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DOI: 10.1055/s-0040-1706536
Continuous-Flow Reactions Mediated by Main Group Organometallics
In memory of Professor Jun-ichi Yoshida
Abstract
The generation of reactive organometallic reagents in batch is often complicated by the low thermal stability of these important synthetic intermediates and can require low reaction temperatures and special reaction conditions. However, the use of continuous-flow setups and microreactors has led to a revolution in this field. In this short review, an overview is given of recent advances in this area, with a focus on the main group organometallics of Li, Na, and K.
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Key words
flow chemistry - organolithium compounds - organosodium compounds - organomagnesium compounds - Barbier conditionsBiographical Sketches
Johannes H. Harenberg was born in Berlin (Germany) in 1992. After his undergraduate studies at the Ludwig-Maximilians-Universität (Munich), he joined the research group of Professor Paul Knochel for his master´s thesis and started his Ph.D. in the same group in 2019. His current research work is focused on the application of alkali organometallic species in continuous flow.
Niels Weidmann was born in Bensheim (Germany) in 1991. He studied chemistry at the Ludwig-Maximilians-Universität (Munich) and joined the research group of Professor Paul Knochel in 2017. His research focuses on the preparation of lithium, sodium, and potassium organometallics by metalation and halogen–metal exchange in continuous flow.
Paul Knochel was born 1955 in Strasbourg (France). He did his undergraduate studies at the University of Strasbourg (France), and his Ph.D. at the ETH-Zürich with Professor D. Seebach. He spent four years at the CNRS at the University Pierre and Marie Curie in Paris with Professor J.-F. Normant and one year of postdoctoral studies at Princeton University in the laboratory of Professor M. F. Semmelhack. In 1987, he accepted a position as assistant professor at the University of Michigan at Ann Arbor, MI. In 1991, he became full professor at that university, and in 1992, he moved to Philipps-University at Marburg (Germany) as C4-Professor in Organic Chemistry. In 1999, he moved to the chemistry department of Ludwig-Maximilians-University in Munich (Germany). His research interests include the development of novel organometallic reagents and methods for use in organic synthesis, asymmetric catalysis, and natural product synthesis. Professor Knochel has received many distinguished prizes, including the Berthelot Medal of the Academie des Sciences (Paris), the IUPAC Thieme Prize, the Otto Bayer Prize, the Leibniz Prize, the Arthur C. Cope Scholar Award, the Karl Ziegler Prize, the Nagoya Gold Medal, the H. C. Brown Award, and the Paul Karrer gold medal. He is member of the Académie des Sciences, the Bavarian Academy of Science, the German Academy of Sciences Leopodina, and the Center for Advanced Studies. In 2009 he received the ERC grant ‘New Organometallics.’ He is the author of over 900 publications (H-index = 93).
Introduction
The generation of reactive organometallic reagents in batch is often complicated by the low thermal stability of these important synthetic intermediates[1] and can require low reaction temperatures or special reaction conditions (concentration, additives, or special solvent mixtures). In several cases, the batch procedure leads only to low yields of products due to the short lifetime and difficult handling of the organometallic reagents generated in situ. Recently, the use of continuous-flow setups and microreactors has led to a revolution in this field, and pioneering works by the groups of Ley,[2] Yoshida,[3] Organ,[4] and others[5] have popularized the performance of reactions involving highly reactive organometallics in continuous flow. In this short review, we give an overview of some of the advances in this field that have been reported in recent years. The review focuses on main group organometallics of Li, Na, and K.[6]
# 2
Early Work Using Lithium Organometallics in Continuous Flow
In academic research, the use of microreactors in which the residence time is well defined has allowed important developments to be made in alkali-metal chemistry, with applications in organic synthesis. This focus on synthetic methodology is especially apparent in the work of Yoshida, who, as early as 2007, showed that the control of the residence time in a microtube reactor permits flow-trapping of (2-bromophenyl)lithium (2), generated from 1,2-dibromobenzene (1) by a Br/Li-exchange in a continuous-flow setup. The lithiated arene 2 did not undergo competitive elimination to form benzyne (3); instead, quenching by various electrophiles was readily achieved, leading to products of type 4 (Scheme [1]).[7]
The use of a microflow system allowed a remarkably simple synthesis of nonsymmetrical diarylethene derivatives of type 5, which are difficult to prepare in batch. Low temperatures were not necessary, and the substitution reaction on octafluorocyclopentene (6) proceeded at 10 °C with the highest yield (Scheme [2]).[8]
Yoshida showed also that the stereoselective lithiation of functionalized organic molecules could be achieved advantageously in continuous flow. Thus, the lithiation of the stilbene oxide 7 proceeded at –48 °C within 23.8 seconds (Scheme [3]). After flow-quenching with Me3SiCl, the tetrasubstituted epoxide 8 was obtained with high stereoselectivity in almost quantitative yield.[9]
The palladium-catalyzed cross-coupling of aryllithiums has been achieved in batch by using toluene as solvent with appropriate Pd catalysts.[10] Yoshida reported the performance of such cross-couplings (Murahashi cross-couplings) at 50 °C [residence time (t R) = 94 s] by using a microreactor and Organ’s catalyst PEPPSI-SIPr (5%) in cyclopentyl methyl ether (CPME) (Scheme [4]). When generated through Br–Li exchange using BuLi, aryllithium intermediates such as 2-thienyllithium are prone to undergo side reactions, such as the nucleophilic attack by BuBr, as well as further Br–Li exchanges. Those side reactions were suppressed under flow conditions.[3b]
Asymmetric carbolithiations have been achieved on conjugated enynes, leading to chiral allenes.[11] By using a flow microreactor, Yoshida and co-workers generated the highly reactive carbenoid 10 by lithiation of trans-1,2-dichloroethene (9) with BuLi at 0 °C (t R = 0.055 s) (Scheme [5]). After electrophilic quenching and a second lithiation with s-BuLi at –78 °C (t R = 4.6 s), a second functionalized carbenoid was generated, which, after a second electrophilic trapping, led to trans-dichloroalkene derivatives such as 11. Under batch conditions, the (2-halovinyl)lithiums rapidly decomposed as a result of β-elimination. The flash-chemistry approach permitted their handling within ultrafast reaction times, outpacing the decomposition.[12]
These studies paved the way for further use of alkali organometallics in continuous flow and their applications in organic synthesis. Recent developments are described below.
# 3
Recent Developments Involving Lithium Organometallics in Continuous Flow
3.1Generation of Lithium Organometallics in Continuous Flow
The selective lithiation of organic molecules has been achieved by halogen/lithium exchange,[13] oxidative addition of lithium metal,[14] or directed lithiation with a lithium base.[15] All these reactions proceeded in continuous flow, often allowing the use of convenient reaction temperatures and providing increased selectivity. For example, ortho-bromoaryl benzylic ethers such as 12 were readily lithiated by a Br/Li-exchange with t-BuLi, leading to the aryllithium species 13 that could be trapped by various electrophiles to provide products of type 14 (Scheme [6]). With longer reaction times, the lithium reagent 13 underwent intramolecular lithiation of the more-acidic benzhydryl position, giving the lithiated species 15, which, after electrophilic quenching, afforded ethers of type 16. Further increases in the reaction time favored a 1,2-Wittig rearrangement, leading to a trityl alcoholate 17, which, after protonation, furnished triphenylmethanol (18).
By performing this reaction in continuous flow and choosing the appropriate residence time, the group of Yoshida and Kim showed that selective formation of one of the products 14, 16, or 18 could be favored.[16] A related reaction-time control was achieved by Yoshida and Kim[17] in controlling the occurrence of a 1,3-anionic Fries rearrangement, as well as [1,4]-, [1,5]-, or [1,6]-anionic Fries-type rearrangements.[18]
The lithiation of diazo compounds can be complicated because the highly energetic lithiated derivatives are unstable and decompose instantaneously at higher temperatures. Thus, the lithiation of ethyl diazoacetate 19 with LDA was realized advantageously in continuous flow by Wirth and co-workers, leading to ethyl diazo(lithio)acetate (20) under mild and safe conditions (–78 °C, 0.2 min) (Scheme [7]).[19] After the addition of acetophenone as an electrophile, the desired tertiary alcohol 21 was obtained in 62% yield.
Similarly, the lithiation of various azobenzenes such as 22a or 22b, which are valuable photoswitches, was achieved with TMPLi (TMPH = 2,2,6,6-tetramethylpiperidine) in continuous flow (Scheme [8]).[20] Because the resulting lithiated azobenzenes 23a and 23b are highly unstable, prone to decomposition, and require ultrashort residence times, a Barbier-type procedure was designed in which the lithiated azobenzene 23 was generated in the presence of a soluble metal salt, such as MgCl2·LiCl or ZnCl2. Under these conditions, the lithiation could be performed at 0 °C within 20 seconds, permitting the functionalization of the unsymmetrical azobenzenes 22a and 22b to give the azobenzene building blocks 24a and 24b in yields of 65 and 81%, respectively.
This in situ metalation was also applied to the selective lithiation of 1,2-dicyanobenzene (25) at a convenient temperature (0 °C for 20 s) with ZnCl2 as the trapping metallic salt (Scheme [9]). Under these mild conditions, the resulting dicyanoarylzinc reagent 26 was produced and trapped in a Negishi cross-coupling leading to the functionalized biphenyl 27 in 82% yield.[21]
These Barbier-type reactions were quite general and, whereas the Barbier-type reaction for the iodolysis of ethyl 4-bromobenzoate (28) under batch conditions produced the desired iodide 29 in 53% yield, the corresponding reaction in continuous flow at 0 °C gave the desired product 29 in 95% yield (Scheme [10]).[22] In several cases, these Barbier-metalations permit the replacement of TMPLi by the much cheaper c-Hex2NLi (Cy2NLi). Thus, the metalation of 1,2-dichloropyridazine (30) with Cy2NLi in the presence of ZnCl2·2LiCl in a continuous-flow setup (0 °C, 40 s) provided the corresponding zinc reagent 31 (Scheme [10]).[23] After a Negishi cross-coupling reaction with 3-iodoanisole, the desired pyridazine 32 was obtained in 77% yield.
This Barbier procedure in continuous flow is also very useful for performing Br/Li-exchange reactions of organozinc or diorganomagnesium reagents bearing azido or nitro groups, such as 33 and 34 (Scheme [11]).[24] An extension to heterocyclic reagents such as the diquinolinylmagnesium species 35 is also possible.[25]
The generation of lithiated heterocycles in continuous flow is of particular interest in the case of oxadiazoles, because these heterocycles have a tendency to fragment. Thus, the continuous-flow lateral lithiation of the 1,3,4-oxadiazole 36 proceeded within 1.3 seconds at 25 °C to give the derivative 37 in quantitative yield (Scheme [12]). Similar batch metalations at the same temperature led to ring fragmentation within 10 seconds.[26] The lateral lithiation of aziridine 38 by using s-BuLi·TMEDA in toluene produced the allylic lithium species 39 which, at 60 °C, underwent ring closure to form the benzylic lithium species 40; this was further trapped with Me3SiCl to give the tetrahydroisoquinoline 41 in 98% yield (Scheme [12]).[27]
The generation of benzylic lithium compounds is an important synthetic task, and the Yoshida group has reported a convenient preparation of benzylic lithium species by a direct insertion of lithium by using lithium naphthalenide. Thus, the reaction of benzyl chloride with lithium naphthalenide at 20 °C and a flowrate of 9 mL/min led to a high yield of BnLi within 1.3 ms; this product readily reacted with benzaldehyde to give 1,2-diphenylethanol in 80% yield.[28] Alternatively, benzylic lithiums can be prepared from the corresponding benzylic iodides by an I/Li-exchange performed by using t-BuLi (2.5 equiv) in continuous flow under Barbier-type conditions at –78 °C with t R of 0.1 seconds. In this way, the iodide 42 was converted into the corresponding benzylic lithium species 43, which was trapped by an aldehyde, present in the reaction mixture, to give alcohol 44 in 62% yield (Scheme [13]). This synthesis was extended to pyridine derivatives, and the iodide 45 was converted in flow into the corresponding lithium reagent 46; this was quenched with an aldehyde to give alcohol 47 in 92% yield; 47 was not detected when a Barbier-type procedure was performed under batch conditions.[29] Transmetalations in continuous flow have also been used to generate the boronic esters required for Suzuki–Miyaura cross-couplings.[30]
# 3.2
Preparation of Acyllithiums and Lithium Carbenoids in Continuous Flow
Lithium reagents can permit reactivities opposite to these obtained by standard carbonyl chemistry (umpolung of reactivity),[31] and the search for useful acyl anions has been extensive.[31] The use of continuous-flow setups has markedly facilitated the preparation of such reagents, which otherwise are commonly generated in the presence of an electrophile. The Yoshida group showed that the treatment of carbamoyl chlorides such as 48 with lithium naphthalenide (LiNp) permitted the preparation of the carbamoyllithium 49 at –78 °C. Selective acylation of 49 with methyl chloroformate (–78 °C, 1.7 s) generated the 1,2-dicarbonyl compound 50, which underwent a subsequent flow reaction with aryllithium 51 to give the expected product 52 in 55% yield (Scheme [14]). This PMB-protected amide is a formal precursor of a potential sodium-channel blocker.[32] [33]
Alternatively, various formamides such as 53 and 54 have been lithiated in continuous flow at 25 °C with residence times of 60 seconds in the presence of the electrophiles (ketones, aldehydes, Weinreb amides, allylic bromides, N-morpholinoamides, or isocyanates) to give a range of polyfunctional amides such as 55 and 56 under very mild conditions, demonstrating the utility of Barbier conditions in continuous flow (Scheme [15]).[34]
Lithium carbenoids are highly reactive intermediates that usually need to be generated at low temperatures.[35] The use of a continuous-flow process improved this method considerably. Hafner and Sedelmeier and their co-workers showed that (dichloromethyl)lithium could be readily obtained from CH2Cl2 and BuLi in continuous flow at –30 °C (0.5 s), avoiding the formation of the carbene species and its consecutive decomposition. Quenching with aldehydes led to dichloro derivatives such as 57, whereas Matteson homologation with boronic esters led to α-chloroboronic esters such as 58 (Scheme [16]).[36]
Recently, this methodology has been extended by the group of Nagaki and Luisi for the preparation of LiCH2F and LiCH(I)F by using flow microreactors to overcome the need for internal quenching conditions, previously reported as necessary in batch reactions.[37] The group of Ley and Kirschning has prepared LiCHBr2 in this way,[38] whereas Kappe and co-workers used continuous flow for a convenient synthesis of difluoromethyl derivatives, including α-(difluoromethyl)amino acids, from fluoroform.[39] Kappe and Cantillo have also developed a simple flow preparation of LiCH2Br, starting from CH2Br2.[40]
The performance of synthesis in continuous flow often has significant advantages over conventional batch conditions, and Jamison and co-workers showed that CO2 can react selectively with two different organolithium reagents. Remarkably, Grignard reagents could also be used in such sequential reactions. Thus, the treatment of aryl-, alkenyl- or alkylmagnesium reagents with CO2 at 25 °C (<1 min reaction time) followed by the addition of a lithium reagent gave the desired ketones, such as 59, in satisfactory yields (Scheme [17]). Similar batch reactions often give tertiary alcohols or symmetric ketones as byproducts.[41] [42] [43]
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# 4
Sodium and Potassium Organometallics in Continuous Flow
The sodiation of arenes and heteroarenes is an important synthetic goal because sodium has a relatively low toxicity and is only moderately expensive. Collum recently showed that the sodiation of aromatics was possible by using sodium diisopropylamide in (2,2-dimethoxyethyl)amine (DMEA) at a low temperature.[44] Alternatively, in continuous flow, several of these reactions can be performed at –20 °C. In addition, various substrates can be sodiated that are not tolerated under conventional batch conditions due to aryne formation. Thus, treatment of 1,3-dichlorobenzene (60) with NaDA in continuous flow gave the sodiated arene 61, which reacted readily with benzaldehyde to give the alcohol 62 in 95% yield (Scheme [18]).[45]
This type of metalation was extended to potassium derivatives by using potassium diisopropylamide (KDA) complexed with TMEDA in hexane. Such metalations proceeded at –78 to 25 °C, and the reaction of the benzonitrile 63 with KDA·TMEDA gave the arylated potassium derivative 64, which, after quenching with dicyclopropyl ketone, furnished the tertiary alcohol 65 in 62% yield (Scheme [18]).[46] By using the Schlosser base (t-BuLi–t-BuOK), benzylic positions of various aromatics were metalated, and this method in continuous flow permitted a three-step synthesis of ibuprofen. Ley and co-workers used KHMDS or t-BuOK to metalate CHCF3 under continuous reaction conditions in a flow-reaction setup to produce trifluorinated methyl derivatives in high yields.[47]
# 5
Conclusion
Whereas the generation of certain Li, Na, or K intermediates by conventional batch-chemistry techniques has proved elusive, many of these intermediates are now readily accessible by taking advantage of the improved mass- and heat-transfer environment created in small reacting channels in continuous flow. Milder reaction conditions (avoiding cryogenic temperatures) and more-selective reactions are often possible. The perfect control of residence times in modern flow microreactor setups and the simple handling associated with commercial pump apparatus greatly facilitates the performance of reactions in continuous flow. We predict that the use of these reactions will further expand in in the near future and that they will be performed on a daily basis in chemistry laboratories.
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References and Notes
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Corresponding Author
Publication History
Received: 07 August 2020
Accepted after revision: 06 September 2020
Article published online:
09 October 2020
© 2020. Thieme. All rights reserved
Georg Thieme Verlag KG
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References and Notes
- 1 Yoshida J.-i. Flash Chemistry: Fast Organic Synthesis in Microsystems. Wiley; Chichester: 2008
- 2a Browne DL, Baumann M, Harji BH, Baxendale IR, Ley SV. Org. Lett. 2011; 13: 3312
- 2b Brodmann T, Koos P, Metzger A, Knochel P, Ley SV. Org. Process Res. Dev. 2012; 16: 1102
- 2c Polyzos A, O’Brien M, Petersen TP, Baxendale IR, Ley SV. Angew. Chem. Int. Ed. 2011; 50: 1190
- 2d Ley SV, Fitzpatrick DE, Ingham RJ, Myers RM. Angew. Chem. Int. Ed. 2015; 54: 3449
- 3a Wakami H, Yoshida J.-i. Org. Process Res. Dev. 2005; 9: 787
- 3b Nagaki A, Kenmoku A, Moriwaki Y, Hayashi A, Yoshida J.-i. Angew. Chem. Int. Ed. 2010; 49: 7543
- 3c Yoshida J.-i. Chem. Rec. 2010; 10: 332
- 3d Kim H, Nagaki A, Yoshida J.-i. Nat. Commun. 2011; 2: 264
- 4a Comer E, Organ MG. J. Am. Chem. Soc. 2005; 127: 8160
- 4b Price GA, Bogdan AR, Aguirre AL, Iwai T, Djuric SW, Organ MG. Catal. Sci. Technol. 2016; 6: 4733
- 4c Price GA, Hassan A, Chandrasoma N, Bogdan AR, Djuric SW, Organ MG. Angew. Chem. Int. Ed. 2017; 56: 13347
- 5a Yoshida J.-i, Nagaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
- 5b Cantillo D, Kappe CO. ChemCatChem 2014; 6: 3286
- 5c Degennaro L, Carlucci C, De Angelis S, Luisi R. J. Flow Chem. 2016; 6: 136
- 5d Movsisyan M, Delbeke EI. P, Berton JK. E. T, Battilocchio C, Ley SV, Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
- 5e Yoshida J.-i, Kim H, Nagaki A. J. Flow Chem. 2017; 7: 60
- 5f Colella M, Nagaki A, Luisi R. Chem. Eur. J. 2020; 26: 19
- 6 Woltornist RA, Ma Y, Algera RF, Zhou Y, Zhang Z, Collum DB. Synthesis 2020; 52: 1478
- 7a Usutani H, Tomida Y, Nagaki A, Okamoto H, Nokami T, Yoshida J.-i. J. Am. Chem. Soc. 2007; 129: 3046
- 7b Nagaki A, Ichinari D, Yoshida J.-i. J. Am. Chem. Soc. 2014; 136: 12245
- 7c Nagaki A, Takabayashi N, Tomida Y, Yoshida J.-i. Org. Lett. 2008; 10: 3937
- 8 Ushiogi Y, Hase T, Iinuma Y, Takata A, Yoshida J.-i. Chem. Commun. 2007; 2947
- 9 Nagaki A, Takizawa E, Yoshida J.-i. J. Am. Chem. Soc. 2009; 131: 1654 ; corrigendum: J. Am. Chem. Soc. 2009, 131, 3787
- 10 Vila C, Giannerini M, Hornillos V, Fañanás-Mastral M, Feringa BL. Chem. Sci. 2014; 5: 1361
- 11 Tomida Y, Nagaki A, Yoshida J.-i. J. Am. Chem. Soc. 2011; 133: 3744
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