A highly regioselective sp³ C–H amination of tertiary amides based on Fe(II) complex catalysts

Abstract

A highly regioselective sp³ C–H amination of aryl amides with N-substituted pyrrolidin-2-ones has been developed with a catalyst Fe(II) complex with TBHP as a benign oxidant. This facile method can offer rapid access to the amination reaction of N-substituted pyrrolidin-2-ones in moderate to excellent yields.

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In recent years, heterocyclic compounds containing N, N′-methylenediformamide skeletons have attracted more and more attention because they play very important roles in the pharmaceutical industry (Scheme 1). Lunec and co-workers described compound 1 as small-molecule inhibitors of the MDM2-p53 interaction based on an isoindolinone scaffold.¹ Recently, there have been some reports on an isoindolo[2,1-a]quinazoline derivative (compound 2) as a potent inhibitor of TNF-α,² and benzimidazo[2,1-a]isoindolone (compound 3) showed Batracylin-comparable anti-tumor activity as well as its ability to induce unscheduled DNA synthesis in rat hepatocytes.³

Scheme 1 Representative structures of N, N′-methylenediformamide skeleton molecules.

Transition metal-catalyzed C–N formation has represented a powerful and efficient protocol in organic amine chemistry.⁴ Although many ground-breaking contributions have been devoted to the forging of C–N bonds, such as Buchwald–Hartwig C–N coupling reaction,⁵N-arylation of amides⁶ and the Ullmann condensation reaction,⁷ the prefunctionalized starting materials seriously limit the use of such methods.⁸ Therefore, a direct C–H bond amination reaction based on transition metal catalysis is highly desirable and of great significance.⁹ To the best of our knowledge, the work on highly regioselective amination of sp³ C–H bonds remains elusive.¹⁰ Up to now, only a few examples for amination methods of sp³ C–H bonds have been reported, however, expensive metal catalysts, such as Ru, Pd and Rh, should be employed.¹¹ Meanwhile, considerable toxicity of those catalysts also limits their applications and possible improvements. Compared with those noble metals, iron catalysis has received considerable attention in modern synthetic chemistry.¹² In this paper, we reported a highly Fe(II)-catalyzed regioselective amination of sp³ C–H bonds adjacent to nitrogen atoms under mild conditions.

Initially, we selected benzamide 4a and 5a as the model substrates in the presence of 10 mol% FeCl₃ with 1.5 equiv of tertbutyl hydroperoxide (TBHP) as the oxidant and CH₃CN as the solvent under air at 80 °C. However, only traces of 6a could be detected (Table 1, entry1). To our delight, 61%, 52% and 64% yields of product 6a could be obtained by using Fe(II) as a catalyst in butanone, acetonitrile and decane, respectively (Table 1, entries 2–4), which also demonstrates that decane is the best solvent for amination reaction of sp³ C–H bonds. It was found that N-(1-methyl-5-oxopyrrolidin-2-yl)benzamide is the main product, but N-((2-oxopyrrolidin-1-yl)methyl)benzamide and N-(1-methyl-2-oxopyrrolidin-3-yl)-benzamide as by-products could not be detected. Meanwhile, if other metal salts were used, such as Fe₂(SO₄)₃, CuCl₂, CuBr, CuBr₂, Cu(OAc)₂, CuSO₄, Pd(OAc)₂ and Ni(Ac)₂, the results showed that these metal salts were proved to be less effective or totally ineffective (see ESI†), indicating that Fe(II) is the best catalyst in this reaction system. Then, some commercially available ligands were used to produce the corresponding Fe(II) complex catalysts (Table 1, entries 13–16), 6,6′-dimethyl-2,2′-bipyridine L1 shows better chemoselectivity and produces higher yields. Moreover, we also sifted out different oxidants; for instance, with O₂, PIA, DTBP, H₂O₂ and MnO₂, the desired product 6a was not obtained (entries 5–9). Fortunately, a yield of 84% could be obtained in N₂ instead of air if the amination reaction was carried out using 20% Fe(II) and 3.5 equiv TBHP (Table 1, entry 17). Therefore, the optimal conditions for the amination reaction of sp³ C–H bonds were established as L1 (20%), Fe(II) (20%), TBHP (3.5 equiv compared to 4), n-decane (2 mL) in nitrogen atmosphere.

Table 1 Optimization of amination condition^a

Entry	Catalyst	Solvent	Ligand	Oxidant	Yield (%)^b
a The reaction was carried out with 4a (0.1 mmol), 5a (0.3 mmol), catalyst (0.01 mmol), L (0.01 mmol), oxidant (0.1 mmol) and 2 mL solvent at 90 °C under air for 24 h. b The yield of 6a. c Iodobenzene diacetate. d Di-tert-butylperoxide. e Catalyst (0.005 mmol). f Catalyst (0.015 mmol). g Catalyst (0.02 mmol). h Under nitrogen atmosphere. i 3.5 equiv TBHP (70% in H2O).
1	FeCl3	CH3CN	—	TBHP	trace
2	FeCl2·4H2O	CH3COC2H5	—	TBHP	61
3	FeCl2·4H2O	CH3CN	—	TBHP	52
4	FeCl2·4H2O	decane	—	TBHP	64
5	FeCl2·4H2O	decane	—	O2	trace
6	FeCl2·4H2O	decane	—	PIA^c	trace
7	FeCl2·4H2O	decane	—	DTBP ^d	0
8	FeCl2·4H2O	decane	—	H2O2	trace
9	FeCl2·4H2O	decane	—	MnO2	trace
10^e	FeCl2·4H2O	decane	—	TBHP	49
11^f	FeCl2·4H2O	decane	—	TBHP	68
12^g	FeCl2·4H2O	decane	—	TBHP	72
13^g	FeCl2·4H2O	decane	L1	TBHP	79
14^g	FeCl2·4H2O	decane	L2	TBHP	65
15^g	FeCl2·4H2O	decane	L3	TBHP	73
16^g	FeCl2·4H2O	decane	L4	TBHP	52
17^ghi	FeCl2·4H2O	decane	L1	TBHP	84
18	—	decane	L1	TBHP	0
19	FeCl2·4H2O	decane	L1	—	0

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The scope of the Fe(II)-catalyzed amination of sp³ C–H bonds has been explored under the optimized conditions mentioned above. Table 2 lists various yields of the desired amination products. With respect to amide derivatives, both aryl amides and aryl sulfonamides (Table 2, entries 8–9 and 12) can react with N-substituted tert-amides. It was found that amides with electron-donating groups (Table 2, entries 2, 3, 6 and 7) have higher reactivity than those containing electron-deficient groups (Table 2, entries 4 and 5). We also found that the tertiary amides, such as N-substituted cycloamides show better reaction activities than N-substituted piperidin-2-one (Table 2, entry 15). In addition, with N-ethylpyrrolidin-2-ones (Table 2, entries 10–12), moderate yields could be afforded, and only trace products 6m and 6n were obtained owing to steric hindrance (entries 13 and 14). Herein, we chose 1-methylpyrrolidin-2-one as a substrate to explain regioselectivity of the amination reaction. This substrate has three different hydrogen atoms from N-methylene, N-methyl or methylene of the amide group, which are potentially susceptible to the amination reaction. Interestingly, the result indicates that only the product 6a arises from the C–H reaction of the N-methylene group. It can be attributed to the reason that stereoelectronic factor plays an important role in C–H regioselectivity of the amination reaction, that is, a favorable alignment of the C–H bond with the nitrogen lone pair can lead to C–H bond cleavage at the ring.¹³ It can further be demonstrated as shown in the proposed mechanism where radical intermediate 41 can favorably form intermediate 43 (Scheme 2).

Scheme 2 The proposed mechanism of the C–H amination process.

Table 2 The scope of the iron-catalyzed amination^a

Entry	Time/h	Product	Yield (%) ^b
a Reaction conditions: 4 (0.1 mmol), 5 (0.3 mmol), L1 (20 mmol%), FeCl2·4H2O (20 mmol%), TBHP (3.5 equiv compared to 4), n-decane (2 mL) in nitrogen atmosphere, at 90 °C. b Isolated yield.
1	4		84
2	4		87
3	3		89
4	4		63
5	4		62
6	3		74
7	3		82
8	4		71
9	4		69
10	4		60
11	4		58
12	3		56
13	4		28
14	4		37
15	4		32

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The proposed mechanism of the present C–H amination process is shown in Scheme 2. We found that the reaction rate and yield dramatically decrease under our standard coupling conditions when radical scavenger BHT (2,6-di-tert-buthyl-p-cresol) was added to the amination reaction system of benzamide and N-methylpyrrolidin-2-one. Herein, a free radical reaction process would be involved. According to some relevant reports¹⁴ and our experimental results, we think that the tert-butyl radicals could react with N-methyllpyrrolidin-2-one through a single-electron transfer (SET) to afford the more stable radical intermediate 41 while t-BuOOH produces tert-butyl radicals and hydroxyl in the presence of Fe(II) salts. It is probable that the radical cation 41 first reacts with Fe(III) to produce cation 42 which then combines with Fe(II), ligand 6,6′-dimethyl-2,2′-bipyridine L1 and amide to form the complex 43. The amination product could be produced after the removal of the Fe(II) catalyst.

In summary, we have described a direct and regioselective amination reaction based on an efficient and inexpensive Fe(II) complex catalyst with TBHP as a benign oxidant. This reaction also offers a facile method for the construction of C–N bonds.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 20972065, 21074054, 51173078, 21172106) and National Basic Research Program of China (2010CB923303).

References

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Footnote

† Electronic supplementary information (ESI) available: Synthesis, experimental details, NMR spectra, MS spectra of important compounds, and Competition experiment data. See DOI: 10.1039/c2ra20707a

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