Letter pubs.acs.org/OrgLett
Modular Route to Azaindanes Qi Huang* and Samir Z. Zard* Laboratoire de Synthèse Organique, CNRS UMR 7652 Ecole Polytechnique, Palaiseau 91128 Cedex, France S Supporting Information *
ABSTRACT: A convergent radical based route to azaindanes is described, relying on the degenerative addition transfer of various substituted S-(pyridylmethyl)-O-ethyl dithiocarbonates (xanthates) to functional alkenes followed by radical cyclization onto the pyridine ring activated by protonation with trifluoroacetic acid. In one case, a richly decorated cyclohepta[b]pyridine could be assembled swiftly by allowing the first adduct to N-phenylmaleimide to undergo addition to N-allylphthalimide prior to cyclization.
H
Scheme 1. Illustrations of the Two Main Routes to Azaindanes
eteroaromatics, and heterocycles in general, are key structural elements in a large proportion of medicinally relevant compounds.1 Devising practical and flexible routes to diverse new heterocyclic substances has been and remains a worthwhile endeavor. In this respect, the pyridine nucleus is a particularly important synthetic target. Yet, despite much effort, some pyridine derivatives have remained comparatively inaccessible. This is the case for azaindanes (cyclopentenopyridines), such as 1 and 2 (Figure 1). The first is an orally active,
traditional methods. Our route capitalizes on the ability of xanthates (dithiocarbonates) to mediate both inter- and intramolecular additions onto alkenes to create the cyclopentane portion of the azaindane.7 As outlined in Scheme 2,
Figure 1. Examples of biologically active azaindanes.
Scheme 2. Radical-Based Route to Azaindanes potent 5HT2c agonist and a promising candidate for the treatment of obesity.2 The second is a potent aldosterone synthase inhibitor belonging to a series of azaindanes and related cycloalkenylpyridine derivatives.3 Synthetic approaches to this class of compounds have relied hitherto on essentially two broad strategies, both of which hinge on the construction of the pyridine ring. The first, illustrated by the preparation of chloropyridine 5 via intermediates 3 and 4 (Scheme 1), has served to prepare azaindane 1.2,4 The second strategy exploits the cycloaddition of an azadiene, such as in the inverse electronic demand Kondrat’eva reaction; it is exemplified in Scheme 1 by the sequence 6 → 7 + 8 used to obtain azaindane 2.3,5 In either case, decoration of the cyclopentane portion is often accomplished later, usually via the pyridine N-oxides.6 Both of these approaches suffer from serious limitations in terms of scope and functional group tolerance, in view of the rather harsh reagents and experimental conditions required. We now report a completely different access to azaindanes that provides richly substituted structures inaccessible by © 2017 American Chemical Society
addition of S-pyridylmethyI xanthate 9 (W = N) to an alkene 10 proceeds via radicals 11 and 12 to give a new xanthate 13 (normally isolated).8 Further exposure to stoichiometric amounts of peroxide regenerates adduct radical 12 under conditions that favor ring closure onto the pyridine nucleus to give azaindane 16 after oxidation of intermediate radical 14 into the corresponding cation 15 by electron transfer to the peroxide. Received: June 13, 2017 Published: July 12, 2017 3895
DOI: 10.1021/acs.orglett.7b01772 Org. Lett. 2017, 19, 3895−3898
Letter
Organic Letters
chromatographic purification of the concentrated filtrate. The ability to isolate the product by filtration allowed us to prepare gram quantities of azaindane 20a (photo in Scheme 3) without the need for chromatography. A lower regioselectivity, but also a notably higher combined yield of isomeric azaindanes 20c and 21c, was observed starting with adduct 19c. These azaindanes contain a latent vicinal diamino motif.14 No prematurely reduced material 22c was found. The ring closure in this case is particularly favored by a polarity match between the moderate nucleophilic character of radical 23 and the electrophilic pyridine. Indeed, the cyclization in this instance was accomplished in the absence of TFA.15 Unfortunately, the vinylidene carbonate derived adduct 19d proved unstable to the presence of TFA, and cyclization in its absence proceeded poorly to give 20d along with unidentified products. Comparable results were obtained with open-chain alkene traps, as indicated by the examples collected in Scheme 4. The
While we have employed a conceptually related approach to fuse various aliphatic chains to arenes and heteroarenes, including pyridines,9 the synthesis of indanes (W = C) has so far proved problematic, in contrast to the structurally related indolines. Numerous indolines were readily prepared, but only very few indanes could be made, and the yields were erratic and generally modest.10 This difference may be traced to the significant difference in the strain inherent in both structures. N-Methylindoline, for example, is about 4 kcal/mol less strained than indane.11 Since the radical cyclization step (i.e., 12 to 14) is reversible, increased strain will disfavor the cyclized form in the case of the indane (W = C). Furthermore, the poor oxidizing power of the peroxide makes it incapable of draining rapidly the equilibrium toward the penultimate cation intermediate (i.e., 14 to 15; benzene series, W = C). In the present case, we hoped that the higher reactivity toward radicals of a pyridine as compared to a benzene ring would compensate for the increased strain and result in a more useful synthesis of azaindanes 16 (pyridine series, W = N). The radicophilicity of the pyridine ring could moreover be enhanced by protonation, as was shown many years ago by Minisci and co-workers.12 Finally, there is one additional considerable advantage related to the intermolecular addition of xanthate 9 to alkene 10, which proceeds with reasonable efficiency even on unactivated alkenes in the pyridine series, in contrast to benzyl xanthates which add only to activated, and preferably electrophilic, alkenes.13 We therefore prepared adducts 19a and 19b by the usual dilauroyl peroxide (DLP) mediated radical addition of xanthate 18a to N-phenyl- and N-ethylmaleimide, respectively (Scheme 3). The starting xanthate 18a is obtained by reaction of
Scheme 4. Extension to Open-Chain Alkene Partners
Scheme 3. First Examples of Azaindane Formation intermolecular addition step proceeded uneventfully and afforded the expected adducts 19e−k in variable but useful yields. The cyclization mediated by stoichiometric peroxide again furnished a mixture of the two isomeric azaindanes 20e− k and 21e−k with modest regioselectivity. Small amounts (5− 15%) of reduced noncyclized side products (not shown) were observed in all cases in the present study, except for the Nvinylphthalimide adduct 19i, which gave the highest combined yield of isomeric azaindanes 20i and 21i. Furthermore, while the addition/cyclization to allyl trimethylsilane (→19h → 20h and 21h) took place in the usual manner, the same sequence starting with vinyl trimethylsilane gave rise to the desilylated azaindanes 20l and 21l. This is the result of an acid induced proto-desilylation of intermediates 20k and 21k as pictured in the lower part of Scheme 4. We next replaced the chlorine atom with other substituents. Starting with xanthates 18b−f, and employing only two olefinic partners, N-vinyl- and N-allylphthalimide, the corresponding adducts 24a−e and 25a−e were prepared and subjected to the ring-closing conditions (Scheme 5). Whereas the intermolecular addition proceeded somewhat more efficiently with Nallylphthalimide (except for derivatives 24b,c), the cyclization leading to 26a−e and 27a−e was significantly better with adducts 24a−e derived from N-vinylphthalimide. This is presumably due to a better polarity matching between the radical and the electron poor pyridine ring. A geminal phthalimido group is modestly electron-donating, whereas a vicinal phthalimido group exerts an inductive electron-withdrawing effect, which is detrimental to the cyclization. Indeed, the yield of CF3-substituted azaindane 28b was particularly low, and no attempt was made to isolate the minor regioisomer 29b.
commercial chloride 17 with potassium O-ethyl xanthate.12 We were pleased to find that exposure of adducts 19a,b to stoichiometric DLP in refluxing DCE in the presence of 1.2 equiv of trifluoroacetic acid furnished a useful combined yield of the corresponding isomeric azaindanes 20a and 21a and 20b and 21b, in both cases accompanied by a small quantity of simply reduced noncyclized side-products 22a and 22b. There is, hence, a moderate preference for attack at the carbon adjacent to the nitrogen of the pyridine. Interestingly, both major products 20a and 20b were highly crystalline and precipitated directly from the reaction medium in coincidentally the same yield of 44%. Further amounts were isolated by 3896
DOI: 10.1021/acs.orglett.7b01772 Org. Lett. 2017, 19, 3895−3898
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Organic Letters Scheme 5. Variations on the Pyridine Substituents
Scheme 7. Further Variations on the Pyridine Substituents. Divergent Behavior between Ester and Cyano Groups
In the case of adduct 24a, the minor azaindane 27a could not be easily purified, and its yield was not determined. Placing the substituent on the 2-position of the pyridine ring, as in xanthate 30a, should lead to adducts that can cyclize in only one way (Scheme 6). Thus, adducts 31a−c to N-vinyl-
Scheme 5).17 The poor result with 35a is presumably also caused by a competing ipso attack at position 2 of the pyridine. An unusual extension of this work, which further underscores the versatility of xanthate chemistry, is displayed in Scheme 8. It
Scheme 6. Synthesis of Functional Cyclopenta[c]pyridines
Scheme 8. Modular Route to Functional Cyclohepta[b]pyridines
and N-allylphthalimide and N-phenylmaleimide underwent ring closure upon exposure to stoichiometric peroxide to provide the expected azaindanes 32a−c. The large difference in yield across the substituents evaluated again reflects the untoward effects of a polarity mismatch between the incipient radical and the electron-withdrawing pyridine nucleus. Methoxy- and methoxycarbonyl-substituted analogues 32d,e were prepared in the same way from precursors 31d,e (Scheme 7). However, we were initially surprised to find that cyanopyridine adduct 31f, itself obtained in good yield, gave rise to a complex mixture upon attempted cyclization. The most plausible cause is a faster closure of intermediate radical 33 onto the nitrile group leading to iminyl radical 34, which could then evolve into a myriad of unwanted products. This conjecture is supported by the normal behavior of the corresponding ester 31e. The nitrile and the carboxylate groups are similar in electron-withdrawing ability, but the latter is a very poor trap for radicals and does not compete with the desired cyclization. Trifluoromethylated adduct 31g afforded the corresponding azaindane 32g in modest yield, whereas a complex mixture was obtained from the fluoro-substituted analog 31h. This disappointing result is probably due to an ipso attack of the intermediate radical on the fluorine-bearing position.16 In the case of addition−cyclization using N-allylphthalimide and xanthates 30b,c,e,f, the ring closure was surprisingly more efficient with the trifluoromethyl than with the methoxy derivative, furnishing azaindanes 36a and 36b in 13% and 72% yield, respectively (cf. cyclization of 25b and 25e in
represents a new modular route to cyclohepta[b]pyridines that exploits the fact that cyclization to the pyridine ring is relatively sluggish in the absence of TFA and can be overtaken by an intermolecular addition to an alkene. Thus, the addition of xanthate 19a to N-allylphthalimide competes successfully against the ring closure to give adduct 37 instead of isomeric azaindanes 20a and 21a. Further exposure of the former to the peroxide in the presence of TFA now results in the formation of cyclohepta[c]pyiridine 38 as the major product in 60% yield and as a 1.4:1 mixture of epimers. The cyclohepta[c]pyiridine motif is found in several biologically active substances, most notably in BMS-846372, 39, a very potent and promising antimigraine drug.18 Except for specific cases where a suitably 3897
DOI: 10.1021/acs.orglett.7b01772 Org. Lett. 2017, 19, 3895−3898
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(4) (a) Prelog, V.; Szpilfogel, S. Helv. Chim. Acta 1945, 28, 1684. (b) Ishiguro, T.; Morita, Y.; Ikushima, K. Yakugaku Zasshi 1958, 78, 268. (c) Breitmaier, E.; Bayer, E. Tetrahedron Lett. 1970, 11, 3291. (d) Kusumi, T.; Yoneda, K.; Kakisawa, H. Synthesis 1979, 1979, 221. (5) (a) Kondrat’eva, G. Y. Khim. Nauka Prom-st 1957, 2, 666. (b) Boger, D. L. Chem. Rev. 1986, 86, 781. (c) Boger, D. L. Tetrahedron 1983, 39, 2869. (d) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (6) Beschke, H. Aldrichimica Acta 1978, 11, 13. (7) For reviews on the xanthate transfer, see: (a) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519. (b) Quiclet-Sire, B.; Zard, S. Top. Curr. Chem. 2006, 264, 201. (8) While the synthesis of 16 could, in principle, be accomplished in one pot, isolation of intermediate xanthate 13 simplifies the analysis of the reaction mixtures. (9) For a review of applications to the synthesis of heteroaromatics, see: El Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol. Chem. 2012, 10, 5707. (10) (a) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533. For a Mn(III)-based radical route to indanes, see: (b) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L.; Santi, R. J. Org. Chem. 1989, 54, 2713. For a discussion of the Mn(III) oxidation mechanism and the slowness of the ring-closure step to the aromatic ring, see: (c) Snider, B. B. Tetrahedron 2009, 65, 10738. For a recent general review on the synthesis of indanes and indenes, see: (d) Gabriele, B.; Mancuso, R.; Veltri, L. Chem. - Eur. J. 2016, 22, 5056. (11) Verevkin, S. P.; Emel’yanenko, V. N. J. Phys. Chem. A 2011, 115, 1992. (12) (a) Punta, C.; Minisci, F. Trends Het. Chem. 2008, 13, 1. (b) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27, 79. (c) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. (13) Ferjancic, Z.; Quiclet-Sire, B.; Zard, S. Z. Synthesis 2008, 2008, 2996. (14) Han, S.; Zard, S. Z. Org. Lett. 2014, 16, 5386. (15) We thank Dr S. Han for performing a preliminary experiment. (16) For examples of radical ipso attacks on fluorinated pyridines, see: (a) Laot, Y.; Petit, L.; Zard, S. Z. Org. Lett. 2010, 12, 3426. (b) Laot, Y.; Petit, L.; Tran, N. D. M.; Zard, S. Z. Aust. J. Chem. 2011, 64, 416. (c) Liu, Z.; Qin, L.; Zard, S. Z. Org. Lett. 2014, 16, 2704. (17) Blackmond and Baran have found that, for radical attacks on pyridines, an alkoxy group deactivates the meta position and an electron-withdrawing group at C2 deactivates position C6: O’hara, F.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2013, 135, 12122. (18) Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.; Gulianello, M.; Huang, Y.; Kostich, W.; Lentz, K. A.; Mercer, S. E.; Schartman, R.; Signor, L.; Browning, M.; Macor, J. E.; Dubowchik, G. M. ACS Med. Chem. Lett. 2012, 3, 337. (19) For recent examples, see: (a) Desai, L. V.; Hay, M. B.; Leahy, D. K.; Wei, C.; Fanfair, D.; Rosner, T.; Hsiao, Y. Tetrahedron 2013, 69, 5677. (b) Leahy, D. K.; Fan, Y.; Desai, L. V.; Chan, C.; Zhu, J.; Luo, G.; Chen, L.; Hanson, R. L.; Sugiyama, M.; Rosner, T.; Cuniere, N.; Guo, Z.; Hsiao, Y.; Gao, Q. Org. Lett. 2012, 14, 4938. (c) Yoshizumi, T.; Ohno, A.; Tsujita, T.; Takahashi, H.; Okamoto, O.; Hayakawa, I.; Kigoshi, H. Synthesis 2009, 2009, 1153. (20) For recent examples, see: (a) Pan, B.; Liu, B.; Yue, E.; Liu, Q.; Yang, X.; Wang, Z.; Sun, W.-H. ACS Catal. 2016, 6, 1247. (b) Wu, K.; Huang, Z.; Liu, C.; Zhang, H.; Lei, A. Chem. Commun. 2015, 51, 2286. (c) Srimani, D.; Ben-David, Y.; Milstein, D. Chem. Commun. 2013, 49, 6632.
substituted pyridine is readily available and allows construction of the adjoining cycloheptane,19 most approaches rely on building the pyridine ring starting from a cycloheptanone.20 We uncovered one limitation to cyclohepta[c]pyiridines when we attempted to close adduct 40 derived from addition of xanthate 19i to N-phenylmaleimide. A complex mixture was obtained, caused apparently by a competing 1,5-hydrogen atom translocation converting intermediate radical 41 into useless radical 42, in preference to the desired cyclization to tricyclic product 43. This internal abstraction of a benzylic-type hydrogen is geometrically disfavored in the case of xanthate 37 because of the trans disposition of the two chains across the rigid five-membered ring platform. In summary, we have described an expedient, modular approach to azaindanes that complements more traditional routes. Many functional groups are tolerated, especially polar functional motifs generally incompatible with ionic or organometallic methods. The strategic ability of the xanthate transfer process to mediate the successive formation of more than one carbon−carbon bonds is indeed unique and allows easy access to richly decorated azaindanes and, in some cases, cyclohepta[b]pyridines, that should be of interest to medicinal chemists.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01772. Experimental procedures, full spectroscopic data, and copies of 1H and 13C NMR for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
* E-mail:
[email protected]. * E-mail:
[email protected]. ORCID
Samir Z. Zard: 0000-0002-5456-910X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Ecole Polytechnique for a scholarship to Q.H. and Mr. Shiwei Ren (Ecole Polytechnique) for technical assistance. DEDICATION This article is affectionately dedicated to Dr. Tarek S. Mansour, formerly of Wyeth-Ayerst. REFERENCES
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DOI: 10.1021/acs.orglett.7b01772 Org. Lett. 2017, 19, 3895−3898
