Organolithium processes under continuous flow conditions

Abstract

The present invention relates to a method for forming C-C bonds using organolithium compounds under continuous flow conditions in a microreactor or mesoreactor system, wherein an 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 in situ or in a subsequent second reaction step to form an organic secondary product, and the organolithium compound RLi is used as a hydrocarbon solution or hydrocarbon mixture solution, and the RLi concentration is at least 3M, preferably at least 4M. [Selection diagram] None

Description

[Technical Field]

[0001] The present invention relates to a method for forming CC bonds using organolithium compounds under continuous flow conditions in a microreactor or mesoreactor system. [Background technology]

[0002] Organometallic species of group 1 main group elements, especially organolithium compounds, are essential tools in organic synthesis, since they act as carbanion equivalents and can be used directly or indirectly in a variety of carbon-carbon (CC) bond reactions. The most important reactions are additions to unsaturated functional groups, e.g., 1,2-additions to carbonyl compounds or carbon-nitrogen (CN) double and triple bonds; deprotonation reactions and halogen / metal exchange reactions. Organolithium compounds are also used in transmetallations (e.g., to form organozinc or organocuprate compounds) and in transition metal-catalyzed CC coupling reactions. These reactions have been known for quite some time and are reviewed in the corresponding textbooks (B.J. Wakefield, "Organolithium Methods", Academic Press, 1999). London, 1988, etc.).

[0003] Due to their favorable solubility and stability, organolithium compounds RLi, in which R is an alkyl group with 2 to 12 carbon atoms, are preferably produced and used as hydrocarbon solutions. Many of these organolithium products, such as the butyllithium isomers n-butyllithium, sec-butyllithium, and tert-butyllithium, as well as hexyllithium and octyllithium, are available on an industrial scale as solutions in hexane, heptane, cyclohexane, toluene, and the like. These solutions all have in common the complete absence of donor solvents such as ethers or amines. Lithium alkyls are highly soluble in such donor compounds, but these mixtures have poor thermal stability. For example, butyllithium decomposes in THF at 0°C with a half-life of 23.5 hours. Upon decomposition, 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 of the positive effect they can have on reactivity and selectivity. Butyllithium exists essentially as hexameric aggregates in hydrocarbons. The addition of THF disrupts these aggregates, forming larger, more reactive dimeric and trimeric species.

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

[0006] Organolithium compounds, primarily n-butyllithium and hexyllithium, are increasingly being used in continuous processes ("flow processes") in microreactors and mesoreactors. The driving force behind this trend is primarily safety considerations, as organolithium compounds are highly reactive and can ignite in air. Furthermore, significantly improved mixing conditions, faster heat dissipation, and the resulting controllable, usually shorter residence times allow reactions to be carried out at higher (but not ultra-low) temperatures than in classical batch processes. This allows for 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, available standard organolithium reagents are used as dilute hexane solutions with concentrations of 1.5-2.5 M (M = mol / l; 15-23 wt % for butyllithium) (see US 2016 / 0090361 A1).

[0007] However, the significantly larger surface area of ​​flow reactors compared to batch reactors and the smaller diameter of their channel structures are also disadvantages for reactions using butyllithium. Flow rate reductions and blockages, known as "reactor fouling," are frequently observed. These phenomena are due to various causes, such as the precipitation of salts in general or lithium hydroxide in particular (S. Laue, V. Haverkamp, ​​L. Mleczko, Org. Proc. Res. Dev. 2016, 20, 480-6). These phenomena mean that flow reactors cannot be performed stably for long periods of time, and therefore require frequent intervening cleaning cycles. This offsets the fundamental advantage of continuous reactions.

[0008] Furthermore, reaction yields are often lower than in batch processes under similar reaction conditions.

[0009] A method that avoids the drawbacks of the prior art, i.e., when organolithium compounds are used under continuous reaction control (flow reaction), Prevents solids settling and reactor fouling, and Allows reaction yields at least equivalent to those of batch methods There is a need for a method. Summary of the Invention

[0010] According to the present invention, in a method for forming a C-C bond under continuous flow conditions in a microreactor or 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 then be reacted with an electrophile in situ or in a subsequent second reaction step to form an organic secondary product, and the organolithium compound RLi is used as a hydrocarbon solution or hydrocarbon mixture solution, and the concentration of RLi is at least 3 M, preferably at least 4 M, to achieve the objective.

[0011] The drawbacks of the prior art are overcome by using more concentrated organolithium compounds in hydrocarbon solvents. Preferably, RLi concentrations of at least 3 M, particularly preferably at least 4 M, are 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, a concentration of at least 39 wt. % or at least 53 wt. %.

[0012] The method according to the invention further provides a hydrocarbon solvent, which is more concentrated than in the established prior art, as well as a butyllithium solution dissolved in the 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 of the components mentioned are introduced together into a flow microreactor or mesoreactor and mixed. 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 blend (i.e., a homogeneous mixture), simultaneously, or immediately after the lithium intermediate is formed. The donor solvent can be added according to variants A to D (Figure 1). In method A, the donor solvent is pumped separately into the reactor module. In method B, the donor solvent is mixed in two mixing modules: one with the more concentrated RLi solution and one 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. DETAILED DESCRIPTION OF THE INVENTION

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

[0014] The use of a more concentrated RLi solution reduces the amount of hydrocarbon solvent added to the reaction system, i.e., increases the weight ratio of donor solvent to hydrocarbon. Surprisingly, this approach has been found to generally reduce the tendency for solids to form, i.e., to operate continuous reactions for extended periods without the need for intervening wash / rinse cycles. After combining all components (i.e., organolithium solution, donor solvent, substrate, and optionally electrophilic reagent), and before reaction workup, e.g., hydrolysis, the weight fraction of hydrocarbon solvent in the reaction mixture (not counting 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 wt. %, and particularly preferably at most 8 wt. %.

[0015] Furthermore, yield increases are generally observed compared to batch procedures. Surprisingly, however, no first-order effect was observed, but an optimum was observed at a specific RLi concentration. The exact location of this optimum depends on the specific reaction and the individual materials used. In general, for butyllithium, the optimum RLi concentration is in the range of about 3M to 8M (26 to 75% by weight), with 3.5 to 7M (32 to 64% by weight) being particularly preferred.

[0016] Depending on the intended reaction type, substances capable of reacting with organolithium compounds can be used as substrates. 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 directing functional groups. In halogen / lithium exchange reactions, substances containing halogen ligands (preferably iodide and bromide) attached to the scaffolding aromatic or heteroaromatic system are preferred. The halogenated aromatic or heteroaromatic compounds may have one or more functional groups selected from the group consisting of F, Cl, Br, CN, COR, OR, OH, NR, NHR, NH, PR, P(O)R, CONR, CONHR, SR, SH, CF, and NO.

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

[0018] More concentrated organolithium reagents are used as solutions in hydrocarbon solvents, preferably containing hexane, heptane, octane, toluene, ethylbenzene, cumene, and / or xylene.

[0019] In the case of a deprotonation or halogen / lithium exchange reaction, the lithium intermediate is reacted with an electrophile, which is selected from carbonyl compounds (aldehydes, ketones, esters of carboxylic acids, carboxamides), nitriles, imines, halogens, halogen compounds, disulfides, and water. [Example]

[0020] The following examples illustrate the invention.

[0021] overview All reactions were carried out in a Vapourtec flow reactor system (4 pumps R2 / R4). Chemicals were obtained from Sigma Aldrich without further purification. More concentrated butyllithium solutions were provided by Albemarle.

[0022] Example 1: Regioselective deprotonation of N-methylpyrazole with butyllithium and subsequent reaction with boronic acid electrophiles [ka] The reaction according to the method described above was carried out batchwise at −5° C. using 1.6 M butyllithium in hexane. After reaction with isopropoxypinacol borate at −78° C. and warming to room temperature, the boronated species was obtained in 51% yield (WO 2007 / 120729 A2, p. 62).

[0023] The same reaction was investigated in a flow system. The experimental setup is shown in Figure 2.

[0024] The starting materials, butyllithium (BuLi) and N-methylpyrazole (pyrazole), in a 0.8 M THF solution were placed in a loop and uniformly mixed using a 400 μL static mixer with a pump. From a separate loop, isopropoxypinacol borate (boronate), also in a 0.8 M THF solution, was added to the other product stream at room temperature. The combined product streams were sent to a 10 mL retention time module P4 for reaction. The retention time in P4 was approximately 5 minutes.

[0025] The reaction solution was quenched with acid, worked up, and characterized by NMR spectroscopy using an internal standard. The results are listed in the table below. [Table 1]

[0026] When a 1.6 M (15 wt%) solution of BuLi in hexane is used, there is a relatively high proportion of hexane in the reaction mixture, 17%. The product yield of 29% is unsatisfactory and is below the comparative value for the batch reaction (51%). When the BuLi concentration is increased to 3.2 M and 5.3 M (corresponding to 29 wt% and 49 wt%), a very significant yield increase of 61% and 66%, respectively, is observed. When the BuLi concentration is further increased to 8 M (73 wt%), a slight decrease in product yield is observed, but it is still comparable to the batch procedure.

[0027] It was observed that when a 1.6 M BuLi solution was used, the reaction mixture was clearly turbid (solids precipitated) before the reaction was stopped, whereas when more concentrated BuLi solutions were used, a homogeneous clear solution was present.

[0028] Example 2: Lithium-halogen exchange with 5-bromopyrimidine and subsequent addition to bis(4-chlorophenyl) ketone Lithium-bromine exchange of 5-bromopyrimidine (bromide) is carried out in a batchwise manner at −95° C. Using 1.6 M butyllithium in hexane, the yield is 34% (HM Taylor, CD Jones, JD Village, KS Hirsch, TJ Kress, D. Weaver, J. Med. Chem. 1987, 30, 1359-65, Table I, ex. 1). [ka]

[0029] Reactions on the Vapourtec R2 / R4 (Figure 3) were carried out as follows: Three addition loops, each with a volume of 2 ml, were charged with the starting materials. All components were used as solutions containing THF (see table below for details). BuLi solutions of different concentrations were diluted with THF to the desired volume of 2 ml before being charged into the loops. All starting materials were used in a 1:1:1 molar ratio.

[0030] The two substrate streams, bis(4-chlorophenyl)ketone (ketone) and bromide, were combined using a T-piece and mixed, followed by the addition of BuLi solution. The combined streams were pumped into a static mixer where they were vigorously mixed. The mixture was then transferred to residence time module P4, where the actual reaction took place. Both the static mixer and residence time module were cooled to -78°C using a dry ice / acetone bath. 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 in an aliquot.

[0031] The reaction results are shown in the table below. [Table 2]

[0032] A very low product yield of 22% is observed when a dilute 1.6 molar BuLi solution is used. Increasing the BuLi concentration or decreasing the proportion of hexane in the reaction mixture significantly increases the yield; when a 5.3 molar (49 wt%) solution is used, the yield is 42%, significantly higher than the batch reaction result (34%). [Brief explanation of the drawings]

[0033] [Figure 1] [Figure 2] [Figure 3]

Claims

1. 1. A method for forming organic secondary products via C-C single bond formation in a microreactor or mesoreactor system under continuous flow conditions, comprising: reacting an organic substrate with an organolithium compound in the presence of a donor solvent to form a Li intermediate in said system; and reacting the Li intermediate with an electrophile in situ or in a subsequent second reaction step to form an organic secondary product; The organolithium compound is used as a hydrocarbon solution or a hydrocarbon mixture solution, and the concentration of the organolithium compound in the solution is at least 3M; and the organic substrate is a halogenated aromatic or heteroaromatic compound; The organolithium compound is represented by the formula RLi, where R is an alkyl group having 2 to 12 C atoms; The donor solvent is selected from the group consisting of ethers, amines, sulfoxides, and phosphorus triamides; and the electrophile is a carbonyl compound, and the carbonyl compound is selected from the group consisting of an aldehyde, a ketone, a carboxylic acid ester, and a carboxamide; The method.

2. 2. The method of claim 1, wherein butyllithium or hexyllithium is used as the organolithium compound, and wherein 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.

3. 3. The method of claim 2, wherein 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.

4. 3. The method according to claim 1, wherein the concentration of the organolithium compound in the solution is in the range of 3 to 8M.

5. 5. The method of claim 4, wherein the concentration of the organolithium compound in the solution is in the range of 3.5 to 7M.

6. The method according to any one of claims 1 to 5, characterized in that the hydrocarbon solvent comprises hexane, heptane, octane, toluene, ethylbenzene, cumene, and / or xylene.

7. 2. The method of claim 1, wherein 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, ammonia, trimethylamine, triethylamine, tributylamine, tetramethylethylenediamine, 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 thereof is used as the donor solvent.

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