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

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• . Results and Discussion In order to generate the core indole unit through a robust synthetic sequence we decided to investigate the treatment of a 2-chloronitrobenzene 9 with ethyl cyanoacetate (10) as the nucleophile in a base-mediated SNAr reaction (Scheme 1). The resulting adduct 11 would then be

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

• Runjun Devi and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2017, 13, 571–578, doi:10.3762/bjoc.13.56

• Sharpless asymmetric dihydroxylation as the sole source of chirality [27]. For the synthesis of chroman derivative 2, first a base-mediated intramolecular SNAr reaction was envisioned for the aryl C–O bond formation under transition-metal-free conditions [28][29][30]. The additional benefit of this strategy

• (±)-14 we were in a position to investigate the key cyclization involving an intramolecular SNAr to deliver 2. Unfortunately, all attempts of cyclizing (±)-14 to obtain chroman derivative (±)-2 under various SNAr reaction conditions were not successful. Treatment of (±)-14 with KOt-Bu/THF (65 °C), NaH

• /DMF (80 °C), NaH/DMSO (100 °C) and KOt-Bu/toluene (110 °C) did not lead to any conversion. However, more forcing conditions such as NaH/NMP (130 °C) resulted in a to partial decomposition of the starting material. These results indicated that an intramolecular SNAr reaction of triol (±)-14 to form

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

• Sundaravel Vivek Kumar,
• Shanmugam Muthusubramanian,
• J. Carlos Menéndez and
• Subbu Perumal

Beilstein J. Org. Chem. 2015, 11, 1707–1712, doi:10.3762/bjoc.11.185

• , these compounds were available only through multistep sequences, most notably one involving as the final step an SNAr reaction with the amine and having the serious limitation of requiring the presence of an additional strong electron-withdrawing group at C-5 [42][43][44]. Our protocol requires only two

A facile synthetic route to benzimidazolium salts bearing bulky aromatic N-substituents

• Gabriele Grieco,
• Olivier Blacque and
• Heinz Berke

Beilstein J. Org. Chem. 2015, 11, 1656–1666, doi:10.3762/bjoc.11.182

• -benzenediamines 5, 6, 7 and 8. i) Pd(dba)2, P(t-Bu)3, t-BuONa, toluene, 92 °C. ii) Pd(dba)2, P(t-Bu)3, t-BuONa, toluene, 115 °C. iii) SNAr reaction: 2-chloropyridine, neat, 185 °C, microwave. Previous synthesis of the benzannulated NHCs 3-Cl and 4-BF4. Ring closure. i) (EtO)3CH, HCl (conc.), HCOOH, 80 °C [44]. ii

Star-shaped tetrathiafulvalene oligomers towards the construction of conducting supramolecular assembly

• Masahiko Iyoda and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2015, 11, 1596–1613, doi:10.3762/bjoc.11.175

• of α-protons of pyrroles in the 1H NMR spectra: δ 6.89 (38), 6.41 (40), 5.93 ppm (42). Star-shaped TTF 10-mer 44 was also synthesized by SNAr reaction of the sodium salt of 36 with decafluorobiphenyl (44%) [75] (Figure 13). In the CV measurements (Figure 14), tetrasubstituted 40 shows typical two

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• syntheses of two lead compounds reported earlier by AstraZeneca. The first one details the flow synthesis of a potent 5HT1B antagonist (28) that was assembled through a five step continuous synthesis including a SNAr reaction, heterogeneous hydrogenation, Michael addition–cyclisation and final amide

• flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up. The final arylation of 50 was intended to be performed as a SNAr reaction

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• structure of 3. Molecular structure of methyl ester 6a. Molecular structure of 7. SNAr reaction of 2-fluoronitrobenzene (2a) with diethyl 2-fluoromalonate (1). Synthesis of benzyl fluoride derivative 5. Synthesis of pyridyl fluoride 7. SNAr reactions using fluoromalonate derivatives. Synthesis of methyl

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• simple phosphines [137][138][148][149]. The group of Imamoto reported the SNAr reaction of P-chiral secondary phosphine boranes 13c with halobenzenechromium complexes 72 in the presence of sec-butyllithium [150]. The stereochemistry at the phosphorus atom was retained during the substitution when it was

• electronegative fluorine atom is needed for the SNAr reaction to take place, even though the arenechromium complexes are already very electron-deficient aromatic compounds. The same group also developed a P-chiral ligand, QuinoxP 74, via deprotonation of chiral secondary phosphine borane 13d with n-butyllithium

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• structures of pioglitazone and rosiglitazone show common structural features bearing a distal pyridine ring linked to the thiazolidinedione pharmacophore. In rosiglitazone the pyridine unit is introduced via an SNAr reaction between N-methylethanolamine (1.44) and 2-chloropyridine (1.43) which in turn is

• readily prepared by chlorination of 2-pyridone (1.42) with phosphorous oxychloride (Scheme 8) [31][32]. The resulting primary alcohol 1.45 is then subjected to a second SNAr reaction with 4-fluorobenzaldehyde [33]. A Knoevenagel condensation of the aldehyde functionality in compound 1.47 with

• strong P1 base polymer-supported BEMP gave the corresponding ether adduct which was then converted to the desired secondary amine 1.64 via direct amidation and borane-mediated reduction. Next an SNAr reaction on 2-fluoropyridine (1.66) followed by oxidation of the benzylic alcohol using immobilised