Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• intercepts the nitroalkene 3 in a Michael-type addition forming intermediate B. Hydrolysis regenerates catalyst 1 that can then selectively condense with the α,β-unsaturated aldehyde 4 to form chiral iminium ion intermediate C. Iminium ion C reacts with intermediate B in a further Michael-type reaction. The

• nitroalkene derivatives with low reagent excess and high enantioselectivity; this reaction represents the first step in the Enders triple cascade catalytic cycle. The use of acetaldehyde in a two-component cascade reaction was previously reported by Enders [27]; however, the scope of this reaction is limited

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• bulkier. The obtained nitrocyclopropane was transformed into furan upon treatment with tin(II) chloride via a ring-opening/ring-closure process. Keywords: acetoxyiodine; conjugate addition; dihydrofuran; nitroalkene; nitrocyclopropane; Introduction 3-Arylated 2-nitrocyclopropane-1,1-dicarbonylic acid

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• of the catalyst loading to 1 mol % of (S,S)-C1, required a longer reaction time, up to 216 hours and this Michael addition gave only 27% yield of the product (Table 1, entry 11). Additionally, attempting the Michael addition of 3-phenylpropanal (6c) to nitroalkene 9 catalyzed by (S,S)-C1 without any

• nitroalkene 9. The reaction in the presence of 3 mol % (S,R)-C2 provided the product 10b in 70% yield and 85:15 dr and 75:25 er (Table 1, entry 14). Here, we have also tested the influence of only basic additive on the reaction and the product was obtained with 73% yield (Table 1, entry 15). The reaction

• without a base went much less efficiently (Table 1, entry 16), similarly to the reaction performed without acid additive and base (Table 1, entry 17). The product 10c by Michael addition of hexanal 6b to nitroalkene 9 was obtained with only 40% yield with comparable diastereoselectivity (Table 1, entry 18

Nitroalkene reduction in deep eutectic solvents promoted by BH₃NH₃

• Chiara Faverio,
• Monica Fiorenza Boselli,
• Patricia Camarero Gonzalez,
• Alessandra Puglisi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2021, 17, 1041–1047, doi:10.3762/bjoc.17.83

• report the results of our explorative studies, aimed to develop a chemoselective nitroalkene reduction in DESs, with the goals to establish a reliable and reproducible protocol to isolate the product without the use of any organic solvent and to assess the recovery and the recyclability of the DES

One-pot and metal-free synthesis of 3-arylated-4-nitrophenols via polyfunctionalized cyclohexanones from β-nitrostyrenes

• Haruyasu Asahara,
• Minami Hiraishi and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2020, 16, 1830–1836, doi:10.3762/bjoc.16.150

• with Danishefsky’s diene could be conducted in one pot to directly afford the corresponding nitrophenols. Moreover, a heteroaryl group, e.g., a thienyl group could be introduced into the nitrophenol framework. Keywords: 3-arylated-4-nitrophenol; Danishefsky’s diene; Diels–Alder reaction; nitroalkene

• nitroalkene properties and consequently suppressed the Diels–Alder reaction with 2. It is noteworthy that not only the benzene ring, but also a heteroaromatic ring could be introduced into the nitrophenol framework by using this method (Table 3, entry 5). Conclusion β-Nitrostyrene 1a underwent a Diels–Alder

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• proposed mechanism for 1,3-dicarbonyl compounds [47] to explain how Ni catalysts are able to activate the substrates. The postulated catalytic cycle is summarized in Scheme 1. We assume that the β-ketosulfone coordinates to the Ni complex generating Ni-enolate B. The nitroalkene is activated by

• coordinated to Ni in more Lewis acidic equatorial position, whereas the nitroalkene is positioned in apical by avoiding the steric repulsion of benzyl groups (TS2-I and 2-II vs TS1-I and 1-II, Scheme 2). Additional hydrogen bonding between the hydrogen atom of the amino group and the oxygen atom of the

• nitroalkene in TS2-I and 2-II may also help to rigidify the transition state and improve the stereoselectivities. The observed (2R,3S)-diastereoselectivity in the presence of catalyst 7a stems from the addition of the Re face of the β-ketosulfone to the Si face of the nitroalkene in TS2-I. We suppose that the

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• search for new methodologies towards the rapid assembly of chromene analogs is of utmost importance for many researchers. In this regard, 3-nitrochromenes are easily available building blocks for chromene and chromane derivatives and are highly reactive due to the presence of the nitroalkene moiety

• prove the plausibility of the one-pot three-component reaction, we commenced our trials with the synthesis and isolation of 3-nitro-2H-chromene (3) as reported in the literature [15], followed by the 1,3-dipolar cycloaddition of the nitroalkene moiety with organic azides. We based the 1,3-dipolar

• equivalent nitroalkene, 1.2 equivalents of salicylaldehyde and 0.1 equivalents of DABCO as catalyst in the first step at 40 °C, and 2 equivalents of benzyl azide, 2 equivalents of acetic acid, 0.3 equivalents of BHT as antioxidant, 4 Å MS and DMF under argon atmosphere at 120 °C in the second step. Crude NMR

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• ovarian carcinoma cells [43]. Khalaf et al. reported a new class of neutral, non-cationic minor groove binders derived from distamycin where the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. These conjugates exhibit

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide

• reaction mixture. Nitroaldol product 5 was then dehydrated using the CuCl/DCC protocol [16] to nitroalkene 6. Overall, this sequence afforded the desired racemic Michael acceptor 6 in total 36% yield over four steps. With Michael acceptor 6 in hands, we started to investigate the 1,4-addition of dimethyl

• afford diastereoisomeric catalysts (Sa,R,R)-C8, and (Sa,S,S)-C8, respectively. In the Michael addition of dimethyl malonate to the racemic nitroalkene 6, the cinchona-based catalysts C1–C3 performed poorly and provided the desired Michael adduct 7 in less than 10% yields (Table 1, entries 1–3). The lower

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• then reacted with the β-nitroalkene to furnish radical intermediate 38, which was reduced by the Eosin Y radical cation to yield the expected product after elimination of NO2. This proposed mechanism can rationalise several limitations of the reaction, such as its incompatibility with aliphatic β

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• produce compound 98 [213] (Figure 28A). A second example corresponds to the nucleophilic addition of N-heterocyclic phosphine 99 to a nitroalkene (phospho-Michael reaction) as shown in Figure 28B. The thiourea unit in 99 plays a crucial role by assuming intramolecular interaction with the nitro function

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• substituted thiourea-based organocatalysts were screened for the reaction to achieve stereoselective adducts through hydrogen bonding. Only with 2.5 mol % of thiourea-based catalyst B, α-nitrocyclohexanone and nitroalkene derivatives could undergo a Michael addition to yield up to 95% of the desired product

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• possibility of accelerating the formation of the enamine intermediate and simultaneously activating the nitroalkene by using a combination of organocatalyst OC4, a Brønsted acid and an achiral thiourea. Thus the reaction was repeated in the presence of a combination of benzoic acid and N,N'-diphenylthiourea

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• derivative which undergoes a Henry-type reaction with nitromethane in the first flow step (Flow I). The resulting nitroalkene undergoes an asymmetric addition catalyzed by a supported PS–(S)-pybox–calcium chloride catalyst at 0 °C using two columns (Flow II). This is the enantio-determining step of the

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• yields and with high enantioselectivity to α,β,β-trisubstituted nitroalkenes 161 using a thiourea organocatalyst 101b (Scheme 38) [66]. This report was the first example of enantioselective addition to a trisubstituted nitroalkene and was the first example of conjugate addition–enantioselective

• . However, thioacetic acid (160a) also adds in good yield and high enantioselectivity to unstrained nitroalkenes 163 (Scheme 38b). Additions to β-cyclohexyl and β-4-tetrahydropyran nitroalkenes as well as an acyclic β,β-dimethyl nitroalkene all proceeded with good conversion when the reaction temperature

• nitroalkene [67]. α,β-Unsaturated phosphonates and phosphine oxides Transition metal catalysts In 2006, Hayashi and co-workers reported the first conjugate addition–enantioselective protonation of allenes 165 bearing a phosphine oxide (Scheme 39) [68]. Incorporation of the phosphine oxide allowed for

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• electronic character of the β-aryl substituent of nitroalkene 5 (compounds 6–8). Different substituents either at the nitrogen atom of the starting imidazolone (compounds 9–11) or at the 5-position (compound 12) of the ring are also well tolerated. Reactions with β-alkyl nitroolefins in the presence of C1

• an heuristic model (Figure 3) to account for the experimentally encountered selectivity where the catalyst is proposed to act in a bifunctional way. In this proposal the imidazolone would be coordinated to the two NH bonds of the squaramide and the ortho-ArH in C1, whilst the nitroalkene would form a

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• described [29]. To a stirred solution of 2-nitrocyclohexanone (43 mg, 0.3 mmol) and nitroalkene (0.45 mmol, 1.5 equiv) in an adequate solvent (0.4 mL), catalyst VI (15 mg, 0.015 mmol, 0.05 equiv) was added and the reaction mixture was stirred at room temperature in a Wheaton vial until the reaction was

• enantiomeric excess was determined by chiral-phase HPLC analysis using mixtures of hexane/isopropanol as eluent. Method B, under ball-milling conditions: Catalyst VI (15 mg, 0.015 mmol, 0.05 equiv), 2-nitrocyclohexanone (43 mg, 0.3 mmol) and nitroalkene (0.45 mmol, 1.5 equiv) were transferred to a clean, dry

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• dual role of catalyst 4 in the activation of the substrates. Thus, in the transition state TS1 (Figure 3a), the substrates and catalyst would form a ternary complex where the thiourea moiety would activate the nitro group of the nitroalkene through hydrogen bonds. Simultaneously, the oxygen atom of the

• hydroxy group would interact with the NH of the indole by a weak hydrogen bond, driving the attack to the Si face of the nitroalkene in a stereocontrolled manner. In a recent study of this F–C alkylation, Herrera’s group has provided computational evidence of the reaction pathway, which confirms the

• of the authors’ mechanistic hypothesis, the β-nitroalkene derivatives 7 are proposed to react with the indoles 2 in the presence of the organocatalyst ent-6 to afford the intermediates 9 with excellent enantioselectivity (Scheme 5). Furthermore, a bifunctional activation mode through the transition

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• Michael addition of the enol of the α-keto-amide 78 to nitroalkene 79, subsequent Michael addition of nitronates to the second equivalent of nitroalkene 79 and finally a Henry-type reaction between nitronate and the highly electrophilic carbonyl of the α-keto-amide, resulting in the final product 76. In

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• general for a variety of nitroalkene Michael acceptors and nitroacetate donors. For this reason, we initially studied the reaction using squaramide 4 as catalyst that leads to the formation of syn-3 adducts. In this sense, and as it can be seen in Table 1, the reaction performed excellently in almost all

• at the nitroalkene reagent were also tested and those also reacted very efficiently, leading to the formation of adduct syn-3l–m in high yield and good stereoselection (Table 1, entries 12 and 13). Functionalized nitroalkene 2n also performed well in the reaction, providing the corresponding addition

• consequence of the very likely decomposition of these rather unstable nitroalkene reagents. Finally, we also surveyed the use of a nitroacetate donor with a bulkier substituent such as 1b which also performed very well in the reaction with trans-β-nitrostyrene (2a), para-methoxy-trans-β-nitrostyrene (2e) or

Cathodic hydrodimerization of nitroolefins

• Michael Weßling and
• Hans J. Schäfer

Beilstein J. Org. Chem. 2015, 11, 1163–1174, doi:10.3762/bjoc.11.131

• formation; 1,4-dinitrocompounds; electrosynthesis; nitroalkene; Introduction Olefins being activated by an electron withdrawing group can be hydrodimerized by cathodic reduction [1][2]. Thereby, the cathode serves as cheap, versatile, immobilized and mostly non-polluting reagent providing economical and

• hydrodimerization) or a α,ß-coupling with aliphatic nitro alkenes having acidic α-protons. ß,ß-Coupling can be achieved in good to high yield (41–95%) at high current densities [18]. In the reduction of 3,3-dimethyl-1-nitrobut-1-ene the intermediate radical anion has been identified by ESR. Nitroalkene 4 is

• new reaction proceeds through a radical anion of the nitroalkene generated in a catalytic redox process. For ß-isopropyl-nitroethylene the radical anion has been identified by ESR [20]. Results and Discussion Investigation of the cathodic hydrodimerization of nitroalkene 1 to hydrodimer 2 The cathodic

Sequential Diels–Alder/[3,3]-sigmatropic rearrangement reactions of β-nitrostyrene with 3-methyl-1,3-pentadiene

• Peter A. Wade,
• Alma Pipic,
• Matthias Zeller and
• Panagiota Tsetsakos

Beilstein J. Org. Chem. 2013, 9, 2137–2146, doi:10.3762/bjoc.9.251

• nitroalkene Diels–Alder reactions have been proposed. Denmark et al. favor a stepwise process proceeding via a zwitterion intermediate [11][14]. Alkene stereointegrity is normally retained, presumably owing to a cyclic conformation dictated by charge interaction between the cation center and tin nitronate

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

• James C. Anderson,
• Andreas S. Kalogirou,
• Michael J. Porter and
• Graham J. Tizzard

Beilstein J. Org. Chem. 2013, 9, 1737–1744, doi:10.3762/bjoc.9.200

• KOH provided α-keto acid 11 in excellent yield [48], and the corresponding acid chloride 12 was prepared in situ by treatment with oxalyl chloride [49]. For the synthesis of β-nitroamine 8 we decided to make use of the reductive nitro-Mannich reaction as the starting nitroalkene 13 is readily

• via β-nitroamine 9 was investigated. A reductive nitro-Mannich reaction between nitroalkene 18 [54] and freshly prepared imine 19 in CH2Cl2 followed by rapid flash chromatography gave β-nitroamine 20 with complete conversion and dr >95:5 [55]. As before immediate reduction with Zn/HCl gave the PMP

• (21): To a solution of nitroalkene 18 (202 mg, 2.00 mmol), in CH2Cl2 (12.0 mL) was added Superhydride® (2.20 mL, 1 M in THF, 2.20 mmol) and the mixture stirred for 15 min at rt. The mixture was cooled to −78 °C before the dropwise addition of a solution of freshly prepared imine 19 (564 mg, 4.00 mmol

A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-γ-aminated nitroalkenes derived from L-α-amino acids

• Vera Lúcia Patrocinio Pereira,
• André Luiz da Silva Moura,
• Daniel Pais Pires Vieira,
• Leandro Lara de Carvalho,
• Eliz Regina Bueno Torres and
• Jeronimo da Silva Costa

Beilstein J. Org. Chem. 2013, 9, 832–837, doi:10.3762/bjoc.9.95

• the same route employed for (−)-2b and utilized as standard (Figure 1). The racemic nitroalkene (+/−)-2b showed a very good separation factor in the chromatograph chiral column used. Figure 1 shows that (−)-2b prepared from L-phenylalanine was enantiomerically pure (enantiomeric excess > 99%). HPLC