Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• that bear two functional groups. In order to avoid competitive reactions, these groups need to be compatible with the components of the Ugi reaction or the intermediates generated during the reaction. Thus, an amine can rarely be directly incorporated as an additional functional group, because of

• [11]. Different strategies have been developed to avoid these competitive reactions, the most common ones being the use of protecting groups (Ugi/deprotection/cyclization strategy) [12][13][14] or of surrogates of amines [15]. However, direct incorporation of the second amine without derivatization is

• the most desirable strategy from the point-of view of sustainability. This has been achieved following two different approaches: the blockage of the amine group throughout the reaction by the incorporation of an additional group on the carbonyl component [16][17][18] or the use of amine groups with a

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• tert-butylsulfinyl cleavage, yielding the 17-allyl-17-amine hydrochlorides 121a,b diastereomers. These hydrochlorides were then acrylated with acryloyl chloride. When starting from 121a, the bis-acylated compound 122a1 was only detected in traces (3% yield), with the mono-acylated derivative 122a2

• ester under basic conditions was carried out, followed by the transformation of the carboxyl group to the amides 165 and 166 by treatment with thionyl chloride and the corresponding amine. Tetraoxanes were obtained from ketones 163, 165, and 166 by a peroxyacylation reaction using an acidic hydrogen

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• pentacyclic secondary amine 97 bearing the ester linker in the C1 side chain in one pot. After removal of SfmC by precipitation and centrifugation, the reaction mixture containing secondary amine 97 was subjected to the reductive amination using 2-picoline borane as a hydride source, yielding tertiary amine

• chemo-enzymatic total synthesis of jorunnamycin A (103). SfmC-catalyzed enzymatic conversion followed by cyanation and N-methylation also converted substrate analog 101 to the corresponding pentacyclic tertiary amine 102 in 18% overall yield based on peptidyl aldehyde 101. Subsequent simple chemical

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• [34]. In reductive amination, the substrate is usually an aldehyde or amine. After the formation of the iminium ion, it is reduced with the appropriate reagent to form the N-methylated amino acid. Different methods have been established using for example benzaldehyde as a protection group, sodium

• triethylsilane in TFA-CH3Cl, resulting in the N-methylated amino acid as the final product [38]. The third method for chemical N-methylation involves the use of protection groups that also enhance the reactivity of the primary amine (Figure 2). Once the amine is deprotonated, an electrophilic methylation reagent

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• NRPS-derived macrolactam ureidopeptide, bulbiferamide (27, Figure 10), was isolated and characterized from a coral-derived Microbulbifer sp. C10-1 by Igarashi and co-workers [7]. The ureido linkage did not allow for the peptide main chain in 27 to possess a terminal primary amine and none of the side

• chains possessed a nucleophilic primary amine. Curiously, the macrocyclizing amide bond was found to exist between a Trp side chain indole nitrogen and the C-terminal carboxylate. To the best of our knowledge, this was the first example of the involvement of a Trp indole in macrolactam formation in

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• yields, with the authors proposing that HFIP aided in stabilising the electrochemically generated benzylic radical cation intermediates. Secondary and tertiary benzylic substrates bearing halogen, ester, protected amine and alkyl functional groups tolerated the reaction conditions well. The authors

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• 10.3762/bjoc.20.136 Abstract The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine–Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent

• -covalent catalysis via bifunctional hydrogen-bonding organocatalysts. The C-4 nucleophilicity of pyrazolin-5-ones was also explored in enantioselective reactions with α,β-unsaturated carbonyl compounds through covalent catalysis with chiral amine-based catalysts; however, it has achieved limited success

• who reported a chiral amine-catalysed aza-Michael addition reaction of pyrazolin-5-ones with α,β-unsaturated ketones to access β-(3-hydroxypyrazol-1-yl)ketones (Scheme 1a) [22]. The developed reaction was restricted to α,β-unsaturated ketones with aliphatic substituents (Scheme 1a) [22]. Ji and Wang

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• ; primary amine; Introduction Aniline derivatives possessing arylmethyl substituents at the ortho position are an important class of amines. They have a wide variety of practical applications, ranging from anti-depression [1], being δ receptor stimulants in analgesic pharmaceuticals [2], to antioxidant

• was placed (E)-2-arylidene-3-cyclohexenone 2 (0.2 mmol), primary aliphatic amine 3 (2.0 mmol) and DME (2 mL). The reaction mixture was stirred at 60 °C and the reaction process was monitored by TLC analysis. After completion, the solvent was concentrated under reduced pressure and the residue was

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• 21gd could be isolated in quantitative yield with this technique, avoiding additional purification steps for the azide intermediate without any losses in product formation. The developed procedure was exemplarily transferred to solid-phase synthesis. In quantitative yields, 5-methyl-1H-pyrazol-3-amine

• pyrazole–triazole hybrids: synthesis of azides 7 or 8 from amines and organohalides and subsequent CuAAC to larger heterocyclic systems 9 or non-substituted amine products 10; Sakai reaction of α-ketoacetal 11 for the synthesis of N-substituted derivative 13 [14][16][17][18][19]. Synthesis of pyrazolyl

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• catalyst is first excited and then transfers one electron to the thiocarbamate moiety to form a thiocarbamate radical anion, with change in oxidation state from III to IV. Next, the sacrificial electron donor Hünig base successfully converts [Ir(IV)] to [Ir(III)], with concurrent formation of an amine

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• ] cycloaddition between maleic anhydride and secondary amine occurs first, followed by the corresponding amidation (Figure 3, path II) [110]. Although IMDAF reactions involving furan systems bearing amide functionality are generally reversible [134], the formation of the addition products in high yields in this

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• polymerization, and solvent oxidation. For aniline and o-anisidine, predominant oxidative polymerization occurred, leading to the formation of the respective polyaniline polymers as major products. For methyl anthranilate, the oxidative polymerization was suppressed due to the delocalization of amine lone pair

• of quinones having exceptional radical-stabilizing abilities. The best example in nature is the radical pathway in the catechol oxidation process [56][57][58]. The structure of o-anisidine resembles catechol as it has two adjacent electron-donating functions (NH2 and OMe). For o-anisidine, the amine

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• using 5-amino-1-benzyl-3,3-dimethoxyindolin-2-one (1) [12] and benzyl isocyanide (4), as amine and isocyanide components, respectively. Different carboxylic acids 2 and aldehydes/ketones 3 were evaluated using ZnF2 as catalyst (10 mol %) and MeOH as the solvent (Scheme 2 and Figure 2). A library of α

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• are of substantial importance for the fine chemical industry, pharmaceuticals, agrochemicals, dyes, and natural products [25]. The synthesis of amine derivatives can be accomplished using many powerful techniques, including Buchwald–Hartwig and Ullmann cross-coupling reactions, hydroamination

• aldehydes or ketones, undergo base-assisted condensation reactions with amines providing the corresponding imines. In the last step, the active manganese hydride complexes reduce the imine compounds and afford the desired alkylated amine products (Scheme 2B). Several well-defined manganese complexes have

• synthesis of amines and imines using Mn-pincer catalyst [37]. When t-BuOK (1 equiv) was used as a base, alkylated amine products were observed selectively using alcohol as an alkylating agent, whereas when t-BuONa (1.5 equiv) was used as base, alkylated imine products were isolated (Scheme 6). This

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• -cored halides can be broadened by converting C–Hal functions into different functional groups. For example, aldehyde and amine functionalities can be readily derived from C(sp3)–Hal functions through hydrolysis–oxidation [13] or substitution [14], respectively. This is of significant interest in the

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• ]. In stark contrast, a method for the synthesis of drug-like tetrazole compound libraries involving a building block approach have remained elusive, with success being reported thus far only with the tetrazole amine [14][15]. The use of a tetrazole building block in MCRs would have all the advantages

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• was formed (internal standard: PhCF3, Table 1, entry 1). Pleasingly, changing the base to K2CO3 led to the formation of 2a in 7% 19F NMR yield (Table 1, entry 2), while the selectivity of the reaction could be switched significantly upon employing organic amine bases (Table 1, entries 3 and 4). Using

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• schistosomiasis [22][23][24][25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities. A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces

• highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26][27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H

• -pyrazino[2,1-a]isoquinolin-6(5H)-ones 6c–k in 73–79% yields. The presence of electron-donating or electron-withdrawing groups on the aromatic ring did not show significant effects on the Heck reaction. Products 6c–k were obtained in higher yields than products 6a,b. We believe that the secondary amine in

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• esterification of alcohol (±)-5 gave redox active ester (±)-6, which was itself shown to be a suitable substrate for nickel-catalysed decarboxylative cross coupling reactions to aryl-substituted BCPs (±)-7. Oxidation of alcohol (±)-8 gave acid (±)-9 which yielded amine (±)-10 after a Curtius rearrangement

• ) [32]. The synthesis of the corresponding 2-aza-1,5-BCHs 13 was achieved by an intramolecular photochemical [2 + 2] cycloaddition. They were able to employ this synthetic route to synthesise a variety of 1,2-BCPs (±)-14 bearing a protected amine in the bridge position. In early 2023, MacMillan and co

• rearrangement, amine (±)-27 was then accessible in one additional step. Formation of redox active ester (±)-28 from acid (±)-26 allowed photochemical Minisci reaction to 1,2-BCH (±)-29 and borylation to boronic ester (±)-30. Synthesis of phenol isostere (±)-31 was possible through oxidation of boronic ester

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• produced during the process of amine-based carbon dioxide capture technologies [13][14]. These linear nitramines from these reactions pose their own health and environmental consequences [13]. Therefore, strategies to remediate linear nitramines are needed. Compared to cyclic nitramines [1][2][15][16

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• suitable for the coupling to peptides on resin, prepared by solid-phase peptide synthesis (SPPS) [35]. The detailed conditions for the amide-forming reaction were optimized using biscarboxylic acid-substituted C60 derivative 3 and a similar peptide with a primary amine derived from γ-aminobutyric acid

• on resin, a GABA residue was attached to the N-terminus of the peptide in order to provide a less-hindered primary amine, enabling an efficient amide conjugation reaction with biscarboxylic acid-substituted C60 derivative 3. Compound 3 was prepared by Prato reaction of C60 and an N-glycine derivative

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• polyketides or peptides, and form an ester bond. Then, they catalyze either intramolecular macrocyclization to give macrolactones or macrolactams with attacking of internal nucleophiles (alcohols or amine), or hydrolysis to release linear acids or peptides (Scheme 1b). Although TE domains may display

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• )amine) [33] in toluene. Conclusion To summarize, an approach toward 4-azido-6,7-dimethoxy-2-alkyl/arylsulfonylquinazolines was developed employing a sulfonyl group dance caused by the azide–tetrazole equilibrium in quinazolines. 4-Azido-6,7-dimethoxy-2-alkyl/arylsulfonylquinazolines were obtained using

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε

• process (Scheme 1c). In this process, the hybrid α-ester alkylpalladium radical species from diazo ester adds to the double bond of 1,3-dienes or allenes, followed by the allylpalladium radical-polar crossover path. As with the classical Tsuji–Trost reaction, a subsequent nucleophilic attack of an amine

• and linear amine 3b were found to readily participate in this protocol, furnishing the corresponding products 4a–c in 61–84% yields. To our delight, this MCR strategy was compatible with a wide variety of complex bioactive molecules, including tetrahydropapaverine, (R)-duloxetine, sertraline

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• incorporating the unsaturated oxazole counterparts has not been explored. Results and Discussion Reaction of ynamide 1a with the N-acylpyridinium-N-aminide reagent 2 proceeded in good yield to afford oxazole 3 bearing a C-2 methyleneamino moiety as the first example of a free secondary amine in this annulation

• introduce a formamide motif in place of the amine or imine to allow the use of more forcing cyclisation conditions (Scheme 1a, path c). Oxazole 8a was obtained in good yield from 1a using only a slight excess of nitrenoid 7 and 2 mol % catalyst loading. Heating 8a in the presence of POCl3 afforded the 3