Reaction of some 2-quinolone derivatives with phosphoryl chloride: Synthesis of novel phosphoric acid esters of 4-hydroxy-2-quinolone

Article abstract of DOI:10.1002/jhet.1082

3-Chloroquinoline-2,4-diones do not react with phosphoryl chloride, however, 2,4-dichloroquinolines and/or 4-chloroquinolin-2-ones are formed in the presence of N,N-dimethylaniline. Along with these compounds, small quantities of novel dihydrogen phosphates of 4-hydroxyquinolin-2-ones were isolated. We outline a simple procedure that allows for the preparation of these compounds in moderate to good yields. All compounds were characterized by ¹H and ¹³C NMR, IR, EI-MS, and ESI-MS spectroscopy, and in select cases by ³¹P NMR spectroscopy.

Full text of DOI:10.1002/jhet.1082

E100
Reaction of Some 2‐Quinolone Derivatives with Phosphoryl
Chloride: Synthesis of Novel Phosphoric Acid Esters of
4‐Hydroxy‐2‐quinolone
Vol 50
Ondřej Rudolf,a Vladimír Mrkvička,a Antonín Lyčka,b,c
a
a
*
Michal Rouchal, and Antonín Klásek
aDepartment of Chemistry, Faculty of Technology, Tomas Bata University,
762 72 Zlín, Czech Republic
bResearch Institute for Organic Syntheses (VUOS), Rybitví 296,
532 18 Pardubice 20, Czech Republic
cDepartment of Analytical Chemistry, Faculty of Chemical Technology
University of Pardubice, 53210 Pardubice, Czech Republic
*
E-mail: klasek@ft.utb.cz
Received June 20, 2011
DOI 10.1002/jhet.1082
Published online 11 February 2013 in Wiley Online Library (wileyonlinelibrary.com).
3‐Chloroquinoline‐2,4‐diones do not react with phosphoryl chloride, however, 2,4‐dichloroquinolines and/or 4‐
chloroquinolin‐2‐ones are formed in the presence of N,N‐dimethylaniline. Along with these compounds, small
quantities of novel dihydrogen phosphates of 4‐hydroxyquinolin‐2‐ones were isolated. We outline a simple proce-
dure that allows for the preparation of these compounds in moderate to good yields. All compounds were charac-
terized by 1H and 13C NMR, IR, EI‐MS, and ESI‐MS spectroscopy, and in select cases by 31P NMR spectroscopy.
J. Heterocyclic Chem., 50, E100 (2013).
INTRODUCTION
corresponding 1‐substituted 4‐chloroquinoline‐2‐ones [15,
16].
Phosphoryl chloride (phosphoryl trichloride, phosphorus
oxychloride) is a popular reagent for the conversion of
─CO─NH─ groups to ─C(Cl)═N─ groups. Therefore,
it is not surprising that more than 600 reactions that describe
the conversion of quinoline‐2‐ones to 2‐chloroquinolines
have been reported in the literature. 1‐Unsubstituted 4‐
hydroxyquinoline‐2‐ones react with phosphoryl chloride
or a mixture of phosphoryl chloride and phosphorus pen-
tachloride to give 2,4‐dichloroquinolines [1–4]. To date,
more than 230 2,4‐dichloroquinolines are known, and some
of them exhibit interesting biological activity. For example,
the 7‐dimethylamino‐3‐methyl derivative exhibits antiviral ac-
tivity [5], the 3‐butyl‐6‐(3,5‐dimethyl‐pyrazol‐1‐yl) derivative
is mildly active against Staphyllococcus aureus and Saccharo-
myces cerevisiae [6], the 3‐(2‐chloroethyl)‐8‐methyl derivative
has the ability to inhibit (H+/K+)‐ATPase affinity in lyophi-
lized gastric vesicles [7], and the 3,7‐dichloro and 3‐chloro‐
6,7‐difluoro derivatives exhibit affinity for pentacyclidine and
glycine binding sites on NMDA receptors [8].
The dealkylation during the formation of 2‐chloroquino-
lines occurs when 1‐substituted quinoline‐2‐ones react
with phosphoryl chloride. This happens most frequently
in the presence of phosphorus pentachloride. This class
of reactions was studied extensively in the mid‐twentieth
century [9–14]. A series of studies since 1982 have found
that reactions of 1‐substituted 4‐hydroxyquinoline‐2‐ones
with phosphoryl chloride produce high yields of the
In 1991, Stadlbauer et al. [17] reported that the reaction
of some 1‐alkyl‐3‐aryl‐7‐methoxy‐4‐hydroxyquinoline‐2‐
ones with phosphoryl chloride leads, without any catalyst,
not only to the expected 1‐alkyl‐3‐aryl‐7‐methoxy‐4‐chlor-
oquinoline‐2‐ones but also to 3‐aryl‐2,4‐dichloro‐7‐
methoxyquinolines.
As a part of our institute’s systematic research into 3,3‐
disubstituted 1H,3H‐quinoline‐2,4‐diones we decided to
study the previously undescribed reaction of 3‐alkyl/aryl‐
3‐chloroquinoline‐2,4‐diones 2 with phosphoryl chloride.
We expected that 3‐alkyl/aryl‐2,3‐dichloro‐3H‐quinolin‐
4‐ones 3 would be formed, which subsequently could be
reacted with amines to give two different types of the products
suitable for biological testing.
RESULTS AND DISCUSSION
The initial 3‐alkyl/aryl‐3‐chloroquinolin‐2,4‐diones 2
(Scheme 1) were prepared by reacting 3‐alkyl/aryl‐4‐
hydroxyquinolin‐2‐ones 1 with sulfuryl chloride [18,19].
The preliminary experiments were carried out by boiling
of starting compounds 2a,c−e,g,h in phosphoryl chloride
(Table 1, Method A). In most cases, only the starting mate-
rial was isolated despite an extended reaction time (Table 1,
entries 1, 6, 8, and 11). Compound 4c was isolated in addition
to recovered starting material only with two starting
© 2013 HeteroCorporation

February 2013
Synthesis of Novel Phosphoric Acid Esters of 4-Hydroxy-2-quinolone
E101
Scheme 1
place. However, instead of the expected 3‐alkyl/aryl‐2,3‐
dichloro‐3H‐quinolin‐4‐ones 3, only 2,4‐dichloroquinolines
4a−c were obtained from all starting compounds except those
that have a phenyl group at position 1 (Table 1). These results
show that the dealkylation of the N(1) atom proceeds in all
compounds that have an alkyl group on the nitrogen atom in
position 1, but conversion is low in the case of N‐benzyl
derivatives.
N‐Phenyl substituted compounds 2j−m react differently
under of the same reaction conditions (Table 1, Method B).
Mainly starting material was recovered; however,
compounds 5k−m were also isolated in small quantities
(Table 1, entries 17–19).
The conversion of 3‐chloro‐1‐phenylquinoline‐2,4‐diones
2k−m to their corresponding 4‐chloroquinolin‐2‐ones 5 is a
net reduction. Therefore, we considered a cleavage of the C
(3)─Cl bond as the first reaction step in the transformation
of compounds 2k−m. The transfer of a chlorine atom (or a
bromine atom or a thiocyanato group) from position 3 of the
corresponding quinoline‐2,4‐diones to a nucleophile has been
observed previously [20–22]. Hydroxide ions [20], sulfide
ions [21], amines [22], thioalcohols [22], or activated aromatic
compounds [22] can act as nucleophile.
compound (2c and 2i), both of which bear a phenyl group in
position 3.
Hence, we carried out further experiments in the presence
of N,N‐dimethylaniline (DMA), which is frequently used as
a catalyst in the reaction of amides with phosphoryl chloride.
Under these conditions (Table 1, Method B), the reactions take
In the case of compounds 2k−m, DMA can act as a nucle-
ophile. We found that the reaction of 2c and 2m with DMA in
chloroform, acetic acid, ethanol, or toluene solution affords
compounds 1. Unfortunately, we did not succeeded in
isolating the expected 4‐chloro‐N,N‐dimethylaniline from the
complex reaction mixture. Conversion of 2f to 1f also
Table 1
Reactions of 3‐chloroquinoline‐2,4‐diones 2 with phosphoryl chloride (Method A: in the absence of a catalyst; Method B: in the presence of DMA).
Substituents
Entry
2
R1
H
R2
Method
Time (h)
Product(s) (yield, %)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
a
a
b
c
c
d
d
e
e
f
g
g
h
i
i
j
Bu
A
B
B
A
B
A
B
A
B
B
A
B
B
A
B
B
B
B
B
120
5
8
60
5
2a (47)b
4a (83)
H
H
Bn
Ph
4b (75)
2c (32)b, 4c (40)
4c (84)
Me
Me
Bu
Bn
10
18
23
30
10
30
30
8
18
16
30
20
20
30
2d (92)b
4a (65)
2e (92)b
4b (46)
Me
Et
Ph
Ph
4c (70)
2g (92)b
4c (54)
Bn
Bn
Bu
Ph
2h (77)b, 4a (5)
2i (30)b, 4c (4)
4c (60)
Ph
Ph
Ph
Ph
Me
Bu
Bn
Ph
2j (73)b
k
l
m
2k (18)b, 5k (11)
2l (28)b, 5l (4)
2m (32)b, 5m (12)
aRefers to isolated percent yield of pure product.
bRecovered starting compound.
Journal of Heterocyclic Chemistry
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E102
O. Rudolf, V. Mrkvička, A. Lyčka, M. Rouchal, and A. Klásek
Vol 50
Table 2
Reaction of 4‐hydroxyquinolin‐2‐ones 1 with phosphoryl chloride (methods A and B: see Table 1; Method A1: modified Method A).a
Substituents
Entry
1
R1
R2
Method
Time (h)
Product(s) (yield, %)b
1
2
3
a
b
c
H
H
H
Bu
Bn
Ph
A1
A1
A1
B
0.6
0.6
0.6
5
4a (79)
4b (77)
4c (74)
4
c
4c (97)
5
6
7
8
d
e
f
Me
Me
Me
Bu
Bn
Ph
A
1
5d (93)
A1
A1
A1
A1
A1
A1
A1
A1
A1
A
A1
A
A1
A
A1
B
0.5
0.5
6
0.5
0.5
6
0.5
6
0.5
0.7
0.7
1
5e (41), 7e (3)
4c (2), 5f (57), 7f (2)
4c (15), 5f (60)
4c (1), 5g (60), 7g (3)
4a (7), 5h (19), 7h (28)
4a (19), 5h (25), 7h (24)
4c (1), 5i (30), 7i (4)
4c (31), 5i (39), 7i (15)
5j (59), 7j (5)
5k (39), 7k (22)
5k (65)
f
9
g
h
h
i
i
j
k
k
l
Et
Bn
Ph
Bu
10
11
12
13
14
15
16
17
18
19
20
21
Bn
Ph
Ph
Ph
Ph
Ph
Me
Bu
Bu
Bn
5l (33), 7l (9)
5l (36), 7l (32)
5m (33)
l
0.7
0.7
0.7
2
m
m
m
Ph
Ph
5m (80)
5m (79)
aSee Experimental.
bRefers to isolated percent yield of pure product.
proceeds in the presence of N,N‐dimethyl‐p‐toluidine. How-
ever, facile transport of a chlorine atom from 2m was apparent
in its reaction with 2‐sulfanylbenzothiazole. In addition to 1m,
2,20‐dithiobis(benzothiazole) was isolated. These results are
similar to the transfer of thiocyanato groups from 3‐thiocyana-
toquinoline‐2,4‐diones to 2‐sulfanylbenzo‐thiazoles [22].
However, the reaction of 2f with 2,5‐dimethylaniline leads
only to N‐alkylation along with formation of compound 6f.
To clarify the reaction mechanism, we also carried out the
reaction of compounds 1 with phosphoryl chloride (Table 2).
In the absence of a catalyst, compounds 4a−c were obtained
in high yields from 1a−c (Methods A and A1). The reaction
times were much shorter than those necessary for the conver-
sion of 2a−c to 4a−c. However, compounds 1e−m provide, in
low yields, compounds 4, but only if the starting compounds
have a phenyl group at position 3 or a benzyl group at position
1 (1f−i). The yield of 4 can be increased by increasing the re-
action time (cf. entries 7–8, 10–11, and 12–13 in Table 2). The
main (or the only) products isolated from the reaction of 1d−m
with phosphoryl chloride were compounds 5. As we expected,
compounds 1 bearing the N‐phenyl group afford mainly (or
exclusively) compounds 5. The NMR data of all products 4
and 5 are compiled in Table 3.
product of the reaction of compounds 2k−m, as long as
they bear a phenyl group at position 1. In the case of N‐
unsubstituted or N‐alkyl substituted compounds 2a−i,
compound 1 is an intermediate, which is subsequently eno-
lized to intermediate A. Then, the reaction of A with phos-
phoryl chloride produces intermediate B which dealkylates
to compound 4. The enolization of 1 in the formation of A
is, as hypothesized by Bell et al. [23], facilitated by the cat-
alytic effect of DMA. The resulting compound is converted
to its hydrochloride, which protonates the carboxamide
group and facilitates its enolization and subsequent dealky-
lation through intermediate B. If DMA is not present in the
reaction mixture, the extent of enolization is lower, so
mainly compounds 5 were obtained from 1 (Table 2).
Unfortunately, when compounds 2 and phosphoryl chloride
reacted in the presence of DMA, a significant quantity of an
intensely blue compound was formed. This compound was
1
isolated and its melting point, IR, and H and 13C NMR
spectra were identical to those published [24] for 4,40,400‐tris
(dimethylaminotritylium) chloride (crystal violet, gentian
violet, methyl violet 6B). An EI‐MS spectrum of this
compound (MW 408) exhibits a peak at m/z 373, which is
almost identical to the mass of 4,40,400‐tris(dimethylamino)-
triphenyl‐methane (leuco crystal violet, MW 373.5) [24]. In
the literature, we found no information about this unintended
side product of the reaction of secondary amides with phospho-
ryl chloride in the presence of DMA, although it must have
been observed. When we refluxed a solution of DMA in
The proposed reaction mechanism of the conversion of 2
to 4 is depicted in Scheme 2. We anticipated that after
transfer of the chlorine atom from 2 to a nucleophile, inter-
mediate compound 1 would arise and react with phospho-
ryl chloride to give compound 5, which is the final minor
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of Novel Phosphoric Acid Esters of 4‐Hydroxy‐2‐quinolone
E103
Table 3
1H and 13C NMR data (δ, ppm) of compounds 2, 4, and 5 in DMSO‐d6.
2h
4a
4b
4c
5d
5e
5f
Position
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
2
3
4
4a
5
6
7
8
–
–
–
–
8.00
7.30
7.71
7.28
–
166.9
68.0
–
–
–
150.5
132.0
141.9
125.2
124.1
128.8
131.2
128.4
145.6
–
–
–
–
151.0
132.0
143.3
125.2
124.4
129.0
131.6
128.5
145.9
–
–
–
–
149.5
133.0
142.4
125.0
124.6
129.0
131.9
128.5
146.3
–
–
–
–
159.9
131.6
139.5
118.2
125.2
122.7
131.1
115.0
138.1
30.0
–
–
–
160.2
130.2
140.8
118.2
125.5
122.9
131.6
115.2
138.3
30.2
–
–
–
159.7
131.5
140.3
118.3
126.0
122.9
132.0
115.2
138.8
30.2
187.7
119.2
128.3
123.9
137.0
116.6
141.3
46.0
–
–
–
–
–
–
8.20
7.80
7.90
8.01
–
8.27
7.86
7.95
8.07
–
8.29
7.88
8.00
8.13
–
7.98
7.40
7.70
7.60
–
8.02
7.42
7.73
7.64
–
8.09
7.46
7.80
7.70
–
8a
10(N)
5.48
–
–
–
3.69
3.71
3.72
5.23a
–
20(N)
136.1
126.3
128.8
127.4
35.6
26.8
22.3
13.7
–
–
–
–
–
–
–
–
30.9
29.9
22.3
13.7
–
–
–
–
–
4.52
–
7.22
7.34
7.26
–
–
–
–
–
–
–
–
–
7.46
7.60
7.54
–
–
–
–
–
–
–
–
–
–
–
28.6
29.5
22.3
13.9
–
–
–
–
–
4.18
–
7.34
7.29
7.21
–
–
–
–
–
–
–
–
7.38
7.50
7.46
–
–
–
–
30(N)
7.36
7.41
7.33
2.39
1.33
1.33
0.89
–
40(N)
50(N)
–
–
–
–
–
10(C‐3)
20(C‐3)
30(C‐3)
40(C‐3)
50(C‐3)
3.03
1.62
1.48
0.98
–
36.4
137.1
127.0
128.7
126.6
135.6
129.6
128.6
128.8
–
2.79
1.52
1.39
0.95
–
34.2
138.5
128.4
128.4
126.3
135.1
130.0
127.9
128.0
–
5g
5h
5i
5j
5k
5l
5m
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
Position
2
3
4
4a
5
6
7
8
–
–
–
159.3
131.5
140.5
118.6
126.4
122.9
132.2
115.0
137.8
37.8
12.7
–
–
–
–
–
8.03
7.37
7.60
7.48
–
160.3
131.7
140.2
118.6
125.5
122.9
131.1
115.5
137.3
45.6
136.6
126.5
128.8
127.2
28.7
–
–
–
–
160.1
131.5
140.9
118.7
126.3
123.1
132.0
115.6
138.1
45.7
136.5
126.7
128.8
127.3
135.0
130.1
128.0
128.1
–
–
–
–
160.3
128.1
140.4
118.2
125.1
123.0
130.8
115.7
139.0
137.7
129.0
130.2
129.0
–
–
–
–
–
8.06
7.39
7.52
6.59
–
160.0
132.1
140.3
118.2
125.2
123.0
131.0
115.7
139.1
137.6
129.0
130.2
129.0
–
–
–
–
–
8.08
7.42
7.55
6.62
–
160.2
130.7
141.7
118.2
125.5
123.1
131.3
115.8
139.3
138.4
128.5
130.2
129.1
–
–
–
–
159.7
131.9
141.1
118.3
126.0
123.1
131.9
115.8
139.8
137.6
129.0
130.2
129.0
–
–
–
–
8.11
7.43
7.78
7.74
–
4.37
1.30
–
–
–
–
7.38
7.50
7.45
–
8.13
7.42
7.70
7.53
–
5.63
–
7.31
7.36
7.30
–
8.05
7.40
7.51
6.61
–
8.16
7.45
7.60
6.67
–
8a
10(N)
20(N)
30(N)
40(N)
50(N)
10(C‐3)
20(C‐3)
30(C‐3)
40(C‐3)
50(C‐3)
5.61
–
–
–
–
–
7.39
7.69
7.62
–
2.53
–
–
–
–
7.39
7.69
7.61
–
2.83
1.59
1.43
0.96
–
7.42
7.68
7.61
–
4.21
–
7.38
7.32
7.24
7.45
7.69
7.63
–
7.23
7.35
7.26
2.88
1.60
1.43
0.97
–
–
–
135.10
130.1
128.0
128.1
–
14.9
–
–
–
–
28.4
29.6
22.4
13.9
33.9
–
134.6
130.2
128.0
128.2
–
29.6
22.4
13.9
–
7.47
7.52
7.47
–
137.6
128.4
128.5
126.3
7.45
7.52
7.43
–
–
aProchiral methylene group.
phosphoryl chloride under aerobic conditions for 20 hours,
crystal violet was obtained in 40% yield. This result shows that
under these reaction conditions DMA oxidizes to N‐methylfor-
manilide and the subsequent Vilsmeier‐Haack reaction between
these two compounds generates N,N‐dimethylbenzaldehyde
[25]. This compound subsequently reacts with two molecules
of DMA and, under aerobic conditions, crystal violet is
produced.
Highly hydrophilic products besides 4 and 5 were
obtained in small quantities from the reaction of 1e−l with
phosphoryl chloride (Table 2). The IR spectra of these
compounds showed two broad bands of low intensity
approximately in the ranges of 2320−2360 and 2560
−2800 cm−1. These bands correspond to the OH stretching
vibrations of phosphoric acid esters, which usually appear
in the regions of 2100−2300 and 2560−2700 cm−1 [26].
The IR and analytical data suggest the presence of phos-
phoric acid fragment in the structure of the isolated com-
pounds. Therefore, we suggest structure 7 for those
compounds. In the electron impact mass spectra of com-
pounds 7, a higher peak appears at a m/z that corresponds
to 4‐hydroxyderivatives 1. The course of the fragmentation
is also almost identical to that of compounds 1. It stands to
reason that esters 7 decompose during EI‐MS acquisition
Journal of Heterocyclic Chemistry
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O. Rudolf, V. Mrkvička, A. Lyčka, M. Rouchal, and A. Klásek
Vol 50
Table 4
and produces 1. Hence, a softer ionization technique,
namely electrospray, was used to obtain the proper MS
data for compounds 7. The ESI‐IT‐MS experiments were
carried out in both positive and negative scanning mode.
However, due to the acidic character of esters 7, the nega-
tive ionization was more suitable for the MS analyses. In
the first‐order mass spectra, one dominant signal at m/z
corresponding to the [M–H]– ion was accompanied by m/z
signals about twice as high (exactly [2M–H]– and [2M–2H
+Na]–) for all examined structures. Moreover, the peak
corresponding to the [2M–H–H3PO4]– ion was observed in
the negative ESI mass spectra of compounds 7a–c, 7e, and
7j–m.
To the best of our knowledge, compounds 7 have not
been described in the literature. Only some phosphoric acid
tri‐esters, based on the 4‐hydroxy‐2‐quinolone scaffold,
have been reported. (3‐Chloro‐2‐oxo‐1,2‐dihydroquinolin‐
4‐yl) dimethyl and diethyl phosphates, prepared by the re-
action of 3,3‐dichloroquinoline‐2,4(1H,3H)‐dione with
their corresponding trialkyl phosphites, were noted for their
anticholinesterase activity [27]. Several 1,3‐disubstituted
(2‐oxo‐1,2‐dihydroquinolin‐4‐yl) diethyl phosphates,
prepared by the Perkow reaction of fluorinated 3‐acyloxy-
quinoline‐2,4‐diones with triethyl phosphate, exhibit sig-
nificant cytostatic activity toward leukemic K‐562 cells
and breast carcinoma MCF‐7 cells [28].
Preparation of dihydrogen phosphates 7 from 4‐hydroxy‐2‐quinolones 1
(Method C).
Substituents
Product
Entry
1
R1
R2
(yield, %)a
1
2
3
4
5
6
7
8
9
10
11
12
13
a
H
H
H
Bu
Bn
Ph
Bu
Bn
Ph
Ph
Bu
Ph
Me
Bu
Bn
Ph
7a (54)
7b (49)
7c (51)
7d (34)
7e (39)
7f (48)
7g (34)
7h (37)
7i (32)
7j (64)
7k (56)
7l (83)
7m (78)
b
c
d
e
f
g
h
i
Me
Me
Me
Et
Bn
Bn
Ph
Ph
Ph
Ph
j
k
l
m
aRefers to isolated percent yield of pure compound.
structures. Proton spectra were assigned using gs‐COSY.
Protonated carbons were assigned by gs‐HMQC and qua-
ternary carbons by gs‐HMBC. The J(31P, 13C) coupling
n
constants were used to assign the quaternary carbons situ-
ated near the phosphorus atom. 31P NMR chemical shifts
in compounds 7 are very similar, being in the range −5.1
to −5.7 ppm. All NMR data are compiled in Table 5.
Therefore, we decided to prepare phosphoric esters 7
through a route that would provide higher yields. We
found that the reaction of 1 with phosphoryl chloride at
low temperature in the presence of pyridine leads to the
formation of desired compounds 7. According to the TLC
analysis, the conversion of 1 to 7 is almost quantitative.
Unfortunately, isolation and especially crystallization of
the product are troublesome in some cases. One contribut-
ing cause is the low hydrolytic stability of compounds 7,
which convert to 1 in alkaline media and even in an acetic
acid solution at elevated temperature. Nevertheless, most
of the compounds 7 were obtained in moderate to good
yields (Table 4).
CONCLUSIONS
In conclusion, we would like to emphasize that our
results reveal new information about the behavior of reactive
quinoline‐2,4‐dione systems. We found that 3‐chloroquinoli-
nediones do not react with phosphoryl chloride. However,
in the presence of DMA, the chlorine atom is split‐off from
these compounds and 2,4‐dichloroquinolines and/or 4‐
chloroquinoline‐2‐ones are formed. We have prepared several
new compounds 4 and 5 in good yield.
A significant result of our experiments is the isolation of
minor compounds 7, whose formation during the reaction
of 1 with phosphoryl chloride has not been previously de-
scribed. We outlined a simple procedure for the preparation
of compounds 7, which are suitable for biological testing
as well as further synthetic elaboration.
The 1H, 13C, and 31P NMR spectra of all prepared
compounds 7a−m are in agreement with the proposed
Scheme 2
EXPERIMENTAL
General. Melting points were determined on a Kofler block or
Gallencamp apparatus. IR (KBr) spectra were recorded on a
Mattson 3000 spectrophotometer. NMR spectra were recorded
1
on a Bruker Avance spectrometer (500.13 MHz for H, 125.76
MHz for 13C), and on a Bruker Avance II 400 spectrometer
1
(161.97 MHz for 31P) in DMSO‐d6. H and 13C chemical shifts
are given on the δ scale (ppm) and are referenced to internal
TMS (δ = 0.0). 31P chemical shifts were referred to external
neat 85% H3PO4 in a co‐axial capillary (δ = 0.0). All 2D
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Synthesis of Novel Phosphoric Acid Esters of 4‐Hydroxy‐2‐quinolone
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O. Rudolf, V. Mrkvička, A. Lyčka, M. Rouchal, and A. Klásek
Vol 50
experiments (gradient‐selected (gs)‐COSY, NOESY, gs‐HMQC,
gs‐HMBC) were performed using manufacturer’s software. The
positive‐ion EI mass spectra were measured on a Shimadzu QP‐
2010 instrument within the mass range m/z = 50–600 using
direct inlet probe (DI). Samples were dissolved in
dichloromethane (30 μg/mL), and 10 μL of the solution was
evaporated in DI cuvette at 50°C. The ion source temperature
was 200°C; the energy of electrons was 70 eV. Only signals
exceeding relative abundance of 5% are listed. The ESI‐MS
solution of sodium hydroxide (10%). The precipitated product
was filtered off with suction, washed with water, dried, and
recrystallized from an appropriate solvent. In case when the
product was of pasty consistence, the mixture was extracted
with chloroform (three times, 30 mL each). After evaporation,
the residue was crystallized from an appropriate solvent or
column chromatographed. In all cases, the mother liquors were
separated by column chromatography. Compounds 7 were
isolated by the extraction of the chloroform solutions of crude
reaction product or mother liquors with aqueous solution (6%)
of sodium hydrogen carbonate. The aqueous extract was
acidified with 5% hydrochloric acid and extracted with
chloroform. The chloroform solution was dried, filtered,
evaporated in vacuo, and crystallized to give product 7.
spectra were recorded on an amaZon
X ion‐trap mass
spectrometer (Bruker Daltonics, Bremen, Germany) equipped
with an electrospray ion source. Individual samples were
infused into the ESI source as methanol solutions via a syringe
pump at a constant flow rate of 4 μL min−1. The other
instrument conditions were as follows: electrospray voltage 4.2
kV, drying gas temperature 220°C, drying gas flow 6.0 dm3
min–1, nebulizer pressure 8.0 psi. Nitrogen was used as
nebulizing as well as drying gas. Column chromatography was
carried out on silica gel (Merck, grade 60, 70–230 mesh) using
chloroform/ethanol (in ratios from 99:1 to 8:2) (S1), successive
mixtures of benzene/ethyl acetate (in ratios from 99:1 to 8:2)
(S2) and isopropylalcohol/acetic acid (9:1) (S3). Reactions as
well as the course of separation and also the purity of
substances were monitored by TLC (elution systems benzene/
ethyl acetate (4:1) (S4), chloroform/ethanol (9:1 and 1:1) (S5
and S6), chloroform/ethyl acetate (7:3) (S7), and
tetrahydrofuran/acetic acid (4:1) (S8) on Alugram® SIL G/
UV254 foils (Macherey‐Nagel). Elemental analyses (C, H, N)
were performed with a EA Flash EA 1112 Elemental Analyzer
(Thermo Fisher Scientific).
Preparation of 3‐alkyl/aryl‐3‐chloroquinolin‐2,4(1H,3H)‐
diones (2). Starting compounds 2a−m were prepared by the
reaction of 3‐alkyl/aryl‐4‐hydroxyquinolin‐2‐ones 1 with sulfuryl
chloride according to the procedure described in literature [18,19].
One novel derivative (2h) was prepared.
1‐Benzyl‐3‐butyl‐3‐chloroquinoline‐2,4(1H,3H)‐dione (2h).
Compound was prepared from 1h and sulfuryl chloride in 63%
yield. Colorless crystals, mp 69−72°C (cyclohexane); IR
(KBr) ν: 2953, 2930, 2969, 1706, 1678, 1599, 1488, 1467,
1360, 1304, 1207, 1167, 950, 774, 755, 731, 698, 662, 626,
526 cm−1; For NMR spectra see Table 3; EI‐MS (m/z, %) 341
(M+, 3), 307 (8), 306 (17), 285 (8), 265 (7), 174 (9), 92 (9),
91 (100), 65 (9). Anal. Calcd. for C20H20ClNO2: C, 70.27; H,
5.90; N, 4.10. Found: C, 70.31; H, 5.92; N, 4.10.
General procedure for the reaction of compounds 1, 2 and
6 with phosphoryl chloride. Method A. N,N‐Dimethylaniline
(DMA, 1.5 mL) was added to a solution of starting compound
(3 mmol) in phosphoryl chloride (15 mL) and the reaction
mixture was heated under reflux for the time given in Table 1.
After cooling, the reaction mixture was poured onto crushed ice
(100 g) and extracted with chloroform (3 × 50 mL). The extract
was filtered through a short column of silica gel to removing of
crystal violet, the filtrate was evaporated to dryness and the
residue was extracted with benzene or ethyl acetate. The extract
was evaporated to dryness and the residue was crystallized from
an appropriate solvent or separated by column chromatography.
Method A1. Appropriate starting compound (2 mmol) was
dissolved in phosphoryl chloride (10 mL) and the mixture was
heated under reflux for the time given in Table 2. After cooling,
phosphoryl chloride was evaporated, the residue was mixed
with crushed ice (100 g) and, after 10 min of stirring, the
acidity was adjusted to pH 5 by successive addition of a
Method B. The reaction was carried out analogously to
Method A, but the addition of DMA was omitted.
3‐Butyl‐2,4‐dichloroquinoline (4a). Compound was prepared
from 1a, 1h (Method A1, Table 2), 2a and 2d (Method B,
Table 1). Colorless crystals, mp 47−49°C (hexane); IR (KBr) ν:
2961, 2924, 2858, 1571, 1557, 1482, 1466, 1454, 1384, 1367, 1328,
1303, 1277, 1219, 1149, 1141, 1087, 1048, 961, 916, 802, 764, 724,
707, 699, 598 cm−1; For NMR see Table 3; EI‐MS (m/z, %): 255
(23), 254 (M+, 5), 253 (36), 218 (8), 214 (13), 213 (18), 212 (65),
211 (28), 210 (100), 197 (7), 176 (22), 175 (9), 174 (31), 153 (8),
152 (11), 151 (5), 141 (7), 140 (46), 139 (10), 127 (10), 126 (11),
125 (8), 114 (16), 113 (18), 101 (6), 99 (8), 89 (6), 88 (8), 87 (9), 77
(7), 76 7), 75 12), 74 (6), 73 (6), 63 (18), 62 (7), 51 (9), 43 (21), 41
(25). Anal. Calcd. for C13H13Cl2N: C, 61.43; H, 5.16; N, 5.51.
Found: C, 61.28; H, 5.15; N, 5.55.
3‐Benzyl‐2,4‐dichloroquinoline (4b). Compound was prepared
from 1b (Method A1, Table 2), 2b, and 2e (Method B, Table 1).
Colorless crystals, mp 71−72°C (hexane); For 4b, mp 72−73°C
(ethanol) was referred [1]; For NMR see Table 3; EI‐MS (m/z,
%): 289 (14), 288 (5), 287 (22), 254 (6), 253 (6), 252 (19), 251
(9), 250 (7), 217 (25), 216 (100), 215 (9), 214 (13), 189 (8),
126 (13), 125 (6), 113 (6), 108 (27), 95 (15), 94 (6), 89 (6), 63
(11), 51 (11). Anal. Calcd. for C16H11Cl2N: C, 66.69; H, 3.85;
N, 4.86. Found: C, 66.75; H, 3.83; N, 4.89.
2,4‐Dichloro‐3‐phenylquinoline (4c). Compound was
prepared from 1c,f,g,i, (Method A1, Table 2), 2c,f,g, and 2i
(Method B, Table 1). Colorless crystals, mp 85−87°C (hexane);
For 4c, mp 90°C was referred [29]; For NMR see Table 3; EI‐MS
(m/z, %): 276 (11), 275 (69), 274 (18), 273 (100), 240 (15),
239 (9), 238 (45), 204 (10), 203 (60), 202 (26), 201 (19), 177
(9), 176 (27), 175 (17), 174 (7), 151 (11), 150 (13), 149 (7),
136 (10), 126 (6), 123 (5), 120 (9), 119 (24), 105 (5), 101
(23), 99 (11), 98 (8), 88 (45), 87 (20), 86 (7), 77 (9), 76 (9),
75 (26), 74 (15), 63 (11), 62 (9), 51 (19), 50 (11). Anal.
Calcd. for C15H9Cl2N: C, 65.72; H, 3.31; N, 5.11. Found: C,
65.91; H, 3.32; N, 5.14.
3‐Butyl‐4‐chloro‐1‐methylquinolin‐2‐one (5d). Compound was
prepared from 1d (Method A, Table 2) in 93% yield. Colorless
crystals, mp 67−70°C (hexane); IR (KBr) ν: 3079, 3029, 2956,
2929, 2859, 1633, 1592, 1573, 1497, 1461, 1412, 1351, 1316,
1299, 1280, 1253, 1216, 1167, 1107, 1087, 1047, 1019, 943,
904, 812, 777, 753, 733, 662, 609, 593, 504 cm−1; For NMR
see Table 3; EI‐MS (m/z, %): 249 (M+, 11), 234 (8), 222 (10),
221 (5), 220 (31), 215 (8), 214 (48), 209 (33), 208 (17), 207
(100), 206 (20), 179 (7), 178 (11), 172 (7), 144 (8), 143 (9),
142 (8), 140 (6), 128 (13), 116 (6), 115 (20), 102 (6), 101 (8),
89 (5), 77 (5). Anal. Calcd. for C14H16ClNO: C, 67.33; H, 6.46;
N, 5.61. Found: C, 67.44; H, 6.46; N, 5.65.
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3‐Benzyl‐4‐chloro‐1‐methylquinolin‐2‐one (5e). Compound
was prepared from 1e in 41% yield besides 7e (Method A1,
Table 2). Colorless crystals, mp 133−138°C (benzene‐ethyl
acetate). For 5e, mp 122°C (ligroin) was reported [16]; IR
(KBr) ν: 3059, 3026, 1638, 1613, 1591, 1567, 1492, 1453,
1349, 1333, 1314, 1290, 1211, 1091, 1047, 1027, 950, 937,
880, 849, 757, 736, 695, 645, 620, 592 cm−1; For NMR see
Table 3; EI‐MS (m/z, %): 285 (34), 284 (23), 283 (M+, 100),
282 (12), 267 (10), 266 (25), 249 (14), 248 (77), 247 (19), 233
(12), 232 (16), 231 (10), 220 (7), 218 (10), 217 (7), 216 (6),
205 (7), 204 (16), 203 (8), 189 (5), 178 (7), 177 (5), 142 (10),
128 (5), 124 (34), 116 (6), 115 (13), 108 (9), 102 (13), 101 (9),
95 (6), 91 (11), 88 (7), 77 (7), 75 (6), 65 (8), 63 (7), 51 (6).
Anal. Calcd. for C17H14ClNO: C, 71.96; H, 4.97; N, 4.94.
Found C, 72.03; H, 4.93; N, 4.81.
4‐Chloro‐1‐methyl‐3‐phenylquinolin‐2‐one (5f). Compound
was prepared from 1f in 57% yield besides 4c and 7f (Method
A1, Table 2). Colorless crystals, mp 121−122°C (benzene‐
cyclohexane); For 5f, mp 106°C (aqueous ethanol) was
reported [15]; IR (KBr) ν: 1630, 1608, 1560, 1586, 1567,
1496, 1458, 1444, 1330, 1313, 1239, 1062, 965, 844, 754,
745, 697, 668, 609, 524 cm‐1; For NMR see Table 3; EI‐MS
(m/z, %): 271 (21), 270 (42), 269 (64), 268 (M+, 100), 253 (6),
205 (6), 204 (12), 190 (8), 176 (6), 117 (25), 102 (13), 89 (6),
88 (9), 76 (5). Anal. Calcd. for C16H12ClNO: C, 71.25; H,
4.48; N, 5.19. Found: C, 71.38; H, 4.51; N, 5.13.
4‐Chloro‐1‐ethyl‐3‐phenylquinolin‐2‐one (5g). Compound
was prepared from 1g in 60% yield besides 4c and 7g (Method
A1, Table 2). Colorless crystals, mp 124−125°C (benzene‐
cyclohexane); IR (KBr) ν: 3050, 2984, 1635, 1609, 1601, 1587,
1564, 1488, 1452, 1374, 1337, 1309, 1294, 1216, 958, 921, 844,
818, 782, 752, 695, 662, 612 cm−1; For NMR see Table 3;
EI‐MS (m/z, %): 285 (20), 284 (31), 283 (M+, 60), 282 (66), 257
(13), 256 (36), 255 (38), 254 (100), 238 (10), 220 (7), 219 (14),
205 (5), 204 (16), 203 (7), 191 (6), 190 (15), 176 (9), 165 (9),
164 (6), 163 (6), 110 (10), 102 (13), 96 (5), 89 (9), 88 (11), 75
(5), 63 (5). Anal. Calcd. for C17H14ClNO: C, 71.96; H, 4.97; N,
4.94. Found: C, 71.95; H, 4.98; N, 4.81.
1‐Benzyl‐3‐butyl‐4‐chloroquinolin‐2‐one (5h). Compound
was prepared from 1h in 25% yield besides 4a and 7h (Method
A1, Table 2). Colorless crystals, mp 77−79°C (hexane‐
cyclohexane); IR (KBr) ν: 2955, 2925, 2859, 1634, 1614, 1593,
1567, 1492, 1462, 1425, 1320, 1129, 1076, 934, 754, 703, 649,
458 cm‐1; For NMR see Table 3; EI‐MS (m/z, %): 325 (M+, 9),
290 (13), 285 (5), 283 (16), 194 (10), 192 (30), 92 (8), 91 (100),
65 (12). Anal. Calcd. for C20H20ClNO: C, 73.72; H, 6.19; N, 4.30.
Found: C, 73.85; H, 6.20; N, 4.42.
696, 666, 513 cm−1
; For NMR see Table 3; EI‐MS
(m/z, %): 271 (26), 270 (44), 269 (M+, 79), 268 (100), 234
(7), 233 (5), 206 (6), 205 (8), 204 (23), 140 (12), 135 (6),
128 (9), 117 (9), 103 (8), 102 (36), 101 (12), 89 (7), 88
(7), 77 (20), 76 (6), 75 (6), 63 (7), 51 (16). Anal. Calcd.
for C16H12ClNO: C, 71.25; H, 4.48; N, 5.19. Found: C,
71.48; H, 4.48; N, 4.97.
3‐Butyl‐4‐chloro‐1‐phenylquinolin‐2‐one (5k). Compound was
prepared from 1k in 65% yield (Method A1, Table 2). Colorless
crystals, mp 98−99°C (hexane); IR (KBr), ν: 2952, 2927, 2863,
1640, 1612, 1595, 1564, 1492, 1455, 1350, 1328, 1302, 1277,
1250, 1219, 1128, 1105, 1078, 1025, 977, 925, 908, 856, 813,
778, 753, 697, 671, 658, 631, 559, 518 cm−1; For NMR see
Table 3; EI‐MS (m/z, %): 311 (M+, 8), 296 (11), 284 (10), 283
(7), 282 (29), 277 (16), 276 (78), 271 (33), 270 (37), 269 (100),
268 (65), 240 (9), 217 (7), 205 (10), 204 (34), 203 (6), 128 (5),
102 (9), 77 (17), 51 (10). Anal. Calcd. for C19H18ClNO: C,
73.19; H, 5.82; N, 4.49. Found: C, 73.37; H, 5.86; N, 4.71.
3‐Benzyl‐4‐chloro‐1‐phenylquinolin‐2‐one (5l). Compound
was prepared from 1l in 36% yield besides 7l (Method A1,
Table 2). Colorless crystals, mp 170−173 °C (benzene‐hexane).
For 5l, mp 146–148°C was reported [16]; IR (KBr), ν: 3080,
3026, 3001, 2934, 1645, 1609, 1596, 1563, 1492, 1452, 1428,
1349, 1328, 1291, 1247, 1215, 1186, 1162, 1108, 1073, 1029,
977, 942, 923, 901, 880, 827, 773, 755, 745, 735, 696, 651,
623, 511, 584, 519 cm−1; For NMR see Table 3; EI‐MS (m/z,
%): 348 (8), 347 (36), 346 (M+, 29), 345 (100), 344 (15), 328
(12), 311 (18), 310 (76), 309 (15), 308 (12), 280 (12), 266 (11),
232 (13), 218 (6), 217 (5), 216 (14), 205 (5), 204 (23), 203 (8),
173 (6), 155 (6), 139 (8), 134 (9), 91 (9), 77 (20), 51 (13).
Anal. Calcd. for C22H16ClNO: C, 76.41; H, 4.66; N, 4.05.
Found: C, 76.58; H, 4.71; N, 4.08.
1,3‐Diphenyl‐4‐chloroquinolin‐2‐one (5m). Compound was
prepared from 1m in respective yields 80% (Method A1) or
79% (Method B, Table 2); Colorless crystals, mp 186−188°C
(benzene‐hexane); For 5m, mp 164−166°C was reported [15];
IR (KBr) ν: 1652, 1605, 1589, 1560, 1489, 1451, 1349, 1310,
1292, 1261, 1224, 1177, 1151, 1056, 1017, 970, 914, 898, 837,
806, 780, 763, 745, 734, 698, 671, 634, 606, 567, 521 cm−1
;
For NMR see Table 3; EI‐MS (m/z, %): 333 (25), 332 (M+, 47),
331 (73), 330 (100), 268 (5), 267 (17), 266 (14), 265 (8), 195
(5), 165 (12), 164 (5), 148 (8), 134 (20), 133 (15), 121 (8), 77
(11), 51 (9). Anal. Calcd. for C21H14ClNO: C, 76.02; H, 4.25;
N, 4.22. Found: C, 76.08; H, 4.21; N, 4.28.
General procedure for the preparation of dihydrogen
phosphates 7 from 4‐hydroxy‐2‐quinolones 1 (Method C). A
stirred suspension of compound 1 (2 mmol) in pyridine (0.485
mL, 6 mmol) and acetonitrile (5 mL) was cooled to 0°C and
phosphoryl chloride (0.92 g, 0.559 mL, 6 mmol) was added in
one portion. The mixture was stirred at 0°C for 1 h and then
warmed slowly to the room temperature. In most cases, the
suspension changed into a turbid solution. After overnight
stirring, water (1 mL) was added under cooling and the mixture
was evaporated to dryness in vacuo. The residue was crushed
with water (10 mL), the precipitate was filtered off, dried, and
recrystallized from an appropriated solvent. In several cases (7b,
7g), the precipitate was purified by trituration with the solution
of sodium hydrogen carbonate (6%); the solution was filtered,
the filtrate was acidified with concentrated hydrochloric acid,
the precipitate was filtered off and recrystallized from
appropriate solvent. If the precipitate was of gummy or pasty
character (7d), it was decanted three times with water, dried,
1‐Benzyl‐4‐chloro‐3‐phenylquinolin‐2‐one (5i). Compound
was prepared from 1i in 39% yield besides 4c and 7i (Method
A1, Table 2). Colorless crystals, mp 197−199°C (benzene‐
cyclohexane); IR (KBr) ν: 2956, 1635, 1608, 1600, 1588, 1565,
1489, 1453, 1444, 1312, 1064, 1028, 948, 906, 781, 757, 708,
694, 671, 662, 639, 535 cm−1; For NMR see Table 3; EI‐MS
(m/z, %): 347 (15), 346 (19), 345 (M+, 44), 344 (32), 310 (12),
204 (16), 190 (5), 92 (8), 91 (100), 65 (16), 57 (5). Anal. Calcd.
for C22H16ClNO: C, 76.41; H, 4.66; N, 4.05. Found: C, 76.54;
H, 4.69; N, 3.94.
4‐Chloro‐3‐methyl‐1‐phenylquinolin‐2‐one (5j). Compound
was prepared from 1j besides 7j in 59% yield (Method A1,
Table 2). Colorless crystals, mp 223−224°C (ethyl acetate);
IR: 3069, 3056, 2923, 1645, 1613, 1593, 1567, 1491,
1452, 1351, 1322, 1296, 1216, 1121, 1020, 911, 767, 753,
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and recrystallized from an appropriate solvent or column
chromatographed using solvent system S1 or S3. The mother
liquors were extracted with ethyl acetate, the extract was dried,
evaporated to dryness and column chromatographed using
solvent system S3. The results are given in Table 4.
3‐Butyl‐1,2‐dihydro‐2‐oxoquinolin‐4‐yl dihydrogen phosphate
(7a). Compound was prepared from 1a in 54% yield (Method C,
Table 4); Colorless crystals, mp 226−230°C (benzene‐DMF); IR
(KBr) ν: 2960, 2934, 2863, 2356br, 1649, 1606, 1526, 1467, 1449,
1331, 1274, 1220, 1187, 1127, 1071, 940, 886, 794, 755, 650, 625,
557, 459 cm‐1; For NMR see Table 5; EI‐MS (m/z, %): 217 (19),
202 (8), 200 10), 188 (26), 176 (11), 175 (100), 174 (38), 161 (14),
120 (21), 119 (9), 115 (5), 92 (18), 77 (14), 65 (11), 55 (23), 44
(10). ESI‐MS (m/z, %): 615.1 [2M–2H+Na]– (5), 593.1 [2M–H]–
(83), 495.2 [2M–H–H3PO4]– (24), 476 (24), 296.1 [M–H]– (100).
Anal. Calcd. for C13H16NO5P: C, 52.53; H, 5.43; N, 4.71. Found:
C, 52.57; H, 5.52; N, 4.88.
3‐Benzyl‐1,2‐dihydro‐2‐oxoquinolin‐4‐yl dihydrogen phosphate
(7b). Compound was prepared from 1b in 49% yield (Method C,
Table 4). Colorless crystals, mp 246−250°C (DMF‐benzene); IR
(KBr) ν: 3427, 3067, 3030, 2948, 2799, 2362br, 1650, 1604, 1529,
1494, 1455, 1379, 1334, 1299, 1275, 1220, 1185, 1133, 1100, 944,
895, 788, 774, 759, 735, 702, 677, 650, 625, 556, 526 cm−1; For
NMR see Table 5; EI‐MS (m/z, %): 252 (18), 251 (100), 250 (26),
235 (6), 234 (32), 222 (7), 204 (8), 174 (8), 173 (6), 172 (7), 146
(18), 131 (23), 125 (10), 124 (5), 120 (16), 103 (13), 93 (6), 92
(18), 91 (25), 90 (8), 89 (7), 77 (22), 76 (7), 65 (16), 63 (7), 51
(11); ESI‐MS (m/z, %): 683.1 [2M–2H+Na]– (5), 661.1 [2M–H]–
(8), 563.2 [2M–H–H3PO4]– (88), 348.0 [2M–H+H2O]– (56), 330.1
[M–H]– (100). Anal. Calcd. for C16H14NO5P: C, 58.01; H, 4.26; N,
4.23. Found: C, 57.85; H, 4.40; N, 4.37.
1,2‐Dihydro‐2‐oxo‐3‐phenylquinolin‐4‐yl dihydrogen phosphate
(7c). Compound was prepared from 1c in 51% yield (Method C,
Table 4); Colorless crystals, mp 245−255°C (DMF‐benzene); IR
(KBr) ν: 2790, 2351br, 1674, 1607, 1537, 1502, 1447, 1366, 1334,
1287, 1127, 1110, 1074, 989, 938, 886, 863, 801, 760, 680, 651,
560, 500, 458 cm−1; For NMR see Table 5; EI‐MS (m/z, %): 238
(16), 237 (99), 236 (100), 180 (8), 121 (7), 120 (92), 119 (9), 118
(6), 92 (44), 91 (7), 90 (10), 89 (9), 77 (16), 76 (10), 65 (23), 64
(7), 63 (11), 51 (7), 44 (21); ESI‐MS (m/z, %): 655.1 [2M–2H
+Na]– (28), 633.1 [2M–H]– (49), 535.1 [2M–H–H3PO4]– (7), 316.1
[M–H]– (100). Anal. Calcd. for C15H12NO5P: C, 56.79; H, 3.81; N,
4.42. Found: C, 56.72; H, 3.85; N, 4.47.
respective yields 3% (Method A1, Table 2) or 39% (Method C,
Table 4). Colorless crystals, mp 170−185°C (water); IR (KBr) ν:
3030, 2946, 2931, 2853, 2320br, 1631, 1611, 1577, 1495, 1461,
1418, 1373, 1330, 1222, 1181, 1101, 1030, 959, 898, 867, 787,
751, 704, 627, 583, 532 cm−1; For NMR see Table 5; EI‐MS (m/z,
%): 266 (14), 265 (73), 264 (18), 248 (20), 236 (6), 160 (12), 149
(35), 134 (11), 131 (14), 128 (9), 127 (12), 126 (18), 125 (10), 124
(7), 123 (9), 115 (7), 114 (15), 113 (9), 112 (17), 111 (17), 110 (9),
109 (13), 104 (16), 103 (10), 100 (7), 99 (11), 98 (16), 97 (28), 96
(14), 95 (18), 91 (17), 86 (12), 85 (17), 84 (13), 83 (32), 82 (13), 81
(20), 77 (16), 74 (57), 73 (15), 72 (80), 71 (35), 70 (18), 69 (53), 68
(11), 67 (22), 60 (24), 59 (100), 58 (6), 57 (58), 56 (18), 55 (64), 54
(9), 45 (8), 44 (15), 43 (78), 42 (13), 41 (58); ESI‐MS (m/z, %):
711.1 [2M–2H+Na]– (13), 689.2 [2M–H]– (29), 591.2 [2M–H–
H3PO4]– (5), 344.1 [M–H]– (100). Anal. Calcd. for C17H18NO6P:
C, 56.20; H, 4.99; N, 3.86. Found: C, 56.39; H, 4.89; N, 3.72.
1,2‐Dihydro‐1‐methyl‐2‐oxo‐3‐phenylquinolin‐4‐yl dihydrogen
phosphate hydrate (7f). Compound was prepared from 1f in
respective yields 2% (Method A1, Table 2), or 48% (Method C,
Table 4). Colorless crystals, mp 212−217°C (water); IR (KBr) ν:
3642, 3313, 3198, 3083, 3057, 3034, 2948, 2660br, 2178br, 1629,
1590, 1574, 1450, 1460, 1418, 1367, 1285, 1237, 1142, 1103, 960,
882, 850, 805, 774, 754, 699, 683, 629, 563, 554, 493 cm−1; For
NMR see Table 5; EI‐MS (m/z, %): 251 (34), 250 (36), 162 (7),
155 (6), 139 (9), 134 (18), 127 (12), 125 (20), 111 (28), 105 (20),
97 (40), 96 (16), 95 (23), 85 (43), 71 (62), 57 (80), 43 (100); ESI‐
MS (m/z, %): 683.1 [2M–2H+Na]– (24), 661.1 [2M–H]– (41),
330.1 [M–H]– (100). Anal. Calcd. for C16H16NO6P: C, 55.02; H,
4.62; N, 4.01. Found: C, 54.86; H, 4.66; N, 4.11.
1,2‐Dihydro‐1‐ethyl‐2‐oxo‐3‐phenylquinolin‐4‐yl dihydrogen
phosphate hydrate (7g). Compound was prepared from 1g in
respective yields 3% (Method A1, Table 2) or 34% (Method C,
Table 4). Colorless crystals, mp 150−160°C (water); IR (KBr) ν:
3584, 3324, 3051, 2978, 2936, 2875, 2560, 2260br, 1640, 1620,
1606, 1593, 1499, 1456, 1368, 1305, 1222, 1144, 1113, 1085,
1040, 979, 884, 847, 819, 780, 753, 702, 681, 633, 533, 505 cm−1;
For NMR see Table 5; EI‐MS (m/z, %): 266 (16), 265 (88), 264
(82), 238 (6), 237 (55), 236 (100), 180 (7), 146 (10), 132 (10), 130
(16), 120 (39), 118 (10), 92 (11), 91 (15), 90 (8), 89 (6), 77 (30), 76
(8), 65 (8), 63 (6), 44 (24); ESI‐MS (m/z, %): 711.1 [2M–2H+Na]–
(12), 689.1 [2M–H]– (67), 641.2 [2M–H–48]– (17), 344.1 [M–H]–
(100), 296.1 [M–H–48]– (11). Anal. Calcd. for C17H18NO6P: C,
56.20; H, 4.99; N, 3.86. Found: C, 56.10; H, 4.99; N, 3.85.
3‐Butyl‐1,2‐dihydro‐1‐methyl‐2‐oxoquinolin‐4‐yl dihydrogen
phosphate (7d). Compound was prepared from 1d in 34% yield
(Method C, Table 4). Colorless crystals, mp 162−170°C (water); IR
(KBr) ν: 3396br, 2965, 2930, 2878, 2716br, 2359br, 2329, 2208br,
1631, 1610, 1557, 1503, 1457, 1420, 1376, 1332, 1292, 1226, 1154,
118, 1100, 1085, 1057, 958, 880, 811, 785, 755, 743, 684, 614, 547,
521 cm−1; For NMR see Table 5; EI‐MS (m/z, %): 231 (26), 216
(7), 214 (5), 203 (12), 202 (13), 190 (22), 189 (100), 188 (28), 186
(9), 160 (17), 146 (26), 145 (6), 136 (14), 135 (12), 134 (42), 133
(15), 132 (6), 131 (7), 128 (5), 127 (11), 126 (7), 125 (5), 119 (6),
118 (6), 117 (7), 114 (26), 112 (6), 106 (6), 104 (6), 99 (7), 97 (10),
96 (7), 91 (7), 84 (11), 83 (13), 82 (5), 79 (12), 77 (32), 72 (21), 71
(6), 70 (9), 69 (27), 68 (10), 67 (14), 63 (9), 60 (13), 59 (33), 57
(18), 55 (19), 53 (9), 45 (9), 43 (19), 41 (25), 40 (7); ESI‐MS (m/z,
%): 643.2 [2M–2H+Na]– (27), 621.2 [2M–H]– (37), 310.1 [M–H]–
(100). Anal. Calcd. for C14H18NO5P: C, 54.02; H, 5.83; N, 4.50.
Found: C, 54.22; H, 5.89; N, 4.56.
1‐Benzyl‐3‐butyl‐1,2‐dihydro‐2‐oxoquinolin‐4‐yl dihydrogen
phosphate (7h). Compound was prepared from 1h in 28%
yield besides 4a and 5h (Method A1, Table 2) or 37% (Method
C, Table 4). Colorless crystals, mp 220−225°C (ethyl acetate); IR
(KBr) ν: 3450, 3064, 3030, 2964, 2928, 2861, 2679, 2321, 2190,
1625, 1607, 1526, 1499, 1455, 1444, 1383, 1334, 1259, 1229,
1207, 1181, 1145, 1114, 1044, 1019, 959, 877, 799, 763, 734,
699, 648, 577, 552, 526 cm−1; For NMR see Table 5; EI‐MS (m/z,
%): 307 (20), 278 (5), 265 (26), 264 (9), 174 (37), 132 (5), 92 (9),
91 (100), 65 (10); ESI‐MS (m/z, %): 795.2 [2M–2H+Na]– (10),
773.2 [2M–H]– (12), 386.1 [M–H]– (100). Anal. Calcd. for
C20H22NO5P: C, 62.01; H, 5.72; N, 3.62. Found: C, 61.88; H,
5.67; N, 3.40.
1‐Benzyl‐1,2‐dihydro‐2‐oxo‐3‐phenylquinolin‐4‐yl dihydrogen
phosphate (7i). Compound was prepared from 1i in 4% yield
besides 4c and 5i (Method A1, Table 2) or 32% (Method C, Table
4). Colorless crystals, mp 235−247 °C (water); IR (KBr) ν: 3057,
3032, 2971, 2944, 2360br, 2340br, 1642, 1597, 1573, 1496, 1453,
1437, 1357, 1314, 1299, 1247, 1161, 1125, 1078, 1034, 971, 951,
3‐Benzyl‐1,2‐dihydro‐1‐methyl‐2‐oxoquinolin‐4‐yl dihydrogen
phosphate hydrate (7e). Compound was prepared from 1e in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of Novel Phosphoric Acid Esters of 4‐Hydroxy‐2‐quinolone
E109
880, 855, 823, 805, 766, 741, 731, 703, 644, 605, 557, 535, 516, 501
cm−1; For NMR see Table 5; EI‐MS (m/z, %): 327 (63), 326 (52), 236
(8), 220 (18), 152 (5), 91 (100), 77 (10), 65 (14), 46 (15), 45 (14), 44
(26); ESI‐MS (m/z, %): 835.1 [2M–2H+Na]– (8), 813.2 [2M–H]–
(24), 406.1 [M–H]– (100). Anal. Calcd. for C22H18NO5P: C, 64.87;
H, 4.45; N 3.44; Found: C, 64.81; H, 4.51; N, 3.58.
1,2‐Dihydro‐3‐methyl‐2‐oxo‐1‐phenylquinolin‐4‐yl dihydrogen
phosphate (7j). Compound was prepared from 1j besides 5j in 5%
yield (Method A1, Table 2) or 64% (Method C, Table 4). Colorless
crystals, mp 242−247°C (ethyl acetate); IR (KBr) ν: 2956, 2927,
2361, 2332br, 1633, 1596, 1552, 1492, 1459, 1387, 1366, 1343,
1313, 1249, 1223, 1168, 1157, 1141, 1108, 1043, 957, 844, 783,
756, 695, 683, 642, 569, 520 cm−1; For NMR see Table 5; EI‐MS
(m/z, %): 252 (17), 251 (100), 250 (90), 222 (9), 196 (11), 195 (34),
194 (9), 167 (27), 166 (12), 146 (11), 140 (6), 139 (7), 92 (9), 91
(7), 83 (9), 77 (23), 51 (14); ESI‐MS (m/z, %): 683.1 [2M–2H
+Na]– (12), 661.1 [2M–H]– (7), 563.2 [2M–H–H3PO4]– (13), 510.1
(23), 330.1 [M–H]– (100). Anal. Calcd. for C16H14NO5P: C, 58.01;
H, 4.26; N, 4.23. Found: C, 58.21; H, 4.33; N, 4.17.
3‐Butyl‐1,2‐dihydro‐2‐oxo‐1‐phenylquinolin‐4‐yl dihydrogen
phosphate hydrate (7k). Compound was prepared from 1k in 22%
yield besides 5k (Method A, Table 2) or 56% (Method C, Table 4).
Colorless crystals, mp 232−237°C (ethyl acetate); IR (KBr) ν:
3426br, 3083, 3065, 2958, 2937, 2920, 2876, 2830, 2668br,
2333br, 1621, 1499, 1457, 1437, 1378, 1349, 1334, 1316, 1288,
1266, 1251, 1228, 1202, 1161, 1110, 1075, 1052, 971, 952, 852,
804, 788, 772, 762, 748, 738, 697, 685, 676, 643, 568, 558, 525
cm−1; For NMR see Table 5; EI‐MS (m/z, %): 293 (16), 278 (10),
276 (11), 265 (7), 264 (32), 252 (17), 251 (100), 250 (60), 237 (9),
196 (16), 195 (11), 168 (7), 167 (9), 166 (6), 77 (16), 51 (6), 44 (7);
ESI‐MS (m/z, %): 767.2 [2M–2H+Na]– (13), 745.2 [2M–H]– (10),
647.3 [2M–H–H3PO4]– (33), 372.1 [M–H]– (100). Anal. Calcd. for
C19H22NO6P: C, 58.31; H, 5.67; N, 3.58. Found: C, 58.11; H, 5.45;
N, 3.40.
3‐Benzyl‐1,2‐dihydro‐2‐oxo‐1‐phenylquinolin‐4‐yl dihydrogen
phosphate hydrate (7l). Compound was prepared from 1l in 32%
yield besides 5l (Method A1, Table 2) or 83% (Method C, Table 4).
Colorless crystals, mp 178−182°C (DMF‐benzene); IR (KBr) ν:
3430br, 3083, 3026, 2975, 2934, 2802br, 2359br, 1643, 1599,
1570, 1494, 1457, 1372, 1326, 1305, 1263, 1226, 1158, 1090,
1048, 1021, 969, 956, 931, 820, 769, 756, 743, 705, 686, 643, 598,
570, 562, 545, 521 cm−1; For NMR spectra see Table 5; EI‐MS
(m/z, %): 328 (24), 327 (100), 326 (26), 310 (17), 250 (5), 248 (12),
222 (17), 196 (17), 195 (11), 167 (14), 166 (7), 131 (9), 103 (8), 92
(5), 91 (13), 77 (20), 51 (8), 44 (7); ESI‐MS (m/z, %): 835.2
[2M–2H+Na]– (11), 813.2 [2M–H]– (8), 715.3 [2M–H–H3PO4]–
(13), 406.2 [M–H]– (100). Anal. Calcd. for C22H20NO6P: C, 62.12;
H, 4.74; N, 3.29. Found: C, 62.11; H, 4.86; N, 3.47.
Isolation of crystal violet.
A. Chloroform extracts obtained using the Method A were fil-
tered through a short column of silica gel. The adsorbed blue
compound was obtained by washing of the column with eth-
anol, evaporating the filtrate to dryness and crystallization of
the residue from ethanol. In all cases, crystal violet, identical
to the authentic sample, was obtained in yields of 10–20%.
B. The mixture of DMA (5 mL, 39.4 mmol) and phosphoryl
chloride (50 mL) was heated to reflux for 20 h. The reaction
mixture was cooled, poured onto ice (100 g) and the mixture
was extracted with chloroform. After drying and evaporation
of the extract, the residue was crystallized from ethanol. Blue
1
crystals of mp 202−204°C (dec.), whose IR and H NMR
spectra were identical to those of crystal violet (C25H30N3Cl,
MW 407.98) [24] were obtained in 64% yield. For commer-
cial crystal violet (Aldrich), mp 205°C (dec.) is presented; EI‐
MS (m/z, %): 374 (13), 373 (47), 372 (16), 254 (21), 253
(100), 252 (68), 238 (7), 237 (26), 208 (8), 186 (10), 126
(18), 118 (6), 18 (8).
Reactions of compounds 2 with some nucleophiles.
A. A solution of 2‐sulfanylbenzothiazol (334.5 mg, 2 mmol) and
2f (571.5 mg, 2 mmol) in chloroform (50 mL) was stirred at
room temperature for 2 h and subsequently heated to reflux
for 3 h. After cooling, the mixture was evaporated to dryness
and the residue was column chromatographed. 4‐Hydroxy‐1‐
methyl‐3‐phenyl‐2‐quinolone (1f), (382 mg, 76%) of mp 223
−225°C (ethanol) and 2,20‐dithiobis(benzothiazole) (256 mg,
77%) of mp 177−178°C (benzene) were obtained. Both
compounds were identical in all respects to the authentic
specimens [22].
B. A solution of 2,5‐dimethylaniline (121 mg, 1 mmol) and 2f
(285.7 mg, 1 mmol) in chloroform (25 mL) was stirred at
room temperature for 1 h and subsequently heated to reflux
for 6 h. After cooling, deposited 2,5‐dimethylaniline hydro-
chloride (31%) was filtered with suction. The filtrate was
evaporated to dryness and column chromatographed on silica
gel. Besides starting compound 2f (42%), 3‐(2,5‐dimethylphe-
nylamino)‐1‐methyl‐3‐phenylquinoline‐2,4(1H,3H)‐dione (6f)
was obtained in 31% yield. Colorless crystals, mp 202−210°C
(benzene‐hexane); IR (KBr) ν: 3409, 3055, 3021, 2937, 2916,
2859, 1704, 1664, 1599, 1585, 1519, 1493, 1471, 1447, 1420,
1354, 1305, 1296, 1189, 1169, 1133, 1105, 1056, 1037, 1001,
914, 792, 765, 745, 735, 717, 699, 651, 588, 545, 529 cm−1;
For NMR see Table 5; EI‐MS (m/z, %): 371 (7), 370 (M+,
24), 337 (5), 222 (13), 209 (13), 208 (73), 194 (5), 193 (7),
126 (13), 120 (14), 114 (17), 112 (11), 105 (13), 104 (11),
103 (7), 98 (11), 97 (13), 96 (7), 95 (10), 91 (6), 86 (9), 84
(5), 83 (16), 82 (6), 81 (11), 79 (12), 77 (16), 74 (29), 73
(7), 72 (64), 71 (7), 70 (7), 69 (29), 67 (14), 60 (20), 59
(100), 57 (18), 56 (10), 55 (47), 54 (8), 44 (14), 43 (35), 41
(34). Anal. Calcd. for C24H22N2O2: C, 77.81; H, 5.99; N,
7.56. Found: C, 77.52; H, 6.04; N, 7.48.
1,2‐Dihydro‐1,3‐diphenyl‐2‐oxo‐quinolin‐4‐yl dihydrogen
phosphate (7m). Compound was prepared from 1m in 78%
yield (Method C, Table 4). Colorless crystals, mp 177−181°C
(DMF‐benzene); IR (KBr) ν: 3410br, 3132, 3096, 3065,
2840br, 1636, 1596, 1568, 1526, 1494, 1454, 1363, 1316,
1268, 1230, 1194, 1166, 1143, 1099, 1073, 1023, 963, 869,
824, 802, 787, 758, 700, 682, 641, 608, 576, 554, 522 cm‐1;
For NMR spectra see Table 5; EI‐MS (m/z, %): 314 (19), 313
(91), 312 (100), 256 (5), 196 (35), 195 (23), 167 (27), 166
(7), 157 (6), 152 (5), 139 (6), 127 (8), 105 (9), 89 (6), 77
(18), 51 (10), 46 (11), 45 (14), 44 (15); ESI‐MS (m/z, %):
807.2 [2M–2H+Na]– (22), 785.2 [2M–H]– (11), 687.3 [2M–H–
H3PO4]– (74), 392.2 [M–H]– (100). Anal. Calcd. for C21H16NO5P:
C, 64.13; H, 4.10; N, 3.56. Found: C, 63.91; H, 4.25; N, 3.53.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E110
O. Rudolf, V. Mrkvička, A. Lyčka, M. Rouchal, and A. Klásek
Vol 50
[3] Ahvale, A. B.; Prokopcova, H.; Sefcovicova, J.; Steinschifter,
W.; Taeubl, A. E.; Uray, G.; Stadlbauer, W. Eur J Org Chem 2008, 3, 563.
[4] Tagawa, Y.; Kawaoka, T.; Goto, Y. J Heterocyclic Chem
1997, 34, 1677.
[5] Nasr, M.; Drach, J. C.; Smith, S. H.; Shipman, C.; Burckhalter,
J. H. J Med Chem 1988, 31, 1347.
[6] Patel, H. V.; Vyas, K. A.; Fernandes, P. S. Indian J Chem Sect
B 1990, 29, 836.
[7] Leach, C. A.; Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S.
M.; Parsons, M. E.; Price, C. A.; Wiggal, K. J. J Med Chem 1992, 35,
1845.
[8] Jung, J.‐C.; Oh, S.; Kim, W.‐K.; Park, W.‐K.; Kong, J. Y.,
Park, O.‐S. J Heterocyclic Chem 2003, 40, 617.
[9] Mislow, K.; Koepfli, J. B. J Am Chem Soc 1946, 68, 1553.
[10] Lutz R. E.; Codington, J. F.; Rowlett R. J., Jr.; Deinet, A. J.;
Bailey, P. S. J Am Chem Soc 1946, 68, 1810.
[11] Capps, J. D. J Am Chem Soc 1947, 69, 176.
[12] Irwing, T. A.; Greene, J. L., Jr.; Peterson, J. G.; Capps, J. D. J
Am Chem Soc 1950, 72, 4069.
[13] de Arce M. D.; Greene, J. L., Jr.; Capps, J. D. J Am Chem Soc
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[14] Blankenstein, W. E.; Capps, J. D. J Am Chem Soc 1954, 76,
3211.
C. A solution of DMA (121 mg, 1 mmol) and compound 2 (1
mmol) in corresponding solvent (25 mL) was stirred at room
temperature for 1 h and subsequently heated to reflux for 4.5
h. After cooling, the solution was evaporated to dryness and
column chromatographed on silica gel. In all cases, besides
the starting compound, only compounds 1 were isolated from
the complex reaction mixture in the following yields: (a) in
chloroform: 1f (37%); (b) in acetic acid: 1c (81%); (c) in eth-
anol: 1c (12%); d) in toluene: 1f (6%).
Conversion of compounds 7 to 1.
A. A solution of 7m (50 mg) in 3% solution of potassium car-
bonate (5 mL) was stirred at 100°C for 4.5 h. After cooling
and acidification with concentrated hydrochloric acid, the
precipitate was filtered off with suction, washed with wa-
ter and dried. 1,3‐Diphenyl‐4‐hydroxyquinolin‐2‐one
(1m), mp 231−234°C, identical in all respect to the au-
thentic sample, was isolated in 41% yield.
B. A solution of 7m (101 mg) in acetic acid (10 mL) was
heated to reflux for 2.5 h. The reaction mixture was evaporated
to dryness and the residue was crystallized from ethanol.
Colorless crystals, mp 232−234°C (ethanol), identical in
all respects to 1m, were isolated in 30% yield.
[15] Stadlbauer, W.; Kappe, T. Monatsh Chem 1982, 113, 751.
[16] Stadlbauer, W. Monatsh Chem 1986, 117, 1305.
[17] Stadlbauer, W.; Laschober, R.; Kappe, T. Monatsh Chem
1991, 122, 853.
[18] Stadlbauer, W.; Lutschounig, H.; Schindler, G.; Kappe, T.
Monatsh Chem 1992, 123, 617.
[19] Kafka, S.; Klásek, A.; Polis, J.; Košmrlj, J. Heterocycles 2002,
57, 1659.
[20] Huffman, J. W. J Org Chem 1961, 26, 1470.
[21] Klásek, A.; Polis, J.; Mrkvička, V. J Heterocyclic Chem 2002,
39, 1315.
[22] Klásek, A.; Mrkvička, V. J Heterocyclic Chem 2003, 40, 747.
[23] Bell, D.; Eltoum, A. O. A.; O’Reilly, N. J.; Tipping, A. E. J
Fluorine Chem 1993, 64, 151.
[24] Spectral Database for Organic Compounds SDBS. National In-
stitute of Advanced Industrial Science and Technology: http://www.aist.
go.jp/RIODB/SDBS.
[25] Matsubara, H.; Yasuda, S.; Sugiyama, H.; Ryu, I.; Fujii, Y.;
Kita, K. Tetrahedron 2002, 58, 4071.
Acknowledgments. This study was supported by the Ministry of
Education, Youth and Sports of the Czech Republic (Grant No.
MSM 7088352101), the Czech Science Foundation (Grant No.
203/07/0320), and the internal grant of TBU in Zlín (No. IGA/
10/FT/10/D), funded from the resources of specific university
research. The authors thank Mrs. H. Geržová (Faculty of
Technology, Tomas Bata University in Zlín) for technical help.
[26] Sokrates, G. Infrared Characteristic Group Frequencies. Wiley:
Chichester, 1998; pp.177–187.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet