Angewandte Communications Chemie International Edition:DOI:10.1002/anie.201910639 Organocatalysis German Edition:DOI:10.1002/ange.201910639 Chalcogen Bonding Catalysis of aNitro-Michael Reaction PatrickWonner,Alexander Dreger,Lukas Vogel, Elric Engelage,and Stefan M. Huber* Abstract: Chalcogen bonding is the non-covalent interaction quinolines,[6c,d,13] and to avery recent report on the activation between Lewis acidic chalcogen substituents and Lewis bases. of carbonyl compounds.[14] In particular, the activation of Herein, we present the first application of dicationic tellurium- nitro compounds has not been reported thus far for XB[15] or based chalcogen bond donors in the nitro-Michael reaction ChB organocatalysis. between trans-b-nitrostyrene and indoles.This also constitutes Herein, we present the first such activation of anitro the first activation of nitro derivatives by chalcogenbonding derivative by ChB.Tothis end, the Michael addition of 5- (and halogen bonding). The catalysts showed rate accelera- methoxyindole to trans-b-nitrostyrene (Scheme 1) was chosen tions of more than afactor of 300 compared to strongly Lewis as arobust benchmark reaction.[16] acidic hydrogen bond donors.Several comparison experi- ments,titrations,and DFT calculations support achalcogen- bonding-based mode of activation of b-nitrostyrene. Non-covalent organocatalysis has thus far been dominated by hydrogen bonding (HB), with primarily (thio)urea deriv- atives being used as catalyst backbones.[1] Nonetheless,other weak interactions such as anion–p interactions,[2] halogen Scheme 1. Benchmark reaction for catalyst activity:The reaction of bonding (XB),[3] and chalcogen bonding (ChB)[4] have indole 1 with trans-b-nitrostyrene(2). DCM= dichloromethane. attracted ever-increasing interest lately,and particularly the first two modes are now also established in organocatalysis.[5] In contrast, the application of ChB donors as intermolecular In XB organocatalysis,neutral molecule activation has Lewis acidic catalysts is ahardly explored concept, and first mostly been achieved with iodine-based catalysts,[17] and the examples were only published in 2017.[6] This is somewhat heavier chalcogens are similarly known to produce stronger surprising as ChB offers several potential advantages such as noncovalent Lewis acids (Te > Se > S).[4,18] Interestingly,pre- its high directionality (with interaction angles of ca. 1808)[7] vious ChB catalysts were mostly based on Sand Se,with the and manifold options to fine-tune the binding strength (by very few examples of Te-based catalysts[11c,d,12b] being variation of the chalcogen substituent, the core structure,and/ restricted to neutral compounds[12b] or derivatives in which or the second substituent on the chalcogen). Still, most the Te substituent is bound to aneutral moiety (in an overall reports on ChB have thus far focused on its intramolecular monocationic compound).[11c,d] In this study,wedecided to use,[8] on applications in supramolecular[9] and solid-state focus on dicationic bidentate selenium- and especially tellu- chemistry,[10] as well as on anion recognition processes.[11] rium-based compounds,toachieve maximum Lewis acidity. ChB-based catalysts and activators were previously Charged backbone structures are provided by triazolium units mainly employed in halide abstraction reactions,inwhich as 1) their neutral analogues are stable compounds and very Lewis basic anions act as substrates.[6a,b,12] Thecoordina- already strong anion acceptors[11c] and 2) the synthesis of tion of ChB donors to neutral compounds is surely weaker in their cationic analogues should be feasible by simple alkyla- strength, and so their activation is more challenging (even tion.[11d] Thesecond substituent on the chalcogen was chosen though the transition state may of course still be charged). to be phenyl in order to prevent apossible dealkylation of this Indeed, this concept has hitherto been limited to ahandful of group by nucleophilic attack.[6a] examples in which ChB donors enable the reduction of Thesynthesis of all compounds followed the same strategy:Commercially available 1,3-diethynylbenzene (4) [*] P. Wonner,A.Dreger,L.Vogel, E. Engelage, Prof. Dr.S.M.Huber was converted into 1,3-bis(triazole)benzene derivative 5 by an FakultätfürChemie und Biochemie azide–alkyne 1,3-dipolar cycloaddition reaction in quantita- Ruhr-UniversitätBochum tive yield (Scheme 2).[19] Deprotonation with LDAinthe Universitätsstraße 150, 44801 Bochum (Germany) presence of the corresponding diphenyldichalcogenide pro- E-mail:[email protected] vided neutral compounds 6Ch and—in the case of tellurium— Supportinginformation and the ORCID identification number(s) for also the mono-chalcogenated analogue 8Ch.[20] In the final the author(s) of this article can be found under: alkylation step,several different counterions were introduced https://doi.org/10.1002/anie.201910639. to allow for asystematic investigation of their effect on 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. catalytic activity:MeOBF ·Et O, MeOTf,and MeNTf led KGaA. This is an open access article under the terms of the Creative 3 4 2 2 directly to the respective dicationic chalcogen bond donors Commons AttributionNon-CommercialNoDerivs License, which F Ch-X [6a,21] F Te-BAr 4 permitsuse and distribution in any medium, provided the original 7 , whereas BAr 4 derivative 7 was obtained by Te-BF4 F [16d,21, 22] work is properly cited, the use is non-commercial, and no anion exchange from 7 with TMABAr 4. To the modifications or adaptations are made. best of our knowledge,this is the first report on dicationic Angew.Chem. Int.Ed. 2019, 58,16923 –16927 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 16923 Angewandte Communications Chemie Table 1: 1HNMR yields of product 3 (Scheme 1) in the presence of several reference compounds as catalyst candidates. Forfurther data see the SupportingInformation. Entry Catalyst Cat. loading [mol%] Yield of 3 [%] 1– – < 5 2 10 20 5 3 6S 20 < 5 4 6Se 20 < 5 5 6Te 20 < 5 6 12H-BF4 20 < 5 7 13I-BF4 20 < 5 no background reaction even after 120 h(Table 1, entry 1). This allowed us to follow the reaction at room temperature by 1HNMR spectroscopy and to easily monitor catalyst stability. As hydrogen bonding catalysis has been reported for this reaction,[16b] we then tested thiourea derivative 10 (Figure 2), which did not produce noticeable yields of product 3 (Table 1, entry 2) under these more diluted conditions. Scheme 2. Synthesis of chalcogen bond donors 7Ch-X and 9Ch-X.i)CuI, TBTA, OctN ,THF, dark, rt, 48 h; ii)LDA, THF, (PhCh) , 78 258C, 3 2 À ! 24 h; iii)for Me3OBF4 or MeOTf: DCM, rt, 24 h; for MeNTf2 :toluene, F reflux, 24 h; iv) TMABAr 4,CHCl3,rt, 24 h. TBTA = tris((1-benzyl-4- triazolyl)methyl)amine, Oct =octyl, THF = tetrahydrofuran;LDA = lithium diisopropylamide;Tf=trifluoromethanesulfonyl, TMA = tetra- F methylammonium;BAr 4 = tetrakis[3,5-bis(trifluoromethyl)phenyl]bo- rate. tellurium-based chalcogen bond donors that are stable under ambient conditions.X-ray structural analysis of single crystals of compound 7Te-OTf (Figure 1) confirmed the strong Lewis acidity of the Te substituents,which were coordinated by triflate and by water. Ch H-BF4 First, the benchmark nitro-Michael reaction (Scheme 1; Figure 2. Lewis acidic reference compounds 10, 11 , 12 ,and 13I-BF4 . overall concentration:36mm)was run in the presence of various reference compounds to exclude other modes of activation than chalcogen bonding (Table 1). Under the Next, elemental chalcogens (S,Se, Te)and all correspond- reaction conditions shown in Scheme 1, there was virtually ing variants of chalcogen compounds 6Ch and 11Ch (Ch = S, Se, Te)were applied in the reaction to rule out any chalcogen- based activation not related to ChB,but none of the catalyst candidates led to any product formation (see Table 1, entries 3–5 and the Supporting Information). Thesame was true for the hydrogen and iodine analogues 12H-BF4 and 13I-BF4 of ChB donors 7Ch-X (Table 1, entries 6and 7). While this is somewhat surprising with regard to XB donor 13I-BF4 ,italso clearly demonstrates that neither the triazolium units nor the BF4À counterion are catalytically active. These findings were further corroborated by comparison F experiments with NaBF4,NEt4OTf, and NMe4BAr 4,all of which showed no conversion into product 3 (see the Supporting Information). Even strong Lewis or Brønsted acids such as AlCl3 or HBF4·Et2Oexhibited only (very) weak activity even with aloading of 40 mol%(see the Supporting Information), which confirms that hidden acid catalysis can be Figure 1. X-ray crystal structure of 7Te-OTf.[31] The bond angles are 1778 excluded in the ChB catalysis discussed below. S-BF4 Se-BF4 (C2-Te2-O2) and 1718 (C1-Te1-O1). The sum of the Te Ovan der With these results in hand, ChB donors 7 , 7 ,and À Waals radii is 3.58 . 7Te-BF4 were applied in the benchmark reaction at acatalyst 16924 www.angewandte.org 2019 The Authors. Published by Wiley-VCH VerlagGmbH &Co. KGaA,Weinheim Angew.Chem.Int. Ed. 2019, 58,16923–16927 Angewandte Communications Chemie loading of 20 mol%. Forall three compounds,noindications of catalyst decomposition were observed by 1HNMR spec- troscopy.With tellurium-based catalyst 7Te-BF4 ,compound 3 was obtained in 78%yield after 48 h(Table 2, entry 3) Table 2: 1HNMR yields of product 3 (Scheme 1) in the presence of 20 mol%ofchalcogen bond donors 7Ch-X. Entry Catalyst Yield of 3 [%] 1 7S-BF4 < 5 2 7Se-BF4 < 5 3 7Te-BF4 78 4 7Te-OTf 7 5 7Te-NTf 2 < 5 F 6 7Te-BAr 4 81 7 9Te-BF4 20 Figure 3. Time versus yield profile for the formation of 3 in the S-BF4 whereas the sulfur-and selenium-based catalysts 7 and presence of different catalysts. 7Se-BF4 were virtually inactive (Table 2, entries 1and 2).