An efficient method for the preparation of 2,2,4-trisubstituted 1,2-dihydroquinolines using catalytic amount Bi(OTf) 3 as catalyst

Substituted 1,2-dihydroquinolines have been synthesised from substituted anilines and methyl pyruvate using catalytic amounts of commercially available Bi(OTf) 3 as a catalyst under microwave-assisted conditions. This method is simple, easy to work up, inexpensive, with a broad substrate scope and short reaction times. The reaction provides 1,2-dihydroquinolines (19 examples) in good yields (34-97% yields).


Introduction
2] In addition, 1,2-dihydroquinoline derivatives are versatile intermediates in organic chemistry.8] In the literature, numerous methods describe the synthesis of 1,2-dihydroquinolines.Typically aryl amines were reacted with a range of different compounds such as ketones, 9 unsaturated ketones 10 , 2,2-dimethoxy propane, 11 aldehyde, 12 alkynes, 13 alcohol, 14 glycerine, 15 ketoester [16][17] in the presence of Lewis acid or Brønsted acid catalysts.To date there have been few methods published for the synthesis of 1,2-dihydroquinoline derivatives using -ketoesters.Waldman et al 16 have reported the formation of 1,2-dihydroquinolines using α-keto ester in the presence of AuCl3 (5 mol%)/AgSbF6 (15 mol%) as catalyst.However, large amounts of gold and silver salts have to be applied which is expensive.Recently, Ji et al 17 reported the preparation of these compounds using Brønsted acid (HNO3, 10 mol%) in combination with In(OTf)3 (1 mol%).Additionally, harsh reaction conditions are required which limits the substrate scope.
We now report the synthesis of substituted 1,2-dihydroquinolines employing anilines and methyl pyruvates.The reactions are catalysed using catalytic amounts of commercially available Bi(OTf)3 under microwave-assisted conditions.

Results and Discussion
Due to the pharmaceutical importance of 1,2-dihydroquinolines and inspired by Waldman et al 16 we endeavoured to identify more appropriate and easier methods for the synthesis of these compounds.Initially various Lewis acids and protic acids were investigated.As demonstrated, Lewis acid or Bronsted acids are needed for the synthesis of 1,2-dihydroquinolines, as no reaction occurs without a catalyst.In this study Bi(OTf) 3 has been selected as the catalyst since it is cheap and stable in the presence of air and moisture.Furthermore, it has been demonstrated that Bi(OTf)3 is a good catalyst for many transformations, including Friedel-Crafts alkylation, 18 synthesis of 1,2-dihydroquinolines, 19 deprotection of O,O acetals, 20 and the aza-Cope rearrangement. 21As seen in Table 1, various Lewis acids [Sc(OTf)3, Cu(OTf)2, Zn (OTf)3, Yb(OTf)3, Bi(OTf)3] were tested in this synthesis.Among these Bi(OTf)3 was the most effective catalyst which gave the products in very high yields (71%) (Table 1, entry 5).Additionally, various protic acids were also evaluated.However, inferior yields were observed (Table 1, entries 6-9).When 15 mol % trifluoromethanesulfonic acid was used a slight increase in yield was observed (Table 1, entry 7).However, the use of trifluoromethanesulfonic acid is not desirable as it is typically difficult to handle and in certain solvents is less soluble due to droplet formation.No product was observed in the absence of a catalyst after five hours (Table 1, entry 10).Several solvents were employed in the reaction of para-phenoxy aniline and methyl pyruvate (Table 2).Acetonitrile was found to be an effective solvent 22 and a high yield of (3b) (70%) was observed after of 3.5 hours (Table 2, entry 3).When the reaction was refluxed in acetonitrile the yield slightly improved (75%) but the reaction took longer (7 hours) (Table 2, entry 5).In this reaction toluene was observed to be as effective as acetonitrile (Table 2, entry 2). a Reactions were carried out with para-phenoxy aniline (1 eq), methyl pyruvate (2.2 eq).b Isolated yield after silica gel chromatography.
When the condensation reaction of the aniline derivatives with methyl pyruvate was investigated at room temperature a moderate yield was observed after a long period of time (Table 3).When performed in chloroform, the condensation of 2,5-dimethoxyaniline with methyl pyruvate provided a low yield (10 %) after six days (Table 3, entry 10).The condensation of oacetyl aniline with methyl pyruvate provided trace amounts of product after 2 days (Table 3, entry 1).When the same reaction was performed in acetonitrile 3a was obtained in low yield (22%) (Table 3, entry 1).When various electron withdrawing groups, such as para-cyano, nitro and acetyl aniline, were tested no product was obtained after 3-4 days (Table 3, entries 24, 26  and 28).When electron withdrawing groups were present on aniline at room temperature, either no reaction occurred or a reaction with very low yield was observed (Table 3, entries 1, 2, 24, 26  and 28).As seen in Tables 1, 2, and 3, the best results for the synthesis of 1,2-dihydroquinolines were observed with acetonitrile, Bi(OTf)3 (5 mol%) and a microwave irridation system.For this reason, the condensation of aniline derivatives with methyl pyruvate was tried using microwave irridiation/acetonitrile /Bi(OTf) 3 (5 mol%).The results are seen in Table 3.In the presence of electron withdrawing or donating groups on aniline, the expected 1,2-dihydroquinolines derivatives were obtained in very good yields and in shorter time (Table 3, entries 3, 11, 15, 25,  27 and 29).At the end of the reaction of para acetyl aniline with methyl pyruvate at room temperature, instead of the expected product (3l), intermediate product ( 4) was produced in 54% yield (Scheme 1).When the reaction was repeated using microwave irridation, the expected product (3l) was produced in 91% yield (Table 3, entry 25).Scheme 1. Reaction of p-acetyl aniline (1 eq) and methyl pyruvate (2.2 eq).
The mechanism of the reaction was explained by Waldman 16 and Ji 17 .Ji suggests that imines or enamines are formed as a result of the reaction of p-methoxyaniline and methyl pyruvate as 39% imine and a trace amount of enamine were isolated.Neither Waldman 16 nor Ji 17 isolated intermediate product ( 4) which can be synthesised through the ring opening of lactone. 23Our experiments support the formation of enamines and imines but these intermediate products are rapidly transformed to product (4) in 54% yield (Scheme 1).The structures of 3a 24 , 3k 25 , 3o 26 , 3p 27 , 3l 28 and 3q 29 were determined by X-ray crystallography.
When the same conditions were used with 2-chloro 3-amino pyridine, instead of the expected product (10), by-product (9) was produced in 23% yield (Scheme 2).The mechanism for the formation of 9 involves the initial generation of intermediate (6), then imine intermediate ( 6) is transformed into enamine intermediate (7).As seen in Scheme 3, by-product (9) was obtained from enamine (7) which with a second mol of methyl pyruvate forms an intermediate alcohol by a 1,2-addition which subsequently cyclises to the product (9) (Scheme 3).The X-ray structure of by-product (9) 30 was shown in Figure 1.

Conclusions
In this study we report the effective Bi(OTf)3 (5 mol%) catalysed synthesis of 1,2dihydroquinolines. Microwave irridation was found to be most effective to provide a series of 1,2-dihydroquinolines with both electron withdrawing and electron donating substituents.Characteristics of this study include: (i) one-pot reaction providing products in good yield, (ii) the starting materials are cheap and easily obtained, (iii) performing reactions using microwave irridation is safer and easier than under reflux, (iv) the products can easily be purified by column chromatography, (v) the 1,2-dihydroquinolines (3a-3r) obtained are useful in medicinal chemistry.

Experimental Section
General.Acetonitrile, chloroform were distilled from calcium hydride immediately prior to use.Dimethyl formamide, toluene , nitromethane were distilled before use.All aniline derivatives, Bi(OTf)3 and methyl pyruvate are commercially available.Compounds 3a, 16 3n, 3o, 3i and 3c 17 previously reported in the literature.Column chromatography was performed using MN silica gel (particle size 0.040-0.063mm).For thin-layer chromatography (TLC), silica gel coated aluminium plates (Merck, silica gel 60 F254) were used and chromatography was performed using silica gel Merck 60 (particle size 0.063-0.20 mm), visualised by UV irradiation. 1 H-NMR and 13 C-NMR were recorded on a Mercury 300 or 400 spectrometer in CDCl3 or MeOD.Data are reported in the following order: chemical shift () in ppm; multiplicities are indicated bs (broadened singlet), s (singlet), d (doublet), m (multiplet), dd (double doubled); coupling constants (J) are in Hertz (Hz). 13C NMR spectra were acquired on a broad band decoupled mode.Mass spectra was conducted on GC-MS Shimadzu QP2010 (column: Equity®-5, length × I.D. 30 m × 0.25 mm, df 0.25 μm, lot # 28089-U, Supelco).HRMS were measured on a Finnigan MAT 95 or LTQ Orbitrap XL spectrometer.IR spectra were measured in a Perkin-Elmer ATR apparatus and are reported in terms of frequency of absorption (cm -1 ).Microwave, CEM marked, Discover SP-D With explorer 12 Hybrid was used.This work was presented in 25th National Chemistry Congress as a poster. 31

General procedure for the synthesis of 1,2-dihydroquinolines under room temperature
The N-substituted aniline (100 mg, 1 eq) was dissolved in acetonitrile (1.5 ml) in a screw-capped test tube and Bi(OTf)3 (5 mol%, 0.05 eq) and methyl pyruvate (2.2 eq) was added to the mixture.This mixture were stirred at room temperature (For the time see: Table 3) until the starting material was completely consumed as monitored by tlc.The resultant residue was direcly purified by flash chromatography on silica (EtOAc:Cyclohexane 2:98).All solid products were recrystallized over pentan and ethyl acetate.
General procedure for the synthesis of 1,2-dihydroquinolines under microvawe conditions N-Substituted aniline (100 mg, 1 eq) was dissolved in acetonitrile (1.5 ml) then Bi(OTf)3 (5 mol%, 0.05 eq) and methyl pyruvate (2.2 eq) were added to the solution.This mixture were heated by microwave irradiation (10 bar, 150 watt, 100 o C, See for the time: Table 1,2 and 3).The progress of the reaction was monitored through tlc.The resultant residue was direcly purified by flash chromatography on silica (EtOAc:Cyclohexane 2:98).All solid products were recrystallized over pentan and ethyl acetate.By this method the following compounds were prepared.

Table 1 .
Effect of catalyst on reaction between o-acetyl aniline and methyl pyruvate a Reaction were carried out with ortho-acetyl aniline (1 eq), methyl pyruvate (2.2 eq).bIsolated yield after silica gel chromatography.c 15 mol% acid was used.

Table 2 .
Effect of solvent on reaction between p-phenoxy aniline and methyl pyruvate