The study of cyclization of N-acylphenacyl anthranilates with ammonium salts under various conditions

Article abstract of DOI:10.3987/COM-06-10899

N-Acylphenacyl anthranilates were heated with ammonium salts in organic acid or NMP, and formation of various heterocyclic compounds was observed. Reaction results are strongly influenced by reaction conditions. The most interesting are imidazole derivati

Full text of DOI:10.3987/COM-06-10899

HETEROCYCLES, Vol. 71, No. 2, 2007
269
HETEROCYCLES, Vol. 71, No. 2, 2007, pp. 269 - 280. © The Japan Institute of Heterocyclic Chemistry
Received, 28th September, 2006, Accepted, 28th December, 2006, Published online, 29th December, 2006. COM-06-10899
THE
STUDY
OF
CYCLIZATION
OF
N-ACYLPHENACYL
ANTHRANILATES WITH AMMONIUM SALTS UNDER VARIOUS
CONDITIONS
Pavel Hradil,a,b,* Martin Grepl,b,c Jan Hlavac,a and Antonin Lyčkad
a
Department of Organic Chemistry, Palacky University, Tr Svobody 8, 771 46
Olomouc, Czech Republic, hradil@farmak.cz
b Farmak a.s., 771 17 Olomouc, Czech Republic
c Department of Analytical Chemistry, Palacky University, Tr Svobody 8, 771 46
Olomouc, Czech Republic
d
Research Institute for Organic Syntheses, Rybitví 296, 532 18 Pardubice-20
Czech Republic
Abstract – N-Acylphenacyl anthranilates were heated with ammonium salts in
organic acid or NMP, and formation of various heterocyclic compounds was
observed. Reaction results are strongly influenced by reaction conditions. The
most interesting are imidazole derivatives with various anelated rings.
INTRODUCTION
3-Amino-2-phenyl-4(1H)-quinolinone derivatives exhibit very interesting biological activities. The
simplest way for preparation of these compounds is cyclization of 2'-amino-2,4-diphenyl oxazoles or
N-phenacyl anthranilamides.1 In contrast, phenacyl anthranilates, N-phenacyl anthranilamides are
sometimes hardly available. It was proved that some oxazole derivative can also serve as an alternative
starting material.1 For this reason, 2'-amino-2,4-diphenyl oxazole derivatives synthesis was studied.
RESULTS AND DISCUSSION
Preparation of 2,4-disubstituted oxazole and imidazole derivatives by reaction of esters of
2-hydroxyketones with ammonium acetate in acetic acid was described a long time ago.2
Unfortunately
this
reaction
fails
in
the
case
of
phenacyl
anthranilate,
and
2-hydroxymethyl-4-oxo-2-phenyl-1,2,3,4-tetrahyroquinazoline derivatives are prepared in this way.3
For this reason, the behavior of various N-acylphenacyl anthranilates at similar conditions was tested.
The cyclization did not go in a way that we expected, and various heterocyclic compounds were prepared
depending on reaction conditions.

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HETEROCYCLES, Vol. 71, No. 2, 2007
Formyl derivative (4a) was prepared by a reaction of salt formyl anthranilic acid (2) with phenacyl
bromide (3a) (Scheme 1). The remaining acyl derivatives (4b-e) were prepared from phenacyl
anthranilate (1) by acylation, acyl chloride or acetanhydride (Ac2O) with catalysis by p-toluensulfonic
acid (p-TsOH), in high yield.
O
OH
COOH
N
H
90%
NHCHO
6
N
2
O
N
Br
N
HCOOH
HCOONH4
R = H
3a
N(C2H5)3
+
5a
AcO-NH4
+
AcOH
R= H
O
O
AcO-NH4
AcOH
+
N
RCOX
H+
O
O
N
O
N
O
NH
NH2
4a -e
R
1
5b-e
yields (%)
3b-e
O
R
cmpd.
R
H
X
cmpd. yield (%)
A
B
C
a
b
c
d
e
4a
4b
4c
4d
4e
69%
97%
96%
93%
84%
5b
5c
5d
5e
21 18 16
68 24 45
51 14 25
10 15 33
CH3
CH(CH3)2
(CH2)14CH3 Cl
Ph Cl
OAc
Cl
Scheme 1
The melting of these acyl anthranilates (4) with ammonium acetate and acetic acid in ratio 1 g acetic acid
and 1 g ammonium acetate to 1 mmol of phenacyl ester was tested at the beginning.
A complicated mixture was received by reaction of a compound (4a). When ammonium formate and
formic acid were used instead of acetic acid and ammonium acetate, the quinolinone (6)4 was formed in
high yield (Scheme 1). The synthesis of quinolinone (6) by cyclization of phenacyl anthranilate (1) in
PPA with normal heating4 or micro wave irradiation5 is known.
The compound (4b) reacted in a different way. The starting material (4b) was not observed after 30
minutes in the melt. The reaction mixture was poured into water and the precipitated solid was filtered off.
An amount of the compound was formed in this way, but one was dominant. Dried solid was stirred
with acetone and insoluble part was a clean compound, later identified as 5b. Additional quantity was

HETEROCYCLES, Vol. 71, No. 2, 2007
271
isolated by column chromatography from the mother liquor (toluen :EtOAc 1 :1). No positive influence
of longer reaction time on the yield of compound (5b) and on the number of impurities was observed.
The same conditions were used for the cyclization of compounds (4a and 4c-d). For aliphatic acyl
derivatives, the dominant imidazo[1,2-c]quinazoline derivatives (5) were formed. In this way compounds
1
(5c and 5d) were prepared. The compounds (5) were analyzed in detail using two dimensional H,13C
NMR spectra and for compound (5b) also 1H,15N HMBC spectrum. The 1H,13C and 15N chemical shifts
are collected in Experimental. The following numbering of atoms was used for this purpose (Figure 1).
10
3´
11
12
2´
1´
1
9
4´
N
8
2
7
N
5
N
4
3
6
Figure 1
Table 1
Yields of compound (5)
Cmp.
Method A
Method B
Method C
mp
solvent
Yield (%) time (h) Yield (%) time (h) Yield (%) time (h)
(°C)
5b
5c
5d
5e
21
68
51
0.5
1
0.5
1
18
24
14
15
3
5
16
3
16
45
25
33
2
2.5
5
214-216 acetone
218-221 MeOH
87- 94
MeOH
10*
2
145 - 148 MeOH
* yield of compound (10e) was 11%
The behavior of derivatives (4) in terms of dependence on the temperature and ratio of ammonium acetate
and acetic acid was tested, by using three conditions (method A-C). If the amount of ammonium acetate
was smaller than described in method A, the reaction was slower and some starting material was present
in the reaction mixture after 10 hours of heating. Better results were achieved if the amount of acetic
acid was 4 times higher than ammonium acetate and if 1 g of ammonium acetate was used for 1 mmol of
acetyl derivative (4b) (method B). When the reaction was performed in a glass autoclave at a
temperature of 190 °C, the reaction time was shortened and the yield was improved (method C).
The usage of different ammonium sources and reaction conditions were tested. Inseparable mixtures
were mostly received, and positive results were received in only few cases.
If cyclization of compound (4b) was done in N-methylpyrrolidone (NMP) and ammonium carbonate, a
bunch of compounds was formed also, but there were not traces of compound (5b), in the reaction
mixture. Small amount of compounds (7 and 8)6,7 and dominant compound (9b)8 were isolated by
column chromatography (Scheme 2).

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HETEROCYCLES, Vol. 71, No. 2, 2007
O
O
N
N
N
(NH4)2CO3
NMP
NH2
O
O
+
+
O
N
NH
NH
CH3
H3C
O
7,3%
4,4%
54%
4b
7
8
9b
Scheme 2
The mechanism of the formation of these compounds starts by the first reaction step - aminolysis of ester
bond. Compound (9b) and 2-hydroxyacetophenone are formed. The next step is the reaction of
2-hydroxyacetophenone with ammonium, cyclization of imine and final oxidation and formation of
pyridazine derivatives (Scheme 3). It is not clear what the oxidation agent is, but the quantity of
pyrazine derivatives formed is so small that it could be oxygen from the air or some compound in the
reaction mixture.
(NH4)2CO3
HO
HO
O
NH
N
N
oxidation
N
N
N
N
N
N
+
+
8
Scheme 3
If the compound (4b) was heated with ammonium acetate in NMP, the reaction mixture was more
complex. Compounds (5b, 7, 8 and 9b) apart from many other different unidentified compounds were
found. There was no advantage if different sources of ammonium such as ammonium hydroxide,
ammonium chloride, ammonium sulfite, and urea were tested.
Cyclization of compound (4e) took a slightly different course. Apart from compound (5e), significant
amounts of compounds (10e) were received (Method A). In the case of the reaction of benzoyl
derivative (4e) with ammonium acetate, acetic acid and NMP imidazo derivative (10e) was dominant.
9
Compound (9e) was isolated also from the reaction mixture. During this reaction formation of
compound (5e) was not observed (Scheme 4). Milder reaction conditions were also tested, the reaction
of compound (4e) was done with ammonium acetate in acetic acid and ethanol, the reaction time was
longer, compounds (5e) were not formed and compounds (10e and 9e) were dominant, but a large
amount of unknown compounds were also formed.

HETEROCYCLES, Vol. 71, No. 2, 2007
273
O
CONH2
NH
N
O
AcO-NH4
N
+
O
H
+
NH
AcOH, NMP
NH
O
O
O
6%
26%
4e
9e
10e
Scheme 4
The 1H and 13C NMR data of compound (10e) were measured and analyzed in the same way as those for
compounds (5). The following numbering of atoms was used for this purpose (Figure 2).
21
20
19
4
18
3
N
7
8
5
6
2
N1
9
10
15
11
H
12 NH
16
17
13
14
O
Figure 2
Isolation of imidazole derivative (10e) from the cyclization mixture uphold the mechanism of the
cyclization of compounds (4b-d). It is probably the reaction step followed by the ring closing and
formation of compounds (5) (Scheme 5).
O
O
N
NH3
NH3
O
O
NH3
O
O
NH
-H2O
NH
-H2O
NH
NH
4
O
R
O
R
R
O
N
N
-H2O
-H2O
N
N
NH2
OH
N
H
N
NH
O
NH
R
R
R
O
5
10
Scheme 5

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HETEROCYCLES, Vol. 71, No. 2, 2007
Imidazoquinazolines (5) were formed only at higher temperature, in acid conditions.
EXPERIMENTAL
Melting points were measured in the Kofler apparatus and are uncorrected. TLC was performed on
Polygram Sil G/UV254 with UV light detection and mobil phase n-hexane : ethylacetate 7 : 3. Infrared
spectra (KBr disks) were taken with an ATI Unicam Genesis FTIR instrument. MS characterisation was
carried out using the DEP-CI-MS-MS (direct exposure probe-chemical ionisation-tandem mass
spectrometry) technique with quadrupole ion trap mass analyzer and methane as a CI reagent gas. NMR
spectra were measured with a Bruker Avance 300 spectrometer operating at 300 MHz (1H) and 75 MHz
(13C) Bruker Avance 500 spectrometer operating at 500.13 MHz (1H), 125.76 MHz (13C) and 50.68 MHz
(15N). The compounds were dissolved in DMSO-d6 and measured at 300 K. Construction of the
microwawe reactor was described recently.10
13
1H and C chemical shifts were referenced to the central signal of the solvent (δ = 2.55 (1H). (δ = 39.6
15
(13C)). The N chemical shifts were referred to external neat nitromethane in a co-axial capillary (δ =
0.0). All 2D experiments (gradient-selected (gs)-COSY, gs-HMQC, gs-HMBC) were performed using
manufacturer’s software. Proton signals were assigned using gs-COSY. Protonated carbons were
15
assigned by gs-HMQC and quaternary carbons gs-HMBC. The N chemical shifts of compound (5b)
were read from gs-1H,15N-HMBC spectrum
2-Oxo-2-phenylethyl 2-Formylaminobenzoate (4a)
Mixture of N-formyl anthranilic acid (2) (8.26 g, 50 mmol), Et3N (5.3 g, 7.3 mL, 52.4 mmol), acetone
(100 mL) and phenacylbromide (3a) (9.95 g, 50 mmol) was stirred at rt for 3 hours. Then acetone was
evaporated under vacuo and residuum was stirred with water. Precipitated solid was filtered off, and
isolated product was crystallized from MeOH. The yield of compound (4a) was 9.8 g (69 %), mp 92.5 –
96°C.
Anal. Calcd for C16H13NO4 C, 67.84; H, 4.63; N, 4.94. Found C, 67.90; H, 4.78; N, 4.41.
Full MS, m/z (relative intensity) 284 (2) [M+H]+, 312 [M+C2H5]+, 324 [M+C3H5]+, 255 [M+H-CHO]+
,
188, 176, 148 (100) [C6H4NHCO(CO)]+, 120, 105 [C6H5CO]+, 91; MS2(284,w3,EV1), m/z 265, 255 (100),
225, 197, 148, 133, 120, 105.
1H NMR (DMSO-d6, 300 MHz) δ 10.59 (1H, s), 8.53 (1H, s), 8.50 (1H, s), 8.11 (1H, dd, J = 8.0, 1.2 Hz),
8.03 (2H, d, J = 8.0 Hz), 7.77-7.55 (4H, m), 7.28 (1H, ddd, J = 7.7, 7.5, 1.1 Hz), 5.81 (2H, s); 13C NMR
(DMSO-d6, 75 MHz) δ 192.5, 165.9, 160.9, 139.1, 134.5, 134.0, 133.7, 130.9, 128.9, 127.8, 123.4, 121.1,
116.2, 67.4.
2-Oxo-2-phenylethyl 2-Acetylaminobenzoate (4b)

HETEROCYCLES, Vol. 71, No. 2, 2007
275
Phenacyl ester (1) (15.8 g, 61.9 mmol) was dissolved in EtOAc (80 mL) and Ac2O (14.9 g, 146 mmol)
and p-TsOH (50 mg) were added. The reaction mixture was refluxed with stirring for 4 h.
Phenacylester (1) was not observed on TLC. Compound (4b) was filtered off after the cooling. Part of
the product was isolated from the mother liquor (2 g). Total yield was 17g (96.6 %), mp 162-163 °C.
Anal. Calcd.for C17H15NO4 C, 68.68; H, 5.09; N, 4.71. Found C, 68.79; H, 5.23; N, 4.47.
Full MS, m/z (relative intensity) 298 (3) [M+H]+, 326 [M+C2H5]+, 338 [M+C3H5]+, 280 [M+H-H2O]+ 255
,
[M+H-COCH3]+ 238, 202, 190, 162 (100) [C6H4NHCOCH3(CO)]+, 144, 120, 105 [C6H5CO]+, 91;
,
MS2(298,w3,EV1), m/z 255 (100), 224, 197, 175, 162, 133, 120, 105.
1H NMR (DMSO-d6, 300 MHz) δ 10.45 (1H, s), 8.33 (1H, dd, J = 8.4, 0.8 Hz), 8.09-8.01 (3H, m),
7.78-7.55 (4H, m), 7.28 (1H, ddd, J = 7.7, 7.5, 1.1 Hz), 5.81 (2H, s), 2.12 (3H, s); 13C NMR (DMSO-d6,
75 MHz) δ 192.6, 168.5, 166.3, 139.8, 134.2, 134.0, 133.7, 130.7, 128.9, 127.8, 123.0, 121.0, 116.9, 67.3,
24.5.
2-Oxo-2-phenylethyl 2-i-Butyrylaminobenzoate (4c)
Phenacylester (1) (10 g, 39.2 mmol) was dissolved in acetone (60 mL) and Et3N (6.5 mL, 4.54 g, 45
mmol) and i-butyryl chloride (4.8 g, 45 mmol) were added. The reaction mixture was refluxed with
stirring for 1 h. Phenacylester (1) was not observed on TLC, the reaction mixture was concentrated
under vacuo and residuum was stirred with water, precipitated solid was filtered off, and crystallized from
acetone. The yield was 12.2 g (95.6 %), mp 92 – 93.5°C.
Anal. Calcd for C19H19NO4 C, 70.10; H, 5.89; N, 4.31. Found C, 70.52; H, 6.01; N, 4.66.
Full MS, m/z (relative intensity) 326 (5) [M+H]+, 354 [M+C2H5]+, 366 [M+C3H5]+, 308 [M+H-H2O]+ 255
,
[M+H-COCH(CH3)2]+ 230, 218, 190 (100) [C6H4NHCOCH(CH3)2(CO)]+, 172, 160, 146, 120, 105
,
[C6H5CO]+, 91; MS2(326,w3,EV1), m/z 282, 264, 255 (100), 224, 206, 197, 190, 188, 175, 162, 133, 120.
1H NMR (DMSO-d6, 300 MHz) δ 10.55 (1H, s), 8.42 (1H, dd, J = 8.4, 0.8 Hz), 8.08 (1H, dd, J = 8.7, 1.4
Hz), 8.07-8.01 (2H, m), 7.78-7.55 (4H, m), 7.25 (1H, ddd, J = 7.8, 7.4, 0.9 Hz), 5.81 (2H, s), 2.60 (1H, m),
1.13 (6H, d, J = 6.8 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 192.5, 175.0, 166.5, 140.2, 134.4, 134.0, 133.6,
130.7, 128.9, 127.8, 122.9, 120.7, 116.4, 67.4, 35.9, 19.1.
2-Oxo-2-phenylethyl 2-Palmitoylaminobenzoate (4d)
Compound (4d) was prepared according to the procedure 4c. The yield was 93%, mp 62-64°C (MeOH).
Anal. Calcd.for C31H43NO4 C, 75.42; H, 8.78; N, 2.84. Was found C, 75.71; H, 9.03; N, 2.59.
Full MS, m/z (relative intensity) 494 (20) [M+H]+, 522 [M+C2H5]+, 534 [M+C3H5]+, 476 [M+H-H2O]+
,
416, 398, 386, 359, 358 (100), 356, 342, 329, 312, 297, 255 [M+H-CO(CH2)14CH3]+ 178, 161, 149, 137,
,
120, 105 [C6H5CO]+, 91; MS2(494, w3, EV1), m/z 448, 408, 359, 358 (100), 357, 338, 313, 256.
1H NMR (DMSO-d6, 300 MHz) δ 10.45 (1H, s), 8.39 (1H, dd, J = 8.4, 0.8 Hz), 8.09-8.01 (3H, m),

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HETEROCYCLES, Vol. 71, No. 2, 2007
7.78-7.55 (4H, m), 7.25 (1H, ddd, J = 7.9, 7.5, 1.0 Hz), 5.81 (2H, s), 2.37 (2H, t, J = 7.3 Hz), 1.59 (2H,
m), 1.30-1.13 (24H, m), 0.85 (3H, t, J = 6.9); 13C NMR (DMSO-d6, 75 MHz) δ 192.5, 171.3, 166.4, 140.0,
134.3, 134.0, 133.7, 130.7, 128.9, 127.8, 122.9, 120.8, 116.6, 67.3, 37.1, 31.2, 28.9, 28.8, 28.6, 28.4, 24.8,
22.0, 13.8.
2-Oxo-2-phenylethyl 2-Benzoylaminobenzoate (4e)
Compound (4e) was prepared according to the procedure 4c. The yield was 84 %, mp 163.5 – 166°C.
Anal. Calcd for C22H17NO4 C, 73.53; H, 4.77; N, 3.90. Found C, 73.82; H, 4.94; N, 3.51.
Full MS, m/z (relative intensity) 360 (5) [M+H]+, 388 [M+C2H5]+, 400 [M+C3H5]+, 342 [M+H-H2O]+ 282,
,
264, 252, 237, 224 (100) [M+H-OCH2COC6H5]+ 207, 197, 179, 146, 120, 105 [C6H5CO]+, 91;
,
MS2(360,w3,EV1), m/z 237, 224 (100), 207, 196, 179, 146.
1H NMR (DMSO-d6, 300 MHz) δ 11.50 (1H, s), 8.65 (1H, dd, J = 8.4, 0.8 Hz), 8.19 (1H, dd, J = 8.0, 1.4
Hz), 8.06-8.00 (2H, m), 7.96-7.89 (2H, m), 7.80-7.52 (7H, m), 7.32 (1H, ddd, J = 7.8, 7.7, 1.1 Hz), 5.81
13
(2H, s); C NMR (DMSO-d6, 75 MHz) δ 192.3, 167.0, 164.7, 140.4, 134.7, 134.2, 134.0, 133.6, 132.1,
130.9, 128.9, 127.8, 126.9, 123.4, 120.7, 116.3, 67.6.
5-Substituted-2-phenylimidazo[1,2-c]quinazoline (5)
Method A
Acyl derivative (4) (8 mmol) was heated with mixture AcOH (10 g) and ammonium acetate (10 g) for 30
min under reflux (temperature 130 °C). When the starting material was not observed on TLC (n-hexane:
EtOAc 7: 3), water (100 mL) was added and solution was neutralized by sodium carbonate to pH 5 to7
and precipitated product was filtered off. After drying the product was purified by column
chromatography in toluene - EtOAc mixture and crystallized.
Method B
Acyl derivative (4) (1 mmol) was heated with mixture AcOH (5 g) and ammonium acetate (1.25 g)
under the reflux (temperature probably 130 °C). When the starting material was not observed on TLC
(n-hexane: EtOAc 7: 3), reaction mixture was worked on as in the process A.
Method C
Acyl derivative 4 (1 mmol) was heated with mixture AcOH (5 g) and ammonium acetate (1.25 g) in glass
autoclave tube to 190 °C. When the starting material was not observed on TLC (n-hexane: EtOAc 7: 3),
reaction mixture was worked on as in the process A.
5-Methyl-2-phenylimidazo[1,2-c]quinazoline (5b)
Results are summarized in Table 1.

HETEROCYCLES, Vol. 71, No. 2, 2007
277
Anal. Calcd for C17H13N3 C, 78.74; H, 5.05; N, 16.20. Found C, 78.39; H, 5.22; N 16.00.
Full MS, m/z (relative intensity) 260 (100) [M+H]+, 288 [M+C2H5]+, 300 [M+C3H5]+;
MS2(260,w3,EV1.5), m/z 256, 233 (100) [M+H-HCN]+ , 220, 218, 206, 202, 193, 165, 157, 143, 130, 117,
103.
1H NMR (DMSO-d6, 500 MHz) δ 8.61 (H-3,1H, s), 8.45 (H-11,1H, d, J = 7.7 Hz), 8.11 (H-2´,2H, d, J =
7.5 Hz), 7.86 (H-8,1H, d, J = 7.9 Hz), 7.77 (H-9, 1H, m)7.72 (H-10, 1H, m), 7.50 (H-3´,2H, dd, J = 7.7,
13
7.4 Hz), 7.37 (H-4´,1H, dd, J = 7.4, 1.7Hz), 2.89 (CH3, 3H, s); C NMR (DMSO-d6, 125 MHz) δ 146.4
(C-5), 143.5 (C-2), 142.5 (C-13), 140.6 (C-7), 133.1 (C-1´), 129.8 (C-9), 128.7 (C-3´), 127.9 (C-4´),
15
127.4 (C-10), 127.3 (C-8), 125.6 (C-2´), 122.1(C-11), 117.6 (C-12), 109.1 (C-3), 20.8 (CH3), N NMR
(DMSO-D6, 50.68 MHz) δ -127.1 (N-6, correlations with proton H-8 and protons of methyl group in
gs-1H,15N-HMBC spectrum), - 141.4 (N-1, correlation with proton H-3 in gs-1H,15N-HMBC spectrum),
-182.5 (N-4, correlations with proton H-3 and protons of methyl group in gs-1H,15N-HMBC spectrum).
5-Isopropyl-2-phenylimidazo[1,2-c]quinazoline (5c)
Results are summarized in Table 1.
Anal. Calcd for C19H17N3 C, 79.41; H, 5.96; N, 14.62. Found C, 79.80; H, 6.13; N 14.30.
Full MS, m/z (relative intensity) 288 (100) [M+H]+, 316 [M+C2H5]+, 328 [M+C3H5]+, 259.
MS2(288,w3,EV1.5), m/z 272 (100), 259, 246, 245 [M+H-CH(CH3)2]+ 220, 183, 168, 118.
,
1H NMR (DMSO-d6, 500 MHz) δ 8.78 (H-3, 1H, s), 8.47 (H-11, 1H, dd, J = 7.5, 1.7 Hz), 8.14 (H-2´ 2H,
dd, J = 8.0, 1.3 Hz), 7.89 (H-8 1H, dd, J = 7.9, 1.0 Hz), 7.73 (H-9, 1H, ddd, J = 7.9, 7.1, 1.7 Hz), 7.67
(H-10 1H, ddd, J = 7.7, 7.1, 1.2 Hz), 7.50 (H-3´, 2H, dd, J = 7.7, 7.3 Hz), 7.37 (H-4´, 1H, dd, J = 7.5,
13
1.7Hz), 3.69 (CH, 1H, m), 1.46 ((CH3)2 6H, d, J = 6.6 Hz); C NMR (DMSO-d6, 125 MHz) δ 153.2
(C-5), 143.6 (C-2), 142.8 (C-13), 140.4 (C-7), 133.2 (C-1´), 129.9 (C-9), 128.6 (C-3´), 127.9 (C-4´),
127.7 (C-10), 127.6 (C-8), 125.6 (C-2´), 122.1 (C-11), 117.7(C-12), 108.6 (C-3), 31.2 (CH), 19.8 (CH3)2.
5-Heptadecyl-2-phenylimidazo[1,2-c]quinazoline (5d)
Results are summarized in Table 1.
Anal. Calcd for C31H41N3 C, 81.71; H, 9.07; N, 9.22. Found C, 81.60; H, 9.43; N, 8.88.
Full MS, m/z (relative intensity) 456 (100) [M+H]+, 484 [M+C2H5]+, 496 [M+C3H5]+ , 440, 426, 412, 398,
384, 370, 356, 342, 328, 315, 301, 289, 272, 259; MS2(456,w3,EV1.5), m/z 454, 440, 426, 412, 398, 384,
370, 356, 342, 328, 314, 300, 286, 272, 258, 246, 234, 220.
1H NMR (DMSO-d6, 500 MHz) δ 8.69 (H-3, 1H, s), 8.45 (H-11, 1H, dd, J = 7.8, 1.5 Hz), 8.13 (H-2´, 2H,
dd, J = 7.7, 1.3 Hz), 7.88 (H-8, 1H, dd, J = 7.9, 1.3 Hz), 7.73 (H-9, 1H, ddd, J = 7.6, 7.2, 1.5 Hz), 7.67
(H-10,1H, ddd, J = 7.9, 7.1, 1.3 Hz), 7.50 (H-3´, 2H, dd, J = 7.9, 7.3 Hz), 7.37 (H-4´,1H, dd, J = 7.4,
1.7Hz), 3.20 (2H, t, J = 7.3 Hz), 1.95 (2H, m), 1.48 (2H, m), 1.37 (2H, m), 1.25 (20H, m) (all CH2), 0.84

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13
(3H, t, J = 7.0 Hz); C NMR (DMSO-d6, 125 MHz) δ 149.1 (C-5), 143.5 (C-2), 142.6 (C-13), 140.5
(C-7), 133.1 (C-1´), 129.9 (C-9), 128.6 (C-10), 128.6 (C-3´), 127.9 (C-8), 127.5 (C-4´), 125.6 (C-2´),
122.1 (C-11), 117.6 (C-12), 108.7 (C-3), 32.9, 31.2, 28.9, 28.6, 28.6, 28.5, 25.1, 22.0 (all CH2)., 13.8
(CH3).
2,5-Diphenylimidazo[1,2-c]quinazoline (5e)
Results are summarized in Table 1.
Anal. Calcd for C22H15N3 C, 82.22; H, 4.70; N, 13.08. Found C, 82.10; H, 4.89; N, 13.20.
Full MS, m/z (relative intensity) 322 (100) [M+H]+, 350 [M+C2H5]+, 362 [M+C3H5]+;
MS2(322,w3,EV1.5), m/z 317, 305, 295 (100) [M+H-HCN]+, 266, 244, 235, 217, 205, 190, 165, 139, 116.
1H NMR (DMSO-d6, 500 MHz) δ 8.53 (H-11,1H, dd, J = 7.5, 1.5 Hz), 8.38 (H-3,1H, s), 8.12 (H-2´, 2H,
dd, J = 7.5, 1.4 Hz), 8.02 (H-2´´, 2H, m), 7.97 (H-8, 1H, dd, J = 7.7, 1.4 Hz), 7.82-7.64 (H-9, H-10, H-3´´,
H-4´´, 5H, m), 7.45 (H-3´, 2H, dd, J = 7.9, 7.1 Hz), 7.36 (H-4´, 1H, ddd, J = 7.3, 7.2, 1.1 Hz); 13C NMR
(DMSO-d6, 125 MHz) δ 146.5 (C-5), 143.7 (C-2), 143.5 (C-13), 140.7 (C-7), 133.0 (C-1´), 132.9 (C-1´´),
130.9 (C-4´´), 130.2 (C-9), 128.8 (C-3´´), 128.7(C-2´´), 128.6 (C-3´), 128.2 (C-10), 128.0 (C-8), 127.9
(C-4´), 125.9 (C-2´), 122.2 (C-11), 117.8 (C-12), 109.3 (C-3).
3-Hydroxy-2-phenylquinolin-4(1H)-one (6)
Formyl phenacyl anthranilate (4a) (0.6 g, 2.1 mmol), ammonium formate (2g) and formic acid (20 g)
were heated under reflux for 5 h in microwave reactor. Then formyl anthranilate (4a) was not observed
on TLC, water was added into the reaction mixture and precipitated solid was filtered off, and crystallized
from BuOH. The yield of compound (6) was 0.45 g (90 %), mp 275-278 °C (lit.,4 278-281°C).
Cyclization of compound (4b) with ammonium carbonate in NMP
Mixture of acetyl derivative (4b) (1.15 g, 3.87 mmol) and ammonium carbonate (2.3 g, 23.94 mmol) in
NMP (5.5 mL) was heated for 30 min at temperature 140 °C. The starting material was not observed on
TLC (n-hexane: EtOAc 7 :3). Then 100 mL of water was added. Solid compound was filtered off and
water layer was extracted by EtOAc (5 x 75 mL), organic layer was dried by sodium sulfate and after the
filtration EtOAc was evaporated in vacuo. The rest was mixed with Et2O and precipitated solid was
filtered off. Together with product from mother liquor was isolated 2-acetylaminobenzamide (9b) 340
mg (54%), mp 180 °C (lit.,8 mp 180 °C).
Anal. Calcd for C9H10N2O2 C, 60.66; H, 5.66; N, 15.72. Found C, 61.00; H, 5.78; N, 16.10.
Full MS, m/z (relative intensity) 179 (2) [M+H]+, 207 [M+C2H5]+, 219 [M+C3H5]+, 162 (100)
[M+H-NH3]+, 144 [M+H-NH3-H2O]+ 136, 120; MS2(162,w3,EV1), m/z 144 (100), 120, 116, 92, 89, 65.
,
1H NMR (DMSO-d6, 300 MHz) δ 11.55 (1H, s), 8.42 (1H, d, J = 8.3 Hz), 8.22 (1H, s), 7.78 (1H, d, J =

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279
7.9, 1.0 Hz), 7.69 (1H, bs), 7.45 (1H, ddd, J = 7.8, 7.6, 1.1 Hz), 7.10 (1H, ddd, J = 7.8, 7.6, 1.0 Hz), 2.1
(3H, s); 13C NMR (DMSO-d6, 75 MHz) δ 170.6, 168.0, 139.5, 132.0, 128.4, 122.2, 120.0, 119.7, 24.8.
Mother liquor was evaporated until dryness and divided by column chromatography on silicagel in
toluene. 2,5-Diphenylpyrazine (7) 74 mg (7.3 %) was isolated, mp 193.5 -194 °C. (lit.,6 195 °C)
Anal. Calcd for C16H12N2 C, 82.73; H, 5.21; N, 12.06. Found C, 84.20; H, 5.38; N, 12.00.
Full MS, m/z (relative intensity) 233 (100)[M+H]+, 261 [M+C2H5]+, 273 [M+C3H5]+, 204, 179, 158, 130,
102, 91; MS2(233,w3,EV1.5), m/z 206[M+H-HCN]+, 204, 179, 178, 155, 130, 128, 115, 103 (100).
13
1H NMR (DMSO-d6, 300 MHz) δ 9.33 (2H, s), 8.20 (4H, dd, J = 8.4, 1.6 Hz), 7.63-7.47 (6H, m); C
NMR (DMSO-d6, 75 MHz) δ 149.6, 141.0, 135.6, 129.8, 129.0, 126.5.
The compound 2,6-diphenylpyrazine (8) 42 mg (4.4 %) was isolated by column chromatography - eluent
toluene : EtOAc 1 :1., mp 87-89 °C. (lit.,7 87-88°C)
Anal. Calcd for C16H12N2 C, 82.73; H, 5.21; N, 12.06. Found C, 82.53; H, 5.28; N, 12.08.
Full MS, m/z (relative intensity) 233 (100)[M+H]+, 261 [M+C2H5]+, 273 [M+C3H5]+, 204, 179, 158, 130,
102, 91; MS2 (233, w3, EV1.5), m/z 206 [M+H-HCN]+, 204, 179, 178, 155, 130, 128 (100), 115, 103.
Cyclization of compound (4e) by heating in the presence of ammonium acetate, acetic acid in NMP
Mixture of ammonium acetate (3 g), AcOH (3 g) and benzoyl derivative (4e) (0.61 g, 2.0 mmol) in
N-mehylpyrrolidone (6 g) was heated by single mode microwave under the reflux for 1 min (energy 100
W). (Starting material was not observed by TLC). Then the reaction mixture was diluted by water and
precipitated solid was filtered off at 50 °C. Solid compound was washed by hot water (30 mL), after
drying product was crystallized from toluene and N-[2-(4-phenyl-1H-imidazol-2-yl)phenyl]benzamide
(10e) was received in yield 176 mg ( 26 %), mp 252 – 257 °C.
Anal. Calcd for C22H17N3O C, 77.86; H, 5.05; N, 12.38. Found C, 78.05; H, 5.34; N, 11.99.
Full MS, m/z (relative intensity) 340 (100) [M+H]+, 368 [M+C2H5]+,380 [M+C3H5]+, 322 [M+H-H2O]+
,
311, 262, 133, 105, 91; MS2(340,w3,EV1.0), m/z 322, 311, 295, 262.
1H NMR (DMSO-d6, 500 MHz) δ 13.58 (H-12, 1H, s), 13.05 (H-1, 1H, s), 8.85 (H-10, 1H, dd, J = 8.4,
0.9 Hz), 8.12 (H-15, 2H, dd, J = 8.1, 1.3 Hz), 8.02 (H-7, 1H, dd, J = 7.9, 1.1 Hz), 7.90 (H-5, 1H, d, J =
2.2 Hz), 7.81 (H-19, 2H, dd, J = 7.7, 1.4 Hz), 7.65 (H-17, 1H, dd, J = 7.7, 1.4 Hz), 7.55 (H-16, 2H, m),
7.44 (H-9, 1H, m), 7.40 (H-20, 2H, m), 7.29 (H-21, 1H, m), 7.25 (H-15, 1H, m),
13C NMR (DMSO-d6, 125 MHz) δ 165.3 (C-13), 145.3(C-2), 140.0 (C-4), 136.7 (C-11) 135.3 (C-14),
133.4 (C-18), 131.8 (C-17), 129.0 (C-9), 128.7 (C-16), 128.4 (C-20), 127.4 (C-15) 126.7 (C-21), 125.7
(C-7), 124.7 (C-19), 123.1 (C-8), 120.0 (C-10), 116.4 (C-6), 114.3 (C-5).
Solid compound was isolated from the water layer after the cooling. Later it was identified as
2-benzoylaminobenzamide (9e). Yield was 30 mg (6 %), mp 214 - 215 °C (lit.,9 211 -213°C)

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Anal. Calcd for C14H12N2O2 C, 69.99; H, 5.03; N, 11.66. Found C, 70.40; H, 5.32; N, 11.20.
Full MS, m/z (relative intensity) 241(3) [M+H]+, 269 [M+C2H5]+, 281 [M+C3H5]+, 224 [M+H-NH3]+, 252
[M+C2H5-NH3]+, 264 [M+C3H5- NH3]+, 196, 163, 146, 105, 91; MS2(241,w3,EV1.0), m/z 239, 223, 196,
179, 163, 146, 137, 118, 105.
1H NMR (DMSO-d6, 300 MHz) δ 12.95 (1H, s), 8.71 (1H, dd, J = 8.4, 0.9 Hz), 8.42 (1H, s), 7.96 (2H, dd,
J = 7.0, 1.6 Hz), 7.91 (1H, dd, J = 7.9, 1.3 Hz), 7.85 (1H, s), 7.66-7.53 (4H, m), 7.18 (1H, ddd, J = 7.8,
13
7.6, 1.1 Hz); C NMR (DMSO-d6, 75 MHz) δ 171.1, 164.3, 140.0, 134.6, 132.5, 131.9, 128.8, 128.7,
126.9, 122.5, 119.9, 119.1.
ACKNOWLEDGEMENT
We are grateful to the Ministry of Education, Youth and Sport of the Czech Republic, for the grant
MSM6198959216.
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