The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• delivers the desired 1,4-triazole regioisomer without the need for a metal catalyst that requires stringent purification afterwards. Due to the reduced reactivity of 100 the crucial cycloaddition step was conducted neat at elevated temperature (210 °C) yielding pure 102 within short residence times (5–30

Stereoselective cathodic synthesis of 8-substituted (1R,3R,4S)-menthylamines

• Carolin Edinger,
• Jörn Kulisch and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2015, 11, 294–301, doi:10.3762/bjoc.11.34

• the configuration at position 4 resulting in a complex diastereomeric mixture. Alternatively, reduction of menthone oxime can be achieved, either employing Bouveault–Blanc conditions [41], or via hydrogenolysis at a transition metal catalyst [42]. Both approaches lead to the desired product as a

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• -substituted on the phenyl side-rings by a large variety of substituents, as well as stereo- and regioselectivity (particularly for the bulky groups). Nevertheless, due to the most common metal catalyst (palladium) this method is significantly more expensive and less environmentally friendly than radical-based

Exploration of C–H and N–H-bond functionalization towards 1-(1,2-diarylindol-3-yl)tetrahydroisoquinolines

• Michael Ghobrial,
• Marko D. Mihovilovic and
• Michael Schnürch

Beilstein J. Org. Chem. 2014, 10, 2186–2199, doi:10.3762/bjoc.10.226

• catalyst instead of copper since palladium has been widely recognized as powerful transition metal catalyst involved in C2-arylations of azoles [25][33][46][47][55][56][57][58]. C2-Arylation of 1-(indol-3-yl)-N-PG-THIQs 4 was expected to be challenging since the C3 position of the indole is blocked by the

P(O)R₂-directed Pd-catalyzed C–H functionalization of biaryl derivatives to synthesize chiral phosphorous ligands

• Rong-Bin Hu,
• Hong-Li Wang,
• Hong-Yu Zhang,
• Heng Zhang,
• Yan-Na Ma and
• Shang-dong Yang

Beilstein J. Org. Chem. 2014, 10, 2071–2076, doi:10.3762/bjoc.10.215

• ]. In particular, their special effects of enhancing the metal-catalyst efficiency and of controlling chiral induction has continually prompted synthetic chemists to probe efficient methods generating access to chiral, enantiomerically pure phosphorus compounds used in pharmaceutical, agrochemical and

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• papers appeared reporting on organocatalyzed asymmetric hydrophosphinations. The organocatalytic process has the advantage that in contrast to a metal-catalyzed method, it cannot undergo product inhibition as a result of the coordination ability of phosphorus to a metal catalyst. The addition of

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• great chemical diversity of the products of MCRs. Moreover, imines can participate in MCRs as electrophilic or nucleophilic partners, azadienes, dienophiles and 1,3-dipoles. All these reactions may benefit from the presence of a Lewis acid, a Brønsted acid or a transition metal catalyst. Silver

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• ]. This reaction sequence constitutes a very nice example of a formal [4 + 3]-cycloaddition, without the use of a transition metal catalyst. Donaldson and coworkers [193] used the DVCPR en route towards the core skeleton of the sesquiterpenoid guianolide family [194][195]. Starting from readily prepared

An investigation of the observed, but counter-intuitive, stereoselectivity noted during chiral amine synthesis via N-chiral-ketimines

• Thomas C. Nugent,
• Richard Vaughan Williams,
• Andrei Dragan,
• Alejandro Alvarado Méndez and
• Andrei V. Iosub

Beilstein J. Org. Chem. 2013, 9, 2103–2112, doi:10.3762/bjoc.9.247

• resolution. Furthermore, in a further effort to investigate the possibility of metal catalyst induced isomerization, we reduced imines 2a–e using significantly higher loadings of Pd/C or Pt/C at 22 °C than noted in Table 2, but found no inconsistency pointing to isomerization.) These overall findings are

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• α-bromodiazoacetamides to thermolyse at ambient temperature without the use of a metal catalyst, offers the reactivity of the bromocarbene amides under genuinely mild reaction conditions. Halocarbonyl carbenes and carbene/carbenoid stabilisation In their ground state, the halocarbonyl carbenes

Simple and rapid hydrogenation of p-nitrophenol with aqueous formic acid in catalytic flow reactors

• Rahat Javaid,
• Shin-ichiro Kawasaki,
• Akira Suzuki and
• Toshishige M. Suzuki

Beilstein J. Org. Chem. 2013, 9, 1156–1163, doi:10.3762/bjoc.9.129

• thin metal-catalyst coating layer over the inner surface of a tubular reactor. Co-plating of Pd and Ag yielded mixed distributed Pd and Ag inner surfaces, which further gave a porous Pd surface by preferential dissolution of Ag by HNO3. A hollow tubular reactor combined with the catalytic inner surface

• suitable for Pd plating, also acts as a barrier to prevent intermetallic diffusion of Ti and the metal catalyst. The TiO2 surface was activated with Pd seeds before electroless plating. Plating of Pd was then conducted according to the procedure described in previous reports [10][11][12]. By 5 h plating at

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

• Martina Bonsignore,
• Maurizio Benaglia,
• Laura Raimondi,
• Manuel Orlandi and
• Giuseppe Celentano

Beilstein J. Org. Chem. 2013, 9, 633–640, doi:10.3762/bjoc.9.71

• selectivity was achieved by tuning the metal catalyst. In the trichlorosilane-mediated reductions in this work we aimed to exploit the imine activation by the acid proton of the carboxylic group, which can act at the same time as a Lewis basic site to coordinate the silicon atom and hopefully control the

New simple synthesis of ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thiones: Direct formation from carbon disulfide and (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles

• Qiuping Ding,
• Yuqing Lin,
• Guangni Ding,
• Fumin Liao,
• Xiaoyan Sang and
• Yi-Yuan Peng

Beilstein J. Org. Chem. 2013, 9, 460–466, doi:10.3762/bjoc.9.49

• and efficient method to construct ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thione derivatives has been developed from carbon disulfide and (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles under mild conditions, without the need for a metal catalyst. The newly developed method

Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation

• Kei Murakami and
• Hideki Yorimitsu

Beilstein J. Org. Chem. 2013, 9, 278–302, doi:10.3762/bjoc.9.34

• cyclopropenes Increasing the reactivity of alkynes and alkenes is another strategy to achieve intermolecular carbometalation reactions. For example, strained alkenes are highly reactive toward carbometalation. The reactions of cyclopropenes took place without the aid of a metal catalyst (Scheme 16) [81

Tandem aldehyde–alkyne–amine coupling/cycloisomerization: A new synthesis of coumarins

• Maddi Sridhar Reddy,
• Nuligonda Thirupathi and
• Madala Haribabu

Beilstein J. Org. Chem. 2013, 9, 180–184, doi:10.3762/bjoc.9.21

• aminoindolizines, 2-(aminomethyl)indoles, imidazopyridines, butenolides and 1,2-dihydroisoquinoline derivatives, respectively, combining these two approaches successfully. Along the same lines, we investigated a reaction between ethoxyacetylene, pyrrolidine and salicylaldehyde in the presence of a transition-metal

• catalyst. That, after consecutive A3 coupling, cycloisomerization and hydrolysis of the resultant vinyl ether intermediate, should produce coumarins (Scheme 1, (d)). The reason for the selective 6-endo-dig cyclization of such a cooperative-catalysis reaction has been well documented through DFT

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

Iridium-catalyzed intramolecular [4 + 2] cycloadditions of alkynyl halides

• Andrew Tigchelaar and
• William Tam

Beilstein J. Org. Chem. 2012, 8, 1765–1770, doi:10.3762/bjoc.8.201

• –94%). These results are the first examples of cycloadditions of alkynyl halides using an iridium catalyst. Keywords: alkynyl halide; cycloaddition; diene-tethered alkyne; iridium; transition-metal catalyst; Introduction Iridium complexes have been used as catalysts for a wide variety of reactions

Arylglycine-derivative synthesis via oxidative sp³ C–H functionalization of α-amino esters

• Zhanwei Xu,
• Xiaoqiang Yu,
• Xiujuan Feng and
• Ming Bao

Beilstein J. Org. Chem. 2012, 8, 1564–1568, doi:10.3762/bjoc.8.178

•  1, reactions 1–3). However, these reactions need expensive arylboronic acids (Petasis reaction) [4][5][6][7][8][9] and suitable leaving groups [10][11][12] as well as a metal catalyst (Polonovsky reaction; this route requires the preparation of amine N-oxide in advance) [13][14]. We have recently

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• cleavage seems to depend on the nature of the metal catalyst. Nevertheless, these results do provide inspiration for the development of similar C–H functionalization catalysis involving metal carbenes or silylenes (or perhaps even electrophilic nitrenes). Utility of M═E FLPs in C–H functionalization Given

Synthesis of a novel chemotype via sequential metal-catalyzed cycloisomerizations

• Bo Leng,
• Stephanie Chichetti,
• Shun Su,
• Aaron B. Beeler and
• John A. Porco Jr.

Beilstein J. Org. Chem. 2012, 8, 1338–1343, doi:10.3762/bjoc.8.153

• 1,2-hydride shift to intermediate 27 followed by elimination of the metal catalyst [25] to afford the observed cyclopropane product 6. An alternative reaction pathway may be invoked for the ethyl-substituted substrate 22 leading to product 23 (Scheme 4). After initial cyclization of the enol ether

Double N-arylation reaction of polyhalogenated 4,4’-bipyridines. Expedious synthesis of functionalized 2,7-diazacarbazoles

• Mohamed Abboud,
• Emmanuel Aubert and
• Victor Mamane

Beilstein J. Org. Chem. 2012, 8, 253–258, doi:10.3762/bjoc.8.26

• -pentylaniline (6a) was investigated with several ligands in toluene at 120 °C, and in the presence of Pd2(dba)3 as the source of metal catalyst (Scheme 2). Ligands such as Xantphos [33], biaryl monophosphines [34] and t-Bu3P [35] were tested since they were found to be very effective in the selective C-5

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

• -4,5-diyl)dimethanol. Phenyl-TADDOL (T1) = tetraphenyl-(2,2-dimethyl-1,3-dioxolane) derivative; 1-naphthyl-TADDOL (T2) = tetra-1-naphthyl-(2,2-dimethyl-1,3-dioxolane) derivative. Halogenation of β-ketocarbonyl compounds: Importance of enolization and the potential role of a metal catalyst. Qualitative

Scaling up of continuous-flow, microwave-assisted, organic reactions by varying the size of Pd-functionalized catalytic monoliths

• Ping He,
• Stephen J. Haswell,
• Paul D. I. Fletcher,
• Stephen M. Kelly and
• Andrew Mansfield

Beilstein J. Org. Chem. 2011, 7, 1150–1157, doi:10.3762/bjoc.7.133

• the Pd-monolith catalyst The Suzuki–Miyaura reaction is a widely used method in organic synthesis for the selective formation of aryl–aryl carbon–carbon bonds in the synthesis of high-value fine chemicals and intermediates in the pharmaceutical industry. This reaction requires a metal catalyst, such

Efficient gold(I)/silver(I)-cocatalyzed cascade intermolecular N-Michael addition/intramolecular hydroalkylation of unactivated alkenes with α-ketones

• Ya-Ping Xiao,
• Xin-Yuan Liu and
• Chi-Ming Che

Beilstein J. Org. Chem. 2011, 7, 1100–1107, doi:10.3762/bjoc.7.126

• conducted on the design and utilization of dual-metal catalyst systems in organic synthesis [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] (for recent examples of Au/Pd-cocatalysis see [30][31][32][33]; for Au/Mo-cocatalysis see [31][35]; for Au/Ag-cocatalysis see [36][37][38]; for Au/Yb

• ]. Using a combination of 5 mol % of (t-Bu)2(o-diphenyl)PAuCl and 15 mol % of AgOTf as a dual-metal catalyst system lead to the formation of pyrrolidine derivative 3a as a 5.3:1 mixture of two diastereomers in 67% yield (Table 1, entry 4). The yield increased from 58% to 67% as the mol ratio of 2a to 1a

• mixture did not have a noticeable effect on the yield of 3a (Table 1, entries 8–11). To identify further the optimal reaction conditions for the gold(I)/silver(I)-cocatalyzed cascade reaction, a number of dual-metal catalyst systems, composed of 15 mol % of silver salt with 5 mol % of gold(I) complex in