Synthesis of 3,3-dialkyl-1-(2-furyl)-3,4-dihydro-isoquinolines and their reaction with maleic anhydride

Article abstract of DOI:10.1007/s10593-013-1189-1

The cyclocondensation of dialkylbenzylcarbinols with 2-cyanofuran in the presence of H₂SO₄ gave 3,3-dialkyl-1-(2-furyl)-3,4- dihydroisoquinolines. Analogously, naphthalene derivatives form 4-(2-furyl)benzo[f]isoquinolines. The Diels-

Full text of DOI:10.1007/s10593-013-1189-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS OF 3,3-DIALKYL-1-(2-FURYL)-3,4-DIHYDRO-
ISOQUINOLINES AND THEIR REACTION WITH MALEIC
ANHYDRIDE
A. G. Mikhailovskii1*, Z. G. Aliev2, O. V. Surikova1, and N. G. Efremova1
The cyclocondensation of dialkylbenzylcarbinols with 2-cyanofuran in the presence of H2SO4 gave
3,3-dialkyl-1-(2-furyl)-3,4-dihydroisoquinolines. Analogously, naphthalene derivatives form 4-(2-fu-
ryl)benzo[f]isoquinolines. The Diels–Alder reaction of 2,2-dimethyl-4-(2-furyl)-1,2-dihydrobenzo[f]iso-
quinoline with maleic anhydride proceeds at N(1) and C(4) of the isoquinoline system to give exo-
19,19-dimethyl-1-(2-furyl)-15-oxa-18-azapentacyclo[10.5.2.02,11.O4,9.O13,17]nonadeca-2,4,6,8,10-pentaene-
14,16-dione. The structure of this dione product was proven by X-ray structural analysis.
Keywords: 2-cyanofuran, dialkylbenzylcarbinols, 2,2-dialkyl-4-(2-furyl)-1,2-dihydrobenzo[f]isoquinoli-
nes, 3,3-dialkyl-1-(2-furyl)-3,4-dihydroisoquinoline, exo-19,19-dimethyl-1-(2-furyl)-15-oxa-18-aza-
pentacyclo[10.5.2.02,11.04,9.013,17]nonadeca-2,4,6,8,10-pentaene-14,16-dione, maleic anhydride, naphthalene
derivatives, cyclocondensation.
There have been only a few reports of compounds containing both isoquinoline and furan systems in
their structure. We have already studied the cyclocondensation of nitriles to obtain isoquinolines containing
other heterocyclic systems, such as coumarin, as substituents [1, 2]. In the present work, we investigated the
feasibility of using this method for the synthesis of furan derivatives.
Carbinols 1a-e were found to react with 2-cyanofuran in a two-phase benzene–H2SO4 system, to give
3,3-dialkyl-1-(2-furyl)-3,4-dihydroisoquinoline derivatives 2a-e. Analogously, naphthalene derivatives 3a,b
underwent this reaction to give benzo[f]isoquinolines 4a,b.
The characteristics of these furan derivatives are given in Table 1. Derivatives 2e and 4a,b were
characterized as crystalline bases, while the other products were characterized as picrates.
1
The H NMR spectra of these products presented in Table 2 contain signals for the furan ring protons,
among which we should note the doublet for H-4 proton of the furan ring at 6.51-6.80 ppm in the spectra of the bases
and at 7.03-7.07 ppm in the spectra of the picrates. The signals of the aromatic picric acid protons appear at
8.47-8.60 ppm. All the other signals correspond to the protons of the substituents in the structure of these molecules.
_______
*To whom correspondence should be addressed, e-mail: neorghim@pfa.ru.
1Perm State Pharmaceutical Academy, 2 Polevaya St., Perm 614990, Russia.
2Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Akademika Semenova Ave.,
Chernogolovka 142432, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1774-1779, November, 2012.
Original article submitted May 5, 2011.
0009-3122/13/4811-1659©2013 Springer Science+Business Media New York
1659

Furan derivatives 2a-e, 4a,b contain two diene fragments, namely, furan and 1-azadiene units, which
permits us to regard these compounds as potential reagents in the Diels–Alder reaction for the preparation of
new polycyclic systems. We studied the reaction of these products with maleic anhydride and were able to
isolate product 5, which resulted from the addition of maleic anhydride to furan derivative 4a.
R1
R
R1
R1
R1
R
R
N
R
+
CN
OH
O
O
1a–e
2a–e
R1
N
R1
R1
R1
OH
+
CN
O
O
4a,b
3a,b
1, 2 а R = H, R1 = Ме; b R = H, R1+R1 = (CH2)5; c R = OМе, R1 = Me;
d R = OМе, R1 = Et; e R = OMe, R1+R1 = (CH2)4. 3, 4 a R1 = Me, b R1+R1 = (CH2)5
O
H
Me
Me
N
O
H
O
4a
O
+
O
H
O
O
5
Analysis of the spectra of this compound indicated the impossibility of determining the structure of
product 5 by ordinary spectral methods. Therefore, the structure of this compound was confirmed by X-ray
structural analysis (Fig. 1).
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
Mp, °С
С
H
N
C15H15NOC6H3N3O7
C18H19NOC6H3N3O7
C17H19NO3C6H3N3O7
C19H23NO3C6H3N3O7
C19H21NO3
55.43
55.51
58.23
58.30
53.61
53.70
55.30
55.35
73.23
73.29
82.81
82.88
83.72
83.78
73.92
73.98
3.92
3.99
4.54
4.48
4.25
4.31
4.72
4.83
6.71
6.80
6.12
6.22
6.65
6.71
5.02
5.13
12.45 180-181
12.33
11.28 167-168
11.33
11.05 153-154
10.89
10.44 159-161
10.33
67
62
71
66
72
75
64
42
2а
2b
2c
2d
2е
4а
4b
5
4.53
4.50
5.17
5.09
4.53
4.44
103-105
108-109
95-97
C19H17NO
C22H21NO
C23H19NO4
3.94
3.75
236-238
1660

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The bond lengths and angles in the product 5 were in good accord with the values typical for the
corresponding atoms. The major part of the benzo[f]isoquinoline fragment had a planar structure, while the
nitrogen-containing fragment of the bicyclic system and the five-membered residue of the anhydride were
opposite to each other. Both axial hydrogen atoms at C(2) and C(3) occupied exo positions, which indicates that
the reaction is stereospecific. The furan ring was found to be perpendicular to the isoquinoline fragment. There
were no hydrogen bonds or shortened intermolecular contacts in the crystal.
The structure of compound 5 was also confirmed by spectral data. The IR spectrum of this compound
1
had characteristic bands for C=O and NH groups at 1700 and 3150 cm-1, respectively. The H NMR spectrum
had signals for naphthalene and furan fragments, as well as for two methyl groups, which, in contrast to the
starting derivative 4a, were not equivalent and appeared as individual singlets at 0.59 and 1.40 ppm. The maleic
anhydride fragment protons (2,3-CH) were seen as a two-proton multiplet at 4.04-4.24 ppm, while the 4-CH
proton appeared as a one-proton doublet at 4.20 ppm. The mass spectrum displayed a molecular ion peak (m/z
373) and fragment ion peaks (m/z 275 and 260) due to elimination of maleic anhydride, i.e., the thermal reverse
cycloaddition, with subsequent loss of a methyl group.
Fig. 1. Structure of furan derivative 5 from X-ray diffraction data.
Analysis of the structure of derivative 5 shows that neither the furan unit nor the azadiene group serve
as the dienophile when maleic anhydride is used; instead, 1,4-addition occurs at the 3,4-dihydroisoquinoline
fragment. A possible explanation for this reaction path is formation of energetically-favored conjugated
structure B, which contains an active dienamine fragment.
Me
Me
Me
NH
Me
N
H
H
O
O
B
A
Thus, an investigation of the cyclocondensation of dialkylbenzylcarbinols with 2-cyanofuran, which has
the potential for decomposition in the presence of acids, showed that cyclocondensation proceeds despite the
presence of concentrated sulfuric acid. The furan in this case tolerated the presence of acid, apparently because
the isoquinolinium cation formed in the acid medium was an acceptor relative to the furan ring. The direction of
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the cyclocondensation reaction may be explained by assuming that of the three possible diene fragments
(azadiene, furan, and the above-mentioned dienamine fragment), the latter was the most active, bearing the
greatest electron density.
EXPERIMENTAL
1
The IR spectra were recorded on a Specord M-80 spectrometer in vaseline mull. The H NMR spectra
were recorded on a Bruker DRX-300 spectrometer (300 MHz) for bases of compounds 2e and 4a,b in CDCl3,
and in DMSO-d6 for the other compounds, with HMDS (δ 0.05 ppm) as internal standard. The electron impact
mass spectrum was recorded on a Finnigan MAT INCOS 50 mass spectrometer at 70 eV. The purity of the
bases of the compounds synthesized was monitored by thin layer chromatography on Silufol UV-254 plates
with 1:3:6 acetone–ethanol–chloroform as the eluent, using UV light or bromine vapor for visualization.
2-Cyanofuran was prepared according to a known procedure [3].
1-(2-Furyl)-6,7-(R1)2-3,3-(R2)2-3,4-dihydroisoquinolines (2a-e) and 4-(2-Furyl)-2,2-(R2)2-1,2-dihydro-
benzo[f]isoquinolines (4a,b) (General Method). Glacial acetic acid (2 ml) and concentrated sulfuric acid
(4 ml) were added consecutively to a mixture of 2-cyanofuran (1.12 g, 12 mmol) and the corresponding carbinol
1a-e or 3a,b (10 mmol) in benzene (30 ml). In the case of dihydroisoquinolines 2a,b, acetic acid was not added.
The mixture was vigorously stirred for 15 min at 60-70°C, cooled to 20°C, and diluted by adding ice water (150
ml). The benzene layer was separated. The aqueous phase was made basic by adding a sufficient quantity of
25% ammonium hydroxide. The base formed as either a crystalline or oily precipitate. For the crystalline
compounds (2e, 4a,b), the precipitate formed was filtered off, dried, and recrystallized from petroleum ether
(fraction 70-100°C). The other compounds, which precipitated as oily bases, were extracted with ether. The
ethereal extract was dried over sodium hydroxide, and the ether was distilled off. The residue was dissolved in a
minimum amount of 2-propanol, and picric acid (2.29 g, 10 mmol) solution in 2-propanol (150 ml) was added.
The yellow crystalline precipitate that formed was filtered off, dried, and recrystallized from 2-propanol.
exo-1-(2-Furyl)-19,19-dimethyl-15-oxa-18-azapentacyclo[10.5.2.02,11.04,9.013,17]nonadeca-2,4,6,8,10-
pentaene-14,16-dione (5). A solution of base 4a (2.75 g, 10 mmol) in toluene (30 ml) was heated at reflux for
30 min with maleic anhydride (0.98 g, 10 mmol). The solvent was evaporated in vacuum. The crystalline
precipitate was filtered off, dried, and recrystallized from 2-propanol. IR spectrum, ν, cm-1: 1700 (C=O), 3150
(NH). 1H NMR spectrum, δ, ppm (J, Hz): 0.59 (3H, s, CH3); 1.40 (3H, s, CH3); 2.09 (1H, s, NH); 4.04-4.24 (2H,
2
m, H-2,3); 4.20 (1H, d, J = 2, H-4); 6.60-7.05 (3H, m, H Fur); 7.43-8.12 (6H, m, H Ar). Mass spectrum, m/z
(Irel, %): 373 [M]+ (8), 275 (32), 260 (100).
X-ray Structural Analysis of Pentaenedione 5. The unit cell parameters of tetragonal crystals of
pentaenedione 5 were as follows: a 24.303(3), b 24.303(2), c 12.572(3) Å; α 90°, β 90°, γ 90°, V 7425(2) Å3;
M 373.39; dcalc 1.336 g/cm3; μ 0.092 mm-1; Z 16, space group I41/a. The set of experimental reflections was
obtained on a Kuma Diffraction KM-4 automatic four-circle diffractometer with χ-4 geometry, using
ω/2θ-scanning with monochromatized MoKα radiation (2θ ≤ 50%). A total of 4095 independent reflections
(Rint = 0.0796) were measured. No correction for absorption was introduced. The structure was solved by the
direct method using the SIR 92 program [4], with subsequent calculation of electron density maps. The
hydrogen atoms of the methyl and aromatic groups were given geometrically, while the other hydrogen atoms
were revealed from the electron density difference map. The positions of the non-hydrogen atoms were refined
anisotropically by the full-matrix method of least squares using the SHELX-97 program set [5] to R1 = 0.0730
and wR2 = 0.1205 for 3233 reflections with I ≥ 2σ(I), R1 = 0.2344 and wR2 = 0.1706 over all 4095 reflections
with GOOF 0.894. Complete data set for the structure of pentaenedione 5 was deposited at the Cambridge
Crystallographic Data Center (CCDC deposit 908576).
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REFERENCES
1.
A. G. Mikhailovskii and N. N. Polygalova, in: V. G. Kartsev (editor), Selected Methods for the
Synthesis and Modification of Heterocycles. Isoquinolines: Chemical and Biological Activity [in
Russian], Vol. 7, International Charitable Scientific Partnership Foundation (ICSPF), Moscow (2008),
p. 237.
2.
3.
A. G. Mikhailovskii and M. I. Vakhrin, Khim. Geterotsikl. Soedin., 1198 (2004). [Chem. Heterocycl.
Compd., 40, 1036 (2004)].
N. S. Zefirov (editor), Organic Chemistry Laboratory Textbook [in Russian], BINOM Laboratoriya
Znanii, Moscow (2010), p. 333.
4.
5.
A. Altomare, G. Cascarano, C. Giacovazzo, and A. Gualardi, J. Appl. Crystallogr., 26, 343 (1993).
G. M. Sheldrick, SHELXL-97: Programs for Crystal Structure Analysis, University of Göttingen
(1998).
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