No Stirring Necessary: Parallel Carbonylation of Aryl Halides with CO and Various Alcohols under Pressure
SCHEME 1. Carbonylation of 4-Bromoacetophenone
Hans-Ulrich Blaser,† Martin Diggelmann,‡ Hans Meier,† Fre´de´ric Naud,† Elke Scheppach,‡ Anita Schnyder,† and Martin Studer*,† Solvias AG, R-1055.6, CH-4002 Basel, Switzerland, and Syngenta AG, R-1060, CH-4002 Basel, Switzerland
[email protected] Received January 28, 2003
Abstract: The parallel carbonylation of aryl halides with 6-25 bar of CO in 1-mL vials in a standard autoclave was investigated. 4-Bromoacetophenone and 2-chloropyridine were used as model substrates with 102 different Onucleophiles (primary and secondary alcohols, phenols). No inertization during the loading was necessary. Fifty esters (43 new, yield up to 60%) were isolated and characterized. Ether, ester, ketone, and sometimes even olefin functions were usually tolerated. The new method is suitable for screening and small scale products synthesis.
Palladium-catalyzed reactions are an important tool in organic synthesis for the formation of C-C, C-N, and C-O bonds and, indeed, various technical applications are found in the fine chemicals industry.1 Due to the versatility and high functional group tolerance of most Pd catalysts, there is also growing interest in parallel synthesis with the goal of applying these reactions in combinatorial chemistry and to synthesize compound libraries.2 Carbonylation with CO in the presence of various nucleophiles is of special importance due to the usefulness of the products and the high atom economy of the method.3 However, using the gaseous and highly toxic CO under pressure at elevated temperatures requires high-pressure autoclaves. Since it was always assumed that stirring of the biphasic reaction mixture is necessary, this methodology has so far be limited to single experiments. The use of alternative CO sources (no gaseous CO required) was recently described by Hosoi et al. for the synthesis of amides with DMF and POCl3,4 and by Kaiser et al. for microwave assisted reactions with Mo(CO)6, albeit at rather high temperature.5 However, both methods only have a limited value for screenings. To the best of our knowledge, no simple parallel procedure for carbonylations with CO has been reported up to now. Our goal was to show that it is possible to perform multiple parallel carbonylations in a standard autoclave without the need to stir, and that the new method allows catalyst screening as well as the synthesis and isolation of acid derivatives on a milligram scale. The experimental conditions for carbonylation were chosen as described by Ma¨gerlein et al.6 (See Scheme 1). We reasoned that if we use solvents with relatively high †
Solvias AG. Syngenta AG. (1) Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101. (2) Schiedel, M.-S.; Briehn, C. A.; Ba¨uerle, R. J. Organomet. Chem. 2002, 653, 200. (3) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6, 1097. (4) Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4, 2849. (5) Kaiser, N.-F. K.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2002, 4, 109. ‡
SCHEME 2. Parallel Carbonylation of 2-Chloropyridine
solubility for CO, carbonylation without stirring might be possible at elevated pressure. In preliminary tests, we carried out a few experiments with 4-bromoactophenone, a substrate that is relatively easy to carbonylate.6,7 For this purpose we used 1-mL vials closed with a rubber septum perforated with a small hollow shaft needle. The loading was carried out in air, and the vials were placed in a 300-mL autoclave. To ensure a good heat transfer, the autoclave was always filled with approximately 200 mL of quartz sand. Working in neat n-butanol we obtained 100% conversion in 14 h without stirring. The isolated yield was 28% compared to 72% previously reported with stirring (ref 6; see Scheme 1). Even though this yield is significantly lower, it is nevertheless useful for preparations on small scale and the synthesis of compound libraries. One possible explanation for the low yield is a stronger competition by reduction due to lower CO concentration in the solution. Next we investigated the effect of solvents containing 4 equiv of n-butanol. DMF, acetonitrile, diglyme, and DMSO were found to be suitable, as indicated by a large product peak in the LC trace. Similar results were obtained with other simple alcohols. However, 4-bromoacetophenone is very reactive and therefore not a very representative substrate. Furthermore, many of the esters produced were not suitable for analysis and isolation on a standard high throughput setup since the LC-MS typically uses electrospray ionization. Therefore, most of the products were impossible to detect by MS, and product analysis and workup were extremely timeconsuming. (6) Ma¨gerlein, W.; Beller, M.; Indolese, A. F. J. Mol. Catal. A: Chem. 2000, 156, 213. (7) (a) Beller, M.; Ma¨gerlein, W.; Indolese, A. F.; Fischer, C. Synthesis 2001, 1098 and references cited. (b) Beller, M.; Indolese, A. F. Chimia 2001, 684 and references cited.
10.1021/jo034112v CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003
J. Org. Chem. 2003, 68, 3725-3728
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FIGURE 1. Isolated yields in the carbonylation of 2-chloropyridine in the presence of primary alcohols. A single asterisk indicates isolated esters containing 2-10% impurities according to 1H NMR. A double asterisk identifies 11-30% impurities found in the isolated esters.
For these reasons we decided to use 2-chloropyridine, which is a more relevant substrate and is also established as a model.7a Similar reaction conditions proved to be optimal, except for the ligand. Ligand screening experiments indicated that 1,3-bis(diphenylphosphino)propane (dppp) was better suited than 1,3-bis(diphenylphosphino)ferrocene (dppf) under our conditions (Scheme 2). Again high conversion and 48% yield were obtained with n-butanol/DMF in preliminary experiments without stirring. The next step was to vary the alcohol component to check the scope of our setup. For this purpose we chose 102 alcohols and phenols with a wide structural diversity: 59 primary alcohols (Figure 1), 31 secondary alcohols (Figure 2), and 12 phenols (Figure 3). To test functional group tolerance, some of these also carried reactive functional groups such as alkenes, alkynes, and others. In all cases, 12 parallel reactions were carried out in 1-mL vials placed in the 300-mL autoclave. The results are summarized in Figures 1-3; for clarity, only ranges of isolated yields are given in the figures. As before, the conversion of 2-chloropyridine was high in all reactions investigated. This means that in cases where no product was isolated either dehalogenation had taken place or 3726 J. Org. Chem., Vol. 68, No. 9, 2003
other side products were formed. Since the scope of this investigation was the development of a preparative procedure, the side products were not analyzed further. Of the 59 primary alcohols tested, 30 gave products in 1-60% yield (upper part of Figure 1, for statistical details see Table 1). A cursory inspection allowed the following conclusions: (a) ether, ester, and ketones groups were usually tolerated, and in one case even an unsaturated alcohol worked; (b) for alcohols containing sulfur groups, alkynes, aldehydes, or three-membered rings, no ester could ever be isolated; (c) alcohols with the OH group in a benzylic position also gave no product except for the parent benzyl alcohol; and (d) besides these effects, there was no obvious correlation between the type of functional group in the alcohol and ester yields. In some cases the product might be too volatile or too lipophilic to be detected and isolated with our setup, but there is not enough evidence to support this hypothesis. Figure 2 shows the results obtained with secondary alcohols. As expected these were less reactive nucleophiles than the primary alcohols. However, they showed a very similar pattern concerning functional group toler-
FIGURE 2. Isolated yields in the carbonylation of 2-chloropyridine in the presence of secondary alcohols. A single asterisk indicates isolated esters containing 2-10% impurities according to 1H NMR. A double asterisk identifies 11-30% impurities found in the isolated esters.
FIGURE 3. Isolated ester yields in the carbonylation of 2-chloropyridine in the presence of phenols. TABLE 1. Analysis of the Results Obtained in the Parallel Carbonylation of 2-Chloropyridine nucleophile
primary alcohol
no. of experiments products isolated purity (>98/>90>70%) average yield (%)
59 30 17/5/8 30
secondary alcohol 31 12 7/1/4 12
phenol
total
12 7 7/0/0 14
102 49 31/6/13 23
ance. Here, 12 out of 31 experiments gave the desired ester and also here a successful example with an unsaturated alcohol was found. Figure 3 shows the results obtained with phenols. Remarkably, the desired esters could be obtained as clean
products in 7 out of 12 examples. Aromatic aldehydes, nitro groups, and nitriles were not tolerated, but tertiary amines, esters, ethers and in one case even an allyl group were. Furthermore, two sterically hindered phenols with two ortho substituents also gave the desired product. Table 1 shows a statistical analysis of the results. Over all, about half of the (sometimes highly functionalized) alcohols tested gave the corresponding esters in useful yields. About 2/3 of the isolated products were analytically pure (>98% by NMR). Even though the yields were usually not very high, they were sufficient for analytical purpose and small-scale (library) synthesis. As shown above, this method also has some limitations. These can be due to chemical reasons (functional group tolerance J. Org. Chem, Vol. 68, No. 9, 2003 3727
SCHEME 3.
Carbonylation of 2-Chloropyridine with a Phenol with and without Stirring
of carbonylation), analytical (only products containing a sufficiently basic function can be analyzed by ES+-MS) or handling problems (loading under air can poison catalyst), or due to our workup procedure (standard LC method and isolation procedure might not be suitable for all products). However, as the system has not been optimized, it is expected that more products/higher yields could be obtained if necessary. To compare the results obtained with 2-chloropyridine without stirring to those in a stirred autoclave, we investigated the reaction depicted in Scheme 3 in more detail. We isolated this sterically demanding ester in 17% yield with stirring compared to 11%. Thus on small-scale comparable results can be obtained without stirring even with relatively unreactive alcohols. To carry the parallelization one step further, we performed the same experiments in a standard 96-deep well plate. Because of its relatively large size, we could not use the 300-mL autoclave but had to resort to a 16 L vessel instead. This led to a much longer time span between the loading of the reaction mixture, the closing of the autoclave, and the start of the reaction, resulting most likely in some catalyst decomposition (no inert conditions). Furthermore, heat transfer was much more difficult to ensure, handling was more cumbersome, and last but not least it was not very economical to fill an almost empty 16-L vessel with the relatively expensive CO, and using only a very small fraction of it. Nevertheless, in many cases we found the desired esters, and even a few products with alcohols which gave no ester in the setup described above. Most likely, an optimized apparatus would also allow reliable carbonylation in 96deep well plates. In conclusion, we have demonstrated that a simple reaction setup allows the rapid screening of aryl halide carbonylation in the presence of alcohols in DMF allowing the preparation of the corresponding esters on a milligram scale. No stirring and no inert conditions are necessary with 4-bromoacetophenone and 2-chloropyridine as substrates. Forty nine different esters (43 new compounds) were synthesized, isolated, and characterized by MS and 1H NMR. While in some cases it was not clear why no product was obtained, we were able to rapidly synthesize a wide variety of valuable products and to identify trends and reactivity patterns.
ridine and 24 µL of Et3N, 600 µL of a stock solution of the alcohol (4 equiv with regard to 2-chloroypridine) in DMF was added. The vial was closed with a rubber stopper, which was glued to the vial. To allow gas diffusion, the rubber stopper was perforated with a small hollow shaft needle. To homogenize the mixture, the vial was shaken manually and then transferred into a 300-mL stainless steel autoclave filled with approximately 200 mL of quartz sand. After adding the other 11 vials loaded with the same procedure, the autoclave was closed and checked for leaks with He (50 bar). After releasing the helium, the autoclave was pressurized with CO to 25 bar and heated to 130 °C with a heating rate of 80 °C/h. After 14 h, the autoclave was cooled to room temperature, depressurized, purged with nitrogen, and opened to the atmosphere. Workup. The reaction mixtures were filtered over cotton to remove solid Pd-residues. In some cases it was necessary to add small amounts of DMF to dissolve crystallized Et3N‚HCl. The clear solutions were analyzed by LC-MS after dissolving 10 µL of the reaction mixture in 600 µL of CH3CN. Then, the samples were separated by preparative HPLC-MS. After the separation, 100-µL fractions were drawn from each of the vials containing the separated products and again analyzed on the analytical LCMS machine. The vials containing the products of interest were evaporated to dryness by blowing warm nitrogen over or in a vacuum centrifuge. The evaporated vials were weighted to determine the product yield and the pooled products were analyzed by NMR. Scale-Up Experiment. Synthesis of 3: Allylphenol (1.0 g), 100 µL of 2-chloropyridine, and 260 µL of Et3N were dissolved in 25 mL of DMF and placed in a 100-mL autoclave fitted with a magnet-driven hollow shaft stirrer. After the addition of 23.0 mg of PdCl2(PhCN)2 and 47 mg of dppp, the autoclave was closed and checked for leaks with He (50 bar). As described for the parallel experiments, CO (25 bar) was introduced after releasing the helium and the autoclave was heated to 130 °C with a heating rate of 80 °C/h. After 14 h, the autoclave was cooled to room temperature, carefully depressurized, purged with nitrogen, opened, and unloaded. The reaction mixture was filtered through a cartridge filled with silica gel and the filtrate was purified by flash chromatography (column 3.5 × 35 cm2, EtOAc/ cyclohexane 1:1 as eluent). After removing the solvent, 70 mg (17%) of the desired ester was isolated as a pale yellow-green oil. Rf 0.21; 1H NMR (499.9 MHz, CDCl3, 298 K) δ 8.85-8.87 (m, 1 H), 8.29 (d, J ) 7.8 Hz, 1 H), 7.91 (dpt, J ) 7.7 Hz, 1.8 Hz, 1 H), 7.54-7.56 (m, 1 H), 7.19 (pt, J ) 7.9 Hz, 1 H), 6.87-6.90 (m, 2 H), 5.86-5.95 (m, 1 H), 5.00-5.05 (m, 2 H), 3.80 (s, 3H), 3.38 (d, J ) 6.6 Hz, 2 H); 13C{1H} NMR (125.0 MHz, CDCl3, 298 K) δ 162.9, 151.3, 150.2, 147.5, 138.4, 137.1, 135.9, 133.5, 127.2, 126.6, 125.8, 121.8, 116.4, 110.4, 56.0, 34.6; MS (ESP+) 270.1 (M + H), 311.1 (M + CH3CN), 333.1 (M + CH3CN + Na).
Acknowledgment. We thank Heinz Steiner for discussion and technical help.
Experimental Section Typical Experiment for 12 Parallel Reactions without Stirring in a 300-mL Autoclave. PdCl2(PhCN)2 (2.0 mg) and 4.0 mg of 1,3-bis(diphenylphosphino)propane (dppp) were placed in a 1-mL glass vial. After the addition of 12 µL of 2-chloropy-
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Supporting Information Available: 1H NMR and MS data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO034112V
