Formation of 6-chloro-4-phenyl-2-quinolone in reaction of dimethyl sulfate with 2-(acetylamino)-5-chlorobenzophenone under phase-transfer conditions [7]

Full text of DOI:10.1007/s11176-005-0037-0

Russian Journal of General Chemistry, Vol. 74, No. 9, 2004, pp. 1467 1468. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 9, 2004,
pp. 1579 1580.
Original Russian Text Copyright
2004 by Popova, Kulikov, Piotrovskii.
LETTERS
TO THE EDITOR
Formation of 6-Chloro-4-phenyl-2-quinolone in Reaction
of Dimethyl Sulfate with 2-(Acetylamino)-5-chlorobenzophenone
under Phase-Transfer Conditions
N. N. Popova, S. V. Kulikov, and L. B. Piotrovskii
KUPE Company, St. Petersburg, Russia
Research Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg, Russia
Received January 26, 2004
3
-Substituted 4-phenyl-2-quinolones exhibit a con-
containing a mixture of NaOH and K CO , as well
2 3
spicuous biologic activity [1], but the procedure of
their synthesis, developed in the referred work, is
unsuitable for preparing 3- unsubstituted derivatives,
such as 6-chloro-4-phenyl-2-quinolone (I) and its
N-methyl analog (II). At the same time, these com-
pounds can be prepared from 2-(acetylamino)-5-chloro-
benzophenone (III) [2] and 2-(N-acetyl-N-methyl-
amino)-5-chlorobenzophenone (IV). To prepare com-
pound IV, alkylation of ketone III with dimethyl
sulfate under phase-transfer conditions at elevated
temperatures was tried [3].
as tetrabutylammonium hydrosulfate as catalyst, no
compound IV was formed. From the reaction mixture
we isolated quinolone II as the major product (yield
85%) and quinolone I (yield 13%) [4]. The latter was
also formed by refluxing ketone III in toluene with a
mixture of NaOH and K CO in the presence of a
2
3
phase-transfer catalyst. The composition and structure
of compounds I and II were confirmed by elemental
1
analysis and H NMR spectroscopy.
Ketone IV is prepared in quantitative yield by the
procedure in [3] but at 18 20 C. Treatment of com-
pound IV with a mixture of ethanol and 20% H SO
2
4
Under the conditions described in [3], i.e. by reflux- (1:2, v/v) provides 5-chloro-2-(methylamino)benzo-
ing compound III [2] and dimethyl sulfate in toluene
phenone (V) in 98% yield [2].
Me
NH
Ph
O
N
O
+
O
Me
Cl
Cl
Cl
Ph
NH
(
CH O) SO
3 2 2
I
II
O
Cl
O
Me
Ph
III
I
18 20 C
N
20% H2SO4
NH
Me
Me
O
O
Cl
Ph
IV
Ph
V
Thus, the reaction of benzophenone I with di-
methyl sulfate, performed as described in [3], involves
both N-methylation and cyclization and gives a mix-
ture of 2-quinolones. Lowering the reaction tempera-
ture to 18 20 C allows substituted benzophenone IV
to be prepared in quantitative yield.
2-(N-Acetyl-N-methylamino)-5-chlorobenzo-
1
070-3632/04/7409-1467 2004 MAIK Nauka/Interperiodica

1
468
POPOVA et al.
Cl 13.17; N 5.19. C H ClNO. Calculated, %: C
phenone (IV). A solution of 4.9 ml of dimethyl sul-
fate was added dropwise with stirring to a suspension
of 9.9 g of compound III [2], 4.9 g of NaOH, 9.86 g
of K CO , and 1.22 g of tetrabutylammonium hydro-
sulfate in 50 ml of toluene, maintaining the tempera-
ture at 18 20 C. After 2-h stirring at the same tem-
perature, the reaction mixture was filtered, and the
precipitate was washed with toluene. The organic
layer was washed with water (3 20 ml), dried with
magnesium sulfate, and evaporated in a vacuum. The
oily reaction product was dried in a vacuum over
KOH P O , yield 10.4 g (ca. 100%), R 0.33
1
6
12
70.92; H 4.50; Cl 13.05; N 5.12.
Quinolone I was isolated from the mother liquor
2
3
by preparative TLC in system B, yield 1.2 g (13%),
1
mp 260 263 C. H NMR spectrum, , ppm: 6.63 s
(
(
1H, CH), 7.44 7.60 m (8H, Ar H), 12.22 br.s
1H, NH). Found, %: C 69.91; H 4.18; N 5.39.
C H ClNO. Calculated, %: C 70.45; H 3.91; N 5.48.
1
5
10
1
The H NMR spectra were measured on a Bruker
CXP-300 spectrometer (300 MHz) in CD Cl . Thin-
2
2
layer chromatography was performed on silica gel
plates (Merck) in ethyl acetate hexane, 1:4 (system
A) and 1:1 (system B). The melting points were
determined in an open capillary.
2
5
f
(system A).
5
-Chloro-2-(N-methylamino)benzophenone (V)
[2]. Compound IV, 10.4 g, was refluxed in 150 ml of
a mixture of 20% H SO and ethanol (2:1, v/v). After
cooling, the reaction product was filtered off, washed
2
4
ACKNOWLEDGMENTS
with water, and dried in a vacuum, yield 8.7 g (98%),
The work was financially supported by INTAS
(grant no. 01-0651).
1
mp 94 95 C, R 0.28 (system A). H NMR spectrum,
f
,
ppm: 2.93 s (3H, CH ), 6.74 d.d (1H, Ar H, J
3
8
Hz) and 7.3 7.6 m (7H, Ar H).
REFERENCES
N-Methyl-6-chloro-4-phenyl-2-quinolone (II)
1
2
. Hewawasam, P.P., Fan, W.W., Knipe, J.J., Moon, S.L.,
Boissard, C.G., Gribkoff, V.K., and Starrett, J.E.,
Bioorg. Med. Chem. Lett., 2002, vol. 12, no. 13,
p. 1779.
and 6-chloro-4-phenyl-2-quinolone (I) were pre-
pared similarly to ketone IV, starting from 9.9 g of
compound III, but in toluene under reflux. After
4
0 min, the reaction mixture was cooled, diluted with
. Sternbach, L.H., Frayer, R.I., Metlesics, W., Sach, G.,
and Stempel, A., J. Org. Chem., 1962, vol. 27, no. 11,
p. 3781.
equal volume of toluene, and filtered. The filtrate was
washed with water, dried with magnesium sulfate, and
evaporated in a vacuum. The residue was recrystal-
lized from ethanol to obtain 8.29 g (85%) of quino-
3. Gajda, T. and Zwierzak, A., Synthesis, 1981, no. 12,
1
lone II, mp 143 146 C, R 0.64 (system B). H NMR
p. 1005.
f
spectrum, , ppm: 3.71 s (3H, CH ), 6.63 s (1H, CH),
4. Bell, S.C., Sulkowski, T.S., Gochman, C., and Child-
3
7
.37 7.56 m (8H, Ar H). Found, %: C 71.24; H 4.45;
ress, S.J., J. Org. Chem., 1962, vol. 27, no. 2, p. 562.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 9 2004