Synthesis of 1,2,3,4-Tetrahydroquinolines Using AlCl3 in Aqua Mediated

  • Behbahani, Farahnaz K. (Department of Chemistry, Karaj branch, Islamic Azad University) ;
  • Ziaei, Parisa (Department of Chemistry, Karaj branch, Islamic Azad University)
  • Received : 2013.10.13
  • Accepted : 2013.12.17
  • Published : 2014.02.20


Catalytic performance of Lewis acids have been investigated in the synthesis of 1,2,3,4-tetrahydroquinolines via cyclocondensation reaction of aniline derivatives with cyclic enol ethers such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran. The catalytic activity of various of these catalysts in different solvents was compared with other classical catalysts such as KSF clay (1.5 g), $InCl_3$ (10-20 mol%), $ZrOCl_2$ (10 mol%), $Sc(OTf)_3$ (3 mol%), PANI-$InCl_3$ (10 mol%), $I_2$ (20 mol%), $InCl_3$ (5 mol%), 4-npa (25 mol%) and Cellulose-$SO_3H$ (0.03 g).




Tetrahydroquinoline derivatives exist in the variety of natural products and pharmaceutical agents that show broad biological activities.1 Several synthetic procedures for the preparation of tetrahydroquinoline derivatives have been reported.2 Also three-component-reaction of a substituted aniline, an aryl aldehyde, and an electron-rich olefin using Lewis acid has also been reported.3 Recently, tetrahydroquinolines have been synthesized via a diamino coupling of aniline derivatives and cyclic enol ethers catalyzed by InCl3 in water4 or CH3CN,5 KSF clay,6 Sc(OTf)3 in [Bmim]PF6,7 iodine molecular,8 ZrOCl2,9 PANI−InCl3,10 4-npa,11 Cellulose− SO3H12 and FeCl3−NaI and TMSCl-NaI by aryl azids1314 have also been reported. However, a number of modified methods under improved conditions have been reported, many of them suffer from drawbacks such as utilizing of stiochemetric amounts of reagents including FeCl3−NaI (1.5:1, reagent:substrate), iodine (20 mol%) in CH2Cl2, InCl3 (5 mol%), KSF clay (1.5 g) and TMSCl-NaI (1.5:1, reagent. substrate). Owing to their significant biological activity, there is still a need for a simple, green and general procedure for the one-pot synthesis of tetrahydroquinolines under catalytic conditions.

On the other hand, Lewis acids accelerate a wide range of organic reactions by binding to and thereby activating reactants. This activation often results in rate increases of many orders of magnitude compared with the thermal reaction.

Lately, AlCl3 has been employed for the synthesis of 5- benzoylacenaphthene,15 selective synthesis of 2-aryl-2H- and 4-aryl-4H-3,5-diformylpyrans from acetal with aromatic aldehydes, 16 catalytic asymmetric arylation of aldehydes,17 catalytic beckmann rearrangement of ketoximes,18 conversion of isopropenyl acetate into 3-acetyl- and 3,5-diacetyl-2,6- dimethyl-4H-pyran-4-ones,19 one-pot four-component synthesis of 1,4-dihydropyridines and their aromatization,20 hydrosilylation of alkynes with hydropolysilanes,21 cycloadditions of activated cyclopropanes and aromatic aldehydes,22 synthetic routes to sterically hindered unsymmetrical diaryl ketones via arylstannanes,23 one-pot preparation of 1,1,3- triheteroaryl compounds of crotonaldehyde and indole,24 1- substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10- diones,25 synthesis of 5-amino-4-arylazo-3-methyl-1Hpyrazoles and 5-aryl-3-methylpyrazole[3,4-e] [1,2,3,4] tetrazines26 and oxidation of alcohol.27

The replacement of environmental hazardous catalysts in various processes, with green catalysts, solvent-free and on water reaction is of the innovative trends. In recent years, with the increase of environmental consciousness in chemical research and industry, efficient, economic and clean procedures have received increased attention. Thus, water has become an intriguing reaction medium, and has particularly captured the interest of organic chemists.30−33 Reactions previously thought impossible in water are now a reality. In many cases the catalyst and/or the aqueous medium can be recovered and reused, thereby reducing the environment impact of the reaction process.34 Many Lewis acids also work well in aqueous medium,35 and even AlCl3, SnCl2 and TiCl4 which are previously used under anhydrous conditions are excellent catalysts in water.31

Ongoing previously our research to introduce the green protocol for the synthesis of heterocyclic compounds using eco-friendly catalysts,2829 we interest to report catalytic synthesis of pyrano-and furano-quinoline derivatives using aryl amines, 3,4-dihydro-2H-pyran (DHP) and 2,3-dihydrofuran (DHF) in water or solvent-free and in the presence of Lewis acids as catalyst under mild condition (Scheme 1).

Scheme 1.Synthesis of pyrano- and furano [3,2-c]quinolines.



In this study, the effect of various parameters such as catalyst type, solvent type, temperature, and reaction time on the yield of products were studied and compared with those obtained using other reagents. That also found AlCl3 catalyst in water as a solvent is an eco-friendly catalyst for aforementioned cyclocondensation reaction

Effect of the Solvent

The cyclocondensation reaction of 4-methoxyaniline with cyclic enol ethers, such as 3,4-dihydro-2H-pyran was carried out in various solvents, such as water, acetonitrile, ethanol, dimethylsulfoxide, toluene, carbon tetrachloride and under solvent-free condition. We found that water is the most effective solvent (Table 1). It is noteworthy to mention that heating of the reactants in neat water without any catalyst did not give the products even in prolonged reaction time.

Table 1.aReaction condition: 4-methoxyaniline (1.0 mmol), 3,4-dihydro-2H-pyran (2.2 mmol). bIsolated yield. cDetermined by 1H NMR spectroscopy.

Effect of the Catalyst Type

Comparison of AlCl3, Al(NO3)3.9H2O, Al(DS)3.3H2O, Al2O3, AlO3C9H21 showed that the higher activity could be achieved with AlCl3 (Table 2). Although it is difficult to offer an explanation for the different activity between these Lewis acids, certainly there is a relationship between the cation activity and structure of anion. By changing the constituent anion the acid strength of Al3+ as well as its catalytic activity is able to vary in a wide range.

Table 2.aReaction condition: 4-methoxyaniline (1.0 mmol) and 3,4-dihydro- 2H-pyran (2.2 mmol) at 50 ºC. bIsolated yield. cDetermined by 1H NMR spectroscopy. dAluminum tris (dodecyl sulfate) trihydrate.

This methodology has been generalized by reaction of series of substituted aryl amines with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran to give pyrano-and furano-quinolines as illustrated in Table 3. The results showed that aryl amines bearing electron donating groups are more reactive than those of with electron withdrawing groups. Furthermore by employing 4-nitroaniline, the desired products could be obtained upon reaction with 3,4-dihydro-2H-pyran under similar conditions in longer reaction time and less yield (Table 3, entry 7). In most cases, the products were obtained as a mixture of endo- and exo-isomers. In all cases the existence of the endo isomer is predominant. The ratio of isomers was determined from the 1H NMR spectra of the products. The stereochemistry of the isomers was assigned on the basis of coupling constants and chemical shifts of protons which was accordant with the presentation of the literature.13 It is noteworthy that our method has several advantages including mild conditions, good yields, short reaction times and simple operation and work-up. Additionally, the protocol does not require anhydrous solvents adopted the principles of green chemistry point of view.

Table 3.aReaction condition: 4-methoxyaniline (1.0 mmol), 3,4-dihydro-2H-pyran (2.2 mmol). bIsolated yield. cDetermined by 1H NMR spectroscopy.

The plausible mechanism of the product formation is shown in Scheme 2. Z. Lei and co-worker27 have previously been reported that AlCl3 is hydrolyzed to oligomers [Al2(OH)nCl6−n]m in aqueous phase, the hydrolyzed products have been regarded as water-soluble supporter the in situ formed Al−OH was possibly applied as key intermediate for alcohol oxidation. On the other hand AlCl3 is a hard Lewis acid that coordinates hard basic centers like the oxygen atom of a carbonyl group and that of enol ether activating the reagent for a nucleophilic attack. Thus either AlCl3 or Al−OH may catalyzed an aza-Diels-Alder process of 2− azadiene which is generated in situ from cyclic enol ether and aniline derivatives using Al+3 catalyst, with another equivalent of cyclic enol resulting in the formation of trahydroquinoline

Scheme 2.The proposed reaction mechanism for AlCl3 -catalyzed pyrano quinoline derivative.

To show the merits and advantages of using AlCl3 as a catalyst in the synthesis of 4-(9-methoxy-3,4,4a,5,6,10bhexahydro- 2H-pyrano[3,2-c]quinolin-5-yl)butan-1-ol (Table 3, entry 2), our protocol was compared with previously reported methods (Table 5). From the results reported, the advantages of our method are evident regarding the yields of the reactions which are very important in chemical industry especially when it is combined by green reaction conditions.

Table 4.aReaction condition: aryl amine (1.0 mmol), DHF (2.2 mmol) and AlCl3 (15 mol%). bIsolated yield. cDetermined by 1H NMR spectroscopy.



Materials and Methods

1H NMR spectra were recorded on a Bruker ARX 300 MHz using CDCl3 and DMSO as the solvent and TMS as an internal standard. IR spectra were recorded on KBr pellets using a FT-IR Bruker Tensor 27 spectrometer. The reactions were monitored by TLC. All solvents and reagents were purchased from Aldrich and Merck with high-grade quality and used without any purification and Al(DS)3.3H2O was prepared via previously reported protocol in literature. 36 All products were known and their physical and spectral data were compared with those of authentic samples (lit. [4-14]).

General Procedure for the Synthesis of 1,2,3,4-Tetrahydropyranoquinolines Using AlCl3. A Typical Procedure

A mixture of aniline derivatives (1 mmol), cyclic enol ether (2.2 mmol) and of AlCl3 (15.0 mol%) in water (5.0 ml) was stirred at ambient temperature or at 50 ℃ for an appropriate time (Table 3,4). The progress of the reaction was monitored by TLC (ethyl acetate:n-hexane 2:3). Upon completion of the reaction, ethylacetate (15×2) was added and the organic layer was separated. After drying of organic phase (Na2SO4), and evaporation of the solvent, the crude product was afforded which was directly subjected to thin layer chromatography. The product was as a mixture of endo/exo isomers. The aqueous layer that remained after the work-up of the reaction can be reused.

Physical and Spectra Data for New Products

5-(4-hydroxybutyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[ 3,2-c]quinolin-7-ol (entry 8, Table 3)

IR (KBr, cm−1): 3412.13, 2937.56, 2859.81, 1615.09, 1509.02, 1448.08, 1377.66, 1204.37, 1073.40, 860, 743.04. endo-isomer 1H NMR (DMSO, 300 MHz): δ 1.25−1.7 (m, 10H), 1.9 (m, 1H, H6), 3.25 (m, 1H), 3.35−3.42 (m, 2H), 3.54 (t, J = 6.2 Hz, 2H), 4.5 (s, 1H, OH), 4.94 (d, J = 5.46, 1H, H5), 6.43 (t, J = 7.6, 1H, Ar−H), 6.55 (d, J = 7.5, 1H, Ar− H), 6.67 (d, J = 7.5, 1H, Ar−H).

exo-isomer 1H NMR (DMSO, 300 MHz: δ 1.25−1.7 (m, 10H), 1.8 (m, 1H, H6), 3.32 (m, 1H ), 3.4 (m, 3H), 3.72 (m, 1H), 4.16 (s, 1H, OH), 4.33 (d, J = 2.45, 1H, H5), 6.32 (t, J = 7.6, 1H, Ar−H), 6.53 (d, J = 7.5, 1H, Ar−H), 7.61 (d, J = 7.5, 1H, Ar−H).

4-(7,9-dimethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2- c] quinolin-5-yl)butan-1-ol (entry 11, Table 3)

IR (KBr, cm−1): 3391.28, 2932.78, 2854.42, 1589.90, 1507.42, 1466.06, 1378.23, 1211.64, 1056.65, 861.78, 790.

endo-isomer 1H NMR (CDCl3, 300 MHz): δ 1.4−1.8 (m, 10H), 2.1 (m, 1H, H6), 2.3 (s, 6H), 3.36 (m, 1H), 3.61 (m, 2H), 3.65 (t, J = 6.43, 2H), 5 (d, J = 5.46, 1H, H5), 6.46 (d, J = 7.4,1H, Ar−H), 6.87 (d, J =7.4, 1H, Ar−H).

exo-isomer 1H NMR (CDCl3, 300 MHz). δ 1.4−1.8 (m, 10H), 1.95 (m, 1H, H6), 2.2 (s, 6H), 3.51 (m, 1H), 3.73 (m, 3H), 3.99 (m, 1H), 4.4 (d, J = 2.33, 1H, H5), 6.46 (d, J = 7.4, 1H, Ar−H), 6.87 (d, J = 7.4, 1H, Ar−H).

3-(6-chloro-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin- 4-yl)propan-1-ol (entry 8, Table 4)

IR (KBr, cm−1): 3426.20, 2941.11, 2848.95, 1598.87, 1510.12, 1464.34, 1375.00, 1205.08, 1077.68, 867.48, 743.17.

endo-isomer 1H NMR (CDCl3, 300 MHz). δ 1.72−1.86 (m, 5H), 1.92−2.01 (m, 1H), 2.60 (m, 1H), 3.43 (m, 1H), 3.53 (m, 2H) , 3.65 (m, 2H), 5.08 (d, J = 7.0, 1H), 6.65 (t, J = 7.3, 1H), 7.12 (d, J = 7.8, 1H), 7.17 (d, J = 7.9, 1H).

exo-isomer 1H NMR (CDCl3, 300 MHz). δ 1.72−1.86 (m, 5H), 1.92−2.01 (m, 1H), 2.62 (m, 1H), 3.65 (m, 2H), 3.77 (m, 2H), 3.96 (m, 1H), 4.55 (d, J = 5.25, 1H), 6.59 (t, J =7.3, 1H), 7.12 (d, J = 7.8, 1H), 7.20 (d, J = 7.9, 1H).

Table 5.aAryl amine: 4-methoxyaniline, enolether: DHP. bIsolated yield. cDetermined by 1H NMR spectroscopy.

3-(6,8-dimethyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin- 4-yl)propan-1-ol (entry 10, Table 4)

IR(KBr, cm−1): 3418.59, 2933.96, 2857.92, 1588.07, 1505.30, 1455.47, 1378.91, 1213.52, 1058.02 , 865.678, 794.48.

endo-isomer 1H NMR (CDCl3, 300 MHz): δ 1.60−1.92 (m, 5H), 1.98−2.02 (m, 1H), 2.25 (s, 6H), 2.60 (m, 1H), 3.32 (m, 1H), 3.80 (m, 2H), 3.90 (m, 2H), 5.26 (d, J = 8.523, 1H), 6.55 (d, J = 7.45, 1H), 7.88 (d, J = 7.47, 1H).

exo-isomer 1H NMR (CDCl3, 300 MHz): δ 1.60−1.92 (m, 5H), 1.98−2.02 (m, 1H), 2.25 (s, 6H), 2.60 (m, 1H), 3.69 (m, 2H), 3.74 (m, 2H), 3.98 (m, 1H), 4.57 (d, J = 5.025, 1H), 6.55 (d, J = 7.45, 1H), 7.88 (d, J = 7.47, 1H).



In summary, we reported efficient, simple and green conditions for the synthesis of tetrahydro pyrano and furano quinoline derivatives as endo/exo isomers. The employed catalyst for this process is rather inexpensive, non-stinking, nontoxic hence this is a practical protocol.


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