Vol. 30, No. 4 (2018)
An Innovative Approach for the Synthesis of 7-Hydroxyquinolin-2(1H)-one 835
6.27-6.30 (m, 2H), 2.71 (t, J) 7.8 Hz, 2H), 2.36 (t, J) 7.2 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 170.8, 156.7,
139.2, 128.5, 144.0, 109.1, 102.6, 31.1, 24.2; FTIR (KBr):
3109, 2955, 1655, 1593, 1523, 1433, 1401, 1231, 1166, 1030,
803, 742 cm-1; C9H9NO2 [M -1] calcd. 162.86.
scopy. After dehydrogenation reaction, alkene product would
be detected in 1H NMR with significant coupling constant 9.4
Hz at 7.73 and 6.62 δ ppm values, it indicates the presence of
alkene protons in the compound 1. 13C NMR significant alkene
carbons would be observed at 140.0 and 117.4 δ ppm and
peaks at 31.1 and 24.2 δ ppm disappeared, these peaks related
to sp3 carbons in compound 4.
Oxidation-dehydrogenation reaction depends on the
certain parameters such as reaction temperature, solvent,
solvent volume and mole equivalents of reagents.
In our initial study, the oxidation of 7-hydroxy-1,2,3,4-
tetrahydro-2-quinolinone was carried out in higher dilution
of solvent (20 volumes of THF) at room temperature with 1.8
eq of DDQ, reaction not gone for the completion even after
24 h, corresponding compound 1 was isolated in 45 % yield
(entry 1, Table-1).Another set of experiment conducted at 45-
50 °C, other conditions same as mentioned in the entry 1, reaction
completed after 8 h, quenched the reaction with sodium hydro-
gen carbonate, yield was 63 %, due to the presence of more
quantity of THF, yield was dropped. To improve the yield,
sequentially reaction optimization carried out by reducing the
DDQ reagent equivalents from 1.8 to 1.1 eq and solvent volume
from 20 volumes to 5 volumes, finally reaction conversion
time reduced drastically from 8 to 2 h, all the results captured
in the Table-1. While THF was used as solvent in all these
cases, other solvents screened in the reaction such as dioxane,
dichloroethane and DMF, however these solvents were found
to be less effective in the synthesis of compound 1 (entries 6,
7 & 8 in Table-1).
Synthesis of 7-hydroxyquinolin-2(1H)-one (1): To a
solution of compound 4 (25 g, 0.153 mol, 1.0 eq) in THF (125
mL) at room temperature under a nitrogen atmosphere and
stirred for 10-15 min, 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) added portion wise (37.16 g, 0.163, 1.07 eq)
to the reaction mixture. Stirred the reaction at 45-50 °C for
2 h. The progress of the reaction monitored by TLC, reaction
mixture was cooled to 25-30 °C, added NaHCO3 (27.5 g, 0.327,
2.14 eq) and water (250 mL) to the reaction mixture, stirred
for 1 h at room temperature, solid filtered and washed with
water (50 mL). Wet cake was triturated with Isopropyl alcohol
(75 mL), filtered and washed with isopropyl alcohol (25 mL)
to obtain pure compound 1 (18.5 g, 0.114 mol, 75 %) as an
off-white solid, m.p. 233-235 °C. 1H NMR (400 MHz, DMSO-
d6) δ (ppm) 11.47 (br s, 1H), 10.07 (s, 1H), 7.73 (d, J) 9.44
Hz, 1H), 7.43 (d, J) 8.52 Hz, 1H) 6.67 (s, 1H) 6.61 (d, J) 6.48
Hz, 1H), 6.20 (d, J) 9.4 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6) δ (ppm) 162.3, 159.5, 140.7, 140.0, 129.2, 117.4, 112.3,
111.5, 99.8; C9H7NO2 [M-1] calcd. 160.1.
RESULTS AND DISCUSSION
The target compound 7-hydroxyquinolin-2(1H)-one (1)could
be prepared from commercially available 3-hydroxy aniline (2)
reaction with 3-chloropropionyl chloride to give 3-(3-hydroxy-
phenylamino) propanoyl chloride (3), followed by intermole-
cular Friedel-Crafts cyclization to obtain 7-hydroxy-1,2,3,4-
tetrahydro-2-quinolinone (4), this process previously reported
[11]. Finally, DDQ mediated oxidation-dehydrogenation of
compound 2 yield the compound 1 (Scheme-I).
As part of the reaction, during work up few issues
encountered during the quenching and isolation of the product.
As per the literature after completion of reaction, quenching
with aqueous sodium hydroxide, red colour clear solution
observed, a product was not isolated. Due to presence of pheno-
lic group in the compound 2, it reacts with sodium hydroxide
to form corresponding sodium phenoxide, it is highly soluble
in water, poor extractability in organic solvents such as dichlo-
romethane and ethyl acetate. This layer would be acidified
with hydrochloric acid to get solid but poor yields were obser-
ved. To overcome all these challenges sodium hydroxide was
replaced with sodium hydrogen carbonate to give precipitate
in the direct reaction mass, pure product was isolated with
good yields. The reason would be, weak basic nature of sodium
hydrogen carbonate was unable to form the sodium phenoxide
ion of compound 1.
TABLE-1
REAGENT MOLE EQUIVALENT OPTIMIZATION TABLE
DDQ
(mol. Eq)
Temp.
(°C)
Yield
(%)e
Entry
Solvent
Time (h)
1
2
3
4
5
6
7
8
1.8
1.8
1.1
1.1
1.1
1.1
1.1
1.1
25-30
45-50
45-50
45-50
45-50
45-50
45-50
45-50
THFa
THF
24
12
8
4
2
8
6
8
45
60
65
70
75
55
70
64
THFb
THFc
THFd
Dioxane
DCE
DMF
aTHF 20 volumes, bTHF 15 volumes, cTHF 10 volumes, dTHF 5
volumes, eIsolated yield.
To demonstrate the further scope of compound 1 structure
elaboration was carried out via reaction with 1-bromo-4-chloro
butane (5) in the presence of K2CO3 and DMF to give 7-(4-
chlorobutoxy)quinolin-2(1H)-one (6), compound 6 further
reaction with 1-(benzo[b]thiophen-4-yl)piperazine (7) in the
presence of potassium carbonate, sodium iodide in DMF to
give brexpiprazole [12] (Scheme-II).
The final isolated product was confirmed by spectroscopic
techniques such as 1H NMR, 13C NMR, IR and mass spectro-
DDQ
THF
AlCl3
N,N-Dimethyl
O
O
1.NaHCO3
2. HCl
NaHCO3
acetamide
+
O
N
H
OH
Cl
HO
N
O
Cl
Cl
HO
N
H
HO
NH2
H
2
4
3
1
Scheme-I: Synthesis of 7-hydroxyquinoline-2(1H)-one (1)