3.1 Preparation of Organometallic Reagents in Batch and Continuous Flow
3.1.5 Reactions of Organometallic Species in Continuous Flow Systems
Not only the generation of reactive organometallic species has benefited from the use of flow micro-reactors but also their subsequent reactions. These reactions are often exothermic and fast, which gives rise to side-product formation as well as mixing-dependent yields and selectivity.113 A recent example was reported by process chemists involved in the synthesis of an intermediate en route to verubecestat, a promising drug candidate for the treatment of Alzheimer’s disease (C, Scheme 14).114 The yield of the key addition reaction of lithiated methyl sulfonamide A-Li to the chiral ketimine B electrophile was found to be strongly dependent on the quality of mixing. Studies showed that competing proton transfer reactions between A-Li and the electrophile B or the intermediate C-Li took place competitively in inhomogeneous (batch) reaction mixtures, thereby consuming the active reagent A-Li and diminishing the yield. Working under high-flowrate/fast mixing conditions with static mixing devices allowed the kinetically favored pathway to proceed without sidereactions and leading to C. The application of cryogenic temperatures was obsolete with 0.13 s residence time under
112 M. R. Becker, M. A. Ganiek, P. Knochel, Chem. Sci. 2015, 6, 6649.
113 a) H. O. House, D. D.Traficante, R. A. Evans, J. Org. Chem. 1963, 28, 349; b) H. O. House, D. D.Traficante, J. Org. Chem. 1963, 28, 356.
114 D. A. Thaisrivongs, J. R. Naber, N. J. Rogus, G. Spencer, Org. Process Res. Dev. 2018, 22, 403.
flow conditions, and cooling was only applied to guarantee stability of A-Li during the operation and to remove the reaction heat sufficiently. Notably, the reaction was performed on a pilot-plant scale with stable runs over several hours and delivering batches of > 100 kg product. The authors concluded, that their report likely describes the largest scale experiments involving a controlled mixing-sensitive reaction.
Scheme 14: Synthesis of intermediate C en route to Verubecestat in a flow setup on pilot-plant scale.
Furthermore, Yoshida’s group reported an interesting study regarding the chemoselective addition of aryl lithium reagents to carbonyl groups (Scheme 15).115 Thus, aryl organolithium reagents were reacted with bis-electrophiles bearing two different carbonyl functions, such as an aldehyde and a ketone. Interestingly, the selectivity for addition of PhLi to an aldehyde over a ketone (in bis-electrophile D) was shown to be impractically low in a batch flask, furnishing equimolar amounts of the desired product E and double addition product F (25 – 28%) in batch, along with ketone addition product G (7%) and remaining starting material D. Conducting the reaction under flow conditions at various flowrates demonstrated that the product distribution is favorably shifted towards the desired product of exclusive addition to the aldehyde, E, (70%) as mixing was improved via higher flowrates.
The principle was subsequently applied to chemoselectively obtain addition products in high yields with various bis-electrophiles as well with as flash-chemistry derived83 functionalized organolithium nucleophiles.Finally, a sequential twofold addition of different nucleophiles was realized, providing the expected diol in 61% over three steps, which confirmed the high chemoselectivity under the optimized flow conditions.
115 A. Nagaki, K. Imai, S. Ishiuchi, J.‐i. Yoshida, Angew. Chem. Int. Ed. 2015, 54, 1914.
Scheme 15: Chemoselective addition of aryllithium reagents (bold marking) to bis-electrophiles and its dependency on the mixing quality.
A last example from the Jamison group highlights the advantageous use of a flow micro-reactor setup for gas/liquid interphasic reactions.116 The oxidation of alkyl Grignard reagents by molecular oxygen or dry air are well-known and provide a route to alcohols without using toxic reagents. However, this reaction gave only low yields in batch for the conversion of PhMgBr to phenol (17%), likely caused by inefficient interphasic mixing of the reactive species with oxygen and competitive reactions of the involved aryl radicals in the liquid phase (Scheme 16).
Scheme 16: Oxidation of aryl Grignard compounds with O2 enabled by enhanced interfacial mass transfer in a flow reactor.
The interfacial surface and reactions between gaseous O2 and the liquid THF phase was greatly enhanced,33 leading to an improved 53% yield of phenol within 3 min under otherwise similar
116 Z. He, T. F. Jamison, Angew. Chem. Int. Ed. 2014, 53, 3353.
conditions. Further pressurizing the system with dry air and applying −15 °C reaction temperature gave a quantitative yield of phenol. Subsequently, a broad range of aryl and heteroaryl Grignard reagents was converted to the corresponding phenols, including examples with challenging functionalization.
4 Objectives
Based on previous results in the batch metalation and flow magnesiation of acrylate derivatives, the scope of continuous flow acrylate metalations should be investigated to demonstrate possible extensions of this acrylate functionalization under convenient reaction conditions. Especially the use of TMPZnCl·LiCl for zincations in continuous flow systems was not yet investigated and it was envisioned that a process intensification could be achieved with scalable high temperature zincation reactions (Scheme 17).117
Scheme 17: Continuous flow magnesiation and zincation and subsequent in-line electrophile quench of substituted acrylonitriles, acrylates and nitroolefins.
Furthermore, the application of flow methods for the improved handling of highly unstable (thio)carbamoyllithium species should be investigated. The aim was to develop a convenient, near- ambient temperature process, which starts from easily available (thio)formamides. In situ trapping methods should be applied if necessary. An extension of the functional group tolerance of this chemistry was proposed as a desirable goal. Mechanistical insights regarding the structure and energetics of lithiated formamides should be gained to allow further extension of this chemistry (Scheme 18).118
Scheme 18: Continuous flow preparation and reactions of carbamoyllithiums for nucleophilic amidation.
Moreover, a flow in situ trapping halogen-lithium exchange was planned in analogy to prior batch and flow in situ trapping metalations. The fact that halogen-lithium exchanges are extremely fast reactions should facilitate an exchange even in presence of a metal salt additive and thereby enable an in situ
117 This project was developed in cooperation with Dr. Matthias R. Becker and Dr. Marthe Ketels. The project was commenced by Maximilian A. Ganiek during the work on Master’s thesis and finalized during the PhD studies, see: M. A. Ganiek, Metalation and Reactions of Functionalized Acrylate Derivatives using TMP-Bases in a Continuous Flow System, Master Thesis, 2015, LMU München.
118 This project was developed in cooperation with Dr. Matthias R. Becker in synthetic aspects and with Dr.
Guillaume Berionni and Prof. Dr. Hendrik Zipse in theoretical aspects.
transmetalation of the newly generated aryllithium compound, thus minimizing the possibility for decomposition. This would effectively combine the generality of the halogen-lithium exchange reaction with the functional group tolerance of, for example, zinc organometallic reagents. The use of flow conditions was estimated to play a critical role to achieve mild conditions. The aim was therefore to develop a suitable continuous flow reaction protocol and to demonstrate that aromatic organometallics bearing highly sensitive groups can be accessed and reacted under mild conditions.
Furthermore, the scope of the reaction should be extended to other unsaturated substrates such as halopyridines (Scheme 19).119
Scheme 19: In situ trapping halogen-metal exchange of (hetero)arenes in the presence of metal salt additives.
Another project entailed the functionalization of a novel triazaphenantrene scaffold, which was sythesized from two pyridine units and showed potentially interesting optical properties. The developed synthesis route allowed for modification of two positions in the ring by the judicious choice of starting materials, however the C6-position was unlikely to be easily functionalized in an analogous fashion. The vicinity of two coordinating nitrogen atoms to the C6 position indicated instead the use of organometallic reagents to achieve a functionalization of the azaphenantrene scaffold. The functionalization could apply batch or flow methods, and should allow installing various organic residues (R3, Scheme 20).120
Scheme 20: Functionalization of a novel triazaphenantrene by means of chemical modification of the C6-position. Dotted lines indicate the newly formed bond.
119 This project was developed in cooperation with Dr. M. Ketels and Niels Weidmann, see: M. Ketels, Dissertation, LMU München, 2018 and N. Weidmann, Dissertation, LMU München.
120 This project was developed in cooperation with Dr. Sarah Fernandez and Mariia Karpacheva in synthetic aspects, optical measurements were performed and interpreted by Fabian C. Hanusch, Stephan Reuter, Prof. Dr.
Thomas Bein and Dr. Florian Auras.
The last project comprises the development of a convenient ester chloro-homologation method121 from economically attractive and easily available chloroactetic acid dianions (Scheme 21).122
Scheme 21: Ester chloromethylation and bis-chloromethylation with chloroacetic acid lithium enolates. Right side: potential postfunctionalizations of the mono- and bis-chloro ketone products leading to heterocycles and substitution products.
Resorting to enolate-derived nucleophiles instead of the typically employed lithium carbonoids would avoid halomethane precursors, which have an increasingly restricted accessibility due to environmental legislation. Moreover, practical and mild conditions and an increased functional group tolerance could be possibly obtained by using enolate type reagents. Potential advantages over the halogenation of ketones, which is an alternative entry to chloroketones, should additionally be demonstrated by accessing products, which are difficult to obtain under halogenation conditions. The instable lithium dianions suggest a flow procedure to ensure convenient reaction conditions, since scattered previous reports of batch use of chloroacetic acid dianion often suggest excess reagent use and cryogenic conditions in all cases. An extension of the method for the synthesis of dichloroketones was not yet described in the literature; however a realization would give access to another useful class of chloroketones. Postfunctionalization of the obtained chloroketones should underline the utlity of the obtained bis-electrophilic chloroketone compounds. For this purpose, development and demonstration of cyclocondensation reactions leading to functionalized heterocycles and cross-couplings with zinc organometallics were proposed.
121 The term homologation is referring to a conversion of one member of a homologous series into the other by changing the number of a repetitive unit, which can be a methylene bridge -(CH2)- group, see: T. E. Brown, H.
E. LeMay, B. E. Bursten, C. Murphy, P. Woodward, M. E. Stoltzfus, Chemistry: The Central Science, 13 ed, Pearson Education, London, .2014. The term homologation is also used less strictly throughout acknowledged resources (compare the different definition bandwith: F. A. Carey, R. J. Sundberg, Advanced OrganicChemistry Fifth Edition Part B: Reactions and Synthesis, Springer, New York, 2007, 784–786; R. Brückner, Advanced Organic Chemistry, Elsevier, Amsterdam, 2002, 453–457) Typically also reactions are included in the definition of homologation reactions, which enable a reaction sequence leading to overall homologation through introduction of a carbon unit and a simple functional group interconversion. Example: The Seyferth-Gilbert reaction converts an aldehyde (R-CHO) into an alkyne (R-C≡CH), which is not a homologation by strict definition. However, if a consecutive hydrolysis is performed, the product of an overall homologation is obtained (R-CH2CHO). Likewise the herein presented “chloro-homologation” can be conceived as being part of a homologation sequence, R-C(O)Cl→R-C(O)OMe→R-C(O)CH2Cl, and it was shown that even the direct R-C(O)Cl→R-C(O)CH2Cl conversion is viable. In the case of the reaction R-C(O)OMe→R-C(O)CHCl2 however,
“ester→dichloroketone elongation” or “dichloromethylation” is a more suitable description in accordance with the above cited textbook by R. Brückner.
122 This project was developed in cooperation with Dr. Maria V. Ivanova and is based on preliminary attempted chloro-homologations by S. Sevinc and Dr. Martin Benjamin (Novartis Pharma AG).