Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• reaction of isatin, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (i.e. kojic acid) and malononitriles or cyanoacetates (Scheme 32) [51]. Compared to other Lewis acids, Cu(OTf)2 proved to be the best. Mechanistically, the process begins with a Knoevenagel-type condensation between isatin and the cyano

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• cascade triple-Michael (Michael/Michael/oxa-Michael) reaction between curcumins and isatylidene malononitriles, giving spiro-oxindoles in excellent yields and diastereoselectivities [36]. Sahu et al. introduced a one-pot multicomponent reaction of curcumin, arylaldehyde and 2-aminobenzothiazole to

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• -acetate for the efficient synthesis of diverse spiro tetrahydrocarbazoles. In the presence of CuSO4, the multicomponent reactions of aromatic aldehydes, 2-methylindole and various cyclic dieneophiles such as 3-phenacylideneoxindoles, isatylidene malononitriles and the in situ generated 5-arylidene-1,3

• of 7:1. As shown in Scheme 3, a wide range of aromatic aldehydes with different substituents on the aromatic ring reacted smoothly to give the desired products 2a–e in good yields and with good to excellent diastereoselectivity. On the other hand, we also tested various isatylidene malononitriles

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• Hui Zheng Ying Han Jing Sun Chao-Guo Yan College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.18.68 Abstract The tri(n-butyl)phosphine-catalyzed reaction of isatylidene malononitriles and bis-chalcones in chloroform at 65 °C afforded

• compounds [60][61][62][63][64][65][66] and in order to demonstrate the potential synthetic value of the nucleophilic phosphine-catalyzed annulation reaction, herein we wish to report the tri(n-butyl)phosphine-catalyzed reaction of isatylidene malononitriles and bis-chalcones for the synthesis of

• the reaction was developed by using various substrates and the results are summarized in Table 2. It was found that all reactions proceeded smoothly to give the expected spiro[cyclohexane-1,3'-indolines] 3a–z in moderate to good yields. The isatylidene malononitriles with different substituents at the

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• the In(III)-catalyzed reductive cyclization of isatylidene malononitriles using the Hantzsch ester as reducing agent for the synthesis of dispirocyclopentanebisoxindole. Our work utilizes tosylhydrazine as chemoselective reducing agent for 3-phenacylideneoxindoles and thereafter base-catalyzed

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• to synthesise indoloquinolizidines [5]. Moreover, six-membered and five-membered cyclic 1,3-diketones have been investigated in reactions with acetates of nitroalkenes [6], cyanoacrylates and benzylidene malononitriles [7], ortho-hydroxy-benzhydryl alcohols [8], α,β-unsaturated pyrazolamides [9] and

• in carbohydrate chemistry [15]. Cyclic six-membered 1,2-diketones have been shown to react with benzylidene malononitriles [7][16], β-nitrostyrenes [17] and substituted propionaldehydes [18]. For a while, there were no examples related to cyclopentane-1,2-dione (CPD). In 2004, the first instance of

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• substituted methylene malononitriles 92, affording a variety of pyrano[3,2-c]chromene derivatives 93 (Scheme 29) [64]. The catalyst used in this reaction was the dehydroabietylamine-cinchone-squaramide derivative 94. The products were obtained with good to excellent yields and enantioselectivities with both

• via domino reaction between 4-hydroxycoumarins (1) and substituted methylene malononitriles 92. Conjugated addition of 4-hydroxycoumarins 1 to nitroolefins 95. Michael addition of 4-hydroxycoumarin 1 to α,β-unsaturated ketones 2 promoted by primary amine thiourea bifunctional catalyst 97

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• aldehyde and malononitriles undergoes Knoevenagel condensation resulting in alrylidene intermediate B. This is followed by Michael addition of imine A on the activated alrylidene intermediate B and subsequent intramolecular cyclization C and aromatization D affords the target molecules 123 (Scheme 46). N

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• potential values of 2-substituted malononitriles and 2-substituted acetylacetones are usually higher than those of o-quinones, so that in the case of 6b and 6d two first distinct waves could be attributed to subsequent reductions of the dioxolene fragment. Further reductions correspond to processes on the

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• radical recombination with the nickel species produce 66. Finally, an elimination of Ar-H closes the catalytic cycle. A similar mechanism was proposed with method B. Radical reactions This part is related to radical reactions not involving alkali metals and focuses on the reduction of malononitriles and

• developments using these compounds. Bu3SnH and N-heterocyclic carbene boranes The reductive decyanation of malononitriles to mononitriles using tributyltin hydride/AIBN in benzene was unexpectedly discovered by Curran and Seong [114]. Later, they made a full study and successfully reduced to mononitriles a

• variety of mono- and dialkylated malononitriles but under these conditions, the reduction of cyanoacetates failed [115]. Synthetic applications of this methodology were later described [116][117][118]. Chiba et al. have developed a concise and stereoselective methodology for the preparation of highly

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

• in high yield and enantioselectivity. Only when R1 was phenyl did the enantioselectivity of the thiol addition drop below 91.5:8.5 er to 85:15 er. The addition of a variety of α-substituted malononitriles 126e also proceeded in high yield and enantioselectivity. During the exploration of different

• -substituted vinyl ketones 118 via an enamine catalysis conjugate addition–enantioselective protonation pathway (Scheme 30). Lou first applied this strategy of reduction–conjugate addition–enantioselective protonation to α,β-unsaturated malononitriles 132a, to provide the product in comparable yield and

• enantioselectivity as when the enantioselective conjugate addition was performed using α-substituted malononitriles (126e, Scheme 29) [57]. In a subsequent report, Lou and co-workers demonstrated that Meldrum’s acid derivatives 132b were also operative in the reduction–conjugate addition–enantioselective protonation

(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

• malononitriles 104 and α,α-dicyanoalkenes 105. The process yielded highly functionalized spiro-oxindole dienes 106. The products were obtained in good to excellent yields (up to 97%) and enantioselectivities (up to 96%), but the diastereoselectivities were moderate (up to 7.9:1) (Scheme 34) [53]. In 2015, Soós

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• salts, were used for the oxidative functionalization at the α-position of carbonyl compounds. N-Hydroxyimides and N-hydroxyamides 204 are involved in the oxidative C–O coupling with 1,3-dicarbonyl compounds and their hetero analogues, such as 2-substituted malononitriles and cyanoacetic esters, 205 in

A simple copper-catalyzed two-step one-pot synthesis of indolo[1,2-a]quinazoline

• Chunpu Li,
• Lei Zhang,
• Shuangjie Shu and
• Hong Liu

Beilstein J. Org. Chem. 2014, 10, 2441–2447, doi:10.3762/bjoc.10.254

• -iodophenyl)acetamides with malononitriles and substituted o-iodobenzaldehydes was investigated. As summarized in Table 2, the desired products 4a–4q were obtained in moderate to good yields (34–72%) by treatment of various substituted N-(2-iodophenyl)acetamides 1a–1k with active methylene compounds 2a–2c and

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• and co-workers proved that these reactions could be performed in a convenient one-pot manner. For example, the one-pot reactions of isatins, malononitriles (precursors of activated alkene), and MBH adducts produced corresponding spirooxindoles with the same enantioselectivity as that between activated

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• only requires implementing multiple reactors to work in parallel [29]. We have recently developed a method to synthesize polysubstituted 2-halonicotinonitriles in high yields via enamine intermediates 5 by reacting alkylidene malononitriles in the presence of acetic anhydride with N,N-dimethylformamide

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

Chiral multifunctional thiourea-phosphine catalyzed asymmetric [3 + 2] annulation of Morita–Baylis–Hillman carbonates with maleimides

• Hong-Ping Deng,
• De Wang,
• Yin Wei and
• Min Shi

Beilstein J. Org. Chem. 2012, 8, 1098–1104, doi:10.3762/bjoc.8.121

• effective catalysts in the [3 + 2] annulation of MBH carbonates with isatylidene malononitriles to give the desired products in high yields with high enantioselectivities [50]. Furthermore, our group recently also synthesized a series of L-phenylalanine-derived multifunctional thiourea-phosphine catalysts

Recent advances in the gold-catalyzed additions to C–C multiple bonds

• He Huang,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2011, 7, 897–936, doi:10.3762/bjoc.7.103

• malononitriles 375 and N-Boc-protected imines 374 (Scheme 60) [176]. In the alkyne hydroamination (which is based on a bifunctional organocatalytic Mannich-type reaction, subsequent gold-catalyzed alkyne hydroamination and isomerization) thiourea-based hydrogen bonding organocatalyst 373 and PPh3AuNTf2 proved to

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• involve the reactions of β-ketonitriles, malononitrile, alkylidenemalononitriles and their derivatives with hydrazines, as well as some novel miscellaneous methods. Keywords: alkylidenemalononitriles; 5-aminopyrazoles; hydrazines; β-ketonitriles; malononitriles; Review The 5-aminopyrazole system

• hydrazines with malononitrile follows a similar course to yield 67, [48][49] which is the 1-substituted analog of 64 (Scheme 17). However, with substituted malononitriles 66 no such dimerization is possible and the condensation with hydrazine hydrate results in the smooth formation of 3,5-diaminopyrazoles 68

• -hydrazinopyrazole. Synthesis of 3,5-diaminopyrazoles with substituted malononitriles. Synthesis of 3,5-diamino-4-oximinopyrazole. Synthesis of 4-arylazo-3,5-diaminopyrazoles. Synthesis of 3- or 5-amino-4-cyanopyrazoles. Synthesis of triazenopyrazoles. Synthesis of 5(3)-aminopyrazoles. Synthesis of 3-substituted 5