One-step metal-free construction of fluorescent 5-aryl-2,3-dicyanofurans from simple aryl ketones with DDQ

Abstract

A variety of fluorescent 5-aryl-2,3-dicyanofurans were prepared by the treatment of electron-rich aryl ketones with DDQ. The presence of an alkoxy substituent on the benzene ring in the substrates was essential for an efficient cyclization to occur. This novel approach allows the metal-free construction of furan rings from simple aryl ketones.

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Direct utility of C–H functionalization to create C–C and C–heteroatom bonds is of great significance and also a challenge to synthetic chemists. Direct C–H functionalization represents a highly attractive strategy for an ideal chemical synthesis. Compared to traditional chemical reactions, such coupling reactions based on C–H activation¹ have an inherent advantage in that they do not require substrates with highly functionalized groups, such as organohalides or organometallic species. However, these coupling reactions^1g–i usually involve the presence of terminal alkyne C_sp–H bonds, arene/alkene C_sp2–H bonds and C_sp3–H bonds adjacent to heteroatoms (N, O and S) or π-systems. Ketones with α-H atoms undergo such oxidative coupling but usually act as nucleophiles.²

α-Functionalization of carbonyl compounds represents one of the most versatile and valuable procedures in organic synthesis. With such a strategy, various important synthetic building blocks such as 1,4-dicarbonyl compounds,³ 1-arylated or alkynylated ketones/esters⁴ could be readily prepared. Although some progress has been made, such functionalization is currently limited to readily available α-halocarbonyl compounds. The direct oxidative α-C–H functionalization of carbonyl compounds usually refers to such transformations as halogenation and oxygenation. The application of oxidative functionalization of simple ketones to construct heterocycles is still rare.⁵

Furans are important fundamental structures with many interesting optoelectronic and biological properties.⁶ Further-more, they occur widely in a variety of natural products, pharmaceuticals and organic solar cell dyes, and also serve as versatile building blocks in organic synthesis. Generally, further functionalization of the furan ring itself is an efficient approach to the synthesis of furans by means of Stille or Heck reactions.⁷ Alternatively, metal-catalyzed intramolecular annulation of alkyne-containing substrates or their equivalents has also been developed.⁸ However, the requirement to pre-functionalize the starting materials in these two strategies limited their application. Besides, oxidative intermolecular cyclization using basic starting materials, mediated by the use of metal catalysts, provided another facile approach to furans.⁹ It is no doubt that such direct oxidative formation of C–C/C–O bonds in one step via C–H functionalization would be an attractive approach to synthesize the furan scaffold.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a well-known oxidant in organic chemistry. In recent years, it has been successfully used in cross dehydrogenative coupling (CDC) for C–X (X = C, N, O, S, etc.) bond formation based on C–H activation.^2g,10 During our continued investigation to DDQ-mediated CDC reactions,¹¹ we accidentally discovered that DDQ can also serve as a maleonitrile building block¹² when simple electron-rich aryl ketones were used as reactant partner, which meanwhile led to an efficient approach toward preparing 5-aryl-2,3-dicyanofurans from simple aryl ketones. To the best of our knowledge, only very few examples regarding 2,3-dicyanofurans have been documented.^12,13

Herein, we report our efforts on the construction of polysubstituted furan derivatives from simple aryl ketones via C–H functionalization/C–C and C–O bond formation by using DDQ without the requirement of a metal catalyst (Scheme 1).

Scheme 1 A novel approach for the construction of furan derivatives.

With this discovery in mind, we set out to optimize the reaction parameters based on a model reaction of 1-(4-methoxyphenyl)ethanone (1a) with DDQ in 1,2-dichloroethane (DCE) in a sealed tube.

Selected results are compiled in Table 1. Firstly, the variation of the amount of DDQ was investigated. When the ratio of DDQ/1a was 1.2, 2.0 and 2.5, the conversion of 1a to 5-(4-methoxyphenyl)furan-2,3-dicarbonitrile (2a) went gradually to completion (Table 1, entries 1–3). When 3.0 equivalents of DDQ were used, the reaction went to completion and the optimum yield (52%) of 2a was obtained (Table 1, entry 4). Continued increasing the DDQ amount (4.0 equiv.) did not afford better yield. Next, several other solvents such as benzene, HOAc, MeCN, MeNO₂, EtOAc and dichloromethane (DCM) were examined (Table 1, entries 5–10) using the optimum 3/1 ratio of DDQ/1a. Compared to DCE, MeCN, MeNO₂ and DCM gave moderate yields while with HOAc and EtOAc the yields were poor. Furthermore, reacting 1a with neat DDQ furnished a 36% yield of 2a. The effects of reaction temperature and time on the yield of 2a were also investigated. When the reaction was carried out at 80 or 120 °C, 2a was produced in a lower yield (Table 1, entries 12 and 13). No reaction was observed at ambient temperature. When the reaction time was shortened to 10 h or increased to 15 h, the yield of 2a still remained essentially the same. In an attempt to further improve the reaction yield, metal catalysts such as CuBr, CuBr₂, CuCl₂ and Cu(OAc)₂ were used. Much to our disappointment, they were ineffective and even led to a decrease in the yield (Table 1, entries 16–19). Thus, the optimal conditions for such transformation were established to be as follows: a DDQ/ketone molar ratio of 3.0, in DCE as solvent, at a temperature of 100 °C for 13 h under N₂ without any metal catalyst. Under such optimal reaction conditions, the yield of 2a was 52%.

Table 1 Reaction parameters of 1a with DDQ^a

Entry	DDQ/1a^b	Solvent	Temp (°C)	Time (h)	Yield^c (%)
a Reaction conditions: 1a (0.5 mmol), solvent (2 mL), N2 in sealed tube. b The molar ratio. c Isolated yield. d CuBr (5 mol %). e CuBr2 (5 mol %). f CuCl2 (5 mol %). g Cu(OAc)2 (5 mol %).
1	1.2	DCE	100	13	20
2	2.0	DCE	100	13	31
3	2.5	DCE	100	13	37
4	3.0	DCE	100	13	52
5	3.0	benzene	100	13	36
6	3.0	HOAc	100	13	14
7	3.0	MeCN	100	13	43
8	3.0	MeNO2	100	13	47
9	3.0	EtOAc	100	13	21
10	3.0	DCM	100	13	44
11	3.0	Neat	100	13	36
12	3.0	DCE	80	13	43
13	3.0	DCE	120	13	40
14	3.0	DCE	100	10	50
15	3.0	DCE	100	15	52
16^d	3.0	DCE	100	13	32
17^e	3.0	DCE	100	13	32
18^f	3.0	DCE	100	13	22
19^g	3.0	DCE	100	13	13

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Next, we sought to probe the scope and limitations of the substrate on these DDQ-mediated annulation reactions. The reaction was attempted using acetophenone, 1-(p-tolyl)ethanone and 1-(4-chlorophenyl)ethanone in place of 1a. However, it was found that they were unreactive and none of the desired furan derivatives were obtained. These results implied that the presence of the electron-donating methoxy substituent on the benzene ring of the substrate was crucial for such oxidative intermolecular cyclization to occur.

These findings pointed to the importance of an electron-rich substrate so we investigated changing the position of the methoxy group on the benzene ring and tested the ortho- and meta-analogues of 1a. Delightedly, substrate 1b, with the methoxy substitutent in the ortho-position, was found to be effective and gave the desired product 2b in moderate yield. However, we were disappointed to find that the meta-methoxy group 1c yielded none of the desired product under the same conditions, even using a longer reaction time and a higher reaction temperature. Furthermore, 1-(3,5-dimethoxyphenyl)-ethanone (1d), with two methoxy groups located at the meta-positions of the benzene ring, also gave no desired furan product. On the basis of the above experimental facts, therefore, we tentatively conclude that an ortho- and/or a para-alkoxy group is essential for such oxidative annulation. Gratifyingly, replacement of a methoxy group with an ethoxy group afforded similar yield (Table 2, 2bvs.2e). However, replacing a methoxy group with a benzyloxyl one resulted in a relatively lower yield (Table 2, 2f). This was attributed to competitive DDQ-mediated debenzylation under such oxidative conditions,¹⁴ which could be supported by the fact that 1-(2-hydroxyphenyl)ethanone was detected. Introduction of a methyl group into the benzene ring of substrate 1f could promote this transformation and enhance the yield of 2g (Table 2, 2fvs.2g). Furthermore, two alkoxy substituents located at different positions on the benzene ring were investigated (Table 2, 2h–k). All the substrates tested gave satisfactory yields. Substrates 1h, i, k, with both alkoxy groups at ortho-/para- or ortho-/ortho-positions, gave relatively better yields. In particular, substrate 1i, 1-(2,4-diethoxyphenyl)ethanone, gave rise to 2i, 5-(2,4-diethoxyphenyl)furan-2,3-dicarbonitrile, in 62% yield. It is notable that substrate 1j with two ortho-/meta-methoxy groups afforded 2j in a less than satisfactory yield of 26%. To directly functionalize furan ring at 4-position, 1-(4-methoxyphenyl)-propan-1-one (1l) was used for this oxidative reaction under the established conditions. As is all known, substrate 1l is vulnerable to oxidative elimination, providing α, β-unsaturated ketone using DDQ. Interestingly, substrate 1l reacted smoothly to form a tetrasubstituted furan 2l in 47% yield. The oxidative reaction went equally well with substrates 1m–n, in which the naphthyl ring could be considered as an electron-rich benzene ring,¹⁵ with a ortho- or para-methoxy group. In addition, attempts were made to use 1-(2-hydroxyphenyl)ethanone, 1-(2-hydroxy-4-methoxyphenyl)ethanone, and 2-acetylphenyl acetate as substrates for this protocol. As expected, it was found that no desired furan products were obtained and the ketones were largely unreacted.

Table 2 Scope of the oxidative cylization of various aryl ketones 1 with DDQ^ab

a Reaction conditions: ketones 1 (0.5 mmol), DDQ (1.5 mmol), DCE (2 mL), N₂ in sealed tube. b Isolated yield.

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To further identify product structure, the molecular structure of furan 2f was determined by X-ray diffraction as shown in Fig. 1 together with the atom numbering scheme using Mercury software.¹⁶ The central C8⋯C13 benzene ring is inclined to the furan ring at 4.32(17)° such that the phenyl-furan-dicarbonitrile unit is close to planar.

Fig. 1 X-ray structure of compound 2f.

To probe whether radical species are produced in this oxidative cyclization, the radical scavenger TEMPO was utilized in the cyclization of 1a (Scheme 2). As expected, the formation of the desired product 2a is completely inhibited by the addition of 6 equivalents of TEMPO. This result indicates that this reaction may involve radical intermediates.

Scheme 2 Radical-trapping experiment.

Based on the above experimental results and our earlier work,^12a a tentative mechanism for this protocol is proposed, as depicted in Scheme 3. Firstly, 1a reacts with DDQ to form an adduct (geminate radical ion pair) via single electron transfer (SET), followed by radical combination and subsequent proton transfer to give rise to the intermediate I. Secondly, I undergoes intramolecular addition followed by proton transfer, affording the intermediate II. Thirdly, with the aid of a second molecule of DDQ, II converts from the diol form to a dione form and a subsequent retro-Diels Alder reaction occurs to yield the product 2a, together with the intermediate IV. Hydrolysis of IV followed by intramolecular cyclization produces 2,3-dichloro-5-hydroxyfuran-2(5H)-one V. Finally, V is subjected to dehydrogenation at the presence of a third molecule of DDQ, affording the side-product 2,3-dichloromaleic anhydride. This interpretation of the reaction is further supported by the observation that washing the reaction mixture with a dilute solution of aqueous NaHCO₃ could simplify the work-up.

Scheme 3 Proposed mechanism for the formation of 2,3-dicyanofurans solely using 3 equivalents of DDQ.

It's well known that fluorescent substances are of vital importance in a variety of fields.¹⁷ Facile and efficient construction of fluorescent core frameworks using new synthetic methodologies is starting to attract great interest.¹⁸ To our delight, all the obtained 5-aryl-2,3-dicyanofurans were found to possess significantly strong photonic fluorescence both in solution and in the solid state (see Fig. S1 in the ESI†).

Such fluorescent properties are due to the molecular coplanarity as revealed in X-ray crystallographic analysis, facilitating a “push–pull” π-electron system. Novel fluorescent probe molecules and solar cell dyes will be achieved using this reaction protocol combined with the metal-catalyzed coupling technique.

In conclusion, we have developed a metal-free and efficient approach to the synthesis of fluorescent 5-aryl-2,3-dicyano-furans using DDQ in moderate to good yields. This novel protocol allows the construction of a furan core from simple aryl ketones in one step. Further investigations into the reaction mechanism and applications of this protocol in the production of fluorescent probes and solar cell dyes are still on-going.

Acknowledgements

Supports of this work by the National Natural Science Foundation of China (21202010 & 21275022), and the Hunan Provincial Natural Science Foundation of China (12JJ4021) are gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra45462b

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