TBAI-Catalyzed Oxidative Coupling of Benzyl Ketones to Synthesize 2,3-Diaryl-1,4-Diketones in Water

Abstract

An efficient and green route of C–C bond formation was disclosed to construct 2,3-diaryl-1,4-diketones from α-methylene ketones by the catalysis of tetrabutylammonium iodide (TBAI) with tert-butyl hydroperoxide (TBHP) as an oxidant in water. This reaction affords the desired products in good to excellent yields from readily available materials, with a broad substrate scope, good functional group tolerance, and mild reaction conditions. Furthermore, tetrasubstituted furan and pyrrole were smoothly constructed from α-methylene ketones in one pot with 96 and 90% yields, respectively.

Introduction

2,3-Diaryl-1,4-diketones are intermediates of great important in organic chemistry and material science fields. They have been widely used to construct various five-membered heterocycles, such as furans,¹ pyrroles,² and pyrrolones.³ Additionally, 2,3-disubstituted-1,4-diketones are also key substructures in natural products and pharmaceuticals.⁴ Therefore, many synthetic methods have been developed to produce 2,3-diaryl-1,4-diketones. Generally, the transition-metal-catalyzed C–C bond formation has been a powerful strategy to prepare the target compounds.⁵ In 2011, Lei’s group,⁶ for example, developed a novel Pd-catalyzed C–C bond formation method from zinc ketone enolates and α-chloroketones in THF for 10–16 h to construct 2,3-diaryl-1,4-diketones (Scheme 1a). Yamaguchi’s group subsequently reported that a smooth RhH(PPh₃)₄ catalyzed the oxidative coupling reaction of aryl benzyl ketones,⁷ producing 2,3-diaryl-1,4-diketones in PhCl at refluxing temperature (Scheme 1b). Additionally, 3,3-dimethyl-1-methylthio-2-butanone was used as the oxidant, which was converted to 3,3-dimethyl-2-butanone, releasing environmentally unfriendly and foul-smelling dimethyl disulfide. In 2015, Wang’s group⁸ achieved the Cu-promoted C–C bond formation from two C(sp³)-H bonds access to 2,3-diaryl-1,4-diketones with excellent yields in xylene at 140 °C, and then the Ag-catalyzed coupling reaction of two C(sp³)-H bonds was also disclosed by this group⁹ under a similar system, affording the desired products (Scheme 1c).

Scheme 1. Construction of 2,3-Diaryl-1,4-diketones.

Although great progress has been made to form C–C bonds from C(sp³)–H bonds,¹⁰ the metal-free-catalyzed oxidative coupling of two C(sp³)–H bonds for the synthesis of 2,3-diaryl-1,4-diketones is still challenging. Moreover, most of the reported reactions still have some drawbacks, such as high reaction temperatures, long reaction times, expensive catalysts, and complex ligands. Consequently, the development of a much more efficient method to synthesize 2,3-diaryl-1,4-diketones under mild conditions with environmentally friendly and low-cost reagents is highly desirable.

In addition, the avoidance of toxic organic solvents and the use of more green solvents are important factors from the perspective of sustainable synthesis. Water has been considered as a green solvent in synthetic organic chemistry owing to its abundance, low cost, nontoxicity, and nonflammability.¹¹ Meanwhile, when compared to transition-metal catalysts, tetrabutylammonium iodide (TBAI)¹² has been regarded as a powerful nonmetal catalyst in organic synthesis for the construction of various compounds. In accordance with green and sustainable principles, we developed TBAI-catalyzed dehydrogenation oxidative coupling of benzyl ketones to synthesize 2,3-diaryl-1,4-diketones using tert-butyl hydroperoxide (TBHP) as an oxidant in water (Scheme 1d).

Results and Discussion

Initially, deoxybenzoin 1a was treated as a model substrate to investigate the oxidative coupling reaction conditions. To our delight, the desired product 2a was obtained in 88% yield with 50 mol % TBAI as a catalyst, 3.0 equiv TBHP as an oxidant in H₂O at 100 °C for 5 h (Table 1, entry 1). When the loading of oxidant TBHP was increased to 4.0 equiv, the yield of 2a was decreased to 78% (Table 1, entry 2). However, 2.0 equiv TBHP could give the corresponding product 2a in 84% yield (Table 1, entry 3). Subsequently, the amount of catalyst TBAI was screened and optimized (Table 1, entries 4–6). It was found that the 30 mol % TBAI was the best catalyst amount, producing the target product 2a in 94% yield (Table 1, entry 5). Reducing the reaction temperature to 60 °C also gave the desired product 2a in 93% yield (Table 1, entry 7), whereas a significantly decreased yield (78%) was obtained at room temperature (Table 1, entry 8). Additionally, the reaction did not occur in the absence of catalyst TBAI (Table 1, entry 9), and 2a was synthesized only in a 17% yield without TBHP (Table 1, entry 10). Consequently, the optimized conditions were achieved when the reactions were carried out with 30 mol % TBAI as a catalyst and 3.0 equiv TBHP as an oxidant in H₂O at 60 °C for 5 h (Table 1, entry 7).

Table 1. Optimization of Reaction Conditions for the Synthesis of 2a^a.

entry	catalyst (mol %)	[O] (equiv)	T (°C)	yield (%)b
1	TBAI (50)	TBHP (3)	100 °C	88
2	TBAI (50)	TBHP (4)	100 °C	78
3	TBAI (50)	TBHP (2)	100 °C	84
4	TBAI (100)	TBHP (3)	100 °C	86
5	TBAI (30)	TBHP (3)	100 °C	94
6	TBAI (20)	TBHP (3)	100 °C	83
7	TBAI (30)	TBHP (3)	60 °C	93c
8	TBAI (30)	TBHP (3)	rt	78
9		TBHP (3)	60 °C	NR
10	TBAI (30)		60 °C	17

^aUnless otherwise specified, reactions were carried out using 1a (0.3 mmol), catalyst (TBAI), and oxidant (TBHP) in H₂O (2.0 mL).

^bIsolated yields.

^cDiastereomeric ratio (dr = 0.29:1) was determined by ¹H NMR spectroscopic analysis.

Under optimal reaction conditions (Table 1, entry 7), the scope of the oxidative coupling reaction of α-methylene ketones to construct 2,3-diaryl-1,4-diketones was explored, and the results are shown in Scheme 2. First, various substrates 1 with different substituents R¹ on the aromatic ring Ar¹ were examined. To our delight, both electron-rich and electron-deficient groups (R¹) in substrates 1 successfully afforded the desired products in moderate to excellent yields (2a–2l). Among them, substrates 1 bearing electron-rich groups R¹ (such as −CH₃, −OCH₃, −^tBu) gave the corresponding products 2b–2e in 88, 95, 94, and 82% yields, respectively. In addition, when phenyl-substituted α-methylene ketone 1f was employed, the expected product 2f was smoothly obtained, albeit with a somewhat low yield (40%). Furthermore, substrates 1g–1k carrying different halide substitutions (−F, −Cl, −Br, −I) on the aromatic ring Ar¹ were efficiently transformed into the target products 2g–2k in 60–92% yields. Notably, acetyl-substituted 1l was well proceeded, producing the desired product 2l in 53% yield, probably due to both electron-withdrawing effect and α-methyl competition of the acetyl group. Encouragingly, further studies indicated that substrates (1m–1p) containing furan, thiophene, and naphthalene smoothly generated the corresponding products 2m–2p in 44–85% yields.

Scheme 2. Substrate Scope of α-Methylene Ketones Bearing Various Aromatic Ring Ar^1.,,

Reaction conditions: 1 (0.3 mmol), TBAI (0.09 mmol), TBHP (0.9 mmol), H₂O (2 mL), 60 °C, and 5 h.

Isolated yields.

Diastereomeric ratio (dr) was determined by ¹H NMR spectroscopic analysis.

Subsequently, the scope of the oxidative coupling reaction of α-methylene ketones bearing both electron-donating and electron-withdrawing groups R² on the aromatic ring Ar² was investigated (Scheme 3). When substrates 1q and 1r with −CH₃ and −OCH₃ on the phenyl ring Ar² were carried out under the standard reaction conditions, the expected products 2q and 2r were synthesized in 82 and 84% yields, respectively. Moreover, various electron-withdrawing groups such as −F, −Cl, −Br, and −NO₂ were also well-tolerated, furnishing the desired products 2s–2v in moderate to excellent yields (52–98%). Compared with the electron-donating groups (such as −CH₃, −OCH₃), the electron-withdrawing groups (such as −F, −NO₂) could reduce the electron density of the benzene ring to enhance the acidic nature of α-methylenes, easily forming the enolized structure 1a′ (Scheme 6) to generate subsequently the desired products 2 under the standard reaction conditions. Remarkably, substrates 1w and 1x containing the −Cl group at the meta and ortho positions were all compatible in this reaction, and the corresponding products 2w–2x were easily formed in 91–95% yields.

Scheme 3. Substrate Scope of α-Methylene Ketones Bearing Various Aromatic Ring Ar^2,,

Reaction conditions: 1 (0.3 mmol), TBAI (0.09 mmol), TBHP (0.9 mmol), H₂O (2 mL), 60 °C, and 5 h.

Isolated yields.

Diastereomeric ratio (dr) was determined by ¹H NMR spectroscopic analysis.

Scheme 6. Proposed Mechanism.

To further expand the potential applicability of this method, a gram-scale reaction of 1a was performed under the standard reaction conditions for 6 h, giving the expected product 2a (1.08 g) in 85% yield (Scheme 4a). Meanwhile, some transformations of 1a were also studied (Scheme 4b,c), and the tetrasubstituted furan 3 and pyrrole 4 were produced in a one-pot procedure with 96 and 90% yields, respectively.

Scheme 4. Gram-Scale Reaction and Derivatization.

In addition, to illustrate the reaction mechanism, several control experiments were employed (Scheme 5). When substrates 5 and 6 were used under the optimized reaction conditions, no desired products were observed, indicating that the phenyl was crucial for the transformation of α-methylene ketones (Scheme 5, 1 and 2). This result illustrated that the conjugate enolized structure 1a′ (Scheme 6) was easy to form due to the aryl groups under the standard reaction conditions. As a result, all of the reactions proceeded smoothly and afforded the corresponding products in good to excellent yields. Furthermore, radical-trapping experiments were conducted to probe the reaction type. The 1.5 equiv TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was used as the radical scavengers, still forming the expected product 2a in excellent yield (94%), and increasing the amount of TEMPO to 3.0 equiv afforded 2a in 95% yield (Scheme 5, 3). These results suggested that a radical pathway might not be involved during the reaction.

Scheme 5. Control Experiments.

Based on the above results and previous literature reports,¹³ a plausible mechanism was described in Scheme 6. First, TBAI was oxidized to [ⁿBu₄N]⁺[IOx]⁻ (x = 1, 2) by TBHP. Subsequently, the enolized form 1a′ coordinated with [ⁿBu₄N]⁺[IO_x]⁻ to give the intermediate A. Finally, 1a′ nucleophilically attacked the intermediate A to generate the expected product 2a.

Conclusions

In summary, we have developed an efficient and green TBAI-catalyzed dehydrogenation oxidative coupling reaction from readily available benzyl ketones with TBHP as an oxidant for the synthesis of 2,3-diaryl-1,4-diketones in water. This method exhibits broad substrate scope, good functional group tolerance, and mild reaction conditions under an environmentally friendly catalytic system, providing various desired products in moderate to excellent yields. Meanwhile, a gram-scale synthesis was further studied, and an excellent yield was obtained under the standard reaction conditions. Additionally, the tetrasubstituted furan and pyrrole were constructed in a one-pot procedure with 90–96% yield. Further studies on the mechanism and applications of this reaction are in progress by our group.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c06216.

• Full experimental details and characterization data for all products (PDF)

The authors declare no competing financial interest.