A metal-free synthesis of diaryl-1,2-diketones by C–C triple bond cleavage of alkynones

Abstract

A novel and environmentally benign protocol for diaryl-1,2-diketones was developed. Various diaryl-1,2-diketones were afforded in moderate to excellent yields by C–C triple bond cleavage of alkynones using molecular oxygen as an oxidant. A plausible reaction mechanism was proposed that accounts for all the experimental results. The products are important building blocks in organic synthesis and could be converted to various synthons via diverse transformations.

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Diaryl-1,2-diketones represent an important structural moiety that appears in numerous bioactive compounds¹ and is broadly utilized for constructing various complex and highly valuable molecules.² Therefore, substantial efforts for the development of efficient synthetic strategies towards such a structure have been undertaken. The direct oxidation of internal alkynes, which could be accessible via the Sonogashira coupling reaction, appears to be the most straightforward method to synthesize the diaryl-1,2-diketones.³ The oxidation of benzoins or hydrobenzoins in the presence of metal catalysts, such as gold,⁴ palladium,⁵ nickel,⁶ vanadium,⁷ ruthenium,⁸ thymine iron(III),⁹ molybdenum,¹⁰ and chromium trioxide,¹¹ has also been reported. Recently, building diaryl-1,2-diketones from 1,3-diaryldiketones through the C–C bond cleavage has been explored as an alternative strategy.¹² However, the drawbacks associated with these procedures, such as the requirement of transition metals and toxic and/or expensive starting materials, low chemo-selectivity, and harsh reaction conditions, limit their wide application in chemical industries.

In the past few years, alkynones have emerged as versatile building blocks for the construction of complicated heterocyclic rings, such as triazoles,¹³ indoles,¹⁴ quinolines,¹⁵ chromones,¹⁶ furans,¹⁷ and isoxazoles.¹⁸ Recently, we have developed a tandem condensation of o-halo/methoxyarylynones with allylic alcohols to build 3-allyl-chromones catalyzed by PBu₃ under metal-free conditions.²⁰ However, the cleavage of the C–C triple bond¹⁹ in alkynones, one of the most challenging subjects in synthetic organic chemistry, has not been reported in the literature. Herein, we present a novel and environmentally friendly method for the preparation of diaryl-1,2-diketones by oxidative C–C triple bond cleavage of alkynones using molecular oxygen as an oxidant (Scheme 1).

Scheme 1 Oxidative cleavage of alkynones.

The reaction of 1,3-diphenylprop-2-yn-1-one 1a with an allyl alcohol was initially conducted at 90 °C in the presence of K₂CO₃ as a base in DMSO under an O₂ (1 atm) atmosphere. The expected product 3a was not observed, but diphenyl-1,2-diketone 2a was obtained in 63% yield (Scheme 1 and Table 1, entry 1). Further studies were focused on screening of the additives (entries 2–6). 1-Butanol, benzyl alcohol, and H₂O gave similar results. H₂O was chosen as an additive because of its advantages in terms of economy and environment (entry 6). Increasing or decreasing the ratio of H₂O–DMSO resulted in decreasing the yield of benzil 2a (entries 7–10). The bases were also screened (entries 11–22). Cs₂CO₃, Na₂CO₃, and K₃PO₄ provided 63%, 48%, and 50% yields, respectively (entries 11–13), while weaker bases showed low efficiency (entries 14 and 15) and stronger bases did not exhibit reactivity (entries 16–22). The solvent also played a crucial role in this transformation (entries 6 and 23–30). DMSO, DMF, and NMP afforded the desired product 2a in 65%, 55%, and 48% yields, respectively. Only a trace amount of 2a was observed for other solvents, such as THF, 1,4-dioxane, DCE, toluene, EtOH, and water (entries 25–30). Further optimization of the reaction parameters revealed that the combination of DMSO as a solvent and O₂ as an oxidant were necessary to get diaryl-1,2-diketone derivatives successfully. On the basis of the screening reactions above, the optimal reaction conditions were identified as follows: K₂CO₃ as a base and DMSO–H₂O (50 : 1) as the solvent under an oxygen atmosphere at 90 ^°C for 8 h.

Table 1 Screening various parameters for synthesis of diphenyl-1,2-diketone 2a from 1,3-diphenylprop-2-yn-1-one^a

Entry	Additive	Solvent	Base	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), additive/DMSO (40 μl : 2 ml), base (0.5 mmol), under an O2 atmosphere at 90 °C for 8 h. b Isolated yield based on 1a. c H2O–DMSO (50 μl : 2 ml). d H2O–DMSO (60 μl : 2 ml). e H2O–DMSO (30 μl : 2 ml). f H2O–DMSO (20 μl : 2 ml). g 60 °C. h 70 °C. DMSO = dimethylsulfoxide, NMP = 1-methylpyrrolidin-2-one.
1	Allyl alcohol	DMSO	K2CO3	63
2	Methanol	DMSO	K2CO3	25
3	Ethanol	DMSO	K2CO3	30
4	1-Butanol	DMSO	K2CO3	62
5	Benzyl alcohol	DMSO	K2CO3	50
6	H 2 O	DMSO	K 2 CO 3	65
7	H2O	DMSO	K2CO3	55^c
8	H2O	DMSO	K2CO3	50^d
9	H2O	DMSO	K2CO3	58^e
10	H2O	DMSO	K2CO3	53^f
11	H2O	DMSO	Cs2CO3	63
12	H2O	DMSO	Na2CO3	48
13	H2O	DMSO	K3PO4	50
14	H2O	DMSO	Et3N	15
15	H2O	DMSO	Li2CO3	20
16	H2O	DMSO	EtONa	None
17	H2O	DMSO	NaH	None
18	H2O	DMSO	KOtBu	None
19	H2O	DMSO	NaOtBu	None
20	H2O	DMSO	LiOtBu	None
21	H2O	DMSO	NaOH	None
22	H2O	DMSO	KOH	None
23	H2O	DMF	K2CO3	55
24	H2O	NMP	K2CO3	48
25	H2O	THF	K2CO3	Trace^g
26	H2O	Dioxane	K2CO3	Trace
27	H2O	DCE	K2CO3	Trace
28	H2O	Toluene	K2CO3	Trace
29	H2O	EtOH	K2CO3	Trace^h
30	—	H2O	K2CO3	Trace

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With the optimized reaction conditions in hand, the generality and scope for the substrates were investigated as illustrated in Table 2. Generally, alkynones with electron-donating substituents (OMe, Me, tBu) (entries 2–6) provided the corresponding products in higher yields than those bearing electron-withdrawing groups (F, Cl) (entries 7–10). As for regioisomeric substrates, alkynones with substituents in Ar–R¹ (entries 3, 5, 8, and 10) could be transformed into the corresponding diaryl-1,2-diketone products in similar yields as those with substituents in Ar–R² (entries 2, 4, 7, and 9). Additionally, alkynones with substituents in Ar–R¹ and Ar–R² were also investigated under the standard reaction conditions. The corresponding diaryl-1,2-diketones were obtained in moderate to excellent yields regardless of the electron-donating or electron-withdrawing groups at benzene rings (entries 11–15). It is worth noting that alkynone with two methoxyl groups provided an excellent yield because of the strong electron-donating effect (entry 11). However, when the substituents were at the ortho position of the aromatic ring, the yield decreased maybe due to the steric hindrance (entries 16–18). Moreover, alkynones possessing a naphthyl and thienyl ring were tolerated in this oxidation reaction system and provided the desired products 2o and 2p in 60% and 51% yields, respectively (entries 19 and 20). The transformation of alkynones with the aliphatic group was also attempted, but no desired products were observed.

Table 2 Generality and scope of alkynones to diaryl-1,2-diketones^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 (0.5 mmol), H2O–DMSO (40 μl : 2 ml), K2CO3 (0.5 mmol), under an O2 atmosphere for 8 h. b Isolated yield on 1.
1			65
2	R^1 = OMe, R^2 = H, 1b	2b	70
3	R^1 = H, R^2 = OMe, 1b′		72
4	R^1 = Me, R^2 = H, 1c	2c	67
5	R^1 = H, R^2 = Me, 1c′		69
6	R^1 = t-Bu, R^2 = H, 1d	2d	66
7	R^1 = Cl, R^2 = H, 1e	2e	38
8	R^1 = H, R^2 = Cl, 1e′		45
9	R^1 = F, R^2 = H, 1f	2f	40
10	R^1 = H, R^2 = F, 1f′		44
11	R^1 = OMe, R^2 = OMe, 1g	2g	93
12	R^1 = Me, R^2 = Me, 1h	2h	60
13	R^1 = t-Bu, R^2 = OMe, 1i	2i	65
14	R^1 = F, R^2 = OMe, 1j	2j	53
15	R^1 = F, R^2 = F, 1k	2k	40
16	R = OMe, 1l	2l	52
17	R = Me, 1m	2m	50
18	R = F, 1n	2n	35
19			60
20			51

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The initially proposed mechanism suspected that 1,3-diaryldiketone might serve as an intermediate in this transformation. Unexpectedly, no desired product 2a was detected when 1,3-diphenyldiketone was subjected under the optimal reaction conditions (Scheme 2, eqn (1)). To gain more insight of the reaction mechanism, 1,3-diphenylprop-2-yn-1-one and 1,3-bis(4-methoxyphenyl)prop-2-yn-1-one were treated in one pot under the standard reaction conditions (Scheme 2, eqn (2)). The potential crossover products were not detected by GC-MS, which indicated that this transformation probably occurred through an intramolecular process. In order to confirm the source of the oxygen atom of diaryl-1,2-diketone, the controlled experiments were conducted involving H₂O¹⁸ and O₂¹⁸, respectively. The results showed that the oxygen atom of the diaryl-1,2-diketone derived from O₂, but not from H₂O. Furthermore, CO₂ was generated and caused the clear limewater to become cloudy (Scheme 2, eqn (3) and (4)).

Scheme 2 The controlled experiments for exploring the reaction mechanism.

According to the results obtained and the literature,²¹ the mechanistic pathways of this oxidative cleavage metathesis are proposed and presented in Scheme 3. The initial step of the reaction involved the formation of 1,2-dioxetene A from the alkynone 1 with molecular oxygen. Then thermally inducing the transformation of intermediate A gave 1,2,3-tricarbonyl compound B. Subsequently, activation of the β-keto or the α-keto moiety of compound B in the presence of K₂CO₃ led to intermediates C, D, and D′, followed by C–C bond cleavage and the carbon immigration to intermediates E, F and F′, respectively. Finally, the elimination of carbon monoxide (CO) from intermediates E, F and F′ provided the desired diaryl-1,2-diketone 2 and 2′. Simultaneously, the gas carbon dioxide (CO₂) was formed by the oxidation of CO with molecular oxygen.

Scheme 3 Plausible reaction mechanism.

In conclusion, we have developed a novel and environmentally benign method for the synthesis of diaryl-1,2-diketones with high chemo-selectivity by C–C triple bond cleavage of alkynones. The oxidation of triple bond, cleavage of C–C bond and carbon immigration were involved in this procedure.

Acknowledgements

Financial support was provided by NSF of China (21202048), Program for Minjiang Scholar program (10BS216), Xiamen Southern Oceanographic Center (13GYY003NF16), NSF of Fujian Province, China (2013J01050) and Fundamental Research Funds of Huaqiao University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details See DOI: 10.1039/c4qo00174e

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