Copper(II) ketimides in sp³ C–H amination

Abstract

Commercially available benzophenone imine (HN=CPh₂) reacts with β-diketiminato copper(II) tert-butoxide complexes [Cu^II]–O^tBu to form isolable copper(II) ketimides [Cu^II]–N=CPh₂. Structural characterization of the three coordinate copper(II) ketimide [Me₃NN]Cu–N=CPh₂ reveals a short Cu-N_ketimide distance (1.700(2) Å) with a nearly linear Cu–N–C linkage (178.9(2)°). Copper(II) ketimides [Cu^II]–N=CPh₂ readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R–N=CPh₂ products in a process that competes with N–N coupling of copper(II) ketimides [Cu^II]–N=CPh₂ to form the azine Ph₂C=N–N=CPh₂. Copper(II) ketimides [Cu^II]–N=CAr₂ serve as intermediates in catalytic sp³ C–H amination of substrates R–H with ketimines HN=CAr₂ and ^tBuOO^tBu as oxidant to form N-alkyl ketimines R–N=CAr₂. This protocol enables the use of unactivated sp³ C–H bonds to give R–N=CAr₂ products easily converted to primary amines R–NH₂via simple acidic deprotection.

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Introduction

Transition metal-catalysed sp³ C–H amination protocols have gained immense attention in the synthetic community over the past couple of decades.^1–4 A majority of these protocols proceed via metal–nitrene^2,5 [M]=NR′ or metal–amide [M]–NR′R′′ intermediates.^1,6 Extensive studies on such intermediates and underlying mechanisms have paved the way towards more efficient sp³ C–H amination protocols.¹

Related metal–ketimide [M]–N=CR′R′′ intermediates, however, have received less attention in C–H amination chemistry. The strong metal–N_ketimide interaction makes ketimides effective spectator ligands. For instance, ketimides stabilize high valent homoleptic Mn(IV),⁷ Fe(IV)⁸ and Co(IV)⁹ complexes (Fig. 1a). In some cases, ketimides can also form via nickel and copper arylimido/nitrene intermediates [M]=NAr via C–C coupling at the para-position of the aryl nitrene ligand (Fig. 1b). While this reactivity was initially uncovered with nickel β-diketiminato complexes,¹⁰ reversible C–C bond formation/cleavage in related copper complexes provides access to terminal copper nitrenes [Cu]=NAr that participate in sp³ C–H amination.^11,12

Fig. 1 Transition metal–ketimide complexes.

Fewer examples of ketimides exist, however, in which the ketimide ligand serves as a reactive functional group in discrete transition metal complexes.¹³ Metal ketimide intermediates have been proposed in several Pd-catalysed cross-coupling reactions of aryl (Fig. 1c)¹⁴ and alkyl halides (Fig. 1d)¹⁵ with benzophenone imine. Cu-catalysed photoredox cross-coupling reactions of redox-active alkyl esters (Fig. 1e)¹⁶ and Cu-catalysed benzylic sp³ C–H amination with benzophenone imine (Fig. 1f)¹⁷ are among other examples that may be mediated by metal–ketimide intermediates. Moreover, Stahl and colleagues have proposed copper(II) ketimides in the N–N oxidative coupling of imines Ar₂C=NH to azines Ar₂C=N–N=CAr₂ under aerobic or electrocatalytic conditions (Fig. 1g).^18,19

Herein we describe discrete first-row transition metal–ketimide complexes intimately involved in C–H amination chemistry. Building upon the Kharasch–Sosnovsky reaction,^20–22 we previously demonstrated that copper(II) alkyl amides [Cu^II]–NHR′,²³ anilides [Cu^II]–NHAr,^6,24 and aryloxides [Cu^II]–OAr²⁵ serve as key intermediates in a radical relay protocol for sp³ C–H functionalisation (Fig. 2). Formed via acid–base^6,23,24 or transesterification²⁵ reactions between [Cu^II]–O^tBu with H-FG or Ac-FG reagents, these copper(II) complexes [Cu^II]–FG capture sp³-C radicals R˙ generated via H-atom abstraction from R–H to furnish the functionalized product R-FG. We anticipated that the relatively high acidity of the imine N–H bond²⁶ coupled with a preference for binding at copper with softer N-donors should enable the formation of [Cu^II]–N=CAr₂ species from [Cu^II]–O^tBu complexes and HN=CPh₂ allow for an examination of copper(II) ketimides in C–H amination catalysis.

Fig. 2 Mechanism of C–H functionalisation via β-diketiminato copper(II) intermediates [Cu^II]–FG.

Results and discussion

Synthesis and characterization of copper(II) ketimides

Monitored by UV-vis spectroscopy, addition of benzophenone imine (1 equiv.) to a solution of [Me₃NN]Cu-O^tBu (2a) in toluene at −80 °C results in decay of the characteristic UV-vis absorption of 2a at 470 nm with growth of a new band at 570 nm (Fig. S2†). Performed on a preparative scale, this new species [Me₃NN]Cu–N=CPh₂ (3a) may be isolated as dark purple crystals from pentane at −35 °C in 78% yield (Fig. 3a).

Fig. 3 (a) Synthesis and structure of copper(II) ketimides. (b) Synthesis and structure of copper(I) imine adducts.

The X-ray crystal structure of [Me₃NN]Cu–N=CPh₂ (3a) (Fig. 3a) reveals the Cu–N_ketimide distance of 1.700(2) Å, significantly shorter than the Cu–N bond found in the copper(II) amide [Cl₂NN]Cu–NHAd (1.839(9) Å)²³ and copper(II) anilide [Cl₂NN]Cu–NHAr^Cl₃ (1.847(3) Å).⁶ Copper(II) ketimide 3a possesses a nearly linear Cu–N3–C24 angle of 178.9(2)°. The short Cu–N_ketimide distance and linear Cu–N3–C24 angle support effective sp hybridization at the ketimide N atom. These values remarkably differ from those in the homoleptic copper(I) ketimide [Cu–N=CPh₂]₄ with bridging ketimide ligands that lead to a square-like tetrameric structure with Cu–N distances 1.847(2)–1.861(2) Å and Cu–N–Cu angles of 94.17(9)–98.25(9).²⁷ To outline differences between coordination of anionic ketimide ligands and their neutral ketimine counterparts, we prepared the corresponding benzophenone imine adducts [Me₃NN]Cu(NH=CPh₂) (4a) and [Cl₂NN]Cu(NH=CPh₂) (4b) (Fig. 3b). These copper(I) complexes feature substantially longer Cu–N_ketimine distances of 1.8940(14) and 1.8937(14) Å. These ketimine adducts 4a and 4b each exhibit a pronounced bend in the Cu–ketimide linkage with Cu–N–C angles of 132.68(12) and 130.25(12)° consistent with sp² hybridization at N.

UV-vis analysis of copper(II) ketimide [Me₃NN]Cu–N=CPh₂ (3a) reveals the presence of a single low energy absorption band at 570 nm (ε = 1910 M⁻¹ cm⁻¹) in toluene at room temperature. The EPR spectrum of 3a in a mixture of toluene and pentane at room temperature shows a signal centred at g_iso = 2.081 with very well resolved coupling to ^63/65Cu (A_Cu = 298.0 MHz) and additional hyperfine modelled with three equivalent ¹⁴N nuclei (A_N = 35.0 MHz) (Fig. S13†). The related copper(II) ketimide [Cl₂NN]Cu–N=CPh₂ (3b) prepared from [Cl₂NN]Cu-O^tBu (2b) and HN=CPh₂ exhibits a similar spectroscopic profile. The UV-vis spectrum of [Cl₂NN]Cu–N=Ph₂ (3b) exhibits a single absorption at 520 nm (ε = 3120 M⁻¹ cm⁻¹) in toluene at room temperature and possesses a similar isotropic EPR spectrum to that of 3a (Fig. S14†). Unfortunately, the greater thermal sensitivity of [Cl₂NN]Cu–N=Ph₂ (3b) has precluded its crystallographic characterization.

DFT calculations reveal remarkably high unpaired electron density on the ketimide N atom of both 3a (0.58) and 3b (0.61) (Fig. 4 and S23†). These values are significantly higher than values reported for related three coordinate β-diketiminato Cu(II) anilides [Cu^II]–NHAr (0.23–0.25)⁶ and a copper(II) amide [Cu^II]–NHAd (0.49).²³ We rationalize this as a result of a 2-center 3-electron π interaction between the highest energy d orbital at the copper(II) center destabilized by the β-diketiminato N-donors and a p orbital of the sp-hybridized ketimide N atom (Fig. 4a). In addition, the orthogonal orientation of the Cu–N_ketimide π-interaction relative to the conjugated ketimide N=CPh₂ π system further limits the delocalization of unpaired electron density away from the ketimide N atom (Fig. 4b and c).

Fig. 4 (a) Electronic structure of copper(II) ketimides. (b) SOMO and (c) spin density plot of copper(II) ketamide 3a (net spin α: blue, net spin β: red, 0.001 isospin value).

Copper(II) ketimide reactivity: radical capture and N–N bond formation

The ability of many β-diketiminato copper(II) complexes to participate in catalytic sp³ C–H functionalisation via radical relay (Fig. 2) encouraged us to assess the reactivity of copper(II) ketimides 3 towards alkyl radicals. We find that [Cu^II]–N=CPh₂ species 3a and 3b capture alkyl radicals R˙ to provide the corresponding R–N=CPh₂ products (Fig. 5a). [Cu^I] is anticipated to form in these radical capture reactions that correspond to step d in the radical relay catalytic cycle (Fig. 2). For instance, reaction of 3a and 3b with (E/Z)-azobis(α-phenylethane) at 90 °C that generates the benzylic radical PhCH(˙)Me upon heating provides the alkylated imine PhCH(N=CPh₂)Me in 40% and 74% yields, respectively. Generation of Cy˙ radicals in the presence of 3a and 3b by heating ^tBuOO^tBu in cyclohexane (via H-atom abstraction by ^tBuO˙ radicals) provides Cy-N=CPh₂ in 58% and 41% yields, respectively.

Fig. 5 Reactivity of copper(II) ketimides. ^a 2 equiv. diazene radical precursor.

Upon heating to 60 °C, copper(II) ketimides 3a and 3b undergo N–N coupling to form benzophenone azine Ph₂C=N–N=CPh₂ isolated in 66% and 90% yields, respectively (Fig. 5b). This represents a competing reaction for radical capture at copper(II) ketimides 3a and 3b.

Copper(II) ketimides in sp³ C–H amination

With a fundamental understanding of copper(II) ketimide formation and reactivity, we explored these complexes in catalytic C–H amination via radical relay. Using ethylbenzene as a model R–H substrate, we screened a modest range of copper(I) β-diketiminato catalysts 1 that possess different electronic and steric properties (Table 1). The catalyst [Cl₂NN]Cu (1b) provides the highest yield compared to more electron-rich (1a and 1c) and electron-poor (1d) catalysts. Increasing the ^tBuOO^tBu oxidant amount does not significantly improve the yield. Lowering the temperature from 90 °C reduces the yield drastically (Table S1†), possibly due to binding of the ketimine HN=CAr₂ to the copper(I) catalyst (Fig. 3b) that inhibits ^tBuOO^tBu activation.²⁸

Table 1 Copper catalysed C–H amination of ethylbenzene with benzophenone imine^a

Entry	Catalyst	(X, R^1, R^2)	Yield (%)
a Conditions: 50 equiv. R–H. All yields determined by ^1H NMR
1	[Me3NN]Cu 1a	(Me, Me, Me)	34
2	[Cl2NN]Cu 1b	(Me, Cl, H)	65
3	[^tPr2NN]Cu 1c	(Me, ^tPr, H)	30
4	[Cl2NNF6]Cu 1d	(CF3, Cl, H)	42

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While (1-(tert-butoxy)ethyl)benzene forms in trace amounts via C–H etherification,²⁸ the azine Ph₂C=N–N=CPh₂ is the main byproduct in these catalytic C–H amination reactions, representing non-productive consumption of H–N=CPh₂. In a previous study of C–H amination with anilines H₂NAr employing the [Cl₂NN]Cu/^tBuOO^tBu catalyst system, electron-poor anilines provided the highest yields in the face of competing diazene ArN=NAr formation.²⁴ Copper(II) anilido intermediates [Cu^II]–NHAr serve as intermediates in C–H amination with anilines H₂NAr; those derived from electron-poor anilines H₂NAr (e.g. Ar = 2,4,6-Cl₃C₆H₂) proved more resistant to reductive bimolecular N–N bond formation.^6,24

To examine whether similar electronic changes in the ketimine H–N=CAr₂ could similarly promote more efficient catalysis, we explored two electron-poor ketimine derivatives H–N=CAr₂ (Ar = 4-CF₃C₆H₄ and 4-FC₆H₄) in C–H amination (Table 2). Although the p-CF₃ substituted imine provides a higher C–H amination yield with cyclohexane (C–H BDE = 97 kcal mol⁻¹),²⁹ the increase in yield is modest with the benzylic substrate ethylbenzene (C–H BDE = 87 kcal mol⁻¹).²⁹ No significant differences were observed between benzophenone imine and the p-F substituted analogue.

Table 2 Copper catalysed C–H amination with benzophenone imine derivatives^a

Entry	Ar	Yield (%)
a Conditions: 10 equiv. R–H, 1.2 equiv. ^tBuOO^tBu, 1 mol% [Cl2NN]Cu, 90 °C, 24 h. Yields are determined by ^1H NMR.
1		44 (5a)	40 (5b)
2		51 (5a-CF3)	56 (5b-CF3)
3		36 (5a-F)	39 (5b-F)

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While electron-poor imines can give somewhat higher C–H amination yields, we most broadly examined the commercially available H–N=CPh₂ to survey the scope of R–H substrates in sp³ C–H amination (Table 3). Ethers such as THF, 1,4-dioxane, or even 12-crown-4 undergo C–H amination at the α-carbon in relatively high yields (6a–6d). Amination of the benzylic secondary C–H bonds in heteroaromatic substrates occurs (6f–6g), though yields may be lower due to the possibility of coordination of these substrates and/or products to the copper(I) centre that can decrease the rate of reoxidation with ^tBuOO^tBu.²⁸ Aromatic substrates with benzylic C–H bonds undergo C–H amination in moderate to high yields (6h–6k). Cycloalkanes with stronger, unactivated sp³ C–H bonds give moderate yields with electron-poor ketimine HN=CAr′₂ (Ar′ = 4-CF₃C₆H₄) (6l–6o). The bicyclic eucalyptol undergoes C–H amination in 32% yield (6e). These aminated products may be isolated either as synthetically versatile protected primary amines R–N=CPh₂via column chromatography (6a–6g) or as the primary ammonium salts [R–NH₃]Cl via deprotection upon simple acidic work up (6h–6o) under mild conditions. The potential to use recovered benzophenone from deprotection of ketimine products and azine byproducts to regenerate the Ph₂C=NH starting material³⁰ enhances the overall atom economy of this amination protocol.

Table 3 Copper catalyzed sp³ C–H amination with ketimines HN=CAr₂^a

a Conditions: 10 equiv. R–H, 1.2 equiv. ^tBuOO^tBu, 1 mol% [Cl₂NN]Cu, 90 °C, 24 h. b Yields with HN=CPh₂. c Yields with HN=CAr′₂ (Ar′ = 4-CF₃C₆H₄). ¹H NMR yields (isolated yields) for 6f and 6g.

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Conclusions

The isolation of mononuclear copper(II) ketimides [Cu^II]–N=CPh₂ reveals the role that they play as intermediates in sp³ C–H amination. These reactive intermediates readily form via acid–base exchange between [Cu^II]–O^tBu and HN=CPh₂, amenable to spectroscopic and structural investigation. Importantly, [Cu^II]–N=CPh₂ complexes efficiently intercept alkyl radicals R˙ generated via H-atom abstraction by ^tBuO˙ from substrates R–H that ultimately enable the C–H amination of unactivated sp³ C–H substrates. DFT analysis reveals a significant amount of unpaired electron density at the ketimide N atom of 0.58 and 0.61 e⁻ for [Me₃NN]Cu–N=CPh₂ (3a) and [Cl₂NN]Cu–N=CPh₂ (3b) (Fig. 4 and S23†), respectively, opening a facile pathway for C–N bond formation with radicals R˙ to form R–N=CPh₂ products (Fig. 5a). Moreover, this spin density at the ketimide N-atom likely facilitates N–N bond formation via copper(II) ketimides [Cu^II]–N=CPh₂ to give the azine Ph₂C=N–N=CPh₂ (Fig. 5b), a competing pathway in sp³ C–H functionalisation. Use of the more electron-poor ketimine HN=CAr′ (Ar′ = 4-CF₃C₆H₄) extends the scope of catalysis to unactivated sp³ C–H bonds in cycloalkanes (Table 3; entries 6l–6o). Nonetheless, facile N–N bond formation also by copper(II) ketimides [Cu^II]–N=CAr₂ underscores the role that they may play in the (electro)catalytic copper(II) promoted oxidative N–N coupling of benzophenone imine to form benzophenone azine (Fig. 1g).¹⁸

Experimental section

Detailed experimental procedures are provided in the ESI.†

Data availability

All synthetic procedures, characterization data, spectroscopic data, computational data, supplementary figures and tables, and detailed crystallographic information can be found in the ESI.† Crystallographic data are available via the Cambridge Crystallographic Data Centre (CCDC): 1940417, 1945374, 1940418, 1945375, 1940420, 2035780.

Author contributions

I. U. J. and A. B. prepared and characterized the metal complexes, I. U. J. performed reactivity and computational studies with metal complexes, I. U. J., R. P., K. N., and N. L. K. carried out catalytic amination experiments, isolating and characterizing organic products, J. A. B. solved and refined X-ray diffraction data, T. H. W. guided the research and assisted with data analysis, I. U. J. and T. H. W. wrote the manuscript with input from all authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to NSF (CHE-1665348 and CHE-1955942) for support of this work.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1940417, 1940418, 1940420, 1945374, 1945375 and 2035780. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc01990b

‡ Current Address: Department of Chemistry, Towson University, 8000 York Road, Towson, MD, 21252, USA.

§ Current Address: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824, USA.

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