Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• 4-ethoxybenzaldehyde was condensed with diacetyl monoxime under acidic conditions. The resulting oxazole N-oxide 9 was converted to the chloromethyloxazole 10 via selective chlorination with phosphorous oxychloride in good yield. Addition of thioglycolic acid led to the carboxylic acid 11, which was

Synthesis of 2,3-dihydronaphtho[2,3-d][1,3]thiazole-4,9-diones and 2,3-dihydroanthra[2,3-d][1,3]thiazole-4,11-diones and novel ring contraction and fusion reaction of 3H-spiro[1,3-thiazole-2,1'-cyclohexanes] into 2,3,4,5-tetrahydro-1H-carbazole-6,11-diones

• Lidia S. Konstantinova,
• Kirill A. Lysov,
• Ljudmila I. Souvorova and
• Oleg A. Rakitin

Beilstein J. Org. Chem. 2013, 9, 577–584, doi:10.3762/bjoc.9.62

• %, respectively). Sulfur monochloride is known as a powerful chlorinating agent for chlorination of aromatic and heteroaromatic compounds [14][15]. In an attempt to increase the sulfurating ability of S2Cl2 the complex 8 obtained from S2Cl2 and 2 equiv of DABCO [16] was used. We have recently shown that this

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• biomacromolecules at high concentrations of strong acids, a polystyrene resin was chosen that contains a tritylchloride linker. The resin was obtained by treatment of Merrifield resin with p-hydroxytriphenylmethyl alcohol and subsequent chlorination [49][50]. This tritylchloride linker allowed a mild cleavage of

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• pyridine 16, which was isolated in 61% yield. Further deprotection of the primary alcohol with TBAF followed by chlorination with thionyl chloride finally gave the desired chloromethylpyridine 17, an intermediate used for the preparation of sarizotan 19 at Merck KGaA by coupling of this pyridine fragment

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• chlorination of cyclohexane (72) with sulfuryl chloride under 15 W black-light irradiation (Scheme 23); however, the reaction was relatively inefficient and productivity was low (0.18 mmol/h) [75]. A biphasic photocyanation of pyrene (74, Scheme 24) was shown to be efficient in a polymer microchannel reactor

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• reported the use of a mutant of A. pretiosum blocked in Asm12 (chlorination) and Asm21 (carbamoylation) and therefore producing proansamitocin (2) in good yield (up to 106 mg/L of fermentation broth) [17]. Additionally, we isolated small amounts of O-methyl proansamitocin 7 (2.3 mg/L), 10-epi

• (Scheme 1). While examining the fermentation extract for byproducts we were able to identify two new metabolites, 15 and 16. Formation of compound 15 can be traced back to inefficient chlorination, a phenomenon that we have encountered before in other feeding experiments with proansamitocin [25]. More

• File 1). Fermentation products, proansamitocin (2) and derivatives 7–9, of the Asm12 and Asm21-blocked (chlorination, carbamoylation) mutant strain A. pretiosum Δasm12/21 (yields given as isolated product per volume of fermentation broth) [17]. Summary of ansamitocin biosynthesis and structure of the

Regioselective chlorination and bromination of unprotected anilines under mild conditions using copper halides in ionic liquids

• Han Wang,
• Kun Wen,
• Nurbiya Nurahmat,
• Yan Shao,
• He Zhang,
• Chao Wei,
• Ya Li,
• Yongjia Shen and
• Zhihua Sun

Beilstein J. Org. Chem. 2012, 8, 744–748, doi:10.3762/bjoc.8.84

• Science, Shanghai, 201620, China 10.3762/bjoc.8.84 Abstract By using ionic liquids as solvents, the chlorination or bromination of unprotected anilines at the para-position can be achieved in high yields with copper halides under mild conditions, without the need for potentially hazardous operations such

• as supplementing oxygen or gaseous HCl. Keywords: halogenation; ionic liquids; oxydation; regioselectivity; solvent effects; Introduction Chlorination and bromination of aromatic rings are classical and widely performed transformations, which are useful in many multistep organic-synthesis

• procedures. Regioselectivity with electron-rich substrates such as aniline will predominantly produce para- and ortho-substitutions. However, chlorination or bromination of aniline derivatives is often performed with protected anilines. This increases both the cost of synthesis and the environmental impact

Synthesis of functionalized macrocyclic derivatives of trioxabicyclo[3.3.0]nonadiene

• Sabine Leber,
• Gert Kollenz and
• Curt Wentrup

Beilstein J. Org. Chem. 2012, 8, 738–743, doi:10.3762/bjoc.8.83

• concave, axially chiral [1], bridged bisdioxine diacid dichloride 3 is obtained by acid hydrolysis and subsequent chlorination of the surprisingly stable α-oxoketene 2, itself obtained by dimerization of dipivaloylketene (1) (Scheme 1) [2][3]. The concave structure of 3 and its derivatives together with

• dipivaloylketene (1), which slowly dimerizes to the dimeric oxoketene 2 at room temperature [2][3]. Hydrolysis and subsequent chlorination with thionyl chloride afforded the bisdioxine diacid dichloride 3 [3]. 4,4’-(2-Nitro-1,4-phenylene)bis(4-oxabutanol) (7): Diol 6 was prepared according to the literature [18

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• nitrile oxides involves the dehydration of primary nitro compounds [21]. Aryl nitrile oxides are more commonly prepared by chlorination of aldoximes followed by dehydrohalogenation of the resulting hydroximoyl chlorides, or by direct oxidative dehydrogenation of the aldoximes (Scheme 2) [17]. While the

• chemical shift of the C(H)=N proton [34]. Attempted methods for the chlorination of aryl aldoximes to aryl hydroximoyl chloride include the use of N-chlorosuccinimide [35], chloramine-T [36], biphasic sodium hypochlorite [37][38], and tert-butyl hypochlorite [39]. These methods led to either no reaction or

Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of “super-trifluoromethyl” arene chemistry and its industry

• Teruo Umemoto,
• Lloyd M. Garrick and
• Norimichi Saito

Beilstein J. Org. Chem. 2012, 8, 461–471, doi:10.3762/bjoc.8.53

• 1940s. The first step was chlorination of ArCH3 to ArCCl3 with Cl2 and the second step was its conversion to ArCF3 with HF or SbF3 [24][25][26]. A large number of trifluoromethyl arenes are currently produced on a large scale and used in many areas such as medicines, agrochemicals, dyes, materials for

• %) with p-dichlorobenzene (major) and trichlorobenzene (minor), which were formed by cleavage of the C–S bond, in the case of the major byproduct, and further chlorination, in the case of the minor one, during the reaction. The complete removal of the byproducts from 3f was difficult due to similar

• –mass analysis. When the reaction was conducted with the addition of KHF2, the purity greatly increased to 97% (run 5). The occurrence of an intermolecular side chlorination reaction was clearly demonstrated by the experiment of run 6 in which benzene was used as an additive. The distilled product 3b

Organic synthesis using (diacetoxyiodo)benzene (DIB): Unexpected and novel oxidation of 3-oxo-butanamides to 2,2-dihalo-N-phenylacetamides

• Wei-Bing Liu,
• Cui Chen,
• Qing Zhang and
• Zhi-Bo Zhu

Beilstein J. Org. Chem. 2012, 8, 344–348, doi:10.3762/bjoc.8.38

• (Scheme 2). To the best of our knowledge, there are several reports on chlorination and bromination reactions with PhI(OAc)2 and a halogen source such as TMSBr, lithium halide or pyridinium halide [32][33][34]. Also, there are several reports on the synthesis of difunctionalized acetamide derivatives [35

The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors

• Kimberley A. Roper,
• Heiko Lange,
• Anastasios Polyzos,
• Malcolm B. Berry,
• Ian R. Baxendale and
• Steven V. Ley

Beilstein J. Org. Chem. 2011, 7, 1648–1655, doi:10.3762/bjoc.7.194

• (Table 1, entry 7) to completion, it was found that heating the monolith resulted in the production of an impurity, at 29.7% conversion by 1H NMR (with 64.5% conversion to the bromide). This was identified as 1-(chloromethyl)-4-iodobenzene, i.e., the starting material underwent chlorination rather than

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• acids) [76][77][78] also catalyzed the chlorination of β-ketoesters with N-chlorosuccinimide or N-chlorosulfonamides as halogenating agents [43]. The Lewis acid catalyzed halogenations of β-ketoesters present an interesting alternative to either radical or neutral noncatalyzed reaction modes. Catalytic

• (Table 3). Results for either fluorination (→6-F) with F–TEDA or the more soluble reagent NFSI (N-fluorobenzenesulfonimide) and NCS (N-chlorosuccinimide) for chlorination [43] (→6-Cl) are displayed in Table 3. Above ambient temperature, increasing temperatures give lower selectivity (Table 3, entries 1–3

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents

• Paul Knochel,
• Matthias A. Schade,
• Sebastian Bernhardt,
• Georg Manolikakes,
• Albrecht Metzger,
• Fabian M. Piller,
• Christoph J. Rohbogner and
• Marc Mosrin

Beilstein J. Org. Chem. 2011, 7, 1261–1277, doi:10.3762/bjoc.7.147

• yield, as well as the sPLA2 inhibitor 123, in a short reaction sequence (Scheme 19) [46]. Using TMPMgCl·LiCl (41), it is possible to prepare fully substituted indoles, such as 128 (Scheme 20) [47]. Thus, starting from the aniline 124, an ortho-directed chlorination with N-chlorosuccinimide at 90 °C

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

• replaced by an N-acylated amide which is suggested to mimic the C-terminus of angiotensin II [49]. The imidazole ring of losartan, an antihypertensive and angiotensin II blocker is formed in a condensation reaction between valeroamidine 160 and dihydroxyacetone [50]. It was found that direct chlorination

• of the imidazole 162 also forms the dichlorination product 164 (as shown in Scheme 33) with formaldehyde as a by-product which proved difficult to suppress and made purification of the reaction mixture problematic. Hence, a sequence involving silyl protection, chlorination and deprotection was

A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

• Benedikt Sammet,
• Mathilde Brax and
• Norbert Sewald

Beilstein J. Org. Chem. 2011, 7, 243–245, doi:10.3762/bjoc.7.32

• tolerated. Both the methoxy and the chloro substituent are required for full biological activity [1][2][3][4]. The previously published synthetic route to unit B precursor 4 involves a three-step modification of D-tyrosine by chlorination, protecting group introduction and double methylation followed by a

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

• chains have been limited to trifluoromethylated compounds. This was due to the unique preparation (at that time) of such compounds by means of two consecutive reaction steps: the chlorination of the side chain followed by replacement of the chlorine atoms by fluorine. This procedure enabled only the

• chlorination with only minor amounts of bis-(CF3S) products (Scheme 12). Aryl magnesium [78] and -mercury [79] compounds have been employed for the introduction of CF3S groups. Such reactions proceed in ether or THF at low temperatures; however, the yields of aryltrifluoromethyl sulfides do not exceed 50–60

Synthesis of bis(3-{[2-(allyloxy)ethoxy]methyl}-2,4,6-trimethylbenzoyl)(phenyl)phosphine oxide – a tailor-made photoinitiator for dental adhesives

• Norbert Moszner,
• Iris Lamparth,
• Jörg Angermann,
• Urs Karl Fischer,
• Frank Zeuner,
• Thorsten Bock,
• Robert Liska and
• Volker Rheinberger

Beilstein J. Org. Chem. 2010, 6, No. 26, doi:10.3762/bjoc.6.26

• . The identity of compound 4 was established by an independent synthesis of the compound from 2-(allyloxy)ethanol and 3-(chloromethyl)-2,4,6-trimethylbenzoyl chloride 3, prepared by chlorination of 3-(chloromethyl)-2,4,6-trimethylbenzoic acid with thionyl chloride. In the third step, the

• in acetonitrile (10−3 mol/L). DSC-plot of a mixture of Bis-GMA (42 wt %), UDMA (37 wt %), TEGDMA (21 wt %) and the PI WBAPO or BAPO. Bisacylphosphine oxide with improved solubility in polar solvents. Etherification of 3-(chloromethyl)-2,4,6-trimethylbenzoic acid and chlorination of 1. Rearrangement

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

• Magnus Rueping and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2010, 6, No. 6, doi:10.3762/bjoc.6.6

• , lower toxicity, and the fact that only stoichiometric amounts of water are generated as the side product the FC alkylation with benzyl-, allyl- and propargyl alcohols presented a first and important step toward an environmental friendly process. In 1986, Uemura et al. investigated the chlorination of

• authors explained this observation with a chlorination of 1-phenylethanol 1 and subsequent FC alkylation of the formed benzyl chloride and toluene. However, more surprisingly the reaction yield could be improved to 93% if only catalytic amounts (10 mol%) of TeCl4 were present (Scheme 3) [2]. Although the

Palladium- catalyzed cross coupling reactions of 4-bromo- 6H-1,2-oxazines

• Reinhold Zimmer,
• Elmar Schmidt,
• Michal Andrä,
• Marcel-Antoine Duhs,
• Igor Linder and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2009, 5, No. 44, doi:10.3762/bjoc.5.44

• chlorination of 6H-1,2-oxazines 1a,b by addition of chlorine and subsequent base-induced dehydrochlorination. The expected 4-chloro-6H-1,2-oxazines 6a,b were obtained in good yields. In analogy to the aforementioned bromination, the chlorination of 3-phenyl-6H-1,2-oxazine 1a also led to dihalogenation

• . HRMS (80 eV, 40 °C) m/z calcd for C12H1179Br2NO2: 358.9157; found: 358.9160. Chlorination of 6H-1,2-oxazine 1b, typical procedure Chlorine gas was passed into diethyl ether (28 mL) at −30 °C until the solution became dark yellow. Then, 6H-1,2-oxazine 1b (0.200 g, 1.00 mmol) was added and the reaction

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• also employed in a similar flow system for the asymmetric α-chlorination of acid chlorides (Scheme 7) [31][32]. This cinchona alkaloid derivative served the dual purpose of dehydrohalogenation and asymmetric induction, and was found to be reusable at least up to 100 times, after regeneration each time

• by flushing with a solution of i-PrNEt2 in THF. A diastereoselective synthesis of the metalloproteinase inhibitor BMS-275291 24 was developed using this column-based flow approach, with this α-chlorination reaction as a key step (Scheme 7) [32]. The Michael addition of indanone 26 to methyl vinyl

• flow. Asymmetric synthesis of ß-lactams. α-Chlorination of acid chlorides in flow. Asymmetric Michael reaction in continuous flow. Enantioselective addition of Et2Zn to benzaldehyde using monolithic chiral amino alcohol. Continuous-flow hydrolytic dynamic kinetic resolution of epibromohydrin (32

Synthesis of methylenebisamides using CC- or DCMT- activated DMSO

• Qiang Wang,
• Lili Sun,
• Yu Jiang and
• Chunbao Li

Beilstein J. Org. Chem. 2008, 4, No. 51, doi:10.3762/bjoc.4.51

• on the chlorination [10] and etherification [11] of benzyl alcohols and from other references [12][13][14], we believe the reaction between 2,4,6-trichloro[1,3,5]triazine (cyanogen chloride, or CC) and DMSO produces a reactive sulfonium salt intermediate. Therefore, it was of interest to study the

Ru-catalyzed dehydrogenative coupling of carboxylic acids and silanes - a new method for the preparation of silyl ester

• Guo-Bin Liu and
• Hong-Yun Zhao

Beilstein J. Org. Chem. 2008, 4, No. 27, doi:10.3762/bjoc.4.27

• chlorination of silanes, either with chlorine gas [7] or with hydrochloric acid under Pd/C catalysis [25][26], the synthesis of silyl esters from the corresponding silanes requires two reaction steps. Some newer synthetic protocols to silyl esters have been developed and a lot of literature focuses itself on

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• works well with electron-deficient anisoles cannot be applied to anisole itself. In fact, halogen attack on the phenyl ring proceeds more easily than radical chlorination of the methyl group. Louw and Franken could show that with elemental chlorine, photostimulated in refluxing tetrachloromethane

• , essentially trichloromethylanisole is obtained [20]. The fluorination of the trichloromethyl ether succeeds then easily as shown above. The chlorination/fluorination sequence described above can be simplified by producing the trichloromethyl aryl ethers without isolation and through in situ conversion into

• developed an approach based on the readily accessible, although highly toxic aryl chlorothionoformates 1. They can be cleanly converted by chlorination into trichloromethyl aryl ethers [17]. This step is then followed by fluorination using antimony trifluoride and a catalytic amount of antimony

Development of potential manufacturing routes for substituted thiophenes – Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for a new family of 2,6-dihaloaryl 1,2,4-triazole insecticides

• John W. Hull Jr.,
• Duane R. Romer,
• David E. Podhorez,
• Mezzie L. Ash and
• Christine H. Brady

Beilstein J. Org. Chem. 2007, 3, No. 23, doi:10.1186/1860-5397-3-23

• /debromination procedure developed for 3-methylthiophene gave 2,4-dibromo-3-methylthiophene. Carboxylic acid functionality was then introduced either by a Grignard metallation followed by carbonation with CO2, or by a palladium catalyzed carbonylation procedure under CO pressure. The vapor phase chlorination of

• thiophene ring without isolation of the tribromo intermediate 6. The final low-melting acid chloride 1 was readily purified by vacuum distillation on a 250 g laboratory scale to remove a small amount of tar and gave 1 as a light-yellow colored product. Vapor Phase Chlorination Studies. Routes to 3,4,5

• from 2-chloromethyl-3,4,5-trichlorothiophene. [21] However, since 2-thiophenecarbonitrile 20 was commercially available, we investigated the vapor phase chlorination of this starting material as a potential convenient manufacturing route to 3 that could be carried out on a multi-Kg scale (Scheme 3