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Synthesis of perhydro-N-(2,2-disubstituted-3-aminopropyl) heterocycles as potentially bioactive compounds and fragments for combinatorial chemistry

  • Sargis S. Hayotsyan EMAIL logo , Gevorg G. Mkryan , Asya A. Aghekyan and Gagik S. Melikyan
Published/Copyright: September 1, 2012
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 18 Issue 4

Abstract

A new method for the preparation of perhydro-­N-(2,2-disubstituted-3-aminopropyl) heterocycles that allows to obtain a large variety of corresponding derivatives with high to moderate yields using simple procedures is described.

Keywords: 2,2-disubstituted-1,3-diaminopropane; ethyl cyanoacetate; perhydroheterocycles

Introduction

The 2,2-disubstituted-1,3-diaminopropane fragment is a fairly common moiety in several biologically active ­compounds. N-Cyclohexyl-1,3-diaminopropane acts as a spermine synthase inhibitor, thus suppressing cancer (particularly human breast cancer) cell growth (Huber et al., 1995). Other types of 1,3-diamino fragments are contained in several pharmaceutical substances, such as apridine, desipiramine, ethylmemazine, and many other analogous compounds.

The common way for the construction of N,N-disubstituted-2,2-disubstituted-1,3-diaminopropanes is through the hydrogenation of corresponding α,α-disubstituted-β-aminonitriles or oximes with lithium aluminum hydride (Zaugg et al., 1953; Hine et al., 1975). Sodium in ethanol (Faust et al., 1959) can also be used for the hydrogenation of the oximes. 1,3-Dinitropropanes have also been reduced with hydrogen over a Raney nickel at 20°C and elevated pressures (Lamm et al., 1970).

Results and discussion

In the current report, a new way for the synthesis of N-(3-amino-2,2-disubstituted) perhydroheterocycles 3a–x starting from a cyanoacetic ester is described. In the first step, the reaction between ethyl cyanoacetate and the corresponding perhydro-NH heterocycles furnished the amides of cyanoacetic acid 1. These products 1 were converted into the corresponding α,α-disubstituted amides 2 by alkylation with appropriate alkyl halides. Then the amides 2 were reduced with lithium aluminum hydride (LAH) (Mndzhoyan et al., 1971) to give the desired N-(3-amino-2,2-dialkyl)-perhydroheterocycles 3a–x in yields of about 70% (Scheme 1). Some of the obtained compounds (3b,c,h,i,k) are highly reactive toward carbon dioxide from the air. Accordingly, after distillation, they were converted into stable oxalates and further characterized in that form.

Scheme 1
Scheme 1

Conclusions

A new, inexpensive, and highly convenient method for the synthesis of N-substituted perhydroheterocycles is described. These compounds are interesting as individual substances as well as the fragments for the combinatorial chemistry.

Experimental section

All initial compounds were of commercial grade and used without further purification. Yields refer to the isolated compounds. Melting points were determined on SMP-10 melting point apparatus. Infrared spectra were recorded in KBr pellets on a Nicolet Avatar 330 spectrometer. 1H NMR spectra were obtained in a DMSO-d6 solution at 30°C, at 300 MHz, on a Varian Mercury 300 VX spectrometer, with TMS as internal standard.

General procedure for the synthesis of N-(3-amino-2,2-disubstituted)-perhydroheterocycles 3a–x

A mixture of ethyl cyanoacetate (10.7 mL, 0.1 mol) and corresponding perhydroheterocycle (0.1 mol) was stirred for 2 h at room temperature and afterward kept at room temperature for 2 days. The resultant crystals of 1 (yield 70–80%) were filtered and washed with diethyl ether.

Further, a solution of corresponding amide 1 (0.05 mol) in DMSO (100 mL) was treated with NaOH (8 g, 0.2 mol), and the mixture was treated dropwise with methyl iodide (7 mL, 0.11 mol) at 15–20°C or with α,ω-dichloro derivative ClCH2YCH2Cl (0.055 mol) at 50–55°C and then heated at 80–85°C for 2 h. After cooling, the mixture was extracted with benzene (3×50 mL), and the extract was washed with water, dried with MgSO4 and concentrated on a rotary evaporator. The residue was distilled under reduced pressure (2–3 mm Hg).

To obtain compounds 3a–x, the solution of amide 2 (0.02 mol) in dry diethyl ether (10 mL) was added dropwise to the stirred solution of LAH (6.08 g, 0.16 mol) in dry diethyl ether (30 mL) over 20 min. Then the mixture was heated under reflux for 12 h and quenched with water (20 mL) on the ice/water bath. The precipitate was filtered off and washed with ether. The filtrate and the ether were combined and dried with anhydrous sodium sulfate. After the removal of the solvent, the residue was distilled under reduced pressure. In the case when the amine was unstable in a free form, the distillate was treated with oxalic acid, and the resultant oxalate was crystallized from water and dried at 50–60°C/20 mm Hg.

2,2-Dimethyl-3-pyrrolidinopropan-1-amine (3a)

Yield 77%; bp 59–60°C/2 mm Hg; IR: 3417, 3387, 3329 cm-1; 1H NMR: δ 0.81 (s, 6H, 2CH3), 1.05–1.21 (br, 2H, NH2), 1.67–1.72 (m, 4H, (CH2)2), 2.27 (s, 2H, NCH2), 2.40 (s, 2H, CH2NH2), 2.52–2.57 (m, 4H, (CH2)2N). Anal. Calcd for C9H20N2: C, 69.17; H, 12.90; N, 17.93. Found: C, 69.06; H, 12.83; N, 18.04.

2,2-Dimethyl-3-piperidinopropan-1-amine (3b)

Yield 75%; bp 61–62°C/3 mm Hg; (mp of oxalate 143–145°C); IR: 3431, 3392, 3342 cm-1; 1H NMR of oxalate: δ 0.98 (s, 6H, 2CH3), 1.42 (dd, J = 11 Hz and 6 Hz, 2H, CH2CH2CH2), 1.60 (td, J = 11 Hz and 6 Hz, 4H, CH2CH2CH2), 2.39 (s, 2H, NCH2), 2.53–2.63 (m, 4H, (CH2)2N), 2.83 (s, 2H, CH2NH2), 5.04–6.99 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C10H22N2: C, 70.53; H, 13.02; N, 16.45. Found: 70.30; H, 12.93; N, 16.30.

3-Azepano-2,2-dimethylpropan-1-amine (3c)

Yield 73%; bp 65–67°C/2 mm Hg; (mp of oxalate 140–142°C); IR: 3419, 3389, 3332 cm-1; 1H NMR of oxalate: δ 1.16 (s, 6H, 2CH3), 1.68 (br, 4H), and 1.86 br (4H, (CH2)4), 2.94 (br, 2H, CH2N), 3.23 (br, 4H, (CH2)2N), 3.48 (br, 2H, CH2NH2), 12.43 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C13H26N2O4: C, 56.91; H, 9.55; N, 10.21. Found: C, 57.15; H, 9.42; N, 10.49.

2,2-Dimethyl-3-(4-methylpiperazino)propan-1-amine (3d)

Yield 85%; bp 85–90°C/2 mm Hg; IR: 3425, 3393, 3341 cm-1; 1H NMR: δ 0.78 (s, 6H, 2CH3), 0.90–1.30 (br, 2H, NH2), 2.11 (s, 2H, CH2N), 2.15 (s, 3H, CH3N), 2.25–2.30 (m, 4H, (CH2)2N), 2.39 (s, 2H, CH2NH2), 2.44–2.50 (m, 4H, (CH2)2N). Anal. Calcd for C10H23N3: C, 64.81; H, 12.51; N, 22.68. Found: C, 64.98; H, 12.39; N, 22.57.

3-(3,4-dihydroisoquinolin-2(1H)-yl)-2,2-dimethylpropan-1-amine (3e)

Yield 69%; bp 148–150°C/2 mm Hg; IR: 3427, 3381, 3341 cm-1; 1H NMR: δ 0.85 (s, 6H, 2CH3), 1.95 (brs, 2H, NH2), 2.31 (s, 2H, CH2N), 2.47 (s, 2H, CH2NH2), 2.71–2.85 (m, 4H, NCH2CH2), 3.66 (s, 2H, NCH2Ar), 6.86–6.92 (m, 1H), and 6.94–7.04 (m, 3H, Ar). Anal. Calcd for C14H22N2: C, 77.01; H, 10.16; N, 12.83. Found: C, 76.97; H, 10.03; N, 12.95.

1-Aminomethyl-1-(pyrrolidinomethyl)cyclopentane (3f)

Yield 68%; bp 135–136°C/2 mm Hg; IR: 3422, 3379, 3335 cm-1; 1H NMR: δ 1.22–1.32 (m, 2H) and 1.44–1.58 (m, 6H, (CH2)4), 1.37–1.61 (br, 2H, NH2), 1.66–1.73 (m, 4H, (CH2)2), 2.41 (s, 2H, NCH2), 2.48–2.53 (m, 6H, (CH2)2N and CH2NH2). Anal. Calcd for C11H22N2: C, 72.47; H, 12.16; N, 15.37. Found: C, 72.55; H, 12.01; N, 15.26.

1-Aminomethyl-1-(pyrrolidinomethyl)cyclohexane (3g)

Yield 67%; bp 140–141°C/2 mm Hg; IR: 3420, 3380, 3330 cm-1; 1H NMR: δ 1.18–1.47 (m, 10H, (CH2)5), 1.67–1.74 (m, 4H, (CH2)2), 2.43 (s, 2H, NCH2), 2.55–2.62 (m, 4H, (CH2)2N), 2.66 (s, 2H, CH2NH2), 4.10 (brs, 2H, NH2). Anal. Calcd for C12H24N2: C, 73.41; H, 12.32; N, 14.27. Found: C, 73.54; H, 12.15; N, 14.12.

4-Aminomethyl-4-(pyrrolidinomethyl)tetrahydro-4H-pyran (3h)

Yield 65%; bp 145–146°C/2 mm Hg; (mp of oxalate 150–151°C); IR: 3429, 3381, 3329 cm-1; 1H NMR of oxalate: δ 1.42–1.50 (m, 4H, 2CH2), 1.71–1.74 (m, 4H, (CH2)2), 2.73–2.80 (m, 4H, (CH2)2N), 2.81 (s, 2H, NCH2), 3.07 (s, 2H, CH2NH2), 3.48–3.64 (m, 4H, (CH2)2O), 5.70–6.70 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C11H22N2O: C, 66.62; H, 11.18; N, 14.13. Found: 66.45; H, 11.29; N, 14.23.

1-Aminomethyl-1-(piperidinomethyl)cyclopentane (3i)

Yield 68%; bp 138–140°C/2 mm Hg; (mp of oxalate 149–150°C); IR: 3430, 3389, 3345 cm-1; 1H NMR of oxalate: δ 1.34–1.49 (m, 5H) and 1.58–1.72 (m, 9H, 7CH2), 2.59–2.68 (m, 6H, 3NCH2), 2.93 (s, 2H, CH2NH2), 6.06–6.09 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C14H26N2O4: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.55; H, 9.26; N, 9.89.

1-Aminomethyl-1-(piperidinomethyl)cyclohexane (3j)

Yield 70%; bp 150–155°C/2 mm Hg; IR: 3425, 3375, 3327 cm-1; 1H NMR: δ 1.13–1.44 (m, 10H, (CH2)5), 1.15–1.65 (br, 2H, NH2), 1.46–1.56 (m, 6H, (CH2)3), 2.12 (s, 2H, NCH2), 2.37–2.45 (m, 4H, (CH2)2N), 2.52 (s, 2H, CH2NH2). Anal. Calcd for C13H26N2: C, 74.23; H, 12.46; N, 13.32. Found: C, 74.35; H, 12.34; N, 13.19.

4-Aminomethyl-4-(piperidinomethyl)tetrahydro-4H-pyran (3k)

Yield 65%; bp 160–162°C/2 mm Hg; (mp of oxalate 148–150°C); IR: 3427, 3384, 3321 cm-1; 1H NMR of oxalate: δ 1.38–1.52 (m, 6H, (CH2)3), 1.57 (dt, J = 11 Hz and 6 Hz, 2CH2), 2.49 (s, 2H, NCH2), 2.52–2.62 (br, 4H, (CH2)2N), 3.09 (s, 2H, CH2NH2), 3.53–3.61 (m, 4H, (CH2)2O), 5.28–6.70 (br, 4H, NH2 + H2C2O4). Anal. Calcd for C14H26N2O5: C, 55.61; H, 8.67; N, 9.26. Found: C, 55.48; H, 8.49; N, 9.32.

1-Aminomethyl-1-(azepanomethyl)cyclopentane (3l)

Yield 75%; bp 127–130°C/3 mm Hg; IR: 3432, 3395, 3335 cm-1; 1H NMR: δ 1.21–1.44 (m, 4H) and 1.50–1.63 (m, 12H, 8 CH2), 1.84 (br, 2H, NH2), 2.41 (s, 2H, CH2N), 2.49 (s, 2H, CH2NH2), 2.63–2.70 (m, 4H, (CH2)2N). Anal. Calcd for C13H26N2: C, 74.23; H, 12.46; N, 13.32. Found: C, 74.52; H, 12.39; N, 13.46.

1-Aminomethyl-1-(azepanomethyl)cyclohexane (3m)

Yield 78%; bp 128–134°C/2 mm Hg; IR: 3430, 3390, 3341 cm-1; 1H NMR: δ 1.12–1.48 (m, 10H, (CH2)5), 1.56 (br, 8H, (CH2)4), 2.35 (s, 2H, CH2N), 2.53 (s, 2H, CH2NH2), 2.65–2.70 (m, 4H, (CH2)2N), 2.40–3.00 (br, 2H, NH2). Anal. Calcd for C14H28N2: C, 74.94; H, 12.58; N, 12.48. Found: C, 74.81; H, 12.49; N, 12.61.

4-Aminomethyl-4-(azepanomethyl)tetrahydro-4H-pyran (3n)

Yield 58%; bp 142–145°C/2 mm Hg; IR: 3423, 3378, 3328 cm-1; 1H NMR: δ 1.33–1.38 (m, 4H, 2 CH2), 1.57 (br, 8H, (CH2)4), 1.50–1.70 (br, 2H, NH2), 2.44 (s, 2H, CH2N), 2.63 (s, 2H, CH2NH2), 2.67–2.73 (m, 4H, (CH2)2N), 3.46–3.56 (m, 4H, (CH2)2O). Anal. Calcd for C13H26N2O: C, 68.98; H, 11.58; N, 12.38. Found: C, 68.82; H, 11.71; N, 12.47.

1-Aminomethyl-1-(4-methylpiperazinomethyl)cyclopentane (3o)

Yield 72%; bp 128–130°C/3 mm Hg; IR: 3418, 3393, 3341 cm-1; 1H NMR: δ 1.20–1.32 (m, 2H) and 1.39–1.58 (m, 6H, (CH2)4), 2.10–2.50 (br, 2H, NH2), 2.15 (s, 3H, CH3N), 2.25 (s, 2H, CH2N), 2.25–2.33 (m, 4H, (CH2)2N), 2.39–2.47 (m, 4H, (CH2)2N), 2.45 (s, 2H, CH2NH2). Anal. Calcd for C12H25N3: C, 68.20; H, 11.92; N, 19.88. Found: C, 68.05; H, 11.83; N, 19.78.

1-Aminomethyl-1-(4-methylpiperazinomethyl)cyclohexane (3p)

Yield 81%; bp 136–138°C/3 mm Hg; IR: 3420, 3384, 3337 cm-1; 1H NMR: δ 1.14–1.45 (m, 10H, (CH2)5), 2.14 (s, 3H, CH3N), 2.18 (s, 2H, CH2N), 2.23–2.33 (m, 4H, (CH2)2N), 2.44–2.49 (m, 4H, (CH2)2N), 2.51 (s, 2H, CH2NH2), 2.55–3.05 (br, 2H, NH2). Anal. Calcd for C13H27N3: C, 69.28; H, 12.08; N, 18.64. Found: C, 69.08; H, 12.17; N, 18.70.

4-Aminomethyl-4-(4-methylpiperazinomethyl)tetrahydro-4H-pyran (3q)

Yield 77%; bp 154–155°C/2 mm Hg; IR: 3429, 3378, 3335 cm-1; 1H NMR: δ 1.37 (dd, J = 6.6, 4.7 Hz, 4H, 2 CH2), 1.05–2.09 (br, 2H, NH2), 2.16 (s, 3H, CH3N), 2.27 (s, 2H, CH2N), 2.28–2.33 (m, 4H, (CH2)2N), 2.47–2.52 (m, 4H, (CH2)2N), 2.62 (s, 2H, CH2NH2). Anal. Calcd for C12H25N3O: C, 63.40; H, 11.08; N, 18.48. Found: C, 63.51; H, 11.02; N, 18.51.

1-Aminomethyl-1-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}cyclopentane (3r)

Yield 68%; bp 175–176°C/2 mm Hg; IR: 3418, 3389, 3327 cm-1; 1H NMR: δ 1.30–1.42 (m, 2H) and 1.45–1.63 (m, 6H, (CH2)4), 2.19–2.90 (br, 2H, NH2), 2.45 (s, 2H, CH2N), 2.53 (s, 2H, CH2NH2), 2.73–2.78 (m, 2H), and 2.80–2.86 (m, 2H, NCH2CH2), 3.64 (s, 2H, NCH2Ar), 6.89–6.95 (m, 1H), and 6.99–7.04 (m, 3H, Ar). Anal. Calcd for C16H24N2: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.51; H, 9.95; N, 11.59.

1-Aminomethyl-1-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}cyclohexane (3s)

Yield 65%; bp 182–185°C/2 mm Hg; IR: 3431, 3386, 3325 cm-1; 1H NMR: δ 1.22–1.49 (m, 10H, (CH2)5), 2.37 (s, 2H, CH2N), 2.54–2.90 (br, 2H, NH2), 2.59 (s, 2H, CH2NH2), 2.73–2.83 (m, 4H, NCH2CH2), 3.65 (s, 2H, NCH2Ar), 6.85–6.91 (m, 1H), and 6.96–7.02 (m, 3H, Ar). Anal. Calcd for C17H26N2: C, 79.02; H, 10.14; N, 10.84. Found: C, 79.15; H, 10.06; N, 10.79.

4-Aminomethyl-4-{[3,4-dihydroisoquinolin-2(1H)-yl]methyl}tetrahydro-4H-pyran (3t)

Yield 62%; bp 195–198°C/2 mm Hg; IR: 3426, 3379, 3329 cm-1; 1H NMR: δ 1.39–1.46 (m, 4H, 2 CH2), 2.46 (s, 2H, CH2N), 2.68 (s, 2H, CH2NH2), 2.76–2.85 (m, 4H, NCH2CH2), 2.75–3.03 (br, 2H, NH2), 3.52–3.57 (m, 4H, (CH2)2O), 3.68 (s, 2H, NCH2Ar), 6.89–6.94 (m, 1H), and 6.99–7.04 (m, 3H, Ar). Anal. Calcd for C16H24N2O: C, 73.81; H, 9.29; N, 10.76. Found: C, 73.70; H, 9.45; N, 10.55.

1-Aminomethyl-(1-morpholinomethyl)cyclopentane (3u)

Yield 61%; bp 148–149°C/3 mm Hg; IR: 3422, 3382, 3335 cm-1; 1H NMR: δ 1.21–1.34 (m, 2H) and 1.42–1.59 (m, 6H, (CH2)4), 2.27 (s, 2H, CH2N), 2.30–2.78 (br, 2H, NH2), 2.41–2.45 (m, 4H, (CH2)2N), 2.50 (s, 2H, CH2NH2), 3.54–3.58 (m, 4H, (CH2)2O). Anal. Calcd for C11H22N2O: C, 66.62; H, 11.18; N, 14.13. Found: C, 66.44; H, 11.38; N, 14.36.

1-Aminomethyl-1-(morpholinomethyl)cyclohexane (3v)

Yield 60%; bp 120–122°C/3 mm Hg; IR: 3425, 3376, 3328 cm-1; 1H NMR: δ 1.10–1.50 (br, 2H, NH2), 1.15–1.46 (m, 10H, (CH2)5), 2.18 (s, 2H, CH2N), 2.43–2.48 (m, 4H, (CH2)2N), 2.54 (s, 2H, CH2NH2), 3.50–3.57 (m, 4H, (CH2)2O). Anal. Calcd for C12H24N2O: C, 67.88; H, 11.39; N, 13.19. Found: C, 68.01; H, 11.16; N, 12.98.

1-Aminomethyl-4-morpholinomethyl-tetrahydro-4H-pyran (3w)

Yield 70%; bp 152–153°C/2 mm Hg; IR: 3421, 3385, 3330 cm-1; 1H NMR: δ 1.32–1.40 (m, 4H, 2 CH2), 2.16–2.40 (br, 2H, NH2), 2.26 (s, 2H, CH2N), 2.44–2.48 (m, 4H, (CH2)2N), 2.63 (s, 2H, CH2NH2), 3.47–3.57 (m, 8H, 2 (CH2)2O). Anal. Calcd for C11H22N2O2: C, 61.65; H, 10.35; N, 13.07. Found: C, 61.52; H, 10.46; N, 13.25.

1-Aminomethyl-1-(4-benzylpiperazinomethyl)cyclopentane (3x)

Yield 52%; bp 155–156°C/3 mm Hg; IR: 3420, 3380, 3341 cm-1; 1H NMR: δ 1.20–1.32 (m, 2H) and 1.40–1.60 (m, 6H, (CH2)4), 1.86–2.12 (br, 2H, NH2), 2.27 (s, 2H, NCH2C), 2.33–2.43 (m, 4H, (CH2)2N), 2.43–2.50 (m, 4H, (CH2)2N), 2.47 (br, 2H, NH2), 3.42 (s, 2H, PhCH2), 7.13–7.28 (m, 5H, Ph). Anal. Calcd for C18H29N3: C, 75.21; H, 10.17; N, 14.62. Found: C, 75.35; H, 10.02; N, 14.48.

Corresponding author: Sargis S. Hayotsyan, Scientific Technological Centre of Organic and Pharmaceutical Chemistry, National Academy of Sciences, 26 Azatutyan Avenue, 0014 Yerevan, Armenia

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Received: 2012-6-7
Accepted: 2012-7-19
Published Online: 2012-09-01
Published in Print: 2012-10-01

©2012 Walter de Gruyter GmbH & Co. KG, Berlin/Boston

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https://doi.org/10.1515/hc-2012-0093
Keywords for this article
2,2-disubstituted-1,3-diaminopropane; ethyl cyanoacetate; perhydroheterocycles
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Preliminary Communication
  4. Synthesis of novel NHC-pyrrole-NHC C-N-C Pincer proligands
  5. Research Articles
  6. Synthesis of new tetracyclic paullone derivatives as potential CDK inhibitors
  7. Keto furanylidene building blocks from silyl ethers of monoalkynylated β-keto carbonyls with iron(III) chloride hexahydrate-iodine
  8. Synthesis of perhydro-N-(2,2-disubstituted-3-aminopropyl) heterocycles as potentially bioactive compounds and fragments for combinatorial chemistry
  9. Pirfenidone structural isosteres: design, synthesis and spectral study
  10. Synthesis and characterization of new metallophthalocyanines bearing macrocyclic N3O2 groups on peripheral positions
  11. Synthesis and antimicrobial evaluation of substituted benzimidazolyl fluoroquinolones under conventional and microwave irradiation conditions
  12. Synthesis of novel 2,6-bis(5-t-butylbenzo[b]furan-2-ylcarbonyl)pyridines
  13. An efficient synthesis of 2-substituted benzoxazoles using cerium(III) chloride/sodium iodide as catalyst
  14. Efficient one pot synthesis of triazolotriazine, pyrazolotriazine, triazole, isoxazole and pyrazole derivatives
  15. Synthesis of novel trifluoromethyl-containing heterocycle-fused troponoid compounds
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