A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• this method (Scheme 30b). 1.3 Metal-assisted anodic oxidation 1.3.1 Mn-assisted anodic oxidation. The Ackermann group was the first to achieve an C–H azidation by use of a manganese-catalyzed anionic oxidation using “traceless electrons” [42]. By employing inexpensive sodium azide and a manganese salen

• complex, C(sp3)–H bonds underwent azidation with high chemoselectivity, even in the absence of a directing group. The proposed mechanism involves the formation of the active catalyst Mn(III)(N3) via ligand exchange, followed by anodic oxidation to a Mn(IV)(N3)2 complex. This high–valent Mn(IV) species

• undergoes hydrogen-atom transfer (HAT) leading to alkyl radical formation. The manganese-catalyzed azide radical transfer then delivers the product. Unactivated secondary and tertiary C–H bonds, as well as benzylic C–H bonds, were prone to azidation, with the reactivity order being: benzylic > tertiary

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• Christopher Mairhofer David Naderer Mario Waser Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstrasse 69, 4040 Linz, Austria 10.3762/bjoc.20.135 Abstract We herein report the oxidative α-azidation of carbonyl compounds by using NaN3 in the presence of dibenzoyl

• . Keywords: azidation; nitration; organocatalysis; oxidation; quaternary ammonium iodides; Introduction Organic compounds containing an azide functionality are highly valuable synthesis targets that offer considerable potential for various applications and further manipulations [1][2][3][4][5][6][7][8][9

• remarkable advancement in this field (Scheme 1B [31]). In contrast to previous oxidative quaternary ammonium iodide catalysis reports [28][29][30], this method does not require the use of TMSN3, thus presenting an efficient oxidative α-azidation protocol utilizing NaN3, which arguably represents the most

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• azido-hydration reaction [18]. The homopropargylic azide was obtained in only 28% yield using phenyl vinyl ketone. Based on reported aza-alkynylation reactions [19][20][21][22][23] and modern azidation methods using radical chemistry [17][24][25][26] three approaches could be envisaged. All of them

• elimination of the organometallic intermediate would lead to the desired product (Scheme 1B, reaction 1). Unfortunately, this approach will not be compatible in the case of azidation since the copper, azides and alkynes present in the mixture are expected to undergo alkyne–azide cycloaddition reactions [28

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• of recent interest, with exciting preliminary decarboxylative azidation results obtained under thermal conditions by Hongli Bao and co-workers [44]. An asymmetric iron (NON) pincer catalyst IV was employed to decarboxylate benzylic peroxyesters and form enantiomerically enriched benzylic azides. An

• beautiful decarboxylative azidation examples, combining iron-mediated photodecarboxylation via LMCT and azide RLT (Scheme 5) [11]. Irradiating a substoichiometric amount of iron(III) nitrate hydrate III in the presence of carboxylic acid, TMS azide, and sodium carbonate allows for direct synthesis of alkyl

• : Groves reported decarboxylative fluorination employing catalyst V. III: Bao reported asymmetric decarboxylative azidation through use of BOX-derived iron catalyst IV. Our lab reported decarboxylative azidation of aliphatic and benzylic acids. I: The reaction proceeds via LMCT and RLT catalysis without

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• of Science, Charles University, 128 43 Prague 2, Czech Republic 10.3762/bjoc.19.25 Abstract The first continuous flow method was developed for the synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin starting from native β-cyclodextrin through three reaction steps, such as monotosylation, azidation

• and reduction. All reaction steps were studied separately and optimized under continuous flow conditions. After the optimization, the reaction steps were coupled in a semi-continuous flow system, since a solvent exchange had to be performed after the tosylation. However, the azidation and the

• reduction steps were compatible to be coupled in one flow system obtaining 6-monoamino-6-monodeoxy-β-cyclodextrin in a high yield. Our flow method developed is safer and faster than the batch approaches. Keywords: azidation; continuous flow; β-cyclodextrin; H-cube; 6-monoamino-6-monodeoxy-β-cyclodextrin

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• conversion of cholesterol 1 into diene 9, bromide 4, and azides 5 and 6. Manipulations for bromination and azidation of cholesterol. Supporting Information Supporting Information File 75: X-ray crystallography and NMR spectra. Supporting Information File 76: Crystallographic information files for compounds

Electrochemical vicinal oxyazidation of α-arylvinyl acetates

• Yi-Lun Li,
• Zhaojiang Shi,
• Tao Shen and
• Ke-Yin Ye

Beilstein J. Org. Chem. 2022, 18, 1026–1031, doi:10.3762/bjoc.18.103

• have reported a manganese dioxide-catalyzed radical azidation of enol acetates to afford the corresponding azidoketones using dioxygen as the oxidant (Scheme 1A) [14]. The adoption of electrosynthesis in green and sustainable redox transformations has been experiencing a dynamic renaissance [15][16][17

• vinyl acetates has been developed to afford the corresponding α-fluorinated [26], -arylated [27], and -sulfenylated [28] ketones (Scheme 1B). In addition, electrochemical azidation [29][30][31][32][33] has also become a robust and reliable synthetic tool to incorporate azido functionality [34][35] into

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

• resulting cyanoalkyl radical then adds to the alkene to form a new alkyl radical. This radical is captured by a high-valent CuIII complex, which undergoes a reductive elimination to give the target product (Scheme 12). In 2018, Reiser and co-worker [63] established a CuII-catalyzed oxo-azidation of vinyl

• represents a new platform for copper-based photocatalysis (see section 3.3). In 2019, Yu et al. [64] developed a similar copper-catalyzed azidation of activated alkenes with 1-azido-1,2-benziodoxole as the azide radical precursor (Scheme 14). 3.3 Functionalization of alkynes A series of photoinduced copper

• functionalization reactions Benzylic or α-amino C–H groups and even the stable C(sp3)–H group were functionalized through the corresponding benzylic radical, α-amino radical, or alkyl radical. In 2016, Greaney and co-workers [92] investigated the direct C–H azidation with benzylic C–H compounds 47 and the Zhdankin

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly

• biological sciences. Recently, great attention has been paid to synthesize organic azido compounds via various transformations. In 2020, we reported an efficient method for the synthesis of fully substituted azidopyrroles 41 via Cu- and Mn-co-mediated aerobic oxidative cyclization/azidation reaction of 2

• functionalizations of pyrrole derivatives, such as iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, and alkylation. The proposed mechanism generally involves two kinds of intramolecular cyclizations: one is 6-endo-dig cyclization to promote the formation of pyridine ring

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• in the azidation of inert C(sp3)–H bonds using organic electrosynthesis in a straightforward procedure, enabling the azidation of a series of primary, secondary and tertiary alkyl moieties (Scheme 22B and C) [144]. In general, the new methodology proved to be resource-economic and straightforward

• , operating under mild conditions without the need of directing groups, using traceless electrons as sole redox reagents, presenting high scope and chemoselectivity. The robustness of the reaction was proved by the late-stage modification of pharmaceutically relevant compounds by promoting the azidation of a

• retinoic acid receptor agonist analogue 63 and an estrone acetate derivative 64 (Scheme 22D). A seminal work involving manganese-catalyzed C–H organic electrosynthesis and photoredox catalysis was reported in the same year by Lei and co-workers, also regarding the azidation of alkyl scaffolds (Scheme 23A

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

• operationally simple fluorination strategy suitable for bioactive structural motifs. Manganese-catalyzed late-stage C–H azidation In organic synthesis, organic azides are of considerable significance in the fields of medicinal chemistry, chemical biology, and nanotechnology as they can participate in elegant

• conjugative transformations, such as azide–alkyne [3 + 2]-cycloaddition [30][31][32][33][34][35][36][37]. Based on their previous late-stage fluorination studies [22][25], Groves et al. further showcased a manganese(III)–salen-catalyzed azidation process using an aqueous azide solution as a convenient azide

• source to execute facile C–H azidation of pharmaceutical-like complex molecules (Scheme 3) [38]. In this study, the regioselectivity is governed not only by electronic and steric effects of the manganese catalysts 5 and 10 but also by the electronic properties of the substrates. Pregabalin is an

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• desired nucleosides 59 and 60, respectively (Scheme 13) [47]. Vilarrasa and co-workers [47] also synthesized the double-headed nucleosides 63 and 64 with downwards orientation of the additional nucleosides at the C-3′ position. The synthesis was carried out via formation of anhydride 61. Azidation

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• of purine [73][74][75][76] or alkylation of inosine or guanosine derivatives (Ib→II, Scheme 1) [30][36]. In the next step, azide can be introduced either by a second SNAr reaction on the C2-halo derivative or by diazotization/azidation at C2. Then, the Cu(I)-catalyzed azide–alkyne cycloaddition

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• phosphite. The SNAr–Arbuzov reaction between 2,6-dichloropurine derivative 1 and triethylphosphite gave product 2a in 82% yield (Scheme 3) [12]. Next, attempts to substitute the chlorine atom at the purine C2 position were made using either NaN3 or TBAN3. Azidation experiments were tried in solvents such as

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• ) acetylation, (ii) azidation, and (iii) cycloaddition to produce IV–VIII. In spite of the broad scope and synthetic utility, it is evident that the multistep synthetic methodology is the only existing module for cycloaddition reactions. Our research group is focused on developing one-pot synthetic

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

• . Other organic dyes, including several acridinium salts, have been successfully applied in organophotocatalytic decarboxylation protocols. For example, rhodamine 6G (OD14, E(PC+*/PC) ≈ 1.2 V) [42] was used for the photocatalytic decarboxylative azidation of cyclic amino acids and rose bengal (OD15) [43

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• , and no significant selectivity was observed when nonsymmetrical iodonium salts were reacted under the optimized reaction conditions. Later in 2015, Greaney and co-workers described the copper-photocatalyzed azidation of styrene olefins and the concomitant introduction of a nucleophile (Scheme 9) [26

• active [Cu(I)] catalyst. Finally, the solvent or the nucleophile introduced to the reaction medium reacted with the latter. Later, Greaney and co-workers reported the photocatalytic azidation of benzylic C–H bonds (Scheme 10) [27]. Using the Sauvage catalyst [Cu(I)(dap)2]PF6 and the Zhdankin reagent, a

• haloperfluoroalkylation of alkenes and alkynes. Chlorosulfonylation of alkenes catalyzed by [Cu(I)(dap)2]Cl. aNo Na2CO3 was added. b1 equiv of Na2CO3 was used. Copper-photocatalyzed reductive allylation of diaryliodonium salts. Copper-photocatalyzed azidomethoxylation of olefins. Benzylic azidation initiated by [Cu(I

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• ; the first step in the synthesis of Tamiflu [18]. Results and Discussion Continuous-flow synthesis of ethyl (3S,4R,5R)-3-azido-4,5-bis(methanesulfonyloxy)cycohex-1-enecarboxylate (5). Mesyl shikimate azidation is a pivotal step in our proposed Tamiflu route. Mesyl shikimate 4 in the presence of a

• azidation reaction (Scheme 3). We herein present a comprehensive study on various mesyl shikimate 4 azidation procedures; with goal of safely and selectively making azide 5 in flow. Continuous flow C-3 mesyl shikimate azidation using sodium azide (NaN3). A continuous flow system fitted with a 19 µL reactor

• Kalashnikov and co-workers’ [20] explanation on NaN3 basicity-induced aromatisation resulting in undesired azide 5a. Therefore, an excess of NaN3 increases reaction basicity resulting in the undesired azide 5a being favoured. The continuous flow mesyl shikimate 4 azidation was highly regio- and

Homo- and hetero-difunctionalized β-cyclodextrins: Short direct synthesis in gram scale and analysis of regiochemistry

• Gábor Benkovics,
• Mihály Bálint,
• Éva Fenyvesi,
• Erzsébet Varga,
• Szabolcs Béni,
• Konstantina Yannakopoulou and
• Milo Malanga

Beilstein J. Org. Chem. 2019, 15, 710–720, doi:10.3762/bjoc.15.66

• reproducibility, ease of product purification, scalability of the reactions and versatility of the substituents introduced. Specifically, the prepared ditosylated β-CDs were separated using preparative reversed-phase column chromatography and their structures were elucidated by NMR experiments. Azidation led to

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• , CDCl3) δ 153.3, 152.9, 151.7, 145.9, 130.8, 44.7, 31.6, 29.8, 28.6, 26.6, 22.5, 14.0 ppm; HRMS–ESI (m/z): [M + H]+ calcd for C12H17Cl2N4, 287.0825; found, 287.0826. Azidation: NaN3 (5.88 g, 90.5 mmol, 3.0 equiv) was added to a solution of 9-alkyl-2,6-dichloro-9H-purine (30 mmol, 1.0 equiv) in acetone

Copper(I)-catalyzed tandem reaction: synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and alkynes

• Muhammad Israr,
• Changqing Ye,
• Munira Taj Muhammad,
• Yajun Li and
• Hongli Bao

Beilstein J. Org. Chem. 2018, 14, 2916–2922, doi:10.3762/bjoc.14.270

• the azidation of organic halides, such as aliphatic halides, vinyl halides, or aromatic halides with sodium azide [24][25][26][27]. Organic triflates [28] and organic boronic acids [29][30][31] can also be used as alternative precursors for organic azides, when reacted with sodium azide. However

Cobalt bis(acetylacetonate)–tert-butyl hydroperoxide–triethylsilane: a general reagent combination for the Markovnikov-selective hydrofunctionalization of alkenes by hydrogen atom transfer

• Xiaoshen Ma and
• Seth B. Herzon

Beilstein J. Org. Chem. 2018, 14, 2259–2265, doi:10.3762/bjoc.14.201

• of the azidation reagent (p-acetamidobenzenesulfonyl azide (p-ABSA)) and additive equivalents (see Supporting Information File 1, Table S1, entries 19–28), the tertiary alkyl azide 4i was obtained in 79% yield (Table 1, entry 9). To broaden the scope of C–N coupling process via HAT, we investigated

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• ) [119]. This approach was extended by Besset et al. to D-fructose and a range of unprotected mono- and disaccharides, again showing a preference of the reaction for the anomeric position instead of the primary [120]. Anomeric azidation was also investigated on diverse unprotected hexopyranoses by Larabi

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• catalytic benzoyloxy-trifluoromethylation using Togni’s reagent 5 (Scheme 4 and Scheme 5), the 1,2-benzoyloxy-azidation of alkenes can be performed in the presence of a copper catalyst with the azidobenziodoxolone ABX 40. The reaction takes place in dichloromethane using the copper(II) complex Cu(OTf)2 as

• for the 1,2-benzoyloxy-azidation reaction. Based on a preliminary observation made during their study on catalytic trifluoromethylation of enamides [49], the group of Gillaizeau has reported the catalytic conversion of enamides with various ABX derivatives 44 [50]. A screening of various metal

• . Catalytic asymmetric benzoyloxy-alkynylation of diazo compounds. Catalytic 1,2-benzoyloxy-azidation of alkenes. Catalytic 1,2-benzoyloxy-azidation of enamides. Catalytic 1,2-benzoyloxy-iodination of alkenes. Seminal study with cyclic diaryl-λ3-iodane. Synthesis of alkylidenefluorenes from cyclic diaryl-λ3