Synthesis of 4-methyl-2,3-disubstituted quinoline scaffolds via environmentally benign Fe(III) catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline

Abstract

Environmentally benign Fe(III)-catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline derivatives to the substituted quinoline scaffolds with good to excellent yield in shorter reaction time is described.

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Introduction

Quinoline scaffolds receive much attention due to their pharmacological activity and their presence in the numerous biologically active natural products, particularly in alkaloids.¹ Among the numerous methodologies reported for the synthesis of these scaffolds,² the Friedländer method is an important one; it involves the reaction of 2-aminoacetophenone and a carbonyl compound possessing an active methylene group, in the presence of base or acid.^3,4 Recently modified Friedländer methods^2,4 and transition metal-catalysed reactions have received considerable attention,⁵ having the advantages of higher yield and shorter reaction time. In spite of these advantages, the above methods suffer from functionalising substituent at the aryl ‘A’ ring of the quinoline scaffolds (Scheme 1, eqn (1)). Substitution of an aryl ‘A’ ring influences the electronic properties of a molecule, which may affect its biological activity. Metal residues are not allowed to be present in pharmaceutical industries; for this reason, biocompatible iron-catalysed environmentally benign methods are preferred.⁶ To overcome the above issues we planned the synthesis of 4-methyl-2,3-disubstituted quinolines having an aryl ‘A’ ring with varying substituents indirectly and under environmentally benign conditions. From the previous results, we found that a 2-ethynylaniline in which substitution is possible in the aryl ring is the best choice for an alternative to 2-aminoacetophenone with restricted substitution possibilities (Scheme 1, eqn (2)).⁷

Scheme 1 Concept of synthesis of 4-methyl-2,3-disubstituted quinolines.

To test this hypothesis, we have to choose the correct catalyst that would facilitate condensation of 2-ethynylaniline and 1,3-diketone and further cyclization (Scheme 1, eqn (3), path a), rather than intramolecular cyclization of 2-ethynylaniline followed by coupling of 1,3-diketone, which has already been reported by Antonio Arcadi et. al. (Scheme 1, eqn (3), path b).⁸ A β-enamino carbonyl compound was formed from the condensation of 2-ethynylaniline and 1,3-diketone having bi-nucleophile character,^9,10 which would prefer 6-exo-dig cyclization (C-nucleophile) (Scheme 1, eqn (3), path a1) and aromatization to the expected 4-methyl-2,3-disubstituted quinolines over the 5-endo-dig cyclized product as reported by Hiromichi Fujioka et. al. (N-nucleophile) (Scheme 1, eqn (3), path a2).^10a

Results and discussion

With above-mentioned task to test this methodology, first we chose an iron salt as catalyst from the interesting results of iron-catalysed synthesis of α-carbonyl furan derivatives by Huanfeng Jiang et. al.^6d and iron-catalysed construction of oxa- and azacycles through the Prins cyclization by Martín et. al.^6g It was observed that 1 equivalent of 1a and 1 equiv. of 2a with Fe(OTs)₃·6H₂O as catalyst at 80 °C with 1,2-DCE as solvent gave the expected product at a 52% yield with a trace amount of the condensation product 4 and intramolecular cyclized product 5 as a side product (Table 1, entry 1). FeCl₃ and FeCl₂ gave reduced yields of 41% and 36%, respectively (Table 1, entry 2 and 3 respectively). Changing to toluene as a choice of solvent at 110 °C, the yield increased to 81% (Table 1, entry 4). When the above-mentioned reaction was carried out at room temperature, only traces of 3a was obtained (Table 1 entry 5). Increasing or decreasing the catalyst loading resulted in decreased yield (Table 1, entries 6,7 and 8). When the reaction was carried out in ethanol as solvent at 80 °C, only 11% of 3a with 3-ethoxy-5,5-dimethylcyclohex-2-enone as a major product was obtained (Table 1, entry 9). On further attempts, we found that 1.5 equivalent of 1a and 1 equivalent of 2a with 0.1 equivalent of catalyst Fe(OTs)₃·6H₂O at 110 °C gave the best yield of 3a at 86% (Table 1, entries 10–12). No trace of product was identified when the reaction was carried out in the absence of catalyst (Table 1, entry 13). Finally, we achieved Fe(OTs)₃·6H₂O-catalysed sequential condensation, cyclization and aromatization of 1,3-diketone and 2-ethynylaniline in a one-pot manner. To the best of our knowledge this is the first report of the synthesis of 4-methyl-2,3-disubstituted quinolines by an iron(III)-catalysed reaction of 2-ethynylaniline and 1,3-diketones.

Table 1 Optimization of reaction condition for 3a

Entry	Catalyst (equivalents)	Solvent	Temp (°C)	Yield^b of 3a (%)
a 1 equivalent of 1a and 1 equivalent of 2a under nitrogen atmosphere for 2 h.b Isolated yield.c Trace amount of 4 and 5 was observed.d We observed 3-ethoxy-5,5-dimethylcyclohex-2-enone as a major product.e 1.2 equivalents of 1a.f 1.5 equivalents of 1a.g 2.0 equivalents of 1a.
1	Fe(OTs)3·6H2O (0.1)	1,2-DCE	80	52^c
2	FeCl3 (0.1)	1,2-DCE	80	41^c
3	FeCl2 (0.1)	1,2-DCE	80	36^c
4	Fe(OTs)3·6H2O (0.1)	Toluene	110	81
5	Fe(OTs)3·6H2O (0.1)	Toluene	R.T	Trace
6	Fe(OTs)3·6H2O (0.05)	Toluene	110	69
7	Fe(OTs)3·6H2O (0.2)	Toluene	110	77
8	Fe(OTs)3·6H2O (0.5)	Toluene	110	70
9	Fe(OTs)3·6H2O (0.1)	Ethanol	80	11^d
10^e	Fe(OTs)3·6H2O (0.1)	Toluene	110	81
11^f	Fe(OTs)3·6H2O (0.1)	Toluene	110	86
12^g	Fe(OTs)3·6H2O (0.1)	Toluene	110	78
13	Fe(OTs)3·6H2O (0)	Toluene	110	—

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The product structure was confirmed by comparing the NMR of isolated compound 3a with previously reported data.^4d After confirming the product structure and with optimal reaction conditions in hand, we tested the scope of the reaction and the results are presented in Table 2. All the six-membered cyclic 1,3-diketone gave a similar yield compared to parent dimedone (Table 2, entries 1–4), whereas five-membered cyclic 1,3-diketone gave a reduced yield of 73% (Table 2, entry 5). The diketone 1d exclusively afforded the single isomer 3d, whose structure was confirmed by 2D NMR experiments. We distinguished between the possible isomeric structures 3d and 3d′ by HMBCs. The aliphatic 2CH₃ give a signal at 1.24 ppm with 6 integral values in ¹H NMR, which give HSQCs with 24.8 ppm carbon. In HMBCs, two CH₃ protons gave a correlation with 205.5 ppm carbonyl carbon, which clearly confirms the structure of 3d and excludes the possibility of 3d′. If the structure were 3d′, then two CH₃ protons would not give HMBCs with 205.5 ppm carbonyl carbon (Fig. 1). Diketones like acetyl acetone, ethyl and methyl acetoacetate gave reduced yield when compared with dimedone (Table 2, entries 6–8). Next, we studied the effect of substituents on the 2-ethynylaniline, and the similar yields obtained: the substituents on the 2-ethynylaniline aryl ring had no effect (Table 2, entries 9–12). 2-[(trimethylsilyl)ethynyl]aniline (2f) gave a reduced yield of 77% with trace amounts of condensation product (Table 2, entry 13).

Table 2 Substrate scope of the reaction

Entry	Substrate 1	Substrate 2	Product 3	Yield^a of 3 (%)
a Isolated yield.b Trace amount of 3-(2-(2-(trimethylsilyl)ethynyl)phenylamino)-5,5-dimethylcyclohex-2-enone was observed.
1				86
2		2a		82
3		2a		84
4		2a		81
5		2a		73
6		2a		78
7		2a		74
8		2a		75
9	1a			84
10	1a			85
11	1a			83
12	1a			81
13	1a		3a	77^b

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Fig. 1 Confirmation of 3d by HMBCs.

In further attempts to synthesize 4-aminoquinoline derivatives from 1,3-diketone 1 and 2-amino benzonitrile 7, only cyclic 1,3-diketones (1a and 1b) gave the expected product whereas acyclic 1,3-diketone (1g and 1h) failed. When comparing dimedone 1a (Table 3, entry 1) and cyclohexa-1,3-dione 1b (Table 3, entry 2), the former gave comparatively more yield. The acyclic 1,3-diketone reaction proceeded to enamine formation and failed to further cyclize (Table 3, entry 3 and 4).

Table 3 Attempt to 4-aminoquinoline derivatives

Entry	Substrate 1	Substrate 7	Product 8	Yield^a^,^b of 8 (%)
a Isolated yield.b Reaction time 12 h.c Reaction precede up to enamine formation and failed to further cyclization.
1				68
2		7		53
3		7	—^c	—
4		7	—^c	—

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From the intermediate 4 obtained in Table 1, (entries 1–3) we concluded that the reaction goes through the intermediate 4. Based on the previous report, we proposed a plausible mechanism for this cascade cyclization, in which iron acts as a Lewis acid (Scheme 2).^6f,11 Initial activation of carbonyl group of 1,3-diketone 1a and subsequent condensation with 2a leads to the intermediate 4. The triple bond of 4 is activated by the catalyst and 6-exo-dig cyclization with enone carbon C2 to give intermediate II via I. Elimination of a proton and protodemetallation of intermediate II gave intermediate III, which on further aromatisation led to the product 3a.

Scheme 2 Plausible mechanism for 3a.

The mechanism was further confirmed by control experiments: the reaction of intermediate product 4 under standard conditions (Table 1, entry 11) gave a quantitative yield of 3a (Scheme 3, eqn (1)), which shows that the reaction mechanism goes through the intermediate 4. Also, to check whether the reaction goes through the Lewis acid-catalysed hydration of 2-ethynylaniline and followed (release of water on enamine formation) by the reaction of 1a and 2a under the 0.1 equivalent of catalyst Fe(OTs)₃·6H₂O at 110 °C of toluene reflux in the presence of 4 Å molecular sieves, we found that it gave the expected product in a similar yield when compared to the Table 1, entry 11 (Scheme 3, eqn (2)). This proves the proposed mechanism, where the initial enamine formation is followed by Fe(III)-catalysed C-cyclization directly onto the alkyne and not through the acid-catalysed hydration of the alkyne (Scheme 3).

Scheme 3 Control experiments for the confirmation of reaction mechanism.

When compared to the report by Zhu et al.,^9a our method has the advantages of a shorter reaction time and use of a catalytic amount of biocompatible iron catalyst, whereas in the Zhu et al. report, the reaction required longer time and use of a stoichiometric amount of p-toluenesulfonic acid in the reaction medium. In addition, our report is mechanistically different from the report by Zhu et al.

Conclusions

In conclusion, we have described the synthesis of 4-methyl-2,3-disubstituted quinoline in a cascade manner that features environmentally benign biocompatible and inexpensive iron(III) as a catalyst with only water as the side product, with good to excellent yield in a shorter reaction time using readily available starting materials. In this method, substitutions are possible in the aryl ‘A’ ring of quinoline, which is difficult using the previously reported methods. Further reactions of 2-ethynylanilines and 1,3-diketone are underway in our lab.

Experimental section

General methods

Purification of crude compounds was done by column chromatography using silica gel (100–200 mesh, Himedia). FTIR spectra were recorded on a Perkin-Elmer Spectrum Two TM IR spectrometer; absorbances are reported in cm⁻¹. NMR spectra were recorded on a Bruker 400 MHz spectrometer. The chemical shifts are reported in parts per million (ppm) relative to the internal standard TMS (δ = 0 ppm) for ¹H NMR (recorded at 400 MHz) and relative to the central CDCl₃ resonance (δ = 77.16 ppm) for ¹³C NMR (recorded at 100 MHz). The coupling constants J are given in Hz. High-resolution mass spectra were recorded on Q-TOF micro mass and JEOL GCMATE II GC-MS spectrometers. All solvents and commercially available chemicals were used as received and 2-alkynylaniline derivatives (2a–f) were prepared according to the literature reports.¹²

General procedure for synthesis of compounds 3a–3l

To a stirred solution of the 1,3-diketone 1 (1.5 equiv.) in toluene, the 2-ethynylaniline 2 (1.0 equiv.) and Fe(OTs)₃·6H₂O (0.1 equiv.) were added, and the resulting mixture was heated at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine solution and dried over Na₂SO₄. Removal of the solvent under reduced pressure and purification by column chromatography furnished the desired product. For all new compounds (3d and 3i–3l), spectral data are given below and for the reported compounds (3a–3c, 3e–3h, 8a, and 8b), see ref. 2 and 4.

3,4-Dihydro-2,2,9-trimethylacridin-1(2H)-one (3d)

Compound 3d was prepared by general procedure above. After purification by column chromatography (PE : EtOAc 6 : 4) the desired compound was isolated as a brownish orange viscous fluid. IR (Neat) ν_max: 475, 757, 797, 861, 960, 1073, 1138, 1115, 1194, 1258, 1385, 1425, 1495, 1563, 1613, 1681, 2864, 2927, 2964, 3070 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 3.26 (t, J = 6.5 Hz, 2H), 2.94 (s, 3H), 2.02 (t, J = 6.5 Hz, 2H), 1.24 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ = 205.5, 161.4, 150.1, 147.8, 131.4, 129.0, 127.7, 126.3, 125.4, 125.1, 43.6, 34.9, 30.5, 24.8, 16.2; HRMS (ESI/[M + H]⁺) calcd for C₁₆H₁₈NO, 240.1388, found 240.1393.

3,4-Dihydro-3,3,7,9-tetramethylacridin-1(2H)-one (3i)

Compound 3i was prepared by general procedure above. After purification by column chromatography (PE : EtOAc 6 : 4) the desired compound was isolated as a yellow viscous liquid. IR (Neat) ν_max: 579, 615, 694, 718, 769, 804, 859, 1063, 1102, 1176, 1231, 1287, 1349, 1365, 1447, 1522, 1560, 1595, 1673, 2852, 2924, 3068 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 2.97 (s, 2H), 2.85 (s, 3H), 2.46 (s, 2H), 2.37 (s, 3H), 0.94 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ = 200.9, 160.2, 149.0, 146.9, 136.2, 133.8, 128.9, 127.7, 124.5, 124.2, 54.9, 48.5, 32.21, 28.4, 22.0, 16.0; HRMS (ESI/[M + H]⁺) calcd for C₁₇H₂₀NO, 254.1545, found 254.1545.

7-Chloro-3,4-dihydro-3,3,9-trimethylacridin-1(2H)-one (3j)

Compound 3j was prepared by general procedure above. After purification by column chromatography (PE : EtOAc 6 : 4) the desired compound was isolated as a brownish yellow viscous liquid. IR (Neat) ν_max: 453, 512, 573, 651, 697, 833, 888, 971, 1090, 1132, 1116, 1214, 1277, 1300, 1337, 1369, 1386, 1468, 1565, 1606, 1682, 2871, 2933, 2956, 3045 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 3.14 (s, 2H), 2.99 (s, 3H), 2.65 (s, 2H), 1.12 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ = 200.5, 161.5, 148.7, 146.7, 132.4, 132.3, 130.9, 128.5, 124.8, 124.6, 54.9, 48.5, 32.2, 28.4, 16.1; HRMS (ESI/[M + H]⁺) calcd for C₁₆H₁₇ClNO, 274.0999, found 274.1002.

3,4-Dihydro-3,3,9-trimethyl-7-nitroacridin-1(2H)-one (3k)

Compound 3k was prepared by general procedure above. After purification by column chromatography (PE : EtOAc 6 : 4) the desired compound was isolated as a yellow viscous liquid. IR (Neat) ν_max: 435, 495, 580, 646, 691, 741, 856, 895, 912, 971, 1066, 1123, 1214, 1266, 1303, 1371, 1445, 1488, 1521, 1564, 1617, 1687, 2851, 2950, 3106 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 9.20 (s, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 3.23 (s, 2H), 3.15 (s, 3H), 2.72 (s, 2H), 1.16 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ = 199.9, 165.2, 151.7, 150.5, 145.5, 131.1, 126.9, 125.5, 124.8, 122.8, 54.7, 48.8, 32.2, 28.4, 16.4; HRMS (ESI/[M + H]⁺) calcd for C₁₆H₁₇N₂O₃, 285.1239, found 285.1240.

3,4-Dihydro-5-methoxy-3,3,9-trimethyl-7-nitroacridin-1(2H)-one (3l)

Compound 3l was prepared by general procedure above. After purification by column chromatography (PE : EtOAc 6 : 4) the desired compound was isolated as a brownish yellow viscous liquid. IR (Neat) ν_max: 513, 613, 740, 790, 846, 874, 1058, 1110, 1182, 1247, 1338, 1372, 1395, 1490, 1528, 1564, 1585, 1615, 1688, 2871, 2958, 3107 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ = 8.80 (s, 1H), 7.88 (s, 1H), 4.20 (s, 3H), 3.32 (s, 2H), 3.12 (s, 3H), 2.71 (s, 2H), 1.15 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ = 200.1, 164.2, 156.1, 151.7, 145.7, 142.7, 127.6, 126.1, 114.2, 102.9, 57.1, 54.8, 49.0, 32.3, 28.4, 16.7; HRMS (ESI/[M + H]⁺) calcd for C₁₇H₁₉N₂O₄, 315.1345, found 315.1345.

Acknowledgements

One of the authors, M.S. thanks the Council of Scientific and Industrial Research, New Delhi, India for the research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra for all new compounds. See DOI: 10.1039/c4ra03666b

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