Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• -1,2,4-triazolo[1,5-a]pyridine derivatives by H/D exchange of 1-aminopyridinium cations followed by the reaction with acetylenes and nitriles. Results and Discussion N-Aminopyridinium salts are easily available via direct N-amination of parent pyridines. Salt 1a was prepared by N-amination of pyridine

• with hydroxylamine-O-sulfonic acid followed by the reaction with HBF4 according to a previously described method [30]. Salts 1b,c were prepared by direct N-amination of the corresponding pyridines with O-mesitylsulfonylhydroxylamine. In view of difficulties in obtaining experimental pKa values of

Exploring endoperoxides as a new entry for the synthesis of branched azasugars

• Svenja Domeyer,
• Mark Bjerregaard,
• Henrik Johansson and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2017, 13, 644–647, doi:10.3762/bjoc.13.63

• ready access to the two lactol isomers 29,30 in quantitative yield (≈1:1 ratio of isomers) [10][22][23]. Lactol isomers 29,30 could potentially serve as precursors for the formation of substituted piperidines via reductive amination or be oxidised to yield lactones or lactam derivatives. Conclusion

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

• )anthraquinones with a series of cations demonstrated their high binding affinity to Cu2+, Al3+, and Cr3+. Keywords: amination; aminocholanes; bile acids; cation complexation; Cu-catalysis; diaminoanthraquinone; Pd-catalysis; Introduction Bile acids are known to ensure vital processes in vertebrate organisms

• macrocycles by Pd-catalyzed Buchwald–Hartwig amination [36]. Though this method is often preferable for the macrocyclization in comparison to classical nucleophilic substitution [28][31], it is limited to bile acid derivatives bearing groups with C(sp2)–Hal bonds. In addition, the use of bile acid moieties

• saturated with hydroxy groups was inconvenient for the syntheses of bis(polyoxamino) derivatives by Pd-catalyzed amination [34][35]. Direct metal-catalyzed arylation of aminocholanes has not yet been employed in the synthesis of cholane-based ligands. Here, we report a new and efficient synthesis of

Highly reactive, liquid diacrylamides via synergistic combination of spatially arranged curing moieties

• Maximilian Maier,
• Magnus S. Schmidt,
• Markus Ringwald and
• Christoph P. Fik

Beilstein J. Org. Chem. 2017, 13, 372–383, doi:10.3762/bjoc.13.40

• ) were measured using an Anton Paar Abbemat 200 refractometer at 20 °C. General procedure for the synthesis of N,N’-diacyl-N,N’-dialkyl-1,4-diamines 1–6 Amination a) Synthesis of 1,4-but-2-enediamine: Potassium carbonate (2.5 equiv) was added to the alkylamine (15 equiv) and cooled to 0–5 °C. The

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

• 10.3762/bjoc.13.36 Abstract The use of γ-Al2O3 as a heterogeneous catalyst in scCO2 has been successfully applied to the amination of alcohols for the synthesis of N-alkylated heterocycles. The optimal reaction conditions (temperature and substrate flow rate) were determined using an automated self

• ., boron salts from reductive amination [4]. Hydrogenation offers a greener approach but is often only applicable to simple substrates due to chemoselectivity issues. An approach that has received much attention recently is the concept of hydrogen borrowing catalysis [5][6][7][8][9][10][11][12][13][14][15

• could be successfully applied to the amination of alcohols, we chose to employ a self-optimising reactor (Figure 1, see Supporting Information File 1 for details) to streamline the optimisation process using 5-amino-1-pentanol (1) as the model substrate and methanol as the alkylating agent (Scheme 1

First DMAP-mediated direct conversion of Morita–Baylis–Hillman alcohols into γ-ketoallylphosphonates: Synthesis of γ-aminoallylphosphonates

• Marwa Ayadi,
• Haitham Elleuch,
• Emmanuel Vrancken and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2906–2915, doi:10.3762/bjoc.12.290

• were prepared by reductive amination of γ-aminophosphonyl ketones using sodium borohydride [41], or by conjugate addition of diethyl methylphosphonite to 2-cyclohexenone followed by Bucherer–Bergs amino acid synthesis [42]. Another synthetic approach for a series of α-fluorinated-γ-aminophosphonates

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• nucleosidation of 4-chloroimidazo[4,5-c]pyridine and 1,2,3,5-tetraacetyl-ß-D-ribofuranose in the presence of chloro acetic acid to yield the corresponding 6-chloro-3-deazapurine nucleoside (Scheme 1) [22]. Subsequent attempts to convert the chlorine atom directly by amination under various conditions failed

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

• Chao Yang,
• Kai Lin,
• Lan Huang,
• Wei-dong Pan and
• Sheng Liu

Beilstein J. Org. Chem. 2016, 12, 2490–2494, doi:10.3762/bjoc.12.243

• synthesis of 9-methoxycarbonylindolo[3,2-a]carbazole derivatives. The key steps in this approach involved an aromatic amination and an oxidative biaryl coupling. Via the present route, indolo[3,2-a]carbazole derivatives are available in 3–4 steps based on commercially available starting materials. Keywords

β-Amino functionalization of cinnamic Weinreb amides in ionic liquid

• Yi-Ning Wang,
• Guo-Xiang Sun and
• Gang Qi

Beilstein J. Org. Chem. 2016, 12, 2372–2377, doi:10.3762/bjoc.12.231

• amides [21][22][23][24][25][26]. Another approach was the direct amination of α,β-unsaturated Weinreb amides by using lithium (S)-N-benzyl-N-α-methylbenzylamide as the nitrogen source [27][28][29]. Recently, a new chiral N-phosphonylimine chemistry was developed by the Li group. By reacting N

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• class of sulfur-containing pro-nucleophiles in a highly enantio- and diastereoselective conjugate addition to nitroalkenes, providing α,α-disubstituted α-mercapto carboxylic acids [5]. Since then, several asymmetric variants using 5H-thiazol-4-ones as nucleophiles have been disclosed; such as amination

Experimental and theoretical investigations into the stability of cyclic aminals

• Edgar Sawatzky,
• Antonios Drakopoulos,
• Martin Rölz,
• Christoph Sotriffer,
• Bernd Engels and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 2280–2292, doi:10.3762/bjoc.12.221

• structures with various applications in medicinal chemistry [20][21]. The syntheses of tetrahydroquinazolines are well described using different approaches: the majority relies on the direct α-amination of o-aminobenzaldehydes with heating or microwave irradiation [22][23][24], by condensation of diamines

• tetrahydroquinazoline core (Scheme 4b). Thus, anthranilic acid was alkylated by reductive amination with acetone and NaBH4 in two steps to yield the isopropyl-substituted derivative 14. The derivative 14 and the commercially available N-phenylanthranilic acid were converted to amides 15a,b under standard conditions

DNA functionalization by dynamic chemistry

• Zeynep Kanlidere,
• Oleg Jochim,
• Marta Cal and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2016, 12, 2136–2144, doi:10.3762/bjoc.12.203

• containing ON1 and four nucleobases in the presence of a DNA-template: a) TC; b) TG; c) TT; d) TA. The chromatograms were performed after reductive amination of the samples (for more details see Supporting Information File 1). Representative HPLC chromatograms obtained using elevated pH, for samples

• collected from first purification step (in Figure 4 marked with dashed line). The samples were collected from the reaction of ON1 and four nucleobases in the presence of a DNA-template: a) TC; b) TG; c) TT; d) TA. The chromatograms were obtained after reductive amination of the samples (for more details see

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• -von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany 10.3762/bjoc.12.176 Abstract Starting from (S)-β-phenylalanine, easily accessible by lipase-catalyzed kinetic resolution, a chiral triamine was assembled by a reductive amination and finally cyclized to form the title compound 10. In the crystals

• reductive amination to form 18 (58%). After removal of the Boc protecting group (quant.), triamine 19 was reacted with dimethyl trithiocarbonate in refluxing nitromethane. The thiourea intermediate was activated in situ by S-alkylation with MeI. Upon further heating the final cyclization occured forming the

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• avoid. However, the desired product 6 can be isolated using basic alumina chromatography. Reductive amination with acetone, mediated by AcOH and NaOAc was also pursued as an alternative strategy [18]. While being much easier to purify due to the elimination of the bis-alkylation product, the yield of

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

• of 3-chloro-1H-pyrrole-2-carboxylic acid (13) using the Vilsmeier reagent [9], followed by further amination to produce 1H-pyrrole-2-carboxamide 14 in good to excellent yield [9]. A reaction mixture of 14 with NaOH, NH4Cl, and NaClO led to the formation of the N-aminopyrrole 15 [11]. The addition of

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• few decades [20][21][22]. General approaches for the synthesis of chiral 3-substituted-3-aminooxindole derivatives include the amination of various 3-monosubstituted oxindoles [23][24][25][26][27] and the nucleophilic addition to ketimines derived from isatin derivatives [28][29][30][31][32][33][34

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

• -phenylpropan-2-one (76% yield) was observed instead. For the amination of benzyl-substituted diketone 1d both of the above utilized methods failed to provide the desired compound 2d. While treatment with ammonium formate exclusively leads to deacetylation of the starting material to 4-phenylbutan-2-one, the

• oxidative coupling of acetylacetone 1a employing iodosylbenzene in the presence of boron trifluoride in methanol [41] followed by the standard amination procedure indeed furnished β-enaminoketone 2i in moderate yield (Scheme 3). This intermediate could be N-acylated via its potassium salt with activated

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• of thiazol-4(5H)-ones as pronucleophiles in asymmetric catalytic reactions has been investigated in the Michael addition reaction to nitroalkenes and α-silyloxyenones, phosphine-catalyzed γ-addition to allenoates and alkynoates, α-amination reactions and iridium-catalyzed allylic substitution

• . 2.2.2 α-Amination reactions. Thiazolones 2 have also been investigated in the α-amination reaction with tert-butyl azodicarboxylate in the presence of the ureidopeptide like catalysts C5 and C8 (Scheme 18) [85]. In these cases better enantioselectivity was observed with catalyst C8, and thiazolones

• mechanism for the C6-catalyzed γ-addition of thiazol-4(5H)-one to allenoates. Adapted from [36], copyright 2015 The Royal Society of Chemistry. Catalytic enantioselective α-amination of thiazolones promoted by ureidopeptide like catalysts C5 and C8 [85]. Iridium-catalized asymmetric allyllation of

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• separated by column chromatography. After debenzylation, the resultant primary amines were connected with amido aldehydes 6 substituted with different moieties R and R' by reductive amination with R being either a hydroxy group or a hydrogen and R' representing an alkyl, allyl, ester or a protected amino

• followed by an azide reduction, Boc protection, saponification of the ester, peptide coupling with the amino acid 17, oxidative cleavage of the double bond to give 18 and an intramolecular reductive amination in order to construct the seven-membered ring. Methylation with subsequent acidic global

• diastereoselectively converted with a Grignard reagent into the amine 53 as a key step of the synthesis [78]. Cbz protection followed by ozonolysis with subsequent reductive amination and hydrogenolysis led to the 1,3-diamine 54. The cyclisation to the guanidine functionality was achieved with the novel

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• , Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China 10.3762/bjoc.12.72 Abstract A highly enantioselective α-amination of 3-substituted oxindoles with azodicarboxylates catalyzed by amino acids-derived chiral phosphine

• tetrasubstituted carbon center have been recognized as core building blocks for the preparation of many biologically active and therapeutic compounds [2][3][4][5][6][7]. As a type of commercially available electrophilic amination reagents, azodicarboxylates have been extensively used in both asymmetric

• organocatalysis and metal catalysis for the construction of this type of structures. For example, Chen et al. reported the first organocatalytic enantioselective amination reaction of 2-oxindoles catalyzed by biscinchona alkaloid catalysts [8]. Zhou [9][10] and Barbas [11][12], have independently reported similar

(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

• desired products in excellent yields and selectivities. In order to broaden the utility of this methodology, the authors reduced the nitro group to an amine. The product was in situ transformed to the tricyclic product 102, through a diastereoselective reductive amination, that controlled the

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• leads to an intermediate α-aminoperoxy structure, which quickly collapses to the oxaziridine 71. Formation of C–X bonds α-functionalisation In two separate reports, Zhou and co-workers demonstrate the use of di-tert-butyl azodicarboxylate 72 (DBAD) in the direct amination of several different substrates

• -amination using β-ICPD. Meng’s cupreidine catalyzed α-hydroxylation. Shi’s biomimetic transamination process for the synthesis of α-amino acids. β-Isocupreidine catalyzed [4 + 2] cycloadditions. β-Isocupreidine catalyzed [2+2] cycloaddition. A domino reaction catalyst by cupreidine catalyst CPD-30. (a

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• Minami Odagi Yoshiharu Yamamoto Kazuo Nagasawa Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city, 184-8588, Tokyo, Japan 10.3762/bjoc.12.22 Abstract An asymmetric α-amination of β-keto esters with azodicarboxylate in the

• presence of a guanidine–bisurea bifunctional organocatalyst was investigated. The α-amination products were obtained in up to 99% yield with up to 94% ee. Keywords: α-amination; bifunctional catalyst; guanidine; hydrogen-bonding catalyst; urea; Introduction Asymmetric α-amination of β-keto esters is an

• particular, catalytic asymmetric α-amination of β-keto esters has been widely explored, using both metal catalysts and organocatalysts [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. We have developed a series of guanidine–bis(thio)urea bifunctional organocatalysts, and have used them in a variety of

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• and dialkylamines, heating with potassium carbonate in DMF gave good results (Table 1, entries 5–9). Finally, the reaction with potassium hydroxide was sluggish even under high temperature (Table 1, entry 10) and for amination, heating with aqueous ammonia solution in DMSO in a pressure vessel was

• oxidative nucleophilic substitution for hydrogen reactions (ONSH) with organolithium or magnesium species or in vicarious nucleophilic substitution reactions (VNS) with carbon, oxygen or nitrogen nucleophiles [29]. VNS is a very powerful process for selective alkylation, amination and hydroxylation of

• the use of liquid ammonia as a co-solvent (Table 2, entry 5). For direct amination 1,1,1-trimethylhydrazinium iodide was used, which upon deprotonation with strong base provided the nitrogen nucleophile containing the leaving group (Me3N) (Table 2, entry 6). High regioselectivities were observed in