Dimethylformamide as a Carbon Monoxide SCHEME 1 Source in Fast Palladium-Catalyzed Aminocarbonylations of Aryl Bromides Yiqian Wan, Mathias Alterman,* Mats Larhed, and Anders Hallberg* Department of Organic Pharmaceutical Chemistry, BMC, carbon monoxide limit the use of carbonylation reactions Uppsala University, P.O. Box 574, for the small-scale synthesis of compound libraries.2 SE-751 23 Uppsala, Sweden More than three decades ago, Corey and Hegedus reported the use of several equivalents of the hazardous [email protected]; Ni(CO)4 as a combined C-X activator and liquid carbon [email protected] monoxide source3 for efficient aminocarbonylation reac- tions with vinyl bromides. Recently, our laboratory Received May 24, 2002 reported that the less harmful Mo(CO)6 acts as a solid carbon monoxide releasing reagent4 in microwave-as- 5 Abstract: Dimethylformamide (DMF) acts as an efficient sisted palladium-catalyzed carbonylation reactions. This source of carbon monoxide and dimethylamine in the pal- technique of in situ delivery of carbon monoxide is very ladium-catalyzed aminocarbonylation (Heck carbonylation) suitable for high-throughput organic synthesis. However, of p-tolyl bromide to provide the dimethylamide. Addition it is obvious that the concept of in situ liberation would of amines to the reaction mixture in excess delivers the be even more appealing if inexpensive organic materials, corresponding aryl amides in good yields. The amines preferably the solvent itself, could serve as the source of employed, benzylamine, morpholine, and aniline, all consti- carbon monoxide. In fact, the common solvent dimeth- tute good reaction partners. The reaction proceeds smoothly ylformamide (DMF) has previously been utilized as a with bromobenzene and more electron-rich aryl bromides, liquid carbon monoxide source but only for preparation but electron-deficient aryl bromides fail to undergo ami- of inorganic metal-carbonyl complexes.6 nocarbonylation. The reactions are conducted at 180-190 We herein report that dimethylformamide is an excel- °C for 15-20 min with microwave heating in a reaction lent carbon monoxide precursor in fast palladium- mixture containing imidazole and potassium tert-butoxide: catalyzed aminocarbonylations of aryl bromides. In the the latter is required to promote decomposition of the DMF presence of potassium tert-butoxide (KOt-Bu), imidazole, solvent at a suitable rate. The beneficial effects of controlled and various amines, the corresponding aryl amides were microwave irradiation as an energy source for the rapid isolated in moderate to high yields after reaction times heating of the carbonylation reaction mixture are demon- of 15-20 min at 180-190 °C. strated. The carbonylation procedure reported herein, which In an ongoing medicinal chemistry program,7 we relies on the in situ generation of carbon monoxide, serves wished to synthesize N-arylated imidazoles, which we as a convenient alternative to other carbonylation methods planned to prepare by Buchwald-Hartwig aminations and is particularly applicable to small-scale reactions where using a strong base.8 In a model reaction, we employed short reaction times are desired and the direct use of carbon imidazole and 4-bromotoluene as reactants with DMF as monoxide gas is impractical. solvent but were surprised to find that the dimethylamide 1, rather than the aryl imidazole, was the predominant product, formed in good yield by controlled microwave Palladium-catalyzed aminocarbonylation (Heck carbo- heating at 180 °C for 15 min (Scheme 1). This finding nylation) is a selective and useful method for the direct encouraged us to study the scope and limitations of DMF synthesis of aryl amides from aryl halides.1 Carbon as a potential carbon monoxide precursor for carbonyla- monoxide gas is the most commonly employed source of tion reactions in more detail. the carbonyl group in these transformations.1c-e The recent interest in new high-throughput chemistry tech- (2) (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. niques has redirected focus toward the automated han- Comb. Chem. 2002, 4,95-105. (b) Larhed, M.; Hallberg, A. Drug dling of liquids and solids rather than the development Discovery Today 2001, 6, 406-416. (c) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1692. of special gas delivery systems that, in theory, also could (3) Corey, E. J.; Hegedus, L. S. J. Am. Chem. Soc. 1969, 91, 1233- make the direct use of reactive gases feasible for provid- 1234. ing reactants in fast reactions. Today, the somewhat (4) Kaiser, N.-F. K.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2002, 4, 109-111. troublesome gas handling procedure and the toxicity of (5) (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584. (b) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989. (6) (a) Rusina, A.; Vlcek, A. A. Nature 1965, 206, 295-296. (b) Serp, (1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, P.; Hernandez, M.; Richard, B.; Kalck, P. Eur. J. Inorg. Chem. 2001, 39, 3318-3326. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 2327-2336. 39, 3327-3331. (c) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaint- (7) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.; Lo¨vgren, ner, C. W. J. Mol. Catal. A: Chem. 1995, 104,17-85. (d) Soderberg, S.; Classon, B.; Danielson, U. H.; Kvarnstro¨m, I.; Vrang, L.; Unge, T.; B. C. In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Samuelsson, B.; Hallberg, A. J. Med. Chem. 1999, 42, 3835-3844. Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, (8) (a) Hartwig, J. F. Modern Amination Methods; Wiley-VCH: 1995; Vol. 12, pp 241-291. (e) Yamamoto, A.; Kayaki, Y.; Nagayama, Weinheim, 2000. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. K.; Shimizu, I. Synlett 2000, 925-937. 1999, 576, 125-146. 10.1021/jo025965a CCC: $22.00 © 2002 American Chemical Society 6232 J. Org. Chem. 2002, 67, 6232-6235 Published on Web 07/20/2002 SCHEME 2 180 °C. By increasing the amount of base to 1.5 equiv, the yield of 2 was improved to 73%, while 2.0 equiv resulted in somewhat lower isolated yields. A consider- able amount of starting material was recovered after shortening the reaction time to 10 min (53% yield) or after performing the reaction at 150 °C for 15 min (3% yield), but a minor improvement was achieved (76% yield) by performing the reaction at 190 °C for 15 min.9 The preparative results obtained with various aryl bromides and different amines are shown in Table 2. As TABLE 1. Palladium-Catalyzed Aminocarbonylation of apparent from Table 2, benzylamine, aniline, and the 4-Bromotoluene under Different Reaction Conditions secondary amine morpholine were all suitable amines for isolated the aminocarbonylation reaction with 4-bromotoluene, yield producing isolated yields of the amides 2-4, ranging from a entry solvent precatalyst ligand additive base of 2 (%) 76% to 78% with high selectivities (<5% of 1). The yield 1 DMF Pd(OAc)2 dppf imidazole KOt-Bu 63 of 1, which relies on the liberation of dimethylamine from 2 DMF Pd(OAc)2 dppp imidazole KOt-Bu 37 the solvent, was slightly lower (59%, entry 1). In addition, 3 DMF Pd(OAc)2 binap imidazole KOt-Bu 49 4 DMF Pd(OAc)2 PPh3 imidazole KOt-Bu 0 electron-rich and sterically hindered aryl bromides also 5 DMF Pd(OAc)2 P(o-Tol)3 imidazole KOt-Bu 0 afforded high yields of 5-7 (70-94%), while no trace of 6 DMF Pd(OAc)2 imidazole KOt-Bu b c the desired aryl amide was observed in reactions with 7 DMF Pd(OAc)2 dppf N-Me-imidazole KOt-Bu 0 c electron-deficient 4-bromobenzonitrile or 4-bromobenzo- 8 DMF Pd(OAc)2 dppf DMAP KOt-Bu 0 c 9 DMF Pd(OAc)2 dppf KOt-Bu 0 trifluoride. Instead, 4-benzylaminobenzonitrile and 4-ben- 10 DMF dppf imidazole KOt-Bu 0d zylaminobenzotrifluoride, derived from competing Buch- d 11 DMF Pd(OAc)2 dppf imidazole K2CO3 0 wald-Hartwig aminations,8 were isolated as the major 12 DMAc Pd(OAc) dppf imidazole KOt-Bu 0c 2 products. In the absence of any aryl bromide, transami- a Reaction conditions: 4-bromotoluene (0.75 mmol), benzyl- dation occurred and N-formylbenzylamine was isolated amine (3.0 mmol), additive (0.75 mmol), KOt-Bu (0.75 mmol), in 67% yield. palladium acetate/ligand (0.038 mmol/0.038 mmol), solvent (1 mL), and microwave heating (180 °C, 15 min). bVial eruption. cN-Benzyl- We postulate that the aminocarbonylation reactions 4-methylaniline was the major product. dN-Benzylformamide was proceed as outlined in Scheme 3. It is well established the major product. that DMF decarbonylates under heating to yield carbon monoxide and dimethylamine in the presence of base.10 However, the present methodology is, to the best of our First, we decided to employ benzylamine as an external knowledge, the first example where the carbon monoxide amine to assess whether aryl amides other than aryl is both liberated from the solvent and thereafter utilized dimethylamides were accessible. Thus, 4-bromotoluene in an efficient organic carbonylation procedure.6b (0.75 mmol), benzylamine (3.0 mmol), imidazole (0.75 As apparent from the pressure graphs, that we antici- mmol), KOt-Bu (0.75 mmol), and palladium acetate/dppf pate to reflect the liberation of these gases, KOt-Bu, not (0.038 mmol/0.038 mmol) were warmed with a microwave imidazole or the palladium catalyst,6b,11 seems to promote synthesizer in sealed Pyrex vessels to 180 °C in DMF. this decomposition upon heating to 180 °C (Figure 1A). The aryl benzylamide 2 could be isolated in 63% yield Both of the two components formed by the DMF decar- after a reaction time of 15 min (Scheme 2).