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A Five-Component Synthesis of Hexasubstituted Benzene

2002; Wiley; Volume: 41; Issue: 22 Linguagem: Inglês

10.1002/1521-3773(20021115)41

1521-3773

Pierre Janvier, Hugues Bienaymé, Jieping Zhu,

Synthetic Organic Chemistry Methods

Angewandte Chemie International EditionVolume 41, Issue 22 p. 4291-4294 CommunicationFree Access A Five-Component Synthesis of Hexasubstituted Benzene† Pierre Janvier, Pierre Janvier Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France, Fax: (+33) 1-69077247Search for more papers by this authorHugues Bienaymé Dr., Hugues Bienaymé Dr. Chrysalon, 11 Avenue Albert Einstein, 69100 Villeurbanne, FranceSearch for more papers by this authorJieping Zhu Dr., Jieping Zhu Dr. zhu@icsn.cnrs-gif.fr Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France, Fax: (+33) 1-69077247Search for more papers by this author Pierre Janvier, Pierre Janvier Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France, Fax: (+33) 1-69077247Search for more papers by this authorHugues Bienaymé Dr., Hugues Bienaymé Dr. Chrysalon, 11 Avenue Albert Einstein, 69100 Villeurbanne, FranceSearch for more papers by this authorJieping Zhu Dr., Jieping Zhu Dr. zhu@icsn.cnrs-gif.fr Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France, Fax: (+33) 1-69077247Search for more papers by this author First published: 12 November 2002 https://doi.org/10.1002/1521-3773(20021115)41:22 3.0.CO;2-DCitations: 84 † Financial support from the CNRS and a doctoral fellowship from Rhodia (PJ) is gratefully acknowledged. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Seven functional groups are involved in a highly ordered five-component domino process, which leads to a biologically relevant polyheterocycle. In this one-pot transformation, the formation of seven chemical bonds provides a hexasubstituted benzene core (see scheme; CSA = camphorsulfonic acid). Bis(indolyl)maleimides and indolo[2,3-a]carbazole alkaloids constitute a rapidly growing family of natural products with diverse biological activities.1 Thus, rebeccamycin (1)2 and staurosporine (21 )3 are potent topoisomerase I and protein kinase C inhibitors, respectively. Structurally, this class of compounds is characterized by an hexasubstituted benzene ring with a fused indolo (forming an indolocarbazole entity) and a fused lactam or an imide ring with a pendant sugar moiety. The novelty of the structures combined with their interesting biological profile have stimulated numerous synthetic efforts from both academic and industrial researchers.4 Transition-metal-mediated cyclization of appropriately functionalized enynes5 and Diels–Alder cycloaddition of furan6 are two main strategies used for the synthesis of hexasubstituted benzenes.7 Although high level of structural complexity can be generated from these two key transformations, the overall efficiency is often counter-balanced by efforts associated with the synthesis of linear precursors. In connection with our continued interest in the development of highly efficient synthesis of druglike polyheterocycles,8 we report herein a conceptually new strategy for the synthesis of hexasubstituted benzenes 3 based on a novel one-pot five-component domino process.9, 10 The underlying principle of our synthesis is shown in Scheme 1. A recently developed three-component reaction based on Ugi chemistry pioneered by Ugi and co-workers9 provides the 5-aminooxazole 7,11 Reaction of the latter with acyl chloride 8 (X=Cl) should give 5,6-dihydrofuro[2,3-c]pyrrol-4-one 10 following a sequence of acylation, intramolecular Diels–Alder cycloaddition and retro-Diels–Alder cycloreversion.12 Addition of a second dienophile 11 to the reaction mixture should initiate an intermolecular Diels–Alder reaction of furan6, 7e to give, after directed fragmentation, the hexasubstituted benzenes 3. The development of conditions for the three-component synthesis of oxazole that are compatible with the subsequent two cycloaddition-based domino processes would enable a five-component synthesis of hexasubstituted benzene 3. The sequence would allow rapid and efficient construction of structurally complex molecules from readily available starting materials. Scheme 1Open in figure viewerPowerPoint Five-component synthesis of hexasubstituted benzene. Whereas the cycloaddition of oxazole with acetylene is a well-established method for furan synthesis,12 the corresponding reaction of 5-aminooxazole was, to the best of our knowledge, unknown. To test the feasibility of the overall process, the reaction between purified 5-aminooxazole 7 a and acyl chloride 8 a13 was first examined (Scheme 2). The reaction proceeded smoothly to provide the 5,6-dihydrofuro[2,3-c]pyrrol-4-one 10 a (>95 % yield). A triple domino sequence involving acylation/intramolecular Diels–Alder cycloaddition/retro Diels–Alder cycloaddition could explain the reaction outcome. On the other hand, the reaction of 7 a with dimethylacetylenedicarboxylate (DMAD) provided the Michael adduct 13; no Diels–Alder cycloaddition took place. Attempts to promote the cycloaddition between 13 and DMAD led only to the recovery of starting materials or to degradation under forcing conditions. Scheme 2Open in figure viewerPowerPoint From 5-aminooxazole to hexasubstituted benzene. The reaction of the resulting aminofuran with N-phenylmaleimide (11 a) in toluene was next examined. When this reaction was performed at 70 °C in toluene, we were able to isolate the unstable oxa-bridged intermediate 12 a-1 as a mixture of two diastereomers in 47 % yield. However, on heating the solution in toluene at reflux, hexasubstituted benzene was produced directly. In view of the similar reaction conditions leading to the production of 10 a and 3 a, we reasoned that it might be possible to combine these two domino processes. In the event, heating a solution of oxazole 7 a and acyl chloride 8 a in the presence of triethylamine for 12 h, followed by addition of N-phenylmaleimide 11 a, provided 3 a in over 90 % overall yield (Scheme 2). Encouraged by the efficiency of the two consecutive domino processes, we set out to explore conditions that would enable its combination with the three-component synthesis of 5-aminooxazole 7. Initial results regarding the quest for this one-pot five-component domino process with lithium bromide gave unsatisfactory results.14 On the other hand, a stoichiometric amount of ammonium chloride15 and a catalytic amount of camphorsulfonic acid (CSA, 10 %) were able to promote the five-component domino process, which led to the hexasubstituted benzene 3 a in 40 and 52 % yields, respectively (Scheme 3, X=Cl). Subsequent experiments indicated that the use of pentafluorophenyl ester 8 b (X=OC6F5) instead of the acyl chloride 8 a (X=Cl) provided an improved yield of 3 a (67 %). Significantly, in this operationally simple five-component domino process, at least seven reactive functionalities participated in the chemical transformation that led to the concomitant creation of seven chemical bonds (two CN and five CC bonds) and a biologically relevant polyheterocycle. Scheme 3Open in figure viewerPowerPoint One-pot five-component synthesis of polyheterocycles with an hexasubstituted benzene core under various conditions. The use of three different amines, three aldehydes, one isocyanoacetamide, two pentafluorophenyl 3-arylprop-2-ynoates, and three dienophiles as starting materials allowed the synthesis of the polyheterocycles shown in Scheme 4. The potential and general applicability of this five-component domino process are readily seen from these selected examples. Scheme 4Open in figure viewerPowerPoint Five-component synthesis of polyheterocycles with an hexasubstituted benzene core: selected structures. In conclusion, we have developed a novel five-component domino process for the synthesis of highly functionalized polyheterocycles from simple and readily accessible starting materials. The overall process leads to the creation of seven chemical bonds and delivers five elements of diversity into the compact polyheterocycle, thus providing a large increase in molecular complexity. This constitutes a rare example in which more than four reagents were assembled together to provide a biologically relevant scaffold.16 The operational simplicity and good chemical yield made these novel heterocycle syntheses highly attractive in diversity-oriented parallel synthesis.17 Experimental Section Typical procedure: Heptanal 5 a (20.0 μL, 0.144 mmol) was added to a solution of butylamine (4 a, 15.2 μL, 0.156 mmol) in dry toluene (1.0 mL). After the mixture was stirred at room temperature for 30 min, isocyanide 6 (29.0 mg, 0.120 mmol) and camphorsulfonic acid (3.0 mg, 0.012 mmol, 0.1 equiv) were added successively. The reaction mixture was stirred at 60 °C until the disappearance of isonitrile. The reaction mixture was cooled to 0 °C. Et3N (83.6 μL, 0.60 mmol) was added, followed by a solution of pentafluorophenyl ester 8 b (64.0 mg, 0.2 mmol) in toluene (1.0 mL). Stirring was continued at room temperature for 30 min and at 110 °C for 12 h. N-Phenylmaleimide (23.0 mg, 0.132 mmol) was then added. The reaction mixture was stirred for an additional 15 min at 110 °C. After being cooled to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and evaporated under reduced pressure. The crude reaction mixture was purified by preparative TLC (silica gel, eluent: AcOEt/heptane=1:2) to give the corresponding hexasubstituted benzene 3 a (46.6 mg, 67 %) as a slight yellow oil. IR: =3011, 2963, 2931, 2862, 1764, 1714, 1684, 1600, 1502, 1438, 1383, 1234 cm−1; 1H NMR (CDCl3, 250 MHz): δ=7.58–7.28 (m, 10 H), 5.01 (t, J=3.5 Hz, 1 H), 3.95 (ddd, J=6.8, 9.2, 13.8 Hz, 1 H), 3.61 (m, 4 H), 3.00 (ddd, J=5.0, 8.9, 13.8 Hz, 1 H), 2.95 (m, 4 H), 2.63 (m, 1 H), 2.09 (m, 1 H), 1.62 (m, 2 H), 1.33 (sextet, J=7.2 Hz, 2 H), 1.19 (m, 6 H), 1.02 (m, 1 H), 0.92 (t, J=7.2 Hz, 3 H), 0.84 (t, J=6.6 Hz, 3 H), 0.69 ppm (m, 1 H); 13C NMR (CDCl3, 75 MHz): δ=165.9, 165.8, 165.3, 149.1, 143.6, 137.4, 137.1, 134.6, 131.5, 130.1, 129.7, 129.1, 129.0, 128.2, 128.1, 127.7, 127.6, 126.7, 126.0, 67.0, 57.0, 52.0, 39.7, 31.4, 29.9, 28.9, 28.5, 22.4, 21.8, 20.2, 13.9, 13.7 ppm; MS (ES, positive mode): m/z [M+H]+: 580.0 References 1For reviews, see: Google Scholar 1aG. W. Gribble, S. J. 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