Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• % yield. Additional experiments were then carried out using N-methoxy-2-(prop-1-en-2-yl)benzamide with different substituents R2. Both electron-donating (methyl, alkoxy, dimethylamino) and electron-withdrawing substituents (fluoro, chloro, trifluoromethyl) were well tolerated on the phenyl ring and gave

• , respectively, the substrates could be successfully converted to the products 3b–d and 2f in 52–87% yield with this method. In addition, a good or high yield of 3-methylisoquinolinones 3e–k, with different substituents on the phenyl ring, was also obtained. It is worth noting that when an electron-withdrawing

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• salts. The oxidative behavior of substituted diarylamines is known to be very diverse and strongly influenced by the substituents in the phenyl rings as well as by the type of the oxidant. Diarylamines can serve as precursors for a wide variety of practically useful compounds such as diarylnitroxides

• diphenylamines yielding N,N-diarylbenzidines and N,N-diaryldihydrophenazines were reported in [21]. By varying the reaction conditions and additional substituents in the phenyl rings, a possibility for the selective oxidation of ortho-(2-pyridyl)diphenylamine to the corresponding nitroxide, as well as the

• equivalent nitrogen atoms (aN = 6.56 G) as well as additional triplet splitting provided by hyperfine interaction with a pair of equivalent protons (aH = 1.89 G). In contrast, only traces of this admixture were detected for the diarylamines with electron-withdrawing substituents. This is in line with our

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• . It can be observed that the 5-monosubstituted diazo derivatives, and especially those with no substituents in position 5, form the target products in lower, often moderate yields (see products 3i,j,n and 3r,s,t) compared to the 5,5-disubstituted (spirocyclic) analogues. This result may be related to

• the lower stability of the less-substituted β-lactam derivatives under thermolysis conditions. Additional alkyl substituents sterically shield the ring and prevent an unwanted nucleophilic attack leading to product degradation. In reactions with alcohols and mercaptans, the corresponding esters 3k–n,r

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• SAR study was achieved creating N-arylimidazolethylamine counterparts 55–59 (Scheme 9). It was shown, that electron-withdrawing substituents at the pyridine 5-position lowered the antagonistic activity for this small family. Conformationally restricted cyclopropylhistamine analogues were disclosed by

• ). Later, the authors expanded the histaprodifen family by SAR exploration of small substituents in the phenyl rings (compounds 67–78, Scheme 11) [59][60]. While pEC50 values varied very subtle, a histamine relative potency screening revealed a general reduction in potency. Following the same assay

• second generation series, i.e., compounds 91–94 (Scheme 12), featuring simple hydrocarbon substituents was elaborated. This collection showed good activities, demonstrating the tolerance of introducing bulky moieties at position C2 or N1 of the imidazole ring. Researchers also described positive membrane

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• aliphatic and aromatic aldehydes, both with electron-donating (ED) and electron-withdrawing (EW) substituents. It is worth mentioning that Gd triflate is much cheaper than scandium triflate, and that in this study the so called “gadolinium break” phenomenon [6], a discontinuity in the lanthanide properties

• different combinations of starting materials and elucidating the effect of substituents on each of the partners [1]. Since 2019, research has been focused on broadening its scope with the aim of moving towards a more sustainable chemistry or to impart specific properties to the final products, therefore a

• the tolerability of a wide range of aldehydes, starting from one of the most used, benzaldehyde, passing through heteroaromatic and aliphatic structures with different substituents. In this context, some examples where the aldehyde functionality is incorporated into sugar derivatives, natural

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• of photocatalysts by tuning their redox and photophysical properties. Thus, we successfully developed a one-pot, three-component synthetic method with those substituents in 5-aryldeazaflavins 1 on the deazaisoalloxazine core or on the phenyl ring by condensation of N-substituted anilines, aromatic

• substituents at positions 7 and 8 of the deazaalloxazine ring (see Figure 1 for numeration) showed the best reactivity as reductive photocatalysts. Such an outcome of MCR opens up the possibility of their production on a larger scale for commercial needs. However, the synthesis of the 7- and 8-methoxy

• methyl substituents were chosen to enhance the photophysical properties and photostability of the desired photocatalysts. It should be noted that our method encountered limitations when applying strongly deactivated anilines substituted with CF3 or acetyl groups, with no formation of 5

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• without substituents on the carbon–carbon double bond have remained a formidable challenge. To address this limitation, we report herein the asymmetric bromolactonization of 5-hexenoic acid derivatives catalyzed by a BINOL-derived chiral bifunctional sulfide. Keywords: asymmetric catalysis

• to asymmetric halolactonizations, especially for the synthesis of chiral γ-butyrolactones and δ-valerolactones via the reaction of 4-pentenoic acid and 5-hexenoic acid derivatives (Scheme 1). Notably, however, substituents on the carbon–carbon double bond of alkenoic acid substrates are generally

• required to achieve highly enantioselective halolactonizations (Scheme 1a) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates without substituents on the carbon–carbon double bond have

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• contains two trifluoromethyl groups in the sidearm which could alter the electronic effects significantly. We therefore decided to prepare a small series of monocyclic trifluoro(aryl)-λ5-iodanes, where the sidearm substituents were changed stepwise from methyl to trifluoromethyl groups, so that we also

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• conventional thermal heating, amide 10a was isolated, albeit in a lower yield and accompanied with tar formation. In addition to the 1H, 13C NMR spectra and mass spectrometry data, the structure of compound 10d was established by X-ray diffraction analysis (Figure 3). It was also found that the substituents at

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• radical (potassium nitrosodisulfonate) [13] or catalytic systems like methyltrioxorhenium(VII) (MeReO3) [14] and 2-iodobenzenesulfonic acids (IBS)/Oxone® [15] led to either p-quinones or o-quinones, depending on the substituents in the para-position to the hydroxy group. Recently, hypervalent iodine

• transfer [50]. Unsubstituted PAHs display multielectron oxidation, but one-electron waves occur with electron-donating substituents in suitable positions. Panizza et al. [38] observed two one-electron oxidations in their cyclic voltammetry studies of 1a in water and proposed the formation of a naphthyloxy

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

• substituents of the new heterocycle rather than functionalization on C-3 (Scheme 22). Spirothiazolidine steroids Horiuchi et al. introduced a novel synthetic approach for the preparation of steroidal spiro 1,3-thiazolidines from 2α-bromo-3-oxo steroids, exemplified by compound 76 [46]. Initially, treatment of

• as a 17β-HSD3 inhibitor [42]. The same research group reported a new family of 3-spiromorpholinones derived from ADT bearing hydrophobic substituents [43][62]. The synthetic key step involved a regioselective aminolysis of the oxirane 131 with different ʟ- or ᴅ-amino acids (53–99% yields) to obtain

• inhibitors of 17β-HSD3 in a microsomal fraction of rat testes. Their androgenic effect on androgen-sensitive cells LAPC-4 was also evaluated. According to the biological results, compounds 134 and 136 with substituents in (S)-configuration were better inhibitors than the (R)-isomers. Furthermore, tertiary

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• (Table 1, entry 9). The notable influence of steric and electronic parameters of the PG prompted us to investigate a range of sterically diverse alkyl substituents. Interestingly, while only fragmentation products were obtained for methyl and benzyl groups (Table 1, entries 10 and 11), the sterically

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• } and 1{8}) or showed low conversion (halogenated derivatives 1{9–11}); 4-aminopyrimidines 1{12–16} also demonstrated low conversion; pyridine derivatives with electron-withdrawing substituents (such as NO2 at C-3 or C-5 positions, as well as CN, SO2NH2, or C(O)NH2 at the C-3 atom) did not work

• }). Some of these results (e.g., on the reactivity of aminopyrimidine derivatives) were in accordance with the previous literature data [21][29]. Meanwhile, electronic effects of the substituents in the amino heterocycle reported in the previous works were somewhat contradictory. Whereas for the NO2 group

• wide range of aminopyridines, pyrazines, and pyridazines, it worked poorly for aminoazoles, aminopyrimidines, substrates with strong electron-withdrawing groups, and substrates bearing additional dialkylamino or alkoxy substituents. The electronic nature was a major limiting factor for other two

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

• was effective for the stereoselective fluorination of benzylic positions ortho to aldehyde substituents (Figure 9). The choice of a bulky amino, transient, directing group dictated the stereochemical outcome and promoted the C–F reductive elimination through an inner-sphere pathway. A competitive C–O

• bond formation for substrates bearing primary benzylic positions, attributed to the faster rate of SN2 at the less hindered carbon. The scope was limited to substrates bearing secondary benzylic sites, with various functional groups tolerated. However, substrates bearing electron-donating substituents

• on the arene were unsuccessful. Without substituents on the ring, aryl C–H activation and subsequent C–O bond formation occurred along with benzylic fluorination (7) (low efficiency). The presence of a p-methoxy group resulted in a switch in selectivity to acyloxylation 8’ as the major product. The

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

• 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

• -ones 2 (Scheme 2, lower part) with diverse substituents (Br, Cl, F, Me or CN) in the para-position of the N-aryl group. These substrates reacted smoothly with α,β-unsaturated ketone 1c and the corresponding products 3cb–cf were obtained in good yields (61–85.5%) and good to excellent

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• , the incorporation of pyridyl groups that are commonly found in pharmaceutically active compounds are also possible (8). In general, the catalytic efficiency of this new electrophotochemical protocol was found to be relatively independent of the electronic properties of the aryl substituents and the

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• different sizes and substituents are tolerated on the aryl aglycon, we decided to replace the aryl aglycon by photoswitchable azobenzene in both O- and S-galactosides (Figure 1B) to investigate their binding affinity and the influence of the photoisomerization on the lectin interaction. The ammonium group

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• rings. The triangles indicate a product having α-substituents. (c) Crystal structure of DH-ER-KR tridomain (PDB ID 8G7W) [24]. DH, KRS, ER, KRC are colored in cyan, pink, yellow, and purple, respectively. The lid of KR catalytic pocket is colored in red. The co-crystallized cofactor is represented as

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

• of 3-cyclohexanones caused by the strong electron-withdrawing effect, which made 3a as a base rather than a nucleophile under such conditions. The location of substituents was found to affect the product yield greatly, considering that the reactions worked better with 3-cyclohexenones bearing a para

• good yields. The electronic properties of the substituents, irrespective of their positions on benzylamines, displayed no substantial disparity on the reaction outcomes, leading to the formation of 4ab–ap in 50–80% yields. Both the heteroarylmethylamines and sterically hindered α-methylbenzylamine

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• investigate the effects of different substituents R2 and R3. When the methyl substituent (R2) was replaced with an aryl group, the corresponding thiocyanated products 2l–o could be obtained in acceptable to moderate yields. On the other hand, the method was equally applicable to the substrate bearing two aryl

• substituents (R2 and R3), albeit the reaction afforded product 2n in a much lower yield, possibly caused by steric congestion. In addition, when the aryl substituent of R1 was replaced with a tert-butyl group, this method also worked well to give product 2o in moderate yield. Notably, when the C3 and C5

• product 2q in good yield. Furthermore, we turned our attention to the applicability of this protocol for the selenocyanation of the pyrazole skeleton (Scheme 3). Gratifyingly, the method was equally applicable to selenocyanation of pyrazoles bearing various substituents, with the corresponding

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• -ynedioate usually gave the expected tricyclic products in good yields. However, the reaction with diethyl but-2-ynedioate afforded products 4p, 4r and 4t in moderate to lower yields. The 5,6- unsubstituted dihydropyridines with various substituents showed marginal effects on the yields. These results

• though there are four chiral carbon atoms in the products. It can be found that all reactions proceeded smoothly to give the expected polycyclic compounds 6a–k in satisfactory yields. The substituents on the three components showed very little effect on the yields. These results showed that this reaction

A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors

• Nicole Javaly,
• Theresa M. McCormick and
• David R. Stuart

Beilstein J. Org. Chem. 2024, 20, 1428–1435, doi:10.3762/bjoc.20.125

• electronic structure (bonding) and molecular structure (geometry) in diarylhalonium salts. We found a periodic trend with respect to the percentage of s- and p-orbital character used by the central atom to bond to the aryl substituents for a series of isoelectronic diaryl chalcogen and diarylhalonium

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

• followed by the addition of diisopropylamine, either in a one-pot synthesis or in two consecutive steps (Table 1). Subsequently, different aliphatic and aromatic substituents were attached to the pyrazole nitrogen by nucleophilic substitution with suitable organohalides 16 and cesium carbonate [3]. Due to

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• ). Huang et al. set up a clean crossed-Cannizzaro-aldol reaction strategy of isatin derivatives 88 and 90 with paraformaldehyde under microwave irradiation to furnish 3,3-disubstituted oxindole derivatives 89a–h and 91a–d [92]. The representative 3-hydroxymethyloxindole adducts with varying substituents

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

• in a satisfactory yield. Various hydrocinnamic acids having electron-donating and electron-withdrawing substituents provided the targeted products 3a–c in good yield. Heterocycles containing carboxylic acids also provided the products 3d–g in moderate to good yield. Aliphatic carboxylic acids, under

• was applicable to various carboxylic acids with electron-donating as well as electron-withdrawing substituents but unfortunately, aliphatic acids were not effective in this reaction. In addition, several control experiments, such as fluorescence quenching and Stern–Volmer studies, were done to analyze

• terminal arylalkynes bearing electron-donating and electron-withdrawing substituents were well compatible with this method. The procedure is limited to electron-withdrawing and electron-neutral aryl halides. The presence of a conjugated substituent in the p-position of an aryl halide is crucial for