Organolithium process under continuous flow conditions

Abstract

To provide methods for forming CC bonds with use of organolithium compounds under continuous flow conditions in a micro or meso reactor system.SOLUTION: An organic substrate is reacted with an alkyl lithium compound in the presence of a donor solvent to form an Li intermediate, which is reacted with an electrophile in situ or in a subsequent second reaction step to form an organic secondary product, and an organolithium compound RLi is used as a hydrocarbon solution or a hydrocarbon mixed solution, and the RLi concentration is at least 3 M, preferably at least 4 M.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for forming a C—C bond using an organolithium compound under continuous flow conditions in a microreactor system or a mesoreactor system.

Background Art

[0002] Organometallic species of Group 1 typical elements, particularly organolithium compounds, act as carbanion equivalents and are an essential means in organic synthesis because they can be used directly or indirectly in various carbon-carbon (C—C) bond reactions. The most important reactions are addition to unsaturated functional groups, for example, 1,2-addition to carbonyl compounds or double and triple bonds of carbon-nitrogen (C—N); deprotonation reactions as well as halogen / metal exchange reactions. Organolithium compounds are also used in transmetalation (for example, the formation of organozinc compounds or organocopper compounds) and in C—C coupling reactions catalyzed by transition metals. These reactions have been known for quite some time and are outlined in the corresponding textbooks (B. J. Wakefield, “Organolithium Methods”, Academic Press London, 1988, etc.).

[0003] Since organolithium compounds have good solubility and stability, organolithium compounds RLi having an alkyl group R with 2 to 12 carbon atoms are preferably produced and used as hydrocarbon solutions. Many of such organolithium products, for example, n-butyllithium, sec-butyllithium and tert-butyllithium which are butyllithium isomers, as well as hexyllithium and octyllithium, are available industrially as solutions in hexane, heptane, cyclohexane, toluene and the like. All of these solutions commonly contain no donor solvents such as ethers or amines. Lithium alkyls are very soluble in such donor compounds, but these mixtures have only insufficient thermal stability. For example, butyllithium decomposes at 0 °C in THF with a half-life of 23.5 hours. When decomposition occurs, ethylene and enolate of acetaldehyde are formed. C4H8O + C4H9Li → H2C=CH2 + LiO-CH=CH2 + C4H 10

[0004] However, donor solvents are essential for many reactions using RLi compounds because they can have a positive effect on reactivity and selectivity. Butyllithium essentially exists as a hexameric aggregate in hydrocarbons. By adding THF, these aggregates are destroyed and more reactive dimeric and trimeric species are formed.

[0005] When such reaction acceleration by donor solvents is required, donor solvents are generally used only in situ, that is, they are added only using the substrates used in individual reactions. The reaction temperature is selected such that the desired reaction proceeds much faster than the attack on the donor solvent. Many reactions using organolithium compounds are carried out at low temperatures (often in the temperature range of -100 to 0 °C). For example, the bromine / lithium exchange reaction is known to occur very rapidly at -78 °C in the presence of THF or diethyl ether, so side reactions, that is, attacks on the solvent, are irrelevant.

[0006] Organolithium compounds, mainly n-butyllithium and hexyllithium, are increasingly being used in continuous processes (so-called "flow processes") in microreactors and mesoreactors. The factors behind this trend are mainly safety considerations, as organolithium compounds are highly reactive and can ignite in air. Furthermore, due to significantly improved mixing conditions, faster heat dissipation, and the resulting controllable and usually shorter residence times, reactions can often be carried out at higher (but not cryogenic) temperatures than in classical batch processes, enabling process intensification and savings through reduced energy consumption. For an overview, see A. Nagaki and J.-I. Yoshida, Top. Organomet. Chem. (2016) 57, 137-76. Generally, commercially available standard organolithium reagents are used as diluted hexane solutions with concentrations of 1.5 - 2.5 M (M = mol / l; 15 - 23 wt% in the case of butyllithium) (see US2016 / 0090361A1). However, the significantly larger surface area of flow reactors compared to batch reactors and the small diameter of their channel structures can also be a drawback in reactions using butyllithium. Reduced flow rates and blockages, so-called "reactor fouling", are often observed. These phenomena are caused by different reasons, such as the precipitation of salts in general or specifically lithium hydroxide (S. Laue, V. Haverkamp, L. Mleczko, Org. Proc. Res. Dev. 2016, 20, 480-6). These phenomena mean that flow reactions cannot be carried out stably over long periods, and thus it is necessary to intervene with cleaning cycles repeatedly. The basic advantages of continuous reactions are thereby offset.

[0007] Moreover, the reaction yields are often lower compared to batch methods under similar reaction conditions.

[0008] Furthermore, the reaction yields are often lower compared to batch methods under similar reaction conditions.

[0009] A method for avoiding the drawbacks of the prior art, i.e., when an organolithium compound is used under continuous reaction control (flow reaction), ● preventing solid precipitation and reactor fouling, and ● enabling at least equivalent reaction yields compared to batch methods is needed.

Summary of the Invention

[0010] According to the present invention, in the case of a method for forming a C-C bond under continuous flow conditions in a microreactor system or a mesoreactor system, an organic substrate is reacted with an organolithium compound in the presence of a donor solvent to form a Li intermediate, which can be reacted with an electrophilic reagent in situ or in a subsequent second reaction step to form an organic secondary product. The organolithium compound RLi is used as a hydrocarbon solution or a hydrocarbon mixed solution, and the RLi concentration is at least 3 M, preferably at least 4 M, to achieve the object.

[0011] The drawbacks of the prior art are overcome by using a more concentrated organolithium compound in a hydrocarbon-based solvent. Preferably, an RLi concentration of at least 3 M, particularly preferably at least 4 M, is used. In the case of butyllithium, this corresponds to a concentration of at least 27 wt% or at least 36 wt%, and in the case of hexyllithium, it corresponds to a concentration of at least 39 wt% or at least 53 wt%.

[0012] The method according to the invention further provides a hydrocarbon solvent that is more concentrated than in the case of established prior art, as well as a butyllithium solution dissolved in a substrate and one or more donor solvents. These donor solvents are selected from the group consisting of ethers, amines, sulfoxides, phosphorus triamides, and similar functionalized substances. All the components mentioned are fed and mixed together into a flow-type microreactor or a mesoreactor. The reaction according to the invention is, for example, an addition, deprotonation, or halogen / lithium exchange reaction, and the resulting lithium intermediate can be reacted with an electrophile by known methods. Depending on the reaction system, the electrophile can be added to the reaction system as a formulation (i.e., a homogeneous mixture), simultaneously, or immediately after the lithium intermediate is formed. The donor solvent can be added according to variants A - D (Figure 1). In method A, the donor solvent is pumped separately into the reactor module and in method B, it is mixed in two mixing modules, a mixing module with the more concentrated RLi solution and a mixing module with the substrate. In method C, the donor solvent is only added to the substrate, and in method D, the donor solvent is only added to the more concentrated RLi solution.

Embodiments for Carrying Out the Invention

[0013] Reactors for small-scale continuous processes are called microreactors (channel structure less than 1 mm) or mesoreactors (channel structure from more than 1 mm to the centimeter range) depending on their dimensions, i.e., the diameter of their channel structure. They are available from various suppliers, for example, Corning Glass, Vapourtec, Fraunhofer-ICT-IMM, or Ehrfeld Mikrotechnik, etc.

[0014] By using a more concentrated RLi solution, the amount of hydrocarbon solvent added to the reaction system is reduced, i.e., the weight ratio of the donor solvent to the hydrocarbon is increased. Surprisingly, this approach generally results in a reduced tendency for solids to form, i.e., it has been found that the continuous reaction can be operated for a long period without the need to insert a washing / rinsing cycle. After combining all the components (i.e., the organolithium solution, the donor solvent, the substrate, and optionally the electrophile), and before the reaction treatment, e.g., before hydrolysis, the weight ratio of the hydrocarbon solvent in the reaction mixture (not considering the alkane RH or halide R-Hal (Hal = Cl, Br, or I) optionally formed from the organolithium compound RLi in the reaction) is at most 11% by weight, particularly preferably at most 8% by weight.

[0015] Furthermore, generally, an increase in yield is observed compared to the batch method. However, surprisingly, no primary effect was observed, but optimal conditions were observed at a specific RLi concentration. Exactly where these optimal conditions exist varies depending on the specific reaction and the individual substances used. Generally, in the case of butyllithium, the optimal conditions for the RLi concentration are in the range between about 3M and 8M (26 - 75% by weight), particularly preferably in the range between 3.5 and 7M (32 - 64% by weight).

[0016] Substances capable of reacting with the organolithium compound can be used as substrates depending on the intended reaction type. In the case of deprotonation, these are preferably CH - acidic compounds, i.e., substances with a higher acidity than that of aliphatic CH compounds, such as aromatic or heteroaromatic compounds with an orienting functional group. In the halogen / lithium exchange reaction, substances containing a halogen ligand (preferably iodide and bromide) bonded to a scaffolding aromatic or heteroaromatic system are preferred. The halogenated aromatic or heteroaromatic compounds can have one or more functional groups selected from the group consisting of F, Cl, Br, CN, CO2R, OR, OH, NR2, NHR, NH2, PR2, P(O)R2, CONR2, CONHR, SR, SH, CF3, NO2.

[0017] From the group of ethers, the following compounds are preferably used as donor solvents: 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. From the group of amines, the following compounds are preferably used: ammonia, trimethylamine, triethylamine, tributylamine, tetramethylethylenediamine (TMEDA), bis(2-dimethylaminoethyl)(methyl)amine (PMDTA). In addition, hexamethylphosphoramide (HMPA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) are also preferably used.

[0018] The more concentrated organolithium reagent is used as a solution dissolved in a hydrocarbon solvent. The hydrocarbon solvent preferably contains hexane, heptane, octane, toluene, ethylbenzene, cumene, and / or xylene.

[0019] In the case of deprotonation or halogen / lithium exchange reactions, the lithium intermediate is reacted with an electrophilic reagent, and such electrophilic reagents are selected from carbonyl compounds (aldehydes, ketones, esters of carboxylic acids, carboxamides), nitriles, imines, halogens, halogen compounds, disulfides, and water.

Examples

[0020] The present invention will be described by the following examples.

[0021] Overview All reactions were carried out in a flow reactor system (4 pumps R2 / R4) manufactured by Vapourtec. Chemicals were obtained from Sigma Aldrich and no further purification was performed. The more concentrated butyllithium solution was provided by Albemarle.

[0022] Example 1: Regioselective Deprotonation of N-Methylpyrazole with Butyllithium and Subsequent Reaction with a Boronic Acid Electrophile

Chemical formula

[0023] The same reaction was investigated in a flow manner. The experimental setup is shown in the figure (Figure 2).

[0024] A 0.8 M THF solution of butyllithium (BuLi) and N-methylpyrazole (pyrazole) as starting materials was arranged in a loop and uniformly mixed by a pump using a static mixer with a volume of 400 μl. Isopropoxypinacol borate (boronate), also as a 0.8 M THF solution, from another loop was added to the other product stream at room temperature. The combined product stream was sent to the reaction in a residence time module P4 with a volume of 10 ml. The residence time in P4 was about 5 minutes.

[0025] The reaction of the reaction solution was stopped using an acid, subjected to reaction treatment, and examined by NMR spectroscopy using an internal standard. The results are described in the following table.

Table 1

[0026] When using a 1.6 M (15 wt%) hexane solution of BuLi, there is a relatively high proportion of hexane, 17%, in the reaction mixture. The product yield of 29% is insufficient and below the comparative value (51%) for batch reactions. When the BuLi concentration was increased to 3.2 M and 5.3 M (equivalent to 29 wt% and 49 wt%), very clear increases in yield of 61% and 66% were observed, respectively. When the BuLi concentration was further increased to 8 M (73 wt%), a slight decrease in product yield was observed, but it was still equivalent to the batch method.

[0027] When using a 1.6 M BuLi solution, before the reaction stopped, the reaction mixture was clearly turbid (a solid had precipitated), but when using a more concentrated BuLi solution, it was observed that a homogeneous clear solution was present.

[0028] Example 2: Lithium-halogen exchange with 5-bromopyrimidine and subsequent addition to bis(4-chlorophenyl) ketone The lithium-bromine exchange of 5-bromopyrimidine (bromide) was carried out at -95 °C by a batch method. When using a 1.6 M hexane solution of butyllithium, 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, Table I, ex. 1).

Chemical formula

[0029] The reaction in Vapourtec R2 / R4 (Figure 3) was carried out as follows. Three addition loops with a capacity of 2 ml each were filled with starting materials. All components were used as THF-containing solutions (see the following table for details). BuLi solutions with different concentrations were diluted with THF to a desired volume of 2 ml and then filled into the loops. All starting materials were used in a 1:1:1 molar ratio.

[0030] Two substrate streams of bis(4-chlorophenyl) ketone (ketone) and bromide were combined using a T-piece, mixed, and then a BuLi solution was added. The combined stream was pumped into a static mixer where it was vigorously mixed. The mixture was then transferred to residence time module P4 where the actual reaction occurred. Both the static mixer and the residence time module were cooled to -78 °C using a dry ice / acetone bath. The reaction of the product stream exiting the residence time module was quenched with saturated ammonium chloride solution. HPLC analysis was used to confirm the completion of the reaction for the aliquots.

[0031] The reaction results are described in the table below.

Table 2

[0032] Using a 1.6 molar diluted BuLi solution, a very low product yield of 22% is observed. Increasing the BuLi concentration or decreasing the proportion of hexane in the reaction mixture leads to a significant increase in the yield, and when a 5.3 molar (49 wt%) solution is used, the yield is 42%, significantly higher than the batch reaction result (34%).

Brief Description of the Drawings

[0033]

Figure 1

Figure 2

Figure 3

Claims

1. 1. A method for forming C-C bonds using organolithium compounds under continuous flow conditions in a microreactor or mesoreactor system, comprising: The organic substrate is reacted with an alkyllithium compound in the presence of a donor solvent to form a Li intermediate, which can be reacted with an electrophile, either in situ or in a subsequent second reaction step, to form an organic secondary product; The organolithium compound RLi is used as a hydrocarbon solution or a mixed hydrocarbon solution, and the RLi concentration is at least 3M, preferably at least 4M. The method according to claim 1,

2. 2. The method according to claim 1, characterized in that the organolithium compound is selected from alkyllithium compounds RLi, where R is an alkyl group having 2 to 12 C atoms.

3. 3. The method according to claim 1 or 2, characterized in that butyllithium or hexyllithium is used as the organolithium compound, and that the butyllithium concentration is at least 27% by weight or the hexyllithium concentration is at least 39% by weight.

4. 4. The method of claim 3, wherein the butyllithium concentration is at least 36% by weight or the hexyllithium concentration is at least 53% by weight.

5. The method according to claims 1 to 3, characterized in that the organolithium concentration is in the range of 3 to 8M.

6. The method of claim 5, wherein the organolithium concentration is in the range of 3.5 to 7M.

7. 7. The method according to claims 1 to 6, characterized in that the organolithium compound is present as a solution dissolved in a hydrocarbon solvent, which preferably contains hexane, heptane, octane, toluene, ethylbenzene, cumene, and / or xylene.

8. The method according to claims 1 to 7, characterized in that the donor solvent is selected from the group consisting of ethers, amines, sulfoxides, phosphorus triamides.

9. 9. The process according to claim 8, 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, tetramethylethylenediamine, bis(2-dimethylaminoethyl)(methyl)amine, hexamethylphosphoramide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or any mixture thereof is used as donor solvent.

10. The weight percentage of hydrocarbon solvent in the reaction mixture after combining the organolithium solution, the donor solvent, the substrate, and the electrophile components and before reaction workup is at most 11% by weight, ignoring the alkane RH or the halide R-Hal (Hal=Cl, Br, or I) optionally formed in the reaction from the organolithium compound. The method according to any one of claims 1 to 9, characterized in that

11. 11. The process according to claim 10, characterized in that the weight proportion of hydrocarbon solvent is at most 8% by weight.

12. The method according to claims 1 to 11, characterized in that a carbonyl compound 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 electrophilic reagent.

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