An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• -boronate 11 (5 → 6), and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild and selective electrophilic chlorination agent. This 7-step route from 16 has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity

• 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models. Keywords: brain penetration; 1-chloro-1,2-benziodoxol-3-one; electrophilic chlorination; LP-922056; Notum inhibitor; Introduction The Wnt

• group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6); and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild selective electrophilic chlorination agent. 4-Chlorothieno[3,2-d]pyrimidine (3) was either

A combinatorial approach to improving the performance of azoarene photoswitches

• Joaquin Calbo,
• Aditya R. Thawani,
• Rosina S. L. Gibson,
• Andrew J. P. White and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2019, 15, 2753–2764, doi:10.3762/bjoc.15.266

• (Table 2). In both series, di-ortho-chlorination is predicted to provide the higher overlap in π–π* bands between Z and E, for which a less efficient E-to-Z photoconversion is therefore expected. In addition to the band separation, the n–π* transition is required to be relatively intense for the Z-isomer

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• ]. Norfloxacin (1) is considered to be the first broad band antibiotic and its structurally related cousin ciprofloxacin (2) is one of the most prescribed antibiotics even after 20 years of clinical use. We elected 1 as a synthetic target for our novel approach towards FQs (Scheme 4). Chlorination of

Metal-free mechanochemical oxidations in Ertalyte^® jars

• Andrea Porcheddu,
• Francesco Delogu,
• Lidia De Luca,
• Claudia Fattuoni and
• Evelina Colacino

Beilstein J. Org. Chem. 2019, 15, 1786–1794, doi:10.3762/bjoc.15.172

• , entries 7 and 8) other than NaHCO3 significantly reduces the alcohol-to-aldehyde conversions. Based on these preliminary results, we decided to replace aqueous NaOCl (bleach) with Ca(OCl)2 that has been reported previously as a valid alternative to NaOCl aqueous solutions for mechanochemical chlorination

• furfural (10b), but in low and irreproducible yields together with significant amounts of byproducts. As expected, the reaction with conjugated alcohols (cinnamic alcohol, propargyl alcohol, etc.) was less successful due to the competing chlorination of the multiple bonds. Prompted by these findings, we

Introduction of an isoxazoline unit to the β-position of porphyrin via regioselective 1,3-dipolar cycloaddition reaction

• Xiujun Liu,
• Xiang Ma and
• Yaqing Feng

Beilstein J. Org. Chem. 2019, 15, 1434–1440, doi:10.3762/bjoc.15.143

• Vilsmeier reaction was carried out after insertion of Cu2+ into the cavity of TPP. In the presence of concentrated H2SO4 the Cu2+ was removed to give the 2-formyl derivative TPP-CHO. Subsequently, the formyl group was reduced by NaBH4, accompanied with chlorination by SOCl2, to afford the chloromethyl

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• studied this reaction and found that the phosphorylation step should be conducted under strictly controlled temperature conditions in the range of −5 to 0 °C to prevent the undesired 5′-chlorination which occurs at higher temperatures, and to avoid slow reaction rates at lower temperatures. Lee et al. [27

Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• ring-opening and chlorination of cyclopropanols with aldehydes. Ag(I)-catalyzed ring-opening/alkynylation of cyclopropanols with EBX. Na2S2O8-promoted ring-opening/alkylation of cyclopropanols with acrylamides. Cyclopropanol ring-opening initiated tandem cyclization with acrylamides or 2

Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis

• Tobias Fiedler,
• Michał Barbasiewicz,
• Michael Stollenz and
• John A. Gladysz

Beilstein J. Org. Chem. 2018, 14, 2354–2365, doi:10.3762/bjoc.14.211

• (12) in 94% yield using triphosgene, a standard reagent for the chlorination of phosphorus–hydrogen bonds [49]. Since a direct reaction with an excess of the Grignard reagent BrMg(CH2)6CH=CH2 would give 11, a dead end, initial conversion to the bis(borane) adduct 12·2BH3 was envisioned. However

A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

• Katherine E. Jolley,
• Michael R. Chapman and
• A. John Blacker

Beilstein J. Org. Chem. 2018, 14, 2220–2228, doi:10.3762/bjoc.14.196

• (Figure 2). Using a 5-stage variant, various unsymmetrical N-chloramines were produced with unprecedented productivities (Table 1). The rapid nature of this chlorination step makes in situ generation and consumption feasible in flow mode. Comparing Table 1, entries 1 and 3, the 5-stage CSTR, with one

• may be more of a problem in batch with the longer reaction time [48]. Conclusion A continuous-flow approach to prepare and handle unstable N-chloramines is reported. The method exploits the superior mixing of a CSTR compared with classical batch, to enable fast N-chlorination of amines under biphasic

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• 6-chloro derivative 13 as starting material, easily accessible from deoxyadenosine via enzymatic deamination, acetylation [37] and chlorination. This compound reacted cleanly and yielded 67% of the TEMPO conjugate 14. After deacetylation (15) and tritylation (16), amidite building block 7 was

• similar way as 13 by enzymatic deamination of adenosine, acetylation [46] and chlorination. A clean reaction with amino-TEMPO compound 10 then produced 78% of compound 18. Ester hydrolysis (19) and tritylation afforded 20 which was silylated with 1.8 equiv of TBS chloride. Although the 3’-silylated and

An unusual thionyl chloride-promoted C−C bond formation to obtain 4,4'-bipyrazolones

• Gernot A. Eller,
• Gytė Vilkauskaitė,
• Algirdas Šačkus,
• Vytas Martynaitis,
• Ashenafi Damtew Mamuye,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2018, 14, 1287–1292, doi:10.3762/bjoc.14.110

• acetonitrile [31]. Moreover, we investigated the reaction of 1a with SO2Cl2. Here, two reaction products – 8 and 9 – were isolated, whereas in both cases chlorination not only at the pyrazole C4 but also in the 4-position of the phenyl ring took place (Scheme 5). The reaction mechanism for the transformation 1

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• -benzosuberone 246 with Ac2O/AcOH/HCl (Scheme 39) [161]. The olefin 249, derived from reduction, chlorination, and elimination of 247, was converted by SeO2 in refluxing dioxane or xylene to the acetamido-benzotropone 250, which in turn can be hydrolyzed to 2-hydroxy-4,5-benzotropone (238). 5.1.2. Reactions of 2

Iodine(III)-mediated halogenations of acyclic monoterpenoids

• Laure Peilleron,
• Tatyana D. Grayfer,
• Joëlle Dubois,
• Robert H. Dodd and
• Kevin Cariou

Beilstein J. Org. Chem. 2018, 14, 1103–1111, doi:10.3762/bjoc.14.96

• halofunctionalizations of acyclic monoterpenoids were performed using a combination of a hypervalent iodine(III) reagent and a halide salt. In this manner, the dibromination, the bromo(trifluoro)acetoxylation, the bromohydroxylation, the iodo(trifluoro)acetoxylation or the ene-type chlorination of the distal

• yield and reaction times and excess reagents were required to reach completion (Table 1, entry 8). Using directly 1.5 equivalents of both PIFA and TBAI did not suffice to improve the yield, whether in acetonitrile or in dichloromethane (Table 1, entries 9 and 10). When chlorination was attempted with a

• transformations (dibromination, bromo(trifluoro)acetoxylation, bromohydroxylation, iodo(trifluoro)acetoxylation and ene-type chlorination) which were applied to substrates 1b–e in order to explore their scope. Bromination Dibromination Application of the dibromination protocol to neryl acetate (1b) proceeded

Preparation, structure, and reactivity of bicyclic benziodazole: a new hypervalent iodine heterocycle

• Akira Yoshimura,
• Michael T. Shea,
• Cody L. Makitalo,
• Melissa E. Jarvi,
• Gregory T. Rohde,
• Akio Saito,
• Mekhman S. Yusubov and
• Viktor V. Zhdankin

Beilstein J. Org. Chem. 2018, 14, 1016–1020, doi:10.3762/bjoc.14.87

• efficient electrophilic atom-transfer reagents useful for conversion of various organic substrates to the corresponding products of azidation [7][8][9][10][11], amination [12][13], cyanation [14][15][16][17], alkynylation [18][19][20], or chlorination [21][22]. Recently, Zhang and co-workers reported the

Chlorination of phenylallene derivatives with 1-chloro-1,2-benziodoxol-3-one: synthesis of vicinal-dichlorides and chlorodienes

• Zhensheng Zhao and
• Graham K. Murphy

Beilstein J. Org. Chem. 2018, 14, 796–802, doi:10.3762/bjoc.14.67

• . Experimental evidence suggests that a radical mechanism is involved. Keywords: allene; chlorination; hypervalent iodine; synthetic methods; vinyl chloride; Introduction Organochlorine compounds are vital as polymer precursors [1], as pharmaceuticals [2][3] and agrochemicals [4][5][6] and as functional

• vicinal-dichlorination of phenylallenes; however, no such chlorination reaction has yet been achieved [29][30][31][32][33][34]. Recent reports of reactions between hypervalent iodine reagents and phenylallenes have highlighted the possible product outcomes achievable through ionic and radical reaction

• ][44][45], there is potential for the selective generation of diverse, poly-chlorinated scaffolds. Reported here are the results of these investigations, and while indiscriminate chlorination of 2 was observed with 1a, 1b reacted chemo- and regioselectively to give 2,3-dichlorides (3) or chlorodienes

Palladium-catalyzed ortho-halogenations of acetanilides with N-halosuccinimides via direct sp² C–H bond activation in ball mills

• Zi Liu,
• Hui Xu and
• Guan-Wu Wang

Beilstein J. Org. Chem. 2018, 14, 430–435, doi:10.3762/bjoc.14.31

• ], we have independently investigated the solvent-free ortho-iodination of acetanilides under ball-milling conditions [45]. In addition, the current reaction can be extended to ortho-bromination and ortho-chlorination by using the corresponding N-halosuccinimides. Herein, we report these regioselective

• N-halosuccinimides. The influence of the milling frequency on the reaction of 1a with NIS. Palladium-catalyzed ortho-iodination of 1a in toluene. Plausible mechanism. Palladium-catalyzed ortho-bromination and chlorination of 1a in a ball mill. Optimization of the reaction conditions.a Substrate

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

•  41. 7-Chloropyrazolo[1,5-a]pyrimidines 140 obtained by 4-H/cyano/carboxylate-5-aminopyrazoles 126 (X = H, Y = R) and β-ketoesters 81 followed by chlorination with POCl3, were converted to 7-aminopyrazolo[1,5-a]pyrimidines 142 and 7-methoxy/thiomethoxypyrazolo[1,5-a]pyrimidines 143 on treatment of NIS

• -amines 198 possessing 4-(1H-benzimidazol-2-yl)phenylamine moiety at C4 position and primary as well as secondary amines at C6 position starting from 5-aminopyrazole-4-carboxamide (194). Compound 194 was treated with urea to give 1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (195) followed by chlorination

• . Chlorination of pyrazolo[3,4-d]pyrimidine derivative 211 with phosphorus oxychloride afforded 4-chloro-1H-pyrazolo[3,4-d]pyrimidine derivative 212. The chloro and nitro groups were manipulated to introduce a 3,6-dihydropyran group at position-4 by Stille reaction which provided 4-(4-(3,6-dihydropyran-4-yl)-1H

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• that CF3SO2Cl reacts under reductive conditions while CF3SO2Na requires oxidative conditions. Electrophilic chlorination is obviously the exclusive preserve of CF3SO2Cl that has been exploited with emphasis in enantioselective chlorination. Keywords: chlorination; fluorine; sulfur

• trifluoromethylsulfonylation reactions. We now focused this second part of the review on the similarly diverse uses of trifluoromethanesulfonyl chloride plus chlorination. This review appears in two parts that are published back-to-back. We encourage the readers to refer to Part 1 for a general introduction in the field [1

• the presence of Eosin Y under visible light irradiation (Scheme 2) [9]. Acetophenone derivatives with various substitution patterns as well as aliphatic or heteroaromatic ketones were equally well tolerated. This methodology offered the advantage of minimising the chlorination side reaction

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• reactions, the versatility of these two reagents is presented in other reactions such as sulfonylation and chlorination. This first part is dedicated to sodium trifluoromethanesulfinate. Keywords: fluorine; sulfur; trifluoromethylation; trifluoromethylsulfenylation; trifluoromethylsulfonylation

Syntheses, structures, and stabilities of aliphatic and aromatic fluorous iodine(I) and iodine(III) compounds: the role of iodine Lewis basicity

• Tathagata Mukherjee,
• Soumik Biswas,
• Andreas Ehnbom,
• Subrata K. Ghosh,
• Ibrahim El-Zoghbi,
• Nattamai Bhuvanesh,
• Hassan S. Bazzi and
• John A. Gladysz

Beilstein J. Org. Chem. 2017, 13, 2486–2501, doi:10.3762/bjoc.13.246

• probed by DFT calculations. Keywords: chlorination; copper mediated perfluoroalkylation; crystal structure; DFT calculations; fluorous; hypervalent iodine; nucleophilic substitution; polar space group; Introduction A number of fluorous alkyl iodides, usually of the formula RfnCH2CH2I or RfnI (Rfn = CF3

• methylene group, RfnCH2ICl2, have been isolated for n = 8 and 10 as depicted in Scheme 1 [17][20]. Although partition coefficients are not available for the iodide Rf8CH2I (the byproduct that would form in most chlorination reactions), they would fall between those of Rf8I (88.5:11.5 for CF3C6F11/toluene

• starting material. Attempted syntheses of RfnICl2. Prior to the efforts described in the previous sections, iodine(III) dichlorides derived from perfluoroalkyl iodides RfnI were considered as targets. Since these lack sp3 carbon–hydrogen bonds, they are not susceptible to possible chlorination or other

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• (Scheme 23). α,β-Unsaturated carbonyl compounds could also undergo a trans-bromination reaction efficiently within 40 min. Following to Wang’s report, Stolle and co-workers also reported a similar method of aryl bromination and chlorination using NaBr and NaCl, respectively, in the presence of oxidizing

• ) under solvent-free ball milling condition [88]. Aryl rings containing electron donating groups worked efficiently to yield 70–98% of mono or dibromo derivatives within 2 h. Similarly, NIS led to aryl iodination in near quantitative yield and NCS failed to produce any chlorination product (Scheme 25

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• most important field of application of this catalytic principle. Based on several highly spectacular recent reports, we thus wish to discuss some of the most important achievements in this field within the context of this review. Keywords: amination; chlorination; fluorination; hydroxylation

• conditions [90]. Key to success in this spectacular report was the use of the systematically optimized sulfonamide-containing phosphonium salt J1. With this catalyst, they were able to achieve high selectivities in the α-chlorination of 1 with N-chlorophthalimide (13) as the Cl-source under H2O-rich

• -chlorination of β-ketoesters 1, by using N-chlorosuccinimide (14) as the Cl-transfer agent [76]. In continuation of our efforts to develop bifunctional ammonium salts D for asymmetric catalysis we have also recently investigated the asymmetric synthesis of α-chloroketoesters 12 [92]. We found that catalyst

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

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

• obtained 2,8-bis(RCO)-substituted derivatives as building blocks for the synthesis of more complicated ICZ-containing compounds [42][43][44]. In addition, other research groups have previously reported convenient methods for C12-formylation, azo-coupling, bromination and chlorination of 6-mono-substituted

Mechanochemistry-assisted synthesis of hierarchical porous carbons applied as supercapacitors

• Desirée Leistenschneider,
• Nicolas Jäckel,
• Felix Hippauf,
• Volker Presser and
• Lars Borchardt

Beilstein J. Org. Chem. 2017, 13, 1332–1341, doi:10.3762/bjoc.13.130

• of 0.20 cm3 g−1 and a surface area of 291 m2 g−1. Indeed, the high temperature chlorination reaction is essential to obtain the full porosity of the desired carbon. However, when we conducted the mechanochemical polymerization in the presence of small amounts of ethanol (liquid-assisted grinding, LA