Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• natural products [1][2] and chlorination is the most common functionalization of this type [1][2]. Among other effects, chlorination enhances the electrophilicity of the modified carbon and alters the biological activities of drug(-like) molecules [3][4]. As aliphatic C–H groups are ubiquitous in organic

• previously characterized WelO5, it showed enhanced chlorination activity towards 1, distinct from WelO5. This study, along with the recent characterizations of WelU1 and WelU3 enzymes in H. welwitschii IC-52-3 [16], collectively provides the molecular basis for the altered structural diversity between the

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• evaluated as chiral organocatalysts in the enantioselective α-chlorination of β-ketoesters, with excellent results obtained after optimisation of the organocatalyst structure [12]. In an effort to identify new, easily accessible and tuneable organocatalysts with the privileged pyrrolidine motif from the

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• the chlorination and other C–H functionalization of (2-pyridyl)arenes. Together with this work, some other work on C–H acyloxylation provided an indirect pathway for the synthesis of phenols from arenes [54]. In 2014, Shi and co-workers designed a removable bidentate functional group, which could

A novel method for heterocyclic amide–thioamide transformations

• Walid Fathalla,
• Ibrahim A. I. Ali and
• Pavel Pazdera

Beilstein J. Org. Chem. 2017, 13, 174–181, doi:10.3762/bjoc.13.20

• chlorination of the heterocyclic amides to afford the corresponding chloroheterocycles. Secondly, the chloroherocycles and N-cyclohexyl dithiocarbamate cyclohexylammonium salt were heated in chloroform for 12 h at 61 °C to afford heteocyclic thioamides in excellent yields. Keywords: heterocyclic amides

• heterocyclic amides attracted our attention: as a first step, we applied a chlorination of heterocyclic amides, followed by thiation via reaction with thiourea on the basis of reagent-promoted desulfurylation of isothiourea under strong basic conditions [8][9]. Aiming to continue our reseach work on the

Synthesis of multi-lactose-appended β-cyclodextrin and its cholesterol-lowering effects in Niemann–Pick type C disease-like HepG2 cells

• Keiichi Motoyama,
• Rena Nishiyama,
• Yuki Maeda,
• Taishi Higashi,
• Yoichi Ishitsuka,
• Yuki Kondo,
• Tetsumi Irie,
• Takumi Era and
• Hidetoshi Arima

Beilstein J. Org. Chem. 2017, 13, 10–18, doi:10.3762/bjoc.13.2

• -specific cholesterol-lowering agent. The schematic representation of the synthesis of multi-Lac-β-CD (5) is shown in Figure 1. Briefly, per-NH2-β-CD (4) was synthesized by chlorination (per-chloro-β-CD (2)) and azidation (per-azido-β-CD (3)) of primary hydroxy groups of β-CD 1, as reported previously [17

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• first chlorination step, leading to a reaction mixture which contained acrylamide 4 as the main product formed (entry 5, Table 2). This ability to halt the cascade at the acrylamide intermediate 4 or push through to the α-thio-β-chloroacrylamide Z-3 highlights the enhanced control of reaction

• intermediates 4 and 5 as product impurities [3]. The stoichiometry of NCS used for the continuous process was also further optimized (Table 5). It was found that, at 130 °C, 2 equivalents of NCS resulted in the lowest levels of the impurities arising from reaction intermediates and over-chlorination byproducts

A new protocol for the synthesis of 4,7,12,15-tetrachloro[2.2]paracyclophane

• Donghui Pan,
• Yanbin Wang and
• Guomin Xiao

Beilstein J. Org. Chem. 2016, 12, 2443–2449, doi:10.3762/bjoc.12.237

• on the benzene ring make parylene D superior to parylene N and parylene C. There are some creative strategies for the synthesis of 4,7,12,15-tetrachloro[2.2]paracyclophane (Figure 2), the precursor of parylene D [8]. Theoretically, direct chlorination of [2.2]paracyclophane is an ideal route to

Synthesis of medronic acid monoesters and their purification by high-performance countercurrent chromatography or by hydroxyapatite

• Elina Puljula,
• Jouko Vepsäläinen and
• Petri A. Turhanen

Beilstein J. Org. Chem. 2016, 12, 2145–2149, doi:10.3762/bjoc.12.204

• esterified via chlorination of the triester [33] or directly by using alkylhalides. Many of these strategies are sensitive to moisture and require dry conditions, or alternatively lead to the formation of mixtures of different mixed tetraesters of medronic acid. Additionally, we encountered one previously

• unreported problem in the chlorination reaction of trimethyl methylene-BP with oxalyl chloride, i.e., we observed that the triester readily formed a dimer with itself during the chlorination reaction according to the 1H and 31P NMR spectra. Dimerization has been previously observed with clodronic acid

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• TiO2 nanoparticle assemblies using H2O2 [51]. Geminal chloronitroso compounds are synthesized or in situ generated from their corresponding oximes by chlorination. As halogen source elemental chlorine [52][53][54], nitrosyl chloride [55], alkyl hypochlorites [56], N-chlorourea [57], tert-butyl

Synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones: Rearrangement of pyrrolo[1,2-d][1,3,4]oxadiazines and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles

• Kkonnip Son and
• Seong Jun Park

Beilstein J. Org. Chem. 2016, 12, 1780–1787, doi:10.3762/bjoc.12.168

• using a more convenient and facile approach than those that have been previously reported in the literature [9][10][11][12]. Results and Discussion Our studies started with the synthesis of aminopyrrolocarbamate 10. The preparation of compound 10, which is illustrated in Scheme 2, involved chlorination

Synthesis of 2-substituted tetraphenylenes via transition-metal-catalyzed derivatization of tetraphenylene

• Shulei Pan,
• Hang Jiang,
• Yanghui Zhang,
• Yu Zhang and
• Dushen Chen

Beilstein J. Org. Chem. 2016, 12, 1302–1308, doi:10.3762/bjoc.12.122

• halogenation of tetraphenylene attracted our attention. The Wang group reported an efficient and mild protocol for a gold-catalyzed direct C–H halogenation of arenes with N-halosuccinimides [56][57]. Therefore, we initially investigated the chlorination of tetraphenylene by subjecting it to Wang’s conditions

• -catalyzed acetoxylation of tetraphenylene (1). The AuCl3-catalyzed chlorination of tetraphenylene (1). The AuCl3-catalyzed bromination of tetraphenylene (1). The AuCl3-catalyzed iodination of tetraphenylene (1). The Pd(OAc)2-catalyzed carbonylation of tetraphenylene (1). Supporting Information Supporting

Synthesis of highly functionalized 2,2'-bipyridines by cyclocondensation of β-ketoenamides – scope and limitations

• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1170–1177, doi:10.3762/bjoc.12.112

• compound 3f. This subsequent chlorination of picolinic acid chloride is known from the literature to proceed under enforced conditions [27][28]. On the other hand, a selective synthesis of 3a is possible in 73% yield by coupling of β-enaminoketone 2a with picolinic acid under assistance of BOP as reagent

• (see Supporting Information File 1). The in situ generation of the acid chloride with thionyl chloride was possible without the undesired chlorination with the more electron-deficient 6-methoxycarbonyl-substituted 2-pyridine carboxylic acid delivering with 2a the desired β-ketoenamide 3g with excellent

• the accidental chlorination of the picolinic acid precursor (Scheme 2) – offered the option to perform two subsequent coupling reactions in a controlled fashion. In the first step, the more reactive nonaflate moiety of 5g was efficiently substituted by a phenyl group under standard Suzuki reaction

From steroids to aqueous supramolecular chemistry: an autobiographical career review

• Bruce C. Gibb

Beilstein J. Org. Chem. 2016, 12, 684–701, doi:10.3762/bjoc.12.69

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• of intermediates have been proposed to be the reactive intermediates in many reactions such as aldol, Michael, Mannich, and α-functionalization (α-chlorination, α-amination, α-fluorination) reactions. Proline-type organocatalysts are considered priviliged, because their corresponding enamines exist

Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

• Mohammed Salah Ayoup,
• David B. Cordes,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 2671–2676, doi:10.3762/bjoc.11.287

• gave low yields in our hands. Nucleophilic substitution with the resultant benzyl iodide 20 using azide gave the corresponding benzyl azide 21 in good yield [16]. Chlorination to generate 23 was accomplished by treatment with mesyl chloride/Et3N in a one pot protocol, presumably via mesylate 22, as

Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

• Hang Ren,
• Haoyun An,
• Paul J. Hatala,
• William C. Stevens Jr,
• Jingchao Tao and
• Baicheng He

Beilstein J. Org. Chem. 2015, 11, 2509–2520, doi:10.3762/bjoc.11.272

• Stille and Suzuki cross-coupling reactions. 3’-Deoxy-3’-fluororibofuranosyl 2-chloropurine nucleosides 17–20 were synthesized by the similar strategy from the key intermediate 42. DME–water was found to be an efficient solvent system for Suzuki reaction on challenging substrates. De-chlorination of the 6

Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

• A. John Blacker and
• Katherine E. Jolley

Beilstein J. Org. Chem. 2015, 11, 2408–2417, doi:10.3762/bjoc.11.262

• solutions of N,N-dialkyl-N-chloramines produced continuously will enable their use in tandem flow reactions with a range of nucleophilic substrates. Keywords: amine; biphasic; chloramine; chlorination; continuous flow chemistry; CSTR; static mixer; sodium hypochlorite; tube reactor; Introduction N

• organozinc reagents to give amines [1]; iii) aldehydes to give amides [5][6][7]; iv) base to give imines [8]; v) alkyl and aryl C–H bonds in the presence of acid and visible light to form heterocycles [9][10]. Furthermore they have also been used for chlorination of aromatics in the presence of acid [11

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• roles of both reaction medium and halogen source. Notably, attempts in the chlorination of the alkene C–H bond under identical atmosphere were not successful. In the reaction process, a single electron transfer (SET) from the aryl ring to the coordinated Cu(II) complex 3 to the Cu(I) species 4 was the

• rate-limiting step. In 2011, Cheng and co-workers discovered an alternative route of a C–H chlorination protocol of 2-arylpyridines by employing acyl chlorides 6 as chlorinating reagents [33]. A range of mono-chlorinated 2-arylpridines 2 were obtained in the presence of Cu(OAc)2 and Li2CO3 under O2

• atmosphere (Scheme 2). In the same year, Shen and co-workers reported the Cu-catalyzed sp2 C–H chlorination of 2-arylpyridines by using the salt LiCl as a new chlorine source in the presence of CrO3 and Ac2O [34]. Due to the oxidizing potency of the CrO3, the application scope of the method was not broad

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

• 328 in ethanol saturated with ammonia was heated in a stainless sealed tube for 3 days to deliver the pyridinone derivative 329 (87%). Further, chlorination of the pyridinone 329 afforded the chloropyridine 330 (93%). Subsequently, hydrogenolysis of the pyridine derivative 330 gave the target

Intermolecular addition reactions of N-alkyl-N-chlorosulfonamides to unsaturated compounds

• Gerold Heuger and
• Richard Göttlich

Beilstein J. Org. Chem. 2015, 11, 1226–1234, doi:10.3762/bjoc.11.136

• and polar pathways as competing mechanisms and has developed a nice copper-catalyzed oxidative amidation of alkenes whilst Muñiz [27] in a recent publication proposes a polar sulfonamido-chlorination mechanism of alkenes. Similar, intramolecular and intermolecular additions of N-chlorosulfonamides and

• ], which produced the corresponding N-chloro compounds 2a and 2b in quantitative yield (Scheme 1). Other procedures for the synthesis of these compounds including N-chlorination with an fivefold excess of Oxone® in the presence of NaCl/Al2O3 [35] or deprotonation and reaction with NCS [36][37] did not lead

• -chlorosulfonamides. Proposed mechanism of the chlorination. Ring opening in the case of cationic or radical intermediates. Addition to unsaturated alcohols prone to halocyclization. Optimized addition reactions of 2a with styrene. Addition reactions of 2a with styrene derivatives. Addition reactions of 2a with

Self-assembly of heteroleptic dinuclear metallosupramolecular kites from multivalent ligands via social self-sorting

• Christian Benkhäuser and
• Arne Lützen

Beilstein J. Org. Chem. 2015, 11, 693–700, doi:10.3762/bjoc.11.79

• commercially available 2-aminopyridine (4) (Scheme 4) following mostly literature-known protocols. The electrophilic iodination of aminopyridine 4 gave iodide 5 in good yield. Compound 5 was then subjected to a Sandmeyer-like chlorination to 6 which in turn was transformed in a Sonogashira reaction with

Electrochemical oxidation of cholesterol

• Jacek W. Morzycki and
• Andrzej Sobkowiak

Beilstein J. Org. Chem. 2015, 11, 392–402, doi:10.3762/bjoc.11.45

• oxygen is possible. A stereoselective electrochemical method of the chlorination of steroidal Δ5-olefins was described by Takayama et al. [38]. The oxidation of cholesterol was carried out in an undivided cell under constant current conditions in CH2Cl2/MeCN/H2O (2:2:1), the cathode and anode being

• chlorination of some Δ5-steroids (Scheme 5) was reported by Milisavljević and Vukićević [40]. The electrolyses were carried out in dichloromethane under galvanostatic conditions with a graphite anode in an undivided cell. The supporting electrolyte tetraethylamonium chloride was a source of chloride ions

• the Gif system. Electrochemical oxidation of cholesteryl acetate (1a) with dioxygen and iron–picolinate complexes. Electrochemical chlorination of cholesterol catalyzed by FeCl3. Electrochemical chlorination of Δ5-steroids. Electrochemical bromination of Δ5-steroids in different solvents. Direct

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

A facile synthesis of functionalized 7,8-diaza[5]helicenes through an oxidative ring-closure of 1,1’-binaphthalene-2,2’-diamines (BINAMs)

• Youhei Takeda,
• Masato Okazaki,
• Yoshiaki Maruoka and
• Satoshi Minakata

Beilstein J. Org. Chem. 2015, 11, 9–15, doi:10.3762/bjoc.11.2

• due to background side-reactions such as chlorination on the aromatic rings and oxidative oligomerization of BINAMs. Furthermore, this new oxidative method was found to be applicable in the ring-closing reaction of 1,1’-biphenyl-2,2’-diamine (3) leading to benzo[c]cinnoline (4) in a good yield

• , although the modification of the reaction temperature was required (Scheme 4, for the detailed modification study of reaction conditions, see Supporting Information File 1). A possible reaction pathway of the oxidative ring-closure of 1a leading to 2a is illustrated in Scheme 5. Chlorination of an amino

• group of 1a with t-BuOCl would generate N-monochlorinated BINAM (Int-A) and release t-BuOH. The N-chlorination would induce umpolung reactivity of the amino moiety because of the attachment of electronegative halogen species on the N atom [27][28][29][30], and thereby an intramolecular nucleophilic unit

Synthetic strategies for the fluorescent labeling of epichlorohydrin-branched cyclodextrin polymers

• Milo Malanga,
• Mihály Bálint,
• István Puskás,
• Kata Tuza,
• Tamás Sohajda,
• László Jicsinszky,
• Lajos Szente and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 3007–3018, doi:10.3762/bjoc.10.319

• modified β-CD was then copolymerized with epichlorohydrin in a ratio that resulted in the formation of a water-soluble copolymer. The azo dye modified β-CD epichlorohydrin copolymer was used as a molecular fluorescent sensor for the detection of chloroform, one of the chlorination byproducts in water. Here