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Article Cite This: ACS Omega 2019, 4, 10534−10538
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Environmentally Benign, Base-Promoted Selective Amination of Polyhalogenated Pyridines Chao Sun,† Wubing Yao,*,†,‡ Xu Chen,† Yiwen Zhao,† Qiqi Wei,† Zishuang Chen,† Jiashou Wu,† Feiyue Hao,†,‡ and Huiping Xie‡ †
School of Pharmaceutical and Materials Engineering, Taizhou University, Jiaojiang 318000, China Zhejiang Hisoar Pharmaceutical Company Limited, Taizhou 318000, PR China
‡
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S Supporting Information *
ABSTRACT: An environmentally benign, highly efficient, and basepromoted selective amination of various polyhalogenated pyridines including the challenging pyridine chlorides to 2-aminopyridine derivatives using water as solvent has been developed. Featuring the use of the new method, the reaction is extended to the transformation on a large scale. Mechanistic studies indicate that the pathway involving a base aidant dissociation of N,Ndimethylformamide to generate dimethylamine is likely.
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INTRODUCTION 2-Aminopyridine-halogenated analogues are value-added feedstocks to develop natural products,1 fine chemicals,2 and biologically active molecules.3 Furthermore, they are also commonly used as multipurpose building blocks for the preparation of ligands in organometallic chemistry.4 Thus, the applications have created enormous attention and demand to develop highly chemoselective, efficient, and practical methods for the preparation of 2-aminopyridine derivatives. The chemoselective amination of polyfunctional pyridines is important for rapid diversification.5 In recent years, several efficient approaches mainly occupied by the noble-metal Pd catalyst systems to synthesize 2-aminopyridine derivatives have been reported.6 These works represent great advancement in catalytic polyhalogenated pyridine amination. However, such methods may be undesirable for pharmaceutical production, as the protocols involve using large amounts of precious metal resources, typically increasing the cost of the preparation process.7 Therefore, the development of low-cost and environmentally benign methods for the selective amination of polyhalogenated pyridine derivatives is of great interest. According to the report,8 avoiding the use of noble transition metals and employing water as solvent is one of the important characteristics of environmental synthesis. However, chemoselective amination of polyhalogenated pyridine derivatives using these processes are still in its infancy.9 Park,10a Woydziak,10b and Gong10c reported a convenient approach for the synthesis of aromatic amines through potassium hydroxide-promoted amination of aryl halides, albeit using excessive amino sources as solvent and coupling reagents (Scheme 1a).11 Recently, Li et al. have © 2019 American Chemical Society
Scheme 1. Amination of Aromatic Halides
developed sodium hydroxide-assisted amination of 2-fluoropyridine derivatives with acetamidine hydrochloride to form 2aminopyridines (Scheme 1b).8 However, the substrate is restricted to 2-fluoropyridine analogues, which is well known for its high reactivity in the nucleophilic substitution.11 Despite these advances, the highly selective, environmentally benign nonmetal systems for the coupling of polyhalogenated pyridines with amines are extremely rare, and the substrate Received: April 10, 2019 Accepted: June 7, 2019 Published: June 18, 2019 10534
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conducted well with only 2.0 equiv of NaOtBu and DMF (entry 13). With the optimized conditions in hands (Table 1, entry 11), we examined the substrate scopes with respect to polyhalogenated pyridines for the amination processes. As shown in Table 2, the bromo substituent at any position on 2-
scopes are also very restricted. Therefore, for the polyfunctional pyridine scaffolds, it is of synthetic interest and necessary to continue development of synthetic methods that have environmental, practical, and high selectivity. Herein, we demonstrated that sodium tert-butoxide was highly active for site-selective amination of polyhalogenated pyridines with various amino sources under mild conditions (Scheme 1c). This novel protocol provided a practical and environmental access to construct 2-aminopyridine halides and proceeded to completion with 3.0 equiv of NaOtBu, employing water as solvent in most cases.
Table 2. Substrate Scopes of the Polyhalogenated Pyridinesa
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RESULTS AND DISCUSSION N,N-Dimethylformamide (DMF) was generally used as a multipurpose block for numerous units in amination protocols.12 Thus, our initial studies focused on selective amination of 2,5-dibromopyridine (1a) using DMF (2a) as the coupling partner by examining the catalytic activities of commonly available bases (Table 1, entries 1−5). It was Table 1. Optimization of Reaction Conditionsa
entry
base
sol.
yield 3a (%)
yield 4 (%)
yield 5 (%)
1 2 3 4 5 6b 7b 8b 9b 10b 11b,c 12b,c,d 13b,c,e
NaOtBu KOH KOMe KOAc K2CO3 NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu NaOtBu
DMF DMF DMF DMF DMF EtOH H2O PhMe MeCN DCM H2O H2O H2O
84 81 42 0 0 68 73 44 39 0 99(95) 36 81
0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0
a
Reaction conditions: 1a (0.5 mmol), 2a (2 mL), base (1.5 mmol, 3.0 equiv), at 140 °C, 6 h. Yields were determined by GC using 1,2dimethoxybenzene as an internal standard; the value in the parentheses is isolated yield. b2a (1.0 mmol, 2.0 equiv), solvent (2.0 mL). c12 h. d100 °C. eNaOtBu (1.0 mmol, 2.0 equiv).
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), NaOtBu (1.5 mmol), H2O (2 mL), at 140 °C, 12 h. Yields shown are of isolated products. b2a (0.6 mmol), NaOtBu (0.75 mmol).
bromopyridine was compatible (3a−3d), providing the yields of products ranging from 51 to 95%. Notably, the reaction of 1a with 1.2 equiv of 2a and 1.5 equiv of NaOtBu could give a monosubstituted product in 77% yield with excellent selectivity. In addition, when a chloro group was at the 3-, 4-, or 5-position of 2-bromopyridine, the processes also takes priority at the 2-position, offering the products in moderate to excellent yields (3e−3h). The pyridine moiety containing an electron-donating substituent, such as methyl, also underwent the amination process smoothly, offering the unique product in a satisfying yield. Importantly, almost all of the selected 2fluoropyridine derivatives could be selectively converted to 2aminopyridine derivatives in good yields (3l−3o) by treatment of NaOtBu. Despite the low-cost advantages of employing aryl chlorides as coupling partners, the examples of selective amination of polyhalogenated heterocycles are extremely rare.6 The abovementioned good outcomes prompted us to continue to
determined that the most suitable base was NaOtBu when the reaction was run at 140 °C using DMF as solvent (entry 1). However, when the reaction was performed using KOAc (entry 4) or K2CO3 (entry 5), only starting material 1a was recovered. Further optimization revealed that solvents had important impacts on the amination process. A survey of solvents established H2O as the optimal reaction medium, giving product 3a in 73% yield (entry 7). As indicated in the table, the protocol did not proceed in DCM (entry 10), resulting in the large amounts of 1a recovering in the reaction. Further optimization revealed that extending the reaction time to 12 h further improved the yield to 99% (entry 11). However, lowering the temperature of the process down to 100 °C resulted in inefficient amination reaction with only 36% yield of 3a after 12 h (entry 12). On the contrary, the optimization result indicated that this protocol could be 10535
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Table 4. Substrate Scopes of the Aminesa
evaluate the amination of more challenging pyridine chlorides. Delightfully, by using the standard condition, functional groups including chloro, bromo, methyl, and nitro could all be tolerated (3b, 3a, and 3p−3h). Moreover, to demonstrate the synthetic utility further, we examined the amination of 2,3,5,6tetrachloropyridine with DMF. Excitingly, our reaction system allowed for the highly selective formation of the monoaminated pyridine (3r) in 78% yield. In addition, we turned our attention to test the halogenated 2-iodopyridines. Pleasingly, the 2-iodopyridine ring bearing the chloro (3g) or bromo (3a) group at its 5-position exhibited high efficiency and excellent selectivity as well. The substrate scopes of reactions via altering N,Ndimethylamide analogues as the amino source were also studied. As summarized in Table 3, by using NaOtBu as the Table 3. Substrate Scopes of the Amide Derivativesa
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), NaOtBu (1.5 mmol), H2O (2 mL), at 140 °C, 12 h. Yields shown are of isolated products.
Scheme 2. Large-Scale Reaction
In order to investigate the possible mechanism of this amination protocol, control experiments were conducted (Scheme 3). First, to examine the possibility of a radical mechanism, the reactions in the standard conditions by using commercially available radical scavengers, such as 9,10dihydroanthracene, BHT (butylated hydroxytoluene), and
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), NaOtBu (1.5 mmol), H2O (2 mL), at 140 °C, 12 h. Yields shown are of isolated products.
promoter, most of aromatic and aliphatic dimethylamides underwent amination reactions smoothly. It is worth noting that all alkyl amide derivatives (2b−2e), including sterically hindered isopropylamide 2f, were all well tolerated in the transformations, selectively giving the corresponding amines in moderate to excellent yields. It is generally known that aromatic amides are ineffective to this process on account of the low nucleophilicity.13 However, to our delight, a methyl substituent at any position on the aromatic ring was compatible (2h−2j), providing products in high yields and with exclusive selectivity. Remarkably, functionalities including phenyl (2k), amino (2l), ether (2m), and halide (2n−2p) groups were also tolerated. The selective amination was also successfully extended to the aliphatic amines (Table 4). Most transformations of alkylamines with 1a were remarkable in their regiospecificity for the functionalization of pyridine derivatives in the ortho position (3s−3a). Nevertheless, the sterically hindered amines were incompatible for reactions due to low nucleophilicity (3y−3z). With the highly active and excellent selectivity system in hands, we sought to demonstrate the synthetic utility of the reaction (Scheme 2). Employing 3.0 equiv of NaOtBu in water, the selective amination of 1a could be scaled up to 0.5 mol, providing the desired 3a in 92% isolated yield.
Scheme 3. Control Experiments
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EXPERIMENTAL SECTION Materials. H2O (distilled water) was obtained from Taizhou University and used as received. Sodium tert-butoxide (98%), TEMPO (98.5%), BHT (99%), 9,10-dihydroanthracene (98%), and trimethylphosphine (97%) were purchased from Energy Chemical and used as received. Potassium hydroxide (99.99%) and mercury (99.999%) were purchased from Aladdin and used as received. All of the pyridine halides, solvents, tertiary amides, and other bases were obtained from commercial suppliers and used as received. Analytical Methods. NMR spectra were recorded on AVANCE (III) HD 400 MHz. 1H NMR chemical shifts were internally referenced to the tetramethylsilane signal or solvent residual signals. 13C NMR chemical shifts were internally referenced to solvent signals. GC and GC−MS were performed on the Shimadzu GC-2010 plus spectrometer and GCMS-QP 2010 Plus spectrometer, respectively. HSGC was performed on a DANI HSS 86.50 spectrometer. Highresolution MS was performed on the Analytical Laboratory of Taizhou University. Typical Procedures for the Amination of Polyhalogenated Pyridines. Under air atmosphere, a 10 mL Schlenk tube was charged with 2,5-dibromopyridine (0.5 mmol), DMF (1.0 mmol, 2.0 equiv), NaOtBu (1.5 mmol, 3.0 equiv), and distilled water (2.0 mL). The reaction mixture was stirred at 140 °C. After 12 h, the reaction was cooled to 25 °C and quenched by exposing the solution to air. Then, the reaction mixture was dried with anhydrous magnesium sulfate. The combined organic layers were analyzed by GC/GC−MS with 1,2-dimethoxybenzene as an internal standard. After that, the product was purified by silica gel column chromatography using an ethyl acetate/petroleum ether mixture.
TEMPO (2,2,6,6-tetramethylpiperidinooxy) were conducted (eq 1). However, these processes indicated that the yields of 3a comparing with the protocol in the absence of radical scavengers remained nearly constant. Similarly, the addition of heterogeneous catalyst poisons Hg and PMe3 also showed no inhibition on the yields of the products (eq 2).14 Therefore, these results indicated that the process was likely to be homogeneous using the standard conditions and excluded the radical mechanism. In addition, to get some hint for the plausible mechanism, the reactions of 2,5-dibromopyridine with DMF and dimethylamine promoted by NaOtBu gave the products all in 99% gas chromatography (GC) yields (eq 3). Obviously, the data indicates that DMF is likely to serve mainly as a source of dimethylamine for the process, which has been widely utilized in synthetic reactions.12 To prove this hypothesis, we performed a blank test, performing the reaction in the absence of 2,5-dibromopyridine under the standard conditions (eq 4). With the analysis of the reaction mixture by headspace GC (HSGC) and GC−mass spectrometry (MS), we discovered that dimethylamine and t-butanol were formed in the process. However, owing to the similar molecular weight of nitrogen with carbon monoxide, we could not confirm whether carbon monoxide was formed in this protocol. As shown in Scheme 4, there are two plausible descriptions of the selective amination process involving DMF initiation of Scheme 4. Two Proposed Mechanisms
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01031.
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mechanistic cycles. Based on the reported works, the protocol initiated the nucleophilic attack of DMF on the C2-position of the polyhalogenated pyridine followed by release of CO, producing the corresponding 2-aminopyridine halide (route A).9a,15a The other is the process with base aidant dissociation of DMF to generate dimethylamine, and then reacts with the NaOtBu, providing the nucleophile species and t-butanol in situ (route B).9a,15b Based on the reported works,9a,15a,b the control experiments (Scheme 3, eqs 1−4) and kinetic studies (Figures S1−S3), the pathway B was more likely.
NMR spectra for all pure substrates and products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Wubing Yao: 0000-0002-4244-4609 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the China Postdoctoral Science Foundation (2017M621972), Zhejiang Post-Doctoral Preferential Fund Project (zj20180084), Natural Science Foundation of Zhejiang Province (LQ19B020001), Science and Technology Plan Project of Taizhou (1803gy04), Zhejiang University Student Science and Technology Innovation Activity Plan Project, Chemical Engineering & Technology of Zhejiang Province First-Class Discipline (Taizhou University), and Project of Taizhou and Taizhou University Fund for Excellent Young Scholars. The authors also thank Lanzhou University for the support.
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CONCLUSIONS In summary, we developed an environmental and universal base-promoted method for the amination of various fluoro-, bromo-, iodo-, and even chloro-pyridine derivatives using water as solvent, providing halogenated 2-aminopyridine derivatives in moderate to excellent yields with high selectivity. Overall, this novel protocol provides a facile and practical access to the construction of 2-aminopyridines and offers an useful alternative to the current methods, employing excess amino sources or the widely used palladium catalysts. 10537
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(10) (a) Cho, Y. H.; Park, J. C. A very convenient dimethylamination of activated aromatic halides using N,N-dimethylformamide and ethanolamines. Tetrahedron Lett. 1997, 38, 8331−8334. (b) Garcia, J.; Sorrentino, J.; Diller, E. J.; Chapman, D.; Woydziak, Z. R. General method for nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide. Synth. Commun. 2016, 46, 475−481. (c) Yang, C.; Zhang, F.; Deng, G.-J.; Gong, H. Amination of aromatic halides and exploration of the reactivity sequence of aromatic halides. J. Org. Chem. 2019, 84, 181−190. (11) (a) Amii, H.; Uneyama, K. C−F Bond Activation in Organic Synthesis. Chem. Rev. 2009, 109, 2119−2183. (b) Cai, J.; Huang, S.; He, R.; Chen, L.; Chen, D.; Jiang, S.; Li, B.; Li, Y. Access to functionalized thienopyridines via a reagent-capsule-assisted coupling, thiolation and cyclization cascade sequence. Org. Biomol. Chem. 2017, 15, 333−337. (c) Li, Y.; Luo, X.; Shao, Y.; Chen, L. 2Acetylthienopyridine Synthesis via Thiolation and Copper-Catalyzed Cyclization of o-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate. J. Org. Chem. 2018, 83, 8768−8774. (12) Ding, S.; Jiao, N. N,N-Dimethylformamide: A Multipurpose Building Block. Angew. Chem., Int. Ed. 2012, 51, 9226−9237. (13) Almond-Thynne, J.; Blakemore, D. C.; Pryde, D. C.; Spivey, A. C. Site-selective Suzuki-Miyaura coupling of heteroaryl halidesunderstanding the trends for pharmaceutically important classes. Chem. Sci. 2017, 8, 40−62. (14) (a) Anton, D. R.; Crabtree, R. H. Dibenzo[a,e]cyclooctatetraene in a proposed test for heterogeneity in catalysts formed from soluble platinum-group metal complexes. Organometallics 1983, 2, 855−859. (b) Yao, W.; Li, R.; Jiang, H.; Han, D. An additive-free, base-catalyzed protodesilylation of organosilanes. J. Org. Chem. 2018, 83, 2250−2255. (c) Fu, S.; Shao, Z.; Wang, Y.; Liu, Q. Manganese-catalyzed upgrading of ethanol into 1-butanol. J. Am. Chem. Soc. 2017, 139, 11941−11948. (15) (a) Agarwal, A.; Chauhan, P. M. S. Convenient dimethylamino amination in heterocycles and aromatics with dimethylformamide. Synth. Commun. 2004, 34, 2925−2930. (b) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. Dimethylformamide as a carbon monoxide source in fast palladium-catalyzed aminocarbonylations of aryl bromides. J. Org. Chem. 2002, 67, 6232−6235.
DEDICATION Dedicated to Professor Qizhong Zhou on the occasion of his 47th birthday
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REFERENCES
(1) (a) Newman, D. J.; Cragg, G. M.; Snader, K. M. The influence of natural products upon drug discovery (Antiquity to late 1999). Nat. Prod. Rep. 2000, 17, 215−234. (b) Rabanal, F.; Cajal, Y. Recent advances and perspectives in the design and development of polymyxins. Nat. Prod. Rep. 2017, 34, 886−908. (2) (a) Yan, R.-L.; Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. Cu(I)-catalyzed synthesis of imidazo[1,2-a]pyridines from aminopyridines and nitroolefins using air as the oxidant. J. Org. Chem. 2012, 77, 2024−2028. (b) Cao, H.; Liu, X.; Zhao, L.; Cen, J.; Lin, J.; Zhu, Q.; Fu, M. One-Pot regiospecific synthesis of imidazo[1, 2-a]pyridines: a novel, metal-free, threecomponent reaction for the formation of C-N, C-O, and C-S bonds. Org. Lett. 2014, 16, 146−149. (3) (a) Müller, S.; Rodriguez, R. G-Quadruplex interacting small molecules and drugs: from bench toward bedside. Expert Rev. Clin. Pharmacol. 2014, 7, 663−679. (b) Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.; Jones, L. H.; Fadeyi, O. Modern advances in heterocyclic chemistry in drug discovery. Org. Biomol. Chem. 2016, 14, 6611−6637. (4) (a) Fuhrmann, H.; Brenner, S.; Arndt, P.; Kempe, R. Octahedral Group 4 Metal Complexes That Contain Amine, Amido, and Aminopyridinato Ligands: Synthesis, Structure, and Application in α-Olefin Oligo- and Polymerization. Inorg. Chem. 1996, 35, 6742− 6745. (b) Yu, R. P.; Darmon, J. M.; Hoyt, J. M.; Margulieux, G. W.; Turner, Z. R.; Chirik, P. J. High-Activity iron catalysts for the hydrogenation of hindered, unfunctionalized alkenes. ACS Catal. 2012, 2, 1760−1764. (5) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Chemoselectivity: the mother of invention in total synthesis. Acc. Chem. Res. 2009, 42, 530− 541. (6) (a) Peng, Z.-H.; Journet, M.; Humphrey, G. A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine. Org. Lett. 2006, 8, 395−398. (b) Fairlamb, I. J. S. Regioselective (site-selective) functionalisation of unsaturated halogenated nitrogen, oxygen and sulfur heterocycles by Pd-catalysed cross-couplings and direct arylation processes. Chem. Soc. Rev. 2007, 36, 1036−1045. (c) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. Origin of regioselectivity in Palladium-catalyzed cross-coupling reactions of polyhalogenated heterocycles. J. Am. Chem. Soc. 2007, 129, 12664−12665. (d) Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. Theoretical bond dissociation energies of halo-heterocycles: trends and relationships to regioselectivity in Palladium-catalyzed crosscoupling reactions. J. Am. Chem. Soc. 2009, 131, 6632−6639. (e) Keylor, M. H.; Niemeyer, Z. L.; Sigman, M. S.; Tan, K. L. Inverting conventional chemoselectivity in Pd-catalyzed amine arylations with multiply halogenated pyridines. J. Am. Chem. Soc. 2017, 139, 10613−10616. (f) Young, I. S.; Glass, A.-L.; Cravillion, T.; Han, C.; Zhang, H.; Gosselin, F. Palladium-Catalyzed site-selective amidation of dichloroazines. Org. Lett. 2018, 20, 3902−3906. (7) (a) Sun, C.-L.; Shi, Z.-J. Transition-Metal-Free coupling reactions. Chem. Rev. 2014, 114, 9219−9280. (b) Wan, J.-P.; Gao, Y.; Wei, L. Recent advances in transition-metal-free oxygenation of alkene C=C double bonds for carbonyl generation. Chem.Asian J. 2016, 11, 2092−2102. (8) Li, Y.; Huang, S.; Liao, C.; Shao, Y.; Chen, L. Transition-metalfree access to 2-aminopyridine derivatives from 2-fluoropyridine and acetamidine hydrochloride. Org. Biomol. Chem. 2018, 16, 7564−7567. (9) (a) Sharma, A.; Mehta, V. P.; Van der Eycken, E. A convenient microwave-assisted desulfitative dimethylamination of the 2(1H)pyrazinone scaffold using N,N-dimethylformamide. Tetrahedron 2008, 64, 2605−2610. (b) Brzozowski, Z.; Sławiński, J. Reaction Products of Activated Aromatic and Heteroaromatic Chlorides withN,N-Disubstituted Formamides. Synth. Commun. 2010, 40, 1639−1645. 10538
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