2-Hydroxyindoline-3-triethylammonium Bromide: A Reagent for

Letter pubs.acs.org/OrgLett

2‑Hydroxyindoline-3-triethylammonium Bromide: A Reagent for Formal C3-Electrophilic Reactions of Indoles Takumi Abe,*,† Takuro Suzuki,‡ Masahiro Anada,‡ Shigeki Matsunaga,‡ and Koji Yamada*,† †

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 0610293, Japan Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 0600812, Japan

‡

S Supporting Information *

ABSTRACT: A novel indole-2,3-epoxide equivalent, 2hydroxyindoline-3-triethylammonium bromide, was found to be a convenient reagent for formal C3-electrophilic reactions of indoles with various nucleophiles. By taking advantage of the nucleophilic character of the oxygen of the 2-hydroxyindoline, the interrupted retro-Claisen and interrupted Feist− Bénary reactions with 1,3-dicarbonyl compounds were efficiently achieved.

I

Scheme 1. Reactions Using Indole-2,3-epoxides

ndoles generally act as nucleophiles at the C3 position, and many reports exist on their functionalization at this position using electrophiles.1 In contrast, C3-nucleophilic substitution has been limited because the transformation requires an umpolung of the C3 position of indoles.2 Such an umpolung relies on the oxidation of indoles to generate C3-electrophilic reagents, such as N-hydroxyindoles,3 3-halogenoindolines,4 and indolenium ions.5 In contrast, Nakatsuka6 and Vincent7 reported direct C3 umpolung of indoles using AlCl3 or FeCl3 that does not require preoxidation of indoles. However, these methods were only applicable to arenes6,7a or dienals7b as nucleophiles. Therefore, an alternative C3-electrophilic reagent is highly desirable to achieve the introduction of various nucleophiles at the C3 position of indoles. In 1993, Foote and Zhang reported an oxidative rearrangement of unstable indole-2,3-epoxides generated in situ using dimethyldioxirane (Scheme 1a).8 The epoxides could potentially be used as C3-electrophilic reagents due to the electrophilic nature of the C2 and C3 positions. However, the reaction using the unstable epoxides generated in situ must be conducted at low temperature, and therefore, their use as C3 electrophilic reagents has not been possible so far. We recognized the potential importance of an indole-2,3epoxide that is bench stable and weighable in air and envisioned its function as a C3 electrophile to react with various nucleophiles (Scheme 1b). As a part of our research devoted to the development of novel methodologies for the synthesis of alkaloids,9 herein we report that 2-hydroxyindoline-3-triethylammonium bromide is a useful reagent for a formal C3 electrophilic reaction of indoles. We first investigated the stability and reactivity of 3bromoindoline 2 and N-protected indole-2,3-epoxide 4 (Scheme 2). The reaction between N-Ts indole 1 and NBS in acetone resulted in the isolation of 3-bromoindoline 2, but 2 spontaneously dehydrated into 3 at rt within 1 day. When 2 was © 2017 American Chemical Society

treated with Et3N, unexpected compound 5 was isolated in 84% yield instead of the expected epoxide 4. The structure of 5 was confirmed unambiguously by X-ray analysis.10 It was stable and storable over a year at ambient temperature and was handled under air without any care for moisture. We envisioned that the reactivity profile of 5 would be equivalent to the indole-2,3-epoxide, and so 5 can be a stable synthetic equivalent of unstable 4 and 2. The compound 5 was successfully synthesized in one-pot, gram quantity without column chromatography purification (75% yield). We tested an amination of 5 to investigate its reactivity (Table 1). As expected, the reaction between 5 and aniline in Received: June 25, 2017 Published: August 1, 2017 4275

DOI: 10.1021/acs.orglett.7b01940 Org. Lett. 2017, 19, 4275−4278

Letter

Organic Letters Table 2. Dehydration of 6aa

Scheme 2. Unexpected Preparation of 5

a

entry

conditions

yieldb (%)

1 2 3 4 5

TsOH, toluene, 100 °C, 2 h TsOH, AcOEt, reflux, 2 h BF3·Et2O (2 equiv), MeCN, 50 °C, 2 h BF3·Et2O (2 equiv), AcOEt, 50 °C, 5 h BF3·Et2O (5 equiv), AcOEt, 50 °C, 3 h

0 30 13 30 87

6a (0.2 mmol), solvent (2 mL). bIsolated yields.

Scheme 3. Screening of Various Aminesa,b

Table 1. Amination of 5a

a

entry

PhNH2 (equiv)

conditions

1 2 3 4

1.1 1.1 1.1 2

DMF, rt, 24 h DMF, 50 °C, 2 h AcOEt, reflux, 1 h DMF, 50 °C, 2 h

yieldb (%) 49 75 93 59

(6a) (6a) (6a) (6b)

6a (0.2 mmol), solvent (4 mL). bIsolated yields.

a

5 (0.5 mmol), AcOEt (5 mL). bIsolated yields. c5 (5 mmol), AcOEt (50 mL).

the presence of Et3N as base led to formation of 3-aminated product 6a (Table 1, entry 1). The temperature had a crucial effect on the yield of 6a. While the reaction performed at rt gave a 49% yield, an improved yield was obtained when the reaction temperature was increased to 50 °C (entry 2). A number of solvents were screened, and AcOEt afforded the highest yield (entry 3). Furthermore, the 2,3-diaminated compound 6b was formed in 59% yield when excess of aniline (2 equiv) was used in DMF (entry 4). We next investigated the dehydration of 6a to obtain indole 7a (Table 2). The reaction did not proceed when TsOH was used in toluene or AcOEt (entries 1 and 2). BF3·Et2O in MeCN gave 7a in 13% yield (entry 3). Further screening revealed that a suitable solvent and excess amount of BF3·Et2O were required for affording 7a. The highest yield (87%) was obtained when 5 equiv of BF3·Et2O was used in AcOEt, although 2 equiv of BF3·Et2O gave a 30% yield (entries 4 and 5). With the optimized conditions in hand, the scope of the nucleophile was investigated (Scheme 3). These reaction conditions could be applied to various anilines bearing either electron-donating or electron-withdrawing group on the benzene ring and gave products 7a−e in 85−44% yield. In aminations with alkylamines, allyl amine resulted in low yield of 7f due to the product’s instability. However, other primary and secondary amines gave products 7g−i in 83−53% yield.11 More

importantly, this amination is also amenable to scale-up. We conducted the amination of 5 with N-methylaniline on a 5 mmol (5, 2.35 g) scale and found the amination was as efficient as the 0.5 mmol scale reaction (7b). Encouraged by the above success, we further explored the utility of 5 in the C3-electrophilic reaction with other nucleophiles under the standard conditions (Scheme 4). Dehydration conditions were modified depending on the nucleophiles (method A: BF3·Et2O; method B: TsOH). Of all nucleophiles screened, phenols (9a−d with method A),12 indoles (9e and 9f with method B),13 and tetrahydrocarbolin (9g with method B) reacted smoothly with 5 to give products in 94−39% yield. Furthermore, 2,3-difunctionalization is also possible in addition to simple C3 electrophilic monofunctionalization. Diamines also underwent facile electrophilic reaction to give 9h and 9i in one step without dehydration process (method C).14 As straightforward synthetic methods to access 2,3diaminoindoles are limited,15 the present protocol using 5 as a stable key intermediate is synthetically useful. To further explore the reactivity of 5, 1,3-dicarbonyl compounds were used (Scheme 5).16 Meldrum’s acid smoothly reacted with 5 to afford lactone 10 (Scheme 5a). Subsequently, 10 was dehydrated in good yield using TsOH to give indole acetic acid 11. Surprisingly, unlike Meldrum’s acid, the reaction 4276

DOI: 10.1021/acs.orglett.7b01940 Org. Lett. 2017, 19, 4275−4278

Letter

Organic Letters Scheme 4. Screening of Various Nucleophilesa,b

Retro-Claisen reactions are distinguished by the C−C bond cleavage of a β-carbonyl compound to generate an ester and enolatecarbanion, serving as a versatile precursor.17 Thus, 5 could interrupt the retro-Claisen reaction by capturing both an ester and an enolatecarbanion.18 Retro-Claisen reaction with indoles have not been reported to date, so this is the first example of an interrupted retro-Claisen reaction of indoles. When a cyclic 1,3-dicarbonyl compound was used, the unexpected dihydrofuran 16 was obtained in 47% yield (Scheme 5c). The subsequent aromatization of 16 afforded 3substituted indole 17. The interrupted Feist−Bénary (IFB) reaction, developed by Calter, is the condensation of αhaloketones and 1,3-dicarbonyl compounds to provide dihydrofurans.19 There is no precedent of using indoles as substrates in the IFB reaction. The results presented here strongly suggest that 5 is a versatile substrate with a wide-scope application potential in organic synthesis. To further demonstrate the usefulness of 5, the synthesis of the antimalarial alkaloid cryptolepine20 was carried out (Scheme 6). Formylation of 7b, sequential imine formation Scheme 6. Total Synthesis of Cryptolepine

a

5 (0.5 mmol), AcOEt (5 mL). bIsolated yields. c5 (5 mmol), AcOEt (50 mL).

Scheme 5. Reaction of 1,3-Dicarbonyl Compounds

of 18, and cyclization completed the synthesis of cryptolepine (19), which was obtained in 59% overall yield from 5. 1H and 13 C NMR spectra of 19 were identical to those reported for the natural product. In summary, we have developed a novel and bench stable equivalent of indole-2,3-epoxide, 2-hydroxyindoline-3-triethylammonium bromide (HITAB), which was found to be a convenient reagent for formal C3-electrophilic reactions of indoles with nucleophiles. By taking advantage of the nucleophilic character of the oxygen of the 2-hydroxyindoline, interrupted retro-Claisen and interrupted Feist−Bénary reactions with 1,3-dicarbonyl compounds were achieved. Moreover, the synthetic potential of the ammonium bromide was demonstrated by the short synthesis of cryptolepine. We believe that the bench-stable ammonium bromide should find an interesting application to produce diverse indoles.

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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.7b01940. Synthesis procedures and spectral and characterization data, including 1H and 13C NMR spectra (PDF) X-ray data for 5 (CIF)

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with pentane-2,4-dione afforded unexpected compound 14 in 76% yield (Scheme 5b). The subsequent aromatization of 14 provided 15. A plausible mechanism for the formation of 14 is depicted in Scheme 5b. Nucleophilic attack of pentane-2,4dione to 5 gives 2-hydroxyindoline 12. A subsequent nucleophilic attack on the carbonyl moiety by oxygen and a retro-Claisen reaction of 13 are believed to occur, leading to 14.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Takumi Abe: 0000-0003-1729-1097 4277

DOI: 10.1021/acs.orglett.7b01940 Org. Lett. 2017, 19, 4275−4278

Letter

Organic Letters Notes

Am. Chem. Soc. 2016, 138, 1057. (d) Sato, S.; Hirayama, A.; Ueda, H.; Tokuyama, H. Asian J. Org. Chem. 2017, 6, 54. (14) For recent reports of the synthesis of 2,3-diaminoindoles, see: (a) Sheng, G.; Huang, K.; Chi, Z.; Ding, H.; Xing, Y.; Lu, P.; Wang, Y. Org. Lett. 2014, 16, 5096. (b) Mannes, P. Z.; Onyango, E. O.; Gribble, G. W. J. Org. Chem. 2016, 81, 12478. (15) Anumandla, D.; Acharya, A.; Jeffrey, C. S. Org. Lett. 2016, 18, 476. (16) (a) Pelkey, E. T.; Barden, T. C.; Gribble, G. W. Tetrahedron Lett. 1999, 40, 7615. (b) Pelkey, E. T.; Gribble, G. W. Synthesis 1999, 1999, 1117. (17) (a) Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 7793. (b) Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133, 14785. (c) Grenning, A. J.; Van Allen, C. K.; Maji, T.; Lang, S. B.; Tunge, J. A. J. Org. Chem. 2013, 78, 7281. (d) Maji, T.; Ramakumar, K.; Tunge, J. A. Chem. Commun. 2014, 50, 14045. (e) Roudier, M.; Constantieux, T.; Quintard, A.; Rodriguez, J. Org. Lett. 2014, 16, 2802. (f) Xu, C.; Zhang, L.; Luo, S. J. Org. Chem. 2014, 79, 11517. (18) For the first example of capturing both esters and enolatecarbanions in a retro-Claisen reaction, see: Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2016, 138, 3978. (19) (a) Calter, M. A.; Zhu, C. Org. Lett. 2002, 4, 205. (b) Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209. (c) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127, 14566. (d) Calter, M. A.; Li, Na. Org. Lett. 2011, 13, 3686. (e) Calter, M. A.; Korotkov, A. Org. Lett. 2011, 13, 6328. (f) Albrecht, Ł.; Ransborg, L. K.; Gschwend, B.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 17886. (g) Sinha, D.; Biswas, A.; Singh, V. K. Org. Lett. 2015, 17, 3302. (20) (a) Gellért, E.; Hamet, R.; Schlitter, E. Helv. Chim. Acta 1951, 34, 642. (b) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Curr. Org. Chem. 2011, 15, 1036. (c) Parvatkar, P. T.; Parameswaran, P. S. Curr. Org. Synth. 2016, 13, 58.

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.) Grant-in-Aid for Young Scientists (B). REFERENCES

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DOI: 10.1021/acs.orglett.7b01940 Org. Lett. 2017, 19, 4275−4278