Iron-catalyzed efficient intermolecular amination of C(sp³)–H bonds with bromamine-T as nitrene source

Abstract

[Fe(N4Py)(CH₃CN)](ClO₄)₂ can efficiently catalyze intermolecular nitrene insertion of sp³ C–H bonds with bromamine-T as the nitrene source, forming the desired tosylprotected amines with NaBr as the by-product.

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Nitrogen-containing compounds are abundant in nature and their important applications in biology and medicine have been widely documented. Metal-mediated C–N bond formation via a C–H activation strategy is a highly attractive chemical process for synthesis of valuable nitrogen-containing compounds.¹ This C–H bond amination method can ideally install an amino group in an organic skeleton in a single step, avoiding tedious multiple-step functional group transformations. In recent years, complex of rhodium-,² ruthenium-,³ copper-,⁴ cobalt-catalyzed⁵ this transformation with iminoiodane, azides, bromamine-T, and tosyloxycarbamates as the nitrene precursors have been reported. Ochiai and co-workers reported a method for the direct and chemoselective amination of aliphatic C–H bonds under metal-free conditions, in which N-triflylimino-λ³-bromane functions as an active organonitrenoid species.⁶ Very recently, there has been a surge of interest in developing iron catalysts for atom- and group-transfer reactions for the C–N bond formation because of the natural abundance and biocompatibility of iron.⁷ In literature, oxoiron(IV) centers in nonheme ligand have been characterized in both enzymes⁸ and model systems⁹ and have been shown to efficiently catalyze the hydroxylation of C–H bonds.¹⁰ Now, studies on nonheme iron-catalyzed amination of C(sp³)–H bonds via nitrogen group insertion have emerged as a powerful methodology for C–N bond formation.¹¹ However, development of nonheme iron catalysts for intermolecular amination of C(sp³)–H bonds remain a challenge. Complex [Fe(N4Py)(CH₃CN)](ClO₄)₂ (1) (N4Py = N,N-bis(2-pyridyl-methyl)bis(2-pyridyl)methylamine, Fig. 1) was designed and synthesized by Que and co-workers, and has significant oxygen activation.¹² Imidoiron units are nitrogen analogues of oxoiron species. It should be capable of catalyze the amination of C–H bonds. In this paper, we reported that 1 is an efficient nonheme iron catalyst for intermolecular amination of the C(sp³)–H bond using bromamine-T as nitrene source.

Fig. 1 Structure of N4Py and [Fe(N4Py)(CH3CN)].

Initially, we investigated the catalysis conditions, including optimization of nitrene sources, solvent and temperature. The results are summarized in Table 1. Using ethyl benzene 2a as a model substrate, we systematically evaluated its catalytic C–H bond nitrene insertion with different nitrene sources catalyzed by complex 1. The reagent PhINTs and related iminoiodane derivatives have been widely used as primary nitrene sources in amination of C–H bonds by iron catalysts.¹¹ Treatment of ethyl benzene with PhINTs (1.5 equiv.) in the presence of catalytic amount of [Fe(N4Py)(CH₃CN)](ClO₄)₂ (5 mol%) in acetonitrile under 80 °C for 8 h form the desired product 3a in 12% yield (Table 1, entry 1). In contrast, using chloramine-T as nitrene sources, no reaction detected under similar reaction conditions (entry 2). We then examined the TsNBrNa (bromamine-T) as nitrene sources. Under similar reaction conditions, 1 catalyzed the amination to give 3a in 62% yield (entry 3). The effects of temperature and solvent were also examined. The reaction in acetonitrile at 80 °C for 4 h gave the best result (entries 4–10, 81% yield). The yield of 3a increased by decreasing the temperature (entry 3 with entry 4) and the reaction time (entry 3 with entry 6), because the product 3a decomposed slowly at high temperature with iron salt under air. No decomposition of 3a detected at 80 °C for 8 h, while 5% of 3a decomposed with iron complex 1 at the same condition. When the amination reaction stopped, we found the iron complex 1 was decomposed and the free ligand N4Py can be isolated. So we added Fe(ClO₄)₂·6H₂O (5 mol%) into the acetonitrile solution of 3a, 13% of 3a decomposition was detected after 8 h at 80 °C under air. No reaction was observed in the absence of catalyst or with Fe(ClO₄)₂ as catalyst at 80 °C (entries 11 and 12).

Table 1 Optimization of conditions^a

Entry	Catalyst	N source	Solvent	T (°C)	Yield (%)
a Ethylbenzene (0.3 mmol), nitrene source (0.45 mmol), catalyst (5 mol%), solvent (2 mL), 8 h.b NR = no reaction.c Reaction time: 4 h.
1	1	PhINTs	CH3CN	80	12
2	1	TsNClNa	CH3CN	80	NR^b
3	1	TsNBrNa	CH3CN	80	62
4	1	TsNBrNa	CH3CN	40	76
5	1	TsNBrNa	CH3CN	r.t.	71
6^c	1	TsNBrNa	CH3CN	80	81
7^c	1	TsNBrNa	CH2Cl2	40	38
8^c	1	TsNBrNa	DCE	80	46
9^c	1	TsNBrNa	CHCl3	60	21
10^c	1	TsNBrNa	CH3NO2	80	55
11^c	Fe(ClO4)2	TsNBrNa	CH3CN	80	NR
12^c	—	TsNBrNa	CH3CN	80	NR

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With the optimized conditions, we examined the substrate scope of [Fe(N4Py)(CH₃CN)](ClO₄)₂ catalyzed amination of C(sp³)–H bonds with bromamine-T. As depicted in Table 2, a variety of sp³ C–H bonds of benzylic and heterocycles reacted with bromamine-T in the presence of 1 to give corresponding products in good to excellent yields.

Table 2 1 catalyzed C–H amination with bromamine-T^a

Entry	Substrate	Product	Yield^b (%)
a Substrate (0.3 mmol), TsNBrNa (0.45 mmol), 1 (5 mol%), CH3CN (2 mL), 4 h.b Isolated yield.c NR = no reaction.
1			78
2			76
3			69
4			82
5			86
6			73
7			76
8			80
9			44
			37
10			83
11			72
12			76
13			52
14		3i	70
15			NR^c

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1 readily catalyzed amination with various substituted benzylic C–H bonds, including electron-donating or electron-withdrawing substituents on the aryl ring, to give the corresponding products in moderate to good yield (Table 2, entries 1–5). While 1,2,3,4-tetrahydronaphthalene 2g and indan 2h were employed, the corresponding isolated yield were 73% and 76% (entries 6 and 7). In both of the cases, high chemoselectivity toward benzylic C–H bonds was observed. Notably, 1 can active the C–H bond of toluene. The reaction, however, didn't afford the corresponding amine product. Instead, the corresponding imine product 3i was isolated in 80% yield (entry 8), presumably formed from the initial amine via a secondary reaction.⁵ When o-xylene was used as the substrate, corresponding amine 3ja and imine product 3jb were obtained in 44% and 37% yields (entry 9). While only 3jb was detected in 70% yield, when 2 equiv. TsNBrNa added into the reaction mixture. In cases of cycloethers, the amination reaction occurred at the position adjacent to O atoms (entries 10–12).

The corresponding amination products were obtained in good yields. While 2n was employed, the imine compound was detected as the only product in 52% yield (entry 13). We find that our standard condition was also effective for the amination of acyclic ether 2o (entry 14). In the case, the hemiaminal products could not be isolated, since elimination of alcohol leading to imine 3i was observed. The fact that hemiaminals are imine equivalents has been reported.¹³ We also used the ethylether 2p as substrate, but no reaction was detected (entry 15).

The catalyst loading for the amination reaction can be reduced to 3 mol% without significantly affecting the product yield. As an example, using ethyl benzene 2a as substrate, 3a was obtained in 79% yield under the same reaction conditions over 4 h. Moreover, the N4Py ligand is robust and can be reused for catalysis simply by addition of a new batch of Fe(ClO₄)₂·6H₂O to the reaction mixture. A solution containing 1 (3 mol%), TsNBrNa (0.45 mmol) and substrate 2a (0.3 mmol) was stirred at 80 °C for 4 h. The substrate conversion of 2a was 100% as detected by ¹H NMR spectroscopy. The catalysis stopped, presumably, 1 underwent demetalation to give free N4Py ligand. Without isolation of the ligand, a new batch of Fe(ClO₄)₂·6H₂O (3 mol%), TsNBrNa (1.5 equiv.) and 2a (0.3 mmol) was added to the reaction mixture, which was allowed to stir for another 4 h. The added Fe(ClO₄)₂·6H₂O reacted with the N4Py to regenerate complex 1 in situ, as evidenced by its absorption λ_max at 458 nm. The in situ generated 1 subsequently catalyzed the amination of 2a to 3a. This process was repeated 3 times to afford the 3a with 75% yield after 3 runs.

Conclusions

In summary, we have demonstrated that the nonheme iron complex [Fe(N4Py)(CH₃CN)](ClO₄)₂ (1) is an active catalyst for the intermolecular amination of various C(sp3)–H bonds with bromamine-T at mild conditions. The benefit of using bromamine-T as the nitrene source was the innocent NaBr as the by-product. Efforts are underway to design and synthesize new nonheme iron complexes to further improve the scope and efficacy of the C–H amination system, including amination of unfunctional aliphatic carbon chains.

Acknowledgements

We thank the financial support of National Natural Science Foundation of China (21102107), National Mega Project on Major Drug Development (2011ZX09401-302), Special Financial Grant from the China Postdoctoral Science Foundation (2012T50664) and the Scientific and Technological Innovative Research Team of Wuhan (2013070204020048).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and compound characterization. See DOI: 10.1039/c4ra02240h

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