A catalyst-free approach to 3-thiocyanato-4H-chromen-4-ones

Abstract

A facile and efficient approach to 3-thiocyanato-4H-chromen-4-ones was realized at room temperature. In the presence of KSCN and K₂S₂O₈, various enaminones underwent thiocyanation and cyclization, affording 3-thiocyanatochromenones in good yields. In addition, one-pot synthesis of 3-thiocyanatochromenones from 2-hydroxylacetophenones was also developed.

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Introduction

Aryl thiocyanates are versatile intermediates for various sulfur-containing derivatives such as sulfides, thiocarbamates and related heterocyclic compounds.¹ Aryl thiocyanates can be prepared via two classic methods. One is the direct electrophilic thiocyanation of electron-rich arenes² and another is the coupling of diazonium salt with metal thiocyanates under Sandmeyer-type conditons.³ Metal-catalyzed coupling reaction of aryl halide or analogue with thiocyanate salt has been developed recently, which is a good complement to the traditional methods.⁴ In these reported approaches, preformed or prefunctionalized aromatic rings are needed. From the point of view of atom- and step-economy, a tandem thiocyanation/cyclization reaction, where the heterocyclic is constructed at the same time, is highly desirable.

Chromones and their derivatives exit widely in natural products and have been identified with a variety of biologicalactivities.⁵ Therefore, the synthesis of chromone derivatives has been studied extensively.⁶ For example, sulfenylation with TsNHNH₂, TsCl or TsNa,^6a–c regioselective oxidative amination with azoles,^5c trifluoromethylthiolation^6e were reported recently. However, the synthesis of thiocyanatochromenones is overlooked. It is well-known that functional groups affect biological activity, thus the combination of thiocyanates with chromones may generate new biologically active compounds. Nevertheless, we found the reported methods^2a,d such as I₂/KSCN, K₂S₂O₈/KSCN at elevated temperature were invalid for the thiocyanation of chromones, indicating that the thiocyanation of chromones is more difficult than we imagined. We hypothesized that dimethyl amino group in enaminones can serve as an activation group, which could facilitate the thiocyanation, and act as a leaving group for cyclization. Herein, we report a facile, efficient, and metal-free method to synthesize 3-thiocyanato-4H-chromen-4-one with simple and readily available KSCN as the sulfur source under mild conditions.

Results and discussion

Firstly, (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (1a) and KSCN were used to test our hypothesis. In the presence of K₂S₂O₈, the reaction did undergo as we expected, affording the product in 70% yield (Table 1, entry 1). After optimization of the amounts of KSCN and K₂S₂O₈, an increased yield (85%) was obtained by stirring the mixture in DCE at room temperature for 6 h. When DCE was replaced by other solvents, the reactions gave lower yields (entries 5–13). Notably, we found that a decreased yield was obtained when the reaction was conducted under an argon atmosphere (entry 14 vs. entry 4). Therefore, the optimal reaction conditions are following: 1a (0.4 mmol), K₂S₂O₈ (2 equiv.), KSCN (3 equiv.), DCE (2 mL); stirring under air atmosphere at room temperature for 6 h.

Table 1 Optimization of reaction conditions^a

Entry	KSCN (equiv.)	K2S2O8 (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.4 mmol), solvent (2 mL), open flask.b Isolated yields, n.d = no detected.c The reaction is carried out under argon atmosphere.
1	2	1.5	DCE	70
2	1	1.5	DCE	62
3	3	1.5	DCE	80
4	3	2	DCE	85
5	3	2	CH3CN	17
6	3	2	H2O	63
7	3	2	THF	n.d
8	3	2	DMF	24
9	3	2	1,4-Dioxane	19
10	3	2	HOAc	54
11	3	2	CH2Cl2	31
12	3	2	EA	7
13	3	2	EtOH	20
14^c	3	2	DCE	50
15	3	0	DCE	n.d

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With the optimized reaction conditions in hand, the scope of substrates was investigated, and the results are summarized in Scheme 1. To our delight, most of the tested substrates afforded good yields. All halo-substituted compounds gave the corresponding 3-thiocyanato-4H-chromen-4-ones in excellent yields (3c–3e, 3g–3k). The substrates bearing halo substituents at the para-position or meta-position of the phenol groups achieved similar yields (3c vs. 3g, 3d vs. 3h, 3e vs. 3i). When the benzene moiety was replaced by a naphthalene moiety for compounds 1, the corresponding 3-thiocyanatochromone 3f was obtained in good yield. Enaminones containing a CN or NO₂ substituent at the para-position of the phenol group hardly underwent this transformation (data not shown).

Scheme 1 Exploration of substrate scope. Reaction conditions: 1 (0.4 mmol), KSCN (2 equiv.), DCE (2 mL), open flask. Isolated yields.

Various enaminones 1 were prepared via the condensation of 2-hydroxyacetophenones with DMF–DMA. We wondered if the condensation and the thiocyanation would occur in one pot to provide a convenient way to 3-thiocyanatochromones. This hypothesis was investigated by the following experiments: the mixture of 2-hydroxyacetpheone (1 mmol) and DMF–DMA (1 mmol) was refluxed for 60 minutes. After cooling to room temperature, KSCN (3 mmol), K₂S₂O₈ (2 mmol), and DCE (5 mL) were added. Then the resulting mixture was stirred at room temperature for 6 hours under open flask. To our delight, 81% isolated yield of 3a was obtained (Scheme 2). Encouraged by this result, we applied this one-pot strategy to other 2-hydroxyacetophenones. As shown in Scheme 2, the tested 2-hydroxyacetophenones proceeded well, affording the desired products in moderate to good yields.

Scheme 2 Scope of 2-hydroxyacetophenones for the one-pot thiocyanation.

To demonstrate the utility of this method, we conducted the reaction on a gram scale; the yield was obtained in 89% with a slight increase (Scheme 3). Furthermore, the potential synthetic utilities of 3 were also investigated (Scheme 4, for details see the ESI†). As shown in Scheme 4, the SCN group of the product 3a could undergo cycloaddition reaction with NaN₃ to afford 3aa in 71% yield.

Scheme 3 Synthesis of 3a on a gram scale.

Scheme 4 Synthetic utility of this reaction.

To gain further insight into the reaction mechanism, several control experiments were performed (Scheme 5). When (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one instead of enaminone 1a was subjected to the reaction, the expected 2-thiocyanato-1H-inden-1-one was not observed (Scheme 5, eqn (1)). This result shows that the hydroxy group of enaminones might play a key role in the reaction. Chromone did not provide the product, indicating that chromone was not involved in the reaction process (Scheme 5, eqn (2)). When TEMPO (2,2,6,6-tetra-methyl-1-piperi-dinyloxy) was added into the reaction system, a distinctly decreased yield was obtained (Scheme 5, eqn (3)). Besides, the formation of (SCN)₂ was not observed (for experiments see ESI†).

Scheme 5 Control experiments.

On the basis of the experimental results above and previous related literature,^2d,6e,7,8 a plausible mechanism is proposed in Scheme 4. Firstly, SCN radical was generated by the oxidation of KSCN.^2d Subsequently, the addition of SCN radical to the double bond of 1 gave radical intermediate A,⁸ which was oxidized to carbocation intermediate B. Finally, the intramolecular cyclization of B followed by the elimination of N,N-dimethylamine afforded the desired product 3 (Scheme 6).

Scheme 6 Proposed mechanism.

Conclusions

In summary, we have developed a facile and efficient approach to 3-thiocyanato-4H-chromen-4-one with easily available KSCN as thiocyanation agents. 2-Hydroxyacetophenones also give moderate to good yields through one-pot two-step reactions. Importantly, the finally product can converted into other useful structures. This method enriches current chromone chemistry and sulfur chemistry, and will be a highly valuable and practical approach in pharmaceutical industry. Further studies on the applications of this reaction are in progress in our laboratory.

Acknowledgements

This work was supported financially by the National Program on Key Basic Research Project of China (973 Program, 2013CB328905) and the National Science Foundation of China (Grant No. 21202107, 21321061 and J1103315).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra13303g

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