Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• to handle hazardous components such as hydrazine and molecular oxygen, which represent alternative reagents for selective reduction of C=C double bonds. In fact, combination of hydrazine hydrate (N2H4·H2O) and O2 provide diimide (HN=NH) as reducing agent. Nevertheless, this strategy is rarely used in

• traditional batch chemistry for safety reason. Kappe and co-workers recently developed a reduction of the alkene to the corresponding alkane, by a catalyst-free generation of diimide by oxidation of hydrazine monohydrate (N2H4·H2O) with molecular oxygen [89][90]. The flow system set-up is reported in Scheme

A self-assembled cyclodextrin nanocarrier for photoreactive squaraine

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2016, 12, 2535–2542, doi:10.3762/bjoc.12.248

• irradiation of benzothiazole-squaraines results in a photodegradation process. Rapozzi et al. assume that oxidation probably involves through formation of a π-complex between the electron-rich enamine double bond and molecular oxygen. In comparison to the photo-oxidation of enaminon or other electron-rich

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• mannopeptimycin gene clusters, three pairs of enzymes were found to have high sequence homology, mmpP/endP, mppR/endR and mmpQ/endQ [49][50]. MppP is a PLP-dependent hydroxylase and catalyses the conversion of L-arginine (18) and molecular oxygen to 2-oxo-4-hydroxy-5-guanidinovaleric acid (20, Scheme 1) [51]. The

A flow reactor setup for photochemistry of biphasic gas/liquid reactions

• Josef Schachtner,
• Patrick Bayer and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2016, 12, 1798–1811, doi:10.3762/bjoc.12.170

• gas in the liquid phase which is pressure-dependent according to Henry’s law [69]. Reaction parameters of a model photooxygenation The often poor selectivities of reactions with molecular oxygen (being a triplet biradical in its ground state) [70] have prompted applications of microflow reactors to

• . Following an optimized Schenck ene reaction procedure, N-methyl-1,2,3,6-tetrahydrophthalimide (1a) was reacted with molecular oxygen in the presence of methylene blue as sensitizer (Scheme 6). The resultant hydroperoxide motif (2a) constitutes a valuable carbocyclic building block. For reasons of

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• Abstract A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the

Biradical vs singlet oxygen photogeneration in suprofen–cholesterol systems

• Fabrizio Palumbo,
• Francisco Bosca,
• Isabel M. Morera,
• Inmaculada Andreu and
• Miguel A. Miranda

Beilstein J. Org. Chem. 2016, 12, 1196–1202, doi:10.3762/bjoc.12.115

• light. The latter involves energy transfer from the photosensitizer triplet excited state to ground state molecular oxygen [5][6]. Ketoprofen (KP) is a nonsteroidal anti-inflammatory drug that contains the benzophenone (BZP, Figure 1) chromophore and displays a n,π triplet excited state [7][8][9

• assess the capability of dyads 1–3 to photosensitize the production of excited singlet molecular oxygen (1O2 or 1Δg), time-resolved near infrared emission studies were carried out in dichloromethane using perinaphthenone (PN) as standard. The formation of this reactive oxygen species was detected by its

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• , benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial

• ; catalyzed; molecular oxygen; oxygenation; Introduction Direct oxidation of C(sp3)–H bonds is a useful and fast method to convert fairly unreactive substrates to useful functional groups for organic synthesis like alcohols, ketones, aldehydes and carboxylic acids. Classical oxidation protocols rely on the

• organocatalysis in combination with molecular oxygen has received a great deal of attention from the scientific community [4][5][6][7]. Molecular oxygen is considered to be the greenest oxidant available and it is already widely employed by the commodity chemical industry [8]. However, when looking at the

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• sequestration, CO2 concentrations steadily decreased, leading to average atmospheric concentrations of 200 ppm over the last 400,000 years [44]. During this time, oxygen levels steadily increased through the action of photosynthetic organisms that oxidise water to produce molecular oxygen [43]. Consequently

Recent advances in copper-catalyzed C–H bond amidation

• Jie-Ping Wan and
• Yanfeng Jing

Beilstein J. Org. Chem. 2015, 11, 2209–2222, doi:10.3762/bjoc.11.240

• initiated by the Cu(II)-based bidentated intermediate 38, which proceeded via a series of different intermediate states 39–41 to provide products 37 in the presence of tert-butyl peroxide. By means of the assistance of molecular oxygen, Nicholas and John [58] devised the copper-catalyzed 2-amidation and

• activation of alkyne C–H bonds were also implemented. In 2008, Stahl et al. [73] reported the first copper-catalyzed alkyne amidation via the oxidation with molecular oxygen. The synthetic protocol exhibited excellent tolerance to the C–H functionalization by reacting not only with lactams, but also with

• of o-halobenzamides 82 and (benzo)imidazoles 87 for the one-pot synthesis of (benzo)imidazoquinazolinones 88 under the catalysis of CuI and assistance of L-proline. A subsequent oxidation using molecular oxygen was required for the final formation of products. According to the results, the mechanism

Molecular-oxygen-promoted Cu-catalyzed oxidative direct amidation of nonactivated carboxylic acids with azoles

• Wen Ding,
• Shaoyu Mai and
• Qiuling Song

Beilstein J. Org. Chem. 2015, 11, 2158–2165, doi:10.3762/bjoc.11.233

• the system. Given the growing demand for environmentally benign synthesis [24], it is highly desirable to bring forth a green, sustainable and simple new protocol for the activation of carboxylic acids. Molecular oxygen is an ideal oxidant owing to its negligible cost, availability and sustainability

• amidation reaction from carboxylic acids with peroxycarboxylate as the key intermediate, which represents a novel activation mode with molecular oxygen as the activating reagent. Most remarkably, in sharp contrast to previous reports (which used complex N-containing ligands to form copper superoxide

• product under similar conditions (Table 1, entry 5), inferring that molecular oxygen was not just acting as an oxidant to convert Cu(I) into Cu(II), but that it might be involved in the reaction. Further screening of solvents and ligands revealed that p-xylene and pyridine are the optimal choices. The

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

• , which allowed the synthesis of various 2-(o-haloaryl)pyridines with improved selectivity towards mono-halogenation in the presence of a copper catalyst [35]. As outlined in Scheme 4, the presence of molecular oxygen as the alternative oxidant enabled most entries providing monohalogenated products with

• via oxidation by Cu(II) and release of Cu(I). The presence of molecular oxygen regenerated the Cu(I) species to the Cu(II) catalyst via re-oxidation. In their subsequent study, Gusevskaya et al. found that anilines were also able to be halogenated via a similar operation. However, the products were

• was both the catalyst and the source of iodine in the reactions. It was believed that the iodination took place via in situ generated molecular I2 via the oxidation by molecular oxygen since the author successfully observed the presence of I2 during chromatography process. In the same year

Aerobic addition of secondary phosphine oxides to vinyl sulfides: a shortcut to 1-hydroxy-2-(organosulfanyl)ethyl(diorganyl)phosphine oxides

• Svetlana F. Malysheva,
• Alexander V. Artem’ev,
• Nina K. Gusarova,
• Nataliya A. Belogorlova,
• Alexander I. Albanov,
• C. W. Liu and
• Boris A. Trofimov

Beilstein J. Org. Chem. 2015, 11, 1985–1990, doi:10.3762/bjoc.11.214

• the P(O)H species to molecular oxygen has been reported for example for Ph2P(O)H [30]. Then, the radical addition of A to vinyl sulfide, proceeding in an anti-Markovnikov manner, takes place. Subsequently, a 1,2-intramolecular transfer of an H atom within the radical adduct B (from PCH2 group to

Copper-catalyzed aerobic radical C–C bond cleavage of N–H ketimines

• Ya Lin Tnay,
• Gim Yean Ang and
• Shunsuke Chiba

Beilstein J. Org. Chem. 2015, 11, 1933–1943, doi:10.3762/bjoc.11.209

• the construction of oxaspirocyclohexadienones as well as in the electrophilic cyanation of Grignard reagents with pivalonitrile as a CN source. Keywords: C–C bond cleavage; copper; ketimines; molecular oxygen; radical; Introduction Alkylideneaminyl radicals (iminyl radicals) have been utilized for

• % yield formed through hydrolysis of unreacted N–H imine 1fb during the aqueous work-up. Therefore molecular oxygen is indispensable to achieve the present cyanation through the C–C bond cleavage of the N–H ketimine. It was found that use of CuBr2 as the catalyst resulted in formation of 5b in higher

Pd(OAc)₂-catalyzed dehydrogenative C–H activation: An expedient synthesis of uracil-annulated β-carbolinones

• Biplab Mondal,
• Somjit Hazra,
• Tarun K. Panda and
• Brindaban Roy

Beilstein J. Org. Chem. 2015, 11, 1360–1366, doi:10.3762/bjoc.11.146

• % yield of 5a with 52% conversion of starting material. Increasing the temperature to 90 °C (Table 1, entry 2) afforded 63% yield of 5a with 80% conversion of 4a. Then different oxidants [Cu(OTf)2, PhI(OAc)2, K2S2O8, (NH4)2S2O8, p-benzoquinone (BQ), oxone, AgOAc, molecular oxygen] were examined under

• with Cu(OAc)2 (Table 1, entry 7). The use of K2S2O8 increased the yield of 5a to 83% (Table 1, entry 5) with complete conversion of starting material; AgOAc further increased the yield to 91% (Table 1, entry 9). Molecular oxygen also used as an oxidant resulted in a low 30% yield of 5a (Table 1, entry

Eosin Y-catalyzed visible-light-mediated aerobic oxidative cyclization of N,N-dimethylanilines with maleimides

• Zhongwei Liang,
• Song Xu,
• Wenyan Tian and
• Ronghua Zhang

Beilstein J. Org. Chem. 2015, 11, 425–430, doi:10.3762/bjoc.11.48

• the presence of TEMPO. Conclusion In conclusion, we report an efficient metal-free method for the synthesis of corresponding tetrahydroquinolines from N,N-dimethylanilines and maleimides using molecular oxygen as oxidant and Eosin Y as catalyst under the irradiation of visible light. The protocol is

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids

• Johanna Trenner and
• Evgeny V. Prusov

Beilstein J. Org. Chem. 2015, 11, 323–327, doi:10.3762/bjoc.11.37

• turned to the alternative oxidation of enolates with molecular oxygen in the presence of triethyl phosphite as originally described by Hartwig [12][13][14][15]. Application of these conditions resulted in a clean conversion to the 5-hydroxy-3-acyltetramic acid but again, the isolated yield of the product

• amounts of Pd trifluoroacetate/dppp [18] gave no conversion. In summary, we have developed a simple and efficient method for the synthesis of 5-hydroxy-3-acyltetramic acids by oxidation of the corresponding bisenolates with molecular oxygen. We have also investigated the cleavage of various protecting

• Johanna Trenner Evgeny V. Prusov Department of Medicinal Chemistry, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany 10.3762/bjoc.11.37 Abstract Oxidation of the bisenolates of 3-acyltetramic acid to the corresponding 5-hydroxylated compounds using molecular

Pd/C-catalyzed aerobic oxidative esterification of alcohols and aldehydes: a highly efficient microwave-assisted green protocol

• Marina Caporaso,
• Giancarlo Cravotto,
• Spyros Georgakopoulos,
• George Heropoulos,
• Katia Martina and
• Silvia Tagliapietra

Beilstein J. Org. Chem. 2014, 10, 1454–1461, doi:10.3762/bjoc.10.149

• friendly microwave-assisted oxidative esterification of alcohols and aldehydes in the presence of molecular oxygen and a heterogeneous catalysis (Pd/C, 5 mol %). This efficient and ligandless conversion procedure does not require the addition of an organic hydrogen acceptor. The reaction rate is strongly

• Selective oxidations of alcohols are some of the most important transformations in organic synthesis. Therefore, reactions that employ reusable heterogeneous catalysts and molecular oxygen are highly desirable from atom economy and environmental impact point of view [1][2][3]. A number of methods have been

• presence of molecular oxygen or air have been described [23][25][40][41][42][43], however, the main limit of this process is its lack of selectivity, as has already been reported. Several Pd-catalyzed procedures have been optimized and Ag [31][32] or Bi salts [40], hydrosilanes [33] or specially designed

Cyclization–endoperoxidation cascade reactions of dienes mediated by a pyrylium photoredox catalyst

• Nathan J. Gesmundo and
• David A. Nicewicz

Beilstein J. Org. Chem. 2014, 10, 1272–1281, doi:10.3762/bjoc.10.128

• % yield after 5 hours (Table 1, entry 1). The observed endoperoxide was attributed to a 5-exo cyclization mode of the diene cation radical followed by capture of molecular oxygen. The use of acetonitrile as solvent gave none of the desired adducts (Table 1, entry 2). Further improvement of the chemical

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• ) [235]. This reaction gives β-hydroxyketones as by-products that are formed as a result of the decomposition of dioxolanes 14. Cyclopropanols 15a–g are readily oxidized by molecular oxygen in the presence of Mn(II) abietate or acetylacetonate (Scheme 6) [236]. Presumably, the reaction proceeds via the

• the Co(II)/Et3SiH/O2 system (Isayama–Mukaiyama reaction) Peroxysilylation of alkenes with molecular oxygen in the presence of triethylsilane catalyzed by cobalt(II) diketonates was described for the first time by S. Isayama and T. Mukaiyama in 1989 [246][247]. Currently, this approach is one of the

Synthesis of enantiomerically pure N-(2,3-dihydroxypropyl)arylamides via oxidative esterification

• Akula Raghunadh,
• Satish S More,
• T. Krishna Chaitanya,
• Yadla Sateesh Kumar,
• Suresh Babu Meruva,
• L. Vaikunta Rao and
• U. K. Syam Kumar

Beilstein J. Org. Chem. 2013, 9, 2129–2136, doi:10.3762/bjoc.9.250

• by the Breslow intermediate 11 to provide the corresponding Aldol products [36]. Studer et al. reported the preparation of acids by an oxidation of Breslow intermediates with molecular oxygen [37][38][39]. The highly activated Breslow intermediate 11 formed by the addition of the NHC to the aldehydes

Aerobic radical multifunctionalization of alkenes using tert-butyl nitrite and water

• Daisuke Hirose and
• Tsuyoshi Taniguchi

Beilstein J. Org. Chem. 2013, 9, 1713–1717, doi:10.3762/bjoc.9.196

• 10.3762/bjoc.9.196 Abstract Water induces a change in the product of radical multifunctionalization reactions of aliphatic alkenes involving an sp3 C–H functionalization by an 1,5-hydrogen shift using tert-butyl nitrite and molecular oxygen. The reaction without water, reported previously, gives nitrated

• molecular oxygen, an alkoxy radical 26 is formed from the peroxynitrite intermediate (ROONO) generated by the reaction of the peroxy radical (ROO•) intermediate with t-BuONO. The alkoxy radical causes an 1,5-hydrogen shift to give the corresponding alkyl radical 27 followed by formation of another alkoxy

Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review

• Lucio Melone and
• Carlo Punta

Beilstein J. Org. Chem. 2013, 9, 1296–1310, doi:10.3762/bjoc.9.146

• -catalysts, they are activated to the corresponding N-oxyl radical species and become able to promote radical chains, involving molecular oxygen, directly or indirectly. Most of the examples reported in the literature describe the use of these N-hydroxy derivatives in the presence of transition-metal

• the O2-mediated selective oxidation of organic compounds and looking for environmentally safe alternatives to metal catalysis. Keywords: autoxidation; free-radicals; metal-free; molecular oxygen; N-hydroxyphthalimide; Introduction The development of efficient and cheap catalytic systems for the

• selective oxidation of organic substrates under mild and environmentally benign conditions represents one of the major challenges in organic synthesis [1]. In this context, the replacement of traditional oxidants, often used in stoichiometric amounts, with molecular oxygen is mandatory in order to improve

Copper-catalyzed aerobic aliphatic C–H oxygenation with hydroperoxides

• Pei Chui Too,
• Ya Lin Tnay and
• Shunsuke Chiba

Beilstein J. Org. Chem. 2013, 9, 1217–1225, doi:10.3762/bjoc.9.138

• aerobic oxygenation of aliphatic C–H bonds with hydroperoxides, which proceeds by 1,5-H radical shift of putative oxygen-centered radicals (O-radicals) derived from hydroperoxides followed by trapping of the resulting carbon-centered radicals with molecular oxygen. Keywords: copper; 1,4-diols; free

• radical; 1,5-H radical shift; hydroperoxides; molecular oxygen; Introduction Aliphatic sp3 C–H bonds are ubiquitous components in organic molecules but rather inert towards most of the chemical reactions. It thus remains as one of the most challenging topics in organic synthesis to develop catalytic

• radicals (C-radicals) could be trapped by molecular oxygen to form new C–O bonds. For instance, the Cu-catalyzed aerobic reaction of N-alkylamidines afforded aminidyl radicals (N-radicals) by single-electron oxidation and deprotonation of the amidine moiety, which was followed by 1,5-H-radical shift to

Substituent effect on the energy barrier for σ-bond formation from π-single-bonded species, singlet 2,2-dialkoxycyclopentane-1,3-diyls

• Jianhuai Ye,
• Yoshihisa Fujiwara and
• Manabu Abe

Beilstein J. Org. Chem. 2013, 9, 925–933, doi:10.3762/bjoc.9.106

• molecular oxygen (decay trace at 580 nm, Figure 2c); and (d) the activation parameters (Table 1) are similar to those for the decay process of DRa, in particular, the high (ca. 1012 s−1) pre-exponential Arrhenius factors (logA) are indicative of a spin-allowed reaction to the ring-closed products CPc–g [34