Polyethylene glycol as support and phase transfer catalyst in aqueous palladium-catalyzed cross-coupling reactions

Xia Min, Wang Yanguang
(Department of Chemistry, Zhejiang University, Hangzhou 310027, China)


AbstractExcellent yields and purity were obtained in the aqueous palladium-catalyzed Suzuki, Sonogashira, Still and Heck reactions under mild conditions using polyethylene glycol (PEG) as soluble polymeric support and phase transfer catalyst as well.

The construction of libraries of compound using combinatorial and parallel synthesis has witnessed dramatic developments in recent years[1]. Insoluble polymers of all kinds have thus been examined as possible supports, providing significant advantages over many conventional solution phase routes. However, such an approach requires a great deal of developmental time and efforts to work up synthetic conditions on solid supports since generally slower kinetics and variations in behavior. Furthermore, it is always difficult in following reactions and characterizing products still attached to the polymer by routine analytical methodologies (e.g. H, 13C-NMR, I.R., TLC, etc.)
The use of soluble polymers, i.e. polymers which are soluble in one medium but insoluble in another and purity can therefore be carried out through precipitation by filtering and washing away unwanted materials after each operation, have overcome the drawbacks of working on insoluble supports to great extent. While the research on the preparation of peptides, olignonucleotieds and oligosaccharieds on soluble supports has been extensive, the synthesis of small molecules, especially the synthesis by transitional metal catalyzed reactions, has been very few [2,13]. So far, polyethylene glycol (PEG) appears to be the most promising and versatile soluble polymer in liquid phase synthesis[3]
It was reported that iodobenzoate and iodophenol could be carried out cross-coupling reaction in water without organic cosolvent under phosphine-free palladium catalysts, thus avoiding phosphine-related side reactions[5]. Aqueous reaction conditions offer a safe, economic and environmentally benign alternative in organic synthesis, but are often limited by spare solubility of reactants in water. In some reactions related to ligandless palladium catalyst, phase transfer catalyst (PTC) is necessary to carry out reactions under mild conditions and increase the yields[6]. Furthermore, PEG has been investigated as thermally stable, recoverable, inexpensive water-soluble and nontoxic PTC, presumably operating by the same mechanism as crown ether[7]. Here, we report the aqueous palladium-catalyzed Suzuki, Sonogashira, Still and Heck reactions using PEG as soluble polymeric support and phase transfer catalyst as well.
We have observed that no additional PTC was needed when 4-iodobenzoate bound immobilized PEG 4000 was coupled with sodium tetraphenylborate (), aryl boronic acids (), aryltributylstannanes () alkenyl () and alkynyl compounds () in water. The reactions required lower temperatures and shorter time with improvement of yields compared with those analogous reactions in solution phase 8-11,14, utilizing the intrinsic solubility and phase transfer catalytic properties of the polymeric support. Only very recently the combined use of PEG as polymeric support and PTC was reported[12,13]
It was found that aryl iodides gave incomplete conversion in water with organoboronic acids under palladium acetate by tetrabutylammonium bromide as PTC[14]. In our reaction, however, due to the intrinsic catalytic activity of the polymeric support, the cross-coupling reaction of PEG 4000 bound 4-iodobenzoate with phenylboronic acid (2a) or 4-methylphenylboronic acid (2b) was carried out at 60 for 2 hours in excellent yields and purity in the presence of NaCO (Table 1, entry 2,3). Because the reactant of sodium tetraphenylborate () was excessive, the PEG 4000 bond 4-iodobenzoate was converted nearly quantitatively into pure product (entry ) in the absence of the additional base (Scheme 1).

                               Scheme 1

Bumagin et al reported that aryl halides were carried out the Sonogashira reaction with terminal acetylenes in water under the co-catalyst of Pd(PPhCl/CuI in the presence of 10% BuN [9]. The catalytic amount of tributylamine was used as indispensable PTC. In our case, the cross-coupling reaction of terminal acetylenes () with PEG bound 4-iodobenzoate under Pd (OAc)/CuI in water could be taken place at room temperature in excellent yields and appropriately quantitative purity without any additional PTC (Scheme 2,Table 1,entry 4,5,6).

                               Scheme 2

Normally, the reaction temperature for Still reaction is high. Thanks to the cuprous effect, this reaction can undergo under mild conditions at the help of catalytic CuI [10]. When phenyltributylstannane (4a) and 4-methylphenyltributystannane (4b) coupled with PEG bound 4-iodobenzoate in water in the presence of Pd(OAc)/CuI, the reaction could take place at room temperature within 1 hour in high yields and purity (Scheme 3,Table 1, entry 7,8).

                               Scheme 3

Water was found to be an effective medium for Heck reaction[8,11]. However, the yields were quite low without equal amount of PTC such as quaternary ammonium salts. Due to the PTC property, PEG bound 4-iodobenzoate could react with styrene (5a), propenol (5b) or acrylic acid (5c) in water without additional PTC in excellent yields and purity (Scheme 4, Table 1, entry 9,10). However, it appeared that electronic-withdrawing carboxyl group had electronic effect on the coupling of acrylic acid (5c) with PEG bound 4-iodobenzoate in relatively low yield and purity (Table 1, entry 11). This result is in accordance with Bumagins report that long time was needed and low yield was obtained in the case of the reaction of acrylic acid with diaryliodonium salts bearing electronic-withdrawing groups in water under Pd(OAc) as catalyst[15]

                                Scheme 4

Although known reducing agent such as tertiaryl phosphine[16] were not present under ligandless conditions in this system, the above all reaction mixtures darkened and palladium metal began to deposit soon after the addition of the catalyst and immediately upon heating. This indicated that Pd (II) was readily reduced by some other constitute in the mixture. Pd (0) is not known to be able to exist in solution in the absence of strong donor or acceptor ligands[17]. PEG has been described as PTC presumably operating by the same mechanism as crown ether[7]. It seems to be likely that PEG is able to stablize the Pd (0) species. It was reported that the ligandless cross-coupling reactions with PEG as PTC could also proceed under heterogeneous procedure on palladium metal[18]. All these show that PEG acts double roles as soluble support and PTC as well.

Table1Palladium-catalyzed reactions on PEG bound 4-iodobenzoate in water a, g

Entry Substrate Time (h) Temp.
Observed MS (%)
(base, molecular ion)
yield (%)
    60 198 198 89 99.18
  2a   60 198 198 92 99.43
  2b   60 212 212 86 98.88
  3a   r.t. 222 222 91 98.13
  3b   r.t. 131 176 84 98.34
  3c   r.t. 129 202 87 98.97
b,c 4a   r.t. 198 198 90 99.17
b,c 4b   r.t. 212 212 86 98.65
  5a 0.5 60 105 178 83 94.33
10 5b   60 179 224 83 90.39
11 5c   60 148 —– 71 75.74

a. the reaction was carried out with 1.5g PEG bound 4-iodobenzoate, 5%mmol Pd(OAC), 1.5mmol corresponding substrate and 1.5mmol base in 8mL water at proper temperature for needed time; b. 10%mmol CuI; c. without 1.5mmol base; d. based on the loading of original HO-PEG-OH with 0.5mmol/g; e. determined by GC analysis; f. (m-44) peak; g. all the compounds were characterized by H-NMR, FT-IR, MS.

The PEG bound products were subjected to a very efficient cleavage from the support with 1N NaOH aqueous solution at 50 for 3 hours. The process could be monitored by TLC with the disappearance of the original point. Through extraction with either after acidification under 5N HCl aqueous solution to pH 3~4, the crude products were determined with purity more than 90% by GC analysis (Table 1).
In summary, we have shown a liquid-phase methodology for the palladium-catalyzed cross-coupling reactions in water on soluble support of PEG 4000. The reaction not only provide corresponding products in excellent yields and purity, but also were carried out under mild conditions due to the contribution of PEG bound substrates as PTC. It is potential for these reactions to be assumed for the combinatorial and parallel synthesis on the soluble polymeric support.

General procedure for the preparation of PEG bound 4-iodobenzoate: at room temperature, 2g PEG 4000 (with loading capacity of 0.5mmol/g), 4-iodobenzoic acid (0.496g, 2mmol), dicyclohexylcarbodiime (DCC, 0.412g, 2mmol) and N,N-dimethylaminopyridine (DMAP, 0.024g, 0.2mmol) were dissolved in anhydrous CHCl (10mL) and the resulting mixture was stirred at 37° overnight. After filtration, the filtrate was precipitated with ether, the resulting white solid was washed with ether for several times and dried over vacco to provide the PEG bound 4-iodobenzoate in quantitatively.
Typical procedure for the preparation of entry 6 is as follows: at room temperature, 1.5g PEG bound 4-iodobenzoate, 1-hexyne (0.123g,1.5mmol) and sodium carbonate (0.16g, 1.5mmol) in 8mL water were injected into the mixture of palladium acetate (0.0182g,0.075mmol) and cuprous iodide (0.029g,0.15mmol) under nitrogen. The resulted solution was stirred at room temperature for 2 hours. The water was coevaporated with 2mL toluene at 60° under reduced pressure. Then toluene (10mL) added and the mixture centrifuged. The clear supernatant was precipitated with 50mL cold ether and filtered, washing with ether for three times. The crude PEG bound product was redissolved in 5mL dichloromethane, the precipitated and washed with cold ether for three times, drying in vacco for the next sequence.
The saponification of PEG bound product was representative as below: 1.4g PEG bound 4-hexynl benzoate was dissolved in NaOH aqueous solution (1N, 15mL) and heated at 50° for 3 hours (tested by TLC until the original point disappeared). After cooled to room temperature, the solution was acidificated with HCl aqueous solution (5N) to pH within 3~4. By extracting with ether (2×5mL), the combined organic layer was dried over anhydrous sodium sulfate and given the crude product 4-hexynl benzoic acid as yellow solid (0.131g, 87%). The crude purity of this compound was determined to be 98.97% by GC analysis. H-NMR(500MHz,CDCl) 0.97 (t,3H),1.49 (h,2H),1.61 (p,2H),2.45 (t,2H), 7.71(d, J=8.4Hz,2H), 8.02 (d, J=8.4Hz,2H) FT-IR(KBr) 2953, 2670, 2252, 1688, 1606, 1425, 1281, 1120, 908, 732 MS m/z (%) 202 (45), 187(45), 159 (51), 142 (18), 129 (100), 115 (56), 77(14)