Letter Cite This: Org. Lett. 2017, 19, 5517-5520
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Electrocatalytic Minisci Acylation Reaction of N‑Heteroarenes Mediated by NH4I Qing-Qing Wang,† Kun Xu,†,‡ Yang-Ye Jiang,† Yong-Guo Liu,§ Bao-Guo Sun,§ and Cheng-Chu Zeng*,† †
Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science & Bioengineering, Beijing University of Technology, Beijing 100124, China ‡ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, China § Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University, Beijing 100048, China S Supporting Information *
ABSTRACT: An electrochemical C−H acylation of electron-deficient Nheteroarenes with α-keto acids is reported. This first electrochemical Minisci acylation reaction proceeded using NH4I as a redox catalyst. A broad Nheteroarene scope and high functional group tolerance are observed. Selective monoacylation of N-heteroarenes is achieved via control of acyl radical at a low concentration. The results of cyclic voltammetry and control experiments disclose that the electrogenerated I2 is likely the active species to initiate the oxidative decarboxylation of carboxylate anion via an acyl hypoiodite intermediate. The electrochemical Minisci acylation provides a straightforward approach for the late-stage functionalization of pharmacophores.
D
irect C−H functionalization of electron-deficient Nheteroarenes with carbon-centered radicals via a radical substitution process, known as Minisci reactions, has provided a versatile and powerful access to structural diversification of medically relevant molecules without the need of protection/ deprotection sequences.1−3 Minisci reactions are considered complementary to the conventional Friedel−Crafts alkylation and acylation reactions with opposite reactivity and selectivity. Despite their significance, Minisci acylation reactions have been less explored compared with alkylation reactions. Typically, Minisci acylation is proceeded using Fe(II)/tBuOOH or Fe(II)/(NH4)2S2O8 redox systems and aldehydes as acyl radical precursors.4 Alternatively, Ag(I)/(NH4)2S2O8 has been employed to induce oxidative decarboxylation of αketo acids for the Minisci acylation reactions.5 Minisci-type C− H acylation transformation has also been achieved via aerobic oxidation of aldehydes and protonated N-heteroarenes, catalyzed by NHPI and Co salts.6 While much effort has been devoted to the Minisci acylation reaction, most of the reported methods require transition-metal catalysts and excess amounts of toxic oxidants. The use of excess strong oxidizing reagents frequently brings about overoxidation of the desired products as well as producing large amounts of environmentally deleterious waste. Moreover, when multiple positions are available in a heterocyclic ring, selective monoacylation is difficult to achieve since acyl group would activate the heteroarene, leading to easier polysubstitution. Minisci acylation reaction is believed to proceed via the addition of an acyl radical to an electron-deficient Nheteroarene. Using a mass-free electron as the reagent, this electrochemistry affords an environmentally benign method to generate radicals and radical ions7 and more likely provides an alternative solution to the Minisci acylation reaction. To this end, we have carried out a program on electrocatalytic oxidative © 2017 American Chemical Society
coupling mediated by simple halide ions for the formation of new chemical bonds.8 From our recent explorations,8d,9 we have observed that the anodic oxidation of sulfinate in the presence of halide ion could be applied to efficient synthesis of sulfonamide and 3-sulfonyl oxindoles. In sharp contrast, sulfonyl radical generated from the direct anodic oxidation gave a lower yield of sulfonamide or a trace of 3-sulfonyl oxindoles. The reaction of sulfinate anion with molecular halogen generates sulfinyl hypohalite A, which exists as an equilibrium with its homolytic fragment, the oxygen-centered sulfonyl radical B, and the sulfur-centered sulfonyl radical C.10 From this point of view, sulfinyl hypohalite A essentially is a masked sulfonyl radical. This reversible equilibrium controls the sulfonyl radical to a low concentration, which diminish its propensity to undergo decomposition and other side reactions, thereby improving the efficiency of the desired radical coupling or addition reactions (Scheme 1a). Scheme 1. Minisci C−H Acylation of N-Heteroarenes
Received: August 21, 2017 Published: October 2, 2017 5517
DOI: 10.1021/acs.orglett.7b02589 Org. Lett. 2017, 19, 5517−5520
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Organic Letters Scheme 2. Scope of N-Heteroarenea
Based on this understanding, we envisioned that analogous chemistry may also occur when a carboxylate anion is subjected to anodic oxidation under the mediation of halide ion, generating acyl hypohalite D, a proposed intermediate as in the Hunsdiecker reaction.11 Homolytic breaking of the O−X bond would provide carboxylate radical E and, after decarboxylation, yield alkyl radical (R = alkyl) or acyl radical (R = acyl). Consequently, Minisci reactions with Nheteroarenes may occur (Scheme 1b). Herein, we report the first example of electrochemical Minisci acylation reactions of electron-deficient N-heteroarenes with α-keto acids.12 This metal- and oxidant-free protocol uses cheap and easily available NH4I as a redox catalyst with a low catalyst loading, thereby providing an efficient and environmentally benign route to acylated N-heteroarenes. Notably, similar to the reactions of electrogenerated sulfonyl hypohalites, by control of acyl radical to relatively low concentration, a selective monoacylation reaction is achieved (Scheme 1b). To demonstrate this proposal, quinoxaline 1a and pyruvic acid 2a were initially selected as model compounds to optimize the reaction conditions (Scheme s1). After screening of temperature, solvent, redox catalyst, additive, and working electrode (see Table s1 for the details), we concluded that the constant current electrolysis is preferable at 3 mA/cm2 in an undivided cell equipped with LiClO4/CH3CN using 15 mol % of NH4I at 70 °C. The presence of hexafluoroisopropanol (HFIP) as additive is of importance in the stabilizing radical.13 Under the optimal conditions, 3aa was isolated in 56% yield (73% yield based on the recovered 1a). In contrast, only 9% yield of 3aa was obtained when the Minisci reaction was performed in the absence of NH4I. This observation further proves that the control of acyl radical concentration via electrochemical generation of acyl hypoiodite is essential for this reaction. In addition, the acetyl group of product 3aa was anchored on the electron-deficient pyrazine unit, instead of electron-rich benzene ring, indicating a Minisci-type reaction occurs, rather than a conventional Friedel−Crafts acylation. With the optimal reaction conditions in hand, we turned to investigate the scope and generality of this protocol (Scheme 2). It was observed that substituents with different electronic properties attached to the phenyl ring of the quinoxaline cycle were tolerated, giving the corresponding products 3ba−fa in good yields. Their structures were identified after comparing their 13C NMR data with that of 3ba, which was confirmed by single-crystal X-ray analysis (CCDC 1559232). 2-Substituted quinoxalines were also suitable substrates for the Minisci acylation reaction. For example, when 2-methylquinoxaline 1g was subjected to react with 2a under the standard conditions, acylated product 3ga was isolated in 44% yield. However, in the case of 2-chloroquinoxaline, it also gave 3aa (16% yield), maybe stemming from the simultaneous dechlorination of the in situ generated 3ha due to the utilization of an undivided cell. Next, pyrazines 1i−m were examined. It was observed that chloro and methoxy substitutents direct predominantly ortho acylation, thus giving the 2,3-disubstituted pyrazines 3ja and 3ka in respective 22% and 29% yields, whereas the cyano group directs meta substitution to give 2,6-disubstituted product 3la in 31% yield. This substituent-directing effects is consistent with the previous report.14 The disubstituted pyrazine, 1m, participated in this decarboxylative process with a high reactivity as well, giving product 3ma in 65% yield. Other electron-deficient six-membered N-heterocycles, such as pyridazine, pyridine, and quinoline, were also found to be
Reaction conditions: graphite plate anode (2 cm × 2 cm), graphite plate cathode (2 cm × 2 cm), 1 (1.0 mmol), 2a (3.0 mmol), 0.1 M LiClO4/CH3CN (15 mL), NH4I (0.15 mmol), HFIP (2 mmol) was added, 70 °C, undivided cell, 6.0 h. b3aa was isolated in 16% yield. a
feasible under this electrocatalytic system to give products 3na, 3oa, and 3pa in 43%, 39%, and 36% yields, respectively. It is noteworthy that this reaction showed satisfactory tolerance of halogen groups, which provides useful handles for further transformations through cross-coupling reactions. The reactivity of different α-keto acids was also investigated (Scheme 3). Aliphatic α-keto acids bearing linear and branched Scheme 3. Scope of α-Keto Acidsa
Reaction conditions: graphite plate anode (2 cm × 2 cm), graphite plate cathode (2 cm × 2 cm), 1a (1.0 mmol), 2 (3.0 mmol), 0.1 M LiClO4/ CH3CN (15 mL), NH4I (0.15 mmol), HFIP (2 mmol), 70 °C, undivided cell, 6.0 h.
a
chains went through this decarboxylation process smoothly to afford the desired products 3ab−ae in moderate yields. Aromatic α-keto acids were also compatible in this transformation, giving the corresponding product 3af and 3ag in 65% and 54% yield, respectively. Our protocol proved to be superior to the conventional Minisci acylation reaction. As shown in Scheme 4, when the reaction of 1b with 2a was repeated following the known chemical procedure,5b a mixture of 2-acetyl product 3ba and 3acetyl product 3ba′ was afforded in 36% and 31% yields, respectively, whereas 3ba was exclusively formed in 62% yield under the electrocatalytic conditions. To understand the possible reaction mechanism, cyclic voltammograms were measured first. As shown in curve b of Figure 1, no obvious oxidation peak was observed for PhCOCOOH, 2f, in the region of 0.0−2.0 V vs Ag/AgNO3, 5518
DOI: 10.1021/acs.orglett.7b02589 Org. Lett. 2017, 19, 5517−5520
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Organic Letters
acylation reaction (Scheme s3e). Protonation of the quinoxaline is required since the reaction of 1a with 2-oxo-2phenylacetate failed to give the desired 3af (Scheme s3f); instead, in the reaction of 1a with 2-oxo-2-phenylacetic acid, 2f, 6% and 20% yields of the product 3af were afforded when I2 was added in one batch or slowly (Scheme s3g). On the basis of CV analyses and control experiments described above as well as related references,12 a plausible mechanism for the electrochemical acylation of heterocycles is outlined in Scheme 5. The interaction of α-keto carboxylic acid
Scheme 4. Selectivity Difference of Minisci Acylation under Different Conditions
Scheme 5. Proposed Mechanism for the Electrochemical Decarboxylative Acylation of N-Heteroarenes
Figure 1. Cyclic voltammograms of NH4I and related compounds in 0.1 M LiClO4/CH3CN using glass carbon working electrode, Pt wire, and Ag/AgNO3 (0.1 M in CH3CN) as counter and reference electrode at 100 mV/s scan rate: (a) background, (b) PhCOCOOH (5.0 mmol/ L), (c) PhCOCOONa (5.0 mmol/L), (d) NH4I (2 mmol/L), (e) NH4I (2 mmol/L) and PhCOCOOH (5.0 mmol/L), (f) NH4I (2 mmol/L) and PhCOCOONa (5.0 mmol/L).
2 and N-heteroarenes 1 affords corresponding α-keto carboxylate anion and protonated N-heteroarenes. In addition, the anodic oxidation of iodide ion generates I2. Followed by a homogeneous reaction of in situ generated I2 with αketocarboxylate anion, acyl hypoiodite 4 was generated, along with the regeneration of iodide ion. Owing to the instability of acyl hypoiodite 4, it undergoes homolytic dissociation to give iodine radical and aroyloxy radical 5. Iodine radical abstracts a hydrogen radical from environment to form HI. Decarboxylation of aroyloxy radical 5 gives acyl radical 6, which adds to protonated N-heteroarenes to afford adduct 7. After further oxidation and deprotonation, the Minisci acylated products 3 are finally afforded. Simultaneously, the cathodic reduction of proton gives hydrogen. Notably, in the course of electrolysis, the iodide ion is regenerated; therefore, only a catalytic amount of iodide is required. In summary, we have disclosed the first electrochemically decarboxylative Minisci acylation of electron-deficient Nheteroarenes. This protocol employs simple and cheap NH4I as the redox catalyst, avoiding utilization of transition metals and excess amounts of external oxidant, thereby providing an environmentally benign method to Minisci acylation reactions. In the course of electrolysis, acyl hypoiodite is proposed to generate and control the concentration of acyl radical, which ensures the selective monoacylation. The electrochemical protocol could be applied to acylate a wide range of Nheteroarenes, such as quinoxaline, pyrazines, pyridazine, and pyridine. We anticipate that this electrochemical protocol will be particularly useful in the rapid and straightforward diversification of relevant pharmacophores. Further application of this electrochemical protocol for the Minisci reaction is underway in our group.
whereas the corresponding carboxylate anion gave an oxidation wave at 1.06 V vs Ag/AgNO3 (curve c). CV of NH4I (curve d) exhibits two couples of reversible redox waves, with the oxidation peaks at 0.36 V (Ox1) and 0.68 V (Ox2) vs Ag/ AgNO3 (0.1 M in CH3CN) corresponding to the oxidation of iodide to form I2 and I3− to I2, respectively (Scheme s2, eqs 1 and 3).15 The electrochemical behavior of iodide ion did not change in the presence of 2f (curve e), indicating that the in situ generated iodine is not able to oxidize 2f. However, when 2f anion was added, an obvious catalytic current was observed; the peak currents of Ox1 and Ox2 increase dramatically from 6.0 to 11.9 μA and 5.9 to 11.8 μA, respectively, while the reduction peak current intensity of C1 and C2 did not decrease (Figure 1, curve e vs curve f).8d Since halogenation of carboxylates is reported to generates acyl hypohalites,13 it is reasonable to propose that the oxidative catalytic current in curve f is due to a homogeneous chemical reaction of the in situ electrogenerated I2 and I3− with 2f anion to regenerate iodide, along with the formation of acyl hypoiodite (scheme s2, eqs 4 and 5). On the other hand, as the acyl hypoiodite is not stable, its homolytic dissociation forms aroyloxy radical and iodine radical, which gives reduction peaks upon scanning back in CV experiments (scheme s2, eq 6). Control experiments further demonstrate that electrogenerated I2 is more likely the active species to initiate the decarboxylative radical coupling of carboxylate anion (Scheme s3a-c). The electrochemical acylation reaction is also believed to proceed via a radical process since anodic oxidation of 1a and pyruvic acid under the standard conditions in the presence of radical scavengers, such as TEMPO or BHT gives no desired 3aa (Scheme s3d). Competitive experiments of 1b and 1e disclose that electron-withdrawing substitution benefits the 5519
DOI: 10.1021/acs.orglett.7b02589 Org. Lett. 2017, 19, 5517−5520
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Am. Chem. Soc. 2016, 138, 8400−8403. (f) Xiong, P.; Xu, H.-H.; Xu, H.-C. J. Am. Chem. Soc. 2017, 139, 2956−2959. (g) Yang, Q.-L.; Li, Y.Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. J. Am. Chem. Soc. 2017, 139, 3293−3298. (h) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77−81. (i) Fu, N.-K.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Science 2017, 357, 575−579. (8) (a) Chen, J.; Yan, W.-Q.; Lam, C. M.; Zeng, C.-C.; Hu, L.-M.; Little, R. D. Org. Lett. 2015, 17, 986−989. (b) Xu, K.; Zhang, Z.-L.; Qian, P.; Zha, Z.-G.; Wang, Z.-Y. Chem. Commun. 2015, 51, 11108− 11111. (c) Jiang, Y.-Y.; Liang, S.; Zeng, C.-C.; Hu, L.-M.; Sun, B.-G. Green Chem. 2016, 18, 6311−6319. (d) Kang, L.-S.; Luo, M.-H.; Lam, C. M.; Hu, L. M.; Little, R. D.; Zeng, C.-C. Green Chem. 2016, 18, 3767−3774. (e) Liang, S.; Zeng, C.-C.; Luo, X.-G.; Ren, F.-Z.; Tian, H.-Y.; Sun, B.-G.; Little, R. D. Green Chem. 2016, 18, 2222−2230. (f) Liang, S.; Zeng, C.-C.; Tian, H.-Y.; Sun, B.-G.; Luo, X.-G.; Ren, F.Z. J. Org. Chem. 2016, 81, 11565−11573. (9) Jiang, Y.-Y.; Wang, Q.-Q.; Liang, S.; Hu, L.-M.; Little, R. D.; Zeng, C.-C. J. Org. Chem. 2016, 81, 4713−4719. (10) (a) Meesin, J.; Katrun, P.; Pareseecharoen, C.; Pohmakotr, M.; Reutrakul, V.; Soorukram, D.; Kuhakarn, C. J. Org. Chem. 2016, 81, 2744−2752. (b) Buathongjan, C.; Beukeaw, D.; Yotphan, S. Eur. J. Org. Chem. 2015, 2015, 1575−1582. (c) Kadari, L.; Palakodety, R. K.; Yallapragada, L. P. Org. Lett. 2017, 19, 2580−2583. (11) The formation of acyl hypohalites is also reported; see: (a) Candish, L.; Freitag, M.; Gensch, T.; Glorius, F. Chem. Sci. 2017, 8, 3618−3622. (b) Perry, G. J. P.; Quibell, J. M.; Panigrahi, A.; Larrosa, I. J. Am. Chem. Soc. 2017, 139, 11527−11536. (12) Electrochemical Minisci-type alkylation was reported; see: O’Brien, A. G.; Maruyama, A.; Inokuma, Y.; Fujita, M.; Baran, P. S.; Blackmond, D. G. Angew. Chem., Int. Ed. 2014, 53, 11868−11871. (13) (a) Kirste, A.; Elsler, B.; Schnakenburg, G.; Waldvogel, S. R. J. Am. Chem. Soc. 2012, 134, 3571−3576. (b) Riehl, B.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Synthesis 2016, 49, 252−259. (14) Houminer, Y.; Southwick, E. W.; Williams, D. L. J. Org. Chem. 1989, 54, 640−643. (15) (a) Allen, G. D.; Buzzeo, M. C.; Villagrán, C.; Hardacre, C.; Compton, R. G. J. Electroanal. Chem. 2005, 575, 311−320. (b) Damljanovic, I.; Stevanovic, D.; Vukicevic, M.; Vukicevic, R. D. Carbohydr. Res. 2011, 346, 2683−2687. (c) Bentley, C. L.; Bond, A. M.; Hollenkamp, A. F.; Mahon, P. J.; Zhang, J.-J. J. Phys. Chem. C 2015, 119, 22392−22403.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02589. Experimental details, conditional optimization, control experiments, characterization data, and NMR spectra and HRMS of all new compounds (PDF) X-ray data for 3ba (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Cheng-Chu Zeng: 0000-0002-5659-291X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by grants from the National Key Technology R&D Program (2017YFB0307502, 2011BAD23B01) and the National Natural Science Foundation of China (No. 21272021, 21472011). Z.C.C. is thankful for financial support from the Open Project Program of Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University (BTBU).
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REFERENCES
(1) For reviews on Minisci reactions, see: (a) Duncton, M. A. J. MedChemComm 2011, 2, 1135−1161. (b) Tauber, J.; Imbri, D.; Opatz, T. Molecules 2014, 19, 16190−16222. (2) For selected examples on Minisci C−H alkylations, see: (a) McCallum, T.; Barriault, L. Chem. Sci. 2016, 7, 4754−4758. (b) Wang, Y.-X.; Li, G.; Yang, G.; He, G.; Chen, G. Chem. Sci. 2016, 7, 2679−2683. (c) Li, G.-X.; Morales-Rivera, C. A.; Wang, Y.-X.; Gao, F.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2016, 7, 6407−6412. (d) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem. Sci. 2017, 8, 3512−3522. (e) Matsui, J. K.; Molander, G. A. Org. Lett. 2017, 19, 950−953. (f) Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. ACS Catal. 2017, 7, 4057−4061. (3) For selected examples on Minisci C−H acylations, see: (a) Ali, W.; Behera, A.; Guin, S.; Patel, B. K. J. Org. Chem. 2015, 80, 5625− 5632. (b) Siddaraju, Y.; Prabhu, K. R. Tetrahedron 2016, 72, 959−967. (c) Laha, J. K.; Patel, K. V.; Dubey, G.; Jethava, K. P. Org. Biomol. Chem. 2017, 15, 2199−2210. (4) (a) Désaubry, L.; Bourguignon, J. J. Tetrahedron Lett. 1995, 36, 7875−7876. (b) Phillips, O. A.; Murthy, K. S. K.; Fiakpui, C. Y.; Knaus, E. E. Can. J. Chem. 1999, 77, 216−222. (5) (a) Sato, N.; Matsuura, T. J. Chem. Soc., Perkin Trans. 1 1996, 1, 2345−2350. (b) Fontana, F.; Minisci, F.; Barboss, M. C. N.; Vismara, E. J. Org. Chem. 1991, 56, 2866−2869. (6) (a) Minisci, F.; Recupero, F.; Cecchetto, A.; Punta, C.; Gambarotti, C.; Fontana, F.; Pedulli, G. F. J. Heterocycl. Chem. 2003, 40, 325−328. (b) Minisci, F.; Recupero, F.; Cecchetto, A.; Gambarotti, C.; Punta, C.; Paganelli, R.; Pedulli, G. F.; Fontana, F. Org. Process Res. Dev. 2004, 8, 163−168. (7) For some reviews on organic electrochemistry, see: (a) Yoshida, J. I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265−2299. (b) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492. (c) Ogibin, Y. N.; Elinson, M.; Nikishin, N. Russ. Chem. Rev. 2009, 78, 89−140. For recent examples, see: (d) Frankowski, K. J.; Liu, R.-Z.; Milligan, G. L.; Moeller, K. D.; Aubé, J. Angew. Chem., Int. Ed. 2015, 54, 10555−10558. (e) Hayashi, R.; Shimizu, A.; Yoshida, J. J. 5520
DOI: 10.1021/acs.orglett.7b02589 Org. Lett. 2017, 19, 5517−5520
