Synthesis of 3,5-Disubstituted Anilines via Sequential Mo-Catalyzed Deoxygenative Benzene Formation and Pd-Catalyzed Amination Reactions

Abstract

The substituted anilines play a pivotal role as structural motifs in agrochemicals, organic polymers, and pharmaceuticals, and great efforts have been dedicated to advancing their synthesis. However, the highly efficient and selective synthesis of meta,meta-disubstituted anilines remains a challenge. Here, the synthesis of meta,meta-disubstituted anilines via sequential Mo-catalyzed deoxygenative benzene formation and Pd-catalyzed amination reactions is reported. By employing this method, a wide range of meta,meta-disubstituted anilines were accessed with up to 89% yield from readily accessible ynones, allylic amines, and amines.

 

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Key words

molybdenum catalysis - palladium catalysis - deoxygenative benzene formation - C–N bond cross coupling - 3,5-disubstituted anilines

Biographical Sketches

Gang Fang was born in Zhejiang, China. He graduated from Xiamen University in 2022 with a B.Sc. degree in Chemical Biology. He is continuing his graduate studies at the Xiamen University under the supervision of Professor Chun-Xiang Zhuo. His research is currently focused on the development of novel molybdenum catalysis.

Yi-Zhe Yu was born in Anhui, China, in 1996. He received his B.Sc. degree in 2017 from Anhui Normal University. He is now performing Ph.D. studies under the supervision of Prof. Chun-Xiang Zhuo’s laboratory at the College of Chemistry and Chemical Engineering at Xiamen University. His research interests include development of novel molybdenum catalysis and molybdenum catalysts.

Chun-Xiang Zhuo received his B.Sc. in chemistry from Hunan University in 2009. He completed his Ph.D. at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (SIOC) in 2014 under the supervision of Prof. Shu-Li You before doing postdoctoral studies with Prof. Alois Fürstner at Max-Planck-Institut für Kohlenforschung. In April 2019, he joined the Department of Chemistry at Xiamen University as a Professor to start his independent research. His current research interests include development of novel synthetic methodology, asymmetric catalysis, natural product synthesis, and medicinal chemistry.

Introduction

Aniline serves as a pivotal structural motif in agrochemicals, organic polymers, and pharmaceuticals (Figure [1] A).[1] Therefore, great efforts have been devoted to the synthesis of anilines over the past few decades.[1] However, the effective and selective synthesis of meta-substituted anilines via the electrophilic aromatic substitution remains a challenge because the amino group is an electron-donating substituent that can only steer the incoming reagents to the para or ortho-position of the aryl ring.[2] Alternatively, a classical reaction sequence that consists of stepwise functionalization of the meta-position of nitrobenzene and reduction of the nitro group to amine could produce meta-substituted anilines. Nevertheless, issues such as harsh reaction conditions and low reactivity might impede further application of this process.

Figure 1 ASelected examples of bioactive molecules containing 3,5-disubstituted anilines; B: Mo-catalyzed deoxygenative benzene formation for the synthesis of 3,5-disubstituted bromobenzenes; C: This work: synthesis of 3,5-disubstituted anilines via sequential Mo-catalyzed deoxygenative benzene formation and Pd-catalyzed amination reactions.

On the other hand, transition-metal-catalyzed amination reaction of meta-halide-substituted arenes has been employed as an efficient method to prepare meta-substituted anilines.[3] This approach often faced the similar selectivity issue since meta-substituted aromatic substrates were prepared typically through electrophilic aromatic substitution. Recent advances such as transition-metal-facilitated meta-C–H functionalization of directing group decorated aniline derivatives[4] as well as direct C–H amination of the aromatic substrates,[5] and de novo synthesis of anilines based on benzene-forming reactions[6] could provide alternative approaches to the meta-substituted anilines. However, issues such as overfunctionalization, low efficiency, or the requirement for complex substrates might be encountered. Despite these advances, the development of efficient and convenient strategy for the construction of meta-substituted anilines using readily accessible starting materials is still in high demand.

Our research group has been devoted to the development of molybdenum-catalyzed deoxygenative functionalization reactions of carbonyl compounds.[7] [8] Recently, we reported a novel Mo-catalyzed deoxygenative benzene-forming reaction that utilized readily accessible ynones and allylic amines as starting materials.[7f] Interestingly, when 2-bromo-N-methylallylamine (2a) was used, the meta,meta-disubstituted bromobenzene (3′) was obtained in moderate yield (Figure [1] B). Accordingly, we questioned whether the synthesis of meta,meta-disubstituted anilines could be achieved through a two-step sequence that combined our Mo-catalyzed deoxygenative benzene forming reaction[7f] with the Pd-catalyzed C–N bond cross-coupling reaction.[1] [9] Here, we report the synthesis of meta,meta-disubstituted anilines via sequential Mo-catalyzed deoxygenative benzene formation and Pd-catalyzed amination reactions (Figure [1] C). Based on this method, a wide range of meta,meta-disubstituted anilines were accessed with up to 89% yield from readily accessible ynones, allylic amines, and amines.

Initially, the optimization of the reaction conditions of the Mo-catalyzed halobenzene forming reaction was performed using ynone 1a and 2-chloro-N-methylallylamine (2b) as the model substrates (Table [1]). Under identical reaction condition that was used for the formation of bromobenzene product 3′ when 2-bromo-N-methylallylamine (2a) was used as the substrate (Figure [1]B),[7f] 3,5-disubstituted chlorobenzene 3a was obtained in moderate yield (Table [1], entry 1). Further investigation on the loading and types of the reductants revealed that 0.8 equivalent of PPh₃ was optimal for this reaction (entry 8). Finally, screening of the concentration and temperature of the reaction led to the identification of optimal reaction conditions (entry 10). The 3,5-disubstituted chlorobenzene product 3a was obtained in 87% yield under these reaction conditions.

Table 1 Optimization of Reaction Conditions^a

Entry	Reductant	x (equiv)	Temp (°C)	Yield (%) of 3ab
1	DPPO	0.5	160	68
2	DPPO	0.4	160	74
3	DPPB	0.4	160	64
4	DPPP	0.4	160	69
5	PPh2Me	0.8	160	54
6	PPh2 n Pr	0.8	160	72
7	PPh2Cy	0.8	160	47
8	PPh3	0.8	160	75
9c	PPh3	0.8	160	86
10c,d	PPh3	0.8	140	90 (87)

^a Reaction conditions: 10 mol% of Mo(CO)₆, 10 mol% of o-quinone, x equiv of reductant, 1a (0.48 mmol, 2.4 equiv), 2b (0.2 mmol, 1.0 equiv) in toluene (2 mL) at 160 °C. DPPO: 1,8-Bis(diphenylphosphino)octane; DPPB: 1,4-Bis(diphenylphosphino)butane; DPPP: 1,5-Bis(diphenylphosphino)pentane. ⁿ Pr: Propyl; Cy: Cyclohexyl.

^b Yield was determined by GC-MS using 1,3,5-trimethoxybenzene as an internal standard. Yield of isolated product is reported in parentheses.

^c The reaction was performed in 0.4 mL of toluene.

^d The reaction was performed for 12 h.

With the optimal reaction conditions in hand, we next investigated the synthesis of 3,5-disubstituted anilines by combining this Mo-catalyzed deoxygenative chlorobenzene forming reaction with the Pd-catalyzed C–N bond cross-coupling reactions.[10] Pleasingly, the 3,5-disubstituted aniline 5a could be obtained in 83% yield via this two-step sequence using readily accessible ynone 1a, 2-chloro-N-methylallylamine (2b), and piperidine as the starting materials (Scheme [1]).

Scheme 1 The substrate scope: The reaction was performed on 0.2 mmol scale and yields over both steps were reported. ^a The reaction was performed with 2.5 mol% of Pd₂(dba)₃, 10 mol% of Me₄ ^t BuXphos and 2.0 equiv of K₃PO₄ in toluene at 100 °C. ^b The reaction was performed with 1 or 2 mol% of Brettphos-Pd precatalyst, 1 or 2 mol% of Brettphos and 1.2 equiv of NaO ^t Bu in 1,4-dioxane at 85 °C. ^c The reaction was performed with 1 or 2 mol% of Pd₂(dba)₃, 5 mol% of Me₄ ^t BuXphos and 1.2 equiv of K₃PO₄ in ^t BuOH at 110 °C. ^d The reaction was performed with NH₃ (5.0 equiv, 0.4 M in 1,4-dioxane), 2 mol% of Pd₂(dba)₃, 10 mol% of ^t BuDavePhos and 1.4 equiv of NaO ^t Bu in 1,4-dioxane at 80 °C. o-Quinone: 3,5-Di-tert-butyl-o-benzoquinone.

The substrate scope of this 3,5-disubstituted aniline synthesis method was subsequently investigated (Scheme [1]). Reactions of the ynone substrates bearing either electron-donating or electron-withdrawing substituents on the aromatic ring that were attached to the carbonyl moiety (R¹) proceeded, thus providing the corresponding 3,5-disubstituted aniline products 5a–d in moderate to good yields. The reaction also occurred smoothly when the ynone substrates bearing naphthyl or heteroaromatic rings (R¹), such as thienyl and quinoxalinyl, were used (5e–h). In addition, the reactions of ynone substrates, featuring alkyl substituents (R¹) attached to the carbonyl group, also proceeded smoothly (5i–k). Furthermore, ynone substrates featuring several substituted aromatic, heteroaromatic, or alkyl groups (R²) linked to the alkyne moiety readily engaged in this reaction (5l–p). Interestingly, this method facilitated the straightforward synthesis of 3,5-disubstituted aniline products possessing two different alkyl groups (5q) or heterocycles (5r). Unfortunately, no desired meta-phenyl-substituted chlorobenzene was obtained when the ynone substrate bearing terminal alkyne (1-phenylprop-2-yn-1-one) was used under these Mo-catalytic conditions.

The amine scope was subsequently investigated (Scheme [1]). By simply varying the amine components, we successfully synthesized a broad range of valuable meta,meta-disubstituted aromatic amines. Notably, secondary amines, including functionalized piperidine, piperazine, and morpholine, were found to be compatible (5s–v). Additionally, various N-containing heterocycles, such as homopiperazine, pyrrolidine, bicyclic pyrrolidine, spirocyclic amines, aza-heteroarene, and N-methylaniline could be easily incorporated (5w–ac). Moreover, secondary arylamines and amide products were accessed in moderate to good yields using benzylamine, aniline, and acetamide as the coupling partners (5ad–af). Notably, primary arylamine products 5ag and 5ah, which served as cyclooxygenase inhibitors[11] were efficiently prepared in decent yields using ammonia in 1,4-dioxane as the coupling partner. Furthermore, diverse 3,5-di-heteroaryl- or 3,5-di-alkyl-substituted arylamine products 5ai–an could be readily obtained in moderate yields, further illustrating the synthetic potential of this methodology.

This method was also suitable for derivatizing several natural products and drug molecules, demonstrating its potential for use with more complex and biologically relevant molecules 5ao–ba. Notably, these meta,meta-disubstituted aromatic amine-containing molecules, which hold promise for drug discovery processes, were readily obtained in moderate to good yields.

To illustrate the synthetic potential of this strategy, a gram-scale reaction and the synthesis of a bioactive molecule were carried out (Scheme [2]). Specifically, the 3,5-disubstituted aniline product 5at was successfully obtained on a 3 mmol scale in moderate yield (Scheme [2] A). In addition, by employing this meta,meta-disubstituted aniline forming strategy, a potent inhibitor of tubulin polymerization for tumor treatment 6 [12] was readily accessed from amide A-1 and terminal alkyne B-1 (Scheme [2] B). This molybdenum catalysis-based synthetic route was complementary to the previous approach[12] that required two Pd-catalyzed C–C bond cross coupling reactions.

Scheme 2 AA gram-scale reaction; B: Synthesis of a potent inhibitor of tubulin polymerization for tumor treatment.

In summary, we have developed an efficient method for the syntheses of meta,meta-disubstituted anilines. By combining the robust molybdenum-catalyzed meta,meta-disubstituted halobenzene-forming reaction and the powerful Pd-catalyzed C–N bond cross-coupling reaction, an array of diverse 3,5-disubstituted arylamine products were easily accessed from readily accessible ynones, allylic amines, and amines. The synthetic potential of this methodology was showcased through the derivatization of several bioactive molecules, the successful implementation of a gram-scale reaction, and the synthesis of a potent inhibitor of tubulin polymerization for tumor treatment. Further studies on the synthetic transformations of the products are underway in our laboratory.

 

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Procedure for the Synthesis of Chlorobenzene 3a

In a glovebox, to a Young Schlenk tube (10 mL) were added Mo(CO)₆ (5.3 mg, 0.02 mmol, 10 mol%), 3,5-di-tert-butylbenzoquinone (o-quinone; 4.4 mg, 0.02 mmol, 10 mol%), and toluene (0.4 mL) under N₂ atmosphere. The tube was sealed and transferred out of the glovebox. Then the reaction mixture was stirred at 160 °C for 15 min. After cooling to rt, ynone 1a (105.6 mg, 0.48 mmol, 2.4 equiv), PPh₃ (42 mg, 0.16 mmol, 0.8 equiv), and allylic amine 2b (21.1 mg, 0.2 mmol, 1.0 equiv) were added to the reaction mixture under N₂ atmosphere in the glovebox. The tube was sealed and transferred out of the glovebox. Then the mixture was stirred at 140 °C ( Caution: a protective shield should be installed around the Young Schlenk tube because of the risk of explosion due to the increase of vapor pressure during the reaction). After 12 h, the mixture was cooled to rt. The solvents were evaporated under reduced pressure to give a crude mixture, which was purified by flash column chromatography on silica gel to afford product 3a as a white solid; yield: 48.4 mg (87%).

IR (thin film): 2921, 1596, 1564, 1515, 1313, 1108, 1046, 869, 806, 758, 697, 632, 562, 497 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.76–7.72 (m, 1 H), 7.71–7.66 (m, 2 H), 7.64–7.57 (m, 4 H), 7.56–7.51 (m, 2 H), 7.50–7.44 (m, 1 H), 7.38–7.24 (m, 2 H), 2.49 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.29, 143.26, 139.9, 137.8, 136.9, 134.9, 129.6, 128.8, 127.9, 127.1, 126.9, 125.7, 125.6, 124.0, 21.1.

HRMS (EI): m/z [M]⁺ calcd for C₁₉H₁₅Cl: 278.0862; found: 278.0858.

 

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Synthesis of 3,5-Disubstituted Aniline 5a; Typical Procedure

Step 1: In a glovebox, to a Young Schlenk tube (10 mL) were added Mo(CO)₆ (5.3 mg, 0.02 mmol, 10 mol%), 3,5-di-tert-butylbenzoquinone (o-quinone, 4.4 mg, 0.02 mmol, 10 mol%), and toluene (0.4 mL) under N₂ atmosphere. The tube was sealed and transferred out of the glovebox. Then the reaction mixture was stirred at 160 °C for 15 min. After cooling to rt, ynone 1a (105.6 mg, 0.48 mmol, 2.4 equiv), PPh₃ (42 mg, 0.16 mmol, 0.8 equiv), and allylic amine 2b (21.1 mg, 0.2 mmol, 1.0 equiv) were added to the reaction mixture under N₂ atmosphere in the glovebox. The tube was sealed and transferred out of the glovebox. Then the mixture was stirred at 140 °C ( Caution: a protective shield should be installed around the Young Schlenk tube because of the risk of explosion due to the increase of vapor pressure during the reaction). After 12 h, the mixture was cooled to rt. The solvents were evaporated under reduced pressure to give a crude mixture, which was purified by flash column chromatography on silica gel to afford product 3a. Product 3a was directly used for the next step without further purification.

Step 2: Compound 3a was transferred into a Young Schlenk tube (10 mL) by using CH₂Cl₂ (3 × 0.5 mL). The solvents were then removed under a N₂ flow and subsequently under reduced pressure. Then in a glovebox, amine 4 (0.24 mmol, 1.2 equiv), RuPhos (0.9 mg, 0.002 mmol, 1 mol%), RuPhos-Pd precatalyst (1.5 mg, 0.002 mmol, 1 mol%), NaO ^t Bu (0.24 mmol, 23 mg, 1.2 equiv), and THF (0.4 mL) were added to the tube under N₂ atmosphere. The tube was sealed and transferred out of the glovebox. Then the reaction mixture was stirred at 85 °C. After the reaction was complete (monitored by TLC), the mixture was cooled to rt. The solvents were evaporated under reduced pressure to give the crude mixture, which was purified by flash column chromatography on silica gel [Note: Silica gel was soaked with a solution of Et₃N and petroleum ether (Et₃N/PE = 5:95) before using] to afford product 5a as a light yellow oil; yield: 54.4 mg (83% over both steps).

IR (thin film): 3027, 2934, 2854, 2800, 1592, 1514, 1442, 1382, 1223, 1129, 949, 815, 760, 700, 508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.74–7.65 (m, 2 H), 7.65–7.56 (m, 2 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.44–7.37 (m, 1 H), 7.34–7.26 (m, 3 H), 7.22–7.14 (m, 2 H), 3.39–3.27 (m, 4 H), 2.45 (s, 3 H), 1.86–1.76 (m, 4 H), 1.71–1.62 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.9, 142.52, 142.47, 142.0, 139.0, 137.0, 129.3, 128.6, 127.3, 127.1, 117.5, 114.42, 114.37, 50.9, 25.9, 24.3, 21.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₆N: 328.2060; found: 328.2063.

Experimental procedures for the preparation of the rest of compounds 5 and compounds 5at and 6 are provided in the Supporting Information.

 

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Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 04 November 2024

Accepted after revision: 17 December 2024

Accepted Manuscript online:
17 December 2024

Article published online:
23 January 2025