Next Article in Journal
Anion Recognition by Pyrylium Cations and Thio-, Seleno- and Telluro- Analogues: A Combined Theoretical and Cambridge Structural Database Study
Next Article in Special Issue
Synthetic Development of New 3-(4-Arylmethylamino)butyl-5-arylidene-rhodanines under Microwave Irradiation and Their Effects on Tumor Cell Lines and against Protein Kinases
Previous Article in Journal
Protective Effects of Korean Red Ginseng against Alcohol-Induced Fatty Liver in Rats
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 20
Issue 6
10.3390/molecules200611617
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions

by
Elodie Brun
1,†,
Abdelmounaim Safer
2,†,
François Carreaux
1,*,
Khadidja Bourahla
1,
Jean-Martial L'helgoua'ch
1,
Jean-Pierre Bazureau
1 and
Jose Manuel Villalgordo
3
1
Institut des Sciences Chimiques de Rennes, Université de Rennes 1, Campus de Beaulieu, UMR 6226 CNRS, 35042 Rennes Cedex, France
2
LSOA—Laboratoire de Synthèse Organique Appliquée, Department of chemistry, Oran 1 University, 1524 Oran, Algeria
3
Villapharma Research, Parque Tecnologico de Fuente Alamo, E-30320 Murcia, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2015, 20(6), 11617-11631; https://doi.org/10.3390/molecules200611617
Submission received: 28 May 2015 / Revised: 14 June 2015 / Accepted: 15 June 2015 / Published: 23 June 2015
(This article belongs to the Special Issue Microwave-Assisted Organic Synthesis)
Browse Figures
Versions Notes

Abstract

:
We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups.

1. Introduction

The development of new methodologies employing oxygenated boron compounds (i.e., borinic acids R1R2B(OH), boronic acids RB(OH)2 and boric acid H3BO3) as reaction catalysts has received a lot of attention from the organic chemistry community during these past few years [1]. Beside their stability to air and moisture, the growing interest for this class of compounds can also be attributed to the different modes of catalytic reactivity achieved depending on their electronic nature. They can indeed act as Lewis acids but also as activators of functional groups such as hydroxyl and carboxylic groups by reversible covalent interactions [2]. Among them, boric acid was found to be an efficient catalyst in numerous reactions such as selective esterification of α-hydroxycarboxylic and malonic acids [3,4,5], amide formation from carboxylic acids [6,7,8], transamidation of carboxamides [9], trimethylsilylation of alcohols and phenols [10], decarboxylation of cyclic β-enaminoketoesters [11], ipso-hydroxylation of aryl boronic acids [12], aza [13] and thia-Michael addition [14], Friedel-Crafts alkylation of indoles [15] as well as in diverse multicomponent reactions [16,17,18,19].
Condensation reactions of aldehydes with active methylene compounds are very useful to prepare molecules with potential therapeutic relevance such as, for instance, the 1,3-diphenylpropenones also called chalcones. They exhibit diverse pharmacological activities [20,21,22] and more particularly, as anticancer agents [23,24]. Many other drugs as well as pharmacological tools with heterocyclic structures can also include an aldol-type condensation step in their synthesis [25,26], as illustrated in Figure 1.
Molecules 20 11617 g001 550
Figure 1. Selected molecules with high biological value.
Figure 1. Selected molecules with high biological value.
Molecules 20 11617 g001
These condensation reactions can be promoted by a large array of catalysts including Lewis bases and acids but can suffer from limitations related, among other factors, to waste elimination and use of toxic products [27]. Therefore, the development of new methods involving the environmentally benign and cost-efficient catalysts still remains a major challenge. In this context, the use of boric acid as a catalyst in these reactions should be particularly adapted due to its lack of apparent toxicity and its easy removal from a reaction mixture [28]. To the best of our knowledge, only a limited number of articles report the use of boric acid acting as the sole catalyst for aldol condensation and subsequent dehydration to form α,β-unsaturated ketones [29,30]. However, the described conditions require long reaction times at reflux of m-xylene in presence of 50 mol % of catalyst and water removal through a Dean-Stark trap.
As part of our program focused on the development of novel green methods based on organoboron chemistry for the synthesis of molecules with a high biological profile [31,32,33,34,35], we here report our efforts to develop a general procedure for condensation reactions employing boric acid as catalyst. The application of microwave technology as non-conventional energy source was crucial for the implementation of this methodology. Under solvent-free conditions, we have shown that the condensation protocol was efficient from various substrates bearing an activated methylene group. In addition, we found that the condensation reaction with an aldehyde possessing a boronic acid group proceeds without the need to an additional catalyst.

2. Results and Discussion

For the experimental protocol development, we selected the 4-methoxyacetophenone 1a (1 equiv.) and the 4-methoxybenzaldehyde (1.2 equiv.) as model substrates due to the fact that, from a biological point of view, the chalcones bearing electron rich groups are part of the most interesting molecules [20]. After observing very low formation of the expected product 2a, under thermal heating in presence of boric acid for 4 h (Table 1, entry 1), we tried different conditions using microwave irradiation as energy source and without adding any solvent. For a first attempt, we employed 50 mol % of boric acid at 160 °C for 20 min. Under these conditions, chalcone 2a is formed stereoselectively (only E) with an almost complete conversion (95%) compared to 4-methoxyacetophenone (entry 2). Improvement of the reaction conversion when phenyl boronic acid is used instead of boric acid confirms that the catalyst has to act as a Lewis acid during the condensation reaction (entry 3).
Table
Table 1. Optimization of the condensation reaction catalyzed by boric acid a. Molecules 20 11617 i001
Table 1. Optimization of the condensation reaction catalyzed by boric acid a. Molecules 20 11617 i001
EntryCatalyst (mol %)Conditions2a (Conv. %) c2a (yield %) d
1B(OH)3 (50 mol %)Toluene, reflux (4 h)5%-
2B(OH)3 (50 mol %)MWI, 160 °C (20 min) b95%-
3PhB(OH)2 (50 mol %)MWI, 160 °C (20 min) b100%-
4B(OH)3 (10 mol %)MWI, 160 °C (40 min) b75%-
5B(OH)3 (20 mol %)MWI, 160 °C (40 min) b93%70%
a Reaction condition: 4-methoxyacetophenone (1 mmol), 4-methoxybenzaldehyde (1.2 mmol);b Microwave irradiation of the reaction mixture was carried out in a glass tube sealed with a snap cap using the Explorer®24 CEM apparatus (CEM µ Waves, Saclay, France) (P = 300 W); c Conversion based on 4-methoxyacetophenone 1a as the limiting reagent; d Isolated pure product.
Even though phenyl boronic acid is a stronger Lewis acid than boric acid and is easy to handle, we continued our study using boric acid because of its low cost and the fact that it is a more environmentally friendly reagent [36]. Eventually, by changing the irradiation time, we found that it was possible to reduce the quantity of catalyst down to 20 mol % while keeping a good conversion (entry 5). The desired compound 2a has been obtained in a pure form in an acceptable yield (70%) by mere addition, after heating, of a mixture of solvent (H2O/EtOH) and filtration.
The next goal was to extend this protocol to other acetophenone derivatives 1 and aldehydes in order to show the scope and limitations of this process. In all cases described in Scheme 1, chalcones 2 were obtained in a stereoselective manner (>95%) in favor of E isomer as confirmed by the magnitude of the coupling constant between the two vinyl protons (range from 15.5 to 15.8 Hz). The obtained yields after precipitation and filtration were not optimized but we observed slightly better results when bromo group was present on the aromatic ring of aldehydes (2e compared to 2a, 2n compared to 2o). Undoubtedly, the solvent-free conditions are relatively mild compared to basic or acidic media generally implemented in conventional methods to prepare the 1,3-diaryl-2-propen-1-ones. As demonstrated by the synthesis of unknown compounds 2n–p, this new process tolerates the presence of an ester functional group and allows access to functionalized chalcones which may be difficult to prepare by traditional methods. Typically, the aldol condensations in basic media are carried out in the appropriate alcoholic solvent to prevent the transesterification side-reaction. In this regard, our metal-free process can be considered as a complementary methodology of the catalyzed coupling reactions requiring any base such as the oxidative carbonylative vinylation reactions of aryl boronic acids with styrenes which is described in particular as compatible with the carbonyl groups [37].
Molecules 20 11617 g002 550
Scheme 1. Synthesis of various functionalized chalcones.
Scheme 1. Synthesis of various functionalized chalcones.
Molecules 20 11617 g002
Despite the lack of evidence for the postulated mechanism, we can speculate that, under these microwave irradiation conditions, the ketone first reacts with boric acid to form a boron enolate (Scheme 2). The aldol reaction between this species and an aldehyde might then proceed via a six-membered chair-like transition state. Finally, the resulting adduct may undergo a dehydration step assisted by a possible intramolecular coordination of the boron atom with the carbonyl group.
Molecules 20 11617 g003 550
Scheme 2. Proposed catalytic cycle for the formation of α,β-unsatured ketones.
Scheme 2. Proposed catalytic cycle for the formation of α,β-unsatured ketones.
Molecules 20 11617 g003
Five-membered heterocyclic rings such as the thiohydantoin (X = S, Y = NH), hydantoin (X = O, Y = NH), rhodanine or 2-thioxo-1,3-thiazolidin-4-one (X = S, Y = S) and 1,3-thiazolidin-2,4-dione (X = O, Y = S) have attracted our attention as potential substrates in our condensation protocol since they appear as interesting scaffolds for drug discovery [38]. To our delight, in all cases the expected products 3 were obtained in moderate to good yields (Scheme 3).
Molecules 20 11617 g004 550
Scheme 3. Condensation reaction with five-membered heterocyclic rings.
Scheme 3. Condensation reaction with five-membered heterocyclic rings.
Molecules 20 11617 g004
After microwave heating in the presence of 1.2 equivalent of aldehyde, the addition of ethanol in the crude reaction mixture allowed the formation of a precipitate that is filtered to give the 5-arylidene derivatives 3 as a sole isomer whose Z stereochemistry was assigned, in accordance with the literature. In the case of hydantoin, an adjustment of the experimental protocol was necessary to obtain compound 3c in a suitable yield (49%). In a similar way, an increased temperature (180 °C) with thiazolidinedione as substrate was envisaged but without any substantial effect on yield (3j, 44%).
In these last two decades, boronic acid derivatives have become a significant class of compounds with important biological applications [39]. On this basis, we put forth the idea that the condensation reaction involving an aldehyde bearing a boronic group on the aromatic ring might constitute a new route to these organoboron compounds. Without the supplementary addition of catalyst, the reaction between thyohydantoin and 4-formylphenylboronic acid under microwave irradiation afforded the expected product 4 (Scheme 4).
Molecules 20 11617 g005 550
Scheme 4. Condensation reactions involving the 4-formylboronic acid.
Scheme 4. Condensation reactions involving the 4-formylboronic acid.
Molecules 20 11617 g005
The work-up is a simple filtration of the formed precipitate following the addition of a H2O/EtOH mixture in the crude mixture. Unfortunately and unexpectedly, when the reaction was achieved with 4-methoxyacetophenone using the same experimental conditions, product 5 rather than the chalcone containing the boronic acid function was isolated probably as a result of a protonolysis of the C-B bond. Other attempts were made with similar substrates though without any more success showing the difficulty to overcome this side reaction.

3. Experimental Section

All reagents were purchased from Acros (Geel, Belgium), Aldrich (Saint Louis, MI, USA) and were used without further purification. Melting points were determined on a Kofler melting point apparatus (Wagner & Munz, Munich, Germany), and were uncorrected. 1H-NMR spectra were recorded on BRUKER AC 300 P (300 MHz) spectrometer (Bruker, Bremen, Germany), 13C-NMR spectra on BRUKER AC 300 P (75 MHz, Bruker) spectrometer and 11B-NMR spectra on BRUKER AC 300 P (96 MHz, Bruker). Chemical shifts are expressed in part per million downfield from tetramethylsilane as an internal standard. Data are given in the following order: δ value, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad), number of protons, coupling constants J is given in Hz. Reactions under microwave irradiations were realized in the Explorer®24 CEM microwave reactor (CEM France, CEM µ Waves) using borosilicate glass vials of 10 mL equipped with snap caps (at the end of the irradiation, cooling reaction was realized by compressed air). The microwave instrument consists of a continuous focused microwave power output from 0 to 300 W. All the experiments were performed using a stirring option. The target temperature was reached with a ramp of 2 min. and the chosen microwave power stayed constant to hold the mixture at this temperature. The reaction temperature is monitored using calibrated infrared sensor and the reaction time included the ramp period. The microwave irradiation parameters (power and temperature) were monitored by the ChemDriver software package (Version 2.0, CEM µ Waves). High-resolution mass sprectra (HMRS) were recorded on a Bruker Micro-Tof-Q II (Bruker) or on a Waters Q-Tof 2 at the CRMPO (Centre Régional de Mesures Physiques de l’Ouest, Rennes, France) using positive ion Electro-Spray Ionization (ESI, Waters, Manchester, UK). Purifications by column chromatography were all carried out on silica gel by using Acros silica 0.060–0.200 mm, 60 Å. Thin layer chromatography analyses were performed on Merck Silica Gel 60 F254 plates (Merck, Darmstadt, Germany).

3.1. General Procedure for the Condensation Reaction

A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in a cylindrical quartz reactor (Ø = 4 cm). The reactor was introduced into an Explorer®24 CEM apparatus. The stirred mixture was heated at 160 °C (P = 300 W) for 40 min, except for 3c (180 °C). After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz reactor. The resulting precipitated product was filtered off and was purified by recrystallization from ethanol if necessary.

3.2. Physical and Spectroscopic Data of Products

(E)-1,3-Bis-(4-methoxyphenyl)-prop-2-en-1-one (2a) [40]. Pale cream powder, 70% yield, m.p. = 96–98 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.95 (d, 2H, J = 8.7 Hz, Ar-), 7.00 (d, 2H, J = 8.8 Hz, Ar-), 7.45 (d, 1H, J = 15.6 Hz, CH=), 7.62 (d, 2H, J = 8.7 Hz, Ar-), 7.80 (d, 1H, J = 15.6 Hz, CH=), 8.05 (d, 2H, J = 8.8 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.4, 55.5, 113.8, 114.4, 119.6, 127.8, 130.1, 130.7, 131.4, 143.8, 161.5, 163.3, 188.7 ppm; HRMS (ESI+): m/z calcd for C17H16O3 [M + Na]+ 291.0997; found 291.0996.
(E)-3-(4-(Dimethylamino)phenyl)-1-(4-methoxyphenyl)-prop-2-en-1-one (2b) [40]. light yellow powder, 65% yield, m.p. = 128–130 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.05 (s, 6H, N(CH3)2), 3.89 (s, 3H, OCH3), 6.71 (d, 2H, J = 8.7 Hz, Ar-), 6.99 (d, 2H, J = 8.4 Hz, Ar-), 7.37 (d, 1H, J = 15.4 Hz, CH=), 7.57 (d, 2H, J = 8.4 Hz, Ar-), 7.80 (d, 1H, J = 15.4 Hz, CH=), 8.01 (d, 2H, J = 8.7 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 40.2, 55.5, 111.8, 113.7, 116.6, 122.8, 130.3, 130.6, 131.9, 145.0, 151.9, 163.0, 188.9 ppm; HRMS (ESI+): m/z calcd for C18H19NO2 [M + Na]+ 304.1313; found 304.1313.
(E)-1-(4-Methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one (2c) [41]. Yellow powder, 61% yield, m.p. = 128–130 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 6H, OCH3), 6.16 (s, 2H, Ar-), 6.98 (d, 2H, J = 8.8 Hz, Ar-), 7.90 (d, 2H, J = 15.8 Hz, CH=), 8.04 (d, 2H, J = 8.8 Hz, Ar-), 8.24 (d, 1H, J = 15.8 Hz, CH=) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.8, 56.5, 56.8, 57.3, 97.5, 112.1, 114.1, 116.2, 120.6, 131.1, 132.1, 139.7, 143.7, 152.7, 154.9, 163.5, 189.7 ppm; HRMS (ESI+): m/z calcd for C19H20O5 [M + Na]+ 351.1208; found 351.1208.
(E)-1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one (2d) [42]. Pale yellow powder, 66% yield, m.p. = 138–140 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.92 (s, 6H, OCH3), 3.95 (s, 6H, OCH3), 6.88 (s, 2H, Ar-), 7.01 (d, 2H, J = 8.7 Hz, Ar-), 7.43 (d, 1H, J = 15.8 Hz, CH=), 7.73 (d, 1H, J = 15.8 Hz, CH=), 8.05 (d, 2H, J = 8.7 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.9, 56.6, 61.4, 106.0, 114.2, 121.7, 131.0, 131.2, 131.5, 140.7, 144.5, 153.9, 163.8, 189.1 ppm; HRMS (ESI+): m/z calcd for C19H20O5 [M + Na]+ 351.1208; found 351.1209.
(E)-3-(4-Bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (2e) [43]. Pale yellow powder, 75% yield, m.p. = 157–159 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.92 (s, 3H, OCH3), 7.00 (d, 2H, J = 8.9 Hz, Ar-), 7.49–7.61 (m, 5H, Ar, CH=), 7.75 (d, 1H, J = 15.6 Hz, CH=), 8.05 (d, 2H, J = 8.9 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.5, 113.9, 122.4, 124.5, 129.7, 130.8, 130.9, 132.1, 134.0, 142.5, 163.5, 188.3 ppm; HRMS (ESI+): m/z calcd for C16H13BrO2 [M + Na]+ 338.9997; found 338.9996.
(E)-3-(5-Bromobenzo[d][1,3]dioxol-4-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (2f). Pale green powder, 58% yield, m.p. = 120–122 °C; 1H-NMR (CDCl3, 300 MHz) δ= 3.89 (s, 3H, OCH3), 6.16 (s, 2H, OCH2O), 6.72 (d, 1H, J = 8.3 Hz, Ar-), 7.01 (d, 2H, J = 8.9 Hz, Ar-), 7.15 (d, 1H, J = 8.3 Hz, Ar-), 7.90 (d, 1H, J = 15.8 Hz, CH=), 8.01 (d, 1H, J = 15.8 Hz, CH=), 8.07 (d, 2H, J = 8.9 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.4, 102.1, 110.1, 113.8, 117.0, 118.2, 125.9, 127.2, 130.9, 137.4, 147.3, 147.5, 163.5, 188.8 ppm; HRMS (ESI+): m/z calcd for C17H13BrO4 [M + Na]+ 382.9895; found 382.9895.
(E)-3-(4-Bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (2g) [44]. Pale yellow powder, 64% yield, m.p. = 123–124 °C; 1H-NMR (CDCl3, 300 MHz): δ: 3.92 (s, 3H, OCH3), 3.93 (s, 6H, 2 × OCH3), 7.22 (s, 2H, Ar-), 7.42 (d, 1H, J = 15.6 Hz, CH=), 7.48 (d, 2H, J = 8.0 Hz, Ar-), 7.54 (d, 2H, J = 8.0 Hz, Ar-), 7.72 (d, 1H, J = 15.6 Hz, CH=) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 56.6, 56.7, 61.2, 106.4, 122.5, 125.0, 130.0, 131.7, 132.5, 133.5, 134.0, 143.5, 153.4, 189.3 ppm; HRMS (ESI+): m/z calcd for C18H17BrO4 [M + Na]+ 399.0208; found 399.0208.
(E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-one (2h) [43]. Pale yellow powder, 68% yield, m.p. = 74–76 °C; 1H-NMR (CDCl3, 300 MHz): δ: 3.83 (s, 3H, OCH3), 6.96 (d, 2H, J = 8.8 Hz, Ar-), 7.44 (d, 1H, J = 15.7 Hz, CH=), 7.49–7.58 (m, 3H, Ar-), 7.63 (d, 2H, J = 8.8 Hz, Ar-), 7.80 (d, 1H, J = 15.7 Hz, CH=), 8.03 (d, 2H, J = 8.1 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.4, 119.8, 127.7, 128.5, 128.6, 130.2, 130.3, 132.6, 138.5, 144.7, 161.6, 190.6 ppm. HRMS (ESI+): m/z calcd for C16H14O2 [M + Na]+ 261.0891; found 261.0893.
(E)-3-(2,3-Dihydrobenzofuran-5-yl)-1-phenylprop-2-en-1-one (2i). Pale yellow powder, 69% yield, m.p. = 110–112 °C; 1H-NMR (CDCl3, 300 MHz): δ= 3.26 (t, 2H, J = 8.7 Hz, ArCH2), 4.65 (t, 2H, J = 8.7 Hz, CH2O), 6.82 (d, 1H, J = 8.3 Hz, Ar-), 7.31 (d, 1H, J = 15.6 Hz, CH=), 7.41–7.61 (m, 5H, Ar-), 7.79 (d, 1H, J = 15.6 Hz, Ar-), 8.01 (dd, 2H, J = 1.6, 8.5 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ= 29.1, 71.8, 109.7, 118.9, 124.8, 127.6, 128.1, 128.2, 128.4, 130.0, 132.4, 138.4, 145.1, 162.5, 190.4 ppm. HRMS (ESI+): m/z calcd for C17H14O2 [M + Na]+ 273.0891; found 273.0891.
(E)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-prop-2-en-1-one (2j) [45]. Yellow powder, 64% yield, m.p. = 82–84 °C; 1H-NMR (CDCl3, 300 MHz): δ = 4.30 (m, 4H, OCH2CH2O), 6.90 (d, 1H, J = 8.2 Hz, Ar-), 7.14–7.20 (m, 2H, Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.47–7.6 (m, 3H, Ar-), 7.71 (d, 1H, J = 15.6 Hz, CH=), 8.00 (dd, 2H, J = 1.6, 8.5 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 64.2, 64.6, 116.7, 117.0, 117.8, 120.4, 121.2, 122.6, 128.0, 128.4, 128.6, 132.6, 138.5, 143.8, 144.6, 146.0, 190.5 ppm; HRMS (ESI+): m/z calcd for C17H14O3 [M + Na]+ 289.0841; found 289.0841.
(E)-1-(4-Bromophenyl)-3-(4-dimethylamino)phenylprop-2-en-1-one (2k) [46]. Pale yellow powder, 60% yield, m.p. = 140–142 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.07 (s, 6H, N(CH3)2), 6.72 (d, 2H, J = 8.7 Hz, Ar-), 7.30 (d, 1H, J = 15.4 Hz, CH=), 7.54 (d, 2H, J = 8.7 Hz, Ar-), 7.62 (d, 2H, J = 8.7 Hz, Ar-), 7.74 (d, 1H, J = 15.4 Hz, CH=), 7.89 (d, 2H, J = 8.7 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 40.1, 111.8, 116.2, 122.4, 127.1, 129.9, 130.6, 131.7, 137.9, 146.4, 152.2, 189.4 ppm; HRMS (ESI+): m/z calcd for C17H16BrNO [M + Na]+ 352.0313; found 352.0314.
(E)-1-(4-Bromophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (2l) [46]. Pale cream powder, 59% yield, m.p. = 148–150 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OCH3), 6.97 (d, 2H, J = 8.8 Hz, Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.63 (d, 2H, J = 8.8 Hz, Ar-), 7.66 (d, 2H, J = 8.6 Hz, Ar-), 7.82 (d, 1H, J = 15.6 Hz, CH=), 7.90 (d, 2H, J = 8.6 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.7, 114.7, 119.3, 127.6, 127.8, 130.2, 130.6, 132.1, 137.4, 145.5, 162.1, 189.6 ppm; HRMS (ESI+): m/z calcd for C16H13BrO2 [M + Na]+ 338.9997; found 338.9997.
(E)-3-(4-Methoxyphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (2m) [43]. Yellow powder, 65% yield, m.p. = 183–185 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.89 (s, 3H, OCH3), 6.97 (d, 2H, J = 8.7 Hz, Ar-), 7.37 (d, 1H, J = 15.6 Hz, CH=), 7.64 (d, 2H, J = 8.7 Hz, Ar-), 7.84 (d, 1H, J = 15.6 Hz, CH=), 8.14 (d, 2H, J = 8.9 Hz, Ar-), 8.36 (d, 2H, J = 8.9 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.5, 114.6, 118.9, 123.9, 127.0, 129.3, 130.5, 143.5, 146.7, 149.9, 162.3, 189.1 ppm. HRMS (ESI+): m/z calcd for C16H13NO4 [M + Na]+ 306.0742; found 306.0742.
Methyl (E)-4-(3-(4-bromophenyl)acryloyl)benzoate (2n). Pale yellow powder, 62% yield, m.p. = 212–214 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.96 (s, 3H, OCH3), 7.40–7.51 (m, 5H, CH=, Ar-), 7.68 (d, 1H, J = 15.7 Hz, CH=), 7.97 (d, 2H, J = 8.5 Hz, Ar-), 8.10 (d, 2H, J = 8.5 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 52.5, 122.3, 125.2, 128.1, 128.4, 129.9, 132.3, 133.5, 133.7, 141.4, 144.3, 189.8 ppm. HRMS (ESI+): m/z calcd for C17H13BrO3 [M + Na]+ 366.9946; found 366.9946.
Methyl (E)-4-(3-(4-dimethylamino)phenyl)acryloyl)-benzoate (2o). Orange powder, 58% yield, m.p. = 164–166 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.10 (s, 3H, N(CH3)2), 3.96 (s, 3H, OCH3), 6.71 (d, 2H, J = 8.8 Hz, Ar-), 7.30 (d, 1H, J = 15.5 Hz, CH=), 7.55 (d, 2H, J = 8.8 Hz, Ar-), 7.79 (d, 1H, J = 15.5 Hz, CH=), 8.02 (d, 2H, J = 8.6 Hz, Ar-), 8.14 (d, 2H, J = 8.6 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 40.0, 52.3, 111.7, 116.4, 122.2, 128.1, 129.6, 130.6, 132.8, 142.6, 146.8, 152.2, 166.4, 190.0 ppm. HRMS (ESI+): m/z calcd for C19H19NO3 [M + Na]+ 322.1263; found 322.1262.
Methyl (E)-4-(3-methoxyphenyl)acryloyl)-benzoate (2p). Pale yellow powder, 57% yield, m.p. = 144–146 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.83 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.94 (d, 2H, J = 8.7 Hz, Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.61 (d, 2H, J = 8.7 Hz, Ar-), 7.79 (d, 1H, J = 15.6 Hz, CH=), 8.03 (d, 2H, J = 8.4 Hz, Ar-), 8.15 (d, 2H, J = 8.4 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 52.3, 55.3, 114.3, 119.4, 127.2, 128.1, 129.6, 130.3, 133.1, 141.8, 145.5, 161.8, 166.2, 190.0 ppm; HRMS (ESI+): m/z calcd for C18H16O4 [M + Na]+ 319.0946; found 319.0945.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxo-imidazolidin-4-one (3a) [47]. Yellow powder, 75% yield, m.p. ≥ 260 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 6.09 (s, 2H, OCH2O), 6.43 (s, 1H, CH=), 6.97 (d, 1H, J = 8.1 Hz, Ar-), 7.27 (d, 1H, J = 8.1 Hz, Ar-), 7.44 (s, 1H, Ar-), 12.08 (br s, 1H, NH), 12.31 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 102.1, 109.2, 109.7, 112.6, 126.5, 126.7, 126.9, 148.4, 148.9, 166.2, 179.1 ppm; HRMS (ESI+): m/z calcd for C11H8N2O3S [M + Na]+ 271.0153; found 271.0152.
(Z)-5-(4-Methoxybenzylidene)-2-thioxoimidazolidin-4-one (3b) [48]. Yellow powder, 67% yield, m.p. = 211–213 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.81 (s, 3H, OCH3), 6.47 (s, 1H, CH=), 6.98 (d, 2H, J = 8.8 Hz, Ar-), 7.74 (d, 2H, J = 8.8 Hz), 12.07 (br s, 1H, NH), 12.30 (s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 55.4, 113.9, 114.4, 124.0, 124.7, 127.4, 128.3, 132.3, 160.4, 163.9, 177.9 ppm; HRMS (ESI+): m/z calcd for C11H10N2O2S [M + Na]+ 257.0361; found 257.0361.
(Z)-5-(4-Methoxybenzylidene)imidazolidine-2,4-dione (3c) [38]. Yellow powder, 49% yield, m.p. = 202–204 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.79 (s, 3H, OCH3), 6.38 (s, 1H, CH=), 6.95 (d, 2H, J = 8.8 Hz, Ar-), 7.58 (d, 2H, J = 8.8 Hz, Ar-), 10.42 (br s, 1H, NH), 11.16 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 55.2, 108.6, 114.1, 125.4, 131.0, 155.6, 159.4, 165.5, 173.9 ppm; HRMS (ESI+): m/z calcd for C11H10N2O3 [M + Na]+ 241.0589; found 241.0591.
(Z)-5-(4-Methoxybenzylidene)-2-thioxothiazolidin-4-one (3d) [38]. Yellow powder, 90% yield, m.p. = 263–265 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.84 (s, 3H, OCH3), 7.11 (d, 2H, J = 8.7 Hz, Ar-), 7.57 (d, 2H, J = 8.7 Hz, Ar-), 7.60 (s, 1H, CH=), 13.75 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 55.4, 114.9, 124.9, 125.8, 129.7, 132.2, 160.8, 172.9, 197.2 ppm; HRMS (ESI+): m/z calcd for C11H9NO2S2 [M + Na]+ 273.9972; found 273.9972.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxo-thiazolidin-4-one (3e) [49]. Yellow powder, 95% yield, m.p. = 248–250 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 6.13 (s, 2H, OCH2O), 7.11 (m, 3H, Ar-), 7.54 (s, 1H, CH=), 13.74 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 102.5, 109.6, 121.4, 126.3, 127.6, 132.4, 148.6, 149.7, 167.8, 195.3 ppm; HRMS (ESI+): m/z calcd for C11H7NO3S2 [M + Na]+ 287.9765; found 287.9765.
(Z)-5-(4-Chlorobenzylidene)-2-thioxothiazolidin-4-one (3f) [50]. Pale orange powder, 91% yield, m.p. = 230–232 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 7.60–7.64 (m, 5H, CH=, Ar-), 13.89 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 126.2, 129.5, 130.1, 131.8, 132.0, 135.3, 169.3, 195.4 ppm; HRMS (ESI+): m/z calcd for C10H6ClNOS2 [M + Na]+ 277.9477; found 277.9476.
(Z)-5-(4-(Dimethylamino)benzylidene)-2-thioxo-thiazolidin-4-one (3g) [51]. Orange powder, 90% yield, m.p. = 270–272 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.04 (s, 6H, N(CH3)2), 6.83 (d, 2H, J = 8.7 Hz, Ar-), 7.43 (d, 2H, J = 8.7 Hz, Ar-), 7.54 (s, 1H, CH=), 13.59 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 40.3, 112.5, 117.7, 120.1, 133.3, 133.7, 152.1, 169.8, 195.4 ppm; HRMS (ESI+): m/z calcd for C12H12N2OS2 [M + Na]+ 287.0289; found 287.0287.
(Z)-5-(4-Nitrobenzylidene)-2-thioxothiazolidin-4-one (3h) [52]. Yellow powder, 93% yield, m.p. = 254–256 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 7.75 (s, 1H, CH=), 7.87 (d, 2H, J = 8.6 Hz, Ar-), 8.35 (d, 2H, J = 8.6 Hz, Ar-), 14.03 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 124.7, 128.7, 130.3, 131.7, 139.6, 147.9, 169.6, 196.7 ppm; HRMS (ESI+): m/z calcd for C10H6N2O3S2 [M + Na]+ 288.9718; found 288.9719.
(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-2-thioxothiazolidin-4-one (3i) [38]. Yellow powder, 79% yield, m.p. = 228–230 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.85 (s, 3H, OCH3), 6.94–7.17 (m, 3H, Ar-), 7.60 (s, 1H, CH=), 10.13 (br s, 1H, OH), 13.75 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 56.1, 114.8, 116.8, 121.6, 124.8, 125.5, 133.2, 148.6, 150.4, 169.9, 195.9 ppm; HRMS (ESI+): m/z calcd for C11H9NO3S2 [M + Na]+ 299.9922; found 299.9923.
(Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione (3j) [53]. Yellow powder, 44% yield, m.p. = 214–216 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.22 (s, 3H, OCH3), 7.10 (d, 2H, J = 8.7 Hz, Ar-), 7.56 (d, 2H, J = 8.7 Hz, Ar-), 7.75 (s, 1H, CH=), 12.51 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 55.5, 114.9, 125.6, 131.6, 132.0, 160.9, 168.1, 168.3 ppm; HRMS (ESI+): m/z calcd for C11H9NO3S [M + Na]+ 258.0211; found 258.0212.
(Z)-5-(4-Benzilydene-4-boronic acid)-2-thioxo-imidazolidin-4-one (4). Pale Brown powder, 65% yield, m.p. = 242–244 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 7.54 (d, 2H, J = 8.1 Hz, Ar-), 7.62 (s, 1H, CH=), 7.91 (d, 2H, J = 8.1 Hz, Ar-), 13.85 (s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 126.3, 129.8, 132.1, 134.7, 135.4, 169.8, 196.2 ppm (Carbon atoms in α to boron are often non visible in 13C-NMR); 11B NMR (96 MHz, DMSO-d6): 28.30; HRMS (ESI+): m/z calcd for C10H8BNO3S2 [M + Na]+ 287.9936; found 287.9939.
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one (5) [40]. Pale yellow powder, 50% yield, m.p. = 106–108 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.90 (s, 3H, OCH3), 6.98 (d, 2H, J = 8.8 Hz, Ar-), 7.40–7.45 (m, 3H, Ar-), 7.55 (d, 1H, J = 15.7 Hz, CH=), 7.62–7.64 (m, 2H, Ar-), 7.80 (d, 1H, J = 15.7 Hz, CH=), 8.03 (d, 2H, J = 8.8 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.5, 113.8, 121.9, 128.2, 128.3, 128.9, 130.3, 130.8, 144.0, 163.4, 188.8 ppm. HRMS (ESI+): m/z calcd for C16H14O2 [M + Na]+ 261.0891; found 261.0892.

4. Conclusions

We described here an environmentally friendly protocol under microwave irradiation conditions for the preparation of several condensation products. The reaction time is short and non-toxic and cheap boric acid is employed as catalyst. These conditions can be considered as an alternative method to those traditionally described by their compatibility to base-sensitive functional groups. Our preliminary attempts to develop an auto-catalyzed reaction with a substrate bearing a boronic acid function have partly failed. Work is ongoing in our laboratory.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/20/06/11617/s1.

Acknowledgments

We are grateful to the University of Rennes 1 and CNRS for their financial support. Thanks to Ludovic Paquin for his help concerning the use of the microwave apparatus. We are thankful to Laurent Meijer (Manros Therapeutics) for continuous support.

Author Contributions

E.B., A.S., K.B., J.-M.L. performed the experiments. J.-P.B., J.M.V. and F.C. designed research and analyzed the data. F.C. wrote the paper. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References and Notes

  1. Hall, D.G. Boronic Acids; Wiley VCH: Weinheim, Germany, 2005. [Google Scholar]
  2. Zheng, H.; Hall, D.G. Boronic acid catalysis: An atom-economical platform for direct activation and functionalization of carboxylic acids and alcohols. Aldrichim. Acta 2014, 47, 41–51. [Google Scholar]
  3. Houston, T.A.; Wilkinson, B.L.; Blanchfield, J.T. Boric acid catalyzed chemoselective esterification of α-hydroxycarboxylic acids. Org. Lett. 2004, 6, 679–681. [Google Scholar] [CrossRef] [PubMed]
  4. Maki, T.; Ishihara, K.; Yamamoto, H. N-Alkyl-4-boronopyridinium halides versus boric acid as catalysts for the esterification of α-hydroxycarboxylic acids. Org. Lett. 2005, 7, 5047–5050. [Google Scholar] [CrossRef] [PubMed]
  5. Levonis, S.M.; Bornaghi, L.F.; Houston, T.A. Selective monoesterification of malonic acid catalyzed by boric acid. Aust. J. Chem. 2007, 60, 821–823. [Google Scholar] [CrossRef]
  6. Tang, P. Boric acid catalyzed amide formation from carboxylic acids and amines: N-benzyl-4-phenylbutyramide. Org. Synth. 2005, 81, 262–272. [Google Scholar]
  7. Mylavarapu, R.K.; GCM, K.; Kolla, N.; Veeramalla, R.; Koilkonda, P.; Bhattacharya, A.; Bandichhor, R. Boric acid catalyzed amidation in the synthesis of active pharmaceutical ingredients. Org. Process. Res. Dev. 2007, 11, 1065–1068. [Google Scholar] [CrossRef]
  8. Maras, N.; Kocevar, M. Boric acid catalyzed direct condensation of carboxylic acids with benzene-1,2-diamine into benzimidazoles. Helv. Chim. Acta 2011, 94, 1860–1874. [Google Scholar] [CrossRef]
  9. Nguyen, T.B.; Sorres, J.; Tran, M.Q.; Ermolenko, L.; Al-Mourabit, A. Boric acid: A highly efficient catalyst for transamidation of carboxamides with amines. Org. Lett. 2012, 14, 3202–3205. [Google Scholar] [CrossRef] [PubMed]
  10. Rostami, A.; Akradi, J.; Ahmad-Jangi, F. Boric acid as cost-effective and recyclable catalyst for trimethylsilyl protection and deprotection of alcohols and phenols. J. Braz. Chem. Soc. 2010, 21, 1587–1592. [Google Scholar] [CrossRef]
  11. Delbecq, P.; Celerier, J.P.; Lhommet, G. Decarboxylation of cyclic β-enaminoketoesters with boric acid. Tetrahedron Lett. 1990, 31, 4873–4874. [Google Scholar] [CrossRef]
  12. Gogoi, K.; Dewan, A.; Gogoi, A.; Borah, G.; Bora, U. Boric acid as highly efficient catalyst for the synthesis of phenols from arylboronic acids. Heteroat. Chem. 2014, 25, 127–130. [Google Scholar] [CrossRef]
  13. Chaudhuri, M.K.; Hussain, S.; Kantam, M.L.; Neelima, B. Boric acid: A novel and safe catalyst for aza-Michael reactions in water. Tetrahedron Lett. 2005, 46, 8329–8331. [Google Scholar] [CrossRef]
  14. Chaudhuri, M.K.; Hussain, S. Boric acid catalyzed thia-Michael reactions in water or alcohols. J. Mol. Catal. A Chem. 2007, 269, 214–217. [Google Scholar] [CrossRef]
  15. Meshram, M.; Rao, N.N.; Kumar, G.S. Boric acid-mediated mild and efficient Friedel-Crafts alkylation of indoles with nitro styrenes. Synth. Commun. 2010, 40, 3496–3500. [Google Scholar] [CrossRef]
  16. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang, X. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using boric acid as catalyst. Tetrahedron Lett. 2003, 44, 6153–6155. [Google Scholar] [CrossRef]
  17. Zhou, X.; Zhang, M.Y.; Gao, S.T.; Ma, J.J.; Wang, C.; Liu, C. An efficient synthesis of 1,5-benzodiazepine derivatives catalyzed by boric acid. Chin. Chem. Lett. 2009, 20, 905–908. [Google Scholar] [CrossRef]
  18. Karimi-Jaberi, Z.; Keshavarzi, M. Efficient one-pot synthesis of 14-substituted-14H-dibenzo[a,j]xanthenes using boric acid under solvent-free conditions. Chin. Chem. Lett. 2010, 21, 547–549. [Google Scholar] [CrossRef]
  19. Ganguly, N.C.; Roy, S.; Mondal, P. Boric acid-catalyzed one-pot access to 7-aryl-benzopyrano[4,3-b]benzopyran-6,8-diones under aqueous micellar conditions. Synth. Commun. 2014, 44, 433–440. [Google Scholar] [CrossRef]
  20. Ducki, S. The developments of chalcones as promising anticancer agents. IDrugs 2007, 10, 42–46. [Google Scholar] [PubMed]
  21. Singh, P.; Anand, A.; Kumar, V. Recent developments in biological activities of chalcones: A mini review. Eur. J. Med. Chem. 2014, 85, 756–777. [Google Scholar] [CrossRef] [PubMed]
  22. Matos, M.J.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L. Potential pharmaceutical uses of chalcones: A patent review. Expert Opin. Ther. Pat. 2015, 25, 351–366. [Google Scholar] [CrossRef] [PubMed]
  23. As example, see: Valdameri, G.; Gauthier, C.; Terreux, R.; Kachadourian, R.; Day, B.J.; Winnischofer, S.M.B.; Rocha, M.E.M.; Frachet, V.; Ronot, X.; Pietro, A.D.; et al. Investigation of chacones as selective inhibitors of the breast cancer resistance protein: Critical role of methoxylation in both inhibition potency and cytotoxicity. J. Med. Chem. 2012, 55, 3193–3200. [Google Scholar]
  24. Zhu, C.; Zuo, Y.; Wang, R.; Liang, B.; Yue, X.; Wen, G.; Shang, N.; Huang, L.; Chen, Y.; Du, J.; et al. Discovery of potent cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis with affinity-based fluorescence. J. Med. Chem. 2014, 57, 6364–6382. [Google Scholar] [CrossRef] [PubMed]
  25. Ye, X.; Zhou, W.; Li, Y.; Sun, Y.; Zhang, Y.; Ji, H.; Lai, Y. Darbufelone, a novel anti-inflammatory drug, induces growth inhibition of lung cancer cells both in vitro and in vivo. Cancer Chemother. Pharmacol. 2010, 66, 277–285. [Google Scholar] [CrossRef] [PubMed]
  26. Tahtouh, T.; Elkins, J.M.; Filippakopoulos, P.; Soundararajan, M.; Burgy, G.; Durieu, E.; Cochet, C.; Schmid, R.S.; Lo, D.C.; Delhommel, F.; et al. Selectivity, Cocrystal structures, and neuroprotective properties of leuccettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. J. Med. Chem. 2012, 56, 9312–9330. [Google Scholar] [CrossRef] [PubMed]
  27. Mahrwald, R. Modern Aldol Reactions; Wiley VCH: Weinheim, Germany, 2004. [Google Scholar]
  28. The solubility of boric acid in water is higher than those of arylboronic acids allowing a more simple elimination (1 g in 18 mL according to Sigma-Aldrich information, Saint Louis, MI, USA).
  29. Offenhauer, R.D.; Nelsen, S.F. Aldehyde and ketone condensation reactions catalyzed by boric acid. J. Org. Chem. 1968, 33, 775–777. [Google Scholar] [CrossRef]
  30. Nelsen, S.F.; Offenhauer, R.D. Condensation Reactions with Boric Acid. U.S. Patent 3,592,856 A, 13 July 1971. [Google Scholar]
  31. Deligny, M.; Carreaux, F.; Carboni, B. A concise synthesis of (+)-goniodiol using a catalytic hetero Diels-Alder/allylboration sequence. Synlett 2005, 1462–1464. [Google Scholar] [CrossRef]
  32. Carreaux, F.; Favre, A.; Carboni, B.; Rouaud, I.; Boustie, J. First synthesis of (+)-8-methoxygoniodiol and its analogue, 8-deoxygoniodiol, using a three component strategy. Tetrahedron Lett. 2006, 47, 4545–4548. [Google Scholar] [CrossRef]
  33. Favre, A.; Carreaux, F.; Deligny, M.; Carboni, B. Stereoselective synthesis of (+)-goniodiol, (+)-goniotriol, (−)-goniofupyrone and (+)-altholactone using a catalytic asymmetric hetero-Diels-Alder/allylboration approach. Eur. J. Org. Chem. 2008, 29, 4900–4907. [Google Scholar] [CrossRef]
  34. Touchet, S.; Carreaux, F.; Molander, G.A.; Carboni, B.; Bouillon, A. Iridium-catalyzed allylic amination route to a-aminoboronates: Illustration of the decisive role of boron substituents. Adv. Synth. Catal. 2011, 353, 3391–3396. [Google Scholar] [CrossRef] [PubMed]
  35. Hemelaere, R.; Carreaux, F.; Carboni, B. A diastereoselective route to trans-2-aryl-2,3-dihydrobenzofurans through sequential cross-metathesis/isomerization/allylboration reactions: Synthesis of bioactive neolignans. Eur. J. Org. Chem. 2015, 2015, 2470–2481. [Google Scholar] [CrossRef]
  36. As boric acid is coming from the ultimate degradation of phenylboronic acid by oxidation, it can be regarded as the most “green” reagent.
  37. Wu, X.-F.; Neumann, H.; Beller, M. Palladium-catalyzed oxidative carbonylative coupling reaction of arylboronic acids with styrenes to chalcones under mild aerobic conditions. Chem. Asian. J. 2012, 7, 282–285. [Google Scholar] [CrossRef] [PubMed]
  38. Mendgen, T.; Steuer, C.; Klein, C.D. Privileged scaffolds or promiscuous binders: A comparative study on rhodanines and related heterocycles in medicinal chemistry. J. Med. Chem. 2012, 55, 743–753. [Google Scholar] [CrossRef] [PubMed]
  39. Touchet, S.; Carreaux, F.; Carboni, B.; Bouillon, A.; Boucher, J.-L. Aminoboronic acids and esters: From synthetic challenges to the discovery of unique classes of enzyme inhibitors. Chem. Soc. Rev. 2011, 40, 3895–3914. [Google Scholar] [CrossRef] [PubMed]
  40. Syam, S.; Abdelwahab, S.I.; Al-Mamary, M.A.; Mohan, S. Synthesis of chalcones with anticancer activities. Molecules 2012, 17, 6179–6195. [Google Scholar] [CrossRef] [PubMed]
  41. Sharma, N.; Mohanakrishmann, D.; Shard, A.; Sharma, A.; Saima; Sinha, A.K.; Sahal, D. Stilbene-chalcone hybrids: Design, synthesis and evaluation as a new class of antimalarial scaffolds that trigger cell death through stage specific apoptosis. J. Med. Chem. 2012, 55, 297–311. [Google Scholar] [CrossRef] [PubMed]
  42. Ducki, S.; Rennison, D.; Woo, M.; Kendall, A.; Chabert, J.F.D.; McGown, A.T.; Lawrence, N.J. Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and biological evaluation of antivascular activity. Bioorg. Med. Chem. 2009, 17, 7698–7710. [Google Scholar] [CrossRef] [PubMed]
  43. Ashtekar, K.D.; Staples, R.J.; Borhan, B. Development of a formal catalytic asymmetric [4 + 2] addition of ethyl-2,3-butadienoate with acyclic enones. Org. Lett. 2011, 13, 5732–5735. [Google Scholar] [CrossRef] [PubMed]
  44. Salum, L.B.; Altei, W.F.; Chiaradia, L.D.; Cordeiro, M.N.S.; Canevarolo, R.R.; Melo, C.P.S.; Winter, E.; Mattei, B.; Daghestani, H.N.; Santos-Silva, M.C.; et al. Cytotoxic 3,4,5-trimethoxychalcones as mitotic arresters and cell migration inhibitors. Eur. J. Med. Chem. 2013, 63, 501–510. [Google Scholar] [CrossRef] [PubMed]
  45. Khalilullah, H.; Khan, S.; Ahsan, M.J.; Ahmed, B. Synthesis of antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives. Bioorg. Med. Chem. Lett. 2011, 21, 7251–7254. [Google Scholar] [CrossRef] [PubMed]
  46. Ono, M.; Haratake, M.; Mori, H.; Nakayama, M. Novel chalcones as probes for in vivo imaging of b-amyloid plaques in Alzheimer’s brains. Bioorg. Med. Chem. 2007, 15, 6802–6809. [Google Scholar] [CrossRef] [PubMed]
  47. Debdab, M.; Carreaux, F.; Renault, S.; Soundarajan, M.; Fedorov, O.; Filippalopoulos, P.; Lozach, O.; Babault, L.; Tahtouh, T.; Baratte, B.; et al. Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: Modulation of alternative pre-RNA splicing. J. Med. Chem. 2011, 54, 4172–4186. [Google Scholar] [CrossRef] [PubMed]
  48. Gosling, S.; Rollin, P.; Tatibouët, A. Thiohydantoins: Selective N- and S-functionalization for Liebeskind-Strogl reaction study. Synthesis 2011, 3649–3660. [Google Scholar] [CrossRef]
  49. Bourahla, K.; Derdour, A.; Rahmouni, M.; Carreaux, F.; Bazureau, J.P. A practical access to novel 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones via sulfur/nitrogen displacement under solvent-free microwave irradiation. Tetrahedron Lett. 2007, 48, 5785–5789. [Google Scholar] [CrossRef]
  50. Sortino, M.; Delgado, P.; Juarez, S.; Quiroga, J.; Abonia, R.; Insuasty, B.; Nogueras, M.; Rodero, L.; Garibotto, F.M.; Enriz, R.D.; et al. Synthesis and antifungal activity of (Z)-5-arylidenerhodanines. Bioorg. Med. Chem. 2007, 15, 484–494. [Google Scholar] [CrossRef] [PubMed]
  51. Fan, C.; Clay, M.D.; Deyholos, M.K.; Vederas, J.C. Exploration of inhibitors for diaminopimelate aminotransferase. Bioorg. Med. Chem. 2010, 18, 2141–2151. [Google Scholar] [CrossRef] [PubMed]
  52. Zidar, N.; Tomasic, T.; Sink, R.; Rupnik, V.; Kovac, A.; Turk, S.; Patin, D.; Blanot, D.; Contreras Martel, C.; Dessen, A.; et al. Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD Ligase. J. Med. Chem. 2010, 53, 6584–6594. [Google Scholar] [CrossRef] [PubMed]
  53. Xia, Z.; Knaak, C.; Ma, J.; Beharry, Z.M.; McInnes, C.; Wang, W.; Kraft, A.S.; Smith, C.D. Synthesis and evaluation of novel inhibitors of pim-1 and pim-2 protein kinases. J. Med. Chem. 2009, 52, 74–86. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: Samples of the compounds 2c–f, 2j–l, 2o–p, 3b,d,j are available from the authors.

Share and Cite

MDPI and ACS Style

Brun, E.; Safer, A.; Carreaux, F.; Bourahla, K.; L'helgoua'ch, J.-M.; Bazureau, J.-P.; Villalgordo, J.M. Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions. Molecules 2015, 20, 11617-11631. https://doi.org/10.3390/molecules200611617

AMA Style

Brun E, Safer A, Carreaux F, Bourahla K, L'helgoua'ch J-M, Bazureau J-P, Villalgordo JM. Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions. Molecules. 2015; 20(6):11617-11631. https://doi.org/10.3390/molecules200611617

Chicago/Turabian Style

Brun, Elodie, Abdelmounaim Safer, François Carreaux, Khadidja Bourahla, Jean-Martial L'helgoua'ch, Jean-Pierre Bazureau, and Jose Manuel Villalgordo. 2015. "Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions" Molecules 20, no. 6: 11617-11631. https://doi.org/10.3390/molecules200611617

Article Metrics

Back to TopTop