N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• this work. In 2018, Anbarasan and Chaitanya developed an efficient approach for the C–H bond functionalization of aryl compounds containing a directing group using N-(thioaryl)phthalimides 14 in the presence of a palladium catalyst (Scheme 15) [53]. The thiolation occurred in the presence of Pd(OAc)2

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

• )–H and C(sp3)–H bonds by the ortho-alkylation reaction of aromatic carboxamides containing (pyridin-2-yl)isopropylamine (PIP–NH2) as an N,N-bidentate directing group (Scheme 32) [97]. The mechanism study showed that these reactions were a Co(III/IV/II) catalytic cycle, and the coordination of Co with

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• presence of an electron-donating functional group is crucial in the ring to activate it for aromatic electrophilic substitution processes. In 2019, Zhang and co-workers succeeded in the C6-selective aminoalkylation of 2,3-disubstituted indoles 4 without the presence of a directing group in the benzene ring

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

• metal-catalyzed directed and undirected, proximal as well as distal pyridine C(sp2)–H bond functionalizations in detail under different types of reactions. Further, this review excludes the use of pyridine as a directing group for C–H functionalizations and the C–H functionalization of fused pyridines

• . The usage of a bidentate ligand will enhance the trans-effect and shift the coordination towards the ring (Scheme 18b). There are numerous studies reported for directing group or chelate-assisted metal-catalyzed C–H functionalization reactions. However, non-chelate-assisted or undirected C–H

• tricyclic imidazonaphthyridinone derivative having antibacterial properties, with low catalyst loading (0.1 mol %) (Scheme 20b). Later, in 2014, the same authors, using an amide as directing group (DG), developed a protocol for the regioselective C3-alkenylation of pyridines through syn-addition of alkynes

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• substitution pattern, it requires a para-substituted ester as a directing group. The strategy furthermore cannot access 5H-dibenzo[b,f]azepines 1a as the ethylene bridge would cross react with the brominating agent [55][56]. N-Aryl and N-alkyldihydropyridobenzazepines 75 and 76 were synthesised by Tsoung et al

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

• formation of the imine directing group and the C3-functionalization with some vinylsilanes and norbonene. Keywords: biomass; C–H activation; flow; furfural; homogeneous catalysis; Introduction The conversion of biomass derivatives into value-added products is one of the key branches of green chemistry and

• (Scheme 1b). Results and Discussion First optimization with a home-made pulsed-flow setup We undertook the optimization of this flow strategy for the C3-alkylation reaction (Murai reaction) [37][38] of the furfurylimine 1 bearing a removable N,N'-bidentate directing group. In a previous study, this

• formation of ruthenium aggregates [43]. We therefore propose that the active species is a mononuclear carbonyl complex in which the ruthenium is coordinated to the two nitrogen atoms of the directing group (amino-imine). Preheating for 5 minutes at 130 °C would generate it from [Ru3(CO)11(L)], which would

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

• investigated the Ru-catalyzed ring-opening/lactamization of azabenzonorbornadiene derivatives 30 with arylamides 116 (Scheme 21) [64]. Weinreb amides outperformed other arylamides, likely serving as a better directing group for the initial aryl-C–H activation. While the scope of functionalized aryl Weinreb

• C–H activation as well as its involvement in the dehydration process. This reaction proceeded smoothly with a variety of both EWGs and EDGs on the 2-phenylpyridine. Interestingly, when swapping the pyridine directing group for thiophene or furan, yields were improved although quinolinyl and

• anti-β-nitrogen elimination to furnish the ring-opened intermediate [80]. In 2016, Liu reported the Rh(III)/Sc(III)-catalyzed domino reaction of oxabenzonorbornadienes 30 with alkynols 184 directed by a transient hemiketal group (Scheme 33) [81]. The use of a transient directing group avoids 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

• -promoted trifluoromethylthiolation of benzamide derivatives 1 at the ortho-position by C–H bond activation [114]. Indeed, using a bidentate directing group (amide derived from the 8-aminoquinoline), the mono- and difunctionalized compounds were obtained when Cu(OAc)2 (0.5 equiv) and the toxic and volatile

• involved in most cases an electrophilic SCF3 source (R1R2NSCF3). For these transformations, the following working hypothesis was generally suggested (Scheme 4). After coordination of the palladium catalyst to a directing group, the metallacycle A is formed. This latter undergoes an oxidative addition in

• yield (63%). The same year, Besset and co-workers reported a palladium-catalyzed C(sp2)–SCF3 bond formation on amides derived from 8-aminoquinoline as a cleavable directing group in the presence of the Munavalli reagent V (Scheme 9, 12 examples, up to 71% yield) [106]. Depending on the substitution

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• sphere. Notably, the Ni template is an important component of the reaction. It is responsible for chirality induction and facilitates the cyclopropane ring opening, significantly decreasing the reduction potential value. It stabilizes the anion formed and serves as a directing group. Thus, the Ni–Schiff

Synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of ortho-chlorinated arylhydrazones

• Yara Cristina Marchioro Barbosa,
• Guilherme Caneppele Paveglio,
• Claudio Martin Pereira de Pereira,
• Sidnei Moura,
• Cristiane Storck Schwalm,
• Gleison Antonio Casagrande and
• Lucas Pizzuti

Beilstein J. Org. Chem. 2022, 18, 1079–1087, doi:10.3762/bjoc.18.110

• ‐substituents, and others suffer from poor regioselectivity for substrates without a directing group [18][19][21][22]. On the other hand, methods based on metal-free [23], palladium- [24][25], and copper-promoted [26][27][28][29][30][31] intramolecular N-arylation of in situ-generated or isolated o

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• ortho-directed lithiation with tert-butyllithium with carbamate as the directing group followed by electrophilic quench with methyl chloroformate and intramolecular aminolysis. Finally, hydrolysis removed the directing group, affording the final product 239 in 50% yield (Scheme 38) [59]. Structurally

Direct C–H amination reactions of arenes with N-hydroxyphthalimides catalyzed by cuprous bromide

• Dongming Zhang,
• Bin Lv,
• Pan Gao,
• Xiaodong Jia and
• Yu Yuan

Beilstein J. Org. Chem. 2022, 18, 647–652, doi:10.3762/bjoc.18.65

• decades. With the combination of C–H activation, many aminations of aryl compounds have been established [6][7][8][9][10][11][12][13][14][15][16]. However, it is necessary to introduce the directing group into the arene in most successful cases. As a good amino source, phthalimides have been widely

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

• 16 via β-H elimination using (S)-CPA 4 as a ligand (Scheme 7) [51]. The directing group (NH2) facilitated the C–H activation on the other aromatic ring and ensured its coordination with Pd to form palladacycle I-2 to restrict bond rotations and promote exclusive allylic selectivity via β-H1

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• activated derivatives (intramolecular Friedel–Crafts acylation) [29][30][31] found wide application here. In a different approach, a total synthesis of dengibsin (1a) was accomplished by Wang and Snieckus in 15 steps by means of a directed remote metalation [32], using a benzamide residue as the directing

• group (Scheme 2) [33]. In contrast to transition-metal-mediated approaches [27], metal-free oxidative methods are attractive not only from an ecological point of view, but also due to the typically low cost of the applied oxidants. Biarylcarboxaldehydes were cyclized to fluorenones using K2S2O8 [34

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

• the directing group could be removed easily under basic conditions. Keywords: amination; C–H activation; copper; ferrocene; mono-selectivity; Introduction Ferrocene-based compounds have broad applications from asymmetric catalysis to medicinal discovery [1][2][3][4][5][6][7][8]. Therefore, the

• ferrocene carboxylic amide 1a with morpholine (2a) using 8-amonoquinoline as directing group [51][52][53][54][55][56]. The ortho-aminated ferrocenylamide 3a was isolated in 11% yield in the presence of CuI, N-methylmorpholine N-oxide (NMO) and K2CO3 in DMF (Table 1, entry 1). When the reaction was conducted

• in 50% yield (Scheme 4b, 1.32 g). For synthetic utility, the directing group was conveniently removed by refluxing with KOH in EtOH and the benzyl-protected ester 5 was obtained in 75% yield. We also conducted several deuteration experiments to shed a preliminary insight into the mechanism. No H/D

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

• same year, Wu, Li and co-workers described a successful cobalt-Cp*-catalyzed C–H amidation of benzaldehyde derivatives (Scheme 39B), in which the aldehyde portion works as the directing group [198]. After an acid workup using diluted hydrochloric acid, the desired ortho-amidated products were obtained

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

• -economical approach to several tryptophan-containing peptides with significant potential for drug discovery and medicinal chemistry. Positional selectivity was observed at the C2 position due to the presence of the pyrimidine directing group. Interestingly, alkynylative conjugation of tryptophan to a steroid

• peptide–carbohydrate conjugation was achieved using tryptophan-containing peptides 29 and sugar-containing allyl carbonates 30 in chemo- and site-selective manners using a pyridyl directing group. The optimized reaction conditions entailed the use of dimanganese decacarbonyl as the catalyst and sodium

• adjacent directing group (see 31h). This manganese(I)-catalyzed late-stage glycosylation provides hexaglycopeptide conjugate 31m without epimerization. Moreover, the late-stage C–H diversification process enabled bioorthogonal access to glycosylated peptides, such as a fluorescent BODIPY-labeled tryptophan

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

• -functionalized triazoles 182 was synthesized in moderate to high yield through an iridium-catalyzed, directing-group-promoted regioselective [3 + 2]-cycloaddition of alkynes 176 and azides 177. The optimized conditions for this reaction were found to be Ir(cod)Cl2 (2 mol %) and CH2Cl2 at room temperature. 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

• : benzhydrazides; copper; 3-methyleneisoindolin-1-one; removable directing group; Introduction Inexpensive copper-promoted oxidative C−H activations [1][2][3][4][5][6][7][8][9][10][11] have been recognized as competent tools for the efficient assembly and late-stage functionalization of organic molecules due to

• unfortunately proven elusive [35]. 2-(1-Methylhydrazinyl)pyridine (MHP) [36] was identified as a powerful removable bidentate directing group, which found widespread application in various cobalt-catalyzed C−H activations [37][38][39][40]. Thus, our group also accomplished a set of electrochemical cobalt

• C−H/N−H activation. Copper-mediated oxidative C−H/N−H functionalization of hydrazides 1 with ethynylbenzene (2a). Copper-mediated oxidative C−H/N−H functionalization of 1 with alkynes 2. Decaboxylative C−H/N−H activation and cleavage of the directing group. Summary of key mechanistic findings

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

• unactivated olefins [33][34]. The observed competition between protodemetalation and β-hydride elimination steps was elegantly overcome by Engle and co-workers through the use of olefins tethered to the directing group 8-aminoquinoline (AQ) amide. This amide trapped the carbometalated intermediate generated

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

• ]. The regioselectivity is controlled by the formation of a six-membered cyclic intermediate. Directing-group-assisted C(sp3)−H halogenation reactions are efficient for promoting regioselective C(sp3)−H halogenations (Scheme 1c) [24][25][26][27][28]. In these reactions, the C(sp3)–H bond at the β

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

• amount of background reaction and the more rigid xanthone structure acting as a superior stereo-directing group. Further variation to a thioxanthone unit 185, which has a lower triplet energy (ET = 2.7 eV), was used to investigate a similar [2 + 2] photocycloaddition, giving comparable yields and

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

• 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

• benzil (T1 = 53.7 kcal⋅mol−1, Scheme 23). Control reactions revealed that Selectfluor® as the fluorinating agent gave the highest product yield, and light was essential for the reaction. To demonstrate the importance of the ketone directing group, ethylbenzene was employed under the same reaction

• . The authors demonstrated that the transition state for Selectfluor® undergoing HAT at this position (see TS1) was more kinetically accessible, despite the bond dissociate free energies (BDFEs) suggesting C3 functionalization (Scheme 27). 3.4 Directing-group-guided benzylic C–H fluorination In another

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

• metal catalyst X2M into an aromatic C–H bond of a substrate (generally facilitated by the presence of a directing group (DG)), delivers a metal–aryl complex. Coordination and subsequent insertion of an alkene into the M–aryl bond then provides the desired coupling product after β-hydride elimination

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

• David Schönbauer,
• Carlo Sambiagio,
• Timothy Noël and
• Michael Schnürch

Beilstein J. Org. Chem. 2020, 16, 809–817, doi:10.3762/bjoc.16.74

• address a single C–H bond selectively without compromising the others. To circumvent this problem, directing groups can be installed, which guide a metal catalyst to a specific C–H bond [4][5]. In case the directing group is not needed in the final product, this strategy accounts for additional reaction

• steps for the installation and removal of the directing group. However, there is also a good number of substrates containing C–H bonds that are inherently more reactive than others in the same molecule, and in such cases a selective C–H functionalization can be achieved in the absence of any directing

• group [2][6][7]. For example, in tetrahydroisoquinolines (THIQs) the benzylic C1-position is significantly more reactive compared to the others and its selective functionalization has been reported [8]. The THIQ moiety is of special interest due to its presence in several different natural products [9