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

• by cyclodehydration allowed for a straightforward and efficient synthesis of 3,4-dihydroquinazolines with N-aryl substituents bearing electron-withdrawing groups. The sequence involves an initial SNAr displacement, N-acylation and MW-assisted ring closure. Remarkably, the uncatalyzed N-arylation of 2

• reaction promoted by trimethylsilyl polyphosphate (PPSE) is also proposed on the basis of literature data and our experimental observations. Keywords: cyclodehydrations; dihydroquinazolines; microwaves; nitrilium ions; PPSE; SNAr; Introduction Dihydroquinazolines (DHQs) represent heterocyclic cores of

• others, and involve a reduction step which would be incompatible with the presence of nitro or cyano groups [5][13][14][39][68][69][70][71]. The synthetic sequence towards compounds 1 requires the chemoselective arylation of the benzylic amino group of the precursor with active haloaryl derivatives. SNAr

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• how this protocol translates seamlessly to drug discovery in the LSF strategy. In a method that is complementary to their C–H amination strategy, Nicewicz et al. have reported the SNAr-type addition of nucleophiles to methoxybenzene derivatives at the ipso position, as opposed to the C–H amination

Imide arylation with aryl(TMP)iodonium tosylates

• Souradeep Basu,
• Alexander H. Sandtorv and
• David R. Stuart

Beilstein J. Org. Chem. 2018, 14, 1034–1038, doi:10.3762/bjoc.14.90

• , transition metals feature prominently in such methods, but even recent examples employ stoichiometric metal mediators [4]. Metal-free methods by classic SNAr are also attractive, but only possible on very electron-deficient arene substrates [5]. Diaryliodonium salts are useful reagents for metal-free aryl

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

• stability under acidic and basic conditions are also reported. Keywords: benzoic acid; cross-coupling; hydrolysis; SNAr; trifluoromethanesulfonamide; Introduction Very strong organic acids are interesting as catalysts for chemical reactions [1][2] and for facilitation of proton conduction [3]. In order to

• (SNAr) [6][7]. Benzoic acids (e.g., 2) are relatively weak acids, even with highly electron-withdrawing substituents on the aromatic core [8]. Very strong benzoic acid derivatives (e.g., 4 and 6) have been synthesized by replacing one or both of the oxygens of the carboxylate group with the

• 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

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• carbon–halogen bond known [1]. Its low reactivity, in comparison to other C–X bonds, means that it is inert to all but the most harsh reaction conditions, and fluorine can generally be carried through multistep syntheses without concern over side reactions (the exception being SNAr reactions). In recent

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

• coil reactor maintained at 50 °C (Scheme 2). The intensely red coloured solution (anion of the SNAr adduct) [8] which quickly formed was quenched after the incubation period (35–108 min) using a third flow stream of hydrochloric acid (1 M) blended via a dedicated mixer chip before the combined mixture

• product 8 with yields and throughputs. Optimisation experiments for SNAr with ethyl cyanoacetate (10).a Selected optimisation experiments for reductive cyclisation to compound 12.a Supporting Information Supporting Information File 474: Reproductions of 1H and 13C NMR spectra for the reported compounds

Nitration of 5,11-dihydroindolo[3,2-b]carbazoles and synthetic applications of their nitro-substituted derivatives

• Roman A. Irgashev,
• Nikita A. Kazin,
• Gennady L. Rusinov and
• Valery N. Charushin

Beilstein J. Org. Chem. 2017, 13, 1396–1406, doi:10.3762/bjoc.13.136

• through a conventional mechanism of nucleophilic aromatic substitution (SNAr). On the other hand, conversion of the second nitro group, as well as a similar transformation of compound 10b, can possibly be explained in terms of the radical-nucleophilic aromatic substitution (SRN1), since no other electron

• -withdrawing groups, facilitating the SNAr reactions, are present in these aromatics [51]. Such type of nitro–thiolate substitution is a rare phenomenon; only a few reports on this topic are available in the literature [52][53][54]. Some N-nucleophiles are also able to react with 6,12-dinitro-substituted ICZs

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

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• and [18F]5b was accomplished using the SNAr concept. The appropriate precursors and reference compounds were prepared in two steps from simple commercially available starting materials in high yields, but at this stage the building blocks are not appropriate for further labeling purposes. Experimental

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• , nitro(pentafluorosulfanyl)benzenes are widely-available primary industrial products and starting materials to other SF5-benzenes which were prepared by reduction followed by condensation or diazotization chemistry [8][14][15][16], SEAr [17], SNAr [18][19][20][21][22][23][24], or metal-catalyzed cross

• -coupling reactions [25][26][27]. Synthetic methods to novel SF5-containing building blocks are sought after and drive the development of applications of these compounds. In this work, we explore SNAr chemistry of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene which was initially obtained as a minor

• ; redistillation afforded 2 in 99% purity (detected by GC). However, for investigations of SNAr of 2, a more efficient process for its synthesis was required. With higher excess of fluorine, the 2:1 ratio increased. Therefore, the synthesis of 2 by the direct fluorination of 1 was investigated (Scheme 2 and Figure

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

• of nucleophilic aromatic substitutions (SNAr) of benzene-1,2-diamine at 2-chloropyridine (Scheme 1). Once all the different N1,N2-diarylbenzene-1,2-diamines were prepared a method had to be developed to build up the imidazolium salts by ring closure. 3-Cl and 4-Cl could principally be obtained from

• -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

• 30 is estimated to be ca. 1000 times higher than that of the neutral fiber (before doping: σrt 3 × 10−6 S cm−1, after doping: σrt 3 × 10−3 S cm−1) [68]. Star-shaped pyrrole-fused TTF oligomers 38–43 were synthesized by nucleophilic aromatic substitution (SNAr) reactions of fluorinated benzenes with

• 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

• temperature SNAr reactions as key flow steps in the sequence (Scheme 7). One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac [60]. In

• 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

• the diester 3 after the initial SNAr step was not necessary and decarboxylation of crude diester 3 gave 4a very efficiently. Consequently, in all analogous experiments (Table 1), crude product diesters of type 3 were isolated and used without further purification, allowing the ready synthesis of a

• 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

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• combination of deprotection and activation is also possible and is found in the literature as an Ugi Deprotection/Activation–Cyclisation (UDAC). In addition, other MCR-post-condensation reactions, especially for macrocycles, include intramolecular aryl couplings, amidations, SnAr reactions, nucleophilic

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• tripeptide byproduct. Nucleophilic aromatic substitution (SNAr) chemistry contributes to creating useful materials. In 2005, Comer and Organ reported SNAr reactions of 2-fluoronitrobenzene using a flow microreactor system with microwave irradiation (Scheme 9) [69]. Toward making compound-libraries, Schwalbe

• explored a flow microreactor system for sequential transformation towards fluoroquinolone antibiotics such as ciprofloxacin via both inter- and intramolecular SNAr reactions (Scheme 10) [70]. Starting from the acylation reaction of (N-dimethylamino)acrylate with 2,4,5-trifluorobenzoic acid chloride

• [18F]-radiolabeled molecular imaging probes. Flow microreactor synthesis of dipeptides. Flow synthesis involving SNAr reactions. Flow synthesis of fluoroquinolone antibiotics. Highly controlled formation of PFPMgBr. Selective flow synthesis of photochromic diarylethenes. Flow microreactor system for

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

The first example of the Fischer–Hepp type rearrangement in pyrimidines

• Inga Cikotiene,
• Mantas Jonusis and
• Virginija Jakubkiene

Beilstein J. Org. Chem. 2013, 9, 1819–1825, doi:10.3762/bjoc.9.212

• pyrimidine core toward subsequent substitution. The usage of very harsh reaction conditions (prolonged heating for hours or days, high pressure or microwave irradiation of the reaction mixtures) is required to carry out the second SNAr reaction (Scheme 1) [9][10][11][12][13][14]. In 2012 we published a

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

• Magnus Liljenberg,
• Tore Brinck,
• Tobias Rein and
• Mats Svensson

Beilstein J. Org. Chem. 2013, 9, 791–799, doi:10.3762/bjoc.9.90

• include both neutral (NH3) and anionic (MeO−) nucleophiles are quite satisfactory (r = 0.93 to r = 0.99), and SS is thus useful for quantifying both global (substrate) and local (positional) reactivity in SNAr reactions of fluorinated aromatic substrates. A mechanistic analysis shows that the geometric

• QM methods and other parts with MM methods, for example, in enzymes where the active site can be modeled with QM and the remaining structure with MM methods. Predictive models for the SNAr reaction This paper is a continuation of our work on the predictive computational modeling of the synthetically

• and industrially important SNAr and SEAr reactions (nucleophilic and electrophilic aromatic substitution, respectively) [3][4][5]. The putative mechanism for the SNAr reaction involves attack of a nucleophile and the formation of an intermediate σ-complex (also called the Meisenheimer complex

Synthesis of SF₅-containing benzisoxazoles, quinolines, and quinazolines by the Davis reaction of nitro-(pentafluorosulfanyl)benzenes

• Petr Beier and
• Tereza Pastýříková

Beilstein J. Org. Chem. 2013, 9, 411–416, doi:10.3762/bjoc.9.43

• Umemoto’s two-step procedure starting from diaryldisulfides or mercaptoaromatics [21]. We have recently reported SNAr reactions of the nitro group in compounds 3 and 4 with alkoxides and thiolates [22], vicarious nucleophilic substitution (VNS) of the hydrogen with carbon [23][24], oxygen [25] and nitrogen

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• available 7 was converted to methyl ester 15 in 90% yield, due to its ease of handling (Scheme 2) [20]. Next, SNAr displacement of the fluoride of 15 by N-(3-aminopropyl)pyrrolidine (8) proceeded in high yield, 99%, to give aniline 16 [20]. Reduction of the nitro group was nearly quantitative and subsequent

• (11), malonic acid and ammonium acetate under reflux proceeded smoothly, as previously described, to furnish β-amino acid 21 in 73% yield [18]. Methylation of 21 (80%) followed by nitration of 22 (67%), boc protection of 23 and SNAr displacement of the fluoride in 24 with amine 8 (71% over two steps

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• was reduced under hydrogenation conditions to provide aniline 5. o-Fluoronitrobenzene (6) was coupled with the previously formed aniline under SNAr conditions to furnish anilino nitrobenzene 7a (Scheme 1). Alternatively, meta- and para-nitrophenylethanols 8 were combined with o-fluoronitrobenzene (6