(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• Carlos R. Azpilcueta-Nicolas Jean-Philip Lumb Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada 10.3762/bjoc.20.35 Abstract Due to their ease of preparation, stability, and diverse reactivity, N-hydroxyphthalimide (NHPI) esters have found

• many applications as radical precursors. Mechanistically, NHPI esters undergo a reductive decarboxylative fragmentation to provide a substrate radical capable of engaging in diverse transformations. Their reduction via single-electron transfer (SET) can occur under thermal, photochemical, or

• of parameters with which to control reactivity. In this perspective, we provide an overview of the different mechanisms for radical reactions involving NHPI esters, with an emphasis on recent applications in radical additions, cyclizations and decarboxylative cross-coupling reactions. Within these

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

• involved in the activation of DDQ by coordinating the carbonyl oxygen atom which leads to an increase in the oxidation activity of DDQ. Subsequently, Li et al. improved the above method, using a mixture of indium and copper salts as a catalyst, NHPI (N-hydroxyphthalimide) as a co-catalyst to achieve the

• oxidative alkylation of cyclic benzyl ethers with malonates or ketones. Oxygen is used as a terminal oxidant at atmospheric pressure. The key intermediate of this oxidative coupling reaction is benzyl alcohol intermediate C (Scheme 4) [52]. The generation of N–O radicals from NHPI in the presence of oxygen

• important gap. Research progress of coupling reactions and active compounds containing α-C(sp3)-functionalized ethers. Transition-metal-catalyzed CDC pathways. CDC of active methylene compounds in the α-C(sp3) position of ethers. InCl3/Cu(OTf)2/NHPI co-catalyzed CDC reaction. CDC of cyclic benzyl ethers

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

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• carboxylate anion and/or reduction of the corresponding N-hydroxyphthalimide- (NHPI)-derived redox-active ester, although it destroys their stereochemical information [46][47][48][49][50][51]. In addition, the side-chains of aromatic amino acids (mainly electron-rich tryptophan and tyrosine) can be

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• CrO2 [9], PhI(OAc)2/I2 [10], TEMPO [11], NHPI [12], and metal catalysts [13], suffer from serious limitations including the use of metal catalysts, high temperature, risk of explosive hazards, production of large waste, and often low yield (Scheme 1c). Thus, an environmentally benign method that could

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

• -functionalization reactions [74][75][76][77] due to their high reactivity in hydrogen atom abstraction and relatively slow self-decay. One of the most synthetically available and effective catalysts of this family is N-hydroxyphthalimide (NHPI). In the presence of co-catalysts, such as Co(OAc)2, it is partially

• oxidized by molecular oxygen to the phthalimide-N-oxyl radical (PINO) at room temperature and atmospheric oxygen pressure. The NHPI/Co(OAc)2 combination [78][79][80], also known as the Ishii catalytic system is one of the most effective in organic synthesis for the room temperature [78][79] aerobic

• oxidation of substrates with activated CH-bonds, such as alkylarenes (Scheme 6). At higher temperatures, even unactivated alkanes can be functionalized [75][81]. The NHPI/Co(OAc)2 system was successfully employed for the selective oxidation of methylarenes to aromatic carboxylic acids [78] (in AcOH medium

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

• (reaction 3) [27]. Herein, we report a method for the construction of aromatic amines via the copper-catalyzed intermolecular radical amination of arenes with N-hydroxyphthalimide (NHPI) under air. Results and Discussion Initially, N-hydroxyphthalimide (NHPI, 2a) was reacted with benzene, catalyzed by CuBr

• obtained in moderate to high yields. According to the experimental results and our previous work [27][28], a possible reaction mechanism is given in Scheme 4. At first, NHPI combines with triethyl phosphite to form intermediate 4, which is the loss of ethanol to generate intermediate 5. Then, single

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

• nitrate (CAN) [41], 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO)/CuCl [51], K2S2O8 [36], dimethyl sulfoxide (DMSO)/O2 [52], PhI(OAc)2/benzoyl peroxide (BPO) [47], Dess-Martin periodinane, N-bromosuccinimide (NBS), N-hydroxyphthalimide (NHPI)/Co(OAc)2/O2 [53], H2O2/tetrabutylammonium iodide (TBAI) [43], CBr4

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

•  9). In addition to perfluoroalkyl iodides, this protocol was further extended to alkyl halides, trifluoromethylthiolate, amines, cycloketone oxime esters, and carboxylic acid N-hydroxyphthalimide esters (NHPI). In 2018, Peters and Fu [57] explored the copper-catalyzed three-component coupling of

• quinolones 56, indolo[3,2-c]quinolines 57, β-amino acids 58, and 1,4-dihydropyridine derivatives 59 were obtained through this route in moderate yields (Scheme 26). Besides nucleophiles, aromatic amines also reacted with redox-active radical precursors, such as NHPI [95] and N-alkoxyphthalimides 55 [96]. The

• [100] groups reported that NHPI esters (67, 68) have been used as alkyl radical precursors in decarboxylative coupling reactions. These reactions feature a wide substrate scope. Primary, secondary, and tertiary alkyl carboxylic acids exhibit good yield, such as decarboxylative coupling reactions

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• .17.89 Abstract A visible light-mediated heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile has been established using K-modified carbon nitride (CN-K) as a recyclable semiconductor photocatalyst. This protocol, employing readily accessible alkyl N-hydroxyphthalimide (NHPI

• the generation of cyanomethyl radicals from readily available acetonitrile has not been reported yet. Herein, we disclose a CN-K-catalyzed cyanomethylarylation of both unactivated and activated alkenes with acetonitrile utilizing readily available alkyl N-hydroxyphthalimide (NHPI) esters as the

• recyclability, broad substrate scope, and high functional group tolerance (Scheme 1). Results and Discussion Our initial investigation focused on the CN-K photocatalyzed cascade alkyl radical addition/cyclization reaction of the N-arylallylamine 1a with tert-butyl N-hydroxyphthalimide (NHPI) ester (2a), a

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

• an EDA complex. First, the N-hydroxyphthalimide (NHPI) ester 142 is excited to electron acceptor 142* through visible-light intersystem crossing (ISC); diborate 143 combining with pyridine results in electron donor 145. Upon the formation of the EDA complex between 145 and 142*, electron transfer

• occurs, giving radical 146 and radical cation 147, respectively. Finally, radical 146 undergoes decarboxylation to afford an aryl radical and then combines with radical cation 147, yielding product 144 (Scheme 50). It should be noted that only when NHPI is firstly activated can it turn into an electron

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

• -hydroxyphthalimide (NHPI, OD22, similar to the benzophenone photocatalysts OD9 and OD10) can abstract an H atom from the aldehyde substrate 20.1. The resulting acyl radical adds to the (E)-β-nitrostyrene 20.2, and the following denitrosylation affords the chalcones 20.3. Alkenyl and aryl radical ions (radical

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• explored on redox-active alkyl esters derived from N-hydroxyphthalimide (NHPI, 37), in which case the reactions proceeded through a similar radical pathway due to, in part, the alkyl radical surrogate nature of the NHPI esters. The radical generated via decarboxylation of these esters is easily trapped by

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• radical precursor N-hydroxyphthalimide (NHPI), an anionic phase-transfer catalyst (KB(C6F5)4), and a Cu(I)-bisimine complex, to give the corresponding monofluorinated product (Scheme 25). One year later, Weng and co-workers [68] synthesized and characterized a new copper(I) fluoride complex ligated by a

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• hypervalent iodine species as a terminal oxidant. Combinations of ammonium iodate and catalytic N-hydroxyphthalimide (NHPI) were shown to be effective in the selective oxidation of n-butylbenzene directly to 1-phenylbutyl acetate in high yield (86%). This method shows moderate substrate tolerance in the

• oxygenation of substrates containing secondary benzylic C–H bonds, yielding the corresponding benzylic acetates in good to moderate yield. Tertiary benzylic C–H bonds were shown to be unreactive under similar conditions, despite the weaker C–H bond. A preliminary mechanistic analysis suggests that this NHPI

• -iodate system is functioning by a radical-based mechanism where iodine generated in situ captures formed benzylic radicals. The benzylic iodide intermediate then solvolyzes to yield the product ester. Keywords: acetoxylation; benzylic; iodate; NHPI; oxidation; radical; Introduction The ability to

DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

• Soumitra Guin,
• Raman Gupta,
• Debashis Majee and
• Sampak Samanta

Beilstein J. Org. Chem. 2018, 14, 2771–2778, doi:10.3762/bjoc.14.254

• as the requirement of high temperatures or use of strong oxidants (H2O2, oxone, K2S2O8, TBHP, PIDA, NHPI etc.) that are not much compatible with functionality, precluding late-stage functionalization. Moreover, the scope of substitution on the pyridine ring is limited which in turn hampers the

Hypervalent iodine compounds for anti-Markovnikov-type iodo-oxyimidation of vinylarenes

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Mikhail A. Syroeshkin,
• Alexander A. Korlyukov,
• Pavel V. Dorovatovskii,
• Yan V. Zubavichus,
• Gennady I. Nikishin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2018, 14, 2146–2155, doi:10.3762/bjoc.14.188

• radicals that is generated from an inexpensive N-hydroxyphthalimide (NHPI). This radical was used in various aerobic oxidations of bulk chemicals [18][19][43][44]. In the present work imide-N-oxyl radicals were used for the addition to the C=C bonds of styrenes with subsequent functionalization of the

• resulting benzylic radicals. Recently, the precursors of N-oxyl radicals, such as N-hydroxyphthalimide (NHPI), N-hydroxysuccinimide (NHSI), N-hydroxybenzotriazole (HOBt) and hydroxamic acids, have been used in the reactions of radical oxygenation of styrenes [45]. Growth of interest is observed concerning

• styrene (1i) and (E)-stilbene (1j) also underwent the studied transformation giving iodo-oxyimides 3ia (yield 51%) and 3ja (yield 83%). The reaction of NHPI (2a) with p-methoxystyrene under standard conditions led to a complex mixture of products, possibly due to an increased tendency of the substrate to

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• reaction was facilitated at room temperature by N-hydroxyphthalimide (NHPI) and cobalt acetate (Co(OAc)2) as catalysts in acetonitrile (Scheme 20). The reaction followed a free radical mechanism as exemplified by the oxidative dehydrogenation of DHPs. The initial step involved the formation of the

• phthalimide-N-oxyl radical (PINO) via transfer of hydrogen from NHPI to O2. Co2+-assisted this step by associating with oxygen to generate a Co3+–oxygen complex. It then abstracts the hydrogen from NHPI. Next, PINO abstracted a hydrogen from the DHP produced to generate radical X which aromatizes via hydrogen

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• did not work with ortho-substituted arenes. In 2013, Jiao and co-workers reported a hydroxylation protocol for (2-pyridyl)arenes using PdCl2 and N-hydroxyphthalimide (NHPI) as catalyst and molecular oxygen as oxidant [60]. (2-Pyridyl)arenes were converted to the hydroxylated products in toluene at 100

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• conditions. Oxidations of this kind using Oxone® [10][11], NaOCl [12] or especially peroxides [13][14][15][16][17][18][19] as the terminal oxidant are quite numerous. However, transformations using molecular oxygen are rare. Ishii showed that organocatalysts such as N-hydroxyphthalimide (NHPI) in combination

Copper-catalyzed aminooxygenation of styrenes with N-fluorobenzenesulfonimide and N-hydroxyphthalimide derivatives

• Yan Li,
• Xue Zhou,
• Guangfan Zheng and
• Qian Zhang

Beilstein J. Org. Chem. 2015, 11, 2721–2726, doi:10.3762/bjoc.11.293

• amination of allenes [46]. Encouraged by these results, we try to develop copper-catalyzed aminooxygenation of alkenes by using NFSI. Herein, we report a simple and efficient copper-catalyzed three-component aminooxygenation reaction of styrenes with NFSI and N-hydroxyphthalimide (NHPI) derivatives (Scheme

•  1). Initially, we conducted the three-component amnooxygenation of styrene 1a with NFSI and NHPI (2a). After the reaction of 1a (0.3 mmol), NFSI (0.3 mmol, 1.0 equiv) and 2a (0.45 mmol, 1.5 equiv) was performed in the presence of Cu(OTf)2 (10 mol %) in dichloromethane (DCM, 2 mL) under nitrogen

• underwent smoothly, providing the corresponding products 3m (51%) and 3n (53%). The trans-β-methylstyrene (1o) afforded the desired product 3o in a low yield (15%). In addition, NHPI derivatives 2b and 2c were suitable nitrogen sources and the desired 3p and 3q were obtained in 56% and 64%, respectively

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• a catalytic system consisting of (BPMED)CuI (copper(I) bisimine complex), N-hydroxyphthalimide (NHPI), KB(C6F5)4 and KI. The protocol allowed the selective fluorination of various substrates, including cycloalkanes and benzylic compounds using commercially available Selectfluor as fluorine source

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review

• Lucio Melone and
• Carlo Punta

Beilstein J. Org. Chem. 2013, 9, 1296–1310, doi:10.3762/bjoc.9.146

• detrimental for the selectivity of the process and they would not meet the standards of “green chemistry”. An alternative catalytic route is based on the use of N-hydroxy imides (NHIs), and in particular N-hydroxyphthalimide (NHPI), which have found ample application as ideal catalysts for the aerobic

• oxidation of organic substrates [7][8][9][10][11]. NHPI acts as a precursor of the phthalimide N-oxyl (PINO) radical, which is the effective catalyst promoting hydrogen-abstraction processes (Scheme 1). The reactivity of NHPI and PINO is related to the bond dissociation energy (BDE) of the O–H group, which

• , NHPI also behaves as a relatively good hydrogen donor even at low temperatures (kH = 7.2 × 103 M−1s−1) [12], trapping peroxyl radicals before they undergo termination. PINO generation represents the key step of the overall process. Many transition metal salts and complexes have been successfully used