Unexpected Behavior of Enaminones: Interesting New Routes to 1,6-Naphthyridines, 2-Oxopyrrolidines and Pyrano[4,3,2-de][1,6]naphthyridines

Abstract

Reaction of enaminones 1a–d with 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2) in the presence of AcOH/NH₄OAc afforded 7-amino-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile derivatives 9a–d. On the other hand, 2-aminopyrano[4,3,2-de][1,6]naphthyridine-3-carbonitriles 20a–c,e were the only obtained products from the reactions of 1a–d with 2 in the presence of AcOH/NaOAc, while 1d afforded [3,5-bis-(4-chloro-benzoyl)-phenyl]-(4-chloro-phenyl)-methanone 21 under the same condition. The reaction of 2 with diethyl acetylenedicarboxylate in the presence of AcOH/NH₄OAc afforded (4-cyano-5-dicyanomethylene-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid ethyl ester 15B.

1. Introduction

During the last decade we have been involved in a program aimed at exploring the synthetic potentials of enaminones [1] as building blocks for polyfunctionally substituted aromatics and heteroaromatics [1,2,3]. We have in the past successfully developed syntheses of polysubstituted benzenes [4,5] and polysubstituted pyridines [6,7] utilizing enaminones 1a–d as starting materials. In the present article we report our further results in this area where a novel one pot synthesis of 7-amino-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitriles 9a–d, 2-aminopyrano[4,3,2-de][1,6]naphthyrid-ine-3-carbonitrile derivatives 20a–c,e and (4-cyano-5-dicyanomethylene-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid ethyl ester 15B could be achieved. To our knowledge only one derivative of the 2-aminopyrano[4,3,2-de][1,6]naphthyridine-3-carbonitrile system has been reported, prepared via a multistep route [8]. The newly synthesized 2-aminopyrano[4,3,2-de][1,6]naphthyridine-3-carbonitrile derivatives 20a–c,e seem interesting for biological activity investigations as investigations on such polynuclear aromatics are rare [8].

2. Results and Discussion

Although the reaction of enaminone 1c and 3-amino-2-cyanopent-2-enedinitrile (2) in refluxing acetic acid in presence of ammonium acetate (NH₄OAc) has been reported earlier [1,9] to afford 2,4-diamino-5-benzoylisophthalonitrile, with molecular formula C₁₅H₁₀N₄O and molecular mass M⁺ = 262, we found, however, that enaminone 1c and compound 2 react in acetic acid in the presence of NH₄OAc to yield a completely different product with the same molecular formula and molecular mass. Both starting compounds the enaminone 1 and 3-amino-2-cyanopent-2-enedinitrile (2) are bifunctional reactants. The carbonyl group of 1 can form an imine (1 + 2→ 3) or participate in a Knoevenagel reaction with the methylene group of 2 (1 + 2→ 6). Michael-type additions 1+2→ 4 or 1 + 2→ 5 are other alternatives. The subsequent ring closure reactions can lead to the pyridine derivatives 7 or 8. Finally, the 1,6-naphthyridine systems 9–12 can also be generated. The yields obtained from 1a–d are between 75 and 90%. We have depicted all possible end products that could be obtained from reacting 1a–d and 2 in Scheme 1 as secondary carbamides, but their tautomers having a hydrogen atom bound to N-1 or to the oxygen atom have to be considered as well. The structure determination of the reaction products of 1a–d and 3-amino-2-cyanopent-2-enedinitrile (2) proved to be very difficult, because all twelve possible 1,6-naphthyridine derivatives should have similar ¹H- and ¹³C-NMR spectra. Therefore, we performed a series of 2D NMR measurements: (¹H,¹H)COSY, (¹H,¹³C)HSQC, (¹H,¹³C)HMBC, (¹H,¹⁵N)HSQC, (¹H,¹⁵N)HMBC, and INADEQUATE. The final decision was made in favor of the structures 9a–d. Figure 1 and Figure 2 showed the ¹H, ¹³C and ¹⁵N chemical shifts and the results of the 2D-INADEQUATE and the two HMBC measurements which represent the basis for the assignment of the chemical shifts (Scheme 1).

Scheme 1.

Formation of compounds 9a–d.

Figure 1.

Upper part: (¹³C, ¹H)- and (¹⁵N, ¹H) couplings nJ (n = 2–4) according to the crosspeaks observed in the HMBC measurements of 9c. Lower part: Assignment of all ¹H, ¹³C and ¹⁵N signals of 9c. The δ values obtained in CD₃SOCD₃ at room temperature are related to TMS and NH₃ (liquid). The measurements were performed at 14.1 T (600 MHz for ¹H).

Figure 2.

Upper part: (¹³C, ¹H)- and (¹⁵N, ¹H) couplings nJ (n = 2–4) according to the crosspeaks observed in the HMBC measurements of 9d. Lower part: Assignment of all ¹H, ¹³C and ¹⁵N signals of 9d. The δ values obtained in CD₃SOCD₃ at room temperature are related to TMS and NH₃ (liquid). The measurements were performed at 14.1 T (600 MHz for ¹H).

In order to extend this finding further we reacted 3-amino-2-cyanopent-2-enedinitrile (2) with diethyl acetylenedicarboxylate (13) in the presence of AcOH/NH₄OAc. In this case, however, ethyl (4-cyano-5-dicyanomethylene-2-oxo-pyrrolidin-3-ylidene) acetate 15B was obtained as indicated by an X-ray crystal structure determination (Figure 3) [10]. It is believed that compound 2 reacts with 13 to initially afford adduct 14 that cyclizes preferably to the pyrrolidine 15 rather than the alternative pyridine derivative 16 (Scheme 2). Although 15 has been shown to exist as a solid, in DMSO solution only form 15B exists, as indicated by the ¹H-NMR data that showed a singlet at δ = 5.50 ppm for the methylene proton and a broad signal at δ = 2.48 ppm for proton of the dicyanomyl moiety.

Figure 3.

X-ray crystal structure of compound 15A.

Scheme 2.

Formation of compound 15B.

We conducted the same reactions of enaminones 1a–c,e with 3-amino-2-cyanopent-2-enedinitrile (2) in the presence of AcOH/NaOAc. This reaction afforded in this case a different product with molecular formula C₂₀H₁₀N₄O₂S₂ and molecular mass M⁺= 402. It is believed that compound 1a reacted with 3-amino-2-cyanopent-2-enedinitrile (2) to form the highly unsaturated intermediates 17a–c,e and their anions 18a–c,e, respectively (Scheme 3).

Scheme 3.

Formation of compounds 20a–c,e.

The intermediate 18 can undergo a cyclic π-electron shift (6π → 3σ + 3π, valence isomerization) to 19a–c,e. Protonation of 19a–c,e, followed by 1,5-H-shift and dehydrogenation lead finally to the 2-aminopyrano[4,3,2-de][1,6]naphthyridine-3-carbonitrile 20a–c,e. Yields of 20a–c,e amounted to 85–92% when 2:1-mixtures of 1 and 2 were refluxed in AcOH/NaOAc. The reaction of 1d with 2 under the same conditions afforded [3,5-bis-(4-chloro-benzoyl)-phenyl]-(4-chloro-phenyl)-methanone 21 previously obtain by upon refluxing 1d in AcOH. It has been previously observed that 1d readily trimerise on attempted condensation with nucleophils [12].

The structure determination of 20 was based on 2D NMR measurements (COSY, HSQC, HMBC and (¹H, ¹⁵N) HMBC) of 20a and on a crystal structure analysis of 20c (Figure 4 and Figure 5) [11].

Figure 4.

Crystal structure of 20c.

Figure 5.

Left part: (¹³C,¹H) couplings ⁿJ (n = 2–4) according to the crosspeaks observed in HMBC measurement of 20a. Right part: Assignment of all ¹H and ¹³C signals and one ¹⁵N signal of 20a. The δ values obtained in CD₃SOCD₃ at room temperature are related to TMS and NH₃ (liquid). The measurements were performed at 14.1 T (600 MHz for ¹H).

3. Experimental

3.1. General

Melting points are reported uncorrected and were determined with a Sanyo (Gallaenkamp) instrument. Infrared spectra were recorded using KBr pellets and a Perkin-Elmer 2000 FT–IR instrument. ¹H- and ¹³C-NMR spectra were determined by using a Bruker DPX instrument at 600 MHz for ¹H-NMR and 150 MHz for ¹³C-NMR and either CDCl₃ or DMSO-d₆ solutions with TMS as internal standards. Chemical shifts are reported in δ (ppm). Mass spectra were measured using VG Autospec Q MS 30 and MS 9 (AEI) spectrometer, with the EI (70 EV) mode. Elemental analyses were carried out by using a LEOCHNS-932 Elemental Analyzer. X-ray crystal structure determined by using a Single Crystal X-ray Crystallography-Rigaku Rapid II & Bruker X8 Prospector system.

3.2. General Procedure for the Synthesis of 9a–d

A mixture of enaminone 1a–d (0.01 mol) and 3-amino-2-cyanopent-2-enedinitrile (2, 1.32 g, 0.01 mol) in AcOH (25 mL)/NH₄OAc (1 g) was heated under reflux for 2 h (followed until completion by TLC using 1:1 ethyl acetate–petroleum ether as eluent). The mixture was then cooled and poured onto ice-water. The solid, so formed, was collected by filtration and recrystallized from AcOH to give yellow crystals.

7-Amino-5-oxo-2-(thienyl)-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (9a). Yield 75%; mp. 291–292 °C. Anal. Calcd. for C₁₃H₈N₄OS (268.29): C, 58.20; H, 3.01; N, 20.88; S, 11.95%. Found: C, 58.17; H, 3.13; N, 20.65; S, 11.92%; IR (KBr, cm⁻¹): 3471 (NH), 3363, 3295 (NH₂) 2252 (CN), 1652 (CO); ¹H-NMR (DMSO-d₆): δ = 7.05 (br, 2H, NH₂, D₂O exchangeable), 7.21 (t, 1H, J = 4.0, thienyle-H), 7.69 (d, 1H, J = 8.0, CH), 7.77 (d, 1H, J = 4.0, thienyl-H), 7.94 (d, 1H, J = 4.0, thienyl-H), 8.22 (d, 1H, J = 8.0, CH), 11.22 (br, 1H, NH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ = 160.6, 156.1, 155.2, 154.4, 143.6, 136.2, 130.9, 128.6, 127.7, 116.2, 113.5, 112.56, 67.4. MS: m/z (%) 268 (M⁺, 40), 256 (35), 241 (15), 213 (25), 185 (25), 169 (20), 129 (55), 97 (40), 73 (100).

7-Amino-2-(furyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (9b). Yield 80%; mp. 287–289 °C. Anal. Calcd. for C₁₃H₈N₄O₂ (252.23): C, 61.90; H, 3.20; N, 22.21%. Found: C, 61.84; H, 3.31; N, 22.32%; IR (KBr, cm⁻¹): 3424 (NH), 3343, 3240 (NH₂), 2214 (CN), 1662 (CO); ¹H-NMR (DMSO-d₆): δ = 6.72 (t, 1H, J = 4.0, furyl-H), 7.05 (br, 2H, NH₂, D₂O exchangeable), 7.25 (d, 1H, J = 4.0, furyl-H), 7.51 (d, 1H, J = 8.0, CH), 7.94 (d, 1H, J = 4.0, furyl-H), 8.25 (d, 1H, J = 8.0, CH), 11.24 (br, 1H, NH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ = 160.1, 155.3, 154.5, 152.4, 152.3, 145.7, 136.3, 116.4, 113.3, 112.7, 112.6, 111.9, 67.5. MS: m/z (%) 252 (M⁺, 100), 224 (20), 195 (10), 73 (90).

7-Amino-5-oxo-2-phenyl-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (9c). Yield 90%; mp. 253–255 °C. Anal. Calcd. for C₁₅H₁₀N₄O (262.27): C, 68.69; H, 3.84; N, 21.36%. Found: C, 68.65; H, 3.75; N, 21.40%; IR (KBr, cm⁻¹): 3325 (NH), 3251, 3209 (NH₂), 2209 (CN), 1673 (CO); ¹H-NMR (DMSO-d6): δ = 7.07 (br, 2H, NH₂, D₂O exchangeable), 7.52–7.53 (m, 3H, Ph-H), 7.75 (d, 1H, J = 8.0, CH), 8.20–8.21 (m, 2H, Ph-H), 8.28 (d, 1H, J = 8.0, CH), 11.27 (br, 1H, NH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ = 160.8, 160.2, 155.2, 154.3, 137.5, 136.4, 130.3, 128.8 (2C), 127.2 (2C), 116.5, 114.8, 113.1, 67.8. MS: m/z (%) 262 (M⁺, 100), 234 (15), 217 (10), 192 (5), 164 (10), 129 (10), 83 (10), 73 (25).

7-Amino-2-(4-chlorophenyl)-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile (9d). Yield 90%; mp. 275–276 °C. Anal. Calcd. for C₁₅H₉ClN₄O (296.72): C, 60.72; H, 3.06; N, 18.88%. Found: C, 60.70; H, 3.11; N, 18.87%; IR (KBr, cm⁻¹): 3436 (NH), 3324, 3216 (NH₂), 2211 (CN), 1678 (CO); ¹H-NMR (DMSO-d₆): δ = 7.06 (s, 2H, NH₂, D₂O exchangeable), 7.54 (d, 2H, Ph-H), 7.69 (d, 1H, J = 8.0, CH), 8.17 (d, 2H, Ph-H), 8.23 (d, 1H, J = 8.0, CH), 11.25 (br, 1H, NH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ = 160.7, 158.8, 155.2, 154.2, 136.4, 136.2, 135.2, 129.0 (2C), 128.8 (2C), 116.4, 114.6, 113.2, 67.8. MS: m/z (%) 296 (M⁺, 100), 268 (20), 216 (15), 189 (15), 164 (10), 130 (10), 88 (15), 73 (20).

Synthesis of (4-cyano-5-dicyanomethylene-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid ethyl ester (15B). A mixture of 3-amino-2-cyanopent-2-enedinitrile (2, 1.32 g, 0.01 mol) and diethyl acetylenedicarboxylate (13, 1.70 g, 0.01 mol) in AcOH (25 mL)/NH₄OAc (1 g) was refluxed for 2 h (followed until completion by TLC using 1:1 ethyl acetate–petroleum ether as eluent). The mixture was cooled and then was poured onto ice-water. The solid, so formed, was collected by filtration and recrystallized from EtOH to give orange crystals, yield 70%; mp. 200–202 °C. Anal. Calcd. for C₁₂H₈N₄O₃ (256.22): C, 56.25; H, 3.15; N, 21.87%. Found: C, 56.22; H, 3.27; N, 22.00%; IR (KBr, cm⁻¹): 3363 (NH), 2223 (CN), 2211 (2CN), 1695 (CO), 1653 (CO); ¹H-NMR (DMSO-d₆): δ = 1.22 (t, 3H, J = 8.0, CH₃), 2.48 (br, 1H, , J = 8.0, CH), 4.10 (q, 2H, CH₂), 5.50 (s, 1H, CH), 10.84 (br, 1H, NH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ = 169.0, 165.8, 161.3, 138.5, 117.2, 116.0, 115.6, 100.1 (2C), 68.2, 59.0, 14.2. MS: m/z (%) 256 (M⁺, 50), 211 (15), 184 (75), 156 (10), 112 (100), 97 (10), 84 (25), 70 (25), 55 (90).

3.3. General Procedure to Syntheses of 20a–c,e

A mixture of enaminone 1a–e (0.01 mol) and 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2, 1.32 g, 0.01 mol) in AcOH/NaOAc (1 g) was refluxed for 2 h (followed until completion by TLC using 1:1 ethyl acetate–petroleum ether as eluent). The mixture was cooled and then was poured onto ice-water. The solid, so formed, was collected by filtration and recrystallized from AcOH to give yellow crystals.

2-Amino-8-(thiophen-2-yl)-6-(thiophene-2-carbonyl)pyrano-[4,3,2-de][1,6]naphthyridine-3-carbonitrile (20a). Yield 92%; mp. 369–370 °C. Anal. Calcd. for C₂₀H₁₀N₄O₂S₂ (402.45): C, 59.69; H, 2.50; N, 13.92; S, 15.93%. Found: C, 59.72; H, 2.33; N, 13.97; S, 15.86%; IR (KBr, cm⁻¹): 33363, 3295 (NH₂), 2213 (CN), 1642 (CO); ¹H-NMR (DMSO-d₆): δ = 7.27 (t, 1H, J = 4.0, thienyl-H), 7.31 (t, 1H, J = 4.0, thienyl-H), 7.47 (s, 1H, CH), 7.78 (d, 1H, J = 4.0, thienyl-H), 7.86 (br, 3H, thienyl-H, NH₂, D₂O exchangeable), 7.94 (d, 1H, J = 4.0, thienyl-H), 8.16 (d, 1H, J = 4.0, thienyl-CH), 8.98 (s, 1H, CH); ¹³C-NMR (DMSO-d₆): δ = 184.8, 162.1, 160.4, 157.2, 156.2, 154.0, 143.7, 136.1, 135.8, 134.1 (2C), 131.6, 129.3, 129.00, 128.9, 118.1, 115.9, 104.0, 98.3, 77.1 . MS: m/z (%) 402 (M⁺, 100), 373 (15), 319 (25), 263 (5), 236 (5), 187 (10), 111 (30), 83 (5).

2-Amino-6-(furan-2-carbonyl)-8-(furan-2-yl)pyrano[4,3,2-de]-[1,6]naphthyridine-3-carbonitrile (20b). Yield 90%; mp. 375–377 °C. Anal. Calcd. for C₂₀H₁₀N₄O₄ (370.32): C, 64.87; H, 2.72; N, 15.13%. Found: C, 64.88; H, 2.68; N, 15.22%; IR (KBr, cm⁻¹): 3471, 3373(NH₂), 2210 (CN), 1653 (CO); ¹H-NMR (DMSO-d₆): δ = 6.78 (t, 1H, J = 4.0, furyl-H), 6.82 (t, 1H, J = 4.0, furyl-H), 7.19 (d, 1H, J = 4.0, furyl-H), 7.44 (s, 1H, CH), 7.46 (d, 1H, J = 4.0, furyl-H), 7.83 (br, 2H, NH₂, D₂O exchangeable), 8.04 (d, 1H, J = 4.0, furyl-H), 8.24 (d, 1H, J = 4.0, furyl-H), 8.98 (s, 1H, CH); ¹³C-NMR (DMSO-d₆): δ = 179.20, 162.29, 161.98, 160.13, 157.31, 156.08, 151.64, 150.06, 148.72, 147.23, 145.30, 140.47, 121.34, 117.48, 115.76, 113.36, 112.97, 103.98, 97.56, 77.23. MS: m/z (%) 370 (M⁺, 90), 264 (15), 224 (25), 195 (15), 169 (10), 129 (10), 83 (30), 73 (35).

2-Amino-6-benzoyl-8-phenylpyrano[4,3,2-de][1,6]naphthpyrid-ine-3-carbonitrile (20c). Yield 88%; mp. 318–319 °C. Anal. Calcd. for C₂₄H₁₄N₄O₂ (390.11): C, 73.84; H, 3.61; N, 14.35%. Found: C, 73.92; H, 3.6; N, 14.28%; IR (KBr, cm⁻¹): 3445, 3341 (NH₂), 2216 (CN), 1646 (CO); ¹H-NMR (DMSO-d₆): δ = 7.56–7.61 (m, 5H, Ph-H), 7.65 (s, 1H, CH), 7.69–7.86 (m, 7H, Ph-H, NH₂, D₂O exchangeable), 8.72 (s, 1H, CH); ¹³C-NMR (DMSO-d₆): δ = 193.50, 162.10, 160.86, 158.22, 158.31, 156.20, 141.80, 141.10, 137.70, 135.20, 132.90, 131.60, 130.70, 129.60 (2C), 129.30, 128.80 (2C), 125.70, 117.75, 115.77, 104.21, 100.10, 77.10. MS: m/z (%) 390 (M⁺, 100), 373 (15), 313 (65), 257 (10), 230 (10), 188 (5), 181 (5), 105 (20), 77 (25).

2-Amino-6-(4-methoxybenzoyl)-8-(4-methoxyphenyl)pyrano-[4,3,2-de][1,6]naphthyridine-3-carbonitrile (20e). Yield 85%; mp. 325–327 °C. Anal. Calcd. for C₂₆H₁₈N₄O₄ (450.45): C, 69.33; H, 4.03; N, 12.44%. Found: C, 69.40; H, 4.12; N, 12.42%; IR (KBr, cm⁻¹): 3424, 3343 (NH₂), 2214 (CN), 1644 (CO); ¹H-NMR (DMSO-d₆): δ = 3.84 (s, 3H, CH₃), 3.88 (s, 3H, CH₃), 7.07-7.11 (m, 4H, Ph-H), 7.42 (s, 1H, CH), 7.75–7.80 (m, 6H, Ph-H, NH₂, D₂O exchangeable), 8.69 (s, 1H, CH); ¹³C-NMR (DMSO-d₆): δ = 191.90, 163.30, 162.90, 160.82, 158.21, 157.65, 157.50, 156.20, 140.81, 132.11 (2C), 130.16 (2C), 127.50, 123.10, 118.62, 115.53, 114.27 (2C), 114.10 (2C), 103.90, 98.50, 77.15, 55.36, 55.41. MS: m/z (%) 450 (M⁺, 100), 419 (20), 407 (5), 343 (30), 300 (10), 211 (15), 135 (25), 107 (5), 77 (20).

3.4. Synthesis of [3,5-bis-(4-chlorobenzoyl)phenyl]-(4-chlorophenyl)methanone (21)

A mixture of enaminone 1d (2.09 g, 0.01 mol) and 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2, 1.32 g, 0.01 mol) in AcOH/NaOAc (1 gm) was refluxed for 2 h (followed until completion by TLC using 1:1 ethyl acetate–petroleum ether as eluent). The mixture was cooled and then was poured onto ice-water. The solid, so formed, was collected by filtration and recrystallized from AcOH to give faint yellow crystals, yield 80%. This product was also prepared via refluxing 1d in AcOH as described earlier by Elnagdi et al. [12].

4. Conclusions

New simple and efficient routes for the synthesis of 7-amino-5-oxo-5,6-dihydro-1,6-naphthyridine-8-carbonitrile derivatives 9a–d, (4-cyano-5-dicyanomethylene-2-oxo-pyrrolidin-3-ylidene)-acetic acid ethyl ester 15B and 2-aminopyrano[4,3,2-de][1,6]naphthyridine-3-carbonitrile derivatives 20a–c,e from the reaction of enaminones with 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2) have been described. These products look interesting for potential biological evaluation. Moreover, all the products have latent functional moieties that seem interesting precursors to other derivatives of the described ring systems.