Michael Additions of Thiocompounds to-Unsaturated Carbonyl Compounds in Aqueous Media : Stereoselectivity with Unambiguous Characterization by NMR

As reações de crotonaldeído (8) com tiofenol (2) e benzalacetona (10) com 1,2-etanoditiol (11) levam aos produtos de adição de Michael. As reações de tiofenol (2) com (R)-carvona (13) e (S)-perilaldeído (15) levam aos produtos (2S,3R,5S)-5-isopropenil-2-metil-3-feniltio-cicloexanona (14) e (1R,2R,4S)-4-isopropenil-2-feniltio-cicloexano carbaldeído (16), respectivamente. Também é apresentada a elucidação inequívoca da estereoquímica de 14 e 16 por RMN.


Introduction
At this century's threshold, the environmental conditions of our planet Earth are, and should be, one of our most serious concerns.Chemistry research may bring us great advances in the quality of life (e.g., medications, new materials, etc.), but on the other hand, it may also be responsible for several of our environmental pollution problems.
For sustainable development, 1 we must think about strategies to minimize the environmental impact of these technological activities.][4][5][6][7][8] Today, the study of organic reactions using water as a solvent is considered an important strategy in the area of Green Chemistry.0][11][12][13] The Michael reaction, a widely used technique in organic synthesis, 14 is an important tool for the preparation of various polyfunctional compounds via carbon-carbon and carbon-heteroatom bond-forming reactions.In the literature, some examples of Michael reactions in aqueous media can be found.3][24][25][26][27] Recently, it was reported that amphiphilic polymer-supported ammonium hydroxides are efficient heterogeneous catalysts for these reactions. 288] According to King and co-workers, 39 the control of pH is essential for the optimization of the nucleophilic reactions in aqueous media as lateral processes, such as reagent hydrolysis, compete with the desired reaction.Previously, we reported on the Michael additions of propane-1-thiol (1) and thiophenol (2) to cyclohex-2-enone (3) at three pH conditions in aqueous media (pH 7, 10, 13).The best condition for all of the tested reactions was at pH 7 using a 1 mol L -1 NaHCO 3 aqueous solution.The yields were 70% and 95%, respectively (Scheme 1). 38r research also showed that the Michael additions of thiophenol (2) to -unsaturated nitroolefins like 1-nitrocyclohex-1-ene (5) in aqueous media have a good diastereoselectivity; this result is cited in the literature as the first example of this kind of reaction in water that presents diastereoselectivity (Scheme 2). 38,40perimental Thiophenol (2), crotonaldehyde (8), benzalacetone (10), ethane-1,2-dithiol (11), (R)-carvone (13) and (S)-perillaldehyde (15) were used as received (Aldrich).Some of the products were purified by radial chromatography in a Harrison Research Chromatotron.High resolution gas chromatography (HRGC) analyses were performed under two conditions: condition A) HP-5890-II gas chromatograph with FID, using a 30 m (length), 0.25 mm (ID) and 0.5 mm (phase thickness) RTX-5 silica capillary column with H 2 as the gas carrier and a flow division of 1/20; condition B) Varian Star 3400cx gas chromatograph with FID, using a 30 m (length), 0.25 mm (ID) and 0.5 mm (phase thickness) capillary column HP1 for injection on-column, and H 2 as the gas carrier.The analyses were performed in a BRUCKER-300 ( 1 H -300 MHz, 13 C -75 MHz) and in a Varian Mercury ( 1 H -400 MHz, 13 C -100 MHz) in CDCl 3 and C 6 D 6 as solvents, with TMS as the internal standard.
The unambiguous 1 H and 13 C NMR assignments for compounds 14 and 16 were obtained from COSY90, HSQC, HMBC, TOCSY and nOe.All experiments were run with a relaxation delay of 1.5 s, 65K ( 1 H) and 32K ( 13 C) data points for 1D experiments and 2048 × 512 data matrixes for COSY90, TOCSY (mixing time of 25 ms), nOe (mixing time of 300 ms) HSQC and HMBC.Gradient selections were used in all 2D techniques.Zero filling and/or linear predictions were used in all 2D experiments.Pulse programs and data processing were performed using XWINMR 3.5 software from BRUKER.
The FT-IR spectra were recorded on a Nicolet Magna-IR-FT (NaCl film).

Scheme 2. Comparison of the first example of diastereoselectivity of Michael addition in water with classical methods.
were also added.The reaction mixture was then stirred vigorously for 40 min at room temperature.Then, the reaction mixture was neutralized with concentrated hydrochloric acid and extracted with chloroform.The organic extract was dried (using anhydrous Na 2 SO 4 ), and the solvent was evaporated under reduced pressure.The product was purified by radial chromatography using chloroform as a solvent.0.34 g of product was obtained.The following spectroscopic data were obtained: IR (KBr) max /cm -1 2825, 2727, 1724, 748, 693; 1

Michael addition of thiophenol (2) to -unsaturated terpenes
To 10 mL of a 0.5 mol L -1 NaHCO 3 aqueous solution, 20 mmol of thiophenol (2) were added.Soon after, 10 mmol of the respective terpene were also added.The reaction mixture was then stirred vigorously for 24 h at room temperature.The products of each substrate were isolated and characterized as follows: For (R)-carvone (13) (2S,3R,5S)-5-Isopropenyl-2-methyl-3-(phenylthio) cyclohexanone ( 14): The solid product was isolated from the reaction media by filtration and purified by recrystalization using hexane as the solvent; 1.27 g were obtained.For NMR data, see Table 1  For (S)-perillaldehyde (15)   ( 1 R , 2 R , 4 S ) -4 -I s o p r o p e n y l -2 -( p h e n y l t h i o ) cyclohexanecarbaldehyde ( 16): The solid product was isolated from the reaction media by filtration and crystallized using hexane as the solvent.1.77 g of a sample of compound 16 and thiophenol were obtained.In order to obtain a pure sample, this mixture was purified by flash chromatography using hexane:ethyl acetate (9:1); 1.20 g were obtained.For NMR data, see Table 2

Synthesis
In this work, we extended our studies to other unsaturated carbonyl compounds.
The stereochemistry of these reactions is controlled by the axial addition of thiophenol in the first step and by the axial protonation in the next step (Scheme 5).
These reactions (Scheme 4) are reported in the literature using CH 2 Cl 2 or hexane at 0 o C as the solvent and triethylamine as the catalyst, leading to the same products. 41,42However, in the literature, the determination of the stereochemistry of the products was not clear.We report here the unambiguous elucidation of the stereochemistry of 14 and 16.
The methodology developed in this paper presents as an advantage the substitution of a toxic and inflammable organic solvent for water.Furthermore, no temperature control was necessary.Also, in operational work-up, our methodology reduces the product isolation procedure to a filtration step, as these products are insoluble in water.

Stereochemical elucidation with unambiguous spectral assignments of compounds 14 and 16 by NMR
The 1 H NMR spectrum for compound 16 was fully assigned by a combination of homo-and heteronuclear 2D NMR methods, including DQF-COSY, HSQC, HMBC, nOe experiments and 1D-TOCSY.Some important details of the experiments will be commented on.
In the nOe difference experiment, the relative configuration of the H-2 and H-3 hydrogens was established.The selective irradiation of H-2 produces nOe enhancements at H-3 and H-10, and a slight effect at axial hydrogens H-6 and H-4, while the selective saturation of H-3 produces nOe enhancements at H-2 and both H-4 and H-10.The nOe effect on axial and equatorial hydrogen H-4 is very similar.These nOe indicate that hydrogen H-3 is at the equatorial position, because if it were in the axial position this difference would be greater (Figure 2).
With the TOCSY experiment, it was possible to determine the multiplicity of hydrogen H-2 ( 2.49-2.58).Hydrogen H-3 ( 3.98) was selectively saturated in CDCl 3 .The spectrum was obtained with a mixing time of 25 ms at 20 o C. The irradiation changes the multiplet to a double triplet with J 2-7ax 12.37 Hz and J 2-7eq J 2-3 3.10 Hz (Figure 5).These couplings are consistent with H-2 in the axial position.
Finally, the relative configurations of H-3 and H-5 were examined with 1 H nOe difference spectroscopy.Saturation of H-3 in CDCl 3 produces nOe enhancements at H-2 and H-4 axial, while the saturation of H-5 in the C 6 D 6 solvent shows nOe at H-4 equatorial.With this result, it is possible to suggest that H-3 and H-2 are synclinal, as shown in Figure 6.

Conclusions
The present work is an additional relevant contribution to the study of organic reactions in water.The Michael addition reactions of thiophenol to , -unsaturated terpenes in aqueous media show high stereoselectivity in the formation of the products at room temperature, with      good yields.This methodology represents an improvement over previous methods available in the literature in that it: a) uses a non-aggressive solvent; b) substitutes NaHCO 3 for triethylamine as the base; c) can be carried out at room temperature (while in previous procedures low temperatures were needed); and d) the isolation step was reduced to a simple filtration.All of these advantages show progress toward the goal of Green Chemistry.

Figure 3 . 1 H
Figure 3. 1 H NMR spectra of compound 16 in (a) a chloroform solvent and (b) a benzene solvent.

Figure 4 .
Figure 4. COSY spectra showing a cross signals for compound 16 in a chloroform solvent.

Figure 5 .
Figure 5. Selective excitation of hydrogen H-3 in the TOCSY experiment.

Table 2 .
Summary of the 1 H and 13 C data for compound 16