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

• , 4070 Basel, Switzerland 10.3762/bjoc.14.179 Abstract The focus of this review is to provide an overview of the field of organocatalysed photoredox chemistry relevant to synthetic medicinal chemistry. Photoredox transformations have been shown to enable key transformations that are important to the

• value of these methods to medicinal chemistry is considered. An overview of the general characteristics of the photocatalysts as well as some electrochemical data is presented. In addition, the general reaction mechanisms for organocatalysed photoredox transformations are discussed and some individual

• mechanistic considerations are highlighted in the text when appropriate. Keywords: C–H functionalisation; heterocycles; late-stage functionalisation; medicinal chemistry; organic dyes; organic photocatalysts; peptide chemistry; photoredox catalysis; Review 1 Introduction 1.1 Main advantages of

Recent advances in materials for organic light emitting diodes

• Eli Zysman-Colman

Beilstein J. Org. Chem. 2018, 14, 1944–1945, doi:10.3762/bjoc.14.168

• (LEECs), two types of electroluminescent devices; (ii) sensing materials employed in electro-chemiluminescence; and (iii) photocatalysts employed in photoredox catalytic reactions.

Visible light-mediated difluoroalkylation of electron-deficient alkenes

• Vyacheslav I. Supranovich,
• Vitalij V. Levin,
• Marina I. Struchkova,
• Jinbo Hu and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2018, 14, 1637–1641, doi:10.3762/bjoc.14.139

• equivalents of the iododifluoromethyl carbanion [33][34][35][36]. We also demonstrated that iodides 1 can alkylate silyl enol ethers [37] under photoredox conditions [38][39][40]. However, the latter protocol is inapplicable to the addition to electron-deficient alkenes since a radical resulting from the

• product 3a was isolated in 83% yield (Table 1, entry 6). N,N'-Dimethylimidazolidene borane complex (NHC·BH3) was also efficient (Table 1, entry 5), but because of availability and cost issues, sodium cyanoborohydride was used for further studies. We also evaluated the photoredox-mediated

Metal-free formal synthesis of phenoxazine

• Gabriella Kervefors,
• Antonia Becker,
• Chandan Dey and
• Berit Olofsson

Beilstein J. Org. Chem. 2018, 14, 1491–1497, doi:10.3762/bjoc.14.126

• ][8], are present in a variety of dyes [9], and can be applied in chemosensors and dye-sensitized solar cells (Figure 1) [10][11][12]. N-Arylphenoxazines were recently employed as photoredox catalysts in metal-free polymerizations [13]. The first synthesis of phenoxazine dates back more than 100 years

Investigations of alkynylbenziodoxole derivatives for radical alkynylations in photoredox catalysis

• Yue Pan,
• Kunfang Jia,
• Yali Chen and
• Yiyun Chen

Beilstein J. Org. Chem. 2018, 14, 1215–1221, doi:10.3762/bjoc.14.103

• Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China 10.3762/bjoc.14.103 Abstract The alkynylbenziodoxole derivatives are recently developed alkynylation reagents in organic synthesis, which demonstrate excellent radical alkynylation reactivity in photoredox

• radical; alkynylbenziodoxoles; photoredox catalysis; radical alkynylation; Introduction The introduction of the alkynyl group to organic molecules is an important synthetic transformation in organic synthesis [1][2][3][4]. Recently, cyclic iodine(III) reagents (CIR)-substituted alkynes

• group first used alkynylbenziodoxoles for decarboxylative radical alkynylation under silver salt and persulfate conditions [19]. In 2014, the Chen group discovered that alkynylbenziodoxoles (BI-alkyne) readily participated in photoredox catalysis as the radical alkynylation reagent [20], after which

Stepwise radical cation Diels–Alder reaction via multiple pathways

• Ryo Shimizu,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 704–708, doi:10.3762/bjoc.14.59

• reported by Bauld in 1986 [16] and was elegantly revisited by Yoon in 2011 [17] in the field of photoredox catalysis (Scheme 1). The reaction was further studied by Ferreira and Shores [18], followed by a unique mechanistic investigation by Rappé [19]. Although most recent examples of the radical cation

Investigating radical cation chain processes in the electrocatalytic Diels–Alder reaction

• Yasushi Imada,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 642–647, doi:10.3762/bjoc.14.51

• ion chain processes. As an early example, Bauld estimated the chain lengths of cyclodimerizations of cyclohexadiene and trans-anethole (1) [18]. More recently, Yoon has established a straightforward method to estimate the chain length of photoredox processes using the combination of quantum yield and

Diels–Alder cycloadditions of N-arylpyrroles via aryne intermediates using diaryliodonium salts

• Huangguan Chen,
• Jianwei Han and
• Limin Wang

Beilstein J. Org. Chem. 2018, 14, 354–363, doi:10.3762/bjoc.14.23

• coupling products were obtained in moderate to good yields (Scheme 1a) [6]. Later in 2013, Xue and Xiao et al. developed a method of photoredox catalysis in the presence of [Ru(bpy)3]2+ with visible light for the coupling reaction of arenes with unprotected or N-substituted pyrroles, pyrrole substrates

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

• merger of photoredox and Cu catalysis (Scheme 21). In this protocol, the CF3 radical was generated by visible light photoredox, then Cu aryl species were generated through Cu catalysis. Aromatic boronic acids bearing either electron-donating or electron-withdrawing substituents underwent

• trifluoromethylation smoothly to give the corresponding products in high yield. It represented a new example of combining transition metal and photoredox catalysis to achieve the trifluoromethylation of (hetero)aromatic boronic acids. Then, the same group [41] chose a more practical CF3 source, CF3SO2Na (Langlois

• . Trifluoromethylation of boronic acid derivatives reported by the group of Liu. Trifluoromethylation of organotrifluoroborates reported by the group of Huang. Trifluoromethylation of aryl- and vinylboronic acids reported by the group of Shibata. Trifluoromethylation of arylboronic acids via the merger of photoredox and

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

• ; Introduction Visible-light photoredox catalysis has developed into an important tool for organic synthesis in the last two decades. Energy-efficient and cheap visible-light-emitting diodes are perfect light sources allowing chemists now to conduct photocatalyzed reactions without special or expensive equipment

• . Photoredox-active metal complexes or organic dyes are used to initiate photo-induced single-electron transfer (SET) processes upon excitation with visible-light. Such photooxidations or photoreductions yield reactive organic radicals, which can undergo unique bond forming reactions, under very mild

• conditions. The key concepts of photocatalysis and photoredox-catalyzed reactions for carbon–carbon and carbon–heteroatom (C–X) bond formation have been reviewed in detail. However, several new photocatalytic methods for the formation of carbon–sulfur (C–S) bonds were recently reported and we aim to

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• acrylamides were also investigated for the realisation of cascade reactions including a trifluoromethylation step. This was notably the case of unactivated alkenes: Dolbier and co-workers showed that such compounds could be involved in photoredox-catalysed trifluoromethylation reactions, followed by a 6-exo

• -cyanotrifluoromethylations [22] of alkenes under photoredox catalysis. These reactions proceeded through a formyl or a cyano group migration triggered by the addition of the trifluoromethyl radical onto the alkene moiety. Both methodologies were developed using Togni’s hypervalent iodine reagent as the CF3 source, but it

• was found that they also proceeded smoothly with CF3SO2Cl (Scheme 15). Chlorotrifluoromethylation of alkenes: As clearly demonstrated in the works described above, CF3SO2Cl is a reliable CF3 source under photoredox catalysis. However, its use under similar conditions can also allow the simultaneous

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• -trifluoromethylated ketones by reaction of CF3SO2Na under photoredox catalysis. The substrate scope was broad and the reaction proceeded with high functional group tolerance; indeed, aryl-, alkyl-, hetero-functionalised terminal as well as non-terminal vinyl azides 15 were compatible with the reaction conditions. In

• heterocycles. Subsequently, a photoredox-catalysed azotrifluoromethylation of unactivated alkenes was developed by Chen, Xiao and co-workers [32]. The scope was broad for a variety of unactivated alkenes, functionalised or not, and aryldiazonium salts (Scheme 13). Interestingly, the method did not require

• electron oxidation of CF3SO2Na was performed by visible-light activated N-methyl-9-mesitylacridinium as a photoredox catalyst. Two hydrogen atom donors, 20 mol % of methyl thiosalicylate 38 for aliphatic alkenes (or 1 equiv of thiophenol 39 for styrenyl alkenes) and 2,2,2-trifluoroethanol (TFE), worked in

Synthesis of 1,3-cis-disubstituted sterically encumbered imidazolidinone organocatalysts

• Jan Wallbaum and
• Daniel B. Werz

Beilstein J. Org. Chem. 2017, 13, 2577–2583, doi:10.3762/bjoc.13.254

• –Crafts alkylation [23] and in combination with photoredox catalysis (Scheme 1a) [24]. The enantioselective α-alkylation was achieved by merging the common photoredox catalyst Ru(bpy)3Cl2 with imidazolidinone catalyst 3a·TfOH, controlling the stereochemistry of the radical addition via an intermediate

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• starting from an isoquinoline bearing an ester group at C-8. In a photoredox-catalyzed direct C–H arylation a 4-methoxyphenyl residue from a methoxyphenyldiazonium salt was introduced at C-1, and after ester hydrolysis intramolecular Friedel–Crafts acylation afforded menisporphine (2). In continuation of

Mechanochemical borylation of aryldiazonium salts; merging light and ball milling

• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1463–1469, doi:10.3762/bjoc.13.144

• yielded the same negative result proving that ambient light did not mediate the photoredox catalytic borylation reaction under mechanochemical conditions (Table 1, entry 3). Furthermore, neat grinding of a catalyst-free mixture of 1a and 2 under blue LEDs (light-emitting diodes) light did not afford the

• –d were detected. Meaning that the external light contributes to both, heating the reaction mixture to its eutectic and it also initiated the photoredox process. Similarly, a photocatalyzed reaction between 2 and 4-nitrobenzenediazonium tetrafluoroborate (1e), a salt found also to undergo

• milling conditions (vide supra) could have been indeed the result of a photoredox transformation where the organic photocatalyst eosin Y played a key role in triggering the SET process. Conclusion In summary, simultaneous activation of an organic system by light and ball milling techniques has been

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions

• Manuel Anselmo,
• Lisa Moni,
• Hossny Ismail,
• Davide Comoretto,
• Renata Riva and
• Andrea Basso

Beilstein J. Org. Chem. 2017, 13, 1456–1462, doi:10.3762/bjoc.13.143

• therefore designed and synthesized reagents bearing ester or carboxylic functions in a convenient position, for a possible intramolecular attack, to investigate their reactivity. While working on this project, König and Fagnoni reported the photoredox-catalyzed reaction of 2-carboxybenzenediazonium salts

Chemoselective synthesis of diaryl disulfides via a visible light-mediated coupling of arenediazonium tetrafluoroborates and CS₂

• Jing Leng,
• Shi-Meng Wang and
• Hua-Li Qin

Beilstein J. Org. Chem. 2017, 13, 903–909, doi:10.3762/bjoc.13.91

• and to minimize the formation of the byproducts was conducted. As recently surveyed, photoredox catalysts are widely employed for the generation of radicals for diverse radical reactions [19]. Further, the application of aryl radicals generated from aryldiazonium salts under visible light irradiation

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

• residence time. Noël optimized, for the first time, a trifluoromethylation of aromatic heterocycles by continuous-flow photoredox catalysis. The process benefited from the use of microreactor technology and readily available photocatalysts. The process was also employable for perfluoroalkylation. The

• . Trifluoromethylation by continuous-flow photoredox catalysis. Flow photochemical synthesis of 6(5H)-phenanthridiones from 2-chlorobenzamides. Synthesis of biaryls 14a–g under photochemical flow conditions. Flow oxidation of hydrazones to diazo compounds. Synthetic use of flow-generated diazo compounds. Ley’s flow

Green chemistry

• Luigi Vaccaro

Beilstein J. Org. Chem. 2016, 12, 2763–2765, doi:10.3762/bjoc.12.273

• . Turner [10], and “Organic synthesis using photoredox catalysis” by Axel G. Griesbeck [11], proving that green chemistry and sustainability can be approached from many different perspectives. The breadth of chemical and technological innovations makes the definition of novel metrics for the evaluation of

Copper-catalyzed asymmetric sp³ C–H arylation of tetrahydroisoquinoline mediated by a visible light photoredox catalyst

• Pierre Querard,
• Inna Perepichka,
• Eli Zysman-Colman and
• Chao-Jun Li

Beilstein J. Org. Chem. 2016, 12, 2636–2643, doi:10.3762/bjoc.12.260

• , St Andrews, Fife, KY16 9ST, UK 10.3762/bjoc.12.260 Abstract This report describes a highly enantioselective oxidative sp3 C–H arylation of N-aryltetrahydroisoquinolines (THIQs) through a dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)2(dtbbpy)]PF6, and chiral copper

• [2]. The emerging and expanding field of visible-light-mediated photoredox catalysis presents unique opportunities for the conception of new synthetic routes [3][4][5][6][7][8][9][10][11][12]. Upon exposure to visible light, photoredox catalysts can function as both reductant and oxidant, thereby

• providing extremely important tools for potential transition-metal-catalyzed enantioselective reactions of sp3 C–H bonds, which could be carried out at low temperature and under mild reaction conditions [13][14]. We envisioned that combining photoredox catalysis with typical cross-coupling methods will

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• halide (e.g., (±)-16). Subsequently, the achiral radical combines with the chiral Cu catalyst and undergoes an enantioselective bond-formation step in conjunction with the carbazole nucleophile to form α-aminoamide 18. This report fuses both enantioconvergent and photoredox catalysis, two powerful and

• . Enantioconvergent synthesis of phosphines governed by Curtin–Hammett/Winstein–Holness kinetics (TMS = trimethylsilyl, Is = 2,4,6-triisopropylphenyl). Stoltz’ stereoablative oxindole functionalization. Fu’s type II enantioconvergent Cu-catalyzed photoredox reaction. Stereoablative enantioconvergent allylation and

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates. Keywords

• : α-lithiation; C–H functionalization; heterocycle; photoredox catalysis; piperazine; Introduction Piperazine is one of the most important saturated N-heterocycles frequently found in life-saving small-molecule pharmaceuticals [1]. In a recent statistical study done by Njardarson and co-workers

• starting materials. The reaction proceeds with excellent regio- and diastereoselectivity which is presumably due to a regio- and stereoselective alkene insertion into the strained metalla-aziridine intermediate 84. Photoredox catalysis Visible-light photoredox catalysis has emerged as a powerful platform

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• )ureas have been synthesized in order to utilize both hydrogen bonding interactions and enamine formation. In the last 10 years the field has witnessed the development of some new activation modes, such as SOMO catalysis [8] and photoredox organocatalysis [9]. Six-membered rings are found in many natural

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• facilitates the iminium ion isomerization. This year, several examples of improved conditions for CDC reactions have been reported. With the emergence of photoredox catalysis as a powerful technique for organic synthesis, Li’s research group has discovered improved conditions for the CDC reaction of N

• -aryltetrahydroisoquinolines with alkynes (Scheme 11) [33]. By using an iridium-based photoredox catalyst in combination with benzoyl peroxide, iminium ion 7 is formed in situ. This strategy enables reduction of the reaction temperature, ultimately enabling higher enantioselectivities. With respect to the scope of alkynes

• azomethine imines. Su’s CDC of tetrahydroisoquinolines and alkynes under ball milling conditions. Ma’s A3-coupling. Li’s CDC reaction using photoredox catalysis. Liu’s CDC reaction of N-carbamoyltetrahydroisoquinolines. T+BF4– = 2,2,6,6-tetramethylpiperidine N-oxide tetrafluoroborate. Aponick’s alkynylation

Preparative semiconductor photoredox catalysis: An emerging theme in organic synthesis

• David W. Manley and
• John C. Walton

Beilstein J. Org. Chem. 2015, 11, 1570–1582, doi:10.3762/bjoc.11.173

• David W. Manley John C. Walton University of St. Andrews, EaStCHEM School of Chemistry, St. Andrews, Fife, KY16 9ST, UK 10.3762/bjoc.11.173 Abstract Heterogeneous semiconductor photoredox catalysis (SCPC), particularly with TiO2, is evolving to provide radically new synthetic applications. In

• photoredox catalysts (PRCs), have been exploited that enable visible and UVA radiation to be put to use without directly breaking chemical bonds. Typically, PRCs when photoexcited mediate electron transfer between suitable precursor substrates thus generating radical ions and thereby launching fresh

• popularity of homogeneous PRCs is due to their ease of synthesis and stability as well as their excellent photoredox properties. Furthermore, they can be activated by visible light, precluding the requirement for specialized irradiation setups, and their reactivity can be tuned by altering the substitution