Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 6780−6784
Metal-Free Decarboxylative Alkoxylation of 2‑Picolinic Acid and Its Derivatives with Cyclic Ethers: One Step Construction of C−O and C−Cl Bonds Xiaoqiang Yu,† Min He,† Jianglin Wu,† Chuancheng Zhou,† Xiujuan Feng,† Yoshinori Yamamoto,†,‡,§ and Ming Bao*,† †
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023 Liaoning, China Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan § Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
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‡
S Supporting Information *
ABSTRACT: A new strategy for the metal-free decarboxylative alkoxylation of 2-picolinic acid and its derivatives is described. The three-component reaction of 2-picolinic acid or its derivatives, cyclic ethers, and tBuOCl proceeded smoothly in the presence of a catalytic amount of p-chloranil to produce 2alkoxylated pyridines with an ω-chlorine atom in satisfactory to excellent yields. New C−O and C−Cl bonds were generated in one step. The ω-C−Cl bond can be easily transformed to a C−C or C−heteroatom bond, increasing the use of 2-alkoxylated pyridine products in organic synthesis. The electronic property of the substituent linked on the pyridine ring did not influence the reactivity of the 2-picolinic acid substrates.
T
Scheme 1. Synthesis of 2-Alkoxylated Pyridines
he 2-substituted pyridine structural motifs have frequently been found in the frameworks of various natural products, pharmaceuticals, materials, and ligands.1 As a member of this family, 2-pyridyl ethers have attracted considerable attention due to their fungicidal, insecticidal/ acaricidal, and herbicidal activities.2 For example, 2-pyridyl ethers constitute the core structures of commercial drugs and pesticides, such as pre-emergence herbicide, picoxystrobin, and imaging agents (Figure 1).3 Therefore, the development of
Figure 1. Bioactive compounds containing pyridine structural motifs.
new methods for the synthesis of 2-pyridyl ether derivatives has attracted considerable attention. The Ullmann,4 Chan− Lam−Evans,5 and Buchwald−Hartwig6 reactions are traditional methods for the synthesis of 2-pyridyl ether derivatives (Scheme 1, eq 1). In these transition-metal-catalyzed reactions, specific ligands or Lewis acids are generally required because the ligating ability of the nitrogen atom can lead to catalyst deactivation and the electronic properties of specific ring positions can be unfavorable for elementary reactions.7 In addition, the use of organoboronic acids and organohalides as the starting materials causes increasing production cost owing to their tedious and sluggish preparation.8 In the past decade, a rapidly growing number of decarboxylative reactions have been discovered for the regioselective construction of C−C and C−heteroatom © 2018 American Chemical Society
bonds.9 The advantages of using carboxylates as leaving groups for regiospecific coupling is that aromatic carboxylic acids show good stability, low cost, and high commercial availability.10 However, 2-pyridyl ethers are difficult to obtain through the transition-metal-catalyzed decarboxylative cross-coupling reaction of 2-picolinic acids with alcohols (Scheme 1, eq 2).11 We also failed to obtain 2-pyridyl ether by the palladium-catalyzed decarboxylative cross-coupling reaction of 2-picolinic acid with hexan-1-ol.12 The reason could be the generally harsh conditions required by decarboxylative carbometalation to extrude CO2 and the fast protodemetalation of the resulting Received: September 10, 2018 Published: October 11, 2018 6780
DOI: 10.1021/acs.orglett.8b02896 Org. Lett. 2018, 20, 6780−6784
Letter
Organic Letters carbometallic species under such conditions before a C−O bond coupling reaction.9c,11 Conducting research on new strategies of metal-free amidation of quinoline N-oxides,13 we found that the decarboxylation of 2-picolinic acids with tBuOCl and cyclic ethers in the presence of a catalytic amount of p-chloranil proceeds smoothyl to produce 2-alkoxylated pyridine derivatives with an ω-chlorine atom (Scheme 1, eq 3). The results are reported in the current work. In our initial studies, the reaction of picolinic acid (1a) with 1,4-dioxane was chosen as a model reaction to optimize the reaction conditions. The results are shown in Table 1. Several
Table 2. Decarboxylative Alkoxylation of Picolinic Acid and Its Derivatives with 1,4-Dioxanea
Table 1. Optimization of the Reaction Conditionsa
entry
oxidant
1 2 3 4 5 6 7 8 9 10 11 12d 13d,e
BQ DDQ 9,10-PQ m-CPBA p-bromanil p-chloranil none p-chloranil p-chloranil p-chloranil p-chloranil p-chloranil p-chloranil
Cl source t
BuOCl BuOCl t BuOCl t BuOCl t BuOCl t BuOCl t BuOCl KCl NaCl NCS DDQ t BuOCl t BuOCl t
yield (%)b 11 5 8 NRc 52 63 NRc NRc NRc NRc NRc 90 55
a
Reaction conditions: 2-picolinic acid (1a, 0.3 mmol), Cl source (0.3 mmol), oxidant (0.03 mmol, 10 mol %), and 1,4-dioxane (3.0 mL, 33 equiv) under N2 atmosphere at 110 °C for 12 h. bIsolated yield. cNo reaction; starting material 1a was recovered. dUsing 0.5 mmol t BuOCl. eUsing 10.0 equiv of 1,4-dioxane (0.26 mL).
oxidants, including benzoquinone (BQ), 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ), 9,10-phenanthrenequinone (9,10-PQ), m-chloroperoxybenzoic acid (m-CPBA), pbromanil, and p-chloranil, were initially examined using t BuOCl as the chlorine source in dioxane at 110 °C for 12 h (entries 1−6). The use of p-chloranil as an oxidant led to the formation of the desired product 2-(2-(2-chloroethoxy)ethoxy)-pyridine (2a) in relatively high yield (entry 6 vs entries 1−5). No reaction was observed when the mixture of 1a, tBuOCl, and 1,4-dioxane was treated in the absence of an oxidant (entry 7). The chlorine source was subsequently screened using p-chloranil as the oxidant. No reaction was observed when KCl, NaCl, N-chlorosuccinimide (NCS), and DDQ were examined as chlorine sources. To improve the yield of product 2a, we increased the amount of tBuOCl from 0.3 to 0.5 mmol. Gratifyingly, a yield of 90% was attained (entry 12). The yield of 2a was decreased along with the decreased amount of dioxane (entry 13). Therefore, the subsequent reactions of picolinic acid substrates 1 with 1,4-dioxane were performed using chloranil and tBuOCl as the oxidant and chlorine source, respectively, at 110 °C for 12 h. The reactions of the picolinic acid substrates 1a−1r were allowed to proceed under optimal conditions. The results are summarized in Table 2. As described in Table 1, desired 6781
DOI: 10.1021/acs.orglett.8b02896 Org. Lett. 2018, 20, 6780−6784
Letter
Organic Letters Table 2. continued
Table 3. Decarboxylative Alkoxylation of Picolinic Acid and Its Derivatives with Cyclic Ethersa
a
Reaction conditions: 2-picolinic acid (1, 0.3 mmol), tBuOCl (0.5 mmol), p-chloranil (10 mol %), and 1,4-dioxane (3.0 mL) under N2 atmosphere at 110 °C for 12 h. bIsolated yield. cReaction performed for 20 h. dReaction performed for 30 h. eNo reaction was observed, and 1k was recovered completely. fUsing 0.6 mmol tBuOCl (2.0 equiv) and 20 mol % p-chloranil with the reaction mixture treated for 48 h.
product 2a was obtained in 90% yield (entry 1). Reactions of 1b−1d having a methyl group on the pyridine ring at the 3-, 4-, and 5-positions, respectively, afforded the corresponding products in high yields (83−88%, entries 2−4). The reactions of substrates 1e−1g bearing electron-withdrawing groups (CO2Me, NO2, and CF3) on the pyridine ring at the 5position afforded the desired products 2e−2g in 81−90% yields (entries 5−7). These results indicate that the electronic property of the substituent linked on the pyridine ring did not influence the reactivity of 2-picolinic acid substrates. Interestingly, the decarboxylative alkoxylation reaction selectively occurred at the 2-position when the substrates 1h−1j bearing two carboxyl (CO2H) groups on the pyridine ring were treated under optimum conditions (entries 8−10). However, the substrate 1k having two CO2H groups at the 2- and 6-positions did not produce desired product 2k (entry 11); this result can be attributed to the formation of a stable intramolecular hydrogen bond between nitrogen atom and two CO2H groups. The chlorine atom linked on the pyridine ring was tolerated in this type of decarboxylative alkoxylation reaction; the desired products 2l−2o were obtained in moderate to good yields (62−86%, entries 12−15). Product 2o is a type of pre-emergence herbicide. The reactions of substrates 1p−1r having quinoline, isoquinoline, and quinoxaline motifs, respectively, were finally performed. Desired products 2p−2r were obtained in 80−95% yields (entries 16−18). We then examined the reaction with various cyclic ethers under the optimized reaction conditions. The results are summarized in Table 3. The reaction of 2-picolinic acid 1a with tetrahydrofuran produced 2s in only 35% yield (entry 1). Low yields were also observed in the reactions of 1b and 1q with tetrahydrofuran under the optimized reaction conditions (entries 2 and 3). The low yields observed may be attributed to the low boiling point of tetrahydrofuran. The six-membered cyclic ether tetrahydro-2H-pyran afforded the corresponding product 2v in 63% yield (entry 4). The reaction of 1a with oxepane proceeded smoothly in the presence of p-chloranil and t BuOCl to afford the desired product 2w in 80% yield (entry 5). Control experiments were conducted to gain insight into the mechanism of this type of decarboxylative alkoxylation reaction. Only a trace amount of 2a was observed when the reaction of 1a was performed under the optimized reaction conditions in the presence of 1.5 equiv of 2,2,6,6-tetramethyl1-piperidinyloxy (TEMPO) [Scheme 2, eq (1)]. This result suggests that the target reaction may involve a radical process. No decarboxylation reaction occurred when 1a was treated with di-t-butylperoxide instead of tBuOCl; 1a was recovered completely [Scheme 2, eq (2)]. This indicates that the tBuOCl is required for the reaction to proceed. No reaction was observed when nicotinic acid (1s) was treated under the optimized reaction conditions; starting material 1s was
a Reaction conditions: 2-picolinic acid (1, 0.3 mmol), tBuOCl (0.6 mmol), p-chloranil (20 mol %), and cyclic ether (3.0 mL) under a N2 atmosphere at 110 °C for 48 h. bIsolated yield.
Scheme 2. Control Experiments
recovered [Scheme 2, eq (3)]. This phenomenon indicates that the carboxyl group must be linked on the position near the nitrogen atom. A plausible reaction mechanism is depicted in Scheme 3 on the basis of the mechanistic studies described above. Initially, the reaction of p-chloranil with tBuOCl may form the mixture of the tBuO· radical and semiquinone radical A. Semiquinone radical A subsequently reacts with 1a to produce semiquinone radical B and zwitterionic intermediate C. The tBuO· radical derived from tBuOCl reacts with semiquinone radical B to form tBuOH14 and regenerate p-chloranil. Meanwhile, zwitterionic intermediate C releases CO2, resulting in a ylide, N-chloro pyridinium D.15 A resonance possibly exists between ylide D and N-chloro carbene E.16 Subsequently, E undergoes 6782
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Organic Letters
standing Young Scholars Development Growth Plan of Universities in Liaoning Province (LJQ2015027).
Scheme 3. Plausible Mechanism
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(1) (a) Arena, C. G.; Arico, G. Curr. Org. Chem. 2010, 14, 546−580. (b) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161−1172. (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627−646. (d) Henry, G. D. Tetrahedron 2004, 60, 6043−6061. (2) (a) Li, J. J.; Johnson, D. S. Modern Drug Synthesis; Wiley: Hoboken, NJ, 2010. (b) Li, J. J.; Johnson, D. S.; Sliskovic, D. R.; Roth, B. D. Contemporary Drug Synthesis; Wiley-Interscience: Hoboken, NJ, 2004. (3) (a) Zha, Z. H.; Choi, S. R.; Ploessl, K.; Lieberman, B. P.; Qu, W. C.; Hefti, F.; Mintun, M.; Skovronsky, D.; Kung, H. F. J. Med. Chem. 2011, 54, 8085−8098. (b) Ran, Z. J.; Yuan, H. Z.; Cao, A. C. Z.; Qin, H. Chin. J. Pestic. Sci. 2010, 12, 458−462. (c) Ran, Z. J.; Ni, H. W.; Duan, H. X.; Li, N.; Dong, Y. H.; Fu, B.; Xiao, Y. M.; Qin, Z. H. Chin. J. Pestic. Sci. 2009, 22, 41−46. (d) Whitaker, R. L.; Smith, H. Q.; Wash, T.; Pa, M. 3,5-dichloro-2-pyridoxyethyl ethers as herbicide. US 3,894,862[P]. (4) March, J. Advanced Organic Chemistry; Wiley-Interscience: Hoboken, NJ, 1992. (5) For reviews on this topic, see: (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954−6971. (b) Hartwig, J. F. Nature 2008, 455, 314−322. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400−5449. (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046−2067. (6) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933−2936. (b) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937−2940. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941−2067. (7) Shen, Q. L.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734− 7735. (8) Katritzky, A. R.; Taylor, R. J. K. Comprehensive Organic Functional Group Transformations II; Elsevier, Dordrecht, 2004; Chapter 2, p 561. (9) For selected examples, see: (a) Liu, C.; Wang, X. Q.; Li, Z. D.; Cui, L.; Li, C. Z. J. Am. Chem. Soc. 2015, 137, 9820−9823. (b) Zhou, M. X.; Chen, M.; Zhou, Y.; Yang, K.; Su, J. H.; Du, J. F.; Song, Q. L. Org. Lett. 2015, 17, 1786−1789. (c) Hu, G. B.; Gao, Y. X.; Zhao, Y. F. Org. Lett. 2014, 16, 4464−4467. (d) Wang, P. F.; Wang, X. Q.; Dai, J. J.; Feng, Y. S.; Xu, H. Org. Lett. 2014, 16, 4586−4589. (e) Zhang, Y.; Patel, S.; Mainolfi, N. Chemical Science 2012, 3, 3196−3199. (f) Ranjit, S.; Duan, Z. Y.; Zhang, P. F.; Liu, X. G. Org. Lett. 2010, 12, 4134− 4136. (10) For reviews on this topic, see: (a) Rodriguez, N.; Goossen, K. Chem. Soc. Rev. 2011, 40, 5030−5048. (b) Shang, R.; Liu, L. Sci. China: Chem. 2011, 54, 1670−1687. (c) Goossen, L. J.; Rodriguez, N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100−3120. (11) For selected examples, see: (a) Goossen, L. J.; Manjolinho, F.; Khan, B. A.; Rodríguez, N. J. J. Org. Chem. 2009, 74, 2620−2623. (b) Goossen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P.; Fromm, A. Chem. Commun. 2009, 46, 7173−7175. (12) The Pd- and Cu-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid with hexan-1-ol were examined. In these reactions, the protonation reaction occurred to afford pyridine as major product, and the alkoxylation product was not detected at all. For details, see the Supporting Information. (13) Yu, X. Q.; Yang, S. N.; Zhang, Y.; Guo, M. J.; Yamamoto, Y.; Bao, M. Org. Lett. 2017, 19, 6088−6091. (14) The tBuOH is determined by GCMS, and its spectrum is available in the Supporting Information. (15) (a) Haake, P.; Mantecón, J. J. Am. Chem. Soc. 1964, 86, 5230− 5234. (b) Brown, B. R.; Hammick, D. L. J. Chem. Soc. 1949, 659−663. (c) Ashworth, M. R. F.; Daffern, R. P.; Hammick, D. L. J. Chem. Soc. 1939, 0, 809−812. (16) (a) Roselló-Merino, M.; Díez, J.; Conejero, S. Chem. Commun. 2010, 46, 9247−9249. (b) Cabeza, J. A.; Del Río, I.; Pérez-Carreño,
a C−O and C−Cl coupling reaction with 1,4-dioxane to form product 2a. In conclusion, we have developed a new and efficient method to synthesize 2-alkoxylated pyridines under metal-free conditions. The decarboxylative alkoxylation of 2-picolinic acid and its derivatives with tBuOCl and cyclic ethers proceeded smoothly in the presence of a catalytic amount of p-chloranil via a carbene intermediate to afford 2-pyridyl ethers with ωchlorine atom in satisfactory to excellent yields. Further manipulation of a ω-C−Cl bond may produce other useful compounds. The new strategy for generation of a carbene intermediates from 2-picolinic acids was established in the current paper. Further investigations into the synthetic applications of the carbene intermediates are ongoing.
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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/acs.orglett.8b02896. Experimental procedures and characterization data (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xiaoqiang Yu: 0000-0001-9396-3882 Ming Bao: 0000-0002-5179-3499 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21572028 and 21573032) for their financial support. This work was also supported by the Liaoning Natural Science Foundation of China (201602181) and the Out6783
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Organic Letters E.; Sánchez-Vega, M. G.; Vázquez-García, D. Angew. Chem., Int. Ed. 2009, 48, 555−558. (c) Conejero, S.; Lara, P.; Paneque, J. M.; Petronilho, M.; Poveda, L.; Serrano, O.; Vattier, F.; Alvarez, E.; Maya, C.; Salazar, V.; Carmona, E. Angew. Chem., Int. Ed. 2008, 47, 4380− 4383. (d) Song, G. Y.; Zhang, Y.; Su, Y.; Deng, W. Q.; Han, K. L.; Li, X. W. Organometallics 2008, 27, 6195−6201. (e) Á lvarez, E.; Conejero, S.; Lara, P.; López, J. A.; Paneque, M.; Petronilho, A.; Poveda, M. L.; del Río, D.; Serrano, O.; Carmona, E. J. Am. Chem. Soc. 2007, 129, 14130−14131. (f) Á lvarez, E.; Conejero, S.; Paneque, M.; Petronilho, A.; Poveda, M. L.; Serrano, O.; Carmona, E. J. Am. Chem. Soc. 2006, 128, 13060−13061. (g) Owen, J. S.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2004, 126, 8247−8255.
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