Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• metallation deprotonation mechanisms mediated by common catalysts like Pd(OAc)2. Our methodology not only identifies potential activation sites but also addresses the limitations of existing models by including a broader range of directing groups and reaction conditions while maintaining moderate

• reliable regioselectivity predictions that are essential for accelerating innovation in materials science and medicinal chemistry. Keywords: C–H activation; chemical synthesis planning; directing groups; quantum mechanics; regioselectivity prediction; Introduction The activation and functionalization of

• . Nevertheless, the high prevalence of C–H bonds in organic compounds presents a substantial challenge in achieving site-specific functionalization. A principal strategy to circumvent this challenge leverages directing groups (DGs) within the substrate, which coordinate to the metal centre of the catalyst

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• features of the starting material. By exploiting preorganization, steric effects, or directing groups within the substrate, chemists can achieve high levels of regioselectivity, diastereoselectivity, and enantioselectivity without relying on external catalysts or additives. This approach has been

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• with olefins bearing electronic directing groups (such as aryl, boryl, or trifluoromethyl substituents) that guide regioselective hydrocupration, unactivated alkyl-substituted alkenes pose a persistent challenge. The recent breakthrough in CuH-catalyzed enantioselective and diastereoselective allylic

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• functionalization with directing groups, however, achieving similar results without the assistance of a directing group continues to be a significant challenge [53][54]. Radical-based approaches can facilitate C(sp³)–H functionalization without directing groups, however, controlling the selectivity is difficult. In

• limited, which can restrict both reactivity and selectivity. Significant progress has been achieved in C–H activation reactions, with the use of directing groups, which play a crucial role in selectivity and reactivity. However, the use of directing groups requires additional synthetic steps for their

• installation and removal and present challenges with limited substrate compatibility. Future research could focus on designing catalytic systems that reduce dependence on directing groups, such as utilizing transient directing groups to simplify the synthetic process. Moreover, the development of asymmetric

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• usage of directing groups and any metal catalyst. Also, the electronic nature of a substituent at the C4 position of the starting triazole did not negatively impact the regioselectivity. Further, C4 and C5 disubstituted triazoles also produced the N2-arylated product. Remarkably, this is the only

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

• molecules. 1.3.6 Pd-assisted anodic oxidation. In 2023, Ackermann and coworkers reported a Pd-catalyzed anodic oxidation for the alkenylation of arenes without the need for directing groups [57]. Using Pd(OAc)2 as the catalyst, 2-methyl-2-(phenylthio)propanoic acid as the ligand, and 1,4-benzoquinone (BQ

• functionalization of complex molecules without the need for directing groups, thereby simplifying the synthesis process and enhancing the exploration of new drug candidates. 1.3.7 Ir-assisted anodic oxidation. An Ir-electrocatalyzed vinylic C(sp2)–H activation method for the preparation of α-pyrones via annulation

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• mainly via metal-catalyzed C–N or C–C bond formation. Despite recent advances in the area of remote C–H functionalization, this strategy still requires some pre-functionalization of the starting material or the use of directing groups [28][29][30][31][32]. An alternative strategy is based on aromatic

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• bond formation to afford the acyloxylation product was observed, and favoured when using directing groups with less steric bulk. This product had the opposite stereochemistry to the fluorination product suggesting it occurred via a competitive SN2 pathway. This is supported by the selectivity for C–O

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• directing groups could be used as coupling partners. The ligand acts as an activator of the catalyst to promote the reaction, and the iron-bound anion plays a crucial role in catalysis. This reaction might occur via a radical pathway, with the iron catalyst playing a significant role in electron transfer

• coordinated with metal catalysts to control the selectivity and improve the reactivity in metal-catalyzed or -mediated reactions. Therefore, controlling the regioselectivity of CDC reactions by directing groups is of great interest [95][96]. Li et al. reported a cobalt-catalyzed CDC between unactivated C(sp2

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• % yield. Further, Shi and co-workers reported the rhodium-catalyzed directed C–H olefination of pyridines using different directing groups in 2013 [88] (Scheme 20a) and 2014 [89] (Scheme 20c), respectively. In the former study, under optimized conditions of [RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %) in DCE

• group-assisted C3/C4-arylation of pyridines. The authors screened various N-arylamide directing groups 144 out of which N-phenylamide was found to be the better directing group. Then, the authors screened various nicotinic and isonicotinic acids which afforded the desired products 145 and 146 in good

• alkynes 179. Different directing groups 178 were employed resulting in diversified products 180. The proposed mechanism (Scheme 35b) involves coordination of rhodium with isonicotinamide 178 and subsequent ortho-C–H activation generating the five-membered rhodacycle 183. Next, first alkyne 179 insertion

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• functional group tolerance with excellent stereoselectivities. In 2016, Ellman and co-workers demonstrated a Rh- or Co-catalyzed highly diastereoselective tandem C–H bond addition/aldol reaction sequence [96][97]. The C–H activation was promoted by pyridine, pyrazole, or imine directing groups, while the

C3-Alkylation of furfural derivatives by continuous flow homogeneous catalysis

• Grédy Kiala Kinkutu,
• Catherine Louis,
• Myriam Roy,
• Juliette Blanchard and
• Julie Oble

Beilstein J. Org. Chem. 2023, 19, 582–592, doi:10.3762/bjoc.19.43

• most reactive site. In contrast, C3-functionalizations of the formyl-furan unit via directing groups, as well as C4-functionalizations have been much less studied [19][20]. Within the framework of a large project oriented towards the selective formation of new bonds from furfural derivatives without

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• received considerable attention in recent years. Several different arene and directing groups have been investigated; however, they typically result in the exo-selective addition product with the bridge heteroatom intact. Although this limits the applicability of the reaction, the authors noted the use of

• pyrimidyl directing groups, despite reacting, resulted in a mixture of mono- and diarylation products. When investigating substituted oxabenzonorbornadienes both mono- and diarylated products were formed with only moderate yield. When azabenzonorbornadienes 30 were investigated in the same redox-neutral

• tedious process of installation and then removal of directing groups which is a common issue. A variety of substituents were tolerated on both the alkynols 184 and oxabenzonorbornadienes 30; however, substituted oxabenzonorbornadiene derivatives typically had diminished reactivity. Expansion of the

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• % yields, respectively. This reaction proved to be compatible with the presence of an ester (8c) or a halogen (8e). Other directing groups, such as substituted pyridines (9a and 9b) and pyrimidine (9c) turned out to be also efficient in this transformation (Scheme 5, 4 examples, up to 84% yield). The same

• year, the group of Huang reported an elegant and straightforward palladium(II)-catalyzed ortho-selective trifluoromethylthiolation of arenes bearing various directing groups using the nucleophilic trifluoromethylthiolating source AgSCF3 in combination with Selectfluor® as oxidant (Scheme 6, 29 examples

• ) were found to be suitable substrates leading to the corresponding products 12h and 12i in 91% and 83% yields, respectively. The use of other directing groups was also suitable for this transformation such as methyl and cyano-substituted pyridines 13a,b, pyrimidine (13c), pyrazole (13d), as well as the

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• , directing groups are introduced to the substrates covalently to achieve site-selective C–H bond activation, which prospered greatly in the past decades [7][8][9]. Template regulation is also introduced to locate reactive centers in a noncovalent way through hydrogen bonding [10][11][12]. Even though

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• be prepared by asymmetric C–H activation. The C–H activation or functionalization can be achieved by a metal-catalyzed chiral phosphoric acid ligand-assisted method, which offers distinct possibilities to provide various chiral biaryl compounds by changing different directing groups (DGs) [46]. Since

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• Fe or Co catalyst and N-containing directing groups, while an excess of Grignard reagents was used [24][25]. Thereafter, they also reported the Cp*Co-catalyzed ortho-C–H alkenylation of ferrocenes with alkynes [26] and the mono- and di-selectivity could be controlled by the fine-tuned directing

• groups. Kumar and co-workers developed a Cu-mediated C–H chalcogenation and sulfonation of ferrocenes [27][28][29]. The use of a bidentate 1,10-phenathroline ligand was critical to achieve mono-selectivity in the chacogenation reactions [28]. Meanwhile, Co(III)-catalyzed ortho-C–H amidation of ferrocene

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

• often requires relatively high catalyst loadings, directing groups, high reaction temperatures (100–160 °C), stoichiometric additives, or oxidants such as peroxide or silver salts that can be undesirable for large scale synthesis. Recently, photoredox dual catalysis has witnessed significant

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

• , 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

• the need for directing groups, presenting a broad scope and satisfactory yields. The late-stage modification of complex molecules like (+)-artemisinin (69) and a (+)-tetrahydrogibberellic acid analogue 70 could be rapidly achieved in moderate yields (Scheme 25C). In 2014, Brown and Rasik employed

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• exploitation of triazole rings as beneficial directing groups to produce complex triazoles has been screened. Although the postfunctionalization of disubstituted 1,2,3-triazoles may include multistep reactions for the synthesis of this kind of products, it is an easy and efficient strategy (Scheme 1). The

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• alkyne annulation was very recently achieved by Ackermann et al., which gave rapid access to synthetically meaningful isoindolones (Figure 1c) [34]. In spite of these indisputable advances, the successful removal of the directing groups to deliver the free-NH 3-methyleneisoindolin-1-one has thus far

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

• help with the planning of future reactions, throughout Sections 3 and 4, we present the developing mechanistic understanding of these reactions in the literature, including considerations such as triplet-to-triplet energy matching for photosensitization, polarity matching and directing groups for HAT

• process and could not be ruled out (Scheme 20). 3.3 Directing-group-guided C(sp3)–H fluorination 3.3.1 Ketones as directing groups: Related to the curious near-exclusive C2 selectivity of 1-phenylbutan-1-one as reported by Tan and co-workers [198], Lectka and co-workers reported highly selective

• monofluorination of C(sp3)–H bonds that are proximal (β- or γ-) to a carbonyl group [153] (Scheme 21); such selectivity was previously difficult to achieve with PS TTET fluorinations. The ketones, acting as directing groups, served as an elegant method to override the typical polarity matching-governed C(sp3)–H