Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• ], wherein photoexcited decatungstate was employed. Decatungstate is an efficient and versatile hydrogen atom transfer (HAT) catalyst with a growing number of applications. The use of decatungstate in a continuous flow setup led to shorter reaction times, increased scalability, and improved safety with

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• generation of radicals from carbonyl reduction [18] but also manganese(III) acetate as a convenient one-electron oxidant [19]. The next twenty years, the field continued to flourish mainly by way of the decipherment of hydrogen atom transfer (HAT) mechanisms, which led to the establishment of several

• ) [30]. HAT reductions of the C9–C11 alkene followed to deliver arisugacin F (35), phenylpyropene C (36), pyripyropene E (38), and phenylpyropene F (41). The steric bulk of the manganese catalyst employed suppressed the undesired reaction with tetrasubstituted alkenes and led to the exclusive reaction

• of the desired trisubstituted alkene due to stabilization of the incipient radical at C9. Furthermore, HAT reduction served to only deliver the thermodynamic product of the trans-decalin. Similarly, the C9–C11 alkene can serve as an ideal handle to C11-hydroxylated products, such as 42, through a

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• process was explained by the unusual feature in the reactivity of the HSPyf/(SPyf)2 pair compared to other thiols and disulfides revealed by DFT calculations. In the case of the SPyf moiety the free-energy barrier for HAT between C-centered radicals and HSPyf is higher than the barrier for an SPyf group

• transfer between the C-centered radical and (SPyf)2, whereas for Me-, CF3-, Ph-, and C6F5-derived thiols and disulfides HAT is more favorable than thiyl group transfer [123]. Quinone catalysis Quinones are well known as redox-active cofactors in biochemical processes and have found wide synthetic

• application emerged in the last years. For example, a new class of synthetically available and structurally tunable HAT mediators (N-ammonium ylides) was rationally designed for electrochemical CH-oxidation [153] (Scheme 37). By computational studies N-ammonium ylides were chosen for investigation due their

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• UMB32 and UMB136 [33][34]. Zhang developed 4-aminoquinolines for the synthesis of fluorinated analogues of acetylcholinesterase (AChE) inhibitors [35] in cascade reactions, such as one-step syntheses of quinolines. Quinolin-4-ols involving histone acetyltransferases (HAT) inhibitors [36][37], as well as

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• with a medium pressure mercury lamp in Pyrex® glassware triggered a 1,6-HAT leading to biradical X which combined to the racemic pyrrolizidine 68 as a 1:1 mixture of diastereomers. Three more steps gave the target compound 69 in 31% overall yield. Corynoxine Hiemstra et al. used the α-ketoester moiety

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• readily, and is subsequently followed by a hydrogen atom transfer (HAT) process aided by the “dummy group” radical. These reagents thus fit the paradigm of a green methodology as their implicit design and photoactivity allows them to react without the use of external metal catalysts. The intrinsic

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• analysis, the group proposed that Tyr224 is involved in the catalytic mechanism of the FtmOx1-catalyzed endoperoxide formation reaction as an intermediary of hydrogen atom transfer (HAT), similar to Tyr385 in the COX reaction. In this COX-like reaction mechanism (Scheme 5), the Fe(IV)=O species oxidizes

• tyrosyl radical, first abstracts a hydrogen atom from C21 to form a substrate radical intermediate. The following reaction with molecular oxygen and the formation of an endoperoxide bridge generate the C26 radical intermediate. Finally, HAT from Tyr68 produces verruculogen and a tyrosyl radical at Tyr68

• bridge and a C3' radical. Finally, the hydroxylation at C3' by the Fe(III)-OH species yields fumigatonoid A (path 2). At the stage of intermediate 3 in path 1, HAT from an active site residue or reductant to the C3' radical in intermediate 3 generates intermediate 4. Then, the hydroxylation at C3' forms

Sesquiterpenes from the soil-derived fungus Trichoderma citrinoviride PSU-SPSF346

• Wiriya Yaosanit,
• Vatcharin Rukachaisirikul,
• Souwalak Phongpaichit,
• Sita Preedanon and
• Jariya Sakayaroj

Beilstein J. Org. Chem. 2022, 18, 479–485, doi:10.3762/bjoc.18.50

• Wiriya Yaosanit Vatcharin Rukachaisirikul Souwalak Phongpaichit Sita Preedanon Jariya Sakayaroj Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand Division of Biological Science

• , Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand National Biobank of Thailand (NBT), National Science and Technology for Development Agency (NSTDA), Thailand Science Park, Klong Luang, Pathumthani 12120, Thailand School of Science, Walailak University, Thasala

DABCO-promoted photocatalytic C–H functionalization of aldehydes

• Bruno Maia da Silva Santos,
• Mariana dos Santos Dupim,
• Cauê Paula de Souza,
• Thiago Messias Cardozo and
• Fernanda Gadini Finelli

Beilstein J. Org. Chem. 2021, 17, 2959–2967, doi:10.3762/bjoc.17.205

• , Universidade Federal do Rio de Janeiro 149, Athos da Silveira Ramos Ave, Rio de Janeiro RJ, 21941-909, Brazil 10.3762/bjoc.17.205 Abstract Herein we present a direct application of DABCO, an inexpensive and broadly accessible organic base, as a hydrogen atom transfer (HAT) abstractor in a photocatalytic

• HAT step energetics and determined an optimized geometry for the transition state, showing that the hydrogen atom transfer between aldehydes and DABCO is a mildly endergonic, yet sufficiently fast step. The same calculations were performed with quinuclidine, for comparison of both catalysts and the

• differences are discussed. Keywords: C–H functionalization; DABCO; HAT; photocatalysis; Introduction The functionalization of inert C–H bonds is a goal pursued by chemists from decades, due to its ubiquity in organic molecules. This strategy also dismisses tiresome protecting groups and functional group

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• solvent-tuned [129]. In neat CH2Cl2, the reaction produced the expected β-trichloromethyl alkyl azide; however, the reaction was chemoselective for diazidation when tert-butanol was used as co-solvent. The authors hypothesized the presence of the alcohol suppresses the polar-unmatched HAT process from

• a net iminyl-nitrooxylation reaction [140]. In 2020, Wei and co-workers studied an iminyl radical-triggered 1,5-hydrogen atom transfer (HAT) and [5 + 2] annulation processes for the synthesis of azepine derivatives 170 (Scheme 36) [141]. The reaction was tolerable of both electron-donating and

• observed generating spiro succinimidetetrahydropyridine derivatives 172. To understand the chemoselectivity of the reaction, the authors performed a DFT mechanistic study. After the iminyl radical is generated it will undergo a 1,5-HAT to form the more stable alkyl radical which will add across the alkene

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• photoinduced copper-catalyzed α-C(sp3)–H cyclization of aliphatic alcohols with o-aminobenzamide. However, the aliphatic alcohols were limited to methanol and ethanol. In this transformation, α-C(sp3)–H of MeOH/EtOH undergoes a hydrogen atom transfer (HAT) process to synthesize quinazolinones involving ligand

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• transfer (HAT) and nickel catalysis [54]. The catalytic system consisting of iridium photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6, nickel catalyst NiBr2·3H2O, ligand 4,7-dimethoxy-1,10-phenanthroline (4,7-dOMe-phen), and 3-acetoxyquinuclidine was found to be optimal to afford the desired α-amino C–C coupled

• products 7 (Scheme 3). It is worth noting that 3-acetoxyquinuclidine serves as both the HAT catalyst and the base in this reaction system. Furthermore, several cyclic and acyclic amine 6 substrates were used as C‒H nucleophile coupling partners for (hetero)aryl bromides 3. Two additional examples for the

• generation of nucleophilic α-amino radicals 2-IV via a photoredox-mediated HAT process. At the same time, the in situ generated nickel(0) species 2-V by a SET process would undergo oxidative addition into aryl bromide 3, resulting in the electrophilic nickel(II)–aryl intermediate 2-VI. The rapid coupling of

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• is also oxidized to Mn(III)/L–N3. Azide radical addition to Mn(II)/L to form Mn(III)/L–N3 was considered as a possible route. Concurrently, the photocatalyst is irradiated by blue LED light to induce hydrogen atom transfer (HAT) at the C–H bond of substrate 12, generating alkyl radicals and enabling

• to Mn(IV) takes place on the anodic surface, resulting in the formation of a trans-diazide Mn(IV) intermediate (Figure 5). The high-valent manganese(IV) complex is susceptible to HAT from the substrate 14, generating an alkyl radical [45][46]. Subsequently, further azide radical transfer from the

Cerium-photocatalyzed aerobic oxidation of benzylic alcohols to aldehydes and ketones

• Girish Suresh Yedase,
• Sumit Kumar,
• Jessica Stahl,
• Burkhard König and
• Veera Reddy Yatham

Beilstein J. Org. Chem. 2021, 17, 1727–1732, doi:10.3762/bjoc.17.121

• generating oxygen-centered radicals, that lead to carbon-centered radicals through intra/intermolecular hydrogen atom transfer (HAT) processes, radical decarboxylative or radical deformylation [57][58][59]. In continuation of our research interest on visible-light-driven cerium photocatalysis [59][65], we

• involvement of possible intermolecular HAT or 1,2-HAT from the intermediate III to generate the product 2. Conclusion In summary, we have developed a catalytic aerobic oxidation of benzylic alcohols to the corresponding aldehydes without further oxidation and formation of benzoic acids. A variety of primary

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cycloisomerization of diolefins triggered by the MHAT process. Some challenges associated with the development of these reactions were the reversible nature of the HAT and the competition with linear isomerization and reductive pathways (Scheme 18) [72][73]. In 2014, the Shenvi group developed an olefin

• an MHAT process. In 2008, Norton and co-workers [76] developed a pioneering radical cascade approach based on the generation of carbon free radicals from an MHAT process. The rates (kH) of hydrogen atom transfer (HAT) from the chromium metal hydride CpCr(CO)3H to olefins with diverse substitution

• patterns and electronic features were measured previously by the rate of deuterium/hydrogen exchange [77], and the observed constants served as a guide to the regioselectivity prediction of the HAT processes in substrates with different olefins. In substrate 40, for example, the hydrogen atom was

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• ][19][20]. There are several types of transition-metal-catalyzed C(sp3)−H halogenation reactions reported in the literature (Scheme 1b–d). Transition-metal-catalyzed 1,5-hydrogen atom transfer (1,5-HAT) is effective for promoting regioselective C(sp3)−H halogenation reactions (Scheme 1b) [21][22][23

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• reaction mechanism for this transformation is as follows (Scheme 6): Firstly, O-aryloxime 11 forms EDA complex 13 by action of DABCO·(SO2)2 and then undergoes light-promoted single-electron transfer, affording the 2,4-dinitrophenol anion, nitrogen radical 14, and radical 15, respectively. 1,5-HAT (hydrogen

• atom transfer) occurs in nitrogen radical 14 to give radical 16, which further transforms to radical 17 after the addition of sulfur dioxide. Finally, HAT happens between 15 and 17, yielding quaternary ammonium salt 18 and product 12, respectively. In 2017, Chen and colleagues [47] accomplished the

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• photocatalysts used for this reaction, it is proposed the excited state of 9 is sufficiently reducing to initiate the chain mechanism through an oxidative quench. Moving away from electronically activated halides, MacMillan et al. investigated a tricatalytic system, utilising enamine, photoredox, and HAT

• reductively quenches the photocatalyst to form enaminyl radical 13•+. However, in this reaction 13•+ can then add to the alkene to give an alkyl radical 14•+, followed by hydrogen atom abstraction from the thiol, acting as a HAT catalyst, to give iminium ion intermediate 15. Hydrolysis of 15 generates the

• begins with the condensation of 49 with enone 50 to form the iminium ion intermediate 51. Concomitantly, the excited-state photocatalyst generates an alkyl radical R• from R–H, either through HAT ([W] with a benzodioxole derivative) or SET ([Ir] with a tertiary amine). This radical then adds to the β

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• chemoselectivity. Overall, chemo- and regioselective C(sp3)–H fluorinations continue to challenge chemists. Most direct C(sp3)–H fluorinations are reported to proceed under radical pathways involving hydrogen atom transfer (HAT), although proton-coupled electron transfer (PCET) has also been reported [44][49][50

• –H bond is matched to the HAT catalyst. For example, an electrophilic radical abstracts H atoms selectively from the most electron-rich or “hydridic” C–H bond [65]. 1.1.3 Importance of visible light and visible-light photosensitization in synthesis: Unlike many other traditional energy resources

• cleavage reactions [80] and 1,5-HAT [81] and iii) the excited state of the simple organic molecule target can possess an ultrashort lifetime [82] that precludes photochemistry in favor of photophysical or nonradiative deactivation, e.g., fluorescence or internal conversion (IC). Instead of direct UV

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• mild heteroaromatic functionalizations. Last but not least, a HAT-type process inducing the generation of alkyl radicals via selective C–H abstraction from the aliphatic precursors may be combined with a Ni-catalyzed process, thus delivering cross-coupled products. The aim of this review is to present

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• Yeersen Patehebieke School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China 10.3762/bjoc.16.118 Abstract Disulfides are versatile catalysts. They can be photocatalysts, hydrogen atom transfer (HAT) catalysts, cocatalysts, or initiators in photocatalytic reactions

• excellent radical properties also made these thiyl radicals powerful HAT catalysts. They have increasingly been proven useful in various types of organic photoreactions, such as cyclizations, anti-Markovnikov additions, aromatic olefin carbonylations, isomerizations, etc. They are a class of green, economic

• catalytic abilities: they can be a photocatalyst, HAT catalyst, initiator, or cocatalyst in organic synthesis. The thiyl radicals (RS•) formed under illumination conditions have the unique ability of promote radical bond-forming reactions. Their ability to reversibly add to unsaturated bonds, promoting a

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• one aryl group in the β-position (R3 = H, R2 = Ar) and further processing of the reaction mixture with atmospheric oxygen, an aromatization occurs with the formation of isoxazoles (64a,b 55–95%). Presumably, the reaction of TEMPO with oxime 62 affords the iminoxyl radical 65 (Scheme 24). 1,5-HAT in

• yield of 76. A radical mechanism was proposed in which the oxime moiety is oxidized by DDQ to the iminoxyl radical 77, which undergoes 1,5-HAT to give a C-centered radical 78 stabilized by a sulfur atom. 78 is oxidized by DDQ to a carbocation 79, followed by the closure of the oxathiazole ring (Scheme

• promotes the formation of an oxime radical that undergoes 1,5-HAT to form the target product. Oxidative cyclization with the cleavage of π-bond C=C Early examples of oxidative cyclization of iminoxyl radicals with an attack on π-bonds were reported in the 1980s [123]. However, the structure of the products

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• Photocatalytic hydrogen atom transfer (HAT) represents a valuable strategy for accessing C(sp3) radicals. This method allows the direct cleavage of a C–H bond and the consequent generation of alkyl radicals without relying on the presence of redox-active functional groups. This results in a superior atom economy

• compared to other methods for radical generation [56]. Within this field, organic dyes can act as competent photocatalysts for direct HAT processes. Specifically, upon light excitation, photoactive carbonyl compounds, such as benzophenone and its derivatives, reach an electronically excited triplet state

• successfully employed for the generation of C(sp3) radicals via HAT [58]. Interestingly, Wu and co-workers demonstrated that eosin Y (OD13) can also act as a direct HAT catalyst under visible-light irradiation [59]. Organic photoredox catalysis can also drive indirect HAT processes. In these reactions, the

Synthesis and properties of quinazoline-based versatile exciplex-forming compounds

• Rasa Keruckiene,
• Simona Vekteryte,
• Ervinas Urbonas,
• Matas Guzauskas,
• Eigirdas Skuodis,
• Dmytro Volyniuk and
• Juozas V. Grazulevicius

Beilstein J. Org. Chem. 2020, 16, 1142–1153, doi:10.3762/bjoc.16.101

• -doped OLED with three light-emitting layers comprising m-MTDATA:1:PO-T2T was fabricated (Figure 7c). The structure of the device was as follows: HAT-CN (10 nm)/NPB (48 nm)/m-MTDATA (16 nm)/compound 1 (20 nm)/PO-T2T (16 nm)/TSPO1 (4 nm)/TBPi (36 nm). In this device architecture, the common hole/electron

• injecting/transporting/blocking layers hexaazatriphenylenehexacarbonitrile (HAT-CN), N,N′-di(1-naphthyl)-N,N′-diphenyl-(1,1′-biphenyl)-4,4′-diamine (NPB), diphenyl[4-(triphenylsilyl)phenyl]phosphine oxide (TSPO1), 2,2′,2′′-(1,3,5-benzinetriyl)-tris(1-phenyl-1H-benzimidazole) (TPBi), and fluorolithium (LiF

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• capable to induce other types of reactions, such as hydrogen atom abstraction (HAT) processes or triplet state energy transfer processes (EnT). Carbonyl compounds, especially diaryl ketones, have shown great potential as far as their catalytic scope is concerned. Benzophenone or acetophenone (64) and

• , benzaldehyde (8) has also been studied for the ability to carry out HAT processes. In 1975, Obi and co-worker studied the photochemistry of excited benzaldehyde (9) with the use of electron paramagnetic resonance (EPR) [20]. They detected that the generated radicals from this process were the α-hydroxybenzyl

• aryl ketones, could participate in HAT processes as hydrogen atom abstractors [20]. More specifically, aldehydes can absorb irradiation at 300 nm and be excited from their ground state S0 to their singlet state S1 (n,π*), Then, through intersystem crossing (ISC), they can transition to a lower energy