COMMUNICATION DOI: 10.1002/chem.201303872
Direct Route to 1,3-Diketones by Palladium-Catalyzed Carbonylative Coupling of Aryl Halides with Acetylacetone Signe Korsager,[a] Dennis U. Nielsen,[a] Rolf H. Taaning,[a] Anders T. Lindhardt,*[b] and Troels Skrydstrup*[a]
The development of new synthetic protocols for accessing reagent (Scheme 1a). Furthermore, in the latter case, the de1,3-diketones is always of high interest, as such structural veloped conditions proved unsuitable with ketones, such as motifs represent excellent platforms or advanced building acetone or acetophenone, affording low yields of the desired blocks for the preparation of a number of heterocyclic com1,3-diketones. pounds of pharmaceutical and agrochemical interest.[1] TraRecently, the group of Beller published an interesting protocol for the Pd-catalyzed carbonylative a-arylation, which ditionally, the synthesis of 1,3-diketones relies on an aldol reaction between a carbonyl compound and an enolate followed by oxidation of the formed alcohol.[2] Alternatively, enolates have been reacted with activated carboxylic acids leading directly to the 1,3-diketones.[3–5] However, both approaches are not without drawbacks, which include limited starting material availability, restricted functional-group tolerance and the use of strong base. We and others have reported the direct Pd-catalyzed synthesis of 1,3-diketones via a carbonylative a-arylation of enolates.[6–7] However, these transformations were restricted to the use of malonate derivatives or by the need for strong base Scheme 1. Palladium-catalyzed a-arylation coupling conditions affording 1,3-diketones and b-keto esters. cod = (NaHMDS) in the case of 1,5-cyclooctadiene; dba = dibenzylideneacetone. simple ketones to insure complete formation of the enolate demonstrated that indeed acetone and acetophenones can act as viable enolate coupling partners with Cs2CO3 as the [a] S. Korsager, D. U. Nielsen, Dr. R. H. Taaning, Prof. Dr. T. Skrydstrup base (Scheme 1b).[8] This improved reactivity of such subCenter for Insoluble Protein Structures (inSPIN) strates was nevertheless compromised by the need of perInterdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University forming the reaction with the reacting ketone as the solvent. Gustav Wieds Vej 14, 8000 Aarhus C (Denmark) Moreover, the developed conditions were performed with Fax: (+ 45) 8619-6199 aromatic iodides as the electrophile and long reaction times E-mail: [email protected] (up to 36 h) were needed. Hence, the development of alter[b] Dr. A. T. Lindhardt native procedures might still prove useful. Interdisciplinary Nanoscience Center (iNANO) Biological and Chemical Engineering Herein, we wish to report a mild and selective route to Department of Engineering, Aarhus University 1,3-diketones by a three-component Pd-catalyzed carbonylaFinlandsgade 22, 8200 Aarhus N (Denmark) tive a-arylation of acetylacetone with aryl bromides. SubstiFax: (+ 45) 4189-3001 tuted aliphatic 1,3-diketones and 1-aryl-1,3-butadiones all E-mail: [email protected] proved reactive under the developed conditions affording Supporting information for this article is available on the WWW the desired substituted diketones in high isolated yields. The under http://dx.doi.org/10.1002/chem.201303872.
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developed method is ideal for isotope labeling as CO is delivered in stoichiometric amounts to the carbonylative reaction by ex situ generation.[9] In this manner, 13C-labeled 1,3diketones were obtained and even an example of a doublelabeled 1,3-diketone is presented. We recently reported that the combination of Et3N, MgCl2, and the potassium monoester salts of malonates reacted excellently as enolate surrogates in the palladium-catalyzed carbonylative a-arylation of aryl bromides and electron-deficient aryl chlorides (Scheme 1c).[10–11] Acidic workup caused the intermediately formed acylated malonate derivatives to decarboxylate forming the desired b-ketoesters in high yields. We speculated as to whether this approach could be extended to include the synthesis of the corresponding 1,3-diketones. An indication was provided by the reaction of ethyl acetoacetate with 4-bromobenzonitrile, selectively affording the ethyl b-ketoester (1) upon acidic hydrolysis in an 83 % isolated yield (Scheme 1d). Gratifyingly, when acetylacetone was subjected to the developed reaction conditions, the desired triketone was formed exclusively, as observed by 1H NMR spectroscopic analysis of the crude reaction mixture. Selective deacetylation by applying HCl (2 m) at 80 8C proved superior to treatment with formic acid and a 96 % isolated yield of (1) was secured after column chromatography (Scheme 2).
as the nucleophile, the results of which are depicted in Table 1. Both electron-rich and deficient aryl bromides coupled successfully leading to high carbonylative coupling Table 1. Carbonylative a-arylation of acetylacetone with aryl halides.[a]
Scheme 2. Optimized conditions for the carbonylative coupling of 4-bromobenzonitrile with acetylacetone.
Notably, none of the corresponding debenzoylated product was observed after acid hydrolysis.[12] Adding less than one equivalent of MgCl2 caused a significant drop in selectivity with isolation of both 2 and 4-cyanobenzoic acid, after acidic treatment, presumably obtained through hydrolysis of the vinyl benzoate.[10, 13] With no added MgCl2, 4-cyanobenzoic acid was formed exclusively in 86 % isolated yield (see the Supporting Information). Finally, attempts to lower the catalytic loading resulted in an incomplete reaction in combination with loss of selectivity. With the conditions described in Scheme 2 in hand a series of aryl bromides were tested against acetylacetone
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[a] Reaction conditions: Chamber A: Aryl halide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), acetylacetone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h. [b] Deacetylation with HCl performed at 90 8C. [c] Reaction performed by using 4-chlorobenzonitrile as the substrate at 120 8C in 36 h in butyronitrile with Cy2NMe as the base. [d] Reaction run with aryl triflate as substrate. [e] Reaction run at 100 8C with Cy2NMe as the base. [f] Electrophile (0.25 mmol). [g] Reaction run on a 3 mmol scale by using 2.5 mol % of [PdCl2ACHTUNGRE(cod)] and 2.5 mol % of Xantphos.
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yields (4–5, 8–9, 12, and 2, 6–7, 13–16, respectively). Increasing the reaction temperature to 100 8C, while substituting Et3N for Cy2NMe, was required to ensure proper reactivity of ortho-substituted aryl bromides (18–22).[14] Heterocyclic aryl bromides also proved effective affording isolated yields of the desired 1,3-diketones in the range of 60–99 % (compounds 22–26). 1,4-Dibromobenzene underwent a doublecoupling to produce the symmetrical diketone 27 in quantitative yield. One aryl triflate was also tested as the electrophile affording the desired product 9 in a 93 % isolated yield. Finally, an excellent 91 % isolated yield of 2 starting from 4-chlorobenzonitrile, was obtained, but required a reaction temperature of 120 8C and Cy2NMe as the base in butyronitrile to ensure full conversion. Different 1,3-dicarbonyls were then evaluated as the coupling partner in the carbonylative a-arylation (Table 2). To our delight, substituents at the a-position on the pentane-
Table 3. Carbonylative a-arylation of different 1,3-dicarbonyl compounds with aryl bromides.[a]
Table 2. Carbonylative a-arylation of different 1,3-dicarbonyl compounds with aryl bromides.[a]
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), 1,3-diketone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h. [b] Reaction run at 100 8C with Cy2NMe as the base. [c] No addition of MgCl2.
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), 1,3-diketone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h.
2,4-dione core did not interfere with the reaction affording the products 29–31 in acceptable yields as illustrated in Table 2. Omitting the acidic treatment step led to the isolation of triketones in yields reaching quantitative (Table 3). It was observed that 1,3-diketones obtained by using orthosubstituted aryl bromides required higher temperatures to complete the acidic deacetylation. In the case of 1-bromo-2fluorobenzene, no deacetylation occurred leading to the sole isolation of the triketone 36 in 86 % yield. In addition, cyclic 1,3-diketones proved reactive affording the corresponding triketones in high yields (32, 33, and 37). Interestingly, and in contrast to reactions with acetylacetone, the addition of MgCl2 was not required in the carbonylative reaction of tosylated 4-bromophenol leading to 37. Acidic treatment of 33 and 37 led to the corresponding ring-opened 5,7-diketohep-
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tanoic acid derivatives (38 and 39), again, with no sign of the debenzoylated product. The triketone derivatives 33 and 37 resemble the well-known herbicides, mesotrione and sulcotrione, with similar ring-opened soil metabolites, such as 38 and 39.[15] The substituted acetylacetone products obtained in Tables 1 and 2, could in principle, act as substrates in a sequential carbonylative a-arylation. This was achieved by a simple raise in reaction temperature to 100 8C and both 1,3-diaryl-1,3-propandiones 40 and 41 were secured in satisfactory isolated yields of 72 and 68 %, respectively, which demonstrated the usefulness of this protocol for the preparation of non-symmetrical 1,3-diaryl-1,3-diketones. As all carbonylative reactions presented in this work have been performed by using only 1.5 equivalents of CO, the method can, therefore, be effectively adapted for isotope labeling.[9] Applying 13CO from 13COgen, and starting with 4chlorobromobenzene (3 mmol) the corresponding 1,3-diketone 13C-43 was obtained in an 89 % isolated yield (Table 4).[16] Repeating the sequence in the coupling to 4bromoveratrole afforded the double 13C-labeled 1,3-diaryl1,3-propandione 13C2-41 in a 78 % (750 mg) isolated yield. Subjecting 13C2-41 to either hydrazine or hydroxylamine produced the corresponding double-13C2-labeled 3,5-diarylpyrazole or 3,5-diarylisoxazole heterocycles in 81 and 89 % isolated yields (13C2-44 and 13C2-45). Next, it was decided to test the suitability of the developed conditions for scale-up purposes, and hence the car-
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Table 4. Synthesis, labeling and application of 1,3-diaryl-1,3-propandiones.
Figure 1. Possible catalytic cycle for the carbonylative a-arylation with or without added MgCl2.
bonylative coupling protocol was applied to the synthesis of 4-(3-oxobutanoyl)benzonitrile 2. Initial studies on a 3 mmol scale indicated that the catalyst loading could be reduced to 0.5 mol % with no reduction in the product yield. Finally, performing the reaction on a 30 mmol scale afforded the desired 1,3-diketone 2 in 99 % isolated yield (Scheme 3).
Without added MgCl2, competing attack will occur through the now more reactive oxygen affording the vinyl benzoate D, which upon acidic treatment provides the corresponding benzoic acid.[13] In conclusion, reaction conditions were successfully developed for the carbonylative a-arylation of acetylacetone with aryl bromides. The desired 1,3-diketones were obtained by selective deacetylation of the intermediary formed triketone under acidic conditions. All 1,3-diketones were isolated in high yields and the catalytic conditions performed with excellent functional-group tolerance. The initially isolated 1aryl-1,3-diketones could, under near identical conditions, be transformed into their corresponding 1,3-diaryl-substituted 1,3-propandiones. Finally, isotope labeling with 13CO afforded a double 13C-labeled diketone, which was applied towards the synthesis of heterocycles.
Experimental Section 4-(3-Oxobutanoyl)benzonitrile (2, Scheme 1) Chamber A: In an argon filled glovebox, 4-bromobenzonitrile (91 mg, 0.5 mmol), [PdCl2ACHTUNGRE(cod)] (7.1 mg, 0.025 mmol), Xantphos (14.5 mg, 0.025 mmol), acetylacetone (55 mg, 0.55 mmol), MgCl2 (57 mg, 0.6 mmol), dioxane (3.0 mL), and Et3N (280 mL, 2 mmol) were added in this order to chamber A of the two-chamber system, COware.[16] The chamber was sealed with a screwcap fitted with a Teflon seal.
Scheme 3. Example of the gram-scale synthesis of 1,3-diketone 2 (30 mmol scale) and low catalyst loading.
Chamber B (1.5 equiv CO): In an argon filled glovebox, HBF4·PACHTUNGRE(tBu)3 (10.9 mg, 0.0375 mmol), [PdCl2ACHTUNGRE(cod)] (10.7 mg, 0.0375 mmol), 9-methylfluorene-9-carbonyl chloride (182 mg, 0.75 mmol), dioxane (3.0 mL), and Cy2NMe (320 mL, 1.5 mmol) were added to chamber B of the two-chamber system in that order. The chamber was sealed with a screwcap fitted with a Teflon seal.
A possible mechanistic scenario for the catalytic cycle is illustrated in Figure 1. Starting with an oxidative addition step followed by CO insertion affords complex A. Next, the MgCl2-activated complex B attacks A by a nucleophilic acyl substitution or by ligand exchange followed by reductive elimination forming C in both cases. This triketone is then deacetylated with aqueous HCl to form the 1,3-diketone.
The loaded two-chamber system was removed from the glovebox and heated to 80 8C for 18 h. The reaction was quenched with 2 m HCl (2 mL) and stirred for 1 h at 80 8C. The two phases were separated and the water phase was extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous NaSO4, filtrated, and concentrated under vacuum. The crude residue was subjected to flash chromatography by using pentane/CH2Cl2 (1:1– > CH2Cl2) as the eluent. This resulted in 90 mg (96 % yield) of the title product obtained as a colorless solid. 1 H NMR (400 MHz, CDCl3): d = 15.91 (s, 1 H), 7.95 (d, J = 8.55 Hz, 2 H),
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7.73 (d, J = 8.55 Hz, 2 H), 6.19 (s, 1 H), 2.24 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 195.7, 179.7, 138.7, 132.4, 127.4, 118.1, 115.3, 97.6, 26.3 ppm; HRMS: m/z: calcd for C11H9NO2 : 188.0712 [M+H + ]; found: 188.0709.
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Acknowledgements We thank the Danish National Research Foundation (grant no. DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the Lundbeck Foundation, the Carlsberg Foundation, and Aarhus University for generous financial support of this work.
Keywords: 1,3-diketones · carbonylation · homogenous catalysis · isotope labeling · palladium
[1] a) A. V. Kelin, Curr. Org. Chem. 2003, 7, 1691; b) A. V. Kelin, A. Maioli, Curr. Org. Chem. 2003, 7, 1855. [2] a) V. Chandrashaker, M. Taniguchi, M. Ptaszek, J. S. Lindsey, Tetrahedron 2012, 68, 6957; b) S. L. Bartlett, C. M. Beaudry, J. Org. Chem. 2011, 76, 9852; c) Y. Shimizu, S.-L. Shi, H. Usuda, M. Kanai, M. Shibasaki, Angew. Chem. 2010, 122, 1121; Angew. Chem. Int. Ed. 2010, 49, 1103. [3] For acid chlorides, see: a) Y. Nishimura, Y. Miyake, R. Amemiya, M. Yamaguchi, Org. Lett. 2006, 8, 5077; b) A. Riahi, M. Shkoor, O. Fatunsin, M. A. Yawer, I. Hussain, C. Fischer, P. Langer, Tetrahedron 2009, 65, 9300; c) W. M. Muir, P. D. Ritchie, D. J. Lyman, J. Org. Chem. 1966, 31, 3790; d) B. Tu, B. Ghosh, D. A. Lightner, J. Org. Chem. 2003, 68, 8950. [4] For acid anhydrides, see: a) J. B. Paine III, D. Dolphin, J. Org. Chem. 1985, 50, 5598; b) C.-H. Mao, F. C. Frostick Jr., E. H. Man, R. M. Manyik, R. L. Wells, C. R. Hauser, J. Org. Chem. 1969, 34, 1425; c) J. T. Adams, C. R. Hauser, J. Am. Chem. Soc. 1945, 67, 284. [5] For benzotriazole or phenol ester derivatives, see: a) D. Lim, F. Fang, G. Zhou, D. M. Coltart, Org. Lett. 2007, 9, 4139; b) S. R.
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[8] [9]
[10] [11] [12] [13] [14] [15] [16]
Stauffer, C. J. Coletta, R. Tedesco, G. Nishiguchi, K. Carlson, J. Sun, B. S. Katzenellenbogen, J. A. Katzenellenbogen, J. Med. Chem. 2000, 43, 4934; c) K. J. Hale, M. Grabski, J. T. Flasz, Org. Lett. 2013, 15, 370; d) R. H. Erickson, K. J. Natalie Jr., W. Bock, Z. Lu, F. Farzin, R. G. Sherrill, D. J. Meloni, R. J. Patch, W. J. Rzesotarski, J. Med. Chem. 1992, 35, 1526. For some recent reviews on Pd-catalyzed carbonylations, see: a) X.F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1; b) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986; c) J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177; d) R. Grigg, S. P. Mutton, Tetrahedron 2010, 66, 5515; e) A. Brennfhrer, H. Neumann, M. Beller, Angew. Chem. 2009, 121, 4176; Angew. Chem. Int. Ed. 2009, 48, 4114. a) T. M. Gøgsig, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, Angew. Chem. 2012, 124, 822; Angew. Chem. Int. Ed. 2012, 51, 798; b) T. Kobayashi, M. Tanaka, Tetrahedron Lett. 1986, 27, 4745. J. Schranck, A. Tili, P. G. Alsabeh, H. Neumann, M. Stradiotto, M. Beller, Chem. Eur. J. 2013, 19, 12624. For 12C- and 13C labeled CO incorporation see: a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp, T. Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061. For 14C labeled CO incorporation see: b) A. T. Lindhardt, R. Simonssen, R. H. Taaning, T. M. Gøgsig, G. N. Nilsson, G. Stenhagen, C. S. Elmore, T. Skrydstrup, J. Labelled Compd. Radiopharm. 2012, 55, 411. For a review on the use of the MgCl2-NEt3 base system in organic synthesis, see, H. F. Anwar, Synlett 2009, 16, 2711. S. Korsager, D. U. Nielsen, R. H. Taaning, T. Skrydstrup, Angew. Chem. 2013, 125, 9945; Angew. Chem. Int. Ed. 2013, 52, 9763. V. M. Krokhalev, V. I. Saloutin, K. I. Pashkevich, Russ. Chem. Bull. Int. Ed. 1988, 37, 1956. J. Schranck, A. Tlili, H. Neumann, P. G. Alsabeh, M. Stradiotto, M. Beller, Chem. Eur. J. 2012, 18, 15592. The boiling point for Et3N is 88.8 8C and 265 8C for Cy2NMe. L. Maeghe, E. M. Desmet, R. Bulcke, Commun. Agric. Appl. Biol. Sci. 2004, 69, 41. COgen (9-methylfluorene-9-carbonyl chloride) and COware is commercially available from Sigma–Aldrich and SyTracks. Received: October 3, 2013 Published online: && &&, 0000
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Homogenous Catalysis S. Korsager, D. U. Nielsen, R. H. Taaning, A. T. Lindhardt,* T. Skrydstrup* . . . . . . . . . . . . . . . . &&&&—&&&& Direct Route to 1,3-Diketones by Palladium-Catalyzed Carbonylative Coupling of Aryl Halides with Acetylacetone
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Man up your magnesium! By employing a MgCl2/Et3N system, aryl diketones can be generated from the Pdcatalyzed carbonylative a-arylation of acetylacetone with aryl bromides (see
scheme). The method is ideal for the introduction of carbon isotopes into more complex structures, since only stoichiometric amounts of carbon monoxide are employed.
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Direct Route to 1,3-Diketones by Palladium-Catalyzed Carbonylative Coupling of Aryl Halides with Acetylacetone Signe Korsager,[a] Dennis U. Nielsen,[a] Rolf H. Taaning,[a] Anders T. Lindhardt,*[b] and Troels Skrydstrup*[a]
The development of new synthetic protocols for accessing reagent (Scheme 1a). Furthermore, in the latter case, the de1,3-diketones is always of high interest, as such structural veloped conditions proved unsuitable with ketones, such as motifs represent excellent platforms or advanced building acetone or acetophenone, affording low yields of the desired blocks for the preparation of a number of heterocyclic com1,3-diketones. pounds of pharmaceutical and agrochemical interest.[1] TraRecently, the group of Beller published an interesting protocol for the Pd-catalyzed carbonylative a-arylation, which ditionally, the synthesis of 1,3-diketones relies on an aldol reaction between a carbonyl compound and an enolate followed by oxidation of the formed alcohol.[2] Alternatively, enolates have been reacted with activated carboxylic acids leading directly to the 1,3-diketones.[3–5] However, both approaches are not without drawbacks, which include limited starting material availability, restricted functional-group tolerance and the use of strong base. We and others have reported the direct Pd-catalyzed synthesis of 1,3-diketones via a carbonylative a-arylation of enolates.[6–7] However, these transformations were restricted to the use of malonate derivatives or by the need for strong base Scheme 1. Palladium-catalyzed a-arylation coupling conditions affording 1,3-diketones and b-keto esters. cod = (NaHMDS) in the case of 1,5-cyclooctadiene; dba = dibenzylideneacetone. simple ketones to insure complete formation of the enolate demonstrated that indeed acetone and acetophenones can act as viable enolate coupling partners with Cs2CO3 as the [a] S. Korsager, D. U. Nielsen, Dr. R. H. Taaning, Prof. Dr. T. Skrydstrup base (Scheme 1b).[8] This improved reactivity of such subCenter for Insoluble Protein Structures (inSPIN) strates was nevertheless compromised by the need of perInterdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University forming the reaction with the reacting ketone as the solvent. Gustav Wieds Vej 14, 8000 Aarhus C (Denmark) Moreover, the developed conditions were performed with Fax: (+ 45) 8619-6199 aromatic iodides as the electrophile and long reaction times E-mail: [email protected] (up to 36 h) were needed. Hence, the development of alter[b] Dr. A. T. Lindhardt native procedures might still prove useful. Interdisciplinary Nanoscience Center (iNANO) Biological and Chemical Engineering Herein, we wish to report a mild and selective route to Department of Engineering, Aarhus University 1,3-diketones by a three-component Pd-catalyzed carbonylaFinlandsgade 22, 8200 Aarhus N (Denmark) tive a-arylation of acetylacetone with aryl bromides. SubstiFax: (+ 45) 4189-3001 tuted aliphatic 1,3-diketones and 1-aryl-1,3-butadiones all E-mail: [email protected] proved reactive under the developed conditions affording Supporting information for this article is available on the WWW the desired substituted diketones in high isolated yields. The under http://dx.doi.org/10.1002/chem.201303872.
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developed method is ideal for isotope labeling as CO is delivered in stoichiometric amounts to the carbonylative reaction by ex situ generation.[9] In this manner, 13C-labeled 1,3diketones were obtained and even an example of a doublelabeled 1,3-diketone is presented. We recently reported that the combination of Et3N, MgCl2, and the potassium monoester salts of malonates reacted excellently as enolate surrogates in the palladium-catalyzed carbonylative a-arylation of aryl bromides and electron-deficient aryl chlorides (Scheme 1c).[10–11] Acidic workup caused the intermediately formed acylated malonate derivatives to decarboxylate forming the desired b-ketoesters in high yields. We speculated as to whether this approach could be extended to include the synthesis of the corresponding 1,3-diketones. An indication was provided by the reaction of ethyl acetoacetate with 4-bromobenzonitrile, selectively affording the ethyl b-ketoester (1) upon acidic hydrolysis in an 83 % isolated yield (Scheme 1d). Gratifyingly, when acetylacetone was subjected to the developed reaction conditions, the desired triketone was formed exclusively, as observed by 1H NMR spectroscopic analysis of the crude reaction mixture. Selective deacetylation by applying HCl (2 m) at 80 8C proved superior to treatment with formic acid and a 96 % isolated yield of (1) was secured after column chromatography (Scheme 2).
as the nucleophile, the results of which are depicted in Table 1. Both electron-rich and deficient aryl bromides coupled successfully leading to high carbonylative coupling Table 1. Carbonylative a-arylation of acetylacetone with aryl halides.[a]
Scheme 2. Optimized conditions for the carbonylative coupling of 4-bromobenzonitrile with acetylacetone.
Notably, none of the corresponding debenzoylated product was observed after acid hydrolysis.[12] Adding less than one equivalent of MgCl2 caused a significant drop in selectivity with isolation of both 2 and 4-cyanobenzoic acid, after acidic treatment, presumably obtained through hydrolysis of the vinyl benzoate.[10, 13] With no added MgCl2, 4-cyanobenzoic acid was formed exclusively in 86 % isolated yield (see the Supporting Information). Finally, attempts to lower the catalytic loading resulted in an incomplete reaction in combination with loss of selectivity. With the conditions described in Scheme 2 in hand a series of aryl bromides were tested against acetylacetone
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[a] Reaction conditions: Chamber A: Aryl halide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), acetylacetone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h. [b] Deacetylation with HCl performed at 90 8C. [c] Reaction performed by using 4-chlorobenzonitrile as the substrate at 120 8C in 36 h in butyronitrile with Cy2NMe as the base. [d] Reaction run with aryl triflate as substrate. [e] Reaction run at 100 8C with Cy2NMe as the base. [f] Electrophile (0.25 mmol). [g] Reaction run on a 3 mmol scale by using 2.5 mol % of [PdCl2ACHTUNGRE(cod)] and 2.5 mol % of Xantphos.
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yields (4–5, 8–9, 12, and 2, 6–7, 13–16, respectively). Increasing the reaction temperature to 100 8C, while substituting Et3N for Cy2NMe, was required to ensure proper reactivity of ortho-substituted aryl bromides (18–22).[14] Heterocyclic aryl bromides also proved effective affording isolated yields of the desired 1,3-diketones in the range of 60–99 % (compounds 22–26). 1,4-Dibromobenzene underwent a doublecoupling to produce the symmetrical diketone 27 in quantitative yield. One aryl triflate was also tested as the electrophile affording the desired product 9 in a 93 % isolated yield. Finally, an excellent 91 % isolated yield of 2 starting from 4-chlorobenzonitrile, was obtained, but required a reaction temperature of 120 8C and Cy2NMe as the base in butyronitrile to ensure full conversion. Different 1,3-dicarbonyls were then evaluated as the coupling partner in the carbonylative a-arylation (Table 2). To our delight, substituents at the a-position on the pentane-
Table 3. Carbonylative a-arylation of different 1,3-dicarbonyl compounds with aryl bromides.[a]
Table 2. Carbonylative a-arylation of different 1,3-dicarbonyl compounds with aryl bromides.[a]
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), 1,3-diketone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h. [b] Reaction run at 100 8C with Cy2NMe as the base. [c] No addition of MgCl2.
[a] Reaction conditions: Chamber A: Aryl bromide (0.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.025 mmol), Xantphos (0.025 mmol), 1,3-diketone (0.55 mmol), MgCl2 (0.6 mmol), Et3N (2 mmol), and dioxane (3 mL) at 80 8C. Chamber B: COgen (0.75 mmol), Cy2NMe (1.5 mmol), [PdCl2ACHTUNGRE(cod)] (0.0375 mmol), PACHTUNGRE(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 80 8C for 18 h.
2,4-dione core did not interfere with the reaction affording the products 29–31 in acceptable yields as illustrated in Table 2. Omitting the acidic treatment step led to the isolation of triketones in yields reaching quantitative (Table 3). It was observed that 1,3-diketones obtained by using orthosubstituted aryl bromides required higher temperatures to complete the acidic deacetylation. In the case of 1-bromo-2fluorobenzene, no deacetylation occurred leading to the sole isolation of the triketone 36 in 86 % yield. In addition, cyclic 1,3-diketones proved reactive affording the corresponding triketones in high yields (32, 33, and 37). Interestingly, and in contrast to reactions with acetylacetone, the addition of MgCl2 was not required in the carbonylative reaction of tosylated 4-bromophenol leading to 37. Acidic treatment of 33 and 37 led to the corresponding ring-opened 5,7-diketohep-
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tanoic acid derivatives (38 and 39), again, with no sign of the debenzoylated product. The triketone derivatives 33 and 37 resemble the well-known herbicides, mesotrione and sulcotrione, with similar ring-opened soil metabolites, such as 38 and 39.[15] The substituted acetylacetone products obtained in Tables 1 and 2, could in principle, act as substrates in a sequential carbonylative a-arylation. This was achieved by a simple raise in reaction temperature to 100 8C and both 1,3-diaryl-1,3-propandiones 40 and 41 were secured in satisfactory isolated yields of 72 and 68 %, respectively, which demonstrated the usefulness of this protocol for the preparation of non-symmetrical 1,3-diaryl-1,3-diketones. As all carbonylative reactions presented in this work have been performed by using only 1.5 equivalents of CO, the method can, therefore, be effectively adapted for isotope labeling.[9] Applying 13CO from 13COgen, and starting with 4chlorobromobenzene (3 mmol) the corresponding 1,3-diketone 13C-43 was obtained in an 89 % isolated yield (Table 4).[16] Repeating the sequence in the coupling to 4bromoveratrole afforded the double 13C-labeled 1,3-diaryl1,3-propandione 13C2-41 in a 78 % (750 mg) isolated yield. Subjecting 13C2-41 to either hydrazine or hydroxylamine produced the corresponding double-13C2-labeled 3,5-diarylpyrazole or 3,5-diarylisoxazole heterocycles in 81 and 89 % isolated yields (13C2-44 and 13C2-45). Next, it was decided to test the suitability of the developed conditions for scale-up purposes, and hence the car-
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Table 4. Synthesis, labeling and application of 1,3-diaryl-1,3-propandiones.
Figure 1. Possible catalytic cycle for the carbonylative a-arylation with or without added MgCl2.
bonylative coupling protocol was applied to the synthesis of 4-(3-oxobutanoyl)benzonitrile 2. Initial studies on a 3 mmol scale indicated that the catalyst loading could be reduced to 0.5 mol % with no reduction in the product yield. Finally, performing the reaction on a 30 mmol scale afforded the desired 1,3-diketone 2 in 99 % isolated yield (Scheme 3).
Without added MgCl2, competing attack will occur through the now more reactive oxygen affording the vinyl benzoate D, which upon acidic treatment provides the corresponding benzoic acid.[13] In conclusion, reaction conditions were successfully developed for the carbonylative a-arylation of acetylacetone with aryl bromides. The desired 1,3-diketones were obtained by selective deacetylation of the intermediary formed triketone under acidic conditions. All 1,3-diketones were isolated in high yields and the catalytic conditions performed with excellent functional-group tolerance. The initially isolated 1aryl-1,3-diketones could, under near identical conditions, be transformed into their corresponding 1,3-diaryl-substituted 1,3-propandiones. Finally, isotope labeling with 13CO afforded a double 13C-labeled diketone, which was applied towards the synthesis of heterocycles.
Experimental Section 4-(3-Oxobutanoyl)benzonitrile (2, Scheme 1) Chamber A: In an argon filled glovebox, 4-bromobenzonitrile (91 mg, 0.5 mmol), [PdCl2ACHTUNGRE(cod)] (7.1 mg, 0.025 mmol), Xantphos (14.5 mg, 0.025 mmol), acetylacetone (55 mg, 0.55 mmol), MgCl2 (57 mg, 0.6 mmol), dioxane (3.0 mL), and Et3N (280 mL, 2 mmol) were added in this order to chamber A of the two-chamber system, COware.[16] The chamber was sealed with a screwcap fitted with a Teflon seal.
Scheme 3. Example of the gram-scale synthesis of 1,3-diketone 2 (30 mmol scale) and low catalyst loading.
Chamber B (1.5 equiv CO): In an argon filled glovebox, HBF4·PACHTUNGRE(tBu)3 (10.9 mg, 0.0375 mmol), [PdCl2ACHTUNGRE(cod)] (10.7 mg, 0.0375 mmol), 9-methylfluorene-9-carbonyl chloride (182 mg, 0.75 mmol), dioxane (3.0 mL), and Cy2NMe (320 mL, 1.5 mmol) were added to chamber B of the two-chamber system in that order. The chamber was sealed with a screwcap fitted with a Teflon seal.
A possible mechanistic scenario for the catalytic cycle is illustrated in Figure 1. Starting with an oxidative addition step followed by CO insertion affords complex A. Next, the MgCl2-activated complex B attacks A by a nucleophilic acyl substitution or by ligand exchange followed by reductive elimination forming C in both cases. This triketone is then deacetylated with aqueous HCl to form the 1,3-diketone.
The loaded two-chamber system was removed from the glovebox and heated to 80 8C for 18 h. The reaction was quenched with 2 m HCl (2 mL) and stirred for 1 h at 80 8C. The two phases were separated and the water phase was extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous NaSO4, filtrated, and concentrated under vacuum. The crude residue was subjected to flash chromatography by using pentane/CH2Cl2 (1:1– > CH2Cl2) as the eluent. This resulted in 90 mg (96 % yield) of the title product obtained as a colorless solid. 1 H NMR (400 MHz, CDCl3): d = 15.91 (s, 1 H), 7.95 (d, J = 8.55 Hz, 2 H),
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COMMUNICATION
7.73 (d, J = 8.55 Hz, 2 H), 6.19 (s, 1 H), 2.24 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 195.7, 179.7, 138.7, 132.4, 127.4, 118.1, 115.3, 97.6, 26.3 ppm; HRMS: m/z: calcd for C11H9NO2 : 188.0712 [M+H + ]; found: 188.0709.
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Acknowledgements We thank the Danish National Research Foundation (grant no. DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the Lundbeck Foundation, the Carlsberg Foundation, and Aarhus University for generous financial support of this work.
Keywords: 1,3-diketones · carbonylation · homogenous catalysis · isotope labeling · palladium
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Homogenous Catalysis S. Korsager, D. U. Nielsen, R. H. Taaning, A. T. Lindhardt,* T. Skrydstrup* . . . . . . . . . . . . . . . . &&&&—&&&& Direct Route to 1,3-Diketones by Palladium-Catalyzed Carbonylative Coupling of Aryl Halides with Acetylacetone
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Man up your magnesium! By employing a MgCl2/Et3N system, aryl diketones can be generated from the Pdcatalyzed carbonylative a-arylation of acetylacetone with aryl bromides (see
scheme). The method is ideal for the introduction of carbon isotopes into more complex structures, since only stoichiometric amounts of carbon monoxide are employed.
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