Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• the NHC–CuN(SiMe3)2 complexes 42, 45, and 48, respectively. All synthesized complexes were characterized by TGA to explain their thermal behavior. The impact of the N-allyl substituent and backbone character on volatility and thermal stability of the copper amides were investigated and it was found

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• presence of TBHP as oxidant (Scheme 7a) [56]. Various α-ether-alkylated aminocarbonyl compounds were synthesized via this method and it could be extended to various α-amino ketones, α-amino esters, and α-amino amides. The mechanism of these coupling reactions is very similar and is initiated by the attack

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• (P2O5) as a catalyst for the conversion of various aliphatic amines, aromatic amines, sulfonamides and primary amides into N-substituted pyrroles (Scheme 5). These pyrroles were synthesized in 46–100% yields by the modified Clauson–Kaas reaction between amines 10 and 2,5-DMTHF (2) in the presence of

• their expectation thus, they synthesized 13 derivatives of pyrroles in good yields in short reaction times (10–45 min). It has been observed that aromatic amines and amides take a longer time compared to the primary amines and sulfonamides. In another study, Rochais et al. [59] reported in 2004 the

• acids/sulfonates from various primary sulfonamides via sulfonylpyrroles. First, various sulfonylpyrroles 69 were prepared from primary sulfonamides 68 by reaction with 2,5-DMTHF (2) using two methods as shown in Scheme 33. In method 1, amides 68 and 2 were heated in toluene at 100 °C for 30–60 min in

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• organoboron reagents were realized [12]. Also, in terms of suitable Michael acceptors as substrates, unsaturated ketones, aldehydes, esters, thioesters, amides, alkenyl heterocycles and enoyl heterocycles became viable for conjugate additions. The maturity and robustness of this methodology is documented by

• , imines, other Michael acceptors, or alkyl halides. Our group is developing trapping of metal enolates with stabilized carbocations and could show that magnesium enolates generated from enones [22], unsaturated amides [23], or heterocycles reacted with tropylium, dithiolylium or flavylium cations [24

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• serve as bioisostere for aromatic rings, amines, amides, and N-containing heterocycles. Due to the aforementioned qualities, numerous U.S. FDA-approved medications have pyridine scaffolds in their molecules (Figure 1). In this context, the synthesis of the pyridine motif is always there in trend. Many

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• ). α-Bromophenylacetic acid amides (4a,b) were prepared from 2-bromo-2-phenylacetyl chloride [38] and the corresponding amine in DCM or toluene at reduced temperature (see Supporting Information File 1). Thiobenzamides and thiobenzanilides were prepared by magnesium chloride-catalyzed thiolysis of

• commercially available benzonitriles [39] or by thionation of the corresponding N-substituted amides [40] using pyridine–P4S10 as sulfurization agent. Other chemicals and solvents were purchased from Acros Organics, Sigma-Aldrich, and Fluorochem and were used as received. 1H and 13C (APT) NMR spectra were

• theory in N,N-dimethylformamide (SMD). Extended version of Figure 2 involving energies of final products can be found in Supporting Information File 1. Eschenmoser coupling reaction between 3-substituted oxindoles and thioamides. Possible reactions of α-haloketones, esters and amides with primary

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• palladium-catalyzed three-component reactions between arylboronic or carboxylic acids, amides or sulfonamides and different aldehyde components as attractive and broadly applicable alternative to the classical Petasis borono-Mannich reaction (Scheme 1b) [17][18][19][20][21]. Recently, we were able to extend

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

• developed a Lewis acid-promoted conjugate addition to unreactive Michael acceptors such as amides or vinyl heterocycles [60]. Trimethylsilyl triflate or boron trifluoride-activated unsaturated amides underwent highly efficient and enantioselective addition of Grignard reagents. When this methodology was

• alkenyl heteroarenes [61]. The aza-enolates were trapped with various Michael acceptors such as unsaturated ketones, esters, and amides (Scheme 25) [62]. The authors noted a strong substrate dependence of this process. The trapping reaction worked best with benzoxazole-derived substrate, while thiazole

• Lewis acid-mediated generation of magnesium enolates in the trapping reactions with carbocations. Indeed, unsaturated amides, alkenyl heterocycles, or even unsaturated carboxylic acids successfully participated in this process affording structurally interesting products (Scheme 26) [63]. Apart from

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• norbornene derivatives 15 using imides 27 and tetraarylborates 28 (Scheme 5) [37]. The method utilizes C–N bond activation to trigger the reaction. The authors demonstrated a broad reaction scope. Electron-deficient amides were shown to perform worse than their electron-rich counterparts with the p

• investigated the Ru-catalyzed ring-opening/lactamization of azabenzonorbornadiene derivatives 30 with arylamides 116 (Scheme 21) [64]. Weinreb amides outperformed other arylamides, likely serving as a better directing group for the initial aryl-C–H activation. While the scope of functionalized aryl Weinreb

• amides was quite wide, including different EWGs and EDGs, as well as heterocycles, ortho-substitution was not tolerated. The authors applied the methodology for the synthesis of biologically important benzo[c]phenanthridine derivatives 117. Through methylation and subsequent aromatization of the

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• yield (63%). The same year, Besset and co-workers reported a palladium-catalyzed C(sp2)–SCF3 bond formation on amides derived from 8-aminoquinoline as a cleavable directing group in the presence of the Munavalli reagent V (Scheme 9, 12 examples, up to 71% yield) [106]. Depending on the substitution

• pattern on the aromatic ring, the amides were mono- or difunctionalized. Indeed, meta- and ortho-substituted derivatives (21a–d) were selectively trifluoromethylthiolated while para-substituted substrates led to the difunctionalized products 22e and 22f. Within these reaction conditions, the

• primary C(sp3) centers by transition-metal-catalyzed C–H activation with the Munavalli or the Billard reagents as the trifluoromethylthiolation source (Scheme 14) [126]. Using a bidentate directing group, this methodology allowed the functionalization of a large range of aliphatic amides with a primary β

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• the thioamide functionality including base-catalyzed Willgerodt–Kindler reaction [54], Kindler reaction in the presence of sulfated tungstate [55], thionation of amides using thionating reagents [56] and thionation of amides using TsCl (4-toluenesulfonyl chloride) or PSCl3-mediated Beckmann

• , we employed pyrazole-3-carbaldehydes 1 and 4 for the reaction with different 2-aminopyridines F and G towards the preparation of amide tethers as displayed in Scheme 7. The pyrazole-3-carbaldehydes 1 and 4 reacted efficiently with 2-aminopyridine (F) to deliver the pyrazole conjugated amides 1F and

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• ; hydrozirconation; palladium catalysis; Schwartz's reagent; terpenes; Introduction Conjugated dienones are recurring structural motifs in natural products. Several biologically relevant compounds carry (2Ε,4E)-unsaturated ketones or the corresponding esters or amides. Selected examples are clifednamide H (1) which

Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

• William H. Hersh and
• Tsz-Yeung Chan

Beilstein J. Org. Chem. 2023, 19, 36–56, doi:10.3762/bjoc.19.4

• supported by the amide-like CO infrared stretching frequency of 1654 cm−1. This compound further warrants mention since one might suppose that the carbonyl carbon atom would be found near 170 ppm in the 13C NMR spectrum by analogy to amides, but was instead observed at 228 ppm and confirmed by a calculated

Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

• Adwoa P. Nartey,
• Aboagye K. Dofuor,
• Kofi B. A. Owusu,
• Anil S. Camas,
• Hai Deng,
• Marcel Jaspars and
• Kwaku Kyeremeh

Beilstein J. Org. Chem. 2022, 18, 1763–1771, doi:10.3762/bjoc.18.185

• carbonyl carbons of seven amides, two carboxylic acids, and one ester. Also present were forty-one sp3-hybridized carbon signals which were assigned to fourteen methines, fifteen methylenes and twelve methyl groups The 1H NMR spectrum exhibited signals at δH 4.19 (ov., 1H, H-2), 4.08 (dd, J = 8.8, 6.0 Hz

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• addition (if X = H) or proton cleavage in the case of X = OH. Amine mediators are also suitable for the generation of radical species from CH-acidic substrates, such as β-dicarbonyl compounds. This reactivity was used in the dehydrogenative annulation of N-allyl amides with β-dicarbonyl compounds with the

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• ultimately found success with the benzamide derivative 5, which could be prepared from the mixture of 4 and its C7-epimer in 93% yield upon treatment with benzoyl chloride. Recrystallization of the resulting mixture of diastereomeric amides from cyclohexane improved the dr from 83:17 to 95:5 (as determined

• , respectively. At this stage, we started to investigate alternative methods to cleave the amide via reduction. Achieving selective C–N-bond cleavage of amides under reductive conditions is still a largely unsolved problem since a C–O-bond cleavage is typically the preferred mode of reactivity, especially when

• using hydride reducing agents [13]. Nevertheless, specialized conditions for achieving C–N-bond cleavage of amides using SmI2 [13], Tf2O/Et3SiH [14], and stoichiometric Schwartz’s reagent [15] have been reported; however, none of these methods was successful in reducing amide 5 to the desired amine 4

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• showed a modest induction (entry 3). Conclusion Exploratory efforts toward new C1-symmetrical CPAs were described. Four CPAs were synthesized and three evaluated. The syntheses are straightforward, inexpensive, and scalable. Resolution via the separation of diastereoisomeric phosphorus amides could be

1,4,6,10-Tetraazaadamantanes (TAADs) with N-amino groups: synthesis and formation of boron chelates and host–guest complexes

• Artem N. Semakin,
• Ivan S. Golovanov,
• Yulia V. Nelyubina and
• Alexey Yu. Sukhorukov

Beilstein J. Org. Chem. 2022, 18, 1424–1434, doi:10.3762/bjoc.18.148

• cage nitrogen atoms) and/or rotamers (restricted rotation around amide C–N bonds), which is well-known for amides and carbamates (Figure 4a). The activation barriers for the rotation across amide C–N bonds in 4a and 4c estimated by DFT (18.4 and 19.4 kcal/mol, respectively, ωB97XD/Def2TZVP, gas phase

• ) are close to those observed experimentally for amides and carbamates [42][43]. Upon changing the solvent to CD3OD or D2O the spectra become much simpler and a picture expected for a Cs symmetrical structure is observed (for example, cf. 1H NMR spectra of Bn-4c in different solvents shown in Figure 4b

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• 28 (note the missing methyl group) had been reported to be devoid of antimycobacterial effects at 6.25 µg/mL (30 µM) [162]. Moreover, a screening at GSK identified the amides 29 and 30 [163][164], and amine 25 was also reported but only for an effect on M. tuberculosis glutamine synthetase [165

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• -diketo esters 2 (Scheme 1). On the other hand, two carboxylic acid functionalities adjacent to a keto group result in mesoxalic diesters 3, or mesoxalic ester amides 4. The increased electrophilicity of the keto group and the high density of these complex functional groups make such structures attractive

• , (−)-preussochromone D, (−)-jiadifenoxolane A, palau’amine, jatrophen, (−)-hopeanol, (+)-campthotecin, isoretronecanol, corynoxine, (+)-gracilamine, (−)-irofulven. Mesoxalic diester and ester amides as key intermediates: (+)-awajanomycin, (−)-aplaminal, cladoniamide G. α,β-Diketoesters as key intermediates

• diesters and ester amides as key intermediates (+)-Awajanomycin Diethyl mesoxalate (90a) is a valuable building block due to the high density of carbon atoms in high oxidation states. As a vic-tricarbonyl compound, its central keto group is an especially potent electrophile. The Koert group used this

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• ). N-(1-Naphthyl)formamide (6) was obtained in satisfying yield, while the methyl and tert-butyl ester moieties affected the reaction outcome (Scheme 1, amides 7 and 8). Secondary amines were also tested under the developed conditions; N-methylaniline provided the desired product 9 in 39% yield, while

• using secondary aliphatic amines such as dibenzyl- and methylbenzylamine, which provided amides 16 and 17 in 87% and 74% isolated yields, respectively. Furthermore, the methodology allowed us to synthesize a set of aromatic formanilides (amides 18–20, Scheme 2). Indeed, the deactivated p-nitroaniline

• was successfully converted into the corresponding formamide 19 as was the poorly nucleophilic diphenylamine (Scheme 2, amide 20). Lastly, we aimed to apply the procedure to the acylation of a series of amines. To our delight, we successfully extended the methodology to the mechanosynthesis of amides

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• . Several attempts were made to combine the benzothiazine motif with amino acid methyl esters (Scheme 4) using coupling agents (EDC, COMU, T3P®, etc.) or through acid chloride (SOCl2 and (COCl)2) in a flask with stirring or under ball-milling conditions. However, we were unable to isolate the desired amides

• the amino acids. However, these reactions proved to be unsuccessful due to the high reactivity of the bromo derivative. On the contrary, coupling of the less reactive amides formed from pyruvic acid and the amino acids 16a and 16b was accomplished (Scheme 5a), and several different conditions were

• and amides with amino acids. Benzothiazine derivatives with a carboxylic function in the C-3 position exhibit low stability under acidic as well as basic conditions, which complicates the synthetic utilization. As such, direct coupling of 4H-benzo[b][1,4]thiazine-3-carboxylic acid with amino acids

Electrochemical Friedel–Crafts-type amidomethylation of arenes by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborate

• Hisanori Senboku,
• Mizuki Hayama and
• Hidetoshi Matsuno

Beilstein J. Org. Chem. 2022, 18, 1040–1046, doi:10.3762/bjoc.18.105

• amidomethylated products in good to high yields. Keywords: electrochemical oxidation; Friedel–Crafts type amidomethylation; N-acyliminium ion; quasi-divided cell; trialkylammonium salt; Introduction Oxidation of amides generates useful intermediates, N-acyliminium ions, which have been widely used in organic

• synthesis [1][2][3][4]. For example, Friedel–Crafts-type amidomethylation [5][6][7][8][9][10][11][12][13][14][15] proceeds efficiently by the reaction of N-acyliminium ions with electron-rich arenes to give the corresponding amidomethylated products in good yields. Since amides are important intermediates

• -acyliminium ions in chemical methods has been generally accomplished by the reaction of amides with chemical oxidants, such as peroxides and persulfates at high temperature (path a in Scheme 1) [10][11][12][13]. A metal catalyst or a photocatalyst consisting of metals, such as ruthenium or iridium, is also

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• tested in the reaction. To our pleasure, both aliphatic and aromatic amides reacted smoothly and provided the expected products in satisfactory yields, with the acetyl groups being unaffected. This suggested that the N-acetyl groups in N-substituted carbonylimidazoles were well tolerated during the