The Effective oxidant H2O2 for the DoebnerMiller Syntheses of.doc

The Effective oxidant H2O2 for the Doebner-Miller Syntheses of 2, 3-dialkylquinoline via a one-pot reaction of aniline and aldehydeAbstractA convenient and efficient synthesis of substituted quinolines via a simple one-pot reaction of an aniline and aldehyde in the presence of the general Lewis acid AlCl3 and oxidant H2O2 (hydrogen peroxide) was developed. The effect of the oxidant on the yield and selectivity of quinoline derivaties was studied, and the experimental results expressed that when the molar ratio of aniline, aldehyde, and oxidant was 1: 3: 0.5 at 25 C, the yield of quinoline was improved actually compared to the H2O2 was absent, also the reaction time was reduced obviously. As expected, the side product N-alkylaniline was not found, either. Which showed that the selectivity of qunolines was almost 100%. Moreover, the substituent effect was also investigated.Key words：Oxidant (H2O2) Effect, Doebner-Miller synthesis, Quinoline derivativesIntroductionIt is more then one hundred years since the quinolines and their derivaties were explored, which were used for many drugs and agricultural chemicals because of the excellent biological and pharmaceutical properties. As these years, the applications of quinolines extend to antioxidant in synthetic rubber and biology1a-c, metal ions detection in Environmental2a-b, biological science3a-b, and thermally stable transparent materials of electronics, optoelectronics and nonlinear optics4. Thus, the synthesis of quinoline derivatives always has been one of hotspots of chemical research. So far, chemists have explored various ways to synthesize of quinolines, and most of them were the modifications of the traditional methods, for example, Doebner-Miller5a-c, Skraup6a-d and Friedlnder7a-e syntheses, which were generally considered to be the most versatile methods of synthesis of quinolines. However, many of the methods suffer from harsh reaction conditions5c, 8a-b or consist of multiple steps9a-e. Moreover, the applicability of the classical methods was limited to simple quinolines in poor yield5c and low selectivity10a-d since that the by-product N-alkylaniline was competed with quinolines, which leading to the tedious isolation procedure from complex reaction mixtures and the waste of materials. The probable mechanism has been discussed in some papers 10a, 11a-e. First, nucleophilic addition reaction of aniline with aldehyde occurs to give imine 5. Then addition of another molecule of aldehyde (the enol tautomer of aldehyde) to the imine produces a new aldehyde 6, which undergoes cyclization to tetrahydroquinoline 7. The hydroquinoline was undergoing a dehydrate process to dihydroquinoline 8 and at last oxidized to quinoline 3. So there must be a hydrogen-hunter in the reaction mixture. If there is no additional oxidant or oxidative catalyst in the reaction system, the imine could be reduced by the hydrogen from the dihydroquinoline to form N-alkylaniline 4 (Scheme 1) easily. Thus, the yield of quinolines was reduced.Shimizu et al reported the yield of substituted quinolines was promoted by using IrCl2H(cod)2 as catalyst under oxygen10a. Nanni et al reported FeCl3 catalyzed imine to give quinolines in good yield10c. Tokuyama and Takasu described a one-pot process that provides quinolines from imine by the assistance of oxidant DDQ12. Shin-ya et al found that an aerobic condition was able to prevent the reduction of imine effectively 13. And in the classical Skraup method, nitrobenzene was used as an oxidizing agent6a, 14. Our previous work also found that oxidative catalyst could improve the selectivity of quinolines. Thus we expected to introduce an additional oxidant to the reaction mixture to trap the hydrogen from dihydroquinoline in order to avoid the reduction of imine and improve the yield and selectivity of quinolines. In this paper, the inexpensive oxidant H2O2 was chosen to oxidize the active hydrogen under the mild condition to renovate of the quondam harsh condition increasing the yield and selectivity of quinolines.Experiment Section Unless noted otherwise all starting materials were obtained from commercial supplies and were used without further purification. Anhydrous condition and dry nitrogen atmosphere were required for the reaction. The crude products obtained were purified by column chromatography over silica gel (300-400mesh) using diethyl ether /hexane/petroleum ether (1:10:20) as eluent. The yield was calculated on a Shimadzu gas chromatography (GC-14B). Nuclear magnetic resonance 1H (300MHz) and 13C (100MHz) spectra were recorded for CDCl3 solution with TMS as an internal standard (chemical shifts are expressed in parts per Million (ppm, d) downfield from tetramethylsilane (TMS) at 25 C on a JNM-LA300 FT-NMR (JEOL Ltd.) spectrometer. Coupling constants are given in hertz (Hz). GC analysis was performed on SHIMADZU GC-14B equipped with a fused silica capillary column SHIMADZU CBP1-M25-025 and SHIMADZU C-R8A-Chromatopac integrator, and the detection temperature was from 60 C to 270 C through a temperature programming. And the dodecane was an internal standard.General Procedure: To a pretreatmented Shlenck tube that was affording for an anhydrous without oxygen atmosphere, methane dichloride was added as solvent, aluminium trichloride was added as catalyst. Then aniline and aldehyde were added to the solution at the same temperature in proper order, and dodecane, as an internal standard, was added finally. After the solution transformed to light yellow, the reaction mixture was stirred under nitrogen for necessary time at room temperature. After quenching with 3mol/L ammonia solution, the organic products were extracted with 30 mL 3 of diethyl ether. Combined organic extracts were washed with H2O, NaHCO3 (20% aqueous solution), H2O and brine, then dried over anhydrous Na2SO4. Filtration, evaporation and column chromatography on silica gel with diethyl ether: hexane: petroleum ether (1:10:30) as eluent afforded the desired compounds quinoline derivatives and N-alkylanilines. The products were analyzed though GC, GC-MS and NMR. And the yields were determined on gas chromatography using dodecane as internal standard. Result and DiscussionFirst of all, 0.26mL (3mmol) of n-butylaldehyde reacted with 0.09mL (1mmol) of aniline catalyzed by 1.333mg (1mmol) AlCl3 using 8mL methane dichloride as a solvent at 25 C, after 6 hours, afford 1.524mg 3-ethyl-2-propylquinoline, the GC yield was 64%, isolated yield was 48%. And the GC yield of by-product N-butylaniline was 10%. If 0.10mL (30%，1mmol) of H2O2 was added in the reaction mixture, the GC yield of 3-ethyl-2-propylquinoline was increaced to 82%, isolated yield was 70%, and not any N-butylaniline was found (Scheme 2). We chose the reaction of aniline 1a and n-butyraldehyde 2a as a model (Scheme 2), Aluminium trichloride as a medium and dichloromethane as a solvent.At first, we had investigated the influence of equivalent of H2O2, and the results are shown in Table 1. It is obvious that 0.5 equivalent of H2O2 was enough for the reaction. And according to the proposed mechanism in, one preparation of quinoline would release two atoms of hydrogen. Therefore, 1 mole of H2O2 was needed to capture all hydrogen released in system. Maybe the transformation of imine 5 to aldehyde 6 is faster then the step of dihydroquinoline 8 to quinoline 3 (Scheme 1). Although there was hydrogen in system, no imine would be reduced because of the quick transform of 5 to 6. Thus, 0.5 equivalent of H2O2 was abundant. However, the more reasonable explanation of this difference is now on the march. 商榷!Based on the result above, we chose equivalent of 0.5 refer to aniline as the much more appropriate amount of H2O2. We then operated the reaction at different temperature (Table 2). It is clear that the effect of hydrogen peroxide (H2O2) was notable. The yield of 3-ethyl-2-propylquinolines 3a was rose by 14 percent at least under different temperature in Table 2. Although the effect of H2O2 at 0 C and 15 C gave a better result, the control of temperature was harder then 25 C, and the yields of desired quinoline were lower than that at 25 C. And 35 C didnt show obvious improvement compare to 25 C. Thus, in consideration of easy decomposition of H2O2 at 35 C, we selected 25 C, which was very close to the average room temperature, as the reaction temperature. We also found that the reaction time was cut down on 50% at least, was shorted to 1h or less, when H2O2 was used as an oxidant. Moreover, the by-product N-butylaniline was not found as we had expected (Table 2). Next, we investigated the Substituent effect, p-Nitroaniline 1b and p-tolylamine 1c were used and the former didnt show a good performance. The strongly electron-withdrawing groups did not favor the nitrogen atom of anilines to attacking the carbon of carbonyl of the aldehyde, while p-tolylamine 1c gave a good yield a better yield (entry 2 and 3, Table 3). However, the nitrobenzene is an oxidant itself14, so it got a higher yield while H2O2 was absence (entry 2, Table 3). We also used different aldehydes in experiment. Acetaldehyde did not show a good yield maybe due to its self-condensation. It is obvious that the -carbon of aldehyde must bear hydrogen atom, otherwise there would no quinoline products. And benzaldehyde only got the imine N-benzylideneaniline (entry 5, Table 3) instead of quinolines.In summary, we have developed a one-pot synthesis of 2, 3-dialkylquinoline promoted by H2O2 without a side product at a mild condition. And the yield and selectivity of the target products was satisfactory. Further extension of the other oxidant effect into rapid synthesis of quinolines is in progress.Reference(1) (a) Abdel-Aziz, M. M.; Basfar, A. A. Nucl. Instrum. Methods Phys. Res. Sect., B 2001, 185, 346350. (b) Zhao, Z. Z. World Rubber Industry (in Chinese), 2006, 33, 14-18. (c) Halehatty, R; Prakash, N; Halehatty, S; Bhojya, N. et al. 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Chem. 2006, 71, 800-803. (14) Park, K. H.; Joo, H. S.; Ahnm, K. I.; Jun, K. Tetrahedron Lett. 1995, 36, 5943.3-ethyl-2-propylquinoline (3a). 1H NMR (CDCl3, Me4Si) : 8.02 (d, J=7.2Hz, 1H), 7.85 (s, 1H)，7.71(d, J=8.1Hz, 1H), 7.60(t, J=6.9Hz, 1H ),7.43(t, J=6.9Hz, 1H), 2.96(t, J=5.0Hz, 2H), 2.83(q，J=7.5Hz，2H), 1.87-1.7