DOI: 10.1002/ejoc.200701001

A Ruthenium-Catalyzed Approach to the Friedländer Quinoline Synthesis
Hans Vander Mierde,[a] Pascal Van Der Voort,[a] Dirk De Vos,[b] and Francis Verpoort*[a]
Keywords: Nitrogen heterocycles / Ruthenium / Oxidative cyclization / Friedländer reaction
In a modification of the Friedländer reaction, 2-aminobenzyl alcohol is oxidatively cyclized with a variety of ketones to yield substituted quinolines. Of all the ruthenium catalysts that were tested for this reaction, the second-generation Grubbs’ catalyst gives the highest quinoline yield, in combination with KOtBu as a base. The presence of a hydrogen acceptor is required to regenerate the catalyst. Also the reaction mechanism is discussed, and the results show that there are possibly two different pathways towards quinolines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The synthesis of nitrogen-containing heterocycles, such as quinoline, is the subject of extensive research in organic chemistry, because the quinoline scaffold is present in many biologically active compounds. Applications of quinolines in medicinal chemistry include the use as antimalarial,[1,2] antiinflammatory,[3] antiasthmatic,[4] antibacterial,[5] antihypertensive[6] and tyrosine kinase inhibitory agents.[7] Quinoline based polymers are currently investigated for applications as thermally stable transparent materials in the fields of electronics, optoelectronics and nonlinear optics.[8,9] Many traditional methods, such as the Skraup, Doebner– von Miller, Conrad–Limpach, and Pfitzinger syntheses, suffer from harsh reaction conditions, low stereoselectivity or consist of multiple steps, resulting in low overall yields, limiting their applicability.[1] The Friendländer method is generally considered to be the most versatile method of synthesis although its full potential is inhibited due to the use of unstable aminobenzaldehydes. Besides these conventional named reactions, several organometal-catalyzed approaches have recently been developed for the synthesis of the quinoline nucleus. Ruthenium complexes catalyze the reaction of aniline with allyl alcohols,[10] triallylamines,[11] allylammonium chlorides[11] and even alkylamines.[12] Substituted quinolines were synthesized by Arisawa, Theeraladanon et al. via ring closing metathesis of α,ω-dienes derived from 2-isopropenylaniline.[13–15] Other researchers reported the use of Pd,[16–19] Ni,[20] Rh,[21,22] and Co[23,24] complexes for transition-metal
[a] Centre for Ordered Materials, Organometallics and Catalysis, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 (S3), 9000 Ghent, Belgium Fax: +32-9-2644983 E-mail: Francis.Verpoort@UGent.be [b] Centre for Surface Chemistry and Catalysis, K. U. Leuven, Kasteelpark Arenberg 23, 3001 Heverlee Leuven, Belgium
Eur. J. Org. Chem. 2008, 1625–1631

mediated quinoline synthesis. A modified Friedländer protocol (Scheme 1) has been developed by Cho and coworkers.[25]

Scheme 1. The modified Friedländer quinoline synthesis.

Instead of using the unstable 2-aminobenzaldehyde as a starting product it is generated in situ via a catalytic transfer hydrogenation reaction, involving the oxidation of 2aminobenzyl alcohol. RuCl2(=CHPh)(PCy3)2, commonly known as the first-generation Grubbs’ catalyst, was reported to be the best catalyst for this reaction.[25] Other metal complexes that have been successfully employed for the modified Friedländer reaction include CuCl2/O2,[26] Pd/ C,[27] RuCl2(DMSO)4,[28–31] IrCl3 and [IrCl(cod)]2.[32] Given our experience in ruthenium-based catalysis, this remarkable activity for hydrogen transfer reactions of the first-generation Grubbs’ catalyst prompted us to further investigate the potential of similar ruthenium complexes. Here we present a comprehensive overview of our results.

Results and Discussion
In a previous communication,[33] we have compared several ruthenium complexes based on the first and second generation Grubbs’ catalyst and the ruthenium dimer [RuCl2(p-cymene)]2 8 (Figure 1) for the reaction between 2aminobenzyl alcohol (1) and acetophenone (2a, R1 = Ph, R2 = H) which was chosen as a model reaction. The most important results are summarized in Table 1. Although the ruthenium dimer precursor 8 was ineffective, the inclusion of a phosphane ligand (complexes 9a and 9b) proved to be

© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

the presence of at least one phosphane ligand is required to achieve good yields. Complex 5 reaches full conversion after 60 minutes.32] When large pellets are used. Yields determined by GC. so it can undergo a cross-aldol reaction with 2-aminobenzaldehyde [see steps (a).eurjoc. 1626 www. Even more remarkable is the relatively low conversion achieved with 6 while it is similar to 5 in structure. respectively. KOH is used by most other researchers and although KOH is insoluble in dioxane. when the phosphane ligand in 9a or 9b is replaced by an NHC ligand.[33] Based on the conclusions of our previous report. decreased the quinoline yield. catalyst (0. it is revealed that the yields after one hour are not necessarily final yields. This is probably caused by the increased solubility. making it more suitable to stabilize the [RuH2] species with a presumably higher oxidation state compared to the original catalyst. Ruthenium-catalyzed synthesis of quinolines from 1 and acetophenone (2a. De Vos.01 mmol) and KOH (1 mmol) in dioxane (3 mL) at 80 °C for 1 h. R2 = H). The catalysts are still active after one hour of reaction.[a] Entry 1 2 3 4 5 6 7 8 9 Catalyst 4 5 6 7 8 9a 9b 10 11 % Yield 74 100 53 32 15 40 53 14 26 When the reaction is monitored over time (Figure 2). From the results in Table 2. Catalysts tested for the modified Friedländer synthesis. 2a (2 mmol). this not only results in a higher yield.01 mmol) and KOH (1 mmol) in dioxane (3 mL) at 80 °C. Verpoort Figure 1. Org. F. Eur.FULL PAPER H. Variation of the NHC ligand through replacement of one mesityl group by aliphatic groups.31. The role of the base is to abstract an α-proton of the ketone. the conversion after one hour is only 8 % but this can be increased to 67 % with KOH powder. such as methyl or cyclohexyl. Replacing the benzylidene ligand of 4 with a bulkier indenylidene ligand in complex 7 decreases the conversion. Weinheim . It is remarkable that. [a] Reaction conditions: 1 (1 mmol). Monitoring of the reaction over time with different Ru complexes. 2a (2 mmol). it is seldomly specified under which conditions it is added. KOH was added as a 4  solution in methanol (1 mmol. for all experiments in this manuscript. Unless otherwise stated. the conversion does not further increase but drops to 26 %. Typically. 4 after 90 minutes and also 9a and 9b eventually reach full conversion after 6 and 5 hours. The replacement of a phosphane ligand by an N-heterocyclic carbene (NHC) ligand clearly improved catalytic activity.O-bidentate Schiff base ligand in complex 10 did not improve the catalytic activity. Chem. it is also much more practical. We have shown that catalyst 5 was superior to 4. catalyst (0. 7 and 11) was screened for the modified Friedländer reaction. As an added advantage. The pKa value of the α-proton is approximately 16 for 2a. J. This might be attributed to the higher σdonating ability of the NHC ligand. 250 µL). KGaA. R1 = Ph. a series of new complexes (6. An even higher conversion of 74 % is achieved when KOH is added as a 4  solution in methanol. it becomes clear that not only the catalyst determines the reaction rate. Reaction conditions: 1 (1 mmol). Table 1.org Figure 2. The conversion increased from 15 % to 53 % for 9b. resulting in 100 % conversion for 5 after 1 hour compared to 74 % for 4. 1625–1631 © 2008 Wiley-VCH Verlag GmbH & Co. D. P. We are currently unable to explain this peculiar behaviour but apparently. whereas the use of an N. in complex 11. (b) and (c) in Scheme 2].[25. Vander Mierde. beneficial. Van Der Voort. also the base is important. 2008.

comparable to KOH. is achieved. Sodium ethoxide (entry 6) has approximately the same base strength as NaOH.9 17. Grubbs et al. surprising that a cation change from potassium to sodium leads to such a big difference. entry 10) have the advantage of being readily soluble in dioxane. Weinheim 1627 .4. This may be explained by the smaller size of the sodium cation. has a higher basic strength. Proposed reaction mechanism. It is.01 mmol) and base (1 mmol. 2a (2 mmol).[34. 2008. KOtBu. but only 27 % quinoline yield is obtained.eurjoc. [c] in THF. KGaA. an equimolar ratio of base and 1 gives the best results. as can be deducted from entries 3.4 mmol KOH (4  in MeOH) 2. which is reflected in the higher quinoline yield (entry 7). 2a (2 mmol). J. mately 26. Yields determined by GC. however.7 15.[a] Entry 1 2 3 4 5 6 7 8 9 10 11 12 Base (1 mmol) KOH (pellets) KOH (powder) KOH (4  in MeOH) NaOH (powder) NaOH (4  in MeOH) NaOEt (powder) KOtBu (powder) LiHMDS (0.7 15. Both bases have a non-nucleophilic character.6 12. 4 (0. 11 and 12.8 15.8-diazabicyclo[5.0 ≈26[c] 10. Reaction conditions: 1 (1 mmol).35] Organic bases such as triethylamine (entry 9) or 1. either as powder (entry 4) or as a 4  solution in MeOH (entry 5). yet a higher yield. Chem. but maybe LiHMDS is too aggressive and deactivates the catalyst. www. Table 2. Not only the basic strength is important. A higher concentration of base does not further improve the yield. 1625–1631 Figure 3. a different catalytic center may be formed. have also shown the exchange of the chloride ligands with the tert-butoxy group. [b] pKa values of the protonated form of the base. resulting in a lower solubility. as is evidenced by entry 8.7 15. Figure 3 The yield is substantially lower when NaOH is used. catalyst 4 or 5 (0. which implies that. the higher solubility of NaOEt because of the aliphatic ethyl group can explain these results. Influence of the base on quinoline synthesis with 4. Org.0 mmol KOH (4  in MeOH) pKa[b] 15. Lithium bis(trimethylsilyl)amide (LiHMDS) has a pKa of approxiEur.7 15.5  in toluene) Triethylamine DBU 0. Again.7 % Yield 8 64 74 38 48 74 98 27 0 0 67 73 [a] Reaction conditions: 1 (1 mmol). when KOtBu is used. except for entries 11 and 12) in dioxane (3 mL) at 80 °C for 1 h. KOtBu. Although the proton abstraction is base-catalyzed.01 mmol) and base (1 mmol) in dioxane (3 mL) at 80 °C.0]undec-7-ene (DBU.A Ru-Catalyzed Approach to Friedländer’s Quinoline Synthesis Scheme 2. Another common base.7 15. but their low basicity prevents them from being effective bases for this reaction. KOH vs.org © 2008 Wiley-VCH Verlag GmbH & Co.7 15.

1625–1631 . De Vos. Yields determined by GC. With KOH. Van Der Voort. showing the potential of this catalytic system. The calculation of the turn-over frequency (TOF) at the beginning of the reaction (after the first 5 minutes). a problem that is avoided with symmetric ketones (entries 12 and 13). fully quantifies the difference between the catalytical systems. 2 (2 mmol).0 respectively for 4 and 5.FULL PAPER illustrates the effect of the base even better.[33] [c] Isolated yield: 65 %. 1 was treated with a variety of ketones in the presence of 4 and 5 and both KOH and KOtBu were used as base. meaning a TON as high as 8500 was achieved. Verpoort To assess the scope of the modified Friedländer reaction.0 and 17. D.01 mmol) and base (1 mmol) in dioxane (3 mL) at 80 °C for 1 h. KGaA. it is obvious that the second generation outperforms the first generation Grubbs’ catalyst. H. A catalyst loading of 0. 1628 www.7 min–1 (measured after 20 min because of the observed induction period). For almost all ketone substrates. From these results. The results are shown in Table 3. Chem. a maximum yield of 85 % is observed after 5 h. With a catalyst loading of 0. full conversion is reached already after 20 minutes. Vander Mierde. The ratio of 3i/3j and 3k/3l is the same for 4 and 5 as can be expected since the only action of the catalyst is the oxidation of 1 (this is not entirely true.01 %. Ruthenium-catalyzed synthesis of quinolines from 1 and ketones. [d] Isolated yield: 94 %. as will be explained in the discussion of Table 3. The stronger base KOtBu gives better results than KOH for almost all ketones. Entries 9 and 10 illustrate that a mixture of two quinolines is formed when two α-protons are available in an asymmetric ketone. 2008. compared to 60 minutes for KOH. while that of 5 is twice as large (3. The only two exceptions are acetone (entry 8) and 1-indanone (entry 14) were KOH is the preferred base in combination with 5. [e] Value in parentheses is the yield of 3-butyl-2methylquinoline (3j). F. a higher quinoline yield was obtained for 5 compared to 4.1 % still results in full conversion within 1 h. J. With KOtBu and 5.8 min–1). The reaction is inhibited by substrates with strong electron withdrawing groups like NO2 (entry 7). The determination of the turn-over number (TON) for the model reaction of 1 with 2a in the presence of KOtBu and 5 was carried out by lowering the catalyst concentration and measuring the maximum yield. Using KOtBu the TOF increases spectacularly to 14.eurjoc. [b] From ref. Org. complex 4 has a TOF of 1. Weinheim Eur. [f] Value in parentheses is the yield of 2-ethyl-3-propylquinoline (3l). catalyst (0.org © 2008 Wiley-VCH Verlag GmbH & Co. P.[a] [a] Reaction conditions: 1 (1 mmol).

which means that the double bond of chalcone is hydrogenated by the [RuH2] complex. With 3heptanone the difference is less pronounced (3 vs. however. as with a 1:1 ratio. the order of steps (a) and (f) could be reversed. J. This is. resulting in the regeneration of the catalyst.g. followed by the catalytic oxidation and cross aldol reaction. There is however a small but notable difference between KOH and KOtBu. With 1 equivalent of benzophenone (compared to 1). was less effective and the use of nitrobenzene resulted in unwanted side-products. With 2-heptanone. instead of 2 equivalents (Table 4). Org. An other common hydrogen acceptor. a maximum yield of 71 % is achieved. Compound 15 is then hydrogenated by a [RuH2] species. 2. but also one peak which in many cases almost completely overlapped with the ketone peak. [c] No quinoline was formed. in contradiction with the previous statement of catalyst regeneration. Under basic conditions. Eur.9 for KOtBu. a basecatalyzed H2O elimination of 14 results in the trans enone 15. first a condensation reaction between the amine and the ketone to form an imine. not observed. The GC spectra did not only show unreacted starting products 1 and 2 and the quinoline. A plausible reaction mechanism for the modified Friedländer synthesis is presented in Scheme 2. shown in steps (d)–(g). is found when benzyl alcohol is reacted with acetophenone in dioxane in the presence of 4 and KOH (Scheme 3). meaning there is a higher selectivity with KOH. full conversion is reached after 70 minutes. 1. This role can also be fulfilled by another hydrogen acceptor. regenerating the catalyst in the process. Step (j) shows how the catalyst is regenerated by a hydrogen transfer reaction in which ketone 2 is reduced to the alcohol 2Ј. benzophenone. Ru-catalyzed coupling between benzyl alcohol and acetophenone. When the reaction is carried out without hydrogen acceptor. The cis product is not likely to be formed due to steric hindrance. but not exclusively and not to a major extent. To exclude the possibility of [Ru]-catalyzed imine formation. The ketone peak has completely disappeared on the GC spectrum and a new peak of the alcohol has appeared. Chem. Effect of a hydrogen acceptor on quinoline synthesis. Table 4. 2b (1 mmol). The reaction of 1 with 2a in basic media did not lead to imines.6). Proof that the conversion of 15 to 16 occurs. Similar coupling reactions have been performed by Cho et al. the aldol product 14 can cyclize via imine condensation (“imination”) and subsequent H2O elimination in step (i) leads to the quinoline.eurjoc.2 for KOH and 2. This is. two equivalents of ketone were used to perform the reaction: one equivalent for the reaction and the other equivalent as a hydrogen acceptor for the regeneration of the catalyst. but again. Yields determined by GC. KGaA. and it were in fact these findings that led them to the modified Friedländer method.A Ru-Catalyzed Approach to Friedländer’s Quinoline Synthesis the reaction mechanism). Imine condensation and subsequent dehydrogenation lead to the desired quinoline 3. In step (h). Weinheim www. is slightly counterproductive. 2008. however. the aldehyde and the ketone undergo a cross aldol reaction to form 14 in steps (b) and (c). in step (a). the ratio of 3i/3j is 4. When the reaction is carried out with KOH powder in the absence of methanol. First. In an alternative pathway. Exactly for this reason. Theoretically. 1-dodecene. 5 (0. 1625–1631 © 2008 Wiley-VCH Verlag GmbH & Co.01 mmol) and KOH (1 mmol) in dioxane (3 mL) at 80 °C for 1 h. accounting for approximately 0.36. This alcohol is the result of hydrogenation of the ketone by the [RuH2] complex. Instead of the expected chalcone 19. albeit in slightly smaller quantities. The interested Scheme 3.[25. 1 is oxidized to 2-aminobenzaldehyde (12) by the ruthenium catalyst that is hydrogenated to a hydrido-ruthenium complex. This peak was identified as the alcohol equivalent 2Ј of the ketone 2.30 mmol. is indicated in parentheses.50 mmol of the alcohol and a maximum yield of only 50 % is to be expected. the alcohol 2Ј is still formed. but no quinoline.org 1629 . This means that there must be an alternative pathway that allows for catalyst regeneration. i.e. 3-phenylpropiophenone 20 is formed. but the GC spectrum showed many other unidentified compounds. e. achieved after 90 minutes.37] One could argue that also the oxidation of methanol to formaldehyde could be the reason of the reduction of ketone 2.[a] Entry 1 2 3 4 5 6 7 Additive – benzophenone (1 mmol) benzophenone (2 mmol) nitrobenzene (1 mmol) nitrobenzene (2 mmol) 1-dodecene (1 mmol) 1-dodecene (2 mmol) % Yield[b] 51 (71) 91 (100) 83 (100) 0[c] 0[c] 52 72 [a] Reaction conditions: 1 (1 mmol). representing a second method to regenerate the catalyst. The use of other hydrogen acceptors was examined by using only one equivalent of the ketone 2b vs. no imines were formed. [b] The value of the maximum yield. Increasing the amount of benzophenone to 2 equivalents. This means that methanol oxidation certainly contributes to the formation of 2Ј. 0. aniline was treated with 2a in the presence of 4 under standard reaction conditions used for the experiments.

The aqueous phase was extracted with CH2Cl2 (2 ϫ 15 mL) and after evaporation of the combined CH2Cl2 phases.4 mL.01 (m. 4. 6. 1.2. 21 %. 100 % dimethyl polysiloxane.6. N-CH).25.98 (m. 1 H). 7. N 7. General Procedure for Quinoline Synthesis: A mixture of 1 (1 mmol).16 (s. N 5.8.48 (s. Vander Mierde.70 (m.2. 118. C14H17N (199. we have shown that the first and second generation Grubbs’ catalysts are efficient catalysts for the oxidative cyclization of 2-aminobenzyl alcohol with a variety of ketones. 1H NMR (300 MHz. 83. J.0.0 ppm. 5 (Aldrich).1. (b) formation of the thallium salt of the Schiff base.01 (m.25 (t. 10 H.82 (d. 3 H) ppm.23.53 mmol) in 1 mL THF at room temperature.2. Experimental Section All synthetic procedures were performed under argon atmosphere on a vacuum line using standard Shlenck techniques. 134. 2. 70 %).0. 1 H). found C 81.2.5. 1 H). CDCl3. 126. SB aryl H). Solvents were dried and distilled prior to use.85. 2.6. H 6. dealing with the mechanism of the Friedländer synthesis.01 mmol) in 3 mL of 1. 2 (2 mmol. 127. 47 mmol) were dissolved in 25 mL THF. 80.71 (m. 1.3. Aldrich).25 (m.75.81 (s. 22. 13C NMR (300 MHz. arom. C16H13NO (235. p-cymene CH(CH3)2].13 (m.95. (c) A solution of [RuCl2(p-cymene)]2 8 (1.60 (m. 25 °C): δ = 13.0. 1H NMR (300 MHz. 1 H. 3. 2008. 7. 3. 7. 5 mL/ min).70 (m. affording the Schiff base as a viscous yellow oil in good yields (6.4.5. 2.83 (t. but an extra equivalent of ketone also works perfectly. 1 H. helium carrier gas. 1 H).09. 1 H). 2-(4-Methoxyphenyl)quinoline (3e): Pale yellow oil. 124. 8 (Aldrich) and all other chemicals were obtained from commercial sources and used as received. 123. 1 H. arom. 121. The procedure is analogous to that of similar Ru–Schiff base complexes previously published by our group. 3. 5. 1 H).52 (m.6. 1 H. 129.30 (d. Ethyl acetate for column chromatography was of Rotisolv® Pestilyse® quality (Roth). arom. 2. 34. F. 2 H). 102. (b) The Schiff base (0.FULL PAPER reader can find an excellent article by Muchowski and Maddox. 82.43] and our data was in accordance with those results. 7.80 [m. N 5. 120. N 2.7.20 (d.[35] 9a+b.[42] (a) Cyclohexylamine (5. The red band containing the catalyst was collected and the solvent volume was reduced to 1 mL. 25 °C): δ = 8.5. unless otherwise stated).90–7. 145. 22. C 84. which was filtered and suspended in an aqueous 1  NaOH solution (15 mL).08 g. found C 58. 1H and 13C NMR spectra were recorded on a Varian Unity-300 Spectrometer. 25 °C): δ = 161.2.2094 g. Upon addition of hexane (10 mL). The synthesis of 10 is achieved in three steps: (a) synthesis of the Schiff base (SB).eurjoc. 1625–1631 Conclusions In summary.66 Eur.0.15 [both d. 132. 67.2. Weinheim . H 5. C23H30ClNORu (473. 111. 129.7. Compounds 6.9. 56 %. 30.3. C 58. 0. 1 H. 1 H.9.7. ar-CH3). 2 H). 125. Aldrich) was placed in a 7 mL screw-capped vial and allowed to react at 80 °C for 1 h. P.9. 127.97 (m.76 mmol) in 25 mL THF was added to the Schiff base (SB) thallium salt and 1630 www. 2. 117. 130.01): calcd. A sacrificial hydrogen acceptor is required for the regeneration of the catalyst. 1H NMR (300 MHz. 25. 3f–j.5 (2 C). 114. 25 °C): δ = 8. The solvent was evaporated and the resulting product was dissolved again in a minimal amount of ethyl acetate. Chem. 157. CDCl3. 7.40. 1 H.4-dioxane (AldraSORBTM. 7.80–1. Org. 3 H. 35. After 1 h.60.42 (m. Compounds 4 (Aldrich).84. 1 H). 3.5 (2 C). 134. in combination with KOtBu as base. 161.46 (d. Verpoort the mixture was stirred at room temperature. 1 H. KOH: 250 µL of a 4  solution in MeOH. To isolate the quinoline.40] and 11[41] were prepared according to literature procedures. CDCl3.7. 135.3. H). 128. H 8.50– 1.4.3. a red precipitation formed.4. 6. other bases in their original form) and Ru catalyst (0. p-cymene aryl H). CDCl3. CDCl3. C 81. After filtration. D. the solvent was evaporated in vacuo. 18.5. 7. H 6. 0. 35. CH=N). 127. 10 H. 7. p-cymene aryl H). base (1 mmol. p-cymene aryl H).6 ppm. 70 %). A TON as high as 8500 was observed. CDCl3. 25 °C): δ = 7. N 6.7 g. then cooled down to room temperature and dried on MgSO4. The solution was allowed to reflux at 60 °C for 4 h.39. 25 °C): δ = 8.72 g.org © 2008 Wiley-VCH Verlag GmbH & Co.5. cyclohexyl H) ppm. 1 H. 1 H. 126.3. 2 H). After 4 h. 7.76 (m. 1. Merck). 7.80 (m. H).96 (d. 1 H).76 (s. 131.3. 1:4). the resulting solution was concentrated and passed through a second silica gel column (ethyl acetate/hexane mixture. found C 84.44 (m. 2-Ethyl-3-propylquinoline (3l): Pale yellow oil. Benzophenone is a fine choice. The reported quinoline yields were determined by GC. 2. 1 H). arom. OH). CDCl3. 7. SB aryl H). N 2. mmol) was treated with thallium(I) ethoxide (250 µL. 6. 76. 7 (Umicore).9. the solvent was evaporated under reduced pressure and the crude product was used in the next step without further purification.92 (d. Spectroscopic data of 3a–d. SB aryl H). 2-Butyl-3-methylquinoline (3k): Pale yellow oil. CDCl3. 13C NMR (300 MHz.96. 5.07 (d. 7. 130.3.25 µm film thickness. CDCl3.15 (t.7.60. cyclohexyl H).8. Van Der Voort. 1 H). 25. 0. 30. A yellow precipitate of the Tl salt of the Schiff base started to form after a few minutes.8.0. 1 H). 119.28): calcd. 0. H 5. 7.6. A pale yellow precipitate formed upon addition of HCl (4  solution in dioxane.44 (m.68. 8.50 (m. 2 H). that was filtered.5.87 (s.15 (m.1. 25 °C): δ = 157. 1. 5.6. 18.82 (d. 1 H). 7.40 (d.0 mL. In the discussion on the reaction mechanism. 3 H.0. 1. 0. 2 H). 1 H.6.03 (m. leading to quinolines.6 (2 C) ppm. 126. 1 H. H).7. 1 H. 22. All quinolines were fully characterized with 1H and 13C NMR spectroscopy. 1.4.20 (m. 123. 3 H). and (c) reaction of the Tl salt with [RuCl2(p-cymene)]2 to afford 10.7. 26. 1 H. 148. 47 mmol) and salicyladehyde (5.32 mm ϫ 5 m.31 (s. 36.17 g.9 ppm. A grey precipitate of TlCl started to form almost immediately. The catalyst and inorganic salts were removed from the reaction mixture by filtration through a short silica gel column (ethyl acetate). 7. CH(CH3)2] ppm.4. the quinoline was obtained in good yield (typically 5–10 % lower than GC yields). washed with hexane (2 ϫ 5 mL) and dried in vacuo to afford the pure compound 10 in good overall yield (1. 55.93 (d.37. H 8. 2. CH=N). 6. 1. 13C NMR (300 MHz. 134. 7. H). 1 H). De Vos.1116 g. The best results are achieved with the second generation catalyst. Yields were determined from the optimized reaction with 5 and KOtBu. 3 H). 1 H. 1 H). GC measurements were performed on a Finnigan TraceGC Ultra with an Ultra Fast Column Module (UFC-1. 1 H. 70–230 mesh. KGaA. p-cymene aryl H). the experimental results seem to indicate that there are probably two different pathways involved in this modified Friedländer reaction. 6.43 (t. 3m and 3n has previously been reported[30. SB aryl H). 161.[39.0417 g. 5.74. the solvent volume was reduced to 1 mL and the mixture was purified by column chromatography (Silica gel 60. 89 %. 1 H.[38] H. 3 H) ppm. 7. 25 °C): δ = 162. 24.03.29): calcd. 83. 13C NMR (300 MHz.23 (m.04 (m.68. 1H NMR (300 MHz. 97.60 (m. 1 H).44. 1 H. 13. 25 °C): δ = 165. 1 H NMR (300 MHz.19 (m. N-CH).

C. Jacob. Chem. S.0.2. [5] Y. benzyl alcohol (0. Cho. Kim. Smith.7. New York. W. 145. A.52 (t. N 6. T. Phys. Tetrahedron 1997. J. Martinez. Kim. 1 H). Nolan. X. [34] M.03. Ebisu. D. Soc. Catal. Grubbs. 145. [13] M. S.83 (m. Mol. 1. 2002. 2002. CDCl3. J. H. [43] C. Grenelle and Dr. H. [4] D. Tagari. 11H-Indeno[1. 2001. R. J. Suzuki. found C 88. J. A. 461–478. [3] G.30 (t.88. C. P. T. Morizawa.7. M. C. 13C NMR (300 MHz. found C 84. Chem. Chem. Ren. Nakagawa. Huang. S. J. A.1081 g.9. 569–572.37.39 (m. S. S. 25 °C): δ = 8. Cavalier. Henling. A Chem. C. 1. N 6. J.9. B. Sheu. 1979.3. 129.98 (m. [30] R. Oh. 135. N.8 (2 C). 1991. Blouin. 34. J. p. found C 84. 129. 1998. C.2. 3683–3686. 1 mmol) and KOH powder (0. 1 H).9 (2 C). 30. Tetrahedron Lett.98 (m.4. Young. 2005. 133. A. Organometallics 1999. Amer. 2 H). 1972. Stevens. Org. Girard. 46. 3. Jones. Verpoort. L. 1. Y. S. Chem. 1985. 2001. 1572–1574. Chem.5. Ramon. Eur. N. N 7. 92 %. Brand. 1994. 25 °C): δ = 7. Chem. W. 2007. 690. 7079–7082. Van Der Voort.45.8. 233–241. C 85.4. 128. M. 0. S. 125. Bull.50 (dd. T. 7. 32. 125. Org. 7997–8002. 25 °C): δ = 7. 2-Methyl-1. H. CDCl3. Y.95 (d. 3 H). Di Braccio. 21. Martinez. Mitscher in The Organic Chemistry of Drug Synthesis. Diamond. Eur.org 1631 . M. A Chem. Catal. 1885–1886. Organometallics 2001.9 ppm. 526–532.31. Martinez. De V. Organomet. Takahashi. Can. C. 3563–3568.6. H 8. Zelonka. 127. Choi.60. Can. 13C NMR (300 MHz. 2000. 128. 128. N. 7. T. J. Arisawa. 59. J. [36] C. 2005. Ramon. Tetrahedron Lett.3. 29. Kundu. 7. Desmarais. 3 H) ppm. 82. Tanaka. R. CDCl3. Kim. J. 129. 1978. J. E. Ghia. Chen. 2667–2670. Mol. Theeraladanon.05 (s. T. 2001. R.1. Shinyama. Roma.36 (m. Kim.8. 122. A. 3451–3453.98 (d. 15 %. Shim. 127. 182. Wiley-Interscience. Tetrahedron Lett. 2007 Published Online: February 1. C14H15N (197. K. Appl. 2007. M. H. Tetrahedron 2000. [8] S. 127.44 (t. 128. M. Soc. 5398– 5406. J.01 mmol). 46. Bozell. C 88. 3. 1286–1288. J. Chem. Tirelli. Gildchrist in Heterocyclic Chemistry. 1998. 25 °C): δ = 162. D. Organomet. Kocher. Chem. Yus. 1 H). Vander Mierde. R. H 5.8. 239–302. 13397–13418. Chem. 565–570. D. Ren.eurjoc.9. L. 1 mmol). Martinez. G. Theeraladanon. 25 °C): δ = 159. [12] C. 4094–4097. Cho. Terada. A. C. acetophenone (0. L. 62. N. H 7. CDCl3. 42. Verpoort. Proot of Chevron Technology. Riendeau. S. 53. 6. Sakaguchi. 3760–3763. J. Angew. 1. Love. 2576–2577. J. J.4-tetrahydroacridine (3o): White solid.8. S.1. 12. 2 H). 2 H). 1st ed. [6] H.5.28): calcd. 1599–1605. 1 H) ppm. M.4. J. Kim. B. [27] C. F. Ohsugi. Tetrahedron 2006.2. 13. S. M. J.60. C. N. Zilberstein. A. 60. Med. 1 H). M. Sanford. Yus. 1625–1631 © 2008 Wiley-VCH Verlag GmbH & Co. The mixture was passed through a silica gel column (ethyl acetate) and the solvent was evaporated. Godleski. 2000. 39. G. Mahanty. L. [42] B. Shim.4. 22. 180. M. 1021–1035. 3. T. Eur. 5800–5807. Org. [33] H. M. B.9. McVety. Ledoux.24. P. De Vos.5. Watanabe. Yoon.3. J. Chem. 1 H).3. Hartung. Maddox. Chem. Valente. C. Shim. Org. 1 H). Arisawa. K.3. G. Bennett. P. U. 2008 Acknowledgments The authors gratefully acknowledge the Research Fund of Ghent University for financial support during the preparation of this manuscript and Olivier F. 148. Jones. 43. Larock. C 84. Tetrahedron 2003. 26. Cheng. J.76 (m.8. Taguchi. S. T.6.70 (m. 1 H). M. Chem. Guay. Kim. S. Grubbs.0. 100. Dube. K.68.90 (m. [31] R. P. C16H11N (217. 8988–9001. 146. 94 %). [7] M. Commun.29): calcd. Spada. D. W. Eur. 1 H). Lett. 27. Tetrahedron 2006. W. Tetrahedron 2004. Nishida. Kuo. 67–76. C. 1981. D. 19 was obtained as an orange solid (0. Allaert. [20] R. 2000. 8029–8033. Arisawa. 1977.1201 g. 0. J. S. Med. J. Trauthwein.. 9020–9022. C.24–7. Chem. Sheets.0082 g. Ghent for elemental analyses. 2 H). R. 128. Grossi. Szalkiewicz. Friesen. Cho.10. [19] J.55 (t. 141. 38. M. [39] M. X. 1 H). S. O. M.27): calcd. [25] C. G. W. D. [10] Y. 2005. Kim. Thiel. M. [14] C. Oh. J. C. T. Jacob. Mares. S. D. Ed. 6781–6785. 8. Kim.90 (m. 35. B. CDCl3.0. 18. J. Nakamura.4.3. 25 °C): δ = 199. 1999.1984 g.55. CDCl3. vol. Chem. 3607–3614. 1. C. Sanford. Shim. 126. Revue Canadienne de Chim. S. Drozdzak. M. 40. J.45. Y. S.52 (m.10. [41] L. 2 H) ppm. 132.66. 33. Suter. Yus. 125. 133. Das. Cho. Muchowski. 7.6 ppm. Tetrahedron Lett. D. 2003. 25 °C): δ = 161.1. P. S.7. S. 62. M. K. Soc. [38] J. Nakagawa. [15] M. Beller. 31. J. A.0561 g. Shim. K. [18] C. [35] M. Y. 2. Marc G. Kim.8. C. C. Shim. 7. P. 7.7. C. A. [37] C. M. 7.3. 4539–4542. Chem. 127. [2] D. 134.2-b]quinoline (3p): White solid. Pharmacol. Shim. F. [26] C. 127. 337– 347. Ramon. F. 2 H) ppm. 2 H). 130. J.4 ppm. Tetrahedron Lett. S. Y.51 (m. 2 H). Weinheim www. [23] J. 13C NMR (300 MHz. Org. KGaA. Synthesis of 3-Phenylpropiophenone (20): 4 (0. W. 101. J. 2129–2137. B. Nalwa. K. 2008. D. [21] S. 7. N.12. Tetrahedron Lett. A. 7. 2006. Pfister. New J. [22] M. Mattioli. S. R. H. 0. 7. Fang. C14H17N (199. E. C. Brideau. Soc. E. [32] K. Cho. 22. N 7. Cho. 2513–2522. Jafarpour. P.31 (s. J. H 5. Waterman. Y. [24] J. Yus. C. 2006. H.61 (d. S. J. L. 8. S. T. 1974. H. 130. Bioorganic Med. Cho. 0. Nishida.9. 2374–2377. Y.34 (t. Cho. L. Y. 47. N 7. S. 7. Cardiovasc. R. C. 13C NMR (300 MHz. Korivi. Med. Chem. R. 127. 1 H). Chem. A. Shim. Am. M. 2004. S. B. [28] R. 125. 1H NMR (300 MHz. [16] L. F. M. H 8. CDCl3. 490–491. S. 126. A. J. H. [9] H. 1255–1260. Tsuji. T. B. H 7. Chem.03. 2000. Kim. S. 31. S. Ishii. M. M. Catalyst 7 was generously supplied to us by Umicore. Dalton Trans. p. and D. Lednicer. Chem.61 (m. T. Maguire. 140.0326 g. Falgueyret. Chem. 4. 1H NMR (300 MHz. 1311–1313. J.4. [29] R. Korean Chem.3. S.A Ru-Catalyzed Approach to Friedländer’s Quinoline Synthesis (m. A. 3063– 3072. F. 5314–5318.3. J. 2 H). 1 H). G. 1. 56.8. Girard. S. Chem. Tzeng. Kageyama. Nishida. 7987–7989.7 (2 C). Okazoe. 3 H). Cho. 1 mmol) in 3 mL of dioxane were placed in a screw-capped vial and allowed to react for 1 h at 80 °C. Ethier. also thank the FWO Flanders for a project grant. 8982–8987. M. Baird. Theeraladanon. 50. M. [40] R. Hegedus. 1H NMR (300 MHz. C. Kim. London. 37. W. Tetrahedron Lett. [17] R. Received: October 22. J. M. 20. F. D. P. J.3 ppm. Allen.98. J. 34. 68. J. De. [1] T. J. Nishikawa.3 (2 C).20–2. 137. 2005. 1 H). Hsu. 131. J. De Clercq. 690. Pitman Publishing LTD.19 (m. Lett. L. N 6.6. 72.07 (t. 71.1815 g. Kim. Commun. Concilio. 2002. C. 66.09. 7747–7750. Nakagawa. 44. Ramon. 33. 5 H). J.0. R.2. V. C. [11] C.9 (s. Takahashi. 3017–3035. P. A. 2005. 128. Day. Int. 34. 2001. 1 H). Chan. Macromolecules 2001.