Abstract
Piperazine rings are essential motifs frequently found in commercial drugs. However, synthetic methodologies are mainly limited to N-substituted piperazines, preventing structural diversity. Disclosed herein is a straightforward catalytic method for the synthesis of complex C-substituted piperazines based on an uncommon head-to-head coupling of easily prepared imines. This 100% atom-economic process allows the selective formation of a sole diastereoisomer, a broad substrate scope, and a good functional group tolerance employing a bench-stable iridium catalyst under mild reaction conditions. Key to the success is the addition of N-oxides to the reaction mixture, as they notably enhance the catalytic activity and selectivity.
Keywords: piperazines, iridium, homogeneous catalysis, [3 + 3]-cycloadditions, imines, trimethylamine N-oxide
The piperazine ring is a key pharmacophore for a wide range of drugs, including those with antibiotic, antidepressant, anti-HIV, anticancer, antiviral, antimicrobial, and anxiolytic activities (some examples are shown in Figure 1).1 Considerable efforts have been devoted to the development of synthetic routes yielding this privileged drug scaffold, which have traditionally focused on the reduction of diketopiperazines, the reductive amination of dicarbonyl compounds, and transition-metal-catalyzed cyclization reactions.2 These methods often require multistep synthesis, as well as protecting and deprotecting steps.3 More sustainable approaches include a “borrowing hydrogen” method, which uses 1,5-diols and primary amines, the synthesis of 2-substituted piperazines by an iridium photocatalyst,4 and biocatalytic reductive aminations of 1,2-dicarbonyl and 1,2-diamine substrates, which yield piperazines in an atom-economical fashion.5
Figure 1.
Selected examples of pharmaceuticals containing a piperazine motif.
As for any drug, the individual architecture is crucial for the drug–target interactions and therefore directly impacts on the inherent properties and specific function of the resulting molecule.1e Moreover, the increase of molecular complexity and the number of stereogenic centers, also referred to as escaping from flatland, has been deemed key for the exploration of chemical space potentially, leading to unexplored molecular recognition with biological receptors within an active site.6 These altered vectors can be advantageous, leading to chemical diversity and unique pharmaceutical activities.
An analysis of piperazine cores in pharmaceuticals reveals limited structural diversity, with most examples containing substituents on the N atoms, but limited examples of C-substituted piperazines.1a,1c,1d Whereas the functionalization of the nitrogen atoms is relatively straightforward, the postsynthetic functionalization of the carbon atoms can be extremely challenging.7 Therefore, there is great interest in the development of new synthetic routes yielding carbon-substituted piperazines in a straightforward manner.1b
In this context, easily prepared imines featuring the “CH=N—CH2” motif could be valuable synthons to C-substituted piperazines via the dimerization of the highly reactive azomethine ylide isomer (Scheme 1).
Scheme 1. Pathways for Azomethine Ylides from Imines, Zwitterion and Diradical Resonant Forms, and Possible Cycloaddition Reactions.
Although the prevalent reaction mode for these intermediates is [3 + 2]-cycloadditions to imidazolidines,8 selective [3 + 3]-cycloadditions to the piperazine ring have been observed at the stoichiometric level in a few instances. Pioneering works in organometallic chemistry involved complexes bearing deprotonated imines ([R—CH=N—CHR′]−, smif-type ligands) of group 4 transition metals,9 Fe,10 Al,11 and Zn,12 which rendered binuclear complexes with a bridging dianionic piperazine. From these, free piperazines have been rarely isolated.9b,11 More recently, an original combination of aluminum reagents under visible-light irradiation to form piperazines has been reported.13 In this regard, we are not aware of previous examples of such [3 + 3]-cycloadditions at a catalytic level.
Herein, we showcase a powerful atom-economical method for the catalytic synthesis of C-substituted piperazines from formal [3 + 3]-cycloadditions of both aromatic and aliphatic imines. High yields and excellent regio- and diastereoselective control are achieved using [IrCl(cod)(PPh3] (5, cod = 1,5-cyclooctadiene) as a catalyst under mild reaction conditions.
Initial studies started analyzing the response of [{Ir(μ-Cl)(cod)}2] (1) toward PyA—CH=N—CH2PyB (2a; Py = 2-pyridyl), which rendered the neutral complex [IrCl(cod)(PyA—CH=N—CH2PyB)] (3, Figure 2). A chelating coordination mode of the imine to iridium through the nitrogen atoms of the imine and PyA is proposed in 3, as found in related rhodium and iridium complexes.14 A further addition of the imine to 3 gave [Ir(cod)(κ3-N,N′,N''-HL1)]Cl ([4]Cl), where HL1 is an imidazolidine-type ligand (Figure 2). Most likely, the imidazolidine ring results from a 1,3-dipolar cycloaddition of the azomethine ylide moiety with the imine ([3 + 2]-cycloaddition), as described above.8b
Figure 2.
Reaction of [{Ir(μ-Cl)(cod)}2] (1) with 2a in C6D6 to give complex 3 and subsequent reactions either with a second equivalent of 2a to give complex [4]Cl or with PPh3 to yield [IrCl(cod)(PPh3)] (5) and 6a. [Ir] = Ir(cod). The molecular structures (ORTEP, ellipsoids set at 50% probability) of the cation [4]+ and 6a (2R,3R,5R,6R-enantiomer) are shown on the right. For selected bond distances and angles, see the Supporting Information.
To our delight, the addition of PPh3 to 3 rendered the neutral compound [IrCl(cod)(PPh3)] (5) and the piperazine 6a (Figure 2). This reaction highlights the crucial role of PPh3 in providing a divergent reaction pathway that controls the regioselectivity of the reaction to the six-membered piperazine instead of to the five-membered imidazolidine.
It is also worth noting the diastereoselectivity in the synthesis of 6a, since only one diastereoisomer was quantitatively formed, as observed by 1H and 13C{1H} NMR spectroscopy. Notice that the coupling of two imines renders four new C-stereocenters, so that three enantiomeric pairs and three meso forms could be formed a priori from 2a. The absolute configuration of isolated 6a as the 2R,3R,5R,6R and 2S,3S,5S,6S enantiomeric pair (denoted as 2R*,3R*,5R*,6R*) was determined via X-ray crystallographic analysis (Figure 2). This configuration contrasts with that in the previous known examples, which systematically rendered the related isomer 2R*,3R*,5S*,6S*.
The reaction of 3 with PPh3 was monitored by 1H NMR spectroscopy. This reaction mixture cleanly evolved to the piperazine 6a and complex 5 over 22 h, while the uncoordinated imine 2a along with broad resonances for the cod peaks of 5 were initially observed. Accordingly, the direct reaction between equimolar amounts of [IrCl(cod)(PPh3)] (5) and the imine 2a yielded 6a directly in a very good yield in 6 h (Figure S1).
At a catalytic level, using 2 mol% 5 in C6D6 at 25 °C, the reaction was found to be significantly more complicated. A mixture of imidazolidines (34%) along with only an 18% yield of the desired piperazine 6a was obtained after 12 h of reaction (entry 1, Table 1 and Figure 3).
Table 1. Screening of the Reaction Conditions for the Catalytic Synthesis of 6a from 2aa.
| entry | solvent | additive | time (min) | conv. (%)b | select. (%)b |
|---|---|---|---|---|---|
| 1 | C6D6 | 744 | 52 | 11 | |
| 2 | C6D6 | Na2CO3 | 512 | 90 | 77 |
| 3 | C6D6 | NEt3 | 137 | 94 | 96 |
| 4 | CD2Cl2 | NEt3 | 316 | 94 | 61 |
| 5 | CD3CN | NEt3 | 187 | 95 | 72 |
| 6 | C6D6 | NEt3-dist. | 242 | 83 | 80 |
| 7 | C6D6 | Me3NO·2H2O | 93 | 97 | 94 |
| 8 | CD3CN | Me3NO·2H2O | 18 | 95 | 94 |
| 9 | C6D6 | C6H5NO | 199 | 79 | 79 |
| 10 | C6D6 | TEMPO | 246 | 68 | 76 |
Reaction conditions: [IrCl(cod)(PPh3)] (5, 0.0084 mmol), additive (0.084 mmol), and 2a (0.42 mmol) in solvent (total volume = 0.5 mL) at 25 °C.
Selectivity to piperazine. Determined by 1H NMR spectroscopy respect to an internal standard (toluene, 0.075 mmol).
Figure 3.
Plot of conversion (%) vs time (min) for the synthesis of piperazine 6a catalyzed by 5 in C6D6 for Table 1 entries 1 (black), 2 (red), 3 (green), 6 (blue), and 7 (pink). Dashed lines are for visual aid.
Noticeably, the addition of a base such as Na2CO3 or NEt3 resulted in a significant improvement in both regioselectivity and reaction times (entries 2 and 3, Table 1). Moreover, for the more effective NEt3, small differences were observed in CD3CN, while it was found to be slower in CD2Cl2 (entries 3–5, Table 1).
Surprisingly, it was found that the addition of NEt3 purified by distillation resulted in a loss of the catalytic activity (entry 6, Table 1 and Figure 3). Analysis by mass spectroscopy of the unpurified NEt3 indicated that it contained a small amount of triethylamine N-oxide (<5%). Therefore, the effect of N-oxides was analyzed by testing the catalysis in the presence of Me3NO·2H2O, pyridine N-oxide (C6H5NO), and the radical N-oxide TEMPO (2,2,6,6-tetramethylpiperidin-1-yloxyl) (entries 7–10, respectively, Table 1).
Remarkably, the addition of 10 mol equiv Me3NO in C6D6 considerably reduced the reaction time (entry 7). Moreover, the use of a polar solvent, such as CD3CN, which increases the solubility of Me3NO, resulted in 95% conversion in just 18 min (entry 8, Table 1). Through this methodology, the reaction was scaled-up to a gram scale, yielding 6a as an off-white solid with a 94% isolated yield. In the same line, C6H5NO as well as TEMPO also accelerated the reaction, albeit to a lesser extent (entries 9 and 10, respectively, Table 1).
In a parallel experiment, the reaction between [IrCl(cod)(PPh3)] (5) and Me3NO showed that 5 slowly converts to [IrCl(cod)(OPPh3)] with 18% conversion after 24 h. Therefore, it seems unlikely that this reaction has significant impact on is significantly impacted by the time scale of the catalysis. In addition, control experiments in the absence of 5 showed no conversion to piperazine with or without the presence of Me3NO (Table S1).
The prominent role of Me3NO could be derived from its expected ability to act as a hydrogen transfer reagent, as recently reported for related pyridine N-oxides,15 which would provide a low-energy pathway to the azomethine ylide intermediate (Scheme 1, 1,2-hydrogen shift). In this regard, the reduced positive effect of bases and the more active N-oxide radical, TEMPO, could be related to the participation of the probably less reactive anionic [Py—CH=N—CHPy]− (Py2smif) and radical [Py—CH=N—CHPy]● intermediates, respectively.
The substrate scope was investigated under the experimental conditions outlined in entry 7 (Table 1). Although for Py—CH=N—CH2Py the catalysis is faster in acetonitrile (entry 8, Table 1), for the rest of imines acetonitrile resulted in less selective reactions. Ultimately, the best compromise between conversion and selectivity was using C6D6 as the solvent.
As shown in Table 2, the reactions were found to be regioselective to the piperazine ring and diastereoselective to the head-to-head 2R*,3R*,5R*,6R* isomer, as confirmed by NMR spectroscopy and X-ray diffraction studies on selected piperazines (6a, 6d, and 6i, see the Supporting Information).16
Table 2. Scope of the Piperazine Synthesis.a.
Moving the position of the N-atom on the pyridine bonded to the imine carbon using R—CH=N—CH2Py (R = 3-pyridyl, 4-pyridyl) allowed the preparation of piperazines 6b and 6c, although it was associated in increased reaction times relative to 6a. The same applies to imines featuring the heterocycles 2-furanyl and 2-tiophenyl, which rendered 6d and 6e in very good yields. In the same line, Ph—CH=N—CH2Py (2g) produced 6g, although the reaction was found to be very slow. Given the higher thermal stability of these imines (2d, 2e, and 2g), the reactions were performed at 60 °C. In the particular case of R = 2-pyrrolyl, only a trace amount of 6f was obtained, which reveals the negative role of the acidic NH proton on the heterocycle.
Aliphatic imines, R—CH=N—CH2Py (R = iPr and iBu), were found to convert in a facile manner into 6h and 6i, respectively, with relatively short reaction times at 25 °C. Meanwhile, the reaction with the more sterically encumbered aliphatic imine, Et2CH–C=N–CH2Py (2j), dramatically decreased the conversion and selectivity of the reaction, yielding a mixture of expected piperazine 6j and imidazolidines.
Unlike aromatic imines, both aliphatic imines (2h and 2i) converted to the corresponding piperazines in the absence of Me3NO with comparable reaction times (Table S1). Such a difference could be attributed to the electron-donating nature (EDG) of the R group bonded to the imine carbon. Moreover, it was found that an activating group in the R′ position of the imine R—CH=N—CH2R′ is key for the success of the catalysis. Indeed, no reaction occurred with Py—CH=N—CHMe2 (2k) even after 4 days at rt. In the same line, the use of the imine Py—CH=N—CH2Ph (2l) resulted in a considerable loss in the selectivity. A mixture of the piperazine 6l and unidentified products (ratio 1:4) was obtained after 2 days at 60 °C (57% conversion), while the imine Py—CH=N—CH2CO2Me (2m) resulted in a noticeable increase of the reaction rate with a 99% conversion to 6m in less than 10 min. These results agree with an enhanced catalytic activity with imines R—CH=N—CH2R′ featuring electron-donating groups (EDG) bonded to the CH and electron-withdrawing groups (EWG) bonded to the CH2.
In conclusion, we have proved that C-substituted piperazines can be synthesized in a stereospecific and straightforward manner using an accessible iridium catalyst under mild reaction conditions. The developed method is very simple and scalable, as it only requires imines as the starting products. Furthermore, the unique diastereomer obtained has been previously unreported and indicates that a distinct reaction pathway is operating in this catalysis.
Acknowledgments
The generous financial support from MCIN/AEI/10.13039/501100011033 (PID2020-119512GB-I00) and Gobierno de Aragón/FEDER, EU (GA/FEDER, Reactivity and Catalysis Inorganic Chemistry Group, E50_20D) is gratefully acknowledged. A.M.G. is thankful for Grant IJC2018-035231-I funded by MCIN/AEI/10.13039/501100011033, and L.T. thanks MICIIN/FEDER for an FPI fellowship.
Data Availability Statement
Crystallographic data for piperazines 6a, 6d, 6i, and for [4]Cl have been deposited in the Cambridge Crystallographic Data Centre (2218904–2218907).
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.2c05895.
Author Present Address
† Centro Universitario de la Defensa, Ctra. Huesca s/n, 50090 Zaragoza, Spain
The authors declare no competing financial interest.
Supplementary Material
References
- a Vitaku E.; Smith D. T.; Njardarson J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]; b Magriotis P. A. Recent Progress toward the Asymmetric Synthesis of Carbon-Substituted Piperazine Pharmacophores and Oxidative Related Heterocycles. RSC Med. Chem. 2020, 11, 745–759. 10.1039/D0MD00053A. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Shaquiquzzaman M.; Verma G.; Marella A.; Akhter M.; Akhtar W.; Khan M. F.; Tasneem S.; Alam M. M. Piperazine Scaffold: A Remarkable Tool in Generation of Diverse Pharmacological Agents. Eur. J. Med. Chem. 2015, 102, 487–529. 10.1016/j.ejmech.2015.07.026. [DOI] [PubMed] [Google Scholar]; d Romanelli M. N.; Manetti D.; Braconi L.; Dei S.; Gabellini A.; Teodori E. The Piperazine Scaffold for Novel Drug Discovery Efforts: The Evidence to Date. Expert Opin. Drug Discov. 2022, 17, 969–984. 10.1080/17460441.2022.2103535. [DOI] [PubMed] [Google Scholar]; e Meanwell N. A.; Loiseleur O. Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1. J. Agric. Food Chem. 2022, 70, 10942–10971. 10.1021/acs.jafc.2c00726. [DOI] [PubMed] [Google Scholar]
- a Gettys K.; Ye Z.; Dai M. Recent Advances in Piperazine Synthesis. Synthesis 2017, 49, 2589–2604. 10.1055/s-0036-1589491. [DOI] [Google Scholar]; b Sajadikhah S. S.; Nassiri M. Recent Developments in the Synthesis of Piperazines. Chem. Heterocycl. Compd. 2021, 57, 905–907. 10.1007/s10593-021-02998-0. [DOI] [Google Scholar]
- Chamakuri S.; Tang S. A.; Tran K. A.; Guduru S. K. R.; Bolin P. K.; MacKenzie K. R.; Young D. W. A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines. Molecules 2022, 27, 3419. 10.3390/molecules27113419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Jindakun C.; Hsieh S.-Y.; Bode J. W. Iridium-Catalyzed Synthesis of Saturated N-Heterocycles from Aldehydes and SnAP Reagents with Continuous Flow Photochemistry. Org. Lett. 2018, 20, 2071–2075. 10.1021/acs.orglett.8b00611. [DOI] [PubMed] [Google Scholar]; b Gueret R.; Pelinski L.; Bousquet T.; Sauthier M.; Ferey V.; Bigot A. Visible-Light-Driven CarboxyLic Amine Protocol (CLAP) for the Synthesis of 2-Substituted Piperazines under Batch and Flow Conditions. Org. Lett. 2020, 22, 5157–5162. 10.1021/acs.orglett.0c01759. [DOI] [PubMed] [Google Scholar]
- a Nordstrøm L. U.; Madsen R. Iridium Catalysed Synthesis of Piperazines from Diols. Chem. Commun. 2007, 47, 5034–5036. 10.1039/b712685a. [DOI] [PubMed] [Google Scholar]; b Lorentz-Petersen L. L. R.; Nordstrøm L. U.; Madsen R. Iridium-Catalyzed Condensation of Amines and Vicinal Diols to Substituted Piperazines. Eur. J. Org. Chem. 2012, 2012, 6752–6759. 10.1002/ejoc.201201099. [DOI] [Google Scholar]; c Borlinghaus N.; Gergel S.; Nestl B. M. Biocatalytic Access to Piperazines from Diamines and Dicarbonyls. ACS Catal 2018, 8, 3727–3732. 10.1021/acscatal.8b00291. [DOI] [Google Scholar]
- a Lovering F.; Bikker J.; Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. 10.1021/jm901241e. [DOI] [PubMed] [Google Scholar]; b Klein H. F.; Hamilton D. J.; de Esch I. J. P.; Wijtmans M.; O’Brien P. Escape from Planarity in Fragment-Based Drug Discovery: A Synthetic Strategy Analysis of Synthetic 3D Fragment Libraries. Drug Discov. Today 2022, 27, 2484–2496. 10.1016/j.drudis.2022.05.021. [DOI] [PubMed] [Google Scholar]
- Ye Z.; Gettys K. E.; Dai M. Opportunities and Challenges for Direct C–H Functionalization of Piperazines. Beilstein J. Org. Chem. 2016, 12, 702–715. 10.3762/bjoc.12.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Pandey G.; Banerjee P.; Gadre S. R. Construction of Enantiopure Pyrrolidine Ring System via Asymmetric [3 + 2]-Cycloaddition of Azomethine Ylides. Chem. Rev. 2006, 106, 4484–4517. 10.1021/cr050011g. [DOI] [PubMed] [Google Scholar]; b Coldham I.; Hufton R. Intramolecular Dipolar Cycloaddition Reactions of Azomethine Ylides. Chem. Rev. 2005, 105, 2765–2810. 10.1021/cr040004c. [DOI] [PubMed] [Google Scholar]
- a Cariou R.; Gibson V. C.; Tomov A. K.; White A. J. P. Group 4 Metal Complexes Bearing New Tridentate (NNO) Ligands: Benzyl Migration and Formation of Unusual C–C Coupled Products. J. Organomet. Chem. 2009, 694, 703–716. 10.1016/j.jorganchem.2008.11.064. [DOI] [Google Scholar]; b Chen Z.; Wu J.; Chen Y.; Li L.; Xia Y.; Li Y.; Liu W.; Lei T.; Yang L.; Gao D.; Li W. Rapid Access to Substituted Piperazines via Ti(NMe2)4-Mediated C–C Bond-Making Reactions. Organometallics 2012, 31, 6005–6013. 10.1021/om300022u. [DOI] [Google Scholar]; c Frazier B. A.; Wolczanski P. T.; Keresztes I.; DeBeer S.; Lobkovsky E. B.; Pierpont A. W.; Cundari T. R. Synthetic Approaches to (Smif)2Ti (Smif = 1,3-Di-(2-Pyridyl)-2-Azaallyl) Reveal Redox Non-Innocence and C–C Bond-Formation. Inorg. Chem. 2012, 51, 8177–8186. 10.1021/ic300590t. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Frazier B. A.; Wolczanski P. T.; Lobkovsky E. B.; Cundari T. R. Unusual Electronic Features and Reactivity of the Dipyridylazaallyl Ligand: Characterizations of (Smif)2M [M = Fe, Co, Co+, Ni; Smif = {(2-Py)CH}2N] and [(TMS)2NFe]2(Smif)2. J. Am. Chem. Soc. 2009, 131, 3428–3429. 10.1021/ja8089747. [DOI] [PubMed] [Google Scholar]; b Frazier B. A.; Williams V. A.; Wolczanski P. T.; Bart S. C.; Meyer K.; Cundari T. R.; Lobkovsky E. B. C–C Bond Formation and Related Reactions at the CNC Backbone in (Smif)FeX (Smif = 1,3-Di-(2-Pyridyl)-2-Azaallyl): Dimerizations, 3 + 2 Cyclization, and Nucleophilic Attack; Transfer Hydrogenations and Alkyne Trimerization (X = N(TMS)2, Dpma = (Di-(2-Pyridyl-Methyl)-Amide)). Inorg. Chem. 2013, 52, 3295–3312. 10.1021/ic302783y. [DOI] [PubMed] [Google Scholar]
- Trepanier S. J.; Wang S. Alkylaluminum Complexes Containing Pyridyl Amido Ligands. Syntheses and Characterization of AlMe2[N(CH2-2-Py)2], Al2Me5[N(CH2-2-Py)2], and Al2Me4[2,3,5,6-Tetra(2-Pyridyl)Piperazyl], an Unusual Carbon–Carbon Bond Coupling Product. Can. J. Chem. 1996, 74, 2032–2040. 10.1139/v96-232. [DOI] [Google Scholar]
- Westerhausen M.; Bollwein T.; Mayer P.; Piotrowski H.; Pfitzner A. Metallierung Und C-C-Kupplung von 2-Pyridylmethylamin: Synthese Und Strukturen von Methylzink-2-Pyridylmethylamid, Tris(Trimethylsilyl)Methylzink-2-Pyridylmethylamid Und (Z)-1-Amino-1,2-Bis(2-Pyridyl)Ethen. Z. Für Anorg. Allg. Chem. 2002, 628, 1425–1432. 10.1002/1521-3749(200206)628:6<1425::AID-ZAAC1425>3.0.CO;2-7. [DOI] [Google Scholar]
- Suárez-Pantiga S.; Colas K.; Johansson M. J.; Mendoza A. Scalable Synthesis of Piperazines Enabled by Visible-Light Irradiation and Aluminum Organometallics. Angew. Chem., Int. Ed. 2015, 54, 14094–14098. 10.1002/anie.201505608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Tejel C.; Ciriano M. A.; del Río M. P.; van den Bruele F. J.; Hetterscheid D. G. H.; Tsichlis i Spithas N.; de Bruin B. Deprotonation Induced Ligand-to-Metal Electron Transfer: Synthesis of a Mixed-Valence Rh(−I,I) Dinuclear Compound and Its Reaction with Dioxygen. J. Am. Chem. Soc. 2008, 130, 5844–5845. 10.1021/ja711495v. [DOI] [PubMed] [Google Scholar]; b Tejel C.; del Río M. P.; Asensio L.; van den Bruele F. J.; Ciriano M. A.; Tsichlis i Spithas N.; Hetterscheid D. G. H.; de Bruin B. Cooperative Double Deprotonation of Bis(2-Picolyl)Amine Leading to Unexpected Bimetallic Mixed Valence (M–I, MI) Rhodium and Iridium Complexes. Inorg. Chem. 2011, 50, 7524–7534. 10.1021/ic200395m. [DOI] [PubMed] [Google Scholar]; c Tejel C.; Asensio L.; del Río M. P.; de Bruin B.; López J. A.; Ciriano M. A. Developing Synthetic Approaches with Non-Innocent Metalloligands: Easy Access to IrI/Pd0 and IrI/Pd0/IrI Cores. Angew. Chem., Int. Ed. 2011, 50, 8839–8843. 10.1002/anie.201104045. [DOI] [PubMed] [Google Scholar]
- Ciszewski Ł. W.; Gryko D. Pyridine N-Oxides as HAT Reagents for Photochemical C–H Functionalization of Electron-Deficient Heteroarenes. Chem. Commun. 2022, 58, 10576–10579. 10.1039/D2CC03772F. [DOI] [PubMed] [Google Scholar]
- Due the change in the priorities of the substituents on the C atoms in piperazines 6h and 6i, the obtained diastereoisomers are in fact 2S*,3S*,5R*,6R*, but they correspond to the 2R*,3R*,5R*,6R* isomer of 6a.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Crystallographic data for piperazines 6a, 6d, 6i, and for [4]Cl have been deposited in the Cambridge Crystallographic Data Centre (2218904–2218907).