Cope

Letter Cite This: Org. Lett. 2019, 21, 826−829

pubs.acs.org/OrgLett

Direct C4-Benzylation of Indoles via Tandem Benzyl Claisen/Cope Rearrangements Takumi Abe,*,† Yuta Kosaka,† Miku Asano,† Natsuki Harasawa,† Akane Mishina,† Misato Nagasue,† Yuri Sugimoto,† Kazuaki Katakawa,‡ Shunsuke Sueki,‡ Masahiro Anada,‡ and Koji Yamada*,† †

Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 061-0293, Japan Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi 202-8585, Japan

‡

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S Supporting Information *

ABSTRACT: A novel direct C4 benzylation of indoles utilizing 2-benzyloxyindoles has been developed to access 4benzyl-2-oxindoles. This strategy involves the in situ formation of isotoluene intermediates via benzyl Claisen rearrangements, which undergoes Cope rearrangement and aromatization. The method provides the desired products in moderate to high yields and shows good functional group tolerance.

C

Scheme 1. Variants of Aromatic Claisen Rearrangement

laisen rearrangement has proven to be a fundamentally important reaction in organic synthesis.1 Aromatic Claisen rearrangements are more difficult than those of aliphatic Claisen rearrangements because the [3.3]-sigmatropic rearrangement in the former leads to loss of aromaticity (Scheme 1a).2 The benzyl variant of the aromatic Claisen rearrangement is extremely difficult because of the less stabilized isotoluene intermediates, particularly if X = H (Scheme 1b).3,4 Isotoluene intermediates favor [1.3]-sigmatropic rearrangement and polymerization.5 Recently, an elegant tandem Claisen rearrangement/Alder− ene reaction of α-substituted benzyl vinyl ethers was reported by McGeary and co-workers, in which the isotoluene intermediate could be captured by another alkene before the aromatization, affording disubstituted cyclopentanes (Scheme 1c).6 An appropriate choice of the substrates and the one-pot protocol made the challenging Claisen rearrangements feasible in solution. In addition, these results would provide evidence for a concerted [3.3]-sigmatropic mechanism of the benzyl Claisen rearrangement, indicating that the isotoluene intermediates may be captured by various heterocycles. However, to the best of our knowledge, functionalization of heterocycles using these intermediates has not been developed despite the significant potential of the isotoluene intermediate in the benzyl Claisen rearrangement. We have been interested in increasing the feasibility of using isotoluene intermediates for functionalization. As part of ongoing studies that are focused on the indole chemistry,7 we discovered that 2-benzyloxyindoles are unexpected precursors for a tandem benzyl Claisen/Cope © 2019 American Chemical Society

rearrangement, allowing for the synthesis of 4-substituted 2oxindoles in high yields with high site selectivity (Scheme 2). Site-selective C−H functionalization of indoles is a powerful methodology for the atom-economical construction of C−C bonds.8 In particular, C4-selective functionalization without using directing or blocking groups placed at the C3 position is still a challenging task because the C3 position is the most Received: December 25, 2018 Published: January 23, 2019 826

DOI: 10.1021/acs.orglett.8b04120 Org. Lett. 2019, 21, 826−829

Letter

Organic Letters Scheme 2. Unexpected Results Obtained in the Attempted Synthesis of Pyranoindoles

Scheme 3. Synthesis of Substrates 3

electron-rich carbon center in the indole ring.9 Therefore, it is necessary to introduce a directing and blocking group at the C3 position of the indole ring before attempting C4 functionalization. Undoubtedly, the development of new methods for the direct and C4-selective functionalization at the indole ring is still in high demand.10 Herein, we describe a simple and robust protocol to access 2-benzyloxyindoles and leverage their unprecedented reactivity for the C4-selective functionalization of indoles without using the directing group through tandem benzyl Claisen variants. This method enriches our toolbox for efficient and facile entry to various 4-benzyl-2oxindoles and sheds light on the isotoluene intermediates. Our investigation began with the synthesis of 2-benzyloxyindoles 3 from N-Ts indoles 1 (Scheme 3). As per the modified Hoffmann’s method,11 bromoalkoxylation of N-Ts indoles 1 followed by the elimination of HBr gave the desired 2-benzyloxindole 3, which in principle represents a missing substrate in the precedents.12−15 At this stage, we envisioned that 3 would be a precursor for the benzyl Claisen/cyclization sequence, affording the pyranoindole shown in Scheme 2. To examine the feasibility of this sequence, we investigated the thermal reaction of 3 (Table 1). Thermal conditions mediated a benzyl Claisen/Cope rearrangement to produce the unexpected compounds 4a with a small amount of 5a, which resulted from a benzyl rearrangement through the benzyl cation intermediate (run 1).16 Thus, the expected pyranoindole could not be observed. Next, to increase the product yield, we investigated the reaction conditions. Microwave irradiation gave greater selectivity (only 4a) and lower yield (42%) (run 3). Changing the solvents was effective in improving the yield of 4a (runs 3−5). Several conditions were tested, and it was found that the solvent-free reaction slightly improved the yield of 4a (runs 6 and 7). Having established the reaction conditions, we then explored the substrate scope of the rearrangement. As shown in Scheme 4, various 2-benzyloxyindoles 3a−l reacted smoothly to afford 4-benzyl-2-oxindoles 4a−l in 51−92% yields. Electron-withdrawing and -donating groups in the substrates did not affect the product yields. These results suggested the absence of a prohibitively high barrier for operation of the [3.3]-sigmatropic rearrangement pathway.6b Furthermore, this rearrangement could be successfully scaled up to the gram level (4a: 70%), thereby indicating the possibility of further application. Notably, the developed protocol is of great synthetic significance because it is an unprecedented route to 4-

Table 1. Optimization of Reaction Conditionsa

run

time (h)

solvent

temp (°C)

4a, % yieldb

5a, % yieldb

1 2 3 4 5 6 7

24 6 4 15 1 24 1

DMF DMF DMF toluene DMSO

100 150 150c 110 150 100 150

29 42 42 72 71 72 74

trace 5 0 0 7 6 7

a

3a (0.25 mmol) in solvent (2.5 mL). microwave irradiation.

b

Isolated yields. cUnder

benzyl-2-oxindoles. In these transformations, the dearomatized isotoluene intermediates 5 may also undergo rearomatization to afford C3-arylated products. However, the C3-arylated products were not be observed. Thus, the Cope rearrangements are prioritized over the rearomatization. The details are not clear and under investigation. Detailed experiments were carried out to probe the mechanism of this rearrangement. First, a chirality transfer study using α-methylbenzyl substrate 3m revealed a double [3.3]-sigmatropic shift process (Scheme 5). When 3m (>99% ee) was subjected to the optimized reaction conditions, 4m 827

DOI: 10.1021/acs.orglett.8b04120 Org. Lett. 2019, 21, 826−829

Letter

Organic Letters Scheme 4. Substrate Scopea,b

results suggest that this reaction proceeds via a concerted [3.3]-sigmatropic rearrangement mechanism and not via a benzyl cation intermediate. To the best of our knowledge, this is the first example of a chiral transfer in the benzyl Claisen rearrangement.3,4 On the basis of the above-mentioned experiments and the literatures,1−4,6 a plausible mechanism for this rearrangement is proposed, as illustrated in Scheme 6. Initially, [3.3]Scheme 6. Plausible Reaction Pathway

sigmatropic shift of 3a should give the isotoluene intermediate 6a, with the equilibrium favoring the reverse reaction in pathway a. Successive [3.3]-sigmatropic shift of 6a affords 4a. In the minor path b, an intermolecular reaction is proposed to proceed via benzyl cation intermediate 7, from which a trace amount of 3-benzylated product 5a is obtained.16 Because the yield of 5a is low, our system preferentially favors intermediate 6a by an intramolecular reaction. In summary, we have demonstrated that 4-benzyl-2oxindoles can be prepared from 2-benzyloxyindoles via a benzyl Claisen/Cope rearrangement. This strategy involves the in situ formation of isotoluene intermediates, which have drawn less attention from the scientific community until date. To the best of our knowledge, this is the first example of the direct C4-fuctionalization of indoles without using the directing groups at the C3 position.10 This work provides a significant expansion to the site-selective functionalization of indoles and the benzyl Claisen rearrangement. Studies aimed at further applications and investigations of the present tandem reaction for synthesis of indole alkaloids are in progress.

a

3 (0.2 mmol) in no solvent (neat). bIsolated yields.

Scheme 5. Control Experiments

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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.8b04120. Synthesis procedures and spectral and characterization data, including 1H and 13C NMR (PDF)

could be isolated in 76% yield with 95% ee. The absolute stereochemistry of 4m has not been determined so far. These 828

DOI: 10.1021/acs.orglett.8b04120 Org. Lett. 2019, 21, 826−829

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Organic Letters

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(9) For selected reports on C4 functionalization of indoles using directing groups at the C3 position, see: (a) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528. (b) Lv, J.; Wang, B.; Yuan, K.; Wang, Y.; Jia, Y. Org. Lett. 2017, 19, 3664. (c) Lanke, V.; Prabhu, K. R. Chem. Commun. 2017, 53, 5117. (d) Borah, A.; Shi, Z. Chem. Commun. 2017, 53, 3945. (e) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56, 3966. (f) Chen, S.; Feng, B.; Zheng, X.; Yin, J.; Yang, S.; You, J. Org. Lett. 2017, 19, 2502. (g) Kona, C. N.; Nishii, Y.; Miura, M. Org. Lett. 2018, 20, 4898. (h) Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2016, 18, 5496. (10) (a) Leitch, J. A.; Bhonoah, Y.; Frost, C. G. ACS Catal. 2017, 7, 5618. (b) Kalepu, J.; Gandeepan, P.; Ackermann, L.; Pilarski, L. T. Chem. Sci. 2018, 9, 4203. (11) Last, K.; Hoffmann, H. M. R. Synthesis 1989, 1989, 901. (12) For examples using 4-OBn indole as the substrate, see: Smart, B. P.; Oslund, R. C.; Walsh, L. A.; Gelb, M. H. J. Med. Chem. 2006, 49, 2858. (13) For examples using 5-OBn indole as the substrate, see: Pasquini, S.; Mugnaini, C.; Brizzi, A.; Ligresti, A.; Di Marzo, V.; Ghiron, C.; Corelli, F. J. Comb. Chem. 2009, 11, 795. (14) For examples using 7-OBn indole as the substrate, see: Lajiness, J. P.; Jiang, W.; Boger, D. L. Org. Lett. 2012, 14, 2078. (15) For studies on Claisen rearrangement of 2-allyloxy- and propargyloxyindoles, see: (a) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162. (b) Cao, T.; Linton, E. C.; Deitch, J.; Berritt, S.; Kozlowski, M. C. J. Org. Chem. 2012, 77, 11034. (c) Gutierrez, O.; Hendrick, C. E.; Kozlowski, M. C. Org. Lett. 2018, 20, 6539. (d) Kawasaki, T.; Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.; Sekiguchi, H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70, 2957. (e) Kawasaki, T.; Shinada, M.; Ohzono, M.; Ogawa, A.; Terashima, R.; Sakamoto, M. J. Org. Chem. 2008, 73, 5959. (f) Takiguchi, S.; Iizuka, T.; Kumakura, Y.; Murasaki, K.; Ban, N.; Higuchi, K.; Kawasaki, T. J. Org. Chem. 2010, 75, 1126. (16) For examples of the benzyl migration, see: (a) Vanucci-Bacqué, C.; Chaabouni, S.; Fabing, I.; Bedos-Belval, F.; Baltas, M. Tetrahedron Lett. 2014, 55, 528. (b) Hou, S.; Li, X.; Xu, J. J. Org. Chem. 2012, 77, 10856. (c) Shiina, I.; Nagasue, H. Tetrahedron Lett. 2002, 43, 5837.

AUTHOR INFORMATION

Corresponding Authors

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

Takumi Abe: 0000-0003-1729-1097 Shunsuke Sueki: 0000-0003-0951-0018 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.) Grant-in-Aid for Young Scientists (B).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b04120 Org. Lett. 2019, 21, 826−829