See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/236681527 ChemInform Abstract: Fast and Convenient Base-Mediated Synthesis of 3-Substituted Quinolines. Article in Tetrahedron Letters · April 2009 DOI: 10.1016/j.tetlet.2008.10.132 CITATIONS READS 22 77 3 authors, including: Pascal Van Der Voort Francis Verpoort 266 PUBLICATIONS 4,581 CITATIONS 252 PUBLICATIONS 5,042 CITATIONS Ghent University SEE PROFILE Ghent University SEE PROFILE Some of the authors of this publication are also working on these related projects: Conversion of CO2 into fine chemicals and fuel; MOFs for catalysis and gas separation; development of organometallic catalyst for water oxidation ; olefin metathesis View project All content following this page was uploaded by Pascal Van Der Voort on 03 January 2014. The user has requested enhancement of the downloaded file. Tetrahedron Letters 50 (2009) 201–203 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Fast and convenient base-mediated synthesis of 3-substituted quinolines Hans Vander Mierde *, Pascal Van Der Voort, Francis Verpoort * Centre for Ordered Materials, Organometallics and Catalysis, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281—S3, Ghent 9000, Belgium a r t i c l e i n f o a b s t r a c t Article history: Received 29 September 2008 Revised 21 October 2008 Accepted 24 October 2008 Available online 31 October 2008 In a convenient method, 3-substituted quinolines are readily synthesized in a two-step process with initial oxazine formation and subsequent base-mediated cyclization. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Quinoline Oxidation Cyclization Ring-chain tautomerism Oxazine Compounds containing a quinoline framework exhibit a wide variety of pharmacological and biological activities.1 During the last few decades, conventional named methods for their synthesis have been replaced by more efficient organometal-catalyzed approaches.2 Our previous reports had surveyed a rutheniumcatalyzed modification of the Friedländer method in which 2aminobenzylalcohol (1) is oxidatively cyclized with ketones in the presence of a base,3 affording 2-substituted or 2,3-substituted quinolines (Scheme 1a). Recent investigations revealed that this coupling reaction also takes place in the presence of only a strong base without an expensive transition metal catalyst.4 Theoretically, the use of aldehydes instead of ketones should afford 3-substituted quinolines (Scheme 1b), but instead, a complex mixture of unwanted side-products was obtained, mostly as a result of the self-aldol reaction of the aldehyde. A report by Cho and Shim confirmed the difficulties in this approach.5 They presented a step-by-step method, with an initial treatment of 1 in the presence of RuCl2(PPh3)3 and KOH in dioxane for 15 h, followed by the addition of the aldehyde and by stirring for an additional 5 h. Even after long reaction times, only moderate quinoline yields ranging from 34% to 67% were reported. We now present a new fast and convenient method for the synthesis of 3-substituted quinolines in excellent yields. The general reaction mechanism is outlined in Scheme 2. In a two-step procedure, first 1 is reacted with an aldehyde to form the 2-alkyl-2,4-dihydro-1H-benzo[d][1,3]oxazine 2. This O 1 + H (a) R O - H2O 2 ring-chain tautomerism OH a NH2 R R' base N OH benzophenone + H R base (c) oxidation R [Ru] O 1 R N R' 1 b (b) R [Ru] O + R N H diphenylmethanol N R Scheme 1. (a) Synthesis of 2- or 2,3-substituted quinolines from 1 and ketones; (b) Synthesis of 3-substituted quinolines from 1 and aldehydes. N * Corresponding authors. Tel.: +32 9 2644436; fax: +32 9 2644983 (H.V.M). E-mail addresses: Hans.VanderMierde@UGent.be (H. V. Mierde), Francis.Verpoort@ UGent.Be (F. Verpoort). 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.10.132 O R - H2O (e) N strong base O (d) N 3 Scheme 2. General reaction mechanism. R 202 H. V. Mierde et al. / Tetrahedron Letters 50 (2009) 201–203 Table 1 Optimization processa Addition of 4, KOtBu and benzophenone % Yield Entry Sieves 1 (mmol) Aldehydeb (mmol) KOtBu (mmol) Benzophenone (mmol) % Yield 3gc 1 2 3 4 5 6 7 + + + 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2.0 1.0 1.0 1.0 1.0 1.0 2.0 2.0 2.0 1.0 2.0 2.0 KOH, 2.0 — — 1.0 1.0 1.0 1.5 1.0 15 31 44 66 46 44 6 100 80 1 60 2 3 2' 40 3' a Reaction conditions: (i) 1 and aldehyde in 3 ml 1,4-dioxane, 1 h, 80 °C; (ii) 4, base and benzophenone, 1 h, 80 °C. b 3-Phenylbutyraldehyde. c Determined by GC with dodecane as internal standard. 20 Time /min 0 0 oxazine is at equilibrium with the corresponding imine via a ringchain tautomerism that has been well studied and described by others.6 Upon addition of (H2IMes)(PCy3)Cl2Ru = CHPh (4), the second generation Grubbs catalyst, the benzylic alcohol of the imine is oxidized to an aldehyde. The strong base abstracts a proton of the a-carbon next to the imine, and an intramolecular aldol-type cyclocondensation then affords the 3-substituted quinoline 3. In our initial experiments, 2 equiv of aldehyde were used: one equivalent for the reaction with 1 and the other as hydrogen acceptor in the hydrogen transfer reaction. However, only low quinoline yields of 16–40% were obtained and self-aldol products from the aldehyde were found. This self-aldol reaction lowers the amount of necessary hydrogen acceptor, lowering the final quinoline yield as a consequence. Furthermore, 1 was present at the end of the reaction, even though it was completely consumed in the initial oxazine formation (verified by GC). Possibly 2 is decomposed again by water in the reaction mixture. Therefore, an optimization 30 60 90 120 150 180 210 Figure 1. Progression of the reaction with butanal as the aldehyde. process was performed, and the most important results are summarized in Table 1. To eliminate the presence of water, several experiments were carried out with molecular sieves, but with no beneficial effect (entry 3 vs entry 5). Apparently, the presence of water in the reaction mixture is not a major issue, but rather the self-aldol reaction poses the biggest problem. Without an additional hydrogen acceptor (entry 1), the reaction does hardly proceed at all, and the use of a second equivalent of the aldehyde seriously limits the yield because of the aldol side reaction (entry 2). Benzophenone is found to be the ideal ‘inert’ hydrogen acceptor that does not undergo self-condensation, nor cross aldol-reactions with the aldehyde. Equimolar amounts of reagents produced the best results (entry Table 2 Synthesis of 3-substituted quinolines from 1 and aldehydesa Entry Aldehyde 1 O Oxazine Quinoline % Yield [Ru] % Yieldb MPVO 94 97 95 >99 >99 >99 (92) >99 >99 84 78 (73) 85 95 71 98 O 2 O 3 O 2a N H C3H 7 C6H13 3a N O C3H7 2b N H 3b N O C6H13 2c N H 3c N O 4 O N H O N H 2d 3d N O 5 O 6 2e 3e N O 2f N H 3f N O 7 O a N H 2g 3g N Reaction conditions: (i) 1 (1.0 mmol) and aldehyde (1.0 mmol) in 3 ml 1,4-dioxane, 1 h, 80 °C; (ii) 4 and/or KOtBu (1.2 mmol) and benzophenone (1.1 mmol), 2 h, 80 °C. Yields determined by GC with dodecane as internal standard. b Isolated yields of selected compounds in parentheses. H. V. Mierde et al. / Tetrahedron Letters 50 (2009) 201–203 4). The reaction proceeds much slower, when the weaker base KOH is used instead of KOtBu (entry 7). Figure 1 shows the progression of the reaction. The formation of 2 proceeds smoothly, but the conversion to 3 quickly slows down after the addition of 4, KOtBu and benzophenone. This is probably caused by the reaction of KOtBu with water that is released during the reaction (Scheme 1, step e). The resulting KOH is a weaker base, and as a consequence, the reaction continues at a slower rate. When slightly higher amounts of KOtBu and benzophenone were used, the reaction was completed faster, as shown by the filled shape curves 20 and 30 in Figure 1. A further increase in the amount of KOtBu had no additional effect. A variety of aldehydes were subjected to this reaction, and the results are presented in Table 2.7,8 In this ruthenium-catalyzed procedure, good to excellent quinoline yields were achieved for all aldehydes, although the presence of an aromatic ring resulted in lower yields (Table 2, entries 5–7). Recently, we have found that the oxidation reaction can also be mediated by only a strong base such as KOtBu, without the presence of a ruthenium catalyst.4 This oxidation process presumably follows the Meerwein-PonndorfVerley-Oppenauer mechanism (MPVO). The same reactions were performed with only KOtBu, and nearly quantitative quinoline yields were obtained for all aldehydes except phenylacetaldehyde. In conclusion, we have developed a fast and convenient basemediated method that affords 3-substituted quinolines in excellent yields. In a two-step procedure, first, 2-aminobenzylalcohol is reacted with an aldehyde to form an oxazine. Subsequent addition of KOtBu and benzophenone then results in a MPVO oxidation and aldol-type cyclization reaction affording the quinoline. References and notes 1. (a) Gildchrist, T. L. Heterocyclic Chemistry, 1st ed.; Pitman Publishing LTD: London, 1985; (b) Joshi, A. A.; Narkhede, S. S.; Viswanathan, C. L. Bioorg. Med. Chem. Lett. 2005, 15, 73–76; (c) Roma, G.; Di Braccio, M.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000, 35, 1021–1035; (d) Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A.; Ramesh, C.; Harakishore, K.; Gangadasu, B.; Murthy, U. S. N.; Rao, V. J. Bioorg. Med. Chem. 2006, 14, 4600–4609; (e) Martirosyan, A. R.; Rahim-Bata, R.; Freeman, A. B.; Clarke, C. D.; Howard, R. L.; Strobl, J. S. Biochem. Pharmacol. 2004, 68, 1729–1738; (f) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.; Zilberstein, A. J. Med. Chem. 1994, 37, 2129–2137. 2. (a) Jacob, J.; Jones, W. D. J. Org. Chem. 2003, 68, 3563–3568; (b) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem. 2006, 691, 5109–5121; (c) Taguchi, K.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539–4542; (d) Cho, C. S.; Kim, B. T.; Kim, T. J.; Shim, S. C. Chem. Commun. 2001, 2576–2577; (e) Martinez, R.; Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2007, 1599–1605; (f) Martinez, R.; Ramon, D. J.; Yus, M. Tetrahedron 2006, 62, 8988–9001; (g) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873–6877; (h) Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710–2711; (i) Cho, C. S.; Ren, W. X. J. Organomet. Chem. 2007, 692, 4182–4186. 3. (a) Vander Mierde, H.; Van Der Voort, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625–1631; (b) Vander Mierde, H.; Ledoux, N.; Allaert, B.; Van Der Voort, P.; Drozdzak, R.; De Vos, D.; Verpoort, F. New J. Chem. 2007, 31, 1572– 1574. 4. Vander Mierde, H.; Van Der Voort, P.; Verpoort, F. Tetrahedron Lett., in press. doi:10.1016/j.tetlet.2008.09.103 5. Cho, C. S.; Ren, W. X.; Shim, S. C. Bull. Korean Chem. Soc. 2005, 26, 2038–2040. 6. Fulop, F.; Pihlaja, K.; Mattinen, J.; Bernath, G. J. Org. Chem. 1987, 52, 3821–3825. View publication stats 203 7. General experimental procedure for the base-mediated process: Compound 1 (0.1232 g, 1.0 mmol), aldehyde (1.0 mmol) and dodecane (0.0426 g, 0.25 mmol) were dissolved in 3 ml of 1,4-dioxane and were stirred at 80 °C for 1 h. Then, benzophenone (0.2004 g, 1.1 mmol) and KOtBu (0.1347 g, 1.2 mmol) were added, and the solution was allowed to react for 2 h at 80 °C. 30 ll of the solution was passed through a short silica gel column (ethyl acetate) to remove inorganic salts, and the resulting solution was analyzed by GC to determine the yield. Dodecane was used as internal standard. All quinolines were isolated and purified by an acidic/basic extraction as described previously.3a Isolated yields were typically 5–10% lower than GC yields. 8. The oxazines and quinolines were characterized by 1H and 13C NMR spectroscopy on a Varian Unity 300 spectrometer: 2-propyl-2,4-dihydro-1Hbenzo[d][1,3]oxazine (2a): 1H NMR (300 MHz; CDCl3) d 7.06 (t, 1H), 6.90 (d, 1H), 6.80 (t, 1H), 6.67 (d, 1H), 4.93 (d, 1H), 4.80 (d, 1H), 4.54 (t, 1H), 1.70 (m, 2H), 1.54 (m, 2H), 0.98 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.8, 127.6, 125.2, 122.9, 119.9, 117.5, 84.4, 67.9, 37.5, 18.1, 14.2; 2-butyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2b). 1H NMR (300 MHz; CDCl3) d 7.06 (t, 1H), 6.90 (d, 1H), 6.79 (t, 1H), 6.66 (d, 1H), 4.93 (d, 1H), 4.80 (d, 1H), 4.53 (t, 1H), 1.72 (m, 2H), 1.50 (m, 2H), 1.39 (m, 2H), 0.94 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.8, 127.6, 125.2, 122.8, 119.9, 117.5, 84.6, 67.9, 35.1, 26.9, 22.8, 14.2; 2-heptyl-2,4-dihydro-1Hbenzo[d][1,3]oxazine (2c). 1H NMR (300 MHz; CDCl3) d 7.05 (t, 1H), 6.90 (d, 1H), 6.78 (t, 1H), 6.65 (d, 1H), 4.93 (d, 1H), 4.79 (d, 1H), 4.52 (t, 1H), 1.72 (m, 2H), 1.50 (m, 2H), 1.35-1.20 (m, 8H), 0.89 (t, 3H); 13C NMR (75 MHz; CDCl3) d 141.9, 127.6, 125.2, 122.8, 119.9, 117.5, 84.7, 67.9, 35.4, 32.0, 29.7, 29.4, 24.8, 22.9, 14.3; 2-isobutyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2d). 1H NMR (300 MHz; CDCl3) d 7.09 (t, 1H), 6.93 (d, 1H), 6.83 (t, 1H), 6.69 (d, 1H), 4.96 (d, 1H), 4.82 (d, 1H), 4.61 (t, 1H), 1.94 (m, 1H), 1.71 (m, 1H), 1.54 (m, 1H), 1.01 (d, 6H); 13C NMR (75 MHz; CDCl3) d 141.8, 127.6, 125.3, 123.0, 120.0, 117.7, 83.4, 67.9, 44.4, 24.5, 23.3, 22.9; 2-benzyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2e). 1H NMR (300 MHz; CDCl3) d 7.40–7.15 (m, 5H), 7.01 (t, 1H), 6.86 (d, 1H), 6.75 (t, 1H), 6.56 (d, 1H), 4.90 (d, 1H), 4.79 (d, 1H), 4.57 (t, 1H), 3.10 (d, 1H), 2.94 (d, 1H); 13C NMR (75 MHz; CDCl3) d 141.8, 136.3, 129.9, 129.0, 128.4, 127.6, 127.2, 125.2, 122.9, 119.9, 117.2, 84.7, 67.9, 41.8; 2-phenethyl-2,4-dihydro-1H-benzo[d][1,3]oxazine (2f). 1H NMR (300 MHz; CDCl3) d.30–7.09 (m, 5H), 7.04 (t, 1H), 6.88 (d, 1H), 6.78 (t, 1H), 6.62 (d, 1H), 4.85 (d+d, 2H), 4.51 (t, 1H), 2.92–2.75 (m, 2H), 2.02 (m, 2H); 13 C NMR (75 MHz; CDCl3) d 141.8, 128.9 (2 C), 128.8 (2 C), 127.7, 126.6, 126.4, 125.3, 122.9, 120.1, 117.6, 83.9, 67.9, 36.9, 31.0; 2-(2-phenylpropyl)-2,4-dihydro1H-benzo[d][1,3]oxazine (2g). 1H NMR (300 MHz; CDCl3) d 7.29–7.18 (m, 5H), 7.02 (t, 1H), 6.84 (d, 1H), 6.77 (t, 1H), 6.68 (d, 1H), 4.79 (m, 2H), 4.23 (t, 1H), 3.09 (m, 1H), 2.12–1.90 (m, 2H), 1.31 (d, 3H); 13C NMR (75 MHz; CDCl3) d 146.5, 141.9, 128.8 (2 C), 127.5, 127.3 (2 C), 126.6, 125.2, 123.0, 120.0, 117.6, 83.2, 67.8, 43.9, 36.2, 23.1; 3-Ethylquinoline (3a). Pale yellow oil; 1H NMR (300 MHz; CDCl3) d 8.79 (s, 1H), 8.07 (d, 1H), 7.92 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 2.85 (q, 2H), 1.36 (t, 3H); 13C NMR (75 MHz; CDCl3) d 152.1, 146.9, 136.9, 133.6, 129.4, 128.7, 128.5, 127.5, 126.8, 26.5, 15.5; 3-Propylquinoline (3b). Pale yellow oil; 1H NMR (300 MHz; CDCl3) d 8.76 (s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.75 (d, 1H), 7.64 (t, 1H), 7.49 (t, 1H), 2.75 (t, 2H), 1.72 (m, 2H), 0.98 (m, 3H); 13C NMR (75 MHz; CDCl3) d 152.3, 146.9, 135.4, 134.5, 129.3, 128.8, 128.4, 127.6, 126.8, 35.5, 24.5, 13.9; 3-Hexylquinoline (3c). Pale yellow oil; 1H NMR (300 MHz; CDCl3) d 8.77 (s, 1H), 8.08 (d, 1H), 7.92 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.52 (t, 1H), 2.78 (t, 2H), 1.70 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H); 13C NMR (75 MHz; CDCl3) d 152.0, 146.5, 135.7, 129.3, 128.9, 128.5, 127.5, 126.9, 33.4, 31.9, 29.1, 22.8, 14.3; 3-Isopropylquinoline (3d). Pale yellow oil; 1H NMR (300 MHz; CDCl3) d 8.82 (s, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 3.13 (m, 1H), 1.36 (m, 6H); 13C NMR (75 MHz; CDCl3) d 151.2, 146.9, 141.4, 132.3, 129.1, 128.8, 128.5, 127.7, 126.8, 32.1, 23.9; 3-Phenylquinoline (3e). Pale yellow solid; 1H NMR (300 MHz; CDCl3) d 9.17 (s, 1H), 8.24 (s, 1H), 8.14 (d, 1H), 7.83 (d, 1H), 7.71–7.66 (m, 3H), 7.56–7.47 (m, 3H), 7.42 (d, 1H); 13C NMR (75 MHz; CDCl3) d 150.2, 147.6, 138.1, 134.0, 133.3, 129.6, 129.5, 129.4, 128.6, 128.4, 128.3, 127.7, 127.2; 3-Benzylquinoline (3f). Light brown oil; 1H NMR (300 MHz; CDCl3) d 8.81 (s, 1H), 8.07 (d, 1H), 7.87 (s, 1H), 7.72 (d, 1H), 7.65 (t, 1H), 7.50 (t, 1H), 7.34–7.21 (m, 5H), 4.15 (s, 2H); 13C NMR (75 MHz; CDCl3) d 152.4, 147.1, 139.9, 135.1, 134.1, 129.4, 129.2, 129.1, 129.0, 128.6, 127.7, 127.0, 126.8, 39.5; 3-(1-phenylethyl)quinoline (3g). Light brown solid; 1H NMR (300 MHz; CDCl3) d 8.80 (s, 1H), 8.07 (d, 1H), 7.93 (s, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.51 (t, 1H), 7.33– 7.20 (m, 5H), 4.36 (q, 1H), 1.75 (d, 3H); 13C NMR (75 MHz; CDCl3) d 152.0, 146.9, 145.1, 139.2, 133.4, 129.2, 129.1, 128.9, 128.3, 127.9, 127.8, 126.9, 126.8, 42.8, 21.9.