9.1 Introduction

We have learned in Chaps. 4–6 that high-resolution reaction time control using a flow microreactor system allows unstable intermediates to be generated in a short time and be usable in reactions with other compounds without decomposing. An integrated system consisting of micromixers and flow microreactors that are connected to one another will allow multiple reactions to be carried out continuously. This method is called space integration of reactions. The method also allows integration of reactions involving unstable intermediates by setting shorter residence times. This chapter describes the principle and examples of space integration of reactions.

9.2 Integrating Reactions

Synthetic chemistry has achieved many advances by formulating reactions in which one molecule is precisely transformed into another molecule to allow efficient and selective synthesis of the molecules of a desired product. The reaction conditions have been optimized individually for different reactions. However, producing a desired chemical compound with a one-step reaction is often difficult, and it usually requires a combination of multiple reactions. Some recent medical product may require 60 or more steps for its synthesis. In contrast to this, organisms use a wide variety of chemical reactions occurring in a cooperative, coherent and well-ordered manner, and efficiently produce required compounds, whereas synthetic chemistry still remains at an elementary level. Synthetic chemistry using reaction integration combines multiple chemical reactions over time and space to formulate efficient methods for molecular transformation, aiming to precisely and promptly synthesize organic molecules having desired biological activity or physical functionality. As shown in Fig. 9.1, such methods for integration can be classified into three types: time and space integration of reactions, time integration of reactions, and space integration of reactions [1, 2].

Fig. 9.1
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Classification of the way of integrating reactions

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Time and space integration of reactions are the method of integrating reactions occurring at one time in one reactor in a cooperative and interrelated manner, or in a concerted manner. Examples include domino reactions or tandem reactions. Another important example is a concerted catalytic reaction, which involves multiple catalysts or a single catalyst with multiple functions. This approach allows reactive species to be trapped promptly by the coexisting molecules and thus allows the integration of reactions involving extremely short-lived reactive intermediates. However, this approach requires a fixed sequence of reactions, which is primarily determined by the combination of chemical compounds. The sequence cannot be changed. Time and space integration of reactions thus has lower flexibility in its design and execution of reactions than the other two approaches.

Time integration of reactions is the method of integrating a series of reactions occurring successively in one reactor. The reactions occur sequentially on the time axis in the same reactor. This method has been used conventionally as a one-pot sequential synthesis. After one reaction is complete, a substrate(s) or a reagent(s) or a catalyst(s) is added to cause another reaction. This approach cannot be used for reactions in which unstable species, such as short-lived reactive species, occur as intermediates. Time integration of reactions permits easy changes in the sequence of compounds to be added and thus is more flexible in its design and execution of reactions than the time and space integration approach.

Space integration of reactions is the method of integrating reactions occurring in different reactors that are arranged spatially. To allow faster transportation of compounds between the different reactors, a continuous flow system is more advantageous than a batch system. In the book titled “Integrated Chemical Systems” (Wiley, 1994), A.J. Bard proposed and predicted an integrated chemical synthesizer, which has now come to the existence with this approach. Like the time integration approach, space integration of reactions also permits easy changes in the sequence of compounds to be added and is thus highly flexible. Using flow microreactors and setting short residence times to allow use of species having a lifetime of a millisecond, this approach can integrate reactions involving short-lived reactive intermediates. Although the space integration approach is being studied actively only a few research examples are reported for the approach applied to reactions involving short-lived reactive intermediates.

This chapter describes specific examples of the space integration approach using flow microreactors, particularly the approach based on flash chemistry involving short-lived reactive intermediates.

9.3 Synthesizing o-Disubstituted Benzenes by Space Integration of Two Organolithium Reactions [3, 4]

o-Bromophenyllithium generated by the Br–Li exchange reaction of o-dibromobenzene with n-BuLi is known to rapidly undergo elimination of LiBr to give benzyne. If o-bromophenyllithium can readily react with various electrophiles before it undergoes elimination, this process should enable synthesis of various substituted benzenes containing a bromo group at the ortho position. To reduce the elimination and enable the reaction with an electrophile in a batch reactor, the compound reportedly needs to be placed at an extremely low temperature of −110 °C [5]. If this reaction is carried out in a batch reactor at −78 °C, no intended product is obtained. This is presumably because the batch reactor cannot allow reactions to complete in a short time unlike the flow microreactor system and thus fails to prevent o-bromophenyllithium from decomposing into benzyne.

This transformation, however, was successfully carried out using a flow microreactor system. o-Bromophenyllithium was allowed to react with various electrophiles under optimum conditions, or at the temperature of −78 °C and the residence time of 0.82 s.

The product is a bromobenzene derivative with a benzene ring to which one electrophile has been added. The remaining Br group can further undergo a Br–Li exchange reaction if n-BuLi is added, and the resultant aryllithium species can react with another electrophile.

An integrated flow microreactor system consisting of four micromixers and four flow microreactors shown in Fig. 9.2 can perform space integration of such reactions. In micromixer M1, o-dibromobenzene is mixed with n-BuLi. In reactor R1, the Br–Li exchange reaction is carried out. The resultant o-bromophenyllithium is then mixed with a first electrophile (E1) in micromixer M2. The generated intermediate then reacts with n-BuLi to undergo a Br–Li exchange reaction again in M3 and R3. The generated aryllithium species then reacts with a second electrophile (E2) in M4 and R4, affording the corresponding o-disubstituted benzene.

Fig. 9.2
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Synthesis of o-disubstituted benzenes from o-dibromobenzene by space integration of reactions

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Figure 9.3 shows the results obtained with various electrophiles. Importantly, each step requires the setting of the corresponding optimum residence time and temperature, because the initially generated aryllithium species and the subsequently generated aryllithium species would differ in stability and reactivity. As described above, the initially generated o-bromophenyllithium is so unstable that it can readily decompose into benzyne. Therefore, o-bromophenyllithium intermediate needs to be reacted with various electrophiles at −78 °C with a residence time of 0. 82 s. The subsequent Br–Li exchange reaction can be carried out at 0 °C, because the aryllithium species to be generated is relatively stable because it does not contain bromine at the ortho position, which would undergo elimination. Notably, trimethylsilyl triflate should be used as E1 for the reaction of o-bromophenyllithium, whereas chlorotrimethylsilane with lower reactivity can be used as an E2. It is also noteworthy that chlorotributylstannane cannot be used as an E1, because the resulting arylstannane would undergo a Sn–Li exchange reaction in the second lithiation process.

Fig. 9.3
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Synthesis of various o-disubstituted benzenes from o-dibromobenzene

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9.4 Synthesizing TAC-101 by Integration of Three Organolithium Reactions [6]

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid) has attracted attention as a compound with antitumor activity. An ester of this compound can be readily synthesized by using 1,3,5-tribromobenzene as a starting material, and repeating three times the Br–Li exchange followed by the reaction of the generated aryllithium species with an electrophile (Fig. 9.4). For these reactions, a system integrating six micromixers and six flow microreactors is used. When each step uses an optimum residence time, the steps together require a total residence time of 13 s.

Fig. 9.4
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Synthesis of TAC-101 by space integration of organolithium reactions

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The all reactions can be carried out at 0 °C. A laboratory flow microreactor system can produce 100–200 mg of the product per minute. The flow microreactor system easily allows the synthesis of an unsymmetrically substituted compound containing silyl groups with different substituents as well.

9.5 Space Integration of Halogen–Lithium Exchange Reaction and Cross-Coupling Reaction [7]

Although integration of multiple reactions of the same type has been described above, reactions of completely different types can also be integrated. Preparing an aryllithium species through a halogen–lithium exchange reaction and performing space integration of this reaction and the Pd-catalyzed cross-coupling (Murahashi coupling) [5] reaction using the prepared species will now be described.

The halogen–lithium exchange reaction of an aryl halide using a flow microreactor system has been discussed in the previous chapters. If the aryllithium species can be used in a coupling reaction catalyzed by a Pd complex in the flow microreactor system, this would provide an efficient and effective method of synthesis. However, the two reactions cannot simply be carried out sequentially. For example, Br–Li exchange of an ArBr using n-BuLi would produce an aryllithium species (ArLi), whereas this reaction also produces n-butyl bromide (n-BuBr) in the same quantity as the aryllithium species. Typically, a Pd-catalyzed cross-coupling reaction of ArLi with an aryl halide (Ar’X), which is subsequently added as a coupling partner, is slow, and the reaction of ArLi with n-BuBr would thus be predominant. There is another possibility. When the cross-coupling is slow, ArLi can undergo a halogen–lithium exchange reaction with Ar’X to give Ar’Li. This leads to a product derived from the reaction of Ar’Li and n-BuBr as well as the homocoupling products, i.e, Ar–Ar and Ar’–Ar’. A specific example will be described with reference to Fig. 9.5. To solve such problems with the integration of reactions, the Pd-catalyzed cross-coupling reaction may need acceleration to suppress the side reactions. The use of PEPPSI-SIPr containing a carbene ligand as a catalyst was found to accelerate the cross-coupling reaction, which would proceed faster than the side reactions. This enables the synthesis of the desired cross-coupling product with a relatively high yield.

Fig. 9.5
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Integration of Br–Li exchange of p-methoxybromobenzene and Pd-catalyzed cross-coupling with bromobenzene

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The Br–Li exchange reaction of p-methoxybromobenzene and the cross-coupling reaction of the resulting p-methoxyphenyllithium with bromobenzene, catalyzed by PEPPSI-SIPr, were carried out using a flow microreactor system shown in Fig. 9.6, enabling the synthesis of a desired cross-coupling product with a yield of 93 %. Under these conditions, however, the cross-coupling requires a reaction time (94 s at 50 °C in R2), which is much longer than the reaction time taken by the Br–Li exchange reaction (2.6 s at 0 °C in R1). Thus, an unstable aryllithium species containing an ester or a ketone carbonyl group cannot be used in the cross-coupling reaction. A catalyst with much higher activity needs to be developed.

Fig. 9.6
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Space integration of Br–Li exchange of p-methoxybromobenzene and Murahashi coupling with bromobenzene

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Although the present method suffers from the functional group compatibility, various compounds can be synthesized from two different aryl bromides as shown in Fig. 9.7. Heteroaryllithiums, which are readily prepared by H–Li exchange reaction, can be used for the coupling to give heteroaryl–aryl and heteroaryl–heteroaryl coupling products.

Fig. 9.7
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Cross-coupling of two aryl bromides. The left part is derived from the aryllithium intermediate

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