Transition-metal-free one-pot synthesis of alkynyl selenides from terminal alkynes under aerobic and sustainable conditions

• Adrián A. Heredia and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2017, 13, 910–918, doi:10.3762/bjoc.13.92

• inert gas atmosphere the phenyl selenide anion remains unoxidized and can be trapped by methylation. Furthermore, under the current reaction conditions no reduction of Se–Se bonds by the used base t-BuOK as proposed in the literature takes place (Scheme 5B) [44]. To account for the results obtained we

DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

• Johnny N. Naoum,
• Koushik Chandra,
• Dorit Shemesh,
• R. Benny Gerber,
• Chaim Gilon and
• Mattan Hurevich

Beilstein J. Org. Chem. 2017, 13, 806–816, doi:10.3762/bjoc.13.81

• 10.3762/bjoc.13.81 Abstract Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of

• an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein

• proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three Nα-methylation sites that could not be synthesized using the previously described state-of-the-art methods. Keywords: N-methylation; nucleophilic addition; solid phase; somatostatin; sulfonylation; Introduction

Synthesis of ribavirin 2’-Me-C-nucleoside analogues

• Fanny Cosson,
• Aline Faroux,
• Jean-Pierre Baltaze,
• Jonathan Farjon,
• Régis Guillot,
• Jacques Uziel and
• Nadège Lubin-Germain

Beilstein J. Org. Chem. 2017, 13, 755–761, doi:10.3762/bjoc.13.74

• . For the attempted methylation of the 2’-position different conditions were tested (Table 1). As described for other nucleosides [23], the use of MeLi led to compound 13b obtained by an attack from the α-face even if this proceeded with a very low yield (7%). The use of MeMgBr gave an almost 1:1

• mixture by α- and β-attack; this second one can be explained by a magnesium complexation with the base. More interestingly, the methylation proceeded stereoselectively leading to 13b in 87% yield when trimethylaluminium was used [24]. The stereochemical outcome of this reaction was determined by selective

• fluorinated analogue 3 required a more complicated pathway. This included the selective protection of the 3’,5’ positions, the stereoselective methylation and the fluorination of the 2’ position. The synthesized compounds are currently investigated for their antiviral activities. Experimental Experimental

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif

• Tetiana Bykova,
• Nawaf Al-Maharik,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2017, 13, 728–733, doi:10.3762/bjoc.13.72

• elimination. Results and Discussion The Birch reduction of benzonitrile 6 followed by in situ methylation with iodomethane generated cyclohexadiene 7 as previously described [13][14]. Cyclohexadiene 7 was then subjected to a double epoxidation protocol using mCPBA [1][11][15][16]. This generated three

Substitution of fluorine in M[C₆F₅BF₃] with organolithium compounds: distinctions between O- and N-nucleophiles

• Anton Yu. Shabalin,
• Nicolay Yu. Adonin and
• Vadim V. Bardin

Beilstein J. Org. Chem. 2017, 13, 703–713, doi:10.3762/bjoc.13.69

• and 1:0.18, respectively. Nucleophilic methylation of 1-Li also results in a related value 1:(0.10–0.13) (Table 1, Table 2), i.e., the isomer ratio remains constant within the experimental error. Salt 1-N exists in DME as solvent-separated ion pair. Because of this the fluorine atom of BF3 is more

Derivatives of the triaminoguanidinium ion, 5. Acylation of triaminoguanidines leading to symmetrical tris(acylamino)guanidines and mesoionic 1,2,4-triazolium-3-aminides

• Jan Szabo,
• Julian Greiner and
• Gerhard Maas

Beilstein J. Org. Chem. 2017, 13, 579–588, doi:10.3762/bjoc.13.57

• either symmetrical N,N’,N’’-tris(N-acyl-N-benzylamido)guanidines 6 or mesoionic 4-amino-1,2,4-triazolium-3-hydrazinides 7. The latter were converted into 1,2,4-triazolium salts by protonation or methylation at the hydrazinide nitrogen atom. Neutral 1,2,4-triazoles 10 were obtained by catalytic

• acid gave rise to the 3-hydrazinyl-1,2,4-triazolium chlorides 8b,c (Scheme 4) as well-crystallizing colorless or pale yellow solids. Analogously, the reaction of 7b with methyl triflate afforded the 3-(1-methylhydrazinyl)-1,2,4-triazolium triflate 9b by methylation of the exocyclic aminide nitrogen

• atom of the betaine; in contrast to other 1,2,4-triazolium-3-aminides [21][23], methylation with methyl iodide was not successful. Salt 9b forms colorless hygroscopic crystals which assume an orange surface color when exposed to air for some minutes. The structures of 1,2,4-triazolium salts 8b and 9b

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

• Nikolay V. Lukashev,
• Gennadii A. Grabovyi,
• Dmitry A. Erzunov,
• Alexey V. Kazantsev,
• Gennadij V. Latyshev,
• Alexei D. Averin and
• Irina P. Beletskaya.

Beilstein J. Org. Chem. 2017, 13, 564–570, doi:10.3762/bjoc.13.55

• [8]. However, we did not observe complexation of pincer ligands 5c–e with inorganic or organic anions by NMR titration. The attempt to increase the anion affinity for the ligands by exhaustive alkylation of amino groups with trimethyloxonium tetrafluorborate led exclusively to methylation of hydroxy

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• valine and its C-methylation with methionine and the polyol carbons are derived from a glycolysis intermediate, possibly hydroxymalonyl-ACP. Keywords: biosynthesis; butyrolactol; contiguous polyol; hydroxymalonyl-ACP; polyketide; Streptomyces; tert-butyl; Introduction Actinomycetes produce structurally

• hydroxymalonyl-ACP formation in the zwittermicin biosynthesis (ZmaN, ZmaD, ZmaG, and ZmaE) (Figure 6) [24] are present in the downstream of the butyrolactol PKS cluster. Genes coding for O-methyltransferase homologues responsible for O-methylation of hydroxymalonyl-ACP were not found near the cluster

• -27). The origin of the tert-butyl group in polyketide biosynthesis is still unknown, however, the tert-butyl functionality of bottromycin and polytheonamide was shown to be produced by radical C-methylation of the isopropyl group of valine [31][32]. By analogy, the tert-butyl portion of 1 was most

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• catalyst that is often overlooked and it is used merely as a support for other catalysts [39][40][41][42][43]. The use of γ-alumina for the methylation of aniline with dimethyl carbonate has been reported [44]. In this paper, we chose to study the intramolecular and intermolecular alkylation of amino

• led to an increase in the rate of cyclisation and methylation which then allowed for faster flow rates to be used under this operating temperature whilst still maintaining the same yield of 2b (Table 1, entry 1). Hence, three times the amount of material could be processed in the same time using this

• conditions afforded the desired N-methylpyrrolidine (4) in 95% yield. Extending the alkyl chain using 6-amino-1-hexanol (5), however, favoured methylation over intramolecular cyclisation as only 20% of the cyclised product 6 was observed. The major product was 6-(dimethylamino)-1-methoxyhexane (7, Scheme 2

O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside

• Roman Sommer,
• Dirk Hauck,
• Annabelle Varrot,
• Anne Imberty,
• Markus Künzler and
• Alexander Titz

Beilstein J. Org. Chem. 2016, 12, 2828–2833, doi:10.3762/bjoc.12.282

• -methylated carbohydrate ligands was demonstrated (e.g., 2, Figure 1). O-Methylation of carbohydrates is a rare modification, but widespread in nature as it has been observed in bacteria, protozoa, animals and plants but not in mammals [29][30]. Besides fungal and animal tectonins that recognize O-methylated

• glycans in pathogens or parasites, numerous other lectins recognize such O-alkylated ligands, e.g., the pilus adhesin from Pseudomonas aeruginosa PAK [31] or PapG from Escherichia coli [32]. In contrast, methylation of lectin ligands can also prevent binding, as observed with O-methylated fucose and

• mannose for P. aeruginosa LecB or B. cenocepacia BC2L-A [33]. Thus, O-methylation of glycans can tune biological recognition events. In contrast to the literature reports on the synthesis of unmodified seleno glycosides, the synthesis of selectively O-alkylated derivatives to study their interactions with

Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

• Mathew J. Jones,
• Ricardo Callejo,
• Alexandra M. Z. Slawin,
• Michael Bühl and
• David O'Hagan

Beilstein J. Org. Chem. 2016, 12, 2823–2827, doi:10.3762/bjoc.12.281

• relationship. Results and Discussion The preparation of diketones 5a–c and bis-dithianes 6a–c was carried out by previously described methods. The dimethyl-diketone 5c was prepared by double methylation of 5b [25] (Scheme 2). Two different O-alkylated products 7 and 8 were also obtained as significant

A versatile route to polythiophenes with functional pendant groups using alkyne chemistry

• Xiao Huang,
• Li Yang,
• Rikard Emanuelsson,
• Jonas Bergquist,
• Maria Strømme,
• Martin Sjödin and
• Adolf Gogoll

Beilstein J. Org. Chem. 2016, 12, 2682–2688, doi:10.3762/bjoc.12.265

• carbon of the pendant group precursors, with yields of 61% (9), 82% (10) and 65% (12), respectively. Methylation of bipyridyl intermediate 10 by methyl iodide produced viologen derivative 11 after exchanging the iodide for the PF6− anion. For the methylation step drying of both the reactants 10 and

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• correlation between the percentages of cholesterol extraction and the methylation degree of the CDs. This effect was clearly independent of the membrane composition. The expression levels of ABCA1 and ABCG1, as well as the cholesterol efflux to ApoA-I and HDL, were reduced due to cholesterol-methylated β-CD

A direct method for the N-tetraalkylation of azamacrocycles

• Andrew J. Counsell,
• Angus T. Jones,
• Matthew H. Todd and
• Peter J. Rutledge

Beilstein J. Org. Chem. 2016, 12, 2457–2461, doi:10.3762/bjoc.12.239

• ][30], the simplest N-tetraalkyl cyclam derivative, this class of compounds has been extensively investigated [2]. While the N-tetramethyl derivative is readily accessed by treating cyclam with formaldehyde and formic acid [29], this transformation (the Eschweiler–Clarke methylation) [31] is not

Elongated and substituted triazine-based tricarboxylic acid linkers for MOFs

• Arne Klinkebiel,
• Ole Beyer,
• Barbara Malawko and
• Ulrich Lüning

Beilstein J. Org. Chem. 2016, 12, 2267–2273, doi:10.3762/bjoc.12.219

• ). In order to synthesize the respective methoxy compound 5c, commercially available 3-hydroxybenzoic acid (10) was used as starting material (Figure 6). Bromination introduced a bromine atom into the 4 position (11) [19], then the phenol was turned into its methyl ether. This methylation can be

• ” methylation [25] could find a remedy. Steric repulsion between ortho-hydrogen atoms in benzene-1,3,5-tribenzoic acid (BTB) leads to a non-planar structure (left). The exchange of CH units by nitrogen atoms in the central six-membered ring allows a planar structure: 1,3,5-triazine-2,4,6-tribenzoic acid (TATB

Isosorbide and dimethyl carbonate: a green match

• Fabio Aricò and
• Pietro Tundo

Beilstein J. Org. Chem. 2016, 12, 2256–2266, doi:10.3762/bjoc.12.218

• other noxious methylating agents in methylation reactions [24][25][26][27][28][29][30][31][32][33][34][35]. The reactions between the bio-based chemicals D-sorbitol or isosorbide and DMC, are very appealing as they encompass the preparation, as well as the transformation of a renewable resource into

• ) that has potential application as green solvent substitute of high boiling polar solvents. Recently DMI has also appeared as component in the formulation of deodorants [87]. Methylation of isosorbide has been investigated both at reflux and in autoclave conditions via DMC chemistry. It should be

• mentioned that generally methylation of secondary alcohols via DMC chemistry requires high temperatures (>150 °C) and was never obtained in high yield due to the formation of elimination products [88]. However, isosorbide, which incorporates in its backbone secondary hydroxy groups, was quantitatively

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

• Wiesława Perlikowska,
• Remigiusz Żurawiński and
• Marian Mikołajczyk

Beilstein J. Org. Chem. 2016, 12, 2234–2239, doi:10.3762/bjoc.12.215

• at C-5. In fact, 1a and 1c were obtained through a two-step sequence starting with the methylation of (−)-1a and (+)-1c followed by a one-pot Mitsunobu esterification–hydrolysis as shown in Scheme 6. In detail, treatment of rosaprostols (−)-1a and (+)-1c with diazomethane gave the corresponding

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• replaced by the apramycin resistance cassette aac(3)IV [57] using RedET recombineering of pYJ2 in E. coli to generate BAC clone pML1. Tri-parental mating was used [58] to introduce pML1 into E. coli ET12567, a triply methylation-deficient strain that provides higher efficiency of conjugation into many

•  2c and d). Also, it appears that the heterologous host can supply appropriate, as yet unidentified, enzymes to catalyse methylation of the guanidino group and to attach the malonyl sidechain to the hydroxy group at C-23/C-25. Presumably, these are enzymes acting in primary metabolism and therefore

Ionic liquids as transesterification catalysts: applications for the synthesis of linear and cyclic organic carbonates

• Maurizio Selva,
• Alvise Perosa,
• Sandro Guidi and
• Lisa Cattelan

Beilstein J. Org. Chem. 2016, 12, 1911–1924, doi:10.3762/bjoc.12.181

• , P; n = 4, 6, 8, Ph), obtained by the methylation of trialkylphosphines or -amines with nontoxic DMC (Scheme 3, top) [34][35]. Such methyl carbonate onium salts are versatile platforms as they allow access to a number of ionic liquids via anion-metathesis reactions, which produce only CH3OH and CO2

• organocatalysts offers several practical advantages: (i) the synthesis of [P8881][CH3OCO2] involves a halide-free methylation of a trialkyl phosphine with nontoxic DMC, (ii) acetate and phenolate salt derivatives could be obtained from [P8881][CH3OCO2] through a chlorine-free metathesis with acetic acid and

• carbonates obtained through transesterification using phosphonium salts as catalysts. The transesterification of diethyl oxalate (DEO) with phenol catalyzed by MoO3/SiO2. Transesterification of a triglyceride (TG) with DMC for biodiesel production using KOH as the base catalyst. Top: Green methylation of

From supramolecular chemistry to the nucleosome: studies in biomolecular recognition

• Marcey L. Waters

Beilstein J. Org. Chem. 2016, 12, 1863–1869, doi:10.3762/bjoc.12.175

• thus studied the influence of lysine methylation and the significance of the positive charge in our β-hairpin model systems [23][24], and then moved into studying the actual protein–peptide interaction as well, providing the first definitive evidence that cation–π interactions provided the dominant

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• mechanism is reminiscent of the formation of a tetrahydropyridine ring by the berberine bridge enzyme in plant alkaloid biosynthesis. It starts with S-adenosyl-L-methionine (SAM)-dependent methylation of the secondary hydroxy group in 81 by the O-methyltransferase Leu14 (Scheme 14a) [71][72][73][74

• lactone that is decarboxylated towards the xanthone [103]. Studies with recombinant AflM and a lack of isolatable intermediates however made it clear that the order of steps in demethylsterigmatocystin (107) formation needs to be carefully re-evaluated [100]. Methylation by an O-methyltransferase and

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

• or O-nonaflation led to functionalized pyridine derivatives. Scheme 1 illustrates this sequence with the synthesis of two 2,2´-bipyridine derivatives 4a or 5b that were obtained by employing picolinic acid chloride for the N-acylations followed by O-methylation with methyl iodide or by O-nonaflation

Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp² C–H and sp³ C–H bonds

• Nivesh Kumar,
• Santanu Ghosh,
• Subhajit Bhunia and
• Alakesh Bisai

Beilstein J. Org. Chem. 2016, 12, 1153–1169, doi:10.3762/bjoc.12.111

• methylation can be done in the presence of 1.2 equivalents of KOt-Bu and 1.1 equivalents of methyl iodide. This was accompanied with an oxidative coupling using 1.2 equivalents of KOt-Bu and iodine to afford the desired product in 65% yield (Table 1, entries 1 and 2). Optimization studies in search of

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• miuraenamide A (31) the absolute configuration was determined. Marfey´s method was employed to show that L-alanine and N-methyl-D-tyrosine are present. Furthermore, after acid hydrolysis, methylation and application of modified Mosher´s method the absolute configuration at the oxygen bearing C-9 was deduced as