Two-Step Flow Synthesis of Biarylmethanes by Reductive Arylation of Tosylhydrazones

Full Paper

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

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 pressure 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 reaction 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).

Figure 1. By-products isolated under non-optimized reaction conditions

3. Conclusion Entry Tosylhydrazone Boronic acid Product Yielda In summary, we achieved a flow protocol for the formation of tosylhydrazones from aldehydes and their reductive coupling 1 69% with aryl boronic acids to yield the corresponding arylation products. We found that this sequence first reported by the group of Barluenga is ideally suited to be operated under continuous flow conditions although highly reactive carbene inter- 2 70% mediates are supposedly formed under thermal conditions. A special feature of how heat is efficiently generated inside the reactor is the application of electromagnetic induction of the fixed bed material which is based on steel beads. 3 87%

4. Experimental Section 4.1. General. NMR spectra were recorded on a Brucker 4 72% DPX200 spectrometer at 200 MHz (1HNMR)oraBruker AV400 spectrometer at 400 MHz (1H NMR) and at 100 MHz 13 ( C NMR) in CDCl3. Spectra are reported as values in ppm relative to (residual undeuterated) solvent signal as internal 5 73% standard. Mass spectra (EI) were obtained at 70 eV with a type Finnigan Mat 312 or (ESI) with a type Q-Tof Premier (Waters). Melting points were determined in open glass capillaries with an OptiMelt from Stanford Research Systems (Sunnyvale, 6 55% USA) and are uncorrected. Analytical thin-layer chromatography was performed with precoated silica gel 60 F254 plates (Merck, Darmstadt), and the spots were visualized with UV light at 254 nm or by staining with H2SO4/4-methoxybenzalde- hyde in ethanol. Flash column chromatography was performed 7 80% on a Biotage System. The inductors were designed and manufactured by IFF GmbH (Ismaning, Germany). Pumps were obtained from Kna- uer GmbH (Berlin, Germany). The temperature was measured 8 93% on the reactor surface using an IR pyrometer obtained from optris GmbH (LaserSight model). Commercially available reagents and dry solvents were used as received. 4.2. General Procedure for Converting Carbonyl Com- 10 95% pounds 1 to N-Tosyl-Hydrazones 3 under Continues Flow Conditions. A PEEK reactor (12 cm length and 9 mm internal diameter) equipped with PEEK fittings was filled with steel

11 86% Table 4. Tosylhydrazone formation under flow conditions

12 58%

Entry Concentration Flow rate Residence T (°C) Yieldb (mol/L) (mL/min) timea(min) 13 62% 1 0.1 0.2 15 80 92% 2 0.1 0.1 30 80 93% 3 0.1 0.05 60 80 92% a Isolated yields of pure products after evaporation of the solvent and a Based on a void volume of 3 mL. chromatographic purification. b Isolated yields.

13 Two-Step Flow Synthesis of Biarylmethanes

Table 5. Two-step flow protocol for the preparation of 1,1′diaryl alkanes 5 inserted into an inductor so that heating of the steel beads could from ketones and aldehydes 1, respectively, and boronic acids 4 be achieved by the oscillating electromagnetic field generated by the inductor. Two streams fed the system. The first one was pumped into the first reactor while a second stream was added by a T-shaped micromixer located between the two flow reactors. The pressure of at least 75 psi was adjusted by including a backpressure regulator at the end of the flow system. The system was flushed at a flow rate of 0.05 mL/min with dioxane through reactor 1, and the temperature of the first reactor was adjusted to 80°C while the second reactor was heated to 120°C (the temperature was measured at the outlet of each Entry Ketone/Aldehyde Product Reaction Yieldb a reactor). When the flow rate and the temperature of the solution time reached steady values, a solution of the carbonyl compound 1 150 min 87% (0.2 mmol) and p-toluenesulfonyl hydrazide 2 (0.2 mmol) in 1c 21 h 84% dioxane (2 mL) was injected via a sample loop into the first reactor (flow rate 0.05 mL/min). After 60 min a solution of boronic acid in dioxane (0.15 M) was pumped by the second pump at a flow rate 2 150 min 88% of 0.05 mL/min through the T-shaped micromixer over a period of 60 min. The product was collected at the outlet of the second reactor where the stream was led into a flask until no product was detected as judged by TLC analysis. The reaction mixture 3 150 min 60% was concentrated in vacuo, and the crude product was purified by a Based on a total residence time of about 93 min. flash chromatography (petroleum ether/ethyl acetate) to yield the b Isolated yields of pure products after evaporation of the solvent and pure products 5. chromatographic purification. 4.5. Analytical Data. 1-Methoxy-[4-(1-(p-tolyl)ethyl]ben- c Continuous synthesis without injection loop. 1 zene (5a) [3]. Colorless oil; H NMR (400 MHz, CDCl3) δ 7.18–6.96 (m, 6H), 6.82 (d, J = 9.0 Hz, 2H), 4.04 (q, J = 7.1 Hz, 1H), 3.74 (s, 3H), 2.30 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H). beads (diameter 0.8 mm, ~30 g). The inlet of the reactor (3 mL, 1-Methoxy-4-(1-phenylethyl)benzene (5b) [11]. Colorless void volume) was connected to the pump and at the outlet to oil; 1H NMR (400 MHz, CDCl ) δ 7.29–7.24 (m, 2H), 7.22–7.14 a flask (see Table 4). The system was flushed with dioxane 3 (m,3H),7.13(d,J =8.6Hz,2H),6.82(d,J = 8.7 Hz, 2H), 4.10 (q, (flow rate 0.2 mL/min), and the temperature was adjusted to J = 7.2 Hz, 1H), 3.77 (s, 3H), 1.61 (d, J =7.3Hz,3H). 80°C by regulating the PWM (pulse-width modulation). Af- 1-Chloro-4-(1-phenylethyl)benzene (5c) [12]. Colorless oil; 1H ter 5 min, a solution of the carbonyl compound 1 (0.1 eq.) and NMR (400 MHz, CDCl ) δ 7.32–7.29 (m, 2H), 7.27 (d, J = p-toluenesulfonyl hydrazide 2 (1 eq.) in dioxane (1 M) was 3 8.2 Hz, 2H), 7.25–7.20 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 4.15 pumped through the reactor at a flow rate of 0.2 mL/min. The (q, J = 7.2 Hz, 1H), 1.65 (d, J = 7.2 Hz, 1H); 13CNMR crude tosylhydrazone 3 was obtained after removal of the (100 MHz, CDCl3) δ 145.8, 144.8, 131.7, 129.0, 128.4, solvent under reduced pressure. 127.5, 126.2, 44.2, 21.8. 4.3. General Procedure for the Barluenga Boronic Cou- 1-Bromo-3-[1-(4-methoxyphenyl)ethyl]benzene (5d) [13]. pling of N-Tosyl-Hydrazones 3 under Flow Conditions. A Colorless oil; 1H NMR (200 MHz, CDCl ) δ 7.38–7.27 (m, 2H), PEEK reactor (12 cm length and 9 mm internal diameter) was 3 7.16–7.08 (m, 3H), 6.84 (d, J = 8.8 Hz, 2H), 4.07 (q, J = 7.2 Hz, filled with a mixture of steel beads (diameter 0.8 mm, ~28 g) 1H), 3.79 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H). and granular K2CO3 (1 g). The reactor (void volume 3.3 mL) 1-Bromo-4-[1-(p-tolyl)ethyl]benzene (5e). Colorless oil; 1H was connected to an injection loop which was located between NMR (400 MHz, CDCl3) δ 7.40 (d, J =8.5Hz,2H),7.13–7.00 the reactor and the pump (see Tables 1 and Table 2). The system (m, 6H), 4.08 (q, J = 7.2 Hz, 1H), 2.32 (s, 3H), 1.61 (d, J = 7.2 Hz, was flushed with dioxane at a flow rate of 0.1 mL/min, and the 3H); NMR (100 MHz, CDCl3) δ 145.6, 142.7, 135.7, 131.3, temperature was adjusted to 120°C by regulating the PWM. A 129.3, 129.1, 127.4, 119.7, 43.8, 21.8, 20.9; HRMS (ESI) [M+ system pressure of at least 75 psi was adjusted by implement- + + H ] calcd. for C15H16Br , 275.0430; found, 275.0421. ing a backpressure regulator (Upchurch Scientific). When the 3-[1-(3,5-Dimethylphenyl)ethyl]thiophene (5f). Colorless oil; temperature of the solution reached steady values (measured 1 H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 4.9, 3.0 Hz, 1H), at the outlet; after 5 min), a solution of N-tosyl-hydrazones 3 6.98 (d, J = 3.0 Hz, 1H), 6.90 (dd, J = 5.0, 0.8 Hz, 1H), 6.85 (s, (0.2 mmol) and boronic acid 4 (0.3 mmol) in dioxane (2 mL) 1H), 6.83 (s, 2H), 4.09 (q, J = 7.2 Hz, 1H), 2.29 (s, 6H), 1.62 (d, 13 was injected through the sample loop. The reaction mixture was J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 147.4, 146.2, collected until no compounds could be detected in the eluent as 137.8, 127.9, 127.8, 125.2, 119.7, 40.7, 29.7, 22.2, 21.3; HRMS + + judged by TLC. The solution collected was removed under (ESI) [M+H ] calcd. for C14H17S , 217.1045; found, 217.1039. reduced pressure, and the crude product was purified by flash 3-[1-(4-Chlorophenyl)ethyl]-5-fluorobenzo[b]thiophene 1 chromatography (petroleum ether/ethyl acetate) to furnish the (5 g). Colorless oil; H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = pure products 5. 8.8, 4.9 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.16– 4.4. General Procedure for the Two-Step Preparation of 7.10 (m, 3H), 7.05 (dt, J = 8.7, 2.4 Hz, 1H), 4.33 (q, J = 7.0 Hz, 13 1,1′-Diaryl Methanes and Ethanes 5 from Carbonyl Com- 1H), 1.70 (d, J = = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ pounds 1 and Boronic Acids 4 under Flow Conditions. A 161.7, 159.3, 143.4, 128.8, 128.6, 124.1, 124.0, 123.8, 113.2, flow system consisting of two identical PEEK reactors (12 cm 113.8, 108.1, 108.0, 39.0, 22.2; HRMS (ESI) [M+H+] calcd. + length and 9 mm internal diameter) and the first pump were for C16H13ClFS , 291.0405; found, 291.0400. connected in a linear setup (see Table 5). The first reactor was 3-[1-(3,5-Bis(trifluoromethyl)phenyl)ethyl]-N,N-dimethylaniline 1 filled with steel beads (diameter 0.8 mm, ~30 g) while the (5 h). Red oil; H NMR (400 MHz, CDCl3) δ 7.70 (s, 3H), 7.19 second one contained a mixture of steel beads (diameter (t, J = 8.1 Hz, 1H), 6.62 (dd, J = 8.2, 2.3 Hz, 1H), 6.57–6.53 (m, 0.8 mm,~28 g) and granular K2CO3 (1 g). Both reactors were 2H), 4.21 (q, J = 7.2 Hz, 1H), 2.93 (s, 6H), 1.69 (d, J = 7.2 Hz, 14 L. Kupracz and A. Kirschning

13 3H); C NMR (100 MHz, CDCl3) δ 150.84, 149.06, 145.05, (m, 1H), 7.39–7.30 (m, 2H), 7.23–7.16 (m, 4H), 7.01 (s, 1H), 13 131.41 (q, J = = 33.0 Hz), 129.47, 127.72 (dd, J = 1.1, 3.6 Hz), 4.15 (s, 2H), 2.47 (s, 3H); C NMR (100 MHz, CDCl3) 140.6, 123.44 (d, J = 272.4 Hz) 120.07 (td, J = 3.9, 7.8 Hz), 115.55, 138.7, 136.3, 136.0, 135.4, 129.3, 127.0, 124.3, 123.9, 123.1, 111.71, 111.01, 45.06, 40.54, 21.70; HRMS (ESI) [M+H+] 122.8, 121.9, 34.4, 16.1; HRMS (ESI) [M+H+] calcd. for + + calcd. for C18H18F6N , 362.1343; found, 362.1342. C16H15S2 , 271.0610 found, 271.0603. 1-Cyclohexyl-4-methoxybenzene (5i) [14]. Colorless oil; 3-(Thiophen-3-ylmethyl)benzo[b]thiophene (5 t). Red oil; 1 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.9 Hz, 2H), 6.84 H NMR (400 MHz, CDCl3) δ 7.89–7.85 (m, 1H), 7.73–7.69 (d, J = 8.9 Hz, 2H), 6.04–6.01 (m, 1H), 3.80 (s, 3H), 2.40–2.35 (m, 1H), 7.38–7.33 (m, 2H), 7.29–7.26 (m, 1H), 7.1 (s, 1H), 13 (m, 2H), 2.21–2.16(m,2H),1.80–1.74 (m, 2H), 1.68–1.62 (m, 7.01–6.98 (m, 2H), 4.20 (s, 2H); C NMR (100 MHz, CDCl3) 2H), 1.41–1.34 (m, 2H). δ 140.6, 139.7, 138.7, 135.2, 128.5, 125.7, 124.3, 124.0, 122.9, + + 1-Fluoro-2-(4-methoxybenzyl)benzene (5j). Colorless oil; 122.0, 121.6, 29.7; HRMS (ESI) [M+H ] calcd. for C13H11S2 , 1 H NMR (400 MHz, CDCl3) δ = 7.22–6.97 (m, 6H), 6.83 (d, 231.0297; found, 231.0301. J = 8.7 Hz, 2H), 3.94 (s, 2H), 3.78 (s, 3H); 13CNMR Ethyl 2-(benzo[b]thiophen-3-ylmethyl)benzoate (5u). Yellow 1 (100 MHz, CDCl3) 160.89 (d, J = 245.2 Hz) 158.03, 131.91 oil; H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.75, 1.22 Hz, (d, J = 0.7 Hz), 130.87 (d, J = 4.7 Hz), 129.73 (d, J =0.8Hz), 1H), 7.88–7.84 (m, 1H), 7.76–7.72 (m, 1H), 7.41 (dt, J = 7.55, 128.49 (d, J = 15.8 Hz), 127.79 (d, J = 8.0 Hz), 124.01 (d, J = 1.36 Hz, 1H), 7.37–7.29 (m, 3H), 7.22 (d, J = 7.62 Hz, 1H), 3.6 Hz), 115.26 (d, J = 22.1 Hz), 113.89, 55.23, 33.90 (d, J = 6.84 (s, 1H), 4.58 (s, 2H), 4.26 (q, J = 7.13 Hz, 2H), 1.23 (t, J = + + 13 3.1 Hz); HRMS (ESI) [M+H ]calcd.forC14H14FO , 217.1023; 7.13 Hz, 3H); C NMR (100 MHz, CDCl3) δ 167.7, 140.5, found, 217.1020. 140.4, 138.9, 135.7, 132.0, 131.0, 130.7, 130.4, 126.5, 124.2, Bis(4-methoxyphenyl)methane (5 k) [15]. Colorless oil; 124.0, 122.9, 122.8, 121.9, 60.9, 33.0, 14.1; HRMS (ESI) [M+ 1 + + H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.6 Hz, 4H), 6.82 H ] calcd. for C18H17O2S2 , 297.0944; found, 297.0940. (d, J = 8.6 Hz, 4H), 3.86 (s, 2H), 3.77 (s, 6H). (E)-1,2-Bis(4-chlorophenyl)ethene (9) [21]. Yellow oil; 1 1-(4-Methoxybenzyl)-3-nitrobenzene (5 l) [16]. Yellowish H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.6 Hz, 4 H), 1 oil; H NMR (400 MHz, CDCl3) δ 8.08–8.03 (m, 2H), 7.52– 7.33 (d, J = 8.6 Hz, 4 H), 7.02 (s, 2H). 7.48 (m, 1H), 7.44 (dt, J = 7.6, 0.8 Hz, 1H), 7.10 (d, J = 8.7 Hz, N-(4-methoxybenzyl)-N′-(4-methoxybenzylidene)-4- 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.02 (s, 2H), 3.80 (s, 3H); 13C methylbenzenesulfonohydrazide (10). Yellow oil; 1HNMR NMR (100 MHz, CDCl3) 158.4, 143.7, 134.9, 131.4, 129.9, (400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 129.3, 123.6, 121.2, 114.2, 55.3, 40.6; HRMS (ESI) [M+H+] 7.48 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.24 (d, J = + calcd. for C16H11ClFS , 289.0249; found, 289.0252. 8.8 Hz, 2H), 6.85 (d, J = 2.8 Hz, 2H), 6.83 (d, J = 2.8 Hz, 2H), 2-(4-Methoxybenzyl)phenol (5 m) [17]. Yellowish oil; 4.64 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 2.43 (s, 3H); 13C NMR 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H), (100 MHz, CDCl3) δ 161.5, 159.1, 144.0, 134.3, 132.0, 129.5, 7.14–7.09(m,2H),6.89(dt,J = 7.5, 7.5, 1.2 Hz, 1H), 6.84 (d, 129.3, 128.7, 128.4, 127.7, 126.7, 114.2, 114.0, 55.4, 55.3, + + J = 8.7 Hz, 2H), 6.79 (dd, J =7.9,0.8Hz,1H),4.74(s,1H),3.94 52.6, 21.6; HRMS (ESI) [M+H ] calcd. for C23H25N2O4S , (s, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 153.8, 425.1530; found, 425.1535. 131.7, 130.8, 129.6, 127.8, 127.2, 120.9, 115.7, 114.1, 55.3, 35.6. 4,4′-Dimethoxy-1,1′-biphenyl (11) [22]. Colorless solid; 1 21. 2-(4-Chlorobenzyl)phenol (5n) [18]. Yellowish oil; H NMR (200 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 4H), 6.98 1 H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 9.2 Hz, 2H), 7.18– (d, J = 8.8 Hz, 4H), 3.85 (s, 6H). 7.08 (m, 4H), 6.89 (dt, J = 1.1, 7.5 Hz, 1H), 6.77 (dd, J = 0.8, 8.0 Hz, 1H), 4.71 (s, 1H), 3.96 (s, 2H); 13CNMR(100MHz, Acknowledgments. We thank the Fonds der Chemischen CDCl3) δ 153.5, 138.7, 131.9, 130.9, 130.0, 128.6, 127.9, 126.7, Industrie for financial support and Henkel AG & KGaA (Düssel- 121.0, 115.6, 35.5. dorf, Germany), EVONIK Degussa GmbH (Essen, Germany) as 3-(4-Chlorobenzyl)thiophene (5o) [19]. Orange oil; 1H NMR well as IFF GmbH (München, Germany) for technical support. We (400 MHz, CDCl3) δ 7.31–7.26 (m, 3H), 7.15 (d, J = 8.6 Hz, are grateful to Dr. Uwe Schön (Abbott Products GmbH, Hannover, 2H), 6.95–6.92 (m, 1H), 6.91 (dd, J =1.3,4.9Hz,1H),3.97(s, Germany) for helpful discussions. 2H); 13C NMR (100 MHz, CDCl3) δ 140.9, 139.1, 132.0, 130.1, 128.6, 128.3, 125.9, 121.4, 35.9. 4-(4-Methoxybenzyl)-3-methyl-1-phenyl-1H-pyrazole (5p). 1 References Yellowish oil; H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 1.1, 8.7 Hz, 2H), 7.54 (s, 1H), 7.42–7.36 (m, 2H), 7.20 (tt, J = 1. Barluenga, J.; Lonzi, G.; Riesgo, L.; Tomás, M.; López, L. A. J. Am. Chem. Soc. 2011, 133, 18138–18141. 1.1, 7.3 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2. Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735–4740. 2H), 3.80 (s, 3H), 3.76 (s, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, 3. Barluenga, J.; Tomás-Gamasa, M.; Aznar F.; Valdés, C. Nature Chem. 2009, 1, 494–499. CDCl3) δ 158.0, 149.3, 140.1, 132.4, 129.4, 129.3, 126.0, 125.5, + 4. Recent reviews on flow chemistry: (a) Wegner, J.; Ceylan, S.; Kirschning, 121.2, 118.3, 113.9, 55.3, 29.3, 12.1; HRMS (ESI) [M+H ] calcd. A. Adv. Synth. Catal. 2012, 354,17–57; (b) Wegner, J.; Ceylan, S.; Kirschning, + – for C18H19N2O , 279.1492; found, 279.1486. A. Chem. Commun. 2011, 47, 4583 4592; (c) McMullen, J. P.; Jensen, K. F. 1 Annu. Rev. Anal. Chem. 2010, 3,19–42; (d) Yoshida, J.; Kim, H.; Nagaki, A. 3-Benzylbenzo[b]thiophene (5q) [20]. Colorless oil; H NMR ChemSusChem 2011, 4, 331–340. (e) Webb, D.; Jamison, T. F. Chem. Sci. 2010, (400 MHz, CDCl3) δ 7.71–7.67 (m, 1H), 7.87–7.83 (m, 1H), 1,675–680; (f) Marre, S.; Jensen, K. F. Chem. Soc. Rev. 2010, 39, 1183–1202; (g) 7.34–7.25 (m, 6H), 7.24–7.19 (m, 1H), 7.00 (t, J = 1.0 Hz, Illg, T.; Löb, P.; Hessel, V. Bioorg. Med. Chem. 2010, 18,3707–3719; (h) Yoshida, J.-i. Chem. Rec. 2010, 10,332–341; (i) Frost, C. G.; Mutton, L. Green Chem. 2010, 1H), 4.19 (s, 2H). 12,1687–1703; (j) Razzaq, T.; Kappe, C. O. Chem. Asian J. 2010, 5,1274–1289. 3-(4-Methoxybenzyl)benzo[b]thiophene (5r). Yellowish oil; 5. Kirschning, A.; Solodenko, W.; Mennecke, K. Chem. Eur. J. 2006, 12, 1H NMR (400 MHz, CDCl ) δ 7.89–7.83 (m, 1H), 7.71–7.65 (m, 5972–5990. 3 6. For a review on the theory as well as application of inductive heating in 1H), 7.37–7.32 (m, 2H), 7.18 (d, J = 8.6 Hz, 2H), 6.99 (s, 1H), material science, medicine and synthesis see: Kirschning, A.; Kupracz, L.; 6.85 (d, J = 8.6 Hz, 2H), 4.13 (s, 2H), 3.79 (s, 3H); 13CNMR Hartwig, J. Chem. Lett. 2012, 41, 562–570. δ 7. 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