Letter pubs.acs.org/OrgLett
Direct and Selective 3‑Amidation of Indoles Using Electrophilic N‑[(Benzenesulfonyl)oxy]amides Gerardo X. Ortiz, Jr., Brett N. Hemric, and Qiu Wang* Department of Chemistry, Duke University, Durham, North Carolina 27708, United States S Supporting Information *
ABSTRACT: Selective C−H amidation of 1H-indoles at the C3 position is reported as a direct entry to biologically important 3-aminoindoles. This transformation is achieved using novel N-[(benzenesulfonyl)oxy]amides as electrophilic nitrogen agents in the presence of ZnCl2. Interestingly, analogous reactions in the absence of ZnCl2 resulted in the formation of indole aminal products.
Scheme 1. Representative Approaches to 3-Aminoindoles
3-Substituted indoles compose an important skeleton in natural products, functional materials, agrochemicals, and medicines.1 Direct functionalization of indoles at the C3 position is a valuable approach to effectively preparing this class of compounds. For example, many elegant methods have been developed for selective alkylation,2 arylation,3 acylation,4 and sulfonation4d,5 of indoles at the C3 position. However, the analogous direct C−H amination of indoles at the C3 position has not been developed, despite the interesting biological profiles of 3-aminoindoles (Figure 1). For instance, 3-
Figure 1. Examples of biologically valuable 3-aminoindoles.
aminoindole I was reported to promote glucose-dependent insulin secretion for a potential treatment of type 2 diabetes.6 Several 3-aminoindoles (e.g., II) are known to have antiproliferative properties and can function as potent inhibitors of tubulin polymerization7 and as inhibitors of the COX-II enzyme.8 Furthermore, cryptolepine (III) and its derivatives have been reported for their antiplasmodial and antitrypanosomal activities.9 For the synthesis of 3-aminoindoles, several approaches from nonindolic starting materials have been reported (Scheme 1).10 For example, Gevorgyan reported a copper-catalyzed, threecomponent reaction based upon the isomerization of 3aminoindoline intermediates.11 Beller reported a cascade cyclization starting from arylhydrazines and propargylic amides.12 When starting from o-alkynylanilines and an electrophilic nitrogen source, an annulation approach to 3aminoindoles was achieved using either copper or rhodium as a catalyst.13 However, the preparation of 3-aminoindoles directly from indole skeletons often relies on the conventional © XXXX American Chemical Society
reduction of 3-nitrosoindoles or by nucleophilic substitution of 3-bromoindoles, which suffer from a narrow scope and low efficacy.14,15 Thus, a direct and efficient method for the C3amination of indoles is greatly valuable. As part of our research in exploring new electrophilic amination reactions, we report for the first time the selective 3-amidation of indoles using N[(benzenesulfonyl)oxy]amides as a novel electrophilic amidation reagent. Our studies demonstrate that the transformation is also effective for the amidation of pyrroles. Received: February 3, 2017
A
DOI: 10.1021/acs.orglett.7b00358 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Indole Scope for 3-Amidationa
For the synthesis of 3-aminoindoles from readily accessible indoles, a selective C−H amidation of indoles at the C3position is needed, particularly to overcome the possible side reactions at the N1 position. Toward this, our studies began with examining the effects that different metal cations of the deprotonated indoles and different solvents may have on the reaction, as both variables are known to affect the chemoselectivity of alkylations and acylations between the N1- and C3-position of indoles.2b,4a−d,14 First, we identified N[(arylsulfonyl)oxy]-substituted amides (e.g., 2) as most effective among different electrophilic nitrogen sources in the initial reaction screenings with indole 1a.15 With 2a as the preferred electrophilic amide reagent, we next examined different salt forms of 1a for a transmetalation step prior to the electrophilic amidation step (Table 1, entries 1 and 2). Table 1. Optimization for 3-Amidation of Indole 1aa
a Isolated yields shown. Standard conditions: indole 1 (1.0 equiv, 0.4 mmol, 0.2 M), t-BuONa (3.0 equiv), rt, 0.5 h; then ZnCl2 (2.0 equiv), rt, 1 h; then 2a (1.5 equiv), 60 °C. bYield for a 2 mmol scale reaction. c Yield for a 1 mmol scale reaction. dND = not detected. 2Ethoxycarbonylindole recovered in 78% yield. eStep 3 run at 80 °C. f Step 3 run at 40 °C.
comparison to the reaction of simple indole 1a, the reaction of 2-methylindole with 2a was more efficient, forming 7 in 91% yield. However, the reaction of 2-(ethoxycarbonyl)indole failed to form desired product 8, possibly due to the decreased nucleophilicity of the starting indole. Halogenated indoles, including 4-F-, 5-Cl-, and 6-Br-substituted indoles, all readily underwent amidation to afford 9−11 in moderate yields. 7Methylindole was also a competent substrate, forming 3amidoindole 12 in 61% yield. Next, we examined the effect of different substituents at the 5-position for the formation of amides 13−17. Compared to simple indole and 5-vinylindole, electron-rich 5-methoxyindole led to a higher efficiency of amidation with 14 formed in 87% yield. Conversely, 5substituted indoles bearing an electron-withdrawing group such as an ethyl ester or a nitro group hindered the amidation efficiency, giving 15 and 16 in 55% and 45% yields, respectively. Although the presence of a free alcohol on the indole substrate decreased the efficiency, the amidation reaction still occurred to give the desired product 17 in 33% yield. Next, we examined the electrophilic amide scope in the amidation reactions with indole 1b (Scheme 3). The reaction with benzyl-substituted amide precursor readily formed Nbenzylamide 18 in 80% yield. However, the reaction with Ncyclohexyl-substituted amide precursor failed to provide the desired secondary N-alkyl structures 19, possibly due to increased steric hindrance. Beyond benzamide precursors, a pivalamide-derived precursor was also effective in the reaction,
a
Reaction conditions: 1a (1.0 equiv, 0.2 mmol, 0.2 M), t-BuONa (3.0 equiv), rt, 0.5 h; then additive, rt, 1 h; then 2a (1.5 equiv), 60 °C, 24 h. b Yields determined by 1H NMR spectroscopy with CH2Br2 as a quantitative internal standard. c0.90 equiv of 2a remained after 24 h. d 0.77 equiv of 2a remained after 24 h.
Although Grignard reagents were reported to favor the C3acylation of indole, MgCl2 as an additive failed to provide the desired amidation product 3, and only a mixture of byproducts was observed, including N-acylated product 4,16 N-sulfonamide 5, and aminal 6 (entry 1). Encouragingly, the use of ZnCl2 in the transmetalation step successfully increased the formation of 3-amidated indole 3 and suppressed the formation of byproducts (entries 2 and 3), which is consistent with the observed selectivity for alkylation and acylation when the zinc salts of indoles are used.2a,b,4b While 1.0 equiv of ZnCl2 seems best for the reaction in THF (entry 3), using 2.0 equiv of ZnCl2 in DMF gave a superior yield of the desired amide 3 (entry 7); therefore, this was chosen as the standard condition for the rest of our studies. Note that in the absence of a transmetalation step aminal 6 was formed as the major product (entry 5). With standard amidation conditions established, we examined the generality and selectivity of this amidation reaction on various indole substrates (Scheme 2). We first examined the effect of substitution at different positions of the indole ring. In B
DOI: 10.1021/acs.orglett.7b00358 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Scope of Electrophilic Amides and Carbamatesa
Table 2. Pyrrole Reactivity toward Amidationa
a
Isolated yields shown. Standard conditions: 1b (1.0 equiv, 0.4 mmol, 0.2 M), t-BuONa (3.0 equiv), rt; ZnCl2 (2.0 equiv), rt; then 2 (1.5 equiv), 60 °C. bStep 3 run at 50 °C. cND = not detected. a
Isolated yields shown. Standard conditions: pyrrole (1.0 equiv, 0.2 M), t-BuONa (3.0 equiv), rt, 0.5 h; ZnCl2 (2.0 equiv), rt, 1 h; then 2a (1.5 equiv), 60 °C. bStep 3 run at rt. cPyrrole (1.0 equiv, 0.2 M), tBuONa (6.0 equiv), rt, 0.5 h; then ZnCl2 (4.0 equiv), rt, 1 h; then 2a (3.0 equiv), rt. ND = not detected.
producing 20 in 60% yield. The reaction with an acetamide precursor afforded the desired product 21 in 32% yield. The lower yield of 21 is likely due to the deprotonation of the acidic α-protons of the amide and the subsequent formation of unreactive byproducts.17 Meanwhile, electrophilic carbamate derivatives under standard amidation conditions were effective to access C3-carbamate indoles, as evidenced in the formation of 22 and 23 in 86% and 83% yields, respectively. We were also interested in extending this method to the amidation of pyrroles as they represent another important scaffold ubiquitous in natural products and pharmaceuticals.18 Particularly challengingly is the complete resonance delocalization of deprotonated pyrrole salts throughout the ring; thus, the electrophilic reaction may occur at any unsubstituted position.2b,14b,19 Therefore, the amidation of pyrroles was first examined with 2,5-dimethylpyrrole under standard amidation conditions (Table 2). Encouragingly, C3-amidation was achieved, providing 24 in 68% yield (entry 1). Similarly, the C2-amidation of a trisubstituted pyrrole furnished 25 in 84% yield at room temperature. We next performed the amidation of 2,4-disubstited pyrrole to examine the regioselectivity between the C2- and C3-position. Under standard conditions, a mixture of three amidation products was obtained in 83% total yield, including 3-amidated pyrrole 26 (29%), 2-amidated pyrrole 27 (15%), and diamidated pyrrole 28 (29%). When the amidation step was run at room temperature instead of 60 °C, no improvement was observed for the selectivity among three amination products despite an increase in total yield to 93%. However, the diamidation could be achieved selectively by doubling the amount of base, ZnCl2, and electrophilic amide 2a, providing pyrrole 28 as the sole product in 78% yield. At the same time, we briefly explored the selective formation of indole aminal products with N-[(benzenesulfonyl)oxy]amides, as observed in the initial screenings for the formation of 6 (Table 1, entry 5), which to the best of our knowledge has not been previously reported (Scheme 4).20 Encouragingly, when further reaction conditions were explored, the use of DMSO as the solvent instead of THF and the absence of a transmetalation step was found to improve the formation of the
Scheme 4. Selective Formation of Indole Aminal Productsa
a
Isolated yields shown. Reaction conditions: indole 1 (1.0 equiv, 0.4 mmol, 0.2 M), t-BuONa (3.0 equiv), rt, 0.5 h; then 2 (1.5 equiv), rt, 1 h.
aminal product 6 to 78% yield.21 With this modified protocol, different indoles all formed their respective aminal products 29−33. The reactions of different electrophilic amide precursors were also effective, evidenced by the aminal formation of 34 and 35. The decreased yields of 29 and 30 suggested the influence of steric hindrance in this transformation. In summary, we have developed a straightforward procedure for the direct C-amidation of indoles and pyrroles using novel N-[(benzenesulfonyl)oxy]amides as an electrophilic nitrogen source in the presence of ZnCl2. The analogous reactions in the absence of ZnCl2 resulted in the formation of aminal products. Remarkably, no expensive transition-metal catalysts or ligands C
DOI: 10.1021/acs.orglett.7b00358 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(12) (a) Pews-Davtyan, A.; Tillack, A.; Schmole, A. C.; Ortinau, S.; Frech, M. J.; Rolfs, A.; Beller, M. Org. Biomol. Chem. 2010, 8, 1149. (b) Pews-Davtyan, A.; Beller, M. Org. Biomol. Chem. 2011, 9, 6331. (13) (a) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2012, 77, 617. (b) Hu, Z. Y.; Tong, X. F.; Liu, G. X. Org. Lett. 2016, 18, 2058. (14) (a) Cardillo, B.; Casnati, G.; Pochini, A.; Ricca, A. Tetrahedron 1967, 23, 3771. (b) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1973, 499. (c) Yeung, K. S.; Farkas, M. E.; Qiu, Z. L.; Yang, Z. Tetrahedron Lett. 2002, 43, 5793. (d) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.; Eguchi, S. J. Chem. Soc., Perkin Trans. 1 1990, 111. (15) For additional details, see the Supporting Information. (16) (a) Hynes, J.; Doubleday, W. W.; Dyckman, A. J.; Godfrey, J. D.; Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368. (b) Somei, M.; Natsume, M. Tetrahedron Lett. 1974, 15, 461. (c) Weiberth, F. J.; Hanna, R. G.; Lee, G. E.; Polverine, Y.; Klein, J. T. Org. Process Res. Dev. 2011, 15, 704. (17) (a) Hoffman, R. V.; Nayyar, N. K.; Chen, W. T. J. Org. Chem. 1992, 57, 5700. (b) Hoffman, R. V.; Nayyar, N. K.; Chen, W. T. J. Am. Chem. Soc. 1993, 115, 5031. (18) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC Adv. 2015, 5, 15233. (19) (a) Morgan, K. J.; Morrey, D. P. Tetrahedron 1966, 22, 57. (b) Cooksey, A. R.; Morgan, K. J.; Morrey, D. P. Tetrahedron 1970, 26, 5101. (c) Zhang, Y. H.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 2837. (20) Some refereces for the preparation of aminals: (a) Kraxner, J.; Gmeiner, P. Synthesis 2000, 2000, 1081. (b) Love, B. E. J. Org. Chem. 2007, 72, 630. (c) Sakai, N.; Shimamura, K.; Ikeda, R.; Konakahara, T. J. Org. Chem. 2010, 75, 3923. (d) Schiedler, D. A.; Lu, Y.; Beaudry, C. M. Org. Lett. 2014, 16, 1160. (21) Detailed condition optimization is available in the Supporting Information.
are needed in these transformations. Such new reactions offer a direct entry to biologically important 3-aminoindoles and a new class of indole aminal compounds.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00358. Experimental procedures and 1H and 13NMR spectra for all new compounds (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Qiu Wang: 0000-0002-6803-9556 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We acknowledge financial support provided by Duke University and the National Institute of General Medical Sciences of the National Institutes of Health (GM118786). We thank Dr. George Dubay (Duke University) for high-resolution mass spectrometry analysis.
■
REFERENCES
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893. (2) (a) Zhu, X. W.; Ganesan, A. J. Org. Chem. 2002, 67, 2705. (b) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. M.; Srinivas, C. Tetrahedron Lett. 2002, 43, 5185. (c) Prajapati, D.; Gohain, M.; Gogoi, B. J. Tetrahedron Lett. 2006, 47, 3535. (d) Sharma, R.; Chouhan, M.; Sood, D.; Nair, V. A. Appl. Organomet. Chem. 2011, 25, 305. (3) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2007, 129, 241. (4) (a) Bergman, J.; Venemalm, L. Tetrahedron Lett. 1987, 28, 3741. (b) Bergman, J.; Venemalm, L. Tetrahedron 1990, 46, 6061. (c) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 1485. (d) Zhang, Z. W.; Xue, H.; Li, H. L.; Kang, H. P.; Feng, J.; Lin, A. J.; Liu, S. X. Org. Lett. 2016, 18, 3918. (e) Wu, W. L.; Su, W. P. J. Am. Chem. Soc. 2011, 133, 11924. (f) Jiang, T. S.; Wang, G. W. Org. Lett. 2013, 15, 788. (5) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Swamy, T. Tetrahedron Lett. 2003, 44, 6055. (6) Bahekar, R. H.; Jain, M. R.; Goel, A.; Patel, D. N.; Prajapati, V. M.; Gupta, A. A.; Jadav, P. A.; Patel, P. R. Bioorg. Med. Chem. 2007, 15, 3248. (7) Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Di Cristina, A.; Zonta, N.; Balzarini, J.; Brancale, A.; Hsieh, H.-P.; Hamel, E. J. Med. Chem. 2008, 51, 1464. (8) Kumar, A.; Sharma, S.; Archana; Bajaj, K.; Sharma, S.; Panwar, H.; Singh, T.; Srivastava, V. K. Bioorg. Med. Chem. 2003, 11, 5293. (9) Arzel, E.; Rocca, P.; Grellier, P.; Labaeïd, M.; Frappier, F.; Guéritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Quéguiner, G. J. Med. Chem. 2001, 44, 949. (10) (a) Couture, A.; Deniau, E.; Gimbert, Y.; Grandclaudon, P. Tetrahedron 1993, 49, 1431. (b) Seong, C. M.; Park, C. M.; Choi, J.; Park, N. S. Tetrahedron Lett. 2009, 50, 1029. (11) Chernyak, D.; Chernyak, N.; Gevorgyan, V. Adv. Synth. Catal. 2010, 352, 961. D
DOI: 10.1021/acs.orglett.7b00358 Org. Lett. XXXX, XXX, XXX−XXX
