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

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

• 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

• that the B3LYP functional predicts a concerted reaction in some cases, including an intramolecular SNAr reaction, where the M06-2X functional and high level ab initio theory show that the reaction is stepwise [33]. In light of these observations, we investigated the potential energy surface also at the

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• 7-azaindole scaffolds appear in various pharmaceutically important molecules (Figure 1), which are very challenging and lengthy to prepare by the traditional methods [40][41]. In general, nucleophilic aromatic substitution (SNAr) reaction of a halo-precursor of 7-azaindole with a large excess of

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• . Only Sammakia tried the SNAr reaction of unprotected 3-phenyloxindole with chiral electron-deficient 5-halooxazoles, promoted by 1.0 equiv of Cs2CO3 [21], with ca. 1:1 diastereoselectivity obtained. In this context, we are interested in the catalytic economical asymmetric diverse synthesis of 3,3

Exploring chemical diversity via a modular reaction pairing strategy

• Joanna K. Loh,
• Sun Young Yoon,
• Thiwanka B. Samarakoon,
• Alan Rolfe,
• Patrick Porubsky,
• Benjamin Neuenswander,
• Gerald H. Lushington and
• Paul R. Hanson

Beilstein J. Org. Chem. 2012, 8, 1293–1302, doi:10.3762/bjoc.8.147

• possessing a final purity >98%. With the validation completed, the remaining 60 compounds of both libraries I and II were synthesized by the diversification of core benzoxathiazocine 1,1-dioxides scaffolds 1–8 and amine {1–10}. Under the optimal SNAr reaction conditions, libraries I and II were generated and

• values. Representation of Z-scores for the 80 compounds. Proposed library generation by microwave-assisted intermolecular SNAr diversification reaction. Utilization of a reaction pairing strategy for the synthesis of benzoxathiazocine 1,1-dioxides core scaffolds 1–8. Optimization studies for the SNAr

• reaction utilizing sultam 4. Use of a 20-member validation library to probe the reaction scope. Supporting Information Supporting Information File 386: Experimental procedures, tabulated results for all libraries, and full characterization data for 20 representative compounds. Acknowledgements Financial

Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity

• Krzysztof M. Borys,
• Maciej D. Korzyński and
• Zbigniew Ochal

Beilstein J. Org. Chem. 2012, 8, 259–265, doi:10.3762/bjoc.8.27

• . Keywords: 2-nitroaniline derivatives; phenylhydrazones; pesticides; SNAr reaction; tribromomethyl sulfone derivatives; Introduction The rapid growth of the world population results in a continous increase in the demand for food. At the same time, about 35% of the global crops around the world are being

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated S_NAr reaction

• Charlotte Wiles and
• Paul Watts

Beilstein J. Org. Chem. 2011, 7, 1360–1371, doi:10.3762/bjoc.7.160

• towards the SNAr reaction between DCNB (4) and 4-methoxyphenol (5) (residence time = 30 s; reactor temperature = 195 °C). Illustration of the substituent effect on the synthesis of diaryl ethers under continuous flow (residence time = 30 s; reactor temperature = 195 °C). Schematic illustrating the mixing

• conditions employed for the DBU (6) mediated SNAr reaction under continuous flow. Summary of the retention times obtained for the key starting materials and products employed herein.

• -temperature flow reactors, which can be scaled to increase production volume without changing the reaction conditions employed [23][24][25], resulting in a reduction in energy usage per mole. With this in mind, we report herein the translation, and further development, of a microwave method for the SNAr

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second SNAr reaction with a sulfonamide-derived aniline affords pazopanib (Scheme 50) [76

• a nearby phenylalanine residue, whilst the trifluoromethyl group interacts with serine and arginine residues in a lipophilic pocket (Figure 8) [83]. In the discovery chemistry route [84] the heterocycle core was prepared from a SNAr reaction between chloropyrazine (276) and excess hydrazine