(2RS,3aRS,9aRS)-3a-Methyl-2-phenyl-3,3a,9,9a-tetrahydro-1H-benzo[f]indol-4(2H)-one Hydrobromide

Abstract

(2RS,3aRS,9aRS)-3a-methyl-2-phenyl-3,3a,9,9a-tetrahydro-1H-benzo[f]indol-4(2H)-one hydrobromide was first synthesized via a tandem aza-Cope rearrangement and Mannich reaction from (1RS,2SR)-2-amino-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol, which, in turn, was obtained in four steps from commercially available 2,3-dihydro-1H-inden-1-one. The molecular and crystal structure features of the new compounds were characterized using NMR spectroscopy (¹H, ¹³C spectra).

1. Introduction

Development of novel synthetic methodologies for biologically active compounds represents a critical tool for organic chemists. This complex process requires in-depth knowledge of organic chemistry, an understanding of the fundamental principles governing the activity of biologically active compounds, and insight into pharmacokinetics and pharmacodynamics. Recently, the synthesis of saturated heterocyclic compounds has attracted considerable attention, as these structural motifs are frequently encountered in natural products, and methods for their synthesis hold significant interest in constructing new chemical platforms in drug discovery. Pyrrolidine derivatives occupy a prominent position in such investigations, as these compounds exhibit a broad spectrum of biological activities [1,2,3,4,5,6,7]. Various pyrrolidine derivatives demonstrate anticancer [8,9,10,11], antibacterial [12,13,14,15], and antiviral [16,17,18,19,20] activities.

2. Results and Discussion

The synthetic sequence for the preparation of compound 1 is presented in Scheme 1. 2,3-dihydro-1H-inden-1-one 3 was transformed to bromoketone 4 by introducing a bromine atom at the α-position to the carbonyl group, followed by nucleophilic substitution with sodium azide. Subsequently, isopropenylmagnesium bromide was added to azidoketone 5. In general, this reaction should yield a mixture of two diastereomeric pairs of enantiomers, since isopropenylmagnesium bromide can approach from either the azide group side or the opposite side. However, the transformation was carried out in the presence of anhydrous cerium chloride, which ensures stereospecific addition of the Grignard reagent. Further reduction in the azide 6 yielded amino alcohol 7, which was subjected to tandem aza-Cope rearrangement and Mannich reaction conditions to afford the tricyclic pyrrolidine 8 (see Supplementary Materials).

To determine the relative spatial arrangement of substituents in compound 8, 2D NMR spectra were acquired. ROESY spectra showed cross-peaks between the methyl group and the hydrogen atoms at the 2- and 4-positions of the pyrrolidine fragment. Since there are no stereochemical data for the substituents in compound 7, their relative configuration can only be inferred from the known stereochemistry of the substituents in compound 8 and the mechanism of this transformation. To elucidate the structures of compounds 7 and 8 more precisely, it was decided to grow their single crystals. However, both compounds 7 and 8 are oily substances. None of the tested crystallization conditions or various solvent mixtures yielded these compounds in a crystalline form suitable for X-ray diffraction analysis. Therefore, it was decided to modify compounds 7 and 8 (Figure 1). To achieve conditions suitable for growing a single crystal from compound 8, the hydrobromide salt 1 was prepared. To determine the stereochemistry of the substituents in compound 7, an amidation reaction with p-bromobenzoic acid was carried out. Crystals suitable for X-ray diffraction analysis were obtained by recrystallization from a hexane/ethyl acetate mixed solvent solution.

X-Ray Crystallography

X-ray diffraction analysis showed that amino alcohol 2 (Figure 2) crystallizes in the monoclinic space group P2₁/n. The crystal structure is further stabilized by intermolecular hydrogen bonds between O(2)-H(1A)···O(1) (1.995 Å) (Figure 3).

Compound 1 crystallizes in the orthorhombic space group P2₁2₁2₁. The cyclohexane fragment adopts a half-chair conformation, while the pyrrolidine ring exhibits an “envelope” conformation. The anion is slightly disordered over two positions with a ratio of 0.96/0.04 (Figure 4). Two hydrogen bonds are observed: an intramolecular C(12)-H(12A)···Br(11) (2.969 Å) and an intermolecular C(2)-H(2)···Br(1)#1 (3.080 Å), C(2)-H(2)···Br(11)#1 (2.820 Å) (Figure 5).

Detailed crystallographic data for the compounds studied are presented in

Table 1. Crystallographic data for compounds 1 and 2.

	1	2
Formula	C19H20BrNO	C19H18BrNO2
Molecular weight	358.27	372.26
Crystal system	Orthorhombic	Monoclinic
Space group	P212121	P21/n
a, Å	7.8766 (3)	8.9569 (4)
b, Å	11.1570 (4)	7.3922 (2)
c, Å	19.1408 (8)	26.4840 (10)
α, °	90	90
β, °	90	99.513 (3)
γ, °	90	90
Volume, Å3	1682.08	1729.42
Z	4	4
ρcacl, g/cm3	1.415	1.430
μ/mm−1	3.329	3.308
F(000)	736	760
2Θ range/°	4.620 to 66.961	5.013 to 66.918°
Index ranges	−9 ≤ h ≤ 7, −13 ≤ k ≤ 10, −22 ≤ l ≤ 18	−10 ≤ h ≤ 10, −5 ≤ k ≤ 8, −31 ≤ l ≤ 25
Reflections collected	11540	11324
Independent reflections	2748 [R(int) = 0.0489]	3038 [R(int) = 0.1093]
Data/restraints/parameters	2748/0/218	3038/0/226
Goodness of fit on F2	1.032	0.610
Final R indexes [I ≥ 2σ (I)]	R1 = 0.0381, wR2 = 0.0957	R1 = 0.0345, wR2 = 0.0521
Final R indexes [all data]	R1 = 0.0493, wR2 = 0.1029	R1 = 0.1322, wR2 = 0.0687
Largest diff. peak/hole/e Å−3	0.221/−0.488	0.262/−0.251

. Characteristics of main intermolecular and intramolecular hydrogen bonding are presented in

Table 2. Hydrogen bond geometry for amino alcohol 2, Å, and °.

D-H...A	A d(D-H)	d(H...A)	d(D...A)	<(DHA)
O(2)-H(1A)...O(1)#1	0.75 (4)	1.99 (4)	2.731 (4)	170 (5)

and

Table 3. Hydrogen bond geometry for compound 1, Å, and °.

D-H...A	d(D-H)	d(H...A)	d(D...A)	<(DHA)
C(2)-H(2)...Br(1)#1	0.98	3.08	3.892 (5)	141.0
C(2)-H(2)...Br(11)#1	0.98	2.82	3.70 (3)	149.8
C(12)-H(12A)...Br(11)	0.97	2.97	3.58 (5)	122.2
N(1)-H(2)...Br(1)#2	1.04 (6)	2.26 (7)	3.274 (4)	163 (5)
N(1)-H(2)...Br(11)#2	1.04 (6)	2.53 (8)	3.51 (4)	155 (5)
N(1)-H(3)...Br(1)	0.83 (5)	2.41 (5)	3.212 (5)	164 (4)
N(1)-H(3)...Br(11)	0.83 (5)	2.20 (5)	2.97 (2)	155 (4)

.

3. Materials and Methods

¹H and ¹³C NMR spectra were recorded using a Bruker Avance 400 instrument (Billerica, MA, USA) with operating frequencies of 400 and 100 MHz, respectively, and calibrated using residual undeuterated chloroform (δ¹H = 7.27 ppm) and CDCl₃ (δ¹³C = 77.16 ppm) as internal references. The following abbreviations were used to set multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. The purity of the final compounds was checked through liquid chromatography–mass spectrometry (LCMS) via a Shimadzu LCMS-2010A (Kyoto, Japan) using three types of detection systems: EDAD, ELSD, and UV. We used commercial reagents and solvents without further purification. Reactions were monitored by thin-layer chromatography (TLC) performed on Merck TLC Silica gel plates (60 F254) (Darmstadt, Germany), using UV light for visualization and basic aqueous potassium permanganate or iodine fumes as a developing agent.

3.1. 2-Bromo-2,3-dihydro-1H-inden-1-one

2,3-dihydro-1H-inden-1-one (50 g, 1 eq) was dissolved in Et₂O (400 mL), cooled down to 0 °C, and Br₂ (19.38 mL, 1 eq) was added dropwise. The reaction mixture was stirred overnight. The reaction mixture was then washed with a saturated solution of Na₂SO₃, a saturated solution of NaHCO₃, and brine. The organic phase was separated, dried over anhydrous Na₂SO₄, and the solvent was distilled under reduced pressure. The residue was purified by column chromatography. Yield: 66.33 g (83%). R_f = 0.7 in hexane/EtOAc (3:1). ¹H NMR (400 MHz, CDCl₃) δ: 3.44 (dd, 1 H), 3.85 (dd, J = 18.1, 7.5 Hz, 1 H), 4.67 (dd, J = 7.5, 3.2 Hz, 1 H), 7.40–7.50 (m, 2 H), 7.64–7.71 (m, 1 H), and 7.86 (d, J = 7.6 Hz, 1 H).

3.2. 2-Azido-2,3-dihydro-1H-inden-1-one

2-bromo-2,3-dihydro-1H-inden-1-one (60 g, 1 eq) was dissolved in MeCN (285 mL), and NaN₃ (36.96 g, 2 eq) was added and stirred overnight. The solvent was distilled under reduced pressure. The residue was diluted with water, extracted with EtOAc, and washed with brine. The organic phase was separated, dried over anhydrous Na₂SO₄, and the solvent was distilled under reduced pressure. The residue was purified by column chromatography. Yield: 36.31 g (74%). R_f = 0.7 in hexane/EtOAc (3:1). ¹H NMR (400 MHz, CDCl₃) δ: 2.94 (dd, 1 H), 3.51 (dd, J = 17.1, 8.2 Hz, 1 H), 4.33 (dd, J = 8.1, 4.6 Hz, 1 H), 7.40–7.48 (m, 2 H), 7.66 (td, J = 7.5, 1.2 Hz, 1 H), and 7.80 (d, J = 7.4 Hz, 1 H).

3.3. 2-Azido-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol

3.3.1. Anhydrous CeCl₃

CeCl₃*7H₂O (105.92 g, 1 eq) and a magnetic stirrer were placed in a 3-neck round-bottom flask equipped with two glass stoppers and a glass stopcock. The flask was heated in an oil bath without stirring (90 < T < 100 °C. The oil level should be as high as possible, and the parts of the flask that are not covered with oil should be heated with a heat gun periodically under high vacuum (<1 Torr) for 1 h. Then the flask was heated under the same conditions but with slow stirring for one more hour. The white powder formed was CeCl₃*H₂O. Then the temperature was raised to 140–150 °C and maintained for 6–8 h. The flask was cooled to r.t. under high vacuum and filled with nitrogen.

3.3.2. Grignard Addition

Freshly distilled THF (583 mL) was added rapidly to the cooled anhydrous CeCl₃ prepared from CeCl₃*7H₂O, and the resulting slurry was stirred under the nitrogen atmosphere at r.t. for 24 h. The CeCl₃ slurry in THF was cooled to −78 °C, and prop-1-en-2-ylmagnesium bromide (1M in THF, 426 mL, 1.5 eq) was added dropwise at this temperature. The resulting mixture was stirred for 1 h at −78 °C before a solution of 2-azido-2,3-dihydro-1H-inden-1-one (36.31 g, 1 eq) in THF (285 mL) was added dropwise at −78 °C. The mixture was stirred for 2 h at this temperature and then poured into a saturated NH₄Cl solution (1 L) containing acetic acid (24.37 mL, 1.5 eq). The organic layer was separated, and the water layer was extracted with Et₂O. The combined organic phases were dried over Na₂SO₄, evaporated, and purified by column chromatography. Yield: 29.68 g (66%). R_f = 0.7 in hexane/EtOAc (3:1). ¹H NMR (400 MHz, CDCl₃) δ: 1.81 (d, J = 0.6 Hz, 3 H), 2.53 (s, 1 H), 3.06–3.29 (m, 2 H), 4.26 (t, J = 6.5 Hz, 1 H), 5.09 (d, J = 0.7 Hz, 1 H), 5.14 (t, J = 1.4 Hz, 1 H), 7.20–7.36 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃) δ: 19.3, 34.7, 67.1, 85.6, 114.3, 124.1, 124.8, 127.4, 129.0, 139.8, 143.2, and 144.6.

3.4. (1RS,2SR)-2-Amino-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol

LiAlH₄ (7.85 g, 1.5 eq) was suspended in THF (275 mL), cooled down to 0 °C, and a solution of 2-azido-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol (29.68 g, 1 eq) in THF (275 mL) was added dropwise; then the reaction mixture was stirred at 0 °C overnight. Following this, 7.85 mL of water, 7.85 mL of 15% NaOH solution, and 23.55 mL of water were added, and the resulting mixture was stirred for 30 min. The formed precipitate was filtered off, and the filtrate was evaporated and purified by column chromatography. Yield: 16.46 g (63%). R_f = 0.4 in DCM/MeOH (NH₃) (20:1). ¹H NMR (400 MHz, CDCl₃) δ: 1.70 (d, 3 H), 2.73 (dd, J = 15.3, 7.7 Hz, 1 H), 3.18 (dd, J = 15.4, 7.2 Hz, 1 H), 3.68 (t, J = 7.5 Hz, 1 H), 5.09 (dd, J = 2.0, 1.5 Hz, 1 H), 5.23 (dd, J = 1.4, 0.7 Hz, 1 H), and 7.20–7.27 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃) δ: 19.4, 38.1, 57.2, 83.2, 112.6, 124.3, 124.5, 126.6, 128.0, 141.2, 144.6, and 145.8.

3.5. (2RS,3aRS,9aRS)-3a-Methyl-2-phenyl-3,3a,9,9a-tetrahydro-1H-benzo[f]indol-4(2H)-one

2-amino-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol (2 g, 1 eq) was dissolved in toluene (100 mL), and benzaldehyde (2.15 mL, 2 eq), Na₂SO₄ (10.51 g, 7 eq), CSA (2.21 g, 0.9 eq) were added; the resulting mixture was refluxed overnight. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with EtOAc. The organic phase was separated and washed with water and brine. The organic phase was then dried over anhydrous Na₂SO_4, and the solvent was distilled under reduced pressure. Residue was purified by column chromatography. Yield: 1.18 g (40%). R_f = 0.5 in hexane/EtOAc (3:1). ¹H NMR (400 MHz, CDCl₃) δ: 1.35 (s, 3 H), 2.24 (dd, J = 13.5, 9.3 Hz, 1 H), 2.62 (dd, J = 13.4, 6.5 Hz, 1 H), 3.11 (dd, J = 17.4, 2.8 Hz, 1 H), 3.35 (dd, J = 17.4, 4.5 Hz, 1 H), 3.59 (dd, J = 4.4, 2.9 Hz, 1 H), 4.31 (dd, J = 9.3, 6.6 Hz, 1 H), 7.13–7.27 (m, 6 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.52 (td, J = 7.5, 1.4 Hz, 1 H), 8.05 (dd, J = 7.8, 1.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃) δ: 20.9, 29.7, 45.4, 51.8, 59.2, 63.4, 126.6 (s, 3 C), 126.7, 127.5, 128.1 (s, 2 C), 129.0, 130.7, 133.4, 139.6, 144.0, and 202.2.

4. Conclusions

As a result of this study, the target pyrrolidine derivative was obtained, its synthesis was confirmed, and the compounds were characterized by spectral analysis methods. Compounds 1 and 2 were studied by X-ray structural analysis, which allowed the determination of the relative stereochemistry of the substituents.