Synthesis of Diarylamines via Nitrosonium-Initiated C–N Bond Formation

Electron-rich diarylamines, exemplified by anisole-derived amines, play pivotal roles in process chemistry, pharmaceuticals, and materials. In this study, homo-diarylamines were synthesized directly from the C–H activation of electron-rich arenes by sodium nitrate/trifluoroacetic acid and the successive treatment of iron powder. Mechanistic investigations reveal that nitrosoarene serves as the reaction intermediate, and the formation of the second C–N bond between the resulting nitrosoarene and electron-rich arene is catalyzed by the nitrosonium ion (NO+). Thus, hetero-diarylamines were synthesized using preformed nitrosoarenes and various electron-rich arenes. This reaction complements a range of cross-coupling reactions catalyzed by transition metal catalysts.


■ INTRODUCTION
Diarylamines, particularly those based on the structure of anisole, serve as essential building blocks in the synthesis of photomaterials and electronic materials. 1Their electrondonating and hole-transporting properties are crucial for creating advanced materials used in optoelectronics and photovoltaics. 2 The structural motif originating from anisolederived diarylamines is also prevalent in many biologically active compounds.(Figure 1). 3 Consequently, there is a strong demand for an efficient and environmentally friendly protocol for the synthesis of these diarylamines. 4Conventional crosscoupling reactions, including the palladium-catalyzed Buchwald−Hartwig reaction, 5 copper-catalyzed Chan−Evans−Lam reaction, 6 Ullmann-type reaction, 7 and various cross coupling reactions 8 facilitated by transition metal catalysts between arylamines and aryl halides/boronic acids, 9,10 are commonly employed for the synthesis of diarylamines (Scheme 1A).Recently, the merger of photoredox catalysis and transition metal catalysis has also been utilized to form C(sp 2 )−N bonds. 11However, concerns arise from the use of costly and environmentally harmful transition metal catalysts in these coupling processes, along with the presence of their residual contaminants in the final products. 12Alternative methods to synthesize diaryl amines include nucleophilic aromatic substitution (S N Ar) reactions, 13 the insertion of benzyne into amide, 14 coupling reactions between aryl boronic acid and hydroxylamines, 15 desulfinylative Smiles rearrangement, 16 hypervalent-iodine-mediated cross-amination, 17 and the reactions of nitrosoarenes with aryl boronic acids or 1,3,5trimethoxybenzene (Scheme 1B). 18,19In this work, we found that both homo-and hetero-diarylamines can be prepared from electron-rich arenes by nitrosonium (NO + ) ion-initiated C−H activation and C−N bond formation (Scheme 1C).
The reaction conditions were further optimized with n-hexyl phenyl ether (1b, Table 1).The elevated boiling point 22 of 1b is advantageous for facile tracking of 1b and the products diarylamine 3b and primary amine 4b, both of which were generated in this reaction.Following the original conditions of eq 2, only a moderate yield (38%) of 3b was obtained (entry 1).After futile attempts to modify the reaction time and the equivalents of reagents to improve the yields (see Table S1 in the Supporting Information), we conducted the reaction in a range of solvents (entries 2−9) and found that 1,2-dichloroethane and dichloromethane significantly enhanced the yield of 3b to 68% and 70%, respectively (entries 2 and 3).When the reaction scale was increased to 10 mmol 1b, the yield of 3b was maintained (entry 4).While toluene and acetic acid-derived solvents yielded only modest results (entries 5−9), the reactions conducted in methanol, diethyl ether, THF, and DMF failed to produce any diarylamine (Table S1).
The optimized reaction condition (25 °C, 3 h, and the treatment of iron at 50 °C for 3 h) was applied to prepare more diarylamines, and the reaction scope was examined (Table 2).In dichloromethane, the yield of 3a was improved to 66% (entry 1).Compound 3a, pivotal as a precursor to a range of estrogen receptor (ER) antagonists 3c and Spiro-OMeTAD, 23 a crucial hole-transporting material, was traditionally synthesized via a Buchwald−Hartwig coupling reaction conducted at high temperatures (>100 °C).3c,24 All 2-alkyl substituted anisoles (1c−1g, entries 2−6) produced the corresponding diarylamines 3c−3g in 56−68% yields.The structure of 3d was also confirmed by X-ray crystallography (CCDC 2322240, see the Supporting Information).As a Scheme 1. Methods for the Synthesis of Diarylamines  a Sodium nitrate (1.0 mmol) was added to a solution of 1b (178.3 mg, 1.0 mmol), TFA (0.5 mL, 0.74 g, 6.5 mmol), and a solvent (1.0 mL) at 0 °C.After stirring at rt for 3 h under an atmosphere of air (balloon), to the reaction mixture were added iron powder (0.56 g, 10 mmol), acetic acid (1 mL), and water (0.5 mL), and the resultant mixture was stirred at 50 °C for another 3 h.Yields were determined by 1 H NMR using 1,4-dimethoxybenzene as an internal standard.
The Journal of Organic Chemistry result, the reactions were slightly affected by the steric hindrance of these ortho-substituents.On the other hand, employing 2,6-dimethylanisole (1h) necessitated an extended reaction time (16 h) and resulted in a lower yield (32%, entry 7).Both 3-methyl-and 3-methoxy-substituted anisoles, 1i and 1j, respectively, were converted to 3i and 3j smoothly (entries 8 and 9).The substituents on the oxygen atom, such as phenyl and n-hexyl groups, did not affect this reaction, yielding diarylamines 3k−3m, respectively (entries 10−12).4-Methylanisole and toluene did not produce any diarylamines under the reaction condition.Due to the consistent presence of primary amine 4b as a byproduct in Table 1, we initially suspected that 4-nitroanisole was the reaction intermediate, which further reacted with another anisole to yield secondary amine 3.However, treating the mixture of 4-nitroanisole (5a) and anisole (1a) with TFA, a trace of NaNO 3 , and then iron powder yielded only primary amine 4a, with 91% of anisole recovered (eq 3), indicating that nitro-5a is unlikely to be the reaction intermediate.On the other hand, subjecting separately prepared 1-methoxy-4nitrosobenzene (6a) to the mixture of 1a, TFA, and nitrosonium tetrafluoroborate (NOBF 4 ), a source of nitrosonium (NO + ) cation, yielded imine oxide 2 (87%, eq 4), the same product observed in eq 1 derived from the demethylation of 2′ in the absence of iron.It is known that the reaction between NO + and anisole 1a efficiently produces nitroso-6a. 25dditionally, under acidic conditions, sodium nitrate can generate NO + similar to NOBF 4 . 26It is reasonable to propose that nitrosoarene 6a serves as the reaction intermediate and its further reaction with another molecule of anisole to form 2 (through aminium N-oxide 2′ and subsequent demethylation).This speculation was further supported with this experiment: when 1a was replaced with 1c and the reducing workup procedure (iron powder) was applied, a new hetero-diarylamine (3ac) was harvested in 83% yield (eq 5).Clearly, product 3ac was derived from the reaction between nitroso-6a and anisole 1c.In contrast, the corresponding reaction between 1c and nitro-5a only gave primary amine 4a and homo-diarylamine 3c, derived from the reduction of inactive nitro-5a and the sequential nitrosation and coupling reaction of 1c, respectively (eq 6).In addition to NaNO 3 , both NOBF 4 and tert-butyl nitrite, also precursors to generate NO + , 27 could be the source of nitrogen atoms to produce diarylamine 3b with similar yields (eq 7).In these reactions, the formation of primary amine 4b was negligible (<3%).As little as 0.1 equiv of sodium azide, a NO + scavenger, 28 was able to inhibit this reaction completely (eq 48), consistent with a nitrosoniumcatalyzed reaction.
The reaction conditions to generate hetero-diarylamine 3ac using nitrosoarene 6a and anisole 1c were further optimized (Table 3).Without the addition of NOBF 4 , the formation of 3ac was limited (18%, entry 1).The addition of catalytic amounts of NOBF 4 (10−50 mol %) significantly increased the yields of 3ac (entries 2−4), but the difference between 30 or 50 mol % of NOBF 4 applied was very minor (entry 3 versus entry 4).The need for oxygen was shown in the yields of 3ac derived from reactions carried out in atmospheres of oxygen, air, and nitrogen (entry 3 versus entries 5 and 6).The yields were also proportional to the amount of TFA applied (entries 7−9), indicating the requirement of strongly acidic conditions.The detailed study on the preparation of diarylamine 3b with various NO + precursors and the positive effect of oxygen are summarized in Table S2 (Supporting Information).
More hetero-diarylamines were synthesized via the NO +catalyzed C−N bond formation between nitrosoarenes and Table 2. Study on the Substrate Scope a a Sodium nitrate (1.0 mmol) was added to a solution of 1b (178.3 mg, 1.0 mmol), TFA (0.5 mL, 0.74 g, 6.5 mmol), and CH 2 Cl 2 (1.0 mL) at 0 °C.After stirring at rt for 3 h under an atmosphere of air (balloon), to the reaction mixture were added iron powder (0.56 g, 10 mmol), acetic acid (1 mL), and water (0.5 mL), and the resultant mixture was stirred at 50 °C for another 3 h.b The reaction time for the first step was 16 h.
The reaction mechanism to account for the formation of diarylamine 3 is shown in Scheme 2. Under the acidic conditions, sodium nitrate, alkyl nitrite, or nitrogen oxides generated NO + , which reacted with anisoles to form nitrosoarene 6. 25,29 Kochi and Bosch have demonstrated that the affinity of NO + for 4-nitrosoanisole was much higher than that for anisole (K A /K EDA > 20 000) and the structure of adduct 7 (1.0 mmol) was added to a solution of 6a (1.0 mmol), NOBF 4 , TFA, and CH 2 Cl 2 (1.0 mL) at 0 °C.After stirring at rt for 2 h, iron powder (0.56 g, 10 mmol), acetic acid (1 mL), and water (0.5 mL) were added to the reaction mixture, and the resultant mixture was stirred at 50 °C for another 3 h.Yields were determined by 1 H NMR using 1,4-dimethoxybenzene as an internal standard.

The Journal of Organic Chemistry
was NO + σ-bonded to the nitroso group of 6a. 25,30In this work, adduct 7 further reacts with another anisole to yield diarylaminium N-oxide 2′.The absence of homo-diarylamine 3c as the product in eq 5 also aligns with the higher affinity of NO + for 6a than 1c.To our knowledge, a chemical transformation utilizing the nitroso adduct 7 has not been reported, i.e., the C−N bond formation between nitrosoarenes 6 and arenes 1 is indeed catalyzed by the nitrosonium ion.We propose that NO + is regenerated under an atmosphere of oxygen and acidic conditions.The formation of product 2 or 3a from intermediate 2′ depended on the isolation/workup procedures.Specifically, in the presence of iron, 2′ was reduced to 3a, whereas demethylation occurred in the absence of the reducing agent.The high para-selectivity relative to the methoxy substituent, as shown in products 3 of Table 2, is consistent with the observed formation of nitrosoarenes, and the unproductive substrates, such as 4-methylanisole and toluene, can be attributed to the lack of formation of the corresponding nitrosoarenes under these conditions. 25The low yields of some diarylamines, such as 3h, in Table 2, could be due to the sluggish formation of the corresponding nitrosoarenes.This nitrosonium catalysis enables broader substrate compatibility and lowers the reaction temperature in the C−N bond formation between nitrosoarenes and arenes.19c Table 4. Synthesis of Hetero-Diarylamines a a Anisole (1.0 mmol) was added to a solution of nitrosoarene (1.0 mmol), NOBF 4 (0.3 mmol), TFA (0.5 mL, 6.5 mmol), and CH 2 Cl 2 (1.0 mL).After stirring at rt for 2 h under an atmosphere of oxygen (balloon), to the mixture were added iron powder (0.56 g, 10 mmol), acetic acid (1 mL), and water (0.5 mL), and the resultant mixture was stirred at 50 °C for another 3 h.b m-Xylene (2.5 mmol), nitrosoarene (0.5 mmol), NOBF 4 (0.1 × 3 mmol), TFA (0.5 mL, 6.5 mmol), and dichloromethane (0.25 mL) were applied, and the reaction mixture was stirred at rt for 4 h.The reduction and workup procedures were the same as above.

Scheme 2. Proposed Reaction Mechanism
The Journal of Organic Chemistry

■ CONCLUSION
In summary, we have developed a new method to prepare diarylamines via nitrosonium-initiated C−N bond formations.The utilization of dichloromethane as the reaction solvent notably enhanced the formation of aminium N-oxide 2′, which was reduced with iron powder to yield diarylamine.Nitrosoarene is proposed as the reaction intermediate, and its activation by NO + is essential to form the second C−N bond.Thus, the reactions of nitrosonium−nitrosoarene adducts with electron-rich arenes were observed.This protocol utilizes economical, easy to handle and eco-friendly reagents including nitrates/alkyl nitrites as the precursors to NO + , oxygen and iron powder as the oxidizing and reducing agents, respectively. 31Iron stands as an inexpensive reagent and essential nutrient in coastal seawaters, with its comparative toxicity potential (CTP) designated at zero. 32This reaction provides an alternative method to prepare diarylamines.

Figure 2 .
Figure 2. Oak Ridge thermal ellipsoid plot of 2 with ellipsoids set to 50% probability.

Table 1 .
Optimization of Diarylamine Formation a