DOI: 10.1002/chem.201404751
Full Paper
& Homogeneous Catalysis
Palladium-Catalyzed Carbonylative Coupling of (2-Azaaryl)methyl Anion Equivalents with (Hetero)Aryl Bromides Xavier Jusseau,[a] Hongfei Yin,[b] Anders T. Lindhardt,*[a] and Troels Skrydstrup*[b]
Abstract: Conditions for the palladium-catalyzed coupling of (2-pyridyl)acetones with aryl bromides have been developed. Followed by an acid-promoted deacetylation step, the desired 1-(het)aryl-2-(2-pyridyl)ethanones were obtained in good to excellent yields with high functional group tolerance. Test reactions revealed that both the addition of MgCl2 and a specifically positioned heteroatom in the heteroaromatic ring were crucial for product formation indicating the
importance of a chelated intermediate in the reaction mechanism. The reaction conditions proved suitable for a number of 5- and 6-membered heteroaromatic starting materials affording all products in good yields. The utility of the obtained 1-(het)aryl-2-(2-pyridyl)ethanones was demonstrated by the straightforward synthesis of several multiaromatic derivatives in only few additional steps.
Introduction The pyridine ring represents one of the most important heteroaromatic structures being embedded in a wide range of biologically active natural products, pharmaceutical and agrochemical agents, as well as in functional materials.[1–3] Positioning the pyridine ring on the a-carbon to a ketone as illustrated in Scheme 1 with structure 1, provides precursors that can be exploited for the construction of a number of valuable heterocyclic building blocks, including 4H-quinolizin-4-ones,[4] indolizines,[5] imidazo[1,5-a]pyridines,[5b, 6] or pyrazolopyridines.[7] Consequently, the rapid and efficient access to functionalized pyridines of the structural type 1 involving a multi-component approach would be of significant interest. Traditionally, a common procedure for accessing such ketones involves deprotonation of the picoline precursor with strong base (nBuLi, PhLi, LDA or NaNH2) followed by treatment with a corresponding electrophile (Weinreb amides, cyanides, esters, acyl chlorides, or activated esters) leading to moderate yields of the product in most cases and with poor functional
[a] Dr. X. Jusseau, Dr. A. T. Lindhardt Interdisciplinary Nanoscience Center (iNANO) Biological and Chemical Engineering Department of Engineering, Aarhus University Finlandsgade 22, 8200 Aarhus N (Denmark) Fax: (+ 45) 4189-3001 E-mail: [email protected] [b] H. Yin, Prof. Dr. T. Skrydstrup Center for Insoluble Protein Structures (inSPIN) Interdisciplinary Nanoscience Center (iNANO) Department of Chemistry, Aarhus University Gustav Wieds Vej 14, 8000 Aarhus C (Denmark) Fax: (+ 45) 8619-6199 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404751. Chem. Eur. J. 2014, 20, 15785 – 15789
Scheme 1. Carbonylative coupling strategy for preparing 1-(het)aryl-2-(2-pyridyl)ethanones 1.
group tolerance.[8] Alternatively, metal-promoted a-arylation of carbonyl-containing compounds represents a secondary approach.[9] Two methods have been described using acetophenone as the nucleophile. Rossi and Nazareno reported the aromatic radical nucleophilic substitution of 2-chloropyridine promoted by samarium(II) iodide,[10] whereas Stradiotto and coworkers recently proposed the Pd-catalyzed direct coupling between acetophenone and 2-bromopyridine applying the ligand DalPhos and sodium tert-butoxide.[11] Nevertheless, both methods suffer from a lack of compatibility with a number of functional groups, and substituted acetophenones are not readily accessible. Over the last 40 years, transition metal-catalyzed carbonylative couplings have emerged as a powerful tool for the synthesis of a wide variety of carbonyl containing chemicals. In particular, such products are key intermediates for the synthesis of heterocycles, which are at the heart of numerous and currently
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Full Paper marketed drugs.[12] We therefore speculated whether a threecomponent carbonylative coupling approach could be adapted for the construction of ketone 1 from a pyridylmethyl anion equivalent, carbon monoxide and a (het)aryl bromide (Scheme 1). As the high nucleophilicity and basicity of the pyridylmethyl anion would potentially limit the scope of functionalized (het)aryl bromides, we turned to alternative substrates such as potassium (2-pyridyl)acetate 2 or (2-pyridyl)acetone 3, whereby the corresponding enolate generated after deprotonation would be significantly less basic. This hypothesis was supported by our recent and successful carbonylative a-arylations with a variety of dicarbonyl compounds in the presence of the MgCl2/NEt3 combination as a mild basic system for the deprotonation step.[13, 14] Thus, we envisaged that the 2-pyridine ring could act as a carbonyl surrogate. Hence, the Pd-catalyzed carbonylative arylation of (2-pyridyl)acetate (2) or (2pyridyl)acetone (3) would represent a straightforward and valuable approach. Furthermore, this method would permit the isotope labeling of the ketone group with either carbon-13 or carbon-14 arising from an isotopically labeled carbon monoxide, thereby providing an easy access to isotopically labeled heterocycles that are accessible from 1-aryl-2-(2-pyridyl)ethanone 1.[15]
Results and Discussion In order to find the optimized conditions for the Pd-catalyzed carbonylative coupling of the pyridylmethyl anion analogues with aryl bromides, we started to investigate the reaction between 4-bromobenzonitrile and potassium (2-pyridyl)acetate (2) (Table 1). Initially, we carried out the reaction under similar conditions as to those we developed previously for the coupling of potassium malonate monoesters[13] with aryl bromides using [Pd(cod)Cl2] as the palladium source, Xantphos as ligand and
Table 1. Identification of the suitable pyridylmethyl anion.
Entry
Substrate
Solvent[b]
T [8C]
Yield [%][a][b]
1 2 3 4 5 6[c] 7
2 2 2 2 2 2 3
dioxane DME ACN nPrCN nBuCN diglyme dioxane
80 80 80 90 105 150 80
10 n.d. 41 35 23 n.d. 79
[a] All reactions were run in a two-chamber system on 0.5 mmol scale with 1.1 equiv of pyridylmethyl anion, CO was generated from COgen (see Supporting Information), acidic treatment was carried out with HCO2H with substrate 2 and with 2.0 m HCl with substrate 3. [b] Isolated yields. [c] Reaction run without MgCl2 and Et3N. Chem. Eur. J. 2014, 20, 15785 – 15789
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a combination of Et3N and MgCl2 in dioxane at 80 8C for 18 h (entry 1). Unfortunately, after acidic work up of the reaction mixture with formic acid, only 10 % of the desired product was isolated. Aware of possible solubility issues, we undertook a rapid screening of the solvents (entries 2–5). Switching to the more polar solvent acetonitrile led to a significant yield increase (entry 3, 41 %), whereas similar higher boiling point solvents provided less interesting results (entries 4 and 5). In 2010, Liu and co-workers reported the base-free Pd-catalyzed decarboxylative coupling of potassium (2-pyridyl)acetate (2) with aryl halides and triflates in diglyme at elevated temperature.[16] However, when our carbonylative process was conducted under similar conditions no desired product could be identified (entry 6). Gratifyingly, when we switched to the (2pyridyl)acetone (3), the reaction proceeded cleanly using the previously developed conditions. After selective deacetylation of the intermediate diketone applying 2 m HCl at 80 8C for 1 h, a 79 % yield of the desired carbonylated product 1 a could be achieved. According to previous observations that strongly electron-deficient aryl bromides (i.e. 4-bromobenzonitrile) undergo carbonylative coupling with lower yields than with those possessing electron-rich substituents,[17] we assumed that these carbonylative coupling conditions would be satisfactory for exploring the scope of the reaction. Indeed, as shown in Scheme 2, when we tested a range of 4-substituted aryl bromides with the ketone coupling partner 3 with these conditions, the coupling products were successfully isolated in yields ranging from 66–95 %. To our delight, both electron-donating and electron-withdrawing substituents were tolerated at the 4-position (1 b–d and 1 e–i, respectively). Moreover, substituents at the 3-position (4 a and 4 b) also resulted in high conversion into the desired product. However while ortho-substituted aryl bromides could be applied as coupling partners, it was necessary to increase the reaction temperature to 100 8C in order to achieve satisfactory yields of ketones 5 and 6. The afore-mentioned conditions proved to be mild for an interesting range of functionalities such as a tosylate, ketone, amine, as well as amide leading to the corresponding adducts 7–11 in yields from 73–96 %. The reaction with a brominated chalcone applying the optimized condition resulted in a mixture of compounds, but nevertheless, a 38 % of the product 12 could be retrieved. Heterocyclic aryl bromides were also successfully reacted with ketone 3 affording the corresponding compounds 14–17 in good to excellent yields, 50–98 %. Finally, ketone substrates bearing an a-substituent proved feasible, leading to the coupling products 18 and 19 in good yields. To gain insight to the possible role of magnesium chloride, several control experiments were performed.[18] First, we examined the reaction between ketone 3 and 4-bromoanisole under standard conditions though in the absence of MgCl2. A 35 % of conversion was observed and a 13 % yield of 4-methoxybenzoic acid was recovered indicating the importance of MgCl2 for the reactivity. On the other hand, when the carbonylative coupling was conducted with acetophenone in the presence of the MgCl2/Et3N base system, only unreacted starting materials were found. Finally, the importance of the nitrogen position in
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Scheme 3. Proposed mechanism for the carbonylative coupling of aryl bromides with (2-pyridyl)acetone 3.
Scheme 2. Carbonylative coupling of aryl and heteroaryl bromides with (2pyridyl)acetone 3. [a] Reaction carried out at 100 8C and with DIPEA as base. [b] Reaction carried out with the N-Boc protected 5-bromoindole. [c] 0.6 equiv of MgCl2 was used.
the pyridine ring was investigated. Reaction of 1-(pyridin-4-yl)propan-2-one, provided exclusively the benzoic acid derivative in an 84 % yield, suggesting that O-acylation was the major pathway for this carbonylative coupling leading to 4-methoxybenzoic acid after acidic hydrolysis. On the basis of these observations we propose a possible mechanistic scenario for this efficient transformation as depicted in Scheme 3. Oxidative addition of the Pd0 species into the aryl bromide bond followed by CO insertion would generate the palladium acyl complex 21. Then magnesium enolate 22 can directly undergo a nucleophilic substitution with this complex, or a transmetallation step of the magnesium enolate could take place, followed by reductive elimination. Both pathways would lead to the same product 23. The final step involves the acid-mediated deacetylation affording 1-aryl-2-(2-pyridyl)ethanone 1. Prompted by these findings that the nitrogen position is crucial to ensure proper reactivity and selectivity, we envisaged that this method would be suitable for other heterocycles. Therefore, we synthesized a variety of 5- and 6-membered heterocyclic starting materials and submitted them to the optimized carbonylative coupling conditions (Scheme 4). Without surprise, methyl-substituted pyridines and the quinoline derivative, afforded the desired products 24–26 in excelChem. Eur. J. 2014, 20, 15785 – 15789
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Scheme 4. Carbonylative coupling of other (2-azaaryl)methyl anions. [a] Reaction carried out with 0.6 equivalent of MgCl2. [b] The corresponding pyrazolone was isolated in a 53 % yield. [c] Reaction carried out with the N-Boc protected 5-bromoindole.
lent yields (98, 99 and 95 %, respectively). More interestingly, we were delighted to see that the pyridazine, pyrimidine and pyrazine derivatives were also appropriate candidates for this methodology, leading to good to excellent yields of the corresponding coupling products (27–29). Broadening the scope of the reaction to the 5-membered ring heterocycles revealed that both the benzothiazole and 1,2,4-triazole substrates could undergo the carbonylative coupling providing excellent yields of the ketones 30 and 31. Although, the 1,3,4-oxadiazole substrate proved feasible for the carbonylation, only a 39 % yield of ketone 32 could be isolated because of acidic instability of
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Full Paper such structures during the deacetylation step.[19] With the coupling products 33–36 we demonstrate the possibility of introducing two heteroaromatic rings at each terminus in excellent yields. Additionally, the propensity of vinyl bromides as appropriate coupling partners was investigated (Scheme 5). When the coupling of ketone 3 with cyclohexenyl bromide (37) was run, the C C bond forming steps proved again worthy. But more interestingly, an intramolecular Michael addition involving the pyridyl nitrogen atom as the nucleophile took place leading to the formation of the tricyclic structure 38 in a 67 % yield. A single X-ray crystal structure of this compound suggests that 38 is best represented by the zwitterion structure (see Supporting Information).
Scheme 6. Synthesis applications of 1-(4-methoxy-phenyl)-2-(2-pyridyl)ethanone (1 b).
Scheme 5. Carbonylative coupling of ketone 3 with 1-bromocyclohex-1-ene. [a] Reaction carried out with 0.6 equivalent of MgCl2.
Finally, a series of reactions were conducted in order to show the usefulness of the described methodology to achieve relevant heterocyclic building blocks for medicinal chemistry. As depicted in Scheme 6, the carbonylative coupling could be conducted on a 2.5 mmol scale without affecting its efficiency. Replacing COgen by 13COgen afforded 13C-labeled 1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone (1 b) in a good yield. From 1 b, a valuable set of scaffolds could be generated. Oxidative amination of the benzylic C H bond with NIS and tert-butoxy hydroperoxide delivered imidazo[1,5-a]pyridines 39 in a 62 % yield.[20] Condensation with chloroacetone led to the indoziline 40 in good yield as well.[5c] Bromination of the benzylic position in acidic media followed by reaction with thiourea resulted in the formation of the disubstituted thiazolamine 41 in a 58 % yield.[21] Finally, reaction with hydroxylamine followed by sequential treatment with trifluoroacetic anhydride and then iron(II) chloride furnished pyrazolopyridine 42 in a 53 % yield over three steps, including its 13C-isotopically labeled analog in a 46 % yield.[7b]
Conclusion In summary, we have demonstrated that the Pd-catalyzed carbonylative a-arylation of aryl bromides with (2-azaaryl)aceChem. Eur. J. 2014, 20, 15785 – 15789
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tones represents an efficient and straightforward protocol for accessing 1-aryl-2-(2-azaaryl)ethanone derivatives. Control experiments indicated that the combination of a chelating heteroatom positioned correctly in the starting materials and added MgCl2 proved crucial for the desired product outcome. The catalytic system could be extended to a wide range of both 5and 6-membered nitrogen-containing heterocycles. The obtained carbonyl-containing products were easily converted into a variety of multicyclic heteroaromtic structures demonstrating the wide applicability of this building block. Combined with isotope labeling using carbon-13 labeled carbon monoxide, this protocol allows for the synthesis of core-isotope labeled structures in only few steps.
Experimental Section General procedure for the carbonylative coupling: In a glovebox under argon, a 20.0 mL two-chamber system was loaded as follows. To chamber A of the two-chamber system was added in the following order [Pd(cod)Cl2] (7.1 mg, 0.025 mmol, 5.0 mol %), Xantphos (14.5 mg, 0.025 mmol, 5.0 mol %), MgCl2 (57.1 mg, 0.600 mmol, 1.20 equiv), (2-azaaryl)methyl anion (0.550 mmol, 1.10 equiv), aryl bromide (0.500 mmol, 1.00 equiv), followed by the solvent (3.0 mL) and Et3N (279 mL, 2.0 mmol, 4.00 equiv). To chamber B of the two-chamber system was added in the following order [Pd(cod)Cl2] (2.1 mg, 0.008 mmol, 1.0 mol %), HBF4·P(tBu)3 (2.2 mg, 0.008 mmol, 1.0 mol %), COgen (182 mg, 0.750 mmol, 1.00 equiv), solvent (3.0 mL) and Cy2NMe (321 mL, 1.5 mmol, 2.0 equiv). Both chambers were sealed using a screw cap and a Teflon coated silicone seal. The two chamber system was removed from the glovebox and settled in an pre-heated oil bath at 80 8C for 18 h. After this time, the two-chamber system was opened to air and the reaction in chamber A was quenched with
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Full Paper 2.0 mL of 2.0 m HCl then the mixture was stirred for a further hour at 80 8C. The crude mixture was then poured into a solution of saturated NaHCO3 then extracted with EtOAc or DCM. The combined organic layers were washed with brine, then dried over Na2SO4. The solvent was removed under vacuo then the crude mixture was purified through silica gel to afford the title compound. [7]
Acknowledgements We are deeply appreciative of generous financial support from the Danish National Research Foundation (grant no. DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the Carlsberg Foundation, and Aarhus University for generous financial support of this work. Furthermore, we thank the Chinese Scholarship Council for a grant to H.Y. Keywords: aromatic compounds · carbanions · carbonylation · homogeneous catalysis · pyridine [1] a) C. Gonzlez-Bello, L. Castedo, in Modern Heterocyclic Chemistry; (Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011, pp. 1431 – 1525; b) M. Baumann, R. Baxendale, Beilstein J. Org. Chem. 2013, 9, 2265 – 2319; c) M. D. Hill, Chem. Eur. J. 2010, 16, 12052 – 12062. [2] For selected examples of pyridine containing bioactive compounds a) G. Duvey, B. Perry, E. Le Poul, S. Poli, B. Bonnet, N. Lambeng, D. Charvin, T. Donovan-Rodrigues, H. Haddouk, S. Gagliardi, J.-P. Rocher, Bioorg. Med. Chem. Lett. 2013, 23, 4523 – 4527; b) M. Krishnaiah, C. H. Jin, D. Sreenu, V. B. Subrahmanyam, K. S. Rao, D.-H. Son, H.-J. Park, S. W. Kim, Y. Y. Sheen, D.-K. Kim, Eur. J. Med. Chem. 2012, 57, 74 – 84; c) E. DoluSˇic´, P. Larrieu, S. Blanc, F. Sapunaric, B. Norberg, L. Moineaux, D. Colette, V. Stroobant, L. Pilotte, D. Colau, T. Ferain, G. Fraser, M. Galeni, J.-M. Frre, B. Masereel, B. Van den Eynde, J. Wouters, R. Frdrick, Bioorg. Med. Chem. 2011, 19, 1550 – 1561; d) F. Pin, F. Buron, F. Saab, L. Colliandre, S. Bourg, F. Schoentgen, R. Le Guevel, C. Guillouzo, S. Routier, Med. Chem. Commun. 2011, 2, 899 – 903; e) D.-K. Kim, Y.-I. Lee, Y. W. Lee, P. M. Dewang, Y. Y. Sheen, Y. W. Kim, H.-J. Park, J. Yoo, H. S. Lee, Y.-K. Kim, Bioorg. Med. Chem. 2010, 18, 4459 – 4467; f) F. Venturoni, N. Nikbin, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 1798 – 1806. [3] For relevant functionalized materials see: a) W. Guo, X.-D. Chen, M. Du, A. Escuer, Inorg. Chem. Commun. 2012, 15, 184 – 187; b) M. Rakotomalala, M. Katz, E. Voisin, T. C. S. Pace, C. Bohne, V. E. Williams, Can. J. Chem. 2011, 89, 297 – 302. [4] C. W. Muir, A. R. Kennedy, J. M. Redmond, A. J. B. Watson, Org. Biomol. Chem. 2013, 11, 3337 – 3340. [5] a) L.-L. Gundersen, C. Charnock, A. H. Negussie, F. Rise, S. Teklu, Eur. J. Pharm. Sci. 2007, 30, 26 – 35; b) K. Sawada, S. Okada, A. Kuroda, S. Watanabe, Y. Sawada, H. Tanaka, Chem. Pharm. Bull. 2001, 49, 799 – 813; c) S. Hagishita, M. Yamada, K. Shirahase, T. Okada, Y. Murakami, Y. Ito, T. Matsuura, M. Wada, T. Kato, M. Ueno, Y. Chikazawa, K. Yamada, T. Ono, I. Teshirogi, M. Ohtani, J. Med. Chem. 1996, 39, 3636 – 3658. [6] a) A. Kamal, G. Ramakrishna, M. J. Ramaiah, A. Viswanath, A. V. S. Rao, C. Bagul, D. Mukhopadyay, S. N. C. V. L. Pushpavalli, M. Pal-Bhadra, Med. Chem. Commun. 2013, 4, 697 – 703; b) B. W. Trotter, K. K. Nanda, C. S.
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Received: August 6, 2014 Published online on October 10, 2014
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& Homogeneous Catalysis
Palladium-Catalyzed Carbonylative Coupling of (2-Azaaryl)methyl Anion Equivalents with (Hetero)Aryl Bromides Xavier Jusseau,[a] Hongfei Yin,[b] Anders T. Lindhardt,*[a] and Troels Skrydstrup*[b]
Abstract: Conditions for the palladium-catalyzed coupling of (2-pyridyl)acetones with aryl bromides have been developed. Followed by an acid-promoted deacetylation step, the desired 1-(het)aryl-2-(2-pyridyl)ethanones were obtained in good to excellent yields with high functional group tolerance. Test reactions revealed that both the addition of MgCl2 and a specifically positioned heteroatom in the heteroaromatic ring were crucial for product formation indicating the
importance of a chelated intermediate in the reaction mechanism. The reaction conditions proved suitable for a number of 5- and 6-membered heteroaromatic starting materials affording all products in good yields. The utility of the obtained 1-(het)aryl-2-(2-pyridyl)ethanones was demonstrated by the straightforward synthesis of several multiaromatic derivatives in only few additional steps.
Introduction The pyridine ring represents one of the most important heteroaromatic structures being embedded in a wide range of biologically active natural products, pharmaceutical and agrochemical agents, as well as in functional materials.[1–3] Positioning the pyridine ring on the a-carbon to a ketone as illustrated in Scheme 1 with structure 1, provides precursors that can be exploited for the construction of a number of valuable heterocyclic building blocks, including 4H-quinolizin-4-ones,[4] indolizines,[5] imidazo[1,5-a]pyridines,[5b, 6] or pyrazolopyridines.[7] Consequently, the rapid and efficient access to functionalized pyridines of the structural type 1 involving a multi-component approach would be of significant interest. Traditionally, a common procedure for accessing such ketones involves deprotonation of the picoline precursor with strong base (nBuLi, PhLi, LDA or NaNH2) followed by treatment with a corresponding electrophile (Weinreb amides, cyanides, esters, acyl chlorides, or activated esters) leading to moderate yields of the product in most cases and with poor functional
[a] Dr. X. Jusseau, Dr. A. T. Lindhardt Interdisciplinary Nanoscience Center (iNANO) Biological and Chemical Engineering Department of Engineering, Aarhus University Finlandsgade 22, 8200 Aarhus N (Denmark) Fax: (+ 45) 4189-3001 E-mail: [email protected] [b] H. Yin, Prof. Dr. T. Skrydstrup Center for Insoluble Protein Structures (inSPIN) Interdisciplinary Nanoscience Center (iNANO) Department of Chemistry, Aarhus University Gustav Wieds Vej 14, 8000 Aarhus C (Denmark) Fax: (+ 45) 8619-6199 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404751. Chem. Eur. J. 2014, 20, 15785 – 15789
Scheme 1. Carbonylative coupling strategy for preparing 1-(het)aryl-2-(2-pyridyl)ethanones 1.
group tolerance.[8] Alternatively, metal-promoted a-arylation of carbonyl-containing compounds represents a secondary approach.[9] Two methods have been described using acetophenone as the nucleophile. Rossi and Nazareno reported the aromatic radical nucleophilic substitution of 2-chloropyridine promoted by samarium(II) iodide,[10] whereas Stradiotto and coworkers recently proposed the Pd-catalyzed direct coupling between acetophenone and 2-bromopyridine applying the ligand DalPhos and sodium tert-butoxide.[11] Nevertheless, both methods suffer from a lack of compatibility with a number of functional groups, and substituted acetophenones are not readily accessible. Over the last 40 years, transition metal-catalyzed carbonylative couplings have emerged as a powerful tool for the synthesis of a wide variety of carbonyl containing chemicals. In particular, such products are key intermediates for the synthesis of heterocycles, which are at the heart of numerous and currently
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Full Paper marketed drugs.[12] We therefore speculated whether a threecomponent carbonylative coupling approach could be adapted for the construction of ketone 1 from a pyridylmethyl anion equivalent, carbon monoxide and a (het)aryl bromide (Scheme 1). As the high nucleophilicity and basicity of the pyridylmethyl anion would potentially limit the scope of functionalized (het)aryl bromides, we turned to alternative substrates such as potassium (2-pyridyl)acetate 2 or (2-pyridyl)acetone 3, whereby the corresponding enolate generated after deprotonation would be significantly less basic. This hypothesis was supported by our recent and successful carbonylative a-arylations with a variety of dicarbonyl compounds in the presence of the MgCl2/NEt3 combination as a mild basic system for the deprotonation step.[13, 14] Thus, we envisaged that the 2-pyridine ring could act as a carbonyl surrogate. Hence, the Pd-catalyzed carbonylative arylation of (2-pyridyl)acetate (2) or (2pyridyl)acetone (3) would represent a straightforward and valuable approach. Furthermore, this method would permit the isotope labeling of the ketone group with either carbon-13 or carbon-14 arising from an isotopically labeled carbon monoxide, thereby providing an easy access to isotopically labeled heterocycles that are accessible from 1-aryl-2-(2-pyridyl)ethanone 1.[15]
Results and Discussion In order to find the optimized conditions for the Pd-catalyzed carbonylative coupling of the pyridylmethyl anion analogues with aryl bromides, we started to investigate the reaction between 4-bromobenzonitrile and potassium (2-pyridyl)acetate (2) (Table 1). Initially, we carried out the reaction under similar conditions as to those we developed previously for the coupling of potassium malonate monoesters[13] with aryl bromides using [Pd(cod)Cl2] as the palladium source, Xantphos as ligand and
Table 1. Identification of the suitable pyridylmethyl anion.
Entry
Substrate
Solvent[b]
T [8C]
Yield [%][a][b]
1 2 3 4 5 6[c] 7
2 2 2 2 2 2 3
dioxane DME ACN nPrCN nBuCN diglyme dioxane
80 80 80 90 105 150 80
10 n.d. 41 35 23 n.d. 79
[a] All reactions were run in a two-chamber system on 0.5 mmol scale with 1.1 equiv of pyridylmethyl anion, CO was generated from COgen (see Supporting Information), acidic treatment was carried out with HCO2H with substrate 2 and with 2.0 m HCl with substrate 3. [b] Isolated yields. [c] Reaction run without MgCl2 and Et3N. Chem. Eur. J. 2014, 20, 15785 – 15789
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a combination of Et3N and MgCl2 in dioxane at 80 8C for 18 h (entry 1). Unfortunately, after acidic work up of the reaction mixture with formic acid, only 10 % of the desired product was isolated. Aware of possible solubility issues, we undertook a rapid screening of the solvents (entries 2–5). Switching to the more polar solvent acetonitrile led to a significant yield increase (entry 3, 41 %), whereas similar higher boiling point solvents provided less interesting results (entries 4 and 5). In 2010, Liu and co-workers reported the base-free Pd-catalyzed decarboxylative coupling of potassium (2-pyridyl)acetate (2) with aryl halides and triflates in diglyme at elevated temperature.[16] However, when our carbonylative process was conducted under similar conditions no desired product could be identified (entry 6). Gratifyingly, when we switched to the (2pyridyl)acetone (3), the reaction proceeded cleanly using the previously developed conditions. After selective deacetylation of the intermediate diketone applying 2 m HCl at 80 8C for 1 h, a 79 % yield of the desired carbonylated product 1 a could be achieved. According to previous observations that strongly electron-deficient aryl bromides (i.e. 4-bromobenzonitrile) undergo carbonylative coupling with lower yields than with those possessing electron-rich substituents,[17] we assumed that these carbonylative coupling conditions would be satisfactory for exploring the scope of the reaction. Indeed, as shown in Scheme 2, when we tested a range of 4-substituted aryl bromides with the ketone coupling partner 3 with these conditions, the coupling products were successfully isolated in yields ranging from 66–95 %. To our delight, both electron-donating and electron-withdrawing substituents were tolerated at the 4-position (1 b–d and 1 e–i, respectively). Moreover, substituents at the 3-position (4 a and 4 b) also resulted in high conversion into the desired product. However while ortho-substituted aryl bromides could be applied as coupling partners, it was necessary to increase the reaction temperature to 100 8C in order to achieve satisfactory yields of ketones 5 and 6. The afore-mentioned conditions proved to be mild for an interesting range of functionalities such as a tosylate, ketone, amine, as well as amide leading to the corresponding adducts 7–11 in yields from 73–96 %. The reaction with a brominated chalcone applying the optimized condition resulted in a mixture of compounds, but nevertheless, a 38 % of the product 12 could be retrieved. Heterocyclic aryl bromides were also successfully reacted with ketone 3 affording the corresponding compounds 14–17 in good to excellent yields, 50–98 %. Finally, ketone substrates bearing an a-substituent proved feasible, leading to the coupling products 18 and 19 in good yields. To gain insight to the possible role of magnesium chloride, several control experiments were performed.[18] First, we examined the reaction between ketone 3 and 4-bromoanisole under standard conditions though in the absence of MgCl2. A 35 % of conversion was observed and a 13 % yield of 4-methoxybenzoic acid was recovered indicating the importance of MgCl2 for the reactivity. On the other hand, when the carbonylative coupling was conducted with acetophenone in the presence of the MgCl2/Et3N base system, only unreacted starting materials were found. Finally, the importance of the nitrogen position in
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Scheme 3. Proposed mechanism for the carbonylative coupling of aryl bromides with (2-pyridyl)acetone 3.
Scheme 2. Carbonylative coupling of aryl and heteroaryl bromides with (2pyridyl)acetone 3. [a] Reaction carried out at 100 8C and with DIPEA as base. [b] Reaction carried out with the N-Boc protected 5-bromoindole. [c] 0.6 equiv of MgCl2 was used.
the pyridine ring was investigated. Reaction of 1-(pyridin-4-yl)propan-2-one, provided exclusively the benzoic acid derivative in an 84 % yield, suggesting that O-acylation was the major pathway for this carbonylative coupling leading to 4-methoxybenzoic acid after acidic hydrolysis. On the basis of these observations we propose a possible mechanistic scenario for this efficient transformation as depicted in Scheme 3. Oxidative addition of the Pd0 species into the aryl bromide bond followed by CO insertion would generate the palladium acyl complex 21. Then magnesium enolate 22 can directly undergo a nucleophilic substitution with this complex, or a transmetallation step of the magnesium enolate could take place, followed by reductive elimination. Both pathways would lead to the same product 23. The final step involves the acid-mediated deacetylation affording 1-aryl-2-(2-pyridyl)ethanone 1. Prompted by these findings that the nitrogen position is crucial to ensure proper reactivity and selectivity, we envisaged that this method would be suitable for other heterocycles. Therefore, we synthesized a variety of 5- and 6-membered heterocyclic starting materials and submitted them to the optimized carbonylative coupling conditions (Scheme 4). Without surprise, methyl-substituted pyridines and the quinoline derivative, afforded the desired products 24–26 in excelChem. Eur. J. 2014, 20, 15785 – 15789
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Scheme 4. Carbonylative coupling of other (2-azaaryl)methyl anions. [a] Reaction carried out with 0.6 equivalent of MgCl2. [b] The corresponding pyrazolone was isolated in a 53 % yield. [c] Reaction carried out with the N-Boc protected 5-bromoindole.
lent yields (98, 99 and 95 %, respectively). More interestingly, we were delighted to see that the pyridazine, pyrimidine and pyrazine derivatives were also appropriate candidates for this methodology, leading to good to excellent yields of the corresponding coupling products (27–29). Broadening the scope of the reaction to the 5-membered ring heterocycles revealed that both the benzothiazole and 1,2,4-triazole substrates could undergo the carbonylative coupling providing excellent yields of the ketones 30 and 31. Although, the 1,3,4-oxadiazole substrate proved feasible for the carbonylation, only a 39 % yield of ketone 32 could be isolated because of acidic instability of
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Full Paper such structures during the deacetylation step.[19] With the coupling products 33–36 we demonstrate the possibility of introducing two heteroaromatic rings at each terminus in excellent yields. Additionally, the propensity of vinyl bromides as appropriate coupling partners was investigated (Scheme 5). When the coupling of ketone 3 with cyclohexenyl bromide (37) was run, the C C bond forming steps proved again worthy. But more interestingly, an intramolecular Michael addition involving the pyridyl nitrogen atom as the nucleophile took place leading to the formation of the tricyclic structure 38 in a 67 % yield. A single X-ray crystal structure of this compound suggests that 38 is best represented by the zwitterion structure (see Supporting Information).
Scheme 6. Synthesis applications of 1-(4-methoxy-phenyl)-2-(2-pyridyl)ethanone (1 b).
Scheme 5. Carbonylative coupling of ketone 3 with 1-bromocyclohex-1-ene. [a] Reaction carried out with 0.6 equivalent of MgCl2.
Finally, a series of reactions were conducted in order to show the usefulness of the described methodology to achieve relevant heterocyclic building blocks for medicinal chemistry. As depicted in Scheme 6, the carbonylative coupling could be conducted on a 2.5 mmol scale without affecting its efficiency. Replacing COgen by 13COgen afforded 13C-labeled 1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone (1 b) in a good yield. From 1 b, a valuable set of scaffolds could be generated. Oxidative amination of the benzylic C H bond with NIS and tert-butoxy hydroperoxide delivered imidazo[1,5-a]pyridines 39 in a 62 % yield.[20] Condensation with chloroacetone led to the indoziline 40 in good yield as well.[5c] Bromination of the benzylic position in acidic media followed by reaction with thiourea resulted in the formation of the disubstituted thiazolamine 41 in a 58 % yield.[21] Finally, reaction with hydroxylamine followed by sequential treatment with trifluoroacetic anhydride and then iron(II) chloride furnished pyrazolopyridine 42 in a 53 % yield over three steps, including its 13C-isotopically labeled analog in a 46 % yield.[7b]
Conclusion In summary, we have demonstrated that the Pd-catalyzed carbonylative a-arylation of aryl bromides with (2-azaaryl)aceChem. Eur. J. 2014, 20, 15785 – 15789
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tones represents an efficient and straightforward protocol for accessing 1-aryl-2-(2-azaaryl)ethanone derivatives. Control experiments indicated that the combination of a chelating heteroatom positioned correctly in the starting materials and added MgCl2 proved crucial for the desired product outcome. The catalytic system could be extended to a wide range of both 5and 6-membered nitrogen-containing heterocycles. The obtained carbonyl-containing products were easily converted into a variety of multicyclic heteroaromtic structures demonstrating the wide applicability of this building block. Combined with isotope labeling using carbon-13 labeled carbon monoxide, this protocol allows for the synthesis of core-isotope labeled structures in only few steps.
Experimental Section General procedure for the carbonylative coupling: In a glovebox under argon, a 20.0 mL two-chamber system was loaded as follows. To chamber A of the two-chamber system was added in the following order [Pd(cod)Cl2] (7.1 mg, 0.025 mmol, 5.0 mol %), Xantphos (14.5 mg, 0.025 mmol, 5.0 mol %), MgCl2 (57.1 mg, 0.600 mmol, 1.20 equiv), (2-azaaryl)methyl anion (0.550 mmol, 1.10 equiv), aryl bromide (0.500 mmol, 1.00 equiv), followed by the solvent (3.0 mL) and Et3N (279 mL, 2.0 mmol, 4.00 equiv). To chamber B of the two-chamber system was added in the following order [Pd(cod)Cl2] (2.1 mg, 0.008 mmol, 1.0 mol %), HBF4·P(tBu)3 (2.2 mg, 0.008 mmol, 1.0 mol %), COgen (182 mg, 0.750 mmol, 1.00 equiv), solvent (3.0 mL) and Cy2NMe (321 mL, 1.5 mmol, 2.0 equiv). Both chambers were sealed using a screw cap and a Teflon coated silicone seal. The two chamber system was removed from the glovebox and settled in an pre-heated oil bath at 80 8C for 18 h. After this time, the two-chamber system was opened to air and the reaction in chamber A was quenched with
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Full Paper 2.0 mL of 2.0 m HCl then the mixture was stirred for a further hour at 80 8C. The crude mixture was then poured into a solution of saturated NaHCO3 then extracted with EtOAc or DCM. The combined organic layers were washed with brine, then dried over Na2SO4. The solvent was removed under vacuo then the crude mixture was purified through silica gel to afford the title compound. [7]
Acknowledgements We are deeply appreciative of generous financial support from the Danish National Research Foundation (grant no. DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the Carlsberg Foundation, and Aarhus University for generous financial support of this work. Furthermore, we thank the Chinese Scholarship Council for a grant to H.Y. Keywords: aromatic compounds · carbanions · carbonylation · homogeneous catalysis · pyridine [1] a) C. Gonzlez-Bello, L. Castedo, in Modern Heterocyclic Chemistry; (Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011, pp. 1431 – 1525; b) M. Baumann, R. Baxendale, Beilstein J. Org. Chem. 2013, 9, 2265 – 2319; c) M. D. Hill, Chem. Eur. J. 2010, 16, 12052 – 12062. [2] For selected examples of pyridine containing bioactive compounds a) G. Duvey, B. Perry, E. Le Poul, S. Poli, B. Bonnet, N. Lambeng, D. Charvin, T. Donovan-Rodrigues, H. Haddouk, S. Gagliardi, J.-P. Rocher, Bioorg. Med. Chem. Lett. 2013, 23, 4523 – 4527; b) M. Krishnaiah, C. H. Jin, D. Sreenu, V. B. Subrahmanyam, K. S. Rao, D.-H. Son, H.-J. Park, S. W. Kim, Y. Y. Sheen, D.-K. Kim, Eur. J. Med. Chem. 2012, 57, 74 – 84; c) E. DoluSˇic´, P. Larrieu, S. Blanc, F. Sapunaric, B. Norberg, L. Moineaux, D. Colette, V. Stroobant, L. Pilotte, D. Colau, T. Ferain, G. Fraser, M. Galeni, J.-M. Frre, B. Masereel, B. Van den Eynde, J. Wouters, R. Frdrick, Bioorg. Med. Chem. 2011, 19, 1550 – 1561; d) F. Pin, F. Buron, F. Saab, L. Colliandre, S. Bourg, F. Schoentgen, R. Le Guevel, C. Guillouzo, S. Routier, Med. Chem. Commun. 2011, 2, 899 – 903; e) D.-K. Kim, Y.-I. Lee, Y. W. Lee, P. M. Dewang, Y. Y. Sheen, Y. W. Kim, H.-J. Park, J. Yoo, H. S. Lee, Y.-K. Kim, Bioorg. Med. Chem. 2010, 18, 4459 – 4467; f) F. Venturoni, N. Nikbin, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 1798 – 1806. [3] For relevant functionalized materials see: a) W. Guo, X.-D. Chen, M. Du, A. Escuer, Inorg. Chem. Commun. 2012, 15, 184 – 187; b) M. Rakotomalala, M. Katz, E. Voisin, T. C. S. Pace, C. Bohne, V. E. Williams, Can. J. Chem. 2011, 89, 297 – 302. [4] C. W. Muir, A. R. Kennedy, J. M. Redmond, A. J. B. Watson, Org. Biomol. Chem. 2013, 11, 3337 – 3340. [5] a) L.-L. Gundersen, C. Charnock, A. H. Negussie, F. Rise, S. Teklu, Eur. J. Pharm. Sci. 2007, 30, 26 – 35; b) K. Sawada, S. Okada, A. Kuroda, S. Watanabe, Y. Sawada, H. Tanaka, Chem. Pharm. Bull. 2001, 49, 799 – 813; c) S. Hagishita, M. Yamada, K. Shirahase, T. Okada, Y. Murakami, Y. Ito, T. Matsuura, M. Wada, T. Kato, M. Ueno, Y. Chikazawa, K. Yamada, T. Ono, I. Teshirogi, M. Ohtani, J. Med. Chem. 1996, 39, 3636 – 3658. [6] a) A. Kamal, G. Ramakrishna, M. J. Ramaiah, A. Viswanath, A. V. S. Rao, C. Bagul, D. Mukhopadyay, S. N. C. V. L. Pushpavalli, M. Pal-Bhadra, Med. Chem. Commun. 2013, 4, 697 – 703; b) B. W. Trotter, K. K. Nanda, C. S.
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Received: August 6, 2014 Published online on October 10, 2014
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