Cyclocondensation of 2-fluoro-5-nitrobenzaldehyde with amidines. New synthesis of isoquinolines

Article abstract of DOI:10.1023/B:COHC.0000044571.89322.4e

The direction of the cyclocondensation of 2-fluoro-5-nitrobenzaldehyde with five amidines having α-hydrogen atoms has been studied. It was established that depending on the structure of the amidine the main products of the reaction may be not only quinazo

Full text of DOI:10.1023/B:COHC.0000044571.89322.4e

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
CYCLOCONDENSATION OF 2-FLUORO-
5-NITROBENZALDEHYDE WITH AMIDINES.
NEW SYNTHESIS OF ISOQUINOLINES*
D. V. Dar'in, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin
The direction of the cyclocondensation of 2-fluoro-5-nitrobenzaldehyde with five amidines having
α-hydrogen atoms has been studied. It was established that depending on the structure of the amidine
the main products of the reaction may be not only quinazolines but also 3-aminoisoquinolines. A new
convenient route has been found for the synthesis of 3-aminoisoquinolines consisting of the
cyclocondensation of α-acylacetamidines with 2-fluoro-5-nitrobenzaldehyde.
Keywords: amidines as N,N- and C,N-dinucleophiles, isoquinolines, 2-fluoro-5-nitrobenzaldehyde,
cyclocondensation.
The cyclocondensation of amidines with activated ortho-fluorobenzaldehydes was discovered recently,
and is a simple and convenient method for synthesizing 4-unsubstituted quinazolines. Amidines, the behavior of
which was studied in this reaction, react as N,N'-dinucleophiles [2].
In addition it is known that amidines having a hydrogen atom in the α-position to the amidine fragment
may also act as N,C-dinucleophiles in reactions with 1,3-dielectrophiles [3]. In reactions with activated ortho-
fluorobenzaldehydes such amidines might form 2-aminoquinolines 4 or 3-aminoisoquinolines 5, together with
quinazolines 3 isomeric with them.
NH
O2N
CHO
+
R
H2N
F
2
1
R
O2N
O2N
O2N
N
N
+
+
R
N
NH2
NH2
N
4
3
5
R
a R = H; b R = Ph; c R = CONH2; d R = COPh; e R = CO2Et
We have investigated the reaction of substituted acetamidines 2a-e, differing in the nature of the
substituent at the α-carbon atom and consequently in the reactivity of the carbon nucleophilic center, with
aldehyde 1.
_______
* For the preliminary communication see [1].
__________________________________________________________________________________________
St. Petersburg State University, Saint Petersburg 198504, Russia; e-mail: psl@pisem.net. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1036-1042. July, 2004. Original article submitted June 27,
2003.
888
0009-3122/04/4007-0888©2004 Springer Science+Business Media, Inc.

Amidines 2a-c were reacted as the hydrochlorides as we used the conditions described in [2]. Potassium
carbonate was used as base. Amidines 2d and 2e were reacted as the free bases. Judging by the 1H NMR spectra
they exist in the enediamine form (NH2)2C=CHR (R = COPh and CO2Et).
In the reaction of aldehyde 1 with acetamidine 2a, with the least ability to display C-nucleophilic
properties, the main product, as expected, proved to be 2-methyl-6-nitroquinazoline (3a), isolated in 58% yield.
2-Amino-6-nitroquinoline (4a), resulting from participation of the carbon nucleophilic center of acetamidine,
was also successfully isolated from the reaction mixture in ~1.5% yield. The structures of quinazoline 3a and
1
aminoquinoline 4a were confirmed by their H NMR spectra. Compound 4a may be assigned a quinoline
1
structure and not the isomeric isoquinoline, since in its H NMR spectrum a spin-spin interaction is observed
between the protons at positions 3 and 4 with a coupling constant of 9.0 Hz (doublets at 6.89 and 8.13 ppm),
which corresponds to their ortho disposition. Aminoquinoline 4a has been repeatedly described in the literature
[4-6]. Various authors give its melting point in the range 255-265°C. The sample obtained by us decomposed at
~250°C.
Two isomeric compounds were isolated in the reaction with phenylacetamidine (2b). These were
2-benzyl-6-nitroquinazoline (3b) in 18% yield and 2-amino-6-nitro-3-phenylquinoline (4b), purified through the
picrate and isolated in 6% yield. The structures of quinazoline 3b and aminoquinoline 4b were confirmed by
1
their H NMR spectra. To prove the structure of aminoquinoline 4b a NOESY spectrum was taken in which a
cross peak was observed between the signals of the 4-H proton of the heterocycle and the ortho-protons of the
benzene ring, which indicates the relatively close disposition of them both, which occurs only in the quinoline
structure.
In the reaction with carbamoylacetamidine (2c) we isolated only 3-amino-4-carbamoyl-7-
nitroisoquinoline (5c) in 63% yield. It is not possible to draw an unequivocal conclusion between the quinoline
1
4c and isoquinoline 5c structures on the basis of the H NMR spectrum of this compound, since the expected
difference of chemical shifts of the protons for these structures is small, and the character of the spin-spin
interactions is the same. Consequently to demonstrate the structure of this compound the spin-spin interactions
between the 1H and 13C nuclei were studied. A complete assignment of the signals in the 13C NMR spectrum was
carried out on the basis of unidimensional 13C NMR spectra without proton decoupling and DEPT-135 and of
two-dimensional COLOC correlation spectra (with optimization of sensitivity at J = 8 Hz) and HSQC without
broadband decoupling from the 13C nuclei [7]. The chemical shift (156.1 ppm) detected for the signal of the C(1)
atom (or C(4) for quinoline) served to indicate the isoquinoline structure, since the values of the chemical shifts
for unsubstituted structures were 152.0 ppm for C(1) in isoquinoline and 136.1 for C(4) in quinoline [8]. In
13
addition, from the C spectrum without proton decoupling we obtained a value for the direct coupling constant
1
1J(C(1)–H) = 181.5 Hz, at corresponding values for the unsubstituted compounds J(C(1)-H) = 178 Hz
(isoquinoline), and 1J(C(4)–H) = 162 Hz (quinoline) [8]. The chemical shift of the C(1) atom signal and the value
of its direct coupling constant are adequately weighty, but indirect arguments in favor of the fact that the
compound obtained is an isoquinoline. For a direct demonstration, a so-called relay INEPT-INADEQUATE
1
experiment [9] was carried out, designed to clarify spin systems of the form H–13C–13C and including the
1
1
sequential transfer of polarization from the proton to the geminal carbon atom through the JH-C and JC-C
coupling constants.
In the INEPT-INADEQUATE spectrum (Fig. 1) signals of the quaternary carbon atoms linked in both
structures with methine carbon atoms (C(4a), C(7), and C(8a) for isoquinoline and C(4a), C(6), and C(8a) for quinoline),
were observed, as might have been expected, in the form of antiphase doublets with coupling constants
1JC-C ~65 Hz. In the structure of the C(4) atom signal (C(3) for quinoline) at 104.3 ppm the indicated doublet
splitting was absent. In the structure of quinoline 4c the C(3) atom has a vicinal proton (4-H) and the signal of this
atom should be represented as an antiphase doublet. In the structure of isoquinoline 5c the C(4) atom does not
have vicinal protons. On the basis of the shape of the signal at 104 ppm we may confidently assign the structure
of isoquinoline 5c to the compound being investigated.
889

Fig. 1. INEPT-INADEQUATE spectrum of compound 5c.
In addition to the signals of the main substance, a group of low intensity signals was observed in the
1H NMR spectrum of isoquinoline 5c, which may belong to the isomeric aminoquinoline 4c, the content of
which in the reaction product was less than 1%.
On carrying out the reaction of benzoylacetamidine (2d) with aldehyde 1 under the conditions used for
amidines 2a-c, we isolated a reaction mixture with a low content of the main substance strongly contaminated
with side products. On carrying out this reaction without base (method A) the main reaction product was
3-amino-4-benzoyl-7-nitroisoquinoline (5d), isolated in 47% yield. The structure of aminoisoquinoline 5d was
confirmed by its 1H and 13C NMR spectra. In the 1H NMR spectrum the signals of the 1-H, 6-H, and 8-H protons
and the protons of the amino group have chemical shifts close to the signals of the analogous protons of
isoquinoline 5c. The exception was the signal for the proton at position 5 (doublet with coupling constant
9.3 Hz), the displacement of which into the low frequency region by 0.64 ppm in comparison with the signal for
5-H of isoquinoline 5c may be explained by the shielding action of the benzene ring. Assignment of the signals
of the methine carbon atoms in the 13C spectrum was carried out using DEPT and HSQC spectra and the
TABLE 1. Yield of Products from the Reaction of Aldehyde 1 with
Amidines 2a-e
Yield, %
Amidine
3
4
5
58
18
0
1.5
6
0
0
2а
2b
2c
2d
2e
0.5*
2.5*
2*
63
47
37
0
0
_______
* Not isolated.
890

quaternary atoms were assigned by comparison with the position of the signals of the analogous atoms in the
spectrum of aminoisoquinoline 5c. The signal of the C(1) atom was located at 157.8 ppm and the coupling
constant 1J(C(1)–H) = 186.8 Hz, which corresponds to the value expected for an isoquinoline.
On carrying out the same reaction in the presence of triethylamine (method B) aminoisoquinoline 5d is
formed in somewhat lower yield. Signals were detected in the 1H NMR spectrum of the main product which may
be assigned to the isomeric 2-amino-3-benzoyl-6-nitroquinoline (4d), present at 5%. In the HSQC spectrum,
without decoupling from the 13C nuclei, appropriate cross peaks are also observed belonging to monomeric
aminoquinoline 4d, among which may be isolated a cross peak between the signal of the 4-H proton (8.60 ppm)
1
and the signal of the C(4) atom at 147.5 ppm. The value J(C(4)–H) = 166.2 Hz observed at this cross peak
corresponds to that expected for quinoline.
On carrying out the reaction of aldehyde 1 with amidine 2e under the same conditions as in the case of
amidines 2a-c, the main product proved to be dihydropyridine 6e, containing as contaminants 3-amino-4-
ethoxycarbonyl-7-nitroisoquinoline (5e) and 2-amino-3-ethoxycarbonyl-6-nitroquinoline (4e).
NH2
EtO2C
NH
.
4e
1
5e
2e
HCl
+
O2N
+
+
NH2
CO2Et
F
6e
A satisfactory yield of isoquinoline 5e was achieved by gradually adding a solution of amidine 2e as the
free base to the solution of aldehyde 1 (method A). In this way isoquinoline 5e was isolated in 40% yield,
1
containing, judging by the H NMR spectrum, quinoline 4e (6%). The structure of isoquinoline 5e was
demonstrated by a chemical method. Acid 5f (R = CO2H) was obtained by the hydrolysis of ester 5e, the
decarboxylation of which led to isoquinoline 5a. Pure dihydropyridine 6e was obtained in 74% yield by
method B.
The direction of the process as a function of amidine structure may therefore be demonstrated by the
summary Table 1.
The reaction discovered by us represents a new scheme for assembling the isoquinoline ring and
broadens the possibility of synthesizing substituted isoquinolines.
EXPERIMENTAL
The NMR spectra were obtained on a Bruker DPX-300 (300 MHz) instrument in DMSO-d6.
Reaction of Aldehyde 1 with Acetamidine (2a). A mixture of aldehyde 1 [10] (0.84 g, 5 mmol),
acetamidine hydrochloride (0.77 g, 7.5 mmol), potassium carbonate (1.03 g, 7.5 mmol), and molecular sieves 4E
(1.5 g) in dry acetonitrile (40 ml) was boiled with stirring for 4 h. The solid was filtered off and washed with
ethyl acetate. The filtrate was evaporated, and the residue chromatographed on a column. Initially as eluent
hexane–ether was used, gradually increasing the proportion of ether from 20 to 75%. 2-Methyl-6-
nitroquinazoline (3a) (0.55 g, 58%) of mp 150-154°C was isolated. A sample pure for analysis was obtained by
1
recrystallization from methanol–acetonitrile, 3:1. H NMR spectrum, δ, ppm (J, Hz): 2.84 (3H, s, CH3); 8.05
(1H, d, J = 9.1, 8-H); 8.61 (1H, m, J = 9.1, J = 2.5, 7-H); 9.12 (1H, d, J = 2.5, 5-H); 9.78 (1H, s, 4-H). Found, %:
C 57.21; H 3.72; N 22.10. C9H7N3O2. Calculated, %: C 57.14; H 3.73; N 22.21. The column was then eluted
with hexane–ether–ethyl acetate, 1:3:1, as a result of which the second reaction product, 2-amino-6-
nitroquinoline (4a), was isolated in a yield of 0.011 g (1.5%) having mp 250°C (decomp.). (Lit. mp 261°C [4],
891

1
265°C [5], 256°C [6]). A sample pure for analysis was obtained by sublimation at 150°C (1 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 6.89 (1H, d, J = 9.0, 3-H); 7.23 (2H, NH2); 7.50 (1H, d, J = 9.3, 8-H); 8.13 (1H, d,
J = 9.0, 4-H); 8.22 (1H, m, J = 9.3, J = 2.5, 7-H); 8.68 (1H, d, J = 2.5, 5-H).
Reaction of Aldehyde 1 with Phenylacetamidine (2b). A mixture of aldehyde 1 (0.68 g, 4 mmol),
phenylacetamidine hydrochloride [11] (1.1 g, 6.6 mmol), K2CO3 (0.92 g, 6.6 mmol), and molecular sieves 4E
(1.3 g) in dry acetonitrile (40 ml) was boiled with stirring for 5 h. The solid was filtered off, washed with ethyl
acetate, and the solvent evaporated. The residue was chromatographed on a column, which was eluted with
hexane–ether gradually increasing the proportion of ether (5:1, 4:1, 3:1, 2:1, 1:1). 2-Benzyl-6-nitroquinazoline
(3b) was isolated in a yield of 0.19 g (18%) having mp 128-130°C. A sample pure for analysis was obtained by
recrystallization from methanol. 1H NMR spectrum, δ, ppm (J, Hz): 4.43 (2H, s, CH2); 7.20-7.40 (5H, m, C6H5);
8.15 (1H, d, J = 9.2, 8-H); 8.64 (1H, d, J = 9.2, 7-H); 9.27 (1H, s, 5-H); 9.86 (1H, s, 4-H). Found, %: C 67.93;
H 4.26; N 15.70. C15H11N3O2. Calculated, %: C 67.92; H 4.18; N 15.84. 2-Amino-6-nitro-3-phenyl-quinoline
(4b) (0.18 g) was isolated heavily contaminated and after recrystallization from methanol–acetonitrile 3:1, it
contained impurities. The preparation was purified through the picrate. Yield (calculated on aldehyde 1) 6%;
mp 270°C (acetonitrile). Found, %: C 50.45; H 2.87; N 16.52. C15H11N3·C6H3N3O7. Calculated, %: C 51.02;
H 2.85; N 16.99. Pure aminoquinoline 4b of mp 184-188°C was obtained by treating aminoquinoline 4b picrate
with an excess of aqueous KOH solution. 1H NMR spectrum, δ, ppm (J, Hz): 6.83 (2H, NH2); 7.44-7.53 (5H, m,
C6H5); 7.57 (1H, d, J = 9.3, 8-H); 8.10 (1H, s, 4-H); 8.23 (1H, m, J = 9.3, J = 3.0, 7-H); 8.73 (1H, d, J = 3.0,
5-H).
Reaction of Aldehyde 1 with Carbamoylacetamidine (2c). A mixture of aldehyde 1 (0.57 g,
3.4 mmol), amidine hydrochloride 2c (0.7 g, 5.1 mmol), K2CO3 (0.7 g, 5.1 mmol), and molecular sieves 4E
(0.8 g) in dry acetonitrile (40 ml) was boiled for 45 min, then cooled to ~10°C, the solid was filtered off, washed
with ethanol, and with hot water, after which it was stirred with hot DMF (10 ml), the sieves filtered off, and the
reaction product reprecipitated from the filtrate with ethanol–ether, 1:1. 3-Amino-4-carbamoyl-7-
nitroisoquinoline (5c) (0.5 g, 63%) was obtained with mp >300°C. A sample pure for analysis was obtained by
recrystallization from DMF, sequentially boiling in water, ethanol, and acetonitrile, then subliming at 220°C
(1 mm Hg). 1H NMR spectrum, δ, ppm (J, Hz): 6.86 (2H, 3-NH2); 7.83 (1H, d, J = 9.3, 5-H); 7.85 (1H, CONH);
13
8.06 (1H, CONH); 8.24 (1H, m, J = 9.3, J = 2.5, 6-H); 8.93 (1H, d, J = 2.5, 8-H); 9.19 (1H, s, 1-H). C NMR
spectrum, δ, ppm: 104.4 (C(4)), 119.8 (C(8a)); 123.83 (C(5)); 123.85 (C(6)); 126.1 (C(8)); 137.4 (C(4a)); 141.0 (C(7));
1
156.0 (C(3)); 156.1(C(1), J(C-H) = 182 Hz); 168.1 (CO). Found, %: C 51.66; H 3.52; N 24.19. C10H8N4O3.
Calculated, %: C 51.73; H 3.47; N 24.13.
Reaction of Aldehyde 1 with Benzoylacetamidine (2d). Amidine 2d was obtained by the procedure of
[13], H NMR spectrum, δ, ppm: 5.15 (1H, s, =CH); 6.3 (2H, NH2); 6.6 (1H, NH); 7.30-7.70 (5H, C6H5); 10.0
1
(1H, NH).
A. A mixture of aldehyde 1 (0.61 g, 3.6 mmol), amidine 2d (0.48 g, 3.0 mmol), and molecular sieves 4E
(0.8 g) in dry acetonitrile (20 ml) was boiled with stirring for 3 h. The sieves were filtered off, the solvent
evaporated, and the residue crystallized from methanol–acetonitrile, 1:1. Yield of compound 5d was 0.41 g
1
(47%) of mp 192-194°C. H NMR spectrum, δ, ppm (J, Hz): 7.13 (2H, NH2); 7.19 (1H, d, J = 9.3, 5-H); 7.53
(2H, t, m-H); 7.68 (1H, t, p-H); 7.76 (2H, d, o-H); 8.07 (1H, m, J = 9.3, J = 2.5, 6-H); 8.95 (1H, d, J = 2.5, 8-H);
13
9.33 (1H, s, 1-H). C NMR spectrum, δ, ppm: 104.8 (C(4)); 119.9 (C(8a)); 123.4 (C(5)); 124.2 (C(6)); 126.3 (C(8));
129.0 (m-C6H5); 129.4 (o-C6H5); 133.7 (p-C6H5); 137.72, 138.6 (C(4a), ipso-C6H5); 141.2 (C(7)); 156.6 (C(3));
157.9 (C(1), 1J(C–H) = 186.8 Hz); 195.8 (CO). Found, %: C 65.36; H 3.79; N 14.29. C16H11N3O3. Calculated, %:
C 65.53; H 3.78; N 14,33.
B. A mixture of aldehyde 1 (0.34 g, 2 mmol), amidine 2d (0.27 g, 1.7 mmol), and triethylamine (0.22 g,
2.2 mmol) in dry acetonitrile (30 ml) was boiled for 2 h. The solvent was evaporated, and the residue resolved on
a chromatographic column. This was eluted with a hexane–ether mixture, gradually increasing the proportion of
ether (4:1, 3:1, 2:1, 1:1, 1:2). 3-Amino-4-benzoyl-7-nitroisoquinoline (5d) was isolated in this way, and
892

after recrystallization from methanol–acetonitrile, 3:1, contained the isomeric reaction product 2-amino-3-
benzoyl-6-nitroquinoline (4d) (5%). The yield of compound 5d was 0.185 g (37%); mp 192-194°C.
Reaction of Aldehyde 1 with Ethyl Amidinoacetate (2e). Amidine 2e was obtained as the free base by
extracting an aqueous solution of amidine hydrochloride 2e [12] and a 50% excess of potassium carbonate with
ethyl acetate. 1H NMR spectrum, δ, ppm: 1.09 (3H, t, CH3); 3.78 (1H, s, =CH); 3.86 (2H, q, CH2); 5.79 (2H, s,
NH2); 6.9 (2H, NH2).
A. A solution of amidine 2e (0.27 g, 2.1 mmol) in DMF (8 ml) was added dropwise with heating (50°C)
and stirring during 1 h to a mixture of aldehyde 1 (0.39 g, 2.3 mmol), molecular sieves 4E (0.5 g), and
acetonitrile (6 ml). After a further 1 h at 50°C the reaction mixture was poured into water (50 ml), and the
resulting crystals recrystallized from methanol–acetonitrile, 4:1. The yield of 3-amino-4-ethoxycarbonyl-7-
nitroisoquinoline (5e) (containing ~5% 2-amino-3-ethoxycarbonyl-6-nitroquinoline (4e)) was 0.22 g (40%);
1
mp 174-177°C. H NMR spectrum, δ, ppm (J, Hz): 1.39 (3H, t, CH3); 4.42 (2H, q, CH2); 7.92 (2H, NH2); 8.28
(1H, m, J = 9.3, J = 2.5, 6-H); 8.51 (1H, d, J = 9.3, 5-H); 8.89 (1H, d, J = 2.5, 8-H); 9.30 (1H, s, 1-H). Found, %:
C 55.19; H 4.17; N 16.03. C12H11N3O4. Calculated, %: C 55.17; H 4.24; N 16.08.
B. Potassium carbonate (0.61 g, 4.4 mmol) was added to a solution of aldehyde 1 (0.37 g, 2.2 mmol) and
amidine hydrochloride 2e (0.73 g, 4.4 mmol) in DMF (10 ml) and the mixture stirred for 1 h 30 min at ~20°C.
The reaction mixture was then poured into water (40 ml) and the resulting crystals of diethyl 2,6-diamino-4-(2-
fluoro-5-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylate (6e) were filtered off, dried, and recrystallized
1
from dichloromethane. Yield was 0.64 g (74%); mp 178-182°C. H NMR spectrum, δ, ppm: 1.02 (6H, t, CH3);
3.84 (4H, m, CH2); 4.91 (1H, s, 4-CH); 7.12 (4H, NH2); 7.27 (1H, t, 3-Har); 7.99 (2H, m, 4-Har and 6-Har); 8.62
(1H, s, NH). The picrate of 6e was isolated analytically pure, mp 205-207°C. Found, %: C 44.29; H 3.57;
N 15.75. C17H19FN4O6·C6H3N3O7. Calculated, %: C 44.31; H 3.56; N 15.73.
3-Amino-7-nitroisoquinoline (5a). Solutions of isoquinoline 5e (0.2 g, 0.77 mmol) and KOH (0.14 g,
2.5 mmol) in ethanol were mixed and boiled for 2 h 30 min, the solution was cooled, and the precipitated dark-
red crystals filtered off. The potassium salt of 3-amino-7-nitroisoquinoline-3-carboxylic acid (0.12 g, 57%) was
obtained. A solution of the salt (0.1 g) in water (3 ml) was acidified with dilute hydrochloric acid, the
precipitated yellow crystals were filtered off, and dried. Acid 5f (0.06 g, 70%) was obtained; mp >250°C.
1H NMR spectrum, δ, ppm (J, Hz): 8.10 (2H, br. s, NH2); 8.33 (1H, m, J = 9.3, J = 2.5, 6-H); 8.72 (1H, d,
J = 9.3, 5-H); 8.91 (1H, d, J = 2.5, 8-H); 9.29 (1H, s, 1-H); 13.6 (1H, COOH). The obtained acid (0.03 g) was
triturated thoroughly with CaO (0.05 g) and heated at 220°C and 1 mm Hg in a sublimation apparatus. 3-Amino-
7-nitroisoquinoline (5a) (0.01 g, 42%) was isolated with mp 236-238°C (decomp.). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 4.86 (2H, NH2); 6.78 (1H, s, 4-H); 7.61 (1H, d, J = 9.3, 5-H); 8.27 (1H, m, J = 9.3, J = 2.5, 6-H);
8.78 (1H, d, J = 2.5, 8-H); 9.05 (1H, s, 1-H).
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