Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• , compound 7 has a primary alkyl group (n-propyl). This difference reduces steric hindrance and lowers the rotational barrier around the carbon–nitrogen bond, increasing the likelihood of racemization. Results and Discussion N-Propyl-N-cinnamoylamide 7 was prepared from phosphine oxide 8 [32] via an SNAr

• reaction with nucleophilic lithium amide from n-propylamine, the reduction of phosphine oxide 9 by trichlorosilane/triethylamine, and the N-acylation of 10 with cinnamoyl chloride in three steps (Scheme 1). We also analyzed amide compound 7 by HPLC analysis using a chiral stationary phase column with a CD

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• synthesis of iVeliparib-AP6 [5] starts with a nucleophilic aromatic substitution (SNAr) reaction wherein 4-fluorothalidomide (1) reacts with amino-PEG7-OH 2 to give alcohol 3 (Scheme 1). Subsequent alcohol oxidation followed by reductive amination of the resulting aldehyde 4 with veliparib [6][7] provides

• of 6 can evade detection if unaware of this issue. However, the amount of 6 can increase to as much as 20% when conducting the reaction at 0.1–0.3 M, the concentrations generally used for preparative work. Notably, because the SNAr reaction of 1 proceeded slowly, 4-(dimethylamino)thalidomide also

• . Although C2’ and C4’ remain the most electropositive sites, we could not isolate any byproducts corresponding to reactions with glutarimide. The preferred nucleophilic reaction at C1, C3, and C4 can be explained by the fact that the LUMO of 1 resides entirely on phthalimide. The low SNAr reaction rate may

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• chemical reaction was first reported by Schweidtmann et al. [81]. In this study, the multiobjective Bayesian optimization (MOBO) was used to optimize an SNAr reaction (Table 2, entry 1) and an N-benzylation reaction (Table 2, entry 2) using an automated flow reactor. The objectives of the optimization were

• to maximize the space–time yield (STY) while minimizing either the E-factor of the SNAr reaction or the impurity concentration of the N-benzylation reaction. For both reactions, there were four variables to optimize, including metrics for reaction time, reagent concentration, and temperature. After

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• stereoelectronic effects, which results in more than 100 nm red-shift of the fluorescence peak. Conclusion We have successfully prepared seven fluorine triphenylenes (F3 to F12) with various alkyl chain lengths and three bitriphenylene dimers (G55, G66, and G48) with different molecular symmetry by the SNAr

• reaction. This “palladium-free” reaction between 2Li-BPn and C6F5–C6F5 possesses several advantages: easily available starting chemicals, low cost, efficient, and versatile, displaying the potential to synthesize more complicated fluoroarene molecules and polymers. These fluorine-containing triphenylenes

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , and either sodium hydroxide or sodium hydrogen sulfide to obtain a cyclic imine. Subsequently, the U-3CR is performed, where the cyclic imine reacts with an electron-deficient 2-fluorobenzoic acid and an isocyanide to yield a bisamide. Then, the bisamide undergoes an intramolecular SNAr reaction to

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• copper catalyst afforded nearly better results for the arylated products. In 2022, Linde et al., demonstrated a conventional approach for achieving arylations of nitrogen- and oxygen nucleophiles via SNAr reaction, using o-fluorinated diaryliodonium salts 40, which enabled access to a greater range of

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• substitution (SNAr) reaction between 2-chloro-6,7-dimethoxy-4-sulfonylquinazoline derivatives and NaN3, while the second involved an SNAr reaction between 2,4-dichloro-6,7-dimethoxyquinazoline and alkyl/arylsulfinates, followed by substitution with NaN3. Using this developed methodology, the adrenoblockers

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• +) cations, used as visible light fluorescent dyes, have been synthesized via a nucleophilic aromatic substitution (SNAr) reaction with primary alkylamines (e.g., 1a+; Figure 1) [15][16]. The highly planar geometry of the TATA+ core unit induces π–π stacking structures in single-crystal and film states, as

• investigating the ion-pairing assemblies. Results and Discussion The N-(2,6-dimethylphenyl)-substituted triazatriangulenium cation 2+ was synthesized as a BF4− ion pair 2+-BF4− in 19% yield using a modified synthetic procedure for 2+-Cl− [30] (Figure 2). It should be noticed that the SNAr reaction for ring

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• amount of 3,3''-difluoro-1,1':3',1''-terphenyl (6h) as side product, that might derive from an SNAr reaction of 3h with the Grignard reagent of 5h. Moreover, bromoxylenes 5m–o also gave the corresponding products 3m–o, respectively, although the position of substituents affected the yields. On the other

• . Conditions: a) The reaction was carried out at rt for 1–3 h without Mg. b) The side product 6h by SNAr reaction onto 3h was obtained in 8%. Tentative reaction mechanism. Ullmann and Ullmann-type homo-coupling reactions. Rh-catalyzed homo-coupling reactions. Rh-catalyzed homo-coupling reaction by using

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

• Yamashita’s DCPQs 1a (BenzCN) and 2a (XyICN) began via SNAr reaction of commercially available o-phenylenediamines 11a and 11b with building block 13 to afford dihydropyrazine derivatives 8 and 9, respectively, as precipitates in 1,4-dioxane solution. The reaction generates two equivalents of HCl, adding a

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• -arylation using aryl(2,4,6-trimethoxyphenyl)iodonium(III) acetates [13]. In this process, the acetate ligand acted as a base to activate the phenol group and positioned it in proximity to accomplish the smooth SNAr reaction. The synthesis of diaryliodonium(III) salts with various counterions, such as

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

• , which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α1-adrenoceptor blockers terazosin and prazosin by further C2-selective SNAr reaction and azide reduction. Keywords

• resulted in full degradation of the formed product. Consequently, an alternative pathway toward product 8 was explored (Scheme 4). 2-Chloro-4-thioquinazolines 10 were prepared from starting material 7 in an SNAr reaction with thiols in the presence of K2CO3 in good 75–93% yields. Next, thioquinazolines 10

• further optimized since the products were only needed for analytical purposes. Two different pyrrolidine-substituted derivatives were additionally synthesized to prove the regioselectivity of the sulfonyl group dance products (Scheme 8). Compound 16 was obtained in the C4-selective SNAr reaction between

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• ). In this case, the participation of the acenaphthylene derivative seems quite logical, since this should facilitate the SNAr reaction and inhibit the formation of type 7 anions (under the action of methoxide as a base), which are inactive to subsequent nucleophilic attack. Dimethoxyacenaphthylene 14

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• order to obtain higher yields in the intramolecular cyclization step, the authors also investigated the use of a strategy based on an SNAr reaction using an electron-deficient aryl halide. Thus, 4-fluoro-3-nitrobenzaldehyde (118) was subjected to the Still–Gennari reaction, to give the corresponding cis

• route for the preparation of isomeric macrolides of combretastatin D congeners called 11-O-methylcorniculatolide A (5), isocorniculatolide A (7), and 11-O-methylisocorniculatolide A (8), where the key steps comprised an SNAr reaction for the diaryl ether formation and a Mitsunobu reaction for the

• macrolide formation [69]. Thus, the SNAr reaction between the ester 155 and the aldehyde 156 led to the formation of diaryl ether 157 which was subjected to a hydrogenation reaction followed by hydrolysis of the ester group to yield the corresponding seco-acid 159. Subsequent Mitsunobu reaction led to 11

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• ]. In 2010, Echavarren and co-worker completed the formal total synthesis via a Au(I)-catalyzed cyclization (Scheme 2c) [13]. In 2018, Pabbaraja and co-workers disclosed the synthesis of macarpine by constructing ring C through the domino Michael addition/SNAr reaction of nitromethane to an ynone

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• of purine [73][74][75][76] or alkylation of inosine or guanosine derivatives (Ib→II, Scheme 1) [30][36]. In the next step, azide can be introduced either by a second SNAr reaction on the C2-halo derivative or by diazotization/azidation at C2. Then, the Cu(I)-catalyzed azide–alkyne cycloaddition

• transformations requires heating the reaction mixtures up to 60 °C for 24 h. An SNAr reaction with a non-trivial alcohol was demonstrated on the example of 2',3'-O-isopropylideneuridine and product 3f was isolated after 21 h of heating at 50 °C in 82% yield. It should be noted that tertiary alcohols (e.g., t-BuOH

• regioselectivity of SNAr reactions was proved by 13C NMR comparison of the products 3a–i with similar compounds from literature [61]. Intriguingly, we were able to conserve the acetate protecting groups in product 3j, when the SNAr reaction was performed in the presence of DBU used as base. The artificial

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• EtOH, MeOH, and MeCN in temperature diapasons up to 100 °C, but no conversion of the staring material 2a (R1 = Et) was observed. The change of the solvent to DMF or DMSO resulted in the cleavage of one ethyl ester group [25], but still the SNAr reaction at C2 was not effective. LC–MS analysis of the

• desired triazole derivatives were not obtained. Furthermore, the hydrolysis of the dialkyl ester groups were performed with TMSI [29][30], and phosphonic acid 10 was obtained. The latter was inert to the SNAr reaction with NaN3 at C2 (Scheme 4). SNAr–Arbuzov reaction between 2,6-bistriazolylpurines and P

• (OEt)3 Next, we switched to pathway B (Scheme 2) and prepared 2,6-diazidopurine derivative 5 from 2,6-dichloropurine (11) via a Mitsunobu alkylation and SNAr reaction with NaN3 (Scheme 5) [22]. 2,6-Bistriazolylpurine derivatives 6a–i were obtained in CuAAC reactions with various alkynes in 35–76% yield

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• morpholine amide 7. The synthesis started by selective SNAr reaction with 4 and tert-butyl ((cis)-4-aminocyclohexyl)carbamate affording the intermediate nicotinic acid 5 in 70% yield without the need for chromatography. Subsequent amide coupling using TBTU afforded 2-chloro precursor 6 in excellent yield

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• magnesiation with N,N-dimethylformamide did not lead to the expected bromoaldehyde 15 but provided surprisingly the aminoaldehyde 16. Probably, the intermediate aminoalkoxide delivers dimethylamine during aqueous work-up, followed by SNAr reaction at C-4. Related nucleophilic substitutions have been reported

Synthesis and properties of sulfur-functionalized triarylmethylium, acridinium and triangulenium dyes

• Marco Santella,
• Eduardo Della Pia,
• Jakob Kryger Sørensen and
• Bo W. Laursen

Beilstein J. Org. Chem. 2019, 15, 2133–2141, doi:10.3762/bjoc.15.210

• saturated [37] and unsaturated [38] carbon bridges. Here we report for the first time the introduction of sulfur functionalities into triangulenium dyes by SNAr reaction with ethylthiol nucleophiles in the para-positions accessing several new families of xanthenium, acridinium and triangulenium dyes with

• types of SNAr reactions typical in triangulenium synthesis, exemplified with the synthesis of A3-ADOTA+: step 1, replacement of p-methoxy groups with dialkylamines. Step 2, replacement of o-methoxy groups with a primary amine followed by intramolecular SNAr reaction. Step 3, intramolecular SNAr

Synthesis of benzo[d]imidazo[2,1-b]benzoselenoazoles: Cs₂CO₃-mediated cyclization of 1-(2-bromoaryl)benzimidazoles with selenium

• Mio Matsumura,
• Yuki Kitamura,
• Arisa Yamauchi,
• Yoshitaka Kanazawa,
• Yuki Murata,
• Tadashi Hyodo,
• Kentaro Yamaguchi and
• Shuji Yasuike

Beilstein J. Org. Chem. 2019, 15, 2029–2035, doi:10.3762/bjoc.15.199

• mechanism is as depicted in Scheme 3. The base deprotonates the imidazole ring giving an anion at the 2-position, which reacts with selenium by nucleophilic attack, resulting in C(Het)–Se bond formation. Next, the ring closure proceeds via the SNAr reaction by attack of the selenide anion on the phenyl

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• thiophenols 14 through SN2 reaction with cyclopropyl bromide (15, Scheme 2a) [2][4] or by SNAr reaction between aryl fluorides 16 and cyclopropanethiol (17, (Scheme 2b) [6]. Although simple and attractive, these approaches usually require harsh conditions such as the presence of a strong base and high

• temperatures [18]. In addition, an electron-withdrawing group (EWG) must be present on the aryl fluoride 16 for the SNAr reaction to proceed. Aryl cyclopropyl sulfides can also be accessed by the addition of thiophenols 14 to cyclopropenes 18 (Scheme 2c) [19][20] or to exo-methylenecyclopropanes 20 (Scheme 2d

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• deprotonated starting material 1b was methylated with MeI and further submitted to SNAr reaction with NaN3 according to a previously published procedure [39]. The expected 2,6-diazido-7-deazapurine (3) was obtained in 78% yield. It should be noted that the medium size alkyl chains at N(9) were chosen for

• reported that 2,6-diazidopurine nucleosides exhibit opposite regioselectivity with aliphatic thiols, which do SNAr reactions at C(2) position of purines [50][51]. Taking this information into account, we performed an SNAr reaction between 2,6-diazidopurine 2a and piperidine and obtained the C(2

• the synthetic intermediates obtained in the SNAr reaction (e.g., 6-azido-9-heptyl-2-(piperidin-1-yl)purine (6b)) exists in both tetrazolo- and azido-tautomeric forms in CD3CN solution. The presence of the latter permits the CuAAC reaction with terminal acetylenes and gave a rise to the title compounds

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

• Nadia Gruber,
• Jimena E. Díaz and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2018, 14, 2510–2519, doi:10.3762/bjoc.14.227

• , avoiding the use of protecting groups, and affording the desired heterocycles in good to excellent overall yields. A suitable balance between reactivity and selectivity was achieved in the SNAr reaction which, to our knowledge, is the first report on a successful uncatalyzed N-monoarylation of the

• unprotected diamine performed under equimolar conditions. These results are of particular relevance due to the wide use of the SNAr reaction in synthetic organic chemistry. The cyclization of functionalized 2-ABAs was performed efficiently under MW irradiation using PPSE as the dehydrating agent. This

Synthesis and stability of strongly acidic benzamide derivatives

• Frederik Diness,
• Niels J. Bjerrum and
• Mikael Begtrup

Beilstein J. Org. Chem. 2018, 14, 523–530, doi:10.3762/bjoc.14.38

• of the corresponding imidoyl chlorides 10 with PCl5 in POCl3, followed by the additional reaction with trifluoromethanesulfonamide (1) and protonation by sulfuric acid (Scheme 1) [10]. In recent years, we have reported high yielding catalyst-free N-arylation by SNAr reaction of mono- or