DOI: 10.1002/chem.201406549
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Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza-Heterocycles Sabin Llona-Minguez,*[a] Matthieu Desroses,[a] Artin Ghassemian,[a] Sylvain A. Jacques,[a] Lars Eriksson,[b] Rebecka Isacksson,[a] Tobias Koolmeister,[a] Pl Stenmark,[c] Martin Scobie,[a] and Thomas Helleday[a] Abstract: A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitrohaloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug-like” molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic b-aminophosphonate motif.
Pyrrole-containing bicyclic systems such as indoles,[1] azaindoles,[2] and thienopyrroles[3] are privileged scaffolds in the medicinal chemistry literature (Figure 1). As part of a fragmentbased drug discovery effort, we were interested in expanding our existing fragment library with a diverse set of 3-substituted pyrrole-containing heterocyclic systems. 3-Substituted indoles, bearing aryl substituents in particular, have been the focus of intense research over the past decade, which has led to significant advances in synthetic methods. Transition-metal-catalyzed reactions using activated arene substrates, such as aryl halides or boronates, allow the direct and selective N1-, C2-, or C3-arylation of indoles,[4] although C3-regioselective arylation methods have not been reported for any other pyrrole-containing bicyclic core, which are often prepared in four synthetic steps from the 3-unsubstituted parent compounds.[5] The reductive cyclization of nitro-compounds by organic phosphites was first reported by Cadogan et al.[6] The proce-
Figure 1. Pharmacologically active compounds displaying 3-substituted pyrrole-containing bicyclic systems
dure has been applied in the preparation of a wide range of heterocyclic scaffolds, including carbazoles, indoles, indazoles, and triazoles,[7] and is of considerable interest to the synthetic community.[8] The true nature of the Cadogan reaction has not been elucidated, although a nitrene-based mechanism is generally accepted.[7, 9] The reductive cyclization of substituted ortho-nitro-vinylarenes, also known as the Cadogan–Sundberg indole synthesis, furnishes 2-substituted indole cores,[7] whereas unsubstituted ortho-nitro-vinylarenes lead to 3-substituted systems. This transformation has mainly been the subject of reductive N-heterocyclizations catalyzed by transition metals such as Pd,[10] Mo,[11] Sn,[12] Ru,[13] Rh,[14] and non-metals such as Se,[15] often requiring the presence of carbon monoxide. To our surprise, literature examples of phosphite-mediated deoxygenations of primary ortho-nitro-vinylarenes are rare, low-yielding, and the required vinyl intermediates are obtained from rather inconvenient synthetic routes (Scheme 1).[16] We reasoned that an improved synthetic route to these substrates was required to fully exploit the potential of this “extended” Cadogan–Sundberg reaction and allow the rapid generation of these interesting fragments. Vinyl-containing N-methyliminodiacetic acid boronate (MIDA) reagents have recently become commercially available,
[a] Dr. S. Llona-Minguez, Dr. M. Desroses, A. Ghassemian, Dr. S. A. Jacques, R. Isacksson, T. Koolmeister, Dr. M. Scobie, Prof. T. Helleday Science for Life Laboratory Division of Translational, Medicine & Chemical Biology Department of Medical Biochemistry & Biophysics Karolinska Institutet, Stockholm, 171 21 (Sweden) E-mail: [email protected] Homepage: http://www.helleday.org [b] Dr. L. Eriksson Department of Materials and Environmental Chemistry Stockholm University, Stockholm, 106 91 (Sweden) [c] Dr. P. Stenmark Department of Biochemistry and Biophysics Stockholm University, Stockholm, 106 91 (Sweden) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406549. Chem. Eur. J. 2015, 21, 1 – 6
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Scheme 1. Phosphite-mediated reductive cyclization of primary ortho-nitrovinylarenes.
allowing direct Pd-catalyzed vinylation reactions.[17] MIDA boronates are air- and chromatography-stable boronic acid surrogates,[18] compatible with a wide variety of reactions,[19] providing an improved alternative to unstable boron reagents. We envisioned that Pd-catalyzed vinylation of a wide range of ortho-nitro-haloarenes using this new class of building blocks, followed by a reductive cyclization, would give access to diverse pyrrole-containing pharmacophores (Scheme 1). To explore the feasibility of this synthetic approach, we first attempted synthesis of 3-phenyl-1H-indole 1 b (Scheme 2), a simple and odorless indole derivative. Initial investigations using 1-bromo-2-nitrobenzene as the model substrate showed that Pd(PPh3)4/K2CO3 in 1,4-dioxane/water is an effective system for the vinylation step, and no further method development was investigated. The reaction setup is rather simple, without the need of solvent degassing or inert atmosphere. The resulting ortho-nitro-vinylarene 1 a (Scheme 3) was then treated with P(OMe)3, P(OEt)3, or P(nBu)3 under conventional heating or microwave irradiation. Heating in neat P(OEt)3 at 180 8C delivered a clean, fast, and high-yielding conversion to 1 b, with no traces of ethylated or ethoxylated side-products. Encouraged by the initial results, we decided to apply the Suzuki protocol to generate a set of ortho-nitrovinyl derivatives, including diverse-substituted benzene (Scheme 3; 2 a to 13 a), pyridine (14 a, 15 a, 16 a, and 17 a), thiophene (18 a), pyrazole (19 a), imidazole (20 a and 21 a), benzimidazole (22 a), and quinoxaline (23 a) systems (Scheme 4). The protocol proved to be robust and consistently delivered fast and clean conversions across the set, irrespective of halide (Cl- for 7 a, 13 a, 15 a, 17 a, 18 a, 19 a, 20 a, 21 a, and 22 a;[20] Br- for the rest of the examples), neighboring functional groups (sulfone 12 a and sulfonamide 13 a were isolated in lower yields) or heterocyclic core with the exception of 3 a, where milder conditions were required for a satisfactory conversion (see Supporting Information, Suzuki–Miyaura coupling reaction conditions &
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Scheme 2. Cadogan–Sundberg cyclization: indoles. Reaction conditions: vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage values show isolated yields.
B, adapted from Burke et al.).[18] The resulting ortho-nitro-vinylarenes were subjected to the phosphite-mediated reductive cyclizations (Scheme 2). The nature of the substituent adjacent to the alkene moiety plays an important role in the nitrene insertion step as seen in 1 b, 2 b, and 3 b, which followed the reactivity order: Ph > Me > H. Electron-donating (6 b and 9 b) or -withdrawing substituents (7 b, 8 b, 11 b, 12 b, and 13 b) in the benzene did not influence the reaction efficiency, with the exception of methyl substitution ortho- to the nitro- (4 b) or the vinyl- (5 b) group, which required longer reaction times. It is worth noting that aniline 10 b rapidly decomposed to black tar upon heating in P(OEt)3. As expected by this broad functional group tolerance, the cyclization step was also applicable to the more complex and “drug-like” compound 13 b[20] (Scheme 2). The method also fared well with most heterocyclic cores (Scheme 5), with clean conversions by LC-MS analysis in general. Reaction speed was greatly decreased in the case of azaindole 14 b and pyrrolopyrazole 19 b, without significant formation of side-products after several hours of heating. In the case of pyridine 16 b, the reaction proceeded rapidly and longer reaction times led to the formation of a bis-alkylated side-product. Unfortunately, imidazole-containing substrates such as 20 b, 21 b, and 22 b rapidly decomposed, even after 5 min of heating in P(OEt)3. 2
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Scheme 4. Suzuki cross-coupling: heterocyclic core scope. Reaction conditions: haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K2CO3 (2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values show isolated yields.
Table 1. Optimization of the Cadogan–Sundberg reaction conditions. Entry Heating method 1 2 3 4 5
Scheme 3. Suzuki cross-coupling: MIDA boronate and functional group scope. Reaction conditions: Haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K2CO3 (2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values show isolated yields. [a] Reaction conditions: haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K3PO4 (7 equiv), and Pd(dppf)Cl2 .CH2Cl2 (0.1 equiv).
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1 b [%][a]
P(OEt)3 P(OMe)3 P(OEt)3 P(OMe)3 P(nBu)3
45 36 95 29 0
180 150 180 180 80
30 min 30 min 30 min 30 min 16 h
[a] Conversions were determined by LC-MS, based on area under the curve integration at 254 nm of 1 a vs. 1 b. [b] Vinyl arene (0.15 mmol), phosphite (0.5 mL). [c] See Genung et al.[8c]
The pyrrolopyrazole scaffold is a rare motif in the chemical literature,[21] and the substitution pattern present in 19 b (Scheme 5) has not been previously reported. Intrigued by this unusual 5–5 bicyclic system, we decided to confirm its structure by means of single-crystal X-ray diffraction. Careful re-crystallization of the trifluoroacetate salt of 19 b from ethanol allowed us to obtain material suitable for the study (Figure S3 in the Supporting Information). The crystals diffracted to 1 resolution and the electron density for 19 b was of very good quality (Figure S1 in the Supporting Information). 19 b crystallized in the space group P21 (Table 1 in the Supporting Information). The unit cell contained two molecules of 19 b and two molecules of trifluoroacetic acid (TFA) (Figure 2 b). Nitrogen N1 of 19 b is likely to be protonated and thereby positively charged with the negatively charged TFA molecule as counter ion. The crystal lattice was built up by a network of hydrogen bonds Chem. Eur. J. 2015, 21, 1 – 6
microwave heating[b] microwave heating[b] heating block[b] heating block[b] heating block[c]
Reducing agent Temp [8C] Time
between 19 b and TFA (S2 in the Supporting Information). 19 b was well-ordered and agreed with the expected chemical structure (Figure 2 a). The position of the three fluorine atoms of the TFA molecule was not clearly defined, as shown by their anisotropic ellipsoids (Figure 2 b). Unexpectedly, during the course of these investigations we discovered that allyl quinoxaline 24 a was cyclized to aminophosphonate 24 b (Scheme 6). Although the nature of this transformation has not been studied in detail, we suggest a plausible mechanism that involves insertion of nitrene A into the vicinal alkene bond to generate aziridine B,[22] followed by ring opening at the less sterically hindered end by a P(OEt)3 and a subsequent Arbuzov reaction (C, see Scheme 6). We are currently investigating the scope of this new reaction, and results will be reported in due course. 3
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Scheme 5. Cadogan–Sundberg cyclization: pyrrole-containing heterocycles. Reaction conditions: Vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage values show isolated yields.
ment library. Both synthetic steps follow a straight forward setup, are amenable to parallel synthesis, and have a broad functional-group tolerability/heterocyclic-core scope. Additionally, we have reported on the unusual formation of a cyclic baminophosphonate upon reductive cyclization of an orthonitro-allylarene.
Figure 2. A) Anisotropic ellipsoids representing the crystal structure of 19 b. B) The unit cell, containing two molecules of 19 b and two molecules of TFA.
In summary, we have developed a simple protocol to access diverse 3-substituted pyrrole-containing bicyclic systems: a robust vinylation reaction using commercially available MIDA boronates generates ortho-nitro-vinylarenes, which are subsequently cyclized under phosphite-mediated conditions to furnish the desired heterocyclic cores as part of an internal frag-
Experimental Section The Supporting Information contains experimental procedures, analytical data, copies of 1H and 13C NMR spectra for novel compounds, and X-ray crystal structure coordinates and data files for compound 19 b. CCDC 1038003 contains 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.
Acknowledgements
Scheme 6. Suggested mechanism for the formation of cyclic b-aminophosphonate 24 b from ortho-nitro-allylarene 24 a. Percentage values show isolated yields.
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We would like to acknowledge Dr. Cynthia Paulin and Dr. Olov Wallner for useful discussions on NMR spectroscopy, Dr. Pawel Baranczewski (UDOPP, Uppsala University) for HR-MS determina-
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Communication tions, the Laboratories for Chemical Biology at Karolinska Institutet (LCBKI) (http://www.cbcs.se/lcbki/) and ChemAxon (http://www.chemaxon.com) for technical support. We would also like to thank the Knut and Alice Wallenberg Foundation, Vinnova, the Swedish Research Council, Swedish Cancer Society, the Swedish Pain Relief Foundation, and the Torsten and Ragnar Sçderberg Foundation for funding.
[9] H. Majgier-Baranowska, J. D. Williams, B. Li, N. P. Peet, Tetrahedron Lett. 2012, 53, 4785 – 4788. [10] a) A. Kasahara, T. Izumi, S. Murakami, K. Miyamoto, T. Hino, J. Heterocycl. Chem. 1989, 26, 1405 – 1413; b) B. C. Sçderberg, S. R. Rector, S. N. O’Neil, Tetrahedron Lett. 1999, 40, 3657 – 3660. [11] P. B. Huleatt, J. Lau, S. Chua, Y. L. Tan, H. A. Duong, C. L. L. Chai, Tetrahedron Lett. 2011, 52, 1339 – 1342. [12] M. Akazome, T. Kondo, Y. Watanabe, Chem. Lett. 1992, 769 – 772. [13] C. Crotti, S. Cenini, B. Rindone, S. Tollari, F. Demartin, J. Chem. Soc. Chem. Commun. 1986, 784 – 786. [14] E. Ucciani, A. Bonfand, J. Chem. Soc. Chem. Commun. 1981, 82 – 83. [15] Y. Nishiyama, R. Maema, K. Ohno, M. Hirose, N. Sonoda, Tetrahedron Lett. 1999, 40, 5717 – 5720. [16] a) S. Gronowitz, I. Ander, Acta. Chem. Scand. Series B 1975, B29, 513 – 523; b) M. Somei, F. Yamada, C. Kaneko, Chem. Lett. 1978, 7, 1249 – 1250; c) B. Li, J. D. Williams, N. P. Peet, Tetrahedron Lett. 2013, 54, 3124 – 3126. [17] E. P. Gillis, M. D. Burke, Aldrichimica Acta 2009, 42, 17 – 27. [18] D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2009, 131, 6961 – 6963. [19] E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2008, 130, 14084 – 14085. [20] Clean conversion by LC-MS analysis of the crude reaction mixture, but low isolated yield, probably due to poor solubility in organic solvents. [21] a) F. Anizon, B. Pfeiffer, M. Prudhomme, Tetrahedron Lett. 2006, 47, 433 – 436; b) H. M. Ibrahim, S. Makhseed, R. M. Abdel-Motaleb, A.-M. AbdelSalam Makhlouf, M. H. Elnagdi, Heterocycles 2007, 71, 1951 – 1966; c) M. L. R. Heffernan, J. M. Dorsey, Q. K. Fang, R. J. Foglesong, S. C. Hopkins, M. L. Jones, S. W. Jones, C. O. Ogbu, J. B. Perales, M. Soukri, K. L. Spear, M. A. Varney (Sepracor Inc., USA) US20080058395A1, 2008, p. 111; d) T. Sparey, P. Abeywickrema, S. Almond, N. Brandon, N. Byrne, A. Campbell, P. H. Hutson, M. Jacobson, B. Jones, S. Munshi, D. Pascarella, A. Pike, G. S. Prasad, N. Sachs, M. Sakatis, V. Sardana, S. Venkatraman, M. B. Young, Bioorg. Med. Chem. Lett. 2008, 18, 3386 – 3391; e) W. M. Abdou, R. F. Barghash, M. S. Bekheit, Arch. Pharm. 2012, 345, 884 – 895; f) M. Nayak, H. Batchu, S. Batra, Tetrahedron Lett. 2012, 53, 4206 – 4208. [22] E. P. Farney, T. P. Yoon, Angew. Chem. Int. Ed. 2014, 53, 793 – 797; Angew. Chem. 2014, 126, 812 – 816.
Keywords: aminophosphonate · boronate · cyclization · heterocycles · MIDA · nitrene [1] T. I. Richardson, C. A. Clarke, K.-L. Yu, Y. K. Yee, T. J. Bleisch, J. E. Lopez, S. A. Jones, N. E. Hughes, B. S. Muehl, C. W. Lugar, T. L. Moore, P. K. Shetler, R. W. Zink, J. J. Osborne, C. Montrose-Rafizadeh, N. Patel, A. G. Geiser, R. J. S. Galvin, J. A. Dodge, ACS Med. Chem. Lett. 2011, 2, 148 – 153. [2] a) M. Hammond, D. G. Washburn, T. H. Hoang, S. Manns, J. S. Frazee, H. Nakamura, J. R. Patterson, W. Trizna, C. Wu, L. M. Azzarano, R. Nagilla, M. Nord, R. Trejo, M. S. Head, B. Zhao, A. M. Smallwood, K. Hightower, N. J. Laping, C. G. Schnackenberg, S. K. Thompson, Bioorg. Med. Chem. Lett. 2009, 19, 4441 – 4445; b) M. C. Bryan, J. R. Falsey, M. Frohn, A. Reichelt, G. Yao, M. D. Bartberger, J. M. Bailis, L. Zalameda, T. S. Miguel, E. M. Doherty, J. G. Allen, Bioorg. Med. Chem. Lett. 2013, 23, 2056 – 2060. [3] D. Bonafoux, A. Abibi, B. Bettencourt, A. Burchat, A. Ericsson, C. M. Harris, T. Kebede, M. Morytko, M. McPherson, G. Wallace, X. Wu, Bioorg. Med. Chem. Lett. 2011, 21, 1861 – 1864. [4] L. Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673 – 714. [5] F. Salituro, L. Farmer, R. Bethiel, E. Harrington, J. Green, J. Court, J. Come, D. Lauffer, A. Aronov, H. Binch, D. Boyall, J.-D. Charrier, S. Everitt, D. Fraysse, M. Mortimore, F. Pierard, D. Robinson (Vertex Pharmaceuticals Incorporated, USA) WO2005095400A1, 2005, p. 432. [6] J. I. G. Cadogan, M. Cameron-Wood, Proc. Chem. Soc. 1962, 361. [7] J. J. Li, E. J. Corey, Name Reactions in Heterocyclic Chemistry II, John Wiley & Sons, Hoboken, NJ, 2011. [8] a) J. Balog, Z. Riedl, G. Hajos, Tetrahedron Lett. 2013, 54, 5338 – 5340; b) R. A. Irgashev, A. A. Karmatsky, P. A. Slepukhin, G. L. Rusinov, V. N. Charushin, Tetrahedron Lett. 2013, 54, 5734 – 5738; c) N. E. Genung, L. Wei, G. E. Aspnes, Org. Lett. 2014, 16, 3114 – 3117.
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COMMUNICATION & Heterocycles S. Llona-Minguez,* M. Desroses, A. Ghassemian, S. A. Jacques, L. Eriksson, R. Isacksson, T. Koolmeister, P. Stenmark, M. Scobie, T. Helleday && – && Vinylic MIDA Boronates: New Building Blocks for the Synthesis of AzaHeterocycles
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Old dog, new tricks: A two-step synthesis of structurally diverse pyrrolecontaining bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” ni-
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trene insertion, resulting in a new pyrrole ring. This approach has a wide substrate tolerance and it is applicable in the preparation of more complex “druglike” molecules. Interestingly, an orthonitro-allylarene derivative furnished a cyclic b-aminophosphonate motif.
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Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza-Heterocycles Sabin Llona-Minguez,*[a] Matthieu Desroses,[a] Artin Ghassemian,[a] Sylvain A. Jacques,[a] Lars Eriksson,[b] Rebecka Isacksson,[a] Tobias Koolmeister,[a] Pl Stenmark,[c] Martin Scobie,[a] and Thomas Helleday[a] Abstract: A two-step synthesis of structurally diverse pyrrole-containing bicyclic systems is reported. ortho-Nitrohaloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug-like” molecules. Interestingly, an ortho-nitro-allylarene derivative furnished a cyclic b-aminophosphonate motif.
Pyrrole-containing bicyclic systems such as indoles,[1] azaindoles,[2] and thienopyrroles[3] are privileged scaffolds in the medicinal chemistry literature (Figure 1). As part of a fragmentbased drug discovery effort, we were interested in expanding our existing fragment library with a diverse set of 3-substituted pyrrole-containing heterocyclic systems. 3-Substituted indoles, bearing aryl substituents in particular, have been the focus of intense research over the past decade, which has led to significant advances in synthetic methods. Transition-metal-catalyzed reactions using activated arene substrates, such as aryl halides or boronates, allow the direct and selective N1-, C2-, or C3-arylation of indoles,[4] although C3-regioselective arylation methods have not been reported for any other pyrrole-containing bicyclic core, which are often prepared in four synthetic steps from the 3-unsubstituted parent compounds.[5] The reductive cyclization of nitro-compounds by organic phosphites was first reported by Cadogan et al.[6] The proce-
Figure 1. Pharmacologically active compounds displaying 3-substituted pyrrole-containing bicyclic systems
dure has been applied in the preparation of a wide range of heterocyclic scaffolds, including carbazoles, indoles, indazoles, and triazoles,[7] and is of considerable interest to the synthetic community.[8] The true nature of the Cadogan reaction has not been elucidated, although a nitrene-based mechanism is generally accepted.[7, 9] The reductive cyclization of substituted ortho-nitro-vinylarenes, also known as the Cadogan–Sundberg indole synthesis, furnishes 2-substituted indole cores,[7] whereas unsubstituted ortho-nitro-vinylarenes lead to 3-substituted systems. This transformation has mainly been the subject of reductive N-heterocyclizations catalyzed by transition metals such as Pd,[10] Mo,[11] Sn,[12] Ru,[13] Rh,[14] and non-metals such as Se,[15] often requiring the presence of carbon monoxide. To our surprise, literature examples of phosphite-mediated deoxygenations of primary ortho-nitro-vinylarenes are rare, low-yielding, and the required vinyl intermediates are obtained from rather inconvenient synthetic routes (Scheme 1).[16] We reasoned that an improved synthetic route to these substrates was required to fully exploit the potential of this “extended” Cadogan–Sundberg reaction and allow the rapid generation of these interesting fragments. Vinyl-containing N-methyliminodiacetic acid boronate (MIDA) reagents have recently become commercially available,
[a] Dr. S. Llona-Minguez, Dr. M. Desroses, A. Ghassemian, Dr. S. A. Jacques, R. Isacksson, T. Koolmeister, Dr. M. Scobie, Prof. T. Helleday Science for Life Laboratory Division of Translational, Medicine & Chemical Biology Department of Medical Biochemistry & Biophysics Karolinska Institutet, Stockholm, 171 21 (Sweden) E-mail: [email protected] Homepage: http://www.helleday.org [b] Dr. L. Eriksson Department of Materials and Environmental Chemistry Stockholm University, Stockholm, 106 91 (Sweden) [c] Dr. P. Stenmark Department of Biochemistry and Biophysics Stockholm University, Stockholm, 106 91 (Sweden) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406549. Chem. Eur. J. 2015, 21, 1 – 6
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Scheme 1. Phosphite-mediated reductive cyclization of primary ortho-nitrovinylarenes.
allowing direct Pd-catalyzed vinylation reactions.[17] MIDA boronates are air- and chromatography-stable boronic acid surrogates,[18] compatible with a wide variety of reactions,[19] providing an improved alternative to unstable boron reagents. We envisioned that Pd-catalyzed vinylation of a wide range of ortho-nitro-haloarenes using this new class of building blocks, followed by a reductive cyclization, would give access to diverse pyrrole-containing pharmacophores (Scheme 1). To explore the feasibility of this synthetic approach, we first attempted synthesis of 3-phenyl-1H-indole 1 b (Scheme 2), a simple and odorless indole derivative. Initial investigations using 1-bromo-2-nitrobenzene as the model substrate showed that Pd(PPh3)4/K2CO3 in 1,4-dioxane/water is an effective system for the vinylation step, and no further method development was investigated. The reaction setup is rather simple, without the need of solvent degassing or inert atmosphere. The resulting ortho-nitro-vinylarene 1 a (Scheme 3) was then treated with P(OMe)3, P(OEt)3, or P(nBu)3 under conventional heating or microwave irradiation. Heating in neat P(OEt)3 at 180 8C delivered a clean, fast, and high-yielding conversion to 1 b, with no traces of ethylated or ethoxylated side-products. Encouraged by the initial results, we decided to apply the Suzuki protocol to generate a set of ortho-nitrovinyl derivatives, including diverse-substituted benzene (Scheme 3; 2 a to 13 a), pyridine (14 a, 15 a, 16 a, and 17 a), thiophene (18 a), pyrazole (19 a), imidazole (20 a and 21 a), benzimidazole (22 a), and quinoxaline (23 a) systems (Scheme 4). The protocol proved to be robust and consistently delivered fast and clean conversions across the set, irrespective of halide (Cl- for 7 a, 13 a, 15 a, 17 a, 18 a, 19 a, 20 a, 21 a, and 22 a;[20] Br- for the rest of the examples), neighboring functional groups (sulfone 12 a and sulfonamide 13 a were isolated in lower yields) or heterocyclic core with the exception of 3 a, where milder conditions were required for a satisfactory conversion (see Supporting Information, Suzuki–Miyaura coupling reaction conditions &
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Scheme 2. Cadogan–Sundberg cyclization: indoles. Reaction conditions: vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage values show isolated yields.
B, adapted from Burke et al.).[18] The resulting ortho-nitro-vinylarenes were subjected to the phosphite-mediated reductive cyclizations (Scheme 2). The nature of the substituent adjacent to the alkene moiety plays an important role in the nitrene insertion step as seen in 1 b, 2 b, and 3 b, which followed the reactivity order: Ph > Me > H. Electron-donating (6 b and 9 b) or -withdrawing substituents (7 b, 8 b, 11 b, 12 b, and 13 b) in the benzene did not influence the reaction efficiency, with the exception of methyl substitution ortho- to the nitro- (4 b) or the vinyl- (5 b) group, which required longer reaction times. It is worth noting that aniline 10 b rapidly decomposed to black tar upon heating in P(OEt)3. As expected by this broad functional group tolerance, the cyclization step was also applicable to the more complex and “drug-like” compound 13 b[20] (Scheme 2). The method also fared well with most heterocyclic cores (Scheme 5), with clean conversions by LC-MS analysis in general. Reaction speed was greatly decreased in the case of azaindole 14 b and pyrrolopyrazole 19 b, without significant formation of side-products after several hours of heating. In the case of pyridine 16 b, the reaction proceeded rapidly and longer reaction times led to the formation of a bis-alkylated side-product. Unfortunately, imidazole-containing substrates such as 20 b, 21 b, and 22 b rapidly decomposed, even after 5 min of heating in P(OEt)3. 2
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Scheme 4. Suzuki cross-coupling: heterocyclic core scope. Reaction conditions: haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K2CO3 (2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values show isolated yields.
Table 1. Optimization of the Cadogan–Sundberg reaction conditions. Entry Heating method 1 2 3 4 5
Scheme 3. Suzuki cross-coupling: MIDA boronate and functional group scope. Reaction conditions: Haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K2CO3 (2 equiv), and Pd(PPh3)4 (0.1 equiv). Percentage values show isolated yields. [a] Reaction conditions: haloarene (0.3 mmol, 1 equiv), MIDA boronate (1.1 equiv), K3PO4 (7 equiv), and Pd(dppf)Cl2 .CH2Cl2 (0.1 equiv).
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1 b [%][a]
P(OEt)3 P(OMe)3 P(OEt)3 P(OMe)3 P(nBu)3
45 36 95 29 0
180 150 180 180 80
30 min 30 min 30 min 30 min 16 h
[a] Conversions were determined by LC-MS, based on area under the curve integration at 254 nm of 1 a vs. 1 b. [b] Vinyl arene (0.15 mmol), phosphite (0.5 mL). [c] See Genung et al.[8c]
The pyrrolopyrazole scaffold is a rare motif in the chemical literature,[21] and the substitution pattern present in 19 b (Scheme 5) has not been previously reported. Intrigued by this unusual 5–5 bicyclic system, we decided to confirm its structure by means of single-crystal X-ray diffraction. Careful re-crystallization of the trifluoroacetate salt of 19 b from ethanol allowed us to obtain material suitable for the study (Figure S3 in the Supporting Information). The crystals diffracted to 1 resolution and the electron density for 19 b was of very good quality (Figure S1 in the Supporting Information). 19 b crystallized in the space group P21 (Table 1 in the Supporting Information). The unit cell contained two molecules of 19 b and two molecules of trifluoroacetic acid (TFA) (Figure 2 b). Nitrogen N1 of 19 b is likely to be protonated and thereby positively charged with the negatively charged TFA molecule as counter ion. The crystal lattice was built up by a network of hydrogen bonds Chem. Eur. J. 2015, 21, 1 – 6
microwave heating[b] microwave heating[b] heating block[b] heating block[b] heating block[c]
Reducing agent Temp [8C] Time
between 19 b and TFA (S2 in the Supporting Information). 19 b was well-ordered and agreed with the expected chemical structure (Figure 2 a). The position of the three fluorine atoms of the TFA molecule was not clearly defined, as shown by their anisotropic ellipsoids (Figure 2 b). Unexpectedly, during the course of these investigations we discovered that allyl quinoxaline 24 a was cyclized to aminophosphonate 24 b (Scheme 6). Although the nature of this transformation has not been studied in detail, we suggest a plausible mechanism that involves insertion of nitrene A into the vicinal alkene bond to generate aziridine B,[22] followed by ring opening at the less sterically hindered end by a P(OEt)3 and a subsequent Arbuzov reaction (C, see Scheme 6). We are currently investigating the scope of this new reaction, and results will be reported in due course. 3
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Scheme 5. Cadogan–Sundberg cyclization: pyrrole-containing heterocycles. Reaction conditions: Vinyl arene (0.15 mmol), P(OEt)3 (0.5 mL). Percentage values show isolated yields.
ment library. Both synthetic steps follow a straight forward setup, are amenable to parallel synthesis, and have a broad functional-group tolerability/heterocyclic-core scope. Additionally, we have reported on the unusual formation of a cyclic baminophosphonate upon reductive cyclization of an orthonitro-allylarene.
Figure 2. A) Anisotropic ellipsoids representing the crystal structure of 19 b. B) The unit cell, containing two molecules of 19 b and two molecules of TFA.
In summary, we have developed a simple protocol to access diverse 3-substituted pyrrole-containing bicyclic systems: a robust vinylation reaction using commercially available MIDA boronates generates ortho-nitro-vinylarenes, which are subsequently cyclized under phosphite-mediated conditions to furnish the desired heterocyclic cores as part of an internal frag-
Experimental Section The Supporting Information contains experimental procedures, analytical data, copies of 1H and 13C NMR spectra for novel compounds, and X-ray crystal structure coordinates and data files for compound 19 b. CCDC 1038003 contains 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.
Acknowledgements
Scheme 6. Suggested mechanism for the formation of cyclic b-aminophosphonate 24 b from ortho-nitro-allylarene 24 a. Percentage values show isolated yields.
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We would like to acknowledge Dr. Cynthia Paulin and Dr. Olov Wallner for useful discussions on NMR spectroscopy, Dr. Pawel Baranczewski (UDOPP, Uppsala University) for HR-MS determina-
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Communication tions, the Laboratories for Chemical Biology at Karolinska Institutet (LCBKI) (http://www.cbcs.se/lcbki/) and ChemAxon (http://www.chemaxon.com) for technical support. We would also like to thank the Knut and Alice Wallenberg Foundation, Vinnova, the Swedish Research Council, Swedish Cancer Society, the Swedish Pain Relief Foundation, and the Torsten and Ragnar Sçderberg Foundation for funding.
[9] H. Majgier-Baranowska, J. D. Williams, B. Li, N. P. Peet, Tetrahedron Lett. 2012, 53, 4785 – 4788. [10] a) A. Kasahara, T. Izumi, S. Murakami, K. Miyamoto, T. Hino, J. Heterocycl. Chem. 1989, 26, 1405 – 1413; b) B. C. Sçderberg, S. R. Rector, S. N. O’Neil, Tetrahedron Lett. 1999, 40, 3657 – 3660. [11] P. B. Huleatt, J. Lau, S. Chua, Y. L. Tan, H. A. Duong, C. L. L. Chai, Tetrahedron Lett. 2011, 52, 1339 – 1342. [12] M. Akazome, T. Kondo, Y. Watanabe, Chem. Lett. 1992, 769 – 772. [13] C. Crotti, S. Cenini, B. Rindone, S. Tollari, F. Demartin, J. Chem. Soc. Chem. Commun. 1986, 784 – 786. [14] E. Ucciani, A. Bonfand, J. Chem. Soc. Chem. Commun. 1981, 82 – 83. [15] Y. Nishiyama, R. Maema, K. Ohno, M. Hirose, N. Sonoda, Tetrahedron Lett. 1999, 40, 5717 – 5720. [16] a) S. Gronowitz, I. Ander, Acta. Chem. Scand. Series B 1975, B29, 513 – 523; b) M. Somei, F. Yamada, C. Kaneko, Chem. Lett. 1978, 7, 1249 – 1250; c) B. Li, J. D. Williams, N. P. Peet, Tetrahedron Lett. 2013, 54, 3124 – 3126. [17] E. P. Gillis, M. D. Burke, Aldrichimica Acta 2009, 42, 17 – 27. [18] D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2009, 131, 6961 – 6963. [19] E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2008, 130, 14084 – 14085. [20] Clean conversion by LC-MS analysis of the crude reaction mixture, but low isolated yield, probably due to poor solubility in organic solvents. [21] a) F. Anizon, B. Pfeiffer, M. Prudhomme, Tetrahedron Lett. 2006, 47, 433 – 436; b) H. M. Ibrahim, S. Makhseed, R. M. Abdel-Motaleb, A.-M. AbdelSalam Makhlouf, M. H. Elnagdi, Heterocycles 2007, 71, 1951 – 1966; c) M. L. R. Heffernan, J. M. Dorsey, Q. K. Fang, R. J. Foglesong, S. C. Hopkins, M. L. Jones, S. W. Jones, C. O. Ogbu, J. B. Perales, M. Soukri, K. L. Spear, M. A. Varney (Sepracor Inc., USA) US20080058395A1, 2008, p. 111; d) T. Sparey, P. Abeywickrema, S. Almond, N. Brandon, N. Byrne, A. Campbell, P. H. Hutson, M. Jacobson, B. Jones, S. Munshi, D. Pascarella, A. Pike, G. S. Prasad, N. Sachs, M. Sakatis, V. Sardana, S. Venkatraman, M. B. Young, Bioorg. Med. Chem. Lett. 2008, 18, 3386 – 3391; e) W. M. Abdou, R. F. Barghash, M. S. Bekheit, Arch. Pharm. 2012, 345, 884 – 895; f) M. Nayak, H. Batchu, S. Batra, Tetrahedron Lett. 2012, 53, 4206 – 4208. [22] E. P. Farney, T. P. Yoon, Angew. Chem. Int. Ed. 2014, 53, 793 – 797; Angew. Chem. 2014, 126, 812 – 816.
Keywords: aminophosphonate · boronate · cyclization · heterocycles · MIDA · nitrene [1] T. I. Richardson, C. A. Clarke, K.-L. Yu, Y. K. Yee, T. J. Bleisch, J. E. Lopez, S. A. Jones, N. E. Hughes, B. S. Muehl, C. W. Lugar, T. L. Moore, P. K. Shetler, R. W. Zink, J. J. Osborne, C. Montrose-Rafizadeh, N. Patel, A. G. Geiser, R. J. S. Galvin, J. A. Dodge, ACS Med. Chem. Lett. 2011, 2, 148 – 153. [2] a) M. Hammond, D. G. Washburn, T. H. Hoang, S. Manns, J. S. Frazee, H. Nakamura, J. R. Patterson, W. Trizna, C. Wu, L. M. Azzarano, R. Nagilla, M. Nord, R. Trejo, M. S. Head, B. Zhao, A. M. Smallwood, K. Hightower, N. J. Laping, C. G. Schnackenberg, S. K. Thompson, Bioorg. Med. Chem. Lett. 2009, 19, 4441 – 4445; b) M. C. Bryan, J. R. Falsey, M. Frohn, A. Reichelt, G. Yao, M. D. Bartberger, J. M. Bailis, L. Zalameda, T. S. Miguel, E. M. Doherty, J. G. Allen, Bioorg. Med. Chem. Lett. 2013, 23, 2056 – 2060. [3] D. Bonafoux, A. Abibi, B. Bettencourt, A. Burchat, A. Ericsson, C. M. Harris, T. Kebede, M. Morytko, M. McPherson, G. Wallace, X. Wu, Bioorg. Med. Chem. Lett. 2011, 21, 1861 – 1864. [4] L. Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673 – 714. [5] F. Salituro, L. Farmer, R. Bethiel, E. Harrington, J. Green, J. Court, J. Come, D. Lauffer, A. Aronov, H. Binch, D. Boyall, J.-D. Charrier, S. Everitt, D. Fraysse, M. Mortimore, F. Pierard, D. Robinson (Vertex Pharmaceuticals Incorporated, USA) WO2005095400A1, 2005, p. 432. [6] J. I. G. Cadogan, M. Cameron-Wood, Proc. Chem. Soc. 1962, 361. [7] J. J. Li, E. J. Corey, Name Reactions in Heterocyclic Chemistry II, John Wiley & Sons, Hoboken, NJ, 2011. [8] a) J. Balog, Z. Riedl, G. Hajos, Tetrahedron Lett. 2013, 54, 5338 – 5340; b) R. A. Irgashev, A. A. Karmatsky, P. A. Slepukhin, G. L. Rusinov, V. N. Charushin, Tetrahedron Lett. 2013, 54, 5734 – 5738; c) N. E. Genung, L. Wei, G. E. Aspnes, Org. Lett. 2014, 16, 3114 – 3117.
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Received: December 18, 2014 Published online on && &&, 0000
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COMMUNICATION & Heterocycles S. Llona-Minguez,* M. Desroses, A. Ghassemian, S. A. Jacques, L. Eriksson, R. Isacksson, T. Koolmeister, P. Stenmark, M. Scobie, T. Helleday && – && Vinylic MIDA Boronates: New Building Blocks for the Synthesis of AzaHeterocycles
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Old dog, new tricks: A two-step synthesis of structurally diverse pyrrolecontaining bicyclic systems is reported. ortho-Nitro-haloarenes coupled with vinylic N-methyliminodiacetic acid (MIDA) boronates generate ortho-vinyl-nitroarenes, which undergo a “metal-free” ni-
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trene insertion, resulting in a new pyrrole ring. This approach has a wide substrate tolerance and it is applicable in the preparation of more complex “druglike” molecules. Interestingly, an orthonitro-allylarene derivative furnished a cyclic b-aminophosphonate motif.
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