Synthesis of 2-substituted oxazoloquinazolinones

Article abstract of DOI:10.1007/s10593-018-2394-8

[Figure not available: see fulltext.] The reaction of methyl 2-isothiocyanatobenzoate and 1-azido-3-(4-substituted phenyl)propan-2-ones in the presence of triphenyl phosphine in dioxane by heating produced tricyclic (Z)-2-(4-substituted benzylidene)-2,3-d

Full text of DOI:10.1007/s10593-018-2394-8

DOI 10.1007/s10593-018-2394-8
Chemistry of Heterocyclic Compounds 2018, 54(11), 1070–1074
Synthesis of 2-substituted oxazoloquinazolinones
1
1
Olga Bobiļeva *, Einārs Loža
1
Latvian Institute of Organic Synthesis,
1 Aizkraukles St., Riga LV-1006, Latvia; e-mail: olga_bobileva@osi.lv
2
Published in Khimiya Geterotsiklicheskikh Soedinenii,
018, 54(11), 1070–1074
Submitted July 16, 2018
Accepted November 1, 2018
2
The reaction of methyl 2-isothiocyanatobenzoate and 1-azido-3-(4-substituted phenyl)propan-2-ones in the presence of triphenyl
phosphine in dioxane by heating produced tricyclic (Z)-2-(4-substituted benzylidene)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-ones
instead of the expected methyl 2-{[5-(4-substituted benzyl)oxazol-2-yl]amino}benzoates. A one-pot procedure for the synthesis of
2
-substituted 5H-oxazolo[2,3-b]quinazolin-5-ones from appropriate azidomethyl ketones and 2-isothiocyanatobenzoate was developed.
Keywords: 2-aminooxazole, α-azido ketone, isothiocyanate, oxazoloquinazolinone, cyclocondensation.
Oxazoles are frequently occurring heterocycles in drug-
like compounds. One of the applications of oxazoles in
medicinal chemistry is based on their ability to act as
conditions produced (Z)-2-(4-bromobenzylidene)-2,3-di-
hydro-5H-oxazolo[2,3-b]quinazolin-5-one (5a) in 56% yield
instead of the expected 2-arylaminooxazole structure
(Table 1, entry 1). The correctness of structure 5a was
proved unequivocally by crystallographic data (Fig. 2). It is
noteworthy that only (Z)-isomer formed in this reaction. In
addition, the literature search revealed that such particular
scaffold containing an exocyclic benzylidene group as in
compound 5a is not described at all. Performing this
reaction at 0°C or at room temperature as well as changing
triphenylphosphine to more active tributylphosphine led to
the formation of a complex mixture of compounds, as it
was described by Dhar.7
1–3
bioisosteres of an amide group. In connection with our
search for new and efficient agonists of HCA2 (hydroxy-
4
carboxylic acid receptor 2) we were interested in replacing
the amide functional group in the well known anthranilic
5
acid-based agonist (structure A) with a 2-aminooxazole
moiety as, e.g., in structure B (Fig. 1).
For the possible synthesis of structures B containing
both anthranilic acid and 2-aminooxazole moieties, we
chose the strategy based on the reaction of α-azido ketones
and isothiocyanates in the presence of phosphine. This
reaction is a convenient general method for the preparation
of 2-arylaminooxazoles and it proceeds via β-keto carbodi-
Being interested in the generality of this unusual
transformation, we briefly tested the behavior of some
azidomethyl ketones 2b–e (Table 1, method A). Thus,
azidomethyl benzyl ketones 2b and 2c, containing electron-
donating 4-methyl group or electron-acceptor 4-nitro group
in the benzyl part of the molecule, produced benzylidene
derivatives 5b (41%) and 5c (20%), respectively, by
treatment with triphenyl phosphine and isothiocyanate 3
(Scheme 1). Besides, a minor amount of required
2-arylaminooxazole 4b (17%) was isolated from the
reaction mixture in the case of 4-methyl benzyl ketone 2b,
whereas 4-nitrobenzyl ketone 2c afforded required
6
imide intermediate formation. In our studies, we employed
7
the synthetic protocol introduced by Dhar according to
which a mixture of appropriate α-azido ketone, isothio-
cyanate, and triphenylphosphine is heated in dioxane to 90°C.
We started our studies with 1-bromo-3-(4-bromophenyl)-
propan-2-one (1a), which served as a starting material for
the synthesis of azidomethyl benzyl ketone 2a by sodium
azide treatment (Scheme 1, Table 1). Quite surprisingly,
the reaction of azido ketone 2a and commercially available
methyl 2-isothiocyanatobenzoate (3) under the Dhar
2
-arylaminooxazole 4c (14%) and aromatic 5H-oxazolo-
[
2,3-b]quinazolin-5-one 6c (40%) (Table 1, entries 3 and 4).
However, azidomethyl ketone 2d containing better
electron-withdrawing ethoxycarbonyl group than the sub-
stituted phenyl in compounds 2a–c yielded solely 2-aryl-
aminooxazole derivative 4d in the reaction with isothio-
Figure 1. 2-Aminooxazole as a possible amide group bioisostere.
0
009-3122/18/54(11)-1070©2018 Springer Science+Business Media, LLC
1070

Chemistry of Heterocyclic Compounds 2018, 54(11), 1070–1074
Scheme 1
Table 1. Substituents and yields of compounds 4b–e, 5a–c, 6a,c–g
Several methods have been reported for the synthesis of
–10
thiazole-fused quinazolones,8
but only few tricyclic
11
1
Entry Azide Method Product(s)
R
–
R
Yield, %
56
oxazole-fused quinazolones are known. Buchwald et al.
1
2
3
2a
–
A
From 5a
A
5a
6a
4b
4-BrC
6
H
4
has observed the formation of the parent compound
(4-BrC
(4-MeC
6
H
4
)CH
)CH
2
64
5
H-oxazolo[2,3-b]quinazolin-5-one in his studies of palla-
2b
6
H
4
2
–
17
dium-catalyzed C–N cross coupling between 2-amino-
oxazole and aryl chloride bearing a methyl ester group in
the ortho position in the presence of sodium phenolate at
elevated temperature. To the best of our knowledge, the
only reported synthesis of 2-substituted 5H-oxazolo[2,3-b]-
quinazolin-5-one is based on the cyclization of a quin-
azolinedione derivative and subsequent dehydration of the
resulting dihydrooxazole.12
5
b
–
4-MeC
–
6
H
4
41
4
2c
A
4c
(4-NO
(4-NO
2
C
6
H
4
)CH
2
2
14
5
6
c
c
–
4-NO
2
C
6
H
4
60*
2
C
6
H
4
)CH
–
–
–
–
–
–
–
5
6
7
8
9
2d
2d
2e
2e
2f
A
B
A
B
B
B
4d
6d
4e
6e
6f
CH
CH
2
CO
CO
2
Et
Et
44
40
53
76
48
71
2
2
Me
Me
Ph
We have demonstrated that 5-substituted 2-arylamino-
oxazoles can be easily cyclocondensed in the presence of a
base to obtain the corresponding 2-substituted 5H-oxazolo-
[2,3-b]quinazolin-5-ones and this reaction can be performed
in a one-pot process (Scheme 1, method B). Thus, azido-
methyl ketones 2d,e were treated with isothiocyanate 3
under the Dhar conditions until TLC analysis of the
reaction mixture showed a full consumption of starting
compounds 2d,e and the formation of oxazoles 4d,e. Then
the reaction mixture was supplemented with anhydrous
potassium carbonate and stirred at 80°C for 1 h. This
procedure resulted in the cyclocondensation of oxazoles
4d,e into 2-substituted 5H-oxazolo[2,3-b]quinazolin-5-ones
6d,e (Table 1, entries 6 and 8). By the methodology
described above, 2-bromomethyl ketones 1f,g were con-
verted into tricycles 6f,g as well (Table 1, entries 9 and 10).
Since dihydrooxazolo[2,3-b]quinazolin-5-one 5a can be
isomerized into aromatic 5H-oxazolo[2,3-b]quinazolin-
5-one 6a by a slow process under quite harsh conditions
and the only product of cyclocondensation of amino-
oxazoles 4d–g is 5H-oxazolo[2,3-b]quinazolin-5-ones 6d–g,
we suppose that 2-benzylidenedihydrooxazolo[2,3-b]quin-
azolin-5-ones 5a–c are formed from β-keto carbodiimide
intermediate, but not from 2-aminooxazoles, e.g., 4b,c.
In conclusion, the possibility of obtaining 2-substituted
1
0
2g
6g
1
*
Isolated yield of a mixture of compounds 5c and 6c (5c:6c = 1:2 ( H NMR)).
cyanate 3 under the Dhar conditions (Table 1, entry 5).
Similar was the outcome of the reaction of 1-azidopropan-
2
-one (2e), which did not contain an extra electron-
withdrawing group in the molecule, and isothiocyanate 3.
2
-Arylaminooxazole derivative 4e was isolated as the only
product of this reaction (Table 1, entry 7).
We have found that dihydrooxazolo[2,3-b]quinazolin-
5
-one 5a can be slowly converted (conversion 93%) into
a priori thermodynamically more stable aromatic 2-sub-
stituted 5H-oxazolo[2,3-b]quinazolin-5-one 6a (yield 64%)
by heating in dioxane at 80°C in the presence of K
2
CO for
3
7
days (Table 1, entry 2).
5
H-oxazolo[2,3-b]quinazolin-5-ones in a one-pot process
from azidomethyl ketones and methyl 2-isothiocyanato-
benzoate via 5-substituted 2-arylaminooxazole inter-
mediates was demonstrated. A method for the synthesis of
2
-benzylidenedihydrooxazolo[2,3-b]quinazolin-5-ones from
appropriate azidomethyl ketones and methyl 2-isothio-
cyanatobenzoate has been developed.
Figure 2. The molecular structure of compound 5a with atoms
represented by thermal vibration ellipsoids of 50% probability.
1
071

Chemistry of Heterocyclic Compounds 2018, 54(11), 1070–1074
Experimental
(300 MHz, CDCl ), δ, ppm: 8.25–8.19 (2H, m, H-3,5); 7.42–
3
7
.36 (2H, m, H-2,6); 4.06 (2H, s, CH
2
N
3
); 3.90 (2H, s,
), δ, ppm:
1H and 13C NMR spectra were recorded at ambient
temperature on a Bruker Fourier 300 (300 and 75 MHz,
respectively) or Varian OXFORD 400 spectrometers (400
CH
). C NMR spectrum (75 MHz, CDCl
200.5; 147.5; 140.0; 130.7; 124.1; 57.5; 46.5.
13
2
3
2-Azido-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (2g)
was prepared from 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-
ethan-1-one (1g) (0.21 g, 1.01 mmol) and sodium azide
and 100 MHz, respectively). Chemical shifts are referenced
1
to the residual solvent signal ( H NMR CDCl
3
: 7.26 ppm
: 77.16 ppm and
: 39.52 ppm). LCMS was performed on a Waters
1
3
and DMSO-d
DMSO-d
6
: 2.50 ppm; C NMR CDCl
3
(78 mg, 1.21 mmol). Yield 0.17 g (98%), colorless oil.
1
6
H NMR spectrum (300 MHz, CDCl
3
), δ, ppm: 4.07–3.95
); 3.52–3.35 (2H,
); 2.74–2.60 (1H, m, CH); 1.81–1.71 (4H, m,
Acquity UPLC system connected to a Micromass Q-TOF
micro hybrid quadrupole time-of-flight mass spectrometer
operating in the electrospray ionization (ESI) positive and
negative ion mode and using reverse-phase Acquity UPLC
BEH C18 column (1.7 μm, 2.1 × 50 mm) on a gradient of
(2H, m, 2OCH
m, 2OCH
OCH CH
δ, ppm: 205.5; 67.0; 55.8; 45.3; 27.8.
Preparation of oxazoles 4b–e and (Z)-2-(benzylidene)-
2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-ones 5a–c
a
H
b
); 4.01 (2H, s, CH
2
N
3
a
H
b
13
2
2
). C NMR spectrum (100 MHz, CDCl ),
3
1
0–95% MeCN in 0.1% aqueous HCO H. HRMS (ESI)
2
was performed on a Waters Synapt G2-Si Mass Spectro-
meter in positive ionization mode. Melting points were
determined on a Gallenkamp melting point apparatus.
Chemicals and reagents were obtained from commercial
suppliers and were used without further purification. TLC
analyses were performed with Merck F254 Alumina Silica
Plates using UV visualization or staining.
(General method A). Triphenylphosphine (1 equiv) was
added to a solution of azido ketone 2a–e (1 equiv) and
isothiocyanate 3 (1 equiv) in dioxane (2 ml/mmol) under
argon, and evolution of gas was observed. The mixture was
stirred for 5 min at room temperature, then refluxed for 2 h,
cooled to room temperature, and evaporated. The residue
was purified by column chromatography on silica gel or by
Previously described α-halo ketones 1a–d were prepared
from corresponding aryl carboxylic acids by the reported
crystallization from CH
2
Cl .
2
(Z)-2-(4-Bromobenzylidene)-2,3-dihydro-5H-oxazolo-
[2,3-b]quinazolin-5-one (5a) was prepared from azido
ketone 2a (101 mg, 0.40 mmol), isothiocyanate 3 (77 mg,
0.40 mmol), and triphenylphosphine (105 mg, 0.40 mmol).
1
3
14
Dakin–West aryl ketone synthesis
– bromination
reaction sequence. α-Halo ketones 1e–g were bought from
commercial sources.
Preparation of α-azido ketones 2a–g (General method).
Caution! α-Azido ketones are potentially explosive com-
pounds and should be handled with care. A mixture of
α-bromo ketone 1a–g (1 equiv) and sodium azide (1.1–
The product was crystallized from CH
2
Cl
2
. Yield 80 mg
(56%), white solid, mp 238–239°C. H NMR spectrum
(300 MHz, DMSO-d ), δ, ppm (J, Hz): 8.09 (1H, dd,
1
6
J = 7.9, J = 1.2, H quinazolinone); 7.79 (1H, ddd, J = 8.5,
J = 7.2, J = 1.5, H quinazolinone); 7.65–7.58 (2H, m,
H Ar); 7.58–7.51 (3H, m, H Ar, H quinazolinone); 7.44
(1H, ddd, J = 7.9, J = 7.2, J = 1.1, H quinazolinone); 6.02
1
.2 equiv) in MeOH or Me CO (2.5 ml/mmol) was stirred
2
for 2–17 h and then the solvent was evaporated. The
residue was partitioned between water and EtOAc, the organic
13
layer was washed with water, brine, dried over Na
2 4
SO , and
(1H, t, J = 1.7, CH); 5.01 (2H, d, J = 1.7, CH ). C NMR
2
1
5
16
17
evaporated. α-Azido ketones 2d, 2e, and 2f have been
previously reported in literature. α-Azido ketones 2a–c,g
do not ionize under ESI LCMS mode conditions and are
too unstable to obtain elemental analysis.
spectrum (75 MHz, DMSO-d ), δ, ppm: 159.1; 154.3;
6
148.1; 144.7; 134.8; 132.5; 131.6; 129.9; 126.2; 126.1;
125.2; 119.9; 119.1; 102.0; 46.7. Found, m/z: 355.0092
+
[M+H] . C17
H
12BrN
2
O . Calculated, m/z: 355.0077.
3
1
-Azido-3-(4-bromophenyl)propan-2-one (2a) was
prepared from 1-bromo-3-(4-bromophenyl)propan-2-one
1a) (0.63 g, 2.16 mmol) and sodium azide (0.17 g,
Methyl 2-{[5-(4-methylbenzyl)oxazol-2-yl]amino}-
benzoate (4b) and (Z)-2-(4-methylbenzylidene)-2,3-
dihydro-5H-oxazolo[2,3-b]quinazolin-5-one (5b) were
obtained as mixture from azido ketone 2b (47 mg, 0.25 mmol),
isothiocyanate 3 (48 mg, 0.25 mmol), and triphenyl-
phosphine (65 mg, 0.25 mmol). The products were sepa-
rated by column chromatography on silica gel using EtOAc
in petroleum ether as a mobile phase, gradient 5–60%.
(
1
2
.61 mmol). Yield 0.54 g (99%), brown solid. H NMR
spectrum (300 MHz, CDCl ), δ, ppm: 7.52–7.45 (2H, m,
H-3,5); 7.13–7.05 (2H, m, H-2,6); 3.99 (2H, s, CH );
),
3
2
N
3
1
3
3
.72 (2H, s, CH
δ, ppm: 201.4; 132.2; 131.6; 131.2; 121.8; 57.1; 46.6.
-Azido-3-(4-methylphenyl)propan-2-one (2b) was pre-
pared from 1-bromo-3-(4-methylphenyl)propan-2-one (1b)
0.31 g, 1.36 mmol) and sodium azide (0.11 g, 1.64 mmol).
2
). C NMR spectrum (75 MHz, CDCl
3
1
Compound 4b (in 45% EtOAc). Yield 14 mg (17%),
1
colorless oil. H NMR spectrum (300 MHz, CDCl
3
), δ, ppm
(
(J, Hz): 10.84 (1H, s, NH); 8.55 (1H, dd, J = 8.6, J = 1.0,
H-3); 8.01 (1H, dd, J = 8.2, J = 1.7, H-6); 7.54 (1H, ddd,
J = 8.6, J = 7.3, J = 1.7, H-4); 7.22–7.09 (4H, m, H Ar);
6.94 (1H, ddd, J = 8.2, J = 7.3, J = 1.0, H-5); 6.61 (1H, t,
1
Yield 0.22 g (83%), colorless oil. H NMR spectrum
(
300 MHz, CDCl
3
), δ, ppm: 7.19–7.13 (2H, m, H Ar); 7.14–
.05 (2H, m, H Ar); 3.96 (2H, s, CH ); 3.71 (2H, s, CH );
). C NMR spectrum (75 MHz, CDCl ),
7
2
2
N
3
2
1
3
.34 (3H, s, CH
3
3
J = 1.2, H oxazole); 3.92 (3H, s, OCH
3
); 3.89 (2H, s, CH
2
);
),
13
δ, ppm: 202.2; 137.4; 129.8; 129.6; 129.3; 56.8; 47.2; 21.2.
2.34 (3H, s, CH
3
). C NMR spectrum (75 MHz, CDCl
3
1
-Azido-3-(4-nitrophenyl)propan-2-one (2c) was pre-
pared from 1-bromo-3-(4-bromophenyl)propan-2-one (1c)
0.35 g, 1.36 mmol) and sodium azide (0.11 g, 1.63 mmol).
δ, ppm: 169.0; 155.5; 145.3; 142.3; 136.5; 135.0; 134.1;
131.1; 129.4; 128.6; 122.5; 120.0; 117.3; 112.7; 52.2; 31.6;
+
(
21.2. Found, m/z: 323.1408 [M+H] . C19
lated, m/z: 323.1390.
H
19
N
2
O . Calcu-
3
1
Yield 0.30 g (99%), brown solid. H NMR spectrum
1
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Chemistry of Heterocyclic Compounds 2018, 54(11), 1070–1074
Compound 5b (in 60% EtOAc). Yield 30 mg (41%),
phosphine (105 mg, 0.40 mmol). The product was purified
by column chromatography on silica gel using Et O in
petroleum ether as a mobile phase, gradient 17–25%. Yield
49 mg (53%), white solid. Compound contains 5% PPh S.
), δ, ppm (J, Hz):
10.85 (1H, s, NH); 8.53 (1H, dd, J = 8.6, J = 1.1, H-3); 8.02
(1H, dd, J = 8.1, J = 1.6, H-6); 7.54 (1H, ddd, J = 8.6,
J = 7.4, J = 1.6, H-4); 6.94 (1H, ddd, J = 8.1, J = 7.4, J = 1.1,
1
yellow solid. H NMR spectrum (300 MHz, CDCl
3
),
2
δ, ppm (J, Hz): 8.23 (1H, dd, J = 7.9, J = 1.0,
H quinazolinone); 7.73 (1H, ddd, J = 7.9, J = 7.3, J = 1.5,
H quinazolinone); 7.61 (1H, d, J = 7.9, H quinazolinone);
3
1
H NMR spectrum (300 MHz, CDCl
3
7
.54 (2H, d, J = 7.8, H Ar); 7.45–7.36 (1H, ddd, J = 7.9,
J = 7.3, J = 1.1, H quinazolinone); 7.16 (2H, d, J = 7.8, H Ar); 5.78
1H, t, J = 1.7, CH); 5.00 (2H, d, J = 1.7, CH ); 2.35 (3H, s,
), δ, ppm: 160.1;
(
2
1
3
CH
3
). C NMR spectrum (100 MHz, CDCl
3
H-5); 6.55 (1H, q, J = 1.3, H oxazole); 3.93 (3H, s, OCH
3
);
). C NMR spectrum (100 MHz,
), δ, ppm: 169.0; 155.0; 142.5 (2C); 135.0; 131.1;
121.8; 120.0; 117.2; 112.7; 52.3; 10.8. Found, m/z:
13
1
1
2
54.2; 148.4; 141.0; 137.8; 135.2; 129.7; 129.5; 128.6;
2.26 (3H, d, J = 1.3, CH
CDCl
3
26.9; 126.8; 125.7; 119.3; 105.7; 46.5; 21.4. Found, m/z:
3
+
91.1140 [M+H] . C18
H
15
N
2
O . Calculated, m/z: 291.1128.
3
+
Methyl 2-{[5-(4-nitrobenzyl)oxazol-2-yl]amino}benzoate
4c) was prepared from azido ketone 2c (53 mg, 0.25 mmol),
233.0928 [M+H] . C12
H
13
N
2
O . Calculated, m/z: 233.0921.
3
(
2-(4-Bromobenzyl)-5H-oxazolo[2,3-b]quinazolin-5-one
(6a). A solution of dihydro-5H-oxazolo[2,3-b]quinazolin-
isothiocyanate 3 (46 mg, 0.24 mmol), and triphenyl-
phosphine (63 mg, 0.24 mmol). The product was purified
by column chromatography on silica gel using EtOAc in
5-one (5a) (28 mg, 0.08 mmol) and K
2
CO (11 mg,
3
0.08 mmol) was heated in a closed vial under argon atmo-
petroleum ether as a mobile phase, gradient 5–60%. Yield
sphere at 80°C for 7 days. The reaction mixture was diluted
1
1
2 mg (14%), yellow solid. H NMR spectrum (300 MHz,
with EtOAc, washed with water, dried over Na
2
SO , and
4
CDCl
3
), δ, ppm (J, Hz): 10.93 (1H, s, NH); 8.54 (1H, dd,
evaporated. The product was purified by column
chromatography on silica gel using MeOH in CH Cl as a
mobile phase, gradient 1–3%. Yield 18 mg (64%), white
solid. 1H NMR spectrum (400 MHz, CDCl
), δ, ppm
J = 8.6, J = 1.0, H-3); 8.25–8.15 (2H, m, H'-3,5); 8.02 (1H,
dd, J = 8.0, J = 1.6, H-6); 7.56 (1H, ddd, J = 8.6, J = 7.4,
J = 1.6, H-4); 7.47–7.40 (2H, m, H'-2,6); 6.97 (1H, ddd,
J = 8.0, J = 7.4, J = 1.0, H-5); 6.70 (1H, s, H oxazole); 4.04
2
2
3
(J, Hz): 8.30 (1H, ddd, J = 8.1, J = 1.6, J = 0.6,
H quinazolinone); 7.75 (1H, ddd, J = 8.3, J = 7.0, J = 1.6,
H quinazolinone); 7.66 (1H, ddd, J = 8.3, J = 1.2, J = 0.6,
H quinazolinone); 7.52–7.47 (2H, m, H-3,5); 7.41 (1H,
ddd, J = 8.1, J = 7.0, J = 1.2, H quinazolinone); 7.35 (1H, t,
J = 1.4, H oxazole); 7.23–7.17 (2H, m, H-2,6); 3.96 (2H, d,
1
3
(
2H, s, CH
2
); 3.92 (3H, s, OCH
3
). C NMR spectrum
(
100 MHz, CDCl
3
), δ, ppm: 169.1; 155.9; 147.2; 144.8; 143.0;
1
42.1; 135.1; 131.2; 129.6; 124.1; 123.6; 120.4; 117.3; 112.9;
+
5
2.4; 31.8. Found, m/z: 354.1095 [M+H] . C18
H
16
N
3 5
O .
Calculated, m/z: 354.1084. Besides, by column chromato-
graphy an inseparable mixture of isomeric (Z)-2-(4-nitro-
benzylidene)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-
1
3
J = 1.4, CH
2
). C NMR spectrum (100 MHz, CDCl ),
3
δ, ppm: 157.5; 152.5; 148.1; 146.8; 135.0; 133.1; 132.3;
5
-one (5c) and 2-(4-nitrobenzyl)-5H-oxazolo[2,3-b]quin-
130.8; 127.1; 126.8; 124.9; 121.9; 117.3; 106.1; 32.1.
+
azolin-5-one (6c) was obtained. Yield 46 mg (60%),
Found, m/z: 355.0087 [M+H] . C17
H
12BrN
2
O . Calculated, m/z:
2
1
H NMR ratio 1:2. Characteristic signals of these structures
355.0077.
1
in H NMR spectrum (300 MHz, CDCl
3
), δ, ppm (J, Hz):
Synthesis of oxazoloquinazolinones 6d–g (General
method B). Phosphine (1 equiv) was added to a solution of
azido ketone 2d–g (1 equiv) and isothiocyanate 3 (1 equiv)
in dioxane (2 ml/mmol) under argon, and evolution of gas
was observed. The mixture was stirred for 5 min at room
temperature, then refluxed for 2 h, and cooled to room
temperature. TLC showed full conversion of azido ketone
compound 5c: 5.95 (1H, t, J = 2.0, CH); 5.13 (2H, d,
J = 2.0, CH ); compound 6c: 8.33 (1H, ddd, J = 8.1,
J = 1.4, J = 0.5, H quinazolinone); 4.14 (2H, s, CH ). LCMS,
2
2
+
+
m/z: compound 5c: 321 [M+H] ; compound 6c: 321 [M+H] .
Methyl 2-{[5-(2-ethoxy-2-oxoethyl)oxazol-2-yl]amino}-
benzoate (4d) was prepared from azido ketone 2d (68 mg,
0
.40 mmol), isothiocyanate 3 (77 mg, 0.40 mmol), and tri-
2d–g and formation of oxazole 4d–g. K
2
CO (1 equiv) was
3
phenylphosphine (105 mg, 0.40 mmol). The product was
purified by column chromatography on silica gel using
added to the reaction mixture and the mixture was refluxed
for 1 h. The mixture was cooled to room temperature,
EtOAc in petroleum ether as a mobile phase, gradient 7–
diluted with CH
2
Cl , washed with water, brine, and
2
1
3
0%. Yield 53 mg (44%), colorless oil. H NMR spectrum
concentrated. The residue was purified by chromatography
on silica gel.
(
300 MHz, CDCl
1H, dd, J = 8.6, J = 1.0, H-3); 8.02 (1H, dd, J = 8.1, J = 1.6,
H-6); 7.55 (1H, ddd, J = 8.6, J = 7.2, J = 1.6, H-4); 6.96
1H, ddd, J = 8.1, J = 7.2, J = 1.0, H-3); 6.80 (1H, s,
3
), δ, ppm (J, Hz): 10.93 (1H, s, NH); 8.55
(
Ethyl 2-(5-oxo-5H-oxazolo[2,3-b]quinazolin-2-yl)acetate
(6d) was prepared from azido ketone 2d (69 mg, 0.40 mmol),
isothiocyanate 3 (77 mg, 0.40 mmol), triphenylphosphine
(
H oxazole); 4.21 (2H, q, J = 7.1, OCH
2
CH
); 1.29 (3H, t, J = 7.1,
). C NMR spectrum (75 MHz, CDCl ), δ, ppm:
3
); 3.93 (3H, s,
(105 mg, 0.40 mmol), and K
2
CO (55 mg, 0.40 mmol). The
3
OCH
OCH
3
); 3.65 (2H, d, J = 0.8, CH
2
product was purified by column chromatography on silica
gel using EtOAc in petroleum ether as a mobile phase,
13
2
CH
3
3
1
1
3
69.0; 168.8; 155.7; 142.2; 138.7; 135.0; 131.1; 124.5;
gradient 15–70%. Yield 44 mg (40%), yellow solid.
1
20.3; 117.3; 112.9; 61.5; 52.3; 31.7; 14.3. Found, m/z:
H NMR spectrum (300 MHz, CDCl ), δ, ppm (J, Hz): 8.34
3
+
05.1140 [M+H] . C15
H
17
N
2
O
5
. Calculated, m/z: 305.1132.
(1H, ddd, J = 8.1, J = 1.5, J = 0.5, H quinazolinone); 7.77
(1H, ddd, J = 8.4, J = 6.9, J = 1.5, H quinazolinone); 7.72
(1H, t, J = 1.3, H oxazole); 7.69 (1H, ddd, J = 8.4, J = 1.3,
J = 0.5, H quinazolinone); 7.43 (1H, ddd, J = 8.1, J = 6.9,
Methyl 2-[5-methyloxazol-2-yl)amino]benzoate (4e)
was prepared from azido ketone 2e (40 mg, 0.40 mmol),
isothiocyanate 3 (77 mg, 0.40 mmol), and triphenyl-
1
073

Chemistry of Heterocyclic Compounds 2018, 54(11), 1070–1074
J = 1.3, H quinazolinone); 4.26 (2H, q, J = 7.1, OCH
2
CH
CH
), δ, ppm: 166.9;
3
);
3
X-ray structural analysis of compound 5a. Diffraction
data were collected on a Bruker-Nonius KappaCCD
diffractometer using graphite monochromatic MoKα
radiation (λ 0.71073 Å). The crystal structure was solved
by direct methods using the SHELXS97 software and
refined by full-matrix least squares using the SHELXL97
3
.77 (2H, d, J = 1.3, CH
2
); 1.31 (3H, J = 7.1, OCH
2
).
1
3
C NMR spectrum (75 MHz, CDCl
3
1
1
[
57.5; 152.2; 148.1; 140.9; 135.0; 127.1; 126.7; 124.9;
17.2; 108.0; 62.2; 32.2; 14.2. Found, m/z: 273.0869
+
M+H] . C14
H
13
N
2
O . Calculated, m/z: 273.0870.
4
(6e)12
software. Crystallographic data of compound 5a have
18
2
-Methyl-5H-oxazolo[2,3-b]quinazolin-5-one
was prepared from azido ketone 2e (40 mg, 0.40 mmol),
isothiocyanate 3 (77 mg, 0.40 mmol), triphenylphosphine
been deposited at the Cambridge Crystallographic Data
Center (deposit CCDC 1840303).
(
105 mg, 0.40 mmol), and K
2
CO (55 mg, 0.40 mmol). The
3
1
product was purified by column chromatography on silica
gel using EtOAc in petroleum ether as a mobile phase,
The Supplementary information file containing the H
and 13C NMR spectra of compounds 2a–c,g, 4b–d, 5a,b,
and 6a,d–g is available at the journal website at http://
link.springer.com/journal/10593.
1
gradient 8–60%. Yield 61 mg (76%), yellow solid. H NMR
spectrum (300 MHz, CDCl ), δ, ppm (J, Hz): 8.33 (1H, dd,
3
J = 8.1, J = 1.5, H quinazolinone); 7.77 (1H, ddd, J = 8.4,
J = 6.9, J = 1.6, H quinazolinone); 7.72–7.67 (1H, m,
H quinazolinone); 7.47–7.36 (2H, m, H quinazolinone,
Financial support from the internal grant of the Latvian
Institute of Organic Synthesis is acknowledged. We thank
Dr. phys. Anatoly Mishnev for performing X-ray analysis.
1
3
H oxazole); 2.41 (3H, d, J = 1.5, CH
3
). C NMR spectrum
(
75 MHz, CDCl
3
), δ, ppm: 157.4; 152.5; 148.1; 144.7;
References
1
2
34.7; 127.0; 126.6; 124.6; 117.2; 105.4; 11.8. Found, m/z:
+
01.0666 [M+H] . C11
H
9
N
2
O . Calculated, m/z: 201.0659.
2
1
. Ciapetti, P.; Giethlen, B. In The practice of medicinal
chemistry; Wermuth, C. G., Ed.; Academic Press: London,
2008, 3rd ed., p. 290.
2-Phenyl-5H-oxazolo[2,3-b]quinazolin-5-one (6f) was
prepared from azido ketone 2f (65 mg, 0.40 mmol),
isothiocyanate 3 (77 mg, 0.40 mmol), triphenylphosphine
(
2. Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
3
. Elzein, E.; Ibrahim, P.; Koltun, D. O.; Rehder, K.; Shenk, K. D.;
Marquart, T. A.; Jiang, B.; Li, X.; Natero, R.; Li, Y.; Nguyen, M.;
Kerwar, S.; Chu, N.; Soohoo, D.; Hao, J.; Maydanik, V. Y.;
Lustig, D. A.; Zeng, D.; Leung, K.; Zablocki, J. A. Bioorg.
Med. Chem. Lett. 2004, 14, 6017.
105 mg, 0.40 mmol), and K
2
CO (55 mg, 0.40 mmol). The
3
product was purified by column chromatography on silica
gel using CH Cl in petroleum ether as a mobile phase,
gradient 15–100%. Yield 50 mg (48%), white solid.
2
2
1
H NMR spectrum (300 MHz, CDCl
1H, dd, J = 8.1, J = 1.4, H quinazolinone); 7.97 (1H, s,
H oxazole); 7.83–7.71 (4H, m, H-2,6, H quinazolinone);
3
), δ, ppm (J, Hz): 8.37
4
. Bobileva, O.; Ikaunieks, M.; Duburs, G.; Mandrika, I.;
Petrovska, R.; Klovins, J.; Loza, E. Bioorg. Med. Chem. 2017,
25, 4314.
(
1
3
7
.56–7.41 (4H, m, H-3,4,5, H quinazolinone). C NMR
), δ, ppm: 157.6; 152.0; 148.1;
46.0; 135.0; 130.5; 129.4; 127.2; 126.8; 125.7; 125.0;
5. Shen, H. C.; Ding, F.-X.; Luell, S.; Forrest, M. J.; Carballo-
Jane, E.; Wu, K. K.; Wu, T.-J.; Cheng, K.; Wilsie, L. C.;
Krsmanovic, M. L.; Taggart, A. K.; Ren, N.; Cai, T.-Q.;
Deng, Q.; Chen, Q.; Wang, J.; Wolff, M. S.; Tong, X.;
Holt, T. G.; Waters, M. G.; Hammond, M. L.; Tata, J. R.;
Colletti, S. L. J. Med. Chem. 2007, 50, 6303.
spectrum (100 MHz, CDCl
3
1
1
C
+
24.8; 117.3; 103.5. Found, m/z: 263.0832 [M+H] .
. Calculated, m/z: 263.0815.
-(Tetrahydro-2H-pyran-4-yl)-5H-oxazolo[2,3-b]quin-
azolin-5-one (6g) was prepared from azido ketone 2g
65 mg, 0.40 mmol), isothiocyanate 3 (77 mg, 0.40 mmol),
triphenylphosphine (105 mg, 0.40 mmol), and K CO
55 mg, 0.40 mmol). The product was purified by column
16
2
H
11
N
2
O
2
6
. Frøyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 60, 81.
. Dhar, T. G. M.; Guo, J.; Shen, Z.; Pitts, W. J.; Gu, H. H.;
Chen, B. C.; Zhao, R.; Bednarz, M. S.; Iwanowicz, E. J. Org.
Lett. 2002, 4, 2091.
7
(
2
3
(
8. Pellón, R. F.; Docampo, M. L.; Fascio, M. L. Synth. Commun.
2007, 37, 1853.
chromatography on silica gel using MeOH in CH
2
2
Cl as a
9. Yadav, A. K.; Dhakad, P.; Sharma, G. R. Tetrahedron Lett.
mobile phase, gradient 1–10%, then the product was
washed with EtOAc and petroleum ether mixture, 1:4.
2
013, 54, 6061.
1
10. Liu, M.; Shu, M.; Yao, C.; Yin, G.; Wang, D.; Huang, J. Org.
Lett. 2016, 18, 824.
1
Yield 76 mg (71%), white solid. H NMR spectrum
(
400 MHz, CDCl ), δ, ppm (J, Hz): 8.31 (1H, ddd, J = 8.1,
3
1. Olsen, E. P. K.; Arrechea, P. L.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2017, 56, 10569.
J = 1.6, J = 0.6, H quinazolinone); 7.75 (1H, ddd, J = 8.4,
J = 7.0, J = 1.6, H quinazolinone); 7.66 (1H, ddd, J = 8.4,
J = 1.2, J = 0.6, H quinazolinone); 7.41 (1H, d, J = 1.5,
H oxazole); 7.41 (1H, ddd, J = 8.1, J = 7.0, J = 1.2,
H quinazolinone); 4.07 (2H, ddd, J = 11.6, J = 4.0, J = 2.3)
1
2. Sinha, S. K. P.; Thakur, M. P. J. Indian Chem. Soc. 1974, 51, 453.
13. Tran, K.-V.; Bickar, D. J. Org. Chem. 2006, 71, 6640.
14. Choi, H. Y.; Chi, D. Y. Org. Lett. 2003, 5, 411.
1
5. Yasohara, Y.; Kizaki, N.; Hasegawa, J.; Wada, M.; Kataoka, M.;
Shimizu, S. Tetrahedron: Asymmetry 2001, 12, 1713.
6. Dyke, J. M.; Groves, A. P.; Morris, A.; Ogden, J. S.;
Catarino, M. I.; Dias, A. A.; Oliveira, A. M. S.; Costa, M. L.;
Barros, M. T.; Cabral, M. H.; Moutinho, A. M. C. J. Phys.
Chem. A 1999, 103, 8239.
and 3.53 (2H, td, J = 11.6, J = 2.3, 2OCH
2
); 2.97 (1H, ttd,
1
J = 11.5, J = 3.9, J = 1.5, CH); 2.03–1.76 (2H, m) and 1.81
1
3
(
2H, dtd, J = 13.0, J = 11.5, J = 4.3, 2OCH
), δ, ppm: 157.6; 152.4; 151.0;
48.1; 134.9; 127.1; 126.7; 124.8; 117.2; 104.1; 67.1; 32.8;
2
CH
2
). C NMR
spectrum (100 MHz, CDCl
3
1
2
1
7. Boyer, J. H.; Straw, D. J. Am. Chem. Soc. 1952, 74, 4506.
8. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found
Crystallogr. 2008, A64, 112.
+
9.7. Found, m/z: 271.1095 [M+H] . C15
H
15
N
2
O . Calcu-
3
1
lated, m/z: 271.1077.
1
074