Organolithium process under continuous flow conditions

Abstract

The invention relates to methods for CC bond formation using organolithium compounds under continuous flow conditions in a micro or mesoreactor system, wherein an organic substrate is reacted with an alkyl lithium compound in the presence of a donor solvent to form a Li intermediate, which can be reacted in situ or subsequently in a second reaction step with an electrophile to form an organic secondary product, the organolithium compound RLi being used as a solution in a hydrocarbon or hydrocarbon mixture and the RLi concentration being at least 3 M, preferably at least 4 M.

Claims

1. A method for CC bond formation under continuous flow conditions in a microreactor or mesoreactor system, characterized by: reacting an organic substrate in the system with an organolithium compound in the presence of a donor solvent to form a Li intermediate, and reacting the Li intermediate in situ or subsequently in a second reaction step in the system with an electrophile to form an organic secondary product, the organolithium compound being used as a solution in a hydrocarbon or hydrocarbon mixture, and the organolithium compound concentration of the solution being in the range of 3.2 M to 8 M.

2. The method according to claim 1, characterized in that the organolithium compound is represented by the formula RLi where R=alkyl group having 2-12 C atoms.

3. The method according to claim 1, characterized in that either butyllithium or hexyllithium is used as the organolithium compound and that, when butyllithium is used, the butyllithium concentration is at least 27% by weight of the solution, and when hexyllithium is used, the hexyllithium concentration is at least 39% by weight of the solution.

4. The method according to claim 3, characterized in that the butyllithium concentration is at least 36% by weight of the solution, and the hexyllithium concentration is at least 53% by weight of the solution.

5. The method according to claim 1, characterized in that the organolithium compound concentration of the solution is in the range of 3.5 M 7 M.

6. The method according to claim 5, characterized in that the hydrocarbon solvent comprises hexanes, heptanes, octanes, toluene, ethylbenzene, cumene, and/or xylenes.

7. The method according to claim 6, characterized in that the donor solvent is selected from the group of ethers, amines, sulfoxides, and phosphorus triamides.

8. The method according to claim 7, characterized in that dimethyl ether, diethyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, methyl tert-amyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 4-methyltetrahydropyran, 1,2-dimethoxymethane and higher glymes; ammonia, trimethylamine, triethylamine, tributylamine, tetramethylethylene diamine, bis(2-dimethylaminoethyl)(methyl)amine, hexamethylphosphoramide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or any mixture of any two or more of the foregoing is used as the donor solvent.

9. The method according to claim 8, characterized in that the weight proportion of hydrocarbon solvent, without taking into account the alkane RH or halide R-Hal (Hal=Cl, Br, or I) optionally formed from the organolithium compound in the reaction in the reaction mixture, after combining the solution, the donor solvent, the substrate, and the electrophile components and before workup is at most 11% by weight.

10. The method according to claim 9, characterized in that the weight proportion of hydrocarbon solvent is a maximum of 8% by weight.

11. The method according to claim 10, characterized in that carbonyl compounds selected from the group consisting of aldehydes, ketones, carboxylic acid esters, carboxamides or nitriles, imines, halogens, halogen compounds, disulfides, and water are used as the electrophile.

12. The method according to claim 1 characterized in that the hydrocarbon solvent comprises hexanes, heptanes, octanes, toluene, ethylbenzene, cumene, and/or xylenes.

13. The method according to claim 1, characterized in that the donor solvent is selected from the group of ethers, amines, sulfoxides, phosphorus triamides.

14. The method according to claim 13, characterized in that dimethyl ether, diethyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, methyl tert-amyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 4-methyltetrahydropyran, 1,2-dimethoxymethane and higher glymes; ammonia, trimethylamine, triethylamine, tributylamine, tetramethylethylene diamine, bis(2-dimethylaminoethyl)(methyl)amine, hexamethylphosphoramide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or any mixture of any two or more of the foregoing is used as the donor solvent.

15. The method according to claim 1, characterized in that the weight proportion of hydrocarbon solvent, without taking into account the alkane RH or halide R-Hal (Hal=Cl, Br, or I) optionally formed from the organolithium compound in the reaction in the reaction mixture, after combining the solution, the donor solvent, the substrate, and the electrophile components and before workup is at most 11% by weight.

16. The method according to claim 15, characterized in that the weight proportion of hydrocarbon solvent is a maximum of 8% by weight.

17. The method according to claim 16, characterized in that carbonyl compounds selected from the group consisting of aldehydes, ketones, carboxylic acid esters, carboxamides or nitriles, imines, halogens, halogen compounds, disulfides, and water are used as the electrophile.

18. The method according to claim 1, characterized in that carbonyl compounds selected from the group consisting of aldehydes, ketones, carboxylic acid esters, carboxamides or nitriles, imines, halogens, halogen compounds, disulfides, and water are used as the electrophile.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 illustrates variant methods by which the donor solvent can be handled in accordance with one aspect of the invention.

(2) FIG. 2 schematically illustrates the experimental setup of the flow mode reaction referenced in Example 1 below.

(3) FIG. 3 schematically illustrates the reaction in the Vapourtec R2/R4 referenced in Example 2 below.

EXAMPLES

(4) The invention is illustrated by the following examples.

(5) General

(6) All reactions were carried out in a flow reactor system (4 pumps R2/R4) from Vapourtec. The chemicals were obtained from Sigma Aldrich without further purification. More concentrated butyllithium solutions were provided by Albemarle.

Example 1

(7) Regioselective Deprotonation of N-methylpyrazole with Butyllithium and Subsequent Reaction with a Boronate Electrophile

(8) The reaction according to:

(9) ##STR00001##
was carried out in batch mode with 1.6 M butyllithium solution in hexane at −5° C. After reaction with isopropoxypinacol borate at −78° C. and warming to room temperature, the borylated species was obtained in a yield of 51% (WO2007/120729A2, p. 62).

(10) The same reaction was investigated in flow mode. The experimental setup is shown in the figure (FIG. 2):

(11) The starting materials butyllithium (BuLi) and the N-methylpyrazole (pyrazole) as a 0.8 M solution in THF were placed in loops and mixed homogeneously by means of pumps in a static mixer with a volume of 400 μl. The isopropoxypinacol borate (boronate) from another loop, also as 0.8 M solution in THF, was added to the other product stream at room temperature. The combined product stream was allowed to react in a residence time module P4 with a volume of 10 ml. The residence time in P4 was approx. 5 minutes.

(12) The reaction solution was quenched with acid, worked up and examined by NMR spectroscopy using an internal standard. The results are set forth in the following table:

(13) TABLE-US-00001 Experi- Concen- Loop Wt % hexane ment Starting tration size/ Yield in reaction number Loop material (mol/l) ml (%) mixture  1* 1 Pyrazole 0.8 2 3 Boronate 0.8 2 29 13 2 BuLi 1.6 1 2 1 Pyrazole 0.64 2.5 3 Boronate 0.8 2 61 5.5 2 BuLi 3.2 0.5 3 1 Pyrazole 0.59 2.7 3 Boronate 0.8 2 66 2 2 BuLi 5.3 0.3 1 Pyrazole 0.57 2.8 4 3 Boronate 0.8 2 51 0.6 2 BuLi 8 0.2 *Comparative example, not according to the invention

(14) When using the 1.6 M (15% by weight) BuLi solution in hexane there is a relatively high hexane proportion of 17% in the reaction mixture. The product yield of 29% is unsatisfactory and is below the comparative value of the batch reaction (51%). When the BuLi concentration is increased to 3.2 and 5.3 M (corresponding to 29 and 49% by weight), very clearly increased yields of 61 and 66%, respectively, are observed. With a further increase of the BuLi concentration to 8 M (73% by weight), a slight drop in the product yield is noted, but it is still on a par with the batch procedure.

(15) When using the 1.6 M BuLi solution, it was observed that the reaction mixture was clearly cloudy before quenching (solids had precipitated), while homogeneous, clear solutions were present when using the more concentrated BuLi solutions.

Example 2

(16) Lithium-Halogen Exchange at 5-Bromopyrimidine with Subsequent Addition to bis(4-chlorophenyl)ketone

(17) The lithium-bromine exchange of 5-bromopyrimidine is carried out in a batch procedure at −95° C. Using the 1.6 M solution of butyllithium in hexane, the yield is 34% (H. M. Taylor, C. D. Jones, J. D. Davenport, K. S. Hirsch, T. J. Kress, D. Weaver, J. Med. Chem. 1987, 30, 1359-65, see Table I, ex. 1).

(18) ##STR00002##

(19) The reaction in the Vapourtec R2/R4 (FIG. 3) was carried out as follows: three addition loops, each with a volume of 2 ml, were filled with the starting materials. All components were used as THF-containing solutions (for details, see table below). BuLi solutions with different concentrations were diluted with THF to the desired volume of 2 ml before filling into the loop. All starting materials were used in a molar ratio of 1:1:1.

(20) The two substrate streams of the ketone and the bromide were combined using a T-piece and mixed and then the BuLi solution was added. The combined streams were pumped into a static mixer and mixed there vigorously. The mixture was then transferred to a residence time module P4, in which the actual reaction took place. Both the static mixer as well as the residence time module were cooled to −78° C. by means of a dry ice/acetone bath. The product stream flowing from the residence time module was quenched with a saturated ammonium chloride solution. Aliquots were checked for reaction completion using HPLC analysis.

(21) The reaction results are set forth in the following table:

(22) TABLE-US-00002 Experi- Concen- Loop Wt % hexane ment Starting tration volume Yield in reaction. number Loop material (mol/l) (ml) (%) mixture  1* 1 Ketone 1.6 2 22 2 Bromide 1.6 2 23 3 BuLi 1.6 2 2 1 Ketone 1.6 2 34 2 Bromide 1.6 2 9 3 BuLi  3.2** 2 3 1 Ketone 1.6 2 42 2 Bromide 1.6 2 4 3 BuLi  5.3** 2 4 1 Ketone 1.6 2 31 2 bromide 1.6 2 1 3 BuLi  8** 2 *Comparative experiment, not according to the invention; **BuLi/hexane concentration used, diluted to a volume of 2 ml with THF

(23) When using the dilute 1.6 molar BuLi solution a very low product yield of 22% is observed. With an increase in the BuLi concentration or a decrease in the proportion of hexane in the reaction mixture, the yield increases significantly and, when using the 5.3 molar (49% by weight) solution, it is at 42% significantly higher than the result of the batch reaction (34%).