Synthesis of N-Containing Heterocycles Based on α-Amino Acids. 1. 8,9-Dimethoxy-5,6-Dihydro-3-Phenyl-1-Alkylimidazo[5,1-a]Isoquinolines

Article abstract of DOI:10.1007/s10600-019-02908-z

Cyclization of α-benzoylamino-N-[2-(3,4-dimethoxyphenyl)ethyl]alkyl amides by POCl₃ was studied. Spectral analyses and an X-ray crystal structure analysis found that the synthesized compounds contained 5,6-dihydroimidazo[5,1-a]isoquinoline core

Full text of DOI:10.1007/s10600-019-02908-z

DOI 10.1007/s10600-019-02908-z
Chemistry of Natural Compounds, Vol. 55, No. 6, November, 2019
SYNTHESIS OF N-CONTAINING HETEROCYCLES BASED
ON α-AMINO ACIDS. 1. 8,9-DIMETHOXY-5,6-DIHYDRO-
3-PHENYL-1-ALKYLIMIDAZO[5,1-a]ISOQUINOLINES
1*
1
2,3
D. B. Tukhtaev, A. Sh. Saidov, K. K. Turgunov,
2
2
V. I. Vinogradova, and B. Tashkhodzhaev
Cyclization of α-benzoylamino-N-[2-(3,4-dimethoxyphenyl)ethyl]alkyl amides by POCl was studied.
3
Spectral analyses and an X-ray crystal structure analysis found that the synthesized compounds contained
5,6-dihydroimidazo[5,1-a]isoquinoline cores.
Keywords: α-amino acids, 3,4-dimethoxyphenethylamine, N-benzoyl-α-amino acid amides, cyclization,
5,6-dihydroimidazo[5,1-a]isoquinolines.
The synthesis of multifunctional drug conjugates containing in one molecule several pharmacophores capable of
interacting with various biological targets is a current thrust of medicinal chemistry.
The significance of imidazole derivatives in medicine can hardly be overestimated. Medicines used to treat fungal,
viral, oncological, and other diseases are based on them owing to their broad spectra of biological and pharmacological
activities [1, 2]. The imidazole core appears in vitamins, enzymes, and amino acids. Tricyclic imidazole derivatives containing
a bridgehead N atom, e.g., imidazo[1,2-a]pyrimidines, imidazo[1,2-b]quinolines and -isoquinolines are especially interesting
to researchers. Imidazo[1,2-a]pyrimidines exhibited antimicrobial [3]; imidazoquinazolines, antitumor [4] and
antihypertensive[5]; and imidazo[1,2-a]quinoline, antibacterial activity [6].
Pettit et al. isolated from a blue marine sponge Cribrochalina sp. cribrostatin 6 with anticancer and antibacterial
activity and a structure based on the imidazo[5,1-a]isoquinoline skeleton [7−9]. Recently, total syntheses of cribrostatin 6 and
its biologically active analogs were developed [10–12].
Imidazo-N-heterocycles were synthesized in several studies from azanaphthalene [13, 14] or aminomethylisoquinoline
derivatives [15]. Several approaches to the synthesis of imidazoisoquinolines using amino acids were developed [16]. For
example, imidazo[1,5-a]isoquinolines with anti-inflammatory activity [17] were prepared from N-Boc-protected amino acids
[18] or glycine [19].
Considering the inexhaustible possibilities of α-amino acids for constructing heterocyclic compounds, we used
α-amino acids and homoveratrylamine as important building blocks to synthesize imidazo[1,5-a]isoquinolines.
Previously, the synthesis of N-benzoyl-α-amino acid amides from 3,4-dimethoxyphenethylamine was reported by us
[20]. Herein, cyclization of amides 1a−e and preparation of 5,6-dihydroimidazo[1,5-a]isoquinoline derivatives (2a−e) are reported.
7
6
H CO
3
H CO
3
5
2''
POCl
3
4''
N
HN
R
O
3
H CO
3
t°
H CO
3
10b
O
10
6''
N
1
R
N
H
1a-e
2a-e
R = H (a); CH CH (b); CH CH CH (c); CH(CH )CH (d); CH CH(CH )CH (e)
2
3
2
2
3
3
3
2
3
3
1) Samarkand State University, Republic of Uzbekistan, e-mail: davlatuzb@mail.ru; 2) S. Yu. Yunusov Institute of
the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent; 3) Turin Polytechnic
University, 100095 Tashkent, Uzbekistan. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November−December,
2019, pp. 961−964. Original article submitted May 27, 2019.
©
0009-3130/19/5506-1119 2019 Springer Science+Business Media, LLC
1119

TABLE 1. Intermolecular H-bonds in the Crystal (d, distance; D, donor; A, acceptor)
°
°
D–H...A
d(D…A), A
d(Í…A), A
∠(DHA), deg
Symmetry
Î1w–H1…Cl1
Î2w–H1…Cl1
Î3w–H1…Cl1
Î1w–H2…O2w
O2w–H2…O3w
N1–H…O1w
3.114
3.190
3.180
2.815
2.763
2.724
2.22
2.30
2.23
1.94
1.81
1.88
168
170
177
161
154
165
x,y,z
x,y,z
-x,-y,-z
x,y,z
x,y,z
0.5+x,0.5-y,0.5+z
C4′′
C6′′
O2w
C2′′
Ñ6
Ñ5
N4
O3w
Ñ7
O2w
Cl 1
C1′′
C8
C9
C3
N2
O1w
C10a
C10b
C10
C1
C1
Cl 1
O2w
′
O1w
C2
′
O3w
O3w
O2w
C3
′
O1w
Cl 1
O1w
Fig. 1. Molecular structure of 2c⋅HCl⋅3H O (H-bonds in the crystal are shown).
2
The presence of two carbamides in the prepared amides opened the possibility of forming in one step a mutually
condensed tricyclic system containing a bridgehead N atom and imidazole and isoquinoline moieties.
Amides 1a−e were cyclized using Bischler−Napieralski reactions with POCl , using it as a reagent and solvent.
3
Heating for 4−6 h on a boiling-water bath produced imidazo[1,5-a]isoquinolines 2a−e in 61−82% yields.
The structures of the synthesized compounds were confirmed using IR and PMR spectroscopy. IR spectra of 2a−e, in
contrast to 1a−e, lacked bands for amide carbonyls. PMR spectra of 2a−e contained resonances for aromatic isoquinoline
protons H-7 and H-10 as two singlets at δ 6.70−6.97 and 7.10−7.18 ppm whereas those of 1a−e had three resonances for
aromatic protons that were characteristic of a 1,3,4-substituted aromatic ring.
Compound 2c was used as an example to prove its structure by an X-ray crystal structure analysis (XSA). The
hydrochloride salt of 2c crystallized as a trihydrate. Figure 1 shows the molecular structure of 2c⋅HCl⋅3H O. Atom N1 was
2
protonated in the crystal of the 2c salt. The six-membered heterocycle in cationic 2c adopted a distorted boat conformation
(with symmetry passing through the centers of the C10b–C10a and C5–C6 bonds). The other aromatic rings were strictly
planar. The benzene ring on C3 was rotated relative to the plane of the imidazole ring by 40°. The bond lengths in the
°
protonated aromatic five-membered heterocycle were C10b–N4 [1.401(5) A ], C10b–C1 [1.361(6)], C1–N2 [1.380(5)],
N2–C3 [1.351(6)], and C3–N [1.345(5)] and were characteristic of imidazole [21].
–
The asymmetric unit in the crystal included protonated cationic 2c, Cl , and three waters of crystallization (Ow).
–
H-bonds Cl…H–O, N–H…O, and O–H…O were observed in the crystal. H atoms of three water molecules surrounded Cl .
–
The N1 proton approached an unshared electron pair of O1w. The other H atoms of water molecules and Cl formed
a six-membered ring because of symmetry elements (Fig. 1). Table 1 lists the parameters of these H-bonds.
EXPERIMENTAL
IR spectra were recorded from KBr pellets on an FTIR System 2000 instrument (PerkinElmer). PMR spectra were
taken in CDCl with HMDS internal standard on a Unity-400+ spectrometer (400 MHz, Varian). R values were determined
3
f
1120

on LSL
(5/40 μm) silica gel plates using CHCl −MeOH (12:1, 1), C H –MeOH (10:1, 2), and CHCl −MeOH (8:1, 3).
3 6 6 3
254
Melting points of all synthesized compounds were determined on a Stuart SMP20 Melting Point Apparatus.
General Method for Synthesizing Dihydroimidazo[5,1-a]isoquinolines 2a−e. Amixture of amide 1a−e (1.1 mmol)
and POCl (5.5 mmol) was refluxed on a water bath for 4−6 h. The course of the reaction was monitored by TLC. The reaction
3
mixture was poured into ice, made basic with NH OH solution (25%) to pH 9, and extracted with CHCl . The extracts were
4
3
evaporated. The solid was either triturated with Me CO or dissolved in MeOH before producing the hydrochloride.
2
The MeOH was evaporated. The solids (2b−e) were crystallized from Me CO.
2
8,9-Dimethoxy-3-phenyl-5,6-dihydroimidazo[5,1-a]isoquinoline (2a), C H N O , was prepared from 1a
19 18
2 2
1
(0.4 g, 1.17 mmol) and POCl (0.6 mL). Yield 74% (0.265 g), mp of base 172–174°C (Me CO), R 0.81 (system 3). Í NMR
3
2
f
spectrum (400 MHz, ÑDCl , δ, ppm, J/Hz): 2.92 (2Í, t, J = 6.6, Í-6), 3.84 (3Í, s, OCH ), 3.88 (3Í, s, ÎÑÍ ), 4.18 (2Í, t,
3
3
3
J = 6.8, Í-5), 6.70 (1Í, s, Í-10), 7.01 (1Í, s, H-7), 7.33 (1Í, s, H-1), 7.36 (1Í, dt, J = 2.6, 7.3, H-4′′), 7.41 (2Í, dt, J = 2.3,
7.4, H-3′′, 5′′), 7.59 (1Í, dt, J = 2, 6.9, H-2′′, 6′′).
8,9-Dimethoxy-3-phenyl-1-ethyl-5,6-dihydroimidazo[5,1-a]isoquinoline (2b), C H N O , was prepared from
21 22
2 2
1b (0.4 g, 1.08 mmol) and POCl (0.5 mL). Yield 61% (0.22 g), mp of hydrochloride 244–245°C (Me CO), R 0.34 (system 2).
3
2
f
1
Í NMR spectrum (400 MHz, ÑDCl , δ, ppm, J/Hz): 1.38 (3Í, t, J = 7.5, CH ), 2.91 (2Í, t, J = 6.4, H-6), 2.97 (2Í, q, J = 7.5,
3
3
CH ), 3.86 (3Í, s, OCÍ ), 3.89 (3Í, s, OCÍ ), 4.16 (2Í, t, J = 6.4, H-5), 6.75 (1Í, s, H-10), 7.07 (1Í, s, H-7), 7.39 (1Í, dt,
2
3
3
J = 2.7, 7.7, H-4′′), 7.44 (2Í, dt, J = 2.1, 7.4, H-3′′, 5′′), 7.60 (2Í, dt, J = 2.4, 8.6, H-2′′, 6′′).
8,9-Dimethoxy-3-phenyl-1-propyl-5,6-dihydroimidazo[5,1-a]isoquinoline (2c), C H N O , was prepared from
22 24
2 2
1c (0.5 g, 1.3 mmol) and POCl (0.6 mL). Yield 76% (0.34 g), mp of hydrochloride 219–221°C (Me CO), R 0.77 (system 1).
3
2
f
–1
1
IR spectrum (ν, cm ): 3393, 3053, 2961, 2868, 1635, 1544, 1512, 1464. Í NMR spectrum (400 MHz, ÑD ÎD, δ, ppm, J/Hz):
3
1.01 (3Í, t, J = 7.3, Í-4′), 1.79 (2Í, q, J = 7.6, Í-3′), 2.95 (2Í, t, J = 7.8, Í-2′), 2.99 (2Í, t, J = 7.7, Í-6), 3.79 (3Í, s, ÎÑÍ ), 3.81
3
(3Í, s, ÎÑÍ ), 4.26 (2Í, t, J = 7, Í-5), 6.95 (1Í, s, Í-10), 7.10 (1Í, s, Í-7), 7.59 (1Í, dt, J = 1.8, 6, H-4′′), 7.62 (2Í, dt,
3
13
J = 2, 6.1, H-3′′, 5′′), 7.69 (2Í, dt, J = 2.2, 8, H-2′′, 6′′). C NMR spectrum (100 MHz, ÑD ÎD, δ, ppm): 14.23 (C-5′), 23.58
3
(C-4′), 28.14 (C-6), 29.19 (C-3′), 44.9 (C-5), 56.74 (OCH ), 56.96 (OCH ), 109.41 (C-10), 113.32 (C-7), 118.17 (C-10a), 123.88
3
3
(C-6a), 127.94 (C-2′′), 128.17 (C-6′′), 129.28 (C-1′′), 130.76 (C-3′′), 130.85 (C-5′′), 133.58 (C-4′′), 143.38 (3), 150.27 (C-9),
151.68 (C-8).
8,9-Dimethoxy-3-phenyl-1-isopropyl-5,6-dihydroimidazo[5,1-a]isoquinoline (2d), C H N O , was prepared from
22 24
2 2
1d (0.4 g, 1.04 mmol) and POCl (0.5 mL). Yield 70% (0.25 g), mp of hydrochloride 253–255°C (Me CO), R 0.79 (system 1).
3
2
f
–1
1
IR spectrum (ν, cm ): 3627, 3394, 2551, 1631, 1514, 1489. Í NMR spectrum (400 MHz, ÑDCl , δ, ppm, J/Hz): 1.40 (6Í,
3
d, J = 6.8, 2CH ), 2.86 (2Í, t, J = 6.3, H-6), 3.31 (1Í, q, J = 6.8, Í-2′), 3.85 (3Í, s, OCÍ ), 3.89 (3Í, s, OCÍ ), 4.09 (2Í, t,
3
3
3
J = 6.9, Í-5), 6.74 (1Í, s, H-10), 7.10 (1Í, s, H-7), 7.32 (1Í, dt, J = 2.2, 7.2, H-4′′), 7.39 (2Í, dt, J = 1.6, 7.6, H-3′′, 5′′), 7.57
13
(2Í, dt, J = 1.5, 6.9, H-2′′, 6′′). C NMR spectrum (100 MHz, ÑD ÎD, δ, ppm): 22.03 (C-3′, 2a), 26.75 (C-6), 29.30 (C-2′),
3
44.35 (C-5), 56.73 (OCH ), 57.02 (OCH ), 109.98 (C-10), 113.36 (C-7), 118.19 (C-10a), 124.25 (Ñ-6a), 126.72 (C-1), 128.59
3
3
(C-1′′), 130.73 (C-2′′, 6′′), 131.08 (C-3′′, 5′′), 133.65 (C-4′′), 134.72 (Ñ-10b), 144.14 (C-3), 150.27 (C-9), 151.74 (Ñ-8).
8,9-Dimethoxy-3-phenyl-1-isobutyl-5,6-dihydroimidazo[5,1-a]isoquinoline (2e), C H N O , was prepared from
23 26
2 2
1e (0.5 g, 1.25 mmol) and POCl (0.7 mL). Yield 82% (0.37 g), mp 202–204°C (Me CO), R 0.44 (system 2). IR spectrum
3
2
f
–1
1
(ν, cm ): 3447, 2958, 1629, 1547, 1512, 1465. Í NMR spectrum (400 MHz, ÑDCl , δ, ppm, J/Hz): 1.02 (6Í, d, J = 6.6,
3
2ÑÍ ), 2.09 (1Í, q, J = 6.8, Í-3′), 2.86 (2Í, d, J = 7.3, Í-2′), 3.01 (2Í, t, J = 6.4, Í-6), 3.83 (3Í, s, ÎÑÍ ), 3.85 (3Í, s,
3
3
ÎÑÍ ), 4.26 (2Í, t, J = 6.4, Í-5), 6.97 (1Í, s, Í-10), 7.18 (1Í, s, Í-7), 7.60 (1Í, dt, J = 1.4, 6, Í-4′′), 7.62 (2Í, dd, J = 1.7,
3
13
6.6, Í-3′′, 5′′), 7.69 (2Í, dt, J = 1.9, 6, Í-2′′, 6′′). C NMR spectrum (100 MHz, ÑD ÎÑD , δ, ppm): 23.02 (C-4′, 3a), 29.62
3
3
(Ñ-3′), 30.61 (Ñ-4), 36.02 (Ñ-2′), 44.52 (Ñ-5), 57.05 (OCH ), 57.27 (OCH ), 109.98 (Ñ-10), 113.96 (Ñ-7), 119.63 (Ñ-10a),
3
3
125.95 (Ñ-6a, 1), 128.73 (Ñ-2′′, 6′′), 131.06 (Ñ-3′′), 131.42 (Ñ-5′′), 133.72 (Ñ-10b), 144.77 (Ñ-3), 150.99 (Ñ-9), 152.16 (Ñ-8).
+
ESI-MS (+ESI TIC Scan Frag=125.0 V) m/z 363 [M+H] .
XSA Experiment. Unit-cell constants of 2c⋅HCl⋅3H O were determined and refined on a CCD Xcalibur Ruby
2
diffractometer (Oxford Diffraction) using Cu Kα-radiation (T = 288 K). The crystals were monoclinic, space group P2 /n,
1
°
Z = 4 (C H N O ⋅Cl). The unit-cell constants were a = 13.310(1), b = 7.3861(8), c = 23.443(2) A , β = 100.19(1)°.
22 31
2 2
A three-dimensional dataset of reflections was collected on the diffractometer. Absorption corrections were applied using the
SADABS program [22]. The structure was solved by direct methods using the SHELXS-97 program suite [23] and refined
using SHELXL-2014/7 software [24]. All nonhydrogen atoms were refined by anisotropic full-matrix least-squares methods
2
(over F ). H atoms on C atoms were positioned geometrically and refined using a rider model with fixed isotropic shift
parameters U = nU , where n = 1.5 for methyls and 1.2 for others (U is the equivalent isotropic shift parameter
iso
eq
eq
1121

of the corresponding C atoms). H atoms of water molecules and NH groups were found in difference electron-density syntheses
and refined isotropically using the DFIX instruction. The final agreement factor over all 4571 reflections was 16.3%; over
2026 reflections with I > 2σ(I), 8.7%. Data from the XSA analysis were deposited as a CIF file in the Cambridge Crystallographic
Data Centre (CCDC 1948404).
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