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Synthesis 2022; 54(04): 910-924
DOI: 10.1055/a-1547-0196
special topic
Cycloadditions – Established and Novel Trends – in Celebration of the 70th Anniversary of the Nobel Prize Awarded to Otto Diels and Kurt Alder

The Synthesis of Five-Membered N-Heterocycles by Cycloaddition of Nitroalkenes with (In)Organic Azides and Other 1,3-Dipoles

Shandev Pookkandam Parambil‡
a   Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
b   Department of Applied Chemistry, Cochin University of Science and Technology, Kerala 682022, India
,
Santhini Pulikkal Veettil‡
a   Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
,
Wim Dehaen  ∗
a   Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
› Author Affiliations

W.D. acknowledges financial support from Fonds Wetenschappelijk Onderzoek, KU Leuven (grant C14/19/78).
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Abstract

Cycloaddition reactions have emerged as rapid and powerful methods for constructing heterocycles and carbocycles. [3+2] Cyclo­additions of nitroalkenes with various 1,3-dipoles have been an interesting research area for many organic chemists. This review outlines the synthesis of N-substituted and NH-1,2,3-triazoles along with other five-membered N-heterocycles through cycloaddition reactions of nitro­alkenes.

1 Introduction

2 Synthesis of 1,2,3-Triazoles

2.1 Synthesis of NH-1,2,3-Triazoles

2.2 Synthesis of N-Substituted 1,2,3-Triazoles

3 Synthesis of Pyrrolidines and Pyrroles

4 Synthesis of Pyrazoles

5 Conclusion


#

Key words

nitroalkenes - 1,3-dipolar cycloaddition - azides - triazoles - pyrrolidines - pyrroles - pyrazoles
1

Introduction

Nitroalkenes are versatile synthons for the construction of a wide range of heterocycles and carbocycles. High electrophilicity attributed to the strong electron-withdrawing nitro group make them susceptible to a range of organic transformations. Important reactions include Michael addition reactions, cycloadditions, Mannich reactions, and Morita­–Baylis–Hillman reactions.[1] [2] [3] [4] [5] [6] Moreover, the possibility of functional group transformations (nitro to amines, nitriles, carbonyl compounds, hydroxylamines, nitrones etc.), and easy preparation (Henry reaction, nitration of alkene, nitrodecarboxylation etc.) have also expanded their versatility in many organic reactions.[7–10]

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Prof. Dr. Wim Dehaenwas born in Kortrijk, Belgium. He obtained his PhD in 1988 under the guidance of Prof. G. L’abbé on a study concerning the rearrangements of 5-diazoalkyl-1,2,3-triazole derivatives. After postdoctoral stays in Israel (1988–1990), Denmark (3 months in 1990), the UK (3 months in 1994), and the KU Leuven (Belgium) in 1998, he becoming a full professor at the same university in 2004. To date, over 590 publications have appeared in international journals on his work on heterocyclic and supramolecular chemistry. Dr. Shandev Pookkandam Parambil was born in Kerala, India. He obtained his PhD in 2018 from Cochin University of Science and Technology, Kerala, India with Dr. P. A. Unnikrishnan. He then joined the group of Prof. Wim Dehaen at KU Leuven, Belgium in 2019. During postdoctoral research, he has worked on the synthesis and functionalization of organo­boron complexes and other fluorescent dyes. Currently he is an assistant professor at the Department of Applied Chemistry, Cochin University of Science and Technology, Kerala, India. Dr. Pulikkal Veettil Santhini is a native of Kerala, India. In 2018, she obtained her Ph.D. degree in Chemical Sciences from the Academy of Scientific and Innovative Research (AcSIR) at CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvanathapuram under the combined supervision of Dr. K. V. Radhakrishnan and Dr. R. Luxmi Varma. Recently, she was awarded a PDM Fellowship to carry out her postdoctoral research with Prof. Wim Dehaen. Her research work focuses on heterocyclic and medicinal chemistry.

Cycloaddition and annulation reactions have emerged as among the most powerful methods in organic synthesis, with an ability to generate heterocycles, polyheterocycles and carbocycles with high regio- and stereoselectivity through concerted, stepwise, or sequential processes. Over the past few years, rapid growth in this area has witnessed elegant works showcasing the unique reactivity of nitroalkenes­ in various annulations and 1,3-dipolar cyclo­addition reactions, leading to the synthesis of a range of heterocycles. The mechanism of the annulation can follow two pathways (1) concerted cycloaddition with retention of stereochemistry, or (2) Michael addition/cyclization (Michael­ initiated ring closure).[11] [12]

Initial attempts at the synthesis of carbocycles and heterocycles via various annulation reactions of nitroalkenes were reviewed in detail by Namboothiri et al. in 2014 in three consecutive reviews.[13] [14] [15] Since then, significant progress has been achieved concerning cycloaddition reactions.[16] We will discuss the results of our studies on triazole synthesis from nitroalkenes and also incorporate details on the reports of other research groups in the same area, combined with syntheses of various other five-membered N-heterocycles that result from nitroalkenes and other 1,3-dipoles. Dipoles such as nitrile imines, nitrones, nitronic acid esters, and nitrile N-oxides will not be discussed here, because, to our knowledge, no recent work has appeared on these systems. Rather, we will focus on five-membered, nitrogen­-containing heterocycles such as triazoles, pyrrolidines, pyrroles, and pyrazoles.


# 2

Synthesis of 1,2,3-Triazoles

Among the nitrogen-containing heterocycles, 1,2,3-triazoles have received wide attention due to their stability towards metabolic degradation, capacity for hydrogen bonding, and reactivity with proteins in different forms. Moreover, 1,2,3-triazoles have been regarded as bioisosteres of the amide moiety because of their similar spatial structure and electronic effects.[17] [18] [19] Significant attention has focused on the synthesis and transformation of triazole derivatives into valuable heterocyclic scaffolds over the past few years.[20–22]

Triazole derivatives in general are synthesized by using copper(I)- and ruthenium(II)-mediated azide–alkyne cyclo­addition reactions, which are commonly referred to as click reactions (CuAAC and RuAAC).[23] [24] [25] [26] CuAAC is limited to terminal alkynes for the synthesis of 1,4-disubstituted triazoles, whereas RuAAC is selective for the synthesis of the complementary 1,5-disubstituted 1,2,3-triazoles and the latter method also works well for internal alkynes. As an alternative approach to azide–alkyne cycloaddition, olefins were utilized in the place of alkynes for the synthesis of 1,2,3-triazoles.[27,28] This azide-olefin method proceeds via an unstable triazoline cycloadduct[29–31] that requires a transformation in situ into the stable triazole. The first method involves the oxidative azide-olefin cycloaddition (OAOC), where the triazoline will be further oxidized into triazole. The second method involves an elimination reaction after triazoline formation and then furnishes the triazole, which is known as eliminative azide-olefin cyclo­addition (EAOC). Thus, olefins bearing leaving groups such as nitroalkenes, vinyl sulfones and vinyl acetates, and enamines obtained in situ from various carbonyl and dicarbonyl compounds, have already been reported as substrates for the synthesis of 1,2,3-triazoles via the EAOC pathway. Here we have summarized the developments on the metal- and organo-catalyzed synthesis of NH- and N-substituted 1,2,3-triazoles from nitroalkenes.

2.1

Synthesis of NH-1,2,3-Triazoles

The synthesis of NH-1,2,3-triazoles from nitroalkenes with sodium azide was first realized by Zefirov et al., in 1971.[32] The respective triazole 2 was obtained in 60% yield with the formation of sym-triaryl benzenes 3 as side product (Scheme [1]). A reasonable mechanism for this transformation was revealed later in 2005 by Quiclet-Sire and Zard from the reaction of a substituted nitroalkene 6 and excess amount of NaN3 (2–4 equiv) at 80–90 °C in DMSO as solvent.[33] It has been proposed that the intermediate nitronate anion I was formed in the first step and then cyclized to the triazoline intermediate II, which underwent elimination of nitrite to deliver NH-1,2,3-triazoles 7 as final products (Scheme [1]). Hydroxymethyl substituted 1,2,3-triazoles 9 were available in low yield from the same work through a multicomponent reaction of nitroalkene 8, sodium azide, and formaldehyde in methanol by capturing the nitronate anion I formed in situ with formaldehyde (Scheme [2]).

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Scheme 1 Synthesis of NH-1,2,3-triazoles and mechanism
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Scheme 2 Synthesis of hydroxymethyl substituted triazoles through a multicomponent reaction of nitro olefin, sodium azide and formaldehyde

In 2007, a multicomponent strategy for the construction of vinyl substituted NH-1,2,3-triazoles 12 by 1,3-dipolar cycloaddition of β-alkyl substituted nitroalkene 10, aryl aldehyde 11 and sodium azide at room temperature was reported by Shi and co-workers.[34] This reaction proceeds through the formation of a 1-aryl diene: the Henry reaction of the deprotonated nitroalkene with aldehyde, followed by azide-1,3-dipolar cycloaddition to yield vinyl substituted triazole (Scheme [3]). The presence of l-proline as a catalyst significantly improved the yield to 89%.

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Scheme 3 Synthesis of vinyl substituted triazoles

The cycloaddition of simple aryl nitroolefins and NaN3 was accompanied by a significant amount of cyclotrimerization of nitroalkene under neutral conditions. To overcome this, a catalytic amount of various Brønsted acids were introduced to the reaction mixture by Guan and co-workers in 2014.[35] Especially, the use of 0.5 equiv of p-TsOH in DMF at 60 °C resulted in the formation of NH-1,2,3-triazoles in excellent yield (98%) without forming any trimerized product (Scheme [4]). By utilizing these optimized reaction conditions, a wide variety of 4-aryl NH-1,2,3-triazoles were synthesized. Moreover, disubstituted nitro­alkenes 13 could also be used in the 1,3-dipolar cycloaddition reaction to give 4,5-disubstituted NH-1,2,3 triazoles 14 in nearly quantitative yield under standard reaction conditions. This class of 4-aryl NH-1,2,3-triazoles were found to be important precursors for compounds with potent biological activities.

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Scheme 4 p-TsOH catalyzed cycloaddition of aryl nitroolefin and NaN3

Later, Lin and co-workers modified Guan’s method by using NaHSO3/Na2SO3 instead of p-TsOH in the multicomponent reaction of aldehyde 11, nitroalkane 15, and sodium azide for the synthesis of 4-aryl NH-1,2,3-triazoles 14 (Scheme [5]).[36] A series of aldehydes and nitro compounds were utilized in this one-pot reaction, but the overall yield of this reaction was found to be only moderate.

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Scheme 5 NaHSO3/Na2SO3 catalyzed multicomponent reaction of aldehyde­, nitroalkane, and sodium azide

Another interesting work by Guan et al. describes the synthesis of NH-1,2,3-triazoles 14 under neutral reaction conditions.[37] In all the previous reports in strongly acidic reaction media, the explosive and toxic hydrazoic acid was generated during the reaction. To circumvent this, a safer protocol using an ammonium acetate and acetic acid buffer system was introduced in the same multicomponent reaction (Scheme [6]). The extent of cyclotrimerization was decreased and the product was formed in excellent yields. This method was extended to a wide substrate scope including various aldehydes 11 with electron-donating and electron-withdrawing substitutes, and to different nitro­alkanes 15. Moreover, the synthetic utility of the method was highlighted by performing a gram-scale synthesis under the same reaction conditions.

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Scheme 6 Synthesis of NH-1,2,3-triazoles under neutral reaction conditions

Furthermore, nitroallylic acetates 16 and nitroallylic sulfones 18 were exploited in an azide-cycloaddition reaction into structurally modifiable triazolyl esters 17 and sulfone derivatives 19 in good yields (Scheme [7]).[38] A sequential Morita–Baylis–Hillman reaction followed by azide alkyne cycloaddition/denitration was also successively carried out in one pot to yield 4,5-disubstituted NH-1,2,3-triazoles. The mechanism of the reaction involves two steps, the first step is the regioselective 1,3-dipolar cycloaddition of nitroallylic derivatives 16 or 18 either with sodium azide or hydrazoic acid (possibly generated in situ) to form a triazoline intermediate I (Scheme [8]). In the second step, the elimination of HNO2 was accelerated by an additional activation of the nitro group with p-TsOH through H-bonding, leading to the formation of the desired 1,4-disubstituted triazoles 17 or 19.

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Scheme 7 Cycloaddition of nitroallylic acetates and nitroallylic sulfones
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Scheme 8 Mechanism of PTSA-assisted elimination

Anisimova and co-workers studied the reaction of 3-nitro-and 3-bromo-3-nitroacrylates 20 and 21 with sodium azide in methanol under mild reaction conditions (18–20 °C, 2 h) (Scheme [9]).[39] Triazolylcarboxylate 22 and vinyl azide 23 were obtained from 3-nitroacrylate 20, whereas 3-bromo-3-nitroacrylate 21 reacted in a similar way to give nitrotriazolyl carboxylate 24 and regioisomeric vinyl azides 25 and 26. The formation of vinyl azides was explained by the elimination of a nucleofugal substituent (nitro group or bromine atom) from the primarily arising intermediate, the azidonitro anion.

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Scheme 9 Reaction of 3-nitro- and 3-bromo-3-nitroacrylates with sodium­ azide

Sridhar et al. also worked on the Lewis acid mediated sodium azide-nitroalkene cycloaddition reaction[40] and have used ZrCl4 for the reaction. The reaction proceeds in two separate steps: first the Henry reaction and then a formal cycloaddition (Scheme [10]). The two-step protocol was extended to different aldehydes, allowing the synthesis of the corresponding triazoles 27.

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Scheme 10 ZrCl4-catalyzed reaction

Wang et al. investigated the use of Amberlyst 15 for the synthesis of NH-1,2,3-triazoles,[41] and reported that the reaction proceeded with excellent yield under mild reaction conditions. In this work, both sterically and electronically divergent nitroalkenes showed promising reactivity with sodium azide. The authors were able to recover the catalyst by simple filtration and its reuse was possible up to eight times without loss of catalytic activity.

Later in 2016, an aluminum(III) chloride-catalyzed three-component reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles was reported by Chen and co-workers.[42] In contrast to the above method by Sridhar et al., separation of nitroalkene intermediates from the reaction mixture was avoided. Thus it became possible to incorporate sensitive functional groups in the scope of the reaction and to synthesize ester and heteroaryl substituted NH-1,2,3-triazoles.

Fluorine-containing heterocycles are important structural motifs in pharmaceuticals and agrochemicals.[43] Nenajdenko and co-workers reported the first synthesis of 4-fluoro-5-aryl-1,2,3-triazoles 29 through the reaction of sodium azide and α-fluoronitroalkenes 28.[44] In the presence of sulfamic acid, the slow addition of nitroalkene in DMSO as solvent resulted in the formation of products in good yields (Scheme [11]). The presence of sulfamic acid substantially increased the trapping of nitrous acid and the suppression of the polymerization of the intermediate anion formed during the reaction.

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Scheme 11 Synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles

Continuous-flow chemistry methods have gained much attention in recent years. In 2019, Zhang and co-workers reported the acetic acid promoted cycloaddition between β-nitrostyrenes and sodium azide in a continuous-flow reactor.[45] The continuous-flow microreactor provided a safe environment for the use of dangerous reagents such as NaN3 and nitroalkenes, and the respective triazoles were formed in less than four minutes. Due to the high temperature, the reaction in the continuous-flow microreactor exhibited better chemoselectivity than in a sealed tube. A one-pot, three-component reaction of aldehydes, nitromethane, and NaN3 was also successfully carried out by using the same method. Notably, the synthesis in a continuous-flow reactor appears to be appropriate to produce safe industrial-level­ scale-up of 4-aryl-NH-1,2,3-triazoles.

In the last decades, nanoparticles have emerged as a green and robust catalytic systems for the synthesis of various­ heterocycles.[46] The Sun group reported a core–shell–shell structured heterogeneous catalyst, Fe3O4@nSiO2-SO3H@MS-NHCOCH3 (n = nonporous, MS = microporous SiO2) for the multicomponent reaction of aldehyde 11, nitromethane 30, and sodium azide (Scheme [12]).[47] The core of the catalyst is a Fe3O4 sphere, which gives the catalyst magnetic separability; the inner layer silica shell was grafted with SO3H groups, and the outer shell was functionalized with acetylated NH2 groups. The core–shell–shell nanoparticles smoothly catalyzed the synthesis of 1,2,3-triazole 27 under mild conditions, and the products were obtained in high yields. This bifunctional solid catalyst gave excellent selectivity and higher yield than the previously reported HOAc/NH4OAc system.[37] Moreover, the inner sphere located acid center prevents the release of hydrazoic acid, which was generated in situ. This confirms the safety of the heterogeneous catalyst. The authors also investigated the reusability of the catalyst and found that the catalyst was robust, without leaching of the active component. Further, the catalyst could be retrieved without loss by using a magnetic bar at the end of the reaction.

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Scheme 12 Multicomponent synthesis of 5-aryl-1,2,3-NH-triazoles

Recently, graphitic carbon nitride (g-C3N4) material were utilized to anchor desired metals, which allows their direct use as heterogeneous catalysts.[48] Banerjee and co-workers developed Cu@g-C3N4 for the [3+2]cycloaddition of nitroalkenes/alkynes with sodium azide for the synthesis of NH-1,2,3-triazoles 27 (Scheme [13]). In general, a wide range of nitroalkenes were suitable, and the short reaction time, use of water as reaction medium, and reusability of the catalyst made this protocol environmentally friendly in nature.

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Scheme 13 Cu@g-C3N4 catalyzed synthesis of 5-aryl-1,2,3-NH-triazoles

Phukan and co-workers employed ZnO nanoparticles in the multicomponent synthesis of 4-aryl-NH-1,2,3-triazoles 27.[49] This protocol offers an efficient and highly economical alternative to the existing methods and the reactions proceeded smoothly in the green solvent polyethyleneglycol (PEG) 400 under aerobic conditions. The reaction exhibited a broad substrate scope, with easily available and electronically diverse starting materials, resulting in excellent yields of the desired products. Moreover, the catalyst was used several times without loss of catalytic activity with retention of morphology and crystal structure.


# 2.2

Synthesis of N-Substituted 1,2,3-Triazoles

The organocatalyzed synthesis of heterocycles has received much attention over the past decade with the aim to circumvent the use of metal catalysts.[50] [51] Ramachary et al. developed the organocatalyzed synthesis of N-functionalized 1,2,3-triazoles from activated enones and organic azides.[52,53] Inspired by this work, we developed an efficient metal-free, three-component reaction to synthesize 1,4,5-trisubstituted 1,2,3-triazoles 33 from readily available building blocks, such as aldehydes 31, nitroalkanes 15, and organic azides 32 (Scheme [14]).[54] The optimization studies showed that by using 5 mol% morpholine:TsOH as bifunctional catalyst and 5 mol% BHT as additive in toluene at 100 °C, the yield of the product was increased considerably, with >99% regioselectivity. Here, the nitroalkene formed in situ (Knoevenagel condensation of aldehydes and substituted nitroalkene) followed by intermolecular cycloaddition with organic azide. This resulted in the formation of a 1,4,5-trisubstituted 1,2,3-triazoline intermediate, and then the loss of HNO2 afforded the desired product. The high regio­selectivity is clearly due to the action of the electron-withdrawing nitro group resulting in a partial positive charge on the β-carbon of the nitroalkene. A wide range of aromatic and aliphatic aldehydes were applicable under these optimized reaction conditions. Furthermore, the significance and versatility of this MCR was proven by synthesizing bitriazoles 34, tetraarylporphyrin functionalized with four fully substituted 1,2,3-triazole groups 37, lactone fused triazole 35 and coumarin fused triazole derivatives 36.

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Scheme 14 Organocatalyzed multicomponent reaction for the synthesis of N-substituted triazoles

Fused 1,2,3-triazoles are interesting molecules with potent biological activities. The main drawbacks of our previous method were the requirement for high concentration, high temperature (100 °C), and long reaction times (48–72 h). To overcome this and also for the synthesis of fused triazoles, we envisioned the introduction of a bifunctional substrate having aldehyde and azide functionality in a single molecule and combine this with nitroalkane.[55] We selected 2-(azidomethyl)benzaldehyde 38 and ethyl nitroacetate 15 as the model substrates, and, interestingly, a triazole-fused isoindoline 39 was obtained by a tandem sequential proline-catalyzed Knoevenagel condensation/ intramolecular azide–nitroalkene cycloaddition. Replacing the morpholine: TsOH catalyst with proline, changing the solvent from toluene to acetonitrile, and reducing the temperature (50 °C) and time (12 h) from our previously reported intermolecular MCRs (Scheme [15]) were the optimized reaction conditions for the synthesis of functionalized [a]-fused 1,2,3-triazoles.

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Scheme 15 Synthesis of fused triazoles

Realizing the importance of triazolochromenes, a mechanochemically assisted metal-free sequential one-pot, three-component reaction towards fully substituted triazolo­chromenes 40 was also developed by our group.[56] The regio­selective synthesis of triazolochromene was carried out in two steps; initially, the isolation of nitrochromene 41 formed by the reaction of nitrostyrene 8 with salicylaldehyde 40 and further cycloaddition with azides 42 (Scheme [16]). The product was obtained in 67% yield along with a side product 44, which was formed by oxidation and ring opening of triazolochromene 43.

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Scheme 16 Synthesis of triazolochromene

To avoid the isolation of nitrochromene, a one-pot, two-step reaction was designed, optimized, and executed (Scheme [17a]) for the synthesis of diverse triazolochromenes. Ball milling was reported to be a convenient method for the synthesis of 3-nitrochromene. Thus, we applied solvent-free conditions for the in situ syntheses of 3-nitro-2H-chromenes 41, followed by consecutive 1,3-dipolar cycloaddition in a reaction vial. In this way, products from solid salicylaldehydes could be obtained in good yields. However, a significant decrease in yield was observed in case of the liquid salicylaldehydes. The synthetic utility of the newly developed protocols was shown by gram-scale syntheses (Scheme [17b]). Moreover, post-functionalization via Pd catalysis gave biologically relevant analogues.

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Scheme 17 Ball-milling assisted synthesis of triazolochromenes

The applications of bi-1,2,3-triazole derivatives are underexplored due to the limited number of reports on their synthesis. Recently, we have reported a multicomponent pathways toward novel unsymmetrically tetra-ortho-substituted­ 5,5′-bi-1,2,3- triazoles 49 from formyl triazoles 48, nitroalkanes 15 and azides 32.[57] The novel bitriazoles cannot readily be accessed by any other previous method. The previously reported three-component reaction from our laboratory has been extended here by replacing the aryl and alkyl aldehyde with triazole aldehyde. The reaction proceeded slowly with alkyl azides but various substituted nitroalkanes were well tolerated under the optimized reaction condition (Scheme [18]). Moreover, a complementary synthesis of 4-nitro substituted nonsymmetrical tetra-ortho­-substituted 5,5′-bi-1,2,3-triazoles 51 (as mixtures of atropisomers) was illustrated by Cu catalyzed oxidative [3+2]-cycloaddition reaction of 5-nitrovinyl-appended 1,2,3-triazole 50 with various alkyl and aryl azides 32 (Scheme [19]).

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Scheme 18 Synthesis of bi-triazole
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Scheme 19 Cu-catalyzed oxidative [3+2]-cycloaddition reaction of 5-nitrovinyl-appended 1,2,3-triazole with various alkyl and aryl azides

Inspired by the classical syntheses of 1,2,3-triazole by 1,3-dipolar cycloaddition between alkynes and azides, Roy et al. investigated the use of α-fluoronitroalkenes 28 as surrogates of fluoroalkynes in cycloaddition reactions with organic azides to generate fluorinated 1,5-disubstituted 1,2,3-triazoles.[58] Interestingly, a novel library of 1,5-disubstituted 4-fluoro-1,2,3-triazoles 52 were synthesized with excellent regioselectivity in the presence of trifluoroacetic acid (TFA) as catalyst. α-Fluoronitroalkenes 28 were synthesized in two steps starting from the condensation of the corresponding aldehydes with tribromofluoromethane, and this was followed by radical-based nitration–debromination. Since the reactivity of α-fluoronitroalkene was low in comparison to simple nitroalkene, the yield of the cycloaddition was found to be in the moderate to fair range. The reaction was versatile with respect to aryl and aliphatic azides and α-fluoronitrostyrenes (Scheme [20]).

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Scheme 20 Synthesis of 1,5-disubstituted 4-fluoro-1,2,3-triazoles

In 2016, Tiwari and co-workers developed an efficient synthesis of 1,5-disubstituted 1,2,3-triazolyl glycoconjugates via metal-free [3+2] cycloaddition of glycosyl azido alcohol 53 with nitroalkenes 1.[59] After a competitive optimization study between p-TsOH and various ammonium salts including phase-transfer catalysts, it was observed that the reaction in the presence of one equivalent of tetrabutyl­ammonium fluoride (TBAF) as catalyst in DMF at 100 °C afforded the maximum reaction yield. Thus, a wide range of 1,5-disubstituted glyco-triazoles 54 were achieved in good yield. It is noteworthy that the reaction also proceeded with good yield with substrates having acid-sensitive groups (Scheme [21]).

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Scheme 21 Synthesis of 1,5-disubstituted 1,2,3-triazolyl glycoconjugates

In 2014, Wang et al. reported the selective synthesis of 1,5-disubstituted 1,2,3-triazoles 55 via Ce(OTf)3-catalyzed [3+2] cycloaddition of azides 32 with nitroalkenes 1 at 100 °C in toluene.[60] A variety of nitrostyrenes bearing electron-neutral, -donating, and -withdrawing groups on the aryl ring underwent cycloaddition with azide and furnished the desired products in good to excellent yields (Scheme [22]). The scope of the reaction was also checked with aryl azides, the reaction proceeded with lower yield and extended reaction time. The reaction has several advantages such as readily available starting materials and a less expensive catalyst, and the reaction did not require an inert atmosphere.

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Scheme 22 Ce(OTf)3-catalyzed [3+2] cycloaddition of azides with nitroolefins­

In 2015, Chen et al. disclosed copper-catalyzed [3+2] cycloaddition/oxidation reaction of organic azides 32 with nitroalkenes 1 for the synthesis of 1,5-disubstituted 4-nitro-1,2,3-triazoles 56.[61] This reaction proceeded through the dehydrogenation of the intermediate triazoline rather than elimination of HNO2, resulting in higher atom economy. After a series of optimization studies, it was observed that the use of 5 mol% Cu(OTf)2, 25% AcOH in DMF at 110 °C in the presence of air as oxidant gave the maximum yield for the reaction. Consequently, the desired NO2-substituted 1,2,3-triazole 56 could be synthesized with high selectively for the first time, from readily available building blocks, in moderate to high yields (Scheme [23]). A plausible mechanism for the reaction was proposed and is illustrated in Scheme [24]. Initially, the regioselective 1,3-dipolar cycloaddition of nitroalkene 1 with azide 32 affords the triazoline intermediate I. Then a radical II is generated with the help of the Cu(II) catalyst. Subsequent loss of another electron produces the cationic intermediate II. Finally, the loss of a proton results in the desired NO2-substituted 1,2,3-triazole. On the basis of the mechanism, it is clear that radical intermediate II was stabilized by the aryl group. Therefore, the cycloaddition/oxidation reaction with aliphatic nitroalkene always resulted in 1,5-disubstituted 1,2,3-triazoles 55 rather than NO2 substituted triazoles 56.

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Scheme 23 Synthesis of 1,5-disubstituted 4-nitro-1,2,3-triazoles
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Scheme 24 Mechanism of Cu-catalyzed synthesis of 1,5-disubstituted 4-nitro-1,2,3-triazoles

#
# 3

Synthesis of Pyrrolidines and Pyrroles

Pyrrolidines are significant building blocks in medicinal chemistry and asymmetric synthesis. They are widely used as auxiliaries as well as ligands for asymmetric synthesis.[62] [63] [64] [65] Metal- and organocatalyzed 1,3-dipolar cycloaddition reactions of azomethine ylides with various dipolarophiles are an efficient and straightforward way to synthesize pyrrolidine derivatives.

Castelló et al. reported an efficient method for enantioselective synthesis of polysubstituted exo-4-nitroprolinates 59 by using copper(II)- or silver(I) complexes of chiral phosphoramide L-1 catalyst via 1,3-dipolar cycloaddition between nitroalkenes 57 and azomethine ylide tautomers 58 prepared from α-amino acid derived imino esters (Scheme [25]).[66] Cycloaddition of methyl benzylideneglycinate with nitroalkene was promoted by (Sa,R,R)-1·AgOBz. (Sa,R,R)-1·Cu(OTf)2 was a suitable catalyst for cycloadditions of α-substituted imino esters and (Sa,R,R)-1·AgOTf worked best for aromatic aldehydes except benzaldehyde.

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Scheme 25 Synthesis of polysubstituted exo-4-nitroprolinates

Zhou et al. described the effectiveness of highly stable imidazolium-tagged ferrocenyl oxazoline phosphine ligands L-2 for the asymmetric 1,3-dipolar cycloaddition of azomethine ylide tautomers 60 with nitroalkenes 57 (Scheme [26]).[67] They observed that 10 mol% of CuClO4 with planar chiral imidazolium-tagged FimiOXAP ligand (L-2) is an efficient system for asymmetric 1,3-dipolar cycloaddition. Even in the presence of weak base, the pyrrolidine derivatives 61 were obtained in good yields with excellent enantioselectivity (up to 99% ee) and, importantly, the Michael adducts were not observed during the reaction. Advantageously, the asymmetric 1,3-dipolar cycloaddition in DCM/ionic liquid combination proceeded with very good yield. Moreover, the catalyst could be reused for at least five times with greater than 91% ee.

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Scheme 26 Asymmetric 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes

In 2015, an efficient asymmetric synthesis of 3,4-diaminopyrrolidines 65 was reported by Deng et al.[68] using chiral N,O-ligands L-3 prepared from a 1,2-dihydroimidazo[1,2-aquinoline motif, via 1,3-dipolar cycloaddition reaction of glycinimines 62 with novel β-phthalimidonitroethene 63 (Scheme [27]). The excellent diastereo-(dr up to 98:2) and enantioselectivities (ee up to 99%) are mainly found due to the ‘synergistic steric effects’ caused by chiral 1-methyl and 4-iodo groups present in the 4-iodo-DHIPOH ligand L-3/Cu(CH3CN)4BF4 complex. A Raney Ni-catalyzed reduction and deprotection of phthalimide 64 leads to the biologically relevant 3,4-diaminopyrrolidines 65 in excellent yields. Additionally, the synthetic utility was confirmed by a gram-scale reaction for the synthesis of 65 in 94% yield, 96:4 dr, and 97% ee.

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Scheme 27 Synthesis of 3,4-diamino pyrrolidines

Wang et al. described asymmetric 1,3-dipolar cycloaddition of nitroalkenes 8 with N-2,2,2-trifluoroethylisatin ket­imines 66 catalyzed by cinchona alkaloid-derived squaramide C-1 for the synthesis of 5′-trifluoromethyl-spiro[pyrrolidin-3,2′-oxindoles] 67 (Scheme [28]).[69] They observed that both the reactivity and stereoselectivity is controlled by steric effects rather than by electronic effects of the substrate. It is worth noting that C2F5-substituted ketimine did not give the product even after a long reaction time, probably because of the large size of the C2F5 group. Moreover, the nitro group of the final compound 67 was reduced to an amino group using NiCl2·6H2O and NaBH4 in MeOH with retention of both enantio- and diastereoselectivity.

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Scheme 28 Synthesis of 5′-trifluoromethyl-spiro[pyrrolidin-3,2′-oxindoles]

An enantioselective synthesis of polysubstituted spiro-nitroprolinates 69 was reported by Cossío et al. via 1,3-dipolar cycloaddition using α-imino γ-lactones 68 as azomethine ylide precursors and nitroalkenes 57 catalyzed by (R,R)‑Me-DuPhos·AgF (Scheme [29]).[70] The catalyst has a dual role because the fluoride behaves as a base in the course of the reaction. The spiro-nitroprolinate cycloadducts were obtained in high enantio- and diastereomeric ratios. The configurations of the products were determined by X-ray crystallographic analysis in addition to DFT calculations.

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Scheme 29 Synthesis of polysubstituted spiro-nitroprolinates

In 2016, Wang et al. described the synthesis of enantioenriched heterocycles bearing methylisoxazole and pyrrolidines 71 and 72 via Ag-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloadditions of azomethine ylides 60 with 4-nitro-5-styrylisoxazoles 70 (Scheme [30]).[71] It was observed that the imino ester with most of the substituents and differently substituted halogenated aryl ring gave products with good diastereo- and stereoselectivities. Among the dipolarophiles, 3-methyl-4-nitro-5-arylisoxazoles 60 afforded high yields and excellent diastereoselectivities in the cycloaddition reaction. In addition, the absolute configurations of the products were confirmed by X-ray analysis.

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Scheme 30 Ag-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloadditions of azomethine ylides with 4-nitro-5-styrylisoxazoles

Xiao et al. reported a copper-catalyzed asymmetric regio-reversed [3+2] cycloaddition of iminoesters 58 with nitroolefins 8.[72] Nitroolefins having either electron-donating or electron-withdrawing moieties on the β-aryl ring reacted well with the imino ester and produced the corresponding pyrrolidine products 73 in high yields and with excellent enantioselectivity (92–99% ee) (Scheme [31]). This procedure also showed excellent reaction efficiency and enantioselectivity at the gram-scale. Moreover, several synthetic transformations were carried out, including selective ester reduction with LiAlH4 and nitro group reduction with Zn dust without reduction in either yield or enantiomeric excess.

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Scheme 31 Copper-catalyzed asymmetric regio-reversed [3+2] cyclo­addition of imino esters with nitro olefins
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Scheme 32 Thiourea-organocatalyzed synthesis of tetrasubstituted pyrrolidines
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Scheme 33 Thiourea-organocatalyzed synthesis of 3,4-dihydro­coumarin fused pyrrolidine

Thiourea-organocatalyzed synthesis of tetrasubstituted pyrrolidines 75 in high enantiomeric excess (up to >99%) and excellent endo-selectivity was reported by Alemán et al. using azomethine ylides 74, derived from salicylaldehyde, and nitroalkenes 46.[73] The reaction employs monoactivated azomethine ylides, by utilizing a intramolecular hydrogen-bonding interaction between the o-hydroxy group and the nitrogen of the imine (Scheme [32]). The reactivity of the methylene is enhanced by this interaction. Different thiourea and squaramide based catalysts were screened as organocatalysts, and Takemoto’s catalyst (Cat-1) was found to be the best for this reaction. Nitroalkenes with electron-donating or electron-withdrawing groups were well tolerated, but longer reaction times were needed for electron-donating alkyl residues. EWG (electron withdrawing groups) or EDG (electron donating groups) at the dipole were also successfully employed in this reaction. In addition, 3,4-dihydrocoumarin fused pyrrolidines 78 were also synthesized by the same group using a double annulative process and the intramolecular displacement of a phosphonate group 77 (Scheme [33]).

An interesting approach by using copper catalysis with phosphoramidite-thioether ligands L-6 and L-7 led to dia­stereodivergent asymmetric synthesis of endo- and exo-pyrrolidines 79 and 80, and was reported by Xiao et al. in 2018.[74] The enantioselective induction was facilitated by the chiral environment formed from coordination of P and S atoms of the ligands with Cu. Two sets of optimal conditions were established by employing ligand L-6 and L-7. At lower reaction temperature –5 °C, the ligand L-6 afforded endo-79 in 85% isolated yield with >19:1 d.r. and 94% ee. Interestingly, complete diastereochemical inversion was observed by replacing the cyclohexyl methyl group on the N atom of the ligand with a benzyl group. Nitroolefins with EWG and EDG substituent at the ortho-, meta- and para-positions and azomethine ylides with EDG and EWG substituents at the para-positions of the benzene ring were well tolerated in this protocol. The products with endo-79 and exo-80 were obtained in high yields and with excellent diastereo- and enantioselectivity. This methodology was also successful at gram scale with good yields and stereoselectivity (90–94% ee) (Scheme [34]).

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Scheme 34 Copper-catalyzed diastereodivergent asymmetric synthesis of tetrasubstituted pyrrolines

A multi-kilogram scale synthesis of the tetrasubstituted pyrrolidine 83 core of ABBV-3221 via copper-catalyzed enantioselective­ [3+2] cycloaddition was developed by Hartung­ et al. in 2019.[75] Different Segphos and push-pull bidentate ferrocenyl ligands were screened and it was observed that ferrocenyl ligand L-8 afforded the highest enantioselectivity (99.5:0.5 er endo-product; er, enantiomeric ratio), full conversion, and good diastereoselectivity (83:17 dr endo/exo). It was also found that the solvent had a striking impact on the yield, diastereoselectivity and enantioselectivity, and the product was isolated using direct crystallization from the reaction mixture (Scheme [35]).

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Scheme 35 Multi-kilogram-scale synthesis of tetrasubstituted pyrrolidine

In continuation, Greszler and co-workers reported an endo-selective synthesis of densely functionalized pyrrolidines 86 via copper-catalyzed cycloaddition of nitroalkenes 84 and azomethine ylides 85.[76] The greatest advantage of this protocol is that even quaternary substituted nitro­alkenes and heteroaromatic and hindered ortho-substituted arenes on the azomethine ylide were well tolerated. Low catalyst loading (1 mol%), readily available starting materials, and easy product purification were added highlights of this strategy (Scheme [36]).

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Scheme 36 Synthesis of densely functionalized pyrrolidines via copper-catalyzed cycloaddition of nitroalkenes and azomethine ylides

The synthesis of pyrroles from nitro alkenes has been mainly realized by (1) annulation with enamine, (2) Barton­–Zard reaction, and (3) annulation with azomethine ylides.[77] [78] [79] [80] [81] [82] [83] These reactions have been well reviewed by Namboothiri et al. in 2014. Here, we describe the recent developments in the synthesis of pyrroles by the cycloaddition of nitroalkene.

In 2014, Wang et al. developed an innovative route for the selective synthesis of polysubstituted pyrroles 89 through the (3+2) cycloaddition of aziridines 88 and nitroalkenes 13 catalyzed by copper(II) under aerobic conditions (Scheme [37]).[84] This method involves the regioselective cleavage of the C–C bond of aziridine to azomethine ylide, followed by Cu-catalyzed (3+2) cycloaddition with β-nitroalkene. Exploration of the scope of the annulation showed that a β-nitrostyrene with an EDG on the aryl ring gave good yields compared with those bearing an EWG. Nitroalkenes­ derived from aliphatic aldehydes also participated but with lower yields. The scope of the reaction was also checked for aziridines; those bearing EWG on the benzene ring gave better yields than those with EDG.

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Scheme 37 Copper(II)-catalyzed synthesis of polysubstituted pyrroles through the [3+2] cycloaddition of aziridines and nitro alkenes
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Scheme 38 Copper-catalyzed synthesis of fluorinated pyrrolidines

Tabolin et al. in 2021 reported a copper-catalyzed synthetic route to construct fluorinated pyrrolidines 90 and 91 by the reaction of α-fluoronitroalkene 28 and azomethine ylide precursor 60 via [3+2] cycloaddition (Scheme [38]).[85] The reaction was carried out in THF solvent using 5 mol% Cu(OTf)2 as the catalyst and 2.5 equiv Et3N as the base. The reaction provided diverse β-fluoro-β-nitropyrrolidine derivatives with an excellent substrate scope and high regio­selectivity. Further oxidation using 2,3-dichloro-5,6-dicy­ano-1,4-benzoquinone (DDQ) and HNO2 elimination by K2CO­3 resulted in the generation of fluorinated pyrrole 92 analogues in quantitative yields.


# 4

Synthesis of Pyrazoles

Pyrazoles and their derivatives are important hetero­cyclic scaffolds with varied biological properties including antimalarial, antiviral, antiglaucoma, antiparasitic, anti­parkinson, antihypercholestrolemia, antihypertensive, antipsychotic, antimicrobial, antifungal, antitubercular, anti-inflammatory, analgesic, anticancer activities.[86] [87] [88] [89] Commercialized drugs such as Celebrex, Viagra, Lonazolac and Acompalia contain a pyrazole core.[90–92] Furthermore, pyrazole derivatives are used extensively in C–H activation reactions and as ligands in various coupling reactions.[93] [94] Among the most common methods for the synthesis of pyrazole scaffolds are cyclocondensations of hydrazines with 1,3-dicarbonyl compounds or their derivatives, and 1,3-dipolar cycloaddition of diazo compounds with alkenes or alkynes.[95]

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Scheme 39 1,3-Dipolar cycloaddition reaction of 2-phenacyl- or alkoxycarbonylmethyl benzothiazolium bromides with 3-nitrochromenes
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Scheme 40 Synthesis of trifluoromethylated pyrazolidines

Yan et al. reported the diastereoselective synthesis of tetrahydrobenzo[d]chromeno[3′,4′:3,4]pyrrolo[2,1-b]thiazoles 97 via triethylamine-mediated 1,3-dipolar cycloaddition reaction of 2-phenacyl- or alkoxycarbonylmethyl benzothiazolium bromides 94 with 3-nitrochromenes 95 in ethanol at room temperature. The respective dehydrogenated benzo[d]chromeno[3′,4′:3,4]pyrrolo[2,1-b]thiazoles 97 were also synthesized by adding excess DDQ (Scheme [39]).[97]

Hu et al. developed an interesting approach towards the synthesis of trifluoromethylated pyrazolidines 99 via a [3+2] cycloaddition reaction between trifluoromethylated N-acylhydrazones 98 and nitroolefins 8 in the presence of potassium hydroxide under phase-transfer catalysis. In addition, pyrazolidines were transformed into the respective NH-pyrazoles 100 in good yields (Scheme [40]).[98]

Ma et al. demonstrated the synthesis of multisubstituted cyanopyrazoles 101, 102 and 103 from nitroalkenes 13 and diazoacetonitrile (N2CHCN) via transition-metal-free [3+2] cycloaddition reaction using 1.5 equiv of Cs2CO3 in THF at room temperature (Scheme [41]).[96] The feasibility of this strategy by one-pot reaction was investigated using N2CHCN generated in situ, but the yield was lower than that using pure diazoacetonitrile. Nitrostyrenes with different substitution on the phenyl ring, and nitroalkenes attached to polycyclic groups and, interestingly, nitrodienes, nitroenynes, tri-substituted and allyl substituted nitroalkenes were well suitable for this methodology. Also, this procedure gave a mixture of 3-cyanopyrazoles and 5-cyanopyrazoles by utilizing a one-pot, three-component reaction of nitroalkenes, N2CHCN, and alkyl halides.

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Scheme 41 Synthesis of multisubstituted cyanopyrazoles

Shibata et al. reported the synthesis of attractive drug candidates pyrazole triflones 105 (triflyl group at the third position) by reacting ((trifluoromethyl)sulfonyl)ethan-1-one 104 with nitroalkenes 13 in the presence of a base. In this report, a variety of pyrazole triflones were prepared from nitroalkenes having different EWG and EDG.[99] The methodology worked well with differently substituted aryl rings and heterocyclic variants on the nitroolefin counterpart. It is notable that a reactive anionic triflyldiazomethane anionic species was formed in the first step, which was subsequently reacted with nitroalkene to furnish pyrazole triflones (Scheme [42]).

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Scheme 42 Synthesis of pyrazole triflones

# 5

Conclusion

Cycloaddition reactions of nitroalkenes are an efficient strategy for constructing five-membered N-heterocycles. The importance of this methodology has been demonstrated by the number of articles and reviews that have appeared in the last 10 years. Here, we have discussed their potential reactivity in 1,3-dipolar cycloaddition to various dipolarophiles, mainly for the synthesis of NH and N-substituted 1,2,3-triazoles. Nitroalkenes are found to be reactive in both metal-catalyzed and organocatalytic reactions. Although many developments have been reported in the cycloaddition of nitroalkenes, in the future it is likely that there will be more advances in synthesizing various functionalized heterocyclic frameworks.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Wim Dehaen
Molecular Design and Synthesis, Department of Chemistry, KU Leuven
Celestijnenlaan 200F, 3001 Leuven
Belgium   

Publication History

Received: 31 May 2021

Accepted after revision: 09 July 2021

Accepted Manuscript online:
09 July 2021

Article published online:
19 August 2021

© 2021. Thieme. All rights reserved

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Prof. Dr. Wim Dehaenwas born in Kortrijk, Belgium. He obtained his PhD in 1988 under the guidance of Prof. G. L’abbé on a study concerning the rearrangements of 5-diazoalkyl-1,2,3-triazole derivatives. After postdoctoral stays in Israel (1988–1990), Denmark (3 months in 1990), the UK (3 months in 1994), and the KU Leuven (Belgium) in 1998, he becoming a full professor at the same university in 2004. To date, over 590 publications have appeared in international journals on his work on heterocyclic and supramolecular chemistry. Dr. Shandev Pookkandam Parambil was born in Kerala, India. He obtained his PhD in 2018 from Cochin University of Science and Technology, Kerala, India with Dr. P. A. Unnikrishnan. He then joined the group of Prof. Wim Dehaen at KU Leuven, Belgium in 2019. During postdoctoral research, he has worked on the synthesis and functionalization of organo­boron complexes and other fluorescent dyes. Currently he is an assistant professor at the Department of Applied Chemistry, Cochin University of Science and Technology, Kerala, India. Dr. Pulikkal Veettil Santhini is a native of Kerala, India. In 2018, she obtained her Ph.D. degree in Chemical Sciences from the Academy of Scientific and Innovative Research (AcSIR) at CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvanathapuram under the combined supervision of Dr. K. V. Radhakrishnan and Dr. R. Luxmi Varma. Recently, she was awarded a PDM Fellowship to carry out her postdoctoral research with Prof. Wim Dehaen. Her research work focuses on heterocyclic and medicinal chemistry.
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Scheme 1 Synthesis of NH-1,2,3-triazoles and mechanism
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Scheme 2 Synthesis of hydroxymethyl substituted triazoles through a multicomponent reaction of nitro olefin, sodium azide and formaldehyde
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Scheme 3 Synthesis of vinyl substituted triazoles
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Scheme 4 p-TsOH catalyzed cycloaddition of aryl nitroolefin and NaN3
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Scheme 5 NaHSO3/Na2SO3 catalyzed multicomponent reaction of aldehyde­, nitroalkane, and sodium azide
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Scheme 6 Synthesis of NH-1,2,3-triazoles under neutral reaction conditions
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Scheme 7 Cycloaddition of nitroallylic acetates and nitroallylic sulfones
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Scheme 8 Mechanism of PTSA-assisted elimination
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Scheme 9 Reaction of 3-nitro- and 3-bromo-3-nitroacrylates with sodium­ azide
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Scheme 10 ZrCl4-catalyzed reaction
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Scheme 11 Synthesis of 4-fluoro-5-aryl-1,2,3-NH-triazoles
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Scheme 12 Multicomponent synthesis of 5-aryl-1,2,3-NH-triazoles
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Scheme 13 Cu@g-C3N4 catalyzed synthesis of 5-aryl-1,2,3-NH-triazoles
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Scheme 14 Organocatalyzed multicomponent reaction for the synthesis of N-substituted triazoles
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Scheme 15 Synthesis of fused triazoles
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Scheme 16 Synthesis of triazolochromene
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Scheme 17 Ball-milling assisted synthesis of triazolochromenes
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Scheme 18 Synthesis of bi-triazole
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Scheme 19 Cu-catalyzed oxidative [3+2]-cycloaddition reaction of 5-nitrovinyl-appended 1,2,3-triazole with various alkyl and aryl azides
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Scheme 20 Synthesis of 1,5-disubstituted 4-fluoro-1,2,3-triazoles
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Scheme 21 Synthesis of 1,5-disubstituted 1,2,3-triazolyl glycoconjugates
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Scheme 22 Ce(OTf)3-catalyzed [3+2] cycloaddition of azides with nitroolefins­
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Scheme 23 Synthesis of 1,5-disubstituted 4-nitro-1,2,3-triazoles
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Scheme 24 Mechanism of Cu-catalyzed synthesis of 1,5-disubstituted 4-nitro-1,2,3-triazoles
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Scheme 25 Synthesis of polysubstituted exo-4-nitroprolinates
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Scheme 26 Asymmetric 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes
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Scheme 27 Synthesis of 3,4-diamino pyrrolidines
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Scheme 28 Synthesis of 5′-trifluoromethyl-spiro[pyrrolidin-3,2′-oxindoles]
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Scheme 29 Synthesis of polysubstituted spiro-nitroprolinates
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Scheme 30 Ag-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloadditions of azomethine ylides with 4-nitro-5-styrylisoxazoles
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Scheme 31 Copper-catalyzed asymmetric regio-reversed [3+2] cyclo­addition of imino esters with nitro olefins
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Scheme 32 Thiourea-organocatalyzed synthesis of tetrasubstituted pyrrolidines
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Scheme 33 Thiourea-organocatalyzed synthesis of 3,4-dihydro­coumarin fused pyrrolidine
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Scheme 34 Copper-catalyzed diastereodivergent asymmetric synthesis of tetrasubstituted pyrrolines
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Scheme 35 Multi-kilogram-scale synthesis of tetrasubstituted pyrrolidine
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Scheme 36 Synthesis of densely functionalized pyrrolidines via copper-catalyzed cycloaddition of nitroalkenes and azomethine ylides
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Scheme 37 Copper(II)-catalyzed synthesis of polysubstituted pyrroles through the [3+2] cycloaddition of aziridines and nitro alkenes
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Scheme 38 Copper-catalyzed synthesis of fluorinated pyrrolidines
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Scheme 39 1,3-Dipolar cycloaddition reaction of 2-phenacyl- or alkoxycarbonylmethyl benzothiazolium bromides with 3-nitrochromenes
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Scheme 40 Synthesis of trifluoromethylated pyrazolidines
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Scheme 41 Synthesis of multisubstituted cyanopyrazoles
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Scheme 42 Synthesis of pyrazole triflones