Palladium-Catalyzed, Modular Synthesis of Highly Functionalized Indoles and Tryptophans by Direct Annulation of Substituted o-Haloanilines and Aldehydes Yanxing Jia and Jieping Zhu* Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
[email protected] ReceiVed July 15, 2006
One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-haloanilines and aldehydes has been developed. Coupling of ortho-iodoaniline with aldehyde is realized under mild ligandless conditions [Pd(OAc)2, DABCO, DMF, 85 °C], whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes. A variety of orthohaloanilines with different electronic properties are suitable substrates, and aldehydes including chiral ones participated in this reaction without racemization. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl5-oxopentanoate, derived from L-glutamic acid, with ortho-haloanilines provides a rapid access to the ring-A-substituted tryptophans in good to excellent yields.
Introduction The indole nucleus is one of the most important heterocycles due to its presence in a vast number of bioactive natural products, pharmaceuticals, and agrochemicals.1 Since the discovery of Fischer indole synthesis in 1883, synthesis and functionalization of indoles has been the subject of intensive research for over 100 years, and a variety of well-documented traditional and modern methods are now available.2,3 However, the development of general and efficient methods for preparation of functionalized indoles from simple and easily accessible starting materials remains an active research field.4 In this (1) For recent reviews on indole-containing natural products, see: (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278-311. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73-103. (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761-793. For leading references on the physiological activity of indole derivatives, see: (d) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L. S.; Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny, A. D. J. Med. Chem. 2005, 48, 3141-3152. For recent references on the total synthesis of indole alkaloids, see: (e) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342-5344. (f) Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem., Int. Ed. 2005, 44, 3892-3895. (g) Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038-15039. (2) Gribble, G. W. Contemp. Org. Synth. 1994, 1, 145-172. (3) For a recent general review on the construction of the indole ring, see: Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
context, palladium-catalyzed transformations have had a major impact on indole synthesis, and indeed a range of catalytic protocols has been developed for the synthesis of functionalized indoles from simple starting materials.5,6 Thus the intramolecular Heck reaction7 involving 5-exo cyclization followed by doublebond isomerization has been widely used for the synthesis of substituted indole derivatives since the initial disclosure of Mori8 (4) For recent reports on indoles synthesis without a Pd catalyst, see: (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732-4734. (b) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054-4055. (c) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546-10547. (d) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776-5777. (e) Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058-1059. (f) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060-1061. (5) For reviews on palladium-catalyzed synthesis of indoles, see: (a) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113-1126. (b) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309. (c) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198. (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-3160. (e) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920. (6) For recent reports on Pd-catalyzed indole synthesis, see: (a) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168-15169. (b) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003, 42, 3042-3044. (c) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403-406. (d) Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valde´s, C. Chem.sEur. J. 2005, 11, 22762283. (e) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549-3552. (f) Mukai, C.; Takahashi, Y. Org. Lett. 2005, 7, 5793-5796. 10.1021/jo061471s CCC: $33.50 © 2006 American Chemical Society
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Pd-Catalyzed Synthesis of Indoles and Tryptophans
and Hegedus.9 Arguably, the palladium-catalyzed cyclization of ortho-alkynylanilines/anilides10 and Larock annulation of ortho-haloanilines with internal alkynes11 are among the most powerful synthetic methods recently developed for the construction of indoles. On the other hand, palladium-catalyzed cyclization of ortho-haloanilino enamines has also been developed since the initial report of Kibayashi.12 In most cases, enamines are stabilized by conjugation with a carbonyl group (enaminones) and are synthesized in a separate step by one of the following methods: (a) condensation of ortho-haloanilines with 1,3dicarbonyl compound13 or R-keto ester;14 (b) Michael addition of anilines to ethynyl ketone;15 (c) palladium-catalyzed oxidative amination of electron-deficient olefins;16 (d) Buchwald-Hartwig amination of vinylogous amides;17 and (e) Wittig reaction of trifluoroanilides.18 A breakthrough came in 1997 when Chen and co-workers at Merck Research Laboratories19 reported a one-pot annulation process starting from the ortho-iodoaniline and cyclic ketones.20,21 Surprisingly, aldehydes have not been used as a reaction partner in this annulation process, though this would produce highly demanding 2-unsubstituted indole derivatives. Indeed, it has been noted in Chen’s original paper that this annulation works well with cyclic ketones, but less efficiently with acyclic ketones. To get the parent 2-unsubstituted indoles, the authors advocated the use of acylsilane or pyruvic acid since both carboxyl and silyl groups can be removed after the annulation reaction. In connection with a total synthesis project, we had occasion to examine this reaction, and we detail herein that ortho-iodoaniline reacted efficiently with a variety of aldehydes in the presence of palladium catalyst to afford the 2-unsubstituted indoles, including enantiomerically pure tryptophan derivatives.22 We document also the develop(7) (a) Heck, R. F. Org. React. 1982, 27, 345-390. (b) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-3066. (d) Amatore, C.; Jutard, A. Acc. Chem. Res. 2000, 33, 314-321. (e) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2964. (8) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 1037-1040. (9) Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980, 45, 2709-2710. (10) For a review, see: Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671-2681. (11) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 66896690. (b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652-7662. (c) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412-420. (d) From ortho-chloroaniline, see: Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129-4132. (12) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 29382942. (13) Michael, J. P.; Chang, S.-F.; Wilson, C. Tetrahedron Lett. 1993, 34, 8365-8368. (b) Chen, L.-C.; Yang, S.-C.; Wang, H.-M. Synthesis 1995, 385-386. (c) Watanabe, T.; Arai, S.; Nishida, A. Synlett 2004, 907-909. (14) (a) Koerber-Ple´, K.; Massiot, G. Synlett 1994, 759-760. (b) For solid phase synthesis, see: Yamazaki, K.; Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011-6019. (15) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215-218. (16) (a) Bozell, J. J.; Hegedus, L. S. J. Org. Chem. 1981, 46, 25612563. (b) Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927-928. (17) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2, 1109-1112. (18) Latham, E. J.; Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1997, 2059-2063. (19) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676-2677. (20) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526-4528. (21) Lachnace, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571-2577. (22) Part of this work has been published as a preliminary communication: Jia, Y.; Zhu, J. Synlett 2005, 2469-2472.
ment of conditions that allow the use of ortho-chloroaniline and ortho-bromoaniline as coupling partners, extending thus significantly the application scope of this reaction. Results and Discussion Annulation of ortho-Iodoanilines and Aldehydes. In the course of our efforts toward the total synthesis of complestatin (chloropeptin II),23 we needed an efficient method for the preparation of benzenoid-substituted tryptophan. Literature search indicated that a variety of methodologies have been developed, including (a) enzymatic resolution of racemic compounds;24 (b) tryptophan synthetase catalyzed alkylation of indole by L-serine;25 (c) functionalization of the cyclic tautomer of tryptophan;26 (d) enantioselective hydrogenation of dehydrotryptophan;27 (e) diastereoselective28 and enantioselective29 alkylation of indole derivatives; (f) enantioselective ene reaction;30 (g) The Fischer indole synthesis;31 and (h) palladiumcatalyzed Larock heteroannulation reaction.32 However, most of these methodologies suffer from a number of disadvantages. Thus, the alkylation strategy is complicated by competitive nucleophilicity at C-3 versus C-2, N-1 and requires a presynthesis of the indole core,33 whereas the traditional Fischer indole synthesis often failed to deliver indoles with electron-deficient hydrazines and m-substituted phenylhydrazines usually yielded a mixture of 4- and 6-substituted indoles.34 The synthesis of substituted tryptophans by Larock annulation reaction required multistep synthesis of chiral internal silylalkynes.32 The limitation of the current available synthetic approaches to access ringA-substituted tryptophan derivatives prompted us to develop an alternative synthesis of this class of amino acids, and Chen’s one-step annulation protocol seems to be highly promising in order to reach this goal. (23) Shinohara, T.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc 2005, 127, 7334-7336. (24) (a) Allen, M. C.; Brundish, D. E.; Wade, R. J. Chem. Soc., Perkin Trans. 1 1980, 1928-1932. (b) Konda-Yamada, Y.; Okada, C.; Yoshida, K.; Umeda, Y.; Arima, S.; Sato, N.; Kai, T.; Takayanagi, H.; Harigaya, Y. Tetrahedron 2002, 58, 7851-7861. (25) (a) Lee, M.; Phillips, R. S. Bioorg. Med. Chem. Lett. 1992, 2, 15631564. (b) Kaiser, M.; Groll, M.; Renner, C.; Huber, R.; Moroder, L. Angew. Chem., Int. Ed. 2002, 41, 780-783. (26) (a) Hino, T.; Taniguchi, M. J. Am. Chem. Soc. 1978, 100, 55645565. (b) Taniguchi, M.; Anjiki, T.; Nakagawa, M.; Hino, T. Chem. Pharm. Bull. 1984, 32, 2544-2554. (27) (a) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. (b) Wang, W.; Xiong, C.; Yang, J.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 7717-7719. (28) Liu, R.; Zhang, P.; Gan, T.; Cook, J. M. J. Org. Chem. 1997, 62, 7447-7456. (29) Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J. J. Org. Chem. 2003, 68, 9835-9838. (30) (a) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443-1446. (b) Drury, W. J., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006-11007. (31) Gorohovsky, S.; Meir, S.; Shkoulev, V.; Byk, G.; Gelleman, G. Synlett 2003, 1411-1414. (32) (a) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66, 4525-4542. (b) Li, X.; Yin, W.; Srirama Sarma, P. V. V.; Zhao, H.; Ma, J.; Cook, J. M. Tetrahedron Lett. 2004, 45, 85698573. (c) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611-3614. (33) Zhu, X.; Ganesan, A. J. Org. Chem. 2002, 67, 2705-2708. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 31993202. (c) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592-4593. (d) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125-3129. (34) For recent examples of Fisher indole syntheses, see: (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1025110263. (b) Ref 31. (c) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6, 79-82. (d) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37, 4869-4872.
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Jia and Zhu SCHEME 1
SCHEME 2
TABLE 1. Palladium-Catalyzed Heteroannulation of o-Iodoaniline (1a, R1 ) R2 ) H) and ω-Amino Aldehyde 4aa
entry
base
1 2 3 4 5 6 7d
K2CO3 PMP DABCO DABCO DABCO DABCO DABCO
additive
TBAClc TBAIc TBAIc
T (°C)
time (h)
yield (%)b
85 85 85 85 85 105 85
8 10 8 8 20 7 8
0 0 81 0 48 40 0
a General reaction conditions: concentration ) 0.2 M in DMF, Pd(OAc) 2 (0.05 equiv) as palladium source except for entry 7, mole ratio ) 1a/4a ) b c 1.1/1 in the presence of 3 equiv of base. Isolated yield. Three equivalents. d Pd(PPh ) was used as catalyst. Abbreviations: PMP ) 1,2,2,6,63 4 pentamethylpiperidine; DABCO ) 1,4-diazabicyclo[2,2,2]octane; TBACl ) tetrabutylammonium chloride; TBAI ) tetrabutylammonium iodide.
We initially examined the annulation reaction of o-iodoaniline 1a (R1 ) R2 ) H) and (2S)-2-N-Boc-5-oxopentanoic acid methyl ester (6a). The aldehyde (6a) was synthesized from N-Boc-Lglutamic acid R-methyl ester 7 via a reduction/oxidation sequence and was found to exist mainly as the cyclic hemiaminal form 6b (Scheme 2).35 Submitting 6a/6b and 1a to Chen’s conditions [Pd(OAc)2, DMF, DABCO, 85 °C] afforded indeed the desired L-tryptophan (8) but in only 15% isolated yield. Although yield remained low, the result was nevertheless encouraging since it proved the feasibility of this approach, which constituted probably one of the shortest routes to 8. Parallel to our work, Baran and co-workers reported a synthesis of racemic 6-hydroxytryptophan using a similar strategy in connection with their total synthesis of stephacidin A.36 Reasoning that hemiacetal 6b may not react properly with aniline to produce the enamine intermediate required for the subsequent key C-C bond forming process, we turned our attention to the enantiomerically pure methyl (S)-2-N,N-di-tertbutoxycarbonyl-5-oxopentanoate 4a (Scheme 2), readily synthesized in four conventional steps from L-glutamic acid.37 The reaction of 1a and 4a in DMF in the presence of palladium acetate was performed under a variety of conditions, and some representative results are summarized in Table 1. As it is seen, the choice of base is of utmost importance since no annulation product was formed when potassium carbonate (entry 1) and 1,2,2,6,6-pentamethylpiperidine (entry 2) were used as bases. However, in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO), the desired L-N,N-di-Boc-tryptophan methyl ester (5a) was produced in 81% yield. We have also briefly examined (35) Bold, G.; Steiner, H.; Moesch, L.; Walliser, B. HelV. Chim. Acta 1990, 73, 405-410. (36) (a) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005, 44, 606-609. (b) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678-8693. (37) (a) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.; Martin, V. S. J. Org. Chem. 1998, 63, 3741-3744. (b) Padron, J. M.; Kokotos, G.; Martin, T.; Markidis, T.; Gibbons, W. A.; Martin, V. S. Tetrahedron: Asymmetry 1998, 9, 3381-3394.
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the effect of additives and found that the yield of 5a decreased in the presence of tetrabutylammonium iodide (TBAI) or tetrabutylammonium chloride (TBACl) (entries 4-6).38 The palladium source also played an important role since no desired product was isolated when Pd(PPh3)4 was used under otherwise identical conditions (entry 7). The enantiomeric purity of 5a was determined to be higher than 92% by its conversion to 8 (CeCl3‚7H2O, NaI, MeCN)39 and subsequent chiral HPLC analysis (cf. Supporting Information). Having established the optimal reaction conditions, the scope of this reaction was examined with respect to anilines by varying systematically the electronic properties of the aromatic ring. As is shown in Table 2, the reaction turned out to be very general and is applicable to both electron-rich and electron-deficient o-iodoanilines. Thus, even with 4-nitroaniline (1f), the corresponding tryptophan 5f was isolated in 74% yield, although the basicity of the amino function in 1f was significantly reduced (entry 6). Steric hindrance was also well tolerated since both 4-methoxytryptophan 5c (entry 3) and 7-methoxytryptophan 5i (entry 9) can be synthesized by this methodology, although 2 equiv of aniline 1c had to be used for the synthesis of 5c. The reaction of N-methylanilines (1b, 1e) with 4a proceeded smoothly, leading to the corresponding tryptophan derivatives (5b, 5e) in excellent yield. 6-Azatryptophan can be similarly prepared starting from 4-iodo-3-aminopyridine (entry 11). Furthermore, the reaction is site-selective since the reaction of 2-iodo-5-chloroaniline with 4a afforded the corresponding 6-chlorotryptophan in 74% yield (5l, entry 12). The presence of a chlorine atom in 5l provided a valuable handle for further functionalization by way of transition-metal-catalyzed processes.40 (38) For halide effects on metal-catalyzed transformations, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26-47. (39) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002, 468470. (40) For a review of palladium-catalyzed cross-coupling reactions of aryl chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211. For recent examples, see: (b) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282-1284. (c) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484-3488. (d) For a recent example of catalytic direct arylation of aryl chloride, see: Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581-591.
Pd-Catalyzed Synthesis of Indoles and Tryptophans TABLE 2. Synthesis of Ring-A-Substituted Tryptophans by Palladium-Catalyzed One-Pot Annulation Reactiona
a General reaction conditions: concentration ) 0.2 M in DMF, 0.05 equiv of Pd(OAc) , 1.1 equiv of o-iodoaniline 1, 1.0 equiv of aldehyde 4a, 3.0 equiv 2 of DABCO, 85 °C. b Isolated yield.
To evaluate the application scope of this one-pot annulation protocol with respect to aldehydes, coupling of ortho-iodoaniline with different aldehydes was next investigated, and the results are summarized in Table 3. As expected, the annulation reaction proceeded without event to afford the corresponding ring-Afunctionalized C-3-substituted indoles in good yields. The presence of a free hydroxy group was well tolerated since 5-hydroxypentanal can be used directly in the annulation reaction to afford indole 5r (entry 6). The 3-phenyl-substituted indole 5o was prepared in good yield from the corresponding phenylacetaldehyde.41 Indole 5p bearing an asymmetric center adjacent to the C-3 carbon was obtained by annulation of (S)citronellal with ortho-iodoaniline without racemization (cf. Supporting Information). The synthesis of this type of indole has been the recent focus, and most of the reported methods called for the asymmetric functionalization of indole, requiring thus the presynthesis of the substituted indole nucleus.42-45 The (41) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363-1366. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050-8057. (42) For a review of stereoselective Friedel-Crafts alkylation reaction, see: Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550-556. (43) For metal-catalyzed additions of indoles to R,β-unsaturated systems, see: (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780-10781. (b) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309-1320. (c) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcı´a, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154-4155. (d) Evans, D. A.; Fandrick, K. R.; Song, H.J. J. Am. Chem. Soc. 2005, 127, 8942-8943.
N-methyl ortho-iodoaniline (1b) reacted with 3-phenylpropinaldehyde efficiently to provide 5s in 76% yield (entry 7). Annulation of ortho-Chloroanilines and Aldehydes. With these results in hand, we were interested in exploring the possibility of replacing the ortho-iodoaniline with much cheaper and readily accessible ortho-chloroaniline and ortho-bromoaniline as the reaction partners of the present annulation process. Although remarkable progress has been achieved in palladiumcatalyzed coupling reactions of aryl chlorides,40 examples using highly deactivated chloroanilines remained relatively rare. As a model reaction, the union of o-chloroaniline 2a with 3-(3,4,5trimethoxyphenyl)propanal 4b in DMA with (t-Bu3P)HBF4 (9) as a supporting ligand20,46 was examined in the presence of a variety of bases and palladium sources. As shown in Table 4, potassium acetate turned out to be the base of choice (entry 1), and DABCO was also capable of promoting the reaction but (44) For organo-catalyzed additions of indoles to R,β-unsaturated systems, see: (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172-1173. (b) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440. (c) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576-6579. (45) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 1759-1762. (b) Dardennes, E.; Kovacs-Kulyassa, A.; Renzetti, A.; Sapi, J.; Laronze, J.-Y. Tetrahedron Lett. 2003, 44, 221-223. (46) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. (b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 27192724. (c) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298. (d) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 63436348.
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Jia and Zhu TABLE 3. Synthesis of Indoles by Palladium-Catalyzed One-Pot
TABLE 4. Annulation Reaction of o-Chloroaniline 2a and
Annulation Reactiona
Aldehyde 4b, Conditions Surveya
entry
Pd cat.
base
1 2 3 4 5 6 7 8 9 10 11 12 13
Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(dba)2 Pd(Ph3P)4 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2
KOAc KOAc KOAc K3PO4 K3PO4 K2CO3 DABCO Cs2CO3 PMP KOAc KOAc DABCO DABCO
additive
MgSO4 HOAc
time (h)
yield (conv.)b
5 5 7 7 8 4 5 6 20 25 12 20 10
57 51c 57 51 14 38 58 (46) 17 33 (56) 15 47 51(78) 0d
a General reaction conditions: concentration ) 0.2 M in DMA, 0.10 equiv of palladium source, 0.20 equiv of (t-Bu3P)HBF4, 1.0 equiv of o-chloroaniline 2a, 1.0 equiv of aldehyde 4b, 3.0 equiv of base, 120 °C. b Isolated yield. c 1.5 equiv of KOAc. d No ligand used. Abbreviations: PMP ) 1,2,2,6,6-pentamethylpiperidine; DABCO ) 1,4-diazabicyclo[2,2,2]octane.
a General reaction conditions: concentration ) 0.2 M in DMF, 0.05 equiv of Pd(OAc)2, 1.1 equiv of o-iodoaniline 1, 1.0 equiv of aldehyde 4, 3.0 equiv of DABCO, 85 °C. b Isolated yield. c 5-Hydroxypentanal (open-chain form) was used as coupling partner.
with low conversion (entry 7). On the other hand, potassium phosphate, potassium carbonate, cesium carbonate, and PMP were less effective as bases. The addition of magnesium sulfate as dehydrating agent did not exert any positive effect. Palladium acetate can also act as palladium source, albeit with slightly reduced yield and longer reaction time (entries 11 and 12). Overall, under optimum conditions [Pd(dba)2, (t-Bu3P)HBF4, KOAc, DMA, 120 °C], the desired indole 5n was isolated in 57% yield. It has to be noted that, in the absence of (t-Bu3P)HBF4, no reaction occurred under otherwise identical conditions (entry 13). To further optimize the reaction conditions, a screening of ligands was carried out (Table 5). The electronrich but sterically less demanding monophosphines (tricyclohexyl phosphine (10), tri-nbutyl phosphine (11), and dicyclohexyl(2,4,6-triisopropylphenyl)phosphine (12)) were found to be ineffective for the present transformation (entries 1-3). The bulky electron-rich biphenyl phosphines, such as 13 (cyclohexyl JohnPhos), 14 (JohnPhos), and 15 (DavePhos), gave inferior results relative to those of (t-Bu3P)HBF4 (entries 4-6), while ligand 16 (2-dicyclohexylphosphino-2′-methylbiphenyl) was as efficient as (t-Bu3P)HBF4. The best result was obtained when X-phos 17 was employed as supporting ligand affording indole 7830 J. Org. Chem., Vol. 71, No. 20, 2006
FIGURE 1. Structure of ligands screened for the annulation of orthochloroaniline (2a) and 3-(3,4,5-trimethoxyphenyl)propanal (4b).
5n in 83% yield (entry 7). As for many other palladiumcatalyzed transformations, the present annulation process is very sensitive to the ligand structure. Thus switching from X-Phos to the structurally very similar but bulkier ligand 18 (tert-butyl XPhos) completely suppressed the desired transformation (entry 9). It is evident that the ability of these biphenyl phosphines as supporting ligands to catalyze, in association with palladium, the annulation reaction relied on the proper combination of two steric factors: the substituent at the phosphorus center and the ortho substituents on the ring B. Moderately encumbered dicyclohexylphosphinyl substituent (ring A) in combination with a hindered 2′,4′,6′-triisopropylphenyl (ring B) was apparently optimum as a supporting ligand for the present transformation. While 0.1 equiv of palladium was used in the above survey of reaction conditions, we were pleased to find that catalyst loading can be decreased. Thus performing the annulation of 2a and 4b in the presence of 0.025 equiv of Pd(dba)2 and 0.050 equiv of ligand 17 provided the desired indole 5n in 85% yield. It is worthy noting that X-Phos is known to be an excellent
Pd-Catalyzed Synthesis of Indoles and Tryptophans TABLE 6. Synthesis of Indoles from ortho-Chloroanilinesa
TABLE 5. Ligand Screening for Annulation Reaction of o-Chloroaniline 2a with Aldehyde 4ba
entry
ligand
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10
PCy3 (n-Bu)3P 12 13 14 15 16 17 18 17
25 20 20 20 20 20 5 4 10 5
