conical flask, previously purged with argon. Trimethylborate, a standard reagent for the production of phenylboronic acids, was used as the electrophilic agent for further functionalization, product isolation and identification.

In a flask I, mix 33 g (36 mL, 0.35 M) trimethylborate and 100 mL dry THF with a mechanical stirrer, a reflux condenser and a dropping funnel, cool the resulting solution to -50 ° C and add the magnesium compound solution over 30 min with vigorous stirring. at -40 to -50 ° C.

The reaction product is partitioned between 50 ml of hydrochloric acid and 50 ml of water under vigorous stirring without additional cooling. The separating funnel separates the water layer and the organic layer. The aqueous solution is diluted three times and extracted with 2x100 ml of diethyl ether. The combined organic layers are dried over sodium sulfate and the solvents are distilled off under vacuum at 50 ° C in a water bath.

The residue is treated with 200 ml of hexane and left in the refrigerator overnight. Filter off the precipitate, wash with cold ethyl acetate and dry in a oven at 100 ° C. 3- (1-adamantyl) -4-methoxyphenylboronic acid yields 2.5 g (5.7%), _m.p. The reaction mixture Gas-liquid HROMATOGRĀFIJASizpēte showed that it as a basic product (78%) of a compound which was eliminated in the result 67% and identified as 2- (1-adamantyl) -anizols (t _hush 100-102 ° C):

NMR (500 MHz, DMSO D6) δ: 1.75 (s, 6H), 2.06 (s, 9H), 3.82 (s, 3) 6.79 6.83 (m, 2H), 7.06 - 7.10 (m, 2H).

Example 2, Reaction was performed as described in Example 1. 50 g (0.16 M) 2- (1-adamethyl) -5-bromoanisole was taken as starting adamantylaryl halide. 4- (1-Adamantyl) -3-methoxyboric acid was obtained in a yield of 3 g (6.8%). According to GHS data, the content of 2- (1-adamantyl) -anisole in the reaction mixture was 81%, which was isolated and identified.

-8Example 3. The reaction is carried out as described in Example 1. 56 g (0.16 M) 3- (1-adamantyl) -5-bromveratrol was taken as the starting adamantylaryl halide. The yield of 3- (1-Adamantyl) -4,5-dimethoxyphenylboronic acid was 3.7 g (7.3%). 3- (1-adamantes) -veratrol yields 74%, according to GHS.

Example 4. The reaction is carried out as described in Example 1. After the vigorous reaction of dibromomethane and magnesium is complete, 50 g (0.16 M) of 2- (1 -adamantyl) -4-bromoanisole is added to 400 ml of dry tetrahydrofuran, maintaining the reaction at 37- 40 ° C. According to GHS, the yield of 2- (1-adamantyl) anisole is 78%. The Grignard reaction at lower temperatures requires the addition of aryl bromide along with an equimolar amount of dibromoethane. [D. E. Pearson, D. Cowan, J. D. Beckler. A Study of the Entrainment Method for Making Grignard J. Org. Chem. 1959, 24 (4), 504-509].

Example 5.1 Into a 1 L flask with a mechanical stirrer, a dropping funnel and a reflux condenser, place 16 g (0.66 M) of magnesium turnings and 200 ml of dry tetrahydrofuran. The reaction is carried out under argon with the addition of 11 g (5 mL, 0.06 M) 1,2-dibromoethane in one portion. After vigorous reaction, the reaction mixture is cooled to 20 ° C and 50 g (0.16 M) of 2- (1-adamantyl) -4-bromanizole and 30 g (0.16 M) of dibromoethane in 400 ml of dry tetrahydrofuran are calculated to the temperature of the mixture should not exceed 22 ° C. The reaction is carried out as described in Example 1 below. The yield of 2- (1-adamantyl) -anisole is 74% according to GHS.

The use of benzaldehyde as an electrophilic reagent which reacts quantitatively with arylmagnesium halide to form arylphenylmethanol gave a similar result. The reaction mixture contained 70-75% of adamantylbenzene and 311% of the desired ariphenylmethanol, according to GHS

R

-9Example 6. Preparation of Grignard regent from 51 g (0.16 M) of 2- (1-adamantyl) -4-bromoanisole was performed as described in Example 1. Further, in a 1 L flask, mix 17 g (16 g) with a mechanical stirrer, a reflux condenser and a dropping funnel. , 5 ml, 0.16 M) of benzaldehyde and 100 ml of dry THF, cool the resulting solution to 0 ° C and add a solution of organo magnesium in 10 min with stirring. The resulting mixture is left for 16 h. in a refrigerator at 0 ° C.

The reaction mixture is partitioned with 25 ml of hydrochloric acid solution in 25 ml of water under vigorous stirring without additional cooling. The separating funnel separates the water and the organic layer, extracting the aqueous layer with 2x100 mL diethyl ether. The combined organic layers are dried over sodium sulfate. (3- (1-adamantyl) -4-methoxyphenyl) phenylmethanol

the yield is 11% according to GCH.

Example 7 Grignard's reagent was prepared from 10 g (0.032 M) 2- (1-adamantyl) -4-bromanisole as described in Example 1. A mixture of D ₂ SO ₄ - D ₂ O was selected as the electrophilic reagent for functionalization and identification of the reaction products.

The reaction mixture is partitioned between 2 ml of D ₂ SO ₄ and 10 ml of heavy water under vigorous stirring without additional cooling. Separate the organic layer and the aqueous layer, extract the aqueous layer with 2x50 mL diethyl ether. The combined organic layers are dried over sodium sulfate and the solvents are completely distilled off under reduced pressure.

Example 8 (according to prototype method). In a 200 ml flask with magnetic stirrer and a dropping funnel, mix 5.14 g (0.016 M) 2- (1-adamantyl) -4-bromoanisole and 60 ml dry THF. Air is expelled from the flask with argon, and all subsequent operations are performed under a weak stream of inert gas. Cool the resulting mixture to -5 ° C and add 3 eq. 0.5 M / zo-PrMgCl LiCL in THF while maintaining the reaction mixture at -5 to 0 ° C.

A-10 / zo-PrMgCI LiCL solution in THF is prepared in advance by concentration titration according to the procedure described in [Krasovskiy, A .; Knochel, P. A convenient titration method for organometallic zinc, magnesium, and ianthanide reagents.

Synthesis 2006, 5, 890-891],

After addition of THF to the / jMo-PrMgCl LiCL solutions, the reaction mixture is aged for 1 h. at 0 ° C and leave at room temperature for 48 h. According to GHS, the conversion of 2- (1-adamantyl) -4-bromoanisole is 9%.

Example 9 (by prototype). The reaction is carried out as described in Example 8. 5.62 g (0.016 M) of 3- (1-adamantyl) -5-bromo-veratrol is used as starting adamantylaryl halide. The conversion of 3- (1-adamantyl) -5-bromo veratrol after 48 hours is 6% according to GHSHdates.

If the reaction is carried out in a mixture of THF and dioxane at 10% by volume, the conversion of adamantylaryl halide is not significantly increased.

Example 10 (by prototype). The reaction is carried out as described in Example 8. A mixture of 5.14 g (0.016 M) of 2- (1-adamantif) -4-bromoanisole in 54 mL of THF and 6 mL of dioxane is used. Conversion of 2- (1-adamantyl) -4-bromoanisole according to GHSH after 48 h. and 13%.

Example 11: Place 1 g (0.042 M) of magnesium turnings and 20 ml of dry THF in a 100 ml flask with magnetic stirrer, reflux condenser and dropping funnel. Add 0.81 g (0.019 M) of crushed anhydrous lithium chloride. Air is expelled from the flask with argon, and all subsequent operations are performed under a weak stream of inert gas. Under vigorous stirring, 1.1 g (0.5 ml, 0.006 M) of 1,2-dibromoethane are added in a single step. Upon completion of the vigorous reaction, a solution of 5.14 g (0.016M) of 2- (1-adamantyl) 4-bromoanisole in 40 ml of dry THF is added dropwise over 30 min to the reaction mixture, maintaining the temperature of the reaction mixture at 55-60 ° C. The resulting reaction mixture is then stirred and heated at slow boiling for an additional 30 min. Stop stirring and decant the resulting Grignard reagent solution from the excess magnesium in a conical flask with a ground-glass stopper, previously purged with argon. Close the stopper and keep the reagent at 0 ° C for 2 hours.

In a -11250 ml flask, stir 3.4 g (3.3 ml, 0.032 M) benzaldehyde and 20 ml dry THF in a magnetic stirrer, a reflux condenser and a dropping funnel, cool the resulting mixture to 0 ° C and add the magnesium organic reagent under constant stirring. solution within 10 min. Leave the mixture in the refrigerator at

0 ° C for 16 hours.

The reaction mixture is partitioned between 5 ml of hydrochloric acid and 5 ml of aqueous solution under vigorous stirring without additional cooling. Separate the organic and aqueous layers in the separatory funnel and extract the aqueous solution with 2x20 ml diethyl ether. The combined organic layers are dried over sodium sulfate. The yield of (3- (1-adamantyl) -4-methoxyphenyl) 10-phenylethanol is 88% according to GCH, with a preparative yield of 59%.

The 1: 1.2 ratio of substituted adamantylaryl halide to lithium chloride has been experimentally found to be optimal. The results in Table 1 (Examples 4, 10, 11-12) show that increasing the molar content of lithium chloride from 0.1 to 1.2 increases the

The yield of Grignard's reagent, but further increasing the amount of lithium chloride to 2 equivalents, does not significantly increase the yield of Grignard's reagent.

Table 1. Effect of molar ratio of arylhalogemd to lithium chloride on the yield of substituted adamantylarylmagnesium halides

Ns Aryl halide 1 eq. Yield% No LiCI to- doses 0.1 eq. LiCI 0.5 eq. LiCI 1 eq. LiCI 1.2 eq. LiCI 1.5 eq. LiCI 2 eq. LiCI 1. Ο — Z V- Br h ₃ c 11th 16th 30th 75 88 87 85 ch ₃ 2. H ₃ cJ (] 0 — Z Br h ₃ c ^z 13th 18th 34 74 89 89 84

-12Example 12. The reaction is carried out as described in Example 11. The Grignard reaction is used

0.07 g (0.0016 M) of crushed anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 0.1 The yield is 16%, according to GHSH.

Example 13. The reaction is carried out as described in Example 11. The Grignard reaction uses 0.34 g (0.008 M) of ground anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 0.5. The yield, according to GCH, is 30%.

Example 14. The reaction is carried out as described in Example 11. The Grignard reaction uses 0.68 g (0.016 M) of ground anhydrous lithium chloride. The molar ratio of substrate to LiCi is 1: 1. The yield, according to GHS, is 75%.

Example 15. The reaction is carried out as described in Example 11. The Grignard reaction uses 1.02 g (0.024 M) of ground anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 1.5. The yield, according to GCH, is 87%.

Example 16. The reaction is carried out as described in Example 11. The Grignard reaction uses 1.36 g (0.032 M) of ground anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 2. The yield, according to GCH, is 85%.

Example 17. The reaction is carried out as described in Example 11. 5.58 g (0.016 M) of 2- [1- (3,5-dimethyladamantyl)] - 4-bromanisole is used as starting adamantylaryl halide. The reaction is carried out without the addition of lithium chloride. (3- (1- (3,5-dimethyladamantyl)] -4-methoxyphenyl) -phenylmethanol yields 13%, according to GHS.

Example 18. The reaction is carried out as described in Example 11. 5.58 g (0.016 M) of 2- [1- (3,5-dimethyladamantyl)] - 4-bromanisole is used as starting adamantylaryl halide. The Grignard reaction uses 0.07 g (0.0016 M) of crushed anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 0.1. the yield is 18% according to GCH.

Example 19. The reaction is carried out as described in Example 18. Grignard's reaction uses 0.34 g (0.008 M) of ground anhydrous lithium chloride. The molar ratio of substrate to LiCI is 1: 0.5. The yield, according to GCH data, is 34%.

-13Example 20. The reaction is carried out as described in Example 18. For the Grignard reaction, 0.68 g (0.016 M) of anhydrous lithium chloride is used. The molar ratio of substrate to LiCI is 1: 1. The yield, according to GCH, is 74%.

Example 21, Reaction is performed as described in Example 18. 0.81 g (0.019 M) ground anhydrous lithium chloride is used for the Grignard reaction. The molar ratio of substrate to LiCl is 1: 1.2. The yield, according to GCH, is 89%.

Example 22. The reaction is carried out as described in Example 18. The Grignard reaction uses 1.02 g (0.024 M) of crushed anhydrous lithium chloride. The molar ratio of substrate to LiCl is 1: 1.5. The yield, according to GCH, is 89%.

Example 23. The reaction is carried out as described in Example 18. 1.36 g (0.032 M) of ground anhydrous lithium chloride is used for the Grignard reaction. The molar ratio of substrate to LiCl is 1: 2. The yield, according to GCH data, is 84%.

The proposed method for the preparation of substituted adamantylaryl magnesium halides was tested on a number of substrates using a 1: 1.2 molar ratio of admantylaryl halide to lithium chloride. Benzaldehyde was used as the electrophilic reagent and the reaction was determined by the GHS method (Examples 11, 21, 24-43). The results are given in Table 2.

Table 2. Yield of Adamantylaryl Magnesium Halides at a molar ratio of adamantylaryl halides 25 to lithium chloride of -1: 1.2

N ° Add- mayor Arylmagnesium halide Arylphenylcarbinol Output, % After GŠH data 1. 11th p— / V-MgBr · LiCl H ₃ c ⁰ \ / - \ H ₃ CV 88

ch ₃ ch ₃ 2. 21st H ₃ cJ | ] 0- / MgBr-LiCl h ₃ c ^ = ⁷ h ₃ cJjJ ⁰ \ / - \ ^H 3C ^ = ⁷ 89 3. 24th 0—? V-MgBrLiC! h ₃ c ^H3C / - _Λ ^oh pA 2- ^(H 3 C ^ == ⁷ 84 4. 25th - ^ y ^> ' ^MsBr ' ^LiCI h ₃ co 92 5. 26th ch ₃ - / A — MgBr · LiCI h ₃ co ch ₃ ffl z ^ z ^0H h ₃ cJ | W yv H3C-0 z \ 91 6th 27th '^^^ - ^^ - MgBr LiCI H ₃ C-0 ^ζ ^ α / Λα ° ^{η HsC} / = ⁷ M h ₃ co f? 90 7th 28th 0— \ / —MgBr LiCf lxv / ^oh 92 ch ₃ ch ₃ 8th 29th ^{h, c} Ax 0 ^ ° V_T ^MgBr ' ^{LiCI h} 3c 4f J ^Ζ ΑΓΑ / ^οη 90

-16Table 2 (continued)

N ° Add- mayor Arylmagnesium halide Arylphenylcarbinol Output, % After GŠH data ch ₃ ch ₃ 11th 32 r ° - MgBr LICENSE H ₃ cJ | J— OH o 87 Q. 0 12th 33 MgBr · LiCI 00y_h ₃ cy = / OH 0 88 o 0 13th 34 H ₃ C _> ? ^I '-CH3 CH? ^CH 3 -MgBr · LiCi 00 H ₃ C. / HsC ^ 'CHs _C hC ^CH 3 OH 0 79 ch ₃ ch ₃ 14th 35 H ₃ cJ | I 0x K ₃ c. ° Λ = / HaC ^ 'CHa ChC ^CH 3 -MgBr - LiCi H ₃ cJ | I 00 h ₃ c. ”HpJ'ch, ChC ^CH 3 OH Ο 80 15th 36 itp- ^{H 3} C. ° HaC ^ 'cHa Η ₃ Α ^Η 3 MgBr LiCi Χ00 h ₃ c. P H ₃ Cv / 'ch ₃ H ₃ C ^CH 3 OH 0 76

-17Table 2 (continued)

Ns Add- mayor Arylmagnesium halide Ariphenylcarbinol Output, % After GŠH data 16th 37 ch ₃ ^H3C ^^ - li ^ y ~ MgBr - LiCI ^H3C Si '° H ₃ C0 _C h ₃ H ₃ C ^CH 3 CHj (Yl r-, oh h ₃ cJ I_ / χ_ / n ₃ c. PO h ₃ cJŅch ₃ H ₃ C ^CH 3 74 17th 38 ₀ -f V- MgBrLiCI b 81 84 18th 39 ch ₃ ^{H, c} <k _O -A χ-MgBrLiCI CH ₃ H ₃ cJl l ΊΤΗ ^! 'o ^z 0 19th 40 ^Η3Ε λλ _o 0) —MgBrLiCI ^HaC / Λ / ^0H 00 / \ Μ 79 20th 41 0-f Y-MgBrLiCl h ₃ c) = / H ₃ C-0 AcAoh ⁰ \ / - \ H3C) = / h ₃ co f) 82

-18Table 2 (continued)

N ° Add- mayor Arylmagnesium halide Arylphenylcarbinol Output, % After GŠH data 21st 42 h ₃ c \, OA 7-MgBrLiCI H ₃ C) = ⁷ h ₃ co ^H 3 ^C p OH) - ( ^H 3 ^C Γ H3C-O? Y 77

Example 24. The reaction is performed as described in Example 11. 5.36 g (0.016 M) of 2- [2- (2-methyladamantyl)] - 45 bromanisole is used as starting adamantylaryl halide. The yield, according to GCH, is 84%.

Example 25, Reaction is performed as described in Example 11. 5.14 g (0.016 M) of 2- (1-adamantyl) -5-bromoanisole is used as starting adamantylaryl halide. The yield, according to GCH, is 92%.

Example 26, Reaction is performed as described in Example 11. 5.6 g (0.016 M) of 2- [1- (3,5-dimethyladamantyl)] - 5-bromanisole are used as starting adamantylaryl halide. The yield is 91% according to GCH.

Example 27. The reaction is carried out as described in Example 11. 5.36 g (0.016 M) of 2- [2- (2-methyladamantyl)] - 5-bromanisole are used as starting adamantylaryl halide. The yield, according to GCH, is 90%.

Example 28. The reaction is carried out as described in Example 11. 6.35 g (0.016 M) of 3- (1-adamantyl) -4- (benzyloxy) bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 92%.

Example 29. The reaction is carried out as described in Example 11. 6.8 g (0.016 M) of 3- [1- (3,5-dimethyladamantyl)] - 425 (benzyloxy) -bromobenzene are used as starting adamantylaryl halide. The yield is 90% according to GCH.

-19Example 30, Reaction is performed as described in Example 11. 6.58 g (0.016 M) of 3- [2- (2-methyladamantyl)] -4- (benzyloxy) -bromobenzene is used as the starting adamantylaryl halide. The yield, according to GHS, is 88%.

Example 31. The reaction is carried out as described in Example 11. 6.35 g (0.016 M) of 3- (benzyloxy) -4- (1-adamantyl) bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 92%.

Example 32. The reaction is carried out as described in Example 11. 6.8 g (0.016 M) of 3- (benzyloxy) -4- [1- (3,5-dimethyladamantyl)] - bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 87%.

Example 33. The reaction is carried out as described in Example 11. 6.58 g (0.016 M) of 3- (benzyloxy) -4- [2- (2-methyladamantyl)] - bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 88%.

Example 34. The reaction is carried out as described in Example 11. 6.74 g (0.016 M) of 3- (1-adamantyl) -4- [1- (irtbutyldimethylsilyloxy)] - bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 79%.

Example 35. The reaction is carried out as described in Example 11. 7.18 g (0.016 M) of 3- [1- (3,5-dimethyladamantyl)] -4- (tert-butyldimethylsilyloxy) -bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 80%.

Example 36, Reaction is performed as described in Example 11. 6.74 g (0.016 M) of 3- (tert-butyldimethylsilyloxy) -4 (1-adamantyl) -bromobenzene are used as starting adamantylaryl halide. The yield, according to GCH, is 76%.

Example 37. The reaction is carried out as described in Example 11. 7.18 g (0.016 M) of 3- (tert-butyldimethylsilyloxy) -4- [1- (3,5-dimethyladamantyl) -bromobenzene are used as starting adamantylaryl halide. The yield, according to GHS, is 74%.

-20Example 38. The reaction is carried out as described in Example 11. 5.36 g (0.016 M) of 3,4-methylenedioxy-5- (1-adamantyl-1-bromobenzene) is used as the starting adamantylaryl halide.

Example 39. The reaction is carried out as described in Example 11. 5.81 g (0.016 M) of 3,4-methylenedioxy-5- [1- (3,5-dimethyladamantyl)] - bromobenzene is used as the starting adamantylaryl halide. The yield, according to GCH, is 84%.

Example 40. The reaction is carried out as described in Example 11. 5.58 g (0.016 M) of 3,4-methylenedioxy-5- [2- (2-methyladamantyl)] - bromobenzene is used as the starting adamantylaryl halide. The yield, according to GCH, is 79%.

Example 41. The reaction is carried out as described in Example 11. 5.62 g (0.016 M) of 3- (1-adamantyl) -5-bromveratrol is used as starting adamantylaryl halide. The yield, according to GCH, is 82%.

Example 42. The reaction is carried out as described in Example 11. 5.84 g (0.016 M) of 3- [2- (2-methyladamantyl)] - 5-bromveratrol are used as starting adamantylaryl halide. The yield, according to GCH, is 77%.

The above results indicate that our invented method for the direct production of lithium chloride substituted adamantylaryl magnesium halides by reaction with metallic magnesium magnesium in dry tetrahydrofuran under argon is general and yields consistently high desired product yields with all substrates used.

The proposed process for the preparation of substituted adamantylarylmagnesium halides also differs in technology and in the ability to easily increase the reaction volume.

Claims (6)

A process for the preparation of substituted adamantylmagnesium halides from substituted adamantylaryl halides by reaction with magnesium in an aprotic inert solvent (Grignard direct reaction), characterized in that the reaction is carried out in the presence of anhydrous lithium salt. 2. A process according to claim 1, wherein the reaction is carried out at -70 ° C to 80 ° C, most preferably at 20 ° C to 70 ° C. 3. The method according to p. 1 or 2, wherein the aprotic inert solvent is tetrahydrofuran. 4. The method of p. 1 to 3, wherein the anhydrous lithium salt is selected from the group consisting of lithium anhydrous chloride, lithium anhydrous bromide, lithium anhydrous iodide, lithium anhydrous sulfate, lithium anhydrous perchlorate, lithium anhydrous tetrafluoroborate, most preferably lithium anhydrous chloride . 5. The method of p. 1 to 4, characterized in that the anhydrous lithium salt is used in a stoichiometric ratio of 0.1 to 5.0 moles per mole of adamantylaryl halide, more preferably 1.2 to 1.5 moles of lithium anhydrous salt per adamantylaryl halide. 6. Process for the preparation of substituted adamantylmagnesium halides (I) according to claim 1. 1-5, characterized in that the adamantylmagnesium halides of the general formula (I) MgHal (R) m wherein A is selected from the group consisting of (1-adamantyl) or (2-adamantyl) groups having from 0 to 6 substituents independently selected from the group consisting of H , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, araigylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, -22heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, OR ¹ and NR ¹ R ² , wherein R ¹ and R ² are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl and heteroaryl; Hal is selected from the group consisting of Cl, Br or I, most preferably Br; R is selected from the group consisting of H, Cl, F, CF _3, F-C _r C ₁₀ alkyl groups, and CRC ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ C ₁₀ alkynyl, C _r C ₁₀ alkoxy groups which can contain fragments selected from the group consisting of O, S and -N (R ⁶ ); and substituents wherein two R ³ substituents together form an alkylenedioxy group; the substituents R -OSiR ³ R ⁴ R ^5, and R ^3, R ^4, R ⁵ are independently selected from the group consisting of C _r C ₁₀ alkyl, (CH _{2) t} (C ₆ -C ₁₀ aryl) and - (CH ₂₂ ) _t (4- to 10-membered heterocycles), where t is an integer from 0 to 5, and the substituents in which the CH ₂ ) _t group contains an inserted CC double or triple bond, and t is from 2 to 5 5; as well as substituents in which the aryl and heterocyclic groups are appropriately fused to C ₆ -C ₁₀ aryl groups, C ₅ -C ₈ saturated cycloalkanes or 5 to 10 membered heterocycles; as well as substituents wherein the aforementioned R, except H, is substituted with 1 to 3 R ⁶ groups and wherein R ⁶ is C 1 -C ⁶ alkyl or C 1 -C ₁₀ alkoxy; but n is 1 or 2; and m is 0 to 3; are prepared from compounds of formula (II) ( ^R ) m wherein A, Hal, R, n and m are as in formula (I) by their reaction with magnesium in an aprotic inert solvent (direct Grignard reaction) in the presence of anhydrous lithium salt.