Electrochemical Reductive Smiles Rearrangement for C–N Bond

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2019, 21, 10−13

Electrochemical Reductive Smiles Rearrangement for C−N Bond Formation Xihao Chang, Qinglin Zhang, and Chang Guo* Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China

Downloaded via TULANE UNIV on January 9, 2019 at 20:09:07 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A conceptually new and synthetically valuable radical Smiles rearrangement reaction is reported under undivided electrolytic conditions. This protocol employs an entirely new strategy for the electrochemical radical Smiles rearrangement. Remarkably, an amidyl radical generated from the cleavage of the N−O bond under reductive electrolytic conditions plays a crucial role in this transformation. Various hydroxylamine derivatives bearing different substituents are suitable in this electrochemical transformation, furnishing the corresponding amides in up to 86% yield.

T

Scheme 1. Radical Smiles Rearrangement

he direct carbon−nitrogen (C−N) bond formation has emerged as one of the most efficient and frequently employed methodologies, allowing access to a wide array of heterocycles and bioactive compounds.1 While great achievements have been accomplished, the development of C−N bond formation from common precursors under mild conditions remains a formidable challenge. In particular, early reports on a C−N bond-forming reaction via Smiles rearrangement under base conditions introduce new methods and strategies for the direct transformation of unactivated C−O bonds, and reshape the field of retrosynthetic analysis.2 The classical Smiles rearrangement is an intramolecular nucleophilic aromatic substitution reaction featuring an anionic N-nucleophile (Scheme 1A).3,4 Moreover, radical versions of the rearrangement reaction have been demonstrated without the requirement for a strong electron-withdrawing group adjacent to the migrating aryl ring.5 In comparison, there are still challenges for the Smiles rearrangement based on N-centered radicals, probably due to the lack of versatile radical initiation methods to achieve high reaction efficiency.6 We recognized that the successful realization of these ideals would enable a new C−N bond-forming reaction under mild conditions that would allow efficient access of constructing aromatic C−N bonds. Perhaps most important, to our knowledge this N-centered radical Smiles rearrangement has not previously been accomplished in a generic format. Recently, electrochemistry has emerged as a powerful technique through which single electron-transfer (SET) reactions can be performed for numerous challenging reactions.7−9 Oxidative N-center radicals, electrochemically generated from N−H precursors,10 show their applications in the C−N bond-forming reactions.11 Typically, the cyclic © 2018 American Chemical Society

voltammogram record of 1a shows an irreversible oxidation wave at 2.25 V versus SCE, thus indicating that 1a would be oxidized at a potential much higher than that of the rearrangement product 3a (Eox 3a = 1.50 V versus SCE). Therefore, even if the radical Smiles rearrangement is successful, overoxidation is inevitable because of the lower oxidative potential of 3a (Scheme 1B). Received: October 5, 2018 Published: December 13, 2018 10

DOI: 10.1021/acs.orglett.8b03178 Org. Lett. 2019, 21, 10−13

Letter

Organic Letters

evaluated their ability to form amide 3a under electrolytic conditions. To our delight, we observed the formation of amide 3a in 77% yield when 2a was employed (entry 2). Further exploration showed that the 2,4-di-NO2-phenyl 2b was superior to 2a and could be converted into 3a in 83% yield (see the Supporting Information for details of further optimization of the reaction conditions). The starting materials were fully recovered when 2c−2e were employed (entries 4−6). The reaction could be conducted under an argon atmosphere without any difference (entry 7). Importantly, no conversion of 3a was observed without the electric current (entry 8), which suggests the rationality of the proposed electrolysis-induced SET mechanism. Under the optimized conditions, the substituents on the migrating aryl ring (Ar1) were first investigated (Scheme 2).

We set out to explore the application of an amidyl radical and the development of novel, base-free electrosynthesis-mediated radical Smiles rearrangement (Scheme 1B). However, there are several challenges associated with the development of this radical rearrangement, such as (1) finding an entirely new strategy to generate amidyl radicals upon electrolytic conditions; (2) avoiding the overoxidation; and (3) identification of electrochemical reaction conditions which afford high yields. Drawing inspiration from the generation of the amidyl radical, which results in hydroamination12 or cross-dehydrogenative coupling processes,13 we speculated that appropriately functionalized hydroxylamine derivatives could serve as general, benchstable N-centered radical precursors. Herein, we report the successful implementation of an amidyl radical and the development of novel, base-free electrosynthesis-mediated radical Smiles rearrangement. To evaluate the feasibility of such a radical rearrangement protocol, we subjected 1a to oxidative electrolysis with Pt as electrodes in an undivided cell under 10 mA constant current with NH4Cl as the electrolyte (Table 1, entry 1). As we have

Scheme 2. Substrate Scopea,b

Table 1. Optimization of the Smiles Rearrangement Reactiona

entry

substrate

yieldb [%]

1 2 3 4 5 6 7c 8d

1a 2a 2b 2c 2d 2e 2b 2b

0 77 83 0 0 0 80 0

a Unless otherwise specified, all of the reactions were performed using 2 (0.2 mmol) with NH4Cl (0.25 M) and DMSO (4 mL) in an undivided at 50 °C. Pt plate cathodes (1 cm × 1 cm), constant current 10.0 mA, 3 h (5.6 F/mol). bIsolated yield. c2.5 mmol scale reaction.

Generally, the desired amide derivative was isolated in high to excellent yields (3a, 3f−3w, 68−84%) irrespective of the position and electric nature of substituents on the migrating aryl moiety. Notably, the scalability of this electroreductive rearrangement was evaluated by performing on a 2.5 mmol scale reaction. Under atmospheric conditions, the gram scale reaction of 2a afforded the corresponding product 3a in high reaction efficiency with 78% yield. Furthermore, the observed electronic effect of substituents in this radical aryl migration is contrary to that observed in the classical anionic Smiles rearrangement, in which strong electron withdrawing groups are required.3b Typically, electron-donating groups in the para position with a variety of functional groups performed well in this radical reaction (3a, 3f−3h). Electron-withdrawing groups, such as halogens, were well-tolerated under the optimized conditions (3i−3k). Moreover, the influence of substituents in the meta and ortho positions was also investigated (3m−3s). Similar behavior of methyl and bromo substituents was

a

Unless otherwise specified, all of the reactions were performed using 2 (0.2 mmol) with NH4Cl (0.25 M) and DMSO (4 mL) in an undivided cell at 50 °C. Pt plate cathodes (1 cm × 1 cm), constant current 10.0 mA, 3 h (5.6 F/mol). bIsolated yield. cUnder argon atmosphere. dWithout the electric current.

predicted (Scheme 1B), the reaction failed because of the competitive electron-transfer processes between 1a and 3a under electrolytic conditions. Therefore, alternative reductive electrosynthesis for the radical smiles rearrangement was considered. For a study of the radical Smiles rearrangement reaction, a series of hydroxylamine derivatives 2a−2e with different functional groups were first investigated by performing cyclic voltammetry studies on model precursors. All of these substrates we tested displayed reduction profiles, while 2a and 2b fell well inside the SET reduction range of 3a (2a, Ered 2a = red −1.48 V versus SCE; 2b, Ered 2b = −1.52 V versus SCE; 3a, E3a = −2.21 V versus SCE). Keeping this information in mind, we 11

DOI: 10.1021/acs.orglett.8b03178 Org. Lett. 2019, 21, 10−13

Letter

Organic Letters observed. Notably, the migration of aryl rings (Ar1) with two or three substituents also occurred in high yields (3v and 3w). Next, the influence of substituents on the aryl ring (Ar2) was investigated (Scheme 2). Electron-donating and electronwithdrawing groups which were located on the para to the amide enabled the transformation to proceed in good to excellent yield (3x−3aa). It was shown that functional groups, such as methoxy, methyl, chloro, and bromo, attached on the aryl ring (Ar2) in 2 were well-tolerated. A bromo group which was located on the para to the phenol group resulted in a good yield (3ab, 77% yield). Furthermore, N-alkyl substituents could be varied to generate corresponding amides in moderate yields (3ac−3ae). We next sought to examine the applicability of this strategy for the late-stage modification. The application of this rearrangement was further extended to the introduction of the nitrogen atom at position C-3 of estrone in high yield (3af, 80% yield), which has been identified as a versatile precursor of biologically active compounds.14 Notably, axially chiral anilines have emerged as versatile building blocks for catalysts, functional materials, and natural products.15 Development of more general strategies for construction of axially chiral aniline derivatives under mild conditions is highly desirable. Under our optimized electrochemical conditions, 6a and 6b were obtained in moderate yields without racemization (Scheme 3).

O-aryl amides serving as a sensitizer of the radical Smiles rearrangement (Scheme 4). Since N-centered radicals are a versatile class of synthetic intermediates,17 we envisaged that an electrolysis-mediated approach for amidyl radical generation would be compatible with hydroamination−cyclization (Scheme 4B).12 Under our optimized electrolytic conditions, the hydroamination ring-opening product 10 was generated. These results indicate that the Smiles rearrangement might go through a radical mechanism which would start with SET reduction of the 2,4-di-NO2-phenyl unit. Then, we conducted a series of control experiments under the optimized reaction conditions to provide insight into the reaction mechanism (Scheme 5). The profile of the yield of 3a Scheme 5. Electric Current Turned On and Off Experiments

Scheme 3. Subsequent Transformation was monitored with the electric current turned on and off at intervals. We found that the Smiles rearrangement occurred smoothly under electric current, and the further conversion stopped in the absence of current source. Therefore, the amidyl radical intermediate generated by electrolysis plays a crucial role in the Smiles rearrangement. On the basis of the above experimental results and previous reports,12,13 a plausible reaction mechanism of the radical Smiles rearrangement is presented in Scheme 6. A single-electron-

Intrigued by the positive reduction potential of the unique role of the 2,4-dinitro-substituted O-aryl amide group (Table 1), we wondered whether a complementary activation mode could be exploited by the generation of amidyl radical by electrolysis (Scheme 4A).16 Cyclic voltammetry experiments were conducted to study the reductive potential of substrates. No obvious difference in the reduction peaks of 2b, 7, and 8 was observed red (2b, Ered 2b = −1.52 V versus SCE; 7, E7 = −1.52 V versus SCE; 8, Ered = −1.52 V versus SCE), indicating the aromatic unit of the 8

Scheme 6. Proposed Reaction Mechanism

Scheme 4. Mechanistic Studies

transfer reduction of 2b by cathodic reduction generates the radical intermediate I. The following N−O bond fragmentation leads to amidyl radical II and subsequently undergoes radical Smiles rearrangement to form an O-centered radical intermediate III. Then cathodic reduction and protonation of III generates the reductive rearrangement product 3a. In summary, we envisioned an entirely new reductive activation mode to generate the amidyl radical for the electrolytic Smiles rearrangement. External chemical reductant and base are avoided in this protocol. Under our optimized undivided electrolytic conditions, a series of amides can be obtained in good to excellent yields under atmospheric conditions. We anticipate that this radical strategy will have 12

DOI: 10.1021/acs.orglett.8b03178 Org. Lett. 2019, 21, 10−13

Letter

Organic Letters

C.; Tian, H.-Y.; Hu, L.-M.; Little, R. D. J. Org. Chem. 2014, 79, 9613. (c) Qian, P.; Su, J.-H.; Wang, Y.; Bi, M.; Zha, Z.; Wang, Z. J. Org. Chem. 2017, 82, 6434. (d) Wang, Y.; Qian, P.; Su, J.-H.; Li, Y.; Bi, M.; Zha, Z.; Wang, Z. Green Chem. 2017, 19, 4769. (e) Hayashi, R.; Shimizu, A.; Yoshida, J.-I. J. Am. Chem. Soc. 2016, 138, 8400. (f) Johnson, B. M.; Francke, R.; Little, R. D.; Berben, L. A. Chem. Sci. 2017, 8, 6493. (g) Wang, Q.-Q.; Xu, K.; Jiang, Y.-Y.; Liu, Y.-G.; Sun, B.-G.; Zeng, C.-C. Org. Lett. 2017, 19, 5517. (9) (a) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77. (b) Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. J. Am. Chem. Soc. 2017, 139, 3293. (c) Wang, P.; Tang, S.; Huang, P.; Lei, A. Angew. Chem., Int. Ed. 2017, 56, 3009. (d) Schulz, L.; Enders, M.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2017, 56, 4877. (e) Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Science 2017, 357, 575. (f) Liu, K.; Tang, S.; Huang, P.; Lei, A. Nat. Commun. 2017, 8, 775. (g) Wu, Z.-J.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 4734. (h) Lennox, A. J. J.; Nutting, J. E.; Stahl, S. S. Chem. Sci. 2018, 9, 356. (i) Ye, K. Y.; Pombar, G.; Fu, N.; Sauer, G. S.; Keresztes, I.; Lin, S. J. Am. Chem. Soc. 2018, 140, 2438. (j) Xiong, P.; Xu, H.-H.; Song, J.; Xu, H.-C. J. Am. Chem. Soc. 2018, 140, 2460. (k) Li, J.; Huang, W.; Chen, J.; He, L.; Cheng, X.; Li, G. Angew. Chem., Int. Ed. 2018, 57, 5695. (10) (a) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2008, 130, 13542. (b) Xu, H.-C.; Campbell, J. M.; Moeller, K. D. J. Org. Chem. 2014, 79, 379. (c) Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2016, 55, 9437. (d) Gieshoff, T.; Kwhl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R. J. Am. Chem. Soc. 2017, 139, 12317. (e) Xiong, P.; Xu, H.-H.; Xu, H.-C. J. Am. Chem. Soc. 2017, 139, 2956. (11) (a) Hou, Z.-W.; Mao, Z.-Y.; Zhao, H.-B.; Melcamu, Y. Y.; Lu, X.; Song, J.; Xu, H.-C. Angew. Chem., Int. Ed. 2016, 55, 9168. (b) Zhu, L.; Xiong, P.; Mao, Z.-Y.; Wang, Y.-H.; Yan, X.; Lu, X.; Xu, H.-C. Angew. Chem., Int. Ed. 2016, 55, 2226. (c) Zhao, H.-B.; Liu, Z.-J.; Song, J.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 12732. (d) Hou, Z.-W.; Mao, Z.Y.; Song, J.; Xu, H.-C. ACS Catal. 2017, 7, 5810. (e) Xiong, P.; Xu, H.H.; Xu, H.-C. J. Am. Chem. Soc. 2017, 139, 2956. (f) Zhao, H.-B.; Hou, Z.-W.; Liu, Z.-J.; Zhou, Z.-F.; Song, J.; Xu, H.-C. Angew. Chem., Int. Ed. 2017, 56, 587. (g) Tang, S.; Wang, S.; Liu, Y.; Cong, H.; Lei, A. Angew. Chem., Int. Ed. 2018, 57, 4737. (h) Hou, Z.-W.; Mao, Z.-Y.; Melcamu, Y. Y.; Lu, X.; Xu, H.-C. Angew. Chem., Int. Ed. 2018, 57, 1636. (12) (a) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J. Am. Chem. Soc. 1998, 120, 7738. (b) Davies, J.; Svejstrup, T. D.; Reina, D. F.; Sheikh, N. S.; Leonori, D. J. Am. Chem. Soc. 2016, 138, 8092. (c) Reina, D. F.; Duncey, E. M.; Morcillo, S. P.; Svejstrup, T. D.; Popescu, M. V.; Douglas, J.; Sheikh, N. S.; Leonori, D. Eur. J. Org. Chem. 2017, 2017, 2108. (13) (a) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed. 2012, 51, 3231. (b) Pandey, G.; Laha, R. Angew. Chem., Int. Ed. 2015, 54, 14875. (14) Singh, S. M.; Gauthier, S.; Labrie, F. Curr. Med. Chem. 2000, 7, 211. (15) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893. (b) Kočovský, P.; Vyskočil, Š .; Smrčina, M. Chem. Rev. 2003, 103, 3213. (c) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384. (d) Ding, K.; Li, X.; Ji, B.; Guo, H.; Kitamura, M. Curr. Org. Synth. 2005, 2, 499. (e) Ding, K.; Guo, H.; Li, X.; Yuan, Y.; Wang, Y. Top. Catal. 2005, 35, 105. (16) (a) Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135, 4640. (b) Walton, J. C. Acc. Chem. Res. 2014, 47, 1406. (c) Hu, X.-Q.; Qi, X.; Chen, J.-R.; Zhao, Q.-Q.; Wei, Q.; Lan, Y.; Xiao, W.-J. Nat. Commun. 2016, 7, 11188. (17) (a) Qin, Q.; Yu, S. Org. Lett. 2014, 16, 3504. (b) Svejstrup, T. D.; Ruffoni, A.; Juliá, F.; Aubert, V. M.; Leonori, D. Angew. Chem., Int. Ed. 2017, 56, 14948. (c) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2018, 57, 744.

extensive applications in the synthesis of complex molecules and provide new enthusiasm for chiral aryl functionalization.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03178. Experimental procedures and spectral data including cyclic voltammograms, 1H and 13C NMR spectra, and HPLC traces (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chang Guo: 0000-0003-4022-9582 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors acknowledge financial support from the National Natural Science Foundation of China (Grant 21702198), and the Anhui Provincial Natural Science Foundation (Grant 1808085MB30).

■

REFERENCES

(1) (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (b) Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564. (2) (a) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346. (c) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43, 8081. (d) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (e) Su, B.; Cao, Z.-C.; Shi, Z.-J. Acc. Chem. Res. 2015, 48, 886. (f) Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48, 1717. (3) (a) Levy, A. A.; Rains, H. C.; Smiles, S. J. Chem. Soc. 1931, 0, 3264. (b) Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452. (c) Janssen-Müller, D.; Singha, S.; Lied, F.; Gottschalk, K.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 6276. (4) (a) Hall, J. E.; Matlock, J. V.; Ward, J. W.; Gray, K. V.; Clayden, J. Angew. Chem., Int. Ed. 2016, 55, 11153. (b) Costil, R.; Dale, H. J. A.; Fey, N.; Whitcombe, G.; Matlock, J. V.; Clayden, J. Angew. Chem., Int. Ed. 2017, 56, 12533. (5) (a) Douglas, J. J.; Albright, H.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2015, 54, 14898. (b) Wang, S.-F.; Cao, X.-P.; Li, Y. Angew. Chem., Int. Ed. 2017, 56, 13809. (c) Li, W.; Xu, W.; Xie, J.; Yu, S.; Zhu, C. Chem. Soc. Rev. 2018, 47, 654. (6) (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Soc. Rev. 2016, 45, 2044. (c) Kärkäs, M. D. ACS Catal. 2017, 7, 4999. (d) Nguyen, L. Q.; Knowles, R. R. ACS Catal. 2016, 6, 2894. (7) (a) Yoshida, J.-I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265. (b) Schäfer, H. J. C. R. Chim. 2011, 14, 745. (c) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492. (d) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230. (e) Jiang, Y.; Xu, K.; Zeng, C. Chem. Rev. 2018, 118, 4485. (f) Waldvogel, S. R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C. J. Chem. Rev. 2018, 118, 6706. (g) Ma, C.; Fang, P.; Mei, T.-S. ACS Catal. 2018, 8, 7179. (h) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2018, 57, 5594. (i) Möhle, S.; Zirbes, M.; Rodrigo, E.; Gieshoff, T.; Wiebe, A.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2018, 57, 6018. (j) Tang, S.; Liu, Y.; Lei, A. Chem. 2018, 4, 27. (8) (a) Chen, J.; Yan, W.-Q.; Lam, C. M.; Zeng, C.-C.; Hu, L.-M.; Little, R. D. Org. Lett. 2015, 17, 986. (b) Gao, W.-J.; Li, W.-C.; Zeng, C.13

DOI: 10.1021/acs.orglett.8b03178 Org. Lett. 2019, 21, 10−13