Comparative Studies on Conventional and Ultrasound-Assisted Synthesis of Novel Homoallylic Alcohol Derivatives Linked to Sulfonyl DibenzeneMoiety in AqueousMedia

Novel homoallylic alcohols incorporating sulfonemoieties were synthesized by the treatment of different carbonyl compounds with allylic bromides in aqueousmedia via sonochemical Barbier-type reaction conditions. Sulfonation of αα-bromoketones with sodium benzenesul�nate in presence of CuI/2,6-lutidine rapidly gave ββ-keto-sulfones in good yields. In general, ultrasound irradiation offered the advantages of high yields, short reaction times, and simplicity compared to the conventional methods. e structures of all the compounds were con�rmed by analytical and spectral data.


Introduction
Ultrasonic assisted organic synthesis as a green synthetic approach is a powerful technique that is being used more and more to accelerate organic reactions [1][2][3][4][5].A large number of organic reactions can be carried out in higher yields, shorter reaction times, or milder conditions under ultrasound irradiation.is can be considered as a processing aid in terms of energy conservation and waste minimization compared to conventional heating.Many metal-mediated organic reactions have been accelerated using ultrasound irradiation [6][7][8][9][10].However, increased temperatures will also increase reaction rates.While making molecules with several sulfone moieties, we compared the effect of ultrasound to conventional heating for improved yields and reaction rates.e aryl sulfone moiety has been found in numerous biologically interesting compounds.ese compounds include antifungal, antibacterial, or antitumor agents [11,12] and inhibitors for several enzymes such as cyclooxygenase-2 (COX-2) [13], HIV-1 reverse transcriptase [14,15], integrin VLA-4 [16], and the ATPase [17].New compounds incorporating aryl sulfone moieties are likely to display interesting biological activity.
Nucleophilic additions to carbonyl groups are one of the cornerstones of organic chemistry.Carbonyl allylation forms homoallylic alcohols which are versatile subunits that can easily be converted to a number of other useful functions [18,19].Synthetic protocols have been developed for allylation of carbonyl compounds in the Barbier reaction including the use of metals such as zinc [20], tin [21], samarium [22], gallium [23], and indium [24].In particular, indium has been shown to be an effective metal in allylations [25][26][27][28][29].In the past few decades, indium has become a popular metal due to the ability of organoindium intermediates to tolerate functionality and ambient conditions along with indium being nontoxic [3,[30][31][32][33].In addition, indium-mediated allylation reactions in aqueous media oen proceed smoothly at room temperature without any additive, while other metals usually require additives and anhydrous organic solvents [34][35][36][37][38][39][40].
-Haloketones have been attracting increasing attention in view of their high reactivity as building blocks for the preparation of compounds of various classes due to their selective transformations with different reagents [41].e sulfonation of -haloketones involves the displacement reaction of halogens with sul�nic acid salts.e reaction proceeds thermally [42] or under phase-transfer catalysis conditions [43] but more conveniently directly from sodium sul�nate under microwave radiation [44].As microwave technology was unavailable for us and we knew that CuI under basic conditions can catalyze C-N, C-O, C-S, and C-C bond formation reactions [45][46][47], we investigated the use of CuI/2,6-lutidine as a catalyst for the reaction of aromatic bromoketone with sodium benzenesul�nate.
Herein, we report the results of the allylation reactions of aldehyde and ketone derivatives containing a sulfone moiety by indium in aqueous media under ultrasound irradiation compared to conventional methods.We also report that CuI/2,6-lutidine catalyzes the sulfonation of -bromoketone at room temperature in DMSO, but even better with sonication.

Experimental Section
e chemicals used in this work were obtained from Fluka and Merck and were used without puri�cation.Indium powder was obtained from Sigma-Aldrich Company as 99.99% pure, but containing 1% Mg as anticaking agent.Melting points were determined on a Bibby Sterilin ltd electrothermal melting point apparatus and are uncorrected.Sonochemical reactions were carried out in a Branson B1510 DTH ultrasound cleaning bath (50 kHz, 245 W). e reactions were monitored by thin layer chromatography using Fluka �F254 silica gel plates with a �uorescent indicator; detection by means of UV light at 254 and 360 nm.e IR spectra were recorded on KBr disks on a Perkin Elmer 2000 FTIR spectrometer.e NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer at 300.13 and 75.47 MHz. 1 H NMR and 13 C NMR spectra were recorded in deuterated chloroform (CDCl 3 ) or dimethyl sulphoxide (DMSO-d6) using TMS as the internal standard. 13C chemical shis were related to that of the solvent.Mass spectra were recorded on ESI-MS ermo LTQ Orbitrap XL, infusion 5 uL/min, resolution: 100 000 at m/z 400, ca. 10 scans/sample averaged.e aryl sulfones 1a,b were prepared according to the literature [48].

Conventional Reactions
General Procedure for Indium-Mediated Barbier-Type Reactions.e carbonyl compound (1a,b or 6a,b) (1 mmol) and the corresponding bromide (3 mmol) in a mixture of THF and H 2 O (3 + 1 mL) were treated with indium (2 mmol).e mixture was vigorously stirred at 50 ∘ C for approximately 12 h.e progress of the reaction was monitored by TLC.Aer completion of the reaction the resulting, mixture was �ltered and extracted with ethyl acetate (3 × 10 mL).e combined organic layers were washed with saturated aqueous NaHCO 3 solution and brine, dried over anhydrous magnesium sulfate, and further dried under reduced pressure.e residue afforded the corresponding homoallylic alcohols (2a,b; 3a,b; 7a,b; 8a,b).e product was puri�ed by column chromatography (SiO 2 ; ethyl acetate/petroleum ether, 1 : 4).

Sonicated Reactions
General Procedure for Synthesis of 2-Bromo-1-Substituted Ethanones.Bromine (1 mmol) was added dropwise to a solution of 1 mmol of the aryl methyl ketone derivatives (1b,4) in glacial acetic acid (10 mL) in a 50 mL Erlenmeyer �ask.e mixture was subjected to ultrasonic irradiation at 25-30 ∘ C for the appropriate time until completion of the reaction (monitored by TLC), then poured over crushed ice.e solid product so-formed was �ltered off, washed with water, dried, and recrystallized from ethanol to afford 2bromo-1-substituted ethanones (5a,b).
Following this procedure 2.0 mmol of other bases Et 3 N, K 2 CO 3 , piperidine, and no base, were used in place of 2,6lutidine to screen the conditions.e yields are summarized in Table 3. e sulfonation of 5a to 6a with 2,6-lutidine in absence of CuI by this procedure gave no reaction.
General Procedure for Indium-Mediated Barbier-Type Reactions.A 50 mL Erlenmeyer �ask was charged with the desired  1 and 2, and the spectral data are given below.

Results and Discussion
We �rst investigated the indium-mediated Barbier procedure for the allylation of the arylsulfonated 4-(phenylsulfonyl)benzaldehyde (1a) and 1-(4-(phenylsulfonyl)phenyl)ethanone (1b).A 50 mL Erlenmeyer �ask was charged with the desired aldehyde 1a or ketone 1b (1 mmol), allylbromide (3 mmol), and indium (2 mmol) in a mixture of THF and H 2 O (3 + 1 mL).e mixture was irradiated in the water bath of an ultrasonic cleaner at 25-30 ∘ C (Scheme 1).e bath had two obvious irradiation hotspots, and the �ask was placed in the center of one of them.
e homoallylic alcohols 2a,b-3a,b were formed in excellent yields using shorter reaction times compared to conventional heating conditions.e results are summarized in Table 1.e conversion rate of carbonyl allylation was notably affected by the temperature, under conventional conditions.At room temperature the reaction gave poor conversion even aer days of reaction (40% yield of 2a).At 35 ∘ C, the reaction improved.When the temperature was increased to 50 ∘ C, we got full conversion within reasonable time, but the yield was limited by some degradation.As THF has a boiling point of 65 ∘ C, further increase in temperature would demand a re�ux setup.But the solvent composition would then change in the reaction on our scale.us, further increase in temperature was refrained.
In order to investigate the regio-and diastereoselectivities of the allylation reaction, cinnamyl bromide was used as an allylation reagent.Allylation reactions involving cinnamyl bromide can provide both an -adduct and a -adduct, and the -adduct can be either a anti-or syn-product.Usually only the -adduct is formed, with a predominant antiselectivity [44][45][46][47][48][49][50][51][52].is can be explained mechanistically by a Felkin-Anh transition state [53], but here it may be more appropriate to refer to the 6-ring chair-like conformation with the large groups in equatorial positions suggested in the transition state (Scheme 2) as a Zimmerman-Traxler transition state [54].We also found that the indium-mediated allylation reaction always produced the -adduct with antiselectivity.ere were no traces of any syn-products under neither reaction conditions.
As shown in Scheme 1 and Table 1, the allylation carried out under ultrasonic irradiation gave excellent yields and shorter reaction times compared with the conventional heated reaction.For example, the product 2a took about 12 h for completion under conventional conditions and the yield of the product was 75%.In comparison, under ultrasonic irradiation, the reaction time was 3 h and the yield 92%.
e facile reaction of the aromatic ketone 1b was promising, so we wanted to introduce substituents to the ketone to challenge the selectivity of the allylation reaction and introduce another sulfone group.e synthesis is outlined in Scheme 3. Earlier experience with the power of ultrasound as a green chemistry technology for mediating organic synthesis [55] prompted us to explore the usefulness of ultrasound here as well.e bromination of acetyl derivatives 1b and 4 to afford the 2-bromo-1-substituted ethanones 5a,b were improved under ultrasound conditions compared to conventional stirring at 25-30 ∘ C, and gave high yields (Table 2).Most of the 2-bromo-1-arylethanone derivatives 5 were synthesized without sonication by the reaction of ketones with bromine in acetic acid with yields of 60-85% [56].Synthesis of 5a,b without sonication was previously also described by Cavelli et al. [49].
Carbonyl compounds 6a-e incorporating another sulfone group was prepared via the reaction of -haloketones with sodium benzeneul�nate under sonication (Scheme 3).e immediate success in converting 5a to 6a (Table 2) was followed by a screening of different bases for the reaction.Copper(I) and copper(II) catalysts has been used with a range of different bases for different bond formations including C-S bonds before [57].But as shown in Table 3; 2,6-lutidine is the superior base together with CuI in this reaction.2,6lutidine as a weak and sterically hindered base has also been the superior base in reactions with sulfonyl azides [58,59], so it may have something to do with the sulfone group.On the other hand 2,6-lutidine also improved the CuBrcatalyzed cross-coupling of arylboronic acids to alkynes [60].at CuI is necessary as a catalyst was demonstrated by the last entry in Table 2, where the reaction was attempted in the absence of CuI.No reaction was observed even aer 12 h of sonication, whereas the reaction with CuI/2,6-lutidine were completed to 93% yield in 1 h.us, treatment of the products 5a-e with sodium benzenesul�nate in the presence of CuI and 2,6-lutidine at room temperature in DMSO under ultrasound irradiation efficiently afforded the corresponding 6a-e (Scheme 3).In order to demonstrate the positive effect of ultrasound irradiation on the reaction, the same reactions in entries 5a,b-6a-e in Table 2 were also investigated under conventional conditions.All reactions carried out without sonication took longer time and gave lower yields than those submitted to ultrasound irradiation.Improvement of chemical reactions by ultrasound is oen ascribed to the high temperature formed when cavitations formed by the ultrasound collapses, sometimes leading to different products than those obtained without sonication.Although the energy delivered through the cleansing bath is not that high, there is still acoustic cavitation in the reaction �ask.In heterogeneous systems the acoustic cavitation is known to vastly improve diffusion rates and accelerate the reactions through microjets formed from asymmetrical collapses of the bubbles, and similar effects can be achieved with high speed mechanical stirring [61].But there are also several examples where ionic reactions are accelerated by physical effects (better mass transport) in homogenous reactions-oen called "false sonochemistry" [62].As we observed no real change of product, the improved reactivity from sonication is probably due to mechanical effects also in our homogenous reactions.e structure of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl)phenyl)ethanone 6a was con�rmed on the basis of its spectral data and high resolution mass analysis.e 1 H NMR spectrum of 6a revealed a singlet signal at  4.52 (CH 2 ) in addition to aromatic protons as a multiplet at  6.67-7.22.Its 13 C NMR spectrum revealed a signal at  62.6 due to CH 2 and a signal at  188.7 due to C=O. e IR spectrum revealed the appearance of a carbonyl absorption band at 1700 cm −1 and sulfone absorption bands at 1152 and 1312 cm −1 .In addition, its high resolution mass spectrum revealed a peak consistent with the formula C 20 H 16 O 5 S 2 .
In the same manner as carried out for 1a,b, the reaction of 6a,b with allyl and cinnamyl bromides resulted in the corresponding homoallylic alcohols (Scheme 4) with good to excellent yields and high steroselectivity as shown as in Table 4. Again, the reactions were greatly enhanced using ultrasound irradiation compared to classical conditions with heating.
Allylation of the brominated derivatives 5a,b were impractical.e conversion rate of the starting materials was poor and both allylation of the carbonyl group and substitution on the bromine occurred in different ratios forming a complex mixture of products.On the other hand, allylation of 1-substituted 2-(phenylsulfonyl)ethanone derivatives 6a,b was excellent with complete conversion and great selectivity.e structures of the latter homoallylic alcohols were established on the basis of their spectral data and high resolution mass analysis.In addition, the structure of these compounds was further con�rmed by 2D NMR (COSY, HETCOR and DEPT).In-depth 1D and 2D NMR spectroscopy analysis of 8b con�rmedthe 1 H NMR assignment: a doublet at  3.11 (J = 15.0Hz) due to one proton of CHHSO 2 Ph,  3.69 (J= 9.

Conclusion
In summary, we have demonstrated that ultrasound irradiation can markedly speed up the allylation of carbonyl compounds containing sulfone moieties via a Barbier-type reaction.Compared to classical stirring methods even at elevated temperatures, ultrasonic irradiation is more efficient.e reaction gave products with excellent regioselectivity, favoring the -adduct with anti-selectivity when cinnamyl halides were employed as the allylation reagents.Although the indium mediated allylation were unable to differentiate between the ketone and the -bromo group, an -sulphone group gave no problems.Sonication also improved the reactivity in the new CuI-catalyzed sulfonation reaction to form -phenylsulfoneketones from sul�nic acid salts and bromoketones.

T 4 :S 2 :
Synthesis of homoallylic alcohols by allylation of 6a,b with allylbromide (alcohols 7a,b) and cinnamyl bromide (alcohols 8a,b) as outlined in Scheme 4. e strong anti-selectivity obtained in the transformation of 1a,b to 3a,b may be explained by a Zimmerman-Traxler transition state.

S 3 :S 4 :
3 Hz) due to CHPh,  4.38 (J = 15.0Hz) due to the other proton of CHHSO 2 Ph,  4.56 (J = 9.9 Hz) due to one proton of CHH=CH and  4.76 (J = 9.9 Hz) due to other proton of CHH=CH.e signal at  5.29 ppm due to OH was D 2 O-exchangeable.Finally, there were multiplet signals Synthesis of 2-bromo-1-substituted ethanones 5a,b and 1-substituted 2-(phenylsulfonyl)ethanones 6a-e under ultrasonic irradiation or conventional conditions.Synthesis of homoallylic alcohols 7a,b-8a,b under ultrasonic irradiation or conventional conditions.at  5.86-8.98due to one proton of -CH 2 CH-CHPh and aromatic multiplets at  6.80-7.56.Its high resolution mass analysis was consistent with the formula C 23 H 21 FO 3 S. e IR spectrum of compound 8b shows one band at 3470 cm −1 due to an OH group.