Benzyllithiums bearing aldehyde carbonyl groups. A flash chemistry approach.

Reductive lithiation of benzyl halides bearing aldehyde carbonyl groups followed by reaction with subsequently added electrophiles was successfully accomplished without affecting the carbonyl groups by taking advantage of short residence times in flow microreactors.


Benzyllithiums Bearing Aldehyde Carbonyl Groups. A Flash Chemistry Approach
Aiichiro Nagaki, a Yuta Tsuchihashi, a Suguru Haraki, a and Jun-ichi Yoshida* a Reductive lithiation of benzyl halides bearing aldehyde carbonyl groups followed by the reaction with subsequently added electrophiles was successfully accomplished without affecting the carbonyl groups by taking advantage of short residence times in flow microreactors.
Chemoselectivity is one of the central issues in chemistry and chemical synthesis. 1 One of the goals in synthetic chemistry is the development of chemoselective transformations without affecting highly reactive functional groups that are not involved in the desired transformation. We have been interested in organolithium reactions without affective aldehyde carbonyl groups as an extreme case of chemoselective transformations. 2 According to textbooks of organic chemistry, organolithiums react with aldehydes very quickly and they are not compatible with each other. On the other hand, aldehyde carbonyl groups are very common functional groups and organolithium reactions are frequently used in organic synthesis. 3 Therefore, if we could perform organolithium reactions without affecting aldehyde carbonyl groups, such reactions would serve as powerful synthetic methods. We took an approach to this challenge based on flash chemistry, 4 in which a highly unstable reactive species are generated and transferred to another location to be used in the next reaction 5 before they decompose by high-resolution residence time control using flow microreactor systems. [6][7][8] In fact, recently, we had already reported the generation and reactions of aryllithiums bearing ketone carbonyl groups. 5e However, in general, aldehyde carbonyl groups are more reactive than ketone carbonyl groups. Therefore, faster generation is necessary to solve the more challenging problem of aldehyde cases. Here, we show that flash chemistry enables the generation of benzyllithiums 9,10,11,12 bearing aldehyde carbonyl groups and their use in the reactions with subsequently added electrophiles without affecting the aldehyde carbonyl groups. We first examined the generation of simple benzyllithiums by reductive lithiation 13 of benzyl halides (Fig. 1). This reaction is problematic because of Wurtz-type coupling, i.e. the coupling of benzyllithiums with starting benzyl halides. It was reported that benzyllithium can be generated from benzyl chloride by using lithium naphthalenide (LiNp) in a mixed solvent (Et2O/THF/light petroleum = 4:3:1) at -95 o C in a conventional batch reactor. 9a However, the reaction in THF and/or at higher temperatures such as -78 o C leads to a dramatic decrease in the yield because of Wurtztype coupling. We envisioned that extremely fast micromixing is effective to avoid undesired Wurtz-type coupling because it is known that the product selectivity of fast consecutive competitive reactions 14 can be dramatically improved by extremely fast micromixing. 15 Thus, we examined the reactions of benzyl halides with LiNp in a flow microreactor system, which consists of two Tshaped micromixers M1 (φ = 250 µm) and M2 (φ = 250 µm) and two microtube reactors R1 (φ = 1000 µm, length = 3.5 cm and R2 (φ = 1000 µm, length = 50 cm) shown in Figure 2. For the reactions with very short residence times such as 1.3 ms, a built-in type system shown in Figure 2a (R1: φ = 250 µm, length = 1.0 cm) was used, whereas a conventional modular type system was used for the reactions with longer residence times, (Fig. 2b). Fig. 2 Flow microreactor systems. (a) built-in type system, (b) modular type system Because it is well known that the mixing speed in a micromixer depends on the inner diameter and the flow rate, 16 we examined the reactions with varying the inner diameter of M1 and the flow rates of the solution of benzyl halide and that of LiNp. The 1:1 molar ratio of benzyl halide and LiNp was kept in all experiments. Methanol was used as an electrophile and the reactions were carried out at 20 o C using a conventional modular type system (Fig. 2b). As summarized in Table 1, the yield of the desired protonated product, toluene increased with a decrease in the inner diameter. The yield also increased with an increase in the flow rate. Satisfactory yields were obtained with M1 of 250 µm inner diameter and the total flow rate of 9.0 mL/min for the case of benzyl chloride. In the case of benzyl bromide, higher flow rate was necessary to obtain satisfactory yields, presumably benzyl bromide is more reactive toward benzyllithium than benzyl chloride. Anyway, it is noteworthy that the flow microreactor system enables the generation of benzyllithium at 20 o C, although the reactions should be carried out at -95 o C in a conventional batch macro reactors. It is also advantageous that THF can be used instead of the mixed solvent. Furthermore, benzyl bromide can be used as a starting material, although such transformation is impossible in a conventional batch macro reactor. These remarkable features seem to be ascribed to extremely fast micromixing of a benzyl halide and LiNp at 1:1 molar ratio.  Under the optimized conditions, the reactions of benzyllithium with other electrophiles, such as methyl iodide, aldehydes, ketones, trimethylsilyl chloride, and isocyanates were examined. As shown in Table 2, the corresponding products were obtained in good yields. Notably, the lithiation of 2-(chloromethyl)thiophene followed by the reaction with an electrophile was successfully carried out without ring-opening, although conventional batch reactions often suffer from this side reaction. 17 The productivity of the present method is high enough for laboratory synthesis. In the case of the reaction of benzyllithium with benzophenone, a 15 min operation gave 1.09 g of the desired product (See the Supporting Information for details). With successful generation of benzyllithiums by virtue of extremely fast micromixing in hand, we next examined the generation and reactions of benzyllithiums bearing carbonyl groups. In this case the high-resolution residence time control is critical because such benzyllithiums should be transferred extremely quickly to another location to be used in the reaction with electrophiles before they decompose. Temperature-residence time mapping serves as a powerful tool for optimizing the residence time. Figure 3a shows the contour plots with scattered overlay of the yields of the protonated product for the lithiation of p-propanoylbenzyl chloride, which has a ketone carbonyl group, followed by trapping with methanol. The yield decreases with an increase in the residence time in R1. The yield also decreases with an increase in the temperature although the effect of the temperature is not large. The optimal yield (80%) was obtained with the residence time of 1.3 ms at -78 o C.
The effects of the residence time and the temperature are more significant in the lithiation of p-formylbenzyl chloride, which has an aldehyde carbonyl group (Fig. 3b). As it can be seen obviously by comparing Figs 3a and 3b, p-formylbenzyllithium is significantly less stable than p-propanoylbenzyllithium. With the residence time of 1.3 ms at -78 o C, however, p-formylbenzyllithium can be generated and used in the subsequent reaction with methanol to give the protonated product in a reasonable yield (68%). This means that the aldehyde carbonyl group can survive in the organolithium reaction. Under the optimized conditions several benzyllithiums bearing ketone and aldehyde carbonyl groups were generated and reacted with several electrophiles including phenylisocyanate, benzaldehyde, TMSOTf, and MeOTf. The results are summarized in Table 3. Such transformations are very difficult or practically impossible by using conventional batch macro reactors.
As an application of the present method, we accomplished the synthesis of a π-conjugated system shown in Fig. 4. The reaction of benzaldehyde with (5-formylthiophen-2-yl)methyllithium followed by the elimination with bis[α,αbis(trifluoromethyl)benzenemethanolato]diphenylsulfur (Martin sulfurane) gave aldehyde 1 in 61% isolated yield. The aldehyde carbonyl group in 1 was used for the subsequent reaction with benzyllithium. The subsequent dehydration gave compound 2 (78% isolated yield), in which one thiophene ring and two benzene rings are connected by carbon-carbon double bonds. 18 Table 3 The generation of benzyllithiums bearing ketone and aldehyde carbonyl groups followed by reaction with an electrophile. a b enz yl h a lid es e l ec t ro phil e p ro d uc t yi e ld ( % )  Fig. 4 Synthesis of π-conjugated systems using (5-formylthiophen-2yl)methyllithium.
In conclusion, flash chemistry using flow microreactor systems enables the generation and reactions of benzyllithiums bearing aldehyde carbonyl groups. Extremely fast micromixing is responsible for the generation of benzyllithiums avoiding Wurtz-type coupling, and high-resolution residence time control is responsible for survival of aldehyde carbonyl groups.
The present findings open a new aspect of protecting-groupfree 19 organolithium chemistry.