The Regioselective Arylation of 1,3-Benzodioxoles Yuki Kanai,a Dorian Müller-Borges,a and Herbert Plenioa,* a Organometallic Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 12, 64287 Darmstadt, Germany E-mail: herbert.plenio@tu-darmstadt.de Homepage: https://www.chemie.tu-darmstadt.de/plenio/index.en.jsp Manuscript received: August 17, 2021; Revised manuscript received: December 1, 2021; Version of record online: December 16, 2021 Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202101014 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The direct arylation of 1,3-benzodioxole and 2,2-difluorobenzo[1,3]dioxole with 26 different aryl bromides yields the respective 4-substitued products in yields of >80% requiring between 0.05–1 mol% Na2PdCl4, 30 mol% pivalic acid, 1.3 equivs. K2CO3 and ca. 250 equivs. of diethylace- tamide per Pd at T=120 °C. The nature of the amide and the concentration of the reactants are crucial for the optimization of the reaction conditions. The primary role of the acetamide is that of a ligand to Pd, it is not needed as a solvent. Keywords: Palladium; direct arylation; diethylaceta- mide; homogeneous catalysis; CH-activation Introduction The Suzuki-Miyaura reaction, which is the Pd-cata- lyzed cross-coupling of sp2-C halides with aryl boronic acids, is a versatile method for the synthesis of biaryls Ar� Ar’.[1] This transformation is characterized by excellent tolerance towards functional groups, the commercial availability of a wide range of boronic acids, the facile transformation of aryl chlorides and often requires low catalyst loadings.[2] Nonetheless, there are also disadvantages such as the need for sophisticated ligands for Pd and boronic acid – leading to additional waste, while some heterocyclic boronic acids are unstable.[3] As an interesting alternative, Fagnou et al.[4] pioneered the development of reactions of aryl halides with arenes and heteroarenes, which rely on oxidative additions involving the aryl halides and C� H activation of an arene. Consequently, such direct arylation reactions only require activating groups at one of the two arenes.[5] Intra- and intermolecular direct arylation reactions comprising heteroarenes or of arenes with directing groups are well established, but often require forcing conditions.[5d,6] This is due to the lack of efficient catalysts for such transformations and the high activation barrier due to the low CH-acidity of arenes and high arene distortion energies.[7] A classic mechanistic model for these reactions is the concerted-metalation-deprotonation (CMD) (Figure 1),[5b,6d,8] recently other mechanistic proposals such AMLA, BIES or eCMD are receiving more attention.[9] Initially sterically demanding and electron-rich phosphines as ligands for palladium were believed to play an essential role in such reactions. Tan and Hartwig investigated the mechanism of Pd-catalyzed direct arylations involving non-heterocyclic arenes in more detail and found that the key species in the catalytic cycle is not [LPd(Ar)(OPivalate)] (L=PR3= e.g. P(tBu)3) – instead a dimethylacetamide (DMAc) solvate complex with palladium appears to play an important role.[10] Following the findings of Tan and Hartwig, the interest in ligand design for the develop- ment of palladium-catalyzed direct arylations deterio- rated. Instead the “ligand-free” approach relying on the Pd-DMA solvate complex has been utilized for numerous direct arylation reactions, for example by Doucet et al.[11] and by others.[12] The closely related Pd-catalyzed direct arylation polymerization (DArP) is highly useful for the synthesis of electronic materials.[13] Overall, in recent years there have been few significant breakthroughs in the arylation of simple arene sp2-hybridized C� H bonds employing Pd-only metal catalysts.[14] High palladium loadings (up to UPDATES doi.org/10.1002/adsc.202101014 Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 679 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 679/688] 1 http://orcid.org/0000-0002-2257-983X https://www.chemie.tu-darmstadt.de/plenio/index.en.jsp https://doi.org/10.1002/adsc.202101014 http://crossmark.crossref.org/dialog/?doi=10.1002%2Fadsc.202101014&domain=pdf&date_stamp=2021-12-16 10 mol%) and harsh reaction conditions remain common.[15] In combination with a limited substrate scope, a large excess of one arene and the need for undesirable additives such as stoichiometric silver salts, application of Pd-catalyzed direct arylation still require improvements.[14] In this respect, the arylation of 1,3- benzodioxole serves as an instructive example. In 2006, Fagnou reported the palladium catalyzed aryla- tion of 1,3-benzodioxole with 4-tolylbromide.[4a] The reactions requires 10 mol% of Pd(OAc)2, 30 mol% PtBu2Me and 100 mol% of silver triflate as an additive at a reaction temperature of 145 °C. The only other synthetic methodology leading to 4-arylated 1,3- benzodioxoles was published by Knochel et al. via alumination and ZnCl2 transmetalation, followed by Negishi coupling reactions.[16] The 1,3-benzodioxole motif can be found in many pharmaceuticals (Scheme 1). However, synthetic methodology is lim- ited, since it is difficult to introduce functional groups on the 4-position of 1,3-benzodioxole.[17] Classic electrophilic substitution reactions at 1,3-benzodioxole (halogenation, nitration, acylation) lead to the respec- tive 5-substituted products. Based on this, it is difficult to introduce functional groups at the 4-position. The development of improved approaches to address the 4- position of 1,3-benzodioxole thus appears to be useful. We want to present here a significantly improved procedure for the efficient and regioselective direct arylation of 1,3-benzodioxole with a wide range of different aryl bromides. Results and Discussion Optimization of the reaction conditions. The conditions for the direct arylation of 1,3-benzodioxalane (bdo) with 4-tolylbromide were optimized (Scheme 2). The influence of numerous parameters such as the nature of -solvent (Figure 2),[18] the palladium source (Table 1), the nature of the carboxylate additive (Table 2), of the base (Table 3), the reaction temperature (Table 3), the concentration of the reactants (Figures 4, 5), and the stoichiometric ratio of the 4-tolylbromide and bdo (Figure 6) were studied in detail. Typical solvents used in direct arylation reactions are DMAc or DMF.[8b] Hartwig et al. suggested, that DMAc not only acts as a polar aprotic reaction medium, but that it also coordinates to palladium.[10] Based on the importance of amides, the systematic modulation of the nature of such amides offers good chances to achieve more efficient substrate conversion.[19] According to the general amide formula Figure 1. Concerted-metalation-deprotonation (CMD) mechanism for direct arylation. Scheme 1. 1,3-Benzodioxole derivatives in pharmaceutical chemistry. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 680 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 680/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de R’C(O)NR2 the nature of the alkyl substituents R’ (= H, Me, iPr, tBu) and R (=Me, Et, iPr) were modified and six different amides tested in direct arylation reactions (Figure 2). The established amides DMF and DMAc provide good substrate conversion, but the most efficient direct arylation (Scheme 1) takes place in diethylacetamide (DEAc, R’=Me, R=Et). The Scheme 2.Model reaction for the optimization of the direct arylation of bdo. Figure 2. Turn-over-numbers (ton, conversion) for the reaction 1,3-benzodioxole with 4-tolylbromide with six different amides, following the general procedure outlined in Table 1 (Na2PdCl4 as Pd source). Table 1. Optimization of Pd source for the arylation of bdo. # Pd source ton (conv.%)[a] 1 (MeCN)2PdCl2 264 (53) 2 (cod)PdCl2 110 (22) 3 (cod)PdMeCl 98 (20) 4 [PdCl(C3H5)]2 (0.1 mol%) 23 (5) 5 Pd(OAc)2 96 (19) 6 Pd(acac)2 39 (8) 7 Diimine-PdCl2 102 (20) 8 Na2PdCl4 with IPr-HCl 0.4 mol% 0 (0) 9 Na2PdCl4 with SIPr-HCl 0.4 mol% 0 (0) 10 Pd2(dba)3 (0.1 mol%) 50 (10) 11 Na2PdCl4 DavePhos 0.4 mol% 54 (11) 12 Na2PdCl4 with XPhos 0.4 mol% 117 (23) 13 Na2PdCl4 with cataCXium C 16 (3) 14 zero Pd no conversion 15 Na2PdCl4 (0.2 mol%) 283 (57%) 16 Na2PdCl4 (0.5 mol%) 196 (98%) Reaction conditions: 4-tolylbromide (0.5 mmol, 0.062 mL), 1,3-benzodioxole (5 equiv., 0.287 mL), K2CO3 (1.3 equiv., 90 mg), PivOH (0.3 equiv., 0.018 mL), n-tetradecane (0.025 mL) + Pd source (0.2 mol%) in DEAc (0.15 mL, 1.2 mmol), T=120 °C for 18 h. [a] Determined by gas chromatography using n-tetradecane as an internal standard, based on the conversion of ArBr. Table 2. Optimization of carboxylate for the arylation of bdo. # Carboxylic acid ton (conv.%) 18 1-AdCOOH 74 (15) 19 125 (25) 20 38 (8) 21 <5 22 no tBuCOOH <5 23 tBuCOOH (10 mol%) 246 (49) 24 tBuCOOH (30mol%) 283 (57%) 25 tBuCOOH (50 mol%) 114 (23%) General conditions see Table 1. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 681 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 681/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de latter amide appears to be characterized by an optimum balance of steric bulk and electron-richness. A further increase in the steric bulk in related amides (R’=Me, R= iPr or R’= iPr, R=Et or R’= tBu, R’=Et) leads to much lower substrate conversion. The nature of the palladium source and the use of other ligands should have a significant influence on the catalytic efficiency. In Table 1 the results of testing fifteen different palladium sources are shown. The simple (MeCN)2PdCl2 (entry 1, ton 264, conversion 38% at 0.2 mol% Pd loading) and Na2PdCl4 (entry 15, 16; ton 283, conversion 57% at 0.2 mol% Pd loading) were fou nd to give the best results. At 0.5 mol% of Na2PdCl4 almost quantitative substrate conversion (98%) is observed. In the absence of any added palladium substrate conversion did not happen (Ta- ble 1, entry 14). In conclusion, the simplest Pd sources are the most efficient ones and the addition of NHC or phosphine ligands does not enhance reactivity. Fagnou et al. showed that carboxylates are essential additives in direct arylation reactions, pivalic acid was previously reported to be most efficient one.[20] Larrosa reported the high efficiency of 1-adamantanecarboxylic acid in cooperative Pd� Ag catalyzed C� H arylation reaction,[21] which was tested in our reaction conditions (Table 2, entry 18) and showed much lower reactivity than pivalic acid. Recent reports by Fujihara et al. showed that very bulky carboxylic acids like Table 2, entry 19 are better promoters than pivalic acid in intramolecular and intermolecular direct arylation reactions.[22] However for our model reaction, the conversion is only modest (ton 125, yield 25%). Next, a carboxylic acid combining the pivalate and the amide motif was tested, but again the conversion is poor (Table 2, entry 20) – the same poor conversion is observed for a substituted malonate (Table 2, entry 21). Modifying the amount of pivalate additive was also tested (Table 2, entries 22–25) and the established 30 mol% found to give the best conversion – as was already observed previously.[20] In conclusion, the carboxylate screening did not lead to any improve- ments with respect to the Fagnou work.[8b] With a view to recent reports by Fujihara et al.[22b] on the high efficiency of Rb2CO3, a number of bases were tested in the reaction of bdo and 4-tolylbromide (Table 3). The nature of the base is very important and largely different reactivities are observed – even though it remains unclear, why the various bases behave differently. Again, the classic K2CO3 gives the best results, none of the other bases performs nearly as good. Several temperatures for the direct arylation reaction were tested (Table 3) and 120 °C found to be ideal, considering the maxed ton for the given reaction time of 18 h. Since the reaction mixture for the arylation of bdo is highly concentrated, a large amount of the insoluble base K2CO3 was considered problematic concerning the efficient homogenization of the reaction mixture. 1.3 equivs. of K2CO3 is the lowest amount of base conceivable since 1 equiv. of base is needed for the direct arylation reaction and another 0.3 equivs. for the deprotonation of pivalic acid. Consequently, 1.3 equivs. of K2CO3 was tested and it turns out to be very beneficial for substrate conversion (Table 3, entries 37, 38) – probably because of the more efficient stirring.[23] Table 3. Optimization of base and temperature for the arylation of bdo. # base ton (conv.%) 26 Li2CO3 0 27 Na2CO3 17 (3) 28 Rb2CO3 137 (27) 29 Cs2CO3 0 (0) 30 KHCO3 54 (11) 31 KOAc 0 (0) 32 KOtBu 74 (15) 33 K3PO4 0 34 DIPEA 27 (5) 35 2,4,6-Trimethylpyridine 0 36 DBU 0 37 K2CO3 (2.5 equiv.) 216 (42) 738 K2CO3 (1.3equiv.) 283 (57) temperature (°C) 39 100 120 (24) 40 110 220 (45) 41 120 283 (57) 42 130 246 (49) 43 140 211 (42) General conditions see Table 1. Figure 3. Plot of turn-over-number (ton) vs. amide content (vol %) of the reaction mixture for the arylation of bdo (general reaction conditions, see footnote Table 1, variable amide). UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 682 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 682/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de Concentration dependence of the direct arylation reaction. Hartwig et al. presented convincing evidence for a cooperative, bimetallic mechanism in direct arylation reactions involving pyridine-N-oxides.[24] Mechanistic work by others, support this idea like for example in Pd/Ag-[21c,25] or Pd/Cu-mediated CH-activa- tion reactions[26] or Pd-catalyzed oxidative biaryl coupling[27] or direct arylation reactions.[28] With a view to the potential rate limiting bimolecular step in direct arylation reactions, it is a simple idea to increase the concentration of the reactants in the reaction mixture. This has been considered before, but it seems that previous efforts did not go far enough.[4a] This motivated us to study the effect of the concentration of the reactants in more detail and to test the effect of maximizing substrate concentration in the reaction mixture. The reaction conditions are as follows: 4-tolylbromide (0.5 mmol, 0.062 mL), 1,3- benzodioxole (5 equiv., 0.287 mL), K2CO3 (1.3 equiv., 90 mg), PivOH (0.3 equiv., 0.018 mL), n-tetradecane (0.025 mL) and Na2PdCl4 (0.2 mol%) in amide solvent (variable volumes of DMAc or DEAc) at 120 °C for 18 h. In the following series of experiments, different amounts of amide (DMAc or DEAc) ranging from 0.05 mL to 2.2 mL were added to the reaction mixture (initial volume 0.4 mL) and the conversion of the aryl bromide determined. The addition of amide leads to an increase in the concentration of the respective amide, but at the same time this also results in the dilution of all other reaction components. The effect of this dilution on substrate conversion is shown in Figure 3. The plot of ton vs. vol% amide (DMF and DMc) displays a maximum for the best substrate conversion at ca. 25 vol.% of DEAc and at ca. 45 vol.% of DMAc. Lower and higher amounts of amide solvent lead to a significant decrease in substrate conversion. Notably, the amount of DEAc needed for optimum substrate conversion is much smaller than that of DMAc (despite the slightly higher molecular mass of DEAc). Obtain- ing better substrate conversion with less amide, is also highly practical, since DEAc is more expensive than DMAc. On the other hand, a minimum amount of amide is essential for the reaction to proceed. In the screening system the optimum value of DEAc corre- sponds to approx. 1250 equivalents of DEAc per Pd (Table 1, entry 15). However, since in the highly concentrated reaction mixtures, the reactants make up a very significant portion of the total volume, changing exclusively the concentration of the amide is not straightforward and it is difficult to analyze the effect of the amide solvent. The current experiment does not show whether this activity drop is caused by dilution of the reaction mixture or since an excess of amide inhibits the catalytic transformation. It shows, however, that DEAc is much more efficient than DMAc. It is therefore likely, that DEAc is a better ligand for Pd than DMAc. Variation of DEAc at constant concentrations of all other reaction components. The next experiment was designed to address the question of whether the decrease in the catalytic activity for the direct arylation reaction upon addition of DEAc is due to dilution of the reaction mixture or caused by the inhibition of the active Pd with an excess of amide. In the following series of experiments the total volume of the reaction mixture remains constant[29] and based on this, the concentration of all reactants and of the catalyst is also constant – only the concentration of DEAc varies. This was achieved by adding mesitylene to the reaction mixture, such that the sum of the volumes of mesitylene and DEAC remains constant. This dilution leads to a significant decrease in the catalytic activity, but nonetheless it allows to evaluate the effect of variation of c(DEAc) on substrate conversion. Mesity- lene is expected to be inert with respect to the reaction conditions since plain arenes are characterized by low reactivity in the direct arylation – more importantly, the sp2-CH groups are sterically shielded by three methyl groups lowering their reactivity even further. Without added DEAc insignificant substrate con- version was observed, but even with 0.05 mL of DEAc added a very significant increase is observed.[30] The data in Figure 4 indicate that a minimum volume of DEAc is needed to promote the reaction to ton> 60. In the present reaction system this amount corresponds to approx. 0.2 mL. More DEAc beyond this threshold does not improve conversion to a significant extent, but it also does not seem to inhibit product formation.[31] This series of experiments demonstrates, that the primary role of DEAc is that of a ligand to palladium. As a solvent it could be replaced by other Figure 4. Effect of the volume of added DEAc on the ton for the reaction of bdo with 4-tolylbromide at constant total volume (V(reaction mixture)=0.83 mL=0.4 mL (reactants) +0.43 mL (DEAc+mesitylene), otherwise optimized reaction conditions, see legend Table 1. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 683 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 683/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de liquids such as mesitylene. This dilution series reveals another advantage of DEAC compared to DMAc (Figure 3) as the former amide allows higher concen- trations in the reaction mixture. Effect of reactant concentration on reactivity. To probe the influence of substrate and catalyst concen- tration on reactivity, three batches of the optimized reaction mixture (see legend Table 1) with a total volume of 0.54 mL (each batch containing 0.15 mL of DEAc) were diluted with different amounts of mesity- lene (V(mesitylene)=0.15 mL, 0.45 mL and 1.95 mL) and the substrate conversion determined for each reaction (Figure 5). The dilution of the reaction mixture leads to a pronounced lowering of substrate conversion. This decrease is similar to that found when the reaction mixture is diluted with additional DEAc (Figure 3). Again, we conclude that the concentration of reactants and catalyst has a very strong influence on substrate conversion and that the primary role of DEAc is that of a ligand to palladium. Variation of the equivalents of 1,3-benzodixole relative to the aryl bromide. Next, the stoichiometric ratio of the two reactants was varied. As was shown before, it is advantageous to use a large excess of the CH-active compound relative to the aryl halide. However, using our optimized reaction conditions, a large amount of the CH-active compound relative to 4- tolylbromide also leads to significant dilution of the reactants, which appears to be unfavorable for the catalytic conversion. The plot of ton vs. equivalents of bdo relative to 4-tolylbromide (Figure 6) shows a maximum at five equiv. of bdo relative to 4- tolylbromide. Up to a stoichiometric ration of 5 :1 (bdo: 4-tolylbromide) the presence of more bdo over- compensates the unfavorable dilution of the reaction mixture. At higher ratios bdo/4-tolylbromide the dilution of the reaction mixture leads to a decrease in the overall catalytic activity, which can’t be compen- sated by using more bdo. Variation of the equivalents of 1,3-benzodixole relative to the aryl bromide at constant overall concentration. The same experiment as before was done, but this time the volume of the reaction mixture was diluted with mesitylene such that the total volume of the reaction mixture remains constant: (V(bdo)+ V(mesitylene)=constant). A pronounced increase in the reactivity is observed with increasing ratio bdo/4- tolylbromide. At ratio 1.5 (ton=31), at ratio 3 (ton= 46), at ratio 5 (ton=71), at ratio 7 (ton=108) and at ratio 10 (ton=117). In practical terms, using a smaller excess of bdo gives better results since at very high bdo/4-tolylbromide the dilution effect overcompensates the reactivity increase due to a high bdo/4-tolylbro- mide ratio. Synthesis of arylated bdo. The direct arylation of bdo was done for 25 different aryl bromides and the respective products isolated after purification (Table 4). For all reactions the optimized reaction conditions (Experimental section) were applied. The respective products are typically isolated in yields >80%. Lower yields are observed for aryl bromides with the strongly ewg (R=NO2) substituent. Insignificant amounts of product are formed with aryl bromides with 4-COOEt and 4-CN substituents. The lack of reactivity with 4- CN might be due to the coordination/inhibition of the active Pd catalyst by nitrile coordination. The limited scope of this reaction for arenes with strongly electron- withdrawing NO2 group might be due to the efficient activation of the aryl-Br unit for oxidative addition. The 4-NEt2 substituted product is isolated in moderate yield (67%), which is due to the limited stability of this compound in solution. The arylation of bdo Figure 5. Plot of the ton vs. the amount of added mesitylene denoting the dilution of the reaction mixture (initial volume 0.54 mL). Figure 6. Plot of ton vs. equivalents of bdo relative to 4- tolylbromide. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 684 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 684/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de tolerates steric bulk reasonably well and four ortho- substituted aryl bromides were successfully employed for arylation reactions. The ortho-methyl substituted product is obtained in 83% yield, the ortho-ethyl in 32% while the ortho-isopropyl and the ortho, ortho’- dimethyl product do not form – probably because of the steric bulk of the substituents. However, even 1- bromonaphthalene and 1-bromo-pyrene are efficiently converted into the respective coupling products. For most reactions it is possible to also isolate the excess of bdo during the purification of the respective coupling products enabling a more efficient use of this reaction component. In order to enable the comparison of the present catalytic protocol with recent catalytic systems we have also tested the direct arylation of 2,2- difluorobenzo[1,3]dioxole with three different aryl bromides according to the general procedure in Table 4. The activity of the catalytic system reported here is remarkable (Table 5) and for example the reaction of 4-tolylbromide with 2,2- difluorobenzo[1,3]dioxole requires only 0.05 mol% Na2PdCl4 to achieve >80% product formation. The same reaction was recently reported by Hartwig et al. to produce 55% yield requiring a ten-fold higher Pd- loading (0.5 mol% Pd(OAc)2 and furthermore includ- ing 0.5 equiv. Ag2O additive and 5 mol% of Cy2PtBu ligand).[25c] This again underlines the highly efficient nature of the catalytic system reported here. Table 4. Arylation of bdo with 25 different aryl bromides using the optimized reaction conditions. Yields correspond to the amount of isolated product. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 685 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 685/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de Regioselectivity. The product obtained from bdo and 4-tolylbromide was isolated and characterized by 1H NMR spectroscopy (Figure 7). The integration of methylene protons in the heterocycle shows the excellent regioselectivity of the arylation reaction – which is probably due to the ortho-oxygen substituents. Under the optimized reaction conditions, the 4-sub- stituted product is formed in 98% isomeric purity containing only ca. 2% of 3-substituted isomer. For most direct arylation reaction of bdo, the desired product is formed with more than 95% regioselectivity, even though no optimization of the reaction conditions was done to minimize the amount of the minor substitution product with the other aryl bromides. Comparison of the initial rates of the direct arylation in DEAc and DMAc. The superior catalytic activity of direct arylation reactions in DEAc com- pared to those in DMAc could either be due to a longer life time of the catalytically active species or to an intrinsically higher activity of the DEAc coordinated Pd complex. To evaluate the effect of amide ligand, the initial reactivity of the reaction of 1,3-benzodioxole and 4-tolylbromide under the optimized reaction conditions was monitored by using DEAc and DMAc respectively (Figure 8). The substrate conversions after 30 and 60 minutes of reaction time were determined. With DEAc the Pd complex shows higher initial substrate conversion than in DMAc, which can be due to an intrinsically higher reactivity of the DEAC solvate compared to the DMAc solvate. It is also possible, that the Pd-DEAc derived active species initiates more rapidly than with DMAc. Conclusion Using a newly developed efficient protocol for the direct arylation of 1,3-benzodioxole (bdo) and 2,2- difluorobenzo[1,3]dioxole 26 different aryl bromides were reacted with bdo at 0.05–1 mol% palladium loading to generate a range of different 4-arylated products in yields typically in excess of 80%. Concern- ing the Pd-loading our approach requires approx. 10- times lower catalyst loading than the previous Fagnou protocol.[4a] Furthermore, no silver salt additives or phosphine ligands are needed, it operates at lower temperatures and requires less excess of bdo. The two key improvements are the use of DEAc as a ligand to palladium and the maximization of the reactant concentration in the reaction mixture. The reaction requires a sufficient amount of DEAc to form the respective Pd complex, DEAc is not needed as a Table 5. Arylation of 2,2-difluorobenzo[1,3]dioxole with three aryl bromides using the optimized reaction conditions. Yields correspond to the amount of isolated product. Figure 7. Excerpt of 1H NMR spectrum of 4-(p-Tolyl)-2H-1,3- benzodioxole. Figure 8. Initial rates for the reaction of bdo and 4-tolylbromide under the optimized reaction conditions. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 686 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 686/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense http://asc.wiley-vch.de solvent. This economic use of DEAc easily offsets the higher costs of DEAc compared to DMAc. Experimental Section General procedure for the direct arylation of bdo: Under an inert atmosphere, a Schlenk tube (10 mL) was charged with a magnetic stirring bar and 4-bromotoluene (1 mmol, 0.124 mL), 1,3-benzodioxole (5 mmol, 0.574 mL), K2CO3 (1.3 equiv., 180 mg), PivOH (0.3 equiv., 0.036 mL). Na2PdCl4 (1 mol%, 0.01 mmol, 2.9 mg) in DEAc (0.3 mL, 2.4 mmol) were finally added and the mixture heated to 120 °C for 18 h. After cooling to room temperature, the suspension filtered over a silica plug. The filtrate was evaporated to dryness and the crude product purified by column chromatography (cyclohexane-ethyl acetate). Acknowledgements We are grateful for support of this work via the TU Darmstadt. Open Access funding enabled and organized by Projekt DEAL. References [1] a) A. Suzuki, Angew. Chem. Int. Ed. 2011, 50, 6722– 6737; Angew. Chem. 2011, 123, 6854–6869; b) A. J. J. Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2013, 52, 7362–7370; Angew. Chem. 2013, 125, 7506–7515; c) A. Biffis, P. Centomo, A. Del Zotto, M. Zecca, Chem. Rev. 2018, 118, 2249–2295; d) A. S. Guram, Org. Process Res. Dev. 2016, 20, 1754–1764; e) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270–5298; f) J. P. G. Rygus, C. M. Crudden, J. Am. Chem. Soc. 2017, 139, 18124– 18137. [2] a) C. A. Fleckenstein, H. Plenio, Chem. Eur. J. 2008, 14, 4267–4279; b) C. A. Fleckenstein, H. Plenio, J. Org. Chem. 2008, 73, 3236–3244; c) C. Fleckenstein, S. Roy, S. Leuthäußer, H. Plenio, Chem. Commun. 2007, 2870– 2872. [3] A. J. J. Lennox, G. C. Lloyd-Jones, Isr. J. Chem. 2010, 50, 664–674. [4] a) L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581–590; b) L.-C. Campeau, D. R. Stuart, K. Fagnou, Aldrichimica Acta 2007, 40, 35–41. [5] a) P. Gandeepan, T. Muller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem. Rev. 2019, 119, 2192–2452; b) L. Ackermann, Chem. Rev. 2011, 111, 1315–1345; c) G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38, 2447–2464; d) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238. [6] a) T. Gensch, M. J. James, T. Dalton, F. Glorius, Angew. Chem. Int. Ed. 2018, 57, 2296–2306; Angew. Chem. 2018, 130, 2318–2328; b) N. S. Gobalasingham, B. C. Thompson, Prog. Polym. Sci. 2018, 83, 135–201; c) J. J. Mousseau, A. B. Charette, Acc. Chem. Res. 2013, 46, 412–424; d) L. Wang, B. P. Carrow, ACS Catal. 2019, 9, 6821–6836; e) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281–292. [7] S. I. Gorelsky, Coord. Chem. Rev. 2013, 257, 153–164. [8] a) D. García-Cuadrado, A. A. C. Braga, F. Maseras, A. M. Echavarren, J. Am. Chem. Soc. 2006, 128, 1066– 1067; b) L. David, F. Keith, Chem. Lett. 2010, 39, 1118– 1126; c) S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Org. Chem. 2012, 77, 658–668. [9] a) T. Rogge, J. C. A. Oliveira, R. Kuniyil, L. Hu, L. Ackermann, ACS Catal. 2020, 10, 10551–10558; b) J. Dhankhar, E. González-Fernández, C.-C. Dong, T. K. Mukhopadhyay, A. Linden, I. Čorić, J. Am. Chem. Soc. 2020, 142, 19040–19046; c) L. A. Hammarback, B. J. Aucott, J. T. W. Bray, I. P. Clark, M. Towrie, A. Robinson, I. J. S. Fairlamb, J. M. Lynam, J. Am. Chem. Soc. 2021, 143, 1356–1364; d) B. P. Carrow, J. Sampson, L. Wang, Isr. J. Chem. 2020, 60, 230–258. [10] Y. Tan, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 3308–3311. [11] a) R. Boyaala, R. Touzani, T. Roisnel, V. Dorcet, E. Caytan, D. Jacquemin, J. Boixel, V. Guerchais, H. Doucet, J.-F. Soulé, ACS Catal. 2019, 9, 1320–1328; b) X. Shi, A. Sasmal, J. F. Soule, H. Doucet, Chem. Asian J. 2018, 13, 143–157; c) S. Mao, X. Shi, J.-F. Soulé, H. Doucet, Chem. Eur. J. 2019, 25, 9504–9513; d) X. Shi, S. Mao, J.-F. Soulé, H. Doucet, J. Org. Chem. 2018, 83, 4015–4023; e) A. Battace, M. Lemhadri, T. Zair, H. Doucet, M. Santelli, Adv. Synth. Catal. 2007, 349, 2507–2516. [12] Y.-N. Wang, X.-Q. Guo, X.-H. Zhu, R. Zhong, L.-H. Cai, X.-F. Hou, Chem. Commun. 2012, 48, 10437–10439. [13] a) M. Wakioka, F. Ozawa, Asian J. Org. Chem. 2018, 7, 1206–1216; b) T. Bura, J. T. Blaskovits, M. Leclerc, J. Am. Chem. Soc. 2016, 138, 10056–10071. [14] L.-C. Campeau, N. Hazari, Organometallics 2019, 38, 3– 35. [15] a) Q. Zhao, G. Meng, S. P. Nolan, M. Szostak, Chem. Rev. 2020, 120, 1981–2048; b) L.-Y. Liu, J. X. Qiao, K.- S. Yeung, W. R. Ewing, J.-Q. Yu, J. Am. Chem. Soc. 2019, 141, 14870–14877; c) L.-Y. Liu, J. X. Qiao, K.-S. Yeung, W. R. Ewing, J.-Q. Yu, Angew. Chem. Int. Ed. 2020, 59, 13831–13835; Angew. Chem. 2020, 132, 13935–13939. [16] S. H. Wunderlich, P. Knochel, Angew. Chem. Int. Ed. 2007, 46, 7685–7688; Angew. Chem. 2007, 119, 7829– 7832. [17] N. G. Léonard, M. J. Bezdek, P. J. Chirik, Organometal- lics 2017, 36, 142–150. [18] It may be surprising, that the optimized protocol is already used for the screening experiments and that all modifications described in the Tables lead to less efficient substrate conversion. The reason for this is, that several rounds of screening for the various parameters (which are not described in detail here) were done, to find the best reaction conditions for potentially interde- pendent reaction parameters. [19] The conversions given are based on 4-tolylbromide consumption and were determined by gas chromatog- UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 687 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 687/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense https://doi.org/10.1002/anie.201101379 https://doi.org/10.1002/anie.201101379 https://doi.org/10.1002/ange.201101379 https://doi.org/10.1002/anie.201301737 https://doi.org/10.1002/anie.201301737 https://doi.org/10.1002/ange.201301737 https://doi.org/10.1021/acs.chemrev.7b00443 https://doi.org/10.1021/acs.chemrev.7b00443 https://doi.org/10.1021/acs.oprd.6b00233 https://doi.org/10.1021/acs.oprd.6b00233 https://doi.org/10.1039/c3cs35521g https://doi.org/10.1021/jacs.7b08326 https://doi.org/10.1021/jacs.7b08326 https://doi.org/10.1002/chem.200701877 https://doi.org/10.1002/chem.200701877 https://doi.org/10.1021/jo8001886 https://doi.org/10.1021/jo8001886 https://doi.org/10.1039/B703658B https://doi.org/10.1039/B703658B https://doi.org/10.1002/ijch.201000074 https://doi.org/10.1002/ijch.201000074 https://doi.org/10.1021/ja055819x https://doi.org/10.1021/ja055819x https://doi.org/10.1021/acs.chemrev.8b00507 https://doi.org/10.1021/cr100412j https://doi.org/10.1039/b805701j https://doi.org/10.1039/b805701j https://doi.org/10.1021/cr0509760 https://doi.org/10.1002/anie.201710377 https://doi.org/10.1002/anie.201710377 https://doi.org/10.1002/ange.201710377 https://doi.org/10.1002/ange.201710377 https://doi.org/10.1016/j.progpolymsci.2018.06.002 https://doi.org/10.1021/ar300185z https://doi.org/10.1021/ar300185z https://doi.org/10.1021/acscatal.9b01195 https://doi.org/10.1021/acscatal.9b01195 https://doi.org/10.1021/acscentsci.6b00032 https://doi.org/10.1021/acscentsci.6b00032 https://doi.org/10.1016/j.ccr.2012.06.016 https://doi.org/10.1021/ja056165v https://doi.org/10.1021/ja056165v https://doi.org/10.1021/jo202342q https://doi.org/10.1021/jo202342q https://doi.org/10.1021/acscatal.0c02808 https://doi.org/10.1021/jacs.0c09611 https://doi.org/10.1021/jacs.0c09611 https://doi.org/10.1021/jacs.0c10409 https://doi.org/10.1021/jacs.0c10409 https://doi.org/10.1002/ijch.201900095 https://doi.org/10.1021/ja1113936 https://doi.org/10.1021/ja1113936 https://doi.org/10.1021/acscatal.8b04553 https://doi.org/10.1002/asia.201701455 https://doi.org/10.1002/asia.201701455 https://doi.org/10.1002/chem.201900921 https://doi.org/10.1021/acs.joc.8b00412 https://doi.org/10.1021/acs.joc.8b00412 https://doi.org/10.1002/adsc.200700142 https://doi.org/10.1002/adsc.200700142 https://doi.org/10.1039/c2cc34949c https://doi.org/10.1002/ajoc.201800227 https://doi.org/10.1002/ajoc.201800227 https://doi.org/10.1021/jacs.6b06237 https://doi.org/10.1021/jacs.6b06237 https://doi.org/10.1021/acs.organomet.8b00720 https://doi.org/10.1021/acs.organomet.8b00720 https://doi.org/10.1021/acs.chemrev.9b00634 https://doi.org/10.1021/acs.chemrev.9b00634 https://doi.org/10.1021/jacs.9b07887 https://doi.org/10.1021/jacs.9b07887 https://doi.org/10.1002/anie.202002865 https://doi.org/10.1002/anie.202002865 https://doi.org/10.1002/ange.202002865 https://doi.org/10.1002/ange.202002865 https://doi.org/10.1002/anie.200701984 https://doi.org/10.1002/anie.200701984 https://doi.org/10.1002/ange.200701984 https://doi.org/10.1002/ange.200701984 https://doi.org/10.1021/acs.organomet.6b00630 https://doi.org/10.1021/acs.organomet.6b00630 http://asc.wiley-vch.de raphy. This conversion typically is very similar (within less than 5%) to the isolated yield determined after chromatographic purification of the reaction mixture. [20] M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496–16497. [21] a) M. Batuecas, J. Luo, I. Gergelitsová, K. Krämer, D. Whitaker, I. J. Vitorica-Yrezabal, I. Larrosa, ACS Catal. 2019, 9, 5268–5278; b) D. Whitaker, M. Batuecas, P. Ricci, I. Larrosa, Chem. Eur. J. 2017, 23, 12763–12766; c) D. Whitaker, J. Bures, I. Larrosa, J. Am. Chem. Soc. 2016, 138, 8384–8387; d) P. Ricci, K. Krämer, I. Larrosa, J. Am. Chem. Soc. 2014, 136, 18082–18086; e) A. Panigrahi, D. Whitaker, I. J. Vitorica-Yrezabal, I. Larrosa, ACS Catal. 2020, 10, 2100–2107. [22] a) Y. Tanji, R. Hamaguchi, Y. Tsuji, T. Fujihara, Chem. Commun. 2020, 56, 3843–3846; b) Y. Tanji, N. Mitsu- take, T. Fujihara, Y. Tsuji, Angew. Chem. Int. Ed. 2018, 57, 10314–10317; Angew. Chem. 2018, 130, 10471– 10474; c) T. Fujihara, A. Yoshida, M. Satou, Y. Tanji, J. Terao, Y. Tsuji, Catal. Commun. 2016, 84, 71–74. [23] The total volume of the reaction mixture under optimized conditions is only 0.45 mL and based on this it can make a significant difference, whether 90 mg or 180 mg of insoluble salt are present. [24] Y. Tan, F. Barrios-Landeros, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 3683–3686. [25] a) M. D. Lotz, N. M. Camasso, A. J. Canty, M. S. Sanford, Organometallics 2017, 36, 165–171; b) J.-R. Liu, Y.-Q. Duan, S.-Q. Zhang, L.-J. Zhu, Y.-Y. Jiang, S. Bi, X. Hong, Org. Lett. 2019, 21, 2360–2364; c) A. Tlahuext-Aca, S. Y. Lee, S. Sakamoto, J. F. Hartwig, ACS Catal. 2021, 11, 1430–1434. [26] M. Lesieur, F. Lazreg, C. S. J. Cazin, Chem. Commun. 2014, 50, 8927–8929. [27] D. Wang, Y. Izawa, S. S. Stahl, J. Am. Chem. Soc. 2014, 136, 9914–9917. [28] J. Kim, S. H. Hong, ACS Catal. 2017, 7, 3336–3343. [29] This is true under the assumption that the total volume of DEAc/mesitylene mixtures is equal to the sum of the individual volumes of the pure solvents, which applies in a good approximation. [30] No chemical reactions involving mesitylene were ob- served. [31] The minor change in ton may well be within the error of the experimental reproducibility. But it may also be due to the fact, that replacing mesitylene by DEAc leads to a slight change in the molarity of the respective solvent mixtures. The ratio of molecular mass and density differ by ca. 10% between mesitylene and DEAc. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2022, 364, 679–688 © 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH 688 Wiley VCH Montag, 31.01.2022 2203 / 229354 [S. 688/688] 1 16154169, 2022, 3, D ow nloaded from https://advanced.onlinelibrary.w iley.com /doi/10.1002/adsc.202101014 by T echnische U niversitat D arm stadt, W iley O nline L ibrary on [13/03/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense https://doi.org/10.1021/ja067144j https://doi.org/10.1021/ja067144j https://doi.org/10.1021/acscatal.9b00918 https://doi.org/10.1021/acscatal.9b00918 https://doi.org/10.1002/chem.201703527 https://doi.org/10.1021/jacs.6b04726 https://doi.org/10.1021/jacs.6b04726 https://doi.org/10.1021/ja510260j https://doi.org/10.1021/acscatal.9b05334 https://doi.org/10.1039/D0CC01129K https://doi.org/10.1039/D0CC01129K https://doi.org/10.1002/anie.201804566 https://doi.org/10.1002/anie.201804566 https://doi.org/10.1002/ange.201804566 https://doi.org/10.1002/ange.201804566 https://doi.org/10.1016/j.catcom.2016.06.003 https://doi.org/10.1021/ja2122156 https://doi.org/10.1021/ja2122156 https://doi.org/10.1021/acs.organomet.6b00437 https://doi.org/10.1021/acs.orglett.9b00633 https://doi.org/10.1021/acscatal.0c05254 https://doi.org/10.1039/C4CC03201B https://doi.org/10.1039/C4CC03201B https://doi.org/10.1021/ja505405u https://doi.org/10.1021/ja505405u https://doi.org/10.1021/acscatal.7b00397 http://asc.wiley-vch.de