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

Electrocarboxylation: towards sustainable and efficient synthesis of valuable carboxylic acids

• Roman Matthessen,
• Jan Fransaer,
• Koen Binnemans and
• Dirk E. De Vos

Beilstein J. Org. Chem. 2014, 10, 2484–2500, doi:10.3762/bjoc.10.260

• . Oxidation of chloride, which itself originates in the CCl4 reactant, likely results in partial chlorination of the acetonitrile solvent, releasing protons which in turn cause the formation of chloroform by attacking the cathodically formed carbanions [143]. An undivided electrosynthesis setup with stable

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• dichlorides can be obtained either from chlorination of phosphonic acids [65][66] or from treatment of an allyl chloride such as 61 with phosphorus trichloride followed by hydrolysis to give 62 [15][67]. Reactions of unsymmetrical amines or aminoalcohols such as ephedrine with phosphonic acid dichlorides

• ) followed by chlorination gave chlorodiketone 147. The latter was then treated with sodium carbonate in boiling xylene to afford cyclopentenone 148, presumably via decarbonylation of a cyclopropanone intermediate. Addition of the lithium anion of chiral phosphonamide 64a at low temperature produced adduct

Rasta resin–triphenylphosphine oxides and their use as recyclable heterogeneous reagent precursors in halogenation reactions

• Xuanshu Xia and
• Patrick H. Toy

Beilstein J. Org. Chem. 2014, 10, 1397–1405, doi:10.3762/bjoc.10.143

• reactions discussed above, some of these reactions did not proceed to completion, even when the reaction time was lengthened. Generally, it was observed that the bromination reactions afforded higher product yields than did the corresponding chlorination reactions (Table 2, entries 1–8), except when

• , and realizing that it was returned as the byproduct of the above reactions, we next examined its recyclability in the chlorination of alcohol 4H and aziridine 8B. The results of these studies are shown in Table 4 and Table 5, respectively. In these experiments, the polymer recovered by filtration of

• . Synthesis and applications of rasta resins 16 and 17a,b. Synthesis of bifuncitonal rasta resin 18. Appel reactions using 16.a Halogenation reactions of aldehydes using 16.a Halogenation reactions of aziridines using 16.a Recycling of 16 in the chlorination of 4H.a Recycling of 16 in the chlorination of 8B.a

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• ]pyrimidine 7. Direct chlorination of 1 in a moderate scale (1 g) using POCl3 proved to be very low yielding [28]. It remains unclear if this was due to the poor solubility of PreQ0 or to the presence of unprotected amino functionalities. In order to overcome this issue, the exocyclic amine was protected [14

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• chlorination such as the use of N-chlorosuccinimide or, as reported more recently, CuCl2 produced, in the latter case, 7-6 with full stereocontrol (Scheme 7-iii) as unambiguously determined by X-ray diffraction analysis [31]. The addition of nucleophilic species (amine, alcohol, alkyllithium, etc.) on 7-6 or

• with full stereocontrol. This result indicates that both steps (i.e., the chlorination and subsequently the substitution of the chlorine atom with the nucleophile) were stereocontrolled. The detailed mechanism of each step, which may involve penta-coordinated phosphorus intermediates [28], is not well

Towards allosteric receptors – synthesis of β-cyclodextrin-functionalised 2,2’-bipyridines and their metal complexes

• Christopher Kremer,
• Gregor Schnakenburg and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 814–824, doi:10.3762/bjoc.10.77

• hexacyanoferrate then afforded diamide 24 in moderate yield [38]. Its subsequent chlorination with a mixture of phosphorous pentachloride and phosphoryl chloride furnished dichloride 25 in quantitative yield [38]. Finally, two-fold Suzuki cross-coupling of 25 with 2,6-dimethoxyphenylboronic acid (26) derived from

Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines

• Jian-bo Xie,
• Jian Luo,
• Timothy R. Winn,
• David B. Cordes and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 746–751, doi:10.3762/bjoc.10.69

• the treatment of multiple myeloma and mantle cell lymphoma [21]. This product is usually synthesized in three representative processes: (1) to use (1S,2S,3R,5S)-(+)-2,3-pinanediol as the chiral auxiliary for the addition reaction followed by chlorination and amination [14][15]; (2) to perform copper

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• catalysis; chlorination; fluorination; organocatalyst; organo-fluorine; Introduction Fluorinated organic molecules are of considerable interest in pharmaceutical and agricultural chemistry owing to the unique properties of the fluorine atom [1][2]. These compounds, especially with one or more fluorinated

• α-chloro-α-fluoro-β-keto esters via the sequential chlorination–fluorination of β-keto esters with the Cu(II) complex of SPYMOX [9], a spiro chiral oxazoline ligand developed by our research group [9][10][11][12]. In that study, we succeeded in determining the absolute stereochemistry of the α

Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis

• Tao Wang,
• Patrick Rabe,
• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2767–2777, doi:10.3762/bjoc.9.311

• diazonium salt followed by a Sandmeyer reaction resulted in 4b (61% over two steps). The isomer 4c was efficiently prepared by double methylation of 2-chlororesorcinol (8) with potassium carbonate and methyl iodide in acetone (88%), while 4f was obtained by chlorination of dimethoxybenzene 9 with

• followed by methylation yielded 48% of 10k. Chlorination of veratrole (5) with two equivalents of benzyltrimethylammonium tetrachloroiodate resulted in 10d (45%), while the same procedure starting from 1,4-dimethoxybenzene gave access to 10j (38%). The NMR spectroscopic data and results of GC–MS analyses

• dichlorodimethoxybenzene (10b or 10k) can arise by a second chlorination from the monochlorodimethoxybenzene (4b or 4f, respectively), suggesting that in both organisms the sets of chlorinated compounds arise via one and the same biosynthetic pathway. Known structurally related compounds from fungi are drosophilin A (19

New syntheses of 5,6- and 7,8-diaminoquinolines

• Maroš Bella and
• Viktor Milata

Beilstein J. Org. Chem. 2013, 9, 2669–2674, doi:10.3762/bjoc.9.302

• .9.302 Abstract The synthesis of 5,6- and 7,8-diaminoquinoline derivatives starting from angularly annelated selenadiazoloquinolones is presented. Simple chlorination of the pyridone ring followed by reductive deselenation of the 1,2,5-selenadiazole ring afforded novel 4-chloro-o-diaminoquinolines

• . Dechlorination of 4-chloro-7,8-diaminoquinoline gave 7,8-diaminoquinoline hydrochloride which was successfully employed as starting material in the synthesis of condensed nitrogen heterocycles. Keywords: chlorination; deselenation; nitrogen heterocycles; o-diaminoquinolines; selenadiazoloquinolones

• -benzoselenadiazole skeleton while the pyridine ring can be obtained by transformation of the pyridone core [15]. The synthesis of 7,8-diaminoquinoline (3) starting from selenadiazolo[3,4-h]quinolone 1 is depicted in Scheme 1. In the first step, the aromatization of the pyridone ring by chlorination with POCl3 in DMF

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

• 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

An approach towards azafuranomycin analogs by gold-catalyzed cycloisomerization of allenes: synthesis of (αS,2R)-(2,5-dihydro-1H-pyrrol-2-yl)glycine

• Jörg Erdsack and
• Norbert Krause

Beilstein J. Org. Chem. 2013, 9, 1936–1942, doi:10.3762/bjoc.9.229

• ] (Scheme 4). This protection step was carried out in order to avoid dehydrogenation or chlorination of the secondary amine in the subsequent oxidation steps [64][65]. Acetal cleavage under mild protic conditions furnished the hydroxycarbamate, which underwent two-step oxidation with Dess–Martin periodinane