Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• reaction specifically investigated the dimerization of thiols. Some of the experiments carried out by the group were in a flow chemistry set up, exemplifying the scalability of the procedure. In addition, the oxidant that achieves the transformation is molecular oxygen, making this a very sustainable route

• benzofused heterocycles (indole etc.) – such as benzimidazoles or tetrazolopyridines are often seen in medicinal chemistry. Singh et al. reported a method for preparing 3-arylnitrobenzimidazoles from 2-aminopyridines and nitroalkanes, using green LED Eosin Y photocatalysis, with molecular oxygen as the

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• easy-to-handle potassium (trifluoromethyl)trimethylborate K+[CF3B(OMe)3]− as a CF3 source, molecular oxygen as the oxidant. However, another side reaction, substitution of the boronate by methoxy groups originating from the CF3 source, arose in this transformation. At the same year, the group of Fu

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• reaction conditions. In 2016, Wang and co-workers reported the thiocyanation reaction of indoles with TiO2/MoS2 nanocomposite as heterogeneous photoredox catalyst and molecular oxygen as terminal oxidant (Scheme 27) [62]. They propose that the efficiency of their reaction is due to a separation of

•  28) [63]. The reaction mechanism is different from the previous examples. The photoexcited state of Eosin Y can be quenched reductively by tertiary amines to form an Eosin Y radical anion and an amine radical cation. Molecular oxygen regenerates Eosin Y and is reduced to its superoxide radical anion

• Eosin Y radical anion. After radical addition of the thiocyanate radical to styrene, the anti-Markovnikov intermediate can form a peroxy radical species with molecular oxygen. Consecutive rearrangements give a β-hydroxythiocyanate, which undergoes fast cyclization to the 5-membered heterocyclic product

Mechanically induced oxidation of alcohols to aldehydes and ketones in ambient air: Revisiting TEMPO-assisted oxidations

• Andrea Porcheddu,
• Evelina Colacino,
• Giancarlo Cravotto,
• Francesco Delogu and
• Lidia De Luca

Beilstein J. Org. Chem. 2017, 13, 2049–2055, doi:10.3762/bjoc.13.202

• amounts of the catalyst as well as molecular oxygen instead of air did not result in a significant improvement (Scheme 2, left side). To our great surprise, using Stahl’s catalyst, the mechanically activated oxidation of the model substrate 1a under solvent-free conditions proceed so quickly and

New bio-nanocomposites based on iron oxides and polysaccharides applied to oxidation and alkylation reactions

• Daily Rodríguez-Padrón,
• Alina M. Balu,
• Antonio A. Romero and
• Rafael Luque

Beilstein J. Org. Chem. 2017, 13, 1982–1993, doi:10.3762/bjoc.13.194

• require stoichiometric amounts of inorganic oxidants, which are highly toxic and polluting. Aiming to minimize chemical waste in these catalytic processes, the scientific community is moving towards the use of clean oxidants ("green oxidants"), such as molecular oxygen or H2O2 [39]. Thus, the use of clean

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• section we turn our attention to transition metal-catalyzed aerobic dehydrogenation of C–C and C–N bonds. Molecular oxygen is well established as an oxidant for oxidative dehydrogenation of heterocycles. These reactions occur under open air or excess oxygen pressure. They are classified as aerobic

• oxidation. One of the early examples of such reaction was demonstrated by Han et al. in 2006 [84]. Here in pyridines 71 and pyrazoles 72 were synthesized in excellent yield by the oxidation of 4-substituted Hantzsch 1,4-dihydropyridines 69 and 1,3,5-trisubstituted pyrazolines 70 via molecular oxygen. The

• the aforementioned heteroaromatic compounds in a one-pot reaction from aldehydes with 2-aminobenzylamines and 2-aminobenzyl alcohols with molecular oxygen as the oxidant (Scheme 22). It is a simple and environmentally benign protocol for the generation of these heterocycles (Scheme 22) in excellent

Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• conditions established for WelO5 and AmbO5 [18]. For a 100 µL scale reaction, WelO5* (20 µM final concentration) rapidly converted circa 50% of 1 and 2 (0.5 mM final concentration) to their chlorinated derivatives 1a and 2a within 20 min in the presence of cosubstrate 2OG, cofactor Fe(II) and molecular

• oxygen (Figure 2a, bottom two lanes). Under identical conditions, WelO5 showed a comparable conversion rate of 2 to 2a but was much more sluggish towards 1 (Figure 2a, top two lanes), consistent with our previous observation [17]. While a full steady state kinetic analysis remains challenging due to the

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• Pd(OAc)2 as catalyst and molecular oxygen as oxidant, however, the reaction suffered from low yield (2.3%) [49][50]. In 1997, Seo and co-workers reported an iron-HPA (heteropoly acid)-complex-catalyzed protocol for oxidation of benzene to phenol [51]. In 2005, the Rybak-Akimova group reported that

• DMF in the presence of Cs2CO3 and molecular oxygen, affording 2-(phenylthio)phenols as final products (Scheme 29). A preliminary mechanistic study showed that molecular oxygen participated in the formation of the hydroxy group. This protocol was further applied to the synthesis of quinines. 1.2.2

• did not work with ortho-substituted arenes. In 2013, Jiao and co-workers reported a hydroxylation protocol for (2-pyridyl)arenes using PdCl2 and N-hydroxyphthalimide (NHPI) as catalyst and molecular oxygen as oxidant [60]. (2-Pyridyl)arenes were converted to the hydroxylated products in toluene at 100

Novel β-cyclodextrin–eosin conjugates

• Gábor Benkovics,
• Damien Afonso,
• András Darcsi,
• Szabolcs Béni,
• Sabrina Conoci,
• Éva Fenyvesi,
• Lajos Szente,
• Milo Malanga and
• Salvatore Sortino

Beilstein J. Org. Chem. 2017, 13, 543–551, doi:10.3762/bjoc.13.52

• successfully utilized in photodynamic therapy (PDT). This minimally invasive therapeutic approach has proven to be very well-suited for cancer and bacterial diseases treatment. The PDT is based on the combination of three main components: visible light, a photosensitizer (PS) and molecular oxygen [4][5]. After

• being excited with visible light, the PS – while reverting to the ground state – transfers the energy of its lowest excited triplet state to nearby molecular oxygen. This leads to an in situ generation of singlet oxygen (1O2), which is the main responsible species for cytotoxic reactions in cells [6

• tentatively be attributed to populations of fluorophores probably interacting in a different way with the CD cavity. As outlined in the introduction, singlet oxygen, 1O2, is the key species involved in PDT and it is generated by energy transfer from the excited triplet state of a PS and the nearby molecular

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