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Article

Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies

by
Lucilla Favero
*,
Andrea Menichetti
,
Cosimo Boldrini
,
Lucrezia Margherita Comparini
,
Valeria Di Bussolo
,
Sebastiano Di Pietro
and
Mauro Pineschi
*
Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(23), 7399; https://doi.org/10.3390/molecules26237399
Submission received: 14 October 2021 / Revised: 23 November 2021 / Accepted: 3 December 2021 / Published: 6 December 2021
(This article belongs to the Special Issue Synthesis and Application of Organoboron Derivatives)
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Versions Notes

Abstract

:
The possibility to form new C–B bonds with aziridines using diboron derivatives continues to be a particularly challenging field in view of the direct preparation of functionalized β-aminoboronates, which are important compounds in drug discovery, being a bioisostere of β-aminoacids. We now report experimental and computational data that allows the individuation of the structural requisites and of reaction conditions necessary to open alkyl aziridines using bis(pinacolate)diboron (B2pin2) in a regioselective nucleophilic addition reaction under copper catalysis.

1. Introduction

The ring-opening (RO) reactions of aziridines with nucleophilic reagents are important operations in synthetic organic chemistry to obtain β-substituted amines [1,2,3,4]. Beside the consolidated use of heteroatom- and carbon-based nucleophiles, the use of nucleophilic boron reagents in the RO of strained three-membered heterocycles has come to the fore more recently [5,6,7,8]. The regio- and stereoselective introduction of a boron atom in sp3-rich functionalized molecules is of particular importance in synthetic organic chemistry, considering that the boron atom is easily transformable into hydroxy, amino or halo groups or it can serve as cross-coupling partner [9]. Moreover, there is a consolidated importance of incorporating the boron atom into new and existing drugs [10]. Hence, it is surprising that the ring opening of aziridines comprising the formation of carbon-boron bonds has been described so far only for aziridines bearing an adjacent double or triple bond. For example, allylic aziridines have been regioselectively borylated by using nickel and/or copper catalysts [11], or palladium catalysts as shown by Szabó (Scheme 1, eq. a) [12]. More recently, copper-catalyzed borylative ring openings of three- and four-membered rings bearing an adjacent triple bond including one example of a propargylic aziridines have also been reported (Scheme 1, eq. b) [13]. Aryl aziridines have been recently engaged by Takeda and Minakata in a regioselective borylative ring opening at the less substituted position using Pd/P(t-Bu)2Me as the catalyst and proceeding in neutral reaction conditions (Scheme 1, eq. c) [14]. In any case, these reaction conditions work only for tosyl-protected aryl aziridines, while they are ineffective for alkyl aziridines [15]. Indeed, a borylative ring opening of differently substituted alkyl aziridines has not yet been reported despite its potentiality to access β-aminoboronates, a scaffold of considerable interest in medicinal chemistry (Scheme 1, eq. d) [16,17,18].
We now report our findings about the individuation of the suitable substrates and the necessary reaction conditions to achieve the borylative ring-opening reactions of alkyl aziridines under copper-catalysis. We also report a detailed computational study which attempts to shed some light on the possible mechanistic intricacies of such a transformation.

2. Results and Discussion

2.1. Experimental Data

In studies made during the last several years in our laboratory, we had many confirmations of the difficulties associated with a direct borylation of alkyl aziridines. After an extensive screening of differently protected alkyl aziridines and reaction conditions, we noticed in the literature a direct borylative ring opening of alkyl epoxides with B2pin2 as reported by ** function: S6 = 1.000; SR6 = 1.2610; S8 = 1.039). [38] and 6 − 31 + G(d) basis set for C, H, B, N, O, S and Cl atoms and SDD basis set (Stuttgart RSC 1997 ECP) for Cu [39]. Berny analytical gradient optimization routines were applied for optimization of the minima on the PES [40]. Analytical frequency calculations (T = 298.15 K and 1 atm pressure) were performed in order to verify that Transition States or minima had one or no imaginary frequency, respectively. Several conformers were investigated, and only the less energetic ones were considered here. IRC calculation was also performed in order to verify whether we had indeed found the desired TS structure. Free Energies, obtained by frequency calculation, were corrected using a single point energy obtained with the larger basis set 6-311+G(2d,p) on C, H, B, N, O and Cl atoms and with solvent (THF) simulation by PCM model [41]. No appreciable improvement were found by optimization and frequency calculation with the most CPU expensive basis set 6-311+G(2d,p). See Table S2, Page S7, Supporting Information.

4. Conclusions

To sum up, we have shown the difficulties associated with the development of a general protocol to open the strained ring of protected alkyl aziridines with a nucleophilic boron reagent to give β-aminoboronates. We have now individuated precise reaction parameters (copper salts, protecting group, base and substrates) that can promote the direct borylative ring-opening pathway. The experimental data have also been rationalized theoretically by computational calculation, laying for the first time the foundation for further discoveries in the nucleophilic borylative ring-opening of strained heterocycles.

Supplementary Materials

The following are available online. Synthesis of aziridines 1a–c, 4c–9c, 10 [42,43,44,45,46,47,48,49,50,51,52,53,54,55,56], Scheme S1: Synthetic pathway for the synthesis of aziridines, Table S1: Two-Copper model, substitution of chloride with alkoxide anion: comparison of activation Free Energies corresponding to TS3 and TS4 from N-(2-picolinoyl)-methyl aziridine. Figure S1: Particular of the reaction energy profile comparison between the anti-Markovnikov and Markovnikov pathways of N-2-picolinoyl-methyl aziridine (model with the Et2O molecule), Table S2: One-Copper model, N-(2-picolinoyl)-methyl aziridine: comparison between Free Energies obtained at different theory level. Cartesian Coordinates and Thermochemical data of the optimized structures. Copies of 1H and 13C NMR of all new products and further computational details are provided as Supplementary Materials.

Author Contributions

M.P., project leader. A.M. and C.B., synthesis of aziridines and development of the ring opening. L.F., computational calculations. S.D.P., L.M.C. and V.D.B. contributed equally to the experimental realization, design and analysis of all data. All authors have read and agreed to the published version of the manuscript.

Funding

We thank the University of Pisa for financial.

Acknowledgments

We acknowledge CISUP—Centre for Instrumentation Sharing, University of Pisa—for the acquisition and elaboration of the HMRS spectra.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

No samples are available.

References and Notes

  1. Sabir, S.; Kumar, G.; Verma, V.P.; Jat, J.L. Aziridine Ring Opening: An Overview of Sustainable Methods. ChemistrySelect 2018, 3, 3702–3711. [Google Scholar] [CrossRef]
  2. Nonn, M.; Remete, A.M.; Fülöp, F.; Kiss, L. Recent advances in the transformations of cycloalkane-fused oxiranes and aziridines. Tetrahedron 2017, 73, 5461–5483. [Google Scholar] [CrossRef]
  3. Pineschi, M. Asymmetric Ring-Opening of Epoxides and Aziridines with Carbon Nucleophiles. Eur. J. Org. Chem. 2006, 2006, 4979–4988. [Google Scholar] [CrossRef]
  4. Huang, C.-Y.; Doyle, A.G. The Chemistry of Transition Metals with Three-Membered Ring Heterocycles. Chem. Rev. 2014, 114, 8153–8198. [Google Scholar] [CrossRef] [PubMed]
  5. Pineschi, M. Advances in the Ring Opening of Small-Ring Heterocycles with Organoboron Derivatives. Synlett 2014, 25, 1817–1826. [Google Scholar] [CrossRef]
  6. Pineschi, M.; Boldrini, C. Advances in Organoboron Chemistry towards Organic Synthesis; Fernández, E., Ed.; Thieme: Stuttgart, Germany, 2020; pp. 183–226. Available online: https://www.thieme-connect.de/products/ebooks/series/10.1055/b-00000101 (accessed on 3 December 2021).
  7. Pineschi, M. The Binomial Copper-Catalysis and Asymmetric Ring Opening of Strained Heterocycles: Past and Future Challenges. Eur. J. Org. Chem. 2020, 2643–2649. [Google Scholar] [CrossRef]
  8. Pineschi, M. Boron Reagents and Catalysts for the Functionalization of Strained Heterocycles. Adv. Synth. Cat. 2021, 363, 2325–2339. [Google Scholar] [CrossRef]
  9. Fyfe, J.W.B.; Watson, A.J.B. Recent Developments in Organoboron Chemistry: Old Dogs, New Tricks. Chem 2017, 3, 31–55. [Google Scholar] [CrossRef]
  10. Silva, M.P.; Saraiva, L.; Pinoto, M.; Sousa, M.E. Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications. Molecules 2020, 25, 4323. [Google Scholar] [CrossRef] [PubMed]
  11. Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Nickel-Catalyzed Borylative Ring-Opening of Vinyl Epoxides and Aziridines. Org. Lett. 2009, 11, 3762–3765. [Google Scholar] [CrossRef] [PubMed]
  12. Sebelius, S.; Olsson, V.J.; Szabó, K.J. Palladium Pincer Complex Catalyzed Substitution of Vinyl Cyclopropanes, Vinyl Aziridines, and Allyl Acetates with Tetrahydroxydiboron. An Efficient Route to Functionalized Allylboronic Acids and Potassium Trifluoro(allyl)borates. J. Am. Chem. Soc. 2005, 127, 10478–10479. [Google Scholar] [CrossRef] [PubMed]
  13. Zhao, J.; Szabó, K.J. Catalytic Borylative Opening of Propargyl Cyclopropane, Epoxide, Aziridine, and Oxetane Substrates: Ligand Controlled Synthesis of Allenyl Boronates and Alkenyl Diboronates. Angew. Chem. Int. Ed. 2016, 55, 1502–1506. [Google Scholar] [CrossRef] [PubMed]
  14. Takeda, Y.; Kuroda, A.; Sameera, W.M.C.; Morokuma, K.; Minakata, S. Palladium-catalyzed regioselective and stereo-invertive ring-opening borylation of 2-arylaziridines with bis(pinacolato)diboron: Experimental and computational studies. Chem. Sci. 2016, 7, 6141–6152. [Google Scholar] [CrossRef] [PubMed]
  15. Takeda, Y.; Sameera, W.M.C.; Minakata, S. Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies. Acc. Chem. Res. 2020, 53, 1686–1702. [Google Scholar] [CrossRef]
  16. Šterman, A.; Sosic, I.; Gobec, S.; Casar, Z. Synthesis of aminoboronic acid derivatives: An update on recent advances. Org. Chem. Front. 2019, 6, 2991–2998. [Google Scholar] [CrossRef]
  17. DeGorovoy, A.S.; Gozhina, O.V.; Svendsen, J.S.; Domorad, A.A.; Tetz, G.V.; Tetz, V.V.; Lejon, T. Boron-Containing Peptidomimetics — A Novel Class of Selective Anti-tubercular Drugs. Chem. Biol. Drug. Des. 2013, 81, 408–413. [Google Scholar] [CrossRef]
  18. Li, X.; Hall, D.G. Synthesis and Applications of β-aminoalkylboronic Acid Derivatives. Adv. Synth. Cat. 2021, 363, 2209–2223. [Google Scholar] [CrossRef]
  19. Ahmed, E.-A.M.A.; Lu, X.; Gong, T.-J.; Zhang, Z.-Q.; **ao, B.; Fu, Y. Copper-catalyzed/mediated borylation reactions of epoxides with diboron reagents: Access to β-hydroxyl boronic esters. Chem. Commun. 2017, 53, 909–912. [Google Scholar] [CrossRef] [PubMed]
  20. Martin, A.; Casto, K.; Morris, W.; Morgan, J.B. Phosphine-Catalyzed Heine Reaction. Org. Lett. 2011, 13, 5444–5447. [Google Scholar] [CrossRef] [PubMed]
  21. Heine, H.W.; King, D.C.; Portland, L.A. Aziridines XII. The isomerization of Some cis- and trans-1-p-nitrobenzoyl-2,3-Substituted Aziridines. J. Org. Chem. 1966, 31, 2662–2665. [Google Scholar] [CrossRef]
  22. Sweeney, J.B. Aziridines: Epoxides’ ugly cousin? Chem. Soc. Rev. 2002, 31, 247–258. [Google Scholar] [CrossRef]
  23. Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, J.-H. Regioselectivity in the ring opening of non-activated aziridines. Chem. Soc. Rev. 2012, 41, 643–665. [Google Scholar] [CrossRef] [PubMed]
  24. Di Bussolo, V.; Checchia, L.; Romano, M.R.; Favero, L.; Pineschi, M.; Crotti, P. Aminolysis of glycal-derived allylic epoxides and activated aziridines. Effects of the absence of coordination processes on the regio- and stereoselectivity. Tetrahedron 2010, 66, 689–697. [Google Scholar] [CrossRef]
  25. The anti-periplanar ring opening (in line with the Takeda model) of the not substituted mesyl-aziridine and picolinoyl-aziridine with the THF-Cu-Bpin adduct were investigated. The result shown a ΔΔG‡ of 3 kJ/mol in favour of the sulfonyl aziridine with respect to the N-2(picolinoyl) one in contradiction with the experimental evidence in which the formers are inert while the latter are reactive. See also Supporting Information, pp. S7–S10.
  26. Ney, J.E.; Wolfe, J.P. Synthesis and Reactivity of Azapalladacyclobutanes. J. Am. Chem. Soc. 2006, 128, 15415–15422. [Google Scholar] [CrossRef]
  27. Lin, B.L.; Clough, C.R.; Hillhouse, G.L. Interactions of Aziridines with Nickel Complexes: Oxidative-Addition and Reductive-Elimination Reactions that Break and Make C–N Bonds. J. Am. Chem. Soc. 2002, 124, 2890–2891. [Google Scholar] [CrossRef]
  28. Han, L.; Xu, B.; Liu, T. Mechanisms of the synthesis of trialkylsubstituted alkenylboronates from unactivated internal alkynes catalyzed by copper: A theoretical study. J. Org. Chem. 2018, 864, 154–159. [Google Scholar] [CrossRef]
  29. Kajiwara, T.; Terabayashi, T.; Yamashita, M.; Nozaki, K. Syntheses, Structures, and Reactivities of Borylcopper and -zinc Compounds: 1,4-Silaboration of an α,β-Unsaturated Ketone to Form a γ-Siloxyallylborane. Angew. Chem. Int. Ed. 2008, 47, 6606–6610. [Google Scholar] [CrossRef] [PubMed]
  30. Wyss, C.M.; Bitting, J.; Bacsa, J.; Gray, T.G.; Sadighi, J.P. Bonding and Reactivity of a Dicopper(I) μ-Boryl Cation. Organometallics. 2016, 35, 71–74. [Google Scholar] [CrossRef]
  31. Borner, C.; Anders, L.; Brandhorst, K.; Kleeberg, C. Elusive Phosphine Copper(I) Boryl Complexes: Synthesis, Structures, and Reactivity. Organometallics. 2017, 36, 4687–4690. [Google Scholar] [CrossRef]
  32. Drescher, W.; Kleeberg, C. Terminal versus Bridging Boryl Coordination in N-Heterocyclic Carbene Copper(I) Boryl Complexes: Syntheses, Structures, and Dynamic Behavior. Inorg. Chem. 2019, 58, 8215–8229. [Google Scholar] [CrossRef] [PubMed]
  33. The substitution of the chloride anion with methoxide or tert-butoxide did not determined a significative difference in activation free energy with respect to the chloride one. In particular, we observed a modest decrease of both activation free energies of TS3 and TS4 from chloride towards methoxide/tert-butoxide, and a slight increase of the relative energy between the two steps (slightly bigger for tert-butoxide). This small increment of the relative energy between the TS3 and TS4 is most likely due to the contribution of the dispersion force between the methyl groups of the alkoxide and the pyridine ring in TS4. For more information see Table S1, pp. S6, Supporting Information.
  34. The TS with the shortest PhO-Cu distance (2.87 Å, TS3-B see supplementary material, Figure S2) can be found in the pathway towards the Markovnikov product: Also for the relative intermediates the energy remained particularly high (7.9 kJ/mol) even with a shorter O-Cu distance (2.3 Å). See pp. S133–S136, Supporting Information.
  35. We have also evaluated the possibility that CuCl can stabilize an anti-ring opening for the anti-Markovnikov product; the complex relative to the anti-transition state in which the aziridine nitrogen atom was coordinated to CuCl and the Cu-Bpin was coordinated to the phenoxy oxygen atom possessed a higher energy with respect to Complex-2 (ΔΔG = +74.9 kJ/mol). Although the anti-opening possessed a lower ΔG‡ (+41.7 kJ/mol) with respect to the one of the syn opening (+84.1 kJ/mol), the difference between the TS of anti-opening with respect to the syn one was remarkably in favor of the latter (37.4 kJ/mol). Please see pp. S136–S142, Supporting Information.
  36. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16, Revision A.03; Gaussian, Inc.: Wallingford CT, USA, 2016; Available online: https://gaussian.com (accessed on 3 December 2021).
  37. Ziegler, T. Approximate density functional theory as a practical tool in molecular energetics and dynamics. Chem. Rev. 1991, 91, 651–667. [Google Scholar] [CrossRef]
  38. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H.J. A Consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for 94 elements H-Pu. Chem. Phys. 2010, 132, 154104. [Google Scholar] [CrossRef]
  39. Schuchardt, K.L.; Didier, B.T.; Elsethagen, T.; Sun, L.; Gurumoorthi, V.; Chase, J.; Li, J.; Windus, T.L. Basis Set Exchange: A Community Database for Computational Sciences. J. Chem. Inf. Model. 2007, 47, 1045–1052. [Google Scholar] [CrossRef]
  40. Schlegel, H.B.J. Optimization of equilibrium geometries and transition structures. Comp. Chem. 1982, 3, 214–218. [Google Scholar] [CrossRef]
  41. Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev. 2005, 105, 99–3093. [Google Scholar] [CrossRef]
  42. Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3. J. Am. Chem. Soc. 2006, 128, 6312–6313. [Google Scholar] [CrossRef] [PubMed]
  43. Sommerdijk, N.A.J.M.; Buynsters, P.J.J.A.; Akdemir, H.; Geurts, D.G.; Nolte, R.J.M.; Zwanenburg, B. Aziridines as Precursors for Chiral Amide-Containing Surfactants. J. Org. Chem. 1997, 62, 4955–4960. [Google Scholar] [CrossRef]
  44. Christoffers, J.; Schulze, Y.; Pickardt, J. Synthesis, resolution, and absolute configuration of trans-1-amino-2-dimethylaminocyclohexane. Tetrahedron 2001, 57, 1765–1769. [Google Scholar] [CrossRef]
  45. Namutebi, M.; McGarrigle, E.M.; Aggarwal, V.K. Ring-Opening of NH-Aziridines with Thiols in Ionic Liquids: Application to the Synthesis of Aminosulfide Catalysts for Asymmetric Epoxidation of Aldehydes. Phosphorus Sulfur Silicon Relat. Elem. 2010, 185, 1250–1272. [Google Scholar] [CrossRef]
  46. McLeod, D.C.; Tsarevsky, N.V. Reversible Deactivation Radical Polymerization of Monomers Containing Activated Aziridine Groups. Macromol. Rapid Commun. 2016, 37, 1694–1700. [Google Scholar] [CrossRef] [PubMed]
  47. Schrittwieser, J.H.; Lavandera, I.; Seisser, B.; Mautner, B.; Kroutil, W. Biocatalytic Cascade for the Synthesis of Enantiopure β-Azidoalcohols and β-Hydroxynitriles. Eur. J. Org. Chem. 2009, 2009, 2293–2298. [Google Scholar] [CrossRef]
  48. Namba, K.; Mera, A.; Osawa, A.; Sakuda, E.; Kitamura, N.; Tanino, K. One-Pot Synthesis of Highly Fluorescent 2,5-Disubstituted-1,3a,6a-triazapentalene. Org. Lett. 2012, 14, 5554–5557. [Google Scholar] [CrossRef]
  49. Hanessian, S.; Del Valle, J.R.; Xue, Y.; Blomberg, N. Total Synthesis and Structural Confirmation of Chlorodysinosin A. J. Am. Chem. Soc. 2006, 128, 10491–10495. [Google Scholar] [CrossRef] [PubMed]
  50. Jun, Y.C.; Borch, R.F. Highly Efficient Synthesis of Enantiomerically Enriched 2-Hydroxymethylaziridines by Enzymatic Desymmetrization. Org. Lett. 2007, 9, 215–218. [Google Scholar]
  51. Lebel, H.; Lectard, S.; Parmentier, M. Copper-Catalyzed Alkene Aziridination with N-Tosyloxycarbamates. Org. Lett. 2007, 9, 4797–4800. [Google Scholar] [CrossRef] [PubMed]
  52. Buckley, B.R.; Patel, A.P.; Wijayantha, K.G.U. Observations on the Modified Wenker Synthesis of Aziridines and the Development of a Biphasic System. J. Org. Chem. 2013, 78, 1289–1292. [Google Scholar] [CrossRef]
  53. Ankner, T.; Hilmersson, G. Instantaneous Deprotection of Tosylamides and Esters with SmI2/Amine/Water. Org. Lett. 2009, 11, 503–506. [Google Scholar] [CrossRef]
  54. Hayashi, M.; Shiomi, N.; Funahashi, Y.; Nakamura, S. Cinchona Alkaloid Amides/Dialkylzinc Catalyzed Enantioselective Desymmetrization of Aziridines with Phosphites. J. Am. Chem. Soc. 2012, 134, 19366–19369. [Google Scholar] [CrossRef] [PubMed]
  55. Li, J.; Liao, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chiral magnesium(II)-catalyzed asymmetric ring-opening of meso-aziridines with primary alcohols. Chem. Commun. 2014, 50, 6672–6674. [Google Scholar] [CrossRef] [PubMed]
  56. Wang, L.; Yang, D.; Han, F.; Li, D.; Zhao, D.; Wang, R. Catalytic Asymmetric Construction of Pyrroloindolines via an in Situ Generated Magnesium Catalyst. Org. Lett. 2015, 17, 176–179. [Google Scholar] [CrossRef] [PubMed]
Molecules 26 07399 sch001 550
Scheme 1. State of the art (eq. (a–c)) and aim of the work (eq. (d)).
Scheme 1. State of the art (eq. (a–c)) and aim of the work (eq. (d)).
Molecules 26 07399 sch001
Molecules 26 07399 sch002 550
Scheme 2. Picolinoyl-protected aziridines 4–9c screened under optimized reaction conditions.
Scheme 2. Picolinoyl-protected aziridines 4–9c screened under optimized reaction conditions.
Molecules 26 07399 sch002
Molecules 26 07399 sch003 550
Scheme 3. Ring-opening reaction of aziridine 10 under copper-catalyzed borylative conditions.
Scheme 3. Ring-opening reaction of aziridine 10 under copper-catalyzed borylative conditions.
Molecules 26 07399 sch003
Molecules 26 07399 sch004 550
Scheme 4. Preliminary mechanistic model applied to differently protected non-substituted aziridine (above) and to N-(2-picolinoyl)-methyl aziridine and aziridine 1c (below).
Scheme 4. Preliminary mechanistic model applied to differently protected non-substituted aziridine (above) and to N-(2-picolinoyl)-methyl aziridine and aziridine 1c (below).
Molecules 26 07399 sch004
Molecules 26 07399 g001 550
Figure 1. Comparative calculated reaction energy profile of N-mesyl-azirdine (blue) and N-(2-picolinoyl)-aziridine (black) using the mono-copper-boron borylation adduct (the ΔG values are in kJ/mol). See also Table 2 below.
Figure 1. Comparative calculated reaction energy profile of N-mesyl-azirdine (blue) and N-(2-picolinoyl)-aziridine (black) using the mono-copper-boron borylation adduct (the ΔG values are in kJ/mol). See also Table 2 below.
Molecules 26 07399 g001
Molecules 26 07399 g002 550
Figure 2. Comparative calculated reaction energy profile between the first (blue) and the second model (black) using a dicopper-boron borylation adduct on the non-substituted aziridine (the ΔG values are in kJ/mol).
Figure 2. Comparative calculated reaction energy profile between the first (blue) and the second model (black) using a dicopper-boron borylation adduct on the non-substituted aziridine (the ΔG values are in kJ/mol).
Molecules 26 07399 g002
Molecules 26 07399 g003 550
Figure 3. Reaction energy profile with the second model for the reaction of N-(2-picolinoyl)-methyl aziridine and 1c (the ΔG values are in kJ/mol).
Figure 3. Reaction energy profile with the second model for the reaction of N-(2-picolinoyl)-methyl aziridine and 1c (the ΔG values are in kJ/mol).
Molecules 26 07399 g003
Molecules 26 07399 g004 550
Figure 4. Structure of intermediate I3a for compound 1c with highlighted the η6- coordination of the phenyl ring with the copper atom (orange).
Figure 4. Structure of intermediate I3a for compound 1c with highlighted the η6- coordination of the phenyl ring with the copper atom (orange).
Molecules 26 07399 g004
Molecules 26 07399 g005 550
Figure 5. Particular of the reaction energy profile comparison of the anti-Markovnikov pathway between 1c (without the Et2O molecule; black) and N-2-picolinoyl-methyl aziridine (with the Et2O molecule; blue). The ΔG values are in kJ/mol.
Figure 5. Particular of the reaction energy profile comparison of the anti-Markovnikov pathway between 1c (without the Et2O molecule; black) and N-2-picolinoyl-methyl aziridine (with the Et2O molecule; blue). The ΔG values are in kJ/mol.
Molecules 26 07399 g005
Table
Table 1. Results of the copper-catalyzed borylative ring opening of differently protected aziridines 1a–c a.
Table 1. Results of the copper-catalyzed borylative ring opening of differently protected aziridines 1a–c a.
Molecules 26 07399 i001
Entry a1Cu SaltMLT (h)Conversion (Yield) b
11aCuILi-48<5
21bCuILi-48<5
31cCuILi-48<5
41aCuIK-48<5
51bCuIK-48<5
61cCuIK-20>99 (25)
71cCuINaBinap2082 2c/3c = 0.1
81cCuIKBinap2077 2c/3c = 1.3
91cCuILiBinap2073 2c/3c = 0.3
101cCuIKPPh32066 2c/3c = 0.8
111cCuIKXantphos2028 2c/3c = 0.3
121cCuIKdppb2037 2c/3c = 0.6
13c1cCuClK-271 (60)
14 c,d1cCuClK-575(65)
15 c,d1cCuIK-565 (48)
16 c,e1cCuClK-72<5
a Unless stated otherwise, all reactions were carried out in anhydrous THF at 60 °C using copper salt (0.2 equiv.), 3.0 equiv. of base and 3.0 equiv. of B2pin2. b NMR conversion using α-methylnaphthalene as internal standard. Isolated yields of 2c after chromatographic purification on SiO2 in parentheses. c Reaction carried out at room temperature. d 2.0 equivalents of t-BuOK were used. e 1.5 equivalents of t-BuOK were used.
Table
Table 2. Free energy for the variously N-protected non-substituted aziridine using the model in Figure 1 (see below).
Table 2. Free energy for the variously N-protected non-substituted aziridine using the model in Figure 1 (see below).
N-Picolinoyl ΔG (kJ/mol)N-Ms
ΔG (kJ/mol)		N-Ts
ΔG (kJ/mol)
Complex-1 a0.00.00.0
TS1+79.0+95.3+93.9
I1−19.1+46.9+37.9
TS2−9.7+51.8/
P1 b−211.1−138.8/
a The zero value is represented by the aziridine N-complex with Cu and not by the isolated reagents. b the final product is the one obtained by IRC, so we cannot exclude lower energy conformers.
Table
Table 3. Free energy for the regioselectivity of N-(2-picolinoyl)-methyl aziridine and 1c using the model in Scheme 4.
Table 3. Free energy for the regioselectivity of N-(2-picolinoyl)-methyl aziridine and 1c using the model in Scheme 4.
N-(2-Picolinoyl)-methyl AziridineAziridine 1c
ΔG (kJ/mol)ΔG (kJ/mol)ΔG (kJ/mol)ΔG (kJ/mol)
Anti-MarkovnikovMarkovnikovAnti-MarkovnikovMarkovnikov
Complex-10.00.00.00.0
TS1+78.7+75.2+78.7+77.2
I1−10.2−7.2−17.6−20.3
TS2+4.8+8.3−1.4+8.4
P1−202.0−189.3−221.4−211.4
Table
Table 4. Free energies of the second model calculation on the non-substituted N-(2-piconiloyl) aziridine, Figure 2 (black).
Table 4. Free energies of the second model calculation on the non-substituted N-(2-piconiloyl) aziridine, Figure 2 (black).
ΔG (kJ/mol)
Complex-20.0 *
TS3+82.6
I2+43.2
TS4+69.0
I3+42.6
TS5+56.5
P2−204.7
* The zero value is represented by the aziridine N-complex with Cu and not by the isolated reagents.
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Favero, L.; Menichetti, A.; Boldrini, C.; Comparini, L.M.; Di Bussolo, V.; Di Pietro, S.; Pineschi, M. Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies. Molecules 2021, 26, 7399. https://doi.org/10.3390/molecules26237399

AMA Style

Favero L, Menichetti A, Boldrini C, Comparini LM, Di Bussolo V, Di Pietro S, Pineschi M. Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies. Molecules. 2021; 26(23):7399. https://doi.org/10.3390/molecules26237399

Chicago/Turabian Style

Favero, Lucilla, Andrea Menichetti, Cosimo Boldrini, Lucrezia Margherita Comparini, Valeria Di Bussolo, Sebastiano Di Pietro, and Mauro Pineschi. 2021. "Copper-Catalyzed Ring-Opening Reactions of Alkyl Aziridines with B2pin2: Experimental and Computational Studies" Molecules 26, no. 23: 7399. https://doi.org/10.3390/molecules26237399

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