An easy approach to dihydrochalcones via chalcone in situ hydrogenation

Introduction

Dihydrochalcones are open chain flavonoids, named systematically as propanone derivatives, structurally related to 1,3-diphenylpropenones (chalcones), biosynthesized in plants and exhibiting a wide spectrum of biological activities [1, 2], namely anti-inflammatory [3, 4], anti-infective [5–7], antioxidant [6, 8], and anticarcinogenic [9, 10]. Chalcones are key intermediates for the synthesis of a number of biologically relevant compounds, such as coumarinyl heterocycles with antioxidant actitivity [11], chalcone phthalimidoesters with anti-inflammatory and antimicrobial activities [12] or 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines, which are privileged structures with in vitro cytotoxicity higher than the anticancer drug doxorubicin [13]. A diversity of biological activities has also been reported for dihydrochalcones, namely anti-inflammatory [14], antimicrobial [15], antioxidant [16], and antiviral [17], among others. Therefore, synthetic methodologies for an easy access to chalcone and dihydrochalcone structures, whose chemical and biological properties change according to the substitution pattern of their aromatic rings, remains a challenge for the organic chemistry community.

The presence of the double bond conjugated with the carbonyl group in chalcones predicts the isomeric (Z)- and (E)-chalcones, of which the (E)-isomer is the one found in nature. When synthetic procedures are applied to access chalcones, the (E)-isomer is also the major product formed [18], although stereoselective synthesis of (Z)-chalcones is also possible, as reported by Yoshizawa and Shioiri [19]. Starting from 1,3-diarylpropyn-2-yl silyl ethers, chalcones with (Z)/(E) ratios ranging from 70:30 to 97:3 were prepared in good yields under mild conditions.

Synthesis of chalcones can be achieved by Claisen–Schmidt condensation of an aldehyde and a ketone in basic conditions in yields ranging from 40% to 80% [20, 21], while in acidic conditions yields from 70% to 80% have been reported [22, 23]. Also Suzuki coupling [24, 25], Heck reactions [26, 27], ruthenium-catalyzed cross aldol condensation [28] or alternatively using silica-supported reagents [29] have been described for the preparation of chalcones.

Regarding the synthesis of dihydrochalcones, there are only few reports in the literature. Beyond the acylation and alkylation of arenes with alk-2-enoyl chloride [30], also the treatment of chalcones with the systems Zn/AcOH [31] or with Zn/NH₄Cl/C₂H₅OH/H₂O under ultrasound radiation [32] should be cited. Functionalization as glycosides by chemical [33] or enzymatic [34] procedures has proven relevant to afford molecular entities with a broad range of biological properties, namely antidiabetic [35] and anti-inflammatory activities [36]. Hence, new approaches for dihydrochalcone synthesis are mandatory, in particular for substrates protected with functionalities unstable under acid conditions. Also the preparation of fluorinated dihydrochalcones has been encouraged as well as that of fluorochalcones, some of them previously described as highly active against human melanoma cell line A375 [37]. Some related structures have also proven efficient for the treatment of arthritis in rats [38], while others are known as anti-inflammatory agents [39].

In this paper we present a simple, efficient and scalable methodology for the synthesis of substituted dihydrochalcones, namely 2′,4′-dihydroxy- and 4′-fluoro-2′-hydroxydihydrochalcones, by in situ catalytic hydrogenation of the intermediate chalcone double bond conjugated with a carbonyl group, that is not reduced under these reaction conditions. Chalcone precursors were synthesized by Claisen–Schmidt condensation under microwave irradiation or by the conventional procedure for comparison of reaction time, yield and side product formation.

Results and discussion

Chalcone synthesis started with acetophenone derivatives 1 and 3. Compound 1 was selectively protected with the ethoxymethyl group, easily introduced, stable under the reaction conditions used, and rapidly and efficiently removed. This monoprotected derivative 2 was easily accessed and in very good yield (93.8% isolated yield) (Scheme 1). Aldol condensation of 2 and 3 was carried out in ethanol with p-substituted aromatic aldehydes bearing a halogen, methyl or benzyloxy groups as well as with 5-methylfuran-2-carbaldehyde, in order to confirm the usefulness of this methodology. The reaction was carried out under conventional conditions, at room temperature for 24 h affording chalcones in high yield (Table 1, Scheme 1). Alternatively, microwave irradiation under reaction temperature of 40°C afforded slightly higher yields and a considerable decrease of reaction time from 24 h to 2–3 h. The major advantage of the applied microwave-assisted reaction conditions, when compared to those previously reported using home-conventional microwave ovens or solvent-free reactions [40, 41], is that no side products were formed. The expected stereoselectivity for the (E)-isomer, the single chalcone detected, has been confirmed by NMR through the coupling constant of the olefinic protons (J=14–15 Hz), while for (Z)-chalcone coupling constants of ca. J=11–12 Hz would be expected.

Scheme 1:

Synthesis of 2′,4′-dihydroxy- and 4′-fluoro-2′-hydroxychalcones. Reagents and conditions: i) 1. DIPEA, CH₂Cl₂, 0°C, 15 min; 2. ClCH₂OCH₂CH₃, 0°C, then r.t.; ii) EtOH, aq. NaOH 50% (w/v), r.t, 24 h; iii) EtOH, aq. NaOH 50% (w/v), 40°C, 2–3 h, 250 W; iv) FeCl₃·6H₂O, MeOH, reflux, 2–3 h; v) FeCl₃·6H₂O, MeOH, reflux, 10 or 7 min, 250 W.

Table 1:

Claisen–Schmidt condensation of acetophenones with aromatic aldehydes under conventional conditions and microwave irradiation (MW), carried out in ethanol.

Compound Nr.		ArCHO	Yield (%)
	R		Conv. rt	MW
4	OCH2OCH2CH3	4-methylbenzaldehyde	89.2	92.8
5	OCH2OCH2CH3	4-fluorobenzaldehyde	91.2	86.3
6	OCH2OCH2CH3	4-bromobenzaldehyde	85.0	86.0
7	OCH2OCH2CH3	4-benzyloxybenzaldehyde	92.3	93.8
8	OCH2OCH2CH3	5-methylfuran-2-carbaldehyde	68.9	74.6
9	F	4-methylbenzaldehyde	83.0	95.1
10	F	4-fluorobenzaldehyde	72.6	87.5
11	F	4-bromobenzaldehyde	87.3	93.4
12	F	4-benzyloxybenzaldehyde	89.9	90.5
13	F	5-methylfuran-2-carbaldehyde	84.6	89.9

The present reaction conditions seem to be the best choice for chalcones’ synthesis, affording cleaner reactions and generating products in high yield and in much lower reaction time than under conventional conditions (Table 1).

Removal of the ethoxymethyl group was first tried under the described classical conditions, with 2.5 N HCl in methanol [42], but flavanones were formed either as major or as single reaction products. Alternatively, treatment with FeCl₃·6H₂O in methanol (Scheme 1), afforded only the dihydroxychalcones in high yield within 2–3 h. When the reaction was carried out under microwave irradiation, reaction time was considerably reduced to 7–10 min with a low increase of reaction yield (Table 2).

Table 2:

Deprotection of chalcones by reaction with FeCl₃·6H₂O.

Compound Nr.		Yield (%)
	Ar	Conventional procedure	MW irradiation
14	4-methylphenyl	96.8	97.2
15	4-fluorophenyl	84.6	94.5
16	4-bromophenyl	93.7	98.1
17	4-benzyloxyphenyl	96.7	97.8
18	5-methylfuranyl	90.9	97.6

In situ generation of molecular hydrogen [43] by addition of triethylsilane to palladium-charcoal catalyst is here applied for the first time to afford dihydrochalcones by chalcone hydrogenation (Scheme 2), resulting in rapid and efficient reduction of chalcone olefinic bond. The reaction was carried out at room temperature for 10 min and the yields were, in general, almost quantitative (98.2–99.7%) (Table 3). Reaction completion was also easily detected by discoloration of the yellow-reddish chalcone solution.

Scheme 2:

Synthesis of 2′,4′-dihydroxy- and 4′-fluoro-2′-hydroxydihydrochalcones.

Table 3:

Synthesis of dihydrochalcones by in situ generation of molecular hydrogen.

Compound Nr.	Ar		Yield (%)
		R
19	4-methylphenyl	OH	99.1
20	4-fluorophenyl	OH	99.7
21	phenyl	OH	98.7
22	4-benzyloxyphenyl	OH	99.0
23	5-methylfuranyl	OH	98.2
24	4-methylphenyl	F	99.0
25	4-fluorophenyl	F	99.3
26	phenyl	F	99.4
27	4-benzyloxyphenyl	F	98.2
28	5-methylfuranyl	F	58.4
29a	5-methyltetrahydrofuranyla	F	40.8

^aCompound 29 is a secondary product bearing a tetrahydrofuranyl group resulting from double bond hydrogenation of the furanyl moiety.

All reactions afforded the dihydrochalcone product, but the 4-bromophenyl group was reduced to the phenyl group as shown in compounds 21 and 26. This result could be expected since reductive dehalogenation of aryl halides by triethylsilane catalyzed by palladium chloride under microwave irradiation has been previously reported [44].

Although Kursanov et al. [45] have reported the reduction of substituted furans to tetrahydrofuran derivatives in the presence of triethylsilane, only the fluorochalcone 13 afforded a dihydrochalcone bearing a tetrahydrofuranyl group as a secondary product, as confirmed by NMR. The signals corresponding to furanyl double bonds of compound 28 were easily identified as doublets with small coupling constants (~1.5–2.0 Hz) while those corresponding to the H-2, H-3, H-4 and H-5 protons of compound 29 appear at considerably lower chemical shifts and coupling constants, resulting from furanyl double bond reduction. HMRS also confirmed the molecular mass of this compound.

Conclusion

In this work an efficient and simple synthetic method to afford dihydrochalcones has been developed using for the first time the in situ production of molecular hydrogen by Et₃SiH/Pd-C system to selectively reduce the olefinic bond of chalcones. Chalcone starting materials were synthesized in high yield via conventional or microwave-assisted methodologies, the latter reducing significantly the reaction time, without formation of side products. In addition, it should be highlighted the usefulness the Lewis acid FeCl₃ in promoting chalcone deprotection without flavanone formation. This short synthetic pathway is easily carried out, and has proven scalable and very efficient to afford dihydrochalcones in high overall yield.

Experimental section