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