Copper-mediated C(sp²)–H amination using TMSN₃ as a nitrogen source: redox-neutral access to primary anilines

Abstract

A Cu-mediated direct conversion of aromatic C–H to C–NH₂ assisted by a chelating group was developed. The reaction employed TMSN₃ as a nitrogen source under redox-neutral conditions to provide a variety of N-heterocycle-substituted primary anilines. Neither external oxidant nor additional deprotection or reduction step was required in this process.

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Aromatic amines (anilines) are essential intermediates in the manufacture of agrochemicals, pharmaceuticals, dyes, pigments, and polymers.¹ Primary anilines are particularly useful, because they can serve as starting materials for various aniline derivatives, such as secondary or tertiary anilines, amides, imines, amidines, and carbamates. In addition, they are precursors of many other functional groups, including halides, CN, OH, SH, CF₃, etc. via diazonium salts as intermediates.² Common routes to primary anilines are reduction of aromatic nitro compounds³ and transition-metal-catalyzed amination of aryl halides with ammonia or its surrogates.⁴ Recent efforts have identified that aryl boronic acids⁵ or substituted cyclohexenone oximes⁶ could also be transformed to primary anilines under metal-free or transition-metal-catalyzed conditions. In recent years, substantial achievements have been made in transition-metal-catalyzed C–H functionalization reactions due to their advantages over traditional transformations based on pre-functionalized substrates in atom-economy and step-efficiency.⁷ Direct conversion of aromatic C–H to C–N bonds is one of the major topics in C–H functionalization due to the great importance of anilines in organic synthesis.⁸ Therefore, a range of Pd-, Rh-, Ru-, or Cu-catalyzed systems employing either non-activated amino sources under oxidative conditions, such as amines, amides,⁹ sodium azide/nitrite,¹⁰ or pre-activated amino sources under redox-neutral conditions, such as N-chloroamines,¹¹N-hydroxycarbamates,¹²O-acylhydroxylamines,¹³ nitrosobenzenes,¹⁴ NFSI,¹⁵ sulfonyl/acyl azides,¹⁶ and aryl/alkyl azides¹⁷ have been developed (a, Scheme 1). The corresponding secondary/tertiary aniline derivatives, azides, etc. were produced. To gain access to primary anilines via the aforementioned C–H amination methods, an extra deprotection or reduction step is unavoidable. Therefore, the direct conversion of aromatic C–H bonds to C–NH₂ is highly valuable and similar reports are scarce in the literature.¹⁸

Scheme 1 Chelation assisted C(sp²)–H amination.

Trimethylsilyl azide has been widely used in the synthesis of nitrogen-containing molecules,¹⁹ such as triazoles, tetrazoles, nitriles, azirines, and so on.²⁰ Recently, the group of Jiao reported a copper-catalyzed C–H azidation of primary anilines with TMSN₃ as an azide source directed by the free amino group.²¹ Monguchi and Sajiki developed a general route to primary anilines through Cu⁽⁰⁾-mediated reductive amination of aryl halides with TMSN₃.²² Herein, we report an unprecedented copper(II)-mediated access to primary anilines using TMSN₃ as an amino source in the presence of TFA via a chelation group assisted C–H activation in one pot. Neither external oxidant nor an additional deprotection or reduction step is required in this process (b, Scheme 1).

We initially studied the reaction between 2-phenylpyridine 1a and TMSN₃2a in the presence of copper(I) thiophene-2-carboxylate (CuTc) (30 mol%) and TfOH (1.0 equiv.) in 1,2-dichlorobenzene at 120 °C for 24 h (entry 1, Table 1). To our delight, the desired primary aniline 3a was obtained in 24% yield together with 64% of 1a recovered. Extended reaction times resulted in partial decomposition of the aminated product. TFA was superior to other acidic additives, improving the yield of 3a to 32%. Cu(TFA)₂ can promote the reaction more efficiently than CuTc (36%). Only a trace amount of 3a was detected in the absence of acid, suggesting the essential role of acid in this amination process (entries 2–5). In all of the cases, the starting material 1a cannot be fully consumed, presumably as a result of strong coordination of copper with the two nitrogen atoms in 3a. As expected, the yield of 3a was improved to 88% when the loading of Cu(TFA)₂ was increased to 1.0 equivalent (entry 6). Other copper salts, including Cu(OAc)₂, CuCl₂, Cu(OTf)₂, Cu(hfacac)₂, CuI, and CuBr were also screened (see ESI†). It was intriguing that when Cu(TFA)₂ was replaced by Cu(OAc)₂, no 3a was detectable. When CuCl₂ was applied, only mono- and dichlorinated products were formed. It is obvious that the counter anion of copper is vital for product formation. Screening of solvents resulted in lower yields or no product formation (entries 9–10, and ESI†). It should be noted that NaN₃ can also be used as an amino source instead of TMSN₃, furnishing 1a in 38% yield (entry 11). A control reaction using Pd(TFA)₂ (20 mol%) as catalyst didn't give any of the desired product. When the reaction temperature was lowered to 90 °C, this C–H amination reaction was shut down completely.

Table 1 Optimization of the reaction conditions^a

Entry	Metal (equiv.)	Additive (1.0 equiv.)	Solvent	Time (h)	Yield^b (%)
a Conditions: 1a (0.20 mmol), 2a (0.4 mmol), metal salt, additive (1.0 equiv.), solvent (1.0 mL), Ar, sealed tube, 115 °C. b Yield of isolated 3a, DCB = 1,2-dichlorobenzene. CuTc = copper(I) thiophene-2-carboxylate. c Mono- and dichlorinated products were formed. d NaN3 (0.4 mmol) was used, 41% of 1a was recovered.
1	CuTc (0.3)	TfOH	DCB	24	24
2	CuTc (0.3)	TFA	DCB	24	32
3	CuTc (0.3)	—	DCB	24	Trace
4	CuTc (0.3)	p-TsOH	DCB	24	18
5	Cu(TFA)2 (0.3)	TFA	DCB	24	36
6	Cu(TFA)2 (1.0)	TFA	DCB	12	88
7	Cu(OAc)2 (1.0)	TFA	DCB	24	N.R.
8	CuCl2 (1.0)	TFA	DCB	24	N.D.^c
9	Cu(TFA)2 (1.0)	TFA	Toluene	12	47%.
10	Cu(TFA)2 (1.0)	TFA	DMSO	12	N.R.
11	Cu(TFA)2 (1.0)	TFA	DCB	24	38%^d
12	Pd(TFA)2 (0.2)	TFA	DCB	12	N.R.

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Next, the scope of this C–H amination reaction was investigated under the optimal reaction conditions. 2-Phenylpyridines bearing an electron-donating Me (3b and 3c) or electron-withdrawing CF₃ (3e) group in the pyridine moiety aminated smoothly. However, with a methyl group substituted at C6 of the pyridine the reaction deteriorated dramatically (34%, 3d) probably due to the steric hindrance around the pyridine nitrogen, proving its great importance in chelation with Cu. C–H amination also occurred efficiently on substrates with various substituents on different positions of the phenyl ring. Electron-donating OMe, OBn, and t-Bu (3f–h) as well as electron-withdrawing halogens (3k–l), ester (3m), ketone (3n), NO₂ (3p), and CF₃ (3q) groups on the para position were well tolerated, providing corresponding primary anilines in good to excellent yields. The nitrile group was less compatible with the acidic conditions, furnishing 3o in a lower yield of 44%. It is noteworthy that an alkene group in 3i also survived the reaction. These functional groups provided handles for further transformations on the scaffold. For meta-substituted substrates, amination took place at the less sterically hindered C–H bond exclusively (3r and 3s). Notably, a bipyridine substrate, 2-(pyridin-3-yl)pyridine, produced only one aminated product, 3-(pyridin-2-yl)pyridin-2-amine 3t, regioselectively in 76% yield. Besides pyridine, other heterocycles, such as pyrimidine, pyrazole, and isoquinoline, can also act as viable chelating groups in this amination reaction, providing the corresponding products 3u–w in moderate to good yields. Unlike other chelation assisted C(sp²)–H functionalization reactions where difunctionalization is generally an inevitable side-reaction, no diamination products were observed in any of the cases. Recently, Jiao reported a Pd-catalyzed tandem C–H azidation and N–N bond formation by reacting 2-arylpyridines with sodium azide in the presence of oxidants.²³ However, neither 2-(2-azidophenyl)pyridines as reaction intermediates nor pyrido[1,2-b]indazoles were detected in the current Cu-mediated primary aniline synthesis (Table 2).

Table 2 Scope of C–H amination^a,b

a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Cu(TFA)₂ (1.0 equiv.), TFA (1.0 equiv.), 1, 2-dichlorobenzene (1.0 mL), Ar, sealed tube, 115 °C. b Yield of isolated 3.

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These primary aniline products containing an ortho-N-heterocycle are useful precursors in the synthesis of bidentate nitrogen ligands²⁴ as well as bioactive agents. For example, the N-Ts protected derivative of 3a was an effective bidentate ligand in fluorination chemistry.²⁵ The binding affinity of this class of ligands is tunable, since analogues of 3a can be accessed feasibly by applying this amination method. Pyrazole and isoquinoline substituted primary anilines 3v and 3w are intermediates in the synthesis of apoptosis inducers²⁶ and inhibitors of reverse transcriptase,²⁷ respectively (Scheme 2). Primary aniline 3x, a key intermediate for the synthesis of inhibitors of phosphate transport protein,²⁸ was prepared from 1x under the standard reaction conditions in 62% isolated yield. The previous method to introduce the free NH₂ in 3x involves nitration and reduction steps, which is less atom-economic and step-efficient.

Scheme 2 Application of the primary aniline products.

To gain insight into this C–H amination process, a competition reaction between equal amounts of 1a and deuterated 1a-d₅ in one pot was carried out. The reaction was quenched at the midpoint and the product ratio between 3a and 3a-d₄ was determined to be 2 : 1 by ¹HNMR, suggesting that C–H bond cleavage was likely a rate-limiting step²⁹ (Scheme 3). A possible intermediate, 2-(2-azidophenyl)pyridine 4, was synthesized and subjected to the reaction. Although the yield for the transformation of azide 4 to 3a was low under the standard conditions (32%), a reaction pathway involving azide 4 as an intermediate cannot be fully ruled out.

Scheme 3 Mechanistic studies.

Although the exact mechanism of this free aniline-forming process is not clear at this stage, possible pathways are proposed in Scheme 4.³⁰ In path A, the azido group may be transferred onto the aryl ring first via reductive elimination of a cyclometalated intermediate IA after C–H bond activation. Reduction of IB by Cu⁽⁰⁾ in the presence of acid provides 3a. In path B, the coordinated Cu^(I), generated by disproportionation of Cu^(II), is oxidized to a high valent Cu^(III) species³¹ with concurrent release of N₂. After C–H bond activation and C–Cu bond formation, the cyclometalated Cu^(III) intermediate IIB was formed, followed by reductive elimination. Alternatively, pathway C involving copper nitrenoid insertion into the C–Cu bond is also possible.³²

Scheme 4 Plausible reaction pathways.

Conclusions

In summary, we have developed a copper-mediated process for the direct conversion of aromatic C–H to C–NH₂ bonds. Several N-heterocycles can act as chelating groups to assist the key C–H activation step. The corresponding primary anilines containing an ortho N-heterocycle are obtained under redox neutral conditions without an extra deprotection or reduction step. A range of functional groups are tolerated. The versatility of primary anilines in chemical transformations makes this method particularly useful in diversifying N-heterocycle substituted arenes. The exploration of related transformations and further mechanistic studies are currently under way in our laboratories.

Acknowledgements

We are grateful for financial support of this work by National Science Foundation of China (21202167).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00143e

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