Ultrasound-Assisted Conjugate Addition of Organometallic Reagents to 3-Diethylphosphonocoumarin

Abstract A comparative investigation on the 1,4-conjugate addition of various nucleophiles to diethyl ester of 2-oxo-2H-1-benzopyran-3-phosphonic acid under thermal and ultrasound promoted conditions is presented. The approach enables the usage of a simpler experimental setup and mild reaction conditions as well as excellent yield reproducibility. The trans isomers isolated showed high diastereoselectivity and the absolute structure of one of the products was confirmed by X-ray diffraction analysis.

Ultrasonic irradiation has been reported as an excellent alternative to thermal energy for promoting organic reactions, especially those requiring severe reaction conditions. [1][2][3] It is known that this kind of energy can be used to generate radicals and to initiate electron-transfer processes during reactions. Ultrasound techniques are also used as an environmentally friendly technology in green chemistry and provide another option for improving common reactions that require high temperatures, long reaction times and give unsatisfactory yields. Another aspect is the acceleration of metal-mediated organic reactions under ultrasound (US) due to activation of the metal surface, which is an efficient method for removing impurities and oxidized metal layers. Meanwhile, it can reduce the particle size, bring about modified surfaces of the metal and at the same time speed up the formation of organometallic reagents. 4 The Michael reaction is frequently a first choice chemical reaction in organic synthesis due to the vast variety of Michael acceptors and nucleophiles. Almost any activated alkene can serve as an acceptor e.g. α,β-unsaturated ketones, aldehydes, amides, acids, lactones, phosphonates, phosphoranes, quinones, coumarins. [5][6][7][8][9][10] Also, this addition allows large numbers of hard and soft nucleophiles to react with selected acceptors although competitive 1,2-addition reactions could be expected. Moreover, it is possible to form multiple stereogenic centers within a molecule in a single synthetic step. 11 A number of studies on the 1,4-conjugate addition reaction of nucleophiles to unsaturated carbonyl compounds have reported the necessity of basic or acidic catalysts. 12 Frequently those conditions have involved side reactions; for example, polymerization of the activated alkenes, especially under acidic conditions. In other methods when sensitive substrates are used, the stoichiometric ratios of the reagents have been controlled in order to avoid side reactions. 13 Nowadays one of the most reliable approaches for successful conjugate addition is based on the effect of ultrasonic irradiation. 14 Previous studies in our research group have reported 9,15-18 3-substituted 2-oxo-2H-1-benzopyrans as alternative acceptors in 1,4-conjugate additions with a variety of nucleophiles and in tandem reactions. In the present work, we wish to report our subsequent investigations on the chemical behavior of diethyl-3-phosphonocoumarin in the ultrasound-assisted Michael-type reaction. A series of organometallic compounds were chosen as hard nucleophiles to react with the coumarin system.

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thermodynamically favored and predominates at 25 °C or higher. 5 Theoretical evaluation of the reactivity of the electrophilic centers at C-2 and C-4 in the 3-substituted coumarin system (Scheme 1) using atomic charges, atomic electrostatic potential, XPS binding energies and atomic Fukui indices has shown 19 that coumarins would preferably react with soft nucleophiles at position 2 and with hard nucleophiles at position 4.

Scheme 1 Reaction of coumarin 1 with various organometallic reagents under ultrasound
Conjugate addition of various organometallic reagents to the diethyl ester of 2-oxo-2H-1-benzopyran-3-phosphonic acid 1 was carried out at reflux in Et 2 O/dimethoxymethane to give the products of 1,4-addition 2-7 with yields that varied between 38% and 78% (Scheme 1, Table 1). The organometallic compounds were prepared and utilized under classical conditions (heating) in anhydrous Et 2 O using 3 equivalents of RMX. The addition took place easily with formation of the preferred trans isomer, based on the chemical behavior of benzopyrans from our previous studies. However, the lack of reproducibility in the performed reactions where the yield for each product deviated by up to 30% was an issue.
In order to obtain suitable phosphorus-containing adducts for the Horner-Wadsworth-Emmons olefination of formaldehyde Janecki and co-authors [20][21][22] have presented Michael addition reactions of 5 equivalents of organometallic compounds to substituted 3-diethylphosphonocoumarins in the presence of catalytic amount of CuI. Peculiarly to our predictions in that case products of 1,4-addition were isolated even though soft nucleophiles were used. However, the main disadvantages of the method were long reaction times (2.5-48 h) and the requirement of an inert atmosphere.
Previously, we applied ultrasonic irradiation to the conjugate addition of phosphites to several coumarin systems which greatly increased the reaction rate and product yield. 17 The present study provides more evidence for the effect of sonication on the reaction between preformed organometallic compounds and the diethyl-3-phosphonocoumarin 1 ( Table 1). This method presented the opportunity to overcome the lack of reproducibility and to use a simpler experimental setup with mild conditions. Moreover, the use of ultrasound resulted in faster formation of the organometallic compounds than when heat was used. Because of the ultrasound activation the Michael reaction was accomplished more rapidly and proceeded with excellent yields.
The chemical behavior of diethyl-3-phosphonocoumarin 1 under sonication (Scheme 1) was studied by examining the steric effect of the added alkyl groups of the nucleophile. Comparison of the reaction of 1 with organomagnesium or organozinc compounds with or without ultrasonic irradiation is listed in Table 1 (Methods are given in the Supporting Information). 23 Reactions were performed in a mixture of anhydrous Et 2 O and dimethoxymethane at 40 °C. The crude products were purified by column chromatography or recrystallization.
It can be seen from Table 1 that when bulkier nucleophiles were used the reaction times increased but nevertheless the yields of the products were high. The same correlation was observed when the metal was changed to zinc.

Stereochemistry of the Products
Regarding the stereochemistry of the studied reaction we suggest attack of the nucleophile from the least hindered side of the C3=C4 double bond (Scheme 2). The reaction could be classified as syn-addition because the nucleophile and electrophile approach from the same side of the C3=C4 bond. Therefore, in the isolated products, the two bulkier groups around C3-C4 bond are aligned in an antiperiplanar position.

Scheme 2 Proposed reaction mechanism
To determine the conformation of the isolated products we mainly used NMR data as well as conclusions from previous reports 15,20,24 regarding the conjugate addition of organometallic reagents to 3-substituted coumarins. The isomers were characterized using the vicinal H3-H4 coupling constants, which vary depending on the type of substituent at position 3 of the coumarin system. In the case of electron-donating groups the values for the J constants are between 2-3 Hz while for electron-withdrawing groups this parameter decreases to 0.3-1.3 Hz. These data indicate a trans-gauche configuration of the isomers with an axialpseudoaxial location of the substituents on the C-3 and C-4 atoms.
In Table 2 are presented chemical shifts of the resonance peaks for the H-3 and H-4 protons of compounds 2 to 7 as well as spin-spin interactions between these two protons giving essential information for the conformational preferences in the isolated products. The vicinal coupling constant of the H3-H4 protons had values of ca. 1 Hz from which a dihedral angle of 70-80 degrees (Figure 1) was assumed.
This value confirmed the formation of the trans isomer in all reactions when a nucleophilic addition to the 3-substituted coumarin takes place. Again bulkier groups around the C3-C4 bond have a preferred antiperiplanar arrangement. Comparing the configurations of the compounds obtained in the previous studies, obviously small substituents in the third position in the coumarin system set the configuration to the trans-gauche with typical angle of 60 degrees, whereas the presence of phosphonic and nitromethyl groups 18

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POEt group and H-4 has the C=O group from CH 2 COOR substituent where the resonances were shifted to high-frequencies in both cases (0.05 and 0.5 ppm).
The assumptions from the NMR spectra were in agreement with the single crystal X-ray structure of diethyl(4isopropyl-2-oxochroman-3-yl) phosphonate 4 (CCDC 1451549, Figure 2, Table 3 in the Supporting Information). The single crystal X-ray diffraction confirmed that the product of 1,4-conjugate addition was the trans isomer. As shown in Figure 2, the dihedral angles of H4-C4-C3-H3 and CH 2 -C4-C3-P1, determined from the molecular structure in the crystal, displayed values of 73.69° and 162.87°, respectively, confirming the pseudoaxial antiperiplanar disposition of the two substituents around C3-C4 bond. In summary, we have reported the application of thermal and ultrasonication conditions for the reaction of the diethyl ester of 2-oxo-2H-1-benzopyran-3-phosphonic acid 1 with organometallic compounds. The Michael-type addition proceeded with better yields and shorter reaction times when ultrasonic irradiation was applied. This approach enables the usage of a simpler experimental setup and mild reaction conditions as well as excellent yield reproducibility.
Importantly, the method is useful for the preparation of 3,4-disubstituted chromanes with an exact configuration of the C3-C4 bond. The stereochemistry of products 2-7 was determined by NMR spectroscopy and the single crystal Xray spectra of product 4. All products were isolated as trans isomers with a pseudoaxial antiperiplanar disposition of the substituents at positions 3 and 4. The compared coupling constants of spin-spin interaction of H3-H4 protons confirmed the formation of the trans isomer in all cases when nucleophilic addition to 3-substituted coumarins took place.