Persulfate-mediated synthesis of polyfunctionalized benzenes in water via the benzannulation of alkynes and α,β-unsaturated compounds

Gabriela F. P. de Souza and Airton G. Salles Jr *
Department of Organic Chemistry, Institute of Chemistry, University of Campinas, P.O. Box 6154, Campinas, São Paulo 13084-862, Brazil. E-mail:

Received 29th June 2019 , Accepted 1st August 2019

First published on 1st August 2019

A persulfate-promoted metal-free route in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported. In our approach, the targeted products are delivered in high to moderate yields from phenylacetylenes and α,β-unsaturated compounds via the benzannulation reaction. This method has a good scope and gives access to functionalized benzene rings that offer a wealth of opportunities for further functionalization.

Functionalized benzenes are one of the most important classes of compounds in pharmaceuticals, natural products, and functional organic materials1 and the most widely employed precursors in synthetic chemistry.2 Consequently, many approaches have been investigated for the construction of polysubstituted benzene derivatives.3 Well-established aromatic nucleophilic or electrophilic substitution,4 cross-coupling reactions5 and directed metalation6 are prevailing approaches to access substituted benzenes. However, the application of these strategies suffers from regioselectivity issues, limited substrate scope and overreaction. Metal-free or transition-metal catalyzed tandem cyclization reactions have been developed over the years and arguably represent an attractive alternative because of the expedient construction of functionalized benzenes in an atom-economical fashion.7 In this context, benzannulation reactions represent an effective and environmentally suitable protocol to transform acyclic building blocks into structurally valuable benzene skeletons. An ample range of benzannulation reactions have been reported in the literature featuring different chemical feedstocks, catalysts and mechanisms, and as such, this methodology represents a suitable candidate to expand even more the set of tools used to synthesize polysubstituted benzene compounds.8 Herein, we set to explore a metal-free, persulfate mediated benzannulation approach in water to access unprecedented functionalized benzene rings (Scheme 1). Persulfate salts are stable, easy to handle and generate only sulphate as the by-product, thus agreeing with the green chemistry initiative to minimize toxic reagents. By applying our methodology, we were able to employ cheap chemical feedstocks (α,β-unsaturated compounds and alkynes) to obtain a large array of substituents on the central benzene ring in high to moderate yields. Performing a reaction using water as a solvent does not fully guarantee the sustainability of the process as the water, after the reaction, must be clean enough to be reprocessed. Under the optimized conditions, our methodology allows water to come out of the reaction ready to be reused, thus contributing to pollution prevention. Finally, isolation of compounds was performed employing a plug of silica, hence preventing a large amount of waste generation. All the molecules obtained represent a class of compounds that might play a useful role in medicinal chemistry as modulators of insulin receptor function with possible utility in the treatment of hyperglycemia9 and may also exhibit antiapoptotic activity on neuronal cells.10
image file: c9gc02193k-s1.tif
Scheme 1 Previous work and our approach for the benzannulation reaction.

Our studies began by examining the reactivity of phenylacetylene 1a and fumaronitrile 2a in the presence of (NH4)2S2O8 in water (Table 1). By using 1 equiv. of 1a, 1 equiv. of 2a along with (NH4)2S2O8 (2 equiv.) at 85 °C, 69% of the polysubstituted benzene 3a was formed as only one regioisomer (Table 1, entry 1). The structure of 3a was characterized by NMR spectroscopy. Varying the number of equivalents of 1a had a strong impact on the reaction efficiency and, to our delight, the use of 1a[thin space (1/6-em)]:[thin space (1/6-em)]2a in a ratio of 2[thin space (1/6-em)]:[thin space (1/6-em)]1 led to a good improvement in the yield (Table 1, entry 2). 1a[thin space (1/6-em)]:[thin space (1/6-em)]2a in a suitable ratio of 2[thin space (1/6-em)]:[thin space (1/6-em)]1 matches with the presence of two phenylacetylene benzene rings in the final product 3a giving a clue about the mechanism (vide infra). On the other hand, increasing the amount of 2a led to an inferior result (Table 1, entry 3). Variations of the amount of (NH4)2S2O8 had a detrimental effect on the process (Table 1, entries 4 and 5). Changing the reaction temperature to 25 °C completely shut down the transformation (Table 1, entry 6). Lastly, increasing the reaction temperature to 95 °C did not improve the yield (Table 1, entry 7).

Table 1 Optimization of the reaction conditionsa

image file: c9gc02193k-u1.tif

Entry Ratio 1a[thin space (1/6-em)]:[thin space (1/6-em)]2a NH4S2O8 (equiv.) Temperature (T, °C) Yieldb (%)
a General conditions for the optimization: In the sequence, 1.0 mL of water, 1a (0.5 or 1.0 mmol), 2a (0.5 or 1.0 mmol), (NH4)2S2O8, 8 h. b Yield of the isolated product.
1 1[thin space (1/6-em)]:[thin space (1/6-em)]1 2.0 85 69
2 2[thin space (1/6-em)]:[thin space (1/6-em)]1 2.0 85 90
3 1[thin space (1/6-em)]:[thin space (1/6-em)]2 2.0 85 65
4 2[thin space (1/6-em)]:[thin space (1/6-em)]1 1.0 85 56
5 2[thin space (1/6-em)]:[thin space (1/6-em)]1 3.0 85 72
6 2[thin space (1/6-em)]:[thin space (1/6-em)]1 2.0 25 0
7 2[thin space (1/6-em)]:[thin space (1/6-em)]1 2.0 95 88

With the optimized conditions established, we explored the scope of the reaction (Scheme 2). Several unprecedented polyfunctionalized benzenes can be obtained using our approach. Electron-deficient and electron-neutral phenylacetylenes gave the reaction products in an excellent yield. Sterically encumbered 1-bromo-2-ethynylbenzene was also obtained in an excellent yield (Scheme 2, 3n). The rate of the reaction employing electron-rich 1-ethynyl-4-methoxybenzene was notably reduced and to overcome this limitation, we used 4 equiv. of (NH4)2S2O8 and a reaction time of 24 h in order to achieve an acceptable yield (Scheme 2, 3d). This outcome indicates that the electronic nature of the phenylacetylenes plays a significant role in the reactivity. Both cyclic and acyclic α,β-unsaturated ketones gave a diversity of polysubstituted benzenes in a very good yield (Scheme 2), thus evidencing no influence of the ring rigidity on the reactivity. Interestingly, only one regioisomer coming from methyl vinyl ketone or cyclohexenone was obtained (Scheme 2, 3e–h and 3i–n). The nitrile-containing unsaturated compound (fumaronitrile) afforded the products in a high yield and no by-products were observed (Scheme 2, 3a–d).

image file: c9gc02193k-s2.tif
Scheme 2 Scope of the transformation. General conditions: 2 ml of water, 1 (2.0 mmol), 2 (1.0 mmol), (NH4)S2O8 (2.0 mmol, aqueous solution 1.3 M), 85 °C, 8 h. Yields of the isolated products. a[thin space (1/6-em)]Using 4.0 mmol of (NH4)S2O8, 24 h reaction time.

A more sterically encumbered α,β-unsaturated compound (4-phenylbut-3-en-2-one 2d, Scheme 2) was also tested. The reaction was very sluggish and gave the targeted product along with an inseparable by-product using a plug of silica. As we were intending to avoid the use of a regular amount of silica and solvents and consequently reduce the E-factor, we decided to rank it as an unsuccessful substrate and not to employ the usual flash chromatography which would impair the sustainability of the transformation (see the ESI, item 3 for a GC-MS analysis of the product). Finally, internal alkynes (dimethyl but-2-ynedioate 1h and 4-phenylbut-3-yn-2-ol, Scheme 2) were tested and failed to furnish the targeted products (see the ESI item 3 for GC-MS analysis of the products obtained under the reaction conditions).

We then evaluated the green chemistry credentials for our protocol using atomic economy (AE) and E-factor (see the ESI for the calculations).11 Overall, the calculated values were good (E-factor around 185 and AE around 99% for 3 representative reactions) and demonstrated the sustainability of the transformation. To evaluate the purity of the water used as a solvent in our methodology, we performed a simple experiment to probe the nature of the organic residues remaining in the solvent after the reaction (see the ESI for the details). The transformation was carried out in D2O using phenylacetylene and methyl vinyl ketone; the usual workup was executed and then, a sample of D2O was analysed by 1H NMR. Indeed, D2O was obtained from the reaction free of organic compounds except for the residual ethyl acetate employed in the workup.

Next, a series of experiments were performed in order to gain insight into the mechanism of the reaction (Scheme 3). Firstly, we wondered whether this transformation follows a radical pathway, and hence, a radical trapping experiment was conducted. We performed the reaction employing methyl vinyl ketone and phenylacetylene under the optimized conditions in the presence of 2.0 equiv. of TEMPO ((2,2,6,6-tetramethyl-piperidin-1-yl)oxyl, Scheme 3, item I. For additional details, see the ESI). The reaction was completely inhibited but we could not identify any adducts formed between the radical scavenger and radical intermediates. Nevertheless, the inhibition of the transformation suggests that the reaction is most likely based on a radical pathway.

image file: c9gc02193k-s3.tif
Scheme 3 Studies on the mechanism.

To detect any intermediates, we conducted the reaction employing methyl vinyl ketone and phenylacetylene under the optimized conditions and aliquots were taken at different time intervals (5 min, 10 min and 30 min) (Scheme 3, item II. For additional details, see the ESI). The GC-MS and 1H NMR analysis of the crude reaction mixture after 5 min exhibited a peak relative to the product 3i along with the peak of styrene (Fig. S4 and S5 in the ESI). We then observed a gradual disappearance of the peak relative to styrene over time (10 min and 30 min) with a concomitant increase in the intensity of the peak relative to the product (Fig. S4 and S5 in the ESI). It suggests that styrene is a potential intermediate in this transformation. In order to confirm or exclude this hypothesis, we subjected styrene and methyl vinyl ketone to the reaction conditions to check if product 3i could be obtained (Scheme 3, item III). After 4 h, 3i was not observed and unidentifiable byproducts were formed, thus excluding our conjecture. We were very intrigued at this point, and so we hypothesized this transformation could involve three components, namely the styrene (possibly coming from the alkyne), the alkyne per se and the α,β-unsaturated compound. Hence, styrene, 1-ethynyl-4-methylbenzene and methyl vinyl ketone were subjected to the reaction conditions to check this assumption (Scheme 3, item IV). This experiment was designed to furnish a product with different substituents on the phenyl rings. In this way, we could be confident that one phenyl ring comes from styrene and the other comes from 1-ethynyl-4-methylbenzene. Interestingly, the reaction employing these three molecules indeed gave product A (determined by GC-MS) along with 3j (Fig. S6 in the ESI). This outcome strongly indicates the participation of styrene in the reaction mechanism. Lastly, we were curious about the possible generation of styrene from phenylacetylene under the reaction conditions. Thus, we carried out the reaction employing only phenylacetylene (Scheme 3, item V. For additional details, see the ESI). We were delighted to observe peaks relative to styrene in the 1H NMR only after 5 min (Fig. S7 in the ESI). As the reaction progresses, 1,3,5-triarylbenzene is formed and styrene disappears (a discussion about the probable mechanism for the generation of styrene from phenylacetylene can be found in the ESI, item 10).

On the basis of the above experiments and literature precedence, we propose a plausible reaction mechanism for the transformation (Scheme 4, using phenylacetylene and methyl vinyl ketone as representative substrates). Heating an aqueous solution of (NH4)2S2O8 produces a sulfate radical12 (Scheme 4, step I). Addition of such a radical to phenylacetylene13 produces radical B and styrene from radical B (step II). Radical B, styrene and methyl vinyl ketone engage in a 3-component reaction to give radical C (step III). Cyclization of C gives radical D (step IV). Elimination of radical R affords olefin E (step V) and further aromatization concludes the benzannulation reaction allowing the formation of the targeted product (step VI). A rationalization for the regioselectivity is presented in the ESI, item 11.

image file: c9gc02193k-s4.tif
Scheme 4 Proposed reaction mechanism.


Overall, we have presented the preparation of polysubstituted benzene compounds via the benzannulation protocol in water mediated by (NH4)2S2O8 from phenylacetylenes and α,β-unsaturated compounds. The method is metal-free and allows the preparation of unprecedented functionalized benzene rings. Phenylacetylenes bearing different substituents were suitable substrates in this transformation. Different α,β-unsaturated compounds were also found to be competent substrates under our protocol. The reaction provides a novel route to the synthesis of polysubstituted benzene rings under mild conditions from cheap chemical feedstocks. Further studies are underway to improve the method to obtain the heteroproducts (product A in Scheme 3) from styrene, phenylacetylenes and α,β-unsaturated compounds according to the 3-component reaction observed during the mechanistic studies.

Conflicts of interest

There are no conflicts to declare.


We thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo, Brazil) for financial support (Grant FAPESP 2017/18400-6). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c9gc02193k

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