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

• afford propargyl halide C. Finally, intermediate C reacts with the secondary amine to give the propargylamine product D. As outlined in the catalytic cycle, the presence of a base plays a dual role: co-activation of the alkynyl C–H bond through deprotonation and trapping of the HCl produced during the

• . This result suggests the generation of the Fe acetylide intermediate type A. On the other hand, Tang et al. prepared a derivative of intermediate C and subjected it to reaction with piperidine under optimized reaction conditions (DBU in MeOH at 80 °C) and obtained the propargylamine product D [66

• ]. Based on this result, the implication of intermediate C in the reaction mechanism was demonstrated. However, an alternative pathway from intermediate A to the propargylamine product has been proposed when copper is used as the catalyst. In this case, the activation of the C–X bond of the dihaloalkane

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

• the coupling with copper triflate as catalyst, without ligand, co-catalyst or other additives. The reaction involved the formation of the imine XVII followed by alkynylation to propargylamine XVIII, cyclization, and oxidation to quinoline 23 (Scheme 17) [34]. Three component oxidative annulation to

• other hand, 4-(α-tetrasubstituted)alkyl-1,2,3-triazoles 45 can be obtained by a two-step reaction of cyclohexanone, amines, silylacetylene, and aryl or alkyl azides in the presence of copper(II) catalysts (Scheme 34) [53]. In a first step, there is the formation of a propargylamine derivative XLIII

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• trifluoroethanol as the solvent and at room temperature [23][24][25][26]. In the initial reaction, propargylamine served as a bifunctional reagent, with the primary amine group participating in the first step and the terminal alkyne promoting the subsequent heteroannulation. (Scheme 2). As observed in our previous

• trifluoroethanol to Et3N for the subsequent catalysis). Thus, this protocol enabled a straightforward and rapid synthesis of highly 2-substituted indoles under mild reaction conditions, highlighting the versatility of propargylamine as a bifunctional reagent in post-Ugi-azide transformations. Our group pioneered

• reaction is utilized as a post-Ugi-azide reaction, using propargylamine as a key bifunctional reagent. The results of cytotoxic activity were moderate. However, the information obtained from this study, together with that obtained with previously described analogs, provide important information for

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• ,O-acetal derived from diethyl mesoxalate (DEMO) undergoes elimination of acetic acid upon treatment with a base, leading to the formation of N-acylimine in situ. Lithium acetylide readily attacks the imino group to afford N,1,1-tricarbonylated propargylamines. When the resulting propargylamine

• reacts with butyllithium, ring closure occurs between the ethynyl and carbamoyl groups, yielding 2,5-disubstituted oxazole-4-carboxylates. This cyclization also occurs when the propargylamine is heated with ammonium acetate, resulting in double activation. Keywords: acid amide; diethyl mesoxalate; N

• -acylamine; oxazole; propargylamine; Introduction Propargylamine is an important motif in the synthesis of heterocyclic compounds [1][2][3][4] and drug discovery [5][6] due to its multifunctionality, which includes a basic and nucleophilic amino group, an electrophilic and dipolarophilic triple bond, and an

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• study several small molecule probes were used including propargylamine, a glutamine derivative, N6-propargyladenosine and a tyrosine derivative to document the thiotriazole formation during CuAAC. The two selected examples of adenosine and glutamine-derived diagnostic ions are shown in Figure 8E. Since

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• an oxygen in the heterocyclic ring as opposed to nitrogen in azepines, are known from natural sources (compounds 13–18 as examples) [17][18][19][20][21][22][23][24][25], the application thereof in a clinical setting is limited (Figure 5). Novartis CGP 3466 (19), a propargylamine derivative, showed

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• propargylamine. The reaction was allowed to go to completion in 48 h at room temperature whereupon the reaction mixture was absorbed on silica and subjected to column chromatography for isolation of the product. To our sheer amazement, the product turned out to be not the initial adduct 4a but rather 9H-benzo[f

• azide-containing aromatic aldehydes 3a–i in the reaction with 1 and propargylamine (Scheme 2). The yields of products 5 were generally fair to good for all the aldehydes tested, even for doubly azide-substituted aldehyde 3c. However, the yield diminished somewhat for chloro-substituted aldehydes 5g–h

• , heterocyclic azido aldehydes 3k,l failed to react with 1 and propargylamine (Figure 3). Having established the scope and limitations of the 9H-benzo[f]bis([1,2,3]triazolo)[1,5-a:1',5'-d][1,4]diazepine (5) synthesis, we proceeded to look at the variations in the alkyne-containing amine component for this

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• complex of cobalt and N-heterocyclic ligand supported on carbon nanotubes and pure cobalt nanoparticles was developed [37]. Propargylamine derivatives were synthesized in extremely high yields in green solvents by this catalyst. The catalytic system can be easily recovered and reused 7 times without any

Exfoliated black phosphorous-mediated CuAAC chemistry for organic and macromolecular synthesis under white LED and near-IR irradiation

• Azra Kocaarslan,
• Zafer Eroglu,
• Önder Metin and
• Yusuf Yagci

Beilstein J. Org. Chem. 2021, 17, 2477–2487, doi:10.3762/bjoc.17.164

• propargyl acrylate (Alk-4), the rate of clicking slightly decreased in the case of propargylamine (Alk-2), but still gave high yields. Therefore, it can be concluded that Alk-2 and Alk-1 exhibit relatively lower efficiency probably due to the additional coordination of the CuI catalyst. Notably, the

• ) was purchased from Merck. All chemicals and solvents were used as received without further purification for synthesis of black phosphorus. Benzyl bromide (Merck), phenylacetylene (Sigma), propargylamine (Sigma), propargyl alcohol (Sigma), d-dimethyl sulfoxide, (DMSO-d6, Merck), N,N,N’,N’’,N

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• -nucleophile; CF3-aldimine; fluorinated propargylamine; Introduction In recent years, substitution of hydrogen by fluorine atoms or fluorine-containing groups usually provides unexpected biological and physicochemical properties, which thus has become an established approach for the development of

• pharmaceuticals [1][2][3][4][5][6][7][8][9], agrochemicals [10][11][12][13][14], and advanced materials [15][16][17][18][19]. On the other hand, chiral propargylamine represents a very important type of organic intermediates, which has been successfully used in the synthesis of natural products and biologically

• relevant heterocyclic compounds [20][21][22][23][24]. Thus, fluorinated propargylamine, in particular, chiral trifluoromethylpropargylamine, should be considered of great research interest due to the apparently advantageous pharmaceutical profile of CF3-containing drugs [25][26]. For example, DPC 961

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones

• Valeria Nori,
• Antonio Arcadi,
• Armando Carlone,
• Fabio Marinelli and
• Marco Chiarini

Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95

• ): To a solution (0.25 M) of the propargylamine 1 (1 equiv) [48] in anhydrous dichloromethane (5 mL) were added at room temperature, under N2 atmosphere, 2-iodobenzoyl chloride (1.5 equiv) and anhydrous triethylamine (2 equiv). The reaction mixture was stirred under N2 until complete consumption of the

• starting propargylamine (monitored by TLC). Then the reaction mixture was diluted with ethyl acetate, washed with a solution of NH4Cl (0.5 M), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/EtOAc) to afford the N-benzyl-2

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• attributed this to a stabilization of the NH proton by hydrogen bonds to the triazole nitrogen and methoxy oxygen atoms. The initial step in the synthesis of 120 is the enantioselective synthesis of the propargylamine 118 through the reaction of propargyl acetate 117 with the corresponding amine. This

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• ) MeOH, TEA, 48 h, yield 32%; b) (i) 5-azidopentanoic acid, DCC, DCM, 90 min, rt; (ii) 4-DMAP, DCM, 8 h, rt, 86%; c) dansylated propargylamine, CuI, TBTA, THF, MW, 70 °C, 2 h, yield 64%. Supporting Information Supporting Information File 294: Additional experimental data. Acknowledgements This work was

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

• ). However, the reaction was unsuccessful with aliphatic and low-boiling aldehydes (as the reaction was taking place at high temperature). The reaction mechanism involved a Cu-NPs-mediated C–H bond activation of the alkyne which further reacted with the iminium ion to form propargylamine 45 and Cu NPs were

• again released into the system. The propargylamine formed went through 5-exo-dig cyclization to form IPs (Scheme 16). An unprecedented CuI-catalyzed two-component synthesis of isoxazolylimidazo[1,2-a]pyridines 49 was reported by the group of Rajanarendar under aerial conditions. Differently substituted

• might be due to the formation of Cu(II)-mediated propargylamine 68 from the alkyne and Schiff base-copper complex that was cyclized and aromatized to form the target compound 67 (Scheme 24). Kumar et al. have described a Cu(OTf)2-catalyzed three-component reaction for the synthesis of imidazo[1,2-a

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• through an addition of copper acetylide, generated from terminal alkyne and copper, to the imine formed by the reaction between the amine and the formyl group. Then, the secondary propargylamine intermediate would act as a nucleophile in a cyclization process to form the lactam ring. The same

• equivalents of 2-formylbenzoic acid (33) in an Ugi three-component reaction with methanol as solvent at room temperature to afford tetrahydrodiisoindoloquinoxalinecarboxamides 43 (Scheme 12). More recently, Shafiee et al. [90] utilized propargylamine as the cycle-nitrogen delivering component and then

A three-component, Zn(OTf)₂-mediated entry into trisubstituted 2-aminoimidazoles

• Alexei Lukin,
• Anna Bakholdina,
• Anna Kryukova,
• Alexander Sapegin and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2019, 15, 1061–1064, doi:10.3762/bjoc.15.103

• from the respective isocyanates and propargylamine (or propagyl isocyanate and primary amines), thus could offer an opportunity to synthesize 2-aminoimidazoles 5 in a three-component format. Considering these premises, we started to explore the Zn(OTf)2-catalyzed reaction of 4 with primary amines

• . Herein, we present the preliminary results of these studies. Results and Discussion Urea 4a (prepared by reacting propargylamine with 4-(trifluoromethoxy)benzyl isocyanate) was reacted with an equivalent amount of benzylamine in refluxing toluene in the presence of various Lewis acids. To our delight

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates

• Vladimir A. Burilov,
• Guzaliya A. Fatikhova,
• Mariya N. Dokuchaeva,
• Ramil I. Nugmanov,
• Diana A. Mironova,
• Pavel V. Dorovatovskii,
• Victor N. Khrustalev,
• Svetlana E. Solovieva and
• Igor S. Antipin

Beilstein J. Org. Chem. 2018, 14, 1980–1993, doi:10.3762/bjoc.14.173

• adopted by calix[4]arenes containing non-bulky substituents at the upper rim [34]. Then, azido compounds 4a,b and 8a,b were subjected to copper-catalyzed reaction with 3-bis[2-(tert-butoxycarbonylamino)ethyl]propargylamine (Scheme 3). The syntheses were carried out for 4 hours at 40 °C in toluene and the

• macrocycles’ aromatic rings have been synthesized and used for the preparation of water-soluble triazolyl amphiphilic receptors with two or four polyammonium headgroups by CuAAC reaction with 3-bis[2-(tert-butoxycarbonylamino)ethyl]propargylamine. These macrocycles form stable aggregates in aqueous solutions

• were purchased from either Acros or Sigma-Aldrich and were used without further purification. Solvents were purified according to standard methods [53]. 3-Bis[2-(tert-butoxycarbonylamino)ethyl]propargylamine [54], 1a (5,11,17,23-tetra-tert-butyl-25,27-dibutoxy-26,28-dihydroxycalix[4]arene) [32]; 2a

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• -azidobenzaldehyde (1a), propargylamine (2a), 2-chloroacetic acid (3a) and benzyl isocyanide (4a, Scheme 2). Initially, the condensation of the aldehyde and the amine was effected in MeOH in the presence of 4 Å MS. This was followed by the sequential addition of chloroacetic acid and the isocyanide which, after 24

• , we investigated the effect of the substitution pattern on the propargylamine 2. For this, we chose easily available propargylamines 2b and 2c which gave moderate to good yields (60 and 40%, respectively) of diketopiperazine-fused triazolobenzodiazepine 7e and 7f. Furthermore, halogen substituents

• the synthesis of hydantoin-fused triazolobenzodiazepines starting from the Ugi reaction of o-azidobenzaldehyde (1a), propargylamine (2a), trichloroacetic acid (9) and benzyl isocyanide (4a, Scheme 5). The Ugi adduct was subjected to base-induced ring closing with NaOEt in EtOH which furnished the

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• assume that strong bases do not only lead to desilylation, but also induce decomposition of the propargylamine system (see below). Kracker et al. recently demonstrated the substitution of the labile tert-butylsulfinyl group of compounds 7a–c by the more versatile Boc protective group in yields of 56–94

• is competing with deprotonation of the methylene moiety giving rise to the formation of the azaenolate (Figure 5). The resulting anion is reprotonated during aqueous work-up, leading to the starting sulfinylimine 5. Benzyl-substituted N-sulfinyl propargylamine 6h was prepared by the addition of

• (trimethylsilyl)ethynyllithium to N-sulfinylimine 5h. The starting material 5h and the addition product 6h were isolated in a 7:3 ratio indicating deprotonation to be the predominant reaction. The phenylalanine analogous N-sulfinyl propargylamine 7h was isolated in only 12% yield (over two steps, referring to

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

• 2016 Juaristi and co-workers have reported Ugi 4-component reactions (4-CR) by liquid-assisted grinding (LAG) using MeOH. Equimolar amounts of benzaldehyde, chloroacetic acid, tert-butyl isocyanide, and propargylamine in the presence of 2 mol % InCl3, under ball-mill yielded the desired Ugi product in

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

• Somaia Kamouka and
• Wesley J. Moran

Beilstein J. Org. Chem. 2017, 13, 1823–1827, doi:10.3762/bjoc.13.177

• conditions studied. With the optimal cyclization conditions in hand, the scope of this cyclization process was investigated for a range of propargylamides 4 which are readily accessible from propargylamine by amidation and Sonogoshira coupling (Scheme 2) [39]. The cyclization was successful in all cases

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• the Mizoroki–Heck coupling. We were aware that we would perhaps face a greater challenge in terms of generating the desired 6-membered exocyclic product rather than the undesired 7-membered endocyclic product [18]. Starting from commercially available propargylamine, tosylated compound 1 was prepared

• Scheme 2). We envisioned that the reductive removal of this protective group would allow for an easier isolation of the volatile final product. Unfortunately, an alkylation of the Cbz-protected propargylamine 10 was unsuccessful. To circumvent this issue an initial protection of the amine 10 using o-NsCl

• -protective group (see Scheme 3). The second strategy started with an N-alkylation of the commercially available N-methyl propargylamine with homoallyl bromide providing the tertiary amine 21 in 69% yield which was used without further purification. The subsequent treatment with n-BuLi and trapping with ethyl

Energy down converting organic fluorophore functionalized mesoporous silica hybrids for monolith-coated light emitting diodes

• Markus Börgardts and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 768–778, doi:10.3762/bjoc.13.76

• fluorophore derivatives 4 and 5 were accessible by Williamson ether synthesis [24]. The alkyne-functionalized green benzofurazane derivate 6 was obtained by nucleophilic aromatic substitution of 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (3) with propargylamine. The alkyne-functionalized derivatives 4, 5 and 6