Cyclocondensation of α-acylacetamidines with esters of 2-fluoro-5-nitrobenzoic and 4-chloro-2-methyl-5-pyrimidinecarboxylic acids

Article abstract of DOI:10.1007/s10593-008-0064-y

The cyclocondensation of α-acylacetamidines with esters of 2-fluoro-5-nitrobenzoic and 4-chloro-2-methyl-5-pyrimidinecarboxylic acids leads to condensed azines. The reaction proceeds chemoselectively such that the α-carbon atom of the amidine replaces the

Full text of DOI:10.1007/s10593-008-0064-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
CYCLOCONDENSATION OF
α-ACYLACETAMIDINES WITH ESTERS
OF 2-FLUORO-5-NITROBENZOIC AND
4-CHLORO-2-METHYL-5-PYRIMIDINE-
CARBOXYLIC ACIDS
D. V. Dar'in, S. G. Ryazanov, S. I. Selivanov, P. S. Lobanov, and A. A. Potekhin*
The cyclocondensation of α-acylacetamidines with esters of 2-fluoro-5-nitrobenzoic and
4-chloro-2-methyl-5-pyrimidinecarboxylic acids leads to condensed azines. The reaction proceeds
chemoselectively such that the α-carbon atom of the amidine replaces the halogen atom in the aromatic
ring, while the amino group reacts with the ester group.
Keywords: α-acylacetamidines, C,N-dinucleophiles, aromatic dielectrophiles, enediamines,
1-isoquinolinones, pyrido[4,3-d]pyrimidines, aromatic nucleophilic substitution, cyclocondensation.
In a continuation of our study of the reactivity of α-acylacetamidines with aromatic dielectrophiles
[1, 2], we investigated the reactions of amidines 1a-c with esters 2 and 4. α-Acylacetamidines 1a-c exist in
DMSO-d6 solution in the enediamine tautomeric form, which accounts for their C,N-dinucleophilic properties
upon reaction with dielectrophiles.
α-Acylacetamidines 1a-c act as C,N-dinucleophiles in their reactions with ester 2 and selectively give
the corresponding isoquinolines 3 in good yield. The reactions with amidines 1a and 1b were carried out at
room temperature. The reaction with benzoylacetamidine 1c proceeds more slowly and required heating to 50°C.
We should note that our proposed method for the synthesis of isoquinolines 3 complements a recently
reported method for the synthesis of analogous 3-aminoisoquinolines from amides of 2-chloro-5-nitrobenzoic
acid and aryl and hetaryl acetonitriles [3, 4].
The reaction of amidines 1a and 1b with ester 4 proceeds smoothly at room temperature over 60-100 h
and pyrido[4,3-d]pyrimidines 5a and 5b are formed in high yield. The reaction with amidine 1c proved rather
slow as in the case of ester 2 but significant tar formation occurred upon attempting to carry out this reaction
with heating. On the other hand, carrying out this reaction at room temperature required 60 days. The major
product was also pyrido[4,3-d]pyrimidine 6c, which was isolated chromatographically as a mixture of E- and Z-
isomers as indicated by the double set of signals in the 1H and 13C NMR spectra.
_______
* Deceased.
__________________________________________________________________________________________
St. Petersburg State University, 198504 St. Petersburg, Russia; e-mail: pslob@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 589-594, April, 2008. Original article submitted
October 16, 2007.
0009-3122/08/4404-0461©2008 Springer Science+Business Media, Inc.
461

O
O2N
O2N
CO2Me
F
NH2
NH
COR
+
H2N
NH2
COR
O
2
1a–c
3a–c
O
CO2Et
N
NH
NH2
N
NH
N
1
+
+
Me
N
N
Me
N
Cl
Me
N
H
COR
COR
4
5a–c
6a–c
1, 3, 5 a R = N(CH2)4, b R = OEt; 1, 3, 5, 6 c R = Ph
Yield, %: 3 a 80, b 83, c 57; 5 a 85, b 81, c 64; 6 c 5
1
The structures of all isoquinolines 3 and pyrido[4,3-d]pyrimidines 5a and 5b were proven by H and
13C NMR spectroscopy as well as by their NOESY correlational spectra, in which cross peaks were observed
between the signals of the protons of the substituent R and signals of the protons H-5 for the isoquinolines and
the methyl group at C-2 for the pyrido[4,3-d]pyrimidines, indicating an NOE between these protons. The
structure of pyrido[4,3-d]pyrimidine 5c, for which the corresponding NOE in the NOESY spectrum was not
observed, was confirmed by the chemical shift of the ring carbonyl group carbon atom (C-5, 161.1 ppm), which
depends strongly on the arrangement of the nitrogen atom and carbonyl group in the ring (chemical shifts for
C-2 and C-4 in 2- and 4-pyridones are 162.3 and 175.7 ppm, respectively [5]), and corresponds within 1 ppm to
the chemical shifts of the analogous carbon atoms in isoquinolines 3 and pyrido[4,3-d]pyrimidines 5a and 5b.
The reactivities of amidines 1a-c toward ester 4 differ strongly and correlate qualitatively with the
electronic properties of the substituents at the carbonyl group. Amidine 1a, which has a strong electron-donor
pyrrolidinyl substituent, reacts over 60 h, while amidine 1b (OEt) requires 100 h and amidine 1c requires
1500 h. We may assume that the reaction commences as nucleophilic replacement of the chlorine atom by the
carbon nucleophilic site and, then, rapid cyclization occurs with participation of the amino group. Thus, the rate
of the reaction is a function of the nucleophilicity of the α-carbon atom of the amidine, which depends on the
electronic properties of the substituent at the amidine carbonyl group.
The carbonyl carbon atom in acid chloride 7 is much more electrophilic than aromatic atoms C-2. Thus,
we might expect the formation of other products in the reaction of compound 7 with α-acylacetamidines. The
reaction of compound 7 with amidine 1b led to a complex mixture of many components, which could not be
separated or analyzed. On the other hand, a synthetic result was achieved with the less reactive amidine 1c. This
reaction was carried out with a two-fold excess of amidine.
O
O
NH2
O2N
230°C
91%
O2N
COCl
F
O2N
NH
N
H
1c
+
COPh
N
54%
F
H
COPh
8 (E + Z)
9
7
(E + Z)
The initially formed N-benzoylation product 8 was isolated as a mixture of E- and Z- isomers. Upon
heating above the melting point, these isomers cyclize to give quinazoline 9 in high yield.
462

The use of triethylamine leads to more tar formation and significantly reduces the yield of
N-benzoylation product 8, while less basic pyridine does not hinder the formation and precipitation of the
starting amidine.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker DPX 300 spectrometer at 300 and 75 MHz,
respectively, in DMSO-d6 as the solvent. The signals of the solvent at δ 2.50 ppm (for the 1H NMR spectra) and
δ 39.7 ppm (for the 13C NMR spectra) were used as the internal standard. The coupling constants in the 1H NMR
spectra were measured to the first-order approximation. The elemental analysis was carried out on a
Hewlett-Packard HP-185B CHN-analyzer. The purity of the compounds and reaction course were followed by
thin-layer chromatography on Silufol UV-254 plates.
3-Amino-7-nitro-4-pyrrolidinocarbonylisoquinolin-1(2H)-one (3a). A mixture of ester 2 [6] (0.3 g,
1.5 mmol), amidine 1a [2] (0.31 g, 2 mmol), and DMF (2 ml) was stirred at room temperature for 72 h and then
added to water (35 ml). The crystals formed were filtered off and dried at 130°C to give isoquinolinone 3a
(0.36 g, 80%). An analytically pure sample was obtained by recrystallization from ethanol, mp 335-344°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.83 (4H, m, N(CH2CH2)2); 3.15 (1H, m, N(CH2CH2)2); 3.26 (1H, m,
N(CH2CH2)2); 3.53 (2H, m, N(CH2CH2)2); 6.47 (2H, s, NH2); 7.24 (1H, d, J = 9.0, H-5); 8.20 (1H, dd, J = 2.3
and J = 9.0, H-6); 8.72 (1H, d, J = 2.3, H-8); 11.24 (1H, s, NH). 13C NMR spectrum, δ, ppm: 25.0, 26.3
(N(CH2CH2)2); 46.3, 47.7 (N(CH2CH2)2); 92.8 (C-4); 118.0 (C-4a); 123.3 (C-5); 124.7 (C-6); 127.5 (C-8);
141.2, 143.2 (C-7, C-8a); 148.4 (C-3); 161.6 (C-1); 165.0 (CON(CH2CH2)2). Found, %: C 55.64; H 4.75;
N 18.34. C14H14N4O4. Calculated, %: C 55.63; H 4.67; N 18.53.
Ethyl Ester of 3-Amino-7-nitro-1-oxo-1,2-dihydro-4-isoquinolinecarboxylic Acid (3b). A solution
of ester 2 (0.33 g, 1.65 mmol) and amidine 1b [2] (0.22 g, 1.7 mmol) in DMF (3 ml) was maintained for 80 h
at room temperature and then poured into water (30 ml). The crystalline precipitate was filtered off and dried at
130°C to give compound 3b (0.38 g, 83%); mp 336-339°C (decomp.). An analytical sample was prepared by
1
recrystallization from acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 1.36 (3H, t, J = 7.3, CH3); 4.32 (2H, q,
J = 7.3, CH2); 7.68 (2H, s, NH2); 8.26 (1H, dd, J = 2.2 and J = 9.2, H-6); 8.55 (1H, d, J = 9.2, H-5); 8.72 (1H, d,
J = 2.2, H-8); 11.37 (1H, s, NH). 13C NMR spectrum, δ, ppm: 14.6 (CH3); 60.5 (CH2); 83.4 (C-4); 119.2 (C-4a);
123.3 (C-5); 125.5 (C-6); 126.9 (C-8); 141.5, 143.5 (C-7, C-8a); 155.1 (C-3); 160.6 (C-1); 167.1 (CO2Et).
Found, %: C 51.66; H 4.02; N 15.20. C12H11N3O5. Calculated, %: C 51.99; H 4.00; N 15.16.
3-Amino-4-benzoyl-7-nitro-1(2H)-isoquinolinone (3c). A solution of ester 2 (0.33 g, 1.65 mmol) and
amidine 1c [7] (0.28 g, 1.7 mmol) in DMF (3 ml) was maintained for 20 h at room temperature and then heated
at 55°C for an additional 20 h. The mixture was poured into water (25 ml). The solution was decanted off the
oil formed, which was heated at reflux in acetonitrile (15 ml) and cooled. The crystalline precipitate was filtered
off and dried to give isoquinolinone 3c (0.26 g). A crystalline precipitate formed from the aqueous mother
liquor, which was heated at reflux in acetonitrile (5 ml) and cooled. An additional compound 3c (30 mg) was
filtered off. The total yield of 3c was 0.29 g (57%); mp 328-330°C (decomp.). An analytical sample was
1
obtained by recrystallization from acetonitrile. H NMR spectrum, δ, ppm (J, Hz): 6.84 (1H, d, J = 8.7, H-5);
7.39-7.62 (5H, m, C6H5); 7.70 (2H, s, NH2); 7.89 (1H, d, J = 8.7, H-6); 8.70 (1H, s, H-8); 11.54 (1H, s, NH).
13C NMR spectrum, δ, ppm: 93.6 (C-4); 119.1 (C-4a); 123.4 (C-5); 125.5, 125.9 (C-6, C-8); 128.9 (m-C6H5);
129.1 (o-C6H5); 132.1 (p-C6H5); 141.2, 141.5 (ipso-C6H5, C-7); 144.2 (C-8a); 154.0 (C-3); 161.0 (C-1); 193.5
(COC6H5). Found, %: C 62.15; H 3.65; N 13.60. C16H11N3O4. Calculated, %: C 62.14; H 3.58; N 13.59.
463

7-Amino-2-methyl-8-pyrrolidinocarbonylpyrido[4,3-d]pyrimidin-5(6H)-one (5a). A solution of
ester 4 [8] (0.34 g, 1.7 mmol) and amidine 1a (0.71 g, 4.6 mmol) in DMF (3 ml) was maintained for 60 h at
room temperature. The solvent was distilled off at reduced pressure. The residue was purified by
chromatography on a column packed with 60 g silica gel. Chloroform methanol served as the eluent. The
methanol fraction was gradually increased from 1 to 10%. The yield of 5a was 0.39 g (85%); mp 340-345°C
1
(decomp.). An analytical sample was prepared by recrystallization from 1:1 acetonitrile–methanol. H NMR
spectrum, δ, ppm: 1.70-2.00 (4H, m, N(CH2CH2)2); 2.51 (3H, s, CH3); 3.10-3.60 (4H, m, N(CH2CH2)2); 6.55
(2H, s, NH2); 8.89 (1H, s, H-4); 11.10 (1H, s, NH). 13C NMR spectrum, δ, ppm: 24.4, 25.8 (N(CH2CH2)2); 26.7
(CH3); 45.9, 47.4 (N(CH2CH2)2); 91.3 (C-8); 108.9 (C-4a); 152.4 (C-7); 156.8 (C-4); 157.1 (C-8a); 161.1 (C-5);
164.5 (CON(CH2CH2)2); 169.9 (C-2). Found, %: C 57.26; H 5.60; N 25.64. C13H15N5O2. Calculated, %:
C 57.13; H 5.53; N 25.63.
Ethyl Ester of 7-Amino-2-methyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylic Acid
(5b). A solution of ester 4 (0.34 g, 1.7 mmol) and amidine 1b (0.6 g, 4.6 mmol) in DMF (3 ml) was maintained
for 100 h at room temperature and then cooled to -10°C. The crystalline precipitate was filtered off, thoroughly
washed with water and hot acetonitrile, and dried to give compound 5b (0.34 g, 81%); mp 300-302°C
(decomp.). 1H NMR spectrum, δ, ppm (J, Hz): 1.31 (3H, t, J = 7.3, CH3); 2.56 (3H, s, CH3); 4.24 (2H, q, J = 7.3,
CH2); 7.65 (2H, s, NH2); 8.93 (1H, s, H-4); 11.27 (1H, s, NH). 13C NMR spectrum, δ, ppm: 14.5 (OCH2CH3);
26.9 (CH3); 59.9 (OCH2CH3); 84.5 (C-8); 109.7 (C-4a); 156.7 (C-7); 156.8 (C-4); 159.2 (C-8a); 161.0 (C-5);
167.4 (CO2CH2CH3); 169.9 (C-2). Found, %: C 53.11; H 4.84; N 22.26. Calculated: % C11H12N4O3: C 53.22; H
4.87; N, 22.57.
7-Amino-8-benzoyl-2-methylpyrido[4,3-d]pyrimidin-5(6H)-one
(5c)
and
2-(Benzoylmethy-
lene)-7-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (6c).
A solution of
ester 4 (0.3 g,
1.5 mmol) and amidine 1c (0.6 g, 3.7 mmol) in DMF (3 ml) was maintained for 60 days at room temperature.
The solvent was distilled off at reduced pressure and the residue was subjected to chromatography on a column
packed with 60 g silica gel using chloroform–methanol as the eluent. The methanol fraction was gradually raised
from 0 to 7%. The first fraction was composed of highly impure pyrimido[4,5-d]pyrimidine 6c as a 1:1 mixture
of E- and Z- isomers. The yield after recrystallization from methanol was 20 mg (5%); mp 318-322°C. 1H NMR
spectrum, δ, ppm: 2.61, 2.64 (3H, s, CH3); 6.95 (1H, s, =CH); 7.4-7.9 (5H, m, C6H5); 8.95, 8.97 (1H, s, H-5);
11.3-12.8 (1H, s, NH); 13.65 (0.5H, s, NH); 14.7 (0.5H, s, NH). Found, %: C 63.89; H 4.72; N 18.24.
C15H12N4O2. Calculated, %: C 64.28; H 4.32; N 18.99.
The next chromatographic fraction gave 0.27 g (64%) compound 5c; mp 306-308°C. An analytical
1
sample was prepared by recrystallization from methanol. H NMR spectrum, δ, ppm: 2.04 (3H, s, CH3);
13
7.29-7.49 (5H, m, C6H5); 7.98 (2H, s, NH2); 8.92 (1H, s, H-4); 11.37 (1H, s, NH). C NMR spectrum, δ, ppm:
26.7 (CH3); 93.9 (C-8); 110.2 (C-4a); 128.2 (m-C6H5); 128.5 (o-C6H5); 130.9 (p-C6H5); 143.7 (ipso-C6H5); 157.2
(C-7); 157.3 (C-4); 159.97 (C-8a); 161.6 (C-5); 169.1 (C-2); 195.1 (COC6H5). Found, %: C 64.45; H 4.35;
N 19.93 C15H12N4O2. Calculated, %: C 64.28; H 4.32; N 19.99.
2-(Benzoylmethylene)-6-nitro-2,3-dihydroquinazolin-4(1H)-one (9). A solution of 2-fluoro-5-nitro-
benzoyl chloride 7 [9] (0.305 g, 1.5 mmol) in methylene chloride (10 ml) was added dropwise with stirring over
1 h to a solution of benzoylacetamidine 1c (0.42 g, 3 mmol) in acetonitrile (30 ml). Stirring was continued for
an additional 3 h and the mixture was left overnight at room temperature. The crystalline precipitate was filtered
off, heated at reflux in acetonitrile (30 ml), and cooled to room temperature. Benzoylacetamidine hydrochloride
was filtered off. The combined mother liquors were evaporated in vacuum and the residue was recrystallized
twice from acetonitrile to give N-(1-amino-3-oxo-3-phenylpropenyl)-2-fluoro-5-nitrobenzamide (8) (0.27 g,
1
54%) as a 1:1 mixture of the E- and Z- isomers; mp 196-198°C (with cyclization). H NMR spectrum, δ, ppm:
5.72, 5.82 (0.5H, 0.5H, s, =CH); 7.48-7.53 (3H, m, m-C6H5, p-C6H5); 7.67-7.84 (3H, m, o-C6H5, H-3); 8.25-8.73
(3.5H, m, NH, H-4, H-6); 10.45 (0.5H, s, NH); 11.12 (0.5H, s, NH); 15.29 (0.5H, s, NH). Found, %: C 58.31;
H 3.77; N 12.81. C16H12FN3O4. Calculated, %: C 58.36; H 3.67; N 12.76.
464

Amide 8 (0.1 g, 0.3 mmol) was heated for 20 min at 220°C and an additional 10 min at 240°C. The product was
recrystallized from DMF, heated at reflux in ethanol, filtered off, washed with ether, and dried to
1
give compound 9 (85 mg, 91%) as a 3:2 mixture of the E- and Z- isomers; mp 296-303°C (decomp.). H NMR
spectrum, δ, ppm (J, Hz): 5.86, 5.99 (0.4H, 0.6H, s, =CH-COC6H5); 7.38 (0.4H, d, J = 8.8, H-8); 7.45-7.60,
7.70-7.90 (5.6H, C6H5 and m, H-8); 8.45 (1H, m, H-7); 8.61 (1H, s, H-5); 12.19 (1H, s, NH); 13.93 (0.4H, s,
NH); 14.57 (0.6H, s, NH). Found, %: C 61.90; H 3.55; N 13.49. C16H11N3O4. Calculated, %: C 62.14; H 3.58;
N 13.59.
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