Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Double “Open and Shut” Transformation of γ‑Carbolines Triggered by Ammonium Salts: One-Pot Synthesis of Multiheterocyclic Compounds Takumi Abe,* Haruka Shimizu, Shiori Takada, Takahiro Tanaka, Mai Yoshikawa, and Koji Yamada* Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 0610293, Japan S Supporting Information *
ABSTRACT: A novel cascade reaction of indole-2,3-epoxide equivalents with γ-carbolines by utilizing a double “open and shut” transformation to access multiheterocyclic compounds containing both isotryptamines and pyrimido[1,6-a]indoles has been developed. This strategy utilizes the in situ formation of a bulky quaternary ammonium salt via ammonium exchange, which undergoes Hofmann elimination/vinylogous Mannich/retro-Mannich/cyclization cascade sequences.
γ-Carbolines and pyrimido[1,6-a]indoles represent two important heterocycles due to their rich biological activities (Figure 1).1 For instance, gevotroline 1 is an atypical
Mannich-type reaction,8 Pd-catalyzed cyclocarbonylation,9 Ullmann N-arylation/oxidative C−H amination,10 diamination/oxidative cross-coupling/bicyclization,11 Pd-catalyzed asymmetric dearomative cyclization,12 and the reaction of 2bromomethylazoles and isocyanides.13 Among these strategies, the retro-Mannich/cyclization of γ-carbolines is thought to be the most concise methodology for the synthesis of pyrimido[1,6-a]indoles.14 This reaction proceeds by initial halogenation of the γ-carboline, which then undergoes retro-Mannich fragmentation followed by recyclization to afford the pyrimido[1,6-a]indole (Scheme 1a).7a On the other hand, tetrahydro-γ-carbolines are cyclic analogues of gramines, and the reaction of their ammonium salts with nucleophilic agents must therefore be accompanied by Hofmann elimination with cleavage of the C−N bond, and a vinylogous Mannich reaction of indolenine at the benzylic position, to afford isotryptamines, which are difficult to obtain by other methods (Scheme 1b).15 Despite these advances (Scheme 1a,b), the electrophiles are only limited to electrophilic halogens or halogenated alkyl agents. Thus, finding alternative electrophiles for the reaction with γ-carbolines is appealing. Furthermore, to the best of our knowledge, the synthesis of multiheterocycles containing both isotryptamines or pyrimido[1,6-a]indoles is still challenging. Previously, we reported the bench-stable equivalent of indole-2,3-epoxide, 2-hydroxyindoline-3-triethylammonium bromide (HITAB, 1), which was found to be a convenient reagent for the formal C3-electrophilic reactions of indoles with nucleophiles.16 During the studies on 1, we envisaged a cascade reaction between in situ generated indolenines derived from 1 and γ-carbolines 2 via a Hofmann elimination followed by
Figure 1. Biologically active γ-carbolines and pyrimido[1,6-a]indoles.
antipsychotic agent (Figure 1a). Dimebon2 is an antihistamine drug that has been used in Russia since 1983, which has been proven to be a potent neuroprotective agent for treating Alzheimer’s disease. Moreover, tubastatin A, which acts as a histone deacetylase inhibitor (HDAC6), is expected to find application as an anti-Alzheimer drug in clinical settings.3 Among various representative pyrimido[1,6-a]indole alkaloids, such as (±)-hinckdentine,4 variolins,5 and (−)-vernavosine, variolin B is a potent CDK inhibitor, whereas a (−)-vernavosine ethyl ether derivative is known to exert a relaxation effect on the phenylephedrine-induced contraction in isolated rat aortic rings with a half maximal effective concentration (EC50) of 2.48 μM.6 Therefore, a number of approaches for the synthesis of pyrimido[1,6-a]indoles have been developed. These involve retro-Mannich/cyclization of γ-carbolines,7 © XXXX American Chemical Society
Received: January 30, 2018
A
DOI: 10.1021/acs.orglett.8b00332 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 1. Cascade Reactions of γ-Carbolines
vinylogous Mannich/retro-Mannich/cyclization triggered by another γ-carbolines 2 to afford the multiheterocyclic compounds 3 (Scheme 1c). Based on our ongoing research into the synthesis of heterocycles17 and the aforementioned reactivity of γ-carbolines (Scheme 1a,b), we herein report a novel cascade sequence starting from indole 2,3-epoxide equivalents as electrophiles and γ-carbolines as nucleophiles that furnished difficult-to-access multiheterocyclic compounds. Initially, we investigated the reaction of 2-hydroxyindoline-3ammonium bromide 1a (1.0 equiv) and γ-carboline 2a (2.5 equiv) using Et3N (2.0 equiv) as a base in hexane at 80 °C over the course of 16 h (Table 1, run 1). To our delight, 70% yield of the target compound 3aa was obtained. Encouraged by this initial result, other solvents were also then investigated. Replacement of hexane with benzene and toluene increased the yields of 3aa to 93% and 81%, respectively (runs 2 and 3). Other solvents, such as CHCl3, MeCN, and DMF, turned out to be less efficient in this cascade reaction (runs 4−6), and no reaction occurred in the case of DMSO, THF, and 1,4-dioxane (runs 7−9). Notably, the highest yield was achieved when AcOEt was used (run 10). Further optimization showed that a high reaction temperature was necessary to obtain a high yield (runs 11 and 12). Before further optimization, the impact of the equivalence of the reagents on the conversion was evaluated. The results show that 1.0 equiv of 1a, 2.5 equiv of 2a, and 2.0 equiv of Et3N produced good conversion (runs 13−19). Because it was anticipated that the base might play an important role in this transformation, other bases were investigated to improve the reaction efficiency. Other organic bases such as iPr2NEt, TMEDA, pyridine, DMAP, DBU, and
run
X (equiv)
Y (equiv)
1 2 3 4 5 6 7 8 9
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Et3N (2) Et3N (2) Et3N (2) Et3N (2) Et3N (2) Et3N (2) Et3N (2) Et3N (2) Et3N (2)
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1.0 1.0 1.0 1.0 1.0 1.0 2.5 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
2.5 2.5 2.5 2.5 2.5 2.5 1.0 2.0 1.5 1.1 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Et3N (2) Et3N (2) Et3N (2) Et3N (1.5) Et3N (0.5)
base (Z, equiv)
Et3N (2) Et3N (2) Et3N (2) Et3N (2) iPr2NEt (2) TMEDA (2) pyridine (2) DMAP (2) DBU (2) DABCO (2) K2CO3 (2) Cs2CO3 (2) NaOH (2)
solvent hexane benzene toluene CHCl3 MeCN DMF DMSO THF 1,4dioxane AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt AcOEt
temp (°C)
% yieldb
80 80 80 80 80 80 80 80 80
70 93 81 35 68 7 0 0 0
80 50 rt 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80
95 56 13 73 31 10 27 82 56 41 62 53 70 20 14 76 0 0 0
1a (X ×x 0.5 mmol), 2a (Y × 0.5 mmol), and base (Z × 0.5 mmol) in solvent (20 mL). bIsolated yields.
a
DABCO were less effective than Et3N (runs 20−25). When inorganic bases such as K2CO3, Cs2CO3, and NaOH were used, ammonium bromide 1a was decomposed under the reaction conditions (runs 26−28).18 Having defined the optimal reaction conditions, the substrate scope of this cascade reaction was next evaluated (Scheme 2). The presence of electron-donating or -withdrawing groups at the C-5 position of the indole ring on 1 led to the corresponding products in excellent yields (3ba: 91% yield, and 3ca: 94% yield). The substituents on the nitrogen at the piperidine ring critically influenced the efficacy of this transformation. Replacement of the methyl group with a benzyl substituent at the nitrogen of the piperidine ring compromised the reaction efficiency, and a lower yield of 3 was obtained (3ab: 32% yield, 3bb: 66% yield and 3cb: 0% yield). In the case of 3ab and 3cb, 1a or 1c could be recovered in 54% and 73% yield, respectively. This result suggests that the ammonium exchange reaction would be slow due to the steric hindrance of the benzyl substituent. Electron-donating groups (3ac: 76% yield and 3ad: 93% yield) and electron-withdrawing groups (3ae: 86% yield) B
DOI: 10.1021/acs.orglett.8b00332 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scopea,b
group at the C-6 position had an obvious negative effect on the yield (3af: 43% yield). No product could be obtained when 7-chloro-γ-carboline was used (3ag). Further combinations with substituted 1 and γ-carbolines 2 were also tolerated (3bc: 91% yield, 3be: 92% yield, and 3ce: 44% yield). This cascade reaction could also be performed on a gram scale by treating 1a and 2a with Et3N in AcOEt. As a result, 3aa was obtained in 90% yield (1.18 g), which was comparable to the yield of 3aa on a smaller scale (95% yield, 315 mg). Given that the straightforward synthesis of multiheterocyclic compounds containing both pyrimido[1,6-a]indoles and isotryptamines is unprecedented,19 the present protocol using 1 as an electrophile is synthetically useful. Based on the above results and the literature precedents,7,14,20−24 a plausible reaction pathway for this cascade sequence is depicted in Scheme 3. At first, the ammonium Scheme 3. Plausible Reaction Pathway
exchange of 1a by 2a via the indole 2,3-epoxide 4 affords the bulky ammonium salt 5 with the release of Et3N. Upon Hofmann elimination assisted by Et3N, 5 is converted to the indolenium salt 6,20 which may increase the electrophilicity of the benzylic position of isotryptamine.21 The benzylic position of 6 is then attacked by another 2a molecule to afford the C-3alkylated intermediate 7.22 Subsequently, the retro-Mannich reaction occurred to afford 8.23 Finaly, the intramolecular Mannich-type cyclization of 8 assisted by Et3N gives 3aa with the release of HBr.24 Notably, the significance of this protocol not only is due to its great potential for accessing a variety of multiheterocyclic compounds containing indolines, isotryptamines, and pyrimido[1,6-a]indoles but also represents the first example in which double and different “open and shut” transformations of γ-carbolines are realized in a one-pot manner.
a 1 (0.5 mmol), 2 (1.25 mmol), and Et3N (1.0 mmol) in AcOEt (20 mL) bIsolated yields.
at the C-5 position of the γ-carbolines both resulted in excellent yields. However, γ-carboline with an electron-withdrawing C
DOI: 10.1021/acs.orglett.8b00332 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(11) Zhang, J.; Wu, X.; Gao, Q.; Geng, X.; Zhao, P.; Wu, Y.-D.; Wu, A. Org. Lett. 2017, 19, 408. (12) Douki, K.; Ono, H.; Taniguchi, T.; Shimokawa, J.; Kitamura, M.; Fukuyama, T. J. Am. Chem. Soc. 2016, 138, 14578. (13) Mendiola, J.; Minguez, J. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2000, 2, 3253. (14) For a review, see: Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2011, 46, 1169. (15) (a) Sapi, J.; Grébille, Y.; Laronze, J.-Y.; Lévy, J. Synthesis 1992, 1992, 383. (b) Diker, K.; de Maindreville, M.; Lévy, J. Tetrahedron Lett. 1995, 36, 3511. (c) Yurovskaya, M. A.; Rodionov, I. L. Chem. Heterocycl. Compd. 1981, 17, 794. (d) Lizarzaburu, M. E.; Shuttleworth, S. J. Tetrahedron Lett. 2004, 45, 4781. (16) Abe, T.; Suzuki, T.; Anada, M.; Matsunaga, S.; Yamada, K. Org. Lett. 2017, 19, 4275. (17) (a) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011, 13, 3356. (b) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2012, 2012, 5018. (c) Abe, T.; Nakamura, S.; Yanada, R.; Choshi, T.; Hibino, S.; Ishikura, M. Org. Lett. 2013, 15, 3622. (d) Itoh, T.; Abe, T.; Choshi, T.; Nishiyama, T.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2016, 2016, 2290. (e) Abe, T.; Yamada, K. Org. Lett. 2016, 18, 6504. (f) Abe, T.; Yamada, K. J. Nat. Prod. 2017, 80, 241. (g) Abe, T.; Kida, K.; Yamada, K. Chem. Commun. 2017, 53, 4362. (h) Abe, T.; Haruyama, T.; Yamada, K. Synthesis 2017, 49, 4141. (i) Abe, T.; Takahashi, Y.; Matsubara, Y.; Yamada, K. Org. Chem. Front. 2017, 4, 2124. (j) Abe, T.; Terasaki, M. Helv. Chim. Acta 2018, 101, No. e1700284. (18) The quaternary ammonium salt eliminates the least substituted olefin and a tertiary amine: (a) Spettel, M.; Pollice, R.; Schnürch, M. Org. Lett. 2017, 19, 4287. (b) Brewster, J. H.; Eliel, E. L. Org. React. 1953, 7, 99. (19) Multicomponent Reactions; Zhu, J., Bienaymé, H.; Wiley-VCH: Weinheim, 2005. (20) (a) Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc. 1948, 70, 1703. (b) Baciocchi, E.; Schiroli, A. J. Chem. Soc. B 1968, 401. (21) (a) Tamura, Y.; Morita, I.; Tsubouchi, H.; Ikeda, H.; Ikeda, M. Heterocycles 1982, 17, 163. (b) Tamura, Y.; Tsubouchi, H.; Morita, I.; Ikeda, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1983, 1, 1937. (22) (a) Nagai, Y.; Irie, A.; Uno, H.; Minami, S. Chem. Pharm. Bull. 1979, 27, 1922. (b) de la Herrán, G.; Segura, A.; Csákÿ, A. G. Org. Lett. 2007, 9, 961. (c) Nishimura, T.; Yamada, K.; Takebe, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2008, 10, 2601. (d) Li, S.-G.; Zard, S. Z. Org. Lett. 2013, 15, 5898. (23) (a) Ebnöther, E.; Niklaus, P.; Süess, R. Helv. Chim. Acta 1969, 52, 629. (b) Cattanach, C. J.; Cohen, A.; Heath-Brown, B. J. Chem. Soc. C 1971, 359. (24) (a) Laronze, J.-Y.; Bascop, S.-I.; Sapi, J.; Lévy, J. Heterocycles 1994, 38, 725. (b) Kuehne, M. E.; Bohnert, J. C.; Bornmann, W. G.; Kirkemo, C. L.; Kuehne, S. E.; Seaton, P. J.; Zebovitz, T. C. J. Org. Chem. 1985, 50, 919. (25) Ross, S. P.; Hoye, T. R. Org. Lett. 2018, 20, 100.
In summary, we developed a novel cascade reaction of an indole-2,3-epoxide equivalent with γ-carbolines. The method utilizes double “open and shut” transformations to access multiheterocyclic compounds containing both isotryptamines and pyrimido[1,6-a]indoles from simple starting materials in good to excellent yields. The rapid construction of complex molecules from simple precursors has driven the development of numerous synthetic strategies.19,25 Further applications of this cascade reaction to other multiheterocyclic compounds are currently underway.
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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.8b00332. Synthesis procedures and spectral and characterization data, including 1H and 13C NMR (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Takumi Abe: 0000-0003-1729-1097 Koji Yamada: 0000-0002-5084-7571 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant No. 16K18849 (T.A.) through a Grant-in-Aid for Young Scientists (B).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00332 Org. Lett. XXXX, XXX, XXX−XXX
