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

• to give (SeCN)2 [60]. Then, one selenium atom of (SeCN)2 nucleophilically attacks the iodine center in PhICl2 to generate intermediate A, which was further transformed into intermediate B by release of one molecule of iodobenzene. Next, the nucleophilic attack of chloride anion to the bivalent

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• . Based on our previous findings [17][18][19], the initial nucleophilic addition of α-aminoacetals 2a,b as nitrogen source to the activated heterodiene system of 4-methoxycarbonyl-DDs 1a–f in dichloromethane (DCM) or ethanol (EtOH) at room temperature affords N-aminohydrazone derivatives I (Scheme 2

• ), whose sequential acylation process by iso(thio)cyanates 3a–h gives rise to the asymmetric (thio)urea derivatives (intermediate II). The spontaneous nucleophilic attack of the (thio)amide nitrogen on the terminal methyl ester function at C-4 of the starting azo-ene system provides a regioselective

• yield of 6 was observed alongside a decreased yield of 5, in all those cases that required prolonged reaction times (24–30 h). This event led us to suppose the formation of carbinolamine 6 from N,O-aminal 5 owing to the nucleophilic attack of a water molecule, probably caused by the enriched moisture

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• nucleophiles were incorporated (Scheme 1b) [29][30][31][32][33][34][35][36][37][38][39][40]. Intermolecular hypervalent iodine catalysis with the regioselective additions of two distinct nucleophilic functionalities across an olefin, however, remains challenging with limited solutions [41][42][43][44][45][46

• positive charge was likely built up on the olefin prior to the nucleophilic addition. On the other hand, the electronic nature of the para-substituted benzamides had little impact on the overall reaction rate as both electron-rich and electron-deficient benzamides proceeded with similar kinetic profiles

• difluorinated iodotoluene B. Then, LiBF4 can perform a salt metathesis with B to produce LiF along with the active hypervalent iodoarene catalyst C. The activated hypervalent iodine catalyst C can coordinate to the alkene to form complex D. The nucleophilic oxygen of the amide will attack in the internal

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

• 25 was carried out using the nucleophilic substitution procedure reported above with yields of 63–76%. The anticipated formation of a second regioisomer could not be confirmed due to the limited analytical methods available for compounds on solid supports. The cleavage to obtain azidopyrazole 19g was

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

• converted rather selectively in the order tertiary alcohol< secondary alcohol < primary alcohol. They also proposed a mechanism, which is outlined in Scheme 16. The first step involves deprotonation of alcohol in the presence of base and nucleophilic attack of CS2 to generate a xanthate salt intermediate

• to a phosphine radical cation. The proposed mechanism involves the formation of a phosphine radical cation via SET from photoexcited [Ir(III)] complex. Subsequently, the benzylic alcohol initiates a polar nucleophilic attack on the phosphine radical cation, forming a phosphoranyl radical. This

• radical cation 81 and Mes–Acr because of the favorable π–π stacking. Ethyl vinyl ether, which is the most nucleophilic molecule in the reaction, combined with radical cation 81 to form the oxonium radical 82, which could proceed in two directions: 1) β-elimination, yielding radical 83 and 2) photoinduced

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• -Halochromones Dimethyl acetone-1,3-dicarboxylate The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-bromochromone (15a) afforded product 33 (Scheme 17) [32]. The first step is again a 1,4-addition to give intermediate P. Subsequent cyclization by intramolecular nucleophilic attack of the oxygen atom

• intramolecular nucleophilic attack of the oxygen to the halide to give intermediate U and subsequent ring-cleavage. The reaction of 3-ketoamide 34a (R3 = Me, R4 = Ph) with 3-chloro-, 3-bromo-, and 3-iodochromone showed that the yields strongly depend on the type of halogen atom located at position 3 of the

• 2-salicyloyl-8H-thieno[2,3-b]indoles 39a–i in mostly moderate to good yields (Scheme 21) [41]. The formation of these products can be explained, similarly to the formation of products 35, by 1,4-addition of the carbon atom of 38 to the chromone to give intermediate AB, cyclization by nucleophilic

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

• interest [12][13]. The various approaches used for selenation of aromatic compounds include directed lithiation [14][15], copper-catalyzed selenation [16][17][18], and aromatic nucleophilic substitution reactions [19][20][21][22]. Electrophilic selenium reagents (e.g., phenylselenenyl bromide) have often

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

• corresponding Ugi adduct 5aa in 42% yield (Scheme 2 and Figure 2). Interestingly, N-benzyl-2-(N-(1-benzyl-3,3-dimethoxy-2-oxoindolin-5-yl)acetamido)-3-hydroxy-2-methylpropanamide (5aa) was obtained rather than the predictable compound with a 3-chloro-2-methylpropanamide group. We believe that a nucleophilic

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• in a terpene hydrocarbon, or through nucleophilic water attack, yielding a terpene alcohol [5]. To date, about 80,000 terpenes and terpenoids have been discovered [3], approx. 10% of which are sesquiterpenes, composed of 15-carbon skeletons [6][7]. Sesquiterpenes are mainly distributed in plants and

• diols by addition of water. For each of these intermediates, simple deprotonation or nucleophilic attack by water are possible. Also, hydride shifts can occur first, which widens the chemical space of possible products. Additionally, the presence of multiple stereocenters adds to the rich

Two-fold addition reaction of silylene to C₆₀: structural and electronic properties of a bis-adduct

• Masahiro Kako,
• Masato Kai,
• Masanori Yasui,
• Michio Yamada,
• Yutaka Maeda and
• Takeshi Akasaka

Beilstein J. Org. Chem. 2024, 20, 1179–1188, doi:10.3762/bjoc.20.100

• (LUMOs). In addition, silylenes are characterized by both nucleophilic properties based on the high HOMO levels, and electrophilic properties because of the low LUMO levels [50][51]. The Mulliken charge densities of 2s are also shown in Figure S2 (Supporting Information File 1), which shows that the

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• cytosine deamination involves a nucleophilic attack at the C4 position by a Zn2+-activated water molecule [40][41][42], it was proposed to employ transition state analogues and mimetics of the tetrahedral intermediate formed as inhibitors of these enzymes [43][44][45][46][47]. More than 30 compounds have

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

• undetectable 1H NMR impurities. The application of the same protocol on o-xylene (1, Figure 3) cleanly gave dibromide 1a in almost quantitative yield. Some issues emerged during the isolation step, because of the high lacrimatory activity of 1a [53][54], while 3a lacks the same effect. Higher nucleophilic

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• the basis of readily available 2-chloro-3-nitropyridines via the intramolecular nucleophilic substitution of the nitro group as a key step. The previously unknown base-promoted Boulton–Katritzky rearrangement of isoxazolo[4,5-b]pyridine-3-carbaldehyde arylhydrazones into 3-hydroxy-2-(2-aryl[1,2,3

• ]triazol-4-yl)pyridines was observed. Keywords: aromatic nitro compounds; Boulton–Katritzky rearrangement; isoxazolo[4,5-b]pyridines; nucleophilic substitution; 1,2,3-triazoles; Introduction Nitrogen heterocycles represent a very important class of organic compounds that has found application in various

• shown in Scheme 1C. Since the key step of the synthesis is the intramolecular nucleophilic substitution of the aromatic nitro group, we assumed that the presence of an electron-withdrawing substituent at the pyridine ring would facilitate this transformation. Results and Discussion According to the

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• could be efficiently transformed to tautomerically active, H-bonding capable 1,4-dihydropyrazino[2,3-b]quinoxaline-2,3-diones (Figure 1b, DPQDs) via nucleophilic aromatic substitution (SNAr) at the ipso-CN positions. Here, the lactim–lactam tautomerization of DPQDs to arrive at the more stable 2,3-dione

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• reaction mechanism proceeds with an initial reduction of Pd(II) to Pd(0) followed by oxidative addition on the ArCH2–Cl bond to form the ArCH2–PdII–Cl complex. Then, insertion of CO, from TFBen, takes place followed by nucleophilic displacement and reductive elimination. The obtained compound undergoes

• ) species and the triple bond that promotes an intramolecular nucleophilic attack of the amino group giving a indolcyclopalladium species. This is followed by CO insertion and intramolecular nucleophilic displacement by the hydroxy group to give the indole–PdII-cycle derivate. The reaction ends with a

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

• to acyl fluorides are inspiring greater interest in these compounds. Various synthetic approaches have been investigated with two main strategies being pursued: fluorine-transfer to acyl radicals and nucleophilic fluorination of acyl electrophiles [15]. The latter approach is the most intensively

• unreliable isolation of acyl fluoride intermediates, we next considered whether BT-SCF3-mediated deoxyfluorination of carboxylic acids could be coupled with a subsequent acylation in an overall one-pot process. Selecting amines as nucleophilic coupling partners, a short optimisation study was carried out to

• only 10 mol % of DIPEA (92% 19F NMR yield, Scheme 5b). This reaction could result from base-assisted nucleophilic attack of adventitious water present in the reaction mixture. In addition to addition/elimination of fluoride ions to thioesters 3, a second potential mechanistic pathway exists for the

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

• 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

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• be activated, and the 5-position deactivated for the nucleophilic attack that occurs during the oxidative addition of the metal catalyst. This may explain the formation of only the 6-substituted product during the Sonogashira reaction. As mentioned above, new reaction conditions had to be chosen to

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• , producing the vicinal N-heterocycle-substituted olefin 9 as a mixture of stereoisomers in 65% yield. Finally, 4aa proved to be a viable nucleophilic VBX for the carboiodanation of 3-methoxybenzyne [35], furnishing the new ortho-alkenylated arylbenziodoxole 10 with exclusive C–C bond formation at the distal

(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

• , deiodination at the bridgehead position, and nucleophilic substitution at the alkyl chloride. From 1,2-BCP (±)-4, a variety of 1,2-BCPs were prepared through basic chemical transformations (Scheme 1B) [26]. Selective deprotection gave access to free alcohol-containing 1,2-BCPs (±)-5 and (±)-8. Oxidation and

• ]propellane (129). Gassman reported the initial synthesis of [3.1.1]propellane (129) in 1980 [61], and this was recently optimised by Uchiyama (Scheme 13A) [47]. Cyclisation to the bridged structure 126 was achieved by enolate formation and intramolecular nucleophilic substitution of iodide diester 125. A

• substrate. Employing Lewis acid catalysis Deng and co-workers reported an alternative pathway to indole-derived BCHs. Polysubstituted BCHs were accessed by nucleophilic addition of the indole to the activated bicyclobutane followed by a Mannich cyclisation [81]. The synthesis of wide variety of tri- and

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• angle of 176°, explaining the preference for the different skeletal rearrangements in the two possible configurations at C4 in these rigid ring systems [19][21]. The involvement of the ring-oxygen in nucleophilic displacement reactions in 1,6-anhydroglucose derivatives has also been invoked to explain

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• , enol ethers, and enamides, proved unproductive in generating the anti-Markovnikov product [90]. The authors attribute this outcome to the high stabilization of the corresponding cations from these substrates, rendering them unresponsive to nucleophilic attack by the chloride anion. Notably, neither the

Synthesis of new representatives of A₃B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

• Victoria M. Alpatova,
• Evgeny G. Rys,
• Elena G. Kononova and
• Valentina A. Ol'shevskaya

Beilstein J. Org. Chem. 2024, 20, 767–776, doi:10.3762/bjoc.20.70

• single pentafluorophenyl ring was prepared through the regioselective nucleophilic aromatic substitution reaction of the p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin with 9-mercapto-m-carborane. The reaction of this porphyrin with sodium azide led to the selective substitution of

• biomolecules via the nucleophilic aromatic (SNAr) substitution reactions [15][16]. A variety of nucleophiles such as amines [17][18], alcohols [18][19][20], thiols [17][19][21][22][23], and carboranes [17][24][25][26][27] have been studied in selective SNAr substitution reactions of the p-fluorine atoms in

• conjugates with functionalized linker groups suitable for bioconjugation or which may be efficient for PDT and BNCT improvement. Results and Discussion Synthesis Nucleophilic substitution reactions of the four p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1) are well studied [15][16

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

• increase the ratio of intramolecular nucleophilic attack, resulting in macrocyclic products via preorganization of substrate and enzyme in an active conformation [17][18]. Chemoenzymatic strategies, which merge practical enzymatic transformations with modern organic synthetic methods to increase the

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• , further oxidation would generate the corresponding carbocation, which upon reaction with a nucleophilic alkyne would form the product (Scheme 1B, reaction 3). Based on precedence in the literature, this method should allow to transfer efficiently both aryl- and alkyl-substituted alkynes [41][42][43][44

• since the formation of a stabilized carbocation might be required for the reaction to occur. Xu [41] and Molander [42] previously reported the quenching of similar cationic species by alkynyl-BF3K salts. Boronate 5a was therefore selected as nucleophilic alkyne. Gratifyingly, using Cu(dap)2Cl in DCE

• -component reaction, had surprisingly little influence on the transformation. At lower concentration only a slight decrease of yield was observed, whereas higher concentration led to a similar yield (Table 5, entries 10 and 11). The source of nucleophilic alkyne was evaluated, changing the counter ion from