Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• et al. developed a three-component Mannich-type reaction under oxidative and catalytic conditions that allows the coupling of aryl ketones 18 and saccharine (19) using DMSO as the solvent and the source for a methylene bridge linking the two building blocks (Scheme 15) [49]. Following this strategy

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

• known processes, a particular Mannich-type reaction was realized in water in the presence of a dendritic 2,2’-bipyridine ligand 2 and Cu(OTf)2 (Scheme 2) [16]. The hydrophobic ligand surrounding the metal revealed to be essential for the organic synthesis in water, thus increasing the reaction yields

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• % yield. All the derivatizations were carried out without erosion of enantioselectivity. In 2023, as a follow-up of Zhao’s previous work [32], the same group reported a dihydroquinine-derived squaramide-catalyzed Mannich-type reaction of isocyanoacetates with N-(2-benzothiazolyl)imines [34]. After a

• Mannich-type reaction of isocyanoacetates with N-(2-benzothiazolyl)imines. Enantioselective modified cinchona alkaloid-catalyzed [4 + 2] annulation of γ-butenolides and saccharin-derived 1-azadienes. Chiral tertiary amine-catalyzed [2 + 4] annulation of cyclic 1-azadiene with γ-nitro ketones. Inverse

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• not a classic allylation but rather a Mannich-type reaction, further investigation into the scope and the expansion of this methodology to other substrate classes will be beneficial. Its application to the synthesis of alkaloids and natural products can be also expected. To draw an endline, it is

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• [44] (Scheme 6). El Kaim and Jia reported a Mannich-type reaction of trifluoroacetaldehyde hydrazones with formaldehyde and aromatic aldehydes to obtain valuable starting materials for the generation of other trifluoromethyl-substituted heterocycles. The study demonstrated that the electron

• Brønsted acid-assisted Lewis base catalysis. Synthesis of CF3-pyrazoles and CF3-1,6-dihydropyridazines. Asymmetric reactions of trifluoromethylimines with organometallic reagents. Mannich-type reaction of trifluoroacetaldehyde hydrazones. Synthesis of trifluoromethylated hydrazonoyl halides. Early work of

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• basis for generating and trapping of reactive metal enolates. The conjugate addition of R3Al to cyclic enones catalyzed by a combination of copper(II) naphthenate (CuNaph) and SimplePhos ligand L19 led to the corresponding aluminum enolates. Alexakis and co-workers used these enolates in a Mannich-type

• reaction with the α-aminoether 118. This reagent released an iminium ion into the reaction medium that reacted with the Al enolate 117 [66]. Furthermore, the Mannich adduct was then reacted with Grignard reagents that replaced the dimethylamino group (Scheme 30). Alexakis and co-workers also investigated

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• -hydroxyglutarate (84) in a Mitsunobu reaction to generate the γ-phosphonodepsipeptide 79 in a high yield of 66% (Scheme 27) [28]. Synthesis of phosphonodepsipeptides via the multicomponent condensation of amides, aldehydes, and phosphites followed by alcoholysis with hydroxy esters Previously, the Mannich-type

• reaction of benzyl carbamate, aldehydes, and trialkyl phosphites in acetyl chloride gave rise to N-Cbz-1-aminoalkylphosphonates [40]. When the reactions were conducted in benzene followed by an aminolysis or alcoholysis, phosphonamidates [41], phosphonopeptide [42], and mixed esters [43][44] were obtained

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• convenient source of trifluoromethylated iminium ions 187 (Scheme 45) [117][118][119]. Langlois, Billard, and Blond reported on the Mannich-type reaction between silylated trifluoromethylated hemiaminal derivatives 189 [120] and enolizable ketones 188 [121]. The intermediate formation of trifluoromethylated

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

• Aleksandar Pashev,
• Nikola Burdzhiev and
• Elena Stanoeva

Beilstein J. Org. Chem. 2020, 16, 1456–1464, doi:10.3762/bjoc.16.121

• proposal features a stepwise Mannich-type reaction of the enolized anhydride 17 to the imine component and a subsequent N-acylation reaction to form the lactam target product [24]. A respective Mannich-type intermediate has been recently isolated and subsequently converted into the target lactam product

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

• Seema V. Kanojia,
• Sucheta Chatterjee,
• Subrata Chattopadhyay and
• Dibakar Goswami

Beilstein J. Org. Chem. 2019, 15, 490–496, doi:10.3762/bjoc.15.42

• . However, after the structural revision of the most active stereoisomer, Kobayashi et al. synthesized (1R,3S)-HPA-12 (2, Figure 1) using a Zn-catalyzed asymmetric Mannich-type reaction in water, and unambiguously ascertained the revised configuration by X-ray crystallography [14]. The other syntheses of

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -2,3-dihydro-1H-naphtho[2,1-b]pyrans 32. A plausible mechanism is depicted in Scheme 3. Watt et al. achieved the regioselective condensation of bis(N,N-dimethylamino)methane with various hydroxyisoflavonoids to synthesize C-6- and C-8-substituted isoflavonoids 33 and 34 in a Mannich-type reaction [76

Binding abilities of a chiral calix[4]resorcinarene: a polarimetric investigation on a complex case of study

• Marco Russo and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2698–2709, doi:10.3762/bjoc.13.268

• ) [54] to a Mannich-type reaction with L-proline and formaldehyde (Figure 3). The precursor preCA, in turn, was obtained by an acid-catalysed condensation between resorcinol and butyraldehyde. Of course, the main difference between the syntheses of CAP and CAPS is constituted by the choice of the

Chiral ammonium betaine-catalyzed asymmetric Mannich-type reaction of oxindoles

• Masahiro Torii,
• Kohsuke Kato,
• Daisuke Uraguchi and
• Takashi Ooi

Beilstein J. Org. Chem. 2016, 12, 2099–2103, doi:10.3762/bjoc.12.199

• 464-8602, Japan 10.3762/bjoc.12.199 Abstract A highly diastereo- and enantioselective Mannich-type reaction of 3-aryloxindoles with N-Boc aldimines was achieved under the catalysis of axially chiral ammonium betaines. This catalytic method provides a new tool for the construction of consecutive

• challenging problem regarding the rigorous control of the relative and absolute stereochemistry in the asymmetric Mannich-type reaction of 3-aryloxindoles. Results and Discussion As an initial attempt, the reaction of N-Boc 3-phenyloxindole (2a) with benzaldehyde-derived N-Boc imine 3a [36] was conducted in

• . Conclusion In summary, we have clearly demonstrated that chiral ammonium betaine 1c acts as a uniquely effective catalyst in promoting a Mannich-type reaction between 3-aryloxindoles and N-Boc aldimines with high levels of diastereo- and enantioselectivity under mild conditions. This study greatly expands

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

• Motoyuki Isoda,
• Kazuyuki Sato,
• Yurika Kunugi,
• Satsuki Tokonishi,
• Atsushi Tarui,
• Masaaki Omote,
• Hideki Minami and
• Akira Ando

Beilstein J. Org. Chem. 2016, 12, 1608–1615, doi:10.3762/bjoc.12.157

• -1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan 10.3762/bjoc.12.157 Abstract An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4

• Mannich-type reaction; rhodium–hydride; zinc enolate; Introduction The Mannich reaction is an important and classical C–C bond-forming reaction between an enolizable carbonyl compound and an imine to give the corresponding β-aminocarbonyl compound. For example, Shibasaki and his colleague reported the

• direct synthesis of β-lactams by reductive Mannich-type reactions [14][18][19][20][21]. We recently reported a reductive Mannich-type reaction using a combination of RhCl(PPh3)3 and Et2Zn to give the corresponding syn-β-lactams from α,β-unsaturated esters and imines in good to excellent yields together

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• Mannich-type reaction. As an extension of this work, we then wondered if other electrophilic partners instead of methyl acrylate could be used to generate similar catalytically active species in situ. Also inspired by the Mitsunobu reaction [43], we reported herein the reaction of azodicarboxylates with 3

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• -aminoalcohols have been proved by Nenajdenko and co-workers to be able to induce good levels of diastereoselectivity in the Ugi reaction [17]. Our attention was drawn by 1,3-aminoalcohols of general formula 5 (Scheme 1), which can be obtained by List's organocatalytic Mannich-type reaction of aldehydes with N

Pyrrolidine nucleotide analogs with a tunable conformation

• Lenka Poštová Slavětínská,
• Dominik Rejman and
• Radek Pohl

Beilstein J. Org. Chem. 2014, 10, 1967–1980, doi:10.3762/bjoc.10.205

• derivatives 7–10 were prepared from pyrrolidine azanucleosides 15a–d [5][15] via a Mannich-type reaction with diisopropyl phosphite and aqueous formaldehyde at elevated temperature in good yields (Scheme 1). The obtained diisopropyl esters 17a–d were deprotected by treatment with trimethylsilyl bromide in

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• imines and chiral isocyanides (Scheme 16) [59]. The chiral isocyanides were prepared following an organocatalytic phase-transfer Mannich-type reaction [59], whereas the chiral imines 52a,b were obtained from a bio-catalytic protocol [60]. In particular, the rigid bicyclic imines are powerful starting

Synthesis of meso-substituted dihydro-1,3-oxazinoporphyrins

• Satyasheel Sharma and
• Mahendra Nath

Beilstein J. Org. Chem. 2013, 9, 496–502, doi:10.3762/bjoc.9.53

• type reaction; synthesis; Introduction Porphyrin macrocycles are of crucial interest for their potential applications in diverse fields such as biomimetic models for photosynthesis [1][2], electronic materials [3], catalysis [4] and medicine [5][6]. In the past few decades, the synthesis of porphyrin

• -oxazine ring system were successfully synthesized from 5-(4-aminophenyl)-10,15,20-triphenylporphyrin in good yields. The structures of the target products were established on the basis of spectral data and elemental analyses. Keywords: dihydro-1,3-oxazinoporphyrins; iminoporphyrins; La(OTf)3; Mannich

Arylglycine-derivative synthesis via oxidative sp³ C–H functionalization of α-amino esters

• Zhanwei Xu,
• Xiaoqiang Yu,
• Xiujuan Feng and
• Ming Bao

Beilstein J. Org. Chem. 2012, 8, 1564–1568, doi:10.3762/bjoc.8.178

• arylglycine derivatives has attracted considerable attention. Over the past years, many methods have been developed for the preparation of arylglycine derivatives [3]. Among these, the addition reaction of a carbon nucleophile to imines or iminium ions through Mannich-type reaction appears more useful (Scheme

• with ethyl 2-aminoacetate derivatives is shown in Scheme 3 [16][17][18][19]. mCPBA oxidized 2a to amine N-oxide 4 before being transformed into 3-chlorobenzoic acid. The interaction of 4 with 3-chlorobenzoic acid led to the generation of the iminium ion 5 and 3-chlorobenzoate anion. The Mannich-type

• reaction of 5 with 2-naphthol may have occurred to generate the coupling product 3a. The generated 3-chlorobenzoate anion acted as a proton acceptor. In conclusion, a new strategy for the functionalization of sp3 C–H bonds of amino esters was successfully applied to the coupling reaction of ethyl 2

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