Nitrosobenzenes as a stepping stone for the development of transition metal and metal-free organic transformations: a comprehensive review

Abstract

Over the past few years, there has been exponential progress in the synthesis of value-added molecules utilizing nitroso compounds. The reactions of nitroso compounds with economically cheap reactive precursors have drawn much interest from organic chemists across the globe due to their high regioselectivities; enantioselectivities; and efficiencies for annulation, C–H activations, cycloaddition, Diels–Alder reaction, and notable metal-free reactions. In particular, the nitroso moiety has recently emerged as a powerful synthon and transformable directing group in direct C–H functionalization reactions. In this review, we have broadly discussed recent reports on the versatile applications of nitroso compounds as useful building blocks in the selective synthesis of a diverse range of molecules.

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Nandini R.

Nandini R. received her master's degree in chemistry from REVA University (Bengaluru, India) in 2020. She did her master's project on the “Synthesis of spirocyclic scaffold and its analogue compounds for the CNS therapeutic process” at CSIR-IICT, Hyderabad. Currently, she is a PhD scholar in the catalysis and organic synthesis group under the supervision of Dr Ramesh B. Dateer at the Centre for Nano and Material Science (CNMS) at Jain University (Bengaluru). Her research focuses on the development of sustainable materials for organic transformations. She has submitted her thesis and is awaiting the final defence.

Ramesh B. Dateer

Ramesh B. Dateer is Associate Professor at the Centre for Nano and Material Sciences (CNMS) at Jain University in India. He obtained his PhD in organic chemistry from NTHU-Taiwan in 2013. He is the recipient of many fellowships, including postdoctoral fellowships in Switzerland and the Republic of Korea, the Ramanujan Fellowship, etc. Currently, his research group at CNMS focuses on catalysis and organic synthesis, particularly on metal/metal-free catalysis for the synthesis of N-heterocyclic systems.

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1. Introduction

A major goal of a synthetic chemist is to develop a method that allows the transformation of readily available precursors into target relevant products in an atom and step-economical manner. Indeed, the important challenge is the construction of products with relatively complex cyclic scaffolds from cheaper and biomass-driven starting materials. In this context, nitroso compounds (Ar–N=O) have emerged as important synthetic building blocks in organic synthesis.¹ In particular, the dual reactivity of nitrosoarenes as reactive nucleophiles or electrophiles results in the efficient formation of structurally diverse C–N bonds and N-containing heterocycles.^2,3

In the last few decades, a large number of novel reactions involving nitroso compounds have been broadly discovered (Fig. 1). The regioselective properties of cycloaddition reactions based on nitroso compounds and their ease of availability as starting materials have led to various applications in the construction of natural-product-like molecules.¹⁸ These results demonstrated the applicability of nitroso derivatives in numerous ultramodern synthetic endeavors. The reactions involving nitroso species with transition metals, such as Au, Yb, Cu, Ag, Rh, and reactive precursors, such as carbonyl compounds, ketones, alkenes, esters, amines, and allenes, have been widely studied.^4–7 During these transformations, the reactions mostly include cycloaddition,^8–10 cyclization,^7,11 C–H functionalization,^12,13 Diels–Alder reaction,^14–16 and free radical reaction¹⁷ and deliver synthetically important classes of heterocycles.

Fig. 1 Brief review of reactions using nitroso compounds.

Despite the sequential progress of investigations of new reactions using nitroso compounds in the last decade, a comprehensive review of this topic demonstrating the investigation of the reactivity of nitrosoarenes is still needed in terms of pharmaceutical perspectives. Therefore, this review extensively comprises the recent development of notable transformations containing nitroso compounds, including the utility of the N=O moiety as a powerful and transformable directing group in modern C–H functionalization reactions.

2. The scope of this review

In recent decades, the metal-catalyzed reactions of nitroso compounds have shown broader scope and potential. The reports have demonstrated several aspects of the reactivity of nitroso compounds for the development of new metal-catalyzed reactions. This review has been prepared in line with our significant contribution to the field of metal-catalyzed transformations of nitroso compounds. Therefore, the scope of the review mainly demonstrates the recent advances (i.e., from 2015 to date) in the metal-catalyzed organic transformations utilizing nitroso compounds for the construction of a diverse array of heterocyclic compounds (Fig. 2).

Fig. 2 Utility of nitroso compounds in organic transformations.

3. Methods for the preparation of various nitroso compounds

Nitroso compounds were first synthesized and identified in 1874.^19,20 To date, there have been various methods and approaches to the synthesis of nitroso compounds (Fig. 3). The more elegant direct oxidation of anilines into their corresponding nitroso compounds is the most commonly utilized method. Although many procedures based on this oxidative strategy have been reported, their reliance on the availability of anilines somewhat limits the scope of this reaction.²¹ In addition, the formation of undesired side products, such as azo and azoxy compounds, has been encountered as a major issue associated with this method.²² These limitations associated with oxidation reactions of aryl and heteroaryl nitroso compounds have led chemists to investigate new and mild synthetic methods.

Fig. 3 Different approaches for the synthesis of nitrosoarenes.

For instance, Karola Rück-Braun et al.²² in 2005, discovered a straightforward, high-yielding synthesis of nitrosoarenes bearing various functional groups for the direct synthesis of azoxybenzenes. It has been demonstrated that SeO₂ is suitable for the catalytic oxidation of anilines by hydrogen peroxide, which is a useful addition to the repertoire of known catalysts.

Later, Ioannis N. Lykakis et al.²³ in 2016, demonstrated the first-time use of H₂O₂ as an oxidant, wherein titania-supported gold nanoparticles selectively catalyzed the oxidation of several aryl amines into nitrosoarenes. The authors claimed that active gold nanoparticle species proved to be responsible for the selective catalytic action for the synthesis of nitrosoarenes, even for large-scale reactions. Next, Gerhard Hilt et al.,²⁴ in 2018, reported the synthesis of nitrosoarenes by reacting trimethylsilyl-substituted arenes with NOBF₄. It was a new approach to access nitrosoarenes via a range of starting materials, wherein the ipso-nitrosation intermediate was successfully characterized by ¹⁹F NMR analysis. Subsequently, in 2019, E. Yazdani et al.²⁵ reported a novel greener method for the synthesis of nitrosoarenes catalyzed by tungstate-supported silica-coated magnetite nanoparticles. Here, the catalyst was prepared by linking the tungstate moiety to the core–shell nanoparticles of Fe₃O₄@SiO₂ by a calcination process. The catalyst formation was confirmed by characterization and used for the oxidation of anilines to nitroarenes. Most recently, G. Mailhot and co-workers²⁶ demonstrated the selective oxidation of aromatic amines to nitrosoarenes using TBADT supported on Fe₃O₄ NPs in the presence of hydrogen peroxide (H₂O₂).

4. Metal-catalyzed annulation reactions of nitroso compounds

The highly reactive nitrosoarenes can easily undergo metal-catalyzed cycloadditions using a variety of α-bond motifs, including dienes, alkynes, and allenes. During these transformations, the newly formed cycloadducts undergo the reductive cleavage of the weak N–O bonds to form biologically important 1,2-aminoalcohols.²⁷ The reactivity of nitosoarenes can easily lead to 1,4-aminoalcohols with high diastereomeric and enantiomeric purity. Therefore, catalytic [4 + 2]-cycloadditions of dienes with nitrosoarenes have emerged as the most effective metal-catalysis processes.²⁸ In this section, we present notable recent reports of the annulation reactions of nitroso compounds via transition metal catalytic processes to access value-added products.

In 2016, R. S. Liu and coworkers reported²⁹ the one-pot synthesis of indole derivatives via [3 + 2] annulation catalyzed by copper, using N-hydroxy allenylamines 1 and nitrosoarenes 2 to access substituted indole derivatives. This method is one of the short procedures for the synthesis of highly bioactive molecules like WIN 48098, WIN 53365, and JWH 015 (Fig. 4).

Fig. 4 Structures of WIN 48098, WIN 53365, and JWH 015.

Initially, screening the reaction conditions with various copper salts, oxidants (e.g., O₂ and argon), and iPrCuCl (iPr = 1,3-bis(diisopropylphenyl)imidazole-2-ylidene) with cold toluene led to excellent yields of the expected product. The substrate scope was subsequently studied, wherein the excellent reactivity of various N-hydroxyallenylamine species 1 was seen with electron-donating and electron-withdrawing groups. However, electron-deficient species were more reactive than electron-rich species because the latter undergo single electron transfer (SET) to give nitrones (Scheme 1). Similarly, nitrosoarenes 2 bearing electron-rich and electron-deficient groups produced good to moderate yields (4a–4l, Scheme 2). Based on the control experiments and recent reports of Stahl and co-workers,^30–33 the Cu(II) species present in the iPrCuCl/O₂ system reacts with 1a to form the nitroxyl radical A, which undergoes cyclization to give C, followed by an intermolecular redox reaction with nitrosoarene 2 to form D, and a subsequent 2,3-sigmatropic rearrangement and pinacol-like 1,2-hydrogen shift to yield the desired product 3a (Scheme 3). Next, DBU-mediated structural rearrangements to form ketenimine intermediate I, followed by a 3,3-sigmatropic shift of N-linkage isomer H, give the desired product 4a (Scheme 4).

Scheme 1 The scope of the [3 + 2]-annulation reaction.

Scheme 2 The scope of substituted indole derivatives in copper-catalyzed cycloaddition reactions.

Scheme 3 Postulated mechanisms for [3 + 2] annulations.

Scheme 4 DBU-catalyzed skeletal rearrangement.

In conclusion, the [3 + 2] annulation of N-hydroxy allenylamines 1 with nitrosoarenes 2 to access isoxazolidin-5-ols 3 and indoles 4 has been described through structural rearrangements.

In 2017, R. S. Liu and co-workers reported³⁴ novel [3 + 2] annulations between ground-state ³O₂ (1 bar), allenes, and nitrosoarenes at low temperatures, and effectively produced oxacycles with dioxygen. In earlier reports,^35,36 the singlet state ¹O₂ was unable to react with allenes to produce useful oxygenated compounds. The author demonstrated the structural rearrangement to 3-hydroxy-1-ketonyl-2-imine oxides with less hindered 1-arylallene derivatives, producing oxacycles. Initially, they started the reaction by taking O,N,O-tri functionalized molecule 3a from a mixture of allene 5, nitrosobenzene 2a (1.5 equiv.), and O₂ (1 bar) in cold THF (−15 °C), and obtained a 43% yield. Further, by optimizing different parameters such as time, temperature, and solvent, the authors considered THF and O₂ (1 bar) with nitrosobenzene in three-fold proportions as their optimized condition, giving a 63% yield. After determining the reaction conditions, the reaction scope was explored by varying mono and 1,3-disubstituted allenes, aryl allenes, and 3-substituted phenyl allenes (6b–6k), thus furnishing moderate to good yields (Scheme 5).

Scheme 5 O,N,O-Trifunctionalization of allenes with O₂ and ArNO.

In the case of aryl-methyl allenes, electron-rich nitrosoarenes 2 and O₂ were also reactive to cycloadditions, yielding desired compounds (Scheme 6).

Scheme 6 [3 + 2]-Cycloadditions among O₂, allenes and nitrosoarenes.

However, when trisubstituted allene 5 and 4-methylphenylnitroso 2b reacted under nitrogen, the nitroso-containing cycloadduct 8 was achieved (Scheme 7).

Scheme 7 [3 + 2]-Cycloadditions of allenes and nitrosoarenes under N₂.

From a mechanistic perspective (Scheme 8), the authors demonstrated that allenes 5 reacted with nitrosoarenes 2 to form 1,4-diradical species A, which subsequently captured ³O₂ to form the peroxy diradical B in the triplet state. After the change of the spin state B (triplet) to B′ (singlet), it underwent 3-exo-trig cyclization (more favorable than 5-endo-trig) to give 1,2-oxaziridine diradical C, followed by radical–radical coupling, ultimately yielding compound 6. Once the 1,4-biradical was trapped, a single radical species F was produced. This species quickly undergoes 3-exo-trig cyclization to produce the benzylic radical G. It is anticipated that a second TEMPO radical trapping will produce species I, which is prone to hydrolysis on a silica column to produce the required product 9. In conclusion, the authors highlighted a cheap, efficient, and clean synthesis of 1,3-dihydroxy-2-amino derivatives and anticipated that the idea of nitrosoarenes as diradical precursors would stimulate new synthetic ideas.

Scheme 8 A plausible mechanism for the tri-functionalization of allenes.

Next, in the year 2018, Guichun Fang and co-workers³⁷ established the silver-catalyzed [3 + 1 + 1] annulation reaction of nitrosoarenes 2 with isocyanoacetates 10. This is a straightforward transition metal-catalyzed annulation reaction for the synthesis of 1,4,5-tri-substituted imidazoles 11 and imidazolines 12. Next, the work was extended for the screening of the reaction conditions, wherein nitrosobenzene 2 was reacted with isocyanoacetate 10 in the presence of 1.5 equiv. of Ag₂CO₃, which resulted in a 50% yield. Once the reaction is optimized using DBU as an additive with the appropriate solvent and temperature, the scope of the reaction was evaluated by varying the range of nitrosoarenes 2 and isocyanoacetates 10. The reaction went smoothly, providing a good to excellent yield, irrespective of electron-donating and electron-withdrawing groups (11a–11k, Scheme 9). However, a noticeable result was obtained when the reaction was performed at 30 °C, which gave 1H-imidazolines 12 instead of imidazoles 11 (Scheme 10).

Scheme 9 Scope of the silver-mediated [3 + 1 + 1] annulation of isocyanoacetates 10 and nitrosoarenes 2 to access imidazoles 11.

Scheme 10 The silver-catalyzed [3 + 1 + 1] annulation of isocyanoacetates 10 with nitrosoarenes 2 to access 4,5-dihydro-1H-imidazolines 12.

A series of control experiments was performed to understand the reaction pathway, and the plausible mechanisms were proposed (Scheme 11).

Scheme 11 A plausible mechanism for the silver-promoted [3 + 1 + 1] annulation.

Initially, a silver complex is generated and undergoes cycloaddition with nitrosoarene 2, followed by the removal of AgOCN to furnish an α-imino ester that will then react with another silver complex to give intermediate F. The addition of excess Ag₂CO₃ facilitated protonation and oxidation to yield imidazole 11, and compound 12 was obtained at a reduced temperature (30 °C). Overall, the authors discovered a novel 1,4,5-trisubstituted imidazole or 1H-imidazoline annulation of isocyanoacetates with nitrosoarenes enhanced by silver. This annulation has a wide variety of applications and great functional group tolerance.

In 2019, Yan Xiao et al. reported³⁸ the annulation reaction between azobenzenes 13 and nitrosoarenes 2 catalyzed by rhodium to access phenazines 14. The azo group was utilized during this transition as both a traceless directing group and a component of the final annulated products (14a–14k). Various screenings were done for the reaction by varying different parameters such as ligands, additives, solvents, temperature, and time to get the maximum yield. Later on, the generality of the reaction was tested by investigating the substrate scope of both azobenzenes 13 and nitrosoarenes 2. Electron-donating groups at the para and meta positions of azobenzene were well tolerated, whereas the electron-withdrawing group gave a low yield (Scheme 12). However, ortho-substituted analogs did not work for the reaction. Similarly, different substituents of nitrosobenzenes bearing electron-donating and electron-withdrawing groups were also well tolerated for the reaction, but the ortho-substituted nitrosoarenes failed to work under the reaction conditions (Scheme 13).

Scheme 12 Scope for the annulation of nitrosobenzenes with substituted azobenzenes.

Scheme 13 Substrate scope for the annulation reaction of azobenzenes with substituted nitrosobenzenes.

The group proposed a plausible mechanism wherein ortho C–H bond cleavage in azobenzene 13 leads to metallacycle B. The migratory insertion of the Rh–C bond into the N=O group leads to the formation of rhodacycle C, which then undergoes protonolysis, leading to hydroxylamine D along with the regeneration of the Rh(III) species for the next cycle. With the sequential alkylation of D by dichloroethane (DCE), intermediate F is formed, which undergoes electrophilic aromatic substitution, followed by aromatization, leading to the final product, phenazines 14 (Scheme 14). As an outline, the group demonstrated a simple procedure using easily accessible starting materials for the synthesis of phenazine derivatives catalyzed via a silver complex. They proposed a chelation-assisted mechanism for the proposed reaction.

Scheme 14 Plausible mechanism for the annulation reaction of azobenzenes with nitrosobenzenes.

R. S. Liu and co-workers reported²⁷ nitroso-Povarov reactions via the Au-catalyzed [4 + 2]-annulations of dienes with nitrosoarenes that act as 4π-donors. In this work, allyl gold nitrosonium intermediates attack gold-dienes in a catalytic sequence via a 1,4-addition pathway, resulting in the completion of an intramolecular cyclization. Firstly, vinylallene 15 reacted with the gold catalyst in DCE at RT for 5 min, and the formation of cyclopentadienes 15a′ was ensured before the addition of nitrosobenzene 2 and hence, the role of the catalyst in nitroso annulation was demonstrated. A one-pot reaction condition was developed by varying the catalyst system, time, and solvent to get the optimal conditions, with LAuCl/AgNTf₂ (L = P(t-Bu)₂(o-biphenyl)) as the catalyst system. Later, by following the optimized conditions, the substrate scope was demonstrated. With the vinyl allenes 15 (Scheme 15) initially, and later with substituted nitosoarenes 2 (Scheme 16), the desired compounds 16 and 17 were obtained, respectively. The oxidative nitroso-Povarov reaction was also assessed with various substitutions of acyclic dienes 15 and 4-chlorophenylnitroso derivatives 18 (Scheme 17), wherein all the substituents were well tolerated, giving 19a to 19f in good to moderate yields.

Scheme 15 [4 + 2]-Annulations with various vinyl allenes; L = P(t-Bu)₂(o-biphenyl).

Scheme 16 Catalytic [4 + 2] annulations with various nitrosoarenes; L = P(t-Bu)₂(o-biphenyl).

Scheme 17 [4 + 2]-annulations with various vinyl allenes; L = P(t-Bu)₂(o-biphenyl).

To gain a mechanistic understanding, control experiments were performed and plausible mechanisms were proposed (Scheme 18). Initially, they observed the formation of an O-addition product 15a′′ and suggested that nitrosonium B serves as a bridge. It seems unlikely that 15a′′ is the major intermediate since another relevant 2,4-phenylcyclopentadiene, 15 (R = Ph), is unable to generate a related species. The nitrosoarene 2 can attack the tertiary carbocation at its oxygen atom, but a highly hindered carbocation destabilizes nitrosonium;^39–41 hence, nitrosobenzene 2 preferentially attacks at the carbocation to yield species B, and enables an intramolecular cyclization to produce tricyclic species C and products 16. The authors also explained the oxidative nitroso-Povarov reactions of acyclic 1,3-dienes, wherein the nitrosoarene's initial attack on gold-diene D formed species E, which carries a tertiary carbocation that stabilizes the nitrosonium. When the benzene ring of species E undergoes hydrolysis, a new, more electrophilic pentadienyl cation F that is stabilized by OH is created, which is more electrophilic than species E. The intramolecular cyclisation of species F results in intermediate G, which is further oxidized in air to produce the observed product 19a. In conclusion, the group has successfully reported examples of nitroso-Povarov reactions using gold catalysts.

Scheme 18 A plausible mechanism of [4 + 2]-annulations with various vinyl allenes.

Similar to the previous work, R. S. Liu et al. reported⁴² that nitrosoarenes 2 and cyclopentadienes undergo highly enantioselective nitroso-Povarov reactions in cold dichloroethane, where nitrosoarenes 2 operate as 4π-electron donors and cyclopentadienes as 2π electron donors. Since cyclopentadienes undergo self-dimerizations, they employed 1-allenyl-4-ene 20 as the precursor and initiated the reaction by treating it with the gold catalyst in DCE at 25 °C for 5 min to ensure the formation of cyclopentadienes 20′ before the addition of nitrosobenzene 2. After varying different reaction parameters like a catalyst, ligands, time, temperature, and solvent, they obtained the optimal conditions with L₁(AuCl)₂/AgNTf₂ (L1 = (R)-3,5-tBu-4-MeO-MeOBIPHEP) in DCE (25 °C, 10 min) with 1 equiv. each of 1-allenyl-4-ene 20a and nitrosoarene 2a, giving the desired product 21a in up to 76% yield with 96% ee. Under the optimized conditions, they assessed the new enantioselective reactions with various vinylallenes 20 bearing electron-donating and withdrawing substituents, and obtained good yields with excellent ee values (Scheme 19). They observed that even heteroaryl-substituted vinylallenes proved to be good for enantioselective annulations.

Scheme 19 Enantioselective nitroso-Povarov reaction with various vinylallenes.

The authors mentioned that nitrosoarenes 2b to 2j bearing electron-donating and withdrawing groups at meta and para positions gave desirable yields (22b to 22j, Scheme 20). However, alkenes and heterocyclic systems were unreactive. Notable results were obtained when the authors varied the substitutions on both starting materials (Scheme 21). The para-phenyl-substituted vinylallenes (20b–20d) reacted well with nitrosofluorobenzene, 2f, giving products in good yield with excellent enantioselectivity. Similarly, various 3-substituted-4-fluorophenylnitrosos 2, further provide the corresponding desired products 22 with 87–97% ee.

Scheme 20 Enantioselective nitroso-Povarov reaction with various nitrosoarenes.

Scheme 21 Scope of [5 + 1]-annulations.

According to the hypothesized mechanism (Scheme 22), the nitroso species 2f undergoes an oxygen attack at the π-diene A, which proceeds trans to a gold catalyst, resulting in the allyl gold species B that contains a nitrosonium moiety. This A–B transformation is reversible, as shown by the different ee values of the products (−)-23a and (+)-4f. The observed product (+)-22f is produced by ring-closing intermediate B to produce the cis-fused bicyclic species C. Alternatively, intermediate B can produce intermediates D and E successively before a ring closure by being trapped with water. The O₂-oxidative aromatization of the resultant cyclization species F, which yields compound (−)-23a and water, is the last step. They also carried out ¹⁸O-labeling studies to demonstrate that both water and O₂ are involved in the reactions; these results suggest a mechanism involving nitrosoarenes as nucleophiles and gold-π-dienes as electrophiles. In conclusion, the authors reported the first enantioselective nitroso-Povarov reactions using cyclopentadienes and nitrosoarenes in cold DCE. The identical cyclopentadienes interacted successfully with nitroso-4-fluorobenzenes in DCM/THF/H₂O under air using the same chiral gold catalyst, producing oxidative nitroso-Povarov products with high enantioselectivity.

Scheme 22 Postulated mechanisms for the two asymmetric reactions.

In 2020, Peng-Fei Xu and co-workers⁴³ developed a tandem catalytic method for the asymmetric synthesis of spirocyclopentanone pyrazolones with three continuous stereocenters and two quaternary carbons with acceptable stereoselectivity. They began their work in a one-pot process involving α,β-unsaturated ketoester 24 as the model substrate, nitrosobenzene 2, and pyrazolone-5-one 25 for a reaction in DCE with 20 mol% bifunctional catalyst I and 4 Å molecular sieves. Using 91% ee and 7 : 1 dr, the anticipated spiropyrazolone 26 was produced in 72% yield. Further, the reaction using toluene gave better diastereoselectivity. They also observed that high enantioselectivity was observed using a thiourea bifunctional catalyst, and a lower temperature improved the stereoselectivity of the product. Thus, with the optimized conditions, the researchers performed various reactions to check the generality of the reaction. The target products were produced in good yields with good to exceptional diastereo- and enantioselectivities in most cases. Better diastereoselectivities were provided by the electron-donating groups on the substrates, in particular (Scheme 23, 26c, 26e, and 26i), but strong electron-donating groups required prolonged reaction durations.

Scheme 23 Substrate scopes of the pyrazolones in the asymmetric tandem reaction.

The authors subsequently investigated the substrate scope for dicarbonyl compounds, where, due to the strong electrophilicity of the Michael acceptor with electron-withdrawing substituents, the keto-esters with electron-withdrawing groups had greater yields than those with electron-donating groups (Scheme 24, 27b, 27c, and 27e against 27d and 27g).

Scheme 24 Substrate scopes of keto esters and nitrosoarenes in the asymmetric tandem reaction.

In conclusion, the authors were successful in demonstrating a tandem reaction comprising a polarity reversal process under benign conditions. In addition, a feasible and efficient method was established to construct spirocyclopentanone pyrazolone compounds, involving three contiguous stereocenters and two quaternary carbons, with good yields and stereoselectivities. Interestingly, the final products might be rearranged with the Lawesson reagent to produce spirocycloheximide pyrazolones (Scheme 25).

Scheme 25 Synthetic application of the chiral spirocyclopentanone pyrazolone using Lawesson's reagent.

Recently, Jiang Cheng et al.⁴⁴ established the development of a silver-mediated annulation between arylcarbamic acids 28 and nitrosoarenes 2, affording phenazines 29 with moderate to good yields, complexity, and diversity. The reaction conditions were optimized by varying different parameters such as additives, catalyst, solvent temperature, and time, along with arylcarbamic acids 28 and nitrosoarenes 2 to get the best optimized condition. They obtained the desired yield of 76% with AgSbF₆ (1 equiv.) and HOAc (2 equiv.) as an additive, and Ag₂CO₃ (60 mol%) as a catalyst in TFE at 140 °C for 16 h. Under the optimized conditions, the substrate scope of various aryl carbamic acids 28, in which substrates having electron-withdrawing groups worked well, acids possessing electron-donating groups at the para position gave moderate yields, whereas electron-withdrawing groups at the ortho and meta positions showed low reactivity (Scheme 26).

Scheme 26 The substrate scope for the Ag-mediated annulation of arylcarbamic acids.

Further, substituted nitrosoarenes 2 bearing both electron-withdrawing and electron-donating groups at meta and para positions were well tolerated, giving corresponding phenazines 29 in good yields (Scheme 27). However, they noticed that electron-withdrawing groups at the ortho position and multi-substituted nitrosobenzenes showed low reaction efficiency.

Scheme 27 The substrate scope for the Ag-mediated annulation of nitrosoarenes.

Different mechanistic studies were carried out to understand the reaction mechanism, and they concluded that the reaction proceeds via a radical pathway (Scheme 28). Initially, silver complex II is produced by the ortho C–H bond breakage of p-tolylcarbamic acid 28a.^44–46 Secondly, a silver complex III is formed as a result of the coordination and migratory insertion of the Ag–C bond into the N=O group. The radical intermediate V is then produced by decarboxylative oxidation of the hydroxylamine IV that was produced by earlier protonolysis.^47,48 The intermediate V undergoes intramolecular radical addition to produce compound VI, which leads to 3-methylphenazin-5(10H)-ol VII ⁴⁹ via radical elimination. Ultimately, silver action causes compound VII to change into phenazine 29. In conclusion, the steps in this process include the ortho-C–H functionalization of arylcarbamic acids, nitroso group insertion, and decarboxylative annulation; hence, it represents a simple method for creating phenazine frameworks.

Scheme 28 Plausible mechanism for the Ag-mediated annulation reaction.

5. C–H functionalization reactions of nitroso compounds

C–H functionalization has emerged as one of the most straightforward and long-lasting methods for creating diverse molecular scaffolds in recent decades.^50,51 Among these, direct functionalization of the aromatic C–H bond is a very effective technique for fused ring compounds when an appropriate linker is present. These compounds have outstanding qualities for chemical catalysis, the synthesis of photoelectric and energetic materials, and the discovery of new drugs.⁵² The development of numerous techniques has been made possible by the direct C–H bond functionalization facilitated by transition metals.⁵³ Significant benefits were provided by such techniques for the synthesis of various heterocycles and other practical scaffolds and hence, some of the recent methods involving nitroso compounds as one of the reactive species have been elaborated below.

In 2016, M. Baidya and coworkers⁵⁴ reported a flawless N-selective nitroso aldol reaction between aromatic nitroso compounds and silyl enol ethers produced from ketones with a disilane backbone for the α-amination of ketones. Initially, the reaction was performed by reacting silyl enol ether 31a with nitroso compound 2 and Brønsted acid (BAOH) in acetonitrile solvent. Once the silyl enol ether was completed, benzoic acid was introduced into the reaction flask at room temperature, which resulted in the formation of α-amino ketone 32 in 81% yield. After screening the reactions by varying different parameters like acids, solvents, and catalyst loading, it was found that phenylboronic acid gave the desired product in 94% yield. The substrate scope for the metal-free α-amination reaction was explored using the same optimized conditions. The reaction went smoothly for various silyl enol ethers, producing a very high yield (Scheme 29).

Scheme 29 Scope of the α-amination reaction.

Even the silyl enol ethers with heterocycles and cyclic ketones gave desirable yields. Both electron-donating and electron-withdrawing groups of nitrosoarenes worked well for α-amino ketones, producing high yields (33, Scheme 30). However, nitroso compounds bearing electron-withdrawing groups were not productive. In conclusion, the authors have demonstrated a simple, scalable, one-pot synthesis of α-amino ketones with a broad substrate scope.

Scheme 30 Silica gel-promoted N–O bond cleavage for α-amination of ketones through the nitroso-aldol reaction.

In 2016, Q. Wang et al.⁵⁵ reported the effective synthesis of 1H-indazoles by C–H activation and C–N/N–N coupling catalyzed by rhodium and copper, using nitrosobenzenes 2 as convenient aminating reagents. The group disclosed the cooperative catalysis of rhodium and copper in the redox-neutral synthesis of indazoles 35 by coupling imidate esters or N–H imines 34 with nitrosobenzenes 2. Numerous reactions were performed by varying catalyst loading, changing solvents, additives, temperature, and time to obtain the optimal conditions to get an efficient yield. Further, after screening reaction parameters, the generality of the reaction was tested by exploring different substrate scopes of imidate esters 34 (Scheme 31). All the substituents, such as electron-donating groups, electron-withdrawing groups, and halogens, reacted well, producing moderate to good yields with high regioselectivity, irrespective of the positions.

Scheme 31 Substrate scope of imidates in indazole synthesis.

Next, when the substrate scope of nitrosobenzene 2 was examined, a wide range of electron-donating and electron-withdrawing groups reacted smoothly, irrespective of positions, leading to diverse products (36a–36h, Scheme 32).

Scheme 32 Scope of nitrosobenzenes in indazole synthesis.

Later on, with a few mechanistic studies and kinetic experimental results, a tentative, plausible mechanism has been described (Scheme 33). Initially, imidate ester 34 coordinates with the activated Rh(III) catalyst for C–H activation and enters the rhodacycle. Here, the Rh–C bond undergoes migratory insertion into the N=O bond, giving the 6-membered intermediate III, which then undergoes protonolysis to give hydroxylamine IV and give back the Rh(III) species. Next, in the copper cycle, Cu(I) undergoes N–O oxidative addition to give organocupracycle V, and the N–N bond is formed via dehydration followed by reductive elimination to yield the final product 35. Finally, the rhodium and copper-catalyzed reaction with great efficiency and functional group tolerance was established, which took place under redox-neutral conditions. The rhodacyclic imidate complex has also been identified as a crucial step, with water being the sole byproduct.

Scheme 33 Proposed mechanism for the formation of 1H-indazoles.

In 2017, J. Cheng et al.⁵⁶ reported that aldehydes containing nitroso compounds are cyclized bilaterally by Rh(III) to produce unsymmetrical acridines, and C–H functionalization is made possible by a temporary directing group. This method allows for the in situ creation and removal of an imino transitory guiding group in the presence of catalytic amounts of BnNH₂. The C–H amination, cyclization, and aromatization processes were sequential and catalyzed by Rh(III) in this reaction. After varying different reaction parameters such as solvent, temperature, catalyst, and time, the ideal optimized conditions were as follows: benzaldehyde 37, (0.2 mmol), nitrosobenzene 2 (0.3 mmol), Cp*Rh(MeCN)₃(SbF₆)₂ (10 mol%), NaSbF₆ (25 mol%), BnNH₂ (40 mol%), and MgSO₄ (2.0 equiv.) in DCE solvent at 130 °C, for 24 h under an inert N₂ atmosphere. Under these optimized conditions, different substrate scopes were investigated by varying electron-donating and electron-withdrawing groups on both aryl aldehydes (Scheme 34) and nitrosobenzenes (Scheme 35) to give the corresponding acridines 38. However, the low yield was observed in the case of electron-withdrawing groups and, significantly, all of the ortho-, meta- and para-substituted aryl aldehydes performed well in the transition. Surprisingly, just one acridine regioisomer was available for all of the meta-substituted aryl aldehydes, indicating excellent regioselectivities.

Scheme 34 The substrate scope for the cyclization of aryl aldehydes 37 with nitrosobenzene 2a.

Scheme 35 Substrate scope for the cyclization of nitrosoarenes 2 with benzaldehyde 37b.

Even substitutions on nitroso compounds gave excellent results, irrespective of the positions, but two regioisomers were isolated in the case of the meta-substituent in nearly equivalent yields (Scheme 35).

Next, kinetic studies were carried out to gain knowledge about the reaction, which showed that the rate-determining step in this bilateral cyclization was not aryl nitroso but rather the cleavage of the ortho sp² C–H bond in the aromatic aldehyde. Further, to gain insight into the reaction mechanism, a handful of control experiments were performed, which provided evidence for imine formation (as the intermediate), and the solvent DCE played the role of the reductant. This plausible mechanism was outlined, wherein the condensation reaction gave the intermediate imine A, followed by the coordination and migratory insertion of the Rh–C bond into the N=O group, affording rhodacycle C by exchanging the ion with NaSbF₆. Then, the protonolysis and alkylation of D with DCE gave intermediate E, which later followed the Norrish type II pathway to cleave the weak N–O bond and gave the final compound acridine 38 by intramolecular electrophilic aromatic substitution (Scheme 36). To summarize the work, the authors have demonstrated a highly efficient and sustainable method for the synthesis of acridine analogs by simple C–H functionalization.

Scheme 36 Proposed cascade mechanism.

In the same year, G. J. Chuang et al.⁵⁷ reported an effortless additive and catalyst-free method for the synthesis of substituted azoxybenzenes 40a–40k and 40y–40zf, respectively, via a dimerization pathway. After performing various reactions, they found out that the reaction was going smoothly, only by heating in the solvent, and noticed that iPrOH gave an excellent result at 100 °C for 12 h. As shown in Scheme 37 and Table 1, the reaction well tolerated various electron-donating and electron-withdrawing substituents on nitrosobenzenes 2. However low yields were observed in the case of electron donating groups, and longer reaction times were required.

Scheme 37 Substrate scope for the reductive dimerization of nitrosobenzenes.

Table 1 Synthesis of dissymmetrical azoxybenzenes

Substituent	1(R^1R^2)/yield (%)	1(R^2R^1)/yield (%)	1(R^1R^1)/yield (%)	1(R^2R^2)/yield (%)
R^1 = COMe, R^2 = CN	40y (21%)	40z (3%)	40za (13%)	40zb (37%)
R^1 = COMe, R^2 = Br	40zc (10%)	40zd (12%)	40ze (69%)	40zf (0%)

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Further, the team proposed the reductive mechanism for the dimerization of nitrosobenzene 2 to form azoxybenzene 40 (Scheme 38). The first step in the formation of intermediate A is the nucleophilic interaction of the solvent ⁱPrOH on one of the cationic nitrogens on the dimer. This explains the importance of the electron-withdrawing group, which promotes the formation of the dimer. Next, the abstraction of the proton from the solvent followed by the elimination of water leads to the formation of product 40. In summary, the group has established a simple and effective method for azoxybenzene synthesis via reductive dimerization.

Scheme 38 Proposed mechanism for the reductive dimerization of 2 to form 40 in iPrOH.

6. Metal-catalyzed cycloaddition reactions of nitroso compounds

Synthetic chemists widely use transition-metal-catalyzed cross-coupling reactions due to their good step and atom economies, making them potent synthetic techniques for creating valuable compounds.⁵⁸ Numerous procedures for cycloaddition reactions based on nitroso compounds have resulted from their regioselective nature and easy access as starting materials. These methodologies enable the development of new synthetic procedures that resemble natural products.⁵⁹

In 2016, Tristan Chidley and coworkers⁶⁰ established a cascade reaction of donor–acceptor (DA) cyclopropanes catalyzed by Yb(OTf)₃, following a cycloaddition pathway with nitrosoarenes 2. Interestingly, this transformation gained much significance when it provided good yields in the cases of various electron-donating and electron-withdrawing substituents of nitrosoarenes 2, irrespective of the positions (Table 2). However, nitrosoarenes 2 with strong electron-withdrawing or electron-donating groups led to the decomposition of the products.

Table 2 Reaction scope cycloaddition of donor–acceptor cyclopropanes 41

Entry	Ar^1	Ar	Time (h)	Yield (%)
1	Ph	2a, C6H5	13	87
2	Ph	2aa, 3-C6H4Br	24	73
3	Ph	2ab, 4-C6H4Br	24	75
4	Ph	2ac, 3,4-C6H3Cl2	12	91
5	Ph	2ad, 3-C6H4C(O)Me	20	68
6	Ph	2ae, 3-C6H4CO2Et	24	80
7	Ph	2af, 4-C6H4CO2Et	23	78
8	Ph	2ag, 4-C6H5CN
9	Ph	2ah, 4-C6H5OMe
10	2-Thienyl	2ai, C6H5	7	69

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Surprisingly, tetrahydro-1,2-oxazine 42 was formed instead of cycloadduct isoxalidine 41′ and its mechanism is well demonstrated (Scheme 39). In this study, Yb(OTf)₃ (2 equiv.)-activated DA cyclopropanes 41 were used, wherein 1 equivalent of DA cyclopropane 41 was employed to expel dimethyl 2-methylene malonate 44. This was followed by the formation of in situ nitrone 43, which then underwent [3 + 3] cycloaddition with another equivalent of Yb(OTf)₃-activated DA cyclopropane to give the final product 42 instead of cycloadduct 42′ formation.

Scheme 39 Plausible mechanism for the formation of tetrahydro-1,2-oxazine.

Later, inspired by the Meijere group,⁶¹ it was assumed that the product 45 was formed via the azomethine imine intermediate 41-A. As depicted in Scheme 40, zwitterionic intermediate 41-C was formed when the GaCl₃-activated DA cyclopropane was opened by PTAD 41-A. Later, this intermediate could either undergo cyclization to give the cycloadduct 41′ or form a fragment of azomethine imine 41-B and diethyl 2-methylene malonate 41-D, which could further recombine to provide 45. In conclusion, the authors reported the unusual reactivity of cycloadditions of DA cyclopropanes and nitrosoarenes through intermediates, with outstanding yields of single diastereomers. Crossover experiments gave much more evidence to showcase the reaction mechanistically, which in turn opened the door for DA cyclopropane chemistry.

Scheme 40 Our proposed mechanism for de Meijer's report on the cycloaddition of cis-diazene 45 with GaCl₃-activated DA cyclopropane 41.

In 2020, Anisha Purkait et al.⁶² reported Yb and Cu-catalyzed pseudo-three-component annulation reactions between nitrosoarenes and styrene, and series of aryl quinolones were accessed. Initially, the reaction was carried out with nitrosoarene 2 and styrene 46 in the presence of Sc(OTf)₃, resulting in 2,4-diarylquinoline 47 and 4-aryl quinoline 48 in a 3 : 1 ratio at an elevated temperature. However, the replacement of Sc(OTf)₃ with the cost-effective Yb(OTf)₃ gave satisfactory results. After optimizing the reaction conditions, different substrate scopes were investigated by varying both nitrosoarenes 2 and styrenes 46 with electron-donating and electron-withdrawing groups, which were found to be well tolerated and gave good to moderate yields (Scheme 41). Similar results were also obtained when cost-effective Cu(OTf)₃ was used.

Scheme 41 Scope of the annulation reaction of nitrosoarenes 2 and styrenes 46.

The reaction proved to be good for different substrates, producing the desired 3-aryl quinolines 50. Nevertheless, alkyl epoxide took part in the process to produce 3-alkyl quinoline 50p (Scheme 42).

Scheme 42 Scope of the reaction of nitrosoarenes 2 and styrene oxide derivatives 49.

Based on the performed mechanistic studies and literature proceedings, a plausible mechanism was proposed for the [3 + 2 + 1] annulation of nitrosoarene and styrene (Scheme 43). In the beginning, nitrones 51 (53) and 52 (54) were formed, either via the formation of the azodioxy dimer or the radical pathway.^63–67 These metal-coordinated nitrone derivatives underwent a Povarov-type reaction with another equivalent of styrene to produce tetrahydroquinolines 55, which further underwent aromatization and dehydration to give the desired dihydroquinolines 56. Later, based on the control experiments, the authors demonstrated a plausible mechanism for the formation of 3-aryl quinolones (Scheme 44). Accordingly, the nucleophilic nitrosoarene 2 was added to the least hindered site of styrene oxide 49, which was then activated by the coordination with Cu(II), leading to nitrone 60 and aldehyde 61 upon C–C bond cleavage. Next, the in situ generated enolate 49-a from styrene oxide reacts with the metal-coordinated nitrone 60 through the Meinwald rearrangement, either by a concerted or stepwise pathway, to yield N-oxide 62, which then undergoes aromatization and dehydration to furnish 3-aryl quinolines 50. In summary, an unusual annulation reaction was developed using a Lewis acid catalyst, which in turn switched the reaction of nitrosoarene and styrene from [3 + 2] to [4 + 2] cycloaddition to give quinoline derivatives. On the other hand, 3-arylquinolines were obtained in the presence of epoxystyrene via the Meinwald rearrangement.

Scheme 43 Proposed mechanism for the annulation of nitrosoarene 2 and styrene 46.

Scheme 44 Proposed mechanism for the annulation of nitrosoarene 2 and epoxystyrene 49.

Most recently, Xaolan Fang et al.⁶⁸ reported the use of inexpensive copper as a catalyst for the aerobic oxidative cyclization of 2-alkynylanilines 63 with nitrosoarenes 2 to get 4-oxo-4H-cinnolin-2-ium-1-ides 64, which are mechanoluminescent compounds and are quite difficult to synthesize. Initially, the reaction was carried out using 2-(phenylethynyl) aniline 63a and nitrosobenzene 2a to synthesize 4-oxo-2,3-diphenyl-4H-cinnolin-2-ium-1-ide 64a to optimize the reaction conditions. Different copper sources, additives, solvents, and other parameters were varied to obtain the optimal conditions for the reaction as 0.5 mmol 2-(phenylethynyl) aniline 63a and 0.75 mmol of nitrosobenzene 2a in toluene with CuCl as the catalyst (10 mol%), and DMAP (40 mol%) at 100 °C under an air atmosphere.

Under these optimal conditions, the cascade reaction of alkynes and nitrosoarenes was tested (Scheme 45). When the R group of alkynes was varied with different functionalities, the reaction worked well, irrespective of electronic properties. However, the sterically hindered nitrosoarenes (64x to 64z) could not be transformed smoothly.

Scheme 45 Substrate scope for the synthesis of 4-oxo-4H-cinnolin-2-ium-1-ides 64.

Next, mechanistic experiments were carried out to establish the possible reaction mechanism for the formation of 64a (Scheme 46). The first step was the condensation of 2-(phenylethynyl)aniline 63a and nitrosobenzene 2a to give (E)-1-phenyl2-2(2-(phenylethynyl)-phenyl)diazene 64a-1, which formed a complex with Cu(I) and ligand DMAP to give intermediate A, followed by intramolecular cyclization to give intermediate B. Later, this intermediate B was oxidized and the formed peroxide underwent further rearrangement to yield the desired product 64a. In summary, the authors established an inexpensive Cu(I)/DMAP catalytic system for the development of organic luminescent compounds following a green protocol for the synthesis of a wide range of other synthetic applications.

Scheme 46 Proposed mechanism for the synthesis of 4-oxo-4H-cinnolin-2-ium-1-ides 64.

Apart from transition metal-catalyzed cycloaddition reactions involving nitrosoarenes, there have recently been a few reports on the cycloaddition reactions under metal-free conditions (Scheme 47). In 2021, R. S. Liu and colleagues described [2 + 2] alkene/nitroso cycloadditions employing substituted cyclopenta-1,3-dienyl esters as alkene donors and a NaBArF catalyst.⁶⁹ They extracted two cycloadducts in similar amounts for 1,4-substituted cyclopenta-1,3-dien-2-yl acetates, but thermal hydrolysis of this isomeric combination produced the same chemoselective 5-aminocyclop-1-enten-3-one. Then, in 2021, Wenchao Gao et al.⁷⁰ established an effective, additive-free, and catalyst-free technique for the one-pot, three-component synthesis of several isoxazolidines using olefins, nitrosoarenes, and more accessible, safer, and more stable α-carbonyl sulfoxonium ylides as starting materials. In the same year, Li et al.⁷¹ developed a universal metal-free one-pot three-component technique for the highly diastereoselective synthesis of highly functionalized isoxazolidine derivatives using easily accessible malonic acid derivatives, nitrosoarenes, and alkenes as starting materials. Later in the same year, Chen and co-workers⁷² demonstrated a variety of functionalized isoxazolidines via KOH-mediated one-pot three-component cycloaddition synthesis involving hydrazones, olefins, and nitroso compounds. This procedure is an appealing alternative due to its wide substrate scope, strong functional group compatibility, good to exceptional yields, diastereoselectivity for the majority of products, and it is inexpensive with easily accessible promoter and starting ingredients. A mechanism is suggested based on control studies and their earlier reports, with the crucial step being the KOH-promoted production of nitrone intermediates via the interaction of nitroso compounds with hydrazones.

Scheme 47 Metal-free cycloaddition reactions.

7. Metal-catalyzed Diels–Alder cyclization reactions of nitroso compounds

The nitroso aldol (NA) and nitroso hetero-Diels–Alder (NDA) reactions are effective methods for the versatile functionalization of natural compounds containing dienes. The nitroso aldol reaction is a straightforward yet observably effective method for adding a nitrogen atom to a carbonyl group.^73,74

Qing-Qing Cheng et al.⁷⁵ reported the first rhodium-catalyzed cyclization of enoldiazo compounds with nitrosoarenes, where enoldiazoacetamides and nitrosoarenes underwent [3 + 2] cyclization under the catalysis of rhodium(II) octanoate. The reaction proceeded via cleavage of the enol double bond and the amide bond, providing completely substituted 5-derivatives of isoxazolone.

They also observed an astonishing change in the product when they changed the catalyst to rhodium(II) caprolactamate. The reaction followed an unexpected [5 + 1] cyclization instead of exclusively [3 + 2] cyclization. The reaction was initiated by reacting tert-butyldimethylsilyl (TBS)-protected enoldiazoacetamide 70 with nitrobenzene 2 in chloroform at room temperature. This reaction was tested with several commercially available catalysts. Notably, excellent results were obtained when [Rh₂(oct)₄] and [Rh₂(cap)₄] were used, which in turn produced 5-isoxazolones 71 and 1,3-oxazin-4-ones 72, respectively. The generality of the reaction was tested by investigating the substrate scope by changing the substituents of nitrobenzenes, and good to excellent yields were obtained irrespective of the positions (Scheme 48).

Scheme 48 Substrate scope for divergent rhodium-catalyzed cyclization reactions of enoldiazoacetamides 70 with nitrosoarenes 2.

Later on, several control experiments were carried out to understand the reaction mechanism and the role of the catalyst in the selectivity of the product. The proposed mechanism is demonstrated, wherein Rh₂(oct)₄ produces donor–acceptor-substituted cyclopropane 73 by catalyzing a tandem intramolecular cyclization sequence with enoldiazoacetamide 70, and also activates nitrosoarenes 2 for Michael addition, producing intermediate III, which will further undergo either ring closure or cyclopropane opening to deliver the product 71. On the other hand, Rh₂(cap)₄ enables the nitrosoarene to be electrophilically attacked at the diazo carbon, producing the diazonium intermediate V that is then added to the vinylogous position via intramolecular nucleophilic attack. Ensuring ring expansion, which is driven by aziridine ring cleavage, followed by silyl group migration and six-membered ring closure, defines the overall [5 + 1] cyclization. The resulting 4-isoxazoline intermediate VI rapidly rearranges to produce 2-acyl aziridine 72. The former reaction is completed in 6 h, whereas the latter requires a longer reaction time (Scheme 49). Overall, in this study, the author demonstrated first the cyclization between enoldiazo compounds with nitrosoarenes 2 and displayed the excellent selectivity of the rhodium catalyst in the formation of two biologically important heterocycles that opened the door for catalyst-controlled chemo-divergent studies.

Scheme 49 Proposed mechanism for divergent rhodium-catalyzed cyclization reactions.

In 2018, M. Baidya et al.⁷⁶ outlined the asymmetric nitroso aldol reaction of distal dialdehydes for the synthesis of chiral 1,2-oxazinanes, and isoxazolidines. The demanding 1,2-oxazines and isoxazolidines were produced using a straightforward process that employed the tiny organic molecule L-proline as a catalyst in high yields with outstanding enantioselectivities (Scheme 50). The synthesis of physiologically relevant chiral 3-hydroxypiperidine and pyrrolidine derivatives demonstrated the synthetic usefulness of this technique. Several screening reactions were performed to optimize the reaction conditions and a 72% yield was obtained with 93% ee, with L-proline as an organocatalyst and 3,5-di-tert-butylcatechol as an additive. The reaction was later explored for different substrates such as succinaldehyde, adepaldehyde, along with glutaraldehyde and various substitutions of nitrosoarenes with high yield and excellent enantioselectivities. Thus, this group demonstrated the simple, room temperature conditions, and small organic molecule proline as a catalyst for the synthesis of N–O bonds containing chiral heterocycles.

Scheme 50 General reaction – the organocatalytic asymmetric nitroso aldol reaction of distal dialdehydes.

Very recently, Lei Yu and coworkers⁷⁷ described the regio- and enantioselective nitroso Diels–Alder (NDA) reaction of 1,6-diyne esters with nitrosoarenes via a chiral gold(I) complex catalyst. The 3,5,6,8a-tetrahydro-1H-benzo[c][1,2]oxazines 76 can be obtained using the sequential ring creation process in excellent yields and enantiomeric excess. In contrast, comparable NDA reactions of the cycloisomerized 1,6-diyne ester 75 with nitrosoarenes 2 were discovered to generate the N, O heterocyclic product with the reverse regiochemistry when the chiral gold(I) complex catalytic mechanism was absent. Earlier, the reaction was initiated by treating the carboxylic ester with 5 mol% of Au(I) catalyst in DCM at 25 °C for 30 minutes, followed by the addition of nitrosoarenes; the reaction continued for 24 h, obtaining the yield of 13% with 66% ee. After varying different parameters such as ligands, time, temperature, and solvents, the best-optimized condition was established when the temperature was brought down to −60 °C using the [(S)-A/(AuNTf₂)₂] catalyst. This observation helped to establish the optimal condition for the reaction, and the generality of the reaction was evaluated by determining the substrate scope for both 1,6-diyne benzoate 75 and nitrosoarenes 2. When Bz of 1,6-diyne benzoate 75a was replaced with different substituents like Ac (75b), PBB (75c), PNB (75d), or PMB (75e), the reaction went smoothly with excellent yield and enantiomeric excess (Scheme 51).

Scheme 51 [(S)-A/(AuNTf₂)₂]-catalyzed cycloisomerization/regio- and enantioselective NDA reactions of 75b with 2.

Similarly, when substituents of nitrosoarenes 2 were varied with different electron-donating and electron-withdrawing groups, the reactions revealed considerable yield and enantiomeric excess (76s–76x, Scheme 52).

Scheme 52 [(S)-A/(AuNTf₂)₂]-catalyzed cycloisomerization/regio- and enantioselective NDA reactions of 75a or 75e with 2b–g.

Several control experiments and DFT studies were performed to understand the mechanistic path of the reaction, and a tentative mechanism has been produced (Scheme 53). Here, Au(I) catalyzed the 2,3-sigmatropic rearrangement and cyclopropanation of 1,6-diyne ester 75, leading to the formation of cyclopropane IX from the gold carbenoid species VIII. This will further undergo a 1,2-hydride shift to form the 1,3,5-triene intermediate I and regenerate the chiral metal complex.⁷⁸ The organogold species II is then produced by the subsequent coupling of two molecules of nitrosoarene 2 to each of the gold(I) centres of the chiral dinuclear metal complex. Next, this intermediate undergoes different transition states and finally produces N,O-heterocyclic oxazine 76 on giving back the chiral gold complex. In conclusion, a chiral gold complex catalyst was prepared for regio- and enantioselective synthesis of 3,5,6,8a-tetrahydro-1H-benzo[c][1,2]oxazines from 1,6-diyne esters and nitrosoarenes. This process conveys the first NDA reaction method for the [4 + 2] cycloaddition pathway for obtaining a single regioisomer, with excellent enantiomeric values involving chiral organo gold species. Therefore, this method paved the way for new strategies that exploit π- and σ-Lewis acidity via a chiral Au(I) complex.

Scheme 53 Proposed mechanistic rationale for the chiral Au(I) complex-catalyzed cycloisomerization/regio- and enantioselective NDA reactions.

8. Free radical reactions of nitroso compounds

Radical reactions involving nitroso compounds are in great demand for the development of overall and realistic approaches for the synthesis of sterically hindered amines that have a lot of practical value. The diradical nature of nitrosoarenes emerged as an attractive means for the synthesis of several heterocycles via C–N bond formation.⁷⁹ In 2015, David J. Fisher et al.⁸⁰ reported the synthesis of sterically hindered α-amino carbonyl compounds via a radical reaction involving nitrosoarenes catalyzed by the copper catalyst. In considering the drawbacks of previously reported methods for the synthesis of sterically hindered α-amino carbonyl compounds,^81–85 this group proposed a photo-controlled atom transfer radical polymerization (ATRP) via copper-catalyzed atom transfer radical coupling (ATRC) of radical trapping agents like nitrobenzene through single-electron transfer with alkyl halides. The study was initiated by performing several reactions, and the best-optimized condition involved using α-bromoisobutyrate 77 and N-aryl hydroxylamine 78 in THF under standard stoichiometric Cu(0) ATRP conditions,^86–88 and the Sm-mediated reduction of the N–O adduct produced the final product 79. The generality of the reaction was tested by investigating the substrate scope of different α-bromocarbonyl compounds. The reactions with various esters and amides were also successful in giving the desirable α-amino adducts in excellent yields (Scheme 54).

Scheme 54 Scope for the radical reaction of the substituted α-bromocarbonyls 77.

Their approach for the reaction using different substituted N-aryl hydroxylamines 78 also gave desirable yields, which proved that the reaction is compatible for both substrates towards 79 (Scheme 55).

Scheme 55 Scope for the radical reaction involving substituted N-aryl hydroxylamines 78.

The mechanism for this reaction was proposed by replacing the nitrosoarene with N-aryl hydroxylamine 78, which will, in turn, generate the radical trapping nitrosobenzene species B Cu(I)-catalyzed oxidation (Scheme 56). This radical addition will further form nitroxyl radicals, finally producing 79. In conclusion, this noteworthy protocol involves simple, inexpensive copper salts and easily available starting materials for the construction of α-amino carbonyl compounds, which facilitates widespread application in industry.

Scheme 56 Proposed Cu-catalyzed radical addition with the in situ – generated nitroso compounds.

In 2019, Soumen Ghosh and coworkers¹⁷ presented a metal-free method for the synthesis of N-centred radical generation through electron donor–acceptor (EDA) complexes. This strategy involves a single-electron transfer process that is initiated with the help of diisopropylethylamine (iPr₂NEt) or Hantzsch ester (HE). In order to achieve the ideal condition, several reactions were first carried out by adjusting various amine-containing bases, temperature, solvents, and the reaction's impact with and without oxygen. After having the optimized condition in hand, the substrate scope for the synthesis of isoxazolidine 81 was investigated. All electron-donating and electron-withdrawing groups of nitrosoarenes were well suited, irrespective of the positions, providing good to moderate yields. However, when sterically hindered groups of 2-substituted nitrosoarenes were used, aziridine derivatives 82 bearing quaternary chiral centers were observed (Table 3).

Table 3 The synthesis of isoxazolidines 81 and aziridine derivatives 82

Entry	R^1	R^2	R^3	R^4	R^5	Yield 3 (%)	Yield 4 (%)
1	H	H	H	H	Et	81a, 33	—
2	H	OMe	H	H	Et	81b, 28	—
3	H	H	Me	H	Et	81c, 25	—
4	H	H	F	H	Et	81d, 21	—
5	H	H	H	H	^tBu	81e, 30	—
6	H	H	H	H	(L)-Menthyl	81f, 32	—
7	Me	H	Me	H	Et	—	82a, 44
8	iPr	H	H	H	Et	—	82b, 40
9	Cl	H	H	H	Et	—	82c, 23
10	Me	H	H	H	^tBu	—	82d, 46
11	Me	H	H	H	(L)-Menthyl	—	82e, 33

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A similar trend was observed for the synthesis of β-amino acid derivatives. When allylsulfone substituents were allowed to react with nitrosoarenes bearing different electron-donating and electron-withdrawing groups in the presence of Hantzsch ester (HE), satisfactory and well-tolerating results (83a–83h, Table 4) were obtained.

Table 4 The synthesis of β-amino acid derivatives 83

Entry	R^1	R^2	R^3	R^4	Yield 16 (%)
1	H	H	H	Et	83a, 78
2	H	OMe	H	Et	83b, 80
3	H	Br	H	Et	83c, 62
4	H	H	Br	Et	83d, 78
5	H	H	Mr	Et	83e, 65
6	iPr	H	H	Et	83f, 99
7	H	H	H	^tBu	83g, 64
8	H	H	H	(L)-Menthyl	83h, 67

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After understanding the literature reports and experimental results, a mechanism for the formation of an EDA complex between iPr₂NEt and nitrosoarenes has been discussed (Scheme 57). A single-electron transfer (SET) process initiates the reaction by generating an N-centered radical anion. This species adds to allylsulfone 2a, forming intermediate A. Intermediate A then reacts with a second molecule of nitrosoarene to yield a bis-nitroxyl radical anion intermediate B, which is formed with unsubstituted, 3-substituted, and 4-substituted nitrosoarenes. This intermediate is unstable and undergoes rapid C–C bond cleavage to generate nitrone C. The resulting nitrone is highly reactive and undergoes a regioselective [3 + 2] cycloaddition with excess allylsulfone 2a, producing an isoxazolidine derivative. A second nitrone species (referred to as nitrone F) was detected by GC-MS analysis; however, attempts to isolate it in pure form were unsuccessful.

Scheme 57 A mechanistic proposal with preliminary experimental evidence.

In contrast, when a sterically hindered 2-substituted nitrosoarene is used, the reaction proceeds differently. Only one molecule of the nitrosoarene is incorporated, and this is accompanied by the elimination of a phenylsulfonyl radical (PhSO₂˙), resulting in intermediate D, as confirmed by MS and GC-MS analyses. The liberated PhSO₂˙ radical subsequently adds to excess 2a, forming compound E, providing further support for the proposed mechanism. An intramolecular Michael addition then occurs, followed by N–O bond cleavage via a 3-exo-tet ring closure, yielding an aziridine ring intermediate E. This aziridine reacts with another molecule of nitrosoarene, ultimately forming the final product, aziridine 82, which contains both geminal ester and aldehyde functionalities. The product is obtained in excellent yield—up to 47%, which approaches the theoretical maximum of 50%.

In Scheme 57, Fig. 12 illustrates the formation of a charge transfer (CT) band around 550 nm in the presence of iPr₂NEt. A similar CT band is also observed in the presence of HE, indicating a single-electron transfer (SET) from HE to the activated complex, as depicted in Fig. 13.

9. Miscellaneous reactions of nitroso compounds

Nitroso compounds are well explored in various types of reactions due to their versatility and reactive nature as mentioned above. Recent reports are geared towards photocatalysed reactions, regio- and chemoselective rearrangements, and so on; some of them are described below.^89,90 In 2016, Akira Yanagisawa et al.⁹¹ established a procedure for the synthesis of optically active α-aminooxy and α-hydroxy amino carbonyl compounds with excellent enantioselectivity via a chiral phosphine silver complex as a catalyst. This is a novel asymmetric O-nitroso aldol reaction involving alkenyl trifluoroacetate 84 and nitrosoarenes 2. In the beginning, the screening of several parameters such as bases, solvents, temperature, and phosphine complexes was conducted to obtain the optimized reaction condition. Once the optimization was complete, the reaction was evaluated with various substituted nitrosoarenes, which gave well to high yields with excellent enantioselectivities, irrespective of the positions of electron-withdrawing and electron-donating groups (Table 5).

Table 5 Enantioselective o-nitroso aldol reaction of alkenyl trifluoroacetate 84 with various nitrosoarenes 2 catalyzed by (R,R)-QuinoxP*·AgOAc

Entry	Nitrosoarene	R	Product	Yield, %	O/N	ee, % (O-adduct)
1	2a	H	85aa + 86aa	98	99/1	99
2	2b	2-Me	85ab + 86ab	67	>99/1	99
3	2c	4-Me	85ac + 86ac	91	>99/1	99
4	2d	2-Bu	85ad + 86ad	>99	>99/1	96 (S)
5	2e	2-^iPr	85ae + 86ae	67	>99/1	99 (S)
6	2f	2-CF3	85af + 86af	>99	57/43	86
7	2g	4-CF3	85ag + 86ag	54	52/48	72 (S)
8	2h	4-Br	85ah + 86ah	76	93/7	95 (S)
9	2i	3-OMe	85ai + 86ai	95	95/5	97

---

However, nitrosoarenes with bulkier groups similarly decreased the yield due to steric hindrance when substitutions on trifluoroacetate were varied with cyclic and acyclic ketones (Table 6). All the cyclic ketones gave affordable yields with high enantioselectivity, whereas acyclic ketones furnished the opposite N-selectivity.

Table 6 Enantioselective o-nitroso aldol reaction of various alkenyl esters 84b–h with nitrosoarenes 2a and 2b catalyzed by (R,R)-QuinoxP*·AgOAc

Entry	Alkenyl ester	Nitrosoarene	Product	Yield, %	O/N	ee, % (O-adduct)
1		2a	85ba + 86ba	84	90/10	96
2		2a	85ca + 86ca	>99	93/7	95
3		2a	85da + 86da	99	88/12	99
4		2a	85ea + 86ea	94	99/1	99
5		2b	85eb + 86eb	84	93/7	99
6		2a	85fa + 86fa	>99	35/65	92
7		2a	85ga + 86ga	86	40/60	80
8		2b	85gb + 86gb	93	4/96	—
9		2a	85ha + 86ha	10	<1/99	—

---

A plausible mechanism has been elucidated in Scheme 58. Initially, the chiral (R,R)-QuinoxP*·AgOAc complex forms the corresponding AgOMe complex during its reaction with methanol and N,N-diisopropylethylamine as a base. Later, this active AgOMe complex is allowed to react with alkenyl trifluoroacetate 84 to form chiral silver enolate A, which will further undergo a subsequent addition reaction followed by protonation to yield the final optically active α-aminoketone along with the regeneration of the active silver methoxide complex. In conclusion, a new strategy has been developed to access α-aminoketones with high yield and excellent enantioselectivity, up to 99% ee, catalyzed by a chiral silver complex. This is the first method reported for the asymmetric nitroso aldol reaction.

Scheme 58 Plausible catalytic cycle for the asymmetric o-nitroso aldol reaction catalyzed by chiral silver methoxide.

In 2017, Angela van der Werf et al.⁹² reported the synthesis of N-trifluoro methylated hydroxylamines 87 using sodium triflinate (Langlois reagent), which is employed as a CF₃ radical source along with a copper catalyst and an oxidant. This method produced the desired product within 1 h at room temperature. A high yield of 87 was obtained after a thorough screening of the reaction conditions within 1 h at room temperature as a single isomer. Further, the reaction was investigated for the other substituted nitrosoarenes 2, which reacted equally, producing excellent yields irrespective of their positions (Scheme 59). However, more sterically hindered substituents were found to produce lower yields, and overall, electron-rich and less sterically hindered species reacted faster than other species.

Scheme 59 N-Trifluoromethylation of nitrosoarenes.

Later on, based on the observations from the reaction with TEMPO and other previous reports,^93,94 they proposed a radical mechanism for this reaction (Scheme 60). Initially, when the CF₃ radical was added to the nitrosoarenes according to spin trapping experiments,⁹⁵ a metal catalyst was not required. Hydroquinone acts as a hydrogen donor in the reaction and delivers product 87 from the nitroxyl radical intermediate. The thus-obtained semiquinone radical (SQ) was then further oxidized to benzoquinone (BQ) and the nitroarene 2 content increased in the absence of hydroquinone. Secondly, the reaction did not proceed in the absence of copper. Hence, the CF₃ radical from the Langlois reagent involves copper and it was thought that the oxidation of the Langlois reagent was possible in two pathways. In the first pathway, copper is involved in single-electron oxidation, whereas in the second pathway, copper is involved in single-electron reduction. In conclusion, a highly chemoselective and effective method for the synthesis of N-trifluoromethylated hydroxylamines using the mild and affordable bench-stable Langlois reagent with hydroquinone as an important additive has been discussed, which provided high yields.

Scheme 60 Proposed mechanism for the radical reaction of the TEMPO-mediated reaction.

In 2019, R. S. Liu et al.⁹⁶ demonstrated the utilization of nitrosoarenes as 1,4-N,O-functionalization sources by describing the aromatizations of 3-ene-5-siloxy-1,6-diynes 88 with nitrosoarenes 2 to create 4-hydroxy-3-aminobenzaldehyde 89 derivatives. They began their study by carrying out several reactions, and screening was done by varying different parameters like ligands, silver salts, solvents, temperature, and time to get a yield of 88%, which has been proven as highly productive.

Later on, substrate scope was investigated by varying 3-ene-5-siloxy-1,6-diynes 88 and was very effective in producing excellent yields (89a–89m, Scheme 61). Similarly, the reactions were well tolerated for different substituents of nitrosoarenes 2 (Scheme 62).

Scheme 61 Aromatization reactions with substituted 3-ene-5-siloxy-1,6-diynes 88.

Scheme 62 Aromatization of 3-ene-5-siloxy-1,6-diyne 88 with substituted nitrozoarenes 2.

The team was also successful in performing an isotope labeling experiment, which provided a shred of evidence for elucidating the reaction mechanism as discussed in Scheme 63. Here, they hypothesized the synthesis of alkynyl gold B from the terminal alkyne species A, which is facilitated by a weakly basic PhNO. The former is more electron-rich than the latter, hence it coordinates with another gold to form the digold intermediate C. Further, a 1,5-hydride shift of C gives dipole species D, which initiates cyclization to give the 3-nitroxyintermediate E. After the release of LAu⁺, intermediate F, bearing the carbene functionality, is formed, which gives 4-siloxy-3-amino-1-naphthaldehyde H upon reaction with nitrosobenzene, followed by hydrolysis with D₂O. At last, the redox reaction between N-hydroxyaniline and AgX yields PhNO, Ag(0), and a proton, which enables the reduction of H to form diarylamine derivative I, and finally yields product 89. In conclusion, using nitrosoarenes as 1,4-N,O-functionalization species, they created novel gold-catalyzed aromatizations of 3-ene-5-siloxy-1,6-diynes to produce 4-hydroxy-3-aminobenzaldehyde products. ¹⁸O- and ²H-labelling experiments were carried out to envisage the reaction mechanism.

Scheme 63 Postulated mechanism for the aromatization reaction.

In the year 2020, Yu Zhang and co-workers reported⁹⁷ the diazoacetate 91, 2-oxo-3-ynoates 92, and nitrosoarenes 2 in a three-component reaction for the asymmetric catalytic synthesis of epoxides 93 using a chiral N,N′-dioxide/Ni(OTf)₂ complex. Rapid access to many multifunctional chiral epoxides with imino ketone substituents is made possible by this catalytic manifold in moderate to good yields and excellent diastereo- and enantioselectivities. To optimize the reaction conditions, the authors started investigations by selecting methyl 2-oxo-4-phenylbut-3-ynoate 91a, nitrosobenzene 2a, and ethyl diazoacetate 92a as the model substrates. Further, after varying different metal salts and ligands, an optimized condition was set up. Next, the generality of the reaction was tested by investigating the substrate scope for 2-oxo-3-ynoates, in which para- and meta-positions gave good yields and excellent enantioselectivities, whereas a decrease in the yield was observed with ortho-substitution (Scheme 64).

Scheme 64 Substrate scope of 2-oxo-3-ynoates 93.

Similarly, the reaction was well tolerated with electron-donating and withdrawing groups of nitrosoarenes, and showed outstanding results (Table 7).

Table 7 Substrate scope of nitrosoarenes 2 and diazoacetates 93

Entry	R^3	R^4	Yield (%)	Z/E	ee (%)
1	4-ClC6H4	Et	63 (93a)	93/7	97
2	4-BrC6H4	Bn	60 (93b)	92/8	98
3	4-MeC6H4	Bn	51 (93c)	91/9	99
4	3-ClC6H4	Et	41 (93d)	92/8	98
5	C6H5	^nBu	77 (93e)	91/9	99
6	C6H5	Bn	68 (93f)	92/8	98
7	C6H5	2-Furylmethyl	70 (93g)	92/8	98
8	C6H5	C6H5	73 (93h)	90/10	99

---

Control experiments revealed that the reaction proceeded with neither nitrone nor aziridine intermediates, and the reaction mechanism was proposed as follows. Initially, the Ni(OTf)₂ complex activates 2-oxo-3-ynoate and then reacts with diazoacetate and nitrosoarene rather than reacting individually. Hence, the reaction path follows a Darzens-type reaction and [2 + 2] cycloaddition followed by nitrogen release to afford the final epoxides⁹⁸ (Scheme 65). To summarize, an efficient chiral catalyst was used for the asymmetric three-component reaction and series of multifunctional epoxides were accessed.⁹⁹

Scheme 65 Darzens-type reaction and [2 + 2] cycloaddition followed by nitrogen release to afford the final epoxides.

In 2021, R. S. Liu et al.^79,100 revealed that nitrosoarene leads to the formation of nitrone intermediates under gold catalysts, allowing for two different catalytic reactions such as the rearrangement of nitroso-activated cycloheptatriene/benzylidene. Using CuCl and nitrosoarenes 2 as co-catalysts (10–30 mol%), this reaction chain enabled the development of gold-catalyzed aerobic oxidations of cycloheptatrienes 94 to produce benzaldehyde derivatives 95 (Scheme 66). Density functional theory also supported the novel tropylium-benzylidene nitroso-activated rearrangement. Eventually, gold-catalyzed [2 + 2 + 1] annulations between nitrosobenzene and two enol ethers to produce 5-alkoxyisoxazolidines, employing 1,4-cyclohexadiene as a hydrogen donor, using identical nitrosoarenes, were also reported. The authors have performed diverse reactions by employing different parameters, such as the use of different catalyst loadings, solvents, temperature, and time, to get optimized conditions. They found out that LAuCl, where L = P(t-Bu)₂(o-biphenyl) is the ligand, with CuCl (10 mol%) and nitrosoarene 2 (30 mol%) as cocatalysts in DCM at RT for 42 h, worked efficiently. Under these optimized conditions, the reactivity was assessed over various aryl/heteroaryl/alkyl-substituted cycloheptatrienes 94 and nitrosoarenes 2, which afforded the corresponding regioisomers in good to moderate yields with different ratios, and the mechanism was well explained using Density Functional Theory (DFT).¹⁰¹

Scheme 66 Scope for the aerobic oxidation of cycloheptatrienes.

On the other hand, the generality of the reaction was also tested for [2 + 2 + 1] annulation by varying enol ethers and nitrosoarenes. Most of the substituents on enol ethers afforded the cis product as the major product and trans as the minor, whereas the bulkier substituent on the enol ether selectively gave only the cis compound. In parallel, meta-substituted nitrosoarenes gave a mixture of cis and trans compounds, while the para-substituted nitrosoarenes gave the exclusively cis product (Scheme 67).^102,103

Scheme 67 Scope of gold-catalyzed [2 + 2 + 1]-annulations.

Next, this team proposed the reaction mechanism concerning [2 + 2 + 1] annulation, wherein nitrosobenzene first reacts with the gold-alkene F to produce species G of nitrosonium, which is then reduced with 1,4-cyclohexadiene to produce species H and a cyclohexadienyl cation to produce a proton and benzene.^104,105 The intermediate H is protonated to produce enamine I, which then tautomerizes to produce nitrone I′. Nitrone I′ then experiences a dipolar [3 + 2]-cycloaddition to produce the observed isoxazolidine derivative 96, which will be favorable for a big alkoxy group (Scheme 68). Finally, the authors were successful in synthesizing gold-catalyzed benzaldehyde derivatives 95 by aerobic oxidation of cycloheptatrienes 94, and the oxidative rearrangement of 7-nitroxy-cycloheptatriene to N-benzylidene aniline oxide afforded desirable yields and provided the mechanism using DFT studies.^106,107

Scheme 68 Plausible reaction mechanism for gold-catalyzed annulation.

In 2023, R. S. Liu and colleagues¹⁰⁸ reported that a novel cascade oxidative cyclization between nitrosoarenes 2 and allenynes 97a, conducted in the presence of TEMPO/O₂ mixtures, leads to the formation of indanones fused with an aziridine ring. These four-component reactions proceed without the need for catalysts or additives, generate no byproducts, and achieve nearly 100% atom economy. The authors claim that the persistent TEMPO radical is used to intercept long-lived diradical intermediates, forming new single radicals to enable the uptake of oxygen, ultimately affording substituted 1-indanones 98 and 98′ fused with an aziridine ring. After obtaining the optimized conditions with DCE as a solvent at 25 °C for 6 h, the generality of the reaction was tested for various electron-donating and electron-withdrawing substitutions on nitrosoarenes 2, as well as 1-allenyl-2-alkynylbenzene 97. Both the reactants gave moderate to excellent yields under mild reaction conditions with respect to different allenyl substitutions and excellent chemoselectivity (98, Scheme 69).

Scheme 69 Substrate scope of the cascade oxidative cyclization between nitrosoarenes 2 and allenynes 97a.

Mechanistic insights through DFT calculations suggest that the nitrosoarene–allenyne combination forms diradical intermediates, which are trapped by a TEMPO radical to produce a nitroxy radical capable of capturing an O₂ molecule (Scheme 70). This mechanistic model also explains the observed chemoselectivity in nitrosoarenes bearing para-alkyl substituents. To conclude, four-component cascade cyclizations involving allenynes, nitrosoarenes, TEMPO, and O₂ have been successfully developed to produce indanone derivatives fused with an aziridine ring. These reactions proceed without the use of any catalysts, generate no byproducts, and exhibit nearly 100% atom economy.

Scheme 70 Plausible reaction mechanism for 1-indanones.

In 2023, Xing Li and co-workers¹⁰⁹ developed a novel tandem strategy for constructing a range of 3-CF₃-4-acyl-functionalized quinolines 100, starting from easily accessible nitrosoarenes 2 and β-CF₃-1,3-enynes 99. This transformation employs Cu(OTf)₂ as a catalyst and DMAP as a base. The reaction proceeds through a sequential formation of C109–N, C–O, and C–C bonds, with the steric bulk of substituents (R¹) on the nitrosoarene benzene ring significantly influencing both reactivity and site-selectivity (100(a–v), Scheme 71, 28b). This cascade process showcases a unique annulation mechanism, efficient C–H bond activation, the use of simple starting materials, high step-economy, good regioselectivity, formation of three new bonds, and mild reaction conditions. The optimized conditions for the reaction were obtained by changing different reaction parameters such as catalysts, bases, solvents and time. This allowed the investigation of the substrate scope of the reaction, with the substitutions on both nitrosoarenes 2 and 3-CF₃-1,3-enynes 99 providing good to excellent yields (100, Scheme 72). The authors also noticed that in particular, the presence of DMAP effectively suppresses the formation of certain byproducts, while the steric hindrance of substituents on the nitrosoarene benzene ring plays a crucial role in governing the reaction outcome. The mechanistic study suggests that the reaction likely proceeds through a sequence involving [4 + 2] cycloaddition, N–O bond cleavage, cyclization, rearomatization, and aromatization to yield the final products (Scheme 73). In summary, authors established a Cu(OTf)₂-catalyzed, DMAP-mediated cascade reaction between nitrosoarenes and β-CF₃-1,3-enynes, enabling the efficient synthesis of structurally diverse 3-CF₃-4-acyl-functionalized quinolines under mild conditions.

Scheme 71 Substrate scope by varying nitrosoarenes 2.

Scheme 72 Substrate scope by varying β-CF₃-1,3-enynes 99.

Scheme 73 Plausible reaction mechanism for the synthesis of 3-CF₃-4-acyl-functionalized quinolines 100.

Very recently in 2024, Rulong Yan et al.^110,111 developed a new method for synthesizing 3-aminopyrroles utilizing nitrosoarenes and homopropargylic amines as reagents, with iodine (I₂) catalyzing both cyclization and amination steps. Though there were various methods for the synthesis of aminopyrroles 102, the direct reaction using nitrosobenzene as the amination reagent was not reported till then. This metal-free protocol operates under mild conditions, demonstrates excellent tolerance to various functional groups, and provides moderate to good yields both in terms of nitrosobenzenes 2 and a series of homopropargylic amines 101 (Scheme 74). In this approach, nitrosoarenes 2 function as both the amine source and the oxidant, enabling the efficient construction and amination of 3-aminopyrroles. The proposed mechanism begins with iodine converting to HIO and HI in water. The substrate 101a is oxidized by HIO to form a nitrogen-centered radical, which undergoes 5-endo-dig cyclization to generate an enamine radical. This radical reacts with nitrobenzene 2 to form a nitroxyl radical, which is reduced to a hydroxylamine intermediate. Protonation and dehydration of this intermediate lead to a quaternary ammonium salt, which undergoes isomerization and deprotonation to yield the final product, 102aa. In conclusion, using homopropargylic amines and nitrosobenzenes as aminating reagents, the authors have developed I₂-catalyzed amination and intermolecular cascade cyclisation to synthesize a variety of substituted 3-aminopyrroles with moderate to good yields of the desired products (Scheme 75).

Scheme 74 Substrate scope for the synthesis of aminopyrroles 102.

Scheme 75 Plausible reaction mechanism for the synthesis of aminopyrroles 102.

Along the same lines, in 2024, Yuanzhi Xia and group¹¹² reported a low-priced and easily available FeCl₂·4H₂O-catalyzed nitrene transfer reaction of nitrosobenzenes with N-acyloxyamides. The reaction was found to be more compatible in terms of functional group tolerance. By changing the different reaction parameters, the optimal conditions were obtained and employed for testing the generality of the reaction. Under the same reaction conditions, N-pivaloyloxybenzamides 103 and nitrosoarenes 2 bearing electron-withdrawing and donating groups worked extremely well to give the corresponding N-acyl azoxy compounds 104 (Scheme 76).

Scheme 76 Substrate scope for N-acyl azoxy compounds 104.

Based on the control experiments, a simple mechanism involving the iron-catalyzed nitrene transfer reaction was proposed, which included coordination, deprotonation, elimination and a nucleophilic addition to give the desired product (Scheme 77). At the gram-scale, this simple transformation could be completed without any problems in an air atmosphere, and the product's effective reduction and aryl transfer reactions showed its synthetic value.

Scheme 77 Plausible reaction mechanism for the synthesis of N-acyl azoxy compounds 104.

10. Conclusion

This review mainly focuses on the recent trends in various transition metal-catalyzed organic transformations involving nitroso compounds. The highly reactive and easily accessible nitrosoarenes are promising building blocks for annulation reactions, cycloaddition reactions, Diels–Alder reactions, radical reactions, etc., using transition metals, which are carefully categorized and discussed. Importantly, these procedures often offer a wide range of applications for the production of high-value N-heterocycles and sterically hindered secondary amines. They are also promising for application in the late-stage functionalization of natural products and the development of therapeutic targets. The research progress summarized in this review demonstrates a noteworthy level of region-specificity, stereo-selectivity, and regio-specificity in the synthesis of novel and pharmaceutically important drug-like molecules.

11. Future perspectives

Despite the numerous reports wherein the reactivity of nitrosoarenes are tested for large number of organic transformations, these reactions are mainly performed under homogeneous conditions. In this context, catalysis, as discussed above, heterogeneous catalysis using nitrosoarenes and other reactive partners, is still a demanding area for researchers in the coming years. The reactions of nitrosobenzene under heterogeneous catalysis, such as nanocatalysis, metal–organic frameworks,¹¹³ electrocatalysis, etc., have been highly fascinating in recent years due to their unique features such as recyclability and sustainable nature (Fig. 5). Nevertheless, reactions of nitroso compounds following the radical pathways under heterogeneous conditions are still in the early stages, despite the notable advancements. In most processes, nitroso alkanes are incompatible, the synthesis of chiral secondary amines is still a difficult problem in this sector, and the use of radical cation species [ArNO]⁺ in organic synthesis is still extensively unexplored. This calls for more research into asymmetric catalytic systems and innovative reaction models. We anticipate that this study will serve as a helpful resource for scholars with an interest in the subject and encourage further research into the chemistry of nitrosoarene compounds.

Fig. 5 Future perspectives of nitroso compounds in catalysis.

Author contributions

Nandini R.: writing – review & editing, writing – original draft, investigation, data curation, conceptualization; Ramesh B. Dateer: writing – review & editing, validation, supervision, funding acquisition, conceptualization, validation and visualization.

Conflicts of interest

There is no conflict of interest.

Data availability

No primary research results, software or code has been included and no new data were generated or analysed as part of this review.

Acknowledgements

The authors thank Jain University, India, for the infrastructure and financial support.

References

1. L. Yu, J. Diaz, A. A. Kroeger, M. L. Coote and P. W. H. Chan, Chiral Brønsted Acid-Catalyzed Regio-, Diastereo-, and Enantioselective Formal [2 + 2 + 2] Cycloaddition of 3-vinyl-1H-indoles with Nitrosobenzenes, ACS Catal., 2024, 14, 13269–13282.
2. (a) S. Qiu, R. Liang, Y. Wang and S. Zhu, Domino Reaction between Nitrosoarenes and Ynenones for Catalyst-Free Preparation of Indanone-Fused Tetrahydroisoxazoles, Org. Lett., 2019, 21, 2126–2129; (b) D. Dukanya, T. R. Swaroop, S. Rangappa, K. S. Rangappa and B. Basappa, Cyclization of Activated Methylene Isocyanides with Methyl N (N), N′-Di (tri) substituted Carbamimidothioate: A Novel Entry for the Synthesis of N, 1-Aryl-4-tosyl/ethoxycarbonyl-1H-imidazol-5-amines, SynOpen, 2019, 3, 71–76; (c) V. K. Jain and R. Ramapanicker, Diastereoselective synthesis of D-threo-sphinganine, L-erythro-sphinganine and (−)-spisulosine through asymmetric α-hydroxylation of a higher homologue of Garner's aldehyde, Tetrahedron, 2017, 73, 1568–1575.
3. (a) P. D. Jadhav, J. X. Chen and R. S. Liu, Gold(I)-Catalyzed Highly Enantioselective [4 + 2]-Annulations of Cyclopentadienes with Nitrosoarenes via Nitroso-Povarov Versus Oxidative Nitroso-Povarov Reactions, ACS Catal., 2020, 10, 5840; (b) P. Kumar and N. Dwivedi, Proline catalyzed α-aminoxylation reaction in the synthesis of biologically active compounds, Acc. Chem. Res., 2013, 46, 289–299.
4. (a) S. Pradhan, V. Sharma and I. Chatterjee, Nitrosoarene-Catalyzed HFIP-Assisted Transformation of Arylmethyl Halides to Aromatic Carbonyls under Aerobic Conditions, Org. Lett., 2021, 23, 6148–6152; (b) P. Zuman and B. Shah, Addition, reduction, and oxidation reactions of nitrosobenzene, Chem. Rev., 1994, 94, 1621–1641.
5. N. Aljaar, C. C. Malakar, J. Conrad, W. Frey and U. Beifuss, Reaction of 1-nitroso-2-naphthols with α-Functionalized Ketones and Related Compounds: The Unexpected Formation of Decarbonylated 2-Substituted naphtho[1,2-d][1,3]oxazoles, J. Org. Chem., 2013, 78, 154–166.
6. Y. Gao, S. Yang, W. Xiao, J. Nie and X.-Q. Hu, Radical Chemistry of Nitrosoarenes: Concepts, Synthetic Applications And Directions, Chem. Commun., 2020, 56, 13719–13730.
7. C.-N. Chen and R.-S. Liu, Gold-catalyzed [4 + 2] Annulations of Dienes with Nitrosoarenes as 4π Donors: Nitroso-Povarov Reactions, Angew. Chem., Int. Ed., 2019, 58, 9831–9835.
8. Z. Deng, C. Zhu, Y. Hua, G. He, Y. Guo, R. Lu, X. Cao, J. Chen and H. Xia, Synthesis and Characterization of Metallapentalenoxazetes by the [2 + 2] Cycloaddition of Metallapentalynes with Nitrosoarenes, Chem. Commun., 2019, 55, 6237–6240.
9. A. Srivastava, G. Shukla, D. Yadav and M. S. Singh, Access to Fully Substituted Thiazoles and 2,3-Dihydrothiazoles via Copper-Catalyzed [4 + 1] Heterocyclization of α-(N-hydroxy/aryl)imino-β-oxodithioesters with α-Diazocarbonyls, J. Org. Chem., 2017, 82, 10846–10854.
10. X. Li, T. Feng, D. Li, H. Chang, W. Gao and W. Wei, KOAc-Catalyzed One-Pot Three-Component 1,3-Dipolar Cycloaddition of α-Diazo Compounds, Nitrosoarenes, and Alkenes: An Approach to Functionalized Isoxazolidines, J. Org. Chem., 2019, 84, 4402–4412.
11. C. Maitra, P. D. Jadhav, D. Barik, Y.-S. Ho, C.-C. Cheng, M.-J. Cheng, Y.-W. Chiang and R.-S. Liu, Nitrosoarenes Implement Cascade Cyclization of 1-allenyl-2-alkynylbenzenes through Diradical Mechanism, Org. Lett., 2023, 25, 82–86.
12. R.-j. Peng, L. Chen, X.-j. Zhang and M. Yan, Rh(III)-Catalyzed C−H Functionalization of N-Nitrosoanilines with α-Sulfonylcarbenes, Adv. Synth. Catal., 2022, 364, 3567–3572.
13. A. Van der Werf and N. Selander, Para-Selective Halogenation of Nitrosoarenes with Copper(II) Halides, Org. Lett., 2015, 17, 6210–6213.
14. V. Santacroce, R. Duboc, M. Malacria, G. Maestri and G. Masson, Visible-Light, Photoredox-Mediated Oxidative Tandem Nitroso-Diels–Alder Reaction of Arylhydroxylamines with Conjugated Dienes, Eur. J. Org. Chem., 2017, 2095–2098.
15. A. Menichetti, F. Berti and M. Pineschi, Nitroso Diels-Alder Cycloadducts Derived From N-acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity, Molecules, 2020, 25(3), 563.
16. B. Maji and H. Yamamoto, Catalytic Enantioselective Nitroso Diels–Alder Reaction, J. Am. Chem. Soc., 2015, 137, 15957–15963.
17. S. Ghosh, G. Kumar, S. Pradhan and I. Chatterjee, EDA complex directed N-centred radical generation from nitrosoarenes: a divergent synthetic approach, Chem. Commun., 2019, 55, 13590–13593.
18. S. M. Weinreb and R. R. Staib, Synthetic aspects of Diels-Alder cycloadditions with heterodienophiles, Tetrahrdron, 1982, 38, 3087–3128.
19. V. Meyer and J. Locher, Untersuchungen über die Constitution der Nitrolsäuren, Ber. Dtsch. Chem. Ges., 1874, 7, 670–675.
20. V. Meyer and J. Locher, Ueber die Nitrolsäuren und ihre Isomeren, Ber. Dtsch. Chem. Ges., 1874, 7, 786–790.
21. A. Baeyer, Nitrosobenzol und nitrosonaphtalin, Ber. Dtsch. Chem. Ges., 1874, 7, 1638–1640.
22. B. Priewisch and K. Rück-Braun, Efficient Preparation of Nitrosoarenes for the Synthesis of Azobenzenes, J. Org. Chem., 2005, 70, 2350–2352.
23. S. Fountoulaki, P. L. Gkizis, T. S. Symeonidis, E. Kaminioti, A. Karina, I. Tamiolakis, G. S. Armatas and I. N. Lykakis, Titania–Supported Gold Nanoparticles Catalyze the Selective Oxidation of Amines into Nitroso Compounds in the Presence of Hydrogen Peroxide, Adv. Synth. Catal., 2016, 358, 1500–1508.
24. C. Kohlmeyer, M. Klüppel and G. Hilt, Synthesis of Nitrosobenzene Derivatives via Nitrosodesilylation Reaction, J. Org. Chem., 2018, 83, 3915–3920.
25. M. J. Nejad, E. Yazdani, M. K. Miraki and A. Heydari, Tungstate-supported silica-coated magnetite nanoparticles: a novel magnetically recoverable nanocatalyst for green synthesis of nitroso arenes, Chem. Pap., 2019, 73, 1575–1583.
26. P. Cheng, M. Sarakha, C. Mousty, P. Bonnet and G. Mailhot, Tetra-n-butylammonium Decatungstate Supported on Fe₃O₄ Nanoparticles: A Novel Nanocatalyst for Green Synthesis of Nitroso Compounds, Catal. Sci. Technol., 2023, 13, 1000–1008.
27. (a) C. N. Chen and R. S. Liu, Gold–catalyzed [4 + 2] Annulations of Dienes with Nitrosoarenes as 4 Π Donors: Nitroso–Povarov Reactions, Angew. Chem., 2019, 131, 9936–9940; (b) T. E. Kristensen, Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications, Beilstein J. Org. Chem., 2015, 11, 446–468; (c) Y. Hayashi, N. Umekubo and T. Hirama, Prolinate Salts as Catalysts for α-Aminoxylation of Aldehyde and Associated Mechanistic Insights, Org. Lett., 2017, 19, 4155–4158.
28. R. L. Sahani, L.-W. Ye and R.-S. Liu, Synthesis of Nitrogen-Containing Molecules via Transition Metal-Catalyzed Reactions on Isoxazoles, Anthranils And Benzoisoxazoles, Adv. Organomet. Chem., 2020, 73, 195–251.
29. P. Sharma and R. S. Liu, [3 + 2]-Annulations of N-Hydroxy Allenylamines with Nitrosoarenes: One-Pot Synthesis of Substituted Indole Products, Org. Lett., 2016, 18, 412–415.
30. B. L. Ryland, S. D. McCann, T. C. Brunold and S. S. Stahl, Mechanism of Alcohol Oxidation Mediated by Copper(II) and Nitroxyl Radicals, J. Am. Chem. Soc., 2014, 136, 12166–12173.
31. J. E. Steves and S. S. Stahl, Copper(I)/ABNO-Catalyzed Aerobic Alcohol Oxidation: Alleviating Steric and Electronic Constraints of Cu/TEMPO Catalyst Systems, J. Am. Chem. Soc., 2013, 135, 15742–15745.
32. M. Rafiee, K. C. Miles and S. S. Stahl, Electrocatalytic Alcohol Oxidation with TEMPO and Bicyclic Nitroxyl Derivatives: Driving Force Trumps Steric Effects, J. Am. Chem. Soc., 2015, 137, 14751–14757.
33. J. Kim and S. S. Stahl, Cu/Nitroxyl-Catalyzed Aerobic Oxidation of Primary Amines into Nitriles at Room Temperature, ACS Catal., 2013, 3, 1652–1656.
34. J. Liu, M. Skaria, P. Sharma, Y.-W. Chiang and R.-S. Liu, Ground-State Dioxygen Undergoes Metal-Free [3 + 2]-Annulations with Allenes and Nitrosoarenes under Ambient Conditions, Chem. Sci., 2017, 8, 5482–5487.
35. P. Sharma and R. S. Liu, [3 + 2]-Annulations of N-Hydroxy Allenylamines with Nitrosoarenes: One-Pot Synthesis of Substituted Indole Products, Org. Lett., 2016, 18, 412–415.
36. R. K. Howe, Reaction of Nitrosobenzene with Tetramethylallene, J. Org. Chem., 1968, 33, 2848–2851.
37. G. Fang, H. Wang, Q. Liu, X. Cong and X. Bi, Silver–Promoted [3 + 1 + 1] Annulation of Isocyanoacetates with Nitrosoarenes, Asian J. Org. Chem., 2018, 7, 1066–1070.
38. Y. Xiao, X. Wu, H. Wang, S. Sun, J.-T. Yu and J. Cheng, Rhodium-Catalyzed Reaction of Azobenzenes and Nitrosoarenes toward Phenazines, Org. Lett., 2019, 21, 2565–2568.
39. D. Vasu and R. S. Liu, Gold-Catalyzed Cyclization-Cycloaddition Cascade Reactions of Allenyl Acetals with Nitrones, Chem, 2012, 18, 13638–13641.
40. V. V. Pagar, A. M. Jadhav and R. S. Liu, Gold-catalyzed Formal [3 + 3] and [4 + 2] Cycloaddition Reactions of Nitrosobenzenes with Alkenylgold Carbenoids, J. Am. Chem. Soc., 2011, 133, 20728–20731.
41. V. V. Pagar and R. S. Liu, Gold–Catalyzed Cycloaddition Reactions of Ethyl Diazoacetate, Nitrosoarenes, and Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and Benzo [b] azepine Derivatives, Angew. Chem., 2015, 127, 5005–5008.
42. P. D. Jadhav, J.-X. Chen and R.-S. Liu, Gold(I)-Catalyzed Highly Enantioselective [4 + 2]-Annulations of Cyclopentadienes with Nitrosoarenes via Nitroso-Povarov versus Oxidative Nitroso-Povarov Reactions, ACS Catal., 2020, 10, 5840–5845.
43. C. Y. Tan, H. Lu, J. L. Zhang, J. Y. Liu and P. F. Xu, Asymmetric organocatalytic [4 + 1] annulations involving a polarity reversal process: A tandem catalytic approach to highly functionalized spiropyrazolone derivatives, J. Org. Chem., 2020, 85, 594–602.
44. L. Wang, F. Chen, P.-C. Qian and J. Cheng, The Silver-Mediated Annulation of Arylcarbamic Acids and Nitrosoarenes toward Phenazines, Tetrahedron Lett., 2022, 88, 153550.
45. L. Yang, Q. Wen, F. Xiao and G. J. Deng, Silver-Mediated Oxidative Vinylic C–H Bond Sulfenylation of Enamides with Disulfides, Org. Biomol. Chem., 2014, 12, 9519–9523.
46. X. Zhang, B. Liu, X. Shu, Y. Gao, H. Lv and J. Zhu, Silver-Mediated C–H Activation: Oxidative Coupling/Cyclization of N-Arylimines and Alkynes for the Synthesis of Quinolines, J. Org. Chem., 2012, 77, 501–510.
47. Y. Li, M. Lai, Z. Wu, M. Zhao and M. Zhang, Synthesis of 2−Acyl–Substituted Pyrazine Derivatives through Silver–Catalyzed Decarboxylative Coupling Reactions, ChemistrySelect, 2018, 3, 5588–5592.
48. F. Fontana, F. Minisci, M. C. N. Barbosa and E. Vismara, Homolytic Acylation of Protonated Pyridines and Pyrazines with Alpha -Keto Acids: The Problem of Monoacylation, J. Org. Chem., 1991, 56, 2866–2869.
49. L. Wang, F. Chen, P.-C. Qian and J. Cheng, The Silver-Mediated Annulation of Arylcarbamic Acids and Nitrosoarenes toward Phenazines, Tetrahedron Lett., 2022, 88, 153550.
50. R. j. Peng, L. Chen, X. j. Zhang and M. Yan, Rh(III)–Catalyzed C− H Functionalization of N–Nitrosoanilines with α–Sulfonylcarbenes, Adv. Synth. Catal., 2022, 364, 3567–3572.
51. B. Zhou, J. Du, Y. Yang, H. Feng and Y. Li, Rhodium-Catalyzed Direct Addition of Aryl C–H Bonds to Nitrosobenzenes at Room Temperature, Org. Lett., 2013, 15, 6302–6305.
52. A. Van der Werf and N. Selander, Para-Selective Halogenation of Nitrosoarenes with Copper(II) Halides, Org. Lett., 2015, 17, 6210–6213.
53. M. Peng, C.-S. Wang, P.-P. Chen, T. Roisnel, H. Doucet, K. N. Houk and J.-F. Soulé, Merging C–H Bond Activation, Alkyne Insertion, and Rearrangements by Rh(III)-Catalysis: Oxindole Synthesis from Nitroarenes and Alkynes, J. Am. Chem. Soc., 2023, 145, 4508–4516.
54. I. Ramakrishna, H. Sahoo and M. Baidya, Brønsted Acid Mediated N–O Bond Cleavage for A-Amination of Ketones through the Aromatic Nitroso Aldol Reaction, Chem. Commun., 2016, 52, 3215–3218.
55. Q. Wang and X. Li, Synthesis of 1 H-indazoles from Imidates and Nitrosobenzenes via, Synergistic Rhodium/Copper Catalysis, Org. Lett., 2016, 18, 2102–2105.
56. W. Hu, Q. Zheng, S. Sun and J. Cheng, Rh (iii)-Catalyzed Bilateral Cyclization of Aldehydes with Nitrosos toward Unsymmetrical Acridines Proceeding with C–H Functionalization enabled by a Transient Directing Group, Chem. Commun., 2017, 53, 6263–6266.
57. Y.-F. Chen, J. Chen, L.-J. Lin and G. J. Chuang, Synthesis of Azoxybenzenes by Reductive Dimerization of Nitrosobenzene, J. Org. Chem., 2017, 82, 11626–11630.
58. X. Li, L. Zheng, X. Gong, H. Chang, W. Gao and W. Wei, NBS/DBU-Promoted One-Pot Three-Component Cycloaddition of Malonic Acid Derivatives, Nitrosoarenes, and Alkenes: Synthesis of Isoxazolidines, J. Org. Chem., 2021, 86, 1096–1107.
59. F. Zhao, P. Yu, Y. Chen, F. Liu and K. N. Houk, π-Facial Stereoselectivity in Acyl Nitroso Cycloadditions to 5,5-Unsymmetrically Substituted Cyclopentadienes: Computational Exploration of Origins of Selectivity and the Role of Substituent Conformations on Selectivity, J. Org. Chem., 2021, 86, 17082–17089.
60. T. Chidley, N. Vemula, C. A. Carson, M. A. Kerr and B. L. Pagenkopf, Cascade Reaction of Donor–Acceptor Cyclopropanes: Mechanistic Studies On Cycloadditions with Nitrosoarenes and Cis-Diazenes, Org. Lett., 2016, 18, 2922–2925.
61. V. S. Korotkov, O. V. Larionov, A. Hofmeister, J. Magull and A. J. de Meijere, GaCl₃-Catalyzed Insertion of Diazene Derivatives into the Cyclopropane Ring, J. Org. Chem., 2007, 72, 7504–7510.
62. A. Purkait, S. Saha, S. Ghosh and C. K. Jana, Lewis Acid Catalyzed Reactivity Switch: Pseudo Three-Component Annulation of Nitrosoarenes and (Epoxy) Styrenes, Chem. Commun., 2020, 56, 15032–15035.
63. D. Beaudoin and J. D. Wuest, Dimerization of Aromatic C-Nitroso Compounds, Chem. Rev., 2016, 116, 258–286.
64. C. K. Ingold and D. St Weaver, J. Chem. Soc., 1924, 125, 1456.
65. N. Hepfinger and C. E. Griffin, The Course of the Reaction of Styrene and Nitrosobenzene: Formation of 2,3,5-triphenyltetrahydro-1,2,5-oxadiazole-n-oxides as Unstable Intermediates, Tetrahedron Lett., 1963, 4, 1361–1364.
66. P. Singh, D. Boocock and E. F. Ullman, Attempted Formation of the Unknown tetramethylaziridinyl-1-oxyl by Photolysis and Thermolysis of diazetidine-1, 2-dioxide, Tetrahedron Lett., 1971, 12, 3935–3938.
67. J. Y. Kang, A. Bugarin and B. T. Connell, Conversion of Nitrosobenzenes to Isoxazolidines: an Efficient Cascade Process Utilizing Reactive Nitrone Intermediates, Chem. Commun., 2008, 30, 3522–3524.
68. X. Fang, J. Cao, W. Ding, H. Jin, X. Yu and S. Wang, Copper-Catalyzed Aerobic Oxidative Cyclization of 2-Alkynylanilines with Nitrosoarenes: Synthesis of Organic Solid Mechanoluminescence Compounds of 4-Oxo-4H-cinnolin-2-ium-1-ide, Org. Lett., 2021, 23, 1228–1233.
69. J. X. Chen, P. D. Jadhav, C. N. Chen and R. S. Liu, Development of a [2 + 2]-Nitroso/Alkene Cycloaddition Using Sodium Tetrakis [3, 5-bis (trifluoromethyl) phenyl] borate Catalyst: Controlled Chemoselectivity of Two Equilibrating Isomeric Intermediates, Org. Lett., 2021, 23, 6246–6251.
70. X. Li, L. Zheng, X. Gong, H. Chang, W. Gao and W. Wei, NBS/DBU-promoted one-pot three-component cycloaddition of malonic acid derivatives, nitrosoarenes, and alkenes: Synthesis of isoxazolidines, J. Org. Chem., 2021, 86, 1096–1107.
71. X. Li, T. Feng, D. Li, H. Chang, W. Gao and W. Wei, KOAc-Catalyzed one-pot three-component 1, 3-dipolar cycloaddition of α-diazo compounds, nitrosoarenes, and alkenes: An approach to functionalized isoxazolidines, J. Org. Chem., 2019, 84, 4402–4412.
72. P. Zhai, W. Li, J. Lin, X. Li, W. L. Wei and W. Chen, Hydrazones as Substrates in the Synthesis of Isoxazolidines via a KOH-Promoted One-Pot Three-Component Cycloaddition with Nitroso Compounds and Olefins, J. Org. Chem., 2021, 86, 17710–17721.
73. N. Yasukawa, M. Kuwata, T. Imai, Y. Monguchi, H. Sajiki and Y. Sawama, Copper-Catalyzed Pyrrole Synthesis from 3, 6-dihydro-1, 2-oxazines, Green Chem., 2018, 20, 4409–4413.
74. J. Li, H.-Y. Tao and C.-J. Wang, Copper(I)/TF-BiphamPhos Catalyzed Asymmetric Nitroso Diels–Alder Reaction, Chem. Commun., 2017, 53, 1657–1659.
75. Q.-Q. Cheng, M. Lankelma, D. Wherritt, H. Arman and M. P. Doyle, Divergent Rhodium-Catalyzed Cyclization Reactions of Enoldiazoacetamides with Nitrosoarenes, J. Am. Chem. Soc., 2017, 139, 9839–9842.
76. I. Ramakrishna, P. Ramaraju and M. Baidya, Synthesis of Chiral 1,2-oxazinanes and Isoxazolidines via Nitroso Aldol Reaction of Distal Dialdehydes, Org. Lett., 2018, 20, 1023–1026.
77. L. Yu, W. Li, A. Tapdara, S. H. Kyne, M. Harode, R. Babaahmadi, A. Ariafard and P. W. H. Chan, Chiral Gold Complex Catalyzed Cycloisomerization/Regio- and Enantioselective Nitroso-Diels–Alder Reaction of 1,6-Diyne Esters with Nitrosobenzenes, ACS Catal., 2022, 12, 7288–7299.
78. T. Lauterbach, S. Gatzweiler, P. Noesel, M. Rudolph, F. Rominger and A. S. K. Hashmi, Carbene Transfer–A New Pathway for Propargylic Esters in Gold Catalysis, Adv. Synth. Catal., 2013, 355, 2481–2487.
79. S. A. More, R. D. Kardile, T.-C. Kuo, M.-J. Cheng and R.-S. Liu, Gold Catalysts Can Generate Nitrone Intermediates from a Nitrosoarene/Alkene Mixture, Enabling Two Distinct Catalytic Reactions: A Nitroso-Activated Cycloheptatriene/Benzylidene Rearrangement, Org. Lett., 2021, 23, 5506–5511.
80. D. J. Fisher, G. L. Burnett, R. Velasco and J. Read de Alaniz, Synthesis of Hindered A-Amino Carbonyls: Copper-Catalyzed Radical Addition with Nitroso Compounds, J. Am. Chem. Soc., 2015, 137, 11614–11617.
81. N. Momiyama and H. Yamamoto, Simple Synthesis of A-Hydroxyamino Carbonyl Compounds: New Scope of the Nitroso Aldol Reaction, Org. Lett., 2002, 4, 3579–3582.
82. A. Yanagisawa, T. Fujinami, Y. Oyokawa, T. Sugita and K. Yoshida, Catalytic Enantioselective N-nitroso Aldol reaction of γ, δ-Unsaturated δ-Lactones, Org. Lett., 2012, 14, 2434–2437.
83. H. M. Guo, L. Cheng, L. F. Cun, L. Z. Gong, A. Q. Mi and Y. Z. Jiang, l-Prolinamide-Catalyzed Direct Nitroso Aldol Reactions of A-Branched Aldehydes: A Distinct Regioselectivity from that with l-Proline, Chem. Commun., 2006, 4, 429–431.
84. K. Shen, X. Liu, G. Wang, L. Lin and X. Feng, Facile and Efficient Enantioselective Hydroxyamination Reaction: Synthesis of 3−Hydroxyamino–2−Oxindoles Using Nitrosoarenes, Angew. Chem., Int. Ed., 2011, 20, 4780–4784.
85. S. Murru, C. S. Lott, F. R. Fronczek and R. S. Srivastava, Fe-Catalyzed Direct α C–H Amination of Carbonyl Compounds, Org. Lett., 2015, 17(9), 2122–2125.
86. K. Matyjaszewski, Atom Transfer Radical Polymerization (ATRP): Current Status and Future Perspectives, Macromolecules, 2012, 45, 4015–4039.
87. C. Zhang and Q. Wang, Step–Growth Radical Addition–Coupling Polymerization (RACP) for Synthesis of Alternating Copolymers, Macromol. Rapid Commun., 2011, 32, 1180–1184.
88. C. J. Valente, A. M. Schellenberger and E. S. Tillman, Dimerization of poly (methyl methacrylate) chains using radical trap-assisted atom transfer radical coupling, Macromolecules, 2014, 47, 2226–2232.
89. C. Volpe, S. Meninno, A. Roselli, M. Mancinelli, A. Mazzanti and A. Lattanzi, Nitrone/Imine Selectivity Switch in Base–Catalysed Reaction of Aryl Acetic Acid Esters with Nitrosoarenes: Joint Experimental and Computational Study, Adv. Synth. Catal., 2020, 362, 5457–5466.
90. A. Pokluda, M. Kohout, J. Chudoba, M. Krupička and R. Cibulka, Nitrosobenzene: Reagent for the Mitsunobu Esterification Reaction, ACS Omega, 2019, 4, 5012–5018.
91. A. Yanagisawa, Y. Lin, A. Takeishi and K. Yoshida, Enantioselective nitroso aldol reaction catalyzed by a chiral phosphine–silver complex, Eur. J. Org. Chem., 2016, 5355–5359.
92. A. van der Werf, M. Hribersek and N. Selander, N-trifluoromethylation of Nitrosoarenes with Sodium Triflinate, Org. Lett., 2017, 19, 2374–2377.
93. Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond and P. S. Baran, Innate CH Trifluoromethylation of Heterocycles, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 14411–14415.
94. M. Tordeux, B. Langlois and C. Wakselman, Reactions of Bromotrifluoromethane and Related Halides. 8. Condensations with Dithionite and Hydroxymethanesulfinate Salts, J. Org. Chem., 1989, 54, 2452–2453.
95. C. L. Hawkins and M. J. Davies, Detection and Characterisation of Radicals in Biological Materials using EPR Methodology, Biochim. Biophys. Acta, 2014, 1840, 708–721.
96. B. S. Kale and R.-S. Liu, Gold-Catalyzed Aromatizations of 3-ene-5-siloxy-1,6-diynes with Nitrosoarenes to Enable 1,4-N,O-Functionalizations: One-Pot Construction of 4-Hydroxy-3-aminobenzaldehyde Cores, Org. Lett., 2019, 21, 8434–8438.
97. (a) Y. Zhang, H. Pan, W. Liu, W. Cao and X. Feng, Asymmetric Catalytic Synthesis of Epoxides via Three-Component Reaction of Diazoacetates, 2-Oxo-3-ynoates, and Nitrosoarenes, Org. Lett., 2020, 22, 6744–6749; (b) R. Imashiro, T. Yamanaka and M. Seki, Catalytic asymmetric synthesis of glycidic amides via chiral sulfur ylides, Tetrahedron: Asymmetry, 1999, 10, 2845–2851.
98. S. A. More, R. D. Kardile, T. C. Kuo, M. J. Cheng and R. S. Liu, Gold Catalysts Can Generate Nitrone Intermediates from a Nitrosoarene/Alkene Mixture, Enabling Two Distinct Catalytic Reactions: A Nitroso-Activated Cycloheptatriene/Benzylidene Rearrangement, Org. Lett., 2021, 23, 5506–5511.
99. B. List, Introduction: organocatalysis, Chem. Rev., 2007, 107, 5413–5415.
100. T. E. Kristensen, Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications, Beilstein J. Org. Chem., 2015, 11, 446–468.
101. C. Wang, M. Zheng and W. Lin, Asymmetric catalysis with chiral porous metal–organic frameworks: Critical issues, J. Phys. Chem. Lett., 2011, 2, 1701–1709.
102. J. Weng, C. Wang, H. Li and Y. Wang, Novel quaternary ammonium ionic liquids and their use as dual solvent-catalysts in the hydrolytic reaction, Green Chem., 2006, 8, 96–99.
103. P. H. Y. Cheong and K. N. Houk, Origins of selectivities in proline-catalyzed α-aminoxylations, J. Am. Chem. Soc., 2004, 126, 13912–13913.
104. S. L. Poe, A. R. Bogdan, B. P. Mason, J. L. Steinbacher, S. M. Opalka and D. T. McQuade, Use of bifunctional ureas to increase the rate of proline-catalyzed α-aminoxylations, J. Org. Chem., 2009, 74, 1574–1580.
105. A. Wang and H. Jiang, Palladium-catalyzed direct oxidation of alkenes with molecular oxygen: general and practical methods for the preparation of 1, 2-diols, aldehydes, and ketones, J. Org. Chem., 2010, 75, 2321–2326.
106. R. Kumar and I. N. Namboothiri, Regioselective synthesis of sulfonylpyrazoles via base mediated reaction of diazosulfones with nitroalkenes and a facile entry into withasomnine, Org. Lett., 2011, 13, 4016–4019.
107. Y. Hayashi, K. Okano and A. Mori, Synthesis of thieno [3, 2-b] indoles via halogen dance and ligand-controlled one-pot sequential coupling reaction, Org. Lett., 2018, 20, 958–961.
108. C. Maitra, D. Barik, Y. S. Ho, M. J. Cheng and R. S. Liu, Aerobic oxidation/metal-free cyclization cascades of nitrosoarenes and allenynes with TEMPO/O 2: a switch of diradical to single radical intermediates, Org. Chem. Front., 2023, 10, 6180–6184.
109. W. Li, S. Huang, Q. Liu, X. Li and W. Chen, Synthesis of 3-CF 3–4-acyl-substituted quinoline derivatives via a cascade reaction of nitrosoarenes and β-CF 3–1, 3-enynes, Org. Chem. Front., 2023, 10, 6172–6179.
110. J. Qin, S. Jiang, X. Luo, T. Wang, P. Liu, B. Yuan and R. Yan, I₂-catalyzed synthesis of 3-aminopyrrole with homopropargylic amines and nitrosoarenes, Chem. Commun., 2024, 60, 3701–3704.
111. J. H. Qin, Y. Wang, J. Y. Ouyang, M. Liu and X. H. Ouyang, Recent progress in the synthesis of N-substituted arylamines by reductive cross-coupling of nitroarenes, Org. Chem. Front., 2024, 11, 2638–2664.
112. W. Huang, H. Yan, Q. Wang, J. Chen, Y. Luo and Y. Xia, 2024. An iron-catalyzed nitrene transfer reaction of nitrosobenzenes with N-acyloxyamides for accessing N-acyl azoxy molecules, Org. Chem. Front., 2024, 11, 2561–2565.
113. C. Wang, M. Zheng and W. Lin, Asymmetric catalysis with chiral porous metal–organic frameworks: Critical issues, J. Phys. Chem. Lett., 2011, 2, 1701–1709.

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