Green, lithium salt-free synthesis of 2-alkylated 1,4-benzenediols in hydroalcoholic media

ABSTRACT Herein, we describe an efficient, green, and lithium salt-free synthesis of 2-substituted 1,4-benzenediol in water/ethanol as solvent and potassium carbonate as a base. Optimized reaction time, the required equivalent of base and the observed solvent effect are reported. GRAPHICAL ABSTRACT


Introduction
The synthesis of biologically active new compounds is still one of the main challenges of modern organic chemistry (1). Particularly, polyphenols have been widely used as antioxidant, antitumoral and antiparasitic drugs, among other uses (2-4). 2-alkyl-1,4-Benzenediols derivatives have attracted attention as there are few references available about their preparation and potential biological activity (5). Usually, these compounds were synthesized via Friedel-Crafts alkylation (6) of hydroquinone, which have various drawbacks such as polyalkylation, rearrangement reaction and the use of toxic or hazardous reagents (7,8).
In 1997, Ozaki and co-workers (9-11) published a synthesis of this type of compounds starting with 1,4cyclohexanedione and several alkylaldehydes in 1,3dimethyl-2-imidazolidinone (DMI) as the solvent in the presence of lithium chloride at 160°C. The use of no "green" solvents and troublesome work-up as well as the use of lithium salts and extreme temperature make these conditions inappropriate for a large-scale process. Based on green chemistry principles herein, we disclose a new synthetic method for the preparation of 2-alkylated 1,4-benzenediols (12). This strategy involves a tandem aldolic condensation/ isomerization/aromatization between the diketone and the selected aldehyde. The aldolic condensation under basic conditions is followed by an isomerization of the exocyclic alpha-beta unsaturated ketone moiety to the more stable aromatic derivative 2-substituted 1,4-benzenediol ( Figure 1). Using our method we synthesize a library of 2-subtituted-1,4-benzenediols to assay their activity against Leishmania sp. and to complete their structure-activity relationship studies ( Figure 2) (13,14).

Results and discussion
Synthesis of 2-benzyl 1,4-benzenediol (3) The reactions between 1,4-cyclohexanedione (1) and benzaldehyde (2) (Figure 3) were carried out using K 2 CO 3 in the presence of catalytic amount of crown ether (18-crown-6) under different experimental conditions as shown in Table 1. In the course of our study, we examined different parameters such as solvent, temperature and reaction time as well as different molar ratios between 1, 2 and K 2 CO 3 . We obtained low yields under solvent-free conditions (entry 1) or in water as a solvent under reflux (entries 2, 3, and 4). We suggest that these results are affected by poor solubility of benzaldehyde in water and the decomposition of the reagents in the presence of base at reflux. However, when the reaction was performed at room temperature, better yield was achieved (66%). Longer reaction time did not lead to higher conversion as the crude contained significant quantity of impurities. When two equivalents of 1 were used to react in H 2 O/EtOH (9:1) as a solvent, poor yield was obtained (entry 6), whereas excess of benzaldehyde was a more efficient condition (entry 7). Further studies revealed that if the reaction was performed at reflux, 18-crown-6 ether was not necessary. Also, the addition of benzaldehyde in 4 portions for every 15 min improved the outcome of the desired product yielding 84% (entry 8), reaching the yield reported by Ozaki (9) for this compound. Hence, we decided to use this optimized conditions for the syntheses of 2alkyl-1,4-benzenediol derivatives.

Synthesis of hydroxy and methoxy analogs
To explore the scope and limitations of this new protocol, a wide range of substituted hydroxy-and methoxybenzaldehydes ( Figure 5) were reacted with cyclohexanedione (1) under the optimized conditions (see Table 3). This study revealed that free hydroxyl groups contribute to diminish the outcome in spite of the excess of base used in comparison with methoxybenzaldehydes derivatives (7f-7i) (15,16). para-Hydroxyl-substituted benzaldehydes (products 7a and 7e) showed the highest reaction times as the electron-donating effect decreases the reactivity of the carbonyl to nucleophilic attack.

Preparation of analogues possessing EDG and EWG substituents
We continued testing different substituted benzaldehydes bearing either electron-donating or withdrawing groups as reagents ( Figure 6). Except for p-nitrobenzaldehyde (9i) which decomposed during the reaction, all the other aromatic aldehydes containing EDG or EWG gave moderate to good yields of the corresponding products (Table 4; 9a-9h).

Synthesis of alkyl and aryl derivatives of 3
When assaying alkyl aldehydes of different chain lengths and ramifications (Figure 7) we observed that yield increases in the case of medium length chains such as 11b and 11c, but decreases with shorter aldehydes such as formaldehyde and longer aldehydes such as nonanal (Table 5 entries 11a-11g) (9,15,(17)(18)(19)(20). This can be explained by two reasons: the poor solubility of nonanal in the solvent mixture and the use of paraformaldehyde for the synthesis of 2-methyl-1,4-benzenediol (11a). Degradation of formaldehyde under       (21). We had previously developed a synthetic method involving a Wittig reaction for the synthesis of 11b and 11g in three steps affording 28% and 36% overall yield, respectively (14). This fact clearly proves the advantages of the present "green" method compared with the traditional ones. We were able to reduce number of steps with better yields (86% and 90% for 11b and 11g, respectively) that resulted in safer conditions, reagents and solvents. We also tested polycyclic aromatic aldehydes (entries 11h-11j) with similar yields but longer reaction time for 11j, probably due to its very high lipophilicity (15,21).

Conclusions
In summary, we have developed a new green method for the synthesis of 2-alkyl-1,4-benzenediols using1,4cyclohexanedione and a variety of alkyl and aryl aldehyde in hydroalcoholic medium and K 2 CO 3 as a base under reflux. Reaction times were short (under 4 h) in the majority of cases, with the exception of 3,4dihydroxybenzaldehyde which needed 12 h to reach completion. We assayed several alkyl and arylaldehydes with a wide variety of substituents, including electron-donor and electron-acceptor groups. Moderate to excellent yields were obtained with a broad substrate scope. The reaction only failed with nitro substrates. Therefore, the proposed green and simple preparation of 2-alkylated-1,4-benzenediols derivatives allowed us to prepare a library of potentially biologically active compounds.

Experimental
General experimental procedure A solution of K 2 CO 3 (1 mmol) in a water ethanol 9:1 mixture (20 mL) is heated with stirring. Once the solution is under reflux, 1,4-cyclohexanedione (1 mmol) is added slowly. Afterwards, selected aldehyde (2 mmol) is added slowly in 4 portions every 15 min. When the reaction is completed (monitored by TLC), HCl 10% solution is added dropwise while still hot, until neutral (especially with amphotheric compounds) or slightly acidic pH. The aqueous solution is extracted 3 times with ethyl acetate and the collected organic layer is washed with brine, dried under Na 2 SO 4 and evaporated in vacuo. Purification is performed by column chromatography (AcOEt/ Hex; 1/1) In the case of free phenolic aldehyde (6a-6e and 6l) and carboxylic acids substituent (8f), an extra equivalent of base per acidic proton was used.
For the synthesis of dimers 14 and 15, two equivalents of cyclohexanedione and base were used per equivalent of aldehyde.

Disclosure statement
No potential conflict of interest was reported by the authors.

Notes on contributors
Alejandro Peixoto de Abreu Lima graduated in chemistry from Facultad de Química, Universidad de la República in 2014. He is currently working in his Doctoral Thesis, which is focused on the synthesis of speciosins and yanuthones under the supervision of Prof. Enrique Pandolfi.
Natali Graziano worked as research assistant at the Departamento de Química Orgáníca until she obtained her degree. Actually, she works for an agrochemical company.
Enrique Pandolfi received his MSc title Chemistry from the Facultad de Química, Universidad de la República under the supervision of Prof. Patrick Moyna. He moved to Germany to continue his doctoral studies with a DAAD scholarship at the University of Saarlandes in Saarbrücken, under the supervision of Prof. Theophil Eicher in a sandwich program with Facultad de Química (Uruguay). Back to Uruguay, he obtained an assistant position at Facultad de Química and he focuses his research on the synthesis of small natural molecules with potential biological activities. In 2007 he presented a patent application in collaboration with paraguayan researchers that describes the synthesis of a potent natural product against Leishmania sp. He currently teaches basic and advanced organic chemistry and he also supervises ungraduated and postgraduate research students as associate professor of the Department of Organic Chemistry at the Facultad de Química.