Letter Cite This: Org. Lett. 2017, 19, 6136-6139
pubs.acs.org/OrgLett
Synthesis of Benzo[1,4]heterocycles using Palladium Catalyzed Heck Reaction to Vinylogous Carbonates/Carbamates: Unexpected Formation of Indoles via Carbopalladation Intercepted by Nucleopalladation Santosh J. Gharpure* and Dandela Anuradha Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India S Supporting Information *
ABSTRACT: An efficient protocol for the stereoselective synthesis of benzo[1,4]heterocycles via palladium catalyzed Heck reaction on o-halo-aryl-oxa/thia/aza tethered vinylogous carbonates/carbamates/esters has been developed. Unexpected formation of indoles is observed when unprotected 2-iodoaniline tethered vinylogous carbonates are subjected to the Heck reaction. Mechanistic studies indicate that formation of these indoles is an outcome of the interception of the carbopalladation step by nucleopalladation. The method can be used to gain rapid access to the core skeleton of abacopterin A−C.
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enzo[1,4]heterocycles are important scaffolds present in many natural products and biologically active compounds. The natural products abacopterin A−C (1a−c)1 and eruberin A (2)2 (flavan-4-ol glycosides) were isolated from A. penangiana rhizome, which is used as a folk herbal medicine to treat blood stasis, blood circulation barriers, edema, and inflammation in patients suffering from metabolic syndrome. Shelincaoide A (3) was isolated from Pronephrium triphyllum, which has been used to treat ulcerative carbuncle, venomous snake bite, fracture, eczema, itch, and acute and chronic tracheitis.3 Tetrahydrobenzoxazepine (4) is effective against Alzheimer’s disease (Figure 1).4 Structural diversity coupled with biological activity of these benzo[1,4]heterocycles has led to the development of a variety of methods for their synthesis in recent years.5 However, a general strategy that will give access to benzo[1,4]heterocycles with
different heteroatoms is still elusive. Over the past three decades, the Heck reaction has emerged as a powerful reaction to construct heterocycles.6 However, this reaction has found only limited use in coupling with the vinylogous carbonates and carbamates.7 Surprisingly, the Heck reaction is hitherto unexplored in the synthesis of benzo[1,4]heterocycles.8 In a program directed at stereoselective synthesis of oxa- and aza-cycles, particularly using vinylogous carbonates/carbamates, herein we disclose a Pd(II) catalyzed Heck reaction on vinylogous carbonates/carbamates/esters, for the synthesis of benzo[1,4]heterocycles.9 The method is extended to the synthesis of ABC rings of the core structure of abacopterin A−C (1a−c). In order to test the idea of using the Heck reaction for the construction of the benzo[1,4]heterocycles, the synthesis of benzodioxepine 5a was attempted. The known iodo-alcohol10 6a was reacted with the ethyl propiolate (7a) in the presence of a catalytic amount of DABCO to afford the iodo vinylogous carbonate 8a in excellent yield. Iodo vinylogous carbonate 8a was then subjected to Heck reaction conditions using Pd(II) acetate, triphenylphosphine, and trimethylamine as the base in DMF at 100 °C. A facile 7-exo-trig cyclization ensued furnishing the benzo[1,4]dioxepine 5a in good yield and excellent diastereoselectivity favoring the Z-isomer (Scheme 1).11 The formation of the Z-isomer follows the expected path, as the Heck reaction typically involves trans coupling of the aryl halide and activated olefin counterparts. After demonstrating the feasibility of the reaction, focus was turned toward studying the substrate scope. A variety of alkyl and aryl substituted vinylogous carbonates 8b−g smoothly under-
Figure 1. Natural products bearing benzo[1,4]heterocycles.
Received: September 26, 2017 Published: October 30, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03016 Org. Lett. 2017, 19, 6136−6139
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Organic Letters Scheme 1. Heck Reaction for the Synthesis of Benzo[1,4]dioxepine 5a
assembled using this strategy. Further, tosyl, mesyl, and nosyl protection of the nitrogen were tolerated under the reaction conditions employed. In all the cases, the stereochemistry of the Heck product was confirmed by NOE experiments and it was further unambiguously confirmed by X-ray diffraction studies on the benzo[1,4]heterocycles 5d, 5g, 5p, 5s, 5t−u, and 5w.12 The Heck reaction on halo-vinylogous carbamate for the synthesis of benzo[1,4]oxazepine was studied next (Scheme 3).
went the Heck reaction affording the corresponding highly functionalized benzo[1,4]dioxepine derivatives 5b−g. Naphtho[1,4]dioxepine 5h could also be obtained in good yield using this protocol. The carbohydrate derived enantiopure oxa-iodo tethered vinylogous carbonate 8i also participated in cyclization giving rise to corresponding benzo[1,4]dioxepine 5i. It is worth noting that the reaction could be extended to vinylogous esters 8j−l and corresponding benzo[1,4]dioxepines 5j−l were obtained in moderate to good yields (Scheme 2). The
Scheme 3. Heck Reaction on o-Halo-Oxa/Thia Tethered Vinylogous Carbamates 9
Scheme 2. Scope of the Synthesis of Benzo[1,4]heterocycle Derivatives 5
When iodide 9a was subjected to Heck reaction conditions, an inseparable mixture of the benzo[1,4]oxazepine 10a and the saturated derivative 11a was obtained, with the latter presumably formed via a reductive Heck reaction. Thia-tethered vinylogous carbamate 9b furnished exclusively the olefin 12b. Formation of the product 12b is an outcome of a tandem reductive Heck-retroaza-Michael reaction. On the other hand, the vinylogous carbamate 9c gave the Heck product 10c as the only detectable product in good yield and diastereoselectivity. During the study of the scope of the Heck reaction for the synthesis of benzo[1,4]heterocycles, a reaction of unprotected iodo aza-tethered vinylogous carbonates 13a−i was attempted. Interestingly, rather than giving the benzo[1,4]oxazepine 14a−i, indole 15a−i was obtained as the sole product. Furthermore, it was observed that this reaction also worked at room temperature. The substrate scope of this reaction was quite general and the vinylogous carbonates 13a−d bearing acyclic or cyclic alkyl or aryl substituents gave corresponding indoles 15a−d in excellent yields (Scheme 4). The vinylogous carbonates 13e−i having electron-releasing and -withdrawing substituents on the aromatic Scheme 4. Serendipitous Formation of Indole 15 during Heck Cyclization of Iodo Aza-Tethered Vinylogous Carbonates 13
a Z/E ratio was determined on the crude reaction mixtures by 1H NMR. bBromo-vinylogous carbonate was used in the Heck reaction.
strategy was also extended to the synthesis of benzo[1,4]oxathiepines 5m−p. Initial reactions were carried out using bromo thia-tethered vinylogous carbonates 8m′−p′, and the benzo[1,4]oxathiepines 5m−p were obtained in moderate to good yield, respectively. It is pertinent to mention that iodo oxatethered vinylogous carbonate 8p gave the corresponding benzo[1,4]oxathiepines 5p in 87% yield suggesting that the lower yields in other cases are due to use of aryl bromides rather than the presence of sulfur. Not only oxygen and sulfur but even nitrogen containing benzo[1,4]oxazepines 5q−z could be easily 6137
DOI: 10.1021/acs.orglett.7b03016 Org. Lett. 2017, 19, 6136−6139
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Organic Letters
In order to expand the scope of the reaction and to gain access to saturated benzo[1,4]heterocycles potentially applicable in the total synthesis of abacopterin A−C natural products, dioxepine 5a was subjected to various reduction reactions (Scheme 7).
ring underwent cyclization uneventfully to provide functionalized indoles 15e−i, respectively, in excellent yields. The structures of indole 15a−i were determined from their spectral data, which were further unambiguously ascertained with the help of single crystal X-ray diffraction studies on one of the derivatives 15a. To understand the mechanism, the reaction of iodide 13a was carried out in the absence of Pd(OAc)2. No isomerization of carbonate to carbamate was observed, and unreacted 13a was recovered. The reaction carried out in the absence of Et3N gave indole 15a in only 5% yield. Based on these experiments, formation of the indole derivative 15 could be explained based on the mechanism proposed in Scheme 5. Initial reduction of the
Scheme 7. Functionalization of Dioxepine 5a
Scheme 5. Mechanism for the Formation of Indoles 15
When dioxepine 5a was subjected to hydrogenation using Pd/C in EtOAc, the product cis-18 was obtained in excellent yield and diastereoselectivity. Interestingly, trans-18 could also be accessed as the major diastereomer using ionic hydrogenation conditions (TMSOTf/Et3SiH).14 This was further confirmed by subjecting the keto alcohol 19 (obtained when the benzo[1,4]-dioxepine 5a underwent hydrolysis in CDCl3 or when the Heck reaction is subjected to acidic workup) to a reductive etherification reaction using TMSOTf/Et3SiH. These methods certainly offer advantage over conventional radical cyclization of iodo-vinylogous carbonate 8a using n-Bu3SnH and AIBN in refluxing benzene, which resulted in the formation of a diastereomeric mixture (1:1) of the benzo[1,4]dioxepine cis-18 and trans-18 in moderate yield. Finally, the key step was successfully used in the synthesis of the core skeleton of abacopterin A−C (1a−c), whose synthesis is hitherto unreported.1 Our synthesis began with base-catalyzed ring opening of 3,4,6-tri-O-benzyl-D-glucal epoxide (20) with oiodo phenol (16) to furnish the alcohol 21.15,16 Michael addition of the alcohol 21 to ethyl propiolate (7a) gave the iodovinylogous carbonates 22, whereas that to enynone (7b) yielded the vinylogous ester 23 in excellent yield. Finally, iodovinylogous carbonate 22 and vinylogous ester 23 when subjected to the intramolecular Heck reaction afforded the corresponding benzo[1,4]heterocycles 24 and 25, respectively, in moderate yield and excellent diastereoselectivity (Scheme 8). Benzo[1,4]heterocycles 24 and 25 bear the ABC core of the abacopterin A− C (1a−c). In conclusion, a general, stereoselective synthesis of benzo[1,4]hererocycles using a Pd-catalyzed intramolecular Heck reaction on vinylogous carbonate/carbamate/ester was developed. The method was found to be general, giving access to a variety of benzo[1,4]heterocycles in good yield and excellent diastereoselectivities. In the cases where nitrogen was unprotected, an unexpected Heck cascade cyclization resulted in the formation of the indole derivatives as a result of a mechanism involving interception of the carbopalladation step by nucleopalladation. The synthesis of the benzo[1,4]heterocycle can also be carried out in a “one-pot” manner starting from iodo-phenol using an epoxide ring opening− Michael addition−Heck reaction sequence. Finally, the developed method was successfully applied to the synthesis of the core of the natural products abacopterin A−C (1a−c).
Pd(II) acetate A to Pd(0) B is followed by its oxidative addition to the iodide 13 to give the intermediate C. The carbopalladation reaction on C is intercepted by unprotected nitrogen, which acts as a nucleophile generating the intermediate E via an aminopalladation reaction.13 This preference of amino-palladation vs carbopalladation is perhaps due to the fact that while the former proceeds through a five-membered transition state, the latter will have to go through a larger seven-membered transition state. Deprotonation of the ammonium ion derivative E with Et3N furnishes the complex F, which on reductive elimination results in the unstable aminal G. Et3N assisted retro-oxa-Michael on the aminal G provides the indole derivative 15. Since no β-hydride elimination is involved, the indole formation works even at room temperature. This three-step synthesis of benzo[1,4]heterocycles can also be carried out by one-pot sequential reactions. The o-iodophenol (16) was reacted with cyclohexeneoxide (17), which was followed by treatment with ethyl propiolate (7a) and DABCO. Without isolation of the products or any workup, Pd(OAc)2, PPh3, and Et3N were added to finally obtain the benzo[1,4]dioxepine derivative 5a in 66% yield over three steps (Scheme 6). Scheme 6. “One-Pot” Synthesis of Benzo[1,4]dioxepine 5a
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Organic Letters
(4) Fox, B. M.; Beck, H. P.; Roveto, P. M.; Kayser, F.; Cheng, Q.; Dou, H.; Williamson, T.; Treanor, J.; Liu, H.; Jin, L.; Xu, G.; Ma, J.; Wang, S.; Olson, S. H. J. Med. Chem. 2015, 58, 5256. (5) Selected recent examples: (a) Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2008, 73, 1979. (b) Dai, L.-Z.; Shi, M. Eur. J. Org. Chem. 2009, 2009, 3129. (c) Sakai, N.; Watanabe, A.; Ikeda, R.; Nakaike, Y.; Konakahara, T. Tetrahedron 2010, 66, 8837. (d) Nagarjuna Reddy, M.; Kumara Swamy, K. C. Org. Biomol. Chem. 2013, 11, 7350. (e) Ghorai, M. K.; Sahoo, A. K.; Bhattacharyya, A. J. Org. Chem. 2014, 79, 6468. (f) Yang, W.; Sun, J. Angew. Chem., Int. Ed. 2016, 55, 1868. (g) Zhao, J.-J.; Tang, M.; Zhang, H.-H.; Xu, M.-M.; Shi, F. Chem. Commun. 2016, 52, 5953. (h) Shahi, C. K.; Bhattacharyya, A.; Nanaji, Y.; Ghorai, M. K. J. Org. Chem. 2017, 82, 37. (i) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Chauhan, N.; Ghorai, M. K. Org. Lett. 2017, 19, 3438. (6) For a recent review of the Heck reaction, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (d) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062. (7) For Heck reaction on vinylogous carbonate/carbamates, see: (a) Kirschbaum, S.; Waldmann, H. Tetrahedron Lett. 1997, 38, 2829. (b) Fan, Y. C.; Kwon, O. Org. Lett. 2012, 14, 3264. (c) Gharpure, S. J.; Shelke, Y. G.; Reddy, S. R. B. RSC Adv. 2014, 4, 46962. (8) Meyer, A. G.; Bissember, A. C.; Hyland, C.; Smith, J. A.; Williams, C. C.; Zamani, Abel, S.-A. G. In Progress in Heterocyclic Chemistry; Gordon, W. G., John, A. J., Eds.; Elsevier: 2017; Vol. 29, p 579. (9) For reactions on vinylogous carbonate/carbamates, see: (a) Gharpure, S. J.; Nanda, L. N.; Shukla, M. K. Org. Lett. 2014, 16, 6424. (b) Gharpure, S. J.; Prasath, V.; Kumar, V. Chem. Commun. 2015, 51, 13623. For 1,4-heterocycles, see: (c) Gharpure, S. J.; Prasad, J. V. K. J. Org. Chem. 2011, 76, 10325. (d) Gharpure, S. J.; Sathiyanarayanan, A. M. Chem. Commun. 2011, 47, 3625. (e) Gharpure, S. J.; Prasad, J. V. K. Eur. J. Org. Chem. 2013, 2013, 2076. (f) Gharpure, S. J.; Anuradha, D.; Prasad, J. V. K.; Srinivasa Rao, P. Eur. J. Org. Chem. 2015, 2015, 86. (g) Gharpure, S. J.; Nanda, S. K. Org. Biomol. Chem. 2016, 14, 5586. (10) For ring opening reaction: (a) Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 2004, 3597. (b) Albanese, D.; Landini, D.; Lupi, V.; Penso, M.; Scaletti, D. J. Mol. Catal. A: Chem. 2008, 288, 28. (c) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923. (11) For reaction optimization, see Supporting Information. (12) CCDC 1576632−576638, 576640−576642 for compounds 5d, 5g, 5p, 5s, 5t−u and 5w, 10a, 15a, and cis-18′ contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (13) For a review on nucleopalladation, see: (a) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (b) Minatti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142. (c) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945. (d) Li, J.; Grubbs, R. H.; Stoltz, B. M. Org. Lett. 2016, 18, 5449. (e) Yin, G.; Mu, X.; Liu, G. Acc. Chem. Res. 2016, 49, 2413. (f) Backvall, J.-E. Acc. Chem. Res. 1983, 16, 335. (14) The stereochemistry of the dioxepine cis-18 was confirmed by single crystal X-ray diffraction studies on its derivative cis-18′; see Supporting Information. (15) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661. (b) Gordon, D. M.; Danishefsky, S. J. Carbohydr. Res. 1990, 206, 361. (16) Gervay, J.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5448.
Scheme 8. Synthesis of Core of Abacopterin A−C (1a−c)
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03016. Synthetic procedures and characterization data of products (PDF) Crystallographic data for 5d, 5g, 5p, 5s, 5t−u, 5w, 10a, 15a, and cis-18′ (ZIP)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Santosh J. Gharpure: 0000-0002-6653-7236 Dandela Anuradha: 0000-0003-4314-8059 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Council of Scientific and Industrial Research (CSIR), New Delhi, BRNS, Mumbai and SERB, New Delhi for financial support. We thank Mr. Darshan Mhatre of the X-ray facility of the Department of Chemistry, IIT Bombay for collecting the crystallographic data and IRCC, IIT Bombay for funding. We thank Ms. Pritha Verma, Department of Chemistry, IIT Bombay for her help in some substrate preparation. We are grateful to UGC, New Delhi for the award of research fellowship to D.A.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03016 Org. Lett. 2017, 19, 6136−6139
