JBCS

INTRODUCTION

Indane or 2,3-dihydro-1H-indene (1) is a mixed hydrocarbon from the petroleum industry with appropriate basic structure for obtaining derivatives. Rigidity and planarity are important characteristics of the indane skeleton,^1,2 present in several molecules with biological activity, such as indinavir^®, an HIV^2,3 (human immunodeficiency virus) protease inhibitor.^3,4 This hydrocarbon can be modified in several ways, including the insertion of hydroxyl, carbonyl and carbon-carbon double bond functional groups into the pentacyclic ring. Among some of the possible derivatives (Figure 1), 1-indanone (2) is used as a base intermediate in the synthesis of several therapeutic agents such as eranz^® or donepezil hydrochloride, an inhibitor of the enzyme acetylcholinesterase (AChE), used in the treatment of Alzheimer's disease.^5,6

 

 

 

 

There are reports⁷ of acetylcholinesterase inhibition with the use of amides and imides, where some new anilide and imide derivatives of 4-aminopyridine (4AP) have been synthesized and evaluated for anamnesis, cognition-enhancing, and anticholinesterase activity by means of their respective in vitro and in vivo models.

We are interested in the preparation of esters, such as 3a (Figure 1), from the 1-indanone oxime (3) in view of their possible biological activities. Oximes esters can be used as agrochemical and medicinal agents^8-11 and as precursors for the synthesis of bioactive heterocyclic compounds.¹² Thus, the cyclic ketone 1-indanone (2) allowed the easy preparation of its oxime which, in turn, would lead to obtaining the desired esters. The oximes allow the production of amides that are important building blocks in organic synthesis, since they are widely used in the production of plastics, rubbers, papers, colored paints and water and sewage treatment.^13-15 In addition, amides play an important role as feedstock for the production of analgesic-antipyretic drugs.^16,17 The Beckmann rearrangement (BR) is a powerful method in organic synthesis for the preparation of amides or lactams from ketones and is often employed in chemical industry especially for the preparation of e-caprolactam. The conventional BR of ketoximes occurs in the presence of strong Bronsted or Lewis acids such as concentrated sulfuric acid, PCl₅ in diethyl ether, hydrogen chloride in acetic anhydride, resulting in large amount of by-products causing environmental hazards and serious corrosion problems.^18-20 The BR of oximes is more an important case where the constitution of a reaction product is used to assign configuration to its precursor. In this rearrangement the migrating group retains its configuration. However, even when the migrating group is achiral, there is an important stereochemical aspect to the rearrangement: the group that migrates is the trans group to the OH moiety of the oxime. This fact allows one to infer the stereochemistry of the oxime from the nature of the amide formed from it.²¹ In this paper, we report efficient syntheses for cyclic imides from an oxime (3) involving Beckmann-type rearrangement in one-pot reactions.

The use of bioinformatics in developing new drugs has significantly reduced costs and the time required. Understanding the mechanisms of molecular interaction between the receptor and the ligand and rationalizing how a potential drug can act in this process is one of the most significant challenges of molecular biology and a crucial aspect for success in planning new medicines within the rational drug design approach.²²

In this context, research with oximes and their derivatives, such as imides, presents itself as a promising tool in the search for new therapeutic agents through computer simulations. It also enables the investigation of the mechanism of anticholinesterase action.

 

EXPERIMENTAL

General experimental procedures

The reagents and solvents used were purchased from Sigma-Aldrich® (Saint Louis, USA), Vetec^® (Caxias do Sul, Brazil), Synth^® (Diadema, Brazil) and Fluka^® (Munich, Germany). Low resolution mass spectra (EIMS) were obtained on a Shimadzu GC-2010 Plus instrument coupled to a GCMS-QP2010SE mass spectrometer using capillary column (30 m × 0.25 µm) at flow rate of 1.46 mL min^-1 using helium as the carrier gas; high resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF II instrument - method NaFormate_ESI_pos_100-900_Lab-Mass.m. The ¹H and ¹³C NMR (nuclear magnetic resonance) spectra were recorded on a Bruker DPX-300 spectrometer, 300 and 75.5 MHz, respectively, using CDCl₃ as solvent; chemical shifts reported in ppm (d scale) with residual CHCl₃ (d 7.27) as internal standard for ¹H NMR and the central peak of the triplet (d 77.23) of CDCl₃ for ¹³C NMR; spin-spin coupling constant (J) in hertz (Hz). Columns chromatography were performed using silica gel 60 (70-230 mesh, Vetec®) eluted with hexane, hexane:CH₂Cl₂ 9:1, hexane:CH₂Cl₂ 8:2 and CH₂Cl₂. The chemical reactions were monitored by analytical thin layer chromatography (TLC), performed on Merck silica gel 60 F254 plates, visualized by ultraviolet (UV) irradiation (254 nm) and by spraying with vanilin/perchloric acid/EtOH solution followed by heating.

Preparation of (E)-2,3-dihydro-1H-inden-1-one oxime (3)

Ketoxime (3) was synthesized from the 1-indanone, following the procedure described in literature.²⁰ In typical preparation, a flask equipment equipped with reflux condenser was charged with 3.9 mL of EtOH, 2.8 mmol (194.46 mg) of hydroxylamine hydrochloride, 4.0 mmol (328.12 mg) of sodium acetate and 1.0 mmol (132.16 mg) of 2-indanone. The reaction system was heated at 70 ºC for 24 h and, after cooling, the white precipitate was collected by filtration, washed with water and dried to give oxime (3) (93% yield).

General procedure of imides using acid anhydrides

Preparation of imides 5a-5c: reactions of 3 with acid anhydrides

The imides 5a-5c (Figure 3) were obtained by the reaction of the corresponding acid anhydrides a-c with the oxime (3). Thus, to a solution of 3 (100 mg, 0.68 mmol) and dimethylaminopyridine (DMAP, 23 mg, 0.2 mmol) in CH₂Cl₂ (8 mL) were added, in individual experiments, the acid anhydrides a, b and c (2 mmol of each), and the systems were stirred at room temperature for 2 h. Subsequently, the reaction mixtures were extracted with a 5% NaHCO₃ solution (3 × 10 mL). The organic phases (dried with Na₂SO₄) were then evaporated in vacuo and the respective products subjected to silica gel column chromatography using CH₂Cl₂ as eluent to afford 5a (121 mg, 95%), 5b (133 mg, 91%) and 5c (152 mg, 92%).

 

 

General procedure of imides using fatty acid

Preparation of imides 5d-5k: reactions with fatty acids

The imides 5d-5k, (Figure 4) were obtained by the reaction of the corresponding fatty acids d-k with the oxime (3). Thus, to a solution of 3 (0.68 mmol, 100 mg), dicyclohexylcarbodiimide (DCC, 268 mg, 1.3 mmol) and DMAP (1.3 mmol, 158 mg) in CH₂Cl₂ (3 mL) were added, in individual experiments, the fatty acids d (184 μL, 1.3 mmol), e (226 μL, 1.3 mmol), f (224 mg, 1.3 mmol), g (242 mg, 1.3 mmol), h (260 mg, 1.3 mmol), i (333 mg, 1.3 mmol), j (370 mg, 1.3 mmol) and k (410 μL, 1.3 mmol), and the systems were stirred at room temperature for 2 h. Subsequently, CH₂Cl₂ (10 mL) was added to the mixture, it was filtered and extracted with a 5% NaHCO₃ solution (3 × 20 mL). The organic phases (dried with Na₂SO₄) were then evaporated and the respective products subjected to silica gel chromatographic columns using mixtures of hexane + EtOAc in increasing polarity. The pure products (5d-5k) were obtained in average yields of about 81 to 90%: 5d (154 mg, 88%), 5e (165 mg, 85%), 5f (183 mg, 90%), 5g (179 mg, 84%), 5h (198 mg, 89%), 5i (229 mg, 88%), 5j (229 mg, 82%) and 5k (225 mg, 81%).

 

 

(E)-2,3-Dihydroinden-1-one oxime (3)

White solid; mp 147-150 ºC; ¹H NMR (300 MHz, CDCl₃) d 7.65 (1H, d, J 7.6 Hz, H-7), 7.28 (2H, m, H-4, H-6), 7.19 (1H, m, H-5), 3.09 (2H, m, 2H-2), 2.93 (2H, m, 2H-3); ¹³C NMR (300 MHz, CDCl₃) d 164.26 (C-1), 148.65 (C-8), 136.15 (C-9), 130.61 (CH-6), 127.21 (CH-4), 125.82 (CH-5), 121.82 (CH-7), 28.73 (CH₂-2), 26.19 (CH₂-3).

1-Acetyl-3,4-dihydroquinolin-2(1H)-one (5a)

Yellow solid; mp 200-202 ºC; ¹H NMR (300 MHz, CDCl₃) d 7.90 (1H, d, J 7.6 Hz, H-7), 7.43 (1H, t, J 7.2 Hz, H-5), 7.34 (1H, br d, H-4), 7.30 (1H, tl, H-6), 3.04 (2H, m, 2H-3), 3.00 (2H, m, 2H-2), 2.23 (3H, s, 3H-2'); ¹³C NMR (300 MHz, CDCl₃) d 170.50 (C-1), 169.28 (C-1'), 149.95 (C-9), 134.49 (C-8), 132.25 (CH-5), 127.44 (CH-6), 125.82 (CH-4), 123.36 (CH-7), 28.67 (CH₂-3), 27.84 (CH₂-2), 19.90 (CH₂-2'); EIMS m/z (rel. int.) [M]⁺ 189 (48), 147 (100), 119 (30), 91 (22), 43 (37); HRMS m/z [M]⁺ 189.0789 (calcd. for C₁₁H₁₁NO₂, 189.2118), [M + Na]⁺ 212.0681, [C₉H₁₀NO]⁺ 148.0759, [C₉H₈N]⁺ 130.0657.

1-Butyryl-3,4-dihydroquinolin-2(1H)-one (5b)

Yellow liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.43 (1H, t, J 7.6 Hz, H-5), 7.35 (1H, br d, H-4), 7.30 (1H, tl, H-6), 3.08 (2H, m, 2H-3), 3.03 (2H, m, 2H-2), 2.48 (2H, t, J 7.4 Hz, 2H-2'), 1.77 (2H, m, 2H-3'), 1.03 (3H, t, J 6.5 Hz, 3H-4'); ¹³C NMR (300 MHz, CDCl₃) d 171.59 (C-1'), 170.62 (C-1), 149.91 (C-9), 134.56 (C-8), 132.22 (CH-5), 127.45 (CH-6), 125.80 (CH-4), 123.44 (CH-7), 35.13 (CH₂-2'), 28.67 (CH₂-3), 27.86 (CH₂-2), 18.72 (CH₂-3'), 13.94 (CH₃-4'); EIMS m/z (rel. int.) [M]⁺ 217 (11), 147 (100), 130 (40), 103 (16), 71 (40), 43 (44); HRMS m/z [M]⁺ 217.1102 (calcd. for C₁₃H₁₅NO₂, 217.2995), [2M + Na]⁺ 457.2104, [M + Na]⁺ 240.0988, [C₉H₁₀NO]⁺ 148.0756, [C₉H₈N]⁺ 130.0655.

1-Hexanoyl-3,4-dihydroquinolin-2(1H)-one(5c)

Yellow liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.43 (1H, t, J 7.3 Hz, H-5), 7.34 (1H, br d, H-4), 7.30 (1H, tl, H-6), 3.08 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.49 (2H, t, J 7.5 Hz, 2H-2'), 1.74 (2H, m, 2H-3'), 1.37 (4H, m, 4',5'), 0.91 (3H, t, J 6.7 Hz, 3H-6'); ¹³C NMR (300 MHz, CDCl₃) d 171.79 (C-1'), 170.60 (C-1), 149.90 (C-9), 134.57 (C-8), 132.22 (CH-5), 127.45 (CH-6), 125.79 (CH-4), 123.45 (CH-7), 33.23 (CH₂-2'), 31.51 (CH₂-4'), 28.68 (CH₂-3), 27.85 (CH₂-2), 24.90 (CH₂-3'), 22.51 (CH₂-5'), 14.14 (CH₃-6'); EIMS m/z (rel. int.) [M]⁺ 245 (14), 147 (85), 132 (100), 99 (30), 71 (14), 43 (43); HRMS m/z [M]⁺ 245.1415 (calcd. for C₁₅H₁₉NO₂, 245.3261), [C₉H₁₀NO]⁺ 240.0549, [C₉H₁₀NO]⁺ 148.0761, [C₉H₈N]⁺ 130.0659.

1-Heptanoyl-3,4-dihydroquinolin-2(1H)-one(5d)

Yellow liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.43 (1H, t, J 7.3 Hz, H-5), 7.34 (1H, br d, H-4), 7.28 (1H, tl, H-6), 3.08 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.49 (2H, t, J 7.4 Hz, 2H-2'), 1.72 (2H, m, 2H-3'), 1.21-1.42 (6H, m, 4'-6'), 0.88 (3H, t, J 6.4 Hz, 3H-7'); ¹³C NMR (300 MHz, CDCl₃) d 171.74 (C-1'), 170.58 (C-1), 149.89 (C-9), 134.59 (C-8), 132.21 (CH-5), 127.44 (CH-6), 125.78 (CH-4), 123.45 (CH-7), 33.26 (CH₂-2'), 31.64 (CH₂-5'), 29.04 (CH₂-4'), 28.67 (CH₂-3), 27.84 (CH₂-2), 25.17 (CH₂-3'), 22.68 (CH₂-6'), 14.21 (CH₃-7'); EIMS m/z (rel. int.) [M]⁺ 259 (1), 147 (100), 130 (54), 113 (49), 85 (25), 43 (62.5); HRMS m/z [M]⁺ 259.1572 (calcd. for C₁₆H₂₁NO₂, 259.3506), [C₁₁H₉NNaO₂]⁺ 210.1269, [C₉H₁₀NO]⁺ 148.0754, [C₉H₈N]⁺ 130.0653.

1-Nonanoyl-3,4-dihydroquinolin-2(1H)-one(5e)

Yellow liquid; ¹H NMR (300 MHz) d 7.91 (1H, d, J 7.7 Hz, H-7), 7.42 (1H, t, J 7.1 Hz, H-5), 7.34 (1H, br d, H-4), 7.28 (1H, tl, H-6), 3.07 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.48 (2H, t, J 7.5 Hz, 2H-2'), 1.73 (2H, m, 2H-3'), 1.28 (10H, m, 4'-8'), 0.88 (3H, tl, J 7.5 Hz, 3H-9'); ¹³C NMR (300 MHz, CDCl₃) d 171.73 (C-1'), 170.54 (C-1), 149.87 (C-9), 134.58 (C-8), 132.19 (CH-5), 127.4 (CH-6), 125.78 (CH-4) 123.41 (CH-7), 33.25 (CH₂-2'), 31.98 (CH₂-7'), 29.40-29.30 (CH₂-4'-CH₂-6'), 28.66 (CH-3), 27.83 (CH₂-2), 25.21 (CH₂-3'), 22.81 (CH₂-8'), 14.26 (C-9'); EIMS m/z (rel. int.) [M]⁺ 287 (0.1), 147 (100), 130 (70), 115 (30), 103 (74), 89 (23), 77 (60), 63 (29), 51 (43), 39 (25); HRMS m/z [M]⁺ 287.1885 (calcd. for C₁₈H₂₅NO₂, 287.4047), [C₉H₁₀NO]⁺ 148.0760, [C₉H₈N]⁺ 130.0658.

1-Decanoyl-3,4-dihydroquinolin-2(1H)-one(5f)

Brown liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.42 (1H, t, 7.4Hz, H-5), 7.34 (1H, br d, H-4), 7.29 (1H, br t, H-6), 3.07 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.48 (2H, t, J 7.5 Hz, 2H-2'), 1.73 (2H, m, 2H-3'), 1.28 (12H, m, 4'-9'), 0.88 (3H, t, J 6.9 Hz, 3H-10'); ¹³C NMR (300 MHz, CDCl₃) d 171.79 (C-1'), 170.59 (C-1), 149.90 (C-9), 134.57 (C-8), 132.21 (C-5), 127.45 (C-6), 125.79 (C-4), 123.45 (C-7), 33.27 (C-2'), 32.06 (C-8'), 29.90-29.37 (C-4'-C-7'), 28.67 (C-3), 27.85 (C-2), 25.22 (C-3'), 22.86 (C-9'), 14.30 (C-10'); EIMS m/z (rel. int.) [M]⁺ 301 (2), 147 (100), 130 (52), 103 (17), 85 (13), 71 (30), 57 (26), 43 (30); HRMS m/z [M]⁺ 301.2041 (calcd. for C₁₉H₂₇NO₂, 301.4317), [C₁₁H₉NNaO₂]⁺ 210.1272, [C₉H₁₀NO]⁺ 148.0756, [C₉H₈N]⁺ 130.0653.

1-Undecanoyl-3,4-dihydroquinolin-2(1H)-one(5g)

Brown liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.43 (1H, t, J 7.5 Hz, H-5), 7.34 (1H, br d, H-4), 7.28 (1H, br t, H-6), 3.08 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.49 (2H, t, J 7.5 Hz, 2H-2'), 1.74 (2H, m, 2H-3'), 1.27 (14H, m, 4'-10'), 0.88 (3H, t, J 6.2 Hz, 3H-11'); ¹³C NMR (300 MHz, CDCl₃) d 171.75 (C-1'), 170.56 (C-1), 149.88 (C-9), 134.60 (C-8), 132.20 (CH-5), 127.44 (CH-6), 125.49 (CH-4), 123.44 (CH-7), 33.28 (CH₂-2'), 32.08 (CH₂-9'), 29.72-29.37 (CH₂-4'-CH₂-8'), 28.68 (C-3), 27.85 (C-2), 25.23 (CH₂-3'), 22.87 (CH₂-10'), 14.29 (CH₃-11'); EIMS m/z (rel. int.) [M]⁺ 315 (0.1), 169 (16), 147 (100), 130 (35), 103 (15), 85 (16.5), 57 (29), 43 (25); HRMS m/z [M]⁺ 315.2198 (calcd. for C₂₀H₂₉NO₂, 315.4587), [C₉H₁₀NO]⁺ 148.0759, [C₉H₈N]⁺ 130.0656.

1-Dodecanoyl-3,4-dihydroquinolin-2(1H)-one(5h)

Brown liquid; ¹H NMR (300 MHz, CDCl₃) and ¹³C NMR (300 MHz, CDCl₃) see Table 2; EIMS m/z (rel. int.) C₂₁H₃₁NO₂, [M]⁺ 329 (0.1%), [C₁₂H₂₃O]⁺ 183 (10.5), [C₉H₁₀NO]⁺ 148 (19), [C₉H₉NO]⁺ 147 (100), [C₉H₈N]⁺ 130 (45.7), [C₇H₅N]⁺ 103 (23), [C₆H₁₃]⁺ 85 (17), [C₅H₁₁]⁺ 71 (22), [C₄H₉]⁺ 57 (44), [C₃H₇]⁺ 43 (40).

1-Palmitoyl-3,4-dihydroquinolin-2(1H)-one (5i)

White solid; mp 301-303 ºC; ¹H NMR (300 MHz, CDCl₃) d 7.91 (1H, d, J 7.7 Hz, H-7), 7.42 (1H, t, J 7.7 Hz, H-5), 7.34 (br d, H-4), 7.29 (1H, br t, H-6), 3.08 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.48 (2H, t, J 7.4 Hz, 2H-2'), 1.73 (2H, m, 2H-3'), 1.24 (24H, m, 4'-15'), 0.87 (3H, t, J 6.9 Hz, 3H-16'); ¹³C NMR (300 MHz, CDCl₃) d 171.74 (C-1'), 170.55 (C-1), 149.88 (C-9), 134.61 (C-8), 132.20 (CH-5), 127.44 (CH-6), 125.79 (CH-4), 123.44 (CH-7), 33.28 (CH₂-2'), 32.12 (CH₂-14'), 29.89-29.38 (CH₂-4'-CH₂-13'), 28.68 (CH₂-3), 27.85 (CH₂-2), 25.24 (CH₂-3'), 22.89 (CH₂-15'), 14.31 (CH₃-16'); EIMS m/z (rel. int.) C₂₅H₃₉NO₂, [M]⁺ 385 (no peak), 147 (100), 130 (42), 115 (17), 103 (51), 91 (13), 77 (24), 51 (15); HRMS m/z [M]⁺ 385.3056 (calcd. for C₁₉H₂₇NO₂, 385.5939), [C₁₀H₁₇O]⁺ 153.0080, [M + 1]⁺ 386.3053, [M + Na]⁺ 408.2873, [M + K]⁺ 424.2620, [2M + Na]⁺ 793.5853.

1-Stearoyl-3,4-dihydroquinolin-2(1H)-one(5j)

White solid; mp 332-334 ºC; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, d, J 7.7 Hz, H-7), 7.42 (1H, t, J 7.3 Hz, H-5), 7.34 (1H, br d, H-4), 7.30 (1H, br t, H-6), 3.07 (2H, m, 2H-3), 3.02 (2H- m, 2H-2), 2.48 (2H, t, J 7.4 Hz, 2H-2'), 1.73 (2H, m, 2H-3'), 1.25 (28H, m, 4'-17'), 0.87 (3H, t, J 6.8 Hz, 3H-18'); ¹³C NMR (300 MHz, CDCl₃) d 171.73 (C-1'), 170.53 (C-1), 149.87 (C-9), 134.58 (C-8), 132.19 (CH-5), 127.43 (CH-6), 125.78 (CH-4), 123.42 (CH-7), 33.26 (CH₂-2'), 32.11 (CH₂-16'), 29.88-29.37 (CH₂-4'-CH₂-15'), 28.66 (CH₂-3), 27.83 (CH₂-2), 25.22 (CH-3'), 22.87 (CH₂-17'), 14.30 (CH₃-18'); EIMS m/z (rel. int.) C₂₇H₄₃NO₂, [M]⁺ 413 (no peak), 147 (100), 130 (32), 115 (15.5), 103 (35), 91 (12), 77 (20), 51 (13); HRMS m/z [M]⁺ 413.3293 (calcd. for C₂₇H₄₃NO₂, 413.6479), [C₁₀H₁₇O]⁺ 153.0075, [M + 1]⁺ 414.3358, [M + Na]⁺ 436.3177, [2M + Na]⁺ 849.6468.

1-Oleoyl-3,4-dihydroquinolin-2(1H)-one (5k)

Brown liquid; ¹H NMR (300 MHz, CDCl₃) d 7.92 (1H, d, J 7.7 Hz, H-7), 7.42 (1H, t, J 7.0 Hz, H-6), 7.34 (1H, br d, H-4), 7.30 (1H, br t, H-5), 5.34 (2H, t, J 5.4 Hz, H-9, H-10), 3.07 (2H, m, 2H-3), 3.02 (2H, m, 2H-2), 2.48 (2H, t, J 7.6 Hz, 2H-2'), 2.02 (4H, m, 2H-8', 2H-11'), 1.73 (2H, m, 2H-3'), 1.32-1.26 (20H, m, 8'-17'), 0.87 (3H, t, J 6.8 Hz, 3H-18'); ¹³C NMR (300 MHz, CDCl₃) d 171.71 (C-1'), 170.54 (C-1), 149.86 (C-9), 134.56 (C-8), 132.19 (CH-5), 130.19 (=CH-9'), 129.91 (=CH-10'), 127.43 (CH-6), 125.77 (CH-4), 123.42 (CH-7), 33.23 (CH₂-2'), 32.08 (CH₂-16'), 29.95-29.28 (CH₂-4'-CH₂-7' / CH-12'-CH-15'), 28.66 (CH₂-3), 27.83 (CH₂-2), 27.40 (C-8'),^a 27.35 (C-11')^a, 25.18 (CH₂-3'), 22.86 (CH₂-17'), 14.87 (CH₃-18'); EIMS m/z (rel. int.) C₂₇H₄₁NO₂, [M]⁺ 411 (no peak), 147 (100), 130 (32), 115 (15.5), 103 (35), 91 (12), 77 (20), 51 (13); HRMS m/z [M]⁺ 411.3137 (calcd. for C₂₇H₄₁NO₂, 411.6320), [C₉H₈N]⁺ 130.0654, [C₉H₁₀NO]⁺ 148.0752, [C₂₇H₃₈NO₂)]⁺ 408.2897. ^aInterchangeable assignments.

Preparation of binders

The molecules 1, 2, 3, 3a, 4, and 5a-5k were used for the simulation and had their 3D structures created by Chem3D software.²³ The design and structural optimization of each compound was performed using the software Avogadro^®,²⁴ configured to use the Merk molecular force field (MMFF94),²⁵ with cycles of 500 interactions and the steepest algorithm, having the convergence limit of 10e^-7 and later converted to the pdbqt format.

Preparation of proteins

The X-ray crystal structures of protein of AChE (PDB ID: 4EY6) was obtained from the Protein Data Bank repository files, named as the crystalline structure of recombinant human acetylcholinesterase on galantamine complex, classified as hydrolase inhibitor, expression system, and Homo sapiens organism.²⁶ In order for the coupling to occur without interfering with other chemical compounds, the residues present in the PDB file of the AChE that are part of the protein structure, such as ions, molecular water, and the native binder, were removed, loads, and lost atoms. Polar hydrogens were added through the AutoDock suite, version 4.2, and the AutoDock Tools auxiliary tool, version 1.5.4.²⁷

Molecular docking

Molecular docking was performed by using the AutoGrid-AutoDock Vina²⁸ on MGL Tools platform, version 1.5.7.²⁷ The default parameters of the automatic settings were used to set the genetic algorithm parameters. For docking, the active site of AChE (4EY6) with a radius of 6 Å (binding area around inhibitor) was used. The input ligands with full protonation were used in .mol2 format.

The cholinergic hypothesis²⁹ was used for the study on Alzheimer's disease, the enzyme acetylcholinesterase. For the docking of the main protease AChE (4EY6), the following parameters were used: number of grid points in xyz (40 40 40), spacing (0.642), grid center in xyz (-13.50 -43.04 27.64). Other parameters were set to default. To validate the simulations, the redocking technique was performed on the co-crystallized ligand, galantamine^®. The results of predicting protein-ligand interactions by docking studies were visualized using Pymol.³⁰ The 2D-schematic representations of the protein-ligand interactions were generated using Discovery Studio.³¹ To obtain a larger data set, for all simulations (docking and redocking), 50 independent simulations were performed, being possible to obtain 20 poses per simulation. The exhaustiveness criterion equal to 64 was used to improve the partial refinement of the individual coupling calculations.³² The protein structure was kept rigid, while all binding and twists of the ligands were adjusted to rotate.³³

Docking validation

For statistical validation of the simulations, redocking procedures were performed and the RMSD (root mean square deviation) values were evaluated, having as parameter of choice of the best pose, values less than 2 Å.³⁴

To analyze the stability of the complex (proteins/ligand) the affinity energy was used as parameter, which has ideality parameter values below -6.0 kcal mol^-1.³⁵

To assess the strength of the H-bond, the values of the distances between the donor and recipient atoms were used, being classified as strong, the interactions that were between 2.5 and 3.1 Å; as average those that were between 3.1 and 3.55 Å, and weak those with a distance greater than 3.55 Å.³⁶ To validate the simulations, the redocking technique was performed on the co-crystallized ligand galantamine^®, used in antiacetylcholinergic test.³⁷ In addition to reference ligand, the analogues compounds were subjected to the same criteria and simulation conditions.

 

RESULTS AND DISCUSSION

Synthesis and characterization of the compounds

Prior to the preparation of desired esters (3a, for example; Figures 1 and 2), our attention was focused on the obtention of 2,3-dihydro-1H-indene-1-one oxime (3), easily prepared from 1-indanone (2) by reaction with hydroxylamine hydrochloride in the presence of sodium acetate.

Thus, following the literature procedure,^38-40 the transformation of 2 into 3 was performed at excellent yield (93%) suggesting an easy oximation stage. Then, to obtain esters, 3 was treated with carboxylic acid anhydrides in the presence of DMAP as a catalyst and then, with aliphatic carboxylic acids in the presence of DMAP with DCC as a coupling agent, according to the Steglich esterification method. Initially, the reaction with the oxime (3) (Figure 2) was investigated using acetic anhydride as an acyl group donor reagent, hoping to obtain the corresponding oxime ester 3a. The reaction, according to the literature procedure,⁴¹ occurred in the presence of DMAP as catalyst and CH₂Cl₂ as a solvent. Analysis of the ¹H NMR spectrum showed that the product of this reaction had an acetyl group, indicated by the signal at δ_H 2.23 (s, 3H), which is in agreement with the ¹³C NMR spectrum through the two signals at δ_C 170.50 (C=O) and 19.90 (CH₃). The fragments peaks at m/z 147 [M - C₂H₂O]⁺ (100%) and m/z 43 [CH₃CO]⁺ (30%) in the EIMS, are also in agreement with the presence of the acetyl group. The ¹H NMR spectrum also displayed signals to one isolated four-proton (-CH₂-CH₂-) spin fragment {d 3.00 (m, 2H); 3.04 (m, 2H)} and for four aromatic protons d 7.30 (tl, 1H), 7.34 (dl, 1H), 7.43 (t, J 7.2 Hz, 1H) and 7.90 (d, J 7.6 Hz, 1H). The ¹³C NMR spectrum, in turn, revealed two signals due to methylene carbons (d 28.67 and 27.84) and six signals for aromatic carbons d 149.95 and 134.49 (C-2), 132.25, 127.44, 125.82 and 123.36 (CH-4), all confirmed by distortionless enhancement by polarization transfer (DEPT) experiment. Thus, all these data would be in agreement with the formation of the desired ester, that is, 3a. However, the ¹³C NMR spectrum of the product, in addition to the signal at δ_C 170.50, recorded another well-resolved signal at δ_C 169.28, that is, consistent with the presence of another carbonyl group. In addition, in this spectrum, the absence of the signal around δ_C 164.00—corresponding to the oxime carbon (C-1) in the benz-fused cyclopentanone oxime observed in the ¹³C NMR spectrum of compound 3 (or 3a)—supports the presence of the molecular ion peak at m/z 189 ([M]⁺, 48%) and a prominent base peak at m/z 147 (100%), which can be attributed to a McLafferty rearrangement. In turn, the high-resolution mass spectrum (HRMS) suggested the molecular formula C₁₁H₁₁NO₂ ([M]⁺ m/z 189.0789) and contained ion peaks at m/z 130.0657 [C₉H₈N]⁺, 148.9759 [C₉H₁₀NO]⁺ and 212.0683 [C₁₁H₁₁NNaO₂]⁺. From these data we conclude that the product obtained was not the ester 3a, but 5a, an imide, i.e., 1-acetyl-3,4-dihydroquinolin-2(1H)-one in 95% yield (Figure 3).

The chemical shifts at δ_C 170.50 and 169.28 were attributed to carbons C-1 and C-1', respectively, in 5a. Heteronuclear multiple bond correlation (HMBC) experiment showed the correlation of the methyl protons at δ_H 2.23 (CH₃-1') with carbon at δ_C 169.28 (C-1'). In particular, in the structure of imide 5a (as in the other examples), the system 3,4-dihydroquinolin-2-(1H)-one is inserted, admitting, at first hand, that the formation of imides (5a, for example) in the present work, required the generation of amide 4 from oxime (3) (Figure 1). In fact, there are already reports in the literature¹⁹ of the formation of the amide 3,4-dihydro-2(1H)-quinolinone (Figure 2) through the rearrangement of the 1-indanone oxime via Beckmann rearrangement. Therefore, the production of imides in this work would have occurred through a reaction between 4 and carboxylic acid anhydrides (or carboxylic acids). This is unlikely, due to important theoretical and experimental aspects: (i) the very low nucleophilic power of the nitrogen of the amide and, in the case of carboxylic acids, the low electrophilic power of the carbonyl carbon, do not justify the high yields observed in the formation of imides; (ii) normally, the Beckmann rearrangement requires the presence of strong acids such as sulfuric acid or Lewis acids (SnCl₄, SOCl₂, PCl₅, etc.), that is, it occurs under conditions of electrophilic activation of the hydroxyl group of the oxime. Nevertheless, in this study, the reactions occurred in the presence of DMAP with carboxylic acid anhydrides and DMAP/DCC with fatty acids, that is, in both cases under the action of nucleophilic agents, therefore, in basic conditions. Thus, in this work, we are proposing a hypothesized mechanism for the reaction of 3 with carboxylic acid anhydrides in the presence of DMAP using CH₂Cl₂ as a solvent to form imide 5a (as well as 5b and 5c) as described in Scheme 1S, presented in the Supplementary Material.

First, the DMAP nucleophilic species interacts with the anhydride to generate the acylpyridinium intermediate (6). Then, the activated carbonyl carbon of the acylpyridinium is attacked by the oxime (3) to form an oxaziridine, followed by a Beckmann-type rearrangement to give imide 5a (as well as 5b, 5c).

The E stereochemistry of the oxime was inferred from the nature of the imide (5a, final product), in view of the two possible regioisomeric lactams of the oxime (3). This is also in agreement with the product 5a, obtained from oxaziridine as a reaction intermediate, as the expected stereochemistry in a Beckmann rearrangement. We extended this methodology by exploring reactions of oxime (3) with other acid anhydrides (butanoic and hexanoic anhydrides). The results shown in Figure 3 reveal that the reaction worked well, providing the corresponding imides (5b and 5c) also in excellent yields. Complete ¹H and ¹³C NMR data for compounds 5a-5c have been in the Experimental section.

The investigation was then directed to the reactions of oxime (3) with fatty acids. Thus, following the same experimental procedure,⁴¹ we first investigated the reaction of 3 with decanoic acid (5f) hoping to obtain the corresponding oxime ester (oxime decanoate). In these cases, reactions in addition to DMAP also required the presence of DCC as coupling reagent (see Scheme 2S, in Supplementary Material). The proposed mechanism for the reaction of 3 with fatty acids in the presence of DMAP/DCC is similar to that of reactions with anhydrides. Initially, the protonation of the carbodiimide group of DCC by the carboxylic acid induces the attack of the carboxylate anion, originating the reactive O-acylurea. This, in turn, is attacked by DMAP, a nucleophile stronger than the oxime, on the acyl group, originating the highly reactive intermediate acylpyridinium assisted by the expulsion of dicyclohexylurea (DCU) as an excellent leaving group. Finally, the reaction of the oxime with acylpyridinium leads to the oxaziridine which follows the same paths as in the previous cases (Scheme 1, Supplementary Material), leading to the production of imide 5f (a well as 5d, 5e, 5g-5k).

Analysis of the ¹H and ¹³C NMR data, showed that the compound obtained was also an imide, i.e., 1-decanoyl-3,4-dihydroquinolin-2-(1H-one) (5f), 90% yield.

¹H-¹H COSY (homonuclear correlation spectroscopy) NMR spectrum in conjunction with ¹H-¹³C HMQC (heteronuclear multiple quantum coherence) and ¹H-¹³C HMBC experiments confirmed the presence of one isolated four-hydrogen (-CH₂-CH₂-) spin system; furthermore, the HMBC plot showed correlations of the carbonyl carbons δ_C 170.59 (C-1) and 171.79 (C-1') with the hydrogen atoms δ_H 3.02 (m), 2H-2 / 3.08 (m), 2H-3 and 2.49 (t, J 7.4 Hz), 2H-2' / 1.74 (m), 2H-3', respectively. The ¹H and ¹³C NMR spectra of 5f have been rigorously assigned (Table 1) with the aid of heteronuclear single-quantum correlation (HSQC) and HMBC NMR experiments - chemical shifts (d) and multiplicities (J, Hz) of ¹H and ¹³C (as derived from DEPT experiment). The HRMS contained ions at m/z 301.2041 (for C₁₉H₂₇NO₂ [M]⁺), 210.1272 [C₁₁H₉NNaO₂]⁺, 148.9759 [C₉H₁₀NO]⁺ and 130.0657 [C₉H₈N]⁺. Fragment peaks at m/z (%) 155 (20) [C₁₀H₁₉O]⁺, 147 (100) [C₉H₉NO]⁺, 130 (55) [C₉H₈N]⁺, 103 (19) [C₈H₇]⁺, 85 (14) [C₆H₁₃]⁺, 71 (30) [C₅H₁₁]⁺ and 43 (29) [C₃H₇]⁺ in the EIMS {[M]⁺ 301 (1)} also indicated the presence of aromatic and aliphatic moieties. The peaks at m/z (%) 147 (100) [C₉H₉NO]⁺ and 148 (100) [C₉H₁₀NO]⁺ recorded in the EIMS and HRMS spectra, respectively, can be explained by McLafferty rearrangement from the molecular ion.

In order to confirm the results presented in Table 1, the reaction of 3 using another fatty acid, 5h (dodecanoic acid), as substrate was carried out under the same experimental conditions. Comparison of the ¹H and ¹³C NMR data of 5h with those of 5f showed that 5h is also an imide, in this case, 1-dodedecanoyl-3,4-dihydroquinolin-2-(1H-one) (5h), in 89% yield. ¹H-¹H COSY NMR spectrum in conjunction with ¹H-¹³C HMQC and ¹H-¹³C HMBC experiments confirmed the presence of one isolated four-hydrogen (-CH₂-CH₂-) spin system; furthermore, the HMBC plot showed correlations of the carbonyl carbons δ_C 170.57 (C-1) and 171.75 (C-1') with the hydrogen atoms δ_H 3.03 (m), 2H-2 / 3.08 (m), 2H-3 and δ_H 2.49 (t, J 7.4 Hz), 2H-2' / 1.74 (m), 2H-3', respectively. The ¹H and ¹³C NMR spectra of 5h have been rigorously assigned (Table 2) with the aid of HSQC and HMBC NMR experiments - chemical shifts (d) and coupling constants (J, Hz) of ¹H and ¹³C (as derived from DEPT experiment).

 

 

 

 

Hassner and Vazken⁴² observed that after the formation of O-acylurea, another reactive intermediate is formed - a symmetrical anhydride of the carboxylic acid [(RCO)₂O]. In this mechanistic proposal (see Scheme 3S, in Supplementary Material), DMAP reacts with this anhydride to form the activated intermediate acylpyridinium which reacts with the oxime as shown in Schemes 1S and 2S.

By analogy to the above cases, this methodology was then extending by exploring the oxime (3) reactions with other acid fatty acids [heptanoic (5d), nonanoic (5e), undecanoic (5g), hexadecanoic (5i), octadecanoic (5j) and, 5-en-octadecanoic (5k)]. The results shown in Figure 4 reveal that the reaction worked well by affording the corresponding imides (5d, 5e, 5g and 5i-5k) with high yields. All imides obtained have very similar structures, with differences only in the carbon chain originating from the carboxylic acid that reacted with oxime (3). Thus, in the ¹H and ¹³C NMR spectra, the chemical shifts and assignments for 5b-5e, 5g and 5i-5k (see Experimental section) were compared with the respective data from 5a, 5f and 5h.

In silico results

Molecular docking results

The molecular docking method is employed to identify potential non-covalent inhibitors of acetylcholinesterase (AChE). This computational approach, facilitated by a combination of binding affinity (kcal mol^-1) and RMSD using AutoDock Vina, significantly reduces the time required to screen and identify promising compounds from extensive ligand libraries.

In the initial phase of the in silico study of oxime derivatives as AChE inhibitors, a preliminary virtual ranking was established. The binding affinity score from AutoDock Vina was selected due to its strong correlation with binding affinity (primary) energy.⁴³ Consequently, all tested derivatives were identified as the most promising ligands in comparison to the reference ligand, galantamine, following refinement through molecular docking.

The RMSD was initially used for the statistical validation of the complex formation simulations and to determine the best binding pose. The RMSD is calculated by measuring the average distance between atoms of two ligand poses, with validation criteria being RMSD values close to 2 Å. All simulations (docking and redocking) produced RMSD values of 2 Å or less, with the derivative 5i/AChE complex showing a particularly low RMSD of 0.98 Å (Table 3).

 

 

The best poses, selected based on RMSD ranking and binding energy, revealed that the complexes 5i/AChE, 5g/AChE, and 5h/AChE had RMSD values between 0.98 and 1.93 Å, and binding energies of -8.7, -8.5, and -8.4 kcal mol^-1, respectively. In the redocking simulations, the GNT/AChE complex exhibited a binding energy of -6.9 kcal mol^-1. All other derivatives also demonstrated favorable binding energies and RMSD values below 2 Å, surpassing the reference ligands in these metrics.

The structure of AChE is characterized by several key regions that play a crucial role in its catalytic function. These include the catalytic active site (CAS), the acyl binding pocket, the choline binding site (CBS), represented by the Trp86 residue, the peripheral active site (PAS), and a narrow but deep gorge (~ 20 Å) that connects the CAS to the PAS. The CAS, located near the bottom of this gorge, is formed by the catalytic triad residues Ser203, His447, and Glu534,⁴⁴ which are responsible for the hydrolysis of acetylcholine (Figure 5).

 

 

The PAS, situated near the surface of the enzyme, acts as an initial substrate recognition site and facilitates substrate entry. This region is defined by residues such as Asp74 and Trp286, which play a role in the binding and guidance of the substrate toward the active site. Additionally, the PAS has been implicated in the formation of amyloid-β fibrils, further underscoring its relevance beyond the enzymatic activity itself.^45,46

The calculated binding fitness of the ligand 5i surpassed that of the AChE inhibitor galantamine (GNT). Both ligands are well accommodated within the active site of AChE, with their functional groups occupying key pockets of the enzyme. Notably, their ring structures engage with the catalytic triad residues and the acyl pocket through hydrogen bonding and hydrophobic interactions, particularly with Trp86. Additionally, the ligands form hydrogen bonds with other relevant residues.

Furthermore, ligand 5i exhibits hydrophobic interactions with Asp74, located within the peripheral active site (PAS), which accounts for its higher predicted affinity compared to GNT.⁴⁷ This ligand also interacts with the acyl pocket at the Trp286 residue, strengthening its binding profile.

In the case of GNT, the polar environment is stabilized by two hydrogen bonds with Tyr124. The ligand also engages in π-alkyl interactions with Trp86 at the choline-binding site. In addition to these interactions, a salt bridge was observed with Glu202, situated near the CAS. These interactions are summarized in Table 4 and Figures 6a and 6b.

 

 

CONCLUSIONS

In conclusion, an efficient conversion (82 to 95% yield) of oxime in cyclic imides, involving the Beckmann rearrangement (BR), has been developed. The key features of this method are to avoid using catalysts that result in undesired by-products and that requires large amounts of strong acids (sulfuric acid, for example), in addition to occur in one-pot reactions. The mechanism for the formation of imides via a oxaziridine intermediate, followed by BR under Lewis base catalysis, represents a mechanistic proposal. The operationally simple protocol with available substrates offers an efficient access to cyclic imides.

Calculating the physicochemical properties through molecular modeling allowed us to understand the interaction between a ligand and its receptor. The results showed that most derivatives were energetically influenced, especially the 5i analog. They showed a better classification than the others analyzed and the reference ligand, GNT. It should be noted that several more tests and analyses must be carried out until the final goal is completed to optimize time and cost and present significant advantages.

 

SUPPLEMENTARY MATERIAL

Supplementary information (¹H, ¹³C NMR, MS and mechanistic hypothesis of the formation of the main derivatives) is available at http://quimicanova.sbq.org.br/, as a PDF file, with free access.

 

DATA AVAILABILITY STATEMENT

All data are available in the text and supplementary material.

 

ACKNOWLEDGMENTS

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasil and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasil. We thank Dr. Antonio J. R. da Silva e Ari M. da Silva (UFRRJ) for obtaining mass spectra in high-resolution.

 

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Editor handled this article: Jorge M. David