Ene-hydrazide from Enol Triflate for the Regioselective Fischer Indole

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Ene-hydrazide from Enol Triflate for the Regioselective Fischer Indole Synthesis Byeong-Yun Lim, Bo-Eun Jung, and Cheon-Gyu Cho* Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu, Seoul 133-791, Korea S Supporting Information *

ABSTRACT: Ene-hydrazide prepared from enol triflate undergoes a Fischer indolization reaction to give the corresponding indole with complete regioselectivity. The starting enol triflate is readily accessed in regiochemically defined form from the ketone precursor via various wellestablished methods. This new protocol was successfully applied to the synthesis of desbromoarborescidine A, a natural β-carboline alkaloid, difficult to prepare with conventional Fischer indole synthesis.

I

the presence of an acid completed the Fischer indolization process to give indole 7 in 89% yield. Recently, Liang and co-workers noticed its implication as a potential solution to the regioselectivity problem of the Fischer indole synthesis.7 In their report, ene-hydrazide 10 was prepared from acetyl hydrazine 8 through the Cu-catalyzed coupling reaction with alkenyl bromide 9. Subsequent heating in toluene in the presence of ZnCl2 afforded indole 11 in high yield and regioselectivity (eq 3). Their new approach proved to be effective in the synthesis of some pyrrolidinoindoline type natural products. However, general application to more complex polycyclic indole natural products would be much hampered by the difficulties in preparation of the requisite alkenyl halide precursors. The synthesis of a cyclic alkenyl halide would impose an additional challenge, as it invokes the similar regioselectivity problem as the Fischer indole synthesis, should it be prepared from unsymmetrical ketone. In this context, enol triflate would provide a better alternative, because it is much more readily accessed in a regiochemically defined form from the corresponding ketone.8 Herein we report the synthesis of ene-hydrazide from enol triflate and a subsequent indolization reaction as a new entry to the regioselective Fischer indole synthesis. Since there is no report on the coupling reaction of enol triflate with aryl-hydrazine or hydrazide in the literature, we screened catalysts, ligands, solvents, and temperatures to find the best conditions by using aryl hydrazide 129 and enol-triflate 13a as the model system (Table 1). The reaction appeared sensitive to the catalyst type and reaction conditions. As expected, no coupling event was observed when heated in the presence of CuI (entry 1). After extensive experimentation, we found that the conditions in entry 7 are the best, giving rise to the desired ene-hydrazide 14a in 97% yield.10

ndole alkaloids are an important class of natural products possessing intriguing molecular structures and biological activities.1 Over the years, many elaborations have been directed toward the synthesis of indole-based natural products.2 The repertoire of synthetic methods have been particularly enriched with the advance of the transition metal catalyzed C− N coupling reactions. Despite the recent developments, the historic Fischer indole synthesis, reported in 1883, is still the method of choice for its simplicity and reliability.3 However, it suffers from two major drawbacks: the poor availability of the starting aryl hydrazine4 and the lack of regioselectivity. We have shown that aryl hydrazide 1, readily accessed from aryl halide via a C−N coupling reaction with carbazate,5 is an effective surrogate of aryl hydrazine, providing the indole 3 when plugged into the Fischer indole synthesis (eq 1, Scheme 1).6 We have also demonstrated that aryl hydrazide 4 can be coupled with cyclohexenyl iodide 5 to directly afford enehydrazide 6 (eq 2).6d Heating the isolated ene-hydrazide 6 in Scheme 1. Aryl Hydrazide in the Fischer Indole Synthesis

Received: July 11, 2014

© XXXX American Chemical Society

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Table 1. Coupling Reaction with Enol Triflate under Various Conditions

entry

conditions

yield

1 2 3 4 5 6

CuI, 1,10-phen, Cs2CO3, DMF, 80 °C, 48 h Pd2(dba)3, BINAP, Cs2CO3, tol, 80 °C, 48 h Pd2(dba)3, xantphos, Cs2CO3, dioxane, 80 °C, 24 h Pd2(dba)3, tBuXPhos, K2CO3, t-BuOH, 80 °C, 48 h Pd(OAc)2, DPPF, Cs2CO3, tol, 110 °C, 20 h Pd(OAc)2, P(t-Bu)3·HBF4, Cs2CO3, tol, 110 °C, 9 h

trace trace 17% trace trace 97%

Table 2. Indolization of 14f under Various Conditions

Having established the optimal conditions, we applied the protocol to an assortment of enol triflate substrates to examine the reaction scope. As shown in Scheme 2, the reaction

entry

conditions

yield (15f:16f)

1 2 3 4 5 6 7 8 9 10

HCl (aq), MeOH, 70 °C, 0.5 h HCl (aq), EtOH, 85 °C, 0.5 h HCl (aq), dioxane, 105 °C, 0.5 h TsOH·H2O (6 equiv), EtOH, 85 °C, 1 h ZnCl2 (2.2 equiv), toluene, 90 °C, 3 h ZnCl2 (2.2 equiv), THF, 90 °C, 12 h ZnCl2 (4.4 equiv), THF, 90 °C, 1 h ZnCl2 (1.1 equiv), dioxane, 90 °C, 19 h ZnCl2 (2.2 equiv), dioxane, 90 °C, 1 h ZnCl2 (4.4 equiv), dioxane, 90 °C, 1 h

91% (1:1) 92% (1:1) 89% (1:2) 91% (1:30) no reaction incomplete 92% (5:1) 96% (100:0) 95% (100:0) 93% (6:1)

conditions. Among the Lewis acids studied, ZnCl2 provided the best results. When heated in 1,4-dioxane under reflux, indole 15f was obtained as a single isomer in yields greater than 95% (entries 8 and 9). Notably, the reaction did not proceed at all when heated in toluene (entry 5).7 Addition of a large excess of ZnCl2 (4.4 equiv) resulted in isomerization (15f:16f = 6:1, entry 10). The optimal indolization conditions pertaining to entry 9 were then applied to the reaction of various other enehydrazides (Scheme 3). As shown, the reaction proceeded in a

Scheme 2. Coupling Reactions with Other Enol Triflatesa

Scheme 3. Regioselective Fischer Indolizationa

a

Yield after purification by chromatography. b Starting enol triflate has small amount of the inseparable isomer (7%).

conditions proved effective, affording the corresponding enehydrazides 14b−14j mostly in good yields. The enol triflate 13e used in the preparation of ene-hydrazide 14e contained a small amount of inseparable regioisomeric enol triflate.11 All starting enol triflates 13a−13j were prepared from either the corresponding ketones or enones, according to the literature procedures.12 Ene-hydrazide 14f prepared from 3-ethylcyclohexenyl triflate 13f was selected to identify the best reaction conditions with respect to regiochemical outcome and chemical yield, by varying the acid, solvent, and reaction temperature (Table 2). The reaction in EtOH with HCl (aq) at reflux temperature resulted in complete regiochemical scrambling, affording a 1:1 mixture of 15f and 16f (91% total yield, entry 1). Changing the solvent or reaction temperature had little effect (entries 2 and 3). Interestingly, the reaction using TsOH in EtOH afforded thermodynamic isomer 16f as the major product (entry 4). Evidently, the ene-N-Boc group is removed under the conditions and the resulting enamine undergoes the double bond isomerization via the hydrazone intermediate. In order to suppress the N-Boc group deprotection and the subsequent isomerization, the indolization was examined under Lewis acid

a

Yield after purification by chromatography. b 15a and 7 (Scheme 1) are identical compound.

highly regioselective manner to furnish the corresponding indole product in a high yield. The exclusive formations of the indoles 15e, 15g, and 15h clearly demonstrated the effectiveness of this new protocol. Ene-hydrazides with either a five- or seven-membered ring also underwent the indolization reactions to give the indoles 15i and 15j in excellent yields. This new method would be particularly powerful in the synthesis of indole natural products that are not readily accessible from the ketones by way of the conventional Fischer indole synthesis because of the aforementioned regiochemistry issue (Figure 1). For a quick proof of concept, we investigated the synthesis of desbromoarborescidine A, a natural β-carboline alkaloid, from quinolizidinone 17.13 In fact, this bicyclic ketone has been B

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.

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Figure 1. Selected indole natural products not readily accessible with conventional Fischer indole synthesis.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

employed as the substrate for the Fischer indole synthesis, which gave desbromoarborescidine A. Not unexpectedly, the yield is low, as the reaction needs to go through the thermodynamically less favorable ene-hydrazine intermediate.14 Ketone 17 was first converted into enol triflate 18 via deprotonation with LiHMDS followed by quenching with PhNTf2. However, the coupling reaction with hydrazide 12 did not proceed under the conditions, due to the steric congestion (Scheme 4). Further variation of the reaction conditions resulted in no improvement.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the grants from the National Research Foundation of Korea (2011-0022343 and 2014R1A5A1011165).

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REFERENCES

(1) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Eicher, T.; Hauptmann, S. In The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications, 2nd ed.; Wiley-VCH: Weinheim, 2003. (d) Joule, A. Indole and its Derivatives. In Science of Synthesis: Methods of Molecular Transformations (Houben-Weyl); Thomas, E. J., Ed.; Thieme, Stuttgart: 2000; Cat. 2, Vol. 10, p 361. (e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (f) Rahman, A. Indole Alkaloids; Harwood Academic Publisher: Amsterdam, 1998. (g) Sundberg, R. J. Indoles; Academic Press: London, 1996. (2) For recent reviews, see: (a) Inman, M.; Moody, C. J. Chem. Soc. 2013, 4, 29. (b) Bariwal, J.; Van der Eycken, E. Chem. Soc. Rev. 2013, 42, 9283. (c) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. React. 2012, 76, 281. (d) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (3) For reviews, see: (a) Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: Chichester, U.K., 1982. (b) Hugh, D. L. Org. Prep. Proced. Int. 1993, 25, 609. For a recent computational assessment of the reaction mechanism, see: (c) Ç elebi-Ö lçüm, N.; Boal, B. W.; Huters, A. D.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2011, 133, 5752. (4) Hydrazine itself can be coupled with aryl chloride to give aryl hydrazine: (a) Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 8686. More recently, the possible danger of explosion of hydrazine during the coupling reaction was shown to be avoided through the use of flow chemistry: (b) DeAngelis, A.; Wang, D.-H.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 3434. (5) (a) Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542. (b) Lam, M. S.; Lee, H. W.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2008, 49, 6192. (c) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (d) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. (e) Wang, Z.; Skerlj, R. T.; Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543. (6) (a) Park, J.; Kim, S.-Y.; Kim, J.-E.; Cho, C.-G. Org. Lett. 2014, 16, 178. (b) Park, I.-K.; Park, J.; Cho, C.-G. Angew. Chem., Int. Ed. 2012, 51, 2496. (c) Park, I.-K.; Suh, S.-E.; Lim, B.-Y.; Cho, C.-G. Org. Lett. 2009, 11, 5454. (d) Lim, Y.-K.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 1857. (e) Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336. (7) Zhan, F.; Liang, G. Angew. Chem., Int. Ed. 2013, 52, 1266. (8) Unlike vinyl halides, enol triflates are readily accessed from unsymmetrical ketones in regiochemically defined forms through the well documented thermodynamic/kinetic control in the enolate formation step by proper selection of reaction conditions. For a review, see: (a) Scott, W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 21, 47. For preparation from silyl enol ether, see: (b) Martínez, I.; Alford, P. E.; Ovaska, T. V. Org. Lett. 2005, 7, 1133. (c) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 11290. For preparation from enone via asymmetric conjugative addition followed by trapping, see: (d) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930.

Scheme 4. Attempted Synthesis of Desbromoarborescidine A

In order to alleviate the steric hindrance, phenyl hydrazide 20 with only one Boc group was prepared and employed for the coupling reaction with enol triflate 18. Gratifyingly, it underwent the coupling reaction to give the desired enehydrazide 21 in good yield, although the exact yield was difficult to measure due to the rotamer formation. Subsequence indolization by heating in 1,4-dioxane provided desbromoarborescidine A in 73% total yield from enol triflate 18 (64% overall yield from bicyclic ketone 17, Scheme 5). Scheme 5. End-Game Synthesis of Desbromoarborescidine A

In summary, enol triflate is readily coupled with aryl hydrazide to give ene-hydrazide in good yield. The resulting ene-hydrazide undergoes the Fischer indolization reaction, affording the corresponding indole product in a highly regioselective manner. Unlike alkenyl halide, enol triflate can be prepared from the ketone in a regiochemically defined form via various well-established methods. This new protocol was successfully applied to the synthesis of desbromoarborescidine A, a natural β-carboline alkaloid. Currently underway is the synthesis of the indole-based polycyclic alkaloids similarly difficult to access with conventional Fischer indole synthesis. C

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(e) Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182. (f) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835. (9) (a) Kim, K.-Y.; Shin, J.-T.; Lee, K.-S.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 117. (b) Arterburn, J. B.; Rao, K. V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351. (10) All ene-hydrazides 14a−14j were isolated by silica-gel column chromatography and fully characterized by 1H, 13C, IR, and HRMS, for the first time. (11) Detailed synthetic processes for the enol triflates are documented in the Supporting Information. (12) Please see Supporting Information for details. (13) (a) Tong, S. T.; Barker, D. Tetrahedron Lett. 2006, 47, 5017. (b) Hadley, M. S.; King, F. D.; McRitche, B.; Turner, D. M.; Wells, E. A. J. Med. Chem. 1985, 28, 1843. (14) Sparatore, A.; Boido, C. C.; Boido, V.; Sparatore, F.; Debbia, E.; Schito, A. P. Farmaco 1990, 45, 867. (b) Yamada, S.-i.; Kunieda, T. Chem. Pharm. Bull. 1967, 15, 499.

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