Two-Step Flow Synthesis of Biarylmethanes by Reductive Arylation of Tosylhydrazones
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Full Paper Two-Step Flow Synthesis of Biarylmethanes by Reductive Arylation of Tosylhydrazones Lukas Kupracz and Andreas Kirschning* Institute of Organic Chemistry and Center of Biomolecular Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1b, 30167, Hannover, Germany The coupling of tosylhydrazones derived from aldehydes or ketones with aryl boronic acids to yield the corresponding arylation products that was first developed in the group of Barluenga was achieved in a two-step flow protocol. Starting from the respective carbonyl compounds, tosylhydrazones were formed in the first flow step. These were directly transferred into the second reactor to be coupled with boronic acids. Remarkably, carbenes are postulated to be the highly reactive intermediates of this reaction. Both steps required heating which was managed by electromagnetic induction of a fixed bed material based on steel beads. A continuously conducted two-step flow processes over a period of almost 2 days gave the arylation product in 84% yield. Keywords: flow reactor, inductive heating, hydrazones, boronic acids, Barluenga reaction 1. Introduction the electromagnetic power that induces heating of steel beads inside the flow reactor (PEEK: 12 cm length and 9 mm internal Recently, Barluenga and coworkers disclosed a metal-free diameter). The graphical presentation of the flow setup is depicted carbon–carbon bond forming process between tosylhydrazones in Table 1. An injection loop was incorporated between the pump 3 and boronic acids 4. Starting from ketones or aldehydes 1, this and the reactor for introducing a defined amount of a mixture of the very useful new reaction provides arylation products 5 that hydrazone, and the boronic acid was dissolved in dioxane into the otherwise can only be accessed from ketones and aldehydes main stream of dioxane. Behind the flow reactor, a back pressure through lengthy synthesis [1]. valve was located that guaranteed synthesis at temperatures above Commonly, when tosylhydrazones are heated under basic the boiling point of dioxane. The reactor was loaded with a fixed conditions, thermolysis provides diazo compounds. These bed material composed of steel beads (0.8 mm diameter) and the may result in carbene intermediates with subsequent elimination base K CO (4% mass fraction) and was incased by the inductor. or dimerization, the so called Bamford–Stevens reaction [2]. In 2 3 We found that the ideal conditions were mainly dictated by the the presence of an aryl boronic acid, the reductive arylation thermal stability of the tosylhydrazone 3a. When the reaction product 5 is formed, instead (Scheme 1) [3]. Barluenga propo- temperature was raised well above 120°C, we encountered sub- ses two possible routes for rationalizing the formation of the stantial decomposition and reduced yields for product 5.Atlower reductive arylation products 5. Under basic conditions, thermol- temperature and shorter residence time, transformation was incom- ysis of hydrazone 2 is expected to lead to the corresponding plete. In comparison to the batch experiment (entry 9) and Bar- diazo compound 6. From there, the associative route proceeds luenga's work, the yield was similar while the residence time was through boronate 7. Alternatively, a dissociative mechanism shorter compared to corresponding batch conditions in a flask. would first yield a carbene and hence the zwitterionic inter- Based on these optimized conditions, we were able to prepare mediate 8. In both cases, migration of the aryl group results in a small library of arylation products 5 (Tables 2 and 3). Both an alkyl boronic acid which is hydrolyzed by protodeboronation tosylhydrazones that originate from ketones as well as alde- to yield the arylation products 5. hydes underwent reductive arylation in the presence of potas- As part of our research program dedicated to develop mini- sium carbonate at 120°C commonly in good yield. As judged tuarized flow chemistry [4] as an enabling technology [5] for by thin-layer chromatography (TLC), conversions went to organic synthesis, we now report on a flow protocol that follows completion. Barluenga's sequence that allows to prepare alkylation products Obviously, the yields are highly dependent on the stability of 5 starting from ketones or aldehydes 1, respectively. Addition- the tosylhydrazones and the intermediate carbenes. Thus, elec- ally, we show that the required heat can ideally be generated tron deficient as well thiophenyl substituted boronic acids (4d, inside the reactor by inductive heating [6] of ferromagnetic 4f and 4i) yield several by-products as judged by TLC and fixed bed material. Inductive heating has emerged as an effi- liquid chromatography–mass spectrometry (LC–MS). Attemp- cient and safe new option for heating reaction vessels on the ted isolation provided several by-products 9–11 that were fully laboratory scale. We demonstrated that this enabling technique characterized (Figure 1). Homodimer 9 may result from the [7] is particularly powerful when combined with continuous intermediate carbene that originates from tosyl hydrazone 3l. flow processes [8]. It is well established, and particularly, the Alternatively, the carbene can directly insert into the NH bond group of Yoshida showed that flow chemistry is ideally suited to of the tosylhydrazone (e. g. 3i) to yield the N-alkylated hydra- “handle” chemistry with highly reactive intermediates such as zone 10. Both type of by-products can not further undergo carbanions, radicals or carbenes [9]. In the present situation, the reductive coupling. [10] A third type of by-products formed reductive arylation supposedly proceeds via reactive intermedi- under the reaction conditions was biaryl 11 that resulted from ates so that a continuous flow protocol should operate smoothly. homocoupling of the boronic acid. Its formation could not completely be suppressed because the boronic acid had to be 2. Results and Discussion employed in excess without necessarily reducing the yields of First, we transferred Barluenga's batch protocol onto flow arylation products 3. Yields for biaryl by-products were higher conditions by optimizing the flow rate and the heat generated by when longer reaction times were required. To combine hydrazone formation with the reductive aryla- * Author for correspondence: [email protected] tion, we next developed the best conditions for preparing the DOI: 10.1556/JFC-D-12-00021 J. Flow Chem. 2012, 3(1), 11–16 © 2012 Akadémiai Kiadó Two-Step Flow Synthesis of Biarylmethanes Scheme 1. Barluenga's reductive coupling of tosylhydrazones 3 with boronic acids 4 and proposed mechanism tosylhydrazone 3d under continuous flow conditions. We found Table 2. Inductively heated Barluenga reaction under flow conditions that this reaction proceeds rather rapidly at 80°C so that, even at (hydrazones from ketones): PEEK reactor (12 cm length and 9 mm internal flow rates of 0.2 mL/min and a residence time of 15 min, full diameter) filled with steel beads (diameter 0.8 mm, ~28 g) and K2CO3 (1 g), void volume 3.3 mL); solution of N-tosyl-hydrazones 3 (0.2 mmol) conversion took place. Again, heating was provided by induc- and boronic acid 4 (0.3 mmol) in dioxane (2 mL) tive heating of steel beads as fixed bed material. With these two protocols in hand, a flow system was set up that allowed the continuous preparation of 1,1′diaryl alkanes 5 starting from ketones or aldehydes 1 and tosylhydrazide 2 followed by addition of the boronic acid 4 in between both inductively heated flow reactors (Table 5). Again, a back pres- sure regulator allowed to run the reductive arylation at higher temperature and pressure. The flow rates for both processes were set at a flow rate of 0.05 mL/min although the first step in principal proceeds more rapidly. As exemplified below, the a sequence can both be performed starting from ketones (entry 1, Entry Tosylhydrazone Boronic acid Product Yield Table 5) as well as from aldehydes (entries 2 and 3, Table 5) in very good overall isolated yields. We also performed one reac- tion over 21 h in a continuous manner without the use of the 1 84% injection loop (entry 1). This experiment provided the arylation product 5a in slightly reduced isolated yield (84% vs. 87%). 2 78% Table 1. Optimization of the inductively heated Barluenga reaction under flow conditions: PEEK reactor (12 cm length and 9 mm internal diameter; 2 mm wall thickness) filled with steel beads (diameter 0.8 mm, ~28 g) and granular K2CO3 (1 g), void volume 3.3 mL); solution of N-tosyl-hydrazones 3 (0.2 mmol) and boronic acid 4 (0.3 mmol) in dioxane (2 mL) 3 80% 4 85% 5 49% Entry Flow rate (mL/min) Residence time (min) T (°C)a Yieldb 1 0.5 6.6 100 28%c 2 0.2 16.5 100 59%c 3 0.1 33 100 74%c 4 0.05 66 100 85% 6 83% 5 0.1 33 80 5%c 6 0.1 33 120 91% 7 0.1 33 140 85% 8 0.1 33 160 77%d e – 9 120 110 93% 7 59% a Temperature measured at the outlet of the reactor as well as at the outer surface of the PEEK reactor using an IR pyrometer. b Isolated yields of pure product after evaporation of the solvent and chromatographic purification. c Transformations incomplete as judged by LC–MS. 8 21% d Decomposition of N-tosyl-hydrazones as judged by LC–MS. e Batch conditions in an oil bath: solution of N-tosyl-hydrazones 3 a (0.2 mmol), boronic acid 4 (0.3 mmol) and K2CO3 (0.3 mmol) in dioxane Isolated yields of pure products after evaporation of the solvent and (2 mL); temperature of oil bath. chromatographic purification. 12 L. Kupracz and A. Kirschning Table 3. Inductively heated Barluenga reaction under flow conditions (hydrazones from aldehydes): PEEK reactor (12 cm length and 9 mm internal diameter) filled with steel beads (diameter 0.8 mm, ~28 g) and K2CO3 (1 g), void volume 3.3 mL); solution of N-tosyl-hydrazones 3 (0.2 mmol) and boronic acid 4 (0.3 mmol) in dioxane (2 mL).